Certain carbocyclic aryl- and heterocyclic aryl- substituted cyclopropyl N-hydroxyureas, N-hydroxy-carboxamides, and N-acyl-N-hydroxyamines inhibit 5- and/or 12-lipoxygenase and are useful in the treatment of inflammatory disease states.

TECHNICAL FIELD 
This invention relates to novel cyclopropyl compounds possessing 
lipoxygenase inhibitory activity. It also relates to methods and 
compositions for inhibiting lipoxygenase enzymes in humans and animal 
hosts in need of such treatment. 
BACKGROUND OF THE INVENTION 
5-Lipoxygenase is the first dedicated enzyme in the pathway leading to the 
biosynthesis of leukotrienes (Samuelsson, B., Science, 120:568 (1983); 
Hammarstrom, S., Annual Review of Biochemistry, 52:355 (1983)). This 
important enzyme has a rather restricted distribution, being found 
predominantly in leukocytes and mast cells of most mammals. Normally 
5-lipoxygenase is present in the cell in an inactive form; however, when 
leukocytes respond to external stimuli, intracellular 5-lipoxygenase can 
be rapidly activated. This enzyme catalyzes the addition of molecular 
oxygen to fatty acids with cis,cis-1,4-pentadiene structures, converting 
them to 1-hydroperoxy-trans,cis-2,4-pentadienes. Arachidonic acid, the 
5-lipoxygenase substrate which leads to leukotriene products, is found in 
very low concentrations in mammalian cells and must first be hydrolyzed 
from membrane phospholipids through the actions of phospholipases in 
response to extracellular stimuli. The initial product of 5-lipoxygenase 
action on arachidonate is 5-HPETE which can be reduced to 5-HETE or 
converted to leukotriene A4 (LTA4). This reactive leukotriene intermediate 
is enzymatically hydrated to LTB4 or conjugated to the tripeptide 
glutathione to produce LTC4. LTA4 can also be hydrolyzed nonenzymatically 
to form two isomers of LTB4. Successive proteolytic cleavage steps convert 
LTC4 to LTD4 and LTE4. 
Other products resulting from further oxygenation steps have also been 
described (Serhan, C. N., Hamberg, M., and Samuelsson, B., Proceedings of 
the National Academy of Sciences, USA, 81:5335 (1985); Hansson, G., 
Lindgren, J. A., Dahlen, S. E., Hedqvist, P., and Samuelsson, B. FEBS 
Letters, 130: 107 (1984)). 
Products of the 5-lipoxygenase cascade are extremely potent substances 
which produce a wide variety of biological effects, often in the nanomolar 
to picomolar concentration range. (Sirois, P., Advances in Lipid Research, 
R. Paoletti, D. Kritchevesky, editors, Academic Press, 21: 79 (1985). 
The remarkable potencies and diversity of actions of products of the 
5-lipoxygenase pathway have led to the suggestion that they play important 
roles in a variety of diseases. Alterations in leukotriene metabolism have 
been demonstrated in a number of disease states including asthma, allergic 
rhinitis, rheumatoid arthritis and gout, psoriasis, adult respiratory 
distress syndrome, inflammatory bowel (Crohn's) disease, endotoxin shock, 
and ischemia-induced myocardial injury. 
SUMMARY OF THE INVENTION 
In its principal embodiment, the present invention provides compounds 
having lipoxygenase inhibiting activity represented by the following 
structural formula: 
##STR1## 
wherein X and Y are absent or are independently divalent alkylene of from 
one to four carbon atoms, with the proviso that when R.sup.1 is 
carbocyclic aryloxy or heterocyclic aryloxy, X is a divalent alkylene of 
from two to four carbon atoms. 
The group R.sup.1 is selected from hydrogen, and unsubstituted or 
substituted carbocyclic aryl, (carbocyclic aryl)oxy, heterocyclic aryl or 
(heterocyclic aryl)oxy. 
The group R.sup.2 is selected from 
##STR2## 
where Z is hydrogen; a metabolically cleavable group; or a 
pharmaceutically acceptable cation. 
R.sup.3 is selected from hydrogen; alkyl of from one to six carbon atoms; 
cycloalkyl of from three to eight carbon atoms; amino; alkylamino of from 
one to six carbon atoms in which the alkyl group may be optionally 
substituted by hydroxyl, halogen, or carboxyl; dialkylamino in which the 
alkyl groups are independently selected from alkyl of from one to six 
carbon atoms; (cycloalkyl)amino of from three to six carbon atoms; 
2-hydroxyethylamino; N-morpholino; N-thiomorpholino; 
##STR3## 
where n is an integer of from three to eight, and 
##STR4## 
wherein R.sup.9 is hydrogen or alkyl of from one to six carbon atoms. 
R.sup.4 is selected from hydrogen; alkyl of from one to six carbon atoms; 
and cycloalkyl of from three to eight carbon atoms. 
R.sup.5 and R.sup.8 are independently hydrogen or alkyl of from one to four 
carbon atoms, and R.sup.6 and R.sup.7 are independently selected from 
hydrogen; alkyl of from one to four carbon atoms; and halogen. 
In a second embodiment, the present invention provides pharmaceutical 
compositions comprising a compound as defined above in combination with a 
pharmaceutically acceptable carrier. 
In yet another embodiment, the present invention provides a method of 
inhibiting 5-and 12-lipoxygenase activity by administering to a mammal in 
need of such treatment an effective amount of a compound of the present 
invention. 
DETAILED DESCRIPTION 
The compounds of the present invention are effective in inhibiting the 
activity of the 5-ipoxygenase and, as a result, are effective in 
preventing the formation of the products of lipoxygenase action on 
arachidonic acid. As discussed above, various products of the so-called 
"arachidonic acid cascade" of reactions are implicated in a number of 
allergic and inflammatory disease states. The compounds of this invention, 
by inhibiting the action of the lipoxygenase enzymes, are effective in 
treating or ameliorating the effects of these disease states. 
The compounds of this invention comprise substituted cyclopropyl compounds, 
as defined above, falling into one of two main structural subclasses 
represented by the following structural formulae: 
##STR5## 
In structures A and B shown above, the values of R.sup.1, R.sup.3, R.sup.4, 
R.sup.5, R.sup.6, R.sup.7, R.sup.8, X, Y, and Z are as previously defined. 
In the compounds of this invention, Z may be hydrogen (N-hydroxy 
compounds), or Z may be a metabolically cleavable group or a 
pharmaceutically acceptable cation. As used throughout this specification 
and the appended claims, the term "metabolically cleavable group" denotes 
a moiety which is readily cleaved in vivo from the compound bearing it, 
which compound after cleavage remains or becomes pharmacologically active. 
