CA1248127A - N-((6-(lower alkoxy)-5-trifluoromethylthio)-1- naphthalenyl)-thioxomethyl)-n-(lower alkyl)glycines - Google Patents

Abstract

ABSTRACT
The disclosure describes a process which comprises converting a N-[[(6-(lower alkoxy)-5-(tri-fluoromethylthio)-1-naphthalenyl]-carbonyl]-N-methyl-glycine lower alkyl ester into a N-[[(6-lower alkoxy)-5-(trifluoromethylthio)-1-naphthalenyl]-thioxomethyl]-N-methylglycine lower alkyl ester. It also describes the ester produced thereby.

Description

~2~ 27 N-~[6-(J,OWER ALKOXY~5-(TRIFLUOROMETHYLTHIO)-l-NAPHTHALENYL]-THIOXOMETHYLI-N~LOWEX ALKYL)GLYCINES

5 Related ~pplications: Related hereto are Canadian Patent Application Serial No. 372,119, Canadian Patent Application Scrial No. 372,054 and Canadian Patent .~pplication Serial No. 372,024 all filed on March 2,1981.
This application relates to N-~[6-(lower alkoxy~5-(tr;fluoromethylthio~
l-naphthalenyl] thioxomethyl]-N{lower alkyl)glycines, therapeutically acceptableio salts thereof, to a process for their preparation, to methods of use, and to pharma-ceutical compositions thereof. The derivatives have pharmacologic properties which render them beneficial for the treatment of diabetes mellitus and as-sociated conditions.
For many years diabetes mellitus has been treated with two estab-15 lished types of drugs, namely insulin and oral hypoglycemic agents. These drugshave benefited hundreds of thousands of diabetics by improving their well-being and prolonging their lives. However, the resulting longevity of diabetic patients - has led to complications such as neuropathy, nephropathy, retinopathy, cataracts and atherosclerosis. These complications have been linked to the undesirable 20 accumulation of sorbitol in diabetic tissue, which in turn result from the high levels of glucose characteristic of the diabetic patient.
In mammals, including humans, the key enzyme involved in the conver-sion of hexoses to polyols tthe sorbitol pathway~ is aldose reductase. J.H. Kinoshita and collaborators, see J.H. Kinoshita, et al., Biochem. Biophys. Acta., 158, 47225 (1968) and references cited therein, have demonstrated th~t aldose reductase plays a central role in the etiology of galactosemic cataracts by effecting the conversion of galactose to dulcitol (galactitol) and that an agent capable of inhibiting aldose reductase can prevent the dctrimental accumulation of dulcitolin the lens. Furthermore, a relationship between elevated levels of glucose 30 and an undesirable accumulation of sorbitol has been demonstrated in the lens, peripheral nervous cord and kidney of diabetic animals, see A. Pirie and R.
van Heyningen, Exp. E~e Res., 3,124 (1964), L.T. Chylack and J.H. Kinoshita, Invest. Ophthal., 8, 401(1969) and J.D. Ward and R.W.R. Baker, Diabetol., 6, 531 (1970).
1,3-Dioxo-lH-benz[de] isoquinoline-2(3H)-acetic acid has been reported to bc an effective inhibitor of aldose reductase, see D. Dvornik et al., Science, 12~3127

