Derivatives of tetracycline

 

(57) Abstract:

Describes the new derivatives of tetracycline General formula I, where the values of R1, R2, R3, R4specified in paragraph 1 of the claims. Compounds are able to concentrate in the bone tissue and possess inhibiting resorption and promoting the crystallization of action. 7 C.p. f-crystals., 3 Il., 7 table.

The invention relates to compounds that perform new functions inhibitors of bone ratably/promoters osteogenesis.

Normal regeneration of bone is characterized by a balance between bone resorption and osteogenesis, and in the case of the predominance of bone resorption occurs dissolution and reduction of bone components, which leads to bone diseases such as osteoporosis. It is known that sex hormones, for example, estrogen, able to inhibit bone resorption, resulting in used in Europe and America for the prevention and treatment of osteoporosis. However, so far not confirmed that these hormones are concentrated in the bones, and you should not underestimate the possibility oncogenesis due to the introduction of some only of such hormones.

On the other hand, the antibiotics tetracycline ti is s, or to promote the formation of bone. And only in the description of U.S. patent N 4925833 indicated that tetracycline promotiom synthesis of bone proteins in experiments at the cellular level. Although the synthesis of bone proteins and is necessary for bone formation, synthesis of bone proteins little for osteogenesis.

Up to the present time no known substances that promote osteogenesis, and which can be used as preventive and therapeutic agents in bone diseases.

Accordingly, the aim of the present invention is to provide means for the treatment of bone diseases, inhibition of bone resorption and promotes osteogenesis, preferably synergistically, and are able to concentrate in the bones.

The creators of the present invention conducted various studies aimed at solving the above problems, and in the course of these studies it was found that the compounds obtained by covalent binding of the antibiotics tetracycline and type of hormones steroid type, for example, estrogen, with the use of a binder compound, promotirovat osteogenesis, in addition to the ability to inhibit bone resorption and are capable of the present invention provides osteogenesis promoters/inhibitors of bone resorption, having the General formula (I):

X-Y-Z

(where X represents a monovalent group of the following formula (II):

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(where R1represents hydrogen or hydroxyl, R2represents hydrogen or hydroxyl, R3represents hydrogen or methyl and R4represents hydrogen, halogen or dimethylaminopropyl);

Y represents a divalent or trivalent group of the following formula (III), (IV) or (V):

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(where n = 0 to 4 and X represents a direct link,- O - or-NH-);

Z represents a monovalent group formed by removing hydrogen or hydroxyl of compounds of the following formula (VI):

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(where R'1is HO or O=; R'2represents a hydrogen atom or methyl; R'3represents a hydrogen atom, phenyl or substituted phenyl; R'4represents methyl or ethyl; R'5represents hydroxyl, ketogroup or acetyl; R'6represents hydrogen, hydroxyl, methyl, ethinyl or PROPYNYL, or R'5and R'6together form a group =O; R'7represents hydrogen, hydroxyl or =O or R'6and R'7together attached to the oxygens 2,2-dioxypurine group and the symbol marked by simple or double bond), and joining this group Pres, attached at the 11-position, communication (1) in the formula (II) and communication (2) in formulas (III) - (V) are directly connected, the connection (3) in formulas (III) - (V) and any link in the above provisions of formula (VI) are directly connected).

In the above formula (II) halogen, for example: chlorine, fluorine, bromine or iodine, preferably chlorine.

Brief explanations of the charts

In Fig. 1 shows a photograph illustrating the results of experiment No. 3.

In Fig. 2 shows a photograph illustrating the results of experiment No. 3.

In Fig. 3 shows a photograph illustrating the results of experiment No. 3.

In Fig. 1-3 shows the results of the same experiment, repeated three times.

Preferred examples of the monovalent group of formula (II), which is a fragment of the compounds of formula (I) as an active ingredient of a pharmaceutical product of the invention include:

Formula (II-1):

Monovalent group tetracycline represented by formula (II-I) (where (in the formula (II)) R1is hydrogen, R2is hydroxyl, R3is methyl and R4- hydrogen):

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Formula (II-2):

Monovalent group terramicina presented
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Formula (II-3):

Monovalent group chlortetracycline, represented by formula (II-3) (where (in the formula (II)) R1is hydrogen, R2is hydroxyl, R3is methyl and R4- chlorine):

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Formula (II-4):

Monovalent group desoximetasone represented by formula (II-4) (where (in the formula (II)) R1is hydroxyl, R2is hydrogen, R3is methyl and R4- hydrogen):

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Formula (II-5):

Monovalent group aminotetraline represented by formula (II-5) (where (in the formula (II)) R1is hydrogen, R2is hydrogen, R3is hydrogen and R4- dimethylaminopropyl):

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Preferred examples of the monovalent groups of the compounds of formula (VI), which are fragments of the compounds of formula (I) as active ingredients of pharmaceutical preparations of the present invention include the following.

