DERIVES D'AMINOALKYLE-IMIDAZOLE CONDENSES ARYLES ET HETEROARYLES ET LEUR UTILISATION COMME ANTIDIABETIQUES

ARYL AND HETEROARYL FUSED AMINOALKYL-IMIDAZOLE DERIVATIVES AND THEIR USE AS ANTIDIABETICS

Abrégé français

L'invention concerne des composés de formule (I), ou les sels non toxiques pharmaceutiquement acceptables de ceux-ci, X, R¿1?, R¿2?, R¿3?, R¿4?, R¿5?, R¿6?, R¿7?, A, B, C, et D représentant des variables définies dans la description. Ces composés peuvent être utilisés pour traiter l'obésité et le diabète. L'invention concerne également des sondes marquées permettant de localiser des récepteurs cellulaires qui interviennent dans la modulation des niveaux glycémiques.

Abrégé anglais

Disclosed are compounds of formula (I) or the pharmaceutically acceptable non-
toxic salts thereof wherein X, R1, R2, R3, R4, R5, R6, R7, A, B, C, and D are
variables defined herein. Such compounds useful in treatment of obesity and
diabetes. The invention also provides labeled probes for the localization of
cellular receptors that are involved in the modulation of blood glucose levels.

Revendications

WHAT IS CLAIMED IS:
1. A compound of the formula:
<IMG>
or pharmaceutically acceptable non-toxic salts thereof
wherein:
R7 represents H, or C1-C6 alkyl;
when R7 is H, R1 represents 2-, 3-, or 4-picolyl or benzyl,
each of which is optionally mono-, di-, or
trisubstituted independently with
halogen, nitro, trifluoromethyl, cyano, hydroxyl, C1-C6
alkoxy, or C1-C6 alkyl;
amino, mono or di (C1-C6) alkylamino, amino (C1-C6)alkyl, or
mono- or di (C1-C6) alkylamino (C1-C6) alkyl, or mono- or
di (C1-C6) alkylamino (C1-C6) alkoxy;
-O(CH2)nCO2R8 where n is 1,2,3,4, NR8COR9, COR8, CONR8R9
or CO2R9 where R8 and R9 are the same or different
and represent hydrogen or C1-C6 alkyl; or
NR8R9 forms a 5-, 6- or 7-membered heterocycloalkyl
ring;
SO2R8, NHSO2R8, SO2NHR8, SO2NHCOR8, CONHSO2R8 where R8 is
as defined above;
-43-

O(CH2)n-G where n=1,2,3 or 4 and G represents SO2R8,
NHSO2R8, SO2NHR8, SO2NHCOR8, CONHSO2R8, where R8 is
as defined above; or
tetrazole, triazole, imidazole, thiazole, oxazole,
thiophene, or pyridyl;
when R7 represents C1-C6 alkyl, R1 represents C1-C6 alkyl,
cyclopentyl, or cyclopropylmethyl;
R2 represents
hydroxy;
C1-C6 alkyl or C1-C6 alkoxy, each of which is optionally
substituted with amino or mono- or di(C1-
C6) alkylamino, C5-C7 cycloalkylamino or C5-C7
cycloalkoxy; or
O(CH2)nCO2R8 where n=1,2,3 or 4, NR8COR9, COR8, CONR8R9
or CO2R8 where R8 and R9 are the same or different
and represent hydrogen or C1-C6 alkyl; or
NR8R9 forms 5-, 6-, or 7-membered heterocyclic ring;
R3 represents C1-C6 alkyl;
R4 represents C1-C6 alkoxy; or
R4 represents methyl when R1 and R7 are lower alkyl;
R5 and R6 are the same or different and represent
hydrogen or halogen;
C1-C6 alkyl or C1-C6 alkoxy, the alkyl portion of each
being optionally substituted with amino, mono- or
di (C1-C6) alkylamino, or a C5-C7 heterocycloalkyl
group where the heteroatom is nitrogen and the
nitrogen is attached to the parent alkyl portion;
-44-

O(CH2)nCO2R8 where n=1,2,3,4, NR8COR9, COR8, CONR8R9 or
CO2R8 where R8 and R9 are the same or different and
represent hydrogen or straight or branched chain
lower alkyl having 1-6 carbon atoms;
NR8R9 forms a 5-, 6- or 7-membered heterocyclic ring;
X represents a bond, CH2O, or CH=CH; and
A, B, C, and D are the same or different and represent CH or
N with the proviso that not more than two of A, B, C and
D represent N.
2. A compound of the formula
<IMG>
where
R7 is C1-C6 alkyl;
R1 represents benzyl optionally mono-, di-, or trisubstituted
independently with
halogen, nitro, trifluoromethyl, cyano, hydroxyl, C1-C6
alkoxy, or C1-C6 alkyl; or
amino, mono or di (C1-C6) alkylamino, amino (C1-C6)alkyl, or
mono- or di (C1-C6)alkylamino (C1-C6)alkyl, or mono- or
di(C1-C6) alkylamino (C1-C6)alkoxy;
R2 represents
hydroxy;
-45-

C1-C6 alkyl or C1-C6 alkoxy, each of which is optionally
substituted with amino or mono- or di(C1-
C6) alkylamino, C5-C7 cycloalkylamino or C5-C7
cycloalkoxy; or
O(CH2)n CO2R8 where n=1, 2, 3 or 4, NR8COR9, COR8, CONR8R9
or CO2R8 where R8 and R9 are the same or different
and represent hydrogen or C1-C6 alkyl; or
NR8R9 forms 5-, 6-, or 7-membered heterocyclic ring;
R3 represents C1-C6 alkyl;
R4 represents C1-C6 alkoxy; or
R5 and R6 are the same or different and represent
hydrogen or halogen;
C1-C6 alkyl or C1-C6 alkoxy, the alkyl portion of each
being optionally substituted with amino, mono- or
di(C1-C6) alkylamino, or a C5-C7 heterocycloalkyl
group where the heteroatom is nitrogen and the
nitrogen is attached to the parent alkyl portion;
and
X represents a bond or CH2O.
3. A compound according to claim 2, wherein one of R5
and R6 is hydrogen.
4. A compound according to claim 2, wherein R4 is
methoxy, one of R5 and R6 is hydrogen, and the other of R5 and
R6 is alkoxy.
5. A compound according to claim 2, wherein R7 is C4-C6
alkyl.
-46-

6. A compound according to claim 5, wherein X is a
bond.
7. A compound according to claim 2, wherein R1 is
benzyl monosubstituted in the ortho position.
8. A compound according to claim 7, wherein R7 is C4-C6
alkyl and X is a bond.
9. A compound of the formula:
<IMG>
wherein:
R7 represents C1-C6 alkyl;
R1 represents C1-C6 alkyl, cyclopentyl, or cyclopropylmethyl;
R2 represents
hydroxy;
C1-C6 alkyl or C1-C6 alkoxy, each of which is optionally
substituted with amino or mono- or di(C1-
C6) alkylamino, C5-C7 cycloalkylamino or C5-C7
cycloalkoxy; or
O(CH2)n CO2R8 where n=1, 2, 3 or 4 NR8COR9, COR8, CONR8R9
or CO2R8 where R8 and R9 are the same or different
and represent hydrogen or C1-C6 alkyl; or
-47-

NR8R9 forms 5-, 6-, or 7-membered heterocyclic ring;
R3 represents C1-C6 alkyl;
R4 represents C1-C6 alkoxy; or
R4 represents methyl when R1 and R7 are lower alkyl;
R5 and R6 are the same or different and represent
hydrogen or halogen;
C1-C6 alkyl or C1-C6 alkoxy, the alkyl portion of each
being optionally substituted with amino, mono- or
di(C1-C6) alkylamino, or a C5-C7 heterocycloalkyl
group where the heteroatom is nitrogen and the
nitrogen is attached to the parent alkyl portion;
O(CH2)n CO2R8 where n=1, 2, 3 or 4 NR8COR9, COR8, CONR8R9
or CO2R8 where R8 and R9 are the same or different
and represent hydrogen or straight or branched
chain lower alkyl having 1-6 carbon atoms;
NR8R9 forms a 5-, 6- or 7-membered heterocyclic ring;
X represents a bond or CH2O.
10. A compound according to claim 9 wherein R3 and R7
are methyl.
11. A compound according to claim 9 wherein R1 is propyl
or cyclopropylmethyl.
12. A compound according to claim 9 wherein R1 is
cyclopentyl.
13. A compound according to claim 9 wherein X is CH2O.
-48-

