DERIVATIVES OF OXADIAZOLE AND PYRIDAZINE, THEIR
PREPARATION AND THEIR APPLICATION IN THERAPEUTICS
The present invention relates to oxadiazole and pyridazine derivatives, to the
preparation thereof and to the therapeutic use thereof. The present compounds of the
invention inhibit the synthesis of triglycerides and are of use for the treatment of
pathologies in which such inhibition is beneficial, such as in the case of obesity,
dyslipidemia, non-alcoholic hepatic steatosis, non-insulin-dependent type 2 diabetes,
metabolic syndrome and acne.
Triacylglycerides represent the main form of energy storage in eukaryotes, and
may also be the cause of disorders or imbalances in the metabolism of
triacylglycerides, involved in the pathogenesis and the increase of risk of several
pathologies such as obesity, insulin resistance, type 2 diabetes (Reasner C.A., J.
Cardiovasc. Pharmacol. 52:136-44, 2008) and complications arising from this
pathology (Krane and Wanner, Minerva Urol. Nefrol. 59(3):299-316, 2007; King G.L., J.
Periodontol. 79:1527-34, 2008), dyslipidemia, which is characterized by high levels of
plasmatic triglycerides, low levels of high-density lipoproteins (HDL) and the
appearance of small dense low-density lipoproteins (sdLDL) and excessive
postprandial lipidemia (Ginsberg et al., Obesity (Silver Spring). 14: 41S-49S, 2006,
Adiels et al., Curr. Opin. Lipidol. 17: 238-246, 2006, Adiels et al., ATVB 28:1225-
1236,2008), impaired fasting glucose conditions, metabolic acidosis, ketosis, metabolic
syndrome (Eschwege E. Diabetes Metab. 29:6S19-27, 2003), hepatic steatosis
(Parekh and Anania, Gastroenterology 132:2191-2207, 2007), coronary diseases
(Lewis et al., Endocrine Review 23:701 , 2002; Ridker and Silvertown, J. Periodontol.,
79:1544-51 , 2008; McBride P. Curr. Atheroscler. Rep. 10:386-90, 2008), skin diseases
(Chen et al., J. Clin. Invest., 109:175-81 , 2002; Yosipovitch et al., J. Am. Acad.
Dermatol., 56:901-16, 2007), Alzheimer's disease, various immunomodulatory
diseases (Pahan K., Cell Mol. Life Sci., 63:1 165-78, 2006), HIV infection (Kotler D.P.,
J. Acquir. Immune Defic. Syndr., 49:S79-85, 2008), irritable bowel syndrome (Schaffler
et al., Nat. Clin. Pract. Gastroenterol. Hepatol., 2:103-1 1, 2005). Excessive storage of
triacylglycerides in lean tissues, such as the liver, the muscles and other peripheral
tissues, leads to dysfunction in these tissues; whereas reducing the accumulation of
these fats in these peripheral tissues appears to be beneficial in treating lipotoxicity
(Unger, Endocrinology, 144: 5 159-5 165, 2003). The accumulation and an excess of
triacylglycerides in adipose tissue (WAT) leads to obesity, a condition that is associated
with a reduction in lifespan, type I I diabetes, coronary diseases, hypertension, strokes,
and the development of certain cancers (Grundy, Endocrine 13 (2): 155-165, 2000).
DGAT-1 catalyzes the final step of the synthesis of triglycerides (TGs),
converting diacylglycerol and acyl-CoA into triglycerides. There are two isoforms of
diacylglycerol acyltransferase: DGAT-1 (U.S. Pat. No. 6,100,077; Farese et al., Proc.
Nat. Acad. Sci. 95:13018-13023, 1998) and DGAT-2 (Farese et al., J. Biol. Chem. 276:
38870-38876, 2001). DGAT-1 and DGAT-2 share 12% of the amino acid sequence.
A mouse deficient in DGAT-1 is healthy and fertile, and is capable of carrying
out the biosynthesis of triglycerides (Farese et al. Nature Genetics 25: 87-90, 2000). A
mouse deficient in DGAT-1 is resistant to diet-induced obesity, has an increased
sensitivity to insulin (Farese et al. Nature Genetics 25: 87-90, 2000) and to leptin
(Farese et al. J. Clin. Invest. 109:1049-1055, 2002). A mouse deficient in DGAT-1
shows a lower absorption rate of triglycerides and an improvement in the metabolism of
triglycerides. After loading with glucose, a mouse deficient in DGAT-1 shows a lower
glucose and insulin level than mice of wild phenotype, suggesting an improvement in
the metabolism of glucose (Farese et al., J. Biol. Chem. 277: 25474-25479, 2002).
The synthesis of TGs, the size and the proliferation of the sebaceous glands
decrease with inhibition of DGAT-1 in hamsters (J Invest Dermatol 127, 2740-48, 2007)
clearly showing a therapy against skin diseases such as acne that involves this
mechanism.
The inhibition of DGAT-1 by oligonucleotides reduces hepatic TGs suggesting a
therapy against hepatic steatosis that involves this mechanism (Hepatology 50, 434-
442, 2009).
The activity of DGAT-1 in the host cell is required for the replication of the
hepatitis C virus. This mechanism suggests a therapy against hepatitis C via inhibition
of DGAT-1 (Nature Medecine (16)1 1, 1295-1298, 201 1) .
One subject of the present invention is compounds corresponding to the formula (I):
(I)
in which:
• n is equal to 0 or 1;
• D represents an oxygen atom or a bond;
• W represents a nitrogen atom or a -CH- group;
• X 1 represents a nitrogen atom or a -CH=CH- group;
• X2 represents an oxygen atom or a nitrogen atom;
• X3 represents an oxygen atom or a nitrogen atom; one of X 1, X2, X3 being
other than a nitrogen atom, X2 and X3 not being an oxygen atom at the same time;
· R1, R2 are absent or represent,
o independently of one another, a hydrogen atom or a (C1-C4)alkyl group,
o R 1 and R2 may form, with the carbon atom to which they are attached,
a -(C3-C10)cycloalkyl- group;
• Y represents a -(C3-C10)cycloalkyl-, aryl or aryloxy group, said groups being
optionally substituted with one or more substituents chosen from a halogen atom or a
(C1-C6)alkoxy group;
• Z 1 is absent or represents an -NH- function;
• Z2 is absent or represents a methylene group or a
— CH or = —
I H
group;
• Z3 is absent or represents an oxygen atom or a methylene group or a
— CH or = c—
I H
group;
given that Z2 only represents a group when Z3 is present and when it
represents a group, and vice versa, Z2 and Z3 thus forming a double bond;
given that Z2 and Z3, when they are present, may be included in a cycloalkyl
group;
given that when Z3 represents an oxygen atom, Z2 represents a methylene group
or a
— CH or = c—
I H
in the form of an acid, a base or an addition salt with an acid or with a base.
Another subject of the present invention is compounds corresponding to the formula (I):
(I)
in which:
n is equal to 0 or 1;
D represents an oxygen atom or a bond;
W represents a nitrogen atom or a -CH- group;
X 1 represents a nitrogen atom or a -CH=CH- group;
X2 represents an oxygen atom or a nitrogen atom;
X3 represents an oxygen atom or a nitrogen atom; one of X 1, X2, X3 being
other than a nitrogen atom, X2 and X3 not being an oxygen atom at the same time;
• R1, R2 are absent or represent,
o independently of one another, a hydrogen atom or a (C1-C4)alkyl group,
o R 1 and R2 may form, with the carbon atom to which they are attached,
a -(C3-C10)cycloalkyl- group;
• Y represents a -(C3-C10)cycloalkyl-, aryl or aryloxy group, said groups being
optionally substituted with one or more substituents chosen from a halogen atom or a
(C1-C6)alkoxy group;
• Z 1 is absent or represents an -NH- function;
• Z2 is absent or represents a meth lene group or a
group;
• Z3 is absent or represents an oxygen atom or a methylene group or a
— CH or = c—
I group;
= C—
given that Z2 only represents a group when Z3 is present and when it
represents a group, and vice versa, Z2 and Z3 thus forming a double bond;
given that Z2 and Z3, when they are present, may be included in a cycloalkyi
group;
given that when Z3 represents an oxygen atom, Z2 represents a methylene group
or a
— CH or = —
I group;
in the form of an acid, a base or an addition salt with an acid or with a base.
Another subject of the present invention is compounds corresponding to the formula (I):
(I)
in which:
n is equal to 0 or 1;
D represents an oxygen atom or a bond;
W represents a nitrogen atom or a -CH- group;
X 1 represents a nitrogen atom or a -CH=CH- group;
• X2 represents an oxygen atom or a nitrogen atom;
X3 represents an oxygen atom or a nitrogen atom; one of X 1, X2, X3 being
other than a nitrogen atom, X2 and X3 not being an oxygen atom at the same time;
• R1, R2 are absent or represent,
o independently of one another, a hydrogen atom or a (C1-C4)alkyl group,
o R 1 and R2 may form, with the carbon atom to which they are attached,
a -(C3-C10)cycloalkyl- group;
• Y represents a -(C3-C10)cycloalkyl-, aryl or aryloxy group, said groups being
optionally substituted with one or more substituents chosen from a halogen atom or a
(C1-C6)alkoxy group;
• Z 1 is absent or represents an -NH- function;
• Z2 is absent or represents a methylene group or a
— CH or = c—
I H
group;
Z3 is absent or re resents an oxygen atom or a methylene group or a
group;
= c—
given that Z2 only represents a H group when Z3 is present and when it
reprecsennttcs a · grrroiui rp, oarnd vice versa, Z2 and Z3 thus forming a double bond;
given that Z2 and Z3, when they are present, may be included in a cycloalkyl
group;
given that when Z3 represents an oxygen atom, Z2 represents a methylene group
or a
— C H
group;
in the form of an acid, a base or an addition salt with an acid or with a base.
Of course, the ring comprising X 1, X2, X3 is a heteroaryl group, the position of the
double bonds possibly varying depending on the values of X 1, X2, X3 in order to lead
to an electron distribution corresponding to an aromatic ring.
The compounds of formula (I) may comprise one or more asymmetric carbon
atoms. They may thus exist in the form of enantiomers or diastereoisomers. These
enantiomers and diastereoisomers, and also mixtures thereof, including racemic
mixtures, form part of the invention.
In the compounds of formula (I), the substituents borne by the cyclohexyl group
may be in the cis or trans position. The compounds of formula (I) may thus exist in the
form of positional isomers as defined previously. These positional isomers, and also a
mixture thereof, form part of the invention.
The compounds of formula (I) may exist in the form of bases or salified with
acids or bases, especially pharmaceutically acceptable acids or bases. Such addition
salts form part of the invention.
These salts are advantageously prepared with pharmaceutically acceptable
bases, but the salts of other bases that are useful, for example, for purifying or isolating
the compounds of formula (I) also form part of the invention.
In the context of the present invention, and unless otherwise mentioned in the
text, the following definitions apply:
- a halogen atom: a fluorine, a chlorine, a bromine or an iodine;
- an alkyl group: a saturated, linear or branched aliphatic group, which may
contain 1 to 6 carbon atoms (C1-C6). Examples that may be mentioned include methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, ie -butyl and pentyl groups, etc.;
- an alkylene group: a saturated, linear or branched divalent alkyl group as
above, which may contain 1 to 5 carbon atoms. Examples that may be mentioned
include methylene, ethylene and propylene radicals;
- a cycloalkyl group: a cyclic alkyl group which may contain 3 to 10 carbon
atoms. Examples that may be mentioned include cyclopropyl, methylcyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and adamantyl groups, etc.;
- an alkoxy group: a radical of formula O-alkyl, in which the alkyl group is as
defined previously;
- an aryl group: a cyclic aromatic group containing 6 carbon atoms. Examples
of aryl groups that may be mentioned include a phenyl group;
- an aryloxy group: a radical of formula O-aryl, in which the aryl group is as
defined previously;
- a heteroaryl group: a cyclic aromatic group containing between 2 and 6
carbon atoms, in particular between 5 and 6 carbon atoms, and comprising at least one
heteroatom, such as nitrogen, oxygen or sulfur. Examples of heteroaryl groups that
may be mentioned include a pyridyl, oxadiazolyl and pyridazinyl group.
Among the compounds of formula (I) that are subjects of the invention, mention
may be made of a group in which:
• n is equal to 0 or 1;
and/or
• D represents an oxygen atom or a bond;
and/or
• W represents a nitrogen atom or a -CH- group;
and/or
· X 1 represents a nitrogen atom or a -CH=CH- group;
and/or
• X2 represents an oxygen atom or a nitrogen atom;
and/or
• X3 represents an oxygen atom or a nitrogen atom;
one of X 1, X2 and X3 being other than a nitrogen atom and X2 and X3 not
being an oxygen atom at the same time;
and/or
• R1, R2 are absent or represent:
o independently of one another, a hydrogen atom or a (C1-C4)alkyl group;
o R 1 and R2 may form, with the carbon atom to which they are attached,
a -(C3-C10)cycloalkyl- group;
and/or
• Y represents a -(C3-C10)cycloalkyl-, aryl or aryloxy group, said groups being
optionally substituted with one or more substituents chosen from a halogen atom or a
(C1-C6)alkoxy group;
and/or
• Z 1 is absent or represents an -NH- function;
and/or
• Z2 is absent or represents a methylene group or a
— CH or = c—
I group;
and/or
• Z3 is absent or represents an oxygen atom or a methylene group or a
— CH or = c—
group;
= C
|_|
—
given that Z2 only represents a group when Z3 is present and when it
= C
|_|
—
represents a group, and vice versa, Z2 and Z3 thus forming a double bond;
given that Z2 and Z3, when they are present, may be included in a cycloalkyi
group;
given that when Z3 represents an oxygen atom, Z2 represents a methylene group
— CH or = —
or a I group;
in the form of an acid or a base or an addition salt with an acid or with a base.
