Note: Descriptions are shown in the official language in which they were submitted.
1 158254
-1- AHP-7858
_ ~YL)CARBONYL]-N-(LOWER ALKYL~
GLYCINE DERIVATIVES
. ~ _, -- .. . .
~9~atl~ ~ Related hereto is Canadian Patent Application Serial No.
374~469, filed April 2,1981 of G. Dionne et al.
This application relates to a process for preparing N-L(l-napllthalenyl)-
carbonyl]-N-(lower alkyl)glycine derivatives, which are intermediates for the
preparation of N-[(l-naphthalenyl)thioxomethyl]-N-(lower alkyl)glycine derivatives.
The process of this invention produces N-[(l-naphthalenyl)carbonyl~-
10 N-(lower)glycine derivatives which are transformed readily into their corresponding
N-[(l-naphthalenyl)thioxomethyl]-N-(lower alkyl)glycine derivatives. The latter
compounds, thionaphthoylglycines, are useful for treating diabetic complications;
for example, neuropathy, nephropathy, retinopathy, cataracts and atherosclerosis;
and the compounds, and another process for preparing them, are disclosed in
15 Canadian Patent Application Serial No. 372,119) filed March 2,1981 of K. Sestanj
et al. According to that process, the thionaphthoylglycines are prepared by coupling
a carboxyl acffvated derivative of an appropriate l-naphthalenecarboxylic acid
with a glycine ester to obtain the corresponding N-~ naphthalenyl)carbonyl] glycine
ester, the product of the process disclosed hereln. Thereafter, the latter compound
20 is reacted with phosphorus pentasul-fide to obtain the corresponding thionaphthoyl-
glycine ester which, if desired, can be hydrolyzed to give the corresponding acid.
Optionally, the order of the last two steps can be reversed.
The present process provides an alternative proeess for obtaining the
N-[(l-naphthalenyl)carbonyl]-N-(lower alkyl)glycine intermediate in an efficient,
25 inexpensive manner Irom readily available starting materials. A feature of the
process is the reaction of a naphthalenyl Grignard reagent or lithium derivativewith an appropriate lower alkyl isocyanate to obtain the corresponding l-naphthalene-
carboxamide derivative, which in turn is transformed readily by N-alkylation into
the N-[(l-naphthalenyl)carbonyl]-N~(lower alkyl)glycine derivative. Although
30 benzanilide has been obtained by the reaction of phenyl magnesium bromide with
phenyl isocyanate, see Ho Gilman and CoR~ Kinney, J. Am. Chem. Soc., 46, 493
(1924), the addition of a naphthalenyl magnesium halide or lithium derivative to
~ 1582~4
-2- AHP-7858
an alkyl isocyanate appears to be novel and allows the preparation of the objectcompounds of this invention ~y a simple, direct process which avoids the use of
expensive or obnoxious chemicals or the need of protecting groups.
A process is provided ~or preparin~ a compound o~ formula I
O=C-N (R ) -c~l2cooR
4 ~
in which Rl is lower alkyl; R2 is hydrogen or lower alkyl; R3 ~nd R4 each separately
is hydrogen, lower alkyl, lower alkoxy or trifluoromethyl, or R3 is halo and R4
is hydrogen; which comprises transforming the compound of formula II
~,
R4 /~ (I I)
R3
in which R3 and R4 are as defined herein and X is bromo7 chloro or iodo into thecorresponding organometallic compound of formula 111
y
R J~ (1~1)
30 in which R3 and R4 are as defined herein and Y is MgX wherein X is as defined herein or Y is Li;
reacting the organometallic compoun~ of formula III with a lower alkyl isocyanate
of formula RlNCO in which Rl is lower alkvl to obtain the corresponding compoundof formula IV o=C-NHR
1 (IV)
R ~~
. ~ R3
-
~L 15~5~
-3- AHP-7858
in which Rl, R3 and R are as defined herein9 and
condensing the compound of formula IV with a haloacetic acid lower alkyl ester
in the presence of a proton acceptor to obtain the corresponding compound
5 of formula I in which Rl, R3 and R4 are as defined herein and R2 is lower alkyl;
and when the compound of formula I in which Rl, R3 and R4 are as defined
herein and R2 is hydrogen is required, hydrolyzing the compound of formula
I in which Rl, R and R are defined herein and R2 is lower alkyl.
