Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-01-16
2003-12-30
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S312000, C546S153000, C546S157000
Reexamination Certificate
active
06670377
ABSTRACT:
A subject of the present invention is quinoline derivatives, in particular endowed with inhibitory properties of human immuno-deficiency virus integrase.
It also relates to a synthetic process for these derivatives and their biological uses.
The integration of the genomic DNA of HIV in the chromosomes of the infected cell is strictly necessary for the replication of the virus. The viral enzyme which catalyzes the integration of the viral DNA in the chromatin of the host is integrase. Consequently, an integrase inhibitor constitutes ipso facto a candidate for blocking infection by HIV, and possibly an effective therapeutic agent. Of the three viral enzymes which condition the replication of HIV, namely reverse transcriptase, protease and integrase, integrase is the last not to be targeted by any therapeutic agent. In the context of polytherapy, which currently seems to be only method of effectively combatting the rapid development of the virus, obtaining an integrase inhibitor is an essential objective.
Various groups across the world have developed integrase inhibitors, some of these molecules have submicromolar inhibitory activities in vitro, such as quercetagenin. Other compounds had promising activities such as phenyl ethyl esters of caffeic acid, cosalane, 5,8-dihydroxy-1,4-naphthoquinone, cucurmin, 1,10-phenanthroline, primaquine, chloroquine, certain derivatives of podophyllotoxin or also bis-gallic esters. However, the activites of these different products have only been reported in vitro and these products have not been shown to be active in vivo.
More recently, bis-caffeates of quinic acid have been described as active in vivo but depending on protocols involving bringing the drug into contact with the virus beforehand.
The work of inventors in this field has led them to study quinoline derivatives and to demonstrate anti-integrase properties in vitro as well as in vivo, these properties being accompanied by significant innocuity.
A subject of the invention is therefore to provide new quinoline derivatives capable in particular of inhibiting the integrase activity of HIV in vitro and in vivo.
It also relates to a synthetic process for these derivatives which can be easily implemented on an industrial scale.
A subject of the invention is also to exploit the anti-integrase properties of these derivatives for the development of medicaments.
The derivatives according to the invention are characterized in that they correspond to the general formula I
in which
R
a
, R
b
and R
c
, identical or different from one another, represent one or more substituents, themselves identical or different, occupying any position on the rings, this or these substituents being chosen from a —(CH
2
)
n
—Y or —CH═CH—Y group, where Y represents a halogen atom, an —OH, —OR, —COH, —COR, —COOH, —COOR, —COH, —COR, —CONH
2
, —CON(R
x
, R
y
)—CH═NOH, —CO—CH═NOH, —NH
2
, —N(R
x
, R
y
), —NO
2
, —PO(OR)
2
—SH
2
, —SR, —SO
2
R, —SO
2
NHR, CN, or Z(R
c
) radical, where R represents an alkyl radical with 1 to 8 carbon atoms, or an aryl or heterocyclic radical, R
x
and R
y
, identical or different, represent an alkyl radical with 1 to 5 carbon atoms, Z represents an aryl or heterocyclic radical and n is zero or an integer between 1 and 5,
R
b
moreover can represent a hydrogen atom,
and when Y represents a —COOH or —COOR group in R
c
, Z, if it represents an aryl group, includes at least 3 substituents or the quinoline ring is trisubstituted,
X represents an ethylene double bond; or a group chosen from —(CH
2
)
n
—, where n is an integer between 1 and 5; —CH(R
d
)—CH(R
e
)—, R
d
and R
e
, identical or different, representing a hydrogen atom, a halogen atom, a hydroxy or epoxy group; —(CH
2
)
n′
—O—C(O)—(CH
2
)
m
—, —(CH
2
)
n′
—C(O)—O—(CH
2
)
m
—, —(CH
2
)
n′
—O—(CH
2
)
m
—, —(CH
2
)
n′
—NQ—(CH
2
)
m
—, or —(CH
2
)
n′
—S(O)
t
—(CH
2
)
m
—, where n′ is an integer from 0 to 8, m is an integer from 0 to 8, t is zero or an integer equal to 1 or 2, and Q is a hydrogen atom, or an alkyl or aryl radical,
as well as the pharmaceutically acceptable salts of these derivatives, their diastereoisomeric forms and their enantiomeric forms.
