KR890000798B1 - Process for the preparation of n-naphthoylglycine derivatives - Google Patents

Abstract

Title compds. (I)[R1=H, lower alkyl, alkenyl, phenylmethyl; R2=H, lower alkyl; R3=H, lower alkoxy, halo, cyano, nitro, etc.; R4, R5=H, substituted R3 or R4, etc. , useful as a curing agent for diabetes, were prepd.. Thus, a mixt. contg. 14.21g 1-bromo-5(1-methylethenyl)- naphthalene in 140ml diethy ether and ethyl magnesium bromide in 30ml diethyl ether was refluxed, treated with solid CO2, dissolved in diethyl ether, washed with 2N-H2SO4 and 10% NaHCO3 and acidified with 6N-HCl to give 9.7g 5-(1-methylethenyl)-1-naphthalene carboxylic acid.

Description

Method for preparing N-naphthoylglycine derivative

The present invention relates to a method for preparing a therapeutically acceptable salt with an inorganic or organic base of a novel N-naphthoylglycine derivative of the general formula (I) and a compound of the general formula (I) wherein R ² is hydrogen will be :

Wherein R ¹ is hydrogen, lower alkyl, lower alkenyl or phenylmethyl; R ² is hydrogen or lower alkyl; R ³ is selected from the group consisting of hydrogen, lower alkoxy at 6-position of the naphthalene ring or lower alkyl at 4, 5 or 8-position of the naphthalene ring, lower alkoxy, halo, cyano, nitro, trihalomethyl and trihalomethylthio Substituent is selected, and R ⁴ and R ⁵ are each hydrogen; Lower alkyl, lower alkoxy, halo, trihalomethyl, trihalomethylthio, (lower) -alkoxy- (lower) alkoxy, phenyl at different positions, wherein R ³ and R ⁴ are each selected from the 3-7 positions of the naphthalene ring; The methoxy and phenyl rings are substituents selected from the group consisting of phenylmethoxy substituted with lower alkyl, lower alkoxy, halo or trihalomethyl and R ⁵ is hydrogen or R ³ , R ⁴ and R ⁵ are each 4, And a substituent selected from the group consisting of lower alkoxy, halo and trihalomethyl at different positions selected from positions 5 and 6.

The invention also provides N-naphthoylglycine of formula (I), its therapeutically acceptable salts, their use and pharmaceutical compositions thereof.

For years diabetes has been treated with two types of drugs, insulin and oral hypoglycemic agents. These drugs have contributed to hundreds of thousands of people with diabetes by improving their health and extending their lives. However, complications such as neurological disease, kidney disease, retinopathy, cataracts and atherosclerosis have occurred in the life of diabetic patients. These complications are associated with the accumulation of unwanted sorbitol in the tissues of diabetic patients, resulting in high levels of glucose resulting in cataracts of diabetic patients.

In mammals, including humans, the main enzyme for converting hexose to polyols (sorbitol metabolism pathway) is aldose reductase. See J.H. Kinoshita et al., Bioch-em. Biophys. Acta, 158, 472 (1968) and references cited therein] show that aldose reductase can act as a major etiology of galactoseemia cataracts by converting galactose to dulcitol (galititol). Formulations that have been described are described as being able to prevent harmful accumulation of dulcitol in the lens. In addition, in the following text, the correlation between the increase in glucose concentration and the accumulation of unwanted sorbitol in the lens, peripheral nerve infarction and kidney of diabetic animals is described in A. pirie and R. van Heyningen, Exp. Eye Res. , 3,124 (1964): LTChylack JH Kinoshita, Invest Ophthal., 8,401 (1969) and JDWard and RWBaker, Diabetol., 6,531 (1970).

1,3-dioxo-1H-benz [de] isoquinoline-2 (3H) -acetic acid has been reported to be an effective aldose reductase inhibitor [D. Dvornik et al., Science, 182, 1146 (1973). ]. It has been reported to be useful for the treatment of diabetic complications such as diabetic cataracts, neurological diseases, kidney disease and retinopathy. K. Sestanj, N. Simard-Duquesne and D.M. Dvornik, US Pat. No. 3,821,383 (August 8, 1974). Other compounds with similar uses include thioxo-1H-benz [de] -isoquinoline-2 (3H) -acetic acid derivatives (US Pat. No. 4,254,108 (1981.3.3) to K. Ses-tanj) and 1H. -Benz [de] isoquinoline-2 (3H) -acetic acid derivatives (K.Sestanj, US Pat. No. 4,254,108 (1981. 3.3)). (S) -6-Pluoro-2,3-dihydrospiro (4H-1-benzopyran-4,4'-imidazolidine) -2 ', 5'-dione (sorbic) is also known. Another compound that has attracted attention because it has a doze reductase inhibitory action (MJPeterson et al., Metabolism, 28 (Suppl. 1), 456 (1979)). Therefore, these compounds are new important compounds that are close to treating diabetes.

The present invention provides novel N-naphthoylglycine derivatives of general formula (I) which are effective aldose reducing element inhibitors. These novel derivatives are structurally very different from the aldose reductase inhibitors described above. Similar prior art compounds in structure are part of the investigation of the chemical properties of thioacylamino acid groups, such as these compounds, for example by A. Lawson and CESearle, J. Chem. .Soc., 1556 (1957)], N-phenylthioxomethyl-9N-methylglycine. The compounds mentioned last are prepared by thiobenzoylation of several amino acids with (thiobenzoylthio) acetic acid. An important structural difference between these compounds and the derivatization of the present invention is that the substituted aromatic groups on the thion portion of thioamides are different. Thioacylamides are also described in Chem. Abstr., 86, 189582 (1977) for V. I. Cohen et al., Eur. J. Med. Chem. 480 (1976) and Chem. Abstr., 70, 11306a (1969) for von J. Voss and W. Walter, Justus Leibigs Ann. Chem., Abstr., 716, 209 (1968). The thioacyl structures such as Cohen and Bos differ from those of the derivatives of the present invention in that they have at least different types of N-substituents. Another prior art compound that is similar in structure is N-[(1-naphthalenyl) carbonyl] glycine. Chem. Abstr., 61, 4333f (1964) for E. Cioranescu et al., Rev .Chim.Acad.Rep.Populaire Roumaine, 7 (2), 755 (1962)]. Compounds used as chemical intermediates are distinguished from compounds of the invention in that they are amides, not thioamides.

Preferred derivative groups of the present invention are those in which R ¹ is hydrogen, lower alkyl, 2-propenyl or phenylmethyl: R ² is hydrogen or lower alkyl: R ³ is hydrogen, 4 of the lower alkoxy or naphthalene ring at the 6-position of the naphthalene ring; Substituents selected from the group consisting of lower alkyl, lower alkoxy, halo, cyano, nitro and trifluoromethyl at the 5 or 8 position and R ⁴ and R ⁵ are each hydrogen; R ³ and R ⁴ are 3-halo-4-lower alkoxy, 4,6-di (lower alkoxy), 5-halo-6-lower allyl, 5-halo-6-lower alkoxy, 5, 7-dihalo, 5- (trifluoromethyl) -6-lower alkoxy, 5-halo-6-lower alkyl, 5- (trifluoromethylthio) -6-lower alkoxy, 5-halo-6- ( In the group pairs consisting of lower) alkoxy (lower) alkoxy, 5-halo-6- [3- (trifluoromethyl) phenylmethoxy] and 5-halo-6- (4-chlorophenylmethoxy) Or a substituent pair selected and R ⁵ is hydrogen; R ³ , R ⁴ and R ⁵ are 4-lower alkoxy-5-halo-6-lower alkoxy and 4,6-di (lower alkoxy) -5- (trifluoromethyl) groups at different positions of the naphthalene cyclic ring, respectively Or a therapeutically acceptable salt with an organic or inorganic base of a compound of formula (I), which is a substituent selected from among, or a compound of formula (I), wherein R ² is hydrogen.

Another preferred compound group is R ¹ is hydrogen, lower alkyl or phenylmethyl; R ² is hydrogen or lower alkyl; R ³ is 4-halo or 5-halo and R ⁴ and R ⁵ are each hydrogen; R ³ and R ⁴ are naphthalene cyclic 3-halo-4-lower alkoxy, 4,6-di (lower alkoxy), 5-halo-6-lower alkyl, 5-halo-6-lower alkoxy, 5,7- Dihalo, a substituent pair selected from the group pair consisting of 5- (trifluoromethyl) -6-lower alkoxy and 5- (trifluoromethylthio) -6-lower alkoxy and R ⁵ is hydrogen; Organic of a compound of formula (I) wherein R ³ is 4-lower alkoxy, R ⁴ is 5- (trifluoromethyl) and R ⁵ is 6-lower alkoxy, or a compound of formula (I) wherein R ² is hydrogen; or It is a therapeutically acceptable salt with an inorganic base.

Most preferred compound groups are those in which R ¹ is lower alkyl: R ² is hydrogen; R ³ is 5-halo and R ⁴ and R ⁵ are each hydrogen; R ³ and R ⁴ are naphthalene cyclic 3-halo-4-lower alkoxy, 5-halo-6-lower alkoxy, 5- (trifluoromethyl) -6-lower alkoxy and 5- (trifluoromethylthio) Or a substituent pair selected from the group pair consisting of -6-lower alkoxy and R ⁵ is hydrogen; R ³ is 4-lower alkoxy, R ⁴ is 5- (trifluoromethyl) and R ⁵ is 6-lower alkoxy, or a therapeutically acceptable salt with a compound of formula (I) or an organic or inorganic base thereof .

Compounds of formula (I) may be prepared by the process described below. Provided is a method for preventing or controlling diabetes with complications by administering to a diabetic mammal a prophylaxis or reduction of diabetes with complications of a compound of formula (I) or a therapeutically acceptable salt thereof with an organic or inorganic base thereof. do. Complications include neurological disease, kidney disease, retinopathy and cataracts.

A pharmaceutical composition that can be used in the methods described above is prepared by mixing a compound of formula (I) or a therapeutically acceptable salt thereof with an organic or inorganic base thereof with a pharmaceutically acceptable carrier.

Formula (I) compounds of the present invention may exist in isomeric form. More specifically, the intramolecular electron potential is characterized by partial double bonds in the carbon-nitrogen bonds of thioamide groups. This partial double bond feature limits the rotation at the carbon nitrogen bonds to obtain sus and trans isomers and further restricts rotation due to the large adjacent groups. Interconversions between isomers are possible, depending on their physical influences. As evidenced by their physical properties, thermodynamically more stable isomers exist in the form of crystalline compounds and are the major isomers in equilibrium solutions. Also, more stable isomers are more pharmacologically active. Less stable isomers can be separated from more stable isomers by high performance liquid chromatography or thin layer chromatography. Isomeric forms are also included within the scope of the present invention. For convenience, the compounds of the present invention comprising isomeric forms are referred to as compounds of formula (I).

As used herein, the term "lower alkyl" refers to a straight chain alkyl radical containing 1 to 4 carbon atoms or to a branched alkyl radical containing 3 or 4 carbon atoms, for example methyl, ethyl, propyl, 1 -Methylethyl, butyl, 2-methylpropyl and 1,1-dimethylethyl. Preferred lower alkyl radicals contain 1 to 3 carbon atoms.

As used herein, the term "lower alkenyl" refers to a straight chain alkenyl containing 2 to 6 carbon atoms or to a branched alkenyl radical containing 4 to 6 carbon atoms, for example ethenyl, 2- Propenyl, 2-methyl-2-propenyl and 2-ethyl-3-butenyl. Preferred lower alkenyl radicals contain 2 to 3 carbon atoms.

As used herein, the term `` lower alkoxy '' means a straight chain alkoxy radical containing 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms, or a branched alkoxy radical containing 3 or 4 carbon atoms, Methoxy, ethoxy, 1-methylethoxy, butoxy, and hexaneoxy, for example.

