JPH09169665A - Agent for treatment osteoporosis - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide the subject agent containing a specific active substance as an active component and exhibiting an action for promoting the formation of bone and an action for suppressing the lowering of bone density. SOLUTION: The objective agent contains a phosphodiesterase IV inhibiting substance, preferably a xanthine derivative expressed by the formula I [R<1> is a (substituted) 1-6C alkyl; R<2> is H or a lower alkyl; R<3> is a (substituted)lower alkyl; R<4> is H or a 3-7C cycloalkyl] or its pharmacologically allowable salt or a compound expressed by the formula II (R<5> and R<6> are each a lower alkyloxy or a 3-7C cycloalkyloxy; (n) is 0 or 1; X is methylene chain or NH) or its pharmacologically allowable salt, concretely 1,3-di-n-butyl-7-(2-oxopropyl) xanthine, etc., as an active component. The administration dose of the active component to the patient to be treated is preferably 10-1,000mg/day for oral administration and about 1-500mg/day for parenteral administration.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel use of a compound having phosphodiesterase IV (hereinafter referred to as PDEIV) inhibitory activity, which has hitherto been known to be useful as a therapeutic agent for obstructive respiratory disease, That is, the present invention provides a therapeutic agent for osteoporosis based on the bone formation promoting action and the bone density lowering inhibiting action.

[0002]

2. Description of the Related Art Many compounds having a PDEIV inhibitory action have been known so far. Among them, for example, Br.
J. Pharmacol., 97, 889-897 (1989).
Y.), Eur. J. Pharmacol., 267, 317-322.
Page (1994), Biochem. Pharmacol., 48, 12
19-1223 (1994), Biol. Pharm. Bul
l., 18: 431-434 (1995), Jpn. J.
Pharmacol., Vol. 69, pp. 75-82 (1995) and the like include the following general formula (I)

Embedded image (In the formula, R ¹ represents a hydrogen atom or a C ₁ -C ₆ alkyl group which may be substituted with a lower alkyloxy group or an acyl group, R ² represents a hydrogen atom or a lower alkyl group, and R ³ represents Represents a hydrogen atom or a lower alkyl group which may be substituted with an acyl group, and R ⁴ represents a hydrogen atom or C ₃ -C
₇ represents a cycloalkyl group. Xanthine derivative represented by
Ecology, 77, 309-316 (1982), Ne
Uropharmacology, Vol. 22, pp. 267-272 (1983)
, Biochem. J., 241, 535-541 (19).
1987) etc., the following general formula (II)

Embedded image (In the formula, R ⁵ and R ⁶ are the same or different and represent a lower alkyloxy group or a C ₃ -C ₇ cycloalkyloxy group, n represents an integer of 0 or 1, and X represents a methylene chain or —NH. A compound represented by the formula (-) is disclosed, and the description regarding the PDEIV inhibitory action is recognized in all of them. The main ones are summarized in Table 1.

[0003]

[Table 1]

[0004] Osteoporosis is a disease in which bone fracture and bone destruction occur without any sign in most cases due to abnormal reduction of bone mass. Osteoporosis is a disease that is attracting attention as a geriatric disease in the future, as it tends to increase in the elderly population in the future as the average age increases, especially in post-menopausal people, especially in postmenopausal women. . In normal bone,
While bone-forming osteoblasts and bone-destroying osteoclasts work in tandem, bone resorption (pelvic lysis) and bone formation are performed in a well-balanced manner, and there is a constant amount of bone with metabolic turnover. Is kept at.

However, especially after the middle age, this balance is disturbed, the amount of bone resorption physiologically exceeds the amount of bone formation, and when bone resorption is promoted, the bone mass decreases and the bone density becomes coarse. Fractures become more likely and osteoporosis develops. Therefore, it is expected that if bone resorption can be suppressed or inhibited, it will be useful for treatment of osteoporosis, while if it can promote bone formation, it will be useful for treatment of osteoporosis. Furthermore, it is expected that a drug having both the effects of suppressing bone resorption and promoting bone formation will be extremely useful as a therapeutic agent for osteoporosis.

From this point of view, until now, osteoporosis has been treated by treating female hormone (estrogen), calcitonin, active vitamin D ₃ , parathyroid hormone (PTH),
Bisphosphonate derivatives, ipriflavone, etc. have been clinically used.

