Note: Descriptions are shown in the official language in which they were submitted.
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
1
USE OF CBX CANNABINOID RECEPTOR MODULATORS AS
POTASSIUM CHANNEL MODULATORS
FIELD OF THE INVENTION
The present invention relates to the novel use of CBX modulators as KATP
channel
modulators. The present invention also relates to a method of treating,
preventing,
delaying progression of, delaying onset of and/or inhibiting obesity, diabetes
mellitus,
metabolic syndrome, syndrome X, insulinoma, familial hyperinsulemic
hypoglycemia,
male pattern baldness, detrusor hyperreactivity, asthma, neuroprotection,
epilepsy,
analgesia, cardioprotection, angina, cardioplegia, arrhythmia, coronary spasm,
peripheral vascular disease, cerebral vasospasm, appetite regulation,
neurodegeneration, pain - including neuropathic pain and chronic pain - and
impotence
in mammals and humans comprising administering to a subject in need thereof an
effective amount of at least one CBX modulator as KATP channel modulator.
BACKGROUND OF THE INVENTION
Obesity according to the present invention is meant to comprise any increase
in
body fat that results in increased bodyweight, preferably comprising but not
limited to
the medical definition of obesity. Thus, in accordance with the invention,
obesity also
comprises non-medical, e.g. cosmetic overweight. The invention thus also
relates to
non-medical weight loss, such as cosmetic weight loss and includes improving
bodily
appearance in general. In a more narrowed sense, obesity is usually understood
to
denominate a body weight more than 20 % above the ideal body weight. Even in
this
more narrowed sense, obesity is a major health concern in Western societies.
It is
estimated that about 97 million adults in the United States are overweight or
obese.
Obesity is largely the result of a positive energy balance as a consequence of
increased ratio of caloric intake to energy expenditure. The molecular factors
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
2
regulating food intake and body weight are incompletely understood, but
several
genetic factors have been identified.
Epidemiological studies have shown that increasing degrees of overweight and
obesity are important predictors of decreased life expectancy. Obesity causes
or
exacerbates many health problems, both independently and in association with
other
diseases. The medical problems associated with obesity, which can be serious
and
life-threatening, generally include hypertension; type II diabetes mellitus;
elevated
plasma insulin concentrations; insulin resistance; dyslipidemias;
hyperlipidemia;
endometrial, breast, prostate and colon cancer; osteoarthritis; respiratory
complications, such as obstructive sleep apnea; cholelithiasis; gallstones;
arteriosclerosis; heart disease; abnormal heart rhythms; and heart arrythmias.
Obesity
is further associated with premature death and with a significant increase in
mortality
and morbidity from stroke, myocardial infarction, congestive heart failure,
coronary
heart disease, and sudden death.
Obesity is often treated by encouraging patients to lose weight by reducing
their
food intake or by increasing their exercise level and therefore increasing
their energy
output. A sustained weight loss of 5% to 10% of body weight has been shown to
improve the co-morbidities associated with obesity, such as diabetes and
hypertension,
and can lead to improvement of obesity-related conditions such as
osteoarthritis, sleep
apnea and pulmonary and cardiac dysfunction.
Weight loss drugs that are currently used in monotherapy for the treatment of
obesity have limited efficacy and significant side effects. During chronic
treatment
periods of greater than six months the efficacy of most agents decreases
yielding no
more than 10% body weight loss compared to control. Obese humans can easily
mass
over 150 kg and would, therefore, need to lose more than 50% of their body
mass to
return to a normal body mass.
The term "metabolic syndrome" is meant to cover a complex of clinical pictures
which - besides central obesity - mainly comprises hypertension, in particular
arterial
hypertension; insulin resistance, in particular type II diabetes; glucose
intolerance;
dyslipoproteinaemia, in particular as hypertriglyceridaemia, accompanied by
dyslipoproteinaemia occurring with lowered HDL-cholesterol, and also
hyperuricaemia,
which can lead to gout.
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
3
According to information from the American Heart Association, the metabolic
syndrome is closely linked to insulin resistance. Some people are genetically
predisposed to insulin resistance. Acquired factors, such as excess body fat
and
physical inactivity, can elicit insulin resistance and the metabolic syndrome
in these
people. Most people with insulin resistance have central obesity. The biologic
mechanisms at the molecular level between insulin resistance and metabolic
risk
factors are not fully understood and appear to be complex. One group of people
at risk
for developing metabolic syndrome is those with diabetes who have a defect in
insulin
action and cannot maintain a proper level of glucose in their blood. Another
is people,
mainly those with high blood pressure, who are non-diabetic and insulin-
resistant but
who compensate by secreting large amounts of insulin. This condition is known
as
hyperinsulinemia. A third group is heart attack survivors who, unlike
hypertensives,
have hyperinsulinemia without having abnormal glucose levels. The metabolic
syndrome has become increasingly common in higher developed countries like the
United States, where it is estimated that about 20-25 percent of US adults
have it.
There are no well-accepted criteria for diagnosing the metabolic syndrome. The
criteria proposed by the Third Report of the National Cholesterol Education
Program
(NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults (Adult Treatment Panel III) are the most current and
widely used.
According to the ATP III criteria, the metabolic syndrome is identified by the
presence
of three or more of these following components:
a. Central obesity as measured by waist circumference (Men - Greater than
40 inches; Women - Greater than 35 inches).
b. Fasting blood triglycerides greater than or equal to 150 mg/dL.
c. Blood HDL cholesterol (Men - Less than 40 mg/dL; Women - Less than 50
mg/dL)
d. Blood pressure greater than or equal to 130/85 mmHg.
e. Fasting glucose greater than or equal to 110 mg/dL.
The term "syndrome X" is closely related to the term "metabolic syndrome" and
usually is supposed to denominate the identical disease or condition.
According to
information from the American Heart Association, the term "Syndrome X" refers,
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
4
however, additionally to a heart condition where chest pain and
electrocardiographic
changes that suggest ischemic heart disease are present, but where there are
no
angiographic findings of coronary disease. Patients with cardiac syndrome X
also
sometimes have lipid abnormalities.
Therefore, it was an objective of the present invention to provide a more
effective
and/or more selective therapy for obesity, diabetes mellitus, metabolic
syndrome,
syndrome X, insulinoma, familial hyperinsulemic hypoglycemia, male pattern
baldness,
detrusor hyperreactivity, asthma, neuroprotection, epilepsy, analgesia,
cardioprotection,
angina, cardioplegia, arrhythmia, coronary spasm, peripheral vascular disease,
cerebral vasospasm, appetite regulation, neurodegeneration, pain - including
neuropathic pain and chronic pain - and impotence.
ATP-sensitive potassium channel (KATP channel) modulation has been linked to
several potential clinical uses including diabetes, insulinoma, familial
hyperinsulemic
hypoglycemia, male pattern baldness, detrusor hyperreactivity, asthma,
neuroprotection, epilepsy, analgesia, cardioprotection, angina, cardioplegia,
arrhythmia, coronary spasm, hypertension, peripheral vascular disease,
cerebral
vasospasm, appetite regulation, neurodegeneration, pain - including
neuropathic pain
and chronic pain - and impotence (ref. Jahangir et al. J. Mol. Cell.
Cardio/ogy, 2005,
39, 99-112 and references cited therein).
KATP channel openers and their potential use in the inhibition of insulin
secretion
and/or the treatment of metabolic disorders are known e.g. from documents US
6,492,130; WO 02/00223; WO 02/00665 or from R.D. Carr et al., Diabetes 52
(2003)
2513-2518 or J.B. Hansen et al., Current Medicinal Chemistry 11 (2004) 1595-
1615.
The beneficial role of the specific KATP channel opener diazoxide in the
treatment
of i.a. the metabolic syndrome is known e.g. from documents US 5,284,845 or US
6,197,765 or from R. Alemzadeh et al., Endocrinology 133 (2) (1993) 705-712 or
R.
Alemzadeh et al., Journal of Clinical Endocrinology and Metabolism 83 (6)
(1998)
1911-1915.
The KATP channel couples glucose metabolism to insulin secretion. Defective
regulation of KATP channel activity has been reported to contribute to the
etiology of
type 2 diabetes (ref. Ashcroft, J. Clin. Investig. 2005, 115 (8), 2047-2057
and
references cited therein). The KATP channel is an octameric complex of 4
Kir6.x (x = 1
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
or 2) and 4 regulatory SURy subunits (Y = 1, 2A or 2B). The SUR1 regulatory
subunit
is in particular found in pancreas and brain (ref. Aguilar-Bryan et al.,
Science 1995, 268,
423-426). The KATP Kir6.2/SUR1 combination exists in the pancreas. Its
structure has
been determined recently (ref. Mikhailov, EMBO Journal, 2005, 24, (23), 4166-
4175).
5 Recent advances in the discovery of ATP-sensitive potassium channel openers
have
been reviewed (Pirotte et al., Exp Opin. Ther. Patents 2005, 15 (5), 497-504).
Insulin is the main hormone involved in blood glucose homeostasis. Insulin is
involved in the regulation of glycaemia and as a consequence related to type I
and type
II diabetes. Additionally, insulin is involved in lipogenesis and weight gain,
provoking
an anorexigenic action as it provokesa satiety when acting in the brain (ref.
Juan-Pico
et al., Cell Calcium 2006, 39, 155-163 and references cited therein).
Therefore, the regulation of insulin secretion will be useful in the treatment
of
diseases such as diabetus mellitus type I, diabetus mellitus type II, obesity,
metabolic
syndrome and syndrome X.
The endocannabinoid system (refs. (a) De Petrocellis, L. et al., Br. J.
Pharmacol.
2004 141, 765-774; (b) Di Marzo, V. et al., Nature Rev. Drug Discov. 2004, 3,
771-784;
(c) Lambert, D.M. and Fowler, C.J. J. Med. Chem. 2005, 48, 5059-5087) has been
reported to play a role in the physiological regulation of food intake, energy
balance
and glucose and lipid metabolism. The existence of both cannabinoid CB1 and
CB2
receptors has been demonstrated in the endocrine pancreas. It has been
reported that
the endogenous CB112 receptor agonist 2-arachidonoyl glycerol (2-AG) (Figure
2)
through CB2 receptors regulates [Ca2+]; signals in (3-cells in the endocrine
pancreas and
as a consequence (as was concluded by Juan-Pico et al.) it decreases insulin
secretion
(ref. Juan-Pico et al., Cell Calcium 2006, 39, 155-163). Recent advances in
the field of
CB2 receptor ligands have been reviewed by Raitio et al. (Curr. Med. Chem.
2005, 12,
1217-1237).
It has now surprisingly been found that the quantitative effects observed
within
the use of CBX modulators in the indications mentioned herein are greater than
expected and explainable by a single mechanism of CBX modulation. By a more
thorough investigation, it has been proved and demonstrated that CBX
modulators act
as KATP channel modulators. Hence, CBX modulators can be used for and against
all
illnesses and diseases which require opening of KATP channels. More
specifically, CBX
modulators act can be used for treating, preventing, delaying progression of,
delaying
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
6
onset of and/or inhibiting obesity, diabetes mellitus, metabolic syndrome,
syndrome X,
insulinoma, familial hyperinsulemic hypoglycemia, male pattern baldness,
detrusor
hyperreactivity, asthma, neuroprotection, epilepsy, analgesia,
cardioprotection, angina,
cardioplegia, arrhythmia, coronary spasm, peripheral vascular disease,
cerebral
vasospasm, appetite regulation, neurodegeneration, pain - including
neuropathic pain
and chronic pain - and impotence in mammals and humans.
SUMMARY OF THE INVENTION
In a first aspect, the present invention relates to the use of at least one
CBX
modulator wherein the CBX modulator is selected from the group consisting of
CB1
agonists; CB2 agonists; CB2 partial agonists; CB2 antagonists; CB2 inverse
agonists;
and dually acting compounds which are both a CB1 agonist and a CB2 agonist;
and
mixtures thereof, as KATP channel modulator for the prophylaxis, treatment,
delayed
progression, delayed onset and/or inhibition of obesity, diabetes mellitus,
metabolic
syndrome, syndrome X, insulinoma, familial hyperinsulemic hypoglycemia, male
pattern baldness, detrusor hyperreactivity, asthma, neuroprotection, epilepsy,
analgesia, cardioprotection, angina, cardioplegia, arrhythmia, coronary spasm,
peripheral vascular disease, cerebral vasospasm, appetite regulation,
neurodegeneration, pain - including neuropathic pain and chronic pain - and
impotence
in mammals and humans.
