Pyrazolopyrimidines and pyrimidinecarbonitrile acids, their esters or pharmaceutically acceptable salts

 

(57) Abstract:

Usage: in medicine as anti-inflammatory drugs. The inventive Products: pyrazolopyrimidines and pyrimidinecarbonitrile acids, their esters or pharmaceutically acceptable salts of formulas I and II listed in the description, where R1- H, Na, K, C1-C6-alkyl, R2- H, C1-C6-alkyl, benzyloxy, C1-C6-alkoxy, phenyl, R6- H , X is oxygen, R10- H, R11- C1-C6-alkyl, benzyl, allyl, phenyl, benzyloxyindole, alkoxyphenyl, R12- H, halogen, R13Is H, phenyl, pyridinoline, or R12and R13form together halogen-substituted benzene ring. Reagent 1: pyrazolopyrimidine or pyrimidine. Reagent 2: vinylidenediphosphonate. Reaction conditions: in the presence of a strong base in the medium of organic solvent. 2 C. and 10 C. p. F.-ly, 2 tab.

The present invention relates to pyrazolopyrimidine (formula 1) and pyrimidinyl-(formula 2) bisphosphonate esters, acids, and their pharmaceutically acceptable salts that can be used as anti-inflammatory drugs and anti-arthritis.

Unlike other protivo is mainly prostaglandin-sintetaza activity inhibited heterodyne anti-inflammatory agents, and many of the actions of these agents, including side effects caused by inhibition of prostaglandin synthesis. However, compounds of the present invention have anti-inflammatory effect without inhibiting the production of prostaglandin. This fact can be considered as a primary factor, since it is known that at high concentrations, prostaglandins exert anti-inflammatory effects. Compounds of the present invention can be used for the treatment of arthritis and related symptoms, such as inflammation, and to prevent excessive bone growth and regeneration.

Prior art

In U.S. patent N 4746654 disclosed bisphosphonates, used as anti-inflammatory agents.

In Australian patent A-51534/85 disclosed bisphosphonates used for the treatment of metabolic disorders of calcium and phosphorus and for the treatment of arthritis.

In U.S. patent N 3683080 disclosed polyphosphonate, in particular, diphosphonates used for inhibiting anomalous deposition and mobilization of phosphate calceolaria for the treatment of disorders of calcium metabolism.

As for the compounds of formula I, PD 7244-88-021 American chemical society spring conference June 9, 1988) discloses the alkylation of 5,7-dimethylpyrazolo [1,5-a]-pyrimidines.

In the publication Jamanouchi (EP 354-806 A2, February 14, 1990) discloses imidazo [1,2-a] pyridine, imidazo-[1,2-a]imidazoles.

In DE 36265-058 A1 (Bochringer Mannheim) discloses heteroaromatic diphosphonates.

Brief description of the invention

In another embodiment, the present invention includes pyrazolopyrimidine-(formula 1) and pyrimidinyl-(formula 2) bisphosphonic esters and their pharmaceutically acceptable salts, which have the following structural formula:

where X represents O or S;

R1that may be the same or different, are selected from the group consisting of H, Na, K, tromethamine, C1-C6-alkyl, CH2phenyl, phenyl (optionally substituted by 1-5 NO2, halogen, or C1-C4-alkyl), or both, OR1on the same P, taken together with the CH2-CH2CH2-CH2-CH2or CH2-C(CH3)2-CH2form a heterocyclic ring having one phosphorus atom, two atoms of oxygen and three carbon atoms;

R2UOM, C3-C7-cycloalkyl, phenyl (optionally substituted by 1 or 2 phenylamine or 1-5 Halogens, NO2CN, CF3C1-C10-alkyl, C3-C7- cycloalkyl, C1-C6-alkylthio), 2-, 4 - or 5-pyrimidyl (optionally substituted C or 2 fenelli, or by 1-3 Halogens, NO2CN, CF3C1-C10-alkyl, C3-C7-cycloalkyl, C1-C6-alkoxy, or C1-C6-alkylthio), 2-, 3 - or 4-pyridyl (optionally substituted by 1 or 2 fenelli, or 1 to 4 halogen free, NO2CN, CF3C1-C10-alkyl, C3-C7-cycloalkyl, C1-C6- alkoxy or C1-C6-alkylthio), 1 - or 2-naphthalenyl (optionally substituted by 1 or 2 penilai or 1-7 Halogens, NO2CN, CF3C1-C10-alkyl, C3-C7-cycloalkyl, C1-C6- alkoxy or C1-C6-alkylthio);

R3represents H, CN, CO2R1, COR2, CON(R5)2, halogen, NO2CN, CF3C1-C10alkyl, C3-C7cycloalkyl, or phenyl;

R5represents H, C1-C6alkyl or C3-C7-cycloalkyl;

R6represents H, halogen or C1-C6-alkylamino substituted by 1 or 2 penilai or 1 to 5 Halogens, NO2CN, CF3C1-C10-alkyl, C3-C7-cycloalkyl, C1-C6-alkoxy or C1-C6-alkylthio); R11represents H, C1-C6-alkyl, C3-C7-cycloalkyl, allyl, CH2OR14CH2is phenyl, or phenyl (optionally substituted by 1 to 5 NO2, halogen, or C1-C4-alkyl):

R12represents H, C1-C6-alkyl, halogen, NO2;

R13represents hydrogen, C1-C6-alkyl, C3-C7-cycloalkyl, or phenyl (optionally substituted by 1, 2 fenelli, or 1 to 5 Halogens, NO2CN, CF3C1-C10-alkyl, C3-C7-cycloalkyl, C1-C6-alkoxy or C1-C6-alkylthio), 2-, 3-or 4-pyridyl (optionally substituted by 1, 2 penilai or 1 to 4 halogen free, NO2CN, CF3C1-C10-alkyl, C3-C7-cycloalkyl, C1-C6-alkoxy, or C1-C6-alkylthio), 1 or 2-naphthalenyl (optionally substituted by 1, 2 fenelli, or 1 to 7 halogen, NO2CN, CF3C1-C10-alkyl, C3-C7-cycloalkyl, C1-C6-alkoxy or C1-C6-alkylthio), piperidine, morpholine, pyrrolidine, N(R5is CE), having 4 to 7 carbon atoms, 1 to 3 nitrogen atoms, 0 to 2 oxygen atoms and 0 to 2 sulfur atoms; and

R14represents a C1-C6-alkyl, C3-C7-cycloalkyl, allyl, CH2is phenyl, or phenyl (optionally substituted by 1 to 5 NO2, halogen, or C1-C4-alkyl).

