U.S. patent application number 09/942510 was filed with the patent office on 2002-08-15 for 5-asa derivatives having anti-inflammatory and antibiotic activity and methods of treating diseases therewith.
Invention is credited to Ekwuribe, Nnochiri Nkem, Malson, Elizabeth, Riggs-Sauthier, Jennifer A..
Application Number | 20020111334 09/942510 |
Document ID | / |
Family ID | 22858177 |
Filed Date | 2002-08-15 |
United States Patent
Application |
20020111334 |
Kind Code |
A1 |
Ekwuribe, Nnochiri Nkem ; et
al. |
August 15, 2002 |
5-ASA derivatives having anti-inflammatory and antibiotic activity
and methods of treating diseases therewith
Abstract
Compounds are disclosed represented by the following formula: 1
where R.sup.1 is a substituted or unsubstituted phenyl group, and
where Z is selected such that a compound, Z--R.sup.1--NH.sub.2,
formed by cleavage of the azo bond is a non-absorbable antibiotic;
or an ester or pharmacologically acceptable salt of the compound of
Formula I. Compounds of the present invention may be utilized for
the prophylaxis or treatment of various diseases including, but not
limited to, intestinal diseases such as inflammatory bowel disease
and/or traveler's diarrhea, liver diseases such as hepatic
encephalopathy, and/or diseases treatable by a non-absorbable
antibiotic.
Inventors: |
Ekwuribe, Nnochiri Nkem;
(Cary, NC) ; Riggs-Sauthier, Jennifer A.;
(Raleigh, NC) ; Malson, Elizabeth; (Burbank,
CA) |
Correspondence
Address: |
MYERS BIGEL SIBLEY & SAJOVEC
PO BOX 37428
RALEIGH
NC
27627
US
|
Family ID: |
22858177 |
Appl. No.: |
09/942510 |
Filed: |
August 29, 2001 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60228682 |
Aug 29, 2000 |
|
|
|
Current U.S.
Class: |
514/150 ;
534/844; 534/850 |
Current CPC
Class: |
A61P 43/00 20180101;
A61P 1/04 20180101; A61P 31/04 20180101; C07C 311/51 20130101; A61P
1/00 20180101; A61P 1/12 20180101; A61P 29/00 20180101; A61P 25/00
20180101; A61P 1/16 20180101 |
Class at
Publication: |
514/150 ;
534/844; 534/850 |
International
Class: |
A61K 031/655; C07C
311/50; C07C 245/08 |
Claims
That which is claimed is:
1. A compound of the formula: 24where X is --SO.sub.2-- or --CO--
and Y is: 25where n is an integer from 1 to 3; 26or the esters or
pharmacologically acceptable salts thereof.
2. The compound according to claim 1, wherein X is --SO.sub.2-- and
Y is: 27where n is an integer from 1 to 3.
3. The compound according to claim 1,
5-[4-(2carboxy-acetylsulfamoyl)-phen- ylazo]-2-hydroxy-benzoic
acid.
4. The compound according to claim 1,
5-[4-(4-carboxy-butyrylsulfoamoyl)-p- henylazo]-2-hydroxy-benzoic
acid.
5. The compound according to claim 1,
5-[4-(3-carboxy-propionylsulfamoyl)-- phenylazo]-2-hydroxy-benzoic
acid.
6. A pharmaceutical composition for the treatment of an intestinal
disease in subjects in need of such treatment, comprising an amount
effective to treat the intestinal bowel disease of a compound of
the formula: 28where X is --SO.sub.2-- or --CO-- and Y is: 29where
n is an integer from 1 to 3; 30or an ester or pharmacologically
acceptable salt thereof, in admixture with a solid or liquid
pharmaceutical diluent or carrier.
7. The pharmaceutical composition according to claim 6, wherein X
is --SO.sub.2-- and Y is: 31where n is an integer from 1 to 3.
8. The pharmaceutical composition according to claim 6, wherein the
compound is
5-[4-(2-carboxy-acetylsulfamoyl)-phenylazo]-2-hydroxy-benzoic
acid.
9. The pharmaceutical composition according to claim 6, wherein the
compound is
5-[4-(4-carboxy-butyrylsulfoamoyl)-phenylazo]-2-hydroxy-benzo- ic
acid.
10. The pharmaceutical composition according to claim 6, wherein
the compound is
5-[4-(3-carboxy-propionylsulfamoyl)-phenylazo]-2-hydroxy-benz- oic
acid.
11. A method of treating an intestinal disease in a subject in need
of such treatment, said method comprising administering to the
subject an amount effective to treat the intestinal disease of a
compound having the following formula: 32where X is --SO.sub.2-- or
--CO-- and Y is: 33where n is an integer from 1 to 3; 34or an ester
or pharmacologically acceptable salt thereof.
12. The method according to claim 11, wherein X is --SO.sub.2-- and
Y is: 35where n is an integer from 1 to 3.
13. The method according to claim 11, wherein the compound is
5-[4-(2-carboxy-acetylsulfamoyl)-phenylazo]-2-hydroxy-benzoic
acid.
14. The method according to claim 11, wherein the compound is
5-[4-(4-carboxy-butyrylsulfoamoyl)-phenylazo]-2-hydroxy-benzoic
acid.
15. The method according to claim 11, wherein the compound is
5-[4-(3-carboxy-propionylsulfamoyl)-phenylazo]-2-hydroxy-benzoic
acid.
16. The method according to claim 11, wherein the intestinal
disease is Crohn's disease.
17. The method according to claim 11, wherein the intestinal
disease is ulcerative colitis.
18. The method according to claim 11, wherein the intestinal
disease is traveler's diarrhea.
19. A pharmaceutical composition for the treatment of a liver
disease in subjects in need of such treatment, comprising an amount
effective to treat the liver disease of a compound of the formula:
36where X is --SO.sub.2-- or --CO-- and Y is: 37where n is an
integer from 1 to 3; 38or an ester or pharmacologically acceptable
salt thereof, in admixture with a solid or liquid pharmaceutical
diluent or carrier.
20. The pharmaceutical composition according to claim 19, wherein X
is --SO.sub.2-- and Y is: 39where n is an integer from 1 to 3.
