CZ372799A3 - Piperidine compounds and pharmaceutical preparation containing thereof - Google Patents

Abstract

Piperidine Compounds and their Pharmaceutical Compounds are described acceptable acid addition salts or hydrates thereof; \ t prodrugs and pharmaceutical compositions containing the same. Yippee describe the use of piperidine compounds for the manufacture of a medicament for treating or preventing endocrinological disease system, preferably diabetes, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis or ischemiemyocardium, in particular for treating or preventing diabetes independent insulin (NIDDM or diabetestypus 2), which includes treating overnight or treating food / or treatment or prevention of long-term complications, preferably retinopathy, neuropathy, nephropathy, and / or micro- amo-angiopathy. Yippee a method of treating or preventing said is also described disease.

Description

The Piperidine Compounds / pharmaceutical composition is containing the use thereof.

Technical field

The present invention relates to piperidine compounds, to a pharmaceutical composition comprising these compounds, to the use of these compounds as medicaments, to the use of these medicaments for the treatment or prevention of diabetes, particularly non-insulin dependent diabetes (NIDDM or type 2 diabetes), and / or treating or preventing long-term complications, preferably retinopathy, neuropathy, nephropathy and / or micro- and macro-angiopathy, treating hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, or myocardial ischemia, and a method for producing these compounds.

BACKGROUND OF THE INVENTION

Diabetes is characterized by a shared glucose metabolism which is manifested, among other things, by elevated blood glucose levels in diabetic patients. These defects lead to the classification of diabetes into two main groups: type 1 diabetes or insulin-dependent diabetes mellitus (IDDM), which increases when patients lack insulin-producing abdominal β-cells in their pancreas, and type 2 diabetes or non-insulin-dependent diabetes mellitus. (NIDDM), which occurs in patients with non-shared β-cell function, among other abnormalities.

Patients with type 1 diabetes are commonly treated with insulin, while most patients with type 2 diabetes are treated with either sulphonylureas that stimulate β-cell function, agents that increase the patient's sensitivity to insulin or insulin. Among the agents administered to increase tissue sensitivity to insulin, metformin is a representative example.

Although sulfonylureas are widely used in the treatment of NIDDM, this therapy is in most cases unsatisfactory. In a large number of NIDDM patients, sulfonylureas are not sufficient to normalize blood sugar levels, and there is therefore a high risk of acquiring diabetic complications in these patients. Many patients also gradually lose their ability to respond to sulfonylurea treatment and are therefore gradually pushed to insulin treatment. This shift of patients from treatment with oral hypoglycemic agents _and insulin, for the treatment obvykkle ascribed to exhaustion of β-cells in NIDDM patients.

* In normal people as well as in diabetics, the liver produces glucose to avoid hypogleemia. This glucose production results either from the release of glucose from the glucogen stores or from glucogenesis, which is a de novo intracellular glucose synthesis. However, in type 2 diabetes, the regulation of hepatic glucose production is poorly regulated, increased, and may double rapidly overnight. In addition, there is a strong correlation between elevated plasma glucose levels and the rate of hepatic glucose production in these patients (collectively reported by Fronzo Council: Diabetes 1988, 37, 667-687, A. Consoli: Diabetes Care 1992, 15, 430-441). and JEGerich: Horm.Metab.Res. 1992, 26, 18-21. Similarly, hepatic glucose production will increase in type 1 diabetes unless the disease is adequately controlled by insulin treatment.

Since existing forms of diabetes treatment do not lead to sufficient glycemic control and are therefore unsatisfactory, there is a great demand for new tepareutic approaches. Since the liver is known to have increased glucose production in diabetic patients, compounds that inhibit this activity are highly desirable. Recently, patent applications have been submitted inhibitors of specific enzymes of the liver, glucose-6-phosphatase, _d which is necessary for the release of glucose from the liver, for example, German Patent Offenlegungsschrift no. 4,202,183 and 4,202,184 and Japanese Patent No. phhláška. 4-58 565 All these known compounds are benzene derivatives.

Substituted N- (indole-2-carbonyl) glycinamides acting as glycogen phosphorylase inhibitors are described in PCT Publication Nos. WO 96/39 384 and WO 96/39 385.

• · 9 9 • · · 9 9 • · 9 • · 9 9 9 9 • · 9 9 • · 9 · 999 • 9 9 • · • • 9 99 9 9 9 99 9 9 9 • ·

• · ·

Atherosclerosis, a disease of the arteries, is considered to be the leading cause of death in the United States and Western Europe. The pathological sequence leading to atherosclerosis and occlusive heart disease is well known. An early step in this sequence is the formation of fat strips in the carotid, coronary and cerebral arteries and in the aorta. These lesions have a yellow color due to the presence of fat deposits found in smooth muscle cells and, in macrophages, the inner layers of the arteries and the aorta. It is further reported that most of the cholesterol found in the fat strips increases the development of fibrous plaque, which consists of accumulated internal smooth muscle cells with fat and surrounded by extracellular fat, collagen, elastin and proteoglycans. These cells plus the matrix form a fibrous plug that conceals the deeper deposition of cell debris and extracellular fat. This fat is primarily free and esterified cholesterol. Fibrous plaque is slow to form and is likely to calcify and become necrotized over time, leading to complicated damage resulting in arterial occlusion and a tendency to wall thrombosis and arterial muscle spasm, which characterizes advanced atherosclerosis.

Epidemiological evidence has firmly identified hyperlipidemia as the primary risk factor for causing cardiovascular disease (CVD) due to atherosclerosis. Recently, leaders in the medical profession have re-emphasized the reduction of plasma cholesterol levels and in particular the reduction of lipoprotein cholesterol density as a substantial step in the prevention of CVD. It is now known that upper normal limits are significantly lower than previously reported. As a result, large sections of the Western population are now aware of this particularly high risk. These independent risk factors include glucose intolerance, left ventricular hypertrophy, hypertension and male sex. Cardiovascular disease prevails particularly in diabetic subjects, but partly due to the existence of multiple independent risk factors in this population. Successful treatment of hyperlipidemia in the population, and particularly in diabetic subjects, is therefore of paramount importance.

Hypertension (or high blood pressure) is a condition that occurs in the human population as a secondary symptom of various other disorders such as renal arterial stenosis, pheochromocytoma, or endocrine disorders. However, hypertension has also been demonstrated in many patients where the causative agent or disorder is unknown. While this primary hypertension is often associated with such disorders as obesity, diabetes and hypertriglyceridemia, the relationship between these disorders is not elucidated. In addition, many patients exhibit symptoms of high blood pressure in the complete absence of any other sign of disease or disorder.

and

It is known that hypertension can directly lead to heart failure, renal ϊ failure and stroke (cerebral hemorrhage). These conditions are able to cause the death of the patient in a short time. Hypertension may also contribute to the development of atherosclerosis and coronary disease. These conditions gradually weaken the patient and may lead to death in the longer term.

The exact cause of primary hypertension is unknown, although numerous factors ^{w are} believed to contribute to the onset of the disease. These factors include stress, uncontrolled emotions, unregulated hormone release (renin, angiotensin aldosterone system), excess salt and water due to poor kidney function, amplification and hypertrophy of the walls of the vasculature, resulting in reduced bloodstream, and genetic factors.

Treatment of primary hypertension is performed taking into account the foregoing factors. Therefore, large amounts of beta-blockers, vasoconstrictors, angiotensin converting neyme inhibitors and the like have been developed and marketed as antipertensive agents. Treatment of hypertension using these compounds has been shown to be beneficial in preventing death in the short term, such as heart failure, renal failure and cerebral hemorrhage. However, the development of atherosclerosis or heart disease due to hypertension for a long time remains a problem. This means that even if high blood pressure is lowered, the cause of the condition that causes primary hypertension does not respond to this treatment.

Hypertension is associated with elevated blood insulin levels, a condition known as hyperinsulinemia. Insulin, a peptide hormone whose primary effects are

It also helps to promote vascular cell growth and increase renal sodium retention among other things. These latter functions may be related to influencing glucose levels and are known as the causes of hypertension. For example, the growth of peripheral vasculature may be a method of constricting peripheral capillaries while sodium retention increases blood volume. Thus, lowering insulin levels in subjects with hyperinsulinemia may prevent abnormal vascular growth and renal sodium retention due to high insulin levels, and thus alleviate hypertension.

Cardiac hypertrophy is a significant risk factor for sudden death, myocardial infarction and congestive heart failure. These cardiac events are due, at least in part, to increased sensitivity of cardiac muscle damage following ischemia and reperfusion, which may occur in non-hospital patients as well as during surgery. Thus, there is an unexpected medical need to prevent or minimize cardiac muscle events during surgery, particularly myocardial infarction. Both non-cardiac and cardiac surgery are associated with substantial risks of myocardial infarction or death. Some 7 million patients undergoing non-cardiac surgery can be considered to be at risk of developing operational death and serious cardiac complications, in some cases up to 20-25%. In addition, out of the 400,000 patients who undergo coronary bypass surgery annually, myocardial infarction occurs at 5% and death occurs at 1-2%. There is no drug treatment in this field today that reduces cardiac tissue damage in operative myocardial ischemia or that increases the heart's resistance to ischemic events. This treatment is classified as life-saving, reducing hospital stay, increasing quality of life, and lowering the overall cost of healthcare for high-risk patients.

It is an object of the present invention to provide compounds which could be used as medicaments for the treatment of one or more of the above diseases and disorders.

It is a further object of the present invention to provide compounds that can be effectively used in the treatment of diabetes, preferably Type II diabetes, including overnight treatment or food treatment and preferably treatment of elevated plasma glucose levels.

It is yet another object of the present invention to provide compounds that can be effectively used as inhibitors of liver glucose production.

and

It is yet another object of the present invention to provide compounds that can be effectively used as phosphorylase inhibitors.

It has now been found that members of the new group of piperidine compounds have interesting pharmacological properties. For example, the compounds of the invention may be used in the treatment of diabetes. The compounds of the invention are particularly effective as inhibitors of glucose production in the liver. Thus, the compounds of this invention can be used to treat elevated plasma glucose levels in diabetics.

It is therefore an object of the present invention to provide these novel piperidine compounds.

SUMMARY OF THE INVENTION

The compounds of the invention are the piperidine compounds of formula (I)

and pharmaceutically acceptable acid addition salts or hydrates or prodrugs thereof, wherein:

R is a straight or branched alkoxy group having 1 to 6 carbon atoms; or R is a straight or branched alkyl having 1 to 18 carbon atoms, an alkene having 2 to 18 carbon atoms or an alkyne having 2 to 18 carbon atoms, all optionally substituted with cyano, carboxylic acid, trifluoromethyl, hydroxyl, perhalomethyl, halogen, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy, benzyloxycarbonyl or NR 6 in wherein Ri and R ₂ independently represent _hydrogen, alkyl of 1-6 carbon atoms or benzyl, or

R is straight or branched (C 1 -C 18) alkyl, (C 2 -C 18) alkene or (C 2 -C 18) alkyne, all optionally substituted by SR ₃ , wherein R ₃ is C 1 -C 6 alkyl, phenyl or carbonyl (C 1 -C 6 alkyl), or

R represents straight or branched (C 1 -C 18) alkyl, (C 2 -C 18) alkene or (C 2 -C 18) alkyne, all optionally substituted by carbonyl (C 1 -C 6 alkyl) or carbonylphenyl, optionally substituted by methoxy, nitro , a halogen atom or a cyano group, or

R is straight or branched (C 1 -C 18) alkyl, (C 2 -C 18) alkene or (C 2 -C 18) alkyne, all optionally substituted with phenoxy or phenyl optionally substituted with trifluoromethyl, methoxy, (C 1 -C 6) alkyl, carboxylic acid, nitro, cyano, halogen, phenyl, methoxycarbonyl or methylsulfonyl, or

R is a linear or branched alkyl having 1-18 C atoms, alkene having 2 to 18 carbon atoms or alkyne having 2 to 18 carbon atoms, all optionally substituted _w tuované carboxamide (CONR4R5 where one of R ₄ and R ₅ or both are hydrogen or alkyl of 1 to 6 carbon atoms), or

R represents straight or branched (C 1 -C 18) alkyl, (C 2 -C 18) alkene or (C 2 -C 18) alkyne, all optionally substituted with naphthalene, phthalimide, optionally substituted piperidine, imidazoline, 2-thienone, optionally substituted with coumarin, 2-dioxolane, hydantoin, thiohydantoin, 1,2,4-oxadiazoline, optionally substituted with isoxazolidine, tetrahydrofurfuryl, 1,4-benzodioxane or phenylsulfonyl, or glycoside, or

R is C 3 -C 7 cycloalkyl optionally substituted with cyano, carboxylic acid, hydroxyl, oxo, perhalomethyl, halogen, phenyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy, benzyloxycarbonyl, hydroxyalkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, or NR ₁ R ₂ , in which one of R 1 and R ₂ or both is hydrogen, alkyl of 1 to 6 carbon atoms or benzyl.

