JPH0115493B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel dihydro ML-236B and derivatives thereof that have an inhibitory effect on hepatic cholesterol synthesis. Specifically, the present invention relates to dihydro ML-236B and its metal carboxylate salt, amino acid carboxylate salt, amine carboxylate salt, and carboxylic acid ester. More specifically, dihydro ML-236B is represented by the following formula. The carboxylic acid metal salt of dihydro ML-236B is represented by the following formula. (In the formula, M represents a metal element, and n represents the valence of the metal element.) The carboxylic acid amino acid salt and carboxylic acid amine salt of dihydro ML-236B are represented by the following formula. (In the formula, A represents an amino acid or an organic amine.) The carboxylic acid ester of dihydro ML-236B is represented by the following formula. (In the formula, R represents an alkyl group: an unsubstituted benzyl group substituted with alkyl, alkoxy, or halogen; or a phenacyl group unsubstituted or substituted with alkyl, alkoxy, or halogen.) In (),

【ceremony

[Formula] (Δ ⁴ compound) or

[Formula] (Δ ^4a compound) or a mixture thereof. Thus, for example, the expression "dihydro ML-236B" means dihydro(Δ ⁴ )ML-236B or dihydro(Δ ^4a )ML-236B or mixtures thereof. In the above formula (), M is, for example, an alkali metal salt such as sodium or potassium, an alkaline earth metal salt such as calcium or magnesium, an aluminum salt, an iron salt, a zinc salt, a copper salt, a nickel salt or a cobalt salt. Among them, alkali metal salts, alkaline earth metal salts and aluminum salts are preferred, and sodium salts, calcium salts and aluminum salts are most preferred. In the above formula (), when A is an amino acid, for example, arginine, lysine, histidine,
Basic amino acids such as α,γ-diaminobutyric acid and ornithine are preferred. When A is an organic amine, it is an aliphatic, aromatic, cycloaliphatic, heterocyclic or carbohydrate monoamine. Primary alkylamines such as octylamine, t-octylamine, 2-ethylhexylamine; benzylamine, α-methylbenzylamine, phenethylamine, dibenzylamine, methylbenzylamine, N,N-dimethylbenzylamine, N, N-
Primary to tertiary C _7-8 aralkylamine derivatives such as diethylbenzylamine, N-ethyl-N-methylbenzylamine, tribenzylamine; cyclopentylamine, cyclohexylamine, cyclohebutylamine, methylcyclopentylamine, ethylcyclohexylamine , 1- to tertiary 5- to 7-membered saturated alicyclic amine derivatives such as ethylcycloheptylamine, dicyclohexylamine, dimethylcyclopentylamine, dimethylcyclohexylamine, diethylcycloheptylamine; pyrrolidine, N-methylpyrrolidine, piperidine, N - 5- to 6-membered heterocyclic amine derivatives containing one nitrogen atom as a heteroatom such as methylpiperidine; morpholine; leucine methyl ester, glutamic acid diethyl ester, phenylglycine ester, phenylalanine propyl ester, β-phenyl Examples include C _1-3 alkyl ester derivatives of aliphatic or aromatic amino acids such as enylalanine methyl ester; and amine derivatives of carbohydrates such as glucosamine. These amines also include stereoisomers and optical isomers. Preferably t-octylamine, benzylamine, dibenzylamine, N,N-dimethylbenzylamine, cyclohexylamine, dicyclohexylamine, dimethylcyclohexylamine, N-methylpyrrolidine, N-methylpiperidine, morpholine, L-leucine alkyl ester, L-glutamic acid dialkyl ester, D
- phenylglycine alkyl ester, D-glucosamine, optimally t-octylamine,
