CN1163105A - Therapy and prevention for esteoporosis - Google Patents

Abstract

Compounds of formula (I): where R1, R2, R4 and R5 are hydrogen or alkyl and R3 is hydrogen, alkyl or various organic groups, are effective against osteoporosis at doses at which they also effectively control diabetes.

Description

Osteoporotic treatment and give anti-

The present invention relates to a series of known tetrahydrothiazole derivates in osteoporotic treatment with give new purposes in anti-, particularly to also suffer from simultaneously diabetes or prediabetes or with the patient of diabetes diseases related.

Usually observe osteoporosis in aging patient, its quantity increases, especially in postmenopausal women.The quantity of diabetic also increases in recent years.Thereby the quantity of suffering from the patient of osteoporosis and diabetes also demonstrates sizable growth.As a result, osteoporosis, especially in diabetic, treatment and give and anti-ly become more and more important now.

Though, still do not know whether there is direct cause effect relation between the diabetes of some type and the osteoporosis, the osteoporotic reason of diabetic has been proposed some mechanism, be exemplified below:

Because causing CaE, the infiltration polyuria that hyperglycemia is brought out increases;

Because the vitamin D Metabolic disorder causes that kidney calcium heavily absorbs reduction;

The calcium that absorbs from digestive tract reduces;

Owing to chronic reduction magnesium with because the parathyroid hormone malfunction causes the bone metabolism reduction;

Osteogenesis reduces, or insulin action lacks.

Yet, cause that the osteoporotic reason relevant with diabetes is definite as yet, therefore effectively treat and give anti-method and do not find out as yet.

Known many tetrahydrothiazole derivates are used for the treatment of and give anti-diabetes.Such examples of compounds is disclosed in EP678511, EP676398, and EP590793, EP543662, EP549366, EP549365 is among EP708098 and the US4687777.Wherein, believe it is those disclosed among the EP676398 near the chemical compound of The compounds of this invention on the structure.Some prior art documents propose to can be used for treatment and/or give preventing bone rarefaction and diabetes at this disclosed chemical compound.Yet a nearest report [J.Bone﹠amp; Mineral Research, 10 (1), S361 (1995) ,] title is the summary of the article of " effect of thiazolidinedione on rat bone turnover ", by works such as C.Jennermann] when proposing to reach far away treatment and/or giving preventing bone rarefaction, these tetrahydrothiazole derivates, Pioglitazone particularly, one of commercial first-selected person is as reducing determined by bone mineral density (" BMD "), actually cause bone loss, thereby increase osteoporosis.

We have now found that these prior art chemical compounds can be used for treating osteoporosis and diabetes the two, though be not simultaneously because treatment diabetes and osteoporotic the acting under the various dose of treatment show.Particularly, the osteoporotic effective dose of above-mentioned prior art compounds for treating is starkly lower than the required dosage of treatment diabetes.In fact, these prior art chemical compounds cause that bone mineral density descends under the dosage of effective treatment diabetes.Under the osteoporotic dosage of effective treatment, these chemical compounds are being invalid aspect the treatment diabetes, or only part is effective.Because, as mentioned above, diabetes and osteoporosis are found on one's body through the same patient that is everlasting, therefore the doctor must select to use these medicines or treatment diabetes and not treat osteoporosis (also often emitting danger of osteoporosis deterioration) or use these Drug therapy osteoporosises, but is not enough to treat diabetes.In fact, this means any disease that to treat the patient who suffers from osteoporosis and two kinds of diseases of diabetes with these medicines.

Yet, now our the known tetrahydrothiazole derivates that had been surprised to find that some limited type already can be used for treatment and give preventing bone rarefaction and diabetes or prediabetes or with the diabetes diseases associated the two, and find tetrahydrothiazole derivates with this limited type, in treatment dosage in full force and effect during diabetes, they also can effectively treat osteoporosis.

Used chemical compound is that Japan Patent is openly applied for clear 60-51189 among the present invention, among US4572912 and the EP139421 in the disclosed chemical compound certain some, they have been suggested and have been used for the treatment of and give anti-diabetes in these documents, but not mentionedly can be used for the treatment of and give preventing bone rarefaction.

We now have found that a series of tetrahydrothiazole derivates, and they in the same time, can be used as the medicine of treatment osteoporosis and diabetes to same patient.

Like this, the invention provides thiazolidine compound and preparing the purposes for the treatment of and giving in the preventing bone rarefaction medicine, wherein said thiazolidine compound is formula (I) chemical compound or its pharmaceutically acceptable salt: Wherein: R ¹And R ²Be same to each other or different to each other and respectively represent hydrogen atom or have the alkyl of 1 to 5 carbon atom; R ³The expression hydrogen atom, aliphatic acyl with 1 to 6 carbon atom, cycloalkane partly has the carbonyl naphthene of 5 to 7 carbon atoms, benzoyl, the naphthoyl base, benzoyl or naphthoyl base that at least one α substituent group of being defined has below replaced, the heterocyclic acyl that has 1 to 3 nitrogen-atoms and/or oxygen atom and/or heteroatomic 4 to 7 annular atomses of sulphur atom at heterocyclic moiety, phenylacetyl group, hydrocinnamoyl, by phenylacetyl group or the hydrocinnamoyl that at least one halogenic substituent has replaced, cinnamoyl partly has the alkoxy carbonyl group or the benzyloxycarbonyl group of 1 to 6 carbon atom at alkoxyl; R ⁴And R ⁵Be same to each other or different to each other and respectively represent hydrogen atom, have the alkyl of 1 to 5 carbon atom or have the alkoxyl of 1 to 5 carbon atom, or R ⁴And R ⁵Expression has the alkylenedioxy group of 1 to 4 carbon atom together; N is 1,2 or 3; Y and Z are same to each other or different to each other, and each represents oxygen atom or imino group; Be selected from substituents alpha: have the alkyl of 1 to 4 carbon atom, have the alkoxyl of 1 to 4 carbon atom, halogen atom, hydroxyl, amino has the alkyl amino of 1 to 4 carbon atom, has the dialkyl amido of 1 to 4 carbon atom and nitro at each moieties.

