Excretion of nonprotein nitrogen into the intestine by prostanoic acid derivatives

A method for improvement of excretion of nonprotein nitrogen into the intestines which comprises administering, to a subject in need of such improvement, a prostanoic acid derivative in an amount effective in improving excretion of nonprotein nitrogen into the intestines.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention relates to a method for improvement of excretion of 
nonprotein nitrogen into the intestines which comprises administering a 
prostanoic acid derivative to a subject. 
The object of the present invention is to improve excretion, via the 
intestinal wall, of nonprotein nitrogen such as urea nitrogen, creatinine 
etc., as the substitute means for the treatment, such as extracorporeal 
dialysis, peritoneal dialysis, etc., for removal of the above nitrogens, 
in a subject whose nonprotein nitrogen concentration in the blood is 
elevated by e.g. renal insufficiency. 
Renal insufficiency refers to a condition in which renal function is 
injured by renal diseases such as glamerulonephritis, nephrotic syndrome, 
nephrosclerosis, renal carcinoma, lupus nephritis etc. One important 
parameter for renal insufficiency is the excreting function of kidney an 
especially the concentration of nonprotein nitrogen such as urea, 
creatinine etc. in the blood which are pooled in the body by injured 
excretion. Symptom of uremia appears as the pooling progresses. 
Traditional means effective in the treatment of renal insufficiency is the 
so-called dialysis in which the blood is contacted with a dialysate with a 
semipermeable membrane between them whereby substances in the blood may be 
removed through diffusion by osmotic gradient. The dialysis include 
hemokialysis in which the arterial blood is introduced into an artificial 
kidney and returned to a vein and peritoneal dialysis in which blood 
substances are dispersed into a dialysate, which is introduced into the 
peritoneal cavity and discharged periodically, through capillary vessels 
serving as a semipermeable membrane. However, the former has disadvantage 
that it requires a sergical operation such as shunt operation while the 
latter has disadvantages that it has inferior dialysis efficacy and 
requires infection-preventing measures. 
BACKGROUND INFORMATION 
The present inventor and co-workers formerly discovered that 
15-keto-16-halo-prostaglandins (hereinafter, prostaglandin is referred to 
as PG) have an enteropooling activity (activity of pooling water in 
intestines) (EP-A-310305). Enteropooling activity of 
16,16-dimethyl-PGE.sub.2 has also been described in Prostaglandins, 11, 
809-828(1976). However, nothing has been reported about a compound having 
an activity of excreting nonprotein nitrogen into intestines. 
As a result of extensive studies about the properties of PG compounds, the 
present inventors unexpectedly discovered that these compounds have an 
activity of excreting nonprotein nitrogen in the blood into the 
intestines. 
SUMMARY OF THE INVENTION 
In a first aspect, the present invention provides a method for improvement 
of excretion of nonprotein nitrogen into the intestines which comprises 
administering, to a subject in need of such improvement, a prostanoic acid 
derivative in an amount effective in improving excretion of nonprotein 
nitrogen into the intestines. 
In a second aspect, the present invention provides a use of a prostanoic 
acid derivative for the manufacture of a medicament for improvement of 
excretion of nonprotein nitrogen into the intestine. 
In a third aspect, the present invention provides a pharmaceutical 
composition for improvement of excretion of nonprotein nitrogen into the 
intestine comprising a prostanoic acid derivative in association with a 
pharmaceutically acceptable carrier, diluent or excipient. 
DETAILED DESCRIPTION OF THE INVENTION 
As used herein, the term "nonprotein nitrogen" includes urea, uric acid, 
creatine, creatinine, amino acids, ammonia etc., with urea and creatinine 
being most important. 
The words "excretion into the intestine" mean active or passive transport 
of substances (water, nonprotein nitrogen etc.) in the body fluid, 
principally in the blood, into the intestine ranging from duodenum to 
large intestine, principally into small intestine. 