Metabolically cleavable groups form a class of groups well known to 
practitioners of the art. They include, but are not limited to such groups 
as alkanoyl (such as acetyl), unsubstituted and substituted carbocyclic 
aroyl (such as benzoyl and 1- and 2-naphthoyl), alkoxycarbonyl (such as 
ethoxycarbonyl), trialkylsiyl (such as trimethyl- and triethylsilyl), 
monoesters formed with dicarboxylic acids (such as succinyl), and the 
like. Because of the ease with which the metabolically cleavable groups of 
the compounds of this invention are cleaved in vivo, the compounds bearing 
such groups act as pro-drugs of other lipoxygenase inhibitors. The 
compounds bearing the metabolically cleavable groups have the advantage 
that they may exhibit improved bioavailability as a result of enhanced 
solubility and/or rate of absorption conferred upon the parent compound by 
virtue of the presence of the metabolically cleavable group. 
The term "pharmaceutically acceptable cation" denotes non-toxic cations 
including, but not limited to, cations derived from the alkaline and 
alkaline earth metals such as lithium, sodium, potassium, calcium, 
magnesium and the like as well as the ammonium ion and non-toxic cations 
derived from protonation of primary, secondary, and tertiary amines as 
well as quaternary ammonium ions. Examples include methylammonium, 
ethylammonium, dimethylammonium, trimethylammonium, triethylammonium, 
tetramethylammonium, tetraethylammonium, and the like. 
The term "carbocyclic aryl" as used throughout this specification and the 
appended claims means a group having a single or multiple concatenated or 
fused aromatic carbocyclic rings, exemplified by phenyl; biphenylyl, 1- or 
2-naphthyl and the like. 
The term "heterocyclic aryl" means a group having an aromatic single or 
fused ring system containing one oxygen atom, one sulfur atom, one, two, 
or three nitrogen atoms, one oxygen atom and one nitrogen atom, or one 
sulfur atom and one nitrogen atom. Heterocyclic aryl groups are 
exemplified by 2-, 3-, or 4-pyridyl; 2-, 4-, or 5-pyrimidyl; 2- or 
3-furanyl; 2- or 3-pyrrolyl; 2- or 3-thienyl; 2- or 3-benzo[b]thienyl; 2- 
or 3-benzofuranyl; 2-, 3-, or 4-quinolyl; 2- or 3-indolyl; 2- or 
4-thiazolyl; 2- or 3-benzothiazolyl, and imidazolyl. 
The term "(carbocyclic aryl)oxy" denotes a carbocyclic aryl group as 
defined above, connected to the parent molecular moiety through an oxygen 
atom. Similarly, the term "(heterocycluic aryl)oxy means a heterocyclic 
group as defined above, attached to the parent molecular moiety through an 
oxygen atom. 
The term "substituted (carbocyclic aryl)" or "substituted (heterocyclic 
aryl)" as used herein mean, respectively, a carbocyclic aryl group or 
heterocyclic aryl group, as those terms are defined above, substituted by 
one or more substituent groups selected from alkyl of from one to six 
carbon atoms; haloalkyl of from one to six carbon atoms; cycloalkyl of 
from four to twelve carbon atoms; alkoxy of from one to six carbon atoms; 
alkylthio of from one to six carbon atoms; carbocyclic aryl, heterocyclic 
aryl, (carbocyclic aryl)oxy, (heterocyclic aryl)oxy, (carbocyclic 
aryl)thio, alkoxy(carbocyclic aryl), alkoxy(heterocyclic aryl), wherein 
the alkoxy portion contains from one to six carbon atoms; 
alkyl(carbocyclic aryl) or alkyl(heterocyclic aryl) wherein the alkyl 
portion contains from one to six carbon atoms; alkylthio(carbocyclic aryl) 
or alkylthio(heterocyclic aryl) wherein the alkylthio portion contains 
from one to six carbon atoms; (carbocyclic aryl)alkylene and (heterocyclic 
aryl)alkylene wherein the alkylene portion contains from one to six carbon 
atoms; (carbocyclic aryl)alkoxy and (heterocyclic aryl)alkoxy wherein the 
alkoxy portion contains from one to six carbon atoms; (Carbocyclic 
aryl)alkylthio and (heterocyclic aryl)alkylthio wherein the alkylthio 
portion contains from one to six carbon atoms; alkanoyl of from one to 
eight carbon atoms; alkoxycarbonyl of from two to eight carbon atoms; 
amino; alkylamino of from one to six carbon atoms; dialkylamino in which 
the alkyl groups are independently selected from alkyl of from one to six 
carbon atoms; aminocarbonyl; alkylamino-carbonyl of from two to eight 
carbon atoms; dialkylamino-carbonyl in which the alkyl groups are 
independently selected from alkyl of from one to six carbon atoms; 
(N-alkyl-N-alkanoyl)amino of from three to twelve carbon atoms; 
(N-alkyl-N-alkoxycarbonyl)amino of from three to twelve carbon atoms; 
(N-alkyl-N-aminocarbonyl)amino of from two to twelve carbon atoms; 
(N-alkyl-N'-alkylaminocarbonyl)amino of from three to twelve carbon atoms; 
(N-alkyl-N', N'-dialkylaminocarbonyl)amino of from three to twelve carbon 
atoms; hydroxy; halogen; and cyano. 
The term "alkyl" denotes a univalent radical derived by the removal of a 
single hydrogen atom from a straight or branched saturated hydrocarbon. 
Examples include, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, 
iso-butyl, tert-butyl, pentyl, iso-pentyl and the like. "Haloalkyl" means 
an alkyl group as just defined, substituted by one or more halogen atoms 
(fluorine, chlorine, bromine or iodine, fluorine and chlorine being 
preferred). "Cycloalkyl" means a univalent radical derived by the removal 
of a single hydrogen atom from a saturated hydrocarbon containing at least 
one carbocyclic ring. Examples include, cyclobutyl, cyclopentyl, 
cycolhexyl, methylcyclopentyl, ethylcyclohexyl, norbornanyl, and the like. 
The term "alkoxy" means an alkyl group, as previously defined, attached to 
the parent molecular moiety through an oxygen atom. Likewise, "alkylthio 
denotes an alkyl group attached through a sulfur atom to the parent 
molecular moiety. 
The terms "(carbocyclic aryl)alkylene" and "(heterocyclic aryl)alkylene" 
denote a carbocyclic opr heterocyclic aryl group as defined above, 
attached to the parent molecular moiety through a divalent straight or 
branched saturated hydrocarbon group to the parent molecular moiety. 
Examples include 1- and naphth-1-ylmethyl, naphth-2-ylmethyl, 
2-phenylethyl, 3-pyridylpropyl, benzo[b]thienylmethyl and the like. 
