Note: Descriptions are shown in the official language in which they were submitted.
s
131~
--1--
LEUKOTRIENE ANTAGONISTS
BACKGROUND OF THE INVENTION
_
"Slow Reacting Substance of Anaphylaxis" (SRS-A)
has been shown to be a highly potent bronchoconstricting
substance which is released primarily from mast cells and
basophils on antigenic challenge. SRS-A has been propos~d
as a primary mediator in h~an asthma. SRS-A, in addition
to its pronounced effects on lung tissue, also produces
permeability changes in skin and may be involved in acute
cutaneous allergic reactions. Further, SRS-A has been
shown to effect depression of ventricular contraction and
potentiation of the cardiovascular effects of histamine.
The discovery of the naturally occurring
leukotrienes and their relationship to 5RS-A has
reinforced interest i~ SRS-A and other arachidonate
metabolites. SRS-A derived from mouse, rat, guinea pig
and man have all been ~haracterized as mixtures of
leukotriene-C4 (LTC4), leu~otriene-D4 (LTD4) and
leukotriene-E4 (LTE4), the structural formulae of
which are represen~ed below.
~ Glu
o~ I
2~ LTC4 R'' - Cys-Gly
5 11 SR~ LTE4 R" = Cys
- 2 - ~3~65~
1 Leukotrienes are a group of eicosanoids formed
from arachidonio acid metabolism via the lipo~ygenase
pathway. These lipid derivatives originate from LTA4
and are of two types: (1) those containing a
5 sulfidopeptide side chain (LTC~, LTD4, and hTE4),
and (2) those that are nonpeptidic (LTB~). Leukotrienes
comprise a group of naturally occurring substances that
have the potential to contribute significantly to the
pathogenesis of a variety of inflammatory and ischemic
disorders. The pathophysiological role of leukotrienes
has been the focus of recent intensive studies.
As summarized by Lefer, A.M., Biochemical
Pharmacoloqy, 35, 2, 123-127 (1986~ both the peptide and
non-peptide leukotrienes exert microcirculatory actions,
15 promoting leakage of fluid across the capillary
endothelial membrane in most types of vascular beds.
LTB4 has potent chemotactic actions and contributes to
the recruitment and adherence of mobile scavenger cells to
the endothelial membrane. LTC4, LTD~ and LTE4
20 stimulate a variety of types of muscles. LTC4 and
LTD~ are potent bronchoconstrictors and effective
stimulators of vascular smooth muscle. This
vasoconstrictor effect has been shown to occur in
pulmonary, coronary, cerebral, renal, ~nd mesenteric
vasculatures-
Leukotrienes have been implicated in a number of
pulmonary diseases. Leukotrienes are known to be potent
bronchoconstrictors in humans. hTC and LTD have been
shown to be potent and selective peripheral airway
agonists, being more active than histamine. [See Drazen,
J.M. et al., Proc. ~at'l. ~cad. Sci. U~A, 77, 7, 4354-4358
(1980)]. LTC4 and LTD4 have been shown to increase
the release of mucus from human airways in vitro. ~See
Marom, Z. et al., m. Rev. Respir. Dis., 126, 449-451
(1982).] The leukotriene antagonists of the present
3 13:~6~
1 invention can be useful in the treatment of allergic or
non-allergic hronchial asthma or pulmonary anaphylaxis.
The presence of leukotrienes in the sputum of
patients having cystic fibrosis chronic bro~chitis, and
bronchiectasis at levels likely ~o have pathophy~iological
efects has been demonstrated by Zakrzewski et al. [See
Zakrzewski, J. T. et al., Prostaqlandins, 28, 5, 641
(lg~4).] Treatmen~ of these diseases constitutes
additional possible utility for leukotriene antagonists.
Leukotrienes have been identified in the nasal
secretions of allergic subjects who underwent ln vivo
challenge with specific antigen. The release of the
leukotrienes was correlated with typical allergic signs
and symptoms. [See Creticos, P.S. et al., New Enqland J.
of Med., 310, 25/ 1626-1629 (1984).] This suggests that
allergic rhinitis is another area of utility for
leukotriene antagonists.
The role of leukotrienes and the specificity and
selectivity of a particular leukotriene antagonist in an
animal model of the adult respiratory distress syndrome
was investigated by Snapper et al. [See Snapper, J.R. et
al., Abstracts of Int'l Conf. on Prostaqlandins and
Related Comp., Florence, Italy, p. 495 (June 1986).]
Elevated concentrations o LTD4 were shown in pulmonary
edema fluid of patients with adult respiratory distress
syndrome. [See Matthay, M. et al. J. Clin. Immunol., 4,
479-483 (1984).] Markedly elevated leukotriene levels
have been shown in the edema fluid of a patient with
pulmonary edema after cardiopulmonary bypass. [See
Swerdlow, B.N., et al., Anesth. Analq., 65, 306-308,
(1986).] LTC and LTD have also been shown to have a
direct systemic arterial hypotensive effect and produce
~31~
1 vasoconstriction and increased vasopermeability. ~See
Dra~en et al., ibid.] This suggests leukotriene
antagonists can also be useful in the areas of adul~
respiratory distress syndrome, pulmonary edema, and
hypertension.
Leukotrienes have also been directly or
indirectly implicated in a variety of non-pulmonary
diseases in the ocular, dermatologic, cardiovascular,
renal, trauma, inflammatory, carcinogenic and other areas.
Further evidence of leukotrienes as mediators of
allergic reactions is provided by the identification of
leukotrienes in tear fluids from subjects following a
conjunctival provocation test and in skin blister fluids
after allergen challenge in allergic skin diseases and
conjunctival mucosa. [See Bisgaard, H., et al., Allerqy,
40, 417-423 (1985).] Leukotriene immunoreactivity has
also been shown to be present in the aqueous humor of
human patients with and without uveitis. The
concentrations of leukotri~nes were sufficiently high that
these mediators were expected to contribute in a
meaningful way to tissue responses. [See Parker, J.A. et
al., A h Ophthalmol, 104, 722-724 ~1986).3 It has also
besn demonstrated that psoriatic skin has elevated levels
of leukotrienes. [See Ford-Hutchinson, J. AllerqY Clin.
