CA1187093A - N-(substituted-naphthoyl)glycine derivatives - Google Patents
N-(substituted-naphthoyl)glycine derivativesInfo
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Abstract
ABSTRACT OF THE DISCLOSURE
Herein disclosed are N-(substituted-naphthoyl)glycine derivatives having aldose reductase inhibiting activity. The derivatives are useful for treating diabetic complications.
Herein disclosed are N-(substituted-naphthoyl)glycine derivatives having aldose reductase inhibiting activity. The derivatives are useful for treating diabetic complications.
Description
(CANADA) N-(SUBSTITUTED-NAPHTHOYL)GLYCINE DERIVATIVES
Related Appli~ations: Related hereto are Canadian Patent Application Serial No. 372,1197 filed March 2,1981, Canadian Patent Application 5erial No. 372,054,filed March 2,1981 and Canadian Patent Application Serial No. 38~,991, filed October 15, l9gl.
This application relates to N-(substituted-naphthoyl)glycine deriva-tives, therapeutically acceptable salts thereof, a process for their preparation, an intermediate used in the process, and to methods of use and to pharmaceuticalcompositions thereof. The derivatives have pharmacologic properties which render them beneficial for the treatment of diabetes mellitus and associated conditions.
For many years diabetes mellitus has been treated with two esta-blished types of drugs, namely insulin and oral hypoglycemic agents. These drugs have benefited hundreds of thousands of diabetics by improving their well-being and prolonging their lives. Howevel 9 the resulting longevity of diabetic patients has led to complications such as neuropathy, nephropathy, retinopathy, cataracts and atherosclerosis. These compli~ations have been linked to the undesirable accumulation of sorbitol in diabe~ic tissue, which in turn result from the high levels of glucose characteristic of the diabetic patient.
In mammals, including humans, the key en~yme involved in the conver-sion of hexoses to polyols (the sorbitol pathway) is aldose reductase. J.H. Kinoshita and coIlaborators, see J.H. Kinoshita el al., Biochem. Biophys. A~ta, 158,472 (1968) and references cited thereiIl; have demonstrated that aldose reductase plays a central role in the etiology of galactosemic cataracts by effeeting the conversion of galactose to dulcitol (galactitol) and that an agent capable of inhibiting aldose reductase can prevent the detrimental accumulation of dulcitolin the lens. Furthermore, a relationship between elevated levels of glucose and an undesirable accumulation of sorbitol has been demonstrated in the lens, peripheral nervous cord and kidney of diabetic animals, see ~. Pirie and R.
van Heyningen, Exp. Eye Res., 3,124 ~1964); L.T. Chylack and J.H. ~inoshita, Invest. Ophthal., 8, 401(1969) and J.D. Ward and R.W.R. Baker, Diabetol.~ 6, 531 (197~).
Related Appli~ations: Related hereto are Canadian Patent Application Serial No. 372,1197 filed March 2,1981, Canadian Patent Application 5erial No. 372,054,filed March 2,1981 and Canadian Patent Application Serial No. 38~,991, filed October 15, l9gl.
This application relates to N-(substituted-naphthoyl)glycine deriva-tives, therapeutically acceptable salts thereof, a process for their preparation, an intermediate used in the process, and to methods of use and to pharmaceuticalcompositions thereof. The derivatives have pharmacologic properties which render them beneficial for the treatment of diabetes mellitus and associated conditions.
For many years diabetes mellitus has been treated with two esta-blished types of drugs, namely insulin and oral hypoglycemic agents. These drugs have benefited hundreds of thousands of diabetics by improving their well-being and prolonging their lives. Howevel 9 the resulting longevity of diabetic patients has led to complications such as neuropathy, nephropathy, retinopathy, cataracts and atherosclerosis. These compli~ations have been linked to the undesirable accumulation of sorbitol in diabe~ic tissue, which in turn result from the high levels of glucose characteristic of the diabetic patient.
In mammals, including humans, the key en~yme involved in the conver-sion of hexoses to polyols (the sorbitol pathway) is aldose reductase. J.H. Kinoshita and coIlaborators, see J.H. Kinoshita el al., Biochem. Biophys. A~ta, 158,472 (1968) and references cited thereiIl; have demonstrated that aldose reductase plays a central role in the etiology of galactosemic cataracts by effeeting the conversion of galactose to dulcitol (galactitol) and that an agent capable of inhibiting aldose reductase can prevent the detrimental accumulation of dulcitolin the lens. Furthermore, a relationship between elevated levels of glucose and an undesirable accumulation of sorbitol has been demonstrated in the lens, peripheral nervous cord and kidney of diabetic animals, see ~. Pirie and R.
van Heyningen, Exp. Eye Res., 3,124 ~1964); L.T. Chylack and J.H. ~inoshita, Invest. Ophthal., 8, 401(1969) and J.D. Ward and R.W.R. Baker, Diabetol.~ 6, 531 (197~).
-2- AHP-780G 2 (CANADA) 1,3-Dioxo-lH-benz[de] isoquinoline-2(3H)-acetic acid has been reported to be an effective inhibitor of aldose reductase, see D. Dvornik et al., Science, 182,1146 ~1973~, and to be useful for the treatment of diabetic complications such as diabetic cataracts9 neuropathy, nephropathy and retinopathy, see K.
Sestanj, N. Simard-Duquesne and D.M. Dvornik, U.S. Patent No. 3,821,383, June 28,1974. Other compounds having a similar utility are the thioxo-lH-benz~deJ -isoquinoline-2(3H~acetic acid derivatives of K. Sestanj, U.S. Patent No. 4,254,108, March 3, 1981 and lH-benz[de3 isoquinoline-2(3H)-acetic acid derivatives of K.
Sestanj, V.S. Patent No. 4,254,1097 March 3,1981. (S)-6-Fluoro-2,3-dihydrospiro~4H-1-ben~opyran-4,4'-imidazolidine)-2',5'-dione (sorbinil) is still another compound $hat has received attention because of its aldose reductase inhi~iting properties ~see M.J. Peterson et al., Metabolism, 28 (Suppl. 1), 456 ~1979). Accordingly, these compounds represent an important new approach for the treatment of diabetes mellitus.
The present application discloses novel N-(substituted-naphthoyl)gly-cine derivatives~ represented below by formula I, which are effeetive inhibitorsof 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 thioacylaminoacids, e~g. N-phenyl-thioxomethyl-N-methylglycine~ prepared by A. Lawson and C.E. Searle, J. Chem.
Soc., 1556 (1957) as part of a chemical investigation of the chemical propertiesOI such compounds. These last mentioned compounds were prepared by thi~
benzoylation of various amino acids with (thiobenzoylthio)acetic acid. An irn-portant structural difference between these compounds and the present derivatives is the different type of aromatic group substituted on the tIlione portion of the thioamide. Thioacylamides also have been reported [see Cilem. Abstr., 86,1895$2f (1977) for V.I. Cohen et ~I., EurO J. Med. Chem., 5, 480 (1976) and Chem. Abstr., 70,11306a (1969) for von J. Voss and W. Walter, Justus I.eibigs Ann. Chem., 716, 209 (1968)]. The structures of the thioacylamides of Cohesl et al and Yoss et al differ from the structure of the present derivatives by havillg at least a different type of N-substitution. Another close prior art compour1d, on Q structural basis, is N-L~l-naphthalenyl~carbonyl~ glycine, [see Chem. Abstr.,
Sestanj, N. Simard-Duquesne and D.M. Dvornik, U.S. Patent No. 3,821,383, June 28,1974. Other compounds having a similar utility are the thioxo-lH-benz~deJ -isoquinoline-2(3H~acetic acid derivatives of K. Sestanj, U.S. Patent No. 4,254,108, March 3, 1981 and lH-benz[de3 isoquinoline-2(3H)-acetic acid derivatives of K.
Sestanj, V.S. Patent No. 4,254,1097 March 3,1981. (S)-6-Fluoro-2,3-dihydrospiro~4H-1-ben~opyran-4,4'-imidazolidine)-2',5'-dione (sorbinil) is still another compound $hat has received attention because of its aldose reductase inhi~iting properties ~see M.J. Peterson et al., Metabolism, 28 (Suppl. 1), 456 ~1979). Accordingly, these compounds represent an important new approach for the treatment of diabetes mellitus.
The present application discloses novel N-(substituted-naphthoyl)gly-cine derivatives~ represented below by formula I, which are effeetive inhibitorsof 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 thioacylaminoacids, e~g. N-phenyl-thioxomethyl-N-methylglycine~ prepared by A. Lawson and C.E. Searle, J. Chem.
Soc., 1556 (1957) as part of a chemical investigation of the chemical propertiesOI such compounds. These last mentioned compounds were prepared by thi~
benzoylation of various amino acids with (thiobenzoylthio)acetic acid. An irn-portant structural difference between these compounds and the present derivatives is the different type of aromatic group substituted on the tIlione portion of the thioamide. Thioacylamides also have been reported [see Cilem. Abstr., 86,1895$2f (1977) for V.I. Cohen et ~I., EurO J. Med. Chem., 5, 480 (1976) and Chem. Abstr., 70,11306a (1969) for von J. Voss and W. Walter, Justus I.eibigs Ann. Chem., 716, 209 (1968)]. The structures of the thioacylamides of Cohesl et al and Yoss et al differ from the structure of the present derivatives by havillg at least a different type of N-substitution. Another close prior art compour1d, on Q structural basis, is N-L~l-naphthalenyl~carbonyl~ glycine, [see Chem. Abstr.,
-3 1~HP-780G-2 (CANADA) 61, 43X3f (1964~ for E. Cioranescu et al., Rev. Chim. Acad~ Rep. Populaire Rou-maine, 7 (2~, 755 (1962)]. The cornpound, which has been used as a chemical intermediate, is distinguished from the compounds of the present invention by being ~2 amide and not a thioamideO
Summary of the Invention The N-(substituted-naphthoyl)glycine derivatives of this invention are represented by form~a I
S-C-N(R ~-CH2COOR
0 ~ 2 (I) wherein Rl is lower alkyl; R2 is hydrogen or lower alkyl; R3 is a lower alkoxy at position 6 of the naphthalene ring, and R4 and R5 each is hydrogen; or R3, R4 and R5 each is a substîtuent at different positions selected from positions 47 5 and 6 of the naphthalene ring, the substituent being selected from the group consisting of lower alkoxy, halo and trihalomethyl; or a therapeutically acceptable salt with an organic or inorganic base of the compound of formula I wherein R2 is hydrogen.
A group of preferred derivatives is represented by the compounds of formlùa I wherein Rl is lower alkyl; R2 is hydrogen or lower alkyl; R3 is a lower alkoxy at position 6 of the naphthalene ring, and R4 and R5 each is hydrogen; or R3 is 4~10wer alkoxy, R4 is 5-halo or 5-(trifluoromethyl) and R5 is 6-lower alkoxy; or when R2 is hydrogen a therapeutically acceptable salt thereof with an organic or inorganic base.
