Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-12-26
2004-03-02
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S248000, C544S235000, C544S237000, C544S239000
Reexamination Certificate
active
06699868
ABSTRACT:
This application is a national stage filing of PCT International Application No. PCT/FI01/00241, filed on Mar. 12, 2001. This application also claims the benefit of priority under 35 U.S.C. § 119(a) to Finnish patent application No. 20000577, filed on Mar. 13, 2000.
The present invention relates to pyridazinyl phenyl hydrazone compounds and pharmaceutically acceptable salts and esters thereof. The invention also relates to pharmaceutical compositions comprising such compounds as active ingredients. The compounds of the invention increase the calcium sensitivity of contractile proteins of the cardiac muscle and are thus useful in the treatment of congestive heart failure.
Congestive heart failure is characterized by a decrease in cardiac output and an increase in right and left ventricular filling pressure. These hemodynamic conditions can produce symptoms of dyspnea, fatigue and edema.
The contraction in cardiac muscle is triggered by the binding of calcium to contractile proteins. Series of phosphodiesterase isoenzyme III (PDE III) inhibitors are in clinical trials for the treatment of congestive heart failure. These compounds increase the contractility of the cardiac muscle and produce vasodilatation. However, it is known that the long-term application of those compounds may lead to calcium overload in the cardiac muscle and trigger arrhythmias. It is therefore desired to develop medicaments acting by a mechanism which would increase cardiac contractility without producing calcium overload. The increase of calcium sensitivity of contractile proteins would be such a mechanism.
Pyridazinyl phenyl hydrazone compounds have been described earlier in European patent application EP 383449. The compounds show calcium dependent binding to contractile proteins of the cardiac muscle, as well as PDE III inhibiting activity. In the specific examples one 1-acetyl-1-phenyl methylidene derivative is disclosed (Ex. 16). While the 1-acetyl-1-phenyl methylidene derivative has some effect in cardiac contractility, it does not increase the calcium sensitivity of contractile proteins.
Certain pyridazinyl phenyl hydrazone compounds appear as intermediates in European patent applications EP 223937 and EP 280224. However, the compounds are not specifically characterized. Mertens, A. et al., J. Med. Chem. 1990, 33, 2870-2875,discloses a phenyl, 4-methoxyphenyl and 2-hydroxyphenyl derivatives of pyridazinyl phenyl hydrazone compounds as intermediates.
It has now been found that compounds of formula (I) are potent in increasing the calcium sensitivity of contractile proteins in the cardiac muscle:
in which
R
1
to R
4
means hydrogen, alkyl, alkenyl, aryl, arylalkyl, carboxyalkyl, hydroxyalkyl or halogenalkyl, or R
2
and R
3
form a ring of 5-7 carbon atoms,
R
5
to R
9
means hydrogen, alkyl, alkenyl, aryl, arylalkyl, acyl, hydroxy, alkoxy, alkoxycarbonyl, amino, acylamino, alkylamino, aryloxy, halogen, cyano, nitro, carboxy, alkylsulfonyl, sulfonamido or trifluoromethyl,
wherein each aryl residue defined above by itself or as a part of another group may be substituted,
and pharmaceutically acceptable salts and esters thereof,
provided that a) when R
1
, R
2
, R
3
, R
5
, R
6
, R
8
and R
9
are hydrogen and R
4
is methyl, R
7
is not hydrogen or methoxy and b) when R
1
, R
2
, R
3
, R
5
, R
6
, R
7
and R
8
are hydrogen and R
4
is methyl, R
9
is not hydroxy.
The invention also relates to compounds of formula (I) in which R
1
, R
2
, R
3
, R
5
, R
6
, R
8
and R
9
are hydrogen, R
4
is methyl, and R
7
is hydrogen or methoxy, or in which R
1
, R
2
, R
3
, R
5
, R
6
, R
7
and R
8
are hydrogen, R
4
is methyl and R
9
is hydroxy and pharmaceutically acceptable salts and esters thereof, for use as a medicament.
In a class of preferred compounds and pharmaceutically acceptable salts and esters are compounds of formula (I) wherein R
5
to R
9
are independently hydrogen, C
1-6
alkyl, C
1-6
alkenyl, C
6-10
aryl, C
7-12
arylalkyl, C
1-6
acyl, hydroxy, C
1-6
alkoxy, C
1-6
alkoxycarbonyl, amino, C
1-6
acylamino, C
1-6
alkylamino, C
6-10
aryloxy, halogen, cyano, nitro, carboxy, C
1-6
alkylsulfonyl, sulfonamido or trifluoromethyl. In a subclass of this class of compounds and pharmaceutically acceptable salts thereof are compounds of formula (I) wherein R
5
to R
9
are independently hydrogen, hydroxy, C
1-6
alkyl, C
1-6
alkoxy, carboxy, C
1-6
alkoxycarbonyl or nitro. In a subclass of this class of compounds and pharmaceutically acceptable salts thereof are compounds of formula (I) wherein R
5
is hydroxy, C
1-6
alkyl, C
1-6
alkoxy, carboxy, C
1-6
alkoxycarbonyl or nitro, most preferably hydroxy or nitro.
