JPH1135470A - Parathormone production promoter containing vitamin d3 derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a parathormone production promoter capable of being orally administered for hypoparathyroidism and cartilaginous metabolic disorder by formulating a specific compound having an antagonistic action as an active ingredient. SOLUTION: This parathormone production promoter contains an active vitamin D3 antagonist as an active ingredient. The active vitamin D3 antagonist used herein is e.g. a compound of the formula [(m) is 0-3; (n) is 0 or 1; X is 0, S or NH; R1 and R2 are each H or a 1-4C alkyl], especially preferably (23 R)-1α-hydroxy-27-nor-25-methylene vitamin D3 -26,23-lactone. The active ingredient is usually administered at a daily dose of 1-100 mg/person.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an active vitamin D
₍₃ ) A therapeutic agent based on a parathyroid hormone (hereinafter also referred to as "PTH") production promoting action containing an antagonist as an active ingredient. More specifically, the present invention relates to a therapeutic agent for, for example, hypoparathyroidism and cartilage metabolism disorder.

[0002]

2. Description of the Related Art PTH is a polypeptide consisting of 84 amino acids, and its main target organs include bone, cartilage and kidney. After binding to the receptor of the target cell, PTH promotes production of intracellular cyclic adenosine monophosphate (cAMP), phosphorylation of intracellular proteins, calcium influx into cells, stimulation of cell membrane phospholipid metabolic pathway, intracellular enzymes It is known to initiate various intracellular and extracellular cascades such as activation of lysosomal enzymes and secretion of lysosomal enzymes. The expression of the PTH gene is mainly active vitamin D ₃ are known to undergo suppression regulation by (Proceedings of National Academy of Sciences USA, 89,
8097, 1992).

It is known that various diseases occur when an abnormality occurs in the amount of PTH produced in a living body. One of them is idiopathic or postoperative hypoparathyroidism due to decreased production of PTH. As a therapeutic agent for this disease, the administration of PTH is an ideal treatment method, but a PTH preparation that can be administered orally has not been developed so far. Therefore, if a drug capable of promoting PTH production by oral administration or the like is developed, it will be useful as an ideal therapeutic agent for idiopathic or postoperative hypoparathyroidism.

[0004] Furthermore, PTH is used for the proliferation and differentiation of chondrocytes,
It is also known to have an effect on cartilage matrix synthesis. For example, it has an effect of promoting growth and matrix synthesis on growth plate chondrocytes (cellular and calcium,
6, 112-122, 1994), and a proteoglycan synthesis promoting action (Calcified Tissue International, 50, 61-66, 1992) and the like. Degradation of cartilage components due to degradation of cartilage cells, destruction of cartilage matrix, etc., is thought to cause various cartilage metabolic disorders, but PTH is considered to be a cartilage metabolic disorder. The lack of cartilage and the regenerating of degenerated cartilage, which are common in E. coli.

[0005] On the other hand, effects on osteoblasts have also been reported, including, for example, a growth-promoting effect (Endocrinology, 118, 2444-2449, 1986), IGF
Promoting collagen synthesis through I production (Journal of Clinical Investigation, 83,
60-65, 1989), and an osteogenesis-promoting action and an increase in bone mass in osteoporosis model animals (Journal of the Japanese Society for Bone Morphometry, 3, 55-62, 1993). These reports indicate that treatment with PTH can be an effective therapeutic agent for cartilage metabolic disorders and bone metabolic disorders, and clinical bone formation effects have been studied using intramuscular injection. . However, intramuscular injections have problems such as a short half-life and bone hyperplasia that may be associated with a transient increase in body concentration. Drugs that maintain the promotion of PTH production by oral administration or the like are not available. If present, more effective therapeutic effects can be expected.

