JPH0625258A - Thiazatetracycloundecadiene derivative - Google Patents

Abstract

PURPOSE:To provide the subject new compound having activity to reduce levels of the triglycerides or low-specific gravity lipoproteins in the blood, useful as a preventive/medicine for hyperlipemia. CONSTITUTION:The compound of formula I [R<1>-R<4> are each H or 1-6C alkyl; R<5> is H, (nitro-substituted)aryl or 2-7C alkoxycarbonyl; R<6> and R<7> are each 1-6C alkyl; R is cyano, aromatic acyl or 2-7C alkoxycarbonyl; (n) is 1-6], e.g. trimethyl-3-methylthio-4-thio-1-azatetracyclo-[5,4,0,0<5>,<11>,0<6>,<8 >]undeca-2,9-diene--2,5,6- tricarboxylate. The compound of the formula I can be obtained by reaction of a pyridinium ylide derivative of formula II with an acetylenedicarboxylic ester of formula III.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a thiazatetracycloundecadiene derivative useful as a medicine.

More specifically, the present invention has the effect of lowering the amounts of triglyceride and low-density lipoprotein (LDL) in blood, and is useful as a prophylactic and therapeutic agent for hyperlipidemia.

[0003]

[Chemical 2]

(In the formula, R ¹ , R ² , R ³ and R ⁴ may be the same or different and each is a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, and R ⁵ is a hydrogen atom,
It is an aryl group which may be substituted with a nitro group or a lower alkoxycarbonyl group having 2 to 7 carbon atoms, R ⁶ and R ⁷ may be the same or different and each is a lower alkyl group having 1 to 6 carbon atoms. R is a cyano group, an aromatic acyl group or a lower alkoxycarbonyl group having 2 to 7 carbon atoms, and n is an integer of 1 to 6), and a novel thiazatetracycloundecadiene derivative represented by It relates to these acid addition salts.

[0005]

BACKGROUND OF THE INVENTION The thiazatetracycloundecadiene derivative represented by the general formula (I) of the present invention is a completely novel compound, and hitherto relates to a compound having such a thiazatetracycloundecadiene skeleton. No reports have been made.

[0006]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide the above-mentioned general formula (I) which has a blood triglyceride and low density lipoprotein (LDL) lowering effect and is useful as a prophylactic and therapeutic agent for hyperlipidemia. The present invention provides a novel thiazatetracycloundecadiene derivative represented by and an acid addition salt thereof.

[0007]

Means for Solving the Problems The inventors of the present invention have conducted diligent research to find out a new compound having a blood triglyceride lowering action. The present invention has been completed by reducing the amount of specific gravity lipoprotein (LDL) and finding that it is useful as a preventive and therapeutic agent for hyperlipidemia.

Here, in the compound represented by the general formula (I) of the present invention, the alkyl group means a straight-chain or branched alkyl group, and the alkoxycarbonyl group means a straight-chain or branched alkyl group. Refers to an alkoxycarbonyl group having a group. The aryl group means an aromatic hydrocarbon group such as a phenyl group and a naphthyl group, and the aromatic acyl group means an acyl group having an aromatic hydrocarbon group such as a benzoyl group and a naphthoyl group.

The thiazatetracycloundecadiene derivative represented by the general formula (I) of the present invention is a novel compound and can be produced as follows. That is, the general formula

[0010]

[Chemical 3]

A pyridinium ylide derivative represented by the general formula: wherein R, R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meanings as described above.

[0012]

[Chemical 4]

It can be produced by reacting with an acetylenedicarboxylic acid ester represented by the formula (R ⁶ and R ⁷ have the same meanings as described above).

The reaction of the present production method for producing the thiazatetracycloundecadiene derivative represented by the general formula (I) of the present invention is carried out by using the compound of the general formula

[0015]

[Chemical 5]

(Wherein R, R ¹ , R ² , R ³ , R ⁴ , R
⁵ , R ⁶ , R ⁷ and n have the same meanings as described above), and proceed via the pyridothiazepine derivative. When the thiazatetracycloundecadiene derivative of the general formula (I) of the present invention is produced, the pyridothiazepine derivative may be isolated once and further reacted, or the reaction may be continuously performed without isolation. Good. The isolation and purification operation of the intermediate of the present production method does not significantly affect the improvement of the purity and yield of the target compound of the present invention to be obtained, and therefore it is simpler and more efficient to perform it continuously.

The above-mentioned processes for preparing the compounds of general formula (I) according to the invention are generally carried out in an inert solvent.

As the inert solvent, for example, chloroform, methylene chloride, benzene, ethanol, methanol and the like can be used.

