PATEN'l, SPECIFICATION
`XO DRA WI::-iGS
`~
`~ (21) Application No. 1197/68
`(22) Filed 9 Jan. 1968
`(31) Convention Application No. 608 997
`(32) Filed 13 Jan. 1967 in
`?"-(
`~ (33) United States of America (US)
`~ (31) Convention Application No. 694 771
`~ (33) United States of America (US)
`(45) Complete Specification published 4 Nov. 1970
`,-..(
`(51) International Classification C 07 d 5/04, 7/04, 87/28, 27/04, 29/12,
`51/70; C 07 c 63/52, 69/76, 103/10; A 61 k 27/00
`
`(11) 1211134
`
`(32) Filed 7 Dec. 1967 in
`
`(r' ¥
`
`• •
`
`ERRATA
`
`SPECIFICATION No. 1,211,134
`
`" reaJJ "R2
`
`Page 2, line 27, fm· "hydroxyl" ?'ead "hy(cid:173)
`droxy"
`Page 2, line 33, for "Rw' read "R16
`"
`Page 3, line 25, fa?' "thiether" read "thio(cid:173)
`ether"
`Page 5, line 53, for "R2 and R10
`or R10
`"
`Page 7, line 34, fa?' "Carboxylnaphthalene''
`?'ead "Carboxynaphthalene"
`Page 11, line 53, for "dimethoxyoxyethane"
`read "dimethoxyethane"
`Page 12, line 2, for "evaluation" read "evo-
`h
`lution"
`Page 18, line 19, for "naP/ihylacerates" read
`"naphthylacetate"
`Page 18, line 59, for "mthoxycarbonylmethyl"
`reaJd "methoxycarbonylmethyl"
`Page 23, line 54, for "methyl'' read "methyl-
`ene"
`" read "R6
`Page 29, line 39, for "R3
`"
`Page 31, line 19, for "Rw' read "R16"
`Page 33. line 3, for "Claim 24" 1·ead "Claim
`34"
`Page 37, line 1, for "accoding" read accord(cid:173)
`ing"
`THE PATENT OFFICE
`5th 'January 1971
`
`8B2A3 8B2Y 8B3AX 8B3B2A2 8B3BX 8B3C2 8B3Y
`8B4
`
`(54) IMPROVEMENTS IN OR RELATING TO NAPHTHALENE
`DERIVATIVES
`
`(71) We, SYNTEX CORPORATION, a Panamanian Corporation of Apartado Postal
`7386, Panama, Panama, do hereby declare the invention for which we pray that a
`patent may be granted to us, and the method by which it is to be performed to be
`_B~cr;~cular!y described in and by the following s~~~ment: -
`'
`
`

`
`P ATEN1., SPECIFICATION
`
`(ll) 1211134
`
`...
`
`(32) Filed 7 Dec. 1967 in
`
`NO DRAWINGS
`(22) Filed 9 Jan. 1968
`(21) Application No. 1197/68
`(31) Convention Application No. 608 997
`(32) Filed 13 Jan. 1967 in
`(33) United States of America (US)
`(31) Convention Application No. 694 771
`(33) United States of America (US)
`(45) Complete Specification published 4 Nov. 1970
`(51) International Classification C 07 d 5/04, 7/04, 87/28, 27/04, 29/12,
`51/70; C 07 c 63/52, 69/76, 103/10; A 61 k 27 fOO
`(52) Index at acceptance
`C2C 1E1K3 1E3Kl 1E3K3 1E3K6 1E4K3 1E7 A
`1E7B2 1E7C2 1E7D1 1E7D2 1E7E1 1E7E2 1E7Fl
`1E7F2 1E7J 1E7N3 1E7N4 1E7Pl 1G3A 1G3B
`1G6A1 1G6A3 1G6B6 1K2A1 1K2A2 1K2C2 1M1C2
`lQllJ 1Q11A lQllB lQllC 1Q11D lQllG
`lQlA 1Q2 1Q4 1Q5 1Q6B2 1Q6C 1Q7A 1Q7B
`lQSA 1Q8C 1Q9A 1Q9B 1Q9Dl 1Q9D2 1Q9E
`1G9Fl 1Q9F2 1Q9K 1Q9L 20Y 222 226 227 22Y
`29X 29Y 30Y 321 323 326 32Y 342 344 345 34Y
