Use of oxazole compounds to treat osteoporosis

An oxazole compound having the formula (I): ##STR1## in which A is a group of the formula --CH.sub.2 OR.sup.2 (wherein R.sup.2 is a hydrogen atom, an optionally substituted hydrocarbon residue, an optionally substituted heterocyclic group or an acyl group) or an aldehyde group, B is an optionally substituted phenyl group, R.sup.1 is a hydrogen atom or an optionally substituted alkyl group, and n is an integer of 0 to 6, provided that when n is 2, R.sup.1 is an optionally substituted alkyl group, or its salt, which is useful as a therapeutic agent for metabolic bone diseases including osteoporosis.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
This invention relates to oxazole compounds. More particularly, it relates 
to oxazole compounds which possess activities for preventing bone loss and 
increasing bone mass, and thus useful as therapeutic agents for 
osteoporosis. 
2. Prior Arts 
Various compounds have been prepared to provide therapeutic agents for 
osteoporosis, which however leave problems to be improved on regarding 
both points of activity and side-effect. 
4,5-Diaryloxazole-2-alkanoic acid derivatives which show antiinflammatory 
activity have been known (see U.S. Pat. No. 3,578,671 and Japanese Patent 
Publication No. Sho 49(1974)-38268). 
As the result of studies on 4-aryloxazole compounds, some of the present 
inventors found that 4-aryloxazole compounds having a substituent at the 
2-position possessed activities for lowering blood sugar and improving 
glucose tolerance. 
Our further earnest studies resulted in that 4-aryloxazole compounds having 
substituents at the 2- and 5-positions were prepared and found to possess 
activities for preventing bone loss as well as increasing bone mass. 
SUMMARY OF THE INVENTION 
This invention, provides an oxazole compound having the formula (I): 
##STR2## 
in which A is a group of the formula --CH.sub.2 OR.sup.2 (wherein R.sup.2 
is a hydrogen atom, an optionally substituted hydrocarbon residue, an 
optionally substituted heterocyclic group or an acyl group) or an aldehyde 
group, B is an optionally substituted phenyl group, R.sup.1 is a hydrogen 
atom or an optionally substituted alkyl group, and n is an integer of 0 to 
6, provided that when n is 2, R.sup.1 is an optionally substituted alkyl 
group, or its salt; 
and a therapeutic agent for osteoporosis, which comprises an oxazole 
compound having the formula (I'): 
##STR3## 
in which A' is a group of the formula --CH.sub.2 OR.sup.2 (R.sup.2 is a 
hydrogen atom, an optionally substituted hydrocarbon residue, an 
optionally substituted heterocyclic group or an acyl group), an aldehyde 
group or an optionally esterified or amidated carboxyl group, and B is an 
optionally substituted phenyl group, R.sup.1 is a hydrogen atom or an 
optionally substituted alkyl group, and n is an integer of 0 to 6, or its 
salt. 
PREFERRED EMBODIMENT OF THE INVENTION 
In the above mentioned formulae (I) and (I'), examples of the substituents 
in the optionally substituted phenyl group of B are a halogen atom, nitro 
group, cyano group, an alkoxy group which may be substituted or an alkyl 
group which may be substituted. One to four, preferably one or two of 
these substituents which are the same or different may be substituted on 
the benzene ring. The halogen atom includes fluorine, chlorine, bromine 
and iodine, among which fluorine and chlorine are preferable. 
Examples of the alkoxy groups in the alkoxy group which may be substituted, 
are straight or branched chain alkoxy groups preferably having 1-10 carbon 
atoms, such as methoxy, ethoxy, propoxy, butoxy, tert-butoxy, pentyloxy, 
hexyloxy, heptyloxy and nonyloxy. 
Examples of the alkyl groups in the alkyl group which may be substituted, 
are straight or branched chain alkyl groups preferably having 1-10 carbon 
atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 
sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, 
nonyl or decyl, and cyclic alkyl groups preferably having 3-7 carbon 
atoms, such as cyclopropyl, cyclobutyl, cyclohexyl or cycloheptyl. 
Examples of the substituents on the substituted alkyl or alkoxy groups are 
a halogen such as fluorine, chlorine, bromine or iodine, hydroxy or a 
C.sub.1-6 alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, 
pentyloxy or hexyloxy. The number of the substituent is preferably one to 
three. 
Specifically, the substituted alkoxy group may be trifluoromethoxy, 
difluoromethoxy, 2,2,2-trifluoroethoxy, 1,1-difluoroethoxy, 
1,1-difluoropropoxy and 2,2,3,3-tetrafluorobutoxy. 
Also, the substituted alkyl group may be trifluoromethyl, trifluoroethyl, 
difluoromethyl, trichloromethyl, hydroxymethyl, 1-hydroxyethyl, 
2-hydroxyethyl, methoxymethyl, ethoxymethyl, 1-methoxyethyl, 
2-methoxyethyl, 2,2-dimethoxyethyl and 2,2-diethoxyethyl. 