The term "alkanoyl" denotes a hydrogen atom (in the case of formyl) or an 
alkyl group, as defined above, attached to the parent molecular moiety 
through a carbonyl group. Examples include formyl, acetyl, propionyl, 
butyryl, and the like. "Alkoxycarbonyl" denotes and ester group, as that 
term is commonly understood, attached through its carbonyl group, to the 
parent molecular moiety. Examples include --COOC.sub.2 H.sub.5, 
--COO(phenyl) and the like. 
The term "aminocarbonyl" denotes the group H.sub.2 NC(O)--. 
"Alkylaminocarbonyl" means the group (alkyl)NHC(O)-- where alkyl is as 
previously defined. Similarly, "dialkylaminocarbonyl" denotes 
(alkyl).sub.2 NC(O)-- where the alkyl groups may be the same or different. 
"(N-Alkyl-N-alkanoyl)amino" denotes the group 
##STR6## 
where the alkyl groups may be the same or different and are as defined 
above. 
The term "(N-alkyl-N-alkoxycarbonyl)amino" denotes the group 
##STR7## 
where the alkyl groups may be the same or different and are as defined 
above. 
The term "(N-alkyl-N-aminocarbonyl)amino" means an alkyl-substituted urea 
group of the formula 
##STR8## 
where alkyl is as defined above. 
Similarly, the term "(N-alkyl-N'alkylaminocarbonyl)-amino" denotes a group 
having the structure 
##STR9## 
where the alkyl groups may be the same or different and are as defined 
above. 
The term "(N-alkyl-N',N'-dialkylaminocarbonyl)amino denotes a group of the 
structure 
##STR10## 
where the alkyl groups may be the same or different and are as defined 
above. 
"Halogen" means fluoro, chloro, bromo- or iodo, with fluoro- and chloro- 
being preferred. 
In all of the above structures, the "wiggle" bonds attaching the groups Y 
and R.sup.5 to the cyclopropyl ring are meant to indicate that the 
attachment of R.sup.5 may be cis- or trans- to that of the group R.sup.8. 
The compounds of structure A form a class of aryl substituted cyclopropyl 
compounds (when X is absent) or arylalkyl substituted cyclopropyl 
compounds (when X is present) which compounds may have the 
--N(OZ)COR.sup.3 group attached directly to the cyclopropyl ring (when Y 
is absent), or may have the --N(OZ)COR.sup.3 group attached to the 
cycopropyl group through an intervening straight or branched alkylene 
group (when Y is present). 
When R.sup.3 is hydrogen, alkyl or cycloalkyl, the compounds of structure A 
comprise N-hydroxy-N-alkanoylamino compounds including, but are not 
restricted to the following representative examples: 
N-(1-trans-(2-phenylcyclopropyl)methyl)-N-hydroxyacetamide; 
N-(1-trans-(2-(4-methylphenyl)cyclopropyl)methyl)-N-hydroxyacetamide; 
N-(1-trans-(2-(4-methylphenyl)cyclopropyl)ethyl)-N-hydroxyacetamide; 
N-(1-trans-(2-(4-bromophenyl)cyclopropyl)methyl)-N-hydroxyacetamide; 
N-(1-trans-(2-(4-bromophenyl)cyclopropyl)ethyl)-N-hydroxyacetamide; 
N-(1-trans-(2-(4-methoxyphenyl)cyclopropyl)ethyl)-N-hydroxyacetamide; 
N-(1-trans-(2-napthyl)cyclopropyl)ethyl)-N-hydroxyacetamide; 
N-(1-trans-(2-(2-furanyl)cyclopropyl)ethyl)-N-hydroxyacetamide; 
N-(1-trans-(2-(benzo[b]thien-2-yl)cyclopropyl)ethyl)-N-hydroxyacetamide; 
N-(1-trans-(2-(2-thienyl)cyclopropyl)methyl)-N-hydroxyacetamide; 
N-(1-trans-(2-(2-furyl)cyclopropyl)methyl)-N-hydroxyacetamide; and 
N-(1-trans-(2-(2-thienyl)cyclopropyl)ethyl)-N-hydroxyacetamide. 
Compounds of formula A above when R.sup.3 is amino, alkylamino, or 
dialkylamino, comprise N-hydroxy urea compounds which are exemplified, but 
not limited to the following: 
A. Compounds in which R.sup.1 is unsubstituted or substituted carbocyclic 
aryl or carbocyclic aryloxy as exemplied by: 
N-(1-cis-(2-phenylcyclopropyl)methyl-N-hydroxyurea; 
N-(trans-(2-phenylcyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(4-methylphenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(4-isopropylphenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(4-(2-methyl-1-propyl)phenyl)cyclopropyl)-methyl)-N-hydroxyur 
ea; 
N-(1-trans-(2-(4-biphenylyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(2-trifluoromethylphenyl)cyclopropyl)-methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3-trifluoromethylphenyl)cyclopropyl)-methyl)-N-hydroxyurea; 
N-(1-trans-(2-(4-trifluoromethylphenyl)cyclopropyl)-methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3,5-bis(trifluoromethyl)phenyl)cyclopropyl)-methyl)-N-hydrox 
yurea; 
N-(1-trans(2-(4-fluorophenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(2,4-difluorophenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3,4-difluorophenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(2-bromophenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3-bromophenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(4-bromophenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(4-chlorophenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3,4-dichlorophenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3,5-dichlorophenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3-chloro-4-fluorophenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(4-methoxyphenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(4-methylthiophenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(4-(dimethylamino)phenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3,4-dimethoxyphenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3,5-dimethoxyphenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3,4,5-trimethoxyphenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3,4-diethoxyphenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3-ethoxy-4-methoxyphenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(3-benzyloxy-4-methoxyphenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(4-benzyloxy-3-methoxyphenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(3,4-dibenzyloxyphenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3,4-methylenedioxyphenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3,4-ethylenedioxyphenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(4-methoxy-3-methylphenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3-methoxy-4-methylphenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(2,3-dimethyl-4-methoxyphenyl)cyclopropyl)-methyl)-N-hydroxyu 
