Note: Descriptions are shown in the official language in which they were submitted.
~.~36~
-1- AHP-780Ç
N-NAPHTHOYL~LYCINE DERIVATIVES
-
This application relates to N-naphthoylglycine derivatives, thera-
peutically acceptable salts thereof, a process for their preparation, and to methods
of use and to pharmaceutical compositions thereof. The derivatives hsve pharma-
5 cologic properties which render them beneficial for the treatment of diabetesmellitus and associated conditions.
For many years diabetes mellitus has been b~eated with two established
types of drugs, n~mely insulin and oral hypoglycemic agents. These drugs have
benefited hundreds of thousands of diabetics by improving their well-being and
10 prolonging their lives. However, the resulting longevity of diabetic patientshas led to complications such as neuropsthy, nephropathy, retinopathy snd cat-
aracts. These complications have been linked to the undesirable accumul~tion
of sorbitol in diabetic tissue, which in turn result from the high levels of glucose
characteristic of the diabetic patient.
ln mammals, including humans, the key enzyme involved in the conver-
sion of hexoses to polyols (the sorbitol pathway) is nldose reductase. J.H. Kinoshita
and collaborators, see J.H. Kinoshita, et al., Biochem. Biophys. Acta., 158, 472tl968) snd references cited therein, have demonstrated that aldose reductase
plays a centrsl role in the etiology of galactosemic catarscts by effecting the
20 conversion of galactose to dulcitol (galsctitol) and that an agent cspable ofinhibiting aldose reductase can prevent the detrimental accumulation of dulcitolin the lens. Furthermore, a relationship between elevated levels of glucose
snd an ~desirable accumulation of sorbitol has been demonstrated in the lens,
peripheral nervous cord and kidney of diabetic animals, see A. Pirie and R.
25 van Heynir4~en, Exp. Eye Res., 3,1~4 (1964); L.T. Chylack and J.H. Kinoshita,Invest. Ophthal., 8, 401(1969) snd J.D. Ward and R.W.R. Baker, Diabetol., 6,
531 (1970).
1,3-Dioxo-lH-benz~de] isoquinoline-2~3H~acetic scid has been reported
~;
~3~
-~- AHP-7806
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 ~ataracts, neuropathy, nephropathy and retinopathy, see K.
Sestanj, N. Simard-Duquesne and D.M. Dvornik, U.S~ Patent No. 3,821,3~3, June
28,1974. Other compounds having a similar utility are the thioxo-lH-benz~de]-
5 isoquinoline-2(3H~acetic ~cid derivatives of K. Sestan;, Canadian Patent Appli-
cation 363,675, filed October 31,1980. ~S~6-Fluoro-2,3-dihydrospiro(4H-l-benzo-
pyran-4,4'-imidazolidine~2',5'-dione (sorbinil) is still another compound that
has received attention because of its aldose reductase inhibiting properties
(see M.J. Peterson et al., Metabolism, 28 (SuppL 1), 456 (1979). Accordingly,
10 these compounds represent an important new approach for the treatment of
diabetes mellitus.
The present application discloses novel N-naphthoylglycine derivatives,
represented below by formula I, which are effective inhibitors of aldose reductase.
These new derivatives are structurally quite different from the above noted
15 aldose reductase inhibitors. Close prior art compounds, on a structural basis,
appear to be a group of thioacylaminoacids, e.g. N-phenylthioxomethyl-N-methyl-
glycine, prepared by A. Lawson and C.E. Searle, J. Chem. Soc., 1556 ~1957) as
part of a chemical investigation of the chemical properties of such compounds.
These last mentioned compounds were prepared by thiobenzoylation of various
20 amino acids with (thiobenzoylthio)acetic acid. An important structural difference
between these compounds and the present derivatives is the different type of
aromatic group substituted on the thione portion of the thioamide. Thioacyl-
amides also have been reported [see Chem. Abstr., 86,189582f (1977) for V.I.
Cohen et al., Eur. J. Med. Chern., 5, 480 (1976) and Chem. Abstr., 70,11306a
25 (1969) for von J. Voss and W. Walter, JustlLs Leibigs Ann. Chem., 716, 209 (1968)].
The structures of the thioacylamides of Cohen _ 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-naphthnlenyl)carbonyl]glycine, ~see Chem. Abstr., 61, 4333f ~1964) for E.
30 Cioranescu et 1., Rev. Chim. Acad. Rep. Populaire Roumaine, 7 (2), ~55 (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.
SummarV of the lnvention
The N-naphthoylglycine derivatives of this invention are represented
35 by formula I
" .
, . ... . . .
~3~
~3~ ~P-7806
S=C-N~Rl )-(:ll (:OOR-
~,t~ 3 ( I)
, R4
wherein Rl is hydrogen, lower alkyl, lower alkenyl or phenylmethyl, R is hydrogen
or lower alkyl; R is hydrogen or a substituent at position 4, 5 or 8 of the naph-
thalene ring, the substituent being selected from the group consisting of lower
alkyl, lower alkoxy, halo, cyano, nitro and trihalomethyl, and R is hydrogen;
or R3 and R each is a substituent at different positions selected from positions3 to 7 of the naphthalene ring, and the substituents being selected from the
group consisting of lower alkyl, lower alkoxy, halo, trihalomethyl, (lower)alkoxy-
(lower~alkoxy, phenylmethoxy and phenylmethoxy substituted on the phenyl
portion with a lower alkyl, lower alkoxy, halo or trihalomethyl; or a therapeutically
acceptable snlt with an organic or inorganic bnse of the compound of formula
I wherein R is hydrogen.
~ group of preferred derivativcs is represented by the compollnds
of formula I wherein Rl is hydrogen, lower nlkyl, 2-propenyl or phenylmethyl;
R2 is hydrogen or lower alkyl; R3 is hydrogen or a substituent at positions 4,
5 or 8 of the naphthalene ring, the substituents being selected from the group
consisting of lower alkyl, lower aLcoxy, halo, cyano, nitro and trifluoromethyl,and R4 is hydrogen; or R3 and R4 are a pair of substituents on the naphthalene
ring, each substituent being at a different position of the ring, the pair of su~
stituents being selected from the group of pairs consisting of 3-halo-4-lower
25~ alkoxy, S-halo-6-lower alkyl, 5-halo-6-lower alkoxy, 5,7-dihalo, 5-(trifluoromethyl~
6-lower alkoxy, 5-halo-6-(lower)aIkoxy(lo'wer)alkoxy, 5-halo-6-[3-(trifluoromethyl~
phenylmethoxy] and 5-halo-6-(4-chlorophenylmethoxy); or a therapeutically
acceptable salt with an organic or inorganic base of the compound of formula
I wherein R is hydrogen.
Another preferred group of the compounds is represented by the
compounds of formula I wherein Rl is hydrogen, lower alkyl or phenylmethyl;
R2 is hydrogen or lower alkyl; R3 is 4-halo or 5-halo and R4 is hydrogen, or
~.~36'~
-4- AHP-7806
3 4
R and R are a pair of substltuents on the naphthalene rlng selected from
the group of pairs consisting of 3-halo-4-lower alkoxy, 5-halo-6-lower aL"yl,
5-halo-6-lower alkoxy, 5,7-dihalo and 5-trifluoromethyl-6-lower alkoxy; or a
therapeutically acceptable salt with an organic or inorganic base of the compound
of formula I wherein R is hydrogen.
A most preferred group of the compounds is represented by the
compounds of formula I wherein Rl is lower alkyl; R2 is hydrogen, R3 is 5-halo
and R4 is hydrogen; or R3 and R4 are a pair of substituents on the naphthalene
ring selected from the group of pairs consisting of 3-halo-4-lower a~coxy, 5-
hal~6-lower alkoxy and 5-(trifluoromethyl~6-lower alkoxy; or a therapeutically
acceptable salt thereof with an organic or inorganic base.
The compounds of formula I can be prepared by a process described
hereinafter.
~ 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
acceptaMe carrier, forms a pharmaceutical composition which can be used
according to the preceding method.
Detailed Description of the Invention
The term 'qower alkyl" as used herein means a straight chain alkyl
radical containing from one to four carbon atoms or a branched chain alkyl
radical containing three or four carbon atoms and includes methyl, ethyl, propyl,
l-methylethyl, butyl, 2-methylpropyl and l,l-dimethylethyl. Preferred lower
alkyl radicals contain from one to three carbon atoms.
The term 'qower alkenyl" as used herein means a straight chain alkenyl
radical containing from two to six carbon atoms, or a branched chain alkenyl
radical containing from four to six carbon atoms and includes, for example,
ethenyl, 2-propenyl, 2-methyl-2-propenyl and 2-ethyl-3-butenyl. Preferred
lower alkenyl radicals contain two to three carbon atoms.
~36'~
-5- AHP-7806
The term 'qower allcoxy" as used h~rein means a straight chain alkoxy
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, ethoxy, l-methylethoxy, butoxy and hexanoxy.
The term "halo" 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 àcid and are included within
the scope of this invention. The acid is transformed in excellent yielcl into
the corresponding therapeutically acceptable salt by neutralization of said acidwith the appropriate inorganic or or~anic base. The salts are adrninistered
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 acceptaMe alkali metals or alkaline earth
metals, for example, sodium, potassium, magnesium, calcium ancl the like.
Suitable organic bases include the following amines: benzylamîne; 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; mon~, di- &nd trialkanol-
amines, the alkanol radicals of which contain up to three carbon atoms, for
exarnple, mono-, di- and triethanolami~e; a~ylen~diamines which contain up
to six carbon atoms, such as hexamethylenediamine; cyclic saturated or un-
saturated bases containing up to six carbon atoms, such as pyrrolidine, piperidine,
morpholine, pipera7ine 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 salts, for example
the N-methylpyridinium, N-methyl-N-(2-hydroxyethyl~morpholinium N,N-di-
methylmorpholinium, N-methyl-N-(2-hydroxyethyl)-morpholinium7 N,N-dirnethyl-
~ ,~
~3~
-6- AHP-~80~i
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. ~or example, in the case of the inorganic salts,
it is preferred to dissGlve 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. ~or example, such use of sodium hy~roxide,
sodium carbonate or sodium bicarbonate gives a solution of the sodiurn salt.
Evaporation of the solution or addition of a water-miscible solvent of a more
moderate polarity, for example, a lower allcanol, for instance, butanol, or a
lower alkanone, for instance, ethyl methyl l~etone, gives the solid inorganic
lS salt if that form is desired.
To produce an amine salt, the acidic compound of formula I is dissolved
in a suitable solvent of either moderate or low polarity, for example, ethanol,
methanol, ethyl acetate, diethyl ether and benzene. At least an equivalent
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 obtainedin solid form by addition of a miscible diluent of lower polarity, for example,
benzene or petroleum ether, or by evaporation. If the amine is relatively vol-
atile, 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 quate~nary ammonium are produced by
mixing the acid of form~da 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, either alone or in dosage forms, i.e., capsules
or tablets, combined with pharmacologically acceptable excipients, see below.
