CA1236480A - N-naphthoylglycine derivatives - Google Patents

Abstract

ABSTRACT
compound of formula I

(I) wherein R1 is hydrogen, lower alkyl, lower alkenyl or phenylmethyl; R2 is hydrogen or lower alkyl; R3 is hydrogen or a substituent at position 4, 5 or 8 of the naphthalene ring, the substituent being selected from the group consisting of lower alkyl, lower alkoxy, halo, cyano, nitro and trihalomethyl, and R4 is hydrogen; or R3 and R4 each is a substituent at different positions selected from positions 3 to 7 of the naphthalene ring, the substituents being selected from the group consisting of lower alkyl, lower alkoxy, halo, trihalomethyl, (lower) alkoxy(lower)alkoxy, phenylmethoxy and phenylmethoxy substituted on the phenyl portion with a lower alkyl, lower alkoxy, halo or trihalomethyl; or a therapeutically acceptable salt with an organic or inorganic base of the compound of formula I wherein R2 is hydrogen. The pre-paration of this compound is also disclosed. Compounds of this type have pharmacology properties which render them beneficial for the treatment of diabetes mellitus and associated conditions. Also disclosed is an amidoester of formula II

Description

~.~36~

-1- AHP-780Ç

N-NAPHTHOYL~LYCINE DERIVATIVES
-This application relates to N-naphthoylglycine derivatives, thera-peutically acceptable salts thereof, a process for their preparation, and to methods of use and to pharmaceutical compositions thereof. The derivatives hsve pharma-5 cologic properties which render them beneficial for the treatment of diabetesmellitus and associated conditions.
For many years diabetes mellitus has been b~eated with two established types of drugs, n~mely insulin and oral hypoglycemic agents. These drugs have benefited hundreds of thousands of diabetics by improving their well-being and 10 prolonging their lives. However, the resulting longevity of diabetic patientshas led to complications such as neuropsthy, nephropathy, retinopathy snd cat-aracts. These complications have been linked to the undesirable accumul~tion of sorbitol in diabetic tissue, which in turn result from the high levels of glucose characteristic of the diabetic patient.
ln mammals, including humans, the key enzyme involved in the conver-sion of hexoses to polyols (the sorbitol pathway) is nldose reductase. J.H. Kinoshita and collaborators, see J.H. Kinoshita, et al., Biochem. Biophys. Acta., 158, 472tl968) snd references cited therein, have demonstrated that aldose reductase plays a centrsl role in the etiology of galactosemic catarscts by effecting the 20 conversion of galactose to dulcitol (galsctitol) and that an agent cspable ofinhibiting aldose reductase can prevent the detrimental accumulation of dulcitolin the lens. Furthermore, a relationship between elevated levels of glucose snd an ~desirable accumulation of sorbitol has been demonstrated in the lens, peripheral nervous cord and kidney of diabetic animals, see A. Pirie and R.
25 van Heynir4~en, Exp. Eye Res., 3,1~4 (1964); L.T. Chylack and J.H. Kinoshita,Invest. Ophthal., 8, 401(1969) snd J.D. Ward and R.W.R. Baker, Diabetol., 6, 531 (1970).
1,3-Dioxo-lH-benz~de] isoquinoline-2~3H~acetic scid has been reported ~;

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-~- AHP-7806 to be an effective inhibitor of aldose reductase, see D. Dvornik et al., Science, 1_,1146 (1973), and to be useful for the treatment of diabetic complications such as diabetic ~ataracts, neuropathy, nephropathy and retinopathy, see K.
Sestanj, N. Simard-Duquesne and D.M. Dvornik, U.S~ Patent No. 3,821,3~3, June 28,1974. Other compounds having a similar utility are the thioxo-lH-benz~de]-5 isoquinoline-2(3H~acetic ~cid derivatives of K. Sestan;, Canadian Patent Appli-cation 363,675, filed October 31,1980. ~S~6-Fluoro-2,3-dihydrospiro(4H-l-benzo-pyran-4,4'-imidazolidine~2',5'-dione (sorbinil) is still another compound that has received attention because of its aldose reductase inhibiting properties (see M.J. Peterson et al., Metabolism, 28 (SuppL 1), 456 (1979). Accordingly, 10 these compounds represent an important new approach for the treatment of diabetes mellitus.
The present application discloses novel N-naphthoylglycine derivatives, represented below by formula I, which are effective inhibitors of aldose reductase.
These new derivatives are structurally quite different from the above noted 15 aldose reductase inhibitors. Close prior art compounds, on a structural basis, appear to be a group of thioacylaminoacids, e.g. N-phenylthioxomethyl-N-methyl-glycine, prepared by A. Lawson and C.E. Searle, J. Chem. Soc., 1556 ~1957) as part of a chemical investigation of the chemical properties of such compounds.
These last mentioned compounds were prepared by thiobenzoylation of various 20 amino acids with (thiobenzoylthio)acetic acid. An important structural difference between these compounds and the present derivatives is the different type of aromatic group substituted on the thione portion of the thioamide. Thioacyl-amides also have been reported [see Chem. Abstr., 86,189582f (1977) for V.I.
Cohen et al., Eur. J. Med. Chern., 5, 480 (1976) and Chem. Abstr., 70,11306a 25 (1969) for von J. Voss and W. Walter, JustlLs Leibigs Ann. Chem., 716, 209 (1968)].
The structures of the thioacylamides of Cohen _ al and Voss et al differ from__ the structure of the present derivatives by having at least a different type of N-substitution. Another close prior art compound, on a structural basis, is N-[(l-naphthnlenyl)carbonyl]glycine, ~see Chem. Abstr., 61, 4333f ~1964) for E.
30 Cioranescu et 1., Rev. Chim. Acad. Rep. Populaire Roumaine, 7 (2), ~55 (1962)].
The compound, which has been used as a chemical intermediate, is distinguished from the compounds of the present invention by being an amide and not a thioamide.
SummarV of the lnvention The N-naphthoylglycine derivatives of this invention are represented 35 by formula I
" .
, . ... . . .

~3~

~3~ ~P-7806 S=C-N~Rl )-(:ll (:OOR-~,t~ 3 ( I) , R4 wherein Rl is hydrogen, lower alkyl, lower alkenyl or phenylmethyl, R is hydrogen or lower alkyl; R is hydrogen or a substituent at position 4, 5 or 8 of the naph-thalene ring, the substituent being selected from the group consisting of lower alkyl, lower alkoxy, halo, cyano, nitro and trihalomethyl, and R is hydrogen;
or R3 and R each is a substituent at different positions selected from positions3 to 7 of the naphthalene ring, and the substituents being selected from the group consisting of lower alkyl, lower alkoxy, halo, trihalomethyl, (lower)alkoxy-(lower~alkoxy, phenylmethoxy and phenylmethoxy substituted on the phenyl portion with a lower alkyl, lower alkoxy, halo or trihalomethyl; or a therapeutically acceptable snlt with an organic or inorganic bnse of the compound of formula I wherein R is hydrogen.
~ group of preferred derivativcs is represented by the compollnds of formula I wherein Rl is hydrogen, lower nlkyl, 2-propenyl or phenylmethyl;
R2 is hydrogen or lower alkyl; R3 is hydrogen or a substituent at positions 4, 5 or 8 of the naphthalene ring, the substituents being selected from the group consisting of lower alkyl, lower aLcoxy, halo, cyano, nitro and trifluoromethyl,and R4 is hydrogen; or R3 and R4 are a pair of substituents on the naphthalene ring, each substituent being at a different position of the ring, the pair of su~
stituents being selected from the group of pairs consisting of 3-halo-4-lower 25~ alkoxy, S-halo-6-lower alkyl, 5-halo-6-lower alkoxy, 5,7-dihalo, 5-(trifluoromethyl~
6-lower alkoxy, 5-halo-6-(lower)aIkoxy(lo'wer)alkoxy, 5-halo-6-[3-(trifluoromethyl~
phenylmethoxy] and 5-halo-6-(4-chlorophenylmethoxy); or a therapeutically acceptable salt with an organic or inorganic base of the compound of formula I wherein R is hydrogen.
Another preferred group of the compounds is represented by the compounds of formula I wherein Rl is hydrogen, lower alkyl or phenylmethyl;
R2 is hydrogen or lower alkyl; R3 is 4-halo or 5-halo and R4 is hydrogen, or ~.~36'~

R and R are a pair of substltuents on the naphthalene rlng selected from the group of pairs consisting of 3-halo-4-lower alkoxy, 5-halo-6-lower aL"yl, 5-halo-6-lower alkoxy, 5,7-dihalo and 5-trifluoromethyl-6-lower alkoxy; or a therapeutically acceptable salt with an organic or inorganic base of the compound of formula I wherein R is hydrogen.
A most preferred group of the compounds is represented by the compounds of formula I wherein Rl is lower alkyl; R2 is hydrogen, R3 is 5-halo and R4 is hydrogen; or R3 and R4 are a pair of substituents on the naphthalene ring selected from the group of pairs consisting of 3-halo-4-lower a~coxy, 5-hal~6-lower alkoxy and 5-(trifluoromethyl~6-lower alkoxy; or a therapeutically acceptable salt thereof with an organic or inorganic base.
The compounds of formula I can be prepared by a process described hereinafter.
~ method is provided for preventing or relieving diabetes mellitus associated complications in a diabetic mammal by administering to said mammal a prophylactic or alleviating amount of the compound of formula I or thera-peutically acceptable salt thereof with an organic or inorganic base.
The compound of formula I, or a therapeutically acceptable salt thereof with an organic or inorganic base, when admixed with a pharmaceutically acceptaMe carrier, forms a pharmaceutical composition which can be used according to the preceding method.
Detailed Description of the Invention The term 'qower alkyl" as used herein means a straight chain alkyl radical containing from one to four carbon atoms or a branched chain alkyl radical containing three or four carbon atoms and includes methyl, ethyl, propyl, l-methylethyl, butyl, 2-methylpropyl and l,l-dimethylethyl. Preferred lower alkyl radicals contain from one to three carbon atoms.
The term 'qower alkenyl" as used herein means a straight chain alkenyl radical containing from two to six carbon atoms, or a branched chain alkenyl radical containing from four to six carbon atoms and includes, for example, ethenyl, 2-propenyl, 2-methyl-2-propenyl and 2-ethyl-3-butenyl. Preferred lower alkenyl radicals contain two to three carbon atoms.

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The term 'qower allcoxy" as used h~rein means a straight chain alkoxy radical containing from one to six carbon atoms, preferably one to three carbon atoms, or a branched chain alkoxy radical containing three or four carbon atoms,and includes methoxy, ethoxy, l-methylethoxy, butoxy and hexanoxy.
The term "halo" as used herein means a halo radical and includes fluoro, chloro, bromo and iodo.
The term "ar" as used mean an aromatic radical containing at least one benzene ring. The preferred aromatic radical is phenyl.
The compounds of formula I wherein R2 is hydrogen form salts with suitable therapeutically acceptable inorganic and organic bases. These derived salts possess the same activity as their parent àcid and are included within the scope of this invention. The acid is transformed in excellent yielcl into the corresponding therapeutically acceptable salt by neutralization of said acidwith the appropriate inorganic or or~anic base. The salts are adrninistered usually in the same manner as the parent acid compounds. Suitable inorganic bases to form these salts include, for example, the hydroxides, carbonates or bicarbonates of the therapeutically acceptaMe alkali metals or alkaline earth metals, for example, sodium, potassium, magnesium, calcium ancl the like.
Suitable organic bases include the following amines: benzylamîne; lower mono-, di- and trialkylamines, the alkyl radicals of which contain up to three carbon atoms, such as methylamine, dimethylamine, trimethylamine, ethylamine, di-and triethylamine, methylethylamine, and the like; mon~, di- &nd trialkanol-amines, the alkanol radicals of which contain up to three carbon atoms, for exarnple, mono-, di- and triethanolami~e; a~ylen~diamines which contain up to six carbon atoms, such as hexamethylenediamine; cyclic saturated or un-saturated bases containing up to six carbon atoms, such as pyrrolidine, piperidine, morpholine, pipera7ine and their N--alkyl and N-hydroxyalkyl derivatives, such as N-methyl-morpholine and N-(2-hydroxyethyl~piperidine, as well as pyridine.
Furthermore, there may be mentioned the corresponding quaternary salts, such as the tetraalkyl (for example tetramethyl~, alkyl-alkanol (for example methyl-triethanol and trimethyl-monoethanol) and cyclic ammonium salts, for example the N-methylpyridinium, N-methyl-N-(2-hydroxyethyl~morpholinium N,N-di-methylmorpholinium, N-methyl-N-(2-hydroxyethyl)-morpholinium7 N,N-dirnethyl-~ ,~

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-6- AHP-~80~i piperidinium salts, which are characterized by having good water-solubility.
In principle, however, there can be used all the ammonium salts which are phy-siologically compatible.
The transformations to the salts can be carried out by a variety of methods known in the art. ~or example, in the case of the inorganic salts, it is preferred to dissGlve the acid of formula I in water containing at least one equivalent amount of a hydroxide, carbonate, or bicarbonate corresponding to the inorganic salt desired. Advantageously, the reaction is performed in a water-miscible, inert organic solvent, for example, methanol~ ethanol, dioxane, and the like in the presence of water. ~or example, such use of sodium hy~roxide, sodium carbonate or sodium bicarbonate gives a solution of the sodiurn salt.
Evaporation of the solution or addition of a water-miscible solvent of a more moderate polarity, for example, a lower allcanol, for instance, butanol, or a lower alkanone, for instance, ethyl methyl l~etone, gives the solid inorganic lS salt if that form is desired.
To produce an amine salt, the acidic compound of formula I is dissolved in a suitable solvent of either moderate or low polarity, for example, ethanol, methanol, ethyl acetate, diethyl ether and benzene. At least an equivalent amount of the amine corresponding to the desired cation is then added to that solution. If the resulting salt does not precipitate, it can usually be obtainedin solid form by addition of a miscible diluent of lower polarity, for example, benzene or petroleum ether, or by evaporation. If the amine is relatively vol-atile, any excess can easily be removed by evaporation. It is preferred to use substantially equivalent amounts of the less volatile amines.
Salts wherein the cation is quate~nary ammonium are produced by mixing the acid of form~da I with an equivalent amount of the corresponding quaternary ammonium hydroxide in water solution, followed by evaporation of the water.
The compounds of this invention and their addition salts with pharma-ceutically acceptable organic or inorganic bases may be administered to mammals,for example, man, cattle or rabbits, either alone or in dosage forms, i.e., capsules or tablets, combined with pharmacologically acceptable excipients, see below.

