11111111111111111111111111111111111111111
`
`111101111
`11111
`5,760,068
`5,760,068
`5,760,068
`Jun. 2, 1998
`Jun. 2, 1998
`Jun. 2, 1998
`
`1111111111111
`
`US005760068A
`US005760068A
`US005760068A
`‘
`[11] Patent Number:
`nu Patent Number: (cid:9)
`[11] Patent Number:
`[45] Date of Patent:
`[45] Date of Patent: (cid:9)
`[45] Date of Patent:
`
`11111111111111 11111111 Iii 11111
`
`United States Patent [19]
`United States Patent [19]
`United States Patent [191
`Talley et al. (cid:9)
`Talley et al.
`Talley et a1.
`
`SUBSTITUTED PYRAZOLYL
`
`[54] SUBSTITUTED PYRAZOLYL [54] SUBSTITUTED PYRAZOLYL
`[54]
`BENZENESULFONAMIDES FOR THE
`BENZENESULFONAMIDES FOR THE
`BENZENESULFONAMIDES FOR THE
`TREATMENT OF INFLAMMATION
`TREATMENT OF INFLAMMATION
`TREATMENT OF INFLAMMATION
`
`Inventors: John J. Talley. St. Louis. Mo.; Thomas
`[75] Inventors: John J. Talley, St. Louis. Mo.; Thomas
`[75] Inventors: John J. Talley, St. Louis, Mo.; Thomas
`[751
`D. Penning. Elmhurst; Paul W. Collins.
`D. Penning, Elmhurst; Paul W. Collins,
`D. Penning, Elmhurst; Paul W. Collins,
`Deer?eld.‘ both of 111.; Donald J.
`Deerfield, both of M.; Donald J.
`Deerfield, both of Ill.; Donald J.
`Rogier, Jr.. St. Louis. Mo.; James W.
`Rogier, Jr., St. Louis, Mo.; James W.
`Rogier, Jr., St. Louis, Mo.; James W.
`Malecha. Libeityvillcg Julie M.
`
`Malecha, Libertyville; Julie M. Malecha, Libertyville; Julie M.
`Miyashiro. Chicago. both of 111.;
`
`Nllyashiro, Chicago, both of Ill.; Nllyashiro, Chicago, both of Ill.;
`Stephen R. Bertenshaw. Brentwood.
`
`Stephen R. Bertenshaw, Brentwood. Stephen R. Bertenshaw, Brentwood.
`
`Mo.; Ish K. Khanna, Vernon Hills. Ill.; Mo.; Ish K. Khanna, Vernon Hills. Ill.;
`Mo.; Ish K. Khanna. Vernon Hills. 111.;
`Matthew J. Graneto. St. Louis. Mo.;
`
`Matthew J. Graneto, St. Louis, Mo.; Matthew J. Graneto, St. Louis, Mo.;
`Roland S. Rogers. Richmond Heights.
`
`Roland S. Rogers, Richmond Heights, Roland S. Rogers, Richmond Heights,
`Mo.; Jeffery S. Carter. Chesterfield.
`
`Mo.; Jeffery S. Carter, Chesterfield, Mo.; Jeffery S. Carter, Chesterfield,
`Mo.; Stephen H. Docter. Mt. Prospect;
`
`Mo.; Stephen II. Docter, Mt. Prospect; Mo.; Stephen II. Docter, Mt. Prospect;
`Stella S. Yu. Morton Grove. both of 111.
`
`Stella S. Yu, Morton Grove, both of Ill. Stella S. Yu, Morton Grove, both of 111.
`
`Assignee: G.D. Searle & Co.. Skolde. 111.
`[73] Assignee: G.D. Searle & Co., Skokie. [73] Assignee: G.D. Searle & Co., Skokie. M.
`
`[73]
`648,113
`648,113
`
`648,113
`[21] Appl. No.: [21] Appl. No.: (cid:9)
`[211
`Appl. No.:
`Nov. 14, 1994
`Nov. 14, 1994
`[221
`Nov. 14, 1994
`
`[22] PCT Filed: [22] PCT Filed: (cid:9)
`PCT Filed:
`PCT/US94/12720
`PCT/US94/12720
`
`PCT/US94/12720
`[86] PCT No.: [86] PCT No.: (cid:9)
`[36]
`PC!‘ No.:
`Sep. 6, 1996
`§ 371 Date:
`Sep. 6, 1996
`§ 371 Date: (cid:9)
`§ 371 Date: (cid:9)
`Sep. 6, 1996
`§ 102(e) Date: Sep. 6, 1996
`
`§ 102(e) Date: Sep. 6, 1996 § 102(e) Date: Sep. 6, 1996
`[87] PCT Pub. No.: W095/15316
`[87] PCT Pub. No.: W095/15316
`[371
`PCI‘ Pub. No.: WO95/15316
`PCT Pub. Date: Jun. 8, 1995
`PCT Pub. Date: Jun. 8, 1995
`PCI‘ Pub. Date: Jun. 8, 1995
`
`Related U.S. Application Data
`Related U.S. Application Data
`Related U.S. Application Data
`
`
`[63] Continuation-in-part of Ser. No. 223,629, Apr. 6, 1994, Pat. [63] Continuation-in-part of Ser. No. 223,629, Apr. 6, 1994, Pat.
`Continuation-impart of Ser. No. 223,629. Apr. 6, 1994, Pat.
`[63]
`
`No. 5,521207, which is a continuation-in-part of Ser. No. No. 5,521,207, which is a continuation-in-part of Ser. No.
`No. 5,521 ,207, which is a continuation-in-part of Ser. No.
