EP0419561A1 - Composes heterobicycliques presentant une activite anti-inflammatoire - Google Patents

Composes heterobicycliques presentant une activite anti-inflammatoire

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Publication number
EP0419561A1
EP0419561A1 EP89907545A EP89907545A EP0419561A1 EP 0419561 A1 EP0419561 A1 EP 0419561A1 EP 89907545 A EP89907545 A EP 89907545A EP 89907545 A EP89907545 A EP 89907545A EP 0419561 A1 EP0419561 A1 EP 0419561A1
Authority
EP
European Patent Office
Prior art keywords
pyrrolo
dihydro
pyridin
compound
formula
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.)
Pending
Application number
EP89907545A
Other languages
German (de)
English (en)
Inventor
Pauline C. Ting
Margaret H. Sherlock
Wing C. Tom
James J. Kaminski
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 Corp
Original Assignee
Schering Corp
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Filing date
Publication date
Application filed by Schering Corp filed Critical Schering Corp
Publication of EP0419561A1 publication Critical patent/EP0419561A1/fr
Pending legal-status Critical Current

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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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • 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]
    • 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
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to certain heterobicyclic compounds having antiinflammatory activity and antiallergic conditions and to pharmaceutical compositions and methods employing such compounds.
  • U.S. Patent No. 4,569,942 discloses certain 2-oxindole-1-carboxamide compounds having an acyl substituent at the 3 -position as having analgesic and antiinflammatory activities.
  • European published patent Application No. 0 175 551 discloses 1,3-diacyl-2-oxindole compounds, while European published patent Application Nos. 0 181 136 and 0 173 520 disclose substituted 2-oxindole-3-carboxamides and tricyclic and quadracyclic compounds including the 2-oxindole-3-carboxamide unit as antiinflammatory agents.
  • the art also includes numerous, disclosures of 3,3-disubstituted 2-oxindoles, as pharmaceutically active compounds, e.g. British Patent No. 1,132,318, Dutch Patent Application No. 6604752 (anti-inflammatory), and South African Patent 68-01099 (antidepressants).
  • 1,3-dihydro-3,3-dimethyl-2H-[2,3-b]-pyridin-2-one is disclosed by Ficken et al. in J. Chem. Soc. 747-89 (1961). No pharmaceutical utility is mentioned for the compound.
  • R is substituted phenyl, and are useful for inflammatory conditions.
  • A represents a fused 5- or 6-membered heterocyclic aromatic ring containing 1 to 3 heteroatoms in the ring, each heteroatom independently represents O, S, N or NR6 wherein R 6 in the group NR 6 is hydrogen or C i to C 4 alkyl; the dotted lines represent optional double bonds, such that when the bond to X is a double bond, X is O or S; and when the bond to X is a single bond, X is -OR 1 0 wherein R 10 is alkyl or aralkyl;
  • T 2 and T 3 independently represent S, SO or SO 2 ; m and n independently represent 0 or 1 ;
  • R 1 represents hydrogen, alkyl, aryl, aralkyl, or a 5- or 6-membered heterocyclic aromatic ring having from 1 to 3 heteroatoms in the ring, each heteroatom independently selected from NR 6 , O, S or N atoms;
  • R 2 and R 3 independently represent - hydrogen with the proviso at least one of R 2 and R 3 is not hydrogen;
  • D represents an alkylene group having from 1 to 4 carbon atoms and R 4 is alkyl, aryl or aralkyl;
  • each Y substituent independently represents -OH, hydroxyalkyl, alkyl, halogen, -NO 2 , alkoxy, alkoxyalkyl, alkylthio, -CF 3 , -CN, cycloalkyl, alkynyloxy, alkenyloxy, -S(O)p-R 4 (wherein R 4 is defined above and p is an integer from 0 to 2), -CO-R 5 (wherein R 5 represents -OH, - NH 2 , -NHR 4 , N(R 4 )2 or -OR 4 in which R 4 is as defined above), - O-D-CUR 5 (wherein D is defined above and R 5 is as defined above), -
  • halogen - represents fluoro, chloro, bromo or iodo
  • alkyl including the alkyl portions of alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl
  • alkyl represents straight and branched hydrocarbon chains and contains from 1 to 6, preferably 1 to 4, carbon atoms; for example methyl (ie. -CH 3 ), ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl and the like.