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Advantageously the compounds of this invention may be given orally. However, lhe method of administering the present active ingredients of this invention is not to be construed as limited to a particulnr mode of administration. ~or example, the compounds may be administered topically directly to the eye in the form of drops of sterile, buffered ophthalmic solutions, preferably of pH
7.2 - 7.6. Also, they may be administered orally in solid form containing such excipients as starch, milk sugar, certain types of clay and so forth. They may also be administered orally in the form of solutions or they may be injected parenterally. For parenteral administration they may be used in the form of a sterile solution, preferably of pH 7.2 - 7.6, containing a pharmaceutically acceptable bufferO
The dosage of the present therapeutic agents will vary with the form of administration and the particular com~ound chosen. Furthermore, it will vary with the particular host under treatment. Generally, treatment is initiated with small dosages substantially less than the optimal dose of the compound. Thereafter, the ~osage is increased by small increments until e~ficacyis obtained. In general, the compounds of this invention are most desirably ad-ministered at a concentration level that will generally afford effective resultswithout causing any harmful or deleterious side effects. For topical administration a 0.05 - 0.2% solution may be administered dropwise to the eye. The frequency of instillation varies with the subject under treatment from a drop every two or three days to once daily. For oral or parenteral administration a preferred level of dosage ranges from about 0.1 mg to about 200 mg per kilo of body weightper day, although aforementioned variations will occur. However, a dosage level that is in the range of from about 3.0 mg to about 30 mg per kilo of body weightper day is most satisfactory.
Unit dosage forms such as capsules, tablets, pills and the like may contain from about 5.0 mg to about 250 m~ of the active ingredients of this in-vention, preferably with a significant quantity of a pharmaceutical carrier.
Thus, for oral administration, capsules can contain from between about 5.0 mg to about 250 mg of the active ingredients of this invention with or without a pharmaceutical diluent. Tablets, either effervescent or noneffervescent, can .~

~3G~

-8- ~HP-7806 contain between about 5.0 to 250 mg of the active ingredients of this invention together with conventional pharmaceutical carriers. Thus, tablets which may be coated and either effervescent or noneffervescent may be prepared according to the known art. Inert diluents or carriers, for example, magnesium carbonate or lactose, can be used together with conventional disintegrating agents for example, magnesium stearate.
Syrups or elixirs suitable for oral admînistration can be prepared from water soluble salts, for example, sodium N-[[5-~trifluoromethyl~6-methoxy-l-naphthalenyl] thioxomethyl]-N-methylglycinate, and may advantageously contain glycerol and ethyl alcohol as solvents or preservatives.
The compound of formula I, or a therapeutically acceptable salt there-of, also can be used in combination with insulin or oral hypoglycemic agenes to produce beneficial effect in the treatment of diabetes mellitus. In this instance, commercially available insulin preparations or oral hypoglycemic agents, exem-plified by acetohexamide~ chlorpropamide, tola~amide, tolbutamide and phenformin, are suitable. The compound of formula I, or a therapeutically acceptable sult thereof, can be administered sequentially or simultaneously with insulin or the oral hypoglycernic agent. Suitable methods of administration, compositions and doses of the insulin preparation or oral hypoglycemic agent are described in medical textbooks; for instance, "Physicians' Desk Reference", 34 ed., Medical EconomicsCo., Oradell, N.J., U.S.A., 1980. When used in combination, the compound of formula I, or its therapeutically acceptable salt, is administered as described previously.
The comp~und of form~a I, or its therapeutically acceptable salt, can be admin-istered with the oral hypoglycem;c agent in the form of a pharmaceutical com-position comprising effective amounts of e~ch agent.
The aldose reductase inhibiting effects of the cornpounds of formula I
and their pharmaceutically acceptable salts with organic or inorganic bases can be demonstrated by employing an in vitro testing procedure similar to that described by S. Hayman and J. 11. Kinoshita, J. Biol. Chem., 240, 877 (1965). In the present case the procedure of Hayman and Kinoshita is modified in that the final chroma-tography step is omitted in the preparation of the enzyme from bovine lens.
The following results were obtain~d when the foregoing listed compounds of formula I were evaluated in the above in vitro test.

~L~36'~

-9- AHP-7806 -~~

% Inhibition at Example Different Molar In Which Concentr~tions Coml~ound of ] ~ormula I Compound (in vitro) Rl R2 R3 R4 Is PrePared 10 5 10 610 7 _ _ _ _ _ _ CH3 CH3 5-Br H 3 8 CH3 H 5-Br H 32 93 87 47 H H 3-Cl 4-CH30 32 61 16 CH3 H 4-Br H 33 91 77 32 CH3 H 8-Br H 34 88 75 24 CH3 H 5-Br 6-CH3(CH2)40 37 93 91 55 CH3 H 5-Cl H 40 91 83 40 CH3 H 5-Br 6-CH30 41 99 91 72 CH3 H 5-Br 6-CH3 42 92 88 55 CH3 H ~Cl H 44 88 73 25 CH3 H 3-Cl ~CH30 45 85 78 33 CH3 H 5-Cl 7-Cl 46 88 75 29 CH3 H 5-I ~ 6-CH30 47 98 95 72 CH3 H 5-Br 6-CH30(CH2)3C 49 92 87 38 CH3 H 5-CH2=C(CH3) H 50 92 74 19 CH3 H 5-(CH3~2CfI H 51 91 72 21 CH3 H 5-C~3 6-CH30 52 98 94 65 CH3 H 5-Br 6-~(3-CF3-C6H~)CE~203 53 86 37 11 CH3 H 5-Br 6-[(4-CI-C6H4)CH20] 53a &8 44 4 CH3 H 5-CF3 H 53b 93 84 33 H H 5-Br H 54 54 14 n C3H7 H 5 Br H 55 91 70 19 .

% Inhibition ~t Example Different Molar In Which Concentrations Compound of Formula I _ _ _ Compound (in vitro3 Rl R~ R3 R4 Is Prepared 10 5 10~10 7 CH2=CH-CH2 H 5-Br _ _ 56 92 77 27 C2H5 H 5-Br H 57 85 72 24 n-C4Hg H 5-Br H 58 86 65 19 CH2C6H5 H 5-Br 59 86 69 20 The aldose reductase inhibiting property of the compounds of this invention and the utilization of the compounds in preventing, diminishing and alleviating diabetic complications are demonstrable in experiments using galacto-semic rats, see Dvornik et al., cited above. Such experiments are exernplified hereinbelow after the listing of the following general comments pertaining to these experiments:
(a) Four or more groups of six male r~ts, 50-70 g, Sprague-Dawley strain, were used. The first group, the control group, was fed a mixture of laboratory chow (rodent laboratory chow, Purina) and glucose at 20% (W/W
%) concentration. The untreated galactosemic group was fed a similar diet in which galactose is substituted for glucose. The third group was fed a diet prepared by mixing a given amount of the test compound with the galactose containing diet. The concentration of galactose in the diet of the treated groups was the same as that for the untreated~galactosemic group.
(b) After four days, the animals were killed by decapitation.
The eyeballs were removed and punctured with a razor blade; the freed lenses were rolled gently on filter paper and weighed. The sciatic nerves were dissected as completely as possible and weighed. Both tissues were frozen and can be kept up to two weeks before being analyzed for dulcitol.
(c) The polyol determination was performed by a modification o the procedure of M. Kraml and L. Cosyns, Clin. Biochem., ~, 373 (1969).
Only two minor reagent changes were made: (a) The rinsing mixture was an aqueous 5% (w/v) trichloroacetic acid solution and (b) the stock solution was prepared by dissolYing 25 mg of dulcitol in 100 ml of an aqueous trichloroaceticacid solution.lN.B.: For each experiment the average value found in the ffssue from rats fed the glucose diet was subtracted from the individuPl values found in the corresponding rat tissue to obtain the amount of polyol accumulated.
The following tabulated results show t}~at the compounds of this 5 invention diminish the accumulation of dulcitol in the lenses and sciatic nerves of rats fed galactose. The figures under L and N represent the percentage de-crease of dulcitol accumulation in the tissues of the lens and sciatic nerve, respectively, for treated rats as compared to untreated rats.

10 Compound of Formula I Dose L N
Rl R2 R3 R4mg/kg/day . ~
CH3 H 5-Br H 189 24 79 CH3 H S-Cl H 156 34 7n CH3 H 5-Br 6-CH30162 34 ~ 32 - ~27 CH3 H ~Cl 7-Cl ~52 29 45 CH3 H s-CF3 6-CH3026 lS 94 CH3 H ~CF3 H 11 2 36 Process The preparation of the compounds of formula I is illustrated by the following scheme wherein R, R and R are as defined hereinbefore and COOR
30 is an ester group which may be, for example, & lower ~lkyl or an ar(lower)alkyl ester; i~e., R is lower alkyl or artiower)alky1.

_ . , . _. . . .. ._ _ .. . . .

0-C-N~R )-CH2CUOR S -C-Nl(R )-CH2COOR

5R ~ P2S5 R
R4 (II) R (III) 1 hydrolysis 1 hydrolysis O =C-N(R )-~H2COO~.

R3 ~ ~ p2s5 I=(R2_H) 15R4 (IV) More specifically, a process for preparing the compounds of formula I comprises:
(a) reacting nn amidoester of formula II wherein Rl, R3 nnd R4 are as defined herein and R is lower alkyl or ar(lower)alkyl with phosphorus penta-20 sLdfide to give the corresponding thioxoester of formula ~II wherein Rl9 R3, R4 and R are as defined herein; or (b) hydrolyzing the thioxoester of formula m s~herein Rl, R3, R4 and R are as defined herein to obtain the corresponding compound of formula I wherein Rl, R3 and R4 are as defined herein and R2 is hydrogen; or (c) hydrolyzing the amido~ster of formula II wherein Rl, R3, R4 and R are as defined herein to obtain the corresponding amidoacid of form~a IV wherein Rl, R3 and R4 are as defined herein, and reacting the lust-named compound with phosphorus pentasulfide to obtain the corresponding compound of formula I wherein Rl, R3 and R are as defilled herein and R is hydrogen.
Referring to the above section (a) of the last paragraph, the thioxo-ester of Iormula III includes those corresponding compounds of iormula l wh~reinR is lower ~lkyl, when R of the compound of formula m is lower alkyl. For ~6'~
-i3~ P-7~16 clarity and convenience in thc following discussion of ihe process, these lattercompounds of formula 1 are included in the discussion and preparation of the compounds of formula IIl.
Still more specifically, the starting mater;al of formula II can be S prepared by coupling a naphthalenecarboxylic ~cid of form~a Y wherein R and R4 are ss defined herein with an aminoacid ester of formula YI wherein Rl and R are as defined herein.
COOI I
~ I ~ N~l(R )-( Il2( (~~ ~~ l l R (~;) (~1 ) The compounds of formula V and VI ~re known or can be prepar~
by known methods. For example, see "Elsevierls Encyclopaedia of Organie Chemistry,"
F. Radt, Ed., Series III, Vol. 12B, Elsevier Publishing Co., Amsterdarn, 1953, pp 3965-4473. The preparation of a mlmber of the naphthalenecnrboxylic acids is illustrated by exampl~s 1 nnd ln to lj t]cscribed hereinafter. The coupling of the naphthalenecarboxylie acid V and the amino ncid ester Yl is done prefernbly by the "carboxyl activation" coupling procedure. Descriptions of carboxyl-acti-vating groups are found in general tcxtbooks of peptide chemistry; for example K.D. Kopple, "Peptides and Amino Acids", W.A. Benjamin, lne., New York, 1966, pp. 45-51, and E. SchrBder and K. Ll~bke, "The Peptides"; Vol. 1, Academic Press, New York, 1965, pp. ~7-128. Examples of the aetivated form of the terminal carboxyl are the aeid chloride, acid bromide, anhydride, azide, activated ester,or O-acyl urea of a dialkylcarbodiimide. Preferred activated forms of the car-boxyl are the acid chloride or the l-benz'otriazolyl, 2,4,5-trichlorophenyl or succin-imido activated esters.
Returning to the flow diagram again, the amidoester of formula II
is reacted under anhydrous eonditions with about two to five molar equivalents of phosphorus pentasulfide in an inert solvent, e g. ~cylene or toluene, to obtain the corresponding thioxoester of formula III. This reaetion is performed con-:

veniently at temperatures ranging from 80 to about 150~ C and at times ranging from 20 minutes to four hours. Preferably, the reaction is performed in the presence of an organic base for instance, N-ethyl morpholine, triethylamine or pyridine.
Thereafter, the thioxoester of formula m is hydrolyzed with a hy-drolyzing agent to give the corresponding product of formula I in which R2 is hydrogen. Generally speaking, this conversion is ml~st conveniently performed by employing a base as the hydrolyzing agent. The hydrolysis is performed in the presence of sufficient water, followed by acidification of the reaction mixture, to yield the desired acid. However, it should be understood that the manner of hydrolysis for the process of this invention is not intended to be Iimited tobasic hydrolysis since hydrolysis under acidic eonditions and other variations, for example, treatment with lithium iodide in collidine ~see L.F. Fieser and M.
Fieser, 'TReagents for Organic Synthesis", John Wiley and Sons, Inc., New York, 1969, pp. 615-617), also are applicable. Hydrolysis under acidic conditions is preferred when the ester is a tert butyl ester.
For basic hydrolysis, a preferred ernbodiment involves subjecting the ester to the action of a strong base, for example, sodium or potassium hy-droxide, in the presence of sufficient water to effect hydrolysis of the ester.
The hydrolysis is performed using a suitable solvent, for example, metl~nol, ethanol or 2-methoxyethanol. The reaction mixture is maintained at a temperatureof from about 25 to 100 C or at the reflux temperature of the solvent employed until hydrolysis occurs. Usllnlly from 10 minutes to 6 hours is sufficient for this hydrolysis. The reaction mixture is then rendered acidic with an acid, for example, acetic acid, hydrochloric acid or sulfuric acid, to release the free acid.
Alternatively, the amidoester of formula II can be hydrolyzed under the same conditions as described hereinbefore to give the corresponding amido-acid of formula IV ~herein Rl9 R3 and R are as defined herein. The latter com-pound, when reacted with phosphorus pentasulfide in the manner described herei~
before, then gives the corresponding compound of formula I wherein Rl, R3 and R4 are as defined herein and R is hydrogen. Note that the standard first step of the work up of the pentasulfide reaction mixture requires that the reaction mixture be decomposed in water. This action causes any corresponding thi~
acid, present in the reaction mixture as a result of the carboxy group reacting with phosphorus pentasulfide, to be converted to the desired carboxylic acid.

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The amidoacid of formula IV also can be prepared by a previously reported process involving the reaction of the appropriate naphthalenecarboxylicacid chloride with the appropriate aminoacid corresponding to the aminoacid ester of formula VI in the presence of a base (proton acceptor). This process has been used to prepare N-~(l-naphthalenyl)carbonyll glycine, see Chem. Abstr.,61, 4333 f (1964) for E. Cioranescu, et al., Rev. Chim., Acad. Rep. Populaire Roumaine, 7 (2), 755 (1962). However, this known process for preparing N~
naphthalenyl)carbonyll glycine is inferior, based on yields, to the present process.
An interesting aspect of this invention is that certain an~idoesters of formula II and certain amidoacids of formula IV having the following formula O-C-N(R )-a~2COOR

R3 R~

wherein Rl is lower alkyl, lower alkenyl or phenylmethyl; R3 is a substituent at position 4, 5 or 8 of the naphthalene ring, the substituent being selected from the group consisting of lower alkyl, lower alkoxy, halo, cyano, nitro and trihalo-methyl, and R4 is hydrogen; or R3 and R each is a substituent at different posi-20 tions of the naphthalene ring, the positions selected from positions 3 to 7 andthe substituents being selected from the group consisting of lower alkyl, lower alkoxy~ halo, trihalomethyl, (lower)alkoxy(lower)alkoxy, phenylmethoxy and phenyl-metho2y substituted on the phenyl portion with alower alkyl, lower alkjoxy, haloor trihalomethyl; and R is hydrogen or lower alkyl, or a therapeutically~acceptable 25 salt thereof with an organic or inorganic base, also have aldose reductase inhibit-ing effects. For example, in the above noted in vitro test, the following results were obtained for the amidoacids, described in example 60:
N-[(5-brom~l-naphthalenyl)carbonyl]-N-methylglycine (10 5, 64%;10~, 21%); and N-[[5~tri~1uoromethyl~6-methoxy-1-naphthalenyl] carbonyl]-N~methylglycine 30 (10 5, 94~;10~, 93%;10 , 60%1. Accordingly, the latter amîdoesters, amidoacids and the therapeutically acceptable s lS with organic or inorganic bases, of the amidoacids are included within the scope of this invention.

~3~

The following examples illustrate further this invention.

