Pharmaceutical composition containing an imidazolidinetrione derivative or pharmaceutically acceptable salt thereof

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to pharmaceutical compositions containing imidazolidinetrione derivatives or pharmaceutically acceptable salts thereof having hypoglycemic and hypolipidemic effects.
An abnormal increase or unbalance of blood glucose or lipids causes various morbid symptoms. Diabetes causes acidosis inducing diabetic coma, microangiopathy such as retiopathy or nephrosis, and promotes arteriosclerosis. Hyperlipidemia is not only a direct cause of arteriosclerosis but also causes the development of various symptoms such as ischemic heart disease, and often involves the complication of diabetes.
Oral sulfonylureas and biguanides having a hypoglycemic effect have been conventionally used for the treatment of diabetes, but they tend to promote certain side effects such as excessive hypoglycemia and lactic acidosis. Insulin, a well-known antidiabetic, can only be administered intravenously due to its chemical nature, and therefore, is troublesome and inconvenient to use.
As a result of the investigations for orally administrable hypoglycemic compounds having greater safety that known compounds to solve the problem mentioned above, the inventors have found that imidazolidinetrione derivatives and pharmaceutically acceptable salts thereof have an excellent hypoglycemic effect, i.e., they lower the abnormally high level of blood glucose to the normal level without excessive hypoglycemia, as well as low toxicity and great safety.
An object of the present invention is to provide pharmaceutical compositions containing imidazolidinetrione derivatives or pharmaceutically acceptable salts thereof as an active ingredient, which are useful as orally administrable drugs to treat and prevent diabetics and/or hyperlipidemia, and also various diseases caused by them.
The present invention relates to pharmaceutical compositions containing at least one imidazolidinetrione derivative or a pharmaceutically acceptable salt thereof represented by the following formula (I): ##STR3## wherein each of R.sub.1 and R.sub.2, which may be the same or different, is hydrogen, an alkyl group, a cycloalkyl group or ##STR4## and each of R.sub.3 and R.sub.4, which may be the same or different, is hydrogen, halogen, a nitro group, a lower alkyl group or a lower alkoxy group.
Each of R.sub.1 and R.sub.2, which may be the same or different, is hydrogen, an alkyl group, preferably a straight or branched alkyl group having 1 to 20 carbon atoms, such as methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, iso-pentyl, neo-pentyl, tert-pentyl, hexyl, iso-hexyl, dimethylbutyl, heptyl, octyl, nonyl, decyl or stearyl; a cycloalkyl group, preferably having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; ##STR5## When one of R.sub.1 and R.sub.2 is ##STR6## the other substituent is preferably hydrogen.
Each of R.sub.3 and R.sub.4, which may be the same or different, is hydrogen, halogen, such as fluoride, chloride or bromide, a lower alkyl group, preferably a straight or branched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, or a lower alkoxy group, preferably a straight or branched alkoxy group having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, sec-butoxy, or tert-butoxy.
The imidazolidinetrione derivatives include not only novel compounds but also known compounds. However, it has not been reported that such compounds have hypoglycemic and hypolipidemic effects.
Preferred compounds of the present invention are indicated as follows:
imidazolidinetrione
1-methylimidazolidinetrione
1-ethylimidazolidinetrione
1-butylimidazolidinetrione
1-iso-butylimidazolidinetrione
1-tert-butylimidazolidinetrione
1-hexylimidazolidinetrione
1-(1,3-dimethyl)butylimidazolidinetrione
1-decylimidazolidinetrione
1-cyclopentylimidazolidinetrione
1-cyclohexylimidazolidinetrione
1,3-dimethylimidazolidinetrione
1-cyclopentyl-3-ethylimidazolidinetrione
1,3-dicyclohexylimidazolidinetrione
1-benzylimidazolidinetrione
1-(2-fluorobenzyl)imidazolidinetrione
1-(3-fluorobenzyl)imidazolidinetrione
1-(4-fluorobenzyl)imidazolidinetrione
1-(2-chlorobenzyl)imidazolidinetrione
1-(4-chlorobenzyl)imidazolidinetrione
1-(4-bromobenzyl)imidazolidinetrione
1-(3-nitrobenzyl)imidazolidinetrione
1-(4-nitrobenzyl)imidazolidinetrione
1-(2-methylbenzyl)imidazolidinetrione
1-(3-methylbenzyl)imidazolidinetrione
1-(4-methylbenzyl)imidazolidinetrione
1-(2-methoxybenzyl)imidazolidinetrione
1-(3-methoxybenzyl)imidazolidinetrione
1-(4-methoxybenzyl)imidazolidinetrione
1-(3,4-dimethoxybenzyl)imidazolidinetrione
1-(3,4-dichlorobenzyl)imidazolidinetrione
The imidazolidinetrione derivatives of the present invention include pharmaceutically acceptable salts of the compounds of the above-mentioned formula (I) with alkali metals such as sodium or potassium, with alkaline earth metals such as calcium, magnesium or barium, with other metals such as aluminum, or with organic bases such as ammonium or organic amines.