14. A compound according to claim 13, wherein R1 is
propyl or cyclopropylmethyl.
15. A compound according to claim 9, wherein R1 is
propyl or cyclopropylmethyl and one of R5 and R6 is hydrogen.
16. A compound according to claim 9, wherein R1 is
propyl, R4 is methoxy or methyl, one of R5 and R6 is hydrogen,
and the other of R5 and R6 is alkoxy.
17. A compound of the formula:
<IMG>
wherein:
R7 represents C1-C6 alkyl;
R1 represents C1-C6 alkyl, cyclopentyl, or cyclopropylmethyl;
R2 represents
hydroxy;
C1-C6 alkyl or C1-C6 alkoxy, each of which is optionally
substituted with amino or mono- or di(C1-
C6) alkylamino, C5-C7 cycloalkylamino or C5-C7
cycloalkoxy; or
-49-

O(CH2)n CO2R8 where n=1, 2, 3 or 4 NR8COR9, COR8, CONR8R9
or CO2R8 where R8 and R9 are the same or different
and represent hydrogen or C1-C6 alkyl; or
NR8R9 forms 5-, 6-, or 7-membered heterocyclic ring;
R3 represents C1-C6 alkyl;
R4 represents C1-C6 alkoxy; or
R4 represents methyl when R1 and R7 are lower alkyl;
R5 and R6 are the same or different and represent
hydrogen or halogen;
C1-C6 alkyl or C1-C6 alkoxy, the alkyl portion of each
being optionally substituted with amino, mono- or
di(C1-C6) alkylamino, or a C5-C7 heterocycloalkyl
group where the heteroatom is nitrogen and the
nitrogen is attached to the parent alkyl portion;
O(CH2)n CO2R8 where n=1, 2, 3 or 4, NR8COR9, COR8, CONR8R9
or CO2R8 where R8 and R9 are the same or different
and represent hydrogen or straight or branched
chain lower alkyl having 1-6 carbon atoms;
NR8R9 forms a 5-, 6- or 7-membered heterocyclic ring;
X represents a bond or CH2O.
18. A compound according to claim 17 wherein R3 and R7
are methyl.
19. A compound according to claim 17 wherein R1 is
propyl or cyclopropylmethyl.
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20. A compound according to claim 17 wherein R1 is
cyclopentyl.
21. A compound according to claim 17 wherein X is CH2O.
22. A compound according to claim 21, wherein R1 is
propyl or cyclopropylmethyl.
23. A compound according to claim 17, wherein R1 is
propyl or cyclopropylmethyl and one of R5 and R6 is hydrogen.
24. A compound according to claim 17, wherein R1 is
propyl, R4 is methoxy or methyl, one of R5 and R6 is hydrogen,
and the other of R5 and R6 is alkoxy.
25. A compound of the formula
<IMG>
where
R7 is hydrogen or C1-C6 alkyl;
R1 represents benzyl optionally mono-, di-, or trisubstituted
independently with
halogen, nitro, trifluoromethyl, cyano, hydroxyl, C1-C6
alkoxy, or C1-C6 alkyl; or
-51-

amino, mono or di(C1-C6) alkylamino, amino(C1-C6)alkyl, or
mono- or di(C1-C6)alkylamino(C1-C6)alkyl, or mono- or
di(C1-C6)alkylamino(C1-C6)alkoxy;
R2 represents
hydroxy;
C1-C6 alkyl or C1-C6 alkoxy, each of which is optionally
substituted with amino or mono- or di(C1-
C6)alkylamino, C5-C7 cycloalkylamino or C5-C7
cycloalkoxy; or
O(CH2)n CO2R8 where n=1, 2, 3 or 4, NR8COR9, COR8, CONR8R9
or CO2R8 where R8 and R9 are the same or different
and represent hydrogen or C1-C6 alkyl; or
NR8R9 forms 5-, 6-, or 7-membered heterocyclic ring;
R3 represents C1-C6 alkyl;
R4 represents C1-C6 alkoxy; or
R5 and R6 are the same or different and represent
hydrogen or halogen;
C1-C6 alkyl or C1-C6 alkoxy, the alkyl portion of each
being optionally substituted with amino, mono- or
di(C1-C6) alkylamino, or a C5-C7 heterocycloalkyl
group where the heteroatom is nitrogen and the
nitrogen is attached to the parent alkyl portion;
and
X represents a bond or CH2O.
26. A compound according to claim 25, wherein one of R5
and R6 is hydrogen.
-52-

27. A compound according to claim 25, wherein R4 is
methoxy, one of R5 and R6 is hydrogen, and the other of R5 and
R6 is alkoxy.
28. A compound according to claim 25, wherein R7 is C4-
C6 alkyl.
29. A compound according to claim 25, wherein X is a
bond.
30. A compound according to claim 25, wherein R1 is
benzyl monosubstituted in the ortho position.
31. A compound according to claim 30, wherein R7 is C4-
C6 alkyl and X is a bond.
32. A compound according to Claim 1, which is ((2,4-
dimethoxyphenyl)-N-(3-methylbutyl)-N-({1-[(2-
methylphenyl)methyl]benzimidazol-2-yl}methyl)carboxamide
33. A compound according to claim 1, which is 2-(2,3-
dimethylphenoxy)-N-methyl-N-[(1-propylbenzimidazol-2-
yl)ethyl]acetamide.
34. A compound according to claim 1, which is 2-(2,3-
dimethylphenoxy)-N-{[1-(cyclopropylmethyl)benzimidazol-2-
yl]ethyl}-N-methylacetamide.
-53-

35. A compound according to claim 1, which is (2,4-
dimethoxyphenyl)-N-({1-[(2-chlorophenyl)methyl]benzimidazol-
2-yl}methyl)-N-(3-methylbutyl)carboxamide.
36. A compound according to claim 1, which is (2,4-
dimethoxyphenyl)-N-(3-methylbutyl)-N-({3-[(2-
methylphenyl)methyl]imidazolo[5,4-b]pyridin-2-
yl}methyl)carboxamide.
37. A compound according to claim 1, which is 2-(2,3-
dimethylphenoxy)-N-methyl-N-[(-propylimidazolo[5,4-b]pyridin-
2-yl)ethyl]acetamide.
38. A compound according to claim 1, which is 2-(2,3-
dimethylphenoxy)-N-{[1-(cyclopentyl)-6-chlorobenzimidazol-2-
yl]ethyl}-N-methylacetamide
39. A pharmaceutical composition comprising a compound
as claimed in claim 1 and a pharmaceutically acceptable
carrier or excipient.
40. A method of treating diabetes, comprising
administering to a patient in need of such treatment an
effective amount of a compound according to Claim 1, or a
pharmaceutically acceptable salt thereof.
41. A method of treating obesity or eating disorders,
comprising administering to a patient in need of such
-54-

treatment an effective amount of a compound according to
Claim 1, or a pharmaceutically acceptable salt thereof.
42. The use of a compound of claim 1 for the
manufacture of a medicament for the treatment of diabetes or
obesity.
43. A process for the preparation of a compound of
claim 1.
44. A method for localizing receptors in a tissue sample
comprising:
contacting the sample with a detectably-labeled compound of
claim 1 under conditions that permit binding of the compound
to the receptors, washing the sample to remove unbound
compound, and detecting the bound compound.
45. The method of claim 44, wherein the receptors
modulate blood glucose levels.
46. The method of claim 44, wherein the receptors are
GLP-1 receptors.
47. A packaged pharmaceutical composition comprising the
pharmaceutical composition of claim 39 in a container and
instructions for using the composition to treat a patient
suffering from a disorder responsive to modulation of blood
glucose levels.
-55-

48. The packaged pharmaceutical composition of claim
47, wherein said patient is suffering from obesity or
diabetes.
-56-

Description

CA 02369549 2001-10-02
WO 00/59887 PCT/US00/08569
ARYL AND HETEROARYL FUSED AMINOALKYL-IMIDAZOLE DERIVATIVES AND THEIR USE AS
ANTIDIABETICS
BACKGROUND OF THE INVENTION
This application claims the benefit of U.S. Provisional
Application no. 60/127,656, filed on April 2, 1999.
Field of the Invention
This invention relates to 1-benzylimidazole derivatives,
and more specifically, to the use of such compounds as
pharmaceutical agents, e.g., as modulators of blood glucose
levels. This invention also relates to pharmaceutical
compositions comprising such compounds and to the use of such
compounds in treating a variety of disorders associated with
feeding and food metabolism. Additionally, this invention
relates to the use such compounds as probes for the
localization of cellular receptors that are involved in the
modulation of blood glucose levels.
BACKGROUND
Diabetes mellitus is a chronic syndrome of impaired
carbohydrate and fat metabolism resulting from insufficient
insulin secretion and/or target tissue insulin resistance.
It occurs in two major forms: insulin-dependent diabetes
mellitus (IDDM, Type 1) and non-insulin-dependent diabetes
mellitus (NIDDM, Type 2). These forms differ in their
etiology, age of onset and treatment. Type 1 is often
characterized by onset during childhood and the patients
typically become fully dependent upon exogenous insulin to
sustain life. The disorder is associated with a lack of
insulin prod~zction by the pancreatic Islets of Langerhans.