The formula (VI-1):

Monovalent group of estrone represented by formula (VI-1) (where (in the formula (VI), R'5and R'6together form a group =O and R'7- hydrogen):

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The formula (VI-2):

Monovalent group estradiol represented by formula (VI-2) (where (in the formula (VI), R'5is hydroxyl, R'6is hydrogen and R'7- hydrogen):

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The formula (VI-3):

The B> - ethinyl and R'7- hydrogen):

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The formula (VI-4):

Monovalent group estriol represented by formula (VI-4) (where (in the formula (VI), R'5is hydroxyl, R'6is hydrogen and R'7- hydroxyl):

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The connecting group in the compounds of the above formulas (VI) - (VI-4) may be in the 3-position, 6-position or 17-position.

The compounds of formula (VI) can be also represented by monovalent groups obtained by removing a hydrogen or hydroxyl group of the following compounds:

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Accordingly, the active component of the pharmaceutical preparation of the present invention can be identified with the following code; for example:

/II-1/-/III/-(3) /V-1/ (the number in parentheses () indicate the position of the linking group in formula /VI-1/. Possible variants of such combinations are presented in table A (see below).

Connections, described above, can be obtained by known methods. For example, a binder compound of formula (III-V) the first is connected with a steroid compound of the formula (VI) and received the product the accession connected with the connection tetracycline.

Attach tie the SNO following reaction scheme:

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In addition, the compound in which R'5is hydroxyl and R'6is hydrogen or ethinyl can be obtained, for example, by the following reaction:

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To attach the binding of the compounds of formulas (III) - (V) in the 6-position of the steroid compounds of the formula (VI) is first in the 6-position of the steroid compound is administered group =O, followed by the following reaction:

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Then to the reaction product of the binder connection to steroid compound can be attached tetracycline connection by linking N-atom binding compounds with the N-atom of the amide group of tetracycline compounds with formaldehyde.

The pharmaceutical preparations of the present invention can be prepared in a unit dosage form for oral or parenteral administration, for example: intravenous injection, intradermal injection, intramuscular injection, intraperitoneal injection, and so on, an Effective daily dose for a human is equal to 0.2 - 200 mg oral introduction and 0.1 - 100 mg of parenteral introduction. Compounds of the present invention are characterized by extremely low toxicity, and is LD50the compound I obtained in example 1, for example, for mice sostavlaem, determined by administration. In the case of oral administration, the pharmaceutical preparation may be in the form, such as capsules, tablets, granules, powder, liquid preparation, etc. These forms receive the usual way. Liquid preparations can be obtained, for example, by dissolving or suspendirovanie active component of the present invention in an acceptable environment, for example, water, buffer solution, etc. Powder preparation can be prepared by mixing the active ingredient with a powdery filler such as starch, e.g. corn starch and/or sugar, such as lactose.

Tablets can be obtained by mixing the active component with a filler, for example, the above filler and a binder agent, for example, starch paste and compressing the mixture in teletrauma car. Granules can be prepared by mixing the active ingredient with the excipient, binding agent, and so on, dilution of the mixture with a liquid, e.g. water and/or glycerin, a screening of the resulting product through a sieve with its granulation and drying the obtained granules. Capsules can be prepared by kapsulirovaniem the above powder or granules in capsules matched what derounian active component in physiological saline or a buffer salt, such as, for example, phosphate buffer solution. Parenteral dosage forms can be dried by freezing the products before use, must be dissolved or suspended, and additives for freeze-drying can be a saccharide, for example, lactose or conventional additives for freeze-drying.

Examples

The following are specific examples of compounds of the present invention. However, the scope of the invention as a whole is not limited to these examples.

Example of synthesis 1

Synthesis of 1-1

3 chloroethoxy-17-okestra-1,3,5(10)-triens (compound 1-1)

To the toluene solution obtained by mixing 27.1 g of estrone, 22.2 g of 3-chloroethoxy-17-okestra-1,3,5(10)-triens and a small number of triethylenediamine add the NaOH solution. After establishing pH 10 the reaction continued for 4 hours and the solvent evaporated. By recrystallization of the solid residue from the alcohol produced compound (1-1, R7= H), yield 79%

So pl. 86 - 88oC.

Elemental analysis: C, 72.4, H 4.3, Cl 10.71.

Synthesis of 1-2

N-[17-okestra-1,3,5(10)-trien-3-oxyethyl]-piperazine (compound 1-2)

A mixture of 7.8 g of the above compound (1-1), 46.6 g of anhydrous piperazine and 120 ml timelooking solid residue from ethanol and acetone receive a white crystalline compound (VI), yield 85%.

So pl. 140 - 142oC.

Elemental analysis: C, 75.2, H 9.2, N 7.4.

Synthesis of 1-3

N-4-[17-okestra-1,3,5(10)-trien-3-oxyethyl] -piperazine-1 - methyltetrazole (compound 1-3)

A mixture of 3.8 g of the above compound (1-2), 0.03 g of metatarsalgia and 15 ml of isopropanol is heated 2 hours at 40oC. After adding 3.5 g of tetracycline the mixture is stirred for 5 hours. Upon completion of the reaction the reaction product is filtered and washed with isopropanol and ethyl ether. As a result, the compound (1-3) in the form of a yellow solid substance (R1= R4= H, R2= OH, R3= CH3), yield 95%.

So pl. 160oC (decomp.).

Elemental analysis: C 67.21, H 7.12, N 6.67.

