Fenamic acid hydroxamate derivatives having cyclooxygenase and 5-lipoxygenase inhibition

The present invention is novel selected hydroxamic acid derivatives of fenamic acids having 5-lipoxygenase and cyclooxygenase inhibiting properties, pharmaceutical compositions for treating conditions advantageously affected by the inhibition and methods for treating these conditions in mammals, including humans suffering therefor.

BACKGROUND OF THE INVENTION 
The present invention is novel derivatives of fenamic acids. Such fenamic 
acids include mefenamic acids of U.S. Pat. No. 3,138,636; flufenamic acids 
of U.S. Pat. No. 3,144,387 meclofenamate and tolfenamic acids of U.S. Pat. 
No. 3,313,848; and niflumic acids, flunixin, and olonixin of U.S. Pat. No. 
26,655. 
Other anthranilic acid derivatives of the fenamic series previously known 
include the generic compounds of the British Patent No. 989,951 or formula 
##STR1## 
wherein Ar is .alpha.,.alpha.,.alpha.-trifuoro-m-tolyl; 2,3-xylyl, or 
2,6-dichloro-m-tolyl, in U.S. Pat. No. 3,852,333. 
The present novel derivatives include selected hydroxamic acids thereof 
which are heretofore unknown. 
Among related aminobenzhydroxamic acids previously disclosed are compounds 
of the formula 
##STR2## 
wherein R' is a saturated fatty hydrocarbon radical; phenyl, phenylalkyl, 
wherein the rings are optionally substituted by lower alkyl or lower 
alkoxy; or an aromatic heterocyclic group. This disclosure is in Japanese 
Application 24578/67, filed Apr. 2, 1964 by the Takeda Chemical Industry 
Co., Ltd. as an o-aminobenzhydroxamic acid analgesic derivative having 
less toxicity and analgesic, anticatarrhic, and antifebrile activity. 
Other related disclosures include U.S. Pat. No. 4,029,815 to compounds of 
the formula 
##STR3## 
wherein X.sub.5 is trifluoromethyl, difluoromethyl, or nitro, X.sub.4 is 
H, Br, Cl, or nitro, and Q may be NHOH. These compounds have utility as 
antidiarrheal agents. 
Cyclized o-aminobenzhydroxamic-O-methylesters of the formula 
##STR4## 
wherein R" is alkyl, aralkyl, or a basic side chain and R'" is H, Cl, or 
Br; are disclosed by Wolf, E. and Kohl, H. in "Cyclisiarungareaktionen von 
am Aminostickstoff Substituierten 
o-Aminobenz-hydroxamsaure-O-methylesteror," Ann. Chem. Liebigs, 1975, 
1245-1251. 
Wolf and Kohl also disclose an intermediate hydroxamic acid derivative from 
which the cyclized o-aminobenzhydroxamic-O-methylesters are made. The 
intermediate is 
##STR5## 
wherein R.sub.c, R.sub.e, and R.sub.d are as defined below. 
Other cyolized o-aminobenzyhydroxamic acids disclosed are 
##STR6## 
wherein R.sub.a is CH.sub.2 CO.sub.2 C.sub.2 H.sub.5, C.sub.6 H.sub.3 
Cl(p)NO2(m) and suggesting that R.sub.a may also be SO.sub.2 C.sub.6 
H.sub.4 CH.sub.3 (p); and 
##STR7## 
wherein R.sub.b is H or phenyl; R.sub.c is H, CH.sub.2 C.sub.6 H.sub.5, 
C.sub.6 H.sub.4 Cl(p), CH.sub.2 C.sub.6 H.sub.4 Cl(p), C.sub.6 H.sub.5, or 
CH.sub.3 ; R.sub.e is H or NO.sub.2 ; and R.sub.d is H or Cl. However, 
Wolf and Kohl do not disclose activity for these cyclized compounds and, 
further, do not make obvious the present invention. 
Broadly, hydroxamic acid derivatives of selected aryl ring systems are 
disclosed in European Application Publication No. 0 196 184 having 
surprisingly high potency particularly by inhalation, oral efficacy, and 
with a surprisingly long duration of action. However, these aryl ring 
systems are in no way related to the present fenamic acid type compounds. 
Two disclosures by Summers et al, (1) J. Med. Chem., 1987, 30, 574-80 and 
(2) In Vivo Characterization of Hydroxamic Acid Inhibitors of 
5-Lipoxygenase disclosed at a seminar in early September, 1987 (Abstract) 
disclose hydroxamic acids as inhibitors of 5-lipoxygenase, however, the 
disclosures do not extend beyond very limited representative examples not 
including any fenamic acid derivatives. 
Additional references related to the present invention, particularly for 
the substituents therein for L.sub.1 and L.sub.2, include a disclosure for 
reduction of the substituent in the carboxy-containing side chain of 
anilinophenyl group in J55013-227 of Derwent Abstract No. 17678C/10; and 
various fused nitrogen-containing ring systems in J54151-963 in Derwent 
Abstract No. 02846C/02, J54073-771 in Derwent Abstract No. 55094B/30, 
J54073-750 in Derwent Abstract No. 550855/30, J54073-737 in Derwent 
Abstract No. 55078B/30, J54070-265 in Derwent Abstract No. 51907B/28, 
J54063-073 in Derwent Abstract No. 48163B/26, J54063-042 in Derwent 
Abstract No. 48147B/26, DL-134-520 in Derwent Abstract No. 39059B/21, and 
JA2489/67 in Derwent Abstract No. 29861, U.S. Pat. No. 3,325,499 in 
Derwent Abstract No. 27,108 and 3,317,524 in Derwent Abstract No. 26,495. 
Also in CA73(2):10333g 1-phenyl-3-isatinoxime is disclosed. The compounds 
disclosed in each of these references is not now the present invention 
because the particular substituents noted as L.sub.1 and NOR.sub.7 found 
in the present invention are not included or made obvious from the 
references. 
Thus, the present invention are to selected novel derivatives of fenamates 
and pharmaceutically acceptable acid addition or base salts thereof, 
pharmaceutical compositions for treating inflammation, arthritis, pain, 
pyrrhia, and the methods for such treatment. 
Finally, known related cyclized compounds include the quinazolinedione 
derivatives disclosed in U.S. Pat. No. 3,794,643 which are different from 
the present cyclized derivatives by unobvious substituents, particularly 
at the nitrogen between the carbonyls. 
SUMMARY OF THE INVENTION 
The present invention is a novel compound of the formula (I) 
##STR8## 
wherein (1) R.sub.1 is (i) 
##STR9## 
(ii) 
##STR10## 
wherein R.sub.6 is hydrogen, lower alkyl, aryl, aralkyl, or cycloalkyl of 
from three to ten carbons having three to seven ring carbons; R.sub.7 is 
independently H, lower alkyl, or acyl; and R.sub.8 is H or lower alkyl; 
with the proviso that when R.sub.1 R.sub.7 cannot be methyl when R.sub.5 
is para-chloro and R.sub.3 and R.sub.4 are hydrogen, and (iii) as defined 
together with R.sub.2 below; 
(2) --R.sub.2 is H, lower alkyl, or taken together with --R.sub.1 is 
##STR11## 
wherein L.sub.1 is oxygen or H.sub.2 ; and R.sub.7 is independently as 
defined above; and 
(3) R.sub.3, R.sub.4, R.sub.5, and R.sub.11 are independently hydrogen, 
fluoro, chloro, bromo, trifluoromethyl, lower alkyl, CN, hydroxy, lower 
alkoxy, --S(O).sub.n -lower alkyl, NO.sub.2, or NR.sub.9 R.sub.10 wherein 
R.sub.9 and R.sub.10 are independently H, lower alkyl, or acyl and n is an 
integer of 0 through 2, with the further proviso that when R.sub.1 is 
##STR12## 
then R.sub.3, R.sub.4, or R.sub.5 cannot all be hydrogen or then one or 
two of R.sub.3, R.sub.4, or R.sub.5 cannot be alkyl when the other one or 
two of R.sub.3, R.sub.4, or R.sub.5 is hydrogen, and when R.sub.1 is 
##STR13## 
and one of R.sub.3, R.sub.4, or R.sub.5 is ortho-alkyl then one other of 
R.sub.3, R.sub.4, or R.sub.5 cannot be meta-nitro, meta-difluoromethyl, or 
meta-trifluoromethyl when R.sub.11 is H, Br, Cl, or nitro and 
pharmaceutically acceptable acid addition or base salts thereof. 
