Derivatives of pyrazole or their pharmaceutically acceptable salts

 

(57) Abstract:

Usage: in the pharmaceutical industry. The inventive derivatives of pyrazole f-ly 1, where C=0, or COR4optional connection, P= 0-1, R and R independently of one another H, (C2-C6)alkyl, substituted or unsubstituted phenyl, benzyl, naphthyl, pyridyl, R2-N,(C1-C6alkyl, -CH2COOH, (C1-C4) alkoxy PINES2WITH(A)(A)t-Y, t=1, A is NH,Y is phenyl substituted CF3and/or l, R4(C1-C6)alkyl, -CH2COOH, (C1-C4)alkoxy PINES2-, R3-H, or a group of f-l is 2 or 3, where a is 0 or S, X-Hal, m=0-2, n=0-1, Q is NH(C1-C6)alkyl, S, R5group [CH(R6)]q(CH2)r-R, where R6WITH1-C6alkyl, q=0-1, r-0-2, R7-H,(C1-C8)alkyl, pentafluorophenyl, pyridyl, tetrahydronaphthyl, indolyl, chinoline, substituted or unsubstituted phenyl or naphthyl, or a group (Q)n-R5-2-tetrahydroisoquinoline, or their pharmaceutically acceptable salts. 8 C. p. F.-ly. Connection structure of f-crystals 1, 2, 3: 2 C. and 6 C.p. f-crystals, 16 PL.

The invention relates to biologically active pyrazolidinone. More specifically, the invention concerns certain substituted personal gland, and with gastrin receptors, such as receptors of the stomach. The compounds are antagonists of CCK and gastrin and find application in the treatment and prevention of CCK-gastrin-mediated disorders of the gastrointestinal, Central nervous and appetite regulatory systems of warm-blooded vertebrates, especially humans.

Cholecystokinin (CCK) is neuropeptid detected in gastrointestinal tissue and in the tissues of the Central nervous system. I believe that CCK plays an important role in the regulation of appetite. Among the effects of cholecystokinin may be noted the stimulation of peristalsis of the colon, stimulates contraction of the gallbladder, the stimulation of secretion pancreatically enzymes and inhibition of gastric emptying. CCK provides dopamine in some neurons of the midbrain and therefore may also play a role in the functioning of the dopaminergic systems in the brain. Gastrin is neuropeptide found mostly in the gastrointestinal tract. He is one of the main stimulators of secretion of gastric acid. He also has an effect of promoting growth in a number of gastrointestinal tissues.

Antagonists of CCK and Gus is straley nervous systems, as well as in the modulation of appetite regulatory systems of warm-blooded vertebrates. Think of CCK (gastrinoma receptor family consists of three subtypes of receptors for which the location of the receptor is the prototype given in parentheses: CCK-A (pancreas), CCK-b (brain) and gastrin (the fundus of the stomach).

The literature describes several classes of antagonists of CCK receptors. One class comprises derivatives of cyclic nucleotides, for example, dibutyryl-cyclic GMP (guanosine 5' monophosphate). Other recognised class of antagonists of CCK include With leaf fragments and analogues of CCK. Another class of receptor antagonists of CCK are amino acid derivatives, including proglumide derived glutaramic acid, and N-acetryptine,such as p-chlorobenzoyl-L-tryptophan. More fresh substituted aminophenolate compound is described as antagonists of CCK in the published application Europatent N 0166355. Due to the wide range of potential clinical applications of CCK - binding compounds intensive research work is carried out to identify other compounds exhibiting the properties of binding to CCK receptors.

The invention is aimed at developing new with the suitable treatment and prevention of CCK-mediated disorders of the gastrointestinal and Central nervous systems, and as modulators of appetite regulatory systems of warm-blooded vertebrates, especially humans. As antagonists of gastrin they are particularly useful in the treatment and prevention of gastrointestinal ulcers and tumors of gastrointestinal origin.

