Pyrimidinone-1,3-oxathiolane derivatives with antiviral...

Details Pyrimidinone-1,3-oxathiolane derivatives with antiviral... Pyrimidinone-1,3-oxathiolane derivatives with antiviral...

2000-01-31

2001-04-10

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C544S317000

Reexamination Certificate

active

06214833

ABSTRACT:

The present invention relates to antiviral nucleosides and, more particularly, relates to 1,3-oxathiolane derivatives endowed with reverse transcriptase inhibitory activity Since the discovery of HIV virus, responsible for AIDS, remarkable efforts have been made in the attempt of identifying an effective therapy.
Some nucleoside derivatives, such as zidovudine, zalcitabine, didanosine and stavudine (USP Dictionary of USAN and International Drug Names, 1997, pages 774, 772, 228 and 669 respectively), have become of clinical use, each other sometimes in association.
All these drugs act as reverse transcriptase inhibitors (RT-inhibitors).
In fact, reverse transcriptase is an enzyme involved in the intracellular replication of the virus because it catalyses the DNA transcription from the viral RNA.
Therefore, the RT-inhibitors act in a very early vital stage of the viral replication and this is the reason of their remarkable therapeutic interest.
On the other hand, the prolonged use of RT-inhibitors used up to now in therapy is practically impossible because of the appearance of resistance, side-effects and toxic effects mainly connected with their low selectivity.
Very recently, (2R-cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-2(1H)-pyrimidinone, better known with the common name lamivudine (USP Dictionary of USAN and International Drug Names, 1997, page 398), a compound described in the International patent application no. WO 91/17159 (IAF Biochem International Inc.) as more potent and less toxic antiviral than zidovudine, zalcitabine, didanosine and stavudine has entered the clinical use.
Lamivudine is the levorotatory enantiomer (2R,5S) of the compound known with the code BCH-189 described in the European patent application no. 0 382 526 (IAF Biochem International Inc.).
Notwithstanding the progress obtained in these last years in the treatment of AIDS, the disease still has a huge medical and social relevance for its extreme seriousness and for its fast spread.
Therefore, there is still a very high need of new drugs endowed with an always greater efficacy and with an always minor toxicity, then particularly suitable for prolonged therapies too.
The International patent application no. WO 95/32200 (Laboratoire Laphal) describes derivatives of lamivudine and of BCH-189 characterised by the presence of an acyl or arylalkoyl group deriving from a mono or bicyclic nitrogen containing heterocycle, as substituent of the amino group.
We have now found that by introducing a nitrogen containing chain of formula
wherein
R is a hydrogen atom, a linear or branched C
1
-C
6
alkyl group, a C
3
-C
7
cycloalkyl group or a group selected among
wherein q is an integer from 1 to 3; p is an integer from 1 to 4; Het is a 5 or 6 member heterocycle containing 1 or 2 heteroatoms selected among oxygen, nitrogen and sulfur and R
3
is a hydrogen or halogen atom, a trifluoromethyl group or a C
1
-C
3
alkoxy group;
R
1
and R
2
, the same or different, are hydrogen atoms, phenylalkoxycarbonyl groups having from 1 to 3 carbon atoms in the alkoxy moiety, C
2
-C
6
alkoxycarbonyl groups or C
2
-C
6
alkylcarbonyl groups;
W is a single bond, an oxygen atom or a —CH(Alk)— group wherein Alk is a linear or branched C
1
-C
3
alkyl group;
r is 0 or 1;
n=x when r is 0
n=y when r is 1;
x is an integer from 1 to 6;
y is an integer from 2 to 7;
m is an integer from 2 to 7;
onto a function of lamivudine which can be acylated, the antiviral activity of lamivudine is remarkable strengthened.
Therefore, object of the present invention are compounds of formula
wherein
R
a
and R
b
, the same or different, are hydrogen atoms, acyl groups deriving from a lower carboxylic acid or chains of formula
wherein
R is a hydrogen atom, a linear or branched C
1
-C
6
alkyl group, a C
3
-C
7
cycloalkyl group or a group selected among
wherein q is an integer from 1 to 3; p is an integer from 1 to 4; Het is a 5 or 6 member heterocycle containing 1 or 2 heteroatoms selected among oxygen, nitrogen and sulfur and R
