EP0528957A1 - Antagonistes de leucotriene sous forme d'acide alcanoique a anneau de cinq membres - Google Patents

Antagonistes de leucotriene sous forme d'acide alcanoique a anneau de cinq membres

Info

Publication number
EP0528957A1
EP0528957A1 EP91910099A EP91910099A EP0528957A1 EP 0528957 A1 EP0528957 A1 EP 0528957A1 EP 91910099 A EP91910099 A EP 91910099A EP 91910099 A EP91910099 A EP 91910099A EP 0528957 A1 EP0528957 A1 EP 0528957A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
compound
pharmaceutically acceptable
phenyl
acceptable salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP91910099A
Other languages
German (de)
English (en)
Other versions
EP0528957A4 (en
Inventor
James Simpson Frazee
John Gerald Gleason
Ralph Floyd Hall
Irene Nijole Uzinskas
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of EP0528957A1 publication Critical patent/EP0528957A1/fr
Publication of EP0528957A4 publication Critical patent/EP0528957A4/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • This invention relates to heteroaromatic five-memembered ring alkanoic acid derivatives which are useful for treating diseases associated with leukotrienes.
  • SRS-A 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 ch lenge.
  • 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 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.
  • SRS-A derived from mouse, rat, guinea pig and man have alL been characterized as mixtures of leukotriene-C4 (LTC4), leukotriene-D4 (LTD4) and leukotriene-E4 (LTE4).
  • both the peptide and non-peptide leukotrienes exert microcirculatory actions, 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 endothelial membrane.
  • LTD4 and LTE4 stimulate a variety of. types of muscles.
  • LTC4 and LTC4 stimulate a variety of. types of muscles.
  • LTD4 potent bronchoconstrictors and effective stimulators of vascular smooth muscle. This vasoconstrictor effect has been shown to occur in pulmonary, coronary, cerebral, renal, and mesenteric vasculatures.
  • Leukotrienes have been implicated in a number of pulmonary diseases. Leukotrienes are known to be potent bronchoconstrictors in 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., Proc. Nat'l. Acad. Sci. USA. 77, 7, 4354-4358 ( 1980 )]. LTC4 and LTD4 have been shown to increase the release of mucous from human airways in vitro. [See Marom, Z. et al., Am. Rev. Res p ir. Pis... 126, 449-451 (1982).] The leukotriene antagonists of the present invention can be useful in the treatment of allergic or non-allergic bronchial asthma or pulmonary anaphylaxis.
  • 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. Another area of utility for leukotriene antagonists is in the treatment of cardiovascular diseases. Since peptide leukotrienes are potent coronary vasoconstrictors, they are implicated in a variety of cardiac depression. Synthetic leukotrienes have been shown to be powerful myocardial depressants, their effects consisting of a decrease i contractile force and coronary flow. The cardiac effects of
  • LTC4 and LTD4 have been shown to be antagonized by a specific leukotriene antagonist, thus suggesting usefulness of leukotriene antagonists in the areas of myocardial depression and cardian anaphylaxis. [See Burke, J.A., et al., J. Pharmacology and Experimental Therapeutics. 221, 1, 235-241 (1982).]
  • 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..
  • R ⁇ is not substituted on A or B;
  • X is 0 or S(0) q where q is 0, 1 or 2 with the proviso that Rj is not alkylthio or phenylthioalkyl when q is 1 or 2;
  • Rl is C8 to C13 alkyl, C7 to C12 alkoxy, C7 to C12 alkylthio, C ⁇ o to C12 1-alkynyl, 10-undecynyloxy, 11-dodecynyl, phenyl-C4 to Ci 0 alkyl, phenyl-C3 t0 C9 alkoxy, phenylthio-C3 to Co alkyl with each phenyl optionally mono substituted with bromo, chloro, trifluoromethyl, Ci to C4 alkoxy, methylthio or trifluoromethylthio, furyl-C4 to C10 alkyl, trifluoromethyl-C to C12 alkyl or cyclohexyl- C4 to C10 alkyl;
  • A is S, O, or N;
  • B is CH or NR2