In another embodiment, the present invention includes the use of these compounds for the safe and efficient treatment of diseases of man and the lower animals associated with metabolic phosphate and calcium, as well as for the treatment of inflammatory processes. Such diseases are osteoporosis, Paget's disease, periodontal disease, rheumatoid arthritis, osteoarthritis, neuritis, bursitis, impaired mineralization of soft tissues, ankylosing spondylitis (Bechterew's disease ), atherosclerois, multiple myeloma bone, metastatic bone disease, and calcification of the left mitral valve. These compounds do not inhibit cyclooxegenase or lipoxygenases the arachidonic acid metabolism and therefore can be the basis of a new method of treatment of inflammatory diseases.

Method of treatment of inflammatory diseases is the introduction animal in need of such l is retene can be administered orally, intramuscular, intravenous, intradermal, intra-articular, subcutaneous, or intraperitoneal. An effective amount is the amount of active compound, in which the symptoms of inflammation or arthritis, such as pain or discomfort can be eased or reduced or may be increased mobility of the affected areas. The usual dose is from about 0.001 mg to about 1.0 g, depending on the specific method and frequency of administration and purpose.

Detailed description of the present invention

The present invention includes pyrazolopyrimidine (formula 1) and pyrimidine (formula 2) bisphosphonic esters, acids, and their pharmaceutically acceptable salts having the following structural formulas 1 and 2. These compounds, in particular, are used for the treatment of arthritis and related symptoms, such as inflammation, excessive bone growth or regeneration. In formulas 1 and 2, the values of the variables are defined as follows.

The carbon content of various hydrocarbon-containing parts are shown by the index denoting the minimum and maximum number of atoms in particular, i.e. the index of the Ci-Cjspecifies the number of PR is Ermin C1-C3-alkyl refers to alkyl of 1 to 3 carbon atoms, inclusive, or stands, ethyl, propylene, and isopropyl.

In accordance with the above, the term C1-C6-alkyl means methyl, ethyl, propyl, butyl, pentyl, hexyl, and isomeric forms. The term C3-C7-cycloalkyl means cyclopropane, CYCLOBUTANE, cyclopentane, Cycloheptane, and their isomeric forms.

The term "halogen" means fluorescent-, chloro, bromo-, and idgruppo.

The term C1-C8alkylthio means methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, Reptilia, ontatio, and their isomeric forms.

The term C1-C8-alkoxy means methoxy, ethoxy, propoxy, butoxy, pentox, hexose, heptose, octoate and their isomeric forms.

Pharmaceutically acceptable salts are salts that are used for the introduction of compounds of the present invention; such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, mesilate, maleate, malonate, succinate, tartrate, citric acid, etc., These salts may be in hydrated form.

Bisphosphonic esters, acids and derivatives (formula 1) of pinasok shown in examples 1 to 13 (of the Connection and on). The General structure pyrazolopyrimidinones heterocyclic ring may be obtained by standard methods, well known to specialists. For example, the synthesis of pyrazolo 1,5-and pyrimidines described M. Elnagdi, G. E. H. Elgemil and M. R. H. Elmog, hayar in Advanced in Hetererocyclic chemistry v. 41, S. 319, M. R. H. Elmoghay ar and other synthesis of pyrimidine derivatives and related compounds described in Ar ch. Pharm (Wenheim ), 316, c. 697 702 (1983); and T. Hovison etc. and 3-zameshannye 5,7-dimethylpyrazolo(1,5-a) pyrimidines described in J. Med. Chem. S. 645 -648 (1974).

One of the methods of synthesis of compounds of formula 1 of the present invention is carried out by dissolving pyrazolopyrimidine in a suitable solvent (THF, pyridine or mixtures thereof). This liquid add drop by drop to a solution of THF at 78oC (although this solution may also be located at 0oC) strong kinetic reasons (hexamethyldisilazide lithium or diisopropylamide lithium), and the resulting solution was stirred for about 30 minutes at -78oC (although this solution may also be at 0oC). Then to the cold reaction mixture is added vinylidenediphosphonate either in pure form or in a solution of THF, after which the reaction mixture is heated to room temperature. Specific processing conditions described in the examples.

Join the specified group of the formula 1 are fluorescent, which allows us to trace these compounds in biological tissue.

The compound of formula 1 of the present invention were investigated in models of inflammation by analyzing granuloma reaction of delayed-type hypersensitivity (DTH GRA). This analysis is described Dunn, C. J. et. al. "Development of a delayed-type hypersensitivity pyogenic granuloma model in the mouse for the study of chronic immune-mediated inflammatory diseas", Agents and Actions, 27, 3/41 (1989) and "Musine Delayed Type Hypersensivity pyogenic granuloma", Int.J. Immunopharmc. 12, 8, 899-904 (1990)-

Briefly, MBSA sensitized mice had TH-granuleme (TH GRA) lesions induced by subcutaneous implantation of m BSA-soaked filter, which was given in 9 days. To determine the response to the defeat, the mice were injected compounds. The results were recorded to the licensing 10 20% was considered as an indicator protivoglaucomnoe activity. Inhibition of over 30% is a good activity.

