EP0532674A1 - Antagonistes de leucotrienes - Google Patents

Antagonistes de leucotrienes

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Publication number
EP0532674A1
EP0532674A1 EP91912310A EP91912310A EP0532674A1 EP 0532674 A1 EP0532674 A1 EP 0532674A1 EP 91912310 A EP91912310 A EP 91912310A EP 91912310 A EP91912310 A EP 91912310A EP 0532674 A1 EP0532674 A1 EP 0532674A1
Authority
EP
European Patent Office
Prior art keywords
compound
mmol
acid
phenyloctyl
mixture
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Withdrawn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
EP91912310A
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German (de)
English (en)
Other versions
EP0532674A4 (en
Inventor
John Gerald Gleason
Ralph Floyd Hall
Irene Uzinskas
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Publication of EP0532674A1 publication Critical patent/EP0532674A1/fr
Publication of EP0532674A4 publication Critical patent/EP0532674A4/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • C07D333/26—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • SRS-A LEUKOTRIENE ANTAGONISTS BACKGROUND OF THE INVEN ⁇ ON "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 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), the structural formulae of which are represented below.
  • the compounds and pharmaceutical compositions of the instant invention are valuable in the treatment of diseases in subjects, including human or animals, in which leukotrienes are a factor.
  • R l is (L) a -(CH2) b -(T) c -B wherein a is 0 or 1; b is 3 to 14; c is 0 or 1; L and T are independently oxygen, sulfur, or CH 2 with the proviso that L and T are not sulfur when q is 1 or 2;
  • B is Ci- 4 alkyl, ethynl, trifluoromethyl, isopropenyl, furanyl, thienyl, cyclohexyl, or phenyl optionally monosubstituted with Br, Cl, CF3, C 1 - 4 alkyl, C 1 -4 alkoxy, methylthio, or trifluoromethylthio;
  • R2 and A are independently selected from H, CF3, C 1 -4 alkyl, C 1 - 4 alkoxy, F, Cl, Br, I, OH, NO2 or NH 2 ; or
  • R l and A are H and R 2 is (L) a -(CH 2 ) b -(T) c -B wherein a, b, c, L, T, and B are as defined above;
  • Y is COR3 or (CHX) n (CH 2 ) p -Z wherein R3 is OH, NH 2 , aryloxy or Ci- 6 alkoxy; p is 0 or 1; x is H, OH, C 1 - 4 alkyl, C 1 - 4 alkoxy, or F; and Z is COR3, or tetrazolyl; R is
  • s m is 0 to 6, but m is 1 to 6 when w is imidazole;
  • R 4 and R5 are independently hydrogen or C 1 - 4 alkyl at any position when m is not 0;
  • W is a 5-membered ring heteroaryl group selected from tetrazolyl, thiazolyl, triazolyl, thienyl, furyl, oxazolyl, thiadiazolyl, pyrrolyl, imidazolyl or pyrazolyl, unsubstituted or substituted with one to three of the group
  • R 4 and R5 are as defined above; j is 0 to 6; and V is hydrogen, C 1 - 4 alkyl, COR 3 , SO3H, S0 H, S0 2 NH 2 , COCH 2 OH,
  • This invention further relates to the ester or diester derivatives of the compounds of Formula (I).
  • This invention includes all stereoisomers, racemates, or mixtures thereof.
  • W can be 1,2,3-triazole; 1,3,4-triazole; 1,2,3-thiadiazole, 1,3,4-thiadiazole, and other possible steroisomers.
  • This invention further relates to pharmaceutical compositions comprising a pharmaceutical carrier or diluent and a nontoxic amount of the compound of formula (I). Such compositions are useful for inhibiting the effects of leukotrienes and in treating diseases in which leukotrienes are a factor.
  • This invention further relates to pharmaceutical compositions comprising a pharmaceutical carrier or diluent and nontoxic amounts of a compound of formula (I) and a histamine Hj -receptor antagonist.
  • compositions are useful in inhibiting antigen-induced respiratory anaphylaxis.
  • This invention further relates to methods for inhibiting the effects of leukotrienes.
  • This invention also relates to methods for inhibiting antigen -induced respiratory anaphylaxis comprising administration of an effective amount of the above-described pharmaceutical compositions.
