Derivatives of pyrazole, a method of treating parasitic infection and mode of damage or destruction of parasites

 

(57) Abstract:

Describes new pyrazole derivatives of formula (I), where R1is CN, C1-6alkoxycarbonyl, phenyl or C1-6the alkyl, optionally substituted by one or more halogen atoms; R2is a group of formula II, III or IV, in which R7is H, halogen, three(C1-6alkyl)silicom, C1-6the alkyl (optionally substituted by one or more halogen atoms, OH or C1-6alkoxygroup), C1-6alkoxycarbonyl, phenyl group or 5 - or 6-membered cyclic heterocycle which is saturated or partially or fully unsaturated and contains up to 4 heteroatoms independently selected from up to 4 N atoms, up to 2 O atoms and up to 2 S atoms and which is attached to the alkyl chain through a suitable atom, S or N, where valence allows; and R8, R9and R10each is independently H, halogen, phenyl, optionally substituted by one or more halogen atoms, CN or C1-6alkyl group, optionally substituted by one or more halogen atoms; R3represents H, C1-6alkyl, halogen, NH2, NH(C1-6alkanoyl), NH(C1-6alkoxycarbonyl), N(C1-6alkoxy is C1-6alkyl), where n is 0, 1 or 2; and R4, R5and R6each is independently halogen, C1-6the alkyl substituted by one or more halogen atoms, C1-6alkoxygroup substituted by one or more atoms of halogen, S(O)n(C1-6the alkyl, optionally substituted by one or more halogen atoms), where n is 0, 1 or 2, or SF5or their pharmaceutically or veterinary acceptable salt. These compounds have antiparasiticsthe properties. Also described is a method of treatment of parasitic infections and the way damage or destruction of parasites. 3 S. and 13 C.p. f-crystals, 1 PL.

< / BR>

The present invention relates to the derivatives of pyrazole with antiparasiticsthe properties.

Some antiparasitics pyrazole derivatives are already known. They include fipronil (5-amino-3-cyano-1-(2,6-dichloro-4 - triptoreline)-4-triftormetilfullerenov) and some of its analogs, referred to in International Patent Application WO 87/03781.

In EP 0 658 047 A1 disclosed a number of 4-alkenyl and 4-quinil pyrazoles from H and alkyl in the 1 - position and urethane group in position 5 of the pyrazole as antifungal agents.

Now found a new group the uly I:

< / BR>
where R1is CN, C1-6alkoxycarbonyl, NO2CHO, C1-6alkanoyl, phenyl, optional (optionally) substituted by one or more halogen atoms, or C1-6the alkyl, optionally substituted by one or more halogen atoms;

R2is a group of formula II, III or IV:

< / BR>
in which

R7is H, halogen, carbamoyl, cyano, three (C1-6alkyl) silicom, C1-6the alkyl (optionally substituted by one or more halogen atoms, HE or C1-6alkoxygroup), C1-6alkoxycarbonyl, phenyl group or 5 - or 6-membered cyclic heterocycle which is saturated or partially or fully unsaturated and contains up to 4 heteroatoms independently selected from up to 4 N atoms, up to 2 O atoms and up to 2 S atoms and which is attached to akinrinola link using an appropriate atom C, S, or N, where valence allows;

and R8, R9and R10each is independently H, halogen, phenyl, optionally substituted by one or more halogen atoms, CN or C1-6alkyl group, optionally substituted by one or more halogen atoms;

R3represents H, C1-6alkyl, halogen, NH2, (C1-6alkyl)2, NHCONH (C1-6alkyl), N-pyrrolyl, NHCONH (phenyl, optionally substituted by one or more halogen atoms), N = CH (phenyl), HE, C1-6alkoxy, SH or S (O)n(C1-6alkyl, optionally substituted by one or more halogen atoms), where n is 0, 1 or 2; and R4, R5and R6each is independently H, halogen, C1-6the alkyl, optionally substituted by one or more halogen atoms, C1-6alkoxygroup, optionally substituted by one or more atoms of halogen, S (O)n(C1-6the alkyl, optionally substituted by one or more halogen atoms), where n is 0, 1 or 2, or CH3CO, CN, CONH2, CSNH2, OCF3SCF3or SF5or its pharmaceutically or veterinary suitable salt (hereinafter referred to collectively as "compounds of the invention").

Alkyl groups can be straight, cyclic or branched, where it allows the number of carbon atoms. Halogen means fluorine, chlorine, bromine or iodine.

Pharmaceutically and veterinary suitable salts are well known to those experienced in the art and include, for example, those mentioned Berge et al in J:.Pharm. Sci 66, 1-19 (1997).

R1UB>1-6alkoxycarbonyl group.

R1more preferable is CN, Ph, CO2C2H5CH3, CF3or CO2CH3.

R2preferably is a group of formula II, where R7is H, three (C1-6alkyl) silyl group, a C1-6alkyl group, optionally substituted by one or more halogen atoms, HE or C1-6alkoxygroup, or R7is C1-6alkoxycarbonyl, phenyl group or 5 - or 6-membered cyclic heterocycle, as defined above, halogen,

or a group of the formula III, in which each of R8, R9and R10is H, or a group of the formula III, in which two of R8, R9and R10are halogen and the other is H, CN, phenyl, optionally substituted by one or more halogen atoms, or C1-6the alkyl, optionally substituted by one or more halogen atoms, or a group of formula III in which R8, R9and R10are each independently F, Cl, Br or 1,

or a group of formula III in which R8is H or C1-6the alkyl, optionally substituted by one or more halogen atoms, OH or C1-6alkoxygroup, a R9and R101-6the alkyl, optionally substituted by one or more halogen atoms, OH or C1-6alkoxygroup, or a group of formula III in which R8is H and one of R9and R10is H and the other is CN or C1-6the alkyl, optionally substituted by one or more halogen atoms, OH or C1-6alkoxygroup,

or a group of formula III in which R8is H and one of R9and R10is C1-6alkilani, optionally substituted by one or more halogen atoms, OH or C1-6alkoxygroup,

or a group of formula III in which R8is C1-6the alkyl, optionally substituted by one or more halogen atoms, OH or C1-6alkoxygroup, a R9and R10both are H,

or a group of formula IV.

More preferably R2is a group of formula II in which R7is Si(CH3)3H, CH3CH(CH3)2CH2OH, (CH2)2OH, CO2CH3Ph, Tien-2-yl, CH2OCH3, Br, Cl or CF3,

or a group of formula III in which R8, R9and R10each is H, or a group of formula III in which R8, R9and R10each is what uppoi formula III, in which R8and R10are Br, a R9is H,

or a group of formula III in which R8and R9are Br, a R10is CH3,

or a group of formula III in which R8and R10are Br, a R9is CH3,

or a group of formula III in which R8and R10are Br, a R9is Ph,

or a group of formula III in which R8and R9are Br, a R10is Ph,

or a group of formula III in which R8and R10are Cl, a R9is Ph,

or a group of formula III in which R8and R9are Cl, a R10is Ph,

or a group of formula III in which R8and R10are Cl, a R9is Br,

or a group of formula III in which R8and R9are Cl, a R10is Br,

or a group of formula III in which R8is H, R9and R10are Br,

or a group of formula III in which R8is H, a R10and R9are Cl,

or a group of formula III in which R8is H, a R10and R9are F,

or a group of formula III in which R8is H, a R10is CF3and R9is Cl,

or group who sing the formula III, in which R8is H, a R10is CF3and R9is Br,

or a group of formula III in which R8is H, a R9is CF3and R10is Br,

or a group of formula III in which R8is H, a R10is CF3and R9is F,

or a group of formula III in which R8is H, a R9is CF3and R10is F,

or a group of formula III in which R8and R10are H, a R9is CN,

or a group of formula III in which R8and R9are Br, a R10is CF3,

or a group of formula III in which R8and R10are Br, and R9is CF3,

or a group of formula III in which R8is Br, R9is Br and R10is Cl,

or a group of formula III in which R8is Br, R10is Br and R9is Cl,

or a group of formula III in which R8is CH3, R9and R10are Br,

or a group of formula III in which R8is CH3, R9and R10are F,

or a group of formula III in which R8is CH3, R9and R10are H,

rimula III, in which R8, R9and R10are each Br,

or a group of formula IV.

R3preferably represents H, C1-16alkyl, NH2, NH (C1-6alkanoyl), NH (C1-6alkoxycarbonyl), N (C1-6alkoxycarbonyl)2, NH (C1-6alkyl)2N-pyrrolyl, halogen or S(O)n(C1-6alkyl, optionally substituted by one or more halogen atoms), where n is 0, 1 or 2.

R3more preferably represents H, CH3, NH2N-pyrrolyl, N(CH3)2, NH(CO2(tert-butyl)), N(CO2(tert-butyl))2, NHCOCH3, Br, Cl, SCH3or SCF3.

R4and R6preferred are halogen-free.

R4and R6more preferred are Cl.

R5preferably is C1-6the alkyl, optionally substituted by one or more halogen atoms, C1-6alkoxyl, optionally substituted by one or more halogen atoms, C1-6alkylthiol, optionally substituted by one or more halogen atoms, SF5or halogen.

R5more preferable is CF3, OCF3SCF3or SF5.

Most predpochtitel>/BR>3-cyano-1-(2,6-dichloro-4-trifloromethyl)-4-ethynylpyrene;

3-cyano-1-(2,6-dichloro-4-triftormetilfullerenov)-4-ethynylpyrene;

4-(2-bromo-1,2-dichlorethene-3-cyano-1-(2,6-dichloro-4-trifloromethyl) pyrazole:

3-cyano-1-(2,6-dichloro-4-trifloromethyl)-4-tribromoaniline;

4-(2,2-dibromoethenyl)-3 - cyano-1-(2,6-dichloro-4-triptoreline) pyrazole;

3-cyano-4-(2,2-dichloroethenyl)-1-(2,6-dichloro-4-triptoreline) pyrazole;

3-cyano-1-(2,6-dichloro-4-triptoreline)-4(2,2-deperately) pyrazole;

3-cyano-1-(2,6-dichloro-4-triptoreline)-4-tribromoaniline;

3-cyano-1-(2,6-dichloro-4-triptoreline)-4-trichloroaniline;

4-(2-bromo-1,2-dichloroethenyl)-3-cyano-1-(2,6-dichloro-4-triptoreline) pyrazole;

4-(2-chloro-1,2-dibromoethenyl)-3-cyano-1-(2,6-dichloro-4 - triptoreline) pyrazole;

3-cyano-1-(2,6-dichloro-4-triptoreline)-4-(1-methyl-2,2-dibromoethenyl) pyrazole;

3-cyano-1-(2,6-dichloro-4-triptoreline)-4-(1-methyl-2,2-deperately) pyrazole;

1-(2,6-dichloro-4-triptoreline)-4-ethinyl-3-cryptomaterial;

4-(2-bromo-1,2-dichloroethenyl)-1-(2,6-dichloro-4-triptoreline)- 3-cryptomaterial;

1-(2,6-dichloro-4-triptoreline)-4-ethinyl-3-methylpyrazole.

The compounds of formula (I) possess the dimensional forms. The present invention includes all the individual stereoisomers of compounds of formula (I) and mixtures thereof.

Division of diastereoisomers can be achieved by conventional methods, for example, fractional crystallization, chromatography or HPLC stereoisomeric mixtures of compounds of formula (I) or a suitable salt or derivative. An individual enantiomer of the compounds of formula (I) can also be obtained from a corresponding optically pure intermediate or by separation, such as in HPLC, the corresponding racemate using a suitable chiral substrate, or by fractional crystallization of the diastereomeric salts formed by interaction of the corresponding racemate with a suitable optically active acid or base.

Further, the present invention provides methods of preparing compounds of the invention, which are described below and illustrated with Examples.

Method 1

Obtaining the compounds of formula (I) in which R2is a group of formula II (C CR7), the reaction of the compound of formula V:

< / BR>
in which R1and R3-6defined above, a R2Ais 1, Br or triftormetilfullerenov, with the compound of the formula HC CR7where R7Ivanishin) palladium (II) chloride [PdCl2(PPh3)2] and copper iodide. Alternatively, the appropriate alkylborane compounds derived from HC CR7can be obtained in advance and entered into reaction with the compound of the formula V as defined above.

The reaction is preferably conducted in a solvent which does not adversely influence the reaction (for example, triethylamine and/or dimethylformamide (DMF)).

The compounds of formula 1 in which R2is HC CR7can be transformed into each other using conventional methods: for example, compounds in which R7is C1-6trialkylsilyl group, can be converted into compounds in which R7is H under the action of a base such as potassium carbonate, in a solvent such as methanol.

The compounds of formula V in which R2Ais 1 or Br, can be obtained from corresponding compounds of formula V in which R2Ais H, when interacting with Jodorowsky or brainwashin agent such as N - (iodine or bromine) succinimide.

The compounds of formula V in which R2Ais H, commercially available or available by means of conventional methods, or methods described herein, and their appropriate progenitalis the compounds of formula V, in which R2Ais 1, with suitable vinyl compounds such as vinyl compounds (trialkyl) tin, optionally in the presence of catalytic amounts of Pd connection, and then, if necessary, gorodilova the compounds obtained. The reaction is preferably carried out in the presence of palladium catalyst, such as tetrakis (triphenyl-phosphine) palladium (O) or palladium acetate. The reaction is preferably carried out in a solvent that does not adversely affect the reaction (for example, triethylamine or DMF), at or near the 75oC. Gorodilova carried out using conventional methods.

Method 3

Obtaining the compounds of formula I in which R2is a group of formula IV, the interaction of the compounds of formula V, as defined above, in which R2Ais H, with cyclohexanone. The reaction is preferably carried out in an organic acid (e.g. acetic acid) at or near 120oC.

The compounds of formula V in which R1is CN, NO2CHO, C1-6alkanoyloxy or C1-6alkyl group optionally substituted by one or more halogen atoms; R2Ais H, R3is NH2, OH, C1 the e by halogen atoms); and R4-6defined above, or known, or are available using known techniques.

Method 4

Obtaining the compounds of formula I in which R1is C1-6alkoxycarbonyl, by treatment of the corresponding compounds of formula 1 in which R1is CN, in the presence of an appropriate alcohol. Suitable bases include potassium carbonate and potassium hydroxide. This reaction can be conducted at room temperature or close to it.

Method 5

Obtaining the compounds of formula I in which R3is halogen, in the processing of the corresponding compounds of formula I in which R3is the NH2, alkyl nitrite, such as n-butyl nitrite, and a suitable source of halogen. Suitable sources of halogen includes bromoform. The reaction is preferably carried out in a solvent that does not adversely affect the reaction (e.g., acetonitrile), at or near 70oC.

Method 6

Obtaining the compounds of formula I in which R3is H, by treatment of the corresponding compounds of formula I in which R3is the NH2, alkyl nitrite, such as n-butyl nitrite. The reaction of predpochtitaemye), when the boiling temperature of the solvent under reflux.

Method 7

Obtaining the compounds of formula I in which R3is N-pyrrolidon, by treatment of the corresponding compounds of formula I in which R3is the NH2, 2,5-dialogseminarierna, such as 2,5-dimethoxytetrahydrofuran, in the presence of acid. The reaction is preferably carried out using an organic acid such as acetic acid, at elevated temperatures such as the boiling point under reflux with acetic acid.

Method 8

Obtaining the compounds of formula I in which R3is S(O)n(C1-6alkyl group optionally substituted by one or more halogen atoms), by treatment of the corresponding compounds of formula I in which R3is the NH2, alkyllithium, such as n-butylnitrite, and di (C1-6alkyl optionally substituted by one or more halogen atoms) disulfide, and, if necessary, by oxidation of compounds of formula I in which R3is S(C1-6the alkyl, optionally substituted by one or more halogen atoms). The compound of the formula I, in which R3is S(O)n(C1-6alkyl, optionally replacing the or R3is S(O)n(C1-6the alkyl, optionally substituted by one or more halogen atoms), and n is 0 or 1. This reaction is preferably carried out by heating the compound of formula I, in which R3is the NH2with a disulfide compound in a suitable solvent that does not adversely influence the reaction (e.g. acetonitrile), at elevated temperature, followed by addition of Alternaria and further heating. Oxidation of the sulfide or sulfoxide) can be done using conventional methods, for example, when using perceptionally acid.

Method 3

Obtaining the compounds of formula I in which R2is a group of the formula III, in which each of R9-10is halogen, the interaction of the compounds of formula V in which R1and R3-6defined above, a R2Ais COR8with three (alkyl or aryl) - substituted phosphine and tetrachloride carbon. Tizanidine phosphine is preferably triphenylphosphine.

The compounds of formula V in which R2Ais CO(C1-6alkyl optionally substituted by one or more halogen atoms) can be obtained from the corresponding SOEDINENIYa) = CH2when interacting with an oxidizing system such as N-methylmorpholine oxide/osmium tetroxide (cat. ) /metaperiodate sodium. Alternative compounds of formula V in which R2Ais CO(CH2(C1-5alkyl optionally substituted by one or more halogen atoms), can be obtained from corresponding compounds of formula I in which R2is a group of formula II, where R7is (C1-5alkyl optionally substituted by one or more halogen atoms), hydration, for example, when interacting with the hemihydrate toluensulfonate acid in the crude acetonitrile.

Method 10

Obtaining the compounds of formula I in which R2is a group of formula III in which R8is H and one of R9and R10is halogen and the other CF3the interaction of the compounds of formula V in which R1and R3-6defined above, a R2Ais CHO with a compound of the formula (halogen)3CCF3in the presence of a zinc halide such as zinc chloride, and copper halide such as copper chloride. The reaction is preferably carried out in the presence of a polar solvent such as N,N-dimethylformamide.

Obtaining the compounds of formula I in which R is 1, and the other C (Cl, Br or l)3available in a similar way using the reagents of the formula (Cl, Br or l)3CC (Cl, Br or l)3. Less reactive communication C - halogen bonds are not broken, and C (Cl, Br or l)3the group that contains this link, is transferred as the transfer of the above-mentioned CF3group.

The compounds of formula V in which R2Ais CHO may be obtained from the corresponding compounds of formula I, where R2is atenilol, when interacting with an oxidizing system such as N-methylmorpholine oxide / osmium tetroxide (cat.) / metaperiodate sodium.

Method 11

Obtaining the compounds of formula I in which R2is a group of formula II, the interaction of the compounds of formula V in which R2Ais I, with a compound R7-C C-Sn, such as the connection R7-C C-Sn(alkyl)3. The reaction is preferably carried out in the presence of palladium catalyst, for example tetrakis (triphenylphosphine) palladium (O). The reaction is preferably carried out in a solvent which does not adversely influence the reaction (e.g. dimethylformamide), at or near the 75oC.

Method 12

Obtaining the compounds of formula I in which R2Leesa group of the formula II and R7is H, with a reagent capable of reacting as (R7)+synthon, such as R7Z, where Z is a suitable removable group, such as chlorine, bromine, iodine, or alkyl or sulphonate group, optionally in the presence of a base. The reaction is carried out with the compound R7l, for example, in the presence of copper iodide and connections PdIIsuch as bis (triphenylphosphine) palladium (II) chloride and a base such as triethylamine.

Method 13

Obtaining the compounds of formula I in which R2is a group of formula II, a R7is C1-6alkoxycarbonyl, the interaction of the compounds of formula I in which R2is a group of formula II and R7is CN, with C1-6alcohol, optionally in the presence of a base. Suitable bases include potassium carbonate and potassium hydroxide. The reaction can be conducted at or near room temperature.