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The disease is generally marked by a drastic reduction in the
number of insulin secreting islet beta cells.
NIDDM usually appears later in life (age -40-60) and is
often associated with obesity. Patients with NIDDM show
normal basal levels of insulin but display an abnormal
insulin secretion response (delayed or reduced) to a glucose
load. As the disease progresses, insulin target tissues show
signs of diminished response to insulin (insulin resistence).
Effective treatment of the disorder is usually obtained by
dietary control, with or without the use of oral hypoglycemic
drugs. Sulphonylureas are a class of hypoglycemic compounds
used in the treatment of NIDDM. These drugs exert their
action by causing insulin to be released from intracellular
stores. Care must be taken in the administration of these
agents in order to not induce severe hypoglycemia due to
excessive insulin release. In addition, overdose may deplete
insulin stores to a point requiring administration of
exogenous insulin.
The discovery that glucose administered via the
gastrointestinal tract provides greater stimulation of
insulin release than a comparable glucose challenge given
intravenously led to the identification of certain gut
secreted 'incretin' hormones which augment glucose stimulated
insulin secretion, and the identification of specific cell
surface receptors that modulate the effects of such incretin
hormones. Glucagon-like Peptide-1 (7-36)-amide (GLP-1) is
one such incretin hormone that is secreted from
gastrointestinal L cells in response to food intake and
increases insulin secretion from pancreatic beta cells
-2-

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(Fehmann, H. C.; Goke, R. and Goke, B. (1995) Endocr. Rev.
16: 390-410). GLP-1 exerts its actions via binding to a G-
protein-linked receptor expressed in islet ~3-cells.
Unlike the sulphonylureas, the effects of GLP-1 are
dependent upon plasma glucose concentration in that the
insulinotropic effects of GLP-1 are abolished at low plasma
glucose levels. In addition to its stimulation of insulin
secretion, GLP-1 also increases insulin synthesis (Drucker,
DJ (1987) Proc. Natl Acad. Sci USA 84: 3434-3438), inhibits
glucagon secretion (Kawai (1989) Endocrinology 124: 1768-
1773) and delays gastric emptying (Nauck, MA (1995) Gut
37(2): A124). This combination of actions gives GLP-1 unique
potential therapeutic advantages over other agents presently
used to treat non-insulin dependent diabetes mellitus. In a
clinical trial of patients with NIDDM it was found that
subcutaneous administration of GLP-1 could normalize
postprandial glucose levels (Todd et al. (1997) Eur. J. Clin.
Invest. 27: 533-536). Drugs that mimic the action of GLP-1,
i.e. stimulate insulin secretion from pancreatic ~3-cells, but
only at higher than normal blood glucose levels, are
particularly desirable for us in the treatment of NIDDM.
Such drugs may work by modulating the signal-transducing
activity of the GLP-1 receptor.
In clinical studies GLP-1 has been shown to reduce
appetite and increase satiety in both normal weight and obese
subjects (see, e.g. , Christophe J. Ann. N Y Acad. Sci. (1998)
865:323-335 and Gutwiller, J.P., Am. J. Physio. (1999) 276:
81541-1544). Thus drugs that modulate the activity of the
-3-

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GLP-1 receptor may be useful for the treatment of obesity and
eating disorders.
The effect of a compound on blood glucose levels can be
determined in vivo, through the use a glucose tolerance test,
in which the blood glucose levels laboratory animals
subjected to a glucose challenge are monitored in the
presence and absence of the compound. The effects of test
compounds on glucose tolerance may be evaluated in non-
diabetic laboratory animals as discussed in Inlang et al., J.
Clin. Invest. (1995) 95: 417-421 and Holst, Curr. Opinion in
Endocrinology and Diabetes (1998) 5: 108-115.
Alternatively, the effects of test compounds on blood
glucose levels may be assessed in an animal model of
diabetes, e.g., streptozotocin (STZ)-induced diabetes. Such
assays have been disclosed by Tancrede et al. (Br. J. Exp.
Path. (1983) 64: 117-123), Junod et al. (J. Clin. Inv. (1969)
48: 2129-2139, Rondu et al. (J. Med. Chem. (1997) 40:3793-
3803), and Maloff and Boyd (Diabetologia (1986) 29: 295-
300) .
In vitro experiments that monitor the interaction of the
compound with GLP-1 receptors may also be used to reliably
predict the effects of a compound on blood glucose levels.
In one such experiment the interaction of compounds with GLP-
1 receptors, expressed either recombinantly or naturally in
high abundance in certain cell lines, may be determined by a
cell-based luciferase screen or by binding experiments
measuring competition binding e.g., with a labeled GLP-1
ligand such as GLP-1 or GLP(7-36) peptide.
-4-

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Receptors that are coupled to the GS stimulatory G-
protein subunit transduce intracellular signals via the
adenylate cyclase pathway. Stimulation of these receptors
with an agonist typically results in an elevation of
cytoplasmic cAMP levels which can trigger the subsequent
transcription of a variety of genes, generally those with
promoters containing binding sites (CAMP responsive elements
-- CREs) for the transcription factor, CREB (CRE binding
protein).
Receptor modulation may be measured via measurement of
transcriptional activation of a firefly luciferase reporter
gene. Such an assay may use a Chinese hamster ovary cell
line (CHO-K1) stably transfected with a GLP-1 receptor (a GS
coupled receptor) expression plasmid and a luciferase
reporter plasmid, wherein luciferase expression is under the
transcriptional control of multiple CREs. In these cell
lines, the GLP1 agonist GLP(7-36) peptide stimulates
luciferase expression in a dose dependent manner with a
potency (ECso ~20 pM) similar to the data reported by Gromada
et al. (1995) FEBS Lett. 373: 182-186.
Compounds are screened by seeding 15,000 cells per well
in opaque multi-well plates. Cells are then incubated
overnight in a tissue culture incubator. Compounds are
dispensed to a final concentration of 4 uM in to DMSO. After
6 hours of incubation, cells are assayed for luciferase
activity, which is measured in a luminometer.
SOMMARY OF THE INVENTION
This invention provides compounds of Formula I, below.
The invention also provides compounds of Formula I that bind
-5-

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specifically, and preferably with high affinity, to specific
cellular receptors. Preferably the receptors are cell
surface receptors, and more preferably G-protein coupled
receptors. Even more preferably, the receptors are Secretin-
like receptors. Highly preferred receptors are GLP
receptors, and most preferably, the receptors are GLP-1
receptors. Such compounds are useful in the treatment of
diabetes, especially non-insulin-dependent diabetes mellitus
(Type 2 diabetes), and in the treatment of obesity and eating
disorders.
The invention further comprises methods of treating
patients suffering from diabetes, especially non-insulin-
dependent diabetes mellitus (Type 2 diabetes), obesity or
eating disorders by administering to a patient in need of
such treatment an effective amount of a compound of the
invention. Treatment of human patients, domesticated
companion animals (pets) or livestock animals suffering from
these disorders with an effective amount of a compound of the
invention is encompassed by the invention.
In a separate aspect, this invention provides compounds
that are useful as probes for the localization of specific
receptors. Preferably these receptors modulate blood glucose
levels. Such receptors are preferably so localized in tissue
samples, especially tissue sections. Such probes are also
useful for measuring levels of such receptors expressed in
tissue samples or cell membrane preparations of tissue
samples and for localizing receptors in living patients
(e. g., via PET scanning).
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The invention also comprises a method for altering the
signal-transducing activity of a cell surface GLP1 receptor,
said method comprising exposing cells expressing such a
receptor to an effective amount of a compound of the Formula
I, below.
The invention also provides pharmaceutical compositions
comprising compounds of Formula I, including packaged
pharmaceutical compositions. Packaged pharmaceutical
compositions may include a container and instructions for
using the composition to treat a patient in need thereof.
Particulary, the invention includes packaged pharmaceutical
compositions that include a container and instructions for
using the composition to treat a patient suffering from
diabetes, obesity or eating disorders.
Accordingly, a broad embodiment of the invention is
directed to compounds of Formula I:
Ra
w
R R5
X \
A
N N~ \Rs
RZ C. I N R O
D
R~
I
or the pharmaceutically acceptable non-toxic salts thereof
wherein:
R~ represents H, or C1-C6 alkyl;
when R, is H, R1 represents 2-, 3-, or 4-picolyl or benzyl,
each of which is optionally mono-, di-, or
trisubstituted independently with