  • Ri is (L)a-(CH2)b-(T)c-B wherein a is 0 or 1; b is 3 to 14; c is 0 or 1;
  • L and T are independently oxygen, sulfur, or CH2 with the proviso that L and T are not sulfur when q is 1 or 2;
  • B is Cl-4 alkyl, ethynl, trifluoromethyl, isopropenyl, furanyl, thienyl, cyclohexyl, or phenyl optionally monosubstituted with Br, Cl, CF3, Cl-4 alkyl, Cl-4 alkoxy, methylthio, or trifluoromethylthio;
  • R2 and A are independently selected from H, CF3, Cl-4 alkyl, Cl-4 alkoxy, F, Cl, Br, I, OH, N02 or NH2; or
  • Rl and A are H and R2 is (L)a-(CH2)b-(T)c-B wherein a, b, c, L, T, and B are as defined above;
  • Y is COR3 or (CHX)n(CH2)p-Z wherein
  • R 3 is OH, NH2, aryloxy or Cl-6 alkoxy; n is 0 or 1; p is 0 or 1;
  • X is H, OH, Cl-4 alkyl, Cl-4 alkoxy, or F
  • Z is COR 3 , or tetrazolyl
  • n 0 to 6;
  • R 4 and R 5 are independently hydrogen or C 1 - 4 alkyl at any position when m is not 0;
  • W is thienyl substituted with one to three of the group
  • I 5 j is 0 to 6;
  • V is hydrogen, Cl-4 alkyl, COR 3 , S0 3 H, S0 2 H, S0 2 NH 2 , COCH 2 OH, CHOHCH 2 OH, or tetrazolyl, with R 3 as defined above; or a pharmaceutically acceptable salt thereof.
  • W can be 1,2,3-triazole; 1,3,4-triazole; 1,2,3-thiadiazole, 1,3,4-thiadiazole, and other possible steroisomers.
  • the compounds of this invention further comprise the ester and diester derivatives of the compounds of Formula (I).
  • the preferred compounds of this invention are those where m is 0, 1 or 2; thienyl is substituted with one of the groups
  • j is 0 or 1 and R 4 and R5 are hydrogen and V is COR 3 , SO 3 H, S0 2 H, SO 2 NH 2 , COCH 2 OH, CHOHCH 2 OH, or tetrazolyl, with R 3 as defined above; or a pharmaceutically acceptable salt thereof.
  • a subgeneric class of these compounds are those represented by structural formula (I) wherein Y is CO2H. Particular members of this subgeneric class are exemplified by the following compounds:
  • a second subgeneric class of these compounds are those represented by structural formula (I) where Y is CH2COOH.
  • Particular members of this subgeneric class are exemplified by the following compounds:
  • a third subgeneric class of these compounds are those represented by structural formula (I) where Y is CH(OH)COOH.
  • Y is CHXCOOH or derivatives of this acid such as its esters, amides and salts.
  • X is C ⁇ -C 4 alkoxy, particularly methoxy.
  • Exemplary compounds are:
  • Some of the compounds of formula (I) contain one or two asymmetric centers. This leads to the possibility of two or four stereoisomers for each compound.
  • the present invention includes all such stereoisomers, racemates, or mixtures thereof.
  • the compounds of the present invention are capable of forming salts with known pharmaceutically acceptable bases, according to procedures well known in the art.
  • acceptable bases include inorganic and organic bases, such as ammonia, arginine, organic amines, alkaline earth and alkali metal bases.
  • a compound of formula (II) 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 an appropriate thiol selected to give, after removal of ester protective groups, the desired product of formula (I).
  • the compounds of the formula (I) wherein Y is CH(X)C02H, wherein X is H, C1.4 alkyl, or Cj _4 alkoxy are prepared by reacting the appropriate aldehyde of the formula (II) 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-hydroxy-propionate derivative which is reacted directly with a substituted thiol in trifluoroacetic acid.
  • an esterified bromoacetate conveniently t-butyl bromoacetate
  • the compounds of the formula (I) wherin Y is CH(X)C ⁇ 2H wherein X is H, C1.4 alkyl, Cj _4 alkoxy, or fluoro are prepared from a propionate precursor of the following structural formula (IV)
  • RJ O is a conventional ester protective group, such as t-butyl or Cj -4 alkyl
  • RJ I is hydrogen, C ⁇ _4 alkyl, C1.4 alkoxy, or fluoro.