Method 14

Obtaining the compounds of formula I in which R2is a group of formula II, a R7is C1-6alkoxycarbonyl, by the oxidation of compounds of formula I in which R2is a group of formula II and R7is CH2OH, by the formation of the corresponding acid with posyandu potassium in alcohol.

Method 15

Obtaining the compounds of formula I in which R3is NH (C1-6alkanoyl), the interaction of the compounds of formula I in which R3is the NH2with allermuir agent such C1-6alkanoyl (chloride, bromide or iodide). This process is preferably carried out with the acid chloride of the acid and the acid acceptor such as pyridine.

Method 16

Obtaining the compounds of formula I in which R3is N (C1-6alkoxycarbonyl)2, the interaction of the compounds of formula I in which R3is the NH2with di(C1-6alkyl) dicarbonate. This process is preferably carried out using the basic system, such as triethylamine / 4-dimethylaminopyridine (DMAP) in a solvent such as DMF.

Method 17

Obtaining the compounds of formula I in which R3is NH (C1-6alkoxycarbonyl), the interaction of the compounds of formula I in which R3is N (C1-6alkoxycarbonyl)2with acid. This process is preferably performed using triperoxonane acid (TFU) in a solvent such as methylene chloride.

Method 18

Obtaining the compounds of formula I in which R3predstavlja
alkylating agent such as alkyl (chloride, bromide or iodide). Preferably the reaction is carried out using alkylated. Preferably the reaction is carried out in the presence of a base such as NaH. Preferably the reaction is carried out in a suitable solvent, such as THF.

The compounds of formula I in which R3is amino derivative, can be obtained from compounds of the formula I, in which R3is the NH2using conventional methods, such as the above.

Method 19

Obtaining the compounds of formula I in which R2is a group of the formula III, in which some or all of the R8, R9and R10are halogen, the interaction of the compounds of formula I, where R2represents a group of formula II with halogen, optionally in the presence of a base. An example is the interaction of alkyne, in which R7is H, butyllithium, then with a source of halogen, preferably in an ether solvent, with the formation of compounds, where R8, R9and R10all are halogen-free. The interaction of alkyne with any R7the group with a source of halogen (such as Cl, Br2or I2) leads to 1,2-dehalogenation SOEDINENIYa the compounds of formula V, in which R2Ais I, with a compound of formula HC CR7in the presence of utility, of zinc chloride and palladium compounds. The reaction is preferably carried out in the presence of a suitable base, such as triethylamine and in a suitable solvent such as DMF.

Preferably alkyne was dissolved in a suitable solvent, such as THF, is treated with butyllithium at low temperature, then add the zinc chloride in the solvent and bring the temperature to ambient. Preferably the mixture is again cooled and added a compound of palladium, such as bis (triphenylphosphine) palladium chloride, with a compound of formula V in which R2Ais I. Preferably, the reaction temperature then increases, for example, the boiling point of the solvent under reflux.

Method 21

Obtaining the compounds of formula I in which R2is a group of formula II, where R7is halogen, the interaction of the compounds of formula I in which R2is a group of formula III in which R is H, a R9and R10are halogen-free, with a base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

Method 22

Obtaining the compounds of formula I, soedineniya formula V, in which R2Ais COR8with connection R9R10C = Ti. Example of a combination of R9R10C = Ti is-chloro - methylene-[bis (cyclopentadienyl)titani]dimethylamine ("reagent Tebbe"). Preferably the compound of formula V in which R2Ais COR8, is dissolved in an inert solvent, such as tetrahydrofuran (THF), cooled in an inert atmosphere, then added the connection of the vinylcarbene titanium and leave the mixture to heat up.

Method 23

Obtaining the compounds of formula I in which R2is a group of formula III, where R8is H by reaction of compounds of formula V in which R2Ais CHO with a compound R9R10CH - phosphonium (Wittig reaction), R9R10CH - silyl compound (rafinirovaniyu by Petersen) or R9R10CH-phosphate compound (reaction Horner - Emmons or reaction Wordsworth - Ammonia) in the presence of a base. Such reagents are available commercially or through conventional methods.

Method 24

Obtaining the compounds of formula I in which R2is a group of formula III, the interaction of the compounds of formula V in which R2Ais H, with a compound of formula R8COCHR9R<) at elevated temperatures, such as about 120oC.

Method 25

If desired or necessary, turn the compound of formula I, its pharmaceutically or veterinary suitable salt. Pharmaceutically or veterinary suitable salt of the compounds of formula (I) is easily obtained by mixing together solutions of the compounds of formula (I) and the desired acid or base, respectively. This salt can be planted from the solution and separated by filtration or highlight other ways, such as by evaporation of the solvent.

Compounds of the invention are available or using any of the methods described herein in the Methods and Examples, or conventional methods known to experts in the field of technology, or their suitable applications using methods known in the art.

Compounds of the invention can be extracted and cleaned by conventional methods. Having years of experience in the art it is obvious that for sensitive functional groups necessary to protect and unprotect during the synthesis of the compounds of the invention. This can be achieved using conventional methods described, for example, in the publication "Protective groups in organic synthesis" T. V. Green and P. G. M. Wuts, John Wiley and Sons Inc., 1991.

Compounds of the invention is neither particularly useful for the treatment of ectoparasites.

Turning first to the compounds of the invention for a person, provided:

a) pharmaceutical compositions comprising compounds of the invention in a mixture with a pharmaceutically suitable auxiliary medicinal substance, diluent or carrier suitable for local administration;

b) the compound of the invention for use as a drug;

(C) the use of compounds of the invention in the manufacture of antiparasitics drug; and

d) a method of treating a parasitic infection in a patient, comprising introducing an effective amount of compounds of the invention to the patient.

With regard to the use of compounds of the invention for animals, these compounds can be entered by themselves or in part, suitable for the considered special uses and for certain species of an animal host, which is treated and participating parasite. The ways in which you can type compounds include oral in the form of capsules, pills, tablets, or injections of medication, or poured or applied composition, or, alternatively, they can be administered by injection (e.g. subcutaneously, intramuscularly or intravenously) or in the form of the implant, elvet the usual way in accordance with standard pharmaceutical and veterinary practice. These capsules, pills or tablets prepared by mixing the active ingredient with suitable finely chopped diluent or carrier containing additional loosening agent and/or binder such as starch, lactose, talc, or magnesium stearate. Oral doses are prepared by dissolution or suspension of the active ingredient in a suitable medium. The compositions introduced by injection, is prepared in the form of a sterile solution, which may contain other substances, for example enough salts or glucose to make the solution isotonic with blood. Acceptable liquid carriers include vegetable oils such as sesame oil, etc., glycerides, such as triacetin, etc., esters such as benzyl, benzoate, isopropyl myristate and derivatives of fatty acids propylene glycol, etc. as well as organic solvents such as pyrrolidone, glycerol - formal, etc., Liquid formulations are prepared by dissolution or suspension of the active ingredient in the liquid carrier such that the final composition contains from 0.5 to 60% by weight of the active ingredient. Solid formulations are prepared by methods well known in the art.

These compounds batorego treated the severity and type of infection and the body weight of the host. For parenteral, local and oral administration of a typical dose limits of the active ingredient is 0.1 to 50 mg per kg of body weight of the animal, preferably within 1 to 5 mg per kg

Alternatively, the connection can be entered with food animals and for this purpose it is possible to prepare a concentrated food additive or premix for mixing with the normal animal feed.

The compound of the present invention are used to combat Arthropoda, plant nematodes, worms or protozoa parasites. In particular, the compounds of the present invention can be used in the field of veterinary and livestock in agriculture and to protect the public health from Arthropoda, worms or protozoa which are parasitic internally or externally on vertebrates, particularly warm-blooded vertebrates, such as humans and domestic animals, for example in cattle, sheep, goats, horses, pigs, poultry, dogs, cats and fish, for example Acarina, including ticks (for example, lxodes, the species Boophilus, such as Boophilus microplus, Amblyomma species, species Hyalomma, Rhipicephalus species, for example, Rhipicephalus appendiculatus, species Haemaphysalis, Dermacentor species, species Orplid Chorioptes, the Demodex species, species Eutrombicula) Diptera (e.g. species of Aedes, Anopheles species, the species Musca, Hypoderma species, species Gastrophilus, Simulium species); Hemiptera (e.g., Triatoma species); Phthiraptera (e.g. species of Damalinia, Linognathus species) Siphonaptera (e.g., species Ctenocephalides); Dictyoptera (e.g., species Periplaneta species Blatella); Htmenoptera, e.g. Monomorium pharaonis); for example against infections of the gastro-intestinal tract caused by parasitic round worms, for example members of the family Trichostrongylidae, Nippostronylus brasiliensis, Trichinella spiralis, At contortus, Trichostronylus colubriformis, Nematodirus battus, Ostertagia circumcincta, Trichostrongylus axei, Cooperia and Hymenolepis Pope, against and in the treatment of protozoal diseases caused by, for example, Eimeria species, e.g. Eimeria tenella, Eimeria acervulina, Eimeria brunetti, Eimeria maxima, Eimeria necatrix, Eimeria bovis, Eimeria zuerni and Eimeria ovinoidalis; Trypanosoma cruzi, Leishmania, Plasmodium, Babesia, Trichomonadidae, Histomonas, Giardia, Toxoplasma, Entamoeba histolytica and Theileria species; for the protection of stored products, for example cereals, including grain and krupchatka, peanuts, animal feed, timber and household products such as carpets and fabrics, from Arthropoda, rather beetles, including weevils, moths and mites, for example Ephestia species (Ognevka mill), species of Anthrenus (koreeda), Tribolium species (khruschak small flour), Sitophilus (grain weevil), a species of Acarus (mites), for the production areas and to combat mosquito larvae in waterways, wells, tanks, or other flowing or standing water; for the treatment of foundations, structures, and soils to prevent attacks on buildings of termites, for example, species Reticu-litermes, species Heterotermes, species Coptoterms, in agriculture, against adults, larvae and eggs of Lepidoptera (butterflies and moths), e.g., Heliothis species, such as Heliothis virescens (bollworm), Heliothis armioera and Heliothis zea, Spodoptera species, such as S. exempta, S. littoralis (Egyptian caterpillar cotton Cutworm), S. eridania (southern marching worm), Mamestra configurata (Bertha marching worm); Earias species, for example E. insulana (Egyptian boxed worm), species Pectinophora such as Pectinophora gossypiela (pink box worm), Ostrinia species, such as O. nubilalis (European corn borer), Trichoplusia ni (bollworm cabbage), species Pieris (mermaidy), species Laphyqma (marching worms), species of Agrotis and "Amantes" (podgryzayuschie scoop), species Wiseana (porina mol), species Chilo (grinder stalks of rice), species Tryporyza and species of Diatraea (Ognevka sugar cane and rice grinder), Sparganothis pilleriana (grape moth), Cydia pomonella (Codling moth), Archips species (tortrix), Plutella xylos-tella (cabbage moth); against adults and larvae of Coleoptera (beetles), e.g. Hypothenemus hampei (grinder Zostera California), species Hylesinus (bark beetle), Anthonomus grandis (weevil nosie), types of Gonocephalum (false wireworms, Agriotes species (wireworms), species Dermolepida and Heteronychus (beetle larvae), Phaedon cochleariae (mustard beetle), Lissorhoptrus oryzophilus (rice weevil water), Melioethes (pillowy beetle), species Ceutorhynchus species Rhynchophorus and Cosmopolites (root weevils), against Hemiptera, for example, species of Psylla, species Bemisia species Trialeurodes, species of Aphis, species Myzuz, Megoura viciae, species of Phylloxera, species of Adelges, Phorodon humuli (cotton aphid), species Aeneolamia, species Nephotettix (tolstokorova ambrosia tripartite), species of Empoasca species Nilaparvata species Perkinsiella, types of Pyrilla, species Aonidiella (scale red orange), a species of Coccus, species Pseudococcus, species of Helopeltis (mosquitoes), Lygus species, species of Dysdercus species Oxycarenus, species Nezara; Nymenoptera, for example, Athalia species and species Cephus (sawflies), species of Atta (ants listorezy); Diptera, for example, types of Hylemyia (root flies), species of Atherigona and species Chlorops (flies), species of Phytomyza (moth - miners), species Ceratitis (Drosophila); Thysanoptera such as Thrips tabaci: Orthoptera such as Locusta and species Schistocerca (locust) and wingless, for example, species of Gryllus and species Acheta; Collembola, for example, types of Sminthurus and species Onychiurus (springtails), Ioptera, for example, species Odontoterms (termites), Dermaptera, for example, species Forficula (earwig), as well as other Arthropoda agricultural significance such as Acari (mites), for example, of the species Tetranychus, Panonychus species is affected), species Scutigerella (simfile), species Oniscus (woodlice) and species of Triops (crustaceans); nematodes affecting plants and trees that are important for agriculture, forestry and horticulture either directly or by spreading bacterial, viral, mycoplasmataceae or fungal plant diseases, nematodes root growths, such as types of Meliodogyne (e.g., M. incognita); bubble nematodes, such as Globodera species (e.g., Globodera rostochiensis, Heterodera species (e.g. H. avenae); Radopholus species (such as R. Similis); affected nematodes, such as Pratylenchus species (such as P. pratensis); types Belonoliamus (e.g., B. gracilis); Tylenchulus species (e.g., T. semipene - trans); types Rotylenchius (for example, R. reniformis); Rotylenchus species (e.g., R. robustus); Helicotylenchus species (e.g., H. multicinctus), Hemicycliophora species (e.g., H. gracilis); Criconemoides species (e.g., C. similis); Trichodorus species (e.g., T. primitivus); nematode worms, such as Xiphinema species (e.g., X. diversicaudatum); the Longidorus species (e.g. L. elongatus); Hoplolaimus species (e.g., H. coronatus); Aphelenchoides species (e.g., A. ritzemabosi, A. besseyi); stem and bulb nematodes, such as Ditylenchus species (e.g., D. dipsaci).

Compounds of the present invention is also useful for combating arthropod or nematode pests of plants. The active compound is usually applied is 25 kg of active compound per hectare of cultivated hearth. In ideal conditions, depending on the pest, confront, adequate protection may have fewer. On the other hand, adverse weather conditions, pest resistance and other factors may require the use of the active ingredient in higher proportions. For foliar application, you can use the number from 1 g to 1000 g/ha

When the pest is born in the land, the compositions containing the active ingredient uniformly spread on the treated area by any suitable means. If desired, they can be applied in General to the field or area in which a growing crop, or in close proximity to the seed or plant, which must be protected from destruction. The active ingredient can be incorporated into the soil by spraying water on this area, or to submit it to the natural action of rain. If desired, during or after application, the composition can be distributed into the soil mechanically, for example, when plowing or disking. Can be applied before planting, at planting, after planting, but before you begin to germinate or after emergence.

Compounds of the invention can be applied to the soil in solid or liquid Sistemi nematodes, amazing aerial parts of plants (for example, the above Aphelenchoides species and species of Ditylenchus).

Compounds of the invention are useful for pest control, which are parts of the plant remote from the point of application, for example, eating the leaves insects destroy connections, applied to the roots. In addition, these compounds are able to reduce the attack on the plant using antivitiligo and repellent effects. Compounds of the invention are particularly useful

for the protection of field, forage, plantation, greenhouses, orchards and vineyard or ornamental crops and of plantation and forest trees, for example cereals (such as maize, wheat, rice, sorghum), cotton, tobacco, vegetables and salads (such as beans, brassicas, curcurbits, lettuce, onions, tomatoes and peppers), field crops (such as potatoes, sugar beets, peanuts, soybeans, oilseeds cabbage), sugar cane, grassland and forage crops (such as maize, sorghum, Lucerne sowing), plantations (such as tea, coffee, cocoa, bananas, spices), orchards and groves (such as fruits and one-seeded fruit, citrus, kiwifruit, avocado, mango, olives and nuts), vineyards, ornamental plants, flowers and custard the nursery.

Also they are useful for the protection of timber (standing, cut, converted, stored or building) from damage by sawflies (e.g., Urocerus) or beetles (e.g. scolytids, platypodids, lyctids, bostrychids, cerambycids, anobiids), or termites, for example, species Reticulitemnes, species Heterotermes, Coptotermes species.

They are applicable for the protection of stored products such as grains, fruits, nuts, spices and tobacco, regardless of, the whole whether they, ground or make up products from damage by moths, beetles and mites. Protected from damage by moths and beetles are also animal products, such as skin, hair, wool and feather in natural or transformed (e.g., carpets or fabric); in addition, stored meat and fish from damage by beetles, mites and flies.

Compounds of the invention are useful in the fight against Arthropoda, worms or protozoa which are harmful or spread or act as vectors of diseases of man and domestic animals, for example, mentioned earlier, and in particular, when dealing with ticks, lice, fleas, gallicae and biting, nudeanime and myiasis flies. Compounds of the invention are useful in the fight against Arthropoda, worms or protozoa that are found in domestic animal which, parenterale, subcutaneously or topically.

Coccidiosis, a disease caused by infections with protozoan parasites of the genus Eimeria, is an important potential cause of economic losses in domestic animals and birds, especially those who grew up or are in intensive conditions. For example, can be affected cattle, sheep, pigs and rabbits, however, the disease is particularly significant for poultry, in particular chickens.

The disease in poultry is usually transmitted by birds share an infectious organism from droppings on contaminated litter or earth, or feeding, or drinking water. The disease is manifested by bleeding, accumulation of blood in the caecum, the appearance of blood in the litter, weakness and digestive disorders. This disease usually results in death of the animal, but the market value of poultry survivors of severe infections is significantly reduced as a result of this infection.

The introduction of small amounts of compounds of the invention preferably in combination with bird food effectively to prevent or greatly reduce cases of coccidiosis. These compounds are effective against both forms of the caecum (duration">

Compounds of the invention also have an inhibiting effect against the oocyst, significantly reducing the number and/or sporulation occurred oocysts.

Therefore, according to a further aspect of the invention, there is provided veterinary antiparasitics compositions comprising a compound of the invention in a mixture with a compatible ancillary medicinal substance, diluent or carrier. The composition is preferably suitable for local administration.

In addition, the invention provides a compound of the invention for use as antiparasitics; and a method of treatment of hearth parasitic infection, which includes the treatment of this lesion an effective amount of compounds of the invention. Preferably the hearth is the skin or fur of the animal, or plant, or seed, or the area surrounding the plant or seed.

In addition, the invention provides a method of neutralization or destruction of the parasite, including the introduction mentioned the parasite or its center of an effective amount of the compounds of formula (I) or its salt or composition, as described earlier.

It should be understood that reference to treatment includes prevention, as well as the region is/BR> Adult flies (Stomoxys calcitrans) gathered and put to sleep using CO21 I the acetone solution containing the test compound was injected directly into the chest flies. After that, the flies were carefully placed in a 50 ml test tube, covered with wet gauze to come to after CO2. Control experiments was the introduction of them in 1 I of acetone. Mortality was assessed 24 hours after a dose.

The invention is illustrated by the following examples, in which the melting point were determined using the apparatus for Gallenkamp melting and inaccurate; NMR data were obtained using a Bruker AC300 or AM300; mass spectrometric data were obtained on Finnigan Mat. TSQ 7000 Fisons Instruments Trio 1000 - calculated and observed the above ions are related to the isotopic composition of the lowest mass.

