WO1993011768A1 - Composes a base de pyridyle destines au traitement du psoriasis - Google Patents

Composes a base de pyridyle destines au traitement du psoriasis Download PDF

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Publication number
WO1993011768A1
WO1993011768A1 PCT/US1992/010582 US9210582W WO9311768A1 WO 1993011768 A1 WO1993011768 A1 WO 1993011768A1 US 9210582 W US9210582 W US 9210582W WO 9311768 A1 WO9311768 A1 WO 9311768A1
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WIPO (PCT)
Prior art keywords
compound
salt
aliphatic
acid
methoxyphenyl
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PCT/US1992/010582
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English (en)
Inventor
Robert A. Daines
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Smithkline Beecham Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof

Definitions

  • This invention relates to the use of certain heterocycle-substituted pyridine compounds useful for treating diseases arising from or related to leukotrienes, particularly leukotriene B4. As such there utility lies in antagonizing the affects of leukotrienes.
  • the family of bioactive lipids known as the leukotrienes exert pharmacological effects on respiratory, cardiovascular and gastrointestinal systems.
  • the leukotrienes are generally divided into two sub-classes, the peptidoleukotrienes (leukotrienes C4, D4 and E4) and the dihydroxy leukotrienes (leukotriene B4).
  • This invention is primarily concerned with the hydroxyleukotrienes (LTB) but is not limited to this specific group of leukotrienes.
  • the peptidoleukotrienes are implicated in the biological response associated with the "Slow Reacting Substance of Anaphylaxis" (SRS-A). This response is expressed in vivo as prolonged bronchoconstriction, in cardiovascular effects such as coronary artery vasoconstriction and numerous other biological responses.
  • SRS-A Slow Reacting Substance of Anaphylaxis
  • the pharmacology of the peptidoleukotrienes include smooth muscle contractions, myocardial depression, increased vascular permeability and increased mucous production.
  • LTB4 exerts its biological effects through stimulation of leukocyte and lymphocyte functions. It stimulates chemotaxis, chemokinesis and aggregation of polymorphonuclear leukocytes (PMNs).
  • PMNs polymorphonuclear leukocytes
  • Leukotrienes are critically involved in mediating many types of cardiovascular, pulmonary, dermatological, renal, allergic, and inflammatory diseases including asthma, adult respiratory distress syndrome, cystic fibrosis, psoriasis, and inflammatory bowel disease.
  • Leukotriene B4 was first described by Borgeat and Samuelsson in 1979, and later shown by Corey and co-workers to be 5(S),12(R)-dihydroxy- (Z,EJE,Z)-6,8,10,14-eicosatetraenoic acid.
  • LTB4 It is a product of the arachidonic acid cascade that results from the enzymatic hydrolysis of LTA4. It has been found to be produced by mast cells, polymorphonuclear leukocytes, monocytes and macrophages. LTB4 has been shown to be a potent stimulus in vivo for PMN leukocytes, causing increased chemotactic andchemokinetic migration, adherence, aggregation, degranulation, superoxide production and cytotoxicity. The effects of LTB4 are mediated through distinct receptor sites on the leukocyte cell surface that exhibit a high degree of stereospecificity.
  • LTB4 has been established as an inflammatory mediator in vivo. It has also been associated with airway hyper-responsiveness in the dog as well as being found in increased levels in lung lavages from humans with severe pulmonary dysfunction.
  • the compounds and pharmaceutical compositions of this invention are valuable in the treatment of diseases in subjects, including human or animals, in which leukotrienes are a factor.
  • This invention relates to compounds of formula I
  • Z is O, NH, NCH3 or S(O) q where q is 0, 1 or 2; m is 1 - 8; R is C to C20-a ⁇ ph tic, unsubstituted or substituted phenyl-Cj to C Q- aliphatic where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo, or R is C ⁇ to C20- aliphatic-O-, or R is unsubstituted or substituted phenyl-C ⁇ to CiQ-aliphatic-O- where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo;
  • Rl is R2, - Ci to C5 aliphatic)R2, -(Ci to C5 aliphatic)CHO, -(Ci to C5 aIiphatic)CH2OR3; R2 is tetrazol-5-yl or COOH or a salt, ester or amide thereof; and
  • R3 is H or lower alkyl.
  • this invention relates to compositions comprising a compound of formula I, or a salt thereof, in admixture with a carrier. Included in these compositions are those suitable for pharmaceutical use and comprising a pharmaceutically acceptable excipient or carrier and a compound of formula I which may be in the form of a pharmaceutically acceptable salt.
  • Processes for making these compounds are also included in the scope of this invention, which processes comprise: a) forming a salt, or b) forming an ester; c) oxidizing a thio ether to the sulfoxide or sulfone; d) forming a compound of formula I by treating a 6-halomethylpyridyl compound with the appropriate mercaptan, or hydroxy compound.
  • “Aliphatic” is intended to include saturated and unsaturated radicals. This includes normal and branched chains, saturated or mono or poly unsaturated chains where both double and triple bonds may be present in any combination.
  • the phrase “lower alkyl” means an alkyl group of 1 to 6 carbon atoms in any isomeric form, but particularly the normal or linear form.
  • “Lower alkoxy” means the group lower alkyl-O-.
  • “Acyl-lower alkyl” refers to the group (O)C-lower alkyl where the carbonyl carbon is counted as one of the carbons of the 1 to 6 carbons noted under the definition of lower alkyl.
  • “Halo” refers to and means fluoro, chloro, bromo or iodo. The phenyl ring may be substituted with one or more of these radicals.
  • substituents may be the same or different, such as where there are three chloro groups, or a combination of chloro and alkyl groups and further where this latter combination may have different alkyl radicals in the chloro/alkyl pattern.