In a second aspect, the invention also relates to a method of treating,
preventing,
delaying progression of, delaying onset of and/or inhibiting obesity, diabetes
mellitus,
metabolic syndrome, syndrome X, insulinoma, familial hyperinsulemic
hypoglycemia,
male pattern baldness, detrusor hyperreactivity, asthma, neuroprotection,
epilepsy,
analgesia, cardioprotection, angina, cardioplegia, arrhythmia, coronary spasm,
peripheral vascular disease, cerebral vasospasm, appetite regulation,
neurodegeneration, pain - including neuropathic pain and chronic pain - and
impotence
in mammals and humans comprising administering to a subject in need thereof an
effective amount of at least one CBX modulator wherein the CBX modulator is
selected
from the group consisting of CB1 agonists; CB2 agonists; CB2 partial agonists;
CB2
antagonists; CB2 inverse agonists; and dually acting compounds which are both
a CB1
agonist and a CB2 agonist; and mixtures thereof, and wherein the CBX modulator
has
KATP channel modulating properties.
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
7
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment of the present invention, the CBX modulators are used as
KATP
channel modulators for the prophylaxis, treatment, delayed progression,
delayed onset
and/or inhibition of obesity, diabetes mellitus, metabolic syndrome, syndrome
X,
insulinoma, familial hyperinsulemic hypoglycemia, male pattern baldness,
detrusor
hyperreactivity, asthma, neuroprotection, epilepsy, analgesia,
cardioprotection, angina,
cardioplegia, arrhythmia, coronary spasm, peripheral vascular disease,
cerebral
vasospasm, appetite regulation, neurodegeneration, pain - including
neuropathic pain
and chronic pain - and impotence in mammals and humans. More specifically, if
the
CBX modulators are used for the prophylaxis, treatment, delayed progression,
delayed
onset and/or inhibition of the metabolic syndrome and/or syndrome X, it is
understood
that the metabolic syndrome and/or syndrome X comprise disorders or diseases
selected from the group consisting of hypertension, in particular arterial
hypertension;
insulin resistance, in particular diabetes mellitus type II; glucose
intolerance;
dyslipoproteinaemia, in particular as hypertriglyceridaemia accompanied by
dyslipoproteinaemia occurring with lowered HDL-cholesterol and hyperuricaemia.
Suitable KATP channel modulators are preferably compounds which have effects
as full or partial openers at the Kir6.2/SUR1 KATP channel, and/or the Kir6.2/
SUR2 KATP
channel. Effective are those compounds which exhibit an IC50 value [pmol] of
less than
50 in a test for the affinity of the compounds in binding to the sulfonylurea
(= SUR) and
potassium channel opener site (= KCO) of rat and/or human isoforms of SUR1
and/or
SUR2 - e.g. the test model provided below. Compounds with an effect as full or
partial
openers at the Kir6.2/SUR1 KATP channel, in particular as selective openers at
the
Kir6.2/SUR1 KATP channel are preferred. A compound with an effect as full or
partial
opener at the Kir6.2/SUR1 KATP channel is understood to be selective if its
IC50 value at
the Kir6.2/SUR1 KATP channel, as measured in the aforementioned binding test,
is less
than half, more preferred only a quarter, of the IC50 value of that same
compound at the
Kir6.2/SUR2 KATP channel.
It has surprisingly been found that CBX modulators from distinct structural
classes
act as potent and SUR1/SUR2 selective KqTp Kir6.2 channel modulators. CBy
modulators in this invention are CB1 agonists; CB2 agonists; CB2 partial
agonists; CB2
antagonists; CB2 inverse agonists; and dually acting compounds which are both
a CB1
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
8
agonist and a CB2 agonist; and mixtures thereof. KATP channel modulators are
preferably SUR1/KATp Kir6.2 channel modulators, in particular SUR1/ KATP
Kir6.2
channel modulators or partial SUR1/KATp Kir6.2 channel modulators. Preferred
CBx
modulators are compounds which have effects as modulators at the Kir6.2/SUR1
KATP
channel, at the Kir6.2/SUR2B KATP channel, the Kir6.1/ SUR2B KATP channel,
and/or at
the Kir6.2/SUR2A KATP channel.
In a preferred embodiment of the present invention, the KATP channel modulator
is
a KATP channel opener.
CBx modulator which are suitable for use as KATP channel modulator in the
sense
of the present invention are selected from, but not limited to the group
consisting of: 3-
(1,1-dimethyl-butyl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-
benzo[c]chromene; N-
Adamantyl-4-pentyl-5-phenyl-thiazole-2-carboxamide; N-{1,3,3-Trimethyl-endo-(1
S)-
bicyclo[2.2.1 ]hept-2-yl}-1-[1-(4-methyl)-benzyl-5-(4-chloro-3-methyl-phenyl)-
1 H-pyrazol-
3-carboxamide; (2-lodo-5-nitro-phenyl)-[1-(1-methyl-piperidin-2-ylmethyl)-1 H-
indol-3-
yl]-methanone; {4-[4-(1,1-Dimethyl-heptyl)-2,6-dimethoxy-phenyl]-6,6-dimethyl-
bicyclo[3.1.1]hept-2-en-2-yl}-methanol; 3-(1,1-Dimethyl-heptyl)-9-
hydroxymethyl-6,6-
dimethyl-6a,7,10,10a-tetrahydro-6H-enzo[c]chromen-1-ol; Icosa-5,8,11,14-
tetraenoic
acid 2-hydroxy-l-hydroxymethyl-ethyl ester; 1-Aziridin-1-yl-henicosa-6,9,12,15-
tetraen-
2-one; Noladineether; 4,4,4-Trifluoro-butane-l-sulfinic acid 3-(2-
hydroxymethyl-indan-
4-yloxy)-phenyl ester, compound with form aldehyde; 7-Methoxy-2-oxo-8-
pentyloxy-
1,2-dihydro-quinoline-3-carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)-amide; N-
(1-{4-[4-
Chloro-2-(2-fluoro-benzenesulfonyl)-benzenesulfonyl]-phenyl}-ethyl)-
methanesulfonamide; [6-lodo-2-methyl-l-(2-morpholin-4-yl-ethyl)-2,3-dihydro-1
H-indol-
3-yl]-(4-methoxy-phenyl)-methanone; 1-(4-Chloro-phenyl)-2-(2-chloro-phenyl)-5-
ethyl-
1H-imidazole-4-carboxylic acid piperidin-1-ylamide; (2-Methyl-l-propyl-2,3-
dihydro-lH-
indol-3-yl)-naphthalen-1-yl-methanone; 5-(1, 1 -Dimethyl-heptyl)-2-[5-hydroxy-
2-(3-
hydroxy-propyl)-cyclohexyl]-phenol; (2-Methyl-3-morpholin-4-ylmethyl-3,4-
dihydro-5-
oxa-2a-azacenaphthylen-1-yl)-naphthalen-1-yl-methanone; 5-(4-Chloro-phenyl)-1-
(2,4-
dichloro-phenyl)-4-methyl-lH-pyrazole-3-carboxylic acid piperidin-1-ylamide; 5-
(4-
Bromo-phenyl)-1-(2,4-dichloro-phenyl)-4-ethyl-1 H-pyrazole-3-carboxylic acid
piperidin-
1-ylamide; 1-[Bis-(4-chloro-phenyl)-methyl]-3-[(3,5-difluoro-phenyl)-
methanesulfonyl-
methylene]-azetidine; 4-Chloro-N-{[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-
pyrazol-l-
yl]-methylamino-methylene}-benzenesulfonamide; N-{Amino-[3-(4-chloro-phenyl)-4-
phenyl-4,5-dihydro-pyrazol-1-yl]-methylene}-4-chloro-benzenesulfonamide; N-{[3-
(4-
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
9
Chloro-phenyl)-4-pyridin-3-y1-4,5-dihydro-pyrazol-1-yl]-methylamino-methylene}-
4-
trifluoromethyl-benzenesulfonamide; 4-Chloro-N-{[3-(4-chloro-phenyl)-4-pyridin-
3-yl-
4,5-dihydro-pyrazol-1-yl]-methylamino-methylene}-benzenesulfonamide; 4-Chloro-
N-
{[3-(4-chloro-phenyl)-4-(3-fluoro-phenyl)-4,5-dihydro-pyrazol-1-yl]-
methoxyamino-
methylene}-benzenesulfonamide; Morpholine-4-sulfonic acid [3-(4-chloro-phenyl)-
4-
phenyl-4,5-dihydro-pyrazol-1-yl]-methylamino-methyleneamide; N-{[3-(4-Chloro-
phenyl)-4-(3-fluoro-phenyl)-4,5-dihydro-pyrazol-1-yl]-methylamino-methylene}-
N,N-
dimethyl-sulfonamide; Azepane-l-sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-
4,5-
dihydro-pyrazol-1-yl]-methylamino-methyleneamide; 4-Chloro-N-{[3-(4-chloro-
phenyl)-
4-phenyl-4,5-dihydro-pyrazol-l-yl]-[(1-methyl-pyrrolidin-3-ylmethyl)-amino]-
methylene}-
benzenesulfonamide; 1-(4-Chloro-phenyl)-5-phenyl-4,5-dihydro-1 H-pyrazole-3-
carboxamidine; N-{[3-(4-Chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-
methylamino-methylene}-4-trifluoromethyl-benzene-sulfonamide; Piperidine-l-
sulfonic
acid [3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-methylamino-
methyleneamide; Piperidine-l-sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-4,5-
dihydro-
pyrazol-1-yl]-(2-dimethylamino-ethylamino)-methyleneamide; N,N-Diethylamino-l-
sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-
methylsulfanyl-
methyleneamide; 2-Amino-1-[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-
yl]-3-
(3,4-dichloro-phenyl)-propan-l-one; Morpholine-4-sulfonic acid [3-(4-chloro-
phenyl)-4-
phenyl-4,5-dihydro-pyrazol-1-yl]-methylamino-methyleneamide; N,N-Dimethylamino-
l-
sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]-(2-
fluoro-
ethylamino)-methyleneamide; Piperidine-l-sulfonic acid [3-(4-chloro-phenyl)-4-
(3-
fluoro-phenyl)-4,5-dihydro-pyrazol-1 -yl]-methylamino-methyleneamide; 5-(4-
Chloro-
phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid
piperidine-1-
ylamide; 1-(4-Chloro-phenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic
acid
piperidin-l-ylamide; Piperidine-l-sulfonic acid [1-(4-chloro-phenyl)-5-phenyl-
4,5-
dihydro-1H-pyrazol-3-yl]-methylamino-methyleneamide; Morpholine-4-sulfonic
acid [1-
(2,4-dichloro-phenyl)-5-phenyl-4,5-dihydro-1 H-pyrazol-3-yl]-methylamino-
methyleneamide; 4-Chloro-N-[[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-
1-yl]-
(2-fluoro-ethylamino)-methylene]-benzenesulfonamide; 4-Chloro-N-[[3-(4-chloro-
phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-(2-fluoro-ethylamino)-methylene]-
benzenesulfonamide; N-{Amino-[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-
1 -
yl]-methylene}-4-chloro-benzenesulfonamide; 4-Chloro-N-[3-(4-chloro-phenyl)-4-
phenyl-4,5-dihydro-pyrazole-1 -carbonyl]-benzenesulfonamide; 4-Chloro-N-[[3-(4-
chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-(2-ethylamino-ethylamino)-
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
methylene]-benzenesulfonamide; 4-Chloro-N-{[3-(4-chloro-phenyl)-4-phenyl-4,5-
dihydro-pyrazol-1-yl]-[(1-methyl-pyrrolid in-2-ylmethyl)-amino]-methylene}-
benzenesulfonamide; 4-Chloro-N-[[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-
pyrazol-l-
yl]-(4-pyrrolidin-1-yl-butylamino)-methylene]-benzenesulfonamide; 4-Chloro-N-
{[3-(4-
