U.S. patent application number 13/662387 was filed with the patent office on 2013-05-02 for bile acid recycling inhibitors for treatment of pediatric cholestatic liver diseases.
This patent application is currently assigned to Lumena Pharmaceuticals, Inc.. The applicant listed for this patent is Lumena Pharmaceuticals, Inc.. Invention is credited to Bronislava GEDULIN, Michael Grey, Niall O'Donnell.
Application Number | 20130109671 13/662387 |
Document ID | / |
Family ID | 48168608 |
Filed Date | 2013-05-02 |
United States Patent
Application |
20130109671 |
Kind Code |
A1 |
GEDULIN; Bronislava ; et
al. |
May 2, 2013 |
Bile Acid Recycling Inhibitors for Treatment of Pediatric
Cholestatic Liver Diseases
Abstract
Provided herein are methods of treating or ameliorating a
pediatric cholestatic liver disease by non-systemically
administering to an individual in need thereof a therapeutically
effective amount of a pediatric formulation comprising an Apical
Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI) or a
pharmaceutically acceptable salt thereof. Also provided are methods
for treating or ameliorating a pediatric liver disease, decreasing
the levels of serum bile acids or hepatic bile acids, treating or
ameliorating pruritis, reducing liver enzymes, or reducing
bilirubin comprising non-systemically administering to an
individual in need thereof a therapeutically effective amount of a
pediatric formulation comprising an ASBTI or a pharmaceutically
acceptable salt thereof.
Inventors: |
GEDULIN; Bronislava; (Del
Mar, CA) ; Grey; Michael; (Rancho Santa Fe, CA)
; O'Donnell; Niall; (Encinitas, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Lumena Pharmaceuticals, Inc.; |
San Diego |
CA |
US |
|
|
Assignee: |
Lumena Pharmaceuticals,
Inc.
San Diego
CA
|
Family ID: |
48168608 |
Appl. No.: |
13/662387 |
Filed: |
October 26, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61607503 |
Mar 6, 2012 |
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|
61607487 |
Mar 6, 2012 |
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61553094 |
Oct 28, 2011 |
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Current U.S.
Class: |
514/211.08 ;
514/211.09; 514/249; 514/337; 514/431 |
Current CPC
Class: |
A61K 9/1623 20130101;
A61K 9/2013 20130101; A61K 45/06 20130101; A61K 9/0053 20130101;
A61K 31/155 20130101; A61K 9/1611 20130101; A61P 1/14 20180101;
A61P 3/06 20180101; A61P 43/00 20180101; A61K 9/0056 20130101; A61K
31/4985 20130101; A61K 31/5377 20130101; A61P 1/10 20180101; C07D
281/10 20130101; A61P 17/04 20180101; C07D 337/08 20130101; C07D
409/10 20130101; A61P 35/00 20180101; C07D 487/08 20130101; A61P
1/18 20180101; A61K 31/38 20130101; A61K 9/2018 20130101; A61P
13/02 20180101; A61K 9/2059 20130101; A61K 31/554 20130101; A61K
31/7042 20130101; A61K 9/1635 20130101; A61K 9/2009 20130101; A61K
31/495 20130101; A61K 31/4436 20130101; A61K 31/41 20130101; A61K
9/2027 20130101; A61K 9/2054 20130101; C07H 15/26 20130101; A61K
9/2081 20130101; A61P 1/16 20180101; A61K 31/4995 20130101; A61P
7/00 20180101; A61K 9/1617 20130101; A61K 31/4965 20130101 |
Class at
Publication: |
514/211.08 ;
514/431; 514/249; 514/337; 514/211.09 |
International
Class: |
A61K 31/554 20060101
A61K031/554; A61P 1/16 20060101 A61P001/16; A61K 31/4436 20060101
A61K031/4436; A61K 31/38 20060101 A61K031/38; A61K 31/4995 20060101
A61K031/4995 |
Claims
1. A method for treating or ameliorating a pediatric cholestatic
liver disease comprising non-systemically administering to a
pediatric patient a therapeutically effective amount of a
pharmaceutical composition comprising an Apical Sodium-dependent
Bile Acid Transporter Inhibitor (ASBTI) or a pharmaceutically
acceptable salt thereof.
2. A method for treating or ameliorating pruritis comprising
non-systemically administering to a pediatric patient suffering
from a pediatric cholestatic liver disease a therapeutically
effective amount of a pharmaceutical composition comprising an
Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI) or
a pharmaceutically acceptable salt thereof.
3. A method for treating or ameliorating pediatric hypercholemia
comprising non-systemically administering to a pediatric patient a
therapeutically effective amount of a pharmaceutical composition
comprising an Apical Sodium-dependent Bile Acid Transporter
Inhibitor (ASBTI) or a pharmaceutically acceptable salt
thereof.
4. A method for decreasing the level of serum bile acids or hepatic
bile acids in a pediatric patient suffering from a pediatric
cholestatic liver disease comprising non-systemically administering
to the patient a therapeutically effective amount of a
pharmaceutical composition comprising Apical Sodium-dependent Bile
Acid Transporter Inhibitor (ASBTI) or a pharmaceutically acceptable
salt thereof.
5. The method of claim 4, wherein the method comprises decreasing
at least 20% of serum bile acid or hepatic bile acid levels in the
patient.
6. The method of claim 1, wherein the method comprises reducing
xanthoma, serum lipoprotein X, liver enzymes, bilirubin,
intraenterocyte bile acids/salts, or necrosis and/or damage to
hepatocellular architecture.
7. The method of claim 1, wherein the composition is a pediatric
dosage form.
8. The method of claim 7, wherein the pediatric dosage form is
selected from a solution, syrup, suspension, elixir, powder for
reconstitution as suspension or solution, dispersible/effervescent
tablet, chewable tablet, gummy candy, lollipop, freezer pops,
troches, oral thin strips, orally disintegrating tablet, sachet,
soft gelatin capsule, and sprinkle oral powder or granules.
9. The method of claim 1, wherein the dosage of the ASBTI is
between about 10 .mu.g/kg/day and about 300 .mu.g/kg/day.
10. The method of claim 1, wherein the dosage of the ASBTI is any
dosage from about 14 .mu.g/kg/day to about 280 .mu.g/kg/day.
11. The method of claim 1, wherein the dosage of the ASBTI is any
dosage from about 14 .mu.g/kg/day to about 140 .mu.g/kg/day.
12. The method of claim 1, wherein the dosage comprises between 0.1
to 20 mg of the ASBTI.
13. The method of claim 1, wherein the pediatric cholestatic liver
disease is progressive familial intrahepatic cholestasis (PFIC),
PFIC type 1, PFIC type 2, PFIC type 3, Alagille syndrome,
Dubin-Johnson Syndrome, biliary atresia, post-Kasai biliary
atresia, post-liver transplantation biliary atresia, post-liver
transplantation cholestasis, post-liver transplantation associated
liver disease, intestinal failure associated liver disease, bile
acid mediated liver injury, pediatric primary sclerosing
cholangitis, MRP2 deficiency syndrome, neonatal sclerosing
cholangitis, a pediatric obstructive cholestasis, a pediatric
non-obstructive cholestasis, a pediatric extrahepatic cholestasis,
a pediatric intrahepatic cholestasis, a pediatric primary
intrahepatic cholestasis, a pediatric secondary intrahepatic
cholestasis, benign recurrent intrahepatic cholestasis (BRIC), BRIC
type 1, BRIC type 2, BRIC type 3, total parenteral nutrition
associated cholestasis, paraneoplastic cholestasis, Stauffer
syndrome, drug-associated cholestasis, infection-associated
cholestasis, or gallstone disease.
14. The method of claim 1, wherein the pediatric cholestatic liver
disease is characterized by one or more symptoms selected from
jaundice, pruritis, cirrhosis, hypercholemia, neonatal respiratory
distress syndrome, lung pneumonia, increased serum concentration of
bile acids, increased hepatic concentration of bile acids,
increased serum concentration of bilirubin, hepatocellular injury,
liver scarring, liver failure, hepatomegaly, xanthomas,
malabsorption, splenomegaly, diarrhea, pancreatitis, hepatocellular
necrosis, giant cell formation, hepatocellular carcinoma,
gastrointestinal bleeding, portal hypertension, hearing loss,
fatigue, loss of appetite, anorexia, peculiar smell, dark urine,
light stools, steatorrhea, failure to thrive, and renal
failure.
15. The method of claim 1, wherein the pediatric patient is between
6 months to 12 years old.
16. The method of claim 1, wherein less than 10% of the ASBTI is
systemically absorbed.
17. The method of claim 1, wherein the ASBTI is a compound of
Formula II: ##STR00072## wherein: q is an integer from 1 to 4; n is
an integer from 0 to 2; R.sup.1 and R.sup.2 are independently
selected from the group consisting of H, alkyl, alkenyl, alkynyl,
haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino,
alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl, alkenyl,
alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl,
dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally
are substituted with one or more substituents selected from the
group consisting of OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.10R.sup.wA.sup.-, SR.sup.9,
S.sup.+R.sup.9R.sup.10A.sup.-,
P.sup.+R.sup.9R.sup.10R.sup.11A.sup.-, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, COR.sup.9CN, halogen, oxo, and
CONR.sup.9R.sup.10, wherein alkyl, alkenyl, alkynyl, alkylaryl,
alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally
have one or more carbons replaced by O, NR.sup.9,
N.sup.+R.sup.9R.sup.10A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.9A.sup.-, P.sup.+R.sup.9R.sup.10A.sup.-, or phenylene,
wherein R.sup.9, R.sup.10, and R.sup.w are independently selected
from the group consisting of H, alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, and
alkylammoniumalkyl; or R.sup.1 and R.sup.2 taken together with the
carbon to which they are attached form C.sub.3-C.sub.10 cycloalkyl;
R.sup.3 and R.sup.4 are independently selected from the group
consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl,
heterocycle, OR.sup.9, NR.sup.9R.sup.10, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, and SO.sub.3R.sup.9, wherein R.sup.9 and R.sup.10
are as defined above; or R.sup.3 and R.sup.4 together .dbd.O,
.dbd.NOR.sup.11, .dbd.S, .dbd.NNR.sup.11R.sup.12, .dbd.NR.sup.9, or
.dbd.CR.sup.11R.sup.12, wherein R.sup.11 and R.sup.12 are
independently selected from the group consisting of H, alkyl,
alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl,
heterocycle, carboxyalkyl, carboalkoxy alkyl, cyclo alkyl,
cyanoalkyl, OR.sup.9, NR.sup.9R.sup.10, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN, halogen,
oxo, and CONR.sup.9R.sup.10, wherein R.sup.9 and R.sup.10 are as
defined above, provided that both R.sup.3 and R.sup.4 cannot be OH,
NH.sub.2, and SH, or R.sup.11 and R.sup.12 together with the
nitrogen or carbon atom to which they are attached form a cyclic
ring; R.sup.5 and R.sup.6 are independently selected from the group
consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocycle, quaternary heterocycle, quarternary heteroaryl,
OR.sup.9, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9,
and -L.sub.z-K.sub.z; wherein z is 1, 2 or 3; each L is
independently a substituted or unsubstituted alkyl, a substituted
or unsubstituted heteroalkyl, a substituted or unsubstituted
alkoxy, a substituted or unsubstituted aminoalkyl group, a
substituted or unsubstituted aryl, a substituted or unsubstituted
heteroaryl, a substituted or unsubstituted cycloalkyl, or a
substituted or unsubstituted heterocycloalkyl; each K is a moiety
that prevents systemic absorption; wherein alkyl, alkenyl, alkynyl,
aryl, cycloalkyl, heterocycle, quaternary heterocycle, and
quaternary heteroaryl can be substituted with one or more
substituent groups independently selected from the group consisting
of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl,
cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle,
quaternary heteroaryl, halogen, oxo, R.sup.15, OR.sup.13,
OR.sup.13R.sup.14, NR.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13,
SO.sub.2R.sup.13, SO.sub.3R.sup.13, NR.sup.13OR.sup.14,
NR.sup.13NR.sup.14R.sup.15, NO.sub.2, CO.sub.2R.sup.13, CN, OM,
SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14, C(O)NR.sup.13R.sup.14,
C(O)OM, CR.sup.13, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, wherein: A.sup.- is a
pharmaceutically acceptable anion and M is a pharmaceutically
acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl,
polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be
further substituted with one or more substituent groups selected
from the group consisting of OR.sup.7, NR.sup.7R.sup.8,
S(O)R.sup.7, SO.sub.2R.sup.7, SO.sub.3R.sup.7, CO.sub.2R.sup.7, CN,
oxo, CONR.sup.7R.sup.8, N.sup.+R.sup.7R.sup.8R.sup.9A.sup.-, alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl,
quaternary heterocycle, quaternary heteroaryl, P(O)R.sup.7R.sup.8,
P.sup.+R.sup.7R.sup.8R.sup.9A.sup.-, and P(O)(OR.sup.7) OR.sup.8
and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether,
aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have
one or more carbons replaced by O, NR.sup.7,
N.sup.+R.sup.7R.sup.8A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.7A.sup.-, PR.sup.7, P(O)R.sup.7,
P.sup.+R.sup.7R.sup.8A.sup.-, or phenylene, and R.sup.13, R.sup.14,
and R.sup.15 are independently selected from the group consisting
of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl,
cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle,
quaternary heteroaryl, quaternary heteroarylalkyl, and -G-T-V--W,
wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and
polyalkyl optionally have one or more carbons replaced by O,
NR.sup.9, N.sup.+R.sup.9R.sup.10A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.9A.sup.-, PR, P.sup.+R.sup.9R.sup.10A.sup.-,
P(O)R.sup.9, phenylene, carbohydrate, C.sub.2-C.sub.7 polyol, amino
acid, peptide, or polypeptide, and G, T and V are each
independently a bond, --O--, --S--, --N(H)--, substituted or
unsubstituted alkyl, --O-alkyl, --N(H)-alkyl, --C(O)N(H)--,
--N(H)C(O)--, --N(H)C(O)N(H)--, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted aryl, substituted or unsubstituted arylalkyl,
substituted or unsubstituted alkenylalkyl, alkynylalkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted heterocycle, substituted or unsubstituted
carboxyalkyl, substituted or unsubstituted carboalkoxyalkyl, or
substituted or unsubstituted cycloalkyl, and W is quaternary
heterocycle, quaternary heteroaryl, quaternary heteroarylalkyl,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
P.sup.+R.sup.9R.sup.10R.sup.11A.sup.-, OS(O).sub.2OM, or
S.sup.+R.sup.9R.sup.10A.sup.-, and R.sup.13, R.sup.14 and R.sup.15
are optionally substituted with one or more groups selected from
the group consisting of sulfoalkyl, quaternary heterocycle,
quaternary heteroaryl, OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10, SO.sub.2OM, SO.sub.2NR.sup.9R.sup.10,
PO(OR.sup.16)OR.sup.17, P.sup.+R.sup.9R.sup.10R.sup.11A.sup.-,
S.sup.+R.sup.9R.sup.10A.sup.-, and C(O)OM, wherein R.sup.16 and
R.sup.17 are independently selected from the substituents
constituting R.sup.9 and M; or R.sup.14 and R.sup.15, together with
the nitrogen atom to which they are attached, form a cyclic ring;
and is selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl,
alkylammoniumalkyl, and arylalkyl; and R.sup.7 and R.sup.8 are
independently selected from the group consisting of hydrogen and
alkyl; and one or more Rx are independently selected from the group
consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl,
arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl,
polyether, quaternary heterocycle, quaternary heteroaryl,
OR.sup.13, NR.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13,
S(O).sub.2R.sup.13, SO.sub.3R.sup.13, s+R.sup.13R.sup.14A.sup.-,
NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15, NO.sub.2,
CO.sub.2R.sup.13, CN, OM, SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14,
NR.sup.14C(O)R.sup.13, C(O)NR.sup.13R.sup.14,
NR.sup.14C(O)R.sup.13, C(O)OM, COR.sup.13, OR.sup.18,
S(O).sub.nNR.sup.18, NR.sup.13R.sup.18, NR.sup.18R.sup.14,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
P.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, amino acid, peptide,
polypeptide, and carbohydrate; wherein alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl,
haloalkyl, polyether, quaternary heterocycle, and quaternary
heteroaryl can be further substituted with OR.sup.9,
NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9,
S(O).sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9,
CN, halogen, CONR.sup.9R.sup.10, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17,
P.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
S.sup.+R.sup.9R.sup.10A.sup.-, or C(O)M, wherein W is O or NH,
R.sup.31 is selected from wherein R.sup.18 is selected from the
group consisting of acyl, arylalkoxycarbonyl, arylalkyl,
heterocycle, heteroaryl, alkyl, wherein acyl, arylalkoxycarbonyl,
arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle,
and quaternary heteroaryl optionally are substituted with one or
more substituents selected from the group consisting of OR.sup.9,
NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9,
S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo,
CO.sub.3R.sup.9, CN, halogen, CONR.sup.9R.sup.10, SO.sub.3R.sup.9,
SO.sub.2OM, SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17, and
C(O)OM, wherein in R.sup.x, one or more carbons are optionally
replaced by O, NR.sup.13, N.sup.+R.sup.13R.sup.14A.sup.-, S, SO,
SO.sub.2, S.sup.+R.sup.13A.sup.-, PR.sup.13, P(O)R.sup.13,
P.sup.+R.sup.13R.sup.14A.sup.-, phenylene, amino acid, peptide,
polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said
polyalkyl, phenylene, amino acid, peptide, polypeptide, and
carbohydrate, one or more carbons are optionally replaced by O,
NR.sup.9, R.sup.9R.sup.10A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.9A.sup.-, PR.sup.9, P.sup.+R.sup.9R.sup.10A.sup.-, or
P(O)R.sup.9 wherein quaternary heterocycle and quaternary
heteroaryl are optionally substituted with one or more groups
selected from the group consisting of alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,
arylalkyl, halogen, oxo, OR.sup.13, NR.sup.13R.sup.14, SR.sup.13,
S(O)R.sup.13, SO.sub.2R.sup.13, SO.sub.3R.sup.13,
NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15, NO.sub.2,
CO.sub.2R.sup.13, CN, OM, SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14,
C(O)NR.sup.13R.sup.14, C(O)OM, COR.sup.13, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, provided that both R.sup.5
and R.sup.6 cannot be hydrogen or SH; provided that when R.sup.5 or
R.sup.6 is phenyl, only one of R.sup.1 or R.sup.2 is H; provided
that when q=1 and R.sup.x is styryl, anilido, or anilinocarbonyl,
only one of R.sup.5 or R.sup.6 is alkyl; or a pharmaceutically
acceptable salt, solvate, or prodrug thereof.
18. The method of claim 17, wherein: q is 1; n is 2; R.sup.x is
N(CH.sub.3).sub.2; R.sup.7 and R.sup.8 are independently H; R.sup.1
and R.sup.2 is alkyl; R.sup.3 is H, and R.sup.4 is OH; R.sup.5 is
H, and R.sup.6 is selected from the group consisting of alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary
heterocycle, quarternary heteroaryl, OR.sup.9, SR.sup.9,
S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, and
-L.sub.z-K.sub.z; wherein z is 1, 2 or 3; each L is independently a
substituted or unsubstituted alkyl, a substituted or unsubstituted
heteroalkyl, a substituted or unsubstituted alkoxy, a substituted
or unsubstituted aminoalkyl group, a substituted or unsubstituted
aryl, a substituted or unsubstituted heteroaryl, a substituted or
unsubstituted cycloalkyl, or a substituted or unsubstituted
heterocycloalkyl; each K is a moiety that prevents systemic
absorption; wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocycle, quaternary heterocycle, and quaternary heteroaryl can
be substituted with one or more substituent groups independently
selected from the group consisting of alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,
arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen,
oxo, R.sup.15, OR.sup.13, OR.sup.13R.sup.14, NR.sup.13R.sup.14,
SR.sup.13, S(O)R.sup.13, SO.sub.2R.sup.13, SO.sub.3R.sup.13,
NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15, NO.sub.2,
CO.sub.2R.sup.13, CN, OM, SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14,
C(O)NR.sup.13R.sup.14, C(O)OM, CR.sup.13, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, wherein A.sup.- is a
pharmaceutically acceptable anion and M is a pharmaceutically
acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl,
polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be
further substituted with one or more substituent groups selected
from the group consisting of OR.sup.7, NR.sup.7R.sup.8,
S(O)R.sup.7, SO.sub.2R.sup.7, SO.sub.3R.sup.7, CO.sub.2R.sup.7, CN,
oxo, CONR.sup.7R.sup.8, N.sup.+R.sup.7R.sup.8R.sup.9A.sup.-, alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl,
quaternary heterocycle, quaternary heteroaryl, P(O)R.sup.7R.sup.8,
P.sup.+R.sup.7R.sup.8R.sup.9A.sup.-, and P(O)(OR.sup.7)OR.sup.8 and
wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,
haloalkyl, cycloalkyl, and heterocycle can optionally have one or
more carbons replaced by O, NR.sup.7, N.sup.+R.sup.7R.sup.8A.sup.-,
S, SO, SO.sub.2, S.sup.+R.sup.7A.sup.-, PR.sup.7, P(O)R.sup.7,
P.sup.+R.sup.7R.sup.8A.sup.-, or phenylene, and R.sup.13, R.sup.14,
and R.sup.15 are independently selected from the group consisting
of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl,
cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle,
quaternary heteroaryl, quaternary heteroarylalkyl, and -G-T-V--W,
wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and
polyalkyl optionally have one or more carbons replaced by O,
NR.sup.9, N.sup.+R.sup.9R.sup.10A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.9A.sup.-, PR, P.sup.+R.sup.9R.sup.10A.sup.-,
P(O)R.sup.9, phenylene, carbohydrate, C.sub.2-C.sub.7 polyol, amino
acid, peptide, or polypeptide, and G, T and V are each
independently a bond, --O--, --S--, --N(H)--, substituted or
unsubstituted alkyl, --O-alkyl, --N(H)-alkyl, --C(O)N(H)--,
--N(H)C(O)--, --N(H)C(O)N(H)--, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted aryl, substituted or unsubstituted arylalkyl,
substituted or unsubstituted alkenylalkyl, alkynylalkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted heterocycle, substituted or unsubstituted
carboxyalkyl, substituted or unsubstituted carboalkoxyalkyl, or
substituted or unsubstituted cycloalkyl, and W is quaternary
heterocycle, quaternary heteroaryl, quaternary heteroarylalkyl,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
P.sup.+R.sup.9R.sup.10R.sup.11A.sup.-, OS(O).sub.2OM, or
S.sup.+R.sup.9R.sup.10A.sup.-, and R.sup.9 and R.sup.10 are
independently selected from the group consisting of H, alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle,
ammoniumalkyl, arylalkyl, and alkylammoniumalkyl; R.sup.11 and
R.sup.12 are independently selected from the group consisting of H,
alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl,
alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cyclo
alkyl, cyanoalkyl, OR.sup.9, NR.sup.9R.sup.10, SR.sup.9,
S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN,
halogen, oxo, and CONR.sup.9R.sup.10, wherein R.sup.9 and R.sup.10
are as defined above, provided that both R.sup.3 and R.sup.4 cannot
be OH, NH.sub.2, and SH, or R.sup.11 and R.sup.12 together with the
nitrogen or carbon atom to which they are attached form a cyclic
ring; R.sup.13, R.sup.14 and R.sup.15 are optionally substituted
with one or more groups selected from the group consisting of
sulfoalkyl, quaternary heterocycle, quaternary heteroaryl,
OR.sup.9, NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
SR.sup.9, S(O) R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo,
CO.sub.2R.sup.9, CN, halogen, CONR.sup.9R.sup.10, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17,
P.sup.+R.sup.9R.sup.10R.sup.11A.sup.-,
S.sup.+R.sup.9R.sup.10A.sup.-, and C(O)OM, wherein R.sup.16 and
R.sup.17 are independently selected from the substituents
constituting R.sup.9 and M; or R.sup.14 and R.sup.15, together with
the nitrogen atom to which they are attached, form a cyclic ring;
and is selected from the group consisting of alkyl, alkenyl,
alkynyl, cyclo alkyl, aryl, acyl, heterocycle, ammoniumalkyl,
alkylammoniumalkyl, and arylalkyl; or a pharmaceutically acceptable
salt, solvate, or prodrug thereof.
19. The method of claim 17, wherein the compound of Formula II is
##STR00073##
20. The method of claim 17, wherein the compound of Formula II is
##STR00074##
21. The method of claim 17, wherein the compound of Formula II is
##STR00075##
22. The method of claim 1, wherein the ASBTI is a compound of
Formula I: ##STR00076## wherein: R.sup.1 is a straight chained
C.sub.1-6 alkyl group; R.sup.2 is a straight chained C.sub.1-6
alkyl group; R.sup.3 is hydrogen or a group OR.sup.11 in which
R.sup.11 is hydrogen, optionally substituted C.sub.1-6 alkyl or a
C.sub.1-6 alkylcarbonyl group; R.sup.4 is pyridyl or optionally
substituted phenyl or -L.sub.z-K.sub.z; wherein z is 1, 2 or 3;
each L is independently a substituted or unsubstituted alkyl, a
substituted or unsubstituted heteroalkyl, a substituted or
unsubstituted alkoxy, a substituted or unsubstituted aminoalkyl
group, a substituted or unsubstituted aryl, a substituted or
unsubstituted heteroaryl, a substituted or unsubstituted
cycloalkyl, or a substituted or unsubstituted heterocycloalkyl;
each K is a moiety that prevents systemic absorption; R.sup.5,
R.sup.6, R.sup.7 and R.sup.8 are the same or different and each is
selected from hydrogen, halogen, cyano, R.sup.5-acetylide,
OR.sup.15, optionally substituted C.sub.1-6 alkyl, COR.sup.15,
CH(OH)R.sup.15, S(O).sub.nR.sup.15, P(O)(OR.sup.15).sub.2,
OCOR.sup.15, OCF3, OCN, SCN, NHCN, CH.sub.2OR.sup.15, CHO,
(CH.sub.2).sub.pCN, CONR.sup.12R.sup.13,
(CH.sub.2).sub.pCO.sub.2R.sup.15,
(CH.sub.2).sub.pNR.sup.12R.sup.13, CO.sub.2R.sup.15, NHCOCF.sub.3,
NHSO.sub.2R.sup.15, OCH.sub.2OR.sup.15, OCH.dbd.CHR.sup.15,
O(CH.sub.2CH.sub.2O).sub.nR.sup.15,
O(CH.sub.2).sub.pSO.sub.3R.sup.15,
O(CH.sub.2).sub.pNR.sup.12R.sup.13,
P(CH.sub.2).sub.pN.sup.+R.sup.12R.sup.13R.sup.14 and --W--R.sup.31,
wherein W is O or NH, and R.sup.31 is selected from ##STR00077##
wherein p is an integer from 1-4, n is an integer from 0-3 and,
R.sup.12, R.sup.13, R.sup.14 and R.sup.15 are independently
selected from hydrogen and optionally substituted C.sub.1-6 alkyl;
or R.sup.6 and R.sup.7 are linked to form a group ##STR00078##
wherein R.sup.12 and R.sup.13 are as hereinbefore defined and m is
1 or 2; and R.sup.9 and R.sup.10 are the same or different and each
is selected from hydrogen or C.sub.1-6 alkyl; and salts, solvates
and physiologically functional derivatives thereof.
23. The method of claim 22, wherein the compound of Formula I is
##STR00079##
24. The method of claim 1, wherein the ASBTI is a compound of
Formula III: ##STR00080## wherein: each R.sup.1, R.sup.2 is
independently H, hydroxy, alkyl, alkoxy, --C(.dbd.X)YR.sup.8,
--YC(.dbd.X)R.sup.8, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted alkyl-aryl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted alkyl-cycloalkyl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted alkyl-heteroaryl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted alkyl-heterocycloalkyl, or -L-K; or R.sup.1 and
R.sup.2 together with the nitrogen to which they are attached form
a 3-8-membered ring that is optionally substituted with R.sup.8;
each R.sup.3, R.sup.4 is independently H, hydroxy, alkyl, alkoxy,
--C(.dbd.X)YR.sup.8, --YC(.dbd.X)R.sup.8, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted alkyl-cycloalkyl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted alkyl-heteroaryl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted alkyl-heterocycloalkyl, or -L-K; R.sup.5 is H,
hydroxy, alkyl, alkoxy, --C(.dbd.X)YR.sup.8, --YC(.dbd.X)R.sup.8,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted alkyl-cycloalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
alkyl-heteroaryl, substituted or unsubstituted heterocycloalkyl,
substituted or unsubstituted alkyl-heterocycloalkyl, each R.sup.6,
R.sup.7 is independently H, hydroxy, alkyl, alkoxy,
--C(.dbd.X)YR.sup.8, --YC(.dbd.X)R.sup.8, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted alkyl-cycloalkyl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted alkyl-heteroaryl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted alkyl-heterocycloalkyl, or -L-K; or R.sup.6 and
R.sup.7 taken together form a bond; each X is independently NH, S,
or O; each Y is independently NH, S, or O; R.sup.8 is substituted
or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted alkyl-cycloalkyl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted alkyl-heteroaryl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted alkyl-heterocycloalkyl, or -L-K; L is A.sub.n,
wherein each A is independently NR.sup.1, S(O).sub.m, O,
C(.dbd.X)Y, Y(C.dbd.X), substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted cycloalkyl, or substituted or
unsubstituted heterocycloalkyl; wherein each m is independently
0-2; n is 0-7; K is a moiety that prevents systemic absorption;
provided that at least one of R.sup.1, R.sup.2, R.sup.3 or R.sup.4
is -L-K; or a pharmaceutically acceptable prodrug thereof.
25. The method of claim 1, wherein the ASBTI is a compound of
Formula IV: ##STR00081## wherein R.sup.1 is a straight chain
C.sub.1-6 alkyl group; R.sup.2 is a straight chain C.sub.1-6 alkyl
group; R.sup.3 is hydrogen or a group OR.sup.11 in which R.sup.11
is hydrogen, optionally substituted C.sub.1-6 alkyl or a C.sub.1-6
alkylcarbonyl group; R.sup.4 is pyridyl or an optionally
substituted phenyl; R.sup.5, R.sup.6 and R.sup.8 are the same or
different and each is selected from: hydrogen, halogen, cyano,
R.sup.15-acetylide, OR.sup.15, optionally substituted C.sub.1-6
alkyl, COR.sup.15, CH(OH)R.sup.15, S(O).sub.pR.sup.15,
P(O)(OR.sup.15).sub.2, OCOR.sup.15, OCF.sub.3, OCN, SCN, NHCN,
CH.sub.2OR.sup.15, CHO, (CH.sub.2).sub.pCN, CONR.sup.12R.sup.13,
(CH.sub.2).sub.pCO.sub.2R.sup.15,
(CH.sub.2).sub.pNR.sup.12R.sup.13, CO.sub.2R.sup.15, NHCOCF.sub.3,
NHSO.sub.2R.sup.15, OCH.sub.2OR.sup.15, OCH.dbd.CHR.sup.15,
O(CH.sub.2CH.sub.2O).sub.nR.sup.15,
O(CH.sub.2).sub.pSO.sub.3R.sup.15,
O(CH.sub.2).sub.pNR.sup.12R.sup.13 and
O(CH.sub.2).sub.pN.sup.+R.sup.12R.sup.13R.sup.14 wherein p is an
integer from 1-4, n is an integer from 0-3 and R.sup.12, R.sup.13,
R.sup.14 and R.sup.15 are independently selected from hydrogen and
optionally substituted C.sub.1-6 alkyl; R.sup.7 is a group of the
formula ##STR00082## wherein the hydroxyl groups may be substituted
by acetyl, benzyl, or --(C.sub.1-C.sub.6)-alkyl-R.sup.17, wherein
the alkyl group may be substituted with one or more hydroxyl
groups; R.sup.16 is --COOH, --CH.sub.2--OH, --CH.sub.2--O-Acetyl,
--COOMe or --COOEt; R.sup.17 is H, --OH, --NH.sub.2, --COOH or
COOR.sup.18; R.sup.18 is (C.sub.1-C.sub.4)-alkyl or
--NH--(C.sub.1-C.sub.4)-alkyl; X is --NH-- or --O--; and R.sup.9
and R.sup.10 are the same or different and each is hydrogen or
C.sub.1-C.sub.6 alkyl; and salts thereof.
26. The method of claim 1, wherein the ASBTI is a compound of
Formula V: ##STR00083## wherein: R.sup.v is selected from hydrogen
or C.sub.1-6alkyl; One of R.sup.1 and R.sup.2 are selected from
hydrogen or C.sub.1-6alkyl and the other is selected from
C.sub.1-6alkyl; R.sup.x and R.sup.y are independently selected from
hydrogen, hydroxy, amino, mercapto, C.sub.1-6alkyl,
C.sub.1-6alkoxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkylS(O).sub.a wherein
a is 0 to 2; R.sup.z is selected from halo, nitro, cyano, hydroxy,
amino, carboxy, carbamoyl, mercapto, sulphamoyl, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkoxy,
C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl).sub.2carbamoyl,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N--(C.sub.1-6-alkyl)sulphamoyl and
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl; n is 0-5; one of R.sup.4 and
R.sup.5 is a group of formula (VA): ##STR00084## R.sup.3 and
R.sup.6 and the other of R.sup.4 and R.sup.5 are independently
selected from hydrogen, halo, nitro, cyano, hydroxy, amino,
carboxy, carbamoyl, mercapto, sulphamoyl, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkoxy,
C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl).sub.2carbamoyl,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N--(C.sub.1-6alkyl)sulphamoyl and
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl; wherein R.sup.3 and R.sup.6
and the other of R.sup.4 and R.sup.5 may be optionally substituted
on carbon by one or more R.sup.17; X is --O--, --N(R.sup.a)--,
--S(O).sub.b-- or --CH(R.sup.a)--; wherein R.sup.a is hydrogen or
C.sub.1-6alkyl and b is 0-2; Ring A is aryl or heteroaryl; wherein
Ring A is optionally substituted on carbon by one or more
substituents selected from R.sup.18; R.sup.7 is hydrogen,
C.sub.1-6alkyl, carbocyclyl or heterocyclyl; wherein R.sup.7 is
optionally substituted on carbon by one or more substituents
selected from R.sup.19; and wherein if said heterocyclyl contains
an NH group, that nitrogen may be optionally substituted by a group
selected from R.sup.20; R.sup.8 is hydrogen or C.sub.1-6-alkyl;
R.sup.9 is hydrogen or C.sub.1-6alkyl; R.sup.10 is hydrogen, halo,
nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl,
hydroxyaminocarbonyl, C.sub.1-10alkyl, C.sub.2-10alkynyl,
C.sub.2-10alkynyl, C.sub.1-10alkoxy, C.sub.1-10alkanoyl,
C.sub.1-10alkanoyloxy, N--(C.sub.1-10alkyl)amino,
N,N--(C.sub.1-10alkyl).sub.2amino, N,N,N--(C.sub.1-10alkyl).sub.3
ammonio, C.sub.1-10alkanoylamino, N--(C.sub.1-10alkyl)carbamoyl,
N,N--(C.sub.1-10alkyl).sub.2carbamoyl, C.sub.1-10alkylS(O).sub.a
wherein a is 0 to 2, N--(C.sub.1-10alkyl)sulphamoyl,
N,N--(C.sub.1-10alkyl).sub.2sulphamoyl,
N--(C.sub.1-10alkyl)sulphamoylamino, N,N--(C.sub.1-10alkyl).sub.2
sulphamoylamino, C.sub.1-10alkoxycarbonylamino, carbocyclyl,
carbocyclylC.sub.1-10alkyl, heterocyclyl,
heterocyclylC.sub.1-10alkyl,
carbocyclyl-(C.sub.1-10alkylene).sub.p-R.sup.21--(C.sub.1-10alkylene).sub-
.q- or
heterocyclyl-(C.sub.1-10alkylene).sub.r--R.sup.22--(C.sub.1-10alkyl-
ene).sub.s-; wherein R.sup.10 is optionally substituted on carbon
by one or more substituents selected from R.sup.23; and wherein if
said heterocyclyl contains an --NH-- group, that nitrogen may be
optionally substituted by a group selected from R.sup.24; or
R.sup.10 is a group of formula (VB): ##STR00085## wherein: R.sup.11
is hydrogen or C.sub.1-6-alkyl; R.sup.12 and R.sup.13 are
independently selected from hydrogen, halo, carbamoyl, sulphamoyl,
C.sub.1-10alkyl, C.sub.2-10alkynyl, C.sub.2-10alkynyl,
C.sub.1-10alkanoyl, N--(C.sub.1-10alkyl)carbamoyl,
N,N--(C.sub.1-10alkyl).sub.2carbamoyl, C.sub.1-10alkylS(O).sub.a
wherein a is 0 to 2, N--(C.sub.1-10alkyl)sulphamoyl,
N,N--(C.sub.1-10alkyl).sub.2sulphamoyl,
N--(C.sub.1-10alkyl)sulphamoylamino,
N,N--(C.sub.1-10alkyl).sub.2sulphamoylamino, carbocyclyl or
heterocyclyl; wherein R.sup.12 and R.sup.13 may be independently
optionally substituted on carbon by one or more substituents
selected from R.sup.25; and wherein if said heterocyclyl contains
an --NH-- group, that nitrogen may be optionally substituted by a
group selected from R.sup.26; R.sup.14 is selected from hydrogen,
halo, carbamoyl, sulphamoyl, hydroxyaminocarbonyl, C.sub.1-10alkyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl, C.sub.1-10alkanoyl,
N--(C.sub.1-10alkyl)carbamoyl,
N,N--(C.sub.1-10alkyl).sub.2carbamoyl, C.sub.1-10alkylS(O).sub.a
wherein a is 0 to 2, N--(C.sub.1-10alkyl)sulphamoyl,
N,N--(C.sub.1-10alkyl).sub.2sulphamoyl,
N--(C.sub.1-10alkyl)sulphamoylamino,
N,N--(C.sub.1-10alkyl).sub.2sulphamoylamino, carbocyclyl,
carbocyclylC.sub.1-10alkyl, heterocyclyl,
heterocyclylC.sub.1-10alkyl,
carbocyclyl-(C.sub.1-10alkylene).sub.p-R.sup.27--(C.sub.1-10alkylene).sub-
.q- or heterocyclyl-(C.sub.1-10alkylene),
--R.sup.28--(C.sub.1-10alkylene).sub.a-; wherein R.sup.14 may be
optionally substituted on carbon by one or more substituents
selected from R.sup.29; and wherein if said heterocyclyl contains
an --NH-- group, that nitrogen may be optionally substituted by a
group selected from R.sup.30; or R.sup.14 is a group of formula
(VC): ##STR00086## R.sup.15 is hydrogen or C.sub.1-6alkyl; and
R.sup.16 is hydrogen or C.sub.1-6alkyl; wherein R.sup.16 may be
optionally substituted on carbon by one or more groups selected
from R.sup.31; or R.sup.15 and R.sup.16 together with the nitrogen
to which they are attached form a heterocyclyl; wherein said
heterocyclyl may be optionally substituted on carbon by one or more
R.sup.37; and wherein if said heterocyclyl contains an --NH--
group, that nitrogen may be optionally substituted by a group
selected from R.sup.38; m is 1-3; wherein the values of R.sup.7 may
be the same or different; R.sup.17, R.sup.18, R.sup.19, R.sup.23,
R.sup.25, R.sup.29, R.sup.31 and R.sup.37 are independently
selected from halo, nitro, cyano, hydroxy, amino, carbamoyl,
mercapto, sulphamoyl, hydroxyaminocarbonyl, C.sub.1-10alkyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl, C.sub.1-10alkoxy,
C.sub.1-10alkanoyl, C.sub.1-10alkanoyloxy,
N--(C.sub.1-10alkyl)amino, N,N--(C.sub.1-10alkyl).sub.2amino,
N,N,N--(C.sub.1-10alkyl).sub.3 ammonio, C.sub.1-10alkanoylamino,
N--(C.sub.1-10alkyl)carbamoyl,
N,N--(C.sub.1-10alkyl).sub.2carbamoyl, C.sub.1-10alkylS(O).sub.a
wherein a is 0 to 2, N--(C.sub.1-10alkyl)sulphamoyl,
N,N--(C.sub.1-10alkyl).sub.2sulphamoyl, N--(C.sub.1-10alkyl)
sulphamoylamino, N,N--(C.sub.1-10alkyl).sub.2sulphamoylamino,
C.sub.1-10alkoxycarbonylamino, carbocyclyl,
carbocyclylC.sub.1-10alkyl, heterocyclyl,
heterocyclylC.sub.1-10alkyl, carb
ocyclyl-(C.sub.1-10alkylene).sub.p-R.sup.32--(C.sub.1-10alkylene).sub.q-
or heterocyclyl-(C.sub.1-10alkylene),
--R.sup.33--(C.sub.1-10alkylene).sub.s-; wherein R.sup.17,
R.sup.18, R.sup.19, R.sup.23, R.sup.25, R.sup.29, R.sup.31 and
R.sup.37 may be independently optionally substituted on carbon by
one or more R.sup.34; and wherein if said heterocyclyl contains an
--NH-- group, that nitrogen may be optionally substituted by a
group selected from R.sup.35; R.sup.21, R.sup.22, R.sup.27,
R.sup.28, R.sup.32 or R.sup.33 are independently selected from
--O--, --NR.sup.36--, --S(O).sub.x--, --NR.sup.36C(O)NR.sup.36--,
--NR.sup.36C(S)NR.sup.36--, --OC(O)N.dbd.C--, --NR.sup.36C(O)-- or
--C(O)NR.sup.36--; wherein R.sup.36 is selected from hydrogen or
C.sub.1-6alkyl, and x is 0-2; p, q, r and s are independently
selected from 0-2; R.sup.34 is selected from halo, hydroxy, cyano,
carbamoyl, ureido, amino, nitro, carbamoyl, mercapto, sulphamoyl,
trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy,
vinyl, allyl, ethynyl, formyl, acetyl, formamido, acetylamino,
acetoxy, methylamino, dimethylamino, N-methylcarbamoyl,
N,N-dimethylcarbamoyl, methylthio, methylsulphinyl, mesyl,
N-methylsulphamoyl, N,N-dimethylsulphamoyl, N-methylsulphamoylamino
and N,N-dimethylsulphamoylamino; R.sup.20, R.sup.24, R.sup.26,
R.sup.30, R.sup.35 and R.sup.38 are independently selected from
C.sub.1-6alkyl, C.sub.1-6alkanoyl, C.sub.1-6alkylsulphonyl,
C.sub.1-6alkoxycarbonyl, carbamoyl, N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl
and phenylsulphonyl; and wherein a "heteroaryl" is a totally
unsaturated, mono or bicyclic ring containing 3-12 atoms of which
at least one atom is chosen from nitrogen, sulphur and oxygen,
which heteroaryl may, unless otherwise specified, be carbon or
nitrogen linked; wherein a "heterocyclyl" is a saturated, partially
saturated or unsaturated, mono or bicyclic ring containing 3-12
atoms of which at least one atom is chosen from nitrogen, sulphur
and oxygen, which heterocyclyl may, unless otherwise specified, be
carbon or nitrogen linked, wherein a CH.sub.2-- group can
optionally be replaced by a --C(O)-- group, and a ring sulphur atom
may be optionally oxidised to form an S-oxide; and wherein a
"carbocyclyl" is a saturated, partially saturated or unsaturated,
mono or bicyclic carbon ring that contains 3-12 atoms; wherein a
--CH.sub.2-- group can optionally be replaced by a --C(O) group; or
a pharmaceutically acceptable salt or in vivo hydrolysable ester or
amide formed on an available carboxy or hydroxy group thereof.
27. The method of claim 26, wherein the compound of Formula V is
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((R)-1--
carboxy-2-methylthioethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3-
,4,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((S)-1--
carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2-
,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((S)-1--
carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,-
5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((S)-1--
carboxybutyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahyd-
ro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((S)-1--
carboxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5--
benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((S)-1--
carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-b-
enzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((S)-1--
carboxy-2-(R)-hydroxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tet-
rahydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N-(2-sulph-
oethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2-
,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((S)-1--
carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahyd-
ro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((R)-1--
carboxy-2-methylthioethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetra-
hydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N-{(S)-1-[-
N--((S)-2-hydroxy-1-carboxyethyl)carbamoyl]propyl}carbamoyl]benzyl}carbamo-
ylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((S)-1--
carboxy-2-methylpropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahyd-
ro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((S)-1--
carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahy-
dro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-{(R)-.alpha.-carboxy-4-h-
ydroxybenzyl}carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-
; or
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N-(car-
boxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-ben-
zothiadiazepine; or a pharmaceutically acceptable salt thereof.
28. The method of claim 1, wherein the ASBTI is a compound of
Formula VI: ##STR00087## wherein: R.sup.v and R.sup.w are
independently selected from hydrogen or C.sub.1-6alkyl; one of
R.sup.1 and R.sup.2 is selected from hydrogen or C.sub.1-6alkyl and
the other is selected from C.sub.1-6alkyl; R.sup.x and R.sup.y are
independently selected from hydrogen or C.sub.1-6alkyl, or one of
R.sup.x and R.sup.y is hydrogen or C.sub.1-6alkyl and the other is
hydroxy or C.sub.1-6alkoxy; R.sup.z is selected from halo, nitro,
cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkoxy, C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy,
N--(C.sub.1-6alkyl)amino, N,N--(C.sub.1-6alkyl).sub.2amino,
C.sub.1-6alkanoylamino, N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl).sub.2carbamoyl, C.sub.1-6 alkylS(O).sub.a
wherein a is 0 to 2, C.sub.1-6alkoxycarbonyl,
N--(C.sub.1-6alkyl)sulphamoyl and
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl; n is 0-5; one of R.sup.4 and
R.sup.5 is a group of formula (VIA): ##STR00088## R.sup.3 and
R.sup.6 and the other of R.sup.4 and R.sup.5 are independently
selected from hydrogen, halo, nitro, cyano, hydroxy, amino,
carboxy, carbamoyl, mercapto, sulphamoyl, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkoxy,
C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl).sub.2carbamoyl,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N--(C.sub.1-6alkyl)sulphamoyl and
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl; wherein R.sup.3 and R.sup.6
and the other of R.sup.4 and R.sup.5 may be optionally substituted
on carbon by one or more R.sup.17; X is --O--, --N(R.sup.a)--,
--S(O).sub.b-- or --CH(R.sup.a)--; wherein R.sup.a is hydrogen or
C.sub.1-6alkyl and b is 0-2; Ring A is aryl or heteroaryl; wherein
Ring A is optionally substituted on carbon by one or more
substituents selected from R.sup.18; R.sup.7 is hydrogen,
C.sub.1-6alkyl, carbocyclyl or heterocyclyl; wherein R.sup.7 is
optionally substituted on carbon by one or more substituents
selected from R.sup.19; and wherein if said heterocyclyl contains
an NH group, that nitrogen may be optionally substituted by a group
selected from R.sup.20; R.sup.8 is hydrogen or C.sub.1-6alkyl;
R.sup.9 is hydrogen or C.sub.1-6alkyl; R.sup.10 is hydrogen, halo,
nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl,
hydroxyaminocarbonyl, C.sub.1-10alkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, C.sub.1-10alkoxy, C.sub.1-10alkanoyl,
C.sub.1-10alkanoyloxy, N--(C.sub.1-10alkyl)amino,
N,N--(C.sub.1-10alkyl).sub.2amino, N,N,N--(C.sub.1-10alkyl).sub.3
ammonio, C.sub.1-10alkanoylamino, N--(C.sub.1-10alkyl)carbamoyl,
N,N--(C.sub.1-10alkyl).sub.2carbamoyl, C.sub.1-10alkylS(O).sub.a
wherein a is 0 to 2, N--(C.sub.1-10alkyl)sulphamoyl,
N,N--(C.sub.1-10alkyl).sub.2sulphamoyl,
N--(C.sub.1-10alkyl)sulphamoylamino, N,N--(C.sub.1-10alkyl).sub.2
sulphamoylamino, C.sub.1-10alkoxycarbonylamino, carbocyclyl,
carbocyclylC.sub.1-10alkyl, heterocyclyl,
heterocyclylC.sub.1-10alkyl,
carbocyclyl-(C.sub.1-10alkylene).sub.p-R.sup.21--(C.sub.1-10alkylene).sub-
.q- or
heterocyclyl-(C.sub.1-10alkylene).sub.r--R.sup.22--(C.sub.1-10alkyl-
ene).sub.s-; wherein R.sup.10 is optionally substituted on carbon
by one or more substituents selected from R.sup.23; and wherein if
said heterocyclyl contains an --NH-- group, that nitrogen may be
optionally substituted by a group selected from R.sup.24; or
R.sup.10 is a group of formula (VIB): ##STR00089## wherein:
R.sup.11 is hydrogen or C.sub.1-6alkyl; R.sup.12 and R.sup.13 are
independently selected from hydrogen, halo, nitro, cyano, hydroxy,
amino, carbamoyl, mercapto, sulphamoyl, C.sub.1-10alkyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl, C.sub.1-10alkoxy,
C.sub.1-10alkanoyl, C.sub.1-10alkanoyloxy,
N--(C.sub.1-10alkyl)amino, N,N--(C.sub.1-10alkyl).sub.2amino,
C.sub.1-10alkanoylamino, N--(C.sub.1-10alkyl)carbamoyl,
N,N--(C.sub.1-10alkyl).sub.2carbamoyl, C.sub.1-10alkylS(O).sub.a
wherein a is 0 to 2, N--(C.sub.1-10alkyl)sulphamoyl,
N,N--(C.sub.1-10alkyl).sub.2 sulphamoyl,
N--(C.sub.1-10alkyl)sulphamoylamino,
N,N--(C.sub.1-10alkyl).sub.2sulphamoylamino, carbocyclyl or
heterocyclyl; wherein R.sup.12 and R.sup.13 may be independently
optionally substituted on carbon by one or more substituents
selected from R.sup.25; and wherein if said heterocyclyl contains
an --NH-- group, that nitrogen may be optionally substituted by a
group selected from R.sup.26; R.sup.14 is selected from hydrogen,
halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto,
sulphamoyl, hydroxyaminocarbonyl, C.sub.1-10alkyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl, C.sub.1-10alkoxy,
C.sub.1-10alkanoyl, C.sub.1-10alkanoyloxy,
N--(C.sub.1-10alkyl)amino, N,N--(C.sub.1-10alkyl).sub.2amino,
N,N,N--(C.sub.1-10alkyl).sub.3 ammonio, C.sub.1-10alkanoylamino,
N--(C.sub.1-10alkyl)carbamoyl,
N,N--(C.sub.1-10alkyl).sub.2carbamoyl, C.sub.1-10alkylS(O).sub.a
wherein a is 0 to 2, N--(C.sub.1-10alkyl)sulphamoyl,
N,N--(C.sub.1-10alkyl).sub.2sulphamoyl,
N--(C.sub.1-10alkyl)sulphamoylamino,
N,N--(C.sub.1-10alkyl).sub.2sulphamoylamino,
C.sub.1-10alkoxycarbonylamino, carbocyclyl,
carbocyclylC.sub.1-10alkyl, heterocyclyl,
heterocyclylC.sub.1-10alkyl,
carbocyclyl-(C.sub.1-10alkylene).sub.p-R.sup.27--(C.sub.1-10alkylene).sub-
.q- or
heterocyclyl-(C.sub.1-10alkylene).sub.r--R.sup.28--(C.sub.1-10alkyl-
ene).sub.s-; wherein R.sup.14 may be optionally substituted on
carbon by one or more substituents selected from R.sup.29; and
wherein if said heterocyclyl contains an --NH-- group, that
nitrogen may be optionally substituted by a group selected from
R.sup.30; or R.sup.14 is a group of formula (VIC): ##STR00090##
R.sup.15 is hydrogen or C.sub.1-6alkyl; R.sup.16 is hydrogen or
C.sub.1-6alkyl; wherein R.sup.16 may be optionally substituted on
carbon by one or more groups selected from R.sup.31; n is 1-3;
wherein the values of R.sup.7 may be the same or different;
R.sup.17, R.sup.18, R.sup.19, R.sup.23, R.sup.25, R.sup.29 or
R.sup.31 are independently selected from halo, nitro, cyano,
hydroxy, amino, carbamoyl, mercapto, sulphamoyl,
hydroxyaminocarbonyl, amidino, C.sub.1-10alkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, C.sub.1-10alkoxy, C.sub.1-10alkanoyl,
C.sub.1-10alkanoyloxy, (C.sub.1-10alkyl).sub.3silyl,
N--(C.sub.1-10alkyl)amino, N,N--(C.sub.1-10alkyl).sub.2amino,
N,N,N--(C.sub.1-10alkyl).sub.3ammonio, C.sub.1-10alkanoylamino,
N--(C.sub.1-10alkyl)carbamoyl,
N,N--(C.sub.1-10alkyl).sub.2carbamoyl, C.sub.1-10alkylS(O).sub.a
wherein a is 0 to 2, N--(C.sub.1-10alkyl)sulphamoyl,
N,N--(C.sub.1-10alkyl).sub.2sulphamoyl,
N--(C.sub.1-10alkyl)sulphamoylamino,
N,N--(C.sub.1-10alkyl).sub.2sulphamoylamino,
C.sub.1-10alkoxycarbonylamino, carbocyclyl,
carbocyclylC.sub.1-10alkyl, heterocyclyl,
heterocyclylC.sub.1-10alkyl,
carbocyclyl-(C.sub.1-10alkylene).sub.p-R.sup.32--(C.sub.1-10alkylene).sub-
.q- or heterocyclyl-(C.sub.1-10alkylene),
--R.sup.33--(C.sub.1-10alkylene).sub.s-; wherein R.sup.17,
R.sup.18, R.sup.19, R.sup.23, R.sup.25, R.sup.29 or R.sup.31 may be
independently optionally substituted on carbon by one or more
R.sup.34; and wherein if said heterocyclyl contains an --NH--
group, that nitrogen may be optionally substituted by a group
selected from R.sup.35; R.sup.21, R.sup.22, R.sup.27, R.sup.28,
R.sup.32 or R.sup.33 are independently selected from --O--,
--NR.sup.36--, --S(O).sub.x, --NR.sup.36C(O)NR.sup.36--,
--NR.sup.36C(S)NR.sup.36--, --OC(O)N.dbd.C, --NR.sup.36C(O)-- or
--C(O)NR.sup.36--; wherein R.sup.36 is selected from hydrogen or
C.sub.1-6alkyl, and x is 0-2; p, q, r and s are independently
selected from 0-2; R.sup.34 is selected from halo, hydroxy, cyano,
carbamoyl, ureido, amino, nitro, carbamoyl, mercapto, sulphamoyl,
trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy,
vinyl, allyl, ethynyl, formyl, acetyl, formamido, acetylamino,
acetoxy, methylamino, dimethylamino, N-methylcarbamoyl,
N,N-dimethylcarbamoyl, methylthio, methylsulphinyl, mesyl,
N-methylsulphamoyl, N,N-dimethylsulphamoyl, N-methylsulphamoylamino
and N,N-dimethylsulphamoylamino; R.sup.20, R.sup.24, R.sup.26,
R.sup.30 or R.sup.35 are independently selected from
C.sub.1-6alkyl, C.sub.1-6alkanoyl, C.sub.1-6alkylsulphonyl,
C.sub.1-6alkoxycarbonyl, carbamoyl, N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl
and phenylsulphonyl; or a pharmaceutically acceptable salt, solvate
or solvate of such a salt, or an in vivo hydrolysable ester formed
on an available carboxy or hydroxy thereof, or an in vivo
hydrolysable amide formed on an available carboxy thereof.
