Use pyridylmethyl as a therapeutic agent

 

(57) Abstract:

The present invention relates to the field of medicine and for the application of tetraalkyl esters pyridinedimethanol acid for treatment of bone diseases, such as osteolytic bone disease associated with malignant tumor, Paget's disease, and primary and secondary osteoporosis, pharmaceutical compositions and treatment of bone disease. The invention improves the efficiency of the treatment. 3 S. and 4 C.p. f-crystals, 1 Il., 6 table.

The present invention relates to a specific group of tetrapyrrol eredivision acid for use as therapeutic agents, particularly for use in cases of bone.

Bisphosphonates represent a therapeutic agent used for the treatment of pathological fracture of bones of various origin, such as osteolytic bone disease nature associated with malignant tumors, Paget's disease and osteoporosis. They are analogous to physiological inorganic pyrophosphates. The basic P-C-P structure bifosfonatami allows the formation of a large number of different is SS="ptx2">

In General, bisphosphonates inhibit osteoclasts, the cells responsible for bone resorption. Known bisphosphonates bind to bone matrix, while they are dissolving osteoclasts and decrease the activity of these osteoclasts. They inhibit bone resorption both in vitro and in vivo. For known bifosfonatami characterized by limited absorption from the gastrointestinal tract, the rapid disappearance in the bone tissue and in the urine in unchanged form.

The basis of the present invention is the idea of creating derivative bifosfonatami with high bioavailability after oral administration, which, in addition, have low affinity to the bone. This would avoid the side effects without loss antiresorptive activity.

In patents US 4447256, DE 3831578 (Suzuki et el); JP 55089210, JP 55098105, JP 55043054, P 55043055 (Nissan chemical industries) discloses a method of obtaining some tetraalkyl esters pyridinemethanol acid. In accordance with these patents, the described compounds can be used as herbicides.

In the patent EP 337706 (Isomura et al.) disclosed receipt was cilil or heterocyclization of tetrapyrrol iminomethylene the Ana.

In the patent US 4973576 (Sakamoto et al.) revealed some isoxazolidinone tetraalkyl esters aminomethylphosphonic acids, which have been tested in the treatment of arthritis. Bioavailability their oral low.

In the patent EP 282309 disclosed azole-aminomethylphosphonate acids and their lower alkalemia esters. Terrafire not been studied.

In the patent EP 325482 reveals cycloalkyl-aminomethylphosphonate acids and their esters. Terrafire not been studied.

The present invention belongs to the group of pyridyl-bifosfonatami with new pharmacological and pharmacokinetic profile. These new pyridylmethyl not inhibit bone resorption in vitro, but is able to inhibit bone resorption iv vivo.

Pyridylmethyl not associated with bone matrix and apparently require metabolic activation.

Thus, the present invention relates to tetraalkyl esters pyridyl-aminomethylphosphonic acids that can be substituted on the pyridine ring, in particular, to derive methylenephosphonic acid of General formula 1.

< / BR>
in which each of the radicals on the Rupp, each of X and Y is independently from each other hydrogen, a linear or branched saturated C1-C5is an alkyl group, halogen, a hydroxyl group, a C1-C5-alkoxy, benzyloxy, acyloxy, a nitrogroup, triptorelin group or NR5R6where R5and R6can be the same or different and represent hydrogen, C1-C5-alkyl or - acyl, intended for use as therapeutic agents.

Groups X and Y, as well as essential amino patterns in methylenephosphonic acid can replace any one of clauses 2 to 6 in pyridinium ring. Groups X and Y are preferably hydrogen or hydroxyl group, in the latter case, preferred one or two hydroxyl groups. Peregrina group is preferably a 2-pyridyloxy group.

Halogen represents fluorine, chlorine, bromine or iodine.

C1-C5is an alkyl group represents a linear or branched group such as methyl, ethyl, n-, i-propyl, n-, i - and t-butyl or-pentyl, preferably methyl or ethyl. The alkyl group in the alkoxy group, as in the case of X and Y, can be Prevx group, as in the case of X and Y or in the definition of R5or R6represents preferably a lower alkyl carbonyl group which contains from 1 to 5 carbon atoms and a has the value given above, preferably it is methyl or ethyl. Groups from R1to R4preferably have the same values and are predominantly ethyl.