The female hormone (estrogen) has both bone resorption inhibitory action and bone formation promoting action, and inhibits the progression of osteoporosis. However, in the long-term administration of this drug, in addition to gastrointestinal symptoms such as abdominal distension and nausea, the occurrence of breast cancer / endometrial cancer, endometrial bleeding / increased ligament / breast pain, etc. There is a possibility that serious side effects peculiar to it may occur, and side effects such as abnormal glucose metabolism and lipid metabolism, and venous thrombosis are also recognized. Therefore, there seems to be a problem with safety in long-term administration.

Calcitonin has a strong therapeutic effect because it binds to the calcitonin receptor on osteoclasts and inhibits bone resorption by osteoclasts. In addition, it is considered that an analgesic action is expressed in the central nervous system through interaction with other hormones, etc., and approval for pain improvement in osteoporosis has been obtained. However, since calcitonin is a peptide, it cannot be administered orally and must be injected intramuscularly twice a week. Intramuscular injection is particularly painful and it is not possible to receive continuous treatment for a long period of time. In addition, there is a risk of shock associated with injections, careful administration is required, and the frequency of side effects such as gastrointestinal symptoms such as nausea, vomiting, loss of appetite, and cardiovascular symptoms such as hot flushes and burning sensations. However, there are still problems such as high chemical resistance and chemical resistance.

Active vitamin D ₃ is believed to promote calcium absorption in the small intestine and calcium reabsorption in the kidney, improving the bone resorption / bone formation balance in bone. However, it also has the effect of differentiating from pre-osteoclasts to osteoclasts, which may adversely affect the treatment of osteoporosis. Further, due to its mechanism of action, it is known that if the dose is excessive, hypercalcemia is likely to occur, resulting in kidney damage and digestive organ damage due to calcification. Therefore, it is necessary to check the serum calcium concentration on a regular basis during treatment, which is very difficult to use clinically.

Parathyroid hormone (PTH) is a biological substance secreted from the parathyroid gland due to a decrease in blood calcium concentration, and is a single-chain peptide that has long been known to have an effect of increasing bone mass. Is. However, while this increases bone mass in intermittent administration, it causes a marked increase in bone resorption when continuously administered. According to recent studies on osteoporosis, osteoporosis is classified into high rotational osteoporosis in which bone resorption and bone formation are actively performed and low rotational osteoporosis in which bone resorption and bone formation are poor, based on bone biopsy. Has become clear. Above PTH
Has the effect of enhancing bone turnover and increasing bone mass, and is therefore considered to be applicable only to low-rotation osteoporosis.

Pyrophosphoric acid has been known as a substance having a calcification inhibiting action, and a bisphosphonate derivative in which oxygen is replaced by a substituted carbon has a calcification inhibiting action as well as a bone loss reducing action, Although it is expected as a therapeutic agent for osteoporosis, it has a problem that the half-life of bone concentration is extremely long and causes osteomalacia.

In addition to the above, there has been an attempt to apply vitamin K, which is said to have an action of activating a calcium K-dependent protein in bone produced from osteoblasts and suppressing calcium excretion, as a therapeutic agent for osteoporosis. Ipriflavone, which is a synthetic derivative of the active ingredient (flavonoid) of the plant Purple sardine palm (Alfalfa), has also been applied as a bone loss reducing agent. Ipriflavone directly suppressed the formation of osteoclasts and indirectly suppressed the activity of osteoclasts,
Further, by promoting the proliferation of osteoblasts, it exerts an effect of suppressing bone loss. Further, there are attempts to administer fluorine, vitamin D, calcium agents, etc., but they have not been effective means for fundamentally treating osteoporosis.

The inventors of the present invention have extensively studied various pharmacological actions of various compounds, and the above-mentioned general formulas (I) and (II), which are known to have a therapeutic effect on obstructive respiratory diseases, etc. It has been found that the PDEIV inhibitor represented by the above has a new effect of promoting bone formation and an effect of suppressing decrease in bone density. Such knowledge has never been reported until now.

[0014]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a drug having both excellent efficacy and safety in view of the current state of the therapeutic agent for osteoporosis. In particular, the present invention provides a compound which has both an action of promoting bone formation and an action of suppressing decrease in bone density and which is extremely useful as a therapeutic agent for osteoporosis. Moreover, since the compounds represented by the general formulas (I) and (II) according to the present invention have a therapeutic effect on obstructive respiratory diseases due to PDEIV inhibitory action, have they been clinically used for a long time? Alternatively, it is in the development stage, and its safety has already been confirmed.