-2- AHP-7399 182,1146 (1973), and to be useful for the treatment of diabetic complications such as diQbetic cataracts, neuropathy, nephropathy and retinopathy, see K.
Sestanjs N. Simard-Duquesne and D.M. Dvornik, U.S. Patent No. 3,821,383, June 5 28,1974. Other compounds having a similar utility are the thioxo-lH-b~z[de3-isoquinoline-2(3H~acetic acid derivatives of K. Sestanj, U.S. Patent No.4,254,108 issued March 3, 198l and lH-benztde]isoquinoline-2(3H~
acetic acid derivatives of K. Sestanj, U.S. Patent No. 4,254,109, issued March 3, 1981. (S~6-Fluoro-2,3-dihydrospiro(4H-l-benzopyran-4,4'-10 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 1, Metabolism, 28 (Suppl. 1), 456 (1979). Accordingly, these compounds re-present an important new approach for the treatment of diabetes mellitus.
The novel compounds of the present application, represented below 15 by formula I, are effective inhibitors of aldose reductase. These new derivatives are structurally quite different from the above noted aldose reductase inhibitors.
Close prior art compounds, on a structural basis, appear to be a group of thio-acylaminoacids, e.gO N-phenylthioxomethyl-N-methylglycine, prepared by A.
Lawson and C.E. Searle, J. Chem. Soc., 1556 (1957) as part of a chemical investi-20 gation of the chemical propertie~s o~ such compounds. These last mentionedcompounds were prepared by thiobenzoylation of various amino acids with (thiobenzoylthio)acetic acid An irnportant structural difference between these compounds and the present derivatives is the different type of aromatic group substituted on the thione portion of the thioamide. Thioacylamides also have 25 been reported [see Chem. Abstr., 86,189582f (1977) for V.I. Cohen et al., Eur.
J. Med. Chem., 5, 480 (1976) and Chem. Abstr., 70,11306a (1969) for von J. Voss and W. Walter, Justus Leibigs Ann. Chem., 716, 209 (1968)]. The structures of the thioacylamides of Cohen et al and Voss et al differ from the structure of the present derivatives by having at least a different type of N-substitubon.30 Another close prior art cornpound, on a structural basis, is N-[(l-naphthalenyl~
carbonyl] glycine, [see Chem. Abstr., 61, 4333f (1964) for F. Cioranescu et al.,Rev. Chim. Acad. Rep. Populaire Roumaine, 7 (2), 755 (1962~.

_. !

-3- AHP-79g9 The compounds of this invention are represented by form~da I
S=C-N(R )Cl~2C00ll R20~ 2 (1) wherein Rl is lower alkyl ~nd R2 is lower Qlkyl, or a thPrapeutically accept-able salt thereof with an organic or inorganic base.
A preferred group of the compounds is represented by formlda I
wherein Rl is methyl and R2 is lower alkyl, or a therapeutically acceptable 15 salt thereof with an organic or inorganic base.
The preferred compound is the compound of formula I wherein is methyl and R is methyl, or a therapeutically acceptable salt thereof with `~ an organic or inorganic base.
The compound of form~da l can be prepared by a process wherein 20 a corresponding ester of the compound of formula I is hydrolyzed. In a pre-ferred embodiment, the ester is represented by form~a II
S--C-N(Rl)C1~2COOR

SC~3 - wherein Rl and R2 are as defined herein and R is lower alkyl or ar(lower)alkyl.
A method is provided for preventing or relieving diabetes mellitus 30 associated complications in a diabetic mammal by administering to said mammala prophylactic or alleviating amount of the compound of formula I or thera-peutically acceptable salt thereof with an or~anic or inorganic base. These complicat;ons include neuropathy, nephropathy, retinopathy and cataracts.
The compound of formula I, or a therapeutically acceptable salt 35 thereof with an organic or inorganic base, when admixed with a pharmaceutic lly .

:. , ....................................... .,: . :
,.