The compounds of formula I may be present as a mixture of enantiomers which, if desired, may be resolved into the individual pure enantiomers. This resolution can conveniently be carried out by fractional crystallization from various solvents, salts of compounds of formula I with optically active acids or other methods known per se, for example, by chiral column chromatography. The present invention encompasses all isomers, whether resolved or existing as mixtures.

Examples of pharmaceutically acceptable salts are acid addition salts with non-toxic acids, either inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, or organic acids such as formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid , propionic acid, succinic acid, gluconic acid, lactic acid, citric acid, ascorbic acid, benzoic acid, emonic acid, methanesulfonic acid, ethanesulfonic acid, malonic acid, oxalic acid, maleic acid, tartaric acid, tartaric acid, fumaric acid, acid mandelic acid, cinnamic acid, picric acid, and the like, and include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Sciences 1977, 66, 2, incorporated herein by reference, pharmaceutically acceptable metal salts such as for lithium, sodium, potassium and magnesium salts and the like. Hydrates capable of forming the present compounds are also considered to be pharmaceutically acceptable acid addition salts. Acid addition salts may be obtained as the direct products of compound synthesis. Alternatively, the free base may be

9

99 99 99

9 9 9 9 9 9

9 · 9 9 9 9 9 999 999

9

999 99 99 99. Dissolve in a suitable solvent containing the appropriate acid and isolate the salt by evaporating the solvent or otherwise separating the salt and solvent. The compounds of this invention can form solvates with standard, low molecular weight solvents using methods known to those skilled in the art.

In the above structural formula and in the present description, the following terms have the meanings indicated:

The term C 1 -C 6 alkoxy as used herein, alone or in combination, means a straight or branched monovalent substituent containing a C 1 -C 6 alkyl group which is bonded by an ethereal oxygen atom having a free valence by bonding an ether oxygen and having 1 to 6 carbon atoms, e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, and pentoxy.

The term cycloalkyl having 3 to 7 carbon atoms as used herein means a saturated cyclic hydrocarbon group having a specified number of carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

The term halogen atom means a fluorine, chlorine, bromine or iodine atom.

The term perhalomethyl means trifluoromethyl, trichloromethyl, tribromomethyl or tri-methyl.

The term alkyl of 1 to 6 carbon atoms as used herein, alone or in combination, means a straight or branched, saturated hydrocarbon chain with a designated number of carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, sec. butyl, isobutyl, tert-butyl, pentyl, 2-methylbutyl, 3-methylbutyl, 4-methylpentyl, neopentyl, hexyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1,2,2-trimethylpropyl and the like. The term alkyl of 1 to 18 carbon atoms, as used herein, is also used.

4 9 «4» 9 98 ·

9 9 9 4 *

4 4 9

4 9 9 «

No. 4,999,999 to include secondary alkyl of 3 to 18 carbon atoms and tertiary alkyl of 4 to 18 carbon atoms.

The term prodrug, as used herein, means, for example, compounds of Formula I which are prodrugs of drug and which upon administration release the drug in vivo by some chemical or physiological means. Examples of such prodrugs are esters that cleave to liberate the corresponding free acid. Further examples of such prodrugs are compounds of formula I into which an ester group has been introduced and which upon cleavage liberate the corresponding free alcohol of formula I.

Some of the above terms may occur more than once in Formula I above, and in these circumstances each term will be defined independently of the others.

In a preferred embodiment, the present invention relates to compounds of formula I wherein R is a straight or branched alkoxy group having 1 to 6 carbon atoms.

In another preferred embodiment, the present invention relates to compounds of formula I wherein R is straight or branched (C 1 -C 18) alkyl, (C 2 -C 18) alkene or (C 2 -C 18) alkyne, all optionally substituted with cyano, carboxylic acid, trifluoromethyl, hydroxyl, perhalomethyl, halogen, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, carbonylalkoxy (C 1 -C 6), benzyloxycarbonyl or NR 6 in which R 1 and R 4 ₂ independently represent halogen, alkyl of 1 to 6 carbon atoms or benzyl.

In another preferred embodiment, the present invention relates to compounds of formula I wherein R is straight or branched (C 1 -C 18) alkyl, (C 2 -C 18) alkene or (C 2 -C 18) alkyne, all optionally substituted with SR ₃ wherein R ₃ is C 1 -C 6 alkyl, phenyl, or carbonyl (C 1 -C 6 alkyl).

4 4 4

4 4 4

4 • 99

4 4

4944 44

944 * ·

In another preferred embodiment, the present invention relates to compounds of formula I wherein R is straight or branched (C 1 -C 18) alkyl, (C 2 -C 18) alkene or (C 2 -C 18) alkyne, all optionally substituted with carbonylalkyl (s). Or carbonylphenyl, optionally substituted with methoxy, nitro, halogen or cyano.

In another preferred embodiment, the invention relates to compounds of formula I wherein R is straight or branched (C 1 -C 18) alkyl, (C 2 -C 18) alkene or (C 2 -C 18) alkyne, all optionally substituted with phenoxy or phenyl optionally substituted by trifluoromethyl, methoxy, C1-C6 alkyl, carboxylic acid, nitro, cyano, halogen, phenyl, methoxycarbonyl or methylsulfonyl.

In another preferred embodiment, the invention relates to compounds of formula I wherein R is straight or branched (C 1 -C 18) alkyl, (C 2 -C 18) alkene or (C 2 -C 18) alkyne, all optionally substituted with carboxamide (CONR) ₍ R ₄ , wherein one of R ₄ and R ₅ or both is hydrogen or C 1 -C 6 alkyl).

In another preferred embodiment, the invention relates to compounds of formula I wherein R is straight or branched (C 1 -C 18) alkyl, (C 2 -C 18) alkene or (C 2 -C 18) alkyne, all optionally substituted with naphthalene, phthalimide , optionally substituted piperidine, imidazoline, 2-thienone, optionally substituted with coumarin, 2-dioxolane, hydantoin, thiohydantoin, 1,2,4-oxadiazoline, optionally substituted with isoxazolidine, tetrahydrofurfuryl, 1,4-benzodioxane or phenylsulfonyl, or glycoside.

• Φ · · · · φ · · · · · · · · · · ·

In another preferred embodiment, the present invention relates to compounds of formula (I) wherein R is C 3 -C 7 cycloalkyl optionally substituted with a cyano group. , carboxylic acid, hydroxyl, oxo, perhalomethyl, halogen, phenyl, (C 1 -C 6) alkoxy, (C 1 -C 6) alkoxy, carbonyl, benzyloxycarbonyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl carbon or NR ₁ R ₂ in which one of R 1 and R ₂ or both is hydrogen, alkyl of 1 to 6 carbon atoms or benzyl.

The present invention also relates to the use of the novel compounds of formula I as described herein for the manufacture of a medicament, in particular for the manufacture of a medicament for the treatment and / or prevention of hyperglycemia or diabetes mellitus, preferably NIDDM. The compounds of the present invention reduce elevated plasma glucose levels and are thus useful in the treatment and prevention of various diseases of the endocrinological system, particularly those related to carbohydrate metabolism and especially glucose metabolism, e.g. hyperglycemia, diabetes mellitus and especially non-insulin dependent diabetes mellitus ( NIDDM) including long-term complications such as retinopathy, neuropathy, nephropathy and micro- and macro-angiopathy. In addition, the present compounds are useful for the prophylactic treatment of hyperlipidemia, hypertension, liver and gallbladder disease, and atherosclerosis associated with diabetes. The present compounds are particularly useful in the treatment of diseases related to the liver enzyme glycogen phosphorylase activity due to their ability to inhibit said enzymatic activity.

Thus, in another aspect, the present invention relates to a compound of formula I, pharmaceutically acceptable acid addition salts, hydrates or prodrugs thereof for use as a therapeutically active agent, preferably for use as a therapeutically active agent for treating or preventing diseases of the endocrinological system, preferably hyperglycemia. or diabetes.

· · · · · · · · · · · ·

Furthermore, the invention also relates to the use of the compounds of formula I according to the invention for the manufacture of medicaments useful for the treatment or prevention of hyperglycemia or diabetes.

The invention also relates to a method of treating or preventing diseases of the endocrinological system, preferably diabetes, in a subject in need thereof, comprising administering an effective amount of a compound of the invention.

The compounds of the invention may be prepared by a variety of synthetic routes, including the methods described below:

a) reacting a compound of formula II

(II), with NH ₂ R, where R is as defined above, to give a compound of formula III

OH

Where R is as described above, followed by debenzylation of a compound of formula III by catalytic reduction to form a compound of general formula R (III), where R is as defined above. of formula I, or

b) reacting a compound of formula III wherein R is hydrogen with RX, wherein R is as defined above and X is a leaving group, e.g., a halogen atom, followed by debenzylation by catalytic reduction to form a compound of formula I, or

c) reacting a compound of formula III wherein R is hydrogen with RCHO where R is as described above in the presence of a reducing agent such as sodium cyanoborohydride followed by debenzylation by catalytic reduction to form a compound of formula I, or

d) reaction of a compound of formula IV '0'

-R '(IV),' N '

AND

R wherein R is hydrogen and R 'is hydrogen or C 1 -C 4 alkyl, with a sodium or lithium salt forming agent of a compound of Formula IV, followed by quenching with acid to form a compound of Formula V

O

JL R '(V), using methods described in the literature (e.g., Aust. J. Chem. 1983, 36, 601-608). ); an example of a salt-forming agent is LDA, and examples of reagents that stop the reaction are hydrochloric acid and ammonium chloride,

e) reacting a compound of formula V with a reducing agent such as lithium aluminum hydride, borane or similar hydrides to form a compound of formula VI

and

R (VI) wherein R is as described above,

f) reacting a compound of formula VI with agents such as tert-butyl peroxide, trifluoroperacetic acid, m-chloroperbenzoic acid, hydrogen peroxide or the like, so as to introduce the epoxide function to give a compound of formula VII-I

(VII) wherein R is as defined above; this reaction can be performed with an unprotected hydroxymethyl group using the Sharpless epoxidation technique using titanium compounds and tartrates to enhance stereoselectivity (e.g., J. Org. Chem. 1984, 49, 3707-3711), or with a hydroxyl group protected by known compounds. 44 • »4 • ·» 4

4 4

4 * 4 4 4

44 44 44

444 4 · · ·

4 4 4 * 4 4 44 44 * * 44 * 4 4 4 4

444 hydroxyl protecting groups (Green and Wuts: Protective Groups in Organic Synthesis, Wiley & Sons, Inc., 1990.); preferably, this reaction may be carried out with a salt (eg, trifluoroacetate) of a compound of formula VI to prevent N-oxide formation (eg, Monatsch. Chemie 1986, 117, 859-865), and

g) reacting a compound of formula VII with an agent which causes the opening of an epoxide ring, e.g., potassium hydroxide, to form a compound of formula I wherein R is as described above, or

h) reacting a compound of formula IV wherein R is alkyl and R 'is hydrogen or C 1 -C 4 alkyl with a dealkylating agent such as 1-chloroethyl chloroformate, 3,3,3-trichloroethyl chloroformate , chloroformic acid phenyl ester, or the like, such that N-dealkylation occurs to give the compound of formula VIII

wherein R 'is as defined above (J. Org. Chem. 1984, 49, 2081-2082; Aust. J. Chem. 1983, 36, 601-608),

i) reacting a compound of formula VIII with an N-protecting agent using methods known in the art (Greene and Wuts: Protective Groups in Organic Chemistry ¹ , Wiley and Sons, Inc. 1990.) to give a compound of formula IX; · ·· ♦ · Β · · · · · · · ·

ΒΒΒ ΒΒΒ ΒΒΒ · · · · · · · · · · · ·

ΒΒΒ «Β β * · α • * Β Β • Β Β · ΒΒΒ ΒΒΒ

wherein Pg is an easily removable N-protecting group and R 'is as defined above; examples of readily removable N-protecting groups are the Boc group or the CBZ group, and

j) reacting a compound of formula IX using reaction sequences

d) -e) -f) -g) with subsequent deprotection of the N-atom resulting in a compound of formula I wherein R is hydrogen, or

k) reacting a compound of formula X

ir ₆ wherein R ₆ may be the aforementioned R or the aforementioned protecting group Pg, with a compound capable of protecting a hydroxymethyl group such as acetyl chloride or similar acylating agents, to form a compound of formula XI

(XI), ι <• <<

• · · · · · ·

wherein R ₆ is as above and R ₆ is as defined above. represents an acyl radical such as acetyl, alkyl (C 2 -C 18) carbonyl, menthyloxyacetyl, camphanoyl, α-methoxy-α- (trifluoromethyl) phenylacetyl or the like, either as separate enantiomers or as racemic mixtures; the acylating agent may preferably be an optically active carboxylic acid derivative such as R - (+) - α-methoxy-α- (trifluoromethyl) phenylacetic acid, (-) - menthyloxyacetic acid, (-O-camphanoic acid, or optical antipodes thereof) acids, and

l) reacting a compound of formula XI using reaction sequence f) -g) followed by deprotection at nitrogen and oxygen to form a compound of formula I wherein R is either as above or a hydrogen atom, or

m) reacting a compound of formula I wherein R is hydrogen with a compound of formula XII

OH

AND

R (XII) (I) wherein Su is a substrate and L is a linker to form a compound of formula XIII

O

The OH substrate may be any insoluble or partially insoluble material to which the compounds can be covalently attached; the substrates may be selected from the group consisting of any kind of organic or inorganic polymer or oligomeric compound. Preferably, the substrate may be selected from the group consisting of polystyrene, polyethylene glycol (PEG), polyethylene glycol attached to polystyrene, polyacrylamides, polyamides, polysaccharides, and silicates; different types of solvents or protecting groups may be used depending on the type of substrate selected;

linker L is a molecule with at least two reaction sites that allow covalent attachment to other molecules or substrate; the ether linkage of the linker to the substrate or the linker to other molecules attached thereto, or the linker itself, must be cleavable by selective exposure to an activator, such as a selected chemical activator, or under other specific conditions such as strong acid or electromagnetic radiation or metal catalysis;

n) reacting a compound of formula XIV wherein Su and L are as defined above for RX, wherein R is as defined above and X is a leaving group, e.g., a halogen atom, to form a compound of formula XV

o) reacting a compound of formula XV wherein R, Su and L are as defined above with a resolving agent, e.g., a strong base, to form a compound of formula I wherein R is as defined above.