  • alkenyloxy - represents straight and branched hydrocarbon chains having at least one carbon to carbon double bond, and unless otherwise specified, contains from 3 to 6 carbon atoms, the alkenyl group thereof being bonded to an adjacent structural element through an oxygen atom;
  • alkynyloxy - represents straight and branched hydrocarbon chains having at least one carbon to carbon triple bond, and unless otherwise specified, contains from 3 to 6 carbon atoms, the alkynyl group thereof being bonded to an adjacent structural element through an oxygen atom;
  • alkylene - represents divalent, straight or branched hydrocarbon chains having from 1 to 4 carbon atoms, such alkylene group being bonded to two adjacent structural elements from the same or different carbon atoms; substituted phenyl - represents a phenyl group substituted with one to three Y groups and the Y groups may be the same or different;
  • cycloalkyl - represents saturated carbocyclic rings having from 3 to 7 carbon atoms, for example cyclopropyl
  • spirocarbocyclic ring - a cycloalkyl moiety containing 3 to 7 carbon atoms covalently bonded to an adjacent structural element through one carbon atom in the cycloalkyl moiety;
  • aryl - represents a carbocyclic moiety containing at least one benzenoid-type ring, with the aryl groups preferably containing from 6 to 15 carbon atoms, for example, phenyl, napthyl, indenyl, indanyl, and the like.
  • aralkyl - represents an aryl moiety of 6 to 15 carbon atoms covalently bonded to an alkyl moiety of one to six carbon atoms such as, for example, benzyl, phenylethyl, and the like; trifluoromethyl - represented by -CF 3 ; cyano - represented by -CN; nitro - represented by -NO 2 ; hydroxyalkyl - an alkyl moiety in which one or more of the hydrogens is replaced by a hydroxy moiety, such as, for example, hydroxymethyl (i.e. -CH 2 OH), hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxyhexyl and the like.
  • alkylthio - refers to an alkyl group bonded to a sulfur atom, for example, methylthio (ie. CH 3 S-), ethylthio and the like.
  • alkylsulfinyl - refers to an alkyl group bonded to a sulfinyl group, for example methylsulfinyl(ie.CH 3 SO-), ethylsulfinyl and the like
  • alkylsulfonyl - refers to an alkyl group bonded to a sulfonyl group, for example, methylsulfonyl(ie.CH 3 SO 2 -), ethylsulfonyl and the like.
  • alkoxyalkyl - represents an alkoxy moiety of 1 to 6 carbon atoms covalently bonded to an adjacent structural element through an alkyl moiety of 1 to 6 carbon atoms.
  • heterocyclic aromatic ring (R 1 ) - represents cyclic groups having at least one NR 6 , O, S and/or N in the ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the aromatic heterocyclic groups, preferably containing from 2 to 14 carbon atoms, e.g., 2-, 3- or 4- pyridyl, 2- or 3-furyl, 2- or 3-thienyl, 2-, 4- or 5-thiazolyl, 2- or 4-imidazoyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, 3- or 4-pyridazinyl, 3-,5- or 6-[1,2,4-triazinyl], 2-, 3-, 4-, 5-, 6- or 7-benzofuranyl,2-, 3-, 4-, 5-, 6-
  • R 1 is C 1 to C 4 alkyl, phenyl, substituted phenyl, 2-, 3 - or 4-pyridyl, 2- or 3-furyl, 2- or 3-thienyl, 2-, 4- or 5-thiazoyl and 2- or 4-imidazolyl with phenyl and substituted phenyl being most preferred.
  • A represents a pyridine ring
  • each Y defined as Y 1 independently represents hydrogen, halogen preferably chloro or fluoro, alkoxy preferably methoxy, alkylthio preferably methylthio, alkylsulfinyl preferably methylsulfinyl, or alkylsulfonyl preferably methylsulfonyl
  • R 2 and R 3 ie. m and n are zero
  • X is O or S, preferably O wherein the Y 1 substituent(s) can be in any available position(s).
  • Y 1 is as above defined.
  • R 2 and R 3 both represent methyl or ethyl or one represents methyl or ethyl and the other is halogen, preferably fluoro, are particularly useful.
  • Y, ring A, T 2 , T 3 , m, n, R 1 , R 2 and R 3 are as defined hereinbefore.
  • ring A is
  • X is O, more preferably where T 2 is S and n is zero.
  • Y 1 R 7 , T 2 , D, Rland R 4 are as defined hereinbefore.
  • Y 1 is hydrogen
  • R 1 is phenyl
  • D is
  • R 4 and R 7 are methyl, otherwise known as 1,3-dihydro-3-(2-acetoxy-ethylthio)-3-(1-oxoethyl)-N-phenyl-2-H-pyrrolo(2,3-b)pyridin-2-one.