The present invention is also a pharmaceutioal composition for the 
treatment of conditions advantageously affected by the inhibition of 
5-lipoxygenase and/or cyclooxygenase which comprises administering an 
amount effective for inhibiting 5-lipoxygenase and/or cyclooxygenase of a 
novel compound of the formula (I) 
##STR14## 
wherein (1) R.sub.1 is 
##STR15## 
wherein R.sub.6 is hydrogen, lower alkyl, aryl, aralkyl, or cycloalkyl of 
from three to ten carbons having three to seven ring carbons; R.sub.7 is 
independently H, lower alkyl, or acyl; and R.sub.8 is H or lower alkyl; 
and as defined together with R.sub.2 below; 
(2) 
##STR16## 
is H, lower alkyl, or taken together with 
##STR17## 
is 
##STR18## 
wherein L.sub.1 is oxygen or H.sub.2 ; and R.sub.7 is independently as 
defined above; and 
(3) R.sub.3, R.sub.4, R.sub.5, and R.sub.11 are independently hydrogen, 
fluoro, chloro, bromo, trifluoromethyl, lower alkyl, CN, hydroxy, lower 
alkoxy, --S(O).sub.n -lower alkyl, NO.sub.2, or NR.sub.9 R.sub.10 or 
NO.sub.2 wherein R.sub.9 and R.sub.10 are independently H, lower alkyl, or 
acyl; and n is an integer of 0 through 2; with the proviso that when 
R.sub.1 is 
##STR19## 
then R.sub.3, R.sub.4, or R.sub.5 cannot all be hydrogen or then one or 
two of R.sub.3, R.sub.4, or R.sub.5 cannot be alkyl when the other one or 
two of R.sub.3, R.sub.4, and R.sub.5 is hydrogen, and when R.sub.1 is 
##STR20## 
and one of R.sub.3, R.sub.4, or R.sub.5 is ortho-alkyl then one other of 
R.sub.3, R.sub.4, or R.sub.5 cannot be meta-nitro, meta-difluoromethyl, or 
meta-trifluoromethyl when R.sub.11 is H, Br, Cl, or NO.sub.2 ; and 
pharmaceutically acceptable acid addition or base salts thereof and a 
pharmaceutically acceptable carrier. 
Further, the present invention also provides a method of use for a 
composition of a compound of the formula (I), as defined herein before, or 
physiologically acceptable acid addition or base salt thereof for use as 
an inhibitor of the lipoxygenase and/or cyclooxygenase enzymes of the 
mammalian including human arachidonic acid metabolism, which method 
comprises inhibition of such enzymes by administration to a mammal of a 
ipoxygenase and/or cyclooxygenase inhibiting amount of any such compound 
or salt in unit dosage form, and to use of any such compound or salt in 
the manufacture of lipoxygenase and/or cyclooxygenase inhibitor agents. 
Further, the present invention also provides any compound or composition of 
formula (I) (as hereinbefore defined) or physiologically acceptable salt 
thereof, for use as a medical therapeutic and/or prophylactic agent, to 
methods of medical therapeutic and/or prophylactic treatment by 
administration to a mammal of a medically therapeutic and/or prophylactic 
effective amount of any such compound or salt, and to use of any such 
compound or salt in the manufacture of medical therapeutic and/or 
prophyactic agents. The kinds of medical therapy and prophylaxis pertinent 
to the foregoing and therefore in that sense comprising part of the 
present invention, are elaborated by way of example in the following 
paragraphs which are not intended to be construed as in any way limiting 
the scope of these aspects of said invention. 
The most preferred compound of the present invention is 
1-(2,6-dichloro-3-methylphenyl)-2,3-dihydro-3-hydroxy-4(1H)-quinazolinone, 
which is shown in Example 35 hereinafter. 
DETAILED DESCRIPTION OF THE INVENTION 
In the compounds of formula (1) the term "lower alkyl" is meant to include 
a straight or branched alkyl group having one to four carbon atoms, such 
as, for example, methyl, ethyl, propyl, or butyl, and isomers thereof. 
Lower alkoxy is O-alkyl or of from one to four carbon atoms as defined 
above for "lower alkyl". 
Acyl is a 
##STR21## 
optionally substituted by a lower alkyl, fluoro, chloro, bromo, 
trifluoromethyl, hydroxy, or lower alkoxy; and wherein the lower alkyl is 
as defined above. 
Cycloalkyl of from three to ten carbons having from three to seven ring 
carbons includes cyclopropyl, cyclobutyl, methylcyclotrityl, 
ethylcyclobutyl, dimethylcyclobutyl, cycopentyl, and the like. 
Aryl is phenyl unsubstituted and substituted with from one to three 
substituents selected from the group consisting of hydroxy, lower alkoxy, 
fluoro, chloro, bromo, trifluoromethyl, lower alkyl, CN, --S(O).sub.n 
-lower akyl wherein n is as defined above, NO.sub.2, or NR.sub.9 R.sub.10 
wherein R.sub.9 and R.sub.10 are independently as defined above. 
An aralkyl is an aryl as defined above attached through a lower alkylenyl 
wherein the alkylenyl is of from one to four carbons such as methylenyl, 
1,2-ethylenyl, 1,1-ethylenyl, propylenyl, and the like. 
Appropriate compounds of formula (I) are useful in the free base form, in 
the form of base salts where possible, and in the form of acid addition 
salts. The three forms are within the scope of the invention. In practice, 
use of the salt form amounts to use of the base form. Pharmaceutically 
acceptable salts within the scope of the invention may be those derived 
from mineral acids such as hydrochloric acid and sulfuric acid; and 
organic acids such as ethanesulfonic acid, benzenesulfonic acid, 
p-toluenesulfonic acid, and the like, giving the hydrochloride, sulfamate, 
ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like, 
respectively or those derived from bases such as suitable organic and 
inorganic bases. Examples of pharmaceutically acceptable base addition 
salts with compounds of the present invention include organic bases which 
are nontoxic and strong enough to form such sats. These organic bases form 
a class whose limits are readily understood by those skilled in the art. 
Merely for purposes of illustration, the class may be said to include 
mono-, di-, and trialkylamines, such as methylamine, dimethylamine, and 
triethylamine; mono-, di-, or trihydroxyalkylamines such as mono-, di-, 
and triethanolamine; amino acids such as arginine, and lysine; guanidine; 
N-methylglucosamine; N-methylglucamine; L-glutamine; N-methylpiperazine; 
morpholine; ethylenediamine; N-benzylphenethylamine; 
tris(hydroxymethy)-aminomethane; and the like. (See for example, 
"Pharmaceutical Salts," J. Pharm. Sci., 66(1):1-19 (1977).) Salts of 
inorganic bases include sodium, potassium, calcium or the like. 
The acid addition sats of said basic compounds are prepared either by 
dissolving the free base or acid of compound I in aqueous or aqueous 
alcohol solution or other suitable solvents containing the appropriate 
acid or base and isolating the salt by evaporating the solution, or by 
reacting the free base of compound I with an acid as well as reacting 
compound I having an acid group thereon with a base such that the 
reactions are in an organic solvent, in which case the salt separates 
directly or can be obtained by concentration of the solution. 
The compounds of the invention may contain an asymmetric carbon atom. Thus, 
the invention includes the individual stereoisomers, and mixtures thereof. 
The individual isomers may be prepared or isolated by methods known in the 
art. 
By virtue of their lipoxygenase inhibitory properties, said compounds and 
salts find application in the treatment and/or prophylaxis of any 
condition where a lipoxygenase inhibitor is indicated, especially 
spasmogenic and allergic conditions, psoriasis, and as utility in 
cytoprotection. 
By virtue of their cycooxygenase inhibitory properties, said compounds and 
salts find application in the treatment and/or prophylaxis of any 
condition where a cyclooxygenase inhibitor is indicated, especially 
pyresis, pain, and inflammation. 
By virtue of both their lipoxygenase and cyclooxygenase inhibitory 
properties, said compounds and salts find application in the treatment 
and/or prophylaxis of any condition where a dual 
lipoxygenase/cyclooxygenase inhibitor is indicated, especially any 
condition involving blood platelet aggregation or inflammation. In the 
case of inflammation, the compounds and salts are particularly suited to 
the treatment and/or prophylaxis of conditions associated with 
infiltration of leukocytes into inflamed tissue. 
In determining when a lipoxygenase, cyclooxygenase, or dual 
lipoxygenase/cyclooxygenase inhibitor is indicated, of course inter alia, 
the particular condition in question and its severity, as well as, the 
age, sex, weight, and the like of the subject to be treated, must be taken 
into consideration and this determination is ultimately at the discretion 
of the attendant physician. 
Examples of the aforesaid spasmogenic conditions are those involving smooth 
muscle tissue, especially airway smooth muscle constriction such as 
intrinsic asthma--(including intrinsic or idiopathic bronchial asthma and 
cardiac asthma), bronchitis and arterial smooth muscle constriction such 
as coronary spasm (including that associated with myocardial infarction, 
which may or may not lead to eft ventricular failure resulting in cardiac 
asthma) and cerebral spasm or `stroke`. Other examples include bowel 
disease caused by abnormal colonic muscular contraction such as may be 
termed `irritable bowel syndrome`, `spastic colon`, or `mucous colitis`. 
Examples of the aforesaid allergic conditions are extrinsic asthma (from 
which it will be appreciated that said compounds and salts are 
particularly favorable as antiasthmatic agents), allergic skin diseases 
such as eczema having a total or partial allergic origin, allergic bowel 
disease (including coeliac disease) and allergic eye conditions such as 
hay fever (which may additionally or alternatively affect the upper 
respiratory tract) and allergic conjunctivitis. Examples of the aforesaid 
tumors are skin neoplasms, both benign and malignant. 
