HK1164845A - Hydrochlorides of aminopiperidinyl-xanthine, their preparation and their use - Google Patents

Description

Aminopiperidine xanthine hydrochloride, preparation method and application thereof

The invention relates to a divisional application of Chinese invention patent application (application date: 26.7.2006; application number 200680028040.0; name of the invention: hydrochloride and hydrate of 1- [ (3-cyano-pyridine-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3-amino-piperidine-1-yl) -xanthine, a preparation method thereof and application thereof as a medicament).

Technical Field

The present invention relates to novel substituted xanthines of the formula

Tautomers, enantiomers, mixtures thereof, salts thereof and hydrates thereof, especially physiologically acceptable salts thereof with inorganic or organic acids (e.g. hydrochloride), which have valuable pharmacological properties, especially an inhibitory effect on the activity of dipeptidyl peptidase-IV (DPP-IV), the preparation thereof, the use thereof for the prevention or treatment of diseases or disorders which are associated with increased DPP-IV activity or which can be prevented or alleviated by decreasing the DPP-IV activity, especially type I or type II diabetes, pharmaceutical compositions containing a compound of the general formula (I) or a physiologically acceptable salt thereof and processes for the preparation thereof.

Background

Xanthine derivatives which have an inhibitory effect on DPP-IV are known from WO 02/068420, WO02/02560, WO 03/004496, WO 03/024965, WO 04/018468, WO 04/048379, JP 2003300977 and EP 1338595.

Disclosure of Invention

The object of the present invention is to provide novel compounds of formula I, especially salts having advantageous properties for medical use.

In addition to its actual efficacy for the desired indication, the active substance also meets other requirements to be able to be used as a medicament. This parameter is to a large extent related to the physicochemical properties of the active substance.

Examples of such parameters, but not limited thereto, are the stability of the activity of the starting material under different environmental conditions, the stability during the preparation of the pharmaceutical formulation and the stability in the final composition of the pharmaceutical formulation. Therefore, the pharmaceutically active substances used for the preparation of pharmaceutical compositions should have a high stability, which must be ensured even under different environmental conditions. This is absolutely necessary to prevent the use of pharmaceutical compositions which, in addition to the active substance itself, contain, for example, decomposition products thereof. In this case, the active substance may be present in the pharmaceutical formulation in an amount less than the specified amount.

The content of the pharmaceutically active substance is reduced by moisture absorption due to the weight gain caused by moisture absorption. Drugs with a tendency to absorb moisture have to be protected during storage, for example by adding suitable desiccants or by storing the drug in a protected environment from moisture. Furthermore, if the pharmaceutical substance is placed in an environment that is not protected in any way from moisture, and moisture absorbed during manufacture may reduce the content of the pharmaceutically active substance. Therefore, the pharmaceutically active substance should preferably be only slightly hygroscopic.

Since the crystal modification of the active substance is important for reproducible active substance contents of the formulation, it is desirable to keep as clear as possible any polymorphic form of the active substance in crystalline form. If the active substance has a different polymorphic modification, it is necessary to ensure that the crystalline modification of the substance is not altered in the subsequent preparation of the medicament. Otherwise, this has a detrimental effect on the reproducible effectiveness of the drug. In contrast, an active substance characterized by having only a small number of polymorphic forms is a preferred active substance.

Another criterion of particular importance in certain cases for the choice of formulation or the choice of process for manufacturing the formulation is the solubility of the active substance. For example, if pharmaceutical solutions (e.g. infusion solutions) are prepared, sufficient solubility of the active substance in physiologically acceptable solvents is necessary. For oral drugs, sufficient solubility of the active substance is also of paramount importance.

The problem of the present invention is to provide a pharmaceutically active substance which is characterized not only by a high pharmacological effectiveness but also by the fact that the above-mentioned physicochemical requirements are met as far as possible.

