CA2012137C - Dibenzoheterocyclic hydroxamic acids and hydroxy ureas as inhibitors of 5-lipoxygenase - Google Patents

Abstract

Compounds having the formula I:

(see formula I) are inhibitors of the 5-lipoxygenase enzyme. These compounds are useful as anti-asthmatic, anti-allergic, anti-inflammatory, and cytoprotective agents. They are also useful in treating diarrhea, hypertension, angina, platelet aggregation, cerebral spasm, premature labor, spontaneous abortion, dysmenorrhea, and migraine.

Description

TITLE OF THE INVENTION
DIBENZOHETEROCYCLIC HYDROXAMI(: ACIDS AND HYDROXY
UREAS AS INHIBITORS OF 5-LIP03LYGENASE.
BACKGROUND OF THE INVENTION
The leukotrienes and their biological activities, especially their role in various disease states, have been extensively studied. Their properties are described in the book Leukotrienes and Linoxyg~nase, Ed., J. Rokach, Elsevier, New York, 1989.
Inhibitors of the 5-li.poxygenase enzyme will prevent the biosynthesis of the various leukotrienes, and hence have a beneficial effect in those disease states in which the leukotrierues contribute to the disease.
Various derivatives of hydroxylamine have been described as inhibitors of the 5-lipoxygenase enzyme. Representative compounds are to be found in the following patent documents: EP 196,184, EP
279,263, WP 87/04152, U.K. 2,191,194 and U.S.
4,822,811.

2012.37 BUMMARY OF THE INVENTION
The present invention relates to compounds having activity as inhibitors of the 5-lipoxygenase enzyme, to methods for their i>reparation, and to methods and pharmaceutical formulations for using these compounds in mammals (es;pecially humans).
Because of their activity as inhibitors of 5-lipoxygenase, the compounds of the present invention are useful as anti-asthmatic, anti-allergic, and anti-inflananatory agents and are useful in treating allergic rhinitis and chronic bronchitis and for amelioration of skin diseases like psoriasis and atopic eczema. These compounds are also useful to inhibit the pathologic actions of leukotrienes on the cardiovascular and vascular systems for example, actions such as result in angina or endotoxin shock. The compounds of the present invention are useful in the treatment of inflammatory and allergic diseases of the eye, including allergic conjunctivitis. The compounds are also useful as cytoprotective agents and for the treatment of migraine headache.
Thus, the compounds of the present invention may also be used to treat or prevent mammalian (especially, human) disease states such as erosive gastritis; erosive esophagitis; inflammatory bowel disease; ethanol-induced hemorrhagic erosions;
hepatic ischemia; noxious agent-induced damage or necrosis of hepatic, pancreatic, renal, or myocardial tissue; liver parenchymal damage caused by hepatoxic agents such as CC14 and D-galactosamine; ischemic renal failure; disease-induced hepatic damage; bile salt induced pancreatic or gastric damage; trauma- or ~o~~~~~

stress-induced cell damage; and glycerol-induced renal failure.
The compounds of this invention are inhibitors of the biosynthesi.: of 5-lipoxygenase metabolites of arachidonic acid, such as 5-HPETE, 5-HETE and the leukotrienes. Leukotrienes B4, C4, D4 and E4 are known to contributes to various disease conditions such as asthma, psoriasis, pain, ulcers and systemic anaphylaxis. Thus inhibition of the synthesis of such compounds will alleviate these and other leukotriene-related disease states.
DETAILED DESCRIPTION OF THE In'fVENTION
The compounds of the present invention are represented by formula I:
R' R3 X
OM
R ~ Q) n ~ C~ R4) a ~ m N~Y

2 0 I'O
I
Wherein:
Rl, R2 and R3 are independently:
a) hydrogen, b) lower alkyl, c) lower cycloalkyl, d) lower alkoxy, e) lower alkanoyloxy;

f ) -CF3 g) -CN, h) -N02, i) -OR4, j) -N(R4)2, -NCOR4,, -N(R4)CON(R4)2, -SRS -S(0)R5~ --S(0)2R5> -s(0)2NR4~
k) 1) -COR4, -COOR4, --CON(R4)2 m) halogen;

R4 is .
a) hydrogen, b) R5;
R5 is:
a) C1-C4 alkyl;
R6 is:
a) hydrogen, b) C1 to C4 alkyl, c) -COR4, d) -s(0)2R4 e) -RSAr;
R~ is:
a) hydrogen, b) lower alkyl, c) Ar-lower alkyl, Ar is:
a) Rl substituted f~henyl, b) Rl substituted furyl, c) R1 substituted t:hienyl;

GB40 - ;i - 18049 20127 3l X is:
a) X1~
b) -CH=CH-, c) _CH2_CH2_~
d) _CH2X1_~
e) _X1CH~_, f ) -NR~ ;
X1 is:
a) 0, to b) S, c) S(0), d) S(0)2, e) NR6;

Y is:
a) R4.
b) _N(R4)2~
M is:
a) hydrogen, b) -COAr, c) -CO-alkyl;
m is 1 to 5;
n is 0 to 2;
and pharmaceutically acceptable salts thereof.
Alkyl, alkenyl, and alkynyl are intended to include linear and branched structures and combinations thereof.
As used herein, the term ~~alkyl~~ includes .i~

~0~~~.3°~

"lower alkyl" and extends to cover carbon fragments having up to 20 carbon atoms. Examples of alkyl groups include octyl, nonyl, u:ndecyl, dodecyl, tridecyl, tetradecyl, pentadec;yl, eicosyl, 3,7-diethyl-2,2-dimethyl-4-pro;pylnonyl, and the like.
As used herein, the term "lower alkyl"
includes those alkyl groups of from 1 to 7 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, and the like.
to The term "cycloalkyl" refers to a hydrocarbon containing one or more rings having from 3 to 12 carbon atoms, with the hydrocarbon having up to a total of 20 carbon atoms. Examples of cycloalkyl groups are cyclopropyl, cyclopentyl, cycloheptyl, aldamantyl, cyclododecylmethyl, 2-ethyl-1- bicyclo[4.4.0]decyl and the like.
"Cycloalkenyl" groups include those alkenyl groups of 3 to 20 carbon atoms, which include a ring of 3 to 12 carbon atoms, and in which the alkenyl double bond may be located anywhere in the alkenyl group. Examples of cycloalken.yl groups are cyclopropen-1-y1, cyclohexen-3-y1, 2-vinyladamant-1-yl, 5-methylenedodec-1-y1, and the like.
As used herein, the term "lower alkoxy"
includes those alkoxy groups c~f from 1 to 7 carbon atoms of a straight, branched, or cyclic configuration. Examples of lower alkoxy groups 3o include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like.
As used herein the term "lower alkylthio"
includes those alkylthio groups of from 1 to 7 carbon atoms of a straight, branched or cyclic configuration. Examples of lower alkylthio groups include methylthio, propylthio, isopropylthio, cycloheptylthio, etc. By way of illustration, the propylthio group signifies -SCH2CH2CH3; "lower alkylsulfinyl" and "lower alkylsulfonyl" refer to the sulfoxides and sulfones of "lower alkylthio".
Halogen includes F, C1, Br, and I.
It is intended that the definitions of any substituent (e. g., R1, R2, R3, etc.) in a particular molecule be independent of its definitions elsewhere in the molecule. Thus, -N(R3)2 represents -NH2, -NHCH3, -N(CH3)C2H5, etc.
The term "alkanoyl" refers to the acyl residue of an alkanoic acid of up to 20 carbon atoms. Examples, of alkanoyl groups include formyl, acetyl, 2-ethylhexanoyl, eicosanoyl, etc. The term "aroyl" refers to the acyl residue of a benzoic acid carrying an R1 substituent. Examples of aroyl groups include benzoyl, 4-chlorobenzoyl, 3-cyanobenzoyl, etc.
Some of the compounds described herein contain one or more asymmetric: centers and may thus give rise to diastereomers and' optical isomers. The present invention is meant to comprehend such possible diastereomers as well. as their racemic and resolved, enantiomerically pure forms and pharmaceutically acceptable salts thereof.
The pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt, thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term ~~~.~~.3"~

"pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,NI-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine~, tromethamine and the like.
When the compound of t;he present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, malefic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particularly preferred are citric, hydrobromic, hydrochloric, malefic, phosphoric, sulfuric and tartaric acids.
It will be understood that in the discussion of methods of treatment which follows, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
The ability of the compounds of Formula I to inhibit the 5-lipoxygenase enzyme makes them useful for inhibiting the symptoms induced by the leukotrienes in a human subject. This inhibition of the mammalian biosynthesis of leukotrienes indicates that the compounds and pharmaceutical compositions thereof are useful to treat, prevent, or ameliorate in mammals and especially in humans: 1) pulmonary conditions including diseases such as asthma, 2) allergies and allergic reactions such as allergic rhinitis, contact dermatitis, allergic conjunctivitis, and the like, 3) inflammation such as arthritis or inflammatory bowel disease, 4) pain, 5) skin conditions such as psoriasis and the like, 6) cardiovascular conditions such as angina, endotoxin shock, and the like and 7) renal insufficiency arising from ischaemia induced by immunological or chemical (cyclosporin) etiolo~;y and that the compounds are cytoprotective agents.
The cytoprotective activity of a compound may be observed in both animals and man by noting the increased resistance of the gastrointestinal mucosa to the noxious effects of strong irritants, for example, the ulcerogenic effects of aspirin or indomethacin. In addition to lessening the effect of non-steroidal anti-inflammatory drugs on the ~0~.~~.3~
GB40 - to -- 18049 gastrointestinal tract, animal studies show that cytoprotective compounds will prevent gastric lesions induced by oral administration of strong acids, strong bases, ethanol, hypertonic saline solutions and the like.
Two assays can be used to measure cytoprotective ability. These assays are; (A) an ethanol-induced lesion assay and (B) an indomethacin-induced ulcer assay and are described in EP 140,684.
The magnitude of prophylactic or therapeutic dose of a compound of Formula I will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound of Formula I and its route of administration. It will also vary according to the ages, weight and response of the individual patient. In general, the daily dose range for anti-asthmatic, anti-allergic or anti-inflammatory use and generally, uses other than cytoprotection, lie within they range of from about 0.001 mg to about 100 mg per k;g body weight of a mammal, preferably 0.01 mg to about 10 mg per kg, and most preferably 0.1 to 1 mg peer kg, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.
For use where a compo.:ition for intravenous administration is employed, a suitable dosage range for anti-asthmatic, anti-inflammatory or anti-allergic use is from about 0.001 mg to about 25 mg (preferably from 0.01 mg to about 1 mg) of a compound of Formula I per kg of body weight per day and for cytoprotective use from about 0.1 mg to about 2~~.~~3'~

100 mg (preferably from about 1 mg to about 100 mg and more preferably from about 1 mg to about 10 mg) of a compound of Formula I per kg of body weight per day.
In the case where an oral composition is employed, a suitable dosage range for anti-asthmatic, anti-inflammatory or anti-allergic use is, e.g. from about 0.01 mg to about 100 mg of a compound of Formula I per kg of body weight per day, preferably from about 0.1 mg to about 10 mg per kg and for cytoprotective use from 0.1 mg; to about 100 mg (preferably from about 1 mg to about 100 mg and more preferably from about 10 mg to about 100 mg) of a compound of Formula I per kg of body weight per day.
For the treatment of diseases of the eye, ophthalmic preparations for ocular administration comprising 0.001-1% by weight solutions or suspensions of the compounds crf Formula I in an acceptable ophthalmic formulation may be used.
2o The exact amount of a compound of the Formula I to be used as a cytoprotective agent will depend on, 'n r alia, whether it is being administered to heal damaged cells or to avoid future damage, on the nature of the damaged cells (e. g., gastrointestinal ulcerations vs. nephrotic necrosis), and on the nature of the causative agent. An example of the use of a compound of the Formula 7: in avoiding future damage would be co-administrat:ion of a compound of the Formula I with a non-steroidal anti-inflammatory drug that might otherwise cause such damage (for example, indomethacin). For ;>uch use, the compound of Formula I is administered i:rom 30 minutes prior up to 30 minutes after administration of the NSAID.

~o~~~~~
__ GB40 - 12 -- 18049 Preferably it is administered prior to or simultaneously with the NSAID, (for example, in a combination dosage form).
Any suitable route of administration may be employed for providing a mammal, especially a human with an effective dosage of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage formic include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
The pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids.
The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and ~on the nature of the active ingredient. They may 'be conveniently 3o Presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
For administration by inhalation, the compounds of the present invention are conveniently ~0~~13'~

delivered in the form of an aerosol spray presentation from pressurized packs or nebulisers.
The compounds may also be delivered as powders which may be formulated and the powder composition may be inhaled with the aid of an insufflation powder inhaler device. The preferred delivery system for inhalation is a metered dose inhalation (MDI) aerosol, which may be formulated as a suspension or solution of compound I in suitable propellants, such to as fluorocarbons or hydrocarbons.
Suitable topical formulations of Compound I
include transdermal devices, aerosols, creams, ointments, lotions, dusting powders, and the like.
In practical use, the compounds of Formula I
can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agent:> and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, 3o binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid GB40 - 14. - 2 01213 l 18049 preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
In addition to the common dosage forms set out above, the compounds of Formula I may also be administered by controlled release means and/or delivery devices such as those described in U.S.
Patent Nos. 3,845,770; 3,916,899; 3,536,809;
3,598,123; 3,630,200 and 4,008,719r Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a 2o non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with t:he carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable GB40 _ .~5 _ 2 01213 ~ 18049 machine, the active ingredient in a free-f lowing form such as powder or granules, optionally mined with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Desirably, each tablet contains from about 2.5 mg to about 500 mg of the active ingredient and each cachet or capsule contains from about 2.5 to about 500 mg of the active ingredient.
The following are examples of representative pharmaceutical dosage forms' for the compounds of Formula I:
~~ectab~a SusR~nsion (I.M.~
Compound of Formula I 10 Methylcellulose 5.0 Tween *80 0 . 5 Benzyl alcohol 9.0 Benzalkonium chloride 1.0 Water for injection to a total volume of 1 ml Tablet mg/tablet Compound of Formula I 25 Microcrystalline Cellulose 415 Providone* 14.0 Pregelatinized Starch 43.5 Magnesium Stearate 2_.5 f,'psule ~ capsule Compound of Formula I 25 Lactose Powder 573.5 Magnesium Stearate ~.5 *Trademark 2~~.2~~'~

Aerosol Per canister Compound of Formula I 24 mg Lecithin, NF Liquid Concentrate 1.2 mg Trichlorofluoromethane, NF 4.025 gm Dichlorodifluoromethane, NF 12.15 gm In addition to the compounds of Formula I, the pharmaceutical compositions of the present invention can also contain other active ingredients, such as cyclooxygenase inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), peripheral analgesic agents such as zomepirac diflunisal and the like. The weight ratio of the compound of the Formula I to the second active ingredient may be varied and will depend upon th.e effective dose of each ingredient. Generally, an effective dose 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 compound of the Formula I to the NSAID will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200.
Combinations of a compound of the Formula I and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
NSAIDs can be characterized into five groups:
(1) the propionic acid derivatives;
(2) the acetic acid derivatives;
(3) the fenamic acid derivatives;

(4) the biphenylcarbc~xylic acid derivatives;

(5) the oxicams or a pharmaceutically acceptable salt thereof.

~o~~~~~

The propionic acid derivatives which may be used comprise: alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fen.oprofen, fluprofen, flurbiprofen, ibuprofen, indop~rofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, prano-profen, suprofen, tiaprc~fenic acid, and tioxaprofen. Structurally related propionic acid derivatives having similar analgesic and anti-inflammatory properties a.re also intended to be included in this group.
to Thus, "propionic acid derivatives" as defined herein are non-narcotic analge~sics/non-steroidal anti-inflammatory drugs having; a free -CH(CH3)COOH or -CH2CH2COOH group (which optionally can be in the form of a pharmaceutically acceptable salt group, e.g., -CH(CH3)C00-Na+ or -CH2CH2C00-Na+), typically attached directly or via a carbonyl function to a ring system, preferably to an aromatic ring system.
The acetic acid derivatives which may be used comprise: indomethacin, which is a preferred NSAID, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin and zome~pirac. Structually related acetic acid derivatives having similar analgesic and anti-inflammatory properties are also intended to be encompassed by this group.
Thus, "acetic acid derivatives" as defined herein are non-narcotic analge~sics/non-steroidal anti-inflammatory drugs having; a free -CH2COOH group (which optionally can be in the form of a pharmaceutically acceptable salt group, e.g.