29. The method of claim 28, wherein the compound of Formula VI is
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N'-(c-
arboxymethyl)
carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine-
;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N'--((S)--
1-carb
oxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetr-
ahydro-1,5-benzothiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N'-(c-
arboxymethyl)
carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine-
;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N'--((S)--
1-carb
oxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5--
benzothiazepine; or a pharmaceutically acceptable salt thereof.
30. The method of claim 1, wherein the composition further
comprises a bile acid sequestrant or binder.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C.
.sctn.119(e) of U.S. Provisional Application No. 61/553,094, filed
Oct. 28, 2011, U.S. Provisional Application No. 61/607,487, filed
Mar. 6, 2012, U.S. Provisional Application No. 61/607,503, filed
Mar. 6, 2012, which are incorporated herein by reference in their
entirety.
BACKGROUND OF THE INVENTION
[0002] Pediatric cholestatic liver diseases affect a small
percentage of children, but therapy results in significant
healthcare costs each year. Currently, many of the pediatric
cholestatic liver diseases require invasive and costly treatments
such as liver transplantation and surgery. An effective and less
invasive treatment that is suitable for the pediatric population is
not available.
[0003] It is well understood and accepted that the therapeutic
needs of children are sufficiently different than those of adults
as to require specific studies of medications in children. For
example, oral administration of a solid dosage form of medication
is painless and simple for most adult patients, but for the
pediatric patient population, swallowing an oral solid dosage form
produced for adults can be problematic. In addition, the drugs used
in solid dosages often have an unpleasant taste. More importantly,
oral administration of adult medication targeting cholestatic liver
diseases may result in side effects such as diarrhea and intestinal
discomfort. Such problems pose a safety risk and affect compliance.
Effective and acceptable forms of pediatric medication for
pediatric cholestastatic liver diseases are needed.
SUMMARY OF THE INVENTION
[0004] Provided herein are therapeutic compositions and methods for
treating or ameliorating a pediatric cholestatic liver disease or
pediatric cholestasis. In certain embodiments, provided herein are
methods for treating or ameliorating a pediatric cholestatic liver
disease comprising non-systemically administering to a pediatric
patient a therapeutically effective amount of a composition
comprising an Apical Sodium-dependent Bile Transporter Inhibitor
(ASBTI) or a pharmaceutically acceptable salt thereof. In certain
embodiments, provided herein are methods for treating or
ameliorating a pediatric cholestatic liver disease comprising
administering to an individual in need thereof a therapeutically
effective amount of a composition comprising a non-systemically
absorbed ASBTI or a pharmaceutically acceptable salt thereof. In
certain embodiments, provided herein are methods for treating or
ameliorating a pediatric cholestatic liver disease comprising
non-systemically administering to a pediatric patient a
therapeutically effective amount of a pediatric dosage form
comprising an Apical Sodium-dependent Bile Transporter Inhibitor
(ASBTI) or a pharmaceutically acceptable salt thereof. In certain
embodiments, provided herein are methods for treating or
ameliorating a pediatric cholestatic liver disease comprising
administering to an individual in need thereof a therapeutically
effective amount of a pediatric dosage form comprising a
non-systemically absorbed ASBTI or a pharmaceutically acceptable
salt thereof.
[0005] In certain embodiments, provided herein are pediatric dosage
forms comprising a pediatric dosage of a non-systemically absorbed
Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI) or
a pharmaceutically acceptable salt thereof. In some embodiments,
provided herein are pediatric dosage forms comprising any
non-systemically absorbed ASBTI or a pharmaceutically acceptable
salt thereof described herein. In some embodiments, provided herein
are pediatric dosage forms comprising any non-systemically absorbed
ASBTI or a pharmaceutically acceptable salt thereof and a second
agent described herein.
[0006] Provided herein are therapeutic compositions and methods for
treating or ameliorating pruritis. In certain embodiments, provided
herein are methods for treating or ameliorating pruritis comprising
non-systemically administering to a pediatric patient suffering
from a pediatric cholestatic liver disease a therapeutically
effective amount of a composition comprising an ASBTI or a
pharmaceutically acceptable salt thereof. In certain embodiments,
provided herein are methods for treating or ameliorating pruritis
comprising administering to an individual in need thereof a
therapeutically effective amount of a composition comprising a
non-systemically absorbed ASBTI or a pharmaceutically acceptable
salt thereof. In certain embodiments, provided herein are methods
for treating or ameliorating pruritis comprising non-systemically
administering to a pediatric patient suffering from a pediatric
cholestatic liver disease a therapeutically effective amount of a
pediatric dosage form comprising an ASBTI or a pharmaceutically
acceptable salt thereof. In certain embodiments, provided herein
are methods for treating or ameliorating pruritis comprising
administering to an individual in need thereof a therapeutically
effective amount of a pediatric dosage form comprising a
non-systemically absorbed ASBTI or a pharmaceutically acceptable
salt thereof.
[0007] Provided herein are therapeutic compositions and methods for
treating or ameliorating pediatric hypercholemia. In certain
embodiments, provided herein are methods for treating or
ameliorating pediatric hypercholemia comprising non-systemically
administering to a pediatric patient a therapeutically effective
amount of a composition comprising an ASBTI or a pharmaceutically
acceptable salt thereof. In certain embodiments, provided herein
are methods for treating or ameliorating pediatric hypercholemia
comprising administering to an individual in need thereof a
therapeutically effective amount of a composition comprising a
non-systemically absorbed ASBTI or a pharmaceutically acceptable
salt thereof. In certain embodiments, provided herein are methods
for treating or ameliorating pediatric hypercholemia comprising
non-systemically administering to a pediatric patient a
therapeutically effective amount of a pediatric dosage form
comprising an ASBTI or a pharmaceutically acceptable salt thereof.
In certain embodiments, provided herein are methods for treating or
ameliorating pediatric hypercholemia comprising administering to an
individual in need thereof a therapeutically effective amount of a
pediatric dosage form comprising a non-systemically absorbed ASBTI
or a pharmaceutically acceptable salt thereof.
[0008] Provided herein are therapeutic compositions and methods for
lowering serum bile acid concentrations or hepatic bile acid
concentrations. In certain embodiments, provided herein are methods
for decreasing serum bile acid levels or concentrations or hepatic
bile acid levels or concentrations comprising non-systemically
administering to a pediatric patient suffering from a pediatric
cholestatic liver disease a therapeutically effective amount of a
composition comprising an ASBTI or a pharmaceutically acceptable
salt thereof. In certain embodiments, provided herein are methods
for decreasing serum bile acids or hepatic bile acids comprising
administering to an individual in need thereof a therapeutically
effective amount of a composition comprising a non-systemically
absorbed ASBTI or a pharmaceutically acceptable salt thereof. In
certain embodiments, provided herein are methods for decreasing
serum bile acid levels or concentrations or hepatic bile acid
levels or concentrations comprising non-systemically administering
to a pediatric patient suffering from a pediatric cholestatic liver
disease a therapeutically effective amount of a pediatric dosage
form comprising an ASBTI or a pharmaceutically acceptable salt
thereof. In certain embodiments, provided herein are methods for
decreasing serum bile acids or hepatic bile acids comprising
administering to an individual in need thereof a therapeutically
effective amount of a pediatric dosage form comprising a
non-systemically absorbed ASBTI or a pharmaceutically acceptable
salt thereof.
[0009] In some embodiments, compositions and methods provided
herein decrease serum or hepatic bile acid levels by at least 50%,
45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10%, as compared to the
levels prior to administration of the compositions provided herein
or as compared to control subjects. In some embodiments, methods
provided herein decrease serum or hepatic bile acid levels by at
least 30%. In some embodiments, methods provided herein decrease
serum or hepatic bile acid levels by at least 25%. In some
embodiments, methods provided herein decrease serum or hepatic bile
acid levels by at least 20%. In some embodiments, methods provided
herein decrease serum or hepatic bile acid levels by at least
15%.
[0010] Provided herein are therapeutic compositions and methods for
treating or ameliorating xanthoma. In certain embodiments, provided
herein are methods for treating or ameliorating xanthoma comprising
non-systemically administering to a pediatric patient suffering
from a pediatric cholestatic liver disease a therapeutically
effective amount of a composition comprising an ASBTI or a
pharmaceutically acceptable salt thereof. In certain embodiments,
provided herein are methods for treating or ameliorating xanthoma
comprising administering to an individual in need thereof a
therapeutically effective amount of a composition comprising a
non-systemically absorbed ASBTI or a pharmaceutically acceptable
salt thereof. In certain embodiments, provided herein are methods
for treating or ameliorating xanthoma comprising non-systemically
administering to a pediatric patient suffering from a pediatric
cholestatic liver disease a therapeutically effective amount of a
pediatric dosage form comprising an ASBTI or a pharmaceutically
acceptable salt thereof. In certain embodiments, provided herein
are methods for treating or ameliorating xanthoma comprising
administering to an individual in need thereof a therapeutically
effective amount of a pediatric dosage form comprising a
non-systemically absorbed ASBTI or a pharmaceutically acceptable
salt thereof.
[0011] In some embodiments, provided herein are compositions and
methods decreasing serum lipoprotein X levels or concentrations
comprising non-systemically administering to a pediatric patient
suffering from xanthoma a therapeutically effective amount of a
composition comprising an ASBTI or a pharmaceutically acceptable
salt thereof. In certain embodiments, provided herein are methods
for decreasing serum lipoprotein X comprising administering to an
individual in need thereof a therapeutically effective amount of a
composition comprising a non-systemically absorbed ASBTI or a
pharmaceutically acceptable salt thereof. In certain embodiments,
provided herein are methods for decreasing serum lipoprotein X
levels or concentrations comprising non-systemically administering
to a pediatric patient suffering from xanthoma a therapeutically
effective amount of a pediatric dosage form comprising an ASBTI or
a pharmaceutically acceptable salt thereof. In certain embodiments,
provided herein are methods for decreasing serum lipoprotein X
comprising administering to an individual in need thereof a
therapeutically effective amount of a pediatric dosage form
comprising a non-systemically absorbed ASBTI or a pharmaceutically
acceptable salt thereof.
[0012] In certain embodiments, described herein are compositions
and methods for reducing serum levels of bilirubin, gamma-glutamyl
transpeptidase or gamma-glutamyl transferase (GGT), or liver
enzymes, such as alkaline phosphatase, ALT and AST, in an
individual in need thereof comprising non-systemically
administering a therapeutically effective amount of a composition
of an ASBTI or a pharmaceutically acceptable salt thereof. In some
embodiments, methods comprise administering a therapeutically
effective amount of a composition comprising a non-systemically
absorbed ASBTI or a pharmaceutically acceptable salt thereof. In
certain embodiments, described herein are methods for reducing
serum levels of bilirubin, gamma-glutamyl transpeptidase or
gamma-glutamyl transferase (GGT), or liver enzymes, such as
alkaline phosphatase, ALT and AST, in an individual in need thereof
comprising non-systemically administering a therapeutically
effective amount of a pediatric dosage form of an ASBTI or a
pharmaceutically acceptable salt thereof. In some embodiments,
methods comprise administering a therapeutically effective amount
of a pediatric dosage form comprising a non-systemically absorbed
ASBTI or a pharmaceutically acceptable salt thereof.
[0013] In certain embodiments, methods provided herein comprise
administering compounds that inhibit the ASBT or any recuperative
bile salt transporter. In certain embodiments, use of the compounds
provided herein reduces or inhibits recycling of bile acid salts in
the gastrointestinal tract. In some embodiments, the methods
provided herein reduce intraenterocyte bile acids/salts or reduce
necrosis and/or damage to intestinal or hepatocellular
architecture.
[0014] In certain embodiments, the methods described herein treat
or ameliorate a pediatric cholestatic liver disease by increasing
intraluminal concentrations of bile acids/salts, which are then
excreted in the feces, thereby reducing overall bile acid and serum
bile acid or hepatic bile acid load in an individual in need
thereof. In certain embodiments, increasing intraluminal bile acid
concentrations according to methods described herein provide
protection and/or control of the integrity of an individual's liver
and/or intestine that has been injured by cholestasis and/or
cholestatic liver disease.
[0015] In certain embodiments, the methods described herein treat
or ameliorate pruritis by increasing intraluminal concentrations,
and/or reducing serum concentrations, or hepatic concentrations of
bile acids/salts in an individual in need thereof. In certain
embodiments, increasing intraluminal bile acid concentrations
according to methods described herein provide protection and/or
control of the integrity of an individual's liver and/or intestine
that has been injured by a cholestatic liver disease.
[0016] In certain embodiments, the methods described herein lower
serum bile acid concentrations or hepatic bile acid concentrations
by increasing intraluminal concentrations of bile acids/salts in an
individual in need thereof. In certain embodiments, increasing
intraluminal bile acid concentrations according to methods
described herein provide protection and/or control of the integrity
of an individual's liver and/or intestine that has been injured by
a cholestatic liver disease.
[0017] In certain embodiments, provided herein is an ASBTI or a
pharmaceutically acceptable salt thereof for use in the treatment
of a pediatric cholestatic liver disease, wherein the ASBTI is
non-systemically absorbed or is formulated to be non-systemically
absorbed. In some embodiments, provided herein is a pharmaceutical
composition for use in the treatment of a pediatric cholestatic
liver disease, wherein the composition comprises a pediatric dosage
form of an ASBTI and a pharmaceutically acceptable excipient,
wherein the ASBTI is non-systemically absorbed or is formulated to
be non-systemically absorbed. In some embodiments, a composition
provided herein is suitable for non-systemically administering to
the distal ileum, colon, and/or rectum.
[0018] In certain embodiments, provided herein is an ASBTI or a
pharmaceutically acceptable salt thereof for use in the treatment
of pruritis in a pediatric patient suffering from a pediatric
cholestatic liver disease, wherein the ASBTI is non-systemically
absorbed or is formulated to be non-systemically absorbed. In some
embodiments, provided herein is a pharmaceutical composition for
use in the treatment of pruritis, wherein the composition comprises
a pediatric dosage form of an ASBTI and a pharmaceutically
acceptable excipient, wherein the ASBTI is non-systemically
absorbed or is formulated to be non-systemically absorbed. In some
embodiments, a composition provided herein is suitable for
non-systemically administering to the distal ileum, colon, and/or
rectum.
[0019] In certain embodiments, provided herein is an ASBTI or a
pharmaceutically acceptable salt thereof for use in lowering serum
bile acid concentrations or hepatic bile acid concentrations in a
pediatric patient suffering from a pediatric cholestatic liver
disease, wherein the ASBTI is a non-systemically absorbed or is
formulated to be non-systemically absorbed. In some embodiments,
provided herein is a pharmaceutical composition for use in lowering
serum bile acid concentrations or hepatic bile acid concentrations,
wherein the composition comprises a pediatric dosage form of an
ASBTI and a pharmaceutically acceptable excipient, wherein the
ASBTI is non-systemically absorbed or is formulated to be
non-systemically absorbed. In some embodiments, a composition
provided herein is suitable for non-systemically administering to
the distal ileum, colon, and/or rectum.
[0020] In some embodiments, an ASBTI provided herein is minimally
absorbed or formulated to be minimally absorbed. In some
embodiments, a pediatric dosage form of an ASBTI is
non-systemically administered to the distal ileum, colon, and/or
rectum of an individual in need thereof. In some embodiments, an
ASBTI is non-systemically administered to the ileum, colon or
rectum of an individual in need thereof. In some embodiments, less
than 50%, less than 40%, less than 30%, less than 20%, less than
10%, less than 9%, less than 8%, less than 7%, less than 6%, less
than 5%, less than 4%, less than 3%, less than 2%, or less than 1%
of the ASBTI is systemically absorbed. In a preferred embodiment,
less than 10% of the ASBTI is systemically absorbed. In another
preferred embodiment, less than 5% of the ASBTI is systemically
absorbed. In another preferred embodiment, less than 1% of the
ASBTI is systemically absorbed.
[0021] In one aspect, provided herein is a method for treating a
pediatric cholestatic liver disease in an individual in need
thereof comprising non-systemically administering to the distal
gastrointestinal tract of the individual in need thereof a
therapeutically effective amount of a pediatric dosage form of an
ASBTI or a pharmaceutically acceptable salt thereof. In one aspect,
provided herein is a method for treating pruritis in an individual
in need thereof comprising non-systemically administering to the
distal gastrointestinal tract of the individual in need thereof a
therapeutically effective amount of a pediatric dosage form of an
ASBTI or a pharmaceutically acceptable salt thereof. In one aspect,
provided herein is a method for lowering serum bile acid
concentrations in an individual in need thereof comprising
non-systemically administering to the distal gastrointestinal tract
of the individual in need thereof a therapeutically effective
amount of a pediatric dosage form of an ASBTI or a pharmaceutically
acceptable salt thereof. In some embodiments, the distal
gastrointestinal tract is jejunum, ileum, colon, or rectum. In some
embodiments, the distal gastrointestinal tract is ileum, colon, or
the rectum. In some embodiments, the distal gastrointestinal tract
is jejunum. In some embodiments, the distal gastrointestinal tract
is ileum.
[0022] In certain embodiments, the pediatric cholestatic liver
disease is progressive familial intrahepatic cholestasis (PFIC),
PFIC type 1, PFIC type 2, PFIC type 3, Alagille syndrome,
Dubin-Johnson Syndrome, biliary atresia, post-Kasai biliary
atresia, post-liver transplantation biliary atresia, post-liver
transplantation cholestasis, post-liver transplantation associated
liver disease, intestinal failure associated liver disease, bile
acid mediated liver injury, pediatric primary sclerosing
cholangitis, MRP2 deficiency syndrome, neonatal sclerosing
cholangitis, a pediatric obstructive cholestasis, a pediatric
non-obstructive cholestasis, a pediatric extrahepatic cholestasis,
a pediatric intrahepatic cholestasis, a pediatric primary
intrahepatic cholestasis, a pediatric secondary intrahepatic
cholestasis, benign recurrent intrahepatic cholestasis (BRIC), BRIC
type 1, BRIC type 2, BRIC type 3, total parenteral nutrition
associated cholestasis, paraneoplastic cholestasis, Stauffer
syndrome, drug-associated cholestasis, infection-associated
cholestasis, or gallstone disease. In some embodiments, the
pediatric cholestatic liver disease is a pediatric form of liver
disease described herein.
[0023] In certain embodiments, a pediatric cholestatic liver
disease is characterized by one or more symptoms selected from
jaundice, pruritis, cirrhosis, hypercholemia, neonatal respiratory
distress syndrome, lung pneumonia, increased serum concentration of
bile acids, increased hepatic concentration of bile acids,
increased serum concentration of bilirubin, hepatocellular injury,
liver scarring, liver failure, hepatomegaly, xanthomas,
malabsorption, splenomegaly, diarrhea, pancreatitis, hepatocellular
necrosis, giant cell formation, hepatocellular carcinoma,
gastrointestinal bleeding, portal hypertension, hearing loss,
fatigue, loss of appetite, anorexia, peculiar smell, dark urine,
light stools, steatorrhea, failure to thrive, and/or renal
failure.
[0024] In certain embodiments, the pediatric patient is a new born,
a pre-term new born, an infant, a toddler, a pre-schooler, a
school-age child, a pre-pubescent child, post-pubescent child, an
adolescent, or a teenager under the age of eighteen. In some
embodiments, the pediatric patient is a new born, a pre-term new
born, an infant, a toddler, a pre-schooler, or a school-age child.
In some embodiments, the pediatric patient is a new born, a
pre-term new born, an infant, a toddler, or a pre-schooler. In some
embodiments, the pediatric patient is a new born, a pre-term new
born, an infant, or a toddler. In some embodiments, the pediatric
patient is a new born, a pre-term new born, or an infant. In some
embodiments, the pediatric patient is a new born. In some
embodiments, the pediatric patient is an infant. In some
embodiments, the pediatric patient is a toddler.
[0025] In certain embodiments, the individual is an infant less
than 2 years of age. In some cases, for any of the methods and/or
compositions described herein, the individual is an infant between
0 to 18 months of age. In some cases, for any of the methods and/or
compositions described herein, the individual is an infant between
1 to 18 months of age. In some cases, for any of the methods and/or
compositions described herein, the individual is an infant between
2 to 18 months of age. In some cases, for any of the methods and/or
compositions described herein, the individual is an infant between
3 to 18 months of age. In some cases, for any of the methods and/or
compositions described herein, the individual is an infant between
4 to 18 months of age. In some cases, for any of the methods and/or
compositions described herein, the individual is an infant between
6 to 18 months of age. In some cases, for any of the methods and/or
compositions described herein, the individual is an infant between
18 to 24 months of age. In some cases, for any of the methods
and/or compositions described herein, the individual is an infant
between 6 to 12 months of age. In some instances, for any of the
methods and/or compositions described herein, the individual is a
child of between about 2 to about 10 years of age. In some
instances, the individual is less than about 10 years old. In some
instances, the individual is between about 10 to about 17 years
old.
[0026] In some cases, for any of the methods and/or compositions
described herein, the individual is a child between 6 months to 12
years of age.
[0027] Provided herein, in certain embodiments, are therapeutic
methods and compositions using compounds that inhibit the Apical
Sodium-dependent Bile Transporter (ASBT) or a pharmaceutically
acceptable salt thereof, or any recuperative bile salt transporter
for treatment of a pediatric cholestatic liver disease or pruritis
or for lowering serum bile acid concentrations. In certain
instances, use of the compounds provided herein reduces or inhibits
recycling of bile acid salts in the gastrointestinal tract. In some
embodiments, the methods provided herein reduce intraenterocyte
bile acids/salts and/or damage to ileal or hepatocellular
architecture caused by a pediatric cholestatic liver disease and/or
allow for regeneration of the intestinal lining or liver. In some
embodiments, the bile transport inhibitors are non-systemic
compounds. In other embodiments, the bile acid transporter
inhibitors are systemic compounds delivered non-systemically. In
other embodiments, the bile acid transporter inhibitors are
systemic compounds. In certain embodiments, the bile transport
inhibitors described herein enhance enteroendocrine peptide
secretion by intestinal L-cells.
[0028] In some embodiments of the methods described above, the
ASBTI is a compound of Formula I or a pharmaceutically acceptable
salt thereof, as described herein. In some embodiments of the
methods described above, the ASBTI is a compound of Formula II or a
pharmaceutically acceptable salt thereof, as described herein. In
some embodiments of the methods described above, the ASBTI is a
compound of Formula III or a pharmaceutically acceptable salt
thereof, as described herein. In some embodiments of the methods
described above, the ASBTI is a compound of Formula IV or a
pharmaceutically acceptable salt thereof, as described herein. In
some embodiments of the methods described above, the ASBTI is a
compound of Formula V or a pharmaceutically acceptable salt
thereof, as described herein. In some embodiments of the methods
described above, the ASBTI is a compound of Formula VI or Formula
VID or a pharmaceutically acceptable salt thereof, as described
herein.
[0029] In some embodiments, provided herein is a method for
treating or ameliorating a pediatric cholestatic liver disease
comprising non-systemically administering to an individual in need
thereof a therapeutically effective amount of a pediatric dosage
form of an ASBTI of Formula I or a pharmaceutically acceptable salt
thereof. In some embodiments, provided herein is a method for
treating or ameliorating pruritis comprising non-systemically
administering to an individual in need thereof a therapeutically
effective amount of a pediatric dosage form of an ASBTI of Formula
I or a pharmaceutically acceptable salt thereof. In some
embodiments, provided herein is a method for increasing the levels
of an enteroendocrine peptide or hormone in an individual suffering
from a pediatric cholestatic liver disease comprising
non-systemically administering to the individual in need thereof a
therapeutically effective amount of a pediatric dosage form of an
ASBTI of Formula I or a pharmaceutically acceptable salt thereof.
In some embodiments, provided herein is a method for lowering serum
bile acid concentrations or hepatic bile acid concentration
comprising non-systemically administering to an individual in need
thereof a therapeutically effective amount of a pediatric dosage
form of an ASBTI of Formula I or a pharmaceutically acceptable salt
thereof.
[0030] In some embodiments, provided herein is a method for
treating or ameliorating a pediatric cholestatic liver disease
comprising non-systemically administering to an individual in need
thereof a therapeutically effective amount of a pediatric dosage
form of an ASBTI of Formula II or a pharmaceutically acceptable
salt thereof. In some embodiments, provided herein is a method for
treating or ameliorating pruritis comprising non-systemically
administering to an individual in need thereof a therapeutically
effective amount of a pediatric dosage form of an ASBTI of Formula
II or a pharmaceutically acceptable salt thereof. In some
embodiments, provided herein is a method for increasing the levels
of an enteroendocrine peptide or hormone in an individual suffering
from a pediatric cholestatic liver disease comprising
non-systemically administering to the individual in need thereof a
therapeutically effective amount of a pediatric dosage form of an
ASBTI of Formula II or a pharmaceutically acceptable salt thereof.
In some embodiments, provided herein is a method for lowering serum
bile acid concentrations or hepatic bile acid concentration
comprising non-systemically administering to an individual in need
thereof a therapeutically effective amount of a pediatric dosage
form of an ASBTI of Formula II or a pharmaceutically acceptable
salt thereof.
[0031] In some embodiments, provided herein is a method for
treating or ameliorating a pediatric cholestatic liver disease
comprising non-systemically administering to an individual in need
thereof a therapeutically effective amount of a pediatric dosage
form of an ASBTI of Formula III or a pharmaceutically acceptable
salt thereof. In some embodiments, provided herein is a method for
treating or ameliorating pruritis comprising non-systemically
administering to an individual in need thereof a therapeutically
effective amount of a pediatric dosage form of an ASBTI of Formula
III or a pharmaceutically acceptable salt thereof. In some
embodiments, provided herein is a method for increasing the levels
of an enteroendocrine peptide or hormone in an individual suffering
from a pediatric cholestatic liver disease comprising
non-systemically administering to the individual in need thereof a
therapeutically effective amount of a pediatric dosage form of an
ASBTI of Formula III or a pharmaceutically acceptable salt thereof.
In some embodiments, provided herein is a method for lowering serum
bile acid concentrations or hepatic bile acid concentration
comprising non-systemically administering to an individual in need
thereof a therapeutically effective amount of a pediatric dosage
form of an ASBTI of Formula III or a pharmaceutically acceptable
salt thereof.
[0032] In some embodiments, provided herein is a method for
treating or ameliorating a pediatric cholestatic liver disease
comprising non-systemically administering to an individual in need
thereof a therapeutically effective amount of a pediatric dosage
form of an ASBTI of Formula IV or a pharmaceutically acceptable
salt thereof. In some embodiments, provided herein is a method for
treating or ameliorating pruritis comprising non-systemically
administering to an individual in need thereof a therapeutically
effective amount of a pediatric dosage form of an ASBTI of Formula
IV or a pharmaceutically acceptable salt thereof. In some
embodiments, provided herein is a method for increasing the levels
of an enteroendocrine peptide or hormone in an individual suffering
from a pediatric cholestatic liver disease comprising
non-systemically administering to the individual in need thereof a
therapeutically effective amount of a pediatric dosage form of an
ASBTI of Formula IV or a pharmaceutically acceptable salt thereof.
In some embodiments, provided herein is a method for lowering serum
bile acid concentrations or hepatic bile acid concentration
comprising non-systemically administering to an individual in need
thereof a therapeutically effective amount of a pediatric dosage
form of an ASBTI of Formula IV or a pharmaceutically acceptable
salt thereof.
[0033] In some embodiments, provided herein is a method for
treating or ameliorating a pediatric cholestatic liver disease
comprising non-systemically administering to an individual in need
thereof a therapeutically effective amount of a pediatric dosage
form of an ASBTI of Formula V or a pharmaceutically acceptable salt
thereof. In some embodiments, provided herein is a method for
treating or ameliorating pruritis comprising non-systemically
administering to an individual in need thereof a therapeutically
effective amount of a pediatric dosage form of an ASBTI of Formula
V or a pharmaceutically acceptable salt thereof. In some
embodiments, provided herein is a method for increasing the levels
of an enteroendocrine peptide or hormone in an individual suffering
from a pediatric cholestatic liver disease comprising
non-systemically administering to the individual in need thereof a
therapeutically effective amount of a pediatric dosage form of an
ASBTI of Formula V or a pharmaceutically acceptable salt thereof.
In some embodiments, provided herein is a method for lowering serum
bile acid concentrations or hepatic bile acid concentration
comprising non-systemically administering to an individual in need
thereof a therapeutically effective amount of a pediatric dosage
form of an ASBTI of Formula V or a pharmaceutically acceptable salt
thereof.
[0034] In some embodiments, provided herein is a method for
treating or ameliorating a pediatric cholestatic liver disease
comprising non-systemically administering to an individual in need
thereof a therapeutically effective amount of a pediatric dosage
form of an ASBTI of Formula VI or a pharmaceutically acceptable
salt thereof. In some embodiments, provided herein is a method for
treating or ameliorating pruritis comprising non-systemically
administering to an individual in need thereof a therapeutically
effective amount of a pediatric dosage form of an ASBTI of Formula
VI or a pharmaceutically acceptable salt thereof. In some
embodiments, provided herein is a method for increasing the levels
of an enteroendocrine peptide or hormone in an individual suffering
from a pediatric cholestatic liver disease comprising
non-systemically administering to the individual in need thereof a
therapeutically effective amount of a pediatric dosage form of an
ASBTI of Formula VI or a pharmaceutically acceptable salt thereof.
In some embodiments, provided herein is a method for lowering serum
bile acid concentrations or hepatic bile acid concentration
comprising non-systemically administering to an individual in need
thereof a therapeutically effective amount of a pediatric dosage
form of an ASBTI of Formula VI or a pharmaceutically acceptable
salt thereof.
[0035] In certain embodiments, an ASBTI is any compound described
herein that inhibits recycling of bile acids/salts in the
gastrointestinal tract of an individual. In certain embodiments, an
ASBTI is
(-)-(3R,5R)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phen-
yl-1,4-benzothiazepine1,1-dioxide; ("Compound 100A") or any other
salt or analog thereof. In certain of any of the aforementioned
embodiments, an ASBTI is
1-[4-[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydr-
o-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]butyl]4-aza-1-azoniabi-
cyclo[2.2.2]octane methane sulfonate salt ("Compound 100B") or any
other salt or analog thereof. In certain embodiments, an ASBTI is
N,N-dimethylimido-dicarbonimidic diamide ("Compound 100C") or any
salt or analog thereof. In certain embodiments, an ASBTI is any
commercially available ASBTI including but not limited to SD-5613,
A-3309, 264W94, S-8921, SAR-548304, BAR1-1741, HMR-1453, TA-7552,
R-146224, or SC-435. In some embodiments, an ASBTI is
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((R)-1--
carboxy-2-methylthio-ethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,-
3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((S)-1--
carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2-
,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((S)-1--
carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,-
5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((S)-1--
carboxybutyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahyd-
ro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((S)-1--
carboxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5--
benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((S)-1--
carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-b-
enzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((S)-1--
carboxy-2-(R)-hydroxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tet-
rahydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N-(2-sulph-
oethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2-
,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((S)-1--
carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahyd-
ro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((R)-1--
carboxy-2-methylthioethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetra-
hydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--{(S)-1--
[N--((S)-2-hydroxy-1-carboxyethyl)carbamoyl]propyl}carbamoyl]benzyl}carbam-
oylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((S)-1--
carboxy-2-methylpropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahyd-
ro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((S)-1--
carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahy-
dro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-{(R)-.alpha.-carboxy-4-h-
ydroxybenzyl}carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-
; or
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N-(car-
boxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-ben-
zothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N'-(c-
arboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-ben-
zothiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N'--((S)-1-
-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrah-
ydro-1,5-benzothiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N'-(c-
arboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-ben-
zothiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N'--((S)-1-
-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-be-
nzothiazepine; or a pharmaceutically acceptable salt thereof;
1-[[5-[[3-[(3S,4R,5R)-3-butyl-7-(dimethylamino)-3-ethyl-2,3,4,5-tetrahydr-
o-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenyl]amino]-5-oxopentyl]amin-
o]-1-deoxy-D-glucitol; or
Potassium((2R,3R,4S,5R,6R)-4-benzyloxy-6-{3-[3-((3S,4R,5R)-3-butyl-7-dime-
thylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepi-
n-5-yl)-phenyl]-ureido}-3,5-dihydroxy-tetrahydro-pyran-2-ylmethyl)sulphate
ethanolate, hydrate. In certain embodiments, an ASBTI is 264W94
(Glaxo), SC-435 (Pfizer), SD-5613 (Pfizer), or A3309
(Astra-Zeneca).
[0036] In certain embodiments, methods provided herein further
comprise administration of a second agent selected from ursodiol,
UDCA, cholestyramine/resins, antihistamine agents (e.g.,
hydroxyzine, diphenhydamine), rifampin, nalaxone, Phenobarbital,
dronabinol (CB1 agonist), methotrexate, corticosteroids,
cyclosporine, colchicines, TPGS--vitamin A, D, E, or K optionally
with polyethylene glycol, zinc, and a resin or sequestrant for
absorbing bile acids or an analog thereof. In certain embodiments,
methods provided herein further comprise administration of a second
agent selected from a bile acid or salt with reduced toxicity or a
hydrophilic bile acid such as ursodiol, norursodiol,
ursodeoxycholic acid, chenodeoxycholic acid, cholic acid,
taurocholic acid, ursocholic acid, glycocholic acid,
glycodeoxycholic acid, taurodeoxycholic acid, taurocholate,
glycochenodeoxycholic acid, or tauroursodeoxycholic acid.
[0037] In certain embodiments, provided herein are pediatric dosage
forms such as a solution, syrup, suspension, elixir, powder for
reconstitution as suspension or solution, dispersible/effervescent
tablet, chewable tablet, gummy candy, lollipop, freezer pops,
troches, oral thin strips, orally disintegrating tablet, sachet,
soft gelatin capsule, and sprinkle oral powder or granules.
[0038] In some embodiments, the pediatric dosage of an ASBTI is
between about 1 .mu.g/kg/day and about 10 mg/kg/day. In some
embodiments, the pediatric dosage of an ASBTI is between about 5
.mu.g/kg/day and about 1 mg/kg/day. In some embodiments, the
pediatric dosage of an ASBTI is between about 10 .mu.g/kg/day and
about 300 .mu.g/kg/day. In some embodiments, the pediatric dosage
of an ASBTI is any dosage from about 14 .mu.g/kg/day and about 280
.mu.g/kg/day. In some embodiments, the pediatric dosage of an ASBTI
is any dosage from about 14 .mu.g/kg/day and about 140
.mu.g/kg/day. In some embodiments, the pediatric dosage of an ASBTI
is between about 5 .mu.g/kg/day and about 200 .mu.g/kg/day. In some
embodiments, the pediatric dosage of an ASBTI is between about 10
.mu.g/kg/day and about 200 .mu.g/kg/day. In some embodiments, the
pediatric dosage of an ASBTI is between about 10 .mu.g/kg/day and
about 175 .mu.g/kg/day. In some embodiments, the pediatric dosage
of an ASBTI is between about 10 .mu.g/kg/day and about 150
.mu.g/kg/day. In some embodiments, the pediatric dosage of an ASBTI
is between about 10 .mu.g/kg/day and about 140 .mu.g/kg/day. In
some embodiments, the pediatric dosage of an ASBTI is between about
25 .mu.g/kg/day and about 140 .mu.g/kg/day. In some embodiments,
the pediatric dosage of an ASBTI is between about 50 .mu.g/kg/day
and about 140 .mu.g/kg/day. In some embodiments, the pediatric
dosage of an ASBTI is between about 70 .mu.g/kg/day and about 140
.mu.g/kg/day. In some embodiments, the pediatric dosage of an ASBTI
is between about 10 .mu.g/kg/day and about 100 .mu.g/kg/day. In
some embodiments, the pediatric dosage of an ASBTI is 10
.mu.g/kg/day. In some embodiments, the pediatric dosage of an ASBTI
is 20 .mu.g/kg/day. In some embodiments, the pediatric dosage of an
ASBTI is 30 .mu.g/kg/day. In some embodiments, the pediatric dosage
of an ASBTI is 35 .mu.g/kg/day. In some embodiments, the pediatric
dosage of an ASBTI is 40 .mu.g/kg/day. In some embodiments, the
pediatric dosage of an ASBTI is 50 .mu.g/kg/day. In some
embodiments, the pediatric dosage of an ASBTI is 60 .mu.g/kg/day.
In some embodiments, the pediatric dosage of an ASBTI is 70
.mu.g/kg/day. In some embodiments, the pediatric dosage of an ASBTI
is 80 .mu.g/kg/day. In some embodiments, the pediatric dosage of an
ASBTI is 90 .mu.g/kg/day. In some embodiments, the pediatric dosage
of an ASBTI is 100 .mu.g/kg/day. In some embodiments, the pediatric
dosage of an ASBTI is 110 .mu.g/kg/day. In some embodiments, the
pediatric dosage of an ASBTI is 120 .mu.g/kg/day. In some
embodiments, the pediatric dosage of an ASBTI is 130 .mu.g/kg/day.
In some embodiments, the pediatric dosage of an ASBTI is 140
.mu.g/kg/day. In some embodiments, the pediatric dosage of an ASBTI
is 150 .mu.g/kg/day. In some embodiments, the pediatric dosage of
an ASBTI is 175 .mu.g/kg/day.
[0039] In some embodiments, provided herein are pediatric dosages
of an ASBTI between 14 .mu.g/kg/day and 140 .mu.g/kg/day, or
between 14 .mu.g/kg/day and 280 .mu.g/kg/day.
[0040] In some embodiments, the pediatric dosage of an ASBTI is
between about 0.5 mg/day and about 40 mg/day. In some embodiments,
the pediatric dosage of an ASBTI is between about 0.5 mg/day and
about 30 mg/day. In some embodiments, the pediatric dosage of an
ASBTI is between about 1 mg/day and about 20 mg/day. In some
embodiments, the pediatric dosage of an ASBTI is between about 1
mg/day and about 10 mg/day. In some embodiments, the pediatric
dosage of an ASBTI is between about 1 mg/day and about 5 mg/day. In
some embodiments, the pediatric dosage of an ASBTI is 1 mg/day. In
some embodiments, the pediatric dosage of an ASBTI is 5 mg/day. In
some embodiments, the pediatric dosage of an ASBTI is 10 mg/day. In
some embodiments, the pediatric dosage of an ASBTI is 20 mg/day. In
some embodiments, the pediatric dosage of an ASBTI is between 0.5
mg/day and 5 mg/day. In some embodiments, the pediatric dosage of
an ASBTI is between 0.5 mg/day and 4.5 mg/day. In some embodiments,
the pediatric dosage of an ASBTI is between 0.5 mg/day and 4
mg/day. In some embodiments, the pediatric dosage of an ASBTI is
between 0.5 mg/day and 3.5 mg/day. In some embodiments, the
pediatric dosage of an ASBTI is between 0.5 mg/day and 3 mg/day. In
some embodiments, the pediatric dosage of an ASBTI is between 0.5
mg/day and 2.5 mg/day. In some embodiments, the pediatric dosage of
an ASBTI is between 0.5 mg/day and 2 mg/day. In some embodiments,
the pediatric dosage of an ASBTI is between 0.5 mg/day and 1.5
mg/day. In some embodiments, the pediatric dosage of an ASBTI is
between 0.5 mg/day and 1 mg/day. In some embodiments, the pediatric
dosage of an ASBTI is between 1 mg/day and 4.5 mg/day. In some
embodiments, the pediatric dosage of an ASBTI is between 1 mg/day
and 4 mg/day. In some embodiments, the pediatric dosage of an ASBTI
is between 1 mg/day and 3.5 mg/day. In some embodiments, the
pediatric dosage of an ASBTI is between 1 mg/day and 3 mg/day. In
some embodiments, the pediatric dosage of an ASBTI is between 1
mg/day and 2.5 mg/day. In some embodiments, the pediatric dosage of
an ASBTI is between 1 mg/day and 2 mg/day. In some embodiments, the
pediatric dosage of an ASBTI is 0.5 mg/day. In some embodiments,
the pediatric dosage of an ASBTI is 1 mg/day. In some embodiments,
the pediatric dosage of an ASBTI is 1.5 mg/day. In some
embodiments, the pediatric dosage of an ASBTI is 2 mg/day. In some
embodiments, the pediatric dosage of an ASBTI is 2.5 mg/day. In
some embodiments, the pediatric dosage of an ASBTI is 3 mg/day. In
some embodiments, the pediatric dosage of an ASBTI is 3.5 mg/day.
In some embodiments, the pediatric dosage of an ASBTI is 4 mg/day.
In some embodiments, the pediatric dosage of an ASBTI is 4.5
mg/day. In some embodiments, the pediatric dosage of an ASBTI is 5
mg/day. In some embodiments, the pediatric dosage described herein
is the dosage of the total composition administered.
[0041] In some embodiments, the pediatric dosage form comprises 0.5
mg of the ASBTI. In some embodiments, the pediatric dosage form
comprises 1 mg of the ASBTI. In some embodiments, the pediatric
dosage form comprises 2.5 mg of the ASBTI. In some embodiments, the
pediatric dosage form comprises 5 mg of the ASBTI. In some
embodiments, the pediatric dosage form comprises 10 mg of the
ASBTI. In some embodiments, the pediatric dosage form comprises 20
mg of the ASBTI.
[0042] In certain embodiments, the pediatric dosage of an ASBTI is
given once a day. In some embodiments, the pediatric dosage of an
ASBTI is given q.d. In some embodiments, the pediatric dosage of an
ASBTI is given once a day in the morning. In some embodiments, the
pediatric dosage of an ASBTI is given once a day at noon. In some
embodiments, the pediatric dosage of an ASBTI is given once a day
in the evening or night. In some embodiments, the pediatric dosage
of an ASBTI is given twice a day. In some embodiments, the
pediatric dosage of an ASBTI is given b.i.d. In some embodiments,
the pediatric dosage of an ASBTI is given twice a day, in the
morning and noon. In some embodiments, the pediatric dosage of an
ASBTI is given twice a day, in the morning and evening. In some
embodiments, the pediatric dosage of an ASBTI is given twice a day,
in the morning and night. In some embodiments, the pediatric dosage
of an ASBTI is given twice a day, at noon and in the evening. In
some embodiments, the pediatric dosage of an ASBTI is given twice a
day, at noon and in the night. In some embodiments, the pediatric
dosage of an ASBTI is given three times a day. In some embodiments,
the pediatric dosage of an ASBTI is given t.i.d. In some
embodiments, the pediatric dosage of an ASBTI is given four times a
day. In some embodiments, the pediatric dosage of an ASBTI is given
q.i.d. In some embodiments, the pediatric dosage of an ASBTI is
given every four hours. In some embodiments, the pediatric dosage
of an ASBTI is given q.q.h. In some embodiments, the pediatric
dosage of an ASBTI is given every other day. In some embodiments,
the pediatric dosage of an ASBTI is given q.o.d. In some
embodiments, the pediatric dosage of an ASBTI is given three times
a week. In some embodiments, the pediatric dosage of an ASBTI is
given t.i.w.
[0043] Provided in certain embodiments herein are methods and
dosage forms (e.g., oral or rectal dosage form) for use in the
treatment of a pediatric cholestatic liver disease or pruritis, or
lowering serum bile acid concentrations comprising a
therapeutically effective amount of an ASBTI, or a pharmaceutically
acceptable salt thereof, and a carrier. In some embodiments,
provided herein is a method for treating cholestasis and/or a
cholestatic liver disease comprising orally administering a
therapeutically effective amount of a minimally absorbed ASBTI, or
a pharmaceutically acceptable salt thereof, to an individual in
need thereof. In some embodiments, provided herein is a method for
treating cholestasis and/or a cholestatic liver disease comprising
orally administering a therapeutically effective amount of a
minimally absorbed ASBTI, or a pharmaceutically acceptable salt
thereof, to an individual in need thereof. In some embodiments, the
ASBTI, or salt thereof is a minimally absorbed ASBTI. In specific
embodiments, the dosage form is an enteric formulation, an ileal-pH
sensitive release formulation, or a suppository or other suitable
form.
[0044] In some embodiments, a composition for use in the treatment
of a pediatric cholestatic liver disease or pruritis, or lowering
serum bile acid concentrations comprises at least one of a
spreading agent or a wetting agent. In some embodiments, the
composition comprises an absorption inhibitor. In some cases an
absorption inhibitor is a mucoadhesive agent (e.g., a mucoadhesive
polymer). In certain embodiments, the mucoadhesive agent is
selected from methyl cellulose, polycarbophil,
polyvinylpyrrolidone, sodium carboxymethyl cellulose, and
combinations thereof. In some embodiments, the enteroendocrine
peptide secretion enhancing agent is covalently linked to the
absorption inhibitor. In certain embodiments, the pharmaceutical
composition comprises an enteric coating. In some embodiments, a
composition for use in treatment of cholestasis, a cholestatic
liver disease or pruritis described above comprises a carrier. In
certain embodiments, the carrier is a rectally suitable carrier. In
certain embodiments, any pharmaceutical composition described
herein is formulated as a suppository, an enema solution, a rectal
foam, or a rectal gel. In some embodiments, any pharmaceutical
composition described herein comprises an orally suitable
carrier.
[0045] In some embodiments, a pediatric dosage form comprising an
ASBTI is administered orally. In some embodiments, the ASBTI is
administered as an ileal-pH sensitive release formulation that
delivers the ASBTI to the distal ileum, colon and/or rectum of an
individual. In some embodiments, the ASBTI is administered as an
enterically coated formulation. In some embodiments, oral delivery
of an ASBTI provided herein can include formulations, as are well
known in the art, to provide prolonged or sustained delivery of the
drug to the gastrointestinal tract by any number of mechanisms.
These include, but are not limited to, pH sensitive release from
the dosage form based on the changing pH of the small intestine,
slow erosion of a tablet or capsule, retention in the stomach based
on the physical properties of the formulation, bioadhesion of the
dosage form to the mucosal lining of the intestinal tract, or
enzymatic release of the active drug from the dosage form. The
intended effect is to extend the time period over which the active
drug molecule is delivered to the site of action (the ileum) by
manipulation of the dosage form. Thus, enteric-coated and
enteric-coated controlled release formulations are within the scope
of the present invention. Suitable enteric coatings include
cellulose acetate phthalate, polyvinylacetate phthalate,
hydroxypropylmethylcellulose phthalate and anionic polymers of
methacrylic acid and methacrylic acid methyl ester.
[0046] In some embodiments, the methods and compositions provided
herein further comprise administration of a bile acid sequestrant
or binder for reducing gastrointestinal side effects. In some
embodiments, methods comprise administering a labile bile acid
sequestrant, wherein the labile bile acid sequestrant has a low
affinity in the colon or rectum of the individual for at least one
bile acid. In some embodiments, a labile bile acid sequestrant
provided herein releases a bile acid in the colon or the rectum of
a human. In some embodiments, a labile bile acid sequestrant
provided herein does not sequester a bile acid for excretion or
elimination in feces. In some embodiments, a labile bile acid
sequestrant provided herein is a non-systemic labile bile acid
sequestrant. In some embodiments, non-systemic labile bile acid
sequestrant is less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%,
15%, 20%, 25%, 30%, 35%, 40%, 45% absorbed systemically. In some
embodiments, the labile bile acid sequestrant is lignin or a
modified lignin. In some embodiments, the labile bile acid
sequestrant is a polycationic polymer or copolymer. In certain
embodiments, the labile bile acid sequestrant is a polymer or
copolymer comprising one or more N-alkenyl-N-alkylamine residues;
one or more N,N,N-trialkyl-N--(N'-alkenylamino)alkyl-azanium
residues; one or more N,N,N-trialkyl-N-alkenyl-azanium residues;
one or more alkenyl-amine residues; cholestyramine, cholestipol, or
cholesevelamor a combination thereof.
[0047] In some embodiments of the methods described above, a
pediatric dosage form comprising an ASBTI is administered before
ingestion of food. In some embodiments of the methods described
above, a pediatric dosage form comprising an ASBTI is administered
with or after ingestion of food.
[0048] In some embodiments, the methods provided herein further
comprise administration of vitamin supplements to compensate for
reduced digestion of vitamins, in particular fat-soluble vitamins,
in an individual with a pediatric cholestatic liver disease,
pruritis, or elevated serum bile acid levels or concentrations. In
some embodiments, the vitamin supplements comprise fat-soluble
vitamins. In some embodiments, the fat-soluble vitamins are vitamin
A, D, E, or K.
[0049] In some cases, for any of the methods described above,
administration of an ASBTI reduces intraenterocyte bile acids/salts
in an individual in need thereof. In some embodiments, the methods
described herein reduce accumulation of bile acids/salts in ileal
enterocytes of an individual in need thereof. In some cases, for
any of the methods described above, administration of an ASBTI
inhibits transport of bile acids/salts from ileal lumen into
enterocytes of an individual in need thereof. In some cases, for
any of the methods described above, administration of an ASBTI
increases ileal luminal bile acids/salts in an individual in need
thereof. In some cases, for any of the methods described above,
administration of an ASBTI reduces damage to intestinal (e.g.,
ileal cells) or hepatocellular (e.g., liver cells) architecture
associated with a pediatric cholestatic liver disease or elevated
serum or hepatic bile acid concentrations in an individual in need
thereof. In some cases, for any of the methods described above,
administration of an ASBTI regenerates intestinal lining or liver
cells that have been injured by cholestasis and/or by a cholestatic
liver disease in an individual suffering from a cholestatic liver
disease.
[0050] In some embodiments, provided herein are methods for the
treatment of a pediatric cholestatic liver disease comprising
administration of a therapeutically effective amount of a pediatric
dosage form comprising a combination of an ASBTI and ursodiol to an
individual in need thereof. In some embodiments, provided herein
are methods for the treatment of a pediatric cholestatic liver
disease comprising administration of a therapeutically effective
amount of a combination of an ASBTI and a resin or sequestrant for
absorbing bile acids to an individual in need thereof. In some
embodiments, an ASBTI is administered in combination with one or
more agent selected from the group consisting of ursodiol,
norursodiol, UDCA, ursodeoxycholic acid, chenodeoxycholic acid,
cholic acid, taurocholic acid, ursocholic acid, glycocholic acid,
glycodeoxycholic acid, taurodeoxycholic acid, taurocholate,
glycochenodeoxycholic acid, tauroursodeoxycholic acid,
cholestyramine/resins, antihistamine agents (e.g., hydroxyzine,
diphenhydamine), rifampin, nalaxone, Phenobarbital, dronabinol (CB1
agonist), methotrexate, corticosteroids, cyclosporine, colchicines,
TPGS--vitamin A, D, E, or K optionally with polyethylene glycol,
zinc, a resin or sequestrant for absorbing bile acids.
[0051] In some embodiments, the methods provided herein further
comprise partial external biliary diversion (PEBD) therapy.
[0052] Provided in some embodiments herein is a kit comprising any
composition described herein (e.g., a pharmaceutical composition
formulated for rectal administration) and a device for localized
delivery within the rectum or colon. In certain embodiments, the
device is a syringe, bag, or a pressurized container.
BRIEF DESCRIPTION OF THE DRAWINGS
[0053] FIG. 1. Oral administration of 264W94 dose-dependently
increased bile acids in the feces. Fecal bile acid concentrations
were elevated up to 6.5 fold with an ED.sub.50 of 0.17 mg/kg, when
compared to vehicle treated rats. Fecal NEFA also slightly
increased in 264W94 treated rats. Plasma bile acid concentrations
were decreased dose-dependently in 264W94 treated rats.
[0054] FIG. 2. Plasma bile acid levels of ZDF rats after
administration of ascending doses of SC-435 and LUM002. Male ZDF
rats (n=4) were administered vehicle, SC-435 (1, 10 or 30 mg/kg) or
LUM002 (0.3, 1, 3, 10 or 30 mg/kg) by oral gavage twice a day for 2
weeks. Plasma bile acid levels were determined at the end of the
second week. Data are expressed as mean values .+-.SEM.
[0055] FIG. 3. Serum bile acid (SBA) analysis of healthy subjects
after administration of ascending multiple oral doses of LUM001 a
randomized, double-blind, placebo-controlled study. Shown in the
graphs are data from the 0.5 (n=16), 1.0 (n=8), 2.5 (n=8), 5.0
(n=8) and 10 (n=8) mg dosing groups. On Day 1, blood was drawn for
baseline SBA at approximately 30 minutes before and after breakfast
and 30 minutes after lunch and dinner. Samples were obtained on day
14.
[0056] FIG. 4. Fecal bile acid analysis of healthy subjects after
administration of ascending multiple oral doses of LUM001 a
randomized, double-blind, placebo-controlled study. Fecal samples
were collected for all panels except the dose-titration panel, 2.5
(2) and 5 mg (2), on Days 9 through 14 and 23 through 28.
[0057] FIG. 5. Fasting serum bile acid levels and morning
post-prandial peak in children under the age of 12. LUM001 was
administered once-a-day (QD) in the morning for fourteen days. The
placebo patients had an average fasting serum bile acid level of
8.6 .mu.mol/L and a post-prandial peak serum bile acid level of
11.9 .mu.mol/L. For the LUM001 treated patients the values were 6.5
.mu.mol/L and 9.2, respectively, representing a 24% and 23%
decrease.
DETAILED DESCRIPTION OF THE INVENTION
[0058] Bile acids/salts play a critical role in activating
digestive enzymes and solubilizing fats and fat-soluble vitamins
and are involved in liver, biliary, and intestinal disease. Bile
acids are synthesized in the liver by a multistep, multiorganelle
pathway. Hydroxyl groups are added to specific sites on the steroid
structure, the double bond of the cholesterol B ring is reduced and
the hydrocarbon chain is shortened by three carbon atoms resulting
in a carboxyl group at the end of the chain. The most common bile
acids are cholic acid and chenodeoxycholic acid (the "primary bile
acids"). Before exiting the hepatocytes and forming bile, the bile
acids are conjugated to either glycine (to produce glycocholic acid
or glycochenodeoxycholic acid) or taurine (to produce taurocholic
acid or taurochenodeoxycholic acid). The conjugated bile acids are
called bile salts and their amphipathic nature makes them more
efficient detergents than bile acids. Bile salts, not bile acids,
are found in bile.
