Nitrate salts and pharmaceutical compositions on their basis

 

(57) Abstract:

The invention relates to new and nitrate salts of compounds of formulas (I) to(VI), which can be used in medicine for the treatment of bone disorders such as abnormalities in bone and joints. These compounds have an increased therapeutic activity and improved gastrointestinal tolerance in comparison with the bases of formulas (I) to(VI). 3 B.C. and 2 C.p. f-crystals, 5 PL.

Nitrate salts of the compounds selected from the following classes:

class F1

alendronate disodium;

class F2A

piroxicam;

methotrexate;

penicillamine;

tramadol;

class F2B

comaximal.

The present invention relates to compositions that are used in the treatment and prevention of bone disorders, such as disorders of the bone and joints. In particular, it relates to compositions having improved therapeutic activity and improved gastrointestinal tolerance.

From prior art it is known that pharmacological treatment of bone disorders involves therapy aimed at controlling patof from the prior art for pharmacological treatment of disorders of the musculoskeletal and articular systems, can be mentioned the following (see “New Guide to Medicine & Drugs”, Brit. Med. Association, 1997, page 115; “Martindale, The Extra Pharmacopeia, I. 31, 1996, pp. 11-13):

- diphosphonates (alendronate, pamidronate, risedronate, and so on);

“oxicam”, that is, piroxicam, tenoxicam, aminopyrine; comaximal, penicillamine; methotrexate, etc.

They are drugs with reduced efficiency and cause anxiety, causing damage to the gastrointestinal tract, particularly the stomach. Diphosphonates also cause damage to the esophagus.

Other compounds used in the treatment of bone disorders are antileukotriene drugs, for example ibudilast, pranlukast and so on; aminosalicylate.

The efficacy and gastrointestinal tolerance of these medicines are not optimal.

Compounds that can bypass the shortcomings identified for medicines used in bone disorders, yet were not available from the prior art.

Felt the need for available compounds for use in the treatment of bone disorders with improved therapeutic characteristics and tolerance and/compozitie based on them, with improved pharmacological properties.

The object of the present invention are nitrate salts of compounds with therapeutic activity against bone disorders, or their pharmaceutical compositions, and mentioned compounds are characterized in that they contain at least one reactive group capable of forming salts with nitric acid, and the above compounds selected from the following classes:

class F1

the connection is known as alendronate disodium;

class F2A

known as piroxicam;

known as methotrexate;

known as penicillamine;

known as tramadol;

class F2B

known as comaximal.

Predecessors to obtain the salts of the present invention preferably are selected from the following:

class F1: alendronate;

class F2A: piroxicam;

class F2B: comaximal.

In the compositions according to the present invention can also be used isomers of compounds belonging to the above classes, if they are available. Examples of isomers are CIS-, TRANS-, ownest compared to the other, for example, D shape compared to the L form, or Vice versa.

Salts of compounds belonging to the above classes, contain at least one mole of nitrate ions/mol connection. Preferably the ratio between the moles of nitrate ions and moles predecessor equal to one. Salt with a higher molar ratio can be obtained when the molecule has other primary amino group, can form a salt.

Of the salts of the present invention can be obtained corresponding pharmaceutical compositions in accordance with well known techniques in the art using conventional fillers (see, for example, the book “Remington's Pharmaceutical Sciences, 15a Ed.”).

Dose of salts of the invention in their pharmaceutical compositions are the same and mostly lower than the dose of their predecessors, related to the above classes. However, since they are generally more tolerant, they can be used in higher doses than their predecessors, without the emergence of side effects typical for precursors at high doses.

