JP2002515064A - New heterocyclic compounds - Google Patents

Abstract

  (57) [Summary] Novel piperidine compounds are provided which treat and / or prevent (such as overnight treatment or diet, and long-term complications of diabetes, and especially non-insulin dependent diabetes mellitus (NIDDM or type 2 diabetes). Retinopathy, neuropathy, nephropathy, and the treatment or prevention of microangiopathy, macroangiopathy); hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atheroma It is effective in treating atherosclerosis or myocardial ischemia.

Description

DETAILED DESCRIPTION OF THE INVENTION                            New heterocyclic compounds   The present invention relates to novel compounds, the use of said compounds as medicaments, diabetes, Treatment and / or prevention of non-phosphorus dependent diabetes mellitus (NIDDM, ie type 2 diabetes) (Overnight treatment or diet, and long-term complications (eg, retinopathy, Treatment or prevention of neuropathy, nephropathy, and microangiopathy, macroangiopathy) ); Hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia Use of said agent in the treatment of atherosclerosis or myocardial ischemia; Pharmaceutical compositions containing the compounds, as well as methods of preparing the compounds.   Diabetes is a disease that is particularly manifested by increased blood glucose levels in diabetic patients. Characterized by defects in the metabolism of Lucose. Due to fundamental deficiencies, diabetes has two main Classified as required: Patients lack insulin-producing beta cells in pancreatic glands Type 1 diabetes, or insulin demanding diabetes (IDDM), and Type 2 diabetes, which impairs β-cell function and in addition causes a series of other abnormalities, Non-dependent diabetes mellitus (NIDDM).   Patients with type 1 diabetes are currently being treated with insulin but have type 2 diabetes The majority of patients respond to sulfonylurea, which stimulates β-cell function, Treatment with either a tissue-sensitizing drug or insulin. I Among the drugs applied to increase tissue sensitivity to insulin, metformin Is a typical example.   Sulfonylureas are widely used in the treatment of NIDDM, but this treatment Often not satisfactory. In many NIDDM patients, sulfo Nilurea is not enough to normalize blood sugar levels, so patients High risk of urinary complications. Also, many patients are treated with sulfonylureas Increasing insulin treatment as the ability to respond to treatment gradually decreases Can be This transition of patients from oral hypoglycemic drugs to insulin therapy Usually due to β-cell depletion in NIDDM patients.   Normal people and diabetics produce glucose in the liver to avoid hypoglycemia. Live. This glucose production is based on glucose from accumulated glycogen. Release of glucose or gluconeogenesis, which is an intracellular de novo synthesis of glucose . However, the regulation of hepatic glucose production in type 2 diabetes is well controlled. It is excessive and can be doubled after an overnight fast. Besides, these Patients should have increased plasma glucose levels during fasting and increased rates of hepatic glucose production. A strong correlation exists (R.A.De Fronzo: Diabetes 37 (1988), 667-687; A.C. onsoli: Diabetes Care 15 (1992), 430-441; and J.E.Gerich: Horm.Metab.Res. 26 (1992), 18-21). Similarly, in type 1 diabetes, the disease becomes insulin therapy If not better controlled, hepatic glucose production will increase.   Current forms of diabetes treatment do not lead to adequate glycemic control and are therefore unsatisfactory There is a strong need for new therapeutic approaches because they are not spoiled. Diabetic liver It is known that glucose production is increased in Compounds are highly desirable. Recently the liver needed for the release of glucose from the liver Patent Application for Inhibitor of Glucose-6-Phosphatase For example, German Offenlegungsschrift Nos. 4,202,183 and 4,202,184, Japanese Patent Application No. 4-58565 has been filed. All of these known compounds It is a benzene derivative.   Substituted N- (indole-2-acting as an inhibitor of glycogen phosphorylase (Carbonyl) -glycinamide is disclosed in PCT Publication Nos. WO96 / 39384 and WO96 / 3938. 5 disclosed.   Atherosclerosis, a disease of the arteries, is fatal in the United States and Western Europe. Is recognized as the cause. A series of pathological processes leading to atherosclerosis Is well known. The earliest steps in this series of pathological processes involve the carotid artery, coronary artery "Fat streaks" are formed in the pulses, cerebral arteries, and aorta. Such lesions Are macrophages primarily in smooth muscle cells and in the innermost layers of arteries and aorta. Is colored yellow due to the deposition of lipids found in In addition, it is found in fatty streaks It is hypothesized that many of cholesterol then cause the development of "fibrous plaque" Is done. Fibrous plaque is a lipid-rich, extracellular lipid, collagen From the accumulation of intimal smooth muscle cells, surrounded by elastin and proteoglycans Success Things. The cells and the matrix are composed of cell debris and many extracellular lipids. Form a fiber cap over the deeper deposits. The lipids are mainly free lipids and Esterified cholesterol. Fibrous plaques form slowly and eventually Calcification, necrosis, and progression to “complicated lesions” occur when arterial occlusion and Mural thrombosis and arterial muscle spasm characterizing the progression of atherosclerosis Cause   Epidemiological evidence suggests cardiovascular disease (CVD) due to atherosclerosis Hyperlipidemia has indeed been established as a major risk factor for causing cholesterol. In recent years, medical Expert leaders believe that cholesterol in plasma is an essential step in preventing CVD. New in lowering terol levels, especially low-density lipoprotein cholesterol Emphasis. "Normal" upper bound is significantly lower than previously recognized It is known today. As a result, the majority of Westerners are at particularly high risk. Is understood today. These independent risk factors include glucose intolerance, left Includes ventricular hypertrophy, hypertension, and being male. Cardiovascular disease, diabetes It is particularly prevalent among sick people, which at least in part poses an independent risk to them. This is because the risk factors overlap. Therefore, for the general public, especially those with diabetes Of particular importance medically is the successful treatment of hyperlipidemia in mice.   Hypertension (ie, high blood pressure) can be caused by various other disorders, such as renal artery stenosis, A condition that occurs in people as a secondary symptom of pheochromocytoma or endocrine disorders. I However, hypertension occurs in many patients whose causative agent or disorder is unknown. Has also been testified. Such “essential” hypertension is associated with obesity, diabetes and high blood pressure. Often associated with disorders such as triglyceridemia Was not disclosed. In addition, many patients have any other disease or disorder. Presents symptoms of hypertension without any signs of hypertension.   Hypertension can lead directly to heart failure, renal failure and stroke (cerebral hemorrhage) Are known. This situation can cause the patient to die quickly. You. Hypertension also causes atherosclerosis and the development of coronary disease. Can get. This situation gradually weakened the patient and led to long-term death. It is possible to   Although the exact cause of essential hypertension is unknown, several factors contribute to the pathogenesis of the disease. It is believed to be the first cause. These factors include stress, uncontrolled information. Movement, unregulated hormone release (renin, angiotensin and aldosterone), Excessive salt and water due to renal insufficiency, thickening of the walls of the vascular system leading to stenosis of the blood vessels and There are hypertrophy, as well as genetic factors.   Treatment of essential hypertension is performed with attention to the aforementioned factors. Therefore, extensive Β-blockers, vasoconstrictors, angiotensin converting enzyme inhibitors, etc. Developed and marketed as a drug. Treatment of hypertension using these compounds To prevent short-term deaths such as heart failure, renal failure and cerebral hemorrhage. I knew it. However, atherosclerosis due to long-term hypertension Or the development of heart disease remains a problem. This treatment lowers high blood pressure, The underlying cause of essential hypertension means that it does not respond to this treatment.   Hypertension is an increase in blood insulin levels, a condition known in hyperinsulinemia. Related to the situation. Insulin has its main functions of glucose utilization, protein Is a peptide hormone that promotes quality synthesis and the formation and storage of neutral lipids And, more particularly, to promote vascular cell proliferation and increase kidney sodium retention To work. These latter functions can be performed without affecting glucose levels. It is a known cause of hypertension. For example, increased peripheral vascular system Proliferation can cause narrowing of peripheral capillaries, while sodium storage Retention increases blood volume. Therefore, insulin in hyperinsulinemia patients Decreased levels are caused by abnormal blood vessel growth and kidney Can prevent sodium retention, thereby reducing hypertension.   Cardiac hypertrophy is critical in the development of sudden death, myocardial infarction, and congestive heart failure It is a risk factor. What happens to these hearts, at least in part, Myocardium is damaged after ischemia and reperfusion, which can occur during the surgical setting. Increased sensitivity. Harmful things that occur in myocardium during surgery, especially during surgery Medical needs to prevent or minimize myocardial infarction have not been met. Below the heart Both external and cardiac operations carry a significant risk of myocardial infarction or death. Approximately 7 million patients who have undergone noncardiac surgery have died during surgery and have severe heart complications It is believed that there is a danger of as much as 20-25% of the disease occurring continuously. Besides, the crown every year 5% of myocardial infarction during surgery among 400,000 patients undergoing coronary artery bypass surgery And the mortality rate is calculated to be 1-2%. Due to myocardial ischemia during surgery Reduce damage to the incoming heart tissue or reduce the risk of ischemic episodes There are currently no drug treatments in the field that increase the tolerance of the drug. This Treatment helps save the lives of high-risk patients, reduces hospital stays, and improves quality of life Is expected to reduce overall health and medical expenses.   