In the chemical compound of the present invention, R ¹When expression had the alkyl of 1 to 5 carbon atom, this was the straight or branched alkyl with 1 to 5 carbon atom, and example comprises methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group and isopentyl, wherein methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group and amyl group are preferred.Wherein, the alkyl with 1 to 4 carbon atom more preferably, methyl is most preferred.

R wherein ²And R ⁵Expression has the alkyl of 1 to 5 carbon atom, and this can be the straight or branched alkyl with 1 to 5 carbon atom, and example comprises methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, amyl group and isopentyl, methyl wherein, ethyl, propyl group, isopropyl, butyl, isobutyl group and amyl group are preferred.Wherein, the alkyl with 1 to 3 carbon atom more preferably, methyl is most preferably.

R wherein ³The expression aliphatic acyl, this can be the straight or branched base with 1 to 6 carbon atom, preferably has the alkanoyl of 1 to 6 carbon atom; formoxyl for example, acetyl group, propiono; bytyry, isobutyryl, valeryl; isovaleryl, valeryl or caproyl, wherein formoxyl; acetyl group, propiono, bytyry; isobutyryl, valeryl and caproyl are preferred.Those aliphatic acyls, particularly alkanoyl with 1 to 4 carbon atom are preferred, and acetyl group is most preferred.

R wherein ³The expression aromatic acyl group, this is benzoyl or naphthoyl base, wherein aromatic ring can be unsubstituted, or is replaced by at least one above-mentioned definition and following substituents alpha of giving an example.The example of such substituents alpha comprises:

Alkyl with 1 to 4 carbon atom, it can be the straight or branched group, for example methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl and the tert-butyl group, wherein our preferable methyl and tert-butyl group;

Alkoxyl with 1 to 4 carbon atom, it can be the straight or branched group, methoxyl group for example, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy, wherein our preferred methoxyl group; Halogen atom, for example fluorine, chlorine, bromine and iodine atom, wherein our preferred fluorine atom and chlorine atom;

Hydroxyl;

Amino;

Alkyl amino with 1 to 4 carbon atom, it can be the straight or branched base, methylamino for example, ethylamino, third amino, isopropylamino, fourth amino, isobutyl amino, the amino and uncle's fourth amino of Zhong Ding, wherein our preferred methylamino;

The dialkyl amido that has 1 to 4 carbon atom at each moieties, it can be the straight or branched base, dimethylamino for example, diethylamino, dipropyl amino, diisopropylaminoethyl, dibutylamino, diisobutyl amino, two sec-butyl amino, di-t-butyl amino, N-methyl-N-ethylamino, N-methyl-N-propyl group amino, N-methyl-N-isopropyl propyl group amino, N-methyl-N-butyl amino, N-methyl-N-isopropyl butyl amino, N-methyl-N-sec-butyl amino, N-methyl-N-tert-butyl group amino, N-ethyl-N-propyl group amino, N-ethyl-N-isopropyl amino, N-ethyl-N-butyl amino, N-ethyl-N-isobutylamino, N-ethyl-N-sec-butyl amino, N-ethyl-N-tert-butyl group amino, N-propyl group-N-isopropyl amino, N-propyl group-N-butyl amino, N-propyl group-N-isobutylamino, N-propyl group-N-sec-butyl amino, N-propyl group-N-tert-butyl group amino, N-isopropyl-N-butyl amino, N-isopropyl-N-isobutylamino, N-isopropyl-N-sec-butyl amino, N-isopropyl-N-tert-butyl group amino, N-butyl-N-isobutylamino, N-butyl-N-sec-butyl amino, N-butyl-N-tert-butyl group amino, N-isobutyl group-N-sec-butyl amino, the amino and N-sec-butyl-N-tert-butyl group amino of the N-isobutyl group-N-tert-butyl group, wherein our preferred dimethylamino; With

Nitro.

R wherein ³Benzoyl or naphthoyl base that expression has replaced, there is no particular limitation to substituent number at this, except position (7 of 5 of benzoyl situations or the naphthoyl base situations) number that for example may may be replaced with suitably influenced by sterically hindered.Yet, our preferred 1 to 3 substituent group usually.More than a substituent situation, these substituent groups each other can be identical or different.

