EP0495917A1 - Inhibiteurs de lipoxygenase - Google Patents

Inhibiteurs de lipoxygenase

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Publication number
EP0495917A1
EP0495917A1 EP19900916941 EP90916941A EP0495917A1 EP 0495917 A1 EP0495917 A1 EP 0495917A1 EP 19900916941 EP19900916941 EP 19900916941 EP 90916941 A EP90916941 A EP 90916941A EP 0495917 A1 EP0495917 A1 EP 0495917A1
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EP
European Patent Office
Prior art keywords
compound
alkyl
formula
aryl
same
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.)
Ceased
Application number
EP19900916941
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German (de)
English (en)
Inventor
Neng-Yang Shih
Pietro Mangiaracina
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Sharp and Dohme LLC
Original Assignee
Schering Corp
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Publication of EP0495917A1 publication Critical patent/EP0495917A1/fr
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • 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
    • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
    • C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
    • C07C45/292—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups with chromium derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/20—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms
    • C07C47/277—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/007—Esters of unsaturated alcohols having the esterified hydroxy group bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/734—Ethers

Definitions

  • This invention relates to certain phenyl-alkyl- phenyl compounds which are useful as inhibitors of the lipoxygenase pathways in the metabolism of arachidonic acid.
  • a number of lipoxygenase inhibitors are known. For example, International Application Number
  • D, E, F, X, Y, Z may be H; OH; O-alkyl; or O-acyl optionally substituted with hydroxy, alkoxy, substituted amino, carboxyl, or carbalkoxyl;
  • R 1 to R 6 may be H; lower alkyl or lower alkoxyl optionally substituted with hydroxy, alkoxy, substituted amino, carboxyl, or carbalkoxyl; carbonyl; alkoxy; aryl; or aralkyl; and n may be 0 to 5.
  • Arachidonic acid is metabolized by means of the enzymes 5-lipoxygenase and cyclooxygenase into various leukotrienes, including slow reacting substances, and prostaglandins which cause allergic reactions,
  • 5-lipoxygenase reduces the manifestation of the symptoms of allergic reactions, e.g. chronic obstructive lung disease such as asthma, allergic or seasonal rhinitis, bronchitis, and the like;
  • inflammatory diseases such as arthritis, bursitis, tendonitis, gout and inflammatory bowel disease;
  • hypoproliferative skin disease a symptom of which is accelerated skin cell production manifested by flaking, scales or papular lesions, e.g., psoriasis, lichenified eczema, dandruff, and the like.
  • One embodiment of this invention provides compounds represented by
  • R 1 and R 2 are the same or different and are selected from:
  • substituent is selected from aryl, substituted aryl, heteroaryl, -OR 5 , and
  • substituted aryl wherein one or more of the ring hydrogens are independently substituted by substituents selected from alkyl and -O-alkyl;
  • R 3 and R 4 are the same or different and are independently selected from H, R 1 and R 2 ;
  • (C) U, V, and Z are the same or different and are independently selected from H, R 1 , R 2 , -OR 10 , -O(CH 2 ) m R 8 , -OC(O)R 9 , and -OC(O)NR 6 R 7 ; and
  • n is an integer from 1 to 8.
  • R 5 is selected from H, alkyl, aryl, alkaryl, aralkyl, cycloalkyl, and heteroaryl with the proviso that said heteroaryl group is bound through a ring carbon;
  • R 6 and R 7 are the same or different and are independently selected from H, alkyl, aryl, aralkyl, acyl substituted aryl, cycloalkyl and heteroaryl, with the proviso that when R 6 and/or R 7 is a heteroaryl group said heteroaryl group is bound by a ring carbon;
  • R 8 is selected from aryl, substituted aryl, and heteroaryl, with the proviso that said heteroaryl group is bound through a ring carbon;
  • R 9 is selected from H, alkyl, aryl, substituted aryl, aralkyl, cycloalkyl, and heteroaryl, with the proviso that said heteroaryl group is bound through a ring carbon;
  • n is an integer from 1 to 4.
  • R 10 is selected from H and alkyl; and.
  • R 1 1 is selected from H, -OR 5 , -NR 6 R 7 , and - NR 5 OH.
  • Preferred compounds of this invention are represented by Formula 2:
  • R 12 and R 13 are the same or different and are independently selected from U, V, and Z as defined for Formula 1 and R 1 , R 2 , R 3 , R 4 and W are as defined for Formula 1. More preferred compounds of this invention are represented by Formula 3:
  • R 14 and R 15 are the same or different and are independently selected from H, and alkyl and R 1 , R 2 , R 3 , R 4 , and W are as defined for Formula 1.
  • Preferred compounds of Formula 4 are represented by Formulas 5 and 6: (5)
  • X is selected from -C(O)H, -C(O)OH, -C(O)OCH 3 and -C(O)NHOH, and
  • R 1 and R 2 are independently selected from alkyl, substituted alkyl, aryl and substituted aryl-- i.e., aryl substituted with at least one group selected from halo, alkyl, hydroxy, alkoxy, phenoxy, amino, alkylamino, and dialkyiamino. Most preferably R 1 and R 2 are the same and represent an alkyl group having from 1 to 3 carbon atoms, and even more preferably the alkyl group is a methyl group.