Immunol., 74, 437-440 (1984~.]. Local effects of
intracutaneous injections of synthetic leukotrienes in
human skin were demonstrated by Soter et al. (See Soter et
al., J. Clin Invest Dermatol, 80, llS-ll9 (1983).3
Cutaneous vasodilation with edema formation and a
neutrophil infiltrate were induced. Leukotriene synthesis
inhibitors or leukotriene antagonists can also be useful
in the treatment of ocular or dermatological diseases such
as allergic conjunctivitis, uveitis, allergic dermatitis
or psoriasis.
- 5 - 1 31~
1 ~nother area of utility for leukotriene
antagonists is in the trea-tment of cardiovascular
diseases. Since peptide leukotrienes are potent coronary
vasoconstrictors, they are implicated in a variety of
cardiac disorders including arrhythmias, conduction blocks
and cardlac depression. Synthetic leukotrienes have been
shown to be powerul myocardial depressants, their Qffects
consis~ing of a decrease in contractile force and coronary
flow. The cardiac effects of LTC4 and LTD4 have been
shown to be antagonized by a speciic leukotrien~
antagonist, thus suggesting usefulness of leukotriene
antagonists in the areas of myocardial depression and
cardiac anaphylaxis. [See Burke, J.A., et al., J.
Pharmacolo~y_and ExPerimental Therapeutics, 221, 1,
235-241 (1982).]
LTC4 and LTD4 have been measured in the body
fluids or rats in endotoxic shock, but are rapidly cleared
from the blood into the bile. Thus leukotrienes are
formed in ischemia and shock. Specific inhibitors of
leukotriene biosynthesis reduce the level of leukotrienes
and therefore reduce manifestations of traumatic shock,
endotoxic ~hock, and acute myocardial ischemia.
Leukotriene receptor antagonists have also been shown to
reduce manifestations o endotoxic shock and to reduce
extension of infarct si~e. Administration of peptide
leukotrienes has been shown to produce significant
ischemia or shock. [See Lefer, A.M., Biochemical
Pharmacoloqy, 35, 2, 123-1~7 (1986~.] Thus further areas
of utility for leukotriene antagonists can be the
treatment of myocardial ischemia, acute myocardial
infarction, salvage of ischemic myocardium, angina,
cardiac arrhythmias, shock and atherosclerosis.
- 6 - .~ 3~ll6 ~
Leukotriene antagonists can also be useful in the
area of renal ischemia or renal failure. Badr et al. have
shown that LTC4 produces significant elevation of mean
arterial pressure and reductions in cardiac output and
renal blood flow, and that such effects can be abolished
by a specific leukotriene antagonist. [See Badr, K.F. et
al., Circulation Research, 54, 5, 492-499 (1984).
Leukotrienes have also been shown to have a role in
endotoxin-induced renal failure and the effects of the
leukotrienes selectively antagonized in this model of
renal injury. [See Badr, K.F., et al., KidneY
International, 30, 474-480 ~1986).] LTD4 has been shown
to produce local glomerular constrictor actions which are
prevented by treatment with a leukotriene antagonist.
[See Badr, K.F. et al., KidneY International, 29, 1, 328
(1986). LTC4 has been demonstrated to contract rat
glomerular mesangial cells in culture and thereby effect
intraglomerular actions to reduce fiItration surface
area. [See Dunn, M.J. et al., Kidnev International, 27,
1, 25S ~19B5). Thus another area of utility for
leukotrie~e antagonists can be in the treatment o
glomerulonephritis.
Leukotrienes have also been indicated in the area
of transplant rejsction. An increase in cardiac and renal
allograft survival in the presence of a leukotriene
receptor antagonist was documented by Foegh et al. [See
Foegh, M.L. et al. Advances in Prostaqlandin,
Thromboxane, and Leukotriene Research, 13, 209-~17
~1985).] Rejection of rat renal allografts was shown ~o
produce increased amounts of LTC4. [See Coffman, T.M.
et al., Kidney International, 29, 1, 332 ~1986).
A further area of utility for leukotriene
antagonists can be in treatment of tissue trama, burns, or
fractures. A significant increase in the production of
- 7 - -1 3 1 ~
cysteinyl leukotrienes was shown after mechanical or
thermal trauma sufficient to induce tissue edema and
circulatory and respiratory dysfunction. [See Denzlinger,
C. et al., Science, 230, 330-332 (1985).]
Leukotrienes have also been shown to have a role
in acute in1ammatory actions. LTC~ and LTD4 have
potent effects on vascular caliber and permeability and
LTB4 increases leukocyte adhesion to the endothelium.
The arteriolar constriction, plasma leakage, and leukocyte
adhesion bear close resemblence to the early events in
acute inflammatory reactions. [See Dahlen, S.E. et al.,
Proc. Natl. Acad. Sci. USA, 78, 6, 3a87-3891 (1981).]
Mediation of local homeostasis and inflammation by
leukotrienes and other mast cell-dependent compounds was
also investigated by Lewis et al. [See Lewis, R.A. et
al., Nature, 293, 103-108 (1981). Leukotriene antagonists
can therefore be useful in the treatment of inflammatory
diseases including rheumatoid arthritis and gout.
Cysteinyl leukotrienes have also been shown to
undergo enterohepatic circulation, and thus are indicated
in the area of inflammatory liver disease. [See
Denzlinger, C. et al., Prostaqlandins Leukotrienes and
MedicinQ, 21, 321-32~ ~1986).] Leukotrienes can also be
important mediators of inflammation in inflammatory bowel
disease. [See Peskar, B.M. et al., Aqents and Actions,
lB, 381-383 (1986).] Leukotriene antagonists thus can be
useful in the treatment of i~flammatory liver and bowel
disease.
Leukotrienes have been shown to modulate IL-l
production by human monocytes. [See Rola-Pleszczynski, M.
et al., J. of Immun., 135, 6, 3958-3961 (1985). This
suggests that leukotriene antagonists may play a role in
IL-l mediated functions of monocytes in inflammation and
immune reactions.
