N-acylamino-1-hydroxyethylidene-1,1-bisphosphonic acid and method of production thereof

 

(57) Abstract:

Usage: in medicine as anti-inflammatory drugs. The essence of the invention: N-acylamino-1-hydroxyethylidene-1,1-bisphosphonic acid of the formula RNH-A-C(OH)[PO3H2]2, where A is -(CH2)3- or -(CH2)5, R is the residue of ibuprofen. Reagent 1: RCOCl, where R is as described above. Reagent 2: H2N-A-C(OH)[PO3H2]2, where A is as above. Reaction conditions: in an aqueous medium in the presence of alkali. 2 C.p. f-crystals, 2 tab.

The invention relates to compounds of General formula (I):

,

where A is -(CH2)ngroup, and n includes the interval between 1 and 10, R is an acyl residue of a known anti-inflammatory compounds belonging to the class of salicylic, akriluksusnoy, arylpropionate, Anthranilic, 4,5-dihydroxy - or 4,5,8-trihydroxy-9,10-dihydro-9,10-dioxo-2-intracisternally and nicotinic acid.

Examples of known anti-inflammatory acids, acyl residues which form a group R as defined in formula (I) are listed below:

salicylic acid: salicylic acid, acetylsalicylic acid, 5-aminosalicylic acid, diflunisal, fendosal;

allow Azin, cloirec, diclofenac, etodolac, fenclofenac, indobufen, indomethacin, medicinova acid, sulindac, tolmetin, zomepirac;

propionic acid: alminoprofen, benoxaprofen, bulochnikova acid, carprofen, flurbiprofen, ibuprofen, Ketoprofen, loxoprofen, naproxen, oxaprozin, proteinemia acid, penerapan, pirprofen, pranoprofen, suprofen, tiaprofenic acid;

Anthranilic acid: flutamida acid, meclofenamic acid, marennikova acid, niflumova acid, lobenzarit, taftalenovaya acid;

4,5-dihydroxy - or 4,5,8-trihydroxy-9,10-dihydro-9,10-dioxo-2-antratsenovoe acid: diacerin, Tianjin.

Partial preference is given to compounds of the formula (I), where R is a 2-acetoxybenzoic, the remnants of diflunisal, ibufenac, naproxen, indomethacin, diazirine. The most preferred compounds are those in which n is 3 or 5.

In cases where the residue R contains one or more chiral carbon atoms, the present invention includes the individual enantiomers, razemicescuu mixture and diastereoisomer these substances.

The present invention also relates to the salts diphosphines acid, Symi.

The compounds of formula (I) are obtained by condensation of the known anti-inflammatory compounds with known derivative-aminoalkyl-1-hydroxy-1,1-diphosphines acid, which are already used in therapy due to their podavlyayushego action on bone absorption, but also action directed against the formation of urinary stones.

w-aminoalkyl-1-hydroxy-1,1-diphosphonate acid described in the applications to the Italian patent N IT 1230503 and IT 220518 and applications at the German patent N DE-OS 2,534,391 and DE-OS 3,540,150.

Derivatives of alkyl-1-hydroxy-1,1-diphosphines acid, condensed with an anti-inflammatory through the remnants of a relationship, known from EP-A-84822.

On the contrary, the compounds of the present invention differ amide bond between the amino group w-aminoalkylphosphonic acid and the carboxyl group of anti-inflammatory compounds.

Contrary to what you may assume, the pharmacological properties of the compounds of formula (I) are not properties of typical "Pro-drugs", which can release in vivo two connections, independently with typical therapeutic action.

Indeed, it has been unexpectedly identified who may be numbered among the compounds, liberating in vivo known pharmacologically active acid RCOON. This is even more astonishing is the fact that aminoalkylphosphonic component is completely devoid of anti-inflammatory activity.

The compounds of formula (I) are obtained by reaction of compounds of formula (II):

,

where A has the above meaning,

with the compound of the formula RCOOH, where R is the group defined above, or their reactive derivatives (chloride, anhydride, imidazolium and others ).

The reaction is preferably performed in aqueous medium in the presence of alkali using a reactive derivative of carboxyl group R-molecules, such as the acid chloride.

The advantageous properties of the compounds of the present invention make them useful in the treatment of diseases of the musculoskeletal system.

Therefore, the compounds of the present invention can be used to prepare pharmaceutical compositions by mixing with a suitable environment for these drugs and/or with other medications that can help their therapeutic action.