Examples of the alkyl groups in the optionally substituted alkyl group 
which is represented by R.sup.1, are any one of straight, branched or 
cyclic chain alkyl groups preferably having 1-10 carbon atoms such as 
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 
pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl or decyl, or 
cyclopropyl, cyclobutyl, cyclohexyl or cycloheptyl. 
Examples of the substituents on the optionally substituted alkyl groups of 
R.sup.1 are a halogen such as fluorine, chlorine, bromine or iodine, 
hydroxyl or a C.sub.1-6 alkoxy such as methoxy, ethoxy, propoxy, 
isopropoxy, butoxy, pentyloxy or hexyloxy. The number of the substituent 
is preferably one to three. 
Specifically, the substituted alkyl group with respect to R.sup.1 may be 
trifluoromethyl, trifluoroethyl, difluoromethyl, trichloromethyl, 
hydroxymethyl, methoxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 
methoxyethyl, ethoxyethyl, 1-methoxyethyl, 2-methoxyethyl, 
2,2-dimethoxyethyl, 2,2-diethoxyethyl or the like. 
The hydrocarbon residue in the optionally substituted hydrocarbon residue 
of R.sup.2 includes alkyl, aralkyl, alkenyl and aromatic groups. The alkyl 
group as mentioned here may be a straight, branched or cyclic chain alkyl 
having 1-10 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, 
isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, 
heptyl, octyl, nonyl or decyl, or cyclopropyl, cyclobutyl, cyclopentyl, 
cyclohexyl or cycloheptyl. 
The aralkyl group may be a phenyl-C.sub.1-4 alkyl such as benzyl, phenethyl 
or 3-phenylpropyl. 
The alkenyl group may be preferably the one having 2-10 carbon atoms, such 
as allyl, vinyl, crotyl, 2-penten-1-yl, 3-penten-1-yl, 2-hexen-1-yl, 
3-hexen-1-yl, 2-cyclopentenyl, 2-cyclohexenyl, 2-methyl-2-propen-1-yl or 
3-methyl-2-buten-1-yl. 
The aromatic group may be a C.sub.6-14 aryl such as phenyl, naphthyl, 
anthryl or phenanthryl. 
Examples of the heterocyclic groups in the optionally substituted 
heterocyclic group of R.sup.2 include a 5-7 membered heterocycle 
containing one sulfur, nitrogen or oxygen atom; a 5 or 6 membered 
heterocycle containing two to four nitrogen atoms, and a. 5 or 6 membered 
heterocycle containing one or two nitrogen atoms and one sulfur or oxygen 
atom, which may be condensed with a 6 membered ring containing two or less 
nitrogen atom, a benzene ring or a 5 membered ring containing one sulfur 
atom. Specifically, the heterocyclic group may be 2-pyridyl, 3-pyridyl, 
4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, 
thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrido[2,3-d]pyrimidyl, 
benzopyranyl, 1,8-naphthyridyl 1,5-naphthyridyl, 1,6-naphthyridyl, 
1,7-naphthyridyl, quinolyl, thieno[2,3-b]pyridyl, tetrazolyl, 
thiadiazolyl, oxadiazolyl, triazinyl, triazolyl, thienyl, pyrrolyl, 
pyrrolinyl, furyl, pyrrolidinyl, benzothienyl, indolyl, imidazolidinyl, 
piperidyl, piperidino, piperazinyl, morpholinyl or morpholino. 
Examples of the acyl groups of R.sup.2 are the hydrocarbon residue of 
R.sup.2 combined with a carbonyl or sulfonyl group, such as a C.sub.1-10 
acyl formed from a C.sub.1-10 alkyl, phenyl-C.sub.1-4 alkyl, C.sub.2-10 
alkyl, phenyl, naphthyl, anthryl or phenanthryl and a carbonyl or sulfonyl 
group. 
The esterified carboxyl groups of A' are e.g., a group of the formula 
--COOR.sup.3 (R.sup.3 is an ester residue). Examples of the ester residues 
of R.sup.3 are the optionally substituted hydrocarbon residues or 
optionally substituted heterocyclic groups as mentioned with respect to 
R.sup.2. These residues or groups may be substituted by one to three of a 
halogen, a C.sub.1-4 alkoxy or the like. 
Examples of the amidated carboxyl groups of A' are e.g., a group of the 
formula --CO--N(R.sup.4)(R.sup.5) in which R.sup.4 and R.sup.5 being, the 
same or different, are a hydrogen atom, an optionally substituted 
hydrocarbon residue or an optionally substituted heterocyclic group. 