21. The pharmaceutical composition according to claim 19, wherein
the compound is
5-[4-(2-carboxy-acetylsulfamoyl)-phenylazo]-2-hydroxy-benzoic
acid.
22. The pharmaceutical composition according to claim 19, wherein
the compound is
5-[4-(4-carboxy-butyrylsulfoamoyl)-phenylazo]-2-hydroxy-benzo- ic
acid.
23. The pharmaceutical composition according to claim 19, wherein
the compound is
5-[4-(3-carboxy-propionylsulfamoyl)-phenylazo]-2-hydroxy-benz- oic
acid.
24. A method of treating a liver disease in a subject in need of
such treatment, said method comprising administering to the subject
an amount effective to treat the liver disease of a compound having
the following formula: 40where X is --SO.sub.2-- or --CO-- and Y
is: 41where n is an integer from 1 to 3; 42or an ester or
pharmacologically acceptable salt thereof.
25. The method according to claim 24, wherein X is --SO.sub.2-- and
Y is: 43where n is an integer from 1 to 3.
26. The method according to claim 24, wherein the compound is
5-[4-(2-carboxy-acetylsulfamoyl)-phenylazo]-2-hydroxy-benzoic
acid.
27. The method according to claim 24, wherein the compound is
5-[4-(4-carboxy-butyrylsulfoamoyl)-phenylazo]-2-hydroxy-benzoic
acid.
28. The method according to claim 24, wherein the compound is
5-[4-(3-carboxy-propionylsulfamoyl)-phenylazo]-2-hydroxy-benzoic
acid.
29. The method according to claim 24, wherein the liver disease is
hepatic encephalopathy.
30. A compound of the formula: 44where R.sup.1 is a substituted or
unsubstituted phenyl group, and where Z is selected such that a
compound, Z--R.sup.1--NH.sub.2, formed by cleavage of the azo bond
is a non-absorbable antibiotic; or an ester or pharmacologically
acceptable salt of the compound of Formula I.
31. The compound according to claim 30, wherein Z is a moiety
comprising carbonyl, sulfur, sulfinyl or sulfonyl; and a primary,
secondary or tertiary amine.
32. The compound according to claim 30, wherein Z is a moiety
comprising sulfur, sulfinyl or sulfonyl; and a primary, secondary
or tertiary amine.
33. The compound according to claim 30, wherein Z is --X--V, where
X is carbonyl, sulfur, sulfinyl or sulfonyl; and V is a moiety
comprising a primary, secondary or tertiary amine.
34. The compound according to claim 33, wherein X is sulfur,
sulfinyl or sulfonyl.
35. The compound according to claim 33, wherein V is --NH--Y, where
Y is selected from the group consisting of: 45where X' is O or S;
46where n=1 to 10, and X"=O or S; and 47where R.sup.2 is hydrogen
or hydroxy, and R.sup.3 is selected from the group consisting of:
48
36. The compound according to claim 33, wherein V is: 49where
R.sup.4 is substituted or unsubstituted phenyl, and R.sup.5 is
selected from the group consisting of: 50where R.sup.6 is a linear
or branched alkyl having 1 to 10 carbon atoms.
37. The compound according to claim 36, wherein R.sup.4 is an
unsubstituted phenyl group.
38. The compound according to claim 36, wherein R.sup.6 is a linear
or branched alkyl having 1 to 4 carbon atoms.
39. A pharmaceutical composition for the treatment of a disease
that is treatable by a non-absorbable antibiotic in subjects in
need of such treatment, comprising an amount effective to treat the
disease of a compound of the formula: 51where R.sup.1 is a
substituted or unsubstituted phenyl group, and where Z is selected
such that a compound, Z--R.sup.1--NH.sub.2, formed by cleavage of
the azo bond is a non-absorbable antibiotic; or an ester or
pharmacologically acceptable salt of the compound of Formula I, in
admixture with a solid or liquid pharmaceutical diluent or
carrier.
40. The pharmaceutical composition according to claim 39, wherein Z
is a moiety comprising carbonyl, sulfur, sulfinyl or sulfonyl; and
a primary, secondary or tertiary amine.
41. The pharmaceutical composition according to claim 39, wherein Z
is a moiety comprising sulfur, sulfinyl or sulfonyl; and a primary,
secondary or tertiary amine.
42. The pharmaceutical composition according to claim 39, wherein Z
is --X--V, where X is carbonyl, sulfur, sulfinyl or sulfonyl; and V
is a moiety comprising a primary, secondary or tertiary amine.
43. The pharmaceutical composition according to claim 42, wherein X
is sulfur, sulfinyl or sulfonyl.
44. The pharmaceutical composition according to claim 42, wherein V
is --NH--Y, where Y is selected from the group consisting of:
52where X' is O or S; 53where n=1 to 10, and X"=O or S; and 54where
R.sup.2 is hydrogen or hydroxy, and R.sup.3 is selected from the
group consisting of: 55
45. The pharmaceutical composition according to claim 42, wherein V
is: 56where R.sup.4 is substituted or unsubstituted phenyl, and
R.sup.5 is selected from the group consisting of: 57where R.sup.6
is a linear or branched alkyl having 1 to 10 carbon atoms.
46. The pharmaceutical composition according to claim 45, wherein
R.sup.4 is an unsubstituted phenyl group.
47. The pharmaceutical composition according to claim 45, wherein
R.sup.6 is a linear or branched alkyl having 1 to 4 carbon
atoms.
48. A method of treating a disease treatable by a non-absorbable
antibiotic in a subject in need of such treatment, said method
comprising administering to the subject an amount effective to
treat the disease of a compound having the following formula:
58where R.sup.1 is a substituted or unsubstituted phenyl group, and
where Z is selected such that a compound, Z--R.sup.1--NH.sub.2,
formed by cleavage of the azo bond is a non-absorbable antibiotic;
or an ester or pharmacologically acceptable salt of the compound of
Formula I.
49. The method according to claim 48, wherein Z is a moiety
comprising carbonyl, sulfur, sulfinyl or sulfonyl; and a primary,
secondary or tertiary amine.
50. The method according to claim 48, wherein Z is a moiety
comprising sulfur, sulfinyl or sulfonyl; and a primary, secondary
or tertiary amine.
51. The method according to claim 48, wherein Z is --X--V, where X
is carbonyl, sulfur, sulfinyl or sulfonyl; and V is a moiety
comprising a primary, secondary or tertiary amine.