~(l-Methylethenyl~l-naphthalenecarboxylic Acid (V, R3 = 5-CH2 = C(CH3) and R = H) In a nitrogen atmosphere, a solution of l-bromo-5-(1-methylethenyl~
naphthalene [14.21 g, described by W.F. Short and H. Wang, J. Chem. Soc., 991 (1950)3 in diethyl ether (140 ml) was added dropwise to a mixture of ethyl magnesium bromide (prepared from 2.94 g of mugnesium and 4.29 ml of ethyl bromide) in diethyl ether (30 ml) at 0 C. The mixture was stirred at 20 C for 18 hr and then heated at reflux for 1 hr. The cooled solution was poured onto an excess of solid carbon dioxide The mixture was dissolved in diethyl ether. The resulting solution was washed with a 2N aqueous solution of H2S04, brine and 10% aqueous NaHCO3(4x). The basic washes were combined and made acidic (pH3) with 6N
aqueous HCl. The resulting solid was collected9 washed with water and dried to give 9.7 g of the title compound; mp 138-140 C; NMR(CDC13) ô 2.15 (s, 3EI), 5.0 ~c 5.38 (2s, 2H), 8.0 (m, 6H), 10.75 (SJ lH).
EXAMPLE la 5~ Methylethyl~l-naphthalenecarboxylic Acid (V, ~3 = 5-(CH3)2CH and R4 = ~) ~(l-Methylethenyl~l-naphthalenecarboxylic acid t4.36 g, described in Example 1), dissolved in ethanol (150 ml), was hydrogenated using 5% palladium on charcoal as catalyst at 20 C. Absorption of hydrogen was complete after 3 hr. The catalyst was removed by filtration. The filtrate was evaporated to give the title compound; mp 14~-150 C; NMR(CDC13) ~ 1.4 (d, J = 7Hz~ 6H), 3.75 (septuplet, J = 7Hz, lH), 8.0 (m, 6H), 10.1 (s, lH).
EXAMPLE lb 5-Bromo-6-methoxy-1-naphthalenecarboxylic Acid (V, R3 = 5-Br and R4 = 6-CH3O) A solution of bromine (2.49 ml, 45 mmoles~ in glacial acetic acid (50 ml) was added dropwise to a stirred solution of 6-methoxy-1-naphthalen~
carboxylic acid [8.9 g, 44 mmoles, described by C.C. Price, et al., J. Am. Chem.Soc., 69, 2261 (1947)] in glacial acetic acid (300 rnl), cooled in an ice bath. The res~ting precipitate was collected and washed with acetic acid and then water.
Crystallization of collected precipitate from glacial acetic acid gave the titlecompound; mp 262-264~ C; NMR(DMSO-d6) ~ 3.96 (s, 3H), 7.5-7.8 (m, 3H), 7.95 (d, lH), 8.25 (d, lH), 8.82 (d9 lH).

..~

~ ~3~

EX AM PLE lc 5-Bromo-6-methyl-1-naphthalenecarboxylic Acid (V, R3 = 5-Br and R4 = 6-CH3) By following the procedure of Example lb, but replacing 6-methoxy-l-naphthalcnecarboxylic acid with an equivalent amount of 6-methyl-1-naphth-alenecarboxylic acid, described by C.C. Pric~ et al, J. Am. Chem. Soc.l 63, 1857 (1941), the title compound; mp 253-255 C [after crystallization Irom ethan~]-methanol ~3:1)], NMR (DMSO-d6) ,5 2.6 (s, 3H), 8.0 (m, 5H), 10.5 (broad, lH), was obtained.
EXAMPLE ld 3-Chloro-~-methoxy-l-naphthalenecarboxylic Acid (V, R3 = 3-Cl and R4 = 4-CH3O3 3-Chloro-4-methoxy-1-naphthalenecarboxaldehyde [15.5 g, 70.2 mmoles, described by A J. Ablewhite and K.R.H. Wooldridge, J. Chem. Soc. (C), 2488 (1967)] was added to a suspension of silver oxide in 109~ sodium hydroxide (16.9 g of sodium hydroxide in 170 ml of water) and dioxane (100 ml). The mixture was stirred and heated at 80 C for 7 hr. The precipitate was removed by filtration through diatomaceous earth (sold under the trademark Celite). The clear filtratewas evuporated to dryness. The residue was dissolved in water. The solution wns acidified and the resultin~ prccipit~te was scpara~ed by filtration. The pre-cipitate wn~s dissolved in ethyl Qcetate. 'I`he resu]ting so]ution was extractedwith saturated sodium bicarbollate solution. The combined aqueous extracts were acidified. The resulting precipitate was separated by filtration and recry-stallized from ethanol-water to give the title compound; mp 187-189~ C; NMR
(Dl~lSO-d6) ~ 4.0 (s, 3H), 8.15 (m, SH), 13.3 (broad lH); IR (Nujol*) 2900,1700,1260,1160 cm 1; UV~max (EtOH) 303 (~ ~,400), 231(56,300); Anal. Calcd: C, 60.90~6 ?, H, 3.83% Found: C, 60.71% H, 3.87~.
EXAMPLE le 5,7-Dichloro-l-naphthalenecarboxylic Acid~Y, R = 5-Cl and R4 = 7-Cl) Sulfuryl chloride (36.8 g, 273 mmoles) was added dropwise to a stirred suspension of benz[c,d] indole-2(1H~one (20 g, 119 mrnoles) in glacial acetic acid ~0 (275 ml) at 20 to 22 C. The mixture was heated at reflux for 1.5 hr, cooled and filtered. The collected solid was washed with glacial acetic acid and recrystallized from toluene to afford 6,8-dichloro-benz[c,d] indole-2(1H)-one, mp 265 C, des-cribed by Y.T. Rozhinskii, Zhur. Org. Khim., 8, 2388 (1972). A mixture of the latter compound (14 g, 58.8 mmoles3 in 2% aqueous sodium hydro~ide was refluYed ~5 for 4 hr. The mixture was cooled, mixed with sodium nitrite (3.8 g, 55 mmoles3 Nl~jol is a trademark for a brand of white mincral oil -18- AI~P-7806 and added dropwisc to u coolcd (()-5 C) solution Or concentrnted sulfuric ~cid - (45 ml) in ~ater (180 ml). The diazonium salt wus saltcd out by addition of sodiurn bromide, collected by filtration and while still wet (drying dan6erous) ~as ~dded to a solution of sodium hypophosph~te (39.2 g of Nal~2P02.H 20) in water (100 ml). The mixture was stirred at 20-22~ C for 48 hr. The resulting solid was collected by filtration and suspended in saturated sodium bic~rbonale (~00 ml). The insolubie material was collected by filtration and resuspcnded in hot, saturuted sodium bic~rbonate (200 ml). The suspension ~vas filtered and the filtr~lte was cooled.The resulting precipitate of the sodium salt o~ the product was collected by filtration.
The free acid was prepared by suspending the sodium salt in water and render-ing the suspension acidic. More product was obtained by acidification of filtrates of the sodium salt. The combined crops were recrystallized from ethanol to yield 5.8 g of the title compound; mp 253-254 C; NMR (DMSO-d6) ~ 8.3 (m, raH), 10.6 (broad, lH), UV~max (EtOH) 333 nm ( 2,350), 298 (7,000), 230 (53,300~.
EXAMPLE lf S-lod~6-;nethoxy-1-naphthalenecarboxylic Acid (Y, R3 = 5-I and R4 = 6-CH30) lodinc (7.08 g) ~nd iodic acid (2.78 g) were added to a stirred solutio of 6-rnelhoxy~ naphthnlenccarboxylic acid methyl ester n5 L~ 69.~ mrnoles, described by C.C. Price et al., J. Arner. Chem. Soc., 69, 2261(1947)] în 8096 acetic acid (110 ml) and 98~6 sulfuric acid (0.97 ml). The solution was heated at 50 C for 5 hr, cooled and poured into water (100 ml). After the nddition of sodium bisulfite to destroy the unreacted iodine, the precipitate was collected,washed with water and recrystallized from ethanol to afford the corresponding methyl ester of the tltle compound; mp 98-99 C; N~IR (CDC13) ~ 3.95 (s, 3H), 4.00 (s, 3H), 8.00 (m, 5H). A mixture of the latter ester (7.1 g, 21 mmoles), 10%
aqueous sodiurn hydroxide (35 ml3 and methanol (l9.S ml) was heated at re1ux for 1 hr. The solution was cooled to ice bat~ temperature and made acidic with lN aqueous hydrochloride~ The resulting precipitate was coJlected, washed with water and dried under reduced pressure over phosphorus pentoxide to give 7 g of the title compound; mp 259-261 C; NMR (DMSO-d6) ~ 4.0 (s, 3H), 8.15 (m, 5H), 10.56 (broad, lH).
EX AM PLE lg 5-Cyano-6-methoxy-1-naphthalenecarboxylic Acid (V, R3 = 5-CN and R4 = 6-CH30) 3~ A solution of bromine (26.6 g, 0.167 mole) in glacial acetic acid (25 ml) -]9- AHP-7806 was added dropwise to a cooled suspcnsion of 6-methoxy-1-n~phthalenecarboxyljc acid methyl ester (30 g, 0.13 9 moles) in glacial acetic acid (2.75 ml). The pre-cipitate was collected~ washed with water and crystallized from ethanol to give 33.3 g of 5-brom~6-methoxy-1-naphthalenecarboxylic acid methyl ester; mp 119 C; NMR (CDC13) ~ 3.97 (s, 31~), 4.03 (s, 3H), 7.35 (d, J = 9.25Hz, lH), 7.4(m, lH), 8 05 (d, J = fi.75 Hz, lH3, 8.45 (d, J = 8.25 Hz" lH), 8.9 (d, J = 9.25, ]H).
The latter ester (10.1 g, 34 mmoles) and Cu2(CN)2.H2O (3.4 g, 17 mmoles) in distilled dimethylfornnamide (75 ml) containing 15 drops of pyridine was heated at 180 C for 5 hr. The hot mixture was poured into a mixture of ice (SD g) and ~0 conc. NH40H (50 ml). The resulting precipitate was col]ected, washed with water, dried and recrystallized from chloroform-ethyl acetate to afford 5.6 g of 5-cyano-6-methoxy-1-naphthalenecarboxylic acid methyl ester: mp 210-211 C, NMR (CDC13) ~ 3.95 (s, 3H), 4.15 (s, 3H). To a stirred solution of the latter ester (5.95 g, 24.66 mmoles) in 2-methoxyethanol (100 ml) at 20-22 C, 4N nqueous NaOH solution (12.3 ml) was added. The reaction mixture was stirred at 20-2~ C
for 60 hr, diluted with water, cooled to Q C and rendered acidic with IN aqueous HCI. The precipitate was collected and dried to yield 5.6g of the title compound;
mp ~290 C; NMR (DMSO-d6) ~ 4.1 (s, 31-1), 8.1 (m, 5TI).
EX AM PLE lh 5-(Trifluoromethyl~6-methoxy-1-naphthalenecarboxylic ~cid (V, R = 5-CF3 and R4 = 6-CH30) A mi~ture of 5-iodo-6-methoxy-1-naphthalenecarboxylic acid methyl ester (10.26 g, 30 mmoles, described in Example lf), trifluoromethyl iodide (12 g, 61.2 mmoles), freshly prepared copper powder (5.7 g, prepared according to the procedure of R.Q. Brewster and T. Groening, 'IOrganic Syntheses", Coll. Vol.
Il, John Wiley and Sons, New York, N.Y., U.S.A., 1948, p. 445) nnd pyridine (45 ml) was charged into a stainless steel autoclàve. The vessel was shaken and heated at 120 C for 20 hr and cooled to room temperature. The mixture was diluted -with diethyl ether-ethyl acetate (1:1). The insoluble material was removed by filtration. The filtrate was washed with IN aqueous HCl, water and dried (MgSO4).
The solvent ~as removed under reduced pressure. The residue wns crystallized from ethanol to give 6.4 g of 5-(trifluoromethyl~6-methoxy-1-naphthalenecar-bo~ylic acid methyl ester; mp 79-80 C; NMR (CDC13) ~ 3.95 (s~ 6H)1 8.00 (m, SH~. A mixture of the latter ester (6.3 g, 27 rnmoles), IN ~3queous NaOH solution (34.12 ml) and methanol (l00 ml) Wf~5 stirred at 20-22 C for 4 hr. The mixture ~ ~
was adjusted to pH 7 with IN aqueous HCI, methanol was removed from the mixture by distillation ~nd the concentrated mixture was made acidic (pH 2) with IN
aqueous HCI. The resulting precipltate was collected and dried to yie]d 6 g oî
the title compound; mp 218-219 C; Nl~ (D~SO-d6) ~ 4.0 (s, 3H), 8.3 (m, 5H), 10.6 (broad, IH).
EXAMPLE li 5-Bromo-6-~3-(trifluoromethyl)phenylmethoxy]-1-naphthalenecarboxylic Acid [V, R3 = 5-Br and R = 6-[(3-CF3~6H4~CH2O] ) A rnixture of 5-bromo-6-methoxy-1-naphthalenecarboxylic acid (33.35 g, 0.11 moles, described in example lb) in glacial acetic acid (460 ml) and 4796 aqueous HBr(417 ml) was heated at reflL~ for 9 hr. The resulting precipitate was collected, washed with water and dried over P2O5 under reduced pressure. The precipitate was recrystallized from ethanol-water to give 21.45 g of 5-bromo 6-hydroxy- --l-naphthalenecarboxylic acid; mp > 225 C; Nl~IR (DMSO-d6) ~ 8.0 (m, 5H), 11.0 (broad, IH), 12.6 (broad, lH).
The Iflttbr acid (1.2 g, ~.5 mmoles) was suspended in dry dimethyl-formamide (DMF, 25 ml). Sodium hydride (~.43 g, 9.0 rnmoles, 50% mineral oil suspension) wns addcd in smaII portions to the stirred suspension. Stirring was continued until the evolution of hydrogen ceased. A solution of 3-(trifluoromethyl~
phenylmethyl chloride (2.63 g, 13.5 mmoles) in dry DMF (5 ml) was added dropwiseand the mixture was heated to 50-60 C for 1 hr. rhe solvent was evaporated under reduced pressure to dryness. The residue was triturated with water. The solid WQS separated from the water by filtration. The collected solid was washedwith hexane to remove residual mineral oil ànd then recrystalIized from ethanol-water to give 1.7 g of 5-bromo-6-~(3-trifluoromethyl)phenylmethoxy]-1-naphthalen~
carboxylic acid, 3-trifluoromethyl ester; mp 114-115 C, IR (CHC13) 1715 cm 1.
A mixture of the latter ester (1.7 g, 2.9 mmoles), methanol (20 ml) and lN aqueous NaOH (4 ml) was stirred for 24 hr at 20-22 C. Additional IN
aqueous NaOH was added and the mixture was stirred at 40 C for 3 hr. The solvent was evaporated. The residue wns dissolved in water ~Lnd the solution ~`
~3~

made acidic The resulting precipitate was collectedl, washed with water, dried and recrystallized from ethanol to give 1.0 g of the title compound; mp 2Z9-230~ C;
NMR (DMSO-d6~ ~ 5.5 (s, 2H), 8.1 (m, 9H), 10.5 (broad, lH).
5-Bromo-6-(4-chlorophenylm ethoxy~l-naphthalenecarboxyli c acid, NMR (DMSO-d6~ ~ 5.4 (s, 2H), 7.7 (m, 9H), 11.0 (broad, lH), is obtained by ~ollow ing the procedure of Example li but replacing 3-(trifluoromethyl)phenylrnethyl chloride with an equivalent amount of 4-chlorophenylmethyl chloride. Likewise, 5-bromo-6-(3-methoxypropoxy~l-naphthalenecarboxylic, IR (mineral oil) 2900, 1670 cm 1 is obtained by replacement with 3-methoxypropyl chloride.
EXAMPLE lj S-(Trinuoromethyl~l-naphthalenecarboxylic Acid (V, R3 = 5~F3 and R4 = H) A mixture of 5-iod~l-naphthalenecarboxylic acid methyl ester [8.8 g, 28 mmoles, described by C. Seer and R. School, Justus Leibigs Ann. Chem., 398, 82 (1913)], trifluoromethyl iodide (12 g, 61.2 mmoles), freshly prepared copper powder (5.7 g, prepared according to the procedure of R. Q. Brewxter and T.
Groening, "Organic Syntheses", Coll. Vol. II, John Wiley and Sons, New York, N.Y., U.S.A., 1948, p. 445) and pyridine (45 rnl) was charged into a stainless steel autoclave. The vessel was shaken and heated at 130 C for 24 hr and cooled to room temperature. The mixture was filtered to remove insoluble material.
The filtrate was washed with lN aqueous HCl, water and brine, dried (MgS04) and concentrated to dryness. The residue was crystallized from methanol to give 4.3 g of 5~trifluoromèthyl~1-naphthalenecarboxylic acid methyl ester, NMR
(CD~3) ~ 4.0 (s, 3H), 8.0 (m, 6H).
The ester (4.25 g, 16.72 mmoles) was suspended in methanol (100 ml).
A 2N aqueous NaOH soluffon (16.72 ml, 2 equivalents) was added to the suspensionr The mixture was stirred at 20-22 C for 18 hr. The res~ting clear solution was adjusted to pH 8 with lN aqueous HCl and concentrated unde~ reduced pressure.
The concentrate was adjusted to pH 3 with lN aqueous HCl. The resulting pre-cipitate was collected, washed with water and dried under reduced pressure to give the ~tle compound; mp 206-208 C.