Among the compounds of formula (I) that are subjects of the invention, mention
may be made of a group in which:
• n is equal to 0 or 1;
and/or
• D represents an oxygen atom or a bond;
and/or
• W represents a nitrogen atom or a -CH- group;
and/or
• X 1 represents a nitrogen atom or a -CH=CH- group;
and/or
• X2 represents an oxygen atom or a nitrogen atom;
and/or
· X3 represents an oxygen atom or a nitrogen atom;
one of X 1, X2 and X3 being other than a nitrogen atom and X2 and X3 not
being an oxygen atom at the same time;
and/or
• R1, R2 are absent or represent:
o independently of one another, a hydrogen atom or a (C1-C4)alkyl group;
o R 1 and R2 may form, with the carbon atom to which they are attached,
a -(C3-C10)cycloalkyl- group;
and/or
• Y represents a -(C3-C10)cycloalkyl-, aryl or aryloxy group, said groups being
optionally substituted with one or more substituents chosen from a halogen atom or a
(C1-C6)alkoxy group;
and/or
• Z 1 is absent or represents an -NH- function;
and/or
· Z2 is absent or represents a methylene group or a
— CH or = c—
I group;
and/or
• Z3 is absent or represents an oxygen atom or a methylene group or a
— CH or = c—
I H
group;
C
|_|
—
given that Z2 only represents a group when Z3 is present and when it
= C|_|—
represents a group, and vice versa, Z2 and Z3 thus forming a double bond;
given that Z2 and Z3, when they are present, may be included in a cycloalkyi
group;
given that when Z3 represents an oxygen atom, Z2 represents a methylene
— CH
group or a group;
in the form of an acid or a base or an addition salt with an acid or with a base.
Among the latter compounds, mention may be made of those in which:
• n is equal to 0 or 1;
• D represents an oxygen atom or a bond;
· W represents a -CH- group;
• X 1 represents a nitrogen atom or a -CH=CH- group;
• X2 represents an oxygen atom or a nitrogen atom;
• X3 represents an oxygen atom or a nitrogen atom; one of X 1, X2 and X3 being
other than a nitrogen atom and X2 and X3 not being an oxygen atom at the same time;
· R1, R2 are absent or represent:
o independently of one another, a hydrogen atom or a (C1-C4)alkyl group;
o R 1 and R2 may form, with the carbon atom to which they are attached,
a -(C3-C10)cycloalkyl- group;
• Y represents a -(C3-C10)cycloalkyl-, aryl or aryloxy group, said groups being
optionally substituted with one or more substituents chosen from a halogen atom;
• Z 1 is absent or represents an -NH- function;
• Z2 is absent;
• Z3 is absent or represents a methylene group;
in the form of an acid or a base or an addition salt with an acid or with a base.
Among the latter compounds, mention may be made of those in which:
n is equal to 1;
D represents a bond;
W represents a -CH- group;
· X 1 represents a nitrogen atom or a -CH=CH- group;
X2 represents an oxygen atom or a nitrogen atom;
X3 represents an oxygen atom or a nitrogen atom; one of X 1, X2 and X3 being
other than a nitrogen atom;
• R1, R2 represent a hydrogen atom or a (C1-C4)alkyl group;
• Y represents an aryl group;
• Z 1 is absent;
• Z2 is absent;
• Z3 represents a methylene group;
in the form of an acid or a base or an addition salt with an acid or with a base.
Among the latter compounds, mention may be made of those in which:
n is equal to 0 or 1;
D represents an oxygen atom;
W represents a -CH- group;
X 1 represents a nitrogen atom or a -CH=CH- group;
X2 represents a nitrogen atom;
X3 represents an oxygen atom or a nitrogen atom; one of X 1, X2 and X3 being
other than a nitrogen atom;
• R1, R2 represent:
o independently of one another, a hydrogen atom or a (C1-C4)alkyl group;
o R 1 and R2 may form, with the carbon atom to which they are attached,
a -(C3-C10)cycloalkyl- group;
• Y represents a -(C3-C10)cycloalkyl-, aryl or aryloxy group, said groups being
optionally substituted with one or more halogen atoms;
• Z 1 is absent or represents an -NH- function;
• Z2 is absent;
• Z3 is absent;
in the form of an acid or a base or an addition salt with an acid or with a base.
Among the latter compounds, mention may be made of those
n is equal to 1;
D represents a bond;
W represents a -CH- group;
X 1 represents a nitrogen atom;
X2 represents an oxygen atom;
X3 represents a nitrogen atom;
R1, R2 represent a hydrogen atom;
Y represents an aryl group;
Z 1 is absent;
Z2 is absent;
• Z3 represents a methylene group;
in the form of an acid or a base or an addition salt with an acid or with a base.
Among the latter compounds, mention may be made of those in which:
· n is equal to 0 or 1;
• D represents an oxygen atom or a bond;
• W represents a -CH- group;
• X 1 represents a -CH=CH- group;
• X2 represents a nitrogen atom;
· X3 represents a nitrogen atom;
• R1, R2 are absent or represent a hydrogen atom;
• Y represents a -(C3-C10)cycloalkyl- or aryl group;
• Z 1 is absent or represents an -NH- function;
• Z2 is absent;
· Z3 is absent or represents a methylene group;
in the form of an acid or a base or an addition salt with an acid or with a base.
Among the latter compounds, mention may be made of those in which:
• n is equal to 1;
· D represents an oxygen atom or a bond;
• W represents a -CH- group;
• X 1 represents a nitrogen atom;
• X2 represents a nitrogen atom;
• X3 represents an oxygen atom;
· R1, R2 represent:
o independently of one another, a hydrogen atom or a (C1-C4)alkyl group;
o R 1 and R2 may form, with the carbon atom to which they are attached,
a -(C3-C10)cycloalkyl- group;
• Y represents an aryl or aryloxy group, said groups being optionally substituted
with one or more substituents chosen from a halogen atom;
• Z 1 is absent;
• Z2 is absent;
• Z3 is absent or represents a methylene group;
in the form of an acid or a base or an addition salt with an acid or with a base.
Among the compounds of formula (I) that are subjects of the invention, mention may be
made o a group in which n is equal to 0.
Among he compounds of formula (I) that are subjects of the invention, mention may be
made o a group in which n is equal to 1.
Among he compounds of formula (I) that are subjects of the invention, mention may be
made o a group in which D represents an oxygen atom.
Among he compounds of formula (I) that are subjects of the invention, mention may be
made o a group in which D represents a bond.
Among he compounds of formula (I) that are subjects of the invention, mention may be
made o a group in which W represents a -CH- group.
Among he compounds of formula (I) that are subjects of the invention, mention may be
made o a group in which W represents a nitrogen atom.
Among he compounds of formula (I) that are subjects of the invention, mention may be
made o a group in which X 1 represents a nitrogen atom.
Among he compounds of formula (I) that are subjects of the invention, mention may be
made o a group in which X 1 represents a -CH=CH- group.
Among he compounds of formula (I) that are subjects of the invention, mention may be
made o a group in which X2 represents an oxygen atom.
Among he compounds of formula (I) that are subjects of the invention, mention may be
made o a group in which X2 represents a nitrogen atom.
Among he compounds of formula (I) that are subjects of the invention, mention may be
made o a group in which X3 represents an oxygen atom.
Among :he compounds of formula (I) that are subjects of the invention, mention may be
made o a group in which X3 represents a nitrogen atom.
Among the compounds of formula (I) that are subjects of the invention, mention may be
made of a group in which X 1 represents a nitrogen atom, X2 and X3 represent a
nitrogen atom or an oxygen atom.
Among the compounds of formula (I) that are subjects of the invention, mention may be
made of a group in which X 1 represents -CH=CH-, X2 and X3 represent a nitrogen
atom.
Among the compounds of formula (I) that are subjects of the invention, mention may be
made of a group in which R1, R2 represent, independently of one another, a hydrogen
atom or a (C1-C4)alkyl group.
Among the compounds of formula (I) that are subjects of the invention, mention may be
made of a group in which R1, R2 form, with the carbon atom to which they are
attached, a -(C3-C10)cycloalkyl group, more particularly a cyclopropyl group.
Among the compounds of formula (I) that are subjects of the invention, mention may be
made of a group in which Y represents a -(C3-C10)cycloalkyl group.
Among the compounds of formula (I) that are subjects of the invention, mention may be
made of a group in which Y represents an aryl group, more particularly a phenyl group,
said group being optionally substituted with one or more substituents chosen from a
halogen atom, more particularly a fluorine atom or a (C1-C6)alkoxy group, more
particularly a methoxy group.
Among the compounds of formula (I) that are subjects of the invention, mention may be
made of a group in which Y represents an aryloxy group, more particularly a phenyloxy
group.
Among the compounds of formula (I) that are subjects of the invention, mention may be
made of a group in which Z 1 is absent.
Among the compounds of formula (I) that are subjects of the invention, mention may be
made of a group in which Z 1 represents an -NH- function.
Among the compounds of formula (I) that are subjects of the invention, mention may be
made of a group in which Z2 is absent.
Among the compounds of formula (I) that are subjects of the invention, mention may be
made of a group in which Z2 represents a methylene group.
Among the compounds of formula (I) that are subjects of the invention, mention may be
made of a group in which Z2 and Z3 represent a
— CH
group, thus forming a cycloalkyl group.
Among the compounds of formula (I) that are subjects of the invention, mention may be
made of a group in which Z2 and Z3 represent a
group, thus forming a double bond.
Among the compounds of formula (I) that are subjects of the invention, mention may be
made of a group in which Z3 is absent.
Among the compounds of formula (I) that are subjects of the invention, mention may be
made of a group in which Z3 represents an oxygen atom and Z2 represents a
methylene group or a
— CH or = c—
I group.
Among the compounds of formula (I) that are subjects of the invention, mention may be
made of a group in which Z3 represents an oxygen atom and Z2 represents a
meth lene group or a
group.
Among the compounds of formula (I) that are subjects of the invention, mention may be
made of a group in which Z3 represents a methylene group.
Among the compounds of formula (I) that are subjects of the invention, mention
may especially be made of the following compounds:
- trans{4-[4-(5-benzyl[1 .2.4]oxadiazol-3-ylcarbamoyl)phenyl]cyclohexyl}acetic
acid
- trans{4-[4-(3-benzyl[1 .2.4]oxadiazol-5-ylcarbamoyl)phenyl]cyclohexyl}acetic
acid
- cis-4-[4-(3-benzyl[1 .2.4]oxadiazol-5-ylcarbamoyl)phenoxy]cyclohexanecarboxylic
acid
- cis-4-{4-[3-(3,5-difluorobenzyl)[1 .2.4]oxadiazol-5-ylcarbamoyl]phenoxy}cyclohexanecarboxylic
acid
- cis-4-{4-[3-(1-phenylcyclopropyl)[1 .2.4]oxadiazol-5-ylcarbamoyl]phenoxy}-
cyclohexanecarboxylic acid
- cis-4-{4-[3-(1-methyl-1-phenylethyl[1 .2.4]oxadiazol-5-ylcarbamoyl]phenoxy}-
cyclohexanecarboxylic acid
- cis-4-[4-(3-phenoxymethyl[1 .2.4]oxadiazol-5-ylcarbamoyl)phenoxy]cyclohexanecarboxylic
acid
- {4-[4-(6-benzylpyridazin-3-ylcarbamoyl)phenyl]cyclohexyl}acetic acid
- cis-4-[4-(6-cyclopentylaminopyridazin-3-ylcarbamoyl)phenoxy]cyclohexanecarboxylic
acid
- cis-4-[5-(3-benzyl[1 .2.4]oxadiazol-5-ylcarbamoyl)pyridin-2-yloxy]cyclohexanecarboxylic
acid
- trans-2-{4-[4-(3-benzyl[1 .2.4]oxadiazol-5-ylcarbamoyl)phenyl]cyclohexyl}-
cyclopropanecarboxylic acid
- trans-(E)-3-{4-[4-(3-benzyl[1 .2.4]oxadiazol-5-ylcarbamoyl)phenyl]cyclohexyl}-
acrylic acid
- trans-3-{4-[4-(3-benzyl[1 .2.4]oxadiazol-5-ylcarbamoyl)phenyl]cyclohexyl}-
propionic acid
- cis-4-[4-(6-phenylaminopyridazin-3-ylcarbamoyl)phenoxy]cyclohexanecarboxylic
acid
- cis-4-{4-[6-(4-methoxyphenyl)pyridazin-3-ylcarbamoyl]phenoxy}cyclohexanecarboxylic
acid
It should be noted that the above compounds were named in lUPAC nomenclature by
means of the ACDLABS 10.0 ACD/name software (Advanced Chemistry
Development).
In accordance with the invention, the compounds of general formula (I) may be
prepared according to the following processes.
