Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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ALDOS~ REDUCTASE INHIBITION BY 1-(4-CHI.OROBENZOYL~5-M~THOXY-
2-METHYlrlH~IMDOLE-3-ACETIC AC'ID
Background of the Invention
This invention relates to new methods of using 1-(4-chlorobenzoyl)-
5-methoxy-2-methyl-lH-indole-3-acetlc acid or a therapeutically acceptable salt
thereof with an organic or inorganic base for the treatm~nt of complications
associated with diabetes mellitus.
For many years diabetes mellitus has been treated with two established
types of clrugs, namely insulin and oral hypoglycemic agents. These drugs have
benefited hurldreds of thousands of diabetics by improving their well-being and
prolonging their lives. However, the resulting longevity of diabetic patients has
led to complications such as neuropathy, nephropathy, retinopathy and cataraetsOThese complications have been linked to the undesirable accumulation of sorbitolin diabetic tissue, which in turn result from the high levels of glucose characteristic
of the diQbetic patient.
In mammals, including humans, the Icey enzyme involved in the conver-
sion of hexoses to polyols ~the sorbitol pathway) is aldose reductase. J. H. Kinoshita
and collaborators~ see J. H. Kinoshita, et al., ~iochem Biophys. Acta., 158, 472(1968) and references cited therein, have demonstrated that aldose reductase plays
a central role in the etiology of galactosemic cataracts by effecting the conversion
of galactose to dulcitol (galactitol) and that an agent capable of inhibiting aldose
reductase can prevent the detrimental accumulation of dulcitol in the lens. Further-
more, a relationship between elevated levels of glucose and an undesirable accumu-
lation of sorbitol has been demonstrated in the lens, peripheral nervous cord and
kidney of diabetic anim~ls, see A. Pirie and R. van Heyningen, Exp. Eye Res.,
3,124 (1984); L. T. Chylack and J~ H. Kinoshita, Invest. Ophthal., 8, 401(1969) and
J.D. Ward and R.W.R. Balcer, Diabetol., 6, 531 (197U).
1-(4-Chlorobenzoyl)-5-methoxy-2-metnyl-lH-indole-3-acetic acid and
0 its preparation are described by Shen et al., J. Amer. Chem. Soc., ~5, 488 (1963).
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1-(4-Chlorobenzoyl~-5-methoxy-2-methyl-lH-indole-3-acetic acid is generically
known as indomethacin flnd has anti-inilamatory activity, c.f. "Physicians Desk
Reference", 34th edition, Medical Economics Co., Oradell, N.J., U.S.A., 1980
pp 1182-1184.
Surprisingly, indomethacin or its therapeutically acceptable salt thereof
with an organic or inorganic base, now has been found to be a potent inhibitor
of lens aldose reductase. This new found property rende~ indomethacin, or a
salt thereof, useful for the treatment of diabetic complications.
Summary of the Invention
According to the present invention, a method is provided for preventing
or relieving a diabetes mellitus associated condition in a diabetic mammal by
administering to the mammal an alleviating or prophylatic amoLmt of 1-(4-chloro-benzoyl)-5-methoxy-~-methyl-lH-indole-3-acetic acid or a therapeutically accept-able salt thereof with an organic or inorganic base. The latter compound is especially
useful for preventing or relieving a diabetes mellitus associated complication
consisting of cataracts, neuropathy, nephropathy and retinopathy in n diabetic
mammal.
Detailed Description of the Invention
Indomethacin forms salts with suitable therapeutically acceptable
inorganic and organic bases. These derived salts possess the same activity 8S
the parent acid and are included within the scope of this invention. The acid istransformed in excellent yield into the corresponding therapeutically acceptablesalt by neutralization of said acid with the appropriate inorganic or organic base.
The salts are administered in the same manner as the parent acid compound.