. I

- ~24~7 `~

-4- AHP-7999 acceptable cnrrier, forms a pharmaceutical composition which can be used according to the preceding method.
Detailed Description of the Invention The compounds of this invention, represented by formula I~ can exist in rotameric forms. More explicitly, mesomerism imparts a partial double bond character to the carbon-nitrogen bond of the thioamide group. This partial double bond character leads to restricted rotation nbout the carbon nitrogen bond giving rise to cis and trans rotamers3 the restricted rotation being augmented 10 by the blllkiness of neighboring groups. Interconversion of the rotamers is pos-sible and is dependent on the physical environment. As evidenced by its ph~sicalproperties, the thermodynamically more stable rotamer exists exclusively in the crystalline state of the compound and is the predominant isomer present in equilabrated solutions. Furthermore, the more stable rotamer is the more 15 pharmacologically active. The less stable rotamer can be separated from the more stable rotamer by high performance liquid chromatography or by thin yer chromatography. The ro~americ ~orms are included within the scope of - this invention. ~or brevity, the compounds of this invention, including their rotameric forms, will be referred to herein as compounds of formula 1.
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.
'5 The term '~ower alkoxy'l as used herein meuns a straight chain alkoxy radical containing from one to six carbon atoms9 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 chloro, bromo and iodo.
The term "ar" as used mean an aromatic radical containing at least one benzene ring. The preferred aromatic radic~l is phenyl.
The term "organic proton acceptor" as used herein means the organic bases or amines, for instance, triethylamine, pyridine, N-ethylmorpholine, 1,5-diazabicyclo[4.3.0] non-5-ene and the like.

~2~ 27

-5- AHP-7999 The compounds of formula I form salts with suitable therapeutica~ly acceptable inorganic and organic bases. These derived salts possess the same activity as their parent acid and are included within the scope of this invention.
5 The acid is transformed in exceIlent yield into the corresponding therapeutically acceptable salt by neutralization of said acid with the appropriate inorganic or organic base. The salts are administered 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 io acceptable aL<ali metals or alksline earth metals, for example, sodium, potassium, Jnagnesium, calcium and the like. Suitable organic bases include the following amines: benzylamine; lower mono-, di- and trialkylamines, the alkyl radicals of which contain up to three carbal atoms, such as methylamine, dimethylamine, trimethylamine, ethylamine, di-and triethylamine, methylethylamine, and the 15 like; mono--, di- and trialkanolamines, the alkanol radicals of which containup to three carbon atoms, for example, mono-, di- and triethanolamine; alkylene-diamines which contain up to six carbon atoms, such as hexamethylenediamine;
`-- cyclic saturated or unsaturated bases containing up to six carbon atoms, such as pyrrolidine, piperidine, morpholine, piperazine and their N-alkyl and N-hydroxy-20 alkyl 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 methyltriethanol and trimethyl-monoethanol) and cyclic ammonium salts, for example the N-methylpyridinium, N-methyl-N-(2-hydroxyethyl~mor-pholinium N,N~imethylmorpholinium, N-methyl-N~2-hydroxyethyl~morpho-linium, N,N-dimethyl-piperidinium salts, which are characterized by having good water-solubility. ln principle, however, there can be used all the ammoniumf salts which are physiologically compatible.
`~ The transformations to the salts can be carried out by a variety 30 of methods known in the art. For example, in the case of the inorganic salts,it is preferred to dissolve the acid of formula I in water containing at least one equivalent amount of a hydro~cide, carb~nate, or bicarb~nate corresponding to the inorganic salt desired. Advantageously, the reaction is performed in a water-miscible, inert organic solvent, for example, methanol, ethanol, dioxane, 35 and the like in the presence of water. For cxample, such use of sodium hydroxide, 27 (-

-6- AHP-7999 sodium carbonate or sodium bicarbonnte gives a solution of the sodium salt.
Evaporation of the solution or addition of a water-miscible solvent of a more moderate polarity, for example, a ]ower alkanol, for instance, butanol, or a 5 lower alkanone, for instance, ethyi methyl ketone, gives t~e solid inorganic salt if that form is desired.
To produce an amine salt, the acidic compound of formula I is dis-solved in a suitable solvent of either moderate or low polsrity, for example, ethanol, methanol, ethyl acetate, diethyl ether ~nd benzene. At least an equiv-10 alent amount of the amine corresponding to the desired cation is then added to that solution. If the resulting salt does not precipitnte, it can usually be obtained in solid form by addition of a miscible diluent of lower polarity, for example, benzene or petroleum ether, or by evaporation. If the amine is re-latively volatile, any excess can easily be removed by evaporation. It is preferred 15 to use substantially equivalent amounts of the less volatile amines.
Salts wherein the cation is quaternary ammonium are produced by f mixing the acid of formula I ~vith an eqùivalent amount of the corresponding quaternary ammonium hydroxide in water so]ution, followed by evaporation of the water.
20 The compounds of this invention and their addition salts with pharma-ceutically acceptable organic or inorganic bases may be administered to mammals,for exampIe, man, cattle or rabbits, either alone or in dosage forms, i.e., caps~des or tablets, combined with pharmacologically acceptable excipients, see below.
Advantageously the compounds of this invention may be given orally. However~
25 the method of administering the present active ingredients of this invention is not to be construed as limited to a particular mode of administration. For example, the compounds may be administered topically directly to the eye in - i the form of drops of sterile, buffered ophthalmic solutions, preferably of pH