DTH GRA data obtained from compounds of formula 1, are presented in table. 1. When 10 to 20% inhibition, these compounds are considered as compounds with anti-inflammatory activity, and when more than 30% inhibition, as compounds with good activity.

"Markings" corresponds to the notation of examples. Specific compounds have the following symbols

a) (3-(3-Cyano-2,5-dimethyl-pyrazolo(1,5-a)pyrimidine-7-yl)-propylidene)bisphosphonates acid tetraethyl ester;

c) (3-(3-cyano-5-methyl-2-phenyl-pyrazolo(1,5-a)pyrimidine-7-yl)propylidene)bisphosphonates acid tetraethyl ester;

d) (3-(3-bromo-2,5-dimethyl-pyrazolo(1,5-a)pyrimidine-7-yl)propylidene)bisphosphonates acid tetraethyl ester;

(e) (3-(3-nitro-2,5-dimethyl-pyrazolo(1,5-a)pyrimidine-7-yl)propylidene)bisphosphonates acid tetraethyl ester;

f) (3-(2-benzoyloxy-5-methyl-pyrazolo(1,5-a)pyrimidine-7-yl)propylidene)bisphosphonates acid tetraethyl ester;

g) (3-(2-benzyloxy-5-methyl-pyrazolo(1,5-a)pyrimidine-7-yl)propylidene)bisphosphonates acid tetraethyl ester;

h) (3-(2-hexyloxy-5-methyl-pyrazolo(1,5-a)pyrimidine-7-yl)proelite)bisphosphonates acid tetraethyl ester;

(j) (3-(3-iodo-5-methyl-2-phenyl-pyrazolo(1,5-a)pyrimidine-7-yl)proreligion)bisphosphonates acid tetraethyl ester;

k) (3-(3-chloro-5-methyl-2-phenyl-pyrazolo(1,5-a)pyrimidine-7-yl)-propylidene)bisphosphonates acid tetraethyl ester;

l) (3-(3-bromo-5-methyl-2-phenyl - pyrazolo(1,5-a)pyrimidine-7-yl)-propylidene)bisphosphonates acid tetraethyl ester;

m) (3-(3-cyano-2,5-dimethyl - pyrazolo(1,5-a)pyrimidine-7-yl)-propylidene)bisphosphonates acid tetramethyl ester;

n) (3-(3-cyano-2,5-dimethyl - pyrazolo(1,5-a)pyrimidine-7-yl)-propylidene)bis(5,5-dimethyl-2,2-dioxide-1,3,2-dioxaphosphinan), and

o) (3-(6-chloro-3-cyano-2,5-dimethyl - pyrazolo(1,5-a)pyrimidine-7-yl)-propylidene)bisphosphonates acid tetraethyl ester.

Bisphosphonic esters, acids and derivatives (formula 2) pyrimidinyl used as anti-inflammatory drugs and anti-arthritis, receive, as shown in examples 14-17 (Connection, "p-SS"). Synthesis of 4-pyrimidinone can be made well-known ways. In General, complex ketoester treated with the hydrochloride of acetamidine in the presence of a base and get a heterocyclic compound. This base can be sodium hydroxide, sodium carbonate, potassium methoxide notreallyrelevant derivatives synthesized by treating the starting compound with the electrophile in the presence of a base, such as potassium carbonate, sodium hydride or potassium fluoride.

In one method, compounds of formula 2 can be synthesized via the reaction of alkyl pyrimidines with a strong base, such as hexamethyldisilazide lithium or lisaprojekte lithium, followed by treatment with vinylidenefluoride, such as ethylenebis-tetraethyl ester phosphonic acid or 2,2-atrendees(5,5-dimethyl-2,2-)-dioxide-1,3,2-dioxaphosphorinanes). Compounds purified either by chromatography or by crystallization.

The compounds of formula 2 of the present invention were tested in models of inflammation by analyzing granuloma reaction of delayed-type hypersensitivity (DTH CCS), as described above. Also, as in table. 1-2, the results were expressed as percentage inhibition. The higher the inhibition, the more effective is the connection. Inhibition 10 20 were considered as an indicator protivoglaucomnoe activity. Inhibition of over 30 is a good indicator of activity.

DTH GRA-data obtained for compounds of the formula shown in the table. "The designation of the connection corresponds to the notation of examples 14-17. Specific compounds have the following notation:

p-methyl-4-oxo-6-phenyl-4-(3H)- pyrimidinyl))-propylidene)bisphosphonates acid disodium salt;

r) (3-(2-(3-benzyl-4-oxo-6-phenyl-4(3H)- pyrimidinyl))-propylidene)bisphosphonates acid tetraethyl ester;

s) (3-(2-(3-methyl-1-oxo-6-(3-fluorescent-phenyl)4- (3H)-pyrimidinyl))-propylidene)bisphosphonates acid tetraethyl ester;

t) (3-(2-(3-allyl-4-oxo-6-phenyl-4-(3H)- pyrimidinyl))-propylidene)bisphosphonates acid tetraethyl ester;

v) (3-(2-(3-methyl-4-oxo-6-(3-methyl-phenyl)- 4(3H)-pyrimidinyl))-propylidene)bisphosphonates acid tetraethyl ester;

w) (3-(2-(3-methyl-4-oxo-6-(3-methoxy-phenyl)- (3H)-pyrimidinyl))propylidene)bisphosphonates acid tetraethyl ester;

x) (3-(2-(3-methyl-4-oxo-6-(3-trifluromethyl-phenyl)- 4(3H)-pyrimidinyl))-propylidene)Biofactory acid tetraethyl ester;

y) (3-(2-(3-methyl-4-oxo-5-bromo-6-phenyl-4(3H)-pyrimidinyl))-propylidene)bisphosphonates acid tetraethyl ester;