The invention relates to compounds of the formula:

< / BR>
where L denotes 0 or COR4group --- indicates an optional bond, R is a whole number equal to 0 or 1, R and R1independently represent hydrogen, C1-C6alkyl, phenyl, benzyl, naphthyl, pyridyl or substituted phenyl having 1 or 2 substituent selected from the group consisting of C1-C6alkoxy, halo, trifloromethyl, cyano, carbamyl, nitro, amino, -NH (C1-C4the alkyl or benzyl), and N(C1-C4the alkyl)2; R2denotes hydrogen, C1-C6-- alkyl, carboxymethyl,1-C4- alkoxycarbonylmethyl or a group of the formula:

< / BR>
where t is 1 or 0, And denotes-CH2-, -0-, NH or N(C1-C6-alkyl) -, and Y denotes a phenyl or substituted phenyl, as defined above, R4stands WITH1-C6-alkyl, carboxymethyl or1-C4alkoxycarbonylmethyl, R3denotes hydrogen or a group fo the1-C6-alkyl) -, -S - or-0-, and R5denotes a group of the formula/CH(R6)/q -(CH2)rR7where R6denotes hydrogen or C1-C6alkyl, q is 0 or 2; r is 0,1 or 2 and R7denotes hydrogen, C1-C8alkyl, pentafluorophenyl, pyridyl, tetrahydronaphthyl, indolyl, chinoline, phenyl, naphthyl or phenyl or naphthyl, substituted by 1 or 2 substituents selected from the group consisting of (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkylthio, halogen, trifloromethyl, phenyl, phenoxy, phenyl (C1-C4) alkoxy, (C1-C6) alkanoyl, nitro, (C1-C6) alkoxy, carbonyl, methylenedioxy, (C3-C6alkylene, amino, di(C1-C4elcamino, or group of QnR5mean 2-Tetra-hydroisoquinoline, as well as their pharmaceutically acceptable salts, provided that at least one of the groups R or R1means is other than hydrogen or C1-C6- alkyl, and in another condition that at least one of the groups R2and R3means is other than hydrogen, and when R3denotes a group of the formula

< / BR>
then R2means other than a group of the formula

< / BR>
and propacet link.

Thus, the expert is easy to understand that when L is 0, the compound of formula I has the following structure

< / BR>
and when L represents a group COR4the compound of formula I has the following structure:

< / BR>
In the compounds of formula I, the groups R and R1can be in any CIS - or TRANS-configuration relative to the plane of the ring of pyrazolidinone. The TRANS configuration is preferred in accordance with the invention, shown as thermodynamically preferred form.

Used in the description of the term halo refers to fluorine, chlorine or bromine. The term C1-C6alkyl includes both remotemachine and branched alkyl and cycloalkyl, and includes methyl, ethyl, propyl, cyclopropyl, isopropyl, butyl, methylcyclopropyl, cyclobutyl, isobutyl, tert-butyl, pentyl, cyclopentyl, neopentyl, hexyl, cyclohexyl, 2-methyl-pentyl and so on. In alternates WITH1-C6alkoxy alkyl part is described above WITH1-C6alkyl.

The term pharmaceutically acceptable salts encompasses those salts that form a standard acid-base reactions with major groups (such as amino groups) and kolotyluk, pharmaceutically acceptable salts of the invention can be obtained by conventional chemical methods from compounds of the formula I which contain a basic or acidic part. Generally, salt is produced by the interaction of the free base or acid with stoichiometric amounts or with an excess of the desired salt-forming acid or base in a suitable solvent or combination of solvents. Suitable soleobrazutaya acid include inorganic acids such as hydrochloric, Hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and so forth, organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, citric, malic, tartaric, ascorbic, Panova, maleic, ximalayasha, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluensulfonate, methanesulfonate, ethicalfashion, oxalic acid, benzene-acid, picric, cinnamic and like acids. The grounds, which are used to obtain the salts of the compounds of formula I having acidic part, are hydroxides of alkaline or alkaline-earth metals, such as hydroxides of naimisaranya, the triethylamine, trimethylamine, piperidine, pyrrolidine, 2-hydroxyethylamine, bis (2-hydroxyethyl) amine, phenylethylenediamine and similar organic amines.