Incidentally, (23S) -1α-hydroxy-27-nor-25-methylenevitamin D ₃ -26,2
3-lactone and (23R) -1α-hydroxy-2
7-nor-25-methylenevitamin D ₃ -26,23-
Lactone is one of the metabolites of active vitamin D ₃ l [alpha], 25-dihydroxyvitamin D ₃ -26,23-
It is a lactone derivative and can be synthesized by the method described in JP-A-8-13405. These compounds are active vitamin D ₃ l [alpha], 25-suppressing osteoclastogenesis-dihydroxyvitamin D ₃ induced is known (JP-A-8-13405). However, there is a report that vitamin D receptor is not present in osteoclasts (Journal Clinical Investigation, 77, 312-314, 1986) and a report that it is present (Bone, 18, 295-299, 199).
6) There is, by only suppressing a result of osteoclast formation can not be determined that there is the antagonist action against active vitamin D _3. In addition, JP-A-8-13405 does not disclose the effect of such compounds on PTH production.

[0007] Although it is difficult to directly quantify PTH in experimental animals, it is necessary to use as an index the amount of nephrogenic cAMP whose production is enhanced by the action of PTH on renal tubules. It is possible, and this indicator is usually used (all hypercalcemia, written by Kazunori Okano, Shinko Medical Publishing Co., 1996). Therefore, the present inventors consider that P
The study was advanced by evaluating the amount of TH production using the amount of nephrogenic cAMP as an index.

[0008]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to promote PTH production by a compound having an antagonistic effect on active vitamin D ₃ , for example, for oral hypoparathyroidism and cartilage metabolic disorders. The goal is to find a therapeutic agent that can be administered.

[0009]

The present inventors have found that as a result of research, (23S) -1α-hydroxy-27-nor-25
- methylene vitamin D ₃ -26,23- lactone, to restore the reduction in nephrogenic cAMP amount seen when overdose of active vitamin D ₃ to animals to normal levels, and in normal animals administered alone And nephrogenic cAM
They found that the amount of P was increased and found that PTH production could actually be promoted in vivo. The present inventors have further studied based on this finding, and have reached the present invention.

That is, the present invention is a parathyroid hormone production promoter containing an active vitamin D ₃ antagonist as an active ingredient. The present invention also provides active vitamin D
₃ It is a therapeutic agent for hypoparathyroidism containing an antagonist as an active ingredient. The present invention is further a therapeutic agent for cartilage metabolic disorder, which contains an active vitamin D ₃ antagonist as an active ingredient.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The active vitamin D ₃ antagonist suitably used in the present invention is, for example, a compound represented by the following general formula.

[0012]

Embedded image

[Wherein, m represents an integer of 0 to 3;
Or represents 1, and X represents O, S, or NH. R ₁
And R ₂ are each independently a hydrogen atom or C ₁ -C ₄
Represents an alkyl group. The notation --- represents a single bond or a double bond. However, there is no double bond at two places at the same time. Among them, particularly, (23S) -1α-hydroxy-27-nor-25-methylenevitamin D ₃ -26,
23-lactone and (23R) -1α-hydroxy-
27-nor-25-methylenevitamin D ₃ -26,23
-Lactones are preferred, of which the former is preferred. These compounds can be synthesized by the method described in JP-A-8-13405.

On the other hand, hypoparathyroidism includes, for example, idiopathic or postoperative hypoparathyroidism due to decreased PTH production. The cartilage metabolic disorder disease includes, for example, a disease in which cartilage components are degraded due to reduction or destruction of the synthesizing ability of collagen, proteoglycan and the like in chondrocytes or matrix, and cartilage is reduced. Arthropathy, rheumatoid arthritis, rheumatic fever and the like.

A preparation containing the above compound as an active ingredient can be used as a therapeutic agent for hypoparathyroidism and cartilage metabolic disorders based on the PTH production promoting action. The therapeutic agent of the present invention comprises, for example, a vitamin D ₃ antagonist as an active ingredient, and an oral or injection preparation such as a soft capsule, a hard capsule, a tablet, or a syrup using a suitable excipient in a known manner. Thus, it can be used as a therapeutic agent for hypoparathyroidism and cartilage metabolic disorder.