52. The method according to claim 51, wherein X is sulfur, sulfinyl
or sulfonyl.
53. The method according to claim 51, wherein V is --NH--Y, where Y
is selected from the group consisting of: 59where X' is O or S;
60where n=1 to 10, and X"=O or S; and 61where R.sup.2 is hydrogen
or hydroxy, and R.sup.3 is selected from the group consisting of:
62
54. The method according to claim 54, wherein V is: 63where R.sup.4
is substituted or unsubstituted phenyl, and R.sup.5 is selected
from the group consisting of: 64where R.sup.6 is a linear or
branched alkyl having 1 to 10 carbon atoms.
55. The method according to claim 54, wherein R.sup.4 is an
unsubstituted phenyl group.
56. The method according to claim 54, wherein R.sup.6 is a linear
or branched alkyl having 1 to 4 carbon atoms.
57. The method according to claim 48, wherein the disease is
Crohn's disease.
58. The method according to claim 48, wherein the disease is
ulcerative colitis.
59. The method according to claim 48, wherein the disease is
traveler's diarrhea.
60. The method according to claim 48, wherein the disease is
hepatic encephalopathy.
Description
RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/228,682, filed Aug. 29, 2000, the disclosure of
which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to 5-ASA derivatives and
methods of treating diseases therewith.
BACKGROUND OF THE INVENTION
[0003] Many people suffer from inflammatory bowel disease (IBD).
IBD is a generic term used to refer to two inflammatory diseases,
ulcerative colitis and Crohn's disease. Ulcerative colitis is a
chronic inflammatory disease of unknown etiology that affects
various portions of the gastrointestinal (GI) tract, particularly
the lower GI tract, and more particularly the colon and/or rectum.
Crohn's disease is a serious inflammatory disease of the GI tract.
It predominates in the intestine (ileum) and the large intestine
(colon). Various medications are being used to treat inflammatory
bowel disease.
[0004] It is known to use mesalamine, 5-aminosalicylic acid (5-ASA)
to treat ulcerative colitis. While mesalamine may be active in
treating ulcerative colitis, it may be absorbed as it passes
through the GI tract. This absorption may adversely affect the
amount of mesalamine that reaches the lower GI tract, particularly
the colon and rectum.
[0005] Various mesalamine formulations have been introduced in an
attempt to protect mesalamine as it passes through the gut and the
upper GI tract. One such formulation is a delayed-release
formulation that relies on a pH-sensitive coating surrounding the
mesalamine. The coating allows the mesalamine to pass through the
gut and upper GI tract without being absorbed so that the
mesalamine reaches the target (i.e. the lower GI tract,
particularly the colon and/or rectum) intact. In another
formulation, mesalamine microspheres surround a mesalamine core.
This formulation releases mesalamine throughout the GI tract,
rather than targeting the colon specifically. It may be difficult
to predict the bioavailability of the various mesalamine
formulations when administered to a wide variety of individuals. As
a result, it may be difficult to determine the proper dosage for a
given individual.
[0006] It is also known to use sulfasalazine having the following
formula to treat ulcerative colitis. 2
[0007] However, sulfasalazine is metabolized in the body to form
mesalamine (5-aminosalicylic acid (5-ASA)) and sulfapyridine.
Several adverse side affects have been noted from the use of
sulfasalazine including nausea, vomiting, abdominal discomfort, and
headache to name just a few. These adverse side effects are usually
attributed to the activity of sulfapyridine in the GI tract, as
well as that absorbed into the system.
[0008] U.S. Pat. No. 4,412,992 to Chan proposes mesalamine
derivatives. Unlike sulfasalazine, the breakdown of these compounds
in the intestinal tract may not give rise to undesirable metabolic
products. In fact, the non-mesalamine metabolic products may be
innocuous.
[0009] It is also known to use olsalazine having the following
formula to treat ulcerative colitis. 3
[0010] In addition to being relatively expensive to make,
olsalazine may have adverse side effects including diarrhea.
[0011] It is also known to use azathioprine
(6-(1-methyl-4-nitoimidazol-5-- ylthio)purine) in the treatment of
inflammatory bowel disease. Azathioprine has the following chemical
structure: 4
[0012] It is also known to use 6-mercaptopurine, a metabolite of
azathioprine, to treat inflammatory bowel disease. 6-mercaptopurine
has the following chemical structure: 5
[0013] Methotrexate (L-4-amino-N.sup.10-methylpteroyl-glutamic
acid) has also been used to treat inflammatory bowel disease.
Methotrexate has the following chemical structure: 6
[0014] The polypeptide cyclosporine, which has traditionally been
given to transplant patients to prevent organ rejection, has also
been used to treat inflammatory bowel disease. The use of
cyclosporine to treat IBD may be limited, however, by the various
side effects associated with this medication. These side effects
include high blood pressure, kidney damage, tremors, headaches,
seizures, excessive hair growth, excessive gum growth, confusion,
coma, and gout.
[0015] It is also known to use the absorbable antibiotics
metronidazole and ciprofloxacin to treat inflammatory bowel
disease.
SUMMARY OF THE INVENTION
[0016] According to embodiments of the present invention, compounds
are provided having the structure of Formula I: 7
[0017] where R.sup.1 is a substituted or unsubstituted phenyl
group, and where Z is selected such that a compound,
Z--R.sup.1--NH.sub.2, formed by cleavage of the azo bond is a
non-absorbable antibiotic. Preferably, the compound,
Z--R.sup.1--NH.sub.2, is a metabolite formed by in vivo cleavage of
the azo bond. R.sup.1 is preferably an unsubstituted phenyl group.
When R.sup.1 is a substituted phenyl, it is preferably substituted
with lower alkyl.
[0018] According to other embodiments of the present invention,
compounds are provided having the structure of Formula II: 8
[0019] where X is --SO.sub.2-- or --CO-- and Y is: 9 10
[0020] or the esters or pharmaceutically acceptable salts
thereof.
[0021] Pharmaceutical compositions including compounds according to
the present invention in admixture with a pharmaceutical diluent or
carrier are also provided, as are methods of utilizing such
compounds in the treatment or prophylaxis of various diseases
including, but not limited to, inflammatory bowel disease.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] FIG. 1 illustrates a synthesis route for compounds of the
present invention.
