Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
2003-06-19
2004-07-06
Kifle, Bruck (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
active
06759533
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The invention relates to a novel process and novel intermediates for the synthesis of certain non-nucleoside reverse transcriptase inhibitors.
BACKGROUND OF THE INVENTION
The disease known as acquired immune deficiency syndrome (AIDS) is caused by the human immunodeficiency virus (HIV), particularly the strain known as HIV-1. In order for HIV to be replicated by a host cell, the information of the viral genome must be integrated into the host cell's DNA. However, HIV is a retrovirus, meaning that its genetic information is in the form of RNA. The HIV replication cycle, therefore, requires a step of transcription of the viral genome (RNA) into DNA. The transcription of the viral RNA into DNA is accomplished by an enzyme that has been aptly dubbed reverse transcriptase (RT). The HIV virion includes a copy of RT along with the viral RNA.
Reverse transcriptase has three known enzymatic functions. It acts as an RNA-dependent DNA polymerase, as a ribonuclease, and as a DNA-dependent DNA polymerase. Acting as an RNA-dependent DNA polymerase, RT transcribes a single-stranded DNA copy of the viral RNA. Acting as a ribonuclease, RT destroys the original viral RNA, and frees the DNA just produced from the original RNA. Finally, acting as a DNA-dependent DNA polymerase, RT makes a second, complementary DNA strand, using the first DNA strand as a template. The two strands form double-stranded DNA, which is integrated into the host cell's genome by another enzyme called integrase.
Compounds that inhibit the enzymatic functions of HIV-1 reverse transcriptase will inhibit replication of HIV-1 in infected cells. Such compounds are useful in the prevention or treatment of HIV-1 infection in human subjects, as demonstrated by known RT inhibitors such as 3′-aziod-3′-deoxythymidine (AZT), 2′,3′-dideoxyinosine (ddI), 2′,3′-dideoxycytidine (ddC), d4T, 3TC, nevirapine, delavirdine, efavirenz and abacavir, the RT inhibitors thus far approved as drugs for use in the treatment of HIV infection.
As with any antiviral therapy, use of RT inhibitors in the treatment of HIV infection eventually leads to a virus that is less sensitive to the given drug. Resistance (reduced sensitivity) to these drugs is the result of mutations that occur in the reverse transcriptase segment of the pol gene. Several mutant strains of HIV have been characterised, and resistance to known therapeutic agents is due to mutations in the RT gene. Some of the most commonly observed mutant clinically are: the Y181C mutant, in which a tyrosine Y, at codon 181, has been mutated to a cysteine C residue, and K103N where the lysine K at position 103 has been replaced by asparagine N. Other mutants which emerge with increasing frequency during treatment with known antivirals include the single mutants V106A, G190A, Y188C, and P236L: and the double mutants K103N/Y181C, K013N/P225H, K103N/V108I and K103N/L100I.
As therapy of HIV infection using antivirals continues, the emergence of new resistant strains is expected to increase. There is therefore an ongoing need for new inhibitors of RT, with different patterns of effectiveness against the various mutants.
Of particular relevance to the present invention are the HIV-RT inhibitors disclosed by U.S. Pat. No. 6,420,359. These compounds, which are all dipyrido[3,2-b:2′,3′-e] [1,4]diazepin-6-ones bearing a 2-(quinolinyl)oxyethyl or a 2-(1-oxido-quinolinyl)oxyethyl group in the 8-position, have enhanced activity against certain clinically significant mutant strains of HIV-1. It is the object of the present invention to provide an alternative method for making the compounds disclosed by U.S. Pat. No. 6,420,359.
SUMMARY OF THE INVENTION
The invention provides an improved process for making compounds of the general formula I:
wherein:
R
2
is selected from the group consisting of H, F, Cl, C
1-4
alkyl, C
3-4
cycloalkyl and CF
3
;
R
4
is H or Me;
R
5
is H, Me or Et, with the proviso that R
4
and R
5
are not both Me, and if R
4
is Me then R
5
cannot be Et;
R
11
is Me, Et, cyclopropyl, propyl, isopropyl, or cyclobutyl; and
Q is selected from the group consisting of:
as well as pharmaceutically acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
The synthetic method of the invention commences from a starting compound of the formula II
wherein R
2
, R
4
, R
5
and R
11
are as defined above with respect to compounds of the formula I and wherein X is a chlorine, iodine, or bromine, or a fluorosulfonate moiety selected from the group consisting of —OSO
2
F and —OSO
2
(CF
2
)
n
CF
3
wherein n is an integer between 0 and 10. Processes for making starting compounds of the formula II wherein X is bromine are described in U.S. Pat. No. 6,420,359. Compounds wherein X is other than bromine can be made by analogous methods which will be readily apparent to those of ordinary skill in the art.
