U.S. patent application number 10/434371 was filed with the patent office on 2003-11-27 for modified forms of pharmacologically active agents and uses therefor.
This patent application is currently assigned to Medinox, Inc.. Invention is credited to Lai, Ching-San, Wang, Tingmin.
Application Number | 20030220468 10/434371 |
Document ID | / |
Family ID | 27084215 |
Filed Date | 2003-11-27 |
United States Patent
Application |
20030220468 |
Kind Code |
A1 |
Lai, Ching-San ; et
al. |
November 27, 2003 |
Modified forms of pharmacologically active agents and uses
therefor
Abstract
In accordance with the present invention, there are provided
modified forms of nonsteroidal anti-inflamamatory drugs (NSAIDs).
Modified NSAIDs according to the invention provide a new class of
anti-inflammatory agent which provide the therapeutic benefits of
NSAIDs while causing a much lower incidence of side-effects then
typically observed with such agents.
Inventors: |
Lai, Ching-San; (Encinitas,
CA) ; Wang, Tingmin; (San Marcos, CA) |
Correspondence
Address: |
FOLEY & LARDNER
P.O. BOX 80278
SAN DIEGO
CA
92138-0278
US
|
Assignee: |
Medinox, Inc.
|
Family ID: |
27084215 |
Appl. No.: |
10/434371 |
Filed: |
May 7, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10434371 |
May 7, 2003 |
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09715767 |
Nov 17, 2000 |
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6429223 |
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09715767 |
Nov 17, 2000 |
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09602688 |
Jun 23, 2000 |
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6355666 |
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10434371 |
May 7, 2003 |
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10097197 |
Mar 12, 2002 |
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Current U.S.
Class: |
530/331 ;
548/500; 558/482; 560/100; 560/110; 560/71 |
Current CPC
Class: |
A61P 9/08 20180101; A61P
25/00 20180101; A61P 15/00 20180101; A61P 1/00 20180101; A61P 1/18
20180101; A61K 47/555 20170801; A61P 9/04 20180101; A61P 25/06
20180101; A61P 31/06 20180101; A61P 19/00 20180101; A61K 47/545
20170801; A61P 7/08 20180101; A61P 11/00 20180101; A61K 47/54
20170801; A61P 39/02 20180101; A61P 17/06 20180101; A61P 9/10
20180101; A61P 37/08 20180101; A61P 25/18 20180101; A61P 31/18
20180101; A61P 17/02 20180101; A61P 25/16 20180101; A61P 13/12
20180101; A61P 19/02 20180101; A61P 35/00 20180101; A61P 27/02
20180101; A61P 31/04 20180101; A61P 9/00 20180101; A61P 25/10
20180101; A61P 1/16 20180101; A61P 17/00 20180101; A61P 25/04
20180101; A61P 29/02 20180101; A61P 29/00 20180101; A61P 3/04
20180101; A61P 25/28 20180101; A61P 7/00 20180101; A61P 25/24
20180101; A61P 3/10 20180101; A61P 25/14 20180101; A61P 37/02
20180101; A61P 1/02 20180101; A61P 11/06 20180101; A61P 1/04
20180101; A61P 25/22 20180101 |
Class at
Publication: |
530/331 ;
548/500; 560/71; 558/482; 560/110; 560/100 |
International
Class: |
C07K 005/04; C07C
317/22 |
Claims
What is claimed is:
1. A compound having the structure:X--L--Zwherein: X=a
non-steroidal anti-inflammatory drug (NSAID), L=an optional
linker/spacer, Z=a sulfur-containing functional group.
2. A compound according to claim 1 wherein said NSAID is
acetaminophen, aspirin, ibuprofen, choline magnesium salicylate,
choline salicylate, diclofenac, diflunisal, etodolac, fenprofen
calcium, flurobiprofen, indomethacin, ketoprofen, carprofen,
indoprofen, ketorolac tromethamine, magnesium salicylate,
meclofenamate sodium, mefenamic acid, oxaprozin, piroxicam, sodium
salicylate, sulindac, tolmetin, meloxicam, nabumetone, naproxen,
lomoxicam, nimesulide, indoprofen, remifenzone, salsalate,
tiaprofenic acid, or flosulide.
3. A compound according to claim 2 wherein said NSAID is naproxen,
aspirin, ibuprofen, flurbiprofen, indomethacin, ketoprofen, or
carprofen.
4. A compound according to claim 1 wherein Z has the
structure:--Y--S(O).sub.n--Y'--Qwherein: each of Y and Y' are
optionally present, and when present are independently --O--, --S--
or --NR'--, wherein R' is H or an optionally substituted
hydrocarbyl moiety; n is 1 or 2, and Q is H, a metal cation or an
optionally substituted hydrocarbyl moiety.
5. A compound according to claim 1 wherein the sulfur-containing
functional group is sulfonate, reverse sulfonate, sulfonamide,
reverse sulfonamide, sulfone, sulfoxide, sulfinate, or reverse
sulfinate.
6. A compound according to claim 5 wherein the sulfur-containing
functional group is sulfonate or reverse sulfonate.
7. A compound according to claim 6 wherein the sulfur-containing
functional group is a nitro, nitrate, nitrite, nitrosothiol,
nitroglyceryl, S-nitrosocysteinyl, S-nitrosoglutathionyl, oxime or
N-hydroxyguanidinyl substituted aromatic sulfonate.
8. A compound according to claim 7 wherein said aromatic sulfonate
is tosylate or brosylate.
9. A compound according to claim 6 wherein the sulfur-containing
functional group is a nitro, nitrate, nitrite, nitrosothiol,
nitroglyceryl, S-nitrosocysteinyl, S-nitrosoglutathionyl, oxime or
N-hydroxyguanidinyl substituted C1 to C10 alkyl sulfonate.
10. A compound according to claim 9 wherein the alkyl sulfonate is
mesylate or triflate.
11. A compound according to claim 5 wherein the sulfur-containing
functional group is a sulfone.
12. A compound according to claim 11 wherein the sulfur-containing
functional group is a nitro, nitrate, nitrite, nitrosothiol,
nitroglyceryl, S-nitrosocysteinyl, S-nitrosoglutathionyl, oxime or
N-hydroxyguanidinyl substituted C.sub.1 to C.sub.10 alkyl
sulfone.
13. A compound according to claim 12 wherein said sulfone is methyl
sulfone, ethyl sulfone.
14. A compound according to claim 11 wherein the sulfur-containing
functional group is a nitro, nitrate, nitrite, nitrosothiol,
nitroglyceryl, S-nitrosocysteinyl, S-nitrosoglutathionyl, oxime or
N-hydroxyguanidinyl substituted aromatic sulfone.
15. A compound according to claim 14 wherein the sulfur-containing
functional group is a p-substituted aromatic sulfone.
16. A compound according to claim 5 wherein the sulfur-containing
functional group is a sulfonamide or reverse sulfonamide.
17. A compound according to claim 16 wherein the sulfur-containing
functional group is a nitro, nitrate, nitrite, nitrosothiol,
nitroglyceryl, S-nitrosocysteinyl, S-nitrosoglutathionyl, oxime or
N-hydroxyguanidinyl substituted C.sub.1 to C.sub.10 alkyl
sulfonamide.
18. A compound according to claim 17 wherein the sulfur-containing
functional group is methyl sulfonamide.
19. A compound according to claim 16 wherein the sulfur-containing
functional group is a nitro, nitrate, nitrite, nitrosothiol,
nitroglyceryl, S-nitrosocysteinyl, S-nitrosoglutathionyl, oxime or
N-hydroxyguanidinyl substituted aromatic sulfonamide.
20. A compound according to claim 19 wherein the sulfur-containing
functional group is toluene sulfonamide.
21. A compound according to claim 5 wherein the sulfur-containing
functional group is a sulfinate or reverse sulfinate.
22. A compound according to claim 1 wherein L, when present, has
the structure:W--R--wherein: R is optional, and when present is
alkylene, substituted alkylene, cycloalkylene, substituted
cycloalkylene, heterocyclic, substituted heterocyclic, oxyalkylene,
substituted oxyalkylene, alkenylene, substituted alkenylene,
arylene, substituted arylene, alkarylene, substituted alkarylene,
aralkylene or substituted aralkylene, and W is ester, reverse
ester, thioester, reverse thioester, amide, reverse amide,
phosphate, phosphonate, imine or enamine.
23. A formulation comprising a compound according to claim 1 in a
pharmaceutically acceptable carrier therefor.
24. A formulation according to claim 23 wherein said
pharmaceutically acceptable carrier is a solid, solution, emulsion,
dispersion, micelle or liposome.
25. A formulation according to claim 23 wherein said
pharmaceutically acceptable carrier further comprises an enteric
coating.
26. A method for the alleviation of side effects induced by the
administration of a non-steroidal anti-inflammatory drug (NSAID) to
a subject, said method comprising chemically modifying said NSAID
prior to administration to a subject, wherein said NSAID is
chemically modified by covalent attachment thereto of a
sulfur-containing functional group.
27. A method for alleviating the systemic toxicity of a
non-steroidal anti-inflammatory drug (NSAID), said method
comprising chemically modifying said NSAID prior to administration
to a subject, wherein said NSAID is chemically modified by covalent
attachment thereto of a sulfur-containing functional group.
28. A method for reducing the maximum concentration in plasma
achieved upon administration of a non-steroidal anti-inflammatory
drug (NSAID), said method comprising modifying the NSAID by
covalent attachment thereto of a sulfur-containing functional
group.
29. A method for the controlled release in vivo of a non-steroidal
anti-inflammatory drug (NSAID), said method comprising chemically
modifying the NSAID by the covalent attachment thereto of a
sulfur-containing functional group.
30. A method for the treatment of a subject afflicted with a
pathological condition, said method comprising administering to
said subject a therapeutically effective amount of a chemically
modified non-steroidal anti-inflammatory drug (NSAID), wherein the
NSAID is effective for treatment of said condition, and wherein the
modified NSAID is prepared by covalent attachment thereto of a
sulfur-containing functional group.
31. In a method for the administration of a non-steroidal
anti-inflammatory drug (NSAID) to a subject for the treatment of a
pathological condition, the improvement comprising directly or
indirectly covalently attaching said NSAID to a sulfur-containing
functional group prior to administration thereof to said
subject.
32. A method for the preparation of a modified non-steroidal
anti-inflammatory drug (NSAID) having reduced propensity to induce
side effects, said method comprising modifying the NSAID by
directly or indirectly covalently attaching said NSAID to a
sulfur-containing functional group prior to administration thereof
to said subject.
33. In the treatment of a subject suffering from a pathological
condition by administration thereto of a non-steroidal
anti-inflammatory drug (NSAID), the improvement comprising
covalently attaching said NSAID to a sulfur-containing functional
group prior to administration thereof to said subject.
34. A method for the preparation of a protected form of a
non-steroidal anti-inflammatory drug (NSAID), said method
comprising directly or indirectly covalently attaching a
sulfur-containing functional group to said NSAID.
35. A method for reducing the side effects induced by
administration of a non-steroidal anti-inflammatory drug (NSAID) to
a subject, said method comprising directly or indirectly covalently
attaching a sulfur-containing functional group to said NSAID prior
to administration to said subject.
36. A method for enhancing the effectiveness of a non-steroidal
anti-inflammatory drug (NSAID), said method comprising directly or
indirectly covalently attaching a sulfur-containing functional
group to said NSAID.
37. A method for the prevention or treatment of an inflammatory or
infectious disease in a subject in need thereof, said method
comprising administering to said subject an amount of the compound
of claim 1 effective to alleviate said condition.
Description
RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S. patent
application Ser. No. 10/097,197, filed Mar. 12, 2002, now pending,
which is a continuation of U.S. patent application Ser. No.
09/602,688, filed Jun. 23, 2000, now issued as U.S. Pat. No.
6,355,666, and a continuation-in-part of U.S. patent application
09/715,767, filed Nov. 17, 2000, now issued as U.S. Pat. No.
6,429,223, the entire contents of each of which is hereby
incorporated by reference herein.
FIELD OF THE INVENTION
[0002] The present invention relates to novel forms of
pharmacologically active agents, and methods for the preparation
and use thereof. In a particular aspect of the invention, methods
are provided for treating pathological conditions with a modified
form of one or more pharmacologically active agents, thereby
reducing the occurrence of side-effects caused thereby.
BACKGROUND OF THE INVENTION
[0003] Despite the advent of modem pharmaceutical technology, many
drugs still possess untoward toxicities which often limit the
therapeutic potential thereof. For example, although nonsteroid
antiinflammatory drugs (NSAIDs) are a class of compounds which are
widely used for the treatment of inflammation, pain and fever,
NSAIDs (e.g., naproxen, aspirin, ibuprofen and ketoprofen) can
cause gastrointestinal ulcers, a side effect that remains the major
limitation to the use of NSAIDs (see, for example, J. L. Wallace,
in Gastroenterol. 112:10001016 (1997); A. H. Soll et al., in Ann
Intern Med. 114:307319 (1991); and J. Bjarnason et al., in
Gastroenterol. 104:18321847 (1993)).
[0004] There are two major ulcerogenic effects of NSAIDs: (1)
irritant effects on the epithelium of the gastrointestinal tract
and (2) suppression of gastrointestinal prostaglandin synthesis. In
recent years, numerous strategies have been attempted to design and
develop new NSAIDs that reduce the damage to the gastrointestinal
tract. These efforts, however, have largely been unsuccessful. For
example, enteric coating or slow release formulations designed to
reduce the topical irritant properties of NSAIDs have been shown to
be ineffective in terms of reducing the incidence of clinically
significant side effects, including perforation and bleeding (see,
for example, D. Y. Graham et al., in Clin. Pharmacol. Ther. 38:6570
(1985); and J. L. Carson, et al., in Arch. Intern. Med.,
147:10541059 (1987)).
[0005] It is well recognized that aspirin and other NSAIDs exert
their pharmacological effects through the non-selective inhibition
of cyclooxygenase (COX) enzymes, thereby blocking prostaglandin
synthesis (see, for example, J. R. Van in Nature, 231:232235
(1971)). There are two types of COX enzymes, namely COX1 and COX2.
COX1 is expressed constitutively in many tissues, including the
stomach, kidney, and platelets, whereas COX2 is expressed only at
the site of inflammation (see, for example, S. Kargan et al. in
Gastroenterol., 111:445454 (1996)). The prostagladins derived from
COX1 are responsible for many of the physiological effects,
including maintenance of gastric mucosal integrity.
[0006] Many attempts have been made to develop NSAIDs that only
inhibit COX2, without impacting the activity of COX1 (see, for
example, J. A. Mitchell et al., in Proc. Natl. Acad. Sci. USA
90:1169311697 (1993); and E. A. Meade et al., in J. Biol. Chem.,
268:66106614 (1993)). There are several NSAIDs presently on the
market (e.g., rofecoxib and celecoxib) that show marked selectivity
for COX2 (see, for example, E. A. Meade, supra.; K. Glaser et al.,
in Eur. J. Pharmacol. 281:107111 (1995) and Kaplan-Machlis, B., and
Klostermeyer, B S in Ann Pharmacother. 33:979-88, (1999)). These
drugs appear to have reduced gastrointestinal toxicity relative to
other NSAIDs on the market.
[0007] On the basis of encouraging clinical as well as experimental
data, the development of highly selective COX2 inhibitors appears
to be a sound strategy to develop a new generation of
antiinflammatory drugs. However, the physiological functions of
COX1 and COX2 are not always well defined. Thus, there is a
possibility that prostagladins produced as a result of COX1
expression may also contribute to inflammation, pain and fever. On
the other hand, prostagladins produced by COX2 have been shown to
play important physiological functions, including the initiation
and maintenance of labor and in the regulation of bone resorption
(see, for example, D. M. Slater et al., in Am. J. Obstet. Gynecol.,
172:7782 (1995); and Y. Onoe et al., in J. Immunol. 156:758764
(1996)), thus inhibition of this pathway may not always be
beneficial. Considering these points, highly selective COX2
inhibitors may produce additional side effects above and beyond
those observed with standard NSAIDs, therefore such inhibitors may
not be highly desirable.
