(Aminoiminomethyl) amino) alkane-carboxamides and their...

Details (Aminoiminomethyl) amino) alkane-carboxamides and their... (Aminoiminomethyl) amino) alkane-carboxamides and their...

2001-07-10

2003-02-11

Kumar, Shailendra (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C564S193000, C564S196000, C546S296000, C514S378000, C514S626000

Reexamination Certificate

active

06518458

ABSTRACT:

This application is a 371 of PCT/EP99/10468, filed Dec. 30, 1999.
The present invention relates to the use of derivatives of the ((aminoiminomethyl)amino)alkane-carboxamide type in the treatment of pathologies associated with insulin resistance syndrome.
The present invention therefore provides pharmaceutical compositions comprising as active principle a compound of general formula (I)
in which:
R
1
is selected from one of the following groups:
H;
(C
1
-C
20
)alkyl substituted or unsubstituted by one or more of the following groups:
amino, hydroxyl, (C
1
-C
5
)alkyl, (C
1
-C
5
)alkoxy, (C
1
-C
5
)alkylthio, (C
1
-C
5
)alkylamino, trifluoromethyl;
R
2
and R
3
are selected independently from
H;
(C
3
-C
8
)cycloalkyl substituted or unsubstituted by one or more of the following groups:
amino, hydroxyl, (C
1
-C
5
) alkyl, (C
1
-C
5
) alkoxy, (C
1
-C
5
)alkylthio, (C
1
-C
5
)alkylamino, trifluoromethyl;
(C
3
-C
8
)heterocycloalkyl containing one or more heteroatoms selected from N, O and S and substituted or unsubstituted by one or more of the following groups:
amino, hydroxyl, (C
1
-C
5
)alkyl, (C
1
-C
5
)alkoxy, (C
1
-C
5
)alkylthio, (C
1
-C
5
)alkylamino, trifluoromethyl; a nitrogen atom can additionally be substituted by a (C
6
-C
14
) aryl, (C
6
-C
14
) acyl or (C
1
-C
5
) alkyl group;
(C
6
-C
14
)aryl substituted or unsubstituted by one or more of the following groups:
amino, hydroxyl, halogen, (C
1
-C
5
)alkyl, (C
1
-C
5
) alkoxy, (C
1
-C
5
) alkylthio, (C
1
-C
5
) alkylamino, trifluoromethyl, cyano;
(C
1
-C
13
)heteroaryl containing one or more heteroatoms selected from N, O and S and substituted or unsubstituted by one or more of the following groups:
amino, hydroxyl, halogen, (C
1
-C
5
)alkyl, (C
1
-C
5
) alkoxy, (C
1
-C
5
)alkylthio, (C
1
-C
5
) alkylamino, trifluoromethyl, cyano; a nitrogen atom can additionally be substituted by a (C
6
-C
14
)aryl, (C
6
-C
14
)acyl or (C
1
-C
5
) alkyl group;
(C
6
-C
14
)aryl-(C
1
-C
5
)alkyl substituted or unsubstituted by one or more of the following groups:
amino, hydroxyl, halogen, (C
1
-C
5
)alkyl, (C
1
-C
5
)alkoxy, (C
1
-C
5
)alkylthio, (C
1
-C
5
)alkylamino, trifluoromethyl, cyano;
and A is selected from the groups:
—CH
2
—,
—CH
2
—CH
2
—,
—CHR
4
—,
R
4
being selected from:
H;
(C
1
-C
20
) alkyl substituted or unsubstituted by one or more of the following groups:
amino, hydroxyl, (C
1
-C
5
)alkyl, (C
1
-C
5
)alkoxy, (C
1
-C
5
)alkylthio, (C
1
-C
5
)alkylamino, trifluoromethyl;
(C
3
-C
8
)cycloalkyl substituted or unsubstituted by one or more of the following groups:
amino, hydroxyl, (C
1
-C
5
) alkyl, (C
1
-C
5
) alkoxy, (C
1
-C
5
)alkylthio, (C
1
-C
5
)alkylamino, trifluoromethyl;
(C
3
-C
8
) heterocycloalkyl containing one or more heteroatoms selected from N, O and S and substituted or unsubstituted by one or more of the following groups:
amino, hydroxyl, (C
1
-C
5
) alkyl, (C
1
-C
5
) alkoxy, (C
1
-C
5
)alkylthio, (C
1
-C
5
) alkylamino, trifluoromethyl; a nitrogen atom can additionally be substituted by a (C
6
-C
14
) aryl, (C
6
-C
14
) acyl or (C
1
-C
5
) alkyl group;
and their solvates and pharmaceutically acceptable salts.
The heteroaryl groups are selected in particular from pyridyl, pyrimidinyl, furyl, pyrrolyl, thienyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, indolyl, benzofuryl and imidazolyl.
The heterocycloalkyl groups are selected in particular from piperidinyl, morpholinyl, piperazinyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl and tetrahydropyranyl.
A preferred group of compounds of formula I is constituted in which R
1
is H or (C
1
-C
6
)alkyl.
A preferred group of compounds of formula I is constituted in which:
R
2
is selected from