The starting materials used in the synthesis of the compounds of the formulas II and IV are either known or can be prepared in a conventional manner from commercially available materials, for example according to the methods described in the examples.

• · · · · · · · · · ·

The compounds of the invention have one or more asymmetric centers. It is to be understood that stereoisomers (optical isomers) as separated, pure or partially purified stereoisomers or racemic mixtures thereof are included within the scope of the invention.

Preferred compounds of the 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-piperidinediol, (3R, 4R, 5R) -1- (2-hydroxyethyl) -5-hydroxymethyl-3,4-piperidinediol, (3R, 4R, 5R) 4R, 5R) -5-hydroxymethyl-1- (4- (5-hydantoyl) butyl) -3,4-piperidinediol, (3R, 4R, 5R) -5-hydroxymethyl-1- (3-phenylpropyl) -3, 4-piperidinediol, (3R, 4R, 5R) -5-hydroxymethyl-1-methyl-3,4-piperidinediol, (3R, 4R, 5R) -5-hydroxymethyl-1-methoxy-3,4-piperidinediol, (3R) (4R, 5R) -5-hydroxymethyl-1- (4-N, N-diphenylaminobenzyl) -3,4-piperidinediol, (3R, 4R, 5R) -1-acetyl-5-hydroxymethyl-3,4-piperidinediol, (3R, 4R, 5R) -5-hydroxymethyl-1- (3-phenylallyl) -3,4-piperidinediol, (3R, 4R, 5R) -1-allyl-5-hydroxymethyl-3,4-piperidinediol, (3R) (4R, 5R) -1-benzyl-5-hydroxymethyl-3,4-piperidinediol, (3R, 4R, 5R) -1-octyl-5-hydroxymethyl-3,4-piperidinediol, (3R, 4R, 5R) - 2- (3,4-Dihydroxy-5-hydroxymethyl-piperidin-1-yl) -acetamide, (3R, 4R, 5R) (3,4-Dihydroxy-5-hydroxymethyl-piperidin-1-yl) -acetic acid ethyl ester elines, (3R, 4R, 5R) -5-hydroxymethyl-1- (4-trifluoromethyl-benzyl) -3,4-piperidinediol, (3R, 4R, 5R) -1- (2- (4'-fluoroacetophenone)) -5-hydroxymethyl-3,4-piperidinediol, (3R, 4R, 5R) -5-hydroxymethyl-1- (2- (4'-methoxyacetophenone)) - 3,4-piperidinediol, (3R, 4R, 5R) - (2- (4-fluorophenoxy) ethyl) -5-hydroxymethyl-3,4-piperidinediol, (3R, 4R, 5R) -5-hydroxymethyl-1- (4-phenoxybutyl) -3,4-piperidinediol, (3R, 4R, 5R) -1- (4-cyanobutyl) -5-hydroxymethyl-3,4-piperidinediol, (3R, 4R, 5R) -1 (10-decylphthalimido) -5-hydroxymethyl-3,4-piperidinediol (3R, 4R, 5R) -12- (3,4-dihydroxy-5-hydroxymethyl-piperidin-1-yl) - <-lenecanoic acid, ( 3R, 4R, 5R) -5-Hydroxymethyl-1-phenoxyethyl-3,4-piperidinediol, (3R, 4R, 5R) -3- (3,4-dihydroxy-5-hydroxymethyl-piperidin-1-yl) propionic acid and (3R, 4R, 5R) -1- (6-deoxy-1-O-methyl-6-α-D-glucopyranosyl) -5-hydroxymethyl-3,4-piperidinediol or a pharmaceutically acceptable salt, hydrate or prodrug thereof, as or any optical isomer or optical mixture thereof h isomers, including a racemic mixture, or any tautomeric form.

Other compounds of the general formula can be prepared by the above strategy

I. Various functional groups can be introduced into the compounds prepared as described above by methods well known in the art.

Pharmaceutical Compositions: This invention further provides pharmaceutical compositions comprising at least one compound of Formula I, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. These compositions may exist in the form of powders, solutions or suspensions, which may or may not be divided into unit dosage forms or capsules or tablets. Liquid formulations include sterile solutions, suspensions, and emulsions suitable for parenteral administration.

The pharmaceutical compositions of this invention may contain carriers, diluents, absorption enhancers, tablet disintegrating agents, and other additives conventionally used in the art. The powders and tablets preferably contain from 5 to 99, more preferably from 10 to 90 wt. active ingredient. Examples of solid carriers are magnesium carbonate, magnesium stearate, cyclodextrin, dextrin, lactose, sugar, talc, gelatin, pectin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting waxes, and cocoa butter.

· ♦ · ···

The route of administration of the compositions comprising a compound of Formula I may be any route that efficiently transports the active compound to the site of action, preferably the oral or nasal route.

If a solid carrier is used for oral administration, the preparation may be tableted, powdered in hard gelatin capsules, or may be in the form of pellets, it may also be in the form of sachets or lozenges. When a liquid carrier is used, the preparation may exist in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid, such as an aqueous or non-aqueous liquid suspension or solution. For oral administration, tablets, coated tablets or capsules having a talc and / or a sugar as carrier or binding agent or the like are particularly suitable. Preferred carriers for tablets, dragees and capsules include lactose, corn starch and / or potato starch.

Injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil, are particularly suitable for parenteral administration.

A typical tablet, which can be produced by conventional tabletting methods, may comprise:

• ·················································

core: active compound (as free or as salt) 50 mg colloidal silicon dioxide (Aerosil) 1.5 mg Microcrystalline cellulose (Avicel) 70 mg modified cellulose gum (Ac-Di-Sol) 7,5 mg magnesium stearate ad. cover: HPMC approx. 9 mg * Mywacett 9-40 T approx. 0,9 mg

* Acylated monoglyceride used as a film softening agent.

The compounds of the invention may be administered to a mammal, particularly a human, in need of such treatment, prevention, removal, amelioration, or amelioration of the various diseases mentioned above, and in particular of diabetes. These mammals also include animals, both domestic animals such as pets and non-domestic animals such as wild animals.

The regimen for any patient to be treated with the compositions of the present invention should be determined by the skilled artisan. The daily dose to be administered during treatment may be determined by the physician and will depend on the particular compound employed, the route of administration, and the age and condition of the patient. A suitable daily dose may be less than 1 g, preferably in the range of 10 to 200 mg.

Experimental procedure and results: In vivo studies, female ob / ob mice (20 g) were used and fastened for 3 hours. Test compounds or NaCl (0.9% (w / w) control) were administered by intarvenose (hereinafter i.v.). Blood samples were collected from the orbital vein and analyzed for glucose by glucose oxidation.

• · • · · • · • · • • · • • · · • • · • · • · ··· • • • · • • • · • · · • · • ·

Rat hepatocytes were isolated using a standard two-step collagenase technique and cultured on collagen-coated culture dishes for 72 hours in medium 199 with the addition of dexamethasone (0.1 mM), penicillin / streptomycin ((100 µl / 100 mg) / ml) and insulin (1). nM). During the last 24 hours, hepatocytes were cultured in the presence of high amounts of insulin (5 nM) and glucose (15 nM), resulting in the incorporation of glucose into glycogen. Therefore, at the time of the experiment, these cells mimicked the liver of the fed animals.

The experiments were started after 48 hours of culture by washing the cells twice and adding 20 mM HEPES experimental buffer containing a salt balance but without glucose. The test compound was added simultaneously with the experimental buffer. Glucagon (0.5 nM) was added to the same culture after 10 minutes to stimulate glucose production from liver cells. Glucose released into the medium, which represented glucose production by liver cells, was measured 70 minutes after the start of the experiment and standardized for cellular DNA content.

Phosphorylase was either obtained from Sigma or was extracted from rat liver by Stalmans et al. (Eur. J. Biochem. 1974,49,415). Phosphorylase activity was determined by Bergmeyer (Meth. Of Enzymatic Analysis 1983, 2, 293-295, Weinheim (ed.), Verlag Chemie).

The compounds of the invention demonstrate their efficacy by reducing glucagon-mediated increases in plasma glucose.

The present invention is further illustrated by the following examples, which are not to be construed as limiting the scope of protection. The features described in the foregoing description and in the following examples, both separately and in any combination thereof, may be a material for implementing the invention in its various forms.

• ·

(3R, 4R, 5R) -3-Benzyloxy-1-butyl-5-hydroxymethyl-4-piperidinol (3R, 4R, 5R) -3-Benzyloxy-5-hydroxymethyl-4-piperidinol (87mg, 0) , 37 mmol), 1-iodobutane (81 mg, 0.44 mmol, 50 microl), potassium carbonate (154 mg, 1.1 mmol) and dry acetone (8 mL) were stirred at 40 ° C for 24 h under nitrogen atmosphere. . The solvent was evaporated in vacuo and the residue was purified on a silica gel column (eluted with ethyl acetate / methanol / 25% w / w) ammonium hydroxide (6: 1: 1%) to give the free base, (3R, 4R, 5R) - 3-benzyloxy-1-butyl-5-hydroxymethyl-4-piperidinol (yield 72 mg, 67%) ¹ H-NMR spectrum (CD ₃ OD, ppm, δ): 7.4-7.2 (m, 5H) 4.70 (dd, 2H), 3.80 (dd, 1H), 3.54 (m, 1H), 3.34 (m, 1H), 3.25 (d, 1H), 3.08 (m, 2H), 2.38 (t, 2H), 1.85 (dd, 2H), 1.70 (m, 1H), 1.45 (m, 2H), 1.31 (m, 2H) 0.93 (t, 3H).

The following compounds were produced in a similar manner:

(3R, 4R, 5R) -3-Benzyloxy-1-dodecyl-5-hydroxymethylpiperidin-4-ol from (3R, 4R, 5R) -3-benzyloxy-5-hydroxymethyl-4-piperidinol and iododecane. ¹ H-NMR spectrum (CD ₃ OD, ppm, δ): 7.4-7.2 (m, 5H), 4.70 (dd, 2H), 3.80 (dd, 1H), 3.54 ( m, 1H), 3.34 (m, 1H), 3.25 (d, 1H), 3.08 (m, 2H), 2.38 (t, 2H), 1.89 (dd, 2H), 1.78 (m, 1H), 1.5 (m, 2H), 1.3 (m, 18H), 0.9 (t, 3H), (3R, 4R, 5R) -3-benzyloxy-1- (2-hydroxyethyl) -5-hydroxymethyl-4-piperidinol from (3R, 4R, 5R) -3-benzyloxy-5-hydroxymethyl-4-piperidinol and 2-bromoethanol with catalytic amounts of potassium iodide. ¹ H-NMR spectrum (CD ₃ OD + 10% d ₆ -benzene, ppm, δ): 7.5-7.2 (m, 5H), 4.9 (s, 3H), 4.7 (dd, 2H); 3.87 (dd, 1H);

3.1 (m, 5H), 2.7 (t, 2H), 2.2 (d, H), 1.9 (m, 1H). ¹³ C-NMR (CD ₃ OD, ppm, δ):

43.61, 55.18, 55.93, 58.25, 59.68, 61.19, 63.33, 72.75, 73.20, 79.29, 127.76, 128.10,

128,39,138,99. FAB-MS: m / e 281 (M ^& lt ^{; +} & gt ^; );

(3R, 4R, 5R) -5-Benzyloxymethyl-1- (4- (5-hydantoyl) butyl) -3,4-piperidinediol from (3R, 4R, 5R) -3-benzyloxy-5-hydroxymethyl-4-piperidinol and 5- (4-chlorobutyl) hydantoin with catalytic amounts of potassium iodide. ¹ H-NMR spectrum (CD ₃ OD, ppm, δ):

7.4-7.2 (m, 5H), 4.70 (d, 2H), 4.1 (m, 1H), 3.8 (dd, 1H), 3.6-3.0 (m, 6H), 2.4 (m, 2H), 1.3 to 0.9 (m, 8H).