The term ″ halo ″ as used herein refers to halo radicals and includes fluoro, chloro, bromo and iodo.

As used herein, the term ″ ar ″ means an aromatic radical containing at least one benzene ring. Preferred aromatic radicals are phenyl.

Formula (I) compounds wherein R ² is hydrogen form salts with suitable therapeutically acceptable inorganic and organic bases. These salts have the same activity as the parent acid and are included within the scope of the present invention. Neutralization of the acids mentioned with the appropriate inorganic or organic base converts the acids to the corresponding therapeutically acceptable salts in very excellent yields. Salts are usually administered by the same method as the parent acid compound. Suitable inorganic bases for forming these salts are, for example, therapeutically acceptable alkali or earth metals such as hydroxides, carbonates or bicarbonates such as sodium, potassium, magnesium, calcium and the like. Suitable organic bases include the following amines: benzylamine: lower mono-, di- and trialkylamines containing up to 3 carbon atoms of alkyl radicals, for example methylamine, dimethylamine, trimethylamine, ethylamine, Mono-, di- and trialkanolamines having alkanol radicals containing up to 3 carbon atoms, such as di- and triethylamine, methylethylamine, for example mono-, di- and triethanolamines, carbon atoms 6 Up to 6 alkylene-diamines, for example hexamethylenediamine: cyclic saturated or unsaturated bases containing up to 6 carbon atoms, for example pyrrolidine, piperidine, morpholine, piperazine and their N-alkyls And N-hydroxyalkyl derivatives such as N-methyl-morpholine and N (2-hydroxyethyl) piperidine: and pyridine, and also the corresponding quaternary salts such as tetraalkyl (eg , Tetramethyl), alkyl-alkanols (e.g., Methyl-triethanol and trimethyl-monoethanol) and cyclic ammonium salts such as N-methylpyridinium, N-methyl-N- (2-hydroxyethyl) -morpholinium, N, N-dimethylmorpholinium, Mention may be made of N-methyl-N- (2-hydroxyethyl) -morpholinium, N, N-dimethyl piperidinium salts, which are characterized by good solubility in water. In principle, however, any physiologically acceptable ammonium salt can be used. The reaction for conversion to salt can be carried out by various methods known in the art. For example, in the case of inorganic salts, it is preferable to dissolve the acid of general formula (I) in water containing at least 1 equivalent of hydroxide, carbonate or bicarbonate corresponding to the desired inorganic salt. It is advantageous to carry out the reaction in the presence of water in an inert organic solvent which can be miscible with water, for example ethanol, dioxane. For example, the use of sodium hydroxide, sodium carbonate or sodium bicarbonate produces a sodium salt solution. Evaporation of the solution or addition of a more polar water-miscible solvent such as lower alkanols such as butanol or lower alkanones such as ethyl methyl ketone yields the desired solid inorganic salt.

To prepare the amine salts, the acid compounds of general formula (I) are dissolved in suitable solvents of moderate or low polarity, for example ethanol, methanol, ethyl acetate, diethyl ether and benzene. Next, at least one equivalent of the amine corresponding to the desired cation is added to the solution. If the resulting salt does not precipitate, low polar miscible diluents such as benzene or petroleum ether can be added or evaporated to obtain in solid form. If the amine is relatively volatile, evaporation can easily remove excess material. It is preferable to use almost equivalent in amines with less volatility.

Salts whose cations are quaternary ammonium are prepared by mixing the acid of formula (I) with an equivalent aqueous solution of a quaternary ammonium hydroxide followed by evaporation of water.

Addition salts of the compounds of the present invention with pharmaceutically acceptable organic or inorganic bases may be used alone or in combination with the pharmaceutically acceptable excipients described below in a dosage form such as capsules or tablets for mammals such as humans, cattle or rabbits. Can be administered. It is advantageous to administer orally the compounds of the present invention. However, it should not be understood that the method of administering the active ingredient of the present invention is limited to a particular dosage method. For example, the compound may be topically administered directly to the eye in a drop formulation of sterile buffered (preferably pH 7.2 to 7.6) ophthalmic solution. It may also be administered orally in solid formulations containing excipients such as starch, lactose, certain types of clays and the like. It may also be administered orally as a solution or injected parenterally. For parenteral administration it may be used in sterile solution formulations containing a pharmaceutically acceptable buffer and preferably having a pH of 7.2 to 7.6.

The therapeutic dosage of the present invention depends on the method of administration and the particular compound selected. It also depends on the specific patient being treated. In general, treatment begins with a very small amount below the optimal dose of the compound, increasing the dose in small amounts until the effect is achieved. In general, the compounds of the present invention are most preferably administered at a concentration that generally yields effective results without causing adverse side effects. For topical administration, 0.05-0.2% solution may be instilled in the eye. The number of drops may vary from one drop every two to three days to once a day, depending on the patient being treated. For oral or parenteral administration, a dosage range of about 0.1 mg to about 200 mg per kg body weight is preferred, but can be varied as described above. However, the dosage range of about 0.5 to 30 mg / kg body weight per day is most satisfactory.

Unit dose formulations, such as capsules, tablets, pills, and the like, may contain from about 5.0 mg to about 250 mg of the active ingredient of the present invention, preferably with a specific amount of pharmaceutical carrier. Thus, oral dosage capsules may contain from about 0.5 mg to about 250 mg of the active ingredient of the present invention alone or as a mixture with a pharmaceutical diluent. Effervescent or non-foamable tablets may contain conventional pharmaceutical carriers with from about 5.0 mg to about 250 mg of the active ingredient of the present invention. Thus tablets that can be coated and are foamable or non-foamable can be prepared by known methods. Inert carriers or diluents such as magnesium carbonate or lactose can be used in combination with conventional disintegrants such as magnesium stearate.

Syrups or elixirs for oral administration from water-soluble salts, for example sodium N-[[5- (trifluoromethyl) -6-methoxy-1-naphthalenyl] thioxomethyl] -4-methylglycinate It may be prepared and advantageously contains glycerol and ethyl alcohol as solvent or preservative.

The compounds of formula (I) or therapeutically acceptable salts thereof may also be used in combination with insulin or oral hypoglycemic agents to obtain a beneficial effect in the treatment of diabetes. In this case, commercial insulin preparations or oral hypoglycemic agents such as acetohexamide, chloropropamide, tolazamide, tolbutamide and phenformin are suitable. The compound of formula (I) or a therapeutically acceptable salt thereof may be administered sequentially or simultaneously with insulin or an oral hypoglycemic agent. Appropriate methods of administration, composition and dosage of insulin preparations or oral hypoglycemic agents are described in medical textbooks (Physicians' Desk Referenc-e 34ed., Medical Economice Co., Oradell, N.J.U.S.A., 1980). In combination administration, the compound of formula (I) or a therapeutically acceptable salt thereof is administered as described above. The compound of formula (I) or a therapeutically acceptable salt thereof may be administered in the form of a pharmaceutical composition containing an effective amount of each agent together with an oral hypoglycemic agent.

The aldose reductase inhibitory effects of the compounds of formula (I) and their pharmaceutically acceptable salts with organic or inorganic bases are described in S. Hayman and J. H. Kinoshita, J. Biol. Chem. 240,877 (1965)] may be used using in vitro tests similar to those described. The present invention is a modification of the method of Heyman and Kinoshita by eliminating the final chromatographic step in enzyme preparation from bovine lens.

The following results were obtained by evaluating the above general formula (I) compounds by the above in vitro test.

Aldose reductase inhibitory activity of the compounds of the present invention and concentrations for the prevention, reduction and alleviation of diabetic complications of the compounds are demonstrated by experiments using galactosemia rats [Dvornik supra]. These experiments are illustrated below by describing only the general musks related to this: (a) Six males of 50-70 g of Sprag-Dawley rats are used as one group and four or more groups are used. The first group, the control group, received a mixture of 20% (w / w%) concentrations of laboratory food (purine for rodents, Purina) and glucose. Untreated galactosemia groups were fed the same food, replacing galactose with glucose. The third group is fed a food prepared by mixing a certain amount of test compound with a galactose-containing diet. The concentration of galactose in the diet of the treated group was the same as that of the untreated galactosemia group.

(b) After four days the animal is decapitated and killed. Remove the eyeball and make a hole with a razor. The liberated lens is carefully transferred onto the filter paper and weighed. The sciatic nerve is cut as completely as possible to weigh it. Both tissues are frozen and stored for two weeks before dulcitol analysis.

(c) The polyol measurement is carried out by a method of modification of the method described in M. Kramer and L. Cosyns, Clin. Biochem., 2,373 (1969). Only two non-critical reagents were changed: (i) the wash mixture was a 5% (w / v) aqueous trichloroacetic acid solution and (ii) the stock solution was dissolved 25 mg of dolitol in 100 ml aqueous trichloroacetic acid solution. [Note: The polyol measurement is obtained by subtracting the mean value measured in the tissue of the corresponding rat from the individual value measured in the glucose ingested rat tissue per test].

As a result of the following table, the compounds of the present invention were found to reduce the accumulation of dulcitol in the lens and sciatic nerves of rats fed galactose. The values described in sections L and N represent the percent reduction in dulcitol accumulation in the tissues of the lens and sciatic nerve, respectively, compared to treated rats compared to untreated rats.

The preparation method of the compound of general formula (I) is represented by the following scheme, wherein R ¹ , R ³ , R ⁴ and R ⁵ are as described above and COOR is an ester group, for example lower alkyl or ar (lower). As alkyl ester, R is lower alkyl or ar (lower) alkyl:

More specifically, the compound of general formula (I) is prepared as follows: (a) General in which R ¹ , R ³ , R ⁴ and R ⁵ are as defined above and R is lower alkyl or ar (lower) alkyl. The amidoester of formula (II) is reacted with phosphorus pentasulfide to give thioxoesters of the general formula (III) wherein R ¹ , R ³ , R ⁴ , R ⁵ and R are as defined above: (b) R ¹ , R ³ , R ⁴ , R ⁵ and R hydrolyze the thioxoester of general formula (III) as defined above so that R ¹ , R ³ , R ⁴ and R ⁵ are as defined above and R ² groups To yield the corresponding compound of formula (I) which is hydrogen; (c) R ¹ , R ³ , R ⁴ , R ⁵ and R hydrolyze the amidoesters of formula (II) as defined above so that R ¹ , R ³ , R ⁴ and R ⁵ are as defined above. After obtaining the corresponding amido acid of general formula (IV), the obtained compound is reacted with phosphorus pentasulfide to give general formula (I) wherein R ¹ , R ³ , R ⁴ and R ⁵ are as defined above and R ² is hydrogen To yield the corresponding compound.

In the above method (a), when R of the general formula (III) compound is lower alkyl, the thioxo ester of the general formula (III) includes a compound of the corresponding general formula (I) wherein R ² is lower alkyl. . In the following discussion of the method, for convenience or clarity, the latter general formula (I) compounds will be discussed in the preparation of general formula (III) compounds.

More specifically, the starting material of formula (II) can be prepared by coupling the naphthalenecarboxylic acid of formula (V) with the amino acid ester of formula (VI):

Wherein R, R ¹ , R ³ , R ⁴ and R ⁵ are as defined above. Compounds of formulas (V) and (VI) are known compounds or can be prepared by known methods. See, eg, ″ Elsevier's Encyclopaedia of Organic Chemistry ″, F. Radt, Ed., Series III, Vol 12 B, Elsevier Publishing Co., Amsterdam, 1953, PP 3965-4473]. Various methods for producing naphthalenecarboxylic acid are described in Examples 1,1a to 1k and 61 to 63 described later. The coupling reaction between naphthalene carboxylic acid (V) and amino acid ester (VI) is preferably carried out by the "carboxyl activation" coupling method. A description of carboxyl-active groups is described in the general textbook on fabtide chemistry [see, eg, KD Kopple, ″ Peptides and Amino Acids, ″ WABenjamin, Inc., New York, 1966, PP, 45-51, and E. Schroder and K. Lubke, ″ The Peptides ″: Vol. 1, Academic Preess, New York, 1965, PP77-128]. Examples of active forms of terminal carboxyl are 0-acylureas made from acid chloride, acid bromide, anhydride, azide, active ester, or dialkylcarbodiimide. Preferred active forms of carboxyl are acid chlorides or 1-benzotriazolyl, 2,4,5-trichlorophenyl or succinimido active esters.

