Derivatives of L- and DL-4-hydroxyphenylglycine

L- and DL-isomers of compounds of the formula ##STR1## and the pharmaceutically acceptable salts thereof, wherein R is hydrogen or methyl; R.sup.1 is alkynyl, alkenyl or cycloalkyl, each having from three to seven carbon atoms or alkyl having from one to six carbon atoms which may optionally be substituted by one or more groups selected from hydroxy, alkoxy, carboxy, amino, monoalkylamino, dialkylamino, phenyl and phenoxy, any such phenyl or phenoxy being optionally substituted with one or more hydroxy, alkyl or alkoxy groups, said alkyl and alkoxy optional substituents having from one to six carbon atoms; provided that R.sup.1 is other than 4-hydroxy-.alpha.-carboxybenzyl or 4-methoxy-.alpha.-carboxybenzyl. Said compounds are useful in treating diseases and conditions characterized by reduced blood flow, oxygen availability or carbohydrate metabolism in the cardiovascular system. The D-isomers of the compounds of formula (II) are substantially inactive in treating such diseases and conditions.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The invention relates to novel L- and DL-isomers of compounds of formula 
(II) as defined herein and pharmaceutically acceptable salts thereof, 
their use in treating diseases and conditions of mammalian subjects 
including humans, which are characterized by reduced blood flow, reduced 
oxygen availability or reduced carbohydrate metabolism in the 
cardiovascular system; and pharmaceutical compositions thereof. 
2. Description of the Prior Art 
In Belgian Pat. No. 859,151 published on Jan. 16, 1978 (Derwent No. 
08402A/05), assigned to the same assignee, known L- and DL-phenylglycines 
of the formula 
##STR2## 
where R.sub.1 is hydrogen or methyl and R.sub.2 is NH.sub.2, OH or 
completes a carboxylic ester group, are disclosed as being useful in 
treating diseases and conditions characterised by reduced blood flow, 
oxygen availability or carbohydrate metabolism in the cardiovascular 
system. Such conditions include ischaemic heart disease (particularly 
angina pectoris and myocardial infarction), cardiac failure and cerebral 
insufficiency. The compounds are also useful in other diseases involving 
defects in carbohydrate metabolism such as obesity and diabetes. 
In our co-pending application, Ser. No. 900,802 filed Apr. 27, 1978, novel 
derivatives of L- and DL-p-hydroxyphenylglycine of the formula 
##STR3## 
and the pharmaceutically acceptable salts thereof are disclosed as having 
the same utility. In the above formula (Ia) R.sub.1 and R.sub.2 are as 
defined above and R.sub.3 is the residue of certain amino acids. 
SUMMARY OF THE INVENTION 
The present invention provides novel derivatives of L- and 
DL-4-hydroxyphenylglycine of the formula 
##STR4## 
and the pharmaceutically acceptable salts thereof where R is hydrogen or 
methyl; R.sup.1 is a member selected from the group consisting of alkynyl, 
alkenyl and cycloalkyl, each having from three to seven carbon atoms, 
alkyl having from one to six carbon atoms, CH.sub.2 COOH, (CH.sub.2).sub.n 
--NR.sup.2 R.sup.3, CH.sub.2 C.sub.6 H.sub.3 R.sup.4 R.sup.5, 
##STR5## 
dihydroxyalkyl having from three to four carbon atoms wherein said hydroxy 
groups are attached to different carbon atoms, and alkyl having from two 
to six carbon atoms substituted by up to two unlike members selected from 
the group consisting of hydroxy, alkoxy having from one to six carbon 
atoms, carboxy, C.sub.6 H.sub.3 R.sup.4 R.sup.5 and OC.sub.6 H.sub.3 
R.sup.4 R.sup.5 provided that when two of said members are present and are 
hydroxy and said alkoxy, said members are attached to different carbon 
atoms; n is 1 to 4, R.sub.2 and R.sup.3 are each hydrogen or alkyl having 
from one to four carbon atoms; R.sup.4 and R.sup.5 are each hydrogen, 
hydroxy, or alkyl or alkoxy each having from one to four carbon atoms; 
provided that R.sup.1 is other than 
##STR6## 
Those compounds in which R.sup.1 has the above value, and which are 
excluded from the present invention, are included within the subject 
matter of our above-mentioned co-pending application, Ser. No. 900,802 
filed Apr. 27, 1978. 
The derivatives of L-4-hydroxyphenylglycine of formula (I) are preferred, 
the D-form being substantially inactive. It will therefor be appreciated 
that compounds of formula (II) derived from L-4-hydroxyphenylglycine will 
be substantially more active than the corresponding racemic, DL-compounds. 
Pharmaceutically acceptable salts of compounds of the formula (II) include 
acid addition salts with acids containing pharmaceutically acceptable 
anions, e.g. the hydrochloride, hydrobromide, sulphate or bisulphate, 
phosphate or acid phosphate, acetate, maleate, fumarate, succinate, 
lactate, tartrate, citrate, gluconate, saccharate and p-toluene sulphonate 
salts. When R.sup.1 contains a carboxy group, pharmaceutically acceptable 
salts also include salts formed with bases containing pharmaceutically 
acceptable cations, e.g. the sodium, potassium, calcium and ammonium 
salts. 
Especially preferred compounds and salts of formula (II) are those wherein 
R is hydrogen. Especially preferred values for R.sup.1 are alkyl having 
from one to four carbon atoms, --CH.sub.2 C.sub.6 H.sub.4 OH, alkoxyethyl 
or alkoxypropyl having from one to six carbons in the alkoxy group, 
propargyl, cyclopentyl, carboxysubstituted alkyl when derived from the 
naturally occuring L-.alpha.-amino acids and CH.sub.2 CH.sub.2 NR.sup.2 
R.sup.3 where R.sup.2 and R.sup.3 are each methyl, ethyl or propyl. 
Particularly preferred compounds of formula (II) are: 
L-N-(4-hydroxybenzyl)-2-amino-2-(4-hydroxyphenyl)acetamide, 
L-N-(2-methoxyethyl)-2-amino-2-(4-hydroxyphenyl)acetamide, 
L-N-isopropyl-2-amino-2-(4-hydroxyphenyl)acetamide, 
L-N-propargyl-2-amino-2-(4-hydroxyphenyl)acetamide, 
L-N-cyclopentyl-2-amino-2-(4-hydroxyphenyl)acetamide, and 
L-N-(2-diethylamino)ethyl-2-amino-2-(4-hydroxyphenyl)acetamide. 
