JPH083048A - Agent for improving and treating syndrome accompanied by tumor - Google Patents

Abstract

PURPOSE:To obtain an agent for treating syndrome accompanied by tumor, especially a cachexia or improving the symptom, containing a vitamin D derivative as an active ingredient. CONSTITUTION:This agent contains a compound of the formula (R1 is a 1-10C alkyl; R2 is H or OH) as an active ingredient. The agent containing vitamin D derivative is free from especially strong side effect and has good compliance of patients and is effective from the viewpoint of quality-of-life. The compound is properly blended with a proper vehicle, auxiliary agent, etc., and the blend can be prepared in a formulation of oral agent, injection, nasal drop, ointment, etc., according to an ordinary method and the daily dose of the compound is 0.01-1000mum, preferably 1-20mum. The cachexia means a systemic bad state including remarkable weight reduction, anorexia, anemia, etc., due to chronic diseases as main symptoms.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a therapeutic agent for improving paraneoplastic syndrome. More specifically, it relates to a therapeutic agent for improving paraneoplastic syndromes, which contains a vitamin D derivative as an active ingredient.

[0002]

BACKGROUND OF THE INVENTION Paraneoplastic syndrome is associated with various malignant tumors and is associated with blood disorders such as cachexia and leukocytosis, breakdown of body fluid homeostasis represented by electrolyte disorders, metabolic disorders such as hypoglycemia and diabetes, and skin. Lesions, neurological symptoms, serum protein abnormalities,
This refers to symptoms that appear in addition to the direct symptoms of the tumor, such as renal disorders, osteoarthritis disorders, and hyperfunction associated with excess corticosteroids, and these often appear systematically. Of these, cachexia and electrolyte abnormalities are the main ones, respiratory failure,
With circulatory failure, digestive disorders, bleeding, systemic infection, etc.,
It is known as an important cause of death in cancer patients.

[0003] Cachexia refers to a systemic poor state whose main symptoms are marked weight loss, anorexia, anemia, etc. due to compulsive diseases such as cancer cachexia, infectious cachexia, and thyroid gland. Sex cachexia and the like are known as typical ones. Among these cachexia, cancer cachexia is said to be an obstacle to the treatment of cancer because it lowers the resistance to chemotherapy and radiation therapy for cancer (Johana).
T. Dwyer, Cancer, 43, 2077 (1
979), Sarah S. et al. Donaldson et
al. , Cancer, 43, 2036 (1979).
Such).

Conventional treatments for paraneoplastic syndromes have been carried out, for example, for electrolyte abnormalities by administering various replacement fluids and bone resorption inhibitors. However, these are symptomatic treatments, do not suppress the production of causative substances derived from malignant tumors, and are not sufficient for the treatment of paraneoplastic syndromes. In addition, as a treatment for cachexia, conventionally, a method of improving nutritional status by giving a high-fat diet or a high-carbohydrate diet, a high-calorie infusion therapy, or a blood transfusion therapy has been used. Is only symptomatic treatment, and its effect is not sufficient. In addition, many of the currently used anticancer agents have strong side effects, and there is no one that can be said to be effective in improving cachexia, and the development of therapeutic agents for cachexia and improving agents is awaited. is there.

[0005]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a drug for treating paraneoplastic syndrome, particularly cachexia or ameliorating its symptoms.

[0006]

Means for Solving the Problems The present inventor has conducted extensive studies on a remedy for a paraneoplastic syndrome, and as a result, the following general formula (I)

Embedded image (Wherein R ₁ represents an alkyl group having 1 to 10 carbon atoms that may be substituted with one or more hydroxyl groups, and R ₂ represents a hydrogen atom or a hydroxyl group), and a vitamin D derivative represented by the paraneoplastic syndrome The present invention was completed by finding out that it is effective as an improving therapeutic agent for That is, the invention has the general formula (I)

[Chemical 6] (Wherein R ₁ represents an alkyl group having 1 to 10 carbon atoms which may be substituted with one or more hydroxyl groups, and R ₂ represents a hydrogen atom or a hydroxyl group) as an active ingredient. The present invention relates to a therapeutic agent for improving paraneoplastic syndrome. Also,
The present invention has the general formula (I)