These are dibenzylamine, dicyclohexylamine, morpholine, D-phenylglycine alkyl ester, and D-glucosamine. In the above formula (), R is a C _1-6 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl; benzyl, 2-methylbenzyl, 3-methylbenzyl , 4-methylbenzyl, 2-ethylbenzyl, 3-ethylbenzyl, 4-ethylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-ethoxybenzyl, 3-ethoxybenzyl, 4-ethoxybenzyl , 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl,
unsubstituted or substituted benzyl groups with C _1-2 alkyl, C, _-2 alkoxy or halogen, such as 3-bromobenzyl, 4-bromobenzyl; or phenacyl, 2-methylphenacyl, 3-methylphenacyl, 4-methylphenacyl, 2 -ethyl phenacyl, 3-ethyl phenacyl, 4-ethyl phenacyl, 2-methoxy phenacyl, 3-methoxy phenacyl, 4-methoxy phenacyl, 4
-ethoxyphenacyl, 2-chlorfenacyl,
3-chlorfenacyl, 4-chlorfenacyl,
2-bromophenacyl, 3-bromophenacyl,
It represents an unsubstituted phenacyl group such as 4-bromophenacyl or substituted with C _1-2 alkyl, C _1-2 alkoxy or halogen. Preferably R is methyl, ethyl, n-propyl, isopropyl, n-
Butyl, n-hexyl alkyl group; benzyl,
4-methylbenzyl, 4-methoxybenzyl, 4
- Substituted or unsubstituted benzyl group of chlorobenzyl; substituted or unsubstituted phenacyl group of phenacyl, 4-methylphenacyl, 4-methoxyphenacyl, 4-bromophenacyl. Next, typical examples of compounds of the present invention will be given, but the present invention is not limited thereto. 1 Dihydro ML-236B 2 Sodium carboxylic acid salt of 1 3 Potassium salt 4 Calcium salt 5 Aluminum salt 6 Arginine salt 7 Lysine salt 8 Histidine salt 9 α,γ-diaminobutyrate 10 Ornithine salt 11 〃 t-Octylamine salt 12 〃 Dibenzylamine salt 13 〃 Dicyclohexylamine salt 14 〃 Morpholine salt 15 〃 Phenylglycine alkyl ester salt 16 〃 Glucosamine salt 17 〃 Glutamic acid dialkyl ester salt 18 〃 Methyl ester 19 〃 Ethyl ester 20 〃 n -propyl ester 21 〃 isopropyl ester 22 〃 n-butyl ester 23 〃 n-hexyl ester 24 〃 benzyl ester 25 〃 4-methylbenzyl ester 26 〃 4-methoxybenzyl ester 27 〃 4-chlorobenzyl ester 28 〃 phenacyl ester 29 〃 4-Methyl phenacyl ester 30 〃 4-methoxyphenacyl ester 31 〃 4-bromophenacyl ester The dihydro compound of the present invention has an inhibitory effect on hepatic cholesterol synthesis, and can be used as a drug for treating hyperlipidemia, preventing arteriosclerosis, etc. It is used as a useful medicine. The dihydro compound of the present invention has a property that it is less likely to be inactivated in vivo than the original compound before reduction. Examples of the administration form include parenteral administration such as subcutaneous injection, intravenous injection, and intramuscular injection, and oral administration such as tablets, capsules, powders, and granules. The dosage for adults varies depending on the administration route and number of administrations, etc.
The usual dose is 5 to 50 mg per day, once or in divided doses. The compounds of the present invention are all novel compounds, and can be produced, for example, by the following method. (1) The compound having the general formula () above is ML-
236B (Japanese Unexamined Patent Publication No. 155690/1989) was dissolved in a solvent,
Obtained by hydrogenation in the presence of a catalyst. The solvent to be used is not particularly limited as long as it does not participate in this reaction, and for example, alcohols such as methanol, ethanol, and isopropanol, and ethers such as tetrahydrofuran are used. These solvents may be water-containing. The catalysts used include platinum oxide, rhodium colonnade, Raney nickel, nickel boride, and palladium catalysts, with palladium catalysts being preferred. Activated carbon, alumina, calcium carbonate, barium sulfate, etc. are used as a carrier for the palladium catalyst, and activated carbon or barium sulfate is preferable. The palladium concentration used is 1-10%, but 5-10% is used.
