Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-06-11
2001-03-27
Huang, Evelyn Mei (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S112000, C546S183000
Reexamination Certificate
active
06207675
ABSTRACT:
This application is the national phase of PCT/FR97/02248, filed Dec. 10, 1997.
The present invention relates to new pyrrole derivatives of general formula:
which are useful in the treatment and prevention of conditions in which viruses of the herpes family are involved, and/or in which cytokines, including TNF
&agr;
(Tumour Necrosis Factor alpha), are involved.
Viruses of the herpes family are responsible for numerous conditions, some of which can be very serious. It comprises in particular the group &agr;, &bgr; and &ggr; herpesviruses including the herpes simplex viruses 1 and 2, varicella-zoster, cytomegalovirus (CMV), herpesviruses types 6 and 7 (HHV-6 and HHV-7), Epstein-Barr virus and herpesvirus type 8 (HHV-8). The clinical forms due to a herpes simplex infection can vary from benign forms such as herpes labialis to more serious forms such as genital herpes. Herpes simplex may even be responsible for encephalitis putting the patient's life at risk. Varicella-zoster is the virus responsible for varicella and zona, it may also be responsible for more serious conditions including encephalitis. Cytomegalovirus infections are in general a symptomatic in healthy subjects, but can be the cause of morbidity [retinitis (which may lead to blindness), pneumopathies and the like] and of mortality in immunosuppressed subjects (patients suffering from AIDS or any other immunodeficiency, for example after organ transplantation or after anticancer chemotherapy). The cytomegalovirus is also responsible for severe clinical manifestations for the foetus or newborn in the case of a primary infection during pregnancy or during seropositive blood transfusion into a seronegative newborn. The herpesviruses HHV-6 and 7 are responsible for roseola and can be reactivated in immunosuppressed subjects. The HHV-8 virus is involved in Kaposi's sarcoma.
The treatments existing up until now are likely to cause serious side effects. Furthermore, for some of these viruses, the treatments can most often only be used by the intravenous route.
Cytokines (including TNF
&agr;
) are capable of activating various viruses and/or retroviruses, for example the cytomegalovirus or the Human Immuno-deficiency Virus (HIV), and are also capable of activating cellular genes, in particular those involved in inflammatory processes, such as the genes for chemokines, cytokines and adhesion molecules.
In European Applications EP 118 321, EP 147 317 and EP 124 384 and in French Application 2 539 417, there have been described pyrrole derivatives having an antithrombotic activity or serving as intermediates for the preparation of antithrombotic derivatives. Pyrrole derivatives having an anti-TNF ativity have been described in French Application 2 735 476.
In the general formula (I),
R
1
is a carboxamide, cycano, carboxyl, alkyloxycarbonyl, acetyl or imidazolylcarbonyl radical,
R
3
is a hydrogen or halogen atom, or an alkyl or hydroxyl radical, and
Het is a pyridyl, pyridyl N-oxide or thiazolyl radical, and
a) the bond
- - -
is a single bond,
R
2
is a hydrogen or halogen atom, or a cyano, alkyl, al-kyloxy or trihalomethyl radical,
R
4
is a hydrogen atom, and
R
5
is a hydroxyl, alkyloxy, amino or haloacylamino radical, or alternatively
b) the bond
- - -
is a double bond, and
R
2
is a hydrogen or halogen atom, or a cyano, alkyl, alkyloxy, alkenyl or trihalomethyl radical,
R
4
is a hydrogen or halogen atom or an alkyloxy or alkylthio radical which are optionally substituted with carboxyl, alkyloxycarbonyl, amino, alkylamino or dialkylamino in which the alkyl parts can form, with the nitrogen atom to which they are attached, a 4- to 6-membered heterocycle which may, in addition, comprise another heteroatom chosen from nitrogen, oxygen or sulphur, or phthalimido, and
R
5
is a hydrogen atom, it being understood that R
2
cannot be chlorine when simultaneously R
4
and R
5
are hydrogen, and when R
1
is cyano or carboxamido, and Het-R
3
is 3-pyridyl optionally substituted with fluorine at the 2 position, or alternatively when simultaneously R
4
is halogen, R
5
is hydrogen, and when R
1
is cyano or carboxamido and Het-R
3
is 3-pyridyl substituted with methyl, chlorine or fluorine at the 2 position or when R
1
is alkyloxycarbonyl or acetyl and when Het-R
3
is 3-pyridyl,
the alkyl radicals being straight or branched and containing 1 to 4 carbon atoms and the acyl and alkenyl radicals being straight or branched and containing 2 to 4 carbon atoms.
