Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
This is a divi~ion of Application Serial No, 401,054
filed ~pril 15, 1982~
N-(SUBSTITUTED-NAPHTHOYL)GLYCINE DERIVAIIVES
Related AE~c~3tions: Related hereto are Canadian Patent Application Serial
No. 372,119, filed March 2,1981, Canadian Patent Application Serial No. 372,054,filed March 2,1981 and Canadian Patent Application Serial No. 387,991, filed
October 1591981.
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 deriva$ives have pharma¢ologic properties which
render them beneficial for the treatment of diabetes mellitus and associated
conditions.
For rnany years diabetes mellitus has been treated with two esta-
blished types of drugs, namely insulin and oral hypoglycemic agents. These
drugs have benefited hundreds of thousands of diabetics by improving their
well-being and prolonging their livesO However, the res~ting longevity of diabetic
patients has led to complica$ions such as neuropathy, nephropathy, retinopathy~
cataracts and atherosclerosis. These complications have been linked to the
undesirable accumulation o~ sorbitol in diabetic tissue, which in turn result
from the high levels of glucose characteristic of the diabetic patient.
In mammals, including humans, the key enzyme involved in the conver-
sion of hexoses to polyols (the sorbitol pathway) is aldose reductase. J.H. Kino-
shita and collaborators, see J.H. Kinoshita et al, Biochem. Biophys. Acta, 158,
472 (1968) and references cited therein, ha~e demsnstrated that aldose reductaseplays a central role in the etiology of galactosemic cataracts by effecting the
conversion of galactose to dulcitol (galactitol) and that an agent capable of
inhibiting aldose reductase can prevent the 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 A. Pirie and R.
van Heyningen, Exp. Eye Res., 3,124 (1964); L.T. Chylack and J.H. Kinoshita,
Invest. Ophthal., 8, 401(1969) and J.D. Ward and R~W.R. Baker, Diabetol., 6,
531 (1970).
~ ',.
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(CANADA)
1,3-Dioxo-lH-benz[de] isoquinoline-2(3H)-aeetic acid has been reported
to be an effective inhibitor of aldose reductase, see D. Dvornik et al., Science,
1_,1146 (1973), and to be useful for the treatment of diabetic complications
such as diabetic cutaracts, 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[de]-
isoquinoline-2(3H~acetic acid derivatives of K. Sestanj, U.S. Patent No. 4,254,10~,
Mareh 3, 1981 and lH-benz[de] isoquinoline-2(3H)-acetic acid derivatives of K.
Sestanj, U.S. Patent No. 4,254,109, March 3,1981. (S3-6-Fluoro-2,3-dihydrospiro(4H-
1-benzopyran-4,4'-imidazolidine)-2',5'dione (sorbinil) is still another compoundthat has received attention because of its aldose reductase inhibiting properties
(see M.J. Peterson et al., Metabolism, 28 (Supplo 1)~ 456 (1979~. Accordingly,
these compounds represent an important new approacll for the treatment of
diabetes mellitus.
The present application discloses novel N-(substituted-naphthoyl)gly-
cine derivatives, represented below by formula I, which are effective 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., 1$56 (1957~ as part of a chemical investigation of the chemical propertiesof such compounds. These last mentioned compounds were prepared by thi~
benzoylation of various amino acids with (thiobenzoylthio)acetic acid. An im-
portant structural difference between these compounds and the present derivatives
is the different type of aromatic group substituted on the thione portion of
the thioamide. Thioacylamides also have been reported [see Chem. Abstr.,
86,189582f (1977) for V.l. Cohen et al., Eur. J. MedO Chem.3 ~ 480 (1976) and
Chem. Abstr., 70,11306a (1969) for von J. Voss and W. Walter, Justus Leibigs
Ann. Chem., 716, 209 (1968)]. The structures of the thioacylamides of Cohen
et al and Voss et al differ from the structure of the present derivatives by having
at least a different type of N~substitution. Another close prior art compound,
on a structural basis, is N-L(l-naphthalenyl)carbonyl~ glycine, [see Chem. Abstr.,
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(CANADA)
61, 4333f (1964) fs r E. Cioranescu et al, Rev. Chim. Acad. Rep. Populaire Rou-
maine, 7 (2), 755 (1962)]. The compound, which has been used as a chemical
intermediate, is distinguished from the compounds of the present invention
by being an amide and not a thioamide.