The term "prostanoic acid" refers to the basic skeleton, shown by the 
formula below, as the common structural feature of the naturally occurring 
PGs. 
##STR1## 
The primary PGs are classified based on the structural feature of the 
five-membered cycle moiety into PGAs, PGBs, PGCs, PGDs, PGEs, PGFs, PGGs, 
PGHs, PGIs and PGJs, and also on the presence or absence of unsaturation 
and oxidation in the chain moiety as: 
Subscript 1--15-OH 
Subscript 2--5,6-unsaturated-15-OH 
Subscript 3--5,6- and 17, 18-diunsaturated-15-0H 
Further, PGFs are sub-classified according to the configuration of hydroxy 
group at 9 into .alpha.(hydroxy group being in the alpha configuration) 
and .beta.(hydroxy group being in the beta configuration). Some synthetic 
analogues have somewhat modified skeletons. 
The term "derivative" refers to a compound in which one or more atom or 
group in the prostanoic acid shown by the formula (A) is replaced by other 
atom or group or eliminated. Such derivatization includes the 
modifications known in the synthetic PG analogues and other modifications. 
Nomenclature 
Nomenclature of prostanoic acid derivatives herein uses the numbering 
system of prostanoic acid represented in formula (A) shown above. 
While formula (A) shows a basic skeleton having twenty carbon atoms, the 
15-keto-PG compounds used in the present invention are not limited to 
those having the same number of carbon atoms The carbon atoms in Formula 
(A) are numbered 2 to 7 on the a-chain starting from the a-carbon atom 
adjacent to the carboxylic carbon atom which is numbered 1 and towards the 
five-membered ring, 8 to 12 on the said ring starting from the carbon atom 
on which the a-chain is attached, and 13 to 20 on the s-chain starting 
from the carbon atom adjacent to the ring. When the number of carbon atoms 
is decreased in the a-chain, the number is deleted in order starting from 
position 2 and when the number of carbon atoms is increased in the 
a-chain, compounds are named as substituted derivatives having respective 
substituents at position 1 in place of carboxy group (C-1). Similarly, 
when the number of carbon atoms is decreased in the s-chain, the number is 
deleted in order starting from position 20 and when the number of carbon 
atoms is increased in the s-chain, compounds are named as substituted 
derivatives having respective substituents at position 20. Stereochemistry 
of the compounds is the same as that of above formula (A) unless otherwise 
specified. 
In general, PGDs, PGEs and PGFs have (a) hydroxy group(s) on the carbon 
atom(s) at position 9 and/or 11 but in the present specification PGs 
include those having a group other than a hydroxyl group at position 9 
and/or 11. Such PGs are referred to as 9-dehydroxy-9-substituted-PG 
compounds or 11-dehydroxy-11-substituted-PG compounds. 
As stated above, nomenclature of the prostanoic acid derivative is based 
upon the prostanoic acid and sometimes utilizes abbreviation "PG" for 
convenience, when the derivative in question has a partial structural 
common with PGs. These compounds, however, can also be named according to 
the IU naming system. For example, 
13,14-dihydro-15-keto-16R,S-fluoro-PGE.sub.2 is 
(Z)-7-{(1R,2R,3R)-3-hydroxy-2-[(4R,S)-4-fluoro-3-oxo-1-octyl]-5-oxocyclope 
ntyl}-hept-5- enic acid. 
13,14-dihydro-15-keto-20-ethyl-11-dehydroxy-11R-methyl-PGE.sub.2 methyl 
ester is methyl 
7-{(1R,2S,3S)-3-methyl-2-[3-oxo-1-decyl]-5-oxo-cyclopentyl}-hept-5-enoate. 
13,14-dihydro-6,15-diketo-19-methyl-PGE.sub.2 ethyl ester is ethyl 
7-{(1R,2S,3S}-3-hydroxy-2-(7-methyl-3-oxo-1-octyl)-5-oxo-cyclopentyl}-6-ox 
o-heptanoate. 13,14-dihydro-15-keto- 20-ethyl-PGF.sub.2.alpha. isopropyl 
ester is isopropyl (Z)-7-[(1R,2R,3R,5 
S)-3,5-dihydroxy-2-{3-oxo-1-decyl)-cyclopentyl]-hept-5-enoate. 