  • R 3 and R 4 are independently selected from H, alkyl, substituted alkyl, aryl and substituted aryl wherein there is at least one substituent, and said
  • R 3 is an alkyl group having from 1 to 3 carbon atoms, preferably methyl, and R 4 is H.
  • R 3 is an alkyl group having from 1 to 3 carbon atoms, preferably methyl
  • R 4 is H.
  • U, V, and Z are selected from H, - OR 5 , -OR 7 , -O(CH 2 ) m R 8 , OC(O)R 9 , O(CO)NR 5 R 9 and aryl, wherein R 9 is selected from alkyl, aryl and substituted aryl wherein there is at least one substituent as defined for Formula 1.
  • U, V, and Z are each
  • X is -C(O)R 1 1
  • X is selected from -OR 10 , -OC(O)R 9 , -N(OH)C(O)R 10 and - NR 6 R 7
  • X is selected from -C(O)H, - C(O)OH, -C(O)OCH 3 , and -C(O)NHOH when n is 3, and when n is 4, X is selected from -OR 10 and -OC(O)R 9 wherein R 9 and R 10 are as defined for Formula 1. Even more preferably, when n is 4, X is selected from -OH and -OC(O)CH 3 .
  • This invention also provides a method of inhibiting 5-lipoxygenase metabolism of arachidonic acid by administering a composition comprising an effective amount of a compound of Formula 1 to a patient in need of such treatment.
  • this invention also provides a method of treating allergies, inflammation and/or
  • hyperproliferative skin diseases by administering to a patient in need of such treatment a compound of Formula 1.
  • the preferred mode of administration of the compounds of this invention is oral.
  • the preferred dosage amounts are about 10 to 500 mg per day, preferably in a single dose, although divided doses can be used.
  • the preferred mode of administration of the compounds of this invention is oral.
  • the preferred dosage amounts are 10 to 500 mg per day, preferably in a single dose, although divided doses can be used.
  • the preferred mode of administration is topical.
  • the preferred concentration of active compound of this invention in pharmaceutically acceptable topical compositions is from about 0.10 to about 10 percent by weight.
  • Preferred compounds for use in this invention are: (a) 5,7-dimethyl-5,7-bis(3,5-dimethoxy- phenyl)-1 -octanol;
  • alkyl means straight or branched saturated carbon chains, which contain from 1 to 6 carbon atoms such as methyl, ethyl, propyl, iso-propyl, butyl, t-butyl, dimethyl butyl and the like.
  • the preferred alkyl is methyl;
  • acyl means -C(O)-alkyl, -C(O)-alkenyl, -C(O)- alkynyl, -C(O)-cycloalkyl, -C(O)-cycloalkenyl or -C(O)- cycloalkynyl;
  • alkaryl means an aryl group, as defined below, in which an alkyl group, is substituted for one or more of the aryl H atoms;
  • alkenyl means straight or branched carbon chains having at least one carbon to carbon double bond and preferably having from 2 to 6 carbon atoms;
  • aralkyl means an alkyl group, as defined above, in which an aryl group as defined below is
  • alkyl H atoms for example, benzyl, phenethyl and the like;
  • aralkyloxy means an aralkyl as defined above, which is attached to a molecule by an oxygen atom (-O- aralkyl) such as benzyloxy;
  • aroyl means C(O)-aryl wherein aryl is as defined below.
  • the preferred aroyl moiety is benzoyl;
  • aryl means a carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring (e.g., a phenyl or fused ring), all available
  • alkyl i.e. alkaryl
  • hydroxy i.e. alkoxy
  • phenoxy amino
  • alkylamino independently selected from halo, alkyl (i.e. alkaryl), hydroxy, alkoxy, phenoxy, amino, alkylamino and
  • Preferred unsubstituted aryl is the phenyl moiety and preferred substituted aryl is dimethoxy phenyl;
  • Carboxyl means a hydrocarbyl group which contains at least one C(O)OH group
  • cycloalkenyl means a carbocyclic ring having from 3 to 8 carbon atoms and at least one carbon to carbon double bond in the ring;
  • cycloalkyl means a saturated carbocyclic ring having from 3 to 8 carbon atoms
  • halo means fluoro, chloro, bromo or iodo with fluoro, chloro and bromo being preferred;
  • heteroaryl (including the heteroaryl portion of heteroarylmethyl) means heterocyclic aromatic, i.e. cyclic groups having at least one O, S or N heteroatom
  • rings preferably containing from 2 o 14 carbon atoms, e.g., 2-, 3- and 4-pyridyl, 2- and 3- furyl, 2- and 3-thienyl, 2-, 4- and 5-thiazolyl, 2-, 4- and
  • Preferred heteroaryl groups are 2-,
  • heterocyclyl means a substituted or unsubstituted non-aromatic ring containing from 2 to 6 carbon atoms, which may optionally contain at least one carbon-to-carbon double or triple bond, and which contains at least one heteroatom selected from nitrogen, oxygen or sulfur; representative examples of such heterocycles include, but are not limited to: pyrrolidone, piperidine, piperazine, heptamethyleneimine, hexamethyleneimine, homopiperazine, perhydroindole, azetidine, 4-piperidino- piperidine, 1 -azacycloheptane, perhydroisoquinoline, decahydroquinoline, 1 -phenylpiperazine, 4- phenylpiperidine, 1 -(4-fluorophenyl)piperazine, 1 ,3,5- hexahydrotriazine, glycoluril (acetyleneurea), morpholine, phenylmorpholine, thiomorph
  • Certain compounds of this invention may exist in isomeric forms.