(3R, 4R, 5R) -3-Benzyloxy-5-hydroxymethyl-1- (3-phenyl-propyl) -4-piperidinol from (3R, 4R, 5R) -3-Benzyloxy-5-hydroxymethyl-4-piperidinol 3 -bromo-1-phenylpropane with catalytic amounts of potassium iodide. ¹ H-NMR spectrum (CD ₃ OD, ppm, δ): 7.4-

7.1 (m, 10H), 4.70 (dd, 2H), 3.80 (dd, 1H), 3.50 (m, 1H), 3.40 (m, 1H), 3.25 (t 1H, 3.01 (m, 2H), 2.53 (t, 2H), 2.33 (m, 2H), 1.75 (m, 5H).

Example 2 (3R, 4R, 5R) -3-Benzyloxy-1- (3- (cyclohexyl) propyl) -5-hydroxymethyl-4-piperidinol (3R, 4R, 5R) -3-Benzyloxy-5-hydroxymethyl-4- Piperidinol (0.397 g, 1.7 mmol) was dissolved in dry methanol (5 mL). Excess gaseous (2N) HCl in methanol was added. Evaporation to dryness in vacuo gave the hydrochloride salt. This salt was dissolved in dry methanol (20 mL) and sodium cyanoborohydride (0.126 g, 2.0 mmol) was added. HCl gas in methanol (2N) was added dropwise to bring the pH of mixture 6 (two drops). Cyclohexylpropionaldehyde (0.306 mL, 0.281 g, 2.0 mmol) was added and the mixture was stirred under nitrogen at room temperature for 18 hours. HCl gas in methanol (2N) was added several times to maintain the pH of the solution at 6. Concentration in vacuo and purification of this residue on a silica gel column (elution: ethyl acetate / methanol / 25% (w / w) ammonium hydroxide (6: 1) : 1%)) afforded (3R, 4R, 5R) -3-benzyloxy-1- (3- (cyclohexyl) propyl) -5-hydroxymethyl-4-piperidinol (yield 0.58 g, 96% wt). ¹ H-NMR spectrum (CDCl ₃ , ppm, δ): 7.4-7.2 (m, 5H), 4.62 (dd, 2H), 3.68 (m, 3H), 3.52-3 35 (m, 2H), 3.16 (m, 1H), 2.82 (m, 1H), 2.32 (t, 2H), 1.90 (m, 1H), 1.87-1. 59 (m, 5H), 1.44 (m, 2H), 1.15 (m, 7H), 0.88 (m, 2H).

Example 3 (3R, 4R, 5R) -1-Benzyl-3-benzyloxy-5-hydroxymethyl-4-piperidinol

4-O-Benzyl-2-deoxy-2-C-hydroxymethyl-D-glucopyranose (6.0 g, 21.1 mmol) (see preparation WO 95/24 391) was dissolved in methanol (200 mL). Sodium periodate (21.4 g, 100 mmol) in water (200 mL) was added dropwise over 15 minutes. The mixture was stirred at 45-47 ° C for 3.5 hours. The precipitate was filtered off, the mixture was concentrated and purified by flash chromatography on silica gel, eluting with ethyl acetate. The purified product 4-O-benzyl-2-deoxy-2-C-hydroxymethyl-D-xylo-pentodialdose was dissolved in methanol (50 mL) and benzylamine (4.36 g, 40.7 mmol) and sodium cyanoborohydride were added. (1.0 g, 15.9 mmol). The mixture was stirred at room temperature for 3 days. Subsequently, the mixture was acidified to pH 2 with concentrated hydrochloric acid and evaporated to dryness. The residue was dissolved in water (50 mL), adjusted to pH 10 by addition of aqueous sodium hydroxide, and extracted with methylene chloride. The organic phase is dried over magnesium sulphate, evaporated and purified on silica gel, eluting with ethyl acetate. There was thus obtained (3R, 4R, 5R) -1-benzyl-3-benzyloxy-5-hydroxymethyl-4-piperidinol as an oil (yield: 25% by weight). ¹ H-NMR spectrum (CDCl 3, ppm, δ): 7.3-7.1 (m, 10H), 4.8 (s, 2H), 4.55 (dd, 1H), 3.7 (dd, 1H), 3.5 to 2.8 (m, 7H), 1.6 to 1.85 (m, 3H). ¹³ C-NMR (CDCl 3, ppm, δ): 44.07, 55.02, 55.92, 61.65, 62.46, 72.43, 74.05, 80.20, 127.14, 127 , 33, 127.549, 128.54, 128.22, 128.27, 129.42, 137.48, 139.01, 172.84.

The following compounds were prepared in a similar manner:

(3R, 4R, 5R) -3-Benzyloxy-5-hydroxymethyl-1-methyl-4-piperidinol from 4-O-benzyl-2-deoxy-2-C-hydroxymethyl-D-xypyropentodialdose, prepared as described above (2.78 g), methylamine hydrochloride (1.16 g) and sodium cyanoborohydride (0.62 g) in methanol (50 mL). ¹ H-NMR spectrum (CDCl ₃ , ppm, δ): 7.4-7.2 (m, 5H), 4.6 (dd, 2H),

3.8-3.2 (m, 6H), 3.1 (m, 1H), 2.75 (m, 1H), 2.3 (s, 1H), 1.9 (m, 1H), 1 Δ (d, 2H).

• 4

9 4 9

494,999 • ·

¹³ C-NMR (CDCl ₃ , ppm, δ): 42.07, 44.97, 55.59, 56.75, 63.11, 71.27, 75.06, 79 , 12.126.94, 127.01, 127.65,137.38.

(3R, 4R, 5R) -3-Benzyloxy-5-hydroxymethyl-1-methoxy-4-piperidinol from 4-O-benzyl-2-deoxy-2-C-hydroxymethyl-D-xylo-pentodialdose, prepared as described above (0.8

g), methoxyamine hydrochloride (0.54 g) and sodium cyanoborohydride (0.18 g) in methanol (50 mL). Mass spectrum (SP): m / e 267 (M ^& lt ^{; +} & gt ^; ).

Example 4 (3R, 4R, 5R) -1-Butyl-5-hydroxymethyl-3,4-piperidinediol (compound 1) (3R, 4R, 5R) -3-Benzyloxy-1- (butyl) -5-hydroxymethyl-4 -piperidinol (105 mg, 0.4 mmol) was dissolved in ethanol (20 mL) containing aqueous hydrochloric acid (4N, 0.3 mL). Add palladium on carbon (10% w / w, 30 mg). The mixture was hydrogenated at 50 psi hydrogen for 3 hours. Filter through celite and concentrate in vacuo. Purification on a silica gel column (eluting with ethyl acetate / methanol / 25% (w / w) ammonium hydroxide (4: 1: 1%)) gave the free base, (3R, 4R, 5R) -1-butyl-5-hydroxymethyl-3, 4-piperidinediol (yield 53 mg, 74%) as a semi-crystalline compound. Mp 94-95 ° C, mass spectrum (SP): m / e 203 (M ⁺ ), ¹ H-NMR spectrum (CD ₃ OD, ppm, δ): 3.80 (dd, 1H), 3.51 (m, 2H), 3.06 (m, 3H), 2.43 (dd, 2H), 1.91 (dt, 2H), 1.75 (m, 1H), 1.53 (m, 2H) 1.33 (m, 2H); 0.92 (t, 3H).

The following compounds were produced in a similar manner:

(3R, 4R, 5R) -1- (3-Cyclohexyl) propyl-3,4-dihydroxy-5-hydroxymethylpiperidine (compound 2) from (3R, 4R, 5R) -3-benzyloxy-1- (3-cyclohexyl) propyl-5-hydroxymethylpiperidin-4-ol. M.p. 107-108 ° C, mass spectrum (FAB): m / z 272 (M + 1), ¹ H-NMR spectrum (CD ₃ OD, ppm, δ): 3.80 (dd, 1H), 50 (m, 2H), 3.06 (m, 3H), 2.37 (m, 2H), 1.88-1.58 (m, 8H), 1.52 (m, 2H), 1.2 (m, 6H), 0.90 (m, 2H).

9 9

9? (3R, 4R, 5R) -1-Dodecyl-5-hydroxymethyl-3,4-piperidinediol (compound 3) of (3R, 4R, 5R) -3-benzyloxy-1-dodecyl-5-hydroxymethyl-4- piperidinol. Mp 59-60 ° C, mass spectrum (SP): m / e 315 (M ⁺ ), ¹ H-NMR spectrum (CD ₃ OD, ppm, δ):

3.80 (dd, 1 H), 3.51 (m, 2 H), 3.06 (m, 3 H), 2.40 (dd, 2 H), 1.91 (dt, 2 H), 1.75 (m) 1 H, 1.53 (m, 2H), 1.3 (m, 20H), 0.9 (t, 3H).

(3R, 4R, 5R) -1- (2-Hydroxyethyl) -5-hydroxymethyl-3,4-piperidinediol (compound 4) from (3R, 4R, 5R) -3-benzyloxy-1- (2-hydroxyethyl) - Of 5-hydroxymethyl-4-piperidinol. Mass spectrum (SP): m / e 191 (M ^& lt ^{; +} & gt ^; ).

(3R, 4R, 5R) -5-Hydroxymethyl-1- (4- (5-hydantoyl) butyl) -3,4-piperidinediol (compound 5) from (3R, 4R, 5R) -5-benzyloxymethyl-1 - ( 4- (5-hydantoyl) butyl) -3,4-piperidinediol. ¹ H-NMR spectrum (CD ₃ OD, ppm, δ): 4.1 (m, 1H), 3.8 (dd, 1H), 3.6 to 3.1 (m, 6H), 2.55 ( m, 2H)

2.1 to 1.4 (m, 8H).

(3R, 4R, 5R) -5-Hydroxymethyl-1- (3-phenylpropyl) -3,4-piperidinediol (compound 6) from (3R, 4R, 5R) -3-benzyloxy-5-hydroxymethyl-1- (3 (phenylpropyl) -4-piperidinol. ¹ H-NMR spectrum (CD ₃ OD, ppm, δ): 7.2 (m, 5H), 3.80 (dd, 1H), 3.50 (m, 2H), 3.06 (m, 3H) 2.62 (t, 2H), 2.40 (m, 2H), 1.92-1.70 (m, 3H), 1.23 (m, 2H).

(3R, 4R, 5R) -5-Hydroxymethyl-1-methyl-3,4-piperidinediol (compound 7) from (3R, 4R, 5R) -3-benzyloxy-5-hydroxymethyl-1-methyl-4-piperidinol. The crude product was purified on silica gel (eluting with a mixture of ethanol with 25% ammonium hydroxide). Yield 21%. to give (3R, 4R, 5R) -5-hydroxymethyl-1-methyl-3,4-piperidinediol hydrochloride as a hard oil. Mass spectrum (EI): m / e (relative intensities in%): 161 (20) (M +), 144 (31), 126 (13), 100 (16), 70 (16), 58 (16), 44 (100).

(3R, 4R, 5R) -5-Hydroxymethyl-1-methoxy-3,4-piperidinediol (compound 8) from (3R, 4R, 5R) -3-benzyloxy-5-hydroxymethyl-1-methoxy-4-piperidinol. Mass spectrum (SP): m / e 177 (M ^& lt ^{; +} & gt ^; ).

Ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft

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) is mixed with 4-N, N-diphenylaminobenzaldehyde (0.2 g, 0.7 mmol) and sodium cyanoborohydride (0.04 g, 0.6 mmol) in methanol (5 mL). The mixture was stirred at room temperature for 100 hours, acidified to pH 2 with concentrated hydrochloric acid and evaporated to dryness. The residue was dissolved in water, adjusted to pH 10 with aqueous sodium hydroxide, and extracted with methylene chloride. The organic phase is dried over magnesium sulphate and evaporated in vacuo. Purification of the complex mixture on silica gel, eluting with methanol, afforded (3R, 4R, 5R) -5-hydroxymethyl-1- (4-N, N-diphenylaminobenzyl) -3,4-piperidinediol as an oil (1% yield). ¹ H-NMR spectrum (CD 3 OD, ppm, δ): 6.9-7.3 (m, 14H), 3.8 (dd, 1H), 3.5 (m, 4H), 2.9-3, 15 (m, 3H), 1.8 (m, 3H). ¹³ C-NMR (CD 3 OD, ppm, δ): 55.38, 58.34, 61.72, 62.01, 72.22, 123.01, 123.73, 124.32, 129.35, 130.69, 131.59.

