PATENT SPECIFICATION
`~0 DRA Wl!'{GS
`~
`~ (21) Application No. 1197/68
`(22) Filed 9 Jan. 1968
`~ (31) Convention Application No. 608 997
`(32) Filed 13 Jan. 1967 in
`P-!
`(33) United States of America (US)
`~ (31) Convention Application No. 694 771
`~ (33) United States of America (US)
`i ~ (45) Complete Specification published 4 Nov. 1970
`i
`(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
`
`(5~' •. .
`
`ERRATA
`SPECIFICATION No. 1,211,134
`
`Page 2, line 27, jO?· "hydroxyl" read "hy(cid:173)
`droxy"
`Page 2, line 33, for ''R15
`" read "Rw'
`Page 3, line 25, jo1· "thiether" read "thio(cid:173)
`ether"
`Page 5, line 53, for "R2 and R10 " re~ "R2
`or R10
`"
`Page 7, line 34, for "Carboxylnaphthalene''
`rer:rd "Carboxynaphthalene"
`Page 11, line 53, for "dimethoxyoxyethane"
`read "dimethoxyethane"
`Page 12, line 2, for "evaluation" read "evo-
`h
`lution"
`Page 18, line 19, for "narkhylacetates" read
`"naphthylacetate"
`Page 18, line 59, for "mthoxycarbonylmethyl"
`rectd "methox.ycarbonylmethyl"
`Page 23, line 54, for "methyl" 1·ead "methyl-
`ene"
`" read "R6
`Page 29, line 39, for "R3
`Paee 31 line 19 for "R13>' read "RW'
`Page 33: line 3, 'tor "Claim 24" read "Claim
`~ 34"
`Page 37, line 1, for "accoding" read accord(cid:173)
`ing"
`THE PATENT OFFICE
`Sth 1anrurry 1971
`
`"
`
`8B2A3 8B2Y SB3AX 8B3B2A2 8B3BX 8B3C2 8B3Y
`8B4
`
`(54) IMPROVEMENTS IN OR RELATING TO NAPHTHALENE
`DERIVATIVES
`.
`
`(71) We, SYNTEX CoRPORATION, a Panamanian Corporation of Apartado Postal
`7386, Pannma, 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
`'
`P.~!~icularly described in and by the following sta!_ement:-
`-
`·-· -- - ·-·- · · -.·: · ..... _- · ·-· -
`. -·--·- · - .
`.
`
`

`

`P ATEN1., SPECIFICATION
`
`(ll) 1211134
`
`...
`
`(32) Filed 7 Dec. 1967 in
`
`NO DRAWINGS
`(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 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 1K2Al 1K2A2 1K2C2 1M1C2
`lQllJ lQllA lQllB lQllC lQllD lQllG
`lQlA 1Q2 1Q4 1Q5 1Q6B2 1Q6C 1Q7A 1Q7B
`lQSA 1Q8C 1Q9A 1Q9B 1Q9D1 1Q9D2 1Q9E
`1G9F1 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 3AlOA5E
`3AlOA5F 3AlOB2C 3A10B5E 3AlOB5F 3AlOB5G2
`3A10E1 3A10E3A3 3A10E3Cl 3AlOE4A3 3AlOE4A6
`3AlOE5B 3AlOE5E 3AlOE5FlA 3A10E5F2A
`3A10E5F2B 3AlOE5F2B 3AlOE5F2D 3AlOE5F3A
`3A10E5F3C 3AlOE5F3D 3A12A3 3A12B1 3A12B2
`3A12B3 3A12C5 3Al2C6 3Al3A3A3 3Al3A3A4
`3Al3A3B1 3A13A3B2 3Al3A3B3 3A13A3C
`3Al3A3Fl 3A13A3F3 3Al3A3H2 3Al3C10H
`3A13C1B 3Al3C6B 3Al3C9 3A14A2A 3A14A2D
`3A14A7B 3A14B3A 3A14B5 3Al9A2 3A19A3 3Al9Bl
`3A19B2 3A19B3 3Al9C2 3Al9C3 3A19D1 3Al9D2
`3A5ClB3 3A5F3B 3A7V1A3 3A7V1A4 3A7V1E1
`3A7VlE2 3A7V1F1 3A7VlJ1 3A7V1K1 3A7V1K2
`3A7V1K3B 3A7V1L 3A7V1P 3A7V2A3 3A7V2E1
`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
`P3B12B 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: -
`~--··--- ~"~.:. -
`--
`~~
`
`

`

`5
`
`10
`
`15
`
`2
`
`1 ,2il!l' 13 4
`
`2
`
`This invention relates to 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 infiarnmaoion, pain, pyrexia, and pruritus. It further relates to novel
`compound-s 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-nap'hthylacetic acid, a compound
`which can be represented by the formula:
`
`The arabic numerals and the alpha symbol indicate the pos~rions 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 associaoive conditions thereof, by
`administering an effe~tive quantity of a 2-naphthylacetic acid derivative as hereinafter
`defined or the corre:>ponding amide, ester, •hydroxamic acid or addillion salt thereof,
`wnich salt is derived from a pharmaceutically acceptable non-toxic base.
