U.S. patent application number 11/979140 was filed with the patent office on 2008-05-08 for dihydro-1,3,5-triazine amine derivatives and their therapeutic uses.
This patent application is currently assigned to MERCK SANTE. Invention is credited to Daniel Cravo, Liliane Doare, Micheline Kergoat, Didier Mesangeau, Gerard Moinet.
Application Number | 20080108591 11/979140 |
Document ID | / |
Family ID | 8846333 |
Filed Date | 2008-05-08 |
United States Patent
Application |
20080108591 |
Kind Code |
A1 |
Moinet; Gerard ; et
al. |
May 8, 2008 |
Dihydro-1,3,5-triazine amine derivatives and their therapeutic
uses
Abstract
The invention relates to the compounds of general formula (I):
##STR1## in which R1, R2, R3, R4, R5 and R6 are as defined in claim
1. These compounds can be used in the treatment of pathological
conditions associated with the insulin-resistance syndrome.
Inventors: |
Moinet; Gerard; (Orsay,
FR) ; Cravo; Daniel; (Sartrouville, FR) ;
Doare; Liliane; (Viry Chatillon, FR) ; Kergoat;
Micheline; (Bures Sur Yvette, FR) ; Mesangeau;
Didier; (Combs La Ville, FR) |
Correspondence
Address: |
YOUNG & THOMPSON
209 Madison Street
Suite 500
ALEXANDRIA
VA
22314
US
|
Assignee: |
MERCK SANTE
Lyon
FR
69008
|
Family ID: |
8846333 |
Appl. No.: |
11/979140 |
Filed: |
October 31, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11085145 |
Mar 22, 2005 |
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11979140 |
Oct 31, 2007 |
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10181223 |
Jul 15, 2002 |
7034021 |
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PCT/FR01/00241 |
Jan 25, 2001 |
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11085145 |
Mar 22, 2005 |
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Current U.S.
Class: |
514/173 ;
514/245 |
Current CPC
Class: |
C07D 251/52 20130101;
A61K 31/53 20130101; A61P 3/04 20180101; A61P 3/00 20180101; A61P
5/50 20180101; A61P 13/12 20180101; A61P 25/28 20180101; A61P 9/00
20180101; C07D 251/72 20130101; A61P 3/10 20180101; A61K 31/58
20130101; A61P 25/00 20180101; A61P 9/10 20180101; A61P 9/02
20180101; C07D 251/10 20130101; A61P 7/12 20180101; A61P 3/06
20180101 |
Class at
Publication: |
514/173 ;
514/245 |
International
Class: |
A61K 31/58 20060101
A61K031/58; A61K 31/53 20060101 A61K031/53; A61P 25/28 20060101
A61P025/28 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 26, 2000 |
FR |
00/00996 |
Claims
1. A method for inhibiting the formation of advanced glycosylation
end products (AGE) in a patient that has and is being treated for a
neurodegenerative disease, comprising: administering to said
patient in need thereof an effective amount of a compound of
formula (I) ##STR57## in which: R1 and R2 are chosen independently
from the groups: H, (C.sub.1-C.sub.20)alkyl, wherein R3 and R4 are
chosen independently from the groups H, (C.sub.1-C.sub.20)alkyl,
(C.sub.2-C.sub.20) alkenyl, R3 and R4 can form with the nitrogen
atom an n-membered ring (n between 3 and 8) optionally comprising
one or more heteroatoms chosen from N, O, S, R5 and R6 are chosen
independently from the groups: H, (C.sub.1-C.sub.20)alkyl
optionally substituted with hydroxyl, (C.sub.3-C.sub.8)cycloalkyl
optionally substituted with (C.sub.6-C.sub.14) aryl
(C.sub.1-C.sub.5) alkoxy, (C.sub.3-C.sub.8)heterocycloalkyl
carrying one or more heteroatoms chosen from N, O, S,
(C.sub.6-C.sub.14)aryl optionally substituted with hydroxyl,
(C.sub.1-C.sub.13)heteroaryl carrying one or more heteroatoms
chosen from N, O, S, (C.sub.6-C.sub.14)aryl(C.sub.1-C.sub.5)alkyl,
wherein R5 and R6 can form with the carbon atom to which they are
attached an m-membered ring (m between 3 and 8) optionally
comprising one or more heteroatoms chosen from N, O, S and being
capable of being substituted with hydroxyl, (C.sub.1-C.sub.5)alkyl,
(C.sub.6-C.sub.14) aryl(C.sub.1-C.sub.5)alkoxy, wherein when R1 and
R2 represent a hydrogen, or R3 and R4 represent a hydrogen, then R3
and R4 or R1 and R2 are defined as above with the exception of
hydrogen, or a form selected from the group consisting of
tautomeric, enantiomeric, diastereo-isomeric and epimeric or the
pharmaceutically acceptable salt thereof.
