JPH06172372A - Squalene synthetase inhibitor and its use - Google Patents

Abstract

PURPOSE:To provide the subject inhibitor containing a bisphosphonic acid, etc., free from toxicity, excellent in therapeutic effect and useful as a medicine for improving hypercholesterolemia, etc. CONSTITUTION:The objective inhibitor contains a 1,1-bisphosphonic acid compound represented by the formula [R<1> to R<4> are each H or a in alkyl; A is H, a halogen, nitro, a (substituted)hydrocarbon, a (substituted)heterocycle, a (substituted)acyl, a (substituted)amino, a (substituted)hydroxyl group, a (substituted)thiol, etc.; B is H, a halogen, a (substituted)hydrocarbon, a (substituted)heterocycle or a (substituted)carboxyl], its lower alkyl ester or its salt. In addition, the amount of the inhibitor to be used is preferably 10 200mg per day per an adult in the case of oral administration.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a squalene synthase inhibitor containing a 1,1-bisphosphonic acid compound, a lower alkyl ester thereof or a salt thereof, which is useful as a therapeutic agent for hypercholesterolemia.

[0002]

BACKGROUND OF THE INVENTION Hypercholesterolemia is known as the three major risk factors for ischemic heart disease as well as hypertension and smoking. Proper control of blood cholesterol levels is important for preventing and treating this ischemic heart disease. To prevent coronary atherosclerosis
Very important for treatment. Cholestyramin (Cholestyramin) is a drug that lowers blood cholesterol levels.
e), such as Colestipol, which traps bile acids and inhibits their absorption (for example, US Pat. No. 402).
No. 7009), Melinamide (disclosed in French Patent No. 1476596) and the like, which inhibit acylcoenzyme A cholesterol acyltransferase (ACAT) to suppress intestinal absorption of cholesterol, and biosynthesis of cholesterol. Drugs that suppress the inflammation are drawing attention. Especially as a cholesterol biosynthesis inhibitor, 3-hydroxy-3-methylglutaryl coenzyme A
Lovastatin (L that inhibits (HMG-CoA) reductase
ovastatin) (disclosed in US Pat. No. 4,231,938),
Simvastatin (US Pat. No. 4,444)
No. 784), pravastatin
(Disclosed in US Pat. No. 4,346,227) and the like are used for medicines. However, inhibition of HMG-CoA reductase inhibits not only cholesterol biosynthesis but also biosynthesis of other components necessary for the living body such as ubiquinone, dolichol and heme A, and side effects caused by them are concerned. ing.

[0003]

Ubiquinone, dolichol, heme A and the like are known to be biosynthesized from farnesyl pyrophosphate on the cholesterol biosynthetic pathway. Therefore, in order to eliminate side effects due to these defects, In the cholesterol biosynthetic pathway, it is desirable to inhibit the enzyme system of farnesyl pyrophosphate or later. Examples of such an enzyme include squalene synthase. Conventionally, isoprenoid (phosphinylmethyl) phosphonate (Journal of M
edicinal Chemistry, Vol. 31, No. 10, pp. 1869-1871
Page, 1988) and its derivatives (Japanese Patent Laid-Open No. 21328/1989).
No. 8) is known, but it is still insufficient in terms of activity.

[0004]

In view of the above circumstances, the inventors of the present invention have conducted intensive screenings for an excellent squalene synthase inhibitor, and as a result, have hitherto been a bone resorption inhibitory action, an anti-inflammatory action, and an anti-rheumatic disease. 1,1-bisphosphonic acid compounds known to have an action or herbicidal / bactericidal action (JP-A-1-258695, JP-A-1-30829)
No. 0, JP-A-2-184, JP-A-2-185, EP
-A-0337706, JP-A-59-42395,
JP-A-60-174792, JP-A-54-37829
No. JP-A 64-85984, EP-A-24317.
(Disclosed in No. 3) unexpectedly has a squalene synthase inhibitory action and remarkably suppresses the biosynthesis of cholesterol, and completed the present invention.

That is, the present invention provides (1) a 1,1-bisphosphonic acid compound, a squalene synthase inhibitor containing a lower alkyl ester thereof or a salt thereof, (2) 1,1
A bisphosphonic acid compound having the general formula (I)

[0006]

[Chemical 20]

[Wherein R ¹ , R ² , R ³ and R ⁴ are hydrogen or a lower alkyl group, A is hydrogen, halogen, nitro,
Optionally substituted hydrocarbon group, optionally substituted heterocyclic group, optionally substituted acyl group, optionally substituted amino group, optionally substituted hydroxyl group,
Optionally substituted thiol group, Ra-SO-, Ra-
SO ₂ —, Ra—CS— (wherein Ra represents an optionally substituted hydrocarbon group) or an optionally substituted carboxyl group, and B is hydrogen, halogen, or an optionally substituted carbon group. A hydrogen group, an optionally substituted heterocyclic group, or an optionally substituted carboxyl group], which is a compound represented by the above (1), (3) 1,1- Bisphosphonic acid compound is represented by the general formula (II)

[0008]

[Chemical 21]

[In the formula, A'is hydrogen, halogen, nitro, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted acyl group, or an optionally substituted Good amino group, optionally substituted hydroxyl group, optionally substituted thiol group, Ra-SO-, Ra-S
O ₂ — (in the formula, Ra represents an optionally substituted hydrocarbon group) or an optionally substituted carboxyl group, and the other symbols are the same as those defined above. (1) The squalene synthase inhibitor described in (4)
1,1-bisphosphonic acid compound is represented by the general formula (III)

[0010]

[Chemical formula 22]

[In the formula, Z ¹ is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted acyl group, an optionally substituted amino group, or an optionally substituted Optionally a thiol group, Ra—SO ₂ — or Ra
-CS- (in the formula, Ra represents a hydrocarbon group which may be substituted), Z ² represents hydrogen, a hydroxyl group, halogen or an amino group which may be substituted, and other symbols are the same as the above. Meaning], a squalene synthase inhibitor described in (1) above, which is a compound represented by the formula [1], and a 1,1-bisphosphonic acid compound represented by the general formula (IV)

[0012]

[Chemical formula 23]

[Wherein Y ¹ is an optionally substituted C _1-20
Alkyl group, _optionally substituted C _2-20 alkenyl group, _optionally substituted C _6-14 aryl group, _optionally substituted C _7-19 aralkyl group, _optionally substituted acyl group , An optionally substituted heterocyclic group, an amino acid residue or a peptidyl group consisting of 2 to 100 amino acids, R ⁵ represents hydrogen or a lower alkanoyl group, and other symbols have the same meanings as those defined above. (6) 1,1 which is a compound according to the above (1)
-Bisphosphonic acid compound is a general formula (V)

[0014]

[Chemical formula 24]

[In the formula, Y ² is an optionally substituted linear or branched C _1-7 alkyl group, an optionally substituted C _3-7 cycloalkyl group, or an optionally substituted C _6-14
An aryl group or an optionally substituted heterocyclic group is represented by X
Is an oxygen atom or an optionally oxidized sulfur atom, n
₁ represents an integer of ₁ to 20, and other symbols are compounds having the same meanings as the above], and the squalene synthase inhibitor according to the above (5), (7) 1,1-bisphosphonic acid compound is generally. Formula (VI)

[0016]

[Chemical 25]

[Wherein Y ³ represents an optionally substituted cyclic group, n ₂ represents an integer of ₂ to 15, and other symbols have the same meanings as those defined above] (5 ) Squalene synthase inhibitor, (8) 1,1-bisphosphonic acid compound of the general formula (VII)

[0018]

[Chemical formula 26]

[Wherein Y ⁴ represents an alkyl group which may be substituted, and other symbols have the same meaning as above], and the squalene synthase inhibitor according to (5) above,
(9) The 1,1-bisphosphonic acid compound has the general formula (VIII)

[0020]

[Chemical 27]

[Wherein Y ⁵ represents a C _5-20 alkyl group and other symbols have the same meanings as defined above], and the squalene synthase inhibitor according to the above (5), (10) 1,
The 1-bisphosphonic acid compound has the general formula (IX)

[0022]

[Chemical 28]

[In the formula, R ⁶ and R ⁷ are the same or differently substituted hydrocarbon groups, and n ₃ is 2 to 10
Of the squalene synthase inhibitor described in (1) above, wherein the other symbols are compounds represented by the above-mentioned meanings]

[0024]

[Chemical 29]

[In the formula, R ⁸ is hydrogen or a hydroxyl group, Y ⁶ is hydrogen, an optionally substituted alkyl group or an optionally substituted phenyl group, and n ₄ is an integer of 0 to 10 (provided that When R ⁸ is a hydroxyl group, n ₄ is not 0), and other symbols have the same meanings as those defined above], and the squalene synthase inhibitor according to (1) above, (12) 1,
The 1-bisphosphonic acid compound has the general formula (XI)

[0026]

[Chemical 30]

[Wherein R ⁹ is hydrogen, a C _1-6 alkyl group or -CONH ₂ and R ¹⁰ is hydrogen, a C _1-6 alkyl group, a benzyl group or an optionally substituted phenyl group, Y ⁷
Is a linear or branched C _1-6 alkyl group, a C _5-7 cycloalkyl group, an optionally substituted phenyl group or an optionally substituted 5- or 6-membered heterocyclic group, and m is 0 ~ 2
Of the squalene synthase inhibitor according to the above (1), which is a compound represented by the above-mentioned meaning and the other symbols have the same meanings as above, (13) 1,1-bisphosphonic acid compound is represented by the general formula (XII).

[0028]

[Chemical 31]

[Wherein Y ⁸ represents an optionally substituted heterocyclic group, n ₅ represents an integer of 2 to 6, and other symbols have the same meanings as those defined above] The squalene synthase inhibitor described in 1) and (14) 1,1-bisphosphonic acid compound are represented by the general formula (XIII).

[0030]

[Chemical 32]

[Wherein Y ⁹ represents an optionally substituted cyclic group, n ₆ represents an integer of 0 to 15, and other symbols have the same meanings as those defined above] (1 ) Squalene synthase inhibitor, (15) 1,1-bisphosphonic acid compound according to general formula (XIV)

[0032]

[Chemical 33]

[Wherein Y ¹⁰ represents phenyl, pyridyl or pyrimidinyl, n ₇ represents an integer of 4 to 12, and other symbols have the same meanings as above] (7)
The squalene synthase inhibitor described. (16) General formula (XI
V), in which n ₇ is an integer of 4 to 10, squalene synthase inhibitor according to the above (15), (17) general formula (XIV)
Wherein Y ¹⁰ is phenyl, X is S, n ₇ is 7, and R ¹ and R
Squalene synthase inhibitor according to the above (16), wherein ² , R ³ and R ⁴ are hydrogen, (18) Y in the general formula (XIV)
¹⁰ is phenyl, X is S, n ₇ is 10, and R ¹ , R ² , R ³
And R ⁴ is hydrogen, the squalene synthase inhibitor according to the above (16), (19) wherein in the general formula (XIV), Y ¹⁰ is phenyl, X is SO, n ₇ is 9, and R ¹ , R ² , R ³ and R ⁴ above (16) squalene synthetase inhibitors described is hydrogen, (20) in the general formula (XIV), Y ¹⁰ is phenyl, X is SO, n ₇ is 10, and R ^1, R (21) The general formula (XV), wherein squalene synthase inhibitor according to the above (16), wherein ² , R ³ and R ⁴ are hydrogen.