In addition, the imidazolidinetrione derivatives of the invention include their metal complexes, for example, complexes with zinc, iron, etc.
These salts can be prepared from free imidazolidinetrione derivatives or other salts of these derivatives by known methods.
When optical isomers exist in the compounds of the present invention, the present invention includes any of the dl-, l- and d-isomers.
The imidazolidinetrione derivatives of the present invention can be prepared by art-recognized methods. [T. Yonezawa et al, Nippon Kagaku Zasshi, 89, No. 8, 62-64 (1968), Tad L. Patton, J. Org. Chem., 32, No. 2, 383-388 (1967), etc.]
(1) Oxalyl chloride and an N-substituted urea, such as N-alkylurea, N-cycloalkylurea, N-benzylurea, N-halogenated benzylurea, N-nitrobenzylurea, N-alkylbenzylurea or N-alkoxybenzylurea, were stirred in an appropriate solvent such as tetrahydrofuran which does not inhibit the reaction in an ice-water bath or at room temperature; or diethyl oxalate and the above-mentioned N-substituted urea were stirred in an appropriate solvent which does not inhibit the reaction in the presence of an organic base such as an amine or alkali metal alkoxide at room temperature, if desired, by heating to higher temperatures to give the imidazolidinetrione derivatives of the present invention.
(2) The compounds of the invention can also be prepared by usual N-alkylation wherein unsubstituted, 1-alkylsubstituted or 1-cycloalkylsubstituted imidazolidinetrione is reacted with halogenated alkyl.
The resultant compounds of the present invention are purified by usual methods such as distillation, chromatography and recrystallization. They are identified by elemental analysis, melting point, IR, NMR, UV and mass spectrum.
The following examples, which are illustrative describe the preparation of the compounds of the present invention.

EXAMPLE
1-methylimidazolidinetrione (compound 2)
m.p.: 153.degree.-155.degree. C.
IR(KBr): 3210, 1790, 1740, 1718, 1460 cm.sup.-1.
NMR(DMSO-d.sub.6): .delta.=2.92(s, 3H), 11.98(brs, 1H).
MS (m/z): 128 (M.sup.+), 100, 56, 44.
1-ethylimidazolidinetrione (compound 3)
m.p.: 123.degree.-125.degree. C.
IR(KBr): 3200, 2960, 1810, 1785, 1720, 1060 cm.sup.-1.
NMR(DMSO-d.sub.6): .delta.=1.13(t, 3H, J=7 Hz), 3.47(q, 2H, J=7 Hz), 11.96(brs, 1H).
MS (m/z): 142 (M.sup.+), 71, 56, 43.
1-butylimidazolidinetrione (compound 4)
m.p.: 97.degree.-99.degree. C.
IR(KBr): 3200, 2950, 1800, 1785, 1718, 1445 cm.sup.-1.
NMR(DMSO-d.sub.6): .delta.=0.88(t, 3H, J=7 Hz), 1.29(qt, 2H, J.sub.1 =7 Hz, J.sub.2 =7 Hz), 1.52(tt, 2H, J.sub.1 =7 Hz, J.sub.2 =7 Hz), 3.43(t, 2H, J=7 Hz), 11.97 (brs, 1H).
MS (m/z): 170 (M.sup.+), 128, 115, 99, 70, 56, 41.
1-iso-butylimidazolidinetrione (compound 5)
m.p.: 145.degree.-147.degree. C.
IR(KBr): 3170, 2950, 2860, 1800, 1730, 1710 cm.sup.-1. NMR(DMSO-d.sub.6): .delta.=0.85(d, 6H, J=6.4 Hz), 1.90 m, 1H), 3.23(d, 2H, J=6.8 Hz), 11.98(s, 1H).
MS (m/z): 170 (M+), 128, 115, 56, 43, 41, 27.
1-tert-butylimidazolidinetrione (compound 6)
m.p.: 121.degree.-124.degree. C.