One object of the present invention is a medicament for treating one or more of the diseases and disorders mentioned above. Is to provide a compound that can be used as   Another object of the present invention is to treat diabetes, preferably type II diabetes (even overnight treatment). Or preferably includes dietary therapy), and preferably increases plasma glucose levels. It is to provide compounds that can be used effectively to treat.   Still another object of the present invention is to provide a drug for inhibiting glucose production from the liver. An object of the present invention is to provide a compound which can be used for the effect.   Yet another object of the present invention is to provide an effective use as a phosphorylase inhibitor. To provide a compound capable of   Members of a new group of piperidine compounds have interesting pharmacological properties Has been found here. For example, the compounds of the invention may be used in the treatment of diabetes. Can be In particular, the compounds of the invention inhibit glucose production from the liver. It is active as a drug. As a result, the compounds of the present invention can It can be used to treat elevated glucose levels in plasma.   Accordingly, an object of the present invention is to provide such a novel piperidine compound. is there.   The compounds of the present invention have the general formula IAnd a pharmaceutically acceptable acid addition salt or hydrate or a prodrug thereof. ,   Where R is a linear or branched C_1-6Is an alkoxy group; or   R represents a cyano group, a carboxylic acid, a trifluoromethyl group, a hydroxyl group, a perhalomethy; Group, halogen, C_3-7Cycloalkyl group, C_1-6Alkoxy group, C_1-6Alkoki Sicarbonyl group, benzyloxycarbonyl group, or NR₁R_TwoGroup (where R₁ , R_TwoIs hydrogen or C_1-6Alkyl group or benzyl A straight-chain or branched (C_1-18Al Kill group, C_2-18Alkene or C_2-18Alkyne); or   R is SR_ThreeGroup (where R_ThreeIs C_1-6Alkyl group, phenyl group, or carbo Nil (C_1-6Alkyl) group) are all optionally substituted, linear or Branched (C_1-18Alkyl group, C_2-18Alkene or C_2-18Alkyne) Or   R is optionally substituted with a methoxy, nitro, halogen, or cyano group Carbonyl (C_1-6Alkyl) or carbonylphenyl Optionally substituted, linear or branched (C_1-18Alkyl group, C_2-18Alkene Or C_2-18Alkyne); or   R represents a trifluoromethyl group, a methoxy group, C_1-6Alkyl groups, carboxylic acids, Nitro, cyano, halogen, phenyl, methoxycarbonyl, methyls All with a phenoxy or phenyl group optionally substituted by a rufonyl group Optionally substituted, linear or branched (C_1-18Alkyl group, C_2-18Alkene Or C_2-18Alkyne); or   R represents carboxamide (CONR_FourR_FiveGroup, where R_Four, R_FiveAre together or Is hydrogen or C_1-6All are optionally substituted by Straight, branched or branched (C_1-18Alkyl group, C_2-18Alkene or C_{2- 18} Alkyne); or   R is naphthalene, phthalimide, optionally substituted piperidine, imidazoly 2-thienone, optionally substituted coumarin, 2-dioxolan, hydantoin , Thiohydantoin, 1,2,4-oxadiazoline, optionally substituted isooxo Sazo Lysine, tetrahydrofurfuryl group, 1,4-benzodioxane, or phenyl Linear or branched, all optionally substituted by sulfonyl groups or glycosides Branched (C_1-18Alkyl group, C_2-18Alkene or C_2-18Alkyne); Or   R represents a cyano group, a carboxylic acid, a hydroxyl group, an oxo group, a perhalomethyl group, Phenyl group, C_1-6Alkoxy group, C_1-6Alkoxycarbonyl group, benzyl Oxycarbonyl group, hydroxy-C_1-6Alkyl group, C_1-6An alkyl group, or NR₁R_TwoGroup (where R₁, R_TwoIs hydrogen or C_1-6Alkyl A benzyl group or a benzyl group)_3-7Cycloalkyl group It is.   The compounds of formula I can be represented as a mixture of enantiomers, Can be separated into the individual pure enantiomers. This separation is given by the formula By fractional crystallization of a salt of a compound of formula I with an optically active acid from various solvents, or It can be carried out by other methods known per se, for example by chiral column chromatography. Can be. The present invention includes all isomers, whether separated or in mixtures.   Pharmaceutically acceptable salts include non-toxic acids, inorganic acids (eg, hydrochloric acid, hydrobromic acid). , Hydroiodic acid, sulfuric acid and phosphoric acid) or organic acids (eg, formic acid, acetic acid, Fluoroacetic acid, trichloroacetic acid, propionic acid, succinic acid, gluconic acid, lactic acid, Citric acid, ascorbic acid, benzoic acid, embonic acid, methanesulfur Fonic acid, ethanesulfonic acid, malonic acid, oxalic acid, maleic acid, pyruvic acid, sake Acid addition salts with acids such as folic acid, fumaric acid, mandelic acid, cinnamic acid, picric acid) And described in the Journal of Pharmaceutical Science, 66, 2 (1977). Pharmaceutically acceptable salts; incorporated herein by reference; pharmaceutically acceptable gold Genus salts (eg, lithium, sodium, potassium, or magnesium salts) including. Hydrates that can form the compounds of the invention are also pharmaceutically acceptable It is intended as an acid addition salt. Acid addition salts can be obtained as a direct product of compound synthesis. Can be. Alternatively, place the free base in a suitable solvent containing the appropriate acid. Dissolve and separate the salt and solvent by evaporating the solvent or otherwise Thus, the salt can be isolated. The compounds of the present invention can be prepared by methods known to those skilled in the art. For To form solvates with standard low molecular weight solvents.   In the above structural formulas and throughout the present specification, the following terms have the following meanings: Having.   Here, "C" used alone or in combination_1-6Alkoxy group " The term refers to C bonded through the ether oxygen._1-6Straight chain containing an alkyl group or A branched monovalent substituent, wherein an ether oxygen is a free atom from said ether oxygen Having a valence bond and 1 to 6 carbon atoms (e.g., methoxy, ethoxy, Oxy, isopropoxy, butoxy, pentoxy) .   "C" used here_3-7The term "cycloalkyl group" refers to the number of carbon atoms Having a saturated cyclic hydrocarbon group (eg, a cyclopropyl group, a cyclobutyl group, Lpentyl group, cyclohexyl group or cycloheptyl group).   The term "halogen" means fluorine, chlorine, bromine or iodine.   The term "perhalomethyl" refers to trifluoromethyl, trichloromethyl , A tribromomethyl group or a triiodomethyl group.   Here, "C" used alone or in combination_1-6"Alkyl group" The term is a straight or branched chain saturated hydrocarbon chain having the specified number of carbon atoms (eg, For example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, se c-butyl group, isobutyl group, tert-butyl group, n-pentyl group, 2-methylbutyl Group, 3-methylbutyl group, 4-methylpentyl group, neopentyl group, n-hexyl Group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1,2,2-trimethyl Propyl group). "C" used here_1-18"Alkyl group" The word is further C_3-18Alkyl group and tertiary C_4-18Contains an alkyl group.   The term "prodrug" as used herein refers to, for example, Drug precursors that release drugs in vivo via chemical or physiological processes Refers to a compound of formula I These prodrug examples can be handled by decomposition There are esters that release free acids. Other examples of such prodrugs are A stele group is introduced and the decomposition releases the corresponding free alcohol of formula I It is a compound of formula I.   Some of the terms defined above may occur multiple times in Formula I above, but Are defined independently of each other.   In a preferred embodiment, the present invention provides compounds of formula I wherein R is linear or Is branched C_1-6Which is an alkoxy group).   In another preferred embodiment, the present invention provides a compound of formula I wherein R is a cyano group , Carboxylic acid, trifluoromethyl group, hydroxyl group, perhalomethyl group, halogen, C_3-7Cycloalkyl group, C_1-6Alkoxy group, C_1-6An alkoxycarbonyl group, Benzyloxycarbonyl group, or NR₁R_TwoGroup (where R₁, R_TwoIs, independently, Hydrogen, C_1-6Alkyl or benzyl)) Linear or branched (C_1-18Alkyl group, C_2-18Alkene or C_2-18 Alkyne).   In another preferred embodiment, the present invention provides a compound of formula I wherein R is SR_ThreeGroup ( Where R_ThreeIs C_1-6Alkyl group, phenyl group, or carbonyl (C_1-6Archi Linear or branched (C), all of which are optionally substituted by_1-18A Alkyl group, C_2-18Alkene or C_2-18Alkyne).   In another preferred embodiment, the present invention provides a compound of formula I wherein R is methoxy Optionally substituted by a nitro, nitro, halogen, or cyano group (C_1-6All optionally substituted by an (alkyl) group or a carbonylphenyl group , Linear or branched (C_1-18Alkyl group, C_2-18Alkene or C_2-18A Lucin).   In another preferred embodiment, the present invention provides a compound of formula I wherein R is Oromethyl group, methoxy group, C_1-6Alkyl group, carboxylic acid, nitro group, cyano Group, halogen, phenyl group, methoxycarbonyl group, methylsulfonyl group All optionally substituted by optionally substituted phenoxy or phenyl groups , Linear or branched (C_1-18Alkyl group, C_2-18Alkene or C_2-18A Lucin).   In another preferred embodiment, the present invention provides a compound of formula I wherein R is carboxy Samide (CONR_FourR_FiveGroup, where R_Four, R_FiveIs either or both hydrogen, Or C_1-6Alkyl), all of which are optionally substituted Is branched (C_1-18Alkyl group, C_2-18Alkene or C_2-18Alkyne) R] About.   In another preferred embodiment, the present invention provides a compound of formula I wherein R is naphthale , Phthalimide, optionally substituted piperidine, imidazoline, 2-thienone , Optionally substituted coumarin, 2-dioxolan, hydantoin, thiohydanto 1,2,4-oxadiazoline, optionally substituted isoxazolidine, Trahydrofurfuryl group, 1,4-benzodioxane, or phenylsulfonyl Linear or branched (C) all optionally substituted with groups or glycosides_{1- 18} Alkyl group, C_2-18Alkene or C_2-18Alkyne).   In another preferred embodiment, the present invention provides a compound of formula I wherein R is a cyano group , Carboxylic acid, hydroxyl group, oxo group, perhalomethyl group, halogen, phenyl group, C_1-6Alkoxy group, C_1-6Alkoxycarbonyl group, benzyloxycarbonyl Group, hydroxy-C_1-6Alkyl group, C_1-6Alkyl group, or NR₁R_TwoGroup (here In R₁, R_TwoIs hydrogen or C_1-6An alkyl group or Which is optionally substituted with_3-7A cycloalkyl group] I do.   