The invention further provides a method of treating mammalian subjects, 
including humans, suffering from a disease or condition attributable to 
reduced blood flow, oxygen availability or carbohydrate metabolism which 
comprises orally or parenterally administering to said subject a blood 
flow, oxygen availability or carbohydrate metabolism increasing amount of 
a compound of formula (II) or a pharmaceutically acceptable salt thereof. 
Also provided are pharmaceutical compositions comprising a pharmaceutically 
acceptable carrier and a blood flow, oxygen availability or carbohydrate 
metabolism increasing amount of a compound of formula (II) or a 
pharmaceutically acceptable salt thereof. 
DETAILED DESCRIPTION OF THE INVENTION 
The novel compounds of formula (II) may be prepared using the classic 
protecting and coupling techniques of amino-acid chemistry, for example as 
described in "Chemistry of the Amino Acids" by J. P. Greenstein and M. 
Winitz, J. Wiley and Sons, Inc., New York, Vol. 2. Thus the amino group in 
4-hydroxy or 4-methoxyphenylglycine is protected with a selectively 
removable blocking group and the carboxyl group is then reacted with an 
amine, of the formula R.sup.1 NH.sub.2 wherein R.sup.1 is as previously 
defined, for example using a coupling agent or an activated ester 
technique. In the case where the amino component itself contains a 
carboxyl or further free amino group this too requires protection during 
formation of the amide link. The protecting groups are finally removed to 
yield the amides of formula (II). 
A convenient amino-blocking group is the t-butoxycarbonyl group. This group 
is readily introduced by reaction with t-butoxycarbonyl azide by the 
method of Grzonka et al., Synthesis, 661 (1974), and is easily removed 
from the final product by acid treatment. Alternative N-blocking groups 
such as the benzyloxycarbonyl group, which is removed by catalytic 
hydrogenolysis, may also be employed except in those cases where R.sup.1 
is alkenyl or alkynyl. 
Formation of the amides may be achieved in various ways, for example in one 
method, the amine is reacted with a mixed anhydride, prepared from the 
acid by reaction with a chloroformate, e.g., iso-butylchloroformate or 
ethylchloroformate. Such a reaction is performed by adding the 
chloroformate (in slight molar excess, e.g., a 5% excess) to a solution of 
the N-protected-4-hydroxy (or methoxy) phenylglycine dissolved in a 
reaction inert organic solvent, e.g., 1,2-dimethoxyethane or 
tetrahydrofuran, and is advantageously performed at a low temperature, 
e.g., -5.degree. to 0.degree. C. in the presence of a base, e.g, 
triethylamine. 
Formation of the mixed anhydride is generally substantially complete within 
10 minutes under these conditions. The amine component may then be added, 
preferably as a solution in an inert organic solvent, e.g., 
tetrahydrofuran. Formation of the amide is usually complete within several 
hours (e.g., 3 hours) at room temperature. 
Alternatively the amine may be reacted with an activated ester derivative 
prepared from the acid, for example, by reaction with N-hydroxysuccinimide 
and dicyclohexylcarbodiimide. Thus the N-protected-4-hydroxy (or methoxy) 
phenylglycine may be treated in a reaction inert organic solvent (e.g. 
ethyl acetate or tetrahydrofuran) with a slight molar excess of 
N-hydroxy-succinimide and dicyclohexylcarbodiimide to effect formation of 
the succinimido ester. The reaction is performed at a temperature between 
0.degree. C. and room temperature and is ordinarily complete within 
several hours, typically about 3 hours. The precipitate of 
dicyclohexylurea may be removed by filtration, if desired, and the amine 
component may then be added as before; formation of the amide product 
generally being complete within several hours at room temperature, e.g. on 
standing overnight. In either case the product is isolated in a 
conventional manner, for example, by removal of the solvent and is further 
purified, if necessary, by solvent extraction as appropriate to remove 
unreacted starting materials or impurities, or by crystallisation. 
The N-blocking group is then removed. Thus if the t-butoxycarbonyl group is 
employed, this may be removed by acid treatment, e.g., by dissolving the 
product in ethereal hydrogen chloride or with hydrogen bromide in glacial 
acetic acid at room temperature. Slight warming may be necessary 
initially, to dissolve the product, and the deprotection is then generally 
complete within several hours, e.g., overnight. The product is then 
isolated as the hydrochloride or hydrobromide salt by filtration and may 
be further purified as desired by conventional techniques. 
When the amine reacted with the N-protected-4-hydroxy (or 
4-methoxy)phenylglycine is a diamine of formula NH.sub.2 (CH.sub.2).sub.n 
R.sup.2 R.sup.3 wherein n, R.sup.2 and R.sup.3 are as previously defined, 
it is preferable to employ a large molar excess, for example, a 2 to 10 
molar excess of said diamine to favor the formation of the desired 
monoacylated product. If necessary, the product isolated from such 
acylation can be purified, for example, by column chromatography on silica 
gel. The purification can be carried out either before or after removal of 
the N-protecting group, however, it is preferably done after removal of 
the N-protecting group. 
In the case where the amine component contains a carboxyl group, i.e., when 
an amino acid is used in the reaction, the carboxyl group will also 
require protection and this is conveniently achieved by esterification 
typically as the methyl ester. Hydrolysis to yield the free acid is 
preferably performed before removal of the N-protecting group and is 
achieved by alkaline hydrolysis, e.g., by treatment with dilute aqueous 
sodium hydroxide solution at room temperature for 30 minutes. 
Conversion to other pharmaceutically acceptable acid addition salts may be 
achieved in a conventional way e.g. by neutralization to form the free 
base, extraction, and reacidification of the free base with the desired 
acid or by ion exchange chromatography employing an anion exchange resin. 
In the case where R.sup.1 contains a carboxyl group, the free base or an 
acid addition salt may be reacted with sufficient base, for example, 
sodium hydroxide, potassium carbonate or calcium oxide, in the presence of 
water and the aqueous solution evaporated to provide the desired 
carboxylate salt. The latter may also be prepared by treatment of the free 
base or an acid addition salt with a cation exchange resin. 
