U.S. patent application number 11/531671 was filed with the patent office on 2007-03-15 for administration of dipeptidyl peptidase inhibitors.
Invention is credited to Ronald J. Christopher, Paul Covington.
Application Number | 20070060530 11/531671 |
Document ID | / |
Family ID | 37564046 |
Filed Date | 2007-03-15 |
United States Patent
Application |
20070060530 |
Kind Code |
A1 |
Christopher; Ronald J. ; et
al. |
March 15, 2007 |
ADMINISTRATION OF DIPEPTIDYL PEPTIDASE INHIBITORS
Abstract
Pharmaceutical compositions comprising
2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-
-1-ylmethyl]-4-fluoro-benzonitrile and pharmaceutically acceptable
salts thereof are provided as well as kits and articles of
manufacture comprising the pharmaceutical compositions as well as
methods of using the pharmaceutical compositions.
Inventors: |
Christopher; Ronald J.;
(Carlsbad, CA) ; Covington; Paul; (Wilmington,
NC) |
Correspondence
Address: |
TAKEDA SAN DIEGO, INC.
10410 SCIENCE CENTER DRIVE
SAN DIEGO
CA
92121
US
|
Family ID: |
37564046 |
Appl. No.: |
11/531671 |
Filed: |
September 13, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60717560 |
Sep 14, 2005 |
|
|
|
60747280 |
May 15, 2006 |
|
|
|
Current U.S.
Class: |
514/310 ;
514/11.7; 514/20.3; 514/20.6; 514/369; 514/6.7; 514/6.9 |
Current CPC
Class: |
A61K 45/06 20130101;
A61K 38/26 20130101; Y10S 514/866 20130101; A61K 9/2018 20130101;
A61P 31/18 20180101; A61P 35/00 20180101; A61K 31/44 20130101; A61P
3/10 20180101; A61P 43/00 20180101; A61P 3/00 20180101; A61K 31/426
20130101; A61K 31/513 20130101; A61P 5/50 20180101; A61K 31/44
20130101; A61K 2300/00 20130101; A61K 31/513 20130101; A61K 2300/00
20130101; A61K 31/426 20130101; A61K 2300/00 20130101; A61K 38/26
20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/019 ;
514/369 |
International
Class: |
A61K 38/04 20060101
A61K038/04; A61K 31/426 20060101 A61K031/426 |
Claims
1. A method comprising: administering a daily dose of between 1
mg/day and 250 mg/day of Compound I to a patient.
2. A method according to claim 1, wherein the daily dose of
Compound I administered to the patient is between 5 mg and 200
mg.
3. A method according to claim 1, wherein the daily dose of
Compound I administered to the patient is between 5 mg and 150
mg.
4. A method according to claim 1, wherein the daily dose of
Compound I administered to the patient is between 5 mg and 100
mg.
5. A method according to claim 1, wherein the daily dose of
Compound I administered to the patient is 5 mg.
6. A method according to claim 1, wherein the daily dose of
Compound I administered to the patient is 6.25 mg.
7. A method according to claim 1, wherein the daily dose of
Compound I administered to the patient is 10 mg.
8. A method according to claim 1, wherein the daily dose of
Compound I administered to the patient is 20 mg.
9. A method according to claim 1, wherein the daily dose of
Compound I administered to the patient is 25 mg.
10. A method according to claim 1, wherein the daily dose of
Compound I administered to the patient is 50 mg.
11. A method according to claim 1, wherein the daily dose of
Compound I administered to the patient is 100 mg.
12. A method according to claim 1, wherein administering is
performed 1 time per day.
13. A method according to claim 1, wherein administering is
performed 1 time per day as a single dosage.
14. A method according to claim 1, wherein administering is
performed 1 time per day for a period of at least 30 days.
15. A method according to claim 1, wherein administering is
performed 1 time per day for a period of at least 60 days.
16. A method according to claim 1, wherein administering is
performed 1 time per day in the morning.
17. A method according to claim 1, wherein administering is
performed 1 time per day in the morning prior to a first meal of
the day for the patient.
18. A method according to claim 1, wherein administering is
performed by a route selected from the group consisting of orally,
parenterally, intraperitoneally, intravenously, intraarterially,
transdermally, sublingually, intramuscularly, rectally,
transbuccally, intranasally, liposomally, via inhalation,
vaginally, intraoccularly, via local delivery, subcutaneously,
intraadiposally, intraarticularly, intraperitoneally and
intrathecally.
19. A method according to claim 1, wherein administering is
performed orally.
20. A method according to claim 1, wherein administering is
performed to treat type I or type II diabetes disease state of the
patient.
21. A method according to claim 1, wherein said patient has type II
diabetes.
22. A method according to claim 1, wherein said patient is
prediabetic.
23. A method according to claim 1, wherein administering comprises
administering Compound I in combination with one or more
antidiabetic compounds other than Compound I.
24. A method comprising: administering a daily dose of Compound I
to a patient in combination with one or more antidiabetic compounds
other than Compound I.
25. A method according to claim 24, wherein administering comprises
administering Compound I in combination with one or more
antidiabetic compounds selected from the group consisting of
insulin signaling pathway modulators, compounds influencing a
dysregulated hepatic glucose production, insulin sensitivity
enhancers, and insulin secretion enhancers.
26. A method according to claim 24, wherein administering comprises
administering Compound I in combination with one or more
antidiabetic compounds selected from the group consisting of
protein tyrosine phosphatase inhibitors,
glutamine-fructose-6-phosphate amidotransferase inhibitors,
glucose-6-phosphatase inhibitors, fructose-1,6-bisphosphatase
inhibitors, glycogen phosphorylase inhibitors, glucagon receptor
antagonists, phosphoenolpyruvate carboxykinase inhibitors, pyruvate
dehydrogenase kinase inhibitors, alpha-glucosidase inhibitors,
inhibitors of gastric emptying, glucokinase activators, GLP-1
receptor agonists, GLP-2 receptor agonists, UCP modulators, RXR
modulators, GSK-3 inhibitors, PPAR modulators, insulin, and
.alpha..sub.2-adrenergic antagonists.
27. A method according to claim 24, wherein administering comprises
administering Compound I in combination with one or more
antidiabetic compounds selected from the group consisting of GSK-3
inhibitors, retinoid X receptor agonists, Beta-3 AR agonists, UCP
modulators, antidiabetic thiazolidinediones, non-glitazone type
PPAR gamma agonists, dual PPAR gamma/PPAR alpha agonists,
antidiabetic vanadium containing compounds and biguanides.
28. A method according to claim 24, wherein administering comprises
administering Compound I in combination with one or more
antidiabetic compounds selected from the group consisting of
(S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6-yl)methyl-thiazolid-
ine-2,4-dione,
5-{[4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxo-propyl)-phenyl]-methyl}-thi-
azolidine-2,4-dione,
5-{[4-(1-methyl-cyclohexyl)methoxy)-phenyl]methyl}-thiazolidine-2,4-dione-
, 5-{[4-(2-(1-indolyl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione,
5-{4-[2-(5-methyl-2-phenyl-4-oxazoly)-ethoxy)]benzyl}-thiazolidine-2,4-di-
one, 5-(2-naphthylsulfonyl)-thiazolidine-2,4-dione, bis
{4-[(2,4-dioxo-5-thiazolidinyl)-methyl]phenyl}methane,
5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-hydroxyethoxy]-benzyl}-thiazolid-
ine-2,4-dione,
5-[4-(1-phenyl-1-cyclopropanecarbonylamino)-benzyl]-thiazolidine-2,4-dion-
e,
5-{[4-(2-(2,3-dihydroindol-1-yl)ethoxy)phenylmethyl)-thiazolidine-2,4-d-
ione,
5-[3-(4-chloro-phenyl])-2-propynyl]-5-phenylsulfonyl)thiazolidine-2,-
4-dione,
5-[3-(4-chlorophenyl])-2-propynyl]-5-(4-fluorophenyl-sulfonyl)thi-
azolidine-2,4-dione,
5-{[4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}-thiazolidine-2,-
4-dione,
5-{[4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl}-thiazolidine-2-
,4-dione,
5-([2-(2-naphthyl)-benzoxazol-5-yl]-methyl}thiazolidine-2,4-dion- e
and
5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-(4-trifluoromethyl-b-
enzyl)benzamide, including any pharmaceutically acceptable salts
thereof.
29. A method according to claim 24, wherein administering comprises
administering Compound I in combination with metformin, including
any pharmaceutically acceptable salts thereof.
30. A method according to claim 24, wherein administering comprises
administering Compound I in combination with one or more sulphonyl
urea derivatives.
31. A method according to claim 24, wherein administering comprises
administering Compound I in combination with one or more
antidiabetic compounds selected from the group consisting of
glisoxepid, glyburide, glibenclamide, acetohexamide,
chloropropamide, glibornuride, tolbutamide, tolazamide, glipizide,
carbutamide, gliquidone, glyhexamide, phenbutamide, tolcyclamide,
glimepiride and gliclazide, including any pharmaceutically
acceptable salts thereof.
32. A method according to claim 24, wherein administering comprises
administering Compound I in combination with one or more
antidiabetic compounds selected from the group consisting of
incretin hormones or mimics thereof, beta-cell imidazoline receptor
antagonists, and short-acting insulin secretagogues.
33. A method according to claim 24, wherein administering comprises
administering Compound I in combination with insulin.
34. A method according to claim 24, wherein administering comprises
administering Compound I in combination with one or more GLP-1
agonists.
35. A method according to claim 24, wherein administering comprises
administering Compound I in combination with one or more GLP-2
agonists.
36. A method according to claim 24, wherein administering comprises
administering Compound I in combination with extendatide.
37. A method according to claim 24, wherein administering comprises
administering Compound I in combination with one or more
antidiabetic compounds selected from the group consisting of
repaglinide, mitiglinide and nateglinide, including any
pharmaceutically acceptable salts thereof.
38. A method according to claim 24, wherein administering comprises
administering Compound I in combination with one or more
alpha-Glucosidase inhibitors.
39. A method according to claim 24, wherein administering comprises
administering Compound I in combination with one or more
antidiabetic compounds selected from the group consisting of
acarbose, voglibose and miglitol, including any pharmaceutically
acceptable salts thereof.
40. A method according to claim 24, wherein administering comprises
administering Compound I in combination with rosiglitazone,
including any pharmaceutically acceptable salts thereof.
41. A method according to claim 24, wherein administering comprises
administering Compound I in combination with pioglitazone,
including any pharmaceutically acceptable salts thereof.
42. A method according to claim 41, wherein the pioglitazone
comprises pioglitazone HCl.
43. A method according to claim 24, wherein administering comprises
administering Compound I in combination with metformin and
pioglitazone, including any pharmaceutically acceptable salts
thereof.
44. A method according to claim 43, wherein the pioglitazone
comprises pioglitazone HCl.
45. A method according to claim 1, wherein Compound I is
administered as a free base.
46. A method according to claim 1, wherein Compound I is
administered as a pharmaceutically acceptable salt.
47. A method according to claim 1, wherein Compound I is
administered as a succinate salt.
48. A pharmaceutical composition formulated in a single dose form
wherein such single dose form comprises between 1 mg and 250 mg of
Compound I.
49. A pharmaceutical composition according to claim 48, wherein
such single dose form comprises between 5 mg and 200 mg of Compound
I.
50. A pharmaceutical composition according to claim 48, wherein
such single dose form comprises between 5 mg and 150 mg of Compound
I.
51. A pharmaceutical composition according to claim 48, wherein
such single dose form comprises between 15 mg and 100 mg of
Compound I.
52. A pharmaceutical composition according to claim 48, wherein
such single dose form comprises 5 mg of Compound I.
53. A pharmaceutical composition according to claim 48, wherein
such single dose form comprises 6.25 mg of Compound I.
54. A pharmaceutical composition according to claim 48, wherein
such single dose form comprises 10 mg of Compound I.
55. A pharmaceutical composition according to claim 48, wherein
such single dose form comprises 20 mg of Compound I.
56. A pharmaceutical composition according to claim 48, wherein
such single dose form comprises 25 mg of Compound I.
57. A pharmaceutical composition according to claim 48, wherein
such single dose form comprises 50 mg of Compound I.
58. A pharmaceutical composition according to claim 48, wherein
such single dose form comprises 100 mg of Compound I.
59. A pharmaceutical composition according to claim 48, wherein
such single dose form further comprises one or more antidiabetic
compounds other than Compound I.
60. A pharmaceutical composition formulated in a single dose form
wherein such single dose form comprises Compound I and one or more
antidiabetic compounds other than Compound I.
61. A pharmaceutical composition according to claim 60, wherein
such single dose form comprises one or more antidiabetic compounds
selected from the group consisting of insulin signaling pathway
modulators, compounds influencing a dysregulated hepatic glucose
production, insulin sensitivity enhancers, and insulin secretion
enhancers.
62. A pharmaceutical composition according to claim 60, wherein
such single dose form comprises one or more antidiabetic compounds
selected from the group consisting of protein tyrosine phosphatase
inhibitors, glutamine-fructose-6-phosphate amidotransferase
inhibitors, glucose-6-phosphatase inhibitors,
fructose-1,6-bisphosphatase inhibitors, glycogen phosphorylase
inhibitors, glucagon receptor antagonists, phosphoenolpyruvate
carboxykinase inhibitors, pyruvate dehydrogenase kinase inhibitors,
alpha-glucosidase inhibitors, inhibitors of gastric emptying,
insulin, and .alpha..sub.2-adrenergic antagonists.
63. A pharmaceutical composition according to claim 60, wherein
such single dose form comprises one or more antidiabetic compounds
selected from the group consisting of GSK-3 inhibitors, retinoid X
receptor agonists, Beta-3 AR agonists, UCP modulators, antidiabetic
thiazolidinediones, non-glitazone type PPAR gamma agonists, dual
PPAR gamma/PPAR alpha agonists, antidiabetic vanadium containing
compounds and biguanides.