~31~6~
LTA4 has been shown to be a factor in inducing
carcinogenic tumors and is considered a link between acute
immunologic defense reactions and carcinogenesis.
Leukotriene antagonists can therefore possibly have
utility in treatment of some types of carcinogenic
tumors. [See Wischnewsky, G.G. et al. Anticancer Res. 5,
6, 639 (1985).]
Leukotrienes have been implicated in gastric
cytodestruction and gastric ulcers. Damage of gastro
intestinal mucosa because of potent vasoconstric-tion and
stasis of blood flow is correlated with increased levels
of LTC4. Functional antagonism of leukotriene effects
may represent an alternative in treatment of mucosal
injury. [See Dreyling, K.W. et al., British J.
Pharmacoloqy, 88, 236P ~1986), and Peskar, B.M. et al.
Prostaqlandins, 31, 2, 283-293 (1986).] A leukotriene
antagonist has b~en shown to protect against
stress-induced gastric ulcers in rats. [See Ogle, C.W. et
al., IRCS Med. Sci., 14, 114-115 (1986).]
Other areas in which leukotriene antagonists can
have utility because leukotrienes are indicated as
mediators include prevention of premature labor [See
Clayton, J.K. et al., Proceedings of the BPS, 573P, 17-19
Dec. 1984]; treatment of migraine headaches [See
Gazzaniga, P.P. et al., Abstracts Int'l Conf. on
Prosta~landins and Related Comp., 121, Florence, Italy
(June 1986)]; and treatment of gallstones [See Doty, J.E.
et al., Amer. J. of Surqery, 145, 54-61 (1983) and Marom,
3 Z. et al., Amer. Rev. Respir. Dis., 126, 449-451 (19B2).
o
By antagonizing the effects of LTC4, LTD4 and
LTE4 or other pharmacologically active mediators at the
end organ, for example airway smooth muscle, the compounds
and pharmaceutical compositions of the instant invertion
are valuable in the treatment of diseases in subjects,
including human or animals, in which leukotrienes are a
key f actor.
9 :~3~5~
DETAILEV DESCRIPTION OF THE INVENTION
The compounds o this invention are represen~ed
by the following general stru~tural ormula (I~
(O)~ ~R
~2 ~ (I)
Rl
wherein
q is 1 or 2;
1 C8 to C13 alkyl, C7 to C12
alkoxy, C10 to C12 l-alkynyl, 10-undecynyloxy,
ll-dodec-~nyl, phenyl-C4 to C10 alkyl, phenyl-C3 to
Cg alkoxy with the phenyl optionally mono substituted
with bromo, chloro, trifluoromethyl, ~1 to C4 alkoxy,
methylthio or trifluoromethylthio, furyl-C4 to C10
alkyl, trifluoromethyl-C7 to C12 alkyl or
cyclohexyl-C4 to C10 alkyl;
R2 is hydrogen, bromo, chloro, methyl,
trifluoromethyl, hydroxy, Cl to C4 alkoxy or nitro; or
Rl is hydrogen and R~ is C8 to C13 alkyl, C7 to
12 xy, C10 to C12 l-alkynyl, 10-undecynylo
ll-dodecynyl, phenyl-C4 to C10 alkyl, phenyl-C3 to
Cg alkoxy with the phenyl optionally mono substituted
with bromo, chloro, trifluoromethyl, Cl to C4 alkoxy,
methylthio or trifluoromethylthio, furyl-C4 to ClO
alkyl, trifluoromethyl-C7 to C12 alkyl or
cyclohexyl-C4 to C10 alkyl:
- lO - 13~
3 1 2)mCR3' or (C~2~0-1-c-tetraZolyl;
R4
R3 is hydroxy, amino, or Cl to C~ alkoxy;
R4 is hydrogen, methyl, Cl to C4 alkoxy, fluoro or
hydroxy;
m is O, 1, and 2;
R is (CH2)~CHCOR6, CH(CO~H)CH2CO2H, CH2CH2Z or
R8 ~ Rg
N ~ N
R7
n is 0 to 6;
R5 is hydrogen, amino, or NHCOCH2CH2CH(NH2)C02H;
R6 is hydroxy, amino, NHCH2C02H, or Cl to
C6 alkoxY;
Z is SO3H, SO2NH2 or CN;
R7 is hydrogen, Cl to C4 alkyl or C3 to
C4 alkenyl;
R8 is hydrogen, Cl to C4 alkyl, carboxyl or
carboxamido, or (CH2)pCO2Rl~, wherein p is 1 or 2,
R12 is Cl to C6 alkyl, or hydrogen,
when R7 and Rg are hydrogen or Cl to C~ alkyl; and
Rg is hydrogen, Cl to C4 alkyl or
CH2CO2R13 wherein R13 is Cl to C6 alkyl, o
hydrogen, with the proviso that when n is 0, R5 is
hydrogen and further that R7, R8 and Rg are not all
hydrogen; or a pharmaceutically acceptable salt thereof.
The ester and diester compounds of Formula (I)
are subject to the further proviso that R3 and R6 are
not both hydroxy or R3 is not hydroxy if both R12 and
R13 are hydrogen
A particular class of compounds of this invention
3~l~6~
1 are the substituted alkanoic acid analogs of formula ~I)
represented by the s~ructural formula (II)
R2~( CH2 ) 0-3C02H
~l (II)
wherein q, Rl, R2 and R are described above.
Particular members of this class of compounds are
those represented by the stru~tural formula (II) wherein R
is (CH2)1_3CO2H or
R8 Rg
R7
and R~, R2, R7, R8 and Rg are described above.
A subgeneri~ class of these compounds are the
diacid derivatives represented by the following general
structural formula (III)
~cHzcH
Rl
wherein q~ Rl and R2 are described above, and
particularly where Rl is phenylalkyl.