z) (3-(2-(3-methyl-4-oxo-6-(4-bromophenyl)-4(3H)-pyrimidinyl)bisphosphonates acid tetramethyl ester;

aa) (3-(2-(3-methyl-4-oxo-6-(4-bromophenyl)-4(3H)-pyrimidinyl))-propylidene)bisphosphonates acid tetraethyl ester;

bb) (3-(2-(3-methyl-4-oxo-6-(4-methoxyphenyl)-4(3H)-pyrimidinyl))-propylidene)bisphosphonates acid tetraethyl ester;

cc) (3-(2-(3-methyl-4-oxo-6-(4-dimethylaminophenyl)-4(3H)-pyrimidinyl))-propylidene)bisphosphonates acid those who s tetraethyl ester;

gg) (3-(2-(3-benzyl-4-(oxo-6-phenyl-4(3H)-pyrimidinyl))-propylidene)bisphosphonates acid tetraethyl ester;

hh) (3-(2-(3-allyl-4-oxo-phenyl-4(3H)-pyrimidinyl))-propylidene)bisphosphonates acid tetraethyl ester;

ii) (3-(2-(3-ethyl-4-oxo-6-phenyl-4(3H)-pyrimidinyl))-propylidene)bisphosphonates acid tetraethyl ester;

jj) (3-(2-(3-propyl-4-oxo-6-phenyl-4(3H)-pyrimidinyl))-propylidene))bisphosphonates acid tetraethyl ester;

mm) (3-(2-(3-methyl-4-oxo-6-(2,3,5-triflora-4-piperidinophenyl)-4(3H)-pyrimidinyl)) -propylidene)bis(5,5-dimethyl-2,2-dioxide-1,3,2-dioxaphosphinan);

oo) 3-(7-chloro-3-methyl-4(3H)- hintline)-ropolitan)bisphosphonic acid tetraethyl ester;

pp) 3-(7-chloro-3-( a., ., .... -triflora-o-totyl)-4(3H)-hintline)propylidene)bisphosphonates acid tetraethyl ester;

qq) 3-(7-chloro-3-(2-fluorescent-phenyl)-4(3H)-hintline)- propylidene)bisphosphonates acid tetraethyl ester, and

rr) (3-(2-(3-methyl-4-oxo-6-phenyl-4(3H)-pyrimidinyl))- propylidene)bisphosphonates acid teeterboro ester sodium salt.

Example 1 (3-(3-Cyano-2,5-dimethyl-pyrazolo(1,5-a)pyrimidine-7 - yl)propylidene)bisphosphonates acid tetraethyl ester (a) and acid salt (b)

Pyrazolo(1,5-a)pyrimidine (3,02 g, 16.2 mm) suspended in pyridine (40 ml) at 0ooC and stirred for 1 hour. Then the mixture was poured into 10% HCl solution was extracted three times with methylene chloride, dried with magnesium sulfate and evaporated. The sample obtained was purified by chromatography (ethyl acetate, ethyl acetate/acetone 3:1, 2:1, 1:1); and received of 3.97 g of the product (8,16 mm, 50%). The sample was utverjdali when defending, so pl. 49 50oC.

Tetraethyl was heated under reflux in concentrated hydrochloric acid for 12 hours and concentrated solution was synthesized in the corresponding acid of compound "b" of compound "a".

Example 2 (3-(3-Cyano-5-methyl-2-phenyl-pyrazolo(1,5-a)-pyrimidine-7 - yl)propylidene)bisphosphonates acid tetraethyl ester (c)

5,7-Dimethyl-2-phenyl-pyrazolo(1,5-a)pyrimidine-3-carbonitrile (621 mg, 2.50 mm) in pyridine (5.0 ml) at 0oC was treated with a solution of LiHMDS (2.6 ml, 2.6 mm) and was stirred for 30 minutes. Dark red solution was treated with a solution ETE phosphonic acid (750 mg, 2.50 mm) in THF (5 ml). After stirring at 22oC for 1 hour, the reaction mixture was poured into 10% HCl. Organic substances were extracted with methylene chloride, then washed once (each 1 N. HCl solution, sodium bicarbonate, is cromatografia (methylene chloride, methylene chloride/acetone, 9:1, then 1: 9) and received 600 mg of product (1,09 mm, 49%), so pl. 107oC (methyl-t-butyl ether).

Example 3 (3 -(3-Bromo-2,5-dimethyl - pyrazolo(1,5-a)pyrimidine-7-yl)-propylidene)bisphosphonates acid tetraethyl ester (d)

3-Bromo-2,5,7-trimethyl-pyrazolo(1,5-a)pyrimidine (460 mg, 1,92 mm) solution in THF (10 ml) at 0oC and treated with a solution of LiHMDS (2.0 ml, 2.0 mm). After 30 minutes stirring, the solution was added ETE phosphonic acid (576 mg, 1,92 mm) in THF (1 ml). After stirring for 1 hour at 22oC, the reaction mixture was poured into 10% HCl solution. Organic substances were extracted with methylene chloride, then washed once (each) 1 N. HCl solution, sodium bicarbonate, and brine, then the organic matter was dried with magnesium sulfate and evaporated. The sample was purified by chromatography (ethyl acetate, ethyl acetate/acetone 7:4), and received 527 mg (0,975 mm, 51%) of product as an oily substance.

Example 4 (3-(3-Nitro-2,5-dimethyl-pyrazolo(1,5-a)pyridin-7-yl)-propylidene)bisphosphonates acid tetraethyl ester(e)

2,5-7-Trimethyl-3-nitro-pyrazolo(1,5-a)pyrimidine (900 mg, 4,36 mm) was dissolved in pyridine (10 ml) at 0oC, and then treated with a solution of LiHMDS (4.5 ml, 4.5 mm). On the air traffic management at the 22oC, the reaction mixture was poured into 10% HCl solution. Organic substances were extracted with methylene chloride, washed once (each) 1 N. HCl solution, sodium bicarbonate, and brine, then were dried with magnesium sulfate, and evaporated. The sample was purified by chromatography (ethyl acetate, ethyl acetate/acetone 7:4), were 1,374 g (2,71 mm, 62%), oily substance.