  • Another preferred group of compounds is characterized by the general, formula
  • Y 1 , R 1 , R 10 , T 2 and R 2 are as defined hereinbefore.
  • Y 1 is hydrogen
  • R 1 and R 2 are phenyl
  • T 2 is S and R 10 is methyl.
  • Y 1 is hydrogen
  • A is 2-, 3-pyridyl and R 1 represents halophenyl, more preferably chlorophenyl, most preferably 4-chlorophenyl, m and n are zero and R 2 and R 3 are methyl.
  • R 2 and R 3 are as defined hereinbefore and Z is a hydrogen atom or a salt such as sodium, potassium and the like.
  • a number of the compounds may contain an asymmetric center and thus can exist in optically active stereoisomeric forms such as the R and S enantiomer forms.
  • optically active stereoisomeric forms such as the R and S enantiomer forms.
  • the various mixtures and racemates of the above isomers are within the scope of the present invention.
  • Certain compounds of the invention can also form pharmaceutically acceptable salts with organic and inorganic acids, e.g., a pyrido- or pyrazino-nitrogen atoms may form salts with strong acid, while compounds having basic Y substituents such as amino groups also form salts with weaker acids.
  • suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicyclic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those 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 conventional manner.
  • the free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate.
  • a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate.
  • the free base forms differ from the 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 forms for purposes of the invention.
  • some compounds of this invention are acidic, e.g., when Y is OH, and can form salts with inorganic and organic bases.
  • the compounds of formulas I and II may be prepared by general processes known in the art. Basically, the processes comprise either adding one or more of the substituents R 1 , R 2 and R 3 to the existing fused ring nucleus or completing the fused ring structure by an intramolecular condensation. Such processes can be illustrated by the reaction schemes A to N below, in which R 1 , R 2 , R 3 , X and A are as defined above, unless otherwise indicated.
  • R 2 and R 3 are the same:
  • the process is preferably carried out by first adding the base (e.g. sodium hydride, potassium hydride, lithium diisopropylamide, lithium hexamethyldisilazide) to III in an inert solvent (e.g. ether such as diethyl ether, tetrahydrofuran, dioxane or polar aprotic solvents such as N,N- dimethylformamide, N,N-dimethylacetamide, dimethylsulf oxide), preferably under an inert atmosphere (N 2 ), followed by addition of R 2 L wherein L represents a good leaving group, e.g., when R 2 is lower alkyl, L can be chloride, bromide, iodide, mesylate, tosylate, etc.
  • an inert solvent e.g. ether such as diethyl ether, tetrahydrofuran, dioxane or polar aprotic solvents such as N,N- dimethylformamide
  • R 2 L represents halogenating agents such as Br 2 , Cl 2 , diethylaminosulfurtrifluoride (DAST) or N- bromosuccinimide.
  • This ring closure reaction can be carried out by treating the acid (V) or a reactive derivative thereof with a suitable condensation reagent.
  • the reaction could be carried out by the use of paratoluenesulfonic acid.
  • a further possibility is first to activate the acid by reaction with a halogenating agent and the amine with a base.
  • the halogenating agents, bases and solvents referred to above may be used.
  • the preferred solvents for the dehydration reaction are higher boiling protic solvents such as pentanol and hexanol.
  • This intramolecular ring closure reaction may be performed by treating VI with an activating agent such as acetic, acid, trifluoroacetic acid or propionic acid or a dehydrating agent such as dicyclohexylcarbodiimide or 1-ethyl-3-(3- dimethylaminopropyl)-carbodiimide in an inert solvent such as chlorinated hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, chloroform) or ethers (e.g., diethyl ether, tetrahydrofuran or dioxane) at temperatures ranging from 0° to 25°C.
  • an activating agent such as acetic, acid, trifluoroacetic acid or propionic acid
  • a dehydrating agent such as dicyclohexylcarbodiimide or 1-ethyl-3-(3- dimethylaminopropyl)-carbodiimide