N-[(5-Brom~l-naphthalenyl)carbonyl]-N-methylglycine Methyl Ester ~II, Rl and R - CH3, R3 = 5-Br and R4 = H) ~5 .. . . . , . . . _ .. , . . _ . .. . . ...

~3~

Procedure A:
A catalytic amount (5 drops~ of dry DMF was added to a suspension of the starting material of formula V, 5-brom~l-naphthalenecarboxylic acid no g, 39.8 mmoles, described by W.F. Short and H. Wang, J. Chem. Soc., 99û
(1950)], in thionyl chloride ~100ml). The suspension vras heated cautiously to reflux (caution: a vigorous reaction can occur). The mixture was refluxed for 20 min. The mixture was evaporated to dryness. Toluene was added to the solid residue and the mixture was evaporated to dryness. The residue was dissolved in pyridine (100 ml). The solution was cooled in an ice bath. Dry N-methylglycine methyl ester hydrochloride (11.1 g, 79.6 mmoles), a starting material of formulaVI, was added portionwise to the cooled solution. The mixture was stirred for 2 hr at 20 C and then heated at reflux for 1 hr. The pyridine was removed by evaporation. Water was added to the oily residue. The mixture was extracted with ethyl acetate (3 x lS0 ml). The combined extracts were washed with lN
aqueous HCl solution, a saturated solution of sodium bicarbonate and brine.
After drying over MgSO4, the extract was treated with charcoal, filtered and evaporated. The residue was crystallized from diethyl ether or ethanol to give the title compound; mp 91-9~ C; NMR (CDC13) ~ 2.8 ~ 3.25 (2s, 3H), 3.6 ~

3.85 (2s, 3H), 4.35 (broad, 2H), 7.75 (m, 6H); IJV~max (EtOH) 321 nm (~ 775), 316 (1,110), 299 (6,660)~ 289 (9,250~, 279 (7,400), 225 (66,600); Anal. Calcd: C, 53.59%
H, 4.20% N, 4.17%; Found: C, 53.60% H, 4.27% N, 4.21%.
Procedure B:
A mixture of the starting material of formula V, 5-bromo-1-naphthalene-carboxylic acid (12.8 g, 52 mmoles), and l-hydroxybenzotriazole (HOBt, 7.0 g, 52 mmoles) in DMF (200 ml) was prepared. N,N'-dicyclohexylcarbodiimide (DCC, 10.6 g, 52 mmoles) in DMF (30 ml) was added to the mixture. The resulting mixture was stirred at 20 C for 1 hr and then cooled to 0 C. N-Methylglycine methyl ester hydrochloride (7.25 g, 52 mmoles) and thèn N-ethylmorpholine (6.7 ml, 52 mmoles) were added to the cooled mixture. The mixture was stirred for 3 min at 0 C and then for 18 hr at 20 C. Thereafter, the mixture was filtered and concentrated to dryness under reduced pressure. The residue was subjected to chromatography on 325 g of silica gel using ethyl acetate-hexane (1:1) as the ~36~

eluant. The pure fractions were pooled to yield 10.5 g of product which was r~
crystallized from ethyl acetate to give the title compound, identical to the product of procedure A of this example.

N-[(5-Bromo-l-naphthalenyl)thioxomethyl]-N-methylglycine Methyl l~ster (I, RlandR2=CH3,R3=5-BrandR4=H) To a stirred solution of N-[(5-brom~l-naphthalenyl)carbonyl]-N~methyl-glycine methyl ester (35.5 g, 106 mmoles, described in Example 2) in dry pyridine (100 ml), phosphorus pentasulfide (44.5 g, 200 mmoles) was added portionwise.
The mixture was stirred and refluxed for 1.5 hr and then poured into a liter of water at 50 to 80 C (caution: evolution of copious quantities of H2S). The mixture was allowed to cool to 20 to 22 C (room temperature), filtered and the filtratewas extracted with ethyl acetate. The extract was washed with lN aqueous HCl solution, brine, a saturated solution of sodium carbonate and brine, dried (MgSO4), filtered and evaporated to dryness. The residue was recrystallized from ethanol~water (4:1) to give the title compound; mp 85-86 C; NMR (CDC13) ô 3.0 (s, 3H), 3.85 (s, 31-1), 4.58 ~ 5.37 (2d, J = 17, 2H), 7.1-8.3 (m, 6H); UVAmnx (EtOH) 281 nm tE 14,480), 218 (14,480).
By following serially the procedures of Examples 2 and 3 and using the appropriate starting material of formula V instead of 5-bromo-1-naphthalen~
carboxylic acid, other compounds of formula I in which Rl and R2 each is methyl are obtained. Examples of the latter compounds are listed as products in Tables 1 and lI together with the appropriate starting material of formula V used for their preparation.

.~

36'~

TABLE 1 ~~

STARTING MATERIAL PRODUCT:N-~(prefix listed OF FORMULA V below-l-NAPHTHALENYL~
3 4 THIOXOMETHYL]-N-METHYI~
EXAMPLE R R GLYCINE METHYL ESTER
- _ _ 4 4-Br H 4-bromo; NMR (CDC13) ô
2.85 & 3.25 (2s, 3H), 3.6 & 3~85 (2s, 3H), 4.35 (m, 2H), 7.7 (m, 13H), IR (CHC13) 1730,1620 cm 1 8-Br H 8-bromo; I~(CHC13) 1730, 1480,1380,1080 cm ; Nl\IIR (CDC13)~
3.0 (s, 3H), 3.8 (s, 3H)9 3.65 (m, 2H), 7.5 (m, 6H) 6 5-CH30 H 5-methoxy; NMR (CDC13) ,S
2.81~ 3.21 (2s, 3H), 3.58 ~
3.80 (2s, 3H), 3.97 (s, 3H), 4.37 (broad, 2H), 6.80 (d, lH), 7.40 (m, 4H), 8.27 tm, lH); IR (CHC13) 1740,1630,1578 cm~l -7 5-Me H 5-methyl; NMR (CDC13) ~
2.68 (s, 3H), 3.05 (3H), 3.85 (3H), 3.75 ~ 4.9 (m, 2H), 7.6 (s, 6H) 8 ~Br 6-~CH3(CH2)4O] 5-bromo-6-pentyloxy; mp 80-83 C; NMR (CDC13) 0.9 (t9 J = 7Hz, 3H), 1.1-2.0 (broad, 2H), 3.0 (s, 3H), 3.8 (s, 3H), 4.1 (m~ 2H), 7.1-8.5 (broad, 5H) ~ ~3~

_ TABLE I (Continued) STARTING MATERIAL PRODUCT:N-[(prefix listed OF FORMULA V below-l-NAPHTIlALENYL~
THIOXOi~ETHYL~--N-METHYI~

__ 9 ~CN H 5-cyano; NMR (CDC13) ~
3.00 (s, 3H~, 3 85 (s, 3H), 4.45 ~ 5.45 (d, 2H), 7.18 (m, 6H) 9a 4-CN H 4-cyano; NMR tCDC13)~' - 3.1 (s, 3H), 3.85 ~s, 3H), 4.55 ~c 5.25 (2d, J = 17Hz, 2H), 7.0-8.4 (m, 6EI) S-NO2 H 5-nitro; mp 116-117D C
11 5-CI H 5-chloro; mass spectrum, m/e: 301/309 (M ), 274t276 (M -Il, S), 248/246 (M -COOMe~

12 5-Br 6-CH30 5-bromo-6-methoxy; mp 115-117 C; NMR (Cl)C13) ~7 3.00 (s, 3H), 3.84 (s, 3H), 3.98 (s, 3H) 13 5-Br 6-CH3 5-bromo-6-rnethyl; NMR
(CDC13) 5 2.6 ~s, 3H), 3.0 (s, 3H), 3.85 ~s, 3H), 4.5 ~c 5.35 (d, J = 16.5~z, 2H), 7.7 (m, 5H) 14 H H ~; IR (CHCI3) 1735 cm 1 ~No prefi~c as compo~nd is IN-((l-nal7lltll~1ellyl)tllio~;0methyl)-N-m~l:hylglycine metllyl ester ~5 : - -~36'~

TABLE I (Continued) STARTING MATERIAL PRODUCT:N-[(prefix listed OF FORMULA V below-l-NAPHTHALENYL~
3 4 THIOXOMETHYL]--N-METHYI~
EXAMPLE R R GLYCINE METHYL ESTER
~Cl H ~chloro; mp 100-101C;
NMR (CDC13)~ 3.10 & 3.62 (2s, 3E~); 3.90 ~ 3.70 t2s, 3H), 4.04, 4.55 ~ 5.37 (s, 2d, ~ =
16Hz, 2H), 7.2-8.4 (m, 6H);
IR (CHC13) 1740 cm 1; UVAmax (EtOH) 283 nm ~ 7,100), 219 (52,0003; ~nal. Calcd: C, 58.54%
H, 4.5896 N, 4.55%; ~ound:
C, 58.58% H, 4.76% N, 4.58%

16 ~Cl ~CH30 3-chlor~4-methoxy; mp 85-86C; NMR (CDC13)~ 3.05 ts, 3H), 3.85 (s, 3H), 4.00 (S9 3H), 4.58 ~ 5.3 (2d, ~ = 17Hz, 2H), 7.6 (m, SH) 17 5-C1 7-Cl ~ 5,7-dichloro; rn/e; 325/327/
329 (M ), 266, 268, 270 ~M -COOCH3), 223/225/227 ~M -CH3 N CH2 COOCH3) 18 5-I 6- CH30 5-iod~6-methoxy; mp 149-150 C; NMR (CDC13) ~ 3.00 (s, 3H), 3.85 (s, 3H), 3.95 (s, 3H), 4.4 ~e 5.45 (d, 2H), 7.6 (m, 5H) TABLE I (Continued) ~~

STARTING MATERIAL PRODUCT:N-~(prefix listed OF FORMULA V below-l-NAPHTHALENYL~
3 4 THIOXOMETHYL]-N-METHYJ~
EXAMPLE R R GLYCINE METI~YL ESTER
19 5-CN 6-CH30 ~cyano-6-methoxy; mp l64-165 C; NMH (CDC13) ~
3.05 (s, 3H), 3.90 ~s, 3H), 4.07 ~s, 3H), 4.35 ~ 5.55 (d, J = 16.8Hz, 2H), 7.80 (m, 5H) ~ith reference to Table 1, the starting materials of formllla V are described by T.L Jacobs, et al., J. Org. Chem., 11, 2'1 (1946) for exarnple 4; by 11.G. Rule et al., J. Chem. SOC.J 168 tl934) for example 5; by A. Cirardet and N. Lorusso, Helv. Chim. Acta., 49, 471 (19G6) for example 6; by M.a.s. Dewar and P.J. Grisdale, J. Am. Chem. Soc., 84, 3541(1962) for example 7; in example lc for example 8; by M.J.S. Dewar and P.J. Grisdale, J. Am. Chem. Soc~, 84, 3541 (1962) for examples 9, 9a, 10 and 11; in example lb for example 12; in example lc for example 13; by H. Gilman et al., "Organic Syntheses", Coll. Vol. II, John ~Yi1ey and Sons, New York, N.Y., U.S.A., 1948, p. 425 for example 14; by T.L.
Jacobs et ~1., J. Org. Chem., 11 27 (1946) for example 15; in example ld for example 16j in example le for example 17; in example If for example 18; and in example lg for example 19.

, `~

~3~

-28- AHP-78û6 -~-TABLE II

STARTING MATERIAL PRODUCT:N-[[prefix listed OF FORMULA V below-l-NAPHTHALENYI.I-THIOXOMETHYL] -N-METHYI~
EXAMPLE R R _ GLYCINE METHYL ESTER

5-Br 6-[CH30(CH2)30] 5-bromo-6-13-methoxypro-poxy); NMR (CDC13) ~ 2.1 ~m~
4H), 3.35 (s, 6H), 3.55 (m, 4H), 4.25 (t, J = 6Hz, 2H)9 4.45 ~t, 5 = 6Hz, 2H), 7.4 (m, 2H), 8.0 (d, J = 8Hz, lH), 8.4 (d, J =
8Hz, lH), 8.85 (d, J = 8Hz, lH) 21 5-~CH2=C(CH3)] H 5-(1-methylettlenyl); mp ~3-95C~;
NMR (CDCl3) ~ 2.15 (s, 3H), 3.05 (s, 3H), 3.85 (s, 3H), 4.55 & 5.3 (2s, 2H), 5.0 & 5.35 (2s, 2H), 7.6 (m, 6H) 22 5 [(CH3)2CH] H 5-(1-methylethyl); NMR
(CDC13) ~ 1.35 (m, 6H), 3.0 & 3.55 (2s, 3H), 3.65 ~ 3.85 (2s, 3H), 4.95 (2H), 7.5 (m, 6H) 23 5-C~?3 6-CH30 5-(trifluoromethyl~6-methoxy;
mp lûg-110 C; NMR (CDC13) 3.00 (s, 3H), 3.55 (s~ 3H), 3.95 (s, 3H), 4.35 ~ 5.45 (d, 2H), 7.7 (m, 5H) 24 5-Br 6-[(3-CF3-C6H4~ 5 bromo-6-[3-(trifluoromethyl~
CH20] phenylmethoxy]; NMR (CDC13) ~L~36~9 TABLE II (Continued) STARTING MATERIAL PRC)DUCT:N{[prefix listed OF FORMULA V below-l-NAPHTHALENYI~--3 4 THII:)XOMETHYL]-N-METHYI~
5 EXAMPLE R R GLYClNE METHYL ESTER
24 (Cont~d) ~ 3.00 ~s, 3H), 3.85 (s, 3H), 4.4 ~k 5.4 (2d, J = 16.5Hz, 21I), 5.25 (s, 2H), 7.6 ~m, 9H) 24a ~Br ~[(4~1~;E14~ 5-bromo-6~4-chlorophenyl-CH2] methoxy); NMR (CDC~3) 5 3.00 (s, 3H), 3.85 (s, 3H), 4.40 ~c 5.40 (d, 2H), 5.2 (s, 2H), 7.5 m 9H) 24b ~CF3 H ~(tri:Eluoromethyl); NMR
(CDC13)~ 3.00 (s, 3H), 3.85 (s, 3H), 4.5 ~c 5.4 (d, 2H), 7.2--8.3 (m, 6H).