`351 354 366 367 368 3Al 3AlOA4F 3A10A5E
`3AlOA5F 3AlOB2C 3A10B5E 3AlOB5F 3AlOB5G2
`3A10E1 3A10E3A3 3A10E3Cl 3AlOE4A3 3A10E4A6
`3AlOE5B 3A10E5E 3AlOE5FlA 3A10E5F2A
`3A10E5F2B 3AlOE5F2B 3A10E5F2D 3AlOE5F3A
`3A10E5F3C 3AlOE5F3D 3A12A3 3A12B1 3A12B2
`3A12B3 3A12C5 3A12C6 3Al3A3A3 3Al3A3A4
`3Al3A3Bl 3Al3A3B2 3Al3A3B3 3A13A3C
`3Al3A3F1 3A13A3F3 3Al3A3H2 3Al3C10H
`3A13C1B 3Al3C6B 3Al3C9 3A14A2A 3A14A2D
`3A14A7B 3Al4B3A 3A14B5 3Al9A2 3A19A3 3Al9Bl
`3A19B2 3A19B3 3Al9C2 3A19C3 3Al9Dl 3A19D2
`3A5ClB3 3A5F3B 3A7V1A3 3A7V1A4 3A7V1El
`3A7V1E2 3A7V1F1 3A7V1Jl 3A7V1Kl 3A7V1K2
`3A7V1K3B 3A7V1L 3A7V1P 3A7V2A3 3A7V2El
`3A7V2E2 3A7V2K3B 3A7V2K4 3A7V2L 3A7V3A3
`3A7V3E1 3A7V3E2 3A7V3H 3A7V3J3 3A7V3]4
`3A7V3K4 3A7V3L 3A7V3P 3A7V4A3 3A7V4El
`3A7V4J4 3A7V4K4 3A8A2 3A8A3 3A8Bl 3A8B2
`3A8Cl 3A8C3 3A8C4 3A8G 1 3A8G4 3A8G5 3A8H
`3A8J 3A8K 3C5A3 3C5A4 3C5B 3C5C2 3C5C3
`3C5C4 3C5C7 3C5E1 3C5E2 3C5E5 431 435 488
`573 579 5A3 5E2 620 628 62X 62Y 630 650 658
`65X 660 666 668 69Y 701 717 719 73Y 771 790
`79Y KG LQ LR MC MV NC NR PILl P1L2
`P3Bl2B P3B19B P4 P7 PS
`A5B 381 38Y 392 401 40Y 420 421 422 423 426 42Y 430
`433 43Y 480 481 482 483 484 48Y 541 542 544 54Y
`565 566 56Y 595 59Y 606 60Y 640 64Y 664 66Y
`C5E 7B1B2 7B1BX 7B1Y 7B3 8A3C6 8A3Y RB1A2 8HIY
`8B2A3 8B2Y 8B3AX 8B3B2A2 8B3BX 8B3C2 8B3Y
`8B4
`
`(54) IMPROVEMENTS IN OR RELATING TO NAPHTHALENE
`DERIVATIVES
`
`(71) We, SYNTE:X CoRPORATION) a Panamanian Corporation of Apartado Postal
`7386, Panama, Panama, do hereby declare the invention for which we pray that a
`patent may be granted to us, and the method by which it is to be performed, to be
`particularly described in and by the following statement: -
`--
`
`~~
`
`~--··---·~"~.:.-
`
`

`
`2
`
`1,2111,134
`
`2
`
`This invention relates ro novel compositions useful as anti-inflammatory, analgesic,
`anti-pyretic and anti-pruritic agents. It also relates to novel methods for treating con(cid:173)
`ditions marked by inflammanion, pain, pyrexia, and pruritus. It further relates to novel
`compounds which are thus useful and to methods for their preparation, as well as to
`certain novel intermediates thereof.
`The present compounds are derivatives of 2-naphthylacetic acid, a compound
`which can be represented by the formula:
`
`The arabic numerals and the alpha symbol indicate the positions used herein in
`the nomenclature of 2-naphthylacetic acid derivatives.
`The present invention provides compounds applicable for effecting treatment of
`inflammation, pain, pyrexia, and pruritus, as well as associanive conditions thereof, by
`administering an effe.:tive quantity of a 2-naphthylacetic acid derivative as hereinafter
`defined or the correS:ponding amide, ester, hydroxamic acid or addillion salt thereof,
`which salt is derived from a pharmaceutically acceptable non-toxic base.