The invention further relates to the use of the novel compounds of formula I disclosed herein for preparing medicaments. Use, especially in the treatment of hyperglycemia or diabetes (preferably NIDDM) and / or Relates to the use for preparing a medicament for prophylaxis. The compounds of the present invention are Low blood glucose levels in the endocrine system, Diseases involving carbohydrate metabolism, especially glucose metabolism (eg, hyperglycemia, diabetes, Especially long-term complications such as retinopathy, neuropathy, nephropathy, and microvascular For non-insulin dependent diabetes mellitus (NIDDM)) And effective in prevention. Further, the compound of the present invention may be used for hyperlipidemia and hypertension. Of atherosclerosis associated with liver, bile and bile disorders, and diabetes It is effective for preventive treatment. The compounds of the present invention are glycogen phosphoenzymes, liver enzymes. Diseases associated with the activity of the enzyme due to the ability of the compound to inhibit lylase activity It is especially effective for the treatment of   Thus, in another aspect, the present invention is directed to a method for use as a therapeutically active substance. Preferably for the treatment of endocrine disorders (preferably hyperglycemia or diabetes) or Is a compound of general formula I, for use as a therapeutically active substance in prophylaxis, or Was Relates to a pharmaceutically acceptable acid addition salt or hydrate or a prodrug thereof.   In addition, the present invention relates to the use of a compound of formula I according to the invention for treating hyperglycemia or diabetes. Relates to the use for preparing a medicament effective for prevention.   In addition, the present invention provides a method for treating diseases of the endocrine system (preferably, patients) in need of treatment. A method for treating or preventing diabetes, comprising administering an effective amount of a compound according to the present invention. Providing a method.   The compounds of the present invention can be prepared by various synthetic routes, including Includes methods described below   a) Compound of formula (II) With NH_TwoR (where R is as defined above) to form a compound of the general formula (III ) Compound (Where R has the meaning described above) and then contacting the compound of formula (III) Debenzylation by reduction to form a compound of general formula (I); or   b) converting a compound of formula (III) (where R is hydrogen) to RX (where R is as defined above) Wherein X is a leaving group, for example a halogen), and then By native debenzylation to form a compound of general formula (I); or   c) converting a compound of formula (III) (where R is hydrogen) to RCHO (where R is Having the meaning described above in the presence of a reducing agent, such as sodium cyanoborohydride) When React and then debenzylate by catalytic reduction to form a compound of general formula (I) Do; or   d) compounds of formula (IV) (Where R has the meaning described above and R ′ is H or C_1-4(Which is an alkyl group) V) reacting with an agent which causes the formation of a sodium or lithium salt And then quenched with an acid and described in the literature (eg, Aust. J. Chem. 36, (1983), 601- The compound of general formula (V) is formed using the method described in 608).   Examples of salt formers are LDA, and examples of quenching media are hydrochloric acid and ammonium chloride. Nium.; And   e) converting the compound of formula (V) to a reducing agent (eg, lithium aluminum hydride, Or a similar hydride) to form a compound of the general formula (VI) wherein R is as defined above. Is formed). ; And   f) The compound of general formula (VI) is converted to an active substance (for example, tert-butyl hydroperoxide). Ki Cid, trifluoroperacetic acid, metachloroperbenzoic acid, hydrogen peroxide or similar crops Epoxide formation by reacting with the compound of formula (VII) (where R is (Having the stated meaning).   The reaction is performed sterically using complexing agents (eg, titanium compounds and tartrate). Sharpless epoxidation techniques to enhance selectivity (eg, J. Org. Chem. 49 (1984) 3707- 3711) using an unprotected hydroxymethyl group or a known OH protecting group A protected hydroxyl group (Greene nad Wuts, Protecting Groups in Organic Synthesis, Wiley  and sons, INC, 1990). The reaction is preferably carried out with N-oxide Is carried out on salts of (VI) (eg trifluoroacetate) to avoid the formation of (Eg, Monatsh. Chemie 117 (1986) 859-865); and   g) converting the compound of the general formula (VII) to an agent (eg, With potassium hydroxide) to give a compound of the general formula (I) (where R has the meaning given above) To form a compound of; or   h) Formula (IV) wherein R is an alkyl group and R 'is H or C_1-4Al A compound such as 1-chloroethyl chloroformate, Chill, 3,3,3-trichloroethyl chloroformate, phenyl chloroformate or similar Reacts with N) to give N-dealkylation, resulting in a compound of the general formula (VIII) (where R 'has the meaning described above) (J. Org. Chem. 49, (1984), 20). 81-2082; Aust. J. Chem. 36, (1983) 601-608). ; And   i) Compounds of general formula (VIII) can be prepared by methods known in the art (Greene nad Wuts, N-protection is achieved using protecting groups in organic synthesis, Wiley and sons, INC, 1990). Reacts with a scraping agent to form a compound of general formula (IX) (where Pg is easily removable An N-protecting group, wherein R 'has the meaning given above.   Examples of easily removable N-protecting groups are Boc or CBZ groups; hand   j) The compound of the general formula (IX) is reacted using the reaction sequence d) -e) -f) -g). And then the protection of the N-atom is removed to give a compound of general formula (I) wherein R is hydrogen. Leads to the compound; or   k) General formula (X) (Where R₆Is R as defined above, or is a protecting group Pg as described above) The compound is a compound capable of protecting a hydroxymethyl group (for example, Cetyl or a similar acylating agent) to give a compound of the general formula (XI) (Where R₆Has the meaning described above, and R₇Is an acyl residue (eg, an acetyl group, C_2-18Alkylcarbonyl group, methyloxyacetyl group, camphanoyl group, α - Methoxy-α- (trifluoromethyl) phenylacetyl group or similar structure) Are formed as separate enantiomers or racemic mixtures . Preferably, the acetylating agent is a derivative of an optically active carboxylic acid (eg, R- ( −)-Α-methoxy-α- (trifluoromethyl) phenylacetic acid, (−)-methoxyacetic acid, (−)-Camphanic acid, or the optical enantiomer of such an acid derivative); hand   l) reacting a compound of general formula (XI) using reaction routes f) -g), By removing the protection of the N-protecting group and the O-protecting group, the compound represented by the general formula (I) wherein R is Having the meaning or being hydrogen); or   m) A compound of general formula (I) (where R is hydrogen) is converted to a compound of general formula (XII) Where Su is the substrate and L is the linker).Forming a compound of general formula (XIII):   The substrate is any insoluble or partially insoluble substance, which is It can be bonded with a bond. Substrates can be any type of organic or inorganic polymer compound. Or oligomeric compounds. Preferably, the substrate Bound to polystyrene, polyethylene glycol (PEG), polystyrene Polyethylene glycol, polyacrylamide, polyamide, polysaccharide and And silicates. Depending on the selected substrate type, the species Various types of solvents or protecting groups can be used.   The linker L allows at least a covalent bond to another molecule or substrate. Are also molecules having two reactive positions. Linker to substrate or linker Any of the bonds to other molecules attached to the linker itself are activators (eg, (E.g., selected chemical activators), or in other specific situations. (E.g., by treatment with a strong acid, or by exposure to electromagnetic radiation, or Must be cleaved) (by metal catalysis); and   n) a compound of general formula (XIV), wherein Su and L have the meanings given above, RX (where R has the meaning described above and X is a leaving group, for example halogen) To form a compound of general formula (XV):; And   o) Compounds of general formula (XV), wherein R, Su and L have the meanings given above. By reacting with a cleaving agent (for example, a strong base) to obtain a compound of the general formula (I) (where R is as defined above) Is formed).   The starting materials used in the synthesis of the compounds from formulas II and IV are known or Or from commercially available materials to conventional methods, such as those described in the Examples. Can be prepared.   The compounds of the present invention have one or more asymmetric centers, and are stereoisomers (optical isomers). For example, separated, pure or partially purified stereoisomers or Racemic mixtures are intended to be included within the scope of the present invention.   Preferred compounds of the present invention are:   (3R, 4R, 5R) -1-butyl-5-hydroxymethyl-3,4-piperidinediol ,   (3R, 4R, 5R) -1- (3-cyclohexyl) propyl) -3,4-dihydroxy-5 -Hydroxymethylpiperidine,   (3R, 4R, 5R) -1-Dodecyl-5-hydroxymethyl-3,4-piperidinedio Tool,   (3R, 4R, 5R) -1- (2-hydroxyethyl) -5-hydroxymethyl-3,4-pi Peridine diol,   (3R, 4R, 5R) -5-hydroxymethyl-1- (4- (5-hydantoyl) butyl)- 3,4-piperidinediol,   (3R, 4R, 5R) -5-hydroxymethyl-1- (3-phenylpropyl) -piperidi 3,4-diol,   (3R, 4R, 5R) -5-hydroxymethyl-1-methyl-3,4-piperidinediol ,   (3R, 4R, 5R) -5-Hydroxymethyl-1-methoxy-3,4-piperidinedio Tool,   (3R, 4R, 5R) -5-hydroxymethyl-1- (4-N, N-diphenylaminoben (Jill) -3,4-piperidinediol,   (3R, 4R, 5R) -1-acetyl-5-hydroxymethyl-3,4-piperidinedio Tool,   (3R, 4R, 5R) -5-hydroxymethyl-1- (3-phenylallyl) -3,4-pipe Lysine diol,   (3R, 4R, 5R) -1-allyl-5-hydroxymethyl-3,4-piperidinediol ,   (3R, 4R, 5R) -1-benzyl-5-hydroxymethyl-3,4-piperidinedio Tool,   (3R, 4R, 5R) -1-octyl-5-hydroxymethyl-3,4-piperidinedio Tool,   (3R, 4R, 5R) -2- (3,4-dihydroxy-5-hydroxymethyl-piperidine -1-yl) -acetamide,   Ethyl ((3R, 4R, 5R) -3,4-dihydroxy-5-hydroxymethyl-piperi Gin-1-yl) acetate,   (3R, 4R, 5R) -5-hydroxymethyl-1- (4-trifluoromethyl-benzyl) Ru) -3,4-piperidinediol,   (3R, 4R, 5R) -1- (2- (4'-fluoroacetophenone))-5-hydroxymeth Chill-3,4-piperidinediol,   (3R, 4R, 5R) -5-hydroxymethyl-1- (2- (4′-methoxyacetopheno ))-3,4-piperidinediol,   (3R, 4R, 5R)-(2- (4-fluorophenoxy) -ethyl) -5-hydroxymethyl Le-3,4-piperidinediol,   (3R, 4R, 5R) -5-hydroxymethyl-1- (4-phenoxy-butyl) -3,4- Piperidine diol,   (3R, 4R, 5R) -1- (4-cyanobutyl) -5-hydroxymethyl-3,4-piperi Gindiol,   (3R, 4R, 5R) -1- (10-decylphthalimide) -5-hydroxymethyl-3, 4-piperidinediol,   (3R, 4R, 5R) -12- (3,4-dihydroxy-5-hydroxymethyl-piperidi N-1-yl) dodecanoic acid,   (3R, 4R, 5R) -5-hydroxymethyl-1-phenoxyethyl-3,4-piperi Gindiol,   (3R, 4R, 5R) -3- (3,4-dihydroxy-5-hydroxymethyl-piperidine -1-yl) propionic acid,   (3R, 4R, 5R) -1- (6-deoxy-1-O-methyl-6-α-D-glucopyranosi ) -5-Hydroxymethyl-3,4-piperidinediol Or a pharmaceutically acceptable salt or hydrate or its prod as defined herein Lag or a mixture of optical isomers, including any optical isomers or racemic mixtures Or any tautomeric form.   