13,14-dihydro-15-keto-20-methyl-PGF.sub.2.alpha. methyl ester is methyl 
S)- -keto- 
(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-{3-oxo-1-nonyl}-cyclopentyl]-hept-5-e 
nonate. 
Preferred Compounds 
Preferred prostanoic acid derivatives used in the present are those having 
an oxo group at position 15 of the prostanoic acid in place of the hydroxy 
group, or having at least one halogen atom on the prostanoic acid 
skeleton, or having both of these features These derivatives may have a 
single bond (15-keto-PG.sub.1 compounds), a double bond (15-keto-PG.sub.2 
compounds) between positions 5 and 6, or two double bonds 
(15-keto-PG.sub.3 compounds) between positions 5 and 6 as well as 
positions 17 and 18. 
The term "halogen" refers to fluorine, chlorine, bromine and iodine with 
fluorine being preferred. 
Examples of substitution products or derivatives include esters at the 
carboxy group at the alpha chain, pharmaceutically or physiologically 
acceptable salts, unsaturated derivatives having a double bond or a triple 
bond between positions 2 and 3 or positions 5 and 6, respectively, 
substituted derivatives having substituent(s) on carbon atom(s) at 
position 3, 6, 16, 17, 19 and/or 20 and compounds having lower alkyl or a 
hydroxy (lower) alkyl group at position 9 and/or 11 in place of the 
hydroxy group, of the above PGs. 
Examples of substituents present in preferred compounds are as follows: 
Substituents on the carbon atom at position 3, 17 and/or 19 include lower 
alkyl, for example, C.sub.1-4 alkyl, especially methyl and ethyl. 
Substituents on the carbon atom at position 16 include lower alkyl e.g. 
methyl, ethyl etc., hydroxy and halogen atom e.g. chlorine, fluorine, 
phenyl and phenoxy, the last two being unsubstituted or substituted. 
Substituents on the carbon atom at position 20 include saturated and 
unsaturated lower alkyl e.g. C.sub.1-4 alkyl, lower alkoxy e.g. C.sub.1-4 
alkoxy and lower alkoxy (lower) alkyl e.g. C.sub.1-4 alkoxy-C.sub.1-4 
alkyl. Substituents on the carbon atom at position 6 include oxo group 
forming carboxyl. Stereochemistry of PGs having hydroxy, lower alkyl or 
lower (hydroxy) alkyl substituent on the carbon atom at position 9 and/or 
11 may be alpha, beta or mixtures thereof. 
Said derivatives may have an alkoxy, phenoxy or phenyl group at the end of 
the omega chain where the chain is shorter than the primary PGs. 
In the present invention, preferred compounds are those having at least one 
halogen atom on the prostanoic acid derivative, and the position of 
halogen atom is not limited but preferredly on the omega chain and more 
preferredly one or two halogen atoms are present at position 16. 
A group of preferred compounds used in the present invention has the 
formula (I) 
##STR2## 
wherein X and Y are hydrogen, hydroxy, halo, lower alkyl, 
hydroxy(lower)alkyl, or oxo, with the proviso that at least one of X and Y 
is a group other than hydrogen, and 5-members ring may have at least one 
double bond, Z is hydrogen or halogen, A is --CH.sub.2 OH, --COCH.sub.2 
OH, --COOH or its functional derivative, R.sub.1 is bivalent saturated or 
unsaturated, lower or medium aliphatic hydrocarbon residue which is 
unsubstituted or substituted with halo, oxo or aryl, R.sub.2 is saturated 
or unsaturated, lower or medium aliphatic hydrocarbon residue which is 
unsubstituted or substituted with oxo, hydroxy, halo, lower alkoxy, lower 
alkanoyloxy, cyclo(lower)alkyl, aryl or aryloxy, with the proviso the 
third carbon atom counted from 5-membered ring is substituted with an oxo 
group. 