The excipients for liquid or parenteral preparations used in the present invention include, for example, vegetable oil, mineral oil,
Examples include white petrolatum, branched chain fats or oils, high molecular weight alcohols, and the like. Of these, vegetable oils such as cottonseed oil, corn oil, coconut oil, and almond oil, among which triglycerides of medium-chain fatty acids are preferred.

Examples of the excipient of the solid preparation include cellulose derivatives such as crystalline cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and methyl cellulose, polyvinylpyrrolidone, dextrin, cyclodextrin, casein, lactose, mannitol, gelatin and the like. preferable. There is no particular limitation on these amounts, for example, the active ingredient in the therapeutic agent is
It is used in an amount of 4 to 0.2% by weight, preferably 0.0001 to 0.1% by weight.

The dose of the active ingredient is 0.1 to 1000 mg.
/ Day / person, usually about 1 to 100 mg / day / person,
The frequency of administration is usually 1 to 3 times / day, and it is preferable to prepare a preparation so as to satisfy such conditions.

[0019]

【Example】

Example 1 PT by administration of 1α, 25-dihydroxyvitamin D ₃
(23S) -1α-hydroxy-2 against reduced H production
7-nor-25-methylenevitamin D ₃ -26,23-
Action of lactone (1) Mice were purchased from Charles River Japan 6
One week old male ICR lines were used. Feed for animal breeding (MF, manufactured by Oriental Yeast Co., Ltd.) and drinking water (well water treated with 0.4% ± 0.2 ppm of hypochlorite) were freely taken throughout the experiment. The number of animals used was 5 per group. The animals were housed in a polycarbonate breeding gauge for each administration group and kept at a temperature of 23 ± 1 ° C. and a humidity of 55 ± 10%.

(2) As shown in Table 1, the solvent (0.1% Triton X-100) was added to the negative control group (Group 1).
For one week, the positive control group (Group 2) was administered 0.5 mg / kg / day of 1α, 25-dihydroxyvitamin D ₃ for two weeks.

(3) For the vitamin D ₃ antagonist administration group (groups 3 to 5), 1α, 25-
After administration of 0.5 mg / kg / day of dihydroxyvitamin D ₃ , the following week, 1α, 25-dihydroxyvitamin D ₃ and (23S) -1α-hydroxy-27-nor-25-methylenevitamin D ₃ -26 , 23-lactone were combined with 0.5, 5, and 50 mg / kg / day. The administration route was oral administration, and the administration volume was 10 mL / kg.

(4) Approximately 24 hours after the final administration, blood was collected from the heart to obtain serum, and the amount of cAMP and creatinine in the serum was measured. At the same time, the amount of cAMP and the amount of creatinine were measured for urine collected from the bladder. To measure the amount of creatinine, use Hitachi 707
A measurement kit (cAMP enzyme immunoassay (EIA) system) manufactured by Amersham was used to measure the amount of cAMP using a type 0 automatic analyzer.

(5) The amount of nephrogenic cAMP was calculated according to the following equation. (Nephrogenic cAMP amount) = (Urine cAMP excretion amount)-(Serum cAMP amount) Here, the urinary cAMP excretion amount used was a value calculated according to the following equation. (Urine cAMP excretion) = (Urine cAMP) × (Serum creatinine) ÷ (Urine creatinine)

(6) The results are shown in Table 1.