Sum ma~of the Invention
The N-(substituted-naphthoyl)glycine derivatives of this invention
are represented by formula I 1 2
S=C-N (R ) - CH2COOR
~5 ~ (I)
R4 R3
wherein Rl is lower alkyl; R2 is hydrogen or lower alkyl; R3 is Q 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 pOsitiQns 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
R is hydrogen.
A group of preferred derivatives is represented by the compounds
of formula 1 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-lower 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; 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-lower alkoxy, R4 is 5-(trifluoromethyl) and R5 is 6-lower
alkoxy; or when R is hydrogen a therapeutically acceptable salt thereof with
an organic or inorganic base.
8~ 3
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(CANADA)
A process and a key intermediate for the process are described her~
înafter.
A method is provided for preventing or relieving diabetes mellitus
associated complications in a diabetic mammal by administering to said mammal
a prophylactic or alleviating amount of the compound of formula I or thera-
peutically acceptable salt thereof with an organic or inorganic base.
The compound of formula I, or a therapeutically acceptable salt
thereof with an organic or inorganic base, when admixed with a pharmaceutically
acceptable carrier, forms a pharmaceutical composition which can be used
according to the preceding method.
Detailed ~escriptia~ n- ~e In~
The compounds of this invention, represented by formula I, can exist
in rotameric forms. More explicitly, mesomerism imparts a partial double bond
character to the carbon-nitrogen bond of the thioamide group. This partial
lS double bond character leads to restricted rotation about the carbon nitrogen
bond ~iving rise to cis and trans rotamers, the restricted rotation being augmented
by the bulkiness of neighboring groups Interconversion of the rotamers is pos-
sible and is dependent on the physical environment~ As evidenced by its physicalproperties, the thermodynamically more stable rotamer exists exclusively in
the crystalline state of the compound and is the predominant isomer present
in equilabrated solutions. Furthermore, the more stable rotamer is the more
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 included within the scope of
2S this invention. ~or brevity, the compounds of this invention, including their
rotameric forms, are referred to herein as compounds of formula I.
The term '~ower alkyl" as used herein means a straight chain alkyl
radical containing from one to four carbon atoms or a branched chain alkyl
radical containing three or four carbon atoms and includes methyl, ethyl, propyl,
l-methylethyl, butyl, 2-methylpropyl and l,l-dimethylethyl. Preferred lower
alkyl radicals contain from one to three carbon ntoms.
The term 'qower alkoxy'l as used herein means a straight chain alkoxy
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(CANADA~
radical containing from one to six carbon atoms, preferably one to three carbon
atoms, or a branched chain alkoxy radical containing three or four carbon atoms,and includes methoxy, ethoxy1 l-methylethoxy, butoxy and hexanoxy.
The term '1halo7' as used herein means a halo radical and includes
fluoro~ chloro, bromo and iodo.
The term "ar'~ as used mean an aromatic radical containing at least
one benzene ring. The preferred aromatic radical is phenyl.
The compounds of formula I wherein R2 is hydrogen form salts with
suitable therapeutically acceptable inorganic and organic bases. These derived
salts possess the same activity as their parent acid and are included within
the scope of this invention. The acid is trans~ormed in excel:lent yield into
the corresponding therapeutic~ly acceptable salt by neutralization of said acid
with the appropriate inorganie or organic base. The salts are administered
usually in the same manner as the parent acid compounds. Suitable inorganic
bases to form these salts include, for example, the hydroxides, carbonates or
bicarbonates of the therapeutically acceptable alkali metals or alkaline earth
metals, for example, sodium, potassium, magnesium, calcium and the like.
