Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2002-10-10
2004-06-15
Ramsuer, Robert W. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C546S194000, C546S275100, C546S276100, C548S366100
Reexamination Certificate
active
06750338
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the preparation of selected substituted heterocycles that are useful for the treatment of inflammatory diseases. In particular, the application discloses a method for the preparation of a number of substituted heterocycles that are p38 kinase and COX-2 inhibitors. The heterocycles described herein may be useful for the treatment of other disease states.
RELATED ART
Dithietanes have previously been prepared from selected 1,3-dicarbonyl compounds. These so-called active methylene compounds include esters of malonic acid, beta-keto esters, and 1,3-diketones. [(1) Katagiri, N.; Ise, S.; Watanabe, N.; Kaneko, C.,
Chem. Pharm. Bull.
1990, 12, 3242-3248. (2) Okajima, N.; Okada, Y.,
J. Heterocyclic Chem.
1990, 27, 567-574.] Selected dithioles derived from esters of malonic acid have been described as inhibitors of cancer metastasis. [Onaka, S.; Gokou, S. Japanese Patent Application JP 10212239 1998. Certain (1,2,4-triazolyl)ketene S,S-acetals have been previously reported to react with hydrazine to afford pyrazolyl-1,2,4-triazoles. [Huang, Z. N.; Li, Z. M.,
Synth. Commun.
1996, 26, 3115-3120.] Condensation of selected cyclic alpha-oxo-alpha-(1,2,4-triazol-1-yl)ketene N,S-acetals with hydrazine afforded 5-mercaptoalkylamino- and 5-anilinoalkylthiopyrazolyl-1,2,4-triazoles. [(1) Huang, Z. N.; Li, Z. M.,
Heterocycles
1995, 41, 1653-1658.] Historically, 3-amino-pyrazoles have been prepared by a sulfur extrusion rearrangement from 6H-1,3,4-thiadiazine derivatives in the presence of base. [(1) Beyer, H.; Honeck, H.; Reichelt, L.,
Justus Liebigs Ann. Chem.
1970, 741, 45. (2) Schmidt, R. R.; Huth, H.,
Tetrahedron Lett.,
1975, 33. (3) Pfeiffer, W. D.; Dilk, E.; Bulka, E.,
Synthesis,
1977, 196-198.] This experimental protocol normally works adequately for the preparation of simple 3-amino-4-pyrazoles. The 6H-1,3,4-thiadiazine derivatives are in turn prepared by the condensation of alpha-chloroketones with thiosemicarbazides. This in turn necessitates preparing both the requisite alpha-chloroketone and thiosemicarbazide. In general, the aforementioned methodology was not useful for the preparation of the anti-inflammatory pyrazoles of the present invention. The known literature methods for the preparation of pyrazoles described above suffered from poor chemical yields and often gave mixtures of products that necessitated a careful chromatographic separation. In a number of instances, no desired pyrazole at all could be obtained using the methods disclosed in the literature. The present method has the advantage of being more direct (fewer steps) and provides the desired pyrazoles in significantly higher yield and with higher purity. In addition, the present method has the added advantage that it does not rely on the preparation of unstable alpha-chloroketones. Frequently the alpha-chloroketones suffered de-chlorination upon treatment with thiosemicarbazides.
SUMMARY OF THE INVENTION
This invention encompasses a process for the preparation of selected substituted pyrazole derivatives of the Formula A and B useful for the treatment of inflammatory diseases, wherein Y is SR
6
, NR
4
R
5
, or OR
6
.