7.2 - 7.6. Also~ they may be admioistered orully in solid form containing such 30 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 buffer.
35 The dosage of the present therapeutic agents will vary with the form of administration and the particular compound chosen. Furthermore, , ~ ~

~2~L27 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 dosage is incrensed by small increments until efficacy5 is obtained. In general, the compounds of this invention are rnost 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 inst;llation varies with the subject under treatment from a drop every two 10 or hree days to once daily. For orul or parenteral administration a preferred level of dosage ranges from about 0.1 mg to about lO0 mg per kilo of body weightper day, although aforementioned variations will occur. ~-Jowever, a dosage level that is in the range of from about O.S 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 mg of the active ingredients of this in-vention, preferably with a significant quantity of a pharmaceutical carrier.
Thus, for oral administration, caps~es can contain from between about S.0 mg to about 250 mg of the active ingredients of this invention with or without a 20 pharmaceutical diluent. Tablets, either effervescent or noneffervescent, can 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 urt. Inert diluents or carriers, for example, magnesium carbonate 25 or lactose, can be used together with conventional disintegrating agents for ex-ample, magnesium stearate.
Syrups or elixirs suitable for oral administration can be prepared from water soluble salts, for example, sodium N-[[5-(trifluoromethylthio)-6-methoxy-1-naphthalenyl] thioxornethyl]-N-methylglycinate, and may advan-30tageous1y contain ~lycerol 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 agents to produce beneficial effect in the treatment of diabetes mellitus. In this instance, commercially available insulin preparations or oral hypoglycemic agents, exem-~5 ~ i ~
.

(- ~ f

-8- AHP-7999 plified by acetohexamide, chlorpropamide, tolazamide, tolbutamide and phenformin, are suitable. The compound of formula I, or a therapeutically acceptable salt thereof, can be administered sequentially or simultaneously with insulin or the 5 oral hypoglycemic agent. Suitable methods of adminislration, 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 compound of formula I, or its therapeutically acceptable salt, can be admin-istered with the oral hypoglycemic agent in the form of a pharmaceutical com-position comprising effective amounts of each agent.
The aldose reductase inhibiting effects of the compounds of formula 1 and their pharmaceutically acceptable salts with organic or inorganic bases can 15 be demonstrated by employing an in vitro testing procedure similar to that described by S. Hayman and a. H. 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 Gf the enzyme from bovine lens.
For example, when N-~[6-methoxy-5-(trifluoromethylthio~l-naphth-20 alenyl] thioxomethyl]-N-methylglycine, the compound of formula I wherein Rl and R2 are methyl, was evaluated in the above in vitro test, the aldose reductase from the bovine lens was inhibited 94,73 and 9 percent by compound concentrations of l x10 6,1 x10 7 andl x10 8 M, respectively.
The aldose reductase inhibiting property of the compounds of this ~5 invention and the utilization of the compounds in preventing, diminishing andalleviating diabetic complications are demonstrable in experirnents using galacto-semic rats~ see Dvornik et al., cited above. An example of such an experiment ,' is exemplified hereinbelow after the listing of the following general comments pertaining to these experiments:
(a) Four or more groups of six male rats, 50-70 ~, Sprague-Dawley strain, were used. The first group, the control group, was fed a mixture of labo~-atory chow (rodent ls.boratory chow, Purina) and glucose at 20% (W/W %) con-centration. The untreated galactosemic group was fed a similar diet in which galactose is sul:~stituted for glucose. The third group was fed a diet prepared by 35 mixing 8 given amount of the test compound with the galactose containing diet.