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Example of synthesis 2

Synthesis 2-1

N-[17-Hydroxyestra-1,3,5(10)-trien-3-oxyethyl]piperazine (compound 2-1)

In methyl alcohol was dissolved 3.8 g of compound (1-2) of example 1. After adding 0.5 g of bergerat potassium in alkaline conditions, the reaction mixture is heated with stirring for 3 hours. The reaction mixture is neutralized with acid and the methyl alcohol is evaporated. By recrystallization of the obtained solid residue from the alcohol produced white crystals (compound 2-1, R7= H), yield 91%.

So pl. 141 - 142osetil]piperazine-1-methylenedianiline (compound 2-2)

A mixture of 3.84 g of the above compound (2-1), 0.03 g of metatarsalgia and 20 ml of isopropanol is heated 2 hours at 40oC. After adding 3.5 g of tetracycline reaction mixture is stirred for 5 hours. Upon completion of the reaction the reaction product is filtered and washed with isopropanol and ethyl ether. The result is a pale yellow solid matter (compound 2-2) (R1= R4= H, R2= OH, R3= CH3), yield 95%.

So pl. 165oC (decomp.).

Elemental analysis: C, 67.3, H 7.34, N 6.54.

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Example of synthesis 3

Synthesis of N-4-[17-hydroxyestra-1,3,5(10)-trien-3-oxyethyl]-1 - piperazine-1-methylene(oxytetracycline) (compound 3-1)

A mixture of 3.8 g of compound of example 2 (2-1), 0.03 g of metatarsalgia and 20 ml of isopropanol is heated 2 hours at 40oC. After adding 3.5 g terramicina reaction mixture is stirred for 5 hours. Upon completion of the reaction and treatment by the method of example 1-3 get a pale yellow solid matter (compound 3) (R1= R2= OH, R3= CH3, R4= H), the yield of 93%.

So pl. 171oC (decomp.).

Elemental analysis: C, 65.62, H 7.1, N, 6.67.

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Example of synthesis 4

4-1

Synthesis of bis-N,N-[17-okestra-1,3,5(10)-trien-3-oxyethyl]amine (compound 4-1)

So pl. 256 - 259oC.

Elemental analysis: C, 78.5, H 8.6, N 2.31.

4-2

Synthesis of bis-N, N-[17-okestra-1,3,5(10)-trien-3 - oxyethyl]aminomethylenemalonate (compound 4-2)

A mixture of 6.1 g of the above compound (4-1), 0.03 g of metatarsalgia and 20 ml of isopropanol is heated 2 hours at 40oC. After adding 3.5 g of tetracycline reaction mixture is stirred for 8 hours. Upon completion of the reaction obtain a pale yellow solid matter (compound 4-2) (R1= R4= H, R2= OH, R3= CH3), yield 68%.

So pl. 183oC (decomp.).

Elemental analysis: C, 71.1, H 7.21, N 3.89.

The structure of the compounds represented by the following molecular formula:

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Example of synthesis of 5

5-1

Synthesis of bis-N, N-[17-hydroxyestra-1,3,5(10)-trien-3-oxyethyl]amine (compound 5-1)

To 6.1 g of the above compound (4-1) add methyl alcohol and after adding in alkaline conditions 0.5 g borgert potassium reaction mixture is stirred for 5 hours. Then the reaction mixture is neutralized with acid and the methyl alcohol is evaporated. Turgut in -17-hydroxy-group. With the release of 82% of the white matter.

So pl. 193 - 197oC.

Elemental analysis: C 78.41, H 8.51, N 2.33.

5-2.

Synthesis of bis-N, N-[17-hydroxyestra-1,3,5(10)trien-3 - oxyethyl]aminomethylenemalonate (compound 5-2)

A mixture of 5.4 g of compound (5-1) described above, 0.03 g of metatarsalgia and 20 ml of isopropanol is stirred for 2 hours at 40oC. After adding 3.5 g of tetracycline reaction mixture is stirred for 8 hours. Upon completion of the reaction, the obtained pale yellow solid matter (compound 5-2) (R1= R4= H, R2= OH, R3= CH3allocated in the same conditions as in example 1-3, the output 94%

So pl. 171oC (decomp.).

Elemental analysis: C, 71.02, H 7.02, N 3.98.

The structure of the compounds represented by the following molecular formula:

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Example of synthesis 6

6-1.

Synthesis of bis-N, N-[17-hydroxy-17 / -itinerante-1,3,5(10)-trien-3-oxyethyl]amine (compound 6-1)

In a mixture of 100 ml of tetrahydrofuran and 1 g of potassium hydroxide dissolved 6.1 g of compound (4-1) of example 4 and through the mixture with vigorous stirring at 0oC miss gaseous acetylene until the reaction is completed. The addition of acid, the reaction mixture was neutralized to pH 4 and rastvoritelyami white solid compound (6-1), yield 78%.

So pl. 201 - 205oC.

Elemental analysis: C 79.21, H 8.58, N 2.18.

The compound structure is compliant with the following molecular formula:

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6-2.

A mixture of 6.6 g of the above compound (6-1), and 0.03 g of metatarsalgia and 20 ml of isopropanol is heated 2 hours at 60oC. Then added 3.4 g of tetracycline and the reaction mixture is stirred for 8 hours. Upon completion of the reaction processing by the method of example 1-3 with the release of 93% obtain pale yellow solid matter (compound 6-2), i.e., bis-N,N-[17-hydroxy-17-itinerante-1,3,5(10)trien-3-oxyethyl] aminomethylenemalonate (R1= R4= H, R2= OH, R3= CH3).