  • a compound of formula (IV) is reacted with a mixture of alkali metal alkoxide, such as sodium methoxide, and an appropriate thiol to give, after removal of the ester protective group, the desired product of formula (I).
  • the propionate precursors of formula (IV) are prepared from the corresponding aldehydes of formula (II) by general procedures such as reaction with an alkyl (triphenylphosphoranylidene)acetate or by conversion of the aldehyde to a 3-hydroxypropionate derivative, as described above, followed by an elimination reaction to form the double bond. Additionally, the propionate precusor is obtained from a 3-methanesulfonyloxypropionate derivative by treatment with triethylamine.
  • a compound of formula (V) is reacted in an inert solvent with triethylamine and the appropriate thiol selected to give, after removal of ester protective groups, a desired product of formula (I).
  • the epoxide precursors of formula (V) where p is 2 are prepared by reaction of the Grignard derivative of a bromobenzene compound of the formula (VI)
  • epoxide precursors of formula (V) where p is 1 can be prepared by Arndt-Eistert homologation of the compound where p is
  • the epoxide precursors of formula (V) where p is O are prepared by reaction of an aldehyde of the formula (II) with a lower alkyl chloroacetate and an alkali metal alkoxide, such as sodium methoxide in an appropriate solvent such as diethyl ether or methylene chloride.
  • a compound of formula (VII) 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, a product of formula (I).
  • the tetrahydro-4H-pyran-2-one precursors of formula (VII) are prepared by reaction of the Grignard derivative of the bromobenzene compound of formula (VI) with chlorotitanium triisopropoxide followed by reaction with 5-oxovalerate alkyl ester.
  • the aldehydes of the formula (II) are known or readily prepared utilizing the general procedures described as follows.
  • the aldehyde precursors to the compounds of the formula (I) wherein Rj is, for example, an alkyl radical containing 8 to 13 carbon atoms are prepared from the appropriate 2-alkylphenyl-4-,4- dimethyloxazoline [see Meyers et al. J. Org. Chem.. 43 1372 (1978)].
  • the aldehyde precursors of the compounds of the formula (I) wherein Ri 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 by standard methods.
  • the thioalkyl containing aldehyde precursors of the compounds of the formula (I) are prepared by the reaction of the appropriately substituted o-haloalkylthiobenzene (for example, a compound of formula (III):
  • the phenylthioalkyl containing aldehyde precursors of the compounds of the formula (I) are prepared by the reaction of the appropriately substituted haloalkylbenzaldehyde with a thiophenol and triethylamine. .
  • the heteroaryl mercaptan precursors necessary to prepare the compounds of formula (I) are known compounds and are conveniently prepared employing standard chemical reactions.
  • the mercapto derivatives of these precursors are prepared according to known methods. For example, 5-(2-mercaptoethyl)tetrazole can be prepared by adding ⁇ -merceptopropionitrile to a mixture of sodium azide and aluminium chloride in tetrahydrofuran.
  • 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:
  • the compounds of this invention possess biosignificant antagonist activity against leukotrienes.
  • the antagonist activ ' ty of representative compounds of this invention is tabulated below in Table I (other data appears in the preparative examples).
  • the -log KB values were calculated from the above test protocol. Where compounds were tested more than once, the -log K ⁇ values given herein represent the current average data.
  • R is 5 wherein R4 and R5 are H, W is optionally substituted with -(C)jR4R5-V; R2 and A are H; and q is O.
  • 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, such as symptoms of asthma and other hypersensitivity diseases.
  • 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 paraffins and mixtures thereof with water; for solid systems, lactose, kaolin and mannitol; and for aerosol systems, dichlorodifluoro- methane, chlorotrifluoroethane and compressed carbon dioxide propellants.
  • 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.
  • 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 the 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 ampule or an aqueous or nonaqueous liquid suspension.
  • a sterile injectable liquid such as an ampule or an aqueous or nonaqueous liquid suspension.
  • topical administration the pharmaceutical composition will be in the form of a cream or ointment.
  • a compound of formula I is administered to an animal subject, including humans, in a composition comprising a nontoxic amount sufficient to produce an inhibition of the symptoms of an allergic response.