% concentration of catalyst is preferred. The reaction temperature is usually room temperature or lower, preferably about 25°C. The hydrogen pressure is preferably normal pressure. Under these conditions, the reaction can be carried out without further reduction proceeding beyond the dihydro form. (2) The compound having the general formula () can be produced, for example, by the following method. ML-236B carboxylic acid metal salt (Unexamined Japanese Patent Publication No. 1983-
No. 56314) by subjecting it to catalytic reduction according to the method (1) above. It can be obtained by using dihydro ML-236B obtained in the above (1) to form a metal salt according to the method described in JP-A-53-56314. (3) The compound having the general formula () can be produced, for example, by the following method. Amino acid salt of ML-236B carboxylic acid (JP-A-54-28828) or amine salt (JP-A-57-1999)
-123140) by subjecting it to catalytic reduction according to the method (1) above. Dihydro ML-236B obtained in the above (1) is used to prepare an amino acid salt according to the method described in JP-A-54-28828, or JP-A-57-
It can be obtained by converting it into an amine salt according to the method described in No. 123140. (4) The compound having the general formula () can be produced, for example, by the following method. ML-236B carboxylic acid ester
-84954) by subjecting it to catalytic reduction according to the method (1) above. It is obtained by esterifying dihydro ML-236B obtained in the above (1) according to the method described in JP-A-53-84954. It can be obtained by reacting the dihydro ML-236B carboxylic acid obtained in (1) above (which can be obtained by neutralizing a carboxylic acid metal salt) with a diazo compound such as diazomethane. Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to these Examples. Example 1 Dihydro (Δ ⁴ )ML-236B Add 390.5 mg of palladium catalyst (barium sulfate carrier, containing 5% palladium) to a solution of 19.53 g of ML-236B dissolved in 500 ml of ethyl alcohol.
Catalytic reduction was carried out under atmospheric hydrogen pressure at °C. about
The equivalent mole of hydrogen was absorbed in 2.5 hours, and the reaction stopped. After the reaction was completed, the catalyst was separated from the reaction mixture and the liquid was concentrated to obtain a transparent oil.
Add 50 ml of cyclohexane and n-
After dissolving by adding 75 ml of hexane, the mixture was cooled to 5°C to obtain 11.80 g of white powder. The white powder was dissolved in a small amount of acetonitrile and then eluted with 50% acetonitrile using a Lobar column RP-8. After concentrating the eluate, it was recrystallized using 70% methanol to obtain the target compound with a melting point of 102°C as white crystals. Elemental analysis value (%) C ₂₃ H ₃₀ O ₅ Calculated value C, 70.37 H, 9.24 Analysis value C, 70.76 H, 9.26 Mass spectrometry value M ⁺ 392 Infrared absorption spectrum (cm ^-1 , Nujol) 3520,
1735, 1695 Nuclear magnetic resonance spectrum (60MHz, CDCl ₃ , δ,
ppm) 5.40 (1H, multiplet) Example 2 Dihydro (Δ ^4a ) ML-236B In Example 1, the liquid after obtaining 11.80 g of white powder was concentrated under reduced pressure. The obtained oil was washed with n-hexane to obtain 7.37 g of the target compound as a colorless oil. Elemental analysis value (%) C ₂₃ H ₃₆ O ₅ Calculated value C, 70.37 H, 9.24 Analysis value C, 70.18 H, 9.36 Mass analysis value M ⁺ 392 Infrared absorption spectrum (cm ^-1 , liquid film) 3400,
1720 Nuclear magnetic resonance spectrum (60MHz, CDCl ₃ , δ,
ppm) 5.40 (1H, multiplet) Example 3 Dihydro (Δ ⁴ ) ML-236B carboxylic acid sodium salt Dihydro(Δ ⁴ )ML− obtained in Example 1
6.0 g of 236B was suspended in 180 ml of 50% acetone, and an equimolar 20% aqueous solution of caustic soda was added dropwise while keeping the pH below 12. It took about 3 hours at 40°C. After the reaction is complete, add a small amount of 18% hydrochloric acid to the reaction mixture.