64. A pharmaceutical composition according to claim 60, wherein
such single dose form comprises one or more antidiabetic compounds
selected from the group consisting of
(S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6-yl)methyl-thiazolid-
ine-2,4-dione,
5-{[4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxo-propyl)-phenyl]-methyl}-thi-
azolidine-2,4-dione,
5-{[4-(1-methyl-cyclohexyl)methoxy)-phenyl]methyl}-thiazolidine-2,4-dione-
, 5-{[4-(2-(1-indolyl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione,
5-{4-[2-(5-methyl-2-phenyl-4-oxazoly)-ethoxy)]benzyl}-thiazolidine-2,4-di-
one, 5-(2-naphthylsulfonyl)-thiazolidine-2,4-dione,
bis{4-[(2,4-dioxo-5-thiazolidinyl)-methyl]phenyl}methane,
5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-hydroxyethoxy]-benzyl}-thiazolid-
ine-2,4-dione,
5-[4-(1-phenyl-1-cyclopropanecarbonylamino)-benzyl]-thiazolidine-2,4-dion-
e,
5-{[4-(2-(2,3-dihydroindol-1-yl)ethoxy)phenylmethyl)-thiazolidine-2,4-d-
ione,
5-[3-(4-chloro-phenyl])-2-propynyl]-5-phenylsulfonyl)thiazolidine-2,-
4-dione,
5-[3-(4-chlorophenyl])-2-propynyl]-5-(4-fluorophenyl-sulfonyl)thi-
azolidine-2,4-dione,
5-{[4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}-thiazolidine-2,-
4-dione,
5-([2-(2-naphthyl)-benzoxazol-5-yl]-methyl}thiazolidine-2,4-dione
and
5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-(4-trifluoromethyl-be-
nzyl)benzamide, including any pharmaceutically acceptable salts
thereof.
65. A pharmaceutical composition according to claim 60, wherein
such single dose form comprises metformin, including any
pharmaceutically acceptable salts thereof.
66. A pharmaceutical composition according to claim 60, wherein
such single dose form comprises a sulphonyl urea derivative.
67. A pharmaceutical composition according to claim 60, wherein
such single dose form comprises one or more antidiabetic compounds
selected from the group consisting of glisoxepid, glyburide,
glibenclamide, acetohexamide, chloropropamide, glibornuride,
tolbutamide, tolazamide, glipizide, carbutamide, gliquidone,
glyhexamide, phenbutamide, tolcyclamide, glimepiride and
gliclazide, including any pharmaceutically acceptable salts
thereof.
68. A pharmaceutical composition according to claim 60, wherein
such single dose form comprises one or more antidiabetic compounds
selected from the group consisting of incretin hormones or mimics
thereof, beta-cell imidazoline receptor antagonists, and
short-acting insulin secretagogues.
69. A pharmaceutical composition according to claim 60, wherein
such single dose form comprises insulin.
70. A pharmaceutical composition according to claim 60, wherein
such single dose form comprises one or more GLP-1 agonists.
71. A pharmaceutical composition according to claim 60, wherein
such single dose form comprises one or more GLP-2 agonists.
72. A pharmaceutical composition according to claim 60, wherein
such single dose form comprises extendatide.
73. A pharmaceutical composition according to claim 60, wherein
such single dose form comprises one or more antidiabetic compounds
selected from the group consisting of repaglinide, mitiglinide and
nateglinide, including any pharmaceutically acceptable salts
thereof.
74. A pharmaceutical composition according to claim 60, wherein
such single dose form comprises one or more alpha-Glucosidase
inhibitors.
75. A pharmaceutical composition according to claim 60, wherein
such single dose form comprises one or more antidiabetic compounds
selected from the group consisting of acarbose, voglibose and
miglitol, including any pharmaceutically acceptable salts
thereof.
76. A pharmaceutical composition according to claim 60, wherein
such single dose form comprises rosiglitazone, including any
pharmaceutically acceptable salts thereof.
77. A pharmaceutical composition according to claim 60, wherein
such single dose form comprises pioglitazone, including any
pharmaceutically acceptable salts thereof.
78. A pharmaceutical composition according to claim 77, wherein the
pioglitazone comprises pioglitazone HCl.
79. A pharmaceutical composition according to claim 60, wherein
such single dose form comprises metformin and pioglitazone,
including any pharmaceutically acceptable salts thereof.
80. A pharmaceutical composition according to claim 79, wherein the
pioglitazone comprises pioglitazone HCl.
81. A pharmaceutical composition according to claim 48, wherein
such single dose form is adapted for oral administration.
82. A pharmaceutical composition according to claim 48, wherein
such single dose form is a solid formulation adapted for oral
administration.
83. A pharmaceutical composition according to claim 48, wherein
such single dose form is a tablet or capsule adapted for oral
administration.
84. A pharmaceutical composition according to claim 48, wherein
such single dose form comprises an extended release formulation
adapted for oral administration.
85. A pharmaceutical composition according to claim 48, wherein
Compound I is present in the pharmaceutical composition as a free
base.
86. A pharmaceutical composition according to claim 48, wherein
Compound I is present in the pharmaceutical composition in a
pharmaceutically acceptable salt.
87. A pharmaceutical composition according to claim 48, wherein
Compound I is present in the pharmaceutical composition in a
succinate salt.
88. A kit comprising: multiple doses of a pharmaceutical
composition according to claim 48; and instructions which comprise
one or more forms of information selected from the group consisting
of indicating a disease state for which the pharmaceutical
composition is to be administered, storage information for the
pharmaceutical composition, dosing information and instructions
regarding how to administer the pharmaceutical composition.
89. An article of manufacture comprising: multiple doses of a
pharmaceutical composition according to claim 48; and packaging
materials.
90. An article of manufacture according to claim 89, wherein the
packaging material comprises a container for housing the multiple
doses of the pharmaceutical composition.
91. An article of manufacture according to claim 90, wherein the
container comprises a label indicating one or more members of the
group consisting of a disease state for which the compound is to be
administered, storage information, dosing information and/or
instructions regarding how to administer the composition.
92. A method for treating conditions mediated by DPP-IV, which
comprises administering a therapeutically effective amount of
Compound I in combination with one or more antidiabetic compounds
other than Compound I.
Description
RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/717,560 filed Sep. 14, 2005 and U.S. Provisional
Application No. 60/747,280 filed May 15, 2006, each of which is
incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The invention relates to the method of administering
compounds used to inhibit dipeptidyl peptidase IV as well as
treatment methods based on such administration.
DESCRIPTION OF RELATED ART
[0003] Dipeptidyl Peptidase IV (IUBMB Enzyme Nomenclature
EC.3.4.14.5) is a type II membrane protein that has been referred
to in the literature by a wide a variety of names including DPP4,
DP4, DAP-IV, FAP.beta., adenosine deaminase complexing protein 2,
adenosine deaminase binding protein (ADAbp), dipeptidyl
aminopeptidase IV; Xaa-Pro-dipeptidyl-aminopeptidase; Gly-Pro
naphthylamidase; postproline dipeptidyl aminopeptidase IV;
lymphocyte antigen CD26; glycoprotein GP110; dipeptidyl peptidase
IV; glycylproline aminopeptidase; glycylproline aminopeptidase;
X-prolyl dipeptidyl aminopeptidase; pep X; leukocyte antigen CD26;
glycylprolyl dipeptidylaminopeptidase; dipeptidyl-peptide
hydrolase; glycylprolyl aminopeptidase; dipeptidyl-aminopeptidase
IV; DPP IV/CD26; amino acyl-prolyl dipeptidyl aminopeptidase; T
cell triggering molecule Tp103; X-PDAP. Dipeptidyl Peptidase IV is
referred to herein as "DPP-IV."
[0004] DPP-IV is a non-classical serine aminodipeptidase that
removes Xaa-Pro dipeptides from the amino terminus (N-terminus) of
polypeptides and proteins. DPP-IV dependent slow release of
dipeptides of the type X-Gly or X-Ser has also been reported for
some naturally occurring peptides.
[0005] DPP-IV is constitutively expressed on epithelial and
endothelial cells of a variety of different tissues (intestine,
liver, lung, kidney and placenta), and is also found in body
fluids. DPP-IV is also expressed on circulating T-lymphocytes and
has been shown to be synonymous with the cell-surface antigen,
CD-26.
[0006] DPP-IV is responsible for the metabolic cleavage of certain
endogenous peptides (GLP-1 (7-36), glucagon) in vivo and has
demonstrated proteolytic activity against a variety of other
peptides (GHRH, NPY, GLP-2, VIP) in vitro.
[0007] GLP-1 (7-36) is a 29 amino-acid peptide derived by
post-translational processing of proglucagon in the small
intestine. GLP-1 (7-36) has multiple actions in vivo including the
stimulation of insulin secretion, inhibition of glucagon secretion,
the promotion of satiety, and the slowing of gastric emptying.
Based on its physiological profile, the actions of GLP-1 (7-36) are
believed to be beneficial in the prevention and treatment of type
II diabetes and potentially obesity. For example, exogenous
administration of GLP-1 (7-36) (continuous infusion) in diabetic
patients has been found to be efficacious in this patient
population. Unfortunately, GLP-1 (7-36) is degraded rapidly in vivo
and has been shown to have a short half-life in vivo (t.sub.1/2=1.5
minutes).
[0008] Based on a study of genetically bred DPP-IV knock out mice
and on in vivo/in vitro studies with selective DPP-IV inhibitors,
DPP-IV has been shown to be the primary degrading enzyme of GLP-1
(7-36) in vivo. GLP-1 (7-36) is degraded by DPP-IV efficiently to
GLP-1 (9-36), which has been speculated to act as a physiological
antagonist to GLP-1 (7-36). Inhibiting DPP-IV in vivo is therefore
believed to be useful for potentiating endogenous levels of GLP-1
(7-36) and attenuating the formation of its antagonist GLP-1
(9-36). Thus, DPP-IV inhibitors are believed to be useful agents
for the prevention, delay of progression, and/or treatment of
conditions mediated by DPP-IV, in particular diabetes and more
particularly, type 2 diabetes mellitus, diabetic dislipidemia,
conditions of impaired glucose tolerance (IGT), conditions of
impaired fasting plasma glucose (IFG), metabolic acidosis, ketosis,
appetite regulation and obesity.
[0009] Several compounds have been shown to inhibit DPP-IV.
Nonetheless, a need still exists for new DPP-IV inhibitors and
methods of administering such inhibitors for the treatment of
disease.
SUMMARY OF THE INVENTION
[0010] A method is provided comprising: administering a daily dose
of between 1 mg/day and 250 mg/day of Compound I to a patient,
optionally between 2.5 mg and 200 mg of Compound I, optionally
between 2.5 mg and 150 mg of Compound I, and optionally between 5
mg and 100 mg of Compound I. In one variation, a daily dose of 2.5
mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg or 100 mg of
Compound I is administered. In another variation, a once-per-week
dose of 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg or
100 mg of Compound I is administered.
[0011] In one variation, administering is performed 1 time per day
and may optionally be performed 1 time per day as a single dosage.
Optionally, administering is performed 1 time per day for a period
of at least 30 days and optionally for a period of at least 60
days.
[0012] In one variation, administering is performed 1 time per day
in the morning and optionally is performed 1 time per day in the
morning prior to a first meal of the day for the patient.
[0013] In one variation, administering is performed 1 time per week
and may optionally be performed 1 time per week as a single dosage.
Optionally, administering is performed 1 time per week for a period
of at least 30 days and optionally for a period of at least 60
days.
[0014] In one variation, administering is performed 1 time per week
in the morning and optionally is performed 1 time per week in the
morning prior to a first meal of the day for the patient.
[0015] Administering may be performed by a wide range of routes of
administration including, but not limited to a route selected from
the group consisting of orally, parenterally, intraperitoneally,
intravenously, intraarterially, transdermally, sublingually,
intramuscularly, rectally, transbuccally, intranasally,
liposomally, via inhalation, vaginally, intraoccularly, via local
delivery, subcutaneously, intraadiposally, intraarticularly,
intraperitoneally and intrathecally. In one particular variation,
administering is performed orally.
[0016] Compound I may be used to treat a range of diseases. In one
variation, administering Compound I is performed to treat type I or
type II diabetes disease state of the patient. In another
variation, administering Compound I is performed to treat a
pre-diabetic patient. In still another variation, administering
Compound I is performed to treat an inflammatory bowel disease,
Crohn's disease, chemotherapy-induced enteritis, oral mucositis or
Shortened Bowel syndrome.
[0017] In another variation, administering Compound I is performed
to treat a patient suffering from conditions mediated by DPP-IV
such as diabetes and more particularly, type 2 diabetes mellitus;
diabetic dislipidemia; impaired glucose tolerance (IGT); impaired
fasting plasma glucose (IFG); metabolic acidosis; ketosis; appetite
regulation; obesity; complications associated with diabetes
including diabetic neuropathy, diabetic retinopathy and kidney
disease; hyperlipidemia including hypertriglyceridemia,
hypercholesteremia, hypoHDLemia and postprandial hyperlipidemia;
arteriosclerosis; hypertension; myocardial infarction, angina
pectoris, cerebral infarction, cerebral apoplexy and metabolic
syndrome.
[0018] A method is also provided for administering Compound I in
combination with one or more antidiabetic or incretin compounds
other than Compound I. In one variation, such combination therapy
method is performed where a daily dose of between 1 mg/day and 250
mg/day of Compound I, optionally between 2.5 mg and 200 mg of
Compound I, optionally between 2.5 mg and 150 mg of Compound I, and
optionally between 5 mg and 100 mg of Compound I, is administered
to a patient. In one variation, a daily dose of 2.5 mg, 5 mg, 6.25
mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg or 100 mg of Compound I is
administered to a patient in combination with one or more
antidiabetic compounds other than Compound I.
[0019] In one variation, such combination therapy method is
performed where a once-per-week dose of between 1 mg and 250 mg of
Compound I, optionally between 2.5 mg and 200 mg of Compound I,
optionally between 2.5 mg and 150 mg of Compound I, and optionally
between 5 mg and 100 mg of Compound I, is administered to a
patient. In one variation, a once-per-week dose of 2.5 mg, 5 mg,
6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg or 100 mg, 150 mg or 200
mg of Compound I is administered to a patient in combination with
one or more antidiabetic compounds other than Compound I.
[0020] It is noted that several different dosage ranges for
particular antidiabetic and incretin compounds are provided herein.
It is intended for the scope of the present invention to include
drug combinations covering any of the disclosed ranges for Compound
I in combination with any of the dosage ranges described herein for
other antidiabetic or incretin compounds.
[0021] Combination of Compound I with one or more antidiabetic
compounds other than Compound I provides excellent effects such as
1) enhancement in therapeutic effects of Compound I and/or the
antidiabetic compounds; 2) reduction in side effects of Compound I
and/or the antidiabetic compounds; and 3) reduction in a dose of
Compound I and/or the antidiabetic compounds.
[0022] The one or more antidiabetic or incretin compounds
administered in combination with Compound I may optionally be
selected from the group consisting of insulin signaling pathway
modulators, compounds influencing a dysregulated hepatic glucose
production, insulin sensitivity enhancers, and insulin secretion
enhancers.
