Note: Descriptions are shown in the official language in which they were submitted.
W0 91/16889 ~ . 2 ~ 8 ~ ~ 6 ~ Pcr/US9 l /02884
Five-Membered Ring Alkanoic Acid Leukotriene Antagonists
This invention relates to heteroaromatic five-rnemembered ring
S a3~anoic acid derivatives which are useful for ~eating diseases
associated with leukotrienes.
"Slow Reacting Substanee of Anaphylaxis" (SRS-A) has been
. shown to be a highly po~ent bronchoconst~icting substance which is
10 released pnmarily from mast cells and basophils on anLigeniC
challenge. SRS-A has been proposed as a primary mediator in human
asthma. SRS-A, in addition to its pronounced effects on lung tissue.
also produces perrneability changes in skin and may be involved in
acute cutaneous allergic reactions. Further, SRS-A has been shown to
15 effect depression of ventricular contraction and potentiation of the
cardiovascular effects of histamine.
The dis~overy of the naturally occurring leukotrienes and their
rela~ionship ~o SRS-A has reinforced interest in SRS-A and other
arachidonate metabolites. SRS-A derived from mouse, rat, guinea pig
2 0 and man have all been characterized as mixtures of leukot~iene-C4
(LTC4), leukoeriene-D4 (LTD4) and leukotriene-E4 (LTE4).
As summarized by Lefer, A.M., BiQ~m~al Pharmacolo~v, 35, '~
123-127 tl986) both the peptide and non-peptide leukotrienes exert
microcircula~ory actions, promoting leakage of fluid across Ihe
2 5 capillary endothelial membrane in most types of vascular beds. LTB~
has potent chemotactic actions and contribu~es to the recruitrnen~ and
adherence of mobile scavenger cells to endothelial membrane. LTCl,
LTD4 and LT'E4 s~imulate a variety of types of muscles. LTC4 and
LTD4 are potent bronchoconstrictors and effec~ive stimulators of
3 0 vascular smooth muscle. This vasoconstrictor effect has been shown
to occur in pulmonary, coronary, cerebral, renal, and mesenteric
vascul atures .
Leuko~ienes have been implicated in a number of pulmonarv
diseases. Leukotnenes are known to be potent bronchoconstrictors in
3 5 humans. LTC and LTD have been shown to be potent and selective
peripheral airway agonists, being more active than histamine. [See
Drazen, J.M. et al., roc. Nat'L. Acad. Sci USA, 77, 7, 4354-4358 (1980)1.
wo 91/16889 ; ~ 2 0 814 6 2 pcr/us91/o2884
LTC4 and LTD4 have been shown to increase the release of mucous
from human airways in vitro. [See Marom, Z. et al., Arn Rev Respir.
~, 126, 449~51 (1982).] The leukotriene antagonists of ~he presen~
invention can be useful in the treatment of allergic or non-allergic
5 bronchial asthma sr pulmonary anaphylaxis.
Leukotrienes have also been directly or indirectly implicated in
a variety of non-pulmonary diseases in the ocular, dermatologic.
cardiovascular, renal, trauma, inflamma~sry, carcinogenic and other
areas.
Another area of utility for leukotriene antagonis~s is in the
~reatment of cardiovascular diseases. Since peptide leukotrienes are
potent coronary vasoconstrictors, they are implicated in a variety of
cardiac depression. Synthetic leulcotrienes have been shown to be
powerful myocardial depressants, their effects consisting of a
15 de~rease i contractile force and coronary flow. The cardiac effects ot
LTC4 and LTD4 have been shown to be antagonized by a specific
leukotriene an~agonist. thus suggesting usefulness of leukotriene
antagonists in the areas of myocardial depression and cardian
anaphylaxis. [See Burke, J.A., et al.,
20 ~ çs, 221, 1, 235-241 (1982).]
Leukot~iene antagonists can also be useful in the area of renal
ischemia or renal failure. Badr et al. have shown that LTC4 produce~
signiticant elevation of mean arterial pressure and reductions in
cardiac output and renal blood flow, and that such effects can be
2 5 abolished by a speci~lc leukotriene antagonist. [See Badr, K.F. et al..
~irçulation Research, 54, 5, 492-499 (1984). Leukotrienes have also
been shown to have a role in endotoxin enduced renal failure and the
effects of the leukotrienes selectively antagonized in this model of
renal injury. [See Badr, K.F., et al., Kidnev InternatiQnal, 30, 474-48û
3 0 (1986).] LTD4 has been shown to produce local glomerular constrictor
actions. which are prevented by trea~ment with a leuko~riene
antagonist, [See Badr, K.F. et al., Kidnev Tnternational,'~9, 1, 32
(1986). LTC4 has been demonstrated to conlract rat glomerular
mesangial cells in culture and thereby effect intraglomerular actions
35 to reduce filtration surface area. [see Dunn, M.J. et al., Kidnev
Internationa!, 27, 1, 256 (1985). Thus another area of utility for
leukotriene antagonists can be in the treatment of glomerulonephritis.
2081~62
W0 91/16889 ~ PCI/IJS91/02884
By antagonizing the effects of LTC4, LTD4 and LTE4 or other
pharrnacologically active mediators at the end organ, for example
airway smooth muscle, the compounds and pharmaceutical
compositions of the i~stant invention are valuable in the treatment of
S diseases in subjec~s, ineluding huma~n or animals, in which
leukotrienes are a key factor.
Leukotriene antagonists based on 3-phenyl-3-thiopropionic
acids are disclosed in U.S. paten2 4,820,719 and EPO application No.
0 202 759 published 26 November, 1986.