The pH was adjusted to 8.5, and then acetone was distilled off under reduced pressure. When the obtained residue is subjected to freeze-drying, the melting point
6.60 g of the target compound with a temperature of 213° C. (decomposition) were obtained as a hygroscopic powder. Elemental analysis value (%) C ₂₃ H ₃₇ O ₆ Na Calculated value C, 63.87 H, 8.62 Na, 5.32 Analysis value C, 63.25 H, 8.65 Na, 5.75 Infrared absorption spectrum (cm ^-1 , Nujol) 3280,
1725 Example 4 Dihydro (Δ ^4a ) ML-236B carboxylic acid sodium salt In Example 3, dihydro(Δ ⁴ )ML−
When treated in the same manner as in Example 3 using dihydro(Δ ^4a )ML-236B instead of 236B, the melting point was 207.
6.60 g of the target compound were obtained as a hygroscopic powder. Elemental analysis value (%) C ₂₃ H ₃₇ O ₆ Na Calculated value C, 63.87 H, 8.62 Na, 5.32 Analysis value C, 63.48 H, 8.67 Na, 5.54 Infrared absorption spectrum (cm ^-1 , Nujol) 3280,
1725 Example 5 Dihydro (Δ ⁴ ) ML-236B carboxylic acid calcium salt Dihydro(Δ ⁴ )ML− obtained in Example 1
440 mg of 236B was suspended in 60 ml of 50% acetone. Then, the mixture was heated to 40°C, a 20% aqueous solution of caustic soda was added dropwise, and the mixture was stirred at pH 12 for 1 hour. The pH was adjusted to 8.5 by adding 18% hydrochloric acid. Next, a solution of 120 mg of calcium chloride dihydrate dissolved in 10 ml of water was added.
The obtained calcium salt was extracted with dichloroethane. The extract was concentrated under reduced pressure to obtain 370 mg of the target compound having a melting point of 224°C (decomposed) as a white powder. Elemental analysis value (%) C ₄₆ H ₇₄ O ₁₂ As Ca Calculated value C, 64.31 H, 8.68 Analysis value C, 64.95 H, 9.13 Infrared absorption spectrum (cm ^-1 , Nujol) 3250,
1730 Example 6 Dihydro(Δ ⁴ )ML-236B carboxylic acid aluminum salt To the dihydro(Δ ⁴ )ML-236B carboxylic acid sodium solution obtained by saponification in the same manner as in Example 5,
When treated in the same manner as in Example 5 using an aqueous solution of 90.2 mg of aluminum chloride hexahydrate instead of calcium chloride dihydrate, the melting point was 67°C (decomposition point was 120°C).
471 mg of the target compound having the following properties were obtained as a white powder. Elemental analysis value (%) C ₄₆ H ₇₄ O ₁₂ As Al (OH) Calculated value C, 64.02 H, 8.76 Analysis value C, 63.85 H, 9.04 Infrared absorption spectrum (cm ^-1 , Nujol) 3360,
1730 Example 7 Dihydro (Δ ⁴ ) ML-236B carboxylic acid tertiary octylamine salt A dihydro(Δ ⁴ )ML-236B carboxylic acid sodium solution obtained by saponification in the same manner as in Example 5 was
Cooled to ℃. Next, add 18% hydrochloric acid and adjust the pH once.