[0008] Accordingly, there is still a need in the art for modified
forms of NSAIDs which cause a reduced incidence of side-effects,
relative to the incidence of side-effects caused by such
pharmacologically active agents in unmodified form.
BRIEF DESCRIPTION OF THE INVENTION
[0009] In accordance with the present invention, there is provided
a new class of modified NSAIDs which cause a much lower incidence
of side-effects than are typically observed with unmodified NSAIDs
due to the protective effects imparted by modifying the NSAIDs as
described herein.
[0010] There are a number of advantages provided by modified NSAIDs
according to the invention including one or more of the
following:
[0011] (i) reduced irritant effects (e.g., contact irritation) of
NSAIDs,
[0012] (ii) enhanced tissue delivery of the drug as a result of a
decrease in net charges on the molecule, particularly for acidic
NSAIDs such as naproxen, aspirin, diclofenac and ibuprofen, thereby
reducing the quantity of material which must be delivered to
achieve an effective dosage, and
[0013] (iii) reduction in the maximum concentration (C.sub.max)
achieved upon administration to a subject relative to the
unmodified NSAID, while maintaining a therapeutically effective
concentration of the NSAID in plasma of the subject.
[0014] In accordance with the present invention, cleavage of the
modified NSAIDs described herein from the modified group appended
thereto releases the pharmaceutically active agent.
BRIEF DESCRIPTION OF THE FIGURES
[0015] FIG. 1 illustrates the total length of intestinal ulcers
measured after three daily doses of NSAID in unfasted male
Sprague-Dawley rats (150-200 g) treated with vehicle, naproxen, or
equimolar invention composition (compound 19). * P<0.05 by
unpaired t-test.
[0016] FIG. 2 illustrates the total length of intestinal ulcers
measured after 14 daily doses of NSAID in unfasted male
Sprague-Dawley rats (150-200 g) treated with vehicle (bar 7), three
doses of naproxen (bar 1:50 mg/kg, bar 2:45 mg/kg, bar 3:40 mg/kg),
or three equimolar doses of invention composition (compound 19)
(bars 4-6). * P<0.05 by unpaired t-test vs. corresponding dose
of naproxen.
[0017] FIG. 3 illustrates the inhibition of paw volume increases in
the uninjected feet of Lewis male rats in which arthritis was
induced by intradermal injection of adjuvant into the footpad. Rats
were injected on day 0 and treated once daily from days 8 to 15
with vehicle, naproxen (10 mg/kg), or invention composition
(compound 19) at equivalent dose. Paw volumes were measured with a
Plethysmometer on days 5 and 15. Closed circles=naproxen;
squares=invention composition.
[0018] FIG. 4 compares naproxen plasma concentration-time profiles
(n=4, mean.+-.s.d.) after oral administration of naproxen (darkened
circles) at 2 mg/kg and modified naproxen (open triangles) at an
equivalent dose of 2 mg/kg with respect to naproxen in rats. At
predetermined times, blood samples were collected and centrifuged
to obtain the plasma samples. The plasma naproxen levels were
measured by HPLC with a UV detection system.
DETAILED DESCRIPTION OF THE INVENTION
[0019] In accordance with the present invention, there are provided
compounds comprising a modified NSAID, wherein the NSAID is
covalently attached either directly or through a linker molecule to
a sulfur-containing functional group. Exemplary invention compounds
have the structure:
X--L--Z
[0020] wherein:
[0021] X=a non-steroidal anti-inflammatory drug (NSAID),
[0022] L=an optional linker/spacer, and
[0023] Z=a sulfur-containing functional group.
[0024] NSAIDs contemplated for modification in accordance with the
present invention include acetaminophen (Tylenol, Datril, etc.),
aspirin, ibuprofen (Motrin, Advil, Rufen, others), choline
magnesium salicylate (Triasate), choline salicylate (Anthropan),
diclofenac (voltaren, cataflam), diflunisal (dolobid), etodolac
(lodine), fenoprofen calcium (nalfon), flurbiprofen (ansaid),
indomethacin (indocin, indometh, others), ketoprofen (orudis,
oruvail), carprofen, indoprofen, ketorolac tromethamine (toradol),
magnesium salicylate (Doan's, magan, mobidin, others),
meclofenamate sodium (meclomen), mefenamic acid (relafan),
oxaprozin (daypro), piroxicam (feldene), sodium salicylate,
sulindac (clinoril), tolmetin (tolectin), meloxicam, nabumetone,
naproxen, lomoxicam, nimesulide, indoprofen, remifenzone,
salsalate, tiaprofenic acid, flosulide, and the like. Presently
preferred NSAIDs employed in the practice of the invention include
naproxen, aspirin, ibuprofen, flurbiprofen, indomethacin,
ketoprofen, carprofen, and the like. When the NSAID is aspirin, the
sulfur-containing functional groups --CH.sub.2S(O).sub.2CH.sub.3,
--CH.sub.2S(O)CH.sub.3, and --SCH.sub.3 are not presently
preferred.
[0025] Invention compounds can be readily prepared in a variety of
ways either by direct reaction of NSAIDs with the sulfur-containing
functional group or indirectly through a suitable linker
molecule.
[0026] The components of invention compositions are directly or
indirectly covalently attached employing a variety of linkages
(including an optional linker), e.g., ester linkages, disulfide
linkages, amide linkages, immine linkages, enamine linkages, ether
linkages, thioether linkages, imide linkages, sulfate ester
linkages, sulfonate ester linkages, sulfone linkages, sulfonamide
linkages, phosphate ester linkages, carbonate linkages,
O-glycosidic linkages, S-glycosidic linkages, and the like. Such
linkages can be accomplished using standard synthetic techniques as
are well known by those of skill in the art, either by direct
reaction of the starting materials, or by incorporating a suitable
functional group on the starting material, followed by coupling of
the reactants.
[0027] When the NSAIDs contemplated for use herein contain suitable
functionality thereon, e.g., hydroxy, amino, carboxy, and the like,
invention modified NSAIDs can be prepared by direct linkage between
the NSAID and the sulfur-containing functional group.
Alternatively, the NSAIDs can be functionalized so as to facilitate
linkage between the NSAID and the sulfur-containing functional
group. When present, linker/spacer L has the following
structure:
--W--R--
[0028] wherein:
[0029] R is optional, and when present is alkylene, substituted
alkylene, cycloalkylene, substituted cycloalkylene, heterocyclic,
substituted heterocyclic, oxyalkylene, substituted oxyalkylene,
alkenylene, substituted alkenylene, arylene, substituted arylene,
alkarylene, substituted alkarylene, aralkylene or substituted
aralkylene, and
[0030] W is ester, reverse ester, thioester, reverse thioester,
amide, reverse amide, phosphate, phosphonate, imine, enamine,
hydroxymate, or the like.
[0031] Functional groups contemplated by the present invention are
sulfur-based. Examples of suitable sulfur-containing functional
groups include sulfonate, reverse sulfonate, sulfonamide, reverse
sulfonamide, sulfone, sulfoxide, sulfinate, reverse sulfinate, and
the like. In a particular aspect of the invention, the sulfur-based
moiety is sulfonate or reverse sulfonate. In a particularly
preferred aspect of the invention, the sulfonate is an optionally
substituted aromatic sulfonate such as tosylate or brosylate.
[0032] Other preferred sulfur-based functional groups contemplated
by the present invention include sulfones. Preferably, the sulfone
is an optionally substituted alkyl or aromatic sulfone.
[0033] In one aspect of the invention, Z may have the following
structure:
--Y--S(O)n--Y'--Q
[0034] wherein:
[0035] each of Y and Y' are optionally present, and when present
are independently --O--, --S-- or --NR'--, wherein R' is H or an
optionally substituted hydrocarbyl moiety;
[0036] n is 1 or 2, and
[0037] Q is H, a metal cation or an optionally substituted
hydrocarbyl moiety.
[0038] As employed herein, "hydrocarbyl" embraces alkyl,
substituted alkyl, oxyalkyl, substituted oxyalkyl, cycloalkyl,
substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, monocyclic heterocylic, substituted monocyclic
heterocyclic, monocyclic aromatic, monosubstituted monocyclic
aromatic, or the like.
[0039] As employed herein, "alkyl" refers to hydrocarbyl radicals
having 1 up to 20 carbon atoms, preferably 2-10 carbon atoms; and
"substituted alkyl" comprises alkyl groups further bearing one or
more substituents selected from hydroxy, alkoxy (of a lower alkyl
group), mercapto (of a lower alkyl group), cycloalkyl, substituted
cycloalkyl, heterocyclic, substituted heterocyclic, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, aryloxy,
substituted aryloxy, halogen, trifluoromethyl, cyano, nitro,
nitrosothiol (--SNO), nitrate (i.e., nitrous acid ester), nitrone,
nitrite (i.e., nitric acid ester), nitroglyceryl,
S-nitrosocysteinyl, S-nitrosoglutathionyl, oxime,
N-hydroxylguanidinyl, amino, amido, --C(O)H, acyl, oxyacyl,
carboxyl, carbamate, sulfonyl, sulfinyl, sulfonamide, sulfuryl, and
the like.
[0040] As employed herein, "oxyalkyl" refers to the moiety
--O-alkyl-, wherein alkyl is as defined above, and "substituted
oxyalkyl" refers to oxyalkyl groups further bearing one or more
substituents as set forth above.
[0041] As employed herein, "cycloalkyl" refers to cyclic
ring-containing groups containing in the range of about 3 up to 8
carbon atoms, and "substituted cycloalkyl" refers to cycloalkyl
groups further bearing one or more substituents as set forth
above.
[0042] As employed herein, "heterocyclic" refers to cyclic (i.e.,
ring-containing) groups containing one or more heteroatoms (e.g.,
N, O, S, or the like) as part of the ring structure, and having in
the range of 3 up to 14 carbon atoms and "substituted heterocyclic"
refers to heterocyclic groups further bearing one or more
substituents as set forth above.
[0043] As employed herein, "alkenyl" refers to straight or branched
chain hydrocarbyl groups having at least one carbon-carbon double
bond, and having in the range of about 2 up to 12 carbon atoms, and
"substituted alkenyl" refers to alkenyl groups further bearing one
or more substituents as set forth above.
[0044] As employed herein, "alkynyl" refers to straight or branched
chain hydrocarbyl groups having at least one carbon-carbon triple
bond, and having in the range of about 2 up to 12 carbon atoms, and
"substituted alkynyl" refers to alkynylene groups further bearing
one or more substituents as set forth above.
[0045] As employed herein, "monocyclic aromatic" refers to aromatic
groups having in the range of 5 up to 7 carbon atoms and
"monosubstituted monocyclic aromatic" refers to aromatic groups
further bearing one of the substituents set forth above.
[0046] As employed herein, "alkylene" refers to divalent
hydrocarbyl radicals having 1 up to 20 carbon atoms, preferably
2-10 carbon atoms; and "substituted alkylene" comprises alkylene
groups further bearing one or more substituents as set forth
above.
[0047] As employed herein, "cycloalkylene" refers to cyclic
ring-containing groups containing in the range of about 3 up to 8
carbon atoms, and "substituted cycloalkylene" refers to
cycloalkylene groups further bearing one or more substituents as
set forth above.
[0048] As employed herein, "oxyalkylene" refers to the moiety
--O-alkylene-, wherein alkylene is as defined above, and
"substituted oxyalkylene" refers to oxyalkylene groups further
bearing one or more substituents as set forth above.
[0049] As employed herein, "alkenylene" refers to divalent,
straight or branched chain hydrocarbyl groups having at least one
carbon-carbon double bond, and having in the range of about 2 up to
12 carbon atoms, and "substituted alkenylene" refers to alkenylene
groups further bearing one or more substituents as set forth
above.
[0050] As employed herein, "alkynylene" refers to divalent straight
or branched chain hydrocarbyl groups having at least one
carbon-carbon triple bond, and having in the range of about 2 up to
12 carbon atoms, and "substituted alkynylene" refers to alkynylene
groups further bearing one or more substituents as set forth
above.
[0051] As employed herein, "arylene" refers to divalent aromatic
groups having in the range of 6 up to 14 carbon atoms and
"substituted arylene" refers to arylene groups further bearing one
or more substituents as set forth above.
[0052] As employed herein, "alkylarylene" refers to
alkyl-substituted arylene groups and "substituted alkylarylene"
refers to alkylarylene groups further bearing one or more
substituents as set forth above.
[0053] As employed herein, "arylalkylene" refers to
aryl-substituted alkylene groups and "substituted arylalkylene"
refers to arylalkylene groups further bearing one or more
substituents as set forth above.
[0054] As employed herein, "arylalkenylene" refers to
aryl-substituted alkenylene groups and "substituted arylalkenylene"
refers to arylalkenylene groups further bearing one or more
substituents as set forth above.
[0055] As employed herein, "arylalkynylene" refers to
aryl-substituted alkynylene groups and "substituted arylalkynylene"
refers to arylalkynylene groups further bearing one or more
substituents as set forth above.
[0056] Diseases and conditions contemplated for treatment in
accordance with the present invention include inflammatory and
infectious diseases, such as, for example, septic shock,
hemorrhagic shock, anaphylactic shock, toxic shock syndrome,
ischemia, cerebral ischemia, administration of cytokines,
overexpression of cytokines, ulcers, inflammatory bowel disease
(e.g., ulcerative colitis or Crohn's disease), diabetes, arthritis
(e.g., rheumatoid athritis and osteoarthritis), asthma, Alzheimer's
disease, Parkinson's disease, multiple sclerosis, cirrhosis,
allograft rejection, encephalomyelitis, meningitis, pancreatitis,
peritonitis, vasculitis, lymphocytic choriomeningitis,
glomerulonephritis, uveitis, ileitis, inflammation (e.g., liver
inflammation, renal inflammation, and the like), burn, infection
(including bacterial, viral, fungal and parasitic infections),
hemodialysis, chronic fatigue syndrome, stroke, cancers (e.g.,
breast, melanoma, carcinoma, and the like), cardiopulmonary bypass,
ischemic/reperfusion injury, gastritis, adult respiratory distress
syndrome, cachexia, myocarditis, autoimmune disorders, eczema,
psoriasis, heart failure, heart disease, atherosclerosis,
dermatitis, urticaria, systemic lupus erythematosus, AIDS, AIDS
dementia, chronic neurodegenerative disease, pain (e.g., chronic
pain and post-surgical pain), priapism, cystic fibrosis,
amyotrophic lateral sclerosis, schizophrenia, depression,
premenstrual syndrome, anxiety, addiction, headache, migraine,
Huntington's disease, epilepsy, neurodegencrative disorders,
gastrointestinal motility disorders, obesity, hyperphagia, solid
tumors (e.g., neuroblastoma), malaria, hematologic cancers,
myelofibrosis, lung injury, graftversushost disease, head injury,
CNS trauma, hepatitis, renal failure, liver disease (e.g., chronic
hepatitis C), drug-induced lung injury (e.g., paraquat), myasthenia
gravis (MG), ophthalmic diseases, postangioplasty, restenosis,
angina, coronary artery disease, and the like.
[0057] In accordance with another embodiment of the present
invention, there are provided methods for the preparation of
modified NSAIDs, said method comprising covalently attaching a
NSAID to a sulfur-containing functional group. The resulting
compound provides a latent form of the pharmacologically active
agent, releasing the biological activity thereof only when the
compound is cleaved (e.g., by an esterase, amidase or other
suitable enzyme).