IR(KBr): 3170, 1798, 1701, 1366, 1322 cm.sup.-1.
NMR(DMSO-D.sub.6): .delta.=1.51(s, 9H), 11.84(brs, 1H).
MS (m/z): 170 (M.sup.+), 155, 114, 84, 57, 41.
1-hexylimidazolidinetrione (compound 7)
m.p.: 99.degree.-101.degree. C.
IR(KBr): 3200, 2950, 2920, 2850, 1810, 1790, 1720 cm.sup.-1.
NMR(DMSO-d.sub.6): .delta.=0.85(t, 3H, J=6.8 Hz), 1.24(s, 6H), 1.50(tt, 2H, J.sub.1 =7.8 Hz, J.sub.2 =6.8 Hz), 3.40(t, 2H, J=6.8 Hz), 11.95(s, 1H).
MS (m/z): 198 (M.sup.+), 128, 116, 115, 84, 56, 55, 43, 41, 27.
1-(1,3-dimethylbutyl)imidazolidinetrione (compound 8)
m.p.: 61.degree.-65.degree. C.
IR(KBr): 3300, 2950, 2860, 1800, 1720 cm.sup.-1.
NMR(DMSO-d.sub.6): .delta.=0.82(d, 3H, J=6.4 Hz), 0.83(d, 3H, J=6.4 Hz), 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.sup.+), 183, 141, 116, 115, 84, 83, 70, 69, 57, 43, 41, 27.
1-decylimidazolidinetrione (compound 9)
m.p.: 110.degree.-112.degree. C.
IR(KBr): 3200, 2950, 2920, 2850, 1820, 1790, 1730, 1710 cm.sup.-1.
NMR(DMSO-d.sub.6): .delta.=0.84(t, 3H, J=7.2 Hz), 1.23(s, 14H), 1.51(m, 2H), 3.40(t, 2H, J=7.2 Hz), 11.95(s, 1H).
MS (m/z): 254 (M.sup.+), 142, 128, 116, 83, 69, 55, 43, 41, 27.
1-cyclopentylimidazolidinetrione (compound 10)
m.p.: 98.degree.-100.degree. C.
IR(KBr): 3540, 3250, 2945, 2700, 1760, 1725, 1420, 1100 cm.sup.-1.
NMR(DMSO-d.sub.6): .delta.=1.4-1.6(m, 2H), 1.6-2.0(m, 6H), 4.34(tt, 1H, J.sub.1 =7.4 Hz, J.sub.2 =7.4 Hz), 11.90(brs, 1H).
MS (m/z): 182 (M.sup.+), 141, 116, 67, 41.
1-cyclohexylimidazolidinetrione compound 11)
m.p.: 190.degree.-191.degree. C.
IR(KBr): 3180, 2920, 1795, 1730, 1410 cm-1.
NMR(DMSO-d.sub.6): .delta.=1.0-1.4(m, 4H), 1.5-2.0(m, 6H), 3.9(m, 1H), 11.93(brs, 1H).
MS (m/z: 196 (M.sup.+), 128, 116, 82, 67, 55, 41.
1,3-dimethylimidazolidinetrione (compound 12)
m.p.: 152.degree.-153.degree. C.
IR(KBr): 2940 1760, 1730, 1705, 1468, 1300 cm.sup.-1.
NMR(DMSO-d.sub.6): .delta.=2.97(s, 6H).
MS (m/z): 142 (M.sup.+), 114, 86, 70, 58.
1-cyclopentyl-3-ethylimidazolidinetrione (compound 13)
m.p.: 54.degree.-56.degree. C.
IR(KBr): 2940, 2855, 1770, 1715, 1418, 1120, 558 cm.sup.-1.
NMR(DMSO-d.sub.6): .delta.=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=7.4 Hz), 4.37(tt, 1H, J.sub.1 =8.0 Hz, J.sub.2 =8.0 Hz).
MS (m/z): 210 (M.sup.+), 144, 115, 68, 41.
1,3-dicyclohexylimidazolidinetrione (compound 14)
m.p.: 176.degree.-178.degree. C.
IR(KBr): 2925, 2850, 1760, 1728, 1410, 758 cm.sup.-1.
NMR(DMSO-d.sub.6): .delta.=1.0-1.2(m, 2H), 1.2-1.4(m, 4H), 1.4-2.0(m, 14H), 3.81(tt, 2H, J.sub.1 =3.7 Hz, J.sub.2 =12.5 Hz).