Immediately after adjusting the pH to 4.0, tertiary octylamine was added to adjust the pH to 7.8. After the reaction was completed, acetone was distilled off from the reaction mixture under reduced pressure, and the resulting residue was extracted with ethyl acetate. After concentrating the extract under reduced pressure, n-hexane was added for crystallization to obtain 453 mg of the target compound having a melting point of 82°C as a white powder. Elemental analysis value (%) C ₃₁ H ₅₇ O ₆ N Calculated value C, 68.98 H, 10.64 N, 2.59 Analysis value C, 68.63 H, 10.88 N, 2.51 Infrared absorption spectrum (cm ^-1 , Nujol) 3480,
1725 Example 8 Dihydro( ^Δ4 )ML-236B D(-)phenylglycine methyl ester salt To the dihydro(Δ ⁴ )ML-236B carboxylic acid sodium solution obtained by saponification in the same manner as in Example 5,
In place of calcium chloride dihydrate, 225.8 mg of D(-)phenylglycine methyl ester hydrochloride was added. PH changed from 8.5 to 6.2. After the reaction was completed, the reaction mixture was extracted with dichloroethane, and the extract was distilled off under reduced pressure to obtain 431.8 mg of the target compound as an oil. Elemental analysis value (%) C ₃₂ H ₄₉ O ₈ N Calculated value C, 66.76 H, 8.52 N, 2.43 Analysis value C, 66.38 H, 8.62 N, 2.40 Infrared absorption spectrum (cm ^-1 , liquid film) ~ 3300
～, 1700～1760 Nuclear magnetic resonance spectrum (60MHz, CDCl ₃ +
D ₂ O, δ, ppm) 7.30 (5H, singlet) 5.20-5.60 (2H, multiplet) 3.70 (3H, singlet) Example 9 Dihydro (Δ ⁴ ) ML-236B carboxylic acid D (-)
Phenylglycine ethyl ester salt In Example 7, 200.7 mg of D(-)phenylglycine ethyl ester was used instead of tertiary octylamine, and the same procedure as in Example 7 was carried out. The resulting residue was extracted with chloroform, and the effluent was distilled off under reduced pressure to obtain the target compound.
495.4 mg was obtained as an oil. Elemental analysis value (%) C ₃₃ H ₅₁ O ₃ N Calculated value C, 67.21 H, 8.72 N, 2.37 Analysis value C, 66.82 H, 8.40 N, 2.55 Infrared absorption spectrum (cm ^-1 , liquid film) 3340,
3280, 1740, 1725 Nuclear magnetic resonance spectrum (60MHz, CDCl ₃ +
D ₂ O, δ, ppm) 7.30 (5H, singlet) 5.60-5.15 (2H, multiplet) 4.15 (2H, quartet) Example 10 Dihydro (Δ ⁴ ) ML-236B carboxylic acid L-ornithine salt To the dihydro(Δ ⁴ )ML-236B carboxylic acid sodium solution obtained by saponification in the same manner as in Example 5,
189 mg of L-ornithine hydrochloride was added instead of calcium chloride dihydrate. PH changed from 8.5 to 7.0. After the reaction was completed, acetone was distilled off from the reaction mixture under reduced pressure, and then this aqueous solution was adsorbed on a 10 ml column of high porous adsorption resin (Diaion HP-20) and eluted with 60% aqueous methanol. After concentrating the eluate under reduced pressure and lyophilizing it, the melting point was 149.
383.5 mg of the target compound with a temperature of 0.degree. C. (decomposed) was obtained as a white powder. Elemental analysis value (%) C ₂₈ H ₅₀ O ₈ N Calculated value C, 63.85 H, 9.57 N, 5.32 Analysis value C, 63.68 H, 9.26 N, 4.99 Infrared absorption spectrum (cm ^-1 , Nujol), 3400,
1725 Example 11 Dihydro (Δ ⁴ ) ML-236B carboxylic acid methyl ester Dihydro(Δ ⁴ )ML− obtained in Example 3
1390 mg of 236B carboxylic acid sodium salt was dissolved in 7 ml of dimethylformamide. Then 200 mg of potassium carbonate and 576 mg of iodomethyl (95% purity)
was added and stirred at room temperature for 4 hours. After the reaction was completed, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the resulting oil was collected using Lobar.