Examples

Example A1 (illustrative)

5-Amino-3-cyano-1-(2,6-dichloro-4-triptoreline)-4-iterator

To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-triptoreline) pyrazole (5.0 g, compound of Reference Example 1 of EP 295,117 A1) in acetonitrile (60 ml) under stirring at room temperature in portions over 5 minutes was added N-jodatime (3,52 g). Stirring is continued at t the foreign Ministry. It can be used without further purification or, if desired, clear distribution between methylene chloride and water, separated, dried (MgSO4) and the organic layer was evaporated, receiving a yellow solid residue. When grinding with hexane target compound obtained as white crystals, So pl. 213oC (decomp.).

Example A2

5-Amino-3-cyano-1-(2,6-dichloro-4-triptoreline)-4 - trimethylsilylethynyl

To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-triptoreline)-4 iterate (6.96 g, crude product from Example 1) in triethylamine (30 ml) and dimethylformamide (6 ml) under stirring at room temperature was added trimethylsilylacetamide (3 ml), copper iodide (150 g) and bis (triphenylphosphine) palladium (II) chloride (300 mg). The mixture was heated at 50 - 60oC for one hour, then added trimethylsilylacetamide (0.3 ml) and continued stirring and heating for 30 minutes. The cooled reaction mixture was diluted with water (250 ml) and was extracted with ether (250 ml). The organic layer was separated (by addition of brine). The aqueous layer was re-extracted with ether (250 ml). The combined organic extracts were dried (MgSO4) and was evaporated, obtaining the crude product in the form of resin (4,67 g), when the eyes by recrystallization from a mixture of ether/hexane target product was obtained in the form of white crystals with So pl. 181-2oC.

PMR (CDCl3) : 0.2 (s, 9H), 4.1 (user. s, 2H), 7.7 (s, 2H)

MS (thermocapillary): M/Z [M+NH4] 434.2; C16H13Cl2F3N4Si + NH4is 434.0

Example A3

5-Amino-3-cyano-1-(2,6-dichloro-4-triptoreline)-4-ethynylpyrene

To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-triptoreline)-4 trimethylsilylimidazole (2.0 g, crude product from Example A2) in methanol (30 ml) under stirring was added potassium carbonate (1 g). After 10 minutes at room temperature, the reaction mixture was distributed between ether (100 ml) and water (100 ml). The organic layer was separated, washed with brine (100 ml), dried (MgSO4) and was evaporated. When cleaning the residue column chromatography on silica gel with elution methylene chloride:hexane followed by recrystallization from ether, the desired product was obtained as white crystals with So pl. 215-216oC.

PMR (CDCl3) : 3.49 (C. 1H), 4.2 (user. s, 2H), 7.8 (C. 2H)

MS (thermocapillary): M/Z [M+ NH4] 362.4; C13H5Cl2F3N4+ NH4is 362.0.

Example A4

5-Amino-3-cyano-1-(2,6-dichloro-4-triptoreline)-4-(prop-1-inyl) pyrazole

To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-triptoreline)-4 - the clave stainless steel under stirring was added copper iodide (60 mg) and bis (triphenylphosphine) palladium (II) chloride (120 mg). The reaction vessel was cooled to - 70oC and skondensiroval it propyne (2 g). The vessel was tightly closed and heated at 79oC for 18 hours and then left at room temperature for two days. The reaction mixture was distributed between ether and water. The organic layer was separated, washed with brine, dried (MgSO4) and was evaporated. When cleaning the residue column chromatography on silica gel with elution methylene chloride:hexane (1: 1) target product was obtained in the form of white crystals with So pl. 226 - 8oC.

PMR (CDCl3) : 2.2 (s, 3H), 4.19 (user. s, 2H), 7,78 (s, 2H)

MS (thermocapillary): M/Z [M+H] 358.9; C14H7Cl2F3N4+ H is 359.0

Example A5

5-Amino-3-cyano-1-(2,6-dichloro-4-triptoreline)-4-(3-methylbutyl-1 - inyl)pyrazole

To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-triptoreline)-4 - iterate (447 mg, of the compound from Example A1) in triethylamine (10 ml) under stirring at room temperature was added 3-methylbut-1-Jn (0.5 ml), copper iodide (15 mg) and bis(triphenylphosphine)palladium (II) chloride (30 mg). The reaction mixture was heated at 70oC for two hours. Reactio the (MgSO4) and was evaporated. When cleaning the residue column chromatography on silica gel with elution methylene chloride:hexane (1: 1) target product was obtained as pale-yellow crystals with So pl. 210-2oC.

PMR (CDCl3) : 1.3 (d, 6H), 2.83 (d, 1H), 4,0 (user. s, 2H), 7.78 (s, 2H).

MS (thermocapillary): M/Z [M+H] 387.0; C16H11Cl3F3N4+ H is 387.

Example A6

5-Amino-3-cyano-1-(2,6-dichloro-4-triptoreline)-4-(3-hydroxyprop - 1-inyl)pyrazole

To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-triptoreline)-4 - iterate (200 mg, of the compound from Example A1) in triethylamine (2 ml) and dimethylformamide (1 ml) under stirring at room temperature was added propargilovyh alcohol (0.2 ml), copper iodide (10 mg) and bis(triphenylphosphine) palladium (II) chloride (20 mg). The reaction mixture was heated at 70oC for two hours. The reaction mixture is divided between ether (10 ml) and water (10 ml). The organic layer was separated, washed with brine, dried (MgSO4) and was evaporated. When cleaning the residue column chromatography on silica gel with elution with ether: methylene chloride (10:1) target product was obtained as pale-yellow crystals with So pl. 237 - 9oC.

PMR (d6-DMSO) : 4.32 (WHO/SUB>N4O + NH4is 392.0.

Example A7

5-Amino-3-cyano-1-(2,6-dichloro-4-triptoreline)-4- (4-hydroxyben-1-inyl)pyrazole

To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-triptoreline)-4 - iterate (447 mg, of the compound from Example A1) in triethylamine (20 ml) and dimethylformamide (2 ml) under stirring at room temperature was added 3-buten-1-ol (0.5 ml), copper iodide (15 mg) and bis(triphenylphosphine)palladium (II) chloride (30 mg). The reaction mixture was heated at 70oC for two hours. The reaction mixture was distributed between ether (10 ml) and water (10 ml). The organic layer was separated, washed with brine, dried (MgSO4) and was evaporated. When cleaning the residue column chromatography on silica gel with elution with ether, the desired product was obtained as light brown crystals with So pl. 215-6oC.

PMR (CDCl3) : 2.72 (t, 2H), 3.49 (m, 1H), 3.87 (m, 2H), 4.1 (user. s, 1H), 7.8 (s, 2H)

MS (thermocapillary): M/Z [M+ NH4] 406.4; C15H9Cl2F3N4O + NH4is 406.0

Example A8

5-Amino-3-cyano-1-(2,6-dichloro-4-triptoreline)-4 - methoxycarbonylaminophenyl

To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-triptoreline)-4- (3-hydroxyprop-1-inyl)pyrazole (250 mg, the connection of the temperature for two hours. Then added methanol (2 ml) and potassium cyanide (250 mg) and continued stirring for 15 minutes. The reaction mixture was filtered and evaporated to dryness. The residue was purified by chromatography on silica gel with elution methylene chloride. When combined and evaporation of appropriate fractions of the target compound was obtained as light brown crystals with So pl. 201 - 2oC.

PMR (CDCl3) : 3.82 (s, 3H), 4.6 (user. s, 2H), 7.81 (s, 2H)

MS (thermocapillary): M/Z [M+ NH4] 420.5; C15H7Cl2F3N4O2+ NH4is 420.0

Example A9

5-Amino-3-cyano-1-(2,6-dichloro-4-triptoreline)-4-phenylethyl)pyrazole

To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-triptoreline)-4 - iterate (250 mg, of the compound from Example A1) in dimethylformamide (2 ml) under stirring at room temperature was added 2-phenylethynyl-n - botillo (0.6 ml) and tetrakis (triphenylphosphine) palladium (0) (30 mg). The reaction mixture was heated at 75oC for two hours and then left overnight at room temperature. The reaction mixture was distributed between ether and water. The organic layer was separated, washed with brine, dried (MgSO4) and was evaporated. When cleaning the remainder of the column chromatography is spruce product was obtained as a pale yellow crystals with So pl. 265 - 267oC;

PMR (CDCl3) : 4.21 (user. s, 2H), 7.38 (m, 3H), 7,54 (m, 2H), 7.8 (s, 2H).

MS (thermocapillary): M/Z [M+H] 420.8; C19H9Cl2F3N4+ H is 421.0

Example A10

5-Amino-3-cyano-1-(2,6-dichloro-4-triptoreline)-4- (Tien-2-ylethynyl)pyrazole

To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-triptoreline)-4 - ethynylpyridine (200 mg, of the compound from Example A3) in triethylamine (4 ml) and dimethylformamide (1 ml) under stirring at room temperature was added 2-idioten (0.5 ml), copper iodide (15 mg) and bis (triphenylphosphine) palladium (II) chloride (30 mg). The reaction mixture was heated at 60oC for one hour. The reaction mixture was distributed between ether (100 ml) and water (100 ml). The organic layer was separated, washed with brine, dried (MgSO4) and was evaporated. When cleaning the residue column chromatography on silica gel with elution with hexane: methylene chloride (1: 1) target product was obtained as light brown crystals with So pl. 262oC decomp.

PMR (CDCl3) : 4.23 (user. s, 1H), 7.05 (m, 1H), 7.45 (m, 2H), 7.8 (s, 2H)

MS (thermocapillary): M/Z [M+H] 426.6; C17H7Cl2F3N4S + H is 427.0

Example A11

5-Amino-3-cyano-1-(2,6-dichlo the Nile)-4 - iterate (200 mg, the compound from Example A1) in triethylamine (2 ml) and dimethylformamide (1 ml) under stirring at room temperature was added methylpropyloxy ether (0.5 ml), copper iodide (15 mg) and bis (triphenylphosphine) palladium (II) chloride (30 mg). The reaction mixture was heated at 70oC for two hours. The reaction mixture was distributed between ether (50 ml) and aqueous citric acid solution (50 ml, 20 %). The organic layer was separated, washed with water, dried (MgSO4) and was evaporated. When cleaning the residue column chromatography on silica gel with elution chloride methylene target product was obtained as pale-yellow crystals with So pl. 210oC decomp.

PMR (CDCl3) : 3.48 (s, 3H), 4.2V (user. s, 2H), 4.89 (s, 2H), 7.8 (s, 2H)

MS (thermocapillary): M/Z [M+ NH4] 406.0; C15H9Cl2F3N4O + NH4is 406.0

Example A12

5-Amino-1-(2,6-dichloro-4-triptoreline)-3-etoxycarbonyl-4 - ethynylpyrene

To a solution of potassium hydroxide (0.25 g) in ethanol (3 ml) was added 5-amino - 3-cyano-1-(2,6-dichloro-4-triptoreline)-4-trimethylsilylethynyl (0.21 g). After incubation at 30oC for 30 minutes, the reaction mixture was poured into a mixture of water (10 ml) and ice (10 g). Added ether (30 l). The organic layer of Ariel. The residue was purified column chromatography on silica gel (4 g) with elution methylene chloride. When combined and evaporation of appropriate fractions, followed by crystallization from a mixture of ether/hexane target compound was obtained as pale-orange crystals with So pl. 152 - 154oC.

PMR (CDCl3) : 1.42 (t, 3H), 3.49 (s, 1H), 4.11 (user. s, 2H), 4.43 (q, 2H), 7.78 (s, 2H)

MS (thermocapillary): M/Z [M] 391.3; C15H10Cl2F3N3O2is 391.01

Example A13

5-Amino-1-(2,6-dichloro-4-triptoreline)-4-ethinyl-3-methoxycarbonylbenzyl

To a suspension of potassium carbonate (0.03 g) in methanol (2 ml) was added 5-amino - 3-cyano-1-(2,6-dichloro-4-triptoreline)-4-trimethylsilylethynyl (0.03 g). After incubation at 25oC for 40 hours, the reaction mixture was poured into water (10 ml) and was extracted with ether (20 ml x 2). The combined organic layers were dried (MgSO4) and was evaporated. The target compound was obtained by purification of the residue by recrystallization from a mixture of ether/hexane.

PMR (CDCl3) : 3.51 (s, 1H), 3.97 (s, 3H), 4.13 (user. s, 2H), 7.78 (s, 2H)

MS (thermocapillary): M/Z [M] 377.0; C14H8Cl2F3N3O2is 376.99

Example B1 (illustrated)
4-triptoreline)-4 - iterate (447 mg, the compound from Example A1) in pyridine (5 ml) under stirring was added dropwise acetyl chloride (0.5 ml). The reaction mixture was stirred at room temperature for two days, and then was heated for 4 hours at 50oC. the Reaction mixture was distributed between ether (50 ml) and water (50 ml), the organic layer was separated, dried (MgSO4) and was evaporated. The crude product was purified column chromatography on silica gel (40 g) with elution with a mixture of ether: hexane (10:1), obtaining the target compound as white crystals.

MS (thermocapillary): M/Z [M+ NH4] 505.4; C13H6Cl2F3lN4O + NH4is 505.9

Example B2

5-Acetamido-3-cyano-1-(2,6-dichloro-4-triptoreline)-4 - trimethylsilylethynyl

To a solution of 5-acetamido-3-cyano-1-(2,6-dichloro-4-triptoreline)-4 - iterate (80 mg, of the compound from Example B1) in triethylamine (5 ml) under stirring was added trimethylsilylacetamide (0.1 ml), copper iodide (4 mg) and bis (triphenylphosphine) palladium (II) chloride (8 mg). The reaction mixture was heated at 60oC for 1 hour and then poured into water (20 ml) and ether (20 ml). The organic layer was separated, dried (MgSO4) and was evaporated. The crude product was purified column chromatography on what s.

MS (thermocapillary): M/Z [M+NH4] 475.7; C18H15Cl2F3N4OSi + NH4is 476.1

Example B3

5-Acetamido-3-cyano-1-(2,6-dichloro-4-triptoreline)-4-ethynylpyrene

To a solution of 5-acetamido-3-cyano-1-(2,6-dichloro-4-triptoreline)-4 - trimethylsilylimidazole (20 mg, of the compound from Example B2) in methanol (1 ml) was added potassium carbonate (20 mg). The reaction mixture was stirred at room temperature for 40 minutes and then poured into water (20 ml) and ether (20 ml). The organic layer was separated, dried (MgSO4) and was evaporated. The crude product was purified column chromatography on silica gel with elution with ether, obtaining the target compound as white crystals.

PMR (CDCl3) : 2.1 (s, 3H), 3.51 (s, 1H), 7.78 (s, 2H)

MS (thermocapillary): M/Z [M+ NH4] 403.9; C15H7Cl2F3N4O + NH4is 404.0

Example B4

3-Cyano-5-di-(tert-butoxycarbonyl)amino-1-(2,6-dichloro-4-triptoreline)- 4-ethynylpyrene

To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-triptoreline)-4 - ethynylpyridine (1.3 g of the compound from Example A3) in dimethylformamide (4 ml) and triethylamine (20 ml) was added di-tert-BUTYLCARBAMATE (0.9 g) and 4-dimethylaminopyridine (5 mg). And re the .45 g) and continued stirring for two hours. After the reaction mixture was poured into ether (200 ml) and aqueous citric acid solution (200 ml, 20 %). The organic layer was separated, dried (MgSO4) and was evaporated. The crude product was purified column chromatography on silica gel with elution with a mixture of methylene chloride:hexane (1:1), obtaining the target compound in the form of pale yellow crystals with So pl. 227 - 8oC.

PMR (CDCl3) : 1.41 (s, 18H), 3.48 (s, 1H), 7.75 (s, 2H)

Elemental analysis - found: C, 50.66, H 3.88, N, 10.27 %;

for C23H21Cl2F3N4O4C, AT 50.34, H 3.80, N, 10.04 %.

Example B5

3-Cyano-5-di-(tert-butoxycarbonyl)-amino-1-(2,6-dichloro-4 - triptoreline)-4-promaterial

To a solution of 3-cyano-5-di-(tert-butoxycarbonyl)amino-1- (2,6-dichloro-4-triptoreline)-4-ethynylpyridine (100 mg, of the compound from Example B4) in acetone (10 ml) was added silver nitrate (5 mg) and N - bromosuccinimide (80 mg). The reaction mixture was stirred at room temperature for one hour and then poured into ether (100 ml) and water (100 ml). The organic layer was separated, dried (MgSO4) and was evaporated. The crude product was purified column chromatography on silica gel with elution methylene chloride, obtaining the target compound as pale-yellow is Na] 645.0; C23H20BrCl2F3N4O4+ Na is 645.0

Example B6

5-Tert-butoxycarbonylamino-3-cyano-1-(2,6-dichloro-4-triptoreline)- 4-promaterial

To a solution of 3-cyano-5-di-(tert-butoxycarbonyl)amino-1-(2,6-dichloro-4 - triptoreline)-4-promaterial (200 mg, of the compound from Example B5) in anhydrous methylene chloride (2 ml) was added dropwise triperoxonane acid (0.2 ml). After 30 minutes the reaction mixture was treated with ether (10 ml) and saturated aqueous sodium hydrogen carbonate (10 ml). The organic layer was separated, dried (MgSO4) and was evaporated, obtaining the target compound in the form of white crystals with So pl. 168 - 70oC.

PMR (CDCl3) : 1.38 (s, 9H), 6.23 (s, 1H), 7.75 (s, 2H)

MS (thermocapillary): M/Z [M+ NH4] 539.6; C18H12BrCl2F3N4O4+ NH4is 540.0

Example B7 (illustrative)

5-Cyano-1-(2,6-dichloro-4-triptoreline)-4-iodine-5-(N-pyrrolyl)pyrazole

A mixture of 5-amino-3-cyano-1-(2,6-dichloro-4-triptoreline)-4-iterate (0.5 g) and 2,5-dimethoxytetrahydrofuran (1 ml) in acetic acid (5 ml) was boiled for 1 hour. The reaction mixture was poured into diethyl ether (100 ml) and water (100 ml). The organic layer was washed with saturated aqueous who Evoe connection.

PMR (CDCl3) : 6.38 (s, 2H), 6.7 (s, 2H), 7.7 (s, 2H)

MS (thermocapillary): M/Z [M+ NH4] 513.6; C15H6Cl2F3lN4+ NH4is 513.9

Example B8

3-Cyano-1-(2,6-dichloro-4-triptoreline)-5-(N-pyrrolyl)- 4-trimethylsilylethynyl

To a solution of 3-cyano-1-(2,6-dichloro-4-triptoreline)-4-iodine - 5-(N-pyrrolyl) pyrazole (0.55 g) in triethylamine (1 ml) and dimethylformamide (10 ml) under stirring was added trimethylsilylacetamide (1 ml), copper iodide (15 mg) and bis (triphenylphosphine) palladium (II) chloride (30 mg). The reaction mixture was heated at 70oC for 24 hours, then poured into water (100 ml) and diethyl ether (100 ml). The organic layer was dried over MgSO4and evaporated the solvent. The crude product was purified by chromatography on silica gel (50 g) with elution with a mixture of methylene chloride:hexane 1:1, obtaining the target compound as pale brown crystals.