It has surprisingly been found that salts of the compounds of formula I with hydrochloric acid, their enantiomers, mixtures and hydrates thereof meet this need. Particularly suitable for the purposes of the present invention are the monohydrochloride and dihydrochloride salts and the enantiomers thereof, mixtures thereof and hydrates thereof.

The following terms are used synonymously:

the hydrochloride salt formed with hydrochloric acid.

Accordingly, the present invention relates to salts of 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3-amino-piperidin-1-yl) -xanthine with hydrochloric acid, as well as enantiomers, mixtures and hydrates thereof. To this end, they include, for example, the mono-and di-hydrochloride salts of 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3-amino-piperidin-1-yl ] -xanthine and mixtures thereof, including the racemate, and mono-and di-hydrochloride salts of 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (S) -3-amino-piperidin-1-yl ] -xanthine and mixtures thereof (including racemates). The invention further relates to pharmaceutical compositions containing at least one of the above salts or hydrates and to processes for preparing the pharmaceutical compositions.

Due to their ability to inhibit DPP-IV activity, the compounds of general formula I according to the present invention and their corresponding pharmaceutically acceptable salts are suitable for affecting any condition or disease which can be affected by inhibition of DPP-IV activity. It is therefore expected that the compounds according to the invention will be suitable for the prevention or treatment of the following diseases or conditions: such as type I and type II diabetes, prediabetes, decreased glucose tolerance or change in fasting plasma glucose, diabetic complications (e.g., retinopathy, nephropathy or neuropathy), metabolic acidosis or ketosis, reactive hypoglycemia, insulin resistance, metabolic syndrome, dyslipidemia of different origin, arthritis, atherosclerosis and related diseases, obesity, allograft transplantation and osteoporosis caused by calcitonin. Furthermore, such substances are suitable for preventing B-cell degeneration, for example of pancreatic B-cell apoptosis or necrosis. The substance is also suitable for improving or restoring the function of pancreatic cells and, in addition, for increasing the size and number of pancreatic B-cells. Furthermore, and in view of the effects of the hyperglycosidase-like peptides, such as GLP-1 and GLP-2, and their inhibition with DPP-IV, it is expected that the compounds according to the invention will be suitable for achieving especially sedative or tranquillizing effects and have a favourable effect on the post-operative metabolic conditions or on the hormonal stress response, or possibly reduce mortality and morbidity after myocardial infarction. Furthermore, it is suitable for the treatment of any condition which is associated with the above-mentioned effects and which is modulated by GLP-1 or GLP-2. The compounds according to the invention can also be used as diuretics or antihypertensives and are suitable for the prevention and treatment of acute renal failure. The compounds according to the invention are also useful for the treatment of inflammatory diseases of the respiratory tract. It is also suitable for the prevention and treatment of chronic inflammatory bowel disease such as Irritable Bowel Syndrome (IBS), Crohn's disease or ulcerative colitis, and pancreatitis. It is also expected to be useful for various injuries or lesions of the gastrointestinal tract, such as those that occur in colitis and enteritis. Furthermore, DPP-IV inhibitors and thus the compounds according to the invention are expected to be useful for the treatment of infertility or for improving fertility in humans or mammals, especially in cases where infertility is associated with insulin resistance or with polycystic ovary disease. On the other hand, these substances are suitable for influencing sperm motility and are therefore suitable for use as male contraceptives. Furthermore, the substance is suitable for the treatment of growth hormone deficiency symptoms associated with dwarfism and can be used rationally for all indications for which growth hormone is available. Based on their inhibitory effect on DPP-IV, the compounds according to the invention are therefore also suitable for the treatment of various autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, thyroiditis and Basedow's disease. It is also useful in the treatment of viral diseases, and may also be used, for example, in the stimulation of blood formation in HIV infection, in benign prostatic hypertrophy, gingivitis, and in the treatment of neuronal defects and neurodegenerative diseases such as Alzheimer's disease. The compounds described may also be used for the treatment of tumors, in particular for altering tumor invasion, and cancer metastasis; examples here are their use for the treatment of T-cell lymphoma, acute lymphocytic leukemia, cell-based thyroid cancer, basal cell carcinoma or breast cancer. Other indications are stroke, ischemia of various origins, Parkinson's disease and migraine. In addition, other indications include follicular and epidermal hyperkeratosis, increased keratinocyte proliferation, psoriasis, encephalomyelitis, glomerulonephritis, lipodystrophy, and psychosomatic depressive and neuropsychiatric diseases of different origins.