[Chemical 7] (Wherein R ₁ represents an alkyl group having 1 to 10 carbon atoms which may be substituted with one or more hydroxyl groups, and R ₂ represents a hydrogen atom or a hydroxyl group) as an active ingredient. The present invention relates to an agent for improving cachexia. Preferred examples of the compound represented by the general formula (I) include, for example, the general formula (II)

Embedded image (Wherein R ₁ represents an alkyl group having 1 to 10 carbon atoms which may be substituted with one or more hydroxyl groups), and the most preferable compound is represented by the formula (II
I)

[Chemical 9] The compound represented by

The vitamin D derivative of the present invention is a known compound and is described in, for example, Japanese Patent Publication No. 3-74656. Vitamin D is generally known to exhibit various physiological activities such as calcium metabolism regulating action, tumor cell growth inhibiting action, differentiation inducing action, and immunoregulatory action. In addition, it is known that the compound of the present invention having an oxygen atom at the 22-position usually has a very weak side effect of causing vitamin D compounds of this type, such as hypercalcemia, and psoriasis and secondary hyperparathyroidism. It has been reported that it is effective against diseases (for example, JP-A-63-183534, JP-B-6-8).
6382 publication). It is also known to have an antitumor effect, but there are no reports suggesting that it is effective for paraneoplastic syndromes represented by cachexia.

In the present invention, the alkyl group in the alkyl group having 1 to 10 carbon atoms which may be substituted with a hydroxyl group is a linear or branched alkyl group, for example, methyl group, ethyl group, n-propyl group. Group, i-propyl group, n-butyl group, i-butyl group, s-butyl group, t-
In addition to the butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decanyl group and the like can be mentioned. Preferably, 3-methylbutyl group, 3-ethylpentyl group, 4-methylpentyl group, 3- (n-propyl)
Hexyl group, 4-ethylhexyl group, 5-methylhexyl group, 6-methylheptyl group, 5-ethylheptyl group,
Examples thereof include 4- (n-propyl) heptyl group, and more preferably, 3-methylbutyl group, 3-ethylpentyl group, 4-methylpentyl group and the like. The most preferable one is 3-methylbutyl group.

The above alkyl group may or may not be substituted with a hydroxyl group, and examples of the number of hydroxyl groups in the case of being substituted with a hydroxyl group include 1, 2, and
3, etc. are mentioned, preferably 1 or 2, and more preferably 1. Examples of the alkyl group having 1 to 10 carbon atoms, which is substituted with one or more hydroxyl groups, include 3-
Hydroxy-3-methylbutyl group, 2-hydroxy-3
-Methylbutyl group, 4-hydroxy-3-methylbutyl group, 2,3-dihydroxy-3-methylbutyl group, 2,
4-dihydroxy-3-methylbutyl group, 3,4-dihydroxy-3-methylbutyl group, 3-hydroxy-3-
Ethyl pentyl group, 2-hydroxy-3-ethyl pentyl group, 4-hydroxy-3-ethyl pentyl group, 2,3
-Dihydroxy-3-ethylpentyl group, 2,4-dihydroxy-3-ethylpentyl group, 3,4-dihydroxy-3-ethylpentyl group, 4-hydroxy-4-methylpentyl group, 3-hydroxy-4-methyl Pentyl group, 5-hydroxy-4-methylpentyl group, 3,4-
Dihydroxy-4-methylpentyl group, 3,5-dihydroxy-4-methylpentyl group, 4,5-dihydroxy-4-methylpentyl group, 3-hydroxy-3- (n-
Propyl) hexyl group, 4-hydroxy-3- (n-propyl) hexyl group, 2-hydroxy-3- (n-propyl) hexyl group, 2,3-dihydroxy-3- (n-
Propyl) hexyl group, 3,4-dihydroxy-3-
(N-Propyl) hexyl group, 2,4-dihydroxy-
3- (n-propyl) hexyl group, 3-hydroxy-4
-Ethylhexyl group, 4-hydroxy-4-ethylhexyl group, 5-hydroxy-4-ethylhexyl group, 3,
4-dihydroxy-4-ethylhexyl group, 3,5-dihydroxy-4-ethylhexyl group, 4,5-dihydroxy-4-ethylhexyl group, 4-hydroxy-5-methylhexyl group, 5-hydroxy-5-methylhexyl group , 6-hydroxy-5-methylhexyl group, 4,5-
Dihydroxy-5-methylhexyl group, 4,6-dihydroxy-5-methylhexyl group, 5,6-dihydroxy-5-methylhexyl group, 5-hydroxy-6-methylheptyl group, 6-hydroxy-6-methylheptyl group Base,
7-hydroxy-6-methylheptyl group, 5,6-dihydroxy-6-methylheptyl group, 5,7-dihydroxy-6-methylheptyl group, 6,7-dihydroxy-6
-Methylheptyl group, 4-hydroxy-5-ethylheptyl group, 5-hydroxy-5-ethylheptyl group, 6-
Hydroxy-5-ethylheptyl group, 4,5-dihydroxy-5-ethylheptyl group, 4,6-dihydroxy-
5-ethylheptyl group, 5,6-dihydroxy-5-ethylheptyl group, 3-hydroxy-4- (n-propyl)
Heptyl group, 4-hydroxy-4- (n-propyl) heptyl group, 5-hydroxy-4- (n-propyl) heptyl group, 3,4-dihydroxy-4- (n-propyl)
A heptyl group, a 3,5-dihydroxy-4- (n-propyl) heptyl group, a 4,5-dihydroxy-4- (n-propyl) heptyl group and the like can be mentioned, preferably a 3-hydroxy-3-methylbutyl group, 2,3-dihydroxy-3-methylbutyl group, 3,4-dihydroxy-3-methylbutyl group, 3-hydroxy-3-ethylpentyl group, 2,3-dihydroxy-3-ethylpentyl group,
3,4-dihydroxy-3-ethylbenzyl group, 4-hydroxy-4-methylpentyl group, 3,4-dihydroxy-4-methylpentyl group, 4,5-dihydroxy-4
-Methylpentyl group and the like, and more preferably 3-hydroxy-3-methylbutyl group, 3-hydroxy-
Examples thereof include a 3-ethylpentyl group and a 4-hydroxy-4-methylpentyl group. The most preferable one is 3-hydroxy-3-methylbutyl group. Further, in the general formula (I), R ₂ is more preferably a hydroxyl group.