[0023] The one or more antidiabetic or incretin compounds
administered in combination with Compound I may also optionally be
selected from the group consisting of protein tyrosine phosphatase
inhibitors, glutamine-fructose-6-phosphate amidotransferase
inhibitors, glucose-6-phosphatase inhibitors,
fructose-1,6-bisphosphatase inhibitors, glycogen phosphorylase
inhibitors, glucagon receptor antagonists, phosphoenolpyruvate
carboxykinase inhibitors, pyruvate dehydrogenase kinase inhibitors,
alpha-glucosidase inhibitors, inhibitors of gastric emptying,
glucokinase activators, GLP-1 receptor agonists, GLP-2 receptor
agonists, UCP modulators, RXR modulators, GSK-3 inhibitors, PPAR
modulators, metformin, insulin, and .alpha..sub.2-adrenergic
antagonists.
[0024] The one or more antidiabetic or incretin compounds
administered in combination with Compound I may also optionally be
selected from the group consisting of GSK-3 inhibitors, retinoid X
receptor agonists, Beta-3 AR agonists, UCP modulators, antidiabetic
thiazolidinediones, non-glitazone type PPAR gamma agonists, dual
PPAR gamma/PPAR alpha agonists, antidiabetic vanadium containing
compounds and biguanides.
[0025] The one or more antidiabetic or incretin compounds
administered in combination with Compound I may also optionally be
thiazolidinediones selected from the group consisting of
(S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6-yl)methyl-thiazolid-
ine-2,4-dione,
5-{[4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxo-propyl)-phenyl]-methyl}-thi-
azolidine-2,4-dione,
5-{[4-(1-methyl-cyclohexyl)methoxy)-phenyl]methyl}-thiazolidine-2,4-dione-
, 5-{[4-(2-(1-indolyl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione,
5-{4-[2-(5-methyl-2-phenyl-4-oxazoly)-ethoxy)]benzyl}-thiazolidine-2,4-di-
one, 5-(2-naphthylsulfonyl)-thiazolidine-2,4-dione,
bis{4-[(2,4-dioxo-5-thiazolidinyl)-methyl]phenyl}methane,
5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-hydroxyethoxy]-benzyl}-thiazolid-
ine-2,4-dione,
5-[4-(1-phenyl-1-cyclopropanecarbonylamino)-benzyl]-thiazolidine-2,4-dion-
e,
5-{[4-(2-(2,3-dihydroindol-1-yl)ethoxy)phenylmethyl)-thiazolidine-2,4-d-
ione,
5-[3-(4-chloro-phenyl])-2-propynyl]-5-phenylsulfonyl)thiazolidine-2,-
4-dione,
5-[3-(4-chlorophenyl])-2-propynyl]-5-(4-fluorophenyl-sulfonyl)thi-
azolidine-2,4-dione,
5-{[4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}-thiazolidine-2,-
4-dione,
5-{[4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl}-thiazolidine-2-
,4-dione,
5-{[4-((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyra-
n-2-yl)methoxy)-phenyl]-methyl)-thiazolidine-2,4-dione,
5-[6-(2-fluoro-benzyloxy)-naphthalen-2-ylmethyl]-thiazolidine-2,4-dione,
5-([2-(2-naphthyl)-benzoxazol-5-yl]-methyl}thiazolidine-2,4-dione
and
5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-(4-trifluoromethyl-benzyl-
)benzamide, including any pharmaceutically acceptable salts
thereof.
[0026] In one variation, the one or more antidiabetic compounds
administered in combination with Compound I includes metformin. In
one particular variation, the metformin in this combination
comprises one or more pharmaceutically acceptable salts thereof. In
another particular variation, the metformin in this combination
comprises a metformin HCl salt. In still another particular
variation, the metformin in this combination is administered in a
daily dose of between 125 and 2550 mg. In yet another variation,
the metformin in this combination is administered in a daily dose
of between 250 and 2550 mg.
[0027] In another variation, the one or more antidiabetic compounds
administered in combination with Compound I includes one or more
sulphonyl urea derivatives.
[0028] The one or more antidiabetic compounds administered in
combination with Compound I may also optionally be selected from
the group consisting of glisoxepid, glyburide, glibenclamide,
acetohexamide, chloropropamide, glibornuride, tolbutamide,
tolazamide, glipizide, carbutamide, gliquidone, glyhexamide,
phenbutamide, tolcyclamide, glimepiride and gliclazide, including
any pharmaceutically acceptable salts thereof. In one variation,
the one or more antidiabetic compounds administered in combination
with Compound I includes glimepiride.
[0029] The one or more antidiabetic compounds administered in
combination with Compound I may also optionally be selected from
the group consisting of incretin hormones or mimics thereof,
beta-cell imidazoline receptor antagonists, and short-acting
insulin secretagogues.
[0030] In another variation, the one or more antidiabetic compounds
administered in combination with Compound I includes insulin.
[0031] The one or more antidiabetic compounds administered in
combination with Compound I may also optionally be one or more
GLP-1 agonists including, for example, extendatide.
[0032] The one or more antidiabetic compounds administered in
combination with Compound I may also optionally be one or more
GLP-2 agonists including, for example, human recombinant GLP-2.
[0033] The one or more antidiabetic compounds administered in
combination with Compound I may also optionally be one or more
antidiabetic D-phenylalanine derivatives.
[0034] The one or more antidiabetic compounds administered in
combination with Compound I may also optionally be selected from
the group consisting of repaglinide, mitiglinide and nateglinide,
including any pharmaceutically acceptable salts thereof. In one
variation, the one or more antidiabetic compounds administered in
combination with Compound I includes mitiglinide calcium salt
hydrate.
[0035] The one or more antidiabetic compounds administered in
combination with Compound I may also optionally be one or more
alpha-Glucosidase inhibitors.
[0036] The one or more antidiabetic compounds administered in
combination with Compound I may also optionally be selected from
the group consisting of acarbose, voglibose and miglitol, including
any pharmaceutically acceptable salts thereof. In one variation,
the one or more antidiabetic compounds administered in combination
with Compound I includes voglibose. In another variation, the
voglibose in this combination is administered in a daily dose of
between 0.1 and 1 mg.
[0037] The one or more antidiabetic compounds administered in
combination with Compound I may also optionally be rosiglitazone,
including any pharmaceutically acceptable salts thereof. In one
variation, the rosiglitazone in this combination comprises a
rosiglitazone maleate salt
[0038] The one or more antidiabetic compounds administered in
combination with Compound I may also optionally be tesaglitazar,
muraglitazar or naveglitazar, including any pharmaceutically
acceptable salts thereof.
[0039] The one or more antidiabetic compounds administered in
combination with Compound I may also optionally be pioglitazone,
including any pharmaceutically acceptable salts thereof. In one
variation, the pioglitazone in this combination comprises a
pioglitazone HCl salt. In another variation, the pioglitazone in
this combination is administered in a daily dose of between 7.5 and
60 mg. In still another variation, the pioglitazone in this
combination is administered in a daily dose of between 15 and 45
mg.
[0040] The one or more antidiabetic compounds administered in
combination with Compound I may also optionally comprise metformin
and pioglitazone. In one variation, the pioglitazone in this
combination comprises one or more pharmaceutically acceptable salts
thereof. In another variation, the pioglitazone in this combination
comprises a pioglitazone HCl salt. In still another variation, the
pioglitazone in this combination is administered in a daily dose of
between 7.5 and 60 mg. In yet another variation, the pioglitazone
in this combination is administered in a daily dose of between 15
and 45 mg. In another variation of each of the above variations,
the metformin in this combination comprises one or more
pharmaceutically acceptable salts thereof. In one particular
variation, the metformin in this combination comprises a metformin
HCl salt. In another particular variation, the metformin in this
combination is administered in a daily dose of between 125 and 2550
mg. In still another variation, the metformin in this combination
is administered in a daily dose of between 250 and 2550 mg.
[0041] In regard to each of the above embodiments and variations
thereof, Compound I may be administered as a free base or as a
pharmaceutically acceptable salt thereof. In particular variations,
Compound I is administered as a HCl, methanesulfonate, succinate,
benzoate, toluenesulfonate, R-(-)mandelate or benzenesulfonate salt
of Compound I.
[0042] Pharmaceutical compositions are also provided.
[0043] In one embodiment, a pharmaceutical composition is provided
that is formulated in a single dose form wherein such single dose
form comprises between 1 mg/day and 250 mg/day of Compound I,
optionally between 2.5 mg and 200 mg of Compound I, optionally
between 2.5 mg and 150 mg of Compound I, and optionally between 5
mg and 100 mg of Compound I. In particular variations, the
pharmaceutical composition comprises 2.5 mg, 5 mg, 6.25 mg, 10 mg,
20 mg, 25 mg, 50 mg, 75 mg or 100 mg of Compound I.
[0044] In one embodiment, a pharmaceutical composition is provided
that is formulated in a single dose form wherein such single dose
form comprises between 1 mg/week and 250 mg/week of Compound I,
optionally between 2.5 mg and 200 mg of Compound I, optionally
between 2.5 mg and 150 mg of Compound I, and optionally between 5
mg and 100 mg of Compound I. In particular variations, the
pharmaceutical composition comprises 2.5 mg, 5 mg, 6.25 mg, 10 mg,
20 mg, 25 mg, 50 mg, 75 mg or 100 mg of Compound I on a once per
week basis.
[0045] In another embodiment, a pharmaceutical composition is
provided that comprises Compound I and one or more antidiabetic or
incretin compounds other than Compound I in a single dose form.
Optionally, Compound I is present in the single dose form in a
dosage amount between 1 mg/day and 250 mg/day of Compound I,
optionally between 2.5 mg and 200 mg of Compound I, optionally
between 2.5 mg and 150 mg of Compound I, and optionally between 5
mg and 100 mg of Compound I. In particular variations, the
pharmaceutical composition comprises 2.5 mg, 5 mg, 6.25 mg, 10 mg,
20 mg, 25 mg, 50 mg, 75 mg or 100 mg of Compound I.
[0046] Combination of Compound I with one or more antidiabetic
compounds other than Compound I provides excellent effects such as
1) enhancement in therapeutic effects of Compound I and/or the
antidiabetic compounds; 2) reduction in side effects of Compound I
and/or the antidiabetic compounds; and 3) reduction in a dose of
Compound I and/or the antidiabetic compounds.
[0047] According to above embodiment, the one or more antidiabetic
compounds comprised in the pharmaceutical composition may
optionally be selected from the group consisting of insulin
signaling pathway modulators, compounds influencing a dysregulated
hepatic glucose production, insulin sensitivity enhancers,
incretins and insulin secretion enhancers.
[0048] Also according to above embodiment, the one or more
antidiabetic compounds comprised in the pharmaceutical composition
may optionally be selected from the group consisting of protein
tyrosine phosphatase inhibitors, glutamine-fructose-6-phosphate
amidotransferase inhibitors, glucose-6-phosphatase inhibitors,
fructose-1,6-bisphosphatase inhibitors, glycogen phosphorylase
inhibitors, glucagon receptor antagonists, phosphoenolpyruvate
carboxykinase inhibitors, pyruvate dehydrogenase kinase inhibitors,
alpha-glucosidase inhibitors, inhibitors of gastric emptying,
glucokinase activators, GLP-1 receptor agonists, GLP-2 receptor
agonists, UCP modulators, RXR modulators, GSK-3 inhibitors, PPAR
modulators, metformin, insulin, and .alpha..sub.2-adrenergic
antagonists.
[0049] Also according to above embodiment, the one or more
antidiabetic compounds comprised in the pharmaceutical composition
may optionally be selected from the group consisting of GSK-3
inhibitors, retinoid X receptor agonists, Beta-3 AR agonists, UCP
modulators, antidiabetic thiazolidinediones, non-glitazone type
PPAR gamma agonists, dual PPAR gamma/PPAR alpha agonists,
antidiabetic vanadium containing compounds and biguanides.
[0050] Also according to above embodiment, the one or more
antidiabetic compounds comprised in the pharmaceutical composition
may optionally be thiazolidinediones selected from the group
consisting of
(S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6-yl)methyl-thiazolid-
ine-2,4-dione,
5-{[4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxo-propyl)-phenyl]-methyl}-thi-
azolidine-2,4-dione,
5-{[4-(1-methyl-cyclohexyl)methoxy)-phenyl]methyl]-thiazolidine-2,4-dione-
, 5-{[4-(2-(1-indolyl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione,
5-{4-[2-(5-methyl-2-phenyl-4-oxazoly)-ethoxy)]benzyl}-thiazolidine-2,4-di-
one, 5-(2-naphthylsulfonyl)-thiazolidine-2,4-dione,
bis{4-[(2,4-dioxo-5-thiazolidinyl)-methyl]phenyl}methane,
5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-hydroxyethoxy]-benzyl}-thiazolid-
ine-2,4-dione,
5-[4-(1-phenyl-1-cyclopropanecarbonylamino)-benzyl]-thiazolidine-2,4-dion-
e,
5-{[4-(2-(2,3-dihydroindol-1-yl)ethoxy)phenylmethyl)-thiazolidine-2,4-d-
ione,
5-[3-(4-chloro-phenyl])-2-propynyl]-5-phenylsulfonyl)thiazolidine-2,-
4-dione,
5-[3-(4-chlorophenyl])-2-propynyl]-5-(4-fluorophenyl-sulfonyl)thi-
azolidine-2,4-dione,
5-{[4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}-thiazolidine-2,-
4-dione,
5-{[4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl}-thiazolidine-2-
,4-dione,
5-{[4-((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyra-
n-2-yl)methoxy)-phenyl]-methyl)-thiazolidine-2,4-dione,
5-[6-(2-fluoro-benzyloxy)-naphthalen-2-ylmethyl]-thiazolidine-2,4-dione,
5-([2-(2-naphthyl)-benzoxazol-5-yl]-methyl}thiazolidine-2,4-dione
and
5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-(4-trifluoromethyl-benzyl-
)benzamide, including any pharmaceutically acceptable salts
thereof.
[0051] In one variation, the one or more antidiabetic compounds
comprised in the pharmaceutical composition includes metformin. In
one particular variation, the metformin in this combination
comprises one or more pharmaceutically acceptable salts thereof. In
another particular variation, the metformin in this combination
comprises a metformin HCl salt. In still another particular
variation, the metformin in this combination is administered in a
daily dose of between 125 and 2550 mg. In yet another variation,
the metformin in this combination is administered in a daily dose
of between 250 and 2550 mg.
[0052] In another variation, the one or more antidiabetic compounds
comprised in the pharmaceutical composition includes one or more
sulphonyl urea derivatives.