Predecessors salts belonging to the above classes, receive according to the methods described by the model (see the book "the Merck Index 14andEd.", shown here as a reference) ibandronate disodium: EP 252502, the compound of formula (F1e): EP 325482, the compound of formula (F1f): EP 531253, the compound of formula (F1g): EP 592488, the compound of formula (F1h): EP 522576, the compound of formula (F1i): EP 546548, the compound of formula (F1l): EP 561296, the compound of formula (F1m): JP 93032684 (C. A. ref. Vol. 119 226194d), the compound of formula (F1n): JP 93222073 (C. A. ref. Vol. 120 134926m), the compound of formula (F1o): JP 92356496 (C. A. ref. Vol. 119 R), the compound of formula (F1p): WO 93/12122;

class F2A:

piroxicam, methotrexate, penicillamine, tramadol (see Merck Index volume 14aEd.", shown here as a reference);

class F2B:

comaximal (EP 12866); droxicam: "Merck Index, 14aEd."; celecoxib (WO 94/2798), the compound of formula (F2BIV) (WO 95/15315); the compounds of formula F2BV (7-nitroindazole) and F2BVI (1,2-(triptoreline)imidazole), commercially supplied by Lancaster Synthesis, Morecam-England.

Salts according to the present invention receive according to the following methods.

If the connection that is used to obtain salt, available as a free base or as the corresponding salt, which is soluble in an organic solvent, which preferably does not contain hydroxyl groups in the molecule, for example in acetonitrile, ethyl acetate, telno equal to or higher than 10% (wt./vol.), the addition amount of concentrated nitric acid corresponding to the moles of forming a salt of the amine groups present in the compound. Nitric acid is preferably dissolved in the same solvent. Preferably, during and after the addition the mixture is cooled to temperatures in the range of 20-0 C. the Product is mainly removed by filtration and washed with solvent.

When, on the contrary, the substance is not very soluble or available as a soluble salt in the above-mentioned solvents can be used an appropriate mixture of hydroxylated solvents. Examples of such solvents are methyl alcohol, ethyl alcohol and water. The precipitation can be accelerated by diluting the thus obtained mixture of non-polar solvent after the addition of nitric acid.

When the original product forms a salt with hydrochloric acid, can be obtained salt with nitric acid, directly adding silver nitrate to a solution of compounds. After filtering off the silver chloride solution is concentrated and cooled to highlight nitrate salt.

When the original product is salt, to release the corresponding base can also process the sodium or potassium. The base is then extracted with a suitable organic solvent (for example, halogenated solvents, esters, ethers) and dehydrate. The organic solvent is evaporated and then follow the above methods of preparation, dissolving the base in acetonitrile or in other above-mentioned solvents.

The following examples are only meant to illustrate the invention and not limit it.

EXAMPLE 1

Receiving nitrate salts piroxicam

The solution piroxicam (3 g, 9,05 mmol) in acetonitrile (30 ml) and tetrahydrofuran (50 ml) is treated with 4 With 65% nitric acid (0.63 ml) dissolved in acetonitrile (5 ml). The mixture is stirred and left to stand. After 30 minutes at 4 With its filter and collect the precipitate, which is washed with ethyl ether and dried under vacuum.

Get white solid (3,23 g) having a melting point 120-123 C.

Elemental analysis

Calculated, %: C 45,68; N To 3.58; N 14,12; S 8,13.

Found, %: C 45,76; N 3,54; N 14,11; S 8,16.

EXAMPLE 2

Receiving nitrate salt of alendronate

The solution of alendronate (0,92 g, 3.7 mmol) in 50% nitric acid (2 ml) is infused at a temperature of 4 in atroviridis ether and dried under vacuum. Get a white amorphous solid.

Elemental analysis

Calculated, %: 15,39; N To 4.52; N 9,01.

Found, %: C 15,41; N 4,50; N 8,99.

EXAMPLE 3

Receiving nitrate salts penitsillamin

(L)-Penicillamine (5 g, of 33.5 mmole) in methanol (50 ml) is treated at +4 With 65% nitric acid (2.5 ml) dissolved in acetonitrile (7 ml). The mixture is stirred and left to stand. After 15 minutes at 4 With added ethyl ether, the precipitate is filtered off and dried under vacuum. Receive an amorphous solid (3.2 g).

Elemental analysis

Calculated, %: 28,30; N 5, 65; N 13,19; S 15,11.

Found, %: 28,29; N 5, 66; N 13,22; S 15,08.

EXAMPLE 4

Receiving nitrate salt of methotrexate Solution of methotrexate (5 g, 11,00 mmole) in methanol (60 ml) is treated at 4 C with stirring to 65% nitric acid (0,82 ml) dissolved in acetonitrile (5 ml).