~3~
-7- AHP-7806
Advantageously the compounds of this invention may be given orally. However,
lhe method of administering the present active ingredients of this invention
is not to be construed as limited to a particulnr 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 of clay and so forth. They may
also be administered orally in the form of solutions or they may be injected
parenterally. For parenteral administration they may be used in the form of
a sterile solution, preferably of pH 7.2 - 7.6, containing a pharmaceutically
acceptable bufferO
The dosage of the present therapeutic agents will vary with the
form of administration and the particular com~ound 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 ~osage is increased by small increments until e~ficacyis obtained. In general, 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 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 weightper day, although aforementioned variations will occur. However, a dosage level
that is in the range of from about 3.0 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 m~ of the active ingredients of this in-
vention, 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 active ingredients of this invention with or without a
pharmaceutical diluent. Tablets, either effervescent or noneffervescent, can
.~
~3G~
-8- ~HP-7806
contain between about 5.0 to 250 mg of the active ingredients of this invention
together with conventional pharmaceutical carriers. Thus, tablets which may
be coated and either effervescent or noneffervescent may be prepared according
to the known art. Inert diluents or carriers, for example, magnesium carbonate
or lactose, can be used together with conventional disintegrating agents for example,
magnesium stearate.
Syrups or elixirs suitable for oral admînistration can be prepared
from water soluble salts, for example, sodium N-[[5-~trifluoromethyl~6-methoxy-
l-naphthalenyl] thioxomethyl]-N-methylglycinate, and may advantageously contain
glycerol and ethyl alcohol as solvents or preservatives.
The compound of formula I, or a therapeutically acceptable salt there-
of, also can be used in combination with insulin or oral hypoglycemic agenes
to produce beneficial effect in the treatment of diabetes mellitus. In this instance,
commercially available insulin preparations or oral hypoglycemic agents, exem-
plified by acetohexamide~ chlorpropamide, tola~amide, tolbutamide and phenformin,
are suitable. The compound of formula I, or a therapeutically acceptable sult
thereof, can be administered sequentially or simultaneously with insulin or the
oral hypoglycernic agent. Suitable methods of administration, compositions and
doses of the insulin preparation or oral hypoglycemic agent are described in medical
textbooks; for instance, "Physicians' Desk Reference", 34 ed., Medical EconomicsCo., Oradell, N.J., U.S.A., 1980. When used in combination, the compound of formula
I, or its therapeutically acceptable salt, is administered as described previously.
The comp~und of form~a I, or its therapeutically acceptable salt, can be admin-
istered with the oral hypoglycem;c agent in the form of a pharmaceutical com-
position comprising effective amounts of e~ch agent.
The aldose reductase inhibiting effects of the cornpounds 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. 11. 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.
The following results were obtain~d when the foregoing listed compounds
of formula I were evaluated in the above in vitro test.
~L~36'~
-9- AHP-7806 -~~
% Inhibition at
Example Different Molar
In Which Concentr~tions
Coml~ound of ] ~ormula I Compound (in vitro)
Rl R2 R3 R4 Is PrePared 10 5 10 610 7
_ _ _ _ _ _
CH3 CH3 5-Br H 3 8
CH3 CH3 5-CF3 6-CH30 23 9
CH3 H 5-Br H 32 93 87 47
H H 3-Cl 4-CH30 32 61 16
CH3 H 4-Br H 33 91 77 32
CH3 H 8-Br H 34 88 75 24
CH3 H 5-CH30 H 35 83 64 17
CH3 H 5-CH3 H 36 89 74 26
CH3 H 5-Br 6-CH3(CH2)40 37 93 91 55
CH3 H 5-CN H 38 89 79 32
CH3 H 5-N02 H 3SI 91 83 43
CH3 H 5-Cl H 40 91 83 40
CH3 H 5-Br 6-CH30 41 99 91 72
CH3 H 5-Br 6-CH3 42 92 88 55
CH3 H H H 43 85 51 13
CH3 H ~Cl H 44 88 73 25
CH3 H 3-Cl ~CH30 45 85 78 33
CH3 H 5-Cl 7-Cl 46 88 75 29
CH3 H 5-I ~ 6-CH30 47 98 95 72
CH3 H 5-CN 6-CH30 48 98 93 74
CH3 H 5-Br 6-CH30(CH2)3C 49 92 87 38
CH3 H 5-CH2=C(CH3) H 50 92 74 19
CH3 H 5-(CH3~2CfI H 51 91 72 21
CH3 H 5-C~3 6-CH30 52 98 94 65
CH3 H 5-Br 6-~(3-CF3-C6H~)CE~203 53 86 37 11
CH3 H 5-Br 6-[(4-CI-C6H4)CH20] 53a &8 44 4
CH3 H 5-CF3 H 53b 93 84 33
H H 5-Br H 54 54 14
n C3H7 H 5 Br H 55 91 70 19
.
-10- AHP-7806
% Inhibition ~t
Example Different Molar
In Which Concentrations
Compound of Formula I _ _ _ Compound (in vitro3
Rl R~ R3 R4 Is Prepared 10 5 10~10 7
CH2=CH-CH2 H 5-Br _ _ 56 92 77 27
C2H5 H 5-Br H 57 85 72 24
n-C4Hg H 5-Br H 58 86 65 19
CH2C6H5 H 5-Br 59 86 69 20
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 exernplified
hereinbelow after the listing of the following general comments pertaining
to these experiments:
(a) Four or more groups of six male r~ts, 50-70 g, Sprague-Dawley
strain, were used. The first group, the control group, was fed a mixture of
laboratory chow (rodent laboratory chow, Purina) and glucose at 20% (W/W
%) concentration. 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 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 M. Kraml and L. Cosyns, Clin. Biochem., ~, 373 (1969).
Only two minor reagent changes were made: (a) The rinsing mixture was an
aqueous 5% (w/v) trichloroacetic acid solution and (b) the stock solution was
AHP-7806
prepared by dissolYing 25 mg of dulcitol in 100 ml of an aqueous trichloroaceticacid solution.lN.B.: For each experiment the average value found in the ffssue
from rats fed the glucose diet was subtracted from the individuPl values found
in the corresponding rat tissue to obtain the amount of polyol accumulated.
The following tabulated results show t}~at the compounds of this
5 invention diminish the accumulation of dulcitol in the lenses and sciatic nerves
of rats fed galactose. The figures under L and N represent the percentage de-
crease of dulcitol accumulation in the tissues of the lens and sciatic nerve,
respectively, for treated rats as compared to untreated rats.
10 Compound of Formula I Dose L N
Rl R2 R3 R4mg/kg/day
. ~
CH3 H 5-Br H 189 24 79
121 20 70
62 14 53
CH3 H S-Cl H 156 34 7n
CH3 H 5-Br 6-CH30162 34
58 - 78
29 - 58
~ 32
CH3 H 3-C1 4-CH30163 15
- ~27
CH3 H ~Cl 7-Cl ~52 29 45
CH3 H s-CF3 6-CH3026 lS 94
25 CH3 CH3 5-CF3 6-CH3011 10 44
CH3 H ~CF3 H 11 2 36
Process
The preparation of the compounds of formula I is illustrated by the
following scheme wherein R, R and R are as defined hereinbefore and COOR
30 is an ester group which may be, for example, & lower ~lkyl or an ar(lower)alkyl
ester; i~e., R is lower alkyl or artiower)alky1.
_ . , . _. . . .. ._ _ .. . . .
-12- AHP-7806
0-C-N~R )-CH2CUOR S -C-Nl(R )-CH2COOR
5R ~ P2S5 R
R4 (II) R (III)
1 hydrolysis 1 hydrolysis
O =C-N(R )-~H2COO~.
R3 ~ ~ p2s5 I=(R2_H)
15R4 (IV)
More specifically, a process for preparing the compounds of formula
I comprises:
(a) reacting nn amidoester of formula II wherein Rl, R3 nnd R4
are as defined herein and R is lower alkyl or ar(lower)alkyl with phosphorus penta-
20 sLdfide to give the corresponding thioxoester of formula ~II wherein Rl9 R3, R4
and R are as defined herein; or
(b) hydrolyzing the thioxoester of formula m s~herein Rl, R3, R4
and R are as defined herein to obtain the corresponding compound of formula
I wherein Rl, R3 and R4 are as defined herein and R2 is hydrogen; or
(c) hydrolyzing the amido~ster of formula II wherein Rl, R3, R4
and R are as defined herein to obtain the corresponding amidoacid of form~a
IV wherein Rl, R3 and R4 are as defined herein, and reacting the lust-named
compound with phosphorus pentasulfide to obtain the corresponding compound
of formula I wherein Rl, R3 and R are as defilled herein and R is hydrogen.
Referring to the above section (a) of the last paragraph, the thioxo-
ester of Iormula III includes those corresponding compounds of iormula l wh~reinR is lower ~lkyl, when R of the compound of formula m is lower alkyl. For
~6'~
-i3~ P-7~16
clarity and convenience in thc following discussion of ihe process, these lattercompounds of formula 1 are included in the discussion and preparation of the
compounds of formula IIl.
Still more specifically, the starting mater;al of formula II can be
S prepared by coupling a naphthalenecarboxylic ~cid of form~a Y wherein R and
R4 are ss defined herein with an aminoacid ester of formula YI wherein Rl and
R are as defined herein.
COOI I
~ I ~ N~l(R )-( Il2( (~~ ~~ l l
R (~;) (~1 )
The compounds of formula V and VI ~re known or can be prepar~
by known methods. For example, see "Elsevierls Encyclopaedia of Organie Chemistry,"
F. Radt, Ed., Series III, Vol. 12B, Elsevier Publishing Co., Amsterdarn, 1953, pp
3965-4473. The preparation of a mlmber of the naphthalenecnrboxylic acids
is illustrated by exampl~s 1 nnd ln to lj t]cscribed hereinafter. The coupling of
the naphthalenecarboxylie acid V and the amino ncid ester Yl is done prefernbly
by the "carboxyl activation" coupling procedure. Descriptions of carboxyl-acti-
vating groups are found in general tcxtbooks of peptide chemistry; for example
K.D. Kopple, "Peptides and Amino Acids", W.A. Benjamin, lne., New York, 1966,
pp. 45-51, and E. SchrBder and K. Ll~bke, "The Peptides"; Vol. 1, Academic Press,
New York, 1965, pp. ~7-128. Examples of the aetivated form of the terminal
carboxyl are the aeid chloride, acid bromide, anhydride, azide, activated ester,or O-acyl urea of a dialkylcarbodiimide. Preferred activated forms of the car-
boxyl are the acid chloride or the l-benz'otriazolyl, 2,4,5-trichlorophenyl or succin-
imido activated esters.
Returning to the flow diagram again, the amidoester of formula II
is reacted under anhydrous eonditions with about two to five molar equivalents
of phosphorus pentasulfide in an inert solvent, e g. ~cylene or toluene, to obtain
the corresponding thioxoester of formula III. This reaetion is performed con-
:
-14- AHP-7806
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
or pyridine.
Thereafter, the thioxoester of formula m 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 ml~st 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. However, it should be understood that the manner
of hydrolysis for the process of this invention is not intended to be Iimited tobasic hydrolysis since hydrolysis under acidic eonditions and other variations,
for example, treatment with lithium iodide in collidine ~see L.F. Fieser and M.