rea; 
N-(1-trans-(2-(2-bromo-4,5-dimethoxyphenyl)cyclopropyl)-methyl)-N-hydroxyur 
ea; 
N-(1-trans-(2-(3-bromo-4,5-dimethoxyphenyl)cyclopropyl)-methyl)-N-hydroxyur 
ea; 
N-(1-trans-(2-(3-fluoro-4-methoxyphenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3-bromo-4-methoxyphenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(4-ethoxyphenyl)cyclopropyl)methyl-N-hydroxyurea; 
N-(1-trans-(3-isopropoxyphenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(4-isopropoxyphenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3-bromo-4-isopropoxyphenyl)cyclopropyl)-methyl)-N-hydroxyure 
a; 
N-(1-trans-(2-(4-allyloxyphenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(4-butoxyphenyl)cyclopropyl)methyl-N-hydroxyurea; 
N-(1-trans-(2-(4-(2-methylpropoxy)phenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(2-phenylethyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(2-phenoxyphenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3-phenoxyphenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(4-phenoxyphenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3-(4-methylphenoxy)phenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3-methyl-4-phenoxy)phenylcyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(4-methyl-3-phenoxyphenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-3-(4-tert-butylphenoxy)phenyl)cyclopropyl)-methyl)hydroxyurea 
; 
N-(1-trans-(2-(3-(4-fluorophenoxy)phenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3-(3-trifluoromethylphenoxy)phenyl)-cyclopropyl)methyl-N-hyd 
roxyurea; 
N-(1-trans-(2-(3-(4-chlorophenoxy)phenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3-(3,4-dichlorophenoxy)phenyl)cyclopropyl)-methyl)-N-hydroxy 
urea; 
N-(1-trans-(2-(3-(3,5-dichlorophenoxy)phenyl)cyclopropyl)-methyl)-N-hydroxy 
urea; 
N-(1-trans-(2-(4-methoxy-3-phenoxyphenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3-(4-methoxyphenoxy)phenyl)cyclopropyl)-methyl)-N-hydroxyure 
a; 
N-(1-trans-(2-(3-(4-benzyloxyphenoxy)phenyl)cyclopropyl)-methyl)-N-hydroxyu 
rea; 
N-(1-trans-(2-(4-(phenylmethoxy)phenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(4-(1-(4-(methoxyphenyl)ethoxy)phenyl)-cyclopropyl)methyl)-N- 
hydroxyurea; 
N-(1-trans-(2-(4-(1-phenylethoxy)phenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(6-methoxy-2-naphthyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(3,3-difluoro-2-phenylcyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-((3,3-dimethyl)-2-(3-phenoxyphenyl)cyclopropyl)-methyl)-N-hydrox 
yurea; 
N-(1-cis-(2-phenylcyclopropyl)ethyl)-N-hydroxyurea; 
N-(1-trans-(2-phenylcyclopropyl)ethyl)-N-hydroxyurea; 
N-(2-trans-(2-phenylcyclopropyl)ethyl)-N-hydroxyurea; 
N-(1-trans-(2-(4-methylphenyl)cyclopropyl)ethyl)-N-hydroxyurea; 
N-(1-trans-(2-(4-(2-methyl-1-propyl)phenyl)cyclopropyl)-ethyl)-N-hydroxyure 
a; 
N-(1-trans-(2-(4-bromophenyl)cyclopropyl)ethyl)-N-hydroxyurea; 
N-(1-trans-(2-(4-methoxyphenyl)cyclopropyl)ethyl)-N-hydroxyurea; 
N-(1-trans-(2-(3-phenoxyphenyl)cyclopropyl)ethyl)-N-hydroxyurea; 
N-(1-(2-trans-(4-phenoxyphenyl)cyclopropyl)ethyl)-N-hydroxyurea; 
N-(1-trans-(2-(4-phenylmethoxy)phenyl)cyclopropyl)ethyl)-N-hydroxyurea; 
N-(1-trans-(2-(4-(1-phenylethoxy)phenyl)cyclopropyl)ethyl)-N-hydroxyurea; 
N-(1-trans-((3,3-dimethyl-2-phenylcyclopropyl)ethyl)-N-hydroxyurea; 
N-(1-trans-(2-(2-phenethyl)cyclopropyl)ethyl)-N-hydroxyurea; 
N-(1-trans-((2-napthyl)cyclopropyl)ethyl)-N-hydroxyurea; 
N-(1-trans-(2-(6-methoxy-2-naphthyl)cyclopropyl)ethyl)-N-hydroxyurea; 
N-(1-trans-(1-methyl-2-phenylcyclopropyl)ethyl-N-hydroxyurea; 
N-(1-trans-((3,3-dimethyl)-2-(4-(1-phenylethoxy)phenyl)-cyclopropyl)ethyl)- 
N-hydroxyurea; 
N-(1-trans-(2-(3-(4-hydroxyphenoxy)phenyl)cyclopropyl)methyl)-N-hydroxyurea 
; 
N-(1-trans-(2-(3-(4-(2-hydroxyethoxy)phenoxy)phenyl)cyclopropyl)methyl)-N-h 
ydroxyurea; 
N-(2-trans-(2-(3-(4-methylphenoxy)phenyl)cyclopropyl)propyl)-N-hydroxyurea; 
N-(1-trans-(2-(3-(4-ethoxyphenoxy)phenyl)cyclopropyl)methyl-N-hydroxy-N'-cy 
clopropylurea; 
N-(1-trans-(2-(3-(4-ethoxyphenoxy)phenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3-(4-propylphenoxy)phenyl)cyclopropyl)methyl)-N-hydroxyurea. 
N-(1-trans-(2-(3-(2-methylphenoxy)phenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3-(3-methylphenoxy)phenyl)cyclopropyl)methyl)-N-hydroxy-N'-m 
ethylurea; 
N-(1-trans-(2-(3-(3-methylphenoxy)phenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3-(4-ethylphenoxy)phenyl)cyclopropyl)methyl)-N-hydroxy-N'-me 
thylhydroxyurea; 
N-(1-trans-(2-(3-(4-ethylphenoxy)phenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3-(4-fluorophenoxy)phenyl)cyclopropyl)methyl)-N-hydroxy-N'-m 
ethylurea; 
N-(1-trans-(2-(3-(4-methylphenoxy)phenyl)cyclopropyl)methyl)-N-hydroxy-N'-m 
ethylurea; and 
N-(1-trans-(2-(3-(4-methylphenoxy)phenyl)cyclopropyl)ethyl)-N-hydroxyurea. 
B. Compounds in which R.sup.1 is carbocyclic aryl which is substituted by a 
substitued or unsubstituted heterocyclic aryl group, exemplified by: 
N-(1-trans-(2-(3-(2-pyridyloxy)phenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3-(4-pyridyloxy)phenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(4-(1-(4-pyridyl)ethoxy)phenyl)cyclopropyl)-methyl)-N-hydroxy 
urea; 
N-(1-trans-(2-(4-(1-(2-thienyl)ethoxy)phenyl)cyclopropyl)-methyl-N-hydroxyu 
rea; 
N-(1-trans-(2-(3-(2-thienyloxy)phenyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3-(3-pyridyloxy)phenyl)cyclopropyl)methyl)-N-hydroxyurea. 
N-(1-trans-(2-(3-(2-pyridyloxy)phenyl)cyclopropyl)methyl)-N-hydroxy-N'-meth 
ylurea; 
N-(1-trans-(2-(3-(2-pyridyloxy)phenyl)cyclopropyl)ethyl)-N-hydroxyurea. 