`
`160,594, Nov. 30, 1993, Pat. No. 5,466,823. 160,594, Nov. 30, 1993, Pat. No. 5,466,823.
`160,594, Nov. 30, 1993, Pat. No. 5,466,823.
`[51] Int. C1.6 (cid:9)
` A61K 31/415
` A61K 31/415
`[5 1]
`[51] Int. C1.6 (cid:9)
`Int. Cl.6 ................................................. .. A61K 31/415
`
`[52] U.S. Cl. (cid:9)[52] U.S. Cl. (cid:9)
`
` 514/403; 514/406; 514/407 514/403; 514/406; 514/407
`[52]
`514/403; 514/406; 514/407
`US. Cl. .............. ..
`
`[58] Field of Search (cid:9)[58] Field of Search (cid:9)
`514/403, 406,
`[5 3]
`514/403, 406,
`Field of Search ................................... .. 514/403. 406.
`
`514/407 514/407
`514/407
`
`[56] [56]
`
`[561
`
`References. Cited
`References. Cited
`References Cited
`U.S. PATENT DOCUMENTS
`U.S. PATENT DOCUMENTS
`U.S. PATENT DOCUWlENTS
`
`3,940,418 2/1976 Hamilton . 3,940,418 2/1976 Hamilton .
`3,940,418
`211976 Hamilton.
`
`4,146,721 3/1979 Rainer . 4,146,721 3/1979 Rainer .
`4,146,721
`3/1979 Rainer.
`
`5,134,142 7/1992 Matsuo et al. . 5,134,142 7/1992 Matsuo et al. .
`5,134,142
`7/1992 Matsuo et a1. .
`5,315,012 5/1994 Connolly et al. .
`5,315,012 5/1994 Connolly et al. .
`5,315,012
`5/1994 Connolly et a1. .
`
`5,387,693 2/1995 Connolly et al. .
`5,387,693 2/1995 Connolly et al..
`2/1995 Connolly et a1. .
`5,387,693
`FOREIGN PATENT DOCUNIENTS
`FOREIGN PATENT DOCUMENTS
`FOREIGN PATENT DOCUMENTS
`94/75753 10/1993 Australia .
`94/75753 10/1993 Australia .
`94/75753 10/1993 Australia .
`
`347773 12/1989 European Pat. Off. . 347773 12/1989 European Pat. Off. .
`347773 12/1989 European Pat. Oif. .
`477049
`
`3/1992 European Pat. Off.. 3/1992 European Pat. Off. .
`477049
`477049 3/ 1992 European Pat. O?‘. .
`
`554829 8/1993 European Pat. Off.. 554829 8/1993 European Pat. Off. .
`554829 8/1993 European Pat. O?. .
`7/1994 WIPO .
`94/14777
`94/14777
`7/1994 WIPO .
`7/ 1994 WIPO .
`94/14777
`
`OTHER PUBLICATIONS OTHER PUBLICATIONS
`OTHER PUBLICATIONS
`R. Soliman et al, J. Pharm. Sci., 76, 626 (1987).
`R. Soliman et al. J. Pharm. Sci., 76, 626 (1987).
`R. Soliman et al. J. Pharm. Sci., 76, 626 (1987).
`H. Mokhtar, Pak. J. Sci. Ind. Res., 31, 762 (1988).
`H. Mokhtar. Pak. J. Sci. Ind. Res., 31, 762 (1988).
`H. Mokhtar, Pak. J. Sci. Ind. Res., 31, 762 (1988).
`H. Mokhtar et al. Pak. J. Sci. Ind. Res., 34, 9 (1991).
`H. Mokhtar et a1. Pak. J. Sci. Ind. Res., 34, 9 (1991).
`H. Mokhtar et al. Pak. J. Sci. Ind. Res., 34, 9 (1991).
`
`M. Cocco et al, II. Farmaco—Ed. Sci., 40, 272 (1985). M. Cocco et al, II. Farmaco—Ed. Sci., 40, 272 (1985).
`M. Cocco et a1. ll. Farmaco-Ed. Sci., 40, 272 (1985).
`
`R. Soliman et al, J. Pharm. Sci., 72, 1004 (1983). R. Soliman et al, J. Pharm. Sci., 72, 1004 (1983).
`R. Soliman et al. J. Pharm. Sci, 72, 1004 (1983).
`
`H. Feid—Allah, Pharmazie, 36, 754 (1981). H. Feid—Allah, Pharmazie, 36, 754 (1981).
`H. Feid-Allah. Pharmazie, 36, 754 ( 1981).
`
`R. Soliman et al, J. Pharm. Sci., 70, 602 (1981). R. Soliman et al, J. Pharm. Sci., 70, 602 (1981).
`R. Soliman et al. J. Pharm. Sci., 70, 602 (1981).
`Maybridge Chemical CoJRyan Scientific Catalog, Com
`Maybridge Chemical CoiRyan Scientific Catalog, Com-
`Maybridge Chemical CoiRyan Scientific Catalog, Com-
`pound No. BTB 06812 (No date available).
`
`pound No. BTB 06812 (No date available). pound No. BTB 06812 (No date available).
`
`H. Mokhtar et al. Pak. J. Sci. Ind. Res., 33:30-36 (1990). H. Mokhtar et al. Pak. J. Sci. Ind. Res., 33:30-36 (1990).
`H. Mokhtar et a1. Pak. J. Sci. Ind. Res., 33:30-36 (1990).
`
`H. Mokhtar et al. J. Chem. Soc. Pak, 10:414-424 (1988). H. Mokhtar et al. J. Chem. Soc. Pak, 10:414-424 (1988).
`H. Mokhtar et al. J. Chem. Soc. Pak, 10:414-424 (1988).