1 0 ~T~ LED DES~R~IIO~ OF l~ ~Q~
The compounds of this invention are represented by formula (I)
X-R
~A~,~
Rl (I)
wherein Rl is not subs~ituted Oll A or B;
X is O or S(O)q where q is 0, 1 or 2 with the proviso that R1 is
not alkylthio or phenylthioaLkyl when q is 1 or 2;
Rl is C8 to C13 aL~cyl, C7 to C12 aLtcoxy, C7 to C12 alkylthio, Clo
to C12 1-alkynyl, 10-undecynyloxy, ll-dodecynyl, phenyl-C~ to Cl o
alkyl, phenyl-C3 to Cg alkoxy, phenylthio-C3 to Cg alkyl with each
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 Clo aLtcyl;
A is S, O, orN;
B is CH or NR2;
R2 is H, Cl to C13 aLkyl, Clo to Cl~-l-alkynyl, 1 l-docedynyl,
phenyl-C4 tO Clo alkyl with phenyl optionally monosubstituted or
~Y;
3 0 the dotted line between A and B indicates a sin~le bond in one
position and a double bond in the o~her;
wo 91/16889 2 0 81~ 6 2 PCI/US91/02~
Y is R3, CH(R4)tCH2)r"R3, CH(R~ tetr ol-~-yl, or tetrazol-5-yl;
R3 is -CORs where Rs is -OH or OX where X is a pharmaceutically
acceptable cation or a pharmaceutically acceptable ester-forming
group, -CN, -SO3H, -S02NH2, -NHSO2R~ I(NH2)CORs, or -NHcH2coR;t
S or R3 is -N(R6)2 where R6 is H, Cl to C6 alkyl, phenylCI-C6alkyl, or the
tWO R6 ~OUpS are combined to form a cyclic group having 3 to 5
carbons;
R4 is hydrogen, methyl, Cl to C4 alkoxy, fluoro or hydroxy;
R7 is Cl to Clo-alkyl, phenyl or substituted phenyl;
l 0 m is 0, 1, or 2;
R is -tCH2)nD. ~(cH2)nArD or ArD where n is 0-6, Ar is phenyl or
subs~ituted phenyl, thienyl, pyridyl, imidazolyl, tetrazol-5-yl or
thiazolyl and D is -(CH2)nR3, -COR3, ~etræol-5-yl, -CH(NH2)R3,
-NHCH2CORs, -NHSO2R7, -SO3H, -CN, or-SO2NH2; or
a pha~naceutically acceptable salt.
The term phenylthioalkyl is used to mean the thioether radical
where phenyl is bonded to sulfur which is bonded ~o the alkyl moiety,
the radical of the formula
~ } S--(CH2)n-
2~
A preferred class of compounds of this inven~ion are the
substituted alkanoic acid analogs of forrnula (I) where X is S(O)q
where q is 0 and Y is -(CH2)0 3COOH represented by formula (II)
X-R
~(CH2)0.3COOH
~1
I B
Rl (II)
wherein R and Rl are the same as described above, A is S, O or ~ and
B is CH or NR2. The most preferred class of these compounds are
3 0 those where X is S, R is -(CH2)nD, -(CH~)nArD or ArD. Y is -CH~COOH. A
~ U ~
WO 91/168~9 PCr/US91/02884
x-2
is S, O, or N, and B is CH or -NR2 where the group ~Y is no~ R2, and
Rl is Cg ~o Cl3-alkyl or phenyl-C4 to Clo-alkyl. The most prefened
compounds in this category are where J~Y is at the 2-position:
( 1 ) 3-~2-carboxyethylthio)-3 -(3-dodecylthien-2-yl)propionic
S acid;
(2) 3-(2-carboxyethylthio)-3-[3-(8-phenyloctyl)~hien-2-yl]
propionic acid;
(3) 3-(2-carboxyethylthio)-3-(1-dodecyl-lH-imidazol-2-yl)
propionic acid;
(4) 3-(2-carboxyethylthio)-3-[1-(8-phenyloctyl)-lH-imida~ol-
2-yl]propionic acid,
(S) 3-(2-oarboxyethylthio~-3-[3-(8-phenyloctyl)fur-2-yl]
propionic acid, and
(6) 3-(2-carboxyethylthio)-3-(3-dodecylfur-2-yl)propionic
1 5 acid.
A further particular group of compounds of ~his. inven~ion are
those where X is S, Y is -C(OH)HCOR3, R is -(CH2)nD, -(CH2)nArD or ArD,
Rl is Cg to C13-aIkyl or phenyl-C4 to Clo-alkyl, A is S, O, or N and B is
X-R
CH or -NR2 where ~he group ~Y is not R2. The most preferred
X-R
compounds of this group are those where ~Y is at the 2-position:
3 -(2-carboxyethylthio)-3-(3-dodecylthien-2-yl)-~ -
hydroxypropionic acid;
3-(2-carboxyethylthio)-3 -(3 -(8-phenyloc tyl)thien-~ -yl)-2-
hydroxypropionic acid,
2 5 3-(2-carboxyethylthio)-3-( 1 -dodecyl- 1 H-imidazol-~ -yl)-~ -
hydroxypropionic acid,
3-(2-carboxyethylthio)-3-( 1 -(~8~phenyloctyl)- 1 H-imidazol-~ -
yl)-2-hydroxypropionic acid,
3-(2-carboxyethylthio)-3-(3 -dodecylfur-~ -yl)-~ -
3 0 hydroxypropionic acid; and
3-(2-carboxyethylthio)-3-(3-(8-phenyloctyl)fur-~ -vl)-~-
hydroxypropionic acid.
WO 91/16889 PCI/~ IS9l/02884 ~
2 0 ~ 2
Another preferred class of compounds of this inven~ion are the
compounds where Y is (CH2)0- l -tetrazol-S-yl or -CH(OH)-tetrazol-~ -vl .
X is S, R is -(CH2)nD, -(CH~)nArD or A~D, A is O, S or N, B is -CH- or ~TR~
where the group ~Y is not R2, and Rl is C8 to C13-aLIcyl or phenyl-C~
X-R
S to C~lo-alkyl. The most preferred compounds are those where ~Y is
at the 2-position,: ¦
4-thia-5-(3-dodecyl~hien-2-yl)-6-(tetrazol-5-yl)hexanoic acid;
4-thia-5 (1-dodecyl-lH-imidazol-2-yl)-6-(tetrazol-5-
yl)hexanoic acid;
I 0 4-thia-5-(3-( 8 -phenyloctyl)thien-2-yl )-6-( tetrazol-S -
yl)hexanoic acid;
4-thia-5-(1-(8~phenyloctyl)-lH-imidazol-2-yl)-6-(tetrazol-5-
yl)hexanoic acid
4-thia-5-(3-dodecylfur-2-yl)-6-(tetrazol-5-yl)hexanoic acid;
l $ 4-thia-5-(3-(8-phenyloctyl)fur-2-yl)-6-(tetrazol-5-yl)hexanoic
a id;
4-thia-5-(3-dodecylthien-2-yl)-6-hydroxy-6-(teIra~
yl)hexanoic acid;
4-thia-S-(-1 -dodecyl- 1 H-imidazol-2-yl)-6-hydroxy-6-(tetrazol -
2 0 5-yl)hexanoic acid;
4-thia-S-(3-(8-phenyloctyl)thien-2-yl)-6-(te~razol-5-
yl)hexanoic acid;
4-thia-5 (1-(8-phenyloctyl)-lH-imidazol-2-yl)-6-hydroxy-6-
(~etrazol-S-yl)hexanoic acid '
2 5 4-thia-5-(3-dodecylfur-2-yl)-6-hydroxy-6-(te~razol-5-yl)-
hexanoic acid; and
4-~hia-5-(3-(8-phenyloctyl),fur-2-yl)-6-hydroxy-6-(tetrazol-5 -
yl)hexanoic acid.