In the above formula, the term "unsaturated" in the definitions for R.sub.1 
and R.sub.2 is intended to include at least one and optionally more then 
one double bond and/or triple bond isolatedly, separately or serially 
present between carbon atoms of the main and/or side chains According to 
usual nomenclature, an unsaturation between two serial positions is 
represented by denoting the lower number of said two positions, and an 
unsaturation between two distal positions is represented by denoting both 
of the positions. Preferred unsaturation is a double bond at position 2 
and a double or triple bond at position 5. 
The term "lower or medium aliphatic hydrocarbon residue" refers to a 
straight or branched chain hydrocarbyl group having 1 to 14 carbon atoms 
(for a side chain, 1 to 3 carbon atoms being preferred) and preferably 2 
to 8 carbon atoms for R.sub.1 and 6 to 12 carbon atoms for R.sub.2. 
The term "halo" denotes fluoro, chloro, bromo and iodo. 
The term "lower" is intended to include a group having 1 to 6 carbon atoms 
unless otherwise specified. 
The term "lower alkyl" as a group or a moiety in hydroxy(lower)alkyl 
includes saturated and straight or branched chain hydrocarbon radicals 
containing 1 to 6, carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, 
butyl, isobutyl, t-butyl, pentyl and hexyl. 
The term "lower alkoxy" refers to the group lower-alkyl-O- wherein lower 
alkyl is as defined above. 
The term "hydroxy(lower)alkyl" refers to alkyl as defined above and 
substituted with at least one hydroxy group, e.g. hydroxymethyl, 
1-hydroxyethyl, 2-hydroxyethyl and 1-methyl-1-hydroxyethyl. 
The term "lower alkanoyloxy" refers to a group of the formula: RCO--O-- 
wherein RCO-- is an acyl group formed by oxidation of a lower alkyl group 
as defined above, e.g. acetyl. 
The term "cyclo(lower)alkyl" refers to a cyclic group formed by cyclization 
of a lower alkyl group as defined above. 
The term "aryl" includes unsubstituted or substituted aromatic carbocyclic 
or heterocyclic (preferably monocyclic) groups, e.g. phenyl, tolyl, xylyl 
and thienyl. Examples of substituents are halo and halo(lower)alkyl 
wherein halo and lower alkyl being as defined above. 
The term "aryloxy" refers to a group of the formula: ArO- wherein Ar is 
aryl as defined above. 
The term "functional derivative" of carboxy as A includes salts (preferably 
pharmaceutically acceptable salts), esters and amides. 
Suitable "pharmaceutically acceptable salts" includes conventional 
non-toxic salts, and may be a salt with an inorganic base, for example a 
metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, 
etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, 
etc.), ammonium salt, a salt with an organic base, for example, an amine 
salt (e.g. methylamine salt, dimethylamine salt, cyclohexylamine salt, 
benzylamine salt, piperidine salt, ethylenediamine salt, ethanolamine 
salt, diethanolamine salt, triethanolamine salt, 
tris(hydroxymethylamino)methane salt, monomethylmonoethanolamine salt, 
procaine salt, caffeine salt, etc.), a basic amino acid salt (e.g. 
arginine salt, lysine salt, etc.), tetraalkylammonium salt and the like. 
These salts can be prepared by the conventional process, for example from 
the corresponding acid and base or by salt interchange. 