N-(1-trans-(2-(3-(2-thienyloxy)phenyl)cyclopropyl)methyl)-N-hydroxyurea; 
C. Compounds in which R.sup.1 is unsubstituted or substituted heterocyclic 
aryl or heterocyclic aryloxy, exemplified by: 
N-(1-trans-(2-(2-pyridyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3-pyridyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(4-pyridyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(6-methyl-2-pyridyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-(trans-(2-(5-butyl-2-pyridyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(5-bromo-3-pyridyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(2,6-dichloro-4-pyridyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(N'-methyl-2-pyrrolyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(N'-methyl-5-phenyl-2-pyrrolyl)cyclopropyl)-methyl)-N-hydroxy 
urea; 
N-(1-trans-(2-N'-methyl-2-indolyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(4-quinolinyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3-furanyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(5-ethyl-2-furanyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(5-ethoxymethyl-2-furanyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(5-(2-phenylethenyl)-2-furanyl)cyclopropyl)-methyl)-N-hydroxy 
urea; 
N-(1-trans-(2-(5-benzyloxymethyl-2-furanyl)cyclopropyl)-methyl)-N-hydroxyur 
ea; 
N-(1-trans-(2-(5-phenyl-2-furanyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(5-(2,4-difluorophenyl)phenyl-2-furanyl)-cyclopropyl)methyl)- 
N-hydroxyurea; 
N-(1-trans-(2-(5-bromo-2-furanyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-benzofuranyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3-benzofuranyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(benzo[b]thien-2-yl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(2-furanyl)cyclopropyl)ethyl)-N-hydroxyurea; 
N-(1-trans-(2-(5-methylfuran-2-yl)cyclopropyl)ethyl)-N-hydroxyurea; 
N-(1-trans-(2-(5-(3-pyridyl-2-furanyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(5-(3-pyridyl-2-thienyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(benzo[b]thien-2-yl)cyclopropyl)ethyl)-N-hydroxyurea; 
N-(1-trans-(2-(2-thienyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3-thienyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3-methyl-2-thienyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(5-methyl-2-thienyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(4-bromo-2-thienyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(5-bromo-2-thienyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(5-chloro-2-thienyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(5-ethoxymethyl-2-thienyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(5-phenyl-2-thienyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-benzo[b]thien-3-yl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(4-(benzo[b]thien-3-yl)oxy)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(5-(5-methyl-2-thienyl)-2-thienyl)cyclopropyl)-methyl-N-hydro 
xyurea; 
N-(1-trans-(2-(2-thiazolyl)cyclopropyl)methyl-N-hydroxyurea; 
N-(1-trans-(2-(2-benzothiazolyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(2-thienyl)cyclopropyl)methyl)-N-hydroxyacetamide; 
N-(1-trans-(2-(2-furanyl)cyclopropyl)methyl)-N-hydroxyacetamide; 
N-(1-trans-(2-(2-thienyl)cyclopropyl)ethyl)-N-hydroxyacetamide; 
N-(1-trans-(2-(3-(6-methyl-2-pyridyloxy)phenyl)phenyl) 
cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(3-(3-quinonyloxy)phenyl)cyclopropyl) methyl)-N-hydroxyurea. 
N-(1-trans-(2-(3-(2-thiazolyloxy)phenyl)cyclopropyl) methyl)-N-hydroxyurea; 
N-(1-trans-(2-(5-methyl-2-thienyl)cyclopropyl)ethyl)-N-hydroxy-N'-methylure 
a; 
N-(1-trans-(2-(5-methyl-2-thienyl)cyclopropyl)ethyl)-N-hydroxyurea. 
N-(1-trans-(2-(2-furanyl)cyclopropyl)ethyl)-N-hydroxy-N'-methylurea; 
N-(1-trans-(2-(5-methyl-2-furanyl)cyclopropyl)ethyl)-N-hydroxy-N'-methylure 
a; 
N-(1-trans-(2-(3-furanyl)cyclopropyl)methyl)-N-hydroxy-N'-methylurea. 
N-(1-trans-(2-(3-thienyl)cyclopropyl)ethyl)-N-hydroxy-N'-methylurea; 
N-(1-trans-(2-(3-thienyl)cyclopropyl)methyl)-N-hydroxy-N'-methylure; 
N-(1-trans-(2-(3-thienyl)cyclopropyl)methyl)-N-hydroxyurea 
N-(1-trans-(2-(3-thienyl)cyclopropyl)ethyl)-N-hydroxyurea; 
N-(1-trans-(2-(3-furanyl)cyclopropyl)ethyl)-N-hydroxy-N'-methylurea; 
N-(1-trans-(2-(3-furanyl)cyclopropyl)ethyl)-N-hydroxyurea; 
N-(1-trans-(2-(3-furanyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(2-thienyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(2-thienyl)cyclopropyl)ethyl)-N-hydroxyurea; 
N-(1-trans-(2-(2-furanyl)cyclopropyl)methyl)-N-hydroxyurea; 
N-(1-trans-(2-(2-(4-chlorophenoxy)-5-thiazolyl)cyclopropyl) 
methyl)-N-hydroxyurea; and 
N-(1-trans-(2-(2-(5-(4-fluorophenoxy)furanyl)cyclopropyl) 
methyl)-N-hydroxyurea. 
The compounds of structure B comprise aryl cyclopropyl compounds (when X is 
absent) or arylalkyl cyclopropyl compounds (when X is present). The 
compounds may have the --C(O)N(OZ)-- group attached directly to the 
cyclopropyl ring (when Y is absent), or may have the --C(O)N(OZ)-- group 
attached to the cyclopropyl group through an intervening straight or 
branched alkylene group (when Y is present). 
R.sup.4 is hydrogen, alkyl or cycloalkyl, hence the compounds of structure 
B comprise N-hydroxy carboxamide compounds including, but not restricted 
to the following representative examples: 
N-methyl-N-hydroxy-trans-2-phenylcyclopropyl carboxamide; and 
N-methyl-N-hydroxy-trans-2-(3-phenoxyphenyl)cyclopropyl) carboxamide. 
SYNTHESIS OF THE COMPOUNDS OF THE PRESENT INVENTION 
Compounds of this invention are prepared by the following processes. In 
certain cases where the starting aldehyde contains functional groups which 
might interfere with the desired transformation outlined in the following 
methods, it is recognized that common methods of protection of these 
groups followed by deprotection at a later stage in the preparation of the 
desired product can be applied. A general reference source for methods of 
protection and deprotection is T. W. Greene, "Protective Groups in Organic 
Synthesis", Wiley-Interscience, New York, 1981. 
Control of the stereochemistry of the group R.sup.1-- (where X is absent) 
or R.sup.1 --X-- relative to the group --R.sup.2 (when Y is absent) or 
--YR.sup.2 is achieved by the choice of starting olefinic compound 
employed in producing the cyclopropyl ring in compounds of this invention. 