5 chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-[(pyridin-3-ylmethyl)-
amino]-
methylene}-benzenesulfonamide; 1-[3-(4-Chloro-phenyl)-4-phenyl-4,5-dihydro-
pyrazol-
1-yl]-3-(1 H-indol-2-yl)-2-methylamino-propan-1-one; 2-[3-(4-Chloro-phenyl)-4-
phenyl-
4,5-dihydro-pyrazol-1-yl]-5-ethyl-4,5-dihydro-oxazole; 4-Chloro-N-[[3-(4-
chloro-phenyl)-
4-phenyl-4,5-dihydro-pyrazol-1-yl]-(3-hydroxy-2,2-dimethyl-propylamino)-
methylene]-
10 benzenesulfonamide; N,N-Diethylamino-l-sulfonic acid [3-(4-chloro-phenyl)-4-
hydroxy-
4-phenyl-4,5-dihydro-pyrazol-1-yl]-methylamino-methyleneamide; 5-(4-Bromo-
phenyl)-
1-(2,4-dichloro-phenyl)-1 H-pyrazole-3-carbonitrile; 8-Chloro-1-(2,4-dichloro-
phenyl)-
1,3a,4,5,6,10b-hexahydro-1,2-diaza-benzo[e]azulene-3-carboxylic acid piperidin-
l-
ylamide; 5-(4-Bromo-phenyl)-1-(2,4-dichloro-phenyl)-3-[2-(3,5-difluoro-phenyl)-
2-
methanesulfonyl-vinyl]-4-methyl-1H-pyrazole; Piperidine-l-carboxylic acid [5-
(4-chloro-
phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1 H-pyrazol-3-yl]-amide; 1-(4-Chloro-
phenyl)-
2-(2,4-dichloro-phenyl)-5-ethylsulfanyl-1 H-imidazole-4-carboxylic acid
piperidin-l-
ylamide; 2-(2,4-Dichloro-phenyl)-1-(4-trifluoromethyl-phenyl)-1 H-imidazole-4-
carboxylic
acid piperidin-l-ylamide; 1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-
methylsulfanyl-
1 H-imidazole-4-carboxylic acid piperidin-l-ylamide; 1-(4-Chloro-phenyl)-2-
(2,4-
dichloro-phenyl)-1H-imidazole-4-carboxylic acid piperidin-l-ylamide; 1-(4-
Chloro-
phenyl)-2-(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4-carboxylic acid
piperidin-1-
ylamide; 1-(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4-
carboxylic
acid piperidin-l-ylamide; 1-(4-Bromo-phenyl)-5-chloro-2-(2,4-dichloro-phenyl)-
1 H-
imidazole-4-carboxylic acid piperidin-l-ylamide; 1-(4-Bromo-phenyl)-2-(2,4-
dichloro-
phenyl)-5-ethyl-1 H-imidazole-4-carboxylic acid cyclohexylamide; 1-(4-Bromo-
phenyl)-2-
(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4-carboxylic acid pentylamide; 4-
(4-Chloro-
phenyl)-5-(2,4-dichloro-phenyl)-1-methyl-1 H-imidazole-2-carboxylic acid
cyclohexylamide; 4-(4-Chloro-phenyl)-5-(2,4-dichloro-phenyl)-3-methyl-1 H-
imidazole-2-
carboxylic acid cyclohexylamide; 1-(5-Chloro-pyridin-2-yl)-2-(2,4-dichloro-
phenyl)-5-
ethyl-1 H-imidazole-4-carboxylic acid piperidin-l-ylamide; 1-(4-Chloro-phenyl)-
2-(2,4-
dichloro-phenyl)-5-methyl-1 H-imidazole-4-carboxylic acid (4-hydroxy-cyclo-
hexyl)-
amide; 1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methyl-1 H-imidazole-4-
carboxylic
acid azepan-l-ylamide; 2-(2,4-Dichloro-phenyl)-5-ethyl-1-phenyl-1 H-imidazole-
4-
carboxylic acid piperidin-l-ylamide; 2-(1,5-Dimethyl-1H-pyrrol-2-yl)-5-ethyl-1-
phenyl-
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
11
1H-imidazole-4-carboxylic acid cyclohexylamide; 1-(4-Chloro-phenyl)-5-ethyl-2-
(3-
methyl-pyridin-2-yl)-1H-imidazole-4-carboxylic acid piperidin-1-ylamide; 1-(4-
Chloro-
phenyl)-2-(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4-carboxylic acid
piperidin-1-
ylamide; 1-(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4-
carboxylic
acid piperidin-1-ylamide; 1-(4-Bromo-phenyl)-5-chloro-2-(2,4-dichloro-phenyl)-
1H-
imidazole-4-carboxylic acid piperidin-1-ylamide; 1-(4-Bromo-phenyl)-2-(2,4-
dichloro-
phenyl)-5-ethyl-1 H-imidazole-4-carboxylic acid cyclohexylamide; 1-(4-Bromo-
phenyl)-2-
(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4-carboxylic acid pentylamide; 4-
(4-Chloro-
phenyl)-5-(2,4-dichloro-phenyl)-1-methyl-1 H-imidazole-2-carboxylic acid
cyclohexylamide; 4-(4-Chloro-phenyl)-5-(2,4-dichloro-phenyl)-3-methyl-1 H-
imidazole-2-
carboxylic acid cyclohexylamide; 1-(5-Chloro-pyridin-2-yl)-2-(2,4-dichloro-
phenyl)-5-
ethyl-1 H-imidazole-4-carboxylic acid piperidin-l-ylamide; 1-(4-Chloro-phenyl)-
2-(2,4-
dichloro-phenyl)-5-methyl-1 H-imidazole-4-carboxylic acid (4-hydroxy-cyclo-
hexyl)-
amide; 1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methyl-1 H-imidazole-4-
carboxylic
acid azepan-l-ylamide; 2-(2,4-Dichloro-phenyl)-5-ethyl-1-phenyl-1H-imidazole-4-
carboxylic acid piperidin-l-ylamide; 2-(1,5-Dimethyl-1H-pyrrol-2-yl)-5-ethyl-1-
phenyl-
1H-imidazole-4-carboxylic acid cyclohexylamide; 1-(4-Chloro-phenyl)-5-ethyl-2-
(3-
methyl-pyridin-2-yl)-1H-imidazole-4-carboxylic acid piperidin-l-ylamide; 1-(4-
Chloro-
phenyl)-5-ethyl-2-(3-methyl-pyridin-2-yl)-1 H-imidazole-4-carboxylic acid
cyclohexylamide; 1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methyl-1 H-
imidazole-4-
carboxylic acid (4-trifluoromethyl-phenyl)-amide; 2-(2,4-Dichloro-phenyl)-5-
methyl-1-
pyridin-2-yl-1H-imidazole-4-carboxylic acid piperidin-l-ylamide; 1-(4-Chloro-
phenyl)-2-
(2,4-dichloro-phenyl)-5-fluoromethyl-1 H-imidazole-4-carboxylic acid piperidin-
l-ylamide;
1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-hydroxymethyl-1 H-imidazole-4-
carboxylic
acid piperidin-l-ylamide; 1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-
methylsulfanyl-
1H-imidazole-4-carboxylic acid cyclohexylamide; 1-(4-Chloro-phenyl)-2-(2,4-
dichloro-
phenyl)-5-methanesulfonyl-1H-imidazole-4-carboxylic acid piperidin-l-ylamide;
1-(4-
Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methanesulfinyl-1 H-imidazole-4-
carboxylic
acid piperidin-l-ylamide; 5-(4-Chloro-phenyl)-4-(2,5-dichloro-phenyl)-1-methyl-
1 H-
imidazole-2-carboxylic acid piperidin-l-ylamide; 2-(2-Chloro-phenyl)-1-(5-
chloro-
pyridin-2-yl)-5-ethyl-1H-imidazole-4-carboxylic acid piperidin-l-ylamide; 1-(4-
Chloro-
phenyl)-2-(2,4-dichloro-phenyl)-5-(2,2,2-trifluoro-ethyl)-1 H-imidazole-4-
carboxylic acid
piperidin-l-ylamide; N-[1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methyl-1
H-
imidazol-4-yl]-benzamide; 1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-
pyrrolidin-1-
ylmethyl-1 H-imidazole-4-carboxylic acid piperidin-l-ylamide; 2-[1-(4-Chloro-
phenyl)-2-
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
12
(2,4-dichloro-phenyl)-5-methyl-1 H-imidazol-4-yl]-hexan-2-ol; 1-(4-Chloro-
phenyl)-2-
(2,4-dichloro-phenyl)-5-methyl-4-pentyl-1 H-imidazole; 2,5-Dimethyl-l-phenyl-1
H-
imidazole-4-carboxylic acid adamantan-2-ylamide; 1-(4-Chloro-phenyl)-2-(2-
chloro-
phenyl)-5-methylsulfanyl-lH-imidazole-4-carboxylic acid piperidin-1-ylamide; 2-
(2-
Chloro-phenyl)-1-(4-trifluoromethyl-phenyl)-1H-imidazole-4-carboxylic acid
piperidin-1-
ylamide; 5-(4-Chloro-phenyl)-4-(2,4-dichloro-phenyl)-thiazole-2-carboxylic
acid
piperidin-1-ylamide; 5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-1 H-
[1,2,4]triazole-3-
carboxylic acid pyrrolidin-1-ylamide; 1-(4-Chloro-phenyl)-5-(2,4-dichloro-
phenyl)-1H-
[1,2,4]triazole-3-carboxylic acid piperidin-1-yl-amide; 5-Pentyl-4-phenyl-
thiazole-2-
carboxylic acid (hexahydro-2,5-methano-pentalen-3a-yl)-amide; 4-Pentyl-5-
phenyl-
thiazole-2-carboxylic acid (hexahydro-2,5-methano-pentalen-3a-yl)-amide; 1-{(4-
Chloro-benzene-sulfonylimino)-[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-
pyrazol-1-yl]-
methyl}-piperidine-4-carboxylic acid amide; 4-Chloro-N-{[3-(4-chloro-phenyl)-4-
phenyl-
4,5-dihydro-pyrazol-1-yl]-[2-(2-oxo-pyrrolidin-1-yl)-ethylamino]-methylene}-
benzenesulfonamide; 4-Chloro-N-[[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-
pyrazol-l-
yl]-(2-cyano-ethylamino)-methylene]-benzene-sulfonamide; 4-Chloro-N-[[3-(4-
chloro-
phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-(methoxy-methyl-amino)-methylene]-
benzenesulfonamide; 4-Chloro-N-{[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-
pyrazol-l-
yl]-[(piperidin-4-ylmethyl)-amino]-methylene}-benzenesulfonamide; 4-Chloro-N-
[[3-(4-
chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-(piperidin-4-ylamino)-
methylene]-
benzenesulfonamide; and Morpholine-4-sulfonic acid [3-(4-chloro-phenyl)-4-
phenyl-4,5-
dihydro-pyrazol-1-yl]-(cyclopropylmethyl-amino)-methyleneamide.
In another embodiment of the present invention, CBx modulator which are
suitable for use as KATP channel modulator in the sense of the present
invention are
selected from the group consisting of: 3-(1,1-dimethyl-butyl)-6,6,9-trimethyl-
6a,7,10,10a-tetrahydro-6H-benzo[c]chromene; N-Adamantyl-4-pentyl-5-phenyl-
thiazole-2-carboxamide; N-{1,3,3-Trimethyl-endo-(1S)-bicyclo[2.2.1]hept-2-yl}-
1-[1-(4-
methyl)-benzyl-5-(4-chloro-3-methyl-phenyl)-1 H-pyrazol-3-carboxamide; (2-lodo-
5-
nitro-phenyl)-[1-(1-methyl-piperidin-2-ylmethyl)-1H-indol-3-yl]-methanone; {4-
[4-(1,1-
Dimethyl-heptyl)-2,6-dimethoxy-phenyl]-6,6-dimethyl-bicyclo[3. 1. 1 ]hept-2-en-
2-yl}-
methanol; 3-(1,1-Dimethyl-heptyl)-9-hydroxymethyl-6,6-dimethyl-6a,7,10,10a-
tetrahydro-6H-enzo[c]chromen-1 -ol; Icosa-5,8,11,14-tetraenoic acid 2-hydroxy-
1-
hydroxymethyl-ethyl ester; 1-Aziridin-1 -yl-henicosa-6,9,12,15-tetraen-2-one;
Noladineether; 4,4,4-Trifluoro-butane-1-sulfinic acid 3-(2-hydroxymethyl-indan-
4-yloxy)-
phenyl ester, compound with form aldehyde; 7-Methoxy-2-oxo-8-pentyloxy-1,2-
dihydro-
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
13
quinoline-3-carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)-amide; N-(1-{4-[4-
Chloro-2-(2-
fluoro-benzenesulfonyl)-benzenesulfonyl]-phenyl}-ethyl)-methanesulfonamide; [6-
lodo-
2-methyl-1-(2-morpholin-4-yl-ethyl)-2,3-dihydro-1 H-indol-3-yl]-(4-methoxy-
phenyl)-
methanone; 1-(4-Chloro-phenyl)-2-(2-chloro-phenyl)-5-ethyl-1 H-imidazole-4-
carboxylic
acid piperidin-l-ylamide; (2-Methyl-1-propyl-2,3-dihydro-1H-indol-3-yl)-
naphthalen-l-yl-
methanone; 5-(1, 1 -Dimethyl-heptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)-
cyclohexyl]-
phenol; (2-Methyl-3-morpholin-4-ylmethyl-3,4-dihydro-5-oxa-2a-azacenaphthylen-
1-yl)-
naphthalen-l-yl-methanone; 5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-
methyl-1 H-
pyrazole-3-carboxylic acid piperidin-1-ylamide; 5-(4-Bromo-phenyl)-1-(2,4-
dichloro-
phenyl)-4-ethyl-lH-pyrazole-3-carboxylic acid piperidin-1-ylamide; 1-[Bis-(4-
chloro-
phenyl)-methyl]-3-[(3,5-difluoro-phenyl)-methanesulfonyl-methylene]-azetidine.