MS (m/z): 278 (M.sup.+), 197, 115, 83, 67, 55, 41.
1-benzylimidazolidinetrione (compound 15)
m.p.: 169.degree.-170.degree. C.
IR(KBr): 3430, 3200, 1790, 1735 cm.sup.-1.
NMR(DMSO-d.sub.6): .delta.=4.62(s, 2H), 7.24-7.33(m, 5H), 12.08(s, 1H).
MS (m/z): 204 (M.sup.+), 176, 147, 133, 91, 77, 65, 51.
1-(2-fluorobenzyl)imidazolidinetrione (compound 16)
m.p.: 196.degree.-197.degree. C.
IR(KBr): 3430, 3200, 3070, 1795, 1730, 1590 cm.sup.-1.
NMR(DMSO-d.sub.6): .delta.=4.66(s, 2H), 7.14-7.46(m, 4H), 12.11(s, 1H).
MS (m/z): 222 (M.sup.+), 165, 151, 123, 109, 83, 70, 63, 51, 50, 43.
1-(3-fluorobenzyl)imidazolidinetrione (compound 17)
m.p.: 166.degree.-167.degree. C.
IR(KBr): 3430, 3200, 1790, 1735, 1590 cm.sup.-1.
NMR(DMSO-d.sub.6): .delta.=4.65(s, 2H, 7.07-7.40(m, 4H), 12.08(s, 1H).
MS (m/z): 222 (M.sup.+), 165, 151, 122, 109, 83, 70, 63, 51, 50, 43.
1-4-fluorobenzyl)imidazolidinetrione (compound 18)
m.p.: 182.degree.-183.degree. C.
IR(KBr): 3440, 3200, 3070, 1790, 1730, 1600 cm.sup.-1.
NMR(DMSO-d.sub.6): .delta.=4.61(s, 2H), 7.12-7.40(m, 4H), 12.06(s, 1H).
MS (m/z): 222 (M.sup.+), 165, 151, 122, 109, 95, 83, 70, 63, 51, 50, 43.
1-(2-chlorobenzyl)imidazolidinetrione (compound 19)
m.p.: 192.degree.-193.degree. C.
IR(KBr): 3180, 3100, 1780, 1730 cm.sup.-1.
NMR(DMSO-d.sub.6): .delta.=4.68(s, 2H), 7.28-7.50(m, 4H), 12.17(s, 1H).
MS (m/z): 238 (M.sup.+), 203, 167, 132, 125, 89, 77, 70, 63, 51, 50, 43.
1-(4-chlorobenzyl)imidazolidinetrione (compound 20) m.p.: 177.degree.-178.degree. C.
IR(KBr): 3240, 3075, 1780, 1730 cm.sup.-1.
NMR(DMSO-d.sub.6): .delta.=4.62(s, 2H), 7.35-7.40(m, 4H), 12.08(s, 1H).
MS (m/z): 238 (M.sup.+), 181, 167, 132, 125, 89, 77, 70, 63, 51, 50, 43.
1-(4-bromobenzyl)imidazolidinetrione (compound 21)
m.p.: 192.degree.-193.degree. C.
IR(KBr): 3430, 3130, 3050, 1795, 1720 cm.sup.-1.
NMR(DMSO-d.sub.6): .delta.=4.60(s, 2H), 7.52(dt, 2H, J.sub.1 =2.0 Hz, J.sub.2 =8.4 Hz), 7.30(dt, 2H, J.sub.1 =2.0 Hz, J.sub.2 =8.4 Hz), 12.07(s, 1H).
MS (m/z): 282 (M.sup.+), 225, 211, 169, 132, 90, 77, 70, 63, 51, 50, 43.
1-(3-nitrobenzyl)imidazolidinetrione (compound 22)
m.p.: 139.degree.-140.degree. C.
IR(KBr): 3430, 3230, 1790, 1730, 1535 cm.sup.-1.
NMR(DMSO-d.sub.6): .delta.=4.78(s, 2H), 7.63(t, 1H, J=8.0 Hz), 7.82(d, 1H, J=8.0 Hz), 8.13-8.14(m, 1H), 8.24(t, 1H, J=2.0 Hz), 12.08(s, 1H).
MS (m/z): 249 (M.sup.+), 232, 178, 161, 136, 132, 125, 89, 77, 70, 63, 51, 50, 43.
1-(4-nitrobenzyl)imidazolidinetrione (compound 23)
m.p.: 202.degree.-204.degree. C.