2. A method for treating a neurodegenerative disease, comprising:
administering to a patient in the need thereof an effective amount
of a compound of formula (I) ##STR58## in which: R1 and R2 are
chosen independently from the groups: H, (C.sub.1-C.sub.20)alkyl,
wherein R3 and R4 are chosen independently from the groups H,
(C.sub.1-C.sub.20)alkyl, (C.sub.2-C.sub.20) alkenyl, R3 and R4 can
form with the nitrogen atom an n-membered ring (n between 3 and 8)
optionally comprising one or more heteroatoms chosen from N, O, S,
R5 and R6 are chosen independently from the groups: H,
(C.sub.1-C.sub.20)alkyl optionally substituted with hydroxyl,
(C.sub.3-C.sub.8)cycloalkyl optionally substituted with
(C.sub.6-C.sub.14) aryl (C.sub.1-C.sub.5) alkoxy,
(C.sub.3-C.sub.8)heterocycloalkyl carrying one or more heteroatoms
chosen from N, O, S, (C.sub.6-C.sub.14)aryl optionally substituted
with hydroxyl, (C.sub.1-C.sub.13)heteroaryl carrying one or more
heteroatoms chosen from N, O, S,
(C.sub.6-C.sub.14)aryl(C.sub.1-C.sub.5)alkyl, wherein R5 and R6 can
form with the carbon atom to which they are attached an m-membered
ring (m between 3 and 8) optionally comprising one or more
heteroatoms chosen from N, O, S and being capable of being
substituted with hydroxyl, (C.sub.1-C.sub.5)alkyl,
(C.sub.6-C.sub.14) aryl(C.sub.1-C.sub.5)alkoxy, wherein when R1 and
R2 represent a hydrogen, or R3 and R4 represent a hydrogen, then R3
and R4 or R1 and R2 are defined as above with the exception of
hydrogen, or a form selected from the group consisting of
tautomeric, enantiomeric, diastereo-isomeric and epimeric form or
the pharmaceutically acceptable salt thereof.
3. A method for treating neurodegenerative diseases wherein the
formation of advanced glycosylation end products (AGE) is
implicated in a patient, comprising administering to said patient
in need thereof an effective amount of a compound of formula (I)
##STR59## in which: R1 and R2 are chosen independently from the
groups: H, (C.sub.1-C.sub.20)alkyl, wherein R3 and R4 are chosen
independently from the groups H, (C.sub.1-C.sub.20)alkyl,
(C.sub.2-C.sub.20) alkenyl, R3 and R4 can form with the nitrogen
atom an n-membered ring (n between 3 and 8) optionally comprising
one or more heteroatoms chosen from N, O, S, R5 and R6 are chosen
independently from the groups: H, (C.sub.1-C.sub.20)alkyl
optionally substituted with hydroxyl, (C.sub.3-C.sub.8)cycloalkyl
optionally substituted with (C.sub.6-C.sub.14) aryl
(C.sub.1-C.sub.5) alkoxy, (C.sub.3-C.sub.8)heterocycloalkyl
carrying one or more heteroatoms chosen from N, O, S,
(C.sub.6-C.sub.14)aryl optionally substituted with hydroxyl,
(C.sub.1-C.sub.13)heteroaryl carrying one or more heteroatoms
chosen from N, O, S, (C.sub.6-C.sub.14)aryl(C.sub.1-C.sub.5)alkyl,
wherein R5 and R6 can form with the carbon atom to which they are
attached an m-membered ring (m between 3 and 8) optionally
comprising one or more heteroatoms chosen from N, O, S and being
capable of being substituted with hydroxyl, (C.sub.1-C.sub.5)alkyl,
(C.sub.6-C.sub.14) aryl(C.sub.1-C.sub.5)alkoxy, wherein when R1 and
R2 represent a hydrogen, or R3 and R4 represent a hydrogen, then R3
and R4 or R1 and R2 are defined as above with the exception of
hydrogen, or a form selected from the group consisting of
tautomeric, enantiomeric, diastereo-isomeric and epimeric or the
pharmaceutically acceptable salt thereof.
4. The method according to claim 1, wherein the compound is
2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5 triazine or a
form selected from the group consisting of tautomeric,
enantiomeric, diastereoisomeric and epimeric or the
pharmaceutically acceptable salt thereof.
5. The method according to claim 2, wherein the compound is
2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5 triazine or a
form selected from the group consisting of tautomeric,
enantiomeric, diastereoisomeric and epimeric or the
pharmaceutically acceptable salt thereof.
6. The method according to claim 3, wherein the compound is
2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5 triazine or a
form selected from the group consisting of tautomeric,
enantiomeric, diastereoisomeric and epimeric or the
pharmaceutically acceptable salt thereof.
7. The method according to claim 3, wherein compound is of general
formula (I): ##STR60## in which: R1 and R2 are chosen independently
from the(C1-C20)alkyl; R3 and R4 are H; R5 is H; R6 is
(C1-C20)alkyl; as well as the tautomeric, enantiomeric,
diastereoisomeric and epimeric forms and the pharmaceutically
acceptable salts.
8. The compound of formula (I) according to claim 1, in which R1 is
methyl.