In another embodiment of the present invention, CBx modulator which are
suitable for use as KATP channel modulator in the sense of the present
invention are
selected from the group consisting of: 4-Chloro-N-{[3-(4-chloro-phenyl)-4-
phenyl-4,5-
dihydro-pyrazol-l-yl]-methylamino-methylene}-benzenesulfonamide; N-{Amino-[3-
(4-
chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-methylene}-4-chloro-
benzenesulfonamide; 4-Chloro-N-{[3-(4-chloro-phenyl)-4-pyridin-3-yl-4,5-
dihydro-
pyrazol-1-yl]-methylamino-methylene}-benzenesulfonamide; 4-Chloro-N-{[3-(4-
chloro-
phenyl)-4-(3-fluoro-phenyl)-4,5-dihydro-pyrazol-1-yl]-methoxyamino-methylene}-
benzenesulfonamide; N-{[3-(4-Chloro-phenyl)-4-(3-fluoro-phenyl)-4,5-dihydro-
pyrazol-
1-yl]-methylamino-methylene}-N,N-dimethyl-sulfonamide; 5-(4-Chloro-phenyl)-1-
(2,4-
dichloro-phenyl)-4,5-dihydro-1 H-pyrazole-3-carboxylic acid piperidine-l-
ylamide;
Morpholine-4-sulfonic acid [1-(2,4-dichloro-phenyl)-5-phenyl-4,5-dihydro-1 H-
pyrazol-3-
yl]-methylamino-methyleneamide; N-{Amino-[3-(4-chloro-phenyl)-4-phenyl-4,5-
dihydro-
pyrazol-1-yl]-methylene}-4-chloro-benzenesulfonamide; 4-Chloro-N-[[3-(4-chloro-
phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-(2-ethylamino-ethylamino)-
methylene]-
benzenesulfonamide; 4-Chloro-N-{[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-
pyrazol-1-
yl]-[(1-methyl-pyrrolidin-2-ylmethyl)-amino]-methylene}-benzenesulfonamide; 4-
Chloro-
N-{[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-[(pyrid in-3-
ylmethyl)-amino]-
methylene}-benzenesulfonamide; 1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-
ethylsulfanyl-1H-imidazole-4-carboxylic acid piperidin-l-ylamide; 2-(2,4-
Dichloro-
phenyl)-1-(4-trifluoromethyl-phenyl)-1H-imidazole-4-carboxylic acid piperidin-
l-ylamide;
1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methylsulfanyl-1 H-imidazole-4-
carboxylic
acid piperidin-l-ylamide; 1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-ethyl-
1 H-
imidazole-4-carboxylic acid piperidin-l-ylamide; 1-(4-Bromo-phenyl)-2-(2,4-
dichloro-
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
14
phenyl)-5-ethyl-1 H-imidazole-4-carboxylic acid piperidin-l-ylamide; 1-(4-
Bromo-
phenyl)-5-chloro-2-(2,4-dichloro-phenyl)-1 H-imidazole-4-carboxylic acid
piperidin-l-
ylamide; 1-(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4-
carboxylic
acid pentylamide; 1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methyl-1 H-
imidazole-
4-carboxylic acid azepan-l-ylamide; 1-(4-Chloro-phenyl)-2-(2,4-dichloro-
phenyl)-5-
fluoromethyl-1 H-imidazole-4-carboxylic acid piperidin-l-ylamide; 1-(4-Chloro-
phenyl)-2-
(2,4-dichloro-phenyl)-5-methylsulfanyl-1 H-imidazole-4-carboxylic acid
cyclohexylamide;
N-[1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methyl-1 H-imidazol-4-yl]-
benzamide;
2-[1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methyl-1 H-imidazol-4-yl]-
hexan-2-ol;
1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methyl-4-pentyl-1 H-imidazole; 1-
(4-
Chloro-phenyl)-2-(2-chloro-phenyl)-5-methylsulfanyl-1 H-imidazole-4-carboxylic
acid
piperidin-l-ylamide; 2-(2-Chloro-phenyl)-1-(4-trifluoromethyl-phenyl)-1 H-
imidazole-4-
carboxylic acid piperidin-l-ylamide; 5-(4-Chloro-phenyl)-4-(2,4-dichloro-
phenyl)-
thiazole-2-carboxylic acid piperidin-l-ylamide; 1-(4-Chloro-phenyl)-5-(2,4-
dichloro-
phenyl)-1H-[1,2,4]triazole-3-carboxylic acid piperidin-l-yl-amide; 1-{(4-
Chloro-benzene-
sulfonylimino)-[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-l-yl]-methyl}-
piperidine-4-carboxylic acid amide; 4-Chloro-N-{[3-(4-chloro-phenyl)-4-phenyl-
4,5-
dihydro-pyrazol-1 -yl]-[2-(2-oxo-pyrrolidin-1 -yl)-ethylamino]-methylene}-
benzenesulfonamide; 4-Chloro-N-[[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-
pyrazol-1-
yl]-(2-cyano-ethylamino)-methylene]-benzene-sulfonamide; 4-Chloro-N-[[3-(4-
chloro-
phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-(methoxy-methyl-amino)-methylene]-
benzenesulfonamide; Morpholine-4-sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-
4,5-
dihydro-pyrazol-1 -yl]-(cyclopropylmethyl-amino)-methyleneamide.
CB1 agonist or CB2 agonists which are suitable for use as KATP channel
modulator
in the sense of the present invention are selected from, but not limited to
the group
consisting of: L759633; L759656; {4-[4-(1,1-dimethyl-heptyl)-2,6-dimethoxy-
phenyl]-
6,6-dimethyl-bicyclo-[3.1.1]hept-2-en-2-yl}-methanol (= HU308); JWH015; (2-
iodo-5-
nitro-phenyl)-[1-(1-methyl-piperidin-2-ylmethyl)-1H-indol-3-yl]-methanone (=
AM-1241);
3-(1,1-dimethyl-butyl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]-
chromene
(JWH133); N-adamantyl-4-pentyl-5-phenyl-thiazole-2-carboxamide; 6,6,9-
trimethyl-3-
pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol; (bicyclo[2.2.1 ]hept-2-
ylamino)-
(5-pentyl-4-phenyl-thiazol-2-yl)-methane; 5-(1,1-dimethyl-heptyl)-2-[5-hydroxy-
2-(3-
hydroxy-propyl)-cyclohexyl]-phenol (= CP-55,940); (2-methyl-3-morpholin-4-
ylmethyl-
3,4-dihydro-5-oxa-2a-aza-acenaphthylen-l-yl)-naphthalen-l-yl-methanone (= WIN-
55,212-2); ACEA; ACPA; N-adamantyl-4-pentyl-5-phenyl-thiazole-2-carboxamide;
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
methanandamide; anandamide; 2-arachidonoyl glycerol; 2-icosa-5,8,11,14-
tetraenyloxy-propane-1,3-diol (= noladin ether); BAY 38-7271; SAB-378; BAY 59-
3074;
0-1057; GW-1000; PRS-211375; PRS-211359; PRS-211355; PRS-211096; PXS-2076;
AM-577; GW-842166X; and mixtures thereof.
5 In a preferred embodiment of the present invention, the CB2 agonist is a
selective
CB2 agonist and is selected from the group consisting of: 3-(1,1-dimethyl-
butyl)-6,6,9-
trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromene (= JWH 133); L759633;
L759656; {4-[4-(1,1-dimethyl-heptyl)-2,6-dimethoxy-phenyl]-6,6-dimethyl-
bicyclo[3.1.1]hept-2-en-2-yl}-methanol (= HU308); JWH015; (2-iodo-5-nitro-
phenyl)-[1-
10 (1-methyl-piperidin-2-ylmethyl)-1H-indol-3-yl]-methanone (= AM-1241); and
mixtures
thereof.
CB2 antagonist or CB2 inverse agonists which are suitable for use as KATP
channel modulator in the sense of the present invention, are selected from the
group
consisting of: (1) compounds described in documents W001/0588869,
15 PCT/EP2006/060009, W02004/014825; EP1142877; US2002/0072529;
W002/062750; US 6,509,352; and (2) compounds selected from the group
consisting
of: 1-[1-benzyl-5-(4-chloro-3-methyl-phenyl)-1 H-pyrazol-3-yl]-ethanonyl-1,3,3-
trimethyl-
bi-cyclo[2.2.1]hept-2-ylamine (= SR-144528), JTE-907, AM630, and mixtures
thereof;
and (3) mixtures of compounds selected from (1) and (2).
Dually acting compounds which are both a CB1 agonist and a CB2 agonist, and
which are suitable for use as KATP channel modulator in the sense of the
present
invention, are selected from the group consisting of: 2-icosa-5,8,11,14-
tetraenyloxy-
propane-1,3-diol (= noladin ether); and mixtures thereof.
In a preferred embodiment of the present invention, the CBX modulator is
selected from the group consisting of: 6,6,9-trimethyl-3-pentyl-6a,7,8,10a-
tetrahydro-
6H-benzo[c]chromen-l-ol; (bicyclo[2.2.1 ]hept-2-ylamino)-(5-pentyl-4-phenyl-
thiazol-2-
yl)-methane; 3-(1,1-dimethyl-butyl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-
benzo[c]chromene; N-adamantyl-4-pentyl-5-phenyl-thiazole-2-carboxamide;
SR144528;
(2-iodo-5-nitro-phenyl)-[1-(1-methyl-piperidin-2-ylmethyl)-1 H-indol-3-yl]-
methanone; {4-
[4-(1,1-Dimethyl-heptyl)-2,6-dimethoxy-phenyl]-6,6-dimethyl-bicyclo[3.1.1]hept-
2-en-2-
yl}-methanol; and mixtures thereof.
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
16
A set of representative CBX modulators with their affinities on the KATP SUR1
and
SUR2 regulatory subunits (hamster), respectively are depicted in Table 1. (2-
Chloro-4-
methyl-7,7-dioxo-4,7-d ihydro-1,71ambda*6*-dithia-4,6-diaza-inden-5-yl)-(1-
methyl-
cyclopropyl)-amine and 7-Chloro-3-methyl-2H-benzo[1,2,4]thiadiazine 1,1-
dioxide
serve as KATP/SUR1 active reference compounds which are known to those skilled
in
the art. For comparative reasons, Table 1 also lists the CB1 and/or CB2
activities of
various compounds to prove that their activity as CB1 agonists, CB2 agonists,
CB2
partial agonists, CB2 antagonists, CB2 inverse agonists and dually acting
compounds
which are both a CB1 agonist and a CB2 agonist.
Description of the pharmacological test methods
1 . I n vitro binding affinity of the test compounds to rodent K TP channels
Competitive binding experiments were performed to characterize the affinity of
the test compounds for the binding sites for sulfonylureas and KATP channel
openers (=
KCOs) on hamster SUR1. To assess the affinity for the sulfonylurea site
membranes
from COS-cells transiently expressing hamster SUR1 were incubated in the
presence
of [3H]glibenclamide with increasing concentrations of test compounds. The
affinity for
binding to the KCO site was assessed by incubations in the additional presence
of 100
pM MgATP (see Schwanstecher M., et al. Naunyn-Schmiedeberg's Arch. Pharmacol.