Su;table 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 radicals of which contain up to three carbon atoms, for
example, mono-~ di- and triethanolamine; alkylcne-diamines which contain up
to six carbon atoms, such ~s hexamethylenediamine; cyclic saturated or un-
saturated bases containing 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), alkyl-alkanol (for example methyl-
triethanol and trimethyl-monoethanol) and cyclic ammonium saltsl for example
the N-methylpyridinium, N-methyl-N-(2-hydroxyethyl~-morpholinium N,M-di-
methylmorpholiniumj N-methyl-N-(2-hydroxyethyl~-morpnolinium~ N,N-dimethyl-
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(CANADA~
piperidinium salts, which are characterized by having good water-solubility.
In principle, however, there can be used all the ammonium salts which are phy-
siologically compatible.
The transformations to the salts can be carried out by a variety
of methods known in the art. 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 corresponding
to the inorganic salt desired. Advantageously, the reaction is performed in
a water-miscible, inert organic solvent, for example, methanol, ethanol, dioxane,
and the like in the presence of water. For example, sueh 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 lower alkanol, for instance, butanol, or a
lower alkanone, for instance, ethyl methyl ketone, gives the solid inorganie
salt if that form is desired.
To produce an amine salt, the acidic compound of formula I is dis-
solved in a suitable solvent of either moderate or low polarity3 for example,
ethanol, methanol, ethyl acetate, diethyl ether and benzene. At least an~ equiva-
lent amolmt 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, benzene or petroleum ether, or by evaporation. If the amine is re-
latively volatile, any excess can easily be removed by evaporation. It is preferred
to use substantially equivalent amounts of the less volatile amines.
Salts 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 inorganie bases may be administered to mammals,for example, man, cattle or rabbits, either alone or in dosage forms, i.e., capsllles
or tablets, combined with pharmacologically acceptable excipients, see below.
Advantageously the compounds of this invention may be given orally. However,
3~
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(CANADA)
the method oi administering the present active ingredients of this invention
is not to be s~onstrued as limited to a particular mode of administration. ~or
example, the compounds may be administered topically directly to the eye in
the form of drops of sterile, buffered ophthalmic solutions, preferably of pH
7.2 - 7.6. Also, they may be administered orally in .solid form containing such
excipients as starch, milk sugar, certain types OI clay and so forth. They may
also be administered orally in the form of solutions or they may be injected
parenterally. For parenteral administration they rnay be used in the form of
a sterile solution5 preferably of pH 7.2 - 7.6, containing a pharmaceutically
acceptable buff er
The dosage OI the present therapeutic agents will vary with the
Eorm of administration and the particular compound chosen. Furthermore,
it will vary with the particular host under treatment~ Generally, treatment
is initiated with small dosages substantially less than the optimal dose of the
compound. Thereafter; the dosage is increased by small increments until efficacyis obtained. In general9 the compounds of this invention are m~st desirably ad-
ministered at a concentration level thut will generally afford effective resultswithout causing any harmIul or deleterious side effects. For topical administration
a 0.05 - 0.2% solution may be administered dropwise to the eye. The frequency
of instillation varies with the subject under trea1ment from a drop every two
or three days to once daily. For oral or parenteral administrati~n a preferred
level of dosage ranges from about O.l mg to about 200 mg per kilo of body weightper day, ~though aforementioned variations will occur. However, a dosage level
that is in the range of from about 0O5 mg to about 30 mg per kilo of body weightper day is most satisfactory.
Unit dosage forms such as capsules, tablets, pills and the like may
contain from about 5.0 mg to about 250 mg of the active ingredients of this in-
ventionj preferably with a significant quantity of a pharmaceutical carrier.