CA 02369549 2001-10-02
WO 00/59887 PCT/US00/08569
halogen, nitro, trifluoromethyl, cyano, hydroxyl, Cl-C6
alkoxy, or C1-C6 alkyl;
amino, mono or di (Cl-C6) alkylamino, amino (Cl-C6) alkyl, or
mono- or di (Cl-C6) alkylamino (Cl-C6) alkyl, or mono- or
di (Cl-C6) alkylamino (Cl-C6) alkoxy;
-O(CH2)nC02Rg where n is l, 2, 3 or 4, NRgCORg, CORg,
CONRgRg or C02Rg where Rg and Rg are the same or
different and represent hydrogen or C1-C6 alkyl; or
NRgRg forms a 5-, 6- or 7-membered heterocycloalkyl
ring;
S02Rg, NHS02Rg, S02NHRg, S02NHCORg, CONHS02Rg where R$ is
as defined above;
O(CH2)n-G where n=1, 2, 3 or 4 and G represents S02Rg,
NHS02Rg, S02NHRg, S02NHCORg, CONHS02Rg, where R8 is
as defined above; or
tetrazole, triazole, imidazole, thiazole, oxazole,
thiophene, or pyridyl;
when R~ represents C1-C6 alkyl, R1 represents C1-C6 alkyl,
cyclopentyl, or cyclopropylmethyl;
RZ represents
hydroxy;
C1-C6 alkyl or C1-C6 alkoxy, each of which is optionally
substituted with amino or mono- or di(Cl
C6) alkylamino, CS-C, cycloalkylamino or CS-C~
cycloalkoxy; or
O(CH2)nC02Rg where n=1,2,3,4, NRgCORg, CORg, CONRgRg or
C02Rg where Rg and R9 are the same or different and
represent hydrogen or Cl-C6 alkyl; or
_g_