343 (1991) 83-89 and Schwanstecher M. et al., EMBO J. 17 (1998) 5529-5535 (=
Schwanstecher et al., 1998)). For each test compound 4 displacement curves
were
measured (+/- MgATP from the human and hamster isoform). Per curve 9-15
distinct
concentrations were tested covering the relevant range. All measurements were
repeated at least 5 times in independent experiments.
Similar to SUR1 (see above) competitive binding experiments were performed to
characterize the affinity of the test compounds for the binding sites for
sulfonylureas
and KCOs on rat SUR2A. The affinity for the KCO site on SUR2A was assessed by
displacement of [3H]P1075 (see Schwanstecher et al., 1998; Dorschner H. et al.
Mol.
Pharmacol. 55 (1999) 1060-1066 (= Dorschner et al., 1999)). The affinity of
[3H]glibenclamide for the human SUR2 isoforms, however, is too weak to allow
direct
detection of binding using filtration assays. Therefore, two strategies can be
used to
detect binding to the sulfonylurea site on SUR2A. First, binding can be
detected
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
17
indirectly through allosteric displacement of [3H]P1075 (Dorschner et al.,
1999).
Second, a mutated SUR2A (SUR2Av12o5s, see above) with increased affinity for
[3H]glibenclamide allowing direct displacement of this tracer can be used.
This second
approach was chosen to enable discrimination between allosteric and
competitive
interaction with the KCO site and make sure that binding of ligands which do
not induce
allosteric displacement are not missed.
Membranes from COS-cells transiently expressing rat SUR2A were incubated in
the presence of the radioligands with increasing concentrations of test
compounds as
described above. The affinity for binding to the KCO site was assessed by
incubations
in the additional presence of 100 pM MgATP (Schwanstecher et al., 1991 and
1998).
For each test compound 4 displacement curves were measured (displacement of
[3H]P1075 from the rat isoform of the wild type receptor and displacement of
[3H]glibenclamide from the rat isoform of SUR2Av12o5s)- Per curve 9-15
distinct
concentrations were tested covering the relevant range. All measurements were
repeated at least 5 times in independent experiments.
[3H]P1075 (specific activity 116 Ci mmol-') was purchased from Amersham
Buchler (Braunschweig, Germany). [3H]glibenclamide (specific activity 51 Ci
mmol-')
was obtained from NEN (Dreieich, Germany). If suitable, stock solutions were
prepared in dimethylsulfoxide with a final solvent concentration in the media
below 1 %.
SUR- or Kir6.x isoforms were used either subcloned in the pcDNA (hamster
SUR1, mouse Kir6.2) or pCMV vector (rat SUR2A, SUR2B).
Rodent SUR-isoforms and KATP channels were transiently expressed in COS-1
cells as described (see Schwanstecher et al., 1998); Dorschner et al., 1999);
Uhde I. et
al. J Biol Chem 274 (1999) 28079-28082; Gross I. et al. Mol. Pharmacol. 56
(1999)
1370-1373; Markworth E., Diabetes 49 (2000) 1413-1418). A mutated form of the
SUR2 isoforms with the phenylalanine residue in position 1205 substituted with
a
serine (SUR2v12o5s) was used to allow detection of binding to the sulfonylurea
site of
these isoforms by displacement of [3H]glibenclamide (Uhde I., Dissertation
2001).
Briefly, COS-1 cells cultured in DMEM HG (10 mM glucose), supplemented with 10
%
fetal calf serum (FCS), were plated at a density of 5 x 105 cells per dish (94
mm) and
allowed to attach overnight. For transfection the cells were incubated 4 hours
in a Tris-
buffered salt solution containing DNA (5 - 10 pg/ml) plus DEAE-dextran (1
mg/ml), 2
min in HEPES-buffered salt solution plus dimethylsulfoxide (10 %) and 4 hours
in
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
18
DMEM-HG plus chloroquine (100 pM). Cells were then returned to DMEM-HG plus 10
% FCS. Membranes were prepared 60-72 h post transfection as described
(Schwanstecher M. et al., Br. J. Pharmacol. 106 (1992) 295-301 (=
Schwanstecher et
al., 1992)). For binding experiments resuspended membranes (final protein
concentration 5 - 50 pg/ml) were incubated in "Tris-buffer" (50 mM, pH 7.4)
containing
either [3H]glibenclamide (final concentration 0.3 nM or 3 nM and nonspecific
binding
defined by 100 nM or 1 pM glibenclamide for SUR1 or SUR2v1205s-isoforms,
respectively) or [3H]P1075 (final concentration 3 nM, nonspecific binding
defined by
100 pM pinacidil) and increasing concentrations of the test compounds. The
free Mg2+
concentration were kept close to 0.7 mM. ATP (0.1 mM) was added to incubation
media to enable KCO (e.g. diazoxide, [3H]P1075) binding (see Schwanstecher et
al.,
1998). Incubations were carried out for 1 h at room temperature and were
terminated
by rapid filtration through Whatman GF/B filters.
The inhibition constant (Ki value) of the test substances was calculated from
the
respective IC50 value, and was stated as the negative logarithmic value
thereof (pK;).
2. In vitro binding affinity of the test compounds to CB1 receptors
The affinity of the compounds of the invention for cannabinoid CB1 receptors
can be
determined using membrane preparations of Chinese hamster ovary (CHO) cells in
which the human cannabinoid CB1 receptor is stably transfected in conjunction
with
[3H]CP-55,940 as radioligand. After incubation of a freshly prepared cell
membrane
preparation with the [3H]-ligand, with or without addition of compounds of the
invention,
separation of bound and free ligand is performed by filtration over glassfiber
filters.
Radioactivity on the filter is measured by liquid scintillation counting.
3. In vitro binding affinity of the test compounds to CB2 receptors
The affinity of the compounds of the invention for cannabinoid CB2 receptors
can
be determined using membrane preparations of Chinese hamster ovary (CHO) cells
in
which the human cannabinoid CB2 receptor is stably transfected in conjunction
with
[3H]CP-55,940 as radioligand. After incubation of a freshly prepared cell
membrane
preparation with the [3H]-ligand, with or without addition of compounds of the
invention,
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
19
separation of bound and free ligand is performed by filtration over glassfiber
filters.
Radioactivity on the filter is measured by liquid scintillation counting.
Table 1 - CBX modulators with their affinities on the CB1 and/or CB2 receptor
affinities, (cloned human cannabinoid (CB1 and CB2 respectively) receptors
expressed
in CHO cells according to the procedures described hereinabove), expressed as
pK;
values.
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
Affinity to
compound/name chemical name CB1 B2 SUR SUR
1 2
Chiral 3-(1,1-dimethyl-butyl)-
õ 6,6,9-trimethyl-
õ 6a,7,10,10a-tetrahydro-6H- 6.7 7.8 5.9 3.6
benzo[c]chromene
(= JW133)
N-Adamantyl-4-pentyl-5-
/~ \~N phenyl-thiazole-2- 7.8 8.1 4.0 4.0
carboxamide
I Chiral N-{1,3,3-Trimethyl-endo-
'17' (1S)-bicyclo[2.2.1]hept-2-
N= yl}-1-[1-(4-methyl)-benzyl-
5-(4-chloro-3-methyl- 6.2 7.7 6.9 4.8
~ ~ phenyl)-1 H-pyrazol-3-
carboxamide
(= SR 144528)
- (2-lodo-5-nitro-phenyl)-[1-
O-N
(1-methyl-piperidin-2-
0 ylmethyl)-1 H-indol-3-yl]-
methanone 6.6 7.8 5.4 4.7
N \ (= AM-1241)
~
{4-[4-(1,1-Dimethyl-
~ heptyl)-2,6-dimethoxy-
~ phenyl]-6,6-dimethyl-
bicyclo[3.1.1]hept-2-en-2- 6.0 7.8 6.4 3.6
yl}-methanol
(= HU308)
o,
3-(1,1-Dimethyl-heptyl)-9-
0 hydroxymethyl-6,6-
dimethyl-6a,7,10,10a-tetra 7.3 n/a 6.1 5.1
hydro-6H-enzo[c]chromen-
0 1-ol
HU-210
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
21
Affinity to
compound/name Chemical name CB1 B2 SUR SUR
1 2
0 Icosa-5,8,11,14-tetraenoic
~ acid 2-hydroxy-l-
hydroxymethyl-ethyl ester 6.0 5.4 5.6 5.5
(2-AG)
1-Aziridin-1-yl-henicosa-
0 6,9,12,15-tetraen-2-one 7.7 7.1 3.9 4.7
N (ACPA)
~
0
- - ~ O
z
Noladineether 6,9 6,6 5,4 4,4
o ~ F ~ird 4,4,4-Trifluoro-butane-l-
\"' /'~F sulfinic acid 3-(2-
~-o F hydroxymethyl-indan-4- 8,0 7,3 6,0 5,2
yloxy)-phenyl ester;
compound with form
aldehyde (BAY-38-7271)
I I 7-Methoxy-2-oxo-8-
pentyloxy-1,2-dih
0 N 0
~ ydro-quinoline-3-carboxylic 6,0 6,9 6,1 5,9