[0059] Bile salts are excreted by the hepatocytes into the
canaliculi to form bile. The canaliculi drain into the right and
left hepatic ducts and the bile flows to the gallbladder. Bile is
released from the gallbladder and travels to the duodenum, where it
contributes to the metabolism and degradation of fat. The bile
salts are reabsorbed in the terminal ileum and transported back to
the liver via the portal vein. Bile salts often undergo multiple
enterohepatic circulations before being excreted via feces. A small
percentage of bile salts may be reabsorbed in the proximal
intestine by either passive or carrier-mediated transport
processes. Most bile salts are reclaimed in the distal ileum by a
sodium-dependent apically located bile acid transporter referred to
as apical sodium-dependent bile acid transporter (ASBT). At the
basolateral surface of the enterocyte, a truncated version of ASBT
is involved in vectorial transfer of bile acids/salts into the
portal circulation. Completion of the enterohepatic circulation
occurs at the basolateral surface of the hepatocyte by a transport
process that is primarily mediated by a sodium-dependent bile acid
transporter. Intestinal bile acid transport plays a key role in the
enterohepatic circulation of bile salts. Molecular analysis of this
process has recently led to important advances in our understanding
of the biology, physiology and pathophysiology of intestinal bile
acid transport.
[0060] Within the intestinal lumen, bile acid concentrations vary,
with the bulk of the reuptake occurring in the distal intestine.
Bile acids/salts alter the growth of bacterial flora in the gut.
Described herein are certain compositions and methods that control
bile acid concentrations in the intestinal lumen, thereby
controlling the hepatocellular damage caused by bile acid
accumulation in the liver.
[0061] In another aspect, the compositions and methods provided
herein increase bile acid concentrations in the gut. The increased
concentrations of bile acids/salts stimulate subsequent secretion
of factors that protect and control integrity of the intestine when
it is injured by pediatric cholestasis and/or a pediatric
cholestatic liver disease (e.g., a pediatric cholestatic liver
disease associated with pruritis, or a pediatric cholestatic liver
disease associated with elevated serum bile acid concentrations or
hepatic bile acid concentrations).
[0062] In yet another aspect, the compositions and methods
described herein have an advantage over systemically absorbed
agents. The compositions and methods described herein utilize ASBT
inhibitors that are not systemically absorbed. Thus the
compositions are effective without leaving the gut lumen, thereby
reducing any toxicity and/or side effects associated with systemic
absorption. The pediatric formulations described herein have an
advantage over existing adult dosage forms and dosages to reduce
harmful side effects and increase compliance.
[0063] In a further aspect, the compositions and methods described
herein stimulate the release of enteroendocrine hormones GLP-2 and
PYY. Increased secretion of GLP-2 or PYY allows for prevention or
treatment of pediatric cholestasis and/or a pediatric cholestatic
liver disease by controlling the adaptive process, attenuating
intestinal injury, reducing bacterial translocation, inhibiting the
release of free radical oxygen, inhibiting production of
proinflammatory cytokines, or any combination thereof.
[0064] Described herein is the use of inhibitors of the ASBT or any
recuperative bile salt transporter that are active in the
gastrointestinal (GI) tract for treating or preventing pediatric
cholestasis and/or a pediatric cholestatic liver disease in an
individual in need thereof. In certain embodiments, described
herein is the use of inhibitors of the ASBT or any recuperative
bile salt transporter that are active in the gastrointestinal (GI)
tract for treating or preventing pruritis in an individual in need
thereof. In certain embodiments, described herein is the use of
inhibitors of the ASBT or any recuperative bile salt transporter
that are active in the gastrointestinal (GI) tract for lowering
serum bile acid concentrations or hepatic bile acid concentrations
in an individual in need thereof. In certain embodiments, the
methods provided herein comprise administering a therapeutically
effective amount of an ASBTI to an individual in need thereof. In
some embodiments, such ASBT inhibitors are not systemically
absorbed. In some of such embodiments, such bile salt transport
inhibitors include a moiety or group that prevents, reduces or
inhibits the systemic absorption of the compound in vivo. In some
embodiments, a charged moiety or group on the compounds prevents,
reduces or inhibits the compounds from leaving the gastrointestinal
tract and reduces the risk of side effects due to systemic
absorption. In some other embodiments, such ASBT inhibitors are
systemically absorbed. In some embodiments, the ASBTI provided
herein are formulated for non-systemic delivery to the distal
ileum. In some embodiments, an ASBTI is minimally absorbed. In some
embodiments, an ASBTI is non-systemically administered to the colon
or the rectum of an individual in need thereof.
[0065] In some embodiments, such ASBT inhibitors are not
systemically absorbed. In some of such embodiments, such bile salt
transport inhibitors include a moiety or group that prevents,
reduces or inhibits the systemic absorption of the compound in
vivo. In some embodiments, a charged moiety or group on the
compounds prevents, reduces or inhibits the compounds from leaving
the gastrointestinal tract and reduces the risk of side effects due
to systemic absorption. In some other embodiments, such ASBT
inhibitors are systemically absorbed. In some embodiments, the
ASBTI are formulated for non-systemic delivery to the distal ileum.
In some embodiments, an ASBTI is minimally absorbed. In some
embodiments, an ASBTI is non-systemically administered to the colon
or the rectum of an individual in need thereof.
[0066] In some embodiments, less than 50%, less than 40%, less than
30%, less than 20%, less than 10%, less than 9%, less than 8%, less
than 7%, less than 6%, less than 5%, less than 4%, less than 3%,
less than 2%, or less than 1% of the ASBTI is systemically
absorbed. In certain embodiments, ASBTIs described herein inhibit
scavenging of bile salts by recuperative bile acid salt
transporters in the distal gastrointestinal tract (e.g., the distal
ileum, the colon and/or the rectum).
[0067] In some instances, the inhibition of bile salt recycling
results in higher concentrations of bile salts in the lumen of the
distal gastrointestinal tract or portions thereof (e.g., the distal
small bowel and/or colon and/or rectum). As used herein, the distal
gastrointestinal tract includes the region from the distal ileum to
the anus. In some embodiments, the compounds described herein
reduce intraenterocyte bile acids/salts or accumulation thereof. In
some embodiments, the compounds described herein reduce damage to
hepatocellular or intestinal architecture associated with
cholestasis and/or a cholestatic liver disease.
Mammalian Microbiome, Bile Acid Pools and Metabolic
Interactions
[0068] The integrated metabolism of the bile acid pools in the
intestinal lumen lends itself to complex biochemical interactions
between host and microbiome symbionts.
[0069] Bile acids/salts are synthesized from cholesterol in the
liver by a multi-enzyme coordinated process and are crucial for the
absorption of dietary fats and lipid-soluble vitamins in the
intestine. Bile acids/salts play a role in maintaining the
intestinal barrier function to prevent intestinal bacterial
overgrowth and translocation, as well as invasion of underlying
tissues by enteric bacteria.
[0070] Under normal conditions (i.e., when an individual is not
suffering from pediatric cholestasis and/or a pediatric cholestatic
liver disease), symbiotic gut microorganisms (microbiome) interact
closely with the host's metabolism and are important determinants
of health. Many bacterial species in the gut are capable of
modifying and metabolizing bile acids/salts and the gut flora
affects systemic processes such as metabolism and inflammation.
[0071] Bile acids/salts have strong antimicrobial and antiviral
effects--deficiency leads to bacterial overgrowth and increased
deconjugation, leading to less ileal resorption. In animals,
conjugated bile acid feeding abolishes bacterial overgrowth,
decreases bacterial translocation to lymph nodes and reduces
endotoxemia.
[0072] Accordingly, the methods and compositions described herein
allow for replacement, displacement, and/or redirection of bile
acids/salts to different areas of the gastrointestinal tract
thereby affecting (e.g., inhibiting or slowing) growth of
microorganisms that may cause infection-associated cholestasis
and/or a cholestatic liver disease.
Classes of Pediatric Cholestatic Liver Disease
[0073] As used herein, "cholestasis" means the disease or symptoms
comprising impairment of bile formation and/or bile flow. As used
herein, "cholestatic liver disease" means a liver disease
associated with cholestasis. Cholestatic liver diseases are often
associated with jaundice, fatigue, and pruritis. Biomarkers of
cholestatic liver disease include elevated serum bile acid
concentrations, elevated serum alkaline phosphatase (AP), elevated
gamma-glutamyltranspeptidease, elevated conjugated
hyperbilirubinemia, and elevated serum cholesterol.
[0074] Cholestatic liver disease can be sorted
clinicopathologically between two principal categories of
obstructive, often extrahepatic, cholestasis, and nonobstructive,
or intrahepatic, cholestasis. In the former, cholestasis results
when bile flow is mechanically blocked, as by gallstones or tumor,
or as in extrahepatic biliary atresia.
[0075] The latter group who has nonobstructive intrahepatic
cholestasis in turn fall into two principal subgroups. In the first
subgroup, cholestasis results when processes of bile secretion and
modification, or of synthesis of constituents of bile, are caught
up secondarily in hepatocellular injury so severe that nonspecific
impairment of many functions can be expected, including those
subserving bile formation. In the second subgroup, no presumed
cause of hepatocellular injury can be identified. Cholestasis in
such patients appears to result when one of the steps in bile
secretion or modification, or of synthesis of constituents of bile,
is constitutively damages. Such cholestasis is considered
primary.
[0076] Accordingly, provided herein are methods and compositions
for stimulating epithelial proliferation and/or regeneration of
intestinal lining and/or enhancement of the adaptive processes in
the intestine in individuals with cholestasis and/or a cholestatic
liver disease. In some of such embodiments, the methods comprise
increasing bile acid concentrations and/or GLP-2 concentrations in
the intestinal lumen.
[0077] Hypercholemia, and elevated levels of AP (alkaline
phosphatase), LAP (leukocyte alkaline phosphatase), gamma GT
(gamma-glutamyl transpeptidase), and 5'-nucleotidase are
biochemical hallmarks of cholestasis and cholestatic liver disease.
Accordingly, provided herein are methods and compositions for
stimulating epithelial proliferation and/or regeneration of
intestinal lining and/or enhancement of the adaptive processes in
the intestine in individuals with hypercholemia, and elevated
levels of AP (alkaline phosphatase), LAP (leukocyte alkaline
phosphatase), gamma GT (gamma-glutamyl transpeptidase or GGT),
and/or 5'-nucleotidase. In some of such embodiments, the methods
comprise increasing bile acid concentrations concentrations in the
intestinal lumen. Further provided herein, are methods and
compositions for reducing hypercholemia, and elevated levels of AP
(alkaline phosphatase), LAP (leukocyte alkaline phosphatase), gamma
GT (gamma-glutamyl transpeptidase), and 5'-nucleotidase comprising
reducing overall bile acid load by excreting bile acid in the
feces.
[0078] Pruritus is often associated with pediatric cholestasis and
pediatric cholestatic liver diseases. It has been suggested that
pruritus results from bile salts acting on peripheral pain afferent
nerves. The degree of pruritus varies with the individual (i.e.,
some individuals are more sensitive to elevated levels of bile
acids/salts). Administration of agents that reduce serum bile acid
concentrations has been shown to reduce pruritus in certain
individuals. Accordingly, provided herein are methods and
compositions for stimulating epithelial proliferation and/or
regeneration of intestinal lining and/or enhancement of the
adaptive processes in the intestine in individuals with pruritus.
In some of such embodiments, the methods comprise increasing bile
acid concentrations concentrations in the intestinal lumen. Further
provided herein, are methods and compositions for treating pruritus
comprising reducing overall bile acid load by excreting bile acid
in the feces.
[0079] Another symptom of pediatric cholestasis and pediatric
cholestatic liver disease is the increase in serum concentration of
conjugated bilirubin. Elevated serum concentrations of conjugated
bilirubin result in jaundice and dark urine. The magnitude of
elevation is not diagnostically important as no relationship has
been established between serum levels of conjugated bilirubin and
the severity of cholestasis and cholestatic liver disease.
Conjugated bilirubin concentration rarely exceeds 30 mg/dL.
Accordingly, provided herein are methods and compositions for
stimulating epithelial proliferation and/or regeneration of
intestinal lining and/or enhancement of the adaptive processes in
the intestine in individuals with elevated serum concentrations of
conjugated bilirubin. In some of such embodiments, the methods
comprise increasing bile acid concentrations concentrations in the
intestinal lumen. Further provided herein, are methods and
compositions for treating elevated serum concentrations of
conjugated bilirubin comprising reducing overall bile acid load by
excreting bile acid in the feces.
[0080] Increased serum concentration of nonconjugated bilirubin is
also considered diagnostic of cholestasis and cholestatic liver
disease. Portions of serum bilirubin and covalently bound to
albumin (delta bilirubin or biliprotein). This fraction may account
for a large proportion of total bilirubin in patients with
cholestatic jaundice. The presence of large quantities of delta
bilirubin indicates long-standing cholestasis. Delta bilirubin in
cord blood or the blood of a newborn is indicative of pediatric
cholestasis/cholestatic liver disease that antedates birth.
Accordingly, provided herein are methods and compositions for
stimulating epithelial proliferation and/or regeneration of
intestinal lining and/or enhancement of the adaptive processes in
the intestine in individuals with elevated serum concentrations of
nonconjugated bilirubin or delta bilirubin. In some of such
embodiments, the methods comprise increasing bile acid
concentrations concentrations in the intestinal lumen. Further
provided herein, are methods and compositions for treating elevated
serum concentrations of nonconjugated bilirubin and delta bilirubin
comprising reducing overall bile acid load by excreting bile acid
in the feces.
[0081] Pediatric cholestasis and cholestatic liver disease results
in hypercholemia. During metabolic cholestasis, the hepatocytes
retains bile salts. Bile salts are regurgitated from the hepatocyte
into the serum, which results in an increase in the concentration
of bile salts in the peripheral circulation. Furthermore, the
uptake of bile salts entering the liver in portal vein blood is
inefficient, which results in spillage of bile salts into the
peripheral circulation. Accordingly, provided herein are methods
and compositions for stimulating epithelial proliferation and/or
regeneration of intestinal lining and/or enhancement of the
adaptive processes in the intestine in individuals with
hypercholemia. In some of such embodiments, the methods comprise
increasing bile acid concentrations concentrations in the
intestinal lumen. Further provided herein, are methods and
compositions for treating hypercholemia comprising reducing overall
bile acid load by excreting bile acid in the feces.
[0082] Hyperlipidemia is characteristic of some but not all
cholestatic diseases. Serum cholesterol is elevated in cholestasis
due to the decrease in circulating bile salts which contribute to
the metabolism and degradation of cholesterol. Cholesterol
retention is associated with an increase in membrane cholesterol
content and a reduction in membrane fluidity and membrane function.
Furthermore, as bile salts are the metabolic products of
cholesterol, the reduction in cholesterol metabolism results in a
decrease in bile acid/salt synthesis. Serum cholesterol observed in
children with cholestasis ranges between about 1,000 mg/dL and
about 4,000 mg/dL. Accordingly, provided herein are methods and
compositions for stimulating epithelial proliferation and/or
regeneration of intestinal lining and/or enhancement of the
adaptive processes in the intestine in individuals with
hyperlipidemia. In some of such embodiments, the methods comprise
increasing bile acid concentrations concentrations in the
intestinal lumen. Further provided herein, are methods and
compositions for treating hyperlipidemia comprising reducing
overall bile acid load by excreting bile acid in the feces.
[0083] In individuals with pediatric cholestasis and pediatric
cholestatic liver diseases, xanthomas develop from the deposition
of excess circulating cholesterol into the dermis. The development
of xanthomas is more characteristic of obstructive cholestasis than
of hepatocellular cholestasis. Planar xanthomas first occur around
the eyes and then in the creases of the palms and soles, followed
by the neck. Tuberous xanthomas are associated with chronic and
long-term cholestasis. Accordingly, provided herein are methods and
compositions for stimulating epithelial proliferation and/or
regeneration of intestinal lining and/or enhancement of the
adaptive processes in the intestine in individuals with xanthomas.
In some of such embodiments, the methods comprise increasing bile
acid concentrations concentrations in the intestinal lumen. Further
provided herein, are methods and compositions for treating
xanthomas comprising reducing overall bile acid load by excreting
bile acid in the feces.
[0084] In children with chronic cholestasis, one of the major
consequences of pediatric cholestasis and pediatric cholestatic
liver disease is failure to thrive. Failure to thrive is a
consequence of reduced delivery of bile salts to the intestine,
which contributes to inefficient digestion and absorption of fats,
and reduced uptake of vitamins (vitamins E, D, K, and A are all
malabsorbed in cholestasis). Furthermore, the delivery of fat into
the colon can result in colonic secretion and diarrhea. Treatment
of failure to thrive involves dietary substitution and
supplementation with long-chain triglycerides, medium-chain
triglycerides, and vitamins. Ursodeoxycholic acid, which is used to
treat some cholestatic conditions, does not form mixed micelles and
has no effect on fat absorption. Accordingly, provided herein are
methods and compositions for stimulating epithelial proliferation
and/or regeneration of intestinal lining and/or enhancement of the
adaptive processes in the intestine in individuals (e.g., children)
with failure to thrive. In some of such embodiments, the methods
comprise increasing bile acid concentrations concentrations in the
intestinal lumen. Further provided herein, are methods and
compositions for treating failure to thrive comprising reducing
overall bile acid load by excreting bile acid in the feces.
[0085] Symptoms of pediatric cholestasis and pediatric cholestatic
liver disease have been treated with choleretic agents (e.g.,
ursodiol), phenobarbitols, corticosteroids (e.g., prednisone and
budesonide), immunosuppressive agents (e.g., azathioprine,
cyclosporin A, methotrexate, chlorambucil and mycophenolate),
sulindac, bezafibrate, tamoxifen, and lamivudine. Accordingly, in
some embodiments, any of the methods disclosed herein further
comprise administration of an additional active agent selected
from: choleretic agents (e.g., ursodiol), phenobarbitols,
corticosteroids (e.g., prednisone and budesonide),
immunosuppressive agents (e.g., azathioprine, cyclosporin A,
methotrexate, chlorambucil and mycophenolate), sulindac,
bezafibrate, tamoxifen, lamivudine, and combinations thereof. In
some embodiments, the methods are used to treat individuals that
are non-responsive to treatment with choleretic agents (e.g.,
ursodiol), phenobarbitols, corticosteroids (e.g., prednisone and
budesonide), immunosuppressive agents (e.g., azathioprine,
cyclosporin A, methotrexate, chlorambucil and mycophenolate),
sulindac, bezafibrate, tamoxifen, lamivudine, and combinations
thereof. In some embodiments, the methods are used to treat
individuals that are non-responsive to treatment with choleretic
agents. In some embodiments, the methods are used to treat
individuals that are non-responsive to treatment with ursodiol.
Progressive Familial Intrahepatic Cholestasis (PFIC)
PFIC 1
[0086] PFIC 1 (also known as, Byler disease or FIC1 deficiency) is
associated with mutations in the ATP8B1 gene (also designated as
FIC1). This gene, which encodes a P-type ATPase, is located on
human chromosome 18 and is also mutated in the milder phenotype,
benign recurrent intrahepatic cholestasis type 1 (BRIC1) and in
Greenland familial cholestasis. FIC1 protein is located on the
canalicular membrane of the hepatocyte but within the liver it is
mainly expressed in cholangiocytes. P-type ATPase appears to be an
aminophospholipid transporter responsible for maintaining the
enrichment of phosphatidylserine and phophatidylethanolamine on the
inner leaflet of the plasma membrane in comparison of the outer
leaflet. The asymmetric distribution of lipids in the membrane
bilayer plays a protective role against high bile salt
concentrations in the canalicular lumen. The abnormal protein
function may indirectly disturb the biliary secretion of bile
acids. The anomalous secretion of bile acids/salts leads to
hepatocyte bile acid overload.
[0087] PFIC-1 typically presents in infants (e.g., age 6-18
months). The infants may show signs of pruritus, jaundice,
abdominal distension, diarrhea, malnutrition, and shortened
stature. Biochemically, individuals with PFIC-1 have elevated serum
transaminases, elevated bilirubin, elevated serum bile acid levels,
and low levels of gammaGT. The individual may also have liver
fibrosis. Individuals with PFIC-1 typically do not have bile duct
proliferation. Most individuals with PFIC-1 will develop end-stage
liver disease by 10 years of age. No medical treatments have proven
beneficial for the long term treatment of PFIC-1. In order to
reduce extrahepatic symptoms (e.g., malnutrition and failure to
thrive), children are often administered medium chain triglycerides
and fat-soluble vitamins. Ursodiol has not been demonstrated as
effective in individuals with PFIC-1.
[0088] Disclosed herein, in certain embodiments, are methods of
treating PFIC-1 in an individual in need thereof comprising
non-systemically administering a therapeutically effective amount
of an Apical Sodium-dependent Bile Acid Transporter Inhibitor
(ASBTI) or a pharmaceutically acceptable salt thereof. In some
embodiments, such ASBT inhibitors are not systemically absorbed. In
some of such embodiments, such bile salt transport inhibitors
include a moiety or group that prevents, reduces or inhibits the
systemic absorption of the compound in vivo. In some embodiments, a
charged moiety or group on the compounds prevents, reduces or
inhibits the compounds from leaving the gastrointestinal tract and
reduces the risk of side effects due to systemic absorption. In
some other embodiments, such ASBT inhibitors are systemically
absorbed. In some embodiments, the ASBTI are formulated for
non-systemic delivery to the distal ileum. In some embodiments, an
ASBTI is minimally absorbed. In some embodiments, an ASBTI is
non-systemically administered to the colon or the rectum of an
individual in need thereof. In some embodiments, the methods
further comprise administering a therapeutically-effective amount
of a secondary bile acid (e.g., ursodiol), a corticosteroid (e.g.,
prednisone and budesonide), an immunosuppressive agent (e.g.,
azathioprine, cyclosporin A, methotrexate, chlorambucil and
mycophenolate), sulindac, bezafibrate, tamoxifen, lamivudine or any
combination thereof.
PFIC 2
[0089] PFIC 2 (also known as, Byler Syndrome or BSEP deficiency) is
associated with mutations in the ABCB11 gene (also designated
BSEP). The ABCB11 gene encodes the ATP-dependent canalicular bile
salt export pump (BSEP) of human liver and is located on human
chromosome 2. BSEP protein, expressed at the hepatocyte canalicular
membrane, is the major exporter of primary bile acids/salts against
extreme concentration gradients. Mutations in this protein are
responsible for the decreased biliary bile salt secretion described
in affected patients, leading to decreased bile flow and
accumulation of bile salts inside the hepatocyte with ongoing
severe hepatocellular damage.
[0090] PFIC-2 typically presents in infants (e.g., age 6-18
months). The infants may show signs of pruritus. Biochemically,
individuals with PFIC-2 have elevated serum transaminases, elevated
bilirubin, elevated serum bile acid levels, and low levels of
gammaGT. The individual may also have portal inflammation and giant
cell hepatitis. Further, individuals often develop hepatocellular
carcinoma. No medical treatments have proven beneficial for the
long term treatment of PFIC-1. In order to reduce extrahepatic
symptoms (e.g., malnutrition and failure to thrive), children are
often administered medium chain triglycerides and fat-soluble
vitamins Ursodiol has not been demonstrated as effective in
individuals with PFIC-2.
[0091] Disclosed herein, in certain embodiments, are methods of
treating PFIC-2 in an individual in need thereof comprising
non-systemically administering a therapeutically effective amount
of an Apical Sodium-dependent Bile Acid Transporter Inhibitor
(ASBTI) or a pharmaceutically acceptable salt thereof. In some
embodiments, such ASBT inhibitors are not systemically absorbed. In
some of such embodiments, such bile salt transport inhibitors
include a moiety or group that prevents, reduces or inhibits the
systemic absorption of the compound in vivo. In some embodiments, a
charged moiety or group on the compounds prevents, reduces or
inhibits the compounds from leaving the gastrointestinal tract and
reduces the risk of side effects due to systemic absorption. In
some other embodiments, such ASBT inhibitors are systemically
absorbed. In some embodiments, the ASBTI are formulated for
non-systemic delivery to the distal ileum. In some embodiments, an
ASBTI is minimally absorbed. In some embodiments, an ASBTI is
non-systemically administered to the colon or the rectum of an
individual in need thereof. In some embodiments, the methods
further comprise administering a therapeutically-effective amount
of a secondary bile acid (e.g., ursodiol), a corticosteroid (e.g.,
prednisone and budesonide), an immunosuppressive agent (e.g.,
azathioprine, cyclosporin A, methotrexate, chlorambucil and
mycophenolate), sulindac, bezafibrate, tamoxifen, lamivudine or any
combination thereof
PFIC 3
[0092] PFIC3 (also known as MDR3 deficiency) is caused by a genetic
defect in the ABCB4 gene (also designated MDR3) located on
chromosome 7. Class III Multidrug Resistance (MDR3) P-glycoprotein
(P-gp), is a phospholipid translocator involved in biliary
phospholipid (phosphatidylcholine) excretion in the canlicular
membrane of the hepatocyte. PFIC3 results from the toxicity of bile
in which detergent bile salts are not inactivated by phospholipids,
leading to bile canaliculi and biliary epithelium injuries.
[0093] PFIC-3 also presents in early childhood. As opposed to
PFIC-1 and PFIC-2, individuals have elevated gammaGT levels.
Individuals also have portal inflammation, fibrosis, cirrhosis, and
massive bile duct proliferation. Individuals may also develop
intrahepatic gallstone disease. Ursodiol has been effective in
treating or ameliorating PFIC-3.
[0094] Disclosed herein, in certain embodiments, are methods of
treating PFIC-3 in an individual in need thereof comprising
non-systemically administering a therapeutically effective amount
of an Apical Sodium-dependent Bile Acid Transporter Inhibitor
(ASBTI) or a pharmaceutically acceptable salt thereof. In some
embodiments, such ASBT inhibitors are not systemically absorbed. In
some of such embodiments, such bile salt transport inhibitors
include a moiety or group that prevents, reduces or inhibits the
systemic absorption of the compound in vivo. In some embodiments, a
charged moiety or group on the compounds prevents, reduces or
inhibits the compounds from leaving the gastrointestinal tract and
reduces the risk of side effects due to systemic absorption. In
some other embodiments, such ASBT inhibitors are systemically
absorbed. In some embodiments, the ASBTI are formulated for
non-systemic delivery to the distal ileum. In some embodiments, an
ASBTI is minimally absorbed. In some embodiments, an ASBTI is
non-systemically administered to the colon or the rectum of an
individual in need thereof. In some embodiments, the methods
further comprise administering a therapeutically-effective amount
of a secondary bile acid (e.g., ursodiol), a corticosteroid (e.g.,
prednisone and budesonide), an immunosuppressive agent (e.g.,
azathioprine, cyclosporin A, methotrexate, chlorambucil and
mycophenolate), sulindac, bezafibrate, tamoxifen, lamivudine or any
combination thereof.
Benign Recurrent Intrahepatic Cholestasis (BRIC)
BRIC 1
[0095] BRIC1 is caused by a genetic defect of the FIC1 protein in
the canalicular membrane of hepatocytes. BRIC1 is typically
associated with normal serum cholesterol and
.gamma.-glutamyltranspeptidase levels, but elevated serum bile
salts. Residual FIC1 expression and function is associated with
BRIC1. Despite recurrent attacks of cholestasis or cholestatic
liver disease, there is no progression to chronic liver disease in
a majority of patients. During the attacks, the patients are
severely jaundiced and have pruritis, steatorrhea, and weight loss.
Some patients also have renal stones, pancreatitis, and
diabetes.
BRIC 2
[0096] BRIC2 is caused by mutations in ABCB11, leading to defective
BSEP expression and/or function in the canalicular membrane of
hepatocytes.
BRIC 3
[0097] BRIC3 is related to the defective expression and/or function
of MDR3 in the canalicular membrane of hepatocytes. Patients with
MDR3 deficiency usually display elevated serum
.gamma.-glutamyltranspeptidase levels in the presence of normal or
slightly elevated bile acid levels.
Dubin-Johnson Syndrome (DJS)
[0098] DJS is characterized by conjugated hyperbilirubinemia due to
inherited dysfunction of MRP2. Hepatic function is preserved in
affected patients. Several different mutations have been associated
with this condition, resulting either in the complete absence of
immunohistochemically detectable MRP2 in affected patients or
impaired protein maturation and sorting.
Acquired Cholestatic Disease
Pediatric Primary Sclerosing Cholangitis (PSC)
[0099] Pediatric PSC is a chronic inflammatory hepatic disorder
slowly progressing to end stage liver failure in most of the
affected patients. In pediatric PSC inflammation, fibrosis and
obstruction of large and medium sized intra- and extrahepatic
ductuli is predominant.
Gallstone Disease
[0100] Gallstone disease is one of the most common and costly of
all digestive diseases with a prevalence of up to 17% in Caucasian
women. Cholesterol containing gallstones are the major form of
gallstones and supersaturation of bile with cholesterol is
therefore a prerequisite for gallstone formation. ABCB4 mutations
may be involved in the pathogenesis of cholesterol gallstone
disease.
Drug Induced Cholestasis
[0101] Inhibition of BSEP function by drugs is an important
mechanism of drug-induced cholestasis, leading to the hepatic
accumulation of bile salts and subsequent liver cell damage.
Several drugs have been implicated in BSEP inhibition. Most of
these drugs, such as rifampicin, cyclosporine, glibenclamide, or
troglitazone directly cis-inhibit ATP-dependent taurocholate
transport in a competitive manner, while estrogen and progesterone
metabolites indirectly trans-inhibits Bsep after secretion into the
bile canaliculus by Mrp2. Alternatively, drug-mediated stimulation
of MRP2 can promote cholestasis or cholestatic liver disease by
changing bile composition.
Total Parenteral Nutrition Associated Cholestasis
[0102] TPNAC is one of the most serious clinical scenarios where
cholestasis or cholestatic liver disease occurs rapidly and is
highly linked with early death. Infants, who are usually premature
and who have had gut resections are dependent upon TPN for growth
and frequently develop cholestasis or cholestatic liver disease
that rapidly progresses to fibrosis, cirrhosis, and portal
hypertension, usually before 6 months of life. The degree of
cholestasis or cholestatic liver disease and chance of survival in
these infants have been linked to the number of septic episodes,
likely initiated by recurrent bacterial translocation across their
gut mucosa. Although there are also cholestatic effects from the
intravenous formulation in these infants, septic mediators likely
contribute the most to altered hepatic function.
Alagille Syndrome
[0103] Alagille syndrome is a genetic disorder that affects the
liver and other organs. It often presents during infancy (e.g., age
6-18 months) through early childhood (e.g., age 3-5 years) and may
stabilize after the age of 10. Symptoms may include chronic
progressive cholestasis, ductopenia, jaundice, pruritus, xanthomas,
congenital heart problems, paucity of intrahepatic bile ducts, poor
linear growth, hormone resistance, posterior embryotoxon, Axenfeld
anomaly, retinitis pigmentosa, pupillary abnormalities, cardiac
murmur, atrial septal defect, ventricular septal defect, patent
ductus arteriosus, and Tetralogy of Fallot. Individuals diagnosed
with Alagille syndrome have been treated with ursodiol,
hydroxyzine, cholestyramine, rifampicin, and phenobarbitol. Due to
a reduced ability to absorb fat-soluble vitamins, individuals with
Alagille Syndrome are further administered high dose
multivitamins.
[0104] Disclosed herein, in certain embodiments, are methods of
treating Alagille syndrome in an individual in need thereof
comprising non-systemically administering a therapeutically
effective amount of an ASBTI or a pharmaceutically acceptable salt
thereof. In some embodiments, such ASBT inhibitors are not
systemically absorbed. In some of such embodiments, such bile salt
transport inhibitors include a moiety or group that prevents,
reduces or inhibits the systemic absorption of the compound in
vivo. In some embodiments, a charged moiety or group on the
compounds prevents, reduces or inhibits the compounds from leaving
the gastrointestinal tract and reduces the risk of side effects due
to systemic absorption. In some other embodiments, such ASBT
inhibitors are systemically absorbed. In some embodiments, the
ASBTI are formulated for non-systemic delivery to the distal ileum.
In some embodiments, an ASBTI is minimally absorbed. In some
embodiments, an ASBTI is non-systemically administered to the colon
or the rectum of an individual in need thereof. In some
embodiments, the methods further comprise administering a
therapeutically-effective amount of a secondary bile acid (e.g.,
ursodiol), a corticosteroid (e.g., prednisone and budesonide), an
immunosuppressive agent (e.g., azathioprine, cyclosporin A,
methotrexate, chlorambucil and mycophenolate), sulindac,
bezafibrate, tamoxifen, lamivudine or any combination thereof.
Biliary Atresia
[0105] Biliary atresia is a life-threatening condition in infants
in which the bile ducts inside or outside the liver do not have
normal openings. With biliary atresia, bile becomes trapped, builds
up, and damages the liver. The damage leads to scarring, loss of
liver tissue, and cirrhosis. Without treatment, the liver
eventually fails and the infant needs a liver transplant to stay
alive. The two types of biliary atresia are fetal and perinatal.
Fetal biliary atresia appears while the baby is in the womb.
Perinatal biliary atresia is much more common and does not become
evident until 2 to 4 weeks after birth.
Post-Kasai Biliary Atresia
[0106] Biliary atresia is treated with surgery called the Kasai
procedure or a liver transplant. The Kasai procedure is usually the
first treatment for biliary atresia. During a Kasai procedure, the
pediatric surgeon removes the infant's damaged bile ducts and
brings up a loop of intestine to replace them. While the Kasai
procedure can restore bile flow and correct many problems caused by
biliary atresia, the surgery doesn't cure biliary atresia. If the
Kasai procedure is not successful, infants usually need a liver
transplant within 1 to 2 years. Even after a successful surgery,
most infants with biliary atresia slowly develop cirrhosis over the
years and require a liver transplant by adulthood. Possible
complications after the Kasai procedure include ascites, bacterial
cholangitis, portal hypertension, and pruritis.
Post Liver Transplantation Biliary Atresia
[0107] If the atresia is complete, liver transplantation is the
only option. Although liver transplantation is generally successful
at treating biliary atresia, liver transplantation may have
complications such as organ rejection. Also, a donor liver may not
become available. Further, in some patients, liver transplantation
may not be successful at curing biliary atresia.
Xanthoma
[0108] Xanthoma is a skin condition associated cholestatic liver
diseases, in which certain fats build up under the surface of the
skin. Cholestasis results in several disturbances of lipid
metabolism resulting in formation of an abnormal lipid particle in
the blood called lipoprotein X. Lipoprotein X is formed by
regurgitation of bile lipids into the blood from the liver and does
not bind to the LDL receptor to deliver cholesterol to cells
throughout the body as does normal LDL. Lipoprotein X increases
liver cholesterol production by five fold and blocks normal removal
of lipoprotein particles from the blood by the liver.
Compounds
[0109] In some embodiments, provided herein are ASBT inhibitors
that reduce or inhibit bile acid recycling in the distal
gastrointestinal (GI) tract, including the distal ileum, the colon
and/or the rectum. In certain embodiments, the ASBTIs are
systemically absorbed. In certain embodiments, the ASBTIs are not
systemically absorbed. In some embodiments, ASBTIs described herein
are modified or substituted (e.g., with a -L-K group) to be
non-systemic. In certain embodiments, any ASBT inhibitor is
modified or substituted with one or more charged groups (e.g., K)
and optionally, one or more linker (e.g., L), wherein L and K are
as defined herein.
[0110] In some embodiments, an ASBTI suitable for the methods
described herein is a compound of Formula I:
##STR00001##
wherein: R.sup.1 is a straight chained C.sub.1-6 alkyl group;
R.sup.2 is a straight chained C.sub.1-6 alkyl group; R.sup.3 is
hydrogen or a group OR.sup.11 in which R.sup.11 is hydrogen,
optionally substituted C.sub.1-6 alkyl or a C.sub.1-6 alkylcarbonyl
group; R.sup.4 is pyridyl or optionally substituted phenyl or
-L.sub.z-K.sub.z; wherein z is 1, 2 or 3; each L is independently a
substituted or unsubstituted alkyl, a substituted or unsubstituted
heteroalkyl, a substituted or unsubstituted alkoxy, a substituted
or unsubstituted aminoalkyl group, a substituted or unsubstituted
aryl, a substituted or unsubstituted heteroaryl, a substituted or
unsubstituted cycloalkyl, or a substituted or unsubstituted
heterocycloalkyl; each K is a moiety that prevents systemic
absorption; R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are the same or
different and each is selected from hydrogen, halogen, cyano,
R.sup.5-acetylide, OR.sup.15, optionally substituted C.sub.1-6
alkyl, COR.sup.15, CH(OH)R.sup.15, S(O).sub.nR.sup.15,
P(O)(OR.sup.15).sub.2, OCOR.sup.15, OCF.sub.3, OCN, SCN, NHCN,
CH.sub.2OR.sup.15, CHO, (CH.sub.2).sub.pCN, CONR.sup.12R.sup.13,
(CH.sub.2).sub.pCO.sub.2R.sup.15,
(CH.sub.2).sub.pNR.sup.12R.sup.13, CO.sub.2R.sup.15, NHCOCF.sub.3,
NHSO.sub.2R.sup.15, OCH.sub.2OR.sup.15, OCH.dbd.CHR.sup.15,
O(CH.sub.2CH.sub.2O).sub.nR.sup.15,
O(CH.sub.2).sub.pSO.sub.3R.sup.15,
O(CH.sub.2).sub.pNR.sup.12R.sup.13,
O(CH.sub.2).sub.pN.sup.+R.sup.12R.sup.13R.sup.14 and --W--R.sup.31,
wherein W is O or NH and R.sup.31 is selected from
##STR00002## [0111] wherein p is an integer from 1-4, n is an
integer from 0-3 and, R.sup.12, R.sup.13, R.sup.14 and R.sup.15 are
independently selected from hydrogen and optionally substituted
C.sub.1-6 alkyl; or R.sup.6 and R.sup.7 are linked to form a
group
##STR00003##
[0112] wherein R.sup.12 and R.sup.13 are as hereinbefore defined
and m is 1 or 2; and
R.sup.9 and R.sup.10 are the same or different and each is selected
from hydrogen or C.sub.1-6 alkyl; and salts, solvates and
physiologically functional derivatives thereof.
[0113] In some embodiments of the methods, the compound of Formula
I is a compound wherein
R.sup.1 is a straight chained C.sub.1-6 alkyl group; R.sup.2 is a
straight chained C.sub.1-6 alkyl group; R.sup.3 is hydrogen or a
group OR.sup.11 in which R.sup.11 is hydrogen, optionally
substituted C.sub.1-6 alkyl or a C.sub.1-6 alkylcarbonyl group;
R.sup.4 is optionally substituted phenyl; R.sup.5, R.sup.6 and
R.sup.8 are independently selected from hydrogen, C.sub.1-4 alkyl
optionally substituted by fluorine, C.sub.1-4 alkoxy, halogen, or
hydroxy; R.sup.7 is selected from halogen, cyano,
R.sup.15-acetylide, OR.sup.15, optionally substituted C.sub.1-6
alkyl, COR.sup.15, CH(OH)R.sup.15, S(O).sub.nR.sup.15,
P(O)(OR.sup.15).sub.2, OCOR.sup.15, OCF.sub.3, OCN, SCN, HNCN,
CH.sub.2OR.sup.15, CHO, (CH.sub.2).sub.pCN, CONR.sup.12R.sup.13,
(CH.sub.2).sub.pCO.sub.2R.sup.15,
(CH.sub.2).sub.pNR.sup.12R.sup.13, CO.sub.2R.sup.15, NHCOCF.sub.3,
NHSO.sub.2R.sup.15, OCH.sub.2OR.sup.15, OCH.dbd.CHR.sup.15,
O(CH.sub.2CH.sub.2O).sub.pR.sup.15,
O(CH.sub.2).sub.pSO.sub.3R.sup.15,
O(CH.sub.2).sub.pNR.sup.12R.sup.13 and
O(CH.sub.2).sub.pN.sup.+R.sup.12R.sup.13R.sup.14;
[0114] wherein n, p and R.sup.12 to R.sup.15 are as hereinbefore
defined;
with the proviso that at least two of R.sup.5 to R.sup.8 are not
hydrogen; and salts solvates and physiologically functional
derivatives thereof.
[0115] In some embodiments of the methods described herein, the
compound of Formula I is a compound wherein
R.sup.1 is a straight chained C.sub.1-6 alkyl group; R.sup.2 is a
straight chained C.sub.1-6 alkyl group; R.sup.3 is hydrogen or a
group OR.sup.11 in which R.sup.11 is hydrogen, optionally
substituted C.sub.1-6 alkyl or a C.sub.1-6 alkylcarbonyl group;
R.sup.4 is un-substituted phenyl; R.sup.5 is hydrogen or halogen;
R.sup.6 and R.sup.8 are independently selected from hydrogen,
C.sub.1-4 alkyl optionally substituted by fluorine, C.sub.1-4
alkoxy, halogen, or hydroxy; R.sup.7 is selected from OR.sup.15,
S(O).sub.nR.sup.15, OCOR.sup.15, OCF.sub.3, OCN, SCN, CHO,
OCH.sub.2OR.sup.15, OCH.dbd.CHR.sup.15,
O(CH.sub.2CH.sub.2O).sub.nR.sup.15,
O(CH.sub.2).sub.pSO.sub.3R.sup.15,
O(CH.sub.2).sub.pNR.sup.12R.sup.13 and
O(CH.sub.2).sub.pN.sup.+R.sup.12R.sup.13R.sup.14 wherein p is an
integer from 1-4, n is an integer from 0-3, and R.sup.12, R.sup.13,
R.sup.14, and R.sup.15 are independently selected from hydrogen and
optionally substituted C.sub.1-6 alkyl; R.sup.9 and R.sup.10 are
the same or different and each is selected from hydrogen or
C.sub.1-6 alkyl; and
[0116] salts, solvates and physiologically functional derivatives
thereof.
[0117] In some embodiments of the methods, wherein the compound of
Formula I is a compound wherein
R.sup.1 is methyl, ethyl or n-propyl; R.sup.2 is methyl, ethyl,
n-propyl, n-butyl or n-pentyl; R.sup.3 is hydrogen or a group
OR.sup.11 in which R.sup.11 is hydrogen, optionally substituted
C.sub.1-6 alkyl or a C.sub.1-6 alkylcarbonyl group; R.sup.4 is
un-substituted phenyl; R.sup.5 is hydrogen; R.sup.6 and R.sup.8 are
independently selected from hydrogen, C.sub.1-4 alkyl optionally
substituted by fluorine, C.sub.1-4 alkoxy, halogen, or hydroxy;
R.sup.7 is selected from OR.sup.15, S(O).sub.nR.sup.15,
OCOR.sup.15, OCF.sub.3, OCN, SCN, CHO, OCH.sub.2OR.sup.15,
OCH.dbd.CHR.sup.15, O(CH.sub.2CH.sub.2O).sub.nR.sup.15,
O(CH.sub.2).sub.pSO.sub.3R.sup.15,
O(CH.sub.2).sub.pNR.sup.12R.sup.13 and
O(CH.sub.2).sub.pN.sup.+R.sup.12R.sup.13R.sup.14 wherein p is an
integer from 1-4, n is an integer from 0-3, and R.sup.12, R.sup.13,
R.sup.14, and R.sup.15 are independently selected from hydrogen and
optionally substituted C.sub.1-6 alkyl; R.sup.9 and R.sup.10 are
the same or different and each is selected from hydrogen or
C.sub.1-6 alkyl; and salts, solvates and physiologically functional
derivatives thereof.
[0118] In some embodiments of the methods, the compound of Formula
I is a compound
wherein R.sup.1 is methyl, ethyl or n-propyl; R.sup.2 is methyl,
ethyl, n-propyl, n-butyl or n-pentyl; R.sup.3 is hydrogen or a
group OR.sup.11 in which R.sup.11 is hydrogen, optionally
substituted C.sub.1-6 alkyl or a C.sub.1-6 alkylcarbonyl group;
R.sup.4 is un-substituted phenyl; R.sup.5 is hydrogen; R.sup.6 is
C.sub.1-4 alkoxy, halogen, or hydroxy; R.sup.7 is OR.sup.15,
wherein R.sup.15 is hydrogen or optionally substituted C.sub.1-6
alkyl; R.sup.8 is hydrogen or halogen; R.sup.9 and R.sup.10 are the
same or different and each is selected from hydrogen or C.sub.1-6
alkyl; and salts, solvates and physiologically functional
derivatives thereof.
[0119] In some embodiments of the methods, the compound of Formula
I is [0120]
(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl--
1,4-benzothiazepine 1,1-dioxide; [0121]
(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-ben-
zothiazepin-4-ol 1,1-dioxide; [0122]
(.+-.)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,-
4-benzothiazepine 1,1-dioxide; [0123]
(.+-.)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,-
4,-benzothiazepin-4-ol 1,1-dioxide; [0124]
(3R,5R)-7-Bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-
-benzothiazepine 1,1-dioxide; [0125]
(3R,5R)-7-Bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-
-benzothiazepine-4-ol 1,1-dioxide; [0126]
(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-7-
,8-diol 1,1-dioxide; [0127]
(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzoth-
iazepin-7-ol 1,1-dioxide; [0128]
(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzoth-
iazepin-8-ol 1,1-dioxide; [0129]
(.+-.)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-be-
nzothiazepine 1,1-dioxide; [0130]
(.+-.)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazep-
in-8-ol 1,1-dioxide; [0131]
(.+-.)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazep-
ine-4,8-diol; [0132]
(.+-.)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazep-
in-8-thiol 1,1-dioxide; [0133]
(.+-.)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazep-
in-8-sulfonic acid 1,1-dioxide; [0134]
(.+-.)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8,9-dimethoxy-5-phenyl-1,-
4-benzothiazepine 1,1-dioxide; [0135]
(3R,5R)-3-butyl-7,8-diethoxy-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazep-
ine 1,1-dioxide; [0136]
(.+-.)-Trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-ben-
zothiazepine 1,1-dioxide; [0137]
(.+-.)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-1,4-
-benzothiazepine 1,1-dioxide hydrochloride; [0138]
(.+-.)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazep-
in-8-carbaldehyde-1,1-dioxide; [0139]
3,3-Diethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine
1,1-dioxide; [0140]
3,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine
1,1-dioxide; [0141]
3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-4,8-diol
1,1-dioxide; [0142]
(RS)-3,3-Diethyl-2,3,4,5-tetrahydro-4-hydroxy-7,8-dimethoxy-5-phenyl-1,4--
benzothiazepine 1,1-dioxide; [0143]
(.+-.)-Trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-ben-
zothiazepin-4-ol 1,1-dioxide; [0144]
(.+-.)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-1,4-
-benzothiazepin-4-ol 1,1-dioxide; [0145]
(.+-.)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8,9-trimethoxy-5-phenyl-
-1,4-benzothiazepin-4-ol 1,1-dioxide; [0146]
(3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-4,-
7,8-triol 1,1-dioxide; [0147]
(.+-.)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-4,7,8-trimethoxy-5-phenyl-
-1,4-benzothiazepine 1,1-dioxide; [0148]
3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol
1,1-dioxide; [0149]
3,3-Diethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin-8-ol
1,1-dioxide; [0150]
3,3-Dibutyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol
1,1-dioxide; [0151]
(.+-.)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-be-
nzothiazepin-8-yl hydrogen sulfate; or [0152]
3,3-Diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-yl
hydrogen sulfate.
[0153] In some embodiments, the compound of Formula I is
##STR00004## ##STR00005## ##STR00006## ##STR00007## ##STR00008##
##STR00009##
[0154] In some embodiments of the methods, the compound of Formula
I is
##STR00010##
[0155] In some embodiments, the compound of Formula I is not a
structure shown as:
##STR00011##
wherein m represents an integer of 1 or 2, and R.sup.3 and R.sup.4,
which may be mutually different, each represents an alkyl group
having 1 to 5 carbon atoms.
[0156] In some embodiments, an ASBTI suitable for the methods
described herein is a compound of Formula II
##STR00012##
wherein: [0157] q is an integer from 1 to 4; [0158] n is an integer
from 0 to 2; [0159] R.sup.1 and R.sup.2 are independently selected
from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl,
alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio,
(polyalkyl)aryl, and cycloalkyl, [0160] wherein alkyl, alkenyl,
alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl,
dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally
are substituted with one or more substituents selected from the
group consisting of OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.10R.sup.wA.sup.-, SR.sup.9,
S.sup.+R.sup.9R.sup.10A.sup.-,
P.sup.+R.sup.9R.sup.10R.sup.11A.sup.-, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN, halogen,
oxo, and CONR.sup.9R.sup.10, [0161] wherein alkyl, alkenyl,
alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and
cycloalkyl optionally have one or more carbons replaced by O,
NR.sup.9, N.sup.+R.sup.9R.sup.10A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.9A.sup.-, P.sup.+R.sup.9R.sup.10A.sup.-, or phenylene,
[0162] wherein R.sup.9, R.sup.10, and R.sup.w are independently
selected from the group consisting of H, alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, and
alkylammoniumalkyl; or [0163] R.sup.1 and R.sup.2 taken together
with the carbon to which they are attached form C.sub.3-C.sub.10
cycloalkyl; [0164] R.sup.3 and R.sup.4 are independently selected
from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy,
aryl, heterocycle, OR.sup.9, NR.sup.9R.sup.10, SR.sup.9,
S(O)R.sup.9, SO.sub.2R.sup.9, and SO.sub.3R.sup.9, wherein R.sup.9
and R.sup.10 are as defined above; or [0165] R.sup.3 and R.sup.4
together .dbd.O, .dbd.NOR.sup.11, .dbd.S, .dbd.NNR.sup.11R.sup.12,
.dbd.NR.sup.9, or .dbd.CR.sup.11R.sup.12, [0166] wherein R.sup.11
and R.sup.12 are independently selected from the group consisting
of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl,
alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cyclo
alkyl, cyanoalkyl, OR.sup.9, NR.sup.9R.sup.10, SR.sup.9,
S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN,
halogen, oxo, and CONR.sup.9R.sup.10, wherein R.sup.9 and R.sup.10
are as defined above, provided that both R.sup.3 and R.sup.4 cannot
be OH, NH.sub.2, and SH, or [0167] R.sup.11 and R.sup.12 together
with the nitrogen or carbon atom to which they are attached form a
cyclic ring; [0168] R.sup.5 and R.sup.6 are independently selected
from the group consisting of H, alkyl, alkenyl, alkynyl, aryl,
cycloalkyl, heterocycle, quaternary heterocycle, quarternary
heteroaryl, OR.sup.9, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9,
SO.sub.3R.sup.9, and -L.sub.z-K.sub.z; [0169] wherein z is 1, 2 or
3; each L is independently a substituted or unsubstituted alkyl, a
substituted or unsubstituted heteroalkyl, a substituted or
unsubstituted alkoxy, a substituted or unsubstituted aminoalkyl
group, a substituted or unsubstituted aryl, a substituted or
unsubstituted heteroaryl, a substituted or unsubstituted
cycloalkyl, or a substituted or unsubstituted heterocycloalkyl;
each K is a moiety that prevents systemic absorption; [0170]
wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle,
quaternary heterocycle, and quaternary heteroaryl can be
substituted with one or more substituent groups independently
selected from the group consisting of alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,
arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen,
oxo, R.sup.15, OR.sup.13, OR.sup.13R.sup.14, NR.sup.13R.sup.14,
SR.sup.13, S(O)R.sup.13, SO.sub.2R.sup.13, SO.sub.3R.sup.13,
NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15, NO.sub.2,
CO.sub.2R.sup.13, CN, OM, SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14,
C(O)NR.sup.13R.sup.14, C(O)OM, CR.sup.13, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, wherein: [0171] A.sup.- is a
pharmaceutically acceptable anion and M is a pharmaceutically
acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl,
polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be
further substituted with one or more substituent groups selected
from the group consisting of OR.sup.7, NR.sup.7R.sup.8,
S(O)R.sup.7, SO.sub.2R.sup.7, SO.sub.3R.sup.7, CO.sub.2R.sup.7, CN,
oxo, CONR.sup.7R.sup.8, N.sup.+R.sup.7R.sup.8R.sup.9A.sup.-, alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl,
quaternary heterocycle, quaternary heteroaryl, P(O)R.sup.7R.sup.8,
P.sup.+R.sup.7R.sup.8R.sup.9A.sup.-, and P(O)(OR.sup.7) OR.sup.8
and [0172] wherein said alkyl, alkenyl, alkynyl, polyalkyl,
polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can
optionally have one or more carbons replaced by O, NR.sup.7,
N.sup.+R.sup.7R.sup.8A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.7A.sup.-, PR.sup.7, P(O)R.sup.7,
P.sup.+R.sup.7R.sup.8A.sup.-, or phenylene, and R.sup.13, R.sup.14,
and R.sup.15 are independently selected from the group consisting
of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl,
cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle,
quaternary heteroaryl, quaternary heteroarylalkyl, and -G-T-V--W,
[0173] wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and
polyalkyl optionally have one or more carbons replaced by O,
NR.sup.9, N.sup.+R.sup.9R.sup.10A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.9A.sup.-, PR, P.sup.+R.sup.9R.sup.10A.sup.-,
P(O)R.sup.9, phenylene, carbohydrate, C.sub.2-C.sub.7 polyol, amino
acid, peptide, or polypeptide, and [0174] G, T and V are each
independently a bond, --O--, --S--, --N(H)--, substituted or
unsubstituted alkyl, --O-alkyl, --N(H)-alkyl, --C(O)N(H)--,
--N(H)C(O)--, --N(H)C(O)N(H)--, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted aryl, substituted or unsubstituted arylalkyl,
substituted or unsubstituted alkenylalkyl, alkynylalkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted heterocycle, substituted or unsubstituted
carboxyalkyl, substituted or unsubstituted carboalkoxyalkyl, or
substituted or unsubstituted cycloalkyl, and [0175] W is quaternary
heterocycle, quaternary heteroaryl, quaternary heteroarylalkyl,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
P.sup.+R.sup.9R.sup.10R.sup.11A.sup.-, OS(O).sub.2OM, or
S.sup.+R.sup.9R.sup.10A.sup.-, and [0176] R.sup.13, R.sup.14 and
R.sup.15 are optionally substituted with one or more groups
selected from the group consisting of sulfoalkyl, quaternary
heterocycle, quaternary heteroaryl, OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10, SO.sub.2OM, SO.sub.2NR.sup.9R.sup.10,
PO(OR.sup.16)OR.sup.17, P.sup.+R.sup.9R.sup.10R.sup.11A.sup.-,
S.sup.+R.sup.9R.sup.10A.sup.-, and C(O)OM, [0177] wherein R.sup.16
and R.sup.17 are independently selected from the substituents
constituting R.sup.9 and M; or [0178] R.sup.14 and R.sup.15,
together with the nitrogen atom to which they are attached, form a
cyclic ring; and [0179] is selected from the group consisting of
alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle,
ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; and [0180]
R.sup.7 and R.sup.8 are independently selected from the group
consisting of hydrogen and alkyl; and [0181] one or more R.sup.x
are independently selected from the group consisting of H, alkyl,
alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen,
haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether,
quaternary heterocycle, quaternary heteroaryl, OR.sup.13,
NR.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13, S(O).sub.2R.sup.13,
SO.sub.3R.sup.13, S.sup.+R.sup.13R.sup.14A.sup.-,
NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15, NO.sub.2,
CO.sub.2R.sup.13, CN, OM, SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14,
NR.sup.14C(O)R.sup.13, C(O)NR.sup.13R.sup.14,
NR.sup.14C(O)R.sup.13, C(O)OM, COR.sup.13, OR.sup.18,
S(O).sub.nNR.sup.18, NR.sup.13R.sup.18, NR.sup.18R.sup.14,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
P.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, amino acid, peptide,
polypeptide, and carbohydrate, [0182] wherein alkyl, alkenyl,
alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy,
arylalkyl, haloalkyl, polyether, quaternary heterocycle, and
quaternary heteroaryl can be further substituted with OR.sup.9,
NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9,
S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo,
CO.sub.2R.sup.9, CN, halogen, CONR.sup.9R.sup.10, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17,
P.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
S.sup.+R.sup.9R.sup.10A.sup.-, or C(O)M, and [0183] wherein
R.sup.18 is selected from the group consisting of acyl,
arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,
[0184] wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle,
heteroaryl, alkyl, quaternary heterocycle, and quaternary
heteroaryl optionally are substituted with one or more substituents
selected from the group consisting of OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.3R.sup.9, CN,
halogen, CONR.sup.9R.sup.10, SO.sub.3R.sup.9, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17, and C(O)OM,
[0185] wherein in R.sup.x, one or more carbons are optionally
replaced by O, NR.sup.13, N.sup.+R.sup.13R.sup.14A.sup.-, S, SO,
SO.sub.2, S.sup.+R.sup.13A.sup.-, PR.sup.13,
P(O)R.sup.13R.sup.14A.sup.-, phenylene, amino acid, peptide,
polypeptide, carbohydrate, polyether, or polyalkyl, [0186] wherein
in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and
carbohydrate, one or more carbons are optionally replaced by O,
NR.sup.9, R.sup.9R.sup.10A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.9A.sup.-, PR.sup.9, P.sup.+R.sup.9R.sup.10A.sup.-, or
P(O)R.sup.9 [0187] wherein quaternary heterocycle and quaternary
heteroaryl are optionally substituted with one or more groups
selected from the group consisting of alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,
arylalkyl, halogen, oxo, OR.sup.13, NR.sup.13R.sup.14, SR.sup.13,
S(O)R.sup.13, SO.sub.2R.sup.13, SO.sub.3R.sup.13,
NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15, NO.sub.2,
CO.sub.2R.sup.13, CN, OM, SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14,
C(O)NR.sup.13R.sup.14, C(O)OM, COR.sup.13, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, [0188] provided that both
R.sup.5 and R.sup.6 cannot be hydrogen or SH; [0189] provided that
when R.sup.5 or R.sup.6 is phenyl, only one of R.sup.1 or R.sup.2
is H; provided that when q=1 and R.sup.x is styryl, anilido, or
anilinocarbonyl, only one of R.sup.5 or R.sup.6 is alkyl; or a
pharmaceutically acceptable salt, solvate, or prodrug thereof.
