Derivatives of pyrazole, the way they are received, containing pharmaceutical composition and intermediate compounds for the synthesis

 

(57) Abstract:

The invention relates to pyrazole derivative of the General formula I, where g2, g3and g6hydrogen; g4- chlorine atom or bromine, WITH1-C3-alkyl, trifluoromethyl, or phenyl; g5is hydrogen or chlorine atom; w2, w3, w5and w6is hydrogen or chlorine atom; w4is hydrogen, a chlorine atom, a C1-C3-alkyl, C1-C3-alkoxy or nitro; X is a direct bond or the group -(CH2)nN(R3)-, where R3is hydrogen or C1-C3-alkyl; n is 0 or 1; R4is hydrogen or C1-C3-alkyl and, when X is a direct bond, R is a group-NR1R2where R1is hydrogen, C1-C6-alkyl or cyclohexyl, and R2- C1-C6-alkyl, non-aromatic carbocyclic radical WITH3-C15possibly substituted by a hydroxyl group, one or more1-C5-alkilani,1-C5alkoxygroup or halogen; amino group WITH1-C4-alkyl in which the amino may dazamide1-C3-alkyl, cyclohexyl1-C3-alkyl; phenyl, unsubstituted or substituted with halogen, or WITH1-C5-alkilany from pyrrolidinyl, piperidyl, hexahydroazepin, morpholinyl, hinokitiol and oxybutylene, unsubstituted or substituted C1-C3-alkyl or benzyl; 1-adamantaneacetic; C1-C3-alkyl, substituted aromatic heterocycle selected from pyrrolyl, pyridyl or indolyl, unsubstituted or substituted C1-C5-alkyl, or R1and R2form together with the nitrogen atom to which they relate, pyrrolidinyl, piperidyl or morpholinyl; or the group R5that represents phenyl WITH1-C3-alkyl, unsubstituted or substituted C1-C5-alkyl; cyclohexyl1-C3-alkyl, or 2-norbornylene; when X represents a group -(CH2)nN(R3)-, R represents a group R2Athat represents a non-aromatic carbocyclic radical WITH3-C15; phenyl substituted by halogen; phenyl WITH1-C3-alkyl, possibly substituted with halogen; indolyl, possibly substituted C1-C5alkoxygroup; anthracene, or group with other2bin which R2b- cyclohexyl, substituted, phenyl, unsubstituted or substituted by one or two halogen atoms, WITH1-C5-alkyl or C1-C5alkoxygroup or razocaranoj acid with an amine of the formula HNR1R2where R1and R2defined above, or with a primary amine R3NH2where R3has the values defined above obtained intermediate amide restore to obtain the corresponding intermediate aminomethyl derivative, which is subjected to the interaction with the acid chloride of the acid R2ACOCl, where R2Adefined above, or with isocyano R2bN=C=O where R2bdefined above. The target compounds are also produced by interaction of the corresponding derivatives of 3-pyrazolylborate acid derivative diphenylphosphinite with the intermediate amine, which optionally work alkylating agent to obtain the secondary amine and the resulting intermediate amines are subjected to interaction with the acid chloride of the acid R2ACOCl or isocyanate R2bN=C=O where R2Aand R2bdefined above. The target ketone derivatives of pyrazole is obtained by interaction of derivatives of 3-pyrazolylborate acid with the compound of the formula R5MnX1where R5defined above, X1- halogen. The compounds of formula I exhibit an affinity for the receptors cannabinoids. Also proposed pharmaceutical composition having Siroki. The invention also relates to intermediate derived 3-pyrazolylborate acid of formula II where R' is hydrogen or C1-C5-alkyl. 7 C. and 12 C.p. f-crystals, 20 PL.

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The invention concerns new derivatives of pyrazole, method of receiving and containing pharmaceutical compositions.

Many pyrazole derivatives have been described in the literature, in particular in patents EP-A-268554 and DE-A-3910248, which stated pyrazoles with herbicide properties, EP-A-430186 and JP-A-03031840 in which a secure connection, applicable in pictures, and EP-A-418845, which States pyrazoles having anti-inflammatory, analgetic and antithrombin activity.

Currently, it was found that the pyrazoles, which are the subject of the invention have a high affinity receptor for cannabinoids and therefore especially interesting in therapeutic areas where it is known the use of cannabis for therapeutic purposes. Connection9-tetrahydrocannabinol, or9-THC is the main active constituent extracted from Cannabis sativa (Tuner, 1985; Marijuana In 1984, Ed. Harvey, DY, IRL Press, Oxford).

The effect of cannabinoids caused by interaction with specific receptors high with the imental Therapeutics, 1985, 234, 784 - 791; Kaminski et al., 1992, Molecular Pharmacology, 42, 736 - 742).

Characterization of this receptor has become possible with the development of specific synthetic ligands such as CP 55, 940, agonist analogue of 9-THC.

Therapeutic indications cannabinoids affect different areas, such as the immune system, Central nervous system, cardiovascular system or Indochina system (Hollister, Pharmacological Reviews, 1986, 38, 1 - 20 et Renv and Sinha, Progress in Drug Research, 1991, 36, 71 - 114).

In particular, compounds having affinity for the receptors cannabinoids are used as immunomodulators, psychotropic drugs, diseases of the thymus, vomiting, myorelaxation, various neuropathic conditions, mnesticheskih disease, dyskinesia, migraine, asthma, epilepsy, glaucoma, as well as anti-cancer chemotherapy, ischemia and blackness, with a gasp, orthostatic hypotension and heart failure.

More specifically the present invention relates to compounds of the formula I

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where g2-g6and w2-w6- same or different and are independently hydrogen, chlorine atom or bromine, C1-C3-alkyl, C1-C3-alkoxy, trifluoromethyl, nitro-group;
2)nN(R3)-group, where R3is hydrogen or C1-C3-alkyl, and n is zero or one;

R means

-NR1R2group, where R1and R2- independently from each other mean C1-C6-alkyl;

non-aromatic carbocyclic radical C3-C15optionally substituted, amino, C1-C4alkyl group, where the amino group optionally tizamidine C1-C3-alkyl; cycloalkyl C1-C3-alkyl, where cycloalkyl has 3 to 12 carbon atoms; phenyl, unsubstituted or substituted by one or more halogen atoms, C1-C5-alkyl or C1-C5-alkoxygroup; phenyl C1-C3-alkyl; diphenyl C1-C3-alkyl; naphthyl; anthracene, saturated heterocyclic radical of 5 to 8-membered, unsubstituted or substituted C1-C3-alkyl, hydroxyl or benzyl, 1-adamantylamine, aromatic heterocycle, unsubstituted or substituted by one or more halogen atoms, C1-C5-alkyl or C1-C5- alkoxygroup; C1-C3-alkyl, substituted aromatic heterocycle, unsubstituted or substituted by one or more ATO the UB> is as defined above, or R1and R2form together with the nitrogen atom to which they are attached, a saturated 5 - to 8-membered heterocyclic radical, and specified heterocyclic radical is not morpholine, if w2, w3, w4, w5, w6, g2, g3, g4, g5and g6are all hydrogen;

the group R2defined above, if X represents (CH2)nN(R3);

the group R5if X is a direct bond, and R5- C1-C3-alkyl, C3-C12-cycloalkyl, unsubstituted or substituted C1-C5-alkyl, phenyl C1-C3-alkyl, unsubstituted or substituted with halogen or C1-C5-alkyl, cycloalkyl C1-C3-alkyl, where cycloalkyl has 3-12 carbon atoms, unsubstituted or substituted C1-C5-alkyl; 2-norbornylene; or one of their possible salts.

Non-aromatic carbocyclic radicals C3-C15include mono - or polycyclic radicals, condensed or bridged saturated or unsaturated, optionally terpene. These radicals optionally mono - or polyamidine, and the specified(s) Deputy(and) are not semiendogenous from C1-C5- alkyl, C1-C5alkoxyalkyl, halogen or hydroxyradicals, of course, if terpenes or terpene radicals, for example bornyl, methyl or mantener, alkyl groups of terpenes are not considered as substitutes.

Monocyclic radicals include cycloalkyl, such as cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclododecyl, unsubstituted or substituted with at least one C1-C5is an alkyl group, a C1-C5- alkoxygroup, halogen or hydroxy-group.

Condensed bridge or smirnowii di - or tricyclic radicals include, for example, radicals norbornyl, bornyl, isobornyl, nordlandia, adamantyl, Spiro (5,5) undecane, and these radicals are unsubstituted or substituted C1-C5-alkyl.

Under saturated heterocyclic radical of 5 to 8-membered mean heterocyclic non-aromatic mono-, di - or tricyclic condensed or bridging radical, and the heteroatom is S, O or N, or heterocyclic non-aromatic monocyclic radical containing a nitrogen atom or an oxygen atom or sulfur, and these radicals, for example tetrap, hinokitiol, preferably radicals of 1-pyrrolidinyl, 1-piperidinyl, 1-hexahydroazepin, 4-morpholinyl and 4-thiomorpholine.