[0023] FIG. 2 illustrates a synthesis route for compounds of the
present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0024] The invention will now be described with respect to
preferred embodiments described herein. It should be appreciated
however that these embodiments are for the purpose of illustrating
the invention, and are not to be construed as limiting the scope of
the invention as defined by the claims.
[0025] As used herein, the term "inflammatory bowel disease"
includes ulcerative colitis and Crohn's disease.
[0026] As used herein, the term "non-absorbable antibiotic" means a
compound having anti-bacterial activity, which, when delivered
orally, results in less than 2 percent of the compound being
excreted in the urine of the subject, in contrast to the
sulfapyridine metabolite resulting from administration of
sulfasalzine described above.
[0027] According to embodiments of the present invention, compounds
are provided having the structure of Formula I: 11
[0028] where R.sup.1 is a substituted or unsubstituted phenyl
group, and where Z is selected such that a compound,
Z--R.sup.1--NH.sub.2, formed by cleavage of the azo bond is a
non-absorbable antibiotic. Preferably, the compound,
Z--R.sup.1--NH.sub.2, is a metabolite formed by in vivo cleavage of
the azo bond. R.sup.1 is preferably an unsubstituted phenyl group.
When R.sup.1 is a substituted phenyl, it is preferably substituted
with lower alkyl.
[0029] According to other embodiments of compounds of the present
invention, Z is a moiety comprising carbonyl, sulfur, sulfinyl or
sulfonyl; and a primary, secondary or tertiary amine. Preferably, Z
is a moiety comprising sulfur, sulfinyl or sulfonyl; and a primary,
secondary or tertiary amine.
[0030] According to yet other embodiments of compounds of the
present invention, Z is --X--V, where X is carbonyl, sulfur,
sulfinyl or sulfonyl; and V is a moiety comprising a primary,
secondary or tertiary amine. Preferably, X is sulfur, sulfinyl or
sulfonyl. More preferably, X is sulfonyl. In some embodiments, V is
--NH--Y, where Y is selected from the group consisting of: 12
[0031] where X' is O or S; 13
[0032] where n=1 to 10, and X"=O or S; and 14
[0033] where R.sup.2 is hydrogen or hydroxy, and R.sup.3 is
selected from the group consisting of: 15
[0034] In other embodiments, V is: 16
[0035] where R.sup.4 is substituted or unsubstituted phenyl, and
R.sup.5 is selected from the group consisting of: 17
[0036] where R.sup.6 is a linear or branched alkyl having 1 to 10
carbon atoms. Preferably, R.sup.4 is unsubstituted phenyl.
Preferably, R.sup.6 is a linear or branched alkyl having 1 to 6, 7
or 8 carbon atoms, and, more preferably, R.sup.6 is a linear or
branched alkyl having 1 or 2 to 3, 4 or 5 carbon atoms.
[0037] According to preferred embodiments of the present invention,
compounds are provided having the structure of Formula II: 18
[0038] where X is --SO.sub.2-- or --CO-- and Y is: 19
[0039] where n is an integer from 1 to 10, is preferably an integer
from 1 to 6, and is more preferably an integer from 1 to 3; 20
[0040] Compounds of the present invention may be utilized for the
prophylaxis or treatment of various diseases including, but not
limited to, intestinal diseases such as inflammatory bowel disease
and traveler's diarrhea; liver diseases such as hepatic
encephalopathy, liver failure, end-stage liver disease, cirrhosis,
hepatitis, hepatic fibrosis, liver transplantation, and portal
hypertension; and diseases that may be treated or prevented by
administration of a non-absorbable antibiotic such as bacterial
intestinal infections, pseudo membranous colitis, bacterial
overgrowth, elostridium difficile infection, salmonella enteritis,
shigella infections, yersiniosis, E. coli, traveler's diarrhea,
gram negative bacterial infections, gram positive bacterial
infections, tuberculosis, cryptosporidiosis, and microsporidia
infection.
[0041] The compounds of the present invention may also be utilized
in diagnosis of constituents, conditions, or disease states in
biological systems or specimens, as well as for diagnosis purposes
in non-physiological systems. Furthermore, the compounds of the
present invention may have application in prophylaxis or treatment
of condition(s) or disease state(s) in plant systems. By way of
example, the compounds of the present invention may have
insecticidal, herbicidal, fungicidal, and/or pesticidal efficacy
amenable to usage in various plant systems.
[0042] Compounds of the present invention preferably break down in
the intestinal tract by azo reduction to provide 5-ASA and a
non-absorbable antibiotic. For example, according to some
embodiments of the present invention, the compounds of Formula II
above may breakdown in the intestinal tract to form the metabolic
products of Formulae III and IV: 21
[0043] where X is --SO.sub.2-- or --CO-- and Y is: 22
[0044] where n is an integer from 1 to 10, is preferably an integer
from 1 to 6, and is more preferably an integer from 1 to 3; 23
[0045] The metabolic product of Formula III preferably possesses
anti-inflammatory activity, and more particularly may inhibit
prostaglandin synthetase I and II. The metabolic product of Formula
IV preferably possesses antibiotic activity and is a non-absorbable
antibiotic. Accordingly, compounds of the present invention
preferably provide both anti-inflammatory and antibiotic activity,
and thus may be useful in treating various diseases, including, but
not limited to, intestinal diseases, liver diseases, and diseases
that may be treated or prevented by administration of a
non-absorbable antibiotic.
[0046] In therapeutic usage, the present invention contemplates a
method of treating an animal subject having or latently susceptible
to such condition(s) or disease state(s) and in need of such
treatment, comprising administering to such animal an effective
amount of a compound of the present invention that is
therapeutically effective for said condition or disease state.
Subjects to be treated by the compounds of the present invention
include both human and non-human animal (e.g., bird, dog, cat, cow,
horse) subjects, and are preferably mammalian subjects, and most
preferably human subjects.
[0047] Depending on the specific condition or disease state to be
combatted, animal subjects may be administered compounds of the
present invention at any suitable therapeutically effective and
safe dosage, as may readily be determined within the skill of the
art, and without undue experimentation. For example, compounds of
the present invention may be administered at a dosage between about
0.1 and 100 mg/kg, preferably between about 5 and 90 mg/kg, and
more preferably between about 10 and 80 mg/kg.