`These thus useful 2-naphthylacetic acid derivatives can be represented by the
`following general formulae:
`
`5
`
`10
`
`15
`
`5
`
`10
`
`15
`
`R&J<;H R'v::M
`
`20
`
`25
`
`30
`
`J11J[
`"fll[
`wherein each of R 6 (at position ·1, 4, 7 or 8) and R19 (as position 1, 7 or 8) is alkyl,
`trifluoromethyl, fluoro, chloro, hydroxy, hydrolyzable ester, oxyether or thioether, pro- "
`vided that when R1;; and R17 are hydrogen or one of R16 and R17 is methyl or ethyl, I!<
`R19 (when at position 1) is other than hydroxy;
`R' is alkyl, ftuoro, chloro, hydroxy, hydrolyzable ester, oxyether or thioether;
`each of R9 (at posinion il, 4, 7 or 8) and R20 (at position 1, 7 or 8) is alkyJ, fluoro, -
`chloro, hydroxy, hydrolyzable ester, oxyether or thioether, provided that when R8 is
`hydroxy, oxyether or thioether, R9 or R~ 0 is the identical group or alkyl, fluoro, chloro
`or hydrolyzable ester; provided that when one of R9 or R20 is hydroxyl, oxyether or
`thioether, R8 is the identical group or alkyl, fluoro, chloro, or hydrolyzable ester;
`each of R12 and R15 (at position 1 or 4) is hydroxy, oxyether or rhioether;
`each of R 13 (at position 1 or 4) and R14 is alkoxy or alkylthio, provided when R12
`or R15 is alkoxy or alkylthio, R13 or R14 respecnively is a different alkoxy or alkylthio
`group;
`one of R 15 and R 11 is hydrogen, the other being hydrogen, methyl, ethyl, diftuoro·
`methyl, fluoro or chloro; or
`
`20
`
`25
`
`30
`
`

`
`3
`
`1,21111,134
`
`R16 and R17 taken together are alkyHdene, halomethylene or ethylene;
`R18 is hydrogen, alkyl, cycloalkyl, trifiuoromethyl, hydroxymethyl, alkoxymethyl,
`vinyl, ethynyl, fiuoro, chloro, hydroxy, hydrolyzable ester, oxyether, thioether, formyl,
`carboxy, alkoxycarbonyl, acetyl, cyano or aryl;
`R21 is hydrogen, alkyl, cycloalkyl, trifiuoromethyl, fiuoro, chloro, hydroxy, hydro~
`lyzable ester, oxyether, thioether or 'llryl; provided that at least one of R16
`, R17
`, and R21
`is other than hydrogen; provided that rwhen one of R16 and R17 is methyl or ethyl, R21
`is other than hydrogen; or a
`corresponding amide, ester, hydroxamic aoid or pharmaceutically acceptable addi(cid:173)
`tion salt thereof.
`Several classes of novel naphthylacetic acid derivatives of general formulae I(cid:173)
`VIII include those of the following general formulae:
`
`5
`..
`
`io
`
`3
`
`5
`
`10
`
`R# If'#
`
`~~ Ru
`
`R~CtJ0/1 ~t:t>~tJ/1
`ZllF ~~ .zJI
`
`.
`
`RIO /PI/
`
`R9
`R9
`·?<'Y~CCJ0/1 ~C'tJM
`I?~ :m:
`lf'~_..,.l E
`wherein one of R1 and R~ is hydrogen and the other is difiuoromethyl, fiuoro or chloro;
`or
`
`R1 and R~ taken together are alkyHdene, halomethylene, or ethylene;
`R: is trifluoromethyl, hydrolyzable ester, difiuoromethoxy, alkoxymethyloxy, 4'(cid:173)
`alkoxytetrahydropyran-4' -yloxy, tetrahydrofuran-2' -yloxy, tetrahydropyran-2' -yloxy, or
`thioether;
`R1 is cydoalkyl, hydroxymethyl, alkoxymethyl, trifiuoromethyl, vinyl, ethynyl, a
`hydrolyzable ester, alkoxymethyloxy, alkylthiomethylthio, difiuoromethoxy, alkoxy(cid:173)
`methylthio, alkylthiomethyloxy, difiuoromethylthio, formyl, carboxy, alkoxycarbony;l,
`acetyl, cyano, or aryl;
`each of R:; (at position 4, 7 or 8) and R6 (at position 1, 4, 7 or 8) is alkyl, tri(cid:173)
`fluoromethyl, fiuoro, chloro, hydroxy, hydrolyzable ester, oxyether or thiether; pro-·
`vided that R" (when at position 7) is other than alkyl;
`R' is alkyl, cycloalkyl, hydroxymethyl, alkoxymethyl, trifiuoromethyl, vinyl,
`ethynyl, fiuoro, chloro, hydroxy, hydrolyzable ester, oxyether, thioether, formyl, car(cid:173)
`boxy, alkoxycarbonyl, acetyl, cyano or aryl;
`each of R8 and R9 (at position 1, 4, 7 or 8) is alkyl, fiuoro, chloro, hydroxy, hydro(cid:173)
`lyzable ester, oxyether or thioether; provided that when one of R 8 or R9 is !hydroxy,
`oxyether or thioether, the other is the identical group or alkyl, fiuoro, chloro or hydro(cid:173)
`lyzable ester;
`one of R10 and R11 is hydrogen, the other being methyl, ethyl, difiuoromethyl,
`fluoro or chloro; or
`R10 and R11 taken together are alky1idene, halomethylene, or ethylene; provided
`that when one of R10 or R11 is methyl or ethyl, R6 (when at position 1 or 7) is other
`than alkyl; or
`a corresponding amide, ester, hydroxamic acid or pharmaceutically acceptable
`addition salt thereof.
`By the terms which define an "alkyl" grouping are meant lower molecular weight,
`branched, or straight chain hydrocarbon groups of six or less carbon atoms, such as
`methyl, ethyl, propyl, isopropyl, butyl, tertbutyl, pentyl and hexyl. By the term "cyclo(cid:173)
`alkyl" is meant cyclic hydrocarbon groups of three to seven carbon atoms, such as
`cyclopropyl, cyclopentyl and cyclohexyl.
