United States Patent (19) 11 Patent Number: 4,939,145 Lau Et Al

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United States Patent (19) 11 Patent Number: 4,939,145 Lau et al. 45 Date of Patent: Jul. 3, 1990

54). PHENOTHIAZONE DERVATIVES AND ANALOGS OTHER PUBLICATIONS Chemical Abstracts, vol. 72, No. 13, 3-30-70, p. 406 75 Inventors: Cheuk K. Lau, Pierrefonds; Joshua (Fujisawa). Rokach, Laval; Christiane Yoakim; Chemical Abstracts, vol. 90, No. 92-26-79, p. 133 Rejean Fortin, both of Montreal; (Ghizdavu). Yvan Guindon, Ile Bizard, all of Chemical Abstracts, vol. 78, No. 7, 2-19-73, p. 485 Canada (Shvedov). (73) Assignee: Merck Frosst Canada, Inc., Kirkland, Chemical Abstracts, vol. 92, No. 15, 4-14-80, p. 12 Canada (Mitchell). Journal of the Chem. Soc. Perkin Transactionsi, No. 3 21 Appl. No.: 298,716 (1982) (Gilchrist). (22 Filed: Jan. 19, 1989 Chemical Abstracts, vol. 99, No. 9, 8-29-83, p. 622 (Raileanu). Related U.S. Application Data Rev. Roum. Chim. 13833 (1968). Rev. Roum. Chim 25 691 (1980). 60) Division of Ser. No. 3,354, Jan. 14, 1987, Pat. No. . 4,859,667, which is a division of Ser. No. 786,257, Oct. Ann. Chem. 698 186 (1966). 10, 1985, Pat. No. 4,667,032, which is a continuation of Rev. Roum. Chim. 17 1745 (1972). Ser. No. 591,134, Mar. 19, 1984, abandoned, which is a Ann. Chem. 715 122 (1968). continuation-in-part of Ser. No. 559,471, Dec. 12, 1983, Rev. Roum. Chim 13 1241 (1968). abandoned, which is a continuation-in-part of Ser. No. J. Pharm. Sci. 66 1395 (1977). 536,487, Sep. 28, 1983, abandoned, which is a continua Ann. Chem. 614 171 (1958). tion-in-part of Ser. No. 459,924, Jan. 22, 1983, aban J. Bio. Chem. 257 1591 (1982). doned. Prostaglandins 20 627 (1980). 51 Int. Cl...... A61K 31/60; A61K 31/54; Sircar et al., Biochem. Pharm., 32, No. 1, 170-172, 1983. A61K 31/535; A61K 31/525 Hawkey et al., Prostaglandins Leukotrienes and Medi 52 U.S. C...... 514/224.2; 514/161; cine, 10, 405-409, 1983. 514/165; 514/166; 514/183; 514/228.2; Primary Examiner-Mukund J. Shah 514/229.8; 514/250; 514/404; 514/415; Assistant Examiner-E. C. Ward 514/567; 514/568; 514/569 Attorney, Agent, or Firm-Gabriel Lopez; Hesna J. 58. Field of Search ...... 514/161, 165, 166, 183, Pfeiffer 514/228.2, 229.8, 250, 404, 415,567,568, 569, 2242; 544/32, 58.4, 102,334 (57 ABSTRACT Phenothiazone derivatives and analogs thereof, phar (56) References Cited maceutical compositions and methods of treatment are U.S. PATENT DOCUMENTS disclosed. These compounds are useful as inhibitors of mammalian leukotriene biosynthesis. As such, these 2,395,378 2/1946 Miller ...... 514/161 compounds are useful therapeutic agents for treating FOREIGN PATENT DOCUMENTS allergic conditions, asthma, cardiovascular disorders O155623 7/1985 European Pat. Off. . and inflammation. 2247871 4/1973. Fed. Rep. of Germany . 176152 4/1970 France ...... 514/166 6 Claims, No Drawings co 4,939,145 1. 2 roalkyl; or CH2-R12 wherein n is 3 to 4, R12 is PHENOTHAZONE DERVATIVES AND C1-C5 alkyl, dimethylamino or phenyl; ANALOGS (e) phenyl or substituted phenyl as defined above for Rs; Division of Ser. No. 003,354, Jan. 14, 1987, U.S. Pat. 5 (f) COOR6; No. 4,859,667, which is a division of Ser. No. 786,257, (g) Oct. 10, 1985, U.S. Pat. No. 4,667,032, which is a contin uation of Ser. No. 591,134, Mar. 19, 1984, abandoned, O which is a CIP of Ser. No. 559,471, Dec. 12, 1983, aban doned, which is a CIP of Ser. No. 536,487, Sept. 28, 10 C-R4 1983, abandoned, which is a CIP of Ser. No. 459,924, Jan. 12, 1983, abandoned. wherein R4 is H., (CH2). COOR6 wherein n is 0 U.S. Pat. No. 4,667,032, Lau et al., is incorporated to 4, C1-C6 alkyl, CF3, phenyl, or substituted herein by reference in its entirety. phenyl as defined above for Rs; 15 (h) tetrazole; SUMMARY OF THE INVENTION (i) This invention is directed to pharmaceutical composi O tions containing a compound of the Formula I: I 20 -NH-C-R7 R3 N - R I wherein R7 is C1-C6 alkyl, benzyl or phenyl; N (j) -NRsR9 wherein R8 and R9 are independently T X selected from H, phenyl or substituted phenyl as defined above for R5, C1-C4 alkyl, C1-C4 alkyl 25 amino alkyl, or may be joined through the N to R4 Y R2 form a heterocycloalkyl of 5-8 ring atoms; or a pharmaceutically acceptable salt thereof, a method (k) -NHSO2R10 wherein R10 is OH, C1-C16 alkyl, of treatment using said composition and certain novel C-C6-alkoxy, phenyl, or CF3; Formula I compounds. 