WO1995015950A1 - Composes - Google Patents

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Publication number
WO1995015950A1
WO1995015950A1 PCT/US1994/013970 US9413970W WO9515950A1 WO 1995015950 A1 WO1995015950 A1 WO 1995015950A1 US 9413970 W US9413970 W US 9413970W WO 9515950 A1 WO9515950 A1 WO 9515950A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
pyridinyl
compound
alkoxy
phenethyloxy
Prior art date
Application number
PCT/US1994/013970
Other languages
English (en)
Inventor
Robert A. Daines
Original Assignee
Smithkline Beecham Corporation
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 Corporation filed Critical Smithkline Beecham Corporation
Priority to EP95904815A priority Critical patent/EP0733044A4/fr
Priority to JP7516268A priority patent/JPH09506367A/ja
Priority to AU13357/95A priority patent/AU1335795A/en
Priority to US08/656,169 priority patent/US5990314A/en
Publication of WO1995015950A1 publication Critical patent/WO1995015950A1/fr

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Classifications

    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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

Definitions

  • the family of bioactive lipids known as the leukotnenes exert pharmacological effects on respiratory, cardiovascular and gastrointestinal systems.
  • the leukotnenes are generally divided into two sub-classes, the peptidoleukotrienes (leukotrienes C4, D4 and E4) and the dihydroxyleukotrienes (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 (LTB4) was first described by Borgeat and
  • 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 and chemokinetic 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.
  • 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 covers a compound of formula I
  • Rx is hydrogen or lower alkyl
  • R is Cj to C20-aliphatic, unsubstituted or substituted five- membered heteroaryl-Ci to Cio-aliphatic-0-, unsubstituted or substituted phenyl-Ci to Cio-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 Ci to C2()-aliphatic-0-, or R is unsubstituted or substituted phenyl-Ci to Cio-aliphatic-0- where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo;
  • Rl is R4, -(Ci to C5 aliphatic)R4, -(Cl to C5 aliphatic)CHO, -(Cl to C5 aliphatic)CH2OR5;
  • R2 and R3 are independently halo, lower alkoxy, CF3, CN, or lower alkyl;
  • R4 is tetrazol-5-yl or COOH or an ester or amide thereof.
  • R5 is H, lower alkyl, CH 3 (CH 2 ) ⁇ -6CO or phenyl(CH 2 ) ⁇ -3CO.
  • 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. These compounds can also be used for treating diseases, particularly psoriasis and inflammatory bowel disease.
  • 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; or d) forming a compound of formula I by treating a 6- halomethylpyridyl compound with the appropriate mercaptan, hydroxy, or amino 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 hnear 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. Multiple 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.
  • unsubstituted or substituted five-membered heteroaryl means a five-membered aromatic ring which has one or more hetero atoms which are oxygen, sulfur or nitrogen.
  • examples of such rings are furyl, thienyl, tetrazolyl, thiazolyl, isothiazolyl, triazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, imidazolyl or pyrazolyl. Rings may be substituted with one or more lower alkyl groups, preferably methyl.
  • 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 esters 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 R4 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 administering 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, allergic rhinitis and irritable bowel disease.
  • Ocular diseases such as uveitis, and allergic conjunctivitis can also be treated by these compounds.
  • Preferred compounds are those where R is Cg to C20 alkoxy, thienyl-Cito CIQ alkoxy, unsubstituted or substituted thiazolyl-Ci to C10 alkoxy, phenyl-Ci to CIQ alkoxy or substituted-phenylCi to CIQ alkoxy; Ri is -(C ⁇ -C3alkyl) 4, or -(C2-C3alkenyl) 4 and R2 and R3, are both halo.
  • the 2,6- dichloro is a preferred compound. Specific preferred compounds are:
  • the chemistry set out in the '03772 case can be used to convert the starting material, 2,6-lutidine- ⁇ 2,3-diol, to, for example, the 2-(E-2-carboxymethylethenyl)-3-[4-(4-methoxyphenyl)butyloxy]-6- chloromethylpyridine.
  • This is illustrated in Scheme I given below.
  • Novel chemistry, both conditions and the reagent DBU are then used to couple the thiophenol with the chloromethyl substituted pyridine in order to make the basic structure of formula I.
  • Base, or acid can then be used to hydrolyze any ester group, if so desired.
  • a free acid can be obtained from the salt by acidifying a solution of the salt.
  • Esters and amides can be prepared using standard reaction conditions and reagents. Tetrazoles are prepared from the corresponding acid halide, e.g., the acid chloride, by literature methods.
  • a list, not intended to be exhaustive, is as follows: 2,5-dichlorothiophenol, 2,6-dimethylthiophenol, 2,4-dichlorothiophenol, 2-chloro-6-methylthiophenol, 2-chloro-4-fluorothiophenol, 2,4- dichlorobenzyl thiol, 2-chloro-6-fluorobenzyl mercaptan, and 2,4- difluorobenzyl thiol.
  • Other thiols can be made by published chemistry; that chemistry involves converting a haloalkylphenyl (the bromo form is preferred) compound to the corresponding mercaptan by treating the bromo compound with thiourea followed by base hydrolysis.
  • the thiophenols can be prepared by thermal rearrangement of the corresponding thiocarbamate followed by hydrolysis.
  • any ester can be hydrolyzed with acid or base, base is preferred, or that acid can be converted to another ester, an amide or another salt.
  • 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 rehef 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.
  • 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.
  • suitable 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, 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 admimstration.
  • 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.
  • 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 H]-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 have been disclosed in prior published PCT application PCT/US91/03772 which was filed 31 May 1991. The assays disclosed there are incorporated herein by reference. Specific Embodiments
  • Example 1 2-(E-2-Carboxymethylethenyl)-3-r4-(4-methoxyphenyl)butyloxyl-6- chloromethylpyridine hydrochloride 1A l-Iodo-4-(4-metho ⁇ yphenyl)butane.
  • 4-(4- methoxyphenyl)butan-l-ol 9.37g, 52mmol, Aldrich
  • triphenylphosphine 17.8g, 67.6mmol
  • imidazole (10.6g, 156mmol
  • Example 3 Preparation of Free Acids
  • the acid form of any of the foregoing salts were prepared by dissolving the salt in water if it is not already in solution, then acidifying that solution with an acid such as a mineral acid eg. dilute (6N) HCl. The acid was recovered by filtering out the precipitate. In that manner, and using the process disclosed in Examples 1-3, the following compounds were prepared:
  • Example 5 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.
  • Example 6 Inhalation Formulation A compound of formula I, 1 to 10 mg/ml, is dissolved in isotonic saline and aerosoHzed from a nebulizer operating at an air flow adjusted to deliver the desired amount of drug per use.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Dermatology (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à un composé de la formule (I) dans laquelle les différents groupes ont les notations ci-définies. Ce composé et ses analogues sont des antagonistes de leucotriènes et en tant que tels ils peuvent être utilisés dans le traitement de diverses maladies associées aux leucotriènes.
PCT/US1994/013970 1992-06-30 1994-12-05 Composes WO1995015950A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP95904815A EP0733044A4 (fr) 1993-12-08 1994-12-05 Composes
JP7516268A JPH09506367A (ja) 1993-12-08 1994-12-05 化合物
AU13357/95A AU1335795A (en) 1993-12-08 1994-12-05 Compounds
US08/656,169 US5990314A (en) 1992-06-30 1994-12-05 Pharmaceutical pyridine compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US16397493A 1993-12-08 1993-12-08
US08/163,974 1993-12-08