Examples of the esters are aliphatic esters, for example, lower alkyl ester 
e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl 
ester, isobutyl ester, t-butyl ester, pentyl ester, 1-cyclopropylethyl 
ester, etc., lower alkenyl ester e.g. vinyl ester, allyl ester, etc., 
lower alkynyl ester e.g. ethynyl ester, propynyl ester, etc., 
hydroxy(lower) alkyl ester e.g. hydroxyethyl ester, lower 
alkoxy(lower)-alkyl ester e.g. methoxymethyl ester, 1-methoxyetyl ester, 
etc., and aromatic esters, for example, optionally substituted aryl ester 
e.g. phenyl ester, tosyl ester, t-butylphenyl ester, salicyl ester, 
3,4-di-methoxyphenyl ester, benzamidophenyl ester etc., aryl(lower)alkyl 
ester e.g. benzyl ester, trityl ester, benzhydryl ester, etc. Examples of 
the amides are mono- or di- lower alkyl amides e.g. methylamide, 
ethylamide, dimethylamide, etc., arylamide e.g. anilide, toluidide, and 
lower alkyl- or aryl-sulfonylamide e.g. methylsulfonylamide, 
ethylsulfonylamide, tolylsulfonylamide etc. 
Preferred examples of A include --COOH, --COOCH.sub.3, --COOCH.sub.2 
CH.sub.3, COOCH(CH.sub.3).sub.2 and --CONHSO.sub.2 CH.sub.3. 
The configuration of the ring and the .alpha.- and/or omega chain in the 
above formula (I) may be the same as or different from that in the primary 
PGs. However, the present invention also includes a mixture of a compound 
having a primary configuration and that of an unprimary configuration. 
Examples of the typical compounds of the present invention are 15-keto-PGs, 
13,14-dihydro-15-keto-PGs and their e.g. 6-keto-derivatives, .DELTA..sup.2 
-derivatives, 3R,S-methyl-derivatives, 16R,S-methylderivatives, 
16,16-dimethyl-derivatives, 16R,S-fluoroderivatives, 
16,16-difluoro-derivatives, 17S-methylderivatives, 19-methyl-derivatives, 
20-methyl-derivatives and 16-desbutyl-16-phenoxy derivatives. 
When 15-keto-PG compounds of the present invention have a saturated bond 
between positions 13 and 14, these compounds may be in the keto-hemiacetal 
equilibrium by forming a hemiacetal between hydroxy group at position 11 
and ketone at position 15. 
The proportion of both tautomeric isomer, when present, varies depending on 
the structure of the rest of the molecule or kind of any substituent 
present and, sometimes, one isomer may predominantly be present in 
comparison with the other. However, in this invention, it is to be 
appreciated that the compounds used in the invention include both isomers. 
Further, while the compounds used in the invention may be represented by a 
structure or name based on keto-form regardless of the presence or absence 
of the isomers, it is to be noted that such structure or name does not 
intend elimination of the hemiacetal type of compounds. 
In the present invention, any of the individual tautomeric isomers, a 
mixture thereof, or optical isomers, a mixture thereof, a racemic mixture, 
and other isomers such as steric isomers can be used in the same purpose. 
Some of the compounds used in the present invention may be prepared by the 
method disclosed in Japanese Patent Publication (unexamined) No. 
A-52753/1989. 
Alternatively, these compounds may be prepared by a process analogous to 
that described herein or to known processes. 
A practical preparation of the prostanoic acid derivative, e.g. 
13,14-dihydro-15-keto compounds, involves the following steps; referring 
to the synthetic charts(I) to (III), reaction of the aldehyde (2) prepared 
by the Collins 
oxidation of commercially available (-)-Corey lactone (1) with dimethyl 
(2-oxoheptyl)phosphate anion to give .alpha.,.beta.-unsaturated ketone 
(3), reduction of the .alpha.,.beta.-unsaturated ketone (3) to the 
corresponding saturated ketone (4), protection of the carbonyl group of 
the ketone (4) with a diol to the corresponding ketal (5), and 
deprotection of the p-phenylbenzoyl group to give the corresponding 
alcohol (6) followed by protection of the newly derived hydroxy group with 
dihydropyrane to give the corresponding tetrahydropyranyl ether (7). 
According to the above process, a precursor of PGEs wherein the 
.omega.-chain is a 13,14-dihydro-15-keto-alkyl group is prepared. 