Preferred compounds of the present invention presents the following connections:

Tetraethyl ester of [(2-pyridinylamino)methylidene]biphosphonates acid,

Tetraethyl ester [[(3-hydroxy-2-pyridinyl)amino]methylidene] biphosphonates acid,

Tetraethyl ester [[(6-methoxy-Z-pyridyl)amino]methylidene]biphosphonates acid,

Tetraethyl ester [(4-pyridinylamino)methylidene]biphosphonates acid,

Tetraethyl ester [[(5-chloro-2-pyridinyl)amino] methylidene]biphosphonates acid,

Tetraethyl ester [[(5-methoxy-2-pyridinyl)amino]methylidene] biphosphonates acid,

Tetraethyl ester [[(6-amino-2-pyridinyl)amino]methylidene]- biphosphonates acid,

Tetraethyl ester [[(3-nitro-2-pyridinyl)amino]methylidene] biphosphonates acid

Tetraethyl ester [[(3,5-dichloro-2-pyridinyl)amino]methylidene] biphosphonates to the silt ether [[(5-hydroxy-2-pyridinyl)amino]methylidene] biphosphonates acid,

Tetraethyl ester [[(3-chloro-5-trifluoromethyl-pyridinyl)amino] methylidene] biphosphonates acid,

Tetraethyl ester [[(2-chloro-3-pyridinyl)amino]methylidene] biphosphonates acid,

Tetraethyl ester [[(6-chloro-Z-pyridinyl)amino]methylidene] biphosphonates acid,

Tetraethyl ester [[(3-benzyloxy-2-pyridinyl)amino]methylidene] biphosphonates acid,

Tetraethyl ester [[(5-nitro-2-pyridinyl)amino]methylidene] biphosphonates acid,

Tetraethyl ester [[(5-benzyloxy-2-pyridinyl)amino]methylidene] biphosphonates acid.

N-substituted terrafire (aminoalkylated) biphosphonates acid can be obtained by using a known method, that is, when the interaction aminosilane compounds with alkyl-orthoformiate and further interaction thus obtained as an intermediate aminoethanol derivative with dialkylphosphites either as received or purified form.

The second method suitable aminopyridine first reacts with a mixture of formic acid/acetic anhydride. Received formamid then interacts with trihalogen phosphorus and trialkylphosphites.

Terrafire aminoalkylphosphonic acids may be the first reaction of the thus obtained compound after the synthesized with trialkylphosphites (Schrader et al. Synthesis (1986), 372).

The described compounds are used for the treatment in mammals of bone diseases, such as osteolytic bone disease associated with malignant tumors, Paget's disease, and primary and secondary osteoporosis.

The activity of the described compounds was confirmed in animal studies and in vitro. Methods and results of these studies are presented below. In normal growing rats representative compound in the form of tetraethyl ester [(2 - pyridinylamino)matrilin]biphosphonates acid was reduced spontaneous bone resorption, as shown valuation method for the removal of tetracycline in urine and in chronically pre-labeled rats. These compounds were also effective for the prevention of bone rarefaction in cases of experimental porous induced by incision of the sciatic nerve in rats. Not been shown any effect in vitro on tissue culture skull mice, as shown by the test for calcium release. This result suggests that the compound is metabolized before it can be detected pharmacological effect. The parent compound does not show any binding to crystalloidal] biphosphonates acid was investigated in rats. Small amounts of intravenous doses were allocated in the form of parent compound within 24 hours in the urine, supporting the idea of its metabolisation. About half of the oral dose mentioned compounds were subjected to suction in the body of rats.

The following examples illustrate the present invention without limiting it in any way.

Example 1

Synthesis of tetraethyl ester [(2-pyridinylamino)methylidine] biphosphonates acid:

2-aminopyridine (0,2 mol) is mixed with triethylorthoformate (0,8 mol) and iterator of boron TRIFLUORIDE and heat the mixture at a temperature of 150oC for 4 hours, resulting in the distillation formed in the reaction of ethanol. Triethylorthoformate distilled off in vacuum. To the reaction mixture add diethylphosphate (0,4 mol) and heated the mixture at a temperature of 150oC to distillation formed ethanol. The mixture is cooled and the crude product purified via chromatography (eluent: dichloromethane-methanol, 1: 1). The output is 29 grams (37%).

The product obtained has the following physicochemical characteristics:

31P-NMR (CDCl3) 15,52 ppm

1H-NMR (CDCl3(see table. A).