A second class of preferred compounds are those where X is O~
3 0 particularly those p ~alleling the preferred and most preferTed
defi~i~ions for the case where X is S given above. Most preferred
compounds of this group are the following compounds: .
3-(2-carboxyethyloxy)-3-(3-dodecylthien-~-yl)propionic acid:
3-~2-carboxyethyloxy3-3-[3-(8-phenyloctyl)thien-2-yl]-
3 5 propionic acid;
XV~1~62
WO 91/16889 ~ j PCr/US91/02884
3-(2-carboxyethyloxy)-3-( 1 -dodecyl- 1 H-imidazol-2-yl)
propionic acid;
3-(2-carboxyethyloxy)-3-[1-(8-phenyloctyl)-lH-imidazol-~-
yl]propionic acid.
3 -(2-carboxyethyloxy)-3 -(3 -dodecylthien -2-yl)-2 -
hydro~ypropionic acid;
3-(2-carboxye thyloxy)-3 -(1 dodecyl- 1 H-imidazol- 2 -yl) -2 -
hydroxypropionic acid;
4-oxy-5-(3-dodecylthien-2-yl)-6-(tetrazol-5-yl)hexanoic acid;
1 0 4-oxy-5-(3 -(8 -phenylsctyl)thien-2-yl)-6-(tetrazol-5 -
yl?hexanoic acid;
4-oxy-5-(1 -(8-phenyloctyl)-lH-imidazol-2-yl)-6-(tetrazol-5-
yl)hexanoic acid; and
4-oxy-5-( 1 -dodecyl- 1 H-imidazol-2-yl)-6-(tetrazol-5 -
yl)hexanoic acid.
AIl compounds of this invention have at least one assymetric
center due to X being sulfur or oxygen. Some of the compounds of the
fo~nula ~I) contain two asymmetric centers, such as ~hen Ra in the Y
sustituent is other than hydrogen, such as is n~ethyl, methoxy, fluoro
2 0 or hydroxy. Osher asymetric centers may also be present in these
molecules depending on the selection of subsùtuents in any given
compound. In practice, these compounds are prepared as a mixture ot
stereoisomers. all steroisomers, as mixtures or resolved isomers, are
included in this invention. Resolution procedures employing, for
example, optically active amines furnish the separa~ed enantiomers.
Pharmaceutically acceptable esters may be formed from those
compounds having a carboxylic acid function ie when R has the -C(:R~
tenninal groupO Such an ester, or di-ester as the case may be will be
- any ester which, as with pharmacuetically acceptable salts, gives an
3 0 ester which retains tbe activity of the parent compound and does not
impart to the parent acid any unacceptable untoward pharmacologic~l
or toxic affects in the context of its intended use and application.
While it is expected that any carboxylic acid ester may be used. it is
preferred to employ certain esters derived from the following
- 3 5 radicals: Cl to C6 a]kyl, cycloalkyl, aryl, arylalkyl, alkylaryl.
alkylaryla~kyl, arninoalkyl, indanyl, pivaloyloxyn ethyl,
1' ~ t. ~' ',,' 1~
wo 91/16889 2 0 814 6 2 PCr/USg1/02884 ~
acetoxymethyl, propionyloxymethyl, glycyloxymethyl,
phenylglycyloxymethyl, or thienylglycyloxymethyl.
The compounds of the present invention, depending on their
s~ucture, are capable of forming pharmaceutically acceptable salts
5 with acids and bases according ~o procedures well known in the arn
Such salts are those which match the-activity of the parent compound
and do not exhibit untoward or deliberous activity. Acceptable acids
include inorganic and organic acids, such as hydrochloric, sulfuric,
methanesulfonic, benzenesulfonic, p-toluenesulfonic acid and acetic
10 acid. Bases include organic and inorganic bases, such as ammonia,
arginine, organie amines, alkali metal bases and alkaline earth metal
bases. Pipera~ine and ethylenediamine salts are particularly useful in
this invention. Also preferred are the dipotassium, disodium,
dimagnesium, dizinc, and dicalcium salts of the diacid compounds of
15 forrnula (I). Pharmaceut.ically acceptable cations are the same as rhe
just recited base-derived pharmaceutically acceptable salts.
The compounds of the formula ~1) wherein Y is CH2C02H are
prepared by reacting the appropriate aldehydes of the formula VI or
VII, wherein Rl, R2 and A are as described above and an esterified
2 0 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 directlv
with a substituted thiol in ~rifluoroacetic acid. Alternatively. a
2 5 mixture of trimethyl borate and zinc in tetrahydrofuran may be used
to prepare the 3-hydroxypropionate derivative. Preferably,
compounds of formula (I) are prepared from the aldehydes VI or VII
by reaction with lithium diisopropylamide and t-butyl acetate at -
78C to 25C in a suitable solvent such as, for example, THF, to provide
3 0 ~he precursor es2erified 3-hydroxypropionate derivatives which are
converted to the thiol acids with ~ mercaptan in trifluoroacetic acid.
By employing an esterified 2-b,omopropionate in the above reaction
with an aldehydes VI or VII, the compounds of the formula (I)
wherein Y is CH(~H3)C02H are obtained.
WO 91/16889 PCl /US91/02884
.. ~'I; ' ' .~
~A~CE~O ~N~C~IO
.2iQ ~ R2iQ~
Rl (VI) Rl (VII)
.
To prepare the compounds of formula (I) wherein q is l or 2,
the appropriate thio product is conveniently oxidized with sodium
5 period~te or metachloroperben~oic acid to obtain ~he sulfoxide or
sulfone product.
The aldehydes of the forrnula (VI) and (VI1) are known or
readily prepared utilizing the general procedures described as follows.