The compounds according to the invention can also be used in combination with other active substances. Suitable therapeutic agents for use in these combinations include, for example, anti-diabetic agents such as metformin, sulfonylureas (e.g., glyburide, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinediones (e.g., rosiglitazone, pioglitazone), PPAR-gamma agonists (e.g., GI 262570) and antagonists, PPAR-gamma/alpha modulators (e.g., KRP 297), PPAR-gamma/alpha/b modulators, AMPK activators, ACC1 and ACC2 inhibitors, DGAT-inhibitors, SMT3 receptor agonists, 11 β -HSP inhibitors, FGF 19 agonists or mimetics, α -glucosidase inhibitors (e.g. glycolume, voglibose), other DPPIV inhibitors, α 2 antagonists, insulin and insulin analogues, GLP-1 and GLP-1 analogues (e.g. insulinotropic hormone (exendin-4)), or exendin (amylin). Can also be combined with the following substances: SGLT2 inhibitors such as T-1095 or KGT-1251(869682), protein tyrosine phosphatase 1 inhibitors, substances which influence deregulated glucose production in the liver, such as glucose-6-phosphatase or fructose-1, 6-bisphosphatase, inhibitors of glycogen phosphorylase, glucagon receptor antagonists and inhibitors of phosphoenolpyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrokinase, lipid lowering agents, such as HMG-CoA-reductase inhibitors (e.g. simvastatin, atorvastatin), fibrates (e.g. bezafibrate, fenofibrate), nicotinic acid and derivatives thereof, PPAR-alpha agonists, PPAR-delta agonists, ACAT inhibitors (e.g. avasimibe) or cholesterol absorption inhibitors, such as ezetimibe, bile acid binding substances such as cholestyramine, PPAR-alpha agonists, PPAR-delta agonists, ACAT inhibitors (e.g. avasimibe), cholesterol absorption inhibitors, Inhibitors of ileal bile acid transport, HDL-raising compounds, such as CETP inhibitors or ABC1 modulators or LXR α antagonists, LXR β agonists or LXR α/β modulators or obesity treating active substances, such as sibutramine or tetrahydrolipstatin, dexfenfluramine, axokine, cannabinoid 1 receptor antagonists, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists or β 3-agonists such as SB-418790 or AD-9677 and 5HT2c receptor agonists.

In addition, it can be combined with drugs for treating hypertension, such as AII antagonist or ACE inhibitor, diuretic, beta-blocker, Ca-antagonist, etc. or their combination.

The dosages required to achieve the corresponding effects are expediently from 1mg to 100mg, preferably from 1mg to 30mg, administered intravenously and from 1mg to 1000mg, preferably from 1mg to 100mg, administered orally, in each case from 1 to 4 times daily. To this end, the compounds of the formula I prepared according to the invention, optionally in combination with other active substances, can be processed with one or more inert conventional carriers and/or diluents, for example with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetostearyl alcohol, carboxymethylcellulose or fatty substances (e.g. stearin) or suitable mixtures thereof, into conventional galenic preparations, for example tablets or coated tablets, capsules, powders, suspensions or suppositories.

Drawings

FIGS. 1, 3, 5 and 8 show X-ray powder diagrams of example 2 (anhydrous form and monohydrate), example 3 and example 4;

FIGS. 2, 6 and 9 show thermal analyses of examples 2, 3 and 4;

FIGS. 4, 7 and 10 show the absorption characteristics of the free base and the monohydrochloride and dihydrochloride salts of 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -3-amino-piperidin-1-yl) -xanthine (examples 2, 3 and 4).

