Compounds having reversible inhibiting activity of carnitine...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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C546S133000, C546S022000, C548S252000, C564S017000, C564S032000, C564S047000, C564S063000, C564S079000, C564S095000, C514S357000, C514S381000, C514S476000, C514S588000, C514S600000

Reexamination Certificate

active

06369073

ABSTRACT:

The present invention relates to compounds having inhibiting activity against carnitine palmitoyl transferase. The present invention relates also to pharmaceutical compositions containing at least one of these compounds active ingredients and to the use of said compounds in the preparation of medicaments useful in the treatment of pathologies related to a hyperactivity of carnitine palmitoyl-transferase, in particular hyperglycaemic states, such as diabetes and related pathologies and of congestive heart failure.
BACKGROUND OF THE INVENTION
To date, hypoglycaemic therapy is based on the use of drugs having different mechanism of action (Arch. Intern. Med., 1997, 157, 1802-1817).
Insulin and its analogues represent the most used therapy, recurring to the direct hypoglycaemic action of this hormone.
Other compounds act indirectly by stimulating insulin release (sulphonylureas). A different target of hypoglycaemic drugs is represented by the reduction of glucose intestinal absorption through the inhibition of intestinal glucosidases, or by reducing insulin resistance.
Hyperglycaemia is also treated with gluconeogenesis inhibitors, such as biguanides.
Some words have also stressed out the relationship between gluconeogenesis and fatty acid oxidation.
The membrane bound long-chain acylcarnitine transferases, also known as carnitine palmitoyltransferase (CPT), are widely represented in organs and subcellular organelles (Bieber, L. L. 1988 Ann. Rev. Biochem. 57: 261-83). The well-established role of this category of enzymes is the transport of activated long-chain fatty acids through mitochondrial membranes. In this context, the outer mitochondrial membrane CIT I catalyzes the formation of long-chain acylcarnitines that are transported across the mitochondrial membrane by a specific carrier, and reconverted into long-chain acyl-coenzyme A esters by CPT II, which resides in the inner mitochondrial membrane. Long-chain acyl-CoAs are then oxidised to acetyl-coenzyme A, which activates a key gluconeogenetic enzyme: pyruvate carboxylase.
Other works report that diabetic patients have high blood levels of fatty acids, whose liver oxidative fate gives rise to an increase of acetyl-coenzyme A, ATP and NADH. High availability of these compounds maximally stimulates gluconeogenesis, which is in part responsible of the elevated glucose blood levels in diabetic patients. CPT inhibition indirectly reduces the extent of liver gluconeogenesis, and hence blood glucose levels.
CPT inhibitors have been disclosed in J. Med. Chem., 1995, 38(18), 3448-50 and in the corresponding European patent application EP 0 574 355 as potential derivatives with hypoglycaemic activity.
Aminocarnitines N-acylated with —COR residue, wherein R is an aliphatic residue with 1 to 19 carbon atoms are disclosed in WO85/04396 useful for investigating the role of transferases in the body, in particular the specificity of carnitine acyltransferase.
Emeriamine and its analogues are disclosed in EP 0 127 098 and J.Med. Chem. 1987, 30, 1458-1463.
Notwithstanding the mechanism of activity above outlined, to date, drugs inhibiting CPT capable to effectively counteract hyperglycaemia do not exist. For some products, such as tetradecyl glycidic acid, or etomoxir, myocardial hypertrophy have been evidenced as side effects (Life Sci., 1989, 44, 1897-1906).
None of the therapies presently used in clinic is fully satisfying, in particular due to the onset of unwanted side effects, such as severe hypoglycaemia, allergic phenomena, oedema, diarrhoea, intestinal disturbances, kidney toxicity, etc.
The necessity to obtain alternative effective therapies for hyperglycaemia still remains.
ABSTRACT OF THE INVENTION
It has now surprisingly been found that compounds of general formula (I):
wherein: X
+
is selected from the group consisting of N
+
(R
1
,R
2
,R
3
) and P
+
(R
1
,R
2
,R
3
), wherein
(R
1
,R
2
,R
3
), being the same or different, are selected in the group consisting of hydrogen and C
1
-C
9
straight or branched alkyl groups, —CH═NH(NH
2
), —NH
2
, —OH; or two or more R
1
, R
2
and R
3
together with the nitrogen atom, which they are linked to, form a saturated or unsaturated, monocyclic or bicyclic heterocyclic system; with the proviso that at least one of the R
1
, R
2
and R
3
is different from hydrogen;
Z is selected from
—OR
4
,
—OCOOR
4
,
—OCONHR
4
,
—OCSNHR
4
,
—OCSOR
4
,
—NHR
4
,
—NHCOR
4
,
—NHCSR
4
,
—NHCOOR
4
,
—NHCSOR
4
,
—NHCONHR
4
,
—NHCSNHR
4
,
—NHSOR
4
,
—NHSONHR
4
,
—NHSO
2
R
4
,
—NHSO
2
NHR
4
,
—SR
4
,
wherein —R
4
is a C
1
-C
20
saturated or unsaturated, straight or branched alkyl group, optionally substituted with a A
1
group, wherein A
1
is selected from the group consisting of halogen atom, C
6
-C
14
aryl, heteroaryl, aryloxy or heteroaryloxy group, said aryl, heteroaryl, aryloxy or heteroaryloxy groups being optionally substituted with one or more C
1
-C
20
saturated or unsaturated, straight or branched alkyl or alkoxy group and/or halogen atom;
Y