Compounds of the invention bind to receptors of CCK and gastrin in the brain and/or peripheral sites such as the pancreas, gall bladder, stomach and the ileum. Their ability to anlagenservice of CCK and gastrin makes these compounds suitable as pharmaceuticals for the treatment and prevention of painful conditions that can be involved CCK and gastrin, for example, gastrointestinal disorders such as mucous colitis, ulcers, excess pancreatic or gastric secretion, acute pancreatitis, contractility disorders, neoplasms gastrointestinal origin; disorders of the Central nervous system, including the interaction of CCK with dopamine, such as neuroleptic disorders, late dyskinesia, Parkinson's disease, psychosis or syndrome Gilles de La Tourette's, and other disorders of the Central nervous system, in which the causal factor is believed to CCK, such as panic attacks and other forms of anxiety, as well as in modulating appetite accordance with the invention are pyrazolidinone formula I, in which L

the group is 0 and R is 1, and especially those in which R and R1are transconfiguration relative to the plane of the ring of pyrazolidinone. Preferably, R and R1denote phenyl and substituted phenyl. A preferred group of such compounds are those in which Z represents hydrogen and R3denotes a group of the formula:

< / BR>
One series of such preferred compounds of the invention are those compounds, in which denotes sulfur, n is 1, Q denotes-NH and R5denotes phenyl or substituted phenyl.

Another preferred group of compounds exhibiting significant binding to CCK receptors and gastrin are the compounds of formula I, in which L is a group, p is 1, Z represents hydrogen and R3refers to the part defined by the group-CONH / CH (R6)q- (CH2)rR7. Especially preferred compounds in this group are those in which q and r are 0 and R7denotes phenyl, substituted were radioactive, 2-naphthyl or 3-chinoline, R and R1denotes phenyl, naphthyl or substituted phenyl in the TRANS configuration relative to the plane of the ring of pyrazolidinone. When R7means substituted phenyl, preferred mandated-C4-alkylen, benzyloxy and methylthio.

Compounds of the invention can be easily obtained from the corresponding compounds of the formula (III)

< / BR>
The intermediate 3-pyrazolidinone easily obtained by reacting hydrazine with the corresponding ,-unsaturated esters of formula R1-CH C (R) COOR', where R and R1have the above meanings and R1denotes complex atheromatous group, usually WITH1-C6-alkyl. Compounds of the invention typically obtained by acylation or alkylation of 3 - pyrazolidinone formula III under neutral or basic conditions using alleluya or alkylating agents, chosen to obtain the desired compounds of the invention.

In another embodiment of the invention are disclosed pharmaceutical compositions comprising as an active ingredient an effective amount of the compounds of formula I, and pharmaceutically acceptable carrier, excipient or diluent. Such compositions can be obtained for oral or parenteral administration in the treatment and prevention of disorders of the gastrointestinal, Central nervous and appetite systems of warm-blooded invertebrates, especially of man.

On the Orme tablets or capsules, as well as an aqueous solution or suspension. In the case of tablets usual fillers include binding agents, for example syrup, Arabian gum, gelatine, sorbitol, tragakant, polyvinylpyrrolidine (Povidone), methylcellulose, ethylcellulose, the sodium carboxymethyl cellulose, hypromellose, sucrose and starch, fillers and carriers, for example corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid, lubricants such as magnesium stearate, disintegrant, such as crosscarmellose, microcrystalline cellulose, corn starch, alginic acid, and suitable humectants, such as valium. For oral administration in capsule form, useful diluents include lactose and dried corn starch. If oral administration is desired aqueous suspensions of the active ingredient can be combined with emulsifying and suspendresume means, for example, sorbitol, methylcellulose, glucose sugar syrup, gelatinous, hydroxyethylcellulose, carboxymethyl cellulose, gel aluminum stearate or hydrogenated edible oil is a glycol or ethyl alcohol, flavors, such as peppermint, oil of Grushenka, cherry corrigent and so forth, and preservatives, such as methyl or propyl p-hydroxybenzoate or ascorbic acid.