  • a pharmaceutically acceptable ester-forming group covers all esters which can be made from the acid function(s) which may be present in these compounds.
  • the resultant esters will be ones which are acceptable in their application to a pharmaceutical use. By that it is meant that the mono or diesters will retain the biological activity of the parent compound and will not have an untoward or deleterious effect in their application and use in treating diseases.
  • Amides may be formed from acid groups.
  • the most preferred amides are those where the nitrogen is substituted by hydrogen or alkyl of 1 to 6 carbons. The diethylamide is particularly preferred.
  • salts of the instant compounds are also intended to be covered by this invention. These salts will be ones which are acceptable in their application to a pharmaceutical use. By that it is meant that the salt will retain the biological activity of the parent compound and the salt will not have untoward or deleterious effects in its application and use in treating diseases.
  • compositions are prepared in a standard manner.
  • the parent compound dissolved in a suitable solvent, is treated with an excess of an organic or inorganic acid, in the case of acid addition salts of a base, or an excess of organic or inorganic base where R2 is COOH for example.
  • Oxides of the pyridyl ring nitrogen may be prepared by means known in the art and as illustrated herein. These are to be considered part of the invention.
  • a chiral center is created or another form of an isomeric center is created in a compound of this invention, all forms of such isomer(s) are intended to be covered herein.
  • Compounds with a chiral center may be administered as a racemic mixture or the racemates may be separated and the individual enantiomer used alone.
  • these compounds can be used in treating a variety of diseases associated with or attributing their origin or affect to leukotrienes, particularly LTB4.
  • Inflammatory diseases such as psoriasis and inflammatory bowel disease may be treated by applying or a ⁇ -ministering the compounds described herein.
  • these compounds can be used to treat allergic diseases including those of a pulmonary and non-pulmonary nature.
  • these compounds will be useful in antigen-induced anaphylaxis. They are useful in treating asthma and allergic rhinitis.
  • Ocular diseases such as uveitis, and allergic conjunctivitis can also be treated by these compounds.
  • R is Cs to C20 alkoxy, phenyl-C4 to C10 alkoxy or substituted-phenylC4 to CJQ alkoxy;
  • Rj is R2- - C ⁇ -C3alkyl)R2, or -(C2-C3alkenyl)R2.
  • the most preferred compounds are:
  • One generic process comprises preparing a 6-halomethylpyridyl adduct and then condensing that fragment with the appropriate mercaptan or alcohol to make compounds where Z is a sulfur or oxygen atom. Normally this will be a protected product; any acid group will be derivatized in some manner to render it unreactive. Derivatizing groups may be removed to provide a parent functionality, such as an acid or a salt of an acid. Further modifications of these reactive groups can then be carried out, such as forming a salt, an amide, an ester or the like.
  • the starting alcohol represented here as the 3-octyn-l-ol, is commercially available (Lancaster Synthesis).
  • KH and 1,3-diaminopropane are combined and stirred to a homogeneous mix. This can be done at ambient temperature or thereabouts- This mix is then cooled, preferably to about 0°C or thereabouts, whereupon the alcohol is added. Stirring is then commenced at about room temperature for 15 to 20 hours or so. Water is added to quench the reaction and the product is recovered.
  • Protecting the alcohol is accomplished by forming a silyl ether illustrated here as the r-butyldiphenylsilyl ether. Other silyl ethers could be used.
  • the alcohol is dissolved in a polar solvent, for example dimethylformamide, and imidazole is added followed by the desired silane. All this is carried out under an inert atmosphere such as argon. Ambient temperature is acceptable for effecting the reaction.
  • Adding the phenyl group is done in a dry environment using an amine for a solvent and an inert atmosphere.
  • a solvent such as triethylamine under argon
  • a halophenyl compound eg. iodoanisole
  • a palladium catalyst (Ph3P)2PdCl2 and Cul both of the latter in catalytic amounts.
  • Heat is used to effect the reaction, usually a temperature of up to about 50°C will be sufficient
  • Two or more hours, up to six but often about four at the elevated temperature will usually cause the reaction to go to completion.
  • the triple bond is then saturated, preferably by catalytic hydrogenation.
  • the silyl ether can be dissolved in a saturated solvent such as an alcohol, a heavy metal catalyst added (Pd-C) and the mixture put under H2 for a time sufficient to reduce the triple bond. Stirring for 2 to 6 hours will usually effect the reaction.
  • Recovering the alcohol is done by treating the silyl ether with a fluoride source such as tetrabutylammonium fluoride. Reactants are combined at a mildly reduced temperature, eg. 0°C, then the reaction is allowed to run its course at ambient temperature or there about. Several hours may be needed for the reaction to go to completion. Product was recovered by extraction means.
  • Converting the alcohol to the iodo compound is accomplished using a phosphine, imidazole and I2- In actual.practice, this transformation is accomplished by adding to a solution of alcohol under argon, a molar excess of triphenylphosphine, for example, and a three-fold excess of imidazole followed by iodine. Materials are combined at room temperature, but then the reaction pot may be heated to between 50 - 70°C for a brief period, 10 minutes to an hour to complete the reaction. Standard procedures are then used to recover and purify the product.
  • w-thiolalkanoic acid esters and w-hydroxyalkanoic acid esters used in the preparation of these compounds are known and can be purchased from commercial vendors or made by means well known in the art.
  • the starting material is available from Aldrich. It is treated with a mild oxidizing agent such as Mn ⁇ 2 to oxidixe the 2-hydroxymethyl group to the corresponding aldehyde. The R group is then formed.