Fieser, 'TReagents 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 ernbodiment involves subjecting
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, metl~nol,
ethanol or 2-methoxyethanol. The reaction mixture is maintained at a temperatureof from about 25 to 100 C or at the reflux temperature of the solvent employed
until hydrolysis occurs. Usllnlly from 10 minutes to 6 hours is sufficient for this
hydrolysis. The reaction mixture is then rendered acidic with an acid, for example,
acetic acid, hydrochloric acid or sulfuric acid, to release the free acid.
Alternatively, the amidoester of formula II can be hydrolyzed under
the same conditions as described hereinbefore to give the corresponding amido-
acid of formula IV ~herein Rl9 R3 and R are as defined herein. The latter com-
pound, when reacted with phosphorus pentasulfide in the manner described herei~
before, then gives the corresponding compound of formula I wherein Rl, R3 and
R4 are as defined herein and R is hydrogen. Note that the standard first step
of the work up of the pentasulfide reaction mixture requires that the reaction
mixture be decomposed in water. This action causes any corresponding thi~
acid, present in the reaction mixture as a result of the carboxy group reacting
with phosphorus pentasulfide, to be converted to the desired carboxylic acid.
~3~
-15- AHP-7806
The amidoacid of formula IV also can be prepared by a previously
reported process involving the reaction of the appropriate naphthalenecarboxylicacid chloride with the appropriate aminoacid corresponding to the aminoacid
ester of formula VI in the presence of a base (proton acceptor). This process
has been used to prepare N-~(l-naphthalenyl)carbonyll glycine, see Chem. Abstr.,61, 4333 f (1964) for E. Cioranescu, et al., Rev. Chim., Acad. Rep. Populaire
Roumaine, 7 (2), 755 (1962). However, this known process for preparing N~
naphthalenyl)carbonyll glycine is inferior, based on yields, to the present process.
An interesting aspect of this invention is that certain an~idoesters
of formula II and certain amidoacids of formula IV having the following formula
O-C-N(R )-a~2COOR
R3 R~
wherein Rl is lower alkyl, lower alkenyl or phenylmethyl; R3 is a substituent
at position 4, 5 or 8 of the naphthalene ring, the substituent being selected from
the group consisting of lower alkyl, lower alkoxy, halo, cyano, nitro and trihalo-
methyl, and R4 is hydrogen; or R3 and R each is a substituent at different posi-
20 tions of the naphthalene ring, the positions selected from positions 3 to 7 andthe substituents being selected from the group consisting of lower alkyl, lower
alkoxy~ halo, trihalomethyl, (lower)alkoxy(lower)alkoxy, phenylmethoxy and phenyl-
metho2y substituted on the phenyl portion with alower alkyl, lower alkjoxy, haloor trihalomethyl; and R is hydrogen or lower alkyl, or a therapeutically~acceptable
25 salt thereof with an organic or inorganic base, also have aldose reductase inhibit-
ing effects. For example, in the above noted in vitro test, the following results
were obtained for the amidoacids, described in example 60:
N-[(5-brom~l-naphthalenyl)carbonyl]-N-methylglycine (10 5, 64%;10~, 21%); and
N-[[5~tri~1uoromethyl~6-methoxy-1-naphthalenyl] carbonyl]-N~methylglycine
30 (10 5, 94~;10~, 93%;10 , 60%1. Accordingly, the latter amîdoesters, amidoacids
and the therapeutically acceptable s lS with organic or inorganic bases, of the
amidoacids are included within the scope of this invention.
~3~
-16- AHP-7806
The following examples illustrate further this invention.
EXAMPLE 1
~(l-Methylethenyl~l-naphthalenecarboxylic Acid (V, R3 = 5-CH2 = C(CH3) and
R = H)
In a nitrogen atmosphere, a solution of l-bromo-5-(1-methylethenyl~
naphthalene [14.21 g, described by W.F. Short and H. Wang, J. Chem. Soc., 991 (1950)3
in diethyl ether (140 ml) was added dropwise to a mixture of ethyl magnesium
bromide (prepared from 2.94 g of mugnesium and 4.29 ml of ethyl bromide) in
diethyl ether (30 ml) at 0 C. The mixture was stirred at 20 C for 18 hr and
then heated at reflux for 1 hr. The cooled solution was poured onto an excess
of solid carbon dioxide The mixture was dissolved in diethyl ether. The resulting
solution was washed with a 2N aqueous solution of H2S04, brine and 10% aqueous
NaHCO3(4x). The basic washes were combined and made acidic (pH3) with 6N
aqueous HCl. The resulting solid was collected9 washed with water and dried
to give 9.7 g of the title compound; mp 138-140 C; NMR(CDC13) ô 2.15 (s, 3EI),
5.0 ~c 5.38 (2s, 2H), 8.0 (m, 6H), 10.75 (SJ lH).
EXAMPLE la
5~ Methylethyl~l-naphthalenecarboxylic Acid (V, ~3 = 5-(CH3)2CH and R4
= ~)
~(l-Methylethenyl~l-naphthalenecarboxylic acid t4.36 g, described
in Example 1), dissolved in ethanol (150 ml), was hydrogenated using 5% palladium
on charcoal as catalyst at 20 C. Absorption of hydrogen was complete after
3 hr. The catalyst was removed by filtration. The filtrate was evaporated to
give the title compound; mp 14~-150 C; NMR(CDC13) ~ 1.4 (d, J = 7Hz~ 6H),
3.75 (septuplet, J = 7Hz, lH), 8.0 (m, 6H), 10.1 (s, lH).
EXAMPLE lb
5-Bromo-6-methoxy-1-naphthalenecarboxylic Acid (V, R3 = 5-Br and R4 = 6-CH3O)
A solution of bromine (2.49 ml, 45 mmoles~ in glacial acetic acid
(50 ml) was added dropwise to a stirred solution of 6-methoxy-1-naphthalen~
carboxylic acid [8.9 g, 44 mmoles, described by C.C. Price, et al., J. Am. Chem.Soc., 69, 2261 (1947)] in glacial acetic acid (300 rnl), cooled in an ice bath. The
res~ting precipitate was collected and washed with acetic acid and then water.
Crystallization of collected precipitate from glacial acetic acid gave the titlecompound; mp 262-264~ C; NMR(DMSO-d6) ~ 3.96 (s, 3H), 7.5-7.8 (m, 3H), 7.95
(d, lH), 8.25 (d, lH), 8.82 (d9 lH).
..~
~ ~3~
-17- AIIP-7806
EX AM PLE lc
5-Bromo-6-methyl-1-naphthalenecarboxylic Acid (V, R3 = 5-Br and R4 = 6-CH3)
By following the procedure of Example lb, but replacing 6-methoxy-
l-naphthalcnecarboxylic acid with an equivalent amount of 6-methyl-1-naphth-
alenecarboxylic acid, described by C.C. Pric~ et al, J. Am. Chem. Soc.l 63,
1857 (1941), the title compound; mp 253-255 C [after crystallization Irom ethan~]-
methanol ~3:1)], NMR (DMSO-d6) ,5 2.6 (s, 3H), 8.0 (m, 5H), 10.5 (broad, lH),
was obtained.
EXAMPLE ld
3-Chloro-~-methoxy-l-naphthalenecarboxylic Acid (V, R3 = 3-Cl and R4 = 4-CH3O3
3-Chloro-4-methoxy-1-naphthalenecarboxaldehyde [15.5 g, 70.2 mmoles,
described by A J. Ablewhite and K.R.H. Wooldridge, J. Chem. Soc. (C), 2488
(1967)] was added to a suspension of silver oxide in 109~ sodium hydroxide (16.9 g
of sodium hydroxide in 170 ml of water) and dioxane (100 ml). The mixture was
stirred and heated at 80 C for 7 hr. The precipitate was removed by filtration
through diatomaceous earth (sold under the trademark Celite). The clear filtratewas evuporated to dryness. The residue was dissolved in water. The solution
wns acidified and the resultin~ prccipit~te was scpara~ed by filtration. The pre-
cipitate wn~s dissolved in ethyl Qcetate. 'I`he resu]ting so]ution was extractedwith saturated sodium bicarbollate solution. The combined aqueous extracts
were acidified. The resulting precipitate was separated by filtration and recry-stallized from ethanol-water to give the title compound; mp 187-189~ C; NMR
(Dl~lSO-d6) ~ 4.0 (s, 3H), 8.15 (m, SH), 13.3 (broad lH); IR (Nujol*) 2900,1700,1260,1160 cm 1; UV~max (EtOH) 303 (~ ~,400), 231(56,300); Anal. Calcd: C, 60.90~6
?, H, 3.83% Found: C, 60.71% H, 3.87~.
EXAMPLE le
5,7-Dichloro-l-naphthalenecarboxylic Acid~Y, R = 5-Cl and R4 = 7-Cl)
Sulfuryl chloride (36.8 g, 273 mmoles) was added dropwise to a stirred
suspension of benz[c,d] indole-2(1H~one (20 g, 119 mrnoles) in glacial acetic acid
~0 (275 ml) at 20 to 22 C. The mixture was heated at reflux for 1.5 hr, cooled and
filtered. The collected solid was washed with glacial acetic acid and recrystallized
from toluene to afford 6,8-dichloro-benz[c,d] indole-2(1H)-one, mp 265 C, des-
cribed by Y.T. Rozhinskii, Zhur. Org. Khim., 8, 2388 (1972). A mixture of the
latter compound (14 g, 58.8 mmoles3 in 2% aqueous sodium hydro~ide was refluYed
~5 for 4 hr. The mixture was cooled, mixed with sodium nitrite (3.8 g, 55 mmoles3
Nl~jol is a trademark for a brand of white mincral oil
-18- AI~P-7806
and added dropwisc to u coolcd (()-5 C) solution Or concentrnted sulfuric ~cid
- (45 ml) in ~ater (180 ml). The diazonium salt wus saltcd out by addition of sodiurn
bromide, collected by filtration and while still wet (drying dan6erous) ~as ~dded
to a solution of sodium hypophosph~te (39.2 g of Nal~2P02.H 20) in water (100
ml). The mixture was stirred at 20-22~ C for 48 hr. The resulting solid was collected
by filtration and suspended in saturated sodium bic~rbonale (~00 ml). The insolubie
material was collected by filtration and resuspcnded in hot, saturuted sodium
bic~rbonate (200 ml). The suspension ~vas filtered and the filtr~lte was cooled.The resulting precipitate of the sodium salt o~ the product was collected by filtration.
The free acid was prepared by suspending the sodium salt in water and render-
ing the suspension acidic. More product was obtained by acidification of filtrates
of the sodium salt. The combined crops were recrystallized from ethanol to
yield 5.8 g of the title compound; mp 253-254 C; NMR (DMSO-d6) ~ 8.3 (m,
raH), 10.6 (broad, lH), UV~max (EtOH) 333 nm ( 2,350), 298 (7,000), 230 (53,300~.