The compound represented by the general formula (H) used as a starting material is the compound of Bulletin of the Chemical Society of Japan (Bull. Ch.
em. Soc. Jpn. ), 60 volumes, 1867-187
Page 9, 1987, 62, 119-127, 1989, or a method similar thereto.

The compound represented by the general formula (II) has the general formula

[0021]

[Chemical 6]

(Wherein R, R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meanings as described above), and their states differ in reaction conditions and the like. It changes according to.

The compound represented by the general formula (III) used as a starting material is commercially available or can be easily produced by esterifying a commercially available acetylenedicarboxylic acid according to a conventional method. .

In order to carry out the present invention in a suitable manner, it is not always constant depending on the kind of raw material, but usually the above general formula (I
1 to 2 equivalents of the compound represented by I) in chloroform,
Preferably, 1 to 1.1 equivalents of the compound represented by the general formula (III) and the compound represented by the general formula (IV), which is an intermediate, are used at room temperature to the reflux temperature, preferably at the reflux temperature for several hours. Without isolating the pyridothiazepine derivative
It can be efficiently carried out by continuously reacting. The compound of the present invention thus obtained can be easily purified by a usual operation such as column chromatography or fractional crystallization.

The thiazatetracycloundecadiene derivative represented by the general formula (I) of the present invention can be converted to an acid addition salt according to a conventional method. Examples of these salts include hydrochloride and hydrobromide. , Phosphate, sulfate, methanesulfonate,
Examples thereof include benzene sulfonate, p-toluene sulfonate, acetate, citrate, succinate, tartrate and fumarate.

The thiazatetracycloundecadiene derivative represented by the general formula (I) of the present invention markedly reduces blood triglyceride and low-density lipoprotein (LDL) in an in vivo experiment using mice. Shows the action.

Moreover, 250 mg / mouse is given to mice and rats.
Since there are no deaths and no symptoms of poisoning are observed even after oral administration of kg, it is useful as a highly safe prophylactic and therapeutic agent for hyperlipidemia.

The thiazatetracycloundecadiene derivative represented by the general formula (I) of the present invention can be made into a pharmaceutical composition according to a conventional method. Examples of such pharmaceutical composition include tablets, capsules, granules, injections, patches, suppositories and the like.

When the pharmaceutical composition containing the thiazatetracycloundecadiene derivative represented by the above general formula (I) of the present invention is used for treatment, the dose thereof is
The dose can be appropriately adjusted depending on the sex, age, body weight, etc. of the patient, but the dose can be generally orally administered in the range of 5 to 5000 mg per adult and parenterally in the range of 1 to 1000 mg per day.

[0030]

The contents of the present invention will be described in more detail with reference to the following examples and reference examples. The melting points of the compounds in each example are all uncorrected.

Reference Example 1 Dimethyl 5-cyano-4-methylthio-10aH-pyrido [1,2-d] [1,4] thiazepine-1,2-dicarboxylate pyridinium-1- [1-cyano-1
-[(Methylthio) thiocarbonyl]] methylide (0.
624 g) and dimethyl acetylenedicarboxylate (0.4
26 g) of chloroform solution (20 ml) at room temperature for 12
Stir for a reaction to react. Chloroform as a solvent was distilled off from this reaction solution, and then the residue was separated using ether as an eluent by column chromatography using silica gel as a packing material. Eluted red fractions were collected and ether was distilled off by an evaporator. The residue was recrystallized from ether-hexane to give 34% of the title compound as red prism crystals.
Obtained in yield.

Melting point: 127 to 128 ° C. IR (KBr): νCN 2218 cm ⁻¹ νCO 1725 cm ⁻¹ NMR (CDCl ₃ ) δ: 2.52 (3H, s), 3.71 (3H, s),
3.87 (3H, s), 5.26 (1H, brt),
5.46 (1H, m), 5.87 (1H, d), 6.2
0 (1H, m), 6.65 (1H, brd) Elemental analysis value: (as C ₁₅ H ₁₄ N ₂ O ₄ S ₂ )

Reference Examples 2 to 6 The following compounds were obtained in the same manner as in Reference Example 1 using the corresponding derivatives. In addition, Bz in the table represents a benzoyl group.