The aldehyde precursors to the compounds of the formula (I)
10 wherein R1 is, for exarnple, an aL~cyl radical containing 8 to 13 carbon
atoms are prepared from the appropriate 2-methoxyphenyl-4,4-
dimethyloxazoline [see Meyers e~ al. J. Qr~. ~hem., ~, 1372 (1973)].
The aldehyde precursors to the compounds of the formula (I)
wherein R 1 is a 1 -alkynyl radical con~aining 10 to 12 carbon atoms
15 are prepar~d by coupling a halobenzaldehyde with the: appropriate l-
aL~;yne in the presence of cuprous iodide and (P03)2PdC12. [See
Eigahara et al., Svnthesi_. 627 (1980)]. The catalytic hydrogenation of
these alkynyl containing precursors under standard conditions affords
the aldehyde precursors of the compounds of the formula (I) wherein
20 Rl is an alkyl or phenylalkyl radical.
Alternatively, ~he compounds of ~he formula (I) wherein Y is
CH2C02H are prepared from a propionate precursor of Ihe following
structural formulas ~VIII) and (IX).
2~¦~ R,,,~ COORI6
2 5 Rl (VIII) Rl (IX)
wherein R1, R2 and A are described above, and R16 is an es~er
protective group, such as t-butyl. A compound of formula (VIII) or
(IX) is reacted with a mix~ure of alkali metal alkoxide. such as sodium
WO 91/16~89 2 0 8 1 ~ 6 2 Pc-r/uss1/02884 "_~
1 0
methoxide, and substituted thiol to give, after removal of the ester
protective group, products of formula (I).
The propionate precursors of formula (VIII) or (IX) are
prepared from the corresponding aldehydes of formulas (VI) and
S (VII) by general procedures such as reaction with an alkyl
(triphenylphosphoranylidene)aceta~e or by conversion of the
aldehyde to a 3-hydroxypropionate derivative, as described above,
followed by an elimina2ion reaction to form the double bond.
Additionally, the propenoate precursor is obtained from a 3-me~hane-
sulfonyloxypropionate derivative by treatment with triethylamine or
from a 3-acetoxypropionate derivative by treatment with 1,8-
diazabicyclo-[5,4,0]undec-7-ene at elevated temperature, eg. about
90C.
The compounds of the forrnula tI) wherein Y is
CH(OH)(CH2)mCO2H are prepared ~rom an epoxide precursor of ~he
following stmctural formulas (X) and (XI)
R2~l ~COOR I \N;~,
R~ (X) Rl (XI)
wherein Rl, R2, A and m are the sarne as described above, and Rl6 is
- C1 to C6aLIcoxy. A compound of forrnula (X) or (XI) is reacted in an
inert solvent with triethylamine and a substituted thiol selected to
give, after removal of ester protecti~e groups, a product of formula
(I).
The epoxide precursors of fonnula (X) or (XI) where m is 0 are
prepared by reaction of an aldehyde of the formula (VI) or (VII) wi~h
a lower alkyl chloroacetare and an alkali metal alkoxide, such as
sodium methoxide.
Alternatively, the compounds of the formula (I) wherein Y is
CH(OH)COR16 are prepared from a propenoate precursor of formula
(VIII) or (IX) wherein R16 is lower all;yl.
The 2-thioimidazole precursors necessary ~o prepare the R-
heterocyclic derivatives of formula (I) are known compounds or are
wo 9~/16889 P~r/u~ 2l~ fi 2
1 1
conveniently prepared employing standard chemical reactions.
Preferably these reactants bearing a carboxyl or carboxymethyl
substituent as set forth in R8 and R~ above are employed as the
corresponding carboalkoxy derivatives wherein the alkoxy radical
contains from one to six carbon atoms. When pr~sent, the alkoxy
subs~ituent is subsequently hydrolyzed to give the free carboxyl or
carboxymethyl substituted products.
Appropriate modifications of the general processes disclosed,
and as further described iD the Examples provided hereinbelow,
furnish thc various compounds defined by formula (I).
l~ie leuko~iene 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.
The following methodology was employed: In vitrQ: Guinea pig (adul~
male albino Hartley strain) tracheal spiral strips of approximate
dimensions 2 to 3 mm cross-sectional width and 3.5 cm length were
ba~hed in modified Krebs buffer in jacketed 10 ml tissue ba~h and
continuously aeratcd with 95% 0~15% C02. The tissues were
connected via silk suture to force displacement transducers for
2 0 reeording isometric tension. The tissues were equilibrated for 1 hr,
prctreated for 15 minutes with meclofenamic acid (1 mM) to remove
intrinsic prostaglandin responses1 and then pretreated for an
additional 30 minutes with either the test compound or vehicle
control. .9 cumulative concentration-response curve for LTD4 on
2 5 triplicate tissues was generated by successive increases in the bath
concentration of.the LTD4. In order to minimize intertissue
variabiIity, the contractions elicited by LTD4 were standardized as
percentage of the maximum rcsponse obtained to a reference agonist.
carbachol ( I O mM) .
3 0 Calcula~ions: The averages of the ~riplicate LTD4 concentration-
response curves both in the presence and absence of the test
compound w~,re plotted on log graph paper. The concentration of
LTD4 needed to elicit 30% of the contraction elicited by car~achol
measured and defined as ~he EC30. The -log KB value for the ~est
3 5 compound was determined by the following equations:
I. ~30 (presence of test compound? = dose ratio = X
EC30 (presence of vehicle control)
t;
WO 9l;168~9 2 ~ 8 ~ ~ ~ 2 Pc~rtUS9l/02884 ~
1 2
2. KB = concentration of test compound/(X-1)
The compounds of this invention possess an~agonist activity
against leukotrienes, primarily leukotriene D4. The antagonist
5 aetivity of represen~ative compounds of this invention is ~abula~ed
below. The -log KB Yalues were calculated from the above test
protocols. Where compounds were tested more than once, the -log KB
~ralues given herein represent the current average da~a. Compound 3-
(2-carboxyeth~lthio-3-~3-dodecylthien-2-yl)propionic acid at a molar
10 concentration of 10-5 showed a pKB of 6.5 in comparison lo a pKg of
7.3 for a 10-6 molar concen~ation of 2-hydroxy-3(R)-2-
carboxyethylthio)-3-[2-(8-phenyloctyl)phenyl]propionic acid, a
known leukotriene antagonist. Likewise, methyl 2-hydroxy-3-(2-
carboxyethylthio)-3-(3-dodecylimidazol-2-yl)propionate was tes~ed
15 against the afore men~ioned phenylpropionic acid, the imidazole
ha~ing a pKg of 5.9 at a molar concentration of 10-5 and the
phenylpropionic acid having a pKg of 8.3 at a molar concentration of
10-S
The specificity of the antagonist acti~i~y of a number of the
2 0 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 inven~ion comprisea pharmaceutical carrier or diluent and an amount of a compound of
2 5 the formula (I) or a pharmaceutically acceptable salt, such as an alkali
me~al 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 appropria~e pharmaceutical
3 0 carriers or diluents include: for aqueous systems, water; for non-
aqueous systems, ethanol, glycerin, propylene glycol, corn oil,
cot~onseed oil, peanut oil, sesame oil, liquid parafins and .nixtures
thereof with water; for solid systems, lactose, kaolin and mannitol;
and for aerosol systems, dichlorodifluoromethane,
35 chlorotrifluoroe~hane and compressed carbon dioxide. Also. in
addition to the pharmaceutical carrier or diluent, the instant
compositions may include other ingredients such as stabilizers.