With reference to Table II, the starting materials of formula V ~re described in example li? herein, for example 20; in example 1 for example 21;
in example la for example 22; in example~ lh for example 23; in example li for example 24 and example 24a; and in example lj for example 24b.
By following serially the procedures of examples 2 and 3, but using the appropriate starting material of formula VI instead of N-methylglycine, other compolmds of formula I in which R is lower alkyl, R3 is 5-bromo, R4 is hydrogen are obtained. Examples of the latter compounds are listed as products in Table m together with the appropriate starting rnaterial of formula VI used ~3~

TABLE III

STARTING MATERIAL PRODUCT:N-[(5 BROM~l--OF FORMULA VI NAPHTHALENYL)THIOXO--METHYL]~uffix listed EXAMPLE R R below H CH3 glycine methyl ester; mpl26-130~ C; NMR (CDC13)~ 3.8 (s, 3H), 4.6 (d, J = 7H[z, 2H), 7.15-8.15 (m, 6H) 26 ~C3H7 C2H5 N-propylglycine ethyl ester;
NMR (CDC13) ~ 0.65 (t, J =
7Hz, 3H), 1.4 (t, 3H), 1.45 (m, 2H), 3.2 (t, J = 7Hz, 2H), 4.3 (q, J = 7Hz, 2H), 4.35 (d, J =
17Hz, lH), 5.3 (d, J = 17Hz, lH), 7.7 (m, 6H); IR (CHC13) 1740 cm 1 27 CH2=CH-CH2 CH3 N-(2-propenyl)glycine methyl ester; mp 72-74 C

28 C2H5 CH3 N-ethylglycine methyl ester;
NMR (CDC13) ~ 1.10 (t, 3H), 3.35 (q, ~H), 3.85 (s, 3H), 4.40 ~c 5.25 (d, 2H), 7.6 (m, 6H) 29 C4H9 C2~5 N-butylglycine ethyl ester;
NMR (CDC13) ~ 0.65 (t, a =
S.5 Hz, 3H), 1.0 (m, 2H), 1.38 (t, 3H), 1.40 (m, 2H), 3.25 (m, .

- ( ~3~

TABLE m (Continued) _ SIARTING MATERIAL PRODUCT:N-[(5-BROM~l--OF FORMULA YI NAPHTHALENYL)THIOXO--METHYL]-suffix listed s EXAM PLE R R be]Low 29 (Cont'd) 2H), 4.25 dc 5.30 ~d, J = 16Hz, 2H), 7.7 (m, 6H) 3o C6H5CH2 C2H5 N-~phenylrnethyl)glycine ethyl ester; mp 141-142 C; NMR (CDC13) ~ 1.35 ~t, J = 7Hz, 3H), 4.5û
tm, 6H), 7.50 (m, llH)i IR(Nujol * ) 1743 cm~

EXAMI'LE 31 By following serially the procedure of Examples 2 and 3, but using the ~ppropriate starting material of formula V and the appropriate an~inoacid ester of formula VI, still other compounds of formula I in which R is lower alkyl are obtained. For examplel by using 3-chloro-4-methoxy-1-naphthalenecar-boxylic acid, described in Example ld, as the starting material of formula V, and using glycine ethyl ester hydrochloride as the starting material of formula Vl, N-~(3-chlor~4-methoxy-1-naphthalenyl)thioxomethyl] glycine ethyl ester;
IR (CHC13) 3420, 3340,1740,1665 cm 1; via N-[(3-chloro-4-methoxy-1-naph-thalenyl)carbonyl] glycine ethyl ester; rnp 140-141 C; NMR (CDC13) ~ 1.3 ~t, J = 7Hz, 3H), 4.2 (m, 4H~, 6.55 (broad, lH), ~.55 (m, 3H), 8.2 (m, 2H), was obtained.

N~(~Brom~l-naphthalenyl)thioxomethyl]-N-methylglycine (I, Rl = CH3, R2 and R4 = H and R3 = 5-Br) * Trademark ~3~

~32- AHP-7806 A IN aqueous NaOH solution (25 ml) was added to ~ suspeslsion OI
N{(S-brom~l-naphthalenyl)thioxomethyl]-N-methylglycine methyl ester (73 g, 20.7 mmoles; described in Example 3) in methanol (7 5 ml). The mixture was stirred at 20 to 22~ C for 21/2 hr, neutralized to pH 7 with aqueous HCl and 5 concentrated under reduced pressure to remove methanol. The residual solution was rendered acidic (pH = 2) with the addition of aqueous HCl solution and ex-tracted with ethyl acetate. The extract was dried (MgSC)4) and evapor~ted to dryness. The residue was crystallized from ethyl acetate-hexane to giYe 5.3 g of the title compound; mp 181 C; NMR (DMSO-d6) ~ 2.95 (s, 3H), 4.65 10 ~ 5.2 (2d, J = 16.8, 2H), 7.85 (m, 6H), UV~max (E~OH) 285 nm (~ 12,300), 280 (12,400), 221 (42,6û0); IR(Nujol * ) 2900, 1720 crn~; Anal C~lcd: C, 49.72% H, 3.58% N, 4.14%; Found: C, 49.6396 H, 3.63% N, 4.18%.
In the same manner, but replacing N-[(5-bromo-1-naphthalenyl)thioxo-methyl]-N-methylglycine methyl ester with an equivalent amount of N-[~3-chloro-15 4-methoxy-1-naphthalenyl)thioxomethyl] glycine ethyl ester, described in Example 31, N{(3-chloro-4-methoxy-1-naphthalenyl)thioxomethyl]glycine [mp 217C(dec);
NMRtDMSO-d6) ~ 3.96 ts, 3H), 4.42 (d, J = 6Hz7 2H), 7.40 (s, lH), 7.65 (m, 2H), 8.18 (m, 2~); IR (Nujol *) 3I50, 2900,17Z0, 1140 cm ; UV~max (EtOH~ 277 nm (~11,400), 224 (51,300); Anal Calcd: C, 54.28% H, 3.91% N, 4.52%, Found: C, 20 54.26% H, 4.06% N, 4.62%] was obtained.
By following the procedure of Example 32, but replacing N{(5-bromo-l-naphthalenyl)thioxomethyl]-N-methylglycine methyl ester with an equivalent amount of another ester compound of formula I in which R is lower alkyl, or corresponding compound of formula m ir~ which R is artlower)alkyl, the cor-25 responding compound of formula I in which R is hydrogen was obtained. Examples of the latter compounds are listed ~s products in Tables IV, V and VI together Mth a notation to the corresponding compound of formula I in which R is low~
alkyl from which they are prepared. In each case the compound of formula I in which R2 is lower alkyl, the starting material, is noted by the example in 30 which it was prepared.

* Trademark 1~ .

36~

TABLE IV
PRODllCT:N-[(prefix listed NO. OF THE EXAMPLE IN below-l-NAPllTHALENYL~
WHICH START1NG MATE}~IAL IHIOXOMETHYL]-N-METHYI~
EXAMPLE WAS PREPARED GI,YCINE
33 4 4-bromo; mp 1~8-169~C, NMR(Di~lSO-d6) ~ 3.0 (s, 3H), 4.65 ~ 5.15 (d, J = 16.5Hz, 2H), 7.7 (m, 6H); Ansl C~lcd: C, 49.71% H, 3.58% N, 4.14%;
Found: C, 49.56% H, 3.42%
N, 4.22%

_ 34 5 8-bromo; mp 65-85G Ci Anal C~lcd: C, 49.72% H, 3.58% N, 4.14%; Found: C, 53.54% H, 4.05~ N, 4.40~6 6 5-methoxy; mp 120 C;
NMR(Di~S~d6)~ 2.93 (s, 3H), 3.90 (s, 3H), 4.65 ~ 5.16 (2d, J = 17Hz, 2H), 6.95 (2d, J1 7Hz~ J2 = 3Hz, lH), 7.35 (m, 4H), 8.11 (2d, Jl = 8Hz, J2 = 2Hz, lH); IR(Nujol* ~
2900,1734,1715 cm 1; VV~max ~ EtOH) 281 nm( ~ 11,600), 233 (30,6û0); Anal C~lcd: C, 62.279 H, 5.23% N, 4.84~6; Found:
C, 61.62% H, 5.95% N, 4.22%

36 7 5-methyl; mp 190-191C;
Nl~R (CDC13)~ 2.66 (s, 3H), *Tr~3cm;lr};

~5 , TABLE IV (Continued) PR~DUCT:N-[(prefix listed NO. OF THE EXAMPLE IN below-l-NAPHTHALENYL~
WHICH STARTING MATERIAL THIOXOMETHYL~-N-METHYL~
EXAMPLE WAS PREPARED GLYCINE
36 (Contld) 3.05 (s, 3H), 3.85 ~ 5.0 (m, 2H), '7.5 (m, 6H), 8.75 ~broad9 lH3; IR~CHC13) 3000,1755 1720 cm 1; UV~max (EtOH~
282 nm ( ~15,280), 226 (39,690), 218 (41,385); An 1 Calcd: C, 65.90% H, 5.53% M, 5.12%;
Eound: C, 65.79% lH, 5.57%
N, 5.08%

37 8 5-bromo-6-pentyloxy;
mp 211-217C; NMR(DMSO-d6)~
0.9 (t, J = 6Hz, 3H), 1.6 (m, 2H), 2.9 (s, 3H), 4.2 (t, J =
6Hz, 2H~, 3.95 ~ 5.15 (d, J
= 15Hz, 2H), 7.1-8.55 (m, 5H);
IR~Nujol *) 3000, 1650 cm 1 38 9 5-cyano; mp 190-200 C;
NMR (DMSO-d6) ~ 3.00 (s, 3H), 4.65 ~ 5.15 (d, J = 17Hz, 2H), 7.95 (m, 6H~; IR(Nujol* ) 3000, 2230,1730 cm~1; U~max ~(EtOH) 313 nm ( f 5,600), 271 (13,850), 24~ (14,620), 2~2 (48,3~0);
Anal Calcd: C, 63.36~6 H, * Trademark .

~ ~3~'~8~

TABLE IV (Continued~

PRODUCT:N-[(pre~ix listed NO. OF THE EXAMPLE IN below-l-NAPHTHALENYL~
WHICH STARTING MATERIAL THICIXOMETHYL]~N-METHYI~
EXAMPLE WAS PREPARED GLY~CINE
38 (Cont'd) 4.34% N, 9.85%; ~ound: C, 62.01% H, 4.34% N, 9.36%

38a 9a 4-cyano; mp 192-193 C; NMR
(DMSO-d6) ~ 3.0 (s, 3H), 4.7 & 5.2 (d, J = 17Hz, 2H), 7.8 (m, 6H?, 10.05 (broad, lFI);
IR (Nujol * ) 3180, 2230,174S
(with inflection ~t 1755)cm 1 39 10 5-nitro; mp 142-143 C;
NMR (CDC13)~ 3.05 (s, 3H), 4.65 ~ 5.4 ~d, 2H)9 7.9 (m, 6H), 9.4 (broad9 lH); IR(Nujol 2900,1715,1530,1345 cm 1;
UV~max (EtOH) 332 nm ( ~ 4,110) 269 (17,010); Anal C~lcd: C, 55.26% H, 3.96% N, 9.20%;
Found: C, 55.17% H, 3.86%
N, 9.10%

11 5-chloro; mp 153-154 C;
NMR(CDC13) ~ 3.03 (s, 3H), 4.67 ~ 5.33 ~d, J = 17Hz, 2H~, 7.50 (m, 4H), 7.90 (d, J = 8Hz, lH), 8.25 (d, J = 8, lH); IR(CHCl ~) * Trademark ~236~

TABLE IV (Continued) P]RODUCT:N-[(prefix listed NO. OF THE EXAMPLE IN b~low-l-NAPHTHALl~NYI.
WHICH STARTING MATERIAL THIOXOMETHYL]-N-METHYI~
EXAMPLE WAS PREPARED GLYCINE
_ .
40 (Cont'd) 3000, 1720 cm 1; UY~max (EtOH~ 280 nm ~ 16,780), 212 (52,290); Anal Calcd: C, 57.23% H, 4.12% N, 4.77%;
Found: C, 58.02% H, 4.28%
N, 4.94%

41 12 5-bromo-6-methoxy; mp 166-168 C; NMR(CDC13) ~ 3.02 (s, 3H), 4.06 (s, 3H), 4.61 &
5.39 (d, J = 17Hz, 2H); IR(CHC13) 3000, 1718 cm 1, UV~max (EtOH) 341 nrn (4,350), 329 (4,015), 273 (13,150), 237 (51,260);
Anal Calcd: C, 48.92% H, 3.83% N, 3.80%; Found: C;
49.11% H, 3.90% N, 3.91%

42 13 5-bromo-6-methyl; mp 190-192 C; NMR(CDC13) ~
2.6 (s, 3H~, 3.05 (s, 3H), 4.56 ~c 5.3 (d, 2H), 7.6 (m, 5H);
IR(CHC13) 3000,1720 cm 1;
UV~max (EtOH) 280 nm t 14,055), 223 (43,400); Anal Calcd: C, 51.14% H, 4.01%

~.

.

2~

TABLE IY (Continued~

PRODVCT:N-t(prefix listed NO. OF THE EXAMPLE IN bel~w-l-N.APHTHALENYL~
WHICII STARTlNG MATERIAL T:HIOXOMETE~YL3-N-METHYI~
EXAMPLE WAS PREPARED GLYCINE
42 (Cont'd) N, 3.98%; Found~ , 51.21%
H, 4.03% N, 4.00%

43 14 ~; mp 146-147 C; NMR(CDC1 ~ 3.05 ~ 3.70 (2~, 3HI)9 4.û7, 4.75 ~c 5.30 (s, 2d, J -17Hz, 2H), 6.8-8.0 (m, 7H), 9.20 . (broEId~ lH); IRtCHC13) 3000, 1720 (inflecti~n at 1755~cm 1;
UY~max (EtOI-I) 280 nm ( 14,415), 215 (53,~150); ~n~l Cnlcd:
C, 64.87% H, 5.05% N, 5.~0%;
Found: C, 64.8996 H, 5.14%
N, 5.51%

44 15 ~chloro; mp 165-166C;
NMR(CDC13) ~ 3.05 ~ 3.70 (2s7 3~), 4.10, 4.70 ~ 5.3 (s, 2d, J = 17H~, 2H)r 7.2-8.4 (m, 6H), 10.5 ~s, lH), IR~CHCI3) 3000,1725 (with inflection .
at 1765~cm 1; UY?~m~x(EtOH) 283 nm ( E 13,500)~ 220 (49,600);
Anal Calcd: C, 57.24% H, 4.12% N, 4.77%; Found: C, 57.56% H, 402896 N, 4.8496 * No prefix as c~mround is N~ nap1lthalcnyl)thioxomctl)yl)-N-mcthylglycine ~6~
-38- A~1~7806 TABLE IV (Continued) PRODl~CT:N-~(prefix listed NO. OF THE EXAMPL:E IN below-l-NAPHTHALENYL~
WHICH STARTING MATERIAL THIOXOMEI'HYI.]-N-METHYI~
EXAMPLE WAS PREPARED GLYCINEi 16 ~chlor~4-methoxy; mp 138-139 C; NMR~DMS~d6) ~ 3.0 (s, 3H), 3.45 (s, 3H), 4.6 ~ 5.15 ~2d, J = 16.8Hz, 2H), 7.3 (s, lH), 7.8 (m, 4H3;
IR(Nujol * )2900,1723 cm 1;
--. UYAmax (EtOH) 329 nm tE
2,200), 282 (131210), 22Js (53,980);
~nnl Calcd: C, S5.64~6 H, 4.36% N, 4.33%; ~ound: C, 55.63% H, 4.48'J6 N, 4.40%

46 17 5,7-dichloro; mp 174-175 C;
NMR(DMSO-d6) ~2.97 (3H), 4.57 ~ 5.27 (2d, J = 17Hz9 2H), 7.3-8.3 (m, 5H); lRtNujol* ) 3000,1708 cm 1; UVAmax (EtOH) 334 nm ( ~3,050), 273 (15,81û), 226 t63,800); An~l Calcd: C, 51.23% H, 3.38%
N, 4.27%; Found: C, 51.44%
H, 3.52% N, 4.40%

47 18 . 5-iod~6-methoxy; mp 161-163 C; NMR(D~qSO-d6) - ~ 2.95 (s, 3H), 3.95 (s, 3H), 4.6 Sc 5.2 (d, J -17Hz, 21~), ~ Trademark ':-,..