In the text hereinbelow, a "protecting group" (PG) is understood to mean a
group that makes it possible, on the one hand, to protect a reactive function such as a
hydroxyl or an amine during a synthesis and, on the other hand, to regenerate the
intact reactive function at the end of the synthesis. Examples of protecting groups and
of protection and deprotection methods are given in "Protective Groups in Organic
Synthesis", Green et al., 4th Edition (John Wiley & Sons, Inc., New York).
In schemes 1 to 11, the starting compounds and the reactants, when their
method of preparation is not described, are commercially available or are described in
the literature, or else may be prepared according to methods that are described therein
or that are known to those skilled in the art.
In accordance with the invention, the compounds of general formula (I) may be
prepared according to the following processes:
The R group used below represents a -Z1-C(R1 R2) -Y group with R 1, R2, Y, n
and Z 1 as defined previously.
Synthesis of the intermediates
Scheme 1
In scheme 1, the acid chloride of formula (A) for which R represents a benzyl
group is reacted with cyanamide in a polar solvent such as THF in order to give the
acylcyanamide of formula (II). This is reacted with hydroxylamine hydrochloride in the
presence of a base such as pyridine in a protic solvent such as ethanol in order to
result in the aminooxadiazole of formula (III).
Scheme 2
In scheme 2, the acetonitrile of formula (IV) for which R represents a benzyl,
3,5-difluorobenzyl, phenyldimethylmethyl or phenylcyclopropyl group is reacted with
hydroxylamine hydrochloride in the presence of a base such as triethylamine in a polar
solvent such as dichloromethane in order to give the hydroxyamidine of formula (V).
The latter is reacted with trichloroacetyl chloride in the presence of a base such as
pyridine in an apolar solvent such as toluene in order to give the
trichloromethyloxadiazole of formula (VI). This, reacted with aqueous ammonia in a
protic solvent such as methanol gives the aminooxadiazole of formula (VII).
Scheme 3
VIII XI
In scheme 3, the chlorotetrazolopyridazine compound of formula (VIII) is
reacted with the benzylcyclopentylamine of formula (IX) at a temperature between 150
and 200°C, for example 190°C, to give the benzylcyclopentylaminotetrazolopyridazine
compound of formula (X). The reaction of the latter with tributylphosphine at a
temperature between 150 and 200°C, for example at 180°C, provides the
aminopyridazine of formula (XI).
Scheme 4
In scheme 4, the compound of formula (XIV) is prepared by a Horner-
Wadsworth-Emmons reaction starting from ketones of formula (XII) comprising an acid
function protected by a protecting group PG1 such as an ethyl group and derivatives of
formulae (XIII) comprising an acid function protected by a protecting group PG2 such
as a ie/f-butyl group in a polar solvent such as dimethylformamide at room temperature
in the presence of a base such as sodium hydride. The compound of formula (XIV) is
hydrogenated in the presence of a transition metal such as palladium in a polar solvent
such as ethanol in order to give, after recrystallization, the trans compound of formula
(XV). The acid of formula (XVIa) is obtained by hydrolysis of the ester of formula (XV)
in the presence of lithium hydroxide in a mixture of polar solvents such as water,
methanol and tetrahydrofuran.
The compounds of formula (XII) may be prepared according to a scheme described in
the literature (WO 2003/099772).
Scheme 5
In scheme 5, the compound of formula (XIX) is prepared by a Horner-
Wadsworth-Emmons reaction starting from the ketone of formula (XVII) and derivatives
of formulae (XVIII) comprising an acid function protected by a protecting group PG1
such as a methyl group in a polar solvent such as tetrahydrofuran at room temperature
in the presence of a base such as sodium hydride. The compound of formula (XIX) is
hydrogenated in the presence of a transition metal such as palladium in a polar solvent
such as tetrahydrofuran in order to predominantly give the trans compound of formula
(XX). This is converted to the triflate of formula (XXI) using a reactant such as triflic
anhydride in a polar solvent such as dichloromethane, between 0 and 25°C, in the
presence of a base such as triethylamine. The acid of formula (XVIb) is obtained by
hydroxycarbonylation of the triflate of formula (XXI) in a polar solvent such as dioxane,
between 100 and 120°C, by methods chosen from those known to a person skilled in
the art. They include, inter alia, the use of a carbonylation reagent such as
molybdenum hexacarbonyl and of a palladium catalyst such as palladium diacetate.
Scheme 6
In scheme 6, the compound of formula (XXIV) comprising an acid function
protected by a protecting group PG1 , such as a methyl group, is obtained from the acid
of formula (XXII) by selective reaction with a compound known to a person skilled in
the art such as trimethylsilyldiazomethane in a mixture of apolar and polar solvent such
as, respectively, toluene and methanol, at room temperature. The alcohol of formula
(XXIV) is involved in a Mitsunobu reaction with the phenol of formula (XXIII) comprising
an acid function protected by a protecting group PG2, such as a ie/f-butyl group, in a
polar solvent such as tetrahydrofuran, at room temperature in order to give the ether of
formula (XXV). The acid of formula (XXVI) is obtained by deprotection of the
intermediate of formula (XXV) by methods chosen from those known to a person skilled
in the art. These include, for an acid function protected by a protecting group PG2,
such as the ie/f-butyl group, inter alia, the use of trifluoroacetic acid or of hydrochloric
acid in polar solvents such as dichloromethane or dioxane.
Scheme 7 gives details of a synthesis of intermediates in which D represents a
bond or an oxygen atom, W represents a -CH- group or a nitrogen atom, Z2 and Z3
represent methylene groups, a -CH=CH- group or are included in a cyclopropyl. These
compounds will be referred to hereinbelow as compounds of formula (XXVII).
XXVIa XXVII
In scheme 7, the compound of formula (XXVIa) comprising an acid function
protected by a protecting group PG1 , such as a methyl or ie/f-butyl group, is reacted
with ammonia in the presence of a coupling agent such as 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide in a polar solvent such as dioxane in order to give
the amide of formula (XXVII).
It should be noted tha the compounds of general formula (XXVIa) are described
in the literature (WO 10/086551).
Synthesis of molecules of interest
Scheme 8 gives details of a synthesis of the compounds of formula I in which n is
equal to 1 or 0, D represents a bond or an oxygen atom, W represents a -CH- group,
X 1 represents a nitrogen atom or a -CH=CH- group, X2 represents an oxygen or
nitrogen atom, X3 represents an oxygen atom or a nitrogen atom, R 1 and R2 represent
a hydrogen atom, Y represents a phenyl substituted by a substituent chosen from a
halogen atom or a methoxy, Z 1 and Z2 are absent and Z3 represents a methylene
group. These compounds will be referred to hereinbelow as compounds of formula
(XXX).
In scheme 8, the amines of formula (XXVIII) are involved in an amide coupling
reaction with the acids of formula (XVI) comprising an acid function protected by a
protecting group PG3, such as a methyl or ie -butyl group, in order to give the
intermediates of formula (XXIX) by methods chosen from those known to a person
skilled in the art. They include, inter alia, the use of a coupling agent such as CDI in the
presence of DBU in a polar solvent such as DMF at a temperature of 100°C, or EDC in
the presence of HOBt in a polar solvent such as dioxane at a temperature of 80°C in a
microwave device or the acid chloride derived from the acid of formula (XVI) in the
presence of a base such as triethylamine in a polar solvent such as acetonitrile. The
acids of formula (XXX) are obtained after deprotection of the ester of the intermediate
of formula (XXIX) by methods chosen from those known to a person skilled in the art.
The esters of the intermediates of formula (XXIX) are deprotected by methods chosen
from those known to a person skilled in the art. They include, inter alia, the use of
lithium hydroxide in a mixture of polar solvents such as water, methanol and
tetrahydrofuran in the case of a methyl protecting group or in the presence of an acid
such as trifluoroacetic acid in the case of a ie -butyl protecting group.
Scheme 9 gives details of a synthesis of the compounds of formula I in which n is
equal to 1, D represents a bond or an oxygen atom, W represents a -CH- group or a
nitrogen atom, X 1 represents a nitrogen atom, X2 represents an oxygen atom, X3
represents a nitrogen atom, R 1 and R2 represent a hydrogen atom, a methyl group or
may form, with the carbon atom to which they are attached, a cyclopropyl group, Y
represents a phenyl or a phenoxy, Z 1 is absent, Z2 is absent and Z3 represents a
methylene group, Z2 and Z3 represent methylene groups, a -CH=CH- group or are
included in a cyclopropyl. These compounds will be referred to hereinbelow as
compounds of formula (XXXII).
Scheme 9
In scheme 9, the trichloromethyloxadiazole of formula (VI) is reacted with the
amide of formula (XXVII) in the presence of a base such as sodium hydride, in a polar
solvent such as tetrahydrofuran, in order to give the oxadiazoles of formula (XXXI). The
latter is treated by an alkali-metal base such as lithium hydroxide in the case of a
protecting group PG1 such as a methyl group or in the presence of an acid such as
trifluoroacetic acid in the case of a ie/f-butyl protecting group so as to provide the
corresponding carboxylic acid of formula (XXXII).
Scheme 10 gives details of a synthesis of the compounds of formula I in which
n is equal to 0, D represents an oxygen atom, W represents a -CH- group, X 1
represents a -CH=CH- group, X2 represents a nitrogen atom, X3 represents a nitrogen
atom, R 1 and R2 are absent, Y represents a (C3-C10)cycloalkyl group, Z 1 represents
an NH function, Z2 is absent and Z3 represents a methylene group. These compounds
will be referred to hereinbelow as compounds of formula (XXXVII).
Scheme 10
In scheme 10, the aminopyridazine of formula (XXXIII) is reacted with the acid
chloride derived from the acid of formula (XXVI) in the presence of a base such as
triethylamine, in a polar solvent such as acetonitrile, in order to give the imide of
formula (XXXIV). The latter is treated with hydrazine in a basic polar solvent such as
pyridine and gives the amide of formula (XXXV). This, under hydrogen pressure in the
presence of a metal such as palladium and of an acid such as hydrochloric acid
provides the corresponding intermediate of formula (XXXVI). The latter is treated with
an alkali-metal base such as lithium hydroxide in the case of a protecting group PG1 ,
such as a methyl group, in a mixture of polar solvents such as water and
tetrahydrofuran in order to provide the corresponding carboxylic acid of formula
(XXXVII).
Scheme 1 1
In scheme 11, the aminopyridazine of formula (XXXVIII) is reacted with the acid
of formula (XXII) in the presence of a coupling agent (for example, 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide) in a polar solvent such as dioxane, at a
temperature of 80°C in a microwave device in order to give the compound of formula
(XXXIX). The latter is treated with hydrazine in a basic polar solvent such as pyridine
and gives the amide of formula (XL). The latter is treated with an alkali-metal base such
as lithium hydroxide in a mixture of polar solvents such as water and tetrahydrofuran, in
order to provide the corresponding carboxylic acid of formula (XLI).
In schemes 1 to 6, the starting compounds and the reactants, when their
preparation method is not described, are commercially available or are described in the
literature, or else may be prepared according to methods which are described therein
or which are known to a person skilled in the art.
Another subject of the invention, according to another of its aspects, is the
compounds of formulae (XXIX), (XXXI), (XXXIV), (XXXV) and (XXXVI). These
compounds are of use as intermediates for the synthesis of the compounds of formula
(I)-
The examples that follow describe the preparation of certain compounds in
accordance with the invention. These examples are not limiting, and serve merely to
illustrate the present invention. The numbers of the compounds given as examples
refer to those given in the table hereinbelow, which illustrates the chemical structures
and physical properties of a few compounds according to the invention.
The following abbreviations and empirical formulae are used:
ACN acetonitrile
BSA bovine serum albumin
CDI carbonyldiimidazole
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
°C degrees Celsius
C0 2 carbon dioxide
cm2 square centimetres
DIEA diisopropylethylamine
dec. decomposition
DMAP 4-dimethylaminopyridine
DMEM Dulbecco's Minimum Essential Medium Modified
DMF dimethylformamide
DMSO dimethylsulfoxide
EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
EDTA ethylenediaminetetraacetic acid
eq. equivalent
ESI+ electrospray ionization
g gram
g constant force of gravity = 9.81 m-s 2
NMR nuclear magnetic resonance
h hour(s)
H20 water
HOBt hydroxybenzotriazole
HPLC high-performance liquid chromatography
Hz Hertz
LC-MS liquid chromatography-mass spectrometry
M mass
MHz megahertz
mg milligram
mL milliliter
mm millimeter
mmol millimoles
N normal
nM nanomolar
PBS phosphate-buffered saline
m.p. melting point
ppm parts per million
psi pounds per square inch
FCS fetal calf serum
TFA trifluoroacetic acid
THF tetrahydrofuran
UPLC ultra-high performance liquid chromatography
UV ultraviolet
HIV human immunodeficiency virus
m ί microcurie
% percentage
The radioactivity measurement is performed using a Flo One C625TR machine
(Perkin-Elmer) or a MicroBeta counter (Perkin-Elmer).
The proton magnetic resonance spectra ( H NMR), as described hereinbelow,
are recorded at 400 MHz in DMSO-d6, using the peak of DMSO-d5 as the reference.
The chemical shifts d are expressed in parts per million (ppm). The observed signals
are expressed as follows: s = singlet; d = doublet; t = triplet; m = multiplet or broad
singlet.