A most preferred group of the compounds is represented by the compounds of formula I wherein Rl is lower alkyl, I~2 is hydrogen 01 lower alkyl;
R3 is a lower alkoxy at position 6 of the naphthalene ring and R4 and R5 each is hydrogen; or R3 is 4-lower alkoxy, R4 is 5-(trifluoromethyl) and R5 is 6-lower alkoxy; or when R is hydrogen a tllerapeutically acceptable sRlt tllereof with an organic or inorganic base.
Summary of the Invention The N-(substituted-naphthoyl)glycine derivatives of this invention are represented by form~a I
S-C-N(R ~-CH2COOR
0 ~ 2 (I) wherein Rl is lower alkyl; R2 is hydrogen or lower alkyl; R3 is a lower alkoxy at position 6 of the naphthalene ring, and R4 and R5 each is hydrogen; or R3, R4 and R5 each is a substîtuent at different positions selected from positions 47 5 and 6 of the naphthalene ring, the substituent being selected from the group consisting of lower alkoxy, halo and trihalomethyl; or a therapeutically acceptable salt with an organic or inorganic base of the compound of formula I wherein R2 is hydrogen.
A group of preferred derivatives is represented by the compounds of formlùa I wherein Rl is lower alkyl; R2 is hydrogen or lower alkyl; R3 is a lower alkoxy at position 6 of the naphthalene ring, and R4 and R5 each is hydrogen; or R3 is 4~10wer alkoxy, R4 is 5-halo or 5-(trifluoromethyl) and R5 is 6-lower alkoxy; or when R2 is hydrogen a therapeutically acceptable salt thereof with an organic or inorganic base.
A most preferred group of the compounds is represented by the compounds of formula I wherein Rl is lower alkyl, I~2 is hydrogen 01 lower alkyl;
R3 is a lower alkoxy at position 6 of the naphthalene ring and R4 and R5 each is hydrogen; or R3 is 4-lower alkoxy, R4 is 5-(trifluoromethyl) and R5 is 6-lower alkoxy; or when R is hydrogen a tllerapeutically acceptable sRlt tllereof with an organic or inorganic base.
-4- AHP-7806-2 (CANADA) A process and a Icey intermediate for the process are described here-inafter.
A method is provided for preventing or relieving diabetes mellitus associated complications in a diabetic mammal by adminis~ering to said mammal a prophylactic or alleviating amount of the compound of formula I or thera-peutically acceptable salt thereof with an organic or inorganic base.
The compound of formula I, or a therapeuticRlly acceptable salt thereo with an organic or inorganic base, when admixed with a pharmaceutically acceptable carrier, forms a pharmaeeutical composition which can be used IO according to the preceding method.
Detailed Description of the Invention The compounds of this in~ention, represented by formula I, c~n exist in rotameric forms. More explicitly, mesomerism imparts a partial double bond character to the carbon-nitrogen bond of the thio~mide group. This partial double bond character leads to restricted rotation about the carbon nitrogen bond giving rise to eis and trans rotamers, the restricted rot~tion being augmented by the bulkiness of neighbol ing groups~ Interconversion of the rotamers is pos-sible and is dependent on the physical environment. As evideneed by its physicalproperties, the thermodynamically more stable rotamer exists exclusively in ~0 the crystalline state of the compound and is the predominant isomer present in equilabrated solutions. Furthermore9 the more s-table rotamer is the more pharmacologically active. The less stable rotamer can be separated from the more stable rotamer by high performance liquid chromatography or by thin layer chromatography. The rotameric forms are includ~d within the scope of this invention. For brevity, the compounds of this invention~ ineluding~ their rotameric forms, are referred to herein as compounds of formula I.
The term "lower alkyl" as used herein means a straight chain alkyl radical containing from one to four carbon atoms or a bran~hed chain alkyl radical containing three or four carbon atoms and includes methyl, ethyl, propyl, l-methylethyl, butyl, 2-methylpropyl and l,l-dimethylethyl. Preferred lower alkyl radicals contain from one to three carbon atoms.
The terrn 'qower alko~y" as used herein means a straight chain alkoxy
A method is provided for preventing or relieving diabetes mellitus associated complications in a diabetic mammal by adminis~ering to said mammal a prophylactic or alleviating amount of the compound of formula I or thera-peutically acceptable salt thereof with an organic or inorganic base.
The compound of formula I, or a therapeuticRlly acceptable salt thereo with an organic or inorganic base, when admixed with a pharmaceutically acceptable carrier, forms a pharmaeeutical composition which can be used IO according to the preceding method.
Detailed Description of the Invention The compounds of this in~ention, represented by formula I, c~n exist in rotameric forms. More explicitly, mesomerism imparts a partial double bond character to the carbon-nitrogen bond of the thio~mide group. This partial double bond character leads to restricted rotation about the carbon nitrogen bond giving rise to eis and trans rotamers, the restricted rot~tion being augmented by the bulkiness of neighbol ing groups~ Interconversion of the rotamers is pos-sible and is dependent on the physical environment. As evideneed by its physicalproperties, the thermodynamically more stable rotamer exists exclusively in ~0 the crystalline state of the compound and is the predominant isomer present in equilabrated solutions. Furthermore9 the more s-table rotamer is the more pharmacologically active. The less stable rotamer can be separated from the more stable rotamer by high performance liquid chromatography or by thin layer chromatography. The rotameric forms are includ~d within the scope of this invention. For brevity, the compounds of this invention~ ineluding~ their rotameric forms, are referred to herein as compounds of formula I.
The term "lower alkyl" as used herein means a straight chain alkyl radical containing from one to four carbon atoms or a bran~hed chain alkyl radical containing three or four carbon atoms and includes methyl, ethyl, propyl, l-methylethyl, butyl, 2-methylpropyl and l,l-dimethylethyl. Preferred lower alkyl radicals contain from one to three carbon atoms.
The terrn 'qower alko~y" as used herein means a straight chain alkoxy
-5- ~HP-7806-2 (CANADA) radieal containing from one to six carbon atoms, preferably one to three carbon atoms, or a branched chain alkoxy radical containing three or four carbon atoms,and includes methoxy, ethoxy9 l-methylethoxy, butoacy and hexanoxy.
The term "halo" as used herein means Q halo radical and ineludes fluoro, chloro, bromo and iodo.
The term "ar" as used mean an aromatic radical containing at least one benzene ring. The preferred aromatic radical is phenyl.
The compounds of formula I wherein R2 is hydrogen form salts with suitable therapeutically acceptable inorganic and organic bases. These derived salts possess the same activity as their parent acid and are included within the seope of this invention. The acid is kansformed in excellent yield into the corresponding therapeutically acceptable salt by neutralization o~ said acidwith 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 hydroxides9 carbonates or bicarbonates of the therapeutically acceptable alkali metals or alkaline earth metals, for example, sodium, potaxsium, magnesium9 calcium and the likeO
Suitable organic bases include the following amines: benzylamine; lower mono -, di- and trialkylamines, the alkyl radicals of which contain up to three carbon atoms, such as methylamine, dimethylamine, trimethylamine, ethylamine, di-and triethylamine, methylethylamine, and the like; mono-, di- and trialkanol-amines? the alkanol radieals of which contain up 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 un-saturated bases ~ontaining up to six carbon atoms, such as pyrrolidine, piperidine, morpholine, piperazine and their N-alkyl and N-hydroxyalkyl derivatives, such as N-methyl-morpholine and N-(2-hydroxyethyl)-piperidine, as well as pyridine.
Furthermore, there may be mentioned the corresponding quaternary salts, such as the tetraalkyl (for example tetramethyl)9 alkyl-alkanol tfor e~sample methyl-triethanol and trimethyl-monoethanol) and cyclic ammonium salts? for example the N-methylpyridinium? N-methyl-N (2-hydroxyethyl)-morpholinium M,N-di-methylmorpholinium~ N-methyl-N-(2--hydroxyethyl)-morpholinium, N,N-dimethyl--~- AHl?-78n6 2 (CANADA) piperidinium salts, which are chnracterized by having good water-solubility.
In principle, however9 there can be used all the ammonium salts which are phy-siologically compatible.
The transfcrmations to the salts can be carried out by a variety 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 hydroxide, carbonate, or bicarbonate eorresponding to the inorganic salt desired. Advantageously, the reaction is performed in a water-miscible, inert organic solvent, for example, methanol, ethanol, dioxane, lo and the like in the presence of water. For example, such use of sodium hydroxide, sodium carbonate or sodium bicarbonate 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 low~r allcanol, for instance, butanol, or a lower alkanone, for instance, ethyl methyl ketone, gives the solid inorganic salt if that form is desired.
To produce an amine salt, the acidic compound of formula I is dis-svlved in a suitable solvent of either moderate or low polarity, for example, ethanol, methanol, ethyl acetate, diethyl ether Md benzene. At least an~ equiva-lent amount of the amine corresponding to the desired cation is then added to that solution. If the resulting salt does not precipitate, it can usually be obtained in solid form by addition of a miscible diluent of lower polarity, for example, ben~ene Ol petroleum ether~ or by evaporation. If the amine is re-latively volatile, any excess can easily be removed by evaporation. It is preferred to use substantially equivalent amounts of the less volatile amines.
Sal1s wherein the cation is quaternary ammonium are produced by mixing the acid of formula I with an equivalent amount of the corresponding quaternary ammonium hydroxide in water solution, followed by evaporation of the water.
The compounds of this invention and their addition salts with pharma~
ceutically acceptable organic or inorganic bases may be administered to mammals,for example, man, cattle or rabbits, eithar alone or in dosage forms, i.e., capsules or tablets, combined with pharmacologically ncceptable excipients, sea below.
Advantageously the compounds of this invention may be given orally. However, -7- AlIP-7806-2 (CANADA) the method of administering the present active ingredients of this invention is not to be construed as limited to a particular mode of administration. Por example, the compounds may be administered topically directly to the eye in the form of drops of sterile, buffered ophthalmic solutions, preferably of pH
7.2 - 7.5~ Also9 they may be administered orally in solid fol~m containing such excipients as starch, milk sugar, certain types o~ clay ~nd 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 l 0 acceptable buff er.
The dosage of the present therapeutic agents will vary with the form of administration and the particular compound chosen. Furthermore, it will vary with the particular host under tre~tment. Generally, treatment is initiated with sm~ll dosages substantially less than the optimal dose of the compound. Thereater, the dosage is increased by small increments ~mtil efficacyis obtained. In general9 the compounds of this invention are most desirably ad-ministered at a concentration level that will generally afford effective resultswithout causing any harmful or deleterious side effeets~ For topical administration a 0.05 - 0.2% solution may be administered dropwise to the eye. The frequen¢y of instillation varies with the subject under treatment from a drop every two or three days to once daily. For oral or parenteral administration a preferred level of dosage ranges from about 0.1 mg to about 200 mg per kilo of body weightper day, although aforementioned variations will occur. However, a dosage level that is in the range cf from about 0.5 mg to about 30 mg per kilo of body weightper day is most satisfactory.