[0048] The compounds of the present invention may be administered
per se as well as in the form of pharmaceutically acceptable
esters, salts, and other physiologically functional derivatives
thereof.
[0049] The present invention also contemplates pharmaceutical
formulations, both for veterinary and for human medical use, which
comprise as the active agent one or more compound(s) of the present
invention. In such pharmaceutical and medicament formulations, the
active agent preferably is utilized together with one or more
pharmaceutically acceptable carrier(s) therefor and optionally any
other therapeutic ingredients. The carrier(s) must be
pharmaceutically acceptable in the sense of being compatible with
the other ingredients of the formulation and are preferably not
unduly deleterious to the recipient thereof. The active agent is
provided in an amount effective to achieve the desired
pharmacological effect, as described above, and in a quantity
appropriate to achieve the desired daily dose.
[0050] The formulations include those suitable for parenteral as
well as non-parenteral administration, and specific administration
modalities include oral, rectal, buccal, topical, nasal,
ophthalmic, subcutaneous, intramuscular, intravenous, transdermal,
intrathecal, intra-articular, intra-arterial, sub-arachnoid,
bronchial, lymphatic, vaginal, and intra-uterine administration.
Formulations suitable for oral and parenteral administration are
preferred, with formulations suitable for oral administration most
preferred.
[0051] When the active agent is utilized in a formulation
comprising a liquid solution, the formulation advantageously may be
administered orally or parenterally. When the active agent is
employed in a liquid suspension formulation or as a powder in a
biocompatible carrier formulation, the formulation may be
advantageously administered orally, rectally, or bronchially.
[0052] When the active agent is utilized directly in the form of a
powdered solid, the active agent may advantageously be administered
orally. Alternatively, it may be administered bronchially, via
nebulization of the powder in a carrier gas, to form a gaseous
dispersion of the powder which is inspired by the patient from a
breathing circuit comprising a suitable nebulizer device.
[0053] The formulations comprising the active agent of the present
invention may conveniently be presented in unit dosage forms and
may be prepared by any of the methods well known in the art of
pharmacy. Such methods generally include the step of bringing the
active ingredient(s) into association with a carrier which
constitutes one or more accessory ingredients. Typically, the
formulations are prepared by uniformly and intimately bringing the
active ingredient(s) into association with a liquid carrier, a
finely divided solid carrier, or both, and then, if necessary,
shaping the product into dosage forms of the desired
formulation.
[0054] Formulations of the present invention suitable for oral
administration may be presented as discrete units such as capsules,
cachets, tablets, or lozenges, each containing a predetermined
amount of the active ingredient as a powder or granules; or a
suspension in an aqueous liquor or a non-aqueous liquid, such as a
syrup, an elixir, an emulsion, or a draught.
[0055] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared by compressing in a suitable machine, with the active
compound being in a free-flowing form such as a powder or granules
which optionally is mixed with a binder, disintegrant, lubricant,
inert diluent, surface active agent, or discharging agent. Molded
tablets comprised of a mixture of the powdered active compound with
a suitable carrier may be made by molding in a suitable
machine.
[0056] A syrup may be made by adding the active compound to a
concentrated aqueous solution of a sugar, for example sucrose, to
which may also be added any accessory ingredient(s). Such accessory
ingredient(s) may include, for example, flavorings, suitable
preservatives, agents to retard crystallization of the sugar, and
agents to increase the solubility of any other ingredient, such as
a polyhydroxy alcohol, for example glycerol or sorbitol.
[0057] Formulations suitable for parenteral administration
conveniently comprise a sterile aqueous preparation of the active
compound, which preferably is isotonic with the blood of the
recipient (e.g., physiological saline solution). Such formulations
may include suspending agents and thickening agents or other
microparticulate systems which are designed to target the compound
to blood components or one or more organs. The formulations may be
presented in unit-dose or multi-dose form.
[0058] Nasal spray formulations comprise purified aqueous solutions
of the active compound with preservative agents and isotonic
agents. Such formulations are preferably adjusted to a pH and
isotonic state compatible with the nasal mucus membranes.
[0059] Formulations for rectal administration may be presented as a
suppository with a suitable carrier such as cocoa butter,
hydrogenated fats, or hydrogenated fatty carboxylic acid.
[0060] Ophthalmic formulations are prepared by a similar method to
the nasal spray, except that the pH and isotonic factors are
preferably adjusted to match that of the eye.
[0061] Topical formulations comprise the active compound dissolved
or suspended in one or more media, such as mineral oil, petroleum,
polyhydroxy alcohols, or other bases used for topical
pharmaceutical formulations.
[0062] In addition to the aforementioned ingredients, the
formulations of this invention may further include one or more
accessory ingredient(s) selected from diluents, buffers, flavoring
agents, disintegrants, surface active agents, thickeners,
lubricants, preservatives (including antioxidants), and the
like.
[0063] Accordingly, compounds according to the present invention
may be utilized for the prophylaxis or treatment of various
diseases, particularly intestinal diseases, and more particularly
colonic inflammation diseases such as ulcerative colitis.
[0064] Compounds of the present invention may be made using known
starting materials and reagents as will be understood by those
skilled in the art. For example, compounds of the present invention
may be synthesized as illustrated in FIGS. 1 and 2, where Y is as
described above.
[0065] The present invention will now be described with reference
to the following examples. It should be appreciated that these
examples are for the purposes of illustrating aspects of the
present invention, and do not limit the scope of the invention as
defined by the claims.
EXAMPLES
[0066] Melting points were taken on a Laboratory Devices Mel-Temp
II capillary melting point apparatus and are uncorrected.
.sup.1HNMR spectra were obtained on a Varian Unity 300 MHz
spectrometer and chemical shifts (6) are reported as parts per
million (ppm) relative to internal standard tetramethylsilane.
Infrared spectra were obtained with a Nicolet Impact 410.
Ultraviolet and visible spectra were obtained with a Beckman DU
640i spectrophotometer. Fast atom bombardment (FAB) mass
spectroscopy data was obtained by M-Scan Inc. All reagents were
used as received from Aldrich Chemical Co.