The example with unsubstituted benzoyl or naphthoyl base of this replacement comprises benzoyl; the 4-nitro benzoyl; the 3-fluoro benzoyl, 2-chlorobenzene formacyl, 3; 4-dichloro-benzoyl base; the 4-amino benzoyl, 3-dimethylamino benzoyl, 2-anisoyl; 3,5-di-t-butyl-4-hydroxy benzoyl and 1-and 2-naphthoyl.Our preferred unsubstituted benzoyl and 1-naphthoyl, most preferably benzoyl wherein.

R wherein ³The representative ring alkyl-carbonyl, it has 5 to 7 carbon atoms in naphthenic ring, and the total number of carbon atoms is 6 to 8 in whole group like this.This examples of groups comprises the Pentamethylene. carbonyl, cyclohexane extraction carbonyl and cycloheptane carbonyl, and wherein the cyclohexane extraction carbonyl is preferred.

R wherein ³The expression heterocyclic acyl, this is the group that a kind of heterocyclic radical links to each other with carbonyl.Heterocyclic radical partly has 4 to 7 annular atomses, more preferably 5 or 6 annular atomses, and wherein 1 to 3, more preferably 1 or 2, most preferably 1 is nitrogen and/or oxygen and/or sulfur heteroatom.When 3 hetero atoms are arranged in heterocyclic radical, preferably all be nitrogen-atoms or one or two be nitrogen-atoms and correspondingly two or one be oxygen and/or sulphur atom.Heterocyclic radical preferably fragrance.The example of preferred heterocyclic acyl comprises furoyl (more preferably 2-furoyl), thenoyl (more preferably 3-thenoyl), 3-pyridine carbonyl (nicotinoyl) and 4-pyridine carbonyl (different nicotinoyl) base.

R wherein ³When expression phenyl acetyl or phenyl propiono; it has been substituted; preferably on phenyl, replaced by at least one halogenic substituent; halogenic substituent can be a fluorine; chlorine, the bromine or iodine atom can have 1 to 5 such halogenic substituent; preferred 1 to 3 halogenic substituent, more preferably 1 halogenic substituent.This examples of groups comprises the rubigan acetyl group; to the fluorophenyl acetyl group, to the bromophenyl acetyl group, to the iodophenyl acetyl group; the Chloro-O-Phenyl acetyl group; adjacent fluorophenyl acetyl group, o-bromophenyl acetyl group, adjacent iodophenyl acetyl group; the m-chloro phenyl acetyl; between the fluorophenyl acetyl group, a bromophenyl acetyl group, an iodophenyl acetyl group; 2; 4-Dichlorobenzene base acetyl group, 2,4 difluorobenzene base acetyl group; 2; 4-dibromo phenyl acetyl group, 2,4-diiodo-phenyl acetyl; 3-(rubigan) propiono; 3-(to fluorophenyl) propiono, 3-(to bromophenyl) propiono, 3-(to iodophenyl) propiono; 3 (Chloro-O-Phenyl) propiono; 3-(adjacent fluorophenyl) propiono, 3-(o-bromophenyl) propiono, 3-(adjacent iodophenyl) propiono; 3-(chlorphenyl) propiono; 3-(fluorophenyl) propiono, 3-(bromophenyl) propiono, 3-(iodophenyl) propiono; 3-(2; the 4-Dichlorobenzene base) propiono, 3-(2,4 difluorobenzene base) propiono; 3-(2; the 4-dibromo phenyl) propiono and 3-(2,4-diiodo-phenyl) propiono, wherein the rubigan acetyl group is most preferred.

R wherein ³The expression alkoxy carbonyl group, this can be partly to have 1 to 6 carbon atom at alkoxyl promptly to have the straight or branched alkoxy carbonyl group of 2 to 7 carbon atoms altogether, methoxycarbonyl group for example, carbethoxyl group, the third oxygen carbonyl, the different third oxygen carbonyl, butoxy carbonyl, isobutyl boc, secondary butoxy carbonyl, tertbutyloxycarbonyl, penta oxygen carbonyl and own oxygen carbonyl, wherein we preferably have those alkoxy carbonyl groups of 2 to 4 carbon atoms and carbethoxyl group most preferably.

R wherein ⁴The expression alkyl, this is the straight or branched alkyl with 1 to 5 carbon atom, methyl for example, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group and amyl group, wherein we preferably have those alkyl of 1 to 4 carbon atom, the more preferably methyl or the tert-butyl group, most preferable.

R wherein ⁴Or R ⁵The expression alkoxyl, this can be the straight or branched alkoxyl with 1 to 5 carbon atom, methoxyl group for example, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, tert-butoxy and amoxy, those alkoxyls that wherein preferably have 1 to 4 carbon atom, more preferably methoxyl group or tert-butoxy, most preferably methoxyl group.

R wherein ⁴And R ⁵Common expression alkylenedioxy group, it has 1 to 4 carbon atom, and example comprises methylene dioxy base, ethylidene dioxy base, propylidene dioxy base, trimethylene dioxy base and tetramethylene dioxy base, wherein methylene dioxy base and ethylidene dioxy base are preferred.

N is 1,2 or 3, but preferred 1.

Y and Z are same to each other or different to each other, and each represents oxygen atom or imino group, the preferred oxygen atom; Yet preferably the two all is an oxygen atom.