The examples mentioned pharmaceutical compositions include both solid and liquid destination through the mouth, (which is not Obie destination depot-forms (not necessarily), candles and locally applicable forms.

Dosage will be determined in accordance with the specific conditions of the disease and the patient (age, gender, weight), as well as with clinical requirements. The shape of the dose may be dose at one time, containing 2-500 mg of the active ingredient.

Example 1. [4-/2-acetoxybenzoic/-amino-1-hydroxybutylidene]diphosphonic acid

3,18 g (9.8 mmol) Nutrilite-4-amino-1-hydroxyethylidenediphosphonic-three-hydrate in 30 ml of water was added to 1.8 g (45 mmol) of sodium hydroxide, 100 mg of p-dimethylaminopyridine and 200 mg tetradecylammonium-iodide. The resulting solution was cooled to 0oC and added 2,03 g (10.2 mmol) of the chloride of 2-acetoxybenzoic acid, dissolved in 10 ml of diethyl ether. The reaction mixture was stirred for 2 h at room temperature, then was extracted with ethyl ether in aqueous solution, acidified with concentrated HCl while stirring with cooling. Sediment [4-/2-hydroxybenzoyl/-amino-1-hydroxybutylidene]diphosphonic acid was filtered, washed and dried at 70oC, and then transformed into a final product that is specified in the title, by acetylation with acetic anhydride.
Found, C 38,04; H 4,69; N 3,45.

I. To and1H NMR in line.

Example 2. [6-/2-(acetoxybenzoic/-amino-1-hydroxybenzylidene] -dipastena acid

Followed the procedure of example 1, but used of 3.45 g (9.8 mmol) of sodium trihydric-6-amino-1-hydroxyacetophenone-three-hydrate. Besieged [6-/2-hydroxybenzoyl/-amino-1-hydroxybenzylidene] diphosphines acid. To obtain the final product mentioned in the title, repeating the procedure of example 1. The final product has the following characteristics:

So pl. (decomp.) > 150oC;

E. S. for C15H23NO10P2:

Theoretically, C 41,00; H 5,27; N 3,18;

Found, C 40,94; H 5,23; N 3,24.

I. K.1H NMR in line.

Example 3. [4-[5-/2,4-differenl/-2 - hydroxybenzoyl]amino-1-hydroxybutylidene]diphosphonic acid

Repeating the procedure of example 1, using 3,18 g (10.2 mmol) of the chloride 5-/2,4-differenl/-2 - acetoxybenzoic acid. After acidification with concentrated HCl was besieging the final product, specified in the name, which had the following properties: I. pl. (decomp.) >150oC;

E. for C17H10F2NO9P2:

Theoretically, C 42,41; H of 3.97; N 2,90;

Found, C 42,36; H 3,94; N 2, the obtained compounds in examples 4-13.

Example 4. [6-[5-/2,4-differenl/-2-hydroxybenzoyl]-amino-1-hydroxybenzylidene]diphosphonic acid

So pl. (decomp.) >150oC.

E. S. for C19H23F2NO9P2:

Theoretically, C 44,80; H 4,55; N 2,74;

Found, C 44,85; H 4,58; N 2,80.

I. K.1H NMR in line.

Example 5 [4-/4-isobutylphenyl/-acetylamino-1 - hydroxybutylidene]diphosphonic acid

So pl. (decomp.) > 150oC.

E. S. for C16H27NO8P2:

Theoretically, C 45,38; H 6.42 per; N 3,30;

Found, C 45,44; H 6,47; N 3,36.

I. K.1H NMR in line.

Example 6 [6-/4-isobutylphenyl/acetylamino-1 - hydroxybenzylidene]diphosphonic acid.

So pl. (decomp.) >150oC.

E. S. for C18N31NO8P2:

Theoretically, C 47,88; H 6,12; N 3,10;

Found, C 47,93; H 6,14; N 3,18.

Example 7. [4-[2-/4-isobutylphenyl/-propionyl]amino-1-hydroxybutylidene] dipastena acid

So pl. (decomp.) >150oC.

E. S. for C17H29NO8P2:

Theoretically, C 46,67; H of 6.68; N 3,20;

Found, C 46,61; H Of 6.65; N Is 3.27.

I. To and1H NMR in line.

Example 8. [-6-[2-/4-isobutylphenyl/propionyl]amino-1-hydroxide the UB>2:

Theoretically, C 49,02; H 7,14; N 3,00;

Found, C 48,96; H To 7.09; N 2,95.