30 (l) DETALED DESCRIPTION OF THE O INVENTION -C-CH2OH; One embodiment of the present invention is a phar maceutical composition containing a compound of the 35 (m) -SOR11 wherein R11 is C1-C6 alkyl, phenyl or Formula : substituted phenyl as defined above for R5, (CH2)COOR6 wherein m is 1 to 6, CN, formyl or perfluoro-C1-C4 alkyl; R3 9 R (n) -CONRsR9; 8 N 2 (p) -SO2R13 wherein R13 is OH, C1-C6 alkyl, H, T- F-X phenyl or substituted phenyl as defined above for Rs, (CH2)COOR6 wherein m is 1 to 6, CN, R 6 Y 4 R2 formyl or perfluoro-C1-C4 alkyl; 45 (q) NO2; wherein (r) X is in the 1 or 3 position and is O, S or NR wherein R is H, C1-C6 branched or linear alkyl, CN or phenyl; O Y is O, Se, S, SO, SO2 or NR; and the broken line repre 50 sents an optional double bond between the 1 and 2 or O-C-R14; 2 and 3 position; R1, R2, R3 and R4 are independently selected from: (s) (1) hydrogen; (2) alkyl having 1-6 carbon atoms; 55 O (3) alkenyl having 2-6 carbon atoms; O-C-NRR9 (4) -(CH2)M wherein n is 0-6 and M is (a) OR5; (t) (b) halogen; (c) CF3; O (d) SRs wherein R5 is H; lower alkoxy-lower alkyl; I lower acyloxy-lower alkyl; C1-C6 alkyl; benzyl; O-C-OR; phenyl or substituted phenyl wherein the substit uents are C1-C3 alkyl, halogen, CN, CF3, (u) CN; COOR6, CH2COOR6, (CH2)NRsR9 wherein n 65 (v) NR15 R16 wherein R15 and R16 are such that is 0 to 2, C1-C3 alkoxy, OH, halo-C1-C6-alkyl; HNR15R16 is an essential amino acid; or -(CH2)COOR6, wherein m is 0 to 6 and R6 is any two of R1, R2, R3 and R4 are joined (e.g. as H, phenyl, or C1-C6 alkyl; CN; formyl; perfluo -(CH2)3-4-) to add a fourth ring to the three ring 4,939,145 3 4. structure, said ring having 5 or 6 carbon atoms and bonyl function to a ring system, preferably to an aro being saturated or unsaturated; and, T is H, halo matic ring system. gen or CF3. The numbers surrounding Formula I designate the The acetic acid derivatives which may be used com substituent positions. T, R1, R2, R3 and R4 may be posi prise: indomethacin, which is a preferred NSAID, sulin tioned anywhere in the structure. As an example of dac, tolmetin, zomepirac, diclofenac, fenclofenac, al compounds with a fourth ring, compounds of Formula clofenac, ibufenac, isoxepac, furofenac, tiopinac, II may be prepared by linking two of the substituent zidometacin, acemetacin, fentiazac, clidanac, oxpinac, groups; R1, R2, R3, R4: and fenclozic acid. Structurally related acetic acid de 10 rivatives having similar analgesic and anti-inflammatory I properties are also intended to be encompassed by this group. Thus, "acetic acid derivatives' as defined herein are non-narcotic analgesics/non-steroidal anti-inflamma 5 tory drugs having a free -CH2COOH group (which optionally can be in the form of a pharmaceutically acceptable salt group, e.g. -CH2COONa), typi cally attached directly to a ring system, preferably to an aromatic or heteroaromatic ring system. R The fenamic acid derivatives which may be used wherein Z may be CH, CH2 or a bond, the broken lines comprise: mefenamic acid, meclofenamic acid, flufe represent optional double bonds and R represents the namic acid, niflunic acid and tolfenamic acid. Structur substituent groups of Formula I (R, R2, R3, R4 and/or ally related fenamic acid derivatives having similar T) not used to create the fourth ring. analgesic and