Unit dosage forms such as capsules, tablets, pills and the lilce may contain from about 5.0 mg to about 250 mg of the active ingredients of this in-vention, prefera~ly with a significant quantity of a pharmaceutical carrier.
Thus, for oral administration, capsules can contain from between about 5.0 mg to about 250 mg of the active ingredients of this invention with or without a pharmaceutical diluent. Tablets, either effervescent or noneffervescent, can contain between about 5.0 to 250 mg of the active ingredients of this invention -8~ 1~HP-7806-2 (CANADA) together with conventional pharmaceutical curriers. Thus, tablets which may be coated and either efervescent or noneffervescent may be prepared according to the known art. Inert diluents or carriers, for example, magnesium carbonate or lactose, can be used together with conventional disintegrating agents for ex-ample, magnesium stearate.
Syrups or elixirs suitable for oral administration can be prepared rom water soluble salts, for example9 sodium N-~4,6-dimethoxy-5-(trifluoromethyl~
l-naphthalenyl] thioxomethyl]-N-methylglycinate, and may ~dvantageously contain glycerol and ethyl alcohol as solvents or preservatives.
The eompound of formula I~ or R therapeutically acceptable salt ther~
of, also can be used in combination with insulin or oral hypoglycemic agents to produce a beneficial effect in the treatment of diabetes mellitus. In this in-stance, commercially available insulin preparations or oral hypoglycemic agents,exemplified by acetohexamide, chlorpropamide, tolazamide, tolbutamide and phenformin, are suitable. The compound OI formula I, or a therapeutically ac-ceptable salt thereof, can be administered sequentially or simultaneously with insulin or the oral hypoglycemic agent. Suitable methods of administration, com-positions and doses of the insulin preparation or oral hypoglycemic agent are des-cribed in medical textbooks5 for instance, "Physicians' Desk Reference", 34 ed.,Medical Economics Co., 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 tllerapeutically ac-ceptable salt, can be administered with the oral hypoglycemic agent in the form of a pharmaceutical composition comprising effective amounts of each agent.
The aldose reductase inhibi$ing effects of the compounds of formula I
and their pharmaceutically acceptable salts with organic or inorganic bases can be demonstrated by employing an in vitro testing procedure similar to that described by S. Hayman and J. H. Kinoshita, J. Biol. Chem., 240, 877 (19B5). In the present case the procedure of Hayman and Kinoshita is modified in th~t the final chroma-tography step is omitted in the preparation of the enzyme from bovine lens.
For example, when N-[(6-methoxy-1-naphthalenyl)thioxomethyl] N-methylglycine, the compound of formula I wherein Rl is methyl, R2, R4 and R5 (CANADA) each is hydrogen and R3 is 6~methoxy, was evaluated in the above in vitro test, the aldose reductase from the bovine lens was inhibited 91, 81 and 39 percent bycompound concentrations of 1 x 10 571 X lo 6 Imd 1 x 10 7 M, respectively. Likewise, N-[[4,6-dimethoxy-5-(trifluoromethyl)-1-naphthEllenyl] thioxomethyl]-N-methyl-glycine, the compound of forMula I wherein Rl is methyl, R2 is hydrogen9 R3 is 4-methoxy3 R4 is 5-trifluoromethyl and R5 is 6-methoxy, inhibited the aldose reductase 97, 91 and 75 pereent by compowld concentrations of 1 x 10 5,1 x 10 and 1 x ln 7 M, respectively.
The aldose reductase inhibiting property of the compounds of this invention and the utilization of the compounds in preventing, diminishing and alleviating diabetic complications are demonstrable in experiments using galacto-semic rats, see Dvornik et al., cited above. Such experiments are exemplified hereinbelow after the listing of the following general comments pertaining to these experirnents:
(a) Four or more groups of six male rats, 50-70 g, Sprague-Dawley strain, were used. The first group, the contFol group, was fed a mixture of labora-tory chow (rodent laboratory chow, Purina) and glucose at 20% (w/w %) concen-tration. The untreated galactosemic group was fed a similar diet in which galactose is substituted for glucose. The third group was fed a diet prepared by mixing a given amount of the test compound with the galactose containing diet. The concentration of galactose in the diet of the treated groups was the same as that for the untreated galactosemic group.
(b) After four days, the animals were killed by decapitation. The eyeballs were removed and punctured with a razor blade; the freed lenses were rolled gently on filter paper and weighed. The sciatic nerves were dissected as completely as possible and uleighed. Both tissues were frozen and can be kept up to two weeks before being analyzed for dulcitol.
(c) The polyol determination was performed by a modification of the procedure o~ M. Kraml and L. Cosyns, Clin. Biochem., 2, ~73 (1969). Only two minor reagent changes were made: (a) The rinsing mixture was an aqlleous 5% (w/v) trichloroacetic acid solution and (b) the stock solution WRS prepared by dissolving 25 mg of dulcitol in 100 ml of an aqueous trichloroacetic acid so-lution.[N.B.: For each experiment the average value found in the tissue -10- AHP-7~306-2 (CANADA) from rats fed the glucose diet was subtracted from tlle individual values found in the corresponding rat tissue to obtain the amount of polyol accumulated.]
The following tabulated results show that the compounds of this invention diminish the accumulation of dulcitol in the lenses and sciatic nervesof rats fed galactose. The figures under L and N represent the percentage de-crease of dulcitol accumlllation in the tissues of the lens and sciati~ nerve, respectively, for treated rats as compared to untreated rats.
Compound of Formula I Dose L N
1~l R R3 R4 R5 mg/kg/day CH~ H 4-CH30 5-CF3 6-CH 0144 33 85 _ 48 . ~
Process The preparation of the compounds of formula I is illustrated by the following scheme wherein Rl, R3, R4 and R5 are as defined hereinbefore and 2n COC)R is an ester group which may be, for example, a lower alkyl or an ar(lower)-alkyl ester; i.e., R is lower alkyl or ar(lower)allcyl.
O-C-N~Rl)-CH2COOR S_C-N(Rl)-CH2COOR
25~ -- -->- R5~
1 hydrolysis 1 llydl`olysis -C-N(R )-Cll2C00l-1 R ~l~ p2s 5 I ~ R2 1~4 (IV) R
~7~3 More specifically, a process for preparing the compounds of formul~
I comprises:
(a) reaeting an amidoester of formula II wherein Rl~ R3, R4 and R are as defined herein and R is lower alkyl or ar(lower)alkyl with phosphorus pentasulfide to give the corresponding thioxoester of formula III wherein Rl, R3, R4, R5 and R are as defined hereirl; or (b) hydrolyzing the thioxoester of formula III wherein Rl, R, R4, R5 and R are as defined herein to obtain the corresponding cornpound of formula I wherein Rl, R3) R4 and R5 are as defined herein and R2 is hydrogen; or ~c) hydrolyzing the amidoester of formula II wherein Rl, R3, R4, R5 and R are as defined herein to obtain the corresponding amidoacid of formula IV wherein Rl, R3, R4 and R5 are as defined herein, and reacting the last-named compound with phosphorus pentasulfide to obtain the corresponding compound of formula I wherein Rl, R3, R4 and R5 are as defined herein and R2 is hydrogen.~eferring to the above seetion (a) of the last paragraph, the thioxo-ester of formula III includes those correspondin~ compounds of formula I whereinR is lower alkyl, when R of the compound of formula III is lower alkyl. For clarity and convenience in th~ following discussion of the process, these lattercompounds of formula I are included in the diseussion and preparation of the compounds of formula III.
Still more specifically, the starting material, namely t~se key inter-mediate of formula II, can be prepared by coupling a naphthalenecarboxylic acid of formula V wherein R3, R4 and R5 are as defined herein with an aminoacid ester of formula VI wherein Rl and R are as defined herein.
COOII
N~l ( R ) - C~12COOR
(V) (VI) The compounds of formula V and VI are known or c~n be prepared by known methods. For example, see "Elsevier's Encyclopaedia of Organic Chem-istry," F. Radt, ~d., Series III, Vol. 12B, Elsevier Publishing Co., Amsteldam, 7~3 (CANADA) 1953, pp 3965-4473. A preparntion of a naphthalenecarboxylic acid is illustratedby example 1 deseribed hereinafter. The coupling of the naphthalenecarboxylic acid V and the amino acid ester VI is done preferably by the "carboxyl activation"
coupling pro~edure. ~escriptions of carboxyl-activating groups are found in general textbooks of peptide chemistry; for example K.D. Kopple, "Peptides and Amino Acids?', W.A. Benjamin, Inc., New York, 1966, pp. 45-51, and E~. Schr~der and K. Llbke, "The Peptides"; Yol. 1, Academie Press, New York, 1965j pp. 77-128. Examples of the activated form of the terminal carboxyl are the acid chlo-ride, acid bromide, anhydride, azide, activated ester, or O-acyl urea obtained from a dialkylcarbodiimide. Preferred activated forms of the carboxyl are the acid chloride or the l-benæotriazolyl, 2,4,5-trichlorophenyl or succinimido activated esters.
Returning to the flow diagram again, the amidoester of formula II
is reacted under anhydrous conditions with about two to five molar equivalents of phosphorus pentasulfide in an inert solvent, e.g. xylene or toluene, to obtain the corresponding thioxoester of formula III. This re~ction is performed con-veniently at temperatures ranging from 80 to about 150 C and at times ranging from 20 minutes to four hours. Preferably, the reaction is performed in the presence OI an organic base for instance, N-ethyl morpholine, triethylamine or pyridine.
Thereafter, the thioxoester of formLla III is hydrolyzed with a hy-drolyzing agent to give the corresponding product of formula I in which R2 is hydrogen. Generally speaking, this conversion is most conveniently performed by employing a base as the hydrolyzing agent. The hydrolysis is performed in the presence of sufficient water, followed by acidification of the reaction mixture, to yield the desired acid. However7 it should be understood that the manner of hydrolysis for the process of this invention is not intended to be limited tobasic hydrolysis since hydrolysis under aeidic conditions and other variations, for example, treatment with lithium iodide in collidine (see L.F. Fieser and M.
~ieser, 1'Reagents for Organic Synthesis", John Wiley and Sons, Inc., New York, 1969, pp. 615-617), also are applicable~ Hydrolysis under acidic conditions is preferred when the ester is a tert butyl ester.