9. The compound of formula (I) according to claim 1, in which R2 is
methyl.
10. The compound of formula (I) according to claim 1, in which R6
is methyl.
11. The compound of formula (I) according to claim 1, in which
R1=R2=R6=methyl, R3=R4=R5=H as well as the tautomeric,
enantiomeric, diastereoisomeric and epimeric forms and the
pharmaceutically acceptable salts.
Description
[0001] The present invention relates to amine-containing
derivatives of dihydro-1,3,5-triazine which are useful in the
treatment of pathological conditions associated with the
insulin-resistance syndrome.
[0002] Amine-containing derivatives of dihydro-1,3,5-triazine
having hypoglycaemic properties have been described in JP-A-73 64
088 and JP-A-79 14 986.
[0003] The aim of the present invention is to provide novel
compounds having improved properties.
[0004] The subject of the present invention is thus a compound of
general formula (I): ##STR2## in which: R1, R2, R3 and R4 are
chosen independently from the groups: [0005] H, [0006]
(C1-C20)alkyl substituted or otherwise with halogen, (C1-C5)alkyl,
(C1-C5)alkoxy, (C3-C8)cycloalkyl, [0007] (C2-C20)alkylene
substituted or otherwise with halogen, (C1-C5)alkyl, (C1-C5)alkoxy,
[0008] (C2-C20)alkyne substituted or otherwise with halogen,
(C1-C5)alkyl, (C1-C5)alkoxy, [0009] (C3-C8)cycloalkyl substituted
or otherwise with (C1-C5)alkyl, (C1-C5)alkoxy, [0010]
(C3-C8)heterocycloalkyl carrying one or more heteroatoms chosen
from N, O, S and substituted or otherwise with (C1-C5)alkyl,
(C1-C5)alkoxy, [0011] (C6-C14)aryl(C1-C20)alkyl substituted or
otherwise with amino, hydroxyl, thio, halogen, (C1-C5)alkyl,
(C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino,
(C6-C14)aryloxy, (C6-C14)aryl-(C1-C5)alkoxy, cyano,
trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, [0012]
(C6-C14)aryl substituted or otherwise with amino, hydroxyl, thio,
halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,
(C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy,
cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,
[0013] (C1-C13)heteroaryl carrying one or more heteroatoms chosen
from N, O, S and substituted or otherwise with amino, hydroxyl,
thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,
(C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl-(C1-C5)alkoxy,
cyano, trifluoromethyl, carboxyl, carboxymethyl or
carboxyethyl,
[0014] it being possible for R1 and R2, on the one hand, and R3 and
R4, on the other hand, to form with the nitrogen atom an n-membered
ring (n between 3 and 8) comprising or otherwise one or more
heteroatoms chosen from N, O, S and being capable of being
substituted with one or more of the following groups: amino,
hydroxyl, thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy,
(C1-C5)alkylthio, (C1-C5)alkylamino, (C6-C14)aryloxy,
(C6-C14)aryl(C1-C5)alkoxy, cyano, trifluoromethyl, carboxyl,
carboxymethyl or carboxyethyl,
R5 and R6 are chosen independently from the groups:
[0015] H, [0016] (C1-C20)alkyl substituted or otherwise with amino,
hydroxyl, thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy,
(C1-C5)alkylthio, (C1-C5)alkylamino, (C6-C14)aryloxy,
(C6-C14)aryl(C1-C5)alkoxy, cyano, trifluoromethyl, carboxyl,
carboxymethyl or carboxyethyl, [0017] (C2-C20)alkylene substituted
or otherwise with amino, hydroxyl, thio, halogen, (C1-C5)alkyl,
(C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino,
(C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy, cyano, trifluoromethyl,
carboxyl, carboxymethyl or carboxyethyl, [0018] (C2-C20)alkyne
substituted or otherwise with amino, hydroxyl, thio, halogen,
(C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino,
(C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy, cyano, trifluoromethyl,
carboxyl, carboxymethyl or carboxyethyl, [0019] (C3-C8)cycloalkyl
substituted or otherwise with amino, hydroxyl, thio, halogen,
(C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino,
(C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy, cyano, trifluoromethyl,
carboxyl, carboxymethyl or carboxy-ethyl, [0020]
(C3-C8)heterocycloalkyl carrying one or more heteroatoms chosen
from N, O, S and substituted or otherwise with amino, hydroxyl,
thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,
(C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl-(C1-C5)alkoxy,
cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,
[0021] (C6-C14)aryl substituted or otherwise with amino, hydroxyl,
thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,
(C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy,
cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,
[0022] (C1-C13)heteroaryl carrying one or more heteroatoms chosen
from N, O, S and substituted or otherwise with amino, hydroxyl,
thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,
(C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl-(C1-C5)alkoxy,
cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,
[0023] (C6-C14)aryl(C1-C5)alkyl substituted or otherwise with