[0053] In another variation, the one or more antidiabetic compounds
comprised in the pharmaceutical composition includes an
antidiabetic compound selected from the group consisting of
glisoxepid, glyburide, glibenclamide, acetohexamide,
chloropropamide, glibornuride, tolbutamide, tolazamide, glipizide,
carbutamide, gliquidone, glyhexamide, phenbutamide, tolcyclamide,
glimepiride and gliclazide, including any pharmaceutically
acceptable salts thereof. In one variation, the one or more
antidiabetic compounds comprised in the pharmaceutical composition
includes glimepiride.
[0054] In another variation, the one or more antidiabetic compounds
comprised in the pharmaceutical composition includes an
antidiabetic compound selected from the group consisting of
incretin hormones or mimics thereof, beta-cell imidazoline receptor
antagonists, and short-acting insulin secretagogues.
[0055] In another variation, the one or more antidiabetic compounds
comprised in the pharmaceutical composition includes insulin.
[0056] In another variation, the one or more antidiabetic compounds
comprised in the pharmaceutical composition includes one or more
GLP-1 agonists.
[0057] In another variation, the one or more antidiabetic compounds
comprised in the pharmaceutical composition includes one or more
GLP-2 agonists, including human recombinant forms of GLP-2.
[0058] In another variation, the one or more antidiabetic compounds
comprised in the pharmaceutical composition includes one or more
antidiabetic D-phenylalanine derivatives.
[0059] In another variation, the one or more antidiabetic compounds
comprised in the pharmaceutical composition includes an
antidiabetic compound selected from the group consisting of
repaglinide and nateglinide, including any pharmaceutically
acceptable salts thereof. In one variation, the one or more
antidiabetic compounds comprised in the pharmaceutical composition
includes mitiglinide calcium salt hydrate.
[0060] In another variation, the one or more antidiabetic compounds
comprised in the pharmaceutical composition includes one or more
alpha-Glucosidase inhibitors.
[0061] In another variation, the one or more antidiabetic compounds
comprised in the pharmaceutical composition includes an
antidiabetic compound selected from the group consisting of
acarbose, voglibose and miglitol, including any pharmaceutically
acceptable salts thereof. In one variation, the one or more
antidiabetic compounds comprised in the pharmaceutical composition
includes voglibose. In another variation, the voglibose in this
combination is administered in a daily dose of between 0.1 and 1
mg.
[0062] In another variation, the one or more antidiabetic compounds
comprised in the pharmaceutical composition includes rosiglitazone,
including any pharmaceutically acceptable salts thereof. In one
variation, the rosiglitazone in this combination comprises a
rosiglitazone maleate salt.
[0063] The one or more antidiabetic compounds comprised in the
pharmaceutical composition may also optionally be tesaglitazar,
muraglitazar or naveglitazar, including any pharmaceutically
acceptable salts thereof.
[0064] In another variation, the one or more antidiabetic compounds
comprised in the pharmaceutical composition includes pioglitazone,
including any pharmaceutically acceptable salts thereof. In one
particular variation, the pioglitazone in this combination
comprises a pioglitazone HCl salt. In another particular variation,
the pioglitazone in this combination is administered in a daily
dose of between 7.5 and 60 mg. In still another particular
variation, the pioglitazone in this combination is administered in
a daily dose of between 15 and 45 mg.
[0065] In another variation, the one or more antidiabetic compounds
comprised in the pharmaceutical composition includes metformin and
pioglitazone. In one particular variation, the pioglitazone in this
combination comprises one or more pharmaceutically acceptable salts
thereof. In another particular variation, the pioglitazone in this
combination comprises a pioglitazone HCl salt. In still another
particular variation, the pioglitazone in this combination is
administered in a daily dose of between 7.5 and 60 mg. In yet
another particular variation, the pioglitazone in this combination
is administered in a daily dose of between 15 and 45 mg. In a
further variation of each of the above variations, the metformin in
this combination comprises one or more pharmaceutically acceptable
salts thereof. In still a further variation, the metformin in this
combination comprises a metformin HCl salt. In yet a further
variation, the metformin in this combination is administered in a
daily dose of between 125 and 2550 mg. In still a further
variation, the metformin in this combination is administered in a
daily dose of between 250 and 2550 mg.
[0066] In regard to each of the above embodiments and variations
thereof regarding pharmaceutical compositions, Compound I may be
administered as a free base or as a pharmaceutically acceptable
salt thereof. In particular variations, Compound I is administered
as a HCl, methanesulfonate, succinate, benzoate, toluenesulfonate,
R-(-)mandelate or benzenesulfonate salt of Compound I.
[0067] Also in regard to each of the above embodiments and
variations thereof regarding pharmaceutical compositions, the
pharmaceutical composition may optionally be a single dose form
adapted for oral administration, optionally a solid formulation
adapted for oral administration, and optionally a tablet or capsule
adapted for oral administration. The pharmaceutical formulation may
also be an extended release formulation adapted for oral
administration.
[0068] Also in regard to each of the above embodiments and
variations thereof regarding pharmaceutical compositions, the
pharmaceutical composition may be employed to prevent or treat
conditions mediated by DPP-IV such as diabetes and more
particularly, type 2 diabetes mellitus; diabetic dislipidemia;
impaired glucose tolerance (IGT); impaired fasting plasma glucose
(IFG); metabolic acidosis; ketosis; appetite regulation; obesity;
complications associated with diabetes including diabetic
neuropathy, diabetic retinopathy and kidney disease; hyperlipidemia
including hypertriglyceridemia, hypercholesteremia, hypoHDLemia and
postprandial hyperlipidemia; arteriosclerosis; hypertension;
myocardial infarction, angina pectoris, cerebral infarction,
cerebral apoplexy and metabolic syndrome.
[0069] Also in regard to each of the above embodiments and
variations thereof regarding pharmaceutical compositions, the
pharmaceutical composition may optionally be a single dose form
adapted for parenteral (subcutaneous, intravenous, subdermal or
intramuscular) administration, optionally a solution formulation
adapted for parenteral administration, and optionally a suspension
formulation adapted for parenteral administration. The
pharmaceutical formulation may also be an extended release
formulation adapted for oral administration.
[0070] Also provided are kits comprising multiple doses of
pharmaceutical composition according to the present invention.
[0071] In one variation, the kits further comprise instructions
which comprise one or more forms of information selected from the
group consisting of indicating a disease state for which the
pharmaceutical composition is to be administered, storage
information for the pharmaceutical composition, dosing information
and instructions regarding how to administer the pharmaceutical
composition.
[0072] Also provided are articles of manufacture comprising
multiple doses of pharmaceutical composition according to the
present invention. In one variation, the articles of manufacture
further comprise packaging materials such as a container for
housing the multiple doses of the pharmaceutical composition and or
a label indicating one or more members of the group consisting of a
disease state for which the compound is to be administered, storage
information, dosing information and/or instructions regarding how
to administer the composition.
[0073] It is noted in regard to all of the above embodiments that
the embodiments should be interpreted as being open ended in the
sense that the methods may comprise further actions beyond those
specified including the administration of other pharmaceutically
active materials to a patient. Similarly, unless otherwise
specified, the pharmaceutical compositions, kits and articles of
manufacture may further include other materials including other
pharmaceutically active materials.
BRIEF DESCRIPTION OF THE FIGURE
[0074] FIG. 1 illustrates DPP IV inhibition in plasma after a
single oral administration of Compound I in monkey.
DEFINITIONS
[0075] Unless otherwise stated, the following terms used in the
specification and claims shall have the following meanings for the
purposes of this application.
[0076] "Disease" specifically includes any unhealthy condition of
an animal or part thereof and includes an unhealthy condition that
may be caused by, or incident to, medical or veterinary therapy
applied to that animal, i.e., the "side effects" of such
therapy.
[0077] "Pharmaceutically acceptable" means that which is useful in
preparing a pharmaceutical composition that is generally safe,
non-toxic and neither biologically nor otherwise undesirable and
includes that which is acceptable for veterinary use as well as
human pharmaceutical use.
[0078] "Pharmaceutically acceptable salts" means salts which are
pharmaceutically acceptable, as defined above, and which possess
the desired pharmacological activity. Such salts include, but are
not limited to, acid addition salts formed with inorganic acids
such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, phosphoric acid, and the like; or with organic acids such as
acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid,
heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic
acid, lactic acid, malonic acid, succinic acid, malic acid, maleic
acid, fumaric acid, tartaric acid, citric acid, benzoic acid,
o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic
acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,
p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,
p-toluenesulfonic acid, camphorsulfonic acid,
4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic
acid, 4,4'-methylenebis(3-hydroxy-2-ene-1-carboxylic acid),
3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic
acid, lauryl sulfuric acid, gluconic acid, glutamic acid,
hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid
and the like.
[0079] Pharmaceutically acceptable salts also include, but are not
limited to, base addition salts which may be formed when acidic
protons present are capable of reacting with inorganic or organic
bases. Acceptable inorganic bases include, but are not limited to,
sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum
hydroxide and calcium hydroxide. Acceptable organic bases include,
but are not limited to, ethanolamine, diethanolamine,
triethanolamine, tromethamine, N-methylglucamine and the like.
[0080] "Therapeutically effective amount" means that amount of a
compound which, when administered to an animal for treating a
disease, is sufficient to effect such treatment for the
disease.
[0081] "Treatment" or "treating" means any administration of a
therapeutically effective amount of a compound and includes:
[0082] (1) preventing the disease from occurring in an animal which
may be predisposed to the disease but does not yet experience or
display the pathology or symptomatology of the disease,
[0083] (2) inhibiting the disease in an animal that is experiencing
or displaying the pathology or symptomatology of the disease (i.e.,
arresting further development of the pathology and/or
symptomatology), or
[0084] (3) ameliorating the disease in an animal that is
experiencing or displaying the pathology or symptomatology of the
disease (i.e., reversing the pathology and/or symptomatology).
DETAILED DESCRIPTION OF THE INVENTION
1.
2-[6-(3-AMINO-PIPERIDIN-1-YL)-3-METHYL-2,4-DIOXO-3,4-DIHYDRO-2H-PYRIMID-
IN-1-YLMETHYL]-4-FLUORO-BENZONITRILE and Compositions thereof
[0085] The present invention relates generally to the
administration of
2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-
-1-ylmethyl]-4-fluoro-benzonitrile (referred to herein as "Compound
I") whose structure is provided below. ##STR1##
[0086] Example 1 describes one method for synthesizing Compound I.
It is noted that other methods for synthesizing Compound I may be
used as would be appreciated to one of ordinary skill in the
art.
[0087] Compound I may be administered in its free base form and may
also be administered in the form of salts, hydrates and prodrugs
that are converted in vivo into the free base form of Compound I.
For example, it is within the scope of the present invention to
administer Compound I as a pharmaceutically acceptable salt derived
from various organic and inorganic acids and bases in accordance
with procedures well known in the art. As used herein, Compound I
is intended to encompass salts, hydrates and prodrugs of Compound I
unless otherwise specified.
[0088] A pharmaceutically acceptable salt of Compound I preferably
confers improved pharmacokinetic properties as compared to the free
base form Compound I. Pharmaceutically acceptable salts may also
initially confer desirable pharmacokinetic properties on Compound I
that it did not previously possess, and may even positively affect
the pharmacodynamics of the compound with respect to its
therapeutic activity in the body.
[0089] Particular examples of salts, hydrates and prodrugs of
Compound I include, but are not limited to salt forms formed by
inorganic or organic acids, e.g., hydrohalides such as
hydrochloride, hydrobromide, hydroiodide; other mineral acids and
their corresponding salts such as sulfate, nitrate, phosphate,
etc.; alkyl and monoarylsulfonates such as ethanesulfonate,
toluenesulfonate and benzenesulfonate; and other organic acids and
their corresponding salts such as acetate, trifluoroacetate,
tartrate, maleate, succinate, citrate, benzoate, salicylate and
ascorbate. Further acid addition salts include, but are not limited
to: adipate, alginate, arginate, aspartate, bisulfate, bisulfite,
bromide, butyrate, camphorate, camphorsulfonate, caprylate,
chloride, chlorobenzoate, cyclopentanepropionate, digluconate,
dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, fumarate,
galacterate (from mucic acid), galacturonate, glucoheptaoate,
gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate,
heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate,
iso-butyrate, lactate, lactobionate, malate, malonate, mandelate,
metaphosphate, methanesulfonate, methylbenzoate,
monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate,
oxalate, oleate, pamoate, pectinate, persulfate, phenylacetate,
3-phenylpropionate, phosphate, phosphonate and phthalate.
[0090] In particular variations, Compound I is administered as a
HCl, methanesulfonate, succinate, benzoate, toluenesulfonate,
R-(-)mandelate or benzenesulfonate salt of Compound I. Example 1
describes the preparation of the succinate salt form of Compound
I.
2. Administration and Use of Compound I
[0091] The present invention relates generally to a method
comprising administering Compound I to a patient at a daily dose of
between 1 mg/day and 250 mg/day of Compound I to a patient,
optionally between 2.5 mg and 200 mg of Compound I, optionally
between 2.5 mg and 150 mg of Compound I, and optionally between 5
mg and 100 mg of Compound I (in each instance based on the
molecular weight of the free base form of Compound I). Specific
dosage amounts that may be used include, but are not limited to 2.5
mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg and 100 mg of
Compound I per day. It is noted that unless otherwise specifically
specified, Compound I may be administered in its free base form or
as a pharmaceutically acceptable salt. However, the dosage amounts
and ranges provided herein are always based on the molecular weight
of the free base form of Compound I.
[0092] The present invention also relates to a method comprising
administering Compound I to a patient at a once per week dose of
between 1 mg/day and 250 mg/day of Compound I, optionally between
10 mg and 200 mg of Compound I, optionally between 10 mg and 150 mg
of Compound I, and optionally between 10 mg and 100 mg of Compound
I (in each instance based on the molecular weight of the free base
form of Compound I). Specific dosage amounts that may be used
include, but are not limited to 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20
mg, 25 mg, 50 mg, 75 mg and 100 mg of Compound I per week on a
once-per-week regimen. It is noted that unless otherwise
specifically specified, Compound I may be administered in its free
base form or as a pharmaceutically acceptable salt. However, the
dosage amounts and ranges provided herein are always based on the
molecular weight of the free base form of Compound I.
[0093] Compound I may be administered by any route of
administration. In particular embodiments, however, the method of
the present invention is practiced by administering Compound I
orally. This type of administration is advantageous in that it is
easy and may be self-administered by the patient.
[0094] Compound I may be administered one or more times per day. An
advantage of the present invention, however, is that Compound I can
be effectively administered at the dosage levels specified herein
one time per day and may also be administered as a single dosage
form one time a day. By being able to administer Compound I at the
dosage levels specified herein only one time per day and orally, it
is easier for patients to self-administer Compound I, thus
improving the compliance of usage among patients requiring in vivo
inhibition of DPP-IV activity.