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NRgRg forms 5-, 6-, or 7-membered heterocyclic ring;
R3 represents C1-C6 alkyl;
R4 represents Cl-C6 alkoxy; or
R4 represents methyl when Rl and R, are lower alkyl;
RS and R6 are the same or different and represent
hydrogen or halogen;
C1-C6 alkyl or C1-C6 alkoxy, the alkyl portion of each
being optionally substituted with amino, mono- or
di (C1-C6) alkylamino, or a CS-C, heterocycloalkyl
group where the heteroatom is nitrogen and the
nitrogen is attached to the parent alkyl portion;
O(CH2)nC02Rg where n=1,2,3,4, NRgCORg, CORg, CONRgRg or
C02Rg where Rg and Rg are the same or different and
represent hydrogen or straight or branched chain
lower alkyl having 1-6 carbon atoms;
NRgRg forms a 5-, 6- or 7-membered heterocyclic ring;
X represents a bond, CH20, or CH=CH; and
A, B, C, and D independently represent CH or N with the
proviso that not more than two of A, B, C and D
represent N.
These compounds are useful in the diagnosis and
treatment of obesity and diabetes.
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DETAILED DESCRIPTION OF THE INVENTION
The compounds of the instant invention are represented
by the formula I:
R Rs
-i
3
N N X \ \ Rs
B'
R2 C'\ ~ N R O
D
R~
I
or pharmaceutically acceptable non-toxic salts thereof
wherein:
R, represents H, or C1-C6 alkyl;
when R, is H, R1 represents 2-, 3-, or 4-picolyl or benzyl,
each of which is optionally mono-, di-, or
trisubstituted independently with
halogen, nitro, trifluoromethyl, cyano, hydroxyl, C1-C6
alkoxy, or C1-C6 alkyl;
amino, mono or di (Cl-C6) alkylamino, amino (Cl-C6) alkyl, or
mono- or di ( Cl-C6 ) alkylamino ( Cl-C6 ) alkyl , or mono- or
di (Cl-C6) alkylamino (Cl-C6) alkoxy;
-O(CH2)nC02Rg where n is 1, 2, 3 or 4 NRgCORg, CORg,
CONRgRg or C02Rg where Rg and Rg are the same or
different and represent hydrogen or C1-C6 alkyl; or
NRgRg forms a 5-, 6- or 7-membered heterocycloalkyl
ring;
S02Rg, NHS02Rg, S02NHRg, S02NHCORg, CONHS02Rg where RB is
as -def fined above ;
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O(CH2)n-G where n=1, 2, 3 or 4 and G represents S02Rg,
NHS02Rg, S02NHRg, S02NHCORg, CONHS02Rg, where RB is
as defined above; or
tetrazole, triazole, imidazole, thiazole, oxazole,
thiophene, or pyridyl;
when R~ represents C1-C6 alkyl, R1 represents C1-C6 alkyl,
cyclopentyl, or cyclopropylmethyl;
RZ represents
hydroxy;
C,-C6 alkyl or C1-C6 alkoxy, each of which is optionally
substituted with amino or mono- or di(Cl-
C6) alkylamino, CS-C, cycloalkylamino or CS-C,
cycloalkoxy; or
O(CH2)nC02Rg where n=1, 2, 3 or 4 NRgCOR9, CORg, CONRgRg
or C02Rg where Rg and R9 are the same or different
and represent hydrogen or C1-C6 alkyl; or
NRgR9 forms 5-, 6-, or 7-membered heterocyclic ring;
R3 represents C1-C6 alkyl;
R4 represents Cl-C6 alkoxy; or
R4 represents methyl when R1 and R, are lower alkyl;
RS and R6 are the same or different and represent
hydrogen or halogen;
C1-C6 alkyl or C1-C6 alkoxy, the alkyl portion of each
being optionally substituted with amino, mono- or
di (C1-C6) alkylamino, or a CS-C~ heterocycloalkyl
group where the heteroatom is nitrogen and the
nitrogen is attached to the parent alkyl portion;
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0 ( CH2 ) nC02Rg where n=1, 2 , 3 or 4 NRgCORg , CORg , CONRgRg
or C02Rg where Rg and Rg are the same or different
and represent hydrogen or straight or branched
chain lower alkyl having 1-6 carbon atoms;
NRgRg forms a 5-, 6- or 7-membered heterocyclic ring;
X represents a bond, CH20, or CHCH; and
A, B, C, and D are the same or different and represent CH or
N with the proviso that not more than two of A, B, C and
D represent N.
Preferred compounds of the invention are represented by
Formula II
Ra
-i
R R5
3
/ N N~ \Rs
R2 \ I ~>--~ O
N
R~
II
where
R1 represents benzyl optionally mono-, di-, or trisubstituted
independently with
halogen, vitro, trifluoromethyl, cyano, hydroxyl, C1-C6
alkoxy, or C1-C6 alkyl; or
amino, mono or di (Cl-C6) alkylamino, amino (Cl-C6) alkyl, or
mono- or di (Cl-C6) alkylamino (Cl-C6) alkyl, or mono- or
di (Cl-C6) alkylamino (Cl-C6) alkoxy;
RZ represents
hydroxy;
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Cl-C6 alkyl or Cl-C6 alkoxy, each of which is optionally
substituted with amino or mono- or di(Cl-
C6) alkylamino, CS-C, cycloalkylamino or CS-C,
cycloalkoxy; or
O(CH2)nC02Rg where n=1,2,3,4, NRgCORg, CORg, CONRgRg or
C02Rg where Rg and Rg are the same or different and
represent hydrogen or C1-C6 alkyl; or
NRgRg forms 5-, 6-, or 7-membered heterocyclic ring;
R3 represents C1-C6 alkyl;
R4 represents Cl-C6 alkoxy; or
RS and R6 are the same or different and represent
hydrogen or halogen;
C1-C6 alkyl or C1-C6 alkoxy, the alkyl portion of each
being optionally substituted with amino, mono- or
di (C1-C6) alkylamino, or a CS-C, heterocycloalkyl
group where the heteroatom is nitrogen and the
nitrogen is attached to the parent alkyl portion;
and
X represents a bond or CH20.
Preferred compounds of Formula II include those where
one of RS and R6 is hydrogen. Other preferred compounds of II
are those where R4 is methoxy, one of RS and R6 is hydrogen,
and the other of RS and R6 is alkoxy. Still other preferred
compounds of II are those where R, is C4-C6 alkyl.
More preferred compounds of Formula II include those
where wherein X is a bond. Other more preferred compounds of
II are those. where R1 is benzyl monosubstituted in the ortho
position. Particularly preferred compounds of II are those
where R~ is C4-C6 alkyl and X is a bond.
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Other preferred compounds of the invention are
represented by Formula III
Ra
R -~ Rs
3
/ N N \\ ~ v Rs
R2 ~ \~ O
N R~
R~
III
wherein:
R, represents C1-C6 alkyl;
R1 represents Cl-C6 alkyl, cyclopentyl, or cyclopropylmethyl;
RZ represents
hydroxy;
C1-C6 alkyl or C1-C6 alkoxy, each of which is optionally
substituted with amino or mono- or di(Cl-
C6) alkylamino, CS-C, cycloalkylamino or CS-C,
cycloalkoxy; or
O(CH2)nC02Rg where n=1, 2, 3 or 4 NRgCOR9, CORg, CONRgR9
or C02Rg where Rg and R9 are the same or different
and represent hydrogen or C1-C6 alkyl; or
NRgRg forms 5-, 6-, or 7-membered heterocyclic ring;
R3 represents C1-C6 alkyl;
R4 represents Cl-C6 alkoxy; or
R4 represents methyl when Rl and R, are lower alkyl;
RS and R6 are the same or different and represent
hydrogen or halogen;
C1-C6 alkyl or C1-C6 alkoxy, the alkyl portion of each
being optionally substituted with amino, mono- or
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di (Cl-C6) alkylamino, or a CS-C~ heterocycloalkyl
group where the heteroatom is nitrogen and the
nitrogen is attached to the parent alkyl portion;
O(CH2)nC02Rg where n=1, 2, 3 or 4 NRgCOR9, CORg, CONRgR9
or C02Rg where Rg and R9 are the same or different
and represent hydrogen or straight or branched
chain lower alkyl having 1-6 carbon atoms;
NRgR9 forms a 5-, 6- or 7-membered heterocyclic ring;
X represents a bond or CHzO.
Preferred compounds of Formula III include those where R3
and R., are methyl. Other preferred compounds of Formula III
are those where R1 is propyl or cyclopropylmethyl. Still
other preferred compounds of III are those where R1 is
cyclopentyl.
Particularly preferred compounds of Formula III include
those where X is CH20. Other particularly preferred compounds
of III are those where R1 is propyl or cyclopropylmethyl.
Still other particularly preferred compounds of Formula III
are those where R1 is propyl or cyclopropylmethyl and one of
RS and R6 is hydrogen. Other particularly preferred compounds
of Formula III are those where R1 is propyl, R4 is methoxy or
methyl, one of RS and R6 is hydrogen, and the other of RS and
R6 is alkoxy.
Other preferred compounds of the invention are
represented by Formula IV
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Ra
R Rs
3
/ N \N~ \ ' Rs
R2 ~ ~ ' ~
N N R~
R~
IV
wherein:
R, represents C1-C6 alkyl;
R1 represents Cl-C6 alkyl, cyclopentyl, or cyclopropylmethyl;
RZ represents
hydroxy;
C1-C6 alkyl or C1-C6 alkoxy, each of which is optionally
substituted with amino or mono- or di(Cl
C6) alkylamino, CS-C, cycloalkylamino or CS-C,
cycloalkoxy; or
O(CH2)nC02Rg where n=1, 2, 3 or 4 NRgCORg, CORg, CONRgRg
or C02Rg where Rg and Rg are the same or different
and represent hydrogen or C1-C6 alkyl; or
NRgRg forms 5-, 6-, or 7-membered heterocyclic ring;
R3 represents C1-C6 alkyl;
R4 represents Cl-C6 alkoxy; or
R4 can represent methyl when R1 and R, are lower alkyl;
RS and R6 are the same or different and represent
hydrogen or halogen;
C1-C6 alkyl or C1-C6 alkoxy, the alkyl portion of each
being optionally substituted with amino, mono- or
di (C1-C6) alkylamino, or a CS-C, heterocycloalkyl
group where the heteroatom is nitrogen and the
nitrogen is attached to the parent alkyl portion;
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O(CH2)nC02Rg where n=1,2,3,4, NRgCOR9, CORg, CONRgRg or
C02Rg where Rg and R9 are the same or different and
represent hydrogen or straight or branched chain
lower alkyl having 1-6 carbon atoms;
NRgR9 forms a 5-, 6- or 7-membered heterocyclic ring;
X represents a bond or CH20.
Preferred compounds of Formula IV are those where R3 and
R., are methyl. Other preferred compounds of IV are those
where R1 is propyl or cyclopropylmethyl. Still other
preferred compounds of Formula IV are those where R1 is
cyclopentyl. Yet other preferred compounds of IV include
those where X is CH20.
More preferred compounds of IV are those wherein R1 is
propyl or cyclopropylmethyl. Particularly preferred
compounds of Formula IV are those where R1 is propyl or
cyclopropylmethyl and one of RS and R6 is hydrogen. Still
other particularly preferred compounds of IV include those
where R1 is propyl, RQ is methoxy or methyl, one of RS and R6
is hydrogen, and the other of RS and R6 is alkoxy.
Other preferred compounds of the invention are
represented by Formula V
Ra
-i
R Rs
3
N N--~ ~ ~ Rs
R2 ~ ~ O
N N
R~
V
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where
R1 represents benzyl optionally mono-, di-, or trisubstituted
independently with
halogen, nitro, trifluoromethyl, cyano, hydroxyl, C1-C6
alkoxy, or C1-C6 alkyl; or