acid (benzo[1,3]dioxol-5-
ylmethyl)-amide
(JTE-907)
c
c/ I ` N N-(1-{4-[4-Chloro-2-(2-
fluoro-benze
~s nesulfonyl)- 6,0 9,3 5,9 4,7
F o o benzenesulfonyl]-phenyl
o11O }-ethyl)-
methanesulfonamide
(Schering)
[6-lodo-2-methyl-1-(2-
~ morpholin-4-y
I-ethyl)-2,3-dihydro-1 H- 6,7 7,6 5,9 5,0
indol-3-yl]
C N) -(4-methoxy-phenyl)-
methanone
(AM-630)
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
22
Affinity to
compound/name chemical name CB1 B2 SUR SUR
1 2
ci ~ 1-(4-Chloro-phenyl)-2-(2-
~ chloro-phenyl)-5-ethyl-1 H-
imidazole-4-carboxylic acid 7,9 6,0 n/a 4,8
piperidin-l-ylamide
(Bayer)
cl
(2-Methyl-1 -propyl-2,3-
dihydro-lH-i 6,3 6,9 6,1 5,8
ndol-3-yl)-naphthalen-1 -yl-
~ -yl-
methanone (JWH-015)
5-(1,1-Dimethyl-heptyl)-2-
0 [5-hydroxy-2-(3-hydroxy-
propyl)-cyclohexyl]- 9,0 9,3 5,3 5,2
phenol
(CP55940)
0
0.., Chiral
~=== ~~ 5-(1,1-Di methyl-heptyl )-2-
[5-hydroxy-2-(3-hydroxy-
propyl)-cyclohexyl]- 7,2 7,0 5,3 5,3
phenol
(CP55940-entantiomer)
Clird (2-Methyl-3-morpholin-4-
- ylmethyl-3,4-dihydro-5-
oxa-2a-azacenaphthylen-
~/ 1-yl)-naphthalen-l-yl- 7,1 8,1 4,4 5,4
methanone
~ (R(+)-WIN55212-2)
a
5-(4-Chloro-phenyl)-1-(2,4-
a dichloro-phenyl)-4-methyl-
a 1 H-pyrazole-3-carboxylic 8,2 6,0 5,3 5,4
acid piperidin-l-ylamide
(Rimonabant)
O
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
23
Affinity to
compound/name chemical name CB1 B2 SUR SUR
1 2
0
N-No 5-(4-Bromo-phenyl)-1-(2,4-
~ N N dichloro-phenyl)-4-ethyl-
Br c, 1 H-pyrazole-3-carboxylic 7,9 5,9 5,5 5,6
acid piperidin-1-ylamide
(SR-147778)
c
F
o, 1-[Bis-(4-chloro-phenyl)-
0 F methyl]-3-[(3,5-difluoro-
phenyl)-methanesulfonyl- 8,2 n/a 5,3 5,1
N
methylene]-azetidine
(Aventis)
a a
4-Chloro-N-{[3-(4-chloro-
phenyl)-4-phenyl-4,5-
"-" dihydro-pyrazol-l-yl]- 8,4 n/a 6,3 5,4
N N;s ~ methylamino-methylene}-
~ benzenesulfonamide
ci
cl \ 4-Chloro-N-{[3-(4-chloro-
\~`'--; phenyl)-4-phenyl-4,5- 6,3 5,7 6,0 6,1
"-" dihydro-pyrazol-l-yl]-
~N;s ~ methylamino-methylene}-
/ benzenesulfonamide
ci
ci
N-{Amino-[3-(4-chloro-
~ phenyl)-4-phenyl-4,5- 8,4 6,8 6,1 5,4
N-N dihydro-pyrazol-l-yl]-
~"S methylene}-4-chloro-
o benzenesulfonamide
ci
cI N-{[3-(4-Chloro-phenyl)-4-
~ pyridin-3-yl-4,5-dihydro-
pyrazol-l-yl]-methylamino-
N-N
~-- N, ,o methylene}-4- 8,2 - 6,3 4,9
/N o's trifluoromethyl-
, F benzenesulfonamide
F F
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
24
Affinity to
compound/name chemical name CB1 B2 SUR SUR
1 2
4-Chloro-N-{[3-(4-chloro-
N 0,
phenyl)-4-pyridin-3-yl-4,5- 7,1 n/a 5,6 5,4
dihydro-pyrazol-1-yl]-
~ methylamino-methylene}-
benzenesulfonamide
I~J N
F
c, 4-Chloro-N-{[3-(4-chloro-
\ phenyl)-4-(3-fluoro-
phenyl)-4,5-dihydro- 7,7 n/a 5,6 6,1
N-N pyrazol-1-yl]-
\F--",S methoxyamino-
_c/ c" methylene}-
benzenesulfonamide
ci
c Morpholine-4-sulfonic acid
[3-(4-chloro-phenyl)-4-
phenyl-4,5-dihydro- 8,3 n/a 6,3 4,0
N-N pyrazol-1-yl]-methylamino-
)--N,S o methyleneamide
/N O, \00
F
N-{[3-(4-Chloro-phenyl)-4-
c~ (3-fluoro-phenyl)-4,5-
~ dihydro-pyrazol-1-yl]- 8,5 n/a 7,0 5,3
methylamino-methylene}-
N-N N,N-dimethyl-sulfonamide
\F--N'S O
. \
O N-
ci
Azepane-l-sulfonic acid
[3-(4-chloro-phenyl)-4- 7,3 n/a 4,6 4,9
N-N phenyl-4,5-dihydro-pyra
\F--N. , zol-1-yl]-methylamino-
o s methyleneamide
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
Affinity to
compound/name chemical name CB1 B2 SUR SUR
1 2
4-Chloro-N-{[3-(4-chloro-
~ ~ - phenyl)-4-phenyl-4,5-
dihydro-pyrazol-1-yl]-
N~N [(1-methyl-pyrrolidin-3- 9,0 6,0 6,0 4,8
ylmethyl)-amino]-
~ i methylene}-
benzenesulfonamide
1-(4-Chloro-phenyl)-5-
~~ phenyl-4,5-dihydro-1 H- 6,2 6,3 4,0 4,0
a pyrazole-3-carboxamidine
ci
N-{[3-(4-Chloro-phenyl)-4-
phenyl-4,5-dihydro-
\ - F F pyrazol-1-yl]-methylamino
F
N -methylene}-4- 8,4 n/a 6,3 4,2
trifluoromethyl-benzene-
sulfonamide
~ O
N s`
~N
CI Chi al
\ \
Piperidine-l-sulfonic acid
N'N [3-(4-chloro-phenyl)-4- 8,1 n/a 5,8 4,3
~-N phenyl-4,5-dihydro-
N pyrazol-1-yl]-methylamino-
o=S~o methyleneamide
ci
Piperidine-l-sulfonic acid
[3-(4-chloro-phenyl)-4-
N phenyl-4,5-dihydro- 8,6 n/a 4,0 4,0
N
-~-LN^ " pyrazol-1-yl]-(2-
s-0 dimethylamino-ethyl
N amino)-methyleneamide
ci N,N-Diethylamino-l-
sulfonic acid [3-(4-chloro-
N\ phenyl)-4-phenyl-4,5- 7,1 n/a 4,0 4,7
dihydro-pyrazol-1-yl]-
N S methylsulfanyl-
o=s=o methyleneamide
-i N-_,
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
26
Affinity to
compound/name chemical name CB1 B2 SUR SUR
1 2
CI Chiral
~ ~ ~ 2-Amino-l-[3-(4-chloro-
phenyl)-4-phenyl-4,5-
"
" dihydro-pyrazol-1-yl]-3- 6,0 6,2 5,4 4,8
cI " (3,4-dichloro-phenyl)-
~ " o
propan-1-one
~
CI
cl
Morpholine-4-sulfonic acid
[3-(4-chloro-phenyl)-4-
phenyl-4,5-dihydro- 7,7 n/a 4,0 5,5
"-" pyrazol-l-yl]-methylamino-
~0
o " methyleneamide
0
F N,N-Dimethylamino-1-
~N sulfonic acid [3-(4-chloro-
N-N o phenyl)-4-phenyl-4,5-
ci dihydro-pyrazol-l-yl]-(2- 7,5 n/a 4,3 4,0
fluoro-ethylamino)-
methyleneamide
,N 0,s Piperidine-1-sulfonic acid
~N='b [3-(4-chloro-phenyl)-4-(3-
\ N-N fluoro-phenyl)-4,5-dihydro- 7,5 6,1 4,5 6,3
c~ - pyrazol-l-yl]-methylamino
-methyleneamide
F
0
ci N_ NN 5-(4-Chloro-phenyl)-1-(2,4-
~ N ( ~ dichloro-phenyl)-4,5-
c ~/ dihydro-1 H-pyrazole-3- 7,4 6,1 5,4 5,6
carboxylic acid piperidine-
1-ylamide
ci
0
N\ 1-(4-Chloro-phenyl)-5-
N N
~N phenyl-4,5-dihydro-1 H-
0
c pyrazole-3-carboxylic acid 7,2 n/a 4,0 5,1
oll piperidin-l-ylamide
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
27
Affinity to
compound/name chemical name CB1 B2 SUR SUR
1 2
(~ Piperidine-l-sulfonic acid
N~ [1-(4-chloro-phenyl)-5-
N NS-O phenyl-4,5-dihydro-1
H-pyrazol-3-yl]- 7,3 n/a 6,1 4,5
ci methylamino-
~ methyleneamide
N q ~J Morpholine-4-sulfonic acid
c NS-O [1-(2,4-dichloro-phenyl)-5- 6,9 n/a 5,3 5,0
" phenyl-4,5-dihydro-1 H-
\
pyrazol-3-yl]-methylamino-
methyleneamide
a
4-Chloro-N-[[3-(4-chloro-
phenyl)-4-phenyl-4,5-
~ dihydro-pyrazol-1-yl]-(2
-fluoro-ethylamino)- 7,7 n/a 4,6 4,6
C-S-o methylene]-
benzenesulfonamide
a
4-Chloro-N-[[3-(4-chloro-
phenyl)-4-phenyl-4,5-
" dihydro-pyrazol-1-yl]-(2
F N~~N -fluoro-ethylamino)- 6,9 n/a 4,6 5,0
c a methylene]-
benzenesulfonamide
ci
N-{Amino-[3-(4-chloro-
phenyl)-4-phenyl-4,5-
" N dihydro-pyrazol-1-yl]- 7,4 6,4 6,0 5,1
N-'~N methylene}-4-chloro-
0s benzenesulfonamide
~ ci
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
28
Affinity to
compound/name chemical name CB1 B2 SUR SUR
1 2
1~
S 4-Chloro-N-[3-(4-chloro-
o ,"I phenyl)-4-phenyl-4,5-
0/ N dihydro-pyrazole-l- 6,5 n/a 5,5 4,8
carbonyl]-
benzenesulfonamide
ci
i t 4-Chloro-N-[[3-(4-chloro-
phenyl)-4-phenyl-4,5-
dihydro-pyrazol-1-yl]-(2 8,1 n/a 5,1 5,3
-ethylamino-ethylamino)-
- methylene]-
~ ~ Benzenesulfonamide
4-Chloro-N-{[3-(4-chloro-
, phenyl)-4-phenyl-4,5-
~~" " dihydro-pyrazol-1-yl]-[( 8,3 n/a n/a 5,1
1-methyl-pyrrolidin-2-
=S - ylmethyl)-amino]-
methylene}-
benzenesulfonamide
4-Chloro-N-[[3-(4-chloro-
phenyl)-4-phenyl-4,5-
~ dihydro-pyrazol-1-yl]-(4
N o -pyrrolidin-1-yl- 7,4 n/a 4,3 5,4
11 butylamino)-methylene]-
P~ N~o ~ benzenesulfonamide
~% \
c' 4-Chloro-N-{[3-(4-chloro-
~ phenyl)-4-phenyl-4,5-
dihydro-pyrazol-1-yl]-[(
"~N o pyridin-3-ylmethyl)-amino]- 6,4 6,3 5,9 5,7
methylene}-
I benzenesulfonamide
cl
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
29
Affinity to
compound/name chemical name CB1 B2 SUR SUR
1 2
a Chird
~ / ~ ~ 1-[3-(4-Chloro-phenyl)-4-
phenyl-4,5-dihydro-
~ pyrazol-1-yl]-3-(1H-indol- 8,0 6,9 6,6 4,6
2-yl)-2-methylamino-
~ 0 propan-l-one
t ci
2-[3-(4-Chloro-phenyl)-4-
phenyl-4,5-dihydro-
pyrazol-1-yl]-5-ethyl-4,5- 6,2 n/a 5,5 4,4
~~ dihydro-oxazole
4-Chloro-N-[[3-(4-chloro-
c phenyl)-4-phenyl-4,5-
~ dihydro-pyrazol-1-yl]-(3 6,7 6,1 4,5 5,4
-hydroxy-2,2-dimethyl-
"-" " o propylamino)-
~ s methylene]-
/ benzenesulfonamide
ci
0
a
N,N-Diethylamino-l-
sulfonic acid [3-(4-ch
loro-phenyl)-4-hydroxy-4- 7,4 n/a 4,0 5,9
"`N phenyl-4,5-dihydro-
11 N pyrazol-1-yl]-methylamino-
O~S~o methyleneamide
-N
N~ 5-(4-Bromo-phenyl)-1-(2,4-
Br ~ a dichloro-phenyl)-1 H- 6,3 n/a 4,0 5,4
pyrazole-3-carbonitrile
a~
a
8-Chloro-1-(2,4-dichloro-
~ phenyl)-1,3a,4,5,6,10b-
~ hexahydro-1,2-diaza-be 6,9 6,9 5,5 4,0
N N a, nzo[e]azulene-3-carboxylic
N o acid piperidin-1-ylamide