[0190] In some embodiments of the methods, the compound of Formula
II is a compound wherein [0191] q is an integer from 1 to 4; [0192]
n is 2; [0193] R.sup.1 and R.sup.2 are independently selected from
the group consisting of H, alkyl, alkoxy, dialkylamino, and
alkylthio, [0194] wherein alkyl, alkoxy, dialkylamino, and
alkylthio are optionally substituted with one or more substituents
selected from the group consisting of OR.sup.9, NR.sup.9R.sup.10,
SR.sup.9, SO.sub.2R.sup.9, CO.sub.2R.sup.9, CN, halogen, oxo, and
CONR.sup.9R.sup.10; [0195] each R.sup.9 and R.sup.10 are each
independently selected from the group consisting of H, alkyl,
cycloalkyl, aryl, acyl, heterocycle, and arylalkyl; [0196] R.sup.3
and R.sup.4 are independently selected from the group consisting of
H, alkyl, acyloxy, OR.sup.9, NR.sup.9R.sup.10, SR.sup.9, and
SO.sub.2R.sup.9, wherein R.sup.9 and R.sup.10 are as defined above;
[0197] R.sup.11 and R.sup.12 are independently selected from the
group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl,
alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl,
carboalkoxyalkyl, cyclo alkyl, cyanoalkyl, OR.sup.9,
NR.sup.9R.sup.10, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9,
SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN, halogen, oxo, and
CONR.sup.9R.sup.10, wherein R.sup.9 and R.sup.10 are as defined
above, provided that both R.sup.3 and R.sup.4 cannot be OH,
NH.sub.2, and SH, or [0198] R.sup.11 and R.sup.12 together with the
nitrogen or carbon atom to which they are attached form a cyclic
ring; [0199] R.sup.5 and R.sup.6 are independently selected from
the group consisting of H, alkyl, aryl, cycloalkyl, heterocycle,
and -L.sub.z-K.sub.z; [0200] wherein z is 1 or 2; each L is
independently a substituted or unsubstituted alkyl, a substituted
or unsubstituted heteroalkyl, a substituted or unsubstituted aryl,
a substituted or unsubstituted heteroaryl, a substituted or
unsubstituted cycloalkyl, or a substituted or unsubstituted
heterocycloalkyl; each K is a moiety that prevents systemic
absorption; [0201] wherein alkyl, aryl, cycloalkyl, and heterocycle
can be substituted with one or more substituent groups
independently selected from the group consisting of alkyl, aryl,
haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary
heterocycle, quaternary heteroaryl, halogen, oxo, OR.sup.13,
OR.sup.13R.sup.14, NR.sup.13R.sup.14, SR.sup.13, SO.sub.2R.sup.13,
NR.sup.13NR.sup.14R.sup.15, NO.sub.2, CO.sub.2R.sup.13, CN, OM, and
CR.sup.13, [0202] wherein: [0203] A.sup.- is a pharmaceutically
acceptable anion and M is a pharmaceutically acceptable cation;
[0204] R.sup.13, R.sup.14, and R.sup.15 are independently selected
from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,
polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl,
quaternary heterocycle, quaternary heteroaryl, and quaternary
heteroarylalkyl, wherein R.sup.13, R.sup.14 and R.sup.15 are
optionally substituted with one or more groups selected from the
group consisting of quaternary heterocycle, quaternary heteroaryl,
OR.sup.9, NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo,
CO.sub.2R.sup.9, CN, halogen, and CONR.sup.9R.sup.10; or [0205]
R.sup.14 and R.sup.15, together with the nitrogen atom to which
they are attached, form a cyclic ring; and is selected from the
group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, and
arylalkyl; and [0206] R.sup.7 and R.sup.8 are independently
selected from the group consisting of hydrogen and alkyl; and one
or more Rx are independently selected from the group consisting of
H, alkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl,
heterocycle, heteroaryl, OR.sup.13, NR.sup.13R.sup.14, SR.sup.13,
S(O).sub.2R.sup.13, NR.sup.13NR.sup.14R.sup.15, NO.sub.2,
CO.sub.2R.sup.13, CN, SO.sub.2NR.sup.13R.sup.14,
NR.sup.14C(O)R.sup.13, C(O)NR.sup.13R.sup.14,
NR.sup.14C(O)R.sup.13, and COR.sup.13; provided that both R.sup.5
and R.sup.6 cannot be hydrogen; provided that when R.sup.5 or
R.sup.6 is phenyl, only one of R.sup.1 or R.sup.2 is H; provided
that when q=1 and R.sup.x is styryl, anilido, or anilinocarbonyl,
only one of R.sup.5 or R.sup.6 is alkyl; or a pharmaceutically
acceptable salt, solvate, or prodrug thereof.
[0207] In some embodiments, the compound of Formula II is a
compound wherein [0208] q is 1; [0209] n is 2; [0210] R.sup.x is
N(CH.sub.3).sub.2; [0211] R.sup.7 and R.sup.8 are independently H;
[0212] R.sup.1 and R.sup.2 is alkyl; [0213] R.sup.3 is H, and
R.sup.4 is OH; [0214] R.sup.5 is H, and R.sup.6 is selected from
the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocycle, quaternary heterocycle, quarternary heteroaryl,
OR.sup.9, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9,
and -L.sub.z-K.sub.z; [0215] wherein z is 1, 2 or 3; each L is
independently a substituted or unsubstituted alkyl, a substituted
or unsubstituted heteroalkyl, a substituted or unsubstituted
alkoxy, a substituted or unsubstituted aminoalkyl group, a
substituted or unsubstituted aryl, a substituted or unsubstituted
heteroaryl, a substituted or unsubstituted cycloalkyl, or a
substituted or unsubstituted heterocycloalkyl; each K is a moiety
that prevents systemic absorption; [0216] wherein alkyl, alkenyl,
alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and
quaternary heteroaryl can be substituted with one or more
substituent groups independently selected from the group consisting
of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl,
cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle,
quaternary heteroaryl, halogen, oxo, R.sup.15, OR.sup.13,
OR.sup.13R.sup.14, NR.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13,
SO.sub.2R.sup.13, SO.sub.3R.sup.13, NR.sup.13OR.sup.14,
NR.sup.13NR.sup.14R.sup.15, NO.sub.2, CO.sub.2R.sup.13, CN, OM,
SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14, C(O)NR.sup.13R.sup.14,
C(O)OM, CR.sup.13, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, [0217] wherein A.sup.- is a
pharmaceutically acceptable anion and M is a pharmaceutically
acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl,
polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be
further substituted with one or more substituent groups selected
from the group consisting of OR.sup.7, NR.sup.7R.sup.8,
S(O)R.sup.7, SO.sub.2R.sup.7, SO.sub.3R.sup.7, CO.sub.2R.sup.7, CN,
oxo, CONR.sup.7R.sup.8, N.sup.+R.sup.7R.sup.8R.sup.9A.sup.-, alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl,
quaternary heterocycle, quaternary heteroaryl, P(O)R.sup.7R.sup.8,
P.sup.+R.sup.7R.sup.8R.sup.9A.sup.-, and P(O)(OR.sup.7) OR.sup.8
and [0218] wherein said alkyl, alkenyl, alkynyl, polyalkyl,
polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can
optionally have one or more carbons replaced by O, NR.sup.7,
N.sup.+R.sup.7R.sup.8A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.7A.sup.-, PR.sup.7, P(O)R.sup.7,
P.sup.+R.sup.7R.sup.8A.sup.-, or phenylene, and R.sup.13, R.sup.14,
and R.sup.15 are independently selected from the group consisting
of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl,
cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle,
quaternary heteroaryl, quaternary heteroarylalkyl, and -G-T-V--W,
[0219] wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and
polyalkyl optionally have one or more carbons replaced by O,
NR.sup.9, N.sup.+R.sup.9R.sup.10A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.9A.sup.-, PR, P.sup.+R.sup.9R.sup.10A.sup.-,
P(O)R.sup.9, phenylene, carbohydrate, C.sub.2-C.sub.7 polyol, amino
acid, peptide, or polypeptide, and [0220] G, T and V are each
independently a bond, --O--, --S--, --N(H)--, substituted or
unsubstituted alkyl, --O-alkyl, --N(H)-alkyl, --C(O)N(H)--,
--N(H)C(O)--, --N(H)C(O)N(H)--, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted aryl, substituted or unsubstituted arylalkyl,
substituted or unsubstituted alkenylalkyl, alkynylalkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted heterocycle, substituted or unsubstituted
carboxyalkyl, substituted or unsubstituted carboalkoxyalkyl, or
substituted or unsubstituted cycloalkyl, and [0221] W is quaternary
heterocycle, quaternary heteroaryl, quaternary heteroarylalkyl,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
P.sup.+R.sup.9R.sup.10R.sup.11A.sup.-, OS(O).sub.2OM, or
S.sup.+R.sup.9R.sup.10A.sup.-, and [0222] R.sup.9 and R.sup.10 are
independently selected from the group consisting of H, alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle,
ammoniumalkyl, arylalkyl, and alkylammoniumalkyl; [0223] R.sup.11
and R.sup.12 are independently selected from the group consisting
of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl,
alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cyclo
alkyl, cyanoalkyl, OR.sup.9, NR.sup.9R.sup.10, SR.sup.9,
S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN,
halogen, oxo, and CONR.sup.9R.sup.10, wherein R.sup.9 and R.sup.10
are as defined above, provided that both R.sup.3 and R.sup.4 cannot
be OH, NH.sub.2, and SH, or [0224] R.sup.11 and R.sup.12 together
with the nitrogen or carbon atom to which they are attached form a
cyclic ring; [0225] R.sup.13, R.sup.14 and R.sup.15 are optionally
substituted with one or more groups selected from the group
consisting of sulfoalkyl, quaternary heterocycle, quaternary
heteroaryl, OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9, S(O) R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10, SO.sub.2OM, SO.sub.2NR.sup.9R.sup.10,
PO(OR.sup.16)OR.sup.17, P.sup.+R.sup.9R.sup.10R.sup.11A.sup.-,
S.sup.+R.sup.9R.sup.10A.sup.-, and C(O)OM,
[0226] wherein R.sup.16 and R.sup.17 are independently selected
from the substituents constituting R.sup.9 and M; or [0227]
R.sup.14 and R.sup.15, together with the nitrogen atom to which
they are attached, form a cyclic ring; and is selected from the
group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, and
arylalkyl; [0228] or a pharmaceutically acceptable salt, solvate,
or prodrug thereof.
[0229] In some embodiments, the compound of Formula II is a
compound wherein [0230] q is 1; [0231] n is 2; [0232] R.sup.x is
N(CH.sub.3).sub.2; [0233] R.sup.7 and R.sup.8 are independently H;
[0234] R.sup.1 and R.sup.2 is independently C.sub.1-C.sub.4 alkyl;
[0235] R.sup.3 is H, and R.sup.4 is OH; [0236] R.sup.5 is H, and
R.sup.6 is aryl substituted with one or more substituent groups
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl,
heterocycle, arylalkyl, quaternary heterocycle, quaternary
heteroaryl, halogen, oxo, R.sup.15, OR.sup.13, OR.sup.13R.sup.14,
NR.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13, SO.sub.2R.sup.13,
SO.sub.3R.sup.13, NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15,
NO.sub.2, CO.sub.2R.sup.13, CN, OM, SO.sub.2OM,
SO.sub.2NR.sup.13R.sup.14, C(O)NR.sup.13R.sup.14, C(O)OM,
CR.sup.13, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-. [0237] wherein A.sup.- is a
pharmaceutically acceptable anion and M is a pharmaceutically
acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl,
polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be
further substituted with one or more substituent groups selected
from the group consisting of OR.sup.7, NR.sup.7R.sup.8,
S(O)R.sup.7, SO.sub.2R.sup.7, SO.sub.3R.sup.7, CO.sub.2R.sup.7, CN,
oxo, CONR.sup.7R.sup.8, N.sup.+R.sup.7R.sup.8R.sup.9A.sup.-, alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl,
quaternary heterocycle, quaternary heteroaryl, P(O)R.sup.7R.sup.8,
P.sup.+R.sup.7R.sup.8R.sup.9A.sup.-, and P(O)(OR.sup.7) OR.sup.8
and [0238] wherein said alkyl, alkenyl, alkynyl, polyalkyl,
polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can
optionally have one or more carbons replaced by O, NR.sup.7,
N.sup.+R.sup.7R.sup.8A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.7A.sup.-, PR.sup.7, P(O)R.sup.7,
P.sup.+R.sup.7R.sup.8A.sup.-, or phenylene, and R.sup.13, R.sup.14,
and R.sup.15 are independently selected from the group consisting
of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl,
cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle,
quaternary heteroaryl, quaternary heteroarylalkyl, and -G-T-V--W,
[0239] wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and
polyalkyl optionally have one or more carbons replaced by O,
NR.sup.9, N.sup.+R.sup.9R.sup.10A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.9A.sup.-, PR, P.sup.+R.sup.9R.sup.10A.sup.-,
P(O)R.sup.9, phenylene, carbohydrate, C.sub.2-C.sub.7 polyol, amino
acid, peptide, or polypeptide, and [0240] G, T and V are each
independently a bond, --O--, --S--, --N(H)--, substituted or
unsubstituted alkyl, --O-alkyl, --N(H)-alkyl, --C(O)N(H)--,
--N(H)C(O)--, --N(H)C(O)N(H)--, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted aryl, substituted or unsubstituted arylalkyl,
substituted or unsubstituted alkenylalkyl, alkynylalkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted heterocycle, substituted or unsubstituted
carboxyalkyl, substituted or unsubstituted carboalkoxyalkyl, or
substituted or unsubstituted cycloalkyl, and [0241] W is quaternary
heterocycle, quaternary heteroaryl, quaternary heteroarylalkyl,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
P.sup.+R.sup.9R.sup.10R.sup.11A.sup.-, OS(O).sub.2OM, or
S.sup.+R.sup.9R.sup.10A.sup.-, and [0242] R.sup.9 and R.sup.10 are
independently selected from the group consisting of H, alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle,
ammoniumalkyl, arylalkyl, and alkylammoniumalkyl; [0243] R.sup.11
and R.sup.12 are independently selected from the group consisting
of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl,
alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cyclo
alkyl, cyanoalkyl, OR.sup.9, NR.sup.9R.sup.10, SR.sup.9,
S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN,
halogen, oxo, and CONR.sup.9R.sup.10, wherein R.sup.9 and R.sup.10
are as defined above, provided that both R.sup.3 and R.sup.4 cannot
be OH, NH.sub.2, and SH, or [0244] R.sup.11 and R.sup.12 together
with the nitrogen or carbon atom to which they are attached form a
cyclic ring; [0245] R.sup.13, R.sup.14 and R.sup.15 are optionally
substituted with one or more groups selected from the group
consisting of sulfoalkyl, quaternary heterocycle, quaternary
heteroaryl, OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10, SO.sub.2OM, SO.sub.2NR.sup.9R.sup.10,
PO(OR.sup.16)OR.sup.17, P.sup.+R.sup.9R.sup.10R.sup.11A.sup.-,
S.sup.+R.sup.9R.sup.10A.sup.-, and C(O)OM, [0246] wherein R.sup.16
and R.sup.17 are independently selected from the substituents
constituting R.sup.9 and M; or [0247] R.sup.14 and R.sup.15,
together with the nitrogen atom to which they are attached, form a
cyclic ring; and is selected from the group consisting of alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle,
ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; [0248] or a
pharmaceutically acceptable salt, solvate, or prodrug thereof.
[0249] In some embodiments of the methods, the compound of Formula
II is a compound
wherein R.sup.5 and R.sup.6 are independently selected from the
group consisting of H, aryl, heterocycle, quaternary heterocycle,
and quarternary heteroaryl [0250] wherein the aryl, heteroaryl,
quaternary heterocycle and quaternary heteroaryl are optionally
substituted with one or more groups selected from the group
consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,
haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo,
OR.sup.13, OR.sup.13R.sup.14, NR.sup.13R.sup.14, SR.sup.13,
S(O)R.sup.13, SO.sub.2R.sup.13, SO.sub.3R.sup.13,
NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15, NO.sub.2,
CO.sub.2R.sup.13, CN, OM, SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14,
C(O)NR.sup.13R.sup.14, C(O)OM, COR.sup.13, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.- and -L.sub.z-K.sub.z.
[0251] In some embodiments of the methods, the compound of Formula
II is a compound wherein
R.sup.5 or R.sup.6 is --Ar--(R.sup.y).sub.t
[0252] t is an integer from 0 to 5; [0253] Ar is selected from the
group consisting of phenyl, thiophenyl, pyridyl, piperazinyl,
piperonyl, pyrrolyl, naphthyl, furanyl, anthracenyl, quinolinyl,
isoquinolinyl, quinoxalinyl, imidazolyl, pyrazolyl, oxazolyl,
isoxazolyl, pyrimidinyl, thiazolyl, triazolyl, isothiazolyl,
indolyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, and
benzoisothiazolyl; and [0254] one or more R.sup.Y are independently
selected from the group consisting of alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, halo alkyl, cycloalkyl, heterocycle,
arylalkyl, halogen, oxo, OR.sup.13, OR.sup.13R.sup.14,
NR.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13, SO.sub.2R.sup.13,
SO.sub.3R.sup.13, NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15,
NO.sub.2, CO.sub.2R.sup.13, CN, OM, SO.sub.2OM,
SO.sub.2NR.sup.13R.sup.14, C(O)NR.sup.13R.sup.14C(O)OM, COR.sup.13,
P(O)R.sup.13R.sup.14, P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-,
P(OR.sup.13)OR.sup.14, S.sup.+R.sup.13R.sup.14A.sup.-,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.- and -L.sub.z-K.sub.z; [0255]
wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,
haloalkyl, cycloalkyl, and heterocycle can be further substituted
with one or more substituent groups selected from the group
consisting of OR.sup.13, NR.sup.13R.sup.14, SR.sup.13,
S(O)R.sup.13, SO.sub.2R.sup.13, SO.sub.3R.sup.13,
NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15, NO.sub.2,
CO.sub.2R.sup.13, CN, oxo, CONR.sup.7R.sup.8,
N.sup.+R.sup.7R.sup.8R.sup.9A.sup.-, alkyl, alkenyl, alkynyl, aryl,
cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle,
quaternary heteroaryl, P(O)R.sup.7R.sup.8,
P.sup.+R.sup.7R.sup.8A.sup.-, and P(O)(OR.sup.7)OR.sup.8, and or
phenylene; [0256] wherein said alkyl, alkenyl, alkynyl, polyalkyl,
polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can
optionally have one or more carbons replaced by O, NR.sup.7,
N.sup.+R.sup.7R.sup.8A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.7A.sup.-, PR.sup.7, P(O)R.sup.7,
P.sup.+R.sup.7R.sup.8A.sup.-, or phenylene.
[0257] In some embodiments of the methods, the compound of Formula
II is a compound wherein
R.sup.5 or R.sup.6 is
##STR00013##
[0259] In some embodiments of the methods, the compound of Formula
II is a compound wherein n is 1 or 2. In some embodiments of the
methods, the compound of Formula II is a compound wherein R.sup.1
and R.sup.2 are independently H or C.sub.1-7 alkyl. In some
embodiments of the methods, the compound of Formula II is a
compound wherein each C.sub.1-7 alkyl is independently ethyl,
n-propyl, n-butyl, or isobutyl. In some embodiments of the methods,
the compound of Formula II is a compound wherein R.sup.3 and
R.sup.4 are independently H or OR.sup.9. In some embodiments of the
methods, compound of Formula II is a compound wherein R.sup.9 is
H
[0260] In some embodiments of the methods, the compound of Formula
II is a compound wherein one or more R.sup.x are in the 7-, 8- or
9-position of the benzo ring of Formula II. In some embodiments of
the methods, the compound of Formula II is a compound wherein
R.sup.x is in the 7-position of the benzo ring of Formula II. In
some embodiments of the methods, the compound of Formula II is a
compound wherein one or more R.sup.x are independently selected
from OR.sup.13 and NR.sup.13R.sup.14.
[0261] In some embodiments of the methods, the compound of Formula
II is a compound
wherein: q is 1 or 2; n is 2; R.sup.1 and R.sup.2 are each alkyl;
R.sup.3 is hydroxy; R.sup.4 and R.sup.6 are hydrogen; R.sup.5 has
the formula
##STR00014##
wherein t is an integer from 0 to 5; [0262] one or more R.sup.Y are
OR.sup.13 or OR.sup.13R.sup.14; [0263] R.sup.13 and R.sup.14 are
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl,
heterocycle, heteroaryl, quaternary heterocycle, quaternary
heteroaryl, and quaternary heteroarylalkyl; [0264] wherein said
alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl
groups optionally have one or more carbons replaced by O, NR.sup.9,
N.sup.+R.sup.9R.sup.10A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.9A.sup.-, PR.sup.9, P.sup.+R.sup.9R.sup.10A.sup.-,
P(O)R.sup.9, phenylene, carbohydrate, amino acid, peptide, or
polypeptide; [0265] R.sup.13 and R.sup.14 are optionally
substituted with one or more groups independently selected from the
group consisting of sulfoalkyl, quaternary heterocycle, quaternary
heteroaryl, OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10, SO.sub.2OM, SO.sub.2NR.sup.9R.sup.10,
PO(OR.sup.16)OR.sup.17, P.sup.+R.sup.9R.sup.10R.sup.11A.sup.-,
S.sup.+R.sup.9R.sup.10A.sup.-, and C(O)OM, [0266] wherein A is a
pharmaceutically acceptable anion, and M is a pharmaceutically
acceptable cation, [0267] R.sup.9 and R.sup.10 are independently
selected from the group consisting of H, alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, and
alkylammoniumalkyl; [0268] R.sup.11 and R.sup.12 are independently
selected from the group consisting of H, alkyl, alkenyl, alkynyl,
aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle,
carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR.sup.9,
NR.sup.9R.sup.10, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9,
SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN, halogen, oxo, and
CONR.sup.9R.sup.10, wherein R.sup.9 and R.sup.10 are as defined
above, provided that both R.sup.3 and R.sup.4 cannot be OH,
NH.sub.2, and SH; or [0269] R.sup.11 and R.sup.12 together with the
nitrogen or carbon atom to which they are attached form a cyclic
ring; and [0270] R.sup.16 and R.sup.17 are independently selected
from the substituents constituting R.sup.9 and M; [0271] R.sup.7
and R.sup.8 are hydrogen; and [0272] one or more R.sup.x are
independently selected from the group consisting of alkoxy,
alkylamino and dialkylamino and --W--R.sup.31, wherein W is O or NH
and R.sup.31 is selected from
##STR00015##
[0272] or a pharmaceutically acceptable salt, solvate, or prodrug
thereof.
[0273] In some embodiments, a compound of Formula II is
##STR00016## ##STR00017##
or the like.
[0274] In some embodiments of the methods, the compound of Formula
II is
##STR00018##
[0275] In certain embodiments, ASBTIs suitable for the methods
described herein are non-systemic analogs of Compound 100C. Certain
compounds provided herein are Compound 100C analogues modified or
substituted to comprise a charged group. In specific embodiments,
the Compound 100C analogues are modified or substituted with a
charged group that is an ammonium group (e.g., a cyclic aracyclic
ammonium group). In certain embodiments, the ammonium group is a
non-protic ammonium group that contains a quarternary nitrogen.
[0276] In some embodiments, a compound of Formula II is
##STR00019##
[0277] In some embodiments, a compound of Formula II is
1-[[5-[[3-[(3S,4R,5R)-3-butyl-7-(dimethylamino)-3-ethyl-2,3,4,5-tetrahydr-
o-4-hydroxy-1,1-dioxido-1-benzothiepin-5yl]phenyl]amino]-5-oxopentyl]amino-
]-1-deoxy-D-glucitol or SA HMR1741 (a.k.a. BARI-1741).
[0278] In some embodiments, a compound of Formula II is
##STR00020##
[0279] In some embodiments, a compound of Formula II is
potassium((2R,3R,4S,5R,6R)-4-benzyloxy-6-{3-[3-((3S,4R,5R)-3-butyl-7-dime-
thylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepi-
n-5-yl)-phenyl]-ureido}-3,5-dihydroxy-tetrahydro-pyran-2-ylmethyl)sulphate
ethanolate, hydrate or SAR548304B (a.k.a. SAR-548304).
[0280] In some embodiments, an ASBTI suitable for the methods
described herein is a compound of Formula III:
##STR00021##
[0281] wherein: [0282] each R.sup.1, R.sup.2 is independently H,
hydroxy, alkyl, alkoxy, --C(.dbd.X)YR.sup.8, --YC(.dbd.X)R.sup.8,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted alkyl-cycloalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
alkyl-heteroaryl, substituted or unsubstituted heterocycloalkyl,
substituted or unsubstituted alkyl-heterocycloalkyl, or -L-K; or
R.sup.1 and R.sup.2 together with the nitrogen to which they are
attached form a 3-8-membered ring that is optionally substituted
with R.sup.8; [0283] each R.sup.3, R.sup.4 is independently H,
hydroxy, alkyl, alkoxy, --C(.dbd.X)YR.sup.8, --YC(.dbd.X)R.sup.8,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted alkyl-cycloalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
alkyl-heteroaryl, substituted or unsubstituted heterocycloalkyl,
substituted or unsubstituted alkyl-heterocycloalkyl, or -L-K;
[0284] R.sup.5 is H, hydroxy, alkyl, alkoxy, --C(.dbd.X)YR.sup.8,
--YC(.dbd.X)R.sup.8, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted alkyl-aryl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted alkyl-cycloalkyl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted alkyl-heteroaryl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted alkyl-heterocycloalkyl, [0285] each R.sup.6, R.sup.7
is independently H, hydroxy, alkyl, alkoxy, --C(.dbd.X)YR.sup.8,
--YC(.dbd.X)R.sup.8, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted alkyl-aryl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted alkyl-cycloalkyl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted alkyl-heteroaryl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted alkyl-heterocycloalkyl, or -L-K; or R.sup.6 and
R.sup.7 taken together form a bond; [0286] each X is independently
NH, S, or O; [0287] each Y is independently NH, S, or O; [0288]
R.sup.8 is substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted alkyl-aryl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
alkyl-cycloalkyl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted alkyl-heteroaryl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted
alkyl-heterocycloalkyl, or -L-K; [0289] L is A.sub.n, wherein
[0290] each A is independently NR.sup.1, S(O).sub.m, O, C(.dbd.X)Y,
Y(C.dbd.X), substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted cycloalkyl, or substituted or unsubstituted
heterocycloalkyl; wherein each m is independently 0-2; [0291] n is
0-7; [0292] K is a moiety that prevents systemic absorption; [0293]
provided that at least one of R.sup.1, R.sup.2, R.sup.3 or R.sup.4
is -L-K;
[0294] or a pharmaceutically acceptable prodrug thereof.
[0295] In some embodiments of a compound of Formula III, R.sup.1
and R.sup.3 are -L-K. In some embodiments, R.sup.1, R.sup.2 and
R.sup.3 are -L-K.
[0296] In some embodiments, at least one of R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 is H. In certain
embodiments, R.sup.5, R.sup.6, R.sup.7 are H and R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 are alkyl, aryl, alkyl-aryl, or heteroalkyl. In
some embodiments, R.sup.1 and R.sup.2 are H. In some embodiments,
R.sup.1, R.sup.2, R.sup.5, R.sup.6 and R.sup.7 are H. In some
embodiments, R.sup.6 and R.sup.7 together form a bond. In certain
embodiments, R.sup.5, R.sup.6 and R.sup.7 are H, alkyl or
O-alkyl.
[0297] In some embodiments, R.sup.1 and R.sup.3 are -L-K. In some
embodiments, R.sup.1, R.sup.2 and R.sup.3 are -L-K. In some
embodiments, R.sup.3 and R.sup.4 are -L-K. In some embodiments,
R.sup.1 and R.sup.2 together with the nitrogen to which they are
attached form a 3-8 membered ring and the ring is substituted with
-L-K. In some embodiments, R.sup.1 or R.sup.2 or R.sup.3 or R.sup.4
are aryl optionally substituted with -L-K. In some embodiments,
R.sup.1 or R.sup.2 or R.sup.3 or R.sup.4 are alkyl optionally
substituted with -L-K. In some embodiments, R.sup.1 or R.sup.2 or
R.sup.3 or R.sup.4 are alkyl-aryl optionally substituted with -L-K.
In some embodiments, R.sup.1 or R.sup.2 or R.sup.3 or R.sup.4 are
heteroalkyl optionally substituted with -L-K.
[0298] In some embodiments, L is a C.sub.1-C.sub.7alkyl. In some
embodiments, L is heteroalkyl. In certain embodiments, L is
C.sub.1-C.sub.7alkyl-aryl. In some embodiments, L is
C.sub.1-C.sub.7alkyl-aryl-C.sub.1-C.sub.7alkyl.
[0299] In certain embodiments, K is a non-protic charged group. In
some specific embodiments, each K is a ammonium group. In some
embodiments, each K is a cyclic non-protic ammonium group. In some
embodiments, each K is an acyclic non-protic ammonium group.
[0300] In certain embodiments, each K is a cyclic non-protic
ammonium group of structure:
##STR00022##
[0301] In certain embodiments, K is an acyclic non-protic ammonium
group of structure:
##STR00023## [0302] wherein p, q, R.sup.9, R.sup.10 and Z are as
defined above. In certain embodiments, p is 1. In other
embodiments, p is 2. In further embodiments, p is 3. In some
embodiments, q is 0. In other embodiments, q is 1. In some other
embodiments, q is 2.
[0303] The compounds further comprise 1, 2, 3 or 4 anionic
counterions selected from Cl.sup.-, Br.sup.-, I.sup.-,
R.sup.11SO.sub.3.sup.-, (SO.sub.3.sup.---R.sup.11--SO.sub.3.sup.-),
R.sup.11--CO.sub.2.sup.-,
(CO.sub.2.sup.---R.sup.11--CO.sub.2.sup.-),
(R.sup.11).sub.2(P.dbd.O)O.sup.- and
(R.sup.11)(P.dbd.O)O.sub.2.sup.2- wherein R.sup.11 is as defined
above. In some embodiments, the counterion is Cl.sup.-, Br.sup.-,
I.sup.-, CH.sub.2CO.sub.2.sup.-, CH.sub.3SO.sub.3.sup.-, or
C.sub.6H.sub.5SO.sub.3.sup.- or
CO.sub.2.sup.---(CH.sub.2).sub.2--CO.sub.2.sup.-. In some
embodiments, the compound of Formula III has one K group and one
counterion. In other embodiments, the compound of Formula III has
one K group, and two molecules of the compound of Formula III have
one counterion. In yet other embodiments, the compound of Formula
III has two K groups and two counterions. In some other
embodiments, the compound of Formula III has one K group comprising
two ammonium groups and two counterions.
[0304] Also described herein are compounds having the Formula
IIIA:
##STR00024##
[0305] wherein: [0306] each R.sup.1, R.sup.2 is independently H,
substituted or unsubstituted alkyl, or -L-K; or R.sup.1 and R.sup.2
together with the nitrogen to which they are attached form a
3-8-membered ring that is optionally substituted with R.sup.8;
[0307] and R.sup.3, R.sup.4, R.sup.8, L and K are as defined
above.
[0308] In some embodiments of compounds of Formula IIIA, L is
A.sub.n, wherein each A is substituted or unsubstituted alkyl, or
substituted or unsubstituted heteroalkyl, and n is 0-7. In certain
specific embodiments of the compound of Formula IIIA, R.sup.1 is H.
In some embodiments of Formula IIIA, R.sup.1 and R.sup.2 together
with the nitrogen to which they are attached form a 3-8-membered
ring that is optionally substituted with -L-K.
[0309] Also described herein are compounds having the Formula
IIIB.
##STR00025##
[0310] wherein: [0311] each R.sup.3, R.sup.4 is independently H,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted alkyl-aryl, or -L-K; [0312] and R.sup.1, R.sup.2, L
and K are as defined above.
[0313] In certain embodiments of Formula IIIB, R.sup.3 is H. In
certain embodiments, R.sup.3 and R.sup.4 are each -L-K. In some
embodiments, R.sup.3 is H and R.sup.4 is substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
alkyl-aryl containing one or two -L-K groups.
[0314] In some embodiments, an ASBTI suitable for the methods
described herein is a compound of Formula IIIC
##STR00026##
[0315] wherein: [0316] each R.sup.1, R.sup.2 is independently H,
hydroxy, alkyl, alkoxy, --C(.dbd.X)YR.sup.8, --YC(.dbd.X)R.sup.8,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted alkyl-cycloalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
alkyl-heteroaryl, substituted or unsubstituted heterocycloalkyl,
substituted or unsubstituted alkyl-heterocycloalkyl, or -L-K; or
R.sup.1 and R.sup.2 together with the nitrogen to which they are
attached form a 3-8-membered ring that is optionally substituted
with R.sup.8; [0317] each R.sup.3, R.sup.4 is independently H,
hydroxy, alkyl, alkoxy, --C(.dbd.X)YR.sup.8, --YC(.dbd.X)R.sup.8,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted alkyl-cycloalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
alkyl-heteroaryl, substituted or unsubstituted heterocycloalkyl,
substituted or unsubstituted alkyl-heterocycloalkyl, or -L-K;
[0318] R.sup.5 is H, hydroxy, alkyl, alkoxy, --C(.dbd.X)YR.sup.8,
--YC(.dbd.X)R.sup.8, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted alkyl-aryl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted alkyl-cycloalkyl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted alkyl-heteroaryl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted alkyl-heterocycloalkyl, [0319] each R.sup.6, R.sup.7
is independently H, hydroxy, alkyl, alkoxy, --C(.dbd.X)YR.sup.8,
--YC(.dbd.X)R.sup.8, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted alkyl-aryl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted alkyl-cycloalkyl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted alkyl-heteroaryl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted alkyl-heterocycloalkyl, or -L-K; or R.sup.6 and
R.sup.7 taken together form a bond; [0320] each X is independently
NH, S, or O; [0321] each Y is independently NH, S, or O; [0322]
R.sup.8 is substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted alkyl-aryl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
alkyl-cycloalkyl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted alkyl-heteroaryl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted
alkyl-heterocycloalkyl, or -L-K; [0323] L is A.sub.n, wherein
[0324] each A is independently NR.sup.1, S(O).sub.m, O, C(.dbd.X)Y,
Y(C.dbd.X), substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted cycloalkyl, or substituted or unsubstituted
heterocycloalkyl; wherein each m is independently 0-2; [0325] n is
0-7; [0326] K is a moiety that prevents systemic absorption; or a
pharmaceutically acceptable salt thereof.
[0327] In some specific embodiments of Formula I, II or III, K is
selected from
##STR00027##
[0328] In some embodiments, an ASBTI suitable for the methods
described herein is a compound of Formula IV:
##STR00028##
wherein
[0329] R.sup.1 is a straight chain C.sub.1-6 alkyl group;
[0330] R.sup.2 is a straight chain C.sub.1-6 alkyl group;
[0331] R.sup.3 is hydrogen or a group OR.sup.11 in which R.sup.11
is hydrogen, optionally substituted C.sub.1-6 alkyl or a C.sub.1-6
alkylcarbonyl group;
[0332] R.sup.4 is pyridyl or an optionally substituted phenyl;
[0333] R.sup.5, R.sup.6 and R.sup.8 are the same or different and
each is selected from: [0334] hydrogen, halogen, cyano,
R.sup.15-acetylide, OR.sup.15, optionally substituted C.sub.1-6
alkyl, COR.sup.15, CH(OH)R.sup.15, S(O)R.sup.15,
P(O)(OR.sup.15).sub.2, OCOR.sup.15, OCF.sub.3, OCN, SCN, NHCN,
CH.sub.2OR.sup.15, CHO, (CH.sub.2).sub.pCN, CONR.sup.12R.sup.13,
(CH.sub.2).sub.pCO.sub.2R.sup.15,
(CH.sub.2).sub.pNR.sup.12R.sup.13, CO.sub.2R.sup.15, NHCOCF.sub.3,
NHSO.sub.2R.sup.15, OCH.sub.2OR.sup.15, OCH.dbd.CHR.sup.15,
O(CH.sub.2CH.sub.2O)R.sup.15, O(CH.sub.2).sub.pSO.sub.3R.sup.15,
O(CH.sub.2).sub.pNR.sup.12R.sup.13 and
O(CH.sub.2).sub.pN.sup.+R.sup.12R.sup.13R.sup.14 wherein
[0335] p is an integer from 1-4,
[0336] n is an integer from 0-3 and
[0337] R.sup.12, R.sup.13, R.sup.14 and R.sup.15 are independently
selected from hydrogen and optionally substituted C.sup.1-6
alkyl;
[0338] R.sup.7 is a group of the formula
##STR00029## [0339] wherein the hydroxyl groups may be substituted
by acetyl, benzyl, [0340] or --(C.sub.1-C.sub.6)-alkyl-R.sup.17,
[0341] wherein the alkyl group may be substituted with one or more
hydroxyl groups;
[0342] R.sup.16 is --COOH, --CH.sub.2--OH, --CH.sub.2--O-Acetyl,
--COOMe or --COOEt;
[0343] R.sup.17 is H, --OH, --NH.sub.2, --COOH or COOR.sup.18;
[0344] R.sup.18 is (C.sub.1-C.sub.4)-alkyl or
--NH--(C.sub.1-C.sub.4)-alkyl;
[0345] X is --NH-- or --O--; and
[0346] R.sup.9 and R.sup.10 are the same or different and each is
hydrogen or C.sub.1-C.sub.6 alkyl; and salts thereof.
[0347] In some embodiments, a compound of Formula IV has the
structure of Formula IVA or Formula IVB:
##STR00030##
[0348] In some embodiments, a compound of Formula IV has the
structure of Formula IVC:
##STR00031##
[0349] In some embodiments of Formula IV, X is O and R.sup.7 is
selected from
##STR00032##
[0350] In some embodiments, a compound of Formula IV is:
##STR00033##
[0351] In some embodiments, an ASBTI suitable for the methods
described herein is a compound of Formula V:
##STR00034##
wherein:
[0352] R.sup.v is selected from hydrogen or C.sub.1-6alkyl;
[0353] One of R.sup.1 and R.sup.2 are selected from hydrogen or
C.sub.1-6alkyl and the other is selected from C.sub.1-6alkyl;
[0354] R.sup.x and R.sup.y are independently selected from
hydrogen, hydroxy, amino, mercapto, C.sub.1-6alkyl,
C.sub.1-6alkoxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2-amino, C.sub.1-6alkylS(O).sub.a wherein
a is 0 to 2;
[0355] R.sup.z is selected from halo, nitro, cyano, hydroxy, amino,
carboxy, carbamoyl, mercapto, sulphamoyl, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkoxy,
C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2-amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl).sub.2-carbamoyl, C.sub.1-6alkylS(O).sub.a
wherein a is 0 to 2, C.sub.1-6alkoxycarbonyl,
N--(C.sub.1-6-alkyl)sulphamoyl and
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl;
[0356] n is 0-5;
[0357] one of R.sup.4 and R.sup.5 is a group of formula (VA):
##STR00035##
[0358] R.sup.3 and R.sup.6 and the other of R.sup.4 and R.sup.5 are
independently selected from hydrogen, halo, nitro, cyano, hydroxy,
amino, carboxy, carbamoyl, mercapto, sulphamoyl, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkoxy,
C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl).sub.2carbamoyl,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N--(C.sub.1-6alkyl)sulphamoyl and
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl; [0359] wherein R.sup.3 and
R.sup.6 and the other of R.sup.4 and R.sup.5 may be optionally
substituted on carbon by one or more R.sup.17;
[0360] X is --O--, --N(R.sup.a)--, --S(O).sub.b-- or
--CH(R.sup.a)--; [0361] wherein R.sup.a is hydrogen or
C.sub.1-6alkyl and b is 0-2;
[0362] Ring A is aryl or heteroaryl; [0363] wherein Ring A is
optionally substituted on carbon by one or more substituents
selected from R.sup.18;
[0364] R.sup.7 is hydrogen, C.sub.1-6alkyl, carbocyclyl or
heterocyclyl; [0365] wherein R.sup.7 is optionally substituted on
carbon by one or more substituents selected from R.sup.19; and
wherein if said heterocyclyl contains an --NH-- group, that
nitrogen may be optionally substituted by a group selected from
R.sup.20;
[0366] R.sup.8 is hydrogen or C.sub.1-6-alkyl;
[0367] R.sup.9 is hydrogen or C.sub.1-6alkyl;
[0368] R.sup.10 is hydrogen, halo, nitro, cyano, hydroxy, amino,
carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl,
C.sub.1-10alkyl, C.sub.2-10alkynyl, C.sub.2-10alkynyl,
C.sub.1-10alkoxy, C.sub.1-10alkanoyl, C.sub.1-10alkanoyloxy,
N--(C.sub.1-10alkyl)amino, N,N--(C.sub.1-10alkyl).sub.2-amino,
N,N,N--(C.sub.1-10alkyl).sub.3ammonio, C.sub.1-10alkanoylamino,
N--(C.sub.1-10alkyl)carbamoyl,
N,N--(C.sub.1-10alkyl).sub.2carbamoyl, C.sub.1-10alkylS(O).sub.a
wherein a is 0 to 2, N--(C.sub.1-10alkyl)sulphamoyl,
N,N--(C.sub.1-10alkyl).sub.2sulphamoyl,
N--(C.sub.1-10alkyl)sulphamoylamino, N,N--(C.sub.1-10alkyl).sub.2
sulphamoylamino, C.sub.1-10alkoxycarbonylamino, carbocyclyl,
carbocyclylC.sub.1-10alkyl, heterocyclyl,
heterocyclylC.sub.1-10alkyl,
carbocyclyl-(C.sub.1-10alkylene).sub.p-R.sup.21--(C.sub.1-10alkylene).sub-
.q- or
heterocyclyl-(C.sub.1-10alkylene).sub.r-R.sup.22--(C.sub.1-10alkyle-
ne).sub.s-; wherein R.sup.10 is optionally substituted on carbon by
one or more substituents selected from R.sup.23; and wherein if
said heterocyclyl contains an --NH-- group, that nitrogen may be
optionally substituted by a group selected from R.sup.24; or
R.sup.10 is a group of formula (VB):
##STR00036##
[0369] wherein:
[0370] R.sup.11 is hydrogen or C.sub.1-6-alkyl;
[0371] R.sup.12 and R.sup.13 are independently selected from
hydrogen, halo, carbamoyl, sulphamoyl, C.sub.1-10alkyl,
C.sub.2-10alkynyl, C.sub.2-10alkynyl, C.sub.1-10alkanoyl,
N--(C.sub.1-10alkyl)carbamoyl,
N,N--(C.sub.1-10alkyl).sub.2carbamoyl, C.sub.1-10alkylS(O).sub.a
wherein a is 0 to 2, N--(C.sub.1-10alkyl)sulphamoyl,
N,N--(C.sub.1-10alkyl).sub.2sulphamoyl,
N--(C.sub.1-10alkyl)sulphamoylamino,
N,N--(C.sub.1-10alkyl).sub.2sulphamoylamino, carbocyclyl or
heterocyclyl; wherein R.sup.12 and R.sup.13 may be independently
optionally substituted on carbon by one or more substituents
selected from R.sup.25; and wherein if said heterocyclyl contains
an --NH-- group, that nitrogen may be optionally substituted by a
group selected from R.sup.26;
[0372] R.sup.14 is selected from hydrogen, halo, carbamoyl,
sulphamoyl, hydroxyaminocarbonyl, C.sub.1-10alkyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl, C.sub.1-10alkanoyl,
N--(C.sub.1-10alkyl)carbamoyl,
N,N--(C.sub.1-10alkyl).sub.2carbamoyl, C.sub.1-10alkylS(O).sub.a
wherein a is 0 to 2, N--(C.sub.1-10alkyl)sulphamoyl,
N,N--(C.sub.1-10alkyl).sub.2sulphamoyl,
N--(C.sub.1-10alkyl)sulphamoylamino,
N,N--(C.sub.1-10alkyl).sub.2sulphamoylamino, carbocyclyl,
carbocyclylC.sub.1-10alkyl, heterocyclyl,
heterocyclylC.sub.1-10alkyl,
carbocyclyl-(C.sub.1-10alkylene).sub.p-R.sup.27--(C.sub.1-10alkylene).sub-
.q- or
heterocyclyl-(C.sub.1-10alkylene).sub.r-R.sup.28--(C.sub.1-10alkyle-
ne).sub.s-; wherein R.sup.14 may be optionally substituted on
carbon by one or more substituents selected from R.sup.29; and
wherein if said heterocyclyl contains an --NH-- group, that
nitrogen may be optionally substituted by a group selected from
R.sup.30; or R.sup.14 is a group of formula (VC):
##STR00037##
[0373] R.sup.15 is hydrogen or C.sub.1-6alkyl; and R.sup.16 is
hydrogen or C.sub.1-6alkyl; wherein R.sup.16 may be optionally
substituted on carbon by one or more groups selected from
R.sup.31;
[0374] or R.sup.15 and R.sup.16 together with the nitrogen to which
they are attached form a heterocyclyl; wherein said heterocyclyl
may be optionally substituted on carbon by one or more R.sup.37;
and wherein if said heterocyclyl contains an --NH-- group, that
nitrogen may be optionally substituted by a group selected from
R.sup.38;
[0375] m is 1-3; wherein the values of R.sup.7 may be the same or
different;
[0376] R.sup.17, R.sup.18, R.sup.19, R.sup.23, R.sup.25, R.sup.29,
R.sup.31 and R.sup.37 are independently selected from halo, nitro,
cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl,
hydroxyaminocarbonyl, C.sub.1-10alkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, C.sub.1-10alkoxy, C.sub.1-10alkanoyl,
C.sub.1-10alkanoyloxy, N--(C.sub.1-10alkyl)amino,
N,N--(C.sub.1-10alkyl).sub.2amino,
N,N,N--(C.sub.1-10alkyl).sub.3ammonio, C.sub.1-10alkanoylamino,
N--(C.sub.1-10alkyl)carbamoyl,
N,N--(C.sub.1-10alkyl).sub.2carbamoyl, C.sub.1-10alkylS(O).sub.a
wherein a is 0 to 2, N--(C.sub.1-10alkyl)sulphamoyl,
N,N--(C.sub.1-10alkyl).sub.2sulphamoyl,
N--(C.sub.1-10alkyl)sulphamoylamino,
N,N--(C.sub.1-10alkyl).sub.2sulphamoylamino,
C.sub.1-10alkoxycarbonylamino, carbocyclyl,
carbocyclylC.sub.1-10alkyl, heterocyclyl,
heterocyclylC.sub.1-10alkyl,
carbocyclyl-(C.sub.1-10alkylene).sub.p-R.sup.32--(C.sub.1-10alkylene).sub-
.q- or heterocyclyl-(C.sub.1-10alkylene),
--R.sup.33--(C.sub.1-10alkylene).sub.a-; wherein R.sup.17,
R.sup.18, R.sup.19, R.sup.23, R.sup.25, R.sup.29, R.sup.31 and
R.sup.37 may be independently optionally substituted on carbon by
one or more R.sup.34; and wherein if said heterocyclyl contains an
--NH-- group, that nitrogen may be optionally substituted by a
group selected from R.sup.35;
[0377] R.sup.21, R.sup.22, R.sup.27, R.sup.28, R.sup.32 or R.sup.33
are independently selected from --O--, --NR.sup.36--, --S(O).sub.x,
--NR.sup.36C(O)NR.sup.36--, --NR.sup.36C(S)NR.sup.36--,
--OC(O)N.dbd.C--, --NR.sup.36C(O)-- or --C(O)NR.sup.36--; wherein
R.sup.36 is selected from hydrogen or C.sub.1-6alkyl, and x is
0-2;
[0378] p, q, r and s are independently selected from 0-2;
[0379] R.sup.34 is selected from halo, hydroxy, cyano, carbamoyl,
ureido, amino, nitro, carbamoyl, mercapto, sulphamoyl,
trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy,
vinyl, allyl, ethynyl, formyl, acetyl, formamido, acetylamino,
acetoxy, methylamino, dimethylamino, N-methylcarbamoyl,
N,N-dimethylcarbamoyl, methylthio, methylsulphinyl, mesyl,
N-methylsulphamoyl, N,N-dimethylsulphamoyl, N-methylsulphamoylamino
and N,N-dimethylsulphamoylamino;
[0380] R.sup.20, R.sup.24, R.sup.26, R.sup.30, R.sup.35 and
R.sup.38 are independently selected from C.sub.1-6alkyl,
C.sub.1-6alkanoyl, C.sub.1-6alkylsulphonyl,
C.sub.1-6alkoxycarbonyl, carbamoyl, N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl
and phenylsulphonyl; and
[0381] wherein a "heteroaryl" is a totally unsaturated, mono or
bicyclic ring containing 3-12 atoms of which at least one atom is
chosen from nitrogen, sulphur and oxygen, which heteroaryl may,
unless otherwise specified, be carbon or nitrogen linked;
[0382] wherein a "heterocyclyl" is a saturated, partially saturated
or unsaturated, mono or bicyclic ring containing 3-12 atoms of
which at least one atom is chosen from nitrogen, sulphur and
oxygen, which heterocyclyl may, unless otherwise specified, be
carbon or nitrogen linked, wherein a --CH.sub.2-- group can
optionally be replaced by a --C(O)-- group, and a ring sulphur atom
may be optionally oxidised to form an S-oxide; and
[0383] wherein a "carbocyclyl" is a saturated, partially saturated
or unsaturated, mono or bicyclic carbon ring that contains 3-12
atoms; wherein a --CH.sub.2-- group can optionally be replaced by a
--C(O) group;
or a pharmaceutically acceptable salt or in vivo hydrolysable ester
or amide formed on an available carboxy or hydroxy group
thereof.
[0384] In some embodiments, compound of Formula V is
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((R)-1--
carboxy-2-methylthio-ethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,-
3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((S)-1--
carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2-
,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((S)-1--
carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,-
5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((S)-1--
carboxybutyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahyd-
ro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((S)-1--
carboxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5--
benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((S)-1--
carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-b-
enzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((S)-1--
carboxy-2-(R)-hydroxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tet-
rahydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N-(2-sulph-
oethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2-
,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((S)-1--
carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahyd-
ro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((R)-1--
carboxy-2-methylthioethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetra-
hydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N-{(S)-1-[-
N--((S)-2-hydroxy-1-carboxyethyl)carbamoyl]propyl}carbamoyl]benzyl}carbamo-
ylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((S)-1--
carboxy-2-methylpropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahyd-
ro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((S)-1--
carb
oxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrah-
ydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-{(R)-.alpha.-carboxy4-hy-
droxybenzyl}carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
or
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N-(carb-
oxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benz-
othiadiazepine, or a salt thereof.
