Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-10-11
2004-11-16
Aulakh, Charanjit S. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S186000
Reexamination Certificate
active
06818773
ABSTRACT:
BACKGROUND OF THE INVENTION
4-[(Z)-(4-bromophenyl)(ethoxyimino)methyl]-1′-[(2,4-dimethyl-1-oxido-3-pyridinyl)carbonyl]-4′-methyl-1,4′-bipiperidine (formula I) is disclosed in U.S. patent application, Ser. No. 09/562,815 filed May 1, 2000, which is incorporated herein by reference.
The compound of formula I is the base form of the compound of formula X which is an acid salt:
The compound of formula X is an antagonist of the CCR5 receptor and is useful for the treatment of AIDS and related HIV infections. CCR-5 receptors have also been reported to mediate cell transfer in inflammatory diseases such as arthritis, rheumatoid arthritis, atopic dermatitis, psoriasis, asthma and allergies, and inhibitors of such receptors are expected to be useful in the treatment of such diseases, and in the treatment of other inflammatory diseases or conditions such as inflammatory bowel disease, multiple sclerosis, solid organ transplant rejection and graft v. host disease. Patent application, Ser. No. 09/562,815 also teaches a method of making the compounds of formula I, and from I the compound of formula X.
In view of the importance of antagonists of the CCR5 receptor, new, novel methods of making such antagonists are always of interest.
SUMMARY OF THE INVENTION
In an embodiment, the present application teaches a novel, simple process of making a compound of formula I and, via that process, a method of making a compound of formula X if so desired. The compound of formula I is prepared from a compound of formula II:
The process of making I from II comprises:
(a) converting the oxime of formula II to a compound of formula III:
where G is a suitable leaving group selected from the group consisting of CN, Y, benzotriazolyl, OSO
2
R
1
and OCOCY
3
with R
1
being an alkyl or aryl group and Y is a halogen (especially F or Cl); and Q is a suitable N-protecting group defined later;
(b) reacting said compound of formula III with a suitable Grignard reagent in a suitable solvent, followed by work-up, to yield a compound of formula IV:
(c) deprotecting said compound of formula IV to a compound of formula V:
(d) forming the salt of the compound of formula V to form the compound of formula VI:
and
(e) reacting said compound of formula VI with a compound of formula VII:
to yield the compound of formula I (when R
1
is methyl).
The compound of formula VII is separately prepared from a compound of formula VIII:
by a process comprising first oxidizing the compound of formula VIII to a compound of formula IX:
followed by converting the compound of formula IX to the compound of formula VII.
The inventive process to make the compound of formula I has several advantages: it is economical, can be easily scaled-up and has flexibility with respect to varying the amide moiety on the right hand side. Thus, since the amide moiety is formed during the last steps of the process, by varying the reagent carboxylic acid VII, differently structured amides may be produced with relative ease.
REFERENCES:
patent: 6387930 (2002-05-01), Baroudy et al.
patent: WO 00/66559 (2000-11-01), None
Palani, A. et al.: “Discovery of 4-[(Z)-(4-Bromophenyl)-(ethoxyimino)methyl]-1′-[(2,4-dimethyl-3-pyridinyl)carbonyl]-4′-methyl-1,4′-bipiperidineN-Oxide (SCH 351125): An Orally Bioavailable Human CCR5 Antagonist for the Treatment of HIV Infection”,J. Med. Chem. 44(21), 3339-3342 (2001).
Chen Minzhang
D'Sa Bosco Anthony
Gan Tong
Leong William W.
Nielsen Christopher Michael
Aulakh Charanjit S.
Kalyanaraman Palaiyur S.
Schering Corporation
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