`
`R. Soliman et al, J. Pharm. Sci., 72:999-1004 (1983). R. Soliman et al, J. Pharm. Sci., 72:999-1004 (1983).
`R. Soliman et al. J. Pharm. Sci., 722999-1004 (1983).
`M.S. I. Makki et al, Chem. Abstracts, 121:11
`
`M.S. I. Makki et al, Chem. Abstracts, 121:11 (1994). (1994).
`MS. I. Makki et a1, Chem. Abstracts, [21:11 (1994).
`R. Hamilton. J. Heterocyclic Chem, 13, 545 (1976).
`R. Hamilton, J. Heterocyclic Chem., 13, 545 (1976).
`R. Hamilton, J. Heterocyclic Chem., 13, 545 (1976).
`M. Hashem et at. J. Med. Chem., 19, 229 (1976).
`M. Hashem et al. J. Med. Chem., 19, 229 (1976).
`M. Hashem et al. J. Med. Chem, 19, 229 (1976).
`H. Feid-Allah. J. Heterocyclic Chem, 18, 1561 (1981).
`
`H. Feid—Allah, J. Heterocyclic Chem., 18, 1561 (1981). H. Feid—Allah, J. Heterocyclic Chem., 18, 1561 (1981).
`
`H. Mokhtar et al, Pharmazie, 33, 649 (1978). H. Mokhtar et al, Pharmazie, 33, 649 (1978).
`H. Mokhtar et a1. Pharmazie, 33, 649 (1978).
`R. Soliman et al, Pharmazie, 33 (1978).
`R. Soliman et al, Pharmazie, 33 (1978).
`R. Soliman et a1. Pharmazie, 33 (1978).
`Bandaiu et al. Cancer Research. 56. pp. 4566-4569 (1996).
`Bandaru et al, Cancer Research, 56. pp. 4566-4569 (1996).
`Bandaru et al, Cancer Research, 56. pp. 4566-4569 (1996).
`Primary Examiner-Robert W. Ramsuer
`
`Primary Examiner—Robert W. Ramsuer Primary Examiner—Robert W. Ramsuer
`Attorney, Agent, or Fimz-Joseph W. Bulock
`Attorne); Agent, or Firm—Joseph W. Bulock
`Attorne); Agent, or Firm—Joseph W. Bulock
`ABSTRACT
`ABSTRACT
`ABSTRACT
`[57] (cid:9)[57] (cid:9)
`
`[57]
`A class of pyrazolyl benzenesulfonamide compounds is
`
`A class of pyrazolyl benzenesulfonamide compounds is A class of pyrazolyl benzenesulfonamide compounds is
`described for use in treating in?ammation and
`
`described for use in treating inflammation and described for use in treating inflammation and
`in?ammation-related disorders. Compounds of particular
`inflammation-related disorders. Compounds of particular
`inflammation-related disorders. Compounds of particular
`
`interest are defined by Formula II: interest are defined by Formula II:
`interest are de?ned by Formula 11:
`
`4
`
`(11)
`
`H2N —S
`
`3
`
`R2
`
`or a pharmaceutically-acceptable salt thereof.
`or a pharmaceutically-acceptable salt thereof.
`or a pharmaceutically-acceptable salt thereof.
`
`18 Claims, No Drawings
`18 Claims, No Drawings
`18 Claims, No Drawings
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`5.760.068
`5.760.068
`5.760068
`
`R4
`
`5
`RI —1s1,jit
`
`
`1 1
`1
`SUBSTITUTED PYRAZOLYL
`SUBSTITUTED PYRAZOLYL
`SUBSTITUTED PYRAZOLYL
`BENZENESULFONAMIDES FOR THE
`BENZENESULFONAMIDES FOR THE
`BENZENESULFONAMIDES FOR THE
`TREATMENT OF INFLAMMATION
`TREATMENT OF INFLAMMATION
`TREATMENT OF INFLAMMATION
`
`2
`2
`2
`pyrazoles. having a saturated ring bridging the pyrazole and
`
`pyrazoles, having a saturated ring bridging the pyrazole and pyrazoles, having a saturated ring bridging the pyrazole and
`
`a phenyl radical. as antibiotics. a phenyl radical, as antibiotics.
`a phenyl radical. as antibiotics.
`Certain substituted pyrazolyl-benzenesulfonamides have
`
`Certain substituted pyrazolyl-benzenesulfonamides have Certain substituted pyrazolyl-benzenesulfonamides have
`been described in the literature as synthetic intermediates.
`
`been described in the literature as synthetic intermediates. been described in the literature as synthetic intermediates.
`Speci?cally. 4-[5-(4-chlorophenyl)-3-phenyl-lH-pyrazol
`RELATED CASE RELAYED CASE
`
`RELATED CASE
`5 (cid:9) Specifically, 4- [5-(4-chloropheny1)-3-pheny1-1H-pyrazol-
`5 (cid:9) Specifically, 4- [5-(4-chloropheny1)-3-pheny1-1H-pyrazol-
`lyllbenzenesulfonamide has been prepared from a pyrazo
`lyl]benzenesulfonamide has been prepared from a pyrazo-
`lyl]benzenesulfonamide has been prepared from a pyrazo-
`This is an application under 35 USC §37l of International
`
`This is an application under 35 USC §371 of International This is an application under 35 USC §371 of International
`line compound as an intermediate for compounds having
`
`line compound as an intermediate for compounds having line compound as an intermediate for compounds having
`Application PCT/US 94/ 12720. with an international ?ling
`
`Application PCT/US 94/12720, with an international filing Application PCT/US 94/12720, with an international filing
`hypoglycemic activity [R. Soliman et al. J. Pharm. Sci., 76.