amino, mono or di (Cl-C6) alkylamino, amino (Cl-C6) alkyl, or
mono- or di (Cl-C6) alkylamino (Cl-C6) alkyl, or mono- or
di (Cl-C6) alkylamino (Cl-C6) alkoxy;
Rz represents
hydroxy;
C1-C6 alkyl or C1-C6 alkoxy, each of which is optionally
substituted with amino or mono- or di(Cl-
C6) alkylamino, CS-C~ cycloalkylamino or CS-C7
cycloalkoxy; or
O(CH2)nC02Rg where n=1, 2, 3 or 4 NRBCORg, CORg, CONRBRg
or C02Rg where Rg and R9 are the same or different
and represent hydrogen or C1-C6 alkyl; or
NRBRg forms 5-, 6-, or 7-membered heterocyclic ring;
R3 represents C1-C6 alkyl;
RQ represents Cl-C6 alkoxy; or
RS and R6 are the same or different and represent
hydrogen or halogen;
C1-C6 alkyl or C1-C6 alkoxy, the alkyl portion of each
being optionally substituted with amino, mono- or
di (C1-C6) alkylamino, or a CS-C, heterocycloalkyl
group where the heteroatom is nitrogen and the
nitrogen is attached to the parent alkyl portion;
and
X represents a bond or CHZO.
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Preferred compounds of Formula V are those where one of
RS and R6 is hydrogen. Other preferred compounds of Formula V
are those where R4 is methoxy, one of RS and R6 is hydrogen,
and the other of RS and R6 is alkoxy. More preferred
compounds of Formula V include those where R, is C4-C6 alkyl.
Particularly preferred compounds of Formula V include
those where X is a bond. Other particularly preferred
compounds of Formula V are those where R1 is benzyl
monosubstituted in the ortho position. Still other
particularly preferred compounds of Formula V are those where
R., is CQ-C6 alkyl and X is a bond.
In certain situations, the compounds of Formula I may
contain one or more asymmetric carbon atoms, so that the
compounds can exist in different stereoisomeric forms.
These compounds can be, for example, racemates or optically
active forms. In these situations, the single enantiomers,
i.e., optically active forms, can be obtained by asymmetric
synthesis or by resolution of the racemates. Resolution of
the racemates can be accomplished, for example, by
conventional methods such as crystallization in the presence
of a resolving agent, or chromatography, using, for example a
chiral HPLC column.
Representative compounds of the present invention, which
are encompassed by Formula I, include, but are not limited to
the compounds described in the Examples and their
pharmaceutically acceptable acid addition salts. In
addition, if the compound of the invention is obtained as an
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acid addition salt, the free base can be obtained by
basifying a solution of the acid salt. Conversely, if the
product is a free base, an addition salt, particularly a
pharmaceutically acceptable addition salt, may be produced by
dissolving the free base in a suitable organic solvent and
treating the solution with an acid, in accordance with
conventional procedures for preparing acid addition salts
from base compounds.
Non-toxic pharmaceutical salts include salts of acids
such as hydrochloric, phosphoric, hydrobromic, sulfuric,
sulfinic, formic, toluenesulfonic, methanesulfonic, nitric,
benzoic, citric, tartaric, malefic, hydroiodic, alkanoic such
as acetic, HOOC-(CHZ)n-COOH where n is 0-4, and the like.
Those skilled in the art will recognize a wide variety of
non-toxic pharmaceutically acceptable addition salts.
The present invention also encompasses the acylated
prodrugs of the compounds of Formula I. Those skilled in the
art will recognize various synthetic methodologies which may
be employed to prepare non-toxic pharmaceutically acceptable
addition salts and acylated prodrugs of the compounds
encompassed by Formula I.
By "alkyl" or "lower alkyl" in the present invention is
meant C1-C6 alkyl, i.e., straight or branched chain alkyl
groups having 1-6 carbon atoms, such as, for example, methyl,
ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl,
pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-
hexyl, and 3-methylpentyl. Preferred C1-C6 alkyl groups are
methyl, ethyl, propyl, butyl, cyclopropyl or
cyclopropylmethyl.
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By "alkoxy" or "lower alkoxy" in the present invention
is meant C1-C6 alkoxy, i.e., straight or branched chain alkoxy
groups having 1-6 carbon atoms, such as, for example,
methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy,
tert-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy,
hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.
By (hetero) cyclic ring is meant a ring that is either
aliphatic or aromatic and optionally contains at least one
hetero atom. Hetero atoms include nitrogen, sulfur, and
oxygen. Examples of such (hetero) cyclic rings are
cyclohexyl, cyclopentyl, piperidinyl, piperazinyl,
pyrrolidinyl, morpholinyl, etc.
By heteroaryl (aromatic heterocycle) in the present
invention is meant one or more aromatic ring systems of 5-,
6-, or 7-membered rings containing at least one and up to
four hetero atoms selected from nitrogen, oxygen, or sulfur.
Such heteroaryl groups include, for example, thienyl,
furanyl, thiazolyl, imidazolyl, (is)oxazolyl, pyridyl,
pyrimidinyl, imidazolyl, (iso)quinolinyl, naphthyridinyl,
benzimidazolyl, and benzoxazolyl.
As used herein, each alkyl group in a di(C1-C6)alkylamino
group is independent of the other.
Specific examples of heteroaryl groups are the
following:
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R12 R11
13-
R13 -~.~ R
R11' R11'
N R12~ 2'
w \ N y R1
R11 ~ ~3 ~ / ~ , N
R11 ~ ~R13 R11
R12
R12 R12
wherein
L is nitrogen or -CRll;
T is -NR19, oxygen, or sulfur;
Rll and Rllf are the same or different and are
selected from hydrogen, halogen, hydroxy, Cl-C6 alkyl,
(C1-C6) alkoxy, amino, or mono- or di (C1-C6) alkylamino;
R12, Rlzf, and Rl' are the same or different and are
selected from hydrogen, halogen, (Cl-C6) alkyl, (Cl
C6) alkoxy, amino, mono- or di (Cl-C6) alkylamino, hydroxy,
or trifluoromethyl; and
R19 is hydrogen, lower alkyl having 1-6 carbon
atoms.
The invention includes all possible tautomers and
rotamers of the compounds represented by Formula I.
By the term "halogen" in the present invention is meant
fluorine, bromine, chlorine, and iodine.
Thg compounds of general Formula I may be
administered orally, topically, parenterally, by inhalation
or spray or rectally in dosage unit formulations containing
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conventional non-toxic pharmaceutically acceptable carriers,
adjuvants and vehicles. The term parenteral as used herein
includes subcutaneous injections, intravenous, intramuscular,
intrasternal injection or infusion techniques. In addition,
there is provided a pharmaceutical formulation comprising a
compound of general Formula I and a pharmaceutically
acceptable carrier. One or more compounds of general Formula
I may be present in association with one or more non-toxic
pharmaceutically acceptable carriers and/or diluents and/or
adjuvants and if desired other active ingredients. The
pharmaceutical compositions containing compounds of general
Formula I may be in a form suitable for oral use, for
example, as tablets, troches, lozenges, aqueous or oily
suspensions, dispersible powders or granules, emulsion, hard
or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared
according to any method known to the art for the manufacture
of pharmaceutical compositions and such compositions may
contain one or more agents selected from the group consisting
of sweetening agents, flavoring agents, coloring agents and
preserving agents in order to provide pharmaceutically
elegant and palatable preparations. Tablets contain the
active ingredient in admixture with non-toxic
pharmaceutically acceptable excipients which are suitable for
the manufacture of tablets. These excipients may be for
example, inert diluents, such as calcium carbonate, sodium
carbonate, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example, corn
starch, or alginic acid; binding agents, for example starch,
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gelatin or acacia, and lubricating agents, for example
magnesium stearate, stearic acid or talc. The tablets may be
uncoated or they may be coated by known techniques to delay
disintegration and absorption in the gastrointestinal tract
and thereby provide a sustained action over a longer period.
For example, a time delay material such as glyceryl
monosterate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with
an inert solid diluent, for example, calcium carbonate,
calcium phosphate or kaolin, or as soft gelatin capsules
wherein the active ingredient is mixed with water or an oil
medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in
admixture with excipients suitable for the manufacture of
aqueous suspensions. Such excipients are suspending agents,
for example sodium carboxymethylcellulose, methylcellulose,
hydropropylmethylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia;
dispersing or wetting agents may be a naturally-occurring
phosphatide, for example, lecithin, or condensation products
of an alkylene oxide with fatty acids, for example
polyoxyethylene stearate, or condensation products of
ethylene oxide with long chain aliphatic alcohols, for
example heptadecaethyleneoxycetanol, or condensation products
of ethylene oxide with partial esters derived from fatty
acids and a hexitol such as polyoxyethylene sorbitol
monooleate, or condensation products of ethylene oxide with
partial esters derived from fatty acids and hexitol
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anhydrides, for example polyethylene sorbitan monooleate.
The aqueous suspensions may also contain one or more
preservatives, for example ethyl, or n-propyl p-
hydroxybenzoate, one or more coloring agents, one or more
flavoring agents, and one or more sweetening agents, such as
sucrose or saccharin.
Oily suspensions may be formulated by suspending the
active ingredients in a vegetable oil, for example arachis
oil, olive oil, sesame oil or coconut oil, or in a mineral
oil such as liquid paraffin. The oily suspensions may
contain a thickening agent, for example beeswax, hard
paraffin or cetyl alcohol. Sweetening agents such as those