If the two groups in question are attached to the carbon-carbon double 
bond in the starting material in a trans-configuration, the groups will be 
trans in the resulting cyclopropyl product compound. Similarly, employing 
a starting olefin in which the groups R.sup.1 -- (or R.sup.1 --X--) and 
--R.sup.2 or (--YR.sup.2) are in a cis-configuration about the 
carbon-carbon double bond will result in a cyclopropyl product compound in 
which the groups are in a cis-configuration with regard to the ring. While 
compounds of the present invention in which the groups R.sup.1 -- (or 
R.sup.1 --X--) and --R.sup.2 (or --YR.sup.2) are trans to one another on 
the cyclopropyl ring are preferred, the present invention contemplates 
both the cis- and trans-isomeric forms. 
Moreover, when the substituent groups R.sup.6 and R.sup.7 are different, 
there are three chiral centers in the molecules of the compounds of this 
invention, one at each carbon atom of the cyclopropyl ring, leading to the 
possible existence of eight stereoisomeric forms of the compounds. In 
addition, chiral centers present in the alkylene groups --X-- and --Y-- or 
in the various substituent groups present the possibility of additional 
stereoisomeric forms of the compounds of this invention. The present 
invention contemplates all stereoisomeric forms of the compounds 
encompassed within the generic structural formula given above. 
Particular enantiomeric forms of the compounds of this invention can be 
separated from mixtures of the enantiomers by first reacting the compounds 
with a cleavable resolving group which is itself a pure enantiomer to form 
diastereomers which are then separated by techniques well known in the art 
such as chromatography. The cleavable resolving group is then removed by 
known chemical techniques to yield the desired enantiomer in pure form. 
Compounds of the present invention which are in admixture with 
diastereomers are isolated in pure form by physical separation techniques 
such as chromatography. 
In some particular instances, the chemical processes for preparing the 
present compounds may, when a new chiral center is created as a result of 
the reation, lead to the predominance of one enantiomeric form over the 
other. 
The synthetic processess useful for the syntheses of the compounds of this 
invention are generally outlined by the sequence of reactions illustrated 
in Reaction Scheme 1. In Alternative Method A an aldehyde I is converted 
to the a,b-unsaturated acid II (R=OH). This intermediate is then converted 
into an N-methoxy-N-methylamide intermediate III (R=N(OCH.sub.3)CH.sub.3) 
which is subsequently cyclopropanated to provide intermediate V. 
Alternatively the amide III can be converted into a ketone IV (R=alkyl) 
which can be cyclopropanated to provide intermediate VI(R=alkyl). Both V 
and VI can then be converted by a sequence of known procedures to provide 
the novel compounds VII of this invention with inhibitory activity as 
lipoxygenase inhibitors. 
Method B outlines the conversion of the N-methoxy-N-methylamide 
intermediate V (R=N(OCH.sub.3)CH.sub.3) into the corresponding carboxylic 
acid VIII which is then converted to the novel compounds IX of this 
invention with inhibitory activity as lipoxygenase inhibitors. 
##STR11## 
One example of this process is described in Reaction Scheme 2 and involves 
conversion of the aldehyde I into the corresponding a,b-unsaturated 
carboxylic acid II by condensation with malonic acid followed by in situ 
decarboxylation. The carboxylic acid II is then transformed into an 
a,b-unsaturated ketone using methodology described by Weinreb et. al. 
Tetrahedron Letters, 1981, 22(39), 3815. The carboxylic acid II is 
converted to its N-methoxy-N-methylamide III, via its acid chloride, then 
reacted with an organometallic to provide the desired a,b-unsaturated 
ketone IV. The cyclopropyl moiety is then formed using chemistry developed 
by Corey et. al, J. Amer. Chem. Soc., 1965, 87(6), 1353 and Angew. Chem., 
1973, 85, 867 or Johnson et al. J. Amer. Chem. Soc., 1973, 4287. The 
unsaturated ketone IV is treated either with the sodium salt of a 
sulfoxonium salt of the lithiate of a sulfoximine to afford the 
a,b-cyclopropyl ketone V. The ketone V can be readily converted to the 
desired compounds of Formula 1 by known methods. For example, reaction of 
the ketone V with hydroxylamine followed by reduction with 
BH.sub.3.pyridine affords the hydroxylamine VI which can be treated with 
an isocyanate to provide the desire N-hydroxyurea compounds of Formula 2. 
##STR12## 
A more preferred and novel approach to these systems involves subjecting 
the N-methoxy-N-methylamide III, directly to the cyclopropanation 
conditions to afford the cyclopropyl amide X as outlined in Reaction 
Scheme 3. This N-methoxy-N-methylamide intermediate can then be diverted 
into two different pathways to compounds of Formula 2 where R.sub.5 =H. or 
a substituent R. For the case where R.sub.5 is a substituent, the amide X 
is treated with a Grignard reagent, RMgBr, to afford the ketone V, which 
is then carried on to the N-hydroxy urea as described in Reaction Scheme 
2. For cases where R=H, the amide X is treated with diisobutylaluminum 
hydride to afford the aldehyde XI, which is then carried on to the 
N-hydroxy urea in the usual manner. 
##STR13## 
The N-hydroxylamine VI can also be readily converted to compounds of 
Formula 3 by known methods as outlined in Reaction Scheme 4. The 
hydroxylamine is bis-acylated by treatment with an acid chloride and base 
or by treatment with a suitably activated acyl equivalent. This 
intermediate XII is then selectively hydrolyzed to provide the N-hydroxy 
amides of Formula 3. 
##STR14## 
Hydroxamic acids of Formula 4 are prepared as outlined in Reaction Scheme 
5, from the cyclopropyl carboxyaldehyde XI by oxidation with silver oxide 
to the corresponding acid XIII. The acid is converted to the corresponding 
acyl chloride and treated with a hydroxylamine to provide hydroxamic acids 
of Formula 4. 
##STR15## 
All of the chemistry taught above may be performed on compounds possessing 
an alkyl link between the aryl carrier and the cyclopropyl moiety. To 
obtain the a,b-unsaturated acid II which is the common starting point for 
these compounds, the aldehyde I is elaborated by the Wittig reaction with 
a stabilized ylide, followed by hydrolysis of the resulting ester to 
afford the prerequisite acid II. (Reaction Scheme 6) which can be further 
converted to compounds of Formula I as described previously. 
##STR16## 
To obtain compounds where there is an alkyl link between the N-hydroxyurea 
functionality and the cyclopropyl moiety, homologation is performed on the 
aldehyde of type XIV (Reaction Scheme 7). For example, the aldehyde XIV is 
treated under Wittig reaction conditions with the ylide, 
methoxymethylenetriphenylphosphorane to afford the intermediate enol ether 
which is hydrolyzed under acidic conditions to afford the one carbon 
homologated aldehyde XV. This aldehyde can be further converted to 
compound of Formula I as described previously. 