[0058] As readily recognized by those of skill in the art,
invention compounds can be prepared in a variety of ways. See, for
example, Schemes 1A and 1B, wherein NSAID, X, bearing a carboxylic
moiety can be reacted either directly with the sulfur-containing
functional group (Scheme 1A) or indirectly through a linker
molecule (Scheme 1B). 1
[0059] Employing these general reaction schemes, invention modified
NSAIDs can be prepared from a wide variety of pharmacologically
active agents. See, for example, Examples 1-59 provided herein.
[0060] In accordance with yet another embodiment of the present
invention, there are provided methods for reducing the side effects
induced by administration of NSAIDs to a subject, said method
comprising reducing the C.sub.max relative to unmodified NSAIDs
while maintaining a therapeutically effective concentration in
plasma upon administration to a subject in need thereof. The
reduction in C.sub.max is achieved, for example, by covalently
attaching a sulfur-containing functional group containing an
optionally substituted hydrocarbyl moiety to said NSAID prior to
administration to said subject, as depicted in Schemes 1A and
1B.
[0061] In a particular embodiment of the invention, the C.sub.max
is reduced relative to the unmodified NSAID by about 10% to 90%. In
a presently preferred embodiment, the C.sub.max is reduced relative
to the unmodified NSAID by about 20% to 80%. In a most preferred
embodiment, the C.sub.max is reduced relative to the unmodified
NSAID by about 40% to 70%.
[0062] In accordance with still another embodiment of the present
invention, there are provided methods for enhancing the
effectiveness of NSAIDs, said method comprising reducing the
C.sub.max relative to unmodified NSAIDs while maintaining a
therapeutically effective concentration in plasma upon
administration to a subject in need thereof. The enhanced
effectiveness of said NSAIDs is achieved, for example, by
covalently attaching a sulfur-containing functional group
containing an optionally substituted hydrocarbyl moiety to said
NSAID.
[0063] In accordance with a still further embodiment of the present
invention, there are provided improved methods for the
administration of NSAIDs to a subject for the treatment of a
pathological condition, the improvement comprising reducing the
C.sub.max relative to unmodified NSAIDs while maintaining a
therapeutically effective concentration in plasma upon
administration to a subject in need thereof. The improvement is
accomplished, for example, by covalently attaching said NSAID to a
sulfur-containing functional group containing an optionally
substituted hydrocarbyl moiety prior to administration thereof to
said subject.
[0064] Those of skill in the art recognize that the modified NSAIDs
described herein can be delivered in a variety of ways, such as,
for example, orally, intravenously, subcutaneously, parenterally,
rectally, by inhalation, and the like.
[0065] Depending on the mode of delivery employed, the modified
NSAIDs contemplated for use herein can be delivered in a variety of
pharmaceutically acceptable forms. For example, the invention
modified NSAIDs can be delivered in the form of a solid, solution,
emulsion, dispersion, micelle, liposome, and the like.
[0066] Thus, in accordance with still another embodiment of the
present invention, there are provided physiologically active
composition(s) comprising invention modified NSAIDs in a suitable
vehicle rendering said compounds amenable to oral delivery,
transdermal delivery, intravenous delivery, intramuscular delivery,
topical delivery, nasal delivery, and the like.
[0067] Pharmaceutical compositions of the present invention can be
used in the form of a solid, a solution, an emulsion, a dispersion,
a micelle, a liposome, and the like, wherein the resulting
composition contains one or more of the modified NSAIDs of the
present invention, as an active ingredient, in admixture with an
organic or inorganic carrier or excipient suitable for enteral or
parenteral applications. Invention modified NSAIDs may be
compounded, for example, with the usual non-toxic, pharmaceutically
acceptable carriers for tablets, pellets, capsules, suppositories,
solutions, emulsions, suspensions, and any other form suitable for
use. The carriers which can be used include glucose, lactose, gum
acacia, gelatin, mannitol, starch paste, magnesium trisilicate,
talc, corn starch, keratin, colloidal silica, potato starch, urea,
medium chain length triglycerides, dextrans, and other carriers
suitable for use in manufacturing preparations, in solid,
semisolid, or liquid form. In addition auxiliary, stabilizing,
thickening and coloring agents and perfumes may be used. Invention
modified NSAIDs are included in the pharmaceutical composition in
an amount sufficient to produce the desired effect upon the process
or disease condition.
[0068] Pharmaceutical compositions containing invention modified
NSAIDs may be in a form suitable for oral use, for example, as
tablets, troches, lozenges, aqueous or oily suspensions,
dispersible powders or granules, emulsions, hard or soft capsules,
or syrups or elixirs. Compositions intended for oral use may be
prepared according to any method known to the art for the
manufacture of pharmaceutical compositions and such compositions
may contain one or more agents selected from the group consisting
of a sweetening agent such as sucrose, lactose, or saccharin,
flavoring agents such as peppermint, oil of wintergreen or cherry,
coloring agents and preserving agents in order to provide
pharmaceutically elegant and palatable preparations. Tablets
containing inventon modified NSAIDs in admixture with non-toxic
pharmaceutically acceptable excipients may also be manufactured by
known methods. The excipients used may be, for example, (1) inert
diluents such as calcium carbonate, lactose, calcium phosphate or
sodium phosphate; (2) granulating and disintegrating agents such as
corn starch, potato starch or alginic acid; (3) binding agents such
as gum tragacanth, corn starch, gelatin or acacia, and (4)
lubricating agents such as magnesium stearate, stearic acid or
talc. The tablets may be uncoated or they may be coated by known
techniques to delay disintegration and absorption in the
gastrointestinal tract and thereby provide a sustained action over
a longer period. For example, a time delay material such as
glyceryl monostearate or glyceryl distearate may be employed. They
may also be coated by the techniques described in the U.S. Pat.
Nos. 4,256,108; 4,160,452; and 4,265,874, to form osmotic
therapeutic tablets for controlled release.
[0069] In some cases, formulations for oral use may be in the form
of hard gelatin capsules wherein the invention modified NSAIDs are
mixed with an inert solid diluent, for example, calcium carbonate,
calcium phosphate or kaolin. They may also be in the form of soft
gelatin capsules wherein the invention modified NSAIDs are mixed
with water or an oil medium, for example, peanut oil, liquid
paraffin, or olive oil.
[0070] The pharmaceutical compositions may be in the form of a
sterile injectable suspension. This suspension may be formulated
according to known methods using suitable dispersing or wetting
agents and suspending agents. The sterile injectable preparation
may also be a sterile injectable solution or suspension in a
non-toxic parenterally-acceptable diluent or solvent, for example,
as a solution in 1,3-butanediol. Sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil may be employed including synthetic
mono- or diglycerides, fatty acids (including oleic acid),
naturally occurring vegetable oils like sesame oil, coconut oil,
peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like
ethyl oleate or the like. Buffers, preservatives, antioxidants, and
the like can be incorporated as required.
[0071] Invention modified NSAIDs contemplated for use in the
practice of the present invention may also be administered in the
form of suppositories for rectal administration of the drug. These
compositions may be prepared by mixing the invention modified
NSAIDs with a suitable non-irritating excipient, such as cocoa
butter, synthetic glyceride esters of polyethylene glycols, which
are solid at ordinary temperatures, but liquify and/or dissolve in
the rectal cavity to release the drug.
[0072] Since individual subjects may present a wide variation in
severity of symptoms and each drug has its unique therapeutic
characteristics, the precise mode of administration and dosage
employed for each subject is left to the discretion of the
practitioner.
[0073] In general, the dosage of invention modified NSAIDs employed
as described herein falls in the range of about 0.01 mmoles/kg body
weight of the subject/hour up to about 0.5 mmoles/kg/hr. Typical
daily doses, in general, lie within the range of from about 10
.mu.g up to about 100 mg per kg body weight, and, preferably within
the range of from 50 .mu.g to 10 mg per kg body weight and can be
administered up to four times daily. The daily IV dose lies within
the range of from about 1 .mu.g to about 100 mg per kg body weight,
and, preferably, within the range of from 10 .mu.g to 10 mg per kg
body weight.
[0074] In accordance with yet another embodiment of the present
invention, there are provided improved methods for the treatment of
a subject suffering from a pathological condition by administration
thereto of a NSAID, the improvement comprising reducing the
C.sub.max relative to unmodified NSAIDs while maintaining a
therapeutically effective concentration in plasma upon
administration to a subject in need thereof. The improvement is
achieved, for example, by covalently attaching said NSAID to a
sulfur-containing functional group prior to administration thereof
to said subject.
[0075] Thus, invention method for the treatment of a subject
afflicted with a pathological condition comprises administering to
a subject an effective amount of a modified pharmacologically
active agent,
[0076] wherein said pharmacologically active agent is a NSAID, and
is effective for treatment of said condition, and
[0077] wherein said pharmacologically active agent has been
modified to reduce the C.sub.max relative to unmodified NSAIDs
while maintaining a therapeutically effective concentration in
plasma upon administration to a subject in need thereof. The
modification is accomplished, for example, by the covalent
attachment to the NSAID of a sulfur-containing functional
group.
[0078] The invention will now be described in greater detail by
reference to the following non-limiting examples.
[0079] The syntheses described in Examples 1-8 are outlined in
Scheme 2. 2
EXAMPLE 1
[0080] Compound 10 (Scheme 2). A mixture of Naproxen (1) (23 g, 0.1
mol), ethylene glycol (2) (27.9 ml, 0.5 mol) and toluenesulfonic
acid (TsOH) (1.27 g, 6.7 mmol) in CHCl.sub.3 was heated to reflux
for 4 h. The reaction solution was washed with water, 10%
Na.sub.2CO.sub.3 solution and water. The organic layer was dried
(Na.sub.2SO.sub.4) and the solvent was evaporated. The residue was
purified by crystallization from CH.sub.2Cl.sub.2 and hexanes to
give 25.7 g (94%) of the compound 10 as a white crystal; .sup.1H
NMR (CDCl.sub.3) .delta.1.59 (d, 3H), 1.62 (br, 1H, ex D.sub.2O),
3.74 (t, 2H), 3.90 (q, 1H), 3.91 (s, 3H), 4.21 (t, 2H), 7.11 (m,
2H), 7.39 (d, 1H), 7.69 (m, 3H); .sup.13C NMR (CDCl.sub.3)
.delta.18.7, 45.6, 55.5, 61.4, 66.6, 105.8, 119.3, 126.1, 126.2,
127.5, 129.1, 129.5, 133.9, 135.7, 157.9, 175.2; MS (ESI) m/z 273
(M-1).
[0081] Compound 18 (Scheme 2). To a solution of compound 10 (24.5
g, 89 mmol) in 100 ml of pyridine was added tosyl chloride (TsCl)
(34.1 g, 179 mmol). The resulting solution was stirred at 0.degree.
C. for 2.5 h. The reaction solution was then poured into 300 ml of
water and then 200 ml of ether was added. The layers were separated
and the organic phase was washed with water (300.times.5) and dried
(Na.sub.2SO.sub.4). After the solvent was evaporated, the residue
was purified by column chromatography on a silica gel column using
dichloromethane as an eluent to give 35.1 g (92%) of the pale
yellow oil; .sup.1H NMR (CDCl.sub.3) .delta.1.55(d, 3H), 2.40 (s,
3H), 3.91 (q, 1H), 4.18 (m, 4H), 7.12 (m, 2H), 7.24 (m, 2H), 7.37
(d, 1H), 7.66 (d, 1H), 7.70 (m, 4H); MS (ESI) m/z 429 (M+1).
EXAMPLE 2
[0082] Compound 11 (Scheme 2). Compound 11 was prepared as
described above for the preparation of compound 10, this time
employing naproxen (1) and 1,3-propanediol (3). The resulting
compound 11 was purified by crystallization from dichloromethane
and hexanes with a 92% yield. .sup.1H NMR (CDCl.sub.3) .delta.1.59
(d, 3H), 1.78 (m, 2H), 1.87 (br, 1H, D.sub.2O ex), 3.53 (t, 2H),
3.87 (q, 1H), 3.91 (s, 3H), 4.23 (t, 2H), 7.11 (d, 1H), 7.15 (m,
1H), 7.41 (q, 1H), 7.66 (d, 1H), 7.69 (s, 1H), 7.71 (s, 1H);
.sup.13C NMR (CDCl.sub.3) .delta.18.6, 31.8, 45.7, 55.5, 59.2,
61.9, 77.0, 77.2, 77.5, 105.8, 119.2, 126.1, 126.3, 127.4, 129.1,
129.4, 133.9, 135.7, 157.8, 175.3; and MS (ESI) m/z 289.4
(M+1).
[0083] Compound 19 (Scheme 2). Compound 19 was prepared as
described above for the preparation of compound 18, this time
employing compound 11 and TsCl. Compound 19 was purified by
crystallization from ether and hexane with an yield of 95%; .sup.1H
NMR (CDCl.sub.3) .delta.1.54 (d, 3H), 1.91 (m, 2H), 2.42 (s, 3H),
3.79 (q, 1H), 3.92 (s, 3H), 3.99 (t, 2H), 4.10 (t, 2H), 7.11 d,
1H), 7.15 (q, 1H), 7.26 (d, 2H), 7.34 (d, 2H), 7.62(d, 1H), 7.70
(m, 4H); .sup.13C NMR (CDCl.sub.3) .delta.18.5, 21.8, 28.4, 45.5,
55.5, 60.6, 66.9, 105.8, 119.2, 126.0, 126.3, 127.4, 128.0, 129.1,
129.5, 130.1, 133.1, 133.9, 135.6, 145.0, 157.9, 174.5; MS (ESI)
m/z 421.1 (M-1).
EXAMPLE 3
[0084] Compound 12 (Scheme 2). Compound 12 was prepared as
described above for the preparation of compound 10, this time
employing naproxen (1) and 1,4-butanediol (4). Compound 12 was
purified by crystallization from dichloromethane and hexanes with a
90% yield; .sup.1H NMR (CDCl.sub.3) .delta.1.48 (m, 2H), 1.59 (d,
3H), 1.64 (m, 2H), 1.85 (s, 1H, D.sub.2O, ex), 3.52 (t, 2H), 3.85
(q, 1H), 3.89 (s, 3H), 4.10 (t, 2H), 7.10-7.15 (m, 2H), 7.42 (, d,
1H), 7.66-7.7-(m, 3H); MS (ESI) m/z 325.4 (M+Na).
[0085] Compound 20 (Scheme 2). Compound 20 was prepared as
described above for the preparation of compound 18, this time
employing compound 12 and TsCl. The compound 20 was purified by
crystallization from ether and hexane with an yield of 93%; .sup.1H
NMR (CDCl.sub.3) .delta.1.55 (d, 3H), 1.53-1.62 (m, 4H), 2.43 (s,
3H), 3.82 (q, 1H), 3.92 (s, 3H), 3.94 (m, 2H), 4.02 (m, 2H),
7.11-7.15 (m, 2H), 7.30 (d, 2h), 7.38 (d, 1H), 7.64 (d, 1H), 7.70
(d, 2H), 7.75 (d, 2H); MS (ESI) m/z 457.5 (M+1).
EXAMPLE 4
[0086] Compound 13 (Scheme 2). Compound 13 was prepared as
described above for the preparation of compound 10, this time
employing naproxen (1) and 1,5-pentanediol (5). After reaction, the
reaction solution was washed with water and the reaction solvent
was then evaporated under high vaccum to give a quantitative yield
of the compound 13. The compound was used to make compound 21
without further purification; .sup.1H NMR (CDCl.sub.3) .delta.1.28
(m, 2H), 1.46 (m, 2H), 1.55 (d, 3H), 1.59 (m, 2H), 3.51 (t, 2H),
3.85 (q, 1H), 3.91 (s, 3H), 4.09 (t, 2H), 7.11-7.15 (m, 2H), 7.40
(q, 1H), 7.66-7.70 (m, 3H); MS (ESI) m/z 317.5 (M+1).