set forth above, and flavoring agents may be added to provide
palatable oral preparations. These compositions may be
preserved by the addition of an anti-oxidant such as ascorbic
acid.
Dispersible powders and granules suitable for
preparation of an aqueous suspension by the addition of water
provide the active ingredient in admixture with a dispersing
or wetting agent, suspending agent and one or more
preservatives. Suitable dispersing or wetting agents and
suspending agents are exemplified by those already mentioned
above. Additional excipients, for example sweetening,
flavoring and coloring agents, may also be present.
Pharmaceutical compositions of the invention may also be
in the form of oil-in-water emulsions. The oily phase may be
a vegetable oil, for example olive oil or arachis oil, or a
mineral oil, for example liquid paraffin or mixtures of
these. Suitable emulsifying agents may be naturally-
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occurring gums, for example gum acacia or gum tragacanth,
naturally-occurring phosphatides, for example soy bean,
lecithin, and esters or partial esters derived from fatty
acids and hexitol, anhydrides, for example sorbitan
monoleate, and condensation products of the said partial
esters with ethylene oxide, for example polyoxyethylene
sorbitan monoleate. The emulsions may also contain
sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening
agents, for example glycerol, propylene glycol, sorbitol or
sucrose. Such formulations may also contain a demulcent, a
preservative and flavoring and coloring agents. The
pharmaceutical compositions may be in the form of a sterile
injectable aqueous or oleaginous suspension. This suspension
may be formulated according to the known art using those
suitable dispersing or wetting agents and suspending agents
which have been mentioned above. The sterile injectable
preparation may also be sterile injectable solution or
suspension in a non-toxic parentally acceptable diluent or
solvent, for example as a solution in 1,3-butanediol. Among
the acceptable vehicles and solvents that may be employed are
water, Ringer's solution and isotonic sodium chloride
solution. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium.
For this purpose any bland fixed oil may be employed
including synthetic mono-or diglycerides. In addition, fatty
acids such as oleic acid find use in the preparation of
inj ectables .
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The compounds of general Formula I may also be
administered in the form of suppositories for rectal
administration of the drug. These compositions can be
prepared by mixing the drug with a suitable non-irritating
excipient which is solid at ordinary temperatures but liquid
at the rectal temperature and will therefore melt in the
rectum to release the drug. Such materials are cocoa butter
and polyethylene glycols.
Compounds of general Formula I may be administered
parenterally in a sterile medium. The drug, depending on the
vehicle and concentration used, can either be suspended or
dissolved in the vehicle. Advantageously, adjuvants such as
local anesthetics, preservatives and buffering agents can be
dissolved in the vehicle.
Dosage levels of the order of from about 0.1 mg to about
140 mg per kilogram of body weight per day are useful in the
treatment of the above-indicated conditions (about 0.5 mg to
about 7 g per patient per day). The amount of active
ingredient that may be combined with the carrier materials to
produce a single dosage form will vary depending upon the
host treated and the particular mode of administration.
Dosage unit forms will generally contain between from about
1 mg to about 500 mg of an active ingredient.
Frequency of dosage may also vary depending on the
compound used and the particular disease treated. However,
for treatment of most disorders, a dosage regimen of 4 times
daily or less is preferred. For the treatment of obesity or
diabetes, a dosage regimen of 1 or 2 times daily is
particularly preferred.
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It will be understood, however, that the specific dose
level for any particular patient will depend upon a variety
of factors including the activity of the specific compound
employed, the age, body weight, general health, sex, diet,
time of administration, route of administration, and rate of
excretion, drug combination and the severity of the
particular disease undergoing therapy.
Preferred compounds of the invention will have certain
pharmacological properties. Such properties include, but are
not limited to oral bioavailability, low toxicity, low serum
protein binding and desirable in vitro and in vivo half
lifes. Penetration of the blood brain barrier for compounds
used to treat CNS disorders is necessary, while low brain
levels of compounds used to treat periphereal disorders are
often preferred.
Assays may be used to predict these desirable
pharmacological properties. Assays used to predict
bioavailability include transport across human intestinal
cell monolayers, including Caco-2 cell monolayers. Toxicity
to cultured hepatocyctes may be used to predict compound
toxicity. Penetration of the blood brain barrier of a
compound in humans may be predicted from the brain levels of
the compound in laboratory animals given the compound
intravenously.
Serum protein binding may be predicted from albumin
binding assays. Such assays are described in a review by
Oravcova, et al. (Journal of Chromatography B (1996) volume
677, pages 1-27).
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Compound half-life is inversely proportional to the
frequency of dosage of a compound. In vitro half-lifes of
compounds may be predicted from assays of microsomal half-
life as described by Kuhnz and Gieschen (Drug Metabolism and
Disposition, (1998) volume 26, pages 1120-1127).
The present invention also pertains to packaged
pharmaceutical compositions for treating disorders responsive to
GLP receptor modulation, e.g., treatment obesity or diabetes. The
packaged pharmaceutical compositions include a container holding a
therapeutically effective amount of at least one compound of
Formula I supra and instructions for using the treating disorder
responsive to GLP receptor modulation in the patient.
The disclosures of all articles and references mentioned
in this application, including patents, are incorporated
herein by reference.
Compounds of the invention can be prepared using the
reactions depicted in Schemes I to VII. The numbers
appearing below or adjacent the chemical structures in these
schemes refer to intermediates and are not to be confused
with the compound numbers found in the examples.
Scheme 1
NH HC1
1. RNH2 in DMF K2C03 EtO~CI
N~2 DMSO or ~ NH2 R ~ N CI
7 ~--~
> ~ ~ ~ H . > ~ ~ ~R
a a
F 2. [H] N in CHC13 , R
H2, 10% Pd/C R DMF or EtOH
1 or
TiCl3 dil HC1 2 3
or
SnCl2 conc HC1
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Scheme II
O
R, N-H CI~X~Ar \ R\N~
/ ~ > I / ~ > I / ~ -'~(X
N ~N
R~ CH3CN , R~ TEA, toluene N R~ Ar
R R R
4 5
Scheme III
CI R~~ ,,O
-~N
R~ O ~ OR I ~ ~--~ X
I ~ ~ 1. ~ / R~Ar
1. R'NH2 ~ N N
/ I \~ X s
~N R ' / i
~N Ar
R~ 2' ~Br / O
Br
(V n
CI X-Ar
3. NHR~RB R7 N~~
Scheme IV
R'~ ,,O
~N
I ~-( X
~N R~A~
11
R'~ ,.O
I 1. R'NH2 ~ N~ I / R"
i N R > I i ~ X CI ~
N H ~ 2. N~ N R~ Ar R'~ //O
C~X'Ar H I ~ R" ~ ~ N
10 ~ I / ~ A~
12
~ R"
Scheme V
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R'~
\ \
X
~N A~
R~
R'~ ~ w
I \ I 1. R'NH2 \ ~ / R
\
N ~ N~ > N ~ ~ ~ >
R~ ~~N Ar CI ,
H 2. ~ , R7 R '
CI"X'Ar H I ~ R" \ \ X
13
R~
16
I ~ R"
Scheme VI
H HC1
1. RNH2 in DMF Et0 CI
K2C03
\ N02 DMSO or \ NH2 R7 ~~I
> I >
i .H i N R
N CI 2. [H] ~ ~I~ in CHC13 N
H2, 10% PdJC R , R
17 or DMF or EtOH
TiCl3 dil HCl 1g 19
or
SnCl2 conc HC1
5 Scheme VII
NH HC1
1. RNH2 in DMF K2C03 EtO~CI
N \ N~2 DMSO or \ NH2 R~ N \ N CI
\
> ~ / H s I / N
CI 2. H
[ ] N in CHC13 , I
H2, 10% Pd/C R DMF or EtOH R
or
TiCl3 dil HCl 21 22
or
SnCl2 conc HC1
Those having skill in the art will recognize that the
10 starting materials may be varied and additional steps
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employed to produce compounds encompassed by the present
invention, as demonstrated by the following examples.
The following examples illustrate the general procedures
for the preparation of compounds of the invention using the
reactions outlined above in Schemes I-VII. These examples
are not to be construed as limiting the invention in scope or
spirit to the specific procedures and compounds described in
them.
Example 1
General Procedure for the preparation of
chloromethylbenzimidazoles as outlined in Scheme I
1. Imidate hydrochloride:
A solution of 150 mL ( 2.37 mole) of chloroacetonitrile,
139 mL ( 2.37 mole) of ethanol in 1,200 mL of dry benzene is
cooled to 0 oC in an ice/ethanol bath. Dry HC1 gas is
bubbled through the vigorously stirred solution for
approximately 30 min. while the internal temperature is
maintained below 10 oC. The solution is allowed to stand at
rt. overnight. The resulting solid is filtered and washed
with 2L of dry ether and allowed to air dry to afford 328 g
(88%) of imidate hydrochloride.
2. 2-(chloromethyl)-1-[(2-
methylphenyl)methyl]benzimidazole:
N~I
N
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A solution of 27 g (0.13 mole) of (2-aminophenyl)(2-
methylphenyl)amine in 200 mL of anhydrous CHC13 is treated
with 30.81 g (0.19 mole) of imidate at room temperature. The
heterogeneous reaction mixture is allowed to stir for 1 hr.
at room temperature at which time no starting material is
detectable by TLC. 100 mL of saturated NaHC03 is added and
extracted 3 X 100 mL of CH2C12. The extracts are dried over
anhydrous Na2S04, the solvent removed in vacuo, and the
residue chromatgraphed (Si02) with 50% ethyl acetate/hexane
to afford 22 g (62%) of 2-(chloromethyl)-1-((2-
methylphenyl)methyl] benzimidazole. Mass Spec M' 271.
3. 2-(chloroethyl)-1-propylbenzimidazole
N~I
N
A solution of 8 g (0.053 mole) of (2-
aminophenyl)propylamine in 50 mL of anhydrous DMF is treated
with 9.0 g (0.056 mole) of 2-chloro-1-ethoxypropanimine
hydrochloride at 80 °C for 16 hr. The reaction mixture is