[0034]

[Chemical 34]

[Wherein n ₈ is an integer of 11 to 15 and the other symbols are as defined above], or a salt thereof, (22) general formula (XVI)

[0036]

[Chemical 35]

[Wherein each symbol has the same meaning as defined above] or a salt thereof, (23) general formula (XXXII)

[0038]

[Chemical 36]

[Wherein D represents a hydrocarbon group which may be substituted, n ₉ represents 0 or 1, and other symbols have the same meanings], or a salt thereof, (24) D is a general formula

[0040]

[Chemical 37]

[Wherein, n ₁₀ represents an integer of 1 to 3], a compound or a salt thereof according to the above (23), which is a group represented by
(25) D is a general formula

[0042]

[Chemical 38]

[Wherein the symbols in the formula have the same meanings as defined above], the compound or salt thereof according to the above (23), or (2)
6) The 1,1-bisphosphonic acid compound is (21) to
The squalene synthase inhibitor according to (1) above, which is the compound according to any one of (25), and (27) Y ³ is C
_3-7 cycloalkyl group, linear or branched C _1-6
5 to 6 optionally substituted with alkyl groups, halogen or methylenedioxy, and containing 1 to 4 nitrogen atoms
A membered aromatic heterocycle may be substituted with a C _6-14 aryl group which may be condensed or a linear or branched C _1-6 alkyl group, and a benzene ring may be condensed. Good containing 1 to 2 nitrogen atoms and 1 sulfur atom 5
~ 28-membered aromatic heterocyclic group or a 5- to 6-membered aromatic heterocyclic group containing 1 to 4 nitrogen atoms, (28) Y ³ is a phenyl group Or 1-2 which may be substituted with a C _1-4 alkyl group
Squalene synthesis according to the above (7), which is a 5- or 6-membered aromatic heterocyclic group containing 1 nitrogen atom and 1 sulfur atom or a 5- or 6-membered aromatic heterocyclic group containing 1 to 4 nitrogen atoms. Enzyme inhibitor, (29) Squalene synthesis according to the above (8), wherein Y ⁴ is a linear or branched C _1-7 alkyl group which may be substituted with a phenyl group or a C _1-4 alkoxyphenyl group. The present invention provides a therapeutic agent for hypercholesterolemia containing an enzyme inhibitor and a (30) 1,1-bisphosphonic acid compound, a lower alkyl ester thereof or a salt thereof. The 1,1-bisphosphonic acid compound in the present invention means a methylenebisphosphonic acid compound. 1,
The lower alkyl group in the lower alkyl ester of the 1-bisphosphonic acid compound and R ¹ in the above general formula (I),
The lower alkyl group represented by R ² , R ³ and R ⁴ is a linear or branched one having 1 to 4 carbon atoms such as methyl, ethyl, propyl, butyl, isobutyl and tert.
-Butyl and the like are used.

Fluorine, chlorine, bromine and iodine are used as the halogen represented by A, A ', B and Z ² and the halogen used in the present specification.
As the hydrocarbon group in the optionally substituted hydrocarbon group represented by A, A ′, B, Z ¹ , R ⁶ , R ⁷ , Ra and D, an alkyl group, an alkenyl group, an aryl group or the like is used. . The alkyl group may be a linear or branched C _1-20 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl. , Octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, etc., and, for example, C _3-7 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclohexyl or cycloheptyl. Used. The alkenyl group has 2 to 20 carbon atoms.
Are preferred, such as allyl, vinyl,
Crotyl, 2-penten-1-yl, 3-pentene-1
-Yl, 2-hexen-1-yl, 3-hexene-1-
Yl, 2-cyclohexenyl, 2-cyclopentenyl,
2-methyl-2-propen-1-yl, 3-methyl-2
-Buten-1-yl and the like are used.

The alkyl and alkenyl groups exemplified as the hydrocarbon groups represented by A, A ', B, Z ¹ , R ⁶ , R ⁷ , Ra and D are halogen, nitro, cyano and C.
_6-14 aryl group (eg, phenyl, naphthyl, anthryl, etc.), heterocyclic group, optionally substituted acyl group, optionally substituted amino group, optionally substituted hydroxyl group, optionally substituted Good thiol group, Rb-SO-
(In the formula, Rb has the same meaning as Ra), Rc—SO ₂ — (in the formula, R
c is as defined for Ra) or optionally substituted with 1 to 4 carboxyl groups which may be substituted. As these heterocyclic groups and optionally substituted acyl groups, amino groups, hydroxyl groups, thiol groups and carboxyl groups, the same groups as the groups represented by A below can be used.

The above A, A ', B, Z ¹ , R ⁶ , R ⁷ and R
The aryl group exemplified as the hydrocarbon group represented by a is
Those having 6 to 14 carbon atoms are preferable, and for example, phenyl, naphthyl, anthryl, phenanthryl and the like are used. The aryl groups exemplified as the hydrocarbon groups represented by A, A ′, B, Z ¹ , R ⁶ , R ⁷ , Ra and D are halogen; nitro; cyano; halogen, hydroxyl and C, respectively.
1 to 3 linear or branched C _1-7 alkyl group (eg, methyl, ethyl, propyl, etc.) optionally substituted with _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, etc.) or C _3-7 cycloalkyl group (eg, cyclopropyl, cyclopentyl, cyclohexyl, etc.); C _6-14 aryl group (eg, phenyl, naphthyl, anthryl, etc.); heterocyclic group; optionally substituted acyl group; substituted Optionally substituted amino group; optionally substituted hydroxyl group; optionally substituted thiol group; Rd—SO— (in the formula, Rd
Is the same as Ra); Re-SO _2- (wherein Re is the same as Ra) and an optionally substituted carboxyl group is 1
~ 4 may be substituted. As these heterocyclic groups and optionally substituted acyl groups, amino groups, hydroxyl groups, thiol groups and carboxyl groups, the same groups as the groups represented by A below can be used. Among the hydrocarbon groups represented by the above D, preferably a general formula

[0047]

[Chemical Formula 39]

[Wherein n ₁₀ represents an integer of 1 to 3]. The heterocyclic ring in the optionally substituted heterocyclic group represented by A, A ′, B, Z ¹ and Y ⁸ is, for example, a 5- to 7-membered heterocyclic ring containing one sulfur atom, nitrogen atom or oxygen atom. , 5 to 6 containing 2 to 4 nitrogen atoms
Membered heterocycles, 5- to 6-membered heterocycles containing 1 to 2 nitrogen atoms and 1 sulfur atom or oxygen atom, etc. are used, and these heterocycles are 6-membered rings containing 1 to 2 nitrogen atoms. , A benzene ring or a 5-membered ring containing one sulfur atom.

Specific examples of the above-mentioned heterocyclic group include, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrido [2, 3-d] pyrimidinyl, 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, morpholino and the like are used. As the substituent of the heterocyclic group, the same substituents as those of the optionally substituted aryl group exemplified in the optionally substituted hydrocarbon group represented by A above can be used. As the 5- or 6-membered heterocyclic group in the optionally substituted 5- or 6-membered heterocyclic group represented by Y ⁷ , the 5- or 6-membered heterocyclic group represented by A above is used. . As the substituent, the same substituents as those for the heterocyclic group represented by A can be used.

The acyl group in the optionally substituted acyl group represented by A, A'and Z ¹ is an organic carboxylic acid acyl group or a C _1-6 hydrocarbon group (eg, methyl,
C such as ethyl, n-propyl, iso-propyl and hexyl
_1-6 alkyl group, phenyl etc.) having a sulfonic acid acyl group or the like is used, and as the organic carboxylic acid acyl group,
Formyl, C _1-10 alkyl-carbonyl group (eg, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, etc.), C _2-10 alkenyl-carbonyl group (eg, crotonyl, 2-cyclohexenecarbonyl etc.), C _6-14 aryl-carbonyl group (eg, benzoyl etc.), C _7-19 aralkyl-carbonyl group (eg, phenylacetyl etc.), 5- or 6-membered aromatic heterocyclic carbonyl group (eg, nicotinoyl, 4-thiazolylcarbonyl, etc.) 5- or 6-membered aromatic heterocyclic acetyl group (eg, 3-
Pyridylacetyl, 4-thiazolylacetyl, etc.), an amino acid residue or a peptidyl group consisting of 2 to 100 amino acids is used, and as the sulfonate acyl group having a C _1-6 hydrocarbon group, methanesulfonyl, ethane Linear or branched C _1-6 alkylsulfonyl such as sulfonyl is used, and these are further substituted with 1 to 3 substituents such as the above-mentioned halogen atom, hydroxyl group, C _1-6 alkoxy group and amino group. It may be replaced individually. Specific examples of the substituted acyl group include, for example, trifluoroacetyl, 3-cyclohexyloxypropionyl, 4-chlorobenzoyl, 6-chloronicotinoyl, 2-methyl-
4-phenyl-5-thiazolylacetyl or the like is used. The amino acid in the above amino acid residue and the amino acid forming the peptidyl group may be any amino acids and carboxyl groups, but natural amino acids are preferred. A group obtained by removing the OH group from the C-terminal of such an amino acid or peptide is preferably used as the amino acid residue of the present invention.

As the substituents in the substituted amino group represented by A, A ′, Z ¹ and Z ² , the same or different groups defined by Y ¹ and R ⁵ in the general formula (IV) are used. To be C _1-20 alkyl group represented by Y ¹ , C
_2-20 alkenyl group, C _6-14 aryl group, acyl group, heterocyclic group, amino acid residue and peptidyl group consisting of 2 to 100 amino acids (group obtained by removing H from the N-terminus of an amino acid or peptide) The same as those described above are used as), and as the C _7-19 aralkyl group, for example, benzyl, naphthylethyl, trityl and the like are used. Examples of the substituent in the optionally substituted C _2-20 alkenyl group, C _7-19 aralkyl group or acyl group represented by Y ¹ include the above-mentioned halogen atom, C _1-6 alkoxy group (eg, methoxy, Ethoxy, propoxy, etc.),
Mono- or di- (C _1-6 alkoxy) phosphoryl (eg, methoxyphosphoryl, ethoxyphosphoryl, dimethoxyphosphoryl, etc.), phosphono group and the like are used, and the number of substituents is preferably 1 to 3. The substituent in the optionally substituted C _6-14 aryl group represented by Y ^1, those similar to the substituent in the optionally substituted C _6-14 aryl groups used are shown in the following Y ² To be Y
Examples of the substituent of the optionally substituted heterocyclic group represented by ¹ include halogen, C _1-10 alkyl group (eg, methyl, ethyl, propyl, etc.), C _3-10 cycloalkyl group (eg, cyclopropyl). , Cyclopentyl, cyclohexyl, etc.), C _2-10 alkenyl groups (eg vinyl, allyl (all
yl), crotyl, etc.) (may be substituted by one phenyl group) and C _6-14 aralkyl groups (eg, benzyl, phenylethyl, naphthylmethyl, etc.) (phenyl group is C
_1-5 alkoxy group (eg, 1 or 2 may be substituted with methoxy, ethoxy, propoxy, etc.) and the like are used, and the number of substituents is preferably 1 to 3.