  • an inert solvent such
  • this exchange of sulfur for oxygen can possibly be carried out at an earlier stage in the preparation of the final compounds, e.g. where preparing some of the starting compounds (III) to (VIII).
  • the replacement of oxygen by sulfur can be achieved by treating the starting compound with any suitable sulfurylating agent, e.g. Lawesson's reagent or P 2 S 5 in a suitable solvent, e.g. toluene, benzene or xylene at elevated (reflux) temperatures, e.g., 110°C to 140°C.
  • the process is carried out by first treating (VII) with a base and thereafter adding the alkylating reagent LR 1 .
  • the bases, alkylating agents and solvents used may be the same as those referred to above, e.g. under process A.
  • This alkylation reaction can be conveniently carried out by using standard procedures, e.g. similar to those described under process A.
  • Compound (I)(f) wherein T 2 is S can be prepared by treating a compound of formula (III) with N-chlorosuccinimide (NCS) and any suitable sulfide in any suitable solvent.
  • suitable solvents include the chlorinated hydrocarbons cited above, preferably chloroform, or ether solvents such as diethyl ether, tetrahydrofuran, dioxane and the like. The reaction can be carried out at temperatures ranging from 0°C to about 25°C.
  • R 2 is different from R 3 :
  • Compound (f) can be prepared using essentially the same reagents and process conditions as described in process H above.
  • suitable solvents include the chlorinated hydrocarbons cited above, or ether solvents such as diethyl ether, tetrahydrofuran, dioxane and the like. The reaction can be carried out at temperature ranging from 0°C to about 25°C.
  • the solvent employed will vary, depending upon the oxidation agent. Representative solvents include the chlorinated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform and the like; and can include protic solvents such as water, methanol or ethanol.
  • the reaction can be carried out at temperatures in the range of 0°C to ambient, preferably about 25°C to give compound (I) wherein T 2 is SO.
  • T 2 is SO
  • a suitable oxidizing agent for oxidizing SO to SO 2 such as for example, m-chloroperoxybenzoic acid, hydrogen peroxide, sodium perborate, potassium permanganate and the like.
  • the solvent employed will vary, depending upon the oxidation agent. Representative solvents include the chlorinated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform and the like; and can include protic solvents such as water, methanol or ethanol.
  • M Preparation of compounds wherein T 2 is S, and a single bond is at the 2-position:
  • a base such as potassium hydride or potassium diiosopropylamide in a polar aprotic solvent (such as N,N- dimethylformamide, N,N-dimethylacetamide and the like)
  • a polar aprotic solvent such as N,N- dimethylformamide, N,N-dimethylacetamide and the like
  • R 10 L wherein L represents a suitable leaving group, such as for example, chloride, bromide, iodide, mesylate, tosylate and the like to give compound (I) having a single
  • the compounds of formula (II) can be prepared by treating the compounds of formula (I) wherein T 2 is S, SO or SO 2 with a strong base such as sodium hydroxide, in the presence of any suitable solvent at temperatures in the range of reflux, for example 60 to 100°C.
  • suitable solvents include protic solvents such as methanol, ethanol and the like.
  • the compounds of formulas I and ⁇ may be prepared by the following processes as follows.
  • R 2 L wherein L represents a good leaving group such as chloride, bromide, iodide, mesylate, tosylate,and R 2 is as defined hereinbefore in the presence of an inert solvent to give the compound of formula I;
  • R 2 and R3 are the same or different and T 2 and T 3 are not present, react a compound of the formula:
  • an activating agent such as acetic acid, trifluoroacetic acid or propionic acid or a dehydrating agent such as dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide in an inert solvent to give the compound of formula I;
  • R 2 and R 3 are all the same alkyl group, react a compound of the formula:
  • N-chlorosuccinimide N-chlorosuccinimide
  • a suitable sulfide N-chlorosuccinimide
  • T 3 S and R 2 is different from R 3 , react a compound of the formula:
  • N-chlorosuccinimide N-chlorosuccinimide
  • a suitable sulfide N-chlorosuccinimide
  • NCS N-chlorosuccinimide
  • this substituent can be oxidized to -SO-(lower alkyl) and -SO 2 -(lower alkyl); hydroxy groups can be transformed into an alkoxy-, acyloxy-, alkenyloxy- or alkynyloxy- group; primary amino groups can be transformed into -NHR 4 or -N(R 4 ) 2 ; and so on.
  • the starting compounds II to VIII used in the above processes are either known or they may be prepared according to processes well-known in the art.
  • the starting compounds of formula III may be prepared according to the following reaction scheme:
  • Step 1 The preferred leaving groups are chlorine, bromine, mesylate and tosylate and any suitable base such as pyridine or a tertiary amine can be used.
  • a protic high boiling solvent such as water, pentanol and hexanol and the reaction temperature used depends on this solvent (for the above solvents: 100-150°C).
  • Step 2 Any suitable reduction agent for reducing CO to CH 2 can be used, e.g. lithium aluminum hydride, diisobutylaluminum hydride, borane, aluminum hydride, etc. Ethers, tetrahydrofuran and dioxane are preferred solvents. Reaction proceeds at 0°C to 60°C.
  • Step 3 The activation means replacing the OH group by a reactive leaving group and accordingly the activating agent used depends on the desired leaving group.
  • Typical examples are thionyl chloride, phosphorus trichloride, phosphorus oxychloride, oxalyl chloride, mesyl chloride and tosyl chloride.
  • Suitable solvents are chlorinated hydrocarbons (e.g. dichloromethane, 1,2- dichloroethane, chloroform) or ethers, tetrahydrofuran and dioxane.
  • Preferred temperature range is 0°C to 25°C.
  • Step 4 Alkali metal salts of the lower alkanoates or alkali metal hydroxides are the preferred bases, e.g. sodium methoxide, sodium ethoxide, sodium hydroxide.
  • the reaction is usually carried out in a protic solvent (e.g. water, methanol, ethanol) at temperatures between 0°C and 25°C.
  • a protic solvent e.g. water, methanol, ethanol
  • Step 5 Compound (e) is first treated with a base such as n-butyl lithium or sec-butyl lithium in a solvent (e.g. diethyl ether, tetrahydrofuran or dioxane) at lower temperature, e.g. -78°C to 0°C. The mixture is treated with C ⁇ 2 and then the acid is added. Any suitable acid can be used, e.g. acetic acid, trifluoroacetic acid, propionic acid and the like.
  • Step 6 Starting compounds III is obtained by eliminating the SPh - group from the compound (I)-(f).
  • This is preferably achieved by treating (I)-(f) with Zn and trimethylsilyl-chloride (TMSC1) or with Raney nickel in a suitable solvent such as an ether (diethyl ether), tetrahydrofuran or dioxane at room temperature.
  • TMSC1 trimethylsilyl-chloride
  • Raney nickel a suitable solvent such as an ether (diethyl ether), tetrahydrofuran or dioxane at room temperature.
  • the starting compounds of formula IV may be obtained by first treating compound (I)-(f) above with the alkylating or halogenating reagent (R 2 L or R 3 L), followed by elimination of the -SR 2 group:
  • the conditions and reagents for introducing the R 2 group and for the elimination of -SR 2 may be the same as those used in process A and in Step 6 above, respectively.
  • R 2 and R 3 may be achieved by using reagents and conditions as defined for process A.
  • R 4 is alkyl such as ethyl.
  • the last step is a simple hydrolysis of the ester with a base.
  • Starting compounds of formula VI are conveniently prepared by reacting compound (g) above with R 1 NH 2 in the presence of a base (e.g., pyridine or a tertiary amine such as trimethylamine, triethylamine, tributylamine, N-methylmorpholine, N-methylpiperidine) in a high boiling protic solvent (e.g., water, pentanol, hexanol, etc.) at elevated temperature (reflux).
  • a base e.g., pyridine or a tertiary amine such as trimethylamine, triethylamine, tributylamine, N-methylmorpholine, N-methylpiperidine
  • a high boiling protic solvent e.g., water, pentanol, hexanol, etc.
  • the compounds of the invention may thus be used to treat arthritis, bursitis, tendonitis, gout and other inflammatory or hyperproliferative conditions of the skin (ie. eczemas or psoriasis ) and other organs (ie. bowel diseases).