`
`hypoglycemic activity [R. Soliman et al, J. Pharm. Sci., 76, hypoglycemic activity [R. Soliman et al, .1. Pharm. Sci., 76,
`date of Nov. 14. 1994. which is a continuation-in-part of
`
`date of Nov. 14, 1994. which is a continuation-in-part of date of Nov. 14, 1994, which is a continuation-in-part of
`626 (1987)]. 4-[5-[2-(4-Bromophenyl)-2H-l.2.3-triazol-4
`
`626 (1987)]. 4-[5-[2-(4-Bromophenyl)-2H-1.23-triazol-4- 626 (1987)]. 4- [5-[2-(4-Bromopheny1)-2H-1.2 3 -triazol-4-
`U.S. patent application Ser. No. 08/223629. ?led Apr. 6.
`U.S. patent application Ser. No. 08/223,629, filed Apr. 6, U.S. patent application Ser. No. 08/223,629, filed Apr. 6,
`
`yl]-3-methyl-1H-pyrazol- l-yl]benzenesulfonamide has
`10 yl] -3 -methyl- 1H-pyraz ol- 1-yll benzene sulfonamide has
`10 yl] -3 -methyl- 1H-pyraz ol- 1-yll benzene sulfonamide has
`10
`1994, now issued as U.S. Pat. No. 5,521,207, which is a 1994, now issued as U.S. Pat. No. 5,521,207, which is a
`
`1994. now issued as U.S. Pat. No. 5.521.207. which is a
`been prepared from a pyrazoline compound and described as
`been prepared from a pyrazoline compound and described as
`been prepared from a pyrazoline compound and described as
`continuation-in-part of U.S. patent application Ser. No.
`continuation-in-part of U.S. patent application Ser. No.
`continuation-in-part of U.S. patent application Ser. No.
`potentially having hypoglycemic activity [H. Mokhtar. Pak.
`
`potentially having hypoglycemic activity [H. Mokhtar. Pak. potentially having hypoglycemic activity [H. Mokhtar. Pak.
`
`08/160,594, filed Nov. 30, 1993, now issued as U.S. Pat. No. 08/160,594, filed Nov. 30, 1993, now issued as U.S. Pat. No.
`08/160594. ?led Nov. 30. 1993. now issued as U.S. Pat. No.
`J. Sci. Ind. Res., 31. 762 (1988)]. Similarly. 4-[4-bromo-5
`J. Sci. Incl. Res., 31. 762 (1988)]. Similarly, 4-14-bromo-5-
`J. Sci. Incl. Res., 31, 762 (1988)]. Similarly, 4-14-bromo-5-
`5.466.823.
`5,466,823.
`5,466,823.
`[2-(4-chlorophenyl)-2H-1.2.3-triazo1-4yl]-3~methyl
`[2-(4-chloropheny1)-2H-1.2.3-triazol-4y1]-3-methyl-
`[ 2 - (4 - ch lor oph e ny1)- 2 H- 1 .2 .3 -tri azol-4y1] -3-methyl-
`1H-pyrazol-l-y1]benzenesulfonamide has been prepared [H.
`15
`
`15 1H-pyrazol-1-yl]benzenesulfonamide has been prepared [H. 15 1H-pyrazol-1-yllbenzenesulfonamide has been prepared [H.
`FIELD OF THE INVENTION FIELD OF THE INVENTION
`
`FIELD OF THE INVENTION
`
`Mokhtar et al, Pak J. Sci. Ind. Res., 34. 9 (1991)]. Mokhtar et al., Pak J. Sci. Ind. Res., 34. 9 (1991)].
`Mokhtar et al. Pak. J. Sci. Ind. Res., 34. 9 (1991)].
`This invention is in the ?eld of anti-in?ammatory phar
`
`This invention is in the field of anti-inflammatory phar-This invention is in the field of anti-inflammatory phar-
`The phytotoxicity of pyrazole derivatives is described [M.
`
`The phytotoxicity of pyrazole derivatives is described [M. The phytotoxicity of pyrazole derivatives is described [M.
`maceutical agents and speci?cally relates to compounds.
`
`maceutical agents and specifically relates to compounds, maceutical agents and specifically relates to compounds,
`Cocco et al. ll. Farmaco-Ed. Sci., 40. 272 (1985)]. speci?
`
`Cocco et al. 11. Farmaco-Ed. Sci., 40, 272 (1985)]. specifi-Cocco et al. 11. Farmaco-Ed. Sci., 40, 272 (1985)]. specifi-
`compositions and methods for treating in?ammation and
`
`compositions and methods for treating inflammation and compositions and methods for treating inflammation and
`cally for l-[4-(aminosulfonyl)phenyl]-5-phenyl-1H
`
`cally for 144-(aminosulfonyl)pheny1]-5 -phenyl-1H-cally for 144-(aminosulfonyl)pheny1]-5 -phenyl-1H-
`inflammation-associated disorders, such as arthritis.
`inflammation-associated disorders, such as arthritis.
`in?ammation-associated disorders. such as arthritis.
`20
`pyrazole-34dicarboxylic acid.
`20 pyrazole-3,4-dicarboxylic acid.
`20 pyrazole-3,4-dicarboxylic acid.