`
`15
`
`20
`
`25
`
`35
`
`40
`
`45
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`

`
`~~-
`/
`
`4
`
`1,2111,134
`
`By the term "a!koxy" is intended a straight or branched chain hydrocarbon ether
`group of six or less carbon atoms, including methoxy, ethoxy, 2-propoxy, butoxy and 3-
`pentoxy.
`By the terms which define an "alkoxymethyloxy" groQping are meant methylether
`groups substituted with one alkoxy group; typical alkoxymethy,!oxy groups include
`methoxymethyloxy, ethoxymethyloxy and isopropoxymethyloxy.
`By the term "alkylthio" is intended straight or branched chain hydrocarbon thio(cid:173)
`ether groups of six or less carbon atoms, including methylthio, ethylthio, propylthio, 2-
`propylthio, 2-butylthio, pentylthio and 3-hexylthio.
`The term "alkylthiomethyloxy" as used herein denotes methylether groups sub(cid:173)
`stituted with an alkylthio group; typical alkyJ.thiomethyloxy groups include methyl(cid:173)
`thiomethyloxy, 2-propyhhiomethyloxy and pentylthiomethyloxy ..
`The term "alkylthiomethylthio" as used herein denotes methylthio ether groups
`subs~ituted with an alkylthio group, including methyluhiomethylthio and ethylthio(cid:173)
`methylthio.
`By the terms which define an "alkoxymethylthio" grouping are meant methylthio
`ether groups substituted with one a.lkoxy group, such as methoxymethylthio, ethoxy(cid:173)
`merhylthio and 2-propoxymethylthio.
`By the term "aryl" is intended unsubstituted and p-mono substituted phenyl de(cid:173)
`rivanives, such as phenyl, p-tolyl, p-fluorophenyl, p-chlorophenyl, p-hydroxyphenyl,
`p-methoxyphenyl and p-ethylphenyl.
`By the term "halomethy,lene" is meant mono- or dihalomethylene groups wherein
`halo is fiuoro or chloro. The preferred halomethylenes includes fluoromethylene, di(cid:173)
`fiuoromethylene, fiuorochloromethylene, and chloromethylene.
`The term "hydrolyzable ester" as used herein denotes those hydrolyzable ester
`groups conventionally employed in the art, preferably those derived from hydrocarbon
`carboxylic acids or their salts. The term "hydrocarbon carboxylic aoid" defines both
`substituted and unsubstiruted hydrocarbon canboxylic acids. These acids can be com(cid:173)
`pletely saturated or possess varying degrees of unsaturation (including aromatic), can
`be of straight chwin, branched chain, or cyclic structure and, preferably, contain from
`one to twelve carbon atoms inclusive. In addition, they can be substituted by functional
`groups, for example, hydroxy, alkoxy containing up to six carbon atoms inclusive,
`acyloxy containing up to twelve carbon atoms inclusive, nitro, amino and halogeno,
`attached to the hydrocarbon backbone chain. Typical hydrolyzable esters ,thus included
`within the scope of the term and the present invention are acetate, propionate, butyrate,
`valerate, caproate, enanthate, caprylate, pelargonate, acrylate, undecenoate, phenoxy(cid:173)
`acetate, benzoate, phenylacetate, diphenylacetate, diethylacetate, trimethylacetate, t(cid:173)
`butylacetate,
`trimethylhexanoate, methylneopentylacetate, cyclohexylacetate, cyclo(cid:173)
`pentylpropionate, adamantoate, glycolate, methoxyacetate, hemisuccinate, hemiadipate,
`hemi-/3,/~-dimethylglutarate, acetoxyacetate, 2-chloro-'4-nitrobenzoate, aminoacetate,
`/3-
`diethylaminoacetate, piperidinoacetate, /1-chloropropionate, trichloroacetate and
`chlorobutyrate.
`The term "oxyerher" as used herein denotes those ether groups conventionally
`employed in the art, preferably those derived from normal chain, branched chain, aro(cid:173)
`matic hydrocarbons and oxo heterocyclic hydrocarbons. The term "hydrocarbon" de(cid:173)
`fines both saturated and unsaturated hydrocarbons. Those designated hydrocarbons are
`optionally substituted with groups such as hydroxy, alkoxy, halo and alkylthio. Prefer(cid:173)
`ably the hydrocarbons contain from one to twelve caroon atoms inclusive. Typical oxy(cid:173)
`ethers thus include alkoxy, difiuoromethoxy, alkoxymethyloxy, alkylthiomethyloxy,
`tetrahydrofuran-2' -yloxy, tetrahydropyran-2' -yloxy, and 4' -alkoxytetra:hydropyran-4'(cid:173)
`yloxy.
