United States Patent (19) 11 Patent Number: 5,036,067 Girard et al. 45 Date of Patent: Jul. 30, 1991 (54) DBENZOHETEROCYCLIC HYDROXAMIC 2191194A 6/1987 United Kingdom . ACDS AND HYDROXY UREAS AS OTHER PUBLICATIONS INHIBITORS OF 5-LPOXYGENASE P. K. Kadaba, The Synthesis of Some Phenothiazinyl (75) Inventors: Yves Girard; Pierre Hamel; Daniel Ketones and Their Derivatives, J. Het, Chen. 3, 345 Delorme, all of Quebec, Canada (1966). (73) Assignee: Merck & Co., Inc., Rahway, N.J. C. M. Suter, et al., The Directive Influences of Oxygen (21) Appl. No.: 493,527 and Sulfur, J.A.C.S. 58,717 (1936). Primary Examiner-C. Warren Ivy 22 Filed: Mar. 14, 1990 Assistant Examiner-Celia Chang (51) Int, Cl. ..................... A61K 31/54; A61K 31/55; Attorney, Agent, or Firm-Hesna J. Pfeiffer; Gabriel CO7D 279/18; CO7D 281/12 Lopez 52) U.S. C. ................................. 514/224.8; 514/21 i; 514/431; 514/434; 514/436; 540/551; 544/350; 57 ABSTRACT 544/38; 544/39; 549/10; 549/11; 549/12; 549/16; 549/17 Compounds having the formula I: (58) Field of Search .................... 540/551; 544/35, 38, 544/39; 549/10, 11, 12, 16, 17; 514/211, 224.8, R1 R3 431, 434, 436 (56) References Cited U.S. PATENT DOCUMENTS S OM 3,519,622 7/1970 Sutton ................................... 544/35 R2 3,639,612 2/1972 De Long............................... 544/35 (O) ck'l-N-y 4,536,507 8/1985 Rokach et al. ...................... 514/364 O 4,576,940 3/1986 Tahara et al. ....................... 514/212 4,666,907 5/1987 Fortin et al. ........................ 514/223 4,822,811 4/1989 Summers ............................. 514/411 are inhibitors of the 5-lipoxygenase enzyme. These 4,839,354 6/1989 Sunshine et al. 514/226.5 compounds are useful as anti-asthmatic, anti-allergic, 4,845,083 7/1989 Fortin et al. .......................... 54/80 anti-inflammatory, and cytoprotective agents. They are 4,873,259 10/1989 Summers et al. ................... 514/443 also useful in treating diarrhea, hypertension, angina, 4,889,874 12/1989 Haslanger et al................... 514/575 platelet aggregation, cerebral spasm, premature labor, FOREIGN PATENT DOCUMENTS spontaneous abortion, dysmenorrhea, and migraine. 0279263 2/1988 European Pat. Off. 87/04152 12/1986 United Kingdom . 9 Claims, No Drawings 5,036,067 1. DIBENZOHETERoCYCLIC HYDROXAMIC R1 ACDS AND HYDROXY UREAS AS INHIBITORS X OF 5-LPOXYGENASE BACKGROUND OF THE INVENTION OM The leukotrienes and their biological activities, espe 2 i cially their role in various disease states, have been R (O) extensively studied. Their properties are described in O O the book Leukotrienes and Lipoxygenase, Ed., J. Rokach, Elsevier, N.Y., 1989. Wherein: Inhibitors of the 5-lipoxygenase enzyme will prevent R1, R2 and R3 are independently: the biosynthesis of the various leukotrienes, and hence a) hydrogen, have a beneficial effect in those disease states in which 15 b) lower alkyl, the leukotrienes contribute to the disease. c) lower cycloalkyl, Various derivatives of hydroxylamine have been d) lower alkoxy, described as inhibitors of the 5-lipoxygenase enzyme. e) lower alkanoyloxy; Representative compounds are to be found in the fol f) -CF3 lowing patent documents: EP 196,184, EP279,263, WP 20 g) -CN, 87/04152, U.K. 2, 191,194 and U.S. Pat. No. 4,822,811. h) -NO2, i) -OR4, SUMMARY OF THE INVENTION The present invention relates to compounds having activity as inhibitors of the 5-lipoxygenase enzyme, to 25 methods for their preparation, and to methods and phar m) halogen; maceutical formulations for using these compounds in R4 is: mammals (especially humans). a) hydrogen, Because of their activity as inhibitors of 5-lipoxyge b) R5; 30 R5 is: nase, the compounds of the present invention are useful a) C1-C4 alkyl; as anti-asthmatic, anti-allergic, and anti-inflammatory R6 is: agents and are useful in treating allergic rhinitis and a) hydrogen, chronic bronchitis and for amelioration of skin diseases b) C1 to C4 alkyl, like psoriasis and atopic eczema. These compounds are 35 c) -COR4, also useful to inhibit the pathologic actions of leuko d) -S(O)2R, trienes on the cardiovascular and vascular systems for e) -C1-C4; alkylene-Ar example, actions such as result in angina or endotoxin R7 is: shock. The compounds of the present invention are a) hydrogen, useful in the treatment of inflammatory and allergic b) lower alkyl, diseases of the eye, including allergic conjunctivitis. c) Ar-lower alkyl, The compounds are also useful as cytoprotective agents Ar is: and for the treatment of migraine headache. a) R1 substituted phenyl, Thus, the compounds of the present invention may b) R1 substituted furyl, also be used to treat or prevent mammalian (especially, 45 c) R1 substituted thienyl; human) disease states such as erosive gastritis; erosive X is: esophagitis; inflammatory bowel disease; ethanol a) X, induced hemorrhagic erosions; hepatic ischemia; nox b) -CH=CH-, ious agent-induced damage or necrosis of hepatic, pan c) -CH2-CH2-, creatic, renal, or myocardial tissue; liver parenchymal 50 d) -CH2X-, damage caused by hepatoxic agents such as CC14 and e) -XCH2-, D-galactosamine; ischemic renal failure; disease f) NR7; induced hepatic damage; bile salt induced pancreatic or X1 is: gastric damage; trauma-or stress-induced cell damage; a) O, and glycerol-induced renal failure. 