JP2599106B2 - Lipid-lowering agent containing imidazolidinetrione derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a pharmaceutical composition containing an imidazolidinetrione derivative having a blood glucose lowering action and a lipid lowering action and a pharmaceutically acceptable salt thereof as an active ingredient.

[0002]

2. Description of the Related Art Various pathological conditions are caused by abnormal increase or imbalance of blood sugars, triglycerides, cholesterol, phospholipids, free fatty acids and other lipids. That is, diabetes causes acidosis, retinopathy, microangiopathy such as nephropathy, abnormal lipid metabolism, etc., which are the basis of diabetic coma, and promotes arteriosclerosis. Hyperlipidemia not only directly causes arteriosclerosis, but also causes various symptoms such as ischemic heart disease, and is often induced as a complication of diabetes. At present, sulfonylureas and biguanides are generally used as oral hypoglycemic agents. However, these drugs often cause symptoms such as excessive hypoglycemia and lactic acidosis when administered,
Its side effects are problematic. On the other hand, insulin preparations, which are well-known as therapeutic agents for diabetes, can be used only as injections at present, so that the complexity and inconvenience at the time of their application is a heavy burden on patients.

[0003]

DISCLOSURE OF THE INVENTION The present invention relates to an orally durable pharmaceutical composition which is useful for treating or preventing diabetes and / or hyperlipidemia and diseases associated therewith, and which has few side effects and high safety. The purpose is to provide.

[0004]

Means for Solving the Problems In order to solve the above problems, the present inventors have searched for compounds that are effective, safer and orally administrable with hypoglycemic action and hypolipidemic action. Inventive imidazolidinetrione derivative has an excellent hypoglycemic action, that is, an action of returning an abnormally elevated blood sugar level to a normal range without causing excessive hypoglycemic decrease at the time of administration, and further has an excellent lipid lowering action and is safe. The present invention was found to be highly efficient, and the present invention was completed.

The present invention is a pharmaceutical composition containing as an active ingredient at least one of an imidazolidinetrione derivative represented by the following general formula (I) and a pharmaceutically acceptable salt thereof.

Embedded image [In the general formula (I), R ₁ and R ₂ are the same or different and each represents a hydrogen, an alkyl group, a cycloalkyl group, or a group represented by the following general formula (II). ]

Embedded image [In the general formula (II), R ₃ and R ₄ are the same or different and each represents hydrogen, halogen, a nitro group, a lower alkyl group or a lower alkoxy group. ]

In the above formula (I), R ₁ and R ₂ are the same or different and are each independently hydrogen, an alkyl group, preferably methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, hexyl, dimethylbutyl, heptyl,
A linear or branched alkyl group having 1 to 20 carbon atoms such as octyl, nonyl, decyl, stearyl and the like, a cycloalkyl group, preferably 1 carbon atom such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; To 8 cycloalkyl groups or groups represented by the general formula (II). However, when _one of R ₁ and R ₂ is a group represented by the general formula (II), the other is preferably hydrogen.

In the general formula (II), R ₃ and R ₄ are the same or different and are each a halogen such as hydrogen, fluorine, chlorine, bromine, a nitro group, a lower alkyl group, preferably methyl, ethyl, propyl, i-propyl. , Butyl, i
-Butyl, s-butyl, t-butyl and the like, linear or branched lower alkyl groups having 1 to 4 carbon atoms or lower alkoxy groups, preferably methoxy, ethoxy, propoxy,
linear or branched C 1 -C 4 such as i-propoxy, butoxy, i-butoxy, s-butoxy, t-butoxy, etc.
Represents a lower alkoxy group. The imidazolidinetrione derivative of the present invention includes not only a novel substance but also a known substance, but it has not been reported that the compound has a blood glucose lowering action or a lipid lowering action.