Examples of the aforesaid pyretic and painful conditions include fever 
associated with infections, trauma and injury, malignant disease, and 
diseases affecting the immune system (including autoimmune diseases). 
Examples of the aforesaid conditions involving blood platelet aggregation 
are those resulting from thrombosis, including `stroke` having a total or 
partial thrombotic origin, coronary thrombosis, phlebitis, and 
phlebothrombosis (the latter two conditions also possibly being associated 
with inflammation). 
Examples of the aforesaid conditions involving inflammation are 
inflammatory conditions of the lung, joints, eye, bowel, skin, and heart. 
Inflammatory lung conditions which may be so treated and/or prevented 
include asthma and bronchitis (vide supra) and cystic fibrosis (which may 
also or alternatively involve the bowel or other tissue). 
Inflammatory joint conditions which may be so treated and/or prevented 
include rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, 
gouty arthritis, and other arthritic conditions. 
Inflammatory eye conditions which may be so treated and/or prevented 
include uveitis (including intis) and conjunctivitis (vide supra). 
Inflammatory bowel conditions which may be so treated and/or prevented 
include Crohn's disease, ulcerative colitis, and ischemic bowel disease. 
Inflammatory skin diseases which may be so treated and/or prevented include 
those associated with cell proliferation, such as psoriasis and eczema 
(vide supra) and dermatitis (whether or not of allergic origin). 
Inflammatory conditions of the heart which may be so treated and/or 
prevented include coronary infarct damage. 
Other inflammatory conditions which may be so treated and/or prevented 
include tissue necrosis of chronic inflammation and tissue rejection 
following transplant surgery. 
It is also believed that the compound of formula (I) and their 
physiologically acceptable salts are effective agents in the prophylaxis 
and/or treatment of bacterial and fungal infections, thus forming a 
further aspect of the present invention in like manner. 
For medical use, the amount required of a compound of formula (1) or 
physiologically acceptable salt thereof--(hereinafter referred to as the 
active ingredient) to achieve a therapeutic effect will, of course, vary 
both with the particular compound, the route of administration and the 
mammal under treatment and the particular disorder or disease concerned. A 
suitable dose of a compound of formula (I) or physiologically acceptable 
sat thereof for a mammal suffering from, or likely to suffer from any 
condition as described hereinbefore is 0.1 .mu.g-500 mg of base per 
kilogram body weight. In the case of systemic administration, the dose may 
be in the range 0.5 to 500 mg of base per kilogram body weight, the most 
preferred dosage being 0.5 to 50 mg/kg of mammal body weight for Example 5 
to 25 mg/kg; administered two or three times daily. In the case of topical 
administration, e.g. to the skin or eye, a suitable dose may be in the 
range 0.1 ng-100 .mu.g of base per kilogram, typically about 0.1 .mu.g/kg. 
In the case of oral dosing for the treatment or prophylaxis of airway 
smooth muscle constriction, or asthma, or bronchitis in general, due to 
any course, a suitable dose of a compound of formula (I) or 
physiologically acceptable salt thereof, may be as specified in the 
preceding paragraph, but most preferably is from 1 mg to 10 mg of base per 
kilogram, the most preferred dosage being from 1 mg to 5 mg/kg of mammal 
body weight, for example from 1 to 2 mg/kg. In the case of pulmonary 
administration for the latter indications, the dose may be in the range of 
from 2 .mu.g to 100 mg, for example from 20 .mu.g to 0.5 mg, especially 
0.1 to 0.7 mg/kg. 
It is understood that the ordinarily skilled physician or veterinarian will 
readily determine and prescribe the effective amount of the compound to 
prevent or arrest the progress of the condition for which treatment is 
administered. In so proceeding, the physician or veterinarian could-employ 
relatively low doses at first, subsequently increasing the dose until a 
maximum response is obtained. 
While it is possible for an active ingredient to be administered alone, it 
is preferable to present it as a pharmaceutical formulation comprising a 
compound of formula (I) or a pharmacologically acceptable acid addition 
salt thereof and a physiologically acceptable acid addition salt thereof 
and a physiologically acceptable carrier therefor. Such formulations 
constitute a further feature of the present invention. Conveniently, the 
active ingredient comprises from 0.1% to 99.9% by weight of the 
formulation. Conveniently, unit doses of a formulation contain between 0.1 
mg and 1 9 of the active ingredient. For topical administration, the 
active ingredient preferably comprises from 1% to 2% by weight of the 
formulation but the active ingredient may comprise as much as 10% w/w. 
Formulations suitable for nasal or buccal administration, (such as 
self-propelling powder dispensing formulations described hereinafter), may 
comprise 0.1 to 20% w/w, for example 2% w/w of active ingredient. 
The formulations, both for veterinary and for human medical use, of the 
present invention comprise an active ingredient in association with a 
pharmaceutically acceptable carrier therefor and optionally other 
therapeutic ingredient(s). The carrier(s) must be `acceptable` in the 
sense of being compatible with the other ingredients of the formulations 
and not deleterious to the recipient thereof. 
The formulations include those in a form suitable for oral, pulmonary, 
ophthalmic, rectal, parenteral (including subcutaneous, intramuscular, and 
intravenous), intraarticular, topical, nasal, or buccal administration. 
The formulations may conveniently be presented in unit dosage form and may 
be prepared by any of the methods well-known in the art of pharmacy. All 
methods include the step of bringing the active ingredient into 
association with the carrier which constitutes one or more accessory 
ingredients. In general, the formulations are prepared by uniformly and 
intimately bringing the active ingredient into association with a liquid 
carrier or a finely divided solid carrier or both, and then, if necessary, 
shaping the product into the desired formulation. 
Formulations of the present invention suitable for oral administration may 
be in the form of discrete units such as capsules, cachets, tablets, or 
lozenges, each containing a predetermined amount of the active ingredient; 
in the form of a powder or granules; in the form of a solution or a 
suspension in an aqueous liquid or nonaqueous liquid; or in the form of an 
oil-in-water emulsion or a water-in-oil emulsion. The active ingredient 
may also be in the form of a bolus, electuary, or paste. 
A tablet may be made by compressing or molding the active ingredient 
optionally with one or more accessory ingredients. Compressed tablets may 
be prepared by compressing, in a suitable machine, the active ingredient 
in a free-flowing form such as a powder or granules, optionally mixed 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 active ingredient and a suitable carrier moistened with an 
inert liquid diluent. 
Formulations for rectal administration may be in the form of a suppository 
incorporating the active ingredient and a carrier such as cocoa butter, or 
in the form of an enema. 
Formulations suitable for parenteral administration conveniently comprise a 
sterile aqueous preparation of the active ingredient which is preferably 
isotonic with the blood of the recipient. 
Formulations suitable for intraarticular administration may be in the form 
of a sterile aqueous preparation of the active ingredient which may be in 
microcrystalline form, for example, in the form of an aqueous 
microcrystalline suspension. Liposomal formulations or biodegradable 
polymer systems may also be used to present the active ingredient for both 
intraarticular and ophthalmic administration. 
Formulations suitable for topical administration include liquid or 
semi-liquid preparations such as liniments, lotions, applications, 
oil-in-water or water-in-oil emulsions such as creams, ointments or 
pastes; or solutions or suspensions such as drops. For example, for 
ophthalmic administration, the active ingredient may be presented in the 
form of aqueous eye drops as, for example, a 0.1-1.0% solution. 
Formulations suitable for administration to the nose or buccal cavity 
include powder, self-propelling and spray formulations such as aerosols 
and atomizers. The formulations, when dispersed, preferably have a 
particle size in the range of 0.1 to 200 .mu.. 
A particularly valuable form of a pharmaceutical composition of the present 
invention, for use in the prophylaxis or treatment of airway smooth muscle 
constriction, or asthma or bronchitis in general, due to any cause, is one 
suitable for pulmonary administration via the buccal cavity. Preferably 
the composition is such that particles having a diameter of 0.5 to 7 .mu., 
most preferably 1 to 6 .mu., containing active ingredient, are delivered 
into the lungs of a patient. Such compositions are conveniently in the 
form of dry powders for administration from a powder inhalation device or 
self-propelling powder-dispensing containers, for example as a 
self-propelling aerosol composition in a sealed container; preferably the 
powders comprise particles containing active ingredient of which particles 
at least 98% by weight have a diameter greater than 0.5 .mu. and at least 
95% by number have a diameter less than 7 .mu.. Most desirably at least 
95% by weight of the particles have a diameter greater than 1 .mu. at 
least 90% by number of the particles have a diameter less than 6 .mu.. 
The compositions in the form of dry powders preferably include a so]id fine 
powder diluent such as sugar and are conveniently presented in a permeable 
capsule, for example of gelatin. 
Self-propelling compositions of the invention may be either 
powder-dispensing compositions or compositions dispensing the active 
ingredient in the form of droplets of a solution or suspension. 
Self-propelling powder-dispensing compositions include a liquid propellant 
having a boiling point of below 65.degree. F. at atmospheric pressure. 