[0385] In some embodiments, compound of Formula V is
##STR00038##
[0386] In some embodiments, an ASBTI suitable for the methods
described herein is a compound of Formula VI:
##STR00039##
wherein:
[0387] R.sup.v and R.sup.w are independently selected from hydrogen
or C.sub.1-6alkyl;
[0388] one of R.sup.1 and R.sup.2 is selected from hydrogen or
C.sub.1-6alkyl and the other is selected from C.sub.1-6alkyl;
[0389] R.sup.x and R.sup.y are independently selected from hydrogen
or C.sub.1-6alkyl, or one of R.sup.x and R.sup.y is hydrogen or
C.sub.1-6alkyl and the other is hydroxy or C.sub.1-6alkoxy;
[0390] R.sup.z is selected from halo, nitro, cyano, hydroxy, amino,
carboxy, carbamoyl, mercapto, sulphamoyl, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkoxy,
C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl).sub.2carbamoyl,
C.sub.1-6alkyl S(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N--(C.sub.1-6alkyl)sulphamoyl and
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl;
[0391] n is 0-5;
[0392] one of R.sup.4 and R.sup.5 is a group of formula (VIA):
##STR00040##
[0393] R.sup.3 and R.sup.6 and the other of R.sup.4 and R.sup.5 are
independently selected from hydrogen, halo, nitro, cyano, hydroxy,
amino, carboxy, carbamoyl, mercapto, sulphamoyl, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkoxy,
C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl).sub.2carbamoyl,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N--(C.sub.1-6alkyl)sulphamoyl and
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl; wherein R.sup.3 and R.sup.6
and the other of R.sup.4 and R.sup.5 may be optionally substituted
on carbon by one or more R.sup.17;
[0394] X is --O--, --N(R.sup.a)--, --S(O).sub.b-- or
--CH(R.sup.a)--; wherein R.sup.a is hydrogen or C.sub.1-6alkyl and
b is 0-2;
[0395] Ring A is aryl or heteroaryl; wherein Ring A is optionally
substituted on carbon by one or more substituents selected from
R.sup.18;
[0396] R.sup.7 is hydrogen, C.sub.1-6alkyl, carbocyclyl or
heterocyclyl; wherein R.sup.7 is optionally substituted on carbon
by one or more substituents selected from R.sup.19; and wherein if
said heterocyclyl contains an --NH-- group, that nitrogen may be
optionally substituted by a group selected from R.sup.20;
[0397] R.sup.8 is hydrogen or C.sub.1-6alkyl;
[0398] R.sup.9 is hydrogen or C.sub.1-6alkyl;
[0399] R.sup.10 is hydrogen, halo, nitro, cyano, hydroxy, amino,
carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl,
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
C.sub.1-10alkoxy, C.sub.1-10alkanoyl, C.sub.1-10alkanoyloxy,
N--(C.sub.1-10alkyl)amino, N,N--(C.sub.1-10alkyl).sub.2amino,
N,N,N--(C.sub.1-10alkyl).sub.3 ammonio, C.sub.1-10alkanoylamino,
N--(C.sub.1-10alkyl)carbamoyl,
N,N--(C.sub.1-10alkyl).sub.2carbamoyl, C.sub.1-10alkylS(O).sub.a
wherein a is 0 to 2, N--(C.sub.1-10alkyl)sulphamoyl,
N,N--(C.sub.1-10alkyl).sub.2sulphamoyl,
N--(C.sub.1-10alkyl)sulphamoylamino, N,N--(C.sub.1-10alkyl).sub.2
sulphamoylamino, C.sub.1-10alkoxycarbonylamino, carbocyclyl,
carbocyclylC.sub.1-10alkyl, heterocyclyl,
heterocyclylC.sub.1-10alkyl,
carbocyclyl-(C.sub.1-10alkylene).sub.p-R.sup.21--(C.sub.1-10alkylene).sub-
.q- or
heterocyclyl-(C.sub.1-10alkylene).sub.r--R.sup.22--(C.sub.1-10alkyl-
ene).sub.s-; wherein R.sup.10 is optionally substituted on carbon
by one or more substituents selected from R.sup.23; and wherein if
said heterocyclyl contains an --NH-- group, that nitrogen may be
optionally substituted by a group selected from R.sup.24; or
R.sup.10 is a group of formula (VIB):
##STR00041##
wherein:
[0400] R.sup.11 is hydrogen or C.sub.1-6alkyl;
[0401] R.sup.12 and R.sup.13 are independently selected from
hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto,
sulphamoyl, C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
C.sub.1-10alkoxy, C.sub.1-10alkanoyl, C.sub.1-10alkanoyloxy,
N--(C.sub.1-10alkyl)amino, N,N--(C.sub.1-10alkyl).sub.2amino,
C.sub.1-10alkanoylamino, N--(C.sub.1-10alkyl)carbamoyl,
N,N--(C.sub.1-10alkyl).sub.2carbamoyl, C.sub.1-10alkylS(O).sub.a
wherein a is 0 to 2, N--(C.sub.1-10alkyl)sulphamoyl,
N,N--(C.sub.1-10alkyl).sub.2 sulphamoyl,
N--(C.sub.1-10alkyl)sulphamoylamino,
N,N--(C.sub.1-10alkyl).sub.2sulphamoylamino, carbocyclyl or
heterocyclyl; wherein R.sup.12 and R.sup.13 may be independently
optionally substituted on carbon by one or more substituents
selected from R.sup.25; and wherein if said heterocyclyl contains
an --NH-- group, that nitrogen may be optionally substituted by a
group selected from R.sup.26;
[0402] R.sup.14 is selected from hydrogen, halo, nitro, cyano,
hydroxy, amino, carbamoyl, mercapto, sulphamoyl,
hydroxyaminocarbonyl, C.sub.1-10alkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, C.sub.1-10alkoxy, C.sub.1-10alkanoyl,
C.sub.1-10alkanoyloxy, N--(C.sub.1-10alkyl)amino,
N,N--(C.sub.1-10alkyl).sub.2amino, N,N,N--(C.sub.1-10alkyl).sub.3
ammonio, C.sub.1-10alkanoylamino, N--(C.sub.1-10alkyl)carbamoyl,
N,N--(C.sub.1-10alkyl).sub.2carbamoyl, C.sub.1-10alkylS(O).sub.a
wherein a is 0 to 2, N--(C.sub.1-10alkyl)sulphamoyl,
N,N--(C.sub.1-10alkyl).sub.2sulphamoyl,
N--(C.sub.1-10alkyl)sulphamoylamino, N,N--(C.sub.1-10alkyl).sub.2
sulphamoylamino, C.sub.1-10alkoxycarbonylamino, carbocyclyl,
carbocyclylC.sub.1-10alkyl, heterocyclyl,
heterocyclylC.sub.1-10alkyl,
carbocyclyl-(C.sub.1-10alkylene).sub.p-R.sup.27--(C.sub.1-10alkylene).sub-
.q- or
heterocyclyl-(C.sub.1-10alkylene).sub.r--R.sup.28--(C.sub.1-10alkyl-
ene).sub.s-; wherein R.sup.14 may be optionally substituted on
carbon by one or more substituents selected from R.sup.29; and
wherein if said heterocyclyl contains an --NH-- group, that
nitrogen may be optionally substituted by a group selected from
R.sup.30; or R.sup.14 is a group of formula (VIC):
##STR00042##
[0403] R.sup.15 is hydrogen or C.sub.1-6alkyl;
[0404] R.sup.16 is hydrogen or C.sub.1-6alkyl; wherein R.sup.16 may
be optionally substituted on carbon by one or more groups selected
from R.sup.31;
[0405] n is 1-3; wherein the values of R.sup.7 may be the same or
different;
[0406] R.sup.17, R.sup.18, R.sup.19, R.sup.23, R.sup.25, R.sup.29
or R.sup.31 are independently selected from halo, nitro, cyano,
hydroxy, amino, carbamoyl, mercapto, sulphamoyl,
hydroxyaminocarbonyl, amidino, C.sub.1-10alkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, C.sub.1-10alkoxy, C.sub.1-10alkanoyl,
C.sub.1-10alkanoyloxy, (C.sub.1-10alkyl).sub.3silyl,
N--(C.sub.1-10alkyl)amino, N,N--(C.sub.1-10alkyl).sub.2amino,
N,N,N--(C.sub.1-10alkyl).sub.3ammonio, C.sub.1-10alkanoylamino,
N--(C.sub.1-10alkyl)carbamoyl,
N,N--(C.sub.1-10alkyl).sub.2carbamoyl, C.sub.1-10alkylS(O).sub.a
wherein a is 0 to 2, N--(C.sub.1-10alkyl)sulphamoyl,
N,N--(C.sub.1-10alkyl).sub.2sulphamoyl,
N--(C.sub.1-10alkyl)sulphamoylamino,
N,N--(C.sub.1-10alkyl).sub.2sulphamoylamino,
C.sub.1-10alkoxycarbonylamino, carbocyclyl,
carbocyclylC.sub.1-10alkyl, heterocyclyl,
heterocyclylC.sub.1-10alkyl,
carbocyclyl-(C.sub.1-10alkylene).sub.p-R.sup.32--(C.sub.1-10alkylene).sub-
.q- or
heterocyclyl-(C.sub.1-10alkylene).sub.r-R.sup.33--(C.sub.1-10alkyle-
ne).sub.s-; wherein R.sup.17, R.sup.18, R.sup.19, R.sup.23,
R.sup.25, R.sup.29 or R.sup.31 may be independently optionally
substituted on carbon by one or more R.sup.34; and wherein if said
heterocyclyl contains an --NH-- group, that nitrogen may be
optionally substituted by a group selected from R.sup.35;
[0407] R.sup.21, R.sup.22, R.sup.27, R.sup.28, R.sup.32 or R.sup.33
are independently selected from --O--, --NR.sup.36--,
--S(O).sub.x--, --NR.sup.36C(O)NR.sup.36--,
--NR.sup.36C(S)NR.sup.36--, --OC(O)N.dbd.C--, --NR.sup.36C(O)-- or
--C(O)NR.sup.36--; wherein R.sup.36 is selected from hydrogen or
C.sub.1-6alkyl, and x is 0-2;
[0408] p, q, r and s are independently selected from 0-2;
[0409] R.sup.34 is selected from halo, hydroxy, cyano, carbamoyl,
ureido, amino, nitro, carbamoyl, mercapto, sulphamoyl,
trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy,
vinyl, allyl, ethynyl, formyl, acetyl, formamido, acetylamino,
acetoxy, methylamino, dimethylamino, N-methylcarbamoyl,
N,N-dimethylcarbamoyl, methylthio, methylsulphinyl, mesyl,
N-methylsulphamoyl, N,N-dimethylsulphamoyl, N-methylsulphamoylamino
and N,N-dimethylsulphamoylamino;
[0410] R.sup.20, R.sup.24, R.sup.26, R.sup.30 or R.sup.35 are
independently selected from C.sub.1-6alkyl, C.sub.1-6alkanoyl,
C.sub.1-6alkylsulphonyl, C.sub.1-6alkoxycarbonyl, carbamoyl,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl)carbamoyl,
benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;
or a pharmaceutically acceptable salt, solvate or solvate of such a
salt, or an in vivo hydrolysable ester formed on an available
carboxy or hydroxy thereof, or an in vivo hydrolysable amide formed
on an available carboxy thereof.
[0411] In some embodiments, a compound of Formula VI has the
structure of Formula VID:
##STR00043##
wherein:
[0412] R.sup.1 and R.sup.2 are independently selected from
C.sub.1-6alkyl; one of R.sup.4 and R.sup.5 is a group of formula
(VIE):
##STR00044##
[0413] R.sup.3 and R.sup.6 and the other of R.sup.4 and R.sup.5 are
independently selected from hydrogen, halo, nitro, cyano, hydroxy,
amino, carboxy, carbamoyl, mercapto, sulphamoyl, C.sub.1-4alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, C.sub.1-4alkoxy,
C.sub.1-4alkanoyl, C.sub.1-4alkanoyloxy, N--(C.sub.1-4alkyl)amino,
N,N--(C.sub.1-4alkyl).sub.2amino, C.sub.1-4 alkanoylamino,
N--(C.sub.1-4alkyl)carbamoyl, N,N--(C.sub.1-4alkyl).sub.2carbamoyl,
C.sub.1-4alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-4alkoxycarbonyl, N--(C.sub.1-4alkyl)sulphamoyl and
N,N--(C.sub.1-4alkyl).sub.2sulphamoyl; wherein R.sup.3 and R.sup.6
and the other of R.sup.4 and R.sup.5 may be optionally substituted
on carbon by one or more R.sup.14;
[0414] R.sup.7 is carboxy, sulpho, sulphino, phosphono,
--P(O)(OR.sup.a)(OR.sup.b), P(O)(OH)(OR.sub.a), --P(O)(OH)(R.sup.a)
or P(O)(OR.sup.a)(R.sup.b), wherein R.sup.a and R.sup.b are
independently selected from C.sub.1-6alkyl; or R.sup.7 is a group
of formula (VIF):
##STR00045##
[0415] R.sup.8 and R.sup.9 are independently hydrogen,
C.sub.1-4alkyl or a saturated cyclic group, or R.sup.8 and R.sup.9
together form C.sub.2-6alkylene; wherein R.sup.8 and R.sup.9 or
R.sup.8 and R.sup.9 together may be independently optionally
substituted on carbon by one or more substituents selected from
R.sup.15; and wherein if said saturated cyclic group contains an NH
moiety, that nitrogen may be optionally substituted by one or more
R.sup.20;
[0416] R.sup.10 is hydrogen or C.sub.1-4alkyl; wherein R.sup.10 is
optionally substituted on carbon by one or more substituents
selected from R.sup.24;
[0417] R.sup.11 is hydrogen, C.sup.1-4alkyl, carbocyclyl or
heterocyclyl; wherein R.sup.11 is optionally substituted on carbon
by one or more substituents selected from R.sup.16; and wherein if
said heterocyclyl contains an NH moiety, that nitrogen may be
optionally substituted by one or more R.sup.21;
[0418] R.sup.12 is hydrogen or C.sub.1-4alkyl, carbocyclyl or
heterocyclyl; wherein R.sup.12 optionally substituted on carbon by
one or more substituents selected from R.sup.17; and wherein if
said heterocyclyl contains an NH moiety, that nitrogen may be
optionally substituted by one or more R.sup.22;
[0419] R.sup.13 is carboxy, sulpho, sulphino, phosphono,
--P(O)(OR.sup.c)(OR.sup.d), --P(O)(OH)(OR.sup.c),
--P(O)(OH)(R.sup.c) or --P(O)(OR.sup.c)(R.sup.d) wherein R.sup.c
and R.sup.d are independently selected from C.sub.1-6alkyl;
[0420] m is 1-3; wherein the values of R.sup.8 and R.sup.9 may be
the same or different;
[0421] n is 1-3; wherein the values of R.sup.11 may be the same or
different;
[0422] p is 1-3; wherein the values of R.sup.12 may be the same or
different;
[0423] R.sup.14 and R.sup.16 are independently selected from halo,
nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto,
sulphamoyl, C.sub.1-4alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl,
C.sub.1-4alkoxy, C.sub.1-4alkanoyl, C.sub.1-4alkanoyloxy,
N--(C.sub.1-4alkyl)amino, N,N--(C.sub.1-4alkyl).sub.2amino,
C.sub.1-4 alkanoylamino, N--(C.sub.1-4alkyl)carbamoyl,
N,N--(C.sub.1-4 alkyl).sub.2carbamoyl, C.sub.1-4alkylS(O).sub.a
wherein a is 0 to 2, C.sub.1-4alkoxycarbonyl,
N--(C.sub.1-4alkyl)sulphamoyl and
N,N--(C.sub.1-4alkyl).sub.2sulphamoyl; wherein R.sup.14 and
R.sup.16 may be independently optionally substituted on carbon by
one or more R.sup.18;
[0424] R.sup.15 and R.sup.17 are independently selected from halo,
nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto,
sulphamoyl, C.sub.1-4 alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl,
C.sub.1-4alkoxy, C.sub.1-4alkanoyl, C.sub.1-4alkanoyloxy,
N--(C.sub.1-4alkyl)amino, N,N--(C.sub.1-4alkyl).sub.2amino,
C.sub.1-4 alkanoylamino, N--(C.sub.1-4alkyl)carbamoyl,
N,N--(C.sub.1-4 alkyl).sub.2carbamoyl, C.sub.1-4alkylS(O).sub.a
wherein a is 0 to 2, C.sub.1-4alkoxycarbonyl,
N--(C.sub.1-4alkyl)sulphamoyl and
N,N--(C.sub.1-4alkyl).sub.2sulphamoyl, carbocyclyl, heterocyclyl,
sulpho, sulphino, amidino, phosphono, --P(O)(OR.sup.e)(OR.sup.f),
--P(O)(OH)(OR.sup.e), --P(O)(OH)(R.sup.e) or
--P(O)(OR.sup.e)(R.sup.f), wherein R.sup.e and R.sup.f are
independently selected from C.sub.1-6alkyl; wherein R.sup.15 and
R.sup.17 may be independently optionally substituted on carbon by
one or more R.sup.19; and wherein if said heterocyclyl contains an
--NH-- moiety, that nitrogen may be optionally substituted by one
or more R.sup.23;
[0425] R.sup.18, R.sup.19 and R.sup.25 are independently selected
from halo, hydroxy, cyano, carbamoyl, ureido amino nitro, carboxy,
carbamoyl, mercapto, sulphamoyl, trifluoromethyl, trifluoromethoxy,
methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl,
methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy,
methylamino, dimethylamino, N-methylcarbamoyl,
N,N-dimethylcarbamoyl, methylthio, methylsulphinyl, mesyl,
N-methylsulphamoyl and N,N-dimethylsulphamoyl;
[0426] R.sup.20, R.sup.21, R.sup.22, R.sup.23 and R.sup.26 are
independently C.sub.1-4alkyl, C.sub.1-4alkanoyl,
C.sub.1-4alkylsulphonyl, sulphamoyl, N--(C.sub.1-4
alkyl)sulphamoyl, N,N--(C.sub.1-4alkyl).sub.2sulphamoyl,
C.sub.1-4alkoxycarbonyl, carbamoyl, N--(C.sub.1-4alkyl)carbamoyl,
N,N--(C.sub.1-4alkyl).sub.2carbamoyl, benzyl, phenethyl, benzoyl,
phenylsulphonyl and phenyl;
[0427] R.sup.24 is selected from halo, nitro, cyano, hydroxy,
amino, carboxy, carbamoyl, mercapto, sulphamoyl, C.sub.1-4alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, C.sub.1-4alkoxy,
C.sub.1-4alkanoyl, C.sub.1-4alkanoyloxy, N--(C.sub.1-4alkyl)amino,
N,N--(C.sub.1-4alkyl).sub.2amino, C.sub.1-4 alkanoylamino,
N--(C.sub.1-4alkyl)carbamoyl, N,N--(C.sub.1-4alkyl).sub.2carbamoyl,
C.sub.1-4alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-4alkoxycarbonyl, N--(C.sub.1-4alkyl)sulphamoyl and
N,N--(C.sub.1-4alkyl).sub.2sulphamoyl, carbocyclyl, heterocyclyl;
wherein R.sup.24 may be independently optionally substituted on
carbon by one or more R.sup.25; and wherein if said heterocyclyl
contains an --NH-- moiety, that nitrogen may be optionally
substituted by one or more R.sup.26;
[0428] wherein any saturated cyclic group is a totally or partially
saturated, mono or bicyclic ring containing 3-12 atoms of which 0-4
atoms are chosen from nitrogen, sulphur or oxygen, which may be
carbon or nitrogen linked;
[0429] wherein any heterocyclyl is a saturated, partially saturated
or unsaturated, mono or bicyclic ring containing 3-12 atoms of
which at least one atom is chosen from nitrogen, sulphur or oxygen,
which may be carbon or nitrogen linked, wherein a --CH.sub.2--
group can optionally be replaced by a --C(O)-- or a ring sulphur
atom may be optionally oxidised to form the S-oxides; and
[0430] wherein any carbocyclyl is a saturated, partially saturated
or unsaturated, mono or bicyclic carbon ring that contains 3-12
atoms, wherein a --CH.sub.2-- group can optionally be replaced by a
--C(O)--;
[0431] or a pharmaceutically acceptable salt thereof.
[0432] In some embodiments, a compound of Formula IV is
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N'-(c-
arboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-ben-
zothiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N'--((S)-1-
-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrah-
ydro-1,5-benzothiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N'-(c-
arboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-ben-
zothiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N'--((S)-1-
-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-be-
nzothiazepine; or a salt thereof.
[0433] In some embodiments, any compound described herein is
covalently conjugated to a bile acid using any suitable method. In
some embodiments, compounds described herein are covalently bonded
to a cyclodextrin or a biodegradable polymer (e.g., a
polysaccharide).
[0434] In certain embodiments compounds described herein are not
systemically absorbed. Moreover, provided herein are compounds that
inhibit bile salt recycling in the gastrointestinal tract of an
individual. In some embodiments, compounds described herein, may
not be transported from the gut lumen and/or do not interact with
ASBT. In some embodiments, compounds described herein, do not
affect, or minimally affect, fat digestion and/or absorption. In
certain embodiments, the administration of a therapeutically
effective amount of any compound described herein does not result
in gastrointestinal disturbance or lactic acidosis in an
individual. In certain embodiments, compounds described herein are
administered orally. In some embodiments, an ASBTI is released in
the distal ileum. An ASBTI compatible with the methods described
herein may be a direct inhibitor, an allosteric inhibitor, or a
partial inhibitor of the Apical Sodium-dependent Bile acid
Transporter.
[0435] In certain embodiments, compounds that inhibit ASBT or any
recuperative bile acid transporters are compounds that are
described in EP1810689, U.S. Pat. Nos. 6,458,851, 7,413,536,
7,514,421, US Appl. Publication Nos. 2002/0147184, 2003/0119809,
2003/0149010, 2004/0014806, 2004/0092500, 2004/0180861,
2004/0180860, 2005/0031651, 2006/0069080, 2006/0199797,
2006/0241121, 2007/0065428, 2007/0066644, 2007/0161578,
2007/0197628, 2007/0203183, 2007/0254952, 2008/0070888,
2008/0070892, 2008/0070889, 2008/0070984, 2008/0089858,
2008/0096921, 2008/0161400, 2008/0167356, 2008/0194598,
2008/0255202, 2008/0261990, WO 2002/50027, WO2005/046797,
WO2006/017257, WO2006/105913, WO2006/105912, WO2006/116499,
WO2006/117076, WO2006/121861, WO2006/122186, WO2006/124713,
WO2007/050628, WO2007/101531, WO2007/134862, WO2007/140934,
WO2007/140894, WO2008/028590, WO2008/033431, WO2008/033464,
WO2008/031501, WO2008/031500, WO2008/033465, WO2008/034534,
WO2008/039829, WO2008/064788, WO2008/064789, WO2008/088836,
WO2008/104306, WO2008/124505, and WO2008/130616; the compounds
described therein that inhibit recuperative bile acid transport are
hereby incorporated herein by reference.
[0436] In certain embodiments, compounds that inhibit ASBT or any
recuperative bile acid transporters are compounds described in
WO93/16055, WO94/18183, WO94/18184, WO96/05188, WO96/08484,
WO96/16051, WO97/33882, WO98/38182, WO99/35135, WO98/40375,
WO99/64409, WO99/64410, WO00/01687, WO00/47568, WO00/61568, DE
19825804, WO00/38725, WO00/38726, WO00/38727 (including those
compounds with a 2,3,4,5-tetrahydro-1-benzothiepine 1,1-dioxide
structure), WO00/38728, WO01/66533, WO02/50051, EP0864582 (e.g.
(3R,5R)-3-butyl-3-ethyl-1,1-dioxido-5-Phenyl-2,3,4,5-tetrahydro-1,4-benzo-
-thiazepin-8-yl (.beta.-D-glucopyranosiduronic acid, WO94/24087,
WO98/07749, WO98/56757, WO99/32478, WO99/35135, WO00/20392,
WO00/20393, WO00/20410, WO00/20437, WO01/34570, WO00/35889,
WO01/68637, WO01/68096, WO02/08211, WO03/020710, WO03/022825,
WO03/022830, WO03/0222861, JP10072371, U.S. Pat. Nos. 5,910,494;
5,723,458; 5,817,652; 5,663,165; 5,998,400; 6,465,451, 5,994,391;
6,107,494; 6,387,924; 6,784,201; 6,875,877; 6,740,663; 6,852,753;
5,070,103, 6,114,322, 6,020,330, 7,179,792, EP251315, EP417725,
EP489-423, EP549967, EP573848, EP624593, EP624594, EP624595,
EP869121, EP1070703, WO04/005247, compounds disclosed as having
IBAT activity in Drugs of the Future, 24, 425-430 (1999), Journal
of Medicinal Chemistry, 48, 5837-5852, (2005) and Current Medicinal
Chemistry, 13, 997-1016, (2006); the compounds described therein
that inhibit recuperative bile acid transport are hereby
incorporated herein by reference.
[0437] In some embodiments, compounds that inhibit ASBT or any
recuperative bile acid transporter are benzothiepines,
benzothiazepines (including 1,2-benzothiazepines;
1,4-benzothiazepines; 1,5-benzothiazepines; and/or
1,2,5-benzothiadiazepines). In some embodiments, compounds that
inhibit ASBT or any recuperative bile acid transporter include and
are not limited to S-8921 (disclosed in EP597107, WO 93/08155),
264W94 (GSK) disclosed in WO 96/05188; SC-435
(1-[4-[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydr-
oxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]butyl]-4-aza-1-azoniabicyclo[2-
.2.2]octane methanesulfonate salt), SC-635 (Searle); 2164U90
(3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine
1,1-dioxide); BARI-1741 (Aventis SA), AZD 7508 (Astra Zeneca);
barixibat
(11-(D-gluconamido)-N-{2-[(1S,2R,3S)-3-hydroxy-3-phenyl-2-(2-pyridyl)-1-(-
2-pyridylamino)propyl]phenyl}undecanamide) or the like, or
combinations thereof. In some embodiments, an ASBTI is:
##STR00046## ##STR00047## ##STR00048##
[0438] In certain embodiments, compounds described herein have one
or more chiral centers. As such, all stereoisomers are envisioned
herein. In various embodiments, compounds described herein are
present in optically active or racemic forms. It is to be
understood that the compounds of the present invention encompasses
racemic, optically-active, regioisomeric and stereoisomeric forms,
or combinations thereof that possess the therapeutically useful
properties described herein. Preparation of optically active forms
is achieve in any suitable manner, including by way of non-limiting
example, by resolution of the racemic form by recrystallization
techniques, by synthesis from optically-active starting materials,
by chiral synthesis, or by chromatographic separation using a
chiral stationary phase. In some embodiments, mixtures of one or
more isomer is utilized as the therapeutic compound described
herein. In certain embodiments, compounds described herein contains
one or more chiral centers. These compounds are prepared by any
means, including enantioselective synthesis and/or separation of a
mixture of enantiomers and/or diastereomers. Resolution of
compounds and isomers thereof is achieved by any means including,
by way of non-limiting example, chemical processes, enzymatic
processes, fractional crystallization, distillation,
chromatography, and the like.
[0439] The compounds described herein, and other related compounds
having different substituents are synthesized using techniques and
materials described herein and as described, for example, in Fieser
and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John
Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds,
Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989);
Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991),
Larock's Comprehensive Organic Transformations (VCH Publishers
Inc., 1989), March, ADVANCED ORGANIC CHEMISTRY 4.sup.th Ed., (Wiley
1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4.sup.th Ed.,
Vols. A and B (Plenum 2000, 2001), and Green and Wuts, PROTECTIVE
GROUPS IN ORGANIC SYNTHESIS 3.sup.rd Ed., (Wiley 1999) (all of
which are incorporated by reference for such disclosure). General
methods for the preparation of compound as described herein are
modified by the use of appropriate reagents and conditions, for the
introduction of the various moieties found in the formulae as
provided herein. As a guide the following synthetic methods are
utilized.
Formation of Covalent Linkages by Reaction of an Electrophile with
a Nucleophile
[0440] The compounds described herein are modified using various
electrophiles and/or nucleophiles to form new functional groups or
substituents. Table A entitled "Examples of Covalent Linkages and
Precursors Thereof" lists selected non-limiting examples of
covalent linkages and precursor functional groups which yield the
covalent linkages. Table A is used as guidance toward the variety
of electrophiles and nucleophiles combinations available that
provide covalent linkages. Precursor functional groups are shown as
electrophilic groups and nucleophilic groups.
TABLE-US-00001 TABLE A Examples of Covalent Linkages and Precursors
Thereof Covalent Linkage Product Electrophile Nucleophile
Carboxamides Activated esters amines/anilines Carboxamides acyl
azides amines/anilines Carboxamides acyl halides amines/anilines
Esters acyl halides alcohols/phenols Esters acyl nitriles
alcohols/phenols Carboxamides acyl nitriles amines/anilines Imines
Aldehydes amines/anilines Hydrazones aldehydes or ketones
Hydrazines Oximes aldehydes or ketones Hydroxylamines Alkyl amines
alkyl halides amines/anilines Esters alkyl halides carboxylic acids
Thioethers alkyl halides Thiols Ethers alkyl halides
alcohols/phenols Thioethers alkyl sulfonates Thiols Esters alkyl
sulfonates carboxylic acids Ethers alkyl sulfonates
alcohols/phenols Esters Anhydrides alcohols/phenols Carboxamides
Anhydrides amines/anilines Thiophenols aryl halides Thiols Aryl
amines aryl halides Amines Thioethers Azindines Thiols Boronate
esters Boronates Glycols Carboxamides carboxylic acids
amines/anilines Esters carboxylic acids Alcohols hydrazines
Hydrazides carboxylic acids N-acylureas or Anhydrides carbodiimides
carboxylic acids Esters diazoalkanes carboxylic acids Thioethers
Epoxides Thiols Thioethers haloacetamides Thiols Ammotriazines
halotriazines amines/anilines Triazinyl ethers halotriazines
alcohols/phenols Amidines imido esters amines/anilines Ureas
Isocyanates amines/anilines Urethanes Isocyanates alcohols/phenols
Thioureas isothiocyanates amines/anilines Thioethers Maleimides
Thiols Phosphite esters phosphoramidites Alcohols Silyl ethers
silyl halides Alcohols Alkyl amines sulfonate esters
amines/anilines Thioethers sulfonate esters Thiols Esters sulfonate
esters carboxylic acids Ethers sulfonate esters Alcohols
Sulfonamides sulfonyl halides amines/anilines Sulfonate esters
sulfonyl halides phenols/alcohols
Use of Protecting Groups
[0441] In the reactions described, it is necessary to protect
reactive functional groups, for example hydroxy, amino, imino, thio
or carboxy groups, where these are desired in the final product, in
order to avoid their unwanted participation in reactions.
Protecting groups are used to block some or all of the reactive
moieties and prevent such groups from participating in chemical
reactions until the protective group is removed. In some
embodiments it is contemplated that each protective group be
removable by a different means. Protective groups that are cleaved
under totally disparate reaction conditions fulfill the requirement
of differential removal.
[0442] In some embodiments, protective groups are removed by acid,
base, reducing conditions (such as, for example, hydrogenolysis),
and/or oxidative conditions. Groups such as trityl,
dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile
and are used to protect carboxy and hydroxy reactive moieties in
the presence of amino groups protected with Cbz groups, which are
removable by hydrogenolysis, and Fmoc groups, which are base
labile. Carboxylic acid and hydroxy reactive moieties are blocked
with base labile groups such as, but not limited to, methyl, ethyl,
and acetyl in the presence of amines blocked with acid labile
groups such as t-butyl carbamate or with carbamates that are both
acid and base stable but hydrolytically removable.
[0443] In some embodiments carboxylic acid and hydroxy reactive
moieties are blocked with hydrolytically removable protective
groups such as the benzyl group, while amine groups capable of
hydrogen bonding with acids are blocked with base labile groups
such as Fmoc. Carboxylic acid reactive moieties are protected by
conversion to simple ester compounds as exemplified herein, which
include conversion to alkyl esters, or are blocked with
oxidatively-removable protective groups such as
2,4-dimethoxybenzyl, while co-existing amino groups are blocked
with fluoride labile silyl carbamates.
[0444] Allyl blocking groups are useful in the presence of acid-
and base-protecting groups since the former are stable and are
subsequently removed by metal or pi-acid catalysts. For example, an
allyl-blocked carboxylic acid is deprotected with a
Pd.sup.0-catalyzed reaction in the presence of acid labile t-butyl
carbamate or base-labile acetate amine protecting groups. Yet
another form of protecting group is a resin to which a compound or
intermediate is attached. As long as the residue is attached to the
resin, that functional group is blocked and does not react. Once
released from the resin, the functional group is available to
react.
[0445] Typically blocking/protecting groups are selected from:
##STR00049##
[0446] Other protecting groups, plus a detailed description of
techniques applicable to the creation of protecting groups and
their removal are described in Greene and Wuts, Protective Groups
in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York,
N.Y., 1999, and Kocienski, Protective Groups, Thieme Verlag, New
York, N.Y., 1994, which are incorporated herein by reference for
such disclosure.
[0447] In some embodiments, ASBTIs described herein are synthesized
as described in, for example, WO 96/05188, U.S. Pat. Nos.
5,994,391; 7,238,684; 6,906,058; 6,020,330; and 6,114,322. In some
embodiments, ASBTIs described herein are synthesized starting from
compounds that are available from commercial sources or that are
prepared using procedures outlined herein. In some embodiments,
compounds described herein are prepared according to the process
set forth in Scheme 1:
##STR00050##
[0448] In certain embodiments, the synthesis begins with a reaction
of 1,4-diazabicyclo[2.2.2]octane with 4-iodo-1-chloro butane to
provide a compound of structure 1-I. Such compounds are prepared in
any suitable manner, e.g., as set forth in Tremont, S. J. et. al.,
J. Med. Chem. 2005, 48, 5837-5852. The compound of structure 1-I is
then subjected to a reaction with phenethylamine to provide a
compound of structure 1-II. The compound of structure 1-II is then
allowed to react with dicyanodiamide to provide a compound of
Formula I.
[0449] In some embodiments, a first compound of Formula III is
subjected to a further reaction to provide a second compound of
Formula III as shown in Scheme 2 below.
##STR00051##
[0450] A first compound of Formula III, 1-IA, is alkylated with
iodomethane to provide a second compound of Formula III, 1-IB.
Alkylation of 1-IB with a compound of structure 2-II provides a
further compound of Formula III, IC. In an alternative embodiment,
a first compound of Formula III, 1-IA, is alkylated with a compound
of structure 2-I to provide a second compound of Formula III,
1-IC
[0451] In some embodiments, compounds described herein are prepared
according to the process set forth in Scheme 3:
##STR00052## ##STR00053## ##STR00054##
GENERAL DEFINITIONS
[0452] The term "bile acid," as used herein, includes steroid acids
(and/or the carboxylate anion thereof), and salts thereof, found in
the bile of an animal (e.g., a human), including, by way of
non-limiting example, cholic acid, cholate, deoxycholic acid,
deoxycholate, hyodeoxycholic acid, hyodeoxycholate, glycocholic
acid, glycocholate, taurocholic acid, taurocholate,
chenodeoxycholic acid, ursodeoxycholic acid, ursodiol, a
tauroursodeoxycholic acid, a glycoursodeoxycholic acid, a
7-B-methyl cholic acid, a methyl lithocholic acid,
chenodeoxycholate, lithocholic acid, lithocolate, and the like.
Taurocholic acid and/or taurocholate are referred to herein as TCA.
Any reference to a bile acid used herein includes reference to a
bile acid, one and only one bile acid, one or more bile acids, or
to at least one bile acid. Therefore, the terms "bile acid," "bile
salt," "bile acid/salt," "bile acids," "bile salts," and "bile
acids/salts" are, unless otherwise indicated, utilized
interchangeably herein. Any reference to a bile acid used herein
includes reference to a bile acid or a salt thereof. Furthermore,
pharmaceutically acceptable bile acid esters are optionally
utilized as the "bile acids" described herein, e.g., bile
acids/salts conjugated to an amino acid (e.g., glycine or taurine).
Other bile acid esters include, e.g., substituted or unsubstituted
alkyl ester, substituted or unsubstituted heteroalkyl esters,
substituted or unsubstituted aryl esters, substituted or
unsubstituted heteroaryl esters, or the like. For example, the term
"bile acid" includes cholic acid conjugated with either glycine or
taurine: glycocholate and taurocholate, respectively (and salts
thereof). Any reference to a bile acid used herein includes
reference to an identical compound naturally or synthetically
prepared. Furthermore, it is to be understood that any singular
reference to a component (bile acid or otherwise) used herein
includes reference to one and only one, one or more, or at least
one of such components. Similarly, any plural reference to a
component used herein includes reference to one and only one, one
or more, or at least one of such components, unless otherwise
noted. Moreover, as used herein, bile acid/salt mimics or mimetics
described herein are compounds that mimic the agonist signaling
properties of the bile acid/salt, especially at TGR5 (GPBAR1, BG37,
Axor109) receptors. Examples include those described in WO
2010/014836, which is incorporated herein for such disclosure. In
some embodiments, bile acid mimetics include triterpenoid, such as
oleanoic acid, ursolic acid, or the like.
[0453] The term "subject", "patient" or "individual" are used
interchangeably herein and refer to mammals and non-mammals, e.g.,
suffering from a disorder described herein. Examples of mammals
include, but are not limited to, any member of the mammalian class:
humans, non-human primates such as chimpanzees, and other apes and
monkey species; farm animals such as cattle, horses, sheep, goats,
swine; domestic animals such as rabbits, dogs, and cats; laboratory
animals including rodents, such as rats, mice and guinea pigs, and
the like. Examples of non-mammals include, but are not limited to,
birds, fish and the like. In one embodiment of the methods and
compositions provided herein, the mammal is a human.
[0454] Unless otherwise stated, the following terms used in this
application, including the specification and claims, have the
definitions given below with regard to "pediatric" or "pediatric
patients" includes Neonatal (children ages 0 to 4 weeks), Infant
Children (ages 4 weeks to 2 years), Children (ages 2 to 5 years),
Children (ages 6 to 11 years) and Adolescents (12 to 18 years).
[0455] The term "about," as used herein, includes any value that is
within 10% of the described value.
[0456] The term "between," as used herein, is inclusive of the
lower and upper number of the range.
[0457] The term "colon," as used herein, includes the cecum,
ascending colon, hepatic flexure, splenic flexure, descending
colon, and sigmoid.
[0458] The term "composition," as used herein includes the
disclosure of both a composition and a composition administered in
a method as described herein. Furthermore, in some embodiments, the
composition of the present invention is or comprises a
"formulation," an oral dosage form or a rectal dosage form as
described herein.
[0459] The terms "treat," "treating" or "treatment," and other
grammatical equivalents as used herein, include alleviating,
inhibiting or reducing symptoms, reducing or inhibiting severity
of, reducing incidence of, reducing or inhibiting recurrence of,
delaying onset of, delaying recurrence of, abating or ameliorating
a disease or condition symptoms, ameliorating the underlying causes
of symptoms, inhibiting the disease or condition, e.g., arresting
the development of the disease or condition, relieving the disease
or condition, causing regression of the disease or condition,
relieving a condition caused by the disease or condition, or
stopping the symptoms of the disease or condition. The terms
further include achieving a therapeutic benefit. By therapeutic
benefit is meant eradication or amelioration of the underlying
disorder being treated, and/or the eradication or amelioration of
one or more of the physiological symptoms associated with the
underlying disorder such that an improvement is observed in the
patient.
[0460] The terms "prevent," "preventing" or "prevention," and other
grammatical equivalents as used herein, include preventing
additional symptoms, preventing the underlying causes of symptoms,
inhibiting the disease or condition, e.g., arresting the
development of the disease or condition and are intended to include
prophylaxis. The terms further include achieving a prophylactic
benefit. For prophylactic benefit, the compositions are optionally
administered to a patient at risk of developing a particular
disease, to a patient reporting one or more of the physiological
symptoms of a disease, or to a patient at risk of reoccurrence of
the disease.
[0461] Where combination treatments or prevention methods are
contemplated, it is not intended that the agents described herein
be limited by the particular nature of the combination. For
example, the agents described herein are optionally administered in
combination as simple mixtures as well as chemical hybrids. An
example of the latter is where the agent is covalently linked to a
targeting carrier or to an active pharmaceutical. Covalent binding
can be accomplished in many ways, such as, though not limited to,
the use of a commercially available cross-linking agent.
Furthermore, combination treatments are optionally administered
separately or concomitantly.
[0462] As used herein, the terms "pharmaceutical combination",
"administering an additional therapy", "administering an additional
therapeutic agent" and the like refer to a pharmaceutical therapy
resulting from the mixing or combining of more than one active
ingredient and includes both fixed and non-fixed combinations of
the active ingredients. The term "fixed combination" means that at
least one of the agents described herein, and at least one
co-agent, are both administered to a patient simultaneously in the
form of a single entity or dosage. The term "non-fixed combination"
means that at least one of the agents described herein, and at
least one co-agent, are administered to a patient as separate
entities either simultaneously, concurrently or sequentially with
variable intervening time limits, wherein such administration
provides effective levels of the two or more agents in the body of
the patient. In some instances, the co-agent is administered once
or for a period of time, after which the agent is administered once
or over a period of time. In other instances, the co-agent is
administered for a period of time, after which, a therapy involving
the administration of both the co-agent and the agent are
administered. In still other embodiments, the agent is administered
once or over a period of time, after which, the co-agent is
administered once or over a period of time. These also apply to
cocktail therapies, e.g. the administration of three or more active
ingredients.
[0463] As used herein, the terms "co-administration", "administered
in combination with" and their grammatical equivalents are meant to
encompass administration of the selected therapeutic agents to a
single patient, and are intended to include treatment regimens in
which the agents are administered by the same or different route of
administration or at the same or different times. In some
embodiments the agents described herein will be co-administered
with other agents. These terms encompass administration of two or
more agents to an animal so that both agents and/or their
metabolites are present in the animal at the same time. They
include simultaneous administration in separate compositions,
administration at different times in separate compositions, and/or
administration in a composition in which both agents are present.
Thus, in some embodiments, the agents described herein and the
other agent(s) are administered in a single composition. In some
embodiments, the agents described herein and the other agent(s) are
admixed in the composition.
[0464] The terms "effective amount" or "therapeutically effective
amount" as used herein, refer to a sufficient amount of at least
one agent being administered which achieve a desired result, e.g.,
to relieve to some extent one or more symptoms of a disease or
condition being treated. In certain instances, the result is a
reduction and/or alleviation of the signs, symptoms, or causes of a
disease, or any other desired alteration of a biological system. In
certain instances, an "effective amount" for therapeutic uses is
the amount of the composition comprising an agent as set forth
herein required to provide a clinically significant decrease in a
disease. An appropriate "effective" amount in any individual case
is determined using any suitable technique, such as a dose
escalation study.
[0465] The terms "administer," "administering", "administration,"
and the like, as used herein, refer to the methods that may be used
to enable delivery of agents or compositions to the desired site of
biological action. These methods include, but are not limited to
oral routes, intraduodenal routes, parenteral injection (including
intravenous, subcutaneous, intraperitoneal, intramuscular,
intravascular or infusion), topical and rectal administration.
Administration techniques that are optionally employed with the
agents and methods described herein are found in sources e.g.,
Goodman and Gilman, The Pharmacological Basis of Therapeutics,
current ed.; Pergamon; and Remington's, Pharmaceutical Sciences
(current edition), Mack Publishing Co., Easton, Pa. In certain
embodiments, the agents and compositions described herein are
administered orally.
[0466] The term "pharmaceutically acceptable" as used herein,
refers to a material that does not abrogate the biological activity
or properties of the agents described herein, and is relatively
nontoxic (i.e., the toxicity of the material significantly
outweighs the benefit of the material). In some instances, a
pharmaceutically acceptable material may be administered to an
individual without causing significant undesirable biological
effects or significantly interacting in a deleterious manner with
any of the components of the composition in which it is
contained.
[0467] The term "carrier" as used herein, refers to relatively
nontoxic chemical agents that, in certain instances, facilitate the
incorporation of an agent into cells or tissues.
[0468] The term "non-systemic" or "minimally absorbed" as used
herein refers to low systemic bioavailability and/or absorption of
an administered compound. In some instances a non-systemic compound
is a compound that is substantially not absorbed systemically. In
some embodiments, ASBTI compositions described herein deliver the
ASBTI to the distal ileum, colon, and/or rectum and not
systemically (e.g., a substantial portion of the ASBTI is not
systemically absorbed. In some embodiments, the systemic absorption
of a non-systemic compound is <0.1%, <0.3%, <0.5%,
<0.6%, <0.7%, <0.8%, <0.9%, <1%, <1.5%, <2%,
<3%, or <5% of the administered dose (wt. % or mol %). In
some embodiments, the systemic absorption of a non-systemic
compound is <10% of the administered dose. In some embodiments,
the systemic absorption of a non-systemic compound is <15% of
the administered dose. In some embodiments, the systemic absorption
of a non-systemic compound is <25% of the administered dose. In
an alternative approach, a non-systemic ASBTI is a compound that
has lower systemic bioavailability relative to the systemic
bioavailability of a systemic ASBTI (e.g., compound 100A, 100C). In
some embodiments, the bioavailability of a non-systemic ASBTI
described herein is <30%, <40%, <50%, <60%, or <70%
of the bioavailability of a systemic ASBTI (e.g., compound 100A,
100C).
[0469] In another alternative approach, the compositions described
herein are formulated to deliver <10% of the administered dose
of the ASBTI systemically. In some embodiments, the compositions
described herein are formulated to deliver <20% of the
administered dose of the ASBTI systemically. In some embodiments,
the compositions described herein are formulated to deliver <30%
of the administered dose of the ASBTI systemically. In some
embodiments, the compositions described herein are formulated to
deliver <40% of the administered dose of the ASBTI systemically.
In some embodiments, the compositions described herein are
formulated to deliver <50% of the administered dose of the ASBTI
systemically. In some embodiments, the compositions described
herein are formulated to deliver <60% of the administered dose
of the ASBTI systemically. In some embodiments, the compositions
described herein are formulated to deliver <70% of the
administered dose of the ASBTI systemically. In some embodiments,
systemic absorption is determined in any suitable manner, including
the total circulating amount, the amount cleared after
administration, or the like.
[0470] The term "ASBT inhibitor" refers to a compound that inhibits
apical sodium-dependent bile transport or any recuperative bile
salt transport. The term Apical Sodium-dependent Bile Transporter
(ASBT) is used interchangeably with the term Ileal Bile Acid
Transporter (IBAT).
[0471] The term "enhancing enteroendocrine peptide secretion"
refers to a sufficient increase in the level of the enteroendocrine
peptide agent, for example, to treat any disease or disorder
described herein. In some embodiments, enhanced enteroendocrine
peptide secretion reverses or alleviates symptoms of cholestasis or
a cholestatic liver disease.
[0472] In various embodiments, pharmaceutically acceptable salts
described herein include, by way of non-limiting example, a
nitrate, chloride, bromide, phosphate, sulfate, acetate,
hexafluorophosphate, citrate, gluconate, benzoate, propionate,
butyrate, sulfosalicylate, maleate, laurate, malate, fumarate,
succinate, tartrate, amsonate, pamoate, p-toluenenesulfonate,
mesylate and the like. Furthermore, pharmaceutically acceptable
salts include, by way of non-limiting example, alkaline earth metal
salts (e.g., calcium or magnesium), alkali metal salts (e.g.,
sodium-dependent or potassium), ammonium salts and the like.
[0473] The term "optionally substituted" or "substituted" means
that the referenced group substituted with one or more additional
group(s). In certain embodiments, the one or more additional
group(s) are individually and independently selected from amide,
ester, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl,
heteroalicyclic, hydroxy, alkoxy, aryloxy, alkylthio, arylthio,
alkylsulfoxide, arylsulfoxide, ester, alkylsulfone, arylsulfone,
cyano, halo, alkoyl, alkoyloxo, isocyanato, thiocyanato,
isothiocyanato, nitro, haloalkyl, haloalkoxy, fluoroalkyl, amino,
alkyl-amino, dialkyl-amino, amido.
[0474] An "alkyl" group refers to an aliphatic hydrocarbon group.
Reference to an alkyl group includes "saturated alkyl" and/or
"unsaturated alkyl". The alkyl group, whether saturated or
unsaturated, includes branched, straight chain, or cyclic groups.
By way of example only, alkyl includes methyl, ethyl, propyl,
iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, pentyl,
iso-pentyl, neo-pentyl, and hexyl. In some embodiments, alkyl
groups include, but are in no way limited to, methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl,
ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, and the like. A "lower alkyl" is a C.sub.1-C.sub.6
alkyl. A "heteroalkyl" group substitutes any one of the carbons of
the alkyl group with a heteroatom having the appropriate number of
hydrogen atoms attached (e.g., a CH.sub.2 group to an NH group or
an O group).
[0475] The term "alkylene" refers to a divalent alkyl radical. Any
of the above mentioned monovalent alkyl groups may be an alkylene
by abstraction of a second hydrogen atom from the alkyl. In one
aspect, an alkelene is a C.sub.1-C.sub.10alkylene. In another
aspect, an alkylene is a C.sub.1-C.sub.6alkylene. Typical alkylene
groups include, but are not limited to, --CH.sub.2--,
--CH(CH.sub.3)--, --C(CH.sub.3).sub.2--, --CH.sub.2CH.sub.2--,
--CH.sub.2CH(CH.sub.3)--, --CH.sub.2C(CH.sub.3).sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--, and the
like.
[0476] An "alkoxy" group refers to a (alkyl)O-- group, where alkyl
is as defined herein.
[0477] The term "alkylamine" refers to the --N(alkyl).sub.xH.sub.y
group, wherein alkyl is as defined herein and x and y are selected
from the group x=1, y=1 and x=2, y=0. When x=2, the alkyl groups,
taken together with the nitrogen to which they are attached,
optionally form a cyclic ring system.
[0478] An "amide" is a chemical moiety with formula --C(O)NHR or
--NHC(O)R, where R is selected from alkyl, cycloalkyl, aryl,
heteroaryl (bonded through a ring carbon) and heteroalicyclic
(bonded through a ring carbon).
[0479] The term "ester" refers to a chemical moiety with formula
--C(.dbd.O)OR, where R is selected from the group consisting of
alkyl, cycloalkyl, aryl, heteroaryl and heteroalicyclic.
[0480] As used herein, the term "aryl" refers to an aromatic ring
wherein each of the atoms forming the ring is a carbon atom. Aryl
rings described herein include rings having five, six, seven,
eight, nine, or more than nine carbon atoms. Aryl groups are
optionally substituted. Examples of aryl groups include, but are
not limited to phenyl, and naphthalenyl.
[0481] The term "aromatic" refers to a planar ring having a
delocalized .pi.-electron system containing 4n+2.pi. electrons,
where n is an integer. Aromatic rings can be formed from five, six,
seven, eight, nine, ten, or more than ten atoms. Aromatics are
optionally substituted. The term "aromatic" includes both
carbocyclic aryl ("aryl", e.g., phenyl) and heterocyclic aryl (or
"heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term
includes monocyclic or fused-ring polycyclic (i.e., rings which
share adjacent pairs of carbon atoms) groups.
[0482] The term "cycloalkyl" refers to a monocyclic or polycyclic
non-aromatic radical, wherein each of the atoms forming the ring
(i.e. skeletal atoms) is a carbon atom. In various embodiments,
cycloalkyls are saturated, or partially unsaturated. In some
embodiments, cycloalkyls are fused with an aromatic ring.
Cycloalkyl groups include groups having from 3 to 10 ring atoms.
Illustrative examples of cycloalkyl groups include, but are not
limited to, the following moieties:
##STR00055##
and the like. Monocyclic cycloalkyls include, but are not limited
to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
and cyclooctyl.
[0483] The term "heterocyclo" refers to heteroaromatic and
heteroalicyclic groups containing one to four ring heteroatoms each
selected from O, S and N. In certain instances, each heterocyclic
group has from 4 to 10 atoms in its ring system, and with the
proviso that the ring of said group does not contain two adjacent O
or S atoms. Non-aromatic heterocyclic groups include groups having
3 atoms in their ring system, but aromatic heterocyclic groups must
have at least 5 atoms in their ring system. The heterocyclic groups
include benzo-fused ring systems. An example of a 3-membered
heterocyclic group is aziridinyl (derived from aziridine). An
example of a 4-membered heterocyclic group is azetidinyl (derived
from azetidine). An example of a 5-membered heterocyclic group is
thiazolyl. An example of a 6-membered heterocyclic group is
pyridyl, and an example of a 10-membered heterocyclic group is
quinolinyl. Examples of non-aromatic heterocyclic groups are
pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,
tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl,
piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl,
aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl,
oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl,
1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl,
2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl,
dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,
dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,
3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl
and quinolizinyl. Examples of aromatic heterocyclic groups are
pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl,
pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,
oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl,
indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl,
indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl,
pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl,
benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl,
quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl.
[0484] The terms "heteroaryl" or, alternatively, "heteroaromatic"
refers to an aryl group that includes one or more ring heteroatoms
selected from nitrogen, oxygen and sulfur. An N-containing
"heteroaromatic" or "heteroaryl" moiety refers to an aromatic group
in which at least one of the skeletal atoms of the ring is a
nitrogen atom. In certain embodiments, heteroaryl groups are
monocyclic or polycyclic. Illustrative examples of heteroaryl
groups include the following moieties:
##STR00056##
and the like.
[0485] A "heteroalicyclic" group or "heterocyclo" group refers to a
cycloalkyl group, wherein at least one skeletal ring atom is a
heteroatom selected from nitrogen, oxygen and sulfur. In various
embodiments, the radicals are with an aryl or heteroaryl.
Illustrative examples of heterocyclo groups, also referred to as
non-aromatic heterocycles, include:
##STR00057##
and the like. The term heteroalicyclic also includes all ring forms
of the carbohydrates, including but not limited to the
monosaccharides, the disaccharides and the oligosaccharides.
[0486] The term "halo" or, alternatively, "halogen" means fluoro,
chloro, bromo and iodo.
[0487] The terms "haloalkyl," and "haloalkoxy" include alkyl and
alkoxy structures that are substituted with one or more halogens.
In embodiments, where more than one halogen is included in the
group, the halogens are the same or they are different. The terms
"fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy
groups, respectively, in which the halo is fluorine.
[0488] The term "heteroalkyl" include optionally substituted alkyl,
alkenyl and alkynyl radicals which have one or more skeletal chain
atoms selected from an atom other than carbon, e.g., oxygen,
nitrogen, sulfur, phosphorus, silicon, or combinations thereof. In
certain embodiments, the heteroatom(s) is placed at any interior
position of the heteroalkyl group. Examples include, but are not
limited to, --CH.sub.2--O--CH.sub.3,
--CH.sub.2--CH.sub.2--O--CH.sub.3, --CH.sub.2--NH--CH.sub.3,
--CH.sub.2--CH.sub.2--NH--CH.sub.3,
--CH.sub.2--N(CH.sub.3)--CH.sub.3,
--CH.sub.2--CH.sub.2--NH--CH.sub.3,
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.3,
--CH.sub.2--S--CH.sub.2--CH.sub.3, --CH.sub.2--CH.sub.2,
--S(O)--CH.sub.3, --CH.sub.2--CH.sub.2--S(O).sub.2--CH.sub.3,
--CH.dbd.CH--O--CH.sub.3, --Si(CH.sub.3).sub.3,
--CH.sub.2--CH.dbd.N--OCH.sub.3, and
--CH.dbd.CH--N(CH.sub.3)--CH.sub.3. In some embodiments, up to two
heteroatoms are consecutive, such as, by way of example,
--CH.sub.2--NH--OCH.sub.3 and
--CH.sub.2--O--Si(CH.sub.3).sub.3.