Other compounds of general formula 1 can be prepared according to the above strategy. seed Various functional groups are introduced into the compound prepared as described above by methods well known to those skilled in the art. You can enter.Pharmaceutical composition   The present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof, Further provided is a pharmaceutical composition comprising a pharmaceutically acceptable carrier. like this The composition may be in the form of a powder, solution or suspension, which may be in unit dosage form Or may or may not be divided into capsule or tablet forms. liquid The compositions include sterile solutions, suspensions, and emulsions suitable for parenteral injection. You.   The pharmaceutical composition of the present invention comprises a carrier, an excipient, an absorption enhancer, a tablet disintegrant, It may contain other ingredients commonly used in the art. Powders and tablets are preferred Contains 5-99% of the active ingredient, more preferably 10-90% of the active ingredient. Examples of solid carriers include magnesium carbonate, magnesium stearate, cyclodex String, dextrin, lactose, sugar, talc, gelatin, pectin, tragaca Paint, methylcellulose, sodium carboxymethylcellulose, low melting filter There are cervices, and cocoa butter.   The route of administration of a composition containing a compound of Formula I will depend on the active compound at its site of action. Any route to effectively transport to is possible, preferably oral route or nasal route It is their route.   If a solid carrier is used for oral administration, its preparation should be in powder or pellet form. Tablets in hard gelatin capsules in the form of tablets, or troches Or confectionery tablets. If a liquid carrier is used, its preparation is: Syrups, emulsions, soft gelatin capsules, or sterile injectable liquids (for example, Liquid or non-aqueous liquid suspension or solution). Talc and Tablets, dragees, or capsules having carbohydrate carriers and / or binders, etc. The preparations are particularly suitable for oral administration. Preferred for tablets, sugars, and capsules Carriers include lactose, corn starch, and / or potato starch. included.   Particularly suitable for parenteral administration are those active in polyhydroxylated castor oil. Injectable solution or suspension in which the active compound is dissolved, preferably an aqueous solution .   Typical tablets that can be prepared by conventional tableting techniques include: obtain: core: Active compound (as free compound or its salt) 50mg Colloidal silicon dioxide (Aerosil) 1.5mg Cellulose, microcrystal (Avicel) 70mg 7.5mg of modified cellulose rubber (Ac-Di-Sol) Magnesium stearate Ad. coating: HPMC about 9mg * Mywacett 9-40 T about 0.9mg * Acylated monoglycerides used as plasticizers for film coating Do   The compounds of the present invention can be used for the treatment, prevention and elimination of various diseases mentioned above, especially diabetes. Can be administered to mammals, particularly humans, in need of relief or improvement. like this Some mammals include animals, ie domestic animals (eg domestic pets), as well as non-domestic animals (eg wildlife). Object).   Therapy for treating any patient with a compound of the present invention will be determined by those skilled in the art. Should be. The daily dose to be administered in treatment should be determined by a physician This depends on the particular compound used, the route of administration, and the age and condition of the patient. Depends on the situation. Convenient daily doses are less than about 1 g, preferably about 10 It can be in the range of 200 mg.Experimental protocol and results   For in vivo studies, female ob / ob mice (20 g) were used after fasting for 3 hours. Was. Test compound or NaCl (0.9%; control) was injected intravenously (hereafter i.v.). A blood sample was taken from the orbital vein and glucose Glucose was analyzed using the oxidase method.   Rat hepatocytes were isolated using standard two-step collagenase technology. Dexamethasone (0.1 mM) for 72 hours in a collagen-coated culture dish; Phosphorus / streptomycin ((100 μ / 100 mg) / mL) and insulin (1 nM) Addition The culture was performed in the completed medium 199. During the last 24 hours, hepatocytes were treated with high levels of insulin (5 nM) and glucose (15 mM). Incorporation into lycogen occurred. Thus, at this time of the experiment, the cells It is very similar to liver from ingested animals.   The experiment was performed after 48 hours of culture, washing the cells twice, and relaxing the 20 mM HEPES experiment. It was started by the addition of a buffer (with balancing salt but without glucose). Test compounds were added simultaneously with the experimental buffer. Liver for some cultures Glucagon (0.5 nM) after 10 minutes to stimulate glucose production from cells Was added. Glucose released into the medium (this is the glucose production of liver cells) Represents the concentration 70 minutes after the start of the experiment and is based on the DNA content of the cells. (Standardize).   Phosphorylase can be purchased from Sigma or from Stalmans et al. (Eur. J. Biochem. .49 (1974), 415). The activity of phosphorylase is Bergmeyer (1983; in: Meth. Of Enzymatic Analysis, 2, 293-295, Weinheim, (ed .) Verlag Chemie).   The compounds of the present invention can reduce the increase in plasma glucose by glucagon. And the effect is shown.   The present invention is further illustrated by the following examples, which limit the scope of protection. Don't understand it. The features disclosed in the foregoing description and the following examples Understand the present invention in its various forms, separately or in any combination Can be important forExample 1 ( 3R, 4R, 5R) -3-benzyloxy-1-butyl-5-hydroxymethyl-4-pipe Lysinol   (3R, 4R, 5R) -3-benzyloxy-5-hydroxymethyl-4-piperidino (87 mg, 0.37 mmol), 1-iodobutane (81 mg, 0.44 mmol) , 50 μL), potassium carbonate (154 mg, 1.1 mmol) and dry acetone (8 mL) was stirred under a nitrogen atmosphere at 40 ° C. for 24 hours. The solvent is evaporated in vacuum Emitted And elute the residue with a silica gel column (eluent: ethyl acetate / methanol / 25% hydroxide). (6/1/1%). This gives (3R, 4R, 5R) -3-benzene The free base of ruoxy-1-butyl-5-hydroxymethyl-4-piperidinol was obtained. (Yield: 72 mg, 67%).   In a similar manner, the following compounds were prepared   (3R, 4R, 5R) -3-benzyloxy-1-dodecyl-5-hydroxymethylpipe Lysine-4-ol is (3R, 4R, 5R) -3-benzyloxy-5-hydroxymethyl Prepared from ru-4-piperidinol and iodododecane.   (3R, 4R, 5R) -3-benzyloxy-1- (2-hydroxyethyl) -5-hydro Xymethyl-4-piperidinol is (3R, 4R, 5R) -3-benzyloxy-5-hydroxy. A catalytic amount of droxymethyl-4-piperidinol and 2-bromoethanol Prepared using potassium iodide.   (3R, 4R, 5R) -5-benzyloxymethyl-1- (4- (5-hydantoyl) butyl ) -3,4-piperidinediol is (3R, 4R, 5R) -3-benzyloxy-5-hydroxy. Droxymethyl-4-piperidinol and 5- (4-chlorobutyl) hydantoin Prepared using a catalytic amount of potassium iodide.   (3R, 4R, 5R) -3-benzyloxy-5-hydroxymethyl-1- (3-phenyl -Propyl) -piperidin-4-ol is (3R, 4R, 5R) -3-benzyloxy-5 -Hydroxymethyl-4-piperidinol and 3-bucomo-1-phenylpropane Prepared using a catalytic amount of potassium iodide. Example 2 ( 3R, 4R, 5R) -3-benzyloxy-1- (3- (cyclohexyl) propyl) -5- Hydroxymethylpiperidin-4-ol   (3R, 4R, 5R) -3-benzyloxy-5-hydroxymethyl-4-piperidino (0.397 g, 1.7 mmol) was dissolved in dry methanol (5 mL). In HCl_g(2N) was added in excess. Evaporate to dryness in a vacuum Was obtained. Dissolve the salt in dry methanol (20 mL) and add Sodium iodide (0.126 g, 2.0 mmol) was added. HC in methanol l_g(2N) was added dropwise to obtain a mixture having a pH of 6 (2dr). Cyclohexylpro Pionaldehyde (0.306 mL, 0.281 g, 2.0 mmol) was added. Was stirred at room temperature under a nitrogen atmosphere for 18 hours. HCl in methanol_g(2 N) was added several times to maintain the solution at pH = 6. Concentrate in vacuo and remove the residue Silica gel column (eluent ethyl acetate / methanol / 25% ammonium hydroxide ( 6/1/1%)), and purified by (3R, 4R, 5R) -3-benzyloxy-1- (3- (cyclyl) (Rohexyl) propyl) -5-hydroxymethylpiperidin-4-ol was obtained (yield : 058g, 96%). Example 3 ( 3R, 4R, 5R) -1-benzyl-3-benzyloxy-5-hydroxymethylpiperi Gin-4-ol   4-O-benzyl-2-deoxy-2-C-hydroxymethyl-D-glucopyranose ( 6.0 g, 21.1 mmol) (for preparation see WO 95/24391) in methanol ( (200 mL). Sodium periodate (21.4 g) in water (200 mL) , 100 mmol) was added dropwise over 15 minutes. At 45-47 ° C. Stir for 35 hours. The precipitate is filtered, the mixture is concentrated and vinegar as eluent Purification was performed by silica gel flash chromatography using ethyl acetate. Spirit The prepared product, 4-O-benzyl-2-deoxy-2-C-hydroxymethyl-D-ki Sylo-pentodialdose was dissolved in methanol (50 mL) and benzylamide (4 .36 g, 40.7 mmol) and sodium cyanoborohydride (1.0 g, 15. 9 mmol) was added. The mixture was stirred at room temperature for 3 days. Then the mixture Was acidified to pH = 2 using concentrated hydrochloric acid and evaporated to dryness. The residue was washed with water (5 0 mL), adjust the pH to 10 with an aqueous sodium hydroxide solution, and transfer the solution. Extracted with methylene chloride. The organic phase is dried over magnesium sulfate and evaporated, Then, purification was performed on silica gel using ethyl acetate as an eluent. This allows ( 3R, 4R, 5R) -1-benzyl-3-benzyloxy-5-hydroxymethylpiperi Gin-4-ol was obtained as an oil (yield: 25%).   In a similar manner, the following compounds were prepared   (3R, 4R, 5R) -3-benzyloxy-5-hydroxymethyl-1-methyl-pipe Lysine-4-ol was prepared as described above in methanol (50 mL). O-benzyl-2-deoxy-2-C-hydroxymethyl-D-xylo-pentodiald (2.78 g), methylamine hydrochloride (1.16 g) and sodium cyanoborohydride Prepared from lium (0.62 g).   (3R, 4R, 5R) -3-benzyloxy-5-hydroxymethyl-1-methoxy-4- Piperidinol was prepared from 4-O- as prepared above in methanol (50 mL). Benzyl-2-deoxy-2-C-hydroxymethyl-D-xylo-pentodialdose (0.8 g), methoxyamine hydrochloride (0.54 g) and sodium cyanoborohydride (0.18 g). Example 4 ( 3R, 4R, 5R) -1-butyl-5-hydroxymethyl-3,4-piperidinediol (Compound 1)   (3R, 4R, 5R) -3-benzyloxy-1- (n-butyl) -5-hydroxymethyl- 4-Piperidinol (105 mg, 0.4 mmol) was added to an aqueous hydrochloric acid solution (4 N, 0.3 m). L) in ethanol (20 mL) containing palladium on activated carbon ( (10%, 30 mg). The mixture is called_TwoHydrogenated for 3 hours under pressure , Filtered through celite and concentrated in vacuo. Silica gel column (eluent: Purification with ethyl acetate / methanol / 25% ammonium hydroxide (4/1/1%) , (3R, 4R, 5R) -1-butyl-5-hydroxymethyl-3,4-piperidinedione Was obtained as a semi-crystalline compound (yield: 53 mg, 74%).   