The LC/MS column and the examples indicate the peak M+H+ identified by
mass spectrometry. The compounds are analyzed by liquid chromatography (UV
detector at 220 nm) coupled to a mass spectrometer with an electrospray ionization
detector. The analytical method is detailed below:
UPLC/MS - gradient of 3 min - water/ACN/TFA
T Omin: 98% A - T 1.6 to T 2.1 min: 100% B - T 2.5 to T 3 min: 98% A
Route A: water + 0.05% TFA, route B: ACN + 0.035% TFA
Flow rate: 1.0 mL/min - T° = 40°C - injection 2 m I_
Acquity BEH C18 column (50*2.1 mm; 1.7 * mh-i)
Synthesis of the intermediates
Example 1: 5-benzyl[1.2.4]oxadiazol-3-ylamine
1. 1 Synthesis of phenylacetylcyanamide
1.59 mL of phenylacetyl chloride (12 mmol, 1 eq.) are added dropwise to a
solution of 2.30 g of sodium cyanamide (36 mmol, 3 eq.) in 30 mL of THF cooled to
4°C. The reaction medium is brought to reflux for 6 h. After cooling, it is diluted with
ethyl acetate and washed with water. The basic aqueous phase is acidified to pH = 1
and extracted using dichloromethane. The organic phase is dried over sodium sulfate,
filtered and evaporated to give phenylacetylcyanamide which is used as is in the
remainder of the synthesis.
1.2 Synthesis of 5-benzyl[1 .2.4loxadiazol-3-ylamine
Successively added to 20 mL of ethanol are the phenylacetylcyanamide from
the preceding step, 1.25 g of hydroxylamine hydrochloride (18 mmol, 1.5 eq.) and
3.4 mL of pyridine (48 mmol, 4 eq.). After reacting for 36 h, the medium is triturated in
water, filtered and washed with water to give 1.12 g of 5-benzyl[1 .2.4]oxadiazol-3-
ylamine.
M+H+=176.
Example 2 : 3-benzyl[1.2.4]oxadiazol-5-ylamine
2.1 Synthesis of N-hydroxy-2-phenylacetamidine
Placed successively in 60 mL of ethanol are 4.60 mL of phenylacetonitrile
(39.85 mmol, 1 eq.), 3.46 g of hydroxylamine hydrochloride (49.82 mmol, 1.25 eq.) and
8.33 mL of triethylamine (59.78 mmol, 1.5 eq.). The medium is brought to reflux for
3.5 h and evaporated. The residue is taken up in dichloromethane and washed with
water. The organic phase is dried over sodium sulfate, filtered and evaporated. The
residue is chromatographed on silica gel, eluting with a 1/1 ethyl acetate/heptane
mixture. 2.9 g of N-hydroxy-2-phenylacetamidine are obtained.
2.2 Synthesis of 3-benzyl-5-trichloromethyiri .2.41oxadiazole
0.41 mL of trichloroacetyl chloride (3.66 mmol, 1. 1 eq.) are added to a solution,
cooled to 4°C, of 0.5 g of N-hydroxy-2-phenylacetamidine (3.33 mmol, 1 eq.) and of
1 mL of pyridine (12.36 mmol, 3.7 eq.) in 4 mL of toluene. The medium is brought to
85°C for 2.5 h, evaporated and taken up in diethyl ether. The organic phase is washed
with water, dried over sodium sulfate, filtered and evaporated to give 0.83 g of
3-benzyl-5-trichloromethyl[1 .2.4]oxadiazole.
2.3 Synthesis of 3-benzyiri .2.41oxadiazol-5-ylamine
0.83 g of 3-benzyl-5-trichloromethyl[1 .2.4]oxadiazole (3 mmol, 1 eq.) are placed
in 6 mL of methanol and 6 mL of a 7 N aqueous solution of ammonia (42 mmol, 14 eq.)
are added. After 3 days, the medium is evaporated and the residue is
chromatographed on silica gel, eluting with a gradient of ethyl acetate in heptane that
varies from 25% to 50%. 0.270 g of 3-benzyl[1 .2.4]oxadiazol-5-ylamine is obtained.
Example 3 : N-benzyl-N-cyclopentylpyridazine-3,6-diamine
3.1 Synthesis of benzylcvclopentyl[1 .2.4ltriazolo[1 ,5-blpyridazin-6-ylamine
0.8 g of 6-chloro[1 .2.4]triazolo[1 ,5-b]pyridazine (5.14 mmol, 1 eq.) and 0.9 g of
benzylcyclopentylamine (5.14 mmol, 1 eq.) are placed in a sealed tube. The medium is
heated at 190°C for 3 h to give 1.51 g of benzylcyclopentyl[1 .2.4]triazolo[1 ,5-
b]pyridazin-6-ylamine.
M+H+=295.
3.2 Synthesis of N-benzyl-N-cvclopentylpyridazine-3,6-diamine
1.51 g of benzylcyclopentyl[1 .2.4]triazolo[1 ,5-b]pyridazin-6-ylamine (5.14 mmol),
2.08 g of tributylphosphine (10.28 mmol, 2 eq.) and 6 mL of acetonitrile are placed in a
sealed tube. The medium is heated at 180°C for 3 h and the solvent is evaporated. The
residue is taken up in 56 mL of acetic acid and 14 mL of water. The medium is brought
to reflux for 3 h. After cooling, it is brought to basic pH using a saturated aqueous
solution of sodium hydrogen carbonate and extracted two times using ethyl acetate.
The organic phase is evaporated and the residue is chromatographed on silica gel,
eluting with a dichloromethane/methanol/aqueous ammonia gradient that varies from
98/2/0.2 to 92/8/0.8 to give 0.4 g of N-benzyl-N-cyclopentylpyridazine-3,6-diamine.
M+H+=269.
Example 4 : 4-(4- erf-butoxycarbonylmethylcyclohexyl)benzoic acid
4.1 Synthesis of ethyl 4-(4-te/f-butoxycarbonylmethylenecvclohexyl)benzoate
5.63 g of ie -butyl diethylphosphoacetate (20.3 mmol, 1 eq.) are placed in 20
mL of dimethylformamide with stirring. The solution is cooled to a temperature of 4°C
by placing the solution in an ice bath, and 0.536 g of sodium hydride (22.33 mmol,
1. 1 eq.) is then added portionwise. After 30 minutes, 5 g of ethyl 4-(4-oxocyclohexyl)-
benzoate (20.3 mmol, 1 eq.) are added and the ice bath is removed. After stirring for 1
hour, the round-bottomed flask is placed in an ice bath to cool the reaction medium to a
temperature of 4°C, and 0.049 g of sodium hydride (2.04 mmol, 0.1 eq.) is added. The
ice bath is removed and, after 30 minutes, the mixture is poured into 200 mL of 1N
potassium hydrogen sulfate and extracted with 300 mL of diethyl ether. The organic
phase is washed 4 times with brine. The organic phase is dried over sodium sulfate
and evaporated. The residue is chromatographed on silica gel, eluting with a gradient
of methanol in dichloromethane ranging from 0% to 5%. 5.04 g of ethyl 4-(4-ie -
butoxycarbonylmethylenecyclohexyl)benzoate are obtained.
M+H+ = 345.
4.2 Synthesis of ethyl 4-(4-te/f-butoxycarbonylmethylcvclohexyl)benzoate
5.04 g of ethyl 4-(4-ie/f-butoxycarbonylmethylenecyclohexyl)benzoate (14.63
mmol, 1 eq.) and 15 mL of ethanol are placed in a Parr bottle. 0.31 g of 10% palladiumon-
charcoal (0.29 mmol, 0.02 eq.) is added and the reaction medium is placed under
50 psi of hydrogen for 3 hours at a temperature of 25°C. The reaction medium is
filtered and concentrated to give 4.31 g of ethyl 4-(4-ie/f-butoxycarbonylmethylcyclohexyl)
benzoate.
M-isobutene + = 291 .
4.3 Synthesis of 4-(4-te/f-butoxycarbonylmethylcvclohexyl)benzoic acid
3.3 g of ethyl 4-(4-ie/f-butoxycarbonylmethylcyclohexyl)benzoate (9.52 mmol,
1 eq.) are dissolved in 30 mL of a 2/1 mixture of tetrahydrofuran/methanol, then 1.60 g
of lithium hydroxide hydrate (38.10 mmol, 4 eq. dissolved in 10 mL of water) are added.
The reaction medium is stirred for 4 hours at room temperature. The solvents are
evaporated off and an aqueous solution of S0 2 is added. The solid obtained is filtered
off, washed with water and dried to give 2 g of 4-(4-ie/f-butoxycarbonylmethylcyclohexyl)
benzoic acid.
4.4. Synthesis of frans-4-(4-te/f-butoxycarbonylmethylcvclohexyl)benzoic acid
0.5 g of 4-(4-ie/f-butoxycarbonylmethylcyclohexyl)benzoic acid is recrystallized
from ethyl acetate at the reflux point of the solution. After filtration and drying, 0.17 g of
irans-4-(4-ie/f-butoxycarbonylmethylcyclohexyl)benzoic acid is obtained.
H NMR (400 MHz, DMSO-d6) d ppm 12.77 (m, 1H), 7.87 (m, J = 9 Hz, 2H),
7.36 (m, J = 9 Hz, 2H), 2.54 (m, 1H), 2.13 (d, J = 7.3 Hz, 2H), 1.87 to 1.68 (m, 5H),
1.49 (m, 2H), 1.43 (s, 9H), 1.14 (m, 2H).
Example 5 : 4-(4-methoxycarbonylmethylcyclohexyl)benzoic acid
5.1 Synthesis of methyl r4-(4-hydroxyphenyl)cvclohexylidenelacetate
1.69 g of 4-(4-hydroxyphenyl)cyclohexanone (77.22 mmol, 1 eq.) are placed in
100 mL of THF in a 250 mL round-bottomed flask under nitrogen. The solution is
cooled to 4°C on an ice bath and 3 g of 60% sodium hydride (75.04 mmol, 0.97 eq.)
are added portionwise. 16.88 g of methyl dimethylphosphoacetate (92.67 mmol,
1.2 eq.) are placed in 100 mL of THF in another 500 mL round-bottomed flask under
nitrogen. This second solution is cooled on an ice bath and 4.41 g of 60% sodium
hydride ( 1 10.30 mmol, 1.42 eq.) are added portionwise. The ice baths are removed
and the media are stirred at room temperature for 30 minutes. The 4-(4-hydroxyphenyl)
cyclohexanone solution is added to the methyl dimethylphosphoacetate
solution. The reaction medium is stirred for 18 h. 100 mL of a saturated aqueous
ammonium chloride solution is added and the reaction medium is extracted three times
with ethyl acetate. The organic phase is washed with water, dried over magnesium
sulfate, filtered and evaporated to give 17.16 g of methyl [4-(4-hydroxyphenyl)cyclohexylidene]
acetate.
M+H+ = 247.
5.2 Synthesis of methyl [4-(4-hvdroxyphenyl)cvclohexyHacetate
17.16 g of methyl [4-(4-hydroxyphenyl)cyclohexylidene]acetate (69.67 mmol,
1 eq.) are placed in 130 mL of THF in a Parr bottle under nitrogen. 2.96 g of 5%
palladium-on-charcoal ( 1 .39 mmol, 0.02 eq.) is added and the reaction medium is
placed under 50 psi of hydrogen for 3.5 h at 30°C. The reaction medium is filtered and
concentrated to give 16.63 g of methyl [4-(4-hydroxyphenyl)cyclohexyl]acetate in a
trans/cis ratio of 70/30.
M+H+ = 249.
5.3 Synthesis of methyl r4-(4-trifluoromethanesulfonyloxyphenyl)cvclohexyllacetate
16.63 g of methyl [4-(4-hydroxyphenyl)cyclohexyl]acetate (66.96 mmol, 1 eq.)
are placed in 200 mL of dichloromethane. The solution is cooled on an ice bath, and 14
mL of diisopropylethylamine (80.36 mmol, 1.2 eq.) and 13.3 mL of triflic anhydride
(80.36 mmol, 1.2 eq.) are added successively and dropwise while not exceeding 6°C.
The ice bath is removed and the reaction medium is stirred for 18 h. The medium is
poured into ice-water and extracted with dichloromethane. The organic phase is
washed with a 1N aqueous solution of sodium hydroxide, washed with brine, dried over
magnesium sulfate, filtered and evaporated. The residue is chromatographed on silica
gel, eluting with a gradient of ethyl acetate in heptane ranging from 10% to 50%. 17.7 g
of methyl [4-(4-trifluoromethanesulfonyloxyphenyl)cyclohexyl]acetate are obtained in a
trans/cis ratio of 70/30.
M+H+ = 381 .
5.4 Synthesis of 4-(4-methoxycarbonylmethylcvclohexyl)benzoic acid
0.4 g of methyl [4-(4-trifluoromethanesulfonyloxyphenyl)cyclohexyl]acetate ( 1 .05
mmol, 1 eq.) is placed, respectively, in 3 mL of dioxane in one 20 mL microwave tube.