By “aryl” radical is meant a phenyl or naphthyl radical. “Heterocyclic” designates rings with 5 or 6 elements comprising one, two, three or four heteroatoms, chosen from N, S or O. “Halogen” designates a fluorine, chlorine, bromine atom, or a tritralogeno-methyl group, in particular trichloromethyl. “Alkyl” without further explanation designates a radical with 1 to 5 carbon atoms.
A preferred family of derivatives according to the invention comprises at least one ethylene double bond.
In particular, derivatives in which R
a
and/or X represent an ethylenically unsaturated group are concerned.
In a preferred group of this family, X represents an ethylene double bond, and R
a
represents a group chosen from —CH═CH—COOH, —CH═CH—COOR, —CH═CH—COH, —CH═CH—COR, —CH═CH—CONH
2
, —CON(R
x
, R
y
), and —CH═CH—Z(R
c
).
In another group of this family, X represents a —CH(R
d
)—CH(R
e
)—, or —(CH
2
)
n
— group, and R
a
has the meaning given in relation to the above group.
In yet another group, X represents an ethylene double bond and R
a
is a radical chosen from —OH, —COOH, or a pharmaceutically acceptable salt, or CN.
Products of this group have the formula II
in which
R
a
represents at least one substituent chosen from an —OH, —COOH group, or a pharmaceutically acceptable salt, or CN, preferably two substituents one of which is an —OH group and the other has one of the above meanings,
R
c
represents two or three —OH substituents.
In another preferred family of the invention, the quinoline derivatives do not include an ethylene double bond.
A preferred group of this family is constituted by derivatives in which R
a
represents a —(CH
2
)
n
—Y group and X is a —CH(R
d
)—CH(R
e
)—, or —(CH
2
)
n
— group.
In another preferred group of this family, X comprises a heteroatom. This concerns in particular products in which X is a group chosen from —(CH
2
)
n′
—O—C(O)—(CH
2
)
m
—, —(CH
2
)
n′
—C(O)—O—(CH
2
)
m
—, —(CH
2
)
n′
—O—(CH
2
)
m
—, —(CH
2
)
n′
—N(Q)—(CH
2
)
m
—, or —(CH
2
)
n′
—S(O)
t
—(CH
2
)
m
—, where n′ is an integer from 0 to 8, m is an integer from 0 to 8, t is zero or an integer equal to 1 or 2, and Q represents a hydrogen atom, an alkyl or aryl radical.
Particularly advantageous products according to the invention include 2-[2-[(3,4-dihydroxyphenyl)ethenyl]]quinoline, 8-hydroxy-2-[2-[(3,4-dihydroxyphenyl)ethenyl]]quinoline, 8-hydroxy-2-[2-[(3,4-dihydroxyphenyl)ethenyl]]7-quinoline carboxylic acid, the sodium salt of 8-hydroxy-2-[2-[(3,4-dihydroxyphenyl)ethenyl]]7-quinolinecarboxylic acid, 7-cyano-8-hydroxy-2-[2-[(3,4-dihydro-xyphenyl)ethenyl]]quinoline, 8-hydroxy-2-[2-[(3.4,5-trihydroxyphenyl)ethenyl]]7-quinoline carboxylic acid, and 2-[2-[(3,4-dihydroxyphenyl)ethenyl]]5,7-quinolinedicarboxylic acid.
The invention also relates to a synthetic process for the derivatives defined above.
This process is characterized in that it comprises
the reaction of a quinaldine of formula III with an aromatic or heteroaromatic derivative of formula IV carrying the appropriate blocking groups:
in which A and B represent reactive groups capable of generating group X as defined above, R
a
, R
b
, R
c
and Z having the meaning given with regard to formula I, but including blocking groups, and
the elimination of the protective groups.
According to an embodiment of the invention, in order to obtain quinoline derivatives in which X does not represent a heteroatom,
a Perkin-type condensation between a quinaldine of formula V and an aromatic or heteroaromatic derivative of formula VI carrying the appropriate blocking groups was used:
in which the different substituents have the meanings given with regard to formula I, but carrying blocking groups, and
Auclair Christian
D'Angelo Jean
Desmaele Didier
Mekouar Khalid
Mouscadet Jean-Francois
Centre National de la Recherche
Seaman D. Margaret
LandOfFree
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