In a similar manner, the following compounds were prepared   ( 3R, 4R, 5R) -1- (3-Cyclohexyl) propyl) -3,4-dihydroxy-5 -Hydroxymethylpiperidine (Compound 2) Is (3R, 4R, 5R) -3-benzylo Xy-1- (3-cyclohexyl) propyl) -5-hydroxymethylpiperidine-4-o ー Prepared from the ( 3R, 4R, 5R) -1-Dodecyl-5-hydroxymethyl-3,4-piperidinedio (Compound 3) Is (3R, 4R, 5R) -3-benzyloxy-1-dodecyl-5-hydr Prepared from roxymethyl-4-piperidinol. ( 3R, 4R, 5R) -1- (2-hydroxyethyl) -5-hydroxymethyl-3,4-bi Peridine diol (compound 4) Is (3R, 4R, 5R) -3-benzyloxy-1- (2- Prepared from (hydroxyethyl) -5-hydroxymethyl-4-piperidinol. ( 3R, 4R, 5R) -5-hydroxymethyl-1- (4- (5-hydantoyl) butyl)- 3,4-piperidinediol (compound 5) Is (3R, 4R, 5R) -5-benzyloxy Prepared from methyl-1- (4- (5-hydantoyl) butyl) -3,4-piperidinediol did. ( 3R, 4R, 5R) -5-Hydroxymethyl-1- (3-phenylpropyl) -piperidi 3,4-diol (compound 6) Is (3R, 4R, 5R) -3-benzyloxy-5- Prepared from droxymethyl-1- (3-phenylpropyl) -piperidin-4-ol . ( 3R, 4R, 5R) -5-Hydroxymethyl-1-methyl-3,4-piperidinediol (Compound 7) Is (3R, 4R, 5R) -3-benzyloxy-5-hydroxymethyl- Prepared from 1-methyl-piperidin-4-ol. The crude product is converted to silica gel (solvent Synthetic solution: purified with ethanol / 25% ammonium hydroxide) and (3R, 4R, 5R) -5 - Hydroxymethyl-1-methyl-3,4-piperidinediol hydrochloride is converted to 21% Yield resulted in isolation as a hard oil. ( 3R, 4R, 5R) -5-Hydroxymethyl-1-methoxy-3,4-piperidinedio (Compound 8) Is (3R, 4R, 5R) -3-benzyloxy-5-hydroxymethyl Prepared from 1-methoxy-piperidin-4-ol. Example 5 ( 3R, 4R, 5R) -5-hydroxymethyl-1- (4-N, N-diphenylaminobenzyl) ) -3,4-piperidinediol (compound 9)   (3R, 4R, 5R) -5-hydroxymethyl-3,4-piperidinediol (0.1 g , 0.7 mmol) with 4-N, N-diphenylaminobenzaldehyde (0.2 g, 07 mmol) and sodium cyanoborohydride (0.04 g, 0.6 mmol) With methanol (5 mL). Stir the mixture at room temperature for 100 hours And acidified to pH = 2 using concentrated hydrochloric acid and evaporated to dryness. Residue Is dissolved in water, the pH is adjusted to 10 with an aqueous sodium hydroxide solution, and the solution is chlorinated. Extracted with methylene. The organic phase is dried over magnesium sulfate and evaporated in vacuo. I let you. Purifying a hybrid mixture on silica gel using methanol as eluent Gives (3R, 4R, 5R) -5-hydroxymethyl-1- (4-N, N-diphenylamido (Nobenzyl) -3,4-piperidinediol was obtained as an oil (yield: 1%). Example 6 ( 3R, 4R, 5R) -1-Acetyl-5-hydroxymethyl-1-3,4-piperidinedio (Compound 10)   (3R, 4R, 5R) -3-benzyloxy-5-hydroxymethyl-4-piperidino (0.1 g, 0.4 mmol) was dissolved in pyridine (0.5 mL) at approximately 0 ° C. Acetic anhydride (0.5 mL) was added dropwise over 1 minute. Stir at room temperature for 20 hours and dry Evaporate to dryness to obtain the crude product, which is screened using ethanol as eluent. Purified by Lycagel (55% yield). Purified 3-benzyloxy-3-acetate Xy-5-acetoxymethyl-1-acetylpiperidine (75 mg) was added as a catalyst at room temperature. And debenzylated in methanol using 10% Pd / C. Filter and dry And then evaporate to the end of 4-acetoxy-5-acetoxymethyl-1-acetyl-3-pipe. 50 mg crude product of lysinol was obtained, which was The solution was dissolved in dry methanol (4 mL) containing 50 μL of the solution. 4 days at room temperature After stirring for a while, the solution was evaporated to dryness and the (3R, 4R, 5R) -1-acetate was evaporated. Cyl-5-hydroxymethyl-1-3,4-piperidinediol was obtained (yield: 35 m g). Example 7 Methyl 1-methyl-1,2,3,6-tetrahydropyridine-3-carboxylate   Arecoline (15.5 g, 0.1 mol) in tetrahydrofuran (200 mL) Aust. J. Chem. 36 (1983) 601-608, using tetrahydrofuran Diisopropylamine (18.1 g, 0.18 mol) and Added to a solution of 1.5 M n-butyl lithium (108 mL, 0.16 mol) in sun did. The reaction mixture was stirred at -10 C for 20 minutes, cooled to -60 C, and Poured into 10% aqueous hydrochloric acid (185 mL).   According to the procedure described therein, 14 g of crude product were obtained, which were distilled under vacuum (b (p. 85 ° C./0.1 bar) to give 1-methyl-1,2,3,6-tetrahydro Methyl pyridine-3-carboxylate was obtained (yield: 6.8 g). Example 8 ( 1-methyl-1,2,3,6-tetrahydro-3-pyridyl) methanol   1-Methyl-1,2,3,6-te dissolved in dry diethyl ether (250 mL) A solution of methyl trahydropyridine-3-carboxylate (88 g, 0.56 mol) was Lithium aluminum hydride (23 g, 0.6 g) in diethyl ether (500 mL). mol) of the slurry. The mixture was refluxed for 30 minutes. water( 100 mL) and potassium carbonate (100 g, 0.72 mol) were carefully added, The mixture was filtered and evaporated to dryness in vacuo. The residue is vacuum distilled (b p 38-40 ° C./0.2 bar) and give 1 pure fraction of (1-methyl-1,2 (3,6-Tetrahydro-3-pyridyl) methanol was obtained (yield: 15 g). afterwards In distillation (bp 40-60 ° C./0.2 bar) two more fractions Collected (total yield: 53.8 g). Example 9 1-benzyloxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxyl Methyl acid   Arecoline (39.5 g, 0.25 mol) dissolved in dry toluene (20 mL) did. 1-Chloroethyl chloroformate (30.5 mL) was added slowly at 0-5 ° C. . The mixture is heated at 80 ° C. for 2 hours, cooled to room temperature, filtered and in vacuo Evaporated to dryness. Dissolve the residue in methylene chloride (400 mL) and add 10% Extracted with aqueous sodium acid solution. Dry the organic layer over magnesium sulfate and filter And evaporated to dryness to give 1,2,5,6-tetrahydropyridine-3-carboxylic acid. There was obtained methyl acid salt (yield: 30.5 g, 85%).   Methyl 1,2,5,6-tetrahydropyridine-3-carboxylate (1.1 g, 7.8 m m ol) was dissolved in methylene chloride (20 mL) and cooled to -15 ° C. Triethylua (2.2 mL, 15.8 mmol) and benzyl chloroformate (1.2 mL, 8 mL). .4 mmol) in methylene chloride (10 mL) was added. Stir at room temperature for 1.5 hours And then evaporated to dryness. Dissolve the residue in methylene chloride and extract twice with water. Issued. The organic layer is separated, dried, evaporated to dryness in vacuo and Benzyloxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid Chill was obtained as an oil (yield: 2.0 g, 92%). Example 10 ( 1-benzyloxycarbonyl-1,2,3,6-tetrahydro-3-pyridyl) methano Rule   1-benzyloxycarbonyl-1,2,5,6-tetrahydropyridine-3-carbo Methyl phosphate (1 g, 3.6 mmol) was isolated using the methods described in Examples 7 and 8. And then reduced to give (1-benzyloxycarbonyl-1,2,3,6-tetrahydro- 3-Pyridyl) methanol was obtained (yield: 0.32 g, 36%). Example 11 1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxyl Methyl acid   Methyl 1,2,5,6-tetrahydropyridine-3-carboxylate (20.44 g, 14 5 mmol) and triethylamine (25 mL, 180 mmol) in methanol ( 250 mL) and di-tert-butyl dicarbonate (65.48 g, 300 m mol) was added at room temperature. Heat the mixture at 60 ° C. for 30 minutes and allow to dry. so Evaporated and partitioned between water and ethyl acetate. Isolate the organic layer and magnum sulfate Dried over cesium and evaporated to dryness in vacuo. Silica gel (eluent Purification with methylene chloride / methanol (19/1) gave 1-tert-butoxycarbo. Nyl-1,2,5,6-tetrahydropyridine-3-carboxylate as yellow oil (Yield: 349 g, 99%). Example 121-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxyl acid   An aqueous solution (450 mL) of potassium hydroxide (44 g, 0.79 mol) was added to 1-tert- Methyl butoxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxylate ( (34.9 g, 145 mmol) in methanol (450 mL). That blend The mixture was refluxed for 3 hours and evaporated to dryness in vacuo. The residue was treated with hydrochloric acid (4M) And extracted with methylene chloride. Magnesium sulfate organic layer And dried in vacuo to dryness, and dried in 1-tert-butoxycarbohydrate. Nyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid was obtained (yield: 28.4). g, 86%). Example 13 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine-3-carboxyl acid   1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-3-carbo Acid (6.5 g, 28.6 mmol) in dry tetrahydrofuran (150 mL) liquid With 2.5 M butyllithium in hexane (25 mL, 62.5 mmol) and Diisopropylamine (6.37 g) in dry tetrahydrofuran (150 mL) , 63.1 mmol) at <-65 ° C. Stir at -10 ° C for 20 minutes I continued. The mixture was poured into 1M aqueous HCl (100 mL) with ice cooling. It is. The resulting mixture was extracted several times with ethyl acetate (500 mL total). Sulfur organic layer Dry over magnesium silicate and evaporate to dryness in vacuo to give 1-tert-butanol Xycarbonyl-1,2,3,6-tetrahydropyridine-3-carboxylic acid was obtained. Rate: 63 g, 97%). Example 14 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine-3-carboxyl Methyl acid   1,1′-carbonyldiimidazole (4 g, 24 g in methylene chloride (100 mL)) 0.7 mmol) with 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyri Nitrogen was added to a solution of gin-3-carboxylic acid (5 g, 22 mmol) in methylene chloride (200 mL). The solution was added dropwise under a basic atmosphere. Continue stirring for 1 hour, then add methanol (300 mL) And refluxed for 26 hours. A 10% aqueous citric acid solution (100 mL) was added and the The mixture was extracted with methylene chloride. Dry the organic layer over magnesium sulfate and dry. Evaporate to dryness in the air and use a silica gel column (eluent: methylene chloride) / Methanol (90/1)) to give 1-tert-butoxycarbonyl-1,2,3,6 Methyl-tetrahydropyridine-3-carboxylate was obtained as a yellow oil (yield: 39 g, 73%). Example 15 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridyl-3-methanol Le   1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine-3-carbo Methylate (2.35 g, 9.8 mmol) was added to dry diethyl ether (200 m L) under a nitrogen atmosphere. Lithium borohydride (0.6 g, 27.5 mmol ) And 1.0 M lithium triethylborohydride in tetrahydrofuran (3.0 g) , 28.3 mmol) was slowly added dropwise. The resulting mixture was refluxed for 1 hour and 1 Poured into M sodium hydroxide (100 mL) and extracted with methylene chloride. Organic The layers are dried over magnesium sulfate and evaporated to dryness in vacuo, silica gel Column (eluent: methylene chloride / methanol (19/1)). Butoxycarbonyl-1,2,3,6-tetrahydropyridyl-3-methanol colorless (Yield: 1.28 g, 61%). Example 16 3-((1R, 2S, 5R) -2-isopropyl-5-methyl-1-cyclohexyloxy) Acetoxymethyl-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl Le   (-)-Mentoxyacetyl chloride (1.03 g, 4.4 mmol) was added to 1-tert-butyl Toxicarbonyl-1,2,3,6-tetrahydropyridyl-3-methanol (0.59) g, 2.8 mmol) in methylene chloride (50 mL) solution under a nitrogen atmosphere. Added. The mixture is refluxed for 4 hours and evaporated to dryness in vacuo, silica Using a gel column (eluent: methyl tert-butyl ether / methylene chloride (1/20)) Purification and 3-((1R, 2S, 5R) -2-isopropyl-5-methyl-1-cyclohexyl (Roxy) acetoxymethyl-1,2,3,6-tetrahydropyridine-1-carboxylic acid A diastereomeric mixture of tert-butyl was obtained as a colorless oil (yield: 0.5). 