Generally the propellant may constitute 50 to 99.9% w/w of the composition 
whilst the active ingredient may constitute 0.1 to 20% w/w, for example 
about 2% w/w of the composition. The carrier in such compositions may 
include other constituents, in particular a liquid nonionic or solid 
anionic surfactant, or a solid diluent (preferably having a particle size 
of the same order as of the particles of active ingredient) or both. The 
surfactant may constitute from 0.01 up to 20% w/w, though preferably it 
constitutes below 1% w/w of the composition. 
Self-propelling compositions wherein the active ingredient is present in 
solution comprise an active ingredient, propellant,. and co-solvent, and 
advantageously an antioxident stabilizer. The co-solvents may constitute 5 
to 40% w/w of the composition, though preferably less than 20% w/w of the 
composition. 
Compositions of the present invention may also be in the form of aqueous or 
dilute alcoholic solution, optionally a sterile solution, of the active 
ingredient for use in a nebulizer or atomizer. 
Formulations of the present invention may also be in the form of an aqueous 
or dilute alcoholic solution, optionally a sterile solution, of the active 
ingredient for use in a nebulizer or atomizer, wherein an accelerated air 
steam is used to produce a fine mist consisting of small droplets of the 
solution. Such formulations usually contain a flavoring agent such as 
saccharin sodium and a volatile oil. A buffering agent and a surface 
active agent may also be included in such a formulation which should also 
contain a preservative such as methylhydroxybenzoate. 
Other formulations suitable for nasal administration include a coarse 
powder having a particle size of 20 to 500 microns which is administered 
in the manner in which snuff is taken i.e., by rapid inhalation through 
the nasal passage from a container of the powder held close up to the 
nose. 
In addition to the aforementioned ingredients, the formulations of this 
invention may include one or more additional ingredients such as diluents, 
buffers, flavoring agents, binders, surface active agents, thickeners, 
lubricants, preservatives e.g., methylhydroxybenzoate (including 
antioxidants), emulsifying agents, and the like. Any other therapeutic 
ingredient may comprise one or more of the following: antibiotic (e.g., 
antibacterial), antifungal and antiviral agents, and antihistamines 
(particularly peripherally acting antihistamines). However, when such 
other agent(s) are also present, according to another aspect of the 
invention, the compound of formula (1) or physiologically acceptable salt 
thereof and the other agent(s), need not necessarily be present as a 
pharmaceutical formulation as hereinbefore defined, but merely in 
combination or intimate admixture, i.e., optionally, a pharmaceutically 
acceptable carrier need not be present. 
The combination with antihistamines is particularly favored for 
antiasthmatic use. Such an antihistamine may be selected from any compound 
described in European Patent Applications EP 0 859 949 A and EP 0 117 302 
A. The amount and dosage regime for such an antihistamine may be chosen 
from any of those recited in the latter two European Specifications. 
Especially preferred are the antihistamines 
(E)-3-(6-(3-pyrrolidino)-1-(4-tolyl)prop-1E-enyl-(-2-pyridyl)) acrylic 
acid and 
(E)-3-(6-(3-pyrrolidino)-1-(4-tolyl)prop-1E-enyl(-2-pyridyl))propionic 
acid. Another preferred antihistamine is 
(E)-1-(4-methylphenyl)-1-(2-pyridyl)-3-pyrrolidinoprop-1-ene, otherwise 
known as typrolidine. 
Also preferred is the antihistamine known as Seldane. 
The compound of formula (I) and their salts may be prepared generally by 
the following processes and constitute a further aspect of the present 
invention. 
For the preparation of compounds of the formula (I) wherein R.sub.1 is 
##STR22## 
wherein R.sub.6 and R.sub.7 are as defined above, 
a compound of the formula (II) 
##STR23## 
wherein R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.11 are as defined 
above is converted to an acid chloride by treatment with oxalyl chloride, 
thionyl chloride, or the like to obtain the compound of formula (III) 
##STR24## 
wherein R.sub.2 except not to be taken together with R.sub.1, R.sub.3, 
R.sub.4, R.sub.5, and R.sub.11 are as defined above; 
the compound of formula (III) is then treated with the appropriately 
substituted hydroxylamine of the formula (IV) 
##STR25## 
to obtain the compound of formula (I) wherein R.sub.1 is 
##STR26## 
For the preparation of the compounds of formula (I) wherein R.sub.1 is 
##STR27## 
or wherein R.sub.1 is taken together with R.sub.2 and is 
##STR28## 
wherein R.sub.6, R.sub.7, R.sub.8, and L.sub.1 are as defined above; 
(1) A compound of the formula (X) 
##STR29## 
is prepared by decarboxylating the compound of formula (II) wherein 
R.sub.2 is hydrogen and R.sub.3, R.sub.4, R.sub.5, and R.sub.11 are as 
defined above; then 
(2) the compound of the formula (X) is treated with a compound of the 
formula 
##STR30## 
to obtain the compound of the formula (XI) 
##STR31## 
wherein R.sub.3, R.sub.4, R.sub.5, and R.sub.11 are as defined above; 
using conditions analogous to those in U.S. Pat. No. 4,092,430 then 
(3) the compound of formula (XI) is treated with a Lewis acid such as 
AlCl.sub.3, BF.sub.3, or the like, preferably AlCl.sub.3 ; to cyclize the 
compound (XI) to the compound of the formula (I.sub.b) wherein L.sub.2 is 
oxygen which can optionally be further treated with a compound of the 
formula H.sub.2 NOR.sub.7 wherein R.sub.7 is as defined above; to obtain 
the compound of formula (I".sub.b) 
##STR32## 
which is then optionally treated with a nuceophile of the formula 
EQU :OR.sub.8 
wherein R.sub.8 is H or alkyl to obtain the compound of the formula (I) 
wherein R.sub.1 is 
##STR33## 
wherein R.sub.7 is H, lower alkyl, or acyl and R.sub.8 is hydrogen or 
lower alkyl. 
Finally, for the preparation of the compounds of the formula (I) wherein 
R.sub.1 taken together with R.sub.2 is 
##STR34## 
wherein L.sub.1 is oxygen and R.sub.7 is as defined above; 
(i) a compound of the formula (I) wherein R.sub.1 is 
##STR35## 
wherein R.sub.6 is hydrogen is reacted with a compound of the formula 
##STR36## 
to obtain a compound of the formula (I) wherein L.sub.1 is oxygen and 
R.sub.7 is as defined above. 
For the preparation of the compounds of formula I wherein R.sub.1 taken 
together with R.sub.2 is 
##STR37## 
wherein L.sub.1 is H.sub.2 and R.sub.7 is as defined above; 
the compound of the formula (I) wherein R.sub.1 is 
##STR38## 
wherein R.sub.6 is hydrogen and R.sub.7 is as defined above may be reacted 
with formaldehyde to obtain the compound of the formula (I) wherein 
R.sub.1 and R.sub.2 together are 
##STR39## 
wherein L.sub.1 is H.sub.2 and R.sub.7 is as defined above. 
The above reactions are shown in the following Schemes I, II, and III 
followed by details for selected steps. 
##STR40## 
SCHEME I 
Step A: 
Treatment of the compound of formula II with oxalyl chloride/DMF affords 
the acid chloride of formula III, which is directly reacted with an 
appropriately substituted hydroxylamine HNR.sub.6 OR.sub.7 to give rise to 
a compound of the formula I.sub.a. 
SCHEME II 
Thermal decarboxylation of a compound of the formula II.sub.b by means of 
Cu/quinoline affords a compound of formula X, which is converted to the 
acid chloride of formula XI by treatment with oxalyl chloride. Cyclization 
of the compound of formula XI by means of a Lewis acid, preferably 
AlCl.sub.2, then gives rise to a compound of formula I.sub.b (see 
reference in the literature to analogous reactions). 
Conversion of the compound of formula I.sub.b to the corresponding oxime 
analogues of formula I.sub.b is performed by treating the compound of 
formula I.sub.b with an approximately substituted hydroxylamine and an 
organic base (preferably triethylamine). 
Ring opening of the compound of formula I".sub.b by means of hydroxide or 
alkoxide then affords a compound of formula I'".sub.b. 
SCHEME III 
The o-anilinohydroxamic acid of formula I.sub.c is treated with phosgene 
and an appropriate base according to a procedure analogous to such 
procedures in the literature to give the cyclic analogues of formula 
I'.sub.c. Alternatively, treatment of the o-anilinohydroxamic acid of 
formula I.sub.c with formaldehyde under dehydrating conditions affords the 
cyclic analogues of formula I".sub.c. 
SCHEME IV 
The several reactions of this scheme show other means to prepare the 
compounds of the present invention using analogous methods well known in 
the art from starting materials that are known or can be readily prepared 
by known methods and variously exemplified hereinafter. 
One of skill in the art would recognize variations in the sequence and 
would recognize appropriate reaction conditions from analogous reactions 
which may be appropriately used in the processes to make the compounds of 
formula (I) herein. Further, the starting materials are known or can be 
prepared by known methods. 