Example B9

3-Cyano-1-(2,6-dichloro-4-triptoreline)-4-ethinyl-5-(N-pyrrolyl) pyrazole

To a solution of 3-cyano-1-(2,6-dichloro-4-triptoreline)-5-(N-pyrrolyl - 4-trimethylsilylimidazole (0.045 g) in methylene chloride (5 ml) was added dropwise within 5 minutes of Tetra-n-butylammonium fluoride (0.1 ml, 1M in tetrahydrofuran). The reactions is) when the elution methylene chloride. The target compound was obtained as pale-brown crystals, So pl. 161 - 3oC.

PMR (CDCl3) : 3.44 (s, 1H), 6.3 (m, 1H), 6.77 (m, 2H), 7.74 (s, 2H)

MS (thermocapillary): M/Z [M+H] 394.9; C17H7Cl2F3N4+ H is 395.0

Example B10

3-Cyano-1-(2,6-dichloro-4-triptoreline)-5-dimethylamino-4-ethynylpyrene

To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-triptoreline)-4 - trimethylsilylimidazole (0.417 g) in tetrahydrofuran (20 ml) under stirring portions added within 5 minutes sodium hydride (0.1 g, 60% dispersion in oil). Dropwise over 2 minutes added methyl iodide (0.156 ml). After 5 minutes was added sodium hydride (0.05 g) and methyl iodide (0.050 ml) and continued stirring for another 5 minutes. The reaction mixture was poured into water/diethyl ether. The organic layer was dried over MgSO4and evaporated, obtaining the target compound as pale brown crystals.

PMR (CDCl3) : 2.83 (s, 6H), 3.42 (s, 1H), 7.78 (s, 2H)

MS (thermocapillary): M/Z [M+H] 373.2; C15H9Cl2F3N4+ H is 373.02

Example C1

5-Bromo-3-cyano-1-(2,6-dichloro-4-triptoreline)-4-trimethylsilylethynyl

To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-crypto(0.5 ml) under stirring was added dropwise n-butyl nitrite (0.025 ml) for 5 minutes. The mixture was heated at 70oC for 30 minutes, then cooled and evaporated. The residue was purified column chromatography on silica gel (40 g) with elution methylene chloride:hexane (1:4), obtaining the target compound in the form of white crystals with So pl. 130oC (decomp).

PMR (CDCl3) : 0.2 (s, 9H), 7.78 (s, 2H)

MS (thermocapillary): M/Z [M+ NH4] 497.0, C16H11BrCl2F3N3Si + NH4is 497.0

Example C2

5-Bromo-3-cyano-1-(2,6-dichloro-4-triptoreline)-4-ethynylpyrene

To a solution of 5-bromo-3-cyano-1-(2,6-dichloro-4-triptoreline)-4 - trimethylsilylimidazole (43 mg, the compound of Example C1) in methylene chloride (1 ml) under stirring was added dropwise within 5 minutes of Tetra - n-butylammonium fluoride (0.098 ml). Stirring was continued at room temperature for 30 minutes. Then the reaction mixture was poured into methylene chloride (10 ml) and water (10 ml). The organic layer was separated, dried (MgSO4) and was evaporated. The residue was purified column chromatography on silica gel (10 g) with elution with a mixture of methylene chloride:hexane (1: 2), obtaining the target compound in the form of pale yellow crystals with So pl. 134-5oC.

PMR (CDCl3) : 3.55 (s, 1H), 7.8 (s, 2H)

Example C3

5-Bromo-1-(2,6-dichloro-4-triptoreline)-4-ethinyl-3-methoxycarbonylbenzyl

To a solution of 5-bromo-3-cyano-1-(2,6-dichloro-4-triptoreline)-4 - trimethylsilylimidazole (100 mg, of the compound from Example C1) in methanol (1 ml) under stirring was added potassium carbonate (2.9 mg). Stirring was continued at room temperature for 2 hours and then added potassium carbonate (3.0 mg). Stirring was continued for another 4 hours. Then the reaction mixture was poured into ether (10 ml) and water (10 ml). The organic layer was separated, dried (MgSO4) and was evaporated, obtaining the target compound in the form of white crystals with So pl. 198oC

PMR (CDCl3) : 3.6 (s, 1H), 4.09 (s, 3H), 7.79 (s, 2H)

MS (thermocapillary): M/Z [M +H] 441.0; C14H6BrCl2F2N2O2+ H is 440.9

Example C4

3-Cyano-1-(2,6-dichloro-4-triptoreline)-4-trimethylsilylethynyl

To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-triptoreline)-4 - trimethylsilylimidazole (30 mg, of the compound from Example C1) in tetrahydrofuran (10 ml) under stirring was added dropwise n-butyl nitrite (0.025 ml) for 5 minutes. The mixture was boiled for 30 minutes, then cooled and evaporated. The residue was purified column of chromatography the form of white crystals with So pl. 128-9oC.

PMR (CDCl3) : 0.3 (s, 9H), 7.72 (s, 2H); 7.78 (s, 2H)

MS (thermocapillary): M/Z [M+ NH4] 419.0; C16H12Cl2F3N3Si + NH4is 419.0

Example C5

3-Cyano-1-(2,6-dichloro-4-triptoreline)-4-ethynylpyrene

To a solution of 3-cyano-1-(2,6-dichloro-4-triptoreline)- 4-trimethylsilylimidazole (201 mg, the compound of Example C4) in methylene chloride (5 ml) under stirring was added dropwise within 5 minutes of Tetra-n-butylammonium fluoride (0.55 ml). Stirring was continued at room temperature for 30 minutes. Then the reaction mixture was poured into methylene chloride (10 ml) and water (10 ml). The organic layer was separated, dried (MgSO4) and was evaporated. The residue was purified column chromatography on silica gel with elution with a mixture of methylene chloride:hexane (1:4), obtaining the target compound in the form of pale yellow crystals with So pl. 130-2oC.

PMR (CDCl3) : 3.4 (s, 1H), 7.79 (s, 1H + 2H)

MS (thermocapillary): M/Z [M+ NH4] 347.0; C13H4Cl2F3N3+ NH4is 347.0

Example C6

5-Bromoethyl-3-cyano-1-(2,6-dichloro-4-triptorelin)-pyrazole

To a solution of 3-cyano-1-(2,6-dichloro-4-triptoreline)-4 - ethynylpyridine (RA (5 mg). Stirring was continued at room temperature for 60 minutes. Then the reaction mixture was poured into ether (10 ml) and water (10 ml). The organic layer was separated, dried (MgSO4) and was evaporated. The residue was purified column chromatography on silica gel with elution with a mixture of methylene chloride:hexane (2:1), obtaining the target compound in the form of white crystals with So pl. 166-8oC.

PMR (CDCl3) : 7.78 (s, 1 H), 7.79 (s, 2H)

MS (thermocapillary): M/Z [M+ NH4] 425.0; C13H3BrCl2F3N3+ NH4is 424.9

Example C7

4-Chlorethyl-3-cyano-1-(2,6-dichloro-4-triptoreline)-pyrazole

To a solution of 3-cyano-1-(2,6-dichloro-4-triptoreline)-4 - ethynylpyridine (2 g) in acetonitrile (50 ml) under stirring was added N - chlorosuccinimide (4 g) and boiled the mixture was heated at the boiling point under reflux for 1 hour, then left it overnight at room temperature. Added N-chlorosuccinimide (1.2 g) and the mixture is boiled under reflux for 2 hours. Added N-chlorosuccinimide (4 g) and the mixture was heated at the boiling point under reflux for 4 hours. Has the reaction mixture is evaporated in vacuum and chromatographically the residue on silica gel with elution with a mixture hlgt was purified further HPLC on a column (21 x 250 mm DynamaxTM0.005 mm ODS reversed-phase, while elution with a mixture of acetonitrile: 0.005 M aqueous heptanesulfonic acid:methanol (5:4:1) at a rate of 10 ml/minute. When combining the appropriate fractions and evaporation of their non-aqueous components, with subsequent distribution between diethyl ether and saturated aqueous sodium bicarbonate, drying of the organic layer and evaporation of the solvent, the target compound was obtained as white crystals with So pl. 132-4oC.

PMR (CDCl3) : 7.75 (s, 1H), 7.78 (s, 2H)

MS (thermocapillary): M/Z [M+ NH4] 380.9; C13H3Cl3F3N3+ NH4is 380.97

Example C8

3-Cyano-1-(2,6-dichloro-4-triptoreline)-4-ethinyl-5-methylthiophenol

To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-triptoreline)-4 - trimethylsilylimidazole (0.46 g) in acetonitrile (20 ml) under stirring was added dimethyl disulfide (0.108 ml) and heated the mixture up to 50oC. was Added n-butyl nitrite (0.401 ml) and heated the reaction mixture to 70oC for 30 minutes. After cooling to room temperature, was added Tetra-n - butylammonium fluoride (1.2 ml, 1M in hexane). After 10 minutes the reaction mixture was poured into diethyl ether (50 ml) and water (50 ml). The organic layer wysu the Institute with a mixture of methylene chloride:hexane (2:1). When combined and evaporation of appropriate fractions were obtained crystals were washed with hexane. The hexane washings were evaporated and the residue then was chromatographically on silica gel (20 g) with elution with a mixture of diethyl ether:hexane (1:10). When combined and evaporation of appropriate fractions were obtained white crystals with So pl. 85 - 6oC

PMR (CDCl3) : 2.56 (s, 3H), 3.51 (s, 1H); 7.79 (s, 2H)

MS (thermocapillary): M/Z [M+H] 376; C14H6Cl2F3N3S + H is 375.97

Example D1

5-Amino-3-cyano-1-(2,6-dichloro-4-trifloromethyl)-4-iterator

To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifloromethyl)pyrazole (4.1716 g) in acetonitrile (20 ml) under stirring at room temperature was added N-jodatime (2.79 g). After 15 minutes the mixture was evaporated to a dry residue and dissolved the remaining orange solid residue in methylene chloride. This solution was washed with water, then brine, dried (Na2SO4) and was evaporated, obtaining the target compound as pale orange crystals with So pl. 149.5-150.0oC.

PMR (CDCl3) : 3.95 (user. s, 2H), 7.41 (s, 2H)

MS (thermocapillary): M/Z [M+H] 463.1; C11H4Cl2F3IN4O + H is 462.88

Example D2

5-Aminomar-4-trifloromethyl)-4 - iterate (5.489 g) in dimethylformamide (4 ml) under stirring at room temperature was added trimethylsilylacetamide (3.35 ml), iodide copper (0.116 g), bis(triphenylphosphine) palladium (II) chloride (0.228 g) and triethylamine (1 ml). The mixture was heated at 60oC for 2.5 hours. Then added trimethylsilylacetamide (1.675 ml), copper iodide (0.058 g) and bis(triphenylphosphine)palladium (II) chloride (0.114 g) and continued stirring and heating for one hour. The cooled reaction mixture was diluted with water and was extracted with ether. The ether extract was dried (MgSO4) and was evaporated, obtaining the crude product, which was purified column chromatography on silica gel with elution with a mixture of methylene chloride/hexane. When combined and evaporation of appropriate fractions followed by recrystallization their residue from a mixture of methylene chloride/hexane there was obtained the compound in the form of light yellow crystals with So pl. 151.5-152.1oC.

PMR (CDCl3) : 0.26 (s, 9H), 4.15 (user. s, 2H); 7.42 (s, 2H)

MS (thermocapillary): M/Z [M+H] 433.7; C16H13Cl2F3N4OSi + H is 433.03

Example D3

5-Amino-3-cyano-1-(2,6-dichloro-4-trifloromethyl)-4-ethynylpyrene

To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifloromethyl)-4 - trimethylsilylimidazole (0.4657 g) in methylene chloride (5 ml) under stirring and cooling in an ice-water bath menuju bath was removed. Within ten minutes of continued stirring, then the reaction mixture was washed with water. The aqueous layer was washed methylene chloride. The combined organic layers were washed with salt solution, dried (Na2SO4) and was evaporated, obtaining the target compound in the form of oily crystals, which were secretarypantyhose at drying in the oven in white crystals with So pl. 175.7-176.1oC.

PMR (CDCl3) : 3.48 (s, 1H), 4.2 (user. s, 2H), 7.42 (s, 2H)

MS (thermocapillary): M/Z [M+ NH4] 377.9; C13H5Cl2F3N4O + NH4is 378.01

Example D4

3-Cyano-1-(2,6-dichloro-4-trifloromethyl)-4-trimethylsilylethynyl

To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifloromethyl)-4 - trimethylsilylimidazole (4.0 g) in tetrahydrofuran (50 ml) under stirring was added dropwise n-butyl nitrite (3.29 ml). The mixture was boiled under reflux for 3 hours and then evaporated to dryness. The residue was purified column chromatography on silica gel with elution methylene chloride: hexane (3: 1). When combined and evaporation of appropriate fractions followed by recrystallization them of the residue from hexane got the target compound as white crystal is] 418.1; C16H12Cl2F3N3OSi + H is 418.02

Example D5

3-Cyano-1-(2,6-dichloro-4-trifloromethyl)-4-ethynylpyrene

To a solution of 3-cyano-1-(2,6-dichloro-4-trifloromethyl)-4 - trimethylsilylimidazole (2.691 g) in methylene chloride (25 ml) under stirring was added Tetra-n-butylammonium fluoride (6.45 ml of 1M solution in tetrahydrofuran). Stirring was continued for 30 minutes, then the reaction mixture is distributed between water and methylene chloride. The aqueous layer was separated and was twice extracted with methylene chloride. The combined organic layers were washed with salt solution, dried (Na2SO4) and was evaporated. The residue was purified column chromatography on silica gel with elution methylene chloride:hexane (1:1). When combined and evaporation of appropriate fractions were obtained target compound in the form of white crystals with So pl. 95.2 - 96.0oC.

PMR (CDCl3) : 3.39 (s, 1H), 7.40 (s, 2H), 7.77 (s, 1H)

MS (thermocapillary): M/Z [M+ NH4] 363.1; C13H4Cl2F3N3O + NH4is 363.0

Example D6

4-Bromanil-3-cyano-1-(2,6-dichloro-4-trifloromethyl)-pyrazole

To a solution of 3-cyano-1-(2,6-dichloro-4-trifloromethyl)-4-ethynylpyridine (0.5 continued for one hour, then the reaction mixture was evaporated to dryness. The residue is distributed between ether and water. The aqueous layer was separated and was extracted with ether. The combined organic layers were washed with brine, dried (Na2SO4) and was evaporated. The residue was purified column chromatography on silica gel with elution methylene chloride:hexane (1:1). When combined and evaporation of appropriate fractions followed by recrystallization from hexane there was obtained target compound in the form of white crystals with So pl. 123.0-123.8oC.

PMR (CDCl3) : 7.40 (s, 2H), 7.72 (s, 1H)

MS (thermocapillary): M/Z [M+ NH4] 440.9; C13H3BrCl2F3N3O + NH4is 440.91

Example D7 (illustrative)

5-Amino-3-cyano-1-(2,6-dichloro-4-triftormetilfullerenov)-4-iterator

To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-triftormetilfullerenov) pyrazole (10 g) in acetonitrile (50 ml) under stirring at room temperature was added N-jodatime (6.4 g) in acetonitrile (25 ml). After 15 minutes the mixture was evaporated to a dry residue and dissolved the remaining yellow-brown solid residue in methylene chloride (300 ml). This solution was washed with water (75 ml, 3), then brine (50 ml), then dried (MgSO4and upari So pl. 172-174oC.

PMR (CDCl3) : 3.96 (user. s, 2H), 7.81 (s, 2H)

Example D8

5-Amino-3-cyano-1-(2,6-dichloro-4-triftormetilfullerenov)-4 trimethylsilylethynyl

To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-triftormetilfullerenov)-4 - iterate (10 g) in dimethylformamide (45 ml) with stirring at room temperature was added triethylamine (34 ml), trimethylsilylacetamide (6 ml), copper iodide (0.4 g) and bis (triphenylphosphine) palladium (II) chloride (0.4 g). The mixture was heated at 75oC for 6 hours. The cooled reaction mixture was evaporated to dryness and distributed the balance between water and methylene chloride. The organic layer was separated and washed with water and then with saline solution and then dried (Na2SO4) and was evaporated, obtaining the crude product, which was purified column chromatography on silica gel (400 g) with elution methylene chloride. When combined and evaporation of appropriate fractions were obtained oily residue, which was purified column chromatography on silica gel (400 g) with elution with a mixture of methylene chloride/hexane. When combined and evaporation of appropriate fractions followed by recrystallization from a mixture of methylene chloride/hexane there was obtained the target compounds is; .8 (s, 2H)

MS (thermocapillary): M/Z [M+H] 448.9; C16H13Cl2F3N4SSi + H is 449.0

Example D9

Cyano-1-(2,6-dichloro-4-triftormetilfullerenov)-4 - trimethylsilylethynyl

To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-triftormetilfullerenov)- 4-trimethylsilylimidazole (3.0 g) in tetrahydrofuran (18 ml) at boiling under reflux was added with stirring dropwise a solution of n-butyl nitrite (2.4 ml) in tetrahydrofuran (7 ml). Upon completion of addition, the mixture was boiled under reflux for 1 hour, and then left to cool to room temperature. After standing at room temperature overnight the mixture was evaporated to dryness. The residue was purified column chromatography on silica gel (100 g) with elution methylene chloride. When combined and evaporation of appropriate fractions followed by recrystallization of the residue from hexane was obtained target compound in the form of pale yellow crystals with So pl. 129-133oC.

PMR (CDCl3) : 0.29 (s, 9H), 7.72 (s, 1H), 7.8 (s, 2H)

MS (thermocapillary): M/Z [M+H] 434.0; C16H12Cl2F3N3SSi + H is 433.99

Example D10

3-Cyano-1-(2,6-dichloro-4-triftormetilfullerenov) is ol (2.2 g) in methylene chloride (40 ml) under stirring at room temperature was added Tetra-n-butylammonium fluoride (6 ml of a 1M solution in tetrahydrofuran). Stirring was continued for 30 minutes, then the reaction mixture was concentrated to small volume and then distributed between methylene chloride (50 ml) and water (20 ml). The organic layer was separated and washed with water (20 ml), brine (10 ml), dried (Na2SO4) and was evaporated. The residue was purified column chromatography on silica gel (60 g) with elution methylene chloride. When combined and evaporation of appropriate fractions were obtained target compound as off-white glassy crystals with So pl. 118-119oC.

PMR (CDCl3) : 3.39 (s, 1H), 7.80 (s + s, 1H + 2H)

MS (thermocapillary): M/Z [M+ NH4] 379.0; C13H14Cl2F3N3O + NH4is 378.98

Example D11 (illustrative)

5-Amino-3-cyano-1-(2,6-dichloro-4-serpentfather)-4-iterator

To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-serpentfather) pyrazole (18.95 g) in acetonitrile (100 ml) under stirring at room temperature was added N-jodatime (11.5 g) in four portions over five minutes. After 15 minutes the mixture was evaporated to a dry residue and treated the remaining solid residue methylene chloride and water. Nerastvorimaya substance was filtered and dissolved in ethyl acetate. The solution is in So pl. 253oC.

