3-(Amino- or aminoalkyl)pyridinone derivatives and their use...

Details 3-(Amino- or aminoalkyl)pyridinone derivatives and their use... 3-(Amino- or aminoalkyl)pyridinone derivatives and their use...

2001-01-05

2002-09-17

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S350000, C514S351000, C546S297000, C546S298000, C546S300000

Reexamination Certificate

active

06451822

ABSTRACT:

The present invention is concerned with 3-(amino- or aminoalkyl) pyridinone derivatives which inhibit the reverse transcriptase of the Human Immunodeficiency Virus (HIV).
It relates moreover to the use of such compounds for treating HIV-related diseases.
Furthermore it relates to a process for the preparation of these compounds.
It is known that some pyrimidinone and pyridinone derivatives inhibit HIV reverse transcriptase.
In particular, derivatives from 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) are well known for their HIV1 reverse transcriptase inhibitory properties.
European Patent Application EP-0 462 800 (Merck and Company Inc.) discloses pyridinones being substituted on position 3 with an aryl or heterocyclic group, linked to the pyridinone ring through a chain.
Unfortunately, strains resistant to these compounds appeared Thus, their use in therapeutical treatments is questionable.
4-aryl-thio-pyridinones have been more recently disclosed by DOLLE et al. (1995, J. Med. Chem., 38, 4679-4686), and in the corresponding PCT Patent Application WO 97/05 113.
However, their activities are still moderate and their use in human therapy also could lead to the emergence of resistant strains.
The most active thio pyridinones disclosed therein have a 50% inhibitory concentration of virus multiplication (IC
50
) for nevirapine resistant strains of about 260 nM.
The inventors have found a new pyridinone derivative family which show better HIV inhibitory properties.
They have moreover found a new process for obtaining these compounds.
The present invention relates to compounds having the following general formula I.
wherein
Q represents —NR
1
R
2
or —R
0
NR
1
R
2
wherein:
R
o
represents C
1-6
alkanediyl;
R
1
and R
2
each independently represent C
1-6
alkyl or C
3-6
alkenyl; said C
1-6
alkyl and C
3-6
alkenyl may be substituted with one, two or three substituents selected from hydroxy, C
1-4
alkyloxy, C
1-4
alkylthio, aryloxy, arylthio, amino, mono- or di(C
1-4
alkyl)amino and aryl; or
R
1
and R
2
taken together may form a bivalent radical —R
1
—R
2
—wherein —R
1
—R
2
— represents —(CH
2
)
2
—O—(CH
2
)
2
—, —(CH
2
)
2
—NR
7
—(CH
2
)
2
, —(CH
2
)
2
—CH(NHR
7
)—(CH
2
)
2
— or —(CH
2
)
n
, wherein R
7
represents hydrogen or C
1-4
alkyl and n represents 2, 3, 4, 5 or 6;
R
3
represents aryl or a monocyclic or bicyclic heterocycle selected from pyridinyl, pyrimidinyl, thiazolinyl, furanyl, thienyl, imidazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl; said monocyclic or bicyclic heterocycle may optionally be substituted with one, two or three substituents each independently selected from hydroxy, C
1-4
alkyl, C
1-4
alkoxy, halo, trifluoromethyl, dimethylenoxy or phenyl,
R
4
and R
5
each independently represent hydrogen, C
1-6
alkyl, C
3-6
alkenyl, C
1-4
alkoxy, C
1-4
alkyloxy, C
1-4
alkyl, amino, mono- or di(C
1-4
alkyl)amino, formyl, C
1-4
alkylcarbonyl, carboxyl, C
1-4
alkyloxycarbonyl, or C
1-4
alkylaminocarbonyl; wherein C
1-6
alkyl and C
3-6
alkenyl may be substituted with one, two or three substituents selected from hydroxy, C
1-4
alkyloxy, C
1-4
alkyl thio, aryloxy, arylthio, amino, mono- or di(C
1-4
alkyl)amino and aryl; or
R
4
and R
5
taken together form a bivalent radical of formula —R
4
—R
5
— wherein —R
4-
R
5
— represents —CH═CH—CH═CH— or —(CH
2
)
t
—, wherein t represents 3 or 4;
R
6
represents hydrogen, hydroxy, C
1-4
alkyloxy, C
1-6
alkyl, C
3-6
alkenyl, aryl, C
1-4
alkyl, amino, mono- or di(C
1-4
alkyl)amino or alkylaryl;
Y represents O or S;
X represents a radical of formula:
—(CH
2
)
p
—
—(CH
2
)
q
—Z —(CH
2
)
r
— or —CO—
 wherein
p represents 1, 2, 3, 4 or 5;
q represents 0, 1, 2, 3, 4 or 5;
r represents 0, 1, 2 or 3;
Z represents NR