  • Such compounds can also be used to treat allergic conditions such as allergic rhinitis or coryza, hay fever, bronchial asthma and urticaria(hives).
  • NSAID nonsteroidal antiinflammatory drugs
  • cyclooxygenase pathway which converts arachidonic acid to prostaglandins.
  • the NSAIDs have limited efficacy since the cause of rheumatoid arthritis involves more than one mechanism.
  • proinflammatory leukotrienes including a chemoattractant for neutrophils, leukotriene B4, which is formed from arachidionic acid via the
  • a drug that inhibits both the cyclooxygenase and 5-lipoxygenase pathways may be a superior antiinflammatory agent for particular applications relative to one that inhibits only one of these pathways.
  • the sulfur containing compounds of formulas I and II wherein T 2 or T 3 is S, SO or SO 2 inhibit primarily the 5-LO derived products of arachidonic acid metabolism.
  • Such compounds may be more useful for topical applications, such as for treating inflammatory skin diseases
  • Such compounds are also useful for treating allergic conditions such as those described hereinabove.
  • RPAR Reversed Passive Arthus Reaction
  • Groups of 4 male rats were injected in the penile vein with antigen (1 mg BSA in 0.2 mL of saline per rat) and 0.5 hour later injected in the pleural cavity with antibody (1.0 mg antibody protein in the IgG fraction of rabbit anti-BSA in 0.2 mL). Sham control animals were treated as RPAR animals but did not receive BSA antigen. After 4 hours the animals were killed with CO 2 , and the pleural cavities were opened and the exudate drained into a graduated conical glass centrifuge tube containing indomethacin (1.8 ug) and nordihydroguaiaretic acid (NDGA) (15 ug) to block ex vivo metabolite synthesis. The volume of the exudate was measured.
  • the cavity was then washed out with saline-EDTA to achieve a final volume of 5.0 mL.
  • the number of cells were determined in a Coulter Counter. The cells were spun-down (1000 x g) and the exudate supernatant was added to 4 volumes of 95% ethanol and samples were kept on ice for 30 minutes. After removal of the protein precipitate (2,500 x g) the ethanol extract of the exudate was dried under N 2 and then stored at -20°C. For radioimmunoassay (RIA) analysis the samples were redissolved in water to a volume of 1 mL per rat.
  • RIA radioimmunoassay
  • TXB 2 tritiated thromboxane B 2
  • LTE 4 tritiated leukotriene-E4
  • Exudate samples were directly assayed in duplicate with the commercial 3H-TXB 2 RIA kit from New England Nuclear and the 3 H-LTC 4 /D 4 /E 4 kit from Amersham.
  • the assay was validated using reversed-phase HPLC analysis of LTs in the standard procedure described by M.W. Musch, R.W. Bryant, C. Coscollaela, R.F. Myers and M.I. Siegel, Prostaglandins.
  • PMN leukocytes Human polymorphonuclear (PMN) leukocytes (neutrophils) are obtained from normal healthy volunteers by venipuncture and collected with heparin anticoagulant. Neutrophils are isolated by Dextran/Ficol sedimentation as described (Billah et al, J. Biol. Chem. 260. 6899-6906 (1985)). In brief, 30 ml of blood is mixed with 5 ml of dextran (Sigma) solution and kept at 37°C for 30 min. The upper white cell- rich layer is removed and 10 ml is layered on 9 ml of Ficol- Paque solution (Pharmacia) and centrifuged at 280 x g for 10 min. at .5°C.
  • PMN Human polymorphonuclear
  • the supernatant is removed and the neutrophil pellet is resuspended in HEPES buffer containing 25 mM N-2-hydroxyethylpiperazine-N 1 -2 ethanesulfonic acid(HEPES), 125 mM NaCl, 2.5mM KCL, 0.7mM MgCh, 0.5mM and 10mM glucose at pH 7.4.
  • HEPES buffer containing 25 mM N-2-hydroxyethylpiperazine-N 1 -2 ethanesulfonic acid(HEPES), 125 mM NaCl, 2.5mM KCL, 0.7mM MgCh, 0.5mM and 10mM glucose at pH 7.4.
  • the red cells in the suspension are lysed by hypotonic shock.
  • the neutrophils are washed by centrifugation in HEPES buffer two times and finally resuspended at a concentration of 20 x 10 6 cells/ml in the presence of 1 mM CaCl 2 .
  • Neutrophils (0.2 ml of suspension) are preincubated with dimethylsulf oxide (DMSO) vehicle with or without test compound (1 ul) for 4 minutes then incubated for 5 minutes with 14 C-arachidonic acid (Amersham, 59 Ci/mole) at a 9 uM final concentration, and the calcium ionophore A23187 (Calbiochem) at a 1 uM final concentration.