`The term "thioether" as used herein denotes those ether groups conventionally
`employed in the art, preferably those derived from normal chain, branched chain, cyclic
`and aromatic hydrocarbons. The term "hydrocanbon" defines both substituted and un(cid:173)
`substituted hydrocarbons. These hydrocarbons are opcionally substituted with groUips
`such as hydroxy, alkoxy, alkylthio and halo. Preferably the hydrocarbons contain from
`1 to 12 carbon atoms. Typical thioethers thus include alkylthio, difiuoromethylthio,
`alkoxymethylthio and alkylthiomethylthio.
`Also included within the scope of the present invention are the corresponding
`amides, esters, hydroxamic acids, and addiuion salts of the present 2-naphthylacetic
`acids.
`In the preferred embodiment of this invention, the amides, esters, hydroxamric
`acids, or addition salts of the present 2-naphthylacetic acid deflivatives are the preferred
`derivatives when the 2-naphthylacetic acid detTivatives are substituted with tetrahydro-
`
`s
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`4
`
`5
`
`"
`io
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`

`
`"
`
`5
`
`5
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`1,21.1,134
`
`5
`
`tetrahydropyran-2'-yloxy, 4'-alkoxytetrahydropyran-4'-yloxy, alkyl(cid:173)
`fur.an-2'-yloxy,
`methylenedioxy, alkylthiomethyleneoxy, alkoxymethylthio, or alklythiomethylthio.
`The amides of the present novel compound may be derived from conventional
`bases, such as ammonia, methylamine, ethylamine, methylethylamine, dimethylamine,
`diethylamine, pyrrolidine, piperidine, piperazine, N-ethylpiperazine, morpholine, di(cid:173)
`(methoxymethylene)amine,
`isopropylamine, aniline and N - methyl - N - cyclo(cid:173)
`pentylamine. The amides may be prepared by conventional means known to -
`the art, for example, by treating the naphthylacetJic acid derivative with thionyl chloride
`or phosphorus pentachloride, and then treaning the resuiting acid chloride of the naph(cid:173)
`thylacetic acid derivative with an excess of ammonia or an amine.
`The esters may also be prepared by conventional techniques, such as by :preparing
`the acid chloride of the 2-naphthylacetic acid derivanive and then allowing the acid
`chloride to react with an alkanol, such as methanol or ethanol; or iby treating the 2-
`naphthylacetic acid derivative with a diazoalkane, for example, diazomethane or diazo(cid:173)
`ethane; or with an alkanol of 1 to 12 carbon atoms inclusive, for example, methane!,
`ethanol, butanol, or 3-pentanol, in the presence of an acid catalyst such as borontri(cid:173)
`fluoride or p-toluenesu1phonic acid.
`The hydroxamic acid derivatives can be prepared by treating the 2-naphthylacetic
`acid ester derivatives with hydroxylamine (usually as the hydrochloride salt) in the
`presence of base, such as sodium methoxide, in an alkanol solvent, such as methanol or
`ethanol.
`The addition salts can be prepared by conventional techniques from pharmaceuti(cid:173)
`cally acceptable non-toxic bases, including metal salts such as sodium, potasSJium, cal(cid:173)
`cium or aluminium, as well as organic amine salts, such as triethylamine, 2-dimethyl(cid:173)
`amino ethanol, 2-diethylamino ethanol, iys<ine, arginine, histidine, caffeine, procaine,
`N-ethylpiperidine and hydrabamine.
`Of the compounds of Formulae I-VIH of this invention (defined above), the
`preferred derivatives are those wherein each of R 6 (at position 1, 4, 7 or 8) and R19 (at
`position 1, 7 or 8) is fluoro, chloro, methyl, ethyJ, isopropyl, methoxy, methoxymethyl(cid:173)
`oxy, difluoromethoxy, 4'-methoxytetrahydropyran-4'-yloxy, methylthio, difluoro(cid:173)
`methylthio, or methoxymethylthio;
`each of RS, R9 ·(at position 1, 4, 7 or 8) and R20 (at position 1, 7 or 8) is fluoro,
`chloro, methyl, ethyl, isopropyl, methoxy, methoxymethyloxy, difluoromethoxy, 4'(cid:173)
`methoxytetrahydropyran-4'-yloxy, methylthio, difluoromethylthio, or methoxym\!thyl(cid:173)
`thio; provided that when one of R8 and R9 or one of R" and R20 is methoxy, methoxy(cid:173)
`methyloxy, difluoromethoxy, 4-methoxytetrahydropyran-4' -j4oxy, methylthio, difluoro(cid:173)
`methylthio or methoxymethylthio, the other is the identical group, or methyl, ethyl, iso(cid:173)
`propyl, fluoro or chloro;
`each of R12 and RD <at position 1 or 4) is methoxy, difluoromethoxy, methoxy(cid:173)
`methyloxy, 4'-methoxytetrahydropyran-4'-yloxy, methylthio, di,fiuoromethylthio or
`'; (at position 1 or 4) and RH is methoxy or methyl(cid:173)
`methoxymethylthio and each of R1
`thio; provided that RF' or R11 is a different substituent than R12 or Rn respectively;
`one of R10 'and R17 is hydrogen, the. other being hydrogen, methyl or difluoro(cid:173)
`methy;l; or
`R1
`G and R17 taken together are methylene or difluoromethylene;
`R1
`is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, vinyl,
`"
`ethynyl, fluoro, chloro, methoxy, methoxymethyloxy, difluoromethoxy, 4'-methoxy(cid:173)
`tetrahydropyran-4'-yloxy, methylthio, methoxymethylthio, or difluoromethylthio;
`R" 1 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, fluoro,
`chloro, methoxy, methoxymethyloxy, difluoromethoxy, 4-'-methoxytetrahydropyran-4'(cid:173)
`yloxy, methy1thio, methoxymethylthio, or d1ifluoromethylthio; and
`a corre~ponding amide, ester, hydroxamic acid or addition salt thereof.