Further, the substituent in the _optionally substituted C _1-20 alkyl group represented by Y ¹ is Y ² —X— in the general formula (V) (the symbols in the formula have the same meanings as described above).
A group represented by, halogen, C _1-6 alkoxy (eg, methyl, ethyl, propyl, etc.), mono- or di- (C
_1-6 alkoxy) phosphoryl (eg, monomethoxyphosphoryl, dimethoxyphosphoryl, monoethoxyphosphoryl and the like), phosphono group and the like are used, and the number of substituents is preferably 1 to 3. Y ¹ is preferably of formula Y ³ -X- (CH ₂₎ n
^{_{2 -, Y 4 -X- (CH}} 2) n 2 - or D- (symbols in the formula above as defined above) is a group represented by. Y ³ is preferably a C _3-7 cycloalkyl group (eg, cyclohexyl etc.), a linear or branched C _1-6 alkyl group (eg, methyl, ethyl, propyl etc.), halogen or methylenedioxy. May be substituted with
A C _6-14 aryl group (eg, phenyl, naphthyl, etc.) optionally condensed with a 5- or 6-membered aromatic heterocycle containing 4 nitrogen atoms, or a straight-chain or branched C _1-6 alkyl group A 5- or 6-membered aromatic heterocyclic group containing 1 to 2 nitrogen atoms and 1 sulfur atom, which may be substituted with a group or which may be condensed with a benzene ring, or 1 to 4 5- or 6-membered aromatic heterocyclic group containing a nitrogen atom (eg, 2-pyridyl, 3
-Pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, benzopyranyl, tetrazolyl, thiadiazolyl and the like). More preferably Y ³ is a 5- or 6-membered aromatic heterocyclic group containing 1 to 2 nitrogen atoms and 1 sulfur atom which may be substituted with a phenyl group or a C _1-4 alkyl group, or 1 to It is a 5- or 6-membered aromatic heterocyclic group containing 4 nitrogen atoms. Y ⁴ is preferably a linear or branched C _1-7 alkyl group which may be substituted with a phenyl group or a C _1-4 alkoxyphenyl group. A linear or branched C _1-7 alkyl group represented by Y ² , a C _3-7 cycloalkyl group, C
Examples of the _6-14 aryl group and heterocyclic group are the same as above. Examples of the substituent in the optionally substituted linear or branched C _1-7 alkyl group represented by Y ² include halogen, hydroxyl group, C _1-6 alkoxy group (eg, methoxy, ethoxy, propoxy, butoxy). , Hexyloxy, etc.) or an optionally esterified carboxyl group, and the number of substituents is preferably 1 to 3.

Substituents in the optionally substituted C _3-7 cycloalkyl group, C _6-14 aryl group and heterocyclic group represented by Y ² are halogen; nitro; halogen, hydroxyl group and C _{1 respectively. -6} alkoxy (eg, methoxy,
Linear or branched C _1-7 alkyl group (eg, methyl, ethyl, isopropyl, etc.) or C _3-7 cycloalkyl group (eg, optionally substituted with 1 to 3 ethoxy, propoxy, etc.) Cyclopropyl, cyclopentyl, cyclohexyl, etc.); hydroxyl group; linear or branched C _1-6 alkoxy group (eg, methoxy, ethoxy, isopropoxy, etc.); C _4-6 cycloalkoxy group (eg, cyclobutoxy, cyclopentyl) Oxy, cyclohexyloxy);
C _2-6 alkenyloxy group (eg, vinyloxy, allyloxy, crotyloxy, etc.); C _6-14 aralkyloxy group (eg, benzyloxy, phenylethyloxy, naphthylmethyloxy, etc.); C _2-7 alkanoyloxy group (eg, , Acetyloxy, propionyloxy, butyryloxy, etc.); C _6-14 aryloxy group (eg, phenoxy, naphthyloxy, anthryloxy, etc.); thiol group; linear or branched C _1-6 alkylthio group (eg. ,
Methylthio, ethylthio, isopropylthio, etc.); C
_4-7 cycloalkylthio group (eg, cyclopentylthio,
Cyclohexylthio, cycloheptylthio, etc.); C _6-14
Aralkylthio groups (eg, benzylthio, phenylethylthio, naphthylmethylthio, etc.); or C _2-7 alkanoylthio (eg, acetylthio, propionylthio, butyrylthio, etc.) are used, and the number of substituents is 1 to 4. preferable.

The lower alkanoyl group represented by R ⁵ is preferably a C _1-6 alkyl-carbonyl group such as an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, a pivaloyl group or a hexanoyl group, or , C _1-6 hydrocarbon groups (eg, methyl, ethyl,
A sulfonate acyl group having a C _1-6 alkyl group such as propyl or hexyl or phenyl) is used. R
⁵ is preferably hydrogen.

The substituted hydroxyl group represented by A and A'has an appropriate substituent for the hydroxyl group, particularly one having a hydroxyl group-protecting group, such as alkoxy,
Aryloxy is used in addition to alkenyloxy, aralkyloxy, acyloxy and the like. Examples of the alkoxy include linear or branched C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-
Butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, etc.) and cyclic C
_{A 4-6} alkoxy group (eg, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc.) is used, and the alkenyloxy is preferably a C _2-6 alkenyloxy group, for example, allyloxy, crotyloxy, 2-pentenyl. Oxy, 3-hexenyloxy,
2-Cyclopentenylmethoxy and the like are used. The aralkyloxy group is preferably a C _6-19 aralkyloxy group, more preferably a C _6-14 aryl-C _1-4.
An alkyloxy group (eg, benzyloxy, phenethyloxy, etc.) is used, and the acyloxy group is preferably an alkanoyl group such as a C _2-7 alkanoyloxy group (eg, acetyloxy, propionyloxy, n-
Butyryloxy, iso-butyryloxy, hexanoyloxy, etc.) are used, and as the aryloxy group, a C _6-14 aryloxy group (eg, phenoxy, biphenyloxy, etc.) is preferably used. 1 to 1 with a halogen atom, hydroxyl group, C _1-6 alkoxy group (eg, methoxy, ethoxy, propoxy, etc.)
Three may be substituted.

The substituted thiol group represented by A, A'and Z ¹ has an appropriate substituent in the group, particularly a group used as a protecting group for the group, for example,
Alkylthio, aralkylthio, acylthio and the like are used. The alkylthio is preferably a linear or branched C _1-6 alkyl group (eg, methyl, ethyl,
Isopropyl etc.) or C _4-7 cycloalkyl group (eg,
(Cyclopentyl, cyclohexyl, cycloheptyl, etc.)
A group having is used. The aralkylthio is preferably a C _7-19 aralkyl group (eg, benzyl, naphthylmethyl, anthrylethyl, etc.), more preferably C.
A group having a _6-14 aryl-C _1-4 alkyl group is used. As acylthio, preferably an alkanoyl group,
For example, a group having C _2-7 alkanoyl (eg, acetyl, propionyl, butyryl, etc.) is used. These alkylthio, aralkylthio and acylthio may be further, for example, the above-mentioned halogen atom, hydroxyl group, C _1-6 alkoxy group (eg, methoxy, ethoxy, propoxy, etc.).
1 to 3 may be substituted with.

As the substituted carboxyl group represented by A, A'and B, an esterified or amidated carboxyl group is used. Examples of the esterified carboxyl group include, for example, the formula —COOR ¹¹ (in the formula, R
^{And 11} represents an ester residue). As the ester residue represented by R ¹¹ , the optionally substituted hydrocarbon group represented by A or the optionally substituted heterocyclic group is used. Examples of the amidated carboxyl group include, for example, —CON (R ¹² ) (R ¹³ ), where R ¹² and R ¹³ are each hydrogen, an optionally substituted hydrocarbon group or an optionally substituted hydrocarbon group. A group represented by (indicating a heterocyclic group) is used. As the optionally substituted hydrocarbon group represented by R ¹² or R ¹³ or the optionally substituted heterocyclic group, those similar to those represented by A can be used.

The cyclic group in the optionally substituted cyclic group represented by Y ³ and Y ⁹ is an aromatic or non-aromatic homo- or heterocyclic group. As the aromatic homocyclic group, those similar to the aryl group exemplified as the hydrocarbon group represented by A can be used. As the non-aromatic homocyclic group, C _3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like can be used. As the aromatic or non-aromatic heterocyclic group, those similar to the heterocyclic group represented by A above can be used. As the substituents of these cyclic groups, the same substituents as the substituents of the optionally substituted aryl group illustrated in the optionally substituted hydrocarbon group represented by A above can be used. These substituents may be the same or different and 1-4, preferably 1-2, may be substituted on the ring.

The alkyl group and the substituent thereof in the optionally substituted alkyl group represented by Y ⁴ and Y ⁶ are the same as the alkyl group and the substituent thereof exemplified as the hydrocarbon group represented by A above. Is used.
As the C _5-20 alkyl group represented by Y ⁵ , those having 5 to 20 carbon atoms among the alkyl groups exemplified as the hydrocarbon group represented by A above are used. As the C _1-6 alkyl group represented by R ⁹ , R ¹⁰ and Y ⁷ , those having 1 to 6 carbon atoms among the alkyl groups exemplified as the hydrocarbon group represented by A above are used. As the C _5-7 cycloalkyl group represented by Y ⁷ , those having 5 to 7 carbon atoms among the cycloalkyl groups exemplified as the hydrocarbon group represented by A above are used. As the substituent in the optionally substituted phenyl group represented by Y ⁶ , R ¹⁰ and Y ⁷ , the same substituents as the aryl group exemplified as the hydrocarbon group represented by A above can be used. The case where the sulfur atom represented by X is oxidized means a sulfonyl group or a sulfinyl group.

Suitable salts of the 1,1-bisphosphonic acid compound in the present invention are conventional non-toxic salts such as alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt. Inorganic base salts such as salts or ammonium salts; eg methylamine salt, ethylamine salt, propylamine salt, isopropylamine salt, butylamine salt, tertiary butylamine salt, dimethylamine salt, diethylamine salt, trimethylamine salt, triethylamine salt, pyridine Organic base salts such as salts, picoline salts, dicyclohexylamine salts, N, N'-dibenzylethylenediamine salts, such as formates, acetates, trifluoroacetates, maleates, tartrates,
Organic acid addition salts such as methane sulfonate, benzene sulfonate, toluene sulfonate, inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, etc., salts with amino acids such as glutamate, etc. Used.

The 1,1-bisphosphonic acid compound, its lower alkyl ester or its salt used in the present invention is
It can be produced by a known method or a method known per se. For example, JP-A-54-37829 and JP-A-59-4239.
5, JP-A-60-174792, JP-A-1-258.
695, JP-A-1-308290 and JP-A-2-18.
4, JP-A-2-185, EP-A-0337706.
No. 3, Japanese Patent Application No. 3-151484, Japanese Patent Application No. 3-28307
It can be manufactured according to the method described in Japanese Patent No. 3 and Japanese Patent Application No. 3-287984. The bisphosphonic acid derivative used in the present invention can also be produced, for example, by the following method.

[0062]

[Chemical 40]

[Wherein R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R
¹⁸ is the same or different and is a lower alkyl group, X ¹ is an oxygen atom or a sulfur atom, and other symbols are as defined above]

[0064]

[Chemical 41]

[Wherein each symbol has the same meaning as above]

[0066]

[Chemical 42]

[Wherein each symbol has the same meaning as above]

[0068]

[Chemical 43]

[Wherein each symbol has the same meaning as above] In the above formula, the lower alkyl group represented by R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ is a lower alkyl group represented by R ^1. The same as is used. In the methods A to D, the amine derivative (XVII), (XX), (XXI) or (XXII) is replaced with an orthoformate derivative (XVIII) and a phosphite derivative.
(XIX) is reacted with a corresponding amount of bisphosphonate derivative (V-1), (VI-1), (VII-1) or (VIII-1)
Are manufactured respectively. A reaction solvent is not particularly required. The reaction is usually 80 ° C to 200 ° C, preferably 100 ° C to 17 ° C.
It is carried out at 0 ° C for 10 minutes to 24 hours.