So pl. 178oC (decomp.).

Elemental analysis: C, 72.1, H 7.12, N 3.9.

The compound structure is compliant with the following molecular formula:

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Example of synthesis of 7

7-1.

Synthesis of N-[17-okestra-1,3,5(10)-trien-3-oxyethyl] -N-methylamine (compound 7-1)

To the toluene solution of 2.7 g of estrone, 1 g chloroethylamine and a small amount triethylamine add the sodium hydroxide solution. After establishing pH 10 the reaction mixture is kept for 4 hours. The solvent is then evaporated and the recrystallization of the solid residue from CN is C: C, 75.24, H 9.41, N 4.28.

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7-2.

A mixture of 3.3 g of the above compound (7-1), 0.03 g of metatarsalgia and 20 ml of isopropanol is heated 2 hours at 60oC and then add 3.5 g of tetracycline. The reaction mixture is stirred for 8 hours. Upon completion of the reaction processing by the method of example 1-3 with the release of 90% get a pale yellow solid matter (compound 7-2), i.e. N-[17-okestra-1,3,5(10)-trien-3-oxyethyl] -N-methyliminodiacetic (R1= R4= H, R2= OH, R3= CH3).

So pl. 190oC (decomp.).

Elemental analysis: C, 68.8, H 7.72, N 3.62.

The compound structure is compliant with the following molecular formula:

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Example of synthesis 8

8-1.

Synthesis of N-[3,17-dihydroxyethane-1,3,5(10)triene-6 - amino-ethyl]piperazine (compound 8-1)

120 ml of tetrahydrofuran is dissolved 5.2 g of compound (8-0) and to the solution was added 3.2 g AMINOETHYLPIPERAZINE. The reaction mixture is stirred for 2 hours, the THF is removed by evaporation and to the residue add 100 methyl alcohol and 2.8 g of formic acid. Stirring of the reaction mixture is continued for further 3 hours. Methyl alcohol is removed by evaporation and recrystallization from alcohol get connection 8-1.

So pl. 172 - 177oC.

8-2.


A mixture of 4.1 g of the above compound (8-1), 0.03 g of metatarsalgia and 20 ml of isopropanol is heated 2 hours at 50oC. After adding 3.5 g of tetracycline reaction mixture is stirred for 5 hours. Upon completion of the reaction the reaction product is filtered, washed with isopropanol and ethyl ether, and after drying in vacuum to yield 81.2% get pale yellow solid matter (compound 8-2) with a melting point 167oC (decomp.).

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Connection (8-0) obtained in the following way:

1. Getting 17-astroengine

In methyl alcohol was dissolved 4 g of estrone and to the solution at 30oC added dropwise a mixture of 0.8 g of bergerat potassium, 1.76 g of sodium hydroxide and 8.8 ml of water. The reaction mixture was kept for 2 hours, neutralized to neutral reaction of dilute acetic acid and then diluted with water. The formed solid is filtered off, washed with water and dried. By recrystallization of the product from aqueous ethanol with a yield of 97.2% get white crystals with a melting point 173 and 174oC.

2. Getting diacetate 17-astroengine

A solution of 10 g of 17-astroengine in puritaine mixed with 35 ml of acetic acid. The reaction mixture is stirred for one hour and transferred to Ladadika reaction of absolute alcohol with a yield of 97% are white crystals with a melting point of 126 - 128oC.

3. Getting diacetate 6-carbonyl-17-astroengine (Compound (XII))

In benzene dissolve 5 g of the diacetate 17-astroengine, upon cooling, added dropwise 0.45 chromium trioxide and the mixture is dissolved in 30 ml of glacial acetic acid, 20 ml of acetic acid and 30 ml of benzene. Upon completion of the reaction the mixture is stirred for some time and then transferred into the water. The reaction product is extracted with ethyl ether, washed with saturated sodium hydrogen carbonate solution and water, dried, concentrated and the subsequent purification on silica gel obtain the target compound, yield 40%, melting point 173 - 175oC.

Example 9 synthesis

Synthesis of N-4-[17-okestra-1,3,5(10)-trien-3-oxyethyl] -1-piperazine-1-methylenedioxyaniline HCl (compound 9)

A mixture of 2.2 g of compound (1-2), 0.2 g of polyformaldehyde and 100 ml of isopropanol is stirred for 1.5 hours with heating at 60oC, then add 3 g of doxycycline hydrochloride. Then the reaction mixture is stirred for further 2.5 hours at 60oC. Upon termination of the reaction the reaction product is filtered off, washed with isopropanol and ethyl ether, and after drying, get a pale yellow substance (compound 9) with a melting point of 172oC (decomp.), ilen(oxytetracycline) (compound 10)

A mixture of 0.91 g of compound (1-2), 80 mg of polyformaldehyde and 50 ml of isopropanol is heated with stirring for 2 hours at 60oC. After adding 1 g of terramicina the reaction mixture is stirred for further 3 hours at 60oC. the reaction Product is filtered off, washed with isopropanol and ethyl ether, and after drying with exit 89% receive pale yellow solid with a melting point 175oC (decomp.).