PMR (CDCl3) : 3.94 (user. s, 2H), 7.92 (s, 2H)

MS (thermocapillary): M/Z [M+ NH4] 521.9; C10H4Cl2F5lN4S + NH4is 521.88

Example D12

5-Amino-3-cyano-1-(2,6-dichloro-4-serpentfather)-4-trimethylsilylethynyl

To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-serpentfather)-4 - iterate (5.05 g) in dimethylformamide (5 ml) under stirring at room temperature was added copper iodide (0.1 g), bis(triphenylphosphine)palladium (II) chloride (0.2 g), trimethylsilylacetamide (2.9 ml) and triethylamine (1 ml). The mixture was heated at 70oC for 5 hours. The cooled reaction mixture is left to stand overnight at room temperature and then poured into water. The precipitate was filtered and dissolved in methylene chloride (50 ml). After addition of hexane (100 ml) was separated oil. The pooled solution was evaporated, obtaining the crude product, which was purified column chromatography on silica gel (80 g) with elution with a mixture of methylene chloride:hexane (1:9 then 2:8). When combined and evaporation of appropriate fractions followed by recrystallization of the residue from a mixture of diisopropyl ether/hexane was obtained target compound as white microcrystalline Chris): M/Z [M+ NH4] 492.1; C15H13Cl2F5N4SSi + NH4is 492.02

Example D13

5-Amino-3-cyano-1-(2,6-dichloro-4-serpentfather)-4-ethynylpyrene

To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-serpentfather)- 4-trimethylsilylimidazole (0.4 g) in methylene chloride (5 ml) under stirring was added Tetra-n-butylammonium fluoride (1.5 ml of a 1M solution in tetrahydrofuran). After one hour was added Tetra-n-butylammonium fluoride (0.5 ml, 1M solution in tetrahydrofuran). After three hours the reaction mixture was evaporated to dryness. The residue was purified column chromatography on silica gel (6.6 g) with elution by the mixture hexane: ethyl acetate (9: 1, then 4:1, then 2:1) and then ethyl acetate. When combined and evaporation of appropriate fractions followed by recrystallization of the residue from a mixture of ethyl acetate/hexane there was obtained target compound as a yellow microcrystalline crystals with So pl. 251oC.

PMR (d6-DMSO) : 3.31 (s, 1 H), 6.88 (user. C, 2H), 8.47 (s, 2H)

MS (thermocapillary): M/Z [M+H] 403.0; C12H5Cl2F5N4S + H is 402.96

Example E1

5-Amino-3-cyano-1-(2,6-dichloro-4-triptoreline)-4-attemperator

To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-triptoreline) is ur added vinyltris-n-butyl tin (4.25 g) and tetrakis(phenylphosphine)palladium (O) (300 mg). The mixture was heated at 75oC 1 hour, and then cooled and left at room temperature for 60 hours. The reaction mixture was diluted with water and was extracted with ether. The organic layer was separated, washed with brine, dried (MgSO4) and was evaporated, obtaining the crude product as a black oil (6 g) which was purified column chromatography on silica gel (200 g) with elution with a mixture of methylene chloride:hexane (1:1). When combined and evaporation of appropriate fractions were obtained target compound as yellow-brown crystals with So pl. 186 - 7oC.

PMR (CDCl3) : 3.85 (s, 2H), 5.41 (d, 1H), 5.7 (d, 1H), of 6.52 (DD, 1H), 7.8(s, 2H)

MS (thermocapillary): M/Z [M+H] 347.0; C13H7Cl2F3N4+ H is 347.0

Example E2

5-Amino-3-cyano-1-(2,6-dichloro-4-triptoreline)-4-tribromoimidazole

To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-triptoreline)-4 - ethenylpyridine (1035.3 mg of the compound from Example A3) in ether (20 ml), cooled to - 20oC, with stirring, was added dropwise n-utility (2.52 ml, 2.5 M in hexane) over five minutes. After the reaction mixture was cooled to - 78oC and added bromine (0.487 ml) for two minutes. Stopped cooling and left the reaction mixture organic layer was separated, dried (MgSO4) and was evaporated, obtaining the crude product, which was purified column chromatography on silica gel with elution with a mixture of methylene chloride: hexane (1:1). When combined and evaporation of appropriate fractions were obtained target compound in the form of white crystals with So pl. 187oC decomp).

PMR (CDCl3) : 4.04 (s, 2H), 7.8 (s, 2H)

Elemental analysis - found: C, 26.95, H, 0.62, N 9.55 % for C13H4Br3Cl2F3N4C, AT 26.75, H, 0.69, N, 9.60 %

Examples E3a and E3b

5-Amino-3-cyano-4-(E-1,2-dibromethane-1-(2,6-dichloro - 4-triptoreline)pyrazole and

5-Amino-3-cyano-4-(Z-1,2-dibromethane-1-(2,6-dichloro-4-triptoreline) pyrazole

To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-triptoreline)-4 - ethynylpyridine (100 mg, of the compound from Example A3) in ether (1 ml) with gentle shaking dropwise within minutes dropwise added bromine (0.019 ml). After the reaction mixture was evaporated and purified the product column chromatography on silica gel (10 g) with elution with a mixture of methylene chloride:hexane (2:1). When combined and evaporation of the corresponding fractions obtained a mixture of the target compounds in a ratio of approximately 60:40 in the form of white crystals with So pl. 138-141oC, which is next PTS is heptanesulfonic acid:methanol (5:4:1) at a rate of 10 ml/minute. The appropriate fractions were combined and processed by the process of evaporation of nonaqueous components with subsequent distribution between ethyl ether and a saturated aqueous solution of sodium bicarbonate. The organic layer was dried and evaporated, obtaining (i) the Z-isomer of the target compound as yellow-brown crystals, So pl. 175-6oC

{ PMR (CDCl3) : 4.04 (user. s, 2H), 6.92 (s, 1H), 7.82 (s, 2H)} and (ii) E-isomer of the target compound as yellow-brown crystals, So pl. 169-170oC

{PMR (CDCl3) : 3.98 (user. s, 2H), 7.26 (s, 1H), 7.8 (s, 2H)}

MS (thermocapillary): M/Z [M+H] 502.0 C13H5Br2Cl2F3N4+ NH4is 502.8

Example E4

5-Amino-3-cyano-4-(cyclohex-1-enyl)-1-(2,6-dichloro-4-triptoreline) pyrazole

A solution of 5-amino-3-cyano-1-(2,6-dichloro-4-triptoreline) pyrazole (1 g, the compound of Reference Example 1 of EP 295, 117) and cyclohexanone (1.6 ml) in acetic acid (5 ml) was stirred and heated at 120oC in nitrogen atmosphere overnight. The cooled reaction mixture was diluted with water and extracted with ethyl acetate and then ether. The combined organic extracts were washed with saturated aqueous solution of sodium bicarbonate, then with water. After drying (MgSO4) if pariani is using methylene chloride:hexane (1:2), then a mixture of methylene chloride: hexane (1:1). When combined and evaporation of appropriate fractions were obtained target compound in the form of white crystals with So pl. 175-7oC.

PMR (CDCl3) : 1.7 (m, 2H), 1.8 (m, 2H), 2.2 (m, 2H), 2,45 (m, 2H), 3.74 (s, 2H), 5.9 (s, 1 H), 7.78 (s, 2H)

Elemental analysis - found: C, at 50.75, H 3.07, N 13.68 % for C17H13Cl2F3N4C, 50.89; H, 3.27, N, 13.69%

Example E5

5-Amino-3-cyano-4-(E-1,2-dibromopropan-1-yl)-1-(2,6-dichloro-4-triptoreline) pyrazole

To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-triptoreline)pyrazole (0.045 r) in ether (2 ml) under stirring was added dropwise a solution of bromine (0.02 g) in methylene chloride (1.5 ml). After incubation for five minutes at room temperature, the reaction mixture was evaporated and purified column chromatography on silica gel (5 g) with elution with a mixture of methylene chloride: hexane (3:7). When combined and evaporation of the corresponding fractions obtained target compound as white crystals.

PMR (CDCl3) : 2.63 (s, 3H), 3.94 (user. s, 2H), 7.8 (s, 2H)

MS (thermocapillary): M/Z [M+H] 516.2; C14H7Br2Cl2F3N4+ H is 516.84

Example E6

5-Amino-3-cyano-4-(1,2-dibromo-2-phenylethenyl)-1-(2,6-dichloro-4 - triptorelin the methylene (4 ml) under stirring was added dropwise a solution of bromine (0.057 r) in methylene chloride (0.25 ml). After incubation for 20 minutes at room temperature, the reaction mixture was evaporated and the residue purified column chromatography on silica gel (10 g) with elution by hexane and then with hexane containing increasing amounts of methylene chloride. When combined and evaporation of the corresponding fractions obtained target compound in the form of yellow crystals, So pl. 211oC.

PMR (CDCl3) : 4.1 (user. s, 2H), 7.28 (m, 1H), 7.42 (m, 2H), 7.52 (m, 2H), 7.82 (s, 2H)

MS (thermocapillary): M/Z [M+H] 578.7; C19H9Br2Cl2F3N4+ H is 578.86

Example E7

5-Amino-3-cyano-4-(1,2-dichloro-2-phenylethenyl)-1-(2,6-dichloro-4-triptoreline)pyrazole

To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-triptoreline)-4 - fisetinidol (0.5 g) in methylene chloride (20 ml) under stirring was added dropwise a solution of chlorine (0.085 g) in methylene chloride (5 ml). After keeping for 30 minutes at room temperature, the reaction mixture was evaporated and the residue purified column chromatography on silica gel (30 g) with elution by hexane and then with hexane containing increasing amounts of methylene chloride. When combined and evaporation of the corresponding fractions obtained target link is, H), 7.74 (s, 2H)

MS (thermocapillary): M/Z [M+H] 490.8; C19H9Cl4F3N4+ H is 490.96.

Example E8

4-(2-bromo-1,2-dichloroethenyl)-3-cyano-1-(2,6-dichloro-4-trifloromethyl) pyrazole

To a solution of 4-bromanil-3-cyano-1-(2,6-dichloro-4-trifloromethyl) pyrazole (0.4 g) in methylene chloride (10 ml), cooled to - 78oC, was added with stirring a solution of chlorine (0.133 g) in methylene chloride (5 ml). The stirring at - 78oC was continued for two hours after which the reaction mixture is left to warm to room temperature. Stirring was continued overnight, then the reaction mixture was evaporated to dryness. The residue was purified column chromatography on silica gel with elution with a mixture of methylene chloride:hexane (1:1). When combined and evaporation of appropriate fractions followed by recrystallization from cyclohexane got a target compound in the form of white crystals, So pl. 143.4-143.8oC.

PMR (CDCl3) : 7.40 (s, 2H), 7.72 (s, 1 H)

MS (thermocapillary): M/Z [M+H] 494.0; C13H3BrCl4F3N3O + H is 493.82

Example E9

3-Cyano-1-(2,6-dichloro-4-reformational)-4-tribromoimidazole

To a solution of 3-cyano-1-(2,6-dichloro-4-tcheremissine n-utility (0.876 ml of 2.5 M solution in hexane) at this rate, to ensure that the temperature was kept below -40oC. After cooling to -78oC stirring is continued for twenty minutes, then dropwise added bromine (0.187 ml). Stirring was continued for 15 minutes, then the reaction mixture was left to warm to room temperature and continued stirring for another 15 minutes. Then the reaction mixture was distributed between ether and water. The aqueous layer was separated and was extracted twice with ether. The combined organic layers were washed with brine, dried (Na2SO4) and was evaporated. The residue was purified column chromatography on silica gel with elution with a mixture of methylene chloride:hexane (1:2). When combined and evaporation of appropriate fractions followed by recrystallization from hexane there was obtained target compound as white crystals, So pl. 155.9-156.2oC.

PMR (CDCl3) : 7.42 (s, 2H), 7.82 (s, 1H)

MS (thermocapillary): M/Z [M+ NH4] 598.7; C13H3BrCl2F3N3O + NH4is 598.75

Example E10

5-Amino-3-cyano-1-(2,6-dichloro-4-serpentfather)-4-attemperator

To a degassed solution of 5-amino-3-cyano-1-(2,6-dichloro-4 - serpentfather)-4-iterate (5.05 g) and tetrakis (triphenylphosphine) - Rev.-butyl tin (4.5 ml). The mixture was heated to 70oC for 30 minutes and then stood at 70oC for one hour. Added tetrakis (triphenylphosphine) palladium (O) (0.175 g) and Ministry-n - butyl tin (4.5 ml) and continued heating for another hour. The reaction mixture was evaporated and distributed the balance between water and ether. The aqueous layer was extracted with ether. The combined organic layers were washed with brine, dried (MgSO4) and was evaporated, receiving the crude product as a brown paste. When grinding with hexane got brown crystals, which were dissolved in ethyl acetate and was filtered. The filtrate was evaporated and recrystallize the remainder of the toluene, obtaining the target compound as yellow-brown crystals with So pl. 227-228oC.

PMR (CDCl3) : 3.86 (s, 2H), 5.41 (d, 1H), 6.5 (d, 1H), 6.5 (DD, 1H), 7.92 (s, 2H)

MS (thermocapillary): M/Z [M+H] 405.1; C12H7Cl2F5N4S + H is 404.98

Example E11 (Illustrative)

3-Cyano-1-(2,6-dichloro-4-serpentfather)-4-iterator

It is heated to the boiling solution of 3-cyano-1-(2,6-dichloro-4 - serpentfather)-4-iterate (1.23 g) in tetrahydrofuran (35 ml) for thirty minutes was added dropwise with stirring a solution of tert-butyl nitrite (3.1 g) in tetr uciv the target compound in the form of pink crystals with So pl. 179-180oC.

PMR (CDCl3) : 7.66 (s, 1H), 7.9 (s, 2H)

MS (thermocapillary): M/Z [M+ NH4] 506.4; C10H3Cl2F5lN3S + NH4is 506.87

Example E12

3-Cyano-1-(2,6-dichloro-4-serpentfather)-4-attemperator

To a degassed solution of 5-amino-3-cyano-1-(2,6-dichloro - 4-serpentfather)-4-iterate (1.23 g) and tetrakis (triphenylphosphine) palladium (O) (0.09 g) in dimethylformamide (32 ml) under stirring was added at room temperature Ministry-n-butyl tin (4.2 ml). The reaction mixture was heated at 70oC for 1.5 hours. The reaction mixture was evaporated and rubbed the residue with hexane. The obtained crystals were dissolved chloride in methanol and placed in a column with silica gel (60 g). When elution with hexane and then hexane:methylene chloride (4: 1) after combining and concentrating the appropriate fractions were obtained target compound in the form of white crystals with So pl. 156oC.

PMR (CDCl3) : 5.5 (d, 1H), 5.95 (d, 1H), 6.63 (DD, 1H), 7.77 (s, 1H), 7.92 (s, 2H)

MS (thermocapillary): M/Z [M+ NH4] 406.8; C12H6Cl2F5N3S + NH4is 406.99

Example F1 (Illustrative)

3-Cyano-1-(2,6-dichloro-4-triptoreline)-4-iterator

To the foot (720 ml) with stirring for 0.5 hours was added tert-butyl nitrite (144 ml). The stirring and heating continued for 3 hours. The cooled reaction mixture was evaporated and recrystallize the residue from n-propanol, obtaining the target compound in the form of white crystals with So pl. 83-4oC.

PMR (CDCl3) : 7.7 (s, 1H), 7.79(s, 2H)

MS (thermocapillary): M/Z [M+ NH4] 448.8; C11H3Cl2F3N3l + NH4is 448.9

Example E2

3-Cyano-1-(2,6-dichloro-4-triptoreline)-4-attemperator

A solution of 3-cyano-1-(2,6-dichloro-4-triptoreline)-4-iterate (58 g) in dimethylformamide (350 ml) containing vinyltris-n-butyl tin (116 ml) and tetrakis(triphenylphosphine)palladium (O) (3.5 g) was stirred at 75oC for 3 hours. The reaction mixture was poured into water (600 ml) and ether (600 ml). The organic layer was washed with water (5 times), brine (700 ml) and dried over sodium sulfate. When removing the solvent in vacuo followed by crystallization of the residue from propan-2-ol obtained target compound as pale brown crystals with So pl. 75 - 6oC.

PMR (CDCl3) : 5.5 (d, 1H), 5.94 (d, 1H), 6.64 (DD, 1H), 7.64 (s, 1H), 7.77 (s, 2H)

MS (thermocapillary): M/Z [M+ NH4] 349.5; C13H6Cl2F3N3+ NH4is 349.02

Example F3 (Illustrative)o
C.

PMR (CDCl3) : 7.8 (s, 2H), 8.18 (s, 1H), 10.08 (s, 1H)

MS (thermocapillary): M/Z [M+ NH4] 351.3; C12H4Cl2F3N3O + NH4is 351.0

Example F4

4-(2,2-Dibromoethyl)-3-cyano-1-(2,6-dichloro - 4-triptoreline)pyrazole

To a solution of triphenylphosphine (0.983 r) in dry methylene chloride (50 ml) at 0oC added with stirring chetyrehhloristy carbon (0.497 g). The mixture was stirred for 5 minutes and then added 3-cyano-1- (2,6-dichloro-4-triptoreline)-4-formylpyrazole (0.25 g is a promotional mixture was evaporated and the residue purified column chromatography on silica gel with elution methylene chloride, receiving the target compound in the form of white crystals, So pl. 109-110oC.

PMR (CDCl3) : 7.48 (s, 1H), 7.76 (s, 2H), 8.34 (s, 1H)

MS (thermocapillary): M/Z [M+H] 487.2; C13H4Br2Cl2F3N3+ H is 487.8

Example F5a and F5b

4-(Z-1,2-Dibromoethenyl)-3-cyano-1-(2,6-dichloro-4-triptoreline)pyrazole

4-(E-1,2-Dibromoethenyl)-3-cyano-1-(2,6-dichloro-4-triptoreline)pyrazole

To a solution of 5-amino-4-dibromoethenyl-3-cyano-1-(2,6-dichloro-4-triptoreline) pyrazole (mixture of E/Z) (0.3 g) in tetrahydrofuran (2 ml) under stirring was added tert-butyl nitrite (0.21 ml) and heated the mixture at 65oC for 1 hour. The reaction mixture was evaporated and the residue purified column chromatography on silica gel (20 g) with elution by hexane and then hexane:methylene chloride (1:3). The appropriate fractions were combined and evaporated in vacuo and further purified HPLC on a column (21 x 250 mm DynamaxTM0.005 mm ODS reversed-phase when the elution with a mixture of acetonitrile:water (3:2) at a rate of 11 ml/min, having

(i) 4-(Z-1,2-dibromoethenyl)-3-cyano-1-(2,6-dichloro-4-triptoreline) pyrazole in the form of white crystals, So pl. 88-90oC,

{PMR (CDCl3) : 7.7 (s, 1H), 7.8 (s, 2H), 7.87 (s, 1H)

MS (thermocapillary): M/Z [M+ NH4-(E-1,2-dibromoethenyl)-3-cyano-1-(2.6-dichloro-4-triptoreline) pyrazole in the form of white crystals, So pl. 119oC,

{PMR (CDCl3) : 7.0 (s, 1H), 7.8 (s, 2H), 7.98 (s, 1 H)

MS (thermocapillary): M/Z [M+ NH4] 504.3; C13H4Br2Cl2F3N3+ NH4is 504.8}.

Example F6

3-Cyano-4-(2,2-dichloroethenyl)-1-(2,6-dichloro-4-triptoreline)pyrazole

A solution of triphenylphosphine (0.983 g) and carbon tetrachloride (0.145 g) in anhydrous methylene chloride (5 ml) was stirred for 5 minutes at 0oC. and Then added 3-cyano-1-(2,6-dichloro-4-triptoreline)-4 - formylpyrazole (0.25 g) and boiled under reflux the reaction mixture for 5 hours and then evaporated. The residue was purified column chromatography on silica gel with elution methylene chloride. When combined and evaporation of appropriate fractions were obtained target compound as white crystals, So pl. 99-101oC.