Among the compounds of the present invention, particularly preferred compounds are as follows. -Imidazolidine trione-1-methyl imidazolidine trione-1-ethyl imidazolidine trione-1-n-butyl imidazolidine trione-1-i-butyl imidazolidine trione-1-t-butyl imidazolidine trione-1-n- Hexylimidazolidintrione 1- (1,3-dimethylbutyl) imidazolidintrione 1-n-decylimidazolidintrione 1-cyclopentylimidazolidintrione 1-cyclohexylimidazolidintrione 1-3-dimethylimidazolidintrione・ 1-cyclopentyl-3-ethylimidazolidintrione ・ 1,3-dicyclohexylimidazolidintrione ・ 1-benzylimidazolidinetrione

1- (2-fluorobenzyl) imidazolidintrione 1- (3-fluorobenzyl) imidazolidintrione 1- (4-fluorobenzyl) imidazolidintrione 1- (2-chlorobenzyl) imidazolidine Trione 1- (4-chlorobenzyl) imidazolidintrione 1- (4-bromobenzyl) imidazolidintrione 1- (3-nitrobenzyl) imidazolidintrione 1- (4-nitrobenzyl) imidazolidintrione 1- (2-methylbenzyl) imidazolidintrione 1- (3-methylbenzyl) imidazolidintrione 1- (4-methylbenzyl) imidazolidintrione 1- (2-methoxybenzyl) imidazolidintrione 1- (3-methoxybenzyl) imidazo Jintorion-1- (4-methoxybenzyl) imidazolidine-trione-1- (3,4-dimethoxybenzyl) imidazolidine-trione-1- (3,4-dichlorobenzyl) imidazolidine-trione

The imidazolidine trione derivative of the present invention is
Pharmaceutically acceptable salts of the compounds represented by the above general formula (I) are included, for example, as inorganic salts, alkali metals such as sodium and potassium, alkaline earth metals such as calcium, magnesium and barium, and other aluminum And salts with metals and ammonium. Further, a salt with an organic amine may be used. Further, the imidazolidinetrione derivative of the present invention may be in the form of a metal complex compound, for example, a complex compound with zinc, iron and the like.
These salts and metal complex compounds can be produced from the free imidazolidinetrione derivative of the present invention by known methods,
Alternatively, they can be mutually converted. When the compound of the present invention has an optical isomer, the present invention includes any of its dl-, d- and l-forms. The imidazolidinetrione derivative of the present invention can be prepared by a general method [for example, Yonezawa et al., Nihon Kagaku Magazine, Vol. 89, No. 8, 62-64.
(1968) or Patton T.C. L. , J. et al. Or
g. Chem. , Vol. 32, No2, 383-38
8 (1967) etc.].

An example of the manufacturing method will be described below. (1) Oxalyl chloride and N-alkyl urea, N-cycloalkyl urea, N-benzyl urea, N-
Halogenobenzylurea, N-nitrobenzylurea, N-
An N-substituted urea such as an alkyl benzyl urea or an N-alkoxy benzyl urea is stirred under ice cooling to room temperature, or in a suitable solvent that does not inhibit the reaction, for example, an amine,
By stirring diethyl oxalate and the above-mentioned N-substituted urea at room temperature or with appropriate heating in the presence of an organic base such as an alkali metal alkoxide, the desired imidazolidinetrione derivative of the present invention can be obtained.

(2) The compound of the present invention may be prepared by using an alkyl halide as an unsubstituted, 1-alkyl-substituted or 1-cycloalkyl-substituted imidazolidine trione in addition to the production method described in the above item (1). Can also be synthesized by an N-alkylation reaction of The obtained compound of the present invention is
Purification was performed by ordinary means such as distillation, chromatography and recrystallization, and identification was performed by elemental analysis, melting point, IR, NMR, UV, mass spectrum (MS) and the like. The following imidazolidinetrione derivative of the present invention can be produced by the above-mentioned production method. In addition, imidazolidine trione (compound 1) is commercially available.