Example 5 (3-(2-Benzoyloxy-5-methyl-pyrazolo(1,5-a)pyrimidine-7 - yl)propylidene)bisphosphonates acid tetraethyl ester (f)

A) Cyanoacetylene (to 9.91 g, 0.10 mm) and 2,4-pentandiol (10.5 ml, 0.10 M) was heated for 30 minutes in ethanol (20 ml) and acetic acid (0.5 ml). The reaction mixture was cooled to 22oC, and then were treated with 1 N. a solution of sodium hydroxide (120 ml) and heated under reflux for 15 minutes. The stirred mixture was placed in a heated reaction vessel and was titrated up until the solution is neutral, using 12 n HCl solution and then cooled overnight at 0oC. the Obtained solid was collected and recrystallized from ethanol, resulting in a received 8,565 g of the product (0,0525 M, 53%).

5,7-Dimethyl-pyrazolo(1,5-a)pyrimidine-2-ol (3,26 g, 20 mm) in pyridine (60 ml) at 0oC amrabat the (6,30 g, 21 mm) in THF (10 ml) and the reaction mixture was heated to 22oC for 1 hour. After the reaction mixture was extracted three times 1 N. a solution of sodium hydroxide (20 ml) and washed three times with ethyl acetate. The aqueous fraction was neutralized using 12 n HCl solution was extracted three times with ethyl acetate, washed with brine, dried with magnesium sulfate and evaporated. The resulting material was used in subsequent reactions without further purification.

B) the Crude pyrazolo[1,5-a]pyrimidine-2-ol (475 mg, 1,02 mm) in methylene chloride (5 ml) at 0oC was treated with benzoyl chloride (0,12 ml of 1.02 mm) and triethylamine (0.17 ml, 1.2 mm). After stirring for 1 hour, the reaction mixture is extinguished 1 N. HCl solution, was extracted three times with ethyl acetate, washed with sodium bicarbonate, saline, dried with magnesium sulfate and evaporated. The sample was chromatographically (ethyl acetate, ethyl acetate/acetone 1:1), and the resulting product was led when defending. After recrystallization from ether/hexane, received 97 mg of the product (0.17 mm, 17%), so pl. 56 57oC.

Example 6 (3-(2-Benzyloxy-5-methyl-pyrazolo(1,5-a)pyrimidine-7 - yl)propylidene)bisphosphonates acid tetraethyl ester (g)

5,7-Dimethyl-pyrazolo[1,5-ATEM were treated with benzylchloride (1.2 ml, 10 mm). The reaction mixture was stirred for 20 minutes at 120oC, and then poured into excess amount of 1 N. NaOH. Organic matter was extracted twice with ethyl acetate, washed with sodium bicarbonate and brine, dried with magnesium sulfate and evaporated. The product has led after evaporation of hexane, and then recrystallized from hexane using Darco 539 mg Of the mother liquor was given to 248 mg 787 mg of product (3,10 mm, 31%).

Benzyl ether (539 mg, 2.1 mm) in THF (2 ml) was treated at -78oC a solution of LiHMDS (2.2 ml, 2.2 mm) and stirred 30 minutes. Then to the mixture was added N phosphonic acid (630 mg, 2.1 mm) in THF (1 ml) was stirred at 22oC for 1 hour. Then the organic substance was poured into 10% HCl solution was extracted three times with ethyl acetate, washed with sodium bicarbonate and brine, then were dried with magnesium sulfate and evaporated. The obtained product was isolated by chromatography (ethyl acetate, ethyl acetate/acetone, 1 1) and received 547 mg (0,988 mm, 47%), oily substance.

Example 7 (3 -(2-Hexyloxy-5-methyl-pyrazolo(1,5 - a)pyrimidine-7-yl)-propylidene)bisphosphonates acid tetraethyl ester (h)

5,7-Dimethyl-pyrazolo 1,5-and pyrimidine-2-ol (1.63 g, 10 mm), the home (1.5 ml, 10,7 mm). The reaction mixture was stirred for 20 minutes at 120oC, and then poured into excess amount of 1 n NaOH solution. Organic matter was extracted twice with ethyl acetate, then washed with 1 N. HCl solution and brine, dried with magnesium sulfate and evaporated. The product received is not crystallized, resulting in a received 1,876 g (7.6 mm, 76%).

The crude ester (1,876 g, 7.6 mm) was dissolved in THF (5 ml) was cooled to -78oC and was treated with LiHMDS (of 7.6 ml, 7.6 mm). After 30-minute stirring, was added ETE phosphonic acid (2,27, 7 mm), in trace quantities THF and the reaction mixture was stirred for 1 hour at 22oC. Organic matter was poured into 10% HCl solution was extracted three times with ethyl acetate, washed with sodium bicarbonate and brine, dried with magnesium sulfate, and evaporated. The obtained product was purified by chromatography (ethyl acetate, ethyl acetate/acetone 1: 1), and received 1,632 g (2,98 mm, 39%) of product.

Example 8 (3-(5-Methyl-2-phenyl-pyrazolo(1,5-a)pyrimidine-7-yl)propylidene)bisphosphonates acid tetraethyl ester (i)

Pyrazolopyrimidine (1,00 g, 4.5 mm) was dissolved in pyridine (9 ml), cooled to 0oC and was treated with a solution of 4.9 ml, 4.9 mm), and then PES was stirred for another 30 minutes. The reaction mixture was poured into cold 10% HCl solution and washed three times with methylene chloride. The combined organic layers washed with 10% HCl solution, water, NaHCO3NaCl, dried with magnesium sulfate and evaporated. The resulting mixture was chromatographically, elwira with ethyl acetate and then 10% acetone and ethyl acetate. The material obtained was utverjdali when defending. The obtained solid substance was dissolved in ether and precipitated with hexane, so pl. 51 52oC, resulting in a received 0,824 g of the product (1,57 mm, 37%).