Starting L- and DL-4-hydroxyphenylglycines are available commercially as 
are the corresponding 4-methoxy compounds. Methods for resolution of the 
racemic compounds into the D- and L-forms are well known, see for example, 
U.S. Pat. No. 3,976,680. Many of the amines of formula R.sup.1 NH.sub.2 
employed as starting material are commercially available or may be readily 
obtained from available precursors by methods which are well known to 
those skilled in the art. Several comprehensive reviews of methods for 
making such amines are available, see for example, Houben-Weyl, "Methoden 
der Organischen Chemie", 4th edition, Volume XI/I, Georg Thieme Verlag, 
Stuttgart, 1957; Wagner and Zook, "Synthetic Organic Chemistry", John 
Wiley and Sons, Inc., New York, 1953, pp. 653-727; Sandler and Karo, 
"Organic Functional Group Preparation," Academic Press, New York, 1968; 
pp. 318-362 and "Rodd's Chemistry of Carbon Compounds" S. Coffey, Ed., 
Vol. 1 Part B, Elsevier Publishing Co., New York, 1965, pp. 111-121. 
Alkynylamines not commercially available are prepared by methods described 
by Gelin, et al., Bull. Soc. Chem. France, 3079-3082 (1966), Chem. Abstr., 
66, 46058r (1967) and Dumont, et al., ibid. 588-596 (1967), Chem. Abstr., 
115254r (1967). The requisite amino acids of formula R.sup.1 NH.sub.2 
where R.sup.1 is a carboxysubstituted alkyl group are commercially 
available or prepared by methods set forth in the above reviews and in 
Greenstein and Winitz, "Chemistry of the Amino Acids," Vol. 3, J. Wiley 
and Sons, Inc., New York, 1961. 
The requisite diamines of formula R.sup.1 NH.sub.2, if not commercially 
available, are prepared by well known method, e.g., by reduction of the 
corresponding nitriles or amide with lithium aluminum hydride. Many of the 
amino glycols and their alkyl ethers are known. Those that are not are 
prepared by well known techniques such as by hydrolysis or alcoholysis of 
the appropriate epoxynitrile, epoxyaldehyde or epoxyketone to obtain an 
intermediate glycol or monoether thereof, followed by reduction of the 
intermediate nitrile or oxime. 
The compounds of the formula (II) may be administered to patients in 
admixture with or dissolved in a pharmaceutically acceptable carrier 
selected with regard to the intended route of administration and standard 
pharmaceutical practice. For example, they may be administered orally in 
the form of tablets or capsules containing a unit dose of the compound of 
the formula (II) together with such excipients as corn starch, calcium 
carbonate, dicalcium phosphate (CaHPO4), alginic acid, lactose, magnesium 
stearate, talc, or certain complex silicates. The tablets are typically 
prepared by granulating the ingredients together and compressing the 
resulting mixture to tablets of the desired size. The capsules are 
typically prepared by granulating the ingredients together and filling 
them into hard gelatin capsules of the appropriate size to contain the 
ingredients. 
The compounds of the invention may also be administered parenterally, for 
example by intramuscular, intravenous or subcutaneous injection. For 
parenteral administration, they are best used in the form of a sterile 
aqueous solution which may contain other solutes, for example enough salts 
(e.g. sodium acetate, sodium lactate, sodium succinate or sodium chloride) 
or dextrose to make the solution isotonic. A pharmaceutically acceptable 
organic solvent such as polyethylene glycol or ethanol may also replace 
part of the water. An antioxidant such as sodium metabisulphite may also 
be present, typically in an amount up to 0.1% by weight. Such parenteral 
formulations may be prepared by conventional methods. For example, in a 
typical procedure involving the preparation of a succinate-containing 
intravenous formulation, a 0.2 molar solution of succinic acid may be 
mixed with a 0.2 molar solution of sodium hydroxide to give a solution of 
pH 5. The compound of the formula (II) is then typically dissolved in the 
succinate solution in an amount of 1-2% on a weight/volume basis. The 
resulting solution may then be sterilized, for example by filtration, 
through a bacteria-proof filter under aseptic conditions into sterile 
containers. 
Alternatively, stable parenteral formulations based on isotonic saline 
solution may be prepared by successively dissolving an antioxidant, e.g. 
sodium metabisulphite, and sodium chloride in nitrogen-sparged water to 
give an approximately 0.1 molar sodium chloride solution, dissolving the 
compound of formula (II) in solution in an amount of 1-2% on a 
weight/volume basis and adjusting the pH to about 4 with 0.1 N 
hydrochloric acid. The solution is then sterilized and filled into 
containers as already described. Suitable containers are, for example, 
sterile glass vials of an appropriate size to contain the desired volume 
of solution, which volume will typically contain one or more unit doses of 
the compound of the formula (II). The compounds of the formula (II) may 
also be administered by the infusion of a parenteral formulation as 
described above into a vein. 
For oral administration to human patients, the daily dosage level of L-form 
of a compound of the formula (II) will be from 1 to 50, preferably 2-20 
mg./kg. per day for a typical adult patient (70 kg.). For parenteral 
administration the daily dosage level of the L- form of a compound of the 
formula (II) will be from 1-10, preferably 2-5 mg./kg. per day, for a 
typical adult patient. Thus tablets or capsules would contain from 20 mg. 
to 1 g. of the active compound for administration orally up to 4 times a 
day. Dosage units for parenteral administration would contain from 70-700 
mg. of the active compound. The dosage level of the racemic (DL) form of 
the compounds will of course be approximately twice that of the L-form. 
It should of course be appreciated that in any event the physician will 
determine the actual dosage which will be most suitable for the individual 
and it will vary with the age, weight and response of the patient. The 
above dosages are exemplary of the average patient, there may of course be 
individual cases where higher or lower dosage ranges are merited. 
The utility of the compounds of the formula (II) for treating disease or 
conditions characterized by reduced blood flow, oxygen availability or 
carbohydrate metabolism in the cardiovascular system, or other disease or 
condition involving a defect in carbohydrate metabolism, particularly 
diabetes and obesity, is assessed by the their ability: 
(1) to increase the oxidation of glucose and/or pyruvate by isolated rat 
muscle preparations in vitro; 
(2) to increase the proportion of the active form of the enzyme pyruvate 
dehydrogenase (PDH) in organs of animals in vivo; 
(3) to reduce oxygen demand and affect the relative utilization of 
carbohydrate and lipid metabolites by the electrically-paced heart of 
anesthetized dogs in the presence or absence of an isoprenaline stimulus; 
and 
(4) to decrease the blood glucose levels in animals made diabetic by 
chemical lesion of the pancreas. 