To the optionally substituted hydrocarbon residues or optionally 
substituted heterocyclic groups of R.sup.4 or R.sup.5 are applicable those 
mentioned with respect to R.sup.2. These residues or groups may be 
substituted by one to three of a halogen, a C.sub.1-4 alkoxy or the like. 
Examples of substituents on the optionally substituted alkyl group 
mentioned as one group of the optionally substituted hydrocarbon residues 
with respect to R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are a halogen atom 
(e.g., fluorine, chlorine, bromine or iodine), hydroxyl group, a C.sub.1-6 
alkoxy group, an amino group which may be substituted by a C.sub.1-6 alkyl 
or a C.sub.1-10 acyl (e.g., dimethylamino, diethylamino, dipropylamino, 
acetylamino, propionylamino or benzoylamino), a carbamoyl group which may 
be substituted by a C.sub.1-6 alkyl (e.g., dimethylcarbamoyl, 
diethylcarbamoyl or dipropylcarbamoyl), a C.sub.1-6 alkoxycarbonyl group 
(e.g., methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl) or the 
heterocyclic group mentioned above. 
Specifically, the substituted alkyl groups of R.sup.2, R.sup.3, R.sup.4 and 
R.sup.5 may be trifluoromethyl, trifluoroethyl, difluoromethyl, 
trichloromethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 
2,2-dimethoxyethyl, 2,2-diethoxyethyl, 2-pyridylmethyl, 3-pyridylmethyl, 
4-pyridylmethyl, 2-(2-thienyl)ethyl, 3-(3-furyl)propyl, 2-morpholinoethyl, 
3-pyrrolylbutyl, 2-piperidinoethyl, 2-(N,N-dimethylamino)ethyl, 
2-(N-methyl-N-ethylamino)ethyl, 2-(N,N-diisopropylamino)ethyl, 
5-(N,N-dimethylamino)pentyl, N,N-dimethylcarbamoylethyl, 
N,N-dimethylcarbamoylpentyl, ethoxycarbonylmethyl, isopropoxycarbonylethyl 
or tert-butoxycarbonylpropyl. 
Examples of substituents on the optionally substituted aralkyl group 
mentioned as one group of the optionally substituted hydrocarbon residues 
of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are a halogen atom (e.g., 
fluorine, chlorine, bromine or iodine), a C.sub.1-6 alkoxy group, a 
C.sub.1-6 alkyl group, a halogenated C.sub.1-6 alkyl group substituted by 
the above halogen (e.g., trifluoromethyl, difluoromethyl, 
2,2,2-trifluoroethyl or 2,2,2-trichloroethyl) or an amino group which may 
be substituted by a C.sub.1-6 alkyl or a C.sub.1-10 acyl (e.g., 
methylamino, dimethylamino, diethylamino, dibutylamino, propionylamino, 
acetylamino or benzoylamino). 
Specifically, the substituted aralkyl group of R.sup.2, R.sup.3, R.sup.4 
and R.sup.5 may be 4-chlorobenzyl, 3-(2-fluorophenyl)propyl, 
3-methoxybenzyl, 3,4-dimethoxyphenethyl, 4-ethylbenzyl, 
4-(3-trifluoromethylphenyl)butyl, 4-acetylaminobenzyl or 
4-dimethylaminophenethyl. 
Examples of substituents on the optionally substituted aromatic group 
mentioned as the optionally substituted hydrocarbon residues of R.sup.2, 
R.sup.3, R.sup.4 and R.sup.5 are a halogen atom (e.g., fluorine, chlorine, 
bromine or iodine), a C.sub.1-6 alkyl group, a halogenated C.sub.1-6 alkyl 
group substituted by the above mentioned halogen, hydroxy group, a 
C.sub.1-6 alkoxy group, a C.sub.1-10 acyl group, an amino group which may 
be substituted by a C.sub.1-6 alkyl or a C.sub.1-10 acyl (e.g., 
dimethylamino, diethylamino, dipropylamino, acetylamino, propionylamino or 
benzoylamino), a carbamoyl group which may be substituted by a C.sub.1-6 
alkyl (e.g., dimethylcarbamoyl, diethylcarbamoyl or dipropylcarbamoyl), a 
C.sub.1-6 alkoxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl or 
propoxycarbonyl) or the above mentioned heterocyclic group. 
Specifically, the substituted aromatic groups of R.sup.2 , R.sup.3, R.sup.4 
and R.sup.5 may be 4-chlorophenyl, 4-cyclohexylphenyl, 
5,6,7,8-tetrahydro-2-naphthyl, 3-trifluoromethylphenyl, 4-hydroxyphenyl, 
3,4,5-trimethoxyphenyl, 6-methoxy-2-naphthyl, 4-(4-chlorobenzyloxy)phenyl, 
3,4-methylenedioxyphenyl, 4-(2,2,2-trifluoroethoxy)phenyl, 
4-propionylphenyl, 4-cyclohexanecarbonylphenyl, 4-dimethylaminophenyl, 
4-benzoylaminophenyl, 4-diethoxycarbamoylphenyl or 
4-tert-butoxycarbonylphenyl. 