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Example 11 synthesis

Synthesis of N-4-[17-hydroxyestra-1,3,5(10)-triene-3-ethoxyethyl]- piperazine-1-methylenedianiline (compound 11)

A mixture of 4.1 g of N-(17-hydroxyestrone-1,3,5(10)-trien-3-oxyethyl)piperazine, 0.5 g of polyformaldehyde and 50 ml of isopropanol is heated 2 hours at 60oC with stirring. After adding 4 g of tetracycline reaction mixture was kept for 3 hours at 40 - 45oC. the reaction Product is filtered off and washing with isopropanol and ethyl ether with a yield of 68.6% get pale yellow solid matter (compound 11) with a melting point 154oC (decomp.).

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Example 12 synthesis

Synthesis of 17-hydroxyandrost-4-EN-3-acetylethylenediamine

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A mixture of 3.3 g of 3-aminoethoxy-17-hydroxyandrost-4-ene, 0.3 g of metatarsalgia and 40 ml of isopropanol is heated 4 hours at 60

Elemental analysis: C, 66.78, H 7.41, N, 5.38.

Example of synthesis 13

Synthesis of 17-hydroxyandrost-4-EN-3-one-6-methylene(oxyethylenenitrilo) tetracycline

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A mixture of 3.6 g of 6-aminoethoxymethyl-17-hydroxyandrost-4-EN-3-one, 0.3 g of metatarsalgia, 4.5 g of tetracycline and 30 ml of acetone is stirred for 24 hours in the dark at room temperature. Upon completion of the reaction the reaction product is filtered off and washed with acetone and ethyl ether with a yield of 86% receives a yellow solid.

Elemental analysis: C, 67.9, H 7.67, N 5.18.

Example 14 synthesis

Synthesis of 17-hydroxyandrost-3-(oxyethylenenitrilo)tetracycline

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A mixture of 3.35 g of 3-aminoethoxy-17-hydroxyandrost, 0.3 g of metatarsalgia, 4.5 g of tetracycline and 30 ml of acetone is stirred for 30 hours in the dark at room temperature. Upon completion of the reaction the reaction product is filtered off and washed with acetone and ethyl ether with a yield of 85% receives a yellow solid.

Elemental analysis: C, 66.61, H 7.69, N 5.4.

Example 15 synthesis

Synthesis of 17-hydroxy-18-methyl-19-norandro-4-EN-3-one-17 -(butylaminoethyl)tetracycline

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A mixture of 3.7 g of 17-aminoethylamino-17-hydroxy-18-methyl-19-norandro-4-EN-3-one, 0.3 g met the ing the mixture is stirred for 6 hours. Upon completion of the reaction the reaction product is filtered off and washed with isopropanol and ethyl ether with a yield of 85% receives a yellow solid.

Elemental analysis: C, 68.51, H 7.11, N 5.17.

Example 16 synthesis

Synthesis of 16 , 17-dihydroxyethane-1,3,5(10)-triene-3-(oxyethylenenitrilo)tetracycline

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A mixture of 3.3 g of 3-aminoethoxy-16 , 17 / -dihydroxyethane-1,3,5(10)-triens, 0.3 g of metatarsalgia and 50 ml of isopropanol is heated 2 hours at 80oC and then cooled to 40oC. After adding 4.5 g of tetracycline reaction mixture was kept for 6 hours. Upon completion of the reaction the reaction product is filtered off and washed with isopropanol and ethyl ether with a yield of 85% receives a yellow solid.

Elemental analysis: C, 65.48, H 6.82, N 5.13.

Example 17 synthesis

Synthesis of 18-methyl-17-okestra-1,3,5(10)-triene-3-(oxyethylenenitrilo)tetracycline

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A mixture of 3.3 g of 3-aminoethoxy-18-methylestra-1,3,5(10)-triens, 0.3 g of metatarsalgia and 50 ml isopropanol withstand 48 hours in the dark at 30oC. Upon termination of the reaction the reaction product is filtered off and washed with isopropanol and ethyl ether with a yield of 82% receives a yellow solid.

Elemental analysis:tracycline

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A mixture of 3.8 g of 3-aminoethoxy-17-hydroxypregn-4-EN-20-she, 0.3 g of metatarsalgia and 50 ml of isopropanol is heated 2 hours at 60oC. the Reaction mixture is cooled to 40oC and add 4.5 g of tetracycline. Then the reaction mixture is kept for 5 hours at 60oC. Upon termination of the reaction the reaction product is filtered off and washed with acetone and ethyl ether to yield 87% receives a yellow solid.

Elemental analysis: C, 66.52, H 7.37, N 5.01.

Example 19 synthesis

Synthesis of pregna-5-ene-20-one-3-(oxyethylenenitrilo)tetracycline

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A mixture of 3.6 g of 3-aminoethoxymethyl-5-ene-20-she, 0.6 g of metatarsalgia and 40 ml of isopropanol is heated 2 hours at 80oC. the Reaction mixture is cooled to 40oC add 4.5 g of tetracycline and incubated for 6 hours at 40oC. Upon termination of the reaction the reaction product is filtered off and washed with isopropanol and ethyl ether with a yield of 93% receive solid.