According to the invention, the halogen atoms are chosen from fluorine, chlorine, bromine or iodine.
According to the invention, the heterocycles are for example chosen from the morpholine, thiomorpholine, piperidine, pyrrolidine, piperazine, N-alkylpiperazine (for example N-methylpiperazine) or azetidine ring.
According to the invention, the preparation of the products of general formula (I) is carried out by preparing a nitrile intermediate of general formula:
in which Het, R
2
and R
3
are defined as above, by the action of an acrylic derivative of general formula:
in which R
2
is defined as above, with the exception of representing a halogen atom, R′
1
is a cyano or alkyloxycarbonyl radical, and Hal is a halogen atom (for example a chlorine atom) on an acid of general formula:
in which Het and R
3
are defined as above, followed by the steps of introducing the double bond and/or the radicals R
4
and R
5
and/or optionally R
2
, and where appropriate converting the nitrile to an amide, an acid, an ester, an imidazole-containing radical or an acetyl radical, or alternatively, where appropriate, converting the ester radical to an acid, an imidazole-containing radical or an acetyl radical, by any known methods which do not alter the rest of the molecule.
By way of example, the known methods may be in particular methods described in the patent applications cited above, or the methods described in the examples which follow, or methods analogous to these methods.
The reaction of the product of general formula (II) with the acid of general formula (III) is generally carried out using the acid salt (sodium salt for example) in acetic anhydride at a temperature of between 80 and 130° C., or in para-toluenesulphonyl chloride.
When it is desired to obtain the derivative for which R
2
represents cyano, the product obtained is subjected to treatment with isocyanatosulphonyl chloride at a temperature of between 0 and 10° C. in an organic solvent such as acetonitrile.
When it is desired to obtain the derivative for which R
2
represents trihalomethyl or alkenyl, the derivative of general formula (IV) obtained is treated beforehand according to the method described in French Application 2 735 476, or by any method analogous thereto.
When it is desired to obtain the derivative of general formula (IV) for which R
2
represents a halogen atom, the halogenation of the intermediate of general formula (IV) for which R
2
is hydrogen is carried out with an N-halosuccinimide, followed by a reduction of the product obtained, for example by catalytic hydrogenation in an acidic medium, in the presence of palladium on carbon.
The halogenation is carried out with 1 or 3 equivalents of N-halosuccinimide (for example N-chlorosuccinimide). The procedure is advantageously carried out in a chlorinated solvent (dichloromethane or dichloroethane for example) or in a nitrile (acetonitrile for example) at the reflux temperature of the reaction mixture.
When it is desired to obtain a derivative as defined in a), or for which
- - -
is a double bond and R
4
and R
5
are hydrogen atoms, the halogenation of the intermediate of general formula (IV) is carried out with an N-halosuccinimide, followed by the reduction of the product obtained, for example by catalytic hydrogenation in an acidic medium, in the presence of palladium, so as to obtain an intermediate of general formula:
in which Het, R
2
and R
3
are defined as above.
The derivative of general formula (V) can be either reduced in order to obtain a derivative for which R
5
is a hydroxyl radical and then, where approp
Carry Jean-Christophe
Mignani Serge
Nemecek Conception
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Huang Evelyn Mei
Rhone-Poulenc Rorer S.A.
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