3
is a hydrogen or halogen atom, a trifluoromethyl group or a C
1
-C
3
alkoxy group;
R
1
and R
2
, the same or different, are a hydrogen atom, a phenylalkoxycarbonyl group having from 1 to 3 carbon atoms in the alkoxy moiety, a C
2
-C
6
alkoxycarbonyl group or a C
2
-C
6
alkylcarbonyl group;
W is a single bond, an oxygen atom or a —CH(Alk)— group wherein Alk is a linear or branched C
1
-C
3
alkyl group;
r is 0 or 1;
n=x when r is 0
n=y when r is 1;
x is an integer from 1 to 6,
y is an integer from 2 to 7;
m is an integer from 2 to 7;
provided that at least one of R
a
and R
b
is different from a hydrogen atom or from an acyl group deriving from a lower carboxylic acid; tautomeric forms and pharmaceutically acceptable salts thereof.
The compounds of formula I are lamivudine derivatives (prodrugs) which release lamivudine into the organism but are endowed with antiviral activity, as reverse transcriptase inhibitors, more potent than lamivudine on lymphocytes and, particularly, on macrophages.
Notwithstanding in the literature, as already reported, the term lamivudine more commonly refers to the levorotatory enantiomer (2R-cis) of 4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-2(1H)-pyrimidinone, while the corresponding racemate is referred to as the code BCH- 189, for the sake of simplicity in the present context, if not otherwise specified, the term lamivudine refers to the compound of formula
in the form of stereoisomeric mixture as well as in the form of one of the possible isomers thereof.
The compounds of formula I, object of the present invention, can have a single chain, bound to the OH function or to the NH
2
function of lamivudine, or two chains bound to the OH function and to the NH
2
function of lamivudine. Specific examples of compounds of formula I are:
wherein R, R
1
, R
2
, W, n, m and r have the already reported meanings; R′
a
and R′
b
are hydrogen atoms or an acyl group deriving from-a lower carboxylic acid.
In the present description, when not otherwise specified, the term linear or branched C
1
-C
6
alkyl refers to a group selected among methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, neopentyl, isopentyl, tert-pentyl, sec-pentyl, hexyl and isohexyl; the term C
2
-C
7
cycloalkyl refers to a group selected among cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloeptyl; the term C
1
-C
3
alkoxy refers to a group selected among methoxy, ethoxy, propoxy and isopropoxy; the term C
2
-C
6
alkoxycarbonyl refers to a group selected among methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl (also referred to as BOC), sec-butoxycarbonyl and pentoxycarbonyl; the term C
2
-C
6
alkylcarbonyl refers to a group selected among acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and hexanoyl; the term acyl deriving from a lower carboxylic acid refers to a group selected among acetyl, propionyl, butyryl and isobutyryl, the term 5 or 6 member heterocycle containing 1 or 2 heteroatoms selected among oxygen, nitrogen and sulphur refers to a heterocycle selected among thiophene, furan, pyrane, pyrrole, imidazole, pyrazole, isothiazole, thiazole, isoxazole, oxazole, pyridine, pyrazine, pyrimidine and pyridazine, optionally benzocondensed.
A class of preferred compounds of formula I is represented by the compounds having, the (2R,5S) configuration of lamivudine.
Another class of preferred compounds is represented by the compounds of formula I-A.
Within this class, preferred compounds are the compounds wherein R
1
and R
2
are different from hydrogen and, more preferably, are C
2
-C
6
alkoxycarbonyl groups such as, for example, ethoxycarbonyl or tert-butoxycarbonyl groups.
Still more preferred are the compounds of formula I-A wherein R
1
and R
2
are different from hydrogen and R is a group of formula
wherein R
3
and q have the already reported meanings.
Another class of particularly interesting compounds is represented by the

Affiliated with

Also associated with

Rating

Pyrimidinone-1,3-oxathiolane derivatives with antiviral... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Pyrimidinone-1,3-oxathiolane derivatives with antiviral..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Pyrimidinone-1,3-oxathiolane derivatives with antiviral... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2462145