[0015]

Means for Solving the Problems As a result of intensive studies on the pharmacological action of various compounds in order to solve the above problems, the present inventors have found that PDEIV represented by the general formulas (I) and (II) It was surprisingly found that the inhibitory active substance has a bone formation promoting action and a bone density lowering inhibiting action and is extremely useful as a therapeutic agent for osteoporosis. The present invention has been completed based on the above findings.

That is, the present invention provides a therapeutic agent for osteoporosis containing a PDEIV inhibitory active substance as an active ingredient.

According to a preferred embodiment of the present invention, PDEIV
The inhibitory active substance is the xanthine derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof, and the therapeutic agent for osteoporosis, and the PDEIV inhibitory active substance is the compound represented by the general formula (II) or The above-mentioned therapeutic agent for osteoporosis, which is a pharmacologically acceptable salt thereof, is provided. According to a further preferred embodiment of the present invention, the PDEIV inhibitory substance is 1,3-di-n-butyl-7- (2-oxopropyl) xanthine [general name: denbufylline], 1-n-butyl- 3-n-propylxanthine, 1- (2-ethoxyethyl) -3-n-propylxanthine, 3-isobutyl-1-methylxanthine, 4- [3- (cyclopentyloxy) -4-methoxyphenyl] -2- Pyrrolidinone [generic name: rolipram], 4- (3-n-butoxy-4-)
There is provided a therapeutic agent for osteoporosis, which is a compound selected from methoxybenzyl) -2-imidazolidone and a mixture thereof or a pharmacologically acceptable salt thereof.

[0018]

BEST MODE FOR CARRYING OUT THE INVENTION The therapeutic agent for osteoporosis according to the present invention comprises:
It can be clinically administered orally or parenterally, and is a PDEIV inhibitory substance, particularly a xanthine derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof, or the general formula (II). It is characterized by containing the compound shown or a pharmacologically acceptable salt thereof as an active ingredient. Examples of the pharmacologically acceptable salt of the compound according to the present invention include mineral acid salts such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid and phosphoric acid, or acetic acid,
Maleic acid, fumaric acid, citric acid, oxalic acid, malic acid, methanesulfonic acid, p-toluenesulfonic acid, mandelic acid, D-10-camphorsulfonic acid, L-10-camphorsulfonic acid, DL-10-camphorsulfone Acid, L-tartaric acid,
Examples include organic acid salts such as D-tartaric acid, DL-tartaric acid and succinic acid, inorganic alkali salts such as sodium, potassium, calcium and ammonium, or salts of organic bases such as ethanolamine, N, N-dialkylethanolamine and the like. You can

In the above general formulas (I) and (II) of the present invention, a lower alkyloxy group optionally substituted on the C ₁ -C ₆ alkyl group represented by R ¹ and R ⁵ and R ⁶ are represented. Examples of the lower alkyloxy group include: methoxy group, ethoxy group, n-propoxy group, isopropoxy group,
n-butoxy group, isobutoxy group, sec-butoxy group, tert
A butoxy group and the like, and C _{1 to} C _{6 represented} by R ^1.
As the alkyl group of, for example, a methyl group, an ethyl group,
n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group,
Examples of the lower alkyl group represented by R ² and R ³ include an isopentyl group, a neopentyl group and an n-hexyl group, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, Examples of the acyl group which may be substituted on the alkyl group represented by R ¹ and R ³ include an isobutyl group, a sec-butyl group and a tert-butyl group, and examples thereof include an acetyl group, a propionyl group, a butyryl group, Examples include pentanoyl group and hexanoyl group, R
^{As the} C ₃ -C ₇ cycloalkyl group represented by 4,
Examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group. Examples of the C _{3 to} C ₇ cycloalkyloxy group represented by R ⁵ and R ⁶ include a cyclopropyloxy group. , Cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group, cycloheptyloxy group and the like.

The above general formula (I) or (II) of the present invention
Among the compounds represented by, etc., the compound having an asymmetric carbon may have optical isomers, but the present invention also includes these optical isomers and mixtures thereof.