[0070]

[Chemical 44]

[0071] The [wherein, R ¹⁹ represents a lower alkanoyl group, the other symbols are as defined above] in the above formula, a lower alkanoyl group represented by R ^19, similarly to the lower alkanoyl group represented by R ⁵ What is used. In Method E, the compound (V
Compound (VI-2) or (VII-2) is produced by acylating I-1) or (VII-1). This acylation reaction is carried out by reacting compound (VI-1) or (VII-1) with 1 to 2 equivalents of an acylating agent (eg, acid anhydride, acid halide, etc.) in a solvent or without a solvent. Be seen. As the solvent, benzene, xylene, toluene, chloroform, dichloromethane, ethyl acetate, ether, tetrahydrofuran or the like is used, and the temperature is 0 ° C to 100 ° C for 30 minutes to 1
It takes place in 0 hours.

[0072]

[Chemical formula 45]

[In the formula, k represents 1 or 2, and other symbols have the same meanings as above.] The oxidation reaction of Method F is carried out by oxidizing with an oxidizing agent according to a conventional method. As such an oxidizing agent, a mild oxidizing agent that does not substantially act on the skeleton of the sulfur-containing heterocyclic compound, preferably m-chloroperbenzoic acid, hydrogen peroxide,
Peresters, sodium metaperiodate and the like are used. This reaction is carried out in an organic solvent that does not adversely influence the reaction. Examples of the solvent include halogenated hydrocarbons (eg, methylene chloride, chloroform, dichloroethane, etc.), hydrocarbons (eg, benzene, toluene, etc.), alcohols (eg, methanol, ethanol, propanol, etc.), or these And the like are used. Oxidizing agents are compounds (V-2), (VI-2), (VII-2),
When used in an equimolar amount or less than the equimolar amount with respect to (VI-4) or (VII-5), the formula (V-3), (VI-
Among 3), (VII-4), (VI-5) and (VII-6), the compound in which k is 1 is preferentially produced. Formulas (V-3), (VI-3), (VII
-4), (VI-5) and (VII-6), the compound in which k is 2 has the formula (V-
3), (VI-3), (VII-4), (VI-5) and (VII-6)
Of these, the compound in which k is 1 is further oxidized and produced. This method proceeds at a temperature below room temperature (20 ° C to 30 ° C). The temperature is preferably about -50 ° C to 20 ° C.

[0074]

[Chemical formula 46]

[Wherein each symbol has the same meaning as described above] In the G method, the bisphosphonate produced by the AF method
(V-1), (V-3), (VI-1), (VI-2), (VI-3), (V
I-5), (VII-1), (VII-2), (VII-4) and (VII
-6) is hydrolyzed to produce the corresponding bisphosphonic acid. This reaction is carried out using an inorganic acid such as hydrochloric acid or hydrobromic acid or a trialkylsilicon halide in a solvent that does not adversely influence the reaction. When using inorganic acids such as hydrochloric acid or hydrobromic acid,
As the solvent, alcohols such as methanol, ethanol, 2-methoxyethanol, ethylene glycol, propanol and butanol, water, or a mixed solvent thereof is used. The amount of the acid used is usually in a large excess, and the reaction temperature is 0 ° C to 150 ° C, preferably 30 ° C to 100 ° C.
C, reaction time is 1 to 50 hours. When using halogenated alkyl silicons such as chlorotrimethyl silicon, bromo trimethyl silicon, and trimethyl silicon iodide, the solvent is carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane. And the like, halogenated carbons, acetonitrile, a mixed solvent thereof, and the like are used. Among the halogenated alkyl silicons, the amount used is compound (V-1), (V-3), (V
I-1), (VI-2), (VI-3), (VI-5), (VII-1),
4 to 1 for (VII-2), (VII-4) or (VII-6)
It is 0 equivalent, preferably 5 to 8 equivalents. Reaction temperature is -3
0 ° C to 100 ° C, preferably -10 ° C to 50 ° C, and the reaction time is 30 minutes to 100 hours. The bisphosphonic acid thus obtained is converted to a salt by a conventional method using a base such as potassium hydroxide, sodium hydroxide, sodium methoxide, ammonia or an organic amine.

[0076]

[Chemical 47]

[In the formula, Y ¹¹ represents a hydrocarbon group] In the above formula, the hydrocarbon group represented by Y ¹¹ is the same as the hydrocarbon group represented by A. Method H is a conventional method, for example, according to the method described in JP-A-56-73091, in which carboxylic acid derivative (XXII
I) together with phosphorus pentachloride and phosphorous acid at 30 ° C to 150 ° C.
0.5 ° C., preferably 50 ° C. to 130 ° C. for 0.5 to 10 hours,
It is preferably carried out by heating for 1 to 5 hours, and then adding water and further heating.

[0078]

[Chemical 48]

[Wherein, Q ¹ represents a leaving group, and other symbols have the same meanings as above] In the method I, (XXV) is reacted with (XXVI) in the presence of a base (XXVI).
I) is manufactured. The leaving group represented by Q ¹ is, for example, halogen, preferably chlorine, bromine or iodine, or a hydroxyl group activated by esterification, for example, a residue of an organic sulfonic acid (eg, p-toluenesulfonyloxy group). Etc.), alkylsulfonyloxy groups having 1 to 4 carbon atoms (eg, methanesulfonyloxy group, etc.), and diphenylphosphoryloxy groups, which are residues of organic phosphoric acid, dibenzylphosphoryloxy groups, dimethylphosphoryloxy groups, etc. . The reaction of (XXV) and (XXVI) is carried out in a suitable solvent. Examples of the solvent include benzene, toluene,
Aromatic hydrocarbons such as xylene, ethers such as dioxane, tetrahydrofuran and dimethoxyethane, alcohols such as methanol, ethanol and propanol, ethyl acetate, acetonitrile, pyridine, N, N-
Dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,
Examples include 1,2,2-tetrachloroethane, acetone, 2-butanone and a mixed solvent thereof. (XXV) and (XXV
The reaction of I) is carried out by using an appropriate alkali metal hydride such as sodium hydride or potassium hydride, an alkali metal salt such as sodium hydroxide or potassium hydroxide, an amine such as pyridine, triethylamine or N, N-dimethylaniline. It is carried out in the presence of a base, and the amount of these bases used is
About 1 to 5 mol is preferable with respect to (XXVI). This reaction is generally at -20 ° C to 150 ° C, preferably about 0 ° C to 130 ° C,
It takes 1 to 10 hours. The bisphosphonic acid derivative thus obtained can be hydrolyzed to give a bisphosphonic acid, if necessary. This hydrolysis reaction is performed in the same manner as in Method G.

[0080]

[Chemical 49]

[0081] [wherein, Y ¹² represents a hydrocarbon group, the other symbols are as defined above] in the above formula, the hydrocarbon group represented by Y ^12, similar to the hydrocarbon group represented by A Things are used. In method J, aldehyde derivative (XXVIII) and methylenebisphosphonate derivative (XXVI) were treated with tetrahedron (Tetrahed).
Ron), Vol. 30, p. 301 (1974). (XXIX) obtained by condensation of (XXVIII) and (XXVI) is then subjected to catalytic reduction by the method described in the same publication to produce (XXX). The hydrolysis of (XXX) is performed in the same manner as in Method G. Starting compounds of the present invention are, for example, EP-A-464509 and EP-A-491.
It can be produced by a publicly known method described in No. 374 or the like, or a publicly known method. That is, the raw material compound of the present invention can be produced, for example, by the following method.

[0082]

[Chemical 50]

[In the formula, Y ¹³ represents a hydrocarbon group] In the above formula, the hydrocarbon group represented by Y ¹³ is the same as the hydrocarbon group represented by A. In this method, phthalimide derivative (XXXII) is reacted with hydrazine hydrate to produce amine derivative (XXXIII). The reaction of (XXXII) and hydrazine hydrate is carried out in a suitable solvent. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, dioxane, tetrahydrofuran,
Ethers such as dimethoxyethane, alcohols such as methanol, ethanol and propanol, N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,
Examples include 1,2,2-tetrachloroethane and a mixed solvent thereof. The amount of hydrazine hydrate used is the compound (XXX
It is 1 to 10 molar equivalents, preferably 1.2 to 5 molar equivalents to II). This reaction is generally carried out at -20 ° C to 150 ° C, preferably about 0 ° C to 100 ° C for 1 to 10 hours. The compound used in the present invention is a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer,
It can be isolated and purified by chromatography or the like.

The compounds used in the present invention have a squalene synthase inhibitory action, but some of the compounds used in the present invention also inhibit other enzymes in the cholesterol biosynthetic pathway. In any case, the compound used in the present invention suppresses cholesterol biosynthesis, and therefore mammals (eg, mouse, rat, rabbit, dog, cat, cow,
It is useful for the prevention and treatment of hypercholesterolemia and coronary atherosclerosis in pigs, humans, etc.). When the compound of the present invention is administered to humans, the administration method may be either oral or parenteral. Compositions for oral administration include solid or liquid dosage forms, specifically tablets (including sugar-coated tablets, film-coated tablets), pills, granules, powders, capsules (including soft capsules), syrup. Agents, emulsions, suspensions and the like are used. Such a composition is produced by a method known per se and contains a carrier or an excipient that is usually used in the field of formulation. For example,
Carriers for tablets, excipients such as lactose, starch, sucrose,
Magnesium stearate or the like is used.

As the composition for parenteral administration, for example, injections, suppositories and the like are used, and the injections include subcutaneous injections, intradermal injections, intramuscular injections and the like. Such an injection is prepared by a method known per se, that is, by suspending or emulsifying the compound of the present invention in a sterile aqueous or oily solution which is usually used for injection. Examples of the aqueous solution for injection include physiological saline solution, isotonic solution and the like, and may be used in combination with an appropriate suspending agent such as sodium carboxymethyl cellulose, nonionic surfactant and the like, if necessary. Examples of the oily liquid include sesame oil and soybean oil, and solubilizing agents such as benzyl benzoate and benzyl alcohol may be used in combination. The prepared injection solution is usually filled in a suitable ampoule. When the compound of the present invention is used as a therapeutic agent for hypercholesterolemia, the daily dose for an adult is 1 to 500 mg, preferably 10 to 200 mg when orally administered, and no toxicity is observed within this range.

[0086]

EXAMPLES Next, the present invention will be described in more detail by showing experimental examples, test examples, production examples and reference examples. The measurement methods and results of the squalene synthase inhibitory action and the cholesterol biosynthesis inhibitory action of the compound of the present invention are shown. [Method for measuring squalene synthase inhibitory activity] The squalene synthase inhibitory activity is measured as follows using the enzyme solutions shown in Experimental Examples 1 and 2 below. That is, 5 μM
[1- ³ H] farnesyl pyrophosphate (specific activity 25 μCi /
μmole), 1 mM NADPH, 5 mM MgCl ₂ , 6 mM glutathione, 100 mM potassium phosphate buffer (pH 7.
4) and the test drug (added as an aqueous solution or DMSO solution) (total amount 50 μl), the enzyme solution (protein amount 0.8 μg) prepared in Experimental Examples 1 and 2 was added, and the mixture was reacted at 37 ° C. for 45 minutes Let The reaction is stopped by adding a mixed solution of 150 μl chloroform / methanol (1: 2, v / v), and then 50 μl chloroform and 50 μl 3N sodium hydroxide solution are added. 50 μl of a chloroform layer (lower layer) containing a reaction product containing squalene as a main component is mixed with 3 ml of a toluene liquid scintillator, and its radioactivity is measured by a liquid scintillation counter. The squalene synthase inhibitory activity was shown as the concentration (IC ₅₀ , molar concentration (M)) at which the radioactivity incorporated into the chloroform layer was inhibited by 50%.