Under certain circumstances it is necessary to protect either the N or O of 
intermediates in the above noted process with suitable protecting groups 
which are known. Introduction and removal of such suitable oxygen and 
nitrogen protecting groups are well-known in the art of organic chemistry; 
see for example "Protective Groups in Organic Chemistry," J. F. W. McOmie, 
ed., (New York, 1973), pages 43ff, 95ff, J. F. W. McOmie, Advances in 
Organic Chemistry, Vol. 3, 191-281 (1963); R. A. Borssonas, Advances in 
Organic Chemistry, Vol. 3, 159-190 (1963); and J. F. W. McOmie. Chem. & 
Ind.. 603 (1979). 
Examples of suitable oxygen protecting groups are benzyl, 
t-butyldimethylsilyl, ethoxyethyl, and the like. Protection of an N--H 
containing moiety is necessary for some of the processes described herein 
for the preparation of compounds of this invention. Suitable nitrogen 
protecting groups are benzyl, triphenylmethyl, trialkylsilyl, 
trichloroethylcarbamate, trichloroethoxycarbonyl, vinyloxycarbamate, and 
the like. 
Under certain circumstances it is necessary to protect two different 
oxygens with dissimilar protecting groups such that one can be selectively 
removed while leaving the other in place. The benzyl and 
t-butyldimethylsilyl groups are used in this way; either is removable in 
the presence of the other, benzyl being removed by catalytic 
hydrogenolysis, and t-butyldimethylsilyl being removed by reaction with, 
for example, tetra-n-butylammonium fluoride. 
In the process described herein for the preparation of compounds of this 
invention the requirements for protective groups are generally well 
recognized by one skilled in the art of organic chemistry, and accordingly 
the use of appropriate protecting groups is necessarily implied by the 
processes of the charts herein, although not expressly illustrated. 
The products of the reactions described herein are isolated by conventional 
means such as extraction, distillation, chromatography, and the like. 
The salts of the compounds of formula (I) described above are prepared by 
reacting the appropriate base or acid with a stoichiometric equivalent of 
the compounds of formula (I), respectively, to obtain pharmaceutically 
acceptable salts thereof. 
The invention is further elaborated by the representative examples as 
follows. Such examples are not meant to be limiting.

EXAMPLES 
Example 1 
25 2-[(2,6-Dichloro-3-methylphenyl)amino]-N-hydroxy-N-phenylmethylbenzamide 
Meclomen (5.92 g; 0.02 mol) is suspended in CH.sub.2 Cl.sub.2 (150 ml) 
containing DMF (1.46 g, 0.02 mol) and cooled to 0.degree. C. Oxalyl 
chloride is added to the solution over 30 minutes and the resulting yellow 
solution is stirred at 24.degree. C. for 20 hours and then added to a cold 
solution of N-benzylhydroxylamine (2.46 g; 0.02 mol) in THF (60 
ml)--H.sub.2 O (15 ml)--Et.sub.3 N (20 ml) mixture. The solution is 
allowed to come to 24.degree. C. and treated with 2N HCl (160 ml). The 
product is extracted with CH.sub.2 Cl.sub.2. The extracts are dried over 
sodium sulfate and evaporated to dryness. The residue is flash 
chromatographed through SiO.sub.2 gel eluting with CH.sub.2 Cl.sub.2. The 
fractions containing the product are evaporated and the solid residue is 
recrystallized from isopropylether/n-hexane yielding white crystals. Yield 
1.45 g (18.6%); mp 133.degree.-135.degree. C. 
EXAMPLE 2 
Ortho-2,6-dichloro-3-methylanilinobenzhydroxamic acid or 
2-[(2,6-dichloro-3-methylphenyl)amino]-N-hydroxybenzamide 
Ortho-2,6-dichloro-3-methylaniinobenzoic acid (3.0 g) is suspended in 
methylenechloride (75 ml) containing DMF (0.74 g). After cooling to 
0.degree. C., oxalyl chloride (2.8 g) is added dropwise. After the initial 
suspension dissolves, the solution is cannulated into an aqueous THF (125 
ml THF/15 ml water) solution of hydroxylamine-HCl (2.8 g) and 
triethylamine (6.1 g). After stirring for thirty minutes at room 
temperature, the solution is then poured into 2 N aqueous HCl (300 ml). 
The organics are extracted into methylene chloride, dried (MgSO.sub.4), 
and concentrated to afford a residue. Flash chromatography (230 mesh 
silica gel, 20% methylene chloride, 20% ethyl acetate, 60% hexane) affords 
1.1 g (35% yield) of ortho-2,6-dichloro-3-methylanilinobenzhydroxamic 
acid, mp 170.degree.-175.degree. C. 
Microanalysis: C, H, N, 
Calc. C, 54.04; H, 3.89; N, 9.00, 
Found C, 53.80; H, 3.74; N, 8.71. 
Second run: 
2-[(2,6-Dichloro-3-methylphenyl)amino]-N-hydroxybenzamide. 
Yield: 23.35 g (62.6%); mp 158.degree.-159.degree. C., recrystallized from 
ether/n-hexane 
The discrepancy in melting points between the first and second run appears 
to be a mechanical error in the first. 
EXAMPLE 3 
Ortho-2,6-dichloro-3-methylanilinobenz-N-methylhydroxamic acid or 
2-[(2,6-dichloro-3-methylphenyl)amino]-N-hydroxy-N-methylbenzamide 
According to the procedure of Example 2, 
ortho-2,6-dichloro-3-methylanilinobenzoic acid (4.0 g) is reacted with 
N-methylhydroxylamine-HCl (4.5 g) to afford 2.1 g (47% yield) of 
ortho-2,6-dichloro-3-methylanilinobenz-N-methylhydroxamic acid, mp 
117.degree.-124.degree. C. 
Microanalysis: C, H, N. 
Calc. C, 55.40; H, 4.34; N, 8.61. 
Found C, 55.12; H, 4.55; N, 8.98. 
Second run: Yield: 18.8 g (48%); mp 126.degree.-128.degree. C., 
recrystallized from ether/n-hexane. 
EXAMPLE 4 
Ortho-2,6-dichloro-3-methylanilinobenzhydroxamic acid O-methyl ether or 
2.TM.[(2,6-dichloro-3-methylphenyl)amino]-N-methoxybenzamide 
According to the procedure of Example 2, 
ortho-2,6-dichloro-3-methylaniinobenzoic acid (3.0 g) is reacted with 
methoxylamine-HCl (3.4 g) to afford 2.0 g (61% yield) of 
ortho-2,6-dichloro-3-methylanilinobenzhydroxamic acid O-methyl ether, mp 
210.degree.-214.degree. C. 
Microanalysis: C, H, N. 
Calc. C, 55.40; H, 4.34; N, 8.61. 
Found C, 55.09; H, 4.21; N, 8.38. 
Second run: Yield: 30.3 g (77.7%); mp 192.degree.-194.degree. C., 
recrystallized from ethyl acetate. 
The following compounds are prepared following the procedures analogous to 
those of Example 1 above using appropriate starting materials. 
EXAMPLE 5 
2-[(2,6-Dichloro-3-methylphenyl)amino]-N-hydroxy-N1-methylethylbenzamide 
Yield: 5.35 g (38%); mp 152.degree.-153.degree. C., recrystallized from 
acetonitrile. 
EXAMPLE 6 
2-[(2,3-dimethylphenyl)amino-N-hydroxy-N-methylbenzamide 
1,1'-Carbonyl-diimidazole (5.35 g; 0.033 mol) is added to a solution of 
mefanamic acid (7.2% g; 0.03 mol) in dry DMF (100 ml). The solution is 
stirred at 24.degree. C. for 20 hours and then briefly warmed to 
50.degree. C. N-Methylhydroxylamine hydrochloride (2.7 g; 0.032 mo) is 
added to the cooled solution at 24.degree. C. and stirred for two days. 
The reaction mixture is then evaporated to dryness and the residue is 
taken up in CH.sub.2 Cl.sub.2, washed with water, and dried over sodium 
sulfate and evaporated. The residue is flash chromatographed through 
silica gel and eluted with n-hexane-CH.sub.2 Cl.sub.2 -EtOAc (2:1:1) 
yielding a crude product which is rechromatographed through silica gel and 
eluted with n-hexane-CH.sub.2 Cl.sub.2 -EtOAc (4:5:1). The product is 
recrystallized from n-pentane to give white crystals. Yield 1.5 g (18.5%); 
mp 70.degree.-71.degree. C. 
EXAMPLES 7-8 
The following compounds are prepared following the procedures analogous to 
Example 6 as described above using appropriate starting materials. 
2-[(2,3-Dimethylphenyl)amino]-N-methoxybenzamide 
Yield: 6.5 g (48%); mp 151.degree.-152.degree. C., recrystallized from 
ethyl acetate. 
2-(2,3-dimethylphenyl)amino]-N-hydroxy-N-(1-methylethyl)benzamide 
Yield: 6.08 g (78.4%); mp 47.degree.-49.5.degree. C., recrystallized from 
n-pentane. 