- 12- ~31~6~
A second subgeneric class o compounds of formula
~II) are the diacid derivatives represented by the
following structural ormula (IV)
~CH2CH2 C02tl
(o~q
R2~ C 2 H ~ I V
R
wherein q, Rl and R2 are described above, and
particularly where R1 is phenylalkyl.
A third subgeneric class of compounds of formula
(II) are the heterocyclic derivatives represented by the
following general structural formula (V)
R7 -~N ~ R8
(O)q ~\ N lRq
R2~ C02H (V)
Rl
q, Rl, R2, R7, R8 and Rg are described
above.
A further particular class of compounds of this
invention are the hydroxy substituted alkanoic acid
analogs of formula (I) represented by the structural
formula (VI~
() S ~CH2cH2c2
R2 ~ CH COH ~CO2~
1 (VI)
- 13 -
1 wherein q, Rl and R2 are described above, and
particularly where Rl is phenylalkyl.
The compounds of the formula (VI) are exemplified
by the following compounds:
(1) ~(S)-hydroxy-3~R)-(2-~arboxyethylsulfinyl)-
3-[2-(8-phenyloctyl~phenyl]propionic acid; and
(2) 2(S)-hydroxy-3(R)-(2-carboxyethylsulfonyl)-3-
[2-(8-phenyloctyl)phenyl]propionic acid.
A further class of compounds of this invention
are the tetxazolyl substituted analogs of formula ~I)
represented by the structural formula (VII)
()qS ~ ~H2CH2co2H
R2--X( CH2 ) O_l-C -tetrazo lyl
1 (VII)
wherein q, Rl and R2 are described above.
Some of the compounds of the formula (I) con~ain
two asymmetric centers, such as when R4 is methyl,
methoxy, fluoro or hydroxy, or R is CH(CO2H)CH2CO2H.
This leads to the possibility of four stereoisomers for
each such compound. In practice, these compounds are
prepared as a mixture of two stereoisomers. Resolution
procedures employing, for example, optically active amines
furnish the separated enantiomers.
The compounds o the present invention, depending
on their structure, are capable of forming salts with
pharmaceutically acceptable acids and bases, according to
procedures well known in the art. Such acceptable acids
include inorganic and organic acids, such as hydrochloric,
:~3~46~
- 14 -
sulfuric, metha~esulfonic, benzenesulfonic, p-toluene-
sulfonic and acetic acid. Such acceptable bases include
organic and inorganic bases, such as ammonia, arginine,
organic amines, alkali metal bases and alkaline ear~h
metal bases. Of particular utility are the dipotassium,
disodium, dimagnesium, diammonium, and dicalcium salts of
the diacid compounds of formula (I).
The compounds of the formula (I) wherein Y is
1 C02H are conveniently prepared from an aldehyde
precursor of the following structural formula (VIII)
~ Rl (VIII)
wherein Rl and R2 are described above. A compound of
formula ~VIII) is treated with trimethylsilyl cyanide in
the presence of zinc iodide at low temperatures in an inert
solvent to form the trimethylsilyl-protected cyanohydrin.
Treatment of this with gaseous hydrogen chloride in
methanol provides the methyl 2-hydroxyacetate derivative
which is converted to the 2-chloroacetate with thionyl
chloride. This valuable intermediate is then reacted with
a substituted thiol selected to give, after removal of
ester protective groups, a sulfide analogue of formula (I~.
The compounds of the formula (I) wherein Y is
CH2C02H are prepared by reacting the appropriate
aldehyde of the formula (VIII) and an esterified
bromoacetate, conveniently t-butyl bromoacetate, with a
mixture of diethyl aluminum chloride, zinc dust and a
catalytic amount of cuprous bromide at low temperatures in
an inert solvent to give the esterified
3-hydroxypropionate derivative which is reacted directly
1 3 ~
- 15 -
l with a substituted thiol in trifluoroacetic acid.
Alternatively, a mixture of trimethyl borate and zinc in
tetrahydrofuran may be used to prepare the 3-hydroxypro-
pionate derivative. By employing an esterified 2-bromo-
propionate in the above reaction with an aldehyde (VIII~,the sulfide compounds wherein Y is CH(CH3~CO~H are
obtained.
To prepare the desired compounds of formula ~I)
wherein q is l or 2, the appropriate thio product is
conveniently oxidized with sodium periodate or
metachloroperbenzoic acid to obtain the sulfoxide or
sulfone product.
The aldehydes of the formula (VIII) are known or
readily prepared utilizing the gen~ral procedures
described as follows.
ThP aldehyde precursors to the compounds of the
formula (I) wherein Rl is, for example, an alkyl radical
containing 8 to 13 carbon atoms are prepared from ~he
appropriate 2-metho~yphenyl 4,4-dimethyloxazoline [s~e
Meyers et al. J. Orq. Chem., 43 1372 (1978)~.
The aldehyde precursors of the`compounds of the
formula (I) wherein Rl is, for example, an alkoxy
radical containing 7 to 12 carbon atoms are prepared by
the O-alkylation of the appropriate 2-hydroxybenzaldehyde
with the corresponding alkylating agent.
The aldehyde precursors to the compounds of the
formula (I) wherein Rl is a l-alkynyl radical containing
10 to 12 carbon atoms are prepared by coupling a 2-halo-
benzaldehyde with the appropriate l-alkyne in the presence
of cuprous iodide and (P03)~PdC12. [See Hagihara, et al.
Synthesis, 627, (1980)]. The catalytic hydrogenation of
these alkynyl containing precursors under standard condi-
tions affords the aldehyde precursors of the compounds
of the formula (I) wherein Rl is an alkyl or phenylalkyl
radical.
- 16 - 1 3~ ~ ~5~
l Alternatively, the compounds of the formula (I)
wherein Y is CH2CO2H are prepared from a propenoate
precursor of the following structural formula ~IX)
R2 ~CO~Rlo
(IX)
~ Rl
wherein Rl and R2 are described above, and Rlo is an
ester protective group, such as t-butyl. A compound of
formula (IX) is reacted with a mixture of alkali metal
alkoxide, such as sodium methoxide, and substituted thiol
to give, after removal of the ester protective group,
sulfide analogs of formula (I). These are oxidized as
previously described to obtain the desired products of
formula (I).