In another class of preferred compounds and pharmaceutically acceptable salts R
1
to R
4
are independently hydrogen, C
1-6
alkyl, C
1-6
alkenyl, C
6-10
aryl, C
7-12
arylalkyl, C
1-6
carboxyalkyl, C
1-6
hydroxyalkyl or C
1-6
halogenalkyl, or R
2
and R
3
form a phenyl ring. In a subclass of this class of compounds and pharmaceutically acceptable salts thereof are compounds of formula (I) wherein R
1
to R
3
are independently hydrogen or C
1-6
alkyl.
Each aryl residue in each of these preferred classes of compounds, by itself or as part of another group, may be substituted by 1 to 3, preferably 1 or 2, of fluorine, chlorine, bromine, iodine, hydroxy, nitro, carboxy, trifluoromethyl, amino, C
1-4
alkyl, C
1-4
alkoxy, C
1-6
acyl, C
1-6
carboxyalkyl, phenyl, naphthyl, halophenyl, halonaphthyl, benzyl, phenethyl, halobenzyl, halophenethyl, naphthylmethyl, naphthylethyl, C
4-7
cycloalkyl, C
1-4
alkyl C
4-7
cycloalkyl, mono C
1-4
alkylamino, di C
1-4
alkylamino, C
1-6
alkanoylamino, phenylcarbonylamino, naphthylcarbonylamino, cyano, thiol, or C
1-6
alkylthio.
The compounds of formula (I) may contain one or more assymmetric centers and thus they can exist as enantiomers or diastereomers. The invention includes both mixtures and separate individual isomers.
Especially preferred individual compounds of the invention include:
(R)-6-{4-[N′-(4-Hydroxy-3-methoxy-2-nitro-benzylidene)-hydrazino]-phenyl }-5-methyl-4,5-dihydro-2H-pyridazin-3-one;
6-{4-[N′-(4-Hydroxy-3-methoxy-2-nitro-benzylidene)-hydrazino]-phenyl}-5-methyl-4,5-dihydro-2H-pyridazin-3-one;
6-(4-{N′-[1-(2,5-Dihydroxy-phenyl)-ethylidene]-hydrazino}-phenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one;
6-(4-{N-[1-(2,4-Dihydroxy-3-methylphenyl)ethylidene]hydrazino}phenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one;
6-(4-{N′-[Bis-(2,4-dihydroxy-phenyl)-methylene]-hydrazino}-phenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one;
6-(4-{N′-[1-(2,4-Dihydroxy-phenyl)-ethylidene]-hydrazino}-phenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one;
2,6-Dihydroxy-3-{[4-(4-methyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenyl]-hydrazonomethyl }-benzoic acid ethyl ester; and
6-{4-[N′-(3-Ethyl-2,4-dihydroxy-benzylidene)-hydrazino]-phenyl}-5-methyl-4,5-dihydro-2H-pyridazin-3-one.
The compounds of the invention can be prepared by the well known condensation reaction between a carbonyl compound and a hydrazine as shown in Scheme 1:
wherein Ar means
and R
1
to R
9
as defined above.
A suitable method for the preparation of hydrazines (III) is the diazotization of an aniline and reduction as a one pot synthesis. Scheme 2 shows this reaction:
where Ar is as above.
Compounds of formula (II) and (IV) are commercially available or can be prepared using methods known in the literature.
General method 1: In case where R
4
is hydrogen, the reaction of Scheme 1 is generally performed by refluxing a mixture of compounds (II) and (III) in a suitable solvent, such as ethanol, 2-propanol, acetonitrile or acetic acid, for 1-24 hours. The product (I) is filtered.
General method 2: In case where R
4
is not hydrogen, the reaction of Scheme 1 is generally performed by heating a neat mixture of compounds (II) and (III) at 140-170° C. under inert atmosphere. The mixture is then triturated with ethyl acetate and th
Bäckström Reijo
Haikala Heimo
Kaheinen Petri
Kaivola Juha
Levijoki Jouko
Bernhardt Emily
Orion Corporation
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