After 30 minutes at 4 C treated with ethyl ether. The precipitate is filtered off and washed with ethyl ether. Dried under vacuum. Receive an amorphous solid (2.2 g).

Elemental analysis

Calculated, %: 46,42; N. Of 4.44; N 24,35.

Found, %: C 46,44; N 4,40; N 24,39.

EXAMPLE 5

Receiving nitrate salt comaximal

The formed precipitate is filtered off, washed with ethyl ether and dried under vacuum. Get a white solid with a melting point 197-199 C.

Elemental analysis

Calculated, %: C 65,81; N 5,52; N Br11.01.

Found, %: C 65,78; N 5,59; N 11,02.

EXAMPLE 6

Receive (4 nitroxy)butyl ester of 5-amino-2-hydroxybenzoic acid (5-ASA-NO2)

EXAMPLE 6A

Getting 5-tert-butyloxycarbonyl-2-hydroxybenzoic acid

To a suspension of 5-amino-2-hydroxybenzoic acid (15 g, 98 mmol) in dioxane (105 ml) and water (150 ml), add triethylamine (24.6 ml, 176 mmol). To the resulting solution was added di-tert-BUTYLCARBAMATE (25,65 g, 118 mmol). The reaction mixture was allowed to mix at room temperature for 4 days. Ultimately, the solution is concentrated under vacuum to a volume of about 150 ml, cooled with ice and acidified with 5% hydrochloric acid, extragere then with ethyl acetate. Select the organic phase and washed with water. The organic phase is dehydrated sodium sulfate. Mpariwa solvent under mucilago ester 5-tert-butyloxycarbonyl-2-hydroxybenzoic acid

To a solution of 5-tert-butyloxycarbonyl-2-hydroxybenzoic acid (20 g, 85.7 mmol) in tetrahydrofuran (200 ml) is added triphenylphosphine (44,9 g, 171 mmole), and then tetrabromide carbon (56.7 g, 171 mmole). The reaction mixture was allowed to mix at room temperature for 24 hours and then evaporated under vacuum. The resulting residue is purified column chromatography on silicagel (eluent: n-hexane/ethyl acetate, 8/2, vol./vol.), checking the contents of the collected fractions by thin-layer chromatography. The product is obtained by collecting head fractions after elution from the column reagent GVS4used in the synthesis. Fractions are collected and dried. Get white solid (21,16 mg) having a melting point 108-111 C.

EXAMPLE 6C

Getting 4-nitrocellulose ester 5-tert-butyloxycarbonyl-2-hydroxybenzoic acid

A solution of 4-bromatologia ester of 5-amino-2-hydroxybenzoic acid (21,16 g, 57.6 mmol) in acetonitrile (150 ml) is heated at 80 C in the dark for 5 hours with silver nitrate. After cooling to room temperature, filtered off the solid and select the solvent that is then evaporated to dryness, obtaining the remnant that purify colonelganj collected fractions by thin-layer chromatography. The head fractions containing compound, evaporated to dryness, obtaining of 12.6 g of a white solid substance having a melting point of 107-109 C.

EXAMPLE 7 (comparative)

Obtaining cleaners containing hydrochloride salt of 4-nitrocellulose ester of 5-aminosalicylic acid (5-ASA-NO2-HCl).

A solution of 4-nitrocellulose ester 5-tert-butyloxycarbonyl-2-hydroxybenzoic acid (10 g, 28.6 mmole) is dissolved in ethyl acetate (8 ml) and cooled to 0 C. 3M ethyl acetate/Hcl (30 ml), obtained by bubbling gaseous model HC1 ethyl acetate, added with stirring until then, until you get the desired molar concentration of Hcl. The mixture is brought to room temperature and left to mix for 2 hours.

Formed solid substance is filtered off, washed with ethyl ether and dried under vacuum. The resulting product (7,1 g) is a white solid substance having a melting point 136-140 C.

Elemental analysis

Calculated, %: 43,09; N 4,89; N 9,13; Cl To 11.56.