Returning to the schematic diagram, the reaction of the amido ester of general formula (II) with about 2 to 5 molar equivalents of phosphorus sulfide in an inert solvent such as xylene or toluene under anhydrous conditions gives Oxoester is obtained. This reaction is conveniently carried out for 20 minutes to 4 hours in the temperature range of 80 to 150 ℃. Preferably this reaction is carried out in the presence of an organic base such as N-ethyl morpholine, triethylamine or pyridine.

The thioxoester of general formula (III) is then hydrolyzed with a hydrolysis agent to obtain the corresponding product of general formula (I) wherein R ² is hydrogen. In general, this conversion reaction is most conveniently carried out using a base as a hydrolytic agent. After hydrolysis is carried out in the presence of sufficient water, the reaction mixture is acidified to give the desired acid. However, the hydrolysis method, which is the method of the present invention, should not be understood as being limited to basic hydrolysis, which is hydrolyzed under acidic conditions and other modifications, for example, treatment with lithium iodide in collidine [LFFieser and M .Fieser, ″ Reagents for Organic Synthesis ″, John Wiley and Sons, Inc., New York, 1969, pp. 615-617. Hydrolysis under acidic conditions is preferred when the ester is a tertiary butyl ester.

In basic hydrolysis, a preferred aspect is to hydrolyze the ester by reacting the ester with a strong base, such as sodium hydroxide or potassium hydroxide, in the presence of sufficient water. This hydrolysis is carried out using a suitable solvent such as methanol, ethanol or 2-methoxyethanol. The reaction mixture is maintained until hydrolysis at a temperature of about 25-100 ° C. or at the reflux temperature of the solvent used. Usually, 10 minutes to 6 hours is sufficient for hydrolysis. The reaction mixture is then acidified with an acid such as acetic acid, hydrochloric acid or sulfuric acid to liberate the free acid.

Alternatively, the amidoester of general formula (II) is hydrolyzed under the same conditions as described above so that R ¹ , R ³ , R ⁴ and R ⁵ are equivalent to the amido acid of the corresponding general formula (IV) as defined above. Can be obtained. The corresponding compound of formula (I) wherein Amido acid of formula (IV) is reacted with phosphorus pentasulfide by the method described above and then R ¹ , R ³ , R ⁴ and R ⁵ are as defined above and R ² is hydrogen. To obtain. There is a need to decompose the reaction mixture in water in a standard one-step reaction which completes the operation with the pentasulfide reaction mixture. This reacts the carboxyl group with phosphorus pentasulfide to convert the corresponding thio acid present in the reaction mixture to the desired carboxylic acid.

Amido acids of general formula (IV) may be prepared by the above process by reacting a suitable naphthalene carboxylic acid chloride with a suitable amino acid corresponding to an amino acid ester of general formula (VI) in the presence of a base (proton acceptor). This method has been used for the preparation of N-[(1-naphthalenyl) carbonyl] glycine [Chem. Abstr., 61, 4333f (1964) for E. Ciora-nescu, et al., Rev. Chim., Acad., Rep. Populaire Roumaine, 7 (2), 4755 (1962)]. However, the known method for producing N-[(1-naphthalenyl) carbonyl] glycine is worse than the method of the present invention in yield.

Of interest to the present invention are the therapeutically acceptable salts or aldose reductase inhibition of certain amidoesters of formula (II) with certain amido acids of formula (IV) or organic or inorganic bases thereof: It is an effect.

Wherein R ¹ is lower alkyl, lower alkenyl or phenylmethyl: R ³ is a group consisting of lower alkyl, lower alkoxy, halo, cyano, nitro and trihalomethyl at the 4,5 or 8 position of the naphthalene ring And a substituent selected from R ⁴ and R ⁵ are each hydrogen; R ³ and R ⁴ are each lower alkyl, lower alkoxy, halo, trihalomethyl, trihalomethylthio, (lower) -alkoxy (lower) alkoxy, phenylme at different positions selected from the 3-7 positions of naphthalene, respectively; Methoxy and phenyl ring are substituents selected from the group consisting of lower alkyl, lower alkoxy, halo or phenylmethoxy substituted with trihalomethyl and R ⁵ is hydrogen; Or R ³ , R ⁴ and R ⁵ are each a substituent selected from the group consisting of lower alkoxy, halo and trihalomethyl at different positions selected from the 4, 5 and 6 positions of the naphthalene ring and R is hydrogen or lower alkyl.

For example, the in vitro test above was performed on the amido acid described in Example 60 to yield the following results: N-[(5-bromo-1-naphthalenyl) carbonyl] -N-methyl Glycine (10 ^-5 , 64%: 10 ^-6 , 21%) and N-[[(5- (trifluoromethyl) -6-methoxy-1-naphthalenyl] carbonyl] N-methylglycine ( 10 ^-5 , 94%: 10 ^-6 , 93%: 10 ^-7 , 60%). Thus, the therapeutically acceptable salts of the latter amidoesters, amido acids and amido acids with organic or inorganic bases are It is included in the night of invention.

The following examples further illustrate the invention.

Example 1

5- (1-Methylethenyl) -1-naphthalenecarboxylic acid (compound of formula (V) wherein R ³ = 5-CH ₂ = (CCH ₃ ) and R ⁴ and R ⁵ = H)

1-bromo-5- (1-methylethenyl) -naphthalene [14.21 g, WFShort and H. Wamg, J. Chem. Soc, 991 in diethyl ether (140 mL) at 0 ° C. under nitrogen atmosphere. 1950) is added dropwise to a mixture of ethyl magnesium bromide (prepared from 2.94 g magnesium and 4.29 mL ethyl bromide) in diethyl ether (30 mL). The mixture is stirred at 20 ° C. for 18 hours and then heated to reflux for 1 hour. The cooled solution is poured onto excess solid carbon dioxide.

The mixture is dissolved in diethyl ether. The resulting solution is washed with 2N H ₂ SO ₄ aqueous solution, brine and 10% NaHCO ₃ aqueous solution (4 ×). The basic washes are combined and acidified (pH ₃ ) with 6N aqueous HCl solution. The resulting solids were collected, washed with water and dried to give 9.7 g of the title compound:

Melting point 138-140 ° C

NMR (CDCl ₃ ) δ 2.15 (s, 3H), 5.0 and 5.38 (2s, 2H), 8.0 (m, 6H), 10.75 (s, 1H).

Example 1

5- (1-Methylethyl) -1-naphthalenecarboxylic acid (compound of formula (V) wherein R ³ = 5- (CH ₃ ) ₂ CH and R ⁴ and R ⁵ = H)

5- (1-methylethenyl) -1-naphthalenecarboxylic acid (4.36 g, compound of Example 1) dissolved in ethanol (150 mL) was hydrogenated at 20 ° C using 5% palladium on charcoal as a catalyst. Absorption of hydrogen is complete after 3 hours. The catalyst is filtered off. Evaporate the filtrate to afford the title compound.

Melting point 148 to 150 ° C

NMR (CDCl ₃ ) δ 1.4 (d, J = 7 Hz, 6H), 3.75 (7neutral, J = 7 Hz, 1H), 8.0 (m, 6H), 10.1 (s, 1H).

Example 1b

5-Bromo-6-methoxy-1-naphthalenecarboxylic acid (compound of formula (V) wherein R ³ = 5-Br, R ⁴ = 6-CH ₃ O and R ⁵ = H)

A solution of bromine (2.49 mL, 45 mmol) in glacial acetic acid (50 mL) was added to 6-methoxy-1-naphthalenecarboxylic acid [8.9 g, 44 mmol, CCPrice et al., T. Am. Chem in glacial acetic acid (300 mL). . Soc., Described in 69 2261 (1947)] and added to the stirring solution and cooled in an ice bath. The resulting precipitates are collected, washed with acetic acid and washed with water. Crystallization of the collected precipitate with glacial acetic acid gives the title compound:

Melting point 262-264 ° C

NMR (DMSO-d ₆ ) δ 3.96 (s, 3H), 7.5-7.8 (m, 3H), 7.95 (d, 1H), 8.25 (d, 1H), 8.82 (d, 1H).

Example 1c

5-Bromo-6-methyl-1-naphthalenecarboxylic acid (compound of formula (V) wherein R ³ = 5-Br, R ⁴ = 6-CH ₃ and R ⁵ = H)

According to the method of Example 1b, with the exception that 6-methyl-1-naphthalenecarboxylic acid instead of 6-methoxy-1-naphthalenecarboxylic acid [CCPrice dt al., J. Am. Chem. Soc., 63, 1857 (1941) Using the equivalent amount to prepare the title compound:

Melting point 253 to 255 ° C. [after crystallization with ethanol-methanol (3: 1)].

NMR (DMSO-d ₆ ) δ 2.6 (s, 3H), 8.0 (m, 5H), 10.5 (Broad, 1H).

Example 1d

3-Chloro-4-methoxy-1-naphthalenecarboxylic acid (compound of formula (V) wherein R ³ = 3-Cl, R ⁴ = 4-CH ₃ O and R ⁵ = H)

10% hydroxide of 3-chloro-4-methoxy-1-naphthalenecarboxaldehyde [15.5 g, 70.2 mmol, described in AJA blewhite and KRH WOoldidge, J. Chem, Soc. (C), 2488 (1967)] To a suspension of sodium (16.9 g sodium hydroxide in 170 ml water) and silver oxide in dioxane (100 ml). The mixture is stirred and heated at 80 ° C. for 7 hours. The precipitate is filtered off through diatomaceous earth (sold under the trademark Celite). The clear filtrate is evaporated to dryness. The residue is dissolved in water. The solution is acidified and the resulting precipitate is separated by filtration. The precipitate is dissolved in ethyl acetate. The resulting solution is extracted with saturated sodium bicarbonate solution. The aqueous extracts are combined and acidified. The resulting precipitate is filtered off and recrystallized from ethanol-water to afford the title compound:

Melting point 187-189 ° C

NMR (DMSO-d ₆ ) δ 4.0 (s, 3H), 8.15 (m, 5H), 13.3 (Broad, 1H): IR (Newsol *) 2900, 1700, 1260, 1160 Cm- ¹ :

UVλ max (EtOH) 303 (ε 7,400), 231 (56,300):

Elemental analysis

Calculated Value: C; 60.90%, H; 3.83%

Found: C; 60.71%, H; 3.87%

* Newzole is a trademark of colorless mineral oil

Example 1e

5,7-Dichloro-1-naphthalenecarboxylic acid (R ³ = 5-Cl, R ⁴ = 7-Cl and R ⁵ = N)

Sulfuryl chloride (36.8 g, 273 mmol) is added dropwise at 20-22 ° C. to a stirred suspension of benz [cd] indole-2 (1H) -one (20 g, 119 mmol) in glacial acetic acid (275 mL). The mixture is heated for 1.5 hours, cooled and filtered. The solids were collected, washed with glacial acetic acid and recrystallized with toluene to give 6,8-dichloro-benz [cd] indole-2 (1H) -one [melting point 265 ° C., YT Rozhinskii, Zhur. Org. Khim., 8, 2388 (1972). The mixture obtained above (14 g, 58.8 mmol) in 2% aqueous sodium hydroxide solution was refluxed for 4 hours. The mixture is cooled, mixed with sodium nitrite (3.8 g, 55 mmol) and added dropwise to a cold (0-5 ° C.) solution of concentrated equivalent (45 mL) in water (180 mL). Sodium bromide is added and the diazonium salt precipitates, which is collected by filtration and added to a solution of sodium hypophosphite (39.2 g, NaH ₂ PO ₂ , H ₂ O) in water (100 mL) under wet (danger if dry). The mixture is stirred at 20-22 ° C. for 48 hours. The resulting solid is collected by filtration and suspended in saturated sodium bicarbonate (300 mL). Insoluble material is filtered off and resuspended in hot saturated sodium bicarbonate (200 mL). The suspension is filtered and the filtrate is cooled. Sodium salt precipitates of the resulting product are collected by filtration. Free acid is prepared by suspending sodium salt in water and acidifying the suspension. Acidification of the filtrate of sodium salt produces more product. Combine the harvest and recrystallize with ethanol to give 5.8 g of the title compound:

Melting Point 253 ~ 254 ℃

NMR (DMSO-d ₆ ) δ 8.3 (m, 5H), 10.6 (Broad, 1H):

UVλ max (EtOH) 333 nm (ε 2,300), 298 (7,000), 230 (53,300)

Example 1f

5-Udo-6-methoxy-1-naphthalenecarboxylic acid (compound of formula (V) wherein R ³ = 5-I, R ⁴ = 6-CH ₃ O, and R ⁵ = H)

Iodine (7.80 mg) and iodic acid (2.78 g) were added to 6-methoxy-1-naphthalenecarboxylic acid methyl ester [15 g, 69.4 mmol, CCPrice et al. In 80% acetic acid (110 mL) and 98% sulfuric acid (0.97 mL). , J. Amer. Chem. Soc. 69,2261 (1947)]. The solution is heated at 50 ° C. for 5 hours, cooled and poured into water (100 mL). Sodium sulfate was added to decompose unreacted iodine, and the precipitates were collected, washed with water and recrystallized with ethanol to give the methyl ester of the corresponding title compound: melting point 98-99 ° C .: NMR (CDCl ₃ ) δ 3.95 (s, 3H ), 4.00 (s, 3H), 8.00 (m, 5H). A mixture of the latter ester (7.1 g, 21 mmol), 10% aqueous sodium hydroxide solution (35 mL) and methanol (19.5 mL) was heated to reflux for 1 hour. The solution is cooled to ice bath temperature and acidified with 1N aqueous hydrochloric acid solution. The resulting precipitates were collected, washed with water and dried under reduced pressure over phosphorus pentoxide to afford 7 g of the title compound: Melting point 259-261 ° C .: NMR (DMSO-d ₆ ) δ 4.0 (s, 3H), 8.15 (m, 5H), 1056 (Broad, 1H).

Example 1g

5-Cyano-6-methoxy-1-naphthalenecarboxylic acid (compound of formula (V) wherein R ³ = 5-CN, R ⁴ = 6-CH ₃ O, and R ⁵ = H)

A solution of bromine (26.6 g, 0.167 moles) in glacial acetic acid (25 mL) is added dropwise to a cold suspension of 6-methoxy-1-naphthalenecarboxylic acid methyl ester (30 g, 0.139 moles) in glacial acetic acid (2.75 mL). The precipitates were collected, washed with water and crystallized from ethanol to give 33.3 g of 5-bromo-6-methoxy-1 -naphthalenecarboxylic acid methyl ester: melting point 119 DEG C: NMR (CDCl ₃ ) δ 3.97 (s, 3H), 4.03 (s, 3H), 7.35 (d, J = 9.25Hz, 1H), 7.4 (m, 1H), 8.05 (d, J-6.75Hz, 1H), 8.45 (d, J = 8.25Hz, 1H), 8.9 (d, J = 9.25, 1 H). Cu ₂ (CN) ₂ .H ₂ O (3.4 g, 17 mmol) and the latter ester (10.1 g, 34 mmol) in distilled dimethylformamide (75 mL) containing 15 drops of pyridine for 5 hours at 180 ° C. Heat. The hot mixture is poured into a mixture of ice (50 g) and concentrated NH ₄ 0H (5 mL). The resulting precipitate was collected, washed with water, dried and recrystallized with chloroform-ethyl acetate to give 5.6 g of 5-cyano-6-methoxy-1-naphthalenecarboxylic acid methyl ester: Melting point 210-211 ° C. NMR (CDCl ₃ ) δ 3.95 (s, 3H), 4.15 (s, 3H). To a stirred solution of the latter ester (5.95 g, 24.66 mmol) in 2-methoxyethanol (100 mL) was added 4N NaOH aqueous solution (12.3 mL) at 20-22 ° C. The reaction mixture is stirred at 20-22 ° C. for 60 hours, diluted with water, cooled to 0 ° C. and acidified with 1N aqueous CH1 solution. The precipitates are collected and dried to yield 5.6 g of the title compound:

Melting Point:> 290 ℃

NMR (DMSO-d ₆ ) δ 4.1 (s, 3H), 8.1 (m, 5H)

Example 1h

5- (Trifluoromethyl) -6-methoxy-1-naphthalenecarboxylic acid (R ³ = 5-CF ₃ , R = 6 ⁴ -CH ₃ O, R ⁵ = H compound of formula (V) )

5-urido-6-methoxy-1-naphthalenecarboxylic acid methyl ester (10.26 g, 30 mmol, described in Example 1f), trifluoromethyl iodide (12 g, 61.2 mmol), freshly prepared copper powder ( 5.7 g, RQ Brewster and T. Groening. "Organic Synthesis", Coll. Vol. II.Prepared according to the method of John Wiley and Sons, New York, NY, USA, 1948, P. 445) and pyridine (45 ml) Is added to a stainless steel autoclave. The vessel is shaken and heated at 120 ° C. for 20 hours and then cooled to room temperature. The mixture is diluted with diethylether-ethyl acetate (1: 1). Insoluble material is filtered off. The filtrate is washed with 1N aqueous HCl solution, water and dried (MgSO ₄ ). The solvent is removed under reduced pressure. The residue is crystallized with ethanol to give 6.4 g of 5- (trifluoromethyl) -6-methoxy-1-naphthalenecarboxylic acid methyl ester: melting point 79 to 80 ° C .: NMR (CDCl ₃ ) δ 3.95 (s, 6H), 8.00 (m, 5H). The mixture of the obtained ester (6.3 g, 27 mmol), 1N aqueous NaOH solution (34.12 mL) and methanol (100 mL) was stirred at 20 to 22 ° C. for 4 hours.

The mixture is adjusted to pH 7 with 1N HCl aqueous solution, then the mixture is distilled to remove methanol and the concentrated mixture is acidified (pH 2) with 1N HCl aqueous solution. The resulting precipitate is collected and dried to give 6 g of the title compound:

Melting point 218-219 ° C

NMR (DMSO-d ₆ ) δ 4.0 (s, 3H), 8.3 (m, 5H), 10.6 (Broad, 1H).

Example 1i

5-Bromo-6- [3- (trifluoromethyl) phenylmethoxy] -1-naphthalenecarboxylic acid- [R ³ = 5-Br, R ⁴ = 6-[(3-CF ₃ C ₆ H ₄ O) -CH ₂ O] and a compound of formula (V) wherein R ⁵ = H]

A mixture of 5-bromo-6-methoxy-1-naphthalenecarboxylic acid (33.35 g, 0.11 mmol, described in Example 1b) in glacial acetic acid (460 mL) and 47% aqueous HBr solution (417 mL) was refluxed for 9 hours. Heat. The resulting precipitates are collected, washed with water and dried under reduced pressure over P ₂ O ₅ . The precipitate was recrystallized from ethanol-water to give 21.45 g of 5-bromo-6-hydroxy-1-naphthalenecarboxylic acid: melting point> 225 ° C: NMR (DMSO-d ₆ ) δ 8.0 (m, 5H), 11.0 ( Broad, 1H), 12.6 (Broad, 1H). The acid (1.2 g, 4.5 mmol) obtained above is suspended in anhydrous dimethylformamide (DMF, 25 mL). Sodium hydride (0.43 g, 9.0 mmol, 50% mineral oil suspension) is added in small portions to the stirred suspension. Stirring is continued until hydrogen evolution stops. A solution of 3- (trifluoromethyl) -phenylmethyl chloride (2.63 g, 13.5 mmol) in anhydrous DMF (5 mL) is added dropwise and the mixture is heated at 50-60 ° C. for 1 hour. The solvent is evaporated to dryness under reduced pressure. The residue is triturated with water. The solid is filtered off and separated from water. The collected solids were washed with hexane to remove residual mineral oil and recrystallized from ethanol-water to 1.7 g of 5-bromo-6-[(3-trifluoromethyl) phenylmethoxy] -1-naphthalenecarboxylic acid, 3-trifluoro Methyl ester is obtained: melting point 144-115 ° C., IR (CHCl ₃ ) 1.715 cm ⁻¹

The mixture of the above obtained ester (1.7 g, 2.9 mmol), methanol (20 mL) and 1N aqueous NaOH solution (4 mL) is stirred at 20 to 22 ° C for 24 hours. Further 1N NaOH aqueous solution is added and the mixture is stirred at 40 ° C. for 3 hours. Evaporate the solvent. The residue is dissolved in water and the solution is acidified. The resulting precipitate was collected, washed with water, dried and recrystallized with ethanol to yield 1.0 g of the title compound:

Melting Point: 229 ~ 230 ℃

NMR (DMSO-d ₆ ) δ 5.5 (s, 2H), 8.1 (m, 9H), 10.5 (Broad, 1H).

According to the method of Example 1i, except that 5-bromo-6- (4-chlorophenylmethoxy) -1- when the equivalent of 4-chlorophenylmethyl chloride is used instead of 3- (trifluoromethyl) phenylmethyl chloride Naphthalenecarboxylic acid is obtained.

NMR (DMSO-d ₆ ) δ 5.4 (s, 2H), 7.7 (m, 9H), 11.0 (Broad, 1H).

Example 1j

5- (trifluoromethyl) -1-naphthalenecarboxylic acid (compound of formula (V) wherein R ³ = 5-CF ₃ and R ⁴ and R ⁵ = H)

5-iodo-1-naphthalenecarboxylic acid methyl ester [8.8 g, 28 mmol, described in C. Seer and R. Schol, Justus Leibigs Amm. Chem., 398, 82 (1913)], trifluoro methyl iodide (12 g, 61.2 mmol), freshly prepared copper powder (5.7 g, RQ Brewster and T. Groening, "Organic Synthesis", Coll. Vol. II. John Wiley and Sons, New York.NY, USA, 1948, P. Prepared according to the method of 445) and pyridine (45 mL) is placed in a stainless steel autoclave. The vessel is shaken and heated at 130 ° C. for 24 hours to cool to room temperature.

The mixture is filtered to remove insoluble matters. The filtrate is washed with 1N aqueous CH1 solution, water and brine, dried (MgSO ₄ ) and concentrated to dryness. Crystallization of the residue with methanol yields 4.3 g of 5- (trifluoromethyl) -1-naphthalenecarboxylic acid methyl ester. NMR (CDCl ₃ ) δ 4.0 (s, 3H), 8.1 (m. 6H).

The ester (4.25 g, 16.72 mmol) is suspended in methanol (100 mL). To the suspension is added 2N aqueous NaOH solution (16.72 mL, 2 equiv). The mixture is stirred at 20-22 ° C. for 18 hours. The resulting clear solution was adjusted to pH 8 with 1N HCl aqueous solution and concentrated under reduced pressure. The concentrate is adjusted to pH 3 with 1N HCl aqueous solution. The resulting precipitates are collected, washed with water and dried under reduced pressure to afford the title compound:

Melting point 206-208 degreeC

Example 2

N-[(5-bromo-1-naphthalenyl) carbonyl] -N-methylglycine methyl ester (R ¹ and R = CH ₃ , R ³ = 5-Br and R ⁴ and R ⁵ = H Compound of general formula (II))

Method A:

The amount of anhydrous DMF catalyst (5 drops) was calculated from the starting material of formula (V) in thionyl chloride (100 mL), namely 5-bromo-1-naphthalenecarboxylic acid [10 g, 39.8 mmol, WFShort and H. Wang, J. Chem. Soc., Described in 990 (1950). The suspension is carefully heated to reflux (attention: violent reactions may occur). The mixture is refluxed for 20 minutes. The mixture is evaporated to dryness. Toluene is added to the solid residue and the mixture is evaporated to dryness. The residue is dissolved in pyridine (100 mL). The solution is cooled in an ice bath. Anhydrous N-methylglycine methyl ester hydrochloride (11.1 g, 79.6 mmol) and the starting material of formula (VI) are added in portions to the cooling solvent. The mixture is stirred at 20 ° C. for 2 hours and then heated to reflux for 1 hour. Pyridine is removed by evaporation. Water is added to the oily residue. The mixture is extracted with ethyl acetate (3 x 150 mL). The extracts were combined and washed with 1N HCl aqueous solution, saturated sodium bicarbonate solution and brine.