`When one of R 1 and R2 and R10 and R11 or R16 and R11 is methyl, ethyl, difluoro(cid:173)
`methyl, fluoro or chloro, the present 2-naphthylacetic acid derivatives have an asymmet(cid:173)
`ric carbon atom, the a-carbon atom of the acellic acid moiety. Accordingly, t:J.1ese com(cid:173)
`pounds can exist as enantiomorphs. Each of the optical isomers of the present 2-naph(cid:173)
`thylacetic acid derivatives is included within the present invention. In some unstances,
`one enantiomorph exhibits greater anti-inflammatory, analgesic, antdpyretic and anti(cid:173)
`pruritic activity, than the other enantiomonph.
`The present 2-naphthylacetic acid derivatives that eXJist as enantiomorphs can be
`administered as mixtures of enantiomonphs or as resolved enantiomor:phs.
`The optical isomers can ibe resolved by conventional means, suc:h a·s selective bio(cid:173)
`logical degradation; or by the preparation of diastereo-isomer sa:lts of the 2-na;phthyl(cid:173)
`acetic acid derivatives with an alkaloid, such as cinchonidine, and the separation of the
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`1,21,1,134
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`diastereo-isomers by fracnional crystallization. The separated diastereo-isomer salts are
`acid cleaved to yield the respective optical isomers of the 2-naphthylacetic acid deriva-
`.
`ti~
`The above compounds have high therapeutic value in the treatment of vatlious in-
`flammatory conditions, such as of the skin, eyes, respiratory tract, bones, and internal
`organs, contact dermatitis, allergic reactions, and rheumatoid arthnitis. In those cases in
`which the above conditions include pain, pyrexia, and pruritus, coupled with the in-
`flammation, the present compounds are useful for re1ief of these associative conditions
`as well as the principal condition. The present compounds are in addition, however,
`useful for treating pain, pyreXIia, pruritus, and other syndromes thereof per se, such as
`those arising from bone fracture, toothache, bacterial and Vlirus infection, contact with
`poisonous material, neuralgia, neuritis, lacerations, contusions and abrasions.
`The preferred manner of oral administration provides the use of convenient daily
`dosage regimen which can be adjusted according to the degree of affidction. Generally,
`a daily dose of from O.J mg. to 20 mg. of the active compound per kilogram df body
`weight is employed. Most conditions respond to treatment comprising a dosage level
`in a range of 1 mg. to 5 mg. per kilogram of body weight per day. For such oral ad(cid:173)
`ministration, a pharmaceutically acceptable non-.toxic composition is formed by the in(cid:173)
`corporanion of any of the normally employed exdpients. These compositions take the
`form of solutions, suspensions, tablets, pills, capsules, powders and sustained release
`formulations.
`In addition, these compounds can be administered in conjunction with other medi(cid:173)
`cinal agents depending upon the specific condition being treated.
`Thus, for example, a measure of anti-inflammatory activity according to the car-
`rageenin induced edema assay of Winter et al., Proceedings of the Society for Experi-
`menial Biology and Medicine III, 544 ~1962) shows 6-et:hyl-2-naphthylacetic acid and
`6-methoxy-2-n.aphthyl-a-methylace~ic acid to have three times and greater than six
`rimes the activ1ty of phenylbutazone, respectively. Similar standard assays to measure
`analgesic and anti-pyretic activities show 6-rnethoxy-2-naphthyl-a-1llethyJacetic acid to
`have three times and seven Dimes the activity of aspirin in these two respective cate-
`gories.
`The above compounds of the present invention can be readily prepared from
`known starcing compounds.
`One such method by which they can be prepared iniVolves .the reaction ()[ an un-
`substituted or substituted naphthalene with acetyl chloride in nitrobenzene 1in the pre-
`sence of about three molar equivalents of aluminium chloride to afford the correspond-
`ing 2-acetylnaphthalene derivative. The resulting derivanive is heated with rnorpholine
`in the presence of sulphur at 150°C; the resulting produot is refluxed with concentrated
`hydrochloric acid to furnish the corresponding 2-naphthylacetic acid de11ivative.