##STR17## 
LIPOXYGENASE INHIBITORY ACTIVITY OF THE COMPOUNDS OF THIS INVENTION 
Compounds of the present invention are active inhibitors of 5-lipoxygenase 
and/or 12-lipoxygenase as demonstrated by the following data for 
representative compounds. 
Assays to determine 5-lipoxygenase inhibitory activity were performed in 
200 mL incubations containing the 20,000.times.g supernatant from 1.5 
million homogenized RBL-1 cells and various concentrations of the test 
compound. Reactions were initiated by addition of radiolabeled arachidonic 
acid and terminated by acidification and ether extraction. Reaction 
products were separated from nonconverted substrate by thin layer 
chromatography and measured by liquid scintillation spectroscopy. All 
incubations were performed in triplicate. Inhibition of 5-lipoxygenase 
activity was calculated as the ratio of the amount of product formed in 
the presence and absence of inhibitor. IC50 values (concentration of 
compound producing 50% enzyme inhibition) were calculated by linear 
regression analysis of percentage inhibition versus log inhibitor 
concentration plots. (Dyer, R .D.; Haviv, F.; Hanel, A. M.; Bornemier, D. 
A.; Carter, G. W. Fed. Proc., Fed. Am. Soc. Exp. Biol. 1984, 43, 1462A). 
Results for compounds of the foregoing examples are indicated in Table 1. 
TABLE 1 
______________________________________ 
In Vitro Inhibitory Potencies of Compounds of this 
Invention Against 5-Lipoxygenase 
Example IC50 (10.sup.- 6 M) 
______________________________________ 
1a 0.3 
1b 0.2 
2 0.1 
3 1.6 
4 1.8 
7 0.4 
8 0.2 
9 1.8 
10 0.1 
11 0.1 
14 0.13 
16 2.8 
17 0.07 
18 0.2 
20 0.08 
21 0.05 
22 0.9 
23 0.1 
24 0.1 
25 0.1 
26 1.1 
27 1.7 
28 0.1 
29 0.9 
30 0.1 
31 1.4 
32 0.1 
34 0.3 
36 0.06 
37 0.1 
38 0.03 
40 0.2 
42 1.6 
43 5.7 
44 0.1 
45 0.3 
46 0.3 
47 0.3 
48 0.4 
49 0.4 
50 0.1 
51 0.06 
53 0.1 
54 0.3 
56 0.2 
57 0.3 
59 0.7 
60 1.5 
61 0.2 
62 7.6 
63 0.3 
64 1.0 
65 3.6 
66 0.44 
67 0.4 
______________________________________ 
INHIBITION OF LEUKOTRIENE BIOSYNTHESIS 
Inhibition of the biosynthesis of leukotrienes in vivo after oral 
administration of representative test compounds of this invention was 
determined using a rat peritoneal anaphylaxis model in a similar manner as 
that described by Young and coworkers (Young, P. R.; Dyer, R. D.; Carter, 
G. W. Fed. Proc., Fed. Am. Soc. Exp. Biol. 1985, 44, 1185). In this model 
rats were injected intraperitoneally (ip) with rabbit antibody to bovine 
serum albumin (BSA) and three hours later injected ip with BSA to induce 
an antgen-antibody response. Rats were sacrificed 15 minutes after this 
challenge and the peritoneal fluids were collected and analyzed for 
leukotriene levels. Test compounds were administered by gavage one hour 
prior to the antigen challenge. Percent inhibition values were determined 
by comparing the treatment group to the mean of the control group. The 
results of this assay, for representative compounds of the present 
invention, at an oral dose level of 200 mmol/kg are presented in Table 2, 
and at an oral dose of 100 mmol/kg in Table 3. Examination of these data 
demonstrate that compounds of this invention are orally effective in 
preventing the in vivo biosynthesis of leukotrienes. 
TABLE 2 
______________________________________ 
In vivo Leukotriene Inhibitory Activity 
of Compounds of this Invention 
% Inhibition of 
Leukotrienes 
at 200 .mu.mol/kg 
Example oral dose 
______________________________________ 
1 62 
3 100 
4 97 
5 90 
9 61 
10 97 
11 65 
12 68 
13 76 
16 61 
17 81 
19 64 
22 96 
23 93 
25 52 
26 92 
27 99 
28 73 
29 96 
33 84 
34 100 
35 99 
37 93 
39 82 
40 97 
47 100 
______________________________________ 
TABLE 3 
______________________________________ 
In vivo Leukotriene Inhibitory Activity 
of Compounds of this Invention 
% Inhibition of 
Leukotrienes 
at 100 .mu.mol/kg 
Example oral dose 
______________________________________ 
166 91 
167 94 
168 99 
169 98 
170 94 
174 96 
176 87 
178 60 
179 61 
180 85 
188 97 
189 73 
192 71 
193 93 
194 97 
198 90 
______________________________________ 
INHIBITION OF LEUKOTRIENE BIOSYNTHESIS IN VITRO IN HUMAN WHOLE BLOOD 
Inhibition of leukotriene biosynthesis was evaluated in an assay, involving 
calcium ionophore-induced LTB.sub.4 biosynthesis expressed by human whole 
blood. Heparinized (20 U/mL) human blood (0.3 mL) was preincubated with 
test compound or vehicle for 15 min. at 37.degree. C. Eicosanoid 
biosynthesis was initiated by adding calcium ionophore (A23187) in DMSO to 
a final concentration of 50 .mu.M and terminated after 30 min. by rapid 
cooling of the blood in an ice bath and centrifuging at 3.degree. C. for 
10 min at 2500.times.g. The plasma was mixed with 4 volumes of methanol 
and allowed to stand for at least 30 min. at 3.degree. C. prior to 
centrifuging at 1800.times.g for 10 min. The level of LTB.sub.4 in 
aliquots of the methanol-plasma extract was analyzed by radio-immunoassay 
or enyme-immunoassay techniques. The compounds of this invention inhibit 
LTB.sub.4 biosynthesis in human whole blood as illustrated in Table 4. 
TABLE 4 
______________________________________ 
Inhibition of LTB.sub.4 Biosynthesis in Human Whole Blood. 
Inhibition of 
Leukotriene 
Biosynthesis 
Example IC.sub.50 (.mu.M) 
______________________________________ 
160 0.47 
161 0.17 
162 0.25 
163 0.25 
164 0.61 
165 0.74 
166 0.11 
167 0.04 
168 0.05 
169 0.17 
170 89% at 0.1 .mu.M 
171 40% at 0.39 .mu.M 
172a 0.96 
173 0.23 
174 0.14 
175 0.2 
176 0.17 
177 69% at 0.2 .mu.M 
178 64% at 0.2 .mu.M 
179 61% at 0.2 .mu.M 
180 0.69 
181 0.6 
182 0.69 
183 0.62 
184 0.85 
185 0.24 
186 0.47 
187 0.21 
188 0.32 
189 0.68 
190 0.2 
191 0.83 
192 1.2 
193 0.23 
194 0.37 
195 0.19 
196 0.98 
197 1.6 
198 0.97 
199 0.06 
______________________________________ 
The present invention also provides pharmaceutical compositions which 
comprise one or more of the compounds of formula I above formulated 
together with one or more non-toxic pharmaceutically acceptable carriers. 