[0013]

【Example】

1-methylimidazolidinetrione (compound 2) Melting point: 153-155 ° C IR (KBr): 3210, 1790, 1740, 1718, 1460cm ^-1 NMR (DMSO-d ₆ ): δ = 2.92 (s, 3H), 11.98 (brs, 1H) MS (m / z): 128 (M ⁺ ), 100, 56, 44 1-ethylimidazolidin trione (compound 3) Melting point: 123-125 ° C IR (KBr): 3200, 2960, 1810, 1785, 1720, 1060 cm ^-1 NMR (DMSO-d ₆ ): δ = 1.13 (t, 3H, J = 7 Hz), 3.47 (q, 2H, J =
7 Hz), 11.96 (brs, 1H) MS (m / z): 142 (M ⁺ ), 71, 56, 43 1-n-butyl imidazolidine trione (compound 4) Melting point: 97-99 ° C IR (KBr): 3200, 2950, 1800, 1785, 1718, 1445 cm ^-1 NMR (DMSO-d ₆ ): δ = 0.88 (t, 3H, J = 7 Hz), 1.29 (qt, 2H, J
_{1 = 7Hz, J 2 = 7Hz} ), 1.52 (tt, 2H, J 1 = 7Hz, J 2 = 7Hz), 3.43 (t, 2H, J = 7Hz), 11.97 (brs, 1
H) MS (m / z): 170 (M ⁺ ), 128, 115, 99, 70, 56, 41 1-i-butylimidazolidinetrione (compound 5) Melting point: 145-147 ° C IR (KBr): 3170 , 2950, 2860, 1800, 1730, 1710 cm ^-1 NMR (DMSO-d ₆ ): δ = 0.85 (d, 6H, J = 6.4 Hz), 1.90 (m, 1
H), 3.23 (d, 2H, J = 6.8 Hz), 11.98 (s, 1H) MS (m / z): 170 (M ⁺ ), 128, 115, 56, 43, 41, 27

1-t-butylimidazolidintrione (compound 6) Melting point: 121-124 ° C. IR (KBr): 3170, 1798, 1701, 1366, 1322 cm ^-1 NMR (DMSO-d ₆ ): δ = 1.51 (s) , 9H), 11.84 (brs, 1H) MS (m / z): 170 (M ⁺ ), 155, 114, 84, 57, 41 1-n-hexylimididazolidine trione (compound 7) Melting point: 99-101 ° C IR (KBr): 3200, 2950, 2920, 2850, 1810, 1790, 1720
cm ^-1 NMR (DMSO-d ₆ ): δ = 0.85 (t, 3H, J = 6.8 Hz), 1.24 (s, 6
H), 1.50 (tt, 2H, J ₁ = 6.8Hz, J ₂ = 6.8Hz), 3.40 (t, 2H, J = 6.8
Hz), 11.95 (s, 1H) MS (m / z): 198 (M ⁺ ), 128, 116, 115, 84, 56, 55, 4
3, 41, 27 1- (1,3-dimethylbutyl) imidazolidintrione (compound 8) Melting point: 61-65 ° C IR (KBr): 3300, 2950, 2860, 1800, 1720 cm ^-1 NMR (DMSO-d ₆ ): δ = 0.82 (d, 3H, J = 6.4Hz), 0.83 (d, 3H,
J = 6.4Hz), 1.29 (d, 3H, J = 6.8 Hz), 1.36 (m, 1H), 1.51 (m,
1H), 1.83 (m, 1H), 4.12 (m, 1H), 11.94 (s, 1H) MS (m / z): 198 (M ⁺ ), 183, 141, 116, 115, 84, 83,
70, 69, 57, 43, 41, 27 1-n-decyl imidazolidine trione (compound 9) Melting point: 110-112 ° C IR (KBr): 3200, 2950, 2920, 2850, 1820, 1790, 173
0, 1710 cm ^-1 NMR (DMSO-d ₆ ): δ = 0.84 (t, 3H, J = 7.2 Hz), 1.23 (s, 14
H), 1.51 (m, 2H), 3.40 (t, 2H, J = 7.2 Hz), 11.95 (s, 1H) MS (m / z): 254 (M ⁺ ), 142, 128, 116, 83, 69 , 55, 4
3, 41, 27 1-cyclopentyl imidazolidine trione (compound 1
0) Melting point: 98-100 ° C IR (KBr): 3540, 3250, 2945, 2700, 1760, 1725, 142
0, 1100 cm ^-1 NMR (DMSO-d ₆ ): δ = 1.4-1.6 (m, 2H), 1.6-2.0 (m, 6H),
_{4.34 (tt, 1H, J 1} = 7.4Hz, J 2 = 7.4Hz), 11.9 (brs, 1H) MS (m / z): 182 (M +), 141, 116, 67, 41