I. K.1H NMR in line.

Example 9. [4-[2-/6-methoxyphenyl/propionyl]amino-1-hydroxybutylidene]diphosphonic acid

So pl. different. >150oC.

E. for C18H25NO9P2:

Theoretically, C 46,85; H 5,46; N 3,03;

Found, C 46,80; H Vs. 5.47; N 3,00.

I. To and1H NMR in line.

Example 10. [6-[2-(6-methoxymethyl)propionyl]amino-1-hydroxybenzylidene] diphosphonic acid

So pl. (decomp.) >150oC.

E. S. for C20H29NO9P2:

Theoretically, C 49,07; H 5,97; N 2,86;

Found, C 49,02; H 5,96; N 2,90.

Example 11. [4-[1-(4-chlorobenzoyl)-2-methyl-5-methoxy-2-indolyl]acetylamino-1-hydroxybutylidene]diphosphonic acid

So pl. (decomp.) >150oC.

E. S. for C23H27CIN2O10P2:

Theoretically, C 46,90; H to 4.62; N 4,75;

Found, C 46,99; H Of 4.66; N 4,68.

I. K.1H NMR in line.

Example 12. [6-[1-/4-chlorbenzoyl/-2-methyl-5-methoxy-2-indolyl]acetylamino-1-hydroxybenzylidene]diphosphonic acid

So pl. (decomp.) > 150oC.

E. S. for C25H31ClN2O10P2:

Tea in rats

Used materials:

Carrageenin (control);

Carrageenin + ibuprofen (11 and 5.5 mg/kg);

Carrageenin + compound from example 8 (Br-Ax) (25,0 and 12.5 g/kg);

Carrageenin + compound from example 7 (Br-Ab)(25,0 and 12.5 mg/kg).

Note: doses of ibuprofen are equimolar in relation to the corresponding doses of Br-Ab and Br-Ax.

Used animals: male rats S. D. weighing 160-180 g

Group to check:

1) Control (only carrageenin);

2) Ibuprofen (11.0 mg/kg);

3) Ibuprofen 5,5 mg/kg;

4) Br-Ab 25.0 mg/kg;

5) Br-Ab 12.5 mg/kg;

6) Br-Ax 25.0 mg/kg;

7) Br-Ax 12.5 mg/kg

Each group consisted of 5 males, which were chosen to provide a uniform total weight in each group. Animals were inoculable subcutaneously examinees solutions, gomogenizirovannykh in 5% gum Arabic, which is pre-sterilized by filtration using filters "Acrodisc" /Gelman/, pore size of 0.45 mm.

After 1 hour, the animals were slightly anestesiologi using 0.1 ml of 1% aqueous solution carrageenin in sterile saline. Carrageenin was kept under stirring with a magnetic stirrer so that it was possible odero is was possible to repeat the measurement is the most reliable way in the next few hours.

2 hours after carragenine inoculation was again determined the volume of the paws (two-hour data). Subsequently, these measurements were performed after 4 and 6 hours after inoculation. Then figured protection using the following formula:

100 A protection.

The results (table. 1) show that all (verified) compounds of the present invention provide greater protection than the protection of ibuprofen. Moreover, there are pharmacological differences among the compounds of the present invention, related to the length of the methylene part (A in the General formula).

Example 14. In male rats, weighing about 200 g were removed thyroid and parathyroid glands under Nembutal anesthesia. Animals through day were treated with thyroxine throughout their studies. 7 days after surgery from intracardiac puncture the blood was collected and determined the calcium in the blood plasma. Animals with the content of Ca in plasma greater than 2 mm were excluded from the experience, others were treated with test compounds and a retinoid, which was administered subcutaneously in the next three days. 24 hours after the last destination of animals scored, drew blood, and again Fofanova acid.

1. N-Acylamino-1-hydroxyethylidene-1,1-bisphosphonic acid of General formula I

< / BR>
where a group -(CH2)3- or -(CH2)5and RC(O) the rest of ibuprofen.

2. The method of obtaining compounds of formula I on p. 1, characterized in that the acid chloride of the formula R COOH, where RC(O) has the meaning specified in paragraph 1, is subjected to the interaction with the compound of the formula II

< / BR>
where a has the values specified in paragraph 1.