Experimental Example 1 Preparation of rat enzyme Male Sprague-Dawley (SD) rats (6 weeks old) were exsanguinated and killed, and then the liver was excised.
About 10 g of liver was washed with ice-cold physiological saline, and then 15 ml of ice-cold buffer [100 mM potassium phosphate buffer (pH 7.4),
Homogenize in 15 mM nicotinamide, 2 mM MgCl ₂ ], and centrifuge at 10,000 × g for 20 minutes (4 ° C.). The obtained supernatant was further centrifuged at 105,000 × g for 90 minutes (4 ° C.), and then the precipitate was suspended in ice-cold 100 mM potassium phosphate buffer (pH 7.4), and then again subjected to 105,
Centrifuge at 000 × g for 90 minutes (4 ° C.). The precipitate (microsome fraction) thus obtained is cooled with ice to 100 m.
It was suspended in M potassium phosphate buffer (pH 7.4) (protein concentration of about 40 mg / ml, measured by BCA protein assay kit manufactured by Pierce) and used as the enzyme solution.

Experimental Example 2 Preparation of human enzyme Human hepatoma cells HepG2 (about 1 × 10 ⁹ cells) obtained by culturing in Dulbecco's modified Eagle medium containing 10% fetal bovine serum (37 ° C., in the presence of 5% CO ₂ ). ) 10 ml ice-cold buffer [100 mM potassium phosphate buffer (pH 7.4), 30
The cells are disrupted by sonication (twice for 30 seconds) after suspension in mM nicotinamide, 2.5 mM MgCl ₂ ]. A microsome fraction is obtained from the obtained sonicate by the same operation as in Experimental Example 1. This was suspended in ice-cold 100 mM potassium phosphate buffer (pH 7.4) (protein concentration about 4 mg / m
l) and used this as the enzyme solution. [Measurement Method of Cholesterol Biosynthesis Inhibitory Activity] The liver of a male SD rat (6 weeks old) is removed and sliced to a thickness of 500 μm with a taste chopper. 1% bovine serum albumin, 1% glucose, Krebs containing the test compound of [2- ¹⁴ C] acetate and various concentrations of 0.5 pCi - Ringer bicarbonate buffer (pH 7.4) This liver slices 1ml and 150~200mg Is incubated at 37 ° C. for 2 hours.
Cholesterol was extracted from the reaction solution and the amount of cholesterol synthesized from labeled acetic acid was examined and compared with the amount synthesized without addition of the test compound.

Test Example 1 Japanese Patent Application Nos. 3-151484 and 3-283073
Japanese Patent Application No. 3-287984 and Japanese Patent Laid-Open No. 1-308
Compound No. 1-produced according to the method described in No. 290.
20 and compound No. 21 (Production Example 1) were examined for squalene synthase inhibitory activity, and IC ₅₀ (M) shown in Table 1, Table 2 and Table 3 were obtained.

[0090]

[Table 1]

[0091]

[Table 2]

[0092]

[Table 3]

[0093] In an assay system using Test Example 2 Rat Liver Slice [2- ¹⁴ C] compounds on cholesterol biosynthesis from acetic acid number 22 (Example 39 described in Japanese Patent Application No. 3-151484) (20μ
When the effects of M addition) and Compound Nos. 67, 74, and 75 were examined, it was confirmed that, as shown in Table 4, cholesterol biosynthesis was significantly inhibited.

[0094]

[Table 4]

Test Example 3 The squalene synthase inhibitory activities of the compounds produced according to the following Production Examples were examined and IC ₅₀ (M) shown in Tables 5 to 6 were obtained.
Got

[0096]

[Table 5]

[0097]

[Table 6]

Production Example 1 Production of Compound No. 21 (1) Production of tetraisopropyl 2-styrylvinylidene bisphosphonate Tetrahydrofuran (30 ml) with stirring a solution of titanium tetrachloride (2.8 g) in carbon tetrachloride (3.5 ml) under ice cooling. Added to. Cinnamaldehyde (1.0 g) and tetraisopropylmethylenediphosphonate (2.6 g) were added to this mixture, and the mixture was stirred under ice cooling for 30 minutes.
Furthermore, N-methylmorpholine (1.5 g) was added to this mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and a saturated aqueous solution of sodium hydrogencarbonate in this order, and dried (MgSO ₄ ).
The solvent was distilled off to obtain crystals of tetraisopropyl 2-styrylvinylidene bisphosphonate (1.25 g, 36.0%). Recrystallized from isopropyl ether-hexane.
Colorless prism crystals, mp 103-104 ° C. Elemental analysis value: C ₂₂ H ₃₆ O ₆ P ₂ Theoretical value: C, 57.64; H, 7.91 Actual value: C, 57.48; H, 7.64

(2) Production of tetraisopropyl 4-phenylbutylidene-1,1-bisphosphonate Tetraisopropyl 2-styrylvinylidene bisphosphonate (4.0 g), 5% palladium on carbon (1 g) and ethanol (200 ml) were added to a hydrogen stream. Stirred for 2 hours. After the palladium carbon was filtered off, the solvent of the filtrate was distilled off. The residual oily substance was subjected to silica gel column chromatography, and an oily substance of tetraisopropyl 4-phenylbutylidene-1,1-bisphosphonate (2.56 g, was obtained from the fraction eluted with acetone-hexane (1: 1, v / v)). 6
3.7%). NMR (δ ppm, CDCl ₃ ): 1.29-1.33 (24H, m), 1.75-2.05
(4H, m), 2.15 (1H, tt, J = 24.0,6.0H _Z ), 2.63 (2H, t, J = 7.2H
_Z ), 4.67-4.85 (4H, m), 7.13-7.32 (5H, m). Elemental _{analysis: C 22 H 40 O 6 P} 2 and a theoretical: C, 57.13; H, 8.72 Found: C, 56.83; H, 8.93

(3) 4-phenylbutylidene-1,1-
Preparation of Bisphosphonic Acid Tetraisopropyl 4-phenylbutylidene-1,1
-Bisphosphonate (2.0g) in acetonitrile (7ml)
Bromotrimethylsilane (3.0 g) was added to the solution, and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with water (10 ml), stirred at room temperature for 30 minutes and then concentrated to obtain crystals of 4-phenylbutylidene-1,1-bisphosphonic acid (1.0 g, 78.7%). Recrystallized from water-acetone. Colorless prism, mp
191-192 ° C. Elemental analysis value: as C ₁₀ H ₁₆ O ₆ P ₂ theoretical value: C, 40.83; H, 5.48 actual value: C, 40.57; H, 5.59 Production Example 2 Production of compound No. 23 10- (phenylthio) decylamine (5. 78 g), ethyl orthoformate (8.07 g) and diethyl phosphite
A mixture of [HP (O) (OC ₂ H ₅ ) ₂ ] (15.03 g) was added at 150 ° C. to 3
Stir the time. The reaction mixture was concentrated under reduced pressure and the residual oily substance was subjected to silica gel column chromatography. Chloroform-ethyl acetate-methanol (15: 1)
10- (phenylthio) from the part that elutes at 5: 1, v / v)
Decylaminomethylene bisphosphonic acid tetraethyl ester (5.33 g, 44.4%) was obtained as an oil. NMR
(δ ppm in CDCl ₃ ): 1.26-1.45 (14H, m), 1.35 (12H, t, J = 7
Hz), 1.57-1.68 (3H, m), 2.82 (2H, t, J = 7 Hz), 2.92 (2H,
t, J = 7Hz), 3.25 (1H, t, J = 22 Hz), 4.14-4.30 (8H, m), 7.16
-7.36 (5H, m). Production Examples 3 to 28 Production of Compound Nos. 24 to 49 In the same manner as in Production Example 2, the compounds in Tables 7 to 13 were obtained.

[0101]

[Table 7]

[0102]

[Table 8]

[0103]

[Table 9]

[0104]

[Table 10]

[0105]

[Table 11]

[0106]

[Table 12]

[0107]

[Table 13]

Production Example 29 Production of Compound No. 50 6- (Phenylthio) hexylaminomethylenebisphosphonic acid tetraethyl ester (6.85 g) in dichloromethane (100 ml) was added to a solution of metachloroperbenzoic acid under ice cooling.
(2.62 g) was added portionwise over 30 minutes. The reaction mixture was stirred under ice-cooling for 3 hours, washed with saturated aqueous sodium hydrogen carbonate solution and water, and dried (MgSO ₄ ). The solvent was distilled off under reduced pressure, and the residual oily substance was subjected to silica gel column chromatography. From the portion eluted with ethyl acetate-chloroform-methanol (10: 10: 1, v / v), 6-
(Phenylsulfinyl) hexylaminomethylene bisphosphonic acid tetraethyl ester (5.84 g, 82.6)
%) As an oil. NMR (δ ppm in CDCl ₃ ): 1.21-1.
45 (5H, m), 1.34 (12H, t, J = 7 Hz), 1.61-1.80 (4H, m), 2.7
8 (2H, t, J = 7 Hz), 2.81 (2H, t, J = 7Hz), 3.23 (1H, t, J = 22 H
z), 4.13-4.29 (8H, m), 7.50-7.56 (3H, m), 7.58-7.65 (2
H, m). Production Examples 30 to 38 Production of Compound Nos. 51 to 59 In the same manner as in Production Example 29, the compounds shown in Tables 14 to 15 were obtained.

[0109]

[Table 14]

[0110]

[Table 15]

Production Example 39 Production of Compound No. 60 6- (phenylsulfinyl) hexylaminomethylene bisphosphonic acid tetraethyl ester (1.7 g) was dissolved in acetonitrile (25 ml) in bromotrimethylsilane (3.
(05 g) was added and the mixture was stirred at room temperature for 15 hours. Water (0.79 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour, and the precipitated solid was collected by filtration. This solid was added to methanol (1
Suspended in 5 ml), a solution of sodium methoxide in methanol (28%, 2.11 g) was added, followed by water (2 ml) and ether (45 ml). After stirring at room temperature for 1 hour, the precipitated crystals were collected by filtration. Recrystallized from water-methanol to give 6- (phenylsulfinyl) hexylaminomethylenebisphosphonic acid disodium salt (0.57 g, 36
%). Colorless prism crystals. Melting point: 300 ° C or higher. Elemental analysis Calculated as C ₁₃ H ₂₁ NO ₇ SP ₂ Na ₂ · 3 / 2H ₂ O: C, 33.20; H, 5.14; N, 2.98 Analytical value: C, 33.45; H, 4.93; N, 3.01 Production Example 40 -67 Compound Nos. 61 to 88 The compounds of Tables 16 to 19 were obtained in the same manner as in Production Example 39.

[0112]

[Table 16]

[0113]

[Table 17]

[0114]

[Table 18]

[0115]

[Table 19]

Production Example 68 Production of Compound No. 89 12- (Phenylthio) dodecylaminomethylenebisphosphonic acid tetraethyl ester (1.18 g) in acetonitrile (15 ml) was dissolved in bromotrimethylsilane (1.87).
g) was added and the mixture was stirred at room temperature for 15 hours. Water in the reaction mixture
(0.5 ml) was added, and the mixture was further stirred at room temperature for 1 hr and concentrated under reduced pressure. The residue was treated with methanol-ether (1:
It was dissolved in 3,40 ml), a methanol solution of sodium methoxide (28%, 1.57 g) and water (4 ml) were added, and the precipitated crystals were collected by filtration. Recrystallization from water-methanol 12-
There was obtained (phenylthio) dodecylaminomethylenebisphosphonic acid monosodium salt (0.49 g, 48%). Colorless prism crystals. Melting point: 300 ° C or higher. Elemental analysis Calculated as C ₁₉ H ₃₄ NO ₆ SP ₂ Na ・ 1 / 2H ₂ O: C, 45.78; H, 7.08; N, 2.81 Analytical value: C, 46.00; H, 7.01; N, 2.73 Production Example 69 to 72 Production of Compound Nos. 90 to 93 The compounds in Table 20 were obtained in the same manner as in Production Example 68.