amino, hydroxyl, thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy,
(C1-C5)alkylthio, (C1-C5)alkylamino, (C6-C14)aryloxy,
(C6-C14)aryl-(C1-C5)alkoxy, cyano, trifluoromethyl, carboxyl,
carboxymethyl or carboxyethyl,
[0024] it being possible for R5 and R6 to form with the carbon atom
to which they are attached an m-membered ring (m between 3 and 8)
comprising or otherwise one or more heteroatoms chosen from N, O, S
and being capable of being substituted with amino, hydroxyl, thio,
halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,
(C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy,
cyano, trifluoromethyl, carboxyl, carboxymethyl or
carboxyethyl,
[0025] or being capable of forming with the carbon atom a C10-C30
polycyclic residue substituted or otherwise with amino, hydroxyl,
thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,
(C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy,
cyano, trifluoromethyl, carboxyl, carboxymethyl or
carboxyethyl,
[0026] it being possible for the nitrogen atom of a
hetero-cycloalkyl or heteroaryl group to be substituted with a
(C1-C5)alkyl, (C3-C8)cycloalkyl, (C6-C14)aryl,
(C6-C14)aryl(C1-C5)alkyl or (C1-C6)acyl group, with the exclusion
of the compounds of formula I in which:
[0027] a--R1=H, R2=H, R3=H, R5=CH3, R6=CH3 and R4=phenethyl,
phenoxyethyl, 2-phenylthioisopropyl or benzyl;
[0028] b--R1=H, R2=H, R3=H or CH3, R4=H, methyl, butyl or
phenethyl, R5=H or ethyl and R6 is 3-methyl-5-isoxazolyl,
5-methyl-3-isoxazolyl, 3-methyl-5-pyrazolyl or
(5-methyl-3-isoxazolyl)methyl,
[0029] c--R1, R2, R3 and R4 represent a hydrogen atom,
as well as the tautomeric, enantiomeric, diastereo-isomeric and
epimeric forms and the pharmaceutically acceptable salts.
[0030] The expression m-membered ring formed by R5 and R6 is
understood to mean in particular a saturated ring such as a
cyclohexyl, piperidinyl or tetrahydropyranyl group.
[0031] The expression polycyclic group formed by R5 and R6 is
understood to mean an optionally substituted carbon-containing
polycyclic group and in particular a steroid residue.
[0032] A particular group of compounds of formula (I) is that in
which R5 is hydrogen.
[0033] Another particular group of compounds of formula (I) is that
in which R5 and R6 form with the carbon atom to which they are
attached an m-membered ring (m between 3 and 8) comprising or
otherwise one or more heteroatoms chosen from N, O, S and being
capable of being substituted with one or more of the following
groups: (C1-C5)alkyl, amino, hydroxyl, (C1-C5)alkyl-amino,
(C1-C5)alkoxy, (C1-C5)alkylthio, (C6-C14)aryl,
(C6-C14)aryl(C1-C5)alkoxy,
[0034] or form with the carbon atom a C10-C30 poly-cyclic residue
substituted or otherwise with amino, hydroxyl, thio, halogen,
(C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino,
(C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy, cyano, trifluoromethyl,
carboxyl, carboxymethyl or carboxyethyl.
[0035] Another particular group of compounds of formula (I) is that
in which R5 and R6 are chosen independently from the groups: [0036]
(C1-C20)alkyl substituted or otherwise with amino, hydroxyl, thio,
halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,
(C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy,
cyano, trifluoromethyl, carboxyl, carboxymethyl or
carboxyethyl.
[0037] A more particular group of compounds of formula (I) is that
in which R1 and R2 are chosen independently from the groups
specified above with the exception of the hydrogen atom and R3 and
R4 represent a hydrogen. More particularly, a preferred group of
compounds of formula (I) is that in which R1 and R2 are an alkyl,
advantageously methyl, group and R3 and R4 represent a
hydrogen.
[0038] The invention also relates to the tautomeric, enantiomeric,
diastereoisomeric and epimeric forms of the compounds of general
formula (I).
[0039] The compounds of general formula (I) possess basic nitrogen
atoms which may be monosalified or disalified with organic or
inorganic acids.
[0040] The compounds of general formula (I) may be prepared by
reacting a compound of general formula (II) ##STR3## in which R1,
R2, R3 and R4 are as defined above, with a compound of general
formula (III), (IV) or (V) ##STR4## in which R5 and R6 are as
defined above and R7 is a methyl or ethyl group, in a polar solvent
(for example ethanol or dimethylformamide) in the presence of an
organic acid (for example camphorsulphonic acid) or of an inorganic
acid (for example hydrochloric acid).
[0041] The compounds of general formula (II) are biguanides whose
synthesis is routine to every person skilled in the art. We will
cite for example some publications describing the synthesis of such
compounds (FR 1537604, FR 2132396; K. H. Slotta and R. Tschesche,
Ber., 1929 (62b), 1398; S. L. Shapiro, V. A. Parrino, E. Rogow and
L. Freedman, J. Org. Chem., 1959 (81), 3725; S. L. Shapiro, V. A.
Parrino and L. Freedman, J. Org. Chem., 1959 (81), 3728; S. L.