EXAMPLE 9 
2-[(2,3-dimethylphenyl)amino]-N-hydroxybenzamide 
Sodium methoxide (6.48 g; 0.12 mol) is added to a solution of mefanamic 
acid methyl ester (5.11 g; 0.02 mol) and hydroxylamine.multidot.HCl (5.56 
g; 0.08 mol) in methanol (450 ml) and THF (50 ml). The mixture is heated 
to reflux for 20 hours. An additional amount of hydroxylamine.multidot.HCl 
(1.39 g; 0.02 mol) and sodium methoxide (1.62 g; 0.03 mol) is added and 
the heating is continued for an additional three hours. The reaction 
mixture is cooled and quenched with AcOH (60 ml), diluted with water (300 
ml), and concentrated to half the original volume. It is extracted with 
CH.sub.2 Cl.sub.2, washed with water, and dried over sodium sulfate. 
Evaporation of the solvent gives a solid residue which is recrystallized 
from ether - n-hexane to give an off-white solid. Yield 1.5 g (29.2%); mp 
124.degree.-125.degree. C. 
EXAMPLE 10 
2-[(2,6-dichlorophenyl)amino]-N-hydroxybenzamide 
According to the procedure of Example 1, 
2-[(2,6-dichlorophenyl)amino]benzoic acid (J. S. Kaltenbronn, et al., 
Arzneimittel-Forschung/ Drug Research, 33(1), 4a, 621-627 (1983)) (4.1 g) 
is reacted with hydroxylamine hydrochloride (4.04 g) to provide 
2-[(2,6-dichlorophenyl)amino]-N-hydroxybenzamide (2.9 g, 67%); mp 
171-173.degree. C. 
Analysis: 
Calc. C, 52.54; H, 3.40; N, 9.43; Cl, 23.86. 
Found C, 52.26; H, 3.28; N, 9.39; Cl, 23.64. 
EXAMPLE 11 
N-hydroxy-2-(phenylamino)benzamide 
A solution of N-phenylanthranilic acid (5.0 g, 23.4 mmol) and 
carbonyldiimidazole (5.7 g, 35.2 mmol) in dry THF (50 ml) is stirred for 
two hours at room temperature. 0-THP-hydroxylamine (R. N. Warrener, 
Angewardte Chemie, Int. Ed. Engl. 5, 511 (1966)) (5.5 q, 46.8 mmol) is 
added and the reaction mixture is cooled, diluted with ethyl acetate (100 
ml), and extracted with 0.1 N HCl (2.times.100 ml), saturated aqueous 
NaHCO.sub.3 (100 ml), and brine (100 ml). The organic layer is dried 
(MgSO.sub.4) and evaporated. The residue is purified by flash 
chromatography (silica, 10% CHCl.sub.3 /EtOAc). The crude, protected 
hydroxamate is dissolved in methanol (500 ml) and treated with 10 drops of 
concentrated HCl. The reaction mixture is stirred for 10 minutes at room 
temperature and the solvent is evaporated (temperature &lt;35.degree. C.). 
The washed with saturated aqueous NaHCO.sub.3. The organic layer is dried 
(MgSO.sub.4) and evaporated. Flash chromatography (silica, EtOAc) gives 
N-hydroxy-2-(phenylamino)benzamide (3.5 g, 65%, mp 97.degree.-98.degree. 
C. (from isopropyl ether/hexane). 
Analysis C.sub.13 H.sub.12 N.sub.2 O.sub.2 : 
Calc. C, 68.41; H, 5.30; N, 12.27. 
Found C, 68.45; H, 5.27; N, 12.11. 
The following compounds are prepared according to the procedure in Example 
11 from the corresponding carboxylic acids (J. S. Kaltenbronn, et al., 
Arzneimittel-Forschung/Drug Research, 33(1), 4a, 621-627 (1983). 
______________________________________ 
##STR41## 
Example 
Number Ar mp % Yield 
______________________________________ 
12 
##STR42## 107-112.degree. C. 
85% 
13 
##STR43## amorphous foam 
84% 
14 
##STR44## amorphous foam 
94% 
15 
##STR45## 105-110.degree. C. 
75% 
16 
##STR46## 125-129.degree. C. 
91% 
17 
##STR47## amorphous foam 
86% 
18 
##STR48## amorphous foam 
86% 
19 
##STR49## 97-102.degree. C. 
60% 
20 
##STR50## amorphous foam 
98% 
21 
##STR51## amorphous foam 
98% 
22 
##STR52## 97-99.degree. C. 
69% 
23 
##STR53## amorphous foam 
94% 
24 
##STR54## amorphous foam 
96% 
______________________________________ 
EXAMPLE 25 
N-Hydroxy-N-Methyl-2-[(2,6-dichlorophenyl)amino]-benzamide 
According to the procedure of Example 1, 
2-(2,6-dichlorophenyl)amino]benzoic acid (2.0 g) is reacted with 
N-methylhydroxylamine hydrochloride (2.4 g) to afford 
N-hydroxy-N-methyl-2-[(2,6-dichlorophenyl)amino]benzamide (1.2 g, 54%), mp 
137.degree.-140.degree. C. 
Analysis C.sub.14 H.sub.12 Cl.sub.2 N.sub.2 O.sub.2 : 
Calc. C, 54.04; H, 3.89; N, 9.00; Cl, 22.79. 
Found C, 54.13; H, 3.90; N, 8.9g; Cl, 22.80. 
EXAMPLE 26 
2,3-Dihydro-3-hydroxy-1-phenyl-4(1H)quinazolinone 
A mixture of N-hydroxy-2-(phenylamino)benzamide (1.4 g, 6.15 mmol), 
p-toluene sulfonic acid (400 ml), and paraformaldehyde (200 mg, 6.75 mmol) 
in toluene (50 ml) is stirred at room temperature for 30 minutes. The 
reaction mixture is heated for 10 minutes (in an oil bath preheated to 
120.degree.-130.degree. C.) using a Dean-Stark trap to collect water. The 
reaction mixture is cooled and diluted with ethyl acetate (50 ml) and is 
extracted with saturated aqueous NaHCO.sub.3 (4.times.50 ml) and water (50 
ml). The organic layer is dried (MgSO.sub.4) and evaporated. 
Recrystallization from EtOAc/hexane gives 0.6 g (40%) of 
2,3-dihydro-3-hydroxy-1-phenyl-4(1H)-quinazolinone, mp 
156.degree.-160.degree. C. 
Analysis C.sub.14 H.sub.12 N.sub.2 O.sub.2 : 
Calc. C, 69.99; H, 5.03; N, 11.66. 
Found C, 69.66; H, 4.95; N, 11.70. 
The following compounds are prepared according to the procedure of Example 
26. 
__________________________________________________________________________ 
##STR55## 
Prepared 
From 
Example Compound 
Molecular 
Number 
Ar mp % Yield 
of Formula 
__________________________________________________________________________ 
27 
##STR56## 131-137.degree. C. 
10% Example 12 
C.sub.16 H.sub.13 F.sub.3 N.sub.2 
O.sub.2 
28 
##STR57## 162-164.degree. C. 
22% Example 13 
C.sub.15 H.sub.14 N.sub.2 O.sub.2 
29 
##STR58## 137-143.degree. C. 
36% Example 14 
C.sub.14 H.sub.11 ClN.sub.2 O.sub.2 
30 
##STR59## 130-134.degree. C. 
15% Example 15 
C.sub.15 H.sub.13 ClN.sub. 2 O.sub.2 
31 
##STR60## 133-135.degree. C. 
7.5% Example 16 
C.sub.15 H.sub.13 ClN.sub.2 O.sub.2 
32 
##STR61## 128-133.degree. C. 
19% Example 17 
C.sub.14 H.sub.11 ClN.sub.2 O.sub.2 
33 
##STR62## 148-150.degree. C. 
32% Example 18 
C.sub.15 H.sub.14 N.sub.2 O.sub.3 
34 
##STR63## 179-182.degree. C. 
28% Example 19 
C.sub.14 H.sub.10 Cl.sub.2 N.sub.2 
O.sub.2 
35 
##STR64## 197-200.degree. C. 
22% Example 2 
C.sub.15 H.sub.12 Cl.sub.2 N.sub.2 
O.sub.2 
36 
##STR65## 145-150.degree. C. dec 
5% Example 10 
C.sub.14 H.sub.10 Cl.sub.2 N.sub. 2 
O.sub.2 
37 
##STR66## 135-137.degree. C. 
27% Example 20 
C.sub.14 H.sub.10 Cl.sub.2 N.sub.2 
O.sub.2 
38 
##STR67## 166-168.degree. C. 
28% Example 21 
C.sub.15 H.sub.11 F.sub.3 N.sub.2 
O.sub.2 
39 
##STR68## 133-135.degree. C. 
19% Example 22 
C.sub.15 H.sub.11 F.sub.3 N.sub.2 
O.sub.2 
40 
##STR69## 139-142.degree. C. 
30% Example 9 
C.sub.16 H.sub.16 N.sub.2 O.sub.2 
41 
##STR70## 174-176.degree. C. 
15% Example 23 
C.sub.15 H.sub.14 N.sub.2 O.sub.2 
42 
##STR71## 108-110.degree. C. 