Found, %: 43,05; N 4,88; N 9,10; Cl 11,54.

EXAMPLE 8

Receiving nitrate salts 4-nitrocellulose ester of 5-amino-2-hydroxybenzoic acid (5-S-NO2NGO3)

To nitrile (50 ml) and tetrahydrofuran (15 ml) is added silver nitrate (1.19 g, 7 mmol). After 10 minutes, filtered formed salt (AgCl). The solution is left to stand for 30 minutes, then the precipitate is filtered off, washed with ethyl ether and dried under vacuum. Get Sol (1.27 g) in the form of a whitish solid, having a melting point 123-128 C.

Elemental analysis

Calculated, %: 39,66; N 4,50; N 12,61.

Found, %: C 39,70; N A 4.53; N 12,67.

PHARMACOLOGICAL TESTS

EXAMPLE 9

Acute toxicity

The group of 10 rats weighing 20 g were administered a single dose of 100 mg/kg, nitrate salts piroxicam (example 1) orally through the cannula in karboksimetilcelljulozojj water suspension (2% wt./vol.).

The animals were observed for 14 days. None of the animals in the group was not detected the presence of signs of toxicity.

EXAMPLE 10

Gastric toxicity of nitrate salts piroxicam (example 1) in comparison with piroxicam

Three groups of 10 rats each, in which the stomach was empty within 24 hours, oral entered:

5 ml/kg 2% karboksimetilcelljulozojj water suspension

- quantity of nitrate of piroxicam corresponding to 100 mg/kg piroxicam, 5 ml/kg 2% karboksimetilcelljulozojj water is Oxymetazoline water suspension.

After six hours the animals were killed and assessed the degree of gastric damage. The results are presented in table 1, they show that rats treated with nitrate of piroxicam show improved gastrointestinal tolerance compared hydrochloride piroxicam.

EXAMPLE 11

Myeloperoxidase activity 4-nitrocellulose ester of 5-aminosalicylic acid compared with the corresponding hydrochloride and nitrate, were studied on a model of acute colitis.

Were formed 4 groups of 6 animals each. These groups were treated respectively by the media (1% aqueous solution of carboxymethyl cellulose), 100 mg/kg of 5-ASA, 5-ASA-NO2HCl, corresponding to 100 mg/kg of 5-ASA, 5-ASA-NO2NGO3corresponding to 100 mg/kg of 5-ASA.

Animals were treated by rectal above-mentioned compounds in zero time. An hour later, the animals were treated with 0.5 ml 60 mg/ml 2,4,6-trinitrobenzenesulfonic acid in 50% ethyl alcohol. Two hours later, animals were again treated rectal through the same connections and with a 12-hour intervals until a total number of 6 injections.

Measured tissue levels of the enzyme myeloperoxidase (C. Rathakrishnan et al., "Release of oxygen radicals by articular chondrocytes: A study of luminol-dependent chemiluminescence and hydrogen peroxide secretion", J. Bone Miner. Res. 7/10, 1139-1148, 1992).

Myeloperoxidase activity was measured using a modified version of the experimental model described by Bradley et al., J. Invest. Dermatol., 78, 206-209, 1982. From each animal was selected samples of intestinal tissue, which are then suspended in 0.1% bromide of hexadecyltrimethylammonium (50 mg/ml) at pH 6 and homogenized for 15 seconds (transmitter station®RT-7 generator). The samples were frozen and thawed three times before centrifugation (9000 g) for 2 minutes in an Eppendorf centrifuge®Benchtop. Myeloperoxidase activity was measured by adding 7 μl of the supernatant to 200 ál o-dianisidine (Sigma) and measuring the change in optical density at 450 nm for 2 minutes in Microtitre Multiscan®. The reagent contained 0,0005% of hydrogen peroxide as a substrate for the enzyme myeloperoxidase. One myeloperoxidase activity was defined as a unit that can convert micromoles of hydrogen peroxide in water for one minute at 22 C. the Results are presented in table 2 and are expressed in number of units myeloperoxidase activity/mg tissue (wet).