Shapiro, V. A. Parrino and L. Freedman, J. Org. Chem., 1959 (81),
4636).
[0042] The compounds according to the present invention are useful
in the treatment of pathological conditions associated with the
insulin-resistance syndrome (X syndrome).
[0043] Insulin-resistance is characterized by a reduction in the
action of insulin (cf. Presse Medicale, 1997, 26 (No. 14), 671-677)
and is involved in a large number of pathological states, such as
diabetes and more particularly non-insulin-dependent diabetes (type
II diabetes or NIDDM), dyslatupidaemia, obesity, high blood
pressure, as well as certain microvascular and macrovascular
complications such as atherosclerosis, retinopathies and
neuropathies.
[0044] In this regard, reference may be made for example to
Diabetes, vol. 37, 1988, 1595-1607; Journal of Diabetes and its
complications, 1998, 12, 110-119 or Horm. Res., 1992, 38,
28-32.
[0045] In particular, the compounds of the invention have a high
hypoglycaemic activity.
[0046] The compounds according to the present invention can also be
used to treat chronic complications which are in particular due to
the formation of "advanced glycosylation end-products" noted AGEs
which are derived from the glycoxidation reaction between glucose,
its oxidation derivatives and the amino functional groups of
proteins, including the so-called Maillard reactions for glycation
of glyoxal for example.
[0047] Indeed, recently published data clearly show the impact of
AGEs on renal complications (Nephr. Dial. Transplant., 2000, 15
(suppl 2), 7-11), on atherosclerosis, Alzheimer's disease and other
neurodegenerative diseases (Glycoconj. J., 1998, 15 (10), 1039-42;
Brain Res., 2001, 888(2), 256). The formation of AGE may also play
an important part in the pathogenesis of angiopathy, in particular
in diabetics, and also in senility (J. Neuropathol. Exp. Neurol.,
2000, 59 (12), 1094).
[0048] The subject of the present invention is therefore also
pharmaceutical compositions comprising, as active ingredient, a
compound according to the invention.
[0049] These pharmaceutical compositions are particularly intended
for treating diabetes, pathological conditions due to the formation
of AGEs, such as, in particular, renal complications,
atherosclerosis, angiopathy, Alzheimer's disease, neurodegenerative
diseases and senility.
[0050] The pharmaceutical compounds according to the invention may
be provided in forms intended for administration by the parenteral,
oral, rectal, permucosal or percutaneous route.
[0051] They will therefore be provided in the form of injectable
solutions or suspensions or multidose vials, in the form of
uncoated or coated tablets, sugar-coated tablets, capsules, gelatin
capsules, pills, cachets, powders, suppositories or rectal
capsules, solutions or suspensions, for percutaneous use in a polar
solvent, for permucosal use.
[0052] The excipients which are suitable for such administrations
are the derivatives of cellulose or of microcrystalline cellulose,
the alkaline-earth carbonates, magnesium phosphate, starches,
modified starches, lactose for the solid forms.
[0053] For rectal use, cocoa butter or the stearates of
polyethylene glycol are the preferred excipients.
[0054] For parenteral use, water, aqueous solutions, physiological
saline, isotonic solutions are the vehicles most conveniently
used.
[0055] The dosage may vary within wide limits (0.5 mg to 1 000 mg)
according to the therapeutic indication and the route of
administration, as well as the age and weight of the subject.
[0056] By way of example, here are a few biguanides of formula II
used in the synthesis of derivatives of formula I. TABLE-US-00001
TABLE I m.p. in .degree. C. Formula Salt (Kofler) A ##STR5## HCl
223-225 B ##STR6## HCl 176-178 C ##STR7## HCl 230-232 D ##STR8##
HCl 210-212 E ##STR9## HCl 254-256 F ##STR10## HCl 158-160 G
##STR11## HCl 100-102
[0057] The following examples illustrate the preparation of the
compounds of formula I.
EXAMPLE 1
Synthesis of
2-amino-3,6-dihydro-4-dimethyl-amino-6-ethyl-1,3,5-triazine
hydrochloride
[0058] 23 ml of propionaldehyde and 3.6 g of camphor-sulphonic acid
are added to a solution of compound A (25.7 g; 0.155 mol) in 200 ml
of DMF. After refluxing for 2 hours, the solvent is removed under
vacuum and 100 ml of acetonitrile are added. The solid formed is
drained and dried (21.9 g; 69%).
m.p. =218-220.degree. C.