PMR (CDCl3) : 6.9 (s, 1H), 7.8 (s, 2H), 8.2 (s, 1H)

MS (thermocapillary): M/Z [M+ NH4] 417.0; C13H4Cl4F3N3+ NH4is 416.95

Example F7

3-Cyano-1-(2,6-dichloro-4-triptoreline)-4-(2,2-deperately)pyrazole

3-cyano-1-(2,6-dichloro-4-triptoreline)-4-formyl-pyrazole (1.3 g), triphenylphosphine (5.1 g), dibromodifluoromethane (2 g) and dichloromethane 3 hours. The reaction mixture was evaporated and the residue purified column chromatography on silica gel with elution methylene chloride: hexane (9: 1). When combined and evaporation of appropriate fractions were obtained target compound in the form of white crystals with So pl. 75 - 77oC.

PMR (CDCl3) : 5.43 (d, 1H), 7.7 (s, 1H), 7.79 (s, 2H)

MS (thermocapillary): M/Z [M+ NH4] 368.0; C13H4Cl2F5N3+ NH4is 368.0.

Examples F8a and F8b

4-(E-2-Chloro-3,3,3-tryptophanyl)-3-cyano-1-(2,6-dichloro-4 - triptoreline)pyrazole

4-(Z-2-Chloro-3,3,3-tryptophanyl)-3-cyano-1-(2,6-dichloro-4-triptoreline) pyrazole

A solution of 3-cyano-1-(2,6-dichloro-4-triptoreline)-4-formylpyrazole (0.75 g), 1,1,1-trichloro-2,2,2-triptorelin (0.54 ml), acetic anhydride (0.32 ml) in dimethylformamide (2 ml) containing powdered zinc (0.734 g), was heated at 50oC under stirring for 3 hours. The cooled reaction mixture was diluted with water (20 ml) and was extracted with ether (50 ml x 3). The combined organic layers dried and evaporated. The residue was purified column chromatography on silica gel with elution methylene chloride. The appropriate fractions were combined and evaporated and further purified by reversed-phase XP is the following fractions were combined partially evaporated and distributed between ether and water. The organic layer was separated, dried and evaporated received:

4-(E-2-Chloro-3,3,3-tryptophanyl)-3-cyano-1-(2,6-dichloro-4 - triptoreline) pyrazole in the form of white crystals, So pl. 108-110oC.

PMR (CDCl3) : 7.1 (s, 1H), 7.8 (s, 2H), 7.83 (s, 1H).

MS (thermocapillary): M/Z [M+H] 434.0; C14H4Cl3F6N3+ H is 433.94;

and

4-(Z-2-Chloro-3,3,3-tryptophanyl)-3-cyano-1-(2,6-dichloro-4 - triptoreline) pyrazole in the form of white crystals, So pl. 125 - 126oC,

PMR (CDCl3) : 7.36 (s, 1H), 7.8 (s, 2H), 8.42 (s, 1H).

MS (thermocapillary): M/Z [M+ NH4] 434; C14H4Cl3F6N3+ H is 433.94.

Examples F9a and F9b

4-(E-2-Bromo-3,3,3-tryptophanyl)-3-cyano-1-(2,6-dichloro-4-triptoreline) pyrazole

4-(Z-2-Bromo-3,3,3-tryptophanyl)-3-cyano-1-(2,6-dichloro-4 - triptoreline)pyrazole

A solution of 3-cyano-1-(2,6-dichloro-4-triptoreline)-4-formylpyrazole (0.5 g), 1,1,1-tribromo-2,2,2-triptorelin (0.96 ml), acetic anhydride (0.3 ml) in dimethylformamide (2 ml) containing powdered zinc (0.49 g) was heated at 50oWith stirring for 12 hours. The cooled reaction mixture was diluted with methylene chloride (20 ml) and two silica gel with elution methylene chloride. When combined and evaporation of appropriate fractions were obtained:

4-(E-2-Bromo-3,3,3-tryptophanyl)-3-cyano-1-(2,6-dichloro-4 - triptoreline)pyrazole in the form of white crystals.

PMR (CDCl3) : 6.58 (s, 1H), 7.8 (s, 2H), 7.97 (s, 1H).

and

4-(Z-2-Bromo-3,3,3-tryptophanyl)-3-cyano-1-(2,6-dichloro-4 - triptoreline)pyrazole in the form of white crystals, So pl. 125-126oC,

PMR (CDCl3) : 7.68 (s, 1H), 7.8 (s, 2H), at 8.62 (s, 1H).

MS (thermocapillary): M/Z [M+ NH4] 494.6; C14H4BrCl2F5N3+ NH4is 494.92.

Example F10

3-Cyano-1-(2,6-dichloro-4-triptoreline)-4-(Z-2-fluoro-3,3,3-cryptochrome - 1-yl)pyrazole

3-Cyano-1-(2,6-dichloro-4-triptoreline)-4-formylpyrazole (1.25 g), acetic anhydride (0.5 ml), dimethylformamide (50 ml) and powdered zinc (1.2 g) was placed in a steel autoclave of stainless steel and cooled to -40oC. was Added 1,1-dichloro-1,2,2,2-Tetrafluoroethane (1.6 g) and then the contents of the sealed autoclave was heated and stirred at 70oC for 6 hours. The reaction mixture was distributed between ether and water. The organic phase is separated, dried and evaporated. The residue was purified column chromatography on silica gel with elution methylene chloride. When the volume 1H), 7.8 (s, 2H), 8.05 (s, 1 H)

Example F11

3-Cyano-4-(TRANS-2-cyanoethyl)-1-(2,6-dichloro-4-triptoreline)pyrazole

A mixture of 3-cyano-1-(2,6-dichloro-4-triptoreline)-4-iterate (0.864 g), Acrylonitrile (0.264 g), triethylamine (0.4 ml), palladium acetate (0.04 g) and dimethylformamide (10 ml) was stirred in nitrogen atmosphere at 70oC for 6 hours. The reaction mixture was evaporated and distributed between water and methylene chloride. The organic phase is separated, washed with water, brine, dried (Na2SO4) and was evaporated. The residue was purified column chromatography on silica gel (40 g) with elution methylene chloride. When combined and evaporation got a target compound in the form of white crystals, So pl. 144-145oC.

PMR (CDCl3) : 6.19 (d, 1H), 7.34 (d, 1H), 7.8 (s, 2H), 7.81 (s, 1H)

MS (thermocapillary): M/Z [M+ NH4] 373.8; C14H5Cl2F3N4+ NH4is 374.02

Example F12

3-Cyano-1-(2,6-dichloro-4-triptoreline)-4-triftormetilfullerenov

To a solution of triptocaine (0.66 g) in anhydrous tetrahydrofuran (10 ml) at -78oC added with stirring n-utility (3.125 ml of 2.5 M solution in hexane), keeping the temperature below -78oC. After 30 minutes, was added zinc chloride (44 mie three hours. After cooling to 0oC was added bis(triphenylphosphine)palladium chloride (0.12 g) and 3-cyano-1-(2,6-dichloro-4-triptoreline)-4-iterator (1.5 g) and the mixture is boiled under reflux for 6 hours. The cooled mixture was distributed between ether and water. The organic phase is separated, dried and evaporated. The residue was purified column chromatography on silica gel with elution methylene chloride:hexane (3:7). When combined and evaporation got a target compound in the form of pale yellow crystals, So pl. 121-123oC.

PMR (CDCl3) : 7.8 (s, 2H), 7.94 (s, 1H)

MS (thermocapillary): M/Z [M+ NH4] 419.9; C14H3Cl2F8N3+ NH4is 414.80

Example F13

4-(1,2-Dibromo-3,3,3-tryptophanyl)-3-cyano-1-(2,6-dichloro-4-triptoreline) pyrazole

To a solution of 3-cyano-1-(2,6-dichloro-4-triptoreline)-4 - triftormetilfullerenov (0.11 g) in ether (1 ml) under stirring was added bromine (0.015 g). After 24 hours, the mixture was distributed between ether (10 ml) and water (10 ml). The organic phase is separated, dried and evaporated, obtaining the target compound (isomer mixture) as off-white crystals, So pl. 119 - 121oC.

PMR (CDCl3) : 7.8 (s, 2H), 7.9 & 7.94 (s&s, 1H)

allows 555.8.

Examples F14a and F14b

3-Cyano-1-(2,6-dichloro-4-triptoreline)-4-tribromoimidazole

5-Bromo-3-cyano-1-(2,6-dichloro-4-triptoreline)-4-tribromoimidazole

To a solution of 3-cyano-1-(2,6-dichloro-4-triptoreline)- 4-ethynylpyridine (0.25 g) in tetrahydrofuran (10 ml) at - 20oC added with stirring n-utility (0.455 ml of 2.5 M solution in hexane). After 5 minutes the mixture was cooled to -78oC and dropwise added bromine (0.0975 ml). The mixture was left to warm to room temperature for 10 minutes and then poured into water (20 ml) and ether (10 ml). The organic layer was separated, dried and evaporated. The residue was purified column chromatography on silica gel (10 g) with elution by hexane and then hexane: methylene chloride (2:3). When the Association and the process of evaporation obtained target compound as white crystals, So pl. 163-163.5oC and 136 - 139oC, respectively

PMR (CDCl3) : 7.8 (s, 2H), 7.85 (s, 1H)

MS (thermocapillary): M/Z [M + NH4] 582.4; C13H3Br3Cl2F3N3+ NH4is 582.72

PMR (CDCl3) : 7.8 (s, 2H)

MS (thermocapillary): M/Z [M+NH4] 660.7; C13H2Br4Cl2F3N3+ NH4is 660.67

Example F15

3-Cyano-1-(2,6-is dichlorethylene (0.25 g) in methylene chloride (10 ml) under stirring was added chloro (0.049 g) and left overnight. Added chlorine (0.049 g) and again left the mixture on the night. The mixture was evaporated and the residue purified column chromatography on silica gel (50 g) with elution by the mixture hexane : ether: methylene chloride (8:1:1). When combined and evaporation got a target compound in the form of white crystals, So pl. 122-124oC.

PMR (CDCl3) : 7.79 (s, 2H), 7.93 (s, 1H)

MS (thermocapillary); M/Z [M+ NH4] 450.8; C13H3Cl5F3N3+ NH4is 450.91

Example F16

3-Cyano-4-(E-1,2-dibromopropionyl)-1-(2,6-dichloro-4-triptoreline)pyrazole

To a solution of 5-amino-4-(E-1,2-dibromopropyl)-3-cyano-1-(2,6-dichloro-4 - triptoreline) pyrazole (0.06 g) in tetrahydrofuran (1.5 ml) under stirring was added tert-butyl nitrite (0.05 ml). The reaction mixture was heated at 60oC for two hours. Then the reaction mixture was evaporated, the residue purified column chromatography on silica gel (5 g) with elution with hexane: methylene chloride (100:0 to 20:7). When combined and evaporation got a target compound in the form of white crystals, So pl. 134-135oC.

PMR (CDCl3) : 2.64 (s, 1H), 7.78 (s, 1H), 7.79 (s, 2H)

MS (thermocapillary): M/Z [M+ NH4] 518.6: C14H6Br2Cl2F3N3+ NH4SSOL

To a solution of 4-bromanil-3-cyano-1-(2,6-dichloro-4-triptoreline) pyrazole (0.2 g) in methylene chloride (5 ml), cooled to -78oC, under stirring was added chloro (2.17 ml, 0.255 M solution in methylene chloride). The reaction mixture was left to warm to room temperature. After two hours added chlorine (2.17 ml, 0.255 M solution in methylene chloride) and continued stirring for two days, after which the mixture was evaporated to dryness, obtaining the target compound as white crystals, So pl. 128-131oC.

PMR (CDCl3) : 7.80 (s, 2H), 7.92 (s, 1H)

MS (thermocapillary): M/Z [M+ NH4] 495.1; C13H3BrCl4F3N3+ NH4is 494.86

Example F18

4-12-Chloro-1,2-dibromoethenyl)-3-cyano-1-(2,6-dichloro-4-triptoreline)pyrazole

To a solution of 4-chlorethyl-3-cyano-1-(2,6-dichloro-4-triptoreline) pyrazole (0.1203 g) in anhydrous methylene chloride (3 ml) under stirring was added bromine (0.017 ml). Stirring was continued overnight, after which the mixture was evaporated to dryness, obtaining, after recrystallization from hexane the target compound in the form of white crystals, So pl. 135-138oC.

PMR (CDCl3) : 7.80 (s, 2H), 7.83 (s, 1H)

MS (thermocapillary): M/Z [M+ NH4] 538.8; C13ethyl-5-amino-3-cyano-1-(2,6-dichloro 4-triptoreline)pyrazole

To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-triptoreline)-4 - ethynylpyridine (0.345 r) in acetonitrile (5 ml) was added n-toluensulfonate acid (0.5 g) and the mixture was stirred for 2 hours at room temperature, and then poured into water (100 ml) and ether (100 ml). The organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate (50 ml), brine (50 ml), dried (Na2SO4) and was evaporated. The residue was purified column chromatography on silica gel (40 g) with elution methylene chloride:hexane (10: 1). When combined and evaporation got a target compound in the form of white crystals, So pl. 200-201oC.

PMR (CDCl3) : 2.65 (s, 3H), 5.83 (user. s, 2H), 7.82 (s, 2H)

MS (thermocapillary): M/Z [M+NH4] 380.4; C13H7Cl2F3N3O + NH4is 380.03

Example F20 (Illustrative)

4-Acetyl-3-cyano-1-(2,6-dichloro-4-triptoreline)pyrazole

To a solution of 4-acetyl-5-amino-3-cyano-1-(2,6-dichloro-4-triptoreline) pyrazole (0.4 r) in tetrahydrofuran (2 ml) was added dropwise tert-butyl nitrite (0.0262 g). The mixture was boiled under reflux for 30 minutes. The reaction mixture was placed in a column with silica gel (1 g) and suirable by tetrahydrofuran, receiving targeted
MS (thermocapillary): M/Z [M+ NH4] 365.0; C13H6Cl2F3N3O + NH4is 365.02

Example F21

3-Cyano-1-(2,6-dichloro-4-triptoreline)-4-(1-methyl-2,2-dibromoethenyl) pyrazole

A solution of triphenylphosphine (0.94 g) and chetyrehpostovye carbon (0.6 g) in anhydrous methylene chloride (30 ml) was stirred at 0oC for 5 minutes. Then added 4-acetyl-3-cyano-1-(2,6 - dichloro-4-triptoreline) pyrazole (0.25 g) and the mixture is boiled under reflux for 6 hours and then evaporated. The residue was purified column chromatography on silica gel with elution methylene chloride. When combined and evaporation of appropriate fractions were obtained target compound as pale pink crystals with So pl. 119-122oC.

PMR (CDCl3) : 2.35 (s, 3H), 7.79 (c + c, 1H + 2H)

MS (thermocapillary): M/Z [M+ NH4] 518.7; C14H6Br2Cl2F3N3+ NH4is 518.86

Example F22

3-Cyano-1-(2,6-dichloro-4-triptoreline)-4-(1-methyl-2,2 - deperately)pyrazole

4-Acetyl-3-cyano-1-(2,6-dichloro-4-triptoreline)pyrazole (0.5 g), triphenylphosphine (1.884 g), dibromodifluoromethane (0.33 ml) and dichloromethane (50 ml) were placed in a steel autoclave of stainless steel the full-time chromatography on silica gel with elution methylene chloride. When combined and evaporation of appropriate fractions were obtained target compound in the form of white crystals with So pl. 66-68oC.

PMR (CDCl3) : 2.15 (m, 3H), 7.68 (s, 1H), 7.8 (s, 2H)

MS (thermocapillary): M/Z [M + NH4] 398.9; C14H6Cl2F5N3+ NH4is 399.02.

Example F23 (Illustrative)

5-Chloro-3-cyano-1-(2,6-dichloro-4-triptoreline)-4-iterator

To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-triptoreline)-4 - iterate (1 g) in acetonitrile (15 ml) under stirring at 0oC was added dropwise chloride nitrosyl (2.7 ml ~ 1M solution in methylene chloride). The reaction mixture is boiled under reflux for 10 minutes. Then the reaction mixture was evaporated and the residue purified column chromatography on silica gel with elution with hexane:toluene (2:1) and then with toluene. When combined and evaporation of appropriate fractions were obtained target compound as pale orange crystals with So pl. 115.7-116.3oC.

PMR (CDCl3) : 7.8 (s, 2H)

MS (thermocapillary): M/Z [M+H] 466.0; C11H2Cl3F3IN3+ NH4is 465.84.

Example F24

5-Chloro-3-cyano-1-(2,6-dichloro-4-triptoreline)-

4-g) in dimethylformamide (75 ml) at room temperature was added tetrakis(triphenylphosphine) palladium (O) (0.448 g). After 5 minutes dropwise added vinyl-tri-n-butyl tin (11.3 ml) and the mixture was heated at 70oC during the night. The reaction mixture was evaporated and distributed between ether and water. The organic layer was separated, dried and evaporated. The residue was purified column chromatography on silica gel with elution by hexane and then hexane:methylene chloride (2:1). When combined and evaporation of appropriate fractions followed by recrystallization from hexane got a target compound in the form of white crystals, So pl. 69.8-70.4oC.

PMR (CDCl3) : 5.61 (d, 1H), 6.2 (d, 1H), 6.56 (DD, 1H), 7.8 (s, 2H)

MS (thermocapillary): M/Z [M+ NH4] 383.1; C13H5Cl3F3N3+ NH4is 382.98.

Example F25 (Illustrative)

5-Chloro-3-cyano-1-(2,6-dichloro-4-triptoreline)-4-formylpyrazole 4-formylpyrazole

To a solution of 5-chloro-3-cyano-1-(2,6-dichloro-4-triptoreline)-4 - ethenylpyridine (0.6352 g) in acetone (18 ml) was added water (2 ml), osmium tetroxide (0.57 ml, 2.5% solution in tert-butanol) and metaperiodate sodium (0.749 g). After stirring at room temperature for 1 hour added metaperiodate sodium (0.749 g) and continued stirring for 1 hour. The reaction mixture was evaporated and treated the minutes the layers were separated. The aqueous layer was extracted with ethyl acetate. United an ethyl acetate extracts were washed with an aqueous solution of potassium bicarbonate, then brine, dried (Na2SO4) and was evaporated. The residue was purified column chromatography on silica gel with elution with hexane:methylene chloride (2:1). When combined and evaporation of appropriate fractions followed by recrystallization from hexane got a target compound in the form of white crystals, So pl. 145.2-145.9oC.

PMR (CDCl3) : 7.84 (s, 2H), 10.04 (s, 1H)

MS (thermocapillary): M/Z [M+ NH4] 385.3; C12H3Cl3F3N3O + NH4is 384.96.

Example F26

5-Chloro-3-cyano-1-(2,6-dichloro-4-triptoreline)-4-(2,2-dibromoethenyl) pyrazole

To a solution of triphenylphosphine (0.709 g) in dry methylene chloride (2 ml) under stirring at 0oC in dry nitrogen atmosphere was added chetyrehhloristy carbon (0.358 g) in dry methylene chloride (2 ml) for 5 minutes, then added 5-chloro-3-cyano-1-(2,6-dichloro - 4-triptoreline)-4-formylpyrazole (0.2 g) in dry methylene chloride (3 ml). The mixture was left to warm to room temperature and continued stirring overnight. The reaction mixture was washed with water. Aq and (Na2SO4) and was evaporated. The residue was purified column chromatography on silica gel with elution with hexane:methylene chloride (1:1). When combined and evaporation of appropriate fractions followed by recrystallization from hexane got a target compound in the form of white crystals, So pl. 119.1-119.5oC.