anti-inflammatory properties are also In addition to the compounds of Formula I, the phar 25 intended to be encompassed by this group. maceutical compositions can also contain other active Thus, "fenamic acid derivatives' as defined herein ingredients, such as cyclooxygenase inhibitors, non are non-narcotic analgesics/non-steroidal anti-inflam steroidal anti-inflammatory drugs (NSAIDs), periph matory drugs which contain the basic structure: eral analgesic agents such as zonepirac diflunisal and the like. The weight ratio of the compound of the For mula I to the second active ingredient may be varied and will depend upon the effective does of each ingredi ent. Generally, an effective does of each will be used. Thus, for example, when a compound of the Formula I is combined with an NSAID the weight ratio of the 35 ( - ) compound of the Formula I to the NSAID will gener ally range from about 1000:1 to about 1:1000, and pref which can bear a variety of substituents and in which erably from about 200:1 to about 1:200. the free -COOH group can be in the form of a pharma Combinations of a compound of the Formula I and ceutically acceptable salt group, e.g., -COONa. other active ingredients will generally be within the The biphenylcarboxylic acid derivatives which can aforementioned broad range and will preferably be be used comprise: diflunisial and flufenisal. Structurally within the aforementioned preferred range, but in each related biphenylcarboxylic acid derivatives having sini case, an effective dose of each active ingredient should lar analgesic and anti-inflammatory properties are also be used. NSAIDs can be characterized into five groups: 45 intended to be encompassed by this group. (1) the propionic acid derivatives; Thus, "biphenylcarboxylic acid derivatives' as de (2) the acetic acid derivatives; fined herein are non-narcotic analgesics/non-steroidal (3) the fenamic acid derivatives; anti-inflammatory drugs which contain the basic struc (4) the biphenylcarboxylic acid derivatives; and ture: (5) the oxicans or a pharmaceutically acceptable salt thereof. The propionic acid derivatives which may be used comprise: ibuprofen, ibuprufen aluminum, indoprofen, ketoprofen, naproxen, benoxaprofen, flurbiprofen, feno COOH profen, fenbufen, ketoprofen, indoprofen, pirprofen, 55 carprofen, oxaprozin, pranoprofen, miroprofen, tioxa profen, suprofen, alminoprofen, tiaprofenic acid, flu which can bear a variety of substituents and in which profen and bucloxic acid. Structurally related propionic the free -COOH group can be in the form of a pharma acid derivatives having similar analgesic and anti-in ceutically acceptable salt group, e.g., -COONa+. flammatory properties are also intended to be included The oxicans which can be used in the present inven in this group. tion comprise: piroxican, sudoxican, isoxican and 4 Thus, "propionic acid derivatives' as defined herein hydroxyl-1,2-benzothiazine 1,1-dioxide-4-(N-phenyl)- are non-narcotic analgesics/non-steroidal anti-inflam carboxamide. Structurally related oxicans having simi matory drugs having a free -CH(CH3)COOH or lar analgesic and anti-inflammatory properties are also -CH2CH2COOH group (which optionally can be in 65 intended to be encompassed by this group. the form of a pharmaceutically acceptable salt group, Thus, "oxicans' as defined herein are non-narcotic C-8. -CH(CH3)COO-Na+ o -CHCH analgesics/non-steroidal anti-inflammatory drugs 2COONa), typically attached directly or via a car which have the general formula: 4,939,145 5 6 Pharmaceutical compositions comprising the For OH mula I compounds may also contain inhibitors of the biosynthesis of the leukotrienes such as are disclosed in O pending U.S. patent application Ser. Nos. 539,342, filed YiC-N-R Oct. 5, 1983, Ser. No. 459,924, filed Jan. 21, 1983, Ser. No. 539,215, filed Oct. 5, 1983, and Ser. No. 547,161, N filed Oct. 31, 1983, which are hereby incorporated s^ CH3 herein by reference. The compounds of the Formula I may also be used in O combination with leukotriene antagonists such as those disclosed in copending applications U.S. Ser. Nos. wherein R is an aryl or heteroaryl ring system. 