.sup.1H NMR (DMSO-d6, 200 MHz): 1.10 (t, 3H); 1.80 (m, 2H); 3.20
(s, 6H); 4.83 (m, 1H); 7.57 (m, 2H); 8.65 (s, 1H); 8.90 (s, 1H)
.sup.13C NMR (DMSO-d6, 50 MHz): 6.41 (CH3); 27.59 (CH2); 35.64
(CH3); 60.75 (CH); 155.01 (C.dbd.N); 156.67 (C.dbd.N)
EXAMPLE 2
Synthesis of
2,4-bisdimethylamino-3,6-dihydro-6-methyl-1,3,5-triazine
hydrochloride
[0059] 61 ml of acetal and 5 g of camphorsulphonic acid are added
to a solution of compound E (41.10 g; 0.212 mol) in 200 ml of
absolute ethanol. The whole is heated under reflux for 72 hours and
then concentrated. The crude material is triturated with
acetonitrile and the solid formed is drained and then
recrystallized from acetonitrile. 24 g (51.5%) of a solid are
obtained.
m.p. =200-202.degree. C.
.sup.1H NMR (DMSO-d6, 200 MHz): 1.34 (d, 3H); 3.02 (s, 6H); 4.72
(m, 1H); 4.83 (m, 1H); 8.80 (s, 2H)
.sup.13C NMR (DMSO-d6, 50 MHz): 22.59 (CH3); 37.76 (CH3); 59.02
(CH); 156.35 (C.dbd.N)
[0060] The characteristics of these compounds and of other
compounds of formula I are given in Table II below: TABLE-US-00002
TABLE II m.p. in .degree. C. .sup.13C NMR Formula Salt (Kofler)
50.32 MHz 1 ##STR12## HCl 218-220 DMSO-d6 6.41, CH3 27.59, CH2
35.64, 2 CH3 60.75, CH 155.01, 156.67, 2 quaternary C 2 ##STR13##
HCl 200-202 DMSO-d6 22.58, 37.75, 5 CH3 59.01, CH 156.34, 2
quaternary C 3 ##STR14## 193-195 DMSO-d6 32.06, 37.40, 2 CH3 67.85,
158.16, 3 quaternary C 4 ##STR15## HCl 243-245 DMSO-d6 21.66,
25.19, 37.72, 3 CH2 37.89, 2 CH3 67.51, 156.83, 158.24, 3
quaternary C 5 ##STR16## Methane- sulphonate 174-176 DMSO-d6 34.31,
41.36, 44.79, 5 CH3 69.75, 160.30, 161.44, 3 quaternary C 6
##STR17## 138-140 DMSO-d6 28.04, CH2 30.84, 37.40, 3 CH3 42.06,
62.24, 2 CH2 70.00, 158.24, 158.69, 3 quaternary C 7 ##STR18## HCl
150-152 DMSO-d6 27.39, CH2 28.78, 39.14, 40.21, 61.30, 2 CH2 68.46,
156.48, 157.84 3 quaternary C 8 ##STR19## HCl 124-126 DMSO 28.95,
38.65, 2 CH3 42.77, CH2 69.75, quaternary C 115.93, CH2 149.12, CH
155.70, 156.16, 2 quaternary C 9 ##STR20## HCl 149-151 DMSO-d6
26.20, 32.39, 40.73, 6 CH3 46.16, CH 60.09, 158.83, 159.14, 3
quaternary C 10 ##STR21## HCl 239-241 DMSO-d6 37.78, 2 CH3 62.39,
CH 126.66, 129.47, 5 CH 141.87, 156.52, 158.38, 3 quaternary C 11
##STR22## HCl 221-223 DMSO-d6 37.23, 55.60, 3 CH3 61.88, CH 114.32,
127.66, 4 CH 133.17, 156.11, 157.86, 159.93, 4 quaternary C 12
##STR23## HCl 251-253 DMSO-d6 37.75, 2 CH3 62.67, 116.16, 128.16, 5
CH 131.72, 156.64, 158.31, 158.88, 4 quaternary C 13 ##STR24##
>260 DMSO-d6 39.55, 39.71, 2 CH3 65.92, 117.71, 130.17, 5 CH
131.72, 156.64, 158.31, 158.88, 4 quaternary C 14 ##STR25##
Fumarate 172-174 15.48, 29.33, 3 CH3 35.68, CH2 37.43, 2 CH3 65.71,
quaternary C 135.47, 2 CH 156.21, 156.63, 168.35, 4 quaternary C 15
##STR26## HCl 250-252 DMSO-d6 28.74, 37.38, 6 CH3 66.53, 155.28, 3
quaternary C 16 ##STR27## HCl 183-185 DMSO-d6 32.62, 40.96, 5 CH3
69.37, 159.30, 160.19, 3 quaternary C 17 ##STR28## HCl >260
DMSO-d6 22.78, 2 CH3 28.96, 2 CH2 40.13, 2 CH3 42.73, 2 CH2 65.63,
155.42, 155.71, 3 quaternary C 18 ##STR29## HCl 229-231 DMSO-d6
22.97, 37.76, 3 CH3 58.59, CH 157.85, 159.39, 2 quaternary C 19
##STR30## HCl >260 Concise spectrum DMSO-d6 69.06, 159.78,
161.17, 3 quaternary C 20 ##STR31## carbonate 170-180 CF3CO2D
22.43, 25.71, 36.86, 38.71, 43.12, 7 CH2 67.88, quaternary C
127.47, 129.55, 129.93, 5 CH 140.22, 158.72, 159.65, 3 quaternary C
21 ##STR32## Carbonate >140 DMSO-d6 20.51, CH3 24.73, 25.39, 2