PMR (CDCl3) : 7.24 (s, 1H), 7.81 (s, 2H)

MS (thermocapillary): M/Z [M+ NH4] 538.8; C13H3Br2Cl3F3N3+ NH4is 538.81.

Example F27

5-Chloro-3-cyano-1-(2,6-dichloro-4-triptoreline)-4-ethynylpyrene

To a solution of 5-chloro-3-cyano-4-(2,2-dibromoethenyl)-1-(2,6-dichloro-4 - triptoreline) pyrazole (2.12 g) in dimethyl sulfoxide (8 ml) during 15oC was added dropwise with stirring a solution of 1,8-diazabicyclo [5.4.0] undec-7-ene (1.21 ml) in dimethyl sulfoxide (7.9 ml). After 2 hours the reaction mixture was neutralized with 0.5 N hydrochloric acid and then distributed between water and methylene chloride. The aqueous layer was extracted three times methylene chloride. The combined organic layers were washed with brine, dried (Na2SO4) and was evaporated. The residue was purified column chromatography on silica gel with elution with hexane: methylene chloride (1:1). When combining the tion as light pink crystals, So pl. 109.1 -109.9oC.

PMR (CDCl3) : 3.54 (s, 1H), 7.84 (s, 2H)

MS (thermocapillary): M/Z [M+NH4] 380.7; C13H3Cl3F3N3+ NH4is 380.97.

Example F28

4-Bromanil-5-chloro-3-cyano-1-(2,6-dichloro-4-triptoreline)pyrazole

To a solution of 5-chloro-3-cyano-1-(2,6-dichloro-4-triptoreline)-4 - ethynylpyridine (0.499 g) in acetone (5 ml) was added with stirring, N - bromosuccinimide (0.244 g), and then silver nitrate (0.023 g). Stirring is continued for one hour, then the reaction mixture was evaporated to dryness. The residue is distributed between ether and water. The aqueous layer was separated and was extracted with ether. The combined organic layers were washed with brine, dried (Na2SO4) and was evaporated. The residue was purified column chromatography on silica gel with elution methylene chloride: hexane (1: 1). When combined and evaporation of appropriate fractions followed by recrystallization from hexane got a target compound in the form of white crystals, So pl. 152.9-153.4oC.

PMR (CDCl3) : 7.80 (s, 2H)

MS (thermocapillary): M/Z [M+NH4] 459.0; C13H2BrCl3F3N3+ NH4is 458.88.

Example F29

4-(2-bromo-1,2-dichloroethenyl)-5-chloro-methylphenyl) pyrazole (0.42 g) in methylene chloride (10 ml), cooled to -78oC, under stirring was added a solution of chlorine (0.134 g) in methylene chloride (5 ml). Stirring was continued at -78oC for two hours and then the reaction mixture was left to warm to room temperature. Stirring was continued overnight and then the mixture was evaporated to dryness. The residue was purified column chromatography on silica gel with elution methylene chloride: hexane (1:1). When combined and evaporation of appropriate fractions followed by recrystallization from hexane got a target compound in the form of white crystals, So pl. 91.1-91.9oC.

PMR (CDCl3) : 7.80 (s, 2H)

MS (thermocapillary): M/Z [M+NH4] 528.9; C13H2BrCl5F3N3+ NH4is 528.81.

Example F30

3-Cyano-1-(2,6-dichloro-4-triptoreline)-4-(1-methyl-ethen-1-yl) pyrazole

To a solution of 4-acetyl-3-cyano-1-(2,6-dichloro-4-triptoreline) pyrazole (0.75 g) in tetrahydrofuran (5 ml), cooled to -40oC in nitrogen atmosphere, added-chloro - methylene-[bis(cyclopentadienyl)titanium] dimethylamine (5.18 ml, 0.5 M solution in toluene) and the mixture was stirred for 15 minutes and then left to warm to room temperature. After keeping at room shall opinie. The reaction mixture was diluted with ether (50 ml), washed with an aqueous solution of sodium sulfate, dried and evaporated. The residue was purified column chromatography on silica gel with elution methylene chloride: hexane (1: 1). When combined and evaporation of the corresponding fractions obtained target compound in the form of reddish-brown crystals, So pl. 63-64oC.

PMR (CDCl3) : 2.63 (s, 3H), 5.19 (m, 1H), 5.32 (m, 1H), 7.49 (s, 1H), 7.87 (s, 2H)

MS (thermocapillary): M/Z [M+NH4] 363.0; C14H8Cl2F3N3+ NH4is 363.04.

Example F31

3-Cyano-1-(2,6-dichloro-4-triptoreline)-4-(2-methylprop-1-enyl)pyrazole

Isopropyltriphenylphosphonium iodide (0.97 g) in anhydrous ether (10 ml) at room temperature was treated with n-butyllithium (0.9 ml of a 2.5 M solution in hexano). To the resulting dark red solution was added 3-cyano-1-(2,6-dichloro-4-triptoreline)-4 - formylpyrazole (0.6 g) in ether (20 ml) and the mixture was stirred for 2 hours. This solution was washed with water (20 ml) and the separated organic layer was dried (MgSO4) and was evaporated. The residue was purified column chromatography on silica gel with elution methylene chloride. When combined and evaporation of the corresponding fractions obtained t is) : 1.9 (s, 3H), 1.99 (s, 3H), 6.17 (s, 1H), 7.6 (s, 1H), 7.77 (s, 2H)

MS (thermocapillary): M / Z [M+ NH4] 360.2: C15H10Cl2F3N3+ NH4is 360.03.

Example G1 (Illustrative)

5-Amino-1-(2,6-dichloro-4-triftormetilfullerenov)-4-iodine-3 - cryptomaterial

To a solution of 5-amino-1-(2,6-dichloro-4-triftormetilfullerenov)-3 - cryptomaterial (0.182 g) in acetonitrile (3 ml) under stirring at room temperature was added N-jodatime (0.113 g). After 20 minutes the mixture was evaporated to a dry residue and the residue was dissolved in methylene chloride (20 ml). After washing with water (20 ml x 2), brine and dried (MgSO4) the solution has evaporated. The residue was washed with hexane, and sludge was evaporated, obtaining the target compound in the form of whitish crystals, So pl. 126oC.

PMR (CDCl3) : 3.9 (user. s, 2H), 7.80 (s, 2H)

MS (thermocapillary): M/Z [M+H] 490.2; C11H4Cl2F6IN3+ H is 489.88.

Example G2 (Illustrative)

1-(2,6-Dichloro-4-triptoreline)-4-iodine-3-cryptomaterial

To a solution of 5-amino-1-(2,6-dichloro-4-triptoreline)-4-iodine-3 - cryptomaterial (3.3 g) in tetrahydrofuran (25 ml) under stirring at 65oC was added dropwise tert-butyl nitrite (4.22 or oil, which solidified upon standing. During crystallization from propan-2-ol target compound was obtained as yellow crystals, So pl. 109-112oC.

PMR (CDCl3) : 7.7 (s, 1H), 7.77 (s, 2H)

Elemental analysis - found: C, 27.87, H, 0.69, N? 6/15%; for C11H4Cl2F6IN3C, 27.82, H, 0.64, N, 5.90%.

Example G3

1-(2,6-Dichloro-4-triptoreline)-4-ethynyl-3-cryptomaterial

A solution of 1-(2,6-dichloro-4-triptoreline)-4-iodine-3-cryptomaterial (1 g) in dimethylformamide (5 ml) containing vinyltris-n-butyl tin (2 ml) and tetrakis(triphenylphosphine)palladium (O) (0.1 g) was stirred at 75oC for 3 hours. The reaction mixture was evaporated and then distributed between water and ether. The organic layer was separated, washed with water (5), dried (Na2SO4) and was evaporated. The residue was led from the hexane and further purified column chromatography on silica gel with elution with ether. When combined and evaporation of appropriate fractions received a yellow residue, which was further purified high-performance chromatography with reversed-phase silica C18 upon elution with a mixture of acetonitrile: methanol:water (40:20:50). When combined and evaporation of appropriate fractions, followed Perek is P CLASS="ptx2">

PMR (CDCl3) : 5.39 (d, 1H), 5.65 (d, 1H), 6.69 (DD, 1H), 7.8 (s, 1H), 7.81 (s, 2H)

MS (thermocapillary): M/Z [M+ NH4] 391.9; C13H6Cl2F6N2+ NH4is 392.02.

Example G4

5-Amino-1-(2,6-dichloro-4-triptoreline)-3-trifluoromethyl-4 - trimethylethylene

To a solution of 5-amino-1-(2,6-dichloro-4-triptoreline)-4-iodine - 3-cryptomaterial (28 g) in triethylamine (120 ml) and dimethylformamide (24 ml) under stirring at room temperature was added trimethylsilylacetamide (12 ml), copper iodide (0.6 g) and bis(triphenylphosphine)palladium (II) chloride (1.2 g). The mixture was boiled under reflux for 4 hours and then left at room temperature overnight. The reaction mixture was diluted with water (500 ml) and ether (500 ml) and was filtered. The organic layer of the filtrate was separated, dried (MgSO4) and was evaporated, obtaining the crude product in the form of oil, which was purified column chromatography on silica gel with elution methylene chloride: hexane (1: 1). When combined and evaporation of appropriate fractions followed by recrystallization from hexane got a target compound as yellow-brown crystals. So pl. 120-123oC.

PMR (CDCl3) : 0.28 (s, 9H), 4.12 (user. s, 2H), 7.7ptx2">

Example G5

1-(2,6-Dichloro-4-triptoreline)-3-trifluoromethyl-4 - trimethylethylene

To a solution of 5-amino-1-(2,6-dichloro-4-triptoreline)-3-trifluoromethyl-4 - trimethylsilylimidazole (6.39 g) in tetrahydrofuran (50 ml) under stirring at 65oC was added dropwise tert-butyl nitrite (7.15 g) in tetrahydrofuran (10 ml) for one hour. Heating was continued for 2 hours, then the mixture is left overnight at room temperature. After evaporation the residue was dissolved in hexane and decantation with nerastvorim substances. This solution was evaporated and purified column chromatography on silica gel with elution methylene chloride:hexane (1:1). When combined and evaporation of appropriate fractions followed by recrystallization from hexane got a target compound in the form of pale yellow crystals, So pl. 105-108oC.

PMR (CDCl3) : 0.28 (s, 9H), 7.74 (s, 1H), 7.75 (s, 2H)

MS (thermocapillary): M/Z [M+NH4] 461.8; C16H12Cl2F6N2Si + NH4is 462.04.

Example G6

1-(2,6-Dichloro-4-triptoreline)-4-ethinyl-3-cryptomaterial

To a solution of 1-(2,6-dichloro-4-triptoreline)-3-trifluoromethyl-4 - trimethylsilylimidazole (4.6 g) in m for 3 hours, the reaction mixture was concentrated and then distributed between ether (250 ml) and water (250 ml). The organic layer was separated, washed with brine, dried and evaporated, obtaining oil, which was led by hexane, obtaining the target compound in the form of pale yellow crystals, So pl. 95-98oC.

PMR (CDCl3) : 3.27 (s, 1H), 7.75 (s, 2H), 7.79 (s, 1H)

MS (thermocapillary): M/Z [M + NH4] 390.2; C13H4Cl2F6N2+ NH4is 390.0

Example G7

4-Bromanil-1-(2,6-dichloro-4-triptoreline)-3-cryptomaterial

To a solution of 1-(2,6-dichloro-4-triptoreline)-4-ethinyl-3 - cryptomaterial (3.1 g) in acetone (25 ml) under stirring was added N-bromosuccinimide (1.4 g) and silver nitrate (0.14 g). Stirring was continued at room temperature for 2 hours. The reaction mixture was evaporated and distributed the residue between ether and water. The organic layer was separated, washed with salt solution, dried and evaporated. The residue was purified column chromatography on silica gel (10 g) with elution by hexane, and then methylene chloride: hexane (1:1). When combined and evaporation of appropriate fractions followed by recrystallization from hexane got a target compound in the form of white crystals, So pl. 92-94oC.

PMR (CDCl3) : 7.77 (s, 1H), 7.78 (s,2H).

MS (term">

Example G8

4-(2-Bromo-1,2-dichloroethenyl)-1-(2,6-dichloro-4-triptoreline)-3 - cryptomaterial

To a solution of 4-bromanil-1-(2,6-dichloro-4-triptoreline)-3 - cryptomaterial (0.45 g) in methylene chloride (10 ml), cooled to -78oC, under stirring was added dropwise a solution of chlorine (0,142 g) in methylene chloride (5 ml). Stirring was continued at -78oC for 2 hours and then the reaction mixture was left to warm to room temperature over night. The mixture was evaporated and purified column chromatography on silica gel (10 g) with elution by hexane and then methylene chloride:hexane (1: 1). When combined and evaporation of appropriate fractions followed by recrystallization from hexane got a target compound in the form of light yellow crystals, So pl. 57-59oC.

PMR (CDCl3) : 7.77 (s, 1H), 7.79 (s, 2H)

Elemental analysis - found: C, 30.14, H, 0.55, N, 6.67%; for C13H3BrCl4F6N2C, 29.86, H, 0.58, N, 5.36%.

Example G9 (Illustrative)

1-(2,6-Dichloro-4-triptoreline)-3,5-dimethyl-4-iterator

To a solution of 1-(2,6-dichloro-4-triptoreline)-3.5-dimethylpyrazole (0.218 g) in acetonitrile (3 ml) under stirring at room temperature was added Rechnoy chromatography on silica gel (5 g) with elution methylene chloride. When combined and evaporation of appropriate fractions followed by recrystallization from hexane got a target compound as a yellow oil.

PMR (CDCl3) : 2.11 (s, 3H), 2.32 (s, 3H), 7.73 (s, 2H)

MS (thermocapillary): M/Z [M+H] 435.0; C12H8Cl2F3IN2+ H is 434.91.

Example G10

1-(2,6-Dichloro-4-triptoreline)-3,5-dimethyl-4-attemperator

A solution of 1-(2,6-dichloro-4-triptoreline)-3,5-dimethyl-4-iterate (1 g) in dimethylformamide (10 ml) containing vinyltris-n-butyl tin (2 ml) and tetrakis(triphenylphosphine)palladium (O) (0.1 g) was stirred at 75oC for 2 hours, then left overnight at room temperature. The mixture was again heated at 75oC for 2 hours, then added vinyltris-n-butyl tin (2 ml) and the mixture was heated at 75oC for 2 hours. Added tetrakis(triphenylphosphine)palladium (O) (0.1 g) and continued stirring for another 2 hours. The reaction mixture was evaporated and then distributed between water and methylene chloride. The organic layer was separated, washed with water (5), brine, dried (Na2SO4) and was evaporated. The residue was adsorbing on silica gel (20 g) and purified column chromatography on silica gel (150 g) when elwira the om. When combined and evaporation of appropriate fractions followed by recrystallization from hexane got a target compound as a yellow oil.

PMR (CDCl3) : 2.11 (s, 3H), 2.4 (s, 3H), 5.23 (d, 1H), 5.41 (d, 1H), 6.59 (DD, 1H), 7,71 (s, 2H)

MS (thermocapillary): M/Z [M+H] 335.1; C14H11Cl2F3N2+ H is 335.03

Example G11 (Illustrative)

5-Amino-1-(2,6-dichloro-4-triptoreline)-4-iodine-3-methylpyrazole

To a solution of 5-amino-1-(2,6-dichloro-4-triptoreline)-3-methylpyrazole (9 g) in acetonitrile (200 ml) under stirring at room temperature was added N-jodatime (5.5 g). The mixture was boiled under reflux for one hour and then left overnight at room temperature. The mixture was evaporated and rubbed the residue with hot hexane. Precipitated on cooling the precipitate was filtered and dried, obtaining the target compound in the form of whitish crystals, So pl. 116-118oC.

PMR (CDCl3) : 2.24 (s, 3H), 3.68 (user. s, 2H), 7.74 (s, 2H)

MS (thermocapillary): M/Z [M+H] 435.8; C11H7Cl2F3IN3+ H is 435.91.

Example G12 (Illustrative)

1-(2,6-Dichloro-4-triptoreline)-4-iodine-3-methylpyrazole

To a solution of 5-amino-1-(2,6-dichloro-4-triptoreline)- 4-iodine-3-trimeric (2.33 ml). The reaction mixture is allowed to warm to room temperature and then boiled under reflux for 1.5 hours. The reaction mixture was evaporated and the residue purified column chromatography on silica gel with elution methylene chloride:hexane (1: 1). When combined and evaporation of the corresponding fractions obtained a yellow oil which was further purified column chromatography on silica gel with elution methylene chloride:hexane (1:2). When combined and evaporation of the corresponding fractions obtained target compound as white crystals, So pl. 118.5-119.4oC.

PMR (CDCl3) : 2.18 (s, 3H), 7.54 (s, 1H), 7.7 (s, 2H)

MS (thermocapillary): M/Z [M+H] 420.5; C11H6Cl2F3IH2+ H is 419.89.

Example G13

1-(2,6-Dichloro-4-triptoreline)-4-ethynyl-3-methylpyrazole

To a solution of 1-(2,6-dichloro-4-triptoreline)-4-iodine-3 - methylpyrazole (2.06 g) in dimethylformamide (25 ml) was added tetrakis (triphenylphosphine) palladium (O) (0.1 g) and Ministry-n-butyl tin (2 ml). The mixture was heated at 70oC for 2 hours. The mixture was evaporated and distributed between water and ether. The aqueous layer was separated and was extracted twice with ether. The combined organic layers were washed with brine, dried (Na2 the San:ether (9:1). When combined and evaporation of appropriate fractions received a yellow residue, which was purified further high-performance chromatography with reversed-phase silica C18 upon elution with a mixture of acetonitrile:methanol:water (40: 10: 50). When combined and evaporation of appropriate fractions followed by recrystallization from propan-2-ol obtained target compound as white crystals, So pl. 68.1 - 68.7oC.

PMR (CDCl3) : 2.44 (s, 3H), 5.24 (d, 1H), 5.5 (d, 1H), 6.62 (DD, 1H), 7.57 (s, 1H), 7,74 (s, 2H)

MS (thermocapillary): M/Z [M+H] place 321.1; C13H9Cl2F3N2+ H is 321.02.

Example G14

5-Amino-1-(2,6-dichloro-4-triptoreline)-3-methyl-4 - trimethylethylene

To a solution of 5-amino-1-(2,6-dichloro-4-triptoreline)-4-iodine-3 - methylpyrazole (9.1 g) in triethylamine (45 ml) and dimethylformamide (9 ml) under stirring at room temperature was added trimethylsilylacetamide (4.5 ml), copper iodide (0.225 g) and bis (triphenylphosphine) palladium (II) chloride (0.45 g). The mixture was boiled under reflux for 4 hours and left at room temperature overnight. The reaction mixture was evaporated, obtaining the crude product in the form of oil, which was purified column chromatography on silica gel with Elya is ment by recrystallization from hexane got a target compound as yellow-brown crystals, So pl. 121 -123oC.