`The use of styryl pyrazole esters for antidiabetes drugs is
`The use of styryl pyrazole esters for antidiabetes drugs is
`The use of styryl pyrazole esters for antidiabetes drugs is
`BACKGROUND OF THE INVENTION BACKGROUND OF THE INVENTION
`
`BACKGROUND OF THE INVENTION
`
`described [H. Mokhtar et al, Pharmazie, 33, 649-651 described [H. Mokhtar et al, Pharmazie, 33, 649-651
`described [H. Mokhtar et a1. Pharmazie, 33. 649-651
`Prostaglandins play a major role in the in?ammation
`Prostaglandins play a major role in the inflammation
`Prostaglandins play a major role in the inflammation
`(1978)]. The use of styryl pyrazole carboxylic acids for
`(1978)]. The use of styryl pyrazole carboxylic acids for
`(1978)]. The use of styryl pyrazole carboxylic acids for
`process and the inhibition of prostaglandin production.
`process and the inhibition of prostaglandin production, process and the inhibition of prostaglandin production,
`
`
`25 antidiabetes drugs is described [R. Soliman et al, Pharmazie, 25 antidiabetes drugs is described [R. Soliman et al, Pharmazie,
`antidiabetes drugs is described [R. Soliman et a1. Phannazie,
`25
`especially production of PGGz. F‘Gl-I2 and PGE2. has been
`especially production of PGG,„ PGH2 and PGE2, has been especially production of PGG,„ PGH2 and PGE,, has been
`
`
`33, 184-5 (1978)]. The use of 443,4,5-trisubstituted-33, 184-5 (1978)]. The use of 4-[3,4,5-trisubstituted-
`33. 184-5 (1978)]. The use of 4-[3.4.5-trisubstituted
`a common target of anti-in?ammatory drug discovery.
`a common target of anti-inflammatory drug discovery. a common target of anti-inflammatory drug discovery.
`
`pyrazol-1-yl]ben2enesulfonamides as intermediates for sul
`
`pyrazol-1-yl]benzenesulfonamides as intermediates for sul-pyrazol-1-yl]benzenesulfonamides as intermediates for sul-
`However. common non-steroidal anti-in?ammatory drugs
`However, common non-steroidal anti-inflammatory drugs
`However, common non-steroidal anti-inflammatory drugs
`fonylurea anti-diabetes agents is described. and speci?cally.
`
`fonylurea anti-diabetes agents is described, and specifically, fonylurea anti-diabetes agents is described, and specifically,
`1-[4-(aminosulfonyl)phenyl]-3-methyl-5-phenyl-1H
`(NSAIDs) that are active in reducing the prostaglandin
`(NSAIDs) that are active in reducing the prostaglandin-(NSAIDs) that are active in reducing the prostaglandin-
`
`1-[4-(aminosulfonyl)pheny1]-3-methy1-5-phenyl-IH-
`1[4-(aminosulfonyl)pheny1]-3-methyl-5-phenyl- 111-
`induced pain and swelling associated with the in?ammation
`induced pain and swelling associated with the inflammation
`induced pain and swelling associated with the inflammation
`pyrazole-4~carboxylic acid [R. Soliman et al. J. Pharm. Sci.,
`30 pyrazole-4-carboxylic acid [R. Solirnan et al. J. Pharm. Sci.,
`30 pyrazole-4-carboxylic acid [R. Soliman et al, J. Pharm. Sci.,
`30
`process are also active in aifecting other prostaglandin
`process are also active in affecting other prostaglandin-process are also active in affecting other prostaglandin-
`
`72. 1004 (1983)]. A series of 4-[3-substituted methyl-5
`
`72, 1004 (1983)]. A series of 4-[3-substituted methy1-5-72, 1004 (1983)]. A series of 4-[3-substituted methy1-5-
`regulated processes not associated with the in?ammation
`
`regulated processes not associated with the inflammation regulated processes not associated with the inflammation
`phenyl-lH-pyrazol-1-yl]benzenesulfonamides has been pre
`pheny1-1H-pyrazol-1-yl]benzenesulfonamides has been pre-
`pheny1-1H-pyrazol-1-yl]benzenesulfonamides has been pre-
`
`process. Thus. use of high doses of most common NSAIDs process. Thus, use of high doses of most common NSAIDs
`process. Thus. use of high doses of most common NSAIDs
`pared as intermediates for anti-diabetes agents. and more
`
`pared as intermediates for anti-diabetes agents, and more pared as intermediates for anti-diabetes agents, and more
`speci?cally. 4- [3-methyl-5-phenyl- IH-pyrazol- lyl]
`can produce severe side effects. including life threatening
`can produce severe side effects, including life threatening can produce severe side effects, including life threatening
`
`
`specifically, 4-[3-methyl-5-phenyl-IH-pyrazol-lyl] specifically. 4- [3-methy1-5-pheny1-1H-pyrazol-lyl]
`ulcers. that limit their therapeutic potential. An alternative to
`ulcers, that limit their therapeutic potential. An alternative to ulcers, that limit their therapeutic potential. An alternative to
`
`benzenesulfonamide [H. Feid-Allah, Pharmazie, 36, 754
`benzenesulfonamide [H. Feid-Allah. Pharmazie, 36. 754
`35 benzenesulfonamide [H. Feid-Allah, Pharmazie, 36, 754
`35
`NSAIDs is the use of corticosteroids, which have even more NSA1Ds is the use of corticosteroids, which have even more
`
`(1981)]. In addition. l-(4-[aminosulfonyl]phenyl)-5
`N SAIDs is the use of corticosteroids. which have even more
`(1981)]. In addition. 1-(44aminosulfonylIpheny1)-5- 35 (1981)]. In addition. 1-(4-[aminosulfonyl]pheny1)-5-
`
`drastic side elfects. especially when long term therapy is
`drastic side effects, especially when long term therapy is
`drastic side effects, especially when long term therapy is
`phenylpyrazole-3-carboxylic acid has been prepared from
`phenylpyrazole-3-carboxylic acid has been prepared from
`phenylpyrazole-3-carboxylic acid has been prepared from
`involved.