IR(KBr): 3440, 3230, 1780, 1730, 1515 cm.sup.-1.
NMR(DMSO-d.sub.6): .delta.=4.78(s, 2H), 7.65(d, 2H, J=8.0 Hz), 8.18(dt, 2H, J.sub.1 =2.0 Hz, J.sub.2 =8.8 Hz), 12.12(s, 1H).
MS (m/z): 249 (M.sup.+), 219, 178, 132, 106, 89, 78, 77, 70, 63, 51, 50.
1-(2-methylbenzyl)imidazolidinetrione (compound 24)
m.p.: 195.degree.-196.degree. C.
IR(KBr): 3430, 3170, 3080, 1770, 1730 cm.sup.-1.
NMR(DMSO-d.sub.6): .delta.=2.32(s, 3H), 4.59(s, 2H), 7.10-7.27(m, 4H), 12.09(s, 1H).
MS (m/z): 218 (M.sup.+), 147, 104, 91, 77, 65, 51, 43.
1-(3-methylbenzyl)imidazolidinetrione (compound 25)
m.p.: 149.degree.-150.degree. C.
IR(KBr): 3220, 1780, 1760, 1725, 1600 cm.sup.-1.
NMR(DMSO-d.sub.6): .delta.=2.27(s, 3H), 4.58(s, 2H), 7.07-7.22(m, 4H), 12.07(s, 1H).
MS (m/z): 218 (M.sup.+), 147, 132, 105, 91, 77, 65, 51, 43.
1-(4-methylbenzyl)imidazolidinetrione (compound 26)
m.p.: 177.degree.-178.degree. C.
IR(KBr): 3450, 3180, 1800, 1725 cm.sup.-1.
NMR(DMSO-d.sub.6): .delta.=2.26(s, 3H), 4.57(s, 2H), 7.12(d, 2H, J=8.0 Hz), 7.20(d, 2H, J=8.0 Hz), 12.07(s, 1H).
MS (m/z): 218 (M.sup.+), 161, 147, 132, 105, 91, 77, 65, 51.
1-(2-methoxybenzyl)imidazolidinetrione (compound 27)
m.p.: 171.degree.-172.degree. C.
IR(KBr): 3430, 3200, 1805, 1790, 1720, 1600 cm.sup.-1.
NMR(DMSO-d.sub.6): .delta.=3.80(s, 3H), 4.57(s, 2H), 6.87(dt, 1H, J.sub.1 =0.8 Hz, J.sub.2 =7.6 Hz), 6.99(d, 1H, J=8.0 Hz), 7.23-7.28(m, 2H).
MS (m/z): 234 (M.sup.+), 163, 148, 134, 121, 91, 77, 65, 51, 43.
1-(3-methoxybenzyl)imidazolidinetrione (compound 28)
m.p.: 142.degree.-143.degree. C.
IR(KBr): 3210, 2940, 1790, 1735, 1595 cm.sup.-1.
NMR(DMSO-d.sub.6): .delta.=3.72(s, 3H), 4.59(s, 2H), 6.82-7.25(m, 4H), 12.07(s, 1H).
MS (m/z): 234 (M.sup.+), 167, 148, 121, 91, 77, 65, 51, 43.
1-(4-methoxybenzyl)imidazolidinetrione (compound 29)
m.p.: 172.degree.-173.degree. C.
IR(KBr): 3430, 3190, 2850, 1790, 1730, 1585 cm.sup.-1.
NMR(DMSO-d.sub.6): .delta.=3.72(s, 3H), 4.55(s, 2H), 6.87(dt, 2H, J.sub.1 =2.4 Hz, J.sub.2 =8.8 Hz), 7.25(dt, 2H, J.sub.1 =2.4 Hz, J.sub.2 =8.8 Hz), 12.05(s, 1H).
MS (m/z): 234 (M.sup.+), 177, 163, 148, 121, 91, 77, 65, 51, 43.
1-(3,4-dimethoxybenzyl)imidazolidinetrione (compound 30)
m.p.: 171.degree.-174.degree. C.
IR(KBr): 3420, 3250, 2950, 2840, 1780, 1740, 1590 cm.sup.-1.
NMR(DMSO-d.sub.6): .delta.=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.sup.+), 234, 178, 151, 121, 107, 91, 77, 65, 51.
1-(3,4-dichlorobenzyl)imidazolidinetrione (compound 31)
m.p.: 172.degree.-173.degree. C.