Aromatic heterocycles may be mono - or dicklicking, such as pirolli, pyridyl, indolyl, chinoline, thiazolyl, isoindolyl, and these aromatic heterocycle unsubstituted or substituted, e.g. by halogen, C1-C5-alkilani, C1-C5alkoxyalkane. Preferred aromatic heterocycles - pyridyl, pyrrole, indole, 2-indolinyl and 3-indolizinyl radicals.

In the above formula I, preferably at least one of the substituents w2, w3, w4, w5, w6, g2, g3, g4, g5and g6is not hydrogen.

In the above formula I, where R is NR1R2group, preferably:

- R1is hydrogen or an alkyl group of C1-C6and R2is as defined above for (I); or

- R1and R2are each an alkyl group of C1-C6or cycloalkyl group C3-C6; or

- R1is hydrogen or an alkyl group of C1-C6and R2- cycloalkyl C1-C3alkiline the> unsubstituted or substituted as above, phenyl, unsubstituted or substituted by one or more halogen, C1-C3-alkyl or C1-C3alkoxygroup, phenyl C1-C3-alkyl or C1-C3-alkyl, substituted 2 - or 3-indolium.

Particularly preferably, when in the formula I R is NR1R2group, R1is hydrogen or alkyl (C1-C6and R2- non-aromatic carbocyclic radical C3-C15cycloalkyl C1-C3-alkyl, where cycloalkyl C3-C6, 2 - or 3-indolyl C1-C3-alkyl.

Preferred alkyl groups are methyl, ethyl, sawn and isopropyl group.

In formula I above, R is preferably NR1R2group, preferably selected from the following radicals (1) to (74).

If R1and R2with the nitrogen atom to which they are attached, are a saturated heterocyclic radical, it is preferably 5-, 6 - or 7-membered and may contain another heteroatom, in particular oxygen or sulfur, such as pyrrolidine, piperidine, hexahydroazepin, morpholine or thiomorpholine, with refined above Alami, chosen from:

(1) propylamino

(2) butylamino

(3) isopropylamino

(4) diphenhydamine

(5) 2-(N,N'-diethylamino)ethylamino

(6) benzylamino

(7) 2-phenylethylamine

(8) 3-phenylpropylamine

(9) 3,3-diphenylpropylamine

(10) phenylamino

(11) 3-chlorpheniramine

(12) 4-methylphenylamine

(13) cyclopropylamino

(14) cyclopentylamine

(15) cyclohexylamino

(16) cycloheptylamine

(17) cyclooctylamino

(18) cyclododecanone

(19) 2-methylcyclohexylamine

(20) 3-methylcyclohexylamine

(21) CIS-4-methylcyclohexylamine

(22) TRANS 4-methylcyclohexylamine

(23) CIS-4-tertiarylevel

(24) TRANS 4-tertiarylevel

(25) 4 hydroxycyclohexanone

(26) 2-methoxycyclohexanone

(27) 4 ethylcyclohexylamine

(28) 2,6-dimethylcyclohexylamine

(29) N-methylcyclohexylamine

(30) N,N-dicyclohexylamine

(31) endo-2-norbornanamine (or endo-bicyclo[2.2.1]heptane-2-amino)

(32) Exo-2-norbornanamine (or Exo-bicyclo[2.2.1]heptane-2-amino)

(33) 1 adamantylamine

(34) 2-adamantylamine

(35) 1 nordmanniana

(36) (IR)-Borsellino

(37) (IR)-isobutylamino

(38) Spiro[5.5]undecane is but

(42) 2-(N-methyl-2-pyrrolyl)ethylamino

(43) 2-(2-pyridinyl)ethylamine

(44) (2-indolyl)methylamine

(45) N-methyl(2-indolyl)methylamine

(46) 2-(3-indolyl)ethylamine

(47) N-methyl 2-(3-indolyl) ethylamine

(48) 4-(N-benzylpiperidine)amino

(49) 3-quinuclidinone

(50) Exo bicyclo[3.2.1]octane-2-amino

(51) bicyclo[2.2.2]Octan-2-amino

(52) chloro-3-bicyclo[3.2.1]Oct-3-EN-2-amino

(53) bicyclo[2.2.2]Oct-2-EN-5-amino

(54) Exo bicyclo[3.2.1]octane-3-amino

(55) endo bicyclo[3.2.1]octane-3-amino

(56) endo oxa-7-bicyclo[2.2.1]heptane-2-amino

(57) Exo oxa-7-bicyclo[2.2.1]heptane-2-amino

(58) endo-tricyclo[5.2.1.02,6] decane-8-Mino

(59) N-ethyl-1-adamantylamine

(60) tricyclo[2.2.1.02,6]heptane-3-amino

(61) bicyclo[3.3.1]nonan-9-amino

(62) endo-trimethyl-1,3 .3m-bicyclo[2.2.1]heptane-2-amino (or pencillamine)

(63) (1R, 2S - endo) (+) bicyclo[2.2.1] heptane-2-amino

(64) (1R, 2R - Exo) (-) bicyclo[2.2.1] heptane-2-amino

(65) (1S, 2S - endo) (-) bicyclo[2.2.1] heptane-2-amino

(66) (1S, 2S - Exo) (+) bicyclo[2.2.1] heptane-2-amino

(67) 1 piperidylamine

(68) 1 pyrrolidinium

(69) 1 hexahydropyrazino

(70) 4-morpholinium

(71) 4 thiomorpholine

(72) N-methyl Exo bicyclo[2.2.1] heptane-2-amino
in the above formula I preferred those which correspond to the formula Ia

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where w2-w6, g2-g6, R4; R1and R2defined above for formula I.

Among the compounds of formula Ia most preferred are those compounds which correspond to the General formula Ia'

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where w2-w6, g2-g6, R4have the meanings specified for compounds of formula I;

R1is hydrogen or C1-C6-alkyl;

R2- non-aromatic carbocyclic radical C3-C15or a saturated heterocyclic radical of 5 to 8-membered ring selected from 1-pyrrolidinyl, 1-piperidinyl, 1-hexahydroazepin, 4-morpholinyl and 4-thiomorpholine and their salts.

Among the products of formula I which correspond to the following formulas Ia, Ib, Ic, Id, Ie and If, where at least one of the substituents w2-w6, g2-g6is not hydrogen, R1is hydrogen or alkyl (C1-C6, R2is as defined above, R3is hydrogen or an alkyl group of C1-C3, R4is hydrogen or methyl, and R5- cycloalkyl C1-C3-alkyl, and cycloalkyl C3-C6or phenyl C1-C3-alkyl, unsubstituted or substituted in the aromatic cycle of methyl proposednew especially preferred products,

- if R1is alkyl (C1-C6preferred methyl, ethyl, sawn and isopropyl group;

- if R3is alkyl (C1-C3preferred methyl group;

group R2are preferably non-aromatic carbocyclic radicals C3-C15, unsubstituted or substituted alkyl (C1-C4in particular stands, ethyl, propylene, isopropyl or t-bootrom, or two, or three methyl groups, for example methyl-, ethyl-, or t-butylcyclohexyl radical, or dimethyl - or trimethylcyclohexyl radical; cycloalkyl C1-C3alkylamino radicals, where cycloalkyl - C3-C6, alkyl radicals C1-C3substituted 2 - or 3-indolines group; 2 - and 3-indolenine radicals and radicals of 1-pyrrolidinyl, 1-piperidinyl, 1-hexahydroazepin, 4-morpholinyl, 4-thiomorpholine;

group R5are preferably radicals of cyclohexylmethyl, cyclohexylethyl, benzyl, 4-methylbenzyl and Venetia.

Of the products of the above formula I, the preferred products are represented by formula i

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where R4X and R are as defined above for fo the Tyl, and X is a direct link.

Especially preferred compounds of formula i, where R4is hydrogen or methyl, X is a direct bond, and R - NR1R2group, where R1is hydrogen or a methyl group, and R2- non-aromatic carbocyclic radical C3-C15or a saturated heterocyclic radical 5-8-membered ring selected from 1-pyrrolidinyl, 1-piperidinyl, 1-hexahydroazepin, 4-morpholinyl and 4-thiomorpholine and their salts.

Also preferred compounds of formula i, where R4is hydrogen or methyl, X is -(CH2)n-N(R3)-, and R - NR1R2while n is zero or one, R1is hydrogen, R3is hydrogen or a methyl group, and R2is phenyl, unsubstituted or substituted by one or two halogen atoms, C1-C5alkyl or C1-C5alkoxygroup or non-aromatic carbocyclic radical in C3-C15and their salts.

Of the compounds of formula I are also preferred compounds corresponding to the formula ii

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where X and R are as defined above for formula I, and w4is methyl or methoxy group, and their salts, in particular those compounds of formula ii, where w4is methyl or methoxy group, X is a direct bond, and R is NRs radical C3-C15and their salts.