`These thus useful 2-naphthylacetic acid d erivatives can be represented by the
`following general formulae:
`
`I
`
`r
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`wherein each of .R" (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 R's and R" are hydrogen or one of R'" and RH is methyl or ethyl, ~
`R" (when at position 1) is other than hydroxy;
`R' is alky~ fiuoro, chloro, hydroxy, hydrolyzable ester, oxyether or thioether;
`each of R9 (at posinion iJ, 4, 7 or 8) and R20 (at position :}, 7 or 8) is alkyJ, fluoro, -
`chloro, hydroxy, hydrolyzable ester, oxyother or thioetiher, provided that when R~ is
`hydroxy, oxyether or thioether, R9 or R"0 is the identical group or alkyl, fiuoro, chloro
`or hydrolyzable ester; provided that when one of R • or R 20 is hydroxyl, oxyether or
`thioerher, R8 is the identical group or alkyl, fiuoro, ch:loro, or hydrolyzable ester;
`each of R' 2 and R15 (at position 1 or 4) is hydroxy, oxyether or thioether;
`each of ·R" (at position 1 or 4) and R1" is alkoxy or alkylthio, provided when R'"
`or R13 is alkoxy or alkylthio, R'3 or RH respecttively is a different alkoxy or alkylthio
`group;
`one of Ru and R1 ' is hydrogen, the other being hydrogen, methyl, ethyl, diftuoro(cid:173)
`methy I, fl uoro or chloro; or
`
`20
`
`25
`
`30
`
`mn~
`
`

`

`3
`
`1,21111,134
`
`R16 and R17 taken together are alkybidene, halomethylene or ethylene;
`R18 is hydrogen, alkyl, cycloalkyl, trifiuoromethyl, hydroxymethy!, alkoxymethyl,
`vinyl, ethynyl, fluoro, chloro, hydroxy, hy,drolyzable ester, Qxyether, thioether, formyl,
`carboxy, alkoxycarbonyl, acetyl, cyano or aryl;
`Rz1 is hydrogen, alkyl, cycloalkyl, trifluoromethyl, fluoro, chlor~ hydr<lxy, hydro(cid:173)
`lyzable ester, oxyether, 'thioether or 'aryl; provided that at least one of R16
`, R17
`, and R21
`is other than :hydrogen; provided that rwhen one of R1' and R11 is methyl or ethyl, R21
`is other than hydrogen; or a
`corresponding amide, ester, bydroxamic acid or pharmaceutica11y 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
`..
`ro
`
`3
`
`5
`
`10
`
`R# RH
`
`~~ Ru
`
`.
`
`J?~~()OI/ ~COO/I
`:oJ[ ~~ :or
`R'" If'"
`/?9
`.f?.9
`- ~CPtJ/-1 ~C't:?t:?/1
`If'~ IE
`lf'~l .E
`wherein one of R' and R2 is hydrogen and the other is difluoromethyl, fiuoro or chloro;
`or
`
`·~
`
`20
`
`25
`
`. 30 ...