Activity in tests for (1) demonstrates the utility of the compounds in the 
treatment of ischaemic heart disease, cardiac failure, cerebral 
insufficiency, maturity-onset diabetes or obesity. Activity in tests for 
(2) further demonstrates their utility in the treatment of these diseases 
or conditions and, in particular, activity in an animal heart in vivo 
demonstrates utility in the treatment of ischaemic heart disease and 
cardiac failure, while activity in animal brain in vivo is a measure of 
utility in the treatment of cerebral insufficiency. Activity in tests for 
(3) further demonstrates their utility in the treatment of ischaemic heart 
disease and cardiac failure. Activity in test for (4) is a further measure 
of their utility in the treatment of diabetes. 
Representative compounds of the formula (II) have been tested for their 
ability to increase the oxidation of glucose and/or pyruvate as follows: 
Diaphragm tissue is obtained from rats fed on a high fat diet similar to 
`Diet B` described by Zaragoza and Felber [Horm. Metab. Res., 2, 323 
(1970)]. Pyruvate oxidation by such tissue is assessed by measurement of 
the rate of incorporation of carbon-14 from carbon-14-labelled pyruvate 
into carbon dioxide in vitro, as described by Bringolf [Eur. J. Biochem., 
26, 360 (1972)]. The rate of pyruvate oxidation is depressed by 50%-75% 
compared with that by diaphragm tissue from rats fed on a normal diet. 
When the L- and DL-compounds of the formula (II) are added to the medium, 
they are found to stimulate pyruvate oxidation by diaphragm tissue from 
fat-fed rats in a dose dependent manner. 
The degree of stimulation at a concentration of 0.5 mmoles for the 
compounds provided in certain Examples is shown in the following Table: 
______________________________________ 
Compound of Compound of 
Example % Stimulation 
Example % Stimulation 
______________________________________ 
1 72 13 45 
2 108 14 76 
3 15 15 55 
4 82 16 67 
5 23 17 41 
6 38 
______________________________________ 
The degree of stimulation by the corresponding racemic (DL) compounds is 
found to be somewhat lower than the above values. The D-isomers of the 
corresponding compounds do not stimulate pyruvate oxidation to an 
appreciable extent. 
The ability of compounds of formula (II) to increase the proportion of the 
active form of the pyruvate dehydrogenase enzyme has been measured in the 
following test: 
Rats fed on a high fat diet as in the previous test, are treated either 
with placebo or with the compound of formula (II) by subcutaneous or 
intravenous injection or by oral administration. After 11/2 hours the rat 
hearts are removed and homogenized under conditions which minimize changes 
in the proportion of the pyruvate dehydrogenase enzyme (PDHt) which is 
present in the active form, as described by Whitehouse and Randle 
[Biochem. J., 134, 651 (1973)]. The total amount of the enzyme present 
(PDHt) and the amount which is present in the active form (PDHa) are 
assessed by a method similar to that described by Taylor et al. [J. Biol. 
Chem., 248, 73 (1973)]. The fat-feeding process is found to depress the 
ratio PDHa/PDHt from a normal value of about 0.7 to a value in the range 
from 0.05 to 0.2. Treatment of fat-fed rats with L- and DL-compounds of 
formula (II) either parenterally or orally, increases this ratio in a 
dose-dependent manner. 
The increase in the PDHa/PDHt ratio affected by the L-compounds of formula 
(II) at a dosage level of 0.6 mg./kg. via the oral or sub-cutaneous route 
is shown in the following Table: 
______________________________________ 
Com- Com- 
pound PDHa/PDHt ratio 
pound PDHa/PDHt ratio 
of Com- of Com- 
Example 
placebo pound Example 
placebo 
pound 
______________________________________ 
1 0.14 1.00 13 0.14 0.55 
2 0.13 0.65 14 0.14 0.88 
3 0.14 0.56 15 0.18 0.25 
4 0.18 0.73 16 0.12 0.31 
5 0.18 0.88 17 0.18 0.31 
6 0.21 0.78 
______________________________________ 
When the above test is repeated with the corresponding DL-compounds, the 
ratios obtained are somewhat lower. When the corresponding D-isomers are 
employed the ratios do not differ significantly from the placebo values.

The preparation of the novel compounds of the invention is illustrated by 
the following Examples: 
EXAMPLE 1 
A. (L)-N-tert-Butoxycarbonyl-2-(4-hydroxyphenyl)glycine 
This was obtained from L(+)-2-(4-hydroxyphenyl)glycine and 
t-butyloxycarbonylazide by the method of Grzonka and Lammek (Synthesis, 
1974, 661). Crystallisation from hexane-ethyl acetate afforded material 
suitable for further synthesis in yields typically 69-90%, M.P. 
114.degree.-115.degree. C. (decomp.); [.alpha.].sub.D.sup.28 +128.degree. 
(1.02%, methanol). Recrystallisation from aqueous ethanol afforded pure 
material of M.P.=115.degree.-117.degree. C. (decomp.); 
[.alpha.].sub.D.sup.28 +135.degree. (1.01%, methanol). 
B. 
(L)-N-(4-Hydroxybenzyl)-2-(tert-butoxycarbonylamino)-2-(4-hydroxyphenyl)ac 
etamide 
The product from Part A, above, (5.3 g., 0.02 mole) was dissolved in dry 
tetrahydrofuran (50 ml.) and the solution was stirred and cooled to 
0.degree. C. Triethylamine (2.1 g., 0.021 mole) was added followed by 
isobutyl chloroformate (2.77 g., 0.0203 mole), and the mixture was stirred 
and allowed to stand at -5.degree. C. to 0.degree. C. for a few minutes. A 
solution of 4-hydroxybenzylamine (2.82 g., 0.02 mole) in dry 
tetrahydrofuran (10 ml.) was then added dropwise over a period of 10 
minutes to the stirred solution which was allowed to warm to room 
temperature and stirred for a further three hours. The suspension was 
evaporated to dryness and the residual solid was partitioned between water 
and ethyl acetate. The aqueous layer was separated and extracted with 
ethyl acetate. The combined organic extracts were dried over sodium 
sulphate, filtered, and the solvent evaporated to yield an oil which 
solidified on trituration with petroleum ether (b.p. 60.degree.-80.degree. 