Examples of substituents on the optionally substituted heterocyclic group 
of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are a halogen (e.g., fluorine, 
chlorine, bromine or iodine), a C.sub.1-6 alkyl, a halogenated C.sub.1-6 
alkyl group substituted by the above mentioned halogen, a hydroxy group, a 
C.sub.1-6 alkoxy group, a C.sub.1-10 acyl group, an amino group which may 
be substituted by a C.sub.1-6 alkyl or a C.sub.1-10 acyl (e.g., 
dimethylamino, diethylamino, dipropylamino, acetylamino, propionylamino or 
benzoylamino), a carbamoyl group which may be substituted by a C.sub.1-6 
alkyl (e.g., dimethylcarbamoyl, diethylcarbamoyl, or dipropylcarbamoyl), a 
C.sub.1-6 alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl or 
propoxycarbonyl) or the above mentioned heterocyclic group. 
Specifically, the substituted heterocyclic group of R.sup.2, R.sup.3, 
R.sup.4 and R.sup.5 may be 5-chloro-2-pyridyl, 3-methoxy-2-pyridyl, 
5-methyl-2-benzothiazolyl, 5-methyl-4-phenyl-2-thiazolyl, 
3-phenyl-5-isoxazolyl, 4-(4-chlorophenyl)-5-methyl-2-oxazolyl, 
3-phenyl-1,2,4-thiadiazol-5-yl, 5-methyl-l,3,4-thiadiazol-2-yl, 
5-acetylamino-2-pyrimidyl, 3-methyl-2-thienyl, 4,5-dimethyl-2-furyl or 
4-methyl-2-morpholinyl. 
Preferred compounds (I) or (I') are those wherein n is 2 to 4 and R.sup.1 
is a hydrogen atom or a C.sub.1-4 alkyl group or n is 2 and R.sup.1 is a 
C.sub.1-4 alkyl group. 
The object compounds of the invention can be prepared by any one of the 
following methods. Raw materials to be used in the methods can be prepared 
by known methods or analogous ones thereto. 
##STR4## 
In the formulas, R.sup.1, B and n have the same meanings as defined above, 
R.sup.6 is a lower alkyl or aralkyl group and X is a leaving group. 
##STR5## 
In the formulas, the symbols have the same meanings as defined above. 
##STR6## 
In the formulas, the symbols have the same meanings as defined above. 
##STR7## 
In the formulas, the symbols have the same meanings as defined above. 
##STR8## 
In the formulas, the symbols have the same meanings as defined above. 
##STR9## 
In the formulas, the symbols have the same meanings as defined above. 
##STR10## 
In the formulas, the symbols have the same meanings as defined above. 
##STR11## 
In the formulas, the symbols have the same meanings as defined above. 
##STR12## 
In the formulas, B has the same meaning as defined above and R.sup.7 is a 
hydrocarbon residue. 
##STR13## 
In the formulas, the symbols have the same meanings as defined above. 
##STR14## 
In the above formulas, the symbols have the same meaning as defined above. 
In the above formula, the hydrocarbon residues of R.sup.7 have the same 
meaning as illustrated with respect to the above R.sup.2, R.sup.3, R.sup.4 
and R.sup.5. The leaving group of X may be a halogen (e.g., chlorine, 
bromine or iodine) or sulfonyloxy (e.g., mesyloxy, tosyloxy or 
benzenesulfonyloxy). The lower alkyl groups of R.sup.6 may be methyl, 
ethyl, propyl or butyl. 
Details of each the methods are as follows. 
Method A 
The compound (II) or salt thereof is reacted with a dicarboxylic acid 
monoamide (III) to afford the compound (I-1) or salt thereof. The reaction 
can be conducted without solvent or in the presence of an inert solvent. 
Examples of the inert solvents are toluene, xylene, pyridine, 
1,2-dichloroethane, 1,1,2,2-tetrachloroethane, N,N-dimethylformamide or 
dimethylsulfoxide. 
The reaction temperature is about 30.degree. to 200.degree. C., preferably 
60.degree. to 150.degree. C. and the reaction time is about 30 minutes to 
10 hours. The compound (III) is used in about 1 to 10 moles, preferably 
about 1.5 to 4 moles, to one mole of the compound (II) or salt thereof. 
Method B 
Step 1 
Firstly, the compound (IV) or salt thereof is acylated with a dicarboxylic 
acid monohalide (V) to afford the compound (VI) or salt thereof. The 
acylation can be conducted in accordance with a method known per se. For 
instance, it can be conducted in the presence of a base in an inert 
solvent. Examples of the inert solvents are chloroform, dichloromethane, 
ethyl acetate, tetrahydrofuran, water or a mixture thereof. Examples of 
the bases are triethylamine, pyridine, N-methylmorpholine, sodium hydrogen 
carbonate, potassium hydrogen carbonate, sodium carbonate or potassium 
carbonate. Such triethylamine or pyridine can serve as the solvent. 