Pharmaceutical compositions in accordance with the invention also may be formulated for parenteral administration. Such compositions typically take the form of sterile isotonic solutions of the active component in accordance with the standard technology of preparation of medicines.

A suitable dose of a compound of the invention for use as an antagonist of CCK or gastrin in humans will vary depending on age, weight and response of the individual patient, as well as the complexity of the patient's symptoms and the nature of the disease to be treated. Thus, the preferred daily dose is usually determined by the treating physician. However, in most instances, an effective daily dose of the compounds of the invention comprise from 0.05 dose of the compounds of the invention comprise from 0.05 to 50 mg/kg, approximately, and preferably about 0.5-20 mg/kg, in single or shared doses.

The following examples are intended to further describe the compounds of the invention and methods of their Polt at room temperature, unless specified otherwise. The solvent is removed using a rotary evaporator under reduced pressure. Chromatography is carried out on the usually-phase silica columns. Titration is performed with the use of 2:1 DMF N2O as solvent.

Example 1.

1-(4-Chloro-3-triptoreline) aminocarbonyl/-4,5 - diphenyl-3-pyrazolidinone (Method A).

4,5 Diphenyl-3-pyrolidinone (3.00 g, 12.6 mmol) was dissolved in 40 ml of THF under nitrogen, and then for 2 minutes and add a solution of 4-chloro-3-triftormetilfullerenov (2,87 g, 13,0 mol, 1.03 EQ) in 10 ml of THF. Through 2,3 h the solvent is removed in vacuo and the residue proscout using 25 ml of toluene. The obtained solid is crushed, twice promyvatelem and dried in vacuum at 65oWith obtaining 4,94 g (85%) of a solid white color.

1H NMR (d6DMSO) d 3,81 (Shir.s, 1H), 5.56mm (Shir. s, 1H), 7,26 to 7.50 (m, AN), a 7.62 (d, J 9 Hz, 1H), 7,89 (DD, J 3.9 Hz, 1H) 8,13 (Shir. s, 1H), for 9.64 (Shir.s, 1H), 10,90 (Shir.s, 1H); mass spectra (MS) 460 (M+1+).

Analysis for C23H17lF3N3O2:

Calculated With 60,07; N. Of 3.73; N 9,14.

Found, With 59,99; N 36,60; N 8,89.

Example 2.

1-/(4-N, N-Dimethylaminophenyl) aminocarb,63 g, 35,87 mmol, 244 EQ. ) dissolved in 50 ml of toluene under nitrogen, and then add triphosgene (1.45 g, 4,89 mmol, of 0.333 EQ), in the form of a pure solid. The mixture is heated under reflux for 2.5 h, cooled, and then quickly filtered, the collected solid washed twice with toluene and the combined filtrates evaporated in vacuo to obtain crude 4-N, N dimethylaminophenyl isocyanate as to 2.57 g of brown oil, which was re-dissolved in 50 ml of THF, followed by addition of a solution of 4,5 - diphenyl-3-pyrazolidinone (3.50 g, 14,69 mmol, 1.00 equiv.) in 50 ml of THF for 3 minutes Through 20,7 h the solvent is evaporated in vacuum and the product emit chromatography (preparative HPLC, 0-50% gradient Et SLA toluene) in the form of 1.73 g of yellow oil, which slowly crystallizes. Recrystallization from toluene yields a 744 mg (13%) of white crystalline solid.

1H-NMR (d6DMSO) 2,84 (C, 6N), 3,71 (s, 1H), of 5.55 (s, 1H), to 6.67 (d, J 8 Hz, 2H), 7,12 7,52 (m, N), 8,86 (Shir. C. 1H), 10,70, (Shir. C. 1H) 400 MS (M+; PKatitration 4,0, 7,9.

Analysis for C24H24N4O2:

Calculated WITH 71,98; N 6,04; N 13,99;

Found, C 72,08; N The 6.06; N 14,06.

Example 3.