C.) to give the amide (3.9 g., 50%), M.P. 60.degree. C. 
[.alpha.].sub.D.sup.25 +50.7.degree. (1% in methanol). 
C. (L)-N-(4-Hydroxybenzyl)-2-amino-2-(4-Hydroxyphenyl)acetamide 
hydrochloride 
The crude product from Part B (3 g.) was dissolved in ethyl acetate (10 
ml.) and to this was added ethereal HCl (20 ml.) with stirring. A gum was 
rapidly formed which solidified on continued stirring to give a brown 
solid. Stirring was continued overnight, the solid was collected by 
filtration, washed with dry ether and recrystallised from a mixture of 
isopropyl alcohol and diethyl ether to yield the hydrochloride salt (1.3 
g., 42%), M.P. 185.degree.-190.degree. C., [.alpha.].sub.D.sup.25 
+50.7.degree. (1% in methanol). 
Found: C, 58.5; H, 5.8; N, 8.8. C.sub.15 H.sub.16 N.sub.2 O.sub.3.HCl 
requires C, 58.35; H, 5.55, N, 9.05%. 
EXAMPLES 2 TO 6 
The following compounds were prepared by the general method of Example 1 
using L-N-tert-butoxycarbonyl-2-(4-hydroxyphenyl)glycine and the 
appropriate amine. Table I shows the compounds prepared together with 
their melting points, optical rotation and analytical data. 
TABLE I 
__________________________________________________________________________ 
##STR7## (L) 
Example Salt 
m.p. Analysis % 
No. R.sup.1 Form 
.degree.C. 
[.alpha.].sub.D.sup. 25 
(Theoretical in brackets) 
__________________________________________________________________________ 
2 CH(CH.sub.3).sub.2 
HBr 218.degree. 
+67.5.degree. 
C, 45.85 
H, 5.85 
N, 9.8 
(dec.) 
(1% MeOH) 
(C, 45.7 
H, 5.9 
N, 9.7) 
3 C(CH.sub.3).sub.3 
HCl 168.degree. 
+97.6.degree. 
C, 54.9 
H, 7.4 
N, 9.95 
(1% MeOH) 
(C, 54.75 
H, 7.5 
N, 10.6) 
Calculated for 1/4 H.sub.2 O) 
4 CH.sub.2 CCH 
HCl -- +66.6.degree. 
C, 53.4 
H, 5.5 
N, 11.15 
(0.5% MeOH) 
(C, 53.55 
H, 5.6 
N, 11.35) 
(Calculated for 1/3 H.sub.2 O) 
##STR8## HCl 148.degree. (dec.) 
+55.3.degree. (1% MeOH) 
C, 56.8 (C, 56.7 
H, 6.95 H, 7.15 
N, 9.8 N, 10.2) 
(Calculated for 1/4 H.sub.2 O) 
6 CH.sub.2 CH.sub.2 N(CH.sub.2 CH.sub.3).sub.2 
2HCl 
80.degree. 
+70.degree. 
C, 49.8 
H, 8.6 
N, 11.3 
(dec.) 
(1% MeOH) 
(C, 50.05 
H, 8.05 
N, 10.95) 
(Calculated for H.sub.2 O, 2/3 C.sub.3 
H.sub.7 OH) 
__________________________________________________________________________ 
EXAMPLE 7 
(L)-N-(4-Hydroxybenzyl)-2-amino-2-(4-methoxyphenyl)acetamide.HCl 
By employing L(+)-2-(4-melthoxyphenyl)glycine in the procedure of Example 
1, Part A, and carrying the resulting 
(L)-N-t-butoxycarbonyl-2-(4-methoxyphenyl)glycine through the procedures 
of Example I, Parts B and C, the title compound is similarly obtained. 
EXAMPLE 8 
When the procedures of Examples 1 through 7 are repeated, but employing 
racemic 2-(4-hydroxyphenyl)glycine or 2-(4-methoxyphenyl)glycine in place 
of the corresponding L-isomers as starting material in each case, the 
corresponding DL-(racemic)compounds are obtained. 
EXAMPLE 9 
When the procedures of Examples 1 through 8 are repeated, but employing the 
appropriate amine of formula R.sup.1 NH.sub.2 in each case, the following 
compounds are provided as their hydrochloride salts. 
______________________________________ 
##STR9## 
R R.sup.1 
______________________________________ 
H C.sub.6 H.sub.5 CH.sub.2 
H 2-HOC.sub.6 H.sub.4 CH(CH.sub.3) 
H 4-CH.sub.3 OC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 
H 2,3-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2 
H 4-i-C.sub.4 H.sub.9 OC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 
CH.sub.2 
H 3,5-(CH.sub.3).sub.2 C.sub.6 H.sub.3 CH.sub.2 
H 3,4-(HO).sub.2 C.sub.6 H.sub.3 CH.sub.2 
CH.sub.3 CH.sub.3 (CH.sub.2).sub.4 CH(C.sub.6 H.sub.5) 
CH.sub.3 C.sub.6 H.sub.5 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 
CH.sub.3 CH.sub.3 CH.sub.2 
CH.sub.3 n-C.sub.6 H.sub.13 
CH.sub.3 (CH.sub.3 CH.sub.2).sub.2 CH 
CH.sub.3 cyclohexyl 
CH.sub.3 cyclopentyl 
H cycloheptyl 
H cyclohexyl 
H cyclopropyl 
H CH.sub.2 CHCHCH.sub.2 
H CH.sub.2 CCH.sub.2 
H CH.sub.3 (CH.sub.2).sub.3 CHCHCH.sub.2 
H HCCCH.sub.2 CH.sub.2 
H HCC(CH.sub.2).sub.3 CH.sub.2 
CH.sub.3 HCC(CH.sub.2).sub.4 CH.sub.2 
CH.sub.3 CH.sub.3 C CCH.sub.2 
CH.sub.3 CH.sub.3 OCH.sub.2 CH(CH.sub.3) 
CH.sub.3 n-C.sub.4 H.sub.9 OCH.sub.2 CH.sub.2 CH.sub.2 
H CH.sub.3 CH.sub.2 OCH.sub.2 (CH.sub.2).sub.3 CH.sub.2 
H HOCH.sub.2 CH(nC.sub.4 H.sub.9) 