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
Affinity to
compound/name chemical name CB1 B2 SUR SUR
1 2
F
F 5-(4-Bromo-phenyl)-1-(2,4-
0 dichloro-phenyl)-3-[2-(3,5-
N cr's difluoro-phenyl)-2- 7,3 5,9 4,0 4,0
B ci methanesulfonyl-vinyl]-4-
~ methyl-1 H-pyrazole
a
N~N Piperidine-1-carboxylic
N o acid [5-(4-chloro-phenyl)-1-
N (2,4-dichloro-phenyl)-4- 6,9 n/a 4,7 4,7
c,- c' methyl-1 H-pyrazol-3-yl]-
amide
ci
Cl NIN-"ro 1-(4-Chloro-phenyl)-2-(2,4-
~ N s dichloro-phenyl)-5-
c , ethylsulfanyl-1H-imidazole- 7,4 n/a 5,1 5,3
4-carboxylic acid piperidin-
1-ylamide
1-ylamide
ci cl
0 2-(2,4-Dichloro-phenyl)-1-
N~N~N~ (4-trifluoromethyl-phenyl)-
1H-imidazole-4-carboxylic 7,6 n/a 5,6 5,3
FF o acid piperidin-1-ylamide
F
0
c, ~N" 1-(4-Chloro-phenyl)-2-(2,4-
~ dichloro-phenyl)-5-
~ I ~ S methylsulfanyl-lH-imidaz 8,0 6,0 5,1 5,6
ole-4-carboxylic acid
c, piperidin-1-ylamide
0
-N N 1-(4-Chloro-phenyl)-2-(2,4-
~ dichloro-phenyl)-1H- 8,1 6,2 4,5 5,3
imidazole-4-carboxylic
acid piperidin-1-ylamide
~
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
31
Affinity to
compound/name chemical name CB1 B2 SUR SUR
1 2
O
N/N 1-(4-Chloro-phenyl)-2-(2,4-
N dichloro-phenyl)-5-ethyl- 8,7 6,3 5,3 5,5
cl ~ 1 H-imidazole-4-carboxylic
acid piperidin-1-ylamide
CI
o ~
1-(4-Bromo-phenyl)-2-(2,4-
~~ dichloro-phenyl)-5-ethyl- 7,5 n/a 5,4 5,3
1 H-imidazole-4-carboxylic
acid piperidin-1-ylamide
Br
N-~ 1-(4-Bromo-phenyl)-5-
a N N chloro-2-(2,4-dichloro-
CI cl phenyl)-1 H-imidazole-4-car 8,6 n/a 5,4 5,5
boxylic acid piperidin-l-
ylamide
Br
1-(4-Bromo-phenyl)-2-(2,4-
cI dichloro-phenyl)-5-ethyl-
CI & N 1 H-imidazole-4-carboxylic 7,0 6,7 4,0 5,1
acid cyclohexylamide
Br
1-(4-Bromo-phenyl)-2-(2,4-
~I dichloro-phenyl)-5-ethyl-
ol~" 1H-imidazole-4-carboxylic 7,5 n/a 6,1 5,6
acid pentylamide
Br
CI CI
~ 4-(4-Chloro-phenyl)-5-(2,4-
c I _ dichloro-phenyl)-1-methyl-
,N~N 1H-imidazole-2-carboxylic 7,2 n/a 4,0 4,7
^ acid cyclohexylamide
0 N-)
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
32
Affinity to
compound/name chemical name CB1 B2 SUR SUR
1 2
ci ci
4-(4-Chloro-phenyl)-5-(2,4-
C1 dichloro-phenyl)-3-methyl-
_N~N 1H-imidazole-2-carboxylic 7,1 n/a 4,0 4,9
^ acid cyclohexylamide
O N-j
<D 1-(5-Chloro-pyridin-2-yl)-2-
C1 " (2,4-dichloro-phenyl)-5- 7,6 n/a 4,0 4,4
N ethyl-1 H-imidazole
N -4-carboxylic acid
y piperidin-l-ylamide
ci
" 1-(4-Chloro-phenyl)-2-(2,4-
- dichloro-phenyl)-5-methyl-
1 H-imidazole-4-carboxylic 6,6 n/a 4,0 5,0
N Nacid (4-hydroxy-cyclo-
Y ~ hexyl)-amide
C1 ci 1-(4-Chloro-phenyl)-2-(2,4-
~ I dichloro-phenyl)-5-methyl-
N 1 H-imidazole-4-carboxylic 7,2 7,6 5,2 5,7
y" " N acid azepan-1-ylamide
ci o
c, N~ 2-(2,4-Dichloro-phenyl)-5-
~ ~ ethyl-1 -phenyl-1H-
imidazole-4-carboxylic acid 7,0 7,6 4,0 5,3
piperidin-l-ylamide
N 2-(1,5-Dimethyl-1 H-pyrrol-
N
H-
N 2-yl)-5-ethyl-1 -phenyl-1 H-
imidazole-4-carboxylic acid n/a 6,8 4,0 4,0
cyclohexylamide
1-(4=Chloro-phenyl) =5-
N ethyl-2-(3-methyl-pyridin-2-
" yl) 1 H imidazole 4 n/a 6,6 4,0 4,8
~ carboxylic acid piperidin-1-
ylamide
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
33
Affinity to
compound/name chemical name CB1 B2 SUR SUR
1 2
1-(4-Chloro-phenyl)-5-
ethyl-2-(3-methyl-pyridin-2-
N _N yl)-1 H-imidazole-4-
N N carboxylic acid n/a 6,1 4,0 5,5
c~ o ~ cyclohexylamide
1-(4-Chloro-phenyl)-2-(2,4-
cI ""--- dichloro-phenyl)-5-methyl-
N 1 H-imidazole-4-carboxylic
xF acid (4-trifluoromethyl- 6,7 n/a 4,5 5,3
F F phenyl)-amide
CI
a
0 ~ 2-(2,4-Dichloro-phenyl)-5-
r,~-
methyl-1 -pyridin-2-yl-1H-
imidazole-4-carboxylic acid 7,3 6,2 4,0 4,1
piperidin-1-ylamide
1-(4-Chloro-phenyl)-2-(2,4-
dichloro-phenyl)-5-
~ NF fluoromethyl-1 H-imidazol
CI" e-4-carboxylic acid 7,2 6,1 5,2 5,5
I~ J piperidin-1-ylamide
N~ 1-(4-Chloro-phenyl)-2-(2,4-
G N dichloro-phenyl)-5-
N~ ~ hydroxymethyl-1 H-imidazo 7,6 6,2 4,0 4,7
ci le-4-carboxylic acid
piperidin-l-ylamide
Ci
cI NJ~ 1-(4-Chloro-phenyl)-2-(2,4-
dichloro-phenyl)-5-
S_ methylsulfanyl-1 H-imidaz 7,2 6,6 6,3 5,8
cI ole-4-carboxylic acid
cyclohexylamide
CI
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
34
Affinity to
compound/name chemical name CB1 B2 SUR SUR
1 2
1-(4-Chloro-phenyl)-2-(2,4-
dichloro-phenyl)-5-
N methanesulfonyl 1 H-imida
s ~o
, zole-4-carboxylic acid 7,8 n/a 4,0 5,0
~ I piperidin-1-ylamide
o
ci N ~ rvN 1-(4-Chloro-phenyl)-2-(2,4-
~ N ~s` dichloro-phenyl)-5- 7,4 n/a 4,0 4,9
I ~ 0 methanesulfinyl-1 H-imida
ci zole-4-carboxylic acid
piperidin-1-ylamide
Ci
a
N 0 5-(4-Chloro-phenyl)-4-(2,5-
a ~ \ 7 "-0 dichloro-phenyl)-1-methyl-
_ 1 H-imidazole-2-carboxylic 6,7 6,4 4,6 5,0
acid piperidin-1-ylamide
a
cl
" N 2-(2-Chloro-phenyl)-1-(5-
~ chloro-pyridin-2-yl)-5-ethyl-
1H-imidazole-4-carboxylic 7,9 n/a 4,0 4,8
acid piperidin-1-ylamide
C
o ~vJ 1-(4-Chloro-phenyl)-2-(2,4-
cl " " dichloro-phenyl)-5-(2,2,2-
~~ " trifluoro-ethyl)-1 H- 7,5 n/a 4,8 5,7
cl ~ F imidazole-4-carboxylic acid
\ I F F piperidin-1-ylamide
CI
CI "- N-[1-(4-Chloro-phenyl)-2-
(2,4-dichloro-phenyl)-5-
cl " methyl-1 H-imidazol-4-yl]- 7,0 6,3 5,7 5,2
benzamide
CI
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
Affinity to
compound/name chemical name CB1 B2 SUR SUR
1 2
0 'N
ci " 1-(4-Chloro-phenyl)-2-(2,4-
~ i dichloro-phenyl)-5-
c, pyrrolidin-1-ylmethyl-1H 6,3 n/a 4,0 4,6
N
-imidazole-4-carboxylic
acid piperidin-1-ylamide
ci
c
ci
;2-[1-(4-Chloro-phenyl)-2-
c," (2,4-dichloro-phenyl)-5- 6,6 n/a 5,8 5,3
methyl-1 H-imidazol-4-yl]-
hexan-2-ol
ci N 1-(4-Chloro-phenyl)-2-(2,4-
~ N dichloro-phenyl)-5-methyl- 7,0 n/a 5,8 5,3
c' ~ ~ 4-pentyl-1 H-imidazole
~
ci
~ " 2,5-Dimethyl-1 -phenyl-1 H-
imidazole-
" 4-carboxylic acid n/a 9,0 6,0 4,6
adamantan-2-ylamide
1-(4-Chloro-phenyl)-2-(2-
a chloro-phenyl)-5-
I s- methylsulfanyl-1 H- n/a 5,2 8,2 n/a
imidazole-4-carboxylic acid
piperidin-l-ylamide
a
~"-~ 2-(2-Chloro-phenyl)-1-(4-
Cl N _~-N trifluoromethyl-phenyl)-1 H-
" imidazole-4-carboxylic acid 7,0 n/a 6,0 5,7
~ piperidin-l-ylamide
F F
F
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
36
Affinity to
compound/name chemical name CB1 B2 SUR SUR
1 2
ci ci
~ / / \ 5-(4-Chloro-phenyl)-4-(2,4-
- dichloro-phenyl)-thiazole-
- c' 2-carboxylic acid piperidin- 6,7 n/a 5,7 5,5
1
o^N~N-ylamide
0
N"N--\, 5-(4-Chloro-phenyl)-1-(2,4-
~ N dichloro-phenyl)-1 H-
c o, [1,2,4]triazole-3-carboxylic 6,6 n/a 4,0 4,4
acid pyrrolidin-1-ylamide
ci
1-(4-Chloro-phenyl)-5-(2,4-
N NN dichloro-phenyl)-1H-
<D [1,2,4]triazole-3-carboxylic 6,5 n/a 5,0 5,0
' acid piperidin-1-yl-amide
~N0 NJ~q 5-Pentyl-4-phenyl-thiazole-
2-carboxylic acid
(hexahydro-2,5-methano- 6,4 7,0 4,0 4,0
pentalen-3a-yl)-amide
00 4-Pentyl-5-phenyl-thiazole-
~ N acid 7,8 8,1 4,0 4,0
2-carboxylic
(hexahydro-2,5-methano-
pentalen-3a-yl)-amide
1-{(4-Chloro-benzene-
/ N!11 Q ~ sulfonylimino)-[3-(4-chloro-
phenyl)-4-phenyl-4,5-
~ 1 ~AN 0 dihydro-pyrazol-1-yl]- 8,2 n/a 5,5 5,2
-N methyl}-piperidine-4-
carboxylic acid amide
1 / 0
cl HZN
~0 ~ ~ 0 4-Chloro-N-{[3-(4-chloro-
/ o phenyl)-4-phenyl-4,5-
~ dihydro-pyrazol-1-yl]-[2-(2- 8,2 n/a 6,3 5,9
N N-~ o oxo-pyrrolidin-1-yl)-
ethylamino]-methylene}-
X / benzenesulfonamide
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
37
Affinity to
compound/name chemical name CB1 B2 SUR SUR
1 2
4-Chloro-N-[[3-(4-chloro-
~ phenyl)-4-phenyl-4,5-
N 0 dihydro-pyrazol-1-yl]-(2- 7,9 n/a 6,7 5,9
-N " cyano-ethylamino)-
~ methylene]-benzene-
~ sulfonamide
0
/ S a 4-Chloro-N-[[3-(4-chloro-
~ phenyl)-4-phenyl-4,5-
~ N?o, dihydro-pyrazol-1-yl]- 6,7 n/a 5,9 5,9
-N ~ (methoxy-methyl-amino)-
I methylene]-
benzenesulfonamide
~g4 a 4-Chloro-N-{[3-(4-chloro-
~ A o phenyl)-4-phenyl-4,5-
N dihydro-pyrazol-1-yl]-[( 8,6 n/a 6,2 4,9
N piperidin-4-ylmethyl)-
N amino]-methylene}-
~ / benzenesulfonamide
O 4-Chloro-N-[[3-(4-chloro-
N _~S~CI phenyl)-4-phenyl-4,5-
NA O dihydro-pyrazol-1-yl]-
N (piperidin-4-ylamino)- 8,2 n/a 4,5 4,6
methylene]-
~ N benzenesulfonamide
CI
~ o Morpholine-4-sulfonic acid
%\ ~ [3-(4-chloro-phenyl)-4-
"~o phenyl-4,5-dihydro-
~N pyrazol-1-yl]- 8,5 n/a 6,0 5,7
(cyclopropylmethyl-amino)-
methyleneamide
a
The data in Table 1 demonstrate that the tested CBX modulators act selectively
on the SUR1 subunit and/or on the SUR 2 subunit.