520,051 and 520,052, filed Aug. 5, 1983 which are The following NSAIDs may also be used: acemeta hereby incorporated herein by reference and others cin, alminoprofen, amfenac sodium, aminoprofen, ani known in the art such as those disclosed in European trazafen, antrafenine, auranofin, bendazac lysinate, ben 15 Patent Application Nos. 56,172 and 61,800; and in U.K. zydamine, beprozin, broperamole, bufezolac, carprofen, Patent Specification No. 2,058,785, which are hereby cinmetacin, ciproquaZone, clidanac, cloximate, dazida incorporated herein by reference. mine, deboxamet, d3elmetacin, detomidine, dexindo Pharmaceutical compositions comprising the For profen, diacerein, di-fisalamine, difenpyramide, emorfa mula I compounds may also contain as the second ac zone, enfenamic acid, enolicam, epirizole, etersalate, 20 tive ingredient, antihistaminic agents such as benadryl, etodolac, etofenamate, fanetizole mesylate, fenclofenac, dramamine, histadyl, phenergan and the like. Alterna fenclorac, fendosal, fenflumizole, fentiazac, feprazone, tively, they may include prostaglandin antagonists such floctafenine, flunixin, flunoxaprofen, fluoproquazone, as those disclosed in European Patent Application No. fopiirtoline, fosfosal, furcloprofen, furofenac, 11,067 or thromboxane antagonists such as those dis glucametacin, guaimesal, ibuproxam, isofezolac, iso 25 closed in U.S. Pat. No. 4,237,160. They may also con mixim, isoprofen, isoxepac, isoxicam, lefetamine HCl, tain histidine decarboxyase inhibitors such as a leflunomide, lofemizole, lonazolac calcium, lotifazole, fluoromethylhistidine, described in U.S. Pat. No. loxoprofen, lysin clonixinate, meclofenamate sodium, 4,325,961. The compounds of the Formula I may also be meseclazone, miroprofen, nabumetone, nictindole, advantageously combined with an H or H2-receptor mimesulide, orpanoxin, oxametacin, oxapadol, oxapro 30 antagonist, such as for instance cimetidine, ranitidine, zin, perisoxal citrate, pineprofen, pimetacin, piproxen, terfenadine, famotidine, aminothiadiazoles disclosed in pirazolac, pirfenidone, pirprofen, pranoprofen, pro EP No. 40,696 and like compounds, such as those dis glumetacin maleate, proquazone, pyridoxiprofen, closed in U.S. Pat. Nos. 4,283,408; 4,362,736; and sudoxicam, suprofen, talmetacin, talniflumate, tenox 4,394,508. The pharmaceutical compositions may also icam, thiazolinobutazone, thielavin B, tiaprofenic acid, 35 contain a K/H ATPase inhibitor such as ome tiaramide HCl, tiflamizole, timegadine, tioxaprofen, prazole, disclosed in U.S. Pat. No. 4,255,431, and the tolfenamic acid, tolpadol, tryptamid, ufenamate, and like. Each of the references referred to in this paragraph zidometacin. is hereby incorporated herein by reference. The following NSAIDs, designated by company code number, may also be used: 40 480156S, AA861, AD1590, AFP802, AFP860, Rg Ra AI77B, AP504AU8001, BPPC, BW540C, CHI R?. N R NOIN 127, CN100, EB382, EL508, F1044, N GV3658, ITF182, KCNTE16090, KME4, LA2851, MR714, MR897, MY309, ONO3144, 45 N PR823, PV102, PV108, R830, RS2131, SCR152, Re. Y O SH440, SIR133, SPAS510, SQ27239, ST281, SY6001, TA60, TAI-901 TVX2706, U60257, and Rd R WY41770. Finally, NSAIDs which may also be used include the so Tables 8 and 9 describe the novel compounds of the salicylates, specifically aspirin, and the phenylbuta present invention: zones, and pharmaceutically acceptable salts thereof. TABLE 8 NOVEL FORMULAI COMPOUND Rg Ra Rf. N Rh N N Re Y O Rd R Y Ra Rb R Rd Re Rf R S H H CF3 H. H. H. H. S H CF3 CF3 H. H. H. H. S CF H H H. H. H. H.