For b&sic hydrolysis, a preferred embodiment involves subjecting (CANADA) the ester to the action of a strong base, for example, sodium or potassium hy-droxide, in the presence of sufficient water to effect hydrolysis of the ester.
The hydrolysis is performed using a suitable solvent, for example, methanol, ethanol or 2-methoxyethanol. 1`he reaction mixture is rnaintained at a temperature of from about ~5 to 10Q C or at the reflux temperature of the solvent employeduntil hydrolysis occurs. Usually from 10 minutes to 6 hours is suf~icient for this hydrolysis. The reaction mixture is then rendered acidic with an acid, for example, acetic acid, hydrochloric acid or sulfuric acid to release the free acid.
Alternatively, the amidoester of formula II can be hydrolyzed under the same conditions as desclibed hereinbefore to give the corresponding amido-acid of formula IV wherein Rl, R3, R4 and R5 are as defined herein. The latter compound, when reacted with phosphorus pentasulfide in the manner described hereinbefore; then gives the corresponding compound of formula I wherein R ~
R3, R4 and R5 are as defined herein and R2 is hydrogen. Note that the standard first step of the work up of the pentasulfide reaction mixture requires that thereaction mixture be decomposed in water. This action causes any corresponding thioacid, present in the reaction mixture as a result of the carboxy group reacting with phosphorus pentasulfide, to be converted to the desired carboxylie acidu The following examples illustrate further this invention.
_XAMPLE 1 4,6-Dimethoxy-5-(trifluoromethyl)-1-naphthalenecarboxylic Acid (V, R3 = 4-CH30, R = 5-C~3 and R = 6-CH30) A stream of chlorine gas was passed through a cooled solution of NaOH ~17.28 g, 0.432 mole) in water (24 ml) containing 100 g of ice until 1~.7 g2s (0.18 mole) of chlorine was absorbed into the solution. S~lid (4,6-dimethoxy-1-naphthalenyl)ethanone [9.2 g, D.04 mole, described by N.P. Buu Hoi, J. Org. Chem., 21, 1257 (1956)], was added at 20-22 C to the chlorine solution. The mixture _ was stirred at 65 C for one hr, cooled in an ice bath and treated with NaHSO3 (5 g~ in water (20 ml). The mixture was made neutral by the addition of dilute HCl. The resulting precipitate was co~lected, washed well with water, dried over P205 and recrystallized from methanol to give 4,6-dimethoxy-1-naphtIl-alenecarboxylic acid (7.0 g); mp 227-229 C; NMR (DMSO-d6)~ 3~85 (s, 3H)9 (C~NADA) 4.0 ~s, 3H), 7.7 (m, 5H); IR (white mineral oil~ 2900, 1670 cm 1; UV~max (MeOH) 339 nm (~ 4,910), 328 ~4,5û0) 304 (8,180)9 240 (40,100); Anal Calcd: C, 67.23%
H, 5.21%9 Found: C, 67.15% E~, 5.23%.
The latter compound (98.5 g, 0.425 mole) was added to an ice-cooled solution of SOC12 (59.5 g, 0.5 mole) in anhydrous methanol 1225 ml). The mixture was heated at reflux for 18 hr. Another portion of SOC12 (35.5 ml) was added and the reflux was continued for another 7 hr. The mixture was extracted with diethyl ether. The ether extract was washed with water and then aqueous NaHCO3 solution, dried (Na2SO4) Rnd concentrated to dryness.
The soUd residue was crystallized from methanol (720 ml) to give 64 5 g of 4,6-dimethoxy-1-naphth~lenecarboxylic acid methyl ester; mp 102-104 C; NMR
(CDC13) ~ 3.9 ts, ~H), 4.0 (S9 3H), 7.7 (m, 5H).
The latter compound (4.93 g3 Q.02 mole) was suspended in 20%
(v/Y) aqueous acetic acid ~nd concentrated H2$O4 (0.279 ml). The mixture was stirred and heated at 60 C. Iodine (2 g, 0.008 mole~ and periodic acid (2.7~ g, 0.012 mole) was added to the mixture. The reaction mixture was stirred for one hr at the same temperature, cooled, poured into water and extracted with chloroform. The chloroform extract was washed with aqueous sodium bisulphite solution, washed with water and dried (Ma2S04). The chloroform extract was poured onto a column of 250 g of silica gel (prepared with 10~6 (v/v) ethyl acetate in hexane). The column was eluted with 1.5 liters of the same solvent system and then with 20% (v/v) ethyl acetate in hexane. The appropriate fractions were combined to give 5-iodo-4,6-dimethoxy-1-naphthalene-carboxylic acid methyl ester ~1.4 g, 80% pure). The pure compound, mp 120-122 C, was obtained by crystallization from ethyl acetate-hexane.
A mixture of the latter compound (~.1 gg 0.019 mole)~ freshly pre-pared copper powder (4.5 g, prepared according to the procedure OI R..Q. ~3rewster and T. Groening, "Organic Synthesis", Coll. Vol. II, John Wiley and Sons, New York, N.Y., U.S.A., 1948, p. 445), trifluoromethyl iodide (8.5 g, 0.43 mole~
and dry pyridine (35 ml) was heated for 20 hr at 120 C in an autoclave. Afte cooling to 22 to 2~1 C, the mixture was taken up in toluene and the toluene suspension was filtered. The filtrate was concentrated to ~yness under re-~CANADA) duced pressure. The residue was dissolved in chloroform. Insoluble matrial in the chioroform solution was removed by filtration. The filtrate was passed through a column of 75 g of silica gel and the column was elu-ted with chloroIorm.
The pure fractions were combined and crystallized from ethyl acetate-hexane to giYe 2.83 g of 4,6-dimethoxy-S-(trifluoromethyl)-l-naphthalenecarboxylic acid rnethyl ester; mp 120-123 C, NMR (CDC13) ~ 3095 (m, 9H), 6.8 and 8.05 ~2d, J = lOHz, 2H), 7.21 and 9.1 (2d, J = lOHz, 2H).
A suspension of the latter compound (2.83 ~9 02009 mol) in methanol (16.2 ml) and NaOH (5.4 ml OI a 4N ~queous solution) was heated a~ reflux under nitrogen for 10 min. The res7~ting clear solution was cooled in an ice bath and rendered acidic (pH = 3) with 2N aqueous HCl. The precipitate was collected, washed with water and dried over P~C)5 to give 2.7 g OI the title compound, m/e 300 (M ).
N-[[4,6-Dimethoxy-5-~trifluoromethyl)-1-naphthalenyl~ carbonyl]-N-methyl-glycine Methyl Ester (II, Rl and R = CH3~ R - 4-CH30, ~4 - 5-CF3 and R5 = 6-CH30) Procedure A:
A catalytic amount (5 dl`Op5) of dry climethylïormamide (DM~) was added to a suspension of the startin~ material of formula V, 4,6-dimethoxy-5-(trifluoromethyl)-1-naphthalenecarboxylic acid (10 g, 39 mmoles, deseribed in example 1), in thionyl chloride (100 rrl). The suspensiorl was heated cautiously to reflux (eaution: a vigorous reaction can occur~. The mixture was refluxed for 20 min. The mixture was evaporated to clryness. Toluene was added to the solid residue ~d the mixture was evaporated to dryness. The residue wa~
dissolved in pyridine (100 ml). The solution was cooled in an ice bath. Dry N-methylglycine methyl ester hydrochloride (ll.l g7 79.6 mmoles), a starting material of formula VI, was added portionwise to the cooled solution. The mixture was stirred for 2 hr at 20 C and then heated at reflu~ for 1 hr. The pyridine was removed by evaporation. Water was added to the oily residue.
The mixture was extracted with ethyl acetate (3 x 150 ml). The combined extracts were washed with IN aqueous HCl solution, a satJJrated solution of sodium bicarbonate and brine. After drying overMgSV4, the extract was subjected ~7~3 (CANADA) to chromatography on 325 g of silica gel usin~ ethyl acetate-chloroform (3:7) as the eluant. The pure fractions were pooled to yield the title compound as an oil, NMR (CDC13) ~ 2.78 (s, 3H), 3.6 (s, 3H), 3.85 (s, 3H~, 3.95 (s, 3H), 4~35 (m, ~H), 6.7-8.3 (m~ 4H).
Procedul e B:
A mixture of the starting material of formula V, 4,6-dimethoxy-5-(trifluoromethyl)-l-naphthalenecarbo2{ylic acid (2.7 g, 9.0 rnmoles), and 1-hydroxybenzotriazole (HOBt, 1.33 g, 9.9 mmoles) in DMF (12 ml~ was prepared.
N,N'-dicyclohexylcarbodiimide (DCC, 2.04 g, 9O9 mmoles) in DMF (7 ml) was added to the mixture. The resulting mixture was stirred at ~0 C for 1 hr and then cooled to û C. N-Methylglycine me~hyl ester hydrochloride (1.3 g, 9.9 mmoles) and then N-ethylmorpholine (1.3 ml, 9.9 mmoles) were added to the cooled mixture. The mixture was stirred for 30 min at 0 C and then for 18 hr at 2û C. Thereafter, the mixture was filtered and concentrated to dryness under reduced pressure. The residue was subjected to chromatography on 200 g of silica gel using ethyl acetate-chloroform (3:7) as the eluant. The pure fr~ctions were pooled to yield 2.5 g of the title compound, identieal to the product of procedure A of this example.
N ~[4,6-Dimethoxy-5-ttrifluoromethyl)-1-naphthalenyl3thioxomethyl~-N-methyl-glycine Methyl Ester (I, Rl and R2 = CH3, R3 = 4-CH3O~ R4 - 5-CF3 and RS
= 6-C~3O) To a stirred solution of N-[[4,6-dimethoxy-5-(trifluoromethyl)-1-naphthalenyl] carbonyl]-N-methylglycine methyl ester ~2.5 g'9 6.49 mmoles, described in example 2) in dry pyridine (16.2 ml), phosphorus pentasulfide (1.8 g, 8.1 mmoles) was added portionwise. The mixture was stirred and refluxed for 1.5 hr and then poured into water at 50 to 80 C (caution: eYolution of copious quantities of H2S). The mixture was allowed to cool to 20 to 22 C (room temperature), filtered and the filtrate was extracted with ethyl acet~te. The extract was washed with lN aqueous HCl solution, brine, a saturated solution of sodium carbonate and brine, dried (MgS04)9 filtered and evaporated to dry-ness. The residue was subjected to chromatography on silica gel using ethyl acetate-hexane (1:1~ as the eluant. The pure fractions were pooled and cry-(CANAD~) stallized frorn ethyl acetate-hexane to give 1.4 g of the title compound, NMR
(CDC13~ ~ 3.0 (s, 3H), 3.7 (s, 3H), 3.85 ~s, 3H), 3.95 (s, 3H), 4.35 and 5.45 (d, J- 20Hz, 2H), 608-8.2 (m, 4H).