~Z~ 7

-9- AHP-7999 The concentration of galactose in the diet of the treated groups was the same as thqt for the untreated galactosemic group.
(b) After four days, the animals were killed by decapitation. The 5 eyeballs were removed and punctured with a razor blHde; the freed lenses were rolled gently on filter paper and weighed. The SCiQtiC ners~es were dissected ascompletely as possible and weighed. Both tissues were frozen and could be kept up to two weeks before being analyzed for dulcitol.
(c) The polyol determination was performed by a modification of

10 the procedure of M. Kraml and L. Cosyns, Clin. Biochem., 2, 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 dissolving 25 mg of dulcitol in 100 ml of an aqueous trichloroacetic acid solu-tion.EN.B.: For each experisnent the average v~lue found in the tissue from rats15 fed the glucose diet was subtracted from the individual values found in the cor-responding rat tissue to obtain the amount of polyol accumulated].
( ? When N-[[6-methoxy-5-(trifluoromethylthio~l-naphthalenyl] thioxo-methyl]-N-methylglycine was evaluated in the nbove in vivo test, the results appearing in the followin~ table were obtained. In the table, the figures under 20 L, N and D represent the percentage decrease of dulcitol accumulation in the tissues of the lens, sciatic nerve and diaphragm, respectively, for treated rats as compared to untreated rats.

Dose mg/kg/day L N D
20.5 20 96 87 9.1 NS ~ 55 83 4.4 NS 29 83 - * Not Signifi cant Process As noted previously, the compounds of form~da I are prepared pre-ferably by hydrolyzing the corresponding ester of formula Il wherein Rl, R2 and R are as defined herein~
More explicitly, the ester of formula II is hydrolyzed with a hydr~
351yzing agent to give the corresponding product of formula I in which Rl and -~2~ 7 C

R are as defined herein. Generally spe~king, the hydrolysis is performed most conveniently by employing a base as the hydrolyzing agent in the presence of sufficient water. However, it should be understood that the manner of hydrolysis5 for the process of this invention is not intended to be limited to basic hydrolysis since hydrolysis under acidic conditions and other variations, for example) treat-ment with lithium iodide in collidine (see L.F. Fieser and M. Fieser, '~eagents for Organic Synthesis", John Wiley and Sons, Inc., New York, 1969~ pp. 615-617),also are applicable. HydroIysis under acidic conditions is preferred when the 10 ester is a ter-butyl ester.
For basic hydrolysis, a preferred embodiment involves subjecting the ester to the action of a strong base, for example, sodium hydroxide or potas-sium hydroxide, in the presence of sufficient water to effect hydrolysis of the ester. The hydrolysis is performed using a suitable solvent, for example, meth-15 anol, ethanol or 2-methoxyethanol. The reaction mixture is maintained at a temperature of from about 25 to 100 C or at the reflux temperature of the ~- ~ solvent employed until hydrolysis occurs. Usually from 10 minutes to six 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 20 release the free acid of formula 1.
l`he requisite ester of formula II for the preceding hydrolysis step can be prepared by a process which is illustrated by the following reaction scheme wherein Rl and R eaeh is lower alkyl, R is lower alkyl or ar~lower)alkyl, R4 is lower alkyl and X is halo.