Elemental analysis: C, 67.7, H 7.36, N 5.05.

Example 20 synthesis

17-Hydroxyandrost-1,4-Dien-3-(oxyethylenenitrilo)doxycycline

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A mixture of 3.3 g of 3-aminoethoxy-17-hydroxyandrost-1,4-diene, 0.3 g of metatarsalgia and 50 ml of isopropanol is heated 2 hours at 80o

Elemental analysis: C, 67.23, H 7.25, N 5.28.

Example 21 synthesis

Synthesis of 17-methyl-17-hydroxyandrost-4-EN-3-one-6-(methylenedioxyethylamphetamine)doxycycline

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A mixture of 3.8 g of 6-aminoethoxymethyl-17-methyl-17-hydroxyandrost-4-EN-3-one, 0.3 g of metatarsalgia and 25 ml of isopropanol is heated 4 hours at 60oC. Then the reaction mixture is cooled to 40oC add 4.5 g of doxycycline hydrochloride and incubated for 8 hours. Upon termination of the reaction by washing the reaction product with isopropanol and ethyl ether with a yield of 86% receives a yellow solid.

Elemental analysis: C, 63.72, H 7.02, N 5.13.

Example 22 synthesis

Synthesis of 17-methyl-17-hydroxyandrost-3-one-2-(oxyethylenenitrilo)doxycycline

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A mixture of 3.6 g of 2-aminoethoxy-17-methyl-17-hydroxyandrost-3-one, 0.3 g of metatarsalgia and 30 ml of isopropanol is heated 2 hours at 60oC, and then add 4.5 g of doxycycline hydrochloride and the reaction mixture withstand additionally. Upon termination of the reaction by washing the reaction product with isopropanol and ethyl ether with a yield of 91% receives a yellow solid.

Elemental analysis: C, 65.91, H 7.51, N, 5.07.

Example 23 synthesis

Synthesis of 17-methyl-17-hydroxy-19-norandro-4-norandro-4-EN-3-one, 0.3 g metatarsalgia and 50 ml of acetone, incubated 2 hours at 30oC, then add 4.5 g of doxycycline hydrochloride and the reaction mixture incubated for another 30 hours. Upon completion of the reaction the reaction product is filtered and washing with isopropanol and ethyl ether with a yield of 87% and receives a yellow solid.

Elemental analysis: C, 63.64, H 7.03, N 5.18.

Example 24 synthesis

Synthesis of 17-ethinyl-17-hydroxyandrost-5(10)-EN-3-one-6-(methylenedioxyethylamphetamine)doxycycline

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A mixture of 3.7 g of 6-aminoethoxymethyl-17-ethinyl-17-hydroxyandrost-5(10)-EN-3-one, 0.3 g of metatarsalgia and 50 ml of isopropanol is heated 2 hours at 60oC, then add 4.5 g of doxycycline hydrochloride and the reaction mixture is heated for another 8 hours at 40oC. Upon termination of the reaction the reaction product is filtered and washing with isopropanol and ethyl ether with a yield of 87% receives a yellow solid.

Elemental analysis: C, 66.81, H 7.06, N 5.01.

Example 25 synthesis

17-Propylene-17-hydroxy-11-dimethylaminopropanol - 4,9-Dien-3-one-6-(methylenedioxyethylamphetamine)doxycycline

< / BR>
A mixture of 5 g of 6-aminoethoxymethyl-11-(4'-dimethylaminophenyl)-17-propylene-17-hydroxyandrost-4,9-Dien-3-one, 0.3 g of metatarsalgia and 40 ml is drochloride doxycycline and the reaction mixture was kept for 6 hours. Upon completion of the reaction the reaction product is filtered and after washing with isopropanol and ethyl ether to yield 90% receives a yellow solid.

Elemental analysis: C, 68.76, H 6.88, N, 5.72.

Example 26 synthesis

Synthesis of 16,17-isopropylidene-16,17-dixisti-1,3,5(10)- triene-3-(oxyethylenenitrilo)doxycycline

< / BR>
A mixture of 3.7 G. of 16,17-isopropylidene-16,17-dixisti-1,3,5(10)-triene-3-aminoethylamide simple ether, 0.3 g of metatarsalgia and 50 ml of isopropanol is heated 2 hours at 60oC, then add 4.5 g of doxycycline hydrochloride and the reaction mixture was additionally incubated for 8 hours. Upon completion of the reaction the reaction product is filtered and after washing with isopropanol and ethyl ether to yield 95% receives a yellow solid.

Elemental analysis: C, 66.71, H 6.9, N, 5.18.

Example 27 synthesis

Synthesis 3,17-dihydroxyethane-1,3,5(10)-triene-17-acetate - 7-(methylenedioxyethylamphetamine)doxycycline

< / BR>
A mixture of 3.8 g of 7-aminoethoxyethanol-3,17-Dien-17-acetate, 0.3 g of metatarsalgia and 50 ml of isopropanol is heated 4 hours at 60oC, then add 4.5 g of doxycycline hydrochloride and the reaction mixture was additionally incubated for 4 hours. Upon completion of the reaction the reaction product is filtered is from: C 65.34, H 6.68, N 4.95.