IR(KBr): 3430, 3200, 1790, 1735 cm.sup.-1.
NMR(DMSO-d.sub.6): .delta.=4.64(s, 2H), 7.35(dd, 1H, J.sub.1 =2.0 Hz, J.sub.2 =8.0 Hz), 7.59(d, 1H, J=8.0 Hz), 7.66(d, 1H, J=2.0 Hz), 12.06(s, 1H).
MS (m/z): 272 (M.sup.+), 215, 201, 166, 159, 123, 89, 70, 43.
The compounds of the present invention may be produced by each of the above-mentioned preparations, however, these examples do not limit the preparations of the compounds of the present invention.
The following description serves to illustrate pharmaceutical studies of the compounds of the present invention.
(1) Acute toxicity test
The test compounds of the present invention suspended in 0.5% aqueous solution of carboxymethylcellulose (C.M.C.) were orally administered to groups of 4 to 6 ddY-strain male mice (weighing about 19 g) which had fasted for 20 hours. The lethal dose was determined by the number of deaths for 7 days thereafter.
An example of the results is shown in Table 1.
TABLE 1______________________________________Test Compound LD.sub.50 (mg/kg)______________________________________compound 2 about 900compound 3 about 700compound 15 about 1,000______________________________________
(2) Hypoglycemic effect
Groups of 7 Wistar-strain male rats (weighing about 200 g) which were fasted for 18 hours were used for measurement of hypoglycemic effect according to the modified method by Dulin et al. [Dulin, W. L. et al., Proc. Soc. Expl. Med., 107, 245 (1961)]. That is, 0.5 ml/100 g of 20% aqueous solution of glucose was subcutaneously administered to the backs of rats to prevent a decrease in blood glucose level because of the fasting. Immediately thereafter the test drug suspended in 0.5% aqueous C.M.C. solution was orally given, and 2 hours later, the animals underwent laparotomy under pentobarbital anesthesia, then blood was drawn from the vena cava. The obtained blood sample was allowed to stand for 30 minutes to complete the coagulation and was centrifuged to obtain the serum. Blood sugar level was measured according to the mutalotase GOD method [Trinder, Ann. Clin. Biochem., 6, 24 (1979)]. Asterisks indicate significant differences (*: p<0.05, **: p<0.01, ***: p<0.001) from the control.
Results are shown in Tables 2 and 3.
TABLE 2______________________________________ Dosage Blood Glucose DecreaseTest Compound (mg/kg) Level (mg/dl) (%)______________________________________control -- 133 .+-. 6 --compound 2 12.5 109 .+-. 5** 18.0 25 99 .+-. 2** 25.6 50 91 .+-. 4*** 31.6 100 99 .+-. 5** 25.6compound 3 100 100 .+-. 2** 24.8compound 4 100 88 .+-. 7*** 33.8compound 5 100 81 .+-. 1** 39.1compound 6 100 109 .+-. 4* 18.0compound 7 100 102 .+-. 6*** 23.3compound 9 100 109 .+-. 4** 18.0compound 10 100 100 .+-. 4*** 24.8compound 11 100 101 .+-. 2*** 24.1compound 12 100 115 .+-. 4*** 15.0compound 13 100 116 .+-. 5*** 14.7Tolubutamide 100 48 .+-. 1*** 63.9______________________________________
TABLE 3______________________________________ Dosage Blood Glucose DecreaseTest Compound (mg/kg) Level (mg/dl) (%)______________________________________control -- 133 .+-. 4 --compound 15 100 112 .+-. 3** 15.8compound 16 100 118 .+-. 4* 11.3compound 17 100 115 .+-. 2** 13.5compound 18 100 106 .+-. 3*** 20.3compound 23 100 117 .+-. 3** 12.0compound 24 100 116 .+-. 3** 12.8compound 25 100 115 .+-. 3** 13.5compound 26 100 120 .+-. 2* 9.8compound 29 100 120 .+-. 2* 9.8______________________________________
(3) Hypolipidemic effect
The test drugs suspended in 0.5% aqueous C.M.C. solution were orally administered to groups of 8 Wistar-strain male rats (weighing about 185 g) which were fasted for 18 to 20 hours. 2 hours later, the serum was obtained in the same manner described in (2). Serum triglyceride was measured according to the GPO-p-chlorophenol colorimetric determination [Richard W. Spayd et al., Clinical Chemistry, 24, 1343 (1978)], serum free fatty acid was measured according to the Acyl CoA Synthetase-Acyl CoA Oxidase method [Shimizu S. et al., Biochem. Biophys. Res. Commun., 91, 108 (1979)], free fatty acid was measured according to the enzymatic method [Charles C. Allain et al., Clin. Chem., 20, No. 4, 470 (1974)] and total cholesterol was measured according to the enzymatic method [Takayama M. et al., Clinica Chimica Acta, 79, 93 (1977)]. Asterisks indicate significant differences (*: p<0.05, **: p<00.01, ***: p<0.001) from the control.