~36~

TABLE IV (Continued) PRODUCT:N-l(prefix listed NO~ OF THE EXAMPLE I~ below-l-NAPHTHALENYL)--WHlCH STARTING MATERIAL THlOXOMETHYL]-N-METHYIf-EXAMPLE WAS PREPAl~ED GLY NE
S 47 (contld) 7.5 l~m~ 5H); IR (Nujol ~) 29D0, 1720 cm 1; UV)~max (EtOH~
343 nm (~ ~900), 333 (7,250) 308 (12,~00), 273 (20,500~, 240 (74,200); Anal Calcd: C, . 43.39% H, 3.40% N, 3.37%;
Found: C, 42,75% H, 3.3596 N. 3.37%

48 19 5-cyuno-6-methoxy; mp 15S-157 C; NMR(CI)C13)6 3.05 (s, 3H), 4.05 (s, 3H), 4.55 5.45 (d, J = 17Hz, 2H), 7.7 (m, 5H~; IR(CHC13) 2900r 2220, 1725 cm 1; I~/Amax (EtOH) 346 nm (E 5,600), 339 (5,500), 232 (46,500) *Trademark ... . ~ . ..
.

36~

TABLE V

PRODUCT:N-[~prefix listed NO. OF THE EXAMPLE IN b~elow-l-NAPHTHALENYL]-WHICH STA~TING MATERIAL THIOXOMETHYL]-N-METHYI~
EXAMPLE WAS PREPARED GLYCINE
49 20 ~brom~6-(3-methoxy-pro-poxy); NMR(CDC13) ~ 2~1 (q, J = 6Hz, 2H), 3.0 (s, 3H), 3.35 (s, 3H), 3.65 (t, J = 6Hz, 2H), 4.25 (t, J = 6Hz9 2H), 4.55 (d, J = 16Hz, lH[), 5.4 (d, J
= 16~Iz, lH), 7.4 (m, 3H), 7.95 (d, J = 8Hz, lH), 8.2 (d, J -8Hz, IH); IR(CHC13) 2900, 1720 cm 1; UV~max (EtOH) 341 nm ( 3,920), 330 (3,730), 238 (49,400); Anal Calcd: C, 50.69% H, 4.73% N, 3.29%;
Found: C, 50.29% H, 4.89%
N, 3.23%

21 5-(1-methylethenyl); mp 146-148 C; NMR(CDC13) ~
2.2 (s, 3H~, 3.1 (s, 3H~, 4.75 dc 5.35 (d, 2H), 5.05 ~ 5.4 (d, 2H), 7.6 (m, 6H), 8.5 (broad, lH); IR(CHC13) 2900,1760, 1720 cm 1; UVAmax (~tOH) 282 nm ( 14~000)~ 216 (38~901));
Anal Calcd: C, 68.20% H, 5.72% N, 4.68%; C, 69.06%
H, 6.03% N, 4.39%

~L~3~

TABLE V (Continued) PRODUCT:N-[[prefix listed NO. OF THE EXAMPLE IN below-1-NAPHTHALENYL]-WHICH STARTlNG MATERIAL THIOXOMETHYL]-N-METHYI~
EXAMPLE WAS PREPARED _ GLYCINE
51 22 5-(1-rnethylethyl~; mp 136-136 C; NMR(CDC13) 1.40 (m, 6H), 3O05 dc 3.6S (d, 3H), 3.65 (m, lH)~ 5O05 (m, 2H), 7O5 (m, 6H~, 9.60 (broad, lH); IR(CHC13) 2900, 1755, 1720 cm 1; Anal Calcd: C, 67.74% H, 6.35% N, 4.85%;
Found: C, 66.4496 H, 6.56%
N) 4.16%

52 23 5-(trifluoromethyl~6-methoxy;
mp 164-165 C; NMR(CDC13) 3.05 (s, 3H), 3.95 ts, 3H), 4.55 & 5.4 (d, J = 17Hz, 2H), 7.6 (m, 5H), 908 (broad, lH);
IR(CHC13) 2900,1720 cm 1;
UV~max ~EtOH) 337 nm (~ 3,895), 268 (13,260), 226 (49,315); Anal C~lcd: C, 53.78% H, 3.95%
N, 3.92%; Found: C, 53.56%
H, 3.95% N, 3.87%

53 24 5-bromo-6-(3-trifluoromethyl~
phenylmethoxy]; mp 125 C;
NMR (DMSO-d6)~ 3.0 (s, ~3~

TABLE V (Continued) PRODUCT:N-[[prefix listed NO. OF THE EXAMPLE IN below-l-NAPHTHALENYLJ--WHICH STARTING MATERIAL THIOXOMETHYL]-N-METHYI~
EXAMPLE WAS PREPARED GLYC,INE
53 (Cont'd) 3H), 'L.65 ~c 5.25 ~2d, J = 17Hz, 2H~, 5.5 (s, 2H~, 7.8 (m, 9H);
IR (Nujol *) 2900,1720 cm 1;
UV~max (E$0H) 340 nm (F 3,950), 270 (13,90~), 263 (14,20~), 238 (54,200); Anal Calcd C, 51.57~6 H, 3.35% N, 2.73% Folmd:
C, 52.11% H, 3.22% N, 2.94%

53a 24a 5-bromo-6-(4-chlorophenyl-methoxy); mp 88-90 C (dec);
NMR ~DMSO-d6) ~ 2.95 (s, 3H), 4.63 ~ 5.20 (d, J = 17.25Hz, 2H), 5.4 (s, 2H), 7.6 tm, 9H);
IR (CHC13) 3000,1720 cm 1;
UY~max (EtOH) 340 nm (F 3,495), 326 (3, 45~)7 238 (53,480) 53b 24b (5-trifluoromethyl); mp 156-158 C; NMR(CDC13) 3.05 (s, 3H), 4.65 ~ 5~4 (d, J = 17H~, 2H), 7.85 ~m, 6H), 10.4 (b, lH); IR (CHC13) 2900, 172û (with inflection at 1755), 1305 cm 1; UV~max tEtOEI) 278 nm (~ lL2,900), 216 (68,80D);
Anal Calcd: C9 55.03% H, * Trademark ,~_ ~236~
-43- AHP-7~06 TABLE V (Con_nued) PRODUCT:N-~lprefix listed NO. OF THE EXAI\IPLE IN beIow-l-NAPHTHALENYL]--WHICH STARTING MATERIAL l'HIOXOM ETHYL] -N-M ETHYL--EXAMPLE WAS PREPARED C;LYCINE .
I

53b (Cont'd) 3.7n96 N, 4.27% Found: C, 54.69% H, 3.70% N, 4.27 TABLE Vl P~ODUCT:N-1(5 BROMO-l NO. OF THE EXAMPLE IN NAPHTHALENYL)THIOXO-- WHICH STARTING MATERIAL METHYL]-suffix listed -; EXAMPLE WAS PREPARED b~low 5~ 25 glycine; mp 232-237 C; NMR
(DMSO-d6) ~ 4~5 (d, J = 5.S, 2H~, 7~8 (m, 61~)~10.8 (bru~d, lH); IR(Nujol ~ )3200, 1720;
UV~max ~EtOI~) 275 nm ~ ~
11,700), 217 (44J800); An~l Calcd C, 4R.15% H, 3.10% N, 4.30%;
Found: C, 48.65% H, 3.13%
N, 4.37%

26 N-propylglycine; Ni~R(CDC13) 0.65 (t, J = 8Hz, 3H), 1.55 ~sextet, J = 8Hz, 2H), 3.25 (t, J = 8Hz, 3H), 4.55 (d, J
= 17Hz, IH), 5.3 (d, J = 17Hz, IH~, 7.7 (m, 6H); IR~CHCI3) 2900,1723 cm 1; I~VI~max (EtOH~ 277 nm ( c14,80û), 216 *Trad~mark . _ .. . . . . . .

.

TABLE VI (Continued) PRODUCT:N-[(5-BROM~l-NO. OF THE EXAMPLE IN NAPHTHALENYL)THJOXO-WHICH STARTlNG MATERI~ I. M ETHYL~ ~uffix listed EXAMPLI: ~AS PREPARED below _ 55 (Cont'd) ~61,200); Anal Calcd: C, 52.44%
H, 4.41% N/ 3.83~6; Found:
C, 52.53% H, 4.44% N, 3.73%

56 27 N-(2-propylene)glycine: NMR
(CDC13) ~ 3.5 (rn, 2H), 3.9 (m, 2H), 5.4 (m, 3H), 6.95 (m, lH), 7.2-8.~ (m, 6H); IR
(CHC13~ 290091720 with in~lection nt 1760 cm 1; UYAmax (EtOH) 277 nm (E 1~,4003, 219(39,700);
Anrll Calcd: C, 52.76% ~1, 3.87% N, 3.84%; Found: C, 52.93% H, 4.28% Nt 3.68%

57 28 N-ethylglycine; mpl82-1$4~C;
NMR(D,'~qSO-d6) ~.D.95 (t, J = 7Hz, 3H), 3.25 (q, J = 7Hz, 2H), 4.58 dc 5.05 (d, J = 16.5Hz, 2H), 7.7 (m, 6H); IR (Nujol ~ 3 2900,1720 cm 1; UVAmax (EtOH) 276 nm ( E 14,795), 219 (42,305); Anal Calcd: C, 51.149~ H, 4.00% N~ 3.97%;
Found: C, 51.33% H, 4.08%
N, 4.05%
*Tradcmarl;

.

.. ... . . ~ .~
i .

.
~3~

-45- AHP-~806 TABLE VI (Continued) PRODUCT:N-[(5 -BROMO--1--NO. O~ THE EXAMPLE IN NAPEITHALENYL)THIOXO--WHICH STARTING MATERIAL METHYI,]-su~fix listed EXAMPLE WAS PREPARED below 58 29 N-butylglycine; mp 65-68 C
(dec); NMR(CDC13) ~
0.63 (t, J = 5.5Hz, 3H), 1.2 (m, 4H), 3.25 (t, d = 7.5Hz, 2H), 4.5 & 5.3 (d, J = 16.8Hz, 2H), 6.9 (broad, lH), 7.7 (m, 6H); IR(CHC13) 2900,1720 cm 1;
UV)~max (EtOH) 378 nm ( 13,900), 219 (42,000) 59 30 N-(phenylmethyl)glycine; rnp 98 C(decomp); NMR(CDC13) 4.5 ~ 5.35 (d, 2H), 4.45 (m, 2H), 7.6 (m, llH); IR(Nujol *) 2900,1710 cm 1; UV~ma~
(EtOH) 278 nm (15,620), 219 (43,465); Anal Ca}cd: C, 58.01~6 H, 3.94% N, 3.3596: Found:
C, 58.29% H, 4.27% N, 3.24%

N-[~5-Bromo-l-naphthalenyl)carbonyl]-N-methylglycine (IV, Rl = CH3, R3 =
5-Br and R4 = H) N-~(5-Bromo-l-naphthalenyl)carbonyl]-N-methylglycine methyl ester (3.7 g, 11.0 mmoles, described in Example 2) was suspended in methanol (50 ml)~

A solution of lN aqueous NaOH (1302 ml) was added to the suspension. The mixture * Tradem~rk , "

36~

was stirred at 20-22 C for 1.5 hr. The mixture was neutrRlized with aqueous HCl and concentrated under reduced pressure to rerrlove the methanol. The residuf~l solution was made acidic with aqueous HCl and extracted with ethyl acetate. The extract was dried (MgS04), filtered and evaporated to dryness.
The residue was crystalli~ed from ethanol-water to give 3.25 g of the ~tle com-pound; mp 205 C; NMR (DMSO-d6) ~ 2.75 ~c 3.10 (2s, 3H), 2.75 ~ 3.10 (2s, 3H), 3.75 dc 4.25 (2s, 2H), ?.3 - 8.3 (m, 6H); IR (Nujol * ) 1745 with inflection at 1720,1580 cm 1; UV~max (EtOH) 322 nm ( E 680), 316 ~1,000), 299 ~6,510), 289 (9,055), 279 (7,150) 226 (63,080); An~1 C~lcd: C, 52.19% H, 3.76% N, 4.35%;
Fowld: C, 52.09% H, 38.4% N, 4.48%.
By following the procedure of example 60 but replacing N{(5-bromo-l-naphthalenyl)carbonyl]-N-methylglycine methyl ester with an equivalent amount of another ester compound of formula Il in which R is lower alkyl or ar(lower~
~lkyl, the corresponding compound of formula IV is obtained. ~or example, replacem~t with N-[[S-(trifluoromethyl~6-methoxy-1-naphthalerlyl] carbonyl]-N-methylglycine methyl ester, NMR (CDC13) ô 2.85 (s, 3H), 3.5 - 4.5 (m, 2H), 3.4 ~c 3.75 (2s, 6H), 7.0 - 8.4 (m, SH), prepared according to the procedure of example 2, gives N{[5-(trifluorornethyl~6-methoxy-1-naphthanenyl] carbonyll -N-methylglycine, mp 174-175 C; NMR (DMSO-d6)~ 2.75 ~c 3.1 (2s, 3H), 4.03 (s, 3H), 4.30 (d, 2H), 7.8 (m, 5H~; IR (Nujol * ~ 2500,1720 with in~leetion at 1745,1580 cm 1; UV~max (EtOH) 335 nm ( F3,050), 322 (2,700), 295 (5,100), 283 (5,750), 275 (4,450), 220 (57,100); Anal Calcd: C, 56.30% H, 4.13% N, 4.10~6;
Found. C, 55.29% H, 4.02% N, 3.g9%.

* Trademark

Claims (3)

1. A process for preparing a compound of formula I

(I) wherein R1 is hydrogen, lower alkyl, lower alkenyl or phenylmethyl; R2 is hydrogen or lower alkyl; R3 is hydrogen or a substituent at position 4, 5 or 8 of the naphtha-lene ring, the substituent being selected from the group consisting of lower alkyl, lower alkoxy, halo, cyano, nitro and trihalomethyl, and R4 is hydrogen;
or R3 and R4 each is a substituent at different positions selected from positions 3 to 7 of the naphthalene ring, the substituents being selected from the group consisting of lower alkyl, lower alkoxy, halo, trihalomethyl, (lower)alkoxy(lower)alk-oxy, phenylmethoxy and phenylmethoxy substituted on the phenyl portion with a lower alkyl, lower alkoxy, halo or trihalomethyl; or a therapeutically accep-table salt with an organic or inorganic base of the compound of formula I wherein R2 is hydrogen; which comprises:
(a) reacting an amidoester of formula II

(II) wherein R1, R3 and R4 are as defined in this claim and R is lower alkyl with phosphorus pentasulfide to obtain the corresponding compound of formula I
wherein R1, R3 and R4 are as defined in this claim and R2 is lower alkyl; or (b) hydrolyzing the compound of formula III

(III) wherein R1, R3 and R4 are as defined in this claim and R is lower alkyl or ar(lower)alkyl to obtain the corresponding compound of formula I wherein R1, R3 and R4 are as defined in this claim and R2 is hydrogen; or (c) reacting the amidoacid of formula IV

(IV) wherein R1, R3 and R4 are as defined in this claim with phosphorus pentasulfide to obtain the corresponding compound of formula I wherein R1, R3 and R4 are as defined in this claim and R2 is hydrogen; and (d) if required, transforming the compound of formula I wherein R1, R3 and R4 are as defined in this claim and R2 is hydrogen into a coresponding therapeutically acceptable salt of an organic or inorganic base.

2. The compound of formula I, as defined in claim 1, or when R2 is hydrogen a therapeutically acceptable salt thereof with an organic or inorganic base, when prepared by the process of claim 1 or an obvious chemical equivalent thereof.