The method comprises the following specific steps:

FIG. 1: an X-ray powder of the anhydrous form of 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3-amino-piperidin-1-yl ] -xanthine;

FIG. 2: thermal analysis of the anhydrous form of 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3-amino-piperidin-1-yl ] -xanthine;

FIG. 3: an X-ray powder of 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3-amino-piperidin-1-yl ] -xanthine monohydrate;

FIG. 4: absorption characteristics of 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3-amino-piperidin-1-yl ] -xanthine free base;

FIG. 5: an X-ray powder of 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3-amino-piperidin-1-yl ] -xanthine monohydrochloride;

FIG. 6: thermal analysis of 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3-amino-piperidin-1-yl ] -xanthine monohydrochloride;

FIG. 7: absorption characteristics of 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3-amino-piperidin-1-yl ] -xanthine monohydrochloride;

FIG. 8: x-ray powder of 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3-amino-piperidin-1-yl ] -xanthine dihydrochloride;

FIG. 9: thermal analysis of 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3-amino-piperidin-1-yl ] -xanthine dihydrochloride;

FIG. 10: absorption characteristics of 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3-amino-piperidin-1-yl ] -xanthine dihydrochloride.

Examples

The following examples serve to illustrate the invention.

Example 1

D-tartrate salt of the R-enantiomer of 3- (phthalimido) piperidine

a. Hydrogenation:

10.00kg (106.25mol) of 3-aminopyridine, 500g of technical-grade activated charcoal and 65 l of acetic acid are placed in a hydrogenation reactor. 50g of a Cumura catalyst (Nishimura catalyst, a commercially available rhodium/platinum mixed catalyst) was added, suspended in 2.5 l of acetic acid, and the mixture was washed with 2.5 l of acetic acid. It is hydrogenated at 50 ℃ and over 100 bar hydrogen pressure until hydrogen uptake ceases and then hydrogenated for a further 30 minutes at 50 ℃. The catalyst and the activated carbon are filtered off and washed with 10 l of acetic acid.

The reaction can also be successful at lower severe pressures.

b. Acylation:

15.74kg (106.25mol) phthalic anhydride were placed in the reactor and mixed with the hydrogenated filtrate. The mixture was rinsed with 7.5 liters of acetic acid and then the reaction mixture was heated to reflux while about 30% of the acetic acid used was distilled off in 1 hour. The reaction solution was cooled to 90 ℃.

c. Racemate resolution:

a solution of 11.16kg of D- (-) -tartaric acid (74.38mol) in 50 l of absolute ethanol heated to 50 ℃ was dosed to the acylation reaction solution at 90 ℃. It was rinsed with 10 liters of absolute ethanol and stirred at 90 ℃ for 30 minutes, during which time the product crystallized out. After cooling to 5 ℃, the product was centrifuged and washed with absolute ethanol.

d. And (3) recrystallization:

the wet crude product is heated to reflux in a mixture of 50 liters of acetone and 90 liters of water until a solution is formed. The mixture was then cooled to 5 ℃ at which time the product crystallized out. The suspension is stirred for 30 minutes at 5 ℃, the product is centrifuged and finally washed with a mixture of 20 l of acetone and 10 l of water. It was dried in a drying oven at 45 ℃ under an inert atmosphere.

Yield: 11.7-12.5kg

Example 2

Preparation of 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3-amino-piperidin-1-yl ] -xanthine base

a.3-cyano-2- (chloromethyl) -pyridine

165.5g (0.98mol) of 2-hydroxymethyl-3-pyridinecarboxamide are heated with 270ml of phosphorus oxychloride at 90 to 100 ℃ for 1 hour. The reaction mixture was cooled to ambient temperature and then added dropwise to about 800ml of water at a temperature of 50-60 ℃. After hydrolysis of the phosphorus oxychloride, the mixture is neutralized with sodium hydroxide solution with cooling, whereby the product precipitates. It is filtered off, washed with 300ml of water and then dried at 35-40 ℃.