  • DMSO dimethylsulf oxide
  • 14 C-arachidonic acid Amersham, 59 Ci/mole
  • Ca23187 calcium ionophore A23187
  • methanol is exchanged for the initial eluting solvent and by 35 minutes the column is reequilibrated for the next sample.
  • the effluent is analyzed by a continuous flow radioactivity monitor (model ROMONA-D) interfaced with a Hewlett Packard Lab Automation System for quantitation of radioactive products. This includes the major 5-lipoxygenase product, 5-hydroxyeicosatetraenoic acid (5-HETE) which elutes at 20 minutes. The results with and without test compound are used to calculate percent inhibition of 5-HETE production.
  • Blood is collected in acid-citrate-dextrose anticoagulant by venipuncture from normal healthy volunteers who said that they were not on any medication for the previous two weeks. Platelets are isolated by the procedure of Okuma and Uchino (Blood 54:1258-1271(1979)). In brief, blood is centrifuged at 4°C at 200 x g for 10 minutes to sediment red and white cells. The platelet rich plasma (PRP) supernatant is removed and mixed with one-tenth volume of 77mM EDTA, pH 7.2 and prostacyclin sodium salt is added to the PRP at a final concentration of 1 nanogram per milliliter(ng/mL). The PRP is centrifuged at 1700 x g, 4°C for 15 minutes.
  • PRP platelet rich plasma
  • the platelet pellet is resuspended in the HEPES buffer described in the 5- lipoxygenase section above which additionally contained I ng/mL prostacyclin and 0.5mM ethylene glycolbis(B-aminoethyl ether) N,N,N',N'-tetraacetic acid (EGTA) and the suspension is recentrifuged at 1,700 x g, 4°C for 15 minutes.
  • the pellet is resuspended in HEPES buffer containing 0.5 mM EGTA and 1.5 mM CaCl 2 at a cell count of 200,000 cells/ul.
  • Platelets (0.2 ml of suspension) are preincubated with test compounds and the 14 C-arachidonic acid plus the calcium ionophore A23187 stimulant exactly as described for the 5-lipoxygenase assay.
  • the cyclooxygenase product 12-hydroxy-heptadecatrienoic acid (HHT) is isolated and quantitated by the HPLC system used for the 5-lipoxygenase assay. HHT elutes from this system at about eleven minutes. Results are expressed as percent inhibition of HHT production by the test compounds versus the test vehicle alone.
  • Compound No. 35 wherein for Formula (Iiii), Y 1 is H, R 1 is phenyl, T 2 is S and R 10 is methyl, otherwise known as 2-methoxy-1-phenyl-3-(phenylthio)-1H-pyrrolo[2,3-b]pyridine exhibits in the PMN assay a 55 percent inhibition of HHT and an 80 percent inhibition of 5-HETE.
  • Topical dosage forms can be creams, ointments, lotions, transdermal devices (e.g., of the conventional patch or matrix type) and the like.
  • compositions contemplated by the above dosage forms can be prepared with conventional pharmaceutically acceptable excipients and additives, using conventional techniques.
  • pharmaceutically acceptable excipients and additives are intended to include carriers, blinders, flavorings, buffers, thickeners, color agents, stabilizing agents, perfumes, preservatives, lubricants, etc.
  • the compounds of the invention can be administered in an amount ranging from about 0.1 mg/kg to about 100 mg/kg, preferably from 0.1 mg/kg to about 25 mg/kg per day. Determination of the proper dosage of a compound of the invention for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if required.
  • a typical recommended dosage regimen is oral administration of from 10 mg to 1500 mg/day preferably 10 to 750 mg/day, in two to four divided doses to achieve relief of the inflammation symptoms.
  • Step 5 1 -(4-Chlorophenyl) -1 ,3-dihydro-3-(phenylthio )- 2H- pyrrolo[2,3-b]pyridin-2-one (Compound E)
  • Step 6 1 -(4-Chlorophenyl)-1 ,3-dihydro-2H-pyrrolo[2,3 - pyridin-2-one (Compound F)
  • Step 1 1 ,3-Dihydro-3-methyl- 1 -phenyl-3 -(phenylthio)- 2H- pyrrolo[2,3-b]pyridin-2-one (Compound G)
  • Step 2 1 ,3-Dihydro-3-methyl-1 -phenyl-2H- ⁇ yrrolo[2,3-b] pyridin-2-one (Compound H)
  • Step 1 3-[2-(hvdroxy)-ethylthiomethvn-N-phenyl-2-pyridinamine(Compound AD).
  • Step 2 3-[2-(t-butyldimethylsilyloxy)-ethylthiomethyn-N-phenyl-2-pyridinamine(Compound AE):
  • Step 6 1 ,3-Dihydro-3-[2-(acetoxy)-ethylthio]-3-(1 -oxoethyl)-N-phenyl-2H-pyrrolo[2,3-b]pyridin-2-one(Compound AJ)