EXAMPLE lf
S-lod~6-;nethoxy-1-naphthalenecarboxylic Acid (Y, R3 = 5-I and R4 = 6-CH30)
lodinc (7.08 g) ~nd iodic acid (2.78 g) were added to a stirred solutio
of 6-rnelhoxy~ naphthnlenccarboxylic acid methyl ester n5 L~ 69.~ mrnoles,
described by C.C. Price et al., J. Arner. Chem. Soc., 69, 2261(1947)] în 8096
acetic acid (110 ml) and 98~6 sulfuric acid (0.97 ml). The solution was heated
at 50 C for 5 hr, cooled and poured into water (100 ml). After the nddition of
sodium bisulfite to destroy the unreacted iodine, the precipitate was collected,washed with water and recrystallized from ethanol to afford the corresponding
methyl ester of the tltle compound; mp 98-99 C; N~IR (CDC13) ~ 3.95 (s, 3H),
4.00 (s, 3H), 8.00 (m, 5H). A mixture of the latter ester (7.1 g, 21 mmoles), 10%
aqueous sodiurn hydroxide (35 ml3 and methanol (l9.S ml) was heated at re1ux
for 1 hr. The solution was cooled to ice bat~ temperature and made acidic with
lN aqueous hydrochloride~ The resulting precipitate was coJlected, washed with
water and dried under reduced pressure over phosphorus pentoxide to give 7 g
of the title compound; mp 259-261 C; NMR (DMSO-d6) ~ 4.0 (s, 3H), 8.15 (m,
5H), 10.56 (broad, lH).
EX AM PLE lg
5-Cyano-6-methoxy-1-naphthalenecarboxylic Acid (V, R3 = 5-CN and R4 = 6-
CH30)
3~ A solution of bromine (26.6 g, 0.167 mole) in glacial acetic acid (25 ml)
-]9- AHP-7806
was added dropwise to a cooled suspcnsion of 6-methoxy-1-n~phthalenecarboxyljc
acid methyl ester (30 g, 0.13 9 moles) in glacial acetic acid (2.75 ml). The pre-
cipitate was collected~ washed with water and crystallized from ethanol to give
33.3 g of 5-brom~6-methoxy-1-naphthalenecarboxylic acid methyl ester; mp
119 C; NMR (CDC13) ~ 3.97 (s, 31~), 4.03 (s, 3H), 7.35 (d, J = 9.25Hz, lH), 7.4(m, lH), 8 05 (d, J = fi.75 Hz, lH3, 8.45 (d, J = 8.25 Hz" lH), 8.9 (d, J = 9.25, ]H).
The latter ester (10.1 g, 34 mmoles) and Cu2(CN)2.H2O (3.4 g, 17 mmoles) in
distilled dimethylfornnamide (75 ml) containing 15 drops of pyridine was heated
at 180 C for 5 hr. The hot mixture was poured into a mixture of ice (SD g) and
~0 conc. NH40H (50 ml). The resulting precipitate was col]ected, washed with
water, dried and recrystallized from chloroform-ethyl acetate to afford 5.6 g
of 5-cyano-6-methoxy-1-naphthalenecarboxylic acid methyl ester: mp 210-211 C,
NMR (CDC13) ~ 3.95 (s, 3H), 4.15 (s, 3H). To a stirred solution of the latter
ester (5.95 g, 24.66 mmoles) in 2-methoxyethanol (100 ml) at 20-22 C, 4N nqueous
NaOH solution (12.3 ml) was added. The reaction mixture was stirred at 20-2~ C
for 60 hr, diluted with water, cooled to Q C and rendered acidic with IN aqueous
HCI. The precipitate was collected and dried to yield 5.6g of the title compound;
mp ~290 C; NMR (DMSO-d6) ~ 4.1 (s, 31-1), 8.1 (m, 5TI).
EX AM PLE lh
5-(Trifluoromethyl~6-methoxy-1-naphthalenecarboxylic ~cid (V, R = 5-CF3
and R4 = 6-CH30)
A mi~ture of 5-iodo-6-methoxy-1-naphthalenecarboxylic acid methyl
ester (10.26 g, 30 mmoles, described in Example lf), trifluoromethyl iodide (12 g,
61.2 mmoles), freshly prepared copper powder (5.7 g, prepared according to the
procedure of R.Q. Brewster and T. Groening, 'IOrganic Syntheses", Coll. Vol.
Il, John Wiley and Sons, New York, N.Y., U.S.A., 1948, p. 445) nnd pyridine (45 ml)
was charged into a stainless steel autoclàve. The vessel was shaken and heated
at 120 C for 20 hr and cooled to room temperature. The mixture was diluted -
with diethyl ether-ethyl acetate (1:1). The insoluble material was removed by
filtration. The filtrate was washed with IN aqueous HCl, water and dried (MgSO4).
The solvent ~as removed under reduced pressure. The residue wns crystallized
from ethanol to give 6.4 g of 5-(trifluoromethyl~6-methoxy-1-naphthalenecar-
bo~ylic acid methyl ester; mp 79-80 C; NMR (CDC13) ~ 3.95 (s~ 6H)1 8.00 (m,
-20- AHP-7806
SH~. A mixture of the latter ester (6.3 g, 27 rnmoles), IN ~3queous NaOH solution
(34.12 ml) and methanol (l00 ml) Wf~5 stirred at 20-22 C for 4 hr. The mixture ~ ~
was adjusted to pH 7 with IN aqueous HCI, methanol was removed from the mixture
by distillation ~nd the concentrated mixture was made acidic (pH 2) with IN
aqueous HCI. The resulting precipltate was collected and dried to yie]d 6 g oî
the title compound; mp 218-219 C; Nl~ (D~SO-d6) ~ 4.0 (s, 3H), 8.3 (m, 5H),
10.6 (broad, IH).
EXAMPLE li
5-Bromo-6-~3-(trifluoromethyl)phenylmethoxy]-1-naphthalenecarboxylic Acid
[V, R3 = 5-Br and R = 6-[(3-CF3~6H4~CH2O] )
A rnixture of 5-bromo-6-methoxy-1-naphthalenecarboxylic acid (33.35 g,
0.11 moles, described in example lb) in glacial acetic acid (460 ml) and 4796 aqueous
HBr(417 ml) was heated at reflL~ for 9 hr. The resulting precipitate was collected,
washed with water and dried over P2O5 under reduced pressure. The precipitate
was recrystallized from ethanol-water to give 21.45 g of 5-bromo 6-hydroxy- --
l-naphthalenecarboxylic acid; mp > 225 C; Nl~IR (DMSO-d6) ~ 8.0 (m, 5H), 11.0
(broad, IH), 12.6 (broad, lH).
The Iflttbr acid (1.2 g, ~.5 mmoles) was suspended in dry dimethyl-
formamide (DMF, 25 ml). Sodium hydride (~.43 g, 9.0 rnmoles, 50% mineral oil
suspension) wns addcd in smaII portions to the stirred suspension. Stirring was
continued until the evolution of hydrogen ceased. A solution of 3-(trifluoromethyl~
phenylmethyl chloride (2.63 g, 13.5 mmoles) in dry DMF (5 ml) was added dropwiseand the mixture was heated to 50-60 C for 1 hr. rhe solvent was evaporated
under reduced pressure to dryness. The residue was triturated with water. The
solid WQS separated from the water by filtration. The collected solid was washedwith hexane to remove residual mineral oil ànd then recrystalIized from ethanol-water to give 1.7 g of 5-bromo-6-~(3-trifluoromethyl)phenylmethoxy]-1-naphthalen~
carboxylic acid, 3-trifluoromethyl ester; mp 114-115 C, IR (CHC13) 1715 cm 1.
A mixture of the latter ester (1.7 g, 2.9 mmoles), methanol (20 ml)
and lN aqueous NaOH (4 ml) was stirred for 24 hr at 20-22 C. Additional IN
aqueous NaOH was added and the mixture was stirred at 40 C for 3 hr. The
solvent was evaporated. The residue wns dissolved in water ~Lnd the solution
~`
~3~
-21- AHP-7806
made acidic The resulting precipitate was collectedl, washed with water, dried
and recrystallized from ethanol to give 1.0 g of the title compound; mp 2Z9-230~ C;
NMR (DMSO-d6~ ~ 5.5 (s, 2H), 8.1 (m, 9H), 10.5 (broad, lH).
5-Bromo-6-(4-chlorophenylm ethoxy~l-naphthalenecarboxyli c acid,
NMR (DMSO-d6~ ~ 5.4 (s, 2H), 7.7 (m, 9H), 11.0 (broad, lH), is obtained by ~ollow
ing the procedure of Example li but replacing 3-(trifluoromethyl)phenylrnethyl
chloride with an equivalent amount of 4-chlorophenylmethyl chloride. Likewise,
5-bromo-6-(3-methoxypropoxy~l-naphthalenecarboxylic, IR (mineral oil) 2900,
1670 cm 1 is obtained by replacement with 3-methoxypropyl chloride.
EXAMPLE lj
S-(Trinuoromethyl~l-naphthalenecarboxylic Acid (V, R3 = 5~F3 and R4 = H)
A mixture of 5-iod~l-naphthalenecarboxylic acid methyl ester [8.8 g,
28 mmoles, described by C. Seer and R. School, Justus Leibigs Ann. Chem., 398,
82 (1913)], trifluoromethyl iodide (12 g, 61.2 mmoles), freshly prepared copper
powder (5.7 g, prepared according to the procedure of R. Q. Brewxter and T.
Groening, "Organic Syntheses", Coll. Vol. II, John Wiley and Sons, New York,
N.Y., U.S.A., 1948, p. 445) and pyridine (45 rnl) was charged into a stainless steel
autoclave. The vessel was shaken and heated at 130 C for 24 hr and cooled to
room temperature. The mixture was filtered to remove insoluble material.
The filtrate was washed with lN aqueous HCl, water and brine, dried (MgS04)
and concentrated to dryness. The residue was crystallized from methanol to
give 4.3 g of 5~trifluoromèthyl~1-naphthalenecarboxylic acid methyl ester, NMR
(CD~3) ~ 4.0 (s, 3H), 8.0 (m, 6H).
The ester (4.25 g, 16.72 mmoles) was suspended in methanol (100 ml).
A 2N aqueous NaOH soluffon (16.72 ml, 2 equivalents) was added to the suspensionr
The mixture was stirred at 20-22 C for 18 hr. The res~ting clear solution was
adjusted to pH 8 with lN aqueous HCl and concentrated unde~ reduced pressure.
The concentrate was adjusted to pH 3 with lN aqueous HCl. The resulting pre-
cipitate was collected, washed with water and dried under reduced pressure to
give the ~tle compound; mp 206-208 C.
EXAMPLE 2
N-[(5-Brom~l-naphthalenyl)carbonyl]-N-methylglycine Methyl Ester ~II, Rl and
R - CH3, R3 = 5-Br and R4 = H)
~5
.. . . . , . . . _ .. , . . _ . .. . . ...