2U~.~~3'~
GB4o - 18 -- 18049 -CH2C00-Na+), typically attached directly to a ring system, preferably to an aromatic or heteroaromatic ring system.
The fenamic acid derivatives which may be used comprise: flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid.
Structurally related fenamic acid derivatives having similar analgesic and anti-inflammatory properties are also intended to be encompassed by this group.
Thus, "fenamic acid derivatives" as defined herein are non-narcotic analgesics/non-steroidal anti-inflammatory drugs which contain the basic structure:
O N
C02 '~1H
which can bear a variety of su,bstituents and in which the free -COOH group can be in the form of a pharmaceutically acceptable salt group, e.g., -C00-Na+.
The biphenylcarboxylic. acid derivatives which can be used comprise: diflunisal and flufenisal.
Structurally related biphenylc:arboxylic acid derivatives having similar analgesic and anti-inflammatory properties a.re also intended to be encompassed by this group.
Thus, "biphenylcarbo~ylic acid derivatives"
as defined herein are non-narcotic analgesics/non-steroidal anti-inflammatory drugs GB40 - 19 ~- 18049 which contain the basic structure:
cozH
which can bear a variety of substituents and in which the free -COOH group can be in the form of a pharmaceutically acceptable salt group, e.g., -C00-Na+.
The oxicams which can be used in the present invention comprise: isoxicam, piroxicam, sudoxicam and tenoxican. Structurally related oxicams having similar analgesic and anti-inflammatory properties are also intended to be encompassed by this group.
Thus, "oxicams" as defined herein are non_ narcotic analgesics/non-steroi.dal anti-inflammatory drugs which have the general i:ormula:
OH O
"-NFiR
i~
.N.C H3 (O)z wherein R is an aryl or heteroaryl ring system.
The following NSAIDs may also be used:
amfenac sodium, aminoprofen, <initrazafen, antrafenine, auranofin, bendazac lysinate, benzydanine, beprozin, broper<~mole, bufezolac, cinmetacin, ciproquazone, clo:~cimate, dazidamine, ~~1~~.3~
GB40 - 20 ~- 18049 deboxamet, delmetacin, detomid.ine, dexindoprofen, diacerein, di-fisalamine, dife~npyramide, emorfazone, enfenamic acid, enolicam, epirizole, etersalate, etodolac, etofenamate, fanetiz;ole mesylate, fenclorac, fendosal, fenflumiz;ole, feprazone, floctafenine, flunixin, fluno~:aprofen, fluproquazone, fopirtoline, fosfosal, furcloprofen, glucametacin, guaimesal, ibuproxam, isofezol.ac, isonixim, isoprofen, isoxicam, lefetamine HCI, leflunomide, lofemizole, lonazolac calcium, lotifazole, loxoprofen, lysin clonixinate, meclofenamate sodium, meseclazone, nabumetone, nicti.ndole, nimesulide, orpanoxin, oxametacin, oxapadol, perisoxal citrate, pimeprofen, pimetacin, piproxe~n, pirazolac, pirfenidone, proglumetacin mal.eate, proquazone, pyridoxiprofen, sudoxicam, ta~.metacin, talniflumate, tenoxicam, thiazolinobutazone, thielavin B, tiaramide AC1, tiflamizole, timegadine, tolpadol, tryptamid and ufenamate .
The following NSAIDs, designated by company code number (see e.g., Pharma~>roiects), may also be used:
480156S, AA861, AD1590, AFP802., AFP860, AI77B, AP504, AU8001, BPPC, BW540C, CHINOIN 127, CN100, EB382, EL508, F1044, GV3658, ITF182, KCNTEI6090, KME4, LA2851, MR714, MR897, MY309, 0N03144, PR823, PV102, PV108, 8830, RS2131, SCR152, SH440, SIR133, SPAS510, SQ27239, ST281, SY6001, TA60, TAI-901 (4-benzoyl-1-indancarboxylic acid), TVX270Ei, U60257, UR2301, and WY41770.
Finally, NSAIDs which may also be used include the salicylates, specifically acetyl salicylic acid and the phenylbutazones, and 6840 - ;Z1 - 2 01213 7 18049 pharmaceutically acceptable salts thereof.
In addition to indomethacin, other pref erred NSAIDS are acetyl salicylic acid, diclofenac, fenbufen, fenoprofen, flurb~iprofen, ibuprofen, ketoprofen, naproxen, phenylbutazone, piroxicam, sulindac and tolmetin.
Pharmaceutical compositions comprising the Formula I compounds may also contain inhibitors of the biosynthesis of the leukotrienes such as are disclosed in EP 138,481 (April 24,1985), EP 115,394 (August 8, 1984), EP 136,893 (April 10, 1985), and EP
140,709 (May 8, 1985), The compounds of t:he Formula I may also be used in combination with le~ukotriene antagonists such as those disclosed in EP 106,565 (April 25, 1984) and EP 104,885 (April 4, 1984).
and others known in the art such as those disclosed in EP Application Nos. 56,172 (July 21, 1982) and 61,800 (June 10, 1982); and in U.K. Patent Specification No. 2,058,785 (April 15, 1981), Pharmaceutical compositions comprising the Formula I compounds may also contain as the second active ingredient, prostaglandin antagonists such as those disclosed in EP 11,067 (May 28, 1980) or thromboxane antagonists such as those disclosed in U.S. Pat. 4,237,160. They may also contain histidine 3o decarboxylase inhibitors such as a-f luoromethylhistidine, described in U.S. Pat.
4,325,961. The compounds of the Formula I may also be advantageously combined with an H1 or H2-receptor A

GB40 - 22 - 2 01213 l 18049 antagonist, such as for instance acetamazole, aminothiadiazoles disclosed in EP 40,696 (December 2, 1981), benadryl, cimetidine, famotidine, framamine, histadyl, phenergan, ranitidine, terfenadine and like compounds, such as those disclosed in U.S. Patent Nos. 4,283,408; 4,362,736; and 4,394,508. The pharmaceutical compositions may also contain a K+/g+
ATPase inhibitor such as omeprazole, disclosed in U.S. Pat. 4,255,431, and the like. Compounds of Formula I may also be usefully combined with most cell stabilizing agents, such as 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane and related compounds described in British Patent Specifications 1,144,905 an<i 1,144,906. Another useful pharmaceutical composition comprises the Formula I compounds in combination with serotonin antagonists such as methysergide, 'the serotonin antagonists described in ~:ure, Vol. 316, pages 126-131, 1985, and the like., Other advantageous pharmaceutical compositions comprise the Formula I compounds in combination with anti-cholinergics such as ipratropium bromide, bronchodilators such as the beta agonist salbutamol, metaprot:erenol, terbutaline, fenoterol and the like, and the anti-asthmatic drugs theophylline, choline theophyllinate and enprofylline, the calcium antagonists nifedipine, 3o diltiazem, nitrendipine, verapamil, nimodipine, felodipine, etc. and the corticosteroids, hydrocortisone, methylpredni.solone, betamethasone,' degamethasone, beclomethasone, and the like.