Yield: 122.6g (82% of theory)

1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8-bromo-xanthine

202g (0.68mol) of 3-methyl-7- (2-ethynyl-1-yl) -8-bromo-xanthine, 188.5g (1.36mol) of anhydrous potassium carbonate and 1.68 l of N-methyl-2-pyrrolidone were placed in a reactor and heated to 70 ℃. Then 119g (0.75mol) of 2-chloromethyl-3-cyano-pyridine in 240ml of N-methyl-2-pyrrolidone (NMP) were added dropwise. The contents of the reactor were stirred at 70 ℃ for 19 hours. After the reaction was complete, 2.8 liters of water were added to the reaction mixture and cooled to 25 ℃. The product is filtered off, washed with 2 l of water and dried in a drying cabinet at 70 ℃ under an inert atmosphere.

Yield: 257.5g (91% of theory)

1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -phthalimido-piperidin-1-yl) -xanthine

230g (0.557mol) of 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8-bromo-xanthine, 318g (0.835mol) of 3- (phthalimido) piperidine D-tartrate and 1.15 l of N-methyl-2-pyrrolidone were placed in a reactor. The reactor contents were heated to 140 ℃. After this temperature had been reached, 478ml (2.78mol) of diisopropylethylamine were metered in over 20 minutes and the reaction mixture was subsequently stirred for 2 hours at 140 ℃. The reaction mixture was then cooled to 75 ℃ and diluted with 720ml of methanol. Thereafter 2.7 liters of water were added at 68-60 ℃ and the mixture was cooled to 25 ℃. The product is filtered off and washed with 2 l of water. It was dried in a drying oven at 70 ℃ under an inert atmosphere.

The crude product thus obtained is then stirred at boiling temperature into 1 l of methanol, filtered while hot, washed with 200ml of methanol and then dried under an inert atmosphere at 70 ℃.

Yield: 275g (88% of theory)

1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine

412.5g (0.733mol) of 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -phthalimido-piperidin-1-yl) -xanthine were heated to 80 ℃ in 4125ml of toluene. 445ml ethanolamine (7.33mol) were then added to the suspension at 75-80 ℃. To complete the reaction, the mixture was stirred at 80-85 ℃ for an additional 2 hours, at which time solids were produced in the solution. The phases are then separated. The ethanolamine phase was extracted twice with warm toluene (1 liter each time). The combined toluene phases are washed twice with 2 liters each time of warm water at 75-80 ℃. The toluene phase was dried over sodium sulfate, filtered and then the volume was reduced to about 430ml by distillation in vacuo. 1 l of tert-butyl methyl ether are then metered in at 50-55 ℃ and then cooled to 0-5 ℃. The product was isolated by filtration, washed with tert-butyl methyl ether and dried in a drying oven at 60 ℃.

Yield: 273.25g (86.2% of theory)

Melting point: 188 plus or minus 3 ℃ (anhydrous form)

As is clear from the absorption diagram of fig. 4, the anhydrous form of 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine is stable up to about 50% relative humidity; above 50% relative humidity, this form absorbs about 4% of the water and converts to the monohydrate. If the relative humidity is subsequently returned to 50% or less, the anhydrous form is formed again, i.e. the conversion to the monohydrate is completely reversible.

Table 1: x-ray diffraction intensity (normalized) of anhydrous form of 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine

Table 2: x-ray diffraction intensity (normalized) of 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine monohydrate

Example 3

1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3-amino-piperidin-1-yl ] -xanthine monohydrochloride

5.00g of 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3-amino-piperidin-1-yl ] -xanthine base were dissolved in 50ml of methanol. Then 3.0ml of a 3.9 molar solution of hydrogen chloride in isopropanol were added. The solvent was distilled off, and the residue was suspended in 40ml of ethyl acetate and heated under reflux, whereupon a precipitate formed. It is cooled to ambient temperature, the precipitate is filtered off and washed with a little ethyl acetate and dried.