  • the invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures.
  • Certain compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms, e.g., hemihydrate.
  • solvated forms including hydrated forms, e.g., hemihydrate.
  • pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms for purposes of the invention.
  • Certain compounds of the invention will be acidic in nature, e.g., those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable metal and amine salts. Examples of such metal salts are the sodium, potassium, calcium, aluminum, gold and silver salts. Examples of such amine salts are those formed with pharmaceutically acceptable amines such as ammonia, alkylamines,
  • Certain compounds of the invention e.g., those with a basic -NR 6 R 7 group, also form pharmaceutically acceptable salts with organic and inorganic acids.
  • Suitable acids for such salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art.
  • the salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the
  • the free base forms may be any convenient base forms.
  • a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate.
  • the free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base froms for purposes of this invention.
  • the compounds of Formula 1 can be prepared by the processes described below. In these processes the substituents are as described above, unless indicated otherwise. Those skilled in the art will appreciate that in the processes described below the reactions are carried out at a temperature high enough to allow the reaction to proceed at a reasonable rate, but not so high as to cause undue degradation of reactants and/or products. Those skilled in the art will also appreciate that in the following reactions the desired products may be isolated by
  • Equation (abbreviated "EQ") A depicts a method of preparing compounds of Formula 1 wherein W is -
  • R 1 to R 4 are defined as in Formula 1 , U, V, Z are defined as above except OH, OC(O)R 9 and OC(O)NR 6 R 7 are not included.
  • the reaction in EQ A takes place at about room temperature (about 20°C) to 50°C using tetrahydrofuran (THF) and reactive magnesium.
  • the reactive magnesium is prepared by refluxing K, MgCl 2 and Kl together in THF in accordance with known
  • Equation B depicts a method for preparing compounds by converting the -(CH 2 ) 4 OH moiety to -(CH 2 ) 4 alkyl.
  • a compound represented by Formula 9 is reacted with alkylX, where X is a halogen atom, with Br or I being preferred.
  • the reaction takes place in a base and an inert aprotic polar organic solvent.
  • the reaction is carried out at a temperature within the range of about 20°C to refluxing (the boiling point of the organic solvent).
  • the base may be NaH, t-BuOK, Na or CH 3 Li.
  • the organic solvent may be selected from tetrahydrofuran (THF),
  • EQ C depicts a method of preparing compounds of Formula 1 wherein X is -OC(O) R 9 or -OC(O)NR 5 R 9 wherein R 5 and R 9 are as defined for compound 1.
  • the reaction takes place in a base and an inert organic solvent (when pyridine is used, it acts as a base and a solvent).
  • the reaction is carried out at a temperature within the range of about -20°C to about 50°C.
  • the base may be any suitable organic base such as pyridine, 4- dimethylaminopyridine, triethylamine and the like.
  • the inert organic solvent may be selected from CH 2 CI, CHCI 3 , benzene, and pyridine, and the like.
  • pyridine is used as solvent no other base is needed.
  • the reaction is carried out at a temperature of about 0°C to about 20°C.
  • EQ D represents a method for preparing compounds of Formula 1 wherein X is -C(O)H.
  • a compound represented by Formula 10 is reacted with an oxidative agent.
  • the reaction takes place in an inert organic solvent.
  • oxidative agents include but are not limited to CrO 3 /H 2 SO 4 , pyridinium dichromate, DMSO/COCI 2 , pyridinium chlorochromate, and the like.
  • pyridium dichromate is used.
  • inert organic solvents include benzene, dimethyl formamide,
  • dichloromethane and the like.
  • dichloromethane is used.
  • pyridinium dichromate and dichloroethane are used the reaction may conveniently be carried out at room temperature (20°C).
  • EQ E represents a method for preparing compounds of Formula 1 wherein X is -NR 6 R 7 -
  • a compound represented by Formula 12 is reacted with an amine, HNR 6 R 7 , and subsequently reduced to produce a compound represented by Formula 13.
  • the reaction is carried out with a reducing agent such as NaBH 4) NaBH 3 (CN), and the like.
  • a reducing agent such as NaBH 4) NaBH 3 (CN), and the like.
  • NaBH 3 (CN) is used.
  • the reaction is also carried out at a pH in the range of about 4 to about 8.
  • a pH of about 6 is used when NaBH 3 (CN) is used.
  • the pH may be adjusted utilizing standard methods known in the art.
  • the reaction is carried out at a temperature in the range of about 0°C to about 25°C.
  • EQ F depicts a method of preparing compounds of formula 1 wherein X is -N(-OH)C(O)R 10 , wherein R 10 is as defined in the compound of formula 1.
  • a compound of formula 12 is reacted with hydroxylaminehydrochloride (NH 2 OH ⁇ HCI) to produce a compound represented by Formula 12A.