2~~~~~"~
GB40 - 23 ~- 18049 Methods of Synthesis Compounds of the formula I_ of the present invention may be prepared according to the following method. Temperatures are in d'~egrees Celsius, and compound numbers relate to those represented in Scheme 1 below.
The hydroximinoalkyl intermediate III is prepared by addition of hydroxylamine hydrochloride to the ketone II in an alcoholic solvent, such as ethanol, in the presence of an organic nitrogen base, e.g. pyridine. The oxime, III:, is then converted to the hydroxaminoalkyl IV by reduction with a suitable reducing agent, such as pyridine-borane complex, in an acidic alcoholic solvent, e~.g. ethanolic HC1.
Compounds of the formula I_ area then obtained from IV
by addition of trimethylsilyl isocyanate in an organic solvent such as tetrahydrofuran (THF).
Subsequent addition of water allows the necessary hydrolysis to the N-hydroxy urea compounds I of the invention. This portion of the synthesis is repeated below, from the ketone intermediate II, with several variations on the starting material.
For example, phenoxathiin ketone II may be taken through to I_ directly or first oxidized by an oxidant, such as m-chloroperoxy benzoic acid (MCPBA), in an organic solvent, such as methylene chloride, followed by addition of an inorganic base, such as calcium hydroxide, to yield th.e phenoxathiin-10,10-dioxide ketone V. This compound may then be treated like II above to yield the N-[1-(10,10-dioxo-phenoxathiin.-2-yl)ethyl]-N-hydroxy urea compound of formula I_.
Where Rl is hydrogen and R2 is bromine (or chlorine) , addition of a compc>und of formula VI
halophenoxathiin, to a suspension of aluminum chloride in 1,2-dichloro ethane in the presence of an acyl halide, (followed by quenching with ice-water and isolation of the organic fraction and drying over MgS04) yields the halogenated ketone I_~ which may then be treated as was I~ above to yield the N-[1-(8-halophenoxathiin-2-yl)ethyl]-N-hydroxy urea of formula I.
In order to incorporate a cyano functionality into the 8 position of the molecule, the haloketone, as obtained above, may be treated with cuprous cyanide in an organic solvent, such as DMF, followed by precipitation in water and isolation of the organic components. The resultant 8-cyano ketone II may then be treated as was the ketone II
above to yield I_ as, for examF~le, the N-[1-(8-cyanophenoxathiin-2-y1.)ethyl]- N-hydroxy urea derivative.
Where the starting material contains a carboxylic acid moiety ~, as' in dibenzo[b,f]thiepin-3-carboxylic acid and similar compounds, the acid group may be converted into the ketone of formula ~ by treatment with methyl lithium in ether followed by aqueous ammonium chloride and isolation of the organic phase. The ketone thus derived may then be treated as was II above to yield, for example, the N-[1-(Dibenzo[b,f]thiepin-3-y1)ethyl]- N-hydroxy urea of formula I.
Where Rl is hydrogen and R2 is carboxy, a compound of formula V, such as the 2-acetyl-5, 5-dioxo-10,11-dihydro dibenzo [b,f]thiepin-7-carboxylic acid, in an organic solvent such as ethyl GB40 - 25 ~- 18049 acetate, may be esterified by addition of a solution of diazomethane in ether to yield the methyl ester ketone V_. This compound may then be treated like II
above to yield the N-[1-(7-carbomethoxy-5,5-dioxo-10,11-dihydro dibenzo[b,f]thie~pin-2-y1)ethyl]-N-hydroxy urea of formula I_.
Where R1 is hydrogen and R2 is carbomethoxy, a compound of formula I, such as N-[1-(7-carbomethoxy -5,5-dioxo-10,11-dihydro dibenzo [b,f] thiepin-2-yl) ethyl]-N-hydroxy urea, may be hydrolyzed by base, such as aqueous sodium hydroxide, in an alcoholic solvent, such as ethanol to yield the N-[1-(7-carboxy-5,5-dioxo-10,11-dihydro dibenzo[b,f]
thiepin-2-yl)ethyl]-N-hydroxy urea.
Alternatively, the ca.rbomethoxy derivative of formula I_, may be converted to the carboxamide by treatment with N,N-dimethylamino dimethyl aluminum in toluene. Quenching by addition of excess ethyl acetate followed by acidification yields the 2o N-[1-(7-dimethylcarboxamide -5,5-dioxo-10,11-dihydro dibenzo [b,f]thiepin-2-yl)ethyl]-N-hydroxy urea.
The method described above may be applied to the starting ketone TI wherein. X is a nitrogen, as in 2-acetylphenothiazine which may be treated directly as the ketone II above or derivatized first to yield compounds of formula VI I. Th.e derivatization may be accomplished by addition of potassium t-butoxide to the ketone II in DMF. Subsequent addition of methyl iodide, 4-methylthiobenzyl chloride, 4-methylsulfonylbenzyl chloride, or other such alkylating groups followed by addition of ice-water and isolation of the organic phase, allows the preparation of the ketone with the substituted ~0~~~~7 GB40 - 26 ~- 18049 nitrogen. This ketone may then be treated as was II
above to generate the hydroxy urea of formula I_.
Incorporation of a halogen into the substituted nitrogen compounds' VIII just described is most conveniently achieved by using the halogenated starting material, for example, the 2-chloro-8-acetylphenothiazine~ ketone or the 2-chloro-8,10-diacetylphenothiazine ketone, and then proceeding as for the ketone _I:I above.
l0 ~~~.~1~~

SC'1-IFMF T
Rt Re R' Rs X I ~ I ~ X
ZO R [C(R~)a~mtCOsH
VI
VII
gt Rs :x Rt Ra ~ ~ ~ ~ t R~ Ra .-I % X~ '3 (C(R4)a~mtC~Ha s iCHa II O
I [ C(R )a] mtC a (O)n p (C(R4)s)mtC~Ha VIII O
R R
V X
/ ~ (C(R4)s~mIC~CHa ( CI) ° NOM
III
Rt ~ Rs i ~ H
(O)n [C(R4)s~mtCiCHa Rt ~ Ra oM
(O)n [C(R~)t)mH~Y
O
I

~01~13'~
GB40 - 28 ~- 18049 Representative ComBounds Compounds of formula ~X_ and X_ are representative of the invention wherein the substituents are as defined in Tables I and II
respectively:
Table I
x OH
rr~rrHz (O)n CH~~ O
z x:
EXAMPLE # X_ n $1 3 0 0 Cl 4 0 0 Br ' GB40 - 29 ~- 18049 Table ~
OH
s ~ X ~2 R~ ~ I ~ Z Z - ~N~~z CO)n X
i0 EX X_ n_ F Z _R~-6 CH=CH 0 3 H

7 CH=CH 2 3 H

12 CH2-CH2 2 2 7-CON(CH3)2 16 NCH2C6H4-4-S(0)2CH3 0 2 H

GB4o - 3;0 _ 2 01213 l 18049 ssays for Determining Bioloeical Activity Compounds of Formula I can be tested using the following assays to determine their mammalian leukotriene biosynthesis inlhibitory activity.
Determination of Inhibition of 5-Li~~~ eg ease The activity of 5-:lipoxygenase was measured from the conversion of [14C;]-arachidonic acid to 5-HETE and 5,12-diHETEs catalyzed by the 10,000 x g supernatant fraction from rat PMN leukocytes, using the procedure of Riendeau and Leblanc (Biochem.
BirZph3rs. $~.g. Commun. , ~, 534-540, 1986) with minor modifications. The incubation mixture contained 25 mM Na+/K~' phosphate buffer, pH 7.3, 1 mM ATP, 0.5 mM
CaCl2, 0.5 mM mercaptoethanol and an aliquot of the enzyme preparation in a final volume of 0.2 m1. The enzyme was pre-incubated wiith the inhibitor for 2 min at 37°C before initiation of the reaction with the addition of 2 ml of [14C]-a:rachidonic acid (25,000 DPM) in ethanol to obtain a final concentration of 10 mM. Inhibitors were added as 500-fold concentrated solutions in DMSO. After incubation for 10 min at 37°C, the reaction was stopped by adding 0.8 mL of diethyl ether/methanol/1 M citric acid (30:4:1). The s~ples were centrifuged at 1,000 x g for 5 min and the organic phases analyzed by TLC on Baker Si250F-PA
or Whatmari silica gel 60A L1~GF plates using diethyl ether/petroleum ether/acetic acid (50:50:1) as solvent. The amount of radioactivity migrating at 3o the positions of arachidonic acid, 5-HETE and 5,12-diHETEs was determined using a Berthold TLC
analyzer LB 2842. The acti~~ity of 5-lipoxygenase was calculated from the percentage of conversion of *Trademark .s cB4o - 31 - 18049 arachidonic acid to 5-HETE .and 5,12-diHETEs after the min incubation.
Ra~Peritoneal Pol,~tmorphonuclear (Plrll~i) Leukoc3rte Assav Rats under ether anesthesia are injected (i.p.) with 8 mL of a suspension of sodium caseinate (6 grams in ~. 50 mL water). After 15-24 hr. the rats are sacrificed (C02) and the cells from the peritoneal cavity are recovered by lavage with 20 mL
of buffer (Eagles* MEM containing 30 m~ HEPES adjusted to pH 7.4 with NaOH). The cells are pelleted (350 x g, 5 min.), resuspended in lbuffer with vigorous shaking, filtered through lens paper, recentrifuged and finally suspended in buffer at a concentration of 10 cells/mL. A 500 mL aliquot of PMN suspension and test compound are preincubaited for 2 minutes at 37°, followed by the addition of 10 mM A-23187. The suspension is stirred for an additional 4 minutes then bioassayed for LTB4 content by adding an aliquot to a second 500 mL portion of the PMN at 37°C. The LTB4 produced in the first :incubation causes aggregation of the second P1~1, which is measured as a change in light transmission. The size of the assay aliquot is chosen to give a submazimal transmission change (usually -70~) for the untreated control. The percentage inhibition of LT134 formation is calculated from the ratio of transmission change in the sample to the transmission change :in the compound-free control.