Suitable inorganic bases to form these salts include, for example, the hydroxid~s,
carbonates, bicarbonates or alkoxides of the therapeutically acceptable alkali
metals or alkaline earth metals, for example, sodium, potassium, magnesium,
calcium and the like. Suitable organic bases include the following amines; benzyl-
amine; 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, methylethylarnine, and the like; mono-, di-,
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and trialkanolamines, the alkanol radicals of which contain up to three carbon
atoms, for example, mono--, di- and triethanolamine; alkylene~diamines which
contain up to six carbon atoms, such as hexamethylenediamine; cyclic saturated
or unsaturated bases containing up to six carbon atoms, such aspyrrolidine, piper-
idine, morpholine, piperazille and their N-alkyl ~nd N-hydroxylakyl derivatives,such as N-methyl-rnorpholine 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 h imethyl~monoethanol) and cyclic ammonium salts, for example
the N-methylpyridinium, N-methyl-N-(2-hydroxyethyl)-morpholinium N,N-dimethy-
lmorpholinium, ~-methyl-N-(2-hydroxyethyl)-morpholinium, N,N-dimethylpiper-
idinium salts, which are characterized by having good water-solubility. In principle,
however, there can be used all the ammonium salts w~ch are physiologically
compatible.
The transformations to the salts can be c~rried out by a variety
of methods known in the art. For example, in the case of the inorganic salts,
it is preferred to dissolve indomethacin in water containing at least one equivalent
amount of a hydroxidel carbonate, or bicarbonate correspo~ding to the inorganic
salt desired. Advantageously, the reaction is performed in a water-miscible, inert
2() organic solvent, for example, methanol, ethanol, dioxane, and the like in the
presence of water. For example, such use of sodium hydroxide, sodium carbonate
or sodium bicarbonate gives a solution of the sodium salt. Evaporation of the
solution or addition sf a water-mi6cible solvent of a m~re moderate polarity7
for example, a lower alkanol, for instance, butanol, or a lower alkanone, for in-
stance, ethyl methyl ketone, gives the solid inorganic salt if that form is desired.
To produee an amine salt, indomethacin is dissolved in R suitable ~slvent
of either moderate or lower polarity, for example, ethanol, methanol, ethyl acetate7
diethyl ether and benzene. At least an e~uivalent amount of the amine corres-
ponding to the desired eation is then added to that solutisn. If the resulting salt
does not precipitate, it can usllally be obtained in solid form by additlon o~ a mis-
cible diluent of lower polarity, for example, benzene or petroleum ether7 ~P by
evaporation. If the amine is relatively volfltile, any excess can easily be removed
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by evaporation. It is preferred to use substantially equivalent amounts of the
less volatile amines.
~alts wherein the cation is quaternary ammoniuM are produced by
mixing sulindac with an equivalent amount of the corresponding quaternary
ammonium hydroxide in water solution, foUowed by evaporation of the water.
Indomethacin or an addition salt thereof with pharmaceutically
acceptable organic or inorganic bases may be administered to mammals, for
example, mnn, cattle or rabbits, either alone or in dosage forms, i.e., capsulesor tablets, combined with pharmacologically acceptable excipients, see below.
Advantageously indomethacin can be given orally. However, the method of
administering indomethacin is not to be construed as limited to a particular
mode of adminlstration. For example, indomethacin can be administered topicaUy
directly to the eye in the form of drops of sterile, buffered ophthalmic solutions,
preferably of pH 7.2 - 7.6. Topical administration is especially useful for treating
cataracts and retinopathy in a diabetic mammal. Also, it can be adrninistered
orally alone or in so~id form containing such excipients as starch, milk sugar,
certain types of clay and so forth. It can also be administered orally in the
form of a solution or syrup, or it can be injected parenterally. For parenteral
administration it can be used in the form of a sterile solution, prefer~bly of
pH 7.2 - 7.6 containing A pharmaceutically acceptable buffer. Oral and parenteral
administration are the preferred routes for treating neuropathy and nephropathy
in a diabetic mammal.