The propenoate precursors of formula (IX) are
prepared from the corresponding aldehydes of formula
~ ~VIII) by general procedures such as reaction with an
alkyl (triphenylphosphoranylidene)acetate or by conversion
of the aldehydP to a 3-hydroxypropionate derivative, as
described above, followed by an elimination reaction to
form the double bond. Additionally, the propionate
precursor is obtained from a 3-methanesulfonyl-
oxypropionate derivative by treatment with triethylamine.
The compounds of the formula (I) wherein Y is
CH(OH)(CH2)mCO2H are prepared from an epoxide
17 - 131L16~4
1 precursor of the following structural formula (X)
~2~ ~ ,(C~2)m C2R11 (X)
wherein Rl, R2 and m are described above, and Rll is
lower alkyl, such as methyl or ethyl. A compound of
formula (X) is reacted in an inert solvent with
triethylamine and a substituted thiol selected to give,
after removal of ester protective groups and oxidation, a
product of formula (I).
The epoxide precursors of formula (X~ where m is
2 are prepared by reaction of the Grignard derivative of a
bromobenzene compound of the formula (XI)
~ ~ r
Rl
with ~crolein to give the corresponding enol derivative
which is treated with a trialkylorthoacetate, followed by
epoxidation using metachloroperbenzoic acid.
The epoxide precursors of formula ~X) where m is
0 are prepared by reaction of an aldehyde of the formula
~VIII) with a lower alkyl chloroacetate and an alkali
metal alkoxide, such as sodium methoxide.
- 18 -
13~5~
l Alternatively, the compounds of the formula (I)
wherein Y is CH(OH)COR3 are prepared from a propenoate
precursor o formula ~IX) wherein Rlo is lower alkyl.
The compounds of the formula ~I) wherein Y is
(CH2~3CO2H are prepared from a tetrahydro-4H-pyran-
2-one precursor of the followiny structural formul~ (XII)
o
R2,~) (Xll)
.
~ Rl
wherein Rl and R2 are described above. A compound of
formula ~XII) is reacted with a mixture of zinc iodide and
a substituted thiol in an inert solvent or with a
substituted thiol in trifluoroacetic acid to give, after
removal of any ester protective group and oxidation, a
product of formula (I).
The tetrahydro-4H-pyran-2-one precursors of
formula (XII) are prepared by reaction of the Grignard
derivative of the bromoben~ene compound o formula (XI)
with chloro titanium tri-isopropoxide followed by reaction
with 5-oxovalerate alkyl ester.
The 2-thioimidazole precursors necessary to
prepare the R-heterocyclic derivatives of formula (I) are
known compounds or are conveniently prepared employing
standard chemical reactions. Preferably these reactants
bearing a carboxyl or carboxymethyl substituent as set
forth in R8 and R3 above are employed as the
corresponding carboalkoxy derivatives wherein the alkoxy
radical contains from one to six carbon atoms. When
present, the alkoxy substitutent is subsequently
.
-lg ~31~
1 hydrolyzed to give the free carbo~yl or carbo~ymethyl
substituted products.
Appropriate modifications of the general process-
es disclosed furnish the various compounds defined
by formula (I).
The leukotriene antagonist activity of the
compounds of this invention is measured by the ability of
the compounds to inhibit the leukotriene induced
contraction of guinea pig tracheal tissues in vitro and to
inhibit leukotriene induced bronchoconstriction in guinea
pigs in vivo. The following methodologies were employed:
In vitro: Guinea pig (adult male albino Hartley strain)
tracheal spiral strips of approximate dimensions 2 to 3 mm
cross-sectional width and 3.5 cm length were bathed in
modified Krebs buffer in jacketed 10 ml tissue bath and
continously aerated with 95% 2/5% CO2. The tissues
were connected v~a silk suture to force displacement
transducers for recording isometric tension. The tissues
were equilibrated for 1 hr., pretreated for 15 minutes
with meclofenamic acid (1 ~M) to remove intrinsic
prostaglandin responses, and then pretreated for an
additional 30 minutes with either the test compound or
vehicle control. A cumulative concentration-response
curve for LTD4 on triplicate tissues was gen~rated by
~5 successive increases in the bath concentration of the
LTD4. In order to minim.ize intertissue variability, the
contractions elicited by LTD4 were standardized as a
percentage of the maximum response obtained to a
reference agonist, carbachol (10 ~M).
Calculations: The averages of the triplicate LTD4
concentration-response curves both in the presence and
absence of the test compound were plotted on log graph
paper. The concentration of LTD4 needed to elicit
30% of the contraction elicited by carbachol was
measured and defined as the EC30. The -log KB
-- ~ O -- ~ a ~; ~
1 value for the test compound was de~ermined by the
following eq~lations:
1 EC30 (presence of test compound) = dose ratio = X
EC30 ~presence of vehicle control)
2. KB = concentration of test compound/(X-l)
In vivo: Anesthetized, spontaneously breathing guinea
pigs (Adult male albino Hartley strain) were monitored on
a Buxco pulmonary mechanics computer. Changes in airway
resistance ~RL) were calculated by the computer on a
breath-by-breath basis at isovolumic points from signals
measuring airflow and transpulmonary pressure using
differential pressure transducers. Animals were
pretreated with 1 mg~kg of propranolol, iv, followed by
100 puffs of an aqueous solution of test compound or
vehicle control ~y aerosol via a Monaghan nebulizer.
LTD4 was then aerosolized into the airway. The
bronchocons~riction produced was reflected by % changes in
airways resistance relative to the baseline values
obtained prior to injec~ion of the test compound or
vehicle control. Each guinea pig received either vehicle
control or test compound.