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

Abstract

L'invention concerne des composés intermédiaires hétérobicycliques hétérocycliques ainsi que leur utilisation dans le traitement anti-inflammatoire d'états cutanés hyperprolifératifs tels que le psoriasis et l'allergie.
EP89907545A 1988-06-14 1989-06-12 Composes heterobicycliques presentant une activite anti-inflammatoire Pending EP0419561A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US20655088A 1988-06-14 1988-06-14
US206550 2002-07-25

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EP0419561A1 true EP0419561A1 (fr) 1991-04-03

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EP89907545A Pending EP0419561A1 (fr) 1988-06-14 1989-06-12 Composes heterobicycliques presentant une activite anti-inflammatoire
EP89110571A Withdrawn EP0347698A1 (fr) 1988-06-14 1989-06-12 Composés hétérobicycliques ayant une activité anti-inflammatoire

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EP89110571A Withdrawn EP0347698A1 (fr) 1988-06-14 1989-06-12 Composés hétérobicycliques ayant une activité anti-inflammatoire

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EP (2) EP0419561A1 (fr)
JP (1) JPH0747573B2 (fr)
KR (1) KR900701784A (fr)
AU (1) AU3776589A (fr)
WO (1) WO1989012637A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991009598A1 (fr) * 1990-01-05 1991-07-11 Pfizer Inc. Derives de l'azaoxindole
US5023265A (en) * 1990-06-01 1991-06-11 Schering Corporation Substituted 1-H-pyrrolopyridine-3-carboxamides
US5278162A (en) * 1992-09-18 1994-01-11 The Du Pont Merck Pharmaceutical Company 3,3'-disubstituted-1,3-dihydro-2H-pyrrolo[2,3-b]heterocyclic-2-one useful in the treatment of cognitive disorders of man
US5296478A (en) * 1992-10-07 1994-03-22 The Dupont Merck Pharmaceutical Co. 1-substituted oxindoles as cognition enhancers

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Publication number Priority date Publication date Assignee Title
DE1196205B (de) * 1963-08-08 1965-07-08 Basf Ag Verfahren zur Herstellung von 4, 7-Diaza-2-oxindolderivaten
US4569942A (en) * 1984-05-04 1986-02-11 Pfizer Inc. N,3-Disubstituted 2-oxindole-1-carboxamides as analgesic and antiinflammatory agents
US4959368A (en) * 1986-02-24 1990-09-25 Mitsui Petrochemical Industries Ltd. Therapeutic agent for neurological diseases

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Title
See references of WO8912637A1 *

Also Published As

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JPH0747573B2 (ja) 1995-05-24
JPH03501615A (ja) 1991-04-11
AU3776589A (en) 1990-01-12
EP0347698A1 (fr) 1989-12-27
KR900701784A (ko) 1990-12-04
WO1989012637A1 (fr) 1989-12-28

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