Human Poly~norvhonuclear (PMN) Leukocyte LTB4_ Assav A. Preparation oi: Human PMN: Human blood was obtained by antecubital venepuncture from *Trademark GB40 - '_t2 - 18049 w 2012131 consenting volunteers who had not taken medication within the previous 7 days. The blood was immediately added to 109° (v/v) trisodium citrate (0.13 M) or 5% (v/v) sodium heparin (1000 IU/mL).
PMNs were isolated from anticoagulated blood by dextran sedimentation of erythrocytes followed by centrifugation through Ficoll-Hypaque*(specific gravity 1.077), as described by Boyum.l Contaminating erythrocytes were removed by lysis following exposure to ammonium chloride (0.16 M) in Tris buffer (pH 7.65), and the PMNs resuspended at 5 x 105 cells/mL in HEPES (15 mM)-buffered Hanks balanced salt solution containing Ca2+ (1.4 mM) and Mg2+ (0.7 mM), pH 7.4. Viability was assessed by Trypan blue exclusion and was typically greater than 8 .
B. Generation and Radioimmunoassay of LTB4: PMNs (0.5 mL; 2.5 x 105 cells) were placed in plastic tubes and incubated (37°C, 2 min) with test compounds at the desired concentration or vehicle (DMSO, final concentration 0.2~) as control. The synthesis of LTB4 was initiated by the addition of calcium ionophore A23187 (final concentration 10 mM) or vehicle in control samples and allowed to proceed for 5 minutes at 37°C. The reactions were then terminated by the addition of cold methanol (0.25 mL) and samples of the entire P~MN reaction mixture were removed for radioimmunoassa.y of LTB4.
Samples (50 mL) of authentic LTB4 of known concentration in radioimmunoassay buffer (RIA) buffer (potassium phosphate 1 mM; disodium EDTA 0.1 mM;
Thimerosal*0.025 mM; gelatin 0.190, pH 7.3) or PMN
reaction mixture diluted 1:1 with RIA buffer were *Trademark r GB40 ~~3 2 01213 ~ 18049 added to reaction tubes. T'.hereafter [3H]-LTB4 (10 nCi in 100 mL RIA buffer) a:nd LTB4-antiserum (100 mL
of a 1:3000 dilution in RIA buff er) were added and the tubes vortexed. Reactants were allowed to equilibrate by incubation overnight at 4°C. To separate antibody-bound from free LTB4, aliquots (50 mL) of activated charcoal (3% activated charcoal in RIA buffer containing 0.25% Deztrar~*T-70) were added, the tubes vortexed, and allowed to stand at room temperature for 10 minutes ;prior to centrifugation (1500 x g; 10 min; 4°C). The supernatants containing antibody-bound LTB4 were decanted into vials and Aquasol*2 (4 mL) Was added. Radioactivity was quantified by liquid scint illation spectrometry.
Preliminary studies established that the amount of methanol carried into the r;adioimmunoassay did not influence the results. The specificity of the antiserum and the sensitivity of the procedure have been described by Rokach ~ ~.2 The amount of LTB4 Produced in test and control (approx. 20 ng/106 cells) samples were calculated. Inhibitory dose-response curves were constructed using a four-parameter algorithm and from these the IC50 values were determined.
Footnotes:
(1) Boyum, A. Scand. J. Cl:in. Lab. Invest. 1968, (Supp 97), 77.
(2) Rokach, J.; Hayes, E.C.; Girard, Y.; Lombardo, D.L.; Maycock, A.L.; Rosenthal, A.S.; Young, R.N.; Zamboni, R.; Zwee:rink, H.J. Prosta~landins Leukotrienes and Medici~~ 1984, ,~, 21.
*Trademark GB4o - v;4 - 2 01213 l 18049 Asthmatic Rat Assav Rats are obtained from an inbred line of asthmatic rats. Both female <190-250 g) and male (260-400 g) rats are used.
Egg albumin (EA), grade V, crystallized and lyophilized, is obtained from Sigma Chemical Co., St.
Louis. Aluminum hydroxide is obtained from the Regis Chemical Company, Chicago. Methysergide bimaleate was supplied by Sandoz Ltd., Basel.
The challenge and subsequent respiratory recordings are carried out in a clear plastic box with internal dimensions 10 x 6 x 4 inches. The top of the box is removable; in use, it is held firmly in place by four clamps and an airtight seal is maintained by a soft rubber gasket. Through the center of each end of the chamber a Devilbiss*
nebulizer (No. 40) is inserted via an airtight seal and each end of the box also has an outlet. A
Fleisch No. 0000 pneumotach~ograph is inserted into one end of the box and coupled to a Grass volumetric pressure transducer (PT5-A) which is then connected to a Beckman Type R Dynogra;ph through appropriate couplers. While aerosolizing the antigen, the outlets are open and the pmeumotachograph is isolated from the chamber. The outlets are closed and the pneumotachograph and the chamber are connected during the recording of the respiratory patterns. For challenge, 2 mL of a 3'. solution of antigen in saline is placed into each nebuliz~sr and the aerosol is generated with air from a small Potter diaphragm pump operating at 10 psi and a flow of 8 liters/minute.
Rats are sensitized by injecting <subcutaneously) 1 mL of a suspension containing 1 mg *Trademark GB40 - 35 - ~ O 1 2 13 ~ 18049 EA and 200 mg aluminum hydroxide in saline. They are used between days 12 and 24 postsensitization. In order to eliminate the seroitonin component of the response, rats are pretreated intravenously 5 minutes prior to aerosol challenge with 3.0 mgm/kg of methysergide. Rats are then exposed to an aerosol of 3~ EA in saline for exactly 1 minute, then their respiratory profiles are recorded for a further 30 minutes. The duration of continuous dyspnea is measured from the respiratory recordings.
Compounds are generally administered either orally 1-4 hours prior to challenge or intravenously 2 minutes prior to challenge. They are either dissolved in saline or 17e methocel*or suspended in 1%
methocel* The volume injeci:ed is 1 mL/kg (intravenously) or 10 mL/kg (orally). Prior to oral treatment rats are starved overnight. Their activity is determined in terms of their ability to decrease the duration of symptoms of dyspnea in comparison with a group of vehicle-treated controls. Usually, a compound is evaluated at a series of doses and an ED50 is determined. This is defined as the dose (mg/kg) which would inhibit the duration of symptoms by 50%.
The invention is further defined by reference to the following examples, which are intended to be illustrative and not limiting. All 3o temperatures are in degress Celsius.
*Trademark ~o~~~ ~~

EXAMPLE ~
N-[1-(Phenoxathiin-2-~)ethyl~-N-h.~rdroxy urea Step 1 2-(1-Hydroximinoethyl.)phenoxathiin A mixture of 2-acetyl.phenoxathiin (J.A.C.S.
1936, ~, 717) (484 mg, 2 mmol.), hydroxylamine hydrochloride (556 mg, 8 mmol), ethanol (8 mL) and pyridine (4 mL) was stirred at. room temperature for 45 minutes. The ethanol was evaporated and the residue triturated with water until a solid was obtained. Filtration afforded. the title oxime (465 mg) as a cream-colored solid, m.p.. 143-148°C.
Step 2 2-(1-H~rdroxaminoethyl)phenoxathiin The oxime from Step 1 (450 mg, 1.75 mmol) was suspended in ethanol (9 mL~) and, at 0°C, there was added pyridine-borane (325 mg, 3.5 mmol) and 4M
ethanolic hydrogen chloride (H:C1) (1.33 mL, 5.32 mmol). The mixture was stirred at 0°C for 20 minutes, then at room temperature for 1 hour. The ethanol was evaporated and the residue partitioned between water and ether. The aqueous portion was basified with 1N aqueous sodium hydroxide and extracted twice with ether. Drying of the ether and evaporation afforded the title product (408 mg) as an oil which slowly became a white solid, m.p.. 64-67°C.
Step 3 N-f1-(Phenoxathiin-2-~1)ethvll-N-hydroxy urea To a solution of the product from Step 2 (250 mg, 0.965 mmol) in tetrahydrofuran (THF, 4 mL) there was added 85% trimethylsilyl isocyanate (196 mg, 1.45 mmol) and the solution was stirred at room temperature f or 1 hour. Water <4 mL) was added, 2~1~1~'~
rv GB40 - 37 - 18049 stirring was continued for 10 minutes, then the THF
was evaporated; the residue was extracted twice with ether and the crude product obtained from evaporation of the extracts was crystallized from ether to afford the title compound as white crystals, m.p.. dec 155°C
with gassing.
Analysis: Calc~d for C15H14N~~03S: C, 59.58; H, 4.67; N, 9.27; S, 10.61. Found: C, 59.72; H, 4.66;
N~ 9.50; S, 10.34.