The therapeutic agent of the present invention comprises a compound represented by the general formula (I) which is an active compound, and a pharmaceutically acceptable excipient and auxiliary agent which facilitate the formulation of the active compound. An acceptable carrier may be included. The kind of the excipient is not particularly limited, and for example, lactose, sucrose, sugars such as mannitol and sorbitol, celluloses, and / or fillers such as calcium phosphate can be used. The auxiliary agent may be added as necessary, and examples thereof include a binder, a flow regulator, a lubricant and a stabilizer. As the dosage form of the present invention, in addition to oral preparations produced by a usual method for preparing vitamin Ds, parenteral preparations include, for example, liquid preparations such as injectable solutions containing an aqueous solvent as a main component, nasal drops, etc. Although non-invasive preparations, external preparations such as creams, ointments and the like are also possible, oral preparations and injections are preferable.

As a method of administering the drug of the present invention, it is preferable to administer an oral agent or an injection systemically, but in some cases, topical administration such as an external preparation is also possible.

The dose of the vitamin D derivative of the present invention varies depending on age, sex, symptoms and the like, but it is usually 0.01 to 1000 μg per person per day, and 0.1 to 10 μg.
0 μg is preferable, and 1 to 20 μg is particularly preferable. The frequency of administration is not particularly limited, and for example, the above dose may be administered once to three times a day.

[0013]

INDUSTRIAL APPLICABILITY The drug containing the vitamin D derivative of the present invention has no particularly strong side effects, has good patient compliance, and is an effective remedy for paraneoplastic syndrome from the viewpoint of quality of life (QOL). Is.

[0014]

The present invention will be described in more detail with reference to the following examples. In this Example, as the drug of the present invention, 22-oxa-1α, 25-dihydroxyvitamin D3 was used.

[Chemical 10] Was used as the active ingredient.