Thus, for oral administration, capsules can contain from between about 5.0 mg
to about 250 mg of the act;ve ingredients of this invention with or without a
pharmaeeutical diluent. Tablets, either effervescent or noneffervescent, can
contain between about 5.0 to 250 mg of the active ingredients of this invention
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~CANADA)
together with conventional pharmaceutical carriers. Thus, tablets whieh may
be coated and either effervescent or noneffervescent may be prepared according
to the known art. Inert diluents or carriers, for example, magnesium carbonute
or lactose, can be used together with conventionul disintegrating agents for ex-ample, magnesium stearate.
Syrups or elixirs suitable for oral administration can L)e prepared
from water soluble salts, for example, sodium N [~4,5-dimethoxy-5-(trifluoromethyl)-
l-naphthalenyl] thioxomethyl]-N-methylglycinate, and may adv~ntageously contain
glycerol and ethyl alcohol as solvents or preservatives.
The compo~md of formula I, or a therapeutically acceptable salt there-
of, aLso can be used in cornbination 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 of formula I, or a therapeutically ac-
ceptable satt thereof, can be administered sequentially or simultaneously with
insulin or t.he oral hypoglycemic agellt. Suitable methods of administration, com-
positions and doses of the insulin preparation or oral hypoglycemic agent are des-
cribed in medical textbooks; 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 1, or its therapeutically acceptable salt, is administered
as described previously. The compound of formula I9 or its therapeutically a~
ceptable salt, can be administered with the oral hypoglyeemic agent in the form
of a pharmaceutical composition comprising effective amounts of each agent.
The aldose reductase inhibiting 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 (1965~. In the present
case the procedure of Hayman and Kinoshita is modified in that the final chroma-tography step is omitted in the preparation of the enzyme from bovine lens.
For example, when N-[(6-methoxy-1-n~phthalenyl)thioxomethyl]-N-
methylglycine, the compound of foI mula I wherein Rl is methyl9 R2, R4 and R5
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(CANADA)
eaeh 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 5,1 x 10 6 and 1 x 10 7 M, respectively. Likewise9
N-[[4,6-dimethoxy-5-(trifluoromethyl)-1-naphthalenyl] thioxomethyl]-N-méthyl-
glycine, the cornpound of formula I wherein Rl is methyl, R2 is hydrogen, R3 is
4-methoxy, R4 is 5-trifluoromethyl and R5 is 6-methoxy, inhibited the aldose
reductase 97, 91 and 75 percent by compound concentrations of 1 x 10 5,1 x 10 6
and 1 x 10 M, respectively.
The aldose reductase inhibiting property OI the compounds of this
invention and the utilization OI the compounds in preventing9 diminishing and
alleviating diabeltic complications are demonstrable in experiments using galacto-
semie 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, Spr~gue-Dawley
strain, were uæed. The first group, the control ~roup, Wa5 fed ~ mixture of labora-
tory ehow (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 Eed 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 gal~ctosemic group.
(b) After ~our days, the animals were 3cilled 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
cosnpletely as possible and weighed. Both tissues were frozen and can be kept
up to two weeks before being analyzed for dulcitol.
~c) The polyol determination was performed by a modification o~
the procedure of Mo Kraml and L. Cosyns~ Clin. Biochem., 2, 373 (1969). Only
two minor reflgent changes were made: (a) The rinsing mixture was an aqueous
5% (w/v) triehloroacetic acid solution and (b) the stock solution was prepared
by dissolving 25 m~ of dulcitol in 100 ml of an aqueous trichloroacetic acid so-lution.[~B.: For each experiment the ~verage value found in the tissue
3~
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from rats fed the glucose diet was subtracted from the 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 accumulation in the tissues o the lens and sciatic nerve,
respectively, for treated rats as compared to untreated rats.