[0489] A "cyano" group refers to a --CN group.
[0490] An "isocyanato" group refers to a --NCO group.
[0491] A "thiocyanato" group refers to a --CNS group.
[0492] An "isothiocyanato" group refers to a --NCS group.
[0493] "Alkoyloxy" refers to a RC(.dbd.O)O-- group.
[0494] "Alkoyl" refers to a RC(.dbd.O)-- group.
[0495] The term "modulate," as used herein refers to having some
affect on (e.g., increasing, enhancing or maintaining a certain
level).
[0496] The term "optionally substituted" or "substituted" means
that the referenced group may be substituted with one or more
additional group(s) individually and independently selected from
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, aryl, heteroaryl,
C.sub.2-C.sub.6heteroalicyclic, hydroxy, C.sub.1-C.sub.6alkoxy,
aryloxy, arylalkoxy, aralkyloxy, arylalkyloxy,
C.sub.1-C.sub.6alkylthio, arylthio, C.sub.1-C.sub.6alkylsulfoxide,
arylsulfoxide, C.sub.1-C.sub.6alkylsulfone, arylsulfone, cyano,
halo, C.sub.2-C.sub.8acyl, C.sub.2-C.sub.8acyloxy, nitro,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6fluoroalkyl, and amino,
including C.sub.1-C.sub.6alkylamino, and the protected derivatives
thereof. By way of example, an optional substituents may be
L.sup.sR.sup.s, wherein each L.sup.s is independently selected from
a bond, --O--, --C(.dbd.O)--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --NH--, --NHC(.dbd.O)--, --C(.dbd.O)NH--,
S(.dbd.O).sub.2NH--, --NHS(.dbd.O).sub.2--, --OC(.dbd.O)NH--,
--NHC(.dbd.O)O--, --(C.sub.1-C.sub.6alkyl)-, or
--(C.sub.2-C.sub.6alkenyl)-; and each R.sup.s is independently
selected from H, (C.sub.1-C.sub.4alkyl),
(C.sub.3-C.sub.8cycloalkyl), heteroaryl, aryl, and
C.sub.1-C.sub.6heteroalkyl. Optionally substituted non-aromatic
groups may be substituted with one or more oxo (.dbd.O). The
protecting groups that may form the protective derivatives of the
above substituents are known to those of skill in the art and may
be found in references such as Greene and Wuts, above. In some
embodiments, alkyl groups described herein are optionally
substituted with an O that is connected to two adjacent carbon
atoms (i.e., forming an epoxide).
[0497] The term "therapeutically effective amount" or an "effective
amount" as used herein, refers to a sufficient amount of a
therapeutically active agent to provide a desired effect in a
subject or individual. In some embodiments, a "therapeutically
effective amount" or an "effective amount" of an ASBTI refers to a
sufficient amount of an ASBTI to treat cholestasis or a cholestatic
liver disease in a subject or individual.
L-Cells
[0498] Inventors have discovered that enteroendocrine L-cells play
a role in repair. The epithelial barrier is also a key component in
host defence. A further pre-proglucagon splice product, GLP-2, is
secreted by enteroendocrine L-cells in the distal small intestine
and has been shown to improve intestinal wound healing in a TGF-B
(anti-inflammatory cytokine TGF-B), mediated process, small bowel
responding better than large bowel. GLP-2 has also been shown to
ameliorate the barrier dysfunction induced by experimental stress
and food allergy. Again, L-cells are activated by luminal
nutrients, and the barrier compromise observed in TPN may partly
reflect its hyposecretion in the absence of enteral stimuli.
Moreover, GLP-2 is also responsible, at least in part for growth
and adaptation observed in short-bowel models. Therefore, abnormal
enteroendocrine cells (EEC) function may predispose to GI
inflammatory disorders, and the underlying nutrient-EEC-vagal
pathways are targets in the injured gut as contemplated in the
present embodiments.
[0499] L-cells are scattered throughout the epithelial layer of the
gut from the duodenum to the rectum, with the highest numbers
occurring in the ileum, colon, and rectum. They are characterized
by an open-cell morphology, with apical microvilli facing into the
gut lumen and secretory vesicles located adjacent to the
basolateral membrane, and are therefore in direct contact with
nutrients in the intestinal lumen. Furthermore, L-cells are located
in close proximity to both neurons and the microvasculature of the
intestine, thereby allowing the L-cell to be affected by both
neural and hormonal signals. As well as Glucagon-Like Peptide 1
(GLP-1) and Glucagon-Like Peptide 2 (GLP-2), L-cells also secrete
peptide YY (PYY), and glutamate. The cells are just one member of a
much larger family of enteroendocrine cells that secrete a range of
hormones, including ghrelin, GIP, cholecystokinin, somatostatin,
and secretin, which are involved in the local coordination of gut
physiology, as well as in playing wider roles in the control of
cytokine release and/or controlling the adaptive process,
attenuating intestinal injury, reducing bacterial translocation,
inhibiting the release of free radical oxygen, or any combination
thereof. L-cells are unevenly distributed in the gastrointestinal
tract, within higher concentrations in the distal portion of the
gastrointestinal tract (e.g., in the distal ileum, colon and
rectum).
Bile Acid
[0500] Bile contains water, electrolytes and a numerous organic
molecules including bile acids, cholesterol, phospholipids and
bilirubin. Bile is secreted from the liver and stored in the gall
bladder, and upon gall bladder contraction, due to ingestion of a
fatty meal, bile passes through the bile duct into the intestine.
Bile acids/salts are critical for digestion and absorption of fats
and fat-soluble vitamins in the small intestine. Adult humans
produce 400 to 800 mL of bile daily. The secretion of bile can be
considered to occur in two stages. Initially, hepatocytes secrete
bile into canaliculi, from which it flows into bile ducts and this
hepatic bile contains large quantities of bile acids, cholesterol
and other organic molecules. Then, as bile flows through the bile
ducts, it is modified by addition of a watery, bicarbonate-rich
secretion from ductal epithelial cells. Bile is concentrated,
typically five-fold, during storage in the gall bladder.
[0501] The flow of bile is lowest during fasting, and a majority of
that is diverted into the gallbladder for concentration. When chyme
from an ingested meal enters the small intestine, acid and
partially digested fats and proteins stimulate secretion of
cholecystokinin and secretin, both of which are important for
secretion and flow of bile. Cholecystokinin (cholecysto=gallbladder
and kinin=movement) is a hormone which stimulates contractions of
the gallbladder and common bile duct, resulting in delivery of bile
into the gut. The most potent stimulus for release of
cholecystokinin is the presence of fat in the duodenum. Secretin is
a hormone secreted in response to acid in the duodenum, and it
simulates biliary duct cells to secrete bicarbonate and water,
which expands the volume of bile and increases its flow out into
the intestine.
[0502] Bile acids/salts are derivatives of cholesterol.
Cholesterol, ingested as part of the diet or derived from hepatic
synthesis, are converted into bile acids/salts in the hepatocyte.
Examples of such bile acids/salts include cholic and
chenodeoxycholic acids, which are then conjugated to an amino acid
(such as glycine or taurine) to yield the conjugated form that is
actively secreted into cannaliculi. The most abundant of the bile
salts in humans are cholate and deoxycholate, and they are normally
conjugated with either glycine or taurine to give glycocholate or
taurocholate respectively.
[0503] Free cholesterol is virtually insoluble in aqueous
solutions, however in bile it is made soluble by the presence of
bile acids/salts and lipids. Hepatic synthesis of bile acids/salts
accounts for the majority of cholesterol breakdown in the body. In
humans, roughly 500 mg of cholesterol are converted to bile
acids/salts and eliminated in bile every day. Therefore, secretion
into bile is a major route for elimination of cholesterol. Large
amounts of bile acids/salts are secreted into the intestine every
day, but only relatively small quantities are lost from the body.
This is because approximately 95% of the bile acids/salts delivered
to the duodenum are absorbed back into blood within the ileum, by a
process is known as "Enterohepatic Recirculation".
[0504] Venous blood from the ileum goes straight into the portal
vein, and hence through the sinusoids of the liver. Hepatocytes
extract bile acids/salts very efficiently from sinusoidal blood,
and little escapes the healthy liver into systemic circulation.
Bile acids/salts are then transported across the hepatocytes to be
resecreted into canaliculi. The net effect of this enterohepatic
recirculation is that each bile salt molecule is reused about 20
times, often two or three times during a single digestive phase.
Bile biosynthesis represents the major metabolic fate of
cholesterol, accounting for more than half of the approximate 800
mg/day of cholesterol that an average adult uses up in metabolic
processes. In comparison, steroid hormone biosynthesis consumes
only about 50 mg of cholesterol per day. Much more that 400 mg of
bile salts is required and secreted into the intestine per day, and
this is achieved by re-cycling the bile salts. Most of the bile
salts secreted into the upper region of the small intestine are
absorbed along with the dietary lipids that they emulsified at the
lower end of the small intestine. They are separated from the
dietary lipid and returned to the liver for re-use. Re-cycling thus
enables 20-30 g of bile salts to be secreted into the small
intestine each day.
[0505] Bile acids/salts are amphipathic, with the
cholesterol-derived portion containing both hydrophobic (lipid
soluble) and polar (hydrophilic) moieties while the amino acid
conjugate is generally polar and hydrophilic. This amphipathic
nature enables bile acids/salts to carry out two important
functions: emulsification of lipid aggregates and solubilization
and transport of lipids in an aqueous environment. Bile acids/salts
have detergent action on particles of dietary fat which causes fat
globules to break down or to be emulsified. Emulsification is
important since it greatly increases the surface area of fat
available for digestion by lipases which cannot access the inside
of lipid droplets. Furthermore, bile acids/salts are lipid carriers
and are able to solubilize many lipids by forming micelles and are
critical for transport and absorption of the fat-soluble
vitamins.
Pharmaceutical Compositions and Methods of Use
[0506] In some embodiments, compositions described herein are
administered for delivery of enteroendocrine peptide secretion
enhancing agents to a subject or individual. In certain
embodiments, any compositions described herein are formulated for
ileal, rectal and/or colonic delivery. In more specific
embodiments, the composition is formulated for non-systemic or
local delivery to the rectum and/or colon. It is to be understood
that as used herein, delivery to the colon includes delivery to
sigmoid colon, transverse colon, and/or ascending colon. In still
more specific embodiments, the composition is formulated for
non-systemic or local delivery to the rectum and/or colon is
administered rectally. In other specific embodiments, the
composition is formulated for non-systemic or local delivery to the
rectum and/or colon is administered orally.
[0507] In some embodiments, provided herein is a composition
comprising an enteroendocrine peptide secretion enhancing agent
and, optionally, a pharmaceutically acceptable carrier for
alleviating symptoms of pediatric cholestasis or a pediatric
cholestatic liver disease in an individual.
[0508] In certain embodiments, the composition comprises an
enteroendocrine peptide secretion enhancing agent and an absorption
inhibitor. In specific embodiments, the absorption inhibitor is an
inhibitor that inhibits the absorption of the (or at least one of
the) specific enteroendocrine peptide secretion enhancing agent
with which it is combined. In some embodiments, the composition
comprises an enteroendocrine peptide secretion enhancing agent, an
absorption inhibitor and a carrier (e.g., an orally suitable
carrier or a rectally suitable carrier, depending on the mode of
intended administration). In certain embodiments, the composition
comprises an enteroendocrine peptide secretion enhancing agent, an
absorption inhibitor, a carrier, and one or more of a cholesterol
absorption inhibitor, an enteroendocrine peptide, a peptidase
inhibitor, a spreading agent, and a wetting agent.
[0509] In other embodiments, the compositions described herein are
administered orally for non-systemic delivery of the bile salt
active component to the rectum and/or colon, including the sigmoid
colon, transverse colon, and/or ascending colon. In specific
embodiments, compositions formulated for oral administration are,
by way of non-limiting example, enterically coated or formulated
oral dosage forms, such as, tablets and/or capsules. It is to be
understood that the terms "subject" and "individual" are utilized
interchangeably herein and include, e.g., humans and human patients
in need of treatment.
Absorption Inhibitors
[0510] In certain embodiments, the composition described herein as
being formulated for the non-systemic delivery of ASBTI further
includes an absorption inhibitor. As used herein, an absorption
inhibitor includes an agent or group of agents that inhibit
absorption of a bile acid/salt.
[0511] Suitable bile acid absorption inhibitors (also described
herein as absorption inhibiting agents) include, by way of
non-limiting example, anionic exchange matrices, polyamines,
quaternary amine containing polymers, quaternary ammonium salts,
polyallylamine polymers and copolymers, colesevelam, colesevelam
hydrochloride, CholestaGel
(N,N,N-trimethyl-6-(2-propenylamino)-1-hexanaminium chloride
polymer with (chloromethyl)oxirane, 2-propen-1-amine and
N-2-propenyl-1-decanamine hydrochloride), cyclodextrins, chitosan,
chitosan derivatives, carbohydrates which bind bile acids, lipids
which bind bile acids, proteins and proteinaceous materials which
bind bile acids, and antibodies and albumins which bind bile acids.
Suitable cyclodextrins include those that bind bile acids/salts
such as, by way of non-limiting example, .beta.-cyclodextrin and
hydroxypropyl-.beta.-cyclodextrin. Suitable proteins, include those
that bind bile acids/salts such as, by way of non-limiting example,
bovine serum albumin, egg albumin, casein, .alpha.-acid
glycoprotein, gelatin, soy proteins, peanut proteins, almond
proteins, and wheat vegetable proteins.
[0512] In certain embodiments the absorption inhibitor is
cholestyramine. In specific embodiments, cholestyramine is combined
with a bile acid. Cholestyramine, an ion exchange resin, is a
styrene polymer containing quaternary ammonium groups crosslinked
by divinylbenzene. In other embodiments, the absorption inhibitor
is colestipol. In specific embodiments, colestipol is combined with
a bile acid. Colestipol, an ion exchange resin, is a copolymer of
diethylenetriamine and 1-chloro-2,3-epoxypropane.
[0513] In certain embodiments of the compositions and methods
described herein the ASBTI is linked to an absorption inhibitor,
while in other embodiments the ASBTI and the absorption inhibitor
are separate molecular entities. In specific embodiments the bile
acid, bile acid mimic or the modified bile acid is linked to a bile
acid adsorption inhibitor described herein.
Cholesterol Absorption Inhibitors
[0514] In certain embodiments, a composition described herein
optionally includes at least one cholesterol absorption inhibitor.
Suitable cholesterol absorption inhibitors include, by way of
non-limiting example, ezetimibe (SCH 58235), ezetimibe analogs, ACT
inhibitors, stigmastanyl phosphorylcholine, stigmastanyl
phosphorylcholine analogues, .beta.-lactam cholesterol absorption
inhibitors, sulfate polysaccharides, neomycin, plant sponins, plant
sterols, phytostanol preparation FM-VP4, Sitostanol,
.beta.-sitosterol, acyl-CoA:cholesterol-O-acyltransferase (ACAT)
inhibitors, Avasimibe, Implitapide, steroidal glycosides and the
like. Suitable enzetimibe analogs include, by way of non-limiting
example, SCH 48461, SCH 58053 and the like. Suitable ACT inhibitors
include, by way of non-limiting example, trimethoxy fatty acid
anilides such as CI-976,
3-[decyldimethylsilyl]-N-[2-(4-methylphenyl)-1-phenylethyl]-propanamide,
melinamide and the like. .beta.-lactam cholesterol absorption
inhibitors include, by way of non-limiting example,
(3R-4S)-1,4-bis-(4-methoxyphenyl)-3-(3-phenylpropyl)-2-azetidinone
and the like.
Peptidase Inhibitors
[0515] In some embodiments, the compositions described herein
optionally include at least one peptidase inhibitor. Such peptidase
inhibitors include, but are not limited to, dipeptidyl peptidase-4
inhibitors (DPP-4), neutral endopeptidase inhibitors, and
converting enzyme inhibitors. Suitable dipeptidyl peptidase-4
inhibitors (DPP-4) include, by way of non-limiting example,
Vildaglipti,
2S)-1-{2-[(3-hydroxy-1-adamantyl)amino]acetyl}pyrrolidine-2-carbonitrile,
Sitagliptin,
(3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-
-dien-4-yl]-4-(2,4,5-trifluorophenyl)butan-1-one, Saxagliptin, and
(1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1-adamantyl)acetyl]-2-azabicyclo[-
3.1.0]hexane-3-carbonitrile. Such neutral endopeptidase inhibitors
include, but are not limited to, Candoxatrilat and Ecadotril.
Spreading Agents/Wetting Agents
[0516] In certain embodiments, the composition described herein
optionally comprises a spreading agent. In some embodiments, a
spreading agent is utilized to improve spreading of the composition
in the colon and/or rectum. Suitable spreading agents include, by
way of non-limiting example, hydroxyethylcellulose,
hydroxypropymethyl cellulose, polyethylene glycol, colloidal
silicon dioxide, propylene glycol, cyclodextrins, microcrystalline
cellulose, polyvinylpyrrolidone, polyoxyethylated glycerides,
polycarbophil, di-n-octyl ethers, Cetiol.TM.OE, fatty alcohol
polyalkylene glycol ethers, Aethoxal.TM.B), 2-ethylhexyl palmitate,
Cegesoft.TM.C 24), and isopropyl fatty acid esters.
[0517] In some embodiments, the compositions described herein
optionally comprise a wetting agent. In some embodiments, a wetting
agent is utilized to improve wettability of the composition in the
colon and rectum. Suitable wetting agents include, by way of
non-limiting example, ionic or non-ionic surfactants. In some
embodiments, surfactants are selected from, by way of non-limiting
example, SLS, poloxamers (e.g., poloxamer 188), polysorbate (e.g.,
20 or 80), stearyl hetanoate, caprylic/capric fatty acid esters of
saturated fatty alcohols of chain length C.sub.12-C.sub.18,
isostearyl diglycerol isostearic acid, sodium dodecyl sulphate,
isopropyl myristate, isopropyl palmitate, and isopropyl
myristate/isopropyl stearate/isopropyl palmitate mixture.
Vitamins
[0518] In some embodiments, the methods provided herein further
comprise administering one or more vitamins.
[0519] In some embodiments, the vitamin is vitamin A, B1, B2, B3,
B5, B6, B7, B9, B12, C, D, E, K, folic acid, pantothenic acid,
niacin, riboflavin, thiamine, retinol, beta carotene, pyridoxine,
ascorbic acid, cholecalciferol, cyanocobalamin, tocopherols,
phylloquinone, menaquinone.
[0520] In some embodiments, the vitamin is a fat soluble vitamin
such as vitamin A, D, E, K, retinol, beta carotene,
cholecalciferol, tocopherols, phylloquinone. In a preferred
embodiment, the fat soluble vitamin is tocopherol polyethylene
glycol succinate (TPGS).
Bile Acid Sequestrants/Binders
[0521] In some embodiments, a labile bile acid sequestrant is an
enzyme dependent bile acid sequestrant. In certain embodiments, the
enzyme is a bacterial enzyme. In some embodiments, the enzyme is a
bacterial enzyme found in high concentration in human colon or
rectum relative to the concentration found in the small intestine.
Examples of micro-flora activated systems include dosage forms
comprising pectin, galactomannan, and/or Azo hydrogels and/or
glycoside conjugates (e.g., conjugates of D-galactoside,
.beta.-D-xylopyranoside or the like) of the active agent. Examples
of gastrointestinal micro-flora enzymes include bacterial
glycosidases such as, for example, D-galactosidase,
.beta.-D-glucosidase, .alpha.-L-arabinofuranosidase,
.beta.-D-xylopyranosidase or the like.
[0522] In certain embodiments, a labile bile acid sequestrant is a
time dependent bile acid sequestrant. In some embodiments, a labile
bile acid sequestrant releases a bile acid or is degraded after 1,
2, 3, 4, 5, 6, 7, 8, 9, or 10 seconds of sequestration. In some
embodiments, a labile bile acid sequestrant releases a bile acid or
is degraded after 15, 20, 25, 30, 35, 40, 45, 50, or 55 seconds of
sequestration. In some embodiments, a labile bile acid sequestrant
releases a bile acid or is degraded after 1, 2, 3, 4, 5, 6, 7, 8,
9, or 10 minutes of sequestration. In some embodiments, a labile
bile acid sequestrant releases a bile acid or is degraded after
about 15, 20, 25, 30, 35, 45, 50, or 55 minutes of sequestration.
In some embodiments, a labile bile acid sequestrant releases a bile
acid or is degraded after about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours of
sequestration. In some embodiments, a labile bile acid sequestrant
releases a bile acid or is degraded after 1, 2, or 3 days of
sequestration.
[0523] In some embodiments, the labile bile acid sequestrant has a
low affinity for bile acid. In certain embodiments, the labile bile
acid sequestrant has a high affinity for a primary bile acid and a
low affinity for a secondary bile acid.
[0524] In some embodiments, the labile bile acid sequestrant is a
pH dependent bile acid sequestrant. In certain embodiments, the pH
dependent bile acid sequestrant has a high affinity for bile acid
at a pH of 6 or below and a low affinity for bile acid at a pH
above 6. In certain embodiments, the pH dependent bile acid
sequestrant has a high affinity for bile acid at a pH of 6.5 or
below and a low affinity for bile acid at a pH above 6.5. In
certain embodiments, the pH dependent bile acid sequestrant has a
high affinity for bile acid at a pH of 7 or below and a low
affinity for bile acid at a pH above 7. In certain embodiments, the
pH dependent bile acid sequestrant has a high affinity for bile
acid at a pH of 7.1 or below and a low affinity for bile acid at a
pH above 7.1. In certain embodiments, the pH dependent bile acid
sequestrant has a high affinity for bile acid at a pH of 7.2 or
below and a low affinity for bile acid at a pH above 7.2. In
certain embodiments, the pH dependent bile acid sequestrant has a
high affinity for bile acid at a pH of 7.3 or below and a low
affinity for bile acid at a pH above 7.3. In certain embodiments,
the pH dependent bile acid sequestrant has a high affinity for bile
acid at a pH of 7.4 or below and a low affinity for bile acid at a
pH above 7.4. In certain embodiments, the pH dependent bile acid
sequestrant has a high affinity for bile acid at a pH of 7.5 or
below and a low affinity for bile acid at a pH above 7.5. In
certain embodiments, the pH dependent bile acid sequestrant has a
high affinity for bile acid at a pH of 7.6 or below and a low
affinity for bile acid at a pH above 7.6. In certain embodiments,
the pH dependent bile acid sequestrant has a high affinity for bile
acid at a pH of 7.7 or below and a low affinity for bile acid at a
pH above 7.7. In certain embodiments, the pH dependent bile acid
sequestrant has a high affinity for bile acid at a pH of 7.8 or
below and a low affinity for bile acid at a pH above 7.8. In some
embodiments, the pH dependent bile acid sequestrant degrades at a
pH above 6. In some embodiments, the pH dependent bile acid
sequestrant degrades at a pH above 6.5. In some embodiments, the pH
dependent bile acid sequestrant degrades at a pH above 7. In some
embodiments, the pH dependent bile acid sequestrant degrades at a
pH above 7.1. In some embodiments, the pH dependent bile acid
sequestrant degrades at a pH above 7.2. In some embodiments, the pH
dependent bile acid sequestrant degrades at a pH above 7.3. In some
embodiments, the pH dependent bile acid sequestrant degrades at a
pH above 7.4. In some embodiments, the pH dependent bile acid
sequestrant degrades at a pH above 7.5. In some embodiments, the pH
dependent bile acid sequestrant degrades at a pH above 7.6. In some
embodiments, the pH dependent bile acid sequestrant degrades at a
pH above 7.7. In some embodiments, the pH dependent bile acid
sequestrant degrades at a pH above 7.8. In some embodiments, the pH
dependent bile acid sequestrant degrades at a pH above 7.9.
[0525] In certain embodiments, the labile bile acid sequestrant is
lignin or a modified lignin. In some embodiments, the labile bile
acid sequestrant is a polycationic polymer or copolymer. In certain
embodiments, the labile bile acid sequestrant is a polymer or
copolymer comprising one or more N-alkenyl-N-alkylamine residues;
one or more N,N,N-trialkyl-N--(N'-alkenylamino)alkyl-azanium
residues; one or more N,N,N-trialkyl-N-alkenyl-azanium residues;
one or more alkenyl-amine residues; or a combination thereof.
[0526] In some embodiments, the bile acid binder is cholestyramine,
and various compositions including cholestyramine, which are
described, for example, in U.S. Pat. Nos. 3,383,281; 3,308,020;
3,769,399; 3,846,541; 3,974,272; 4,172,120; 4,252,790; 4,340,585;
4,814,354; 4,874,744; 4,895,723; 5,695,749; and 6,066,336. In some
embodiments, the bile acid binder is cholestipol or
cholesevelam.
Methods
[0527] Provided herein, in certain embodiments, are methods for
treating pediatric cholestasis or a pediatric cholestatic liver
disease comprising non-systemic administration of a therapeutically
effective amount of an ASBTI. Provided herein, in certain
embodiments, are methods for treating pediatric cholestasis or a
pediatric cholestatic liver disease comprising contacting the
gastrointestinal tract, including the distal ileum and/or the colon
and/or the rectum, of an individual in need thereof with an ASBTI.
Also provided herein are methods for reducing intraenterocyte bile
acids, reducing damage to hepatocellular or intestinal architecture
caused by cholestasis or a cholestatic liver disease, of an
individual comprising administration of a therapeutically effective
amount of an ASBTI to an individual in need thereof.
[0528] In some embodiments, provided herein is a method of treating
pediatric cholestasis or a pediatric cholestatic liver disease in
an individual comprising delivering to ileum or colon of the
individual a therapeutically effective amount of any ASBTI
described herein. In some embodiments, provided herein are methods
for reducing damage to hepatocellular or intestinal architecture or
cells from cholestasis or a cholestatic liver disease comprising
administration of a therapeutically effective amount of an ASBTI.
In certain embodiments, provided herein are methods for reducing
intraenterocyte bile acids/salts comprising administration of a
therapeutically effective amount of an ASBTI to an individual in
need thereof.
[0529] In some embodiments, the methods provide for inhibition of
bile salt recycling upon administration of any of the compounds
described herein to an individual. In some embodiments, an ASBTI
described herein is systemically absorbed upon administration. In
some embodiments, an ASBTI described herein is not absorbed
systemically. In some embodiments, an ASBTI herein is administered
to the individual orally. In some embodiments, an ASBTI described
herein is delivered and/or released in the distal ileum of an
individual.
[0530] In certain instances, contacting the distal ileum of a
pediatric individual with an ASBTI (e.g., any ASBTI described
herein) inhibits bile acid reuptake and increases the concentration
of bile acids/salts in the vicinity of L-cells in the distal ileum
and/or colon and/or rectum, thereby reducing intraenterocyte bile
acids, reducing serum and/or hepatic bile acid levels, reducing
overall bile acid load, and/or reducing damage to ileal
architecture caused by cholestasis or a cholestatic liver disease.
Without being limited to any particular theory, reducing serum
and/or hepatic bile acid levels ameliorates cholestasis and/or
cholestatic disease.
[0531] Administration of a compound described herein is achieved in
any suitable manner including, by way of non-limiting example, by
oral, enteric, parenteral (e.g., intravenous, subcutaneous,
intramuscular), intranasal, buccal, topical, rectal, or transdermal
administration routes. Any compound or composition described herein
is administered in a method or formulation appropriate to treat a
new born or an infant. Any compound or composition described herein
is administered in an oral formulation (e.g., solid or liquid) to
treat a new born or an infant. In some embodiments, the pediatric
dosage form is selected from a solution, syrup, suspension, elixir,
powder for reconstitution as suspension or solution,
dispersible/effervescent tablet, chewable tablet, lollipop, freezer
pops, troches, oral thin strips, orally disintegrating tablet,
orally disintegrating strip, and sprinkle oral powder or granules.
In some embodiments, a compound or composition described herein is
administered in a method or pediatric dosage form formulation
appropriate to treat children. In some embodiments, a compound or
composition described herein is administered in a method or
pediatric dosage form formulation appropriate to treat adolescents.
In some embodiments, a compound or composition described herein is
administered in a method or pediatric dosage form formulation
appropriate to treat a newborn or an infant. In some embodiments, a
compound or composition described herein is administered in an oral
formulation (e.g., solid or liquid) to treat a newborn or an
infant. In some embodiments, the pediatric dosage form described
herein is administered prior to ingestion of food, with food or
after ingestion of food.
[0532] In certain embodiments, a compound or a composition
comprising a compound described herein is administered for
prophylactic and/or therapeutic treatments. In therapeutic
applications, the compositions are administered to an individual
already suffering from a disease or condition, in an amount
sufficient to cure or at least partially arrest the symptoms of the
disease or condition. In various instances, amounts effective for
this use depend on the severity and course of the disease or
condition, previous therapy, the individual's health status,
weight, and response to the drugs, and the judgment of the treating
physician.
[0533] In prophylactic applications, compounds or compositions
containing compounds described herein are administered to an
individual susceptible to or otherwise at risk of a particular
disease, disorder or condition. In certain embodiments of this use,
the precise amounts of compound administered depend on the
individual's state of health, weight, and the like. Furthermore, in
some instances, when a compound or composition described herein is
administered to an individual, effective amounts for this use
depend on the severity and course of the disease, disorder or
condition, previous therapy, the individual's health status and
response to the drugs, and the judgment of the treating
physician.
[0534] In certain instances, wherein following administration of a
selected dose of a compound or composition described herein, an
individual's condition does not improve, upon the doctor's
discretion the administration of a compound or composition
described herein is optionally administered chronically, that is,
for an extended period of time, including throughout the duration
of the individual's life in order to ameliorate or otherwise
control or limit the symptoms of the individual's disorder, disease
or condition.
[0535] In certain embodiments, an effective amount of a given agent
varies depending upon one or more of a number of factors such as
the particular compound, disease or condition and its severity, the
identity (e.g., weight) of the subject or host in need of
treatment, and is determined according to the particular
circumstances surrounding the case, including, e.g., the specific
agent being administered, the route of administration, the
condition being treated, and the subject or host being treated. In
some embodiments, doses administered include those up to the
maximum tolerable dose. In some embodiments, doses administered
include those up to the maximum tolerable dose by a newborn or an
infant.
[0536] In certain embodiments, about 0.001-5000 mg per day, from
about 0.001-1500 mg per day, about 0.001 to about 100 mg/day, about
0.001 to about 50 mg/day, or about 0.001 to about 30 mg/day, or
about 0.001 to about 10 mg/day of a compound described herein is
administered to an individual in need thereof. In various
embodiments, the desired dose is conveniently presented in a single
dose or in divided doses administered simultaneously (or over a
short period of time) or at appropriate intervals, for example as
two, three, four or more sub-doses per day. In various embodiments,
a single dose is from about 0.001 mg/kg to about 500 mg/kg. In
various embodiments, a single dose is from about 0.001, 0.01, 0.1,
1, or 10 mg/kg to about 10, 50, 100, or 250 mg/kg. In various
embodiments, a single dose of an ASBTI is from about 0.001 mg/kg to
about 100 mg/kg. In various embodiments, a single dose of an ASBTI
is from about 0.001 mg/kg to about 50 mg/kg. In various
embodiments, a single dose of an ASBTI is from about 0.001 mg/kg to
about 10 mg/kg. In various embodiments, a single dose of an ASBTI
is administered every 6 hours, every 12 hours, every 24 hours,
every 48 hours, every 72 hours, every 96 hours, every 5 days, every
6 days, or once a week.
[0537] In the case wherein the patient's status does improve, upon
the doctor's discretion an ASBTI is optionally given continuously;
alternatively, the dose of drug being administered is temporarily
reduced or temporarily suspended for a certain length of time
(i.e., a "drug holiday"). The length of the drug holiday optionally
varies between 2 days and 1 year, including by way of example only,
2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days,
15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120
days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days,
320 days, 350 days, or 365 days. The dose reduction during a drug
holiday includes from 10%-100%, including, by way of example only,
10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%,
75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments the total
single dose of an ASBTI is in the range described above.
[0538] Once improvement of the patient's conditions has occurred, a
maintenance dose is administered if necessary. Subsequently, the
dosage or the frequency of administration, or both, is reduced, as
a function of the symptoms, to a level at which the improved
disease, disorder or condition is retained. In some embodiments,
patients require intermittent treatment on a long-term basis upon
any recurrence of symptoms.
[0539] In certain instances, there are a large number of variables
in regard to an individual treatment regime, and considerable
excursions from these recommended values are considered within the
scope described herein. Dosages described herein are optionally
altered depending on a number of variables such as, by way of
non-limiting example, the activity of the compound used, the
disease or condition to be treated, the mode of administration, the
requirements of the individual subject, the severity of the disease
or condition being treated, and the judgment of the
practitioner.
[0540] Toxicity and therapeutic efficacy of such therapeutic
regimens are optionally determined by pharmaceutical procedures in
cell cultures or experimental animals, including, but not limited
to, the determination of the LD.sub.50 (the dose lethal to 50% of
the population) and the ED.sub.50 (the dose therapeutically
effective in 50% of the population). The dose ratio between the
toxic and therapeutic effects is the therapeutic index and it can
be expressed as the ratio between LD.sub.50 and ED.sub.50.
Compounds exhibiting high therapeutic indices are preferred. In
certain embodiments, data obtained from cell culture assays and
animal studies are used in formulating a range of dosage for use in
human. In specific embodiments, the dosage of compounds described
herein lies within a range of circulating concentrations that
include the ED.sub.50 with minimal toxicity. The dosage optionally
varies within this range depending upon the dosage form employed
and the route of administration utilized.
[0541] In some embodiments, the systemic exposure of a
therapeutically effective amount of any non-systemic ASBTI
described herein (e.g., an ASBTI that comprises a non-systemic
moiety such as L-K or other groups described herein) is reduced
when compared to the systemic exposure of a therapeutically
effective amount of any systemically absorbed ASBTI (e.g. Compounds
100A, 100C). In some embodiments, the AUC of a therapeutically
effective amount of any non-systemic ASBTI described herein (e.g.,
an ASBTI that comprises a non-systemic moiety such as L-K or other
groups described herein) is at least 10%, at least 20%, at least
30%, at least 40%, at least 50%, at least 60%, at least 70%, at
least 80% or at least 90% reduced when compared to the AUC of any
systemically absorbed ASBTI (e.g. Compounds 100A, 100C).
[0542] In some embodiments, the systemic exposure of a
therapeutically effective amount of a compound of Formula I that is
not systemically absorbed (e.g., a compound of Formula I that
comprises a non-systemic moiety such as L-K or other groups
described herein) is reduced when compared to the systemic exposure
of a therapeutically effective amount of Compound 100A. In some
embodiments, the AUC of a therapeutically effective amount of a
compound of Formula I that is not systemically absorbed (e.g., a
compound of Formula I that comprises a non-systemic moiety such as
L-K or other groups described herein) is about 10%, about 20%,
about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or
about 90% reduced when compared to the AUC of a therapeutically
effective amount of Compound 100A. In some embodiments, the AUC of
a therapeutically effective amount of a compound of Formula I that
is not systemically absorbed (e.g., a compound of Formula I that
comprises a non-systemic moiety such as L-K or other groups
described herein) is about 50% reduced when compared to the AUC of
a therapeutically effective amount of Compound 100A. In other
embodiments, the AUC of a therapeutically effective amount of a
compound of Formula I that is not systemically absorbed (e.g., a
compound of Formula I that comprises a non-systemic moiety such as
L-K or other groups described herein) is about 75% reduced when
compared to the AUC of a therapeutically effective amount of
Compound 100A.
[0543] In some embodiments, the systemic exposure of a
therapeutically effective amount of a compound of Formula II that
is not systemically absorbed (e.g., a compound of Formula II that
comprises a non-systemic moiety such as L-K or other groups
described herein) is reduced when compared to the systemic exposure
of a therapeutically effective amount of Compound 100A. In some
embodiments, the AUC of a therapeutically effective amount of a
compound of Formula II that is not systemically absorbed (e.g., a
compound of Formula II that comprises a non-systemic moiety such as
L-K or other groups described herein) is about 10%, about 20%,
about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or
about 90% reduced when compared to the AUC of a therapeutically
effective amount of Compound 100A. In some embodiments, the AUC of
a therapeutically effective amount of a compound of Formula II that
is not systemically absorbed (e.g., a compound of Formula II that
comprises a non-systemic moiety such as L-K or other groups
described herein) is about 50% reduced when compared to the AUC of
a therapeutically effective amount of Compound 100A. In other
embodiments, the AUC of a therapeutically effective amount of a
compound of Formula II that is not systemically absorbed (e.g., a
compound of Formula II that comprises a non-systemic moiety such as
L-K or other groups described herein) is about 75% reduced when
compared to the AUC of a therapeutically effective amount of
Compound 100A.
[0544] In some embodiments, the systemic exposure of a
therapeutically effective amount of a compound of Formula III,
IIIA, IIIB or IIIC is reduced when compared to the systemic
exposure of a therapeutically effective amount of Compound 100C. In
some embodiments, the AUC of a therapeutically effective amount of
a compound of Formula III, IIIA, IIIB or IIIC is about 10%, about
20%, about 30%, about 40%, about 50%, about 60%, about 70%, about
80% or about 90% reduced when compared to the AUC of a
therapeutically effective amount of Compound 100C. In some
embodiments, the AUC of a therapeutically effective amount of a
compound of Formula III, IIIA, IIIB or IIIC is about 50% reduced
when compared to the AUC of a therapeutically effective amount of
Compound 100C. In other embodiments, the AUC of a therapeutically
effective amount of a compound of Formula III, IIIA, IIIB or IIIC
is about 75% reduced when compared to the AUC of a therapeutically
effective amount of Compound 100C.
[0545] In some embodiments, the systemic exposure of a
therapeutically effective amount of a compound of Formula IV that
is not systemically absorbed (e.g., a compound of Formula IV that
comprises a non-systemic moiety such as L-K or other groups
described herein) is reduced when compared to the systemic exposure
of a therapeutically effective amount of Compound 100A. In some
embodiments, the AUC of a therapeutically effective amount of a
compound of Formula IV that is not systemically absorbed (e.g., a
compound of Formula I that comprises a non-systemic moiety such as
L-K or other groups described herein) is about 10%, about 20%,
about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or
about 90% reduced when compared to the AUC of a therapeutically
effective amount of Compound 100A. In some embodiments, the AUC of
a therapeutically effective amount of a compound of Formula IV that
is not systemically absorbed (e.g., a compound of Formula IV that
comprises a non-systemic moiety such as L-K or other groups
described herein) is about 50% reduced when compared to the AUC of
a therapeutically effective amount of Compound 100A. In other
embodiments, the AUC of a therapeutically effective amount of a
compound of Formula IV that is not systemically absorbed (e.g., a
compound of Formula IV that comprises a non-systemic moiety such as
L-K or other groups described herein) is about 75% reduced when
compared to the AUC of a therapeutically effective amount of
Compound 100A.
[0546] In some embodiments, the systemic exposure of a
therapeutically effective amount of a compound of Formula V that is
not systemically absorbed (e.g., a compound of Formula V that
comprises a non-systemic moiety such as L-K or other groups
described herein) is reduced when compared to the systemic exposure
of a therapeutically effective amount of Compound 100A. In some
embodiments, the AUC of a therapeutically effective amount of a
compound of Formula V that is not systemically absorbed (e.g., a
compound of Formula V that comprises a non-systemic moiety such as
L-K or other groups described herein) is about 10%, about 20%,
about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or
about 90% reduced when compared to the AUC of a therapeutically
effective amount of Compound 100A. In some embodiments, the AUC of
a therapeutically effective amount of a compound of Formula I that
is not systemically absorbed (e.g., a compound of Formula V that
comprises a non-systemic moiety such as L-K or other groups
described herein) is about 50% reduced when compared to the AUC of
a therapeutically effective amount of Compound 100A. In other
embodiments, the AUC of a therapeutically effective amount of a
compound of Formula I that is not systemically absorbed (e.g., a
compound of Formula V that comprises a non-systemic moiety such as
L-K or other groups described herein) is about 75% reduced when
compared to the AUC of a therapeutically effective amount of
Compound 100A.
[0547] In some embodiments, the systemic exposure of a
therapeutically effective amount of a compound of Formula VI or VID
that is not systemically absorbed (e.g., a compound of Formula VI
or VID that comprises a non-systemic moiety such as L-K or other
groups described herein) is reduced when compared to the systemic
exposure of a therapeutically effective amount of Compound 100A. In
some embodiments, the AUC of a therapeutically effective amount of
a compound of Formula VI or VID that is not systemically absorbed
(e.g., a compound of Formula VI or VID that comprises a
non-systemic moiety such as L-K or other groups described herein)
is about 10%, about 20%, about 30%, about 40%, about 50%, about
60%, about 70%, about 80% or about 90% reduced when compared to the
AUC of a therapeutically effective amount of Compound 100A. In some
embodiments, the AUC of a therapeutically effective amount of a
compound of Formula VI or VID that is not systemically absorbed
(e.g., a compound of Formula VI or VID that comprises a
non-systemic moiety such as L-K or other groups described herein)
is about 50% reduced when compared to the AUC of a therapeutically
effective amount of Compound 100A. In other embodiments, the AUC of
a therapeutically effective amount of a compound of Formula I that
is not systemically absorbed (e.g., a compound of Formula VI or VID
that comprises a non-systemic moiety such as L-K or other groups
described herein) is about 75% reduced when compared to the AUC of
a therapeutically effective amount of Compound 100A.
[0548] In certain embodiments, the Cmax of a therapeutically
effective amount of any non-systemic ASBTI described herein (e.g.,
an ASBTI that comprises a non-systemic moiety such as L-K or other
groups described herein) is at least 10%, at least 20%, at least
30%, at least 40%, at least 50%, at least 60%, at least 70%, at
least 80% or at least 90% reduced when compared to the Cmax of any
systemically absorbed ASBTI (e.g. Compound 100A).
[0549] By way of example, the Cmax of a therapeutically effective
amount of a compound of Formula III, IIIA, IIIB or IIIC is about
10%, about 20%, about 30%, about 40%, about 50%, about 60%, about
70%, about 80% or about 90% reduced when compared to the Cmax of a
therapeutically effective amount of Compound 100C. In some
embodiments, the Cmax of a therapeutically effective amount of a
compound of Formula III, IIIA, IIIB or IIIC is about 25% reduced
when compared to the Cmax of a therapeutically effective amount of
Compound 100C. In certain embodiments, the Cmax of a
therapeutically effective amount of a compound of III, IIIA or IIIB
is about 50% reduced when compared to the Cmax of a therapeutically
effective amount of Compound 100C. In other embodiments, the Cmax
of a therapeutically effective amount of a compound of Formula III,
IIIA, IIIB or IIIC is about 75% reduced when compared to the Cmax
of a therapeutically effective amount of Compound 100C.
[0550] In certain embodiments, the pharmaceutical composition
administered includes a therapeutically effective amount of a bile
salt, a bile acid mimic, or a bile salt mimic, an absorption
inhibitor and a carrier (e.g., an orally suitable carrier or a
rectally suitable carrier, depending on the mode of intended
administration). In certain embodiments, the pharmaceutical
composition used or administered comprises a bile salt, a bile acid
mimic, or a bile salt mimic, an absorption inhibitor, a carrier,
and one or more of a cholesterol absorption inhibitor, an
enteroendocrine peptide, a peptidase inhibitor, a spreading agent,
and a wetting agent.
[0551] In a specific embodiment, the pharmaceutical composition
used to prepare a rectal dosage form or administered rectally
comprises a bile salt, a bile acid mimic, or a bile salt mimic, an
absorption inhibitor, a rectally suitable carrier, an optional
cholesterol absorption inhibitor, an optional enteroendocrine
peptide, an optional peptidase inhibitor, an optional spreading
agent, and an optional wetting agent. In certain embodiments,
rectally administered compositions evokes an anorectal response. In
specific embodiments, the anorectal response is an increase in
secretion of one or more enteroendocrine by cells (e.g., L-cells)
in the colon and/or rectum (e.g., in the epithelial layer of the
colon and/or rectum). In some embodiments, the anorectal response
persists for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours. In other
embodiments the anorectal response persists for a period between 24
hours and 48 hours, while in other embodiments the anorectal
response persists for persists for a period greater than 48
hours.
[0552] In another specific embodiment, the pharmaceutical
composition used to prepare an oral dosage form or administered
orally comprises a bile salt, a bile acid mimic, or a bile salt
mimic, an absorption inhibitor, an orally suitable carrier, an
optional cholesterol absorption inhibitor, an optional
enteroendocrine peptide, an optional peptidase inhibitor, an
optional spreading agent, and an optional wetting agent. In certain
embodiments, the orally administered compositions evokes an
anorectal response. In specific embodiments, the anorectal response
is an increase in secretion of one or more enteroendocrine by cells
in the colon and/or rectum (e.g., in L-cells the epithelial layer
of the colon and/or rectum). In some embodiments, the anorectal
response persists for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours. In
other embodiments the anorectal response persists for a period
between 24 hours and 48 hours, while in other embodiments the
anorectal response persists for persists for a period greater than
48 hours.
Routes of Administration and Dosage
[0553] In some embodiments, the compositions described herein and
the compositions administered in the methods described herein are
formulated to inhibit bile acid reuptake, or reduce serum or
hepatic bile acid levels. In certain embodiments, the compositions
described herein are formulated for rectal or oral administration.
In some embodiments, such formulations are administered rectally or
orally, respectively. In some embodiments, the compositions
described herein are combined with a device for local delivery of
the compositions to the rectum and/or colon (sigmoid colon,
transverse colon, or ascending colon). In certain embodiments, for
rectal administration the composition described herein are
formulated as enemas, rectal gels, rectal foams, rectal aerosols,
suppositories, jelly suppositories, or retention enemas. In some
embodiments, for oral administration the compositions described
herein are formulated for oral administration and enteric delivery
to the colon.
[0554] In certain embodiments, the compositions or methods
described herein are non-systemic. In some embodiments,
compositions described herein deliver the ASBTI to the distal
ileum, colon, and/or rectum and not systemically (e.g., a
substantial portion of the enteroendocrine peptide secretion
enhancing agent is not systemically absorbed). In some embodiments,
oral compositions described herein deliver the ASBTI to the distal
ileum, colon, and/or rectum and not systemically (e.g., a
substantial portion of the enteroendocrine peptide secretion
enhancing agent is not systemically absorbed). In some embodiments,
rectal compositions described herein deliver the ASBTI to the
distal ileum, colon, and/or rectum and not systemically (e.g., a
substantial portion of the enteroendocrine peptide secretion
enhancing agent is not systemically absorbed). In certain
embodiments, non-systemic compositions described herein deliver
less than 90% w/w of the ASBTI systemically. In certain
embodiments, non-systemic compositions described herein deliver
less than 80% w/w of the ASBTI systemically. In certain
embodiments, non-systemic compositions described herein deliver
less than 70% w/w of the ASBTI systemically. In certain
embodiments, non-systemic compositions described herein deliver
less than 60% w/w of the ASBTI systemically. In certain
embodiments, non-systemic compositions described herein deliver
less than 50% w/w of the ASBTI systemically. In certain
embodiments, non-systemic compositions described herein deliver
less than 40% w/w of the ASBTI systemically. In certain
embodiments, non-systemic compositions described herein deliver
less than 30% w/w of the ASBTI systemically. In certain
embodiments, non-systemic compositions described herein deliver
less than 25% w/w of the ASBTI systemically. In certain
embodiments, non-systemic compositions described herein deliver
less than 20% w/w of the ASBTI systemically. In certain
embodiments, non-systemic compositions described herein deliver
less than 15% w/w of the ASBTI systemically. In certain
embodiments, non-systemic compositions described herein deliver
less than 10% w/w of the ASBTI systemically. In certain
embodiments, non-systemic compositions described herein deliver
less than 5% w/w of the ASBTI systemically. In some embodiments,
systemic absorption is determined in any suitable manner, including
the total circulating amount, the amount cleared after
administration, or the like.
[0555] In certain embodiments, the compositions and/or formulations
described herein are administered at least once a day. In certain
embodiments, the formulations containing the ASBTI are administered
at least twice a day, while in other embodiments the formulations
containing the ASBTI are administered at least three times a day.
In certain embodiments, the formulations containing the ASBTI are
administered up to five times a day. It is to be understood that in
certain embodiments, the dosage regimen of composition containing
the ASBTI described herein to is determined by considering various
factors such as the patient's age, sex, and diet.
[0556] The concentration of the ASBTI administered in the
formulations described herein ranges from about 1 mM to about 1 M.
In certain embodiments the concentration of the ASBTI administered
in the formulations described herein ranges from about 1 mM to
about 750 mM. In certain embodiments the concentration of the ASBTI
administered in the formulations described herein ranges from about
1 mM to about 500 mM. In certain embodiments the concentration of
the ASBTI administered in the formulations described herein ranges
from about 5 mM to about 500 mM. In certain embodiments the
concentration of the ASBTI administered in the formulations
described herein ranges from about 10 mM to about 500 mM. In
certain embodiments the concentration of the administered in the
formulations described herein ranges from about 25 mM to about 500
mM. In certain embodiments the concentration of the ASBTI
administered in the formulations described herein ranges from about
50 mM to about 500 mM. In certain embodiments the concentration of
the ASBTI administered in the formulations described herein ranges
from about 100 mM to about 500 mM. In certain embodiments the
concentration of the ASBTI administered in the formulations
described herein ranges from about 200 mM to about 500 mM.
[0557] In certain embodiments, any composition described herein
comprises a therapeutically effective amount (e.g., to treat
cholestasis or a cholestatic liver disease) of ursodiol. In some
embodiments, ursodiol may be substituted for any other therapeutic
bile acid or salt. In some embodiments, compositions described
herein comprise or methods described herein comprise administering
about 0.01 mg to about 10 g of ursodiol. In certain embodiments, a
composition described herein comprises or a method described herein
comprises administering about 0.1 mg to about 500 mg of ursodiol.
In certain embodiments, a composition described herein comprises or
a method described herein comprises administering about 0.1 mg to
about 100 mg of ursodiol. In certain embodiments, a composition
described herein comprises or a method described herein comprises
administering about 0.1 mg to about 50 mg of ursodiol. In certain
embodiments, a composition described herein comprises or a method
described herein comprises administering about 0.1 mg to about 10
mg of ursodiol. In certain embodiments, a composition described
herein comprises or a method described herein comprises
administering about 0.5 mg to about 10 mg of ursodiol. In some
embodiments, compositions described herein comprise or methods
described herein comprise administering about 0.1 mmol to about 1
mol of ursodiol. In certain embodiments, a composition described
herein comprises or a method described herein comprises
administering about 0.01 mmol to about 500 mmol of ursodiol. In
certain embodiments, a composition described herein comprises or a
method described herein comprises administering about 0.1 mmol to
about 100 mmol of ursodiol. In certain embodiments, a composition
described herein comprises or a method described herein comprises
administering about 0.5 mmol to about 30 mmol of ursodiol. In
certain embodiments, a composition described herein comprises or a
method described herein comprises administering about 0.5 mmol to
about 20 mmol of ursodiol. In certain embodiments, a composition
described herein comprises or a method described herein comprises
administering about 1 mmol to about 10 mmol of ursodiol. In certain
embodiments, a composition described herein comprises or a method
described herein comprises administering about 0.01 mmol to about 5
mmol of ursodiol. In certain embodiments, a composition described
herein comprises or a method described herein comprises
administering about 0.1 mmol to about 1 mmol of ursodiol. In
various embodiments, certain bile acids/salts have different
potencies and dosing is optionally adjusted accordingly. For
example, the investigation in TGR5-transfected CHO cells of TGR5
agonist potency of natural bile acids/salts indicates the following
rank of potency: Lithocholic acid (LCA)>deoxycholic acid
(DCA)>murocholic acid (Moro-CA)>lagodeoxycholic acid
(lago-DCA)>chenodeoxycholic (CDCA)>cholic acid
(CA)>hyodeoxycholic acid (HDCA>ursodeoxycholic acid (UDCA);
and assays on TGR5-transfected CHO cells demonstrate that EC.sub.50
(in .mu.M) for UDCA was 36.4, TauroCA (TCA) 4.95 and LCA 0.58.
[0558] In certain embodiments, by targeting the distal
gastrointestinal tract (e.g., distal ileum, colon, and/or rectum),
compositions and methods described herein provide efficacy (e.g.,
in reducing microbial growth and/or alleviating symptoms of
cholestasis or a cholestatic liver disease) with a reduced dose of
enteroendocrine peptide secretion enhancing agent (e.g., as
compared to an oral dose that does not target the distal
gastrointestinal tract).
Rectal Administration Formulations
[0559] The pharmaceutical compositions described herein for the
non-systemic delivery of a compound described herein to the rectum
and/or colon are formulated for rectal administration as rectal
enemas, rectal foams, rectal gels, and rectal suppositories. The
components of such formulations are described herein. It is to be
understood that as used herein, pharmaceutical compositions and
compositions are or comprise the formulations as described herein.
In some embodiments, rectal formulations comprise rectal enemas,
foams, gels, or suppositories.
[0560] In certain embodiments, liquid carrier vehicles or
co-solvents in the compositions and/or formulations described
herein include, by way of non-limiting example, purified water,
propylene glycol, PEG200, PEG300, PEG400, PEG600,
polyethyleneglycol, ethanol, 1-propanol, 2-propanol, 1-propen-3-ol
(allyl alcohol), propylene glycol, glycerol, 2-methyl-2-propanol,
formamide, methyl formamide, dimethyl formamide, ethyl formamide,
diethyl formamide, acetamide, methyl acetamide, dimethyl acetamide,
ethyl acetamide, diethyl acetamide, 2-pyrrolidone,
N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, tetramethyl urea,
1,3-dimethyl-2-imidazolidinone, propylene carbonate, 1,2-butylene
carbonate, 2,3-butylene carbonate, dimethyl sulfoxide, diethyl
sulfoxide, hexamethyl phosphoramide, pyruvic aldehyde
dimethylacetal, dimethylisosorbide and combinations thereof.
[0561] In some embodiments, stabilizers used in compositions and/or
formulations described herein include, but are not limited to,
partial glycerides of polyoxyethylenic saturated fatty acids.