In a preferred embodiment of this process Rl is methyl, R2 is hydrogen
10 or methyl, R3 is bromo, chloro~ methyl, methoxy or trifluoromethyl, and R4
is hydrogen or methoxy.
Detailed Description of the Invention
The term tqower alkyl" as used herein means a straight chain ~lk
radical containing from one to four carbon atoms or a branched chain alkyl
15 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 one to three carbon atoms.
The term "lower alkoxy" as used herein means a straight chain alkoxy
radical containing from one to six carbon atoms, preferably one ts three carbon
20 atoms, or a br~nched chain alkoxy radical containing three or four carbon atoms,
and includes methoxy, ethoxy, l-methylethoxy~ butoxy and hexanoxy.
The term "halo" as used herein me~ms a halo radical and includes,
fluoro, chloro, bromo and iodo.
The term "inorganic proton acceptor" as used herein means the inorganic
25 bases, preferably the alkali metal hydrides, hydroxides and carbonates, for example,
sodium hydride, sodium hydride-dimethylsulfoxide, potassium hydroxide, sodium
carbonate, potassium carbonate and the likeO
The term "organic proton acceptor" as used herein means the organic
bases or amines, for instance, triethylamine, pyridine, N-ethylmorpholine9 1,5-
30 diazabicyclo[4.3.0~ non-5~ene and the like.
The term "proton acceptor" as used herein means a proton acceptor
selected from an organic proton acceptor and inorganic proton acceptor, as
defined hereinabove.
More specifically, with reference to the process, the compound
35 of formula Il, dissolved in an inert organic solvent for instance diethyl ether
or tetrahydrofuran (THF), is reacted with magnesium according to the conditions
1 15~25~
-~- AHP-7858
of the Grignard reaction. A catalyst, for example 1,2-dibromoethane, can be
used when forming the Grignurd reagent. Preferred conditions or this reaction
include a temperature range from room temperature (20 - 22 C) to 100 C or
5 to the boiling point of the mixture, and fl reaction time of 30 minutes to four
hours. In this manner, the organorlletallic compound of formula III in which
R3 and R4 are as defined herein and Y is M~X in which X is bromo, chloro or
iodo is obtained.
Alternatively, the compound of formula II is reacted with lithium
10 in an inert solvent employing the same techni~ue as that of the Grignard reagent
formation to obtain the compound of formula III in which R3 and R4 are as
defined herein and Y is Li.
The compounds of formula 11 are known or can be prepared by known
methods (see, for example, "Elsevier's ~ncyclopaedia of Organic Chemistry",
15 F. Radt, Ed.~ Series III, vol 12B, Elsevier Publishing Co., Amsterdam, 1953, pp
264 - 321.
Thereafter, the organometallic compound of formula III in which
R3 and R4 are as defined herein and Y is MgX in which X is halo or Y is Li is
reacted with a lower alkyl isocyanate of formula RlCNO in which Rl is lower
20 alkyl in the presence of an inorganic proton acceptor to give the corresponding
compounds of formula IV in which Rl, R3 and R4 are as defined herein.
Practical and convenient conditions for effecting this reaction with
the lower alkyl isocyanate include brin~ing the two reactants in contact with
each other in a non polar, inert solvent at temperatures ranging from 0 to 60 C25 from 3U minutes to six hours. Suitable solventi include diethyl ether, benzene
or tetrahydrofuran.
In the next step, the compound of formula IV is subjected to N-alkyla-
tion with a haloacetic acid lower alkyl ester in the presence of a suitable proton
