Efficient synthesis of 5-heteroatom-containing -pyrazoles

Details Efficient synthesis of 5-heteroatom-containing -pyrazoles Efficient synthesis of 5-heteroatom-containing -pyrazoles

2002-11-01

2004-09-21

Lambkin, Deborah C. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C544S182000, C544S238000, C544S405000, C548S370100

Reexamination Certificate

active

06794512

ABSTRACT:

BACKGROUND OF THE INVENTION
The invention relates to the preparation of sulfonyl pyrazoles useful as anti-inflammatory/analgesic agents. It has now been found that the use of a metal fluoride salt allows processes of preparing sulfonyl pyrazoles containing versatile amino, ether, or thio ether component on the 5-position of the pyrazole ring to be performed at lower temperature, such as room temperature, with consistent higher yields.
The sulfonyl pyrazoles prepared by the methods of the present invention are useful in the treatment of cyclooxygenase (COX) mediated diseases, such as arthritis, neurodegeneration and colon cancer, in mammals, preferably humans, dogs, cats or livestock. Two forms of COX are now known, a constitutive isoform (COX-1) and an inducible isoform (COX-2) of which expression is upregulated at sites of inflammation (Vane, J. R.; Mitchell, et. al.,
Proc. Natl. Acad. Sci. USA
, 1994, 91, 2046). COX-1 appears to play a physiological role and to be responsible for gastrointestinal and renal protection. On the other hand, COX-2 appears to play a pathological role and is believed to be the predominant isoform present in inflammation conditions. Preferred compounds prepared by the methods of the present invention are selective COX-2 inhibitors. Therapeutic use of conventional COX inhibitors is limited due to drug associated side effects, including life threatening ulceration and renal toxicity. Compounds that selectively inhibit COX-2 would exert anti-inflammatory effects without the adverse side effects associated with COX-1 inhibition.
A variety of sulfonylpyrazoles that inhibit COX have been prepared by other methods described in patent publications WO 97/11704, WO 01/40216, EP 1104758, EP 1104759, and EP 1104760; and U.S. Non-Provisional patent application Ser. No. 09/798,752, filed Mar. 2, 2001, and U.S. Non-Provisional patent application Ser. No. 09/824,550, filed Apr. 2, 2001. None of these methods use a fluoride containing salt.
Filed simultaneously with the present application on Nov. 2, 2001, are United States Provisional Applications entitled “Hydrazinyl and Nitrogen Oxide Pyrazoles”; “Heterocyclo-Alkylsulfonyl Pyrazoles”; “5-Heteroatom-Substituted Pyrazoles”; “5-Heterocyclo-pyrazoles”; and “5-(Alkylidene-Cycloalkyl)- and 5-(Alkylidene-Heterocyclyl)-Pyrazoles”, which refer to certain pyrazole COX-2 inhibitors that can be prepared by the present processes of the invention. The aforesaid applications are herein incorporated in their entireties by reference.
SUMMARY OF THE INVENTION
The present invention relates to a process for preparing a compound of formula I:
or the pharmaceutically acceptable salts thereof;
wherein the ring of the formula (R
5
)-A-(SO
m
R
4
) is selected from the group consisting of
m is 0, 1 or 2;
X is >CR
5
or >N;
R
1
is a radical selected from the group consisting of H, —NO
2
, —CN, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkyl-SO
2
—, (C
6
-C
10
)aryl-SO
2
—, H—(C═O)—, (C
1
-C
6
)alkyl-(C═O)—, (C
1
-C
6
)alkyl-O—(C═O)—, (C
1
-C
9
)heteroaryl-(C═O)—, (C
1
-C
9
)heterocyclyl-(C═O)—, H
2
N—(C═O)—, (C
1
-C
6
)alkyl-NH—(C═O)—, [(C
1
-C
6
)alkyl]
2
-N—(C═O)—, [(C
6
-C
10
)aryl]-NH—(C═O)—, [(C
1
-C
6
)alkyl]-[((C
6
-C
10
)aryl)-N]—(C═O)—, HO—NH—(C═O)—, and (C
1
-C
6
)alkyl-O—NH—(C═O)—;
R
2
is a radical selected from the group consisting of H, —NO
2
, —CN, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, (C
3
-C
7
)cycloalkyl, (C
6
-C
10
)aryl, (C
1
-C
9
)heteroaryl, (C
1
-C
9
)heterocyclyl, (C
1
-C
6
)alkyl-O—, (C
3
-C
7
)cycloalkyl-O—, (C
6
-C
10
)aryl-O—, (C
1
-C
9
)heteroaryl-O—, (C
1
-C
9
)heterocyclyl-O—, H—(C═O)—, (C
1
-C
6
)alkyl-(C═O)—, (C
3
-C
7
)cycloalkyl-(C═O)—, (C
6
-C
10