  • This reaction is carried out in an inert alcoholic solvent, usually ethanol, at a temperature about in the range of about 50°C to 100°C in the presence of base such as pyridine or sodium acetate.
  • Conversion of compound 12A to compound 12B can be achieved by following a known procedure as described in Journal of Medicinal Chemistry, Vol. 31 , p.3 (1988).
  • EQ G depicts a method for preparing compounds of Formula 1 wherein X is -C(O)OH, from either a compound of formula 10 or a compound of formula 12.
  • EQ G also depicts a method for preparing an intermediate (Formula 15) to other compounds of Formula 1.
  • a compound of Formula 10 or 12 is reacted with an oxidizing agent to produce a compound of Formula 14.
  • the reaction takes place in an inert organic solvent.
  • oxidizing agents include AgO, PDC (pyridinium dichromate), KMnO 4 , and the like.
  • PDC is used.
  • inert organic solvents include THF, DMF, acetone and the like.
  • DMF or acetone is used.
  • the reaction is usually carried out at a temperature of about 0°C to about 50°C with about 20°C being preferred.
  • the compounds of Formula 14 may be reacted with a halogenating agent to produce a compound of Formula 15.
  • a chlorinating agent such as PCI 5 , SOCI 2 , (COCI) 2 , and the like.
  • SOCI 2 or (COCI) 2 is used.
  • the reaction takes place in an organic solvent such as dichloromethane, benzene, and the like. The reaction is usually carried out at a temperature of about 0°C to about 80°C.
  • EQ H depicts a method for preparing compounds of Formula 1 wherein X is -C(O)OR 5 .
  • a compound of Formula 15 is reacted with R 5 OH, wherein R 5 is as defined for Formula 1 to produce a compound of Formula 16.
  • the reaction takes place at a temperature of about 0°C to about 20°C (room temperature) in the presence of a base, such as triethylamine, in an inert organic solvent such as dichloromethane.
  • EQ I depicts a method for preparing compounds of Formula 1 wherein X is -C(O)NR 6 R 7 .
  • a compound of Formula 15 is reacted with an amine, HNR 6 R 7 , to produce a compound represented by Formula 17.
  • the reaction takes place at a temperature of about 0°C to about 20°C (room temperature) in the presence of base such as triethylamine in an organic solvent such as dichlormethane or benzene .
  • EQ J depicts a method for preparing compounds of Formula 1 wherein X is -C(O)NR 5 OH.
  • a compound of Formula 15 is reacted with HNR 5 OH in an organic solvent.
  • suitable organic solvents include benzene, THF, and the like.
  • THF is used.
  • organic solvent/water combined solvent system is used.
  • the combination is THF and water, 2:1 to 3:1 v/v.
  • the reaction is usually carried out at a temperature of about 0°C to about 20°C (room temperature).
  • EQ K depicts the method of converting compounds of Formula 50 wherein R 1 , R 2 , R 3 and R 4 are as defined for Formula 1 and X is -OR 10 , -CHO, -COOH, -COR 11 , -OC(O)R 9 and -OC(O)NR 5 R 9 to compounds of formula 51 and thereafter to compounds of formula 52 wherein U, V and Z are as defined for Formula 1.
  • Compounds of formula 52, where U V and Z are independently selected from -OH, -OC(O)R 4 and - OC(O)NR 5 R 9 can be prepared from compounds of formula 50 wherein X can be -OR 10 , -CHO, -COOH, -COR 11 , -OC(O)R 9 , and -OC(O)NR 5 R 9 .
  • a compound of formula 50, where X O alkyl, -OC(O)NR 5 R 9 , -C(O)R 11 , -OC(O)R 9 is converted to a
  • Lewis acid is BBr 3 , BCI 3 or AICI 3 .
  • BBr 3 is preferred.
  • the preferred inert organic solvent is CH 2 CI 2 .
  • the reaction is carried at about -78°C to room temperature (about 20°C).
  • the organic base can be triethyl amine or pyridine.
  • the organic solvent can be dichloromethane, pyridine or benzene.
  • the reaction is carried out at temperatures of about -25°C to 50°C.
  • EQs L, L', and M depict methods for preparing a compound of Formula 7 used as a starting material in EQ A.
  • a compound of Formula 19 is reacted with R 1 Li to produce a compound of Formula 20.
  • This reaction takes place in an inert organic solvent such as ether or THF.
  • the conversion of a compound of Formula 19 to a compound of Formula 20 is carried out at a
  • a compound of Formula 20 is reacted with R 2 M to produce a compound of Formula 21 (intermediate for making a compound of Formula 7).
  • M can be Li or MgX, wherein X is Cl or Br.
  • This reaction takes place in an organic solvent such as ether or THF at temperature of about -78°C to about 20°C.
  • a compound of Formula 23 wherein R 1 and R 2 are the same is prepared.
  • a compound of Formula 22 is reacted with two equivalents of R 1 MgX, wherein X is Cl or Br, to produce a compound of Formula 23.
  • This reaction is carried out in an inert organic solvent such as THF, ether, and the like.
  • ethyl ether is used.
  • this reaction may be carried out at a temperature of about -10°C to about 50°C with about 20°C (room
  • the reactant R 1 MgX is prepared by methods well known in the art.