[0095] Advantageously, Compound I is suitable for prolonged
continuous use and may be administered to patients for an extended
period of time. Accordingly, the method may be performed where
Compound I is administered to a patient each day (optionally 1 time
daily) for a period of at least 1 month, optionally for at least 3
months, and, if necessary, optionally for the duration of the
patients disease profile. Because of the long acting DPP-IV
inhibitory affects of Compound I, it is envisioned that a dosing
regiment less frequent than once per day may be employed.
[0096] Advantageously, Compound I may be administered at any time
during the day. Optionally, Compound I is administered daily one
time a day where administration occurs in the morning before meals.
Because Compound I can stimulate insulin secretion when blood
glucose level reaches levels above 100 mg/dl, it may be beneficial
to have Compound I in systemic circulation before an elevation in
blood glucose levels occurs postprandially.
[0097] Compound I may be administered to any patient who would
benefit from a course of treatment leading to the reduction of in
vivo DPP-IV activity. FIG. 1 illustrates and Example 3 describes
the observed effect that administering Compound I has on monkey
plasma DPPIV activity after a single oral administration.
[0098] As can be seen from the data shown in FIG. 1, by
administering Compound I one time per day at the dosage levels
specified herein, Compound I can be effectively used relative to
disease states where it is desired to reduce plasma DPPIV activity.
In view of the data presented, it is believed that when at least
2.5 mg of Compound I is administered to a patient, the patient's
plasma DPPIV activity may be reduced by greater than 60% relative
to baseline for a period of at least at least 6 hours, 12 hours, 18
hours and even 24 hours following administration.
[0099] Examples of particular applications for administering
Compound I include, but are not limited to the prevention, delay of
progression, and/or treatment of conditions mediated by DPP-IV, in
particular diabetes and more particularly, type 2 diabetes
mellitus, diabetic dislipidemia, impaired glucose tolerance (IGT),
impaired fasting plasma glucose (IFG), metabolic acidosis, ketosis,
appetite regulation, obesity and complications associated with
diabetes including diabetic neuropathy, diabetic retinopathy,
inflammatory bowel disease, Crohn's disease, chemotherapy-induced
enteritis, oral mucositis, Shorthened Bowel Syndrome and kidney
disease. The conditions mediated by DPP-IV further includes
hyperlipidemia such as hypertriglyceridemia, hypercholesteremia,
hypoHDLemia and postprandial hyperlipidemia; arteriosclerosis;
hypertension; myocardial infarction, angina pectoris, cerebral
infarction, cerebral apoplexy and metabolic syndrome.
[0100] It is believed that administration of Compound I to type I
or type II diabetic patients following a minimum treatment of at
least 30 days will improve one or more cardiovascular measurements.
Examples of cardiac measurements that may be improved include, but
are not limited to a decrease in mean systolic blood pressure, an
increase in HDL cholesterol, improvement in LDL/HDL ratio and a
reduction in triglycerides.
[0101] It is also believed that administration of Compound I in
combination with one or more antidiabetic compounds to type I or
type II diabetic patients following a minimum treatment of at least
30 days will improve one or more cardiovascular measurements.
Examples of cardiac measurements that may be improved include, but
are not limited to a decrease in mean systolic blood pressure, an
increase in HDL cholesterol, improvement in LDL/HDL ratio and a
reduction in triglycerides.
[0102] It is also believed that administration of Compound I in
combination with one or more antidiabetic or incretin compounds to
patients with gastrointestinal inflammatory disorders (including,
but not be limited to inflammatory bowel disease, Crohn's disease,
chemotherapy-induced enteritis, oral mucositis and Shortened Bowel
Syndrome) following a minimum treatment of at least 30 days will
improve the health of the mucosal lining of the gastrointestinal
tract. Improvement in the health of the mucosal lining of the
gastrointestinal tract may be demonstrated by, but is not limited
to, an increase in the intestinal surface area, reduced
inflammation, and/or increases in absorption of nutrients.
[0103] In one variation, Compound I is administered to a patient
with type 2 diabetes. Patients receiving Compound I may also have a
malfunction in insulin secretion from pancreatic islets rather than
patients who have developed insulin resistance in peripheral
insulin sensitive tissues/organs.
[0104] Advantageously, administering Compound I one time per day,
or one time per week, at the dosage levels specified herein may
also be used to treat patients who are prediabetic. It is believed
that administering Compound I in a patient who is prediabetic
serves to delay development of type II diabetes in that patient.
Sustained increase in blood glucose desensitizes pancreatic islet
function and impairs insulin secretion. By improving cyclic AMP
levels and the calcium dynamics in beta cells, the cells activate
genes repairing damaged cell components and are less vulnerable to
glucose toxicity.
[0105] Administering Compound I one time per day, or one time per
week, at the dosage levels specified herein is expected to have a
range of desirous biological effects in vivo. For example,
administering Compound I one time per day, or one time per week, at
the dosage levels specified herein reduces the patient's blood
glucose level when compared with placebo control. Such a decrease
in postprandial blood glucose levels helps diabetic patients to
maintain lower glucose levels.
[0106] Administering Compound I one time per day, or one time per
week, at the dosage levels specified herein is also expected to
have the affect of increasing the patient's insulin level or
insulin sensitivity. Insulin facilitates entry of glucose into
muscle, adipose and several other tissues. The mechanism by which
cells can take up glucose is by facilitated diffusion through
stimulation of insulin receptor. C-peptide and insulin are protein
chains created by the activation and division of proinsulin (an
inactive precursor to insulin). C-peptide and insulin are created
and stored in the beta cells of the pancreas. When insulin is
released into the bloodstream, equal amounts of C-peptide also are
released. This makes C-peptide useful as a marker of insulin
production. Administering Compound I according to the present
invention is expected to increase the patient's C-peptide
level.
[0107] Administering Compound I one time per day at the dosage
levels specified herein is also expected to have the affect of
decreasing the patient's hemoglobin A1c level by greater than 0.5%
when compared to placebo control after extended treatment with
Compound I. Further, administering Compound I one time per week at
the dosage levels specified herein is also expected to have the
affect of decreasing the patient's hemoglobin A1c level by greater
than 0.2% when compared to placebo control after extended treatment
with Compound I. Hb-A1c values are known to be directly
proportional to the concentration of glucose in the blood over the
life span of the red blood cells. Hb-A1c thus gives an indication
of a patient's blood glucose levels over the previous last 90 days,
skewed to the most recent 30 days. The observed reduction in the
patient's hemoglobin A1c level thus verifies the sustained
reduction in the patient's blood glucose levels as a result of
administering Compound I one time per day at the dosage levels
specified herein.
3. Combination Therapy Including Compound I
[0108] The present invention also relates to the use of Compound I
in combination with one or more other antidiabetic and/or incretin
compounds. Examples of such other antidiabetic compounds include,
but are not limited to insulin signaling pathway modulators, like
protein tyrosine phosphatase (PTPase) inhibitors, and
glutamine-fructose-6-phosphate amidotransferase (GFAT) inhibitors;
compounds influencing a dysregulated hepatic glucose production,
like glucose-6-phosphatase (G6 Pase) inhibitors,
fructose-1,6-bisphosphatase (F-1,6-BPase) inhibitors, glycogen
phosphorylase (GP) inhibitors, glucagon receptor antagonists and
phosphoenolpyruvate carboxykinase (PEPCK) inhibitors; pyruvate
dehydrogenase kinase (PDHK) inhibitors; insulin sensitivity
enhancers (insulin sensitizers); insulin secretion enhancers
(insulin secretagogues); alpha-glucosidase inhibitors; inhibitors
of gastric emptying; glucokinase activators, GLP-1 receptor
agonists, GLP-2 receptor agonists, UCP modulators, RXR modulators,
GSK-3 inhibitors, PPAR modulators, metformin, insulin; and
.alpha..sub.2-adrenergic antagonists. Compound I may be
administered with such at least one other antidiabetic compound
either simultaneously as a single dose, at the same time as
separate doses, or sequentially (i.e., where one is administered
before or after the other is administered).
[0109] Examples of PTPase inhibitors that may be used in
combination with Compound I include, but are not limited to those
disclosed in U.S. Pat. Nos. 6,057,316, 6,001,867, and PCT
Publication Nos. WO 99/58518, WO 99/58522, WO 99/46268, WO
99/46267, WO 99/46244, WO 99/46237, WO 99/46236, and WO
99/15529.
[0110] Examples of GFAT inhibitors that may be used in combination
with Compound I include, but are not limited to those disclosed in
Mol. Cell. Endocrinol. 1997, 135(1), 67-77.
[0111] Examples of G6 Pase inhibitors that may be used in
combination with Compound I include, but are not limited to those
disclosed in PCT Publication Nos. WO 00/14090, WO 99/40062 and WO
98/40385, European Patent Publication No. EP682024 and Diabetes
1998, 47, 1630-1636.
[0112] Examples of F-1,6-BPase inhibitors that may be used in
combination with Compound I include, but are not limited to those
disclosed in PCT Publication Nos. WO 00/14095, WO 99/47549, WO
98/39344, WO 98/39343 and WO 98/39342.
[0113] Examples of GP inhibitors that may be used in combination
with Compound I include, but are not limited to those disclosed in
U.S. Pat. No. 5,998,463, PCT Publication Nos. WO 99/26659, WO
97/31901, WO 96/39384 and WO 9639385 and European Patent
Publication Nos. EP 978279 and EP 846464.
[0114] Examples of glucagon receptor antagonists that may be used
in combination with Compound I include, but are not limited to
those disclosed in U.S. Pat. Nos. 5,880,139 and 5,776,954, PCT
Publication Nos. WO 99/01423, WO 98/22109, WO 98/22108, WO
98/21957, WO 97/16442 and WO 98/04528 and those described in Bioorg
Med. Chem. Lett 1992, 2, 915-918, J. Med. Chem. 1998, 41,
5150-5157, and J. Biol. Chem. 1999, 274; 8694-8697.
[0115] Examples of PEPCK inhibitors that may be used in combination
with Compound I include, but are not limited to those disclosed in
U.S. Pat. No. 6,030,837 and Mol. Biol. Diabetes 1994, 2,
283-99.
[0116] Examples of PDHK inhibitors that may be used in combination
with Compound I include, but are not limited to those disclosed in
J. Med. Chem. 42 (1999) 2741-2746.
[0117] Examples of insulin sensitivity enhancers that may be used
in combination with Compound I include, but are not limited to
GSK-3 inhibitors, retinoid X receptor (RXR) agonists, Beta-3 AR
agonists, UCP modulators, antidiabetic thiazolidinediones
(glitazones), non-glitazone type PPAR gamma agonists, dual PPAR
gamma/PPAR alpha agonists, antidiabetic vanadium containing
compounds and biguanides such as metformin.
[0118] Examples of GSK-3 inhibitors include, but are not limited to
those disclosed in PCT Publication Nos. WO 00/21927 and WO
97/41854.
[0119] Examples of RXR modulators include, but are not limited to
those disclosed in U.S. Pat. Nos. 4,981,784, 5,071,773, 5,298,429
and 5,506,102 and PCT Publication Nos. WO89/05355, WO91/06677,
WO92/05447, WO93/11235, WO95/18380, WO94/23068, and WO93/23431.
[0120] Examples of Beta-3 AR agonists include, but are not limited
to CL-316,243 (Lederle Laboratories) and those disclosed in U.S.
Pat. No. 5,705,515 and PCT Publication Nos. WO 99/29672, WO
98/32753, WO 98/20005, WO 98/09625, WO 97/46556, and WO
97/37646.
[0121] Examples of UCP modulators include agonists of UCP-1, UCP-2
and UCP-3. Examples of UCP modulators include, but are not limited
to those disclosed in Vidal-Puig et al., Biochem. Biophys. Res.
Commun., Vol. 235(1) pp. 79-82 (1997).
[0122] Examples of antidiabetic, PPAR modulating thiazolidinediones
(glitazones) include, but are not limited to,
(S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6-yl)methyl-thiazolid-
ine-2,4-dione (englitazone),
5-{[4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxo-propyl)-phenyl]-methyl}-thi-
azolidine-2,4-dione (darglitazone),
5-{[4-(1-methyl-cyclohexyl)methoxy)-phenyl]methyl]-thiazolidine-2,4-dione
(ciglitazone),
5-{[4-(2-(1-indolyl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione
(DRF2189),
5-{4-[2-(5-methyl-2-phenyl-4-oxazoly)-ethoxy)]benzyl}-thiazolidine-2,4-di-
one (BM-13.1246), 5-(2-naphthylsulfonyl)-thiazolidine-2,4-dione
(AY-31637), bis
{4-[(2,4-dioxo-5-thiazolidinyl)-methyl]phenyl}methane (YM268),
5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-hydroxyethoxy]-benzyl}--
thiazolidine-2,4-dione (AD-5075),
5-[4-(1-phenyl-1-cyclopropanecarbonylamino)-benzyl]-thiazolidine-2,4-dion-
e (DN-108)
5-{[4-(2-(2,3-dihydroindol-1-yl)ethoxy)phenylmethyl)-thiazolidi-
ne-2,4-dione,
5-[3-(4-chloro-phenyl])-2-propynyl]-5-phenylsulfonyl)thiazolidine-2,4-dio-
ne,
5-[3-(4-chlorophenyl])--2-propynyl]-5-(4-fluorophenyl-sulfonyl)thiazol-
idine-2,4-dione,
5-{[4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}-thiazolidine-2,-
4-dione (rosiglitazone),
5-{[4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl}-thiazolidine-2,4-dione
(pioglitazone; marketed under the trademark ACTOS.TM.),
5-[6-(2-fluoro-benzyloxy)-naphthalen-2-ylmethyl]-thiazolidine-2,4-dione
(MCC555),
5-([2-(2-naphthyl)-benzoxazol-5-yl]-methyl}thiazolidine-2,4-dio- ne
(T-174), edaglitazone (BM-13-1258), rivoglitazone (CS-011), and
5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-(4-trifluoromethyl-benzyl-
)benzamide (KRP297).
[0123] Examples of non-glitazone type PPAR gamma agonists include,
but are not limited to N-(2-benzoylphenyl)-L-tyrosine analogues,
such as GI-262570, reglixane (JTT501) and FK-614 and metaglidasen
(MBX-102).
[0124] Examples of dual PPAR gamma/PPAR alpha agonists include, but
are not limited to omega.-[(oxoquinazolinylalkoxy)phenyl]alkanoates
and analogs thereof including those described in PCT Publication
No. WO 99/08501 and Diabetes 2000, 49(5), 759-767; tesaglitazar,
muraglitazar and naveglitazar.