4 g, 48%).   A small amount of the two isomers is applied to a chiral column (eluent: isopropyl alcohol / Butane (5/95)) (Rt 9.6 min and 11.2 min). Example 17 3-((1R, 2S, 5R) -2-isopropyl-5-methyl-1-cyclohexyloxy) Tert-butyl acetoxymethyl-4,5-epoxypiperidine-1-carboxylate   3-chloroperoxybenzoic acid (0.9 g, 5.2 mmol), 3-((1R, 2S, 5 R) -2-Isopropyl-5-methyl-1-cyclohexyloxy) acetoxymethyl- Tert-Butyl 1,2,3,6-tetrahydropyridine-1-carboxylate (0.5 g, 1.2 mmol) and methylene chloride (150 mL) was stirred at room temperature for 20 hours. Was. Additional 3-chloroperoxybenzoic acid (1.1 eq) is added and the mixture is left for 2 hours Reflux. The reaction mixture was extracted with 1M sodium hydroxide and water, Dried over gnesium and evaporated to dryness in vacuo. Residue Purification on a Kagel column (eluent: heptane / ethyl acetate (5/1)) and 3-((1R, 2S, 5R) -2-Isopropyl-5-methyl-1-cyclohexyloxy) acetoxy Tert-Butyl methyl-4,5-epoxypiperidine-1-carboxylate is obtained as an oil. (Yield: 0.34 g, 66%).   The following compounds were prepared in a similar manner.   Tert-butyl 3-hydroxymethyl-4,5-epoxypiperidine-1-carboxylate Is 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridyl-3-meta Prepared from knol. Benzyl 3-hydroxymethyl-4,5-epoxypiperidine-1-carboxylateIs (1-benzyloxycarbonyl-1,2,3,6-tetrahydro-3-pyridyl) methano Was prepared from The NMR signal shows that the two isomers are mixed in about a 1/3 ratio.Example 18 5-hydroxymethyl-3,4-piperidinediol   3-((1R, 2S, 5R) -2-isopropyl-5-methyl-1-cyclohexyloxy ) Tert-Butyl acetoxymethyl-4,5-epoxypiperidine-1-carboxylate (0. 25 g, 0.59 mmol) and a 10% aqueous potassium hydroxide solution were refluxed for 3 hours. I let you. The reaction mixture is evaporated to dryness in vacuo and the mixture is evaporated on a silica gel column (solvent). Synthetic solution: Purified with isopropyl alcohol / 26% ammonium hydroxide (3/1) 5-hydroxymethyl-3,4-piperidinediol was obtained as an oil (yield: 56 mg, 65%).   Chiral TLC (Machery-Nagel 811058 plate; eluent: isopropyl alcohol) // 26% ammonium hydroxide (3/1)), the two isomers are each Rf 0.55 and 0.59 were indicated.   In a similar way,5-hydroxymethyl-3,4-piperidinediolIs 3-hid Tert-butyl roxymethyl-4,5-epoxypiperidine-1-carboxylate or 3- Prepared from benzyl hydroxymethyl-4,5-epoxypiperidine-1-carboxylate did.   In a similar way,5-hydroxymethyl-1-methyl-3,4-piperidinediolIs Prepared from (1-methyl-1,2,3,6-tetrahydro-3-pyridyl) methanol .Example 19 ( 1-methyl-1,2,3,6-tetrahydro-3-pyridyl) methanol   1 M lithium triethylborohydride in tetrahydrofuran (75 mL, 75 mmol) with 1-methyl-1,2,3,6-tetrahydropyridine-3-carboxylic acid Chill (5 g, 31.8 mmol) in dry tetrahydrofuran (200 mL) solution Added slowly. The mixture was refluxed for 3 hours, cooled to room temperature and 1M salt Poured into aqueous acid (150 mL). The aqueous layer was extracted with methylene chloride, The pH was adjusted to 9 with aqueous solution. The solution was extracted with methylene chloride, Dried over magnesium and evaporated to dryness in vacuo. Kugelroh the residue The mixture was distilled (bp: 65-75 ° C / 0.28 mbar) with r to give (1-methyl-1,2,3,6- Tetrahydro-3-pyridyl) methanol was obtained as an oil (yield: 1.9 g, 4 8%). Example 20 1-methyl-1,2,3,6-tetrahydropyridin-3-yl acetate   (1-Methyl-1,2,3,6-tetrahydro-3-pyridyl) methanol (0.7 g, 5 5 mmol), a solution of triethylamine (25 mL), and acetic anhydride (20 mL) Was refluxed for 2 hours. The reaction mixture was extracted with methylene chloride, Umm The pH was adjusted to 10 with an aqueous solution. The solution was extracted with methylene chloride, Dried over magnesium and evaporated to dryness in vacuo. Silica gel residue Column (eluent: methanol / methylene chloride (1/9)). 1,2,3,6-Tetrahydropyridin-3-yl acetate was obtained as an oil (yield (Rate: 069 g, 70%).   A small amount of the two enantiomers was purified by chiral HPLC (chiracel OD 250 × 4.6 mm; Syneresis: isopropyl alcohol / heptane (1/99); RT 16 minutes and 18 minutes) Separated. Example 21 ( 3R, 4R, 5R) -5-Hydroxymethyl-1- (3-phenylallyl) -3,4-piper Zindiol (compound 11)   Wang resin (10 g, 9.2 mmol, Bachem, loading: 0.92 mmol / g) in methylene chloride suspension was added to N, N-diisopropylethylamine (15 mL, 8 mL). 7.8 mmol) and acryloyl chloride (10 mL, 122.7 mmol) did. After stirring slowly for 7 hours, the mixture was filtered and the resin was washed with methylene chloride. (500 mL) and methanol (500 mL). Dry in vacuum, Wa ng resin-O-CO-CH = CH_TwoWas obtained (yield: 9.4 g).   To a suspension of this resin (4 g, 3.7 mmol) in DMF (30 mL) was added (3R, 4R, 5 R) -5-Hydroxymethyl-3,4-piperidinediol (0.9 g, 6.1 mmol) Of DMF (5 mL) was added. Shake the mixture for 22 hours, filter, and The resin to DMF (4 × 25 mL), methylene chloride (4 × 25 mL) and methanol (4 x 25 mL). The resin is dried in vacuum and about 4.1 g of raw material I got   3-Bromo-1-phenyl-1-propene (180 mg, 0.91 mmol) was added to this The resin (190 mg, 0.17 mmol) was added to a suspension in DMF. The mixture Shake for 24 hours, filter, and remove the resin with DMF (5 × 5 mL), methylene chloride ( (3 × 5 mL) and DMF (2 × 5 mL). N, N-diisopropylethyl Amine (0.125 mL, 0.73 mmol) and DMF (3 mL) were added to the resin. Was. Shake the mixture for 24 hours, filter and concentrate the filtrate in vacuo to dryness To give (3R, 4R, 5R) -5-hydroxymethyl-1- (3-phenylallyl) -3,4- Piperidinediol was obtained as an oil (yield: 35 mg, 78%).   The following compounds were prepared in a similar manner.   ( 3R, 4R, 5R) -1-allyl-5-hydroxymethyl-3,4-piperidinedithio (Compound 12) Is (3R, 4R, 5R) -5-hydroxymethyl-3,4-piperidine Prepared from diol and allyl bromide. ( 3R, 4R, 5R) -1-benzyl-5-hydroxymethyl-3,4-piperidinedio (Compound 13) Is (3R, 4R, 5R) -5-hydroxymethyl-3,4-piperidi Prepared from diol and benzyl bromide. ( 3R, 4R, 5R) -1-octyl-5-hydroxymethyl-3,4-piperidinedio (Compound 14) Is (3R, 4R, 5R) -5-hydroxymethyl-3,4-piperidi And 1-iodooctane. ( 3R, 4R, 5R) -2- (3,4-dihydroxy-5-hydroxymethyl-piperidine - 1-yl) -acetamide (compound 15) Is (3R, 4R, 5R) -5-hydroxymethyl Prepared from 1,3,4-piperidinediol and 2-bromoacetamide. Ethyl ((3R, 4R, 5R) -3,4-dihydroxy-5-hydroxymethyl-piperi Zin-1-yl) -acetate (Compound 16) Is (3R, 4R, 5R) -5-hydroxyme Prepared from tyl-3,4-piperidinediol and ethyl bromoacetate. ( 3R, 4R, 5R) -5-hydroxymethyl-1- (4-trifluoromethyl-benzyl ) -3,4-piperidinediol (compound 17) Is (3R, 4R, 5R) -5-hydroxy Cimethyl-3,4-piperidinediol and 4-trifluoromethylbenzyl bromide Prepared from ( 3R, 4R, 5R) -1- (2- (4'-fluoroacetophenone))-5-hydroxymeth Cyl-3,4-piperidinediol (compound 18) Is (3R, 4R, 5R) -5-hydro Xymethyl-3,4-piperidinediol and 2-bromo-4'-fluoroacetoph Prepared from Enone. ( 3R, 4R, 5R) -5-hydroxymethyl-1- (2- (4'-methoxyacetopheno ))-3,4-Piperidinediol (compound 19) Is (3R, 4R, 5R) -5-hydro Xymethyl-3,4-piperidinediol and 2-bromo-4'-methoxyacetoph Prepared from Enone. ( 3R, 4R, 5R) -1- (2- (4-fluorophenoxy) -ethyl) -5-hydroxy Methyl-3,4-piperidinediol (compound 20) Is (3R, 4R, 5R) -5-hydr Roxymethyl-3,4-piperidinediol and 4-fluorophenyl 2-bromo Prepared from ethyl ether. ( 3R, 4R, 5R) -5-Hydroxymethyl-1- (4-phenoxy-butyl) -3,4- Piperidine diol (compound 21) Is (3R, 4R, 5R) -5-hydroxymethyl- Prepared from 3,4-piperidinediol and 4-phenoxybutyl bromide. ( 3R, 4R, 5R) -1- (4-cyanobutyl) -5-hydroxymethyl-3,4-piperi Zindiol (compound 22) Is (3R, 4R, 5R) -5-hydroxymethyl-3,4- Prepared from piperidinediol and 5-bromovaleronitrile. ( 3R, 4R, 5R) -1- (10-decylphthalimide) -5-hydroxymethyl-3, 4-piperidinediol (compound 23) Is (3R, 4R, 5R) -5-hydroxymethyl From 3,4 piperidinediol and N- (10-bromodecyl) phthalimide Prepared. ( 3R, 4R, 5R) -12- (3,4-dihydroxy-5-hydroxymethyl-piperidi N-1-yl) dodecanoic acid (Compound 24) Is (3R, 4R, 5R) -5-hydroxymethyl Prepared from 1,3,4-piperidinediol and 12-bromododecanoic acid. ( 3R, 4R, 5R) -5-Hydroxymethyl-1-phenoxyethyl-3,4-piper Zindiol (compound 25) Is (3R, 4R, 5R) -5-hydroxymethyl-3,4- Prepared from piperidinediol and 2-bromoethylphenyl ether. Example 22 ( 3R, 4R, 5R) -3- (3,4-dihydroxy-5-hydroxymethyl-piperidine- 1-yl) propionic acid (compound 26)   Wang resin-O-CO-CH = CH_Two(2.0 g, 1.84 mmol) in DMF (15 mL ) Add (3R, 4R, 5R) -5-hydroxymethyl-3,4-piperidinediol to the suspension (0.8 g, 5.4 mmol) in DMF (3 mL) was added. 22 Shake for time, filter, and wash the resin with DMF (2 × 20 mL), methanol (3 × 20 mL), DMF (2 × 20 mL), methylene chloride (2 × 20 mL) and methanol (2 × 20 mL). The resin is dried in vacuum and about 2.2 g of raw material Obtained.   To a suspension of this resin (0.5 g, 0.46 mmol) in methylene chloride (5 mL) was added Fluoroacetic acid (5 mL) was added. Shake the mixture for 20 minutes, filter and filter. The liquid was evaporated to dryness in vacuo and (3R, 4R, 5R) -3- (3,4-dihydro (Xy-5-hydroxymethyl-piperidin-1-yl) propionic acid as a yellow oil (Yield: 40 mg, 40%). Example 23 ( 3R, 4R, 5R) -3-benzyloxy-5-hydroxymethyl-1- (2,3,4-tri -O-benzyl-6-deoxy-1-O-methyl-6-α-D-glucopyranosyl) -4-pipe Lysinol   (3R, 4R, 5R) -3-benzyloxy-5-hydroxymethyl-4-piperidino (0.25 g, 0.54 mmol) and methyl 2,3,4-tri-O-benzyl-α- D-glucohexadialose-1,5-pyranoside (0.128 g, 5.4 mmol) Was dissolved in ethanol (50 mL) and palladium on activated carbon (10%, 30 mg) was added. The mixture was prepared at 6 atm. H_TwoHydrogen for 24 hours under pressure Filtered through celite and concentrated in vacuo. Silica gel column (eluent) Purification with ethyl acetate / methanol / (9/1)) gave (3R, 4R, 5R) -3-benzene. Ziroxy-5-hydroxymethyl-1- (2,3,4-tri-O-benzyl-6-deoxy -1-O-methyl-6-α-D-glucopyranosyl) -4-piperidinol as oil (Yield: 71 mg, 19%). Example 24 ( 3R, 4R, 5R) -1- (6-Deoxy-1-O-methyl-6-α-D-glucopyranosyl) -5-hydroxymethyl-3,4-piperidinediol (compound 27)   (3R, 4R, 5R) -3-benzyloxy-5-hydroxymethyl-1- (2,3,4-to R-O-benzyl-6-deoxy-1-O-methyl-6-α-D-glucopyranosyl) -4-pi Peridinol (71 mg, 0.1 mmol) and aqueous hydrochloric acid (4 N, 0.3 mL) were added. Palladium (10 mL) dissolved in ethanol (20 mL) and supported on activated carbon. %, 50 mg). The mixture was added at 1 atm. H_TwoHydrogenate for 3 hours under pressure Filtered through celite and concentrated in vacuo. Silica gel column (eluent: eta (3R, 4R, 5R) by purification on ethanol / 25% ammonium hydroxide (9/1)). -1- (6-Deoxy-1-O-methyl-6-α-D-glucopyranosyl) -5-hydroxymethyl The free base of tyl-3,4-piperidinediol was obtained as a yellow oil (yield: 21 mg, 64%).