N-[1-(10,10-Dioxophenoxathiin-~2-y1)ethyl]-N-hydroxy Step 1 2-Acet~rlphenoxathiin--10,10-dioxide i5 To a solution of 2-acetyl phenoxathiin (J.A.C.S. 1936, ~8-, 717) (484 mg, 2 mmol) in methylene chloride (25 mL) there was added 85%
m-chloroperoxy benzoic acid (MCPBA 1.015 g, 5 mmol) and the mixture stirred at room temperature. After 3 hours, more MCPBA was added (2.50 mg) and stirring was continued for a further hour. Enough methylene chloride was added to dissolves the solids, followed by calcium hydroxide (3 g); after stirring for a further 5 minutes, the mixture was filtered and the filtrate evaporated to a solid residue which was triturated with ether (10 mL) and filtered to afford the sulfone (415 mg) as a white solid, m.p..
163-165°C.
Step 2 N-[1-(10,10-Dioxophenoxathiin-2-y1)ethyl]-N-hydroxy urea Following the procedure of Example 1, Steps 1-3, but substituting the ketone from Step 1 for 2-acetylphenoxathiin as starting material, the title compound was obtained as an of°f-white solid, m.p..
dec 188°C with strong gassing.
EXAMPLE
N 11-C8-Chlorophenoxathiin-2-~~1)ethvl]-N-l~~droxy urea step 1 2-Chloro-8-(1-h3rdroxa~minoethyl ).phenoxathi in To a suspension of 2--chloro-8-(1-hydrox-iminoethyl)phenoxathiin (C. A. ~, 2519a, 1967) (425 mg, 1.456 mmol) in ethanol <12: mL) and THF (5 mL) at room temperature there was addled pyridine-borane (271 mg, 0.3 mL, 2.92 mmol) and 4M ethanolic HC1 (1.1 mL, 4.4 mmole); the mixture was stirred at room temperature overnight, there eras added more pyridine-borane (0.35 mL) and 4M ethanolic HCl (2 mL) and stirring was continued for 2 hours. The solvents were evaporated, the residue diluted with water and ethyl acetate and basified with 1N aqueous NaOH.
From the organic phase a crude product was obtained which was chromatographed on silica gel, eluting with a 1:1 mixture of ethyl acetate-hexane, to afford the title product <344 mg) as a white solid, m.p..
103-105°C.
Step 2 N-[1-(8-Chlorophenoxathiin-2-yl)ethyl]-N-hydrox~ urea To a solution of the product from Step 1 (320 mg, 1.09 mmol) in THF (15 mL) there was added 85% trimethylsilyl isocyanate (295 mg, 2.18 mmol) and the mixture was stirred at room temperature for 45 minutes. After addition of water (5 mL) the mixture was stirred a further 10 minutes, then the THF was ~0~2~~~

evaporated, the residual aqueous suspension diluted with water and filtered to afi=ord the title compound as a white solid, m.p.. dec 1;~3°C (gassing).

N-[1-(8-Bromophenoxathiin-2-3r7~ eth3rl]-N-hvd, roxv urea Step 1 2-Acet3rl-8-bromophenoxathiin To a suspension of aT.uminum chloride (1.2 g, 9 mmol) in 1,2-dichloro ethane' (20 mL) at room temperature there was added acetyl chloride (0.57 mL, 628 mg, 8 mmol) and the mixture stirred for 10 minutes. There was added 2-bromophenoxathiin (J.A.C.S. 1936, ~, 717) (1.8 g, 6.4 mmol) and the mixture was stirred for 18 hours. After quenching with ice water, the organic pc>rtion was collected and the aqueous portion extracted with methylene chloride. The combined organic fractions, after washing 3 times with water and drying over MgS04, were evaporated to a residue ~rhich on crystallization from methanol, followed by column chromatography on silica gel, eluting with a 1:5 mixture of ethyl acetate-hexane, gave the titles product as a white solid (247 mg), m.p.. 143-145°C.
Step 2 N-[1-(8-Bromophenoxat.hiin-2-yl)ethyl]-N-hard r oxv a r a a Following the procedures described in Example 1, Steps 1-3 but, substituting the ketone from Step 1 for 2-acetylphenox:athiin as the starting material, the title product wa.s obtained as a white solid, m.p.. dec 171°C.

~0~~~.~'~

EXAMPLE ~
N-[1-~8-C3~anouhenoxathiin-2-y1.)eth3rl]-N-h3rdrox5r urea Step 1 2-Acetyl-8-c3~anopher~c>xathi in A mixture of 2-acetyl.-8-bromophenoxathiin (from Example 4, Step 1) <1.7?; g, 5.39 mmol) and cuprous cyanide (1.94 g, 21.6 mmol) in N,N-dimethylformamide (DMF, 15~ mL) was refluxed for 7 hours. After cooling, the mixaure was diluted with water and the precipitated solid filtered. This solid was boiled with ethyl acetate (100 mL) and io filtered. The process was repeated with THF (100 mL, then 50 mL) and the combined filtrates evaporated to afford a yellow solid. This was purified by column chromatography on silica gel, eluting with a 1:3 mixture of ethyl acetate-hexane , to afford the title nitrile (774 mg) as a yellow solid, m.p.. 179-183°C.
Step 2 N-[1-(8-Cyanophenoxathiin-2-y1)ethyl]-N-hydroxy araa Following the procedures described in Example 1, Steps 1-3, but substituting the ketone from Step 1 for 2-acetylphenoxathiin as the starting material, the title product was obtained as a cream-colored solid, m.p.. 162° dec with gassing.
EXAMPLE ~
N-jl-(Dibenzo[b,flthiepin-3-~ et X11-N-h~ dt roxy urea Step 1 3-AcetyldibenzoLb f]thiepin To a solution of dibenzo[b,f]thiepin-3-carboxylic acid (U. S. Pat. 4,536,507 (1985)) (415 mg, 1.63 mmole) in THF (20 mL) at 0°C there was added methyl lithium in ether 1.4M (2.56 mL, 3.59 mmol);
the mixture was stirred at 0°C for 1 hour, then ~0~~~~~

poured onto a well-stirred saturated aqueous ammonium chloride solution (100 mL). 'the organic phase was collected, washed twice with lbrine, dried and evaporated. Column chromatog:eaphy on silica gel, eluting with a 1:2 mixture of ethyl acetate-hexane, afforded the title compound as a yellow solid (320 mg), m.p.. 82-84°C.
Step 2 N-[1-Dibenzo[b,f]thiepin-3-yl)ethyl]-N-~Ydroxv urea Following the procedure described in Example 1, Steps 1-3, but substitutin~; the ketone from Step 1 for 2-acetylphenoxathiin as starting material, the title compound was obtained a.> a white solid, m.p..
dec 169°C with gassing.

N-[1-(5,5-Dioxodibenzo[b,f]thi.epin-3-y1)ethyl]-N-hydroxSr urea 2o Following the procedures described in Example 2, Steps 1-2, but substituting 3-acetyldibenzo[b,f]thiepin (>E;xample 6, Step 1) for 2-acetyl phenoxathiin as starting material, the title compound was obtained as a sand-colored solid, m.p..
dec 188° with strong gassing.