Examples 1 through 3
Synthesis of
5-[4-(2-Carboxy-Acetylsulfamoyl)-Phenylazo]-2-Hydroxy-Benzoic
Acid
Example 1
3-(4-Nitro-Benzenesulfonylamino)-3-Oxo-Propionic Acid Ethyl
Ester
[0067] A 250-mL flask was charged with 4-nitrobenzenesulfonamide
(10.8 g, 53.1 mmol) and sodium hydroxide (2.52 g, 63.1 mmol in 25
mL water). The solution was cooled in an ice bath and ethyl
3-chloro-3-oxobutyrate (6.40 mL, 50.0 mmol) was added dropwise. A
precipitate formed, the suspension was allowed to warm to ambient
temperature, and stirred for an additional 3 hours. The precipitate
was removed by vacuum filtration and the filtrate was extracted
with ethyl acetate (3.times.30 mL). The extractions were combined
and dried with MgSO.sub.4. The solution was then concentrated under
reduced pressure and dried under vacuum. The crude product was a
yellow solid with a 57% yield (9.05 g): mp 97.degree. C.; .sup.1H
NMR (DMSO-d.sub.6) .delta.1.17 (3H, t), 3.32 (2H, s), 4.04 (2H, m)
7.71 (1H, s), 8.05 (1H, d, J=9.0 Hz), 8.16 (1H, d, J=8.1 Hz), 8.41
(2H, m); IR (KBr) 2979, 1758, 1690, 1527, 1326, 1207, 1095, 1013,
850, 656 cm.sup.-1; FAB-MS (NBA) m/z 317 (M+H).sup.+.
Example 2
3-(4-Amino-Benzenesulfonylamino)-3-Oxo-Propionic Acid Ethyl
Ester
[0068] To a 250-mL oven dried flask,
3-(4-nitro-benzenesulfonylamino)-3-ox- o-propionic acid ethyl ester
(2.00 g, 6.32 mmol), as obtained from the procedure of Example 1,
was dissolved in absolute ethyl alcohol (100 mL). Palladium (10 wt.
% on activated carbon, 0.20 g, 1.90 mmol) was added and a hydrogen
environment was introduced into the flask. The mixture was then
stirred at ambient temperature for 3 hours. The crude reaction
mixture was filtered through Celite and ethyl alcohol was removed
under reduced pressure. The crude product was dried under vacuum
overnight resulting in a brown oil (93% yield, 1.68 g): .sup.1H NMR
(DMSO-d.sub.6) .delta.1.14 (2H, t), 3.28 (2H, s), 4.07 (2H, m),
6.57 (2H, m), 6.84 (1H, s), 7.44 (1H, d, J=8.1 Hz), 7.52 (1H, d,
J=8.1 Hz); IR (KBr) 2979, 1746, 1639, 1583, 1370, 1295, 1164, 1026,
857, 669 cm.sup.-1; FAB-MS (NBA) m/z 287 (M+H).sup.+.
Example 3
5-[4-(2-Carboxy-Acetylsulfamoyl)-Phenylazo]-2-Hydroxy-Benzoic
Acid
[0069] 3-(4-Amino-benzenesulfonylamino)-3-oxo-propionic acid ethyl
ester (1.81 g, 6.32 mmol), as obtained from the procedure of
Example 2, dissolved in an aqueous solution of HCl (5.5 mL,
36.5-38.0%) and water (3.5 mL) was placed in a 25-mL beaker and
cooled to 0.degree. C. in an ice bath. When the solution stabilized
at 0.degree. C., sodium nitrite (0.44 g, 6.32 mmol) in water (3 mL)
was added dropwise. The temperature was maintained at 0-5.degree.
C. and the resulting diazonium salt solution was stirred for 15
minutes.
[0070] While the diazonium salt solution stirred, a 50-mL beaker
fitted with a thermometer and pH probe (Orion model 420A with Orion
semi-micro pH probe) was charged with salicylic acid, sodium salt
(1.21 g, 7.59 mmol) dissolved in sodium hydroxide (0.76 g, 19.0
mmol in 6 mL H.sub.2O). Using an ice bath, the salicylic acid
solution was cooled to 17.degree. C. and the diazonium salt
solution was slowly added dropwise. Throughout the addition, the pH
was maintained at 13.2-13.3 with the addition of aqueous sodium
hydroxide and the temperature was kept at 17-18.degree. C. with the
addition of ice. After the addition was complete, the resulting
dark red solution was allowed to warm to ambient temperature and
stirring was continued for 1.5 h. Using an ice bath, the solution
was acidified to pH 2-3 with concentrated HCl (36.5-38.0%). A solid
precipitated and was collected by vacuum filtration. The crude
product was obtained as a red solid in 4% yield (116 mg): mp
178.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta.3.28 (2H, s),
7.13 (1H, d, J=9.0 Hz), 7.47 (1H, m), 7.76 (2H, d, J=6.0 Hz), 7.98
(2H, d, J=6.0 Hz), 8.35 (1H, s); IR (KBr) 3574, 1677, 1577, 1477,
1333, 1138, 1095, 838 cm.sup.-1; FAB-MS (NBA) m/z 408 (M+H).sup.+,
430 (M+Na).sup.+.
Examples 4 through 6
Synthesis of
5-[4-(4-Carboxy-Butyrylsulfamoyl)-Phenylazo]-2-Hydroxy-Benzoi- c
Acid
Example 4
5-(4-Nitro-Benzesulfonylamino)-5-Oxo-Pentanoic Acid Methyl
Ester
[0071] A 250-mL, 3-neck flask fitted with a condenser and stir bar
was charged with 4-nitrobenzenesulfonamide (4.02 g, 19.8 mmol) and
anhydrous pyridine (60 mL). The solution was heated to reflux using
an oil bath and methyl 5-chloro-5-oxovalerate (3.28 mL, 23.7 mmol)
was added dropwise. The solution refluxed for 3 hours, cooled to
ambient temperature and continued stirring for 20 hours. The
solution was acidified with HCl (50 mL, 36.5-38%) in water (150 mL)
to pH 1-2 upon which a precipitate formed. The crude product was
obtained by suction filtration as a brown solid (6.59 g): mp
114.degree. C.; .sup.1H NMR (DMSO-d.sub.6): .delta.1.62 (2H, m),
2.19 (2H, m), 2.28 (2H,m) 3.52 (3H, s), 8.15 (2H, d, J=9.0 Hz),
8.42 (2H, d, J=9.0 Hz); IR (KBr) 3205, 1727, 1690, 1527, 1420,
1352, 1319, 1170, 1020, 838, 744 cm.sup.-1; negative FAB-MS (NBA)
m/z 329 (M).sup.-.
