Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1997-12-12
2001-02-27
Fan, Jane (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S226800, C514S338000, C546S112000, C546S270100, C544S047000
Reexamination Certificate
active
06194426
ABSTRACT:
This is a 371 of PCT/Fr96/00887 filed Jun. 12, 1996 now WO 97/00073 filed Jan. 3, 1997.
The present invention relates to a new therapeutic application of pyrrole derivatives of general formula:
in which
Het denotes a ring condensed with pyrrole, such that it forms a pyrrolothiazole, 5,6,7,8-tetrahydroindolizine, dihydropyrrolothiazine or dihydropyrrolizine ring,
R
1
is a carboxamide, cyano, carboxyl, alkoxy carbonyl, acyl or imidazolylcarbonyl radical,
R
2
is a hydrogen or halogen atom or an alkyl, alkenyl, trihalomethyl or cyano radical,
R
3
is a hydrogen or halogen atom or a hydroxyl or alkyl radical, and
Het′ is a pyridyl, pyridyl N-oxide or thiazolyl radical,
it being understood that the alkyl or acyl radicals are straight or branched and contain 1 to 4 carbon atoms and the alkenyl radicals are straight or branched and contain 2 to 4 carbon atoms, and of its salts when they exist.
It is also understood that when R
2
and/or R
3
are halogen, they may be chosen from chlorine, bromine, fluorine or iodine.
Pyrrole derivatives which have an antithrombotic activity or are used as intermediates for the preparation of antithrombotic derivatives have been described in European Applications EP 118 321, EP 147 317 and EP 124 384 and in French Application 2 539 417.
It has now been found that the derivatives of general formula (I) inhibit the effects of the TNF (Tumour Necrosis Factor) and can consequently find an application in all the fields where this mediator is involved. The present invention therefore relates to the application of the pyrrole derivatives of general formula (I) for the preparation of a medication intended for the treatment of the disorders in which the TNF is involved.
The TNF is responsible especially for the activation of the HIV virus especially in chronically infected cells.
Consequently, the products of general formula (I) can be useful for obtaining a medication intended for the prophylaxis and/or therapeutic treatment of retroviral infections and more particularly of AIDS (acquired immunodeficiency syndrome) and of associated syndromes [ARC (AIDS related complex)].
By prophylaxis we imply the treatment of individuals who have been exposed to the HIV viruses (human immunodeficiency viruses), in particular the asymptomatic seropositives who carry the risk of developing the disease in the months and years to come after the primary infection.
The activity of the products of general formula (I) has been revealed as follows:
The effects of the derivatives of general formula (I) on the induction of the HIV-1 virus have been studied on chronically infected cell lines.
U1 cell lines are employed, obtained after infection of the premonocyte line, U937, with the HIV-1 virus and selected according to the ability to increase virus production in response to phorbol myristate acetate (PMA), to the TNF and to other mediators [Folks et al., Science 238, 800 (1987)]. Reverse transcriptase activity is employed as an indicator of virus production. The effect of increasing concentrations of the product to be studied on stimulated cell lines is thus analysed.
Experimental Study
The product to be studied is dissolved in dimethylformamide (DMF). The parent solutions are prepared on the day of the test and stored at a temperature of 4° C. The dilutions are produced so that the DMF concentration remains constant (0.1%)
The cell cultures are sampled in an exponential growth phase and recultured at the rate of a final concentration of 2×10
5
cells/ml, in the presence of various concentrations of the product to be studied. &agr;TNF or PMA is added to all the cultures 30 minutes later.
Each test is done in triplicate, including the controls. Three days later a fraction of supernatant of the cultures is sampled and frozen with a view to the measurement of reverse transcriptase.
The measurement of reverse transcriptase activity is carried out using known techniques, in duplicate [Strebel et al., Nature, 328, 728 (1987)].
The derivatives of general formula (I) are studied at concentrations of from 0.1 nM to 10 &mgr;M.
