AGENT SERVANT A TRAITER OU A PREVENIR LA THROMBOCYTOPENIE

AGENT FOR TREATING OR PREVENTING THROMBOCYTOPENIA

Abrégé anglais

ABSTRACT OF THE DISCLOSURE
An agent for treating or preventing
thrombocytopenia is disclosed. The agent comprises, as
an active ingredient, a compound of the formula (I):

Image (I)

wherein X represents an amino acid residue selected from
the group consisting of l-alanine, L-serine and L-valine,
Y represents a group represented by the following formula

Image

wherein n represents an integer of 1 to 6, A represents a
saturated straight or branched chain aliphatic hydro-
carbon group having 7 to 29 carbon atoms, and Acyl repre-
sents an acyl group having 2 to 6 carbon atoms.

Revendications

WHAT IS CLAIMED IS:
1. An agent for treating or preventing
thrombocytopenia which comprises, as an active
ingredient, a compound of the formula (I):

Image (I)

wherein X represents an amino acid residue selected from
the group consisting of L-alanine, L-serine and L-valine,
Y represents a group represented by the following formula

Image

wherein n represents an integer of 1 to 6, A represents a
saturated straight or branched chain aliphatic hydro-
carbon group having 7 to 29 carbon atoms, and Acyl repre-
sents an acyl group having 2 to 5 carbon atoms.
2. An agent for treating or preventing
thrombocytopenia as claimed in claim 1, wherein the

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active ingredient is N2-[(N-acetylmuramoyl)-L-alanyl-D-
isoglutaminyl]-N6-stearoyl-L-lysine.

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Description

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1 AGENT FOR TREATING OR PREVENTING THROMBOCYTOPENIA

FIELD OF THE INVENTION
This invention relates to an agent for treating
or preventing thrombocytopenia which comprises, as an
active ingredient, a compound of the formula (I):

CH20H .
~0
~ ~ H~OH (I)

HAcyl CONH2
CH3CHCO -X -NHcHcH2cH2co-y
.
wherein X represents an amino acid residue selected from
the group consisting of L-alanine, L-serine and L-valine,
Y represents a group represented by-the following formula
`
COOH
-NHCH(CH2~n~NHc-A

wherein n represents an integer of 1 to 6, A represents a
~saturated straight or branched chain aliphatic hydro-
carbon group having 7 to 29 carbon atoms, and Acyl repre-
~ :sents an acyl group having 2 to 6 carbon atoms.



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1 BACKGROUND OF THE INVENTION
Multipotential stem cells, which can differen-
tiate to granulocytes, monocytes ~macrophages), red blood
cells, platelets, lymphocytes, exist in the bone marrow
of higher animals. The stem cells differentiate to
precursory cells and the cells differentiate to the above
blood cells. On the differentiation, several specific
growth factors function to each blood cell's differentia-
tion. For example, Interleukin~3 functions to the
multipotential stem cells to induce the differentiation
thereof to precursory granulocytes, and granulocyte
growth factors such as granulocyte-colony stimulating
factor function to the precursory cells to induce the
differentiation thereof to granulocytes.
On the other hand, precursory cells such as
megakaryocytes are supposed to require thrombopoietin in
the diffe~entiation thereof to platelets. However, the
detail of the differentiation has not been clarified.
Platelets have a significant role to maintain
the health independently or in cooperation with the other
blood cells. Therefore, when the differentiation to
platelets is inhibited, some diseases caused by reduction
of platelets number appear.
Example of the diseases includes symptomatic
25 ~ thrombocytopenia, idiophatic thrombocytopenia and the




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l like caused by anticancer agent, radiation, blood
disease, etc., and symptoms thereof include bleeding,
coagulation defect and the like.
As the treating method for thrombocytopenia,
only platelets transfusion, which is complicated and
expensive, was used. However, this is not the
fundamental treatment of the disease.
The compound of the formula (I) is disclosed in
U.S. Patent 4,317,771, and has an excellent adjuvant
activity and treating or preventing effect on infection
of microorganisms. However, it has been unknown that the
compound of the formula (I) is effective for treatment or
prevention of thrombocytopenia.
SUMMARY OF l'HE INVENTION
This invention relates to an agent for treating
or preventing thrombocytopenia which comprises a compound
of the formula (I) as an active ingredient.
DETAILED DESCRIPTION OF THE INVENTION
Pharmaceutical preparations containing the
compound of the formula (I) include tablets, capsules,
powders, granules, injections, suppositories, sprays,
dermal preparations and the like. These preparations can
be prepared by known pharmaceutical techniques using
appropriate additives such as excipients, e.g., corn
tarch, lactose, mannitol, etc., binders, e.g.,

