Non-nucleoside reverse transcriptase inhibitors

Details Non-nucleoside reverse transcriptase inhibitors Non-nucleoside reverse transcriptase inhibitors

2002-03-05

2004-04-06

Rao, Deepak (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S256000, C514S337000, C514S367000, C514S371000, C514S380000, C514S407000, C544S328000, C544S329000, C544S336000, C546S282700, C546S283100, C548S163000, C548S192000, C548S246000, C548S364400

Reexamination Certificate

active

06716850

ABSTRACT:

TECHNICAL FIELD
This invention relates to non-nucleoside reverse transcriptase inhibitors active against HIV-1 and having an improved resistance and pharmacokinetic profile. The invention further relates to novel intermediates in the synthesis of such compounds and the use of the compounds in antiviral methods and compositions.
BACKGROUND TO THE INVENTION
Non nucleoside reverse transcriptase inhibitors (NNRTI) bind to an allosteric site on reverse transcriptase and represent an important development in the arsenal of drugs against HIV, particularly HIV-1. International patent application WO 93/03022, discloses thiourea NNRTI which were later denoted “PETT” (phenyl ethyl thiazolyl thiourea) compounds in J Med Chem 39 6 1329-1335 (1995) and J Med Chem 39 21 4261-4274 (1996). International patent application nos. WO99/47501, WO/0039095, WO/0056736, WO00/78315 and WO00/78721 describe thiourea PETT derivatives which have allegedly been optimised against a composite RT binding pocket.
International patent application no WO95/06034 and J Med Chem 42 4150-4160 (1999) disclose urea isosteres of PETT NNRTIs. International patent application no WO99/36406 discloses urea NNRTI compounds with a freestanding cyclopropyl bridge, wherein the phenyl left hand wing bears an obligate 6-hydroxy function and international patent application no WO00/47561 discloses prodrugs of such compounds.
Although the urea and thiourea NNRTI disclosed in the above documents are active against reverse transcriptase, especially that of HIV-1, the nature of the HIV virus with its extreme lack of replicative fidelity and consequent tendency to rapid resistance development prompts a demand for further antiretroviral agents with enhanced antiviral performance against problematic drug escape mutants, notably at the RT 100,103 and/or 181 positions.
Additionally, modern HIV therapy regimes, denoted HAART, Highly Active Anti Retroviral Therapy, administer antivirals as combinations of three or more antivirals of various classes, which combinations are administered for prolonged periods, if not for life. HAART requires the patient to follow a complicated dosing schedule with sometimes dozens of tablets per day taken at various times of the day in some cases before and in other cases after the ingestion of food. There is thus a need for antiretroviral preparations allowing greater flexibility in dosing to facilitate patient compliance.
BRIEF DESCRIPTION OF THE INVENTION
In accordance with a first aspect of the invention there are provided compounds of the formula I:
where;
R
1
is O, S;
R
2
is an optionally substituted, nitrogen-containing heterocycle, wherein the nitrogen is located at the 2 position relative to the (thio)urea bond;
R
3
is H, C
1
-C
3
alkyl,
R
4
-R
7
are independently selected from H, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, haloC
1
-C
6
alkyl, C
1
-C
6
alkanoyl, haloC
1
-C
6
alkanoyl, C
1
-C
6
alkoxy, haloC
1
-C
6
alkoxy, C
1
-C
6
alkyloxy-C
1
-C
6
alkyl, haloC
1
-C
6
alkyloxy-C
1
-C
6
alkyl hydroxy-C
1
-C
6
alkyl, amino-C
1
-C
6
alkyl, carboxy-C
1
-C
6
alkyl, cyano-C
1
-C
6
alkyl, amino, carboxy, carbamoyl, cyano, halo, hydroxy, keto and the like;
X is —(CH
2
)
n
—D—(CH
2
)
m
D is —NR
8
—, —O—, —S—, —S(═O)— or —S(═O)
2
—
R
8
is H, C
1
-C
3
alkyl
n and m are independently 0 or 1;
and pharmaceutically acceptable salts and prodrugs thereof.
The currently preferred value for R
1
is 0, that is a urea derivative, although R
1
as S (ie a thiourea derivative) is also highly potent.
Representative values for R
2
include thiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, indolyl, triazolyl, tetrazolyl, piperidyl, piperazinyl and fused rings such as benzothiazolyl, benzopyridyl, benzodiazolyl, benzimidazolyl, quinolyl, purinyl and the like, any of which can be optionally substituted.