Example 1 A human pancreatic cancer-derived cell line FA-6 was transplanted, and the drug was orally administered to nude mice exhibiting cachexia and electrolyte abnormalities. Grouped 27 days after transplantation (5 animals per group), 2
From the 8th day, the drug (6.25 μg / kg body weight) was orally administered 5 times a week for 3 consecutive days. In the control group, the body weight of the experimental animals was 21.85 ± 2.42 (g) the day after the solvent administration, but was 18.97 ± 15 days after the vehicle administration.
Although a remarkable decrease to 2.45 (g) was observed, the body weights of the group to which the drug was administered 13 times at the same time were 21.85 each.
It was ± 1.79 (g) and 21.45 + 1.38 (g). From this result, it became clear that this drug markedly suppressed the weight loss of tumor-bearing mice. At this time, the ionized calcium in the whole blood of the control group was 1.93 mmo before administration.
1 / l (n = 5), and 2.22 mmol / in 2 weeks
1 (n = 5). On the other hand, in the drug administration group, it was 1.90 mmol / l (n = 5) before the administration, but it decreased to 1.72 mmol / l after 13 administrations.
Furthermore, the control group died in 99.5 days on average, whereas the drug-administered group had an average life extension effect of 166 days, which was 1.67 times.

Example 2 The human pancreatic cancer-derived cell line FA-6 was transplanted, and the drug was intravenously administered to nude mice exhibiting cachexia and abnormal electrolyte states. On the 24th day after transplantation, the animals were divided into groups (5 mice per group), and from the same day, the drug (6.25 μg / kg body weight) was intravenously administered twice or three times a week. Regarding the body weight of the experimental animals, the vehicle-administered group and the drug-administered group were 20.49 each before administration.
(G) (n = 5), 20.62 g (n = 5), whereas it was 1 each on the 18th day after the start of administration after 6 doses.
7.67 (g) (n = 5), 22.01 (g) (n =
It was 5). From this result, it became clear that this drug markedly suppressed the weight loss of tumor-bearing mice. At this time, the ionized calcium in the whole blood of the control group was 2.06 mmol / l (n = 5) before administration, and increased to 2.50 mmol / l (n = 5) in 17 days. On the other hand, in the drug administration group, 2.04 mmol / l (n = 5) before administration
Was 1.65 mmol / l after 6 administrations.
Fell to.

From the above results, it became clear that the drug of the present invention brings about a life-prolonging effect by ameliorating tumor-associated syndromes such as rupture of homeostasis of body fluids and cachexia associated with malignant tumors. This fact indicates that this drug is useful as an ameliorating therapeutic agent for paraneoplastic syndrome.

Claims (11)

[Claims] 1. A compound of the general formula (I) (Wherein R ₁ represents an alkyl group having 1 to 10 carbon atoms which may be substituted with one or more hydroxyl groups, and R ₂ represents a hydrogen atom or a hydroxyl group) as an active ingredient. Paraneoplastic syndrome remedy. 2. The therapeutic agent for improving paraneoplastic syndrome according to claim 1, wherein R ₂ is a hydroxyl group. 3. A compound represented by the general formula (II): A compound represented by the formula (wherein R ₁ represents an alkyl group having 1 to 10 carbon atoms which may be substituted with one or more hydroxyl groups) as an active ingredient.
The therapeutic agent for improving paraneoplastic syndrome according to the description. 4. The therapeutic agent for amelioration of paraneoplastic syndrome according to claim 3, wherein R ₁ is an alkyl group having 1 to 10 carbon atoms substituted with one or more hydroxyl groups. 5. Formula (III): The therapeutic agent for amelioration of paraneoplastic syndrome according to claim 4, which comprises a compound represented by the formula (1) as an active ingredient. 6. The therapeutic agent for improving paraneoplastic syndrome according to claim 1, wherein the paraneoplastic syndrome is cachexia. 7. The therapeutic agent for improving paraneoplastic syndrome according to claim 2, wherein the paraneoplastic syndrome is cachexia. 8. The therapeutic agent for improving paraneoplastic syndrome according to claim 3, wherein the paraneoplastic syndrome is cachexia. 9. The agent for improving paraneoplastic syndrome according to claim 4, wherein the paraneoplastic syndrome is cachexia. 10. The therapeutic agent for improving paraneoplastic syndrome according to claim 5, wherein the paraneoplastic syndrome is cachexia. 11. A compound represented by the general formula (I): (Wherein R ₁ represents an alkyl group having 1 to 10 carbon atoms which may be substituted with one or more hydroxyl groups, and R ₂ represents a hydrogen atom or a hydroxyl group) as an active ingredient. A cachexia treatment agent.