Table 2 shows that in the group aimer 12

Preventing damage to the stomach caused by aspirin, the introduction of alendronate compared with the nitrate salt of alendronate.

Three groups of 5 rats each were treated orally, as shown below.

Group I was treated with alendronate (Alen.) a dose of 80 mg/kg

Group II - 1 hour before a dose of 80 mg/kg of alendronate was administered with oral aspirin (ASP.) a dose of 125 mg/kg

III group - 1 hour before nitrate alendronate (Alen NGO3) in an amount corresponding to 80 mg/kg dose of alendronate was administered orally aspirin dose of 125 mg/kg

Evaluation of gastric lesions was performed, destroying animals three hours after treatment with alendronate or nitrate of alendronate.

The results are presented in table 3, they show that the introduction of nitrate alendronate reduces the level of gastric injury in 4-5 times compared with this value after administration of alendronate.

Pharmacological tests with nitrate salts comaximal and tramadol

Example 13

Inhibitory activity of nitrate salt comaximal on the damage to bovine endothelial cells caused by codingerroraction.

In this test the potential effect comaximal was estimated n the CE. This experiment corresponds to the well-known internal dependencies between oxidative stress, endothelial dysfunction and impaired skeletal system, as described in the Free Radical. Biol. Med., 1997, 22, 269-85; Ann. Biomed. Eng., 1999 July-August, 27 (4), 508-16; Re. Rhum. Engl. Ed., Mar 1999, 66(3), 158-166; Exp. Naphrol., November-December 1996, 4(6), 314-21, and N. Y. Acad.Sci., 26, 673, 120-5.

In the following experimental models studied the inhibitory effect of nitrate comaximal VS hydrochloride comaximal on the damage to bovine endothelial cells caused by codingerroraction. An adapted procedure was described Fiorucci and other aliment oil displayed pure. Pharmacol. Ther., 13, 421-35, 1999. Cumonherface (270 M in ethanol) was grown from bovine endothelial cells, as described Korubane and others, Jpn.J. Pharmacol., 68, 263-9, 1995, and the DNA fragments were taken as the value of the damaged cells. The results were expressed in % of the DNA fragment with a control comparison and are presented in table 4. It is clear that nitrate comaximal has a large cytotoxity activity than the corresponding hydrochloride.

Example 14

Antiseptic activity of nitrate tramadol VS tramadol hydrochloride.

Osteoporosis patients can cause very often the pain, and the treatment of such a disease causes is necessary in order to reduce the risk of fractures, but also to ease the pain. The antiseptic activity of the compounds after their intravenous administration was determined in accordance with the method described by M. Bianchi and others, Brain Res., 797, 163-6, 1998.

Were used rat Sprague Dawley (male) weighing 200-250 g Animals were placed in a transparent plastic chamber and acclimatized for 5 minutes before the test. Light halogen bulb 8V-50W went on the plantar surface of the hind paws of rats through the bottom of the plastic box. The beam had a diameter of about 12 mm was Measured time otdergivanija left hind legs. The experiments were conducted only on rats, in which the hidden state is stable (±2,0 S) for such sequential measurements; the value obtained in the last measurement was considered to be the key hidden.

Nitrate and hydrochloride tramadol was administered intravenously in 0.9% saline solution dose of 16 mg/kg Antiseptic activity was determined after 30 and 120 minutes after administration of the compounds. The results are shown in table 5 and are expressed as the time difference of the latent state before and after handling animals at a specified time (30 or 120 minutes after administration of the compounds).

1. Nitrate salts soedinenii CLASS="ptx2">

piroxicam;

methotrexate;

penicillamine;

tramadol;

Class F2B):

comaximal.

2. Nitrate salts of 4-nitroacetanilide ester of 5-amino-2-hydroxybenzoic acid and 4-nitrocellulose ether [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethynyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid.

3. Nitrate salts on PP.1 and 2, where the connections are represented in the form of their isomers.

4. Nitrate salts on PP.1 and 2, where the salts of the mentioned compounds contain at least 1 mol of nitric acid per 1 mol of compound.

5. Pharmaceutical composition for the treatment of bone disorders, comprising as active principle a compound according to PP.1-3.

 

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