4,939,145 11 12 Table 9 describes the novel compounds of the present TABLE 10 invention having four rings. NOVELCOMPOUNDS OF FORMULA I TABLE 9 Rd O N NOVEL COMPOUNDS OF FORMULA II I N R R R

N 10 S N R2 R Ra R R Rd N t-Bu t-Bu H H R Y O 15 t-Bu t-Bu F H R3 t-Bu t-Bu Me H t-Bu t-Bu SMe H t-Bu t-Bu H OMe Y R R2 R3 R4 S H H S-n-CH4H9 H 2O Formula I includes both novel and known com S OH. H. CH3 H pounds. These compounds may be prepared by any S OCHs H CH3 H process available to the skilled artisan. S H H F H One such process for compounds where X=O in S H H CF H volves the oxidation of the appropriate phenothiazine as S H H C CF 25 illustrated by the following equations. S H H C SCH3 S H H Br C S H H CH3 Br H S H H F Br S H H COCH3 Cl 30 S H H CF CH3 T Ole S H H S-n-C4H9 CH3 S H H CF C S H H Cl CHCOOR Y R2 S H H C *CH(MeCoR 35 S H H Cl COCH3 R3 N R1 S H H H Cl S H H H Br N S H H H F T O S H H H CFs 40 S H H H CH3 R Y R2 S H H H CHOH S H H H OCH3 S H H H SCH3 45 S H H H *COOR R3 NH S H H H *CH2COR S H H H *CH(Me)COR SO2 H H NHPr H T R. Oe SO SO2 H H /-, H Y R2 N N-CH O \-/ R3 N 55 N SO2 H H NH2 H SO2 H H NHPr OCH3 T R S -1,4-dihydro- H S H H NHP OCH3 R Y R2 O H H Cl H 60 O H H Br H Various oxidizing agents and systems are taught in the O H H Br OCH3 art, e.g. PbO2, HNO3, K2Cr2O, K2Cr2O7, iodine, O H H NHP OCH3 FeCl3 and the like. R is H or C to C alkyl 6S Another process useful for preparing some Formula I compounds containing halogen substituents is by direct Table 10 describes additional novel compounds of the halogenation of an appropriate phenothiazone or analog present invention. thereof as illustrated by the following equation. 4,939,145 13 14 -continued OH N N Cl2 5 O Y

10 OH D / N The process requires the use of 2 moles of quinone per O mole of aniline. Any suitable solvent may be used. Ex Y 15 ample of such solvents are acetic acid, lower alkanols, C acetic acid/H2O, loweralkanol/water, other polar sol vents and the like. A preferred solvent is one which will Still another process useful for preparing many of the dissolve A, B and D and in which C is substantially insoluble. The reaction is readily carried out at room Formula I compounds is by the reaction of an appropri 20 temperature-lower temperatures, e.g. as low as -10 ate aniline with an appropriate quinone as illustrated by C, may be used-elevated temperatures may also be the following equation: used but are not required. What is claimed is: 25 1. A pharmaceutical composition for inhibiting mam R3 malian leukotriene biosynthesis or action containing a NH2 pharmaceutically acceptable carrier and an effective T -- amount of a compound of the Formula I:

YH 30 R4 R3 N R1 N O R R3 N R N -R4 Y R2 T N wherein I R2 R4 Y R2 X is in the 1 or 3 position and is O, S or NR; O R is H, C1-C6 branched or linear alkyl, CN or phenyl; Y is O, Se, S, SO, SO2 or NR; and the broken line repre This general process is described in the literature. sents an optional double bond between the 1 and 2 or A specific process for preparing the intermediate 2 and 3 position; 45 R1, R2, R3 and R4 are each independently selected from: phenothiazin-3-one is illustrated by the following equa (1) hydrogen, tion: (2) alkyl having 1-6 carbon atoms, (3) alkenyl having 2-6 carbon atoms, (4) -(CH2)M wherein n is 0-6 and M is NH2 50 (a) ORs, (b) halogen, -- (c) CF3, SH (d) SRs wherein R5 is H; lower alkoxyl-loweralkyl; 55 lower acyloxy-loweralkyl; C1-C6 alkyl; benzyl; phenyl or substituted phenyl wherein the substit A uents are C1-C3 alkyl, halogen, CN, CF3, COOR6, CH2COOR6, (CH2)NRsR9 wherein n O is 0 to 2, C1-C3 alkoxy, OH, halo-C1-C6-alkyl; N -(CH2)COOR6, wherein m is 0 to 6 and R6 is N H, phenyl or C1-C5 alkyl; CN, formyl; perfluor 2 awamm -- alkyl; or CH2-R12, wherein R12 is C1-C5 alkyl, N phenyl or dimethylamino; S O 65 (e) phenyl or substituted phenyl as defined above O for Rs; B C. (f) COOR6; (g) 4,939,145 15 16

C-R4 -o--R.4.

r wherein R14 is H., (CH2). COOR6 wherein n is 0 () to 4, C1-C6 alkyl, CF3, phenyl, or substituted O phenyl as defined above for R5; -o--Nrr; (h) 10 s (s) O O -NH-C-R 15 -O-C-OR; wherein R7 is C1-C5 alkylbenzyl or phenyl; (t) -CN; or (i) -NRsR9 wherein Rs and R9 are independently any two of R, R2, R3 and R4 may be joined to form selected from H, phenyl or substituted phenyl as a fourth ring, which may be saturated or unsaturated, 20 of five or six carbons and; defined above for Rs or C1-C4 alkyl, C1-C4 al T is H, halogen or CF3. kylamino alkyl, or may be joined through the N 2. The composition of claim 1 additionally compris to form a heterocycloalkyl of 5-8 ring atoms; ing a second active ingredient selected from the group (j) -NHSO2R10 wherein R10 is OH, C1-C5 alkyl, 25 consisting of non-steroidal anti-inflammatory drugs; C-C6-alkoxy, phenyl or CF3; peripheral analgesic agents; cyclooxygenase inhibitors; leukotriene antagonists; leukotriene inhibitors; H (k) receptor antagonists; antihistaninic agents; prostaglan din antagonists; and thromboxane antagonists, wherein the weight ratio of said Formula I compound to said 3O second active ingredient ranges from about 1000:1 to -C-CH2OH; 1:OOO, 3. The composition of claim 2, wherein said ratio is (l) -SOR11 wherein R11 is C1-C6 alkyl, phenyl or about 200:1 to 1:200. 4. The composition of claim 2, wherein the second substituted phenyl as defined above for R5, 35 active ingredient is a non-steroidal anti-inflammatory (CH2)COOR6 wherein m is 1 to 6, CN, formyl drug. or perfluoro-C1-C4 alkyl; 5. The composition of claim 3, wherein the non (m) -CONR8R9 steroidal anti-inflammatory drug is indomethacin. 6. The composition of claim 1 additionally compris ing an effective amount of a second active ingredient (o) -SO2R13 wherein R13 is OH, H, C1-C6-alkyl, selected from the group consisting of non-steroidal phenyl or substituted phenyl as defined above for anti-inflammatory drugs; peripheral analgesic agents; Rs, (CH2)COOR6 wherein m is 1 to 6, CN or cyclooxygenase inhibitors; leukotriene antagonists; perfluoro-C1-C4 alkyl; leukotriene inhibitors; H2-receptor antagonists; antihis 45 taminic agents; prostaglandin antagonists; and throm (p) NO2; boxane antagonists. (r)