A preferred subclass includes compounds of formula ii, where w4is methyl or methoxy group, X is -(CH2)n-N(R3)-group, where n is zero or one, R3is hydrogen or a methyl group, and R is-NR1R2group, where R1is hydrogen, and R2is phenyl, unsubstituted or substituted by one or two halogen atoms, C1-C5alkyl or C1-C5alkoxygroup or non-aromatic carbocyclic radical C3-C15or their salts.

Other interesting compounds of the present invention are the compounds of formula I, where w2-w6, g2-g6, R4and X is as defined above for formula I, and R is-NR1R2group, where R1is hydrogen or C1-C6alkyl group, and R2- 2 - or 3-indolyl C1-C3alkyl group, or 2 - or 3-indlela group, and their salts.

From the latest products especially interesting products of the formula iii

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where X is as defined above for formula I, and R is NR1R2group, where R1is hydrogen or C1-C6-alkyl, and R2- 2 - or 3-indolyl C1-C3the alkyl groups of the UB> and w4the chlorine atom, and their salts.

Of the products included in the above formula I, also interesting products of the formula iv

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where X and R are as defined above for formula I, and g4a bromine atom, methyl or trifluoromethyl, and their salts.

In the preferred products of formula iv two atoms of chlorine are in positions 2,3; 2,4; 2,5 or 3,4; and in these preferred products of formula iv preferred those products where X is a direct bond, and R is-NR1R2group, where R1is hydrogen or alkyl C1-C6and R2- non-aromatic carbocyclic radical containing 3-15 carbon atoms.

Possible salts of the compounds of the present invention, in particular compounds of the above formulas I, Ia', i, ii, iii, iv and below Ia, Ib, Ic, Id, Ie, If, include compounds with inorganic or organic acids, which allow the division or the appropriate crystallization products, such as picric or oxalic acid, and those which form pharmaceutically acceptable salts such as hydrochloride, bromohydrin, sulfate, gidrogensulfat, dehydrogenation, methanesulfonate, methyl sulfate, maleate, fumarate, 2-naphthalenesulfonate method of obtaining compounds of formula I, characterized in that the derived 3-pyrazolylborate acid formula

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where w2-w6, g2-g6, R4is as defined above for formula I, or one of its active forms, esters or anhydrides of the acids, process:

or an amine of the formula HNR1R2where R1and R2is as defined above for formula I, to obtain amides of the formula

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where w2-w6, g2-g6, R4, R1and R2is as defined above for formula I,

or optionally a primary amine R3NH2where R3is as defined above for formula I, to obtain the intermediate amides of the formula V

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where w2-w6, g2-g6, R4and R3is as defined above for formula I, to obtain by restoring using metal hydride intermediate amines of formula VI

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where w2-w6, g2-g6, R4and R3is as defined above for formula I, which are transferred to the amide or urea of the formula

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where w2-w6, g2-g6, R5, R3and R4is as defined above for formula I, by reaction respectively with the acid chloride of the acid of formula R2-azide-diphenylphosphoryl the primary environment with subsequent acid treatment to obtain the intermediate amine of the formula

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where w2-w6, g2-g6, R4is as defined for formula I, which is subjected to a carboxylic acid R2COCl or isocyanate R2-N=C=O to obtain, respectively, amides or urea of the formula

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where w2-w6, g2-g6, R4is as defined for formula I, and R3is hydrogen, and the same compounds, where R3is not hydrogen, are prepared on the basis described above primary amine of formula VII is converted into a secondary amine of the formula

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where w2-w6, g2-g6, R4is as defined for formula I, and R3means C1-C5-alkyl, which is then exposed to the carboxylic acid R2COCl or isocyanate R2-N=C=O to obtain amides and urea of formula Id and Ie, as defined above, where R3is not hydrogen,

or ORGANOMETALLIC reagent containing divalent manganese, R5MnX1where R5is as defined for formula I and X is halogen, to obtain a ketone derivative of the formula

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thus obtained compound is then optionally converted into one of its salts.

On preobrazovaniya functions of ester to amide, urea or ketone, through acid and hydrochloride acid.

These esters synthesized by the method described in Berichte, 1887, 20, 2185.

Scheme 1 reactions produce compounds of formulas I through their difficult methyl or ethyl esters (Alk=CH3or C2H5) is presented below.

Circuit 1

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The first stage (a) comprises obtaining a salt of an alkali metal derivative of acetophenone of the formula IV, where R4, g2-g6is as defined above for formula I, in which then add equimolar amount of diethyloxalate (step b) to obtain the complex keeeper formula III.

In the case when R4= H, alkali metal, and preferably is sodium and salt complex keeeper formula III (Alk=CH3) get the method described in Bull. Soc. Chim. Fr., 1947, 14, 1098, using sodium methylate in methanol for phase a).

In the case when R4= CH3, the alkali metal is preferably lithium, a salt complex keeeper formula III (Alk=C2H5) get the procedure described in J. Heterocyclic. Chem. 1989, 26, 1389, using lithium salt hexamethyldisilazane in ethyl ether for phase a).

The obtained t is red acid (step c). By precipitation in ice water get esters of 3-pyrazole of the formula IIa.

These esters (IIa) is then converted into their acid of formula IIb exposure to alkaline agent, for example potassium hydroxide, followed by acidification (step d).

In the above scheme 1 esters of formula IIa, where w2and w4a chlorine atom, w3, w5and w6is hydrogen, g4a chlorine atom, g2, g3, g5and g6is hydrogen and Alk is C1-C5-alkyl, and the corresponding acid of formula IIb are new "key" intermediate materials for the production of compounds of formula i and particularly preferred and, thus, represent another aspect of the invention, these compounds correspond to the formula II a or II b

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If X is represented direct link, amides of the invention of formula Ia

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where w2-w6, g2-g6, R1, R2and R4- defined for formula I, is obtained from the functional derivative of the acid of formula IIb, preferably chloride according to standard methods with a view to their replacement with the amine of the formula HNR1R2obtained by conventional methods, to obtain the compounds of formula Ia in accordance with the invention.

Esle formula Ib and Ic

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where w2-w6, g2-g6, R2, R3and R4defined for formula I, is obtained from the complex ester (IIa) described above, according to the following scheme 2:

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The transition from a complex ester (IIa) to the intermediate amide (V) can be carried out, for example, via the acid chloride of the corresponding acid by reaction with the amine R3NH2in alkanol, for example in ethanol.

The restoration of the amide (V) in the amine (VI) is then through a metal hydride such as lithium hydride and aluminum or preferably a complex of the BIS-THF in solution in THF, heated to a temperature phlegmy. The amine (VI) is then converted into an amide (Ib) or urea (Ic) in accordance with the invention, conventional methods, for example, respectively by reaction with the acid chloride of the acid R2COCl or isocyanate R2-N=C=O.

Amides and urea of the invention of formula Id and Ie

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where w2-w6, g2-g6, R2, R3and R4is as defined for formula I, is obtained from 3-pyrazolidinone acids, previously obtained according to the following scheme 3:

Scheme 3

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Acid (IIb) are transformed into the corresponding amines (VII) by reaction Curtius, using th acid or triperoxonane acid, as described in Synthesis, 1990, 295. Amines (VII) are transformed into amides (Id) or urea (Ie) in accordance with the invention by conventional methods, for example by reaction with an acid chloride of the acid R2COCl in the case (Id) if R3= H or isocyanate R2-N=C=O if (Ie) if R3= H.

Alternative urea (Ie) when R3= H can be obtained by the reverse reaction: acid (IIb) are transformed into the corresponding isocyanates (VIIc), as described in J. Org. Chem. 1961, 26, 3511, according to the following scheme 4.

The reaction of isocyanates (VIIc) with the amine R2NH2gives directly the urea of formula Ie

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To obtain the compounds of formula Id and Ie, where R3is not hydrogen, primary amides (VII) pre-transform into secondary amines (VIIb) serial number of reactions, for example by reaction with an acid chloride of the acid R'3COCl (R'3= C1-C2-alkyl), followed by reduction of amide (VIIa), obtained, for example, by reaction with BIS in THF. If R3is stands, it is preferable to apply the reaction of the amines (VII) tertbutyl dicarbonate, (BOC)2O or with a mixture of formic acid and acetic anhydride, which gives respectively carbamate (VIIa, Z=OtBu) or forms the Ib, R3= CH3).

Secondary amines (VIIb) are then transformed into amides (Id) or urea (Ie) in accordance with the invention, as described above.

Ketone derivatives of the invention according to the formula If

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(If, X is a direct bond, and R = R5)

where w2-w6, g2-g6, R4and R5is as defined for formula I, preferably receive from 3-pyrazolylborate acids (IIb) described above, according to the following scheme 5:

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Acid (IIb) are transformed into the acid chloride acids classical methods; the latter is then transformed into ketone derivative (If) according to the invention by reaction with an appropriate organic reagent containing divalent magnesium, R5MnX1where R5is as defined for formula I and X1is a halogen, preferably a chlorine atom, for example by the method described in Tetrahedron Letters, 1989, 30, 7369.