The dosage of the present therapeutic agent can v~ry with the form
of administrAtion. ~urthermore, it can vary with the particular host under
2s treatment. Generally, treatment is initiated with srnall dosages substantially
less than the optimal dose of the compound. Thereafter, the dosage is increased
by small increments until the optimal effect under the circumstances is reached.In general, indomethacin is mast desirably administered at a concentration
level that will generally afford effective results without causing any harm~ul
,0 or deleterious side effects. For topical administration, a 0.05 to 0.2~ solution
can be ~dministered dropwise to the eye. The frequency of installation varies
with the subject under treatment from a drop every two or three days to once
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daily. For oral or parenteral administrfltion a preferred leYel of dosage rangesfrom abollt O.l mg to about lO mg per kilogram of body weight per day, although
aforementioned variations will occur.
Unit dosage forms such as capsules, tablets, pills and the like can
contain from about 5 mg to about 50 mg of indomethacin~ dependent on the
type of unit dosage, preferably with a slgnificant quantity of a pharmaceutical
carrier. Thus, for oral admin;stration, capsules can contain frorn between aboutS mg to about 50 mg of indomethacin sulindac with or without a pharmaceutical
diluent. Tablets, either effervescent or noneffervescent, can contain between
about 5 to 50 mg of indomethacin together with conventional pharmaceutical
carriers. Thus, tablets which can be coated and either effervescent or non-
effervescent can 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, maize starch and Rlginic
acid and lubricating agents for example, magnesium stearate.
Syrups or elixirs suitable for oral administration can be prepared
from water soluble salts, for example, the sodium salt of indomethacin and
can advantageously contain glycerol and ethyl alcohol as solvents or preservatives.
The compositions and methods of administering indomethacin des-
~0 cribed in the above cited Physicians' Desk Reference can also be used in the treatment of complications a~;ociated with diabetes mellitus.
Indomethacin, or a therapeutically acceptable salt thereof, also
can be used in combination with insulin or oral hypoglycemic agents to produce
beneficial e~fect in the treatment of diabetes mellitus. In this instance, com-
mercially available insulin preparations or oral hypolycemic agents, exemplifiedby acetohexamide, chlorpropamide, tolazamide, tolbutamide and phenformin,
are suitable. Indomethacin, or a therapeutically acceptable salt thereof, can
be administered sequentially or simultaneously with insulin or the oral hypo-
glycemic agent. Suitable methods of administration, compositions ~nd doses
of the insulin preparation or oral hypoglycemic agent are described in medical
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textbooks; for instance, "Physicians' Desk Reference", 3~ ed., Medical EconomicsCo., Oradell, N.J., U.S.A., 1980, "AMA Drug Evaluations", 3rd ed., PSG Publishing
Co., Inc., Littleton, Massachusetts, V.S.A., 1977, pp. 582-598, and 'PIhe Pharm-acological Basis of Therapeutics", L.S. Goodman and A. Gilman, ~ds., 5th ed.,
Macmillan Publishing Co., Inc., New York, N.~.~ U.S.A., 1975, pp. 1507-1533.
When used in combination, indomethacin, or its therapeutically acceptable salt,
is administered as described previously. Indomethacin~ a~ its therapeutically
acceptable salt, can be administered with the oral hypoglycemic agent in the
form of a pharmaceutical composition comprising effective amounts of each
1 o agent.
The aldose reductase inhibiting effects of indomethacin or its pharma-
ceutically acceptable salts with an organic ~r inorganic base 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 t}~t the final chromatogrQphy
step is omitted in the preparation of the enzyme from bovine lens.
The following results were obtained wh~n indomethacin was evaluated
in the above in vitro test:
Compound Concentration (Mole/l) Percent Inhibition
Indomethacin 10-5 52
lo~6 13
The aldose reductase inhibiting property of indomethacin and its utiliza-
tion in diminishing and alleviating diabetic complications can be demonstrable in
e~periments using galactosaemic rats, see D. Dvornik et ~1., Science, 182,1146 (1973).
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