28% Example 24 
C.sub.15 H.sub.14 N.sub.2 O.sub.2 0.1 
H.sub.2 O 
43 
##STR72## amorphous foam 
10 Example 4 
C.sub.16 H.sub.14 Cl.sub.2 N.sub.2 
O.sub.2 
__________________________________________________________________________ 
EXAMPLE 44 
1-(2,6-Dichloro-3-methylphenyl)-3-hydroxy-2,4-(1H,3H)quinazolinedione 
2-[2,6-dichloro-3-methylphenyl)aminobenzoic acid (10.0 g) and DMF (2.5 g) 
are cooled to 0.degree. C. in 200 ml CH.sub.2 Cl.sub.2 under argon. Oxalyl 
chloride (9.4 g) is added dropwise at 0.degree. C. When the initial slurry 
dissolves, the solution is cannulated into a THF solution of 
O-tetrahydropyranyl hydroxylamine (11.9 g) and triethylamine (20.5 g) at 
room temperature. The reaction is stirred at room temperature overnight. 
The solvent is evaporated and the residue is partitioned between ethyl 
acetate and saturated sodium bicarbonate. The organic layer is washed with 
saturated sodium bicarbonate and dried (MgSO.sub.4). Evaporation gives a 
solid residue which is recrystallized from isopropyl ether to give 8 g of 
the 0-tetrahydropyranyl hydroxamic acid, mp 148.degree.-150.degree. C. It 
is taken up in THF and treated with NaH (0.48 g) at 0.degree. C. for 30 
minutes. The reaction is warmed to room temperature and ethylchloroformate 
is added. After one hour, NaH (0.48 g) is added and the reaction is warmed 
to reflux for two hours. The reaction is quenched with water and extracted 
with ethyl acetate. The ethyl acetate layer is washed with brine and dried 
(MgSO.sub.4). Evaporation of ethyl acetate gives 6.0 g of the 
3-0-tetrahydropyranyl quinazolinedione. Two grams of the THP 
quinazolinedione is taken up in methanol and acidified to pH 1 with 
concentrated HCl. The reaction is stirred at room temperature overnight. 
The methanol is evaporated and the residue is taken up in ethyl acetate. 
It is washed with saturated sodium bicarbonate and dried (MgSO.sub.4). The 
solvent is evaporated and the residue is recrystallized from isopropyl 
ether/hexane. Yield of 
1-(2,6-dichloro-3-methylphenyl)-3-hydroxy-2,4-(1H,3H)-quinazolinedione 
=0.6 g (37%), mp 212.degree.-213.degree. C. 
Analysis C.sub.15 H.sub.10 Cl.sub.2 N.sub.2 O.sub.3 : 
Calc. C, 53.43; H, 3.00; N, 8.31; Cl, 21.03. 
Found C, 53.49; H, 2.90; N, 8.22; Cl, 20.84. 
EXAMPLE 45 
1-(2,6-Dichloro-3-methylphenyl)-3-methoxy-2,4-(1H,3H)quinazolinedione 
2-(2,6-Dichloro-3-methYlphenyl)amino-N-methoxybenzamide (1.6 %) is added to 
a THF (20 ml) solution of NaHCO.sub.3 (0.14 g) and ethyl chloroformate 
(0.25 g) at -30.degree. C. under argon. The reaction is allowed to stir 
overnight. The THF is evaporated and the residue is partitioned between 
diethyl ether and water. The organic layer is washed twice with water and 
brine after being dried over magnesium sulfate. The organic layer is 
concentrated to give a white solid, which is dissolved in THF and treated 
with sodium hydride at reflux for one hour under argon. The reaction is 
acidified with 1 N HCl and partitioned between ethyl acetate and water. 
The organic layer is washed with brine and dried (MgSO.sub.4). The solvent 
is evaporated and the residue is adsorbed onto a silica gel pad. The pad 
is washed with chloroform to give the product. Recrystallization from 
CH.sub.2 Cl.sub.2 /Et.sub.2 O gives 0.64 g (52% yield) of 
1-(2,6-dichloro-3-methylphenyl)-3-methoxy-2,4-(1H,3H)-quinazolinedione, mp 
211.degree.-213.degree. C. 
Analysis C.sub.16 H.sub.12 Cl.sub.2 N.sub.2 O.sub.2 : 
Calc. C, 54.72; H, 3.45; N, 7.98; Cl, 20.19. 
Found C, 54.90; H, 3.54; N, 7.99, Cl, 20.16. 
EXAMPLE 46 
(2',6'-Dichloro-3'-methyl)diphenylamine 
A solution of meclofenamic acid (35 g) in quinoline (100 ml) with copper 
powder (3.0 g) is heated at reflux (bath temperature 240.degree. C.) under 
an argon atmosphere for two hours. The reaction mixture is cooled and 
poured over ice water (350 ml). It is acidified by careful addition on 
concentrated HCl (85 ml) and extracted with ether. The organic layer is 
dried (MgSO.sub.4) and evaporated. Flash chromatography (silica, CH.sub.2 
Cl.sub.2) followed by recrystallization from petroleum ether provides 
(2',6'-dichloro-3'-methyl)diphenylamine (21 g, 69%), mp 
77.degree.-79.degree. C. 
EXAMPLE 47 
1-(2,6-Dichloro-3-methylphenyl)-1H indole-2,3-dione 
According to the procedure of A. Sallmann and R. Pfister (U.S. Pat. No. 
4,092,430), a solution of (2',6'-dichloro-3'-methyldiphenylamine (20 g) 
and dimethylaminopyridine (390 mg) and oxalylchloride (15 ml) in 
chloroform (200 ml) is heated at reflux for 16 hours. The reaction mixture 
is cooled, evaporated, and redissolved in dichloroethane (150 ml). The 
resulting solution is added to a suspension of AlCl.sub.3 (32 g) in 
dichloroethane. The reaction mixture is stirred at room temperature under 
an argon atmosphere for 20 hours. The reaction mixture is poured over ice 
water (500 ml) and the layers are separated. The aqueous layer is washed 
with CHCl.sub.3 and the combined organic layers are evaporated. 
Chromatography (silica, CHCl.sub.3) affords pure 
1-(2,6-dichloro-3-methylphenyl)-1H-indole-2,3-dione (12.9 g, 53%), mp 
164.degree.-166.degree. C. 
EXAMPLE 48 
1-(2,3-Dimethylphenyl)-1H-indole-2,3-dione and 
6,7-Dimethyl-1-phenyl-lH-indole-2,3-dione 
According to the procedure of Example 47, (2',3'-dimethyl)diphenylamine (10 
9) is reacted with oxalyl chloride to give a mixture of 
1-(2,3-dimethyl-phenyl)-1H-indole-2,3-dione and 
6,7-dimethyl-1-phenyl-1H-indole-2,3-dione. Flash chromatography (silica, 
CHCls) provides pure 1-(2,3-dimethylphenyl)-1H-indole-2,3-dione (0.82 %, 
6%), mp 183.degree.-187.degree. C. and 
6,7-dimethyl-1-phenyl-1H-indole-2,3-dione (4.4 g, 35%), mp 
147.degree.-149.degree. C. 
EXAMPLE 49 
1-(2,6-Dichloro-3-methylphenyl)-lH-indole-2,3-dione-3-oxime 
A solution of 1-(2,6-dichloro-3-methylphenyl)-1H-indole-2,3-dione (0.3 g) 
and hydroxylamine hydrochloride (0.07 g) in pyridine (2 ml) is stirred at 
room temperature for 20 minutes. The reaction mixture is diluted with 
ethyl acetate (20 ml) and washed with 1 N HCl (2.times.100 ml). The 
organic layer is dried (MgSO.sub.4) and evaporated. Flash chromatography 
(silica, CH.sub.2 Cl.sub.2) followed by recrystallization from isopropyl 
ether affords 1-(2,6-dichloro-3-methylphenyl)-1H-indole-2,3-dione 3-oxime 
(256 mg, 80%), mp 190.degree.-191.degree. C. 
Analysis C.sub.15 H.sub.10 Cl.sub.2 N.sub.2 O.sub.2 : 
Calc. C, 56.10; H, 3.14; N. 8.72: Cl, 22.08. 
Found C, 56.20; H, 3.12; N, 8.76; Cl, 22.0. 
EXAMPLE 50 
6,7-Dimethyl-1-phenyl-1H-indole-2,3-dione-3-oxime 
According to the procedure of Example 49, 
6,7-dimethyl-1-phenyl-1H-indole-2,3-dione (2 g) is converted to 
6,7-dimethyl-1-phenyl-1-H-indole-2,3-dione-3-oxime (1.2 g, 56%), mp 
245.degree.-250.degree. C. dec. 
Analysis C.sub.16 H.sub.14 N.sub.2 O.sub.2 : 
Calc. C, 72.16; H, 5.30; N, 10.52. 
Found C, 71.78; H, 5.25; N, 10.41. 
EXAMPLE 51 
1-(2,3-Dimethylphenyl)-lH-indole-2,3-dione-3-oxime 
According to the procedure of Example 49, 
1-(2,3-dimethylphenyl)-1H-indole-2,3-dione (0.65 g), is converted 
to-1-(2,3-dimethylphenyl)-1H-indole-2,3-dione-3-oxime (0.5 g, 63%), mp 
215.degree.-216.degree. C. 
Analysis C.sub.16 H.sub.14 N.sub.2 O.sub.2 : 
Calc. C, 72.16; H, 5.30; N, 10.52. 