3. The process of claim 1 which comprises reacting the amidoester of formula II wherein R1, R3 and R4 are as defined in claim 1 and R is lower alkyl with phosphorus pentasulfide to obtain the corresponding compound of formula I wherein R1, R3 and R4 are as defined in claim 1 and R2 is lower alkyl.4. The compound of formula 1, as defined in claim 3, when prepared by the process of claim 3 or an obvious chemical equivalent thereof.
5. The process of claim 3 which comprises reacting the amidoester of formula II wherein R1 is hydrogen, lower alkyl, 2-propenyl or phenylmethyl;
R3 is hydrogen or a substituent at positions 4, 5 or 8 of the naphthalene ring, the substituents being selected from the group consisting of lower alkyl, lower alkoxy, halo, cyano, nitro and trifluoromethyl, and R4 is hydrogen; or R3 and R4 are a pair of substituents on the naphthalene ring selected from the group of pairs consisting of 3-halo-4-lower alkoxy, 5-halo-6-lower alkyl, 5-halo-6-lower alkoxy, 5,7-dihalo, 5-(trifluoromethyl)-6-lower alkoxy, 5-halo-6-(lower)-alkoxy(lower)alkoxy, 5-halo-6-[3-(trifluoromethyl)phenylmethoxy] and 5-halo-6-(4-chlorophenylmethoxy); and R is lower alkyl; with phosphorus pentasulfide to obtain the corresponding compound of formula I wherein R1, R3 and R4 are as defined in this claim and R2 is lower alkyl.
6. The compound of formula I wherein R1, R2, R3 and R4 are as defined in claim 5, when prepared by the process of claim 5 or an obvious chemical equivalent thereof.
7. The process of claim 3 which comprises reacting the amidoester of formula II wherein R1 is hydrogen, lower alkyl or phenylmethyl; R3 is 4-halo or 5-halo and R4 is hydrogen; or R3 and R4 are a pair of substituents on the naphthalene ring selected from the group of pairs consisting of 3-halo-4-lower alkoxy, 5-halo-6-lower alkyl, 5-halo-6-lower alkoxy, 5,7-dihalo and 5-(trifluoro-methyl)-6-lower alkoxy; and R is lower alkyl; with phosphorus pentasulfide to obtain the corresponding compound of formula I wherein R1,R3 and R4 are as defined in this claim and R2 is lower alkyl.

8. The compound of formula I wherein R1, R2, R3 and R4 are as defined in claim 7, when prepared by the process of claim 7 or an obvious chemical equivalent thereof.
9. The process of claim 3 which comprises reacting the amidoester of formula II wherein R1 is lower alkyl; R3 is 5-halo and R4 is hydrogen; or R3 and R4 are a pair of substituents on the naphthalene ring selected from the group of pairs consisting of 3-halo-4-lower alkoxy, 5-halo-6-lower alkoxy and 5-(trifluoromethyl)-6-lower alkoxy; and R is lower alkyl; with phosphorus penta-sulfide to obtain the corresponding compound of formula I wherein R1, R3 and R4 are as defined in this claim and R2 is lower alkyl.
10. The compound of formula I wherein R1, R2, R3 and R4 are as defined in claim 9, when prepared by the process of claim 9 or an obvious chemical equivalent thereof.
11. The process of claim 5 wherein R, R1 and R2 each is methyl, R3 is 5-bromo and R4 is hydrogen.
12. N-[(5-Bromo-1-naphthalenyl)thioxomethyl]-N-methylglycine methyl ester, when prepared by the process of claim 11 or an obvious chemical equivalent thereof.
13. The process of claim 5 wherein R, R1 and R2 each is methyl, R3 is 4-bromo and R4 is hydrogen.
14. N-[(4-Bromo-1-naphthalenyl)thioxomethyl]-N-methylglycine methyl ester, when prepared by the process of claim 13 or an obvious chemical equivalent thereof.
15. The process of claim 5 wherein R, R1 and R2 each is methyl, R3 is 8-bromo and R4 is hydrogen.
16. N-[(8-Bromo-1-naphthalenyl)thioxomethyl]-N-methylglycine methyl ester, when prepared by the process of claim 15 or an obvious chemical equivalent thereof.

17. The process of claim 5 wherein R, R1 and R2 each is methyl, R3 is 5-methoxy and R4 is hydrogen.
18. N-[(5-Methoxy-1-naphthalenyl)thioxomethyl]-N-methylglycine methyl ester, when prepared by the process of claim 17 or an obvious chemical equivalent thereof.
19. The process of claim 5 wherein R, R1 and R2 each is methyl, R3 is 5-methyl and R4 is hydrogen.
20. N-[(5-Methyl-1-naphthalenyl)thioxomethyl]-N-methylglycine methyl ester, when prepared by the process of claim 19 or an obvious chemical equivalent thereof.
21. The process of claim 5 wherein R, R1 and R2 each is methyl, R3 is 5-bromo and R4 is 6-pentyloxy.
22. N-[(5-Bromo-6-pentyloxy-1-naphthalenyl)thioxomethyl]-N-methyl-glycine methyl ester, when prepared by the process of claim 21 or an obvious chemical equivalent thereof.
23. The process of claim 5 wherein R, R1 and R2 each is methyl, R3 is 5-cyano and R4 is hydrogen.
24. N-[(5-Cyano-1-naphthalenyl)thioxomethyl]-N-methylglycine methyl ester, when prepared by the process of claim 23 or an obvious chemical equivalent thereof.
25. The process of claim 5 wherein R, R1 and R2 each is methyl, R3 is 5-nitro and R4 is hydrogen.
26. N-[(5-Nitro-1-naphthalenyl)thioxomethyl]-N-methylglycine methyl ester, when prepared by the process of claim 25 or an obvious chemical equivalent thereof.
27. The process of claim 5 wherein R, R1 and R2 each is methyl, R3 is 5-chloro and R4 is hydrogen.
28. N-[(5-Chloro-1-naphthalenyl)thioxomethyl]-N-methylglycine methyl ester, when prepared by the process of claim 27 or an obvious chemical equivalent thereof.
29. The process of claim 5 wherein R, R1 and R2 each is methyl, R3 is 5-bromo and R4 is 6-methoxy.

30. N-[(5-Brom-6-methoxy-1-naphthalenyl)thioxomethyl]-N-methyl-glycine methyl ester, when prepared by the process of claim 29 or an obvious chemical equivalent thereof.
31. The process of claim 5 wherein R, R1 and R2 each is methyl, R3 is 5-bromo and R4 is 6-methyl.
32. N-[(5-Bromo-6-methyl-1-naphthalenyl)thioxomethyl]-N-methyl-glycine methyl ester, when prepared by the process of claim 31 or an obvious chemical equivalent thereof.
33. The process of claim 5 wherein R, R1 and R2 each is methyl, and R3 and R4 each is hydrogen.
34. N-[(1-Naphthalenyl)thioxomethyl]-N-methylglycine methyl ester, when prepared by the process of claim 33 or an obvious chemical equivalent thereof.
35. The process of claim 5 wherein R, R1 and R2 each is methyl, R3 is 4-chloro and R4 is hydrogen.
36. N-[(4-Chloro-1-naphthalenyl)thioxomethyl]-N-methylglycine methyl ester, when prepared by the process of claim 35 or an obvious chemical equivalent thereof.
37. The process of claim 5 wherein R, R1 and R2 each is methyl, R3 is 3-chloro and R4 is 4-methoxy.
38. N-[(3-Chloro-4-methoxy-1-naphthalenyl)thioxomethyl]-N-methyl-glycine methyl ester, when prepared by the process of claim 37 or an obvious chemical equivalent thereof.
39. The process of claim 5 wherein R, R1 and R2 each is methyl, R3 is 5-chloro and R4 is 7-chloro.
40. N-[(5,7-Dichloro-1-naphthalenyl)thioxomethyl]-N-methylglycine methyl ester, when prepared by the process of claim 39 or an obvious chemical equivalent thereof.
41. The process of claim 5 wherein R, R1 and R2 each is methyl, R3 is 5-iodo and R4 is 6-methoxy.
42. N-[(5-Iodo-6-methoxy-1-naphthalenyl)thioxomethyl]-N-methyl-glycine methyl ester, when prepared by the process of claim 41 or an obvious chemical equivalent thereof.
43. The process of claim 3 wherein R, R1 and R2 each is methyl, R3 is 5-cyano and R4 is 6-methoxy.

44.N-[(5-Cyano-6-methoxy-1-naphthalenyl)thioxomethyl]-N-methyl-glycine methyl ester, when prepared by the process of claim 43 or an obvious chemical equivalent thereof.
45. The process of claim 5 wherein R, R1 and R2 each is methyl R3 is 5-bromo and R4 is 6-(3-methoxypropoxy).
46. N-[(5-Bromo-6-(3-methoxypropoxy)-1-naphthalenyl]thioxomethyl]-N-methylglycine methyl ester, when prepared by the process of claim 45 or an obvious chemical equivalent thereof.
47. The process of claim 5 wherein R, R1 and R2 each is methyl, R3 is 5-(1-methylethenyl) and R4 is hydrogen.
48. N-[[5-(1-Methylethenyl-1-naphthalenyl]thioxomethyl]-N-methyl-glycine methyl ester, when prepared by the process of claim 47 or an obvious chemical equivalent thereof.
49. The process of claim 5 wherein R, R1 and R2 each is methyl, R3 is 5-(1-methylethyl) and R4 is hydrogen.
50. N-[[5-(1-Methylethyl-1-naphthalenyl]thioxomethyl]-N-methyl-glycine methyl ester, when prepared by the process of claim 49 or an obvious chemical equivalent thereof.
51. The process of claim 5 wherein R, R1 and R2 each is methyl, R3 is 5-(trifluoromethyl) and R4 is 6-methoxy.
52. N-[[5-(Trifluoromethyl)-6-methoxy-1-naphthalenyl]thioxomethyl]-N-methylglycine methyl ester, when prepared by the process of claim 51 or an obvious chemical equivalent thereof.
53. The process of claim 5 wherein R, R1 and R2 each is methyl, R3 is 5-bromo and R4 is 6-[3-(trifluoromethyl)phenylmethoxy].
54. N-[[5-Bromo-6-[3-(trifluoromethyl)phenylmethoxy]-1-naphthalenyl]-thioxomethyl]-N-methylglycine methyl ester, when prepared by the process of claim 53 or an obvious chemical equivalent thereof.
55. The process of claim 5 wherein R, R1 and R2 each is methyl, R3 is 5-bromo and R4 is 6-(4-chlorophenylmethoxy).
56. N-[[5-Bromo-6-(4-chlorophenylmethoxy)-1-naphthalenyl]thioxomethyl]-N-methylglycine methyl ester, when prepared by the process of claim 55 or an obvious chemical equivalent thereof.

57. The process of claim 5 wherein R, R1 and R2 each is methyl, R3 is 5-(trifluoromethyl) and R4 is hydrogen.
58. N-[[5-(Trifluoromethyl)-1-naphthalenyl]thioxomethyl]-N-methyl-glycine methyl ester, when prepared by the process of claim 57 or an obvious chemical equivalent thereof.
59. The process of claim 5 wherein R and R2 each is methyl, R1 and R4 each is hydrogen and R3 is 5-bromo.
60. N-[(5-Bromo-1-naphthalenyl)thioxomethyl]glycine methyl ester, when prepared by the process of claim 59 or an obvious chemical equivalent thereof.
61. The process of claim 5 wherein R and R2 each is methyl, R1 is propyl, R3 is 5-bromo and R4 is hydrogen.
62. N-[(5-Bromo-1-naphthalenyl)thioxomethyl]-N-propylglycine methyl ester, when prepared by the process of claim 61 or an obvious chemical equivalent thereof.
63. The process of claim 5 wherein R and R2 each is methyl, R1 is 2-propenyl, R3 is 5-bromo and R4 is hydrogen.
64. N-[(5-Bromo-1-naphthalenyl)thioxomethyl]-N-(2-propenyl)glycine methyl ester, when prepared by the process of claim 63 or an obvious chemical equivalent thereof.
65. The process of claim 5 wherein R and R2 each is methyl, R1 is ethyl, R3 is 5-bromo and R4 is hydrogen.
66. N-[(5-Bromo-1-naphthalenyl)thioxomethyl]-N-ethylglycine methyl ester, when prepared by the process of claim 65 or an obvious chemical equivalent thereof.
67. The process of claim 5 wherein R and R2 each is methyl, R1 is butyl, R3 is 5-bromo and R4 is hydrogen.
68. N-[(5-Bromo-1-naphthalenyl)thioxomethyl]-N-butylglycine methyl ester, when prepared by the process of claim 67 or an obvious chemical equivalent thereof.
69. The process of claim 5 wherein R and R2 each is methyl, R1 is phenylmethyl, R3 is 5-bromo and R4 is hydrogen.
70. N-[(5-Bromo-1-naphthalenyl)thioxomethyl]-N-(phenylmethyl)-glycine methyl ester, when prepared by the process of claim 69 or an obvious chemical equivalent thereof.
71. The process of claim 5 wherein R and R2 each is methyl, R1 is hydrogen, R3 is 3-chloro and R4 is 4 methoxy.

72. N-[(3-Chlor-4-methoxy-1-naphthalenyl)thioxomethyl]-glycine methyl ester, when prepared by the process of claim 71 or an obvious chemical equivalent thereof.
73. The process of claim 5 wherein R, R1 and R2 each is methyl, R3 is 4-cyano and R4 is hydrogen.
74. N-[(4-Cyano-1-naphthalenyl)thioxomethyl]-N-methylglycine methyl ester, when prepared by the process of claim 73 or an obvious chemical equivalent thereof.
75. The process of claim 1 which comprises hydrolyzing the compound of formula III wherein R1, R3 and R4 are as defined in claim 1 and R is lower lower alkyl or ar(lower)alkyl to obtain the corresponding compound of formula I wherein R1, R3 and R4 are as defined in claim 1 and R2 is hydrogen; and, if required, transforming the latter compound of formula I into a corresponding therapeutically acceptable salt of an organic or inorganic base.
76. The compound of formula I wherein R1, R2, R3 and R4 are as defined in claim 75, or a corresponding therapeutically acceptable salt thereof with an organic or inorganic base, when prepared by the process of claim 75 or an obvious chemical equivalent thereof.
77. The process of claim 75 which comprises hydrolyzing the compound of formula III wherein R1 is hydrogen, lower alkyl, 2-propenyl or phenylmethyl;
R3 is hydrogen or a substituent at positions 4, 5 or 8 of the naphthalene ring, the substituents being selected from the group consisting of lower alkyl, lower alkoxy, halo, cyano, nitro and trifluoromethyl, and R4 is hydrogen; or R3 and R4 are a pair of substituents on the naphthalene ring selected from the group of pairs consisting of 3-halo-4-lower alkoxy, 5-halo-6-lower alkyl, 5-halo-6-lower alkoxy, 5,7-dihalo, 5-(trifluoromethyl)-6-lower alkoxy, 5-halo-6-(lower)-alkoxy(lower)alkoxy, 5-halo-6-[3-(trifluoromethyl)phenylmethoxy] and 5-halo-6-(4-chlorophenylmethoxy); and R is lower alkyl; to obtain the corresponding compound of formula I wherein R1, R3 and R4 are as defined in this claim and R2 is hydrogen; and, if required, transforming the latter compound of formula I into a corresp~nding therapeutically acceptable salt of an organic or inorganic base.
78. The compoLmd of formula I wherein Rl, R2, R3 and R4 are as defined in cl8im 77, or a corresponding therapeutically acceptable salt thereof with an organic or inorganic base, when prepared by the process of claim 77 or an obvious chemical equivalent thereof.
79. The process of claim 75 which comprises hydrolyzing the compound of formula m wherein R is hydrogen, lower alkyl, or phenylmethyl; R3 is 4-halo cr 5-halo and E24 is hydrogen; or R3 and R4 are a pair of substituents on the naphthalene ring selected from the group of pairs consisting of 3-halo-4-lower alkoxy9 5-halo-6-lower alkyl, 5-h~10-6-lower alkoxy, 5,7-dihalo ~nd 5-(trifluoromethyl~6-lower alkoxy; and R is lower alkyl; to obtain the corresponding compound of formula I wherein Rl, R3 and R4 are as defined in this claim and R is hydrogen; and, if required, transforming the latter compound of formula I into a corresponding therapeutically acceptable salt of an organic or inorFanic base.
80. The compound of formula I wherein Rl, R2, R3 and R4 are as defined in claim ~9, or a corresponding therapeutically acceptable salt thereof with an organic or inorganic base, when prepared by the process of claim 79 or an obvious chemical equivalent thereof.
81. The process of claim 75 which comprises hydrolyzing the compound of formula m wherein Rl is lower ~lkyl; R is 5-halo and R is hydrogen; or R3 and R are a pair of substituents on the naphthalene ring selected from the group of pairs consisting of 3-halo-4~lower alkoxy, 5-halo-6-lower alkoxy and ~(trifluoromethyl~6-lower alkoxy; and R is lower alkyl; to obtain the corresponding compowld of formula I wherein Rl, R3 and R4 are as defined in this claim and R2 is hydrogen; and, if reguired, transforming the latter compound of formula I into a corresponding therapeutically acceptable salt of an organic or inorganic base.
82. The compound of formula I wherein Rl, R2, R3 and R4 are as defined in claim 81, or a corresponding therapeutically acceptable salt thereof with an organic or inorganic b~e, when prepared by the process of claim 82 or an obvious chemical equivalent thereof.