)aryl-(C═O)—, (C
1
-C
9
)heteroaryl-(C═O)—, (C
1
-C
9
)heterocyclyl-(C═O)—, (C
1
-C
6
)alkyl-O—(C═O)—, (C
3
-C
7
)cycloalkyl-O—(C═O)—, (C
6
-C
10
)aryl-O—(C═O)—, (C
1
-C
9
)heteroaryl-O—(C═O)—, (C
1
-C
9
)heterocyclyl-O—(C═O)—, (C
1
-C
6
)alkyl-(C═O)—, (C
3
-C
7
)cycloalkyl-(C═O)—O—, (C
6
-C
10
)aryl-(C═O)—O—, (C
1
-C
9
)heteroaryl-(C═O)—O—, (C
1
-C
9
)heterocyclyl-(C═O)—O—, (C
1
-C
6
)alkyl-(C═O)—NH—, (C
3
-C
7
)cycloalkyl-(C═O)—NH—, (C
6
-C
10
)aryl-(C═O)—NH—, (C
1
-C
9
)heteroaryl-(C═O)—NH—, (C
1
-C
9
)heterocyclyl-(C═O)—NH—, (C
1
-C
6
)alkyl-O—(C═O)—NH—, (C
1
-C
6
)alkyl-NH, [(C
1
-C
6
)alkyl]
2
-N—, (C
3
-C
7
)cycloalkyl-NH—, [(C
3
-C
7
)cycloalkyl]
2
-N—, [(C
6
-C
10
)aryl]-NH—, [(C
6
-C
10
)aryl]
2
-N—, [(C
1
-C
6
)alkyl]-[((C
8
-C
10
)aryl)-N]—, [(C
1
-C
9
)heteroaryl]-NH—, [(C
1
-C
9
)heteroaryl]
2
-N—, [(C
1
-C
9
)heterocyclyl]-NH—, [(C
1
-C
9
)heterocyclyl]
2
-N—, H
2
N—(C═O)—, HO—NH—(C═O)—, (C
1
-C
6
)alkyl-O—NH—(C═)—, [(C
1
-C
6
)alkyl]-NH—(C═O)—, [(C
1
-C
6
)alkyl]
2
-N—(C═O)—, [(C
3
-C
7
)cycloalkyl]-NH—(C═O)—, [(C
3
-C
7
)cycloalkyl]
2
-N—(C═O)—, [(C
6
-C
10
)aryl]-NH—(C═O)—, [(C
6
-C
10
)aryl]
2
-N—(C═O)—, [(C
1
-C
6
)alkyl]-[((C
6
-C
10
)aryl)-N]—(C═O)—, [(C
1
-C
9
)heteroaryl]-NH—(C═O)—, [(C
1
-C
9
)heteroaryl]
2
-N—(C═O)—, [(C
1
-C
9
)heterocyclyl]-NH—(C═O)—, (C
1
-C
6
)alkyl-S— and (C
1
-C
6
)alkyl optionally substituted by one —OH group or by one to four fluoro substituents;
R
3
is a radical selected from the group consisting of
R
6
is a radical independently selected from the group consisting of H, (C
1
-C
6
)alkyl, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, H—(C═O)—, (C
1
-C
6
)alkyl-(C═O)—, (C
1
-C
6
)alkyl-O—(C═)—, H
2
N—(C═O)—, [(C
1
-C
6
)alkyl]-NH—(C═O)—, [(C
1
-C
6
)alkyl]
2
-N—(C═O)—, [(C
8
-C
10
)aryl]-NH—(C═O)—, [(C
1
-C
6
)alkyl]-[((C
6
-C
10
)aryl)-N]—(C═O)—, (C
1
-C
6
)alkyl-O—NH—(C═O)—, (C
6
-C
10
)aryl, (C
3
-C
8
)cycloalkyl, (C
1
-C
10
)heteroaryl and (C
1
-C
10
)heterocyclyl;
R
7
is a radical independently selected from the group consisting of (C
1
-C
6
)alkyl, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, H—(C═O)—, (C
1
-C
6
)alkyl-(C═O)—, (C
1
-C
6
)alkyl-O—(C═O)—, H
2
N—(C═O)—, [(C
1
-C
6
)alkyl]-NH—(C═O)—, [(C
1
-C
6
)alkyl]
2
-N—(C═O)—, [(C
6
-C
10
)aryl]-NH—(C═O)—, [(C
1
-C
6
)alkyl]-[((C
6
-C
10
)aryl)-N]—(C═O)—, (C
1
-C
6
)alkyl-O—NH—(C═O)—, (C
6
-C
10
)aryl, (C
3
-C
8
)cycloalkyl, (C
1
-C
10
)heteroaryl and (C
1
-C
10
)heterocyclyl; or
R
6
and R
7
may optionally be taken together with the nitrogen or the oxygen to which they are attached to form a 3- to 8-membered heterocyclic ring radical; wherein said 3- to 8-membered heterocyclic ring radical may optionally contain at least one nitrogen or one oxygen heteroatom in addition to said nitrogen or said oxygen to which R
6
and R
7
are attached;
wherein said 3- to 8-membered heterocyclic ring radical made up of R
6
and R
7
may optionally be substituted on any ring carbon atom by one to three substituents per ring independently selected from the group consisting of halo, —OH, (C
1
-C
6
)alkyl-O—, and (C
1
-C
6
)alkyl optionally substituted by one to four fluoro moieties;
wherein said 3- to 8-membered heterocyclic ring radical made up of R
6
and R
7
may optionally be substituted on any ring carbon atom by at least one oxo or one (C
1
-C
6
)alkylidene substituent per ring;
R
8
is a radical selected from the group consisting of H, (C
1
-C
6
)alkyl, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, H—(C═O)—, (C
1
-C
6
)alkyl-(C═O)—, (C
1
-C
6
)alkyl-O—(C═O)—, H
2
N—(C═O)—, [(C
1
-C
6
)alkyl]-NH—(C═O)—, [(C
1
-C
6
)alkyl]
2
-N—(C═O)—, [(C
6
-C
10
)aryl]-NH—(C═O)—, [(C
1
-C
6
)alkyl]-[((C
6
-C
10
)aryl)-N]—(C═O)—, (C
1
-C
6
)alkyl

Affiliated with

Also associated with

Rating

Efficient synthesis of 5-heteroatom-containing -pyrazoles does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Efficient synthesis of 5-heteroatom-containing -pyrazoles, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Efficient synthesis of 5-heteroatom-containing -pyrazoles will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3199757