Specific examples of the compound represented by the above general formula (I) or (II) include the following compounds and pharmaceutically acceptable salts thereof. It is not limited to particular details. (1) 1,3-dimethylxanthine [generic name: theophylline] (2) 3-n-propylxanthine [generic name: enprophylline] (3) 1-methyl-3-n-propylxanthine (4) 3-n -Butyl-1-methylxanthine (5) 1-n-butyl-3-methylxanthine (6) 1-methyl-7- (2-oxopropyl) -3
-N-propylxanthine (7) 1,3-di-n-propylxanthine (8) 1-ethyl-3-n-propylxanthine (9) 1-n-butyl-3-n-propylxanthine (10) 1 , 3-di-n-butylxanthine (11) 3-ethyl-1-methylxanthine (12) 1,3-di-n-propylxanthine (13) 1-n-butyl-3-n-propylxanthine (14) ) 1-Methyl-3,7-di-n-propylxanthine (15) 1,7-Dimethyl-3-n-propylxanthine (16) 1,3-Di-n-butyl-7- (2-oxopropyl ) Xanthine [generic name: denbufylline] (17) 7-ethyl-1-methyl-3-n-propylxanthine (18) 7-n-butyl-1-methyl-3-n-propylxanthine (19) 1-n -Pentyl-3-n-propylxanthine (20) 1,3-di-n- Ropyl-8-cyclopentylxanthine (21) 1-n-hexyl-3-n-propylxanthine (22) 4- [3- (cyclopentyloxy) -4-methoxyphenyl] -2-pyrrolidinone [generic name: rolipram] ( 23) 4- (3-n-butoxy-4-methoxybenzyl) -2-imidazolidone

The xanthine derivative represented by the general formula (I) can be prepared, for example, by J. Med. Chem., Vol. 35, 403.
9-4044 (1992), J. Med. Chem., 36.
Vol., Pp. 1380-1386 (1993), Ber., 33.
Volume, 3035 (1900), Bull. Chem. Soc. Jap.
an, 46, 506 (1973), U.S. Pat. No. 34
22107, U.S. Pat. No. 4,289,776, JP-A-6
No. 2-178591, JP-A-1-190685, JP-A-2-233615, JP-A-3-41024, JP-A-3-72480, JP-A-3-167186, JP-A-3-220190, JP-A-3-220190. -163079, JP-A-3-218378 and the like, and the compound represented by the general formula (II) can be produced, for example, according to the method described in U.S. Pat. No. 4,193,926. can do.

The dosage form of the therapeutic agent for osteoporosis according to the present invention includes, for example, oral preparations such as powders, fine granules, granules, tablets, coated tablets and capsules, external preparations such as ointments and patches, and Injectable formulations are included. In the case of formulation, it can be produced by a conventional method using an ordinary formulation carrier.

That is, in order to produce an oral preparation, the compound of the present invention, an excipient, and, if necessary, a binder,
After adding disintegrant, lubricant, coloring agent, flavoring agent, etc.,
Powders, fine granules, granules, tablets, coated tablets, capsules, etc. are prepared by a conventional method.

Examples of the excipient include lactose, corn starch, sucrose, glucose, mannitol, sorbitol,
Crystalline cellulose, silicon dioxide, etc., as the binder,
For example, polyvinyl alcohol, polyvinyl ether,
Methyl cellulose, ethyl cellulose, gum arabic,
Tragacanth, gelatin, shellac, hydroxypropyl methylcellulose, hydroxypropyl cellulose,
Examples of disintegrating agents include polyvinylpyrrolidone, polypropylene glycol / polyoxyethylene block polymer, meglumine, and the like. For example, starch, agar, powdered gelatin, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextrin, pectin,
Examples of lubricants such as carboxymethyl cellulose calcium include magnesium stearate, talc,
Polyethylene glycol, silica, hydrogenated vegetable oil and the like can be added to pharmaceuticals as coloring agents, and as flavoring agents, for example, cocoa powder, peppermint, aroma powder, peppermint oil, dragon brain, cinnamon powder and the like are used. . These tablets and granules may be sugar-coated or may be appropriately coated if necessary.

When producing an injectable preparation, a pH adjusting agent, a solubilizing agent, an isotonicity adjusting agent and the like, and a solubilizing agent, a stabilizing agent and the like are added to the compound according to the present invention. It can be prepared by a conventional method.

The method for producing the external preparation is not particularly limited, and it can be produced by a conventional method. That is, as the base raw material used for formulation, various raw materials commonly used for pharmaceuticals, quasi drugs, cosmetics and the like can be used.