1-cyclohexylimidazolidine trione (compound 11) Melting point: 190-191 ° C. IR (KBr): 3180, 2920, 1795, 1730, 1410 cm ^-1 NMR (DMSO-d ₆ ): δ = 1.0-1.4 (m , 4H), 1.5-2.0 (m, 6H),
3.7-3.9 (m, 1H), 11.93 (brs, 1H) MS (m / z): 196 (M ⁺ ), 128, 116, 82, 67, 55, 41 1,3-dimethylimidazolidintrione (compound 12 Melting point: 152-153 ° C. IR (KBr): 2940, 1760, 1730, 1705, 1468, 1300 cm ^-1 NMR (DMSO-d ₆ ): δ = 2.97 (s, 6H) MS (m / z): 142 ( M ⁺ ), 114, 86, 70, 58 1-cyclopentyl-3-ethylimidazolidintrione (compound 13) Melting point: 54-56 ° C IR (KBr): 2940, 2855, 1770, 1715, 1418, 1120, 558
cm ^-1 NMR (DMSO-d ₆ ): δ = 1.12 (t, 3H, J = 7.4 Hz), 1.4-1.6 (m,
2H), 1.6-2.0 (m, 6H), 3.48 (q, 2H, J = 7.4Hz), 4.37 (tt, 1
H, J ₁ = 8.0 Hz, J ₂ = 8.0 Hz) MS (m / z): 210 (M ⁺ ), 144, 115, 68, 41 1,3-dicyclohexylimidazolidin trione (compound 14) Melting point: 176 − 178 ° C IR (KBr): 2925, 2850, 1760, 1728, 1410, 758 cm ^-1 NMR (DMSO-d ₆ ): δ = 1.0-1.2 (m, 2H), 1.2-1.4 (m, 4H),
1.4-2.0 (m, 14H), 3.81 (tt, 2H, J 1 = 3.7Hz, J 2 = 12.5Hz) MS (m / z): 278 (M +), 197, 115, 83, 67, 55, 41 1-Benzyl imidazolidine trione (compound 15) Melting point: 169-170 ° C IR (KBr): 3430, 3200, 1790, 1735 NMR (DMSO-d ₆ ): δ = 4.62 (s, 2H), 7.24-7.33 ( m, 5H), 1
2.08 (s, 1H) MS (m / z): 204 (M ⁺ ), 176, 147, 133, 91, 77, 65, 51