Example 5
5-(4-Amino-Benzenesulfonylamino)-5-Oxo-Pentanoic Acid Methyl
Ester
[0072] A 250-mL, 3-neck flask fitted with a condenser was charged
with 5-(4-nitro-benzesulfonylamino)--5-oxo-pentanoic acid methyl
ester (6.00 g, 18.2 mmol), as obtained from the procedure of
Example 4, dissolved in methanol (60 mL). A solution of ammonium
chloride (5.64 g, 105 mmol) in water (60 mL) was added along with
iron (3.55 g, 63.6 mmol, 325 mesh powder). The solution refluxed
for 15 hours, cooled to ambient temperature, and was filtered
through Celite. The solvent was removed under reduced pressure and
methanol (200 mL) was added. The solution was filtered and
concentrated under reduced pressure. The crude product was obtained
as an orange solid in 91% yield (4.95 g): mp >260.degree. C.; IR
(KBr) 3117, 2823, 1746, 1596, 1395, 1157 cm.sup.-1; FAB-MS (NBA)
m/z 301 (M).sup.+.
Example 6
5-[4-(4-Carboxy-Butyrylsulfoamoyl)-Phenylazo]-2-Hydroxy-Benzoic
Acid
[0073] 5-(4-Amino-benzenesulfonylamino)-5-oxo-pentanoic acid methyl
ester (4.00 g, 13.3 mmol), as obtained from the procedure of
Example 5, dissolved in an aqueous solution of HCl (13 mL,
36.5-38%) and water (8 mL) was placed in a 100-mL beaker and cooled
to 0.degree. C. in an ice bath. When the solution stabilized at
0.degree. C., sodium nitrite (1.60 g. 39.9 mmol) in water (5 mL)
was added dropwise. The temperature was maintained at 0-5.degree.
C. and the resulting diazonium salt solution stirred for 20
minutes.
[0074] While the diazonium salt solution stirred, a 400-mL beaker
fitted with a thermometer and pH probe (Orion model 420A with Orion
semimicro pH probe) was charged with salicylic acid, sodium salt
(2.56 g. 16.0 mmol) dissolved in sodium hydroxide (1.60 g, 39.9
mmol) in water (5 mL) and sodium carbonate (2.50 g. 23.6 mmol) in
water (5 mL). Using an ice bath, the salicylic acid solution was
cooled to 17.degree. C. and the diazonium salt solution was slowly
added in 3-4 mL portions. Throughout the addition, the pH was
maintained at 13.2-13.3 with the addition of aqueous sodium
hydroxide and the temperature was kept at 17-18.degree. C. with the
addition of ice. After the addition was complete, the resulting
solution was allowed to warm to ambient temperature and stirring
was continued for 1 hour. Using an ice bath, the solution was
acidified to pH 1-2 with concentrated HCl (100 mL, 36.5-38%) in
water (250 mL). A solid precipitated and was collected by suction
filtration. The crude product was obtained as an orange solid in 6%
yield (36.5 mg): mp 192.degree. C.; .sup.1H NMR (DMSO-d.sub.6):
.delta.1.62 (2H, m), 2.13 (2H, m), 2.28 (2H, m), 7.17 (1H, d, J=7.8
Hz), 8.02 (3H, d, J=6.0 Hz), 8.10 (2H, d, J=7.8 Hz), 8.37 (1H, s);
IR (KBr) 3092, 1677, 1441, 1169, 1143, 1070, 851, 659 cm.sup.-1;
FAB-MS (NBA) m/z 434 (M).sup.31 .
Examples 7 through 9
Synthesis of
5-[4-(3-Carboxy-Propionylsulfamoyl)-Phenylazo]-2-Hydroxy-Benz- oic
Acid
Example 7
4-(4-Nitro-Benzenesulfonylamino)-4-Oxo-Butyric Acid Methyl
Ester
[0075] A 500-mL, 3-neck flask fitted with a condenser was charged
with 4-nitrobenzenesulfonamide (8.03 g, 39.7 mmol) and anhydrous
pyridine (150 mL). The solution was heated to reflux using an oil
bath and methyl 4-chloro-4-oxobutyrate (5.90 mL, 47.9 mmol) was
added dropwise. The solution refluxed for 17 hours, cooled to
ambient temperature, and was further cooled to 0-5.degree. C. using
an ice bath. The solution was acidified with conc. HCl (.about.50
mL, 36.5-38%) to pH 3 and poured into a beaker containing
.about.600 grams of ice upon which a precipitate formed. The crude
product was obtained by suction filtration as a brown solid in 92%
yield (11.5 g): mp 156.degree. C.; .sup.1H NMR (DMSO-d.sub.6)
.delta.2.43 (2H, m), 2.50 (2H, m), 3.47 (3H, s), 8.14 (2H, d, J=9.0
Hz), 8.41 (2H, d, J=9.0 Hz); IR (KBr) 3211, 1739, 1706, 1533, 1434,
1348, 1162 cm.sup.-1; FAB-MS (NBA) m/z 317 (M+H).sup.+.
Example 8
4-(4-Amino-Benzesulfonylamino)-4-Oxo-Butyric Acid Methyl Ester
[0076] To a 500-mL, 2-neck flask fitted with an overhead stirrer
and condenser, 4-(4-nitro-benzenesulfonylamino)-4-oxo-butyric acid
methyl ester (10.0 g. 31.6 mmol), as obtained by the procedure of
Example 7, was dissolved in methanol (100 mL). A solution of
ammonium chloride (9.82 g. 184 mmol) in water (100 mL) was added
along with iron (6.19 g, 11 mmol, 325 mesh powder). The solution
was refluxed for 5.5 hours, cooled to ambient temperature and
filtered through Celite. The solvent was removed under reduced
pressure and methanol (400 mL) was added. The solution was filtered
and concentrated under reduced pressure. The crude product was
obtained as a brown solid (9.58 g): mp>260.degree. C.; .sup.1H
NMR (DMSO-d.sub.6) .delta.2.38 (2H, m) 2.48 (2H, m), 3.46(3H, s),
6.56(2H, d, J=8.4 Hz), 7.44 (2H, d, J=8.4 Hz); IR (KBr) 3490, 3386,
3107, 1739, 1697, 1624, 1587, 1435, 1314, 1138, 1083, 980, 840
cm.sup.-1 FAB-MS (NBA) m/z 287 (M+H).sup.+.