The reaction temperature is about -10.degree. to +50.degree. C. and the 
reaction time is about 10 minutes to 5 hours. The compound (V) or salt 
thereof is used in about 1 to 1.2 moles, to one mole of the compound (IV). 
Step 2 
The compound (VI) or salt thereof is subjected to a cyclization to convert 
into the compound (I-1) or salt thereof. The compound (I-1) or salt 
thereof is prepared by cyclizing the compound (VI) or salt thereof with a 
nitrogen-containing cyclizing agent, e.g., urea or ammonia [see J. Org. 
Chem., Vol 25, p.1151]. In case of using ammonia, it is preferably in the 
form of ammonium salt such as ammonium acetate in acetic acid. The 
reaction can be conducted in an inert solvent as described in Step 1. The 
nitrogen-containing clyclizing agent is used in about 0.5 to 10 moles, to 
one mole of the compound (VI) or salt thereof. The reaction temperature is 
about 10.degree. to 150.degree. C., and the reaction time is about 30 
minutes to 6 hours. 
Method C 
Step 1 
Firstly, the compound (VII) or salt thereof is acylated with a dicarboxylic 
acid monohalide (V) to afford the compound (VIII) or salt thereof. This 
method is carried out by the same manner as in Step 1 of Method B. 
Step 2 
The compound (VIII) or salt thereof is subjected to a dehydration ring 
closure reaction to convert into the compound (I-1) or salt thereof. The 
reaction can be conducted in the presence of a dehydrating agent such as 
phosphorus pentachloride, phosphorus oxychloride, phosphoric anhydride or 
the like in a solvent or without solvent. Examples of the solvents to be 
used for this reaction are benzene, toluene, xylene, chloroform, 
dichloromethane, tetrahydrofuran or the like. The dehydrating agent is 
used in about 1 to 10 equivalents, more preferably about 1 to 3 
equivalents, to the compound (VIII). The reaction temperature is about 
0.degree. to 150.degree. C., and the reaction time is about 10 minutes to 
10 hours. 
Method D 
The compound (I-2) or salt thereof can be prepared by hydrolyzing the 
compound (I-1) or salt thereof which was prepared by Methods A and B. The 
hydrolysis can be conducted in the presence of an acid or base in an 
aqueous solvent, in accordance with the conventional methods. 
Examples of the solvents usable include a mixture of water and an organic 
solvent, e.g., alcohols such as methanol or ethanol, ethers such as 
tetrahydrofuran or dioxane, N,N-dimethylformamide, dimethylsulfoxide or 
acetone. 
Examples of the bases include potassium carbonate, sodium carbonate, sodium 
methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydroxide, 
potassium hydroxide or lithium hydroxide. Examples of the acids are 
hydrochloric acid, sulfuric acid, acetic acid or hydrobromic acid. The 
acid or base is preferably used in an excess amount, about 1.2 to 6 
equivalents of base or about 2 to 50 equivalents of acid to the compound 
(I-1) or salt thereof. Usually, the reaction temperature is about 
-20.degree. C. to +150.degree. C., preferably about -10.degree. C. to 
+100.degree. C. and the reaction time is about 10 minutes to 20 hours. 
Method E 
The compound (I-3) or salt thereof can be prepared by esterification of the 
compound (I-2) or salt thereof. The esterification can be conducted in 
accordance with a method known per se. For example, the compound (I-2) or 
salt thereof is directly reacted with an alcohol (R.sup.3 OH) in the 
presence of an acid or with R.sup.3 X in the presence of a base. 
Alternatively, a reactive derivative of the compound (I-2) e.g., the acid 
anhydride, acid halide (such as acid chloride or acid bromide), 
imidazolide or mixed anhydride (such as acid anhydride with methyl 
carbonate, ethyl carbonate or isobutyl carbonate) is reacted with the 
alcohol (R.sup.3 OH). The acids or bases as mentioned in Method D are 
applicable to the above reaction. The reaction can be conducted in a 
similar way to Method F mentioned below (a method for using acid halide). 
Furthermore, the compound (I-3) or salt thereof can be also prepared by 
reacting the compound (I-2) or salt thereof with a diazo compound (e.g., 
diazomethane or diphenyldiazomethane). 