  • a compound of Formula 21 (or Formula 23) is halogenated to produce a compound of Formula 7, wherein G is Br or Cl.
  • the halogenation may be carried out using HX wherein X is a halo atom, with Br or Cl being preferred.
  • This reaction takes place in an organic solvent such as CHCI 3 , dichloromethane and the like. Preferably dichloromethane is used.
  • This reaction is also carried out in the presence of a conventional inert drying agent such as anhydrous MgS ⁇ 4, and the like.
  • the temperature at which this reaction is carried out is within a range of about - 20°C to about 10°C with about 0°C being preferred.
  • EQs N, O and P depict methods for preparing a compound of Formula 8, which is a starting material in EQ A.
  • the compound of Formula 24 in EQ N may be prepared in accordance with the methods of EQ L-M above except R 3 and -CH 2 R 4 groups are used in place of R 1 and R 2 groups.
  • a compound of Formula 24 is reacted with a base to prepare a compound of Formula 8.
  • bases include 1 ,8-Diazabicyclo[5.4.0]undec-7-ene [DBU], triethylamine, 4-dimethylaminopyridine [4-DMAP] and the like.
  • the reaction takes place at a temperature within the range of about 0°C to about 50°C.
  • a base include 1 ,8-Diazabicyclo[5.4.0]undec-7-ene [DBU], triethylamine, 4-dimethylaminopyridine [4-DMAP] and the like.
  • the reaction takes place at a temperature within the range of about 0°C to about 50°C.
  • a compound of Formula 24 in EQ N may be prepared in accordance with the
  • compound of Formula 24 can be passed through basic alumina. This alternative method can be carried out at a temperature of about 20°C.
  • EQ O represents another method of preparing compounds of Formula 8.
  • a compound of Formula 25 is reacted with a Wittig reagent (Formula 29, EQ P below) to produce a compound of Formula 8.
  • This reaction takes place in an organic solvent such as ether, DMSO, THF, and the like. Preferably THF is used. This reaction takes place at a temperature of about 0°C to about 50°C.
  • the Wittig reagent, used in EQ O may be prepared in accordance with well known procedures as exemplified in EQ P.
  • a compound of Formula 28 is reacted with a base such as butyl lithium (BuLi) or NaH.
  • a base such as butyl lithium (BuLi) or NaH.
  • EQ Q(1) and Q(2) depict a method for preparing higher homologs at W of formula 1.
  • the compound of Formula 30 is reacted with a chlorinating agent to form a compound of Formula 31.
  • chlorinating agents examples include (COCI) 2 and SOCI 2 .
  • the compound of Formula 31 is first reacted with diazomethane then reacted with water and Ag2O.
  • This reaction sequence is known as the Arndt-Estert Synthesis (for details see Arndt, F., Eistert, B., Ber., 68, p. 200 (1935) or Aoyama, T., Shioiro, T., Tet, Let., 21 , P. 4461 (1980)).
  • reaction sequences in EQ Q(1 ) and EQ Q(2) can be repeated as often as desired to produce the desired chain length.
  • EQs R(1)-(3) depict a method for preparing compounds of Formula 30.
  • a compound of Formula 33 is prepared when a compound of Formula 10 is reacted with G 2 wherein G is a halogen atom, such as I or Br.
  • G is a halogen atom, such as I or Br.
  • the reaction takes place in the presence of P ⁇ 3 (wherein ⁇ represents phenyl).
  • the reaction is carried out at a temperature of about -10°C to about 20°C.
  • the compound of Formula 33 is reacted with a cyanide, e.g. sodium cyanide, to form a compound of
  • the reaction takes place in an organic solvent such as DME, DMSO or DMF, and the like. Preferably DMF is used. This reaction takes place at a temperature of about 0°C to about 100°C with about 20°C to about 50°C being preferred.
  • organic solvent such as DME, DMSO or DMF, and the like.
  • DMF is used. This reaction takes place at a temperature of about 0°C to about 100°C with about 20°C to about 50°C being preferred.
  • a compound of Formula 30 is then prepared from the compound of Formula 34 by hydrolysis using a strong base, such as NaOH, KOH and the like.
  • the reaction may be carried out at a temperature of about 50°C to about 100°C in aqueous methanol or aqueous diethylene glycol.
  • EQ S(1 ) and EQ S(2) depict a method for preparing a higher homologue of Formula 1 compounds when X is COR 11 and R 11 is H.
  • bases include
  • reaction is carried out at a temperature of about 0°C to about 40°C in an inert solvent such as ethanol or DME.
  • a compound of Formula 35 is reacted with an acid to produce a compound of Formula 36.
  • Suitable acids include HCIO 4 or H 2 SO 4 and the like.
  • the reaction may be carried out at a temperature of about 0°C to about 50°C with about 20°C (room
  • EQ T(1) and EQ T(2) depict a method for producing lower homologous compounds, i.e. those which differ by a -CH 2 -CH 2 - group.
  • a compound of Formula 33 is reacted with a base to produce a compound of Formula 37.
  • Suitable bases include NaNH 2 , DBU and the like.
  • the reaction takes place in an inert organic solvent such as DMSO, THF, DME, and the like.