H CH.sub.3 CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 CH.sub.2 
H iso-C.sub.5 H.sub.11 OCH.sub.2 CH.sub.2 CH.sub.2 
H n-C.sub.6 H.sub.13 OCH.sub.2 CH(CH.sub.3)CH.sub.2 
H CH.sub.3 OCH.sub.2 CH(OH)CH.sub.2CH.sub.2 
H (CH.sub.3).sub.2 NCH.sub.2 CH.sub.2 
CH.sub.3 (CH.sub.3 CH.sub.2).sub.2 NCH.sub.2 (CH.sub.2).sub.4 CH.sub.2 
CH.sub.3 C.sub.6 H.sub.5 OCH.sub.2 CH.sub.2 
CH.sub.3 C.sub.6 H.sub.5 OCH.sub.2 (CH.sub.2).sub.4 CH.sub.2 
CH.sub.3 4-HOC.sub.6 H.sub.4 OCH.sub.2 CH.sub.2 CH.sub.2 
CH.sub.3 2-CH.sub.3 OC.sub.6 H.sub.4 OCH.sub.2 CH.sub.2 
H 2,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 OCH.sub.2 CH.sub.2 
H 2,4-(tert-C.sub.4 H.sub.9 C.sub.6 H.sub.3 OCH.sub.2 CH(OH)CH.su 
b.2 
H 2,4-(CH.sub.3).sub.2 C.sub.6 H.sub.3 OCH.sub.2 CH.sub.2 
CH.sub.2 
H (n-C.sub.3 H.sub.7).sub.2 NCH.sub.2 CH.sub.2 
______________________________________ 
EXAMPLE 10 
(L)-N-(2-hydroxyethyl)-2-amino-2-(4-hydroxyphenyl)-acetamide hydrochloride 
By employing ethanolamine instead of 4-hydroxybenzylamine in the procedure 
of Example 1, Part B and hydrolysing the product by the procedure of 
Example 1, Part C, the title compound is similarly obtained. 
EXAMPLE 11 
(L)-N-(2-aminoethyl)-2-amino-(4-hydroxyphenyl)acetamide Dihydrochloride 
(L)-N-tert-Butoxycarbonyl-2-(4-hydroxyphenyl)glycine, 0.02 mole is 
converted to the corresponding mixed anhydride employing ethyl 
chloroformate in place of isobutyl chloroformate in the procedure of 
Example 1, Part B. The resulting solution in dry tetrahydrofuran is then 
added dropwise under anhydrous conditions to a stirred solution of 
ethylenediamine (12 g, 0.2 mole) in 200 ml of tetrahydrofuran while 
maintaining the mixture at 0.degree. C. The mixture is stirred for an 
additional 30 minutes then allowed to warm to room temperature and stirred 
for four hours. The solvent is evaporated and the residue partitioned 
between water and ethyl acetate. The organic layer is separated, washed 
with dilute aqueous sodium bicarbonate, water, dried (MgSO.sub.4), and 
evaporated to dryness to provide the 2-tert-butoxycarbonyl derivative of 
the desired compound. This is hydrolyzed by the procedure of Example 1, 
Part C to provide the title compound. 
If desired, the product is purified by dissolving it in water, neutralising 
and extracting with ether. The ether extracts are evaporated to a small 
volume and the residue subjected to column chromatography on silica gel. 
The fractions containing the desired product are evaporated to dryness to 
obtain the free base. Alternatively, the free base is taken up in ether, 
an equivalent amount of anhydrous hydrogen chloride added, the 
precipitated hydrochloride salt collected by filtration and dried. 
EXAMPLE 12 
Employing the procedures of Examples 10 and 11 but using the appropriate 
amine of formula R.sup.1 NH.sub.2 in place of the ethanolamine and 
ethylenediamine used in those examples, the following derivatives of 
4-hydroxyphenylglycine and 4-methoxyphenylglycine are obtained as the 
hydrochloride salts. 
______________________________________ 
##STR10## 
R R.sup.1 
______________________________________ 
CH.sub.3 HOCH.sub.2 CH.sub.2 
CH.sub.3 NH.sub.2 CH.sub.2 CH.sub.2 
CH.sub.3 HOCH.sub.2 CH(CH.sub.3) 
CH.sub.3 HOCH.sub.2 CH.sub.2 CH.sub.2 
H (HOCH.sub.2).sub.2 CH 
H HOCH.sub.2 (CH.sub.2).sub.3 CH.sub.2 
H HOCH.sub.2 CH(n-C.sub.4 H.sub.9) 
H HOCH.sub.2 CH(CH.sub.2 CH.sub.3) 
CH.sub.3 HOCH.sub.2 C(CH.sub.3).sub.2 
CH.sub.3 (HOCH.sub.2).sub.2 C(CH.sub.3) 
CH.sub.3 HOCH.sub.2 (CH.sub.2).sub.4 CH.sub.2 
CH.sub.3 (CH.sub.3).sub.2 NCH.sub.2 CH.sub.2 
H (n-C.sub.4 H.sub.9).sub.2 NCH.sub.2 CH.sub.2 CH.sub.2 
H tert-C.sub.4 H.sub.9 NHCH.sub.2 CH.sub.2 
H CH.sub.3 NHCH.sub.2 CH.sub.2 
H tert-C.sub.4 H.sub.9 NHCH.sub.2 CH.sub.2 CH.sub.2 
CH.sub.3 CH.sub.3 CH(NH.sub.2)CH.sub.2 
CH.sub.3 CH.sub.3 CH(CH.sub.2 NH.sub.2) 
CH.sub.3 NH.sub.2 CH.sub.2 (CH.sub.2).sub.4 CH.sub.2 
CH.sub.3 HOCH.sub.2 CH(n-C.sub.4 H.sub. 9) 
______________________________________ 
EXAMPLE 13 
A. 
(L)-N-methyl-2-(tertiary-butyloxycarbonylamino)-2-(4-hydroxyphenyl)acetami 
de 
A solution of dicyclohexylcarbodiimide (5.1 g., 0.0248 mole) in ethyl 
acetate (50 ml.) was added to a stirred solution of 
(L)-N-tert-butoxycarbonyl-2-(4-hydroxyphenyl)glycine (6.0 g., 0.0225 mole) 
and N-hydroxy succinimide (2.7 g., 0.0235 mole) in ethyl acetate (75 ml.). 