. i i ~ 08~ ~ 6~
wo 91/16889 ; ~ -~ Pcr/~lssl/o2884
.
1 3
- antioxidants, preserva~ives, lubricants, suspending agents, viscosity
modifiers and the like, provided that the additional ingredients do no~
have a detrimental effect on the therapeutic action of the instant
compositions .
S The nature of the composition and the pharmaceutical carrier or
diluent will, of course, depend upon the intended roote of
administration, for example parenterally, topically, orally or by
inhalation.
In general, particularly for the prophylactic ~reatment of
asthma, the compositions will be in a form sui~able for administra~ion
by inhalation. Thus the compositions will comprise a suspension or
solution of the ac~ive ingredien~ in wa~er for administration by means
of a conventionaI 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
diluent for administration from a powder inhalation device. In the
above compositions, the amount of carrier or diluent will vary but
preferably. ~ill be the major proportion of a suspension or solution of
the ac~ive ingredient. When the diluent is a solid it may be presen~ in
lesser, equal or greater amounts than the solid active ingredient.
For parenteral administra~ion the pharmaceutical composition
will be in the form of a sterile injectable liquid such as an ampul or an
? 5 aqueous or nonaqueous liquid suspension.
For topical administration the pharmaceutical composition will
be in the form of a cream, ointment, liniment, Ic~ion, pastes, and drops
~uitable for administration to the eye, ear, or nose.
For oral administlation the pharmaceutical composition will be
3 0 in the form of a tablet, capsule, powder, pellet, atroche, lozenge, syrup
liquid, or emulsion.
Usually a compoun~l 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 dise~se in which leukotrienes are a
3 5 factor. When employed in this manner. the dosage of the composi~ion
is selected from the range of from 350 mg to 1000 mo of active
ingredient for each administration. For convenience, equ~l doses will
wo 91/168X9 2 ~ 8 1 4 ~ 2 Pcr/US91/02884 ~
l 4
be administered l ~o 5 ~imes daily with the daily dosage regimen
being selected from about 350 mg to about 5000 mg.
The pharrnaceutical preparations thus described are made
following the conventional techniques of the phamaceutical chemist as
5 appropriate to the desired end product.
Included within the scope of this disclosure is the method of
treating a disease which comprises administering to a subject a
therapeutically effective amount of a compound of formula L
preferably in the form of a pharmaceutical composition. For example,
10 inhibiting the symptoms of an allergic response resulting frorn 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 carried out in dosage units at suitable
intervals or in single doses as needed. Usually this method will be
15 practiced when relief of symptoms is specifically required. However,
the me~hod is also usefully camed out as continuous or prophylactic
treatmenl. It is within the skill of the art to determine by routine
experimentation the effectiYe dosage to be administered ~rom the
dose range set forth above, taking into consideration such factors as
2 0 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, inhibi~ antigen-induced conrrac~ion
of isolated, sensitized guinea pig ~rachea (a model of respiralory
5 anaphy1axis as described by Weichman, B.M., Wasserman, M.A.,
Holden, D.A., Osborn, R.R., Woodward, D.F., Ku, T.W., and Gleason, J.G.. J
Ph~macol. Exp. Ther., 227, 700-705, l 983.
Pharmaceutical compositions, as described hereinaoove, of the
present invention also comprise a pharmaceutical carrier or diluent
30 and a combina~ion 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 kno~ n
3 5 effective dosage for the histamine Hl -receptor antagonist. The
methods of administration described above for the single active
wo 91/16889 Pcr/ussl2o0
l S
ingredient can similarly be employed for ~he combination with a
histamine Hl-receptor anta~onist.
The following examples illustrate the preparation of the
compounds of this invention and their incorporation into
S pharma~eutical composi~ions and as such are not to be considered as
limiting the invention se~ forth in the claims appended hereto.
;E~xam~
>~ ~
2-yl2~rol2ionic acid
(i), ~ ~
A mixture of 3-methyl-2-thiophenecarboxylic acid (lO g, 0.07
mole) and thionyl chloride (20 rnL) was hea~ed a~ 50C for 2 hours. IR
analysis indicated l~omplete conversion to ~he acid chloride. Excess
l 5 thionyl chloride was evaporated and the residue was azeotroped with
dry toluene (3 times). The crude product was dissolved in ether,
s~irred with activated charcoal, filtered and concentrated to provide
3-methyl-2-thiophenecarboxylic acid chloride as an oil: which was not
purified further.
2 0 (ii) ~
A solution of 3-methyl-2-thiophenecarboxylic acid chloride (9 g.
0.056 mole) in di~hloromethane (50 mL) was treated dropwise below
20C with a solution of 2-amino-2-methyl-l-propanol (9.98 g, O.l l~
mole) in dichloromethane (20 mL). The resulting solution was lhen
2 S stirTed at ambient temperature for 2 hours, extrac~ed with water and
the organic phase was dried tMgSO4) and concentrated. This
concentrate was suspended in toluene (lO0 mL), and ~hionyl chloride
(l35 mL, 0.18 mole) was added dropwise to the st~lTed suspension
below 30C. After being sti~red at 25C for l 8 hours, the solvent was
3 0 removed and the residue was partitioned between water and ether.