55 b) S, The compounds of this invention are inhibitors of the c) S(O), biosynthesis of 5-lipoxygenase metabolites of arachi d) S(O)2, donic acid, such as 5-HPETE, 5-HETE and the leuko e) NR6; trienes. Leukotrienes B4, C4, D4 and E4 are known to Y is: contribute to various disease conditions such as asthma, a) R4, psoriasis, pain, ulcers and systemic anaphylaxis. Thus b) -N(R')2; inhibition of the synthesis of such compounds will alle M is: viate these and other leukotriene-related disease states. a) hydrogen, b) -COAr, DETAILED DESCRIPTION OF THE 65 c) -CO-alkyl; INVENTION m is 1 to 5; The compounds of the present invention are repre n is 0 to 2; sented by formula I: and pharmaceutically acceptable salts thereof. 5,036,067 3 4. Alkyl, alkenyl, and alkynyl are intended to include refers to salts prepared from pharmaceutically accept linear and branched structures and combinations able non-toxic bases including inorganic bases and or thereof. ganic bases. Salts derived from inorganic bases include As used herein, the term "alkyl' includes "lower aluminum, ammonium, calcium, copper, ferric, ferrous, alkyl" and extends to cover carbon fragments having up lithium, magnesium, manganic salts, manganous, potas to 20 carbon atoms. Examples of alkyl groups include sium, sodium, zinc and the like. Particularly preferred octyl, nonyl, undecyl, dodecyl, tridecyl, tetradecyl, are the ammonium, calcium, magnesium, potassium and pentadecyl, eicosyl, 3,7-diethyl-2,2-dimethyl-4-propyl sodium salts. Salts derived from pharmaceutically ac nonyl, and the like. ceptable organic non-toxic bases include salts of pri As used herein, the term "lower alky' includes those O mary, secondary, and tertiary amines, substituted alkyl groups of from 1 to 7 carbon atoms. Examples of amines including naturally occurring substituted lower alkyl groups include methyl, ethyl, propyl, iso amines, cyclic amines and basic ion exchange resins, propyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, such as arginine, betaine, caffeine, choline, N,N-diben and the like. zylethylenediamine, diethylamine, 2-diethylaminoe The term "cycloalkyl' refers to a hydrocarbon con 15 thanol, 2-dimethylaminoethanol, ethanolamine, ethyl taining one or more rings having from 3 to 12 carbon enediamine, N-ethylmorpholine, N-ethylpiperidine, atoms, with the hydrocarbon having up to a total of 20 glucamine, glucosamine, histidine, hydrabamine, iso carbon atoms. Examples of cycloalkyl groups are cyclo propylamine, lysine, methylglucanine, morpholine, propyl, cyclopentyl, cycloheptyl, aldamantyl, cy piperazine, piperidine, polyamine resins, procaine, pu clododecylmethyl, 2-ethyl-1-bicyclo[4.4.0)decyl and 20 rines, theobromine, triethylamine, trimethylamine, tri the like. propylamine, tromethamine and the like. "Cycloalkenyl' groups include those alkenyl groups When the compound of the present invention is basic, of 3 to 20 carbon atoms, which include a ring of 3 to 12 salts may be prepared from pharmaceutically accept carbon atoms, and in which the alkenyl double bond able non-toxic acids, including inorganic and organic may be located anywhere in the alkenyl group. Exam 25 ples of cycloalkenyl groups are cyclopropen-1-yl, cy acids. Such acids include acetic, benzenesulfonic, ben clohexen-3-yl, 2-vinyladamant-1-yl, 5-methylenedodec zoic, camphorsulfonic, citric, ethanesulfonic, fumaric, i-yl, and the like. gluconic, glutamic, hydrobromic, hydrochloric, isethi As used herein, the term "lower alkoxy' includes onic, lactic, maleic, malic, mandelic, methanesulfonic, those alkoxy groups of from 1 to 7 carbon atoms of a 30 mucic, nitric, pamoic, pantothenic, phosphoric, suc straight, branched, or cyclic configuration. Examples of cinic, sulfuric, tartaric, p-toluenesulfonic acid and the lower alkoxy groups include methoxy, ethoxy, like. Particularly preferred are citric, hydrobromic, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, hydrochloric, maleic, phosphoric, sulfuric and tartaric and the like. acids. As used herein the term "lower alkylthio' includes 35 It will be understood that in the discussion of meth those alkylthio groups of from 1 to 7 carbon atoms of a ods of treatment which follows, references to the con straight, branched or cyclic configuration. Examples of pounds of Formula I are meant to also include the phar lower alkylthio groups include methylthio, propylthio, maceutically acceptable salts. isopropylthio, cycloheptylthio, etc. By way of illustra The ability of the compounds of Formula I to inhibit tion, the propylthio group signifies -SCH2CH2CH3; the 5-lipoxygenase enzyme makes them useful for inhib "lower alkylsulfinyl' and "lower alkylsulfonyl' refer to iting the symptoms induced by the leukotrienes in a the sulfoxides and sulfones of "lower alkylthio'.