1- (2-Fluorobenzyl) imidazolidinetrione (compound 16) Melting point: 196-197 ° C. IR (KBr): 3430, 3200, 3070, 1795, 1730, 1590 NMR (DMSO-d ₆ ): δ = 4.66 (s, 2H), 7.14-7.46 (m, 4H), 1
2.11 (s, 1H) MS (m / z): 222 (M ⁺ ), 165, 151, 123, 109, 83, 70,
63, 51, 50, 43 1- (3-Fluorobenzyl) imidazolidintrione (Compound 17) Melting point: 166-167 ° C IR (KBr): 3430, 3200, 1790, 1735, 1590 NMR (DMSO-d ₆ ): δ = 4.65 (s, 2H), 7.07-7.40 (m, 4H), 1
2.08 (s, 1H) MS (m / z): 222 (M ⁺ ), 165, 151, 122, 109, 83, 70,
63, 51, 50, 43 1- (4-fluorobenzyl) imidazolidine-trione (Compound 18) mp: 182 - 183 ℃ IR (KBr ): 3440, 3200, 3070, 1790, 1730, 1600 NMR (DMSO-d 6 ): δ = 4.61 (s, 2H), 7.12-7.40 (m, 4H), 1
2.06 (s, 1H) MS (m / z): 222 (M ⁺ ), 165, 151, 122, 109, 95, 83,
70, 63, 51, 50, 43 1- (2-Chlorobenzyl) imidazolidinetrione (compound 19) Melting point: 192-193 ° C IR (KBr): 3180, 3100, 1780, 1730 NMR (DMSO-d ₆ ): δ = 4.68 (s, 2H), 7.28-7.50 (m, 4H), 1
2.17 (s, 1H) MS (m / z): 238 (M ⁺ ), 203, 167, 132, 125, 89, 77,
70, 63, 51, 50, 43 1- (4-chlorobenzyl) imidazolidinetrione (compound 20) Melting point: 177-178 ° C IR (KBr): 3240, 3075, 1780, 1730 NMR (DMSO-d ₆ ): δ = 4.62 (s, 2H), 7.35-7.40 (m, 4H), 1
2.08 (s, 1H) MS (m / z): 238 (M ⁺ ), 181, 167, 132, 125, 89, 77,
70, 63, 51, 50, 43

1- (4-bromobenzyl) imidazolidinetrione (compound 21) Melting point: 192 ° -193 ° C. IR (KBr): 3430, 3130, 3050, 1795, 1720 NMR (DMSO-d ₆ ): δ = 4.60 ( s, 2H), 7.52 (dt, 2H, J ₁ = 2.0H
z, J ₂ = 8.4Hz), 7.30 (dt, 2H, J ₁ = 2.0Hz, J ₂ = 8.4Hz), 12.07
(s, 1H) MS (m / z): 282 (M ⁺ ), 225, 211, 169, 132, 90, 77,
70, 63, 51, 50, 43 1- (3-nitrobenzyl) imidazolidin-trione (Compound 22) mp: 139 - 140 ℃ IR (KBr ): 3430, 3230, 1790, 1730, 1535 NMR (DMSO-d 6 ): δ = 4.78 (s, 2H), 7.63 (t, 1H, J = 8.0H
z), 7.82 (d, 1H, J = 8.0Hz), 8.13-8.14 (m, 1H), 8.24 (t, 1H,
J = 2.0Hz), 12.08 (s, 1H) MS (m / z): 249 (M ⁺ ), 232,178,161,136,132,12
5, 89, 77, 70, 63, 51, 50, 43 1- (4-Nitrobenzyl) imidazolidinetrione (compound 23) Melting point: 202-204 ° C IR (KBr): 3440, 3230, 1780, 1730, 1515 _{NMR (DMSO-d 6):} δ = 4.78 (s, 2H), 7.65 (d, 2H, J = 8.8H
z), 8.18 (dt, 2H , J 1 = 2.0Hz, J 2 = 8.8Hz), 12.12 (s, 1H) MS (m / z): 249 (M +), 219, 178, 132, 106, 89 , 78,
77, 70, 63, 51, 50 1- (2-methylbenzyl) imidazolidine-trione (Compound 24) mp: 195 - 196 ℃ IR (KBr ): 3430, 3170, 3080, 1770, 1730 NMR (DMSO-d 6 ): δ = 2.32 (s, 3H), 4.59 (s, 2H), 7.10-
7.27 (m, 4H), 12.09 (s, 1H) MS (m / z): 218 (M ⁺ ), 147, 104, 91, 77, 65, 51,
43 1- (3-Methylbenzyl) imidazolidinetrione (compound 25) Melting point: 149-150 ° C IR (KBr): 3220, 1780, 1760, 1725, 1600 NMR (DMSO-d ₆ ): δ = 2.27 (s, 3H), 4.58 (s, 2H), 7.07-
7.22 (m, 4H), 12.07 (s, 1H) MS (m / z): 218 (M ⁺ ), 147, 132, 105, 91, 77, 65, 5
1, 43