`
`35
`
`40
`
`45
`
`R 1 and R" taken together are alky}idene, halomethylene, or ethylene;
`R~ is trifluoromerhyl, hydrolyzable ester, difluor()methoxy, alkoxymerhyloxy, 4'~
`alkoxytetrahydropyran-4' -yloxy, tetrahydrofuran-2' -yloxy, tetrahydropyran-2' -yloxy, or
`thioether;
`R' is cycloalkyl, hydroxymethyl, alkoxymethy~ trifiuoromethyl, vinyl, ethynyl, a
`hydrolyzable ester, alkoxymethyloxy, alkylthiomethylthio, difiuoromethoxy, alkoxy(cid:173)
`methylthio, alkylthiomerhyloxy, difluorometh}rlthio, formyl, carboxy, alkoxycarbonyJ,
`acetyl, cyano, or aryl;
`each of R;; {at position 4, 7 or 8) and RG (at position 1, 4, 7 or 8) is alkyl, tri(cid:173)
`fluoromethyl, fluoro, chloro, hydroxy, hydrolyzable ester, {)Xyether or thiether; pro-'
`vided that R" (when at pos~tion 7) is other than alkyl;
`Ri is alkyl, cycloalkyl, ·hydroxymethyl, alkoxymethyl, trifluommethyl, vinyl,
`ethynyl, fiuoro, -chloro, hydroxy, hydrolyzable ester, oxyether, thioether, formyl, car(cid:173)
`boxy, alkoxycarbonyl, acetyl, cyano or aryl;
`each of R~ and RQ (at position 1, 4, 7 or 8) is alkyl, fluoro, chloro, hydroxy, hydro(cid:173)
`lyzable ester, oxyether or thioether; provided that when one of 'R8 or R9 js nydroxy,
`oxye~her or thioether, the other is the identical group or alkyl, fluoro, dlloro or hydro(cid:173)
`Jyzahle ester;
`one of R'0 and R11 is hydrogen, the other being methyl, ethyl, difiuoromethyl,
`fluoro or chloro; or
`R 10 and R11 taken together are alkyiidene, halomcthylene, or ethylene; provided
`that when one of R10 or R" 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 saJ.t mereof.
`By the terms which define an "alkyl" grouping are meant lower molecular weight,
`branched, or straight chain hydrocarbon groups of six or Jess carbon atoms, such as
`methyl, ethyl, propyl, isopropyl, butyl, tertbutyl, pentyl and J1exyl. 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
`
`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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`(:i
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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 condinions 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 add 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 in'Volves .the reaction of 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
`
`' are as defined above.
`, R9 and R1
`wherein R8
`The naphthalenes of formulae A and B are known in the art. Moreover, .they can
`be :prepared by conventional means. For example, :1,2-dirnerhoxybenzene 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 thionyl 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 of naph(cid:173)
`thalenes are separated by conventional means, such as vacuum distillation.
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`'
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`'
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`10 .
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`2S
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`1,Zlll,l34
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`7
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`2-Alkyl, 2-<:ycloalkyl, or 2-aryl substituted naphthalenes, ·the naphthalenes of
`Formula A wherein R' 8 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 et11er to obtain rhe correl>'Ponding 2-alk-yl-, 2-cycloalkyl-, or 2-aryl-3,4-
`dibydronaphthalene which is dehydrogenated by heating with palladiwn 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-ethyluaphthnlenes with a molar
`equivalent of N-bromosuccinimide in a halohydrocarbou sol\rent, such as chloroform,
`methylene chloride, d:ichloroethane, carbontetrachloride, 1,4-dichloroburane, chloro(cid:173)
`benzene, chloroerhane, chlorocyclohexane or dichlorobenzene, in light and in d1e pre(cid:173)
`sence of a trace amount of peroxide, such as benzoyl peroxide, t-butylperox.ide, or
`pero:-• .'yaceric acid, to afford 2 - (a - bromoethyl) - naphthalene. The latter is dehydro(cid:173)
`brominated by treating whh lithium carbonate 3n dimerhylformamide to afford 2 -
`vinylnapbthalene.
`2-Ethynylnaphthalene can be prepared from 2-vinylnaphtbalcne by brominating
`[he latter in a halo hydrocarbon solvent and then debrominating the resulting 2 - (a,p -
`dihromoethyl)naphthalene by conventional means, such as by trea>tment with sodium
`amide 1n ¥iquid ammonia, to furnish the 2-cthynylnaphthalene.
`2-Cyclopropylnaphthll'lene can be prepared from 2-vinylnuphthalcne by refluxing.