Example 2

Received the (0,2 mol) is mixed with triethylorthoformate (0,8 mol) and iterator of boron TRIFLUORIDE and heat the mixture at a temperature of 150oC for 4 hours. Formed during the reaction, the ethanol is distilled off. Triethylorthoformate distilled off in vacuum. To the reaction mixture add diethylphosphate (0,8 mol) and heated the mixture at a temperature of 150oC until distillation of the formed ethanol. The mixture is cooled, and the crude product is cleaned with the use of chromatography (eluent: dichloromethane-methanol, 1: 1). The output is 26.5 grams (32%). (31P-NMR 15,20 ppm, CDCl3)

Similarly can be obtained:

Tetraethyl ester [[(3,5-dichloro-2-pyridinyl)amino]methylidene] biphosphonates acid (31P NMR, 14,59 ppm, CDCl3).

Tetraethyl ester [[(3-chloro-5-trifluoromethyl-pyridinyl)amino] methylidene] biphosphonates acid (31P-NMR, 14,15 ppm; CDCl3.

Tetraethyl ester [[(5-hydroxy-2 - pyridinyl)amino]methylidene]biphosphonates acid (mass spectrum (E1 Mass): 396 M, 350 M-EtOH, 259 M-P(O)(OC2H5)2.

Tetraethyl ester [[(5-nitro-2-pyridinyl)amino]methylidene] biphosphonates acid (31P-NMR, 13,97 ppm; CDCl3).

Tetraethyl ester [[(5-benzyloxy-2-pyridinyl)amino]methylidene] biphosphonates acid.

Tetraethyl ester [[(5-methoxy-2-pyridinyl)amino] methylidene] biphosphonates acid.

Tetraethyl is retroware ether [[(3-hydroxy-2-pyridinyl) amino]methylidene]biphosphonates acid.

2-amino-3-hydroxypyridine subjected to O-benzilidene using benzylchloride in the two-phase system in the presence of a catalyst phase transfer (Bristol et al. Synthesis 1981, 971). 2-amino-3-benzyloxypyridine (0,1 mole) is dissolved in dichloromethane and the resulting solution is cooled to a temperature of 0oC. To the solution was added 50 ml of formic acid/acetic anhydride (5:3) and stirred the mixture overnight at room temperature. The reaction mixture was concentrated, and the residue was washed with diisopropyl ether to obtain 11.4 g of 6-methoxy-3-formamide, 10 ml of trichloride phosphorus and 1.5 ml of triethylphosphite heated at a temperature of 60 -70oC for 1 hour. To the solution was added 3-benzyloxy-rider-2-formamide (0,01 mol) and the resulting mixture was stirred for 5 hours at room temperature. The reaction mixture is concentrated and cleaned chromatography (eluent:dichloromethane-methanol, 2: 1) to give 0.8 g of tetraethyl ester [[(3-benzyloxy-2-pyridinyl) amino]methylidene]biphosphonates acid. Benzyl group hydrogenizing to obtain 0.4 g of tetraethyl ester [[(3 - hydroxy-2-pyridinyl)amino] methylidene]biphosphonates acid (mass spectrum (E1 Mass): 396 M, 350 M-EtOH, 259 M-P(O)(OC2H5)2.

Oppo is a new acid,

Tetraethyl ester [[(6-hydroxy-3-pyridinyl)amino]methylidene] biphosphonates acid,

Example 4

Getting tetraethyl ester [[(6-chloro-Z-pyridinyl) amino]methylidene] biphosphonates acid.

Decisionrelevant receive in accordance with the methodology Cade, J. Chem. Soc., 1959, 2266.

6-chloro-3-aminopyridine alkylate using diethyl - iodotyrosine and sodium amide as the base in accordance with known techniques. The obtained diethyl ether 6-chloro-3-pyridinylamino-methylphosphonic acid (0,5 mol) and N-bromosuccinimide (0,5 mol) in anhydrous carbon tetrachloride is irradiated for 2 hours with the lamp 200 V. the Solid is filtered, washing the residue in cheterehetazhnom chloride carbon and concentrated in vacuo. The obtained diethyl ether 6-chloro-3-pyridinylamino(methyl bromide)-phosphonic acid (0,1 mole) is heated in tetrahydrofuran with triethylphosphite (0,1 mol) at 50oC for 4 hours. The reaction mixture was konzentriert in vacuum. The product is cleaned chromatography (eluent: dichloromethane-methanol, 9:1). The output is 5.1,

The same method can be obtained:

Tetrachromacy ether [[(2-chloro-3-pyridinyl)amino]methylidene] befor CLASS="ptx2">

Tetraethyl ester [(4-pyridinylamino)methylidene]biphosphonates acid.