Example 28 synthesis

Synthesis of 17-hydroxypregn-4-EN-20-one-3-(oxyethylenenitrilo)doxycycline

< / BR>
A mixture of 3.7 g of 3-aminoethoxy-17-hydroxypregn-4-EN-20-she, 0.3 g of metatarsalgia and 40 ml of isopropanol is heated 2 hours at 60oC, then add 4.5 g of doxycycline hydrochloride and the reaction mixture was additionally incubated for 4 hours. Upon completion of the reaction the reaction product is filtered and after washing with isopropanol and ethyl ether with a yield of 92% receives a yellow solid.

Elemental analysis: C at 66.41, H 7.4, N 5.14.

Example 29 synthesis

Synthesis of pregna-4-ene-3,20-dione-6-(methylenedioxyethylamphetamine)doxycycline

< / BR>
A mixture of 3.9 g of 6-aminoethoxyethanol-4-ene-3,20-dione, 0.3 g of metatarsalgia and 50 ml of isopropanol is heated 3 hours at 60oC, then add 4.5 g of doxycycline hydrochloride and the reaction mixture was additionally incubated for 4 hours. Upon completion of the reaction the reaction product is filtered and after washing with isopropanol and ethyl ether with a yield of 93% receives a yellow solid.

Elemental analysis: C, 67.77, H 7.36, N 4.59.

Example 30 synthesis

Synthesis 3,17-dihydroxyethane-1,3,5(10)-triene-11-(4 - phenoxyethylamine)methylenedioxyaniline 6

o
C, then add 4.5 g of doxycycline hydrochloride and the reaction mixture was additionally incubated for 8 hours. Upon completion of the reaction the reaction product is filtered off and washed with isopropanol and ethyl ether with a yield of 89% receives a yellow solid.

Elemental analysis: C, 68.13, H 6.69, N 4.73.

Example 31 synthesis

Synthesis of 17-hydroxy-17-methylandrostan-(3,2-c)pyrazole-N-methylenedianiline

< / BR>
A mixture of 3.29 g of 17-hydroxy-17 - methylandrostan(3,2-c)pyrazole, 0.3 g of metatarsalgia and 30 ml of isopropanol is heated 2 hours at 40oC add 4.5 g of tetracycline and the reaction mixture is stirred for 6 hours. Upon completion of the reaction the reaction product is filtered off and washed with isopropanol and ethyl ether with a yield of 89% receives a yellow solid.

Elemental analysis: C, 67.48, H 7.07, N 7.30.

Experience 1.

The distribution of compounds in the body

In connection 1-3 obtained in synthesis example 1-3, injected radioactive tag3H (0.34 MCI/mg) and the compound injection in the tail vein of the mouse at a dose of 20 Ci/20g Mice in groups of five mice in each kill after 1 minute, 5 minutes, 15 minutes, 30 minutes, 1 hour, 4 hours, 6 hours, 24 hours, 48 hours and 72 hours after injection and guberina bone) and so on and 50 mg of tissue (50 µl blood) is placed in a plastic test tube for analysis. In the test tube is also placed 0.2 ml perchloro acid, 0.4 ml of hydrogen peroxide and a drop of n-oktilovom alcohol and heated on water bath for 45 minutes at 75oC. Then select 0.1 ml of this treated liquid and placed in a flask for storing acquired scintillation solution and mixed with 5 ml of 0.5% acquired scintillation solution. After the solution becomes transparent, it to determine cpm in sample and its radioactivity is placed in FJ 2105 liquid acquired scintillation counter. Separately define dpm 52 samples in four groups of animals (the method of external standard).

The quantity of a drug within the tissue is determined as follows.

The amount of drug in the tissue (cpm/mg) = (cpm sample) + (the number of processed tissue (mg)).

The amount of drug in tissue (μg/mg) = (cpm/mg sample 6) + (efficiency counter (E) 2.22 10 0.34 mCi/mg (specific radioactivity)).

The results, presented in table. 1-4 (see below).

Experience 2.

Analysis on acute toxicity

(1) Sample

Connection 1-3 is a pale as the pH 5 and is a transparent pale yellow liquid. The fluid may be obtained in the laboratory studies of osteoporosis, Department of pharmacy, West China University medical Sians School (UCLMS).

(2) Animals

In the experiments are healthy mice breed Charming, first class, weighing from 18 to 21 grams, half males and half females. Mouse grown Experimental center at UCUMC for growing animals.

(3) Determination of sub-lethal dose (LD50)

Prepared four or five groups of mice receiving a dose equal to the relations (1 : 0.7 - 0.8) in the interval LD 0 - 100%, identified in the preliminary tests. Drug for oral administration is prepared by suspendirovanie solid compounds 1-3 in 1% CMCNa2with the formation of the suspension. For injection solutions of the medicinal product prepared by the method of dilution with low specific gravity by dissolving compounds 1-3 in physiological salt solution and obtain solutions with different concentrations. Animals subjected to starvation (but with free access to water) and after 20 hours at random regardless of gender and weight gain groups of ten mice. The drug is given once daily at a dose of 0.2 ml/10 g, and then the animals examined. Dead (4) test Results

(a) Determining in mice maximally tolerated doses of compounds 1-3.

