The present invention relates to the hydrochloride salt of a fused heterocyclic compound which can improve certain diseases caused by insulin resistance such as hyperglycemia, impaired glucose tolerance (IGT) conditions, diabetic complications (e.g., retinopathy, nephropathy, neurosis, cataracts, coronary artery diseases, etc.), hyperlipidemia, gestational diabetes mellitus (GDM), polycystic ovary syndrome, etc. and exhibits excellent oral absorption.
Further, this invention is directed to a prophylactic and therapeutic agent for diabetes mellitus, hyperglycemia, impaired glucose tolerance, diabetic complications (e.g., retinopathy, nephropathy, neurosis, cataracts, coronary artery diseases), hyperlipidemia, obesity, hypertension, fatty liver, arteriosclerosis, diseases caused by insulin resistance, gestational diabetes, polycystic ovary syndrome, cardiovascular diseases (e.g., ischemic heart disease), cell lesions caused by atherosclerosis or ischemic heart disease (e.g., brain damage induced by stroke), gout, inflammatory diseases (e.g., arthrosteitis, pain, fever, rheumatoid arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergic diseases, asthma, GI ulcer, cachexia, autoimmune diseases, pancreatitis), cancer, osteoporosis, cataracts and the like, which contains said fused heterocyclic compound hydrochloride as an active ingredient.
Furthermore, the present invention concerns a fused heterocyclic compound hydrochloride showing excellent insulin tolerance improving activity, hypoglycemic activity, anti-inflammatory activity, immunoregulatory activity, aldose reductase inhibiting activity, 5-lipoxygenase inhibiting activity, peroxidized lipid production suppressing activity, PPAR activating activity, anti-osteoporosis activity, leukotrienes antagonistic activity, fat cell formation promoting activity, cancer cell proliferation suppressing activity and calcium antagonistic activity.
Insulin and sulfonylurea compounds such as tolbutamide, glipizide, etc. have been used as therapeutic agents for diabetes mellitus and hyperglycemia. Recently, as insulin-independent therapeutic agents for diabetes mellitus, there are known thiazolidinedione derivatives such as troglitazone, pioglitazone, rosiglitazone, etc.
In particular, 5-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]thiazolidin-2,4-dione is disclosed in Japanese Patent Application Publication No. Hei-9(1997)-295970, EP 0745600, and U.S. Pat. No. 5,886,014. However, neither biological data nor physical properties of its hydrochloride, which is the compound of this invention, are disclosed in these documents.
As the result of keen investigations on the synthesis and pharmacology of compounds capable of improving the diseases caused by insulin resistance such as hyperglycemia, impaired glucose tolerance conditions, diabetic complications, hyperlipidemia, gestational diabetes, polycystic ovary syndrome, etc., the present inventors have found that the hydrochloride of a known fused heterocyclic compound shows excellent pharmacological activities.
Accordingly, the novel hydrochloride of a fused heterocyclic compound was obtained by converting a known compound, 5-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]thiazolidin-2,4-dione into its hydrochloride. This shows excellent oral absorption with markedly improved solubility compared to its free compound (compound not in the form of its salt). It can provide excellent pharmacological activities, because this excellent oral absorption will give the required serum concentration at a lower dosage.
The present invention concerns 5-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]thiazolidin-2,4-dione hydrochloride (hereinafter referred to as xe2x80x9cCompound Axe2x80x9d).
Further, this invention is directed to a prophylactic and/or therapeutic agent for diabetes mellitus, hyperglycemia, impaired glucose tolerance, diabetic complications (e.g., retinopathy, nephropathy, neuropathy, cataracts, coronary artery diseases), hyperlipidemia, obesity, hypertension, fatty liver, arteriosclerosis, diseases caused by insulin resistance, gestational diabetes, polycystic ovary syndrome, cardiovascular diseases (e.g., ischemic heart disease), cell lesions (injury) caused by atherosclerosis or ischemic heart disease (e.g., brain damage induced by stroke), gout, inflammatory diseases (e.g., arthrosteitis, pain, fever, rheumatoid arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergic diseases, asthma, GI ulcer, cachexia, autoimmune disease, pancreatitis), cancer, osteoporosis, cataracts and the like containing, as an active ingredient, said Compound A.
The present invention also provides a method of treatment and/or prophylaxis by administering to a human or other mammal in need thereof, an active agent selected from an insulin resistance improving agent, hypoglycemic agent, anti-inflammatory agent, immuno-regulator, aldose reductase inhibitor, 5-lipoxygenase inhibitor, peroxidized lipid production suppressor, PPAR activator, anti-osteoporosis agent, leukotrienes antagonist, fat cell formation promotor, cancer cell proliferation suppressor or calcium antagonist containing Compound A as an active ingredient.