  • R2 is H, Ci to C 1 3 .alkyl, C10 to C ⁇ 2 - 1-alkynyl, 11 -docedynyl, phenyl-C4 to C 10 alkyl with phenyl optionally monosubstituted or
  • Y is R3, CH(R4)(CH2) m R 3> CH(R4)-tetrazol-5-yl, or tetrazol-5-yl;
  • R3 is -COR5 where R5 is -OH or OX where X is a pharmaceutically acceptable cation or a pharmaceutically acceptable ester-forming group, -CN, -SO3H, -SO2NH2, -NHSO2R7, -CH(NH 2 )COR 5 , or -NHCH2COR5, or R3 is -N(Rg)2 where Re is H, Ci to C ⁇ alkyl, phenylCi-C ⁇ alkyl, or the two R$ groups are combined to form a cyclic group having 3 to 5 carbons;
  • R4 is hydrogen, methyl, Cj to C4 .alkoxy, fluoro or hydroxy
  • R7 is Ci to Cio-alkyl, phenyl or substituted phenyl; m is 0, 1, or 2;
  • R is -(CH2) n D, -(CH2) n A ⁇ D or ArD where n is 0-6, Ar is phenyl or substituted phenyl, thienyl, pyridyl, imidazolyl, tetrazol-5-yl or thiazolyl and D is -(CH2) n R3, -COR3, tetrazol-5-yl, -CH(NH2)Rs, -NHCH2COR5, -NHSO2R7, -SO3H, -CN, or -SO2NH2; or a pharmaceutically acceptable salt.
  • phenylthioalkyl is used to mean the thioether radical where phenyl is bonded to sulfur which is bonded to the alkyl moiety, the radical of the formula
  • a preferred class of compounds of this invention are the substituted alkanoic acid analogs of formula (I) where X is S(0) q where q is 0 and Y is -(CH2 ⁇ -3 OOH represented by formula (II)
  • R and R are the same as described above, A is S, O or N and B is CH or NR2.
  • the most preferred class of these compounds are those where X is S, R is -(CH2) n D, -(CH2) n ArD or ArD, Y is -CH2COOH, A X-R is S, O, or N, and B is CH or -NR2 where the group - ⁇ " ⁇ Y is not R2, and
  • R l is C ⁇ to Ci3-alkyl or phenyl-C 4 to Cio-alkyl. The most preferred
  • X-R compounds in this category are where *" ⁇ Y is at the 2-position:
  • a further particular group of compounds of this invention are those where X is S, Y is -C(OH)HCOR3, R is -(CH2) n D, -(CH2) ⁇ ArD or ArD Rl is C ⁇ to Ci3-alkyl or phenyl-C4 to Cio-alkyl, A is S, 0, or N and B is
  • X-R compounds of this group are those where " ⁇ Y is at the 2-position: 3 -(2-carboxyethylthio)-3-(3 -dodecylthien-2-yI)-2- hydroxypropionic acid;
  • Another preferred class of compounds of this invention are the compounds where Y is (CH2)o-i-tetrazol-5-yl or -CH(OH)-tetrazol-5-yl.
  • X is S
  • R is -(CH 2 ) n D.
  • A is O
  • B is -CH- or NR
  • X-R to Cio-alkyl are those where '" ' ⁇ is at the 2-position, :
  • a second class of preferred compounds are those where X is O, particularly those paralleling the preferred and most preferred definitions 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-2-yl)propionic acid 3-(2-carboxyethyloxy)-3-[3-(8-phenyloctyl)thien-2-yl] - propionic acid; 3-(2-carboxyethyloxy)-3-( l -dodecyl- lH-imidazol-2-yl) propionic acid;
  • All compounds of this invention have at least one assymetric center due to X being sulfur or oxygen.
  • Some of the compounds of th formula (I) contain two asymmetric centers, such as when R4 in the sustituent is other than hydrogen, such as is methyl, methoxy, fluoro or hydroxy.
  • Other asymetric centers may also be present in these molecules depending on the selection of substituents in any given compound.
  • these compounds are prepared as a mixture stereoisomers. All steroisomers, as mixtures or resolved isomers, are included in this invention. Resolution procedures employing, for example, optically active amines furnish the separated enantiomers.
  • esters may be formed from those compounds having a carboxylic acid function ie when R has the -COR3 terminal group.
  • Such an ester, or di-ester as the case may be will be any ester which, as with pharmacuetically acceptable suits, gives an ester which retains the activity of the parent compound and does not impart to the parent acid any unacceptable untoward pharmacologic or toxic affects in the context of its intended use and application.
  • esters derived from the following radicals: Ci to C ⁇ alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, alkylarylalkyl, aminoalkyl, indanyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, or thienylglycyloxymethyl.