  • An ether is prepared under basic conditions using an a-halo intermediate. Introducing the acid function at position 2 is accomplished by means of a triphenylphosphoranylidene reagent. The acetate form is illustrated here but other similar reagents could be used.
  • the N- oxide is then formed by means of an oxidant, in this case a peroxy acid. Trifluoroacetic anhydride is used to oxidize the 6-position methyl group.
  • This hydroxymethyl group is then converted to the corresponding halide, (in the hydrohalide form) in this case the chloride, by means of thionyl chloride.
  • An w- thioalkanoic acid ester or w-hydroxyalkanoic acid ester group is then reacted with the 6-chloromethyl compound in the presence of a base, preferably CS2CO3 in this instance.
  • the resulting compound can be saponified using a base to obtain the corresponding salt or, if acidified, the corresponding free acid of the thioether or ether.
  • an oxidant can be used to generate the sulfoxide or the sulfone analogs of the thioethers, depending on whether one or two equivalents of oxidizing agent are used. Preferably this oxidation step will be done before the ester is saponified.
  • compositions of the present invention comprise a pharmaceutical carrier or diluent and some amount of a compound of the formula (I).
  • the compound may be present in an amount to effect a physiological response, or it may be present in a lesser amount such that the user will need to take two or more units of the composition to effect the treatment intended.
  • These compositions may be made up as a solid, liquid or in a gaseous form. Or one of these three forms may be transformed to another at the time of being administered such as when a solid is delivered by aerosol means, or when a liquid is delivered as a spray or aerosol.
  • a disease mediated by LTB4 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 method 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 and the pharmaceutical carrier or diluent will, of course, depend upon the intended route of administration, for example parenterally, topically, orally or by inhalation.
  • topical administration the pharmaceutical composition will be in the form of a cream, ointment, liniment, lotion, pastes, aerosols, and drops suitable for administration to the skin, eye, ear, or nose.
  • the pharmaceutical composition will be in the form of a sterile injectable liquid such as an ampule or an aqueous or non-aqueous liquid suspension.
  • the pharmaceutical composition will be in the form of a tablet, capsule, powder, pellet, atroche, lozenge, syrup, liquid, or emulsion.
  • examples of appropriate pharmaceutical carriers or diluents include: for aqueous systems, water; for non-aqueous systems, ethanol, glycerin, propylene glycol, com 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, 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 amount of carrier or diluent will vary but preferably will be the major proportion of a suspension or solution of the active ingredient.
  • the diluent is a solid it may be present in lesser, equal or greater amounts than the solid active ingredient.
  • Topical formulations will contain between about 0.01 to 5.0% by weight of the active ingredient and will be applied as required as a preventative or curative agent to the affected area.
  • the dosage of the composition is selected from the range of from 50 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 50 mg to about 5000 mg. No unacceptable toxicological effects are expected when these compounds are administered in accordance with the present invention.
  • 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.
  • the receptor binding affinity of the compounds used in the method of this invention is measured by the ability of the compounds to bind to [3-E-Q-LTB4 binding sites on human U937 cell membranes.
  • the LTB4 antagonist activity of the compounds used in the method of this invention is measured by their ability to antagonize in a dose dependent manner the LTB4 elicited calcium transient measured with fura-2, the fluorescent calcium probe.
  • the methods employed are described in the literature, particularly in published PCT application PCT/US91/03772. That procedure is incorporate herein by reference as if set out in full here. Specific Embodiments
  • EXAMPLE 1 4-ri-Oxythia-2-r2-(E-2-carboxyethenylV3-r8-(4-methoxyphenyl')octyloxyl-6- pyridvnethynbutyric acid, dilithium salt 1(a) 7-Octvn-l-ol. 35% KH in mineral oil (27g, 240mmol) under an argon atmosphere was washed with hexane and treated dropwise with 1,3-diaminopropane. The mixture was stirred at room temperature until it became homogeneous.
  • the acid form of any of the foregoing salts may be prepared by dissolving the salt in water, then acidifying that solution with a mineral acid such as dilute (6N) HCl. The acid is recovered by filtering out the precipitate.
  • a mineral acid such as dilute (6N) HCl.
  • Example 3 Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with numerous excipients. Means for making various formulations can be found in standard texts such as Remington's Pharmaceutical Sciences, and similar publications and compendia. Specific examples of formulations are given below.
  • the stearyl alcohol, white wax and white petrolatum are melted together (steam bath for example) and cholesterol and the active ingredient are added. Stirring is commenced and continued until the solids disappear. The source of heat is removed and the mix allowed to congeal and packaged in metal or plastic tubes.
  • the stearyl alcohol and white petrolatum are combined over heat. Other ingredients are dissolved in water, then this solution is added to the warm (ca 50 to 100° C) alcohol/petrolatum mixture and stirred until the mixture congeals. It can then be packed in tubes or another appropriate package form.
  • Example 4 Inhalation Formulation A compound of formula 1, 1 to 10 mg ml, is dissolved in isotonic saline and aerosolized from a nebulizer operating at an air flow adjusted to deliver the desired amount of drug per use.