Preferred compound of the present invention is those formulas (Ia) chemical compound and its pharmaceutically acceptable salt:

Wherein: R ¹, R ², R ⁴And R ⁵Be same to each other or different to each other, each is represented hydrogen atom or has the alkyl of 1 to 5 carbon atom; And R ³The expression hydrogen atom has the aliphatic acyl of 1 to 6 carbon atom, benzoyl, and the naphthoyl base by at least one benzoyl that substituents alpha replaced that defines below or naphthoyl base, or partly has the alkoxy carbonyl group of 1 to 6 carbon atom at alkoxyl; Substituents alpha is selected from the alkyl with 1 to 4 carbon atom, has the alkoxyl of 1 to 4 carbon atom, halogen atom, and hydroxyl, amino has the alkyl amino of 1 to 4 carbon atom, has the dialkyl amido of 1 to 4 carbon atom and nitro at each moieties.

The preferred several groups of chemical compounds of the present invention are those chemical compounds and its pharmaceutically acceptable salt and esters of formula (I) or formula (Ia), wherein: (A) R ¹Expression has the alkyl of 1 to 4 carbon atom.(B) R ²Expression has the alkyl of 1 to 3 carbon atom.(C) R ³The expression hydrogen atom has the aliphatic acyl of 1 to 4 carbon atom, unsubstituted benzoyl or naphthoyl base, or have the alkoxy carbonyl group of 2 to 4 carbon atoms.(D) R ⁴Expression has the alkyl of 1 to 4 carbon atom.(E) R ⁵Expression hydrogen atom or have the alkyl of 1 to 3 carbon atom.

Particularly, our preferred those formulas (I) and formula (Ia) chemical compound, wherein R in above-claimed cpd ¹Such as in top (A) definition, R ²Such as in top (B) definition, R ³Such as in top (C) definition, R ⁴Such as in top (D) definition, R ⁵Such as in top (E) definition.

The preferred several groups of chemical compounds of the present invention are those chemical compounds and its pharmaceutically acceptable salts of formula (I) and formula (Ia), wherein: (F) R ¹Expression has the alkyl of 1 to 4 carbon atom.(G) R ²Expression hydrogen atom or have the alkyl of 1 to 3 carbon atom.(H) R ³Expression hydrogen atom, acetyl group, benzoyl or carbethoxyl group.(I) R ⁴Expression has the alkyl of 1 to 4 carbon atom.(J) R ⁵Expression hydrogen atom or have the alkyl of 1 to 3 carbon atom.

Particularly, our preferred those formulas (I) and formula (Ia) chemical compound, wherein R in above-claimed cpd ¹Such as in above-mentioned (F) definition, R ²Such as in above-mentioned (G) definition, R ³Such as in above-mentioned (H) definition, R ⁴Such as in above-mentioned (I) definition, R ⁵Such as in above-mentioned (J) definition.

The most preferred several groups of chemical compounds of the present invention are those formulas (I) and formula (Ia) chemical compound and its pharmaceutically acceptable salt, wherein: (K) R ¹The expression methyl.(L) R ⁴Expression hydrogen atom or methyl.(M) R ³Expression hydrogen atom, acetyl group or carbethoxyl group.(N) R ⁴The expression methyl or the tert-butyl group.(O) R ⁵Expression hydrogen atom or methyl.

Especially, our preferred those formulas (I) and formula (Ia) chemical compound, wherein R in above-claimed cpd ¹Such as in above-mentioned (K) definition, R ²Such as in above-mentioned (L) definition, R ³Such as in above-mentioned (M) definition, R ⁴Such as in above-mentioned (N) definition, R ⁵Such as in above-mentioned (O) definition.

When The compounds of this invention contained at least one base in its molecule, they can form acid-addition salts like this.The example of this acid-addition salts comprises: with mineral acid halogen acids (for example Fluohydric acid., hydrobromic acid, hydroiodic acid or hydrochloric acid) particularly, nitric acid, perchloric acid, carbonic acid, the salt that sulphuric acid or phosphoric acid generate; With low alkyl group sulfonic acid, methanesulfonic acid for example, the salt that trifluoromethanesulfonic acid or ethylsulfonic acid generate; With aryl sulfonic acid, the salt that generates of benzenesulfonic acid or p-methyl benzenesulfonic acid for example; With organic carboxyl acid, acetic acid for example, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, the salt that gluconic acid or citric acid generate; The salt that generates with aminoacid for example with glutamic acid or salt that day the radon propylhomoserin generates.This acid-addition salts can easily prepare with conventional method.

The compounds of this invention also can with cation for example metal form salt.The example of these salt comprises: with alkali metal, and the salt that generates of sodium, potassium or lithium for example; With alkaline-earth metal, the salt that generates of barium, calcium for example; With other metal, the salt that generates of magnesium or aluminum for example; Ammonium salt; Organic alkali salt, for example with methylamine, dimethyl amine, triethylamine, diisopropylamine, the salt that cyclohexylamine or hexanamine generate; With alkali type amino acid, the salt that generates of lysine or arginine for example.These salt also can easily prepare with conventional method.

The compounds of this invention can various isomeric forms exist.

Like this, carbon atom on 2 on benzodihydropyran ring and the carbon atom on 5 on Thiazolidine ring the two all be asymmetric carbon atom.In formula (I) with (Ia) in each chemical compound of chemical compound, because the stereoisomer that these asymmetric carbon atoms form and etc. mole and not equimolar mixture all only represent by a kind of formula, thereby, the scope of the invention is topped these independent isomers and all mixture thereof.