After drying over MgSO ₄ the extract is treated with charcoal, filtered and evaporated. The residue is crystallized with diethyl ether or ethanol to give the title compound:

Melting Point 91-92 ° C

NMR (CDCl ₃ ) δ 2.8 and 3.25 (2s, 3H), 3.6 and 3.85 (2s, 3H), 4.35 (Broad, 2H), 7.75 (m, 6H)

UVλ max (EtOH) 321 nm (ε 775), 316 (1,110), 299 (6,660), 289 (9,250), 279 (7,400), 225 (66,600)

Elemental analysis

Calculated Value: C; 53.59%, H; 4.20%, N; 4.17%

Found: C; 53.60%, H; 4.27%, N; 4.21%

Method B:

Starting material of formula (V) in DMF (200 mL), namely 5-bromo-1-naphthalene-carboxylic acid (12.8 g, 52 mmol) and 1-hydroxybenzotriazole (HOBt, 7.0 g, 52 mmol) Prepare a mixture of N, N'-dicyclohexylcarbodiimide (DCC, 10.6 g, 52 mmol) in DMF (30 mL) was added to the mixture. The resulting mixture is stirred at 20 ° C. for 1 hour and then cooled to 0 ° C. N-methylglycinemethyl ester hydrochloride (7.25 g, 52 mmol) was added to the cooled mixture, followed by N-ethylmorpholine (6.7 mL, 52 mmol). The mixture is stirred at 0 ° C. for 30 minutes and then at 20 ° C. for 18 hours. The mixture is then filtered and concentrated to dryness under reduced pressure. The residue is chromatographed on 325 g of silica gel with acetate-hexane (1: 1) as eluent. The pure fractions were collected and 10.5 g of product was obtained and recrystallized from ethyl acetate to give the same title compound as the product of this Example Method A.

Example 3

N-[(5-bromo-1-naphthalenyl) thioxomethyl] -N-methylglycine methyl ester (R ¹ and R ² = CH ₃ , R ³ = 5-Br, R ⁴ and R ⁵ = H compound of general formula (I))

Stirring of N-[(5-bromo-1-naphthalenylcarbonyl) carbonyl] -N-methylglycine methyl ester (33.5 g, 106 mmol, described in Example 2) in anhydrous pyridine (100 mL) To the solution was added phosphorus pentasulfide (44.5 g, 200 mmol). The mixture is stirred and refluxed for 1.5 hours and then poured into 1 L of water at 50-80 ° C. (Note: releasing a large amount of H ₂ S). The mixture is cooled to 20-22 ° C. (room temperature) and filtered to extract the filtrate with ethyl acetate. The extract was washed with 1N HCl aqueous solution, brine, saturated sodium carbonate solution and brine, dried (MgSO ₄ ), filtered and evaporated to dryness. The residue is recrystallized from ethanol-water (4: 1) to give the title compound:

Melting Point 85-86 ° C:

NMR (CDCl ₃ ) δ 3.0 (s, 3H), 3.85 (s, 3H), 4.58 and 5.37 (2d, J = 17.2H), 7.1-8.3 (m, 6H):

UVλ max (EtOH) 281 nm (14,480), 218 (14,480).

Other compounds of formula (I) wherein R ¹ and R ² are each methyl by following the methods of Examples 2 and 3 in order using the appropriate starting materials of formula (V) instead of 5-bromo-1-naphthalenecarboxylic acid. Is obtained. Examples of the latter compounds are described in Tables I and II together with the appropriate starting materials of formula (V) used in the preparation as products.

In Table 1, starting materials of general formula (5) are described in the following documents. See T.L. Jacobs et al., J. Org. Chem., 11 27 (1946). For Example 4: H. G. Rule et al., J. Chem. Soc., 168 (1934). For Example 5: A. Girardet and N. Loruaso. Helv. Chim. Acta., 49,471 (1966). For Example 6: M. J. S. Dewar and P. J. Grisdale. J. Am. Chem. Soc., 84,3541 (1962). For Example 7: For Example 8: Described in Example 1c: M. J. S. Dewat and P. J. Grisdale. J. Am. Chem. Soc., 84,3541 (1962). For Examples 9, 9a, 10, and 11: For Example 12, described in Example 1b: For Example 13, described in Example 1e: M. Gilman et al., "Organic Sythesis", Coll . Vol. II. John Wiley and Sons, New York. N.Y.U.S.A. 1984. For P 425, Example 14: T. L. Jacobs et al., J. Org Chem. 11 27 (1946). For Example 15: For Example 16, described in Example 1d: For Example 17, described for Example 1e: For Example 18, described for Example 1f: For Example 19 Example 1g As described in].

In Table II, starting materials of the general formula (V) are as described below. Example 20: Described in Example 1b, Example 21: Described in Example 1, Example 22: Described in Example 1a, Example 23: Described in Example 1h, Examples 24 and 24: Example 1i Technique, Example 24b: Described in Example 1j.

Following the method of Examples 2 and 3 in order using the appropriate starting material of formula (VI) instead of N-methylglycine, another formula wherein R ³ is lower alkyl, R ⁵ is 5-bromo and R ⁴ is hydrogen (I) A compound is obtained. It is shown in Table III together with the appropriate starting materials of the general formula (VI) used in the preparation method as the product of the latter compound.

* product name

Example 31

When the methods of Examples 2 and 3 are carried out in sequence using the appropriate starting material of formula (V) and the amino acid ester of formula (VI), another compound of formula (I) wherein R ³ is lower alkyl Obtained. For example, when 3-chloro-methoxy-1-naphthalenecarboxylic acid of Example 1d is used as starting material of general formula (V) and glycine ethyl ester hydrochloride is used as starting material of general formula (VI), N- [(3-Chloro-4-methoxy-1-naphthalenyl) carbonyl] Glycine ethyl ester [melting point: 140 to 141 ° C .: NMR (CDCl ₃ ) δ 1.3 (t, J = 7 Hz, 3H), 4.2 (m, 4H), 6.55 (Broad, 1H), 7.55 (m, 3H), 8.2 (m, 2H) via N-[(3-chloro-4-methoxy-1-naphthalenyl) thioxomethyl ] Glycineethyl ester is obtained.

IR (CHCl ₃ ) 3420, 3340, 1740, 1665 cm ⁻¹ ;

Melting Point: 217 ° C (Decomposition): NMR (DMSO-d ₆ ) δ 3.96 (s, 3H), 4.42 (d, J = 6Hz, 2H), 7.40 (s, 1H), 7.65 (m, 2H), 8.18 ( m, 2H);

IR (Newsol *) 3150, 2900, 1720, 1140 cm ⁻¹ : UVλ max (EtOH) 277 nm (ε 11,400), 224 (51,300);

Elemental Analysis:

Calculated Value: C; 54.28%, H; 3.91%, N; 4.52%

Found: C; 54.26%, H; 4.06%, N; 4.62%.

Example 32

N-[(5-bromo-1-naphthalenyl) thioxomethyl] -N-methylglycine (R ¹ = CH ₃ , R ² , R ⁴ and R ⁵ = H and R ³ = 5-Br Compound of formula (I))

N-[(5-bromo-1-naphthalenyl) thioxomethyl] -N-methylglycine in 1N NaOH aqueous solution (25 ml) in methanol (75 ml); To a suspension of methyl ester (7.3 g, 20.7 mmol: described in Example 3) is added. The mixture is stirred at 20-22 ° C. for 2 1/2 hours, then neutralized with aqueous HCl solution to pH 7 and concentrated under reduced pressure to remove methanol. To the remaining solution was added an aqueous HCl solution, acidified (pH = 2) and extracted with ethyl acetate. The extract is dried (MgSO ₄ ) and evaporated to dryness. The residue is crystallized from ethyl acetate-hexanes to give 5.3 g of the title compound:

Melting Point: 181 ℃

NMR (DMSOd ₆ ) δ 2.95 (s, 3H), 4.65v5.2 (2d, J = 16.8,2H), 7.85 (m, 6H);

UV lambda max (EtOH) 285 nm (ε 12,300), 280 (12,400), 221 (42,600);

IR (Newsol *) 2900, 1720 cm ⁻¹ ;

Elemental analysis

Calculated Value: C; 49.72%, H; 3.58%, N; 4.1%

Found: C; 49.63%, H; 3.6%, N; 4.18%

N-[(3-chloro-4-methoxy-1-naphthal as described in Example 31 instead of N-[(5-bromo-1-naphthalenyl) thioxomethyl] -N-methylglycine methylester Renyl) thioxomethyl] glycine ethyl ester equivalents are used to obtain N-[(3-chloro-4-methoxy-1 -naphthalenyl) thioxomethyl] glycine by the same method.

Melting point: 217 ° C. (decomposition);

NMR (DMSO-d ₆ ) δ 3.96 (s, 3H), 4.42 (d, J = 6Hz, 2H), 7.40 (s, 1H), 7.65 (m, 2H), 8.18 (m, 2H);

IR (Newsol *) 3150, 2900, 1720, 1140 cm ⁻¹ ;

UV lambda max (EtOH) 277 nm (ε11,400), 224 (51,300);

Elemental analysis

Calculated Value: C; 54.28%, H; 3.91%, N; 4.52%

Found: C; 54.26%, H; 4.06%, N; 4.62%

Esters of other general formula (I) compounds in which R ² is lower alkyl instead of N-[(5-bromo-1-naphthalenyl) thioxomethyl] -N-methylglycine methyl ester or R is ar (lower) alkyl According to the method of Example 32 using the corresponding compound equivalents of phosphorous, the corresponding compound of formula (I) is obtained wherein R ² is hydrogen. Examples of the latter compounds are listed in Tables IV, V and VI together with the corresponding general formula (I) compounds as products, R ² used as starting material in the preparation is lower alkyl. In the case of compounds of formula (I) in which R ² is lower alkyl, the starting materials are indicated as examples of preparation.