Calculations: The average of 3 - 6 animals per
treatment was calculated using the % changes in the
pulmonary parameters for control and test
compound-treated animals. The average % inhibition by
the test compound was calculated from the following
equatlon:
% Inhibition =
(vehicle control) - (test comPound) x 100
RL
(vehicle control)
- 2:L -
11 3 ~
1 The compounds of this invention possess
biosignificant antagonist activity against leukotrienes,
primarily leukotriene D~. The antagonist activity of
representative compounds of this inventioll is tabulated
below (other data appears in the preparative examples).
The -log KB values and the RL values were calculated
from the above test protocols. Where compounds were
tested more than once, the -log KB values given herein
represent the current average data.
ComPounds of the Formula (VI)
Rl R2 ~ In Vitro
, .. ..
-Log KB
-C8H16PhenYl H 1 7.6
-C8H16 phenyl H 2 7.7
The specificity of the antagonist activity of a
number of the compounds of this invention is demonstrated
by relatively low levels of antagonism toward agonists
such as potassium chloride, carbachol, histamine and
PGF2 .
Pharmaceutical compositions of the present
invention comprise a pharmaceutical carrier or diluent and
an amount of a compound of the formula (I) or a
pharmaceutically acceptable salt, such as an alkali metal
salt thereof, sufficient to produce the inhibition of the
effects of leukotrienes.
When the pharmaceutical composition is employed
in the form of a solution or suspension, examples of
appropriate pharmaceutical carriers or diluents include:
for aqueous systems, water; for non-aqueous systems,
- 22 - ~3~
1 ethanol, glycerin, propylene glycol, corn oil, cottonseed
oil, peanut oil, sesame oil, liquid parafins and mixtures
thereof with water; for solid systems, lactose, kaolin and
mannitol; and for aerosol systems, dichlorodifluoro-
methane, chlorotrifluoroethane and compressed carbondioxide. Also, in addition to the pharmaceutical carrier
or diluent, the instant compositions may include other
ingredients such as stabilizers, antioxidants,
preservatives, lubricants, suspending agents, viscosity
modifiers and the like, provided that the additional
ingredients do not have a detrimental effect on the
therapeutic action of the instant compositions.
The nature of the composition and the
pharmaceutical carrier or diluent will, of course, depend
upon the intended route of administration, i.e.
parenterally, topically, orally or by inhalation.
In general, particularly for the prophylactic
treatment of asthma, the compositions will be in a form
suitable for administration by inhalation. Thus the com-
positions will comprise a suspension or solution of theactive ingredient in water for administration by means of
a conventional nebulizer. Alternatively the compositions
will comprise a suspension or solution of the active
ingredient in a conventional liquified propellant or
compressed gas to be administered from a pressurized
aerosol container. The compositions may also comprise the
solid active ingredient diluted with a solid diluen~ for
administration from a powder inhalation device. In the
above compositions, the amount of carrier or diluent will
vary but preferably will be the major proportion of a
suspension or solution of the active ingredient. When the
diluent is a solid it may be present in lesser, equal or
greater amounts than the solid active ingredient.
- 23 -
~ 3 ~
1 For parenteral administration the pharmaceutical
composition will be in the form of a sterile injectable
liquid such as an ampul or an aqueuus or nonaqueous liquid
suspens ion .
For topical administration the pharmaceutical
composition will be in the form of a cream, ointment,
liniment, lotion, pastes, and drops suitable for
administration to the eye, ear, or nose.
For oral administration the pharmaceutical
composition will be in the form of a tablet, capsule,
powder, pellet, atroche, lozenge, syrup, liquid, or
emulsion.
Usually a compound of formula I is administered
to a subject in a composition comprising a nontoxic amount
sufficient to produce an inhibition of the symptoms of a
disease in which leukotrienes are a factor. When employed
in this manner, the doszge of the composition is selected
from the range of from 350 mg. to 1000 mg. of active
ingredient for each administration. For convenience,
equal doses will be administered 1 to 5 times daily with
the daily dosage regimen being selected from about 350 mg.
to about 50D0 mg.
The pharmaceutical preparations thus described are
made following the conventional techniques of the pharma-
ceutical chemist as appropriate to the desired end product.
Included within the scope of this disclosure isthe method of treating a disease, pulmonary or
non-pulmonary, in which leukotrienes are a factor which
comprises administering to a subject a therapeutically
effective amount of a compound o formula I, preferably in
the form of a pharmaceutical composition. For example,
inhibitins the symptoms of an allergic response resulting
rom a mediator release by administration of an effective
amount of a compound of formula I is included within the
scope of this disclosure. The administration may be
- 2~ 3~ 6 ~
l carried out in dosage units at suitable lntervals or in
single doses as needed. Usually this method will be
practiced when relief of symptoms is specifically
reguired. However, the method is also usefully carried ou~
as continuous or prophylactic treatment. It is within ~h~
skill of the art to determine by routine experimentation
the effective dosage to be administered from the dose range
set forth above, taking into consideration such factors as
the degree of severity of the condition or disease being
treated, and so forth.
Compounds of this invention, alone and in
combination with a histamine Hl-receptor antagonist,
inhibit antigen-induced contraction of isolated, sensitized
guinea piy trachea (a model o respiratory anaphylaxis).
Exemplary of compounds of this invention are 2(S)-hydroxy-
3(R)-(2-carboxyethylsulfinyl)-3-[2-(8-phenyloc~yl)phenyl]-
propanoic acid. Exemplary of histamine Hl-receptor
antagonists are mepyramine, chlorpheniramine, and
2-[4-(5-bromo-3-methyl-pyrid-2-yl)butylamino]-5-[(6-methyl-
~ pyrid-3-yl)methyl]-4-pyrimidone and other known
Hl-receptor antagonists.
Pharmaceutical compositions, as described herein-
above, of ~he present invention also comprise a pharma-
ceutical carrier or diluent and a combination of a compound
of the formula (I) or a pharmaceutically acceptable salt
thereof, and an histamine Hl-receptor antagonist in
amounts sufficient to inhibit antigen-induced respiratory
anaphylaxis. The above-defined dosage of a compound of
formula I is conveniently employed for this purpose and
the known effective dosage for the histamine Hl-receptor
antagonist. The methods of administration described above
for the single active ingredient can similarly be employed
for the combination with a histamine Hl-receptor
antagonist.