CH2 39.98, 2 CH3 46.44, 47.91, 2 CH2 58.49, CH 154.58, 156.63,
160.61, 3 quaternary C 22 ##STR33## HCl >260 DMSO-d6 21.18,
24.68, 3 CH2 27.26, CH3 37.00, 2 CH2 37.37, 2 CH3 67.12, 155.89,
156.86, 3 quaternary C 23 ##STR34## HCl 248-250 DMSO-d6 21.17,
24.70, 35.39, 37.04, 6 CH2 37.36, 2 CH3 67.09, 155.90, 156.21, 3
quaternary C 24 ##STR35## HCl >260 Concise spectrum DMSO-d6
67.46, 68.80, 156.76, 157.47, 157.99,159.14, 3 quaternary C 175.90,
176.11, COCH 25 ##STR36## HCl >260 Concise spectrum DMSO-d6
64.87, 69.85, 2 CHOH 66.55, 154.91, 156.19, 3 quaternary C 173.75,
COOH 26 ##STR37## HCl 91-93 DMSO-d6 25.76, 37.28, 3 CH3 43.28, CH2
64.27, CH 115.21, CH2 137.55, CH 159.79, 160.77, 2 quaternary C 27
##STR38## HCl >260 DMSO-d6 25.69, 27.25, 4 CH2 39.13, 2 CH3
67.25, quaternary C 70.01, CH2 72.50, CH 128.17, 128.34, 129.07, 5
CH 139.79, 156.81, 158.30, 3 quaternary C 28 ##STR39## HCl >250
DMSO-d6 29.83, 34.4, 4 CH2 38.83, 2 CH3 66.17, CH 67.06, 156.25,
157.28, 3 quaternary C 29 ##STR40## Carbonate 133-135 DMSO-d6 7.25,
26.81, 2 CH3 34.32, CH2 37.17, 2 CH3 68.59, 156.46, 157.71, 160.78,
4 quaternary C 30 ##STR41## Carbonate 140-144 8.68, 2 CH3 34.54, 2
CH2 37.91, 2 CH3 74.98, 157.84, 159.14, 160.82, 4 quaternary C 31
##STR42## HCl 207-209 DMSO-d6 22.50, 2 CH2 38.00, 2 CH3 39.78, 2
CH2 75.51, 157.18, 158.37, 3 quaternary C 32 ##STR43## Carbonate
decomposes DMSO-d6 14.55, CH3 17.20, CH2 37.45, 2 CH3 39.00, CH2
62.43, CH 157.52, 159.04, 160.65, 3 quaternary C 33 ##STR44## HCl
>260 D2O 37.90, 2 CH3 48.69, CH2 154.82, 156.33, 2 quaternary C
34 ##STR45## Para- toluene- sulphonate 201-203 DMSO-d6 21.65, CH3
25.95, 26.07, 26.58, 26.89, 27.50, 5 CH2 37.56, 2 CH3 44.74, 66.56,
126.32, 129.08, 6 CH 138.99, 145.86, 158.18, 156.86, 4 quaternary C
35 ##STR46## HCl 157-159 DMSO-d6 29.10, 37.86, 4 CH3 65.90, 154.82,
156.33, 3 quaternary C 36 ##STR47## Para- toluene- sulphonate
251-253 DMSO-d6 21.14, 37.26 3 CH3 114.80, 120.70, 126.41, 132.12,
CF3 125.82, 128.54, 4 CH 138.37, 145.49, 155.78, 157.18, 4
quaternary C 37 ##STR48## Para- toluene- sulphonate 159-161 DMSO-d6
21.17, 36.95, 3 CH3 42.60, CH2 62.10, 126.86, 127.21, 128.55,
128.63, 130.32, 10 CH 135.14, 138.30, 145.67, 156.18, 157.44, 5
quaternary C 38 ##STR49## HCl >260 DMSO-d6 37.41, 2 CH3 37.47,
62.73, 4 CH2 64.76, 156.35, 157.77, 3 quaternary C 39 ##STR50## HCl
>260 DMSO-d6 34.12, 2 CH2 38.63, 42.60, 3 CH3 48.72, 2 CH2
64.01, 156.11, 157.78, 3 quaternary C 40 ##STR51## HCl 225-227
DMSO-d6 37.19, 2 CH3 56.58, 107.94, 110.93, 144.00, 4 CH 152.78,
155.85, 157.47, 3 quaternary C 41 ##STR52## Para- toluene-
sulphonate 194-196 DMSO-d6 21.17, 37.03, 3 CH3 60.37, CH 70.05, CH2
115.08, 121.60, 125.84, 128.54, 129.95, 10 CH 138.28, 145.64,
156.40, 157.70, 158.45, 5 quaternary C 42 ##STR53## HCl >260
DMSO-d6 24.12, 37.15, 5 CH3 39.90, quaternary C 68.39, CH 156.57,
158.10, 2 quaternary C 43 ##STR54## HCl decomposes DMSO-d6 22.95,
23.05, 2 CH3 25.87, CH 36.94, 2 CH3 45.71, CH2 62.38, CH 157.15,
157.42, 158.34, 3 quaternary C 44 ##STR55## HCl 213-215 DMSO-d6
15.99, 17.12, 2 CH3 34.57, CH 37.17, 2 CH3 65.68, CH 156.45,
158.12, 2 quaternary C 45 ##STR56## Para- toluene- sulphonate
217-219 DMSO-d6 21.17, CH3 22.53, 24.48, 25.30, 3 CH2 37.20, 2 CH3
40.07, 64.37, 2 CH 125.68, 125.83, 127.19, 128.61, 6 CH 138.53,
145.24, 156.06, 157.36, 4 quaternary C
[0061] Results of pharmacological studies will be given below.