  • the dosage of the composition is easily determined by those skilled in the art and are generally selected from the range of from 350 mg. to 700 mg. of active ingredient for each administration.
  • equal doses will be administered 1 to 4 times daily with the daily dosage regimen being selected from about 350 mg. to about 2800 mg.
  • the pharmaceutical preparations thus described are made following the conventional techniques of the pharmaceutical chemist as appropriate to the desired end product.
  • the method of inhibiting the symptoms of an allergic response which comprises administering to an animal subject a therapeutically effective amount for producing said inhibition 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 method will be practiced when relief of allergic 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 allergic condition being treated, and so forth.
  • Compounds of this invention alone and in combination with a histamine Hi -receptor antagonist, inhibit antigen induced contraction of isolated, sensitized guinea pig trachea (a model of respiratory anaphylaxis).
  • compositions, as described herein-above, 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 a histamine Hi - receptor antagonist in amounts sufficient to inhibit antigen-induced respiratory anaphylaxis.
  • histamine Hj -receptor antagonists include mepyramine, 2-[4-(5-bromo-3-methyl-pyrid-2- yl)butylamino]-5-[(6-methyl-pyrid-3-yl) methyl] -4-pyrimidone and other known Hj -receptor antagonists.
  • the above-defined dosage of a compound of formula I is conveniently employed for this purpose with the known effective dosage for the histamine Hj -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.
  • Example 1(c) The compound of Example 1(c) (17.2 mmol) was dissolved in methylene chloride (20 ml) and stirred at 0°C under argon. Zinc iodide (1.87 mmol) was added, followed by the dropwise addition of trimethylsilyl cyanide (2.45 ml, 18.3 mmoles) dissolved in methylene chloride (30 ml). After 1 hour at 0°C the ice bath was removed and the mixture stirred for 1 hour at room temperature. The solvent was stripped and methanol (100 ml) was added after the residue was cooled in an ice bath. Excess hydrogen chloride was bubbled into the solution while the mixture was stirred at ice bath temperature.
  • Example 1(d) The compound of Example 1(d) (12 mmol) was stirred under argon in an ice bath and thionyl chloride (20 ml) was added in a single portion. The ice bath was removed and the mixture was stirred under argon for 18 hours. The solvent was stripped and the residue was flash chromatographed on 200 grams of silica gel with 20% methylene chloride/carbon tetrachloride as eluant to give the product as a clear colorless liquid.
  • Example 2(a) The compound of Example 2(a) (260 mg, 0.52 mmol) was dissolved in 4.2 ml of methanol and stirred under argon in an ice bath. A IN solution of sodium hydroxide (2.1 ml, 2.1 mmol) was added. The ice bath was removed, and the mixture stirred for 1 hour at ambient temperature during which time a white precipitate formed. The methanol was evaporated and an additional 4 ml of water added to give a slightly turbid mixture which was stirred overnight at ambient temperature. The mixture was acidified with dilute hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and evaporated.
  • Example 3(a) The compound of Example 3(a) (411 mg, 0.82 mmol) was dissolved in 10 ml of methanol and stirred under argon in an ice bath. A 1 N solution of sodium hydroxide (3.2 ml, 3.2 mmol) was added dropwise, the ice bath removed and the mixture stirred overnight at ambient temperature. The solvent was stripped and the residue acidified with dilute hydrochloric acid at ice bath temperature. The crude product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and evaporated.
  • sodium hydroxide 3.2 ml, 3.2 mmol
  • 8-Phenyloctyl bromide was prepared from 8-phenyloctanol, carbon tetrabromide and triphenylphosphine in methylene chloride.
  • a solution of 8-phenyloctanoic acid (19.8 mmol) in sieve dried tetrahydrofuran (5 ml) was reduced with diborane in tetrahydrofuran (30 ml, 29.1 mmol) at 20°C for 4 hours to give 8- phenyloctanol.
  • diborane in tetrahydrofuran (30 ml, 29.1 mmol
  • Example 5(e) The compound of Example 5(e) (524 mg, 1 mmol) was dissolved in methanol (12 ml) and stirred under argon in an ice bath, A IN solution of sodium hydroxide (4 ml, 4 mmol) was added dropwise, the ice bath removed, and the mixture stirred overnight at room temperature. The solvent was stripped and the residue was cooled in an ice bath and acidified with dilute hydrochloric acid. The crude product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated.