* product name

Example 60

N-[(5-bromo-1-naphthalenyl) carbonyl] -N-methylglycine (R ¹ = CH ₃ , R ² = 5-Br and R ⁴ and R ⁵ = H) Compound of

N-[(5-bromo-1-naphthalenyl) carbonyl] -N-methylglycine ethyl ester (3.7 g, 11.0 mmol, compound of formula (II) as described in Example 2) was added to methanol (50 In ml). 1N aqueous NaOH solution (13.2 mL) was added to the suspension. The mixture is stirred at 20-22 ° C. for 1.5 h. The mixture is neutralized with aqueous HCl solution and concentrated under reduced pressure to remove methanol. The residual solution is acidified with aqueous HCl solution and extracted with ethyl acetate. The extract is dried (MgSO ₄ ), filtered and evaporated to dryness. Crystallization of the residue with ethanol-water yields 3.25 g of the title compound. Melting Point: 205 ° C: NMR (DMSO-d ₆ ) δ2.75 & 3.10 (2s, 3H), 3.75 & 4.25 (2s, 2H), 7.3-8.3 (m, 6H):

IR (New Sol *) 1745 (curved at 1720, 1580 cm ⁻¹ ): UVλ max (EtOH) 322 nm (ε 680), 316 (1,000), 299 (6,510), 289 (9,055), 279 (7,150), 226 (63,080):

Elemental analysis

Calculated Value: C; 52.19%, H; 3.76%, N; 4.35%

Found: C; 52.09%, H; 38.4%, N; 4.48%

According to the method of Example 60, wherein R is lower alkyl or ar (lower) alkyl instead of N-[(5-bromo-1-naphthalenyl) carbonyl] -N-methylglycine methyl ester Use of other ester compounds of II) affords the corresponding compounds of the general formula (IV). For example N-[[(5-trifluoromethyl) -6-methoxy-1-naphthalenyl] carbonyl] -N-methylglycine methyl ester prepared according to the method of Example 2 [NMR (CDCl ₃ ) N-[(5-trifluoro) using δ 2.85 (s, 3H), 3.5-4.5 (m, 2H), 3.4 & 3.75 (2s, 6H), 7.0-8.4 (m, 5H)] Rhomethyl) -6-methoxy-1-naphthalenyl) carbonyl] -N-methylglycine is obtained: Melting point: 174 to 175 ° C: NMR (DMSO-d ₆ ) δ 2.75 & 3.1 (2s, 3H) ), 4.03 (s, 3H), 4.30 (d, 2H), 7.8 (m, 5H): IR (Newsol *) 2500, 1720 (curved at 1745, 1580 cm ^-1 ): UVλ max (EtOH) 335 nm ( ε3,050), 322 (2,700), 295 (5,100), 283 (5,750), 275 (4,450), 220 (57,100):

Elemental analysis

Calculated Value: C; 56.30%, H; 4,13%, N; 4.10%

Found: C; 55.29%, H; 4.02%, N; 3.99%

Example 61

4,6-dimethoxy-1-naphthalenecarboxylic acid (compound of formula (V) wherein R ³ = 4-CH ₃ O, R ⁴ = 6-CH ₃ O, and R ⁵ = H)

The chlorine gas flows through a cold solution of NaOH (17.28 g, 0.432 mol) in water (24 ml) containing 100 g of ice until 12.7 g (0.18 mol) of chlorine is absorbed into the solution. Solid (4,6-dimethoxy-1-naphthalenyl) ethanone [9.2 g, 0.04 mol, NPBuu-Noi. J. Org. Chem., 21, 1257 (1956)] is added to the chlorine solution at 20-22 ° C. The mixture is stirred at 65 ° C. for 1 hour, cooled in an ice bath and treated with NaHSO ₃ (5 g) in water (20 mL). Neutralize by adding hydrochloric acid to the mixture. The resulting precipitate was collected, washed well with water, dried over P ₃ O ₅ and recrystallized with ethanol to give 4,6-dimethoxy-1-naphthalenecarboxylic acid (7.0 g): melting point 227 to 229 ° C .: NMR (DMSO-d ₆ ) δ 3.85 (s, 3H), 4.0 (s, 3H), 7.7 (m, 5H): IR (colorless mineral oil) 2900, 1670 cm ^-1 : UVλ max (MeOH) 339 nm (ε 4, 190), 328 (4,500), 304 (8,180), 240 (40,100):

Elemental analysis

Calculated Value: C; 67,23%, H; 5,21%

Found: C; 67.15%, H; 5.23%

Example 62

4,6-dimethoxy-5- (trifluoromethyl) -1-naphthalenecarboxylic acid (R ³ = 4-CH ₃ O, R ⁴ = 5-CF ₃ and R ⁵ = 6-CH ₃ O Compound of V)

4-6-dimethoxy-1-naphthalenecarboxylic acid (98.5 g, 0.425 moles, described in Example 61) is added to an ice solution of SOSl _* (59.5 g, 0.5 moles) in anhydrous methanol (225 mL). The mixture is heated to reflux for 18 hours. Again add a portion of SOCl ₂ (35.5 mL) and continue to reflux for 7 hours. The mixture is extracted with diethyl ether. The ether extract is washed with water, dried with NaH CO ₃ aqueous solution, dried (Na ₂ SO ₄ ), and concentrated to dryness. Crystallization of the solid residue with methanol (720 mL) afforded 64.5 g of 4,6-dimethoxy-1-naphthalenecarboxylic acid methylester: melting point 102-104 ° C. NMR (COCl ₃ ) δ3.9 (s, 6H) , 4.0 (s, 3H), 7.7 (m, 5H).

The compound (4.93 g, 0.02 mol) obtained above is suspended in 20% (V / V) aqueous acetic acid solution and concentrated H ₂ SO ₄ (0.279 mL). The mixture is stirred and heated at 60 ° C. Iodine (2 g, 0.008 mole) and periodic acid (2.76 g, 0.012 mole) are added to the mixture. The reaction mixture is stirred for 1 hour at the same temperature, cooled, poured into water and extracted with chloroform. The chloroform extract is washed with aqueous sodium hyposulfite solution and then with water and dried (Na ₂ SO ₄ ). The chloroform extract is poured onto a column of 250 g of silica gel (using 10% (V / V) ethyl acetate in hexane). The column is eluted with 1.5 L of the same solvent system followed by 20% (V / V) ethyl acetate in hexane. Collecting the appropriate fractions yields 5-uredo-4,6-dimethoxy-1-naphthalenecarboxylic acid methyl ester (1.4 g, 80% purity). Crystallization with ethyl acetate-hexanes affords pure compounds having a melting point of 120-122 ° C.

The latter compound (7.1 g, 0.019 mol), freshly prepared copper powder (4.5 g, RQ Brwester and T. Groening, "Orgnic Synthesis", Coll vol. II.John Wiley and Sons, New York, NYUSA 1948. p. 445 ), Trifluoromethyl iodide (8.5 g, 0.43 mole) and 135 mL of anhydrous pyridine) are heated at 120 ° C. for 20 h in an autoclave. After cooling to 22-24 ° C., the mixture is dissolved in toluene and the toluene suspension is filtered. The filtrate is concentrated to dryness under reduced pressure. The residue is dissolved in chloroform. Filtration removes insoluble matters in chloroform. The filtrate is passed through 75 g of silica gel column and the column is eluted with chloroform. Pure fractions combined and crystallized with ethyl acetate-hexane afforded 2.83 g of 4,6-dimethoxy-5- (trifluoromethyl) -1-naphthalenecarboxylic acid methyl ester: Melting point: 102-123 ° C. NMR (CDCl ₃₎ ) δ 3.95 (m, 9H), 6.8 and 8.05 (2d, J = 10 Hz, 2H), 7.21 and 9.1 (2d, J = 10 Hz, 2H).

A suspension of the latter compound (2.83 g, 0.009 mol) in ethanol (16.2 mL) and NaOH (5.4 mL 4N aqueous solution) is heated to reflux for 10 minutes under nitrogen. The resulting same solution is cooled in an ice bath and acidified (pH = 3) with a 2N HCl aqueous solution. The precipitates are collected, washed with water and dried over P ₂ O ₅ to give 2.7 g of the title compound. m / e 300 (M ⁺ ).

Example 63

5- (trifluoromethylthio) -6-ethoxy-1-naphthalenecarboxylic acid (R ³ = 5-CF ₂ S, R ⁴ = 6-CH ₃ O and R ⁵ = H) compound)

Copper powder (1.84 g, 29 mmol) and Hg (SF ₆ ) ₈ [3.27 g, 8 mmol, EH Man et al., J. Amer. Chem. Soc., 81, 3575 (1969) according to the method of well-mixed mixture is heated at 80 to 100 ℃ for 2.6 hours. The temperature is then raised to 150 ° C. for 30 minutes. The mixture containing CuScF ₈ is cooled to room temperature (about 22-24 ° C.). A solution of 5-iod-6-methoxy-1-naphthalenecarboxylic acid methyl ester (1.87 g, 5.4 mmol, described in 1f on phase) in distilled dimethylformamide (DMF, 10 mL) was added to the mixture. The resulting mixture is stirred at 110-120 ° C. for 3 hours and then at room temperature for 18 hours. Pour the mixture into water. The diluted mixture is extracted with diethyl ethyr (3X). The extract was washed with water to dryness (MgSO ₄ ) and evaporated to dryness to afford the corresponding methyl ester of the title compound (1.7 g) as a solid residue: mp 93-94 ° C .: NMR (CDCl ₃ ) δ 3.90 (s, 3H ), 4.00 (s, 3H), 7.00-9.20 (m, 5H).

The latter ester compound (2.45 g, 7.7 mmol) dissolved in 2-methoxy-ethanol (60 mL) was mixed with aqueous NaOH solution (1N, 15.5 mL). The resulting solution was stirred at room temperature for 24 hours, cooled in an ice bath, acidified (pH = 3) with 1N HCl aqueous solution, and diluted with water. The resulting solids were collected, washed with water and recrystallized with ethanol to give the title compound (1.7 g): Melting Point 204-205 DEG C: NMR (DMSO-d ₆ ) δ 4.00 (s, 3H), 8.20 (m, 5H) , 10.30 (Broad. 1H).

Example 64

Following the methods of Examples 2 and 3 in the order using 4,6-dimethoxy-1-naphthalenecarboxylic acid equivalent of Example 61 instead of 5-bromo-1-naphthalenecarboxylic acid, N-[(4,6-dimethoxy -1-naphthalenyl) -carbonyl] -N-methylglycine methyl ester [NMR (CDCl ₃ ) δ 2.75 (s, 1H), 3.7 (s, 3H), 3.9 (s, 3H), 4.0 (s, 3H), 4.35 (s, 2H), 7.4 (m, 5H)] to N-[(4,6-dimethoxy-1-naphthalenyl) -thioxomethyl] -N-methylglycine methyl ester (R General formula (I) compound of ¹ and R ² = CH ₃ , R ³ = 4-CH ₃ O, R ⁴ = 6-CH ₃ O, and R ⁵ = H) is obtained: melting point 105 to 107 ° C; NMR (CDCl ₃ ) δ3.05 (s, 3H), 3.85 (s, 3H), 3.90 (s, 3H), 4.0 (s, 3H), 4.8 (2d, J = 20Hz, 2H), 7.3 (m, 5H).

6-methoxy-1-naphthalenecarboxylic acid [cc Price et. al., J. Am. chem.soc., 69, 2261 (1947)] N-[(6-methoxy-1-naphthalenyl) carbonyl] -N-methylglycine methyl ester in the same manner using equivalents -[(6-methoxy-1-naphthalenyl) thioxomethyl] -N-methylglycine methyl ester (R ¹ and R ² = CH ₃ and R ³ = 6-methoxy and R ⁴ and R ⁵ = H Phosphorus general formula (I) compound) is manufactured; NMR (CDCl ₃ ) δ3.02 (s, 3H), 3.86 (s, 3H), 3.86 (s, 3H), 3.89 (s, 3H), 4.53 & 4.35 (d, J = 17Hz, 2H), 6.90 -8.10 (m, 6 H).

N-[[4-6-dimethoxy-5- (trifluoromethyl) in the same manner using the 4, 6-dimethoxy-5- (trifluoromethyl) -1-naphthalenecarboxylic acid equivalent of Example 62 -1-naphthalenyl] carbonyl] -N-methylclicin methyl ester [NMR (CDCl ₃ ) δ 2.78 (s, 3H), 3,6 (s, 3H), 3.85 (s, 3H), 3.9 ( s, 3h), 4.35 (m, 2H), 6.7-8.3 (m, 4H)] through N-[[4,6-dimethoxy-5- (trifluoromethyl) -1-naphthalenyl] teeth Oxomethyl] -N-methylglycine methyl ester (R ¹ and R ² = CH ₃ O, R ³ = 4-CH ₃ O, R ⁴ = 5-CF ³ and R ⁵ = 6-CH ₃ O I) compound). NMR (CDCl ₃ ) δ3.0 (s, 3H), 3.7 (s, 3H), 3.85 (s, 3H), 3.95 (s, 3H), 4.35 & 5.45 (2d J = 17Hz, 2H), 6.8-8.2 (m, 4H)].