0.142 g of molybdenum hexacarbonyl (0.53 mmol, 0.5 eq.), 0.024 g of palladium (II)
acetate (0.1 1 mmol, 0.1 eq.), 0.058 g of 1, 1 '-bis(diphenylphosphino)ferrocene (0.1 1
mmol, 0.1 eq.), 0.257 g of 4-dimethylaminopyridine (2.1 mmol, 2 eq.), 0.42 mL of
diisopropylethylamine (2.42 mmol, 2.3 eq.) and 0.38 mL of water (21 .03 mmol, 20 eq.)
are successively added. The tube is heated at 120°C for 10 minutes in a Biotage
microwave machine. The reaction medium is filtered. The filtrate is washed with a
saturated sodium carbonate solution and diluted with diethyl ether. After separation of
the phases by settling, the aqueous phase is acidified with a 5N hydrochloric acid
solution and extracted twice with dichloromethane. The organic phase is dried over
sodium sulphate and concentrated to dryness to give 0.155 g of 4-(4-methoxycarbonylmethylcyclohexyl)
benzoic acid in a trans/cis ratio of 70/30.
Example 6 : c/s-4-(4-methoxycarbonylcyclohexyloxy)benzoic acid
6.1 Synthesis of methyl frans-4-hvdroxycvclohexanecarboxylate
1 g of 4-hydroxycyclohexanecarboxylic acid (6.94 mmol, 1 eq.) is placed in
50 mL of a 4/1 mixture of toluene/methanol. 5.55 mL of a 2 N solution of trimethylsilyldiazomethane
in hexane ( 1 1.10 mmol, 1.6 eq.) is poured dropwise into the reaction
medium with stirring. After 16 hours, the solvents are evaporated to give 1.3 g of
methyl irans-4-hydroxycyclohexanecarboxylate.
6.2 Synthesis of te -butyl c/s-4-(4-methoxycarbonylcvclohexyloxy)benzoate
1. 1 g of methyl irans-4-hydroxycyclohexanecarboxylate (6.95 mmol, 1.35 eq.),
1 g of ie -butyl 4-hydroxybenzoate (5.15 mmol, 1 eq.) and 2.03 g of triphenylphosphine
(7.72 mmol, 1.5 eq.) are placed in 10 mL of tetrahydrofuran at room temperature.
1.5 mL of diisopropyl azodicarboxylate (7.72 mmol, 1.5 eq.) are added dropwise to the
reaction medium with stirring. After 18 hours at room temperature, the medium is
concentrated to dryness and taken up in diethyl ether. The triphenylphosphine oxide is
filtered off. The organic phase is washed with a sodium hydroxide solution, dried over
sodium sulfate, filtered and evaporated to give a residue. This residue is
chromatographed on silica gel, eluting with a gradient of ethyl acetate in heptane
ranging from 0% to 50%. 1.23 g of ie/f-butyl c/s-4-(4-methoxycarbonylcyclohexyloxy)-
benzoate are obtained.
6.3 Synthesis of c/s-4-(4-methoxycarbonylcvclohexyloxy)benzoic acid
0.6 g of ie -butyl c/s-4-(4-methoxycarbonylcyclohexyloxy)benzoate ( 1 .79 mmol,
1 eq.) are placed in 2.5 mL of dichloromethane. The reaction medium is cooled to a
temperature of 4°C, with stirring, in an ice bath. 1 mL of trifluoroacetic acid
(13.46 mmol, 7.5 eq.) is added and the ice bath is removed. After stirring for 5 hours at
room temperature, the medium is concentrated, taken up in diethyl ether, drained and
filtered to give 0.30 g of c/'s -4-(4-methoxycarbonylcyclohexyloxy)benzoic acid.
M+H+ = 279.
Example 7 : Methyl c/s-4-(4-carbamoylphenoxy)cyclohexanecarboxylate
7.1 Synthesis of methyl c/s-4-(4-carbamoylphenoxy)cvclohexanecarboxylate
3 g of c/s-4-(4-methoxycarbonylcyclohexyloxy)benzoic acid (10.78 mmol, 1 eq.)
are dissolved in 40 mL of dioxane. 1.46 g of HOBt (10.78 mmol, 1 eq.), 4.13 g of EDC
(21 .56 mmol, 2 eq.) and 108 mL of a 0.5 N solution of aqueous ammonia (53.90 mmol,
5 eq.) are successively added to the dioxane. After stirring for 18 h, the reaction
medium is evaporated and taken up in dichloromethane. The organic phase is
evaporated, washed using a 1N solution of hydrochloric acid, washed twice with brine,
dried over sodium sulfate, filtered and evaporated to give 2.99 g of methyl c/s-4-(4-
carbamoylphenoxy)cyclohexanecarboxylate.
M+H+=278.
Example 8 : erf-butyl c/'s-(5-carbamoylpyridin-2-yloxy)cyclohexanecarboxylate
This compound is obtained from the carboxylic acid according to preparation 7.1 .
M+H+ = 321 .
Example 9 : erf-butyl rans-(E)-3-[4-(4-carbamoylphenyl)cyclohexyl]acrylate
This compound is obtained from the carboxylic acid according to preparation 7.1 .
Example 10: erf-butyl rans-3-[4-(4-carbamoylphenyl)cyclohexyl]propionate
This compound is obtained from the carboxylic acid according to preparation 7.1 .
Example 11: erf-butyl rans-2-[4-(4-carbamoylphenyl)cyclohexyl]cyclopropane
carboxylate
This compound is obtained from the carboxylic acid according to preparation 7.1 .
Synthesis of molecules of interest
Example 12: rans-{4-[4-(5-benzyl[1.2.4]oxadiazol-3-ylcarbamoyl)phenyl]cyclohexyl}
acetic acid (compound No. 1)
12.1 Synthesis of te/f-butyl frans-{4-r4-(5-benzyiri .2.41oxadiazol-3-ylcarbamoyl)phenyllcvclohexyllacetate
Added to 6 mL of dimethylformamide are 0.318 g of trans-4-(4-tertbutoxycarbonylmethylcyclohexyl)
benzoic acid ( 1 mmol, 1 eq.) and 0.292 g of CDI. After
stirring for 1 h, 0.350 g of 5-benzyl[1 .2.4]oxadiazol-3-ylamine (2 mmol, 2 eq.) and
0.30 mL of DBU (2 mmol, 2 eq.) are added. The medium is brought to 100°C for 24 h.
After cooling, the medium is diluted with ethyl acetate and washed with water. The
organic phase is dried over sodium sulfate, filtered and evaporated. The residue is
chromatographed on silica gel, eluting with a 1/3 ethyl acetate/heptane mixture.
0.060 g of te/f-butyl irans-{4-[4-(5-benzyl[1 .2.4]oxadiazol-3-ylcarbamoyl)phenyl]cyclohexyl}
acetate is obtained.
12.2 Synthesis of frans-{4-[4-(5-benzyl[1 .2.4loxadiazol-3-ylcarbamoyl)phenyllcvclohexyllacetic
acid
0.060 g of ie/f-butyl irans-{4-[4-(5-benzyl[1 .2.4]oxadiazol-3-ylcarbamoyl)phenyl]-
cyclohexyl}acetate are dissolved in 3 mL of dichloromethane and 0.5 mL of
trifluoroacetic acid is added. After 1 h, the medium is evaporated and triturated in ethyl
acetate to give 0.015 mg of irans-{4-[4-(5-benzyl[1 .2.4]oxadiazol-3-
ylcarbamoyl)phenyl]cyclohexyl}acetic acid.
M+H+ = 420.
H NMR (400 MHz, DMSO-d6) d ppm 1.12 (m, 2 H); 1.50 (m, 2 H); 1.74 (m, 1
H); 1.83 (m, 4 H); 2.15 (d, J=6.8 Hz, 2 H); 2.59 (m, 1 H); 3.75 (s, 2 H); 7.21 to 7.40 (m,
5 H); 7.50 (broad d, J=8.9 Hz, 2 H); 7.97 (broad d, J=8.9 Hz, 2 H); 11.43 (broad s, 1 H);
12.02 (broad unresolved m, 1 H).
Example 13: rans-{4-[4-(3-benzyl[1.2.4]oxadiazol-5-ylcarbamoyl)phenyl]cyclohexyl}
acetic acid (compound No. 2)
13.1 Synthesis of te/f-butyl frans- 4- 4-(3-benz i i .2.41oxadiazol-5-ylcarbamoyl)phenyllcvclohexyllacetate
This compound is obtained according to preparation 12.1 starting from
3-benzyl[1 .2.4]oxadiazol-5-ylamine and irans-4-(4-te/f-butoxycarbonylmethylcyclohexyl)
benzoic acid.
13.2 Synthesis of frans-{4-r4-(3-benzviri .2.41oxadiazol-5-ylcarbamoyl)phenyllcvclohexyllacetic
acid
0.190 g of fe/f-butyl irans-{4-[4-(3-benzyl[1 .2.4]oxadiazol-5-ylcarbamoyl)-
phenyl]cyclohexyl}acetate are dissolved in 5 mL of dichloromethane and 2 mL of
trifluoroacetic acid are added. After 1 h, the medium is evaporated and triturated in
ethanol and washed with water to give 0.140 mg of trans-{4-[4-(3-
benzyl[1 .2.4]oxadiazol-5-ylcarbamoyl)phenyl]cyclohexyl}acetic acid.
M+H+ = 420.
H NMR (400 MHz, DMSO-d6) d ppm 1.12 (m, 2 H); 1.50 (m, 2 H); 1.73 (m, 1
H); 1.81 (m, 4 H); 2.15 (d, J=7.0 Hz, 2 H); 2.55 (m, 1 H); 4.03 (s, 2 H); 7.23 to 7.36 (m,
5 H); 7.39 (broad d, J=8.9 Hz, 2 H); 7.91 (broad d, J=8.9 Hz, 2 H); 11.99 (broad
unresolved m, 1 H); 12.32 (broad unresolved m, 1 H).
Example 14: {4-[4-(6-benzylpyridazin-3-ylcarbamoyl)phenyl]cyclohexyl}acetic
acid (compound No. 3)
14.1 Synthesis of methyl {4-r4-(6-benzylpyridazin-3-ylcarbamoyl)phenyllcvclohexyl)-
acetate
0.093 g of 6-benzylpyridazin-3-ylamine (0.5 mmol, 1 eq.), 0.069 g of 4-(4-
methoxycarbonylmethylcyclohexyl)benzoic acid (0.25 mmol, 0.5 eq.), 0.096 g of EDC
(0.5 mmol, 1 eq.) and 0.034 g of HOBt (0.25 mmol, 0.5 eq.) are placed successively
into 3 mL of DMF. After stirring for 6 days, the medium is diluted with ethyl acetate. The
organic phae is washed four times with water, dried over sodium sulfate, filtered and
evaporated. The residue is chromatographed on silica gel, eluting with a gradient of
methanol in dichloromethane ranging from 1% to 2%. 0.043 g of ie/f-butyl {4-[4-(6-
benzylpyridazin-3-ylcarbamoyl)phenyl]cyclohexyl}acetate is obtained in a trans/cis ratio
of 70/30.
14.2 Synthesis of {4-r4-(6-benzylpyridazin-3-ylcarbamoyl)phenyllcvclohexyl)acetic acid
0.043 g of ie/f-butyl {4-[4-(6-benzylpyridazin-3-ylcarbamoyl)phenyl]cyclohexyl}-
acetate (0.1 mmol, 1 eq.) is dissolved in 3 mL of a 2/1 mixture of THF/MeOH. 0.012 g
of lithium hydroxide monohydrate (0.19 mmol, 2 eq.) dissolved in 1 mL of water is
added. After stirring for 18 h, the medium is partially evaporated and diluted with
dichloromethane. The organic phase is washed using a 1N solution of hydrochloric
acid, dried over sodium sulfate, filtered and evaporated. The residue is triturated in an
MeOH/water mixture to give 0.035 g of irans-{4-[4-(6-benzylpyridazin-3-ylcarbamoyl)-
phenyl]cyclohexyl}acetic acid in a trans/cis ratio of 70/30.
M+H+ = 430.
H NMR (400 MHz, DMSO-d6) d ppm 1.13 (m, 1.4 H); 1.50 (m, 1.4 H); 1.58 to
1.89 (m, 5.2 H) 1.73 (m, 0.7 H); 2.15 (d, J=7.0 Hz, 1.4 H); 2.191 (m, 0.3 H); 2.38 (d,
J=7.5 Hz, 0.6 H); 2.56 (m, 0.7 H); 2.64 (m, 0.3 H); 4.27 (s, 2 H); 7.18 to 7.35 (m, 5 H);
7.38 (broad d, J=8.9 Hz, 1.4 H); 7.43 (broad d, J=8.9 Hz, 0.6 H); 7.59 (d, J=9.0 Hz, 1
H); 7.99 (m, 2 H); 8.28 (d, J=9.0 Hz, 1 H); 11.25 (broad s, 1 H); 12.02 (broad
unresolved m, 1 H).