In formula (I) chemical compound, wherein Y and Z the two all represent imino group and wherein Y and Z the two all represent oxygen atom and wherein can multiple tautomeric forms exist when expression oxygen atom among Y and the Z and another expression imino group, as openly applying for clear 60-51189 at Japan Patent, US4572912, illustrated among the EP139421.

In formula (I) with (Ia) in each chemical compound, its tautomer and wait mole and molar mixture such as non-is only represented by a formula entirely, thereby, topped all these tautomers of scope of the present invention and its whole mixture.

The compounds of this invention also can form solvate (for example hydrate), and the present invention comprises all these solvates.

The present invention is in addition also topped, and all are referred to as the chemical compound of " prodrug ", and variation can be translated into any formula (I) compound or its salt through internal metabolism for its.

The special example of formula (I) chemical compound is those formulas (Ia) chemical compounds: R wherein ¹, R ², R ³, R ⁴And R ⁵Such as in the following table 1 definition.Use following abbreviation in the table:

AC: acetyl group,

IBu: isobutyl group,

TBu: the tert-butyl group,

Byr: bytyry,

Bz: benzoyl,

Etc: carbethoxyl group,

Et: ethyl,

Me: methyl,

Pn: amyl group.

Table 1

Compound N o.	????R 1	????R 2	????R 3	????R 4	????R 5
						????1	????Me	????Me	????H	????Me	????Me
????2	????H	????Me	????H	????Me	????Me
						????3	????Me	????H	????H	????H	????H
????4	????Me	????H	????H	????tBu	????H
						????5	????Et	????Me	????H	????Me	????Me
????6	????iBu	????Me	????H	????Me	????Me
						????7	????Pn	????Me	????H	????Me	????Me
????8	????Me	????Me	????Ac	????Me	????Me
						????9	????Me	????Me	????Bz	????Me	????Me
????10	????Me	????Me	????Etc	????Me	????Me
						????11	????Me	????H	????Ac	????Me	????H
????12	????Me	????H	????H	????Me	????H
						????13	????Me	????Me	????Byr	????Me	????Me

Above in the listed chemical compound, preferred chemical compound is compound N o:1.5-[4-(6-hydroxyl-2,5,7, a 8-tetramethyl benzo dihydropyran-2-ylmethoxy) benzyl] thiazolidine-2, the 4-diketone.(4.5-[4-6-hydroxy-2-methyl-7-tert-butyl group benzo dihydropyran-2-ylmethoxy) benzyl] thiazolidine-2, the 4-diketone; (5.5-[4-6-hydroxyl-2-ethyl-5,7,8-trimethyl benzo dihydropyran-2-ylmethoxy) benzyl] thiazolidine-2, the 4-diketone; (6.5-[4-6-hydroxyl-2-isobutyl group-5,7,8-trimethyl benzo dihydropyran-2-ylmethoxy) benzyl] thiazolidine-2, the 4-diketone; (8.5-[4-6-acetoxyl group-2,5,7,8-tetramethyl benzo dihydropyran-2-ylmethoxy) benzyl] thiazolidine-2, the 4-diketone; (10.5-[4-6-carbethoxyl group-2,5,7,8-tetramethyl benzo dihydropyran-2-ylmethoxy) benzyl] thiazolidine-2, the 4-diketone; With its pharmaceutically acceptable salt.

Preferred chemical compound be compound N o.1,4 and 10, most preferred be compound N o.1.

Chemical compound of the present invention is a known compound, and openly applies for clear 60-51189 at for example Japan Patent, is described among US4572912 and the EP0139421.They can prepare described in these documents or prepare with other known method.

Tetrahydrothiazole derivates of the present invention or its pharmaceutically acceptable salt can be through the number of ways administrations.Route of administration is not particularly limited, and presses the form of medicine system system and patient's situation, and as the year order, sex and sick degree are determined.For example work as and use tablet, pill, powder, granule, syrup, liquid preparation, suspending agent, when Emulsion or capsule, these Orally-administrables.When using injection, available itself or mix with general liquid sub such as glucose and aminoacid and to carry out intravenous injection, if desired, they itself can be carried out intramuscular, Intradermal, subcutaneous or intraperitoneal administration.When using suppository, they can be carried out drop rectum with drug.

Chemical compound of the present invention can be individually dosed or with arbitrary additives known such as excipient that is generally used for field of pharmaceutical preparations, binding agent, disintegrating agent, lubricant, solubilizing agent, corrigent or cladding agent mixing administration.This preparation can obtain with known method.