Example 6 (3R, 4R, 5R) -1-Acetyl-5-hydroxymethyl-3,4-piperidinediol (compound 10) (3R, 4R, 5R) -3-Benzyloxy-5-hydroxymethyl-4-piperidinol (0.1 g, 0.4 mmol) was dissolved in pyridine (0.5 mL) at 0 ° C and acetic anhydride (0.5 mL) was added dropwise over 1 min. Stirring was continued for 20 hours. Evaporation to dryness gave a crude product which was purified on silica gel, eluting with ethanol (55% yield). The purified 3-benzyloxy-3-acetoxy-5-acetoxymethyl-1-acetylpiperidine (75 mg) was debenzylated in methanol at room temperature using 10% palladium on carbon catalyst. Filtration and evaporation to dryness yielded 50 mg of crude 4-acetoxy-5-acetoxymethyl-1-acetyl-3-piperidinediol, which was dissolved in dry methanol (4 ml) containing 50 μl! 1% (w / w) sodium methoxide in methanol. Mon 4 ·· • · 0

0 • 0 • 0 0 0 00 00

0 · 0 0 0 0 • · 00 ······

0 0 · 0

After stirring at room temperature for 0 days, the solution is evaporated to dryness. There was thus obtained (3R, 4R, 5R) -1-acetyl-5-hydroxymethyl-3,4-piperidinediol (yield 35 mg). ¹ H-NMR spectrum (CD ₃ OD, ppm, δ): 1.6 (m, 1H, H-5), 2.1 (s, 3H, O-Me), 2.4-2.7 (m 1H, H-6ax), 2.8-3.1 (m, 1H, H-4), 3.2-3.4 (m, 2H, H-2), 3.5-3.7 ( m, 1H, H-5 &apos;)

4.1 (m, 2H, H-5 ' and H-3), 4.4-4.6 (m, 1H, [beta] -6-beta). ¹³ C-NMR (CD ₃ OD, ppm

δ): 24.11, 24.16, 47.01, 48.17, 49.17, 50.14, 51.54, 51.78, 51.98, 54.81, 64.75, 64.84 , 75.28, 75.88, 78.14, 78.36.

Example 7

1-Methyl-1,2,3,6-tetrahydropyridine-3-carboxylic acid methyl ester

A solution of arecoline (15.5 g, 0.1 mol) in tetrahydrofuran (200 mL) was added to a solution of diisopropylamine (18.1 g, 0.18 mol) in tetrahydrofuran (150 mL) and 1.5 M butyllithium in hexane (108 mL). ml, 0.16 mol) according to the procedure described in Aust. J. Chem. 1983, 36, 601-608. The reaction mixture was stirred at -10 ° C for 20 minutes, cooled to -60 ° C, and poured into a solution of 10% (w / w) aqueous hydrochloric acid (185 mL). Work-up according to the literature yields 14 g of crude product which is purified by distillation under vacuum (to 85 ° C / 13 Pa). There was thus obtained 1-methyl-1,2,3,6-tetrahydropyridine-3-carboxylic acid methyl ester (yield 6.8 g). ¹³ C-NMR (CDCl 3, ppm, δ): 42.35, 46.07, 52.30, 54.48, 122.86, 127.78, 173.2.

Example 8 (1-Methyl-1,2,3,6-tetrahydro-3-pyridyl) methanol

A solution of 1-methyl-1,2,3,6-tetrahydropyridine-3-carboxylic acid methyl ester (88 g, 0.56 mol) in dry diethyl ether (250 mL) was slowly added to a suspension of lithium aluminum hydride (23 g, 0.6 mole) in diethyl ether (500 mL). The mixture was refluxed for 30 minutes. Water (100 mL) and potassium carbonate (100 g, 0.72 mmol) were carefully added, the mixture was filtered and evaporated to dryness in vacuo. Odparek se ««

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Β Β Β

ΒΒΒ Β

Β «distilled under vacuum. One pure fraction of (1-methyl-1,2,3,6-tetrahydro-3-pyridyl) methanol was obtained (yield 15 g) (bp 38-40 ° C / 27 Pa). Two further fractions were combined (total yield 53.8 g) for later redistillation (bp 40-60 ° C / 27 Pa). ¹³ C-NMR (CDCl 3, ppm, δ): 36.59, 45.09, 53.92, 56.46, 66.10, 125.43, 126.86. ¹ H-NMR spectrum (CDCl 3, ppm, δ): 2.3 (s, 3H), 2.3 (d, 1H), 2.5 (dd, 1H), 2.7 (m, 1H), 2 Δ (dd, 1H), 3.15 (dd, 1H), 3.7 (m, 1H), 3.8 (dd, 1H), 5.7 (m, 1H), 5.9 (m, 1H).

Example 9

1-Benzyloxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester

Arecoline (39.5 g, 0.25 mol) was dissolved in dry toluene (20 mL). Slowly at 0-5 ° C was added 1-chloroethyl chloroformate (30.5 mL). The mixture was heated at 80 ° C for 2 hours. It is then cooled to room temperature, filtered and evaporated to dryness in vacuo. The residue was dissolved in methylene chloride (400 mL) and extracted with 10% aqueous sodium carbonate. The organic layer was dried over magnesium sulfate, filtered and evaporated to dryness. There was thus obtained 1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester (yield 30.5 g, 85%).

1,2,5,6-Tetrahydropyridine-3-carboxylic acid methyl ester (1.1 g, 7.8 mmol) was dissolved in methylene chloride (20 mL) and cooled to -15 ° C. Triethylamine (2.2 mL, 15.8 mmol) and a solution of benzyl chloroformate (1.2 mL, 8.4 mmol) in methylene chloride (10 mL) were added. The mixture was stirred at room temperature for 1.5 hours, then evaporated to dryness, the residue was dissolved in methylene chloride and extracted twice with water. The organic layer was separated, dried and evaporated to dryness in vacuo. There was thus obtained 1-benzyloxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester as an oil (yield 2.0 g, 92%). ¹ H-NMR spectrum (CDCl ₃ , ppm, δ): 7.35 (m, 5H), 7.08 (m, 1H), 5.15 (s, 2H), 4.17 (dd, 2H), 3.75 (s, 3H), 3.55 (t, 2H), 2.31 (m, 2H).

· · · · · · · Φ φ φ φ φ φ φ φ · · · · ·

Example 10 (1-Benzyloxycarbonyl-1,2,3,6-tetrahydro-3-pyridyl) methanol

1-Benzyloxycarbonyl-1,2,3,6-tetrahydropyridine-3-carboxylic acid methyl ester (1 g, 3.6 mmol) is isomerized and reduced by the methods described in Example 7 and

8. There was thus obtained (1-benzyloxycarbonyl-1,2,3,6-tetrahydro-3-pyridyl) methanol (yield 0.32 g, 36% by weight). ¹ H-NMR spectrum (CDCl ₃ , ppm, δ): 7.28 (m, 5H), 5.68 (m, 2H), 5.10 (s, 2H), 3.87 (m, 2H), 3.7-3.3 (m, 5H); 2.48 (m, 2H). ¹³ C-NMR (CDCl 3, ppm, δ): 156.56, 156.07, 137.04, 128.93, 128.46, 128.23, 126.96, 126.14, 125.60, 72 , 29, 70.87, 67.66, 63.52, 59.38, 44.13, 43.14, 42.67, 38.51.

They did

1-tert-Butoxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester

1,2,5,6-tetrahydropyriine-3-carboxylic acid methyl ester (20.44 g, 145 mmol) and triethylamine (25 mL, 180 mmol) were dissolved in methanol (250 mL). Di-tert-butyl dicarbonate (65.48 g, 300 mmol) was added at room temperature. The mixture was heated at 60 ° C for 30 minutes, evaporated to dryness and partitioned between water and ethyl acetate. The organic layer was isolated, dried over magnesium sulfate and evaporated to dryness in vacuo. Purification on silica gel (eluting with methylene chloride / methanol (19: 1)) gave 1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester as a yellow oil (yield 34.9 g, 99%) wt.). ¹³ C-NMR (CDCl ₃ , ppm, δ): 166.20, 155.14, 138.30, 128.5, 80.37, 52.07, 42.96, 28.81, 25.91. ¹ H-NMR spectrum (CDCl 3, ppm, δ): 7.08 (m, 1H), 4.10 (m, 2H), 3.75 (s, 3H), 3.48 (t, 2H), 2 32 (m, 2H), 1.48 (s, 9H).

• · • · · Φ · • · • • · • • · · • • · * · • · ·· · • • • · • • • • · • · · • · • ·

Example 12

1-tert-Butoxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid

A solution of potassium hydroxide (44 g, 0.79 mol) in water (450 mL) was added to a solution of 1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester (34.9 g, 145 mmol) in methanol (450 mL). The mixture was refluxed for 3 hours. Then it is evaporated to dryness in vacuo. The residue was acidified to pH 2.5 with hydrochloric acid (4M) and extracted with methylene chloride. The organic layer was dried over magnesium sulfate and evaporated to dryness in vacuo. There was thus obtained 1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid (yield 28.4 g, 86%), m.p. Mp 198-202 ° C, ¹³ C-NMR spectrum (DMSO-d 6, ppm, δ): 167.16, 154.77, 138.19, 129.29, 79.91.43.14, 28.92, 25.81.

Example 13

tert -Butoxycarbonyl-1,2,3,6-tetrahydropyridine-3-carboxylic acid

A solution of 1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid (6.5 g, 28.6 mmol) in dry tetrahydrofuran (150 mL) was added dropwise to a mixture of 2.5M butyllithium in hexane ( 25 mL, 62.5 mmol) and diisopropylamine (6.37 g, 63.1 mmol) in dry tetrahydrofuran (150 mL) at <-65 ° C. Stirring was continued at 10 ° C for 20 minutes. The mixture was poured into 1M aqueous HCl (100 mL) under ice-cooling. The resulting mixture was extracted several times with ethyl acetate (total 500 mL). The organic layer was dried over magnesium sulfate and evaporated to dryness in vacuo. There was thus obtained 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine-3-carboxylic acid (yield 6.3 g, 97% by weight). ¹ H-NMR spectrum (CDCl 3, ppm, δ): 5.8-6.0 (m, 2H), 3.8-4.0 (m, 3H), 3.5-3.7 (m, 1H) 3.2 to 3.3 (m, 1H), 1.48 (s, 9H). ¹³ C-NMR (CDCl 3, ppm, δ): 177.5, 155.24, 127.36 (m), 123.09.80.83, 43.43 (m), 42.39 (m), 41.21, 28.77.

• · it

Example 14

1-tert-Butoxycarbonyl-1,2,3,6-tetrahydropyridine-3-carboxylic acid methyl ester

1,1'-Carbonyldiimidazole (4 g, 24.7 mmol) in methylene chloride (100 mL) was added dropwise to a solution of 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine-3-carboxylic acid (5 g, 22 mmol) in methylene chloride (200 mL) under nitrogen. Stirring was continued for 1 hour, then methanol (300 ml) was added and the mixture was refluxed for 26 hours. 10% aqueous citric acid (100 ml) was added and the mixture was extracted with methylene chloride. The organic layer was dried over magnesium sulfate, evaporated to dryness in vacuo and purified on a silica gel column (eluting with methylene chloride / methanol (90: 1)). There was thus obtained 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine-3-carboxylic acid methyl ester as a yellow oil (yield 3.9 g, 73%). ¹³ C-NMR (CDCl 3, ppm, δ): 172.65, 155.04, 127.0 (m), 123.44 (m), 80.34, 52.47, 51.69, 41.38 , 28.80, 28.56. ¹ H-NMR spectrum (CDCl 3, ppm, δ): 5.8-6.0 (m, 2H), 3.7-4.1 (m, 3H), 3.7 (s, 3H), 3, 5-3.6 (m, 2H), 3.2-3.3 (m, 1H), 1.48 (s, 9H).