[0087] Compound 21 (Scheme 2). Compound 21 was prepared as
described above for the preparation of compound 18, this time
employing compound 13 and TsCl. Compound 21 was purified by
crystallization from ether and hexane with a 95% yield; .sup.1H NMR
(CDCl.sub.3) .delta.1.24 (m, 2H), 1.48-1.58 (m, 4H), 1.59 (d, 3H),
2.43 (s, 3H), 3.84 (q, 1H), 3.89 (t, 2H), 3.91 (s, 3H), 4.01 (t,
2H),7.11-7.15 (m, 2H), 7.32 (q, 2H), 7.39 (q, 1H), 7.65 (d, 1H),
7.70 (m, 2H), 7.75 (d, 2H); MS (ESI) m/z 471.7 (M+1).
EXAMPLE 5
[0088] Compound 14 (Scheme 2). Compound 14 was prepared as
described above for the preparation of compound 10, this time
employing naproxen (1) and 1,6-hexanediol (6). After reaction, the
reaction solution was washed with water and the reaction solvent
was then evaporated to give compound 14 as a solid. The compound
was used to make compound 22 without further purification; .sup.1H
NMR (CDCl.sub.3) .delta.1.24 (m, 4H), 1.43 (m 2H), 1.56 (d, 3H),
1.54 (m, 2H), 3.51 (t, 2H), 3.85 (q, 1H), 4.01 (m, 2H), 7.10-7.15
(m 2H), 7.40 (q, 1H), 7.66-7.70 (m, 3H); MS (ESI) m/z 331.7
(M+1).
[0089] Compound 22 (Scheme 2). Compound 22 was prepared as
described above for the preparation of compound 18, this time
employing compound 14 and TsCl. Compound 22 was purified by column
chromatography on a silica gel column using dichloromethane as an
eluent to give compound 22 as a pale yellow oil; .sup.1H NMR
(CDCl.sub.3) .delta.1.12-1.22 (m, 4H), 1.46-1.52 (m, 4H), 1.57 (d,
3H), 2.43 (s, 3H), 3.84 (q, 1H), 3.92 (s, 3H), 3.93 (m, 2H), 4.03
(m, 2H), 7.11-7.77 (m, 10H); MS (ESI) m/z 485.6 (M+1).
EXAMPLE 6
[0090] Compound 15 (Scheme 2). Compound 15 was prepared as
described above for the preparation of compound 10, this time
employing naproxen (1) and di(ethylene glycol) (7). After reaction,
the reaction solution was washed with water and the reaction
solvent was then evaporated to give compound 15. The compound was
used to make compound 23 without further purification; .sup.1H NMR
(CDCl.sub.3) .delta.1.58 (d, 3H), 1.93 (br, 1H, D.sub.2O ex), 3.43
(t, 2H), 3.59 (t, 2H), 3.62 (t, 2H), 3.89 (q, 1H), 3.90 (s, 3H),
4.25 (m, 2H), 7.11-7.15 (m, 2H), 7.40-7.42 (m, 1H), 7.70 (t, 3H);
.sup.13C NMR (CDCl.sub.3) .delta.18.7, 45.6, 55.5, 61.8, 64.0,
69.2, 72.4, 76.9, 77.2, 77.5, 105,7, 119.2, 126.2, 126.4, 127.3,
129.0, 133.9, 135.7, 157.9, 174.8; MS(ESI) m/z 319.3 (M+1).
[0091] Compound 23 (Scheme 2). Compound 23 was prepared as
described above for the preparation of compound 18, this time
employing compound 15 and TsCl. Compound 23 was purified by column
chromatography on a silica gel column using dichloromethane as an
eluent to give the compound as a pale yellow oil with a 93% yield.
.sup.1H NMR (CDCl.sub.3) .delta.1.58 (d, 3H), 2.41 (s, 3H), 3.43
(m, 2H), 3.48(m, 2H), 3.84 (q, 1H), 3.86 (s, 3H), 3.94 (t, 2H),
4.10 (m, 2H), 7.10-7.13 (m, 2H), 7.29 (d, 2H), 7.39 (d, 1H),
7.65-7.75 (m, 5H); .sup.13C NMR (CDCl.sub.3) .delta.18.6, 21.8,
45.5, 55.5, 63.9, 68.7, 69.27, 69.27, 105.8, 119.2, 126.2, 126.4,
127.4, 128.1, 129.0, 129.4, 129.9, 133.9, 145.0, 157.9, 174.7; MS
(ESI) m/z 473.4 (M+1).
EXAMPLE 7
[0092] Compound 16 (Scheme 2). Compound 16 was prepared as
described above for the preparation of compound 10, this time
employing naproxen (1) and 1,3-pentanediol (8). After reaction, the
reaction solution was washed with water and the reaction solvent
was then evaporated to give compound 15 with a 32% yield. The
compound was used to make compound 24 without further purification;
.sup.1H NMR, .sup.13C NMR and MS are consistent with the structure
of compound 16.
[0093] Compound 24 (Scheme 2). Compound 24 was prepared as
described above for the preparation of compound 18, this time
employing compound 16 and TsCl. The compound 24 was purified by
column chromatography on a silica gel column using dichloromethane
as an eluent to give the compound as a pale yellow oil with a 82%
yield. The .sup.1H NMR, .sup.13C NMR and MS are consistent with the
structure of compound 24.
EXAMPLE 8
[0094] Compound 17 (Scheme 2). Compound 17 was prepared as
described above for the preparation of compound 10, this time
employing naproxen (1) and 1,4-cyclohexanediol (8). After reaction,
the reaction solution was washed with water and the reaction
solvent was then evaporated to give compound 17. Compound 17 was
used to make compound 25 without further purification; .sup.1H NMR
(CDCl.sub.3) .delta.1.30-1.45 (m, 6H), 1.56 (d, 3H), 1.80-1.98 (m,
4H), 3.66 (m, 1H), 3.82 (q, 1H), 3.91 (s, 3H), 4.75 (m, 1H), 7.11
m, 2H), 7.39 (d, 1H), 7.65-7.70 (m, 3H); .sup.13C NMR (CDCl.sub.3)
.delta.18.7, 28.2, 28.5, 32.1, 32.2, 45.9, 55.5, 68.9, 72.0, 76.9,
77.2, 77.5, 105.8, 119.1, 126.0, 126.4, 127.2, 129.1, 129.5, 133.8,
136.1, 157.8, 174.4; MS (ESI) m/z 351.4 (M+Na).
[0095] Compound 25 (Scheme 2). Compound 25 was prepared as
described above for the preparation of compound 18, this time
employing compound 17 and TsCl. Compound 25 was purified by column
chromatography on a silica gel column using dichloromethane as an
eluent to give the compound as a pale yellow oil with a 93% yield;
.sup.1H NMR (CDCl.sub.3) .delta.1.50-1.84 (m, 11H), 2.43 (s, 3H),
3.80 (q, 1H), 3.92 (s, 3H), 4.51 (m, 1H), 4.78 (m, 1H), 7.10-7.15
(m 2H), 7.26-7.39 (m, 3H), 7.61-7.75 (m, 5H); MS (ESI) m/z 483.5
(M+H).
[0096] The syntheses described in Examples 9-14 are outlined in
Scheme 3. 34
EXAMPLE 9
[0097] Compound 32 (Scheme 3). Compound 32 was prepared as
described above for the preparation of compound 10, this time
employing ketoprofen (26) and 1,3-propanediol (3). Compound 32 was
purified by column chromatography on a silica gel column using
200:1 CH.sub.2Cl.sub.2/MeOH as an eluent to give compound 32 with a
50% yield. .sup.1H NMR (CDCl.sub.3) .delta.1.55 (d, 3H), 1.82 (m
3H, 1H, D.sub.2O ex), 3.58 (m, 2H), 3.82(m, 1H), 4.25 (m 2H),
7.44-7.82 (m, 9H); MS (ESI) m/z 313.5 (M+H).
[0098] Compound 38 (Scheme 3). Compound 38 was prepared as
described above for the preparation of compound 18, this time
employing compound 32 and TsCl. Compound 38 was purified by column
chromatography on a silica gel column using CH.sub.2Cl.sub.2 as an
eluent to give the compound 38 as a colorless oil with a 81% yield;
.sup.1H NMR (CDCl.sub.3) .delta.1.49 (d, 3H), 1.94 (m, 2H), 2.43
(s, 3H), 3.72 (q, 1H), 4.01 (t, 2H), 4.12 (m, 2H), 7.31-7.78 (m,
13H); MS (ESI) m/z 467.3 (M+H).
EXAMPLE 10
[0099] Compound 33 (Scheme 3). Compound 33 was prepared as
described above for the preparation of compound 10, this time
employing flurbiprofen (27) and 1,3-propanediol (3). After
reaction, the reaction solution was washed in water and the
reaction solvent was then evaporated to give the compound 33 with a
quantitative yield. The compound 33 was used to make compound 39
without further purification; .sup.1H NMR (CDCl.sub.3) .delta.1.54
(d, 3H), 1.79 (t, 1H, D.sub.2O ex), 1.85 (m, 2H), 3.63 (m, 2H),
3.76 (q, 1H), 4.27 (t, 2H), 7.11-7.16(m, 2H), 7.35-7.46 (m, 4H),
7.54 (d, 2H); MS (ESI) m/z 325.4 (M+Na).
[0100] Compound 39 (Scheme 3). Compound 39 was prepared as
described above for the preparation of compound 18, this time
employing compound 33 and TsCl. Compound 39 was purified by
crystallization from ether/hexane system with a 79% yield; .sup.1H
NMR (CDCl.sub.3) .delta.1.50 (d, 3H), 1.96 (m, 2H), 2.42 (s, 3H),
3.68 (q, 1H), 4.03 (t, 2H), 4.15 (t, 2H), 7.05-7.11 (m, 2H),
7.25-7.54 (m, 8H), 7.76 (d, 2H); .sup.13C NMR (CDCl.sup.3)
.delta.18.4, 21.8, 28.4, 45.0, 50.8, 66.9, 115.2, 115.5, 123.68,
123.7, 127.9, 128.0, 129.2, 130.1, 131.0, 133.1, 135.6, 141.75,
141.8, 145.1, 158.9, 160.9, 173.9; MS (ESI) m/z 479.4 (M+Na).
EXAMPLE 11
[0101] Compound 34 (Scheme 3). Compound 34 was prepared as
described above for the preparation of compound 10, this time
employing ibuprofen (28) and 1,3-propanediol (3). After reaction,
the reaction solution was washed in water and the reaction solvent
was then evaporated to give compound 34 with a quantitative yield.
The compound 34 was used to make compound 40 without further
purification; .sup.1H NMR (CDCl.sub.3) .delta.0.89 (d, 6H), 1.49
(d, 3H), 1.79 (t, 2H), 1.78-1.85 (m, 1H), 1.95 (t, 1H, D.sub.2O
ex), 2.45 (d, 2H), 3.53 (m, 2H), 3.71 (q, 1H), 4.22 (m, 2H), 7.09
(d, 2H), 7.26 (d, 2H).
[0102] Compound 40 (Scheme 3). Compound 40 was prepared as
described above for the preparation of compound 18, this time
employing compound 34 and TsCl. Compound 40 was purified by
crystallization from ether/hexane system to give a white solid with
a 96% yield; .sup.1H NMR (CDCl.sub.3) .delta.0.89 (d, 6H), 1.44 (d,
3H), 1.81-1.92 (m, 3H), 2.44 (s, 3H), 3.61 (q, 1H), 3.99 (t, 2H),
4.09 (t, 2H), 7.08 (d, 2H), 7.14 (d, 2H), 7.34 (d, 2H), 7.78 (d,
2H); .sup.13C NMR (CDCl.sub.3) .delta.18.46, 21.80, 22.54, 28.39,
30.32, 45.16, 60.39, 66.92, 127.23, 128.04, 129.50, 130.03, 133.12,
137.68, 140.76, 145.00, 174.54; MS (ESI) m/z 441.5 (M+Na).
EXAMPLE 12
[0103] Compound 35 (Scheme 3). Compound 35 was prepared as
described above for the preparation of compound 10, this time
employing diclofenac (29) and 1,3-propanediol (3). After reaction,
compound 35 was purified by column chromatography on a silica gel
column using 200:1 CH.sub.2Cl.sub.2/MeOH as an eluent to give the
compound 35 as a white solid with a 56% yield. .sup.1H NMR
(CDCl.sub.3) .delta.1.89 (m, 3H, 1H D.sub.2O ex), 3.66 (t, 2H),
3.83 (s, 3H), 4.31 (t, 2H), 6.55 (d, 1H), 6.87 (br, 1H), 6.94-7.00
(m, 2H), 7.11-7.14 (m, 1H), 7.22-7.26 (m, 1H), 7.34 (d, 2H); MS
(ESI) m/z 376.3 (M+Na).
[0104] Compound 41 (Scheme 3). Compound 41 was prepared as
described above for the preparation of compound 18, this time
employing compound 35 and TsCl. Compound 41 was purified by column
chromatography on a silica gel column using CH.sub.2Cl.sub.2 as an
eluent to give the compound 41 as a pale yellow oil and the yield
was 89%; .sup.1H NMR (CDCl.sub.3) .delta.2.02 (m, 2H), 2.43 (s,
3H), 3.73 (s, 2H), 4.09 (t, 2H), 4.17 (t, 2H), 6.53 (d, 1H), 6.99
(s, 1H), 6.93-7.00 (m, 2H), 7.12 (t, 1H), 7.18 (d, 1H), 7.23 (d,
1H), 7.31-7.35 (m, 3H), 7.78 (d, 2H); MS (ESI) m/z 508.3 (M).
EXAMPLE 13
[0105] Compound 36 (Scheme 3). Compound 36 was prepared as
described above for the preparation of compound 10, this time
employing carprofen (30) and 1,3-propanediol (3). After reaction,
compound 36 was purified by column chromatography on a silica gel
column using 200:1 CH.sub.2Cl.sub.2/MeOH as an eluent to give the
compound 36 as a colorless oil with a 54% yield. .sup.1H NMR
(CDCl.sub.3) .delta.1.59 (d, 3H), 1.74 (br, 1H, D.sub.2O ex), 1.80
(m, 2H), 3.53-3.56 (m, 2H), 3.88 (q, 1H), 4.22-4.28 (m, 2H), 7.17
(d, 1H), 7.29-7.35 (m, 3H), 7.94-7.98 (m, 2H), 8.14 (br, 1H);
.sup.13C NMR (CDCl.sub.3) .delta.18.99, 31.84, 46.17, 59.42, 62.10,
109.70, 111.79, 119.79, 120.21, 120.87, 121.92, 124.49, 125.22,
126.09, 138.24, 139.37, 140.55, 175.39; MS (ESI) m/z 332.2
(M+H).
[0106] Compound 42 (Scheme 3). Compound 42 was prepared as
described above for the preparation of compound 18, this time
employing compound 36 and TsCl. Compound 42 was purified by column
chromatography on a silica gel column using CH.sub.2Cl.sub.2 as an
eluent to give the compound 42 as a sticky oil and the yield was
90%; .sup.1H NMR (CDCl.sub.3) .delta.1.55 (d, 3H), 1.91 (m, 2H),
2.39 (s, 3H), 3.83 (q, 1H), 3.97 (t, 2H), 4.09-4.18 (m, 2H), 7.10
(d, 1H), 7.21(d, 2H), 7.32 (s, 2H), 7.38 (s, 1H) 7.65 (d, 2H), 7.91
(d, 1H), 7.98 (s, 1H), 8.54 (s, 1H); .sup.13C NMR (CDCl.sub.3)
.delta.18.83, 21.77, 28.32, 46.08, 60.59, 57.04, 109.97, 111.97,
119.58, 120.06, 120.69, 121.77, 124.38, 125.00, 125.99, 127.95,
129.22, 130.06, 132.90, 138.38, 139.19, 140.69, 145.15, 174.59; MS
(ESI) m/z 486.3 (M+H).