--" 12~8~:27 -Lt- AHP-7999 CoOR4 CoOR4 R o ~ R o (III) (IV) COOHO C-N~R )-CH2COOR

R O~R20~3~ > (Il) SC~3 SC~3 (V) ~VI) ,- With reference to the reaction scheme, the ester of formula Ill where-in R2 and R4 each is lower alkyl and X is halo can be prepared by known methods.For example, see ~'EIeseYier~s Encyclopaedia of Organic Chemistry", F. Radt, 20 Ed., Series III, Vol. 12B, Elsevier Publishing Co., Amsterdam, 1953, pp 3965-4473.
The ester of formula m wherein R2 and R4 each is lower alkyl and X is halo is reacted with trifluoromethylthio copper to give a second ester re-presented by formula IV wherein R~ and R each is lower alkyl. Practical and convenient conditions for effecting this conversion include reacting the ester of form~a III with one to two molar equivalents of trifluoromethylthio copper at 80-120 C for two to six hours in an inert organic solvent, for instance, di-methylformamide, m-xglene or toluene.
Thereafter, the ester of formula IV is hydrolysed to give the corres-ponding naphthalenecarboxylic acid of formula V wherein R2 is lower alkyl.
30SuitabIe conditions for this hydrolysis are the same as those described previously for the hydrolysis of the ester of formula Il to obtain the compound of crmula 1. .
The corresponding naphthalenecarboxylic acid of form~a V wherein R is lower aL'cyl is coupled with an amino acid ester of the form-da NH~Rl~
35CH~CoOR3 wherein R is lower a]kyl and R is lower alkyl or ar(lower~alkyl to give the amidoester of formula VI wherein Rl, R and R are as defined here-in. The coupling is done preferably by the "carboxyl activation" coupling pro-cedure. Descriptions of carboxyl-activating groups are found in general textbooks 5 of peptide chemistry; for example K.D. Kopple, "Peptides and Amino Acids", W.A. Benjamin, Inc., New York, 1966, pp. 45-51 and E. Schr8der and K. LUbke, "The Peptides'' Yol. 1, Academic Press, New York, 1965, p~. 77-128. Examples of the activated form of the terminal carboxyl are the acid chloride, acid bromide, anhydride, azide, activated ester, or ~acyl urea of a dialkylcarbodiimide.
10 Preferred activated forms of the carboxyl are the acid chloride or the l-benzo-triazolyl, 2,4j5-trichlorophenyl or succinimido activated esters.
Finally, the amidoester of formula VI, the product of the above described coupling reaction, is reacted under anhydrous conditions with about two to five molar equivalents of phosphorus pentasulfide in an inert solvent, 15 e.g. xylene or toluene, to give the desired, corresponding thioxoester of formula II. This reaetion is performed conveniently at temperatures ranging from 80 to about 150 C and for a duration rnnging from 20 minutes to four hours. Pre-ferably, the reaction is performed in the presence of an organic proton acceptor;
for instance, N-ethyl morpholine, triethylamine or pyridine.
The fo2Iowing examples illustrate further this invention.

5-lodo-5-methoxy-1-naphthalenecarboxylic Acid Methyl Ester (III, R~ and R4 = CH3 and X = I) Iodine ~7.08 g) and iodic acid (2.78 g) were added to a stirred sol-25 ution of 6-methoxy-1-naphthalenecarboxylic acid methyl ester [15 g, 69.4 mmoles, described by C.C. Price et al., J. Amer. Chem. Soc., 69,2261(1947)] in 80%
acetic acid (110 ml) and 989~ sulfuric acid (0.97 ml). The solution was heated at 50D C for 5 hr, cooled and poured into water (100 ml~. After the addition of sodium bisulfite to destroy the unreacted iodine, the precipitate was col-30 lected, washed with water and recrystallized from ethunol to afford the titlecompound; mp 98-99C; NMR (CDC13) ~ 3.95 (s, 3H), 4.00 (s, 3H), 8.00 (m, 5H).
I~XAMPLE 2 6-Methoxy-5-(trifluoromethylthio~l-naphthalenecarboxylic Acid Methyl Ester 35 (IV, R and R4 = CH3) An intimate rnixture of copper dust (1.84 g, 29 mmoles) and Hg -( SCF3 ) 2 ` ~2~Z7 '.