DETAILED DESCRIPTION OF THE INVENTION
The invention encompasses a process for making a compound of Formula Ia or Ib
wherein:
R
1
is selected from the group consisting of hydrogen, alkyl, O-alkyl, O-cycloalkyl, cycloalkyl, cycloalkenyl, and a 5 or 6 membered heterocycle substituted with one or more substituents selected from the group consisting of C
1-3
alkyl, halo, OH, O-alkyl, cyano, CF
3
, OCF
3
and substituted phenyl wherein the substituents are selected from the group consisting of hydrogen, halo, alkoxy, alkylthio, cyano, CF
3
, OCF
3
, alkyl, SO
2
CH
3
, SO
2
NH
2
, SO
2
NHCOalkyl, SO
2
NHCOalkyl, alkenyl, and alkynyl;
R
2
is selected from the group consisting of pyridyl, pyrimidyl, triazinyl, hydrogen, halo, alkyl, and mono- or di-substituted 6-membered heterocycle wherein the substituent is selected from the group consisting of hydrogen, halo, O-alkyl, S-alkyl, cyano, CF
3
, OCF
3
, alkyl, alkylamino, dialkylamino, and mono or di-substituted phenyl optionally substituted from the group selected from hydrogen, halo, alkoxy, alkylthio, cyano, CF
3
, OCF
3
, alkyl, alkylamino, and dialkylamino;
R
3
is selected from the group selected from hydrogen, alkyl, and phenyl, wherein all but hydrogen may optionally be substituted by one or more of the group consisting of SO
2
CH
3
, halo, alkyl, O-alkyl, S-alkyl, cyano, CF
3
, OCF
3
and SO
2
NH
2
;
R
4
is selected from the group consisting of alkyl, phenyl, cycloalkyl and heterocyclyl optionally substituted by one or more of the group consisting of OH, NH
2
, SH, O-alkyl, NHR
7
, N(R
7
)
2
, alkoxycarbonyl, acyl and halo;
R
5
is selected from the group consisting of alkyl, phenyl, cycloalkyl and heterocyclyl optionally substituted by one or more of the group consisting of OH, NH
2
, SH, S-alkyl, O-alkyl, NHR
7
, N(R
7
)
2
, CO
2
H, halo, alkoxycarbonyl, acyl, heterocyclyl, cycloalkyl, heterocycloalkyl, and heterocyclyl;
R
4
and R
5
taken together may form a ring selected from the group consisting of morpholine, aziridine, thiomorpholine, piperidine, piperazine, and N′-piperazine;
R
7
is selected from the group consisting of alkyl and cycloalkyl;
comprising:
reacting an organometallic reagent of the formula R
2
CH
2
M wherein M is selected from the group consisting of Li, Na, K, and Mg, with an activated form of a carboxylic acid to produce a ketone of Formula Ic;
treating the ketone of Formula Ic with a mixture of carbon disulfide and dihalomethane such as dibromomethane or iodochloromethane in the presence of a base and a solvent to produce the dithietane derivative of Formula Id;
reacting the dithietane derivative of Formula Id with an amine of formula R
4
—NH—R
5
to produce the thioamide of Formula Ie, If, or Ig;
condensing the thioamide of Formula Ie, If or Ig with hydrazine or substituted hydrazine.
In another embodiment of the invention is the process of making compounds of Formula IIa or IIb
wherein:
R
1
is selected from the group consisting of hydrogen, alkyl, O-alkyl, O-cycloalkyl, cycloalkyl, cycloalkenyl, and 5 or 6 membered heterocycle substituted with one or more substituents selected from the group consisting of C
1-3
alkyl, halo, OH, O-alkyl cyano, CF
3
, OCF
3
, and substituted phenyl wherein the substituents are selected from one or more of the group consisting of hydrogen, halo, alkoxy, alkylthio, cyano, CF
3
, OCF
3
, alkyl, SO
2
CH
3
, SO
2
NH
2
, SO
2
NHCOalkyl, SO
2
NHCOalkyl, alkenyl, and alkynyl;
R
2
is selected from the group consisting of pyridyl, pyrimidyl, triazinyl, hydrogen, halo, alkyl, and mono- or di-substituted 6-membered heterocycle wherein the substituent is selected from the group consisting of hydrogen, halo, O-alkyl, S-alkyl, cyano, CF
3
, OCF
3
, alkyl, alkylamino, dialkylamino, and mono or di-substituted phenyl optionally substituted from the group selected from hydrogen, halo, alkoxy, alkylthio, cyano, CF
3
, OCF
3
, alkyl, alkylamino and dialkylamino;
R
3
is selected from the group selected from hydrogen, alkyl, and phenyl wherein all but hydrogen may be substituted by one or more of the group consisting of SO
2
CH
3
, halo, alkyl, O-alkyl, S-alkyl, cyano, CF
3
, OCF
3
, and SO
2
NH
2
;
R
6
is selected from the group consisting of hydrogen, alkyl, phenyl, cycloalkyl and heterocyclyl which may be optionally substituted by one or more of the group consisting of phenyl, substituted phenyl, alkoxycarbonyl, acyl, halo, OH, NH
2
, NHR
3
, N(R
3
)
2
, and cyano, cycloalkyl, heterocycloalkyl, and 3-7 membered heterocycle ring;
comprising:
reacting an organometallic reagent of the formula R
2
CH
2
M wherein M is selected from the group consisting of Li, Na, K, and Mg, with an activated form of a carboxylic acid to produce a ketone of Formula Iic;
treating the ketone of Formula IIc with a mixture of carbon disulfide and dihalo methane such as dibromomethane or iodochloromethane in the pres
Brown David L.
Graneto Matthew J.
Hartmann Susan J.
Metz Suzanne
Stealey Michael A.
Harness & Dickey & Pierce P.L.C.
Pharmacia Corporation
Ramsuer Robert W.
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