  • Example 5(f) The compound of Example 5(f) (495 mg, 0.97 mmol) was treated with a solution of potassium carbonate (415 mg, 3 mmol) in 10 ml of water under argon at ice-bath temperature. The ice bath was removed and the mixture allowed to stir for 15 minutes at room temperature. The solution was then chromatographed on a Ci column; elution was with water to remove the excess base and then with 1:1 (acetonitrile:water). Lyophilization gave the desired compound (524 mg, 92%) as a white hygroscopic solid. Analysis for C27H32N4O4S 2K H2O - Calculated: C,53,62; H,5.67; N,9.26. Found: C53.81; H,5.51 ; N,9.36.
  • a 3 neck 100 ml round bottom flask equipped with a thermometer and stirring bar was cooled to -30°C using a dry ice- acetone bath followed by an ice-methanol bath.
  • the flask was charged with trifluoroacetic acid (20 ml) followed by 5-mercapto-l- (3-carboxypropyl)tetrazole (0.00128 mol, 0.1923 g).
  • the mixture was permitted to cool under argon for 10 minutes.
  • the reaction was stirred for 2 hours at 15°C and was permitted to warm to ambient temperature.
  • the trifluoroacetic acid was evaporated and the resulting oil was chromatographed on Ci 8 packing using 20% water in methanol with 1.0% formic acid to yield the desired product.
  • a solution of diethylaluminum chloride (0.0082 moles, 8.2 ml) in hexane was added to a slurry of zinc dust (0.0111 mol; 0.7248 g) and a catalytic amount of copper (I) bromide (0.0004 mol; 0.0585 g) in anhydrous tetrahydrofuran (40 ml) while stirring under argon at 20°C.
  • the resulting mixture was then cooled to -20°C in an ice- methanol bath.
  • the trifluoroacetic acid was evarporated and azeotroped with methylene chloride.
  • the resulting oil was chromatographed using 30% ethyl acetate in hexane with 0.5% formic acid to provide a 26% yield of desired product.
  • reaction mixture was taken up in hexane (50 ml) and washed with 10 percent sodium hydroxide (2 x 50 ml) and saturated sodium chloride (50 ml).
  • the organic phase was dried over anhydrous magnesium sulfate and charcoal. Evaporation of the volatiles yielded a colorless liquid which was purified by flash chromatography over silica gel with 2 percent ethyl acetate in hexane as eluant to afford the desired product as an oil.
  • Example 9(a) is converted to the desired product.
  • the following compounds are prepared according to the general methods described above from the appropriately substituted hydroxybenzaldehyde and the appropriate alkyl halide:
  • 2-(2-Dodecylthiophenyl)-2-[(l -carboxymethyl-5- tetrazolyl)thio]acetic acid is prepared from 2-(dodecyl- thio)benzaldehyde.
  • 2-(2-He ⁇ tylthio ⁇ henyl)-2-[(l -carboxymethyl-5- tetrazolyl)thio] acetic acid is prepared from 2-(heptylthio)benzaldehyde.
  • Example 5(c) through 5(g) the compound of Example 10(a) is converted to the desired product.
  • Example 12(b) To a solution of 10% sodium hydroxide (50 ml), methanol (12 ml) and ethylene glycol dimethyl ether is added the compound of Example 12(b) (93.9 mmol). The mixture is stirred for 24 hours at 25°C. The reaction mixture is then cooled in an ice-methanol bath to 0°C and is acidified with hydrochloric acid to pH 3.5, is extracted with diethyl ether, is dried over magnesium sulfate, filtered and evaporated. The resulting mixture of isomers is flash chromatographed on silica, and eluted with 30% ethyl acetate in hexane, to give the product.
  • Example 7(a) The compound of Example 7(a) (2.94 g, 10 mmol) was dissolved in diethyl ether (25 ml) and the solution was stirred under argon at 0°C. Methyl chloroacetate (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. A small quantity of water was added, the ether phase separated, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was flash chromatographed on 80 grams of silica gel eluted with 5-30% ethyl acetate/hexane to give the product. fc) Methyl 3-r2-f8-phenyloctyl)phenyll-3-rri -f3-carboxypropyl-5- tetrazolyll thiol -2-hydroxypropionate
  • Example 13(c) The compound of Example 13(c) (549 mg, 1.5 mmol) was dissolved in methanol (6 ml) containing 2% triethylamine and the solution was stirred under argon at room temperature.