Example 15 : c/s-4-[4-(3-benzyl[1 .2.4]oxadiazol-5-ylcarbamoyl)phenoxy]cyclohexanecarboxylic
acid (compound No. 4)
15.1 Synthesis of methyl c/s-4-[4-(3-benzyl[1 .2.41oxadiazol-5-ylcarbamoyl)phenoxylcvclohexanecarboxylate
0.227 g of methyl c/s-4-(4-carbamoylphenoxy)cyclohexanecarboxylate ( 1 mmol,
1 eq.) is dissolved in 5 mL of THF. 0.024 g of sodium hydride ( 1 mmol, 1 eq.) is added
and the stirring is continued for 10 minutes. 0.555 g of 3-benzyl-5-trichloromethyl-
[ 1 .2.4]oxadiazole (2 mmol, 2 eq.) in solution in 2 mL of THF is added dropwise. After
18 h, the medium is diluted with dichloromethane and washed with water. The organic
phase is dried over sodium sulfate, filtered and evaporated to give a residue which is
chromatographed on silica gel, eluting with a gradient of ethyl acetate in heptane that
varies from 25% to 50%. 0.194 g of methyl c/'s-4-[4-(3-benzyl[1 .2.4]oxadiazol-5-
ylcarbamoyl)phenoxy]cyclohexanecarboxylate is obtained.
M+H+=436.
15.2 Synthesis of c/s-4-r4-(3-benzyiri .2.41oxadiazol-5-ylcarbamoyl)phenoxylcvclohexanecarboxylic
acid
0.194 g of methyl c/'s-4-[4-(3-benzyl[1 .2.4]oxadiazol-5-
ylcarbamoyl)phenoxy]cyclohexane carboxylate (0.45 mmol, 1 eq.) is dissolved in 2 mL
of THF. 0.056 g of lithium hydroxide monohydrate ( 1 .34 mmol, 3 eq.) dissolved in 1 mL
of water is added. After stirring for 18 h, the medium is acidified using a 1N solution of
hydrochloric acid to an acid pH and evaporated. The residue is triturated in ethanol to
give 0.095 mg of c/'s-4-[4-(3-benzyl[1 .2.4]oxadiazol-5-
ylcarbamoyl)phenoxy]cyclohexanecarboxylic acid.
M+H+ = 422.
H NMR (400 MHz, DMSO-d6) d ppm 1.56 to 1.89 (m, 8 H); 2.39 (m, 1 H);
4.03 (s, 2 H); 4.62 to 4.74 (m, 1 H); 7.06 (broad d, J=8.9 Hz, 2 H); 7.21 to 7.40 (m, 5
H); 7.96 (broad d, J=8.9 Hz, 2 H); 12.10 (broad s, 1 H); 12.21 (broad s, 1 H).
Example 16: (E)-3-{4-[4-(3-benzyl[1.2.4]oxadiazol-5-ylcarbamoyl)phenyl]cyclohexyl}
acrylic acid (compound No. 3c)
16.1 te/f-butyl f/-ans-(E)-3-{4-r4-(3-benzylH .2.41oxadiazol-5-ylcarbamoyl)phenyllcvclohexyDacrylate
The compound is obtained from te/f-butyl irans-(E)-3-[4-(4-carbamoylphenyl)cyclohexyl]
acrylate and 3-benzyl[1 .2.4]oxadiazol-5-ylamine according to preparation 15.1 .
M+H+ = 488
16.2 frans-(E)-3-{4-r4-(3-benzviri .2.41oxadiazol-5-ylcarbamoyl)phenyllcvclohexyl)-
acrylic acid
0.257 g of ie/f-butyl irans-(E)-3-{4-[4-(3-benzyl[1 .2.4]oxadiazol-5-ylcarbamoyl)-
phenyl]cyclohexyl}acrylate are dissolved in 5 mL of dichloromethane and 0.045 mL
(6.33 mmol, 12 eq.) of trifluoroacetic acid is added. After 18 h, the medium is
evaporated, triturated in diethyl ether and washed with water to give a residue which is
chromatographed on a C18-grafted silica column. The elution is carried out by eluting
with a gradient of water containing 0.1% of TFA in a water/acetonitrile (90/10) mixture
containing 0.1% of TFA (0.1%) varying from 0 to 90% to give 44 mg of irans-(E)-3-{4-
[4-(3-benzyl[1 .2.4]oxadiazol-5-ylcarbamoyl)phenyl]cyclohexyl}acrylic acid.
M+H+ = 432
H NMR (400 MHz, DMSO-d 6) d ppm 1.31 (m, 2 H); 1.55 (m, 2 H); 1.86 (m, 4 H);
2.24 (m, 1 H); 2.59 (m, 1 H); 4.04 (s, 2 H); 5.75 (dd, J=1 .5 and 15.8 Hz, 1 H); 6.82 (dd,
J=6.8 and 15.8 Hz, 1 H); 7.22 to 7.38 (m, 5 H); 7.40 (d, J=8.5 Hz, 2 H); 7.92 (d, J=8.5
Hz, 2 H); 12.14 (broad s, 1 H); 12.32 (broad s, 1 H).
Example 17: rans-3-{4-[4-(3-benzyl[1.2.4]oxadiazol-5-ylcarbamoyl)phenyl]cyclohexyl}
propionic acid (compound No. 3d)
17.1 te/f-butyl frans-3-{4-r4-(3-benzylH .2.41oxadiazol-5-ylcarbamoyl)phenyllcvclohexyllpropionate
The compound is obtained from te/f-butyl irans-3-[4-(4-carbamoylphenyl)cyclohexyl]
propionate and 3-benzyl[1 .2.4]oxadiazol-5-ylamine according to preparation 15.1 .
M+H+ = 490
17.2 f/-ans-3-{4-r4-(3-benzyiri .2.41oxadiazol-5-ylcarbamoyl)phenyllcvclohexyl)propionic
acid
0.195 g of te/f-butyl irans-3-{4-[4-(3-benzyl[1 .2.4]oxadiazol-5-ylcarbamoyl)-
phenyl]cyclohexyl}propionate are dissolved in 4 mL of dichloromethane and 0.03 mL
(4.8 mmol, 12 eq.) of trifluoroacetic acid is added. After 18 h, the medium is evaporated,
triturated in diethyl ether and washed with water to give 0.070 mg of irans-3-{4-[4-(3-
benzyl[1 .2.4]oxadiazol-5-ylcarbamoyl)phenyl]cyclohexyl}propionic acid.
M+H+ = 434
H NMR (400 MHz, DMSO-d 6) d ppm 1.05 (m, 2 H); 1.30 (m, 1 H); 1.39 to 1.52
(m, 4 H); 1.81 (m, 4 H); 2.25 (t, J=7.7 Hz, 2 H); 2.57 (m, 1 H); 4.03 (s, 2 H); 7.20 to
7.36 (m, 5 H); 7.38 (d, J=8.3 Hz, 2 H); 7.91 (d, J=8.3 Hz, 2 H); 11.96 (broad s, 1 H);
12.31 (broad s, 1 H).
Example 18: rans-2-{4-[4-(3-benzyl[1 .2.4]oxadiazol-5-ylcarbamoyl)phenyl]cyclohexyl}
cyclopropanecarboxylic acid (compound No. 3b)
18.1 te/f-butyl frans-2-{4-[4-(3-benzyl[1 .2.41oxadiazol-5-ylcarbamoyl)phenyllcvclohexyDcvclopropane
carboxylate
The compound is obtained from ie/f-butyl irans-2-[4-(4-carbamoylphenyl)cyclohexyl]-
cyclopropanecarboxylate and 3-benzyl[1 .2.4]oxadiazol-5-ylamine according to
preparation 15.1 .
M+H+ = 502
18.2 frans-2-{4-[4-(3-benzyl[1 .2.41oxadiazol-5-ylcarbamoyl)phenyllcvclohexyl)cvclopropanecarboxylic
acid
The compound is obtained from ie/f-butyl irans-2-{4-[4-(3-benzyl[1 .2.4]oxadiazol-5-
ylcarbamoyl)phenyl]cyclohexyl}cyclopropanecarboxylate according to preparation 16.2.
M+H+ = 446
H NMR (400 MHz, DMSO-d 6) d ppm 0.66 to 0.88 (m, 2 H); 0.93 (m, 1 H); 1.09
(m, 1 H); 1.24 (m, 2 H); 1.32 to 1.51 (m, 3 H); 1.75 to 1.93 (m, 4 H); 2.56 (m, 1 H); 4.04
(s, 2 H); 7.20 to 7.42 (m, 7 H); 7.91 (d, J=8.3 Hz, 2 H); 11.92 (broad unresolved m, 1 H);
12.31 (s, 1 H).
Example 19: c/s-4-[5-(3-benzyl[1 .2.4]oxadiazol-5-ylcarbamoyl)pyridin-2-yloxy]-
cyclohexanecarboxylic acid (compound No. 10)
19.1 te/f-butyl c/s-4-r5-(3-benzyiri .2.41oxadiazol-5-ylcarbamoyl)pyridin-2-yloxylcvclohexanecarboxylate
The compound is obtained from te/f-butyl c/s-(5-carbamoylpyridin-2-yloxy)cyclohexanecarboxylate
and 3-benzyl[1 .2.4]oxadiazol-5-ylamine according to preparation
15.1 .
M+H+ = 479
19.2 c/s-4-r5-(3-benzviri .2.41oxadiazol-5-ylcarbamoyl)pyridin-2-yloxylcvclohexanecarboxylic
acid
The compound is obtained from ie -butyl c/s-4-[5-(3-benzyl[1 .2.4]oxadiazol-5-
ylcarbamoyl)pyridin-2-yloxy]cyclohexanecarboxylate according to preparation 13.2.
M+H+ = 423
H NMR (400 MHz, DMSO-d6) d ppm .49 to .97 (m, 8 H); 2.39 (m, 1 H);
4.03 (s, 2 H); 5.25 (m, 1 H); 6.91 (d, J=8.8 Hz, 1 H); 7.1 7 to 7.43 (m, 5 H); 8.21
(dd, J=2.5 and 8.8 Hz, 1 H); 8.77 (d, J=2.5 Hz, 1 H); 12.1 0 (broad s, 1 H); 12.41
(broad s, 1 H).
Example 20: cis 4-[4-(6-cyclopentylaminopyridazin-3-ylcarbamoyl)phenoxy]-
cyclohexanecarboxylic acid (compound No. 9)
20.1 Synthesis of methyl c/s-4-{4-rcis-4-(4-methoxycarbonylcvclohexyloxy)benzoyl(6-
cvclopentylaminopyridazin-3-yl)aminocarbonyllphenoxy)cvclohexanecarboxylate
0.4 g of c/s-4-(4-methoxycarbonylcyclohexyloxy)benzoic acid ( 1 .44 mmol, 1 eq.)
is placed into 5 mL of dichloromethane. Two drops of DMF and 0.24 mL of oxalyl
chloride ( 1 .87 mmol, 1.3 eq.) are successively added. After stirring for 1.5 h, the
medium is evaporated to form c/s-4-(4-methoxycarbonylcyclohexyloxy)benzoyl
chloride. Placed into a round-bottomed flask are 0.4 g of N-benzyl-N-cyclopentylpyridazine-
3,6-diamine ( 1 .49 mmol, 1.04 eq.) and 0.26 mL of triethylamine ( 1 .87 mmol,
1.3 eq.) in 5 mL of acetonitrile and c/s-4-(4-methoxycarbonylcyclohexyloxy)benzoyl
chloride dissolved in 2 mL of acetonitrile is added dropwise. After 2.5 h, the medium is
diluted with dichloromethane, washed with a saturated solution of sodium
hydrogencarbonate, washed twice with water, washed with brine, dried over sodium
sulfate, filtered and evaporated. The residue is chromatographed on silica gel, eluting
with a gradient of ethyl acetate in heptane that varies from 10% to 50%. 0.37 g of
methyl c/s-4-{4-[cis-4-(4-methoxycarbonylcyclohexyloxy)benzoyl(6-cyclopentylaminopyridazin-
3-yl)aminocarbonyl]phenoxy}cyclohexanecarboxylate is obtained.
M+H+ = 789.
20.2 Synthesis of methyl c/s-4-{4-[6-(benzylcvclopentylamino)pyridazin-3-ylcarbamoyllphenoxylcvclohexanecarboxylate
0.32 g of methyl c/s-4-{4-[cis-4-(4-methoxycarbonylcyclohexyloxy)benzoyl-(6-
cyclopentylaminopyridazin-3-yl)aminocarbonyl]phenoxy}cyclohexanecarboxylate
(0.41 mmol, 1 eq.) and 0.03 mL of hydrazine hydrate (0.62 mmol, 1.52 eq.) are placed
in 2 mL of pyridine. After stirring for 18 h, the medium is evaporated and diluted with
dichloromethane. The organic phase is washed with a saturated solution of sodium
hydrogencarbonate, washed with brine, dried over sodium sulfate, filtered and
evaporated. The residue is chromatographed on silica gel, eluting with a gradient of
methanol in dichloromethane that varies from 1% to 5%. 0.2 g of methyl c/s-4-{4-[6-
(benzylcyclopentylamino)pyridazin-3-ylcarbamoyl]phenoxy}cyclohexanecarboxylate is
obtained.
M+H+ = 529.
20.3 Synthesis of methyl c/s-4-r4-(6-cvclopentylaminopyridazin-3-ylcarbamoyl)-
phenoxylcyclohexanecarboxylate
0.220 g of methyl c/s-4-{4-[6-(benzylcyclopentylamino)pyridazin-3-
ylcarbamoyl]phenoxy}cyclohexanecarboxylate (0.42 mmol, 1 eq.) and 20 mL of
methanol are placed in a Parr bottle. 0.07 g of 10% palladium-on-charcoal (0.07 mmol,
0.16 eq.) and 0.05 mL of a 4N solution of hydrochloric acid in dioxane are added. The
reaction medium is put under 50 psi of hydrogen for 10 h at a temperature of 25°C. The
reaction medium is filtered and concentrated. The residue is chromatographed on silica
gel, eluting with a gradient of methanol in dichloromethane that varies from 2% to 5%.