[0125] Examples of antidiabetic vanadium containing compounds
include, but are not limited to those disclosed in the U.S. Pat.
No. 5,866,563.
[0126] Metformin (dimethyldiguanide) and its hydrochloride salt is
marketed under the trademark GLUCOPHAGE.TM..
[0127] Examples of insulin secretion enhancers include but are not
limited to glucagon receptor antagonists (as described above),
sulphonyl urea derivatives, incretin hormones or mimics thereof,
especially glucagon-like peptide-1 (GLP-1) or GLP-1 agonists,
beta-cell imidazoline receptor antagonists, and short-acting
insulin secretagogues, like antidiabetic phenylacetic acid
derivatives, antidiabetic D-phenylalanine derivatives, and
mitiglinide and pharmaceutical acceptable salts thereof.
[0128] Examples of sulphonyl urea derivatives include, but are not
limited to, glisoxepid, glyburide, glibenclamide, acetohexamide,
chloropropamide, glibornuride, tolbutamide, tolazamide, glipizide,
carbutamide, gliquidone, glyhexamide, phenbutamide, tolcyclamide;
glimepiride and gliclazide. Tolbutamide, glibenclamide, gliclazide,
glibornuride, gliquidone, glisoxepid and glimepiride can be
administered in the form that they are marketed under the
trademarks RASTINON HOECHST.TM., AZUGLUCON.TM., DIAMICRONT.TM.,
GLUBORID.TM., GLURENORM.TM., PRO-DIABAN.TM. and AMARYL.TM.,
respectively.
[0129] Examples of GLP-1 agonists include, but are not limited to
those disclosed in U.S. Pat. Nos. 5,120,712, 5,118,666 and
5,512,549, and PCT Publication No. WO 91/11457. In particular,
GLP-1 agonists include those compounds like GLP-1 (7-37) in which
compound the carboxy-terminal amide functionality of Arg.sup.36 is
displaced with Gly at the 37.sup.th position of the GLP-1
(7-36)NH.sub.2 molecule and variants and analogs thereof including
GLN.sup.9-GLP-1 (7-37), D-GLN.sup.9-GLP-1 (7-37), acetyl
LYS.sup.9-GLP-1 (7-37), LYS.sup.18-GLP-1 (7-37) and, in particular,
GLP-1 (7-37)OH, VAL.sup.8-GLP-1 (7-37), GLY.sup.8-GLP-1(7-37),
THR.sup.8-GLP-1 (7-37), GLP-1 (7-37) and
4-imidazopropionyl-GLP-1.
[0130] One particular example of a GLP-1 agonist is Extendatide, a
39-amino acid peptide amide, which is marketed under the trademark
BYETTA.TM.. Exenatide has the empirical formula
C.sub.184H.sub.282N.sub.50O.sub.60S and molecular weight of 4186.6
Daltons. The amino acid sequence for Exenatide is as follows:
H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-
-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-P-
ro-Pro-Ser-NH.sub.2
[0131] Examples of glucagon-like peptide-2 (GLP-2) or GLP-2
agonists include, but are not limited to those disclosed in U.S.
Pat. No. 7,056,886 and PCT Publication Nos. WO 00/53208, WO
01/49314 and WO 03/099854. One particular example of a GLP-2
agonist is TEDUGLUTIDE.TM., a 39-amino acid peptide amide (NPS
Pharmaceuticals, Inc.).
[0132] Examples of beta-cell imidazoline receptor antagonists
include, but are not limited to those described in PCT Publication
No. WO 00/78726 and J. Pharmacol. Exp. Ther. 1996; 278; 82-89.
[0133] An example of an antidiabetic phenylacetic acid derivative
is repaglinide and pharmaceutically acceptable salts thereof.
[0134] Examples of antidiabetic D-phenylalanine derivatives
include, but are not limited to nateglinide
(N-[(trans4-isopropylcyclohexyl)-carbonyl]-D-phenylalanine, EP
196222 and EP 526171) and repaglinide
((S)-2-ethoxy-4-{2-[[3-methy-1-1-[2-(1-piperidinyl)phenyl]butyl]-amino]-2-
-oxoethyl}benzoic acid, EP 0 147 850 A2 and EP 0 207 331 A1).
Nateglinide is intended to include the particular crystal forms
(polymorphs) disclosed in U.S. Pat. No. 5,488,510 and European
Patent Publication No. EP 0526171 B1. Repaglinide and nateglinide
may be administered in the form as they are marketed under the
trademarks NOVONORM.TM. and STARLIX.TM., respectively.
[0135] Examples of alpha-Glucosidase inhibitors include, but are
not limited to, acarbose, N-(1,3-dihydroxy-2-propyl)valiolamine
(voglibose) and the 1-deoxynojirimycin derivative miglitol.
Acarbose is
4'',6''-dideoxy-4'-[(1S)-(1,4,6/5)-4,5,6-trihydroxy-3-hydroxymethyl-2-cyc-
lo-hexenylamino)maltotriose. The structure of acarbose can as well
be described as
O-4,6-dideoxy-4-{[1S,4R,5S,6S]-4,5,6-trihydroxy-3-(hydroxymethyl)-2-cyclo-
hexen-1-yl]-amino)-alpha-D-glucopyranosyl-(1-4)-O-alpha-D-glucopyranosyl-(-
1-4)-D-glucopyranose. (U.S. Pat. No. 4,062,950 and European Patent
Publication No. EP 0 226 121). Acarbose and miglitol may be
administered in the forms that they are marketed under the
trademarks GLUCOBAY.TM. and DIASTABOL 50.TM. respectively.
[0136] Examples of inhibitors of gastric emptying other than GLP-1
include, but are not limited to those disclosed in J. Clin.
Endocrinol. Metab. 2000, 85(3), 1043-1048, and Diabetes Care 1998;
21; 897-893, especially Amylin and analogs thereof such as
pramlintide. Amylin is described in Diabetologia 39, 1996,
492-499.
[0137] Examples of .alpha..sub.2-adrenergic antagonists include,
but are not limited to midaglizole which is described in Diabetes
36, 1987, 216-220. The insulin that may be used in combination with
Compound I include, but are not limited to animal insulin
preparations extracted from the pancreas of bovine and pig; human
insulin preparations genetically synthesized using Escherichia coli
or yeast; zinc insulin; protamine zinc insulin; fragment or
derivative of insulin (e.g., INS-1) and an oral insulin
preparation.
[0138] In one particular embodiment, the antidiabetic compound
administered in combination with Compound I is selected from the
group consisting of nateglinide, mitiglinide, repaglinide,
metformin, extendatide, rosiglitazone, tesaglitazar, pioglitazone,
glisoxepid, glyburide, glibenclamide, acetohexamide,
chloropropamide, glibornuride, tolbutamide, tolazamide, glipizide,
carbutamide, gliquidone, glyhexamide, phenbutamide, tolcyclamide,
glimepiride and gliclazide, including any pharmaceutically
acceptable salts thereof.
[0139] Examples of the preparation and formulation of PTPase
inhibitors, GSK-3 inhibitors, non-small molecule mimetic compounds,
GFAT inhibitors, G6 Pase inhibitors, glucagon receptor antagonists,
PEPCK inhibitors, F-1,6-BPase inhibitors, GP inhibitors, RXR
modulators, Beta-3 AR agonists, PDHK inhibitors, inhibitors of
gastric emptying and UCP modulators are disclosed in the patents,
applications and references provided herein.
[0140] In the case of combination therapy with Compound I, the
other antidiabetic compound may be administered (e.g., route and
dosage form) in a manner known per se for such compound. Compound I
and the other antidiabetic compound may be administered
sequentially (i.e., at separate times) or at the same time, either
one after the other separately in two separate dose forms or in one
combined, single dose form. In one particular embodiment, the other
antidiabetic compound is administered with Compound I as a single,
combined dosage form. The dose of the antidiabetic compound may be
selected from the range known to be clinically employed for such
compound. Any of therapeutic compounds of diabetic complications,
antihyperlipemic compounds, antiobestic compounds or
antihypertensive compounds can be used in combination with Compound
I in the same manner as the above antidiabetic compounds. Examples
of therapeutic compounds of diabetic complications include, but are
not limited to, aldose reductase inhibitors such as tolrestat,
epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat,
CT-112 and ranirestat; neurotrophic factors and increasing
compounds thereof such as NGF, NT-3, BDNF and neurotrophin
production-secretion promoters described in WO01/14372 (e.g.,
4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl-
]oxazole); neuranagenesis stimulators such as Y-128; PKC inhibitors
such as ruboxistaurin mesylate; AGE inhibitors such as ALT946,
pimagedine, N-phenacylthiazolium bromide (ALT766), ALT-711,
EXO-226, pyridorin and pyridoxamine; reactive oxygen scavengers
such as thioctic acid; cerebral vasodilators such as tiapride and
mexiletine; somatostatin receptor agonists such as BIM23190; and
apoptosis signal regulating kinase-1 (ASK-1) inhibitors. Examples
of antihyperlipemic compounds include, but are not limited to,
HMG-CoA reductase inhibitors such as pravastatin, simvastatin,
lovastatin, atorvastatin, fluvastatin, rosuvastatin and
pitavastatin; squalene synthase inhibitors such as compounds
described in WO97/10224 (e.g.,
N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphe-
nyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-ac-
etic acid); fibrate compounds such as bezafibrate, clofibrate,
simfibrate and clinofibrate; ACAT inhibitors such as avasimibe and
eflucimibe; anion exchange resins such as colestyramine; probucol;
nicotinic acid drugs such as nicomol and niceritrol; ethyl
icosapentate; and plant sterols such as soysterol and
.gamma.-oryzanol. Examples of antiobestic compounds include, but
are not limited to, dexfenfluramine, fenfluramine, phentermine,
sibutramine, amfepramone, dexamphetamine, mazindol,
phenylpropanolamine, clobenzorex; MCH receptor antagonists such as
SB-568849 and SNAP-7941; neuropeptide Y antagonists such as
CP-422935; cannabinoid receptor antagonists such as SR-141716 and
SR-147778; ghrelin antagonist; 11.beta.-hydroxysteroid
dehydrogenase inhibitors such as BVT-3498; pancreatic lipase
inhibitors such as orlistat and ATL-962; Beta-3 AR agonists such as
AJ-9677; peptidic anorexiants such as leptin and CNTF (Ciliary
Neurotropic Factor); cholecystokinin agonists such as lintitript
and FPL-15849; and feeding deterrent such as P-57. Examples of the
antihypertensive compounds include angiotensin converting enzyme
inhibitors such as captopril, enalapril and delapril; angiotensin
II antagonists such as candesartan cilexetil, losartan, eprosartan,
valsartan, telmisartan, irbesartan, olmesartan medoxomil,
tasosartan and
1-[[2'-(2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-2-
-ethoxy-1H-benzimidazole-7-carboxylic acid; calcium channel
blockers such as manidipine, nifedipine, nicardipine, amlodipine
and efonidipine; potassium channel openers such as levcromakalim,
L-27152, AL0671 and NIP-121; and clonidine.
[0141] The structure of the active agents identified herein by code
nos., generic or trade names may be taken from the actual edition
of the standard compendium "The Merck Index" or from databases,
e.g. Patents International (e.g. IMS World Publications). The
corresponding content thereof is hereby incorporated by reference.
Any person skilled in the art is fully enabled to identify the
active agents and, based on these references, likewise enabled to
manufacture and test the pharmaceutical indications and properties
in standard test models, both in vitro and in vivo.
4. Compositions Comprising Compound I
[0142] Compound I may be comprised within a pharmaceutical
composition adapted for a variety of routes of administration. For
example, Compound I may be comprised within a pharmaceutical
composition adapted to be administered by a route selected from the
group consisting of orally, parenterally, intraperitoneally,
intravenously, intraarterially, transdermally, sublingually,
intramuscularly, rectally, transbuccally, intranasally,
liposomally, via inhalation, vaginally, intraoccularly, via local
delivery (for example by catheter or stent), subcutaneously,
intraadiposally, intraarticularly, intraperitoneally and
intrathecally. As such, Compound I may be formulated in a variety
of pharmaceutically acceptable compositions including injectable
forms (e.g. subcutaneous, intravenous, intramuscular and
intraperitoneal injections), drip infusions, external application
forms (e.g. nasal spray preparations, transdermal preparations;
ointments, etc.), and suppositories (e.g. rectal and vaginal
suppositories). These different pharmaceutically acceptable
compositions can be manufactured by known techniques conventionally
used in the pharmaceutical industry with a pharmaceutically
acceptable carrier conventionally used in the pharmaceutical
industry.
[0143] As used herein, a composition comprising Compound I is
intended to encompass the free base form of Compound I, salts,
hydrates and prodrugs of Compound I, as well as other materials
that may be included in such composition for its intended purpose,
including other active ingredients, unless otherwise specified.
Particular salt forms of Compound I that may be employed include,
but are not limited to, the HCl, methanesulfonate, succinate,
benzoate, toluenesulfonate, R-(-)mandelate or benzenesulfonate salt
forms of Compound I. As noted above, Compound I may advantageously
be used when administered to a patient at a daily dose of between 1
mg/day and 250 mg/day of Compound I to a patient, optionally
between 2.5 mg and 200 mg of Compound I, optionally between 2.5 mg
and 150 mg of Compound I, and optionally between 5 mg and 100 mg of
Compound I (in each instance based on the molecular weight of the
free base form of Compound I). Specific dosage amounts that may be
used include, but are not limited to 2.5 mg, 5 mg, 6.25 mg, 10 mg,
20 mg, 25 mg, 50 mg, 75 mg and 100 mg of Compound I per day. As
also noted above, it is desirable for Compound I to be administered
one time per day. Accordingly, pharmaceutical compositions of the
present invention may be in the form of a single dose form
comprising between 1 mg/day and 250 mg/day of Compound I,
optionally between 2.5 mg and 200 mg of Compound I, optionally
between 2.5 mg and 150 mg of Compound I, and optionally between 5
mg and 100 mg of Compound I. In specific embodiments, the
pharmaceutical composition comprises 2.5 mg, 5 mg, 6.25 mg, 10 mg,
20 mg, 25 mg, 50 mg, 75 mg or 100 mg of Compound I.
[0144] As also noted above, Compound I may advantageously be used
when administered orally. Accordingly, the compositions of the
present invention may optionally be adapted for oral
administration. In one variation, such pharmaceutical composition
is a solid formulation adapted for oral administration. In this
regard, the composition, for example, may be in the form of a
tablet or capsule. Example 2 provides examples of solid
formulations comprising Compound I adapted for oral administration.