The mixture was stirred at room temperature for 2.5 hours and then cooled 
to 0.degree. C. and the precipitate of dicyclohexylurea was removed by 
filtration. Methylamine (2.4 g. as a 33% solution by weight in ethanol) 
was added to the filtrate and the stirring was continued overnight. Water 
(50 ml.) was added and the mixture shaken and filtered to remove a small 
amount of insoluble material. The organic layer was separated, washed, 
dried over sodium sulphate, filtered and evaporated to give an oil. 
Trituration with warm hexane gave the crude amide as a solid (4.23 g., 
70%; M.P. 165.degree.-167.degree. C., [.alpha.].sub.D.sup.25 
+125.1.degree. (1% in methanol). 
B. (L)-N-methyl-2-Amino-2-(4-hydroxyphenyl)acetamide hydrochloride 
The crude mixture from Part A, above, (2.8 g.) was dissolved in warm ethyl 
acetate (20 ml.), cooled and ethereal HCl (30 ml.) added. The mixture was 
stirred overnight at room temperature and the resulting precipitate was 
collected by filtration and dried to yield the hydrochloride salt (2.1 g., 
75%), M.P. 236.degree.-239.degree. C., [.alpha.].sub.D.sup.25 
+128.2.degree. (1% methanol). Found: C, 49.9; H, 6.1; N, 12.5. C.sub.9 
H.sub.12 N.sub.2 O.sub.2.HCl requires C, 49.9; H, 6.05; N, 12.9%. 
EXAMPLES 14 TO 15 
The following compounds were prepared by the general method of Example 13 
using (L)-N-tert-butyloxycarbonyl-2-(4-hydroxyphenyl)glycine and the 
appropriate amine. Table II shows the compounds prepared together with 
their melting points, optical rotation and analytical data. 
TABLE II 
__________________________________________________________________________ 
##STR11## 
Example Salt 
m.p. Analysis % 
No. R.sup.1 Form 
.degree.C. 
[.alpha.].sub.D.sup.25 
(Theoretical in brackets) 
__________________________________________________________________________ 
14 CH.sub.2 CH.sub.2 OCH.sub.3 
HCl 135.degree. 
+73.0 C, 49.8 
H, 6.6 
N, 10.2 
(with soft- 
(1% MeOH) 
(C, 49.8 
H, 6.65 
N, 10.55) 
ening) (Calculated for 1/4 H.sub.2 O) 
15 
##STR12## HCl 105.degree. (dec.) 
+74.5 (1% MeOH) 
C, 59.1 (C, 58.9 
H, 6.2 H, 6.3 
N, 7.55 N, 
__________________________________________________________________________ 
7.65) 
EXAMPLE 16 
A. N-[(L)-N-tert-Butyloxycarbonyl-2-(4-hydroxyphenyl)glycyl]-L-tyrosine 
(L)-N-tert-Butyloxycarbonyl-2-(4-hydroxyphenyl)glycine (5.23 g., 0.02 mole) 
was dissolved in tetrahydrofuran (50 ml.) and the solution was stirred and 
cooled to -5.degree. C. Triethylamine (2.9 ml., 0.0209 mole) was added 
followed by the dropwise addition of ethylchloroformate (2.2 g., 0.213 
mole) over a period of ten minutes. A solution of L-tyrosine methyl ester 
(3.9 g., 0.020 mole) in tetrahydrofuran (25 ml.) was then added over 
fifteen minutes and the solution was allowed to warm to room temperature 
and stirred for a further three hours. The suspension was evaporated to 
dryness and the residual solid was partitioned between water and ethyl 
acetate. After filtration the organic layer was separated and washed in 
turn with water, 2 N hydrochloric acid, water, dilute sodium bicarbonate 
and water. The solution was dried over sodium sulphate and the solvent 
evaporated to yield a viscous oil. The product was taken up in dioxan (150 
ml.) and water (35 ml.) was added. The solution was stirred at room 
temperature while a solution of sodium hydroxide (2.2 g. in 50 ml. water) 
was slowly added. Stirring was continued for a further one half hour and 
water (35 ml.) was then added and the pH adjusted to 3-7 with aqueous 
citric acid. The product was extracted into ethyl acetate, the extract 
dried and evaporated to give a glass which was triturated with hexane to 
give the N-protected dipeptide as a crystalline solid (4.0 g., 45%). 
B. N-[(L)-2-(4-Hydroxyphenyl)glycyl]-(L)-tyrosine hydrochloride 
The product from Part A, above, was dissolved in ethyl acetate (10 ml.) and 
saturated ethereal HCl (15 ml.) was added. The mixture was stirred at room 
temperature for one half hour and then evaporated to dryness. The residue 
was triturated with warm ethyl acetate (10 ml.) and dried to yield the 
hydrochloride salt (1.75 g. 50%), M.P. 231.degree.-234.degree., 
(decompositon), [.alpha.].sub.D.sup.25 +15.1.degree. (1% methanol). Found: 
C, 55.4; H, 5.2; N, 7.85. C.sub.17 H.sub.18 N.sub.2 O.sub.5.HCl requires 
C, 55.65; H, 5.2; N, 7.65%. 
EXAMPLE 17 
Glycine methyl ester was reacted with 
L-N-tert-butyloxycarbonyl-2-(4-hydroxyphenyl)glycine by the general method 
of Example 16, Part A. The product was dissolved in dioxan and treated 
with ethereal hydrogenchloride as described in Example 16, Part B, to 
yield N-[(L)-2-(4-hydroxyphenyl)glycyl]-glycine hydrochloride dioxanate, 
M.P. 142.degree.-147.degree. C., [.alpha.].sub.D.sup.25 +9.8.degree. (1% 
methanol). Found C, 47.3; H, 5.8; N, 8.0. C.sub.10 N.sub.12 N.sub.2 
O.sub.4.HCl.C.sub.4 H.sub.8 O.sub.2 requires: C, 48.2; H, 6.1; N, 8.0%. 
EXAMPLE 18 
By employing the methyl or ethyl ester of the appropriate amino acid in 
place of L-tyrosine methyl ester and optionally 
(L)-N-tert-butoxycarbonyl-2-4-(methoxyphenyl)glycine in place of the 
corresponding 4-hydroxyphenylglycine derivative in the procedure of 
Example 16, in each case the following compounds are obtained in like 
manner as the hydrochloride salts. 