N-[[5- (trifluoromethylthio) -6-methoxy- by the same method using the 5- (trifluoromethylthio) -6-methoxy-1-naphthalenecarboxylic acid equivalent of Example 63 1-naphthalenyl] carbonyl] -N-methylglycine methyl ester [NMR (CDCl ₃ ) δ3.00 (s, 3H), 3.7 5 (s, 3H), 4.00 (s, 3H), 4.35 and 4.50 ( d, 2H), 7.0-8.5 (m, 5H)] through N-[[5- (trifluoromethylthio) -6-methoxy-1-naphthalenyl] thioxomethyl] -N-methylglycine Obtain methyl ester (a compound of formula (I) wherein R ¹ and R ² = CH ₃ , R ³ = 5-CF ₃ S, R ⁴ = 6-CH ₃ O and R ⁵ = H): Melting point 121-123 C: NMR (CDCl ₃ ) δ3.00 (sm, 3H), 3.75 (s, 3H), 4.00 (s, 3H), 4.35 & 4.5 (d, 2H), 7.0-8.5 (m, 5H).

Example 65

Equivalent to one of the ester compounds of formula (I) wherein R ² in Example 64 is lower alkyl instead of N-[(5-bromo-1-naphthalenyl) thioxomethyl] -N-methylglycine methyl ester To obtain the corresponding compound of formula (I) wherein R ² is hydrogen according to the method of example 32: N-[(4,6-dimethoxy-1-naphthalenyl) thioxomethyl]- N-methylglycine: NMR (CMS Od ₆ ) δ3.05 (s, 3H), 3.90 (s, HH), 3.97 (s, 3H), 4.27 & 4.67 (2d, J = 17 Hz, 2H), 6.50-8.00 (m, 5H), 9.12 (broad, 1H); IR (CHCl ₃ ) 2900, 1720 cm ^-1 : shoulder at uv lambda max (MeOH) 337 nm (ε 10.280), 322 (9.675), 278 (35.385), 242 (66,830), 224 (116,600);

Elemental Analysis:

Calculated Value: C; 60.17%, H; 5.36%, N; 4.38%

Found: C; 58.39%, H; 5.20%, N; 4.80%

N-[(6-methoxy-1-naphthalenyl) -thioxomethyl] -N-methylglycine: melting point 153 to 154 ° C: NMR (DMSO-d ₆ ) δ2.95 (s, 3H), 3.9 ( s, 3H), 4.65 and 5.2 (2d, J = 16.5 Hz, 2H), 7.5 (m, 6H); NMR-[[4,6-dimethoxy-5- (trifluoromethyl) -1-naphthalenyl] thioxomethyl] -N-methylglycine; NMR (CDCl ₃ ) δ3.05 (s, 3H), 3.9 (s, 3H), 3.95 (s, 3H), 4.5 & 5.11 (2d, J = 17Hz, 2H), 6.75 (s, 1H), 7.2 ( m, 4H); IR (CHCl ₃ ) 3000, 1720, 1270, 1130 cm ^-1

Elemental analysis

Calculated Value: C; 52.70%, H; 4.16%, N; 3.61%

Found: C; 52.83%, H; 4.46%, N; 3.75%

N-[[5- (trifluoromethylthio) -6-methoxy-1-naphthalenyl] thioxomethyl] -N-methylglycine: Melting | fusing point 168-169 degreeC; NMR (DMSO-d ₆ ) δ 3.0 (s, 3H), 3.0 (s, 3H), 4.0 (s, 3H), 4.6 & 5.2 (d, J = 16.5 Hz, 2H), 7.7 (m, 5H); IR (colorless mineral oil) 2900, 1720, 1465 cm ^-1 : uv lambda max (MeOH) 342 nm (ε4970), 334 (4800), 230 (46,800).

Claims (20)

A method for producing a compound of formula (I), characterized by reacting an amido ester of formula (II) with phosphorus penta sulfide.

Wherein R ¹ is hydrogen, lower alkyl, lower alkenyl or phenylmethyl; R ² is lower alkyl; R ³ is a group consisting of hydrogen, lower alkoxy at 6-position of naphthalene ring or lower alkyl at 4, 5 or 8-position of naphthalene ring, lower alkoxy, halo, cyano, nitro, trihalomethyl and trihalomethylthio Is a substituent selected from R ⁴ and R ⁵ are each hydrogen or R ³ and R ^* are each lower alkyl, lower alkoxy, halo, trihalomethyl, trihalomethylthio at different positions selected from 3 to 7 positions of the naphthalene ring. And (lower) -alkoxy (lower) alkoxy, phenylmethoxy and phenyl rings are substituents selected from the group consisting of phenylmethoxy substituted with loweralkyl, lower alkoxy, halo or trihalomethyl, and R ⁵ is hydrogen: R ³ , R ⁴ and R ⁵ are substituents selected from the group consisting of lower alkoxy, halo and trihalomethyl at different positions selected from the 4,5 and 6 positions of the naphthalene ring, respectively: R is lower alkyl. 2. A compound according to claim 1, wherein R ¹ is hydrogen, lower alkyl, 2-propenyl or phenylmethyl: R ² is lower alkyl: R ³ is hydrogen, lower alkoxy at 6-position of the naphthalene ring, or 4,5 or the naphthalene ring; A substituent selected from the group consisting of lower alkyl, lower alkoxy, halo, cyano, nitro and trifluoromethyl at the 8-position; R ⁴ and R ⁵ are each hydrogen: R ³ and R ⁴ are different positions on the naphthalene ring 3-halo-4-lower alkoxy, 4,6-di (lower alkoxy), 5-halo-6-lower alkyl, 5-halo-6-lower alkoxy, 5,7-dihalo, 5- (tri Fluoromethyl) -6-lower alkoxy, 5- (trifluoromethylthio) -6-lower alkoxy, 5-halo-6- (lower) alkoxy, 5-halo-6- [3 (-trifluoromethyl ) phenylmethoxy] and 5-halo-6- (4-chloro-phenyl methoxy) one pairs of substituents selected from the group consisting of, R ⁵ is hydrogen, or: R ^3, R ⁴ and R ⁵ are each a naphthalene cyclic phase of 4-lower alkoxy -5-6- haloalkyl of from one location-lower alkoxy and 4,6-di (lower alkoxy) substituted three Jane method selected from the group consisting of 5- (trifluoromethyl). The compound of claim 1, wherein R ¹ is hydrogen, lower alkyl, or phenylmethyl: R ² is lower alkyl: R ³ is 4-halo or 5-halo, and R ⁴ and R ⁶ are each hydrogen: R ² And R ⁴ is 3-halo-4-lower alkoxy, 4,6-di (lower alkoxy), 5-halo-6-lower alkyl, 5-halo-6-lower alkoxy, 5,7-dihalo on naphthalene ring , A pair of substituents selected from the group consisting of 5- (trifluoromethyl) -6-lower alkoxy and 5- (trifluoromethylthio) -6-lower alkoxy and R ² is hydrogen or R ³ is 4- Lower alkoxy, R ⁴ is 5- (trifluoromethyl), and R ⁵ is 6-lower alkoxy. The N-[(5-bromo-1-naphthalenyl) thioxomethyl] -N-methylglycine methyl ester according to claim 1, wherein N-[[5- (trifluoromethyl) -6-methoxy -1-naphthalenyl] thioxomethyl] -N-methylglycine methyl ester: or N-[[5- (trifluoromethylthio) -6-methoxy-1-naphthalenyl] thioxomethyl]- A process for preparing a compound of formula (I) which is N-methylglycine methyl ester. The compound of formula (I) according to claim 1, wherein the compound of formula (I) is N-[[5- (trifluoromethyl) -6-methoxy-1-naphthalenyl] thioxomethyl] -N-methylglycine methyl ester How to manufacture. The compound of claim 1, wherein N-[(5-chloro-1-naphthalenyl) thioxomethyl] -N-methylglycine methyl ester: N-[(5-bromo-6-methoxy-1-naphthal Renyl) Tioxomethyl] -N-methylglycine methyl ester: N-[(3-chloro-4-methoxy-1-naphthalenyl) thioxomethyl] -N-methylglycine methyl ester: N-[(5 , 7-dichloro-1-naphthalenyl) thioxomethyl] -N-methyl glycine methyl ester: N-[[(5-trifluoromethyl) -1-naphthalenyl) thioxomethyl] -N-methyl Glycine methyl ester: N-[[(3-chloro-4-methoxy-1-naphthalenyl) thioxomethyl] glycine methyl ester: or N-[[4,6-dimethoxy-5- (trifluoro A method for producing a compound of formula (I), which is methyl) -1-naphthalenyl] thioxomethyl] -N-methylglycine methyl ester. The N-[(4-bromo-1-naphthalenyl) thioxomethyl] -N-methylglycine methyl ester according to claim 1, wherein N-[(8- (bromo-1-naphthalenyl) thi Oxomethyl] -N-methylglycine methyl ester: N-[(5-methoxy-1-naphthalenyl) thioxomethyl] -N-methylglycine methyl ester: N-[(5-methyl-1-naphthalate Renyl) Tioxomethyl] -N-methyl Glycine Methyl Ester: N-[(5-Bromo-6-pentyloxy-1-naphthalenyl) Tioxomethyl] -N-methylglycine Methyl Ester: N-[[ 5-Cyano-1-naphthalenyl) thioxomethyl] -N-methylglycine methyl ester: N-[[5-nitro-1-naphthalenyl) thioomethyl] -N-methylglycine methyl ester: N -[(5-Bromo-6-methyl-1-naphthalenyl) thioxomethyl] -N-methylglycine methyl ester: N-[(1-naphthalenyl) thioxomethyl] -N-methylglycine methyl Ester: N-[(4-chloro-1-naphthalenyl) thioxomethyl] -N-methylglycine methyl ester: N-[(5-iodo-6-methoxy-1-naphthalenyl) thioxomethyl ] -N-methylglycine methyl ester: N-[(5-cyano-6-methoxy-1-naphthalenyl) thioxomethyl] -N-methylglycine methyl ester: N-[(5-bromo-6 -3- (methoxyprotoxy) -1-naphthalenyl] thioxomethyl] -N-methylglycine methyl ester: N-[[5- (1-methyletheryl) -1-naphthalenyl] thiooxo Methyl] -N-methylglycine methyl ester: N-[[5- (1-methyletheryl) -1-naphthalenyl] thioxomethyl] -N-methylglycinemethyl ester: N-[[(5-bro MO-6- [3- (3-trifluoromethyl) -phenylmethoxy] -1-naphthalenyl] thioxomethyl] -N-methylglycine methyl ester: N-[[5-bromo-6- (4-Chlorophenylmethoxy) -1-naphthalenyl] thioxomethyl] -N-methylglycine methyl ester: N-[(5-bromo-1-naphthalenyl) thioxomethyl] glycine methyl ester: N-[[5-bromo-1-naphthalenyl) thioxomethyl] -N-propylglycine methyl ester: N-[(5-bromo-1-naphthalenyl) thioxomethyl] -N- (2-propenyl) glycine methyl ester: N-[(5-bromo-1-naphthalenyl) thioxomethyl ] -N-methylglycine methyl ester: N-[(5-bromo-1-naphthalenyl) thioxomethyl] -N-butylglycine methyl ester: N-[(5-bromo-1-naphthalenyl ) Tioxomethyl] -N- (phenylmethyl) glycinemethyl ester: N-[(4-cyano-1-naphthalenyl) thioxomethyl] -N-methylglycine methyl ester: N-[(4,6 -Dimethoxy-1-naphthalenyl) -thioxomethyl] -N-methylglycine methyl ester: or N-[(6-methoxy-1-naphthalenyl) thioxomethyl] -N-methylglycine methyl ester Process for preparing a compound of phosphorus general formula (I). A process for preparing a compound of formula (I) or a therapeutically acceptable salt thereof with an organic or inorganic base, characterized in that the compound of formula (III) is hydrolyzed.