[0562] In certain embodiments, surfactants/emulsifiers used in the
compositions and/or formulations described herein include, by way
of non-limiting example, mixtures of cetostearylic alcohol with
sorbitan esterified with polyoxyethylenic fatty acids,
polyoxyethylene fatty ethers, polyoxyethylene fatty esters, fatty
acids, sulfated fatty acids, phosphated fatty acids,
sulfosuccinates, amphoteric surfactants, non-ionic poloxamers,
non-ionic meroxapols, petroleum derivatives, aliphatic amines,
polysiloxane derivatives, sorbitan fatty acid esters, laureth-4,
PEG-2 dilaurate, stearic acid, sodium lauryl sulfate, dioctyl
sodium sulfosuccinate, cocoamphopropionate, poloxamer 188,
meroxapol 258, triethanolamine, dimethicone, polysorbate 60,
sorbitan monostearate, pharmaceutically acceptable salts thereof,
and combinations thereof.
[0563] In some embodiments, non-ionic surfactants used in
compositions and/or formulations described herein include, by way
of non-limiting example, phospholipids, alkyl poly(ethylene oxide),
poloxamers (e.g., poloxamer 188), polysorbates, sodium dioctyl
sulfosuccinate, Brij.TM.-30 (Laureth-4), Brij.TM.-58 (Ceteth-20)
and Brij.TM.-78 (Steareth-20), Brij.TM.-721 (Steareth-21),
Crillet-1 (Polysorbate 20), Crillet-2 (Polysorbate 40), Crillet-3
(Polysorbate 60), Crillet 45 (Polysorbate 80), Myrj-52 (PEG-40
Stearate), Myrj-53 (PEG-50 Stearate), Pluronic.TM. F77 (Poloxamer
217), Pluronic.TM. F87 (Poloxamer 237), Pluronic.TM. F98 (Poloxamer
288), Pluronic.TM. L62 (Poloxamer 182), Pluronic.TM. L64 (Poloxamer
184), Pluronic.TM. F68 (Poloxamer 188), Pluronic.TM. L81 (Poloxamer
231), Pluronic.TM. L92 (Poloxamer 282), Pluronic.TM. L101
(Poloxamer 331), Pluronic.TM. P103 (Poloxamer 333), Pluracare.TM. F
108 NF (Poloxamer 338), and Pluracare.TM. F 127 NF (Poloxamer 407)
and combinations thereof. Pluronic.TM. polymers are commercially
purchasable from BASF, USA and Germany.
[0564] In certain embodiments, anionic surfactants used in
compositions and/or formulations described herein include, by way
of non-limiting example, sodium laurylsulphate, sodium dodecyl
sulfate (SDS), ammonium lauryl sulfate, alkyl sulfate salts, alkyl
benzene sulfonate, and combinations thereof.
[0565] In some embodiments, the cationic surfactants used in
compositions and/or formulations described herein include, by way
of non-limiting example, benzalkonium chloride, benzethonium
chloride, cetyl trimethylammonium bromide, hexadecyl trimethyl
ammonium bromide, other alkyltrimethylammonium salts,
cetylpyridinium chloride, polyethoxylated tallow and combinations
thereof.
[0566] In certain embodiments, the thickeners used in compositions
and/or formulations described herein include, by way of
non-limiting example, natural polysaccharides, semi-synthetic
polymers, synthetic polymers, and combinations thereof. Natural
polysaccharides include, by way of non-limiting example, acacia,
agar, alginates, carrageenan, guar, arabic, tragacanth gum,
pectins, dextran, gellan and xanthan gums. Semi-synthetic polymers
include, by way of non-limiting example, cellulose esters, modified
starches, modified celluloses, carboxymethylcellulose, methyl
cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose and hydroxypropyl methylcellulose. Synthetic polymers
include, by way of non-limiting example, polyoxyalkylenes,
polyvinyl alcohol, polyacrylamide, polyacrylates,
carboxypolymethylene (carbomer), polyvinylpyrrolidone (povidones),
polyvinylacetate, polyethylene glycols and poloxamer. Other
thickeners include, by way of nonlimiting example,
polyoxyethyleneglycol isostearate, cetyl alcohol, Polyglycol 300
isostearate, propyleneglycol, collagen, gelatin, and fatty acids
(e.g., lauric acid, myristic acid, palmitic acid, stearic acid,
palmitoleic acid, linoleic acid, linolenic acid, oleic acid and the
like).
[0567] In some embodiments, chelating agents used in the
compositions and/or formulations described herein include, by way
of non-limiting example, ethylenediaminetetraacetic acid (EDTA) or
salts thereof, phosphates and combinations thereof.
[0568] In some embodiments, the concentration of the chelating
agent or agents used in the rectal formulations described herein is
a suitable concentration, e.g., about 0.1%, 0.15%, 0.2%, 0.25%,
0.3%, 0.4%, or 0.5% (w/v).
[0569] In some embodiments, preservatives used in compositions
and/or formulations described herein include, by way of
non-limiting example, parabens, ascorbyl palmitate, benzoic acid,
butylated hydroxyanisole, butylated hydroxytoluene, chlorobutanol,
ethylenediamine, ethylparaben, methylparaben, butyl paraben,
propylparaben, monothioglycerol, phenol, phenylethyl alcohol,
propylparaben, sodium benzoate, sodium propionate, sodium
formaldehyde sulfoxylate, sodium metabisulfite, sorbic acid, sulfur
dioxide, maleic acid, propyl gallate, benzalkonium chloride,
benzethonium chloride, benzyl alcohol, chlorhexidine acetate,
chlorhexidine gluconate, sorbic acid, potassium sorbitol,
chlorbutanol, phenoxyethanol, cetylpyridinium chloride,
phenylmercuric nitrate, thimerosol, and combinations thereof.
[0570] In certain embodiments, antioxidants used in compositions
and/or formulations described herein include, by way of
non-limiting example, ascorbic acid, ascorbyl palmitate, butylated
hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid,
monothioglycerol, propyl gallate, sodium ascorbate, sodium sulfite,
sodium bisulfite, sodium formaldehyde sulfoxylate, potassium
metabisulphite, sodium metabisulfite, oxygen, quinones, t-butyl
hydroquinone, erythorbic acid, olive (olea eurpaea) oil,
pentasodium penetetate, pentetic acid, tocopheryl, tocopheryl
acetate and combinations thereof.
[0571] Pharmaceutically acceptable preservatives include quaternary
ammonium salts such as benzalkonium chloride, alcohols such as
benzyl alcohol, organic acids or salts and derivatives thereof such
as benzoic acid, sodium benzoate, sorbic acid, potassium sorbate,
propionic acid, sodium propionate, parabens such as methyl
parahydroxybenzoate, propyl parahydroxybenzoate, ethyl
parahydroxybenzoate or butyl parahydroxybenzoate, aqua conservans;
chlorhexidine diacetate, -digluconate. Given the intended use of
the present composition, the preservatives are preferably suitable
for pediatric use. Preferred preservatives are parabens such as
methyl parahydroxybenzoate, propyl parahydroxybenzoate, ethyl
parahydroxybenzoate or butyl parahydroxybenzoate, in particular
methyl parahydroxybenzoate or propyl parahydroxybenzoate. The
preservatives are present in a composition in a concentration in
order to provide sufficient antimicrobial activity in the
preconcentrate composition or in the liquid composition upon
reconstitution. Preferably, the concentration of the preservatives
in a resulting reconstituted liquid composition ranges up to about
3% (w/w), more preferably up to about 2.5% (w/w), more preferably
up to about 2% (w/w), depending on the actual preservative being
used.
[0572] The composition of the present invention may also contain
one or more anti-oxidants, such as, for example, sodium
metabisulfite, sodium bisulfite, sodium sulfite, sodium
thiosulfate, ascorbic acid, BHA (butylhydroxyanisol), BHT
(butylhydroxytoluene), vitamine E, propylgallate, ascorbyl
palmitate, or complex forming agents such as EDTA
(ethylenediaminetetraacetic acid), citric acid, tartaric acid,
sodium-hexametaphosphate and the like. Given the intended use of
the present composition, the antioxidants or the complex forming
agents are preferably suitable for pediatric use. Preferred
antioxidants are BHA, BHT, vitamin E or propylgallate. In some
embodiments, concentration of the antioxidant or antioxidants used
in the rectal formulations described herein is sufficient to
achieve a desired result, e.g., about 0.1%, 0.15%, 0.2%, 0.25%,
0.3%, 0.4%, or 0.5% (w/v).
[0573] The lubricating agents used in compositions and/or
formulations described herein include, by way of non-limiting
example, natural or synthetic fat or oil (e.g., a tris-fatty acid
glycerate and the like). In some embodiments, lubricating agents
include, by way of non-limiting example, glycerin (also called
glycerine, glycerol, 1,2,3-propanetriol, and trihydroxypropane),
polyethylene glycols (PEGs), polypropylene glycol, polyisobutene,
polyethylene oxide, behenic acid, behenyl alcohol, sorbitol,
mannitol, lactose, polydimethylsiloxane and combinations
thereof.
[0574] In certain embodiments, mucoadhesive and/or bioadhesive
polymers are used in the compositions and/or formulations described
herein as agents for inhibiting absorption of the enteroendocrine
peptide secretion enhancing agent across the rectal or colonic
mucosa. Bioadhesive or mucoadhesive polymers include, by way of
non-limiting example, hydroxypropyl cellulose, polyethylene oxide
homopolymers, polyvinyl ether-maleic acid copolymers, methyl
cellulose, ethyl cellulose, propyl cellulose, hydroxyethyl
cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
carboxymethylcellulose, polycarbophil, polyvinylpyrrolidone,
carbopol, polyurethanes, polyethylene oxide-polypropyline oxide
copolymers, sodium carboxymethyl cellulose, polyethylene,
polypropylene, lectins, xanthan gum, alginates, sodium alginate,
polyacrylic acid, chitosan, hyaluronic acid and ester derivatives
thereof, vinyl acetate homopolymer, calcium polycarbophil, gelatin,
natural gums, karaya, tragacanth, algin, chitosan, starches,
pectins, and combinations thereof.
[0575] In some embodiments, buffers/pH adjusting agents used in
compositions and/or formulations described herein include, by way
of non-limiting example, phosphoric acid, monobasic sodium or
potassium phosphate, triethanolamine (TRIS), BICINE, HEPES, Trizma,
glycine, histidine, arginine, lysine, asparagine, aspartic acid,
glutamine, glutamic acid, carbonate, bicarbonate, potassium
metaphosphate, potassium phosphate, monobasic sodium acetate,
acetic acid, acetate, citric acid, sodium citrate anhydrous, sodium
citrate dihydrate and combinations thereof. In certain embodiments,
an acid or a base is added to adjust the pH. Suitable acids or
bases include, by way of non-limiting example, HCL, NaOH and
KOH.
[0576] In certain embodiments, concentration of the buffering agent
or agents used in the rectal formulations described herein is
sufficient to achieve or maintain a physiologically desirable pH,
e.g., about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.8%, 0.9%, or 1.0%
(w/w).
[0577] The tonicity modifiers used in compositions and/or
formulations described herein include, by way of non-limiting
example, sodium chloride, potassium chloride, sodium phosphate,
mannitol, sorbitol or glucose.
Pediatric Dosage Formulations and Compositions
[0578] Provided herein, in certain embodiments, is a pediatric
dosage formulation or composition comprising a therapeutically
effective amount of any compound described herein. In certain
instances, the pharmaceutical composition comprises an ASBT
inhibitor (e.g., any ASBTI described herein).
[0579] In certain embodiments, suitable dosage forms include, by
way of non-limiting example, aqueous or non-aqueous oral
dispersions, liquids, gels, syrups, elixirs, slurries, suspensions,
solutions, controlled release formulations, fast melt formulations,
effervescent formulations, lyophilized formulations, chewable
tablets, gummy candy, orally disintegrating tablets, powders for
reconstitution as suspension or solution, sprinkle oral powder or
granules, dragees, delayed release formulations, extended release
formulations, pulsatile release formulations, multiparticulate
formulations, and mixed immediate release and controlled release
formulations. In some embodiments, provided herein is a
pharmaceutical composition wherein the pediatric dosage form is
selected from a solution, syrup, suspension, elixir, powder for
reconstitution as suspension or solution, dispersible/effervescent
tablet, chewable tablet, gummy candy, lollipop, freezer pops,
troches, oral thin strips, orally disintegrating tablet, orally
disintegrating strip, sachet, and sprinkle oral powder or
granules.
[0580] In another aspect, provide herein is a pharmaceutical
composition wherein at least one excipient is a flavoring agent or
a sweetener. In some embodiments, provided herein is a coating. In
some embodiments, provided herein is a taste-masking technology
selected from coating of drug particles with a taste-neutral
polymer by spray-drying, wet granulation, fluidized bed, and
microencapsulation; coating with molten waxes of a mixture of
molten waxes and other pharmaceutical adjuvants; entrapment of drug
particles by complexation, flocculation or coagulation of an
aqueous polymeric dispersion; adsorption of drug particles on resin
and inorganic supports; and solid dispersion wherein a drug and one
or more taste neutral compounds are melted and cooled, or
co-precipitated by a solvent evaporation. In some embodiments,
provided herein is a delayed or sustained release formulation
comprising drug particles or granules in a rate controlling polymer
or matrix.
[0581] Suitable sweeteners include sucrose, glucose, fructose or
intense sweeteners, i.e. agents with a high sweetening power when
compared to sucrose (e.g. at least 10 times sweeter than sucrose).
Suitable intense sweeteners comprise aspartame, saccharin, sodium
or potassium or calcium saccharin, acesulfame potassium, sucralose,
alitame, xylitol, cyclamate, neomate, neohesperidine
dihydrochalcone or mixtures thereof, thaumatin, palatinit,
stevioside, rebaudioside, Magnasweet.RTM.. The total concentration
of the sweeteners may range from effectively zero to about 300
mg/ml based on the liquid composition upon reconstitution.
[0582] In order to increase the palatability of the liquid
composition upon reconstitution with an aqueous medium, one or more
taste-making agents may be added to the composition in order to
mask the taste of the ASBT inhibitor. A taste-masking agent can be
a sweetener, a flavoring agent or a combination thereof. The
taste-masking agents typically provide up to about 0.1% or 5% by
weight of the total pharmaceutical composition. In a preferred
embodiment of the present invention, the composition contains both
sweetener(s) and flavor(s).
[0583] A flavoring agent herein is a substance capable of enhancing
taste or aroma of a composition. Suitable natural or synthetic
flavoring agents can be selected from standard reference books, for
example Fenaroli's Handbook of Flavor Ingredients, 3rd edition
(1995). Non-limiting examples of flavoring agents and/or sweeteners
useful in the formulations described herein, include, e.g., acacia
syrup, acesulfame K, alitame, anise, apple, aspartame, banana,
Bavarian cream, berry, black currant, butterscotch, calcium
citrate, camphor, caramel, cherry, cherry cream, chocolate,
cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton
candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate,
dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger,
glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit,
honey, isomalt, lemon, lime, lemon cream, monoammonium
glyrrhizinate (MagnaSweet.RTM.), maltol, mannitol, maple,
marshmallow, menthol, mint cream, mixed berry, neohesperidine DC,
neotame, orange, pear, peach, peppermint, peppermint cream,
Prosweet.RTM. Powder, raspberry, root beer, rum, saccharin,
safrole, sorbitol, spearmint, spearmint cream, strawberry,
strawberry cream, stevia, sucralose, sucrose, sodium saccharin,
saccharin, aspartame, acesulfame potassium, mannitol, talin,
sylitol, sucralose, sorbitol, Swiss cream, tagatose, tangerine,
thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry,
wintergreen, xylitol, or any combination of these flavoring
ingredients, e.g., anise-menthol, cherry-anise, cinnamon-orange,
cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime,
lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and
mixtures thereof. Flavoring agents can be used singly or in
combinations of two or more. In some embodiments, the aqueous
liquid dispersion comprises a sweetening agent or flavoring agent
in a concentration ranging from about 0.001% to about 5.0% the
volume of the aqueous dispersion. In one embodiment, the aqueous
liquid dispersion comprises a sweetening agent or flavoring agent
in a concentration ranging from about 0.001% to about 1.0% the
volume of the aqueous dispersion. In another embodiment, the
aqueous liquid dispersion comprises a sweetening agent or flavoring
agent in a concentration ranging from about 0.005% to about 0.5%
the volume of the aqueous dispersion. In yet another embodiment,
the aqueous liquid dispersion comprises a sweetening agent or
flavoring agent in a concentration ranging from about 0.01% to
about 1.0% the volume of the aqueous dispersion. In yet another
embodiment, the aqueous liquid dispersion comprises a sweetening
agent or flavoring agent in a concentration ranging from about
0.01% to about 0.5% the volume of the aqueous dispersion.
[0584] In certain embodiments, pharmaceutical compositions are
formulated in a conventional manner using one or more
physiologically acceptable carriers including, e.g., excipients and
auxiliaries which facilitate processing of the active compounds
into preparations which are suitable for pharmaceutical use. In
certain embodiments, proper formulation is dependent upon the route
of administration chosen. A summary of pharmaceutical compositions
described herein is found, for example, in Remington: The Science
and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack
Publishing Company, 1995); Hoover, John E., Remington's
Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975;
Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms,
Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage
Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams
& Wilkins 1999).
[0585] A pharmaceutical composition, as used herein, refers to a
mixture of a compound described herein, such as, for example, a
compound of Formula I-VI, with other chemical components, such as
carriers, stabilizers, diluents, dispersing agents, suspending
agents, thickening agents, and/or excipients. In certain instances,
the pharmaceutical composition facilitates administration of the
compound to an individual or cell. In certain embodiments of
practicing the methods of treatment or use provided herein,
therapeutically effective amounts of compounds described herein are
administered in a pharmaceutical composition to an individual
having a disease, disorder, or condition to be treated. In specific
embodiments, the individual is a human. As discussed herein, the
compounds described herein are either utilized singly or in
combination with one or more additional therapeutic agents.
[0586] In certain embodiments, the pharmaceutical formulations
described herein are administered to an individual in any manner,
including one or more of multiple administration routes, such as,
by way of non-limiting example, oral, parenteral (e.g.,
intravenous, subcutaneous, intramuscular), intranasal, buccal,
topical, rectal, or transdermal administration routes.
[0587] In certain embodiments, a pharmaceutical compositions
described herein includes one or more compound described herein as
an active ingredient in free-acid or free-base form, or in a
pharmaceutically acceptable salt form. In some embodiments, the
compounds described herein are utilized as an N-oxide or in a
crystalline or amorphous form (i.e., a polymorph). In some
situations, a compound described herein exists as tautomers. All
tautomers are included within the scope of the compounds presented
herein. In certain embodiments, a compound described herein exists
in an unsolvated or solvated form, wherein solvated forms comprise
any pharmaceutically acceptable solvent, e.g., water, ethanol, and
the like. The solvated forms of the compounds presented herein are
also considered to be described herein.
[0588] A "carrier" includes, in some embodiments, a
pharmaceutically acceptable excipient and is selected on the basis
of compatibility with compounds described herein, such as,
compounds of any of Formula I-VI, and the release profile
properties of the desired dosage form. Exemplary carrier materials
include, e.g., binders, suspending agents, disintegration agents,
filling agents, surfactants, solubilizers, stabilizers, lubricants,
wetting agents, diluents, and the like. See, e.g., Remington: The
Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack
Publishing Company, 1995); Hoover, John E., Remington's
Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975;
Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms,
Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage
Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams
& Wilkins 1999).
[0589] Moreover, in certain embodiments, the pharmaceutical
compositions described herein are formulated as a dosage form. As
such, in some embodiments, provided herein is a dosage form
comprising a compound described herein, suitable for administration
to an individual. In certain embodiments, suitable dosage forms
include, by way of non-limiting example, aqueous oral dispersions,
liquids, gels, syrups, elixirs, slurries, suspensions, solid oral
dosage forms, aerosols, controlled release formulations, fast melt
formulations, effervescent formulations, lyophilized formulations,
tablets, powders, pills, dragees, capsules, delayed release
formulations, extended release formulations, pulsatile release
formulations, multiparticulate formulations, and mixed immediate
release and controlled release formulations.
[0590] In certain aspects, the composition or formulation
containing one or more compounds described herein is orally
administered for local delivery of an ASBTI, or a compound
described herein to the colon and/or rectum. Unit dosage forms of
such compositions include a pill, tablet or capsules formulated for
enteric delivery to colon. In certain embodiments, such pills,
tablets or capsule contain the compositions described herein
entrapped or embedded in microspheres. In some embodiments,
microspheres include, by way of non-limiting example, chitosan
microcores HPMC capsules and cellulose acetate butyrate (CAB)
microspheres. In certain embodiments, oral dosage forms are
prepared using conventional methods known to those in the field of
pharmaceutical formulation. For example, in certain embodiments,
tablets are manufactured using standard tablet processing
procedures and equipment. An exemplary method for forming tablets
is by direct compression of a powdered, crystalline or granular
composition containing the active agent(s), alone or in combination
with one or more carriers, additives, or the like. In alternative
embodiments, tablets are prepared using wet-granulation or
dry-granulation processes. In some embodiments, tablets are molded
rather than compressed, starting with a moist or otherwise
tractable material.
[0591] In certain embodiments, tablets prepared for oral
administration contain various excipients, including, by way of
non-limiting example, binders, diluents, lubricants, disintegrants,
fillers, stabilizers, surfactants, preservatives, coloring agents,
flavoring agents and the like. In some embodiments, binders are
used to impart cohesive qualities to a tablet, ensuring that the
tablet remains intact after compression. Suitable binder materials
include, by way of non-limiting example, starch (including corn
starch and pregelatinized starch), gelatin, sugars (including
sucrose, glucose, dextrose and lactose), polyethylene glycol,
propylene glycol, waxes, and natural and synthetic gums, e.g.,
acacia sodium alginate, polyvinylpyrrolidone, cellulosic polymers
(including hydroxypropyl cellulose, hydroxypropyl methylcellulose,
methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, and the
like), Veegum, and combinations thereof. In certain embodiments,
diluents are utilized to increase the bulk of the tablet so that a
practical size tablet is provided. Suitable diluents include, by
way of non-limiting example, dicalcium phosphate, calcium sulfate,
lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch,
powdered sugar and combinations thereof. In certain embodiments,
lubricants are used to facilitate tablet manufacture; examples of
suitable lubricants include, by way of non-limiting example,
vegetable oils such as peanut oil, cottonseed oil, sesame oil,
olive oil, corn oil, and oil of theobroma, glycerin, magnesium
stearate, calcium stearate, stearic acid and combinations thereof.
In some embodiments, disintegrants are used to facilitate
disintegration of the tablet, and include, by way of non-limiting
example, starches, clays, celluloses, algins, gums, crosslinked
polymers and combinations thereof. Fillers include, by way of
non-limiting example, materials such as silicon dioxide, titanium
dioxide, alumina, talc, kaolin, powdered cellulose and
microcrystalline cellulose, as well as soluble materials such as
mannitol, urea, sucrose, lactose, dextrose, sodium chloride and
sorbitol. In certain embodiments, stabilizers are used to inhibit
or retard drug decomposition reactions that include, by way of
example, oxidative reactions. In certain embodiments, surfactants
are anionic, cationic, amphoteric or nonionic surface active
agents.
[0592] In some embodiments, ASBTIs, or other compounds described
herein are orally administered in association with a carrier
suitable for delivery to the distal gastrointestinal tract (e.g.,
distal ileum, colon, and/or rectum).
[0593] In certain embodiments, a composition described herein
comprises an ASBTI, or other compounds described herein in
association with a matrix (e.g., a matrix comprising hypermellose)
that allows for controlled release of an active agent in the distal
part of the ileum and/or the colon. In some embodiments, a
composition comprises a polymer that is pH sensitive (e.g., a
MMX.TM. matrix from Cosmo Pharmaceuticals) and allows for
controlled release of an active agent in the distal part of the
ileum. Examples of such pH sensitive polymers suitable for
controlled release include and are not limited to polyacrylic
polymers (e.g., anionic polymers of methacrylic acid and/or
methacrylic acid esters, e.g., Carbopol.RTM. polymers) that
comprise acidic groups (e.g., --COOH, --SO.sub.3H) and swell in
basic pH of the intestine (e.g., pH of about 7 to about 8). In some
embodiments, a composition suitable for controlled release in the
distal ileum comprises microparticulate active agent (e.g.,
micronized active agent). In some embodiments, a non-enzymatically
degrading poly(dl-lactide-co-glycolide) (PLGA) core is suitable for
delivery of an enteroendocrine peptide secretion enhancing agent
(e.g., bile acid) to the distal ileum. In some embodiments, a
dosage form comprising an enteroendocrine peptide secretion
enhancing agent (e.g., bile acid) is coated with an enteric polymer
(e.g., Eudragit.RTM. S-100, cellulose acetate phthalate,
polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate,
anionic polymers of methacrylic acid, methacrylic acid esters or
the like) for site specific delivery to the distal ileum and/or the
colon. In some embodiments, bacterially activated systems are
suitable for targeted delivery to the distal part of the ileum.
Examples of micro-flora activated systems include dosage forms
comprising pectin, galactomannan, and/or Azo hydrogels and/or
glycoside conjugates (e.g., conjugates of D-galactoside,
.beta.-D-xylopyranoside or the like) of the active agent. Examples
of gastrointestinal micro-flora enzymes include bacterial
glycosidases such as, for example, D-galactosidase,
.beta.-D-glucosidase, .alpha.-L-arabinofuranosidase,
.beta.-D-xylopyranosidase or the like.
[0594] The pharmaceutical composition described herein optionally
include an additional therapeutic compound described herein and one
or more pharmaceutically acceptable additives such as a compatible
carrier, binder, filling agent, suspending agent, flavoring agent,
sweetening agent, disintegrating agent, dispersing agent,
surfactant, lubricant, colorant, diluent, solubilizer, moistening
agent, plasticizer, stabilizer, penetration enhancer, wetting
agent, anti-foaming agent, antioxidant, preservative, or one or
more combination thereof. In some aspects, using standard coating
procedures, such as those described in Remington's Pharmaceutical
Sciences, 20th Edition (2000), a film coating is provided around
the formulation of the compound of Formula I. In one embodiment, a
compound described herein is in the form of a particle and some or
all of the particles of the compound are coated. In certain
embodiments, some or all of the particles of a compound described
herein are microencapsulated. In some embodiments, the particles of
the compound described herein are not microencapsulated and are
uncoated.
[0595] In further embodiments, a tablet or capsule comprising an
ASBTI or other compounds described herein is film-coated for
delivery to targeted sites within the gastrointestinal tract.
Examples of enteric film coats include and are not limited to
hydroxypropylmethylcellulose, polyvinyl pyrrolidone, hydroxypropyl
cellulose, polyethylene glycol 3350, 4500, 8000, methyl cellulose,
pseudo ethylcellulose, amylopectin and the like.
Solid Dosage Forms for Pediatric Administration
[0596] Solid dosage forms for pediatric administration of the
present invention can be manufactured by standard manufacturing
techniques. Non-limiting examples of oral solid dosage forms for
pediatric administration are described below.
Effervescent Compositions
[0597] The effervescent compositions of the invention may be
prepared according to techniques well-known in the art of
pharmacy.
[0598] Effervescent formulations contain and effervescent couple of
a base component and an acid component, which components reach in
the presence of water to generate a gas. In some embodiments, the
base component may comprise, for example, an alkali metal or
alkaline earth metal carbonate, or bicarbonate. The acid component
may comprise, for example, an aliphatic carboxylic acid or a salt
thereof, such as citric acid. The base and acid components may each
independently constitute, for example, 25% to 55% (w/w) of the
effervescent composition. The ratio of acid component to base
component may be within the range of 1:2 to 2:1.
[0599] The effervescent compositions of the invention may be
formulated using additional pharmaceutically acceptable carriers or
excipients as appropriate. For example, one or more taste masking
agents may be used. Dyes may also be used, as pediatric patients
often prefer colorful pharmaceutical combinations. The compositions
may take the form of, for example, tablets, granules or powders,
granules or powders presented in a sachet.
Chewable Tablets
[0600] The chewable tablets of the invention may be prepared
according to techniques well-known in the art of pharmacy.
[0601] Chewable tablets are tablets that are intended to
disintegrate in the mouth under the action of chewing or sucking
and where, in consequence, the active ingredient has greater
opportunity to come into contact with the bitter-taste receptors on
the tongue.
[0602] One method of overcoming this issue is to absorb the active
ingredient onto a suitable substrate. This approach is described in
U.S. Pat. No. 4,647,459.
[0603] Another approach involves forming the active ingredient into
an aggregate along with a pre-swelled substantially anhydrous
hydrocolloid. The hydrocolloid absorbs saliva and acquires a
slippery texture which enables it to lubricate the particles of
aggregate and mask the taste of the active ingredient. This
approach is described in European patent application 0190826.
[0604] Another approach involves employing a water-insoluble
hygroscopic excipient such as microcrystalline cellulose. This
approach is described in U.S. Pat. No. 5,275,823.
[0605] In addition to the above approaches, the chewable tablets of
the present invention can also contain other stand tabletting
excipients such as a disintegrant and a taste-masking agent.
Orodispersible Tablets
[0606] The orodispersible tablets of the invention may be prepared
according to techniques well-known in the art of pharmacy.
[0607] In orodispersible tablets of the invention, the excipient
mixtures is such as to provide it with a disintegration rate so
that its disintegration in the buccal cavity occurs in an extremely
short time and especially shorter than sixty seconds. In some
embodiments, the excipient mixture is characterized by the fact
that the active substance is in the form of coated or non-coated
microcrystals of microgranules. In some embodiments, the
orodispersible tablet comprises one or several disintegrating
agents of the carboxymethylcellulose type or insoluble reticulated
PVP type, one or several swelling agents which may comprise a
carboxymethylcellulose, a starch, a modified starch, or a
microcrystalline cellulose or optionally a direct compression
sugar.
Powders for Reconstitution
[0608] The powder for reconstitution pharmaceutical compositions of
the invention may be prepared according to techniques well-known in
the art of pharmacy.
[0609] In some embodiments, the powder for reconstitution
compositions of the invention comprise an effective amount of at
least one internal dehydrating agent. The internal dehydrating
agent can enhance the stability of the powder. In some embodiments,
the internal dehydrating agent is magnesium citrate or disodium
carbonate. In some embodiments, the powder composition comprises a
pharmaceutically acceptable diluents, such as sucrose, dextrose,
mannitol, xylitol, or lactose.
[0610] Powder compositions of the inventions may be placed in
sachets or bottles for contemporaneous dissolution or for short
term storage in liquid form (e.g. 7 days).
Gummy Candies
[0611] The gummy candies of the invention may be prepared according
to techniques well-known in the art of pharmacy.
[0612] Traditional gummy candy is made from a gelatin base. Gelatin
gives the candy its elasticity, the desired chewy consistency, and
a longer shelf life. In some embodiments, the gummy candy
pharmaceutical composition of the invention includes a binding
agent, a sweetener, and an active ingredient.
[0613] In some embodiments, the binding agent is a pectin gel,
gelatin, food starch, or any combination thereof.
[0614] In some embodiments, the gummy candy comprises sweeteners, a
binding agent, natural and/or artificial flavors and colors and
preservatives. In some embodiments, the gummy candy comprises
glucose syrup, natural cane juice, gelatin, citric acid, lactic
acid, natural colors, natural flavors, fractionated coconut oil,
and carnauba wax.
Liquid Dosage Forms
[0615] The pharmaceutical liquid dosage forms of the invention may
be prepared according to techniques well-known in the art of
pharmacy.
[0616] A solution refers to a liquid pharmaceutical formulation
wherein the active ingredient is dissolved in the liquid.
Pharmaceutical solutions of the invention include syrups and
elixers. A suspension refers to a liquid pharmaceutical formulation
wherein the active ingredient is in a precipitate in the
liquid.
[0617] In a liquid dosage form, it is desirable to have a
particular pH and/or to be maintained within a specific pH range.
In order to control the pH, a suitable buffer system can be used.
In addition, the buffer system should have sufficient capacity to
maintain the desired pH range. Examples of the buffer system useful
in the present invention include but are not limited to, citrate
buffers, phosphate buffers, or any other suitable buffer known in
the art. Preferably the buffer system include sodium citrate,
potassium citrate, sodium bicarbonate, potassium bicarbonate,
sodium dihydrogen phosphate and potassium dihydrogen phosphate,
etc. The concentration of the buffer system in the final suspension
varies according to factors such as the strength of the buffer
system and the pH/pH ranges required for the liquid dosage form. In
one embodiment, the concentration is within the range of 0.005 to
0.5 w/v % in the final liquid dosage form.
[0618] The pharmaceutical composition comprising the liquid dosage
form of the present invention can also include a
suspending/stabilizing agent to prevent settling of the active
material. Over time the settling could lead to caking of the active
to the inside walls of the product pack, leading to difficulties
with redispersion and accurate dispensing. Suitable stabilising
agents include but are not limited to, the polysaccharide
stabilizers such as xanthan, guar and tragacanth gums as well as
the cellulose derivatives HPMC (hydroxypropyl methylcellulose),
methyl cellulose and Avicel RC-591 (microcrystalline
cellulose/sodium carboxymethyl cellulose). In another embodiment,
polyvinylpyrrolidone (PVP) can also be used as a stabilizing
agent.
[0619] In addition to the aforementioned components, the ASBTI oral
suspension form can also optionally contain other excipients
commonly found in pharmaceutical compositions such as alternative
solvents, taste-masking agents, antioxidants, fillers, acidifiers,
enzyme inhibitors and other components as described in Handbook of
Pharmaceutical Excipients, Rowe et al., Eds., 4.sup.th Edition,
Pharmaceutical Press (2003), which is hereby incorporated by
reference.
[0620] Addition of an alternative solvent may help increase
solubility of an active ingredient in the liquid dosage form, and
consequently the absorption and bioavailability inside the body of
a subject. Preferably the alternative solvents include methanol,
ethanol or propylene glycol and the like.
[0621] In another aspect, the present invention provides a process
for preparing the liquid dosage form. The process comprises steps
of bringing ASBTI or its pharmaceutically acceptable salts thereof
into mixture with the components including glycerol or syrup or the
mixture thereof, a preservative, a buffer system and a
suspending/stabilizing agent, etc., in a liquid medium. In general,
the liquid dosage form is prepared by uniformly and intimately
mixing these various components in the liquid medium. For example,
the components such as glycerol or syrup or the mixture thereof, a
preservative, a buffer system and a suspending/stabilizing agent,
etc., can be dissolved in water to form the aqueous solution, then
the active ingredient can be then dispersed in the aqueous solution
to form a suspension.
[0622] In some embodiments, the liquid dosage form provided herein
can be in a volume of between 5 ml to 50 ml. In some embodiments,
the liquid dosage form provided herein can be in a volume of
between 5 ml to 40 ml. In some embodiments, the liquid dosage form
provided herein can be in a volume of between 5 ml to 30 ml. In
some embodiments, the liquid dosage form provided herein can be in
a volume of between 5 ml to 20 ml. In some embodiments, the liquid
dosage form provided herein can be in a volume of between 10 ml to
30 ml. In some embodiments, the ASBTI can be in an amount ranging
from about 0.001% to 90% of the total volume. In some embodiments,
the ASBTI can be in an amount ranging from about 0.01% to 80% of
the total volume. In some embodiments, the ASBTI can be in an
amount ranging from about 0.1% to 70% of the total volume. In some
embodiments, the ASBTI can be in an amount ranging from about 1% to
60% of the total volume. In some embodiments, the ASBTI can be in
an amount ranging from about 1% to 50% of the total volume. In some
embodiments, the ASBTI can be in an amount ranging from about 1% to
40% of the total volume. In some embodiments, the ASBTI can be in
an amount ranging from about 1% to 30% of the total volume. In some
embodiments, the ASBTI can be in an amount ranging from about 1% to
20% of the total volume. In some embodiments, the ASBTI can be in
an amount ranging from about 1% to 10% of the total volume. In some
embodiments, the ASBTI can be in an amount ranging from about 5% to
70% of the total volume. In some embodiments, the ASBTI can be in
an amount ranging from about 5% to 60% of the total volume. In some
embodiments, the ASBTI can be in an amount ranging from about 5% to
50% of the total volume. In some embodiments, the ASBTI can be in
an amount ranging from about 5% to 40% of the total volume. In some
embodiments, the ASBTI can be in an amount ranging from about 5% to
30% of the total volume. In some embodiments, the ASBTI can be in
an amount ranging from about 5% to 20% of the total volume. In some
embodiments, the ASBTI can be in an amount ranging from about 5% to
10% of the total volume. In some embodiments, the ASBTI can be in
an amount ranging from about 10% to 50% of the total volume. In
some embodiments, the ASBTI can be in an amount ranging from about
10% to 40% of the total volume. In some embodiments, the ASBTI can
be in an amount ranging from about 10% to 30% of the total volume.
In some embodiments, the ASBTI can be in an amount ranging from
about 10% to 20% of the total volume. In one embodiment, the
resulted liquid dosage form can be in a liquid volume of 10 ml to
30 ml, preferably 20 ml, and the active ingredient can be in an
amount ranging from about 0.001 mg/ml to about 16 mg/ml, or from
about 0.025 mg/ml to about 8 mg/ml, or from about 0.1 mg/ml to
about 4 mg/ml, or about 0.25 mg/ml, or about 0.5 mg/ml, or about 1
mg/ml, or about 2 mg/ml, or about 4 mg/ml, or about 5 mg/ml, or
about 8 mg/ml, or about 10 mg/ml, or about 12 mg/ml, or about 14
mg/ml or about 16 mg/ml.
Bile Acid Sequestrant
[0623] In certain embodiments, an oral formulation for use in any
method described herein is, e.g., an ASBTI in association with a
labile bile acid sequestrant. A labile bile acid sequestrant is a
bile acid sequestrant with a labile affinity for bile acids. In
certain embodiments, a bile acid sequestrant described herein is an
agent that sequesters (e.g., absorbs or is charged with) bile acid,
and/or the salts thereof.
[0624] In specific embodiments, the labile bile acid sequestrant is
an agent that sequesters (e.g., absorbs or is charged with) bile
acid, and/or the salts thereof, and releases at least a portion of
the absorbed or charged bile acid, and/or salts thereof in the
distal gastrointestinal tract (e.g., the colon, ascending colon,
sigmoid colon, distal colon, rectum, or any combination thereof).
In certain embodiments, the labile bile acid sequestrant is an
enzyme dependent bile acid sequestrant. In specific embodiments,
the enzyme is a bacterial enzyme. In some embodiments, the enzyme
is a bacterial enzyme found in high concentration in human colon or
rectum relative to the concentration found in the small intestine.
Examples of micro-flora activated systems include dosage forms
comprising pectin, galactomannan, and/or Azo hydrogels and/or
glycoside conjugates (e.g., conjugates of D-galactoside,
.beta.-D-xylopyranoside or the like) of the active agent. Examples
of gastrointestinal micro-flora enzymes include bacterial
glycosidases such as, for example, D-galactosidase,
.beta.-D-glucosidase, .alpha.-L-arabinofuranosidase,
.beta.-D-xylopyranosidase or the like. In some embodiments, the
labile bile acid sequestrant is a time dependent bile acid
sequestrant (i.e., the bile acid sequesters the bile acid and/or
salts thereof and after a time releases at least a portion of the
bile acid and/or salts thereof). In some embodiments, a time
dependent bile acid sequestrant is an agent that degrades in an
aqueous environment over time. In certain embodiments, a labile
bile acid sequestrant described herein is a bile acid sequestrant
that has a low affinity for bile acid and/or salts thereof, thereby
allowing the bile acid sequestrant to continue to sequester bile
acid and/or salts thereof in an environ where the bile acids/salts
and/or salts thereof are present in high concentration and release
them in an environ wherein bile acids/salts and/or salts thereof
are present in a lower relative concentration. In some embodiments,
the labile bile acid sequestrant has a high affinity for a primary
bile acid and a low affinity for a secondary bile acid, allowing
the bile acid sequestrant to sequester a primary bile acid or salt
thereof and subsequently release a secondary bile acid or salt
thereof as the primary bile acid or salt thereof is converted
(e.g., metabolized) to the secondary bile acid or salt thereof. In
some embodiments, the labile bile acid sequestrant is a pH
dependent bile acid sequestrant. In some embodiments, the pH
dependent bile acid sequestrant has a high affinity for bile acid
at a pH of 6 or below and a low affinity for bile acid at a pH
above 6. In certain embodiments, the pH dependent bile acid
sequestrant degrades at a pH above 6.
[0625] In some embodiments, labile bile acid sequestrants described
herein include any compound, e.g., a macro-structured compound,
that can sequester bile acids/salts and/or salts thereof through
any suitable mechanism. For example, in certain embodiments, bile
acid sequestrants sequester bile acids/salts and/or salts thereof
through ionic interactions, polar interactions, static
interactions, hydrophobic interactions, lipophilic interactions,
hydrophilic interactions, steric interactions, or the like. In
certain embodiments, macrostructured compounds sequester bile
acids/salts and/or sequestrants by trapping the bile acids/salts
and/or salts thereof in pockets of the macrostructured compounds
and, optionally, other interactions, such as those described above.
In some embodiments, bile acid sequestrants (e.g., labile bile acid
sequestrants) include, by way of non-limiting example, lignin,
modified lignin, polymers, polycationic polymers and copolymers,
polymers and/or copolymers comprising anyone one or more of
N-alkenyl-N-alkylamine residues; one or more
N,N,N-trialkyl-N--(N'-alkenylamino)alkyl-azanium residues; one or
more N,N,N-trialkyl-N-alkenyl-azanium residues; one or more
alkenyl-amine residues; or a combination thereof, or any
combination thereof.
Covalent Linkage of the Drug with a Carrier
[0626] In some embodiments, strategies used for colon targeted
delivery include, by way of non-limiting example, covalent linkage
of the ASBTI or other compounds described herein to a carrier,
coating the dosage form with a pH-sensitive polymer for delivery
upon reaching the pH environment of the colon, using redox
sensitive polymers, using a time released formulation, utilizing
coatings that are specifically degraded by colonic bacteria, using
bioadhesive system and using osmotically controlled drug delivery
systems.
[0627] In certain embodiments of such oral administration of a
composition containing an ASBTI or other compounds described herein
involves covalent linking to a carrier wherein upon oral
administration the linked moiety remains intact in the stomach and
small intestine. Upon entering the colon the covalent linkage is
broken by the change in pH, enzymes, and/or degradation by
intestinal microflora. In certain embodiments, the covalent linkage
between the ASBTI and the carrier includes, by way of non-limiting
example, azo linkage, glycoside conjugates, glucuronide conjugates,
cyclodextrin conjugates, dextran conjugates, and amino-acid
conjugates (high hydrophilicity and long chain length of the
carrier amino acid).
Coating with Polymers: pH-Sensitive Polymers
[0628] In some embodiments, the oral dosage forms described herein
are coated with an enteric coating to facilitate the delivery of an
ASBTI or other compounds described herein to the colon and/or
rectum. In certain embodiments, an enteric coating is one that
remains intact in the low pH environment of the stomach, but
readily dissolved when the optimum dissolution pH of the particular
coating is reached which depends upon the chemical composition of
the enteric coating. The thickness of the coating will depend upon
the solubility characteristics of the coating material. In certain
embodiments, the coating thicknesses used in such formulations
described herein range from about 25 .mu.m to about 200 .mu.m.
[0629] In certain embodiments, the compositions or formulations
described herein are coated such that an ASBTI or other compounds
described herein of the composition or formulation is delivered to
the colon and/or rectum without absorbing at the upper part of the
intestine. In a specific embodiment, specific delivery to the colon
and/or rectum is achieved by coating of the dosage form with
polymers that degrade only in the pH environment of the colon. In
alternative embodiments, the composition is coated with an enteric
coat that dissolves in the pH of the intestines and an outer layer
matrix that slowly erodes in the intestine. In some of such
embodiments, the matrix slowly erodes until only a core composition
comprising an enteroendocrine peptide secretion enhancing agent
(and, in some embodiments, an absorption inhibitor of the agent) is
left and the core is delivered to the colon and/or rectum.
[0630] In certain embodiments, pH-dependent systems exploit the
progressively increasing pH along the human gastrointestinal tract
(GIT) from the stomach (pH 1-2 which increases to 4 during
digestion), small intestine (pH 6-7) at the site of digestion and
it to 7-8 in the distal ileum. In certain embodiments, dosage forms
for oral administration of the compositions described herein are
coated with pH-sensitive polymer(s) to provide delayed release and
protect the enteroendocrine peptide secretion enhancing agents from
gastric fluid. In certain embodiments, such polymers are be able to
withstand the lower pH values of the stomach and of the proximal
part of the small intestine, but disintegrate at the neutral or
slightly alkaline pH of the terminal ileum and/or ileocecal
junction. Thus, in certain embodiments, provided herein is an oral
dosage form comprising a coating, the coating comprising a
pH-sensitive polymer. In some embodiments, the polymers used for
colon and/or rectum targeting include, by way of non-limiting
example, methacrylic acid copolymers, methacrylic acid and methyl
methacrylate copolymers, Eudragit L100, Eudragit S100, Eudragit
L-30D, Eudragit FS-30D, Eudragit L100-55, polyvinylacetate
phthalate, hyrdoxypropyl ethyl cellulose phthalate, hyrdoxypropyl
methyl cellulose phthalate 50, hyrdoxypropyl methyl cellulose
phthalate 55, cellulose acetate trimelliate, cellulose acetate
phthalate and combinations thereof.
[0631] In certain embodiments, oral dosage forms suitable for
delivery to the colon and/or rectum comprise a coating that has a
biodegradable and/or bacteria degradable polymer or polymers that
are degraded by the microflora (bacteria) in the colon. In such
biodegradable systems suitable polymers include, by way of
non-limiting example, azo polymers, linear-type-segmented
polyurethanes containing azo groups, polygalactomannans, pectin,
glutaraldehyde crosslinked dextran, polysaccharides, amylose, guar
gum, pectin, chitosan, inulin, cyclodextrins, chondroitin sulphate,
dextrans, locust bean gum, chondroitin sulphate, chitosan, poly
(-caprolactone), polylactic acid and poly(lactic-co-glycolic
acid).
[0632] In certain embodiments of such oral administration of
compositions containing one or more ASBTIs or other compounds
described herein, the compositions are delivered to the colon
without absorbing at the upper part of the intestine by coating of
the dosage forms with redox sensitive polymers that are degraded by
the microflora (bacteria) in the colon. In such biodegradable
systems such polymers include, by way of non-limiting example,
redox-sensitive polymers containing an azo and/or a disulfide
linkage in the backbone.
[0633] In some embodiments, compositions formulated for delivery to
the colon and/or rectum are formulated for time-release. In some
embodiments, time release formulations resist the acidic
environment of the stomach, thereby delaying the release of the
enteroendocrine peptide secretion enhancing agents until the dosage
form enters the colon and/or rectum.
[0634] In certain embodiments the time released formulations
described herein comprise a capsule (comprising an enteroendocrine
peptide secretion enhancing agent and an optional absorption
inhibitor) with hydrogel plug. In certain embodiments, the capsule
and hydrogel plug are covered by a water-soluble cap and the whole
unit is coated with an enteric polymer. When the capsule enters the
small intestine the enteric coating dissolves and the hydrogels
plug swells and dislodges from the capsule after a period of time
and the composition is released from the capsule. The amount of
hydrogel is used to adjust the period of time to the release the
contents.
[0635] In some embodiments, provided herein is an oral dosage form
comprising a multi-layered coat, wherein the coat comprises
different layers of polymers having different pH-sensitivities. As
the coated dosage form moves along GIT the different layers
dissolve depending on the pH encountered. Polymers used in such
formulations include, by way of non-limiting example,
polymethacrylates with appropriate pH dissolution characteristics,
Eudragit.RTM. RL and Eudragit.RTM.RS (inner layer), and
Eudragit.RTM. FS (outer layer). In other embodiments the dosage
form is an enteric coated tablets having an outer shell of
hydroxypropylcellulose or hydroxypropylmethylcellulose acetate
succinate (HPMCAS).
[0636] In some embodiments, provided herein is an oral dosage form
that comprises coat with cellulose butyrate phthalate, cellulose
hydrogen phthalate, cellulose proprionate phthalate, polyvinyl
acetate phthalate, cellulose acetate phthalate, cellulose acetate
trimellitate, hydroxypropyl methylcellulose phthalate,
hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulose
succinate, carboxymethyl ethylcellulose, hydroxypropyl
methylcellulose acetate succinate, polymers and copolymers formed
from acrylic acid, methacrylic acid, and combinations thereof.
Combination Therapy
[0637] In certain instances, provided herein are combination
compositions and/or therapies comprising any compound described
herein and an additional therapeutic agent. In some embodiments,
the additional therapeutic agent is a L-cell endocrine peptide
enhancer. In some instances, the L-cell endocrine peptide enhancer
is a GLP-2 enhancer. In some embodiments, the GLP-2 enhancer is
GLP-2, a GLP-2 secretion enhancer, a GLP-2 degradation inhibitor,
the like, or a combination thereof. In certain instances, enhanced
GLP-2 concentration provides regeneration of intestinal lining
and/or heals injury to the gastrointestinal structures and/or
reduces induction of cytokines and/or enhances the adaptive
process, attenuates intestinal injury, reduces bacterial
translocation, inhibits the release of free radical oxygen, or any
combination thereof. In some instances, the L-cell endocrine
peptide enhancer is a PYY enhancer. In some instances, the L-cell
endocrine peptide enhancer is an oxyntomodulin enhancer. In some
instances, enhanced PYY or oxyntomodulin secretion heals injury to
intestine caused by an cholestasis or a cholestatic liver
disease.
TGR5 Receptor Modulators
[0638] In some instances, the additional therapeutic agent
modulates bile acid receptors in the gastrointestinal lumen. In
some embodiments, the additional therapeutic agent agonizes or
partially agonizes bile acid receptors (e.g., TGR5 receptors or
Farnesoid-X receptors) in the gastrointestinal tract. In some
embodiments, the additional therapeutic agent is a bile acid
analog. In certain instances the additional therapeutic agent is a
TGR5 agonist. In certain instances, administration of a TGR5
agonist in combination with any of the compounds described herein
enhances the secretion of enteroendocrine peptides from L-cells.
TGR5 modulators (e.g., agonists) include, and are not limited to,
the compounds described in, WO 2008/091540, WO 2008/067219 and U.S.
Appl. No. 2008/0221161.
Enteroendocrine Peptides
[0639] In some embodiments, the additional therapeutic agent is an
enteroendocrine peptide. In some embodiments, enteroendocrine
peptides heals injury to intestine or liver due to a cholestatic
liver disease. Examples of enteroendocrine peptides that are
administered as additional therapeutic agents include and are not
limited to GLP-1 or GLP-1 analogs such as Taspoglutide.RTM.
(Ipsen), or the like.
Combination Therapy with Fat Soluble Vitamins
[0640] In some embodiments, the methods provided herein further
comprise administering one or more vitamins. In some embodiments,
the vitamin is vitamin A, B1, B2, B3, B5, B6, B7, B9, B12, C, D, E,
K, folic acid, pantothenic acid, niacin, riboflavin, thiamine,
retinol, beta carotene, pyridoxine, ascorbic acid, cholecalciferol,
cyanocobalamin, tocopherols, phylloquinone, menaquinone.
[0641] In some embodiments, the vitamin is a fat soluble vitamin
such as vitamin A, D, E, K, retinol, beta carotene,
cholecalciferol, tocopherols, phylloquinone. In a preferred
embodiment, the fat soluble vitamin is tocopherol polyethylene
glycol succinate (TPGS).
Combination Therapy with Partial External Biliary Diversion
(PEBD)
[0642] In some embodiments, the methods provided herein further
comprise using partial external biliary diversion as a treatment
for patients who have not yet developed cirrhosis. This treatment
helps reduce the circulation of bile acids/salts in the liver in
order to reduce complications and prevent the need for early
transplantation in many patients.
[0643] This surgical technique involves isolating a segment of
intestine 10 cm long for use as a biliary conduit (a channel for
the passage of bile) from the rest of the intestine. One end of the
conduit is attached to the gallbladder and the other end is brought
out to the skin to form a stoma (a surgically constructed opening
to permit the passage of waste). Partial external biliary diversion
may be used for patients who are unresponsive to all medical
therapy, especially older, larger patients. This procedure may not
be of help to young patients such as infants. Partial external
biliary diversion may decrease the intensity of the itching and
abnormally low levels of cholesterol in the blood.
Combination Therapy with ASBTI and Ursodiol
[0644] In some embodiments, an ASBTI is administered in combination
with ursodiol or ursodeoxycholic acid, chenodeoxycholic acid,
cholic acid, taurocholic acid, ursocholic acid, glycocholic acid,
glycodeoxycholic acid, taurodeoxycholic acid, taurocholate,
glycochenodeoxycholic acid, tauroursodeoxycholic acid. In some
instances an increase in the concentration of bile acids/salts in
the distal intestine induces intestinal regeneration, attenuating
intestinal injury, reducing bacterial translocation, inhibiting the
release of free radical oxygen, inhibiting production of
proinflammatory cytokines, or any combination thereof or any
combination thereof.
[0645] An ASBTI and a second active ingredient are used such that
the combination is present in a therapeutically effective amount.
That therapeutically effective amount arises from the use of a
combination of an ASBTI and the other active ingredient (e.g.,
ursodiol) wherein each is used in a therapeutically effective
amount, or by virtue of additive or synergistic effects arising
from the combined use, each can also be used in a subclinical
therapeutically effective amount, i.e., an amount that, if used
alone, provides for reduced effectiveness for the therapeutic
purposes noted herein, provided that the combined use is
therapeutically effective. In some embodiments, the use of a
combination of an ASBTI and any other active ingredient as
described herein encompasses combinations where the ASBTI or the
other active ingredient is present in a therapeutically effective
amount, and the other is present in a subclinical therapeutically
effective amount, provided that the combined use is therapeutically
effective owing to their additive or synergistic effects. As used
herein, the term "additive effect" describes the combined effect of
two (or more) pharmaceutically active agents that is equal to the
sum of the effect of each agent given alone. A syngergistic effect
is one in which the combined effect of two (or more)
pharmaceutically active agents is greater than the sum of the
effect of each agent given alone. Any suitable combination of an
ASBTI with one or more of the aforementioned other active
ingredients and optionally with one or more other pharmacologically
active substances is contemplated as being within the scope of the
methods described herein.
[0646] In some embodiments, the particular choice of compounds
depends upon the diagnosis of the attending physicians and their
judgment of the condition of the individual and the appropriate
treatment protocol. The compounds are optionally administered
concurrently (e.g., simultaneously, essentially simultaneously or
within the same treatment protocol) or sequentially, depending upon
the nature of the disease, disorder, or condition, the condition of
the individual, and the actual choice of compounds used. In certain
instances, the determination of the order of administration, and
the number of repetitions of administration of each therapeutic
agent during a treatment protocol, is based on an evaluation of the
disease being treated and the condition of the individual.