  • the temperature, at which the reaction is carried out, is about 20°C (room
  • the compound of Formula 37 is then oxidized to the compound of Formula 38.
  • the oxidation takes place using ozone (O 3 ) and an organic solvent such as
  • EQ U(1 ) and U(2) depict another method for producing lower homologous compounds.
  • a compound of Formula 39 undergoes a series of reactions to produce a compound of Formula 40.
  • R 1 1 is H or an -OR 5 group in which R 5 is alkyl.
  • the compound of Formula 39 is first reacted with a base, preferably lithium diisopropylamide (LDA). This reaction takes place in an organic solvent such as DME, ether or THF, and the like, preferably THF. Then, the resulting compound is reacted with ⁇ SeCI, ⁇ SCI, and the like, preferably ⁇ SeCI. The reactions take place at a temperature of about 0°C to about 20°C. The resulting mixture is then treated with an oxidizing agent such as H2O2 to produce a compound of Formula 40. The oxidizing step takes place at a temperature of about 0°C to about 50°C.
  • LDA lithium diisopropylamide
  • the compound of Formula 40 is oxidized to the compound of Formula 38 using O 3 .
  • the oxidation step takes place in an organic solvent such as dichloromethane, and the like.
  • the reaction takes place at a temperature of about -78°C to about 0°C.
  • protecting groups well known in the art may be used. After the reaction or reactions, the protecting groups may be removed by standard procedures well known in the art
  • Representative compounds of Formula 1 include Formulas 41 -46:
  • the 5-LO inhibitory activity of the compounds of this invention may be demonstrated by the procedures described below.
  • Human polymorphonuclear leukocytes were obtained from normal healthy
  • HEPES N-2- hydroxyethylpiperazine-N 1 -2-ethanesulfonic acid
  • the red cells in the suspension were lysed by hypotonic shock.
  • the neutrophils were washed by centrifugation in HEPES buffer two times and finally resuspended at a concentration of 20x10 6 cells/ml in the presence of 1 mM CaCl 2 .
  • the column was initially eluted at 2 ml/min with 80% of the mixture water:methanol:acetic acid (46:54:0.08) containing 1 mM EDTA adjusted to pH 6.0 with ammonium hydroxide (Pump A) and 20% methanol (Pump B). At 10 minutes, a linear gradient to reach 100% methanol (Pump B) at 27 minutes was established.
  • the compounds of this invention are useful in the treatment of hyperproliferative skin disease. This may be demonstrated by their 5- lipoxygenase inhibitory activity as discussed above or by the Arachidonic Acid Mouse Ear Test as described below.
  • mice Charles River, female, CD, (SD) BR mice, 6 weeks old, are caged 8/group and allowed to acclimate 1-3 weeks prior to use.
  • Arachidonic acid (AA) is dissolved in reagent grade acetone (2 mg/.01 ml) and stored at -20°C for a maximum of 1 week prior to use. Inflammatory reactions are induced by applying 10 ⁇ l of AA to both surfaces of one ear (4 gm total).
  • Test drugs are dissolved in either reagent grade acetone or aqueous ethanol (only if insoluble in acetone) at the same doses selected by Opas et al., Fed.
  • the severity of the inflammation is measured as a function of increased ear weight.
  • a 6 mm punch biopsy is removed 1 hour after AA challenge and weighed to the nearest 0.1 mg. Mean ⁇ standard error and all possible comparisons are made via Duncan's Multiple Range
  • the compounds of this invention can be used to treat allergies in mammals (e.g., humans) and a preferred use is for treating allergic chronic obstructive lung disease (sometimes referred to as COPD or chronic obstructive pulmonary disease).
  • Chronic obstructive lung disease as used herein means disease conditions in which the passage of air into and out of the lungs is obstructed or diminished such as is the case in asthma, allergic or seasonal rhinitis, and/or bronchitis and the like.
  • the compounds of this invention inhibit 5- lipoxygenase (5-LO) activity, which inhibitory activity has been associated with antiallergic, antiinflammatory and antihyperproliferative activity.
  • the compounds of the invention are thus useful for the treatment of allergic diseases as discussed above, inflammatory diseases and hyperproliferative skin diseases.
  • the inflammatory diseases which may be treated include arthritis, bursitis, tendonitis, gout and inflammatory bowel disease.
  • Hyperproliferative skin disease means any condition a symptom of which is accelerated skin cell production, flaking, scales or papular lesions.
  • hyperproliferative skin diseases include for example, psoriasis, lichenified eczema, dandruff and the like.
  • the compounds of this invention can be administered in any number of conventional dosage forms, e.g., topical, oral, parenteral, rectal, transdermal, inhalation and the like.
  • Oral or rectal dosage forms include capsules, tablets, pills, powders, cachets and suppositories.
  • Liquid oral dosage forms include solutions and suspensions.
  • Parenteral preparations include sterile solutions and suspensions.
  • Inhalation administration can be in the form of a nasal or oral spray, or by insufflation.
  • Topical dosage forms can be creams, ointments, lotions, transdermal devices (e.g., of the conventional patch or matrix type) and the like and are preferred for treating hyperproliferative skin diseases.