Compound of Formula I Dose L
Rl R2 R3 R4 R5 mg/kg/day
CH3 H 6-CH30 H E~ 162 - 32
CF~3 H 4-CH30 5-CF3 6-CH30 144 33 85
- 48
Proeess
The preparation of the cornpounds of formula I is illustrated by the
following scheme wherein Rl, R3, R4 and R5 ar~e as defined hereinbefore and
2() COOE~ is an ester group which may be, for example, a lowel alkyl or an ar(lower3-
alkyl ester; i.e., R is lower allcyl or ar(lower)allcyl.
O=C-N~R )-CH2COOR S~C-N(R ~-CH COOR
~II) R ~ ) 2
hydrolysis ¦ hydrolysis
~I
O-C-N(R )--CH2COOH
R ~ 2~ ~ I ( R H)
R4 R3
(IV)
3~
AHP-7806 2
More specifically, a process for preparing the compounds of formula
I comprises:
(a) reacting an amidoester of formula II wherein Rl, R3, R4 and
R5 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 herein; or
(b) hydrolyzing the thioxoester of formula III wherein Rl, R3~ R4,
R5 and R are as defined herein to obtain the corresponding compound 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.Referring to the above section (a) oP the last paragraph, the thioxo-
ester of formula III includes those corresponding compounds of formula I whereinE~ is lower aL~cyl, when R of the compound of formula III is lower alkyl. For
clarity and convenience in the following discussion OI the process, these lattercompounds of formula I are included in the discussion and preparation of the
2U compounds of formula III.
Still more specifically, the starting material, namely the 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 ilerein.
2 S COOH
NH~R ~-GH2COOR ~ II
R R3
(V) (Vl)
The compounds of formula V and VI are Icnown or can be prepared
by known methods. For example, see 'llElsevier's Encyclopaedia of Organic Chem-
istry," F. Radt, Ed., Series III, Yol. 12B, Elsevier Publishing Co., Amsterdam,
~ .
3~
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(CANADA)
1953, pp 3965-4473. A preparation of a naphthalenecarboxylic acid is illustratedby example I described hereinafter. The coupling OI the naphthalenecarboxylic
acid V and the amino acid ester VI is done prcferably by the 'tcarboxyl activation"
coupling procedureO Descriptions of carboxyl-activating groups are found in
general textbooks of peptide chemistry; for example K.D. Kopple9 "Peptides
and Amino Acids", W.A. Benjamin, Inc., New York, 1966, pp. 45-51, and Eo Schr~der
and K. LUbke, "The Peptides"; Vol. 1, Academic Press, New York, 1965, pp. 77-
128. ~xamples of the activated form of the terminal carboxyl are the acid chl~
ride, acid bromide, anhydride, azide, actiYated ester, or O-acyl urea obtained
from a diaLkylc~rbodiimide. Preferred activated forms OI the carboxyl are the
acid chloride or the l-benzotriazolyl, 2,4,5-trichloropherlyl or succinimido activated
esters.
Returning to the flow diagram again, the amidoester of formula II
is reacted ~mder 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 reaction is performed con-
veniently at temperatures ranging from 80 to about 150 C and at times ranging
from 20 minutes to four hours. Preferably, the reaction is performed in the
presence of an organic base for instance, N-ethyl morpholine, triethylamine
2û or pyridine.
Thereafter, the thioxoester of forml~la 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 mixtureJ
to yield the desired acid. However, it should be understood that the manner
of hydrolysis for the process of this invention is not intended to be limited tobasic hydrolysis sin~e hydrolysis under acidic conditions and other variations,
for example, lreatment with lithium iod;de in collidine ~see L.F. Fieser and M.
Pieser, "E~eagents for Organic Synthesis", John Wiley and Sons, Inc., New York,
1969, pp. 615-617~, also are applicable. Hydrolysis under acidic conditions is
preferred when the ester is a tert butyl ester.
For basic hydrolysis, a preferred embodiment involves subjecting
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(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 OI the ester.