By following serially ~he procedure of examples 2 and 3 but replacing 4,6-dimethoxy-5-(trifluorcmethyl)-1-naphthalenecarboxylic acid with an equiv-alent amount of another compound o formula V, other compounds o~ form~a I in which R2 is methyl are obtained. For example, replacement with 6-methoxy-l-naphthalenecarboxylic acid, described by C.C. Price et al., J. Am. Chem.
Soc., 69, 2261(1947) gave N-~(6-methoxy-1-naphthalenyl)thioxomethyl~-N-methyl-glycine methyl ester (I, Rl and R2 = CH3, R3 = 6-methoxy, and R4 and R5 = H), NMR (CDC13) ~ 3.02 (s, 3H~, 3.86 (s, 3H), 3.89 (s, 3H), 4.53 ~c 4.35 (d, J -17H~, 3H~, 6.90-8.10 (m, 6H), was obtained via N-[(6-methoxy-1 naphthalenyl~
carbonyl]-N-methylglycine methyl ester.
N-~[4,6-Dimethoxy-S-(trifluoromethyl)-l-naphthalenyl~ thioxomethyl]-N-methyl-glycine (Rl = CH3, R2 = H, R3 = 4-CH30, R4 = 5-GF3 and R5 = 6-CH30) A 4N aqueous NaOH solution (1.92 ml) was added to a suspension of N-[[4,6~dimethoxy-5-(trifluoromethyl)-1-naphthalenyl] thioxomethyl~ -N-metilylglycine methyl ester (1.55 g, 3 86 mmoles; described in example 3) in methanol (5.8 ml). The mixture was stirred and heated at 60~ C for 5 min under a nitrogen atmosphere. After cooling, the mixture was neutralized to pH 7 with aqueous HCl and extracted with ethyl acetate. The extract wa dried ~MgS04) and evaporated to dryness. The residue was dissolved in diethyl ether and filtered through a column of silica gel (14 g). The appropriate fr~ctions were combined and concentrated to give the title compound; NMR (CDC13) 3.05 ~s, 3~), 3~9 (s, 3H)~ 3.95 (S9 3M), 4.5 ~ 511 (2d, J = 17Hz, 2H), 6.75 ~s, lH)~
7.2 (m, 4H); IR (CHC13) 3000,172û, 1270,1130 cm 1; Anal Calcd: G~ 52.70%
H, 4.16% N, 3.61%~ Found: C, 52.83% H, 4.46% N, 3.57%.
By following the procedure of example ~, but replacing N-[[4,6-dimethoxy 5-(trifluoromethyl3-1-naphthalenyl]thioxonilethyl]-N-methylgly-cine methyl ester with an equivalent amount of another ester compound of formula I in which R is lower alkyl, or a corresponding compound of formula III in which R is ar(lower)aL'cyl, the corresponding compound of formula I in ~87~3 (CANADA) which R2 is hydrogen is obtained. For example, replacement with N-[(6-methoxy-l-naphthalenyl)thioxomethyl]-N-methylglycine methyl ester, described in example 3, gave N-[~6-methoxy-1-naphthalenyl)thioxomethyl]-N-methylglycine; mp 153-154 C, NMR ~DMS~d6) ~ 2.95 (s, 3H), 3.9 (s, 3H), 4.65 and 5.2 (2d, J
= 16.5 Hz, 2H), 7.5 (m, 6H).
The term "halo" as used herein means Q halo radical and ineludes fluoro, chloro, bromo and iodo.
The term "ar" as used mean an aromatic radical containing at least one benzene ring. The preferred aromatic radical is phenyl.
The compounds of formula I wherein R2 is hydrogen form salts with suitable therapeutically acceptable inorganic and organic bases. These derived salts possess the same activity as their parent acid and are included within the seope of this invention. The acid is kansformed in excellent yield into the corresponding therapeutically acceptable salt by neutralization o~ said acidwith 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 hydroxides9 carbonates or bicarbonates of the therapeutically acceptable alkali metals or alkaline earth metals, for example, sodium, potaxsium, magnesium9 calcium and the likeO
Suitable organic bases include the following amines: benzylamine; lower mono -, di- and trialkylamines, the alkyl radicals of which contain up to three carbon atoms, such as methylamine, dimethylamine, trimethylamine, ethylamine, di-and triethylamine, methylethylamine, and the like; mono-, di- and trialkanol-amines? the alkanol radieals of which contain up 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 un-saturated bases ~ontaining up to six carbon atoms, such as pyrrolidine, piperidine, morpholine, piperazine and their N-alkyl and N-hydroxyalkyl derivatives, such as N-methyl-morpholine and N-(2-hydroxyethyl)-piperidine, as well as pyridine.
Furthermore, there may be mentioned the corresponding quaternary salts, such as the tetraalkyl (for example tetramethyl)9 alkyl-alkanol tfor e~sample methyl-triethanol and trimethyl-monoethanol) and cyclic ammonium salts? for example the N-methylpyridinium? N-methyl-N (2-hydroxyethyl)-morpholinium M,N-di-methylmorpholinium~ N-methyl-N-(2--hydroxyethyl)-morpholinium, N,N-dimethyl--~- AHl?-78n6 2 (CANADA) piperidinium salts, which are chnracterized by having good water-solubility.
In principle, however9 there can be used all the ammonium salts which are phy-siologically compatible.
The transfcrmations to the salts can be carried out by a variety 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 hydroxide, carbonate, or bicarbonate eorresponding to the inorganic salt desired. Advantageously, the reaction is performed in a water-miscible, inert organic solvent, for example, methanol, ethanol, dioxane, lo and the like in the presence of water. For example, such use of sodium hydroxide, sodium carbonate or sodium bicarbonate 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 low~r allcanol, for instance, butanol, or a lower alkanone, for instance, ethyl methyl ketone, gives the solid inorganic salt if that form is desired.
To produce an amine salt, the acidic compound of formula I is dis-svlved in a suitable solvent of either moderate or low polarity, for example, ethanol, methanol, ethyl acetate, diethyl ether Md benzene. At least an~ equiva-lent amount of the amine corresponding to the desired cation is then added to that solution. If the resulting salt does not precipitate, it can usually be obtained in solid form by addition of a miscible diluent of lower polarity, for example, ben~ene Ol petroleum ether~ or by evaporation. If the amine is re-latively volatile, any excess can easily be removed by evaporation. It is preferred to use substantially equivalent amounts of the less volatile amines.
Sal1s wherein the cation is quaternary ammonium are produced by mixing the acid of formula I with an equivalent amount of the corresponding quaternary ammonium hydroxide in water solution, followed by evaporation of the water.
The compounds of this invention and their addition salts with pharma~
ceutically acceptable organic or inorganic bases may be administered to mammals,for example, man, cattle or rabbits, eithar alone or in dosage forms, i.e., capsules or tablets, combined with pharmacologically ncceptable excipients, sea below.
Advantageously the compounds of this invention may be given orally. However, -7- AlIP-7806-2 (CANADA) the method of administering the present active ingredients of this invention is not to be construed as limited to a particular mode of administration. Por example, the compounds may be administered topically directly to the eye in the form of drops of sterile, buffered ophthalmic solutions, preferably of pH
7.2 - 7.5~ Also9 they may be administered orally in solid fol~m containing such excipients as starch, milk sugar, certain types o~ clay ~nd 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 l 0 acceptable buff er.
The dosage of the present therapeutic agents will vary with the form of administration and the particular compound chosen. Furthermore, it will vary with the particular host under tre~tment. Generally, treatment is initiated with sm~ll dosages substantially less than the optimal dose of the compound. Thereater, the dosage is increased by small increments ~mtil efficacyis obtained. In general9 the compounds of this invention are most desirably ad-ministered at a concentration level that will generally afford effective resultswithout causing any harmful or deleterious side effeets~ For topical administration a 0.05 - 0.2% solution may be administered dropwise to the eye. The frequen¢y of instillation varies with the subject under treatment from a drop every two or three days to once daily. For oral or parenteral administration a preferred level of dosage ranges from about 0.1 mg to about 200 mg per kilo of body weightper day, although aforementioned variations will occur. However, a dosage level that is in the range cf from about 0.5 mg to about 30 mg per kilo of body weightper day is most satisfactory.
Unit dosage forms such as capsules, tablets, pills and the lilce may contain from about 5.0 mg to about 250 mg of the active ingredients of this in-vention, prefera~ly with a significant quantity of a pharmaceutical carrier.
Thus, for oral administration, capsules can contain from between about 5.0 mg to about 250 mg of the active ingredients of this invention with or without a pharmaceutical diluent. Tablets, either effervescent or noneffervescent, can contain between about 5.0 to 250 mg of the active ingredients of this invention -8~ 1~HP-7806-2 (CANADA) together with conventional pharmaceutical curriers. Thus, tablets which may be coated and either efervescent or noneffervescent may be prepared according to the known art. Inert diluents or carriers, for example, magnesium carbonate or lactose, can be used together with conventional disintegrating agents for ex-ample, magnesium stearate.
Syrups or elixirs suitable for oral administration can be prepared rom water soluble salts, for example9 sodium N-~4,6-dimethoxy-5-(trifluoromethyl~
l-naphthalenyl] thioxomethyl]-N-methylglycinate, and may ~dvantageously contain glycerol and ethyl alcohol as solvents or preservatives.
The eompound of formula I~ or R therapeutically acceptable salt ther~
of, also can be used in combination with insulin or oral hypoglycemic agents to produce a beneficial effect in the treatment of diabetes mellitus. In this in-stance, commercially available insulin preparations or oral hypoglycemic agents,exemplified by acetohexamide, chlorpropamide, tolazamide, tolbutamide and phenformin, are suitable. The compound OI formula I, or a therapeutically ac-ceptable salt thereof, can be administered sequentially or simultaneously with insulin or the oral hypoglycemic agent. Suitable methods of administration, com-positions and doses of the insulin preparation or oral hypoglycemic agent are des-cribed in medical textbooks5 for instance, "Physicians' Desk Reference", 34 ed.,Medical Economics Co., 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 tllerapeutically ac-ceptable salt, can be administered with the oral hypoglycemic agent in the form of a pharmaceutical composition comprising effective amounts of each agent.
The aldose reductase inhibi$ing effects of the compounds of formula I
and their pharmaceutically acceptable salts with organic or inorganic bases can be demonstrated by employing an in vitro testing procedure similar to that described by S. Hayman and J. H. Kinoshita, J. Biol. Chem., 240, 877 (19B5). In the present case the procedure of Hayman and Kinoshita is modified in th~t the final chroma-tography step is omitted in the preparation of the enzyme from bovine lens.