~3~
-22- AHP-7806
Procedure A:
A catalytic amount (5 drops~ of dry DMF was added to a suspension
of the starting material of formula V, 5-brom~l-naphthalenecarboxylic acid
no g, 39.8 mmoles, described by W.F. Short and H. Wang, J. Chem. Soc., 99û
(1950)], in thionyl chloride ~100ml). The suspension vras heated cautiously to
reflux (caution: a vigorous reaction can occur). The mixture was refluxed for
20 min. The mixture was evaporated to dryness. Toluene was added to the solid
residue 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-methylglycine
methyl ester hydrochloride (11.1 g, 79.6 mmoles), a starting material of formulaVI, was added portionwise to the cooled solution. The mixture was stirred for
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 mixture was extracted
with ethyl acetate (3 x lS0 ml). The combined extracts were washed with lN
aqueous HCl solution, a saturated solution of sodium bicarbonate and brine.
After drying over MgSO4, the extract was treated with charcoal, filtered and
evaporated. The residue was crystallized from diethyl ether or ethanol to give
the title compound; mp 91-9~ C; NMR (CDC13) ~ 2.8 ~ 3.25 (2s, 3H), 3.6 ~
3.85 (2s, 3H), 4.35 (broad, 2H), 7.75 (m, 6H); IJV~max (EtOH) 321 nm (~ 775), 316
(1,110), 299 (6,660)~ 289 (9,250~, 279 (7,400), 225 (66,600); Anal. Calcd: C, 53.59%
H, 4.20% N, 4.17%; Found: C, 53.60% H, 4.27% N, 4.21%.
Procedure B:
A mixture of the starting material of formula V, 5-bromo-1-naphthalene-
carboxylic acid (12.8 g, 52 mmoles), and l-hydroxybenzotriazole (HOBt, 7.0 g,
52 mmoles) in DMF (200 ml) was prepared. N,N'-dicyclohexylcarbodiimide (DCC,
10.6 g, 52 mmoles) in DMF (30 ml) was added to the mixture. The resulting mixture
was stirred at 20 C for 1 hr and then cooled to 0 C. N-Methylglycine methyl
ester hydrochloride (7.25 g, 52 mmoles) and thèn N-ethylmorpholine (6.7 ml,
52 mmoles) were added to the cooled mixture. The mixture was stirred for 3
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 325 g of silica gel using ethyl acetate-hexane (1:1) as the
~36~
-23- AHP-78D6
eluant. The pure fractions were pooled to yield 10.5 g of product which was r~
crystallized from ethyl acetate to give the title compound, identical to the product
of procedure A of this example.
EXAMPLE 3
N-[(5-Bromo-l-naphthalenyl)thioxomethyl]-N-methylglycine Methyl l~ster (I,
RlandR2=CH3,R3=5-BrandR4=H)
To a stirred solution of N-[(5-brom~l-naphthalenyl)carbonyl]-N~methyl-
glycine methyl ester (35.5 g, 106 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 for 1.5 hr and then poured into a liter of
water at 50 to 80 C (caution: evolution of copious quantities of H2S). The mixture
was allowed to cool to 20 to 22 C (room temperature), filtered and the filtratewas 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 dryness. The residue was recrystallized from ethanol~water (4:1) to give the title compound; mp 85-86 C; NMR (CDC13) ô 3.0 (s,
3H), 3.85 (s, 31-1), 4.58 ~ 5.37 (2d, J = 17, 2H), 7.1-8.3 (m, 6H); UVAmnx (EtOH)
281 nm tE 14,480), 218 (14,480).
By following serially the procedures of Examples 2 and 3 and using
the appropriate starting material of formula V instead of 5-bromo-1-naphthalen~
carboxylic acid, other compounds of formula I in which Rl and R2 each is methyl
are obtained. Examples of the latter compounds are listed as products in Tables
1 and lI together with the appropriate starting material of formula V used for
their preparation.
.~
36'~
-24- AHP-7806
TABLE 1 ~~
STARTING MATERIAL PRODUCT:N-~(prefix listed
OF FORMULA V below-l-NAPHTHALENYL~
3 4 THIOXOMETHYL]-N-METHYI~
EXAMPLE R R GLYCINE METHYL ESTER
- _ _
4 4-Br H 4-bromo; NMR (CDC13) ô
2.85 & 3.25 (2s, 3H), 3.6 & 3~85
(2s, 3H), 4.35 (m, 2H), 7.7 (m,
13H), IR (CHC13) 1730,1620 cm 1
8-Br H 8-bromo; I~(CHC13) 1730,
1480,1380,1080 cm ; Nl\IIR (CDC13)~
3.0 (s, 3H), 3.8 (s, 3H)9 3.65
(m, 2H), 7.5 (m, 6H)
6 5-CH30 H 5-methoxy; NMR (CDC13) ,S
2.81~ 3.21 (2s, 3H), 3.58 ~
3.80 (2s, 3H), 3.97 (s, 3H), 4.37
(broad, 2H), 6.80 (d, lH), 7.40
(m, 4H), 8.27 tm, lH); IR (CHC13)
1740,1630,1578 cm~l -
7 5-Me H 5-methyl; NMR (CDC13) ~
2.68 (s, 3H), 3.05 (3H), 3.85
(3H), 3.75 ~ 4.9 (m, 2H), 7.6
(s, 6H)
8 ~Br 6-~CH3(CH2)4O] 5-bromo-6-pentyloxy; mp
80-83 C; NMR (CDC13)
0.9 (t9 J = 7Hz, 3H), 1.1-2.0
(broad, 2H), 3.0 (s, 3H), 3.8
(s, 3H), 4.1 (m~ 2H), 7.1-8.5 (broad,
5H)
~ ~3~
-25- AHP-7806
_
TABLE I (Continued)
STARTING MATERIAL PRODUCT:N-[(prefix listed
OF FORMULA V below-l-NAPHTIlALENYL~
THIOXOi~ETHYL~--N-METHYI~
EXAMPLE R3 R4 GLYCINE METHYL ESTER
__
9 ~CN H 5-cyano; NMR (CDC13) ~
3.00 (s, 3H~, 3 85 (s, 3H), 4.45
~ 5.45 (d, 2H), 7.18 (m, 6H)
9a 4-CN H 4-cyano; NMR tCDC13)~'
- 3.1 (s, 3H), 3.85 ~s, 3H), 4.55
~c 5.25 (2d, J = 17Hz, 2H), 7.0-
8.4 (m, 6EI)
S-NO2 H 5-nitro; mp 116-117D C
11 5-CI H 5-chloro; mass spectrum,
m/e: 301/309 (M ), 274t276
(M -Il, S), 248/246 (M -COOMe~
12 5-Br 6-CH30 5-bromo-6-methoxy; mp
115-117 C; NMR (Cl)C13) ~7
3.00 (s, 3H), 3.84 (s, 3H), 3.98
(s, 3H)
13 5-Br 6-CH3 5-bromo-6-rnethyl; NMR
(CDC13) 5 2.6 ~s, 3H), 3.0 (s,
3H), 3.85 ~s, 3H), 4.5 ~c 5.35
(d, J = 16.5~z, 2H), 7.7 (m, 5H)
14 H H ~; IR (CHCI3) 1735 cm 1
~No prefi~c as compo~nd is IN-((l-nal7lltll~1ellyl)tllio~;0methyl)-N-
m~l:hylglycine metllyl ester
~5
: - -
~36'~
-26- AHP-7806
TABLE I (Continued)
STARTING MATERIAL PRODUCT:N-[(prefix listed
OF FORMULA V below-l-NAPHTHALENYL~
3 4 THIOXOMETHYL]--N-METHYI~
EXAMPLE R R GLYCINE METHYL ESTER
~Cl H ~chloro; mp 100-101C;
NMR (CDC13)~ 3.10 & 3.62
(2s, 3E~); 3.90 ~ 3.70 t2s, 3H),
4.04, 4.55 ~ 5.37 (s, 2d, ~ =
16Hz, 2H), 7.2-8.4 (m, 6H);
IR (CHC13) 1740 cm 1; UVAmax
(EtOH) 283 nm ~ 7,100), 219
(52,0003; ~nal. Calcd: C, 58.54%
H, 4.5896 N, 4.55%; ~ound:
C, 58.58% H, 4.76% N, 4.58%
16 ~Cl ~CH30 3-chlor~4-methoxy; mp
85-86C; NMR (CDC13)~ 3.05
ts, 3H), 3.85 (s, 3H), 4.00 (S9 3H),
4.58 ~ 5.3 (2d, ~ = 17Hz, 2H),
7.6 (m, SH)
17 5-C1 7-Cl ~ 5,7-dichloro; rn/e; 325/327/
329 (M ), 266, 268, 270 ~M -
COOCH3), 223/225/227 ~M -
CH3 N CH2 COOCH3)
18 5-I 6- CH30 5-iod~6-methoxy; mp 149-
150 C; NMR (CDC13) ~ 3.00
(s, 3H), 3.85 (s, 3H), 3.95 (s,
3H), 4.4 ~e 5.45 (d, 2H), 7.6
(m, 5H)
27- AHP-7806
TABLE I (Continued) ~~
STARTING MATERIAL PRODUCT:N-~(prefix listed
OF FORMULA V below-l-NAPHTHALENYL~
3 4 THIOXOMETHYL]-N-METHYJ~
EXAMPLE R R GLYCINE METI~YL ESTER
19 5-CN 6-CH30 ~cyano-6-methoxy; mp
l64-165 C; NMH (CDC13) ~
3.05 (s, 3H), 3.90 ~s, 3H), 4.07
~s, 3H), 4.35 ~ 5.55 (d, J = 16.8Hz,
2H), 7.80 (m, 5H)
~ith reference to Table 1, the starting materials of formllla V are
described by T.L Jacobs, et al., J. Org. Chem., 11, 2'1 (1946) for exarnple 4; by
11.G. Rule et al., J. Chem. SOC.J 168 tl934) for example 5; by A. Cirardet and
N. Lorusso, Helv. Chim. Acta., 49, 471 (19G6) for example 6; by M.a.s. Dewar
and P.J. Grisdale, J. Am. Chem. Soc., 84, 3541(1962) for example 7; in example
lc for example 8; by M.J.S. Dewar and P.J. Grisdale, J. Am. Chem. Soc~, 84,
3541 (1962) for examples 9, 9a, 10 and 11; in example lb for example 12; in example
lc for example 13; by H. Gilman et al., "Organic Syntheses", Coll. Vol. II, John
~Yi1ey and Sons, New York, N.Y., U.S.A., 1948, p. 425 for example 14; by T.L.
Jacobs et ~1., J. Org. Chem., 11 27 (1946) for example 15; in example ld for example
16j in example le for example 17; in example If for example 18; and in example
lg for example 19.