When the preparation tablet, use the extensive known carrier in this area, for example: excipient such as lactose, sucrose, sodium chloride, glucose, carbamide, starch, calcium carbonate, Kaolin, crystalline cellulose and silicic acid; Binding agent such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gel solution, carboxymethyl cellulose, the Lac of purification, methylcellulose, potassium phosphate and polyvinylpyrrolidone; Disintegrating agent such as dried starch, the dirty sour sodium of algae, agar powder, Thallus Laminariae (Thallus Eckloniae) powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, dodecyl sodium sulfate, glycerol monostearate, starch and lactose; The disintegrate inhibitor is sucrose for example, glyceryl stearate, cupu oil and hydrogenated oil and fat; Absorb accelerator for example quaternary amine alkali and dodecyl sodium sulfate; Humectant is glycerol and starch for example; Adsorbent is starch for example, lactose, Kaolin, Bentonite and colloidality silicic acid; Lubricant is the purification Talcum for example, stearate, powdery boric acid and Polyethylene Glycol.In addition, tablet can be made into conventional coated tablet such as sucrose coated tablet if desired, gelatine glaze sheet, enteric coatel tablets, thin membrane coated tablet or as double-layer tablet, multilayer tablet.

When the preparation pill, can use the extensive known carrier in this area, for example: excipient such as glucose, lactose, starch, cupu oil, hardened vegetable oils, Kaolin and Talcum; Binding agent is arabic gum for example, tragacanth gum powder, gelatin and ethanol; Disintegrating agent is Thallus Laminariae (Thallus Eckloniae) agar for example.

When preparation suppository, use the extensive known carrier in present technique field, for example: Polyethylene Glycol, cupu oil, higher alcohol, high alcohol ester, gelatin and semi-synthetic glyceride.

When preparation during injection, they can be solution, emulsion or suspension, and they are preferably sterile and be isoosmotic to blood.When these solution of preparation, when emulsion and suspension, use the diluent of the general usefulness in this area, water for example, ethanol, propylene glycol, ethoxy one isooctadecane alcohol, the pure and mild polyoxyethylene sorbitan fatty acid ester of polyoxy-isooctadecane.In the case, in these preparations, can comprise and make the isoosmotic enough sodium chloride of solution, glucose or glycerol; Perhaps can add general solubilizing agent, buffer agent or analgesic.

In addition, can add coloring agent if desired, antiseptic, spice, flavoring agent, sweeting agent and Ren Ke other medicines.

The amount of contained active component is not particularly limited in these preparations, can select in a wide region.Usually, can there be 1-70% (weight) in active component in whole compositions, preferred 1-30% (weight).

Though this dosage depends on symptom especially, year order and patient's body weight and route of administration and medicine agent shape, but to being limited to 5000mg (preferred 1000mg, more preferably 500mg) in adult patient's administration every day, be limited to 5mg (preferred 10mg, more preferably 50mg) down.

Osteoporosis can be determined by measuring bone density.For example can be used on Radioisotope, 37, (9), and 521-524 (1988) or Rinsho-Hoshasen, 35, (1), institute's method of reporting is measured bone density among the 41-48 (1990).

In addition, bone density can be measured with simple photonic absorption method [Science, 142,230-236 (1963)] or quantitative CT method [InVest.Radiol.12,541-551 (1977)].

The effect of The compounds of this invention is tested described in following embodiment.

Embodiment 1 measures bone density

Tested three treated animals: 1.Zucker Diabetic Fatty Mus (" ZDF Mus "): these are experimental animals that spontaneous diabetes are arranged.The medicine of participating in the experiment is thrown in a kind of F2 of routine mash feed and is given these animals.This group is called " test ZDF group ".2. throw the ZDF Mus of the F2 mash feed of giving no medicine.This group is called " contrast ZDF group ".3. throw the normal test Mus (being non-ZDF Mus) of the F2 mash feed of giving no medicine.This group is called " normal group ".

The compound N that will be known as " troglitazone " o.1, i.e. 5-[4-(6-hydroxyl-2,5,7,8-tetramethyl benzo dihydropyran-2-ylmethoxy) benzyl] thiazolidine-2, the 4-diketone is sneaked in the F2 mash feed with the amount of 0.2% w/w, gives to make 13 weeks of ZDF Mus administration 6 weeks.Mean dose is 165 milligrams/kilogram/days.Under this dosage, diabetes are controlled fully.When 19 weeks made, Mus anesthesia is then killed it from the ventral aorta blood-letting.With distal femoral resection to measure its bone mineral density.Use X-ray measurement, use bone mineral density measuring instrument (DCS-600R, Aloka, Japan).

The results are shown in table 2.

Table 2 bone mineral density (mg/cm ²)

	The number of Mus in the group	??????????BMD
			Normal group	????????7	??????187.3±2.3***
Contrast ZDF group	????????7	??????164.6±3.9
			The ZDF that participates in the experiment group	????????7	??????172.8±7.2*

1) the bone mineral density value provides by mean+/-standard error.2) * and * * * represent respectively at P＜0.05 and the P＜0.001 o'clock effective difference with contrast ZDF Mus.

As what clearly illustrate that in table 2, tetrahydrothiazole derivates of the present invention and its pharmaceutically acceptable salt show outstanding improvement to bone mineral density.

Embodiment 2

Troglitazone and Pioglitazone are to the comparison of bone mineral density effect

Repeat the test that embodiment 1 is reported with 4 groups of Mus: 1 normal group (pressing embodiment 1).2 contrast ZDF groups (pressing embodiment 1).Exist the ZDF that participates in the experiment of the troglitazone of 0.2% amount to organize in 3 pairs of feedstuffs, cause average absorption 132 milligrams/kilogram/days (following title " troglitazone ZDF group ").4 exist the ZDF group of participating in the experiment of the Pioglitazone of 0.067% amount in feedstuff, cause average absorption 52.6 milligrams/kilogram/days (following title " Pioglitazone ZDF group ").