  • the 5- mercapto-l -(3-carboxypropyl)tetrazole (282 mg, 1.5 mmol) and triethylamine (0.84 ml, 6 mmol) were dissolved in methanol (9 ml) and added dropwise to the reaction mixture which was then stirred for 5 days at room temperature.
  • Example 14(a) The methyl 2,3-epoxy-3-[2-(8-phenyloctyl)-phenyl]propanoate (0.4g) of Example 14(a) was dissolved in 5 ml of methanol containing 2% triethylamine under an argon atmosphere. The reaction mixture was cooled using an ice/methanol bath. A solution of 0.205 g of 5- mercapto-1-carbethoxymethyltetrazole and 0.61 ml of triethylamine in 5 ml of methanol containing 2% triethylamine was added. The bath was removed and the reaction was permitted to warm to room temperature.
  • Example 14(b) The methyl 2-hydroxy-3-[(l-carboxymethyl-5-tetrazolyl)thio]- propanoate (0.45 g) of Example 14(b) was dissolved in methanol (6.6 ml) and cooled with an ice and methanol bath to which was added 3.3 ml of a 4% solution of sodium hydroxide. The bath was removed and reaction permitted to warm to room temperature overnight. The methanol was then stripped, and the residue was diluted with dilute hydrochloric acid. Extraction with ethyl acetate was followed by drying over magnesium sulfate, filtration, and evaporation. The crude product was flash chromatographed on silica with 30-50% ethyl acetate/hexane. The column was washed with 100% methanol. 40 mg of desired product was recovered.
  • Example 5(d) The compound of Example 5(d) (744 mg, 2 mmol) is dissolved in 25 ml of methylene chloride and stirred under argon at room temperature.
  • Ethyl 5-mercapto-l,3,4-thiadiazole-2-carboxylate (380 mg. 2 mmol) and triethylamine (0.84 ml, 6 mmol) is dissolved in 25 ml of methylene chloride and added to the solution of the compound of Example 5(d). The mixture is stirred under argon for 48 hours. The solvent is evaporated, and the residue is flash chromatographed on silica gel eluted with ethyl acetate/hexane to give the product.
  • Example 16(a) The compound of Example 16(a) (526 mg, 1 mmol) is dissolved in 10 ml of methanol and stirred under argon in an ice bath. A IN solution of sodium hydroxide (4 ml, 4 mmol) is added. The ice bath is removed and the mixture is stirred for 24 hours at room temperature. The solvent is evaporated, the residue cooled in an ice bath, acidified with dilute hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and evaporated to give the product.
  • Example 17(a) The compound of Example 17(a) (494 mg, 1 mmol) is dissolved in 10 ml of methanol and stirred under argon in an ice bath. A IN solution of sodium hydroxide (4 ml, 4 mmol) is added. The ice bath is removed and the mixture is stirred for 24 hours at room temperature. The solvent is evaporated, the residue cooled in an ice bath, acidified with dilute hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and evaporated to give the product.
  • EXAMPLE 18 Preparation of 3-r2-(6-thiophenoxyhexylthio)phenyll- 3-rri -f3-carboxypropyl)-5-tetrazolynthio1-2- hydroxypropanoic acid fa) Preparation of 2-f6-thiophenoxyhexylthio)benzoic acid Thiosalicylic acid (1.2 g, 0.008 mole) and 6-thio- phenoxyhexylbromide (2.5 g, 0.009 mole) are dissolved in dimethylformamide (50 ml) and the solution is stirred under argon. Potassium carbonate (1.5 g, 0.011 mole) is added carefully to the reaction.