[0117]

[Table 20]

Preparation Example 73 Preparation of Compound No. 94 4-phenoxybutylaminomethylenebisphosphonic acid disodium salt monohydrate (2.01 g) and concentrated hydrochloric acid (12 m
The mixture of l) was stirred for 1 hour at room temperature, and the precipitated crystals were collected by filtration. The crystals were added to a mixture of water (50 ml) and tris (hydroxymethyl) aminomethane (0.95 g).
The reaction mixture was freeze-dried to obtain 4-phenoxybutylaminomethylenebisphosphonic acid di [tris (hydroxymethyl) aminomethane] salt (2.22 g, 76.2%) as a colorless powder. Melting point: 98-100 ° C. Calculated as elemental analysis C ₁₉ H ₄₁ N ₃ O ₁₃ P ₂ : C, 39.25; H, 7.11; N,
7.23 Analytical value: C, 39.17; H, 7.25; N,
7.25

Production Example 74 Production of Compound No. 95 6- (phenylthio) hexylaminomethylenebisphosphonic acid tetraethyl ester (1.4 g) in acetonitrile
Bromotrimethylsilane (2.60 g) was added to the solution (20 ml), and the mixture was stirred at room temperature for 15 hours. Water (0.
(7 ml) was added, and the mixture was stirred at room temperature for 1 hour, and the precipitated solid was collected by filtration. This solid was added to a mixture of water (45 ml) and tris (hydroxymethyl) aminomethane (0.46 g). The reaction mixture was lyophilized to give 6- (phenylthio) hexylaminomethylenebisphosphonate di [tris].
(Hydroxymethyl) aminomethane] salt (1.15 g, 6
4.1%) was obtained as a colorless powder. Melting point: 92-94 ° C. Elemental analysis Calculated as C ₂₁ H ₄₅ N ₃ O ₁₂ SP ₂ 1 / 2H ₂ O: C, 39.75; H, 7.31; N, 6.62 Analytical value: C, 39.93; H, 7.39; N, 6.47

Production Examples 75-80 Compound Nos. 96-10
Production of 1 The compounds of Table 21 were obtained in the same manner as in Production Example 74.

[0121]

[Table 21]

Production Example 81 Production of Compound No. 102 11- (phenylthio) undecylaminomethylene bisphosphonic acid tetraethyl ester (2.40 g) in acetonitrile (35 ml) was dissolved in bromotrimethylsilane (3.9).
0 g) was added and the mixture was stirred at room temperature for 15 hours. Water in the reaction mixture
(1.0 ml) was added, and the mixture was further stirred at room temperature for 1 hr and concentrated under reduced pressure. The residue was treated with methanol-ether (1:
3, 80 ml), and a solution of sodium methoxide in methanol (28%, 3.34 g) and water (4 ml) were added,
The precipitated crystals were collected by filtration. Recrystallize from water-methanol 1
1- (Phenylthio) undecylaminomethylenebisphosphonic acid trisodium salt (1.33 g, 59.3%) was obtained. Colorless prism crystals. Melting point: 300 ° C or higher. Elemental analysis Calculated as C ₁₈ H ₃₀ NO ₆ SP ₂ Na ₃ 1 / 2H ₂ O: C, 40.91; H, 5.91; N, 2.65 Analytical value: C, 40.85; H, 6.14; N, 2.54

Production Example 82 Production of Compound No. 103 6- (1-methyl-1,2,3,4) was prepared in the same manner as in Production Example 81.
-Tetrazol-5-ylthio) hexylaminomethylenebisphosphonic acid trisodium salt was obtained. Colorless prism crystals. Melting point: 300 ° C or higher. Elemental analysis _{C 9 H 18 N 5 O 6} SP 2 Na 3 · H 2 O Calculated: C, 22.84; H, 4.26 ; N, 14.80 analysis: C, 23.09; H, 4.25 ; N, 14.65

Production Example 83 Production of Compound No. 104 Methylenebisphosphonic acid tetraisopropyl ester
Oily sodium hydride (60%, 0.24 g) was added to dimethoxyethane (25 ml) (3.44 g), and the mixture was stirred at room temperature for 1 hour, and then (E, E) -farnesyl bromide (1.4
A solution of 3 g) of dimethoxyethane (5 ml) was added dropwise at 0 ° C.
The reaction mixture was stirred at room temperature for 1 hour, poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO ₄ ), the solvent was evaporated under reduced pressure, and the residual oily substance was subjected to silica gel column chromatography. From the part eluted with ethyl acetate-chloroform (1: 1, v / v), (E, E)-
Farnesyl methylene bisphosphonic acid tetraisopropyl ester (1.67 g, 60.9%) was obtained as an oil. NMR (δ ppm in CDCl ₃ ): 1.34 (18H, d, J = 6Hz), 1.3
5 (6H, d, J = 6Hz), 1.60 (6H, s), 1.64 (3H, s), 1.68 (3H, s),
1.95-2.08 (8H, m), 2.17 (1H, tt, J = 6 & 24Hz), 2.61 (1H, tt,
J = 7 & 17Hz), 4.78 (4H, sextet, J = 6Hz), 5.06-5.14 (2H,
m), 5.35 (1H, t, J = 7Hz).

Production Example 84 Production of Compound No. 105 (E) -geranylmethylenebisphosphonic acid tetraisopropyl ester (52.1) was prepared in the same manner as in Production Example 83.
%) As an oil. NMR (δ ppm in CDCl ₃ ): 1.34
(18H, d, J = 6Hz), 1.35 (6H, d, J = 6Hz), 1.60 (3H, s), 1.64 (3
H, s), 1.68 (3H, d, J = 1Hz), 1.93-2.13 (4H, m), 2.17 (1H, t)
t, J = 6 & 24Hz), 2.60 (1H, tt, J = 7 & 17Hz), 4.78 (4H, sextet,
J = 6Hz), 5.05-5.13 (1H, m), 5.35 (1H, t, J = 7Hz).

Production Example 85 Production of Compound No. 106 A solution of (E, E) -farnesylmethylenebisphosphonic acid tetraisopropyl ester (3.0 g) in acetonitrile (40 ml) was mixed with bromotrimethylsilane (5.02).
g) was added and the mixture was stirred at room temperature for 15 hours. Water (1.3 ml) was added to the reaction mixture, and the mixture was further stirred at room temperature for 1 hr and concentrated under reduced pressure. The residue was dissolved in methanol-ether (1: 3, 60 ml) and sodium methoxide in methanol (28%, 4.22 g) and water (2
ml) was added and the precipitated crystals were collected by filtration. Recrystallization from water-methanol gave (E, E) -farnesyl methylene bisphosphonic acid trisodium salt (0.09 g, 3.0%). Colorless prism crystals. Melting point: 300 ° C or higher. Elemental analysis _{C 16 H 27 O 6 P 2} Na 3 · 5 / 2H 2 O Calculated: C, 39.11; H, 6.56 analysis: C, 39.04; H, 6.42

Production Example 86 Production of Compound No. 107 Platinum dioxide (P) was added to a solution of (E, E) -farnesylmethylenebisphosphonic acid tetraisopropyl ester (5.86 g) in ethanol (50 ml) -acetic acid (13 ml).
tO ₂ ) (0.1 g) was added, and catalytic reduction was performed at room temperature and 1 atm. The catalyst was filtered off, the filtrate was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and water and then dried (MgSO ₄ ), and the solvent was evaporated to remove 4,8,12-trimethyltridecylidene-1,1-bisphosphonic acid tetraisopropyl ester (5. 58
g, 94.3%) as an oil. Elemental analysis C ₂₈ H ₆₀ O ₆ P ₂ Calculated: C, 60.63; H, 10.90 analysis: C, 60.53; H, 10.82

Production Example 87 Production of Compound No. 108 4,8,12-Trimethyltridecylidene-1,1-bisphosphonic acid tetraisopropyl ester (3.0 g)
Bromotrimethylsilane (4.97 g) was added to the acetonitrile (40 ml) solution of and the mixture was stirred at room temperature for 15 hours. Water (1.3 ml) was added to the reaction mixture, and the mixture was further stirred at room temperature for 1 hr and concentrated under reduced pressure. The residue was dissolved in methanol-ether (1: 3, 60 ml) and sodium methoxide in methanol (28%, 4.17) was added.
g) and water (2 ml) were added, and the precipitated crystals were collected by filtration.
Recrystallization from water-methanol gave 4,8,12-trimethyltridecylidene-1,1-bisphosphonic acid disodium salt (1.41 g, 58.1%). Colorless prism crystals. Melting point: 300 ° C or higher. Elemental analysis Calculated as C ₁₆ H ₃₄ O ₆ P ₂ Na ₂ · H ₂ O: C, 42.86; H, 8.09 Analytical value: C, 43.00; H, 8.04

Production Example 88 Production of Compound No. 109 Phosphorous acid (H ₃ PO ₃ ) (4.0 g) was added to phosphorus pentachloride (1).
0.16 g) and chlorobenzene (15 ml) were added, and the mixture was stirred at room temperature for 10 minutes. Then 6- (2-
Pyridylthio) caproic acid (7.33 g) was added,
Stir at 0 ° C. for 3 hours. The chlorobenzene layer was removed and water (20 ml) was added to the remaining syrup. The mixture was heated at reflux for 1 hour and concentrated under reduced pressure. The residue was treated with acetone-ethanol to give colorless crystals (1.08
g) was obtained. The crystals were suspended in methanol (8 ml), and sodium methoxide in methanol (28%,
4.19 g), then water (0.5 ml) and ether (20 ml) were added and the mixture was stirred at room temperature for 1 hr, and the precipitated crystals were collected by filtration. Recrystallized from water-methanol to give 1-hydroxy-6- (2-pyridylthio) hexane-1,1-
Bisphosphonic acid trisodium salt (1.52 g, 10.
7%). Colorless prism crystals. Melting point: 300 ° C or higher. Elemental analysis C ₁₁ H ₁₆ NO ₇ SP ₂ Na ₃ Calculated value: C, 30.22; H, 3.69; N, 3.20 Analytical value: C, 29.92; H, 3.99; N, 3.39

Production Example 89 Production of compound No. 110 A mixture of 4- (N-acetyl-N-phenyl) butylaminomethylene-1,1-bisphosphonic acid tetraethyl ester (2.0 g) and concentrated hydrochloric acid (50 ml) was refluxed. Heated for 10 hours. The reaction mixture was concentrated under reduced pressure,
The residue was treated with acetone-ethanol to give a colorless powder. This powder was recrystallized from ethanol-acetone,
4- (phenylamino) butylaminomethylene-1,1
-Bisphosphonate hydrochloride (1.0 g, 61.0%) was obtained. Melting point: 187-189 [deg.] C. Elemental analysis Calculated as C ₁₁ H ₂₀ N ₂ O ₆ P ₂ · HCl · 1/2 (CH ₃ ) ₂ CO: C, 37.19; H, 5.99; N, 6.94 Analytical value: C, 37.51; H, 6.29; N, 7.00