is selected from the group consisting of —COO—, PO
3
H

, —OPO
3
H

, tetrazolate-5-yl;
with the proviso that when Z is —NHCOR
4
, X
+
is trimethylammonium, Y is —COO—, then R
4
is C
20
alkyl;
with the proviso that when Z is —NHSO
2
R
4
, X
+
is trimethylammonium and Y

is —COO—, then R
4
is not tolyl;
with the proviso that when Z is —NHR
4
, X
+
is trimethylammonium and Y

is —COO—, then R
4
is not C
1
-C
6
alkyl.
The present invention further comprises the use of the compounds of the above-mentioned formula (I) as active ingredients for medicaments, in particular for medicaments useful for the treatment of pathologies related to a hyperactivity of carnitine palmitoyl carnitine, such as and in particular hyperglycemic states, diabetes and related pathologies, congestive heart failure and dilatative cardiopathy.
The present invention comprises pharmaceutical compositions containing compounds of formula (I) as active ingredients, in admixture with pharmaceutically acceptable vehicles and excipients.
The present invention comprises also processes for the preparation of compounds of formula (I).
DETAILED DESCRIPTION OF THE INVENTION
Within the scope of the present invention, as examples of C
1
-C
20
linear or branched alkyl group, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and eicosyl and their possible isomers are meant, such as for example isopropyl, isobutyl, tert-butyl.
Examples of C
1
-C
20
linear or branched alkenyl group are methylene, ethylidene, vinyl, allyl, propargyl, butylene, pentylene, wherein the carbon-carbon double bond, optionally in the presence of other carbon-carbon unsaturations, can be situated in the different possible positions of the alkyl chain, which can also be branched within the allowed isomery.
Examples of (C
6
-C
14
) aryl group are phenyl, 1- or 2-naphthyl, anthryl, optionally substituted as shown in the general definitions above-mentioned.
Examples of heterocyclic groups thienyl, quinolyl, pyridyl, N-methylpiperidinyl, 5-tetrazolyl, optionally substituted as shown in the general definitions above-mentioned.
As halogen atom it is intended fluorine, chlorine, bromine, iodine.
The compounds of formula (I) can be also in the form of inner salts.
A first group of preferred compounds comprises the compounds of formula (I) wherein N
+
(R
1
,R
2
,R
3
) is trimethyl ammonium.
A second group of preferred compounds comprises the compounds of formula (I) wherein two or more R
1
, R
2
and R
3
, together with the nitrogen atom, which they are linked to, form a saturated or unsaturated, monocyclic or bicyclic heterocyclic system; for example morpholinium, pyridinium, pyrrolidinium, quinolinium, quinuclidinium.
A third group of preferred compounds comprises the compounds of formula (I) wherein R
1
and R
2
are hydrogen and R
3
is selected from the group consisting of —CH═NH(NH
2
), —NH
2
and —OH.
Within the different embod

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