,
`~
~3~
-28- AHP-78û6 -~-
TABLE II
STARTING MATERIAL PRODUCT:N-[[prefix listed
OF FORMULA V below-l-NAPHTHALENYI.I-
THIOXOMETHYL] -N-METHYI~
EXAMPLE R R _ GLYCINE METHYL ESTER
5-Br 6-[CH30(CH2)30] 5-bromo-6-13-methoxypro-
poxy); NMR (CDC13) ~ 2.1 ~m~
4H), 3.35 (s, 6H), 3.55 (m, 4H),
4.25 (t, J = 6Hz, 2H)9 4.45 ~t,
5 = 6Hz, 2H), 7.4 (m, 2H), 8.0
(d, J = 8Hz, lH), 8.4 (d, J =
8Hz, lH), 8.85 (d, J = 8Hz, lH)
21 5-~CH2=C(CH3)] H 5-(1-methylettlenyl); mp ~3-95C~;
NMR (CDCl3) ~ 2.15 (s, 3H),
3.05 (s, 3H), 3.85 (s, 3H), 4.55
& 5.3 (2s, 2H), 5.0 & 5.35 (2s,
2H), 7.6 (m, 6H)
22 5 [(CH3)2CH] H 5-(1-methylethyl); NMR
(CDC13) ~ 1.35 (m, 6H), 3.0
& 3.55 (2s, 3H), 3.65 ~ 3.85
(2s, 3H), 4.95 (2H), 7.5 (m, 6H)
23 5-C~?3 6-CH30 5-(trifluoromethyl~6-methoxy;
mp lûg-110 C; NMR (CDC13)
3.00 (s, 3H), 3.55 (s~ 3H), 3.95
(s, 3H), 4.35 ~ 5.45 (d, 2H),
7.7 (m, 5H)
24 5-Br 6-[(3-CF3-C6H4~ 5 bromo-6-[3-(trifluoromethyl~
CH20] phenylmethoxy]; NMR (CDC13)
~L~36~9
-29- AHP-7806
TABLE II (Continued)
STARTING MATERIAL PRC)DUCT:N{[prefix listed
OF FORMULA V below-l-NAPHTHALENYI~--
3 4 THII:)XOMETHYL]-N-METHYI~
5 EXAMPLE R R GLYClNE METHYL ESTER
24 (Cont~d) ~ 3.00 ~s, 3H), 3.85 (s, 3H),
4.4 ~k 5.4 (2d, J = 16.5Hz, 21I),
5.25 (s, 2H), 7.6 ~m, 9H)
24a ~Br ~[(4~1~;E14~ 5-bromo-6~4-chlorophenyl-
CH2] methoxy); NMR (CDC~3) 5
3.00 (s, 3H), 3.85 (s, 3H), 4.40
~c 5.40 (d, 2H), 5.2 (s, 2H), 7.5
m 9H)
24b ~CF3 H ~(tri:Eluoromethyl); NMR
(CDC13)~ 3.00 (s, 3H), 3.85
(s, 3H), 4.5 ~c 5.4 (d, 2H), 7.2--
8.3 (m, 6H).
With reference to Table II, the starting materials of formula V ~re
described in example li? herein, for example 20; in example 1 for example 21;
in example la for example 22; in example~ lh for example 23; in example li for
example 24 and example 24a; and in example lj for example 24b.
By following serially the procedures of examples 2 and 3, but using
the appropriate starting material of formula VI instead of N-methylglycine,
other compolmds of formula I in which R is lower alkyl, R3 is 5-bromo, R4
is hydrogen are obtained. Examples of the latter compounds are listed as products
in Table m together with the appropriate starting rnaterial of formula VI used
~3~
-30- AHP-7806
TABLE III
STARTING MATERIAL PRODUCT:N-[(5 BROM~l--
OF FORMULA VI NAPHTHALENYL)THIOXO--
METHYL]~uffix listed
EXAMPLE R R below
H CH3 glycine methyl ester; mpl26-
130~ C; NMR (CDC13)~ 3.8
(s, 3H), 4.6 (d, J = 7H[z, 2H),
7.15-8.15 (m, 6H)
26 ~C3H7 C2H5 N-propylglycine ethyl ester;
NMR (CDC13) ~ 0.65 (t, J =
7Hz, 3H), 1.4 (t, 3H), 1.45 (m,
2H), 3.2 (t, J = 7Hz, 2H), 4.3
(q, J = 7Hz, 2H), 4.35 (d, J =
17Hz, lH), 5.3 (d, J = 17Hz, lH),
7.7 (m, 6H); IR (CHC13) 1740 cm 1
27 CH2=CH-CH2 CH3 N-(2-propenyl)glycine methyl
ester; mp 72-74 C
28 C2H5 CH3 N-ethylglycine methyl ester;
NMR (CDC13) ~ 1.10 (t, 3H),
3.35 (q, ~H), 3.85 (s, 3H), 4.40 ~c
5.25 (d, 2H), 7.6 (m, 6H)
29 C4H9 C2~5 N-butylglycine ethyl ester;
NMR (CDC13) ~ 0.65 (t, a =
S.5 Hz, 3H), 1.0 (m, 2H), 1.38
(t, 3H), 1.40 (m, 2H), 3.25 (m,
.
- (
~3~
-31- AHP-7806
TABLE m (Continued)
_
SIARTING MATERIAL PRODUCT:N-[(5-BROM~l--
OF FORMULA YI NAPHTHALENYL)THIOXO--
METHYL]-suffix listed
s EXAM PLE R R be]Low
29 (Cont'd) 2H), 4.25 dc 5.30 ~d, J = 16Hz,
2H), 7.7 (m, 6H)
3o C6H5CH2 C2H5 N-~phenylrnethyl)glycine ethyl
ester; mp 141-142 C; NMR (CDC13)
~ 1.35 ~t, J = 7Hz, 3H), 4.5û
tm, 6H), 7.50 (m, llH)i IR(Nujol * )
1743 cm~
EXAMI'LE 31
By following serially the procedure of Examples 2 and 3, but using
the ~ppropriate starting material of formula V and the appropriate an~inoacid
ester of formula VI, still other compounds of formula I in which R is lower
alkyl are obtained. For examplel by using 3-chloro-4-methoxy-1-naphthalenecar-
boxylic acid, described in Example ld, as the starting material of formula V,
and using glycine ethyl ester hydrochloride as the starting material of formula
Vl, N-~(3-chlor~4-methoxy-1-naphthalenyl)thioxomethyl] glycine ethyl ester;
IR (CHC13) 3420, 3340,1740,1665 cm 1; via N-[(3-chloro-4-methoxy-1-naph-
thalenyl)carbonyl] glycine ethyl ester; rnp 140-141 C; NMR (CDC13) ~ 1.3 ~t,
J = 7Hz, 3H), 4.2 (m, 4H~, 6.55 (broad, lH), ~.55 (m, 3H), 8.2 (m, 2H), was obtained.
EXAMPLE 32
N~(~Brom~l-naphthalenyl)thioxomethyl]-N-methylglycine (I, Rl = CH3, R2
and R4 = H and R3 = 5-Br)
* Trademark
~3~
~32- AHP-7806
A IN aqueous NaOH solution (25 ml) was added to ~ suspeslsion OI
N{(S-brom~l-naphthalenyl)thioxomethyl]-N-methylglycine methyl ester (73 g,
20.7 mmoles; described in Example 3) in methanol (7 5 ml). The mixture was
stirred at 20 to 22~ C for 21/2 hr, neutralized to pH 7 with aqueous HCl and
5 concentrated under reduced pressure to remove methanol. The residual solution
was rendered acidic (pH = 2) with the addition of aqueous HCl solution and ex-
tracted with ethyl acetate. The extract was dried (MgSC)4) and evapor~ted
to dryness. The residue was crystallized from ethyl acetate-hexane to giYe
5.3 g of the title compound; mp 181 C; NMR (DMSO-d6) ~ 2.95 (s, 3H), 4.65
10 ~ 5.2 (2d, J = 16.8, 2H), 7.85 (m, 6H), UV~max (E~OH) 285 nm (~ 12,300), 280
(12,400), 221 (42,6û0); IR(Nujol * ) 2900, 1720 crn~; Anal C~lcd: C, 49.72% H,
3.58% N, 4.14%; Found: C, 49.6396 H, 3.63% N, 4.18%.
In the same manner, but replacing N-[(5-bromo-1-naphthalenyl)thioxo-
methyl]-N-methylglycine methyl ester with an equivalent amount of N-[~3-chloro-
15 4-methoxy-1-naphthalenyl)thioxomethyl] glycine ethyl ester, described in Example
31, N{(3-chloro-4-methoxy-1-naphthalenyl)thioxomethyl]glycine [mp 217C(dec);
NMRtDMSO-d6) ~ 3.96 ts, 3H), 4.42 (d, J = 6Hz7 2H), 7.40 (s, lH), 7.65 (m, 2H),
8.18 (m, 2~); IR (Nujol *) 3I50, 2900,17Z0, 1140 cm ; UV~max (EtOH~ 277 nm
(~11,400), 224 (51,300); Anal Calcd: C, 54.28% H, 3.91% N, 4.52%, Found: C,
20 54.26% H, 4.06% N, 4.62%] was obtained.
By following the procedure of Example 32, but replacing N{(5-bromo-
l-naphthalenyl)thioxomethyl]-N-methylglycine methyl ester with an equivalent
amount of another ester compound of formula I in which R is lower alkyl, or
corresponding compound of formula m ir~ which R is artlower)alkyl, the cor-
25 responding compound of formula I in which R is hydrogen was obtained. Examples
of the latter compounds are listed ~s products in Tables IV, V and VI together
Mth a notation to the corresponding compound of formula I in which R is low~
alkyl from which they are prepared. In each case the compound of formula
I in which R2 is lower alkyl, the starting material, is noted by the example in
30 which it was prepared.
* Trademark
1~ .