The aqueous layer was extracted with additional ether, and the
combined organic layer was washed ~ h brine, dried tMgSO4) and
concen~rated to 11.9 g of crude ma~erial. This was purified by Qash
chromatography over silica gel with 9: l petroleum ether/ether to
3 5 provide 4,4-dimethyl-2-[2-(3-methylthienvl)]oxazoline as an oil; 90
MHz lH NMR (CDC13): 1.3 ppm (s, 6H), 2.55 (s, 3H), 4.05 ~s. 2H?, 6.~5
(d, lH), 7.25 (d, lH).
?wo ~ s889 pcr/us~l/o2884 ,_
2081~62
1 6
(iii) 4~ ~2 ~ Qdecvl th ie~Lox azoline ~,
To a solution of 4,4-dimethyl-2-E2-(3-methylthienyl)]oxazoline
(2 g, 10.2 mmole) in ethyl ether (15 mL) cooled to -78C was added
dropwise n.-butyl lithiurn (8.8 mL of 2.5 M in hexanes). The resulting
solution was stirred an additional 20 minutes at -78C, and then
stirred for 30 to 40 minutes at 0C. The reaction mixture was
recooled to -78C, and a solution of l-bromodecane (2.58 g, 11 mmole)
in ether (10 rnL) was added slowly. l~e coolant was removed, and
the mixture was stirred at ambient temperature for 18 hours. The
reaction was quenched with saturated NH4Cl solution. The product
was extracted with additional ether, and the organic phase was then
washed with brine, dried and was concentrated. Chromatography
over silica gel with 5% e~hyl ether in petroleum ether afforded the
4,4-dimethyl~2-~2-(3-dodecylthienyl)]oxazoline as an oil; 90 MHz I H
NMR tCDC13): 9.4-1.8 ppm (m, 23H), 1.32 (s, 6H), 2.95 (broad t. 2H),
4.1 (s, 2H), 6.9 (d, lH), 7.3 (d, lH).
(iv) ~ ~-dQdecvlthis~ ~ethYlo~Yazolinium iodide.
A mixture of 4,4-dimethyl-2-[2-(3-dodecylthienyl)]oxazoline
(6.2 g, 31.7 mmole) and methyl iodide (70 rnl,) was refluxed for 24
2 ~ hours under an argon atmosphere. Excess methyl iodide was
evaporated, the semi-solid residue was suspended in petroleum ether
and filtered. The solid was stirred in diethyl ether and filtered to
obtain solid 2-[2-~3-dodecylthienyl)]-3,4,4-trimethyloxazolinium
iodide; mp 148-154C; 90 MHz lH NMR (CDC13): 0.65-1.75 ppm (m~
23H), 1.75 (s, 6H), 2.95 ~broad t, 2H), 3.65 (s, 3H), 5.1 (broad s, ~H),
7.2 (d, lH), 8.1 (d, lH).
(v) 3-dodecy~ ~ thiophenecarboxa~ehvde.
A solution of sodium bis-(2-methoxyethoxy)aluminum hydride
~ in toluene (15 rnL of 0.34 M solution, 5.1 mmole) was cooled to -70C3 0 under an argon atmosphere, and was treated dropwise with a solution
of 7-~2-(3-dodecylthienyl)]-3,4,4-trimethyloxazolinium iodide (4 g,
8.1 mmole) in THF (20 mL) while maintaining the temperature belo~
-~C. ~hen the mixture was stirred at -SC to 10C for 4 hours. E.Yces
hydride reagent was quenched by the slow addition of dilute HCI. and
the mixture was then stirred at 25C fo}- 18 hours. The separated
organic layer was washed wi~h sodium sulfite solution and wa~er, and
the co.~.centrated, dried product was flash chromatographed over silica
wo 91/16889 . , pcr/us91/o2884
. .
gel with 5 % ether in petroleum ether to afford 3-dodecyl-2-
thiophenecarboxaldehyde as an oil; 90 MHz lH NMR (CDC13): 0.75-1.9
ppm (m, 23H), 3.0 (broad t, 2~), 7.0 (d, lH), 7.65 (d, lH), 10.1 (s, lH).
(vi) ~DL~-
Lithium diisopropyl amide was prepared by ~he ad~ition of
n-butyl lithium (1.1 mL of 2.5 M in hexanes) to a solution of
diisopropylamine (288 mg, 2.85 mmole) in THl: (5 rnL) held at -78C
under an argon atmosphere. After being stirred for S minutes,
t-butyl acetate (330 mg, 2.85 mmole) in TX~ (5 rnL) was then added
dropwise, and the resulting solution was stirred at -78C for 15
minutes. Then a solution of 3-dodecyl-2-thiophenecarboxaldehyde
(799 mg, 2.85 mmole) in THF (5 m7 ) was added slowly, and the
resulting mixture was stirred an additional hour at -78C. The
mixture was allowed to slowly warm to ambient tempera~ure, and
stirring was ~hen continued for another hour. Saturated NH4C 1
solution and ether were added, and the organic phase was washed
wi~h brine, dried, concentrated and flash chromatographed over silic~
gel with an elu~on system of 15% of ethyl ether and 85% of petroleum
ether to afford t-butyl 3-[2-(3-dodecylthienyl)]-3-hydroxypropionate
as an oil;
270 MHz lH NMR (CDC13): 0.89 ppm (t,3H), 1.5 (broad s, 18H),
1.49-1.65 (m and s~ llH), 2.55-2.85 (m,4H); 3.44 (s,lH), 5.4 (dd, lH),
6.88 (d,lH), 7.19 (d,lH).
(Yii) ~L2-carboxvethvlthio)~ -dodecvlthien-2-vl~propioniç acid.
2 5 A solution of t-butyl 3-[2-(3-dodecylthienyl)]-3-
hydroxypropionate (400 mg, 1 mmole) in dichloromethane (6 mL)
was cooled to -10C and 3-mercaptopropionic acid (634 mg, 6 mmole
was added. Then tri~uoroacetic acid (8 mL) was added dropwise a~
-10C. After being stirred at -10C for 45 minutes and a~ 0C for 5
3 0 hours, the mixture was partitioned between dichloromethane and
water. The organic extract was washed with water, dried,
concentrated and chromatographed over silica gel with a solution of
80:20 hexaneslethyl ~cetate containing 0.25% of formic acid to
provide 3-(2-carboxyethylthio)-3-(3-dodecylthien-2-yl)propionic ~cid
(oily); 270 MHz lH NMR (CDC13): 0.86 ppm (t.3H), 1.25 (broad s~ 18H~.
1.54 (m,2H), 2.42 (t,2H), 2.46-2.65 (m,4H), 2.68 (dd, 1 H), ~.8~ (dd, I H`).