Yield: 2.7g (50% of theory)

Melting point: 265 +/-5 ℃ (decomposition)

The monohydrochloride salt exhibits a relatively weak hygroscopic character; there is no reversible change in the conversion to the hydrate phase as occurs with the free base between 50% and 60% relative humidity (see absorption characteristics of the monohydrochloride salt in fig. 7). The monohydrochloride also only absorbs water at very high relative humidity (> 80% relative humidity). Humidity-dependent X-ray powder images show no phase change of the monohydrochloride at relative humidities above 80%.

Table 3: x-ray diffraction intensity (normalized) of the anhydrous form of 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3-amino-piperidin-1-yl ] -xanthine monohydrochloride

Example 4

1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3-amino-piperidin-1-yl ] -xanthine-dihydrochloride

1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3-amino-piperidin-1-yl ] -xanthine base (1.00 g; 2.31mmol) were dissolved in 9.5ml of absolute ethanol and 0.5ml of methyl-tert-butyl ether at boiling temperature. Then 1.2ml of a 3.9 molar solution of hydrogen chloride in isopropanol were added. A precipitate formed. After cooling to ambient temperature, the mixture was filtered, washed with a little MTBE and dried.

Yield: 1.04g (89.0% of theory)

Melting point: 205 plus or minus 5 ℃ (decomposition); gaseous HCl evolved over about 150 ℃.

Dihydrochloride salts also exhibit the usual hygroscopic characteristics; there was no reversible change in conversion to the hydrate phase as observed for the free base between 50% and 60% relative humidity (see absorption characteristics of dihydrochloride salt in fig. 10). The dihydrochloride salt continuously absorbs a certain amount of water over the full range of relative humidity. Humidity-dependent X-ray powder images showed no phase change in the humidity range of 10-90% relative humidity.

Table 4: x-ray diffraction intensity (normalized) of the anhydrous form of 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3-amino-piperidin-1-yl ] -xanthine-dihydrochloride

The melting point was determined by DSC using a device supplied by Mettler-Toledo (model: DSC 821). The onset temperature of the corresponding melting peak in the DSC diagram was used as the melting temperature. A heating rate of 10K/min was used and the experiment was performed under a nitrogen atmosphere.

The X-ray powder pattern (except in one case) was recorded using a STOE Stadi P X-ray powder diffractometer. The diffractometer uses CuK_α1Radiation of radiationAnd a position sensitivity detector. The X-ray generator was operated at 40mA and 40 kV.

The X-ray powder pattern of the monohydrate of the free base was recorded using a Bruker D8Advance X-ray powder diffractometer on which a special air humidity cell made by MRI was placed. Recorded at about 72% relative humidity. The Bruker D8Advance used CuK_αRadiation of radiationAnd a position sensitivity detector. The X-ray generator was operated at 30mA and 40 kV.

Example 5

Coated tablet containing 75mg of active substance

1 tablet core contains:

preparation:

the active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half the specified amount of magnesium stearate. A compact of about 13mm in diameter is made in a tablet machine and then rubbed through a 1.5mm mesh size sieve and mixed with the remaining magnesium stearate using a suitable machine. The granules are compressed in a tablet machine into tablets of the desired shape.

The tablet core weight: 230mg

A mould: 9mm, convex surface

The tablet cores thus produced are coated with a film consisting essentially of hydroxypropylmethylcellulose. The finished coated tablets were polished with peak wax.

Coating tablet weight: 245mg of

Example 6

Tablet containing 100mg of active substance

Consists of the following components:

1A tablet contains:

the preparation method comprises the following steps:

the active substance, lactose and starch are mixed together and moistened homogeneously with an aqueous solution of polyvinylpyrrolidone. After the wet composition was screened (2.0mm mesh size) and dried in a tray type dryer at 50 ℃, it was screened again (1.5mm mesh size) and the lubricant was added. Compressing the completed mixture to form a tablet.