The hydrolysis is performed using a suitable solvent, for example, methanol,
ethanol or 2-methoxyethanol. The reaction mixture is maintained at a temperatureof from about 25 to 100 C or at the reflux temperature OI the solvent employeduntil hydrolysis occurs. Usually from lD minutes to 6 hours is sufficient for this
hydrolysis. The reaction mixture is then renclered acidic with an acid, for example,
acetic acid, hydrochloric acid or sulfuric acid to release the free acid.
Alternatively, the amidoester of for~nula Il can be hydrolyzed under
the same conditions as described hereinbefore to give the corresponding amido-
acid of formula IV wherein Rl, R3, Rk 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 Rl~
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 calases 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 carboxylic acid.
The following examples illustrate further this invention.
EXAMPLE' 1
4,6-Dimethoxy-5-(trifluoromethyl)-1-naphthalenecarboxylic As~id (V, R3 = 4-CH3O,IR = 5-C~3 and R = 6-CH3O~
A stream of chlorine gas was passed through a cooled solution o~
NaOH (17~28 g, 0.432 mole) in water (24 ml) containing 100 g of ice until 12.7 g(0.18 mole) of chlorine was absorbed into the solution. Solid (4,6-dimethoxy-1-
naphthalenyl)ethanone ~9.2 g, 0~04 mole, described by N.P. Buu-Hoi~ J. Org. Chem.,
_71257 (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 NaHSO
(5 g) in water (20 ml). The mixture was made neutral by the addition of dilute
HCl~ The resulting precipitate was collected, washed well with water, dried
over P205 and recrystallized from methanol to give 4,6-dimethoxy-1-naphth-
alenecarboxylic acid (7.0 g); mp 227-229C; NMR (DMSO-d6)~ 3.~5 (s, 3H),
-14- AHP-7802-2
(CANADA~
4.0 (s, 3H), 7.7 (m, 5H~; IR (white mineral oil) 2900, 1670 cm 1; UV~max (MeOH)
339 nm (~ 4,910), 328 (4,500) 304 (8,180?, 240 (40,100); Anal Calcd: C, 67.23%
H, 5.21%; ~ound: C, 67.15% H, 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 (225 ml)O 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 NaHC03 solution, dried (Na2SO~ and concentrated to dryness.
The solid resjdue was crystallized from methanol ~720 ml) to give 64.5 g of
4,6-dimethoxy-1-naphthalenecarboxylic acid methyl ester; mp 102-104 C; NMR
(CDC13) ~ `3.9 (SJ 6H), 4.0 (s, 3H)5 7.7 (m, SH).
The latter compound (4.93 g, 0.02 mole) was suspended in 20%
(v/v) aqueous acetic acid and concentrated H2SO4 (0.279 ml). The mixture
was stirred and heated at 60 C. Iodine (2 g, 0.008 mole) and periodic acid
~2.76 g, 0.012 mole) was added to the mixture The reaction mixture was stirred
for one hr at the same temperature, ccoled, poured into water and extracted
with chloroform. The chloroform extraet wa~s washed with aqueous sodium
bisulphite solution, washed with water and driled (Ma2SO4). The chloroform
extract was poured onto a column of 250 g of silica gel (prepared with 10%
(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 fractiGns 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-
~5 122 C, was obtained by crystallization from ethyl acetate-hexane.
A mixture of the latter compound (7.1 ~, 0.û19 mole), fres~y pre~
pared copper powder (4.5 g, prepared according to the procedure of R.Q. Brewsterand T. ~:roening, "Organic Synthesis", Coll. Vol. II, John Wiley and Sons, New
York, N.Y., U.S.A., 1948, p. 4453, trifluoromethyl iodide (8.5 g, û.43 moIe~
and dry pyridine (35 ml) was heated for 20 hr at 120~C in an autoclave~ After
cooling to 22 to 24 C, the mixture was taken up in toluene and the toluene
suspension was filtered. The filtrate was concentrated to dryness under re-
~8~
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~CANADA)
du~ed pressure. The residue was dissolved in chloroform. Insoluble matri~l
in the chloroform solution was removed by filtration. The filtrate was passed
through a column of 75 g of silica gel and the column was eluted with chloroform.