______________________________________ 
##STR13## 
R R.sup.1 
______________________________________ 
H CH.sub.2 CH.sub.2 COOH 
##STR14## 
H 
##STR15## 
CH.sub.3 
##STR16## 
CH.sub.3 
##STR17## 
CH.sub.3 
##STR18## 
H 
##STR19## 
H 
##STR20## 
H 
##STR21## 
______________________________________ 
EXAMPLE 19 
(L)-N-(4-Hydroxybenzyl)-2-amino-2-(4-hydroxyphenyl)acetamide Free Base 
The hydrochloride salt obtained in Example 1, Part C (1.0 g.) dissolved in 
water, is neutralized by addition of 2 N potassium hydroxide or 2 N sodium 
hydroxide and extracted with ethyl ether. The combined extracts are dried 
(MgSO.sub.4) and evaporated to dryness in vacuo to provide the free base. 
The hydrochloride salts provided in Examples 2 through 15 are converted to 
the corresponding free bases in a similar manner. 
EXAMPLE 20 
Isoelectric Precipitation of Dipeptides 
The preparation of dipeptides of formula II wherein R.sup.1 is a 
carboxyl-containing moiety is illustrated as follows: 
N-[(L)-2-(4-Hydroxyphenyl)glycyl]-(L)-tyrosine hydrochloride, obtained as 
described in Example 16, is dissolved in a minimum amount of water. To the 
solution is added dropwise dilute sodium hydroxide solution until the 
isoelectric point is reached (pH 5-6) as evidenced by heavy precipitation. 
The resulting mixture is allowed to stand at 0.degree.-5.degree. C. over 
night and the precipitated dipeptide collected by filtration and dried. 
The remaining dipeptides of formula (II) are obtained in like manner. 
EXAMPLE 21 
Carboxylate Salt Formation 
A dipeptide provided by the procedure of Example 20 is reslurried in a 
small amount of water and one equivalent of sodium hydroxide is added. The 
resulting solution is stirred for 5-10 minutes and evaporated to dryness 
in vacuo to obtain the desired sodium salt. 
When the above procedure is repeated but employing other alkaline reagents 
in place of sodium hydroxide such as, for example, potassium carbonate, 
ammonium hydroxide, the corresponding potassium, ammonium, calcium and 
magnesium salts are similarly obtained. 
EXAMPLE 22 
Acid Addition Salts 
A free base provided by the procedure of Example 19, a dipeptide provided 
as described in Example 20 or a carboxylate salt provided by the procedure 
of Example 21 is reslurried in a small amount of water and an equivalent 
amount of acid (two or three equivalents for a carboxylate salt) such as 
hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, maleic, fumaric, 
tartaric, citric, gluconic, saccharic or p-toluenesulfonic acid is added. 
The resulting mixture is stirred for about 15 minutes then evaporated to 
dryness or precipitated by addition of a cosolvent such as, for example, 
methanol, ethanol or acetone. 
EXAMPLE 23 
Parenteral Solutions 
A. Glacial acetic acid (12.0 gm.,) and sodium acetate anhydrous (16.4 gm) 
are each dissolved in 1000 ml. of freshly distilled water to produce 0.2 
molar solutions. 148.0 ml. of the acetic acid solution is then mixed with 
352.0 ml. of the sodium acetate solution and the mixture made up to 1000 
ml. with freshly distilled water. 
(L)-N-(4-Hydroxybenzyl)-2-amino-2-(4-hydroxyphenyl)acetamide 
hydrochloride, 10 g., is then added and the resulting 1% w/v solution is 
then sterilized by filtration through a suitable bacteria-proof filter 
under aseptic conditions into sterile 50 ml. glass vials, which when 
filled with 30 ml. of the final solution, contain 300 mg. of the active 
ingredient. 
B. Succinic acid (23.62 gm.) and sodium hydroxide 98 g.) are each dissolved 
in 100 ml. of freshly distilled water to produce 0.2 molar solutions. 250 
ml. of the succinic acid solution is then mixed with 267.0 ml. of the 
sodium hydroxide and the mixture made up to 1000 ml. with freshly 
distilled water. 
(L)-N-(2-Methoxyethyl)-2-amino-2-(4-hydroxyphenyl)acetamide is then added 
and the resulting 1% w/v solution is then sterilized as in Part A, above. 
Sterile 50 ml. glass vials, when filled with 40 ml. of the final solution, 
contain 400 mg. of the active ingredient. 
EXAMPLE 24 
The following are typical tablet or capsule formulations containing 
(L)-N-(4-hydroxybenzyl)-2-amino-2-(4-hydroxyphenyl)acetamide hydrochloride 
as active ingredient: 
______________________________________ 
mg./tablet or capsule 
A B C D E 
______________________________________ 
active ingredient 
500 100 100 25 25 
lactose 30 170 -- 220 -- 
corn starch 60 80 -- 105 -- 
microcrystalline cellulose 
-- -- 170 -- 220 
("Avicel")* 
glycine -- -- 80 -- 105 
Fine silica ("Aerosil")* 
-- 0.35 0.35 0.35 
0.35 
Magnesium stearate* 
5 3 3 3 3 
595 353.35 
______________________________________ 
*9:1 blend with sodium lauryl sulphate. "Avicel" and "Aerosil" are 
Trademarks. 
For formulations A, B, and D, the ingredients are thoroughly blended 
together, and then either filled directly into hard gelatin capsules of 
appropriate size, or granulated and compressed into tablets of the desired 
size. For formulations C and E, the ingredients are thoroughly blended 
together and slugged. The slugs are broken down into granules, and then 
either filled into capsules of the appropriate size, or directly 
compressed into tablets of the desired size. 
In formulations A, B and D, the lactose may be replaced by equal amounts of 
calcium carbonate or dicalcium phosphate (CaHPO.sub.4). 
EXAMPLE 25 
Example 24 is repeated using the same amount of racemic 
(DL)-N-(4-hydroxybenzyl)-2-amino-2-(4-hydroxyphenyl)acetamide 
hydrochloride as that of the L-isomer. Of course, twice as many capsules 
or tablets of this example may be required to be taken for a single 
therapeutic administration as are required of the tablets or capsules of 
Example 24.