Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1999-05-27
2000-01-04
Ramsuer, Robert W.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D23156
Patent
active
060111593
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to the preparation of substituted indazole derivatives and to intermediates that may be used in said preparation. The substituted indazole derivatives that may be prepared in accord with the present invention are disclosed in U.S. provisional patent application Ser. No. 60/016,861 (filed May 3, 1996), entitled "Substituted Indazole Derivatives And Related Compounds." The foregoing U.S. provisional patent application is incorporated herein by reference in its entirety.
The substituted indazole derivatives that may be prepared in accord with the present invention are selective inhibitors of phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF), as disclosed in U.S. provisional patent application Ser. No. 60/016,861, referred to above. As such, the substituted indazole derivatives that may be prepared in accord with the present invention are useful in the treatment of asthma, joint inflammation, rheumatoid arthritis, gouty arthritis, rheumatoid spondylitis, osteoarthritis and other arthritic conditions, as well as other conditions or diseases involving PDE type IV or the production of TNF.
SUMMARY OF THE INVENTION
The present invention relates to a process for preparing a compound of the formula ##STR2## or a pharmaceutically acceptable salt of said compound, wherein: R is C.sub.1 -C.sub.10 alkyl or --(CH.sub.2).sub.n (phenyl) wherein n is an integer ranging from 0 to 2, and wherein said R groups are optionally substituted by 1 to 3 substituents independently selected from chloro, fluoro, C.sub.1 -C.sub.6 alkoxy and trifluoromethyl; wherein said R.sup.1 groups are optionally substituted by 1 to 3 substituents independently selected from trifluoromethyl, chloro and fluoro; --C(Y)NR.sup.5 OR.sup.4, or --CN; --OR.sup.4, --CN, --C(Y)R.sup.4, --C(O)OR.sup.4, --C(Y)NR.sup.4 R.sup.5, --C(Y)NR.sup.4 OR.sup.5, --NR.sup.4 OR.sup.5 or --NR.sup.4 R.sup.5 ; ##STR3## or a salt of said compound, wherein R, R.sup.1, R.sup.2 and R.sup.3 are as defined above, with a Lewis acid, such as tin tetrachloride, aluminum trichloride, zinc chloride, or boron trichloride, preferably tin tetrachloride, and tri-(C.sub.6 -C.sub.10 aryl)silyl cyanide, such as triphenylsilyl cyanide, or tri-(C.sub.1 -C.sub.6 alkyl)silyl cyanide, preferably trimethylsilyl cyanide.
In the above process of preparing a compound of the formula 1, or a pharmaceutically acceptable salt of said compound, the cyano moiety and R.sup.3 in formula I are preferably cis to each other as shown below: ##STR4## R is preferably cyclohexyl, cyclopentyl, cyclobutyl, methylene cyclopropyl or isopropyl, R.sup.1 is preferably C.sub.1 -C.sub.2 alkyl optionally substituted by 1 to 3 fluoro substituents, R.sup.2 is preferably H, and R.sup.3 is preferably --C(O)O(C.sub.1 -C.sub.2 alkyl), --CH.sub.2 OH, or --C(O)NH.sub.2.
In a further aspect of the present invention, the above compound of the formula II, or a salt of said compound, is prepared by treating a compound of the formula ##STR5## or a salt of said compound, wherein R and R.sup.1 are as defined for the above compound of formula I and X.sup.1 is iodo, chloro, or bromo, preferably bromo, with an organolithium, cerium or magnesium reagent, such as C.sub.1 -C.sub.10 alkyl lithium, magnesium metal or cerium(III) chloride in combination with an organomagnesium or organolithium reagent, preferably an organolithium reagent such as n-butyllithium, to provide an organometallic intermediate and then treating said organometallic intermediate with a compound of the formula ##STR6## wherein R.sup.2 and R.sup.3 are as defined for the above compound of formula I.
In the above process of preparing the compound of formula II, or a salt of said compound, preferred R, R.sup.1, R.sup.2 and R.sup.3 substituents are as indicated above for the process of preparing a compound of formula I.
In a further aspect of the present invention, the above compound of formula III, or a salt of said compound, is prepared by heating a compound of the formula ##STR7## or a salt of sai
Caron Stephane
Eisenbeis Shane A.
Ginsburg Paul H.
Pfizer Inc
Ramsuer Robert W.
Richardson Peter C.
Speer Raymond M.
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