Alternative ketone derivative (If) can be obtained from acids (IIb) via NITRILES (IIc) according to the following scheme 6:

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Conversion (IIb) (IIc) is a classical method, for example by conversion to the acid chloride acid, followed by aminating (NH3- THF-water) and dehydration recip is received so NITRILES (IIc) are then processed metalloorganicheskie reagents preferably magnetogenesis compounds of the formula R5MgX1to obtain after acid treatment of the ketone derivative (If).

Thus obtained compounds of formula I is isolated in free base form or optionally in the form of a salt according to classic technologies.

If the compound of formula I obtained in free base form, the salt formation is carried out by processing the selected acid in an organic solvent. Treatment of the free base, dissolved, for example, in alcohol, such as isopropanol, with a solution of the chosen acid in the same solvent to obtain the corresponding salt, which is isolated according to the classical technology. Thus have, for example, hydrochloride, bromohydrin, sulfate, gidrogensulfat, dihydrogen phosphate, methanesulfonate, oxalate, maleate, fumarate, 2-naphthalenesulfonate.

At the end of the reaction the compounds of formula I may optionally be isolated in the form of one of their salts, such as hydrochloride or oxalate, in this case, if necessary, the free base can be obtained by neutralizing the named salts of inorganic or organic base, such as hydroxide nutri potassium.

Amines of the formula HNR1R2either commercially available or described in the literature, either obtained by known methods according to the Chapter "Preparation", described below.

Among the preferred amines can be called to the following:

1) bicyclo[3.2.1] octane-2-ylamine, obtained by H. Maskill et al., J. Chem. Soc. Perkin II, 1984, 119;

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2) bicyclo[2.2.2] Octan-2-ylamine, obtained by R. Seka et al., Ber. 1942, 1379;

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3) endo - and Exo-bicyclo[3.2.1]Octan-3-ylamine obtained by H. Maskill et al., J. Chem. Soc. Perkin II, 1984, 1369;

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4) endo - and Exo-oxa-7-bicyclo[2.2.1]heptane-2-ylamine, obtained by W. L. Nelson et al., J. Heterocyclic Chem., 1972, 9, 561;

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5) endo-tricyclo[5.2.1.02,6] Decan-8-amine, obtained by G. Buchbauer et al., Arch. Pharm., 1990, 323, 367;

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6) endo-trimethyl-1,3 .3m-bicyclo[2.2.1] heptane-2-ylamine, obtained by Ingersoll et al., J. Am. Chem. Soc., 1951, 73, 3360;

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7) 3 - methylcyclohexylamine obtained by Smith et al., J. Org. Chem., 1952, 17, 294;

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8) 2,6-dimethylcyclohexylamine obtained by Cornubert et al., Bull. Soc. Chim. Fr., 1945, 12, 367;

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9) 2-methoxycyclohexyl obtained by Noyce et al., J. Am. Soc., 1954, 76, 768;

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10) 4-ethylcyclohexylamine obtained by A. Shirahata et al., Biochem. Pharmacol., 1991, 83, 205;

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11) bicyclo[2.2.2]Oct-2-EN-5-amine, obtained by H. L. Goering et al., J. Am. Chem. Soc., 1961, 83,.1.02,6] heptane-3-ylamine obtained by G. Miller et al. , Chem. Ber., 1965, 98, 1097;

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14) N-methyl-Exo-bicyclo[2.2.1] heptane-2-ylamine, obtained by W. G. Kobalka et al., Synth. Commun., 1991, 20, 231;

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Amines R3NH2commercially available or they are obtained by known methods.

The anhydrides of the acids R2COCl commercially available or are obtained from the corresponding acids by known methods.

Isocyanates R2-N= C= O is also commercially available or are obtained from the corresponding amines (reaction, phosgene) or the corresponding acids (Curtius rearrangement) by known methods.

Compounds of the invention were the subject of biochemical studies.

The compounds of formula I and their salts showed good affinity in vivo to receptors cannabinoids in experiments carried out in the experimental conditions described by Devane et al., Molecular Pharmacology, 1988, 34, 605-613.

Compounds of the invention have affinity for receptors cannabinoids in preparations of isolated organs, electrically stimulated. These experiments were carried out on the ileum of the Guinea pig and samavedam duct mouse Roselt et al. Acta Physiological, Scandinavia, 1975, 94, 142-144 and Nicolau et al., Arch. Int. Pharmacodyn., 1978, 236, 131-136.

Thus, according to another of its aspects the present invention relates to pharmaceutical compositions comprising as an active start compound of formula I or one of its pharmaceutically acceptable salts.

The compounds of formula I, described above, and their pharmaceutically acceptable salts can be used in daily doses of 0.01 to 100 mg per 1 kg body weight of a mammal, preferably in daily doses of from 0.1 to 50 mg/kg human dose may range preferably from 0.5 to 4000 mg per day, in particular from 2.5 to 1000 mg, depending on the patient's age or type of treatment: prophylactic or curative.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal introduction of active principle administered in unit forms, mixed with classical pharmaceutical carriers, to animals and people. The corresponding unitary form of introduction are issued in the form for oral administration such as tablets, gelatin shell, powders, granules, solutions or suspensions for Arutiunov, intranasal or intraocular administration and in the form for rectal administration.

In the pharmaceutical compositions of the present invention the active principle, as a rule, are assigned in units of dosage from 0.5 to 1000 mg, preferably 1-2000 mg called the beginning of the current per unit dosage.

In the manufacture of solid compositions in the form of tablets, the main active principle is mixed with a pharmaceutical carrier, such as gelatin, starch, lactose, magnesium stearate, talc, gum Arabic and similar. Tablets can be coated by a shell of sucrose or other relevant substances, or to process them so that they have a prolonged or delayed activity and that they continuously release a certain amount of current beginning.

The drug is in the form of gelatin capsules get by mixing the active principle with a diluent and pouring the mixture obtained into soft or hard gelatin shell.

The drug is in the form of a syrup or elixir may contain the active principle together with a substance for sweetening, preferably low-calorie, methyl paraben and propyl paraben as an antiseptic, as well as generate active principle in a mixture with dispersing agents or wetting, or agents of education suspension, as polyvinylpyrrolidone, as well as substances for sweetening or correction of taste.

For rectal administration, use candles, which are made with a binder, swelling in the rectal temperature, for example cocoa butter or polyethylene glycols.

For parenteral, intranasal or intraocular destination using aqueous suspensions, isotonic saline solutions or sterile solutions for injection, which contain pharmacologically compatible dispersing agents and/or wetting, for example propylene glycol or butyleneglycol.

For inhalation use aerosol containing, for example, triolein sorbitan or oleic acid, as well as Trichlorofluoromethane, dichlorotetrafluoroethane or any other biologically compatible with the working gas.

The active principle may also be administered in the form of microcapsules, optionally with one or more carriers or additives.

The active principle can also be represented in the form of a complex with a cyclodextrin or cyclodextrin, 2-hydroxypropyl--cyclodextrin or methyl--cyclodextrin.

These takhini, asthma, epilepsy, glaucoma, Parkinson's disease, dyskinesia, neuropathic States, mnesticheskih diseases and diseases of the thymus, vomiting, ischemia, asthma, ortostaticheskoi hypertension or heart failure.

The following examples illustrate the invention without limiting it.

The melting point or decomposition products (T. pl.) were measured in capillary tubes using a Tottoli apparatus.

The enantiomeric excess of the optically active amines (E. I.) was determined by nuclear magnetic resonance 19F after the reaction with the acid chloride of the acid Mosher S(+) J.Org. Chem., 1969, 34, 2543.

The rotational ability, []2D0was measured in the reference system at c = 1.

Preparation.

A. other Amines1R2.

1. (1R, 2S - endo) (+) bicyclo [2.2.1] heptane-2-ylamine.

(1R, 2S - endo) (-) bicyclo [2.2.1] heptane-2-carboxylic acid is obtained in Tetrahedron Letters, 1985, 26, 3095.

The Curtius reaction carried out according to J. Org.Chem, 1961, 26, 3511, she then transformed into the corresponding amine (1R, 2S - endo) (+).

[]2D0= +13,40 (c = 1, EtOH).

E. I. > 95% (CF3) = 6,67 ppm relative to CF3CO2H.

2. (1R,2R - Exo) (-) bicyclo [2.2.1] heptane-realresult its isomer (1R, 2R - Exo) (-) J. Am.Chem.Soc., 1983, 105, 950, then transform, as described in the previous example, the corresponding amine (1R, 2R - Exo) (-).

[]2D0= 17,70 (c=1, EtOH).

E. I. > 94% (determined as described above, (CF3) for 6.81 ppm).

3. (1S, 2R - endo) (-) bicyclo [2.2.1] heptane-2-ylamine.

(1S, 2R - endo) (+) bicyclo [2.2.1] heptane-2-carboxylic acid is obtained in Tetrahedron Letters 1989, 30, 5595, then transform, as described above, in the appropriate amine (1S, 2R - endo) (-).