Preliminary tests revealed the maximum tolerable dose, not leading to death. After 20 mice (10 males and 10 females) receive a single dose of a chemical compound in the maximum concentration and the maximum for oral administration the number of animals observed within 7 days. As a result, no abnormalities in mice not marked not marked fatalities. The maximum tolerated dose (MTD) is >6 g/kg

(b) After injection of compounds 1-3 in the vein of the tail of mice received the results presented in table. 4 (see the end of the description).

(5) Conclusions

The maximum tolerated dose (MTD) of compounds 1-3 with an introduction mouse is at least 6 g/kg, and the toxicity of the compound is extremely small. The value of LD50when intravenous injection in the tail vein of the mouse is 143.11 mg/kg After intravenous injection activity mouse falls, then the mouse starts jumping, there are cramps. The eyeball protrudes out of the socket and white, there is incontinence of urine and feces. Although the main part of the poisoned mice are killed instantly, the small number of surviving the bat is it. No dependence of fatalities sex animal not marked not marked any pathological changes after opening when observed with the naked eye. The tests were carried out at a temperature of 17oC.

Experience 3.

The study of osteogenesis (1)

As the test cells used incubation system the first generation of osteoblasts originating from the cranial roof rats Wistar (female, age 6 months). After the start of incubation in the medium once a day add samples of the drug in the dose of 10-6M, 10-8M or 10-9M on the second and third day (during reproduction). Or connection 1-3 in the above amount is added to the medium once a day for 4 days (the period of calcification), starting from the seventh day from the beginning of the incubation. On the fourteenth day from the beginning of the incubation of the cells stained by von Koss and spend the determination of phosphates. Bone nodes, painted in brown color, visible to the naked eye, and are used as an indicator of osteogenesis. The results, presented in table. 5 (see the end of the description).

In Fig. 1 to 3 shows the results obtained when three povtoreva, the letter B indicates the connection is added to a concentration of 10-9M, the letter C at a concentration of 10-8M and D is at a concentration of 10-6M

From the above results it is evident that the compound of the present invention has the promoting osteogenesis effect.

Experience 4.

The study of osteogenesis (2)

As the test cells used in the incubation system the first generation of bone marrow cells from femur of rats Wistar (female, age 6 months), and compound 1-3 was added once a day in amounts of 10-8M or 10-6M to the environment on the seventh, ninth and eleventh day from the beginning of the incubation period (the period of calcification). Studies conducted by the method of experience 3. The results are shown in table. 6 (see the end of the description).

As shown in the results table, the compound of the present invention has the promoting osteogenesis action.

1. Derivatives of tetracycline General formula I

X-Y-Z

where X represents a monovalent group of the General formula II

< / BR>
where R1represents hydrogen or hydroxyl;

R2represents hydrogen or hydroxyl;

R3representation of General formula III, IV, V or VI

< / BR>
where X' represents a simple bond, -O - or NH;

< / BR>
< / BR>
(2)-(CH2NHmCH2CH2-W- (3)

where m is 0 or 1;

W represents-O-, -och2- simple connection or CC; and when m is 0, W is-OCH2-;

Z represents a monovalent group formed by removing a hydrogen atom or a hydroxyl group in the compound of General formula VII

< / BR>
where is BUT - or O=;

represents a hydrogen atom or methyl;

represents a hydrogen atom, phenyl or substituted phenyl;

represents methyl or ethyl;

represents hydroxyl, ketogroup or acetyl;

represents hydrogen, hydroxyl, methyl, ethinyl or PROPYNYL or together form a group =O;

represents hydrogen, hydroxyl, or together and are connected with an oxygen atom, a 2,2-dioxypurine group;

the symbol denotes a single or double bond,

moreover, groups of formula III - IV attached in the 2 position 3 position 6 position 7 position-or 17-position, or phenyl group attached in the second position of the group Z, and (1) of the formula II and (2) of formulas III - VI are connected directly, and (3) groups of formula III-VI are associated directly with any group of formula tetracyclinefor connection where R1is hydrogen, R2is hydroxyl, R3is methyl, and R4represents hydrogen.

3. Connection on p. 1 in which the monovalent group of formula II is a monovalent group terramicina, where R1is hydroxyl, R2is hydroxyl, R3is methyl, R4represents hydrogen.

4. Connection on p. 1 in which the monovalent group of formula II is a monovalent group doxytetracycline, where R1is hydroxyl, R2is hydrogen, R3represents methyl and R4represents hydrogen.

5. The compound according to any one of paragraphs.1-4, in which monovalent group of formula VI is a monovalent group of estrone, where together form a group =O and a is hydrogen.

6. The compound according to any one of paragraphs.1-4, in which monovalent group of formula VI is a monovalent group estradiol where represents hydroxyl, represents hydrogen and a represents hydrogen.

7. The compound according to any one of paragraphs. 1-4, in which monovalent group of formula VI is a monovalent group astrolgical, where represents hydroxyl, represents Atini is a monovalent group estriol where is hydroxyl, represents hydrogen and a represents hydroxyl.

Priority points:

25.03.93 on PP. 1-8;

29.12.93 on PP. 1-8 clarification signs.

 

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< / BR>
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< / BR>
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< / BR>
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< / BR>
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< / BR>
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< / BR>
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< / BR>
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