1-/(4-Benzyloxyphenyl) amino is dirout in 50 ml of toluene with oxalylamino (5 ml) and heated to a temperature of distillation for 15 minutes The solvent is removed in vacuo, the residue re-dissolved in 30 ml of acetone and an aqueous solution of Na N3(1,16 g, 17.6 mmol, 2.0 EQ.) in 10 ml of N2About added dropwise with external cooling with a water bath. The mixture is stirred for 1 h, diluted with water, extracted twice with toluene, and then the combined extracts washed with water and dried in the presence of sodium sulfate. This solution acylated handle 4,5 - diphenyl-3-pyrazolidinone (1.6 g, 6.8 mmol, 0.76 to equiv.) heated for 30 minutes After an overnight stirring at room temperature the solvent is removed in vacuum and the product emit chromatography (0 to 30% gradient t hexane) in the form of 1.6 g (52%) of white solid, melting point 127 - 130oC.

1H NMR(DCl3d of 3.95 (d, J 6 Hz, 1H), 5,0 (s, 2H), of 5.55(d, J 6 Hz, 1H), 6,8 (d, J 10 Hz, 2H), 6,86 7,46 (m, 10H), 7,05 (d, J 10 Hz, 2H) 8,95 (s, 1H); MS 463 (M+); PKatitration of 7.7.

Analysis for C29H25N3O3:

Calculated WITH 75,14; N 5,44; N 9,07;

Found, 75,15; H 5,49; N 9,14.

Example 4.

1-/(2-/1,2,3,4 Tetrahydronaphthyl) /aminocarbonyl/ 4,5 diphenyl 3 - pyrazolidinone (Method D).

1,2,3,4 - Tetrahydro-2-naphthoic acid (639 mg, 3.63 mmol) was dissolved in 80 ml of benzene under the d (1.12 g, 4,08 mmol, 1.1 EQ.) and Et3N (0,41 g, 4.02 mmol, 1.1 EQ.) and the resulting mixture is heated with reverse cooling for 1 h the Solvent is removed in vacuum, the residue is dissolved in dry THD under nitrogen, and then add 4,5-diphenyl-3-pyrazolidinone (784 mg, 3,29 mmol, of 0.91 equiv.) and the mixture is stirred over night. The solvent is removed in vacuum and the product emit chromatography (25 to 50% gradient of EtOAc: hexane) to 0.92 g (68%) of a white foam. Recrystallization of a sample of 120 mg of i - Pr2: i-D allows to obtain 94 kg of a white solid containing a mixture 1:1 of the two diastereomers in NMR, melting point 82-95o.

1H-NMR (DCl3) 1,46 1,66 (m, 1H), 1,79 of 1.97 (m, 1H), 2,30 2,84 (m, 2H), 2.95 and (apparent triplet of doublet, J 6,16 Hz, 1H), a 3.87 (apparent d, J 6 Hz, 1H), 4.09 to (m, 1H), 5,12 (m, 1H), 5,34 (apparent doublet of doublet, J 6,14 Hz, 1H), 6,86 7,40 (m, 14N), and 9.0 (PTS.Shir. C. 1H); MS 411 (M+).

Analysis for C26H25N3O2:

Calculated With 75,89; H 6,12; N OF 10.21;

Found, C 75,75; N 6,32; N 9,72.

Example 5.

1-/(3-Trifloromethyl/ 4,5 diphenyl-3-pyrazolidinone (Method E).

A solution of 4,5-diphenyl-3-pyrazolidinone (2.0 g, 8.4 mmol) in 50 ml of CH2Cl2and 5 ml of pyridine is treated dropwise with a solution of 3-triptorelin the m Hcl, dried in the presence of sodium sulfate, evaporated and the product emit chromatography (preparative HPLC) in the form of 840 mg 24) foam purple.

1H-NMR (DCl3d a 3.83 (s, 1H), 5,16 (s, 1H), 7,2 to 7.64 (m, 15 NM); MS 410 (M+; PKatitration 7,15.

Analysis for C23H17F3N2O2:

Calculated WITH 67,31; N 4,18; N 6,83;

Found, With 67,52; N 4,16; N 6,66.