`involved.
`involved.
`the above described 4-[3 -methyl-5-phenyl- lH-pyrazol- l-yl]
`
`the above described 4[3-methy1-5-pheny1-1H-pyrazol-1-yl] the above described 4-[3-methyl-5-phenyl-1H-pyrazol-1-yl]
`benzenesulfonamide compound [R. Solirnan et al. J. Parm.
`
`benzenesulfonamide compound [R. Soliman et al, J. Parm. benzenesulfonamide compound [R. Soliman et al, J. Parm.
`Previous NSAIDs have been found to prevent the pro
`Previous NSAIDs have been found to prevent the pro-Previous NSAIDs have been found to prevent the pro-
`
`duction of prostaglandins by inhibiting enzymes in the
`Sci., 70. 602 (1981)].
`Sci., 70. 602 (1981)].
`Sci, 70. 602 (1981)].
`duction of prostaglandins by inhibiting enzymes in the duction of prostaglandins by inhibiting enzymes in the
`
`40
`40
`human arachidonic acidlprostaglandin pathway. including
`human arachidonic acid/prostaglandin pathway, including
`human arachidonic acid/prostaglandin pathway, including
`
`DESCRIPTION OF THE INVENTION DESCRIPTION OF THE INVENTION
`DESCRIPTION OF THE INVENTION
`the enzyme cyclooxygenase (COX). The recent discovery of
`
`the enzyme cyclooxygenase (COX). The recent discovery of the enzyme cyclooxygenase (COX). The recent discovery of
`
`an inducible enzyme associated with inflammation (named an inducible enzyme associated with inflammation (named
`an inducible enzyme associated with in?ammation (named
`A class of compounds useful in treating in?ammation
`A class of compounds useful in treating inflammation-
`A class of compounds useful in treating inflammation-
`“cyclooxygenase lI (COX II)” or “prostaglandin G/H syn
`
`"cyclooxygenase II (COX II)" or "prostaglandin G/H syn-"cyclooxygenase II (COX II)" or "prostaglandin G/H syn-
`
`related disorders is defined by Formula I: related disorders is defined by Formula I:
`related disorders is de?ned by Formula I:
`
`thase IT') provides a viable target of inhibition which more 45 thase IN) provides a viable target of inhibition which more
`thase 11”) provides a viable target of inhibition which more
`45
`45
`elfectively reduces in?ammation and produces fewer and
`
`effectively reduces inflammation and produces fewer and effectively reduces inflammation and produces fewer and
`
`less drastic side effects. less drastic side effects.
`less drastic side effects.
`
`Pyrazoles have been described for use in the treatment of Pyrazoles have been described for use in the treatment of
`Pyrazoles have been described for use in the treatment of
`
`inflammation. U.S. Pat. No. 5,134,142 to Matsuo et al inflammation. U.S. Pat. No. 5,134,142 to Matsuo et al
`in?ammation. U.S. Pat. No. 5.134.142 to Matsuo et al
`described 1.5-diaryl pyrazoles. and speci?cally. l-(4
`described 1,5-diaryl pyrazoles, and specifically, 1-(4- so
`described 1,5-diaryl pyrazoles, and specifically, 1-(4-
`50 (cid:9)
`?uorophenyl)-5-[4-(methylsu1fony1)phenyl]-3
`fl u or oph e n y1)-5 - [4- ( m e th y I s ul fony 1)p he n yl] -3 -
`fl u or oph e n y1)-5 - [4- ( m e th y I s ul fony 1)p he n yl] -3 -
`wherein R1 is selected from aryl and heteroaryl. wherein
`wherein le is selected from aryl and heteroaryl, wherein
`wherein le is selected from aryl and heteroaryl, wherein
`tri?uoromethyl pyrazole. as having anti-in?ammatory activ
`trifluoromethyl pyrazole, as having anti-inflammatory activ-
`trifluoromethyl pyrazole, as having anti-inflammatory activ-
`ity.
`
`le is substituted at a substitutable position with one or more le is substituted at a substitutable position with one or more
`R1 is substituted at a substitutable position with one or more
`
`ity. ity.
`radicals selected from sulfamyl. halo. alkyl. alkoxy.
`
`radicals selected from sulfamyl, halo, alkyl, alkoxy, radicals selected from sulfamyl, halo, alkyl, alkoxy,
`U.S. Pat. No. 3.940.418 to R. Hamilton described tricyclic
`U.S. Pat. No. 3,940,418 to R. Hamilton described tricyclic
`U.S. Pat. No. 3,940.418 to R. Hamilton described tricyclic
`hydroxyl. haloalkyl and
`
`55 hydroxyl, haloalkyl and hydroxyl, haloalkyl and
`4.5-dihydrobenz[g]indazoles as antiin?ammatory agents. In
`
`4,5-dihydrobenz[g]indazoles as antiinflanunatory agents. In 4,5-dihydrobenz[g]indazoles as antiinflanunatory agents. In 55
`55
`addition. R. Hamilton [1. Heterocyclic Chem, 13. 545
`
`addition, R. Hamilton [./. Heterocyclic Chem., 13, 545 addition, R. Hamilton [J. Heterocyclic Chem., 13, 545
`(1976)] describes tricyclic 4.5-dihydrobenz[g]indazoles as
`(1976)] describes tricyclic 4,5-dihydrobenz[g]indazoles as
`(1976)] describes tricyclic 4,5-dihydrobenz[g]indazoles as
`antiin?ammatory agents. U.S. Pat. No. 5.134.155 describes
`
`antiinfianunatory agents. U.S. Pat. No. 5,134,155 describes antiinflanunatory agents. U.S. Pat. No. 5,134,155 describes
`fused tricyclic pyrazoles having a saturated ring bridging the
`
`fused tricyclic pyrazoles having a saturated ring bridging the fused tricyclic pyrazoles having a saturated ring bridging the
`pyrazole and a phenyl radical as KMG-CoA reductase
`pyrazole and a phenyl radical as HMG-CoA reductase 60
`pyrazole and a phenyl radical as HMG-CoA reductase 60
`inhibitors. European publication EP 477.049. published Mar.