5-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]-thiazolidin-2,4-dione (hereinafter referred to as xe2x80x9cCompound Bxe2x80x9d), the free form of Compound A of the present invention, is shown by the structural formula (I): 
Moreover, said Compound A has various isomers. For example, there are optical isomers, depending upon the asymmetry of the 5-carbon atom of the thiazolidine ring. In said structure (I), all the stereoisomers based on these asymmetric carbon atoms as well as the isomeric mixtures in equal amounts or non-equal amounts are shown by a single structure. Thus, all these isomers and their mixtures are included in the present invention.
Furthermore, solvation of said Compound A may occur by allowing it to recrystallize, and such a solvate of the compound A will be covered by the present invention.
The Compound A in the present invention can be prepared by at first synthesizing Compound B according to Example (1) described below and then converting it into the hydrochloride as shown in Example (2) in a conventional manner.
Compound A in the present invention is useful as a prophylactic and/or therapeutic agent for administration to mammals, e.g. humans, for prevention and/or treatment of diabetes mellitus, hyperglycemia, impaired glucose tolerance, diabetic complications (e.g., retinopathy, nephropathy, neurosis, cataracts, coronary artery diseases), hyperlipidemia, obesity, hypertension, fatty liver, arteriosclerosis, diseases caused by insulin resistance, gestational diabetes, polycystic ovary syndrome, cardiovascular diseases (e.g., ischemic heart disease), cell lesions caused by atherosclerosis or ischemic heart disease (e.g., brain damage induced by stroke), gout, inflammatory diseases (e.g., arthrosteitis, pain, fever, rheumatoid arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergic diseases, asthma, GI ulcer, cachexia, autoimmune disease, pancreatitis), cancer, osteoporosis, cataracts and the like.
Compound A in the present invention is administered in the methods of the present invention, for example, by the oral route in such a formulation as tablets, capsules, granules, powders or syrups, or by the parenteral route in such a formulation as injections, suppositories or eye-drops. These formulations may be prepared employing well-known methods by using conventional carriers such as excipients, lubricants, binders, disintegrators, stabilizers, corrigents, diluents and the like.
As for the excipients, there are exemplified organic excipients, for example, sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, xcex1-starch, dextrin and carboxymethyl starch; cellulose derivatives such as crystalline cellulose, low substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose and sodium internal cross-linked carboxymethyl cellulose; arabic gum; dextran; pullulan; and inorganic excipients, for example, silicate derivatives such as light silicic anhydride, synthetic aluminum silicate and magnesium aluminate metasilicate; phosphates such as calcium phosphate; carbonates such as calcium carbonate; and sulfates such as calcium sulfate.
As for the lubricant, there are exemplified stearic acid, metal stearates such as calcium stearate and magnesium stearate; talc; colloidal silica; wax such as beeswax and spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine; fatty acid sodium salts; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; and said starch derivatives.
Examples of the binder are polyvinylpyrrolidone, macrogol and those exemplified as said excipient.
Examples of the disintegrator are those exemplified as said excipient, and chemically modified starches and celluloses such as sodium cross-carmellose, sodium carboxymethyl starch and cross-linked polyvinylpyrrolidone.
Examples of the stabilizer are p-oxybenzoic acid esters such as methylparaben and propylparaben; alcohol derivatives such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; phenol derivatives such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.
Examples of the corrigents are those sweetening agents, souring agents, flavor agents, and the like used conventionally.
The appropriate daily dosage of Compound A in the present invention for a human adult varies depending upon symptoms, age, route of administration and the like. In the case of the oral route the daily dosage is, for example, from 0.01 mg/kg (of the body weight of the human adult) to 2000 mg/kg, and preferably 0.1 mg/kg to 500 mg/kg, and more preferably 0.1 mg/kg to 100 mg/kg in a single dose or in several divided doses in accordance with the symptoms. In the case of intravenous administration, the daily dosage of compound A for a human adult varies from 0.001 mg/kg to 500 mg/kg and preferably 0.01 mg/kg to 50 mg/kg which is preferably administered in a single dose or in several divided doses in accordance with the symptoms of the patient. Dosage for a specific patient is determined by those skilled in the art by applying usual techniques.
USPTO Backgrounds
USPTO Backgrounds