  • the compounds of the present invention are capable of forming pharmaceutically acceptable salts with acids and bases according to procedures well known in the an.
  • 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 acid.
  • Bases include organic and inorganic bases, such as ammonia, arginine, organic amines, alkali metal bases and alkaline earth metal bases. Piperazine 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 formula (I).
  • Pharmaceutically acceptable cations are the same as the just recited base-derived pharmaceutically acceptable salts.
  • the compounds of die formula (I) wherein Y is CH2CO2H are prepared by reacting the appropriate aldehydes of the formula VI or VII, wherein R , R2 and A are as described above 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 with a substituted thiol in trifluoroacetic acid.
  • a mixture of trimethyl borate and zinc in tetrahydrofuran may be used to prepare the 3-hydroxypropionate derivative.
  • compounds of formula (I) are prepared from the aldehydes VI or VII by reaction with lithium diisopropylamide and t-butyl acetate at - 78°C to 25°C in a suitable solvent such as, for example, THF, to provide the precursor esterified 3-hydroxypropionate derivatives which are converted to the thiol acids with a mercaptan in trifluoroacetic acid.
  • a suitable solvent such as, for example, THF
  • the aldehyde precursors to the compounds of the formula (I) wherein Ri is, for example, an alkyl radical containing 8 to 13 carbon atoms are prepared from the appropriate 2-methoxyphenyl-4,4- dimethyloxazoline [see Meyers et al. J. Or?. Chem.. 43. 1372 (1978)].
  • the aldehyde precursors to the compounds of the formula (I) wherein Ri is a 1-alkynyl radical containing 10 to 12 carbon atoms are prepared by coupling a halobenzaldehyde with the appropriate 1 - alkyne in the presence of cuprous iodide and (P ⁇ 3)2PdCl2- [See
  • the compounds of the formula (I) wherein Y is CH2CO2H are prepared from a propionate precursor of the following structural formulas (VIII) and (IX).
  • R ⁇ $ is an ester protective group, such as t-butyl.
  • a compound of formula (VIII) or (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, products of formula (I).
  • the propionate precursors of formula (VIII) or (IX) are prepared from the corresponding aldehydes of formulas (VI) and (VII) by general procedures such as reaction with an alkyl
  • the propenoate precursor is obtained from a 3-methane- 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
  • R ⁇ , R2, A and m are the same as described above, and R g is
  • a compound of formula (X) or (XI) is reacted in an inert solvent with triethylamine and a substituted thiol selected to give, after removal of ester protective groups, a product of formula (I).
  • the epoxide precursors of formula (X) or (XI) where m is 0 are prepared by reaction of an aldehyde of the formula (VI) or (VII) with a lower alkyl chloroacetate and an alkali metal alkoxide, such as sodium methoxide.
  • 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.
  • these reactants bearing a carboxyl or carboxymethyl substituent as set forth in Rg and R9 above are employed as the corresponding carboalkoxy derivatives wherein the alkoxy radical contains from one to six carbon atoms.
  • the alkoxy substituent is subsequently hydrolyzed to give the free carboxyl or carboxymethyl substituted products.
  • 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.
  • the following methodology was 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 continuously aerated with 95% 02/5 CO2. The tissues were connected via 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 mM) 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 generated by successive increases in the bath concentration of .the LTD4.
  • the contractions elicited by LTD4 were standardized as a percentage of the maximum response obtained to a reference agonist, carbachol (10 mM).
  • the concentration of LTD4 needed to elicit 30% of the contraction elicited by carbachol was measured and defined as the EC30.