`
`inhibitors. European publication EP 477,049, published Mar. inhibitors. European publication EP 477,049, published Mar.
`25. 1992. described [4.5-dihydro-1-phenyl-1H-benz[ g]
`wherein R2 is selected from hydrido. halo. alkyl.
`
`25, 1992, described [4,5-dihydro-l-phenyl-1H-benz[g] 25, (cid:9) 1992, described [4,5-clihydro-1 -ph en y1-1 H-be nz [ g]
`
`wherein R2 is selected from hydrido, halo, alkyl, wherein R2 is selected from hydrido, halo, alkyl,
`haloalkyl. cyano. nitro. formyl. carboxyl. alkoxy.
`indazol-3-yl] amides as having antipsychotic activity. Euro
`
`indazol-3-yl]amides as having antipsychotic activity. Euro-indazol-3-yl]amides as having antipsychotic activity. Euro-
`
`haloalkyl, cyano, nitro, formyl, carboxyl, alkoxy, haloalkyl, cyano, nitro, formyl, carboxyl, alkoxy,
`aminocarbonyl. alkoxycarbonyl. carboxyalkyl.
`pean publication EP 347.773. published Dec. 27. 1989.
`pean publication EP 347,773, published Dec. 27. 1989,
`
`aminocarbonyl, alkoxycarbonyl, carboxyalkyl, aminocarbonyl, alkoxycarbonyl, carboxyalkyl,
`pean publication EP 347.773, published Dec. 27. 1989,
`describes [4.5-dihydro-1-phenyl-1H-benz[g]indazol-3yl]
`alkoxycarbonylalkyl. amidino. cyanoamidino. cyanoalkyl.
`65 aLkoxycarbonylalkyl, amidino, cyanoamidino, cyanoalkyl, describes [4.5-dihydro-1-phenyl- 1H-benz[g]indazol-3y1]
`
`describes [4.5 -dih ydro- 1 -phenyl- 1H-ben z [g] indazol-3 yl]
`65 alkoxycarbonylalkyl, amidino, cyanoamidino, cyanoalkyl,
`65
`alkoxycarbonylcyanoalkenyl. aminocarbonylalkyl.
`[J.
`
`propanamides as immunostimulants. M. Hashem et al [J. propanamides as immunostimulants. M. Hashem et al
`propanamides as immunostimulants. M. Hashem et al [J.
`
`alkoxycarbonylcyanoalkenyl, aminocarbonylalkyl. alkoxycarbonylcyanoalkenyl, aminocarbonylalkyl.
`N-alkylaminocarbonyl. N-arylaminocarbonyl. N.N
`Med. Chem., 19, 229 (1976)] describes fused tricyclic
`Med. Chem, 19. 229 (1976)] describes fused tricyclic
`
`N-alkylaminocarbonyl, N-arylaminocarbonyl, N.N- N-alkylaminocarbonyl, N-arylaminocarbonyl, N.N-
`Med. Chem., 19, 229 (1976)] describes fused tricyclic
`
`(I)
`(I)
`
`3
`
`R2
`
`0 H (cid:9)
`R5
`R5
`0 H (cid:9)
`O
`O
`% I /
`%, I /
`
`—S —N=C —N-S-N=C-N ; ;
`
`\
`R5
`125
`
`(cid:9)
`

`

`5.760068
`5,760.068 5,760.068
`
`
`4
`4 4
`
`
`
`R7 (cid:9)R7 (cid:9)
`
`I (cid:9)I (cid:9)
`
`N\ y NH2, (cid:9)N\ y NH2, (cid:9)
`0 (cid:9)0
`
`0
`
`R7 (cid:9)R7 (cid:9)
`
`I (cid:9)I (cid:9)
`l
`./N-Ir NH2' (cid:9)./N-Ir NH2' (cid:9)
`
`N
`/ T
`
`
`R (cid:9)R (cid:9)
`
`I (cid:9)I (cid:9)
`
`NNn2, (cid:9)NNn2, (cid:9)
`
`
`s (cid:9)s (cid:9)
`S
`
`
`R7 R7
`
`I I
`
`N. N.
`
`
`
`0 0
`
`
`R7 (cid:9)R7 (cid:9)
`
`I (cid:9)I (cid:9)
`
`
`R7 R7
`
`I I
`
`
`N (cid:9)N (cid:9)
`CH3; CH3;
`
`y y
`
`
`
`//
`
`/ ‘t NR2,
`
`3
`
`3 3
`dialkylaminocarbonyl. N-alkyl-N-arylaminocarbonyl.
`wherein R5 is alkyl;
`
`wherein R5 is alkyl; wherein R5 is alkyl;
`
`dialkylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, dialkylaminocarbonyl, N-alkyl-N-arylaminocarbonyl,
`cycloalkylaminocarbonyl. heterocyclicaminocarbonyl.