0.15 g of methyl c/s-4-[4-(6-cyclopentylaminopyridazin-3-ylcarbamoyl)phenoxy]cyclohexanecarboxylate
is obtained.
M+H+ = 439.
20.4 Synthesis of c/s-4-[4-(6-cvclopentylaminopyridazin-3-ylcarbamoyl)phenoxylcvclohexanecarboxylic
acid
0.135 g of methyl c/s-4-[4-(6-cyclopentylaminopyridazin-3-ylcarbamoyl)-
phenoxy]cyclohexanecarboxylate (0.31 mmol, 1 eq.) is placed in 4 mL of
tetrahydrofuran and 0.039 g of lithium hydroxide monohydrate (0.92 mmol, 3 eq.)
dissolved in 2 mL of water is added. After stirring for 18 h, the medium is acidified using
a 1N solution of hydrochloric acid and extracted three times with dichloromethane. The
organic phase is dried over sodium sulfate, filtered and evaporated. The residue is
triturated successively in ethyl acetate and diethyl ether to give 0.051 g of c/s-4-[4-(6-
cyclopentylaminopyridazin-3-ylcarbamoyl)phenoxy]cyclohexanecarboxylic acid.
M+H+ = 425.
H NMR (400 MHz, DMSO-d6) d ppm 1.43 to 2.04 (m, 16 H); 2.40 (m, 1 H);
4.18 (m, 1 H); 4.69 (m, 1 H); 7.06 (broad d, J=8.9 Hz, 2 H); 7.12 (broad d, J=7.5 Hz, 1
H); 7.61 (very broad unresolved m, 1 H); 7.92 to 8.02 (m, 3 H); 10.79 (broad s, 1 H);
12.10 (broad unresolved m, 1 H).
Example 2 1: c/s-4-[4-(6-phenylaminopyridazin-3-ylcarbamoyl)phenoxy]cyclohexanecarboxylic
acid (compound No. 11)
2 1. 1 Synthesis of methyl c/s-4-{4-rc/s-4-(4-methoxycarbonylcvclohexyloxy)benzoyl-(6-
phenylaminopyridazin-3-yl)aminocarbonyllphenoxy)cvclohexanecarboxylate
0.053 g of 6-phenylaminopyridazin-3-ylamine (0.28 mmol, 1 eq.), 0.079 g of c/'s-
4-(4-methoxycarbonylcyclohexyloxy)benzoic acid (0.28 mmol, 1 eq.), 0.066 g of EDC
(0.34 mmol, 1.2 eq.), 0.039 g of HOBt (0.28 mmol, 1 eq.) and 0.06 mL of
diisopropylethylamine (0.37 mmol, 1.3 eq.) are successively placed in 1.5 mL of
dioxane in a microwave tube. The medium is heated by microwave at 80°C for 45
minutes. The medium is evaporated. The residue is chromatographed on silica gel,
eluting with a gradient of methanol in dichloromethane that varies from 1% to 3%. The
fractions of interest are evaporated and the residue is washed with ethanol. 0.050 g of
methyl c/s-4-{4-[c/s-4-(4-methoxycarbonylcyclohexyloxy)benzoyl(6-
phenylaminopyridazin-3-yl)aminocarbonyl]phenoxy}cyclohexanecarboxylate is
obtained.
M+H+ = 706.
2 1.2 Synthesis of methyl c/s-4-{4-[6-(phenylamino)pyridazin-3-ylcarbamoyllphenoxy)-
cvclohexanecarboxylate
0.05 g of methyl c/s-4-{4-[c/s-4-(4-methoxycarbonylcyclohexyloxy)benzoyl(6-
phenylaminopyridazin-3-yl)aminocarbonyl]phenoxy}cyclohexanecarboxylate
(0.07 mmol, 1 eq.) and 0.02 mL of hydrazine hydrate (0.42 mmol, 6 eq.) are placed in
0.3 mL of pyridine. After stirring for 5 days, the medium is evaporated and diluted with
dichloromethane. The organic phase is washed using a saturated solution of sodium
hydrogencarbonate. The aqueous phase is extracted 3 times using dichloromethane.
The organic phases are combined, dried over sodium sulfate, filtered and evaporated.
The residue is chromatographed on silica gel, eluting with a gradient of methanol in
dichloromethane that varies from 1% to 2%. 0.04 g of methyl c/s-4-{4-[6-(phenylamino)-
pyridazin-3-ylcarbamoyl]phenoxy}cyclohexanecarboxylate is obtained.
M+H+ = 447.
2 1.3 Synthesis of c/s-4-r4-(6-phenylaminopyridazin-3-ylcarbamoyl)phenoxylcvclohexanecarboxylic
acid
0.04 g of methyl c/s-4-{4-[6-(phenylamino)pyridazin-3-ylcarbamoyl]phenoxy}-
cyclohexanecarboxylate (0.09 mmol, 1 eq.) is placed in 2 mL of tetrahydrofuran and
0.01 1 g of lithium hydroxide monohydrate (0.27 mmol, 3 eq.) dissolved in 1 mL of water
is added. After stirring for 18 h, the medium is acidified using a 6% aqueous sulfurous
acid solution, and filtered. The precipitate is triturated successively in water and ethanol
to give 0.018 g of c/s-4-[4-(6-phenylaminopyridazin-3-ylcarbamoyl)phenoxy]cyclohexanecarboxylic
acid.
M+H+ = 433.
H NMR (400 MHz, DMSO-d6) d ppm 1.60 to 1.89 (m, 8 H); 2.39 (m, 1 H); 4.67
(m, 1 H); 6.94 (t, J=7.8 Hz, 1 H); 7.05 (d, J=9.0 Hz, 2 H); 7.23 (d, J=9.5 Hz, 1 H); 7.30
(t, J=7.8 Hz, 2 H); 7.72 (d, J=7.8 Hz, 2 H); 8.03 (d, J=9.0 Hz, 2 H); 8.09 (d, J=9.5 Hz, 1
H); 9.23 (s, 1 H); 10.86 (s, 1 H); 12.00 (very broad unresolved m, 1 H).
Example 22: c/s-4-{4-[6-(4-methoxyphenyl)pyridazin-3-ylcarbamoyl]phenoxy}-
cyclohexanecarboxylic acid (compound No. 12)
22.1 . Synthesis of methyl c/s-4-{4-[6-(4-methoxyphenyl)pyridazin-3-ylcarbamoyllphenoxylcyclohexanecarboxylate
0.506 g of 6-(4-methoxyphenyl)pyridazin-3-ylamine (2.52 mmol, 2 eq.), 0.350 g of c/'s-
4-(4-methoxycarbonylcyclohexyloxy)benzoic acid (2.52 mmol, 2 eq.), 0.289 g of EDC
( 1 .51 mmol, 1.2 eq.), 0.170 g of HOBt ( 1 .26 mmol, 1 eq.) are successively placed in
6 mL of dioxane in a microwave tube. The medium is heated by microwave at 80°C for
65 minutes. The medium is evaporated. The residue is chromatographed on silica gel,
eluting with a gradient of methanol in dichloromethane that varies from 0% to 5%. The
fractions of interest are evaporated and 0.580 g of methyl c/s-4-{4-[6-(4-methoxyphenyl)
pyridazin-3-ylcarbamoyl]phenoxy}cyclohexanecarboxylate is obtained.
M+H+ = 462.
22.2. Synthesis of c/s-4-{4-r6-(4-methoxyphenyl)pyridazin-3-ylcarbamoyllphenoxy)-
cvclohexanecarboxylic acid
0.250 g of methyl c/s-4-{4-[6-(4-methoxyphenyl)pyridazin-3-ylcarbamoyl]phenoxy}cyclohexanecarboxylate
(0.54 mmol, 1 eq.) is placed in 13.5 mL of a 2/1 mixture of
tetrahydrofuran/water and 0.068 g of lithium hydroxide monohydrate ( 1.63 mmol, 3 eq.)
is added. After stirring for 18 h, the medium is acidified using a 6% aqueous sulfurous
acid solution, and filtered. The precipitate is triturated successively in water and
ethanol. The residue is slurried in ethanol at high temperature and filtered to give
0.150 g of c/s-4-{4-[6-(4-methoxyphenyl)pyridazin-3-ylcarbamoyl]phenoxy}cyclohexanecarboxylic
acid.
M+H+ = 448.
H NMR (400 MHz, DMSO-d6) d ppm 1.59 to 1.91 (m, 8 H); 2.40 (m, 1 H); 3.84
(s, 3 H); 4.69 (m, 1 H); 7.04 to 7.15 (m, 4 H); 8.02 to 8.12 (m, 4 H); 8.20 (d, J=9.3 Hz, 1
H); 8.40 (d, J=9.3 Hz, 1 H); 11.25 (s, 1 H); 12.00 (very broad unresolved m, 1 H).
Tables I and II that follow illustrate the chemical structures and the physical
properties of a few compounds according to the invention, corresponding to the formula
(I).
Table I illustrates compounds of formula (I) according to the invention for which
D is a bond; these compounds are referred to hereinbelow as compounds of formula
(A).
Table II illustrates compounds of formula (I) according to the invention for which
D is an oxygen atom, Z2 and Z3 are absent, these compounds being referred to
hereinbelow as compounds of formula (B).
In these tables:
the compounds of table I are mainly in trans form or exclusively in trans form;
the compounds of table II are exclusively in cis form;
"-" in the "Z1 " column or the "Z2" column or the "R1 " column or the "R2" column
indicates that the corresponding group is absent;
- "* " indicates the bonding atom;
"m.p." represents the melting point of the compound, expressed in degrees
Celsius (°C). "then dec" means "then decomposition of the compound";
"MH+" represents the mass M+H of the compound, obtained by LC-MS
(abbreviation for liquid chromatography-mass spectroscopy);
- "-" in the "MH+" or "m.p." columns indicates that the measurement was not
taken.
43
44

The compounds according to the invention underwent pharmacological trials for
determining their inhibitory effect on the DGAT-1 enzyme, which is involved in the
metabolism of lipids.
These trials consisted in measuring the in vitro inhibitory activity of the
compounds of the invention on the DGAT-1 enzyme by virtue of a phase partitioning
assay (PPA) in 96-well format. The recombinant DGAT-1 protein was produced in Sf9
insect cells transfected with a baculovirus. The reaction was carried out by incubating
the enzyme in the presence of 1,2-di(c/s-9-octadecenoyl)-sn-glycerol and octanoylCoA.
The amount of triacylglycerol formed during the reaction is measured. The inhibitory
activity with respect to the DGAT-1 enzyme is given by the concentration that inhibits
50% of the activity of DGAT-1 (IC50) . The radioactivity is measured using a MicroBeta
counter (Perkin Elmer).
The IC50 values of the compounds according to the invention are less than
10 mM, more particularly between 100 nM and 1 mM, more particularly still less than
100 nM and more particularly between 50 and 100 nM. For example, the IC50 values of
compounds No. 1, 2, 3, 3b, 3c, 3d, 4, 5, 6, 7, 8, 9, 10, 11 and 12 are respectively
0.286, 0.253, 0.89, 0.742, 2.21 , 0.927, 0.056, 0.1 15, 3.76, 5.7, 0.094, 0.051 , 0.081 ,
5.91 and 7.18 mM.
It therefore appears that the compounds according to the invention have an
inhibitory activity on the DGAT-1 enzyme. The compounds according to the invention
may therefore be used for preparing medicaments, in particular medicaments for
inhibiting the DGAT-1 enzyme.
The compounds according to the invention underwent pharmacological trials for
determining their inhibitory effect on triglyceride biosynthesis.
These trials consisted in measuring the in vitro inhibitory activity of the
compounds of the invention on a cell test.
Chang liver cells at 80% confluence are detached with trypsin-EDTA, 4 ml per
175 cm2 flask. After centrifugation at 1300 g for 5 minutes, the cell pellet is washed
once with PBS and then resuspended in whole medium. The number of cells and their
viability are determined on Mallassez cells via the exclusion method with trypan blue.
150 000 cells are inoculated per well into a 24-well plate for a minimum of 3 h in
DMEM medium 4.5 g/l of glucose supplemented with 10% FCS and with antibiotics,
and are maintained at 37°C in an incubator with C0 2 (5%).
After 3 h, the cells have adhered, the medium is removed and replaced
overnight with DMEM medium 4.5 g/l of glucose with 2% of BSA/oleate.
After culturing for 18 h without serum, the test compounds are incubated for
30 min ( 1.3, 10, 30, 100, 300 and 1000 nM) with the cells, followed by addition of [ 4C]
glycerol (0.4 m ί/i I/nnbII ) for an incorporation time of 6 h.
The supernatant is drawn off and the cells are recovered by treatment with
trypsin-EDTA, 100 m I/well, for 5 minutes at 37°C. This cell suspension is then
recovered in an Eppendorf tube and is washed with twice 500 m I of PBS. A
centrifugation at 1300 g for 5 minutes allows recovery of the cell pellet, which may be
frozen at -20°C. In order to extract the lipids from the cell pellet, 400 m I of a
methanol/dichloromethane/trifluoroacetic acid mixture (50/50/0.1%) is used to
resuspend the cells. Next, the cell membranes are destroyed by sonication on a water
bath, for 30 minutes. The samples are filtered through a 0.45 m h filter and then injected
onto a C18 HPLC column of 4.6 75 mm, 3 m h with a mobile phase of 5% (H20 +
0.1% TFA), 70% methanol, 25% dichloromethane, with a flow rate of 1.5 ml/minute.