  • the -log Kg value for the test compound was determined by the following equations:
  • the compounds of this invention possess antagonist activity against leukotrienes, primarily leukotriene D4.
  • the antagonist activity of representative compounds of this invention is tabulated below.
  • the -log K ⁇ values were calculated from the above test protocols. Where compounds were tested more than once, the -log K ⁇ values given herein represent the current average data.
  • Compound 3- (2-carboxyethylthio-3-(3-dodecylthien-2-yl)propionic acid at a molar concentration of 10' 5 showed a pK ⁇ of 6.5 in comparison to a pK ⁇ of
  • 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.
  • 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.
  • examples of appropriate pharmaceutical carriers or diluents include: for aqueous systems, water; for non- aqueous systems, 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, dichlorodifluoromethane, chlorotrifluoroethane and compressed carbon dioxide.
  • the instant compositions may include other ingredients such as stabilizers.
  • compositions and the pharmaceutical carrier or diluent will, of course, depend upon the intended route of administration, for example parenterally, topically, orally or by inhalation.
  • the compositions will be in a form suitable for administration by inhalation.
  • the compositions will comprise a suspension or solution of the active ingredient in water for administration by means of a conventional nebulizer.
  • 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 die solid active ingredient diluted with a solid diluent for administration from a powder inhalation device.
  • 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.
  • the pharmaceutical composition will be in the form of a sterile injectable liquid such as an ampul or an aqueous or nonaqueous liquid suspension.
  • 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.
  • the pharmaceutical composition will be in the form of a tablet, capsule, powder, pellet, atroche, lozenge, syrup. liquid, or emulsion.
  • 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.
  • the dosage of the composition is selected from the range of from 350 mg to 1000 mg of active ingredient for each administration.
  • equal doses will be administered 1 to 5 times daily with the daily dosage regimen being selected from about 350 mg to about 5000 mg.
  • a disease which comprises administering to a subject a therapeutically effective amount of a compound of formula I, preferably in the form of a pharmaceutical composition.
  • a therapeutically effective amount of a compound of formula I preferably in the form of a pharmaceutical composition.
  • the administration may be carried out in dosage units at suitable intervals or in single doses as needed. Usually this memod will be practiced when relief of symptoms is specifically required. However, the method is also usefully carried out as continuous or prophylactic treatment. It is within the 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.
  • compositions, as described hereinabove, of the present invention also comprise a pharmaceutical carrier or diluent and a combination of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, and an histamine Hi - receptor antagonist in amounts sufficient to inhibit antigen- induced respiratory anaphylaxis.
  • a pharmaceutical carrier or diluent and a combination of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, and an histamine Hi - 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 H -receptor antagonist.
  • the methods of administration described above for the single active ingredient can similarly be employed for the combination with a histamine Hi -receptor antagonist.
  • Lithium diisopropyl amide was prepared by the addition of n-butyl lithium (1.1 mL of 2.5 M in hexanes) to a solution of diisopropylamine (288 mg, 2.85 mmole) in THF (5 mL) held at -78 °C under an argon atmosphere. After being stirred for 5 minutes, t-butyl acetate (330 mg, 2.85 mmole) in THF (5 mL) was then added dropwise, and the resulting solution was stirred at -78°C for 15 minutes.