3. Connection on p. 1 of General formula I possess anti-inflammatory activity.

 

Same patents:

The invention relates to new derivatives methylenephosphonic acid of General formula I

< / BR>
in which R1, R2, R3and R4independently are C1-C10the alkyl straight or branched chain, optionally unsaturated, C3-C10-cycloalkyl, optionally unsaturated, aryl, aralkyl, silicom SiR3or hydrogen, in formula I, at least one of the groups R1, R2, R3and R4is hydrogen and at least one of the groups R1, R2, R3and R4different from hydrogen

The invention relates to a method for oksietilidendifosfonovaya acid formula

< / BR>
a highly effective combined and used in power, oil, fragrance, textile, household, medicine, production of mineral fertilizers
The invention relates to chemical technology for reagent collector on the basis of oxyalkylation acids intended for the enrichment of phosphate ores and oxidized ores of non-ferrous metals

The invention relates to new phosphorylated to Surinam General formula

R-- OCH2-COOH,

(I) where R is a saturated or unsaturated aliphatic hydrocarbon residue with a straight or branched chain, containing 6-30 carbon atoms which may be substituted with halogen, -OR, - SR1or-NR1R2group, where R1and R2lowest alkali

The invention relates to a technology for sodium salts of nitrilotriethanol acid (NTF), used as components of detergents, inhibitors and other industries

The invention relates to a new method of obtaining methylenephosphonic acids of the formula I,

where Q1and Q2independently from each other are hydrogen or halogen, by hydrolysis of the corresponding complex tetraeder methylenephosphonic acid of the formula II

where R represents a branched or unbranched alkyl group containing 1-4 carbon atoms, and Q1and Q2have these values

The invention relates to new derivatives methylenephosphonic acid of General formula I

< / BR>
in which R1, R2, R3and R4independently are C1-C10the alkyl straight or branched chain, optionally unsaturated, C3-C10-cycloalkyl, optionally unsaturated, aryl, aralkyl, silicom SiR3or hydrogen, in formula I, at least one of the groups R1, R2, R3and R4is hydrogen and at least one of the groups R1, R2, R3and R4different from hydrogen

The invention relates to medicine, namely to Oncology, and in particular to compositions used for treatment of malignant tumors

The invention relates to new biologically active compound, specifically to the dichloride 2-[5-(2-methylpyridyl]ethyl, bis{2-[5-(2 - methylpyridine)] ethyl}of phosphoryla (I) of the formula I

MeCCHMeCH2CHP=0

possessing antibacterial activity

-diphenylphosphinoethyl, n-2-hydroxy(2-nitroxy)-3,5 - dibromopropylether showing neurotropic activity" target="_blank">

The invention relates to new chemical compounds, namely, N-substituted the hydrazones: N-definiltey - ylacetic, N-2-hydroxy-(I) and N-2-nitroxy (II)-3,5-dibromoindigotin formula

(C6H5)CHNHN=CHwhere X=HE(I), ONa(II) showing neurotropic activity

-diphenylphosphinoethyl, n-diphenylphosphinyl-(2 - hydroxy-3,5-dibromo)phenylmercapturic showing neurotropic activity, and method thereof" target="_blank">

The invention relates to new chemical compounds, namely, bis-phosphorylated N-, N-substituted semicarbazide-N-diphenylphosphinite - Thiel, N-diphenylphosphinyl, (2-hydroxy-3,5-dibromo)phenylmercapturic formula I

(C6H5)Nshowing neurotropic activity

The invention relates to medicine, namely to endocrinology, and can be used for the treatment of autoimmune thyroiditis
Radioprotector // 2049469
The invention relates to experimental biology and medicine and can be used to protect living organisms, when exposed to ionizing radiation

The invention relates to medicine, Pediatrics infectious diseases in children, and may be embedded in children's medical institutions

FIELD: medicine, ophthalmology.

SUBSTANCE: one should apply an autohemocomponent preparation being supernatant liquid of patient's autoblood at increased serotonin content obtained due to irreversible thrombocytic aggregation due to the impact of 0.5 mg ATP per 1.0 ml plasma followed by a 30-min-long centrifuging at the rate of 1000, 2000 and 3000 rot./min for 20, 7 and 3 min, correspondingly. In case of no exudative phenomena on patient's eye bottom the obtained preparation should introduced at the quantity of 7-10 ml once in 48 h for 1 mo (totally, 15 injections). In case of exudative-hemorrhagic phenomena it should be introduced parabulbarly at the volume of 0.5 ml and parenterally - 7.0-10.0 ml once in 48 h for 1 mo per 15 injections, correspondingly. The preparation enables to improve visual functions due to decreased tissue hypoxia and normalization of microcirculation in visual analyzer.

EFFECT: higher efficiency of therapy.

2 cl, 7 dwg, 2 ex

Up!