E. I. > 95% (determined as described above (CF3) = 6,62 ppm).

4. (1S, 2S - Exo) (+) bicyclo [2.2.1] heptane-2-ylamine.

(1S, 2R - endo) (+) acid, obtained in the previous example, is converted into its isomer (1S, 2S - Exo) (+) J. Am. Chem. Soc., 1983, 105, 950, then the isomer is converted into the corresponding amine (1S, 2S - Exo) ( + ) as described above.

E. I. > 94% (determined as described above (CF3) = 6,91 ppm).

5. Exo-3-chlorobicyclo[3.2.1]Oct - 3-enyl-2-amine.

To a solution of 6.1 g of Exo-3-chloro-2-Asadullo[3.2.1]Oct-3-EN obtained from J. Chem. Soc.Perkin. Trans II, 1984, 119, 600 ml of ethanol and 60 ml of CHCl3add 0.4 g PtO2and hydrogenizing in a Parr apparatus at 4 bar and at room temperature until disappearance of the azide function. After filtering celite reactio the constituent Amin. So pl. > 240oC.

6. N-ethyl-Exo-bicyclo[2.2.1]heptane-2-ylamine.

6.1. N-acetyl-Exo-bicyclo[2.2.1]heptane-2-ylamine.

A solution of 3.50 ml acetylchloride in 10 ml of CH2Cl2add Pocatello to a solution of 5.00 g of Exo-bicyclo[2.2.1]heptane-2-ylamine and 6,90 ml of triethylamine in 50 ml of CH2Cl2cooled to 0oC. After 16 hours stirring at room temperature the mixture was poured into 100 ml ice water and the organic phase is separated and washed with 5% HCl solution, then with water, then saturated NaCl. When dried on MgSO4and evaporation of the solvents get 5,80 g of the expected ndimethylacetamide. So pl. = 128oC.

6.2. N-ethyl-Exo-bicyclo[2.2.1]heptane-2-ylamine.

A solution of 5.10 g of the previous derivative in 30 ml of THF, add Pocatello in suspension of 2.18 g of LiAlH4in 30 ml of THF cooled to 0oC, then the mixture is heated to a temperature of phlegmy within 8 hours. The mixture was hydrolized at 0oC 2.2 ml of water, then 2.2 ml of 15% NaOH solution, then 7.5 ml of water. After 15 minutes of stirring the precipitate is filtered and washed in THF, the filtrate is evaporated, and then injected into 50 ml of ethyl ether. This ethereal solution is extracted with 5% HCl, the resulting aqueous phase is neutralized 30% Na the-air traffic management get 3,82 g of pale yellow liquid. By dissolving in ethyl ether and treated with a solution of HCl in the gas phase in anhydrous ethyl ether to obtain a white precipitate, which is filtered, washed with ethyl ether and dried in vacuum. Thus, the gain of 4.16 g of the hydrochloride of the expected amine. So pl. = 145oC (decomposition).

7. N-(H-propyl)-Exo-bicyclo[2.2.1]heptane-2-ylamine.

7.1. N-propionyl Exo-bicyclo[2.2.1]heptane-2-ylamine.

This amide get in the same way as the analogue of N-acetyl described in the previous example 6, using propionate instead of acetylchloride.

7.2. N-(n-propyl)-Exo-bicyclo[2.2.1]heptane-2-ylamine

This amine receive on the basis of the amide obtained above in the same way as the N-ethyl analogue, described in the previous example. Form a salt with HCl/Et2O in a mixture of Et2O/iPr2O and obtain the hydrochloride of the desired amine. So pl. = 230oC (decomposition).

8. Bicyclo[3.3.1]nonan-9-ylamine.

8.1. Bicyclo[3.3.1]nonan-9-ONEXIM.

A solution of 1.83 g of hydroxylamine hydrochloride and 2.95 g of sodium acetate in 22 ml of water are added to a solution 2,43 g of bicyclo[3.3.1]nonan-9-she's in 9 ml of methanol, the mixture is heated to a temperature of phlegmy within 24 hours. After cooling, the mixture is extracted with ethyl is an ode, dried on MgSO4and evaporated. Obtain 3.00 g of the oxime. So pl. = 151oC.

8.2. Bicyclo[3.3.1]nonan-9-ylamine.

To a solution of 1.00 g of the oxime in 250 ml of ethanol and 4 ml of CHCl3add 0.20 g PtO2and hydrogenizing in a Parr apparatus at 6 bar and room temperature for 18 hours. After filtering celite the solvents are evaporated and the residue is crystallized in a mixture of ethanol/heptane. Obtain 0.55 g of the hydrochloride of the desired amine. So pl. > 240oC.

Example 1. N-(2-substituted)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole - 3-carboxamide.

(I) : w2, w4= Cl, R4= H; g4= Cl;

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A) Sodium salt of 4-Chlorobenzilate bromide.

12 g of sodium are dissolved in 250 ml of anhydrous methanol. Then add the mixture to 64.6 ml 4-chloroacetophenone and 67,1 ml diethyloxalate in 600 ml of methanol, keeping the temperature below 10oC. the Reaction mixture was then stirred at room temperature for 3 hours, then add 1 liter of dry ether. Again stirred for 20 minutes, filter, wash the precipitate with ether and dried in vacuum to obtain 74,6 g of the desired sodium salt.

B) Methyl ester of 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid.

C) 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid.

The solution 3,70 g KOH in 35 ml of water are added to a solution of 10.0 g obtained in step B ester in 35 ml of methanol.

The mixture is heated to a temperature of phlegmy for 4 hours, cooled to room temperature and poured into 100 ml of water, then neutralized with 5% HCl solution. The resulting crystals are filtered, washed with water and then with pentane and dried in vacuum. Get to 9.50 g of acid. So pl. = 185oC.

D) the acid chloride of 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid.

5.8 ml of thionyl chloride are added to a suspension of 9.50 g obtained at the previous stage of the acid in 100 ml of toluene, the mixture is heated to a temperature of phlegmy for 3 hours. The solution is then evaporated, then the residue is extracted with 50 ml of toluene, and the solution again evaporated (the process is repeated twice).

Get of 8.28 g of the carboxylic acid.

E) N-(2-substituted)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H - pyrazole-3-carboxamide

A solution of 0.50 g obtained in step D loranger is ritilin in 10 ml of CH2Cl2cooled to 0oC. the Mixture was then stirred at room temperature for 16 hours, then poured into ice water. The mixture is extracted with CH2Cl2and the organic phase is washed successively with 5% HCl solution, water, 5% solution of Na2CO3then a saturated solution of NaCl. When dried on MgSO4and evaporation of the solvent the crude product is crystallized in benzene at high temperatures to obtain 0.32 g of white crystals. So pl. = 203oC.

Example 2. N-(TRANS-4-hydroxycyclohexyl)-1-(2,4-dichlorophenyl)-5-(4 - chlorophenyl)-1H-pyrazole-3-carboxamide.

(I): w2, w4= Cl; g4= Cl, R4= H;

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A) TRANS-4-trimethylcyclohexylamine.

A solution of 1.85 ml of chlorotrimethylsilane in 10 ml of CH2Cl2add Pocatello, and a solution of 2.0 g of the hydrochloride of TRANS-4-hydroxycyclohexanone and of 4.05 ml of triethylamine in 20 ml of CH2Cl2cooled to 0oC. After 16 hours stirring at room temperature the mixture was hydrolized with water and extracted. The organic phase is washed successively with water, 5% solution of Na2CO3and saturated NaCl. When dried on MgSO4and evaporating retval)-5-(4-chlorophenyl)- 1H-pyrazole-3-carboxamide.

A solution of 0.60 g prepared according to example 1D carboxylic acid in 10 ml of CH2Cl2add Pocatello in a solution of 0.35 g of TRANS-4-trimethylcyclohexylamine and 0.32 ml of triethylamine in 10 ml of CH2Cl2cooled to 0oC. After 16 hours stirring at room temperature the mixture was poured into 30 ml ice water and extracted with CH2Cl2. The organic phase is washed successively with 5% HCl and saturated NaCl solution, then dried on MgSO4and evaporated. The crude product is dissolved in 15 ml of THF are added to a solution of 15 ml of 5% HCl and stirred for 1 hour. The mixture is extracted with ether and washed with water, then dried on MgSO4and evaporated to obtain after crystallization in CH3OH 0.20 g of the expected pyrazole. So pl. = 209oC.

Acting in accordance with example 1 described above, for example, derivatives of the acids or esters are described below in table. A receive connection, described in table. I-XII, below.

Example 153. N-(2-substituted)-1-(2,4-dichlorophenyl)-4-methyl-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide.

(I): g4= Cl; w2, w4= Cl; R4= CH3;

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A) A Lithium salt of 2,4-dioxo-(4-chlorphenyl cooled to - 78oC and enter Pocatello solution 10,12 g - 4-chloropropiophenone in 50 ml of ether. After 30 minutes of stirring at -78oC quickly enter into solution 9,16 ml diethylamine in 50 ml of ether, then increase temperature and stirred for 5 hours at room temperature. The resulting pale yellow precipitate was filtered, washed in ether and dried in vacuum. Get 6,32 g of the desired salt.