  • Civ methyl 2-hvdroxy-3-f2-carbomethoxyethylthio-3- ⁇ - dodecylimidazol-2-vDpropionate Civ methyl 2-hvdroxy-3-f2-carbomethoxyethylthio-3- ⁇ - dodecylimidazol-2-vDpropionate.
  • a solution of trans 2-carbomethoxy-3-(l -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.
  • Example 3 3-( 2-Carboxyethylthio')-3-f2-dodecylthien-3-vPpro ⁇ ionic acid
  • the title compound is prep.ared by the method described in Example l(i-vii) by using 2-methyl-3-thiophenecarboxylic acid in place of 3-methyl-2-thiophenecarboxylic acid.
  • Example 5 3-('2-CarboxyethylthioV3-r3- 8-phenyloctyl ' )thien-2-vI1propionic acid
  • the title compound is synthesized from 3-(8-phenyloctyI)-2- thiophenecarboxaldehyde, prepared from 4,4-dimethyl-2-[2-(3- methoxythienyl oxazoline and 8-phenyloctyl bromide following the procedure given in EPO application No. 0 202 759 published 26 November, 1986.
  • Example 2(ii) l -dodecylimidazol-2- carboxaldehyde [Example 2(ii)] in the method outlined in Example l(vi-vii) for 3-dodecyl-2-thiophenecarboxaldehyde.
  • Example l(vi-vii) by using 1 -(8-phenyloctyl)- lH-imidazole-2- carboxaldehyde [which is prepared 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.
  • Example 8 3-f2-Carboxyethylthio)-3- ⁇ -dodecylthien-2-yl- 2-hvdroxypropionic acid
  • the title compound is prepared by the method described in Example 2(iii-v) by using 3-dodecyl-2-thiophenecarboxaldehyde in place of l -dodecylimidazole-2-carboxaldehyde.
  • the title compound is prepared by the method described in Example 2(iii-v) by using 3-dodecyl-2-furancarboxaldehyde in place of 1 -dodecylimidazole-2-carboxaldehyde.
  • the title compound is prepared from 3-dodecyl-2- thiophenecarboxaldehyde by condensation with ethyl 2-(tetrazol-5- yl) acetate (as per EPO application No. 0 202 759 published 26 November, 1986) after which the condensation product is oxidized to methyl 3-(3-dodecylthien-2-yl-3-keto-2-(tetrazol-5-yl)propionate by manganese dioxide in refluxing toluene.
  • This ⁇ -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 methanol to provide the 3-hydroxy derivative, and the title compound is obtained on treatment with 3-mercaptopropionic acid in trifluoroacetic acid as described in Example l(vii).
  • Example 11 4-Thia-5- ⁇ -dodecyl- l H-imidazol-2-yl ' .-6-ftetrazol-5-yDhexanoic acid
  • the title compound is prepared by the method described in Example 10 by using l -dodecylimidazole-2-carb ⁇ xaldehyde in place of 3-dodecyl-2-thiophenecarboxaldehyde.
  • the title compound is prepared from methyl 2-chloro-2-(3- dodecylthien-2-yI)acetate by reaction with methyl 4-hydroxy- benzoate and potassium carbonate in dimethylformamide followed by saponificatio ⁇ of the diester.
  • Step 1 Blend ingredients No. 1, No. 2, No. 3 and No. 4 in a suitable mixer/blender.
  • S ep 2 Add sufficient water portion- wise to the blend from Step
  • Step 3 The wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.3S mm) screen.
  • Step 4 The wet granules are then dried in an oven at 410°F
  • Step 5 The dry granules are lubricated with ingredient No. 5.
  • Step 6 The lubricated granules are compressed on a suitable tablet press.
  • Step 1 Melt ingredient No. 2 and No. 3 together and stir until uniform.
  • 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 the suppositories from moulds and wrap.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Epidemiology (AREA)
  • Pulmonology (AREA)
  • Vascular Medicine (AREA)
  • Immunology (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Composés d'acide alcanoïque possédant un anneau hétérocyclique à cinq membres et un substituant thio, et utiles en tant qu'antagonistes de leucotriène.
EP19910910099 1990-05-01 1991-04-26 Five-membered ring alkanoic acid leukotriene antagonists Withdrawn EP0528957A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US51712090A 1990-05-01 1990-05-01
US517120 1990-05-01