`
`cycloalkylaminocarbonyl, heterocyclicaminocarbonyl, cycloalkylaminocarbonyl, heterocyclicaminocarbonyl,
`
`wherein R6 is one or more radicals selected from halo, wherein R6 is one or more radicals selected from halo,
`wherein R6 is one or more radicals selected from halo.
`carboxyalkylaminocarbonyl.
`
`carboxyalkylaminocarbonyl, carboxyalkylaminocarbonyl,
`alkylthio. alkylsul?nyl. alkylsulfonyl. cyano. carboxyl.
`
`alkylthio, alkylsulfinyl, alkylsulfonyl, cyano. carboxyl. alkylthio, alkylsulfinyl, alkylsulfonyl, cyano. carboxyl.
`aralkoxycarbonylalkylaminocarbonyl. alkylcarbonyl.
`aralkoxycarbonylalkylaminocarbonyl, alkylcarbonyl, aralkoxycarbonylalkylaminocarbonyl, alkylcarbonyl,
`
`alkoxycarbonyl. aminocarbonyl. N-alkylarninocarbonyl.
`
`alkoxycarbonyl, aminocarbonyl, N-alkylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, N-alkylaminocarbonyl,
`alkylcarbonylalkyl. hydroxyalkyl. haloaralkyl.
`alkylcarbonylalkyl, hydroxyalkyl, haloaralkyl, alkylcarbonylalkyl, hydroxyalkyl, haloaralkyl,
`
`N-arylaminocarbonyl. alkyl. alkenyl. N.N
`
`5 N-arylaminocarbonyl, alkyl, alkenyl, N,N-5 N-arylaminocarbonyl, alkyl, alkenyl, N,N-
`LII
`carboxyhaloalkyl. alkoxycarbonylhaloalkyl.
`carboxyhaloalkyl, alkoxycarbonylhaloalkyl, carboxyhaloalkyl, alkoxycarbonylhaloalkyl,
`
`dialkylaminocarbonyl. N-alkyl-N-arylaminocarbonyl.
`
`dialkylaminocarbonyl. N-alkyl-N-arylaminocarbonyl, dialkylaminocarbonyl. N-alkyl-N-arylaminocarbonyl,
`aminocarbonylhaloalkyl. alkylaminocarbonylhaloalkyl.
`
`aminocarbonylhaloalkyl. alkylaminocarbonylhaloalkyl, aminocarbonylhaloalkyl. alkylaminocarbonylhaloalkyl,
`haloalkyl. hydrido. hydroxyl. alkoxy. hydroxyalkyl.
`
`haloalkyl, hydrido, hydroxyl, alkoxy, hydroxyalkyl, haloalkyl, hydrido, hydroxyl, alkoxy, hydroxyalkyl,
`N-alkylamino. N.N-dialkylamino. N-arylamino.
`
`N-alkylamino, N.N-dialkylamino, N-arylamino, N-alkylamino, N.N-dialkylamino, N-arylamino,
`haloalkoxy. sulfamyl. N-alkylaminosulfonyl. amino.
`
`haloalkoxy, sulfamyl. N-alkylaminosulfonyl, amino, haloalkoxy, sulfamyl. N-alkylaminosulfonyl, amino,
`N-aralkylamino. N-alkyl-N-aralkylamino. N-alkyl-N
`N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-
`
`N-alkylamino. N.N-dialkylamino. heterocyclic.
`
`N-alkylamino, N,N-dialkylamino, heterocyclic, N-alkylamino, N,N-dialkylamino, heterocyclic,
`arylamino. aminoalkyl. N-alkylaminoalkyl. N.N
`arylamino. aminoalkyl, N-alkylaminoalkyl, N,N-arylamino. aminoalkyl, N-alkylaminoalkyl, N,N-
`
`cycloalkylalkyl. nitro and acylamino; and
`
`10 cycloalkylalkyl, nitro and acylamino; and 10 cycloalkylalkyl, nitro and acylamino; and
`dialkylaminoalkyl. N-arylaminoalkyl. N-aralkylaminoalkyl.
`dialkylarninoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, dialkylarninoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl,
`
`N-alkyl-N-aralkylarninoalkyl. N-alkyl-N-arylaminoalkyl.
`wherein R7 is selected from hydrido. alkyl. aryl and
`
`wherein R7 is selected from hydrido, alkyl, aryl and wherein R7 is selected from hydrido, alkyl, aryl and
`N-alkyl-N-arallcylaminoalkyl, N-alkyl-N-arylaminoalkyl, N-alkyl-N-arallcylaminoalkyl, N-alkyl-N-arylaminoalkyl,
`
`aralkyl;
`aryloxy. aralltoxy. arylthio. aralkylthio. alkylthio.
`
`aralkyl; aralkyl;
`
`aryloxy, aralkoxy, arylthio, aralkylthio, alkylthio, aryloxy, aralkoxy, arylthio, aralkylthio, alkylthio,
`alkylsul?nyl. alkylsulfonyl. N-alkylaminosulfonyl.
`alkylsulfinyl, alkylsulfonyl, N-alkylaminosulfonyl, alkylsulfinyl, alkylsulfonyl, N-alkylaminosulfonyl,
`
`
`provided R2 and R3 are not identical radicals selected provided R2 and R3 are not identical radicals selected
`provided R2 and R3 are not identical radicals selected
`N-arylaminosulfonyl. arylsulfonyl. N.N
`N-arylaminosulfonyl, arylsulfonyl, N,N-N-arylaminosulfonyl, arylsulfonyl, N,N-
`
`from hydrido. carboxyl and ethoxycarbonyl; further pro
`
`15 from hydrido, carboxyl and ethoxycarbonyl; further pro-15 from hydrido, carboxyl and ethoxycarbonyl; further pro-
`dialkylamin