In another variation, such pharmaceutical composition is a liquid
formulation adapted for oral administration.
[0145] As also noted above, Compound I may advantageously be used
when administered parenterally. Accordingly, the compositions of
the present invention may optionally be adapted for parenteral
administration. In one variation, such pharmaceutical composition
is a solution formulation adapted for parenteral administration. In
another variation, such pharmaceutical composition is a suspension
formulation adapted for parenteral administration.
[0146] As noted above, Compound I may advantageously be used in
combination with one or more other antidiabetic and/or incretin
compounds. Accordingly, the compositions of the present invention
may optionally comprises Compound I in combination with one or more
other antidiabetic or incretin compounds in a combined, single dose
form.
[0147] Optionally, such combined, single dose form comprising
Compound I in combination with one or more other antidiabetic
and/or incretin compounds is adapted for oral administration and
optionally is a solid oral dose form. Alternatively, such combined,
single dose form comprising Compound I in combination with one or
more other antidiabetic and/or incretin compounds can be adapted
for parenteral administration and optionally is a solution dose
form.
[0148] In one variation, such combined, single dose form comprising
Compound I in combination with one or more other antidiabetic
compounds comprises between 1 mg/day and 250 mg/day of Compound I
to a patient, optionally between 2.5 mg and 200 mg of Compound I,
optionally between 2.5 mg and 150 mg of Compound I, and optionally
between 5 mg and 100 mg of Compound I (in each instance based on
the molecular weight of the free base form of Compound I). In
specific embodiments, such combined, single dose form comprising
Compound I in combination with one or more other antidiabetic
compounds comprises 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50
mg, 75 mg, and 100 mg of Compound I.
[0149] Any antidiabetic compound, or set of antidiabetic compounds
may be combined with Compound I to form such combined, single dose
form. In particular embodiments, such combined, single dose form
includes Compound I and one or more members of the group consisting
of insulin signaling pathway modulators, like protein tyrosine
phosphatase (PTPase) inhibitors, and glutamine-fructose-6-phosphate
amidotransferase (GFAT) inhibitors, compounds influencing a
dysregulated hepatic glucose production, like glucose-6-phosphatase
(G6 Pase) inhibitors, fructose-1,6-bisphosphatase (F-1,6-BPase)
inhibitors, glycogen phosphorylase (GP) inhibitors, glucagon
receptor antagonists and phosphoenolpyruvate carboxykinase (PEPCK)
inhibitors, pyruvate dehydrogenase kinase (PDHK) inhibitors,
insulin sensitivity enhancers (insulin sensitizers), insulin
secretion enhancers (insulin secretagogues), alpha-glucosidase
inhibitors, inhibitors of gastric emptying, glucokinase activators,
GLP-1 receptor agonists, GLP-2 receptor agonists, UCP modulators,
RXR modulators, GSK-3 inhibitors, PPAR modulators, metformin,
insulin, and .alpha..sub.2-adrenergic antagonists. Compound I may
be administered with such at least one other antidiabetic compound
either simultaneously as a single dose, at the same time as
separate doses, or sequentially (i.e., where on is administered
before or after the other is administered).
[0150] In one variation, such combined, single dose form comprises
Compound I and an antidiabetic thiazolidinedione. Particular
examples of thiazolidinediones that may be used in this variation
include, but are not limited to
(S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6-yl)methyl-thiazolid-
ine-2,4-dione (englitazone),
5-{[4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxo-propyl)-phenyl]-methyl}-thi-
azolidine-2,4-dione (darglitazone),
5-{[4-(1-methyl-cyclohexyl)methoxy)-phenyl]methyl}-thiazolidine-2,4-dione
(ciglitazone),
5-{[4-(2-(1-indolyl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione
(DRF2189),
5-{4-[2-(5-methyl-2-phenyl-4-oxazoly)-ethoxy)]benzyl}-thiazolidine-2,4-di-
one (BM-13.1246), 5-(2-naphthylsulfonyl)-thiazolidine-2,4-dione
(AY-31637),
bis{4-[(2,4-dioxo-5-thiazolidinyl)-methyl]phenyl}methan-e (YM268),
5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-hydroxyethoxy]-benzyl}--
thiazolidine-2,4-dione (AD-5075),
5-[4-(1-phenyl-1-cyclopropanecarbonylamino)-benzyl]-thiazolidine-2,4-dion-
e (DN-108)
5-{[4-(2-(2,3-dihydroindol-1-yl)ethoxy)phenylmethyl)-thiazolidi-
ne-2,4-dione,
5-[3-(4-chloro-phenyl])-2-propynyl]-5-phenylsulfonyl)thiazolidine-2,4-dio-
ne,
5-[3-(4-chlorophenyl])-2-propynyl]-5-(4-fluorophenyl-sulfonyl)thiazoli-
dine-2,4-dione,
5-{[4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}-thiazolidine-2,-
4-dione (rosiglitazone),
5-{[4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl}-thiazolidine-2,4-dione
(pioglitazone),
5-[6-(2-fluoro-benzyloxy)-naphthalen-2-ylmethyl]-thiazolidine-2,4-dione
(MCC555),
5-([2-(2-naphthyl)-benzoxazol-5-yl]-methyl}thiazolidine-2,4-dio- ne
(T-174), edaglitazone (BM-13-1258), rivoglitazone (CS-011) and
5-(2,4-dioxothiazolidin-5-ylmethyl)-2-met-hoxy-N-(4-trifluoromethyl-benzy-
l)benzamide (KRP297).
[0151] In one particular variation, the thiazolidinedione in such
combined, single dose form is
5-{[4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl}-thiazolidine-2,4-dione
(pioglitazone) and its hydrochloride salt which is marketed under
the trademark ACTOS.TM..
[0152] In another particular variation, the thiazolidinedione is
5-{[4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}-thiazolidine-2,-
4-dione (rosiglitazone) and its maleate salt.
[0153] In another variation, such combined, single dose form
comprises Compound I and a non-glitazone type PPAR gamma
agonist.
[0154] In another variation, such combined, single dose form
comprises Compound I and a biguanide. A particular example of a
biguanide that may be used in this variation is Metformin
(dimethyldiguanide) and its hydrochloride salt which is marketed
under the trademark GLUCOPHAGE.TM..
[0155] In another variation, such combined, single dose form
comprises Compound I and a sulphonyl urea derivative. Particular
examples of sulphonyl urea derivatives that may be used in this
variation include, but are not limited to glisoxepid, glyburide,
glibenclamide, acetohexamide, chloropropamide, glibornuride,
tolbutamide, tolazamide, glipizide, carbutamide, gliquidone,
glyhexamide, phenbutamide, tolcyclamide; glimepiride and
gliclazide. Tolbutamide, glibenclamide, gliclazide, glibornuride,
gliquidone, glisoxepid and glimepiride can be administered in the
form as they are marketed under the trademarks RASTINON
HOECHST.TM., AZUGLUCON.TM., DIAMICRONT.TM., GLUBORID.TM.,
GLURENORM.TM., PRO-DIABAN.TM. and AMARYL.TM., respectively.
[0156] In another variation, such combined, single dose form
comprises Compound I and an antidiabetic D-phenylalanine
derivative. Particular examples of antidiabetic D-phenylalanine
derivatives that may be used in this variation include, but are not
limited to repaglinide and nateglinide which may be administered in
the form as they are marketed under the trademarks NOVONORM.TM. and
STARLIX.TM., respectively.
[0157] In another variation, such combined, single dose form
comprises Compound I and an alpha-Glucosidase inhibitor. Particular
examples of alpha-Glucosidase inhibitors that may be used in this
variation include, but are not limited to acarbose, miglitol and
voglibose which may be administered in the form as they are
marketed under the trademarks GLUCOBAY.TM., DIASTABOL 50.TM. and
BASEN.TM., respectively.
[0158] In one particular embodiment, the antidiabetic compound
administered in combination with Compound I in such combined,
single dose form is selected from the group consisting of
nateglinide, repaglinide, metformin, extendatide, rosiglitazone,
pioglitazone, glisoxepid, glyburide, glibenclamide, acetohexamide,
chloropropamide, glibornuride, tolbutamide, tolazamide, glipizide,
carbutamide, gliquidone, glyhexamide, phenbutamide, tolcyclamide,
glimepiride and gliclazide, including any pharmaceutically
acceptable salts thereof.
[0159] In regard to each of the above embodiments and variations
regarding a combined, single dose form comprising the combination
of Compound I and one or more other antidiabetic compounds, the
pharmaceutical composition may optionally be adapted for oral
administration and in this regard may optionally be a solid
formulation such as a tablet or capsule or may alternatively be in
a liquid formulation adapted for oral administration. The dose of
the antidiabetic compound may be selected from the range known to
be clinically employed for such compound. Any of therapeutic
compounds of diabetic complications, antihyperlipemic compounds,
antiobestic compounds or antihypertensive compounds can be used in
combination with Compound I in the same manner as the above
antidiabetic compounds. Examples of therapeutic compounds of
diabetic complications include, but are not limited to, aldose
reductase inhibitors such as tolrestat, epalrestat, zenarestat,
zopolrestat, minalrestat, fidarestat, CT-112 and ranirestat;
neurotrophic factors and increasing compounds thereof such as NGF,
NT-3, BDNF and neurotrophin production-secretion promoters
described in WO01/14372 (e.g.,
4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl-
]oxazole); neuranagenesis stimulators such as Y-128; PKC inhibitors
such as ruboxistaurin mesylate; AGE inhibitors such as ALT946,
pimagedine, N-phenacylthiazolium bromide (ALT766), ALT-711,
EXO-226, pyridorin and pyridoxamine; reactive oxygen scavengers
such as thioctic acid; cerebral vasodilators such as tiapride and
mexiletine; somatostatin receptor agonists such as BIM23190; and
apoptosis signal regulating kinase-1 (ASK-1) inhibitors. Examples
of antihyperlipemic compounds include, but are not limited to,
HMG-CoA reductase inhibitors such as pravastatin, simvastatin,
lovastatin, atorvastatin, fluvastatin, rosuvastatin and
pitavastatin; squalene synthase inhibitors such as compounds
described in WO97/10224 (e.g.,
N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphe-
nyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-ac-
etic acid); fibrate compounds such as bezafibrate, clofibrate,
simfibrate and clinofibrate; ACAT inhibitors such as avasimibe and
eflucimibe; anion exchange resins such as colestyramine; probucol;
nicotinic acid drugs such as nicomol and niceritrol; ethyl
icosapentate; and plant sterols such as soysterol and
.gamma.-oryzanol. Examples of antiobestic compounds include, but
are not limited to, dexfenfluramine, fenfluramine, phentermine,
sibutramine, amfepramone, dexamphetamine, mazindol,
phenylpropanolamine, clobenzorex; MCH receptor antagonists such as
SB-568849 and SNAP-7941; neuropeptide Y antagonists such as
CP-422935; cannabinoid receptor antagonists such as SR-141716 and
SR-147778; ghrelin antagonist; 11.beta.-hydroxysteroid
dehydrogenase inhibitors such as BVT-3498; pancreatic lipase
inhibitors such as orlistat and ATL-962; Beta-3 AR agonists such as
AJ-9677; peptidic anorexiants such as leptin and CNTF (Ciliary
Neurotropic Factor); cholecystokinin agonists such as lintitript
and FPL-15849; and feeding deterrent such as P-57. Examples of the
antihypertensive compounds include angiotensin converting enzyme
inhibitors such as captopril, enalapril and delapril; angiotensin
II antagonists such as candesartan cilexetil, losartan, eprosartan,
valsartan, telmisartan, irbesartan, olmesartan medoxomil,
tasosartan and
1-[[2'-(2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-2-
-ethoxy-1H-benzimidazole-7-carboxylic acid; calcium channel
blockers such as manidipine, nifedipine, nicardipine, amlodipine
and efonidipine; potassium channel openers such as levcromakalim,
L-27152, AL0671 and NIP-121; and clonidine.
5. Kits and Articles of Manufacture Comprising Compound I
[0160] The present invention also relates to kits comprising a
pharmaceutical composition according to the present invention
comprising Compound I (and optionally one or more other
antidiabetic compounds) where such kit further comprises
instructions that include one or more forms of information selected
from the group consisting of indicating a disease state for which
the pharmaceutical composition is to be administered, storage
information for the pharmaceutical composition, dosing information
and instructions regarding how to administer the pharmaceutical
composition. The kit may also comprise packaging materials. The
packaging material may also comprise a container for housing the
pharmaceutical composition. The container may optionally comprise a
label indicating the disease state for which the pharmaceutical
composition is to be administered, storage information, dosing
information and/or instructions regarding how to administer the
composition. The kit may also comprise additional components for
storage or administration of the composition. The kit may also
comprise the composition in single or multiple dose forms.
[0161] In one embodiment, the pharmaceutical composition in the kit
comprises multiple doses of a pharmaceutical composition according
to the present invention wherein such pharmaceutical composition is
a single dose form that comprises Compound I in one of the dosage
ranges specified herein.
[0162] In another embodiment, the pharmaceutical composition in the
kit comprises multiple doses of a pharmaceutical composition
according to the present invention wherein such pharmaceutical
composition is a single dose form that comprises Compound I and one
or more of the other antidiabetic compounds specified herein.
[0163] The present invention also relates to articles of
manufacture comprising a pharmaceutical composition according to
the present invention comprising Compound I (and optionally one or
more other antidiabetic compounds) where such articles of
manufacture further comprise packaging materials. In one variation,
the packaging material comprises a container for housing the
composition. In another variation, the invention provides an
article of manufacture where the container comprises a label
indicating one or more members of the group consisting of a disease
state for which the composition is to be administered, storage
information, dosing information and/or instructions regarding how
to administer the composition.
[0164] In one embodiment, the pharmaceutical composition in the
article of manufacture comprises multiple doses of a pharmaceutical
composition according to the present invention wherein such
pharmaceutical composition is a single dose form that comprises
Compound I in one of the dosage ranges specified herein.
[0165] In another embodiment, the pharmaceutical composition in the
article of manufacture comprises multiple doses of a pharmaceutical
composition according to the present invention wherein such
pharmaceutical composition is a single dose form that comprises
Compound I and one or more of the other antidiabetic compounds
specified herein.
[0166] It is noted that the packaging material used in kits and
articles of manufacture according to the present invention may form
a plurality of divided containers such as a divided bottle or a
divided foil packet. The container can be in any conventional shape
or form as known in the art which is made of a pharmaceutically
acceptable material, for example a paper or cardboard box, a glass
or plastic bottle or jar, a re-sealable bag (for example, to hold a
"refill" of tablets for placement into a different container), or a
blister pack with individual doses for pressing out of the pack
according to a therapeutic schedule. The container that is employed
will depend on the exact dosage form involved. It is feasible that
more than one container can be used together in a single package to
market a single dosage form. For example, tablets may be contained
in a bottle that is in turn contained within a box.