`The naphthalenes that are used in the above process can be illustrated by the
`follow1ng general formulae:
`
`B
`
`, R 9 and R 1
`wherein R 8
`' are as defined above.
`The naphthalenes of formulae A and B are known in the art. Moreover, .they can
`be :prepared by conventional means. For example, :1,2-dimerhoxybenzene is treated with
`succinic anhydride and aluminium chloride in a hydrocarbon solvent to afford 4 -
`(3',4' - dimethox:ypihenyl) - 4 - oxobutanoic acid. This is reduced by treatment with
`sodium borohydride, dehydroxylated by treating with palladium charcoal catalyst and
`hydrogen to furnish 4 - (3',4' - dimethoxyphenyl) butanoic acid. The corresponding
`ao!d chloride is prepared such as by treatment with thionyrl chloride, and the acid
`chloride is treated with aluminium chloride to afford 6,7 - dimethoxy - 1 - tetralone.
`The tetralone is reduced and hydrogenolyzed by the means means described above to
`furnish 6,7 - dimethoxytetra'ldn which is dehydrogenated by treating with palladium
`charcoal catalyst to afford 2,3 - dimethoxy naphthalene. By utilizing 1 • methyl - 3 -
`fluorobenzene in ,the above process, 5 - fluoro - 7 - methyl - ,1 - tetralone and 5 -
`methyl - 7 - fluoro - 1 - tetralone (as intermediates) and 1 -methyl - 3 - fluoro naph(cid:173)
`thalene and 1 - fluoro - 3 - methyl naphtha:lene are prepared. The mixture m naph(cid:173)
`thalenes are separated by conventional means, such as vacuum distillation.
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`2-Alkyl, 2-cycloalkyl, or 2-aryl substituted naphthalenes, the naphthalenes of
`Formula A wherein R18 is a'lkyl, cycloalkyl or aryl, can be prepared from 2~tetralone
`by treating the latter with an equivalent of an alkyl, cycloalkyl or aryl magnesium
`bromide in an ether to obtain the corresponding 2-alkyl-, 2-cydoalkyl-, or 2-aryl-3,4-
`dihydmnaphtha:lene which is dehydrogenated by heating with palladium charcoal cata(cid:173)
`lyst to afford the corresponding 2-alkyl, 2-cycloalkyl, or 2-aryl naphthalene.
`2-Vinyl naphthalene is prepared by refluxing 2-ethylnaphthalenes with a molar
`equivalent of N-bromosuccinimide in a halohydrocarbon solvent, such as chloroform,
`methylene chloride, dJichloroethane, carbontetrachloride, 1,4-dichlorobutane, chloro(cid:173)
`benzene, chloroethane, chlorocyclohexane or dichlorobenzene, in light and in the :pre(cid:173)
`sence of a trace amount of pemxide, such as benzoyl peroxide, t-butylperoxide, or
`peroxyacetic acid, to afford 2 - (a - bromoethyl) - naphthalene. The latter is dehydro(cid:173)
`brominated by treating with lithium carbonate in dimethylformamide to afford 2 -
`vinylnaphthalene.
`2-Ethynylnaphthalene can be prepared from 2-vinylnaphthalene by brominating
`the latter in a halo hydrocarbon solvent and then debrominating the resulting 2- (a,f3 -
`dibromoethyl)naphthalene by conventional means, such as by treMment with sodium
`amide in Liquid ammonia, to furnish the 2-ethynylnaphthalene.
`2-Cyclopropylnaphtha'lene can be prepared from 2-vinylnaphthalene by refluxing.
`with diiodomethane in the presence of zinc: copper couple.
`2-Cydobutylnaphthalene can be prepared from 2-naphthylmagnesium bromide by
`treating the latter with cyclobutanone to furnish 2 - (1' - hydroxycyclOJbutyl) - naph(cid:173)
`thalene, which is hydrogenolyzed with hydrogen in the presence of "Raney" nickel to
`furnish 2-cyclobutylnaphthalene. "Raney" is a Trade Mark.
`2-Cyclopentylnaphthalene can be prepared by heating naphthalene with cyclo(cid:173)
`pentyl benzene suLphonate. 2-Cyclohexylnaphthalene can be similarly prepared by
`employing cyclohexyl benzene sulphonate.
`2-Acetylnaphthalene can be prepared by treating 2 - {a - bromoethyl) - naph(cid:173)
`thalene, prepared as described above, with sodium acetate in acet:ic aoid to afford 2 -
`(a - ethanoyloxyethyl) - naphthalene which upon base hydrolysis furnishes the 2 -
`(a - hydroxyethyl) - naphthalene. The latter may be oxidized with an equivalent of
`chromium tr1ioxide in glacial acetic acid or SN sulphuric acid to furnish 2 - acetyl(cid:173)
`naphthalene.