Example 15

tert -Butoxycarbonyl-1,2,3,6-tetrahydropyridyl-3-methanol

1-tert-methyl ester 1-1,2,3,6-tetrahydropyridine-3-carboxylic acid butoxycarbones (2.35 g, 9.8 mmol) were dissolved in dry diethyl ether (200 mL) under a hydrogen atmosphere. Lithium borohydride (0.6 g, 27.5 mmol) and 1.0 M lithium triethyl borohydride in tetrahydrofuran (3 g, 28.3 mmol) are added slowly. The resulting mixture was refluxed for 1 hour, poured into 1M sodium hydroxide (100 mL) and extracted with methylene chloride. The organic layer was dried over magnesium sulfate, evaporated to dryness in vacuo and purified on a silica gel column (eluting with methylene chloride / methanol (19: 1)). There was thus obtained 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridyl-3-methanol as a colorless oil (yield 1.28 g, 61% w / w).

· · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Mass spectrum (EI): m / e 213 (M ⁺ ). ¹ H-NMR spectrum (CDCl 3, ppm, δ): 5.71 (m, 2H), 3.95-4.1 (m, 1H), 3.7-3.9 (m, 1H), 2 to 3.7 (m, 3H), 2.35 to 2.45 (m, 1H), 2.12 (t, 1H), 1.8 to 1.9 (m, 1H), 1.48 ( s, 9H). ¹³ C-NMR (CDCl3, ppm, .delta.): 156.0 (m), 126.7 (m), 80.37, 63.5 (m), 44.6 (m), 42.7 (m) ), 38.57, 28.81.

Example 16 3 - (((1R, 2S, 5R) -2-Isopropyl-5-methyl-1-cyclohexyloxy) -acetoxymethyl-1,2,3,6-tetrahydropyridine-1-carboxylic acid butyl ester (-) - Menthoxyacetyl chloride (1,03) g, 4.4 mmol) was slowly added to a solution of 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridyl-3-methanol (0.59 g, 2.8 mmol) in methylene chloride (50 mL) under an atmosphere nitrogen. The mixture was refluxed for 4 hours, evaporated to dryness in vacuo and purified on a silica gel column (eluting with a 1:20 mixture of methyl-tert-butyl ether and methylene chloride). There was thus obtained a diastereomeric mixture of tert-butyl 3 - ((1R, 2S, 5R) -2-isopropyl-5-methyl-1-cyclohexyloxy) acetoxymethyl-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester as colorless oil (yield 0.54 g, 48%).

Smaller amounts of the two isomers were separated on a chiral column (chiracel, eluting with isopropanol / heptane 5:95) (Rt 9.6 min and 11.2 min). Mass spectrum: m / e 409 (M ^& lt ^{; +} & gt ^; ). ¹³ C-NMR (CDCl ₃ , ppm, δ): 171.18, 155.34, 127.7 (m), 127.1 (m), 125.3 (m), 80.67, 80.59 , 80.20, 66.29, 66.23, 65.33, 48.51, 43.4 (m), 42.9 (m), 40.35, 35.36, 34.81, 31.90 , 28.82, 25.87, 23.68, 22.69, 21.38, 16.68.

9 · 9 · 9 · 9 · 9 · 9 · 9 · 9

9 · · ·· · ·

Example 17 3 - (((1R, 2S, 5R) -2-Isopropyl-5-methyl-1-cyclohexyloxy) -acetoxymethyl-4,5-epoxypiperidine-1-carboxylic acid butyl ester

A solution of 3-chloroperbenzoic acid (0.9 g, 5.2 mmol), 3 - ((1R, 2S, 5R) -2-isopropyl-5-methyl-1-cyclohexyloxy) acetoxymethyl-1,2, tert-butyl ester, 3,6-tetrahydropyridine-1-carboxylic acid (0.5 g, 1.2 mmol) and methylene chloride (150 mL) were stirred at room temperature for 20 hours. An additional portion of 3-chloroperbenzoic acid (1.1 equivalents) was added and the mixture was refluxed for 2 h. The reaction mixture was extracted with 1M sodium hydroxide and water, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was purified on a silica gel column (5: 1 heptane / ethyl acetate). There was thus obtained 3 - ((1R, 2S, 5R) -2-isopropyl-5-methyl-1-cyclohexyloxy) -acetoxymethyl-4,5-epoxypiperidine-1-carboxylic acid tert-butyl ester as an oil (yield 0.34 g). 66%). ¹³ C-NMR (CDCl ₃ , ppm, δ): 177.16, 157.08, 82.71, 82.61, 68.28, 66.27, 65.78, 54.43, 53.9, 52.99, 52.35, 50.54, 44.5 (broad), 42.38, 41.22, 36.82, 33.92, 32.13, 30.77, 27.93, 25.72 , 25.1, 23.4, 18.72.

The following compounds were prepared in a similar manner:

B. 3-hydroxymethyl-4,5-epoxypiperidin-1-carboxylic acid was prepared from 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine-3-methanol, ¹ H-NMR (CDCl _3i ppm, δ): 3.6 to 4.0 (m, 4H), 3.35 (t, 1H), 3.1 to 3.3 (m, 3H), 2.23 (m, 1H), 1.48 (s, 9H) and 3-hydroxymethyl-4,5-epoxypiperidine-1-carboxylic acid benzyl ester from (1-benzyloxycarbonyl-1,2,3,6-tetrahydro-2-pyridyl) methanol, ¹³ C-NMR spectrum (CDCl 3) , ppm, δ): 156.21, 155.84, 136.86, 128.95, 128.53, 128.27, 128.24, 67.80, 62.48, 62.13, 61.55, 52.94, 52.40, 50.91, 50.48, 42.99, 42.74, 40.17, 37.56, 37.19, 36.92. ¹ H-NMR spectrum (CDCl 3, ppm, δ): 7.3 (m, 5H), 5.06 (s, 2H), 4.0-2.9 (m, 9H), 2.32 (m, · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

0.25H), 2.20 (m, 0.75H). NMR signals indicate a mixture of the two isomers in a ratio of about 1: 3.

Example 18

5-Hydroxymethyl-3,4-piperidinediol tert. 3 - (((1R, 2S, 5R) -2-Isopropyl-5-methyl-1-cyclohexyloxy) -acetoxymethyl-4,5-epoxypiperidine-1-carboxylic acid butyl ester (0.25 g, 0.59 mmol) and 10 Aqueous potassium hydroxide was refluxed for 3 hours. The reaction mixture was evaporated to dryness in vacuo and purified on a silica gel column (eluted with isopropanol with 25% (w / w) ammonium hydroxide 3: 1). There was thus obtained 5-hydroxymethyl-3,4-piperidinediol as an oil (yield 56 mg, 65%). Chiral TLC (Machery-Nagel 811058 plates, eluting with a mixture of isopropyl alcohol with 26% (w / w) ammonium hydroxide in a 3: 1 ratio) indicated two isomers, Rf 0.55 and 0.59. Mass spectrum: m / e 147 (M +). ¹³ C-NMR (D ₂ O, ppm, δ): 71.52, 68.94, 65.64, 65.54, 60.59, 59.38, 47.03, 45.20, 44.57 , 41.44, 40.98, 35.26.

In a similar manner, 5-hydroxymethyl-3,4-piperidinediol was prepared from the target. 3-hydroxymethyl-4,5-epoxypiperidine-1-carboxylic acid butyl ester or 3-hydroxymethyl-4,5-epoxypiperidine-1-carboxylic acid benzyl ester.

In a similar manner, 5-hydroxymethyl-1-methyl-3,4-piperidinediol was prepared from (1-methyl-1,2,3,6-tetrahydro-3-pyridyl) methanol.

Example 19 (1-Methyl-1,2,3,6-tetrahydro-3-pyridyl) methanol

1M Lithium triethyl borohydride in tetrahydrofuran (75 mL, 75 mmol) was added slowly to a 1-methyl-1,2,3,6-tetrahydropyridine-3-carboxylic acid methyl ester solution. • 9 · 9 · 9 · 9 · · · · · · · · · · · · · · ·

9 9 9 9 9 9

Acid (5 g, 31.8 mmol) in dry tetrahydrofuran (200 mL). The mixture was refluxed for 3 h, cooled to room temperature and poured into 1M aqueous hydrochloric acid (150 mL). The aqueous layer was extracted with methylene chloride. The pH was adjusted to 9 with aqueous sodium hydroxide. The solution was extracted with methylene chloride, which was dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is distilled in a Kugelrohr distillation apparatus (t 65-75 ° C / 0.37 kPa). (1-methyl-1,2,3,6-tetrahydro-3-pyridyl) methanol was obtained as an oil (yield 1.9 g, 48% by weight). ¹³ C-NMR (CDCl ₃ , ppm, δ): 127.28, 126.34, 66.94, 57.31, 54.83, 46.00, 37.58.

Example 20

-Methyl-1,2,3,6-tetrahydropyridin-3-yl acetate

A solution of (1-methyl-1,2,3,6-tetrahydro-3-pyridyl) methanol (0.7 g, 5.5 mmol), triethylamine (25 mL) and acetic anhydride (20 mL) was boiled for 2 hours under reflux. The reaction mixture was extracted with methylene chloride. The pH was adjusted to 10 with aqueous sodium hydroxide. This solution was extracted with methylene chloride, which was dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was purified on a silica gel column (eluting with 1: 9 methanol: methylene chloride). 1-methyl-1,2,3,6-tetrahydropyridin-3-yl acetate was obtained as an oil (yield 0.69 g, 70% by weight). Smaller amounts of the two enantiomers were separated by chiral HPLC (chiracel, external dimensions 250 and 4.6 mm, eluting with isopropanol / heptane 1:99, retention times 16 and 18 minutes). ¹³ C-NMR (CDCl ₃ , ppm, δ): 171.44, 127.97, 125.15, 66.56, 55.13, 54.95, 46.33, 36.48, 21.34. ¹ H-NMR Spectrum (CDCl 3, ppm, δ): 5.78 (m, 1H), 5.61 (m, 1H), 4.0 (m, 2H), 2.91 (m, 2H), 2 64 (m, 2H); 2.35 (s, 3H); 2.28 (m, 1H); 2.06 (s, 3H).

Example 21 (3R, 4R, 5R) -5-Hydroxymethyl-1- (3-phenylallyl) -3,4-piperidinediol (Compound 11)

To a suspension of Wang resin (10 g, 9.2 mmol, Bachem, charge: 0.92 mmol / g) in methylene chloride was added N, N-diisoprapylethylamine (15 mL, 87.8 mmol) and acryloyl chloride (10 mL, 122, 7 mmol). After 7 hours of slow stirring, the mixture was filtered and the resin was washed with methylene chloride (500 mL) and methanol (500 mL). Drying in vacuo gave Wang-O-CO-CH = CH ₂ (9.4 g).

To a suspension of this resin (4 g, 3.7 mmol) in DMF (30 mL) was added a solution of (3R, 4R, 5R) -5-hydroxymethyl-3,4-piperidinediol (0.9 g, 6.1 mmol). in DMF (5 mL). The mixture was shaken for 22 hours, filtered and the resin was washed with DMF (4.times.25 ml), methylene chloride (4.times.25 ml) and methanol (4.times.25 ml). The resin was dried under vacuum. Approximately 4.1 g of material is obtained.

To a suspension of this resin (190 mg, 0.17 mmol) in DMF (5 mL) was added 3-bromo-1-phenyl-1-propene (180 mg, 0.91 mmol). The mixture was shaken for 24 hours, filtered and the resin washed with 5 x 5 ml DMF, 3 x 5 ml methylene chloride and 2 x 5 ml DMF. To this resin was added N, N-diisopropylethylamine (0.125 mL, 0.73 mmol) and 3 mL DMF. The mixture was shaken for 24 hours, filtered and the filtrate concentrated to dryness in vacuo. There was thus obtained (3R, 4R, 5R) -5-hydroxymethyl-1- (3-phenylallyl) -3,4-piperidinediol as an oil (yield 35 mg, 78%). LC-MS: m / e 264 (MH ^&lt; ^{+ &gt;} ). ¹ H-NMR spectrum (CD ₃ OD, ppm, δ): 7.5 (d, 2H), 7.3 (m, 3H), 6.9 (d, 1H), 6.35 (dt, 1H) 3.9 (d, 2H), 3.8 (dd, 1H), 3.7 (m, 2H), 3.55 (m, 2H), 3.4 (t, 1H), 2.76 to 3.0 (m, 2H); 1.95 (m, 1H).

The following compounds were prepared in a similar manner:

(3R, 4R, 5R) -1-allyl-5-hydroxymethyl-3,4-piperidinediol (compound 12) from (3R, 4R, 5R) -5-hydroxymethyl-3,4-piperidinediol and allyl bromide, LC-MS: m / e 188 (MH ^&lt; ^{+ &gt;} ). ¹ H-NMR spectrum (CD ₃ OD, ppm, δ): 5.9-6.1 (m, 1H), 5.5-5.7 (m, 2H), 3.3-3.9 (m , 8H), • · · · · · · · · · · · · · φ • • φ

2.7-3.0 (m, 2Η), 1.95 (m, 1Η). ¹³ C-NMR (CD ₃ OD, ppm, δ): 127.99, 126.77, 72.70, 70.14, 60.71, 60.41, 55.93, 43.12, (3R, 4R, 5R) -1-benzyl-5-hydroxymethyl-3,4-piperidinediol (compound 13) from (3R, 4R, 5R) -5-hydroxymethyl-3,4-piperidinediol and benzyl bromide, LC-MS: m / e 238 (MH ^&lt; ^{+ &gt;} ). ¹ H-NMR spectrum (CD ₃ OD, ppm, δ): 7.5 (m, 5H), 4.24 (s, 2H), 3.6-3.9 (m, 3H), 3.3- 3.5 (m, 3H), 2.7-3.0 (m, 2H), 1.95 (m, 1H).