[0025]

[Table 1]

According to this, it can be seen that administration of 1α, 25-dihydroxyvitamin D ₃ reduces the amount of nephrogenic cAMP to about half that of the negative control group.
This decrease is considered to be the result of suppression of PTH gene expression by 1α, 25-dihydroxyvitamin D ₃ . On the other hand, in the group in which 1α, 25-dihydroxyvitamin D ₃ and (23S) -1α-hydroxy-27-nor-25-methylenevitamin D ₃ -26,23-lactone were used in combination, the amount of nephrogenic cAMP recovered. Recognized, (23
S) -1α-hydroxy-27-nor-25-methylenevitamin D ₃ -26,23-lactone in 5 or 50
In the group administered at mg / kg / day, the level almost recovered to the level of the negative control group. This recovery is due to suppression of PTH gene expression by 1α, 25-dihydroxyvitamin D _3, which is an active vitamin D ₃ antagonist (23S) -1.
This is considered to be the result of release by α-hydroxy-27-nor-25-methylenevitamin D ₃ -26,23-lactone.

[Example 2] (23S) -1α-hydroxy-2 in normal mice
7-nor-25-methylenevitamin D ₃ -26,23,
-Effect of increasing the amount of nephrogenic cAMP by lactone administration (1) The animals used, breeding conditions, etc. were carried out according to the same procedures as in Example 1.

(2) As shown in Table 2, the solvent (0.1% Triton X-100) was added to the negative control group (Group 1).
Administered for a week. For the vitamin D ₃ antagonist-administered group (Groups 2 to 4), after the vehicle was administered for the first week, (23S) -1α-hydroxy-27 was administered for the next week.
- was administered nor-25-methylene vitamin D ₃ -26,23- lactones 0.5,5,50mg / kg / day.
The administration route was oral administration, and the administration volume was 10 mL / kg.

(3) The amounts of cAMP and creatinine in serum and urine were measured by the same procedure as in Example 1, and the amount of nephrogenic cAMP was calculated.

(4) Table 2 shows the results.

[0031]

[Table 2]

According to this, (23)
S) -1α-hydroxy-27-nor-25-methylenevitamin D ₃ -26,23-lactone 50 mg / kg
/ Day, an increase in nephrogenic cAMP was observed. This increase is due to endogenous 1α, 25 in normal mice.
This is considered to be a result of the suppression of PTH gene expression by dihydroxyvitamin D ₃ being released, and an increase in PTH production.

(5) From the results of Examples 1 and 2, the active vitamin D ₃ antagonist (23)
S) -1α-Hydroxy-27-nor-25-methylenevitamin D ₃ -26,23-lactone, in vivo, probably by releasing the action of inhibiting 1α, 25-dihydroxyvitamin D ₃ expression of the PTH gene. It is thought that PTH production can be promoted. Furthermore, this indicates that it can be used as a therapeutic agent for, for example, a disease of hypoparathyroidism and a disorder of cartilage metabolism based on the PTH production promoting action.

[0034]

The (23S) -1α- provided by the present invention.
Hydroxy-27-nor-25-methylenevitamin D ₃
-26,23, - active vitamin D ₃ antagonists, including lactones, PTH production promoter, hypoparathyroidism therapeutic agent, or used as a therapeutic agent for cartilage metabolism diseases.

Claims (5)

[Claims] 1. A parathyroid hormone production promoter comprising an active vitamin D ₃ antagonist as an active ingredient. 2. A therapeutic agent for hypoparathyroidism, comprising an active vitamin D ₃ antagonist as an active ingredient. 3. A therapeutic agent for cartilage metabolic disorders comprising an active vitamin D ₃ antagonist as an active ingredient. 4. The parathyroid hormone production promoter according to claim 1, wherein the active vitamin D ₃ antagonist is a compound represented by the following general formula, or the therapeutic agent according to claim 2 or 3. Embedded image [Wherein, m represents an integer of 0 to 3, n represents 0 or 1, and X represents O, S, or NH. R ₁ and R ₂ each independently represent a hydrogen atom or a C ₁ -C ₄ alkyl group. ] 5. The parathyroid hormone production promoter according to claim 1, wherein the active vitamin D ₃ antagonist is (23S) -1α-hydroxy-27-nor-25-methylenevitamin D ₃ -26,23-lactone. Or the therapeutic agent according to claim 2 or 3.