PMR (CDCl3) : 0.28 (s, 9H), 2.3 (s, 3H), 3.92 (user. s, 2H), 7.82 (s, 2H)

MS (thermocapillary): M/Z [M+H] 406.0; C16H16Cl2F3N3Si + H is 406.05.

Example G15

1-(2,6-Dichloro-4-triptoreline)-3-methyl-4-trimethylethylene

To a solution of 5-amino-1-(2,6-dichloro-4-triptoreline)-3-methyl-4 - trimethylsilylimidazole (1.3 g) in tetrahydrofuran (15 ml) at 65oC dropwise with stirring was added within 15 minutes of tert-butyl nitrite (1.65 g) in tetrahydrofuran (5 ml) and continued heating for 3 hours. The reaction mixture is left to stand at room temperature overnight, then it was evaporated, obtaining the crude product in the form of a resin, which was purified column chromatography on silica gel with elution with a mixture of methylene chloride:hexane (1:1). When combined and evaporation of the corresponding fractions obtained target compound in the form of light yellow crystals, So pl. 76-78oC.

PMR (CDCl3) : 0.28 (s, 9H), 2.43 (s, 3H), 7.62 (s, 1H), 7.72 (s, 2H)

MS (thermocapillary): M/Z [M +H] 391.0; C16H15Cl2F3N2Si + H is 391.04.

Example G16

1-(2,6-Dichloro-4-triptoreline)-4-ethinyl-3-methylpyrazole

To a solution of 1-(2,6-dichloro-4-Arbonet potassium (0.75 g). After keeping at room temperature for 3 hours, the reaction mixture was poured into water (100 ml) and was extracted with ether (50 ml x 2). The combined organic layers were washed with brine, dried and evaporated, obtaining the target compound in the form of a light beige resin.

PMR (CDCl3) : 2.45 (s, 3H), 3.21 (s, 1 H), 7.64 (s, 1H), 7.81 (s, 2H)

MS (thermocapillary): M/Z [M+H] 319.0; C13H7Cl2F3N2+ H is 319.0

Example G17

4-Bromanil-1-(2,6-dichloro-4-triptoreline)-3-methylpyrazole

To a solution of 1-(2,6-dichloro-4-triptoreline)-4-ethinyl-3-methylpyrazole (0.53 g) in acetone (5 ml) under stirring at room temperature was added N-bromosuccinimide (0.295 g) and silver nitrate (0.028 g). Stirring is continued at room temperature for 1 hour. The reaction mixture was evaporated and the residue was dissolved in ether and washed with water. The organic layer was separated, dried and evaporated. The residue was purified column chromatography on silica gel (10 g) with elution by hexane, and then with a mixture of methylene chloride: hexane (1: 1). When combined and evaporation of appropriate fractions followed by recrystallization from hexane got a target compound in the form of a very pale yellow crystals, So pl. 86-89o13
H6BrCl4F3N2C, AT 39.23, H, 1.52, N, 7.04%.

Example G18 (Illustrative)

5-Amino-1-(2,6-dichloro-4-triptoreline)-3-phenylpyrazol

A solution of 2,6-dichloro-4-triftormetilfullerenov (0.245 g) in ethanol (2 ml) was added to benzoylacetonitrile (0.145 g) in ethanol (8 ml) and heated the solution at 80oC for 6 hours. Added glacial acetic acid (1 ml) and the mixture was heated at 80oC for 4 hours and then at 90oC for 2 hours. The reaction mixture was evaporated and the residue was purified column chromatography on silica gel (10 g) with elution methylene chloride. After pooling and evaporation of appropriate fractions followed by further purification of their balance high performance liquid chromatography with reversed-phase silica C18 upon elution with a mixture of methanol: acetonitrile: water (1: 5: 4). When combined and evaporation of the corresponding fractions obtained target compound as white crystals, So pl. 141.5-142.5oC.

PMR (CDCl3) : 3.60 (user. s, 2H), 6.08 (s, 1H). 7.3-7.45 (m, 3H), 7.80 (s, 2H), 7.8-7.85 (m, 2H)

MS (thermocapillary): M/Z [M+H] 372.1; C16H10Cl2F3N2+ H is 372.03.

Example G19 (Illustrative)

5-Amino-1-(2,6-dazole (0.12 g) and N-jodatime (0.08 g) in acetonitrile (5 ml) was left overnight under stirring at room temperature. The mixture was evaporated to dryness and distributed the residue between methylene chloride (15 ml) and water (15 ml). The organic layer was separated and washed with water (20 ml x 2), brine (15 ml) and dried (MgSO4) and was evaporated. The residue was washed with hexane, obtaining the target compound in the form of yellow crystals, So pl. 162-164oC.

PMR (CDCl3) : 3.8 (user. s, 2H), 7.35 (m, 3H), 7.78 (s, 2H), 7,95 (m, 2H)

MS (thermocapillary): M/Z [M+H] 498.1; C16H9Cl2F3IN3+ H is 497.93.

The G20 example (Illustrative)

1-(2,6-Dichloro-4-triptoreline)-4-iodine-3-phenylpyrazol

To a solution of 5-amino-1-(2,6-dichloro-4-triptoreline)-4-iodine-3 - phenylpyrazole (2.5 g) in tetrahydrofuran (50 ml) at 65oC under stirring was added dropwise within 30 minutes, tert-butyl nitrite (3 g) in tetrahydrofuran (20 ml) and continued heating for 3 hours, after which the mixture was left to stand at room temperature overnight. The reaction mixture was evaporated to a oil which was purified column chromatography on silica gel with elution methylene chloride. After combining and concentrating the appropriate fractions are further reviewed by column chromatography on silica gel with elution with hexane, then hexane containing 5% of them got a target compound in the form of cream crystals, So pl. 88-89oC.

PMR (CDCl3) : 7.45 (m, 3H), 7.7 (s, 1H), 7.72 (s, 2H), 7.95 (m, 2H)

MS (thermocapillary): M/Z [M+H] 482.8; C16H8Cl2F3IN2+ H is 482.91.

Example G21

1-(2,6-Dichloro-4-triptoreline)-4-ethynyl-3-phenyl-pyrazole

To a solution of 1-(2,6-dichloro-4-triptoreline)-4-iodine-3-phenylpyrazole (1 g) in dimethylformamide (12 ml) was added tetrakis(triphenylphosphine)palladium (O) (0.07 g) and the mixture was stirred at room temperature for 10 minutes. Added vinyltris-n-butyl tin (1.8 ml) and the mixture was heated at 70oC for 6 hours and then left overnight at room temperature. The reaction mixture was evaporated and distributed between water (50 ml) and methylene chloride (50 ml). The organic layer was separated and was extracted twice with ether. The combined organic layers were washed with brine, dried (MgSO4) and was evaporated. The residue was purified column chromatography on silica gel with elution with hexane containing increasing amounts of ethyl acetate. The appropriate fractions were combined and evaporated, and the residue further purified column chromatography on silica gel with elution with hexane containing increasing amounts of ether. When combined and evaporation sooted H), 6.80 (DD, 1 H), 7.45 (m, 5H), 7.75 (m, 5H)

MS (thermocapillary): M/Z [M+H] 383.3: C18H11Cl2F3N2+ H is 383.00

Making

The preparation of 1: 5-Amino-3-cyano-1-(2,6-dichloro-4-triptoreline) pyrazole used in example A1 was obtained as described in EP-295,117.

Preparation 2: 5-Amino-3-cyano-1-(2,6-dichloro-4-trifloromethyl) pyrazole used in example D1, obtained as described in EP-295,117.

Preparation of 3: 5-Amino-3-cyano-1-(2,6-dichloro-4 - triftormetilfullerenov)pyrazole used in example D7, obtained by using the method mentioned above for the preparation of 2.

Preparation 4: 5-Amino-3-cyano-1-(2,6-dichloro-4-serpentfather) pyrazole used in example D11, obtained as described in WO 93/06089.

Preparation 5: 5-Amino-1-(2,6-dichloro-4-triptoreline)-3 - cryptomaterial used in example G1, obtained as described in WO 87/03781.

Preparation 6: 1-(2,6-dichloro-4-triptoreline)-3,5-dimethylpyrazol used in example G9, obtained as described in Can. J Chem., 1979, 57,904.

Preparation 7: 5-Amino-1-(2,6-dichloro-4-triptoreline)-3 - methylpyrazole, used in example G11, obtained by using the method, that biological test

Found that the compound of Example A3 is causing 100% mortality within the dosage of 0.005-100 g on the fly when using the above method.

1. Derivatives of pyrazole of the formula I

< / BR>
where R1is CN1-6alkoxycarbonyl, phenyl or1-6the alkyl, optionally substituted by one or more halogen atoms;

R2is a group of formula II, III or IV

< / BR>
< / BR>
< / BR>
in which R7is H, halogen, three(C1-6alkyl)silicom,1-6(optionally substituted by one or more halogen atoms, HE or1-6alkoxygroup)1-6alkoxycarbonyl, phenyl group or 5 - or 6-membered cyclic heterocycle which is saturated or partially or fully unsaturated and contains up to 4 heteroatoms independently selected from up to 4 N atoms, up to 2 O atoms and up to 2 S atoms and which is attached to akinrinola link using an appropriate atom, S, or N, where valence allows;

R8, R9and R10each is independently H, halogen, phenyl, optionally substituted by one or more halogen atoms, CN or C1-6alkyl group, optionally substituted by one or more halogen atoms;

R1-6
alkoxycarbonyl)2N(C1-6alkyl)2, NHCONH(C1-6alkyl), N-pyrrolyl, SH or S(O)n(C1-6alkyl), where n is 0,1 or 2;

R4, R5and R6each is independently halogen, C1-6the alkyl substituted by one or more halogen atoms, C1-6alkoxygroup substituted by one or more atoms of halogen, S(O)n(C1-6the alkyl, optionally substituted by one or more halogen atoms), where n is 0, 1 or 2, or SF5,

or their pharmaceutically or veterinary acceptable salt.

2. The compound or salt according to p. 1, where R4and R6is a halogen.

3. The compound or salt according to any preceding paragraph, where R5is C1-6the alkyl substituted by one or more halogen atoms, C1-6alkoxy, substituted by one or more halogen atoms, C1-6alkylthiol, optionally substituted by one or more halogen atoms, SF5or halogen.

4. The compound or salt according to any preceding paragraph, where R1is CN, Ph, CO2WITH2H5CH3, CF3and CO2CH3.

5. The compound or salt according to any preceding paragraph, where R2is a group of the formula)2OH, CO2CH3Ph, Tien-2-yl, CH2OCH3, Br, Cl or CF3or a group of formula III in which R8, R9and R10each is H, or a group of formula III in which R8, R9and R10each is Cl, or a group of formula III in which R8and R9are Br, and R10is H, or a group of formula III in which R8and R10are Br, and R9is H, or a group of formula III in which R8and R9are Br, and R10is CH3or a group of formula III in which R8and R10are Br, and R9is CH3or a group of formula III in which R8and R10are Br, and R9is Ph, or a group of formula III in which R8and R9are Br, and R10is Ph, or a group of formula III in which R8and R10are Cl, and R9is Ph, or a group of formula III in which R8and R9are Cl, and R10is Ph, or a group of formula III in which R8and R10are Cl, and R9is Br, or a group of formula III in which R8and R9are Cl, and R10is Br, or a group of formula III in which R8is N, and R10and R9are Br, rotoroa R8is N, and R10and R9are F, or a group of formula III in which R8is N, and R10is CF3and R9are Cl, or a group of formula III in which R8is N, and R9is CF3and R10are Cl, or a group of formula III in which R8is N, and R10is CF3and R9are Br, or a group of formula III in which R8is N, and R9is CF3and R10are Br, or a group of formula III in which R8is N, and R10is CF3and R9are F, or a group of formula III in which R8is N, and R9is CF3and R10are F, or a group of formula III in which R8and R10are H, and R9is CN, or a group of formula III in which R8and R9are Br, and R10is CF3or a group of formula III in which R8and R10are Br, and R9is CF3or a group of formula III in which R8is Br, R9is Br and R10is Cl, or a group of formula III in which R8is Br, R10is Br and R9is Cl, or a group of formula III in which R8is CH3, RVlada F, or a group of formula III in which R8is CH3, R9and R10are H, or a group of formula III in which R8is H, R9and R10are CH3or a group of formula III in which R8, R9and R10are each Br, or a group of formula IV.

6. The compound or salt according to any preceding paragraph, where R3is N, CH3, NH2N-pyrrolyl, N (CH3)2, NH(CO2(tert-butyl)), N(CO2(tert-butyl))2, NHCOCH3, Br, Cl, SCH3.

7. The compound or salt according to any preceding paragraph, where R4and R6is Cl.

8. The compound or salt according to any preceding paragraph, where R5is CF3, OCF3SCF3or SF5.

9. The compound or its salt under item 1, which is: 3-cyano-1-(2,6-dichloro-4-triptoreline)-4-ethynylpyrene; 3-cyano-1-(2,6-dichloro-4-trifloromethyl)-4-ethynylpyrene; 3-cyano-1-(2,6-dichloro-4-triftormetilfullerenov)-4-ethynylpyrene; 4-(2-bromo-1,2-dichloroethenyl)-3-cyano-1-(2,6-dichloro-4-trifloromethyl)the pyrazole; 3-cyano-1-(2,6-dichloro-4-trifloromethyl)-4-tribromoaniline; 4-(2,2-dibromoethenyl)-3-cyano-1-(2,6-dichloro-4-triptoreline)pyrazole; 3-cyano-4-(2,2 l)pyrazole; 3-cyano-1-(2,6-dichloro-4-triptoreline)-4-tribromoaniline; 3-cyano-1-(2,6-dichloro-4-triptoreline)-4-trichloroaniline; 4-(2-bromo-1,2-dichloroethenyl)-3-cyano-1-(2,6-dichloro-4-triptoreline)pyrazole; 4-(2-chloro-1,2-dibromoethenyl)-3-cyano-1-(2,6-dichloro-4-triptoreline)pyrazole; 3-cyano-1-(2,6-dichloro-4-triptoreline)-4-(1-methyl-2,2-dibromoethenyl)pyrazole; 3-cyano-1-(2,6-dichloro-4-triptoreline)-4-(1-methyl-2,2-deperately)pyrazole; 1-(2,6-dichloro-4-triptoreline)-4-ethinyl-3-cryptomaterial; 4-(2-bromo-1,2-dichloroethenyl)-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-3-cryptomaterial, 1-(2,6-dichloro-4-triptoreline)-4-ethinyl-3-methylpyrazole or their salts.

10. A method of treating a parasitic infection, including the use of biologically active substances, characterized in that the biologically active substance is used as a compound of formula I or its salt PP. 1 to 9, in an effective amount.

11. The method according to p. 10, characterized in that the infection is focal and thus the focus of infection is treated with an effective amount of the compounds of formula I or its salts in PP.1 to 9.

12. The method according to p. 10, characterized in that the infection is treated the patient by introducing him an effective amount of compounds of the Fort is or fur of the animal.

14. The method according to p. 11, characterized in that the islet is a plant or seed.

15. The compound or its salt according to PP.1 - 9 as antiparasitical tools.

16. The way damage or destruction of parasites by the use of biologically active products, characterized in that the biologically active products used as a compound of formula I or its salt PP. 1 to 9, in an effective amount.

Priority points features:

11.08.95 on PP.1 - 16, variation of the radicals R1- R10;

19.01.96 on PP.1 - 16, variation of the radicals R1- R10.

 

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The invention relates to a derivative of khinoksalinona used in medicines and the way they are received

The invention relates to a new benzodiazepine derivative of the formula I given in the text of the description, which are useful as medicines, which have an antagonistic effect against gastrin and/or CCK receptor-and their reception, where R1refers to a group-CH2CH(OH)(CH2)aR4or ketone group,- CH2CO(CH2)aR5where a = 0 or 1; R4- C1-C7-alkyl straight or branched chain or C3-C8-cycloalkyl; R5- C1-C8-alkyl, C3-C8-cycloalkyl,3-C8-cycloalkyl-C1-C8-alkyl, C1-C8-alkyl-C3-C8-cycloalkyl, pyrrolidyl, possibly substituted C1-C8-acyl, carbamoyl,1-C8-alkylamino-C1-C8-alkyl, or adamantylidene; R2is phenyl, substituted C1-C8-alkyl, C1-C8-alkoxyl, nitro, cyano, amino, halogen, C1-C8-alkylaminocarbonyl, di-(C1-C8-alkylaminocarbonyl, carboxy, C1-C8-allmineral, carboxyhemoglobin, carboxy(C1-C8)alkyl, or pyridylethyl, possibly substituted C1-C8-alkyl; R3- peloid in the 7-position of the benzodiazepine ring; W is hydrogen or C1-C8the alkyl in the 8-position of the benzodiazepine ring, or its pharmaceutically acceptable salt

The invention relates to new derivatives benzazepine, which are used as antagonists Organisatorische, to their pharmaceutically acceptable salts, to pharmaceutical compositions containing these compounds as active ingredients and intermediate products for the synthesis of these compounds

The invention relates to new nitrogen-containing heterocyclic compounds possessing biological activity, and more particularly to derivatives of N-substituted azabicycloalkanes

The invention relates to new substituted pyrrole General formula I

< / BR>
where R is hydrogen, hydroxyl;

R1and R2- together group of the formula -(CH2)nand R7is hydrogen, or R1and R7- together group of the formula -(CH2)nand R2is hydrogen;

R3is phenyl, naphthyl which may be substituted with halogen, C1-C7- alkoxy, CF3or benzofuranyl, benzo(b)thienyl, indolyl, substituted by 1-3 substituents selected from the group comprising halogen, C1-C7-alkyl, C1-C7-alkoxy; R4, R5and R6is hydrogen, halogen, C1-C4-alkoxy, C1-C7-alkyl,

R8a group of the formula -(CH2)p-R9or -(CH2)q-R100;

R9is hydrogen, C1-C7-alkylsulphonyl, C1-C7-alkylsulfonyl, aminocarbonyl;

R10is hydroxyl, amino, C1-C7-alkylamino, di(C1-C7)-alkylamino, three(C1-C7)-alkylamino, azido, C1-C7-alkoxy-carbylamine, isothiocyanate, C1-C7-alkylcarboxylic, C1-C7-alkylsulfonate, 6-membered nitrogen-containing saturated gets the SUB>2; W is amino; one of X and Y - O-atom, and the other is O or (H,H);

Z - group-CH - or N-atom;

m, p and q is a number from 0 to 5, n is a number from 1 to 5, provided that m and q represent the number from 2 to 5 when Z Is N-atom, and their pharmaceutically acceptable salts

The invention relates to new derivatives of benzimidazole with valuable properties, in particular a derivative of benzimidazole of General formula (I)

< / BR>
where R1is methyl,

R2- benzimidazole-2-yl, unsubstituted or substituted in position 1 by the stands, imidazol-4-yl substituted in position 1 by alkyl with 1 to 3 carbon atoms, substituted in position 2 by morpholinopropan, 5,6,7,8-tetrahydro-imidazo[1,2 - a]pyridine-2-yl or propanesultone-1-Il,

R3- nonbranched alkyl with 2 to 4 carbon atoms,

R4- amino group, sulfonyl substituted by a residue from the group consisting of dimethylaminopropylamine, cycloalkylcarbonyl, benzylaminocarbonyl in which cycloalkyl part contains 5 or 6 carbon atoms and the phenyl portion may be substituted methoxy group, triptorelin, tert
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