[0167] One particular example of a kit according to the present
invention is a so-called blister pack. Blister packs are well known
in the packaging industry and are being widely used for the
packaging of pharmaceutical unit dosage forms (tablets, capsules,
and the like). Blister packs generally consist of a sheet of
relatively stiff material (preferably stiff transparent plastic
material) covered with a foil. During the packaging process
recesses are formed in the stiff material. The recesses have the
size and shape of individual tablets or capsules to be packed or
may have the size and shape to accommodate multiple tablets and/or
capsules to be packed. Next, the tablets or capsules are placed in
the recesses accordingly and the sheet of relatively stiff material
is sealed against the plastic foil at the face of the foil which is
opposite from the direction in which the recesses were formed. As a
result, the tablets or capsules are individually sealed or
collectively sealed, as desired, in the recesses between the foil
and the sheet. The strength of the sheet is preferably such that
the tablets or capsules can be removed from the blister pack by
manually applying pressure on the recesses whereby an opening is
formed in the foil at the place of the recess. The tablet or
capsule can then be removed via said opening.
EXAMPLES
1. Preparation of
2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-
-1-ylmethyl]-4-fluoro-benzonitrile and Pharmaceutically Acceptable
Salts
[0168] ##STR2##
[0169] A mixture of 2-bromo-5fluorotoluene (2) (3.5 g, 18.5 mmol)
and CuCN (2 g, 22 mmol) in DMF (100 mL) was refluxed for 24 hours.
The reaction was diluted with water and extracted with hexane. The
organics were dried over MgSO.sub.4 and the solvent removed to give
product 3 (yield 60%). .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.
7.60 (dd, J=5.6, 8.8 Hz, 1H), 6.93-7.06 (m, 2H), 2.55 (s, 3H).
2-Bromomethyl-4-fluorobenzonitrile (4)
[0170] A mixture of 4-fluoro-2-methylbenzonitrile (3) (2 g, 14.8
mmol), NBS (2.64 g, 15 mmol) and AIBN (100 mg) in CCl.sub.4 was
refluxed under nitrogen for 2 hours. The reaction was cooled to
room temperature. The solid was removed by filtration. The organic
solution was concentrated to give crude product as an oil, which
was used in the next step without further purification. .sup.1H-NMR
(400 MHz, CDCl.sub.3): .delta. 7.68 (dd, J=5.2, 8.4 Hz, 1H), 7.28
(dd, J=2.4, 8.8 Hz, 1H), 7.12 (m, 1H), 4.6 (s, 2H).
2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluo-
ro-benzonitrile (6)
[0171] A mixture of crude 3-methyl-6-chlorouracil (5) (0.6 g, 3.8
mmol), 2-Bromomethyl-4-fluorobenzonitrile (0.86 g, 4 mmol) and
K.sub.2CO.sub.3 (0.5 g, 4 mmol) in DMSO (10 mL) was stirred at
60.degree. C. for 2 hours. The reaction was diluted with water and
extracted with EtOAc. The organics were dried over MgSO.sub.4 and
the solvent removed. The residue was purified by column
chromatography. 0.66 g of the product was obtained (yield: 60%).
.sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 7.73 (dd, J=7.2, 8.4 Hz,
1H), 7.26 (d, J=4.0 Hz, 1H), 7.11-7.17 (m, 1H), 6.94 (dd, J=2.0,
9.0 Hz, 1H), 6.034 (s, 2H), 3.39 (s, 3H). MS (ES) [m+H] calc'd for
C.sub.13H.sub.9ClFN.sub.3O.sub.2, 293.68; found 293.68.
2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin--
1-ylmethyl]-4-fluoro-benzonitrile, TFA salt (1) (TFA Salt of
Compound I)
[0172] ##STR3##
[0173]
2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl-
)-4-fluoro-benzonitrile (5) (300 mg, 1.0 mmol),
(R)-3-amino-piperidine dihydrochloride (266 mg, 1.5 mmol) and
sodium bicarbonate (500 mg, 5.4 mmol) were stirred in a sealed tube
in EtOH (3 mL) at 100.degree. C. for 2 hrs. The final compound was
obtained as a TFA salt after HPLC purification. .sup.1H-NMR (400
MHz, CD.sub.3OD): .delta.. 7.77-7.84 (m, 1H), 7.16-7.27 (m, 2H),
5.46 (s, 1H), 5.17-5.34 (ABq, 2H, J=35.2, 15.6 Hz), 3.33-3.47 (m,
2H), 3.22 (s, 3H), 2.98-3.08 (m, 1H), 2.67-2.92 (m, 2H), 2.07-2.17
(m, 1H), 1.82-1.92 (m, 1H), 1.51-1.79 (m, 2H). MS (ES) [m+H] calc'd
for C.sub.18H.sub.20FN.sub.5O.sub.2, 357.38; found, 357.38.
2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin--
1-ylmethyl]-4-fluoro-benzonitrile, HCl Salt
[0174] ##STR4##
[0175] The TFA salt of Compound I was suspended in DCM, and then
washed with saturated Na.sub.2CO.sub.3. The organic layer was dried
and removed in vacuo. The residue was dissolved in acetonitrile and
HCl in dioxane (1.5 eq.) was added at 0.degree. C. The HCl salt was
obtained after removing the solvent. .sup.1H-NMR (400 MHz,
CD.sub.3OD): .delta.. 7.77-7.84 (m, 1H), 7.12-7.26 (m, 2H), 5.47
(s, 1H), 5.21-5.32 (ABq, 2H, J=32.0, 16.0 Hz), 3.35-3.5 (m, 2H),
3.22 (s, 3H), 3.01-3.1 (m, 1H), 2.69-2.93 (m, 2H), 2.07-2.17 (m,
1H), 1.83-1.93 (m, 1H), 1.55-1.80 (m, 2H). MS (ES) [m+H] calc'd for
C.sub.18H.sub.20FN.sub.5O.sub.2, 357.38; found, 357.38.
General Procedure for the Preparation of Salts of Compound I.
[0176] The benzonitrile product may be isolated as the free base if
desired, but preferably, the product may be further converted to a
corresponding acid addition salt. Specifically, the benzonitrile
product (approximately 10 mg) in a solution of MeOH (1 mL) was
treated with various acids (1.05 equivalents). The solutions were
allowed to stand for three days open to the air. If a precipitate
formed, the mixture was filtered and the salt dried. If no solid
formed, the mixture was concentrated in vacuo and the residue
isolated. In this way, salts of 34 were prepared from the following
acids: benzoic, p-toluenesulfonic, succinic, R-(-)-Mandelic and
benzenesulfonic.
[0177] The isolation and/or purification steps of the intermediate
compounds in the above described process may optionally be avoided
if the intermediates from the reaction mixture are obtained as
relatively pure compounds and the by-products or impurities of the
reaction mixture do not interfere with the subsequent reaction
steps. Where feasible, one or more isolation steps may be
eliminated to provide shorter processing times, and the elimination
of further processing may also afford higher overall reaction
yields.
2. Exemplary formulations comprising succinate salt of
2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-
-1-ylmethyl]-4-fluoro-benzonitrile
[0178] Provided are examples of tablet formulations that may be
used to administer succinate salt of
2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-
-1-ylmethyl]-4-fluoro-benzonitrile (Succinate salt of Compound I)
according to the present invention. It is noted that the
formulations provided herein may be varied as is known in the
art.
[0179] The exemplary tablet formulations are as follows:
TABLE-US-00001 12.5 mg of Compound I (weight of free base form) per
tablet Core Tablet Formulation (1)
2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4- 17.0 mg
dioxo-3,4-dihydro-2H-pyrimidin-1- ylmethyl]-4-fluoro-benzonitrile
(succinate salt) (2) Lactose Monohydrate, NF, Ph, Eur 224.6 mg
(FOREMOST 316 FAST FLO) (3) Microcrystalline Cellulose, NF, Ph, Eur
120.1 mg (AVICEL PH 102) (4) Croscarmellose Sodium, NF, Ph, Eur
32.0 mg (AC-DO-SOL) (5) Colloidal Silicon Dioxide, NF, Ph, Eur 3.2
mg (CAB-O-SIL M-5P) (6) Magnesium Stearate, NF, Ph, Eur 3.2 mg
(MALLINCKRODT, Non-bovine Hyqual) TOTAL 400.0 mg (per tablet) Film
Coat (12.0 mg in total) (1) Opadry II 85F18422, White - Portion 1
(COLORCON) (2) Opadry II 85F18422, White - Portion 2 (COLORCON) (3)
Opadry II 85F18422, White - Portion 3 (COLORCON)
[0180] TABLE-US-00002 25 mg of Compound I (weight of free base
form) per tablet Core Tablet Formulation (1)
2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4- 34.0 mg
dioxo-3,4-dihydro-2H-pyrimidin-1- ylmethyl]-4-fluoro-benzonitrile
(succinate salt) (2) Lactose Monohydrate, NF, Ph, Eur 207.6 mg
(FOREMOST 316 FAST FLO) (3) Microcrystalline Cellulose, NF, Ph, Eur
120.1 mg (AVICEL PH 102) (4) Croscarmellose Sodium, NF, Ph, Eur
32.0 mg (AC-DO-SOL) (5) Colloidal Silicon Dioxide, NF, Ph, Eur 3.2
mg (CAB-O-SIL M-5P) (6) Magnesium Stearate, NF, Ph, Eur 3.2 mg
(MALLINCKRODT, Non-bovine Hyqual) TOTAL 400.0 mg (per tablet) Film
Coat (12.0 mg in total) (1) Opadry II 85F18422, White - Portion 1
(COLORCON) (2) Opadry II 85F18422, White - Portion 2 (COLORCON) (3)
Opadry II 85F18422, White - Portion 3 (COLORCON)
[0181] TABLE-US-00003 50 mg of Compound I (weight of free base
form) per tablet Core Tablet Formulation (1)
2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2, 68.0 mg
4-dioxo-3,4-dihydro-2H-pyrimidin-1- ylmethyl]-4-fluoro-benzonitrile
(succinate salt) (2) Lactose Monohydrate, NF, Ph, Eur 173.6 mg
(FOREMOST 316 FAST FLO) (3) Microcrystalline Cellulose, NF, Ph, Eur
120.1 mg (AVICEL PH 102) (4) Croscarmellose Sodium, NF, Ph, Eur
32.0 mg (AC-DO-SOL) (5) Colloidal Silicon Dioxide, NF, Ph, Eur 3.2
mg (CAB-O-SIL M-5P) (6) Magnesium Stearate, NF, Ph, Eur 3.2 mg
(MALLINCKRODT, Non-bovine Hyqual) TOTAL 400.0 mg (per tablet) Film
Coat (12.0 mg in total) (1) Opadry II 85F18422, White - Portion 1
(COLORCON) (2) Opadry II 85F18422, White - Portion 2 (COLORCON) (3)
Opadry II 85F18422, White - Portion 3 (COLORCON)
6. Effect of Administration on Plasma DPP-IV Activity
[0182] A single dose of Compound I was administered orally to
monkey at a dosage of 0.3 mg/kg. FIG. 1 illustrates the observed
effect that administering Compound I has on the monkey's plasma
DPPIV activity post dosing. As can be seen, Compound I reduced
DPP-IV activity in monkey's plasma by greater than 90% relative to
baseline at 12 hours post dosing. Thus, as can be seen from the
data shown in FIG. 1, by administering Compound I one time per day
at the dosage levels specified herein, Compound I can be
effectively used relative to disease states where it is desired to
reduce plasma DPPIV activity. In view of the data presented, it is
believed that when at least 25 mg of Compound I is administered to
a patient, the patient's plasma DPPIV activity may be reduced by
greater than 60% relative to baseline for a period of at least at
least 6 hours, 12 hours, 18 hours and even 24 hours following
administration.
7. Effect of Co-Administration with Pioglitazone on Plasma
Glucose
[0183] The effect of administering Compound I in combination with
pioglitazone was investigated by measuring plasma glucose levels in
mice. Male db/db (BKS.Cg-+Lepr.sup.db/+Lepr.sup.db) mice (6 weeks
of age, CLEA Japan (Tokyo, Japan)) were divided into 4 groups (n=7
in each group) comprising Group A to Group D. Group A had free
access to CE-2 powder chow (CLEA Japan) for 21 days. Group B had
free access to CE-2 powder chow (CLEA Japan) containing 0.03% (w/w)
of succinate salt of Compound I for 21 days. The dose of Compound I
in Group B was calculated to be 74.8.+-.2.5 (mean.+-.SD) mg/kg body
weight/day. Group C had free access to CE-2 powder chow (CLEA
Japan) containing 0.0075% (w/w) of pioglitazone hydrochloride for
21 days. The dose of pioglitazone in Group C was calculated to be
17.7.+-.0.6 (mean.+-.SD) mg/kg body weight/day. Group D had free
access to CE-2 powder chow (CLEA Japan) containing 0.03% (w/w) of
succinate salt of Compound I in combination with 0.0075% (w/w) of
pioglitazone hydrochloride for 21 days. The doses of Compound I and
pioglitazone in Group D were calculated to be 63.1.+-.1.9
(mean.+-.SD) mg/kg body weight/day and 15.8.+-.0.5 (mean.+-.SD)
mg/kg body weight/day, respectively. During 21 days of
administration of the powder chow, there were not significant
differences in the administration amount of the powder chow in the
above 4 groups. After 21 days of administration of the powder chow,
blood samples were taken from the orbital veins of the mice by
capillary pipette under feeding condition, and plasma glucose
levels were enzymatically measured by using Autoanalyzer 7080
(Hitachi, Japan).
[0184] The results are shown in Table 1. The values in the table
means average (n=7).+-.standard deviation. TABLE-US-00004 TABLE 1
Plasma Glucose Group (mg/dL) Group A (control) 472.9 .+-. 74.6
Group B (Compound 1) 410.3 .+-. 47.9 Group C (Pioglitazone) 394.4
.+-. 47.9 Group D (Compound I + Pioglitazone) 256.1 .+-. 62.5
[0185] As shown in Table 1, the combination of Compound I with
pioglitazone showed excellent effects of lowering plasma glucose
levels.
[0186] It will be apparent to those skilled in the art that various
modifications and variations can be made to the compounds,
compositions, kits, and methods of the present invention without
departing from the spirit or scope of the invention. Thus, it is
intended that the present invention cover the modifications and
variations of this invention provided they come within the scope of
the appended claims and their equivalents.
* * * * *