The pure fractions were combined and crystallized from ethyl acetate-hexane
to give 2~83 g of 4,6-dimethoxy-5-(trifluoromethyl)-1-naphthalenecarboxylic
acid methyl ester; mp 120-123" C~ NMR (CDC13) ~ 3.95 (m~ 9H), 6.8 and 8.05
(2d7 J ~ lOHz, 2H)~ 7.21 and 9.1 (2d, J = lOHz, 2H)o
A suspension of the lat$er cornpound (2.83 g, Q.OO9 mol) in methanol
(16.2 ml) and NaOH (5.4 ml of a 4N aqueous solution) was heated at reflux
under nitrogen ~or 10 min. The resulting 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 P20S to give 2.7 g of $he title
compound, m/e 300 (M ).
EXAMPLE 2
~-[~4,6-Dimethoxy-5-(trifluoromethyl)-1-naphthalenyl] carbonyl]-N-methyl-
~lycine Methyl Ester (II, Rl and R = CH3, RS = 4-CH30, R4 = 5~CF3 and R5
= 6-CH30)
Procedure A:
A catalytic amount (5 drops) of dry dimethylformamide (DMF)
was added to a suspension of the starting material of formula V, 4,6-dimethoxy-
5-(trifluoromethyl)-1-naphthalenecarboxylic acid (10 g, 3~ mmoles, described
in example 1), in thionyl chloride (100 ml). The suspension was heated cautiously
to reflux (caution: a VigOI~OUS reaction can o~cur~. The mixture was reflu~ed
for 20 min. The mixture was evaporated to dryness. Toluene was added to
the solid residlle and the mixture was evaporated to dryness. The residue was
dissolved in pyridine (100 ml). The solution was cooled in an ice bath. Dry
N-methylglyeine me~hyl ester hydrochloride ~11.1 g, 79.6 mmoles), a starting
material of form~da YI, was added portionwise to the cooled solution. The
mixture was stirred fo~ 2 hr at 20 C and then heated at reflux for 1 hr. The
pyridine was removed by evaporation. Water was added to the oily residue.
The rn;xture was extraced with ethyl acetate (3 x 150 ml). The combined
extracts were washed with lN aqueous HCl solution, a saturated solution of
sodium bicarbonate and brine. After drying overMgS04J the extract was subjected
,
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(CANADA~
to chrornatography on 325 g of silica gel using 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~7
4.35 (m, 2H), 6.7-8.3 ~m, 4H).
Proeedure B: -
A mixture of the starting material of formula V, 4,6-dimethoxy-
5-(trifluoromethyl)-1-naphthalenecarboxylic acid (2.7 g, 9.0 mmoles), and 1-
hydroxybenzotriazole (HOBt, 1.33 g, 9.9 mmoles) in DMF (12 ml) was prepared.
N,N'-dicyclohexylcarbodiimide (DCG, 2.04 g, 9.9 mmoles) in DM~ (7 ml) was
added to the mixture. The resulting m;xture was stirred at 2û C for 1 hr and
then cooled to Q C. N-Methylglycine methyl 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 20 ~ 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 elu~nt. The
pure fractions were pooled to yield 2.5 g of the title compound~ identical to
the product of procedure A of this example.