Pioglitazone is active high than troglitazone, and thereby the effect that reaches the treatment diabetes need less amount.Under the dosage that uses, the two has controlled the diabetes of ZDF Mus fully Pioglitazone and troglitazone.

The results are shown in Table 3 for it.

Table 3

Bone mineral density (mg/cm ²)

	The number of Mus in the group	????????BMD
			Normal group	?????????6	?????187.4±1.5
Contrast ZDF group	?????????6	?????157.0±2.2
			Troglitazone ZDF group	?????????6	?????169.4±1.1***
Pioglitazone ZDF group	?????????6	?????149.3±1.8*

1) the bone mineral density value provides by mean+/-standard error.2) * and * * * represent respectively at P＜0.05 and the P＜0.001 o'clock effective difference with contrast ZDF Mus.

By these results as can be seen, The compounds of this invention (troglitazone) is brought up to similar level to normal mice with BMD from the level of the reduction of contrast ZDF Mus.On the contrary, Pioglitazone is brought down below the level of untreated ZDF Mus with BMD, and this just shows that it has the unfortunate mammiferous osteoporosis of paying effect-initiations or increase trouble diabetes.

Embodiment 3

Troglitazone and Pioglitazone are to the comparison of bone mineral density effect

With 6 groups of Mus, repeat the test reported among the embodiment 1, but 4 weeks only: 1 normal group (pressing embodiment 1).2 contrast ZDF groups (pressing embodiment 1).3 exist the ZDF group of participating in the experiment of the troglitazone of 0.05% amount in feedstuff, cause average absorption 43.5 milligrams/kilogram/days (following title " low troglitazone ZDF group ").4 exist the ZDF group of participating in the experiment of the troglitazone of 0.1% amount in feedstuff, cause average absorption 89.8 milligrams/kilogram/days (following title " high troglitazone ZDF group ").5 exist the ZDF group of participating in the experiment of the Pioglitazone of 0.0125% amount in feedstuff, cause average absorption 12.4 milligrams/kilogram/days (following title " low Pioglitazone ZDF group ").6 exist the ZDF group of participating in the experiment of the Pioglitazone of 0.025% amount in feedstuff, cause average absorption 23.1 milligrams/kilogram/days (following title " high Pioglitazone ZDF group ").

Under these dosage, troglitazone and Pioglitazone be control of diabetes or only part control not.

It the results are shown in table 4.

Table 4

Bone mineral density (mg/cm ²)

	The number of Mus in the group	?????????BDM
			Normal group	????????10	?????153.4±0.9
Contrast ZDF group	?????????5	?????149.8±1.0
			Low troglitazone ZDF group	?????????5	?????156.6±1.5***
High troglitazone ZDF group	?????????5	?????159.8±1.2***
			Low pioglitazone ZDF group	?????????5	?????151.2±0.9
High pioglitazoneZDF group	?????????5	?????151.2±0.7

1) the bone mineral density value provides by mean+/-standard error.2) * * * is shown in effective difference of P＜0.001 o'clock and contrast ZDF Mus.

By these results as can be seen, only troglitazone improves BMD when comparing with contrast ZDF group, and Pioglitazone is invalid.Yet when these dosage troglitazone and Pioglitazone the two to the treatment diabetes be not enough to effectively.

Embodiment 4 acute toxicities

Acute toxicity with the method test troglitazone of routine.

To 3 ddy mice oral administration troglitazone, dosage is 300mg/kg.Whole mices live after 5 days.

Compound N o.2,3,4 and 10 acute toxicity is tested with similar method oral administration.The acute toxicity value finds that overall height is in 300mg/kg.

The preparation capsule is packed into following composition in the ' Yanming ' capsules for clearing:

Compound N is 100mg o.1

Lactose 168.3mg

Corn starch 70mg

Magnesium stearate 1.7mg

Total 340mg

Claims (23)

1 thiazolidine compound is preparing the purposes for the treatment of and giving in the preventing bone rarefaction medicine, and said thiazolidine compound is formula (I) chemical compound or its pharmaceutically acceptable salt:

Wherein: R ¹And R ²Be same to each other or different to each other and respectively represent hydrogen atom or have the alkyl of 1 to 5 carbon atom; R ³The expression hydrogen atom, aliphatic acyl with 1 to 6 carbon atom, cycloalkane partly has the carbonyl naphthene of 5 to 7 carbon atoms, benzoyl, the naphthoyl base, benzoyl or naphthoyl base that at least one α substituent group of being defined has below replaced, the heterocyclic acyl that has 1 to 3 nitrogen-atoms and/or oxygen atom and/or heteroatomic 4 to 7 annular atomses of sulphur atom at heterocyclic moiety, phenylacetyl group, hydrocinnamoyl, by phenylacetyl group or the hydrocinnamoyl that at least one halogenic substituent has replaced, cinnamoyl partly has the alkoxy carbonyl group or the benzyloxycarbonyl group of 1 to 6 carbon atom at alkoxyl; R ⁴And R ⁵Be same to each other or different to each other and respectively represent hydrogen atom, have the alkyl of 1 to 5 carbon atom or have the alkoxyl of 1 to 5 carbon atom, or R ⁴And R ⁵Expression has the alkylenedioxy group of 1 to 4 carbon atom together; N is 1,2 or 3; Y and Z are same to each other or different to each other, and each represents oxygen atom or imino group; Substituents alpha is selected from the alkyl with 1 to 4 carbon atom, has the alkoxyl of 1 to 4 carbon atom, halogen atom, and hydroxyl, amino has the alkyl amino of 1 to 4 carbon atom, has the dialkyl amido of 1 to 4 carbon atom and nitro at each moieties.