  • compositions and pharmaceutical compositions contemplated by the above dosage forms can be prepared with conventional pharmaceutically
  • Such pharmaceutically acceptable excipients and additives are intended to include carriers, binders, flavorings, buffers, thickeners, color agents, stabilizing agents, emulsifying agents, dispersing agents, suspending agents, perfumes, preservatives lubricants, etc.
  • Suitable pharmaceutical acceptable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium
  • Capsules can be made wherein the active compound is inserted into pharmaceutically acceptable capsules as a carrier.
  • the active compounds of this invention can be mixed with pharmaceutically acceptable excipients or be used in finely divided powder form without excipients for inclusion into the capsules.
  • cachets are included.
  • Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. Liquid preparations can also be formulated in solution in polyethylene glycol and/or propylene glycol, which may contain water.
  • Aqueous solutions suitable for oral use can be prepared by adding the active component in water and adding suitable colorants, flavors, stabilizing, sweetening, solubilizing and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the active component in finely divided form in water with viscous material, i.e., pharmaceutically acceptable natural or synthetic gums, resins, methylcellulose, sodium
  • Formulations for topical application may include the above liquid forms, as well as creams, aerosols, sprays, dusts, powders, lotions and ointments which are prepared by combining an active ingredient according to this invention with conventional
  • Ointment and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • bases may, thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as peanut oil or castor oil.
  • Thickening agents which may be used according to the nature of the base include soft paraffin, aluminum
  • polyethylene glycols woolfat, hydrogenated lanolin, beeswax, etc.
  • Lotions may be formulations with an aqueous or oil base and will, in general, also include one or more of pharmaceutically acceptable stabilizing agents,
  • emulsifying agents dispersing agents, suspending agents, thickening agents, coloring agents, perfumes and the like.
  • Powders may be formed with the aid of any suitable pharmaceutically acceptable powder base, e.g., talc, lactose, starch, etc.
  • Drops may be formulated with an aqueous base or non-aqueous base also comprising one or more pharmaceutically acceptable dispersing agents, suspending agents, solubilizing agents, etc.
  • the topical pharmaceutical compositions may also include one or more preservatives or bacteriostatic agents, e.g., methyl hydroxybenzoate, propyl
  • topical pharmaceutical compositions may also contain an active compound of this invention in combination with other active ingredients such as antimicrobial agents, particularly antibiotics,
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • These particular solid form preparations are most conveniently provided in unit dose form and as such are used to provide a single liquid dosage unit. Alternatively, sufficient solid may be provided so that after conversion to liquid form, multiple individual liquid doses may be obtained by measuring predetermined volumes of the liquid form preparation as with a syringe, teaspoon or other volumetric container. When multiple liquid doses are so prepared, it is preferred to maintain the unused portion of said liquid doses under conditions which retard possible decomposition.
  • the solid form preparations intended to be converted to liquid form may contain, in addition to the active material,
  • flavorants pharmaceutically acceptable flavorants, colorants, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like.
  • preparation may be water, isotonic water, ethanol, glycerine, propylene glycol and the like as well as mixtures thereof.
  • solvent utilized will be chosen with regard to the route of administration, for example, liquid preparations containing large amounts of ethanol are not suitable for parenteral use.
  • the compounds of this invention may also be deliverable transdermally for systemic distribution.
  • the transdermal compositions can take the form of creams, lotions and/or emulsions and can be included in a
  • transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • the compounds of this invention may be administered by any conventional mode of administration, by employing an anti-allergic, anti-inflammatory or antihyperproliferative effective amount of a compound of this invention for such mode.
  • the dosages may be varied depending upon the requirements of the patient in the judgment of the attending clinician, the severity of the condition being treated and the particular compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art.
  • Treatment can be initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage should be increased by small increments until the optimum effect under the circumstances is reached.
  • the total daily dosage may be divided and administered in portions during the day if desired.
  • dosages of from about 0.1 to about 100 mg/kg of body weight per day may be administered.
  • parenterally, e.g., intravenously the compounds exhibit antiallergy activity at dosages of from about 0.1 to about 5 mg/kg body weight and preferably about 0.1 to about 2.5 mg/kg, and when administered by inhalation (aerosol or nebulizer) the compounds exhibit antiallergy activity at dosages of about 0.1 to about 5 mg per puff, and one to four puffs may be taken every 4 hours.
  • the dosage to be administered and the route of administration depends upon the particular compound used, the age and general health of the patient and the severity of the allergic condition. Thus, the dose ultimately decided upon must be left to the judgment of a trained health-care practitioner.
  • the compounds of this invention can be any organic compound having the same properties as the compounds of this invention.
  • the compounds of this invention may be administered at doses of about 0.1 to about 100 mg/kg of body weight per day, and preferably about 5 to about 50 mg/kg per day.
  • the total dosages are administered in 2 to 4 divided doses per day.
  • an oral dosage range of from about 5 mg/kg of body weight per day to about 50 mg/kg of body weight per day in divided doses taken at about 4 hour intervals may be used.
  • the compounds of this invention When administered for the treatment of hyperproliferative skin disease, the compounds of this invention may be administered topically, orally, rectally or parenterally, with topically preferred.
  • the amount of compound administered varies widely with the amount of skin being treated, as well as with the concentration of active ingredient applied to the affected area.