Method F 
The compound (I-4) or salt thereof can be prepared by amidating the 
compound (I-1), (I-2) or (I-3), or salt thereof. The amidation can be 
conducted by reacting the compound (I-1) or (I-3) or salt thereof with an 
amine derivative (IX) or salt thereof in an inert solvent (e.g., ethanol, 
propanol, toluene, xylene, pyridine, 1,2-dichloroethane, 
1,1,2,2-tetrachloroethane, N,N-dimethylformamide, or dimethyl sulfoxide) 
or in the absence of any solvent. The reaction temperature is about 
20.degree. to 200.degree. C., and the reaction time is about 10 minutes to 
10 hours. The amine derivative (IX) or salt thereof is preferably used in 
an excess amount, to the compound (I-1) or (I-3) or salt thereof. The 
reaction of the compound (I-2) or salt thereof with the amine derivative 
(IX) can be conducted by the methods known per se. For instance, there are 
a method for directly condensing the compound (I-2) or salt thereof and 
the amine derivative (IX) or salt thereof in the presence of 
dicyclohexylcarbodiimide or the like, or a method for reacting a reactive 
derivative of the compound (I-2) or salt thereof (e.g., acid anhydride, 
acid halide such as acid chloride or acid bromide, imidazolide or mixed 
anhydride such as acid anhydride with methyl carbonate, ethyl carbonate or 
isobutyl carbonate), with the amine derivative (IX) or salt thereof. Among 
these methods, the most convenient one is to use an acid halide or mixed 
anhydride of the compound (I-2). In case of using the acid halide, the 
reaction is preferably conducted in a conventional solvent (e.g., 
chloroform, dichloromethane, ethyl acetate, tetrahydrofuran or water, or 
mixture thereof) in the presence of a base (e.g., triethylamine, 
N-methylmorpholine, sodium hydrogen carbonate, potassium hydrogen 
carbonate, sodium carbonate or potassium carbonate). The amine derivative 
(IX) or salt thereof is used in about 1 to 1.2 moles, to one mole of the 
compound (I-2) or salt thereof. The reaction temperature is preferably 
-10.degree. C. to +50.degree. C., and the reaction time is about 30 
minutes to 10 hours. In case of using the mixed anhydride, the compound 
(I-2) or salt thereof is reacted with a chlorocarbonate (e.g., methyl 
chlorocarbonate, ethyl chlorocarbonate or isobutyl chlorocarbonate) in the 
presence of a base (e.g., triethylamine, N-methylmorpholine, sodium 
hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate or 
potassium carbonate). The reaction is conducted in an inert solvent (e.g., 
chloroform, dichloromethane, ethyl acetate, tetrahydrofuran, water or 
mixture thereof). The reaction temperature is preferably -50.degree. C. to 
+30.degree. C. The amine derivative (IX) is used in about 1 to 1.2 moles, 
to one mole of the compound (I-2). 
Method G 
The reduction can be conducted in accordance with the methods known per se, 
e.g., the reduction with a metal hydride compound, a metallic hydrogen 
complex, diborane or a substituted diborane, or a catalytic hydrogenation. 
(refer to "SHIN JIKKENKAGAKUKOZA (New Experimental Chemistry Handbook)" 
Vol.15 (II) (1976) edited by The Chemical Society of Japan and issued by 
Maruzen Publishing Co., Ltd. of Japan) 
That is, the reaction is conducted by treating the compound (I-1), (I-2) or 
(I-3), or salt thereof with a reducing agent. 
Suitable examples of the reducing agents are metallic hydrogen complexes 
such as alkali metal boron hydrides (e.g., sodium borohydride or lithium 
borohydride) or lithium aluminum hydride; metal hydride compounds such as 
sodium hydride; metals or metal salts such as organic tin compounds (e.g., 
triphenyltin hydride), nickel compounds or zinc compounds; catalytic 
reducing agents using transition metal (e.g., palladium, platinum or 
rhodium) catalysts and hydrogen, and diborane compounds. 
The reduction is conducted in an organic solvent which does not impede it. 
Examples of the solvents are aromatic hydrocarbons such as benzene, 
toluene or xylene; halogenated hydrocarbons such as chloroform, 
dichloromethane, 1,2-dichloroethane or 1,1,2,2-tetrachloroethane; ethers 
such as diethyl ether, dioxane, tetrahydrofuran or ethylene glycol 
monomethylether; alcohols such as methanol, ethanol or propanol; amides 
such as dimethylformamide, or mixture thereof, which are suitably selected 
in accordance with the kind of the reducing agent. 
The reaction temperature is about 0.degree. to 130.degree. C., especially 
10.degree. to 100.degree. C., and the reaction time is about 1 to 24 
hours. 
Method H 
The oxidation can be conducted in accordance with the methods known per se, 
e.g., the oxidation with manganese dioxide, chromic acid (e.g., chromium 
oxide (VI)-pyridine) or dimethyl sulfoxide (refer to "SHIN JIKKENKAGAKU 
KOZA (New Experimental Chemistry Handbook)", Vol. 15 (I-1) and (I-2) 
(1976) edited by The Chemical Society of Japan and issued by Maruzen 
Publishing Co., Ltd. of Japan). 