The &agr;TNF is added at a rate of 10 Units/ml and PMA at 10
−8
M (final concentration).
Some controls do not receive the activator. Other controls do not receive the product to be studied. Others receive neither the product nor the activator.
Results
The decrease in virus production by the derivatives of general formula (I) is significant and dose-dependent in the case of U1 cells treated with ATNF or with PMA. On day 3 a decrease of at least 50% is seen in the production of reverse transcriptase in the case of the Ul cells treated with 10 Units/ml of &agr;TNF and to which products have been added in a concentration of 10 &mgr;M.
Furthermore, the derivatives of general formula (I) have no effect on the viability of the cells at the active concentrations.
By way of example, the results for some products appear in Table I below.
TABLE 1
50% inhibiting
concentration
(nM)
Example No.
R
1
R
2
Het′-R
3
PMA
TNF
a
CONH
2
H
3-Pyridyl
1000
3000
b
CONH
2
H
3-Pyridyl
300
700
c
CONH
2
CH
3
3-Pyridyl
100
240
d
CONH
2
H
3-Pyridyl
1000
3000
e
CONH
2
CH
3
3-Pyridyl
230
110
f
CN
H
3-Pyridyl
1000
10000
g
CN
H
3-Pyridyl
1000
1000
h
COCH
3
H
3-Pyridyl
300
1000
i
CONH
2
H
3-Pyridyl
390
1720
j
COOH
H
3-Pyridyl
3000
1000
The preparation of the products of general formula (I) is performed according to the methods described in the abovementioned patent applications, especially according to the methods described in European Application EP 147 317 or according to the examples which follow, or by analogy with these methods.
When R
1
is a carboxamide, cyano, carboxyl, acyl or alkoxycarbonyl or imidazolylcarbonyl radical, then an acrylic derivative of general formula:
in which R
2
is defined as above and R′
1
is a cyano or acyl radical and Hal is a halogen atom, preferably a chlorine atom, is reacted with an acid of general formula:
in which Het and Het′—R
3
are defined as above, and the product obtained is then optionally hydrolysed either to amide or to acid according to the known methods which do not alter the remainder of the molecule, and the acid obtained is then optionally converted into an ester to obtain a derivative in the case of which R
1
is alkoxycarbonyl, or the acid obtained is optionally converted into an imidazole derivative by the action of carbonyldiimidazole, to obtain a derivative by in the case of which R
1
is imidazolylcarbonyl, and then the pyridyl radical denoting Het′ is optionally oxidized when the intention is to obtain a product in the case of which Het′ denotes pyridyl N-oxide.
The reaction of the product of general formula (II) with the acid of general formula (III) is generally performed in acetic anhydride at a temperature of between 80 and 130° C.
The hydrolysis to amide is performed according to known methods, especially by heating in an alkaline medium in an organic solvent like, for example, t-butanol at a temperature of between 30 and 85° C., or in a concentrated acidic medium at a temperature of between 20 and 100° C.
The hydrolysis to acid is performed according to known methods, especially in a basic medium in an alcohol of high boiling point, for example in the presence of potassium hydroxide in ethylene glycol, at a temperature of between 100° C. and the reflux temperature of the reaction mixture.
The conversion of the acidic functional group to an alkoxycarbonyl radical is performed by the usual esterification methods which do not alter the remainder of the molecule.
The conversion of the acidic functional group to an imidazole radical is performed in a solvent like tetrahydrofuran at a temperature of between 20 and 40° C.
The oxidation of the pyridyl radical is performed by any oxidation method which does not alter the remainder of the molecule. The operation is carried out especially by means of a peracid like m-chlorobenzoic acid, in an alcoholic medium (for example ethanol).
Among the product
Bacque Eric
Bashiardes Georges
Dereu Norbert
Nemecek Conception
Fan Jane
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Rhona-Poulenc Rorer S.A.
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