EXAMPLE 3
N-~[4,6-Dimethoxy-5-(trifluoromethyl)-l naphthalenyl] thioxomethyl] -N-methyl-
glycine Methyl Ester (I, Rl and R2 = CH3, R3 = 4-CH30, R4 = 5-CF3 and R5
= 6-CH30)
To a stirred solution of N-[E4,6-dimethoxy-5-(trifluoromethyl)-1-
naphthalenyl] carbonyl]-N-methylglycine methyl ester (2.5 g, 6.49 mmoles9
described in example 2~ in dry pyridine (16.2 ml~) phosphorus pentasulfid0 (1.8 g,
81 mmoles~ was udded portionwise. The mixture was stirred and refluxed
for 1~5 hr and then poured into water at 50 to 80 C ~caution: evolution of copious
quantities of H2S). The mixture was allowed to cool to 20 to 22C (room
temperature), filtered and the filtrate was extracted with ethyl acetate. The
extract was washed with lN aqueous HCl solution, brine, a saturated solution
of sodium carbonate and brine, dried ~MgSO4), filtered and evaporated to dry-
ness. The residue was subjected to chromatography on silic~ gel using ethyl
acetate-hexane (1:1) as the eluant. The pure fractions were pooled and cry-
3~l~
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(CANADA)
stallized from ethyl acetate-hexane to give l.4 g of the title eompound, 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), 6.8-8.2 (m, 4H).
By following serially the procedure of examples 2 and 3 but replacing
4,6-dimethoxy-5-(trifluoromethyl)-1-naphthalenecarboxylic acid with an equiv-
alent amount of another compound of formula V, other compounds of formula
I in which R2 is methyl are obtained. For example, replacement with 6-methoxy-
l-naphthalenecarbo~lic 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 = 8-methoxy, and R4 and R5
= H), NMR (CDC13) ~ 3.02 (S5 3H), 3.86 (s, 3H), 3.89 (s, 3H), 4.53 ~ 4.35 (d,
J = 17Hz, 3H), 6.90-8.10 (m, 6H), was obtained via N-[(6-methoxy-1-naphthalenyl)-
carbonyl]-N-methylglycine methyl ester.
EXAMPLE 4
~-[~4,6-Dimethoxy-5-(trifluoromethyl)-1-naphthalenyl] thioxomethyl]-N-methyl-
glycine (Rl = CH3, R2 = H, R3 = 4-CH30, R4 = 5-CF3 and R5 = 6-CH3O)
A 4N aqueous NaOH solution (L92 ml~ was added to a suspension
of N-[~4,6-dim ethoxy-5-(trifluoromethyl)-1-naphthalenyl] thioxom ethyl] -N-
methylglycine methyl ester (1.55 g, 3.86 mmoles; described in example 3) in
methanol (5.~ ml). The mixture was stirred and heated at 60 C for 5 min
under a nitrogen atmosphere. After cooling, the mixture was neutrali~ed to
pEI 7 with aqueous HCl and extracted with ethyl acetate. The extract was
dried (MgSO4~ and evaporated to dryness. The residue was dissolved in diethyl
ether and filtered through a column o~ silica gel (14 g). The appropriate fractions
were combined and concentrated to give the title compound; NMR (CDC13)
3.05 (S9 3H), 3.9 (s, 3H), 3.95 ~s, 3H~, 4.5 & 5.11 ~2d, J = 17Hz7 2H), 6.75 (s, lH),
7.~ (m, 4H); IR (CHC13~ 30110,1720,1270,1130 cm 1; Anal Calcd: C, 52.70%
H, 4.16% N, 3.61%; Found: C, 52.83% H, 4.46% N, 3.57%O
By following the procedure of example 4, but replacing N-[[4,8-
dimethoxy-5-(trifluoromethyl)-1-naphthalenyl] thioxomethyl] -N-methylgly-
eine methyl ester with an equivalent amount of another ester compound of
formula I in which R2 is lower alkyl, or a corresponding compound of formula
III in which R is ar(lower)alkyl, the corresponding compound of formula I in
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~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 (DMSO-d6) ~ 2.95 (s, 3H), 3.9 (s, 3H), 4.65 and 5.2 (2d, J
= 16.5 Hz, 2H), 7.5 (m, 6H).