36~
-33- AHP-780
TABLE IV
PRODllCT:N-[(prefix listed
NO. OF THE EXAMPLE IN below-l-NAPllTHALENYL~
WHICH START1NG MATE}~IAL IHIOXOMETHYL]-N-METHYI~
EXAMPLE WAS PREPARED GI,YCINE
33 4 4-bromo; mp 1~8-169~C,
NMR(Di~lSO-d6) ~ 3.0 (s, 3H),
4.65 ~ 5.15 (d, J = 16.5Hz, 2H),
7.7 (m, 6H); Ansl C~lcd: C,
49.71% H, 3.58% N, 4.14%;
Found: C, 49.56% H, 3.42%
N, 4.22%
_ 34 5 8-bromo; mp 65-85G Ci
Anal C~lcd: C, 49.72% H,
3.58% N, 4.14%; Found: C,
53.54% H, 4.05~ N, 4.40~6
6 5-methoxy; mp 120 C;
NMR(Di~S~d6)~ 2.93 (s,
3H), 3.90 (s, 3H), 4.65 ~ 5.16
(2d, J = 17Hz, 2H), 6.95 (2d,
J1 7Hz~ J2 = 3Hz, lH), 7.35
(m, 4H), 8.11 (2d, Jl = 8Hz,
J2 = 2Hz, lH); IR(Nujol* ~
2900,1734,1715 cm 1; VV~max
~ EtOH) 281 nm( ~ 11,600), 233
(30,6û0); Anal C~lcd: C, 62.279
H, 5.23% N, 4.84~6; Found:
C, 61.62% H, 5.95% N, 4.22%
36 7 5-methyl; mp 190-191C;
Nl~R (CDC13)~ 2.66 (s, 3H),
*Tr~3cm;lr};
~5
,
-34- AHP-7806
TABLE IV (Continued)
PR~DUCT:N-[(prefix listed
NO. OF THE EXAMPLE IN below-l-NAPHTHALENYL~
WHICH STARTING MATERIAL THIOXOMETHYL~-N-METHYL~
EXAMPLE WAS PREPARED GLYCINE
36 (Contld) 3.05 (s, 3H), 3.85 ~ 5.0 (m,
2H), '7.5 (m, 6H), 8.75 ~broad9
lH3; IR~CHC13) 3000,1755
1720 cm 1; UV~max (EtOH~
282 nm ( ~15,280), 226 (39,690),
218 (41,385); An 1 Calcd: C,
65.90% H, 5.53% M, 5.12%;
Eound: C, 65.79% lH, 5.57%
N, 5.08%
37 8 5-bromo-6-pentyloxy;
mp 211-217C; NMR(DMSO-d6)~
0.9 (t, J = 6Hz, 3H), 1.6 (m,
2H), 2.9 (s, 3H), 4.2 (t, J =
6Hz, 2H~, 3.95 ~ 5.15 (d, J
= 15Hz, 2H), 7.1-8.55 (m, 5H);
IR~Nujol *) 3000, 1650 cm 1
38 9 5-cyano; mp 190-200 C;
NMR (DMSO-d6) ~ 3.00 (s,
3H), 4.65 ~ 5.15 (d, J = 17Hz,
2H), 7.95 (m, 6H~; IR(Nujol* )
3000, 2230,1730 cm~1; U~max
~(EtOH) 313 nm ( f 5,600), 271
(13,850), 24~ (14,620), 2~2 (48,3~0);
Anal Calcd: C, 63.36~6 H,
* Trademark
.
~ ~3~'~8~
-35- AHP-7806
TABLE IV (Continued~
PRODUCT:N-[(pre~ix listed
NO. OF THE EXAMPLE IN below-l-NAPHTHALENYL~
WHICH STARTING MATERIAL THICIXOMETHYL]~N-METHYI~
EXAMPLE WAS PREPARED GLY~CINE
38 (Cont'd) 4.34% N, 9.85%; ~ound: C,
62.01% H, 4.34% N, 9.36%
38a 9a 4-cyano; mp 192-193 C; NMR
(DMSO-d6) ~ 3.0 (s, 3H), 4.7
& 5.2 (d, J = 17Hz, 2H), 7.8
(m, 6H?, 10.05 (broad, lFI);
IR (Nujol * ) 3180, 2230,174S
(with inflection ~t 1755)cm 1
39 10 5-nitro; mp 142-143 C;
NMR (CDC13)~ 3.05 (s, 3H),
4.65 ~ 5.4 ~d, 2H)9 7.9 (m,
6H), 9.4 (broad9 lH); IR(Nujol
2900,1715,1530,1345 cm 1;
UV~max (EtOH) 332 nm ( ~ 4,110)
269 (17,010); Anal C~lcd: C,
55.26% H, 3.96% N, 9.20%;
Found: C, 55.17% H, 3.86%
N, 9.10%
11 5-chloro; mp 153-154 C;
NMR(CDC13) ~ 3.03 (s, 3H),
4.67 ~ 5.33 ~d, J = 17Hz, 2H~,
7.50 (m, 4H), 7.90 (d, J = 8Hz,
lH), 8.25 (d, J = 8, lH); IR(CHCl ~)
* Trademark
~236~
-36- AHP-7806
TABLE IV (Continued)
P]RODUCT:N-[(prefix listed
NO. OF THE EXAMPLE IN b~low-l-NAPHTHALl~NYI.
WHICH STARTING MATERIAL THIOXOMETHYL]-N-METHYI~
EXAMPLE WAS PREPARED GLYCINE
_ .
40 (Cont'd) 3000, 1720 cm 1; UY~max
(EtOH~ 280 nm ~ 16,780),
212 (52,290); Anal Calcd: C,
57.23% H, 4.12% N, 4.77%;
Found: C, 58.02% H, 4.28%
N, 4.94%
41 12 5-bromo-6-methoxy; mp
166-168 C; NMR(CDC13) ~ 3.02
(s, 3H), 4.06 (s, 3H), 4.61 &
5.39 (d, J = 17Hz, 2H); IR(CHC13)
3000, 1718 cm 1, UV~max
(EtOH) 341 nrn (4,350), 329
(4,015), 273 (13,150), 237 (51,260);
Anal Calcd: C, 48.92% H,
3.83% N, 3.80%; Found: C;
49.11% H, 3.90% N, 3.91%
42 13 5-bromo-6-methyl; mp
190-192 C; NMR(CDC13) ~
2.6 (s, 3H~, 3.05 (s, 3H), 4.56
~c 5.3 (d, 2H), 7.6 (m, 5H);
IR(CHC13) 3000,1720 cm 1;
UV~max (EtOH) 280 nm t
14,055), 223 (43,400); Anal
Calcd: C, 51.14% H, 4.01%
~.
.
2~
-37- AH P-78 06
TABLE IY (Continued~
PRODVCT:N-t(prefix listed
NO. OF THE EXAMPLE IN bel~w-l-N.APHTHALENYL~
WHICII STARTlNG MATERIAL T:HIOXOMETE~YL3-N-METHYI~
EXAMPLE WAS PREPARED GLYCINE
42 (Cont'd) N, 3.98%; Found~ , 51.21%
H, 4.03% N, 4.00%
43 14 ~; mp 146-147 C; NMR(CDC1
~ 3.05 ~ 3.70 (2~, 3HI)9 4.û7,
4.75 ~c 5.30 (s, 2d, J -17Hz,
2H), 6.8-8.0 (m, 7H), 9.20
. (broEId~ lH); IRtCHC13) 3000,
1720 (inflecti~n at 1755~cm 1;
UY~max (EtOI-I) 280 nm (
14,415), 215 (53,~150); ~n~l Cnlcd:
C, 64.87% H, 5.05% N, 5.~0%;
Found: C, 64.8996 H, 5.14%
N, 5.51%
44 15 ~chloro; mp 165-166C;
NMR(CDC13) ~ 3.05 ~ 3.70 (2s7
3~), 4.10, 4.70 ~ 5.3 (s, 2d,
J = 17H~, 2H)r 7.2-8.4 (m,
6H), 10.5 ~s, lH), IR~CHCI3)
3000,1725 (with inflection .
at 1765~cm 1; UY?~m~x(EtOH)
283 nm ( E 13,500)~ 220 (49,600);
Anal Calcd: C, 57.24% H,
4.12% N, 4.77%; Found: C,
57.56% H, 402896 N, 4.8496
* No prefix as c~mround is N~ nap1lthalcnyl)thioxomctl)yl)-N-
mcthylglycine
~6~
-38- A~1~7806
TABLE IV (Continued)
PRODl~CT:N-~(prefix listed
NO. OF THE EXAMPL:E IN below-l-NAPHTHALENYL~
WHICH STARTING MATERIAL THIOXOMEI'HYI.]-N-METHYI~
EXAMPLE WAS PREPARED GLYCINEi
16 ~chlor~4-methoxy; mp
138-139 C; NMR~DMS~d6)
~ 3.0 (s, 3H), 3.45 (s, 3H),
4.6 ~ 5.15 ~2d, J = 16.8Hz,
2H), 7.3 (s, lH), 7.8 (m, 4H3;
IR(Nujol * )2900,1723 cm 1;
--. UYAmax (EtOH) 329 nm tE
2,200), 282 (131210), 22Js (53,980);
~nnl Calcd: C, S5.64~6 H,
4.36% N, 4.33%; ~ound: C,
55.63% H, 4.48'J6 N, 4.40%
46 17 5,7-dichloro; mp 174-175 C;
NMR(DMSO-d6) ~2.97 (3H),
4.57 ~ 5.27 (2d, J = 17Hz9
2H), 7.3-8.3 (m, 5H); lRtNujol* )
3000,1708 cm 1; UVAmax
(EtOH) 334 nm ( ~3,050), 273
(15,81û), 226 t63,800); An~l
Calcd: C, 51.23% H, 3.38%
N, 4.27%; Found: C, 51.44%
H, 3.52% N, 4.40%
47 18 . 5-iod~6-methoxy; mp
161-163 C; NMR(D~qSO-d6)
- ~ 2.95 (s, 3H), 3.95 (s, 3H),
4.6 Sc 5.2 (d, J -17Hz, 21~),
~ Trademark
':-,..
~36~
-39- AHP-7806
TABLE IV (Continued)
PRODUCT:N-l(prefix listed
NO~ OF THE EXAMPLE I~ below-l-NAPHTHALENYL)--
WHlCH STARTING MATERIAL THlOXOMETHYL]-N-METHYIf-
EXAMPLE WAS PREPAl~ED GLY NE
S 47 (contld) 7.5 l~m~ 5H); IR (Nujol ~) 29D0,
1720 cm 1; UV)~max (EtOH~
343 nm (~ ~900), 333 (7,250)
308 (12,~00), 273 (20,500~,
240 (74,200); Anal Calcd: C,
. 43.39% H, 3.40% N, 3.37%;
Found: C, 42,75% H, 3.3596
N. 3.37%
48 19 5-cyuno-6-methoxy; mp
15S-157 C; NMR(CI)C13)6
3.05 (s, 3H), 4.05 (s, 3H), 4.55
5.45 (d, J = 17Hz, 2H), 7.7
(m, 5H~; IR(CHC13) 2900r 2220,
1725 cm 1; I~/Amax (EtOH)
346 nm (E 5,600), 339 (5,500),
232 (46,500)
*Trademark
... . ~ . ..
.