acceptor to give the corresponding compound of formula I in which Rl, R3 and
30 R4 are as defined herein and R2 is lower alkyl.
Practical and convenient conditions for effecting the N-alkylation
include the use o sodium hydride, sodium hydride-dimethylsulfoxide, or an
alkali metal hydroxide or carbonate, for example, sodium hydroxide or potassium
carbonate, triethylamine or pyridine as the proton acceptor. Any solvent which
35 does not interfer with the reaction, can serve as the renction medium. Suitable
,,
. ~
1 ~58254
-5- AHP-7858
solvents include dimethylsulfoxide, dimethylformamide, toluene, acetone and
tetrahydrofuran. Preferred conditions for effecting the N-alkylation include
the use of sodium hydride-dimethylsulfoxide as the proton acceptor and dimethyl
5 sulfoxide as the solvent. Although the optimum temperature and reaction time
will vary depending on the reactants employed, the reaction is performed generally
at 20 to 80 C for a period of 30 minutes to 48 hours~
If desired, the compound of formula I in which Rl, R3 and R4 are
as defined herein and R is lower alkyl is hydrolyzed to the corresponding compound
10 of formula I in which R is hydrogen. The hydrolysis can be performed most
conveniently by employing a base in the presence of sufficient water, followed
by acidification of the reaction mixture to yield the desired acid. However,
it should be ~mderstcod that the manner of hydrolysis for the process of this
invention is not intended to be limited to basic hydrolysis since hydrolysis under
15 acidic conditions and other variations, for example, treatment with lithium
iodide in collidine (see L.F. Fieser and M. Fieser, "Reagents for Organic Synthesis",
John Wiley ~nd Sons, Inc., New York, 1969, pp. 615-617), also are applicable.
Hydrolysis under acidic conditions is preferred for tert butyl esters.
For ~asic hydrolysis, a preferred embodiment involves subjecting
20 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 hyclrolysis 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 lD0 C or at the reflux temperature o~ the solvent employed
25 until hydrolysis is complete. IJsually from 10 minutes to 6 hours is sufficient.
The reaction mixture is then rendered acidic with an acid, for example, acetic
acid, hydrochloric acid or sulfuric acid, to release the free acid.
Subsequently, the compound of formula I, i.e. either the acid (R2 =
hydrogen) or the ester (R2 = lower alkyl), is converted into its corresponding
30 thionaphthoylglycine derivative, the pharmacologically active compo~u~d for
which the product of the present process is an intermediute. This latter con-
version is effected by reacting the compound of formula I with phosphorus
pentasulfide. Convenient conditions for effecting this latter reaction include
reacting the compound of formula I under anhydrous conditions with about two
35 to five molar equivalents of phosphorus pentasulfide in an inert solvent, e.g.
1 1582S~
-6- AHP-7858
xylene or toluene. ~his reaction cun be performed at temperatures ranging
from 8Q to about 150~ C and at times ranging from 20 minutes to four hours.
This reaction also can be performed in the presence of an organic proton acceptor,
5 for instance, N-ethyl morpholine, triethylamine or pyridine. Note that in the
instance where the compound of formula I in which R is hydrogen is reacted
with phosphorus pentasulfide, the standard first step of the work up of the penta~
sulfide reaction mixture requires that the reaction mixture be decomposed
in water. This action causes any corresponding thioacid, present in the reaction10 mixture as a result of the carboxyl group reacting with the phosphorus penta- sulfide, to be converted to the desired carboxylic acid.
The following examples further illustrate this reactioh.
EXAMPLE 1
5-Bromo-N-methyl-l~naphthalenecarboxamide (IV, Rl = CH3, R3 = Br and R4 = H)
A solution of the starting material of formula II, 1,5-dibromonaphthalcne
[1.20 g, 4.2 mmoles, described by H. El. Hodgson and J.S. Whitehurst, J. Chem.
Soc., 80 (1947)] and 1,2-dibromoethane (0.06 ml) in anhydrous freshly distilled
THF (10 ml) was added over a period of 1 min to finely cut magnesium ribbon
tll9 mg, 4.9 mmoles) under a nitrogen atmosphere. The exothermic reaction
20 was completed in 20 min. The reaction mixture was stirred for 0.5 hr. A solution
of the lower alkyl isocyanate, methyl isocyanate (0~18 ml, 4.2 mmoles), in diethyl
ether (5 ml) was added dropwise to the stirred reaction mixture at room tempera-ture (2Q-22 C). The mixture was stirred for an additional 1.5 hr at 20-22 C.
The mixture then was poured into water (125 ml). The aqueous mixture was
25 extracted with ethyl acetate. The extract was washed with water, dried (MgS04)
and evaporated to give the crude product (818 mg). The crude product was purified
by chromatography on silica gel (4S g) using 25% acetone in toluene as eluant.