Example 9 (3-(3-Iodo-5-methyl-2-pyrazolo(1,5-a) pyrimidine-7-yl)propylidene)bisphosphonates acid tetraethyl ester (j)

The connection "i" example 8 (of 0.786 g, 1.5 mm) was dissolved in chloroform (4.8 ml) and treated with N-iodosuccinimide (0,345 g, 1,54 mm) and then heated under reflux for 20 minutes. The resulting solution was cooled and poured into 2 n KOH (6,7 ml). The layers were separated, and the chloroform was washed with water, dried with magnesium sulfate and evaporated. The product was subjected to chromatography on silica gel, elwira 2% ethanol/ethyl acetate. The material was utverjdali when defending, so pl. 81 82oC, and received of 0.741 g (1.14 mm, 76%).

Example 10 (3-(3-Chloro-5-methyl-2-phenyl-pyrazolo(1,5-a) pyrimidine-7-yl)propylidene)bisphosphonic acid is the home (0,418, 3.1 mm) and heated under reflux for 30 minutes. The solution was cooled and poured into a cold solution of 2 n KOH (13 ml). The organic layer was twice washed and separated water and NaCl. The resulting mixture was dried with magnesium sulfate and evaporated, and then chromatographically, elwira a mixture of 2% ethanol and ethyl acetate. The product was utverjdali when defending (so pl. 66 68oC) and received 0,763 g (1,37 mm, 49%) of product.

Example 11 (3-(3-Bromo-5-methyl-2-phenyl-pyrazolo(1,5-a) pyrimidine-7-yl)-propylidene)bisphosphonates acid tetraethyl ester (I)

The connection "i" Example 8 (1,488 g, 2.8 mm) in chloroform (10 ml) was treated with N-bromosuccinimide (0.52 g, 2.9 mm) and the solution was heated under reflux for 25 minutes. After that, the mixture was cooled, separated and poured into a cold solution of 2 n KOH (13 ml). The organic layer was twice washed with water and brine. Then it was dried with magnesium sulfate, and evaporated. The resulting mixture was chromatographically, elwira a mixture of 2% ethanol/ethyl acetate. The product was utverjdali when defending (so pl. 46 48oC) and received 1.47 g (2,44 mm, 87%) of product.

Example 12 (3-(3-Cyano-2,5-dimethyl-pyrazolo(1,5-a)pyrimidine-7-yl)-propylidene)bisphosphonates acid tetramethyl ester (m)

Pyrazolo(1,5-a)Perim. Then added ETE phosphonic acid (1.64 g, of 6.71 mm) and the reaction mixture was heated to 22oC and stirred for 1 hour. The resulting solution was poured into 10% HCl solution was extracted three times with methylene chloride, dried with magnesium sulfate and evaporated. The product was recrystallized from ethyl acetate and received 1,152 g (2,68 mm 40%) so pl. 100 101oC.

Example 13 (3-(3-Cyano-2,5-dimethyl-pyrazolo(1,5-a)pyrimidine-7-yl)-propylidene)bis(5,5 - dimethyl-2,2'-dioxide-1,3,2-dioxaphosphinan) (n)

Pyrazolo(1,5-a)pyrimidine (1.30 grams, 6,98 mm) in pyridine (15 ml) at 0oC was treated with a solution of LiHMDS (of 7.1 ml, 7.1 mm) and stirred 30 minutes. Then added a solid 1.1 tinylogin-bis-(5,5-dimethyl-2,2'-dioxide-1,3,2-dioxaphosphinan)phosphonic acid (of 2.26 g, 6,98 mm), the reaction mixture was heated to 22oC and was stirred for 30 minutes. Then the reaction mixture was poured into 10% HCl solution was extracted three times with methylene chloride, dried with magnesium sulfate and evaporated. The resulting product was recrystallized from a mixture of methylene chloride/hexane and obtained 1,743 g (3,41 mm, 49%) of the product so pl. 258 259oC.

Example 14 (3-(2-(3-Methyl-4 - oxo-6-phenyl-4(3H)-pyrimidinyl))-propylidene)bisphosphonates acid tetraethyl ester (p)

To a solution of HEXAMETHYL the)-she (13,064 g, 65,16 mm) and THF (50 ml). After 30 minutes of stirring at -78oC was added vinylidenediphosphonate (21,6 g 72 mm), the reaction mixture was stirred for 1 hour and heated to 22oC. After this reaction extinguished saturated ammonium chloride, was extracted three times with ethyl acetate, washed twice with saline, dried with magnesium sulfate and evaporated. Then the resulting material was recrystallized from methyl t-butyl ether and received 20,61 g (41,2 mm, 63%) of the product so pl. 83 84oC. the Following compounds were obtained by the method described above:

r) (3-(2-(3-benzyl-4-oxo-6-phenyl)-4(3H)-pyrimidinyl)) -propylidene)bisphosphonates acid tetraethyl ester, so pl. 72 74oC;

(S) (3-(2-(3-methyl-4-oxo-6-(3-fluorescent-phenyl) -4(3H)-pyrimidinyl))-propylidene)bisphosphonates acid tetraethyl ester, so pl. 93,5 95,5oC;

(t) (3-(2-(3-allyl-4-oxo-6-phenyl-4(3H) -pyrimidinyl))-propylidene)bisphosphonates acid tetraethyl ester, so pl. 53 55oC;

(u) (3-(2-(3-bromo-3-methyl-4-oxo-6-phenyl -4(3H)-pyrimidyl))-propylidene)bisphosphonates acid tetraethyl ester, in the form of oily substances, m/e 580, 578 (m+), 443, 441, 293, 291, 288;