N-[1-<10,11-Dihydrodibenzo[b,f]thiepin-3-yl)ethyl]-N-h d~~ urea Following the procedure described in Example 6, Steps 1-2 but substituting 10,11-dihydro-dibenzo[b,f]thiepin-3-carboxylic acid (U. S. Pat.
4,536,507 (1985)) for dibenzo[b,f]thiepin-3-~o~~~~~

carboxylic acid as starting material, the title product was obtained as a cream-colored solid, m.p..
166-168°C.
EXAMPLE ~
N-[1(6H-Dibenz[b,a][1,4]oxathiepin-2-y1]ethyl]-N-hyd r ox<r a r a a Following the procedure described in Example 6, Steps 1-2 but substituting 6H-dibenz[b,e]-l0 [1>4]oxathiepin-2-carboxylic acid (EP Pat. 105692 (1984)) for dibenzo[b,f]thiepin-3-carboxylic acid as starting material, the title compound was obtained as a cream-colored solid, m.p.. dec 141°C.

N-[1-(7-Carbomethoxy-10,11-dih.ydrodibenzo[b,f]-thiepin-2-3~l~eth3rl]-N-hvdroxy urea 1. Methyl 2-acetyl-10,11-dihydrodibenzo-[b,f]thiepin-7-carboxylate To a solution of 2-acetyl-10,11-dihydro-dibenzo[b,f]thiepin-7-carboxylic acid (U. S. Pat.
4,536,507 (1985)) (600 mg, 2.01 mmol) in ethyl acetate (10 mL), was added dropwise a solution of diazomethane in ether until the yellow coloration persisted. Evaporation of the solvent gave the crude title compound as a solid which was used as such.
Step 2 N-[1-(7-Carbomethoxy-10,11-dihydrodibenzo[b, flthiepin-2-y1)ethvll-N-h d~r urea Following the procedure described in Example 1, Steps 1-3 but substituting the ketone from Step 1 for 2-acetylphenoxathiin as starting material, the title product was obtained, m.p.. 167-169°C.

20~~1~'~

N-[1-(7-Carboxy-10,11-dihydrodibenzo[b,f]thiepin-2-~~l)ethyl]-N-hydrox~r urea To a solution of N-[7L-(7-carbomethoxy-10,11-dihydrodibenzo[b,f] thie~pin-2-yl)-ethyl]-N-hydroxy urea from Example 10 (50 mg, 0.134 mmol) in ethanol (1 mL) was added at room temperature a solution of NaOH 1N (0.4 mL, 0.402 mmol) and the resulting mixture was then stirred for 16 hours. A
i0 solution of 1N HC1 was then added until the reaction mixture became slightly acidic:. The resulting mixture was diluted with THF (.50 mL) dried over MgS04 and evaporated. The residue eras triturated with ethyl acetate and the solid ways filtered to afford the title compound, m.p.. 178-180°C.

N-[1-(7-Dimethylcarboxamido-5,5-dioxo-10,11-dihydro-dibenz~~b,~f]thiprpin-2-yl)eth~il]-N-h,~rdrox~~ urea Methyl 2-acetyl-5,5-dioxo-10,11-dihydro-dibenzolb,fl thiepin-7-carbox5rlate Following the procedure described in Example 10, Step 1, but substituting 2-acetyl-5,5-dioxo-10,11-dihydrodibenzo[b,f]thiepin-7-carboxylic acid <U.S. Pat. 4,536,507 (1985)) for 2-acetyl-10,11-dihydrodibenzo[b,f]thiepin-7-carboxylic acid as starting material, the title product was obtained as a solid.
N~N-Dimethyl 2-acetyl-5,5-dioxo-10,11-dihvdrodibenzo[b f]thiepin-7-carboxamide To a solution of the ester from Step 1 (440 mg, 1.28 mmol) in dry toluene (5 mL) was added 20~~~~~

dropwise at room temperature a solution of N,N-dimethylamino dimethyl aluminum 0.8M in toluene (16 mL, 12.8 mmol). The resu7lting solution was heated to 70°C for 2 hours. The reaction mixture was then cooled to 0°C and quenched with excess ethyl acetate followed by addition of 1N aqueous HC1. The solvents were removed under reduced pressure and the resulting solid was filtered, washed with ethyl acetate to afford the title product which was used as such for the next step.
Step 3 N-[1-(7-Dimethylcarboxamido-5,5-dioxo-10,11-dihydrodibenzo[b,f]thiepin-2-yl)eth3rl]_-N-hydroxy urea Following the procedure described in Example 1, Steps 1-3, but substituting; the ketone from Step 2 for 2-acetylphenoxathiin as starting material, the title product was obtained as a cream-colored solid, m.p.. 174-176°C with previous sintering at 168°C.
EXAMPLE ~
N-[1-(Phenothiaz in-2-yl)eth~~ll-N-h~rdrox3i urea Following the procedure described in Example 1, Step 1-3, but substituting 2-acetylphenothiazine (Aldrich) for 2-acetylphenoxathiin as starting material, the title product was obtained as a cream-colored solid, m.p.. 150-152°C (dec).

3o N-fl-(10-Methvlphenothiazin-2-3~1)ethyll-N-h~ d~ rox~~ urea Step 1 2-Ace yl-10-methyl~h~nothiazine To a solution of 2-acetylphenothiazine (Aldrich) (2.41 g, 10 mmol) in dimethylformamide (25 2~1~13'~
GB40 - 45 ~- 18049 mL) was added potassium t-buto~xide (1.5 g, 13.4 mmol) and the mixture was stirred for 15 minutes. Methyl iodide (1.9 g, 13.4 mmol) was then added, dropwise, to the resulting solution and the mixture stirred for 30 minutes. Ice-water was added to the reaction mixture followed by ethyl acetate. The organic layer was decanted, washed with brine, dried over Na2S04 and evaporated to dryness. The oily residue was chromatographed on flash silica gel eluting with 10%
ethyl acetate/hexane to afford the pure title product (1.0 g, 39%).
Step 2 N-[1-(10-Methylphenothiazin-2-yl)-ethyl]-N-h~~droxy urea Following the procedure described in Example 1, Steps 1-3, but substituting the ketone from Step 1 for 2-acetylphenoxathiin as starting material, the title product was obtained, m.p.. 165-167°C (dec).
2 0 EXILE 1,~
N-{1-[10-(4-Methylthiobenzyl)phenothiazin-2-y1]-eth',~1_ -N-hyrdrox3~ urea Following the procedure described in Example 14, Steps 1-2, but substituting 4-methylthiobenzyl chloride for methyl iodide as starting material, the title product was obtained as a foamy solid.
1H NMR (250 MHz, acetone-d6); a 1.32 (d, 3H, J =
7Hz, CH~i3), 2.44 <S, 3H, SCH3), 5.13 (S, 2H, CH2), 5.25 (quartet, 1H, J = 7Hz, CH), 5.9 (broad S, 2H, NH2), 6.9-7.4 (m, 11H, aromatics) and 8.3 (S, 1H, OH).

GB40 - 46 ~- 18049 EXAMPLE _l~
N-fl-[10-(4-Methylsulfonylbenzyl)phenothiazin-2-y1]-eth3~l~~idrox3i urea Following the procedures described in Example 14, Steps 1-2, but substituting 4-methylsulfonylbenzyl chloride for methyl iodide as starting material, the title product was obtained, m.p.. 143-145°C with previous sintering at 132°C.

N-[1-(8-Chloro-10-methylphenot.hiazin-2-yl)ethyl]-N-~rdrox3i urea Following the procedures described in Example 14, Steps 1-2, but substituting 2-acetyl-8-chlorophenothiazine~ (J. Het. Chem. ~, 345, 1966) for 2-acetylphenothiazine as starting material, the title product was obtained as a cream-colored solid, m.p.. 176-177°C.
Analysis: Calc~d for C16H16C1N302S: C, 54.93; H, 4.61; C1, 10.14; N, 12.01; S, 9.16. Found: C, 54.84; H, 4.58; C1, 10.33; N, 12.18; S, 9.30.
EXAMPLE 1$
N-[1-(10-acetyl-8-Chlorophenothiazin-2-yl)ethyl]-N-h3rdroxy urea Following the procedures described in Example 14, Steps 1-2, but substituting 8-chloro-2,10-diacetylphenothiazine (J. Het. Chem. 3, 345, 1966) for 2-acetylphenoxathiin as starting material, the title product was obtained, m.p..
157-159°C.

