Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2000-05-09
2001-12-04
Geist, Gary (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
Reexamination Certificate
active
06326509
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to an improved process for preparing a key intermediate useful in the synthesis of triazole antifungal compounds and other pharmaceutical compounds. In particular, the present invention provides an improved process for preparing a halomethyl benzoic acid chloromethyl ester which can be used, for example, to prepare triazole antifungal agents such as those described by our colleagues in co-pending U.S. Pat. No. 60/103,560 filed Oct. 7, 1998 and U.S. Pat. No. 6,265,584 issued Jul. 24, 2001, all of which applications being hereby incorporated by reference.
The intermediate, halomethyl benzoic acid chloromethyl ester, having the general formula
wherein X is Cl, Br or I and the halomethyl substituent is in the ortho, meta or para position of the phenyl ring is reported in the above-identified applications as being made by reacting the acid chloride of the formula
wherein X is as defined above with paraformaldehyde and zinc chloride in benzene. This method is also described by Iyer et. al. in Syn. Comm., 25, 2739, 1995. It suffers from several disadvantages, e.g. it is necessary to use benzene as the solvent and it requires a chromatography step.
The present inventors have discovered that the same acid chloride of the formula
wherein X is Cl, Br or I and the halomethyl substituent is in the ortho, meta or para position of the phenyl ring can be reacted with SnCl
4
and 1,3,5-trioxane in an inert organic solvent such as methylene chloride to give key intermediate I in improved yields without many of the disadvantages of the above-mentioned process. For example, it is no longer necessary to use benzene as the solvent and the chromatography step is eliminated.
Intermediate I may be used to produce a number of biologically active products as illustrated below by its conversion to triazole antifungal agents.
SUMMARY OF THE INVENTION
The present invention provides a process for preparing the intermediate of the formula
wherein X is Cl, Br or I and the halomethyl substituent is in the ortho, meta or para position of the phenyl ring, which comprises reacting an acid chloride of the formula
wherein X is as defined above and the halomethyl substituent is in the ortho, meta or para position of the phenyl ring with SnCl
4
and 1,3,5-trioxane in an inert organic solvent.
Intermediate I can be employed in the production of pharmaceutical compounds such as azole antifungal agents of the general formula
wherein A is the non-hydroxy portion of a triazole antifungal compound of the type containing a secondary or tertiary hydroxy group and R
1
and R
2
are hydrogen, C
1
-C
6
alkyl or C
2
-C
6
alkyl, said alkyl or alkenyl group being optionally substituted by a hydroxy or dimethylamino group, or R
1
and R
2
taken together with the nitrogen to which they are attached form a heterocyclic group of the formula
where R
7
is hydrogen, CHO, COR
13
or C
1
-C
6
alkyl in which the alkyl group may be optionally interrupted by an oxygen atom or NR
14
and may be substituted by hydroxy, R
8
, R
9
, R
10
, R
11
and R
12
are each independently hydrogen, hydroxy, CONH
2
, or C
1
-C
6
alkyl, said alkyl group being optionally substituted by hydroxy, R
13
is C
1
-C
6
alkyl and R
14
is hydrogen or C
1
-C
6
alkyl; or a pharmaceutically acceptable salt thereof.
A preferred triazole antifungal parent compound for use in preparing the above-mentioned prodrugs is (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol described in U.S. Pat. No. 5,648,372 and having the formula
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The process of the present invention comprises reacting halomethylbenzoyl chloride with SnCl
4
and 1,3,5-trioxane in an inert organic solvent such as methylene chloride. The reaction may be carried out at room temperature and the co-produced dimeric impurity, methanediol bis halomethylbenzoate, may be removed by slurrification in heptane containing ethyl acetate. Upon distillative removal of ethyl acetate, the desired intermediate product may be directly crystallized from heptane.
Example 1 below describes in more detail a preferred embodiment for carrying out the present invention.
Example 2 below describes use of intermediate I to produce a biologically active azole antifungal agent.
The end-products such as (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[m-(N,N-dimethylaminomethyl)-benzoyloxy]methoxy]butane prepared in Example 2 below act as prodrugs of the parent azole antifungal agents when administered in vivo to mammals.
The pharmaceutically active compounds prepared using the intermediate of the present invention, such as Example 2 below, may be used alone or formulated as pharmaceutical compositions comprising, in addition to the active triazole ingredient, a pharmaceutically acceptable carrier, adjuvant or diluent. The compounds may be administered by a variety of means, for example, orally, topically or parenterally (intravenous or intramuscular injection). The pharmaceutical compositions may be in solid form such as capsules, tablets, powders, etc. or in liquid form such as solutions, suspensions or emulsions. Compositions for injection may be prepared in unit dose form in ampules or in multidose containers and may contain additives such as suspending, stabilizing and dispersing agents. The compositions may be in ready-to-use form or in powder form for reconstitution at the time of delivery with a suitable vehicle such as sterile water.
Alternatively, the bioactive azole compounds prepared using the intermediate of the present invention can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, or cream. Additionally, they may be incorporated (at a concentration up to 10%) into an ointment consisting of a white wax or soft, white paraffin base together with the required stabilizers and/or preservatives.
The bioactive azole end-products are useful because they possess pharmacological activities in animals, including particularly mammals and most particularly, humans. Specifically, the azole end-products are useful for the treatment or prevention of topical fungal infections, including those caused by species of Candida, Trichophyton, Microsporum, or Epidermophyton. Additionally, they are useful for the treatment of mucosal infections caused by
Candida albicans
. They can also be used in the treatment of systemic fungal infections caused, for example, by species of
Candida albicans, Cryptococcus neoformans, Aspergillus flavus, Aspergillus fumigatus
, Coccidioides, Paracoccidiodes, Histoplasma, or Blastomyces.
The dosage to be administered for the bioactive azole end-products depends, to a large extent, on the particular compound being used, the particular composition formulated, the route of administration, the nature and condition of the host and the particular situs and organism being treated. Selection of the particular preferred dosage and route of application, then, is left to the discretion of the physician or veterinarian. In general, however, the compounds may be administered parenterally or orally to mammalian hosts in an amount of from about 5 mg/day to about 1.0 g/day. These doses are exemplary of the average case, and there can be individual instances where higher or lower dosages are merited. Furthermore, administration of the compounds can be conducted in either single or divided doses.
The in vitro evaluation of the antifungal activities of the bioactive azole compounds can be performed by determining the minimum inhibitory concentration (MIC). The MIC is the concentration of test compound which inhibits the growth of the test microorganism. In practice, a series of agar plates, each having the test compound incorporated at a specific concentration, is inoculated with a fungal strain and each plate is then incubated for 48 h at 37° C. The plates are examined for the presence or absence of fungal growth, and the re
Bhattacharya Apurba
Chau Melissa
Wang Xuebao
Yang Wangying
Bristol--Myers Squibb Company
Geist Gary
Moon M. P.
Morse David M.
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