cooled to room temperature diluted with 200 mL of ethyl
acetate and washed 3X 100 mL water, 1X 100 mL brine, organic
extracts are dried over anhydrous Na2S04, the solvent removed
in vacuo, and the residue chromatgraphed (Si02) with 30%
ethyl acetate/hexane to afford 3 g (28%) of 2- (chloroethyl) -
1-propylbenzimidazole.
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Example 2
General Procedure for the preparation of
benzimidazoles as shown in Scheme II
((2,4-dimethoxyphenyl)-N-(3-methylbutyl)-N-({1-[(2-
methylphenyl)methyl]benzimidazol-2-yl}methyl)carboxamide
c
Compound 1
A solution of 5.4 mmole 2-(chloromethyl)-1-[(2-
methylphenyl)methyl] benzimidazole in 20 mL of dry
Acetonitrile is treated with 10 mL of isoamylamine for 16 hr
at room temperature. The solvent is removed in vacuo and the
residue is partitioned between 30 mL of ethyl acetate and 10
mL of 1 N NaOH. The ethyl acetate layer is dried over
anhydrous Na2S04 and solvent removed in vacuo to afford 1.6 g
92% ({1-[(2-methylphenyl)methyl]benzimidazol-2-yl}methyl)(3-
methylbutyl) amine. 2,4-dimethoxybenzoylchloride 1.5 eq is
treated with 1.0 eq of ((1-[(2-
methylphenyl)methyl]benzimidazol-2-yl}methyl)(3-methylbutyl)
amine in dichloromethane at room temperature for 1 hr. The
reaction is quenched with 1 N NaOH and partitioned between
dichloromethane and water. The organic layer is dried with
Na2S04 and the solvent removed in vacuo. The residue is
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chromatographed (Si02) with ethyl acetate to afford 95% of
(2,4-dimethoxyphenyl)-N-({1-[(2-
methylphenyl)methyl]benzimidazol-2-yl}methyl)-N-(3-
methylbutyl)carboxamide (Compound 1). Mass Spec M' 486.
Following the above procedures, compounds 11, 12 and 15,
16 are prepared starting from 2-(chloromethyl)imidazolo(5,4-
b]pyridine and 2-(chloromethyl)imidazolo[5,4-c]pyridine
respectivly. (Cleve, G: Gibian, H.; Hoyer, G.; Rahtz, D.;
Schroeder, E.; Schulz, G. Justus Liebigs Ann. Chem. 1971,
747, 158-171)
Example 3
The following compounds are prepared essentially
according to the procedure described in Examples 1-2, and as
shown in Schemes I-VII:
(a) 2-(2,3-dimethylphenoxy)-N-methyl-N-[(1-
propylbenzimidazol-2-yl)ethyl]acetamide M+ 381 amu. (Compound
2)
O
I / ~N~o \
~N
(b) 2-(2,3-dimethylphenoxy)-N-{[1-
(cyclopropylmethyl)benzimidazol-2-yl]ethyl}-N-methylacetamide
M+ 393 amu. (Compound 3)
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O
I w ~NJ~o \
~N
(c) (2,4-dimethoxyphenyl)-N-({1-[(2-
ehlorophenyl)methyl]benzimidazol-2-yl}methyl)-N-(3-
methylbutyl)carboxamide M+507 amu. (Compound 4)
/ O\
O \
I \ ~N~
/ N
CI
(d) (2,4-dimethoxyphenyl)-N-(3-methylbutyl)-N-({3-[(2-
methylphenyl)methyl]imidazolo[5,4-b]pyridin-2-
l0 yl}methyl)carboxamide M' 488 amu. (Compound 5)
,O / I O~
N O \
N- ~N
N
(e) 2-(2,3-dimethylphenoxy)-N-methyl-N-[(3-
propylimidazolo[5,4-b]pyridin-2-yl)ethyl]acetamide M' 381 amu.
(Compound 6)
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O
N N
~-O
N N
(f) 2-(2,3-dimethylphenoxy)-N-f[1-(cyclopentyl)-6-
chlorobenzimidazol-2-yl]ethyl}-N-methylacetamide M' 441 amu.
(Compound 7)
C
Example 4
Assav for Glucagon-like Peptide Receptor Activation
The following assay may be used to quantitate the
effects of compounds on GLP-1 activity.
Glucagon-like peptide 1 receptor activation is carried
out by measuring the second messenger cyclic adenosine
monophosphate (cAMP). The host cell for such studies can be
any that endogenously expresses the Glp-1 receptor, such as
the Rin MSF or HIT - TI5 insulinomas, or a cell line that
expresses the recombinant form of that receptor. For this
purpose, the appropriate cells are plated in the either 24 or
96 well plates and the cells are grown to a 75 to 95% level
of confluence. Cells are usually plated 24 to 48 hours prior
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to assay. Immediately prior to the receptor activation
study, the cells are rinsed with a phosphate buffered saline
solution, and cells are incubated with from 1 to 10 mM
isobutylmethylxanthine, (IBMX). The purpose of IBMX is to
inhibit the enzyme cAMP phosphodiesterase, which breaks down
cAMP. The use of IBMX allows one to more easily detect the
ability of a hormone or drug to activate the Glp-1 receptor.
In a typical assay, either the Glp-1 peptide or drug is added
directly to the 24 or 96 well plate, and is incubated with
the cells for up to 60 minutes at 37°C. After the desired
time, the receptor activation event is terminated by the
addition of hydrochloric acid to the cells, which also lyses
the cells and liberates the cAMP that has accumulated within
the cells. This cellular extract is harvested and
neutralized with sodium hydroxide, and the cells lysates are
cleared by microcentrifugation. The cell extract is then
analyzed in a cAMP radioimmunoassay, such as that
commercially available from NEN Life Science Products or
Amersham. The amount of cAMP generated per well of cells
treated with hormone or drug can be compared to that observed
without the addition of such agent, to obtain an index of
receptor activation. Dose-response curves are also performed
to obtain the level of potency and efficacy of any test
compound.
In the described assay, preferred compounds of the
invention will have 5% or greater stimulation with respect to
GLP-1.
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Example 5
Glucose Tolerance Test
Following overnight fasting adult male (200-300g)
Sprague-Dawley rats are injected orally with either vehicle
or glucose solution in a given concentration. Following
thirty-five minutes of resting in their home cages, the
animals are brought back into the laboratory and restrained
using a BRAINTREE SCIENTIFIC adjustable restrainer. Within
five minutes of restraint, one of the lateral tail veins is
catheterized, and the animals are given intravenous (iv)
injection of either glucagon-like polypeptide 1 (GLP1) or
test compound. Five minutes after iv injection, the animals
are euthanized by decapitation, and trunk blood is collected
in tubes containing EDTA. The plasma levels of insulin and
glucose measured using appropriate radio-immunoassay (RIA)
kits.
Example 6
Stre~tozocin-Induced Diabetes Glucose Tolerance Test
Streptozotocin is an antibiotic extracted from Streptomyces
achromogenes, which when injected into animals, causes
pancreatic ~3-cell degranulation and necrosis. To achieve mild
necrosis of pancreatic (3-cells, which induces a state of
diabetes without affecting normal development and weight
gain, a 35mg/kg/5m1 dose STZ is injected intraperitoneally
(ip) into a group of healthy, naive animals. The control
group animals receive 0.1 N citrate buffer (vehicle, 5m1/kg,
10=16). Five days after ip injections (day5), the diabetic
symptoms are assessed via the following test of glucose
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tolerance. All animals receive an oral injection of
3g/kg/lOml glucose solution between 3:00 and 5:00 PM. Forty
minutes later, their blood glucose levels are measured using
the LIFE SCAN ONE TOUCH glucose monitoring system. Animals
are restrained and a blood sample is taken from a lateral
tail vein. Animals that show substantially higher blood
glucose levels (100 to 250% higher than non-STZ treated
animals, normally 2/3 of STZ treated animals) are used to
assess the effects of test compounds in this animal model of
diabetes. On day 7, following overnight fast, the animals
are subjected to glucose tolerance test using a procedure
identical to that described above. The test compound is
injected iv or orally and IV injection of GLP-1 is used as a
positive control.
Example 7
Preparation of radiolabeled probe compounds of the invention
The compounds of the invention are prepared as
radiolabeled probes by carrying out their synthesis using
precursors comprising at least one atom that is a
radioisotope. The radioisotope is preferably selected from
of at least one of carbon (preferably 14C), hydrogen
(preferably 3H) , sulfur (preferably 35S) , or iodine
(preferably lash. Such radiolabeled probes are conveniently
synthesized by a radioisotope supplier specializing in custom
synthesis of radiolabeled probe compounds. Such suppliers
include Amersham Corporation, Arlington Heights, IL;
Cambridge Isotope Laboratories, Inc. Andover, MA; SRI
International, Menlo Park, CA; Wizard Laboratories, West
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Sacramento, CA; ChemSyn Laboratories, Lexena, KS; American
Radiolabeled Chemicals, Inc., St. Louis, MO; and Moravek
Biochemicals Inc., Brea, CA.
Tritium labeled probe compounds are also conveniently
prepared catalytically via platinum-catalyzed exchange in
tritiated acetic acid, acid-catalyzed exchange in tritiated
trifluoroacetic acid, or heterogeneous-catalyzed exchange
with tritium gas. Such preparations are also conveniently
carried out as a custom radiolabeling by any of the suppliers
listed in the preceding paragraph using the compound of the
invention as substrate. In addition, certain precursors may
be subjected to tritium-halogen exchange with tritium gas,
tritium gas reduction of unsaturated bonds, or reduction
using sodium borotritide, as appropriate.
Example 8
Receptor autoradiography
Receptor autoradiography (receptor mapping) is carried
out in vitro as described by Kuhar in sections 8.1.1 to 8.1.9
of Current Protocols in Pharmacology (1998) John Wiley &
Sons, New York, using radiolabeled compounds of the invention
prepared as described in the preceding Example.
The invention and the manner and process of making and
using it, are now described in such full, clear, concise and
exact terms as to enable any person skilled in the art to
which it pertains, to make and use the same. It is to be
understood that the foregoing describes preferred embodiments
of the present invention and that modifications may be made
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therein without departing from the spirit or scope of the
present invention as set forth in the claims. To
particularly point out and distinctly claim the subject
matter regarded as invention, the following claims conclude
this specification.
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