Production Example 90 Production of Compound No. 111 A solution of (E, E) -farnesylaminomethylenebisphosphonic acid tetraethyl ester (2.50 g) in acetonitrile (25 ml) was mixed with bromotrimethylsilane (2.2).
6 g) was added and the mixture was stirred at room temperature for 3 days. Water (0.7 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour, and the precipitated solid was collected by filtration. This solid was added to methanol (15m
1) Suspended in 1), sodium methoxide in methanol (28%, 0.50 g) was added, followed by water (2 ml) and ether (45 ml). After stirring at room temperature for 1 hour, the precipitated crystals were collected by filtration. Recrystallization from water-methanol gave (E, E) -farnesylaminomethylenebisphosphonic acid monoethyl ester monosodium salt (0.32 g, 14%). Colorless prism crystals. Melting point: 188-189 [deg.] C. Elemental analysis Calculated as C ₁₈ H ₃₄ NO ₆ P ₂ Na · H ₂ O: C, 46.65; H, 7.83; N, 3.02 Analytical value: C, 47.04; H, 7.91; N, 3.12

Production Example 91 Production of Compound No. 112 A solution of (E, E) -farnesylaminomethylenebisphosphonic acid tetraethyl ester (2.42 g) in ethanol (25 ml) was added to sodium hydroxide (0.40 g).
Was added to the ethanol (25 ml) solution and the mixture was stirred under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (5.0 ml), and subjected to ion exchange column chromatography [Amberlite CG-50 (H ⁺ type)], (E,
E) -Farnesylaminomethylene bisphosphonic acid diethyl ester disodium salt (0.75 g, 29%)
Got Colorless powder. Melting point: 116-118 [deg.] C. Elemental analysis Calculated as C ₂₀ H ₃₇ NO ₆ P ₂ Na _2.5 / 5 / 2H ₂ O: C, 44.45; H, 7.83; N, 2.59 Analytical value: C, 44.08; H, 7.60; N, 2.59

Production Example 92 Production of Compound No. 113 In the same manner as in Production Example 90, 6- (phenylthio) hexylaminomethylenebisphosphonic acid monoethyl ester.
A monosodium salt was obtained. Colorless prism crystals. Melting point: 28
2-284 ° C. Elemental analysis Calculated as C ₁₅ H ₂₆ NO ₆ SP ₂ Na · H ₂ O: C, 39.91; H, 6.25; N, 3.10 Analytical value: C, 39.57; H, 6.13; N, 3.27

Production Example 93 Production of Compound No. 114 In the same manner as in Production Example 91, 6- (phenylthio) hexylaminomethylenebisphosphonic acid diethyl ester monosodium salt was obtained. Colorless powder. Melting point: 125-12
7 ° C. Elemental analysis Calculated as C ₁₇ H ₃₀ NO ₆ SP ₂ Na: C, 44.25; H, 6.55; N, 3.04 Analytical value: C, 44.11; H, 6.73; N, 3.27

Reference Example 1 Potassium carbonate (14.55 g) was added to thiophenol (9.67).
g) and 1,10-dibromodecane (26.33 g) N,
It was added to a solution of N-dimethylformamide (120 ml), and the mixture was stirred at room temperature for 3 hours. Then, potassium phthalimide
(16.25 g) was added to the mixture, and the mixture was further stirred at 100 ° C. for 3 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried and the solvent was distilled off (MgSO ₄₎ after under reduced pressure and the residual oil was subjected to silica gel column chromatography. Ethyl acetate-hexane (1:
3, v / v), N-[(10-phenylthio) decyl]
Phthalimide (10.31 g, 29.7%) was obtained. Recrystallized from isopropyl ether-hexane. Colorless needles. Melting point: 61-62 ° C. Reference Examples 2 to 6 In the same manner as in Reference Example 1, the compounds in Table 22 were obtained.

[0136]

[Table 22]

Reference Example 7 Potassium carbonate (9.95 g) was added to 2-mercaptopyrimidine.
(6.73 g) and 1,7-dibromoheptane (15.4)
8 g) of N, N-dimethylformamide (85 ml) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (Mg
SO ₄₎ After the solvent was distilled off under reduced pressure, the residual oil was subjected to silica gel column chromatography. Elution with ethyl acetate-hexane (1: 4, v / v) gave 2- (7-bromoheptylthio) pyrimidine (8.5 g) as an oil.
This oil was dissolved in N, N-dimethylformamide (45 ml), potassium phthalimide (5.44 g) was added, and 1
Stir at 00 ° C. for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgS
After O ₄ ), the solvent was distilled off under reduced pressure, and N- [7- (2-pyrimidinylthio) heptyl] phthalimide (10.36 g, 48.
6%) as an oil. NMR (δ ppm in CDCl ₃ ): 1.
33-1.49 (6H, m), 1.61-1.76 (4H, m), 3.13 (2H, t, J = 7Hz),
3.68 (2H, t, J = 7Hz), 6.93 (1H, t, J = 5Hz), 7.68-7.74 (2H,
m), 7.79-7.86 (2H, m), 8.49 (2H, d, J = 5Hz).

Reference Example 8 In the same manner as in Reference Example 7, N- [8- (2-pyrimidinylthio) octyl] phthalimide was obtained as an oil. Yield 4
8.1%. NMR (δ ppm in CDCl ₃ ): 1.26-1.51 (8H, m),
1.59-1.79 (4H, m), 3.13 (2H, t, J = 7Hz), 3.68 (2H, t, J = 7H
z), 6.94 (1H, t, J = 5Hz), 7.69-7.75 (2H, m), 7.80-7.87 (2
H, m), 8.51 (2H, d, J = 5Hz).

Reference Example 9 In the same manner as in Reference Example 7, N- [9- (2-pyrimidinylthio) nonyl] phthalimide was obtained as an oil. Yield 4
6.5%. NMR (δ ppm in CDCl ₃ ): 1.23-1.47 (10H,
m), 1.60-1.79 (4H, m), 3.13 (2H, t, J = 7Hz), 3.68 (2H, t, J
= 7Hz), 6.94 (1H, t, J = 5Hz), 7.69-7.75 (2H, m), 7.81-7.8
7 (2H, m), 8.51 (2H, d, J = 5Hz).

Reference Example 10 In the same manner as in Reference Example 7, N- [10- (2-pyrimidinylthio) decyl] phthalimide was obtained as an oil. Yield 4
6.8%. NMR (δ ppm in CDCl ₃ ): 1.19-1.47 (12H, m),
1.61-1.79 (4H, m), 3.14 (2H, t, J = 7Hz), 3.68 (2H, t, J = 7H
z), 6.94 (1H, t, J = 5Hz), 7.69-7.75 (2H, m), 7.81-7.87 (2
H, m), 8.51 (2H, d, J = 5Hz).

Reference Example 11 Potassium carbonate (8.29 g) was mixed with 2-naphthalenethiol.
(8.01 g) and 1-bromo-6-chlorohexane
(9.98 g) was added to a solution of N, N-dimethylformamide (65 ml), and the mixture was stirred at room temperature for 3 hours. Then potassium phthalimide (9.26 g) was added to the mixture and another 10
Stir at 0 ° C. for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO
₄ ) After that, the solvent was distilled off under reduced pressure to obtain N- [6- (2-naphthylthio) hexyl] phthalimide (18.56 g, 95.3%). Recrystallized from ethyl acetate-hexane. Colorless plate crystals. Melting point: 109-110 ° C.

Reference Examples 12 to 19 The compounds in Table 23 were obtained in the same manner as in Reference Example 11.

[0143]

[Table 23]

Reference Example 20 In the same manner as in Reference Example 11, N- [6- (2-thiazolylthio) hexyl] phthalimide was obtained as an oil. Yield 9
0.5%. NMR (δ ppm in CDCl ₃ ): 1.33-1.58 (4H, m),
1.62-1.83 (4H, m), 3.20 (2H, t, J = 7Hz), 3.68 (2H, t, J = 7H
z), 7.20 (1H, t, J = 3Hz), 7.66 (1H, d, J = 3Hz), 7.69-7.75
(2H, m), 7.80-7.87 (2H, m).

Reference Example 21 In the same manner as in Reference Example 11, N- [6- (1-methyl-2-imidazolylthio) hexyl] phthalimide was obtained as an oil. Yield 90.7%. NMR (δ ppm in CDCl ₃ ): 1.30-
1.50 (4H, m), 1.67 (4H, m), 3.06 (2H, t, J = 7Hz), 3.61 (3H,
s), 3.67 (2H, t, J = 7Hz), 6.92 (1H, d, J = 1Hz), 7.05 (1H, d,
J = 1Hz), 7.69-7.75 (2H, m), 7.80-7.87 (2H, m).

Reference Example 22 In the same manner as in Reference Example 11, N- [6- (imidazolo [1,2-
a] Pyridin-5-ylthio) hexyl] phthalimide was obtained as an oil. Yield 61.5%. NMR (δ ppm in CDC
l ₃ ): 1.31-1.57 (4H, m), 1.68 (4H, m), 2.99 (2H, t, J = 7H
z), 3.68 (2H, t, J = 7Hz), 6.88 (1H, d, J = 7Hz), 7.16 (1H, dd,
J = 7 & 9Hz), 7.57 (1H, d, J = 9Hz), 7.69 (1H, s), 7.69-7.76 (2
H, m), 7.82 (1H, s), 7.80-7.87 (2H, m).

Reference Example 23 A solution of acetanilide (7.0 g) in N, N-dimethylformamide (50 ml) was added with oily sodium hydride (60 mg).
%, 2.45 g) and stirred at 0 ° C. for 15 minutes, then N
A solution of-(4-bromobutyl) phthalimide (15.3 g) in N, N-dimethylformamide (80 ml) was added dropwise. The mixture was stirred at room temperature for 4 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried (M
After gSO ₄ ) the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-chloroform (1: 9, v / v) to give N- [4- (N-acetyl-N-phenylamino) butyl] phthalimide (9. 21 g, 52.9%) was obtained. Recrystallized from isopropyl ether. Colorless prism crystals. Melting point 83-8
4 ° C.

Reference Example 24 N-[(10-phenylthio) decyl] phthalimide (1
A mixture of 0.1 g), hydrazine monohydrate (2.56 g) and ethanol (75 ml) was heated under reflux for 1 hour. The precipitated crystals were filtered off, and the filtrate was concentrated under reduced pressure. The residual oily substance was subjected to distillation under reduced pressure to obtain 10-phenylthiodecylamine (5.78 g, 85.3%) as an oily substance. Boiling point 174-176 [deg.] C. (0.8 mmHg). Reference Examples 25 to 43 In the same manner as in Reference Example 24, the compounds shown in Tables 24 to 25 were obtained.

[0149]

[Table 24]

[0150]

[Table 25]

Reference Example 44 N- [6- (s-triazolo [4,3-a] pyridine-3
-Ylthio) hexyl] phthalimide (16.5 g),
A mixture of hydrazine monohydrate (4.34 g) and ethanol (135 ml) was heated under reflux for 1 hour. The precipitated crystals were filtered off, and the filtrate was concentrated under reduced pressure to give 6- (s-triazolo [4,3-a] pyridin-3-ylthio) hexylamine as an oil. Yield 87.5%. NMR (δ
_{ppm in CDCl 3): 1.23-1.58 (} 6
H, m), 1.48 (2H, s), 1.72 (2H,
m), 2, 67 (2H, t, J = 7 Hz), 3.15
(2H, t, J = 7 Hz), 6.92 (1H, t, J =
7Hz), 7.30 (1H, ddd, J = 1 & 7 & 9H
z), 7.77 (1H, d, J = 10 Hz), 8.12
(1H, d, J = 7 Hz).