B) Complex ethyl ester 1-(2,4-dichlorophenyl)-4-methyl-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid.

Ester receive the same manner as in example 1B), from the lithium salt obtained above, and purified by recrystallization in isopropyl ether. So pl. = 105oC.

C) Connection 153.

Amide obtained from obtained in step B of ether in the same manner as in example 1C, 1D and 1E, by conversion of ester to acid chloride of the acid, the reaction of the latter with 2-adamantanamine and purification by recrystallization in isopropyl ether. So pl. = 190oC.

Acting on the above-described example 153, get amides described in table. XIII, below.

Example 159. N-[1-(para-tolyl)-5-(4-chlorophenyl)-1H-pyrazole-3-ylmethyl]-N-methylcyclo-hexylcaine.

(I): g4= Cl; w4= CH2
Cl2add Pocatello in 100 ml of 33% solution of methylamine in ethanol. After 2 hours stirring at room temperature, concentrated in vacuo, extract the residue with a mixture of 5% Na2CO3+ AcOEt, lighten, the organic phase is washed with saturated NaCl solution, dried on MgSO4evaporate the solvents. The residue is again extracted with isopropyl ether, the resulting crystals are filtered and dried in vacuum. Gain of 0.44 g of the expected amide. So pl. = 138oC.

B) N-methyl-[1-(p-tolyl)-5-(4-chlorophenyl)-1H-pyrazole-3-yl]methylamine.

8,76 g of the amide obtained above, dissolved in 25 ml of anhydrous THF, add Pocatello at a temperature in the range from 0 to 5oC in 75 ml of 1.0 M BIS in THF. After increasing the temperature to room heated the reaction mixture to a temperature of phlegmy for 16 hours, then cooling poured into an ice bath 18 ml of 6N HCl, stirred for 1 hour and 30 min at room temperature, then distilled THF and concentrated in vacuo. The reaction mixture is alkalinized of NaOH pellets to pH 9 - 10; extracted with ethyl acetate, dried on MgSO4evaporate the solvent and purify the resulting crude product puteoC.

C) Connection 159.

To a solution 0,46 g obtained in the previous step amine in 10 ml of CH2Cl2add sequentially to 0.62 ml of triethylamine, then a solution of 0.23 g of the acid chloride cyclohexane acid in 5 ml of CH2Cl2.

After 15 minutes stirring at room temperature the reaction mixture was concentrated in vacuo and the residue extracted with 30 ml of water and extracted with ethyl acetate. The organic phase is washed successively with 5% Na2CO3, water, then saturated NaCl solution, dried on MgSO4then the solvent is evaporated. The crude product is purified by chromatography on silica gel (25 g). Eluant: toluene/AcOEt 70/30 (vol. /about.). The fractions of pure product was concentrated in vacuo, and the residue is recrystallized with isopropyl ether. Get 0,38 g of the amide. So pl. = 124oC.

Acting on the above-described example 159, get amides described below in tables XIV and XV.

Example 172. N-[1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-ylmethyl] -N'- (4-chlorophenyl) urea.

(I): g4= Cl; w2, w4= Cl; R4= H;

< / BR>
A) 1-(2,4-dichlobenil)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide.

This amide is obtained by way OPI is ka in ethanol. So pl. = 178oC.

B) [1,(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-yl]methylamine.

This amine is produced by a method described in example 159B, by restoring the amide obtained above using VN in THF.

C) Connection 172.

0.20 g of 4-chlorophenylalanine add to 0.45 g amine obtained above, dissolved in 10 ml of toluene, and the reaction mixture was stirred at room temperature for 16 hours.

The solvent is evaporated and the residue is extracted with 20 ml ethyl acetate, washed with water, then dried on MgSO4and the solvent is evaporated. The residue is purified by chromatography on silica gel (20 g). Eluant: toluene/AcOEt 60/40 (vol. /about). Concentration of the fractions of pure product gives a residue which is recrystallized in a mixture of isopropanol/isopropyl ether. Obtain 0.18 g of the expected urea. So pl. = 172oC.

Acting on the above-described example 172, receive urea, described below in table. XVI.

Example 181. N-[1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-yl] cyclohexyl-carboxamide.

(I): g4= Cl; w2, w4= Cl; R4= H;

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A) N-(tertbutoxycarbonyl)-[1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H - pyrazole-3-yl] amine.

To Rast is)-3-pyrazolylborate acid, obtained according to example 1C, then to 1.32 ml of triethylamine and the reaction mixture is heated to a temperature of phlegmy nitrogen for 12 hours. After cooling, the reaction mixture was treated with saturated solution of NaHCO3and extracted with ethyl acetate. After washing with water, then saturated NaCl solution, dried on MgSO4and evaporation of the solvents, the crude product is purified by chromatography on silica gel 70-230 mesh. Eluent: CH3OH/CH2Cl 1/99 (V/V). Get 1,09 g of the desired product.

(B) Hydrochloride of 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3 - yl-ammonium.

1,09 g of product obtained above was dissolved in 20 ml of a saturated solution of HCl in EtOH, diluted to 50%, the reaction mixture is heated to a temperature of phlegmy within 2 hours. The solvent is then evaporated and the residue is grated in ethyl acetate in the phlegm, then filtered and dried in vacuum. Obtain 0.55 g of the hydrochloride.

C) Connection 181.

A solution of 0.11 ml of acid chloride cyclohexanecarbonyl acid in 2 ml of CH2Cl2add Pocatello in a solution of 0.20 g obtained above hydrochloride and to 0.19 ml of triethylamine in 5 ml of CH2Cl2. After 24 hours stirring at room temperature the mixture was washed with th is indicates MgSO4then the solvent is evaporated. The crude product crystallizes in iPr2O. Obtain 0.12 g of the desired amide. So PL = 213oC.

Example 182. N-methyl-N-[1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-yl] substituted-1-carboxamide.

(I): w2= w4= Cl; g4= Cl; R4= H;

< / BR>
A) N-[1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-yl]formamide.

In a mixture of 4 ml of formic acid and 0.5 ml of acetic anhydride, cooled in an ice bath, add small portions of 0.50 g of 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-ylamine obtained in the previous example. After 30 min stirring, the solvents evaporated in vacuo, and the residue is extracted with isopropyl ether. The obtained white solid was filtered, washed with isopropyl ether and dried in vacuum. Get 0,49 g of the expected wavelengths. So pl. = 181oC.

B) N-methyl-[1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-yl]amine.

A solution of 1.15 g obtained in the previous example of formamide in 10 ml of anhydrous THF add Pocatello at room temperature to a suspension of 0.24 g L: AlH4in 40 ml of anhydrous THF. The mixture is then heated in the phlegm for 20 minutes, cooled to 0oC and hydrolyzing of 0.24 ml of water,t in THF, and the filtrate is evaporated to dryness. The residue is extracted with isopropyl ether, filtered and dried in vacuum. Get 1,02 g of the expected amide. So pl.=157oC.

C) Connection 182.

Acting as in example 181C, by reaction of the amine obtained above with chloride, adamantane-1-carboxylic acid get the expected amide, which is purified by chromatography on silicon column. Eluant: AcOEt/toluene 7:93. So pl. = 65oC.

Analogously to example 182 receive connections listed in the table. XVII.

Example 187. N-methyl-[1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-yl] -N'-(4-chlorophenyl) urea.

(I): w2= w4= Cl; g4= Cl; R4= H;

< / BR>
To a suspension of 0.40 g of 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-ylamine obtained by neutralization of the hydrochloride obtained in example 181B, in 15 ml of toluene added 225 mg of 4-chlorophenylalanine and heat the mixture to 40oC for 1 hour, followed by reaction at room temperature for 16 hours. The precipitate is filtered, washed with toluene and dried in vacuum. Get 0,46 g expected urea. So pl. = 215oC.

Example 188. N-[1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-yl]-N'- (4-substituted) urea.

(I): w example 1D, in 320 ml of acetone, cooled to 0oC, add a solution of 2.54 g of sodium azide in 10 ml of water. After 1 hour stirring at 0oC, the precipitate filtered and washed with acetone, then dried in vacuum. Get 9,86 g expected utilised.

B) N-[1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-yl] - N'-(1-substituted) urea.

A solution of 1.00 g acylated obtained above in 5 ml of toluene is heated to a temperature phlegmy within 30 minutes. Once set temperature is added to thus obtained solution of the isocyanate 0.39 g of 1-adamantanamine and stirred the mixture for 1 h 30 min the precipitate was filtered, washed with toluene, then with isopropyl ether, and then purified by tretirovanie in a mixture of acetone/methanol. After drying in vacuum, get to 0.48 g of the expected urea. So pl. = 244oC.

Similarly receive connections listed in the table. XVIII.

Example 191. 1-Cyclohexylmethyl-[1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-yl]-ketone.