Example 9
5-[4-(3-Carboxy-Propionylsulfamoyl)-Phenylazo]-2-Hydroxy-Benzoic
Acid
[0077] 4-(4-Amino-benzesulfonylamino)-4-oxo-butyric acid methyl
ester (11.5 g. 40.2 mmol), as prepared from the procedure of
Example 8, dissolved in an aqueous solution of HCl (35 mL,
36.5-38.0%) and water (25 mL) was placed in a 500-mL beaker and
cooled to 0.degree. C. in an ice bath. When the solution stabilized
at 0.degree. C., sodium nitrite (2.77 g, 40.2 mmol) in water (15
mL) was added slowly in 5 mL portions. The temperature was
maintained at 0-5.degree. C. and the resulting diazonium salt
solution was stirred for 15 minutes.
[0078] While the diazonium salt solution stirred, a 1 L beaker
fitted with a thermometer and pH probe (Orion model 420A with Orion
semimicro pH probe) was charged with salicylic acid, sodium salt
(6.44 g, 40.2 mmol) dissolved in sodium hydroxide (4.83 g, 121 mmol
in 15 mL H.sub.2O) and sodium carbonate (7.54 g, 71.2 mmol in 15 mL
H.sub.2O). Using an ice bath, the salicylic acid solution was
cooled to 17.degree. C. and the diazonium salt solution was slowly
added in 20 mL portions. Throughout the addition, the pH was
maintained at 13.2-13.3 with the addition of aqueous sodium
hydroxide and the temperature was kept at 17-18.degree. C. with the
addition of ice. After the addition was complete, the resulting
dark red solution was allowed to warm to ambient temperature and
stirring was continued for an additional 30 minutes. Using an ice
bath, the solution was acidified to pH 2-3 with concentrated HCl
(300 mL, 36.5-38.0%) in water (500 mL). A solid precipitated and
was collected by suction filtration. The crude product was obtained
as an orange solid in 36% yield (6.24 g): mp 192.degree. C.,
.sup.1H NMR (DMSO-d.sub.6) .delta.2.37 (2H, m), 2.46 (2H, m), 7.14
(1H, d, J=9.0 Hz), 7.97 (1H, d, J=8.4 Hz), 8.00 (2H, d, J=8.4 Hz),
8.06 (2H, d, J=8.4 Hz), 8.34 (1H, s); IR (KBr) 3596, 3536, 3178,
1713, 1680, 1573, 1448, 1334, 1182, 1123, 1063, 851, 791, 612
cm.sup.-1; UV-Vis (MeOH) .lambda..sub.max=353 nm, .epsilon.=23,400
mol.sup.-1 cm.sup.-1 L; FAB-MS (NBA) m/z 420 (M).sup.-.
Example 10
Metabolism of
5-[4-(3-Carboxy-Propionylsulfamoyl)-Phenylazo]-2-Hydroxy-Ben- zoic
Acid (1) Following Oral Delivery
[0079]
5-[4-(3-Carboxy-propionylsulfamoyl)-phenylazo]-2-hydroxy-benzoic
acid (1), a compound of the present invention, and sulfasalazine
(used as a control; not part of the present invention) were orally
dosed to rats. The degradation and the generation of their
metabolites after the oral dosing were measured to be able to
confirm that (1) undergoes bacterial azo reduction and yields its
metabolites, 5-aminosalicylic acid (5-ASA) and C4 sulfanomide.
[0080] This experiment was performed to confirm that (1) undergoes
a bacterial reduction process and yields its metabolites in in-vivo
metabolism. The quantification of its metabolites was also carried
out. Sulfasalazine was used as a control since the same azo bond
cleavage by bacteria occurs with it, which results in
5-aminosalicylic acid and sulfapyridine as its metabolites. (1) was
degraded and its metabolites were produced as expected.
[0081] A total of 7 rats were used for the experiment and
methylcellulose was used as a vehicle. The dosage amount was 100
mg/kg per rat. Three rats were dosed with (1) and the other three
rats were dosed with sulfasalazine. One rat was used as a control
and dosed with methylcellulose. Both urine and feces were collected
over 2 days and analyzed by HPLC.
[0082] Urine was collected each day and 300 .mu.L of aliquot from
each sample was centrifuged for 10 minutes at 5000 g. 80 .mu.L of
supernatant was injected for analysis. Feces was also collected
each day and homogenized with a 1:1 mixture of water and
acetonitrile. This mixture was then centrifuged for 20 minutes at
5000 g. 80 .mu.L of supernatant was injected for analysis.
[0083] A Waters 2690 HPLC was used for sample analysis as
follows:
1 Mobile phase programming: Gradient Mobile phase: A = Water + 0.1%
TFA B = Acetonitrile + 0.1% TFA Flow rate: 1 mL/min. Column:
Phenomenex Max RP, 80 .ANG., 4.6 mm .times. 250 mm PDA settings:
Collected spectrum: 210-400 nm Extracted chromatogram: 280 and/or
other Run time/sample: Approximately 50 min. Flow % Mobile % Mobile
Time (mL/minute) Phase A Phase B -- 1 100 0 40 1 50 50 43 1 5 95 44
1 95 5 50 1 95 5
[0084] For urine, only a very small amount of (1) was detected from
2 days collection and none of its metabolites were detected. For
feces, (1) was not detected, but acetylated 5-ASA and C4
sulfanomide were detected from day 1 collection. No compounds were
detected from day 2 collection. Sulfasalazine was also degraded,
but only one rat showed the generation of sulfapyridine. Most rats
showed acetylated 5-ASA from day 1 collection. No compounds were
detected from day 2 collection. The results from this study show
that both (1) and sulfasalazine undergo azo reduction.
[0085] The foregoing is illustrative of the present invention, and
is not to be construed as limiting thereof. The invention is
defined by the following claims, with equivalents of the claims to
be included therein.
* * * * *