Study of the Antidiabetic Activity in the Nostz Rat
[0062] The antidiabetic activity of the compounds of formula (I)
administered orally was determined on an experimental model of
non-insulin-dependent diabetes induced in rats by
Streptozotocin.
[0063] The non-insulin-dependent diabetes model is obtained in rats
by neonatal injection (on the day of birth) of streptozotocin.
[0064] The diabetic rats used were 8 weeks old. The animals were
kept, from the day of their birth to the day of the experiment, in
an animal house at a controlled temperature of 21 to 22.degree. C.
and subjected to a fixed cycle of light (from 7 am to 7 pm) and
darkness (from 7 pm to 7 am). Their diet consisted of a maintenance
diet, water and food were provided "ab libitum", with the exception
of the 2 hours of fasting preceding the tests when the food is
withdrawn (postabsorptive state).
[0065] The rats were treated by the oral route for one (D1) or four
(D4) days with the product to be tested. Two hours after the last
administration of the product and 30 minutes after anaesthetizing
the animals with sodium pentobarbital (Nembutal.RTM.), 300 .mu.l of
blood sample are collected from the end of the tail.
[0066] By way of example, results obtained are assembled in Table
III. These results show the efficacy of the compounds of formula
(I) in reducing glycaemia in the diabetic animals. These results
are expressed as a percentage variation of glycaemia at D1 and D4
(number of days of treatment) relative to D0 (before the
treatment). TABLE-US-00003 TABLE III 20 mg/kg/D 200 mg/kg/D
Compounds D1 D4 D1 D4 1 -7 -2 -13 -15 2 -11 -10 -12 -12 3 -10 -8
-18 -22 4 0 -1 -20 -10 7 -8 -11 -10 -16 15 -8 -9 -4 -5 17 -12 -8 -8
-14 18 -6 -4 -29 -28 19 -10 -6 -4 -14 21 -7 -2 -21 -24 22 -23 -16
-13 0 25 -4 -11 -7 -6 26 -6 -11 -14 -9 27 -14 -9 -12 -13 28 -4 -1
-4 -13 31 -5 -11 -3 -15 32 2 0 -22 -18 33 -7 -6 -9 -14 34 -5 -15 -6
-21 37 -7 -8 -10 -15 39 -6 -6 -4 -7 40 -8 -12 -18 -18 42 -5 -4 -26
-17 43 -4 -16 -12 -17 44 -7 -6 -22 -25
Study of the Antiglycation Activity
[0067] The compounds (1) are also capable of inhibiting the
so-called Maillard reactions by "capturing effect" on the
.alpha.-dicarbonyl-containing derivatives such as glyoxal--this is
the antiglycation effect. This Maillard reaction inhibiting effect
of the compounds according to the invention was studied in vitro by
assaying ketamines ("fructosamines") produced during the incubation
of albumin with methylglyoxal in the presence or otherwise of a
compound of formula (I) according to the invention.
[0068] A solution of bovine albumin at 6.6 mg/ml in 0.2 M phosphate
buffer, pH 7.4, is incubated with 1 mM methylglyoxal in the
presence or otherwise of a compound according to the invention at a
concentration of 10 mM. The incubation is carried out under sterile
conditions at 37.degree. C. for 6 days. At the end of the
incubation period, the quantity of ketamines is measured with a
commercially available fructosamine assay kit ("FRA" kit, product
reference: 0757055, Roche S.A. products) according to the
manufacturer's instructions.
[0069] By way of example, results obtained under these experimental
conditions are assembled in Table IV: level of fructosamine after
incubation of the albumin with the methylglyoxal in the presence of
compounds (I) according to the invention in relation to the level
of fructosamine when albumin is incubated with methylglyoxal in the
absence of the compounds (I) according to the invention.
TABLE-US-00004 TABLE IV Reduction in the level of Compounds (I)
fructosamines (%) 1 62 10 80 11 89 12 90 13 95 18 69 33 79 34 64 36
66 37 65 40 66 43 68 45 67
* * * * *