[Procedure for Amendment] Article 184-8, Paragraph 1 of the Patent Act [Date of Submission] June 4, 1999 (1999.6.4) [Details of Amendment] Claims 1. Piperidine compounds having general formula I And a pharmaceutically acceptable acid addition salt or hydrate or prodrug thereof, wherein R is either a straight or branched C _1-6 alkoxy group; or R is C _{3- 7} is a linear or branched C _1-18 alkyl group optionally substituted by a cycloalkyl group; or R is a phenylpropyl group; or R is a cyano group, a carboxylic acid, a hydroxyl group, Oxo, perhalomethyl, halogen, phenyl, C _1-6 alkoxy, C _1-6 alkoxycarbonyl, benzyloxycarbonyl, hydroxy-C _1-6 alkyl, C _1-6 alkyl, or NR ₁ A C _3-7 cycloalkyl group optionally substituted by an R ₂ group (wherein R ₁ and R ₂ are _either hydrogen or a C _1-6 alkyl group or a benzyl group) . 2. 2. The compound according to claim 1, wherein R is a linear or branched _C1-6 alkoxy group. 3. A compound according to claim 1, and R is, C _3-7 straight-chain or branched C _1-18 alkyl group optionally substituted by a cycloalkyl group. 4. 4. The compound according to claim 1, wherein R is a dodecyl group. 5. The compound according to claim 1 or 3, wherein R is a linear or branched C _1-18 alkyl group substituted by a C _3-7 cycloalkyl group. 6. The compound according to claim 1, 3 or 5, wherein R is a 3-cyclohexylpropyl group. 7. The compound according to claim 1, wherein R is a 3-phenylpropyl group. 8. A compound according to claim 1, R is a cyano group, a carboxylic acid, a hydroxyl group, an oxo group, perhalomethyl group, a halogen, a phenyl group, C _1-6 alkoxy groups, C _{1 -6} alkoxycarbonyl groups, benzyloxycarbonyl Group, hydroxy-C _1-6 alkyl group, C _1-6 alkyl group, or NR ₁ R ₂ group (where R ₁ and R ₂ are both or one of hydrogen, C _1-6 alkyl group, or A C _3-7 cycloalkyl group optionally substituted with benzyl group). 9. The compound according to claim 1, which is selected from the following compounds: (3-cyclohexyl) propyl) -5-hydroxymethyl-3,4-piperidinediol, 1-dodecyl-5-hydroxymethyl-3,4-piperidinediol, 5 -Hydroxymethyl-1- (3-phenylpropyl) -3,4-piperidinediol, 5-hydroxymethyl-1-methoxy-3,4-piperidinediol, 1-octyl-5-hydroxymethyl-3,4-piperidine A diol, or a pharmaceutically acceptable salt or hydrate thereof, or a mixture of optical isomers, including any optical isomer or racemic mixture, or any tautomeric form. 10. An optical isomer or a mixture of optical isomers, including a racemic mixture, selected from the group consisting of the following compounds: (3R, 4R, 5R) -1- (3-cyclohexyl) propyl) -5-hydroxy Methyl-3,4-piperidinediol, (3R, 4R, 5R) -1-dodecyl-5-hydroxymethyl-3,4-piperidinediol, (3R, 4R, 5R) -5-hydroxymethyl-1- (3 -Phenylpropyl) -3,4-piperidinediol, (3R, 4R, 5R) -5-hydroxymethyl-1-methoxy-3,4-piperidinediol, (3R, 4R, 5R) -1-octyl-5- Hydroxymethyl-3,4-piperidinediol, (3S, 4S, 5S) -1- (3-cyclohexyl) propyl) -5-hydroxymethyl-3,4-piperidinediol, (3S, 4S, 5S) -1- Dodecyl-5-hydroxymethyl-3,4-piperidinediol, (3S, 4 (S, 5S) -5-hydroxymethyl-1- (3-phenylpropyl) -3,4-piperidinediol, (3S, 4S, 5S) -5-hydroxymethyl-1-methoxy-3,4-piperidinediol, (3S, 4S, 5S) -1-octyl-5-hydroxymethyl-3,4-piperidinediol, or a pharmaceutically acceptable salt or hydrate thereof. 11. 11. A compound according to any one of claims 1 to 10 for use as an inhibitor of glucose production. 12. 12. A compound according to any one of claims 1 to 11 for use as an inhibitor of glycogen phosphorylase enzyme activity. 13. 13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 together with one or more pharmaceutically acceptable carriers or excipients. 14． 14. The pharmaceutical composition according to claim 13, which is in the form of an oral dosage unit or a parenteral dosage unit. 15. 13. A compound according to any one of claims 1 to 12 for use in therapy. 16. Used for treating or preventing endocrine disorders, preferably diabetes, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis or myocardial ischemia, more preferably diabetes The compound according to any one of claims 1 to 12 for performing the method. 17． Treatment or prevention of non-insulin dependent diabetes mellitus (NIDDM, ie, type 2 diabetes) (overnight treatment or diet, and / or long-term complications, preferably retinopathy, neuropathy, nephropathy, and / or micro- 13. A compound according to any one of claims 1 to 12 for use in the treatment or prevention of vasculopathy, macroangiopathy). 18. Use of a compound according to any one of claims 1 to 12 for preparing a medicament. 19. For treating or preventing endocrine disorders, preferably diabetes, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis or myocardial ischemia, more preferably diabetes Use of a compound according to any one of claims 1 to 12 for the preparation of a medicament. 20. Treatment or prevention of non-insulin dependent diabetes mellitus (NIDDM, ie, type 2 diabetes) (overnight treatment or diet, and / or long-term complications, preferably retinopathy, neuropathy, nephropathy, and / or micro- Use of a compound according to any one of claims 1 to 12 for the preparation of a medicament for the treatment or prevention of vasculopathy, macroangiopathy). 21. In patients in need of treatment, endocrine disorders, preferably diabetes, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis or myocardial ischemia, more preferably 13. A method for treating or preventing diabetes, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 12. 22. In patients in need of treatment, treatment or prevention of non-insulin dependent diabetes mellitus (NIDDM, ie, type 2 diabetes), and / or long-term complications (preferably retinopathy, neuropathy, nephropathy, and / or 13. A method for treating or preventing vasculopathy or macroangiopathy), comprising administering an effective amount of the compound according to any one of claims 1 to 12 to said patient.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 3/10 A61P 3/10 5/00 5/00 9/00 9/00 9/10 9/10 101 101 9/12 9/12 13/12 13/12 25/00 25/00 27/02 27/02 43/00 111 43/00 111 C07D 401/04 C07D 401/04 C07H 19/04 C07H 19/04 ( 81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM) , AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, GH, GM, GW , HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW (72) Inventor Lundbeck Jane Marie, Denmark, 2900 Grosstorrup, Ebas Are 19 (72) Inventor Sokirde, Birgitte, Denmark, 3900 Baerlo Se, Birke Garden 48 (72) Inventor Lundgren, Kirsten, Denmark, De Code -2000 Furederi Kkusuberugu, N. Jesus Pell sense bay 25

Claims (1)

[Claims]   1. Piperidine compounds having general formula I And a pharmaceutically acceptable acid addition salt or hydrate or a prodrug thereof. hand,   Where R is a linear or branched C_1-6Is an alkoxy group; or   R represents a cyano group, a carboxylic acid, a trifluoromethyl group, a hydroxyl group, a perhalomethy; Group, halogen, C_3-7Cycloalkyl group, C_1-6Alkoxy group, C_1-6Alkoki Sicarbonyl group, benzyloxycarbonyl group, or NR₁R_TwoGroup (where R₁ , R_TwoIs independently hydrogen, C_1-6Alkyl or benzyl) All optionally substituted linear or branched (C_1-18Alkyl group, C_2-18A Lucene or C_2-18Alkyne); or   R is SR_ThreeGroup (where R_ThreeIs C_1-6Alkyl group, phenyl group, or cal Bonil (C_1-6An alkyl) group). Is branched (C_1-18Alkyl group, C_2-18Alkene or C_2-18Alkyne) Or;   R is optionally substituted by a methoxy, nitro, halogen, or cyano group Carbonyl (C_1-6Alkyl) or carbonylphenyl Optionally substituted, linear or branched (C_1-18Alkyl group, C_2-18Alkene Or C_2-18Alkyne); or   R is a trifluoromethyl group, a methoxy group, C_1-6Alkyl groups, carboxylic acids, Nitro, cyano, halogen, phenyl, methoxycarbonyl, methyls All with a phenoxy or phenyl group optionally substituted by a rufonyl group Optionally substituted, linear or branched (C_1-18Alkyl group, C_2-18Alkene , Or C_2-18Alkyne); or   R is carboxamide (CONR_FourR_FiveGroup, where R_Four, R_FiveAre together or Is hydrogen or C_1-6All are optionally substituted by Straight, branched or branched (C_1-18Alkyl group, C_2-18Alkene or C_{2- 18} Alkyne); or   R is naphthalene, phthalimide, optionally substituted piperidine, imidazoly 2-thienone, optionally substituted coumarin, 2-dioxolan, hydantoin , Thiohydantoin, 1,2,4-oxadiazoline, optionally substituted isooxo Sazolidine, tetrahydrofurfuryl group, 1,4-benzodioxane, or Linear or linear, all optionally substituted by a nylsulfonyl group or a glycoside Is branched (C_1-18Alkyl group, C_2-18Alkene or C_2-18Alkyne) Or; or   R represents a cyano group, a carboxylic acid, a hydroxyl group, an oxo group, a perhalomethyl group, Phenyl group, C_1-6Alkoxy group, C_1-6Alkoxycarbonyl group, benzyl Oxycarbonyl group, hydroxy-C_1-6Alkyl group, C_1-6An alkyl group, or NR₁R_TwoGroup (where R₁, R_TwoIs hydrogen or C_1-6Alkyl A benzyl group or a benzyl group)_3-7Cycloalkyl group What is.   2. The compound of claim 1, wherein R is a linear or branched C._1-6Al A compound that is a oxy group.   3. 2. The compound according to claim 1, wherein R is a cyano group, a carboxylic acid, a trifluoro group. Oromethyl group, hydroxyl group, perhalomethyl group, halogen, C_3-7Cycloalkyl group , C_1-6Alkoxy group, C_1-6Alkoxycarbonyl group, benzyloxy carbonyl Or NR₁R_TwoGroup (where R₁, R_TwoIs independently hydrogen, C_1-6Alkyl group Or a benzyl group), all of which are optionally substituted, linear or Branched (C_1-18Alkyl group, C_2-18Alkene or C_2-18Alkyne) Compound.   4. The compound of claim 1, wherein R is SR_ThreeGroup (where R_ThreeIs C_1-6A Alkyl group, phenyl group, or carbonyl (C_1-6Alkyl)) All optionally substituted linear or branched (C_1-18Alkyl group, C_2-18A Luke Or C_2-18Alkyne).   5. 2. The compound according to claim 1, wherein R is methoxy, nitro, halogen. Or a carbonyl optionally substituted by a cyano group (C_1-6Alkyl) group or Is linear or branched, all being optionally substituted by carbonylphenyl groups (C_1-18Alkyl group, C_2-18Alkene or C_2-18Alkyne).   6. The compound according to claim 1, wherein R is a trifluoromethyl group, methoxy. Group, C_1-6Alkyl group, carboxylic acid, nitro group, cyano group, halogen, phenyl Optionally substituted with a methoxycarbonyl group or a methylsulfonyl group Linear or branched, all optionally substituted by xyl or phenyl groups (C_1-18Alkyl group, C_2-18Alkene or C_2-18Alkyne).   