-13- AI~P-7999 [3.27 g, 8 mmoles, prepared according to the method of E.H. Man et al., J. Amer.Chem. Soc., 81, 3575 (1959)] was heated between 80 to 100 C for 2.5 hr. There-after~ the temperature was increased to 150 C for 30 min. The mixture, con-5 taining CuSCF3, was cooled to room temperature (ca. 22 to 24 C)~ A solutionof 5-iodo-6-methoxy-1-naphthalenecarboxylic acid methyl ester (1.87 g, 5.4 mmoles) in distilled dirnethylformamide (DMF, 10 ml) was added to the mixture.
The resulting mixture was stirred at 110 to 120 C for 3 hr, and then at room temperature for 18 hr. The mixture was poured into water. The diluted mixture 10 was extracted with diethyl ether (3 x3. The extract was washed with w~ter, dried (MgSO4) and evaporated to dryness to give the title compound (1.7 g) as a solid residue; mp 93-94 C; NMR (CDC13) ~ 3.90 (s, 3H), 4.00 (s, 3H), 7.00-9.20 (m, 5H).

15 6-A~ethoxy-5-(trifluoromethylthio)-1-naphthalenecarboxylic Acid (V, R2 = CH3)Aqueous NaOH solution (lN, 15.5 ml) was added to a solution of 6-! ` methoxy-5-(trifluoromethylthio)-1-naphthalenecarboxylic acid methyl ester (2.45 g, 7.7 mmoles) in 2-methoxyethanol (60 ml). The resulting solution was stirred at room temperature for 24 hr, cooled in an ice-bath, made acidic ~pH=3)20 by the addition of lN aqueous HCl and diluted with water. The resulting solidwas collected, washed with water and recrystallized from ethQno] to give the title compound (1.7 g); mp 204-205 C; NMR (DMSO-d6) ~ 4.0û (s, 3H), 8.2û
(m, 5H), 10.30 (broad, lH).
XAMPI.E 4 25 N-1~6-Methoxy-5-(trifluoromethylthio)-1-naphthalenyl] c arbonyl] -N-methylglycine Methyl Ester (VI, Rl, R2 and R3 = CH3) Procedure A
-N,N'-Dicyclohexylcarbodiimide (1.39 g, 6.7 mmoles) was added to ~~ a solution of 6-methoxy-5-(trifluoromethylthio)-1-naphthaleneearboxylic acid 30(1.7 g, 5.6 mmoles) and l-hydroxybenzotriazole (1.5 g~ 11.1 mmoles) in distilled DMF ~10 ml). The mixture was stirred at room temperature for one hr. A solution of N-methylglycine methyl ester hydrochloride (1.57 g, 11.2 mmoles) in distilledDMF (10 ml) containing N~thylmorpholine (1.44 ml) was added to the mixture.
The mixture was stirred at 24 C for 18 hr. Therea~ter, the mixture was filtered3;and the filtrate was concentrated wlder reduced pressure. The residue was .. _ ~Z'~12~ !

dissolved in ethyl acetate. The solution was washed successively with lN aqueousI-lCI, water, a saturated aqueous solution of NaHCO3, water and brine, dried (Mg SO4) and concentrated to dryness under reduced pressure to give 2.0 g of 5 the title compound as an oil; NI~IR (Cl~C13) ~ 3.00 (s, 3H), 3.75 (s, 3H), 4.00 (s, 3H), 4.35 and 4.5 (d, 2H), 7.0-8.5 (m, 5H).
Procedure B:
A catalytic amount (5 drops) of dry DMF was added to a suspension of 6-metho~r-S-(trifluoromethylthio)-l-naphthalenecarboxylic acid (10 g, 40 10 mmoles) in thionyl chloride (100 ml). The suspension was 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 ~nd the mixture was evaporated to dryness. The residue was dissolved in pyridine (100 ml). The sollltion was cooled in an ice bath. Dry N-15 methyl~lycine methyl ester hydrochloride (11.1 g, 79.6 mmoles) was added portion-wise to the cooled solution. The mixture was extracted with ethyl acetate (3 x lS0 ml). The combined extracts were washed with IN aqueous HCI solution, - a saturated aqueous solution of NaHC03 and br;ne. After drying over MgS04, the extract was treated with charcoal, filtered and evaporated to give a product20 identical to that obtained by procedure A of this example.