... ., .. ,, . _ . ... . .. . . .. ... . ... . .

83. The process of claim 77 wherein R and R1 each is methyl, R3 is 5-bromo and R4 is hydrogen.
84. N-[(5-Bromo-1-naphthalenyl)thioxomethyl]-N-methylglycine, when prepared by the process of claim 83 or an obvious chemical equivalent thereof.
85. The process of claim 77 wherein R and R1 each is methyl, R3 is 4-bromo and R4 is hydrogen.
86. N-[(4-Bromo-1-naphthalenyl)thioxomethyl]-N-methylglycine, when prepared by the process of claim 85 or an obvious chemical equivalent thereof.
87. The process of claim 77 wherein R and R1 each is methyl, R3 is 8-bromo und R4 is hydrogen.

88. N-[(8-Bromo-1-naphthalenyl)thioxomethyl]-N-methylglycine, when prepared by the process of claim 87 or an obvious chemical equivalent thereof.
89. The process of claim 77 wherein R and Rl each is methyl, R3 is 5-methoxy and R4 is hydrogen.
90. N-[(5-Methoxy-1-naphthalenyl)thioxomethyl]-N-methylglycine, when prepared by the process of claim 89 or an obvious chemical equivalent thereof.
91. The process of claim 77 wherein R and R1 each is methyl, R3 is 5-methyl and R4 is hydrogen.
92. N-[(5-Methyl-1-naphthalenyl)thioxomethyl]-N-methylglycine, when prepared by the process of claim 91 or an obvious chemical equivalent thereof.
93. The process of daim 77 wherein R and R1 each is methyl, R3 is 5-bromo and R4 is 6-pentyloxy.
94. N-[(5-Bromo-6-pentyloxy-1-naphthalenyl)thioxomethyl] -N-methyl-glycine, when prepared by the process of claim 93 or an obvious chemical equivalent thereof.
95. The process of claim 77 wherein R and R1 each is methyl, R3 is 5-cyano and R4 is hydrogen.
96. N-[(5-cyano-1-naphthalenyl)thioxomethyl]-N-methylglycine, when prepared by the process of claim 95 or an obvious chemical equivalent thereof.

97. The process of claim 77 wherein R and R1 each is methyl, R3 is 5-nitro and R4 is hydrogen.
98. N-[(5-Nitro-1-naphthalenyl)thioxomethyl]-N-methylglycine, when prepared by the process of claim 97 or an obvious chemical equivalent thereof.
99. The process of claim 77 wherein R and R1 each is methyl, R3 is 5-chloro and R4 is hydrogen.
100. N-[(5-Chloro-1-naphthalenyl)thioxomethyl]-N-methylglycine, when prepared by the process of claim 99 or an obvious chemical equivalent thereof.
101. The process of claim 77 wherein R and R1 each is methyl, R3 is 5-bromo and R4 is 5-rnethoxy.
102. N-[(5-Bromo-6-methoxy-1-naphthalenyl)thioxomethyl]-N-methyl-glycine, when prepared by the process of claim 101 or an obvious chemical equiva-lent thereof.
103. The process of claim 77 wherein R and R1 each is methyl, R3 is 5-bromo and R4 is 6-methyl.
104. N-[(5-Brom-6-methyl-1-naphthalenyl)thioxomethyl]-N-methyl-glycine, when prepared by the process of claim 103 or an obvious chemical equiva-lent thereof.
105. The process of claim 77 wherein R and R1 each is methyl, and R3 and R4 each is hydrogen.
106. N-[(1-Naphthalenyl)thioxomethyl]-N-methylglycine, when prepared by the process of claim 105 or an obvious chemical equivalent thereof.
107. the process of claim 77 wherein R and R1 each is methyl, R3 is 4-chloro and R4 is hydrogen.
108. N-[(4-Chloro-1-naphthalenyl)thioxomethyl]-N-methylglycine, when prepared by the process of claim 107 or an obvious chemical equivalent thereof.
109. The process of claim 77 wherein R and R1 each is methyl, R3 is 3-chloro and R4 is 4-methoxy.
110. N-[(3-Chloro-4-methoxy-1-naphthalenyl)thioxomethyl]-N-methyl-glycine, when prepared by the process of claim 109 or an obvious chemical equiva-lent thereof.
111. The process of claim 77 wherein R and R1 each is methyl, R3 is 5-chloro and R4 is 7-chloro.

112. N-[(5,7-Dichlor-1-naphthalenyl)thioxomethyl]-N-methylglycine, when prepared by the process of claim 11) or an obvious chemical equivalent thereof.
113. The process of claim 77 wherein R and R1 each is methyl, R3 is 5-iodo and R4 is 6-methoxy.
114. N-[(5-Iodo-6-methoxy-1-naphthalenyl)thioxomethyl]-N-methyl-glycine, when prepared by the process of claim 113 or an obvious chemical equiva-lent thereof.
115. The process of claim 75 wherein R and R1 each is methyl, R3 is 5-cyano and R4 is 6-methoxy.
116. N-[(5-Cyano-6-methoxy-1-naphthalenyl)thioxomethyl]-N-methyl-glycine, when prepared by the process of claim 115 or an obvious chemical equiva-lent thereof.
117. The process of claim 77 wherein R and R1 each is methyl, R3 is 5-bromo and R4 is 6-(3-methoxypropoxy).
118. N-[(5-Bromo-6-(3-methoxypropoxy)-1-naphthalenyl]thioxomethyl]-N-methylglycine, when prepared by the process of claim 117 or an obvious chemical equivalent thereof.
119. The process of claim 77 wherein R and R1 each is methyl, R3 is 5-(1-methylethenyl) and R4 is hydrogen.
120. N-[[5-(1-Methylethenyl)-1-naphthalenyl]thioxomethyl]-N-methyl-glycine, when prepared by the process of claim 119 or an obvious chemical equiva-lent thereof.
121. The process of claim 77 wherein R and R1 each is methyl, R3 is 5-(1-methylethyl) and R4 is hydrogen.
122. N-[[5-(1-Methylethyl)l-naphthalenyl]thioxomethyl]-N-methyl-glycine, when prepared by the process of claim 121 or an obvious chemical equiva-lent thereof.
123. The process of claim 77 wherein R and R1 each is methyl, R3 is 5-(trifluoromethyl) and R4 is 6-methoxy.
124. N-[[5-(Trifluoromethyl)-6-methoxy-1-naphthalenyl]thioxomethyl]-N-methylglycine, when prepared by the process of claim 123 or an obvious chemical equivalent thereof.
125. The process of claim 77 wherein R and R1 each is methyl, R3 is 5-bromo and R4 is 6-[3-(trifluoromethyl)phenylmethoxy].

126. N-[[5-Bromo-6-[3-(trifluoromethyl)phenylmethoxy]-1-naphthalenyl]-thioxomethyl]-N-methylglycine, when prepared by the process of claim 125 or an obvious chemical equivalent thereof.
127. The process of claim 77 wherein R anci Rl each is methyl, R3 is 5-bromo and R4 is 6-(4-chlorophenylmethoxy).
128. N-[[5-Bromo-6-(4-chlorophenylm ethoxy)-1-naphthalenyl]thiox-methyl]-N-methylglycine, when prepared by the process of claim 127 or an obvious chemical equivalent thereof.
129. The process of claim 77 wherein R and R1 each is methyl, R3 is 5-(trifluoromethyl) and R4 is Iydrogen.
130. N-[[5-(Trifluoromethyl)-1-naphthalenyl]thioxomethyl]-N-methyl-glycine, when prepared by the process of claim 129 or an obvious chemical equiva-lent thereof.
131. The process of claim 77 wherein R is methyl, R1 and R4 each is hydrogen and R is 5-bromo.
132. N-[(5-Bromo-1-naphthalenyl)thioxomethyl] glycine, when prepared by the process of claim 131 or an obvious chemical equivalent thereof.
133. The process of claim 77 wherein R is methyl, R1 is propyl, R3 is 5-bromo and R4 is hydrogen.
134. N-[(5-Bromo-1-naphthalenyl)thioxomethy]3-N-propylglycine, when prepared by the process of claim 133 or an obvious chemical equivalent thereof.
135. The process of claim 77 wherein R is methyl, R1 is 2-propenyl, R3 is 5-bromo and R4 is hydrogen.
136. N-[(5-Bromo-1-naphthalenyl)thioxomethyl]-N-2-propenyl)glycine, when prepared by the process of claim 135 or an obvious chemical equivalent thereof.
137. The process of claim 77 wherein R is methyl, R1 is ethyl, R3 is 5-bromo and R4 is hydrogen.
138. N-[(5-Bromo-1-naphthalenyl)thioxomethyl]-N-ethylglycine, when prepared by the process of claim 137 or an obvious chemical equivalent thereof.

139. The process of claim 77 wherein R is methyl, R1 is butyl, R3 is 5-bromo and R4 is hydrogen.
140. N-[(5-Bromo-1-naphthalenyl)thioxomethyl]-N-butylglycine, when prepared by the process of claim 139 or an obvious chemical equivalent thereof.
141. The process of claim 77 wherein R is methyl, R1 is phenylmethyl, R3 is 5-bromo and R4 is hydrogen.
142. N-[(5-Bromo-1-naphthalenyl)thioxomethyl]-N-phenylmethyl)-glycine, when prepared by the process of claim 141 or an obvious chemical equiva-lent thereof.
143. The process of claim 77 wherein R is methyl, R1 is hydrogen, R3 is 3-chloro and R4 is 4-methoxy.
144. N-[(3-Chloro-4-methoxy-1-naphthalenyl)thioxomethyl]- glycine, when prepared by the process of claim 143 or an obvious chemical equivalent thereof.
145. The process of claim 75 wherein R and R1 each is methyl, R3 is 4-cyano and R4 is hydrogen.
146. N-[(4-Cyano-1-naphthalenyl)thioxomethyl]-N-methylglycine, when prepared by the process of claim 145 or an obvious chemical equivalent thereof.
147. A process for preparing a compound of formula II

(II) wherein R1 is hydrogen, lower alkyl, lower alkenyl or phenylmethyl; R3 is a substituent at position 4, 5 or 8 of the naphthalene ring, the substituent being selected from the group consisting of lower alkyl, lower alkoxy, halo, cyano, nitro and trihalomethyl, and R4 is hydrogen; or R3 and R4 each is a substituent at different positions of the naphthalene ring, the positions selected from posi-tions 3 to 7 and the substituents being selected from the group consisting of lower alkyl, lower alkoxy, halo, trihalomethyl, (lower)alkoxy(lower)alkoxy, phenyl-methoxy and phenylmethoxy substituted on the phenyl portion with a lower alkyl, lower alkoxy, halo or trihalomethyl; and R is lower alkyl or ar(lower)alkyl;
or a compound of formula IV

(IV) wherein R1, R3 and R4 are as defined in this claim; which comprises:
(a) coupling a naphthalenecarboxylic acid of the formula wherein R3 and R4 are as defined in this claim with an aminoacid ester of formula NH(R1)-CH2COOR wherein R1 and R are as defined in this claim to obtain the corresponding compound II in which R1, R3, R4 and R are as defined in this claim; and (b) if required, hydrolyzing the latter compound of formula II to obtain the corresponding compound of formula IV; and (c) if required, transforming the compound of formula IV into a corresponding therapeutically acceptable salt of an organic or inorganic base.
148. The compound of formula II, or of formula IV, as defined in claim 147, or a therapeutically acceptable salt of the compound of formula IV thereof with an organic or inorganic base, when prepared by the process of claim 147 or an obvious chemical equivalent thereof.

149. The process of claim 147 wherein R1 is lower alkyl, lower alkenyl or phenylmethyl and R is lower alkyl.
150. The compound of formula II or of formula IV, as defined in claim 149, or a therapeutically acceptable salt of the compound of formula IV thereof with an organic or inorganic base, when prepared by the process of claim 149 or an obvious chemical equivalent thereof.
151. The process of claim 147 for preparing a compound of formula II wherein R1 is lower alkyl; R3 is 4-halo, 5-halo or 5-trifluoromethyl and R4 is hydrogen; or R3 and R4 are a pair of substituents on the naphthalene ring selected from the group of pairs consisting of 3-halo-4-lower alkoxy,5-halo-6-lower alkyl, 5-halo-6-lower alkoxy, 5,7-dihalo and 5-(trifluoromethyl)-6-lower alkoxy; and R is methyl or ethyl.
152. The compound of formula II as defined in claim 151, when prepared by the process of claim 151 or an obvious chemical equivalent thereof.
153. The process of claim 149 which comprises coupling 5-bromo-1-naphthalenecarboxylic acid with N-methylglycine methyl ester to obtain N-[(5-bromo-1-naphthalenyl)carbonyl]-N-methylglycine methyl ester, and hydroly-zing the latter compound to obtain N-[(5-bromo-1-naphthalenyl)carbonyl]-N-methylglycine.
154. N-[(5-Bromo-1-naphthalenyl)carbonyl]-N-methylglycine, when prepared by the process of claim 153 or an obvious chemical equivalent thereof.
155. The process of claim 149 which comprises coupling 5-(trifluoro-methyl)-6-methoxy-1-naphthalenecarboxylic acid with N-methylglycine methyl ester to obtain N-[[5-(trifluoromethyl)-6-methoxy-1-naphthalenyl] carbonyl]-N-methylglycine methyl ester, and hydrolyzing the latter compound to obtain N-[[5-(trifluoromethyl-6-m ethoxy-1-naphthalenyl]carbonyl]-N-methylglycine.
156. N-[[5-(Trifluoromethyl)-6-methoxy-1-naphthalenyl] carbonyl]-N-methylglycine, when prepared by the process of claim 155 or an obvious chemical equivalent thereof.
157. The process of claim 149 which comprises coupling 5-bromo-1-naphthalenecarboxylic acid with N-methylglycine methyl ester to obtain N-[(5-bromo-1-naphthalenyl)carbonyl]-N-m ethylglycine methyl ester.

158. N-[(5-Bromo-1-naphthalenyl)carbonyl]-N-methylglycine methyl ester, when prepared by the process of claim 157 or an obvious chemical equivalent thereof.
159. The process of claim 149 which comprises coupling 5-(trifluoro-methyl)6-methoxy-1-naphthalenecarboxylic acid with N-methylglycine methyl ester to obtain N-[[5-(Trifluoromethyl)-6-methoxy-1-naphthalenyl]carbonyl]-N-methylglycine methyl ester.
160. N-[[5-(Trifluoromethyl)-6-methoxy-1-naphthalenyl]carbonyl]-N-methylglycine methyl ester, when prepared by the process of claim 159 or an obvious chemical equivalent thereof.