Tetraethyl ester [[(6-amino-2-pyridinyl)amino]methylidene] biphosphonates acid.

Tetraethyl ester [[(3-nitro-2-pyridinyl)amino]methylidene] biphosphonates acid.

Tetraethyl ester [[(2-chloro-3-pyridinyl)amino]methylidene] biphosphonates acid.

Tetraethyl ester [[(5-acyloxy-2-pyridinyl)amino]methylidene] biphosphonates acid.

Assessment of the impact on spontaneous resorption of bone with a test for the removal of tetracycline urine in pre-labeled rat:

Used male rats sprag-Share (Spraque-Dawley). Since the first week of life in rats injected subcutaneously solution containing 10 MX/ml (7-3H(N) tetracycline dissolved in physiological solution. Injections are performed 2 times a week for 6 weeks. Each animal receives 20 MX radioactive tetracycline. All rats were given normal food for growing animals and water libitum. One week after the last injection of radioactive tetracycline rats are weighed and begin feeding with the use of diet for adult cats. On the 5th day rats are distributed randomly pacina 2 day injected subcutaneously with various doses daily for 6 days connection 1, representing the tetraethyl ester of [(2-pyridinylamino) methylidene]biphosphonates acid, dissolved in saline. Control animals were given saline. Urine volume was measured and radioactivity was determined in urine samples using liquid-scintillation counter. To determine the maximum inhibition of the excretion of tetracycline calculated data as the ratio results for treated/control animals every day.

Excretion nematerializiranih tetracycline urine reflects the removal of bone during the resorptive processes and thus allows continuous monitoring of the process of bone resorption. As shown in table 1 (compound 1), there is a dose-dependent inhibition of excretion of radioactive tetracycline, indicating that the inhibition of the process of bone resorption.

Impact-induced immobilization osteoporosis in rats.

Rats-males sprag-Share (Spraque-Dawlei), weighing 20025 g, randomly distributed by weight in groups and conduct anaesthesia using Hypnorm/Memunatu and Temesi (Hypnorm/Mebunat and Temqesic). Do the back-side section on the right or left thigh, revealing the relative lateral side limb leave without impact. Compound 1 dissolved in saline solution, administered by subcutaneous injection daily at various doses ranging from 2 days prior to surgery and then to 20 days after neurectomy. Control animals were given only saline. Animals with doubly labelled with fluorochromes receiving it at timed intervals, killed on day 21 after neurectomy and remove parts of the thigh. The hip is placed in the methyl methacrylate, cut and paint. Metatithemi secondary spongiosa and diaphyseal cortical layer of the bone of the thigh animals are histomorphometrical analysis. In control rats the total area of the hip bone is reduced in the immobilized limb. As shown in table 2, compound 1 decreases in a dose-dependent mode size of the femur in the immobilized limb. It was not observed any detrimental impact on the level of deposits of mineral components in cortical bone (data not shown).

Effect on bone in vitro

Newborn mice were labeled with subcutaneous injections45Ca for four days before the killing. Fragments of the bones of the cranial vault was obtained using microdissected receiving were cultured for three days in the presence of compounds 1 and in his absence. Bone resorption is stimulated by the introduction of parathyroid hormone (PTH, 10 nm), was measured inhibitory effect on this stimulated resorption. As shown in Table 3 in vitro has not been demonstrated inhibition of bone resorption, except the use of very high non-physiological concentrations. To determine whether binding of compound 1 with mineral components of bone tetrahydrate14C-Dunadry-clodronate and crystals of hydroxyapatite incubated at room temperature in the buffer based on barbituric acid at physiological pH in the presence and in the absence of compound 1 in different concentrations. After two hours of incubation the mixture was centrifuged and the supernatant measured the percentage of the total specifically bound radioactivity. Up to a concentration of 500 μm was not observed in the binding of compound 1 to hydroxyapatite (table 3).

Pharmacokinetics

Bioavailability was determined on the basis of the total number of compounds excreted in the urine within 24 hours or on the basis of data on the concentrations in the serum at different time points after oral or intravenous administration. Urine samples and to whom matography. In amounts below 10% of the accepted oral dose and 14% of the injected dose of the compound was regarded as the parent compound for 24 hours (table 4, bioavailability 58%). The bioavailability of compound 1, as measured by the concentration in the blood, was 44%.