(3R, 4R, 5R) -1-octyl-5-hydroxymethyl-3,4-piperidinediol (compound 14) from (3R, 4R, 5R) -5-hydroxymethyl-3,4-piperidinediol and 1-iodoctane, LC- MS: m / e 260 (MH ⁺ ), (3R, 4R, 5R) -2- (3,4-dihydroxy-5-hydroxymethyl-piperidin-1-yl) -acetamide (compound 15) from (3R, 4R, 5R) -5-hydroxymethyl-3,4-piperidinediol and 2-bromoacetamide, LC-MS: m / e 205 (MH ⁺ ), ((3R, 4R, 5R) -3,4-dihydroxy-5-hydroxymethyl- piperidin-1-yl) acetate (compound 16) from (3R, 4R, 5R) -5-hydroxymethyl-3,4-piperidinediol and ethyl bromoacetate, LC-MS: m / e 234 (MH ⁺ ), (3R, 4R, 5R) -5-hydroxymethyl-1- (4-trifluoromethyl-benzyl) -3,4-piperidinediol (compound

17) from (3R, 4R, 5R) -5-hydroxymethyl-3,4-piperidinediol and 4-trifluoromethylbenzyl bromide, LC-MS: m / e 306 (MH +), (3R, 4R, 5R) -1- (2) (4'-fluoroacetophenone)) - 5-hydroxymethyl-3,4-piperidinediol (compound

18) from (3R, 4R, 5R) -5-hydroxymethyl-3,4-piperidinediol and 2-bromo-4'-fluoroacetophenone, LC-MS: m / e 284 (MH ⁺ ), (3R, 4R, 5R) -5-hydroxymethyl-1- (2- (4'-methoxyacetophenone)) - 3,4-piperidinediol (compound 19) from (3R, 4R, 5R) -5-hydroxymethyl-3,4-piperidinediol and 2-bromo- 4'-methoxyacetophenone, LC-MS: m / e 296 (MH ⁺ ), φ φφφφφφφφφ φφφφφ φ 3 3 3 3 3 (3R, 4R, 5R) -1- ( 2- (4-fluorophenoxy) ethyl) -5-hydroxymethyl-3,4-piperidinediol (compound 20) from (3R, 4R, 5R) -5-hydroxymethyl-3,4-piperidinediol and 4-fluorophenyl-2-bromoethyl -ether, LC-MS: m / e 286 (MH +), (3R, 4R, 5R) -5-hydroxymethyl-1- (4-phenoxy-butyl) -3,4-piperidinediol (compound 21) from (3R); , 4R, 5R) -5-hydroxymethyl-3,4-piperidinediol and 4-phenoxybutyl bromide, LC-MS: m / e 296 (MH +), (3R, 4R, 5R) -1- (4-cyanobutyl) -5 -hydroxymethyl-3,4-piperidinediol (compound 22) from (3R, 4R, 5R) -5-hydroxymethyl-3,4-piperidinediol and 5-bromvaleronitrile, LC-MS: m / e 229 (MH +), (3R) 4R, 5R) -1 (10-decylphthalimido) -5-hydroxymethyl-3,4-piperidinedio 1 (compound 23) from (3R, 4R, 5R) -5-hydroxymethyl-3,4-piperidinediol and N- (10-bromodecyl) phthalimide, LC-MS: m / e 233 (MH +), (3R, 4R) 5R) -12- (3,4-dihydroxy-5-hydroxymethyl-piperidin-1-yl) -dodecanoic acid (compound 24) from (3R, 4R, 5R) -5-hydroxymethyl-3,4-piperidinediol and 12 -bromododecanoic acid, LC-MS: m / e 346 (MH +) and (3R, 4R, 5R) -5-hydroxymethyl-1-phenoxyethyl-3,4-piperidinediol (compound 25) of (3R, 4R, 5R) -5-hydroxymethyl-3,4-piperidinediol and 2-bromoethylphenyl ether, LC-MS: m / e 286 (MH +).

Example 22 (3R, 4R, 5R) -3- (3,4-Dihydroxy-5-hydroxymethyl-piperidin-1-yl) -propionic acid (Compound 26)

To a suspension of Wang-O-CO-CH = CH ₂ (2.0 g, 1.84 mmol) in DMF (15 mL) was added a solution of (3R, 4R, 5R) -5-hydroxymethyl-3,4-piperidinediol (0.8 g, 5.4 ♦ mm mm mm · · · · · · · mm olu olu olu mmol) in 3 mL DMF. The mixture was shaken for 22 hours, filtered and the resin washed with DMF (2 x 20 mL), methanol (3 x 20 mL), DMF (2 x 20 mL), methylene chloride (2 x 20 mL), and methanol (2 x 20 mL). ml). The resin was dried under vacuum. Approximately 2.2 g of material are obtained.

To a suspension of this resin (0.5 g, 0.46 mmol) in methylene chloride (5 mL) was added trifluoroacetic acid (5 mL). The mixture was shaken for 20 minutes, filtered and the filtrate evaporated to dryness in vacuo. There was thus obtained (3R, 4R, 5R) -3- (3,4-dihydroxy-5-hydroxymethyl-piperidin-1-yl) -propionic acid as a yellow oil (yield 40 mg, 40% w / w). LC-MS: m / e 220 (MH &lt; + &gt;). ¹ H-NMR spectrum (CD ₃ OD, ppm, δ): 3.3-3.9 (m, 8H), 2.8-3.1 (m, 4H), 1.95 (m, 1H).

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-Piperidinol (3R, 4R, 5R) -3-Benzyloxy-5-hydroxymethyl-4-piperidinol (0.25 g, 0.54 mmol) and methyl- (2,3,4-tri-O-benzyl) α-D-glucohexadialdoso-1,5-pyranoside (0.128 g, 5.4 mmol) was dissolved in ethanol (50 mL) and palladium on carbon (10%, 30 mg) was added. Purification on a silica gel column (eluting with a mixture of ethyl acetate and methanol (9: 1)) afforded (3R, 4R, 5R) -3-benzyloxy-5-hydroxymethyl- 1- (2,3,4-tri-O-benzyl-6-deoxy-1-O-methyl-6-D-glucopyranosyl) -4-piperidinol as an oil (yield 71 mg, 19 wt.%). ¹ H NMR NMR _(CDCl3, ppm δ): 7.3 (m, 20H), 5.0 (d, 1H)

4.9 (d, 1H); 4.8 (dd, 2H); 4.5-4.7 (m, 3H); 4.48 (d, 1H); 4.0 (t, 1H); .Delta. (T, 1H);

3.7 (m, 2H), 3.47 (dd, 1H), 3.35 (s, 3H), 3.2-3.4 (m, 3H), 2.5-2.8 (m, 4H), 1.8-2.0 (m, 4H).

Ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft * ft • * * * * * * * * * * * * * * · · · · · · · · Ft ··· ·· ···

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-tri-O-benzyl-6-deoxy-1-O-methyl-6-α-glucopyranosyl) -4-piperidinol (71 mg, 0, 1 mmol) was dissolved in ethanol (20 mL) containing aqueous hydrochloric acid (4N, 0.3 mL) and palladium on carbon (10% (w / w), 50 mg). The mixture was hydrogenated under 50 psi hydrogen for 3 hours, filtered through celite and concentrated in vacuo. Purification on a silica gel column (eluting with a mixture of ethanol with 25% (w / w) ammonium hydroxide (9: 1)) gives the free base, (3R, 4R, 5R) -1- (6-deoxy-1-O-methyl-6- α-D-glucopyranosyl) -5-hydroxymethyl-3,4-piperidinediol, as a yellow oil (yield 21 mg, 64% by weight). LC-MS: m / e 324 (MH ^&lt; ^{+ &gt;} ). ¹ H-NMR spectrum (CD ₃ OD, ppm, δ): 4.64 (d, 1H), 3.7-3.9 (m, 2H), 3.5-3.7 (m, 4H), 3.43 (s, 3H) 3.37 (dd, 1H), 3.05-3.25 (m, 3H), 2.37 (dd, 1H), 2.6 (dd, 1H), 2, Δ (q, 2H), 1.75 (m, 1H).

Claims (23)