For example, when N-[(6-methoxy-1-naphthalenyl)thioxomethyl] N-methylglycine, the compound of formula I wherein Rl is methyl, R2, R4 and R5 (CANADA) each is hydrogen and R3 is 6~methoxy, was evaluated in the above in vitro test, the aldose reductase from the bovine lens was inhibited 91, 81 and 39 percent bycompound concentrations of 1 x 10 571 X lo 6 Imd 1 x 10 7 M, respectively. Likewise, N-[[4,6-dimethoxy-5-(trifluoromethyl)-1-naphthEllenyl] thioxomethyl]-N-methyl-glycine, the compound of forMula I wherein Rl is methyl, R2 is hydrogen9 R3 is 4-methoxy3 R4 is 5-trifluoromethyl and R5 is 6-methoxy, inhibited the aldose reductase 97, 91 and 75 pereent by compowld concentrations of 1 x 10 5,1 x 10 and 1 x ln 7 M, respectively.
The aldose reductase inhibiting property of the compounds of this invention and the utilization of the compounds in preventing, diminishing and alleviating diabetic complications are demonstrable in experiments using galacto-semic rats, see Dvornik et al., cited above. Such experiments are exemplified hereinbelow after the listing of the following general comments pertaining to these experirnents:
(a) Four or more groups of six male rats, 50-70 g, Sprague-Dawley strain, were used. The first group, the contFol group, was fed a mixture of labora-tory chow (rodent laboratory chow, Purina) and glucose at 20% (w/w %) concen-tration. The untreated galactosemic group was fed a similar diet in which galactose is substituted for glucose. The third group was fed a diet prepared by mixing a given amount of the test compound with the galactose containing diet. The concentration of galactose in the diet of the treated groups was the same as that for the untreated galactosemic group.
(b) After four days, the animals were killed by decapitation. The eyeballs were removed and punctured with a razor blade; the freed lenses were rolled gently on filter paper and weighed. The sciatic nerves were dissected as completely as possible and uleighed. Both tissues were frozen and can be kept up to two weeks before being analyzed for dulcitol.
(c) The polyol determination was performed by a modification of the procedure o~ M. Kraml and L. Cosyns, Clin. Biochem., 2, ~73 (1969). Only two minor reagent changes were made: (a) The rinsing mixture was an aqlleous 5% (w/v) trichloroacetic acid solution and (b) the stock solution WRS prepared by dissolving 25 mg of dulcitol in 100 ml of an aqueous trichloroacetic acid so-lution.[N.B.: For each experiment the average value found in the tissue -10- AHP-7~306-2 (CANADA) from rats fed the glucose diet was subtracted from tlle individual values found in the corresponding rat tissue to obtain the amount of polyol accumulated.]
The following tabulated results show that the compounds of this invention diminish the accumulation of dulcitol in the lenses and sciatic nervesof rats fed galactose. The figures under L and N represent the percentage de-crease of dulcitol accumlllation in the tissues of the lens and sciati~ nerve, respectively, for treated rats as compared to untreated rats.
Compound of Formula I Dose L N
1~l R R3 R4 R5 mg/kg/day CH~ H 4-CH30 5-CF3 6-CH 0144 33 85 _ 48 . ~
Process The preparation of the compounds of formula I is illustrated by the following scheme wherein Rl, R3, R4 and R5 are as defined hereinbefore and 2n COC)R is an ester group which may be, for example, a lower alkyl or an ar(lower)-alkyl ester; i.e., R is lower alkyl or ar(lower)allcyl.
O-C-N~Rl)-CH2COOR S_C-N(Rl)-CH2COOR
25~ -- -->- R5~
1 hydrolysis 1 llydl`olysis -C-N(R )-Cll2C00l-1 R ~l~ p2s 5 I ~ R2 1~4 (IV) R
~7~3 More specifically, a process for preparing the compounds of formul~
I comprises:
(a) reaeting an amidoester of formula II wherein Rl~ R3, R4 and R are as defined herein and R is lower alkyl or ar(lower)alkyl with phosphorus pentasulfide to give the corresponding thioxoester of formula III wherein Rl, R3, R4, R5 and R are as defined hereirl; or (b) hydrolyzing the thioxoester of formula III wherein Rl, R, R4, R5 and R are as defined herein to obtain the corresponding cornpound of formula I wherein Rl, R3) R4 and R5 are as defined herein and R2 is hydrogen; or ~c) hydrolyzing the amidoester of formula II wherein Rl, R3, R4, R5 and R are as defined herein to obtain the corresponding amidoacid of formula IV wherein Rl, R3, R4 and R5 are as defined herein, and reacting the last-named compound with phosphorus pentasulfide to obtain the corresponding compound of formula I wherein Rl, R3, R4 and R5 are as defined herein and R2 is hydrogen.~eferring to the above seetion (a) of the last paragraph, the thioxo-ester of formula III includes those correspondin~ compounds of formula I whereinR is lower alkyl, when R of the compound of formula III is lower alkyl. For clarity and convenience in th~ following discussion of the process, these lattercompounds of formula I are included in the diseussion and preparation of the compounds of formula III.
Still more specifically, the starting material, namely t~se key inter-mediate of formula II, can be prepared by coupling a naphthalenecarboxylic acid of formula V wherein R3, R4 and R5 are as defined herein with an aminoacid ester of formula VI wherein Rl and R are as defined herein.
COOII
N~l ( R ) - C~12COOR
(V) (VI) The compounds of formula V and VI are known or c~n be prepared by known methods. For example, see "Elsevier's Encyclopaedia of Organic Chem-istry," F. Radt, ~d., Series III, Vol. 12B, Elsevier Publishing Co., Amsteldam, 7~3 (CANADA) 1953, pp 3965-4473. A preparntion of a naphthalenecarboxylic acid is illustratedby example 1 deseribed hereinafter. The coupling of the naphthalenecarboxylic acid V and the amino acid ester VI is done preferably by the "carboxyl activation"
coupling pro~edure. ~escriptions of carboxyl-activating groups are found in general textbooks of peptide chemistry; for example K.D. Kopple, "Peptides and Amino Acids?', W.A. Benjamin, Inc., New York, 1966, pp. 45-51, and E~. Schr~der and K. Llbke, "The Peptides"; Yol. 1, Academie Press, New York, 1965j pp. 77-128. Examples of the activated form of the terminal carboxyl are the acid chlo-ride, acid bromide, anhydride, azide, activated ester, or O-acyl urea obtained from a dialkylcarbodiimide. Preferred activated forms of the carboxyl are the acid chloride or the l-benæotriazolyl, 2,4,5-trichlorophenyl or succinimido activated esters.
Returning to the flow diagram again, the amidoester of formula II
is reacted under anhydrous conditions with about two to five molar equivalents of phosphorus pentasulfide in an inert solvent, e.g. xylene or toluene, to obtain the corresponding thioxoester of formula III. This re~ction is performed con-veniently at temperatures ranging from 80 to about 150 C and at times ranging from 20 minutes to four hours. Preferably, the reaction is performed in the presence OI an organic base for instance, N-ethyl morpholine, triethylamine or pyridine.
Thereafter, the thioxoester of formLla III is hydrolyzed with a hy-drolyzing agent to give the corresponding product of formula I in which R2 is hydrogen. Generally speaking, this conversion is most conveniently performed by employing a base as the hydrolyzing agent. The hydrolysis is performed in the presence of sufficient water, followed by acidification of the reaction mixture, to yield the desired acid. However7 it should be understood that the manner of hydrolysis for the process of this invention is not intended to be limited tobasic hydrolysis since hydrolysis under aeidic conditions and other variations, for example, treatment with lithium iodide in collidine (see L.F. Fieser and M.
~ieser, 1'Reagents for Organic Synthesis", John Wiley and Sons, Inc., New York, 1969, pp. 615-617), also are applicable~ Hydrolysis under acidic conditions is preferred when the ester is a tert butyl ester.
For b&sic hydrolysis, a preferred embodiment involves subjecting (CANADA) the ester to the action of a strong base, for example, sodium or potassium hy-droxide, in the presence of sufficient water to effect hydrolysis of the ester.
The hydrolysis is performed using a suitable solvent, for example, methanol, ethanol or 2-methoxyethanol. 1`he reaction mixture is rnaintained at a temperature of from about ~5 to 10Q C or at the reflux temperature of the solvent employeduntil hydrolysis occurs. Usually from 10 minutes to 6 hours is suf~icient for this hydrolysis. The reaction mixture is then rendered acidic with an acid, for example, acetic acid, hydrochloric acid or sulfuric acid to release the free acid.
Alternatively, the amidoester of formula II can be hydrolyzed under the same conditions as desclibed hereinbefore to give the corresponding amido-acid of formula IV wherein Rl, R3, R4 and R5 are as defined herein. The latter compound, when reacted with phosphorus pentasulfide in the manner described hereinbefore; then gives the corresponding compound of formula I wherein R ~
R3, R4 and R5 are as defined herein and R2 is hydrogen. Note that the standard first step of the work up of the pentasulfide reaction mixture requires that thereaction mixture be decomposed in water. This action causes any corresponding thioacid, present in the reaction mixture as a result of the carboxy group reacting with phosphorus pentasulfide, to be converted to the desired carboxylie acidu The following examples illustrate further this invention.
_XAMPLE 1 4,6-Dimethoxy-5-(trifluoromethyl)-1-naphthalenecarboxylic Acid (V, R3 = 4-CH30, R = 5-C~3 and R = 6-CH30) A stream of chlorine gas was passed through a cooled solution of NaOH ~17.28 g, 0.432 mole) in water (24 ml) containing 100 g of ice until 1~.7 g2s (0.18 mole) of chlorine was absorbed into the solution. S~lid (4,6-dimethoxy-1-naphthalenyl)ethanone [9.2 g, D.04 mole, described by N.P. Buu Hoi, J. Org. Chem., 21, 1257 (1956)], was added at 20-22 C to the chlorine solution. The mixture _ was stirred at 65 C for one hr, cooled in an ice bath and treated with NaHSO3 (5 g~ in water (20 ml). The mixture was made neutral by the addition of dilute HCl. The resulting precipitate was co~lected, washed well with water, dried over P205 and recrystallized from methanol to give 4,6-dimethoxy-1-naphtIl-alenecarboxylic acid (7.0 g); mp 227-229 C; NMR (DMSO-d6)~ 3~85 (s, 3H)9 (C~NADA) 4.0 ~s, 3H), 7.7 (m, 5H); IR (white mineral oil~ 2900, 1670 cm 1; UV~max (MeOH) 339 nm (~ 4,910), 328 ~4,5û0) 304 (8,180)9 240 (40,100); Anal Calcd: C, 67.23%
H, 5.21%9 Found: C, 67.15% E~, 5.23%.