For instance, the oxidation with dimethyl sulfoxide is conducted in an 
inert solvent such as chloroform, dichloromethane, benzene or toluene in 
the coexistence of an electrophilic agent such as acetic anhydride, 
phosphoric anhydride, dicyclohexylcarbodiimide or chlorine. Dimethyl 
sulfoxide is used in 1 to 5 equivalents, preferably 1 to 2 equivalents, to 
the compound (I-5). The electrophilic agent is used in an equivalent, to 
dimethyl sulfoxide. The reaction temperature is about -50.degree. to 
+60.degree. C., preferably about 0.degree. to 40.degree. C. The reaction 
time is about 0.5 to 50 hours, preferably about 1 to 20 hours. 
Method I 
The acylation can be conducted by the methods known per se, e.g., to react 
the compound (I-5) directly with the carboxylic acid derivative (R.sup.7 
--COOH) in the presence of a condensing agent (e.g., 
dicyclohexylcarbodiimide) or to react the compound (I-5) with a reactive 
derivative of the carboxylic acid derivative (R.sup.7 --COOH) such as the 
acid anhydride, acid halide (e.g., acid chloride or acid bromide), 
imidazolide or mixed anhydride (e.g., acid anhydride with methyl 
carbonate, ethyl carbonate or isobutyl carbonate). The most convenient 
method is to use the acid halide or mixed anhydride of R.sup.7 --COOH. 
In the case of the acid halide, the reaction is usually conducted in a 
solvent (e.g., chloroform, dichloromethane, ethyl acetate, 
tetrahydrofuran, or water, or mixture thereof) in the presence of a base 
(e.g., triethylamine, N-methylmorpholine, sodium hydrogen carbonate, 
potassium hydrogen carbonate, sodium carbonate or potassium carbonate). 
The reaction temperature is about -10.degree. to +50.degree. C. The 
carboxylic acid derivative (R.sup.7 --COOH) is used in 1 to 1.2 moles to 
one mole of the compound (I-5) or salt thereof. 
In the case of the mixed anhydride, it is formed by reacting R.sup.7 --COOH 
with a chlorocarbonate (e.g., methyl chlorocarbonate, ethyl 
chlorocarbonate or isobutyl chlorocarbonate), in the presence of a base 
(e.g., triethylamine, N-methylmorpholine, sodium hydrogen carbonate, 
potassium hydrogen carbonate, sodium carbonate or potassium carbonate). 
The reaction is conducted in an inert solvent (e.g., chloroform, 
dichloromethane, ethyl acetate, tetrahydrofuran, water or mixture 
thereof). The reaction temperature is about -50.degree. to +30.degree. C., 
and the reaction time is about 0.5 to 50 hours. The carboxylic acid 
derivative (R.sup.7 --COOH) is used in about 1 to 1.2 moles, to one mole 
of the compound ( I-5). 
Method J 
In this method, the compound (I-5) or salt thereof is reacted with R.sup.2 
--X in the presence of a base (e.g., sodium hydride, potassium hydride, 
sodium amide, triethylamine, N-methylmorpholine, sodium hydrogen 
carbonate, potassium hydrogen carbonate, sodium carbonate or potassium 
carbonate), thereby affording the compound (I-8). The reaction is 
conducted in an inert solvent (e.g., tetrahydrofuran, dioxane, ether, 
toluene, xylene, benzene, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, 
N,N-dimethylformamide or dimethyl sulfoxide). The reaction temperature is 
about -20.degree. to 100.degree. C., preferably -10.degree. to 50.degree. 
C., and the reaction time is about 0.5 to 20 hours. R.sup.2 --X is used in 
an excess amount, to the compound (I-5) or salt thereof. 
Method K 
Step 1 
The compound (X) or salt thereof is prepared by reacting the compound (I-5) 
or salt thereof with a halogenating agent or a sulfonylating agent. 