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1 hydroxypropyl cellulose, polyvinyl pyrrolidone, etc.,
disintegrators, e.g., low substituted hydroxypropyl
cellulose, crystalline cellulose, etc., and lubricants,
e.g., talc, magnesium stearate, etc. If desired, the
preparations of the present invention can be a slow
release (sustained-release) preparation which can be
prepared using known pharmaceutical techniques.
The agent according to the present invention
can be administered orally or parenter~lly. The dose
level usually ranges from about 100 to about 400 ~g/day
in case of subcutaneous administration or from about 2 to
about 20 mg/day in case of oral administration for adult
human (about 50 to 60 kg body weight). The therapeutic
effect of the agent according to the present invention is
expected to be further enhanced by combining with whole
blood transfusion or platelets transfusion which is a
typical therapeutic method for thrombocytopenia.
The compounds of the foxmula (I) is of low
toxicity~ For example, LD50 of Compound A described in
Example 1 which is a typical compound of the formula (I)
was found to be 600 to 1,000 mg/kg in rats by
subcutaneous injection.
The compound of the formula (I) has an
excellent effect on prevention or treatment of
ehrombooytopenia as illustrated in E~amples hereinafter




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l described and, therefore, the compound is useful as an
excellent agent for preventing or treating
thrombocytopenia.
The present invention is hereinafter
illustrated in greater detail with reference to Examples,
however, it should be understood that these examples are
not to be construed as limiting the present invention.
EXAMPLE
(1) A vial containing:
Compound A 0.2 mg
D-Mannitol 45.0 mg
Potassium dihydrogen phosphate 1.95 mg
Sodium hydrogen phosphate 8.31 mg
(2) An additive solution in ampule containing:
Distilled water for injection l ml
According to the above formulation, a
lyophili~ed injection containing 200 ~g of Compound A was
prepared using known pharmaceutical techniques. In using
this preparation, the additive solution in the ampule is
injected into the vial just before the use to instantly
prepare an injectable solution containing Compound A.
ComPound A: N2-[(N-acetylmuramoyl)-L-alanyl-D-
isoglutaminyl]-N -stearoyl-L-lysine
(an anomeric mixture)


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1 EXAMPLE 2
Compound A (200 ~g) was administered subcuta-
neously to 20 patients with mulignant lymphoma in a
single daily dose for 10 consecutive days from 3 to 5 day
after the starting day of chemotherapy for the above
disease (administered group). Blood test was carried out
on the 7, 10, 14, 17, 21 and 24th days from the starting
day of the chemotherapy. A cross over method was used to
determine the effect of Compound A; that is, the same
patients as above were used as the control group without
administering with Compound A, and the number of
platelets in the administered group was compared to that
in the control group. The result was shown in Table 1
below as mean + standard error.




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131~830


TABLE I
Platelets Nunber )
at the Starting
Day of P1ate!ets_Number ) (,differe ce from the before)
Chemotherapy 7th Day 10th Da~ 14th Da,v17th Day 21st Day 24th DaY
Administered Group -4.3+1.7 -7.Z~1.6 -4.4~2.33.8+1.8 5,9+?,0 0.7t2.1525,7 t 1.9
Control Group -8,9+?,4 -10.7+?.7 -8.~!:2.8-2.3+?,6 3,5+?,4 -3.S~3.3
28.6 + 2.5

a): x 104/mm3
*: ~he difference was significant at the level of 5% or
less by paired t-test.
**: The difference was significant at the level o 1% or
less by paired t-test.

As is apparent from the results in Table 1
above, the increase of platelets number was observed
in the administered group, and a tendency to suppress the
decrease thereof caused by the chemotherapy and to
restore the platelets number was observed.
While the invention has been described in
detail and with reference to specific embodiments
thereof, it will be apparent to one skilled in the art
that various changes and modifications can be made
therein without departing from the spirit and scope
thereof.


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