Using the above tetrahydropyranyl ether (7), 6-keto- PGE.sub.1 s (15) of 
which a group constituted with carbon atoms of position 5, 6 and 7 is 
##STR3## 
may be prepared in the following steps; reduction of the tetrahydropyranyl 
ether (7) with, for example, diisobutyl aluminum hydride to give the 
corresponding lactol (8), reaction of the lactol (8), with the glide 
generated from (4-carboxybutyl)triphenyl phosphonium bromide followed by 
esterification (10), cyclization between the 5,6-double bond and the 
hydroxyl group at position 9 with NBS or iodine to give the halogenated 
compound (11), dehydrohalogenation of the compound (11) with, for example, 
DBU to give the 6-keto compound (13) followed by Jones oxidation and 
removal of the protecting groups. 
Furthermore, PGE.sub.2 s (19) of which a group constituted with carbon 
atoms of position 5, 6 and 7 is 
##STR4## 
may be prepared in the following steps; as shown in the synthetic chart 
II, reduction of the above tetrahydropyranyl ether (7) to give the lactol 
(8), reaction of the resultant lactol (8) with the glide derived from 
(4-carboxybutyl-)triphenyl phosphonium bromide to give the carboxylic acid 
(16) followed by esterification to give ester (17), Jones oxidation of the 
esters (17) to give the compound (18), and removal of the protecting 
groups. 
Using the above tetrahydropyranyl ether (7) as the starting material, the 
compound having 
##STR5## 
may be prepared by using the same process as that for preparing PGE.sub.2 
having --CH.sub.2 CH.dbd.CH-- and subjecting the resultant compound (18) 
to catalytic reduction to reduce the double bond between the position 5 
and 6 followed by removal of the protective groups. 
Synthesis of 5,6-dehydro-PGE.sub.2 s having 
##STR6## 
may be carried out by capturing a copper enolate formed by 1,4-addition of 
a monoalkylcopper complex or a dialkylcopper complex of the following 
formulae: 
##STR7## 
to 4R-t-butyldimethylsilyloxy-2-cyclopenten-1-one with 
6-alkoxycarbonyl-1-iodo-2-hexyne or the derivatives. 
The 11-.beta. type PGEs can be prepared according to the synthetic chart 
III. 
PGE derivatives having a methyl group at position 11 in place of hydroxy 
can be prepared by reacting a dimethyl copper complex with PGA-type 
compound obtained by subjecting 9-hydroxy-11-tosylate to the Jones 
oxidation. Alternatively, they can be prepared by protecting the carbonyl 
of saturated ketone (4) produced by reducing unsaturated ketone (3), 
eliminating p-phenylbenzoyl and tosylating the produced alcohol, treating 
with DBU to form a lactol, introducing the alpha-chain by Wittig reaction, 
oxidizing the alcohol at position 9 to give PGA-type compound, and 
reacting the product with dimethyl copper complex in order to introduce a 
methyl group into position 11 to give an 11-methyl-PGE-type compound, 
which on reduction with e.g. sodium borohydride gives an 
11-methyl-PGF-type compound. An 11-hydroxymethyl-PGE-type compound, is 
obtained by a benzophenone-sensitized photoaddition of methanol of 
PGA-type compound, which is reduced with, e.g. sodium borohydride, to give 
an 11-hydroxymethyl-PGF-type compound. The synthetic route for the 
compounds used in the present invention is not limited to the that 
described above one and may vary using different protecting, reducing 
and/or oxidizating methods. 
Corresponding other PG compounds can be produced analogously. 
##STR8## 
The compounds used in the present invention may be used as a medicine for 
animals and human beings and usually applied systemically or locally by 
such methods as oral administration, intravenous injection (including 
instillation), subcutaneous injection, suppository and the like. While the 
dosage will vary depending on the particular animal or human patient, age, 
body weight, symptom to be treated, desired therapeutic effect, 
administration route, term of treatment and the like, satisfactory effects 
will be obtained with the dosage of 0.001-500 mg/kg administered in 2 to 4 
divided doses a day or as a sustained form. 