1- (4-methylbenzyl) imidazolidintrione (compound 26) Melting point: 177-178 ° C. IR (KBr): 3450, 3180, 1800, 1725 NMR (DMSO-d ₆ ): δ = 2.26 (s, 3H), 4.57 (s, 2H), 7.12
(d, 2H, J = 8.0Hz), 7.20 (d, 2H, J = 8.0Hz), 12.07 (s, 1H) MS (m / z): 218 (M ⁺ ), 161,147,132,105, 91, 77,
65,51 1- (2-methoxybenzyl) imidazolidintrione (compound 27) Melting point: 171-172 ° C IR (KBr): 3430, 3200, 1805, 1790, 1720, 1600 NMR (DMSO-d ₆ ): δ = 3.80 (s, 3H), 4.57 (s, 2H), 6.87 (d
t, 1H, J ₁ = 0.8Hz, J ₂ = 7.6Hz), 6.99 (d, 1H, J = 8.0Hz), 7.23-
7.28 (m, 2H) MS (m / z): 234 (M ⁺ ), 163, 148, 134, 121, 91, 77,
65, 51, 43 1- (3-methoxybenzyl) imidazolidinetrione (compound 28) Melting point: 142-143 ° C IR (KBr): 3210, 2940, 1790, 1735, 1595 NMR (DMSO-d ₆ ): δ = 3.72 (s, 3H), 4.59 (s, 2H), 6.82-
7.25 (m, 4H), 12.07 (s, 1H) MS (m / z): 234 (M ⁺ ), 167, 148, 121, 91, 77, 65, 5
1,43 1- (4-methoxybenzyl) imidazolidinetrione (compound 29) Melting point: 172-173 ° C IR (KBr): 3430, 3190, 2850, 1790, 1730, 1585 NMR (DMSO-d ₆ ): δ = 3.72 (s, 3H), 4.55 (s, 2H), 6.87 (d
t, 2H, J ₁ = 2.4Hz, J ₂ = 8.8Hz), 7.25 (dt, 2H, J ₁ = 2.4Hz, J ₂ = 8.
8Hz), 12.05 (s, 1H) MS (m / z): 234 (M ⁺ ), 177, 163, 148, 121, 91, 77,
65, 51, 43 1- (3,4-dimethoxybenzyl) imidazolidinetrione (compound 30) Melting point: 171-174 ° C IR (KBr): 3420, 3250, 2950, 2840, 1780, 1740, 1590 NMR (DMSO- d ₆ ): δ = 3.71 (s, 3H), 3.72 (s, 3H), 4.54
(s, 2H), 6.82-6.89 (m, 3H), 12.03 (s, 1H) MS (m / z): 264 (M ⁺ ), 234, 178, 151, 121, 107, 91,
77, 65, 51 1- (3,4-dichloro shea benzyl) imidazolidine-trione (Compound 31) mp: 172 - 173 ℃ IR (KBr ): 3430, 3200, 1790, 1735 NMR (DMSO-d 6): δ = 4.64 (s, 2H), 7.35 (dd, 1H, J ₁ = 2.0H
z, J ₂ = 8.0Hz), 7.59 (d, 1H, J = 8.0Hz), 7.66 (d, 1H, J = 2.0H
z), 12.06 (s, 1H) MS (m / z): 272 (M ⁺ ), 215, 201, 166, 159,123, 89,
70, 43

[0019]

Next, the pharmacological action of the compound of the present invention will be described. (1) Acute toxicity Using 4 to 6 ddY male mice (weight around 19 g) in a group fasted for 20 hours, 0.5% CMC-Na
After oral administration of the test drug suspended in the aqueous solution, lethal dose was determined from the number of deaths in 7 days. Table 1 shows an example of the results.