Results are shown in Tables 4 to 7.
TABLE 4______________________________________ Dosage Serum Triglyceride DecreaseTest Compound (mg/kg) Level (mg/dl) (%)______________________________________control -- 65 .+-. 5 --compound 2 100 22 .+-. 1*** 66.2compound 4 100 23 .+-. 1*** 64.6compound 7 100 38 .+-. 3** 41.5compound 11 100 27 .+-. 1*** 58.5compound 12 100 35 .+-. 3*** 46.2Tolubutamide 50 53 .+-. 4 18.5control -- 57 .+-. 4 --compound 15 100 30 .+-. 1*** 47.4compound 16 100 30 .+-. 1*** 47.4compound 17 100 30 .+-. 1*** 47.4compound 18 100 30 .+-. 1*** 47.4compound 21 100 35 .+-. 2** 38.6compound 23 100 38 .+-. 2** 33.3compound 24 100 30 .+-. 1*** 47.4compound 25 100 33 .+-. 2*** 42.1compound 26 100 37 .+-. 1** 35.1compound 29 100 43 .+-. 3* 24.6______________________________________
TABLE 5______________________________________ Dosage Serum Free Fatty DecreaseTest Compound (mg/kg) Acid Level (mEq/l) (%)______________________________________control -- 0.53 .+-. 0.03 --compound 2 100 0.25 .+-. 0.03*** 52.8compound 4 100 0.27 .+-. 0.02*** 49.1compound 11 100 0.34 .+-. 0.01*** 35.8compound 12 100 0.37 .+-. 0.03** 30.2Tolubutamide 50 0.44 .+-. 0.02* 15.7control -- 0.52 .+-. 0.03 --compound 15 100 0.44 .+-. 0.02* 15.4compound 18 100 0.42 .+-. 0.02** 19.2compound 21 100 0.44 .+-. 0.02* 15.2compound 24 100 0.45 .+-. 0.01* 13.5______________________________________
TABLE 6______________________________________ Dosage Total Serum Choles- DecreaseTest Compound (mg/kg) terol Level (mg/dl) (%)______________________________________control -- 44 .+-. 2 --compound 4 100 39 .+-. 1* 11.4compound 11 100 39 .+-. 1* 11.4compound 12 100 39 .+-. 1* 11.4Tolubutamide 50 46 .+-. 1 -4.5control -- 41 .+-. 1 --compound 15 100 33 .+-. 1*** 19.5compound 16 100 33 .+-. 2** 19.5compound 17 100 37 .+-. 1* 9.8compound 18 100 34 .+-. 1*** 17.1compound 21 100 36 .+-. 1** 12.2compound 24 100 36 .+-. 1** 12.2compound 25 100 36 .+-. 1** 12.2compound 26 100 37 .+-. 1** 9.8compound 29 100 36 .+-. 1** 12.2______________________________________
TABLE 7______________________________________ Dosage Serum Phospholipid DecreaseTest Compound (mg/kg) Level (mg/dl) (%)______________________________________control -- 79 .+-. 2 --compound 2 100 59 .+-. 1*** 25.3compound 4 100 58 .+-. 1*** 26.6compound 7 100 66 .+-. 2*** 16.5compound 11 100 60 .+-. 2*** 24.1compound 12 100 61 .+-. 2*** 22.8Tolubutamide 50 75 .+-. 2 5.1control -- 72 .+-. 2 --compound 15 100 52 .+-. 1*** 27.8compound 16 100 54 .+-. 1*** 25.0compound 17 100 58 .+-. 1*** 19.4compound 18 100 56 .+-. 1*** 22.2compound 21 100 57 .+-. 1*** 20.8compound 23 100 65 .+-. 2* 9.7compound 24 100 56 .+-. 1*** 22.2compound 25 100 57 .+-. 2*** 20.8compound 26 100 58 .+-. 1*** 19.4compound 29 100 58 .+-. 1*** 19.4______________________________________
As shown by the above-mentioned results, the imidazolidinetrione derivatives of the present invention have excellent hypoglycemic and hypolipidemic effects.