:! - ` 2 0 81 a~ 6 2 pcr/us9l/o2884
3.34 (s,2H), 4.61 (t,lH), 6,82 (d,lH), 7.32 (d,lH). Anal. Calcd. for
C22H36O4S2:C, 61.64; H, 8.47. ~ound: C, 62.03; H, 8.14.
, ~mJ~1~2
~ ~rbQxvethvl~hio)-
(i) ~
A mixture of 1 8-crown-6 (0.8 g) and potassium t-butoxide (3.9
g, 0.035 mmole) in benzene (50 mL) was stirred for 15 minutes. Then
10 imidazole (2.04 g, 0.03 mole) was added, and, after 30 minutes at
2~C, the mixture was heated to 60C and dodecyl bromide (8.71 g~
0.035 mole) in benzene (20 mL) was added over 15 minutes. This
mixture was heated at 60C for one hour, then cooled, diluted with
water, and the layers were separated. The wa~er-washed, dried
15 organic layer was concentra~ed and the residue was flash
chromatographed over silica gel with 4:1 ethyl acetate/methanol to
provide 1-dodecylimidazole.
lH NMR tCDC13): 0.82-1.02 ppm (m,3H), 1.16-1.54 (m,18H), 1.7
(t,2H), 3.96 (t,2H), 6.92 (s,lH), 7.06 (s,1H), 7.46 (s,lH).
2 0 (ii) ~Q~c~limida~le-2-carboxaldehvde.
A solution of l-dodecylimidazole (~.77 g, 11.7 mmole) in ethyl
ether (100 mL) was cooled to -50C and n-butyl lithium (5 mL of 2.6
M in hexanes) was addPd. After one hour of stirrin" at -50C,
dimethylformamide (2 mT ) was then added and the mixture .was
2 5 allowed to warm to ambient temperature over 30 minutes. The
reaction was diluted wi~h satura~ed NH4CI solution, the ether layer
was separaled and washed with brine, dried and concentrated. This
crude product was chromatographed over silica gel with 50% ethyl
acetate in hcxanes to afford l-dodecylimida~ole-2-carboxaldehyde as
30 an oil; lH NMR (CDC13): 0.78-0.96 ppm (m,3H), 1.15-1.50 (m,18H),
1.58-2.02 (m,2H), 440 (t,2H), 7.16 (s,lH), 7.26 (s,lH), 9.85 (s,lH).
(iii) ~
A solution of l-dodecylimidazole-2-carboxaldehyde (1.4 g, 5 3
mmole) in dichloromethane (25 mL) was cooled to -~0C and tre~ted
3 5 with methyl chloroacetate (763 mg, 7.03 mmole) followed by sodium
methoxide in methanol (1.27 mL of 25% I` aOMe). The temperature
20~62
WO 91/1688g PCr/uSslto2884
.. .. ..
1 9
was raised to 0C, stirred for 2.5 hours at 0C, and then poured into
cold O.SN HCI. The layers were se:parated, and the organic phase was
dried, concentrated and the residuc was flash chromatographed over
silica gel with ethyl acetate to yield of the oily ~rans-2-carbomethoxv
3-(1-dodecylimidazol-2-yl)-oxirane; lH NMR (CDC13): 0.72-0.90 ppm
(m,3H), 1.05-1.40 (m,l 8H), 1.54-1.94 (m,2H), 3.67 (s,lH), 3,82 (s.3H),
3.92 (s,1H), 4.10 (t72H), 6.88 (s,lH), 6.92 (s,lH).
~odeçvlimida~ Y~S~a~e~
A~ ~olution of trans 2-carbomethoxy-3-( 1 -dodecylimidazol-2-
yl)oxirane (1.06 g, 3.16 mmole), methyl 3-mercaptopropionate (4.16
mg, 3.47 mmole), triethylamine (0.47 mL, 3.47 mmole) in methanol
(10 mL) was stirred at ambient temperature for 16 hours. The
sol~cnt was evaporated and the residue was chromatographed over
silica gel with 7:3 hexanes/ethyl aeetate to give methyl 2-hydroxy-3-
(2-carbomethoxyethylthio-3-(1-dodecylimidazol-2-yl)propionate (oil).
lH NMR (CDC13): 0.80-0.94 ppm (t,3H), 1.10-1.50 (m,14H), 1.60-
1.92 (m.2H), 2.22-2.50 (m,2H), 2.72-2.96 (m,2H), 3.67 ~s,6H), 3.88-
4.20 (m,2H), 4.40 (d,lH), 4.75 (d,lH), 6.57 (broad s, lH), 6.88 (s,2H).
2 0 ~v! ~f~.S~-hvdrQxy-3~$.R)-(~-c~r~QxYethYlthioi-3-(1-
A solution of methyl 2-hydroxy-3-(2-carbomethoxyethyl~hio)-
3-(1-dodecylimidazol-2-yl)propionate (400 mg, 0.88 mmole) in
methanol (12 mL) was ~eated with a solution of sodium hydroxide
(96 mg, 2.4 mmole) in water (4 mL). This mixture was stirred at
ambient temperature for 28 hours. The solvents were evaporated,
the residue was dissolved in water (20 mL) and the aqueous solution
was acidified with 3.0 N HCl (0.8 mL). The product was extracted into
1:1 methyl ethyl ketone and ethyl acetate. The washed extrac~s were
3 0 dried, and the solvent was evaporated to afford homogeneous, oily
2(R,S)-hydroxy-3(S ,R)-(2-carboxymethylthio)-3 -(1 -dodecylimidazol -
2-yl)propionic acid;
lH NMR (Me2CO-D6): 0.70-1.01 ppm (m,3H), 1.06-1.60 (m,l~H).
1.67-2.13 (m,2H), 2.36-3.06 (m,4H), 4.20 (t,2H), 4.68 (d,lH), 4.78
3 5 (d,IH), 7.21 (s,1H), 7.36 (s,lH), 10.18 (broad, 3H).
WO`91/16889 2 0 8 ~ ~ 6 2 PCI`/US91/02884 ~
~ .
~ .'
The title compound is prepared by the method described in
Example 1 (i-vii) by using 2-methyl-3-~hiophenecarboxylic acid in
5 place of 3-methyl-2-thiophenecarboxylic acid.
~lç ~
The title compound is prepared by the method described in
10 Exarnple l(i-vii) by using 2-me~hyl-3-furancarboxylic acid in place of
3-methyl-2-thiophenecarboxylic acid.