EXAMPLE 14
[0107] Compound 37 (Scheme 3). Compound 37 was prepared as
described above for the preparation of compound 10, this time
employing indomethacin (31) and 1,3-propanediol (3). After
reaction, compound 37 was purified by column chromatography on a
silica gel column using 200:1; 100:1 CH.sub.2Cl.sub.2/MeOH as an
eluents to give the compound 37 as a pale yellow oil with a 49%
yield. .sup.1H NMR, .sup.13C NMR and MS are consistent with the
structure of compound 37.
[0108] Compound 43 (Scheme 3). Compound 43 was prepared as
described above for the preparation of compound 18, this time
employing compound 37 and TsCl. The compound 43 was purified by
column chromatography on a silica gel column using hexane/ethyl
acetate (3:1) as an eluent to give the compound 43 as a pale yellow
oil and the yield was 71% ; .sup.1H NMR (CDCl.sub.3) .delta.1.97
(m, 2H), 2.36 (s, 3H), 2.44 (s, 3H), 3.63 (s, 2H), 3.83 (s, 3H),
4.05 (t, 2H), 4.15 (t, 2H), 6.66-6.68 (m, 1H), 6.87 (d, 1H), 6.93
(d, 1H), 7.33 (d, 2H), 7.47 (d, 2H), 7.67 (d, 2H), 7.75 (d, 2H); MS
(ESI) m/z 592.0 (M+Na).
[0109] The syntheses described in Examples 15 and 16 are outlined
in Scheme 4. 5
EXAMPLE 15
[0110] Compound 46 (Scheme 4). Compound 46 was prepared as
described above for the preparation of compound 18, this time
employing compound 11 and 44. The compound 46 was purified by
crystallization from ether/hexane system to give the compound 46 as
a white solid . The yield was 95%; .sup.1H NMR (CDCl.sub.3)
.delta.1.58 (d, 3H), 2.00 (m, 2H), 2.73 (s, 3H), 3.87 (q, 1H), 3.90
(s, 3H), 4.10 (t, 2H), 4.18 (t, 2H), 7.10-7.15 (m, 2H), 7.39 (d,
1H), 7.66-7.71 (m, 3H); .sup.13C NMR (CDCl.sub.3) .delta.18.46,
28.55, 37.03, 45.56, 55.47, 55.50, 60.38, 66.36, 105.75, 119.32,
126.09, 126.27, 127.44, 129.06, 129.41, 133.89, 135.68, 157.91,
174.59; MS (ESI) m/z 388.5 (M+Na).
EXAMPLE 16
[0111] Compound 47 (Scheme 4). Compound 47 is prepared as described
above for the preparation of compound 18, this time employing
compound 11 and compound 45. The compound is purified by
crystallization and the yield was 70-90%. The .sup.1H NMR, .sup.13C
NMR and MS are consistent with the structure of compound 47.
[0112] The syntheses described in Examples 17 and 18 are outlined
in Scheme 5. 6
EXAMPLE 17
[0113] Compound 50 (Scheme 5). To a solution of naproxen (1) (1.15
g, 5 mmol), compound 48 (0.62 g, 5 mmol) and dimethylamino pyridine
(DMAP) (0.12 g, 1 mmol) was added dicyclohexyldicarbodiimide (DCC)
(1.03 g, 5 mmol) at 0.degree. C. The resulting solution was stirred
at 0.degree. C. for 1.5 h. After reaction, the solid was filtered
off and the solvent was evaporated. The residue was washed with
ether to give 1.4 g (83%) of compound 50 as a white solid; .sup.1H
NMR (CDCl.sub.3) .delta.1.59 (d, 3H), 2.38 (s, 3H), 3.17 (m, 2H),
3.87 (q, 1H), 3.92 (s, 3H), 4.43 (m, 1H), 4.59 (m, 1H), 7.10 (d,
1H), 7.15 (m, 1H), 7.33 (m, 1H), 7.67 (d, 1H), 7.70 (m, 2H); MS
(ES) m/e 358.2 (M+Na).
EXAMPLE 18
[0114] Compound 51 (Scheme 5). Compound 51 was prepared as
described above for the preparation of compound 50, this time
employing compound 1 (1. 1 5 g, 5 mmol) and 49 (1.16 g, 5 mmol).
The compound was purified by column chromatography on a silica gel
column using 1:1 hexanes/ethyl acetate as eluent to give 0.91 g of
compound 51 as a pale yellow oil; .sup.1H NMR (CDCl.sub.3)
.delta.1.45 (d, 3H), 3.48 (m, 2H), 3.59 (q, 1H), 3.92 (s, 3H), 4.47
(m, 2H), 7.10 (d, 1H), 7.18 (m, 2H), 7.45 (s, 1H), 7.49 (t, 1H),
7.65 (t, 2H), 8.06 (q, 1H), 8.28 (q, 1H), 8.68 (s, 1H); .sup.13C
NMR (CDCl.sub.3) .delta.18.8, 45.2, 55.4, 55.5, 57.9, 105,8, 123.6,
125.9, 127.5, 128.4, 129.0, 129.3, 130.8, 133.7, 133.9, 134.9,
141.5, 148.4, 158.0, 174.0.
[0115] The syntheses described in Examples 19-21 are outlined in
Scheme 6. 7
EXAMPLE 19
[0116] Compound 55 (Scheme 6). A mixture of compound 19 (2.2 g, 5
mmol), compound 52 (0.57 g, 6 mmol) and K.sub.2CO.sub.3 (3.45 g, 25
mmol) in 50 ml of dimethyl formamide (DMF) was stirred for a week.
The reaction solution was poured into 100 ml of water and extracted
with CH.sub.2Cl.sub.2. The organic phase was washed with water
(50.times.5) and dried (Na.sub.2SO.sub.4). The solvent was
evaporated and the residue was purified by column chromatography on
a silica gel column using 3:1 hexane/ethyacetate as an eluent to
give 0.3 g (16%) of compound 55 as a pale yellow oil; .sup.1H NMR
(CDCl.sub.3) .delta.1.60 (d, 3H), 2.38 (s, 3H), 3.17 (m, 2H), 3.87
(q, 1H), 3.92 (s, 3H), 4.45 (m, 1H), 4.59 (m, 1H), 7.10 (s, 1H),
7.14-7.16 (q, 1H), 7.32-7.35 (q, 1H), 7.62 (s, 1H), 7.67-7.71 (m,
2H); MS (ESI) m/z 358.2 (M+Na).
EXAMPLE 20
[0117] Compound 56 (Scheme 6). Compound 56 was prepared as
described above for the preparation of compound 55, this time
employing compound 19 and compound 53. The compound was purified by
column chromatography on a silica gel column using CH.sub.2Cl.sub.2
as an eluent to give compound 56 as a pale yellow oil (33%).
.sup.1H NMR (CDCl.sub.3) .delta.1.54 (d, 3H), 1.72 (m, 2H), 2.83
(m, 2H), 3.80 (q, 1H), 3.92 (s, 3H), 4.10 (t, 2H) 7.07-8,10 (m,
10H); MS (ESI) m/z 442.3 (M+H).
EXAMPLE 21
[0118] Compound 57 (Scheme 6). Compound 57 was prepared as
described above for the preparation of compound 55, this time
employing compound 19 and compound 54. The compound was purified by
column chromatography on a silica gel column using CH.sub.2Cl.sub.2
as an eluent to give compound 57 as a pale yellow oil (11%).
.sup.1H NMR (CDCl.sub.3) .delta.1.55 (d, 3H), 1.80 (m, 2H), 3.03 (m
2H),3.86 (m, 1H), 4.13 (m, 2H), 7.07-7.93 (m, 10H); MS (ESI) m/z
473.4 (M+H).
[0119] The syntheses described in Examples 22 and 23 are outlined
in Scheme 7. 8
EXAMPLE 22
[0120] Compound 60 (Scheme 7). Compound 60 is prepared as described
above for the preparation of compound 50, this time employing
naproxen (1) and compound 58. After reaction the compound is
purified by column chromatography on a silica gel column to give
the compound 60 in a yield from 75-95%.
EXAMPLE 23
[0121] Compound 61 (Scheme 7). Compound 61 is prepared as described
above for the preparation of compound 50, this time employing
naproxen (1)and compound 59. After reaction, the compound is
purified by column chromatography on a silica gel column to give
compound 61 in a yield from 75-95%.
[0122] The syntheses described in Examples 24 and 25 are outlined
in Scheme 8. 9
EXAMPLE 24
[0123] Compound 63 (Scheme 8). Compound 63 is prepared as described
above for the preparation of compound 50, this time employing
naproxen (1) and compound 62. After reaction, the compound is
purified by column chromatography on a silica gel column to give
compound 63 in a yield of 75-95%.
[0124] Compound 66 (Scheme 8). Compound 66 is prepared as described
above for the preparation of compound 18, this time employing
compound 63 and compound 64.
EXAMPLE 25
[0125] Compound 67 (Scheme 8). Compound 67 is prepared as described
above for the preparation of compound 18, this time employing
compound 63 and compound 65.
[0126] The syntheses described in Examples 26 and 27 are outlined
in Scheme 9. 10
EXAMPLE 26
[0127] Compound 70 (Scheme 9). Compound 70 is prepared as described
above for the preparation of compound 60, this time employing
compound 1 and compound 68.
EXAMPLE 27
[0128] Compound 71 (Scheme 9). Compound 71 is prepared as described
above for the preparation of compound 60, this time employing
compound 1 and compound 69.
[0129] The synthesis described in Example 28 is outlined in Scheme
10. 11
EXAMPLE 28
[0130] Compound 73 (Scheme 10). Compound 73 is prepared as
described above for the preparation of compound 60, this time
employing compound 1 and compound 72.
[0131] The synthesis described in Example 29 is outlined in Scheme
11. 12
EXAMPLE 29
[0132] Compound 75 (Scheme 11). To a solution of naproxen 1 (1.15
g, 5.0 mmol) and 1,3-dicyclohexylcarbodiimide (DCC)(1.03 g, 5 mmol)
in 180 ml of anhydrous tedrahydrofuran (THF) was added
4-(2-aminoethyl)benzenesulfonam- ide 74 (1.1 g, 5.5 mmol) at rt.
The resulting mixture was stirred overnight. The resulted solid was
filtered off and the solvent was evaporated. The residue was
partially dissolved in ethyl acetate and filtered to remove more
solid. The filtrate was evaporated and the residue was purified by
flash chromatography on a silica gel column using CH.sub.2Cl.sub.2
and 100:1 CH.sub.2Cl.sub.2-MeOH as eluents to give 0.1 g (5%) of
the compound 75 as a white solid; .sup.1H NMR (DMSO-d.sub.6)
.delta.1.38 (d, 3H), 2.73 (m, 3H, 1H, ex D.sub.2O), 3.68 (q, 1H),
3.86 (s, 3H), 7.13-8.08 (m, 12H, 2H, ex D.sub.2O); MS (ESI) m/z
413.1 (M+H).sup.+ (C.sub.22H.sub.25N.sub.2O.sub.4S require
413.5).
[0133] The syntheses described in Examples 30 and 31 are outlined
in Scheme 12. 13
EXAMPLE 30
[0134] Compound 78 (Scheme 12). To a solution of naproxen 1 (1.15
g, 5 mmol) and benzenesulfonyl hydrazide 76 (0.86 g, 5 mmol) in 50
ml of CH.sub.2Cl.sub.2 was added DCC (1.03 g, 5 mmol) at rt. The
resulting solution was stirred at rt for 26 h. The resulted solid
was filtered off and the filtrate was washed with 5%
Na.sub.2CO.sub.3 solution, 0.5N HCl solution and water. The organic
phase was dried with anhydrous sodium sulfate (Na.sub.2SO.sub.4)
and concentrated. The residue was purified by flash chromatography
on a silica gel column using 5:1 and 2:1 hexanes-EtOAc as eluents
to give 1.44 g (75%) of the compound 78 as a white solid; .sup.1H
NMR (CDCl.sub.3) .delta.1.37 (d, 3H), 3.54 (q, 1H), 3.94 (s, 3H),
7.12-7.77 (m, 13H, 2H, ex D.sub.2O); MS (ESI) m/z 385.0 (M+H).sup.+
(C.sub.20H.sub.21N.sub.2O.sub.4S requires 385.1).
EXAMPLE 31
[0135] Compound 79 (Scheme 12). Compound 79 was prepared by the
similar procedure as described above for compound 78 from
4-methoxybenzenesulfony- l hydrazide 77 (1.01 g, 5 mmol), naproxen
1 (1.15 g, 5 mmol) and DCC (1.03 g, 5 mmol). The compound was
purified by flash chromatography on a silica gel column using 200:1
CH.sub.2Cl.sub.2-MeOH as an eluent to give 0.69 g (33%) of the
compound 79 as a white solid; .sup.1H NMR (CDCl.sub.3) .delta.1.38
(d, 3H), 3.57 (q, 1H), 3.68 (s, 3H), 3.92 (s, 3H), 6.60-8.13 (12H,
2H ex D.sub.2O); MS (ESI) m/z 415.7 (M+H).sup.+
(C.sub.21H.sub.23N.sub.2O.sub.5S requires 415.2).
[0136] The syntheses described in Examples 32-35 are outlined in
Scheme 13. 14
EXAMPLE 32
[0137] Compound 84 (Scheme 13). To a solution of naproxen 1 (1.15
g, 5 mmol) and 2-(methylthio)ethanol 80 (0.46 g, 5 mmol) and
4-(dimethylamino)pyridine (DMAP) (0.12 g, 1 mmol) in 50 ml of
CH.sub.2Cl.sub.2 was added DCC (1.03 g, 5 mmol) at 0.degree. C. The
resulting solution was stirred at 0.degree. C. for 2 h. The solid
was filtered off and the solvent was evaporated. The residue was
partially dissolved in EtOAc and the mixture was filtered to remove
more solid. The filtrate was washed with water (50.times.2), dried
(Na.sub.2SO.sub.4) and concentrated. Recrystallization of the crude
product from hexanes provided 0.96 g of the compound 84 as a white
crystal; .sup.1H NMR (CDCl.sub.3) .delta.1.59 (d, 3H), 2.05 (s,
3H), 2.65 (m. 2H), 3.86 (q, 1H), 3.91 (s, 3H), 4.25 (m, 2H),
7.11-7.25 (m, 2H), 7.41 (d, 1H), 7.67-7.71 (m, 3H); .sup.13C NMR
(CDCl.sub.3) .delta.15.9, 16.8, 32.6, 45.6, 55.5, 63.7, 105.8,
119.2, 126.2, 126.4, 127.4, 129.1, 129.4, 133.9, 135.7, 157.9,
174.7; MS (ESI) m/z 327.4 (M+Na).sup.+ (Cl.sub.7H.sub.20O.sub.3SNa
requires 327.1).
[0138] Compound 50 (Scheme 13). To a solution of compound 84 (0.09
g, 0.3 mmol) in 3 ml of acetone was added m-chloroperoxybenzoic
acid (m-CPBA) (0.25 g, 1.5 mmol). The resulting solution was
stirred at 0.degree. C. for 3 h. A solution of Na.sub.2SO.sub.3 was
added to quench the reaction and then more water was added. The
resulted mixture was filtered and washed with methanol to give a
compound which has the identical .sup.1H NMR and MS properties to
compound 50 produced by the procedure set forth in Example 17
above.