Specific examples of the base material used include animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, and Examples include raw materials such as polyhydric alcohols, water-soluble polymers, clay minerals, and purified water, and if necessary, pH regulators, antioxidants, chelating agents, antiseptic agents, colorants, fragrances, etc. Although it can be added, the base material for the external preparation according to the present invention is not limited to these. In addition, if necessary, other components having a differentiation-inducing action, blood flow promoters, bactericides, anti-inflammatory agents, cell activators, vitamins, amino acids, moisturizers, keratolytic agents, etc. may be added. .

The dose of this drug to a treated patient depends on the symptoms of the patient, but the amount of the active ingredient is usually 10 to 1000 mg / day for oral administration and 1 to 10 mg for parenteral administration in the case of an adult.
It is about 500 mg / day.

[0030]

EXAMPLES The usefulness of the compound of the present invention as a therapeutic agent for osteoporosis will be described in detail below by specifically exemplifying the osteogenesis promoting action and the bone density lowering inhibiting action of the compound of the present invention.

Test method Test substance Test compound 1: 3-isobutyl-1-methylxanthine Test compound 2: 1-n-butyl-3-n-propylxanthine Test compound 3: 1- (2-ethoxyethyl) -3- n-Propylxanthine Test compound 4: Denbufylline Test compound 5: Rolipram Test compound 6: 4- (3-n-Butoxy-4-methoxybenzyl) -2-imidazolidone Control drug: Zaprinast (PDEV inhibitor) Amrinone (PDE III inhibition) Agent) Milrinone (PDE III inhibitor) Salmon calcitonin Estradiol

Preparation of Test Solution, etc. In the in vitro experiment, the test substance was dissolved in dimethylsulfoxide (DMSO) and diluted with the culture medium before use. The final concentration of DMSO was 0.1% or less. In v
In the ivo experiment, the test substance was suspended or dissolved in 0.5% carboxymethylcellulose and orally administered at 0.5 ml per rat. Among the control drugs, estradiol was dissolved in olive oil, and 0.2 ml per rat was injected intramuscularly in the buttocks, and salmon calcitonin was dissolved in physiological saline, and 0.2 ml was subcutaneously injected per rat. The obtained test results were analyzed using Student's T test and Welch's T test.

Test Example 1: Bone formation promoting action Bone formation in an in vitro bone marrow cell culture system Test method Bone marrow cells were isolated from the femurs of Wistar rats (5 to 6 weeks old) and the cell density was 10 ⁶ / Plate in 12-well culture plate at cm ² , 10% fetal bovine serum, 60 μg / ml kanamycin, 10nM dexam
ethasone, 0.2mM ascorbic acid phosphate, β-glyce
It was cultured in a carbon dioxide gas incubator at 37 ° C in α-MEM supplemented with rophosphate. The test substance was added to the cells for 24 hours on the 3rd day of the culture, washed and removed, cultured for another 10 days, fixed with methanol, stained with Alizarine Red S, and the area of the calcification site was measured. . (Method: Kasugai et al.
Bone, Vol. 17, pp. 1 to 4 (1995), Ozawa, Kasugai, Biomaterials, Vol. 16, printing) Test results Calcified area was expressed as a percentage of the control (no test drug administration) group area (Table 2). ). All of the compounds of the present invention (test compounds 1 to 6) showed a significant and concentration-dependent calcification promoting action. In contrast, the PDE V inhibitor zaprinast was found to have a weak calcification promoting effect.
The E III inhibitors amrinone and milrinone had no calcification promoting effect.

[0034]

[Table 2]

Test Example 2: Bone density reduction inhibitory effect (Walker 2
56 / S Tumor-bearing rat model) Walker 256 / S Test method for the effect on the femur of tumor-bearing rats Walker 256 / S causes hypercalciuria, but does not cause hypercalcemia. PTHrP) is independent of PTHrP, but it is a rat breast cancer that reduces estrogen and progesterone secretion and induces osteoporosis-like pathology (Waki et al., Jpn. J. Cancer Res., Vol. 86,
470-476 (1995), Hiramatsu et al., The Pharmaceutical Society of Japan Hokuriku Branch 93rd Regular Meeting, December 1995). This tumor mass 1 mm ³ was subcutaneously transplanted into the back of 10 groups of 6-week-old and 7-week-old Wistar Imamichi female rats, the test substance was administered from the 1st day, and the femur was excised on the 14th day. After the measurement, it was subjected to the following tests. -The amount of bone mineral was measured by a double X-ray bone mineral amount measuring device (Aloka, DCS-600R).・ Bone was dried at 120 ° C for 6 hours, weighed, and after incineration at 800 ° C for 6 hours, the amount of calcium was determined by atomic absorption spectrometry (Hitachi Z 8100) and Fiske-Subarow method (Wako Inorgani).
C Phosphorus-TA test) to measure the amount of inorganic phosphorus. Test Results The compound of the present invention showed a bone mineral density lowering inhibitory effect comparable to salmon calcitonin and estradiol (Table 3). Further, the compound of the present invention suppressed not only the bone density of the femur but also the decrease in dry weight, Ca and inorganic phosphorus concentration (Table 4).