[0034]

[Chemical 7]

[0035]

[Table 1]

Example 1 Trimethyl 3-methylthio-4-thio-1-azatetracyclo [5.4.0.0 ^5,11 . 0 ^6,8 ] Undeca-2,9-diene-2,5,6-tricarboxylate pyridinium-1- [1-methoxycarbonyl-1-
[(Methylthio) thiocarbonyl]] methylide (1.2
A chloroform solution (30 ml) of (05 g) and dimethyl acetylenedicarboxylate (1 g) was heated and refluxed in a water bath for 4 hours to cause a reaction. After the reaction solution was cooled to room temperature, the solvent chloroform was distilled off. The residue was separated by column chromatography using silica gel as a packing material and ether and then chloroform as an eluent. The chloroform eluate was distilled off by an evaporator, and the residue was recrystallized from chloroform-ether-hexane to obtain the target compound as colorless prism crystals in 41% yield.

Melting point: 104 to 106 ° C. IR (KBr): νCO 1725, 1676 cm
_{^{-1 NMR (CDCl 3) δ:}} 2.43 (3H, s), 2.66 (1H, br
t), 3.57 (1H, dd), 3.66 (3H,
s), 3.70 (6H, s), 3.92 (1H, d
d), 5.7~6.5 (2H, m ) Elemental _analysis: (as _{C 16 H 17 NO 6 S 2} )

Examples 2 to 26 The following compounds were obtained in the same manner as in Example 1 using the corresponding derivatives. In the table, Ph represents a phenyl group and p-
NO ₂ Ph represents a p-nitrophenyl group.

[0039]

[Chemical 8]

[0040]

[Table 2]

[0041]

[Table 3]

[0042]

[Table 4]

[0043]

[Table 5]

[0044]

[Table 6]

[0045]

[Table 7]

Example 27 Dimethyl 2-cyano-3-methylthio-4-thio-1
-Azatetracyclo [5.4.0.0 ^5,11 . 0
^6,8 ] undeca-2,9-diene-5,6-dicarboxylate pyridinium-1- [1-cyano-1-[(methylthio) thiocarbonyl]] methylide (1.040 g) and dimethyl acetylenedicarboxylate ( A chloroform solution (30 ml) of 1 g) was heated and refluxed for 4 hours on a water bath to react. This reaction solution was cooled to room temperature and then distilled off with chloroform as a solvent. The residue was separated by column chromatography packed with alumina using ether and then chloroform as an eluent. The chloroform eluate was distilled off,
The residue was recrystallized from chloroform-ether-hexane to give the target compound as colorless prism-like crystals in 26% yield.

Melting point: 157 to 159 ° C. IR (KBr): νCN 2203 cm ⁻¹ νCO 1720 cm ⁻¹ NMR (CDCl ₃ ) δ: 2.47 (3H, s), 2.66 (1H, br)
t), 3.67 (3H, s), 3.71 (3H, s),
3.67 to 3.71 (1H, m), 4.00 (1H, b
rd), 5.7~6.4 (2H, m ) Elemental _analysis: (as _{C 15 H 14 N 2 O 4} S 2)

Example 28 Dimethyl 2-cyano-3-methylthio-4-thio-1
-Azatetracyclo [5.4.0.0 ^5,11 . 0
^6,8 ] Undeca-2,9-diene-5,6-dicarboxylate dimethyl 5-cyano-4-methylthio-10aH-pyrido [1,2-d] [1,4] thiazepine-1,2-di Carboxylate (0.350 g) was added to chloroform (2
0 ml) and heated to reflux for 5 hours on a water bath to react. After cooling the reaction solution to room temperature, the solvent chloroform was distilled off. The residue was separated by column chromatography packed with alumina using ether and then chloroform as an eluent. The chloroform eluate was distilled off, and the residue was recrystallized from chloroform-ether-hexane,
The target compound was obtained as colorless prism crystals in 67% yield.
The values of melting point, infrared absorption spectrum, and nuclear magnetic resonance spectrum are the same as those in Example 27.

Examples 29 to 35 The following compounds were obtained in the same manner as in Example 27 or Example 28 using the corresponding derivatives. In addition, Bz in the table represents a benzoyl group, and the yield represents the yield when the reaction was performed according to the method of Example 27.

[0050]

[Chemical 9]

[0051]

[Table 8]

[0052]

[Table 9]

Claims (1)

[Claims] 1. A general formula: (In the formula, R ¹ , R ² , R ³ and R ⁴ may be the same or different and each is a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, and R ⁵ is a hydrogen atom or a nitro group. Is an optionally substituted aryl group or a lower alkoxycarbonyl group having 2 to 7 carbon atoms, R ⁶ and R ⁷ may be the same or different, each is a lower alkyl group having 1 to 6 carbon atoms, and R is A cyano group, an aromatic acyl group, or a lower alkoxycarbonyl group having 2 to 7 carbon atoms, and n is an integer of 1 to 6), and a thiazatetracycloundecadiene derivative represented by the formula, and an acid addition salt thereof.