Tablet weight: 220mg of

Diameter: 10mm, double-sided, faceted on both sides and grooved on one side.

Example 7

Tablet containing 150mg of active substance

Consists of the following components:

preparation:

the active substance mixed with lactose, corn starch and silica gel was moistened with a 20% aqueous solution of polyvinylpyrrolidone and passed through a sieve having a mesh size of 1.5 mm.

The granules dried at 45 ℃ are again sieved through the same sieve and mixed with the specified amount of magnesium stearate. Tablets were compressed from the mixture.

Tablet weight: 300mg

A mould: 10mm, plane

Example 8

Hard gelatin capsules containing 150mg of active substance

1 the capsule contains:

preparation:

the active substance is mixed with the excipient, passed through a sieve having a mesh size of 0.75mm, and mixed homogeneously in a suitable apparatus. The completed mixture was filled into size 1 hard gelatin capsules.

Filling materials of the capsule: about 320mg

Capsule shell: no. 1 hard gelatin capsule

Example 9

Suppository containing 150mg of active substance

1 suppository contains:

preparation:

after the suppository block is melted, the active substance is distributed homogeneously therein, and the melt is poured into a cooled mold.

Example 10

Suspension containing 50mg of active substance

100ml of suspension contained:

preparation:

distilled water was heated to 70 ℃. The methyl and propyl parabens are dissolved with glycerol and sodium carboxymethyl cellulose under stirring. The solution was cooled to ambient temperature and the active was added with stirring and dispersed homogeneously therein. After the addition and dissolution of sugar, sorbitol solution and aroma, the suspension was evacuated under stirring to remove air.

5ml of suspension contain 50mg of active substance.

Example 11

Ampoule containing 10mg of active substance

Consists of the following components:

active substance 10.0mg

Proper amount of 0.01N hydrochloric acid

Double distilled water to make up 2.0ml

Preparation:

the active substance was dissolved in the necessary amount of 0.01N HCl, isotonic with common salt, sterile filtered and transferred to a 2ml ampoule.

Example 12

Ampoule containing 50mg of active substance

Consists of the following components:

active substance 50.0mg

Proper amount of 0.01N hydrochloric acid

Double distilled water to make up for 10.0ml

Preparation:

the active substance was dissolved in the necessary amount of 0.01N HCl, isotonic with common salt, sterile filtered and transferred to a 10ml ampoule.

Claims (14)

1. Hydrochloride salts of 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3-amino-piperidin-1-yl) -xanthine and hydrates thereof.
2. Hydrochloride salts of 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3-amino-piperidin-1-yl ] -xanthine and hydrates thereof.
3. Hydrochloride salts of 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (S) -3-amino-piperidin-1-yl ] -xanthine and hydrates thereof.
4. 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3-amino-piperidin-1-yl) -xanthine monohydrochloride and hydrates thereof.
5. 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3-amino-piperidin-1-yl) -xanthine dihydrochloride and hydrates thereof.
6. 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3-amino-piperidin-1-yl ] -xanthine monohydrochloride and hydrates thereof.
7. 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3-amino-piperidin-1-yl ] -xanthine dihydrochloride and hydrates thereof.
8. 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (S) -3-amino-piperidin-1-yl ] -xanthine monohydrochloride and hydrates thereof.
9. 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (S) -3-amino-piperidin-1-yl ] -xanthine dihydrochloride and hydrates thereof.
10. 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3-amino-piperidin-1-yl) -xanthine monohydrate.
11. 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3-amino-piperidin-1-yl ] -xanthine monohydrate.
12. 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (S) -3-amino-piperidin-1-yl ] -xanthine monohydrate.
13. 13. Use of a compound according to any one of claims 1 to 12 for the preparation of a pharmaceutical composition for the treatment of type I and type II diabetes, arthritis, obesity, allograft and calcitonin induced osteoporosis.
14. 14. A pharmaceutical composition comprising a salt according to any one of claims 1 to 12 and optionally one or more inert carriers and/or diluents.