Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
  • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C323/56—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
• • 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
  • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C317/00—Sulfones; Sulfoxides
  • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
  • C07C317/46—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
  • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
  • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
  • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
  • C07C45/75—Reactions with formaldehyde

Definitions

• the field of this invention is that of ce ⁇ ain substituted diphenyl-2-propenoates, and homologs thereof, which have been found to be useful for treating diseases arising from or related to leukotrienes, particularly leukotriene B4. As such there utility lies in antagonizing the affects of leukotrienes.
• Trie 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
• 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 Anaphyiaxis" (SRS-A). This response is expressed in vivo as prolonged bronchoconstriction, in cardiovascular effects such as coronary artery vasoconstriction and numerous other biological responses.
• 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).
• 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-(ZJEJE t Z)-
• 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.
• 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. By antagonizing the effects of LTB4, or other pharmacologically active mediators at the end organ, for example airway smooth muscle, 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
• NR X' m is 0 -5;
• R x is hydrogen or lower alkyl
• R is unsubstituted or substituted five-membered heteroaryl- Ci to Cjo-aliphatic-O-, unsubstituted or substituted phenyl-Cj to CiQ-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 Cj to C20-aliphatic-O-, or R is unsubstituted or substituted phenyl-Cj to Ci Q -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 R4, -(Ci to C5 aliphatic)R4, -(Ci to C5 aliphatic)CHO, -(Ci 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; and R5 is H, lower alkyl, CH3(CH2) ⁇ -6 O or phenyI(CH2) ⁇ -3CO.
• this invention relates to compositions comprising a compound of formula 1, 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 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. Multiple substituents may be the same or different, such as where there are three chloro groups, or a combination of chloro and a yl 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.
• 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 anaphyiaxis. 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-Cjto CJQ alkoxy, unsubstituted or substituted thiazolyl-C to C ⁇ Q alkoxy, phenyl-Cj to CJQ alkoxy or substituted-phenylCi to C J Q alkoxy; R ] is -(C ⁇ -C3alkyl)R4, or -(C2- C3alkenyl)R4 and R2 and R3, are both halo.
• the more preferred compounds are those where R is unsubstituted or substituted phenyl-Cj to C ⁇ Q alkoxy, particularly the unsubstituted-phenyl(CH2)2-8-C
• - group, or the p-fluoro- or /?-methoxyphenyl(CH2)2- g-O- group, or CH3(CH2)7-Q-O-; m is 0 - 5, most preferably 0, 1, or 2; R is HO2C- CH CH-, or HO2C-CH2CH2- or a salt, ester or amide derivative thereof. As regards A, the CH2 group is preferred. As regards Z, S(O)q and O are preferred, and in S(O) q q is 1, 2 or 3. Another sub-group of preferred compounds are those where R2 and R3 are halo; methyl or methoxy, particularly where both are halo, methyl or methoxy.
• the 2,6-dichloro is a preferred compound. Specific preferred compounds are
• the salicylaldehyde is converted to the 5-chloromethylbenzaldehyde by combining the aldehyde with aqueous formaldehyde (37%) and concentrated hydrochloric acid, at a reduced temperature in the range of -10 to +10° C or thereabouts. Gaseous HC1 is then bubbled through the solution to saturate with HC1 after which the solution is stirred for a period sufficient to effect the reaction at a reduced temperature, one which is about that of the temperature at which the reactants were combined initially.
• the product, the 5-(chloromethyl)-2-hydroxybenzaldehyde should be formed as a white precipitate which can be recovered by conventional means.
• the 5-(chloromethyl)-2-hydroxybenzaldehyde can then be coupled witii any one of a number of thiophenols or phenhylalkyl mercaptans in the next step.
• a number of thiophenols and thioall ylphenyl compounds useful for making the right hand portion of formula I can be purchased from commercial sources.
• 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. Coupling the thiol with 5-(chloromethyl)-2-hydroxybenzaldehyde is accomplished herein by using l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and an aprotic solvent, for example acetonitrile or acetonitrile and toluene. A slight molar excess of the thiol is used relative to the aldehyde. Moisture is excluded from the system and an inert gas is used, for example argon. The reaction can be carried out at room temperature or there about. The reaction is run until all of the benzaldehyde is consumed; it can be monitored by thin layer chromatography.
• DBU l,8-diazabicyclo[5.4.0]undec-7-ene
• an aprotic solvent for example acetonitrile or acetonitrile and
• Base or acid
• the 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.
• 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.
• 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 pharmaceutical preparations thus described are made following the conventional techniques of the pharmaceutical chemist as appropriate to the desired end product.
• 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
• a compound of formula I is administered to a subject in a composition comprising anontoxic amount sufficient to produce an inhibition of the symptoms of a disease in which leukotrienes are a factor.
• 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. For convenience, 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 [3H]-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 tiiere are incorporated herein by reference.
• Salicylaldehyde (8.7 mL, 65.6 mmol) was added to a solution of aqueous formaldehyde (14 mL, 37%) and cone. HC1 (42 mL) at 0 °C. The reaction solution was then saturated with HC1 gas and stirred at 10 °C. An off- white precipitate was formed which was collected and washed with cold water. The solid was dissolved in CH2Q2 and dried over MgSO4. Evaporation of solvent provided 8.73 g of product. Mp 76-79 °C. Kb. 5-IT(2. 6-DichIorophenyDthio1methyl1-2-hvdroxybenzaldehyde
• Phenethyl alcohol (3.0 g, 24.6 mmol) was dissolved in ethyl amine (7 mL) and CH2CI2 (30 mL). The solution was cooled to 0 °C and tosyl chloride (5.15 g, 27.1 mmol) was added. The reaction was stirred at room temperature for 16 h. Reaction solution was diluted with EtOAc and the organic layer washed with 5% HC1, aq. NaHCO3, and brine and dried (MgSO. 4 ). Evaporation gave 6.84 g of product.
• Example 2 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. OINTMENTS
• Hydrophyllic Petrolatum Ingredients Amount (% Weight/weight.
• the stearyl alcohol, white wax and white petrolatum are melted together (steam bath for example) and cholesterol and d e 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.
• pimple g 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.

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• 1994
  • 1994-12-05 CN CN94194736A patent/CN1139880A/zh active Pending
  • 1994-12-05 WO PCT/US1994/013966 patent/WO1995015752A1/en not_active Application Discontinuation
  • 1994-12-05 AU AU13983/95A patent/AU1398395A/en not_active Abandoned
  • 1994-12-05 JP JP7516266A patent/JPH09506366A/ja active Pending
  • 1994-12-05 NZ NZ278484A patent/NZ278484A/en unknown
  • 1994-12-05 EP EP95905321A patent/EP0732919A4/en not_active Withdrawn
  • 1994-12-05 CA CA002178634A patent/CA2178634A1/en not_active Abandoned
  • 1994-12-08 ZA ZA949786A patent/ZA949786B/xx unknown

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