The pharmaceutical compositions may be specially formulated for oral 
administration in solid or liquid form, for parenteral injection, for 
rectal or vaginal administration, or for topical, buccal, or nasal 
administration. 
The pharmaceutical compositions of this invention can be administered to 
humans and other animals orally, rectally, parenterally (i.e. 
intravenously, intramuscularly, or subcutaneously), intracisternally, 
intravaginally, intraperitoneally, topically (as by powders, ointments, or 
drops), bucally, or as an oral or nasal spray. 
Pharmaceutical compositions of this invention for parenteral injection 
comprise pharmaceutically acceptable sterile aqueous or nonaqueous 
solutions, dispersions, suspensions or emulsions as well as sterile 
powders for reconstitution into sterile injectable solutions or 
dispersions just prior to use. Examples of suitable aqueous and nonaqueous 
cariers, diluents, solvents or vehicles include water, ethanol, polyols 
(such as glycerol, propylene glycol, polyethylene glycol, and the like), 
and suitable mixtures thereof, vegetable oils (such as olive oil), and 
injectable organic esters such as ethyl oleate. Proper fluidity can be 
maintained, for example, by the use of coating materials such as lecithin, 
by the maintenance of the required particle size in the case of 
dispersions, and by the use of surfactants. 
These compositions may also contain adjuvants such as preservative, wetting 
agents, emulsifying agents, and dispersing agents. Prevention of the 
action of microorganisms may be ensured by the inclusion of various 
antibacterial and antifungal agents, for example, paraben, chlorobutanol, 
phenol sorbic acid, and the like. It may also be desirable to include 
isotonic agents such as sugars, sodium chloride, and the like, Prolonged 
absorption of the injectable pharmaceutical form may be brought about by 
the inclusion of agents which delay abdorption such as aluminum 
monostearate and gelatin. 
If desired, and for more effective distribution, the compounds can be 
incorporated into slow release or targeted delivery systems such as 
polymer matrices, liposomes, and microspheres. 
The injectable formulations can be sterilized, for example, by filtration 
through a bacterial-retaining filter, or by incorporating sterilizing 
agents in the form of sterile solid compositions which can be dissolved or 
dispersed in sterile water or other sterile injectable medium just prior 
to use. 
Solid dosage forms for oral administration include capsules, tablets, 
pills, powders, and granules. In such solid dosage forms, the active 
compound is mixed with at least one inert, pharmaceutically acceptable 
excipient or carrier such as sodium citrate or dicalcium phosphate and/or 
a) fillers or extenders such as starches, lactose, sucrose, glucose, 
mannitol, and silicic acid, b) binders such as, for example, 
carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, 
surcrose, and acacia, c) humectants such as glycerol, d) disintegrating 
agents such as agar-agar, calcium carbonate, potato ortapioca starch, 
alginic acid, certain silicates, and sodium carbonate, e) solution 
retarding agents such as paraffin, f) absorption accelerators such as 
quaternaryammonium compounds, g) wetting agents such as, for example, 
cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and 
bentonite clay, and i) lubricants such as talc, calcium stearate, 
magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and 
mixtures thereof. In the case of capsules, tablets and pills, the dosage 
form may also comprise buffering agents. 
Solid compositions of a similar type may also be employed as fillers in 
soft and hard-filled gelatin capsules using such excipients as lactose or 
milk sugar as well as high molecular weight polyethylene glycols and the 
like. 
The solid dosage forms of tablets, dragees, capsules, pills, and granules 
can be prepared with coatings and shells such as enteric coatings and 
other coatings well known in the pharmaceutical formulating art. They may 
optionally contain opacifying agents and can also be of a composition that 
they release the active ingredient(s) only, or preferentially, in a 
certain part of the intestinal tract, optionally, in a delayed manner. 
Examples of embedding compositions which can be used include polymeric 
substances and waxes. 
The active compounds can also be in micro-encapsulated form, if 
appropriate, with one or more of the above-mentione excipients. 
Liquid dosage forms for oral administration include pharmaceutically 
acceptable emulsions, solutions, suspensions, syrups and elixirs. In 
addition to the active compounds, the liquid dosage forms may contain 
inert diluents commonly used in the art such as, for example, water or 
other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, 
isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl 
benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils 
(in particular, cottonseed, groundnut, corn, germ, olive, castor, and 
sesame oils), glycerol, tetrahydrofurfuranyl alcohol, polyethylene glycols 
and fatty acid esters of sorbitan, and mixtures thereof. 
Besides inert diluents, the oral compositions can also include adjuvants 
such as wetting agents, emulsifying and suspending agents, sweetening, 
flavoring, and perfuming agents. 
Suspensions, in addition to the active compounds, may contain suspending 
agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene 
sorbitol and sorbitan esters, microcrystalline cellulose, aluminum 
metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof. 
Compositions for rectal or vaginal administration are preferably 
suppositories which can be prepared by mixing the compounds of this 
invention with suitable non-irritating excipients or carriers such as 
cocoa butter, polyethylene glycol or a suppository wax which are solid at 
room temperature but liquid at body temperature and therefore melt in the 
rectum or vaginal cavity and release the active compound. 
Dosage forms for topical administration of a compound of this invention 
include powders, sprays, ointments and inhalants. The active compound is 
mixed under sterile conditions with a pharmaceutically acceptable carrier 
and any needed preservatives, buffers, or propellants which may be 
required. Opthalmic formulations, eye ointments, powders and solutions are 
also contemplated as being within the scope of this invention. 
Actual dosage levels of active ingredients in the pharmaceutical 
compositions of this invention may be varied so as to obtain an amount of 
the active compound(s) that is effective to achieve the desired 
therapeutic response for a particular patient, compositions, and mode of 
administration. The selected dosage level will depend upon the activity of 
the particular compound, the route of administration, the severity of the 
condition being treated, and the condition and prior medical history of 
the patient being treated. However, it is within the skill of the art to 
start doses of the compound at levels lower than required for to achieve 
the desired therapeutic effect and to gradually increase the dosage until 
the desired effect is achieved. 
Generally dosage levels of about 0.001 mg to about 100 mg, more preferably 
of about 0.01 mg to about 50 mg of active compound per kilogram of body 
weight per day are administered orally to a mammalian patient. If desired, 
the effective daily dose may be divided into multiple doses for purposes 
of administration, e.g. two to four separate doses per day.