~ 3 ~
1 The following examples illustrate the preparation
of the compounds of this invention and their incorporation
into pharmaceutical compositions and as such are not to be
considered as limiting the invention set forth in the
claims appended hereto.
EXAMPLE 1
Preparation of 2-Hydroxy-3-(2-carboxyethylthio~-3-
[2 (8-phenYloctyl)phenyl]~ropionic acid
(a) 2-(8-PhenYloctYl)benzaldehyde
A solution of 8-phenyloctanoic acid (19.8 mmol) in
sieve dried tetrahydrofuran (5 ml~ was reduced with diborane
in tetrahydrofuran (30 ml, 29Ol mmol~ at 0C for 4 hours to
give 8-phenyloctanol. To an ice cold solution of the
octanol (ca. 19.8 mmol) and carbon tetrabromide (21.98 mmol)
in methylene chloride (50 ml) was added triphenylphosphine
(22.30 mmol) in methylene chloride (50 ml~ and the resulting
solution was stirred for 2.5 hours. The volatiles were
evaporated and the residue was taken up in ether (100 ml),
cooled in ice, and filtered. The filtra~e was evaporated
and distilled to afford 8-phenyloctyl bromide as an oil.
To 8-phenyloctylmagnesium bromide (from 24.25 mmol
of 8-phenyloctyl bromide and ~1.27 mmol of magnesium) in
distilled tetrahydrofuran ~40 ml~ was added
2-(2-methoxyphenyl)-4,4-dimethyloxa7.oline (17.10 mmol3 [A.I.
Meyers et al., J. Orq. Chem., 43, 1372 (1978~] in
tetrahydrofuran (20 ml~. After stirring for 24 hours, the
reaction mixture was worked up to yield 2-[2-(8-phenyl-
octyl)phenyl]-4,4-dimethyloxazoline as an oil. A solution
of the oxazoline (11.58 mmol) in methyl iodide (20 ml) was
refluxed under argon for 18 hours. Removal of the volatiles
afforded the corresponding 3,4,4-trimethyl- oxazolinium
iodide as a white solid (mp 76.5-78C).
-- 26
1 To an ice cold solution of the iodide (9.46 mmol~
in methanol (35 ml) was added in portions sodium borohydride
(9.20 mmol). The reaction mixture was allowed to stir for
30 minutes and was then quenched with 5 percent sodium
hydroxide (50 ml). The reaction mixture was extracted with
diethyl ether (2 x 50 ml~ and the
extract was washed with brine (50 ml) and dried over
anhydrous magn2sium sulfate and filtered. E~aporation of
the filtrate afforded an oil which was dissolved in
acetone (50 ml) and 3N hydrochloric acid (10 ml) was
added. The mixture was flushed with argon and stirred for
16 hours at ambient temperature. The volatiles were
removed under vacuum and the residue partitioned between
diethyl ether (50 ml) and water (50 ml). The aqueous
phase was extracted with more diethyl ether (50 ml). The
combined organic phase was washed with brine (50 ml) and
dried over anhydrous magnesium sulfate. Evaporation o
the organic phase yielded an oil which was purified by
flash chromatography over silica gel with 2 percent ethyl
aceta~e in hexane as eluant to afford the desired product
as a colorless oil.
Analysis for C21H~60: Calculated: C, 85.67;
H, 8.90. Found: C, 85.12, 85.22; H, 8.94, 8.96.
(b) Alternative preparation of 2-(8-phenyloctyl)-
benzaldehYde
A solution of 5-hexynyl alcohol (102 mmol) in
pyridine (150 ml), under argon, was cooled to OC and
p-toluenesulfonyl chloride (204 mmol) was added. The
reaction mixture was kept at about 4C for 18 hours,
poured into ice-water and then taken up in ether. The
ether extract was washed with cold 10% hydrochloric acid,
water and brine. The organic layer was dried and concen-
trated ln vacuo to give 5-hexynyl p-toluenesulfonate. A
solution of phenylacetylene (97 mmol) in tetrahydrofuran
- 27 - ~3~
1 (200 ml) containing a trace of ~riphenylmethane was cooled
to 0C and then n-butyl lithium (37.3 ml of 2.6 mol in
hexane) was added dropwise. The resulting solution was
stirred at 0C for 10 minutes and hexamethylphosphoramide
(21 ml) was added dropwise. After stirring for 10 minutes
a solution of 5-hexynyl p-toluenesulfonate (97.~ mmol) in
~etrahydrofuran (200 ml) was added. The reaction mix-
ture was stirred at room temperature for 18 hours, diluted
with ether and the organic layer was washed with water and
brine. The dried organic solution was concentrated and
the product was purified by flash chromatography to give
l-phenylocta-1,7-diyne. A mixture of this compound (43
mmol), 2-bromobenzaldehyde ~35.8 mmol), cuprous iodide
(0.5 mmol) and bis(triphenylphosphine) palladium (II)
chloride (0.7 mmol) in triethylamine (100 ml) was heated
in an oil bath (95C) for onP hour. The reaction mixture
was cooled to 0C, filtered and the filtrate was concen-
trated. The residue was dissolved in ether, washed with
10% hydrochloric acid, water and brine. The organic layer
was dried and concentrated to give a product which was
purified by flash chromatography to yield 2-(8-phenyl-1,7-
octadiynyl)benzaldehyde. A solution of this compound
(24.1 mmol) in ethyl acetate (100 ml) and 10% palladium on
charcoal (1 g) was hydrogenated (40 psi of hydrogen) at
room temperature for 15 minutes. The ca~alyst was
filtered off and the filtrate concentrated to give the
2-(8-phenyloctyl)benzaldehyde.
(c) Methyl trans-3-[2-~8-PhenyloctYl)phenyl]-2,3-
epoxS7proPionate
The compound of Example l(a) or (b~ (2.94 g,
10 mmol) was dissolved in diethyl ether (25 ml) and the
solution was stirred under argon at OC. Methyl chloro-
acetate (1.32 ml, 15 mmol) was added, followed by the
addition of sodium methoxide (810 mg, 15 mmol). The
mixture was stirred for 2.5 hours at ice bath temperature.