36~
-40- AHP-7806
TABLE V
PRODUCT:N-[~prefix listed
NO. OF THE EXAMPLE IN b~elow-l-NAPHTHALENYL]-
WHICH STA~TING MATERIAL THIOXOMETHYL]-N-METHYI~
EXAMPLE WAS PREPARED GLYCINE
49 20 ~brom~6-(3-methoxy-pro-
poxy); NMR(CDC13) ~ 2~1 (q,
J = 6Hz, 2H), 3.0 (s, 3H), 3.35
(s, 3H), 3.65 (t, J = 6Hz, 2H),
4.25 (t, J = 6Hz9 2H), 4.55
(d, J = 16Hz, lH[), 5.4 (d, J
= 16~Iz, lH), 7.4 (m, 3H), 7.95
(d, J = 8Hz, lH), 8.2 (d, J -
8Hz, IH); IR(CHC13) 2900,
1720 cm 1; UV~max (EtOH)
341 nm ( 3,920), 330 (3,730),
238 (49,400); Anal Calcd: C,
50.69% H, 4.73% N, 3.29%;
Found: C, 50.29% H, 4.89%
N, 3.23%
21 5-(1-methylethenyl); mp
146-148 C; NMR(CDC13) ~
2.2 (s, 3H~, 3.1 (s, 3H~, 4.75
dc 5.35 (d, 2H), 5.05 ~ 5.4
(d, 2H), 7.6 (m, 6H), 8.5 (broad,
lH); IR(CHC13) 2900,1760,
1720 cm 1; UVAmax (~tOH)
282 nm ( 14~000)~ 216 (38~901));
Anal Calcd: C, 68.20% H,
5.72% N, 4.68%; C, 69.06%
H, 6.03% N, 4.39%
~L~3~
-41- AHP-7806
TABLE V (Continued)
PRODUCT:N-[[prefix listed
NO. OF THE EXAMPLE IN below-1-NAPHTHALENYL]-
WHICH STARTlNG MATERIAL THIOXOMETHYL]-N-METHYI~
EXAMPLE WAS PREPARED _ GLYCINE
51 22 5-(1-rnethylethyl~; mp
136-136 C; NMR(CDC13)
1.40 (m, 6H), 3O05 dc 3.6S (d,
3H), 3.65 (m, lH)~ 5O05 (m,
2H), 7O5 (m, 6H~, 9.60 (broad,
lH); IR(CHC13) 2900, 1755,
1720 cm 1; Anal Calcd: C,
67.74% H, 6.35% N, 4.85%;
Found: C, 66.4496 H, 6.56%
N) 4.16%
52 23 5-(trifluoromethyl~6-methoxy;
mp 164-165 C; NMR(CDC13)
3.05 (s, 3H), 3.95 ts, 3H),
4.55 & 5.4 (d, J = 17Hz, 2H),
7.6 (m, 5H), 908 (broad, lH);
IR(CHC13) 2900,1720 cm 1;
UV~max ~EtOH) 337 nm (~ 3,895),
268 (13,260), 226 (49,315); Anal
C~lcd: C, 53.78% H, 3.95%
N, 3.92%; Found: C, 53.56%
H, 3.95% N, 3.87%
53 24 5-bromo-6-(3-trifluoromethyl~
phenylmethoxy]; mp 125 C;
NMR (DMSO-d6)~ 3.0 (s,
~3~
-42- AHP-7806
TABLE V (Continued)
PRODUCT:N-[[prefix listed
NO. OF THE EXAMPLE IN below-l-NAPHTHALENYLJ--
WHICH STARTING MATERIAL THIOXOMETHYL]-N-METHYI~
EXAMPLE WAS PREPARED GLYC,INE
53 (Cont'd) 3H), 'L.65 ~c 5.25 ~2d, J = 17Hz,
2H~, 5.5 (s, 2H~, 7.8 (m, 9H);
IR (Nujol *) 2900,1720 cm 1;
UV~max (E$0H) 340 nm (F 3,950),
270 (13,90~), 263 (14,20~), 238
(54,200); Anal Calcd C, 51.57~6
H, 3.35% N, 2.73% Folmd:
C, 52.11% H, 3.22% N, 2.94%
53a 24a 5-bromo-6-(4-chlorophenyl-
methoxy); mp 88-90 C (dec);
NMR ~DMSO-d6) ~ 2.95 (s,
3H), 4.63 ~ 5.20 (d, J = 17.25Hz,
2H), 5.4 (s, 2H), 7.6 tm, 9H);
IR (CHC13) 3000,1720 cm 1;
UY~max (EtOH) 340 nm (F 3,495),
326 (3, 45~)7 238 (53,480)
53b 24b (5-trifluoromethyl); mp
156-158 C; NMR(CDC13)
3.05 (s, 3H), 4.65 ~ 5~4 (d,
J = 17H~, 2H), 7.85 ~m, 6H),
10.4 (b, lH); IR (CHC13) 2900,
172û (with inflection at 1755),
1305 cm 1; UV~max tEtOEI)
278 nm (~ lL2,900), 216 (68,80D);
Anal Calcd: C9 55.03% H,
* Trademark
,~_
~236~
-43- AHP-7~06
TABLE V (Con_nued)
PRODUCT:N-~lprefix listed
NO. OF THE EXAI\IPLE IN beIow-l-NAPHTHALENYL]--
WHICH STARTING MATERIAL l'HIOXOM ETHYL] -N-M ETHYL--
EXAMPLE WAS PREPARED C;LYCINE .
I
53b (Cont'd) 3.7n96 N, 4.27% Found: C,
54.69% H, 3.70% N, 4.27
TABLE Vl
P~ODUCT:N-1(5 BROMO-l
NO. OF THE EXAMPLE IN NAPHTHALENYL)THIOXO-
- WHICH STARTING MATERIAL METHYL]-suffix listed
-; EXAMPLE WAS PREPARED b~low
5~ 25 glycine; mp 232-237 C; NMR
(DMSO-d6) ~ 4~5 (d, J = 5.S,
2H~, 7~8 (m, 61~)~10.8 (bru~d,
lH); IR(Nujol ~ )3200, 1720;
UV~max ~EtOI~) 275 nm ~ ~
11,700), 217 (44J800); An~l Calcd
C, 4R.15% H, 3.10% N, 4.30%;
Found: C, 48.65% H, 3.13%
N, 4.37%
26 N-propylglycine; Ni~R(CDC13)
0.65 (t, J = 8Hz, 3H), 1.55
~sextet, J = 8Hz, 2H), 3.25
(t, J = 8Hz, 3H), 4.55 (d, J
= 17Hz, IH), 5.3 (d, J = 17Hz,
IH~, 7.7 (m, 6H); IR~CHCI3)
2900,1723 cm 1; I~VI~max
(EtOH~ 277 nm ( c14,80û), 216
*Trad~mark
. _ .. . . . . . .
.
-44- AHP-7806
TABLE VI (Continued)
PRODUCT:N-[(5-BROM~l-
NO. OF THE EXAMPLE IN NAPHTHALENYL)THJOXO-
WHICH STARTlNG MATERI~ I. M ETHYL~ ~uffix listed
EXAMPLI: ~AS PREPARED below _
55 (Cont'd) ~61,200); Anal Calcd: C, 52.44%
H, 4.41% N/ 3.83~6; Found:
C, 52.53% H, 4.44% N, 3.73%
56 27 N-(2-propylene)glycine: NMR
(CDC13) ~ 3.5 (rn, 2H), 3.9
(m, 2H), 5.4 (m, 3H), 6.95
(m, lH), 7.2-8.~ (m, 6H); IR
(CHC13~ 290091720 with in~lection
nt 1760 cm 1; UYAmax (EtOH)
277 nm (E 1~,4003, 219(39,700);
Anrll Calcd: C, 52.76% ~1,
3.87% N, 3.84%; Found: C,
52.93% H, 4.28% Nt 3.68%
57 28 N-ethylglycine; mpl82-1$4~C;
NMR(D,'~qSO-d6) ~.D.95 (t,
J = 7Hz, 3H), 3.25 (q, J = 7Hz,
2H), 4.58 dc 5.05 (d, J = 16.5Hz,
2H), 7.7 (m, 6H); IR (Nujol ~ 3
2900,1720 cm 1; UVAmax
(EtOH) 276 nm ( E 14,795),
219 (42,305); Anal Calcd: C,
51.149~ H, 4.00% N~ 3.97%;
Found: C, 51.33% H, 4.08%
N, 4.05%
*Tradcmarl;
.
.. ... . . ~ .~
i
.
.
~3~
-45- AHP-~806
TABLE VI (Continued)
PRODUCT:N-[(5 -BROMO--1--
NO. O~ THE EXAMPLE IN NAPEITHALENYL)THIOXO--
WHICH STARTING MATERIAL METHYI,]-su~fix listed
EXAMPLE WAS PREPARED below
58 29 N-butylglycine; mp 65-68 C
(dec); NMR(CDC13) ~
0.63 (t, J = 5.5Hz, 3H), 1.2
(m, 4H), 3.25 (t, d = 7.5Hz,
2H), 4.5 & 5.3 (d, J = 16.8Hz,
2H), 6.9 (broad, lH), 7.7 (m,
6H); IR(CHC13) 2900,1720 cm 1;
UV)~max (EtOH) 378 nm (
13,900), 219 (42,000)
59 30 N-(phenylmethyl)glycine; rnp
98 C(decomp); NMR(CDC13)
4.5 ~ 5.35 (d, 2H), 4.45 (m,
2H), 7.6 (m, llH); IR(Nujol *)
2900,1710 cm 1; UV~ma~
(EtOH) 278 nm (15,620), 219
(43,465); Anal Ca}cd: C, 58.01~6
H, 3.94% N, 3.3596: Found:
C, 58.29% H, 4.27% N, 3.24%
EXAM PLE 60
N-[~5-Bromo-l-naphthalenyl)carbonyl]-N-methylglycine (IV, Rl = CH3, R3 =
5-Br and R4 = H)
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 (1302 ml) was added to the suspension. The mixture
* Tradem~rk
, "
36~
-46- AHP-7806
was stirred at 20-22 C for 1.5 hr. The mixture was neutrRlized with aqueous
HCl and concentrated under reduced pressure to rerrlove the methanol. The
residuf~l solution was made acidic with aqueous HCl and extracted with ethyl
acetate. The extract was dried (MgS04), filtered and evaporated to dryness.
The residue was crystalli~ed from ethanol-water to give 3.25 g of the ~tle com-
pound; mp 205 C; NMR (DMSO-d6) ~ 2.75 ~c 3.10 (2s, 3H), 2.75 ~ 3.10 (2s,
3H), 3.75 dc 4.25 (2s, 2H), ?.3 - 8.3 (m, 6H); IR (Nujol * ) 1745 with inflection
at 1720,1580 cm 1; UV~max (EtOH) 322 nm ( E 680), 316 ~1,000), 299 ~6,510),
289 (9,055), 279 (7,150) 226 (63,080); An~1 C~lcd: C, 52.19% H, 3.76% N, 4.35%;
Fowld: C, 52.09% H, 38.4% N, 4.48%.
By following the procedure of example 60 but replacing N{(5-bromo-
l-naphthalenyl)carbonyl]-N-methylglycine methyl ester with an equivalent amount
of another ester compound of formula Il in which R is lower alkyl or ar(lower~
~lkyl, the corresponding compound of formula IV is obtained. ~or example,
replacem~t with N-[[S-(trifluoromethyl~6-methoxy-1-naphthalerlyl] carbonyl]-
N-methylglycine methyl ester, NMR (CDC13) ô 2.85 (s, 3H), 3.5 - 4.5 (m, 2H),
3.4 ~c 3.75 (2s, 6H), 7.0 - 8.4 (m, SH), prepared according to the procedure of
example 2, gives N{[5-(trifluorornethyl~6-methoxy-1-naphthanenyl] carbonyll -
N-methylglycine, mp 174-175 C; NMR (DMSO-d6)~ 2.75 ~c 3.1 (2s, 3H), 4.03
(s, 3H), 4.30 (d, 2H), 7.8 (m, 5H~; IR (Nujol * ~ 2500,1720 with in~leetion at
1745,1580 cm 1; UV~max (EtOH) 335 nm ( F3,050), 322 (2,700), 295 (5,100),
283 (5,750), 275 (4,450), 220 (57,100); Anal Calcd: C, 56.30% H, 4.13% N, 4.10~6;
Found. C, 55.29% H, 4.02% N, 3.g9%.
* Trademark