Reference Example 45 In the same manner as in Reference Example 44, 6- (imidazolo [1,2-
a] Pyridin-5-ylthio) hexylamine was obtained as an oil. Yield 95.9%. NMR (δ ppm in CDCl ₃ ): 1.
24-1.53 (6H, m), 1.39 (2H, s), 1.59-1.75 (2H, m), 2.68 (2H,
t, J = 7Hz), 3.00 (2H, t, J = 7Hz), 6.87 (1H, dd, J = 1 & 7Hz), 7.15
(1H, dd, J = 7 & 9Hz), 7.56 (1H, d, J = 9Hz), 7.69 (1H, d, J = 1Hz),
7.83 (1 H.s).

Reference Example 46 In the same manner as in Reference Example 44, 6- (2-benzothiazolylthio) hexylamine was obtained as an oil. Yield 78.3
%. NMR (δ ppm in CDCl ₃ ): 1.27-1.58 (6H, m), 1.37 (2H,
s), 1.84 (2H, m), 2.69 (2H, t, J = 7Hz), 3.35 (2H, t, J = 7Hz), 7.
29 (1H, dt, J = 1 & 8Hz), 7.42 (1H, dt, J = 1 & 8Hz), 7.76 (1H, dd, J
= 1 & 8Hz), 7.87 (1H, d, J = 7Hz).

Reference Example 47 A mixture of N- [4- (N-acetyl-N-phenylamino) butyl] phthalimide (9.2 g), hydrazine monohydrate (10 ml) and ethanol (200 ml) was refluxed to give 1 mixture. Heated for hours. The precipitated crystals were filtered off and the filtrate was concentrated under reduced pressure to give 4- (N-acetyl-N-phenylamino) butylamine (4.55 g, 80.7%) as an oil. NMR (δ ppm in CDCl ₃ ): 1.35-1.65 (4H, m),
1.60 (2H, s), 1.83 (3H, s), 2.69 (2H, t, J = 7Hz), 3.71 (2H, t, J
= 7Hz), 7.33-7.48 (3H, m).

[0155]

INDUSTRIAL APPLICABILITY According to the present invention, a squalene synthase inhibitor useful as a therapeutic agent for hypercholesterolemia and a novel compound having a squalene synthase inhibitory activity are provided.

Front page continuation (72) Inventor Tsuneo Oda 656 Kumecho, Kumecho, Fushimi-ku, Kyoto-shi, Kyoto Prefecture

Claims (30)

[Claims] 1. A squalene synthase inhibitor containing a 1,1-bisphosphonic acid compound, a lower alkyl ester thereof, or a salt thereof. 2. A 1,1-bisphosphonic acid compound represented by the general formula (I): [Wherein R ¹ , R ² , R ³ and R ⁴ are hydrogen or a lower alkyl group, A is hydrogen, halogen, nitro, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group ,
Optionally substituted acyl group, an optionally substituted amino group, an optionally substituted hydroxyl group, an optionally substituted thiol group, Ra-SO-, Ra-SO 2 -, Ra
-CS- (in the formula, Ra represents an optionally substituted hydrocarbon group) or an optionally substituted carboxyl group, B is hydrogen, halogen, an optionally substituted hydrocarbon group, or an optionally substituted hydrocarbon group. A heterocyclic group which may be substituted or a carboxyl group which may be substituted]. 3. A 1,1-bisphosphonic acid compound represented by the general formula (II): [In the formula, A'is hydrogen, halogen, nitro, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted acyl group, or an optionally substituted amino group. , An optionally substituted hydroxyl group, an optionally substituted thiol group, Ra—SO—, Ra—SO ₂ — (wherein Ra represents an optionally substituted hydrocarbon group) or a substituted group. 1 is a compound represented by an optional carboxyl group and the other symbols have the same meanings as defined above.
The squalene synthase inhibitor described. 4. A 1,1-bisphosphonic acid compound represented by the general formula (III): [Wherein Z ¹ is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted acyl group, an optionally substituted amino group, or an optionally substituted good thiol group, Ra-SO ₂ - or Ra-CS- (in the formulas, Ra represents a hydrocarbon group which may be substituted)
And Z ² represents hydrogen, a hydroxyl group, a halogen or an amino group which may be substituted, and the other symbols have the same meanings as those defined above.] The squalene synthase inhibitor according to claim 1. 5. A 1,1-bisphosphonic acid compound represented by the general formula (IV): [In the formula, Y ¹ is an optionally substituted C _1-20 alkyl group,
_Optionally substituted C _2-20 alkenyl group, _optionally substituted C _6-14 aryl group, _optionally substituted C
_7-19 Aralkyl group, optionally substituted acyl group, optionally substituted heterocyclic group, amino acid residue or 2 to
The squalene synthase inhibitor according to claim 1, wherein the squalene synthase inhibitor is a compound represented by a peptidyl group consisting of 100 amino acids, R ⁵ is hydrogen or a lower alkanoyl group, and other symbols are as defined above. 6. A 1,1-bisphosphonic acid compound represented by the general formula (V): [In the formula, Y ² is an optionally substituted linear or branched C _1-7 alkyl group, an optionally substituted C _3-7 cycloalkyl group, an optionally substituted C _{6- 14 an} aryl group or an optionally substituted heterocyclic group, X is an oxygen atom or an optionally oxidized sulfur atom, n ₁ is an integer of ₁ to 20, and other symbols are as defined above] The squalene synthase inhibitor according to claim 5, which is a compound represented by: 7. A 1,1-bisphosphonic acid compound represented by the general formula (VI): [In the formula, Y ³ represents an optionally substituted cyclic group, and n ₂ represents 2
The squalene synthase inhibitor according to claim 5, wherein the squalene synthase inhibitor is a compound represented by an integer of 15 to 15, and other symbols are the same as those defined above. 8. A 1,1-bisphosphonic acid compound represented by the general formula (VII): [In the formula, Y ⁴ represents an optionally substituted alkyl group,
The other symbols are compounds represented by the same meaning as above], The squalene synthase inhibitor according to claim 5. 9. A 1,1-bisphosphonic acid compound represented by the general formula (VIII): The squalene synthase inhibitor according to claim 5, which is a compound represented by the formula: wherein Y ⁵ represents a C _5-20 alkyl group and other symbols have the same meanings as defined above. 10. A 1,1-bisphosphonic acid compound represented by the general formula (IX): [Wherein, R ⁶ and R ⁷ are the same or different hydrocarbon groups which may be substituted, n ₃ is an integer of 2 to 10, and other symbols are as defined above] The squalene synthase inhibitor according to claim 1. 11. A 1,1-bisphosphonic acid compound represented by the general formula (X): [In the formula, R ⁸ is hydrogen or a hydroxyl group, Y ⁶ is hydrogen, an optionally substituted alkyl group or an optionally substituted phenyl group, and n ₄ is an integer of 0 to 10 (wherein R ⁸ is A squalene synthase inhibitor according to claim 1, wherein n ₄ is not 0 in the case of a hydroxyl group, and the other symbols are the same as those defined above]. 12. A 1,1-bisphosphonic acid compound is represented by the general formula (XI): [In the formula, R ⁹ is hydrogen, a C _1-6 alkyl group or -CONH ₂
R ¹⁰ is hydrogen, a C _1-6 alkyl group, a benzyl group or an optionally substituted phenyl group, and Y ⁷ is a linear or branched C _1-6 alkyl group, C _5-7 cycloalkyl A compound, a phenyl group which may be substituted, or a 5- or 6-membered heterocyclic group which may be substituted, m is an integer of 0 to 2, and other symbols are as defined above. The squalene synthase inhibitor according to claim 1. 13. A 1,1-bisphosphonic acid compound represented by the general formula (XII): [Wherein Y ⁸ is an optionally substituted heterocyclic group, n ₅ is an integer of 2 to 6, and other symbols are as defined above]. Squalene synthase inhibitor. 14. The 1,1-bisphosphonic acid compound is represented by the general formula (XIII): [In the formula, Y ⁹ represents an optionally substituted cyclic group, and n ₆ represents 0
The squalene synthase inhibitor according to claim 1, wherein the squalene synthase inhibitor is a compound represented by an integer of 1 to 15 and the other symbols are the same as those defined above. 15. The 1,1-bisphosphonic acid compound has the general formula (XIV): [In the formula, Y ¹⁰ represents phenyl, pyridyl or pyrimidinyl, n ₇ represents an integer of 4 to 12, and other symbols have the same meanings as described above]. Agent. 16. The squalene synthase inhibitor according to claim 15, wherein in the general formula (XIV), n ₇ is an integer of 4 to 10. 17. In the general formula (XIV), Y ¹⁰ is phenyl,
The squalene synthase inhibitor according to claim 16, wherein X is S, n ₇ is 7, and R ¹ , R ² , R ³ and R ⁴ are hydrogen. 18. In the general formula (XIV), Y ¹⁰ is phenyl,
17. The squalene synthase inhibitor according to claim 16, wherein X is S, n ₇ is 10, and R ¹ , R ² , R ³ and R ⁴ are hydrogen. 19. In the general formula (XIV), Y ¹⁰ is phenyl,
The squalene synthase inhibitor according to claim 16, wherein X is SO, n ₇ is 9 and R ¹ , R ² , R ³ and R ⁴ are hydrogen. 20. In formula (XIV), Y ¹⁰ is phenyl,
X is SO, n ₇ is 10, and R ¹ , R ² , R ³ and R ⁴
17. The squalene synthase inhibitor according to claim 16, wherein is hydrogen. 21. The general formula (XV): [In the formula, n ₈ represents an integer of 11 to 15, and other symbols have the same meanings as above], or a salt thereof. 22. The general formula (XVI): [Wherein each symbol has the same meaning as defined above] or a salt thereof. 23. The general formula (XXXII): [Wherein, D represents a hydrocarbon group which may be substituted, n ₉ represents 0 or 1, and other symbols have the same meanings as above], or a salt thereof. 24. D is of the general formula: The compound or a salt thereof according to claim 23, which is a group represented by the formula: wherein n ₁₀ represents an integer of 1 to 3. 25. D is a general formula: The compound or salt thereof according to claim 23, which is a group represented by the formula [wherein the symbols are as defined above]. 26. The 1,1-bisphosphonic acid compound is the compound according to any one of claims 21 to 25.
The squalene synthase inhibitor described. 27. Y ³ is a C _3-7 cycloalkyl group,
It may be substituted with a linear or branched C _1-6 alkyl group, halogen or methylenedioxy, and 1
5-6 membered aromatic heterocycle containing 4 to 4 nitrogen atoms, optionally substituted with a C _6-14 aryl group which may be condensed or a linear or branched C _1-6 alkyl group Well, a 5- to 6-membered aromatic heterocyclic group containing 1 to 2 nitrogen atoms and 1 sulfur atom which may be condensed with a benzene ring or 1 to 4 nitrogen atoms containing 1 to 4 nitrogen atoms The squalene synthase inhibitor according to claim 7, which is an aromatic heterocyclic group. 28. A 5- or 6-membered aromatic heterocyclic group, wherein Y ³ contains 1 to 2 nitrogen atoms and 1 sulfur atom, which may be substituted with a phenyl group or a C _1-4 alkyl group, or The squalene synthase inhibitor according to claim 7, which is a 5- or 6-membered aromatic heterocyclic group containing 1 to 4 nitrogen atoms. 29. The squalene synthase inhibitor according to claim 8, wherein Y ⁴ is a linear or branched C _1-7 alkyl group which may be substituted with a phenyl group or a C _1-4 alkoxyphenyl group. . 30. A therapeutic agent for hypercholesterolemia containing a 1,1-bisphosphonic acid compound, a lower alkyl ester thereof or a salt thereof.