EXAMPLE 33
[0139] Compound 85 (Scheme 13). Compound 85 was prepared by the
similar procedure as described above for compound 84 from naproxen
1 (6.9 g, 30 mmol), methylthiopropanol 81 (3.06 ml, 3.18 g, 30
mmol), DMAP (0.72 g, 6 mmol) and DCC (6.18 g, 30 mmol). The
compound was purified by recrystallization from hexanes to give 6.7
g (70%) of the compound 85 as a white crystal; .sup.1H NMR
(CDCl.sub.3) .delta.1.58 (d, 3H), 1.85 (m, 2H), 1.97 (s, 3H), 2.39
(t, 2H), 3.85 (q, 1H), 3.91 (s, 3H), 4.17 (m, 2H), 7.11-7.15 (m,
2H), 7.39-7.41 (m, 1H), 7.66-7.71 (m, 3H); MS (ESI) m/z 441.5
(M+Na).sup.+. (C.sub.18H.sub.22O.sub.3SNa requires 441.2).
[0140] Compound 88 (Scheme 13). Compound 88 was prepared by the
similar procedure as described above for compound 50 from compound
85 (1.27 g, 4 mmol) and m-CPBA (3.4 g, 20 mmol). The product was
purified by recrystallization from EtOAc-hexanes to give 1.1 g
(80%) of the compound 88 as a white powder; .sup.1H NMR
(CDCl.sub.3) .delta.1.58 (d, 3H), 2.08 (m, 2H), 2.59 (s, 3H), 2.75
(m, 2H), 3.86 (q, 1H), 3.91 (s, 3H), 4.16 (m, 1H), 4.26 (m, 1H),
7.11-7.16 (m, 2H), 7.37-7.39 (m, 1H), 7.66 (s, 1H), 7.70-7.73 (m,
2H); MS (ESI) m/z 373.3 (M+Na).sup.+ (C.sub.18H.sub.22O.sub.3SNa
requires 373.1).
EXAMPLE 34
[0141] Compound 86 (Scheme 13). Compound 86 was prepared by the
similar procedure as described above for compound 84 from naproxen
1 (6.9 g, 30 mmol), methylthiobutanol 82 (3.6 g, 30 mmol), DCC
(6.18 g, 30 mmol) and DMAP (0.72 g, 6 mmol). The product was
purified by recrystallization from hexanes to give 7.3 g (73%) of
the compound 86 as a white solid; .sup.1H NMR (CDCl.sub.3)
.delta.1.54 (m, 2H), 1.58 (d, 3H), 1.67 (m, 2H), 1.96 (s, 3H), 2.40
(t, 2H), 3.85 (q, 1H), 3.89 (s, 3H), 4.09 (t, 2H), 7.10-7.15 (m,
2H), 7.39-7.41 (q, 1H), 7.66-7.70 (t, 3H); .sup.3C NMR
(CDCl.sub.13) .delta.15.35, 18.59, 25.48, 27.74, 33.72, 45,61,
55.3, 64.37, 105.70, 119.08, 126.02, 126.32, 127.24, 129.04,
129.37, 133.80, 135.85, 157.74, 174.76; MS (ESI) m/z 355.3
(M+Na).sup.+ (C.sub.19H.sub.24O.sub.3SNa requires 355.1).
[0142] Compound 89 (Scheme 13). Compound 89 was prepared by the
similar procedure as described above for compound 50 from compound
86 (1.33 g, 4 mmol), m-CPBA (3.5 g, 20 mmol) in 35 ml of acetone.
The product was purified by recrystallization from
CH.sub.2Cl.sub.2-hexane to give 1.13 g (78%) of the compound 89 as
a pale yellow solid; .sup.1H NMR (CDCl.sub.3) .delta.1.57 (d, 3H),
1.73 (m, 4H), 2.56 (s, 3H), 2.82 (m, 2H), 3.65 (q, 1H), 3.90 (s,
3H), 4.08 (m, 1H), 4.15 (m, 1H), 7.10-7.15 (m, 2H), 7.38-7.40 (q,
1H), 7.65 (s, 1H), 7.70 (d, 2H); .sup.13C NMR (CDCl.sub.3)
.delta.18.5, 19.4, 27.5, 40.2, 45.6, 54.2, 55.5, 63.7, 105.8,
119.4, 126.1, 126.3, 127.4, 129.1, 129.4, 133.9, 135.8, 157.9,
174.7; MS (ESI) m/z 387.5 (M+Na).sup.+ (C.sub.19H.sub.24O.sub.5SNa
requires 387.5).
EXAMPLE 35
[0143] Compound 87 (Scheme 13). Compound 87 was prepared by the
similar procedure as described above for compound 84 from naproxen
1 (1.15 g, 5 mmol), 2-(phenylthio)ethanol 83 (0.77 g, 5 mmol), DCC
(1.03 g, 5 mmol) and DMAP (0.12 g, 1 mmol) in 50 ml of
CH.sub.2Cl.sub.2. The product was purified by recrystallization
from hexanes to give 1.0 g (56%) of the compound 87 as a white
powder; .sup.1H NMR (CDCl.sub.3) .delta.1.56 (d, 3H), 3.10 (m, 2H),
3.83 (q, 1H), 3.91 (s, 3H), 4.25 (m, 2H), 7.11-7.40 (m, 8H),
7.65-7.70 (m, 3H); .sup.13C NMR (CDCl.sub.3) .delta.18.7, 32.5,
45.6, 55.5, 63.4, 105.8, 119.2, 126.2, 126.4, 126.8, 127.4, 129.1,
129.2, 129.5, 130.1, 133.9, 135.3, 135.7, 157.9, 174.7; MS (ESI)
m/z 389.5 (M+Na).sup.+ (C.sub.22H.sub.22O.sub.2SNa requires
389.2).
[0144] Compound 90 (Scheme 13). Compound 90 was prepared by the
similar procedure as described above for compound 50 from compound
87 (1.46 g, 4 mmol), m-CPBA (3.5 g, 20 mmol) in 35 ml of acetone.
The product was purified by recrystallization from
CH.sub.2Cl.sub.2-hexane to give 1.2 g (75%) of the compound 90 as a
white solid; .sup.1H NMR (CDCl.sub.3) .delta.1.46 (d, 3H), 3.40 (m,
2H), 3.59 (q, 1H), 3.92 (s, 3H), 4.33 (m, 1H), 4.45 (m, 1H),
7.11-7.85 (m, 11H); .sup.13C NMR (CDCl.sub.3) .delta.18.6, 45.2,
55.2, 55.5, 58.1, 105.8, 119.3, 126.2, 127.4, 128.3, 129.1, 129.4.
129.5, 133.9, 134.1, 135.1, 139.5, 158.0, 174.2; MS (ESI) m/z 399.4
(M+H).sup.+ (C.sub.22H.sub.23O.sub.5S requires 399.5).
[0145] The synthesis described in Example 36 is outlined in Scheme
14. 15
EXAMPLE 36
[0146] Compound 92 (Scheme 14). Compound 92 was prepared by the
similar procedure as described above for compound 84 from
methylthiobenzene alcohol 91 (4.6 g, 30 mmol), naproxen 1 (6.9 g,
30 mmol), DCC (6.18 g, 30 mmol) and DMAP (0.72 g, 6 mmol). The
product was purified by recrystallization from
CH.sub.2Cl.sub.2-hexanes to give 8.6 g (78%) of the compound 92 as
a white crystal; .sup.1H NMR (CDCl.sub.3) .delta.1.58 (d, 3H), 2.45
(s, 3H), 3.89 (q, 1H), 3.92 (s, 3H), 5.05 (q, 2H), 7.11-7.16 (m,
6H), 7.37-7.39 (m, 1H),7.63-7.70 (m, 3H); .sup.13C NMR (CDCl.sub.3)
.delta.15.9, 18.7, 45.7, 55.5, 66.3, 105.8, 119.2, 126.2, 126.5,
126.7, 127.3, 128.9, 129.1, 129.5, 132.9, 133.9, 135.7, 138.8,
157.9, 174.6; MS (ESI) m/z 389.4 (M+Na).sup.+
(C.sub.22H.sub.22O.sub.3Sna requires 389.5)
[0147] Compound 93 (Scheme 14). Compound 93 was prepared by the
similar procedure as described above for compound 50 from compound
92 (1.1 g, 3 mmol), m-CPBA (1.34 g, 7.5 mmol) in 30 ml of acetone.
The product was purified by flash chromatography on a silica gel
column using CH.sub.2Cl.sub.2 as an eluent to give 1.0 g (85%) of
the compound 93 as a white solid; .sup.1HNMR (CDCl.sub.3)
.delta.1.61 (d, 3H), 2.99 (s, 3H), 3.92 (s, 3H), 3.93 (q, 1H), 5.18
(q, 2H), 7.12-7.16 (m, 2H), 7.34-7.39 (m, 3H), 7.66-7.71 (m, 3H),
7.81 (d, 2H); .sup.13C NMR (CDCl.sub.3) .delta.18.5, 44.7, 45.6,
55.5, 65.3, 105.8, 119.4, 126.2, 126.3, 127.5, 127.8, 128.3, 129.1,
129.4, 133.9, 135.3, 140.2, 142.5, 158.0, 174.4; MS (ESI) m/z 398.9
M.sup.+ (C.sub.22H.sub.22O.sub.5S requires 398.5)
[0148] The synthesis described in Example 37 is outlined in Scheme
15. 16
EXAMPLE 37
[0149] Compound 95 (Scheme 15). A mixture of 2,2'-sulfonyldiethanol
94 (12.5 ml, 60% in H.sub.2O, 9.25 g, 60 mmol) and CHCl.sub.3 was
heated to reflux to remove the water and then naproxen 1 (4.6 g, 20
mmol) and 4-toluenesulfonic acid (TsOH) (0.25 g, 1.3 mmol) were
added to the above mixture. The resulting mixture was continued to
reflux for 6 h. The reaction mixture was washed with water twice,
10% Na.sub.2CO.sub.3 solution twice and then water once. The
organic phase was dried (Na.sub.2SO.sub.4) and the solvent was
evaporated. The crude product was recrystallized from
CHCl.sub.3-hexanes to give 0.41 g of the compound 95 as a white
powder; .sup.1H NMR (CDCl.sub.3) .delta.1.60 (d, 3H), 1.85 (bs, 1H,
ex D.sub.2O), 2.51-2.56 (m, 1H), 2.62-2.67 (m, 1H), 3.25-3.28 (m,
2H), 3.48-3.51 (m, 2H), 3.88 (q, 1H), 3.92 (s, 3H), 4.41-4.46 (m,
1H), 4.56-4.61 (m, 1H), 7.11 (d, 1H), 7.15-7.18 (q, 1H), 7.35-7.36
(q, 1H), 7.65 (s, 1H), 7.69-7.74 (m, 2H); .sup.13C NMR (CDCl.sub.3)
.delta.18.3, 45.6, 54.0, 55.5, 55.6, 56.2, 56.3, 58.6, 105.8,
119.8, 126.1, 126.4, 127.7, 129.0, 133.9, 135.2, 158.2, 173.9; MS
(ESI) m/z 389.1 (M+Na).sup.+ (C.sub.18H.sub.22O.sub.6Sna requires
389.1).
[0150] The syntheses described in Examples 38-45 are outlined in
Scheme 16. 17
EXAMPLE 38
[0151] Compound 102 (Scheme 16). A solution of compound 12 (3.02 g,
10 mmol) and methansulfonyl chloride 96 (1.55 ml, 2.29 g, 20 mmol)
in 10 ml of pyridine was stirred at 0.degree. C. for 2 h. 100 ml of
water was added and the resulting mixture was filtered and the
solid was washed with water five times. The compound was purified
by rerecrystallization from CH.sub.2Cl.sub.2-hexanes to give 3.0 g
(79%) of the compound 102 as a white solid; .sup.1H NMR
(CDCl.sub.3) .delta.1.58 (d, 3H), 1.67 (m, 4H), 2.88 (s, 3H), 3.85
(q, 1H), 3.91 (s, 3H), 4.10 (m, 4H), 7.11-7.15 (m, 2H), 7.38-7.40
(q, 1H), 7.65-7.71 (s, 3H); .sup.13C NMR (CDCl.sub.3) .delta.18.6,
24.9, 25.9, 37.5, 45.6, 55.5, 63.9, 69.4, 105.8, 119.2, 126.1,
126.4, 127.4, 129.1, 129.4, 133.9, 136.8, 157.9, 174.8; MS (ESI)
m/z 403.6 (M+Na).sup.+ (C.sub.19H.sub.24O.sub.6Sna requires
403.5).
EXAMPLE 39
[0152] Compound 103 (Scheme 16). Compound 103 was prepared by the
similar procedure as described above for compound 102 from compound
13 (4.74 g, 15 mmol) and compound 96 (2.31 ml, 3.43 g, 30 mmol).
The product was purified by recrystallization from
CH.sub.2Cl.sub.2-hexanes to give 5.1 g (86%) of the compound 103 as
a white solid; .sup.1H NMR (CDCl.sub.3) .delta.1.30 (m, 2H), 1.58
(d, 3H), 1.62(m, 4H), 2.9 (s, 3H), 3.89 (q, 1H), 3.91 (s, 3H),
4.02-4.11 (m, 4H), 7.11-7.15 (m, 2H), 7.39 (d, 1H), 7.66-7.71 (m,
3H); .sup.13C NMR (CDCl.sub.3) .delta.18.5, 22.1, 28.1, 28.8, 37.4,
45.7, 55.5, 64.5, 69.8, 105.8, 119.2, 126.1, 126.4, 127.3, 129.4,
133.9, 135.9, 157.9, 174.9; MS (ESI) m/z 395.1 (M+H).sup.+
(C.sub.20H.sub.27O.sub.6S requires 395.1).
EXAMPLE 40
[0153] Compound 104 (Scheme 16). Compound 104 was prepared by the
similar procedure as described above for compound 102 from compound
14 (3.3 g, 10 mmol) and compound 96 (1.55 ml, 2.31 g, 20 mmol). The
product was purified by recrystallization from
CH.sub.2Cl.sub.2-hexanes to give 1.72 g (42%) of the compound 104
as a white solid; .sup.1H NMR (CDCl.sub.3) .delta.1.21-1.31 (m,
4H), 1.53-1.61 (m, 7H), 2.95 (s, 3H), 3.89 (q, 1H), 3.91 (s, 3H),
4.04-4.12 (m, 4H), 7.12-7.15 (m, 2H), 7.40 (q, 1H), 7.69 (t, 3H);
MS (ESI) m/z 431.4 (M+Na).sup.+ (C.sub.21H.sub.28O.sub.6Sna
requires 431.5).
EXAMPLE 41
[0154] Compound 105 (Scheme 16). Compound 105 was prepared by the
similar procedure as described above for compound 103 from compound
12 (1.5 1 g, 5 mmol) and compound 100 (0.94 ml, 1.28 g, 10 mmol).
The product was purified by flash chromatography on a silica gel
column using CH.sub.2Cl.sub.2 as an eluent to give 1.45 g (74%) of
the compound 105 as a pale yellow oil; .sup.1H NMR (CDCl.sub.3)
.delta.1.35 (t, 3H), 1.57(d, 3H), 1.68 (m, 4H), 3.01(q, 2H), 3.84
(q, 1H), 3,90 (s, 3H), 4.11 (m, 4H); MS (ESI) m/z 417.4
(M+Na).sup.+ (C.sub.20H.sub.26O.sub.6Sna requires 417.5).