Preferred R
2
values include pyrid-2-yl and thiazol-2-yl.
The optional substituents to R
2
can include up to three substituents such as C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
2
-C
6
alkenyl, C
2
-C
8
alkynyl, C
2
-C
8
alkenoxy, C
1
-C
6
alkoxy C
1
-C
6
alkyl, C
1
-C
6
alkanoyl, haloC
1
-C
6
alkyl, C
1
-C
4
alkanoyloxy, C
1
-C
4
alkylthio, amino (including C
1
-C
3
alkyl-substituted amino), carboxy, carbamoyl, cyano, halo, hydroxy, aminomethyl, carboxymethyl, hydroxymethyl, nitro, aryl, (such as phenyl, pyrrol-1-yl, tetrazol-5-yl, triazol-4-yl, pyridyl, pyrimidyl, pyrazinyl, imidazolyl, indolyl, piperidyl, piperazinyl, and the like) substituted (as herein defined) aryl, or —SO
2
Q or —C(═O)Q, where Q is C
1
-C
6
alkyl, halosubstituted C
1
-C
6
alkyl, aryl (as herein defined), substituted (as herein defined) aryl or amino. Heteroatoms in R
2
can be derivatised, such as with C
1
-C
6
alkyl, oxo and the like. The optional R
2
substituent may be ortho or meta to the bond to the (thio)urea function but is preferably para.
Preferred optional substituents to R
2
include ethynyl, phenoxy, pyrrid-1-yl, cyclopropyl, phenyl, halo-substituted phenyl (especially para and meta chloro and fluorophenyl), and dimethylamino. Particularly preferred R
2
substituents include halo (F, Br, Cl and I) and cyano. Preferred halo groups include Cl.
The currently preferred value for R
3
is H.
Preferably R
4
is hydrogen, halo or hydroxy, especially fluoro.
Preferably R
5
is halo, C
1-3
alkylcarbonyl, C
1-3
alkyloxy or H, especially fluoro and most preferably H.
Preferably R
6
is hydrogen, halo, C
1
-C
3
alkyloxy, C
1-3
alkylcarbonyl, cyano or ethynyl, especially methoxy or fluoro and most preferably H.
Preferably R
7
is hydrogen, halo, C
1-3
alkyloxy, or C
1-3
alkylcarbonyl, most preferably fluoro.
Preferably R
5
and R
6
are H and R
4
and R
7
are halo, most preferably both are fluoro. Preferably D is —O—, n is 0, m is 1, R
1
is O, R
2
is substituted pyrid-2-yl and R
3
is H. An alternative preferred embodiment embraces compounds wherein D is —O—, n is 0, m is 1, R
1
is S, R
2
is substituted pyrid-2-yl and R
3
is H.
The compounds of formula I may be administered as a racemic mixture, but preferably the cyclopropyl moiety intermediate the (thio)urea function, X and the phenyl ring (denoted Y below) is at least 75% such as around 90% enantiomerically pure with respect to the conformation:
Prefered optical isomers of the compounds of formula I show a negative optical rotation value. Such isomers, for example when X is —O—CH
2
—, tend to elute less rapidly from a chiral chromatagram, for example chiral AGP 150×10 mm, 5 &mgr;m; Crom Tech LTD Colomn, flow rate 4 ml/min, mobile phase 89 vol % 10 mM HOAc/NH
40
Ac in acetonitrile. On the basis of preliminary x-ray crystallography analysis a presently favoured absolute configuration appears to be:
The currently preferred value for D is —O—. Convenient values for n and m include 1:0 and 1:1. Preferred values of n:m include 0:2 and especially 0:1, that is a chroman derivative. Particularly preferred compounds have stereochemistry corresponding to (1S. 1aR,7bR)-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl. For the sake of clarity, it is noted that the structure:
The expression C
1
-C
n
alkyl, where n is 3, 6, 7 etc or lower alkyl includes such groups as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, 3-methyl pentyl and the like. The term halo refers to chloro, bromo, fluoro and iodo, especially fluoro. C
1
-C
n
alkoxy refers to groups such as methoxy, ethoxy, propoxy, t-butoxy and the like. C
2
-C
n
alkenyl, refers to groups such as vinyl, 1-propen-2-yl, 1-buten-4-yl, 1-penten-5-yl, 1-buten-1-yl and the like. C
1
-C
n
alkylthio includes methylthio, ethylthio, t-butylthio and the like. C
1
-C
n
alkanoyloxy includes acetoxy, propionoxy, formyloxy, butyryloxy and the like. C
2
-C
n
alkenoxy includes ethenyloxy, propenyloxy, iso-butoxyethenyl and the like. HaloC
1
-C
n
alkyl (including complex substituents comprising this moiety such as haloC
1
-C
n
alkyloxy) includes alkyls as defined herein substituted 1 to 3 times by a halogen including trifluormethyl, 2-dic

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