Purification using column RP-8 (70% acetonitrile) yielded 800 mg of the target compound as an oil. Elemental analysis value (%) C ₂₄ H ₄₀ O ₆ Calculated value C, 67.89 H, 9.50 Analysis value C, 67.52 H, 9.68 Mass spectrometry value M ⁺ 424 Infrared absorption spectrum (cm ^-1 , liquid film) 3420,
1730 Nuclear magnetic resonance spectrum (60MHz, CDCl ₃ , δ,
ppm) 5.15-5.50 (2H, multiplet) 3.70 (3H, singlet) Example 12 Dihydro (Δ ⁴ ) ML-236B carboxylic acid n-butyl ester In Example 11, n-
Example 11 below using 529 mg of butyl bromide
When treated in the same manner as above, 640 mg of the target compound was obtained as an oil. Elemental analysis value (%) C ₂₇ H ₄₆ O ₆ Calculated value C, 69.49 H, 9.94 Analysis value C, 69.17 H, 10.05 Mass analysis value M ⁺ 466 Infrared absorption spectrum (cm ^-1 , liquid film) 3380,
1725 Nuclear magnetic resonance spectrum (60MHz, CDCl ₃ , δ,
ppm) 5.15-5.60 (2H, multiplet) 4.10 (2H, triplet) Example 13 Dihydro (Δ ⁴ ) ML-236B carboxylic acid benzyl ester In Example 11, the same procedure as in Example 11 was carried out using 726 mg of benzyl bromide instead of iodomethyl to obtain 1200 mg of the target compound as an oil. Elemental analysis value (%) C ₃₀ H ₄₄ O ₆ Calculated value C, 71.97 H, 8.86 Analysis value C, 71.67 H, 8.95 Mass spectrometry value M ⁺ 500 Infrared absorption spectrum (cm ^-1 , liquid film) 3420,
1725 Nuclear magnetic resonance spectrum (60MHz, CDCl ₃ , δ,
ppm) 7.30 (5H, singlet) 5.15-5.50 (2H, multiplet) 5.10 (2H, singlet) Example 14 Dihydro (Δ ⁴ ) ML-236B carboxylic acid 4-bromophenacyl ester In Example 11, 4-
Using 1181 mg of bromophenacyl bromide, the following treatment was carried out in the same manner as in Example 11, yielding 1560 mg of the target compound.
was obtained as a pale yellow oil. Elemental analysis value (%) C ₃₁ H ₄₃ O ₇ Br Calculated value C, 61.28 H, 7.13 Br, 13.15 Analysis value C, 61.20 H, 7.38 Br, 13.44 Mass analysis value M ⁺ 606 (as Br ⁷⁹ ) Infrared absorption spectrum (cm ^-1 , liquid film) 3420,
1710, 1730, 1745 Nuclear magnetic resonance spectrum (60MHz, CDCl ₃ , δ,
ppm) 7.70 (4H, multiplet) 5.35 (2H, singlet) 5.15 to 5.55 (2H, multiplet)

Claims (1)

[Scope of Claims] 1. Dihydro ML-236B and carboxylic acid metal salts, carboxylic acid amino acid salts, carboxylic acid amine salts, and carboxylic acid esters thereof. 2. The compound according to claim 1, which is dihydro ML-236B. 3. The compound according to claim 1, wherein the dihydro ML-236B derivative is a carboxylic acid metal salt. 4. The compound according to claim 1, wherein the dihydro ML-236B derivative is a carboxylic acid amino acid salt. 5. The compound according to claim 1, wherein the dihydro ML-236B derivative is a carboxylic acid amine salt. 6. The compound according to claim 1, wherein the dihydro ML-236B derivative is a carboxylic acid ester.