N-1~6-Methoxy-5-(trifluoromethylthio)-1-naphthalenyl] thioxomethyl]-N-methyl-glycine Methyl Ester (II, R, R and R3 = CH3) N-[[6-Methoxy-5-(trifluoromethylthio~l-naphthaleny]] carbonyl~-2sN-methylglycine methyl ester (2.0 g~, 5.4 mmoles) was dissolved in dry pyridine (40 ml). Phosphorus pentasulfide (2.37 g, 10.7 mmoles) was added to the pyridinesolution. The mixture was heated at reflux for 4 hr and then poured into warm water at 50 to 30 C (caution: evolution of copious quantities of H2S). The mixture was extracted with ethyl acetate. The extract was washed successively 30with 3N aqueous HCI, water, a saturated aqueous solution of NaHCO3, water and brine, dried (MgS04) and concentrated to dryness. The residue was recry-stallized from ethanol-water to give 1.6 g of the title compound; mp 121-123 C;NMR (CDC13) ~ 3.00 (s, 3H), 3.75 (s, 3H), 4.00 (s, 3H), 4.35 Sc 4.5 (d~ 2H), 7.0-8.5 (m, SH).

2~;27 N-[[6-Methoxy-5-(trifluoromethylthio~l-naphthalenyl] thioxomethyl]-N-methyl-glycine (I, Rl and R2 - CH3) Aqueous NaOH (3.41 mL, 2N) was added to a solution of N-~[6-methoxy-5-(trifluorom ethylthio~l-naphthalenyl] thioxom ethyl] -N-m ethylglycine m ethylester tl.375 g, 3.4 mmoles) in 2-methoxyethanol ~20 ml). The solution was stirred at 20-22 C for 4 hr. Water was added and the cloudy mixture was extracted with ethyl acetate. The agueous layer was made acidic ~pH=3) with lN aqueous 10 HCl and extracted with ethyl acetate. The latter extract was washed successiv~
Iy with water and brine, dried (MgSO4) ànd concentrat~d under reduced pressure.
The residue was crystallized from chloroform-hexane to give the title compound (672 mg); mp 168-169 C; NMR (DMSO-d6) ~ 3.0 (s, 3H), 4.0 (s, 3H), 4.6 ~c 5.2 (d, J = 16.5 Hz, 2H), 7.7 (m, 5H); ir (white mineral oil) 2900,1720, 1465 cm 1;
15 uv~max (MeOH) 342 nm ~ 4970), 334 (4800), 230 (46,80û).
This application is a divisional of Canadian Patent Application ~o. 387,991, filed October 15, 1981.

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Claims (4)

The embodiments of the invention in which an exclusive property or privilege is claimed, are defined as follows:

1. A process which comprises reacting a N-[[(6-(lower alkoxy)-5-(trifluoromethylthio)-1-naphthalenyl]-carbonyl]-N-methylglycine lower alkyl ester with phosphorus pentasulfied and converting it into a N-[[(6-lower alkoxy)-5-(tri-fluoromethylthio)-1-naphthalenyl]-thioxomethyl]-N-methylglycine lower alkyl ester.

2. A process which comprises reacting the compound N-[[6-methoxy-5-(trifluoromethylthio)-l-naph-thalenyl]-carbonyl]-N-methylglycine methyl ester with phosphorus pentasulfide and converting it to the compound N-[[6-methoxy-5-(trifluoromethyl-thio)-1-naphthalenyl}-thioxomethyl]-N-methylglycine methyl ester.

3. N-[[6-(lower alkoxy)-5-(trifluoro-methylthio)-1-naphthalenyl]-thioxomethyl]-N-methyl-glycine lower alkyl ester.

4. The compound of claim 3 which is N-[[6-methoxy-5-(trifluoromethylthio)-1-naph-thalenyl]-thioxomethyl]-N-methylglycine methyl ester.