(I): w2= w4= Cl; g4= Cl; R4= H;

< / BR>
2.5 ml of a solution of 0.625 M MnLi2Cl2in THF (Tetrahedron 1989, 45, 4163) cooled to 0oC and add to it paypalno of 3.12 ml of 0.50 M bromide methylcyclohexylamine to -10oC, and a solution of 0.50 g of the carboxylic acid obtained in example 1D, in 8 ml of THF added Pocatello. The mixture is stirred at room temperature for 5 hours, and then hydrolyzing with a saturated solution of NH4Cl, extracted with ether, washed with water, then saturated NaCl. When dried on MgSO4and evaporation of the solvents, the crude product is purified by chromatography on silica gel 230-400 mesh mesh. Eluant: AcOEt/hexane 5/95 (about./vol.). Thus, the gain of 0.09 g of the expected ketone. So pl. = 118oC.

Example 192. 1-[1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-yl] -2-(methyl-4-phenyl)-1-Etalon.

(I): w2= w4= Cl; g4= Cl; R4= H;

< / BR>
A) 1-(2,4-dichlorophenyl)-3-cyano-5-(4-chlorophenyl)-pyrazole.

The solution to 0.70 g of 1-(2.4-dichlorophenyl)-5-(4-chlorophenyl)-1H - pyrazole-3-carboxamide, obtained in example 172A, and 0.74 ml of chloride of mesila in 6 ml of pyridine is heated to 50oC for 8 hours. The solvent is evaporated in vacuum and the residue is dissolved in 20 ml of CH2Cl2. Washed successively with 5% HCl solution, then with water, then saturated NaCl solution, dried on MgSO4then the solvent is evaporated. The residue is crystallized in isopropyl ether. Obtain 0.66 g of the expected NIT ethyl ether type Pocatello in a solution of 0.73 g nitrile obtained above in 20 ml of ethyl ether. After 2 hours of reaction at room temperature the mixture was hydrolized in 50 ml of 5% hydrochloric acid, and the resulting bio-phase mixture was stirred for 30 minutes. The resulting pink precipitate is filtered, washed with water and ethyl ether, then dissolved in 100 ml of CH2Cl2and mix for 30 minutes in the presence of approximately 10 g of wet silicon dioxide. The silica is then filtered, the filtrate evaporated and the residue is crystallized in a mixture of CH2Cl2/iPr2O. Gain of 0.37 g of the expected ketone. So pl. = 175oC.

Same as above receive connections listed in the table. XIX.

1. Derivatives of pyrazole of the General formula I

< / BR>
in which g2, g3and g6is hydrogen;

g4- chlorine atom or bromine, (C1- C3)alkyl, trifluoromethyl or phenyl;

g5is hydrogen or chlorine atom;

w2, w3, w5and w6is hydrogen or chlorine atom;

w4is hydrogen, chlorine atom, (C1- C3)alkyl, (C1- C3)alkoxy or nitro;

X represents a direct bond or a group -(CH2)n- N(R3)-, in which R3is hydrogen or (C1- C3)alkyl, and n is 0 or unit;
1
R2in which R1is hydrogen, (C1- C3)alkyl or cyclohexyl, and R2- (C1- C6)alkyl, non-aromatic carbocyclic radical C3- C15possibly substituted by a hydroxyl group, one or more (C1- C5)alkilani, (C1- C5)alkoxygroup or halogen; amino group (C1- C4)alkyl in which the amino may dunamase (C1- C3)alkyl; cyclohexyl (C1- C3)alkyl; phenyl, unsubstituted or substituted with halogen or (C1- C5)alkyl; phenyl (C1- C3)alkyl; diphenyl (C1- C3)alkyl; a saturated heterocyclic radical selected from pyrrolidinyl, piperidyl, hexahydroazepin, morpholinyl, hinokitiol and oxybutylene, unsubstituted or substituted (C1- C3)alkyl or benzyl; 1-adamantylamine; (C1- C3)alkyl, substituted aromatic heterocycle selected from pyrrolyl, pyridyl or indolyl, unsubstituted or substituted (C1- C5)alkyl; or R1and R2form together with the nitrogen atom to which they relate, pyrrolidinyl, piperidyl or morpholinyl; or the group R5represents phenyl (C1- C the 2-norbornylene; when X represents a group -(CH2)nN(R3)-, R represents a group R2athat represents a non-aromatic carbocyclic radical C3- C15; phenyl substituted by halogen; phenyl (C1- C3)alkyl, possibly substituted with halogen; indolyl, possibly substituted (C1- C5) alkoxygroup; anthracene; or the group-other2bin which R2b- cyclohexyl; substituted; phenyl, unsubstituted or substituted by one or two halogen atoms, (C1- C5) alkyl or (C1- C5) alkoxygroup; or an acid additive salt.

2. Derivatives of formula (Ia') under item 1

< / BR>
in which w2, w3, w4, w5, w6, g2, g3, g4, g5, g6and R4have the meanings given in paragraph 1;

R1is hydrogen or (C1- C6)alkyl, and R2- non-aromatic carbocyclic radical C3- C15or a saturated heterocyclic radical selected from 1-pyrrolidinyl, 1-piperidinyl, 1-hexahydroazepin and 4-morpholinyl;

or their acid additive salt.

3. Derivatives of formula (i) under item 1,

< / BR>
in which R4X and R have the meanings given to the location or a methyl group, or their acid additive salt.

5. Derivatives of formula (i) under item 3, in which R4is hydrogen or a methyl group, and X is a direct bond, or an acid additive salt.

6. Derivatives of formula (i) under item 3, in which R4is hydrogen or methyl, X is a direct bond, and R is a group-NR1R2in which R1is hydrogen or methyl; R2- non-aromatic carbocyclic radical C3- C12or a saturated heterocyclic radical selected from 1-pyrrolidinyl, 1-piperidinyl, 1-hexahydroazepin and 4-morpholinyl, or their acid additive salt.

7. Derivatives of formula (i) under item 3, in which R4is hydrogen or methyl, X is the group -(CH2)n-N(R3)-, in which n is 0 or 1, and R3is hydrogen or methyl, and R - group-other2bin which R2bis phenyl, unsubstituted or substituted by one or two halogen atoms, (C1- C5)alkyl or a group (C1- C5)alkoxy; cyclohexyl or substituted, or an acid additive salt.

8. Derivatives of formula (i) under item 3, in which R4is hydrogen, and when X represents a direct bond, R is a group-NR1R2in which R1is hydrogen or (C1- C6)alkyl, and R2- (C1- R3and n have the meanings given in paragraph 1, R - group - 2-indolyl, unsubstituted or substituted (C1- C5) alkoxygroup, or their acid additive salt.

9. Derivatives of the formula (ii) under item 1

< / BR>
in which X and R have the meanings given in paragraph 1; W4is methyl or metaxylene group, or an acid additive salt.

10. Derivatives of the formula (ii) under item 9, in which X is a direct bond, R is a group-NR1R2in which R1is hydrogen or a methyl group; R2- non-aromatic carbocyclic radical (C3- C15), or an acid additive salt.

11. Derivatives of the formula (ii) under item 9, in which X is a group -(CH2)nN(R3)- where n is 0 or 1; R3is hydrogen or a methyl group, R is a group-other2bin which R2bis phenyl, unsubstituted or substituted by one or two halogen atoms, (C1- C5)alkyl or a group (C1- C5)alkoxy; cyclohexyl or substituted, or an acid additive salt.

12. Derivatives of the formula (ii) under item 9, in which X represents a direct bond, R is a group-NR1R2in which R1is hydrogen or (C1- C6) alkyl, R2- (C1- C3) alkyl, same, defined in paragraph 1, R - group, 2-indolyl, or their acid additive salt.

13. Derivatives of the formula (iii) under item 1

< / BR>
in which X and R have the meanings given in paragraph 1; g4a bromine atom or a methyl or triptorelin group, or an acid additive salt.

14. The method of obtaining derivatives of pyrazole of the General formula (Ia')

< / BR>
in which g2- g6, w2- w6, R1, R2and R4have the meanings given in paragraph 1, or their acid additive salts, characterized in that the derived 3-pyrazolylborate acid of General formula (IIa)

< / BR>
in which g2- g6, w2- w6and R4have the meanings given in paragraph 1, or its ester, or anhydride or acid chloride, is subjected to the interaction with the amine of the formula HNR1R2in which R1and R2have the meanings given in paragraph 1 of the formula, followed by separation of the target compounds as free base or as an acid additive salt.