The latter compound (98.5 g, 0.425 mole) was added to an ice-cooled solution of SOC12 (59.5 g, 0.5 mole) in anhydrous methanol 1225 ml). The mixture was heated at reflux for 18 hr. Another portion of SOC12 (35.5 ml) was added and the reflux was continued for another 7 hr. The mixture was extracted with diethyl ether. The ether extract was washed with water and then aqueous NaHCO3 solution, dried (Na2SO4) Rnd concentrated to dryness.
The soUd residue was crystallized from methanol (720 ml) to give 64 5 g of 4,6-dimethoxy-1-naphth~lenecarboxylic acid methyl ester; mp 102-104 C; NMR
(CDC13) ~ 3.9 ts, ~H), 4.0 (S9 3H), 7.7 (m, 5H).
The latter compound (4.93 g3 Q.02 mole) was suspended in 20%
(v/Y) aqueous acetic acid ~nd concentrated H2$O4 (0.279 ml). The mixture was stirred and heated at 60 C. Iodine (2 g, 0.008 mole~ and periodic acid (2.7~ g, 0.012 mole) was added to the mixture. The reaction mixture was stirred for one hr at the same temperature, cooled, poured into water and extracted with chloroform. The chloroform extract was washed with aqueous sodium bisulphite solution, washed with water and dried (Ma2S04). The chloroform extract was poured onto a column of 250 g of silica gel (prepared with 10~6 (v/v) ethyl acetate in hexane). The column was eluted with 1.5 liters of the same solvent system and then with 20% (v/v) ethyl acetate in hexane. The appropriate fractions were combined to give 5-iodo-4,6-dimethoxy-1-naphthalene-carboxylic acid methyl ester ~1.4 g, 80% pure). The pure compound, mp 120-122 C, was obtained by crystallization from ethyl acetate-hexane.
A mixture of the latter compound (~.1 gg 0.019 mole)~ freshly pre-pared copper powder (4.5 g, prepared according to the procedure OI R..Q. ~3rewster and T. Groening, "Organic Synthesis", Coll. Vol. II, John Wiley and Sons, New York, N.Y., U.S.A., 1948, p. 445), trifluoromethyl iodide (8.5 g, 0.43 mole~
and dry pyridine (35 ml) was heated for 20 hr at 120 C in an autoclave. Afte cooling to 22 to 2~1 C, the mixture was taken up in toluene and the toluene suspension was filtered. The filtrate was concentrated to ~yness under re-~CANADA) duced pressure. The residue was dissolved in chloroform. Insoluble matrial in the chioroform solution was removed by filtration. The filtrate was passed through a column of 75 g of silica gel and the column was elu-ted with chloroIorm.
The pure fractions were combined and crystallized from ethyl acetate-hexane to giYe 2.83 g of 4,6-dimethoxy-S-(trifluoromethyl)-l-naphthalenecarboxylic acid rnethyl ester; mp 120-123 C, NMR (CDC13) ~ 3095 (m, 9H), 6.8 and 8.05 ~2d, J = lOHz, 2H), 7.21 and 9.1 (2d, J = lOHz, 2H).
A suspension of the latter compound (2.83 ~9 02009 mol) in methanol (16.2 ml) and NaOH (5.4 ml OI a 4N ~queous solution) was heated a~ reflux under nitrogen for 10 min. The res7~ting clear solution was cooled in an ice bath and rendered acidic (pH = 3) with 2N aqueous HCl. The precipitate was collected, washed with water and dried over P~C)5 to give 2.7 g OI the title compound, m/e 300 (M ).
N-[[4,6-Dimethoxy-5-~trifluoromethyl)-1-naphthalenyl~ carbonyl]-N-methyl-glycine Methyl Ester (II, Rl and R = CH3~ R - 4-CH30, ~4 - 5-CF3 and R5 = 6-CH30) Procedure A:
A catalytic amount (5 dl`Op5) of dry climethylïormamide (DM~) was added to a suspension of the startin~ material of formula V, 4,6-dimethoxy-5-(trifluoromethyl)-1-naphthalenecarboxylic acid (10 g, 39 mmoles, deseribed in example 1), in thionyl chloride (100 rrl). The suspensiorl was heated cautiously to reflux (eaution: a vigorous reaction can occur~. The mixture was refluxed for 20 min. The mixture was evaporated to clryness. Toluene was added to the solid residue ~d the mixture was evaporated to dryness. The residue wa~
dissolved in pyridine (100 ml). The solution was cooled in an ice bath. Dry N-methylglycine methyl ester hydrochloride (ll.l g7 79.6 mmoles), a starting material of formula VI, was added portionwise to the cooled solution. The mixture was stirred for 2 hr at 20 C and then heated at reflu~ for 1 hr. The pyridine was removed by evaporation. Water was added to the oily residue.
The mixture was extracted with ethyl acetate (3 x 150 ml). The combined extracts were washed with IN aqueous HCl solution, a satJJrated solution of sodium bicarbonate and brine. After drying overMgSV4, the extract was subjected ~7~3 (CANADA) to chromatography on 325 g of silica gel usin~ ethyl acetate-chloroform (3:7) as the eluant. The pure fractions were pooled to yield the title compound as an oil, NMR (CDC13) ~ 2.78 (s, 3H), 3.6 (s, 3H), 3.85 (s, 3H~, 3.95 (s, 3H), 4~35 (m, ~H), 6.7-8.3 (m~ 4H).
Procedul e B:
A mixture of the starting material of formula V, 4,6-dimethoxy-5-(trifluoromethyl)-l-naphthalenecarbo2{ylic acid (2.7 g, 9.0 rnmoles), and 1-hydroxybenzotriazole (HOBt, 1.33 g, 9.9 mmoles) in DMF (12 ml~ was prepared.
N,N'-dicyclohexylcarbodiimide (DCC, 2.04 g, 9O9 mmoles) in DMF (7 ml) was added to the mixture. The resulting mixture was stirred at ~0 C for 1 hr and then cooled to û C. N-Methylglycine me~hyl ester hydrochloride (1.3 g, 9.9 mmoles) and then N-ethylmorpholine (1.3 ml, 9.9 mmoles) were added to the cooled mixture. The mixture was stirred for 30 min at 0 C and then for 18 hr at 2û C. Thereafter, the mixture was filtered and concentrated to dryness under reduced pressure. The residue was subjected to chromatography on 200 g of silica gel using ethyl acetate-chloroform (3:7) as the eluant. The pure fr~ctions were pooled to yield 2.5 g of the title compound, identieal to the product of procedure A of this example.
N ~[4,6-Dimethoxy-5-ttrifluoromethyl)-1-naphthalenyl3thioxomethyl~-N-methyl-glycine Methyl Ester (I, Rl and R2 = CH3, R3 = 4-CH3O~ R4 - 5-CF3 and RS
= 6-C~3O) To a stirred solution of N-[[4,6-dimethoxy-5-(trifluoromethyl)-1-naphthalenyl] carbonyl]-N-methylglycine methyl ester ~2.5 g'9 6.49 mmoles, described in example 2) in dry pyridine (16.2 ml), phosphorus pentasulfide (1.8 g, 8.1 mmoles) was added portionwise. The mixture was stirred and refluxed for 1.5 hr and then poured into water at 50 to 80 C (caution: eYolution of copious quantities of H2S). The mixture was allowed to cool to 20 to 22 C (room temperature), filtered and the filtrate was extracted with ethyl acet~te. The extract was washed with lN aqueous HCl solution, brine, a saturated solution of sodium carbonate and brine, dried (MgS04)9 filtered and evaporated to dry-ness. The residue was subjected to chromatography on silica gel using ethyl acetate-hexane (1:1~ as the eluant. The pure fractions were pooled and cry-(CANAD~) stallized frorn ethyl acetate-hexane to give 1.4 g of the title compound, NMR
(CDC13~ ~ 3.0 (s, 3H), 3.7 (s, 3H), 3.85 ~s, 3H), 3.95 (s, 3H), 4.35 and 5.45 (d, J- 20Hz, 2H), 608-8.2 (m, 4H).
By following serially ~he procedure of examples 2 and 3 but replacing 4,6-dimethoxy-5-(trifluorcmethyl)-1-naphthalenecarboxylic acid with an equiv-alent amount of another compound o formula V, other compounds o~ form~a I in which R2 is methyl are obtained. For example, replacement with 6-methoxy-l-naphthalenecarboxylic acid, described by C.C. Price et al., J. Am. Chem.
Soc., 69, 2261(1947) gave N-~(6-methoxy-1-naphthalenyl)thioxomethyl~-N-methyl-glycine methyl ester (I, Rl and R2 = CH3, R3 = 6-methoxy, and R4 and R5 = H), NMR (CDC13) ~ 3.02 (s, 3H~, 3.86 (s, 3H), 3.89 (s, 3H), 4.53 ~c 4.35 (d, J -17H~, 3H~, 6.90-8.10 (m, 6H), was obtained via N-[(6-methoxy-1 naphthalenyl~
carbonyl]-N-methylglycine methyl ester.
N-~[4,6-Dimethoxy-S-(trifluoromethyl)-l-naphthalenyl~ thioxomethyl]-N-methyl-glycine (Rl = CH3, R2 = H, R3 = 4-CH30, R4 = 5-GF3 and R5 = 6-CH30) A 4N aqueous NaOH solution (1.92 ml) was added to a suspension of N-[[4,6~dimethoxy-5-(trifluoromethyl)-1-naphthalenyl] thioxomethyl~ -N-metilylglycine methyl ester (1.55 g, 3 86 mmoles; described in example 3) in methanol (5.8 ml). The mixture was stirred and heated at 60~ C for 5 min under a nitrogen atmosphere. After cooling, the mixture was neutralized to pH 7 with aqueous HCl and extracted with ethyl acetate. The extract wa dried ~MgS04) and evaporated to dryness. The residue was dissolved in diethyl ether and filtered through a column of silica gel (14 g). The appropriate fr~ctions were combined and concentrated to give the title compound; NMR (CDC13) 3.05 ~s, 3~), 3~9 (s, 3H)~ 3.95 (S9 3M), 4.5 ~ 511 (2d, J = 17Hz, 2H), 6.75 ~s, lH)~
7.2 (m, 4H); IR (CHC13) 3000,172û, 1270,1130 cm 1; Anal Calcd: G~ 52.70%
H, 4.16% N, 3.61%~ Found: C, 52.83% H, 4.46% N, 3.57%.