The appropriQte fractions were pooled to yield 420 mg of the pure title compoundFor analysis, a sample was recrystallized from methylene chloride and hexane.
30 The recrystallized sample has mp 152-153 C; NMR (CDC13) ~ 3.03 ~d, J = 5Hz,
3H), 6.05 (broad, lE~), 7.B (m, 6H); IR (CHC13) 3450~ 3100,1655,1515 cm 1.
EXAMPLE 2
N-[(5-Bromo-l-naphthalenyl)carbonyl]-N-methylglycine Methyl Ester (I,
and R = CH3, R3 = ~3r and R4 = H)
Sodium hydride (26 mg, 0.55 mmole, 5096 dispersion in oil) was added
to dry dimethylsulfoxide (3 ml) at 55-60 CO The mixture was stirred ~Itil the
efferves~ence ceased. 5-E~rom~N-methyl-l-naphthalenecarboxamide (132 mg,
,
1 ~58254
-7- AHP-7858
0.5 mole, described in l~xample 1) was added to the rnixture and the resulting mixture
was stirred at 55-60 C for 5 min. Methyl bromoacetate (0.045 ml, 0.55 mmole)
was added to the reaction rnixture ~nd $he stirring was continued for 2 hr at 55- 60 C. After cooling, the reaction mixture was poured into 2N aqueous HCl
(50 ml). The res~ting mixture was extracted with ethyl acetate (3 x). The extract
was washed with water, dried (MgSO4) and evaporated to dryness to give 138 mg
of a residue. The residue was subjected to chromatography on silica gel (9 g)
using 20% acetone in toluene as the eluant. The appropriate fractions were pooled
to give 50 mg of an oil which crystallized when triturated in diethyl ether. Re-crystallization of the solid material gave the title compoundt mp 90 - 92 C; NMR
(CDC13) ~ 2.8 & 3.25 (2s, 3H), 3.6 & 3.85 (2s, 3H), 4.35 (broad, 2H), 7.75 (m, 6H);
D~ (CHC13) 1745,1635 cm 1.
EXAMPLE 3
N-[(5-Bromo-l-naphthalenyl)carbonyl]-N-methylglycine (Il Rl = CH3, R2 and R4 = HandR3=Br)
N-[(5 Bromo-l-naphthalenyl)carbonyl]-N-methylglycine methyl ester
(3.7 g, 11.0 mmoles, described in Example 2) was suspended in methanol (50 ml).
A solution of lN aqueous NaOH (13.2 ml) was added to the suspension. The mixturewas stirred at 20-22 C for 1.5 hr. The mixture was neutralized with aqueous
HCl and concentrated under reduced pressure to remove the methanol. The residualsolution was made acidic with aqueous HCl and extracted with ethyl acetate.
The extract was dried (MgS04), filtered and evaporated to dryness. The residue
was crystallized from ethanol-water to give 3.25 g of the title compound; mp
205 C; NMR (DMSO-d6) ~ 2.75 & 3.10 (2s, 3H), 3.75 & 4.25 (2s, 2H), 7.3 - 8.3
(m, 6EI); IR (Nujol*) 1745 with inflection at 1720,1580 cm 1; U~max (EtOH) 322
nm ( 680), 316 (1~000), 299 (6,510), 289 (9,055), 279 (7,150), 226 ~63,080); Anal Calcd:
C, 52.19% H, 3.76% N, 4u35%; Found: C, 52.09% H, 3.84% N, 4.48%.
By following serially examples 1, 2, 3, and optionally 4, and using the
appropriate starting materials of formula II and the appropriate lower alkyl isocyanate,
other compounds of formula I are obtained. For example, by replacing 1,5-dibromo-
naphthalene with ~n equivalent amount of 5-bromo-1-methoxynaphthalene as the
* Nujol is a brand name for a white mineral 3il
,.