PATENT CLAIMS Piperidine compounds of the general formula and their pharmaceutically acceptable acid addition salts or hydrates or prodrugs thereof, in which: R is a straight or branched (C 1 -C 6) alkoxy group; R represents straight or branched (C 1 -C 18) alkyl, (C 2 -C 18) alkene or (C 2 -C 18) alkyne, all optionally substituted with cyano, carboxylic acid, trifluoromethyl, hydroxyl, perhalomethyl, halogen, 3-cycloalkyl or (C 1 -C 6) alkoxy, (C 1 -C 6) alkoxy, (C 1 -C 6) carbonylalkoxy, benzyloxycarbonyl or NR 4 wherein R 1 and R _{2 are} independently halogen, C 1 -C 6 alkyl or benzyl, or R is straight or branched (C 1 -C 18) alkyl, (C 2 -C 18) alkene or (C 2 -C 18) alkyne, all optionally substituted by SR ₃ , wherein R ₃ is C 1 -C 6 alkyl, phenyl or carbonyl (C 1 -C 6 alkyl), or R represents straight or branched (C 1 -C 18) alkyl, (C 2 -C 18) alkene or (C 2 -C 18) alkyne, all optionally substituted by carbonyl (C 1 -C 6 alkyl) or carbonylphenyl, optionally substituted by methoxy, nitro , a halogen atom, or a cyano group; or 9 99 99 · 999 9 9 9 9 9 9 • 9 R is straight or branched (C 1 -C 18) alkyl, (C 2 -C 18) alkene or (C 2 -C 18) alkyne, all optionally substituted with phenoxy or phenyl optionally substituted with trifluoromethyl, methoxy, (C 1 -C 6) alkyl, carboxylic acid, nitro, cyano skyupine, halogen, phenyl, methoxycarbonyl or methylsulfonyl, or R is a straight or branched C1-C18 alkyl, C2-C18 alkene or C2-C18 alkyne, all optionally substituted a carboxamide (CONR ₄ R ₅ wherein one of R ₄ and R ₅ or both is hydrogen or C 1-6 alkyl), or R represents straight or branched (C 1 -C 18) alkyl, (C 2 -C 18) alkene or (C 2 -C 18) alkyne, all optionally substituted with naphthalene, phthalimide, optionally substituted piperidine, imidazoline, 2-thienone, optionally substituted with coumarin, 2-dioxolane, hydantoin, thiohydantoin, 1,2,4-oxadiazoline, optionally substituted with isoxazolidine, tetrahydrofurfuryl, 1,4-benzodioxane or phenylsulfonyl, or glycoside, or R is C 3 -C 7 cycloalkyl optionally substituted with cyano, carboxylic acid, hydroxyl, oxo, perhalomethyl, halogen, phenyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy, benzyloxycarbonyl, hydroxyalkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, or NR 6 in which one of R 1 and R ₂ or both is hydrogen, alkyl of 1 to 6 carbon atoms or benzyl. Piperidine compounds according to claim 1, in which R represents a straight or branched alkoxy group having 1 to 6 carbon atoms. Piperidine Compounds according to claim 1, wherein R represents straight or branched alkyl of 1 to 18 carbon atoms, alkene of 2 to 18 carbon atoms or alkyne of 2 to 18 carbon atoms, all optionally substituted with cyano • anov φ Carboxylic acid, trifluoromethyl, hydroxyl, perhalomethyl, halogen, cycloalkyl of 3 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkoxycarbonyl of 1; C 1-6 alkyl, benzyloxycarbonyl or NR ₁ R ₂ , wherein R 1 and R _{2 are} independently halogen, C 1-6 alkyl or benzyl. The piperidine compounds of claim 1, wherein R is straight or branched (C 1 -C 18) alkyl, (C 2 -C 18) alkene or (C 2 -C 18) alkyne, all optionally substituted with SR ₃ wherein R ₃ is alkyl of 1 to 6 carbon atoms, phenyl or carbonyl (alkyl of 1 to 6 carbon atoms). The piperidine compounds of claim 1, wherein R is straight or branched (C 1 -C 18) alkyl, (C 2 -C 18) alkene or (C 2 -C 18) alkyne, all optionally substituted with (C 1 -C 6) carbonylalkyl ) or carbonylphenyl, optionally substituted by methoxy, nitro, halogen or cyano. The piperidine compounds of claim 1, wherein R is a straight or branched C 1 -C 18 alkyl, C 2 -C 18 alkene or C 2 -C 18 alkyne, all optionally substituted with phenoxy or phenyl optionally substituted with trifluoromethyl , methoxy, C1-C6alkyl, carboxylic acid, nitro, cyano, halogen, phenyl, methoxycarbonyl or methylsulfonyl. The piperidine compounds of claim 1, wherein R is straight or branched (C 1 -C 18) alkyl, (C 2 -C 18) alkene or (C 2 -C 18) alkyne, all optionally substituted with carboxamide (CONR 4 R 5, wherein one of R ₄ and R ₅ or both are hydrogen or alkyl of 1 to 6 carbon atoms). ·· · · · · · · · · · · φφφφφφφφφφφ · · · · · ·φφφφφφφφφφ The piperidine compounds of claim 1, wherein R is straight or branched (C 1 -C 18) alkyl, (C 2 -C 18) alkene or (C 2 -C 18) alkyne, all optionally substituted with naphthalene, phthalimide, or optionally substituted piperidine, imidazoline, 2-thienone, optionally substituted with coumarin, 2-dioxolane, hydantoin, thiohydantoin, 1,2,4-oxadiazoline, optionally substituted with isoxazolidine, tetrahydrofurfuryl, 1,4-benzodioxane or phenylsulfonyl, or glycoside. The piperidine compounds of claim 1, wherein R is C 3 -C 7 cycloalkyl, optionally substituted with cyano, carboxylic acid, hydroxyl, oxo, perhalomethyl, halogen, phenyl, C 1 -C 6 alkoxy, alkoxy (s). (C 1 -C 6) carbonyl, benzyloxycarbonyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl, or NR 6 in which one of R ₍ and R ₂ or both is halogen, C 1 -C 6 alkyl) 6 carbon atoms or benzyl. The piperidine compounds of claim 1, selected from the group consisting of: 1-butyl-5-hydroxymethyl-3,4-piperidinediol, 1- (3-cyclohexyl) propyl-5-hydroxymethyl-3,4-piperidinediol, 1-dodecyl-5-hydroxymethyl-3,4-piperidinediol, 2- (2-hydroxyethyl) -5-hydroxymethyl-3,4-piperidinediol, 5-hydroxymethyl-1- (4- (5-hydantoyl) butyl) -3,4-piperidinediol, 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-piperidinediol or 1-acetyl-5-hydroxymethyl-3,4-piperidinediol, • 0 • 0 0 • 0 0 0 0 0 • 0 0 0 0 0 0 0 0 <0 0 0 0 0 0 0 00 »» 0 0 • 0 0 «0 0 0 0 0 · 0 · 0 0 »0 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) -acetamide, (3,4-dihydroxy-5-hydroxymethyl-piperidine-1 -) - ethyl ester yl) -acetic acids, 5-hydroxymethyl-1- (4-trifluoromethyl-benzyl) -3,4-piperidinediol, 1- (2- (4'-fluoroacetophenone)) - 5-hydroxymethyl-3,4-piperidinediol, 5-hydroxymethyl-1- (2- (4'-methoxyacetophenone)) - 3,4-piperidinediol, (2- (4-fluorophenoxy) ethyl) -5-hydroxymethyl-3,4-piperidinediol, 5-hydroxymethyl-1- (4-phenoxy-butyl) -3,4-piperidinediol, 1- (4-cyanobutyl) -5-hydroxymethyl-3,4-piperidinediol, 1- (10-decylphthalimido) -5-hydroxymethyl-3,4-piperidinediol, 12- (3,4-dihydroxy-5-hydroxymethyl-piperidin-1-yl) -dodecanoic acid, 5-hydroxymethyl-1-phenoxyethyl-3,4-piperidinediol, 3- (3,4-dihydroxy-5-hydroxymethyl- piperidin-1-yl) propionic acid and 1- (6-deoxy-1-O-methyl-6-α-D-glucopyranosyl) -5-hydroxymethyl-3,4-piperidinediol or a pharmaceutically acceptable salt or hydrate thereof, or any optical isomer, or a mixture of optical isomers including a racemic mixture or any tautomeric form. The optical isomer or optical isomer mixture comprising the racemic mixture of claim 10, selected from the group consisting of: (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-piperidinediol, (3R, 4R, 5R) -1- (2-hydroxyethyl) -5-hydroxymethyl-3,4-piperidinediol, (3R, 4R, 5R) -5-hydroxymethyl-1- (4- (5-hydantoyl) butyl) -3,4-piperidinediol, (3R, 4R, 5R) -5-hydroxymethyl-1- (3-phenylpropyl) -3,4-piperidinediol, (3R, 4R, 5R) -5-hydroxymethyl-1-methyl-3,4-piperidinediol, 4 4 4 4 4 4 4 4 4 4 * · 4 9 «5 ·· • 4 44 4444 4 44 44 4 4 4 4 4 4 4 4 4,444,444 4 4 ¢ 9 9 9 (3R, 4R, 5R) -5-Hydroxymethyl-1-methoxy-3,4-piperidinediol, (3R, 4R, 5R) -5-Hydroxymethyl-1- (4-N, N <lifenylaminobenzyl) -3,4-piperidiridiol, (3R, 4R, 5R) -1-acetyl-5-hydroxymethyl-3,4-piperidinediol, (3R, 4R, 5R) -5-hydroxymethyl-1- (3-phenylallyl) - 3,4-piperidinediol, (3R, 4R, 5R) -1-allyl-5-hydroxymethyl-3,4-piperidinediol, (3R, 4R, 5R) -1-benzyl-5-hydroxymethyl-3,4-piperidinediol, (3R, 4R, 5R) -1-octyl-5-hydroxymethyl-3,4-piperidinediol, (3R, 4R, 5R) -2- (3,4-dihydroxy-5-hydroxymethyl-piperidin-1-yl) - acetamide, (3R, 4R, 5R) (3,4-Dihydroxy-5-hydroxymethyl-piperidin-1-yl) -acetic acid ethyl ester, (3R, 4R, 5R) -5-hydroxymethyl-1- (4-trifluoromethyl- benzyl) -3,4-piperidinediol, (3R, 4R, 5R) -1- (2- (4'-fluoroacetophenone)) -5-hydroxymethyl-3,4-piperidinediol, (3R, 4R, 5R) -5- hydroxymethyl-1- (2- (4'-methoxyacetophenone)) - 3,4-piperidinediol, (3R, 4R, 5R) - (2- (4-fluorophenoxy) ethyl) -5-hydroxymethyl-3,4-piperidinediol (SRR, R, SR-S-hydroxymethyl-4-phenoxybutyl-SApiperidinediol, (3R, 4R, 5R) -1- (4-cyanobutyl) -5-hydroxymethyl-3,4-piperidinediol, (3R) 4R, 5R) -1- (10-decylphthalimido) -5-hydroxymethyl-3,4-piperidinediol, (3R, 4R, 5R) -12- (3,4-dihydroxy-5-hydroxymethylpiperidin-1-yl) -dodecanoic acid, (3R, 4R, 5R) -5-hydroxymethyl-1-phenoxyethyl-3,4-piperidinediol, (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-glucopyranosyl) -5-hydroxymethyl-3,4-piperidinediol, (35.45.55) -1-Butyl-5-hydroxymethyl-3,4-piperidinediol, (35.45.55) -1- (3-cyclohexyl) propyl-5-hydroxymethyl-3,4-piperidinediol, (35.45.55) -1-dodecyl -5-hydroxymethyl-3,4-piperidinediol, (35.45.55) -1- (2-hydroxyethyl) -5-hydroxymethyl-3,4-piperidinediol, (35.45.55) -5-hydroxymethyl-1- (4- (5-hydantoyl) butyl) -3,4-piperidinediol, (35.45.55) -5-hydroxymethyl-1- (3-phenylpropyl) -3,4-piperidinediol, (35.45.55) -5-hydroxymethyl-1- methyl-3,4-piperidinediol; (35.45.55) -5-hydroxymethyl-1-methoxy-3,4-piperidinediol, (SSS, SSS-S-hydroxymethyl-1-4-tyn-diphenylaminobenzyl) -Spiperidinediol, (35.45.55) -1-acetyl-5-hydrox ymethyl-3,4-piperidinediol, (35.45.55) -5-hydroxymethyl-1- (3-phenylallyl) -3,4-piperidinediol, (35.45.55) -1-allyl-5-hydroxymethyl-3,4- piperidinediol, (35.45.55) -1-benzyl-5-hydroxymethyl-3,4-piperidinediol, (3S, 4S, 5S) -1-octyl-5-hydroxymethyl-3,4-piperidinediol, (35.45.55) - 2- (3,4-Dihydroxy-5-hydroxymethyl-piperidin-1-yl) -acetamide, (3S, 4S, 5S) (3,4-Dihydroxy-5-hydroxymethyl-piperidin-1-yl) -acetic acid ethyl ester (35.45.55) -5-hydroxymethyl-1- (4-trifluoromethyl-benzyl) -3,4-piperidinediol, (35.45.55) -1- (2- (4'-fluoroacetophenone)) - 5-hydroxymethyl- 3,4-piperidinediol, (35.45.55) -5-hydroxymethyl-1- (2- (4'-methoxyacetophenone)) - 3,4-piperidinediol, (35.45.55) - (2- (4-fluorophenoxy) - ethyl) -5-hydroxymethyl-3,4-piperidinediol, (35.45.55) -5-hydroxymethyl-1- (4-phenoxy-butyl) -3,4-piperidinediol, (35.45.55) -1- (4- cyanobutyl) -5-hydroxymethyl-3,4-piperidinediol, (35.45.55) -1- (10-decylphthalimido) -5-hydroxymethyl-3,4-piperidinediol, (35.45.55) -12- (3,4- dihydroxy-5-hydroxymethyl-piperidin-1-yl) dodecanoic acid, (3 5.45.55) -5-hydroxymethyl-1-phenoxyethyl-3,4-piperidinediol, (35.45.55) -3- (3,4-dihydroxy-5-hydroxymethylpiperidin-1-yl) propionic acid and (35.45. 55) -1- (6-deoxy-1-O-methyl-6-α-glucopyranosyl) -5-hydroxymethyl-3,4-piperidinediol or a pharmaceutically acceptable salt or hydrate thereof. Piperidine compounds according to any one of claims 1 to 12, which are effective as inhibitors of glucose production. Piperidine compounds according to any one of claims 1 to 13, which are effective as inhibitors of glycogen phosphorylase enzymatic activity. • · · · 1 · Β ΒΒ · Β Β < • · • · I · · · · A pharmaceutical composition comprising a piperidinium compound according to any one of claims 1 to 13 together with one or more pharmaceutically acceptable carriers or diluents. 15. A pharmaceutical composition according to claim 14 in the form of an oral dosage unit or a parenteral dosage unit. The piperidine compounds of any one of claims 1 to 13 for therapeutic use. Piperidine Compounds according to any one of claims 1 to 13 for use in treating or preventing diseases of the endocrinological system, preferably diabetes, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis or myocardial ischemia, more preferably diabetes. Piperidine compounds according to any one of claims 1 to 13 for use in the treatment or prevention of non-insulin-dependent diabetes (NIDDM or type 2 diabetes), which comprises overnight treatment or food treatment and / or treatment or prevention of long-term complications, preferably retinopathy, neuropathy, nephropathy and / or micro- and macro-angiopathy. Use of the Piperidine Compounds according to any one of claims 1 to 13 for the manufacture of a medicament. Use of the Piperidine Compounds of any one of claims 1 to 13 for the manufacture of a medicament for treating or preventing diseases of the endocrinological system, preferably diabetes, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis or myocardial ischemia, more preferably diabetes. • · • · ··· Use of the Piperidine Compounds according to any one of claims 1 to 13 for the manufacture of a medicament for the treatment or prevention of non-insulin dependent diabetes (NIDDM or type 2 diabetes), which comprises overnight treatment or food treatment and / or treatment or prevention of long-term complications, preferably retinopathy, neuropathy, nephropathy and / or micro- and macro-angiopathy. 22. A method of treating or preventing diseases of the endocrinological system, preferably diabetes, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, or myocardial ischemia, more preferably diabetes, comprising administering to a subject in need thereof an effective amount of a piperidine compounds according to any one of claims 1 to 13. 23. A method of treating or preventing non-insulin dependent diabetes (NIDDM or type 2 diabetes) and / or treating or preventing long-term complications, preferably retinopathy, neuropathy, nephropathy and / or micro- and macro-angiopathy, characterized in that the subject is in need thereof, administer an effective amount of a Piperidine Compound according to any one of claims 1 to 13.