  • Example 18(c) The compound of Example 18(c) (10 mmol) is dissolved in diethyl ether (25 ml) and the solution is stirred under argon at 0°C. Methyl chloroacetate (15 mmol) is added followed by the addition of sodium methoxide (15 mmol). The mixture is stirred for 2.5 hours at ice bath temperature. A small quantity of water is added, the ether phase is separated, dried over anhydrous sodium sulfate, filtered, and evaporated. The residue is flash chromatographed on 80 grams of silica gel eluted with 5-30% ethylacetate/hexane to give the product. fe) Methyl 3-r2-f6-thiophenoxyhexylthio)phenyl1-3-rri -f3- carboxypropyl-5-tetrazolvnthio1-2-hvdroxypropionate
  • Example 18(d) The compound of Example 18(d) (1.5 mmol) is dissolved in methanol (6 ml) containing 2% triethylamine and the solution is stirred under argon at room temperature.
  • 5-Mercapto-l-(3- carboxypropyl)tetrazole (1.5 mmol) and triethylamine (6 mmol) are dissolved in methanol (9 ml) and are added dropwise to the reaction mixture which is then stirred for 5 days at room temperature.
  • the solvent is stripped and the residue is flash chromatographed on .50 grams of silica gel eluted with 70:30:1 (hexane: ethylacetate: formic acid) to give the desired product.
  • EXAMPLE 22 As a specific embodiment of a composition of this invention, an active ingredient, such as the compound of Example 4, 13, or 14 is dissolved in isotonic saline at a concentration of 1 to 10 mg/ml and aerosolized from a nebulizer operating at an air flow adjusted to deliver the desired aerosolized weight of drug.
  • EXAMPLE 23 As an additional embodiment of a composition of this invention 100 to 1000 mg of an active ingredient, such as the compound of
  • Example 4 13, or 14 is combined with 4 mg of chlorpheniramine maleate with a suitable carrier or excipient.

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Abstract

Composés d'acide alcanoïque dotés de substituants phényle et hétéroarylthio utiles comme antagonistes de leucotriènes et compositions pharmaceutiques contenant lesdits composés. L'invention concerne également des procédés de traitement de maladies dans lesquelles les leucotriènes constituent un facteur, par administration d'une dose efficace des composés ou compositions précités.
EP19910912310 1990-06-06 1991-06-04 Leukotriene antagonists Withdrawn EP0532674A4 (en)

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US533989 1990-06-06

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EP (1) EP0532674A4 (fr)
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AU (1) AU8208391A (fr)
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0296731A1 (fr) * 1987-06-24 1988-12-28 Smithkline Beecham Corporation Antagonistes de leukotriène
EP0296732A1 (fr) * 1987-06-24 1988-12-28 Smithkline Beecham Corporation Antagonistes de leukotriène
US4996214A (en) * 1990-06-28 1991-02-26 Smithkline Beecham Corporation Quinolinyl substituted phenyl/thioalkanoic acid substituted propionic acids and leucotriene antagonist use thereof

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Publication number Priority date Publication date Assignee Title
US4174405A (en) * 1974-02-25 1979-11-13 Uniroyal, Inc. Thiophenes useful in control of acarids
US4138410A (en) * 1974-07-24 1979-02-06 Firmenich & Cie Flavoring agent
IT1139455B (it) * 1981-09-21 1986-09-24 Montedison Spa Processo per la preparazione di acidi alfa-arilpropionici e loro sali alcalini
US4609744A (en) * 1983-04-21 1986-09-02 Merck Frosst Canada Inc. 4-oxo-benzopyran carboxylic acids
DE3700732A1 (de) * 1987-01-13 1988-07-21 Boehringer Mannheim Gmbh Neue carbonsaeurederivate, verfahren zu ihrer herstellung sowie arzneimittel, die diese verbindungen enthalten

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0296731A1 (fr) * 1987-06-24 1988-12-28 Smithkline Beecham Corporation Antagonistes de leukotriène
EP0296732A1 (fr) * 1987-06-24 1988-12-28 Smithkline Beecham Corporation Antagonistes de leukotriène
US4996214A (en) * 1990-06-28 1991-02-26 Smithkline Beecham Corporation Quinolinyl substituted phenyl/thioalkanoic acid substituted propionic acids and leucotriene antagonist use thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO9118889A1 *

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EP0532674A4 (en) 1993-04-07
WO1991018889A1 (fr) 1991-12-12
AU8208391A (en) 1991-12-31
CA2083610A1 (fr) 1991-12-07
JPH05507716A (ja) 1993-11-04

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