15. The method of obtaining derivatives of pyrazole of the General formula (Ib)

< / BR>
in which g2- g6, w2- w6, R3, R4and R have the meanings given in paragraph 1, or their acid-additive with>
- g6, w2- w6and R4have the meanings given in paragraph 1, or its ester, anhydride or acid chloride, is subjected to the interaction with the primary amine R3NH2where R3matter specified in paragraph 1, obtained with the intermediate amide of formula (V)

< / BR>
in which g2- g6, w2- w6, R3and R4have the meanings given in paragraph 1, is subjected to reduction with metal hydride to obtain the intermediate amine of formula (VI)

< / BR>
in which g2- g6, w2- w6, R3and R4have the meanings given in paragraph 1, which is subjected to the interaction with the acid chloride of the acid of formula R2aCOCl, in which R2amatter specified in paragraph 1, or with an isocyanate of formula R2bN= C= O, in which R2bmatter specified in paragraph 1, followed by separation of the obtained target amides of the formula (Ib) in which R is defined above, the group R2aor received target urea of formula (Ib) in which R is a group other2bdefined in paragraph 1, in free form or in the form of an acid additive salts.

16. The method of obtaining derivatives of pyrazole of the General formula (Ic)

< / BR>
in which g2- g)alkyl and R is the group R2aor group-other2bdefined in paragraph 1, or their acid additive salts, characterized in that the derived 3-pyrazolylborate acid of the formula (IIa)

< / BR>
in which g2- g6, w2- w6and R4have the meanings given in paragraph 1, or its ester, anhydride or acid chloride is treated with a derivative diphenylphosphinite in basic medium, followed by treatment with an acid in an alcoholic medium with the intermediate amine of formula (VII)

< / BR>
in which g2- g6, w2- w6and R4have the above specified values,

followed if necessary by the interaction of the amine of formula (VII) with an alkylating agent to obtain the secondary amine of the formula (VIIb):

< / BR>
in which g2- g6, w2- w6and R4have the meanings defined above, and R'3- (C1- C2) alkyl,

and the resulting amine of formula (VII) or formula (VIIb) is subjected to interaction with the acid chloride of the acid of formula R2aCOCl, in which R2ahas the above values, or with the isocyanate of formula R2bN=C=O, followed by separation of the target amide of the formula (Id) or the target urea of formula (Ie):

< / BR>
< / BR>
in which g/BR>in free form or in the form of an acid additive salt.

17. The method of obtaining ketone derivatives of pyrazole of the General formula (If)

< / BR>
in which g2- g6, w2- w6, R4and R5have the meanings given in paragraph 1,

or their acid additive salts, characterized in that the derived 3-pyrazolylborate acid of the formula (IIa)

< / BR>
in which g2- g6, w2- w6and R4have the meanings given in paragraph 1,

or its ester, or anhydride, or acid chloride is treated with an organic compound of divalent manganese formula R5MHP1in which R5has the above meanings, and X1is halogen, followed by separation of the target compounds in free form or in the form of an acid additive salt.

18. The pharmaceutical composition exhibiting affinity with receptors cannabinoids, containing the active principle and a pharmaceutically acceptable additive, characterized in that it contains as active principle pyrazole derivative of the General formula (I) under item 1 in the amount of 0.5 - 1000 mg per unit dosage.

19. Intermediate derivatives of 3-pyrazolylborate acid of General formula (II)

< / BR>


 

Same patents:

The invention relates to a method for producing derivatives taxane General formula (I) by esterification of protected baccatin III or protected 10-desacetyl-baccatin III using the acid of General formula (II)

The invention relates to a new method of obtaining derivatives taxane General formula

< / BR>
which have valuable protivoanemicakimi and antitumor properties

The invention relates to endothelin antagonists, used inter alia for the treatment of hypertension

The invention relates to novel 1,2,4-oxalatotetraaminecobalt, to the way they are received, to the containing compositions and methods for their use as antiviral agents

The invention relates to compounds of the formula

(I)

where R1represents hydrogen, lower alkyl, lower alkenyl, lower quinil, aryl lower alkyl, cycloalkyl lower alkyl, lower alkoxy lower alkyl, hydroxy lower alkyl, amino lower alkyl, mono - or di-lower alkyl, amino lower alkyl, formyl, lower alkylsulphonyl, amino lower alkylsulphonyl, lower alkoxycarbonyl, mono - or di-aryl-substituted lower alkyl, arylcarbamoyl lower alkyl, aryloxy lower alkyl, or lower alkylene

< / BR>
X represents O or S;

W represents hydrogen, halogen, hydroxy, lower alkoxy, aryl lower alkoxy, nitro, trifluoromethyl or

< / BR>
where R3represents hydrogen, lower alkyl or aryl lower alkyl, and R4represents lower alkyl or aryl lower alkyl; or alternatively the groupas a whole represents the

< / BR>
R5is hydrogen, lower alkyl, aryl or aryl lower alkyl; and

Z predepression

The invention relates to new chemical substances, which have valuable pharmacological properties, more particularly to a nitrogen-containing heterocyclic compounds of General formula I

< / BR>
where X is oxygen or sulfur;

Y is carbon or nitrogen;

Z is carbon or nitrogen, and Y and Z are not simultaneously mean nitrogen;

R1and R2independent from each other and denote hydrogen, alkyl with 1 to 6 carbon atoms, halogen, trifluoromethyl, nitrile, alkoxy with 1 to 6 carbon atoms, a group of CO2R7where R7means hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)NR8R9where R8and R9not dependent from each other and denote hydrogen, alkyl with 1 to 3 carbon atoms, methoxy or together with the nitrogen form a morpholine, pyrrolidine or piperidine-NR10R11where R10and R11denote hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)R12where R12means alkyl with 1 to 6 carbon atoms, group-SO2R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has a specified value, and-SO2NR13R14where R13and R142R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has the specified value, -SO2NR13R14where R13and R14have a specified value, a nitrogroup, 1-piperidinyl, 2-, 3 - or 4-pyridine, morpholine, thiomorpholine, pyrrolidine, imidazole, unsubstituted or substituted at the nitrogen by alkyl with 1 to 4 carbon atoms, 2-thiazole, 2-methyl-4-thiazole, dialkylamino with 1 to 4 carbon atoms in each alkyl group, or alkilany ether with 1 to 4 carbon atoms;

R4an ester of formula-CO2R16where R16means alkyl with 1 to 4 carbon atoms, the amide of formula C(O)NR17R18where R17and R18independent from each other and denote hydrogen, alkyl with 1 to 2 carbon atoms, methoxy or together with the nitrogen form a morpholine, piperidine or pyrrolidine, phenyl, unsubstituted or substituted by residues from the group comprising halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, 3-methyl-1,2,4-oxadiazol-5-yl, 2 - or 3-thienyl, 2-, 3 - or 4-pyridyl, 4-pyrazolylborate 4 stands, the ketone of the formula C(O)R19'where R19means alkyl with 1 to 3 carbon atoms, phenyl or 1-Mei-2-yl, a simple ester of the formula-CH2OR20where R20means alkyl with 1 to 3 carbon atoms, thioether formula-CH2SR20where R20has the specified value, the group CH2SO2CH3amines of the formula-CH2N(R20)2where R20has the specified value, the remainder of the formula-CH2NHC(O)R21where R21means methyl, amino or methylamino - group-CH2NHSO2Me2where Me denotes methyl carbamate of the formula CH2OC(O)NHCH3;

R5and R6independent from each other and denote hydrogen or methyl;

n is 0,1 or 2,

Provided that the substituents are not simultaneously have the following meanings: Y and Z is carbon, R1or R2hydrogen, halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, cyano, nitro, trifluoromethyl, R3unsubstituted phenyl and R4group-C(O)OR16'where R16'means hydrogen, alkyl, alkenyl or quinil, group-C(O)N(R18')(R19'), where R18'and R19'denote hydrogen, alkyl with 1 to 6 carbon atoms, phenyl, alkoxy or together with the nitrogen form pyrrolidine, piperidine or morpholine, cyanotic, unsubstituted phenyl and 4-imidazole,

in the form of a racemate or an individual enantiomers and their salts, are inhibitors of leukotriene biosynthesis

The invention relates to new derivatives of hinoklidilkarbinola General formula where n is an integer 1, 2, 3, R1-halogen or trihalomethyl, R2is hydrogen, R3-furanyl, tetrahydrofuranyl, DIOXOLANYL, pyranyl, tetrahydropyranyl, optionally substituted by 1, 2 or 3 substituents selected from the group comprising oxoprop and C1-C3-alkyl

The invention relates to new derivatives of N-(3-hydroxy-4-piperidinyl) (dihydro-2H-benzopyran or dihydrobenzoic) carboxamide, having valuable pharmaceutical properties, namely activity to stimulate gastrointestinal peristalsis

The invention relates to 1,4-disubstituted the piperazines of General formula (I), which means the group-CO - or-CH2-OCO; D - heteroaryl selected from a range including 1, 3, 5-triazinyl, pyrimidinyl and pyridinyl, possibly substituted by one or two substituents selected from a range, including mono-(C1-C6)-alkylamino, mono-(C3-C7)- alkynylamino-, di-(C1-C6)-alkylamino-,

(C1-C6)-alkyl-(C3-C7)-alkylamino and pyrrolidin-I-yl group; Raand Rbis a hydrogen atom or (C1-C3)-alkyl; n is an integer from 1 to 4; their enantiomers, racemic mixtures and their salts with pharmaceutically acceptable acids and bases
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