1 1~8254
-3- AHP-7858
starting material of formula II, N-[(5-methoxy-1-naphthalenyl)thioxornethyl]-N-
methylglycine; mp 120~ C, NMR (DMSO-d6) ~ 2.93 (s, 3H), 3.90 (S7 3H), 4.65 ~c
5.16 (2d, J = 17Hz, 2H), 6.95 (2d, Jl = 7Hz, J2 ~ 3Hz), 7.35 (m, 4H), 8.11 (2d, Jl =
5 8Hz, J2 = 2Hz, lH), is obtained; similarly, replacing 1,5-dibromonaphthalene with
an equivalent amount of 1,5-dichloronaphthalene gives N-[(5-chlor~l-naphthalenyl)-
thioxomethyl3 -N-methyl glycine; mp 153 -154 C, NMR (CDC13) 6 3.û3 (s, 3H),
4.67 & 5.33 (d, J = 17Hz, 2H); similarly, replacing 1,5-dibromonaphthE~lene withan equivalent amount of 5-brom~l-methylnaphthalerle gives N-[(5-methyl-1-naphtha-
10 lenyl)thioxomethyll-N-methylglycine; mp 190 -191 C; NMR (CDC13) ~ 2.66 (s,
3H), 3.05 (s, 3M), 3.85 ~ 5.0 (m, 2H), 7.5 (m, 6H), 8.75 (broad, lH); sirnilarly, replacing
1,5-dibrornonaphthalene with l-~hlor~5-(tr if luoromsthyl)-6-methoxynaphthalene
gives N-[[(5-trifluoromethyl)-6-methoxy-1-naphthalenyl] thioxomethyl]-N-methylgly-
cine; mp 164 -165C; NMR (CDC13) ~ 3.05 (s, 3H), 3.95 (s, 3H), 4.55 ~ 5.4 (d,
15 J = 17Hz, 2H), 7.6 (m, 5iI), 9.8 (broad, lH).
EXAMPLE 4
An example of the subsequent conversion of a N-[(l-naphthalenyl)carbonyl]-
N-~lower alkyl)glycine lower alkyl ester of formula I to its corresponding thi~
naphthoylglycine lower alkyl ester derivative, and subsequent hydrolysis of the
20 lalter compound into its corresponding acid, is EIS follows:
To a stirred solution of N-[(5-brom~-1 naphthalenyl)carbonyl]-N-meth~71-
glycine methyl ester (35.5 g, 108 mmoles, described in Example 2) in dry pyridine
(100 ml), phosphorus pentasulfide (44.5 g, 200 mmoles) was added portionwise.
The mixture was stirred and refluxed ~or 1.5 hr ~nd then poured into a liter of
25 water at 50 to 8QC (caution: evolution of copious quantities of H2S). The mixture
was allowed to cool to 20 to 22C, filtered and the filtrate was extracted with
ethyl acetate. The extract was washed with IN aqueous HCl solution, brine9 a
saturated solution of sodium carbonate and brine, dried (MgSO4), filtered and
evaporated to dryness. The residue was recrystallized from ethanol-water (4:1)
30 to give N-[t5-bromo-1-naphthalenyl)thioxomethyl]-N-methylglycine methyl ester;
mp 85 - 86~ C; NMR (CDC13) ~ 3.0 (s, 3H), 3.85 (s, 3H), 4.58 ~ 5.37 (2d, J = 17,2H), 71- 8.3 (m, 6H); UV~max (EtOH) 281 nm (~ 14,480), 218 (149480~.
A lN aqueous NaOH solution (25 ml) was added to a suspension of N-
~(5-bromo-1-naphthalenyl)thioxomethyl3-N-methylglycine rnethyl ester (7.3 g,
31 ~15~2~4
-9- AHP-7858
20.7 mmsles; describeà above) in methanol (75 ml). The mixture was stirred at
20 to 22 C for 21/2 hr, neutralized to pH 7 with aqueous HCl and concentrated
under reduced pressure to remove methanol. The residual solution was rendered
5 acidic (pH = 2) with the addition of aqueous HCl solution and extracted with ethyl
acetate. The extract was dried (MgSO4) and evaporated to dryness. The residue
was crystallized from ethyl acetate-hexane to give 5.3 g of N-[(5-bromo-1-naphtha-
lenyl)thio~omethyl~-N-methylglycine; mp 181 C; NMR (DMSO-d6) ~ 2.95 (S7 3H)~
4.65 ~c 5.2 (2d, J = 16.8, 2H), 7.85 (m, 6H~; UY1~max (EtOH) 285 nm (~ 12,300), 280
~12,400~, 221(42,600); IR (Nujol* ) 2900,1720 cm 1; Anal Calcd: C, 49.72% H, 3.58%
N, 4.1496; Found: C, 49.63% H, 3.63% N, 4.18%.