(v) (3-(2-(3-methyl-4-oxo-6-(3-methyl-phenyl)-4(3H) -pyrimidyl))-propylidene)bisphosphonates acid tetraethyl ester, so pl. 90 - 91oC; ether, so pl. 65 66oC;

(x) (3-(2-(3-methyl-4-oxo-6-(3-trifluromethyl-phenyl)-4(3H)-pyrimidinyl))-propylidene)bisphosphonates acid tetraethyl ester, so pl. 77 79oC;

(y) (3-(2-(3-methyl-4-oxo-5-bromo-6-phenyl-4(3H)-pyrimidinyl))-propylidene)bisphosphonates acid tetraethyl ester, oily substance, m/e 578 (M+), 441,291,288;

(Z) (3-(2-(3-methyl-4-oxo-6-phenyl-4(3H)-pyrimidinyl))-propylidene)bisphosphonates acid tetramethyl ester, so pl. 106 108oC;

aa) (3-(2-(3-methyl-4-oxo-6-(4-bromophenyl) -4(3H)-pyrimidinyl))-propylidene)bisphosphonates acid tetraethyl ester, so pl. 76 77oC;

bb) (3-(2-(3-methyl-4-oxo-6-(4-methoxyphenyl) -4(3H)-pyrimidinyl))-propylidene)bisphosphonates acid tetraethyl ester, so pl. 81 83oC;

cc) (3-(2-(3-methyl-4-oxo-6-(4-dimethylaminophenyl) -4(3H)-pyrimidinyl))-pyrimidin)bisphosphonates acid tetraethyl ester, so pl. 92 94oC;

dd) (3-(2-(3-methyl-4-oxo-6-(3-dimethylaminophenyl) -4(3H)-pyrimidinyl))-propylidene)bisphosphonates acid tetraethyl ester, so pl. 79oC;

ee) (3-(2-(3-methyl-4-oxo-6-(4-ethoxyphenyl) -4(3H)-pyrimidinyl))-propylidene)bisphosphonates acid tetraethyl ester. so pl. 94 96oC;

ff) (3-(2-(3-methyl-4-oxo-6-(4-were) -4(3H)-pyrimidinyl))-propylidene)bisphosphonates acid tetraethyl afacility ether, so pl. 72 74oC:

(hh)(3-(2-(3-allyl-4-oxo-6-phenyl-4(3H)-pyrimidinyl))-propylidene)bisphosphonates acid tetraethyl ester, so pl. 53 55oC;

(ii) (3-(2-(3-ethyl-4-oxo-6-phenyl-4(3H)-pyrimidinyl))-propylidene)bisphosphonates acid tetraethyl ester, so pl. 79 81oC;

(jj) (3-(2-(3-propyl-4-oxo-6-phenyl-4(3H)-pyrimidinyl)) -propylidene)bisphosphonates acid tetraethyl ester, oily substance, m/e 528 (M+), 483, 391, 301, 288, 241, 199;

(kk) (3-(2-(3-benzoyloxymethyl-4-oxo-6-phenyl-4-(3H) -pyrimidinyl))-propylidene)bisphosphonates acid tetraethyl ester, so pl. of 99.5 100oC;

(ll) (3-(2-(3-methyl-4-oxo-6-phenyl-4(3H)-pyrimidinyl))-propylidene)bis(5,5-dimethyl-2,2-dioxide-1,3,2-dioxaphosphinan), so pl. 244 245oC; and

(mm) (3-(2-(3-methyl-4-oxo-6-(2,3,5-triflora-4-piperidinophenyl)-4(3H)-pyrimidinyl))-propylidene)bis(5,5 - dimethyl-2,2-dioxy-1,3,2-dioxaphosphinan), so pl. 209 210oC.

Example 15 (3-(2-(3-Methyl-4-oxo-6-phenyl-4(3H)-pyrimidinyl))-propylidene)bisphosphonates acid disodium salt (q)

(3-(2-(3-Methyl-4-oxo-6-phenyl-4(3H) -pyrimidinyl))-propylidene)bisphosphonates acid tetraethyl ester (to 2.29 g, 4,58 mm) was heated in concentrated hydrochloric acid (20 ml) under reflux for 24 hours, after which the solution evaporated to dryness. Policystore using methanol, filtered and dried air, resulting in a received 940 mg of the product (mm 2,17, 47%), so pl. > 300oC.

Example 16 (3-(2-(3-Oxo-6-phenyl-4-(3H)-pyrimidinyl)) -propylidene)bisphosphonates acid tetraethyl ester (nn)

(3-(2-(3-Benzoyloxymethyl-4-oxo-6-phenyl-4(3H)-pyrimidinyl) -propylidene)bisphosphonates acid tetraethyl ester (kk) of example 15 (1,00 g 1,65 mm) was dissolved in ethanol (20 ml) was treated with Pearlman catalyst (500 mg) and ammonium formate (1.0 g), then heated to a temperature of distillation. After 1, 5 hours to the solution was added the catalyst (500 mg) and ammonium formate (1.0 g) and the reaction was continued for another 4 hours. Then the reaction mixture was cooled to room temperature, filtered through celite, evaporated, and then chromatographically on silica gel (eluent: ethyl acetate/acetone) and received 138 mg of the product (0.28 mmol, 17%) with T. pl. 94 96oC.