By following the procedure of example ~, but replacing N-[[4,6-dimethoxy 5-(trifluoromethyl3-1-naphthalenyl]thioxonilethyl]-N-methylgly-cine methyl ester with an equivalent amount of another ester compound of formula I in which R is lower alkyl, or a corresponding compound of formula III in which R is ar(lower)aL'cyl, the corresponding compound of formula I in ~87~3 (CANADA) which R2 is hydrogen is obtained. For example, replacement with N-[(6-methoxy-l-naphthalenyl)thioxomethyl]-N-methylglycine methyl ester, described in example 3, gave N-[~6-methoxy-1-naphthalenyl)thioxomethyl]-N-methylglycine; mp 153-154 C, NMR ~DMS~d6) ~ 2.95 (s, 3H), 3.9 (s, 3H), 4.65 and 5.2 (2d, J
= 16.5 Hz, 2H), 7.5 (m, 6H).
Claims (22)
1. A process for preparing a compound of formula I
(I) wherein R1 is lower alkyl; R2 is hydrogen or lower alkyl; R3 is a lower alkoxy at position 6 of the naphthalene ring, and R4 and R5 each is hydrogen; or R3, R4 and R5 each is a substituent at different positions selected from positions 4, 5 and 6 of the naphthalene ring, the substituent being selected from the group consisting of lower alkoxy, halo and trihalomethyl; or a therapeutically acceptable salt with an organic or inorganic base of the compound of formula I wherein R2 is hydrogen; which comprises:
(a) reacting an amidoester of formula II
(II) wherein R1, R3, R4 and R5 are as defined in this claim and R is lower alkyl or ar(lower)alkyl to obtain the corresponding compound of formula I wherein R1, R3, R4 and R5 are as defined in this claim and R2 is hydrogen; or (b) hydrolyzing the compound of formula III
(III) wherein R1, R3, R4 and R5 are as defined in this claim and R is lower alkyl or ar(lower)alkyl to obtain the corresponding compound of formula I wherein R1, R3, R4 and R5 are as defined in this claim and R2 is hydrogen; or (c) reacting the amidoacid of formula IV
(IV) wherein R1, R3, R4 and R5 are as defined in this claim with phosphorus penta-sulfide to obtain the correspoding compound of formula I wherein R1, R3, R4 and R5 are as defined in this claim and R2 is hydrogen; and (d) if required, transforming the compound of formula I wherein R1, R3, R4 and R5 are as defined in this claim and R2 is hydrogen into a corres-ponding therapeutically acceptable salt of an organic or inorganic base.
(I) wherein R1 is lower alkyl; R2 is hydrogen or lower alkyl; R3 is a lower alkoxy at position 6 of the naphthalene ring, and R4 and R5 each is hydrogen; or R3, R4 and R5 each is a substituent at different positions selected from positions 4, 5 and 6 of the naphthalene ring, the substituent being selected from the group consisting of lower alkoxy, halo and trihalomethyl; or a therapeutically acceptable salt with an organic or inorganic base of the compound of formula I wherein R2 is hydrogen; which comprises:
(a) reacting an amidoester of formula II
(II) wherein R1, R3, R4 and R5 are as defined in this claim and R is lower alkyl or ar(lower)alkyl to obtain the corresponding compound of formula I wherein R1, R3, R4 and R5 are as defined in this claim and R2 is hydrogen; or (b) hydrolyzing the compound of formula III
(III) wherein R1, R3, R4 and R5 are as defined in this claim and R is lower alkyl or ar(lower)alkyl to obtain the corresponding compound of formula I wherein R1, R3, R4 and R5 are as defined in this claim and R2 is hydrogen; or (c) reacting the amidoacid of formula IV
(IV) wherein R1, R3, R4 and R5 are as defined in this claim with phosphorus penta-sulfide to obtain the correspoding compound of formula I wherein R1, R3, R4 and R5 are as defined in this claim and R2 is hydrogen; and (d) if required, transforming the compound of formula I wherein R1, R3, R4 and R5 are as defined in this claim and R2 is hydrogen into a corres-ponding therapeutically acceptable salt of an organic or inorganic base.
2. The compound of formula I, as defined in claim 1, or when R2 is hydrogen a therapeutically acceptable salt thereof with an organic or inorganic base, when prepared by the process of claim 1 or an obvious chemical equivalent thereof.
3. The process of claim 1 which comprises reacting the amido-ester of formula II wherein R1, R3, R4 and R5 are as defined in claim 1 and R is lower alkyl with phosphorus pentasulfide to obtain the corresponding com-pound of formula I wherein R1, R3, R4 and R5 are as defined in claim 1 and R2 is lower alkyl.
4. The compound of formula I, as defined in claim 3, when prepared by the process of claim 3 or an obvious chemical equivalent thereof.
5. The process of claim 3 which comprises reacting the amido-ester of formula II wherein R1 is lower alkyl; R3 is a lower alkoxy at position 6 of the naphthalene ring and R4 and R5 each is hydrogen or R3 is 4-lower alkoxy, R4 is 5-halo or 5-(trifluoromethyl) and R5 is lower alkoxy; and R is lower alkyl; with phosphorus pentasulfide to obtain the corresponding compound of formula I wherein R1, R3, R4 and R5 are as defined in this claim and R2 is lower alkyl.
6. The compound of formula I wherein R1, R2, R3, R4 and R5 are as defined in claim 5, when prepared by the process of claim 5 or an obviouschemical equivalent thereof.
7. The process of claim 3 which comprises reacting the amido-ester of formula II wherein R1 is lower alkyl; R3 is a lower alkoxy at position 6 of the naphthalene ring and R4 and R5 each is hydrogen; or R3 is 4-lower alkoxy, R4 is 5-(trifluoromethyl) and R5 is 6-lower alkoxy; and R is lower alkyl;
with phosphorus pentasulfide to obtain the corresponding compound of formula I wherein R1, R3, R4 and R5 are as defined in this claim and R2 is lower alkyl.
with phosphorus pentasulfide to obtain the corresponding compound of formula I wherein R1, R3, R4 and R5 are as defined in this claim and R2 is lower alkyl.
8. The compound of formula I wherein R1, R2, R3, R4 and R5 are as defined in claim 7, when prepared by the process of claim 7 or an ob-vious chemical equivalent thereof.
9. The process of claim 7 wherein R, R1 and R2 each is methyl, R3 is 6-methoxy, and R4 and R5 each is hydrogen.
10. N-[(6-Methoxy-1-naphthalenyl)thioxomethyl]-N-methylglycine methyl ester, when prepared by the process of claim 9 or an obvious chemical equivalent thereof.
11. The process of claim 7, wherein R, R1 and R2 each is methyl, R3 is 4-methoxy, R4 is 5-(trifluoromethyl) and R5 is 6-methoxy.
12. N-[[4,6-Dimethoxy-5-(trifluoromethyl)-1-naphthalenyl] thiox-methyl]-N-methylglycine methyl ester, when prepared by the process of claim 11 or an obvious chemical equivalent thereof.
13. The process of claim 1 which comprises hydrolyzing the com-pound of formula III wherein R1, R3, R4 and R5 are as defined in claim 1 and R is lower lower alkyl or ar(lower)alkyl to obtain the corresponding compound of formula I wherein R1, R3, R4 and R5 are as defined in claim 1 and R2 is hydrogen; and, if required, transforming the latter compound of formula I
into a corresponding therapeutically acceptable salt of an organic or inorganic base.
into a corresponding therapeutically acceptable salt of an organic or inorganic base.
14. The compound of formula I wherein R1, R2, R3, R4 and R5 are as defined in claim 13, or a corresponding therapeutically acceptable salt thereof with an organic or inorganic base, when prepared by the process of claim 13 or an obvious chemical equivalent thereof.
15. The process of claim 13 which comprises hydrolyzing the compound of formula III wherein R1 is lower alkyl, R3 is a lower alkoxy at position 6 of the naphthalene ring and R4 and R5 each is hydrogen; or R3 is 4-lower alkoxy, R4 is 5-halo or 5-(trifluoromethyl)and R5 is 6-lower alkoxy;
and R is lower alkyl to obtain the corresponding compound of formula I wherein R1, R3, R4 and R5 are as defined in this claim and R2 is hydrogen; and, if re-quired, transforming the latter compound of formula I into a corresponding therapeutically acceptable salt of an organic or inorganic base.
and R is lower alkyl to obtain the corresponding compound of formula I wherein R1, R3, R4 and R5 are as defined in this claim and R2 is hydrogen; and, if re-quired, transforming the latter compound of formula I into a corresponding therapeutically acceptable salt of an organic or inorganic base.
16. The compound of formula I wherein R1, R2, R3, R4 and R5 are as defined in claim 15, or a corresponding therapeutically acceptable salt thereof with an organic or inorganic base, when prepared by the process of claim 15 or an obvious chemical equivalent thereof.
17. The process of claim 13 which comprises hydrolyzing the compound of formula III wherein R1 is lower alkyl; R3 is a lower alkoxy at position 6 of the naphthalene ring and R4 and R5 each is hydrogen; or R3 is 4-lower alkoxy, R4 is 5-(trifluoromethyl) and R5 is 6-lower alkoxy; and R is lower alkyl; to obtain the corresponding compound of formula I wherein R1, R3, R4 and R5 are as defined in this claim and R2 is hydrogen; and, if required,transforming the latter compound of formula I into a corresponding therapeu-tically acceptable salt of an organic or inorganic base.
18. The compound of formula I wherein R1, R2, R3, R4 and R5 are as defined in claim 17, or a corresponding therapeutically acceptable salt thereof with an organic or inorganic base, when prepared by the process of claim 17 or an obvious chemical equivalent thereof.
19. The process of claim 17 wherein R and R1 each is methyl and R4 and R5 each is hydrogen and R3 is 6-methoxy.
20. N [(6-Methoxy-1-naphthalenyl)thioxomethyl]-N-methylglycine, when prepared by the process of claim 19 or an obvious chemical equivalent thereof.
21. The process of claim 17 wherein R and R2 each is methyl, R3 is 4-methoxy, R4 is 5-(trifluoromethyl) and R5 is 6-methoxy.
22. N-[[4,6-Dimethoxy-5-(trifluoromethyl)-1-naphthalenyl] thioxo-methyl]-N-methylglycine, when prepared by the process of claim 21 or an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000451229A CA1188318A (en) | 1981-11-13 | 1984-04-03 | N-(substituted-naphthoyl)glycine derivatives |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US321,306 | 1981-11-13 | ||
| US06/321,306 US4439617A (en) | 1981-03-02 | 1981-11-13 | N-Naphthoylglycine derivatives |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000451229A Division CA1188318A (en) | 1981-11-13 | 1984-04-03 | N-(substituted-naphthoyl)glycine derivatives |
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| Publication Number | Publication Date |
|---|---|
| CA1187093A true CA1187093A (en) | 1985-05-14 |
Family
ID=23250060
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| Application Number | Title | Priority Date | Filing Date |
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| CA000401054A Expired CA1187093A (en) | 1981-11-13 | 1982-04-15 | N-(substituted-naphthoyl)glycine derivatives |
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1982
- 1982-04-15 CA CA000401054A patent/CA1187093A/en not_active Expired
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