  • topical compositions contain from about 0.10 to about 10 percent by weight of the active ingredient and are applied as needed according to the judgment of the attending clinician.
  • the compounds of formula I are effective for the treatment of hyperproliferative skin disease at daily doses ranging from about 0.1 mg/kg to about 100 mg/kg of body weight, preferably from about 5 mg/kg to about 50 mg/kg, which may be administered in divided doses.
  • the compounds of this invention When administered rectally, the compounds of this invention may be administered in daily doses ranging from about 0.1 mg/kg to about 100 mg/kg.
  • the compounds of this invention are effective for the treatment of hyperproliferative skin disease in daily doses ranging from about 0.1 mg/kg body weight to about 10 mg/kg body weight which may be administered in divided doses.
  • a remission of the symptoms of the psoriatic patient in most cases, can be expected.
  • one affected by psoriasis can expect a decrease in scaling, erythema, size of the plaques, pruritus and other symptoms associated with psoriasis.
  • the dosage of medicament and the length of time required for successfully treating each individual psoriatic patient may vary, but those skilled in the art of medicine will be able to recognize these variations and adjust the course of therapy accordingly.
  • compositions of this invention exemplify some of the dosage forms of the compositions of this invention.
  • active compound refers to compound 41.
  • this compound may be replaced by equally effective amounts of other compounds, e.g. those of formulas 42, 43, 44, 45 or 46 of this invention.
  • Active compound 100 500 2. Lactose US P 1 06 1 23 3. Corn Starch, Food Grade 40 70
  • Disperse active compound in a portion of the mineral oil Mix and heat to 65°C, a weighed quantity of white petrolatum, the remaining mineral oil and benzyl alcohol, and cool to 50°-55°C. with stirring. Add the dispersed active compound to the above mixture with stirring. Cool to room temperature.
  • the compound of Formula 41 (0.5 g) was stirred at room temperature in 3 ml of pyridine and 1 .0 ml of AC 2 O . The solution was stirred at room temperature for 16 hours, then the solvents were removed using high vacuum. The residue was treated with water and extracted with CH 2 CI 2 . The combined extracts were washed with water and dried (Na 2 SO 4 ). The reaction mixture was purified by flash chromatography (15% EtOAc/Hexanes) yielding the compund of Formula 42 (93%). MS(EI) m/e 472 (M+) .
  • a compound of Formula 41 (0.92 g; 2.14 mmoles) in 2.5 ml of dry CH 2 CI 2 was added to a suspension of 1.21 g (3.21 mmoles) of PDC in dry CH 2 CI 2 (1.0 ml). The mixture was stirred at room temperature under N 2 for 16 hours. The mixture was diluted with Et 2 O and the solid is filtered through "Celite". The reaction mixture was purified by flash chromatography (15% EtOAc/petroleum ether) yielding the compound of Formula 43 (45%). MS(EI) m/e 428 (M+) .
  • reaction mixture was purified by flash chromatography (10% EtOAc/Hexanes) yielding the
  • a compound of Formula 44 (1.64 g) was stirred at room temperature under N 2 in 20 ml of absolute EtOH and 10 ml of 10% aqueous KOH.
  • Oxalyl chloride (0.2 ml; 2.3 mmoles) was added slowly dropwise to a precooled (ice bath) dry CH 2 CI 2 (4.0 ml) solution of the compound of Formula 45 (0.444 g; 1.0 mmoles) and dry DMF (93 ml; 1.2 mmoles). Vigorous gas evolution occurred. After the addition, the solution was stirred for 30 minutes, then was added via syringe dropwise to a precooled (ice bath) solution of NH 2 OH.HCI (0.278 g; 4 mmoles) and Et3N (6 mmoles; 0.64 ml) in THF (1.5 ml) and water (0.75 ml).

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Abstract

On a mis au point des nouveaux composés de la formule (1), un sel ou un solvate pharmaceutiquement acceptable de celle-ci. On a également mis au point des compositions pharmaceutiques contenant des composés de la formule (1), ainsi que des procédés de traitements d'allergies d'inflammations et de dermatoses hyperprolifératives à l'aide des composés de la formule (1).
EP19900916941 1989-10-19 1990-10-17 Inhibiteurs de lipoxygenase Ceased EP0495917A1 (fr)

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DE4124345A1 (de) * 1991-07-23 1993-01-28 Gruenenthal Gmbh Substituierte 3,4-dihydronaphthaline, diese verbindungen enthaltende arzneimittel und verfahren zur herstellung dieser verbindungen und arzneimittel
KR100270410B1 (ko) * 1997-03-06 2000-11-01 성재갑 타이로시네이즈 활성 저해능을 갖는 신규 1,3-디페닐프로판 유도체 및 그의 제조방법
KR19990069212A (ko) * 1998-02-05 1999-09-06 성재갑 타이로시나제 저해활성을 갖는 신규 폴리하이드록시-디페닐메탄유도체 및 그의 제조방법
KR19990069211A (ko) * 1998-02-05 1999-09-06 성재갑 타이로시나제 저해활성을 갖는 신규 폴리하이드록시-디페닐알칸유도체 및 그의 제조방법

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