Found C, 71.92; H, 5.07; N, 10.51. 
EXAMPLE 52 
2-[(2,6-Dichloro-3-methylphenyl)amino]-a-(hydroxylimino)benzene acetic acid 
A solution of 1-(2,6-dichloro-3-methylphenyl)-1H-indole-2,3-dione-3-oxime 
(2.25 9) in 6 N NaOH (10 ml) and 4 ml MeOH is heated at 50.degree. C. for 
two days without a reflux condenser. The resulting residue is taken up in 
water (50 ml) and filtered. It is neutralized with 1 N HCl with ice bath 
cooling. The precipitate is collected by filtration. The residue is air 
dried, dissolved in ether, and filtered. 
2-[(2,6-Dichloro-3-methylphenylamino]-.alpha.-(hydroxylimino)-benzeneaceti 
c acid (0.28 g, 50%) is precipitated from the ether solution by the 
addition of hexane, mp 152.degree.-154.degree. C. dec. 
The usefulness of the compounds of the present invention as inhibitors of 
the 5-lipoxygenase enzyme, cyclooxygenase, or other related biochemical 
actions may be demonstrated by their effectiveness in various standard 
test procedures. A description of each procedure follows. 
ARBL/ARBC Whole Cell 5-Lipoxygenase and Cyclooxygenase Assays 
Materials 
The rat basophilic leukemia cell line (RBL-1) was obtained from the 
American Type Culture Collection (Rockville, Md.). 
Radioimmuno assay (RIA) kits of LTB.sub.4 and PGF.sub.2.sbsb..alpha. were 
obtained from Amersham (Arlington Heiqhts, Ill.) and Seragen (Boston, 
Mass.) respectively. 
All tissue culture media were obtained from GIBCO (Grand Island, N.Y.). 
Method 
RBL-1 cells are grown in suspension culture in Eagle's minimum essential 
medium supplemented with 12% fetal bovine serum at 37.degree. C. in an 
incubator supplied with air-5% carbon dioxide. Cells are harvested by 
centrifugation. They are washed with cold phosphate buffered saline pH 7.4 
(PBS; NaCl, 7.1 %; Na.sub.2 HPO.sub.4, 1.15 g; KH.sub.2 PO.sub.4, 0.2 g; 
and KCl, 0.2 g/l). Cells are finally suspended in PBS containing 1.0 mM 
calcium at a density of 2.times.10.sup.6 cells/ml. Cells are incubated 
with and without test agent (in DMSO) (1% DMSO is without effect on 
arachidonic acid metabolism) for ten minutes at room temperature. Calcium 
ionophore A23187 (5 .mu.M) is added and cells are incubated for seven 
minutes at 37.degree. C. The reaction is stopped by chilling the tubes on 
ice for ten minutes. Cells are separated by centrifugation and the 
supernatant is stored at -20.degree.. Aliquots (100 .mu.l) are analyzed 
for LTB.sub.4 and PGF.sub.2.sbsb..alpha. using radioimmuno assay kits as 
provided by the supplier. 
Table 1 contains biochemical data obtained from this whole cell assay as 
IC.sub.50 s which are calculated as the amount of test compound causing 
50% inhibition of LTB.sub.4 or PGF.sub.2.sbsb..alpha. formation. 
TABLE 1 
______________________________________ 
Entry ARBL.sup.a,b 
ARBC.sup.a,c 
______________________________________ 
Example 2 3.9 1.1 
Example 3 1.5 15.0 
Example 4 16.0 0.55 
Example 10 88% @ 16 .mu.M 
80% @ 16 .mu.M 
Example 9 1.8 60% @ 0.5 .mu.M 
Example 35 3.2 2.2 
Example 49 6.5 28 
Meclomen 24.0 0.10 
______________________________________ 
.sup.a Data are expressed as IC.sub.50 values (.mu.M) for inhibition of 
substrate conversion to product. 
.sup.b IC.sub.50 for LTB.sub.4 inhibition. 
.sup.c IC.sub.50 for PGF.sub.2.sbsb..alpha. inhibition. 
Carrageenan-Induced Rat Foot Paw Edema2 (CFE2) 
Assay: Protocol 
Carrageenan solution (1% w/v) is prepared by dissolving 100 mg carrageenan 
(Marine Colloidal Div., Springfield, N.J.) in 10 ml of sterile saline 
(0.9%) solution (Travenol). The solution is vortexed for 30 to 45 minutes. 
Animals are dosed with compound one hour before carrageenan challenge. 
Foot paw edema is induced by injecting 0.05 ml of the 1% carrageenan 
subcutaneously into the plantar portion of the right hind paw of each rat 
under light anesthesia. Initial foot paw volume is measured immediately 
following carrageenan challenge using mercury plethysmography (Buxco 
Electronics). Edema is measured five hours after carrageenan. The 
difference between the five-hour and the initial paw volume is expressed 
as delta edema. The delta edema for each test group of animals is used to 
calculate the percent inhibition of edema achieved by the compound at the 
test dose compared with the vehicle control group. The ID.sub.25 (the dose 
at which swelling is inhibited by 25%) was calculated by probit analysis 
for the dose at which a result of 25 percent inhibition occurs. 
Mycobacterium--Induced Rat Footpad Edema Assay (MFE): Protocol 
Myobacterium butyricum (5 mg/ml) is suspended in paraffin oil by sonication 
for ten minutes in an ice bath. Footpad edema is induced on Day 0 by 
injecting 0.1 ml of the Mycobacterium mixture into the left hindpaw of 
lightly anesthetized rats. Swelling in the injected hindpaw is determined 
by mercury plethysmography 72 hours after injection. Groups of rats are 
treated with test compounds (suspended in 0.5% hydroxypropyl 
methylcellulose with 0.2% Tween-80) or vehicle one hour before 
Myobacterium injection and on Days 1 and 2. Inhibition of swelling is 
determined by comparing the change in hindpaw volume in compound- and 
vehicle-treated rats. An ID*c (the dose at which swelling is inhibited by 
40%) was calculated by probit analysis. 
Gastric Ulcerogenicity (UD) 
Protocol 
Male outbred Wistar rats (100-250 gms) were fasted for 24 hours. After 
fasting, test compounds were administered orally (in 2 ml/kg of 0.5% 
hydroxypropyl methylcellulose) and the rats were denied access to food and 
water for six more hours. The rats were then sacrificed with CO.sub.2 so 
that the stomachs could be removed, opened along the greater curvature, 
and evaluated for the presence of gastric ulcers. Results are expressed as 
the percent of rats with gastric ulcers at a given dose. 
The results of the CFE-2, MFE, and UD assays for each of the noted 
compounds is shown in the following Table 2. 
TABLE 2 
______________________________________ 
In Vivo Pharmacology 
Entry CFE-2.sup.a MFE.sup.b 
UD.sub.50.sup.c 
______________________________________ 
Example 1 T.sup.d 27.0 N @ 200 
Example 2 0.2 2.5 N @ 200 
Example 3 1.3 24.0 N @ 200 
Meclomen 8.2 0.39 36.0 
______________________________________ 
.sup.a ID.sub.25 in mg/kg PO. 
.sup.b ID.sub.40 in mg/kg PO. 
.sup.c Dose in mg/kg PO which produces a 50% occurrence of ulcers in rats 
N is 0% of rats have ulcers occurring at 200 mg. 
.sup.d Assay was not validated by standard. 
Accordingly, the present invention is 
(a) a compound of formula (I) or an acid addition or base addition salt 
thereof; 
(b) a method for preparing a compound of formula (I) or a pharmacologically 
acceptable acid addition or base salt thereof; 
(c) a pharmaceutical formulation comprising a compound of formula (I) or a 
physiologically acceptable salt thereof and a pharmaceutically acceptable 
carrier therefor; 
(d) a method for preparing such formulations; 
(e) a method for the inhibition of the lipoxygenase and/or cyclooxygenase 
pathways of the arachidonic acid metabolism by use of a nontoxic, 
effective, inhibitory amount of a compound of formula (1) or a 
physiologically acceptable sat thereof; 
(f) a method for the prophylaxis or treatment of disease in a mammal, 
including man, comprising the administration to said mammal of a nontoxic, 
therapeutically or prophylactically effective amount of a compound of 
formula (I) or a physiologically acceptable salt thereof; 
(g) a method for the prophylaxis or treatment of any individual condition 
described herein, in a mammal, including man, comprising the 
administration to said mammal of a nontoxic therapeutically or 
prophylactically effective amount of a compound of formula (I) or a 
physiologically acceptable salt thereof; 
(h) a method for the prophylaxis or treatment of asthma in a mammal, 
including man, comprising administration to said mammal of a nontoxic, 
effective, antiasthmatic amount of a compound of formula (1) or a 
physiologically acceptable salt thereof; 
(i) a compound of formula (I) or a physiologically acceptable salt thereof 
for use in medicine, especially as defined in (f)-(h) above; 
(j) use of a compound of formula (I) or a physiologically acceptable salt 
thereof in the manufacture of medical therapeutic agents, particularly 
those for use as defined in (f)-(h) above; and 
(k) any novel feature described herein.