EXAMPLE 42
[0155] Compound 106 (Scheme 16). Compound 106 was prepared by the
similar procedure as described above for compound 102 from compound
12 (1.51 g, 5 mmol) and compound 97 (1.27 ml, 1.76 g, 10 mmol). The
product was washed with water and dried to give 1.9 g (86%) of the
compound 106 as a pale yellow oil; .sup.1H NMR (CDCl.sub.3)
.delta.1.53 (d, 3H), 1.55-1.63 (m, 4H), 3.81 (q, 1H), 3.91 (s, 3H),
3.94-4.03 (m, 4H), 7.11-7.15 (m, 2H), 7.36 (d, 1H), 7.51(m, 2H),
7.63 (m, 2H), 7.69 (d, 2H), 7.85 (d, 2H); MS (ESI) m/z 443.6
(M+H).sup.+ (C.sub.24H.sub.27O.sub.6S requires 443.5).
EXAMPLE 43
[0156] Compound 107 (Scheme 16). Compound 107 was prepared by the
similar procedure as described above for compound 102 from compound
12 (1.51 g, 5 mmol) and compound 98 (1.55 ml, 2.45 g, 10 mmol). The
product was purified by flash chromatography on a silica gel column
using CH.sub.2Cl.sub.2 as an eluent to give 1.12 g (44%) of the
compound 107 as a white solid; .sup.1H NMR (CDCl.sub.3) .delta.1.56
(d, 3H), 1.60-1.63 (m, 4H), 3.82 (q, 1H), 3.90 (s, 3H), 4.00-4.06
(m, 4H), 7.11-7.15 (m, 2H), 7.36-7.38 (q, 1H), 7.64-7.71 (m, 4H),
7.89 (d, 1H), 8.04 (d, 1H), 8.15 (s, 1H); .sup.13C NMR (CDCl.sub.3)
.delta.18.5, 24.8, 25.7, 45.6, 55.5, 63.7, 70.8, 105.8, 119.2,
125.06, 125.09, 126.3, 127.4, 129.1, 129.4, 130.3, 130.6, 131.2,
132.1, 133.9, 135.8, 137.6, 157.9, 174.8; MS (ESI) m/z 533.3
(M+Na).sup.+ (C.sub.25H.sub.25F.sub.3O.sub.6Sna requires
533.5).
EXAMPLE 44
[0157] Compound 108 (Scheme 16). Compound 108 was prepared by the
similar procedure as described above for compound 102 from compound
12 (1.51 g, 5 mmol) and compound 99 (2.06 g, 10 mmol). The product
was purified by recrystallization from CH.sub.2Cl-.sub.2-hexanes to
give 1.44 g (61%) of compound 108 as a white crystal; 1H NMR and MS
spectra are consistence with the compound 108.
EXAMPLE 45
[0158] Compound 109 (Scheme 16). Compound 109 was prepared by the
similar procedure as described above for compound 102 from compound
13 (1.58 g, 5 mmol) and compound 101 (2.21 g, 10 mmol). The product
was purified by flash chromatography on a silica gel column using
CH.sub.2Cl.sub.2 as an eluent to give 1.5 g (67%) of the compound
109 as a pale yellow oil; .sup.1H NMR (CDCl.sub.3) .delta.1.21-1.26
(m, 2H), 1.50-1.59 (m, 7H), 3.83 (q, 1H), 3.91 (s, 3H), 3.89-4.08
(m, 4H), 7.11-7.26 (m, 2H), 7.37-7.40 (m, 1H), 7.63-7.70 (m, 3H),
8.02 (d, 2H), 8.35 (d, 2H); MS (ESI) m/z 524.6 (M+Na).sup.+
(C.sub.25H.sub.27NO.sub.8Sna requires 524.6).
[0159] The syntheses described in Examples 46 and 47 are outlined
in Scheme 17. 18
EXAMPLE 46
[0160] Compound 111 (Scheme 17). A mixture of compound 20 (4.56 g,
10 mmol), methanesulfonamide 110 (1.9 g, 20 mmol, 2 equiv) and
K.sub.2CO.sub.3 (6.9 g, 50 mmol, 5 equiv) in 100 ml of acetonitril
(CH.sub.3CN) was heated to reflux for 26 h. The solvent was
evaporated and the residue was dissolved and shaken well in water
and EtOAc. The two phases were separated and the organic phase was
washed with water three times, dried (Na.sub.2SO.sub.4) and
concentrated. The crude product was purified by recrystallization
from CH.sub.2Cl.sub.2-hexanes to give 2.53 g (67%) of the compound
111 as an yellow solid; .sup.1H NMR (CDCl.sub.3) .delta.1.38-1.42
(m, 2H), 1.53-1.63 (m, 2H), 1.58 (d, 3H), 2.77 (s, 3H), 2.92-2.96
(m, 2H), 3.85 (q, 1H), 3.91 (s, 3H), 3.99 (bs, 1H, ex D.sub.2O),
4.03-4.07 (m, 1H), 4.11-416 (m, 1H), 7.12-7.16 (m, 2H), 7.38-7.40
(d, 1H), 7.66 (s, 1H), 7.71 (d, 2H); MS (ESI) m/z 402.5
(M+Na).sup.+ (C.sub.19H.sub.25NO.sub.5SNa requires 402.5).
EXAMPLE 47
[0161] Compound 112 (Scheme 17). Compound 112 was prepared by the
similar procedure as described above for compound 111 from compound
22 (2.42 g, 5 mmol) and compound 110 (0.57 g, 6 mmol, 1.2 equiv).
The product was purified by recrystallization from
CH.sub.2Cl.sub.2-hexanes to give 0.9 g (45%) of the compound 112 as
a powder; .sup.1H NMR (CDCl.sub.3) .delta.1.17-1.22 (m, 4H),
1.33-1.37 (m, 2H), 1.56 (d, 3H), 1.52-1.60 (m, 2H), 2.89 (s, 3H),
2.95 (q, 2H), 3.85 (q, 1H), 3.91 (s, 3H), 4.01-4.15 (m, 3H, 1H ex
D.sub.2O), 7.12-7.15 (m, 2H), 7.40 (d, 1H), 7.66-7.76 (m, 3H);
.sup.13C NMR (CDCl.sub.3) .delta.18.5, 25.5, 26.1, 28.5, 30.1,
40.5, 43.2, 45.7, 55.5, 64.6, 105.8, 119.2, 126.1, 126.5, 127.3,
129.1, 129.4, 133.9, 136.1, 157.8, 174.9; MS (ESI) m/z 430.6
(M+Na).sup.+ (C.sub.21H.sub.29NO.sub.5Sna requires 430.6).
[0162] The syntheses described in Examples 48 and 49 are outlined
in Scheme 18. 19
EXAMPLE 48
[0163] Compound 116 (Scheme 18). To a solution of aminopentanol 113
(3.1 g, 30 mmol) and triethylamine (TEA) (4.2 ml, 3.03 g, 30 mmol)
in 50 ml of anhydrous THF was added dropwise p-toluenesulfonyl
chloride 115 (5.7 g, 30 mmol) in 50 ml of THF at 0.degree. C. The
resulting solution was continued to stirr at 0.degree. C. and then
rt for 2 h. To the reaction solution was added 500 ml of water and
the resulted mixture was extracted with EtOAc. The combined organic
phase was washed with water twice, 0.5 N HCl solution once, 5%
NaHCO.sub.3 solution once and water once. The organic phase was
dried (Na.sub.2SO.sub.4) and evaporated under high vacuum to give
4.87 g (63%) of the compound 116 as a white oil. The compound was
used to prepare compound 118 without further purification; .sup.1H
NMR (CDCl.sub.3) .delta.1.33-1.37 (m, 2H), 1.45-1.51 (m, 4H), 2.41
(s, 3H), 2.91 (t, 2H), 3.57 (t, 2H), 7.30 (d, 2H), 7.72 (d, 2H); MS
(ESI) m/z 280.5 (M+Na).sup.+ (C.sub.12H.sub.19NO.sub.3SNa requires
280.4).
[0164] Compound 118 (Scheme 18). To a solution of compound 116
(1.29 g, 5 mmol), naproxen 1 (1.15 g, 5 mmol) and DMAP (0.12 g, 1
mmol) in CH.sub.2Cl.sub.2 was added DCC (1.03 g, 5 mmol) at
0.degree. C. The resulting solution was stirred at 0.degree. C. for
2 h and then at rt for another 2 h. The solid was filtered off and
the solvent was evaporated. The residue was dissolved in EtOAc and
filtered to remove more solid. The filtrate was washed with water
three times, dried (Na.sub.2SO.sub.4) and concentrated. The product
was purified by flash chromatography on a silica gel column using
ethyl ether as an eluent to give 2.06 g (88%) of the compound 118
as a solid; .sup.1H NMR (CDCl.sub.3) .delta.1.13-1.18 (m, 2H),
1.25-1.34 (m, 2H), 1.45-1.51 (m, 2H), 1.55 (d, 3H), 2.40 (s, 3H),
2.77 (q, 2H), 3.81 (q, 1H), 3.90 (s, 3H), 3.96-4.02 (m, 2H), 4.47
(t, 1H, ex D.sub.2O), 7.12-7.14 (m, 2H), 7.26 (d, 2H), 7.38 (d,
1H), 7.65-7.70 (m, 5H); MS (ESI) m/z 492.5 (M+Na).sup.+
(C.sub.26H.sub.31NO.sub.5SNa requires 492.6).
EXAMPLE 49
[0165] Compound 117 (Scheme 18). Compound 117 was prepared by the
similar procedure as described above for compound 116 from
6-amino-1-hexanol 114 (3.5 g, 30 mmol) and compound 115 (5.7 g, 30
mmol). The product was purified by flash chromatography on a silica
gel column using ethyl ether as an eluent to give 6.5 g (80%) of
the compound 117 as a white solid; .sup.1H NMR (CDCl.sub.3)
.delta.1.26-1.29 (m, 4H), 1.43-1.49 (m, 4H), 2.40 (s, 3H), 2.89 (t,
2H), 3.57 (t, 2H), 7.27 (d, 2H), 7.73 (d, 2H); MS (ESI) m/z 272.4
(M+H).sup.+ (C.sub.13H.sub.22NO.sub.3S requires 272.4).
[0166] Compound 119 (Scheme 18). Compound 119 was prepared by the
similar procedure as descibed above for compound 118 from compound
117 (1.36 g, 5 mmol), naproxen 1 (1.15 g, 5 mmol), DCC (1.03 g, 5
mmol) and DMAP (0.12 g, 1 mmol). The product was purified by flash
chromatography on a silica gel column using ethyl ether as an
eluent to give 2.04 g (84%) of the compound 119 as a white solid;
.sup.1H NMR (CDCl.sub.3) .delta.1.11 (m, 4H), 1.23-1.29 (m, 2H),
1.46-1.56 (m, 2H), 1.56 (d, 3H), 2.40 (s, 3H), 2.79 (q, 2H), 3.82
(q, 1H), 3.91 (s, 3H), 3.96-4.05 (m, 2H), 4.43 (t, 1H, ex D.sub.2O
), 7.11-7.14 (m, 2H), 7.26-7.29 (m, 2H), 7.37-7.39 (q, 1H),
7.64-7.72 (m, 5H); .sup.13C NMR (CDCl.sub.3) .delta.18.5, 21.7,
25.4, 26.1, 28.4, 29.5, 43.1, 45.7, 55.5, 64.6, 105.8, 119.1,
126.1, 126.4, 127.3, 129.1, 129.4, 129.8, 133.8, 136.1, 137.2,
143.5, 157.8, 174.1; MS (ESI) m/z 484.7 (M+H).sup.+
(C.sub.27H.sub.34NO.sub.5S requires 484.6).
[0167] The syntheses described in Examples 50 and 51 are outlined
in Scheme 19. 20
EXAMPLE 50
[0168] Compound 123 (Scheme 19). A mixture of naproxen sodium 120
(2.52 g, 10 mmol) and propanesulton 121 (1.22 g, 10 mmol) in 50 ml
of N,N-dimethylformamide (DMF) was stirred at 50-60.degree. C. for
30 min. To the reaction solution was added 150 ml of acetone and
then stood still for 1 h. Filtration and washing by acetone
provided 3.2 g (86%) of the compound 123 as a white powder;
.sup.1HNMR (D.sub.2O ) .delta.1.37 (d, 3H), 1.93-1.97 (m, 2H),
2.74-2.77 (m, 2H), 3.72 (q, 1H), 3.72 (s, 3H), 4.01-4.05 (m, 1H),
4.08-4.11 (m, 1H), 6.97-7.00 (m, 2H), 7.20-7.22 (q, 1H), 7.44 (s,
1H), 7.50 (t, 2H); .sup.13C NMR (D.sup.2O) .delta.16.7, 23.1,
44.4., 46.9, 54.6, 63.2, 105.4, 117.9, 125.1, 125.5, 126.7, 128.1,
128.7, 132.7, 134.9, 156.3, 176.4; MS (ESI) m/z 397.1 (M+Na).sup.+
(C.sub.17H.sub.19Na.sub.2O.sub.5S requires 397.4).
EXAMPLE 51
[0169] Compound 124 (Scheme 19). Compound 124 was prepared by the
similar procedure as described above for compound 123 from
butanesulton 122 (1.02 ml, 1.36 g, 10 mmol) and naproxen sodium 120
(2.52 g, 10 mmol). After reaction, acetone was added and the solid
was filtered and washed with acetone to give 1.3 g (34%) of the
compound 124 as a white powder; .sup.1HNMR (D.sub.2O ) .delta.1.22
(d, 3H), 1.34-1.38 (m, 2H), 1.50-1.56 (m, 2H), 2.65 (t, 2H), 3.44
(s, 3H), 3.47 (m, 1H), 3.74-3.77 (m, 1H), 3.83-3.86 (m, 1H), 6.74
(s, 1H), 6.78-6.81 (d, 1H), 7.05 (d, 1H), 7.22-7.29 (m, 3H); MS
(ESI) m/z 411.2 (M+Na).sup.+ (C.sub.18H.sub.21Na.sub.2O.sub.6S
requires 411.2).
[0170] The synthesis described in Example 52 is outlined in Scheme
20. 21
EXAMPLE 52
[0171] Compound 125 (Scheme 20). To a mixture of diclofenac 29
(2.96 g, 10 mmol), methylsulfonylethanol 48 (1.24 g, 10 mmol) and
DMAP (0.24 g, 2 mmol) in 50 ml of CH.sub.2Cl.sub.2 was added DCC
(2.06 g, 10 mmol) at 0.degree. C. The resulting mixture was stirred
at 0.degree. C. for 2 h. The mixture was filtered and the filtrate
was evaporated. The residue was washed with methanol to give 1.83 g
(92%) of the compound 125 as a white powder; .sup.1H NMR
(CDCl.sub.3) 2.75 (s, 3H), 3.30 (t, 2H), 3.84 (s, 2H), 4.58 (t,
2H), 6.51 (d, 1H), 6.93 (t, 1H), 7.00 (t, 1H), 7.12 (t, 1H), 7.19
(d, 1H), 7.34 (d, 2H); .sup.13C NMR (CDCl.sub.3) .delta.38.5, 42.1,
54.0, 58.8, 118.3, 122.2, 123.4, 124.7, 128.6, 129.1, 129.9, 131.1,
137.6, 142.8, 171.5; MS (ESI) m/z 402.4 M.sup.+
(C.sub.17H.sub.17Cl.sub.2- NO.sub.4S requires 402.4).