2 purposes according to claim 1, wherein thiazolidine compound has formula (Ia): R wherein ¹, R ², R ³, R ⁴And R ⁵Such as claim 1 definition.

3 purposes, wherein R according to claim 1 or 2 ¹Expression has the alkyl of 1 to 4 carbon atom.

4 purposes, wherein R according to claim 1 or 2 ²Expression hydrogen atom or have the alkyl of 1 to 3 carbon atom.

5 purposes, wherein R according to claim 1 or 2 ³The expression hydrogen atom has the aliphatic acyl of 1 to 4 carbon atom, unsubstituted benzoyl or naphthoyl base or have the alkoxy carbonyl group of 2 to 4 carbon atoms.

6 purposes, wherein R according to claim 1 or 2 ⁴Expression has the alkyl of 1 to 4 carbon atom.

7 purposes, wherein R according to claim 1 or 2 ⁵Expression hydrogen atom or have the alkyl of 1 to 3 carbon atom.

8 purposes according to claim 1 or 2, wherein:

R ¹Expression has the alkyl of 1 to 4 carbon atom;

R ²Expression hydrogen atom or have the alkyl of 1 to 3 carbon atom;

R ³The expression hydrogen atom has the aliphatic acyl of 1 to 4 carbon atom, unsubstituted benzoyl or naphthoyl base, or have the alkoxy carbonyl group of 2 to 4 carbon atoms;

R ⁴Expression has the alkyl of 1 to 4 carbon atom; And

R ⁵Expression hydrogen atom or have the alkyl of 1 to 3 carbon atom.

9 purposes, wherein R according to claim 1 or 2 ³Expression hydrogen atom, acetyl group, benzoyl or carbethoxyl group.

10 purposes according to claim 1 or 2, wherein:

R ¹Expression has the alkyl of 1 to 4 carbon atom;

R ²Expression hydrogen atom or have the alkyl of 1 to 3 carbon atom;

R ³The expression hydrogen atom, acetyl group, benzoyl or carbethoxyl group;

R ⁴Expression has the alkyl of 1 to 4 carbon atom; With

R ⁵Expression hydrogen atom or have the alkyl of 1 to 3 carbon atom.

11 purposes, wherein R according to claim 1 or 2 ¹The expression methyl.

12 purposes, wherein R according to claim 1 or 2 ²Expression hydrogen atom or methyl.

13 purposes, wherein R according to claim 1 or 2 ³Expression hydrogen atom, acetyl group or carbethoxyl group.

14 purposes, wherein R according to claim 1 or 2 ⁴The expression methyl or the tert-butyl group.

15 purposes, wherein R according to claim 1 or 2 ⁵Expression hydrogen atom or methyl.

16 purposes according to claim 1 or 2, wherein:

R ¹The expression methyl;

R ²Expression hydrogen atom or methyl;

R ³The expression hydrogen atom, acetyl group or carbethoxyl group;

R ⁴The expression methyl or the tert-butyl group; With

R ⁵Expression hydrogen atom or methyl.

17 purposes according to claim 1, wherein Y represents oxygen atom.

18 purposes according to claim 1, wherein Z represents oxygen atom.

19 purposes, wherein the two expression oxygen atom of Y and Z according to claim 1.

20 purposes according to claim 1, wherein n is 1.

21 purposes according to claim 1 or 2, wherein said thiazolidine compound is one of the following at least:

5-[4-(6-hydroxyl-2,5,7,8-tetramethyl benzo dihydropyran-2-ylmethoxy) benzyl] thiazolidine-2, the 4-diketone;

5-[4-(6-hydroxy-2-methyl-7-tert-butyl group benzo dihydropyran-2-ylmethoxy) benzyl] thiazolidine-2, the 4-diketone;

5-[4-(6-hydroxyl-2-ethyl-5,7,8-trimethyl benzo dihydropyran-2-ylmethoxy) benzyl] thiazolidine-2, the 4-diketone;

5-[4-(6-hydroxyl-2-isobutyl group-5,7,8-trimethyl benzo dihydropyran-2-ylmethoxy) benzyl] thiazolidine-2, the 4-diketone;

5-[4-(6-acetoxyl group-2,5,7,8-tetramethyl benzo dihydropyran-2-ylmethoxy) benzyl] thiazolidine-2, the 4-diketone;

5-[4-(6-carbethoxyl group-2,5,7,8-tetramethyl benzo dihydropyran-2-ylmethoxy) benzyl] thiazolidine-2, the 4-diketone; With its pharmaceutically acceptable salt.

22 according to above-mentioned arbitrary claim in preparation treatment with give the purposes of the anti-osteoporotic medicine of diabetic.

23 purposes according to claim 22, wherein said diabetes are noninsulindependent diabetes.