[0020]

[Table 1]

(2) Hypoglycemic action Male Wistar rats weighing around 200 g were used in groups of 7 to 8 rats. Rats were tested for their hypoglycemic effect of the test drug after an 18-hour fast by the method of Durin et al. [Dulin, W. et al.
L. et al. Proc. Soc. Expl. Me
d. , Vol. 107, 245 (1961)]. In other words, a 20% aqueous glucose solution was applied to the skin on the back of the rat in order to prevent a decrease in blood glucose level due to fasting of the rat.
5 ml / 100 g was administered subcutaneously, and immediately thereafter, 0.5% C
The test drug suspended in the MC-Na aqueous solution was orally administered.
Two hours later, the abdomen was opened under pentobarbital anesthesia, and blood was collected from the abdominal vena cava. The blood was left for 30 minutes to completely coagulate, and then centrifuged to collect serum. Using the obtained serum, the mutarotase GOD method [Trinder, An
n. Clin. Biochem. , Vol. 6,24
(1979)]. Examples of the results are shown in Tables 2 and 3. Note that a significant difference from the control was determined and marked with *. [*: P <0.05, **: p <
0.01, ***: p <0.001]

[0022]

[Table 2]

[0023]

[Table 3] └──────┴────┴──────┴───┘

(3) Lipid-lowering effect Eight male Wistar rats (body weight: about 185 g) in a group were fasted for 18 to 20 hours and then 0.5% CMC-Na
The test drug suspended in the aqueous solution was orally administered. Two hours later, blood was collected in the same manner as in (2) above, and serum was collected. Using the obtained serum, GPO-p-chlorophenol coloring method [Ri
chard W. Spaid et al. , Cli
n. Chem. , Vol. 24, no. 8,1343
(1978)] to convert triglyceride (TG) into A
cyl CoA Synthase-Acyl C
oA Oxidase method [Shimizu S. et al. et
al. , Biochem. Biophys. Res. C
ommun. , Vol. 91, 108 (1979)] to obtain free fatty acids (FFA) by the enzymatic method [Charles
C. Allain et al. , Clin. Che
m. , Vol. 20, no. 4,470 (1974)]
Total cholesterol (T-Chol) and enzyme method [Takayama M. et al. et al. , Cini
ca Chimica Acta, vol. 79,93
(1977)]. Tables 4 to 7 show examples of the results.

[0025]

[Table 4]

[0026]

[Table 5]

[0027]

[Table 6]

[0028]

[Table 7]

[0029]

As is clear from the results of the above pharmacological tests, the imidazolidinetrione derivative of the present invention has an excellent blood glucose lowering effect and significantly lowers blood lipids such as triglycerides, free fatty acid cholesterol, and phospholipids. . The blood glucose lowering effect of the compound of the present invention does not excessively lower the blood glucose level. That is, as is clear from the relationship between the dose of compound 2 and the blood sugar lowering rate in Table 1, even when the dose is increased, the blood sugar level is always maintained in the normal range without excessively lowering the blood sugar level unlike tolbutamide. It is highly useful as a drug for improving abnormal hyperglycemia.

Accordingly, not only treatment for diabetes but also various diseases caused by it, such as diabetic arteriosclerosis, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, diabetic microangiopathy and the like. It is an extremely useful drug for the treatment or prevention of vascular disorders and the like. Since the compound of the present invention is a hypoglycemic agent having characteristics different from insulin as described above, it is particularly effective for non-insulin-dependent diabetes (type II diabetes). The compounds of the present invention also have an excellent lipid-lowering effect, and are useful for treating and preventing hyperlipidemia associated with arteriosclerosis, nephrosis, hypertension, diabetes, obesity and other various diseases.

Diabetes and hyperlipidemia often tend to be combined because glucose metabolism abnormalities due to diabetes and a decrease in lipoprotein lipase activity cause an increase in blood lipids. Therefore, the compounds of the present invention, which have both a blood glucose lowering action and a lipid lowering action, are particularly useful for treating such complications. Since the compound of the present invention can be orally administered with low toxicity and few side effects, it can be safely used for a long period of time, and is particularly advantageous for treating chronic diseases.