The radioactivity is measured using a Flo One C625TR machine (Perkin-Elmer).
The inhibitory activity on triglyceride biosynthesis is given by the concentration
that inhibits 50% of the activity.
The activities of the compounds according to the invention are generally
between 0.01 mM and 10 mM and more particularly between 0.01 and 1 mM .
For example, the activities of compounds Nos. 5 and 8 are, respectively, 0.310
and 0.319 mM .
It is thus seen that the compounds according to the invention have inhibitory
activity on triglyceride biosynthesis.
The compounds according to the invention may thus be used for the
preparation of medicaments, in particular medicaments for inhibiting triglyceride
biosynthesis.
Thus, according to another of its aspects, a subject of the invention is
medicaments comprising a compound of formula (I), or an addition salt thereof with a
pharmaceutically acceptable acid or base of the compound of formula (I).
These medicaments find their use in therapeutics, especially in the treatment
and/or prevention of obesity, dyslipidemia, impaired fasting glucose conditions,
metabolic acidosis, ketosis, hepatic steatosis, insulin resistance, type 2 diabetes and
complications arising from this pathology, lipotoxicity, the accumulation and an excess
of triacylglycerides in adipose tissue (WAT), metabolic syndrome, coronary diseases,
hypertension, skin diseases such as the skin diseases linked to the proliferation of the
sebaceous glands such as acne, Alzheimer's disease, immunomodulatory diseases,
HIV infection, irritable bowel syndrome and certain cancers, and advantageously for
the preparation of a medicament for treating or preventing obesity, dyslipidemia,
impaired fasting glucose conditions, metabolic acidosis, ketosis, hepatic steatosis,
insulin resistance, type 2 diabetes and complications arising from this pathology,
lipotoxicity, the accumulation and an excess of triacylglycerides in adipose tissue
(WAT), metabolic syndrome and hepatitis C.
According to another of its aspects, the present invention relates to
pharmaceutical compositions comprising, as active principle, a compound according to
the invention. These pharmaceutical compositions comprise an effective dose of at
least one compound according to the invention, or a pharmaceutically acceptable salt
of said compound, and also at least one pharmaceutically acceptable excipient. Said
excipients are chosen, according to the desired pharmaceutical form and mode of
administration, from the usual excipients known to those skilled in the art.
In the pharmaceutical compositions of the present invention for oral, sublingual,
subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal,
transdermal or rectal administration, the active principle of formula (I) above, or the
possible salt thereof, may be administered in unit administration form, as a mixture with
standard pharmaceutical excipients, to animals and to man for the prophylaxis or
treatment of the above disorders or diseases.
The appropriate unit administration forms include oral forms such as tablets,
soft or hard gel capsules, powders, granules and oral solutions or suspensions,
sublingual, buccal, intratracheal, intraocular, intranasal and inhalation administration
forms, topical, transdermal, subcutaneous, intramuscular or intravenous administration
forms, rectal administration forms and implants. For topical application, the compounds
according to the invention may be used in creams, gels, ointments or lotions.
By way of example, a unit administration form of a compound according to the
invention in tablet form may comprise the following components:
Compound according to the invention 50.0 mg
Mannitol 223.75 mg
Croscaramellose sodium 6.0 mg
Corn starch 15.0 mg
Hydroxypropyl methyl cellulose 2.25 mg
Magnesium stearate 3.0 mg
There may be particular cases in which higher or lower dosages are
appropriate; such dosages are not outside the scope of the invention. According to the
usual practice, the dosage that is appropriate for each patient is determined by the
doctor according to the mode of administration and the weight and response of said
patient.
According to another of its aspects, the present invention also relates to a
method for treating the pathologies indicated above, which comprises the
administration, to a patient, of an effective dose of a compound according to the
invention, or a pharmaceutically acceptable salt thereof.
CLAIMS
1. A compound corresponding to the formula (I)
in which:
• n is equal to 0 or 1;
• D represents an oxygen atom or a bond;
• W represents a nitrogen atom or a -CH- group;
• X 1 represents a nitrogen atom or a -CH=CH- group;
• X2 represents an oxygen atom or a nitrogen atom;
• X3 represents an oxygen atom or a nitrogen atom; one of X 1, X2, X3 being
other than a nitrogen atom, X2 and X3 not being an oxygen atom at the same time;
• R1, R2 are absent or represent,
o independently of one another, a hydrogen atom or a (C1-C4)alkyl group,
o R 1 and R2 may form, with the carbon atom to which they are attached,
a -(C3-C10)cycloalkyl- group;
• Y represents a -(C3-C10)cycloalkyl-, aryl or aryloxy group, said groups being
optionally substituted with one or more substituents chosen from a halogen atom or a
(C1-C6)alkoxy group;
• Z 1 is absent or represents an -NH- function;
• Z2 is absent or represents a methylene group or a
— CH or
H
group;
Z3 is absent or re resents an oxygen atom or a methylene group or a
group;
= C—
given that Z2 only represents a H group when Z3 is present and when it
= C—
represents a group, and vice versa, Z2 and Z3 thus forming a double bond;
given that Z2 and Z3, when they are present, may be included in a cycloalkyi
group;
given that when Z3 represents an oxygen atom, Z2 represents a methylene group
or a
group;
in the form of an acid, a base or an addition salt with an acid or with a base.
2. The compound of formula (I) as claimed in claim 1, wherein:
• n is equal to 0 or 1;
• D represents an oxygen atom or a bond;
• W represents a -CH- group;
• X 1 represents a nitrogen atom or a -CH=CH- group;
• X2 represents an oxygen atom or a nitrogen atom;
• X3 represents an oxygen atom or a nitrogen atom; one of X 1, X2, X3 being
other than a nitrogen atom, X2 and X3 not being an oxygen atom at the same time;
• R1, R2 are absent or represent,
o independently of one another, a hydrogen atom or a (C1-C4)alkyl group,
o R 1 and R2 may form, with the carbon atom to which they are attached,
a -(C3-C10)cycloalkyl- group;
• Y represents a -(C3-C10)cycloalkyl-, aryl or aryloxy group, said groups being
optionally substituted with one or more substituents chosen from a halogen atom;
• Z 1 is absent or represents an -NH- function;
• Z2 is absent;
• Z3 is absent or represents a methylene group;
in the form of an acid, a base or an addition salt with an acid or with a base.
3. The compound of formula (I) as claimed in claim 1, wherein X 1 represents a
nitrogen atom, X2 and X3 represent a nitrogen atom or an oxygen atom.
4. The compound of formula (I) as claimed in claim 1, wherein X 1
represents -CH=CH-, X2 and X3 represent a nitrogen atom.
5. The compound of formula (I) as claimed in one of the preceding claims,
wherein it is chosen from the following compounds:
trans{4-[4-(5-benzyl[1 .2.4]oxadiazol-3-ylcarbamoyl)phenyl]cyclohexyl}acetic
acid
- trans{4-[4-(3-benzyl[1 .2.4]oxadiazol-5-ylcarbamoyl)phenyl]cyclohexyl}acetic
acid
cis-4-[4-(3-benzyl[1 .2.4]oxadiazol-5-ylcarbamoyl)phenoxy]cyclohexanecarboxylic
acid
- cis-4-{4-[3-(3,5-difluorobenzyl)[1 .2.4]oxadiazol-5-ylcarbamoyl]phenoxy}cyclohexanecarboxylic
acid
- cis-4-{4-[3-(1-phenylcyclopropyl)[1 .2.4]oxadiazol-5-ylcarbamoyl]phenoxy}-
cyclohexanecarboxylic acid
- cis-4-{4-[3-(1 -methyl-1 -phenylethyl)[1 .2.4]oxadiazol-5-ylcarbamoyl]phenoxy}-
cyclohexanecarboxylic acid
- cis-4-[4-(3-phenoxymethyl[1 .2.4]oxadiazol-5-ylcarbamoyl)phenoxy]cyclohexanecarboxylic
acid
- {4-[4-(6-benzylpyridazin-3-ylcarbamoyl)phenyl]cyclohexyl}acetic acid
- cis-4-[4-(6-cyclopentylaminopyridazin-3-ylcarbamoyl)phenoxy]cyclohexanecarboxylic
acid
- cis-4-[5-(3-benzyl[1 .2.4]oxadiazol-5-ylcarbamoyl)pyridin-2-yloxy]cyclohexanecarboxylic
acid
- trans-2-{4-[4-(3-benzyl[1 .2.4]oxadiazol-5-ylcarbamoyl)phenyl]cyclohexyl}-
cyclopropanecarboxylic acid
- trans-(E)-3-{4-[4-(3-benzyl[1 .2.4]oxadiazol-5-ylcarbamoyl)phenyl]cyclohexyl}-
acrylic acid
- trans-3-{4-[4-(3-benzyl[1 .2.4]oxadiazol-5-ylcarbamoyl)phenyl]cyclohexyl}-
propionic acid
- cis-4-[4-(6-phenylaminopyridazin-3-ylcarbamoyl)phenoxy]cyclohexanecarboxylic
acid
- cis-4-{4-[6-(4-methoxyphenyl)pyridazin-3-ylcarbamoyl]phenoxy}cyclohexanecarboxylic
acid
in the form of an acid, a base or an addition salt with an acid or with a base.
6. A process for preparing a compound of formula (I) as claimed in any one of
claims 1 to 5, wherein the ester function of a compound chosen from:
(i) a compound of formula (XXIX):
in which R' represents:
and PG3 represents a protecting group; and
(ii) a compound of formula XXXI):
in which n, Y, Z 1, R 1, R2 and n are as defined in claim 1 and PG1
represents a protecting group; and
(iii) a compound of formula (XXXVI):
in which PG1 represents a protecting group, is deprotected.
7. The process for preparing a compound of formula (I) as claimed in claim 6,
wherein the compound of general formula (XXXVI) is obtained by catalytic
hydrogenation of a compound of formula (XXXV):
in which PG1 represents a protecting group.
8. The process for preparing a compound of formula (I) as claimed in claim 7,
wherein the compound of general formula (XXXV) is obtained by reaction, with
hydrazi -NH2, of a compound of formula (XXXIV):
in which PG1 represents a protecting group.
in which R' represents:
and n, Y, Z 1, R 1, R2 are as defined in claim 1 and PG1 and PG3 represent a
protecting group.
10. A medicament, wherein it comprises a compound of formula (I) as claimed
in any one of claims 1 to 5 or an addition salt of this compound with a pharmaceutically
acceptable acid or base.
1 1 . A pharmaceutical composition, wherein it comprises a compound of formula
(I) as claimed in any one of claims 1 to 5 or a pharmaceutically acceptable salt of this
compound, and also at least one pharmaceutically acceptable excipient.
12. The use of a compound of formula (I) as claimed in any one of claims 1 to 3,
for the preparation of a medicament intended for treating and/or preventing any
disease in which DGAT-1 is involved.
13. The use of a compound of formula (I) as claimed in claim 12, for the
preparation of a medicament for treating and/or preventing obesity, dyslipidemia,
impaired fasting glucose conditions, metabolic acidosis, ketosis, hepatic steatosis,
insulin resistance, type 2 diabetes and complications arising from this pathology,
lipotoxicity, the accumulation and an excess of triacylglycerides in adipose tissue
(WAT), metabolic syndrome, coronary diseases, hypertension, skin diseases such as
the skin diseases linked to the proliferation of the sebaceous glands such as acne,
Alzheimer's disease, immunomodulatory diseases, HIV infection, irritable bowel
syndrome and certain cancers, and advantageously for the preparation of a
medicament intended for treating or preventing obesity, dyslipidemia, impaired fasting
glucose conditions, metabolic acidosis, ketosis, hepatic steatosis, insulin resistance,
type 2 diabetes and complications arising from this pathology, lipotoxicity, the
accumulation and an excess of triacylglycerides in adipose tissue (WAT), metabolic
syndrome and hepatitis C.
14. The compound of formula (I) as claimed in any one of claims 1 to 5, as a
medicament.
15. The compound of formula (I) as claimed in any one of claims 1 to 5, for
treating and/or preventing obesity, dyslipidemia, impaired fasting glucose conditions,
metabolic acidosis, ketosis, hepatic steatosis, insulin resistance, type 2 diabetes and
complications arising from this pathology, lipotoxicity, the accumulation and an excess
of triacylglycerides in adipose tissue (WAT), metabolic syndrome, coronary diseases,
hypertension, skin diseases such as the skin diseases linked to the proliferation of the
sebaceous glands such as acne, Alzheimer's disease, immunomodulatory diseases,
HIV infection, irritable bowel syndrome and certain cancers, and advantageously for
treating or preventing obesity, dyslipidemia, impaired fasting glucose conditions,
metabolic acidosis, ketosis, hepatic steatosis, insulin resistance, type 2 diabetes and
complications arising from this pathology, lipotoxicity, the accumulation and an excess
of triacylglycerides in adipose tissue (WAT), metabolic syndrome and hepatitis C.