As a solid composition of this invention for oral administration, tablets. 
troches, buccals, capsules, pills, powders, granules and the like are 
included. The solid composition containing one or more active substances 
is mixed with at least an inactive diluent, e.g. lactose, mannitol, 
glucose, hydrocypropyl cellulose, fine crystalline cellulose, starch, 
polyvinyl pyrolidone, magnesium aluminate metasilicate. The composition 
may contain additives other than the inactive diluent, for example, 
lubricants e.g., magnesium stearate, a disintegrator e.g. cellulose 
calcium gluconates, stabilizers e.g. a-, b- or x-cyclodextrins, etherated 
cyclodextrins (e.g. dimethyl-a-, dimethyl-b-, trimethyl-b-, or 
hydroxypropyl-b-cyclodextrins), branched cyclodextins (e.g. glucosyl- or 
maltosyl-cyclodextrins), formyl cyclodextrins, sulfur-containing 
cyclodextrins, misoprotols or phospholipids. Such cyclodextrins may 
increase the stability of the compounds by forming an inclusion compounds. 
The stability may be often increased by forming lyposome with 
phospholipids. Tablets and pills may be coated with an enteric or 
gastroenteric film e.g. white sugar, gelatin, hydroxypropylcellulose, 
hydroxypropylmethylcellulose phthalates and the like, if necessary, and 
furthermore they may be covered with two or more layers. Additionally, the 
composition may be in the form of capsules made of substance easily 
absorbed e.g. gelatin. The composition may be in the form of buccals, when 
an immediated effect is desired. For this purpose, base e.g. glycerine, 
lactose may be used. 
Liquid compositions for oral administration include pharmaceutically 
acceptable emulsions, solutions, suspensions, syrups, elixirs and the like 
and contain a generally used inactive diluent e.g. purified water or ethyl 
alcohol. The composition may contain additives e.g. wetting agents, 
suspending agents, sweeteners, flavors, perfumes and preservatives. 
The composition of the present invention may be sprays which may contain 
one or more active ingredients and which can be prepared according to a 
well known methods. 
An injection of this invention for non-oral administration includes serile 
aqueous or nonaqueous solutions, suspensions, and emulsions. Diluents for 
the aqueous solution or suspension include, for example, distilled water 
for injection, physiological saline and Ringer's solution. Diluents for 
the nonaqueous solution and suspension include, for example, propylene 
glycol, polyethylene glycol, vegetable oils e.g. olive oil, alcohols, e.g. 
ethanol and polysorbates. The composition may contain other additives, 
e.g. preservatives, wetting agents, emulsifying agents, dispersing agents 
and the like. These are sterilized by filtration through, e.g. a bacteria- 
retaining filter, compounding with a sterilizer, gas sterilization or 
radiation sterilization. These can be prepared by producing a sterilized 
water or a sterilized solvent for injection before use. 
Another formulation according to the present invention is a rectal or 
vaginal suppository. This can be prepared by mixing at least one active 
compound according to the invention with a suppository base e.g. cacao 
butter and optionally containing nonionic surfactant for improving 
absorption. 
The compounds used in the medicament for improvement of excretion of 
nonprotein nitrogen into the intestines according to the present invention 
have an effect of improving excretion of nonprotein nitrogen in the blood 
into the intestine or as feces. 
Accordingly, the compounds used in the present invention are useful for 
treatment (e.g. prevention, cure, relief and arrest or relief of 
development) of conditions wherein nonprotein nitrogen level in the blood 
is elevated and of uremia, irrespective of cause, e.g. disease, drug or 
food. 
Further, the compounds of the present invention are also useful in case 
where the renal excretion of nonprotein nitrogen is damaged due to reduce 
in or loss of he renal function e.g. by renal failure.