[0172] The synthesis described in Example 53 is outlined in Scheme
21. 22
EXAMPLE 53
[0173] Compound 127 (Scheme 21). To a mixture of 4-amino-1-butanol
126 (9 g, 100 mmol) and K.sub.2CO.sub.3 (34.5 g, 250 mmol, 2.5
equiv) in 200 ml of acetonitril was added dropwise methanesulfonyl
chloride 96 (6.95 ml, 10.3 g, 90 mmol, 3 equiv) in 100 ml of
CH.sub.3CN at 0.degree. C. The resulting solution was stirred at
0.degree. C. for 1 h. The reaction mixture was flittered and the
solvent was evaporated. The residue was purified by flash
chromatography on a silica gel column using 50:1
CH.sub.2Cl.sub.2-MeOH as an eluent to give 3.45 g (21%) of the
compound 127 as a white powder; .sup.1HNMR (CDCl.sub.3)
.delta.1.42-1.49 (m, 4H), 2.89 (s, 3H), 2.91 (q, 2H), 3.39 (q, 2H),
4.39 (t, 2H), 6.91 (t, 1H ex D.sub.2O); .sup.13C NMR (CDCl.sub.3)
.delta.26.1, 29.6, 42.4, 60.2, one peak is covered by DMSO-d.sub.6
peaks; MS (ESI) m/z 190.1 (M+Na).sup.+ (C.sub.5H.sub.13NO.sub.3SNa
requires 190.2).
[0174] Compound 128 (Scheme 21). Compound 128 was prepared by the
similar procedure as described above for the compound 125 from
diclofenac 29 (1.48 g, 5 mmol), compound 127 (0.83 g, 5 mmol), DCC
(1.03 g, 5 mmol) and DMAP (0.12 g, 1 mmol). The product was
purified by recrystallization from CH.sub.2Cl.sub.2-hexanes to give
1.5 g (67%) of the compound 128 as a white powder; .sup.1HNMR
(CDCl.sub.3) .delta.1.57-1.62 (m, 2H), 1.70-1.74 (m, 2H), 2.91 (s,
3H), 3.11 (q, 2H), 3.80 (s, 2H), 4.17 (t, 2H), 4.44 (t, 1H, ex
D.sup.2O), 6.54 (d, 1H), 6.87 (bs, 1H, ex D.sub.2O ), 6.94-7.00 (m,
2H), 7.12 (t, 1H), 7.23 (t, 1H), 7.34 (d, 2H); .sup.13C NMR
(CDCl.sub.3) .delta.25.8, 26.8, 38.8, 40.5, 42.9, 64.7, 118.4,
122.2, 124.3, 124.4, 128.2, 129.1, 129.7, 131.1, 137.9, 142.9,
172.5; MS (ESI) m/z 445.3 M.sup.+
(C.sub.19H.sub.22Cl.sub.2N.sub.2O.sub.4S requires 445.3).
[0175] The synthesis described in Example 54 is outlined in Scheme
22. 23
EXAMPLE 54
[0176] Compound 130 (Scheme 22). Compound 130 was prepared by the
similar procedure as described above for the compound 125 from
diclofenac 29 (1.48 g, 5 mmol), compound 129 (1.22 g, 5 mmol), DCC
(1.03 g, 5 mmol) and DMAP (0.12 g, 1 mmol). The product was
purified by recrystallization from CH.sub.2Cl.sub.2-hexanes to give
1.3 g (50%) of the compound 130 as a white powder; .sup.1H NMR
(CDCl.sub.3) .delta.1.47-1.51 (m, 2H), 1.62-1.66 (m, 2H), 2.41 (s,
3H), 2.90-2.94 (q, 2H), 3.77 (s, 2H), 4.09(t, 2H), 4.34 (t, 1H, ex
D.sub.2O), 6.53 (d, 1H), 6.86 (bs, 1H, ex D.sub.2O ), 6.93-7.00 (m,
2H), 7.11(m, 1H), 7.20 (d, 1H), 7.28-7.35 (m, 4H), 7.72 (d, 2H); MS
(ESI) m/z 544.2 (M+Na).sup.+ (C.sub.25H.sub.26Cl.sub.2N.sub.2-
O.sub.4SNa requires 544.4).
[0177] The synthesis described in Example 55 is outlined in Scheme
23. 24
EXAMPLE 55
[0178] Compound 132 (Scheme 23). To a solution of
4-(hydroxyphenyl)-1-prop- anol 131 (3.04 g, 20 mmol) in 20 ml of
pyridine was added compound 115 (15.2 g, 80 mmol, 4 equiv) at
0.degree. C. The resulting solution was stirred at 0.degree. C. for
2 h and then at rt for another 2 h. To the reaction solution was
added 200 ml of water. The resulting mixture was extracted with
EtOAc twice. The combined organic phase was washed with water five
times, 0.5N HCl solution once, 5% Na.sub.2CO.sub.3 solution once
and water again. The organic phase was dried (Na.sub.2SO.sub.4) and
the solvent was evaporated to give 7.9 g (86%) of the compound 132
as a pale yellow oil; .sup.1H NMR (CDCl.sub.3) .delta.1.90 (m, 2H),
2.4 (s, 6H), 2.6 (t, 2H), 3.98 (t, 2H), 6.82-6.84 (q, 2H), 6.97 (d,
2H), 7.29-7.34 (q, 4H), 7.68 (d, 2H), 7,76 (d, 2H); MS (ESI) m/z
483.3 (M+Na).sup.+ (C.sub.23H.sub.24O.sub.4S.sub.2Na requires
483.5).
[0179] Compound 134 (Scheme 23). A mixture of diclofenac sodium 133
(1.59 g, 5 mmol), compound 132 (2.3 g, 5 mmol) and K.sub.2CO.sub.3
(1.38 g, 10 mmol) was stirred at rt for 22 h. After reaction, water
and EtOAc were added and the two layers were separated. The organic
phase was washed with water four times, dried (Na.sub.2SO.sub.4)
and concentrated. The residue was purified by flash chromatography
on a silica gel column using 5:1 CH.sub.2Cl.sub.2-hexanes as an
eluent to give 1.7 g (59%) of the compound 134 as a pale yellow
oil; .sup.1H NMR (CDCl.sub.3) .delta.1.90-1.96 (m, 2H), 2.43 (s,
3H), 2.60 (t, 2H), 3.79 (s, 3H), 4.12 (t, 2H), 6.55 (d, 1H), 6.87
(t, 3H), 6.94-7.01 (m, 4H), 7.09-7.13 (m, 1H), 7.22-7.35 (m, 5H),
7.69 (d, 2H); .sup.13C NMR (CDCl.sub.3) .delta.22.1, 30.4, 31.8,
32.5, 64.8, 118.7, 122.5, 122.7, 124.5, 124.8, 128.5, 128.9, 129.3,
129.9, 129.95, 130.1, 131.2, 132.9, 138.2, 140.5, 143.1, 145.7,
148.4, 172.7; MS (ESI) m/z 584.3 M.sup.+
(C.sub.30H.sub.27Cl.sub.2NO.sub.5S requires 584.5.sup.1).
EXAMPLE 56
Reduced Numbers of Intestinal Ulcers in Rat Acute and Subacute
Enteropathy Models by the Invention Modified NSAID (Compound 19), a
Prodrug of Naproxen
[0180] NSAIDs are important drugs used to treat acute and chronic
inflammation as well as pain and fever. The major limitation to
NSAID use is the occurrence of gastrointestinal ulcers and
erosions. These side effects are produced by a combination of local
and systemic effects. Attempts have been made to circumvent the
local side effects of NSAIDs by making them as prodrugs, which will
bypass the stomach, but so far this has not been clearly
successful. It is demonstrated here that the invention modified
NSAIDs substantially reduce GI toxicity, while exhibiting dose
equivalent efficacy in anti-inflammation activity in both acute and
chronic inflammation animal models.
[0181] Sprague-Dawley rats (male, 150-200 g), were orally dosed
once daily for either 3 days (acute model) or 14 days (subacute
model). Twenty-four hours after the last dose, the rats were
injected i.v. with Evans Blue (5 ml/kg, 10 mg/ml) to stain the
ulcers. Ten to twenty minutes later the animals were sacrificed by
CO2 inhalation and the intestines removed, opened lengthwise and
the contents removed. The long dimensions of all ulcers were
measured using a ruler and summed to give a total ulcer score.
[0182] In the acute model (FIG. 1), ulceration after dosing with an
invention modified NSAID (compound 19) was 15% of that seen with an
equimolar dose of naproxen. PEG had no ulcerogenic effect. In the
subacute model (FIG. 2), ulceration was less than 5% of that seen
with a corresponding dose of naproxen at all three doses used.
Again, PEG had no effect. These results suggest that invention
modified NSAIDs are much less ulcerogenic than naproxen.
EXAMPLE 57
Reduction of Chronic Hindlimb Inflammation in the Rat Adjuvant
Arthritis Model by the Invention Modified NSAID (Compound 19), a
Prodrug of Naproxen
[0183] NSAIDs are useful in the treatment of both chronic and acute
inflammatory conditions. Efficacy in chronic inflammation can be
estimated using the rat adjuvant arthritis model. In this model
Lewis male rats (175-250 g) are injected intradermally in the
footpad with M. tuberculosis powder suspended in mineral oil at 5
mg/ml. Progressive swelling of the uninjected paw and ankle joint
between days 5 and 15 is measured by plethysmometry.
[0184] Rats were dosed daily by oral gavage with 5 ml/kg of
naproxen at 3 to 30 mg/kg in phosplate buffered saline (PBS) and
with equimolar doses of an invention modified NSAID at 1 ml/kg in
PEG 300. The results (FIG. 3) show that the invention modified
NSAID resulted in antiinflammatory effects comparable to those of
naproxen in this model.
EXAMPLE 58
Reduction of Acute Hindlimb Inflammation in the Rat
Carrageenan-induced Hindlimb Edema Model by the Invention Modified
NSAID (Compound 19) a Prodrug of Naproxen
[0185] Efficacy of NSAIDs in acute inflammation can be estimated by
using intraplantar injection of carrageenan in the rat.
Sprague-Dawley rats (200-250 g male) are injected intradermally in
the footpad with 50 (1 of a 1% carrageenan solution in PBS.
Swelling of the injected paw is measured 3 & 4 hours later,
using a plethysmometer.
[0186] Pretreatment with oral naproxen one hour before the
carrageenan injection at 10 mg/kg resulted in an approximately 50%
reduction in swelling at both time points (Table 1). An equimolar
dose of an invention modified NSAID reduced inflammation to the
same degree at both time points. These results suggest that
invention modified NSAIDs are comparable in effect to naproxen at
10 mg/kg.
1TABLE 1 Effects of naproxen and the invention modified NSATD
(compound 19) on paw volume increase in carrageenan- induced
inflammation in rats. Treatment 4 Hours 5 Hours Vehicle 0.73 .+-.
0.10 0.85 .+-. 0.10 Naproxen (1 mg/kg) 0.63 .+-. 0.07 0.75 .+-.
0.08 Naproxen (10 mg/kg) 0.32 .+-. 0.05* 0.39 .+-. 0.07* Compound
19 (1.75 mg/kg) 0.78 .+-. 0.04 0.93 .+-. 0.04 Compound 19 (17.5
mg/kg) 0.34 .+-. 0.06* 0.40 .+-. 0.06* P < 0.05 vs Vehicle by
unpaired t-test.
[0187] Invention modified NSAIDs are seen to have antiinflammatory
activity similar to naproxen in the chronic adjuvant arthritis and
acute carrageenan hindlimb edema rat models. The tendency to cause
intestinal ulcers is reduced substantially inventon modified NSAID.
Thus, invention modified NSAIDs provide an effective prodrug form
of naproxen with reduced intestinal side effects.
EXAMPLE 59
Plasma Pharmacokinetics of Naproxen and the Invention Modified
NSAID after Oral Administration in Rats
[0188] The invention compound (compound 19) is a naproxen prodrug,
which is a conjugate of naproxen and tosylate. Oral administration
of the invention compound resulted in the release of free naproxen.
The pharmacokinetics of naproxen release from the invention
modified NSAID and its parent drug, naproxen, was evaluated in rats
after oral administration.
[0189] The carotid artery of Sprague-Dawley rat (250-350 g, male)
was catheterized at least one day before drug administration and
flushed with 30% polyvinyl pyrrolidone (PVP) (400 U/mL of heparin)
to maintain patency. At predetermined time points (see Table 2),
blood samples (250 (L) were collected by unhooking the flushing
syringe and letting the blood flow out of the catheter and into the
centrifuge tubes. After centrifugation (13,000 rpm, 10 min,
4.degree. C.), the plasma samples were collected and analyzed in
the same day.
2TABLE 2 Rat group assignment and doses Test Group Dose* Article #
Rat # (mg/kg) Sample Time Naproxen 1 1, 2, 3, Oral 5 min, 0.5, 1,
4, 7, 10, & 4 (2 mg/kg) 13, 16, 19, 22, & 24 hrs Invention
2 5, 6, 7, Oral 15 min, 0.5, 1, 3, 5, 6, 7, Compound & 8 (2
mg/kg) 8, 22, 23, & 24 hrs 19 *Indicates amount of naproxen in
dose.
[0190] Aliquot of plasma sample (100 .mu.L) was mixed with 200
.mu.L of acetonitrile. After vortexing and centrifugation (13,000
rpm, 10 min, 4.degree. C.), 200 (L of supernatant was removed and
added to 300 (L of a 58:42 mixture of 50 mM phosphate buffer (pH
5.0) and acetonitrile. Following vortexing and centrifugation, 25 L
of supernatant was removed and analyzed by HPLC with a UV detection
system.
[0191] The average plasma concentration at each time point was
calculated and utilized in a pharmacokinetic analysis.
Noncompartmental pharmacokinetic analysis was carried out using
WinNolin (Pharsight, Mountainview, Calif.) to calculate the maximum
concentration (C.sub.max), time to maximum concentration
(T.sub.max), area under the curve from zero to the last time point
(AUC.sub.last), the area under the curve from zero to infinite time
(AUC.sub.inf), and the terminal phase half life
(Beta-ti.sub.1/2).
[0192] The AUC.sub.all, AUC.sub.INF, and t.sub.1/2 of naproxen from
naproxen and a modified form of naproxen according to the invention
were found to be similar (Table 3). On the other hand, for the
invention modified form of neproxen, the C.sub.max was lower and
the T.sub.max longer, compared to naproxen (see Table 3).
3TABLE 3 Non-Compartmental Pharmacokinetic Analysis of naproxen and
the invention modified form of naproxen according to the (compound
19) after oral administration in rats Dose* C.sub.max T.sub.max
AUC.sub.all AUC.sub.INF t1/2 Drug (mg/kg) (.mu.g/mL) (hrs)
(.mu.g*hr/mL) (.mu.g*hr/mL) (hrs) N Naproxen 2 7.77 .+-. 4.13 0.5
.+-. 0.5 50 .+-. 6 55 .+-. 7 6.2 .+-. 0.4 4 Invention 2 3.87 .+-.
1.05 6.8 .+-. 1.5 49 .+-. 10 56 .+-. 14 6.8 .+-. 2.7 4 modified
naproxen *Indicates amount of naproxen in dose.
[0193] Following oral naproxen administration, the naproxen plasma
levels were at the highest at the first time-point (5 minutes) then
declined in a bi-exponential manner. In contrast, after oral
administration of a modified form of naproxen according to the
invention, the maximum naproxen levels were observed at a much
later time (T.sub.max of 6.8.+-.1.5 hrs). The similar AUC.sub.all,
AUC.sub.INF, and T.sub.1/2 values but lower C.sub.max and longer
T.sub.max values supports the conclusions drawn from the results
obtained from pharmacological studies, i.e. that a modified form of
naproxen according to the invention conjugate has equivalent
pharmacological efficacy and greatly improved gastrointestinal
safety profile compared to naproxen.
[0194] While the invention has been described in detail with
reference to certain preferred embodiments thereof, it will be
understood that modifications and variations are within the spirit
and scope of that which is described and claimed.
* * * * *