Claims (15)

1. A compound having the formula I:

wherein:
R1, R2 and R3 are independently:
a) hydrogen, b) lower alkyl, c) lower cycloalkyl, d) lower alkoxy, e) lower alkanoyloxy, f) -CF3 g) -CN, h) -NO2, i) -OR4, j) -N(R4)2, -NCOR4, -N(R4)CON(R4)2, k) -SR5, -S(O)R5, -S(O)2R5, -S(O)2NR4, l) -COR4, -COOR4, -CON(R4)2, m) halogen;

R4 is :
a) hydrogen, b) R5:
R5 is:
a) C1-C4 alkyl;
R6 is:
a) hydrogen, b) C1 to C4 alkyl, c) -COR4, d) -S(O)2R4, e) -R5Ar;
R7 is:
a) hydrogen, b) lower alkyl, c) Ar-lower alkyl;
Ar is:
a) R1 substituted phenyl, b) R1 substituted furyl, c) R1 substituted thienyl;
X is:
a) X1, b) -CH=CH-, c) -CH2-CH2-, d) -CH2X1-, e) -X1CH2-, f) -NR7;

X1 is:
a) O, b) S, c) S(O), d) S(O)2, e) NR6;
Y is:
a) R4, b) -N(R4)2;
M is:
a) hydrogen, b) -COAr, c) -CO-alkyl;
m is 1 to 5;
n is 0 to 2;

and pharmaceutically acceptable salts thereof and, in the case said compound of formula I contains one or more asymmetric centers giving rise to diastereomers or optical isomers, its diastereomers and optical isomers in their racemic, resolved or enantiomerically pure forms.

2. A compound of Claim 1 having the formula IX:

wherein the substituents are as follows:
EX X n R1

3 0 0 Cl

4 0 0 Br

5 0 0 CN

3. A compound of Claim 1 having the formula X:

wherein the substituents are as follows:

POSITION

EX X n OF Z R1

6 CH=CH 0 3 H

7 CH=CH 2 3 H

8 CH2-CH2 0 3 H

12 CH2-CH2 2 2 7-CON(CH3)2 16 NCH2C6H4-4-S(O)2CH3 0 2 H
17 NCH3 0 2 8-Cl 18 NCOCH3 0 2 8-Cl 4. A compound according to Claim 1 which is any of the following compounds:
N-[1-(Phenozathiin-2-yl)ethyl]-N-hydroxy urea, N-[1-(10,10-Dioxophenoxathiin-2-yl)ethyl]-N-hydroxy urea, N-[1-(8-Chlorophenoxathiin-2-yl)ethyl]-N-hydroxy urea, N-[1-(8-Bromophenogathiin-2-yl)ethyl]-N-hydroxy urea, N-[1-(8-Cyanophenoxathiin-2-yl)ethyl]-N-hydroxy urea, N-[1-(Dibenzo[b,f]thiepin-3-yl)ethyl]-N-hydroxy urea, N-[1-(5,5-Diozodibenzo[b,f]thiepin-3-yl)ethyl]-N-hydroxy urea, N-[1-(10,11-Dihydrodibenzo[b,f]thiepin-3-yl)ethyl]-N-hydroxy urea, N-[1(6H-Dibenz[b,e][1,4]oxathiepin-2-yl]ethyl]-N-hydroxy urea, N-[1-(7-Carbomethoxy-10,11-dihydrodibenzo[b,f]-thiepin-2-yl)ethyl]-N-hydroxy urea, N-[1-(7-Carboxy-10,11-dihydrodibenzo[b,f]thiepin-2-yl)ethyl]-N-hydroxy urea, N-[1-(7-Dimethylcarbozamido-5,5-diozo-10,11-dihydro-dibenzo[b,f]thiepin-2-yl)ethyl]-N-hydroxy urea, N-[1-(Phenothiazin-2-yl)ethyl]-N-hydroxy urea, N-[1-(10-Methylphenothiazin-2-yl)ethyl]-N-hydroxy urea, N-{1-[10-(4-Methylthiobenzyl)phenothiazin-2-yl]-ethyl}
-N-hydroxy urea, N-{-[10 -(4-Methylsulfonylbenzyl)phenothiazin-2-yl]-eth yl}-N-hydroxy urea, N-[1-(8-Chloro-10-methylphenothiazin-2-yl)ethyl]-N-hydroxy urea, or N-[1-(8-Chloro-10-acetylphenothiazin-2-yl)ethyl]-N-hydrogy urea.
5. A method for the synthesis of a compound of Formula I:

wherein:

R1, R2 and R3 are independently:
a) hydrogen, b) lower alkyl, c) lower cycloalkyl, d) lower alkoxy, e) lower alkanoyloxy, f) -CF3 g) -CN, h) -NO2, i) -OR4, j) -N(R4)2, -NCOR4, -N(R4)CON(R4)2, k) -SR5, -S(O)R5, -S(O)2R5, -S(O)2NR4, l) -COR4, -COOR4, -CON(R4)2, m) halogen;
R4 is :
a) hydrogen, b) R5;
R5 is:
a) C1-C4 alkyl;
R6 is:
a) hydrogen, b) C1 to C4 alkyl, c) -COR4, d) -S(O)2R4, e) -R5Ar;
R7 is :
a) hydrogen, b) lower alkyl, c) Ar-lower alkyl;

Ar is:
a) R1 substituted phenyl, b) R1 substituted furyl, c) R1 substituted thienyl;
X is:
a) X1, b) -CH=CH-, c) -CH2-CH2-, d) -CH2X1-, e) -X1CH2-, f) -NR7;
X1 is:
a) O, b) S, c) S(O), d) S(O)2, e) NR6;
Y is:
a) R4.
b) -N(R4)2;
M is:
a) hydrogen, b) -COAr, c) -CO-alkyl;
m is 1 to 5;
n is 0 to 2;

and pharmaceutically acceptable salts thereof and, in the case said compound of formula I contains one or more asymmetric centers giving rise to diastereomers or optical isomers, its diastereomers and optical isomers in their racemic, resolved or enantiomerically pure forms, which comprises reaction of a compound of formula IV wherein the groups R1, R2, R3, R4, and x are ase defined above in claim 1, and the letters n, m and M are as defined above in claim 1, with an isocyanate to yield the compound I below:

6. A method for the synthesis of a compound of Fomula IX comprising reaction of a compound of formula XI with an isocyanate:

Wherein R1, n and X are as defined in the table below:
X n R1 0 0 Cl 0 0 Br 7. A method for the synthesis of a compound of Formula X comprising reaction of a compound of formula XII with an isocyanate:

Wherein R1, n and X are as defined in the table below:
POSITION

X n OF Z R1 CH=CH 0 3 H
CH=CH 2 3 H

CH2-CH2 2 2 7-CON(CH3)2 NCH2C6H4-4 -S(O)2CH3 0 2 H
NCH3 0 2 8-Cl NCOCH3 0 2 8-Cl 8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Claim 1 and a pharmaceutically acceptable carrier.

9. A pharmaceutical composition of Claim 8 additionally comprising a therapeutically effective amount of a non-steroidal anti-inflammatory drug, cyclooxygenase inhibitors, peripheral analgesic agents, prostaglandin antagonists, leukotriene antagonists, leukotriene biosynthesis inhibitors, H2-receptor antagonists, antihistaminic agents, thromboxane antagonists, thromboxane biosynthesis antagonists, or angiotensin converting enzyme inhibitors.

10. A pharmaceutical composition of Claim 9 wherein the weight ratio of the compound of Claim 1 to that of the additional ingredient of Claim 9 is in the range of from 1000:1 to 1:1000.

11. A medicament for use in treating a mammal suffering from asthmatic, inflammatory, or allergic conditions, said medicament comprising a therapeutically effective amount of a compound of Claim 1 and a pharmaceutically acceptable carrier.

12. The medicament of Claim 11 wherein the mammal is a human.

13. A medicament for use in inhibiting 5-lipoxygenase or 12-lipoxygenase activity in a mammal said medicament comprising a therapeutically effective amount of a compound of Claim 1 and a pharmaceutically acceptable carrier.

14. The medicament of Claim 13 wherein the mammal is a human.

15. The use of the compound of claim 1 for inhibiting 5-lipoxygenase or 12-lipoxygenase activity in a mammal.