8
, C(═O), CHOH, CHNR
8
R
9
; CF
2
, O, S or CH═CH; wherein R
8
and R
9
each independently represent hydrogen or C
1-4
alkyl; or
N-oxides, stereochemically isomeric forms or a pharmaceutically acceptable addition salts thereof.
As used in the foregoing definitions and hereinafter halo defines fluoro, chloro, bromo and iodo; C
1-4
-alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as methyl, ethyl, propyl, butyl and the like; C
1-6
alkyl is meant to include C
1-4
alkyl and the higher homologues thereof containing 5 to 6 carbon atoms such as, for example, pentyl, hexyl or the like; C
3-6
alkenyl defines straight and branched chain hydrocarbon radicals containing one double bond and having from 3 to 6 carbon atoms, such as 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl and the like; and the carbon atom of said C
3-6
alkenyl being connected to a nitrogen atom preferably is saturated; C
1-6
alkanediyl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the like. The term <<C(═O)>> refers to a carbonyl group. Aryl is phenyl or phenyl substituted with one, two or three substituents selected from C
1-4
alkyl, C
1-4
alkyloxy, halo and trifluoromethyl,
Preferred compounds according to the present invention are those in which X represents —CH
2
— or C (═O) and R
3
represents a phenyl group, substituted with two methyl groups, and the most preferred of them are those wherein R
3
represents a phenyl group substituted, in each meta position, with two methyl groups.
Preferably, in the compounds according to the present invention, R
1
and R
2
represent each a methyl group, R
4
represents an ethyl group, R
5
represents a methyl group and/or R
6
represents a hydrogen atom.
The most preferred compound of this invention is the 3-dimethylamino-4-(3,5-dimethylbenzyl)-5-ethyl-6-methylpyridin-2-(1H)-one.
The compounds in which X is —CH
2
—, R
3
represents a phenyl group optionally substituted, Y represents O and R
6
represents a hydrogen atom can be obtained by the general process represented on FIG.
1
.
This first process comprises the following steps:
a) reacting a pyridine (2), substituted in position 2 with an alkoxy group and in position 3 with an amidoalkyl group, with a C
1
-C
6
alkyllithium, resulting in a lithiated derivate (3) of the said pyridine.
b) transforming the lithiated derivate (3) into an organocopper reagent by reacting it with a complex formed by Cu I and dimethyl sulphide.
c) obtaining the pyridinone (4) by reacting the organocopper reagent with.optionally substituted benzyl halide.
d) hydrolysing the protected pyridinone (4) and obtaining the deprotected pyridinone (5).
e) substituting the 3-amine group of the pyridinone (5) and obtaining the pyridinone (6).
This first process is summarized in the reaction Scheme I hereinafter:
In this process R
10
and R
11
represent independently C
1
-C
6
alkyl. In a preferred embodiment, R
10
is a methyl group and R
11
is a tert-butyl group.
The C
1
-C
6
alkyllithium, reacted with the pyridine(2) can be a n-butyllithium.
The optionally substituted benzyl halide used in the step c) is preferably benzyl bromide.
The hydrolysis of the protected pyridinone(4), resulting in its deprotection, is advantageously obtained by adding hydrochloric acid to the pyridinone(4) and refluxing the mixture.
In a preferred embodiment, the amino group in position 3 of the pyridinone ring, deprotected during the step (d) is substituted by alkylation, by the Eschweiler-Clarke reaction.
Compounds wherein X represents —(CH
2
)
q
—Z—(CH
2
)
r
—, Y represents O, R
3
is an optionally substituted phenyl group and R
6
is an hydrogen atom can be obtained by a similar process.
Compounds wherein X represents C (═O), or —CH
2
—, Y represents O, R
3
is an optionally substituted phenyl group and R
6
is an hydrogen atom can be obtained by a second process.
In this second process, the lithiated derivative (3) is reacted with an optionally substituted benzaldehyde, resulting in the intermediates of formula (7).
The intermediate (7) is oxidized to intermediate (8).
The intermediat

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