`2-Carboxylnaphthalene is prepared from 2-acetylnaphthalene by treating the latter
`with aqueous sodium hypochlovite. The 2 - carboxy group is esterified by conventional
`means, described herein, to furnish 2-alkoxycarbonylnaphthalenes. By treating the latter
`with one equivalent of an alkali metal hydroxide, treating the resulting :product with
`diborane in an ether, such as diglyme, (dimethoxydiethyleneglycol), 2-hydroxymethyl(cid:173)
`naphthalene is prepared.
`The 2-hydroxymethyl group can be esterified and etherified by conventional means
`employed to esterify and etherify primary hydroxy groups.
`2~Fonnylnaphthalene can be prepared from 2~hydroxymethylnaphthalene by treat~
`ing the latter with manganese dioxide in a halohydrocarbon solvent.
`2-Cyanonaphthalenes can be prepared by refluxing 2-Jormylnapihthalene Wlith hy(cid:173)
`droxylamine hydrochloride and sodium acetate in ethanol to furnish the corresponding
`oxime which is refluxed with aceDic anhydride tin the presence of an acid catalyst to fur(cid:173)
`nish 2-cyanonaphthalene.
`Alternatively, the above substituems can be introduced on a naphthylacetic acid
`ester derivative by using an ethyl or Vtinyl substituted na:phthylacetic acid ester deriva(cid:173)
`tive as a starting materiaL
`In a preferred embodiment of the present invention, the starting materia:ls are
`not substituted with tr1Ifluoromethyl, difiuoromethoxy, difiuoromethylthio, methyl(cid:173)
`methylenedioxy, alkoxymethylthio, alkylthiomethyloxy, alkylthiomethylthio, tetrahydro(cid:173)
`pyran-2' -yloxy, tetrahydrofuran-2' -yloxy, or 4'-alkoxytetrahydmpyran-4' -yloxy groups,
`but rather, such groups are introduced on the 2-naphthalene acetic acid deritvatU.ve via
`one of the final steps.
`Another method of prepaving the present compounds employs unsubstituted and
`substituted ,1-tetralones and can be illustrated by the following reaction sequence:
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`8
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`wherein alkyl and R18 are defined as above.
`The 1-tetralones, the compounds of Formula C, are heated with two or more
`equivalents of a diaiJkyl carbonate, such as diethyl carbonate, in the presence of one
`or more equivalents of an alkali metal hydvide, such as sodium hydride, or potassium
`hydride, in a hydrocarbon solvent, such as hexane, cyclohexane, heptane, isooctane,
`benzene, toluene or xylene, to afford the corresponding alkoxy carbonyl compounds of
`Formula D. The latter are treated with an alkali metal hydride rin a hydrocarbon sol(cid:173)
`vent; then the resulting products are treated with an a-haloacetic aoid ester, such as
`ethyl a-bromoacetate or methyl a-iodoacetate, to furnish the corresponding 2-alkoxy(cid:173)
`carbonyl-2-(alkoxycarbonylmethyl)-1-tetralones, the compounds of Formula E. The
`latter is hydrolyzed with an acid, such as hydrochlovic acid, sulphuric acid or p-toluene(cid:173)
`sulphoruic acid, to obtain the 2-(carboxymethyl) compounds of Formula F. The latter
`is reduced with a reducing agent, such as sodium borohydride, lithium borohydl'lide;
`or with one equivalent of hydrogen in the presence of Adam's catalyst, to afford the
`hydroxy compounds of formula G which are hydrogenolyzed by treatment with an
`eqUJivalent amount of hydrogen ~n the presence of a hydrogenation catalyst, such as
`platinum or palladium, to furnish the corresponding 1,2,3,4-tetrahydro-2-naphthyl(cid:173)
`acetic acid derivatives, the compounds of Formula H. The compounds of formula H
`are esterified by conventional means, such as the means described above, to afford the
`compounds of Formula I, which are dehydrogenated by heating with palladium charcoal
`catalyst at temperatures of 180°C and higher to furnish the corresponding 2-naphthyl(cid:173)
`acetic acid ester derivatives, the compounds of formula ]. The latter compounds are
`hydrolyzed to the corresponding 2-naphthylacetic acid derirvatJives, the compounds of
`Formula K, by conventJional hydrolysis, such as by treatment with an aqueous meth-
`anolic 5% sodium hydroxide solution.
`Disubstituted tetralones of formula L are also employed in the above process to pre(cid:173)
`pare the corresponding disubstituted 2-naphthylacetic acid derivanives of Formula M:
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`9
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`, ibut only
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`wherein R" is as defined above and R9 ' represents the same substituents as R9
`at poS<ition 4, 7 or 8.
`By treating the compounds of Formula D with an alkali metal hydride and then
`with an a-halocarboxylic acid ester, such as methyl a-bromopropionate, the correspond(cid:173)
`ing 2-alkoxycarbonyl-2-(a-alkoxycarbonylalkyl)...l1-tetralones are obtained. These com(cid:173)
`pounds can be hydrolyzed, reduced, hydrogenolyzed, esterified, dehydrogenated and
`hydrolyzed by the means used to similarly treat compounds of Formula