[0036]

[Table 3]

[0037]

[Table 4]

Test Example 3: Inhibitory effect on bone mineral density reduction (sciatic nerve resection rat model) Effect on femur bone density of sciatic nerve resection rat Test method: Bilateral sciatic nerves were cut from 1 group of 6-week-old female Wistar rats 1 group , (Experiment 1) After 1 week, the test substance was orally administered every other day for 3 weeks, or (Experiment 2) From 4 weeks, the test substance was orally administered every other day for 3 weeks. The bone was extracted and the bone mineral content was measured by a dual X-ray bone mineral content measuring device (Aloka, DCS-600R) and compared with the bone density of the sham operation group. Test Results The compound of the present invention was administered in a dose-dependent manner both in the administration group 1 week after the sciatic nerve resection and in the administration group 4 weeks after the sciatic nerve resection.
The decrease in bone density due to immobilization of the lower limbs was suppressed (Table 5).

[0039]

[Table 5]

Test Example 4 Bone Density Reduction Inhibitory Action (Ovariectomized Rat Model) Action on Thigh Bone Density of Ovariectomized Rats Test Method Bilateral ovariectomy was performed on 8 groups of 19-week-old female Wistar rats 15 From the time it was raised for a week and the bone density decreased enough,
After the oral administration of the test substance every other day for 8 weeks, the femur was removed and a double X-ray bone mineral content measuring device (Aloka, DC
The bone mineral density was measured by S-600R) and compared with the bone density of the sham operation group. It should be noted that the body weight difference between the experimental groups was prevented by adjusting the food intake over the entire experimental period. Test Results The compound of the present invention suppressed the decrease in bone density of the femur (Table 6).

[0041]

[Table 6]

[0042]

EFFECT OF THE INVENTION The PDEIV inhibitory substances represented by the general formulas (I) and (II) of the present invention are extremely useful as therapeutic agents for osteoporosis because they have an action of promoting bone formation and an action of suppressing bone density decrease. .

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 233/34 C07D 233/34 473/06 473/06 C12N 9/99 C12N 9/99

Claims (4)

[Claims] 1. A therapeutic agent for osteoporosis containing a phosphodiesterase IV inhibitory active substance as an active ingredient. 2. A phosphodiesterase IV inhibitory active substance has the following general formula (I): (In the formula, R ¹ represents a hydrogen atom or a C ₁ -C ₆ alkyl group which may be substituted with a lower alkyloxy group or an acyl group, R ² represents a hydrogen atom or a lower alkyl group, and R ³ represents Represents a hydrogen atom or a lower alkyl group which may be substituted with an acyl group, and R ⁴ represents a hydrogen atom or C ₃ -C
₇ represents a cycloalkyl group. ) Is a xanthine derivative or a pharmaceutically acceptable salt thereof.
The therapeutic agent for osteoporosis according to 1. 3. A phosphodiesterase IV inhibitory substance
Is represented by the following general formula (II):(Where R^FiveAnd R⁶Are the same or different and are lower alk
Roxy group or C_Three~ C ₇The cycloalkyloxy group of
, N is an integer of 0 or 1 and X is a methylene chain or
Represents an -NH- group. ) Compound or pharmacology thereof
Therapeutic salt according to claim 1, which is a pharmaceutically acceptable salt.
Agent. 4. A phosphodiesterase IV inhibitory active substance is 1,3-di-n-butyl-7- (2-oxopropyl) xanthine, 1-n-butyl-3-n-propylxanthine, 1- (2- Ethoxyethyl) -3-n-propylxanthine, 3-isobutyl-1-methylxanthine, 4
-[3- (Cyclopentyloxy) -4-methoxyphenyl] -2-pyrrolidinone, 4- (3-n-butoxy-4)
The therapeutic agent for osteoporosis according to claim 1, which is a compound selected from the group consisting of -methoxybenzyl) -2-imidazolidone and a mixture thereof, or a pharmacologically acceptable salt thereof.