The relationship between doses of compound 2 and decrease of blood glucose level show that the compounds of the invention are extremely useful as drugs to improve severe hyperglycemia, since even at high doses, they maintain the blood sugar at nearly normal levels, without excessive hypoglycemia caused by Tolubutamide.
Therefore, the compounds are not only useful as antidiabetics but also as drugs for various diseases caused by diabetes, e.g. diabetic angiopathy, such as diabetic arteriosclerosis, diabetic retinitis, diabetic nephropathy, diabetic neurosis and diabetic microangiopathy. Since the compounds of the invention are different type drugs from insulin as mentioned above, they are especially useful as drugs for noninsulin-dependent (type-II) diabetes mellitus.
The compounds of the invention also have hypolipidemic effects, which makes them useful in treating hyperlipidemia, and in the treatment or the prevention of various diseases caused by hyperlipidemia, such as arteriosclerosis, nephrosis, hypertension, diabetes or obesity.
Since an increase of blood lipids is induced by an abnormal metabolism of glucose or a lowering of lipoprotein-lipase activity caused by diabetes, hyperlipidemia is often caused together with diabetes. Therefore, the compounds of the present invention having both hypoglycemic and hypolipidemic effects are useful as drugs for such complications.
The compounds of the present invention have low toxicity and great safety, so that their long-term continuous administration and oral use are possible.
The compounds of the present invention may be made into pharmaceutical compositions by combination with appropriate medicial carriers or diluents, and may be formulated into preparations in solid, semisolid, liquid or gaseous form such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, aerosols and cataplasms in usual ways for oral or parenteral administrations.
In pharmaceutical dosage forms, the compounds of the present invention may be used in the form of their pharmaceutically acceptable salts, and also may be used alone or on appropriate association, as well as in combination with other pharmaceutically active components.
In case of oral preparations, the compounds may be used alone or combined with appropriate additives to make tablets, powders, granules or capsules, e.g. with conventional additives such as lactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators such as corn starch, potato starch or sodium carboxymethylcellulose; with lubricants such as talc or magnesium stearate; and if desired, with diluents, buffering agents, moistening agents, preservatives and flavoring agents.
Furthermore, they may be made into suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases.
The compounds of the present invention may be formulated into preparations for injections by dissolving, suspending or emulsifying them in aqueous or non-aqueous solvents, such as vegetable oil, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.
In case of inhalations or aerosol preparations, the compounds of the invention in the form of a liquid or minute powder may be filled up in an aerosol container with gas or liquid spraying agents, and if desired, with conventional adjuvants such as humidifying agents added thereto. They may also be applied as pharmaceuticals for non-pressurized preparation such as in a nebulizer or an atomizer.
Cataplasms may be prepared by mixing the compounds with mentha oil, concentrated glycerin, kaolin or other suitable additives.
The desirable dose of the imidazolidinetrione derivatives of the present invention varies with the subject, drug form, method and period of administration. However, in order to obtain desirable effects, generally it is recommended to administer orally 1 to 1000 mg, preferably 5 to 600 mg daily. Unit preparations containing appropriate amounts of the compounds of the present invention are also recommended for administration in 1 to several units daily.
In case of parenteral administrations e.g. injections, doses of the compounds in the order of one tenth to one third of the above dose are preferable as daily doses.
Some prescriptions of the pharmaceutical compositions are shown below as examples which contain the compounds of the present invention as active ingredients.
______________________________________Prescription example 1 (tablet)Component Content in a tablet (mg)______________________________________compound of the invention 100lactose 130corn starch 40magnesium stearate 10Total 280 mg______________________________________Prescription example 2 (capsule)Component Content in a capsule (mg)______________________________________compound of the invention 50lactose 250Total 300 mg______________________________________Prescription example 3 (injection)Component Content in an ampule (mg)______________________________________compound of the invention 10sodium chloride proper amountdistilled water for injection proper amountTotal 1 ml______________________________________Prescription example 4 (ointment)Component Weight (g)______________________________________compound of the invention 1emulsified wax 30white petrolatum 50liquid paraffin 20Total 101 g______________________________________Prescription example 5 (suppository)Component Content in a suppository (mg)______________________________________compound of the invention 20cacao butter 1980Total 2000 mg______________________________________

Pharmaceutical composition containing an imidazolidinetrione derivative or pharmaceutically acceptable salt thereof

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