Publications (2)

Publication Number Publication Date
EP0528957A1 true EP0528957A1 (fr) 1993-03-03
EP0528957A4 EP0528957A4 (en) 1993-05-05

Family

ID=24058448

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19910910099 Withdrawn EP0528957A4 (en) 1990-05-01 1991-04-26 Five-membered ring alkanoic acid leukotriene antagonists

Country Status (5)

Country Link
EP (1) EP0528957A4 (fr)
JP (1) JPH05507082A (fr)
AU (1) AU7902991A (fr)
CA (1) CA2081462A1 (fr)
WO (1) WO1991016889A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7659409B2 (en) 2002-03-19 2010-02-09 Mitsubishi Chemical Corporation 3-Hydroxy-3-(2-thienyl) propionamides and production method thereof, and production method of 3-amino-1-(2-thienyl)-1-propanols using the same
EP1486493A4 (fr) * 2002-03-19 2007-04-04 Mitsubishi Chem Corp Compose de 3-hydroxy-3-(2-thienyl)propionamide, procede de fabrication correspondant, et procede de fabrication d un compose de 3-amino-1-(2-thienly)1-propanol a partir de ce dernier
DE10212301A1 (de) * 2002-03-20 2003-10-02 Bayer Ag Verfahren zur Herstellung von Aryl-aminopropanolen

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4609744A (en) * 1983-04-21 1986-09-02 Merck Frosst Canada Inc. 4-oxo-benzopyran carboxylic acids
US4730005A (en) * 1984-01-19 1988-03-08 Smithkline Beckman Corporation Leukotriene antagonist
AU595193B2 (en) * 1985-04-19 1990-03-29 Smithkline Beckman Corporation Thio substituted acidic derivatives
AR245119A1 (es) * 1988-08-22 1993-12-30 Merrell Dow Pharma Procedimiento para preparar un grupo de fenilalquiltiofenos que estan sustituidos adicionalmente con un grupo acido tiadicarboxilico.
US4954513A (en) * 1988-12-23 1990-09-04 Smithkline Beecham Corporation Leukotriene antagonists

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
No further relevant documents disclosed *
See also references of WO9116889A1 *

Also Published As

Publication number Publication date
WO1991016889A1 (fr) 1991-11-14
CA2081462A1 (fr) 1991-11-02
JPH05507082A (ja) 1993-10-14
EP0528957A4 (en) 1993-05-05
AU7902991A (en) 1991-11-27

Similar Documents

Publication Publication Date Title
US4785004A (en) Aromatic thioethers
CA1334200C (fr) Antagonistes du leucotriene
EP0528957A1 (fr) Antagonistes de leucotriene sous forme d'acide alcanoique a anneau de cinq membres
JPH02124869A (ja) ロイコトリエン拮抗剤のエステルプロドラッグ
US4996214A (en) Quinolinyl substituted phenyl/thioalkanoic acid substituted propionic acids and leucotriene antagonist use thereof
EP0410241B1 (fr) Dérivés d'acides arylalcénoiques à titre d'antagonistes du leucotriène
EP0548291A1 (fr) Acides pyridylthio ou pyridyloxy alcanoiques
AU610528B2 (en) Leukotriene antagonists
EP0296731B1 (fr) Antagonistes de leukotriène
US5314918A (en) Leukotriene antagonists
EP0403249B1 (fr) Antagonistes de leucotriène
US5143931A (en) Leukotriene antagonists containing tetrazolyl groups
AU7769491A (en) 3-naphthyl-3-carboxyalkylthio or oxy substituted alkanoic acid leukotriene antagonists
CA1314654C (fr) Antagonistes des leucotrienes
US5189226A (en) Ortho-substituted benzaldehydes
IE60494B1 (en) Leukotriene antagonists
IE912180A1 (en) Chemical compounds
EP0532674A1 (fr) Antagonistes de leucotrienes

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19921112

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE

A4 Supplementary search report drawn up and despatched

Effective date: 19930315

AK Designated contracting states

Kind code of ref document: A4

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE

17Q First examination report despatched

Effective date: 19930630

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19931031