Publications (1)

Publication Number Publication Date
WO1995015950A1 true WO1995015950A1 (fr) 1995-06-15

Family

ID=22592438

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1994/013970 WO1995015950A1 (fr) 1992-06-30 1994-12-05 Composes

Country Status (5)

Country Link
EP (1) EP0733044A4 (fr)
JP (1) JPH09506367A (fr)
AU (1) AU1335795A (fr)
WO (1) WO1995015950A1 (fr)
ZA (1) ZA949737B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6416733B1 (en) 1996-10-07 2002-07-09 Bristol-Myers Squibb Pharma Company Radiopharmaceuticals for imaging infection and inflammation

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0532550A1 (fr) * 1990-06-07 1993-03-24 Smithkline Beecham Corporation Derives d'acide benzoique utilises dans le traitement de maladies associees au leucotriene
WO1993022285A1 (fr) * 1992-05-01 1993-11-11 Smithkline Beecham Corporation Antagonistes de leucotrienes
IL106156A0 (en) * 1992-06-30 1993-10-20 Smithkline Beecham Corp Pyridinyl compounds
EP0649408A4 (fr) * 1992-06-30 1995-06-21 Smithkline Beecham Corp Procede de production de phenylthiomethylpyridinylalcenoates.
GB9313145D0 (en) * 1993-06-25 1993-08-11 Smithkline Beecham Plc Process

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 108, issued 1988, TANIZAWA et al., "Enantiomeric Specificity at the Deacylation Process of Tryptic Catalysis", see Abstract No. 163953a. *
See also references of EP0733044A4 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6416733B1 (en) 1996-10-07 2002-07-09 Bristol-Myers Squibb Pharma Company Radiopharmaceuticals for imaging infection and inflammation

Also Published As

Publication number Publication date
ZA949737B (en) 1996-09-06
EP0733044A4 (fr) 1997-03-05
JPH09506367A (ja) 1997-06-24
AU1335795A (en) 1995-06-27
EP0733044A1 (fr) 1996-09-25

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