7. 2. The compound according to claim 1, wherein R is carboxamide (CONR_FourR_FiveBase , Where R_Four, R_FiveIs either or both hydrogen or C_1-6Alkyl A straight-chain or branched (C_1-18Al Kill group, C_2-18Alkene or C_2-18Alkyne).   8. 2. The compound of claim 1, wherein R is naphthalene, phthalimide, Substituted piperidine, imidazoline, 2-thienone, optionally substituted bear Phosphorus, 2-dioxolan, hydantoin, thiohydantoin, 1,2,4-oxadi Azoline, optionally substituted isoxazolidine, tetrahydrofurfuryl group, 1,4-benzodioxane or phenylsulfonyl group or glycoside Straight-chain or branched (C_1-18Alkyl group, C_2-18Al Ken or C_2-18Alkyne).   9. The compound according to claim 1, wherein R is a cyano group, a carboxylic acid, a hydroxyl group, Oxo group, perhalomethyl group, halogen, phenyl group, C_1-6Alkoxy group, C_{1 -6} Alkoxycarbonyl group, benzyloxycarbonyl group, hydroxy-C_1-6A Alkyl group, C_1-6Alkyl group, or NR₁R_TwoGroup (where R₁, R_TwoIf together Or one of them is hydrogen, C_1-6Alkyl or benzyl) Optionally substituted C_3-7Compounds that are cycloalkyl groups.   10. The compound according to claim 1, which is selected from the following compounds:   1-butyl-5-hydroxymethyl-3,4-piperidinediol,   1- (3-cyclohexyl) propyl) -5-hydroxymethyl-3,4-piperidinedi Oar,   1-dodecyl-5-hydroxymethyl-3,4-piperidinediol,   1- (2-hydroxyethyl) -5-hydroxymethyl-3,4-piperidinediol ,   5-hydroxymethyl-1- (4- (5-hydantoyl) butyl) -3,4-piperidinedi Oar,   5-hydroxymethyl-1- (3-phenylpropyl) -3,4-piperidinediol ,   5-hydroxymethyl-1-methyl-3,4-piperidinediol,   5-hydroxymethyl-1-methoxy-3,4-piperidinediol,   5-hydroxymethyl-1- (4-N, N-diphenylaminobenzyl) -3,4-pipe Lysine diol, or   1-acetyl-5-hydroxymethyl-3,4-piperidinediol,   5-hydroxymethyl-1- (3-phenylallyl) -3,4-piperidinediol,   1-allyl-5-hydroxymethyl-3,4-piperidinediol,   1-benzyl-5-hydroxymethyl-3,4-piperidinediol,   1-octyl-5-hydroxymethyl-3,4-piperidinediol,   (3,4-dihydroxy-5-hydroxymethyl-piperidin-1-yl) -acetamido Do   Ethyl (3,4-dihydroxy-5-hydroxymethyl-piperidin-1-yl) acetate Tate,   5-hydroxymethyl-1- (4-trifluoromethyl-benzyl) -3,4-piperidi Diol,   1- (2- (4'-fluoroacetophenone))-5-hydroxymethyl-3,4-piper Gindiol,   5-hydroxymethyl-1- (2- (4'-methoxyacetophenone))-3,4-piper Gindiol,   (2- (4-fluorophenoxy) -ethyl) -5-hydroxymethyl-3,4-piperidi Diol,   5-hydroxymethyl-1- (4-phenoxy-butyl) -3,4-piperidinediol ,   1- (4-cyanobutyl) -5-hydroxymethyl-3,4-piperidinediol,   1- (10-decylphthalimide) -5-hydroxymethyl-3,4-piperidinedio Tool,   12- (3,4-dihydroxy-5-hydroxymethyl-piperidin-1-yl) dodeca Acid,   5-hydroxymethyl-1-phenoxyethyl-3,4-piperidinediol,   3- (3,4-dihydroxy-5-hydroxymethyl-piperidin-1-yl) propio Acid,   1- (6-deoxy-1-O-methyl-6-α-D-glucopyranosyl) -5-hydroxy Methyl-3,4-piperidinediol Or a pharmaceutically acceptable salt or hydrate thereof, or any optical isomer Or a mixture of optical isomers, including racemic mixtures, or any tautomeric forms.   11. The optical isomer according to claim 10, which is selected from the group consisting of the following compounds. Or a mixture of optical isomers, including racemic mixtures   (3R, 4R, 5R) -1-butyl-5-hydroxymethyl-3,4-piperidinediol ,   (3R, 4R, 5R) -1- (3-cyclohexyl) propyl) -5-hydroxymethyl- 3,4-piperidinediol,   (3R, 4R, 5R) -1-Dodecyl-5-hydroxymethyl-3,4-piperidinedio Tool,   (3R, 4R, 5R) -1- (2-hydroxyethyl) -5-hydroxymethyl-3,4-pi Peridine diol,   (3R, 4R, 5R) -5-hydroxymethyl-1- (4- (5-hydantoyl) butyl)- 3,4-piperidinediol,   (3R, 4R, 5R) -5-hydroxymethyl-1- (3-phenylpropyl) -3,4-pi Peridine diol,   (3R, 4R, 5R) -5-hydroxymethyl-1-methyl-3,4-piperidinediol ,   (3R, 4R, 5R) -5-Hydroxymethyl-1-methoxy-3,4-piperidinedio Tool,   (3R, 4R, 5R) -5-hydroxymethyl-1- (4-N, N-diphenylaminoben (Jill) -3,4-piperidinediol,   (3R, 4R, 5R) -1-acetyl-5-hydroxymethyl-3,4-piperidinedio Tool,   (3R, 4R, 5R) -5-hydroxymethyl-1- (3-phenylallyl) -3,4-pipe Lysine diol,   (3R, 4R, 5R) -1-allyl-5-hydroxymethyl-3,4-piperidinediol ,   (3R, 4R, 5R) -1-benzyl-5-hydroxymethyl-3,4-piperidinedio Tool,   (3R, 4R, 5R) -1-octyl-5-hydroxymethyl-3,4-piperidinedio Tool,   (3R, 4R, 5R) -2- (3,4-dihydroxy-5-hydroxymethyl-piperidine -1-yl) -acetamide,   Ethyl ((3R, 4R, 5R) -3,4-dihydroxy-5-hydroxymethyl-piperi Gin-1-yl) acetate,   (3R, 4R, 5R) -5-hydroxymethyl-1- (4-trifluoromethyl-benzyl) Ru) -3,4-piperidinediol,   (3R, 4R, 5R) -1- (2- (4'-fluoroacetophenone))-5-hydroxymeth Chill-3,4-piperidinediol,   (3R, 4R, 5R) -5-hydroxymethyl-1- (2- (4′-methoxyacetopheno ))-3,4-piperidinediol,   (3R, 4R, 5R)-(2- (4-fluorophenoxy) -ethyl) -5-hydroxymethyl Le-3,4-piperidinediol,   (3R, 4R, 5R) -5-hydroxymethyl-1- (4-phenoxy-butyl) -3,4- Piperidine diol,   (3R, 4R, 5R) -1- (4-cyanobutyl) -5-hydroxymethyl-3,4-piperi Gindiol,   (3R, 4R, 5R) -1- (10-decylphthalimide) -5-hydroxymethyl-3, 4-piperidinediol,   (3R, 4R, 5R) -12- (3,4-dihydroxy-5-hydroxymethyl-piperidi N-1-yl) dodecanoic acid,   (3R, 4R, 5R) -5-hydroxymethyl-1-phenoxyethyl-3,4-piperi Gindiol,   (3R, 4R, 5R) -3- (3,4-dihydroxy-5-hydroxymethyl-piperidine -1-yl) propionic acid,   (3R, 4R, 5R) -1- (6-deoxy-1-O-methyl-6-α-D-glucopyranosi ) -5-Hydroxymethyl-3,4-piperidinediol   (3S, 4S, 5S) -1-butyl-5-hydroxymethyl-3,4-piperidinediol ,   (3S, 4S, 5S) -1- (3-cyclohexyl) propyl) -5-hydroxymethyl- 3,4-piperidinediol,   (3S, 4S, 5S) -1-Dodecyl-5-hydroxymethyl-3,4-piperidinedio Tool,   (3S, 4S, 5S) -1- (2-hydroxyethyl) -5-hydroxymethyl-3,4-pi Peridine diol,   (3S, 4S, 5S) -5-hydroxymethyl-1- (4- (5-hydantoyl) butyl)- 3,4-piperidinediol,   (3S, 4S, 5S) -5-hydroxymethyl-1- (3-phenylpropyl) -3,4-pi Peridine diol,   (3S, 4S, 5S) -5-hydroxymethyl-1-methyl-3,4-piperidinediol ,   (3S, 4S, 5S) -5-hydroxymethyl-1-methoxy-3,4-piperidinedio Tool,   (3S, 4S, 5S) -5-hydroxymethyl-1- (4-N, N-diphenylaminoben (Jill) -3,4-piperidinediol, or   (3S, 4S, 5S) -1-acetyl-5-hydroxymethyl-3,4-piperidinedio Tool,   (3S, 4S, 5S) -5-hydroxymethyl-1- (3-phenylallyl) -3,4-pipe Lysine diol,   (3S, 4S, 5S) -1-allyl-5-hydroxymethyl-3,4-piperidinediol ,   (3S, 4S, 5S) -1-benzyl-5-hydroxymethyl-3,4-piperidinedio Tool,   (3S, 4S, 5S) -1-octyl-5-hydroxymethyl-3,4-piperidinedio Tool,   (3S, 4S, 5S) -2- (3,4-dihydroxy-5-hydroxymethyl-piperidine -1-yl) -acetamide,   Ethyl ((3S, 4S, 5S) -3,4-dihydroxy-5-hydroxymethyl-piperi Gin-1-yl) acetate,   (3S, 4S, 5S) -5-hydroxymethyl-1- (4-trifluoromethyl-benzyl Ru) -3,4-piperidinediol,   (3S, 4S, 5S) -1- (2- (4'-fluoroacetophenone))-5-hydroxymeth Chill-3,4-piperidinediol,   (3S, 4S, 5S) -5-hydroxymethyl-1- (2- (4'-methoxyacetopheno ))-3,4-piperidinediol,   (3S, 4S, 5S)-(2- (4-fluorophenoxy) -ethyl) -5-hydroxymethyl Le-3,4-piperidinediol,   (3S, 4S, 5S) -5-hydroxymethyl-1- (4-phenoxy-butyl) -3,4- Piperidine diol,   (3S, 4S, 5S) -1- (4-cyanobutyl) -5-hydroxymethyl-3,4-piperi Gindiol,   (3S, 4S, 5S) -1- (10-decylphthalimido) -5-hydroxymethyl-3, 4-piperidinediol,   (3S, 4S, 5S) -12- (3,4-dihydroxy-5-hydroxymethyl-piperidi N-1-yl) dodecanoic acid,   (3S, 4S, 5S) -5-hydroxymethyl-1-phenoxyethyl-3,4-piper Gindiol,   (3S, 4S, 5S) -3- (3,4-dihydroxy-5-hydroxymethyl-piperidine -1-yl) propionic acid,   (3S, 4S, 5S) -1- (6-deoxy-1-O-methyl-6-α-D-glucopyranosi ) -5-Hydroxymethyl-3,4-piperidinediol Or a pharmaceutically acceptable salt or hydrate thereof.   12. The compound according to any one of claims 1 to 11, wherein the compound comprises glucose. Compounds active as raw inhibitors.   13. 13. The compound according to any one of claims 1 to 12, wherein the glycogen Compounds active as inhibitors of phosphorylase enzyme activity.   14． A compound according to any one of claims 1 to 13 wherein the compound is one or more pharmaceutically acceptable. A pharmaceutical composition comprising an acceptable carrier or excipient.   15. 15. An oral dosage unit or a parenteral dosage unit. Pharmaceutical compositions.   16. 14. A compound according to any one of claims 1 to 13 for use in therapy.   17． Endocrine disorders, preferably diabetes, hyperglycemia, hypercholesterolemia, Hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis or myocardial ischemia Claims 1 to 1 for use in the treatment or prevention of blood, more preferably diabetes. 4. The compound according to any one of 3.   18. Treatment of non-insulin dependent diabetes mellitus (NIDDM, ie type 2 diabetes) Is preventative (overnight treatment or diet, and / or long-term Or retinopathy, neuropathy, nephropathy, and / or microangiopathy, macrovascular 14. Use according to any one of claims 1 to 13 for the treatment or prevention of disease). Item.   19. A compound of any one of claims 1 to 13 for preparing a medicament. Use of.   20. Endocrine disorders, preferably diabetes, hyperglycemia, hypercholesterolemia, Hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis or myocardial ischemia For preparing a medicament for treating or preventing blood, more preferably diabetes, Use of a compound according to any one of claims 1 to 13.   21. Treatment of non-insulin dependent diabetes mellitus (NIDDM, ie type 2 diabetes) Is preventative (overnight treatment or diet, and / or long-term Or retinopathy, neuropathy, nephropathy, and / or microangiopathy, macrovascular Claim 1 for the preparation of a medicament for the treatment or prevention of disease). Use of the compound according to any one of items 13 to 15.   22. In patients in need of treatment, endocrine disorders, preferably diabetes, hyperglycemia Disease, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, athero To treat or prevent atherosclerosis or myocardial ischemia, more preferably diabetes 14. The method of claim 1 wherein the compound of any one of claims 1 to 13 is effective in said patient. A method comprising administering.   23. In patients in need of treatment, non-insulin dependent diabetes (NIDDM, That is, treatment or prevention of type 2 diabetes and / or long-term complications (preferably Is retinopathy, neuropathy, nephropathy, and / or microangiopathy, macroangiopathy) A method for treating or preventing a disease, wherein the method according to any one of claims 1 to 13 is used. Administering to the patient an effective amount of a compound.