~ 3 ~
l A small ~uantity of water was added, the ether phase
separated, dxied over anhydrous sodium sulfate, filtered
and evaporated. The residue was 1ash chromatographed on
80 grams of silica gel eluted with 5-30~ ethyl acetate/
hexane to give the product.
(d) Methyl 3-(2-Carbomethoxyethylthio)-3-[2-(8-
phenyloctyl)phenyl]-2-hydroxypropionate
The compound of Example l(c) (1.2 g, 3.28 mmol~
was dissolved in me~hanol (20 ml) containing 2% triethyl-
amine and stirred under argon at room temperature. Methyl3-mercaptopropionate (0.623 ml, 5.45 mmoles) and triethyl-
amine (1.45 ml, 9.84 mmol) were dissolved in methanol
(15 ml) and added dropwise. The mixture was stirred for
18 hours. The solvent was stripped and the residue eluted
with 20% ethyl acetate/hexane to give a mixture of the
desired product and its regioisomer, methyl 2--S2-carho-
methoxyethylthio)-3-[2-(8-phenyloctyl)phenyl]-3- hydroxy-
propionate. The mixture was rechromatographed on lOOg of
neutral alumina to separate the desired product.
(e) Erythro-3-(2-carboxYethylthio)-3-[2-(8
phenyloctyl)phenyl]-2-hYdroxy-
propionic acid
The desired product of Example l(d) (320 mg, 0.66
mmol~ was dissolved in methanol (10 ml~ and stirred under
argon at ice bath temperature. A lN solution of sodium
hydroxide (2.5 ml, 2.5 mmol~ was added dropwise, the ice
bath removed, the mixture stirred at room temperature for
2.5 hours~ and then cooled for 18 hours. After an
additional l hour of stirring at room temperature, the
methanol was stripped, the residue diluted with water and
the pH adjusted to 3.5 with dilute hydrochloric acid.
Extraction with ethyl acetate followed by drying over
anhydrous sodium sulfate, filtration and evaporation gave
the crude product which was flash chromatographed on 20
- 29 - ~3
1 grams of silica gel eluted with 30:70:0.5 ethyl
acetate:hexane:formic acid to yive the free acid product.
(f) Resolution of 3-(2~-carboxyethylthio)~3-[2-(8-
phenyloctyl)phenylJ-2-hydro~ypro~ionic acid
The racemic diacid of Example l(e) (63.5 g, 0.138
mol~ in 700 ml of isopropanol was treated with a solution
of (R)-4-bromo-a-phene~hylamine (57.1 g, 0.286 mol) in
200 ml of isopropanol at 25C. The resulting solution was
stirred for 3 hours, causing crystallization of the 2S,3R
diamine salt. The suspension was cooled to 5C, filtered,
and the salt recrystallized twice from ethanol to give
37.7 g (72%) of 2S,3R diamine salt, m.p. 146-147C;
[a]24 C =-15.8 (C=l, CH30H).
The diamine salt (37.7 g, 0.0497 mol) was. added
in portions to 400 ml of cold 0.5N aqueous hydrochloric
acid. The mixture was extracted with ethyl acetate, and
the ethyl acetate solution washed three times with 0.5N
hydrochloric acid. The ethyl acetate solution was washed
with saturated sodium chloride solution, dried, and
~o concentrated to give 19.5 g (97%) of the desired
2(S)-hydroxy-3(R)-(2-carboxyethylthio)-3-[2-(8-phenyloctyl)-
phenyl]-propionic acid; ~a]24 = -40.8 (C=l, CHC13).
(g) 2(S)-Hydroxy-3(R)-( -carboxyethylsulfinyl)-
3-[2-t8-phenyloctyl)phenyl]propionic acid
A suspension of the compound of Example l~f) (870
mg, 1.9 mmole) in 15 ml of water was treated with NaOH
(152 mg, 3.8 mmol), stirred until solution was complete,
and cooled to 0. A solution of NaIO4 (500 mg) in 8 ml
of water was added. Stirring was continued at 0 for 45
minutes and at 23 for 1 hour. The reaction was acidified
and extracted with ethyl acetate. The extracts were dried
and the solvent evaporated. The residue was
chromatographed over a silica gel column, and the product
eluted with a mixture of ethyl acetate: hexane: acetic
acid (80:20:3), and gave 470 g (52%). nmr
. _ _ . _ _ . . .. . , . _ _ _ . . . ... . ..
- 30 - ~ 31~
1 (CDC13~Me2C0) on the mixture of diastereomers: 8.72
(broad, 3H), 7.62 (d~ and 7.96(d3 (together lH~, 7.20 ~s,
8H), 5.12 (m, lH), 4.82 (m, lH), 2.48 to 2.92 (m, 8H),
1.20 to 1.86 (m, 12H).
EXAMPLE 2
2($)-Hydroxy-3(R)-~2-carboxyethylsulfonyl)-3-[2-(8-
phenyloctyl)phenyl]~ropionic acid.
A solution of the compound of Example l(f)
(930 mg) in 75 ml of CHC13 was treated over 15 minutes
with m-chloroperbenzoic acid (1 g). After 1-1/2 hours at
23, 3 ml of saturated aqueous NaHS03 was added. After
5 minutes 3N HCl was added. The organic layer was
separated, washed with water, dried, and the solvent
removed. The residue ~as chromatographed over a silica
gel column, and eluted with a mixture of ethyl acetate:
chloroform: acetic acid (50:50:1). After a forerun
containing m-chlorobenzoic acid, the product was collected
in the later fractions, and gave 740 g (75~).
nmr ~CDC13/Me2CO) 10.0 ~broad 3H), 8.10 (d, lH), 7.03
to 7.33 (m, 8H), 5.29 (d, lH), 5.03 Sd, lH), 3.24 to 3.60
(m, 2H) 2.46 to 2.92 (m, 6H), 1.16 to 1.88 (m, 12H).