The following compounds were obtained by the method described above:

(oo) 3-(7-chloro-3-methyl-4(3H)-hintline) -propylidene)-bisphosphonate acid tetraethyl ester, so pl. 58 62oC;

(pp) 3-(7-chloro-3-( .., ., ...,., -triflora-o-tolyl)-4(3H) -hintline)-propylidene)bisphosphonates acid tetraethyl ester, so pl. 90 - 92oC; and

(qq) 3-(7-chloro-3-(2-fluorescent-phenyl)- 4(3H)-hintline)-propylidene)Beemer 17 (3-(2-(3-Methyl-4-oxo-6-phenyl-4(3H)-pyrimidinyl))-propylidene)bisphosphonates acid teeterboro ester sodium salt (rr)

(3-2-(3-Methyl-4-oxo-6-phenyl-4(3H)-pyrimidinyl))-propylidene )bisphosphonates acid tetraethyl ester, (p) from example 14 (1.50 g, 3.0 mm ) was dissolved in methylethylketone (10 ml) was treated with sodium iodide (900 mg, 6 mm ) and heated to a temperature of distillation during the night. The obtained white precipitate was collected, washed with acetone and ether and then dried in a vacuum oven, resulting in a received 1,337 g of the product (2,70 mm, 90%), so pl. > 300oC, m/e (M+, 495, 317, 295, 213.

1. Pyrazolopyrimidinones acids, their esters or pharmaceutically acceptable salts of the General formula I

< / BR>
where R1each may be the same or different and are selected from the group consisting of H, Na, K, C1C6-alkyl, or both, OR1form together with the phosphorus atom is unsubstituted or alkyl substituted 1,3,2-dioxaphosphinan;

R2hydrogen, C1C6-alkyl, benzoyloxy, C1C6-alkoxy or phenyl;

R3H, halogen, NO2or CN;

R5C1C6-alkyl;

R6N.

2. Pyrimidinecarbonitrile acids, their esters or pharmaceutically acceptable salts of General formula II

< / BR>
where X is oxygen;

R1hydrogen, lower alkyl, Kali-dioxaphosphinan;

R10N;

R11C1C6- alkyl, benzyl, allyl, unsubstituted or substituted phenyl, benzyloxyindole, unsubstituted or substituted alkoxyphenyl;

R12H, halogen;

R13hydrogen, phenyl, phenyl substituted by halogen, alkyl, alkoxyl or dialkylamino, or halogensubstituted piperidinophenyl,

or R12and R13together form a halogen-substituted benzene ring.

3. Connection on p. 1, where the specified R1ethyl.

4. Connection on p. 1, where the specified R2methyl or phenyl.

5. Connection on p. 1, where the specified R5methyl.

6. Connection on p. 1 of formula 1, which represents a (3-(3-cyano-2,5-dimethyl-pyrazolo (1,5-a) pyrimidine-7-yl)-propylidene)bisphosphonates acid tetraethyl ester; (3-(3-cyano-2,5-dimethyl-pyrazolo (1,5-a)pyrimidine-7-yl)-propylidene)bisphosphonates acid dikalova salt; (3-(3-cyano-5-methyl-2-phenyl-pyrazolo (1,5-a)pyrimidine-7-yl)-propylidene)bisphosphonates acid tetraethyl ester; (3-(3-bromo-2,5-dimethyl-pyrazolo (1,5-a)pyrimidine-7-yl)-propylidene)bisphosphonates acid tetraethyl ester; (3-(3-nitro-2,5-dimethyl-pyrazolo (1,5-a)pyrimidine-7-yl)-propylidene)bisphosphine the acid tetraethyl ester; (3-(2-benzyloxy-5-methyl-pyrazolo (1,5-a)pyrimidine-7-yl)- propylidene)bostonboy acid tetraethyl ester; (3-(2-hexyloxy-5-methyl-pyrazolo (1,5-a)pyrimidine-7-yl)-propylidene)bisphosphonates acid tetraethyl ester; (3-(2-methyl-2-phenyl-pyrazolo (1,5-a)pyrimidine-7-yl)propylidene)bisphosphonates acid tetraethyl ester; (3-(3-iodine-5-methyl-2-phenyl-pyrazolo (1,5-a)pyrimidine-7-yl)-propylidene)bisphosphonates acid tetraethyl ester; (3-(3-chloro-5-methyl-2-phenyl-pyrazolo (1,5-a)pyrimidine-7-yl)-propylidene)bisphosphonates acid tetraethyl ester; (3-(3-bromo-5-methyl-2-phenyl-pyrazolo (1,5-a)pyrimidine-7-yl)-propylidene)bisphosphonates acid tetraethyl ester; (3-(3-cyano-2,5-dimethyl-pyrazolo (1,5-a)pyrimidine-7-yl)-propylidene)bisphosphonates acid tetramethyl ester; (3-(3-cyano-2,5-dimetil-pyrazolo (1,5-a)pyrimidine-7-yl)propylidene)bis(5,5 - dimethyl-2,2-dioxide-1,3,2-dioxaphosphinan) or (3-(6-chloro-3-cyano-2,5-dimethyl-pyrazolo (1,5-a)pyrimidine-7-yl)propylidene) bisphosphonates acid tetraethyl ester.

7. Connection on p. 2, where R11is C1- C3-alkyl.

8. Connection on p. 2, where R13phenyl.

9. Connection on p. 2, where the specified R13phenyl, substituted by halogen, methyl or methoxy.

11. Connection on p. 1, possessing anti-inflammatory activity.

12. Connection on p. 2 having 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 technology for obtaining esters vinylphosphonic acid, which finds wide use as a reactive flame retardants and plasticizers in the production of various polymer materials

The invention relates to the chemistry of phosphorus - organic compounds, and in particular to a new method of obtaining S-triphenylcarbinol esters of dealkylation and tetrathiofulvalene acids of General formula (I)

(RX)SGePh3where R is lower alkyl; X Is 0, S

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 organic chemistry and can be used to obtain phosphonates, which can be used to reduce the Flammability of polymer materials

The invention relates to the chemistry of organophosphorus compounds, namely substituted carbamoylphosphate General formula I,

Pwhere R = CH3Cl, which can find application in agricultural practice as growth regulators for cotton

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

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
Up!