~mple 5
3-('~-Carbo~xvethYl~hio!-3-~3-~8-pheny!Qctyl)thien-2-vllpropionic acid
1~ The title compound is synthesized from 3-(8-phenyloctyl)-2-
thiophenecarboxaldehyde, prepared from 4,4-dimethyl-2-[2-(3-
methoxythienyl]oxazoline and 8-phenyloctyl bromide following ~he
procedure given in EPO application No. 0 202 759 published 26
November, 1 986.
Examp~_6
~-(2-C.arboxYeth~ ~ L~dodecvl-lH-~imidazol-2-vl~propionic ~cid
The title compound is prepared by using 1-dodecylimidazol-~-
carboxaldehyde [Example 2(ii)] in the method outlined in Example
2 5 1 (vi-vii) for 3-dodecyl-2-thiophenecarboxaldehyde.
xamp~
3-(2-carboxvethvlthio-~-rl -f 8-~henvl~ctYI~- I H-imidazol-~-
3 0 The title compound is prepared by the method described in
Example 1 (vi-vii) by using I -(8-phen.yloctyl)- 1 H-imidazole-2-
~,arboxaldehyde ~whieh is Frepared by the methods outlined in
Example 2(i-ii) using 8-phenyloctyl bromide] in place of dodecyl
bromide in place of 3-dodecyl-2-thiophenecarboxaldehyde.
Examp!e 8
3-(2-Carhoxvethvlthio)-3-(3 -dodecvlthien-~ -vl-
~0~1~62
wo 91/16889 ~ Pcr/uss1/o2884
.
2 1
~-hvdr~x~r~ionic acid
The title compound is prepared by the method described in
Example 2(iii-Y) by using 3-dodecyl-2-thiophenecarboxaldehyde in
place of 1-dodecylimidazole-2-carboxaldehyde.
~2!Q2
~-(2-~boxYethylthio~ dQ
~hvdroxv~Q~
l~e ~tle compound is prepared by the method described in
10 Ex~mple 2(iii-v) by using 3-dodecyl-2-furancarboxaldehyde in place
of l-dodecylimidazole-2-carboxaldehyde.
E~am~2~
l 5 ¢tetrazol-5-vl~hexanQlc acid
The title compound is prepared from 3-dodecyl-2-
thiophenecarboxaldehyde by condensation with ethyl 2-(tetrazol-5-
yl) acetate (as per EPO application No. 0 2Q2 759 published 26
November, 1986) after which the condensation product is oxidized to
2 0 méthyl 3-(3-dodecylthien-2-yl-3-keto-2-(~etrazol-5-yl)propionate by
manganese dioxide in refluxing toluene. This B-keto acid is
decarboxylated in hot acetic acid/hydrochloric acid as described in the
above reference, the resulting (3-dodecylthien-2-yl)-5-
methyltetrazolketone is reduced with sodium borohydride in
2 5 methanol to provide the 3-hydroxy derivative, and the ti~le
compound is obtained on treatment with 3-mercaptopropionic acid in
trifluoroacetic acid as described in Example 1 ~vii).
~ample 1, 1
30 4-Thia-5-(1-dodecvl-1~-imidazol-2-yl)-6-(tetrazol-5-vl~hexanoic acid
The title compound is prepared by tke method described in
Example 10 by using 1-dodecylimidazole-2-carboxaldehyde in place
of 3-dodecyl-2-~hiophenecarboxaldehyde.
3 5 Example 12
2-(4-Carbosvphenoxv)-2-(3-dodecvlthien-2-vl)acetic acid
(i) methyl 2-chloro-2-(3-dodecylthien-2-yl)acetate.
WO 9~/16X89 2 0 8 1 ~L 6 2 PCr/US91/02884 ~
22
i
The title compound is prepared from 3-dodecyl-2-thio-
phenecarboxaldehyde 1 (v) following the procedure given in U.S .
Patent No. 4,820,719 for the preparation of methyl 2-chloro-2-(2-
dodecyl-phenyl)acetate frorn 2-dodecylbenzaldehyde.
5 (ii) 2-~4-Carboxyphenoxy)-2-(3-doclecylthien-2-yl)acetic acid
The title compound is prepared from methyl 2-chloro-2-(3-
dodecylthien-2-yl)acetate by reaction with methyl 4-hydroxy-
benzoate and potassium carbonate in dimethylformamide followed by
saponi~lcation of the diester.
ExamR~
Formulations for pharmaceutical use incorporating compounds
of the present invention can be prepared in various forrns and with
numerous exeipients. Examples of such formularions are given below.
n~redients Per Tabiet Per 10,000
I~ets:
1. Ac~ive ingrediont
2 0 (Cpd of Forrn. I) 40 mg 400 g
2. Corn Starch 20 mg 200 g
3. Alginic acid 20 mg 200 g
4. Sodium alginate 20 mg 200 g
5. Mg stearate 1.3_rng~
101.3 mg 1013 g
Procedure for tablets:
Step 1 Blend ingredients No. 1, No. 2, No. 3 and No. 4 in a suitabl~ mixer/blender.
3 0 Step 2 Add sufficient water portion-wise to the blend from Step
1 with careful mixing after each addition. Such addirions
of water and mixing until the mass is of a consistency to
permit its conversion to wet granules.
Step 3 The we~ mass is converted tO granules by passing it
3 5 through an oscillating granulator using a ~o. 8 mesh (.3S
mm) screen.
6 2
WO 91/16889 . `: `, ` . i ~ PCr/US91~02884
23
Step 4 The wet granules are the~n dried in an oven at 410F
(60C) unlil dry.
Step 5 The dry granules are lubricated with ingredient No. S.
Step 6 The lubricated granules are compressed on a suitable
tablet press.
Tn~ nts Pçr ~u~ P~r lQ00 Su~p.
1. Formula I compound40.0 mg 40 g
Active ingredient
2. Polyethylelle Glycol 1350.0 mg 1,350 g
1000
3. polyethylene glycol ~
4000 1 840.0 mg 1 ,840 g
Procedure:
Step 1. Melt ingredient No. 2 and No. 3 cogether and s~ir until
uniform .
20 Step 2. Dissolve ingredient No. 1 in the molten mass from Step 1
and stir until uniform.
Step 3. Pour the molten mass from Step 2 into supository moulds
and chill.
Step 4. Remove ~he suppositories from rnoulds and wrap.