Suitable examples of the halogenating agents are thionyl chloride or 
phosphorus tribromide. The use of such halogenating agent can produce the 
compound (X), X being chlorine or bromine, or salt thereof. The 
halogenation is conducted in an inert solvent (e.g., benzene, toluene, 
xylene, chloroform or dichloromethane) or using an excess amount of the 
halogenating agent to serve as a solvent. The reaction temperature is 
about 10.degree. to 80.degree. C. The halogenating agent is used in about 
1 to 20 moles, to one mole of the compound (I-5) or salt thereof. Suitable 
examples of the sulfonylating agents are mesyl chloride, tosyl chloride or 
benzenesulfonyl chloride, thereby affording the compound (X), X being 
mesyloxy, tosyloxy or benzensulfonyoxy, respectively, or salt thereof. The 
sulfonylation is conducted in an inert solvent (e.g., benzene, toluene, 
xylene, ethylether, ethyl acetate, tetrahydrofuran, chloroform or 
dichloromethane), preferably in the presence of a base (e.g., 
triethylamine, N-methyl-morpholine, sodium hydrogen carbonate, potassium 
hydrogen carbonate, sodium carbonate or potassium carbonate). The reaction 
temperature is about 0.degree. to 130.degree. C., preferably 10.degree. to 
100.degree. C. The reaction time is about 10 minutes to 5 hours. Each of 
the sulfonylating agent and the base is used in about 1 to 1.2 moles, to 
one mole of the compound (I-5) or salt thereof. The compound (X), X being 
iodine, or salt thereof can be prepared by reacting one mole of the 
compound (X), X being chlorine, bromine or sulfonyloxy, or salt thereof as 
thus obtained, with 1 to 3 moles of sodium iodide or potassium iodide. For 
this reaction, such solvent as acetone, methylethyl ketone, ether, 
tetrahydrofuran or dioxane is usable. The reaction temperature is about 
20.degree. to 80.degree. C. 
Step 2 
Subsequently, the compound (X) or salt thereof is reacted with an alcohol 
(R.sup.2 --OH) to prepare the compound (I-8) or salt thereof. The reaction 
is usually conducted in an inert solvent (e.g., ether, chloroform, 
dichloromethane, ethyl acetate, tetrahydrofuran, dioxane or 
N,N-dimethylformamide) in the presence of a base (e.g., triethylamine, 
N-methylmorpholine, sodium hydrogen carbonate, potassium hydrogen 
carbonate, sodium carbonate or potassium carbonate). The reaction 
temperature is about 0.degree. to 100.degree. C., and the reaction time is 
about 5 minutes to 10 hours. The alcohol (R.sup.2 --OH) is used in about 
1-3 moles, to one mole of the compound (X) or salt thereof. 
The salts of the compounds to be employed in the above mentioned Methods 
A-K are similar ones to the salts of the compounds (I) and (I'). 
The compounds or their salts thus obtained can be isolated and purified, 
e.g., by a conventional method such as filtration, concentration, 
concentration under reduced pressure, extraction with solvent, 
redistribution, change of basicity, crystallization, recrystallization, 
distillation, sublimation, salting out or chromatography. 
When the compound (I) or (I') obtained by the above-mentioned Methods has 
an acidic functional group (e.g., free carboxyl group), its salt with a 
pharmaceutically acceptable base may be formed in accordance with the 
conventional method. Examples of such salts are the sodium, potassium, 
aluminum and calcium salts. When the compound (I) or (I') has a basic 
functional group, its salt with a pharmaceutically acceptable acid may be 
formed in accordance with the conventional method. Examples of such salts 
are the hydrochloric acid, sulfuric acid, acetic acid and fumaric acid 
salts. 
As for toxicity of the compounds (I) and (I'), and salt thereof, no death 
was observed on the compounds prepared e.g., by Examples 81 and 83 when 
orally administered in 300 mg/kg to mouse. 
The compounds (I) and (I') and salts thereof possess activities for 
preventing bone loss as well as increasing bone mass in mammals (e.g., 
mouse, rat, rabbit, dog, cat, cow, pig and human being) and their toxicity 
is very low. Thus, they can be used as a therapeutic agent for 
osteoporosis of mammals (e.g., mouse, rat, rabbit, dog, cat, cow, pig and 
human being). 
The compounds of the invention can be administered to human beings through 
any of oral or parental route. 
Compositions for oral administration may be solid or liquid forms, 
specifically tablets (including sugar coated tablets and film coated 
tablets), pills, granules, powders, capsules (including soft capsules), 
syrups, emulsions and suspensions. Such compositions will contain 
conventional carriers or excipients and can be prepared by known methods. 
Examples of carriers or excipients for tablets are lactose, starch, 
sucrose and magnesium stearate. 
Compositions for parental administration are e.g., injections and 
suppositories, the former of which includes subcutaneous, intracutaneous, 
intramuscular or like injections. Such injections can be prepared by 
suspending or emulsifying the compound (I) or (I'), or salt thereof in or 
with sterile aqueous or oily liquids which are usually employed in 
injections, in accordance with the methods known in the art. Examples of 
the aqueous liquids for injections are physiological saline and isotonic 
solution, which may be used together with a suitable suspending agent such 
as sodium carboxy methylcellulose or a nonionic surfactant upon 
circumstances. Examples of the oily liquids are sesame oil and soybean 
oil, which may be used together with a solubilizing agent such as benzyl 
benzoate or benzyl alcohol. The injections thus prepared are usually put 
into ampules. 
The oral dosage of the compounds (I) or (I'), or salts thereof when used as 
therapeutic agent for osteoporosis is 1 to 500 mg/day/adult, preferably 10 
to 150 mg. 
The invention is further illustrated by examples, test examples and 
preparation examples, by which no limitation shall be given.