EXAMPLE 5
The aldose reductase inhibiting effects of the corresponding thiona-
phthoylglycine derivatives3 for which the object compound of the present processlS are intermediates7 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 chromatography step is omitted in the preparation of the enzyme
from bovine lens.
The following results were obtained when the foregoing listed thio-
naphthoyl~lycine derivatives were evaluated in the above in vitro test.
*Nujol is a brand name for a white mineral oil
~ ~58~5~
-10- AHP-7858
% Inhibition at
Different Molar
Coneentrations
(in vitro)
Test Compound 10-5 1o~6 10-7
5 N-[(5-bromo-1-nQphthalenyl)thioxomethyl]-
N-methylglycine 93 87 47
N-[(5-m ethoxy-l-naphthalenyl)thioxomethyl] -
N-m ethylglycine 83 64 17
N-[~S-chloro-l-naphthalenyl)thioxomethyl] -
N-methylglycine - 88 75 29
N-[(5-m ethyl-l-naphthalenyl)thioxomethyl] -
15 N-methylglycine 89 74 26
N-[[~5-trifluoromethyl~6-m ethoxy-l
naphthalenyl] thioxomethyl] -N-methylglycine ~8 94 65
The thionaphthoylglycine derivatives can be administered to mamm~ls,
for example, man, cattle or rabbits, either alone or in dosage forms, i.e., capsules
or tablets, combinPd with pharmacologically acceptable excipients, see below.
Advantageously, the thionaphthoylglycines are given orally. They may be admin-
istered orally in solid form containing such excipients as stareh, milk sugar, certain
types of clay and so forth. They may also be administered orally in the form of
solutions or they may be injected psrenterally. For parenteral administration
they may be used in the form of a sterile solution, preferably of pM 7.2 ~ 7.6,
containing a pharmaceutically acceptable buffer.
The dosage of the thionaphthoylglycines will vary with the form of
administration and the particular compound chosen. Furthermore, it will vary
.
:.
1 ~L5~54
AHP-785~
wlth the particular host under treatment. Generally, treatment is initiated withsmall dosages substantially less than the optimal dose of the compound. There-
after the dosage is increased by small increments until effic~cy is obtained. Ingeneral, the thionaphthoylglyeines are most desiraMy administered at a concen-
tration level that will generaLly afford effective results without causing any harmful
or deleterious side effects. For topical administration a 0.05 - 0.2% solution may
be administered dropwise to the eye. The frequency of instillation varies with
the subject under treatment from a drop every two or three days to once daily.
For oral or parenteral administration a preferred level of dosage ranges from
about 0.1 mg to about 200 mg per kilo of body weight per day, although aforemen-tioned variations will occur. However, a dosage level that is in the range of from
about O.S mg to about 30 mg per kilo of body weight per day is most satisfactory.
Unit dosage forms such as capsules, tablets, pills and the like may
contain from about 5.0 to about 250 mg of the thionaphthoylglycines, dependent
on the type of unit dosage, preferably with a significant quantity of ~ pharma-
ceutical carrier. Thus, for oral administration, capsules can contain from between
about 5.0 to about 250 mg of the active ingredients with or without a pharma-
ceutical diluent. Tablets, either effervescent or noneffervescent, can contain
between about 5.0 to 250 mg of the active ingredients together with conventionalpharmaceutical carriers. Thus, tablets which may be coated and either effervescent
or noneffervescent may be prepared according to the known art. Inert diluents
or carriers, for example, magnesium carbonate or lactose, can be used together
with conventional disintegrating agent~ for example, magnesium stearate.
Syrups or elixirs suitable for oral administration can be prepared from
water soluble salts, for example, sodium N-[[5-(trifluoromethyl)-6-methoxy-1-rlaphtha-
lenyl3 thioxomethyll-N-methylglycinate, and may advantageously contain glycerol
and ethyl alcohol as solvents or preservatives.
.,