The overall density of the tibia shown in the drawing

The introduction of the compound of example 3 immobilized rats leads to a significant increase in density in the tibia as immobilized, and the intact limb in comparison with the control rats, which were injected with saline (NaCl).

PHARMACEUTICAL DRUG

Connection, you can enter enterline, parenteral or subcutaneously in the form of any standard dosage forms, such as tablets, capsules, syrups, solutions or suspensions. Can also be used any adjuvant for the production, dissolution and drug administration as well as buffer solutions, stabilizers or agents that provide the desired viscosity or creating a suspension.

The above adjuvant include, for example, tartrate and citrate buffer solutions, alcohols, EDTA and the other way is incellular, talc, fats and, if necessary, flavorings and sweeteners.

The dose depends on various factors such as route of administration, species, age and individual properties. The daily dose is from about 1 to 1000 mg, typically 10-200 mg per day, and this dose can be injected once or divided into several doses.

A typical composition of the capsules or tablets are presented in table. 5.

For medical use in parenteral administration of the drug can be prepared, for example, in the form of a concentrate for infusion or injection. In the case of concentrate for infusion you can use sterile water, phosphate buffer, NaCl, NaOH or HCl or other known pharmaceutical adjuvant, and in the case of injection can also be any suitable pharmaceutical preservatives.

1. The use of tetrapyrrol pyridinyl-aminomethylenemalonate acid formula 1

< / BR>
in which each of the radicals from R1to R4represents a linear or branched saturated WITH1- C5is an alkyl group, each of X and Y is independently from each other hydrogen, a linear or branched saturated WITH1- When trograph, triptorelin group or NR5R6where R5and R6can be the same or different and represent hydrogen, C1- C5-alkyl or-acyl as an active agent for the preparation of pharmaceutical compositions for the treatment of bone disease, such as osteolytic bone disease associated with malignant tumor, Paget's disease, and primary and secondary osteoporosis.

2. Application under item 1, characterized in that WITH1- C5-alkyl, including alkyl group, a subset of the alkoxy and acyl groups, represents methyl or ethyl, halogen represents chlorine.

3. Application under item 1 or 2, characterized in that the group R1to R4the same and preferably represents ethyl.

4. Application under item 3, characterized in that pyridinoline group represents 2-pyridinyl.

5. Application under item 1, characterized in that the active agent is a:

Tetraethyl ester [[(2-pyridinyl-amino)-methylidene] bisphosphonates acid;

tetraethyl ester [[(3-hydroxy-2-pyridinyl)methylidene]biphosphonates acid;

tetraethyl ester [[(6-methoxy-3-Piri is Oh acid;

tetraethyl ester [[5-chloro-2-pyridinyl)amino] methylidene] biphosphonates acid;

tetraethyl ester [[(5-methoxy-2-pyridinyl)amino]methylidene]biphosphonates acid;

tetraethyl ester [[(6-amino-2-pyridinyl)methylidene] biphosphonates acid;

tetraethyl ester [[(3-nitro-2-pyridinyl)amino]methylidene]biphosphonates acid;

tetraethyl ester [[(3,5-dichloro-2-pyridinyl)amino] methylidene]biphosphonates acid;

tetraethyl ester [[(6-hydroxy-3-pyridinyl)amino] methylidene]biphosphonates acid;

tetraethyl ester [[(5-hydroxy-2-pyridinyl)amino] methylidene]biphosphonates acid;

tetraethyl ester [[(3-chloro-5-trifluoromethyl-pyridinyl)amino]methylidene] biphosphonates acid;

tetraethyl ester [[(2-chloro-3-pyridinyl)amino] methylidene]biphosphonates acid;

tetraethyl ester [[(6-chloro-3-pyridinyl)amino] methylidene]biphosphonates acid;

tetraethyl ester [[(5-nitro-2-pyridinyl)amino]methylidene]biphosphonates acid or

tetraethyl ester [[(5-benzyloxy-2-pyridinyl)amino]methylidene]biphosphonates acid.

6. Pharmaceutical composition for the treatment of bone disease, such as osteolytic bone disease associated with malignant novobrisov the Ki acceptable carrier and an effective amount of the compounds unveiled in PP.1 - 5.

7. A method of treatment of bone disease, such as osteolytic bone disease associated with malignant tumor, Paget's disease, and primary and secondary osteoporosis, including the introduction into the organism of a mammal affected by a disease, an effective amount of the compounds disclosed in paragraphs.1 to 5 or a composition according to p. 6.

 

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EFFECT: higher efficiency of regeneration.

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