Abstract

Cette invention se rapporte à des composés antagonistes des leucotriènes B4.
PCT/US1992/010582 1991-12-13 1992-12-11 Composes a base de pyridyle destines au traitement du psoriasis WO1993011768A1 (fr)

Applications Claiming Priority (2)

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US80651691A 1991-12-13 1991-12-13
US07/806,516 1991-12-13

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WO1993011768A1 true WO1993011768A1 (fr) 1993-06-24

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0675718A4 (fr) * 1992-12-23 1995-08-22 Smithkline Beecham Corp Composes de pyridyle a substitution utiles comme antagonistes des leucotrienes.

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3637714A (en) * 1966-11-16 1972-01-25 Astra Ab 5 - fluoro-3-pyridinemethanol esters thereof and therapeutically acceptable salts thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3637714A (en) * 1966-11-16 1972-01-25 Astra Ab 5 - fluoro-3-pyridinemethanol esters thereof and therapeutically acceptable salts thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS: CA104(21), 1863142, (1985), MISRA. *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0675718A4 (fr) * 1992-12-23 1995-08-22 Smithkline Beecham Corp Composes de pyridyle a substitution utiles comme antagonistes des leucotrienes.
EP0675718A1 (fr) * 1992-12-23 1995-10-11 Smithkline Beecham Corporation Composes de pyridyle a substitution utiles comme antagonistes des leucotrienes

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