The imidazolidine trione derivative of the present invention is
It can be made into a medicament in combination with a suitable pharmaceutical carrier or diluent, formulated in a conventional manner, and formulated into a solid, semi-solid, liquid or aerosol form for oral or parenteral administration Can be. In formulating, the compound of the present invention may be used in the form of a pharmaceutically acceptable salt thereof, the compound of the present invention can be used alone or in an appropriate combination, or a combination with another pharmaceutically active ingredient. It may be.

The preparation for oral administration may be used as it is or together with suitable additives such as lactose, mannitol, corn starch, potato starch and other conventional excipients, as well as crystalline cellulose, cellulose derivatives, gum arabic, corn starch, gelatin and the like. Binder, corn starch, potato starch, disintegrants such as sodium carboxymethylcellulose, talc, lubricating agents such as magnesium stearate, other bulking agents, wetting agents, buffering agents, preservatives, fragrances and the like are appropriately combined with tablets. , Powders, granules or capsules.

Further, the compound of the present invention is mixed with various bases, for example, an oil base such as cocoa oil, an emulsion base, or a water-soluble base such as macrogol, a hydrophilic base, etc. to produce suppositories. can do.

As an injection, an aqueous solvent or a non-aqueous solvent,
For example, a solution or suspension can be prepared using distilled water for injection, physiological saline, Ringer's solution, vegetable oil, synthetic fatty acid glyceride, higher fatty acid ester, propylene glycol, or the like. In this case, if necessary, commonly used additives such as a solubilizer, a tonicity agent, a suspending agent, an emulsifier, a stabilizer and a preservative may be added.

For use as an inhalant or aerosol, the compound of the present invention may be in the form of a solution, suspension or fine powder,
The aerosol container is filled with a gas or liquid propellant and, if desired, with conventional adjuvants such as wetting or dispersing agents. The compound of the present invention may be in a non-pressurized dosage form such as a nebulizer or an atomizer. For formulation as eye drops, a solution or suspension can be formed using an aqueous solvent such as sterile purified water or physiological saline, or a non-aqueous solvent for injection.

As a poultice, it can be formulated by mixing with peppermint oil, concentrated glycerin, kaolin and the like.

The desired dose of the compound of the present invention varies depending on the administration subject, dosage form, administration method, administration period and the like. To obtain the desired effect, the compound of the present invention is generally administered to an adult daily for 1 to 3 days. 1,000 mg, preferably 5 to 600 mg, can be orally administered, and a unit preparation containing an appropriate amount of the compound of the present invention can be administered one to several times a day.
In the case of parenteral administration (for example, injection), the daily dose is preferably a dose level of about 3 to 1/10 of the above dose. The formulation examples of the pharmaceutical composition containing the compound of the present invention as an active ingredient are shown below.

[0039]

[Table 8]

[0040]

[Table 9]

[0041]

[Table 10]

[0042]

[Table 11]

 ──────────────────────────────────────────────────続 き Continuing from the front page (72) Inventor Akira Ishii 442-1, Kawakitayama, Kinashi-sha, Kato-gun, Hyogo Japan Nippon Organ Pharmaceutical Co., Ltd.

Claims (1)

(57) [Claims] 1. A lipid-lowering agent comprising as an active ingredient at least one of an imidazolidinetrione derivative represented by the general formula (I) and a pharmaceutically acceptable salt thereof. Embedded image [In the general formula (I), R ₁ and R ₂ are the same or different and each represents a hydrogen, an alkyl group, a cycloalkyl group, or a group represented by the following general formula (II). [Chemical formula 2] [In the general formula (II), R ₃ and R ₄ are the same or different and each represents hydrogen, halogen, a nitro group, a lower alkyl group or a lower alkoxy group. ]