Wherein R ¹ , R ³ , R ⁴ and, R ⁵ are as defined in claim 1: R ³ is hydrogen and R is lower alkyl or aro (lower) alkyl. 9. A compound according to claim 8, wherein R ¹ is hydrogen lower alkyl, 2-propenyl or phenylethyl: R ² is hydrogen, R ³ is hydrogen, lower alkoxy at 6-position of the naphthalene ring, or 4, 5 or 8-position of the naphthalene ring Is a substituent selected from the group consisting of lower alkyl, lower alkoxy, halo, cyano, nitro and trifluoromethyl of R ⁴ and R ⁵ are each hydrogen; R ³ and R ⁴ are 3-halo-4-lower alkoxy, 4,6-di (lower alkoxy), 5-halo-6-lower alkyl, 5-halo-6-lower alkoxy at different positions on the naphthalene ring, 5,7-dihalo, 5- (trifluoromethyl) -6-lower alkoxy, 5- (trifluoromethylthio) -6-lower alkoxy, 5-halo-6- (lower) alkoxy (lower) alkoxy , 5-halo-6- [3- (trifluoromethyl) phenylmethoxy] and 5-halo-6- (4-chlorophenylmethoxy) are a pair of substituents selected from the group consisting of R ⁵ is hydrogen or ; R ³ , R ⁴ and R ⁵ each represent 4-lower alkoxy-5-halo-6-lower alkoxy and 4,6-di (lower alkoxy) -5- (trifluoromethyl) at different positions on the naphthalene ring. Three substituents selected from the group consisting of: The compound of claim 8, wherein R ¹ is hydrogen, lower alkyl, or phenylmethyl; R ² is hydrogen; R ³ is 4-halo or 5-halo and R ⁴ and R ⁵ are each hydrogen; R ³ and R ⁴ are 3-halo-4-lower alkoxy on a naphthalene ring, 4,6-di (lower alkoxy), 5-halo-6-lower alkyl, 5-halo-6-lower alkoxy, 5,7- Dihalo, a pair of substituents selected from the group consisting of 5- (trifluoromethyl) -6-lower alkoxy and 5- (trifluoromethylthio) -6-lower alkoxy, R ⁵ is hydrogen, or R ³ is 4-lower alkoxy, R ⁴ is 5- (trifluoromethyl) and R ⁵ is 6-lower alkoxy. The compound of claim 8, wherein R ¹ is lower alkyl; R ² is hydrogen; R ³ is 5-halo and R ⁴ and R ⁵ are each hydrogen; R ³ and R ⁴ are 3-halo-4-lower alkoxy, 5-halo-6-lower alkoxy, 5- (trifluoromethyl) -6-lower alkoxy and 5- (trifluoromethylthio) on the naphthalene ring -6 is a pair of substituents selected from the group consisting of lower alkoxy, R ⁵ is hydrogen; R ³ is 4-lower alkoxy, R ⁴ is 5- (trifluoromethyl) and R ⁵ is 6-lower alkoxy. The compound according to claim 8, further comprising: N-[(5-bromo-1-naphthalenyl) thioxomethyl] -N-methylglycine; N-[[5-trifluoromethyl) -6-methoxy-1-naphthalenyl] thioxomethyl] -N-methylglycine; Or N-[[5- (trifluoromethylthio) -6-methoxy-1-naphthalenyl] thioxomethyl] -N-methylglycine. The compound of formula (I) according to claim 8, which is N-[[5- (trifluoromethyl) -6-methoxy-1-naphthalenyl] thioxomethyl] -N-methylglycine Way. The compound according to claim 8, further comprising: N-[(5-chloro-1-naphthalenyl) thiooxofmethyl] -N-methylglycine; N-[(5-bromo) -6-methoxy-1-naphthalenyl] thioxomethyl] -N-methylglycine; N-[(3- (chloro-4-methoxy-1-naphthalenyl) thioxomethyl] -N-methylglycine; N-[(5,7-dichloro-1-naphthalenyl) thioxomethyl] -N-methylglycine; N-[[(5-trifluoromethyl-1-naphthalenyl] thioxomethyl] -N-methylglycine; N-[(3-chloro-4-methoxy-1-naph General formula (I) which is thalenyl) thioxomethyl] glycine or N-[[4,6-dimethoxy-5- (trifluoromethyl) -1-naphthalenyl] thioxomethyl] -N-methylglycine To prepare a compound. The compound according to claim 8, wherein N-[(4-bromo-1-naphthalenyl) thioxomethyl] -N-methylglycine: N-[(8-bromo-1-naphthalenyl) thioxomethyl] -N-methylglycine; N-[(5-methoxy-1-naphthalenyl) thioxomethyl] -N-methylglycine; N-[(5-methyl-1-naphthalenyl) thioxomethyl] -N-methylglycine; N-[(5-bromo-6-pentyloxy-1-naphthalenyl) thioxomethyl] -N-methylglycine; N-[(5-cyano-1-naphthalenyl) thioxomethyl] -N-methylglycine; N-[(5-nitro-1-naphthalenyl) thioxomethyl] -N-methylglycine; N-[(5-bromo-6-methyl-1-naphthalenyl) thioxomethyl] -N-methylglycine; N-[(1-naphthalenyl) thioxomethyl] -N-methylglycine; N-[(4-chloro-1-naphthalenyl) thioxomethyl] -N-methylglycine; N-[(5-iodo-6-methoxy-1-naphthalenyl) thioxomethyl] -N-methylglycine; N-[(5-cyano-6-methoxy-1-naphthalenyl) thioxomethyl] -N-methylglycine; N-[[(5-bromo-6- (3-methoxypropoxy) -1-naphthalenyl] thioxomethyl] -N-methylglycine; N-[[(5- (1-methylethenyl ) -1-naphthalenyl] thioxomethyl] -N-methylglycine; N-[[5- (1-methylethyl) -1-naphthalenyl] thioomethyl] -N-methylglycine; N- [ [5-Bromo-6- [3- (3-trifluoromethyl) phenylmethoxy] -1-naphthalenyl] thioxomethyl] -N-methylglycine; N- [[5-bromo-6 -(4-chlorophenylmethoxy) -1-naphthalenyl] thioxomethyl] -N-methylglycine; N-[(5-bromo-1-naphthalenyl) thioxomethyl] -N-methylglycine N- [5-bromo-1-naphthalenyl) thioxomethyl] glycine; N-[(5-bromo-naphthalenyl) thioxomethyl] -N-propylglycine; N-[(5- Bromo-1-naphthalenyl) thioxomethyl] -N- (2-propenyl) glycine; N-[(5-bromo-1-naphthalenyl) thioxomethyl] -N-ethylglycine; N -[(5-bromo-1-naphthalenyl) thioxomethyl] -N-butylglycine; N-[(5-bromo-1-naphthalenyl) thioxomethyl] -N- (phenylmethyl) Glycine; N-[(4-shi Ano-1-naphthalenyl) thioxomethyl] -N-methylglycine; N-[(4,6-dimethoxy-1-naphthalenyl) thioomethyl] -N-methylglycine; or N-[( 6-methoxy-1-naphthalenyl) thioxomethyl] -N-methyl glycine. A process for preparing the compound of formula (I). Hydrolysis of the amido ester of general formula (II) to give the corresponding amido acid, followed by reaction of this compound with phosphorus pentasulphide, characterized in that the compound of general formula (I) or an organic or inorganic base thereof A method of making a therapeutically acceptable salt.

Wherein R ¹ , R ³ , R ⁴ and R ⁵ are as defined in claim 1; R ² is hydrogen; R is lower alkyl or ar (lower) alkyl. The compound according to claim 16, further comprising: N-[(5-bromo-1-naphthalenyl) thioxomethyl] -N-methylglycine; N-[[5- (trifluoromethyl) -6-methoxy-1-naphthalenyl] thioxomethyl] -N-methylglycine; Or N-[[5- (trifluoromethylthio) -6-methoxy-1-naphthalenyl] thioxomethyl] -N-methylglycine. The compound of formula (I) according to claim 16, wherein the compound of formula (I) is N-[[5- (trifluoromethyl) -6-methoxy-1-naphthalenyl] thioxomethyl] -N-methylglycine. Way. The compound according to claim 16, further comprising: N-[(5-chloro-1-naphthalenyl) thioxomethyl] -N-methylglycine; N-[(5-bromo-6-methoxy-1-naphthalenyl) thioxomethyl] -N-methylglycine; N-[(3-chloro-4-methoxy-1-naphthalenyl) thioxomethyl] -N-methylglycine; N-[(5,7-dichloro-1-naphthalenyl) thioxomethyl] -N-methylglycine; N-[[5- (trifluoromethyl) -1-naphthalenyl] thioxomethyl] -N-methylglycine; N-[(3-chloro-4-methoxy-1-naphthalenyl) thioxomethyl] glycine; Or N-[[4,6-dimethoxy-5- (trifluoromethyl) -1-naphthalenyl] thioxomethyl-N-methylglycine. 17. A compound according to claim 16, wherein N-[(4-bromo-1-naphthalenyl) thioxomethyl] -N-methylglycine: N-[(8-bromo-1-naphthalenyl) thioxomethyl] -N-methylglycine; N-[(5-methoxy-1-naphthalenyl) thioxomethyl] -N-methylglycine; N-[(5-methyl-1-naphthalenyl) thioxomethyl] -N-methylglycine; N-[(5-bromo-6-pentyloxy-1-naphthalenyl) thioxomethyl] -N-methylglycine; N-[(5-cyano-1-naphthalenyl) thioxomethyl] -N-methylglycine; N-[(5-nitro-1-naphthalenyl) thioxomethyl] -N-methylglycine; N [(5-bromo-6-methyl-1-naphthalenyl) thioxomethyl] -N-methylglycine; N-[(1-naphthalenyl) thioxomethyl] -N-methylglycine; N [(4-chloro-1-naphthalenyl) thioxomethyl] -N-methylglycine; N-[(5-iodo-6-methoxy-1-naphthalenyl) thioxomethyl] -N-methylglycine; N-[(5-cyano-6-methoxy-1-naphthalenyl) thioxomethyl] -N-methylglycine; N-[[5-bromo-6- (3-methoxypropoxy) -1-naphthalenyl] thioxomethyl] -N-methylglycine; N-[[5- (1-methylethenyl) -1-naphthalenyl] thioxomethyl] -N-methylglycine; N-[[5- (1-methylethenyl) -1-naphthalenyl] thioxomethyl] -N-methylglycine; N-[[5- (1-methylethyl) -1-naphthalenyl] thioxomethyl] -N-methylglycine; N-[[5-bromo-6- [3- (3-trifluoromethyl) -phenylmethoxy] -1-naphthalenyl] thioxomethyl] -N-methylglycine; N-[[5-bromo-6- (4-chlorophenylmethoxy) -1-naphthalenyl] thioxomethyl] -N-methylglycine; N-[(5-bromo-1-naphthalenyl) thioxomethyl] glycine; N-[(5-bromo-1-naphthalenyl) thioxomethyl] -N-propylglycine; N-[(5-bromo-1-naphthalenyl) thioxomethyl] -N- (2-propenyl) glycine; N-[(5-bromo-1-naphthalenyl) thioxomethyl] -N-ethylglycine; N-[(5-bromo-1-naphthalenyl) thioxomethyl] -N-butylglycine; N-[(5-bromo-1-naphthalenyl) thioxomethyl] -N- (phenylmethyl) glycine; N-[(4-cyano-1-naphthalenyl) thioxomethyl] -N-methylglycine; N-[(4,6-dimethoxy-1-naphthalenyl) thioomethyl] -N-methylglycine; Or N-[(6-methoxy-1-naphthalenyl) thioxomethyl] -N-methylglycine.