Antiviral protease inhibitors

Details Antiviral protease inhibitors Antiviral protease inhibitors

1999-12-14

2001-09-18

Dentz, Bernard (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S284100

Reexamination Certificate

active

06291687

ABSTRACT:

TECHNICAL FIELD
This invention relates to novel protease inhibitors and in particular to inhibitors of the aspartate protease possessed by certain retroviruses, notably HIV. The invention further relates to the use of such protease inhibitors in the treatment of conditions caused by retroviruses and in the preparation of medicaments for this purpose. The invention also relates to novel synthesis methodology for the facile preparation of protease inhibitors and similar chemical structures.
BACKGROUND OF THE INVENTION
Many biological processes are dependent upon the accurate enzymatic abscission of polypeptides at particular amino acid sequences. An example of such an operation is the post-translational processing of the gag and gag-pol gene products of the human immunodeficiency virus HIV to allow for the organisation of core structural proteins and release of viral enzymes. The enzyme responsible for this task, HIV protease, is a virally encoded homodimeric protease belonging to the aspartic protease family of enzymes. The human renin and pepsin enzymes also belong to this family. Inhibition of the HIV protease in cell culture prevents viral maturation and replication and thus this enzyme represents an attractive target for antiviral therapy against HIV in humans.
There are several references in the patent literature describing inhibitors of HIV protease, typically peptidomimetics having a large number of chiral centres. For example, Abbott Laboratories have extensively investigated linear peptidomimetics as described in a series of patent publication commencing with EP 402 654 and culminating in Abbott's application no. WO 94 14436 describing optimized linear peptidomimetics and in particular the compound Ritonavir:
Norvir as this compound is now known, is registered by the FDA and although it has good clinical efficacy, its synthesis is arduous. The synthesis difficulties which have characterized prior art protease inhibitors can be understood by referring to Roche's protease inhibitor saquinavir (Inverase):
According to literature reports, this compound requires a synthesis route of some 20 steps resulting in an overall yield reputed to be around 2%. This difficult synthetic availability will put pressure on treatment cost and production capacity.
Merck's U.S. Pat. No. 5 413 999 describes indanyl pentamine compounds, including its currently marketed product indinavir:
Merck's EP 480 714 discloses a symmetric protease inhibitor having terminal indanolamine groups spaced by a 7 carbon backbone:
These compounds are prepared by complex methodology starting from an alkenediol.
Banyu's Japanese patent application no 7242613 A also describe symmetric protease inhibitors having indanolamne terminal groups spaced by a 7-carbon backbone:
where R is H or lower alkyl. These compounds are prepared by BuLi-alkylation of N,O-isopropylidine-N-[2(R)-hydroxy-(1S)-indanyl]-3-phenylpropanamide with 2-chloro-2-chloromethyl-propene, followed by ozonation, reduction and deprotection.
Vertex' international patent application no WO 94/13629 explores the use of a mannitol carbohydrate precursor to prepare compounds of the formula:
It will be apparent that with these inhibitors, the benzoyl moieties esterified to the C-1 and C-6 hydroxy groups of the mannitol precursor are intended to fill the P1 and P1′ pockets of the HIV protease active site. Amino acid functions, such as valyl, are amide bonded to the C-2 and C-5 hydroxy groups and are intended to fill the P-2 and P-2′ pockets of the enzyme. These compounds are prepared by bridging the 3-and 4-hydroxy groups with isopropylidine, epoxidising and ring opening the terminal hydroxy groups with a nucleophile such as aryl alcohol followed by amidation of the resulting free hydroxy groups with a respective amino acid. Alternatively the isopropylidine-protected mannitol is first amidated on the more active C-1 and C-6 (terminal) hydroxy groups with the amino acid P-2 filling groups and then esterified with the benzoyl moities on the C-2 and C-5 hydroxy groups.
One of Abbott Laboratories' early patent publications in the protease field, EP 402 646, describes a great number of potential approaches to the construction of protease inhibitors.
One of these approaches also employs a carbohydrate precursor which becomes the central backbone of a symmetric protease inhibitor. Examples 305 and 307 of EP 402 646 describe the ring-opening of a mannosaccharodilactone and the addition of terminal valine esters to form a 3,4-O-isopropylidine-bridged adipamide derivative. The aryl groups which are to fit into the P1 and P1′ pockets of the protease are added subsequently via triflate activation at the C-2 and C-5 positions of the carbohydrate backbone and these are later converted to phenylthio groups before the isopropylidine bridge is removed.
The drawbacks with this process are the inevitable inversion of the configurations of C-3 and C-4 and that while reagents such as thiophenyl can be used to displace the triflate leaving group in the manner shown in EP 402 646, this can only produce thioether derivatives for the P1 and P1′ filling groups. At a superficial level it could be thought that the triflate leaving group could be displaced with conventional alkylating reagents such as alkoxide to give an O-alkylated P1/P1′ filling group. However we have discovered in this prior art process that the use of alkoxide tends to eliminate the triflates producing an olefin, instead of the desired O-alkylated substituent.
Magnus Björsne et al in “Synthesis of Potential Candidates for Therapeutic Intervention against the Human Immunodeficiency Virus”, Stockholm University, 1995 describes the compound
the corresponding benzyl ester and the phenylalanine analog. These compounds are prepared from an L-mannaric acid precursor via the steps of
i) bridging the C-3 and C-4 hydroxyls of the hexitol with isopropylidine,
ii) protecting the C-1 and C-6 primary hydroxyls,
iii) O-alkylating the C-2 and C-5 hydroxyls to the aralkyl ethers,
iv) oxidating the C-1 and C-6 primary hydroxyls to carboxylic acids; and
v) condensing the resulting compound with the appropriate amino acid (ester) terminal groups This methodology may be graphically represented as follows:
The appropriate valine or phenylalanine (ester) end unit is then condensed onto the terminal carboxyls in dichloromethane-ThF using HOBt-EDC coupling conditions. Despite the need for protection, oxidation and deprotection steps, the Bjorsne synthesis methodology is an improvement over the very large number of steps in conventional peptidomimetic synthesis (see the discussion of saquinavir above). The Björsne process also avoids the triflate activation, the preferential reactivity of the “wrong” C-3 and C-4 atoms and other drawbacks of the Abbott EP 402 646 process. However the compounds proposed by Björsne have inadequate antiviral properties. The best Björsne compound, where the terminal amines are valine methyl esters (depicted above), has an IC
50
of 5 &mgr;M which should be compared to currently marketed protease inhibitors which have IC
50
values one or more orders of magnitude lower.
We have now discovered a novel group of compounds with antiviral properties in the nanomolar IC
50
range and which lend themselves to a novel carbohydrate based synthesis technique which is even more convenient than those of the prior art discussed above. Accordingly, a first aspect of the invention provides novel compounds of the formula I:
wherein:
A′ and A″ are independently a group of the formula II:
wherein:
R′ is H, CH
3
, C(CH
3
)
2
, —OR
a
, —N(R
a
)
2
, —N(R
a
)OR
a
or —DP
R′″ is H, CH
3
; R
a
is H C
1
-C
3
alky;
D is a bond, C
1-3
alkylene, —C(═O)—, —S(O)— or —S(O)
2
—;
P is an optionally substituted, mono or bicyclic carbo- or heterocycle;
R″ is H, any of the sidechains found in the natural amino acids, carboxacetamide, or a group (CH
2
)
n
DP;
M is a bond or —C(═O)N(R′″)—;
Q is absent a bond,

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