(C
3
-C
8
) cycloalkyl substitued or unsubstituted by one or more of the following groups: amino, hydroxyl, (C
1
-C
5
) alkyl, (C
1
-C
5
)alkoxy, (C
1
-C
5
)alkylthio, (C
1
-C
5
)alkylamino, trifluoromethyl;
(C
6
-C
14
) aryl substituted or unsubstituted by one or more of the following groups: amino, hydroxyl, halogen, (C
1
-C
5
) alkyl, (C
1
-C
5
)alkoxy, (C
1
-C
5
) alkylthio, (C
1
-C
5
)alkylamino, trifluoromethyl, cyano;
(C
1
-C
13
) heteroaryl containing one or more heteroatoms selected from N, O and S and substituted or unsubstituted by one or more of the following groups: amino, hydroxyl, halogen, (C
1
-C
5
) alkyl, (C
1
-C
5
) alkoxy, (C
1
-C
5
)alkylthio, (C
1
-C
5
) alkylamino, trifluoromethyl, cyano;
a nitrogen atom can additionally be substituted by a (C
6
-C
14
) aryl, (C
6
-C
14
) acyl or (C
1
-C
5
) alkyl group.
A particularly preferred group of compounds of formula I is constituted in which R
2
is selected from a (C
6
-C
14
) aryl group possibly substituted as defined above.
To the knowledge of the Applicant, the compounds of formula (I) are novel with the exception of &agr;-guanidinoacetanilide, which is described by Mazundar (Indian Drugs 1989, 27, 5, 292), i.e. the compound of formula I in which R=H, R
2
=phenyl and R
3
=H.
The invention also relates to the tautomeric forms, to the enantiomers, diastereoisomers and epimers of the compounds of general formula (I).
The compounds of general formula (I) have basic nitrogen atoms and can be monosalified or disalified by mineral or organic acids.
The compounds of formula (I) can be prepared by reacting a compound of formula:
with a compound of formula:
in which:
R
5
is selected from —SCH
3
, pyrazolyl or —SO
3
H, and
T is a tert-butyloxycarbonyl or benzyloxycarbonyl protective group.
The compounds of formula (II) can be prepared in accordance with a process in which:
a) a compound of formula:
 in which R
2
and R
3
are as defined above is reacted with an acyl halide of general formula (VI):
in which:
A is as defined above,
L represents a chlorine or bromine atom or an activated ester form,
Z represents a chlorine or bromine atom or a protected amino group, to form a compound of general formula (VII):
 in which R
2
, R
3
, A and Z are as defined above;
b) the compound of general formula (VII) is reacted with potassium phthalimide and then with hydrazine monohydrate or else with a nitride followed by a reduction to form a compound of general formula (II) in which R
1
=H.
In the case where Z is a protected amino group, it is appropriate to deprotect it at this stage to form a compound of general formula (II).
The compounds of general formula (II) in which R
1
is other than H can be obtained by reacting a compound of formula (VII) with an amine of general formula (VIII):
R
1
NH
2
  (VIII).
The compositions according to the present invention are useful in the treatment of pathologies associated with insulin resistance syndrome (syndrome X).
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), dyslipidaemia, obesity, arterial hypertension, and certain microvascular and macrovascular complications such as atherosclerosis, retinopathies and neuropathies.
In this context, 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.
In particular, the compositions of the invention exhibit a strong hypoglycaemic activity.
The compositions according to the present invention can also be used for treating the chronic complications due to the formation of “advanced glycosylation end products”, written AGEs, which result from the glycoxidation reaction between glucose, its oxidation derivatives and the amino functions of proteins, including the so-called Maillard reactions of glycation of glyoxal for example.
The pharmaceutical compositions according to the invention can be provided in forms which are intended for parenteral, oral, rectal, permucous or percutaneous administration.
They will therefore be provided in the form of solutions or suspensions for injection or multi-dose bottles, in the form of plain or c

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