It is preferred to use a compound of the formula II wherein X is bromine.
The starting compound of the formula II initially undergoes a palladium-catalyzed coupling reaction wherein it is caused to arylate a malonate or malonate surrogate of the formula III
wherein,
R
12
is a cyano group or a group of the formula —COOR
14
, wherein R
14
is a C-
1-4
-alkyl group, a C-
1-4
-alkyloxy-C-
1-4
-alkyl group group phenyl, naphthyl, thiophenyl, furyl, pyridyl, imidazole or benzyl, and
R
13
is a cyano group, a group of the formula —COOR
15
(wherein R
15
is a C-
1-4
-alkyl group, a C-
1-4
-alkyloxy-C-
1-4
-alkyl group group phenyl, naphthyl, thiophenyl, furyl, pyridyl, imidazole or benzyl), a group of the formula —SO
2
R
16
(wherein R
16
is a C-
1-4
-alkyl group, phenyl, furyl, pyridyl or benzyl), a group of the formula —P(O)(OR
17
)
2
(wherein R
17
is phenyl, furyl or pyridyl) or a group of the formula —SOR
18
(wherein R
18
is a C-
1-4
-alkyl group, a C-
1-4
-alkyloxy-C-
1-4
-alkyl group group phenyl, naphthyl, thiophenyl, furyl, pyridyl, imidazole or benzyl).
It is preferred to employ a malonate surrogate of the formula III
wherein,
R
12
is a cyano group or a group of the formula —COOR
14
, wherein R
14
is a C-
1-4
-alkyl group, a C-
1-4
-alkyloxy-C-
1-4
-alkyl group group phenyl, naphthyl, thiophenyl, furyl, pyridyl, imidazole or benzyl; and
R
13
is a cyano group, a group of the formula —SO
2
R
16
(wherein R
16
is a C-
1-4
-alkyl group, phenyl, furyl, pyridyl or benzyl), a group of the formula —P(O)(OR
17
)
2
(wherein R
17
is phenyl, furyl or pyridyl) or a group of the formula —SOR
18
(wherein R
18
is a C-
1-4
-alkyl group, a C-
1-4
-alkyloxy-C-
1-4
-alkyl group group phenyl, naphthyl, thiophenyl, furyl, pyridyl, imidazole or benzyl).
The reaction of the compounds of the formulas II and III takes place in an organic solvent, in the presence of a palladium catalyst, a suitable ligand and strong base. Suitable solvents are, by way of non-limiting example, toluene, ethylbenzene, xylene, DMF, DMA, NMP, dioxane and THF, with toluene being preferred. Virtually any palladium catalyst may be used, such as, for example, Pd(OAc)
2
, PdCl
2
, Pd
2
dba
3
and Pd on carbon, with Pd(OAc)
2
being preferred. Suitable bases are, for example, the metal hydrides such as, for example, NaH, the metal alkoxides such as, for example, t-BuOK, t-BuONa and Na-tert-amylate, the metal carbonates such as, for example, Na
2
CO
3
, K
2
CO
3
and CS
2
CO
3
, with NaH being preferred, and the metal phosphates such as, for example, K
3
PO
4
. When the reactant of the formula III is a malonate (compounds wherein R
12
and R
13
are both carboxylic acid ester groups) then suitable ligands will be t-Bu
3
P, one of the ligands described and claimed in U.S. Pat. No. 6,307,087, or a ferrocenyl phosphine such as described in U.S. Pat. Nos. 6,057,456 and 6,072,073. When the reactant of the formula III is not a malonate, but rather a malonate surrogate (a compound wherein R
12
and R
13
are not both carboxylic acid ester groups) the above-mentioned ligands may be employed and, in addition, a triarylphosphine such as, by
Busacca Carl A.
Eriksson Magnus C.
Kim Ji-Young
Boehringer Ingelheim Pharmaceuticals Inc.
Devlin Mary-Ellen M.
Kifle Bruck
Raymond Robert P.
Stempel Alan R.
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