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
38
4. Determination of the K TP openincg effects of compounds through insulin
secretion in rat perifused pancreatic islets
Animals: Male Wistar rats in the weight range 175-200 g were group housed in
standard animal cages at a temperature of 21 2 C and humidity of 55 10%.
Animals
were maintained on a 12 h light-dark cycle (lights on 06.00-18.00 h) with free
access to
standard rodent diet (B&K Universal Ltd standard rat and mouse diet (BK 001
P),
Beekay Feeds, B&K Universal Ltd, Hull, East Riding of Yorkshire) and tap
water. The
rats were accustomed to these conditions for at least one week before
experimentation.
Experimental procedures: After the rats were sacrificed, the branch of the
bile
duct leading to the liver and the duodenal end of the duct in the pancreas
were
clamped and the pancreas distended by injection of ice-cold 0.9 mg/ml
collagenase
solution into the bile duct. The pancreas were then removed and incubated
statically
for 10-12 min at 37 C. Following the incubation, 10 ml of cold buffer was
added and
the suspension shaken vigorously by hand for 1 min. The islets were allowed to
settle
for 5 min on ice and washed three times using ice-cold buffer. Well formed and
good
sized islets from 3 rats were hand-picked (under a low power microscope) and
pooled
and a final selection of islet transferred to the perifusion apparatus.
Oxygenated (95%
02/5% C02) Gey & Gey buffer containing 1 mg/ml bovine serum albumin and 4mM
glucose were used throughout the experiment unless otherwise stated (see
Dickinson
et al. Eur. J. Pharmacol. 1997; 339: 69-76 for further details).
Compounds were either tested at an advised concentration or the solubility was
determined in the experimental conditions and a maximum soluble drug
concentration
used for experiments (DMSO or ethanol will be used as the solvents at a
maximum
0.1 % in the assay buffer).
Two experiments were performed in parallel in two identical, independent sets
of
perifusion apparatus each consisting of sufficient number of chambers. Each
chamber
was loaded with 20 hand-picked islets. Islets were perifused for an initial 30
min period
in media containing 4 mM glucose. Perifusate was then collected at 2 min
intervals for
the remainder of the experiment. After the first 10 min of the experiment (to
collect
baseline insulin values), the media in each chamber was switched to one
containing 11
mM glucose and the relevant drug concentration/vehicle/diazoxide concentration
and
perifusate collected for a further 62 min to produce a total of 36 fractions
for each
chamber. Perifusate samples were then pooled to create three samples per
chamber
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
39
as follows: Baseline (4mM): Samples 1-5 (first 10 minutes); 0-30 minutes (11mM
glucose): Samples 6-21; 30-60 minutes (11 mM glucose): Samples 22-36.
Perifusate
fractions were stored at -75 C until required for insulin assay. Insulin
content of
fractions were assayed using a 96-well ELISA assay (Mercodia). Initial insulin
assays
were performed in triplicate on three pooled fractions from each chamber.
Drugs: All chemicals were obtained from Sigma (or other appropriate commercial
supplier).
Result: The three islet preparations showed a consistent degree of glucose
dependent insulin secretion. The mean insulin secretion at 11 mM glucose was
98.3
12.6 pg/islet/min and 130.4 22.0 pg/islet/min at 0-30 and 30-60 minutes,
respectively.
In the presence of 4 mM glucose this was significantly lower and was 3.8 0.6
pg/islet/min and 3.4 0.1 pg/islet/min at 0-30 and 30-60 minutes,
respectively. Thus,
insulin secretion was increased by 26 times and 38 times by 11 mM glucose at 0-
30
and 30-60 minutes, respectively. Data were initially expressed as a simple
mean of the
three experiments for insulin secretion (pg/islet/min) and multiple t-tests
(against the
corresponding vehicle time period) used to determine potential significant
effects of
treatments. Alternatively, data were also calculated as a % vehicle effect for
each
experimental day. This latter approach was deemed to be the more powerful
analysis
as it corrected for the day to day variation in insulin release from the
islets. Diazoxide
significantly inhibited insulin secretion by an average of 55.3% (0-30 min)
and 58.9%
(30-60 min).
Table 2 - KATP channel openers according to the procedure described
hereinabove, expressed as % inhibition
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
Compound/name Chemical name % Inhibition
0-30 / 30-60
o
11 _
O-N I
a (2-lodo-5-nitro-phenyl)-[1-(1- 97 / 74
methyl-piperidin-2-ylmethyl)-1 H-
N , indol-3-yl]-methanone
-`V~ (= AM-1241)
ci 0 ~/
N
1-(4-Chloro-phenyl)-2-(2-chloro- 59 / 45
phenyl)-5-ethyl-1 H-imidazole-4-
carboxylic acid piperidin-1-ylamide
c' (Bayer)
o
o 5-(1,1-Dimethyl-heptyl)-2-[5- 91 / 56
hyd roxy-2-(3-hyd roxy-p ro pyl )-
cyclohexyl]-phenol
(CP55940)
0
o;rd
(2-Methyl-3-morpholin-4-ylmethyl-
3,4-dihydro-5-oxa-2a-
~ azacenaphthylen-1-yl)- 80 / 35
~ ~O naphthalen-1-yl-methanone
N (R(+)-WIN55212-2)
o;~
o (2-Methyl-3-morpholin-4-ylmethyl-
3,4-dihydro-5-oxa-2a-
P~\Ls azacenaphthylen-1-y1)- 69 / 40
naphthalen-1-yl-methanone
J., ~ (R(+)-WIN55212-2)
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
41
Compound/name Chemical name % Inhibition
0-30 / 30-60
a
5-(4-Chloro-phenyl)-1-(2,4-
a dichloro-phenyl)-4-methyl-1 H-
~ pyrazole-3-carboxylic acid 22 / 18
piperidin-1-ylamide
N
0 (Rimonabant)
cl
4-Chloro-N-{[3-(4-chloro-phenyl)-
4-phenyl-4,5-dihydro-pyrazol-l-yl]- 42 / 22
"-" methylamino-methylene}-
~N;s ~ o' benzenesulfonamide
ci
ci 4-Chloro-N-{[3-(4-chloro-phenyl)-
4-phenyl-4,5-dihydro-pyrazol-l-yl]- 59 / 25
"-" methylamino-methylene}-
~N;s ~ o' benzenesulfonamide
ci
CI
N-{[3-(4-Chloro-phenyl)-4-pyridin-
3-y1-4,5-dihydro-pyrazol-1-yl]-
N-N
\F--N,S o methylamino-methylene}-4- 58 / 31
/" o trifluoromethyl-
F benzenesulfonamide
F F
F
ci / 4-Chloro-N-{[3-(4-chloro-phenyl)-
~ 4-(3-fluoro-phenyl)-4,5-dihydro-
N-" pyrazol-1-yl]-methoxyamino- 90 / 95
~",S methylene}-benzenesulfonamide
-o/
ci
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
42
Compound/name Chemical name % Inhibition
0-30 / 30-60
Morpholine-4-sulfonic acid [3-(4-
chloro-phenyl)-4-phenyl-4,5- 83 / 91
N-N dihydro-pyrazol-1-yl]-
~--N,S o methylamino-methyleneamide
/N O, \00
F
cl I
N-{[3-(4-Chloro-phenyl)-4-(3-
fluoro-phenyl)-4,5-dihydro-pyrazol- 72 / 77
N-N 1-yl]-methylamino-methylene}-
N. 0 N,N-dimethyl-sulfonamide
O. N-
CI Chi al
Piperidine-l-sulfonic acid [3-(4-
P
N N chloro-phenyl)-4-phenyl-4,5- 49 / 40
~-N dihydro-pyrazol-1-yl]-
N methylamino-methyleneamide
o=S~o
ci
Piperidine-1-sulfonic acid [3-(4-
"~" chloro-phenyl)-4-phenyl-4,5-
?L" dihydro-pyrazol-1-yl]-(2- 71 / 64
o s-0 dimethylamino-ethylamino)-
N methyleneamide
~"'-
N Ns-O Piperidine-1-sulfonic acid [1-(4-
N- chloro-phenyl)-5-phenyl-4,5- 84 / 47
ci ~ N dihydro-1 H-pyrazol-3-yl]-
~ I methylamino-methyleneamide
~
a Chird
-[3-(4-Chloro-phenyl)-4-phenyl-
4,5-dihydro-pyrazol-1-yl]-3-(1H- 64 / 53
V/N 1
indol-2-yl)-2-methylamino-propan-
\ ~ ~ 0 1-one
ILI
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
43
Compound/name Chemical name % Inhibition
0-30 / 30-60
a 1-(4-Chloro-phenyl)-2-(2-chloro-
I s- phenyl)-5-methylsulfanyl-1 H- 56 / 36
imidazole-4-carboxylic acid
piperidin-1-ylamide
a
This test provides proof that candidate compounds selected on the basis of
their
affinity for the KATP channel do inhibit glucose-stimulated insulin secretion.
It can be
followed that the candidate compounds function as KATP channel openers under
the
conditions described hereinabove.
All references, including publications, patent applications, and patents,
cited
herein are hereby incorporated by reference to the same extent as if each
reference
there individually and specifically indicated to be incorporated by reference
and were
set forth in its entirety herein.
The use of the terms "a" and "an" and "the" and similar referents in the
context
of this disclosure (especially in the context of the following claims) are to
be construed
to cover both the singular and the plural, unless otherwise indicated herein
or clearly
contradicted by context. All methods described herein can be performed in any
suitable order unless otherwise indicated herein or otherwise clearly
contradicted by
context. The use of any and all examples, or exemplary language (e.g., such
as,
preferred, preferably) provided herein, is intended merely to further
illustrate the
content of the disclosure and does not pose a limitation on the scope of the
claims. No
language in the specification should be construed as indicating any non-
claimed
element as essential to the practice of the invention.
Alternative embodiments of the claimed invention are described herein,
including the best mode known to the inventors for carrying out the claimed
invention.
Of these, variations of the disclosed embodiments will become apparent to
those of
ordinary skill in the art upon reading the foregoing disclosure. The inventors
expect
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
44
skilled artisans to employ such variations as appropriate, and the inventors
intend for
the invention to be practiced otherwise than as specifically described herein.
Accordingly, this invention includes all modifications and equivalents of the
subject matter recited in the claims appended hereto as permitted by
applicable law.
Moreover, any combination of the above described elements in all possible
variations
thereof is encompassed by the invention unless otherwise indicated herein or
otherwise clearly contradicted by context.
The use of individual numerical values are stated as approximations as though
the values were preceded by the word "about" or "approximately." Similarly,
the
numerical values in the various ranges specified in this application, unless
expressly
indicated otherwise, are stated as approximations as though the minimum and
maximum values within the stated ranges were both preceded by the word "about"
or
"approximately." In this manner, variations above and below the stated ranges
can be
used to achieve substantially the same results as values within the ranges. As
used
herein, the terms "about" and "approximately" when referring to a numerical
value shall
have their plain and ordinary meanings to a person of ordinary skill in the
art to which
the disclosed subject matter is most closely related or the art relevant to
the range or
element at issue. The amount of broadening from the strict numerical boundary
depends upon many factors. For example, some of the factors which may be
considered include the criticality of the element and/or the effect a given
amount of
variation will have on the performance of the claimed subject matter, as well
as other
considerations known to those of skill in the art. As used herein, the use of
differing
amounts of significant digits for different numerical values is not meant to
limit how the
use of the words "about" or "approximately" will serve to broaden a particular
numerical
value. Thus, as a general matter, "about" or "approximately" broaden the
numerical
value. Also, the disclosure of ranges is intended as a continuous range
including every
value between the minimum and maximum values plus the broadening of the range
afforded by the use of the term "about" or "approximately." Thus, recitation
of ranges of
values herein are merely intended to serve as a shorthand method of referring
individually to each separate value falling within the range, unless otherwise
indicated
herein, and each separate value is incorporated into the specification as if
it there
individually recited herein.
CA 02650567 2008-10-23
WO 2007/125049 PCT/EP2007/053915
It is to be understood that any ranges, ratios and ranges of ratios that can
be
formed by, or derived from, any of the data disclosed herein represent further
embodiments of the present disclosure and are included as part of the
disclosure as
though they were explicitly set forth. This includes ranges that can be formed
that do
5 or do not include a finite upper and/or lower boundary. Accordingly, a
person of
ordinary skill in the art most closely related to a particular range, ratio or
range of ratios
will appreciate that such values are unambiguously derivable from the data
presented
herein.