[0647] In some embodiments, therapeutically-effective dosages vary
when the drugs are used in treatment combinations. Methods for
experimentally determining therapeutically-effective dosages of
drugs and other agents for use in combination treatment regimens
are described in the literature.
[0648] In some embodiments of the combination therapies described
herein, dosages of the co-administered compounds vary depending on
the type of co-drug employed, on the specific drug employed, on the
disease or condition being treated and so forth. In addition, when
co-administered with one or more biologically active agents, the
compound provided herein is optionally administered either
simultaneously with the biologically active agent(s), or
sequentially. In certain instances, if administered sequentially,
the attending physician will decide on the appropriate sequence of
therapeutic compound described herein in combination with the
additional therapeutic agent.
[0649] The multiple therapeutic agents (at least one of which is a
therapeutic compound described herein) are optionally administered
in any order or even simultaneously. If simultaneously, the
multiple therapeutic agents are optionally provided in a single,
unified form, or in multiple forms (by way of example only, either
as a single pill or as two separate pills). In certain instances,
one of the therapeutic agents is optionally given in multiple
doses. In other instances, both are optionally given as multiple
doses. If not simultaneous, the timing between the multiple doses
is any suitable timing, e.g, from more than zero weeks to less than
four weeks. In addition, the combination methods, compositions and
formulations are not to be limited to the use of only two agents;
the use of multiple therapeutic combinations are also envisioned
(including two or more compounds described herein).
[0650] In certain embodiments, a dosage regimen to treat, prevent,
or ameliorate the condition(s) for which relief is sought, is
modified in accordance with a variety of factors. These factors
include the disorder from which the subject suffers, as well as the
age, weight, sex, diet, and medical condition of the subject. Thus,
in various embodiments, the dosage regimen actually employed varies
and deviates from the dosage regimens set forth herein.
[0651] In some embodiments, the pharmaceutical agents which make up
the combination therapy described herein are provided in a combined
dosage form or in separate dosage forms intended for substantially
simultaneous administration. In certain embodiments, the
pharmaceutical agents that make up the combination therapy are
administered sequentially, with either therapeutic compound being
administered by a regimen calling for two-step administration. In
some embodiments, two-step administration regimen calls for
sequential administration of the active agents or spaced-apart
administration of the separate active agents. In certain
embodiments, the time period between the multiple administration
steps varies, by way of non-limiting example, from a few minutes to
several hours, depending upon the properties of each pharmaceutical
agent, such as potency, solubility, bioavailability, plasma
half-life and kinetic profile of the pharmaceutical agent.
[0652] In certain embodiments, provided herein are combination
therapies. In certain embodiments, the compositions described
herein comprise an additional therapeutic agent. In some
embodiments, the methods described herein comprise administration
of a second dosage form comprising an additional therapeutic agent.
In certain embodiments, combination therapies the compositions
described herein are administered as part of a regimen. Therefore,
additional therapeutic agents and/or additional pharmaceutical
dosage form can be applied to a patient either directly or
indirectly, and concomitantly or sequentially, with the
compositions and formulations described herein.
Kits
[0653] In another aspect, provided herein are kits containing a
device for rectal administration pre-filled a pharmaceutical
composition described herein. In certain embodiments, kits contain
a device for oral administration and a pharmaceutical composition
as described herein. In certain embodiments the kits includes
prefilled sachet or bottle for oral administration, while in other
embodiments the kits include prefilled bags for administration of
rectal gels. In certain embodiments the kits includes prefilled
syringes for administration of oral enemas, while in other
embodiments the kits include prefilled syringes for administration
of rectal gels. In certain embodiments the kits includes prefilled
pressurized cans for administration of rectal foams.
Release in Distal Ileum and/or Colon
[0654] In certain embodiments, a dosage form comprises a matrix
(e.g., a matrix comprising hypermellose) that allows for controlled
release of an active agent in the distal jejunum, proximal ileum,
distal ileum and/or the colon. In some embodiments, a dosage form
comprises a polymer that is pH sensitive (e.g., a MMX.TM. matrix
from Cosmo Pharmaceuticals) and allows for controlled release of an
active agent in the ileum and/or the colon. Examples of such pH
sensitive polymers suitable for controlled release include and are
not limited to polyacrylic polymers (e.g., anionic polymers of
methacrylic acid and/or methacrylic acid esters, e.g.,
Carbopol.RTM. polymers) that comprise acidic groups (e.g., --COOH,
--SO.sub.3H) and swell in basic pH of the intestine (e.g., pH of
about 7 to about 8). In some embodiments, a dosage form suitable
for controlled release in the distal ileum comprises
microparticulate active agent (e.g., micronized active agent). In
some embodiments, a non-enzymatically degrading
poly(dl-lactide-co-glycolide) (PLGA) core is suitable for delivery
of an ASBTI to the distal ileum. In some embodiments, a dosage form
comprising an ASBTI is coated with an enteric polymer (e.g.,
Eudragit.RTM. S-100, cellulose acetate phthalate, polyvinylacetate
phthalate, hydroxypropylmethylcellulose phthalate, anionic polymers
of methacrylic acid, methacrylic acid esters or the like) for site
specific delivery to the ileum and/or the colon. In some
embodiments, bacterially activated systems are suitable for
targeted delivery to the ileum. Examples of micro-flora activated
systems include dosage forms comprising pectin, galactomannan,
and/or Azo hydrogels and/or glycoside conjugates (e.g., conjugates
of D-galactoside, .beta.-D-xylopyranoside or the like) of the
active agent. Examples of gastrointestinal micro-flora enzymes
include bacterial glycosidases such as, for example,
D-galactosidase, .beta.-D-glucosidase,
.alpha.-L-arabinofuranosidase, .beta.-D-xylopyranosidase or the
like.
[0655] The pharmaceutical solid dosage forms described herein
optionally include an additional therapeutic compound described
herein and one or more pharmaceutically acceptable additives such
as a compatible carrier, binder, filling agent, suspending agent,
flavoring agent, sweetening agent, disintegrating agent, dispersing
agent, surfactant, lubricant, colorant, diluent, solubilizer,
moistening agent, plasticizer, stabilizer, penetration enhancer,
wetting agent, anti-foaming agent, antioxidant, preservative, or
one or more combination thereof. In some aspects, using standard
coating procedures, such as those described in Remington's
Pharmaceutical Sciences, 20th Edition (2000), a film coating is
provided around the formulation of the compound of Formula I-VI. In
one embodiment, a compound described herein is in the form of a
particle and some or all of the particles of the compound are
coated. In certain embodiments, some or all of the particles of a
compound described herein are microencapsulated. In some
embodiments, the particles of the compound described herein are not
microencapsulated and are uncoated.
[0656] An ASBT inhibitor (e.g., a compound of Formula I-VI) is used
in the preparation of medicaments for the prophylactic and/or
therapeutic treatment of cholestasis or a cholestatic liver
disease. A method for treating any of the diseases or conditions
described herein in an individual in need of such treatment,
involves administration of pharmaceutical compositions containing
at least one ASBT inhibitor described herein, or a pharmaceutically
acceptable salt, pharmaceutically acceptable N-oxide,
pharmaceutically active metabolite, pharmaceutically acceptable
prodrug, or pharmaceutically acceptable solvate thereof, in
therapeutically effective amounts to said individual.
Screening Process
[0657] Provided in certain embodiments herein are processes and
kits for identifying compounds suitable for treating cholestasis or
a cholestatic liver disease. In certain embodiments, provided
herein are assays for identifying compounds that selectively
inhibits the ASBT by: [0658] a. providing cells that are a model of
intestinal cells; [0659] b. contacting the cells with a compound
(e.g., a compound as described herein); [0660] c. detecting or
measuring the effect of the compound on the inhibition of ASBT
activity.
[0661] In certain embodiments, provided herein are assays for
identifying compounds that are non-systemic compounds by [0662] a.
providing cells that are a model of intestinal permeability (e.g.,
Caco-2 cells); [0663] b. culturing the cells as a monolayer on
semi-permeable plastic supports that are fitted into the wells of
multi-well culture plates; [0664] c. contacting the apical or
basolateral surface of the cells with a compound (e.g., a compound
as described herein) and incubating for a suitable length of time;
[0665] d. detecting or measuring the concentration of the compound
on both sides of the monolayer by liquid-chromatography-mass
spectrometry (LC-MS) and computing intestinal permeability of the
compound.
[0666] In certain embodiments, non-systemic compounds are
identified by suitable parallel artificial membrane permeability
assays (PAMPA).
[0667] In certain embodiments, non-systemic compounds are
identified by use of isolated vascular-perfused gut
preparations.
[0668] In certain embodiments, provided herein are assays for
identifying compounds that inhibit recycling of bile acid salts by
[0669] a. providing cells that are a model of intestinal cells with
apical bile acid transporters (e.g., BHK cells, CHO cells); [0670]
b. incubating the cells with a compound (e.g., a compound as
described herein) and/or a radiolabeled bile acid (e.g., .sup.14C
taurocholate) for a suitable length of time; [0671] c. washing the
cells with a suitable buffer (e.g. phosphate buffered saline);
[0672] d. detecting or measuring the residual concentration of the
radiolabeled bile acid in the cells.
EXAMPLES
Example 1
Synthesis of
1-phenethyl-1-((1,4-diazabicyclo[2.2.2]octanyl)pentyl)imidodicarbonimidic
diamide, iodide salt
##STR00058##
[0673] Step 1: Synthesis of
5-(1,4-diazabicyclo[2.2.2]octanyl)-1-iodo pentane, iodide salt
##STR00059##
[0675] 1,4-diazabicyclo[2.2.2]octane is suspended in THF.
Diiodopentane is added dropwise and the mixture is refluxed
overnight. The reaction mixture is filtered.
Step 2: Synthesis of
N-phenethyl-5-(1,4-diazabicyclo[2.2.2]octanyl)-1-iodo pentane,
iodide salt
##STR00060##
[0677] 5-(1,4-diazabicyclo[2.2.2]octanyl)-1-iodo pentane, iodide
salt is suspended in acetonitrile. Phenethylamine is added dropwise
and the mixture is refluxed overnight. The reaction mixture is
filtered.
Step 3: Synthesis of
1-phenethyl-1-((1,4-diazabicyclo[2.2.2]octanyl)pentyl)imidodicarbonimidic
diamide, iodide salt
[0678] N-phenethyl-5-(1,4-diazabicyclo[2.2.2]octanyl)-1-iodo
pentane, iodide salt is heated with dicyanodiamide in n-butanol for
4 h. The reaction mixture is concentrated under reduced
pressure.
[0679] The compounds in Table 1 are prepared using methods as
described herein, and using appropriate starting materials.
TABLE-US-00002 TABLE 1 Compound No. Structure 1 ##STR00061## 2
##STR00062## 3 ##STR00063## 4 ##STR00064## 5 ##STR00065## 6
##STR00066## 7 ##STR00067## 8 ##STR00068## 9 ##STR00069## 10
##STR00070## 11 ##STR00071##
Example 2
In Vitro Assay for Inhibition of ASBT-Mediated Bile Acid Uptake
[0680] Baby hamster kidney (BHK) cells are transfected with cDNA of
human ASBT. The cells are seeded in 96-well tissue culture plates
at 60,000 cells/well. Assays are run within 24 hours of
seeding.
[0681] On the day of the assay the cell monolayer is washed with
100 mL of assay buffer. The test compound is added to each well
along with 6 mM [.sup.14C] taurocholate in assay buffer (final
concentration of 3 mM [.sup.14C] taurocholate in each well). The
cell cultures are incubated for 2 h at 37.degree. C. The wells are
washed with PBS. Scintillation counting fluid is added to each
well, the cells are shaken for 30 minutes prior to measuring amount
of radioactivity in each well. A test compound that has significant
ASBT inhibitory activity provides an assay wherein low levels of
radioactivity are observed in the cells.
Example 3
In Vitro Assay for Secretion of GLP-2
[0682] Human NCI-H716 cells are used as a model for L-cells. Two
days before each assay experiment, cells are seeded in 12-well
culture plates coated with Matrigel.RTM. to induce cell adhesion.
On the day of the assay, cells are washed with buffer. The cells
are incubated for 2 hours with medium alone, or with test compound.
The extracellular medium is assayed for the presence of GLP-2.
Peptides in the medium are collected by reverse phase adsorption
and the extracts are stored until assay. The presence of GLP-2 is
assayed using ELISA. The detection of increased levels of GLP-2 in
a well containing a test compound identifies the test compound as a
compound that can enhance GLP-2 secretions from L-cells.
Example 4
In Vivo Bioavailability Assay
[0683] The test compounds are solubilized in saline solutions.
Sprague Dawley rats are dosed at 2-10 mg/kg body weight by iv and
oral dosing. Peripheral blood samples are taken from the femoral
artery at selected time periods up to 8 hours. Plasma
concentrations of the compounds are determined by quantitative HPLC
and/or mass spectrometry. Clearance and AUC values are determined
for the compounds.
[0684] For oral dosing, bioavailability is calculated by also
drawing plasma samples from the portal vein. Cannulae are inserted
in the femoral artery and the hepatic portal vein to obtain
estimates of total absorption of drug without first-pass clearance
in the liver. The fraction absorbed (F) is calculated by
F=AUC.sub.po/AUC.sub.iv
Example 5
Assay to Determine Ileal Intraenterocyte and Luminal Bile Acid
Levels
[0685] Ileal luminal bile acid levels in SD rats are determined by
flushing a 3-cm section of distal ileum with sterile, cold PBS.
After flushing with additional PBS, the same section of ileum is
weighed and then homogenized in fresh PBS for determination of
interenterocyte bile acid levels. A LC/MS/MS system is used to
evaluate cholic acid, DCA, LCA, chnodeoxycholic acid, and
ursodeoxycholic acid levels.
Example 6
Animal to Determine Effect of Therapy on Cholestasis or a
Cholestatic Liver Disease
[0686] Mdr2 knock out mouse model of cholestasis or a cholestatic
liver disease induced rats (by carbon tetrachloride/phenobarbital)
is used to test compositions described herein. The animals are
orally administered a composition comprising an ASBTI such as 100B,
264W94; SD5613; SAR548304B; SA HMR1741;
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N--[(R)-.alpha.-[N-(2-sulp-
hoethyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy)-2,3,4,5-tetrahydro-1,-
2,5-benzothiadiazepine;
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N--[(R)-.alpha.-[N--((S)-1-
-carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy)--
2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N--[(R)-.alpha.-[N--((S)-1-
-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy)-2,3,4-
,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((S)-1--
carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahy-
dro-1,2,5-benzothiadiazepine; or
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N--((R)-.alpha.-carboxy-4--
hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-
e.
[0687] Cholestasis or cholestatic liver disease is quantitated by
total bile acid and bilirubin in serum versus that in control
mice/rats administered with placebo. Serum bile acids/salts are
determined by ELISA with specific antibodies for cholic and CCDCA.
Serum bilirubin levels are determined by automated routine assays.
Alternatively, livers of the mice can be harvested and pathology of
the hepatocellular damage can be measured.
Example 7
Investigation of orally delivered LUM001 and
1-[4-[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydro-
xy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]butyl]-4-aza-1-azoniabicyclo[2.-
2.2]octane methane sulfonate (Compound 100B) on plasma GLP-2 levels
in normal rats
[0688] 12-week-old male HSD rats are fasted for 16 h and given oral
dose of 0, 3, 30, 100 mg/kg of the ASBTIs LUM001 or
1-[4-[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydro-
xy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]butyl]4-aza-1-azoniabicyclo[2.2-
.2]octane methane sulfonate (Synthesized by Nanosyn Inc., CA, USA)
in a mixture of valine-pyrrolidine in water (n=5 per group). Blood
samples in volume of 0.6 ml for each time point are taken from the
caudal vein with a heparinized capillary tube 0, 1, 3 and 5 h after
the administration of compounds and plasma GLP-2 level are
determined Aprotinin and 10 .mu.l of DPP-IV inhibitor per ml of
blood are used for blood sample preservation during 10 min
centrifugation and for storage at -70.degree. C. or below. GLP-2
(Active pM) is tested by any commercially available ELISA kits.
Example 8
Tablet Formulation
[0689] 10 kg of a compound of Formula I-VI is first screened
through a suitable screen (e.g. 500 micron). 25 kg Lactose
monohydrate, 8 kg hydroxypropylmethyl cellulose, the screened
compound of Formula I-VI and 5 kg calcium hydrogen phosphate
(anhydrous) are then added to a suitable blender (e.g. a tumble
mixer) and blended. The blend is screened through a suitable screen
(e.g. 500 micron) and reblended. About 50% of the lubricant (2.5
kg, magnesium stearate) is screened, added to the blend and blended
briefly. The remaining lubricant (2 kg, magnesium stearate) is
screened, added to the blend and blended briefly. The granules are
screened (e.g. 200 micron) to obtain granulation particles of the
desired size. In some embodiments, the granules are optionally
coated with a drug release controlling polymer such as
polyvinylpyrrolidine, hydroxypropylcellulose, hydroxypropylmethyl
cellulose, methyl cellulose, or a methacrylic acid copolymer, to
provide an extended release formulation. The granules are filled in
gelatin capsules.
Example 9
Pediatric Formulation
[0690] Disintegrating Tablet Formulation
[0691] The following example describes a large scale preparation
(100 kg) of an ASBTI compound of Formula I-VI (e.g., LUM-001 or
LUM-002).
TABLE-US-00003 Active ingredient (LUM-001) 2.5 kg Lactose
monohydrate NF 47.5 kg Pregelatinized starch NF 18 kg
microcrystalline cellulose NF 17 kg croscarmellose sodium NF 6.5 kg
povidone K29/32 USP 8.5 kg 100 kg
[0692] Pass ASBTI (2.5 kg), lactose monohydrate NF (47.5 kg),
pregelatinized starch NF (18 kg), microcrystalline cellulose NF (17
kg), croscarmellose sodium NF (6.5 kg) and povidone K29/32 USP (8.5
kg) through a #10 mesh screen. Add the screened material to a 600
Collette mixer. Mix for 6 minutes at low speed, without chopper.
Add the direct blend mixture from the previous step to a 20-cubic
foot V-shell PK blender (Model C266200). Pass magnesium stearate NF
(0.5 to 1 kg) through a 10 mesh screen into a properly prepared
container. Add approximately half of the magnesium stearate to each
side of the PK blender and blend for 5 minutes. Add the blended
mixture from the previous step to Kikusui tablet press for
compression into tablets. The compression equipment can be
outfitted to make tooling for 50 mg tablet, 75 mg tablet and 100 mg
tablet.
Example 10
Effervescent Tablet
[0693] The active ingredient, anhydrous monosodium citrate, sodium
bicarbonate and aspartame are mixed together and granulated by the
addition of a solution of the polyvinylpyrrolidone in the alcohol.
The granules obtained after mixing are dried and passed through a
calibrator, and the resulting granules are then mixed with the
sodium benzoate and flavorings. The granulated material is
compressed into tablets using an alternative machine fitted with 20
mm punches.
[0694] A rotative machine fitted with 20 mm punches may also be
used for tabletting.
TABLE-US-00004 Active ingredient 4.4 mg Sodium bicarbonate 20.5 mg
Monosodium citrate anhydrous 20.6 mg Aspartame 1.25 mg
Polyvinylpyrrolidone 1.0 mg Sodium benzoate 1.5 mg Orange flavor
IFF 29G44 0.5 mg Lemon flavor IFF 29M194 0.25 mg Absolute alcohol
for granulation
Example 11
Chewable Tablet
[0695] A 40% (w/w) solution of the Eudragit E100 in ethanol was
added with mixing to the active ingredient and blended until
granules were formed. The resulting granules were dried and then
sieved through a 16 mesh screen.
TABLE-US-00005 Active ingredient 4.0 mg Eudragit E100 0.6 mg
Sorbitol: Direct Compression Grade 18.8 mg Lactose: Direct
Compression Grade 15.6 mg Croscarmellose Sodium Type A 1.2 mg
Aspartame 0.3 mg Aniseed flavoring 0.6 mg Butterscotch flavoring
0.6 mg Magnesium Stearate 0.6 mg Microcrystalline Cellulose 4.7 mg
(Avicel PH102) 47 mg
[0696] The active ingredient granules and extragranular excipients
were put into a cone blender and mixed thoroughly. The resulting
mix was discharged from the blender and compressed on a suitable
rotary tablet press fitted with the appropriate punches.
Example 12
Orodispersible Tablet
[0697] The active ingredient is introduced in a fluidized air bed
installation and a solution of ethylcellulose in ethanol is sprayed
thereon.
[0698] The excipients are sieved and the coated active ingredient
is homogenized with the excipients in a mixing apparatus under dry
conditions.
[0699] Distribution and tabletting are carried out on a compressing
machine equipped with punches having a diameter equal to 16 mm and
a radius of curvature equal to 20 mm.
[0700] The pressure is 15 kNewtons.+-.1. The hardness of the thus
obtained tablets is 50 Newtons.+-.5. The time of disintegration in
the mouth is from 15 to 20 seconds.
TABLE-US-00006 Active ingredient (with ethylcellulose) 4.0 mg
Reticulated polyvinylpyrrolidone 20.0 mg Starch 40 mg Sweetener 1.0
mg Flavor 1.0 mg Magnesium stearate 1.0 mg 67.0 mg
Example 13
Powder Formulation
[0701] A pulverulent mixture of active ingredient and polyvidone (5
parts by weight) is granulated with 7% of purified water
(weight/weight).
[0702] A premix is prepared with the following constituents:
carbasalate calcium (amount corresponding to parts by weight of
acetylsalicylic acid); anhydrous citric acid (168 parts by weight);
sodium bicarbonate (232 parts by weight); lactose (1500 parts by
weight); magnesium citrate (180 parts by weight); potassium
benzoate (250 parts by weight). The premix is then dry
compacted.
[0703] The pulverulent active ingredient mixture and the dry
compacted premix, and the following compounds: aspartame and
artificial vanilla flavoring, which are in powder form, are
mixed.
[0704] The mixture of powders can be packaged directly in
sachets.
TABLE-US-00007 Active ingredient 4.0 mg Polividone 0.2 mg
Carbasalate calcium 2.6 mg Citic acid 6.7 mg Sodium bicarbonate 9.3
mg Lactose 60 mg Magnesium citrate 7.2 mg Potassium benzoate 10 mg
100 mg
Example 14
Gummy Candy
[0705] About 50 lbs of warm water is mixed with about 50 lbs of
gelatin in the mixing tank, to form 100 lbs of gelling compound
having a homogeneous 50/50 blend of water and gelatin. About 0.1%
to 10% of sodium bisulfate by weight is added to the gelling
compound to reduce the pH of the gelling compound to about 3.5.
[0706] In the mixing weigh vessel, the gelling compound is mixed
with about 6 lbs of water, 38.3 lbs of sucrose, and 50 lbs of corn
syrup to form the candy slurry. If the active ingredient is not a
heat sensitive drug, the active ingredient is added to the candy
slurry prior to cooking. About 0.1% sodium citrate by weight is be
added to the candy slurry to maintain the pH of the slurry at about
3.0 to 3.5.
[0707] Next, the candy slurry is heated to a temperature of about
180.degree. F. prior to being passed through the storage buffer
tank, to the static cooker. In the static cooker, the candy slurry
is heated to a temperature of about 240.degree. F. to 245.degree.
F., dehydrating the slurry to a brix of about 78.
[0708] After the candy is cooked, the cooked candy is sent to the
vacuum chamber, where the candy is further dehydrated to a brix of
about 80. After leaving the vacuum, the cooked candy is placed in
the dosier where about 1.5% of strawberry flavoring by weight and
about 1% of red cabbage coloring by weight is added to the cooked
candy. To balance the flavoring, about 0.1% citric acid by weight
and about 0.1% lactic acid by weight is added to the cooked
candy.
[0709] After adding the flavoring and coloring, the cooked candy is
deposited into the mogul machine and then cured. After the candies
are cured, they are added to a tumbling drum to break off any
starch that is remaining on the candies. As the candies are being
tumbled, about 1% fractionated coconut oil by weight and about 1%
carnauba wax by weight is poured into the drum to coat the candies
to prevent them from sticking together.
TABLE-US-00008 Active ingredient (5 mg) 5% Lactic acid 1% Citric
Acid 1% Sucrose 23.5% Corn Syrup 50.0% Gelatin 7% Sodium bisufate
0.1%-10% Flavoring (natural/artificial) 1.5%.sup. Colorant
(natural/artificial) 1.0%.sup.
Example 15
Taste-Masked Liquid Formulations
[0710] An aqueous pharmaceutical composition of the present
invention is formulated by preparing a mixture of
hydroxyethylcellulose dissolved in 50 milliliters of purified water
with 0.5 mL of--orange flavoring agent, with potassium phosphate
dibasic and potassium phosphate monobasic added (from a hot water
mixture). 4.0 mg of active ingredient is then added and mixed until
dissolved. Sodium hydroxide is added to adjust the pH to from about
6.7 to about 6.9.
TABLE-US-00009 Active ingredient 4.0 mg Hydroxyethylcellulose 10 mg
Potassium phosphate dibasic 4.5 mg Potassium phosphate monobasic
4.5 mg Sodium hydroxide 0.1 mL Orange flavoring 0.5 mL Purified
water 50 mL
[0711] Alternative liquid oral formulations are provided below. For
each of the formulations below, a sweetener from 0.5% to 2% such as
sucralose, mannitol, sucrose and/or a flavoring agent from 0.5% to
2% such as grape, cherry, bubble gum, orange, lemon, strawberry can
be added. Polypropylene glycol can be replaced with one of the
PEGs.
TABLE-US-00010 Ingredients Concentration LUM001 0.02 to 4 mg/mL
Propylene glycol 10 to 300 mg/mL Water, q.s. to 1 mL
TABLE-US-00011 Ingredients Concentration LUM001 0.02 to 4 mg/mL PEG
200 (or 300, 400, 600) 10 to 300 mg/mL Water, q.s. to 1 mL
TABLE-US-00012 Ingredients Concentration LUM001 0.02 to 4 mg/mL
Propylene glycol 10 to 300 mg/mL Sodium lauryl sulfate 1 to 10
mg/mL Water, q.s. to 1 mL
TABLE-US-00013 Ingredients Concentration LUM001 0.02 to 4 mg/mL
Propylene glycol 10 to 300 mg/mL Poloxamer 188 1 to 10 mg/mL Water,
q.s. to 1 mL
Example 16
Sachet Formulation
[0712] The following formulation is used to produce a sachet for
pediatric use. A sweetener from 0.5% to 2% such as sucralose,
mannitol, sucrose and/or a flavoring agent from 0.5% to 2% such as
grape, cherry, bubble gum, orange, lemon, strawberry can be added.
Sugar and sodium lauryl sulfate can be exchanged with other
surfactants.
TABLE-US-00014 Ingredients Concentration LUM001 0.05 to 10 mg
Soluble Diluent 10 to 500 mg Sugar 10 to 250 mg Sodium lauryl
sulfate 5 to 50 mg Flavoring agent 10 to 100 mg
Example 17
Animal Study
[0713] Animal Preparation.
[0714] Male Zucker diabetic fatty rats (ZDF/GmiCrl-fa/fa) were
purchased from Charles River (Raleigh, N.C.) and housed under
controlled conditions (12:12 light-dark cycle, 24.degree. C. and
50% relative humidity) with free access to rodent food (Purina
5008, Harlan Teklad, Indianapolis, Ind.). All rats arrived at seven
weeks of age (.+-.3 days). After a one-week acclimation period,
rats were anesthetized with isoflurane (Abbott Laboratories, IL)
and tail-vein blood samples were collected at 9 am without fasting.
Blood glucose levels were measured using a glucometer (Bayer,
Leverkusen, Germany). In order to ensure balanced treatment groups,
ZDF rats were assigned to six treatment groups based upon baseline
glucose: vehicle (0.5% HPMC, 0.1% Tween80) and five doses of 264W94
(0.001, 0.01, 0.1, 1, 10 mg/kg). All treatments were given via oral
gavage twice a day and animals were followed for two weeks with
blood samples collected from tail vein at the end of each week at 9
am without fasting. Fecal samples were collected for 24 hours
during the second week of treatment.
[0715] Measurement of Clinical Chemistry Parameters.
[0716] Non-esterified fatty acids (NEFA), bile acids, and bile
acids in fecal extraction were measured using the Olympus AU640
clinical chemistry analyzer (Beckman Coulter, Irving, Tex.).
[0717] Changes in Fecal Bile Acid Excretion and Plasma Bile Acid
Concentrations
[0718] Oral administration of 264W94 dose-dependently increased
bile acids in the feces. Fecal bile acid concentrations were
elevated up to 6.5 fold with an ED.sub.50 of 0.17 mg/kg, when
compared to vehicle treated rats. Fecal NEFA also slightly
increased in 264W94 treated rats. In contrast, plasma bile acid
concentrations were decreased dose-dependently in 264W94 treated
rats. See FIG. 1.
[0719] Plasma Bile Acid Levels of ZDF Rats After Administration of
Ascending Doses of SC-435 and LUM002.
[0720] Male ZDF rats (n=4) were administered vehicle, SC-435 (1, 10
or 30 mg/kg) or LUM002 (0.3, 1, 3, 10 or 30 mg/kg) by oral gavage
twice a day for 2 weeks. Plasma bile acid levels were determined at
the end of the second week. Plasma bile acid levels were decreased
for all doses of SC-435 and LUM002. Data are expressed as mean
values .+-.SEM. See FIG. 2.
Example 18
Animal Study on the Duration of Action and Time to Onset of ASBTI
Activity of a Single Oral Dose of LUM001 on Postprandial Total
Serum Bile Acids in Beagle Dogs
[0721] Test Compound:
[0722] LUM001--Form I
[0723] Dosage Preparation and Administration:
[0724] LUM001 was dissolved in water at concentrations that
required the administration of 0.2 ml/kg of solution. Solutions
were placed into gelatin capsules, Torpac Inc., size 13 Batch 594,
East Hanover N.J., and administered orally.
[0725] Dogs:
[0726] Male beagle dogs were obtained from Covance Research
Products, Cumberland Va. or Marshall Farms USA, Inc., North Rose
N.Y. A total of 20 dogs, 1 to 5 years old, 6.8 to 15.6 kg body
weight, were used in these experiments. The dogs were conditioned
to a 12 hour light/dark cycle and maintained on a feeding
restriction of 1 hour per day access to food (Richman Standard
Certified Canine Diet #5007, PMI Nutrition, Inc., St Louis Mo.)
from 7 to 8 AM. They were trained to eat a special meal promptly
within 20 minutes when presented (1 can. 397 g, Evanger's 100% Beef
for Dogs, Evanger's Dog and Cat Food Co., Inc., Wheeling Ill.,
mixed with 50 g of sharp cheddar cheese.).
[0727] Serum Total Bile Acid (SBA) Measurement:
[0728] SBA was measured by an enzymatic assay. SBA values are
expressed as .mu.g of total bile acids/ml of serum.
[0729] Control Experiments to Estimate the Rise and Duration of
Elevation in Systemic Serum Bile Acid:
[0730] Previous work demonstrated that SBA of beagle dogs rises to
a peak level one hour after feeding the meal described above, and
remains at a plateau for 4 hours and then declines. To estimate the
details of this plateau, 6 dogs were given a test meal and blood
samples for SBA measurement were collected at -30, 0, 30, 60, 65,
70, 80, 90, 120, 180, 240, 360, 480, 720, 1410 and 1440 minutes
from the time of feeding. Any remaining food was removed 20 min
after it was first presented to the dogs. To establish a method for
extending the elevated plateau of SBA, 6 dogs were given the meal
at 0 hr and an additional 1/2 size meal again 4 hr after their
first meal. Blood samples were taken at 0, 1, 2, 3, 4, 4.5, 6, 7
and 8 hr. The curves for SBA level vs time obtained in these
experiments were used as references for determining blood sampling
times in experiments with LUM001. Wherever possible, experimental
design permitting, in experiments with test compound, each dog
served as its own simultaneous control, and the mean 1 hr SBA value
served as the reference to which all other mean values were
compared.
[0731] Experiments to Measure Time to Onset of Activity of
LUM001:
[0732] LUM001 was administered at 0, 0.01, 0.05, 0.2 and 1 mg/kg,
p.o. to dogs, n=6, 1 hr after feeding the standard experimental
meal. Blood samples for SBA measurement were taken at -30, 0, 30,
60, 65, 70, 80, 90, 120 and 180 minutes from the time of feeding.
Each dog served as its own control, and mean SBA levels were
compared to the mean SBA level at 60 minutes.
TABLE-US-00015 TABLE 1 Onset of Activity of LUM001 on Dog Serum
Bile Acids Serum Bile Acid (.mu.g/ml) SD-5613 Water, 0.01 mg/kg,
0.05 mg/kg, 0.2 mg/kg, 1 mg/kg, Time n = 6 n = 6 n = 6 n = 6 n = 6
(min) Mean sem Mean sem Mean sem Mean sem Mean sem -30 2.2 0.3 1.5
0.1 1.4 0.1 2.4 0.5 2.1 0.2 0 2.0 0.3 1.4 0.1 2.1 0.6 1.9 0.2 2.8
0.4 30 6.9 2.1 5.8 2.5 6.8 2.3 9.1 2.1 7.6 1.8 60 17.8 3.2 14.6 2.8
10.4 1.2 19.1 2.7 13.8 1.4 65 16.6 3.6 13.8 2.4 12.2 1.7 14.9 1.7
13.5 1.4 70 16.2 1.9 14.1 2.2 12.0 1.6 16.7 2.3 15.4 1.8 80 16.1
2.3 12.8 1.8 10.0 1.3 14.3 2.2 12.1 1.4 90 15.2 2.8 11.0 2.0 8.8
1.6 9.8* 0.6 7.4* 1.2 120 15.5 3.6 10.8 1.7 6.5* 1.2 4.8* 0.3 3.0*
0.1 180 14.7 3.1 11.0 1.6 6.5* 1.2 4.0 0.6 2.6* 0.2 All animals
were fed at 0 minutes and dosed at 60 minutes. *= p < 0.05
compared to 60 minute value in the same curve by two-tailed paired
two-sample t-test.
[0733] Experiments to Measure the Duration of Action of LUM001:
[0734] In dogs a single experimental meal produces a postprandial
rise in SBA that is elevated to a peak at 1 hour after feeding and
constant for an additional 3 hours. Previous experiments (2)
indicate that LUM001 remains active for more than 4.5 hours. To
measure the duration of action of an ASBT inhibitor using
postprandial SBA levels requires that in the control situation the
SBA levels remain elevated and constant for the entire period of
compound action, or that the compound be administered long before
the postprandial rise occurs, and remain active in the empty
digestive system for long periods before feeding. Accordingly, two
alternative methods were used to provide a window of constant SBA
elevation that could be used to measure the duration of action of
ASBT inhibitors.
[0735] Method 1: Two Meals for Extended SBA Elevation:
[0736] LUM001 was administered at 0.05 and 0.2 mg/kg, p.o. to 6
dogs 1 hr after feeding them a meal. At 4 hours after the meal was
offered, a second meal of 1/2 the size of the first meal was
offered. It too was consumed as promptly and thoroughly as the
first meal, and provided an extended, constant SBA plateau. Blood
samples for SBA measurement were taken at 0, 1, 1.5, 2, 4, 4.5, 5,
5.5, 6, 6.5, 7, 7.5 and 8 hours from the time of offering the first
meal. Mean SBA levels were compared to the mean SBA level at 1
hour, each dog serving as its own control. The end of activity is
considered to occur at time point at which the mean SBA value is
not significantly lower than the 1 hr mean value.
TABLE-US-00016 TABLE 2 Duration of Action of LUM001 on Dog Serum
Bile Acids I Serum Bile Acid (.mu.g/ml) Water, 0.05 mg/kg, 0.2
mg/kg, SD-5613 n = 6 n = 6 n = 6 Time (hr) Mean SEM Mean SEM Mean
SEM 0 2.5 0.5 1.4 0.1 1.3 0.1 1 13.1 1.3 9.2 1.8 11.1 1.5 1.5 9.6
2.0 9.1 0.6 2 14.6 1.2 6.7 0.6 3.8* 0.4 3 14.4 1.7 4 14.8 1.2 5.1*
0.7 2.5* 0.4 4.5 16.6 1.5 6.4 0.7 3.3* 0.6 5 15.8 2.0 7.0 0.7 3.1*
0.4 6 15.5 2.1 7.0 0.9 3.6* 0.7 7 14.4 2.5 7.4 0.8 3.9* 0.5 8 13.3
1.5 6.5 1.1 5.6* 0.8 All animals were fed a full meal at 0 hour,
dosed orally with the compound at 1 hour and then fed an additional
one-half meal at 4 hours. *=p < 0.05 compared to the mean value
in the same curve at 1 hour by two-tailed paired two-sample
t-test.
[0737] Method 2: One Meal and Extended Interval Between Dosing and
Feeding:
[0738] Alternatively, 6 dogs were dosed with water or LUM001, at
0.05 mg/kg, p.o. at 1.5 hours prior to being fed, or 0.05, or 0.2
mg/kg, at 2 hours prior to feeding. This moved the elevated SBA
plateau out in time from the dose point. Blood samples for SBA
measurement were taken immediately before dosing (0 or 0.5 hr), at
feeding (2 hr), 2.5, 3, 4 and 5 hours after feeding. This allowed
detection of activity out to 5.5 and 6 hours after dosing without
feeding the dogs a second time. Mean SBA levels were compared to
the corresponding mean SBA levels in water treated controls. The
end of activity is considered to occur at the first time point at
which the mean SBA value is not significantly lower than the
corresponding control mean value.
TABLE-US-00017 TABLE 3 Duration of Action of LUM001 on Dog Serum
Bile Acids II Serum Bile Acid (.mu.g/ml) Dosing Time 0.5 hr 0 hr 0
hr Feeding time 2 hr 2 hr 2 hr 2 hr Water, 0.05 mg/kg, 0.05 mg/kg,
0.2 mg/kg, SD-5613 n = 6 n = 9 n = 9 n = 6 Time (hr) Mean SEM Mean
SEM Mean SEM Mean SEM 0 1.7 0.1 1.3 0.1 0.5 1.8 0.3 2 2.0 0.3 1.7
0.1 2.0 0.5 1.7 0.3 2.5 6.9 2.1 2.5 0.6 3 17.8 3.2 9.7 2.6 9.0* 1.4
4.1* 0.6 4 15.5 3.6 12.4 2.0 10.8 1.2 6.5* 0.8 5 14.7 3.1 11.6 2.4
10.6 0.9 7.9* 1.1 *= p < 0.05 vs water treatment by two-tailed
two-sample t-test without assuming equal variances.
[0739] Conclusion:
[0740] In the dog SBA model, the ED.sub.50 dose (0.2 mg/kg) of
LUM001 administered orally 1 hour after feeding significantly
lowered serum bile acid levels within 30 minutes of dosing and
these levels remained significantly lowered for at least 6 hours.
By comparison, a threshold dose of 0.05 mg/kg significantly lowered
SBA levels within approximately 1 to 2 hours after dosing but the
significant decrease was not sustained beyond 3 hours after dosing.
Increasing the dose above the ED.sub.50 level to 1 mg/kg did not
shorten the onset time to significant SBA lowering and still
sustained a maximal suppression for 2 hours after dosing. When
LUM001 was administered 2 hours prior to feeding, a dose of 0.2
mg/kg was required produce a significant effect that was sustained
for at least 2-3 hours after feeding. The results from these
studies indicate that the presence of food in the GI tract has a
significant impact on the pharmacodynamic activity of the ASBT
inhibitor, most likely by altering the residence time of the drug
in the small intestine.
Example 19
A Randomized, Double-Blind, Placebo Controlled, Safety,
Tolerability, Pharmacokinetic, and Pharmacodynamic Study of
Ascending Multiple Oral Doses of LUM001 in Healthy Subjects
[0741] This Phase 1 study was a randomized, double-blind,
placebo-controlled study of ascending multiple oral doses of LUM001
in healthy, adult subjects. This study was conducted at a single
center. There were 13 LUM001 dosing panels: 10, 20, 60, 100, and 20
mg every morning (qAM) (2) (i.e., the regimen was tested a second
time in the study), 5 mg every evening (qPM), 0.5, 1, 2.5, 5, 2.5
(2), 5 (2), and 0.5 to 5 mg qAM dose titration. Most of the dosing
panels included subjects treated with matching placebo. Shown in
the graphs are data from the 0.5 (n=16), 1.0 (n=8), 2.5 (n=8), 5.0
(n=8) and 10 (n=8) mg dosing groups.
[0742] For the qAM dosing panels, LUM001 or placebo was
administered each day of the treatment period (28 days) immediately
prior to the morning meal at approximately 08:00 and after any
necessary blood work was drawn.
[0743] Serum Bile Acid (SBA) Analysis:
[0744] On Day -1, blood was drawn for baseline SBA at approximately
30 minutes before and after breakfast and 30 minutes after lunch
and dinner. During the treatment period, samples were obtained on
days 2, 14 and 28 (14 day results are presented in FIG. 3) at -30,
30, 60 120, and 240 minutes after each of the 3 daily meals for
analysis. For each sample, approximately 3 mL of venous blood were
collected by venipuncture or saline lock.
[0745] SBA were analyzed as part of the routine clinical analysis
of the serum samples collected at each time point.
[0746] Fecal Bile Acid Analysis:
[0747] Fecal samples were collected for all panels except the
dose-titration panel, 2.5 (2) and 5 mg (2), on Days 9 through 14
and 23 through 28 (data shown in FIG. 4). Twenty-four hour FBA
excretions were quantified by Pharmacia for Days 9 through 14 and
23 through 28. Feces were collected in a 24-hour collection
container beginning at 08:00 and ending 24 hours later. This
procedure was followed on Days 9 through 14 and 23 through 28, with
new collection containers issued for each 24-hour period. The
weight of each 24-hour fecal collection was recorded on the CRFs.
Specimens were stored in 24-hour containers, frozen at
approximately -80.degree. C. prior to analysis.
[0748] An aliquot for each 24-hour fecal sample collected on Days
23 through 28 was combined, homogenized, and analyzed for bile acid
species concentrations by ANAPHARM. The fecal bile acid species
evaluated include chenodeoxycholic acid, cholic acid, deoxycholic
acid, and lithocholic acid.
[0749] Conclusion:
[0750] The results showed a significant reduction in serum bile
acids and significant increase in fecal bile acids.
Example 20
Pediatric Study to Test Efficacy of ASBTI in Lowering Serum Bile
Acids in Pediatric Patients
[0751] LUM001 has been administered to forty patients under the age
of 18 years old. Table below shows the exemplary characteristics of
five children who received LUM001. The drug was administered
once-a-day (QD) in the morning for fourteen days. The levels of
systemic exposure of LUM001 were measured on day eight and the drug
was confirmed to be minimally absorbed by the children. These doses
are similar to those using to treat children with cholestatic
diseases.
TABLE-US-00018 TABLE 4 Pharmacokinetics of LUM001 in pediatric
subjects (study NB-00-02-014) LUM001 Subject treatment Dose Average
serum drug Number (mg) Sex .mu.g/kg exposure (ng/ml) 0309 1.0 MALE
35.0 0.0 0304 1.0 MALE 24.3 0.0 0308 1.0 MALE 28.9 0.0 0410 2.5
FEMALE 42.0 0.0 0510 5.0 MALE 168.4 0.0
[0752] The efficacy of LUM001 was determined by measuring total
serum bile acids after eight days of dosing in children and
adolescents under the age of eighteen. Thirty minutes before the
next drug administration, at approximately 8 am in the morning,
serum bile acid levels were measured. The child had refrained from
food for 12 hours prior to this sample thus providing a fasted
level of serum bile acid. After breakfast, serum bile acids were
measured for up to the next 4 hours (8 am to noon) and the peak
serum bile acid concentration noted. LUM001 was shown to generally
decrease both the fasting and post-prandial peak levels of serum
bile acids (see table). In the table below the placebo patients had
an average fasting serum bile acid level of 8.6 .mu.mol/L and a
post-prandial peak serum bile acid level of 11.9 .mu.mol/L. For the
LUM001 treated patients the values were 6.5 .mu.mol/L and 9.2,
respectively, representing a 24% and 23% decrease (see FIG. 5).
TABLE-US-00019 TABLE 5 Fasting SBA and morning post-prandial peak
in pediatric subjects Patients 301 307 405 408 508 304 308 309 401
510 Drug dose (mg) Placebo Placebo Placebo Placebo Placebo 1 1 1
2.5 5 Fasting serum bile 9.1 7.4 10.5 8.3 7.7 5.6 6.8 6.9 6.0 7.4
acid (.mu.mol/l) Morning Post- 11.9 10.7 13.1 13.4 10.4 8.4 9.3
10.0 6.8 11.3 prandial peak (.mu.mol/l)
Example 21
Clinical Trial to Test Efficacy of ASBTI in Treatment and/or
Alleviation of Symptoms of Pediatric Cholestasis or a Pediatric
Cholestatic Liver Disease
[0753] This study will determine efficacy of ASBTI treatment in
patients afflicted with pediatric cholestasis or a pediatric
cholestatic liver disease.
[0754] Subjects under the age of 12, clinically diagnosed with
cholestasis or a cholestatic liver disease will be enrolled.
Subjects may be diagnosed by symptoms such as jaundice, chronic
pruritis, total serum bile acid/bilirubin elevation.
[0755] Subjects who have life threatening renal disease,
cardiovascular disease, or congenital anomalities will be
excluded.
[0756] Subjects will be administered a daily oral dose of compound
LUM001 formulated for release in the distal ileum. Alternatively,
any of the following compounds can be the subject of the clinical
trial: 264W94; SAR548304B; SA HMR1741;
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N--[(R)-.alpha.-[N-(2-sulp-
hoethyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy)-2,3,4,5-tetrahydro-1,-
2,5-benzothiadiazepine;
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N--[(R)-.alpha.-[N--((S)-1-
-carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy)--
2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N--[(R)-.alpha.-[N--((S)-1-
-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy)-2,3,4-
,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((S)-1--
carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahy-
dro-1,2,5-benzothiadiazepine; or
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N--((R)-.alpha.-carboxy-4--
hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-
e.
[0757] The primary endpoint is the proportion of subjects showing
resolution or improvement of baseline signs and symptoms, e.g.,
jaundice, serum levels of bile acids/salts and/or bilirubin,
pruritis.
Example 22
Clinical Trial to Test Efficacy of ASBTI in Treatment and/or
Alleviation of Symptoms of Progressive Familial Intrahepatic
Cholestasis 1 (PFIC-1)
[0758] This study will determine efficacy of an ASBTI for treatment
in pediatric patients afflicted with PFIC1.
[0759] Patients genetically diagnosed with anomalies in ATP8B1,
ABCB11, or ABCB4 gene and who present with PFIC-1 are eligible for
enrollment.
[0760] Inclusion criteria include severe pruritus (greater than
grade II); non-responsive to ursodiol; native liver; genetic or
immunohistochemical findings consistent with PFIC1 or Alagille
syndrome; informed consent; age 12 months or older.
[0761] Exclusion criteria include chronic diarrhea requiring IV
fluid or nutritional interventions; surgical interruption of the
enterohepatic circulation; or decompensated cirrhosis (PT>16 s,
alb<3.0 gr/dl, ascites, diuretic therapy, variceal hemorrhage,
encephalopathy).
[0762] Subjects will be administered a daily oral dose of LUM001
formulated for release in the distal ileum. Alternatively, any of
the following compounds can be the subject of the clinical trial:
264W94; SAR548304B; SA HMR1741;
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N--[(R)-.alpha.-[N-(2-sulp-
hoethyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy)-2,3,4,5-tetrahydro-1,-
2,5-benzothiadiazepine;
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N--[(R)-.alpha.-[N--((S)-1-
-carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy)--
2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N--[(R)-.alpha.-[N--((S)-1-
-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy)-2,3,4-
,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((S)-1--
carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahy-
dro-1,2,5-benzothiadiazepine; or
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N--((R)-.alpha.-carboxy-4--
hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-
e.
[0763] Stage 1 will be a 4 week dose escalation study to determine
patient minimum tolerated dose. Dose 1: 14 ug/kg/day for 7 days;
dose 2: 35 ug/kg/day for 7 days; dose 3; 70 ug/kg/day for 7 days;
dose 4: 140 ug/kg/day for 7 days.
[0764] Stage 2 will be a double-blind placebo controlled cross-over
study. Subjects will be randomized to maximum tolerated dose or
placebo for 8 weeks, followed by a 2 week drug holiday, and
cross-over to receive the alternative regimen for 8 week.
[0765] The primary endpoint is the proportion of subjects showing
resolution or improvement of baseline signs and symptoms, e.g.,
jaundice, serum levels of bile acids/salts and/or bilirubin,
pruritis.
Example 23
Clinical Trial to Test Efficacy of ASBTI in Treatment and/or
Alleviation of Symptoms of Benign Recurrent Intrahepatic
Cholestasis or a Cholestatic Liver Disease (BRIC)
[0766] The purpose of this study is to determine the effect of a
non-systemic ASBTI suspension in treating BRIC. An enteric ileal
pH-release suspension of an ASBTI may also be administered to a
subject once a day.
[0767] Pediatric patients genetically diagnosed with anomalies in
ATP8B1, ABCB11, or ABCB4 gene and present non-chronic but recurrent
cholestasis or a cholestatic liver disease symptoms will be
enrolled.
[0768] Subjects will be administered a daily oral dose of compound
LUM001 formulated for release in the distal ileum. Alternatively,
any of the following compounds can be the subject of the clinical
trial: 264W94; SD5613; SAR548304B; SA HMR1741;
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N--[(R)-.alpha.-[N-(2-sulp-
hoethyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy)-2,3,4,5-tetrahydro-1,-
2,5-benzothiadiazepine;
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N--[(R)-.alpha.-[N--((S)-1-
-carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy)--
2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N--[(R)-.alpha.-[N--((S)-1-
-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy)-2,3,4-
,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((S)-1--
carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahy-
dro-1,2,5-benzothiadiazepine; or
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N#R)-.alpha.-carboxy-4-hyd-
roxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine.
The primary endpoint is the proportion of subjects showing
resolution or improvement of baseline signs and symptoms, e.g.,
jaundice, serum levels of bile acids/salts and/or bilirubin,
pruritis.
Example 24
Clinical Trial to Test Efficacy of ASBTI in Treatment and/or
Alleviation of Symptoms of Total Parenteral Nutrition Associated
Cholestasis or a Cholestatic Liver Disease (TPN-AC)
[0769] The purpose of this study is to determine the effect of a
non-systemic ASBTI suspension in treating TPN-AC. An enteric ileal
pH-release suspension of an ASBTI may also be administered to a
subject once a day.
[0770] Pediatric patients clinically diagnosed with TPN-AC and
associated symptoms will be enrolled.
[0771] Subjects will be administered a daily oral dose of compound
LUM001 formulated for release in the distal ileum. Alternatively,
any of the following compounds can be the subject of the clinical
trial: 264W94; SAR548304B; SA HMR1741;
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N--[(R)-.alpha.-[N-(2-sulp-
hoethyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy)-2,3,4,5-tetrahydro-1,-
2,5-benzothiadiazepine;
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N--[(R)-.alpha.-[N--((S)-1-
-carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy)--
2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N--[(R)-.alpha.-[N--((S)-1-
-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy)-2,3,4-
,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N--((S)-1--
carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahy-
dro-1,2,5-benzothiadiazepine; or
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N#R)-.alpha.-carboxy-4-hyd-
roxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine.
The primary endpoint is the proportion of subjects showing
resolution or improvement of baseline signs and symptoms, e.g.,
jaundice, serum levels of bile acids/salts and/or bilirubin,
pruritis.
Example 25
Clinical Trial to Test Efficacy of LUM-001 in Treatment and/or
Alleviation of Symptoms of FIC1 Disease and Alagille Syndrome
[0772] Pediatric patients who suffer from FIC1 disease (n=15) and
Alagille syndrome (n=20) aged 12 months and older will be
tested.
[0773] Inclusion criteria will include (1) severe pruritus
(.gtoreq.grade II) unresponsive to routine pharmacologic therapy,
(2) native liver, (3) genetic or clinical findings consistent with
FIC1 disease or genetic findings of Alagille syndrome, and (4)
informed consent and assent as appropriate.
[0774] Exclusion criteria will include (1) chronic diarrhea
requiring specific intravenous fluid or nutritional intervention
for the diarrhea and/or its sequelae or (2) surgical interruption
of the enterohepatic circulation, (3) decompensated cirrhosis
(PT>16 s, alb<3.0 gr/dl, ascites, diuretic therapy, variceal
hemorrhage, encephalopathy).
[0775] Stage 1: 4 week dose escalation of LUM-001 (doses based on
adolescent/adult doses) to determine patient maximum tolerated
dose. Dose 1-14 .mu.g/kg/day for seven days; Dose 2-35 .mu.g/kg/day
for seven days; Dose 3-70 .mu.g/kg/day for seven days; Dose 4-140
.mu.g/kg/day for seven days.
[0776] Stage 2: double-blinded placebo controlled cross-over study.
Randomized to maximum tolerated dose or placebo for 8 weeks,
followed by 2 weeks wash out, and crossed-over to receive the
alternative regimen for 8 weeks.
[0777] Possible Stage 3 with open label therapy.
[0778] Primary endpoint: safety and tolerability of LUM-001.
[0779] Secondary endpoints: changes in pruritus scores, clinical
laboratories, fecal bile acid secretion, serum bile acids and serum
7.alpha.-hydroxy-4-cholesten-3-one (7.alpha.C4).
[0780] Baseline assessment will include: FIC1 or Jagged 1
genotyping, complete history and physical, comprehensive clinical
laboratory profile, 72 hour fecal bile acid collection, serum
levels of bile acids, bile acid synthesis marker (7.alpha.C4).
[0781] Stage 1-Baseline assessments (except genotyping, history and
physical) will be repeated at the end of each 7-day treatment
period. Pruritus scoring will be assessed by the parents, child (if
possible) and by clinician(s) at the beginning and end of each
dose.
[0782] Stage 2-Baseline assessments (except genotyping, history and
physical) will be repeated at the end of each 8 week treatment
period.
[0783] LUM-001 was shown to be well-tolerated in a pediatric
multiple-dose study: 2 weeks daily up to 5 mg q.d. (39 treated
subjects aged 10-17).
[0784] While preferred embodiments of the present invention have
been shown and described herein, it will be obvious to those
skilled in the art that such embodiments are provided by way of
example only. Numerous variations, changes, and substitutions will
now occur to those skilled in the art without departing from the
invention. It should be understood that various alternatives to the
embodiments of the invention described herein may be employed in
practicing the invention. It is intended that the following claims
define the scope of the invention and that methods and structures
within the scope of these claims and their equivalents be covered
thereby.
* * * * *