`with diiodomethane in the presence of zinc: copper couple.
`2-Cydobutylnaphthalene can be prepared from 2-n~hthylmagnesium bromide by
`treating the Iauer with cyclobutanone to furnish 2 - {1' ~ hydroxycyclobutyl) - naph(cid:173)
`thalene, which js 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 acetic acid to afford, 2 -
`(« - ethanoyloxyetbyl) - naphthalene wbich upvn base hydrolysis furnishes the 2 -
`(a - hyaroxyethyl) - napl1thalene. The latter may be oxidized with an equivalent of
`chromium trioxide in glacial acetic acid or SN suiphuric acid to .furnish 2 - acetyl(cid:173)
`naphthalene.
`2-Carboxylnaphtbalene is prepared from 2-acetylnaphthalene by treating the latter
`with aqueous sodium tlypochlor<ite. 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
`'Hborane ir1 an ct:her, such as diglyme, (dimetboxydiethyleneglycol), 2-hydroxymethyl~
`naphthalene is prepared.
`The 2-hydroxymethyl group can be esterified and etherified by conventional means
`employed to esterify and etherify primary hydroxy groups.
`2~Formylnaphthalene can be prepared from 2-hydroxymethylnaphthalene by treat(cid:173)
`ing the Iauer with manganese dioX'ide in a halohydrocarbon solvent.
`2-Cyanonaphthalenes can be prepared by refluxing 2..formylnaphrhalene wJ.th hy(cid:173)
`droxylamine hydrochloride and sodium acetate in ethanol to furnish the corresponding
`oxime which ·is refiuxed with acellic anhydride <in the presence of .an acid catalyst to fur(cid:173)
`nish 2-cyanonaphthalene.
`Alternatively, the above suhs.rituents can be introduced on a naphthylacetic acid
`ester derivative by using an ethyl or V'inyl substituted naphthylaceric acid ester deriva(cid:173)
`tive as a starting ma·teriai.
`In a preferred embodiment of the ,pre<:ent ·invention, the starting materia:ls are
`not substinlted with tr•ifiuoromethyl, difiuoromethoxy, diftuoromethyltbio, methyl(cid:173)
`methylenedioxy, alkoxymethylthio, alkylthiometbyloxy, alkyltbiomethylthio, retrahydro(cid:173)
`pyran-2'-yloxy, tetrahydrofuran-2'-yloxy, or 4' -alkoxytetrahydropyran-4' -yloxy groups,
`but rather, such groups are introduced on the 2-napbthaLene acetic acid derivatJive 'Ilia
`one of t:he fmal steps.
`Another method of prepar.ing the present compounds employs unsubstitutcd and
`subsrituted ·1-tetralones and can be illustrated by the following reaction sequence:
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`8
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`1,2111,134
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`8
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`,
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`K
`
`wherein alkyl and R" are defined as above.
`The 1-.tetcalones, the compounds of Formula C, are heated with two or more
`equivalents of a dialkyl carbonate, such as diethyl carbonate, in the presence of one
`or more equivalents of an alkali metal hyd11ide, 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 ~n a hydrocarbon sol(cid:173)
`vent; then the resulting products are .treated wirh an a-haloacetic aoid ester, such as
`ethyl a-bromoacerate or methyl ,t-iodoacetate, to furnish the corresponding 2-alkoxy(cid:173)
`carbonyl-2-(al.koxycarbonylmethyl)-]-tetralones, the compounds of Formula E. The
`latter is hydrolyzed with an acid, such as 'hydcochlorlic acid, sulphuric acid or p-toluene(cid:173)
`sulphonic acid, to obtain the 2-(carboxymethyl) compounds of Formula F. The latter
`is reduced with a reducing agent, such as sodium borohydride, lithium borohydride;
`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
`equivalent amount of hydrogen •in 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 derivarives., 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-naphrhyl(cid:173)
`acetic acid ester derivatives, the compounds of formula J. The latter compounds are
`hydrolyzed to the corresponding 2-naphthylacetic acid derivavives, the compounds of
`Formula K, by convenl!ional 'hydrolysis, such as by trea·tment 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 derivatlives of Formula M :
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`9
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`1,2:111,<134
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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 hydro