Example 6.

1-(4-Chlorophenyl) oxycarbonyl/- 4,5 diphenyl-3-pyrazolidinone (Method F).

A solution of 4,5 diphenyl-3-pyrazolidinone of 1.25 g of 5.26 mmol) in 50 ml l3treat a solution of 4-khlorfenilalanina (1.0 g, 5,26 mmol) in 10 ml of CHC3and stirred over night. The solvent is removed in vacuum and the residue is recrystallized from EtOAc: hexane to obtain 1.6 g (58%) of a solid white color, melting point 175 177oC.

1H-NMR (DCl3d 3,93 (d, j 6 Hz, 1H), 5,62 (d, J 6 Hz, 1H), 6,8 7,5 (m, 15 NM); MS 392 (M+; PKatitration of 7.8.

Analysis for C22H17ClN2O3:

Calculated, 67,26; N 4,36; N 7,13;

Found, With 67,49; N. Of 4.54; N 7,17.

Example 7.

1-/(3,4-Dichlorobenzyl) aminocarbonyl/-4,5-diphenyl-3-pyrazolidinone (Method M).

A solution of 1/(4-nitrophenyl) oeaut to a temperature of distillation within 8 hours The solvent is removed in vacuo, the residue taken in CH2Cl2, washed twice 1 N. Hcl solution and once with buffer solution, pH 7.0 and dried in the presence of sodium sulfate. After removal of the solvent in vacuo the product was then purified by chromatography (0-35% gradient tOAc: hexane) to obtain 250 mg (23%) of a solid.

1H-NMR (CD Cl3d 3,93 (d, j 6 Hz, 1H), 4,28 (giving kV, J 7,15 (JAB) HzDv= 48 Hz, 2H), 5,50 (d, J 6 Hz, 1H), 6,56 (Shir. so J 7 Hz, 1H), 6,92 7,44 (m, 13H), 8,73 (Shir.with. 1H); MS 439 (M+); PKatitration of 8.4.

Analysis for C23H19Cl2N3O2:

Calculated WITH 62,74; N. OF 4.35; N 9,54;

Found, 62,49; N A 4.53; N 9,25.

Example 8.

2-/(4-Chloro-3-triptoreline) aminocarbonyl/ 4,5 - diphenyl-3-pyrazolidinone (Method N)

1-/(4-Chloro-3-triptoreline) aminocarbonyl/ 4,5 - diphenyl-3-pyrazolidinone (2.00 g, 4.35 mmol) in 100 ml of toluene is heated under reflux for 24 hours After removal of the solvent in vacuo the product emit chromatography (CH2Cl2), then recrystallized from i-Pr2O: hexane to obtain 300 mg (15) of a solid white color, melting point 72 74oC.

1H-NMR (CDCl3) 4,22 (d, j 12 Hz, 1H), 4,82 (DD, j 9,12 Hz, 1H), 5,44 (d, j 9 G> Analysis for C23H17Cl F3N3O2:

Calculated WITH 60,07; N. OF 3.73; N 9,14;

Found, With 59,95; N To 3.92; N 8,88.

Example 9.

1-/6-Chloro-2-benzothiazolyl/-4,5-diphenyl-3 pyrazolidinone (Way 0).

The reaction is carried out in a dry nitrogen atmosphere. A suspension of 4,5 - diphenyl-3-pyrazolidinone (1.19 g, 5.00 mmol) in 35 ml of toluene is treated with 0.40 g NaH (60% in mineral oil; the content of the hydride 0.24 g, 10.0 mmol, 2.00 EQ. ) and the mixture was stirred at 45oC for 2 hours was Added 2,6 - dichlorobenzothiazole (1,02 g, 5.00 mmol, 1.00 EQ) and stirring is continued at 80oWith over 20 hours After cooling, the reaction mixture is poured into 30 ml of chilled on ice 5 n Hcl solution, extracted with tOAc and separate the organic phase is washed twice with saline, dried in the presence of sodium sulfate and the solvent evaporated in vacuum. The residue is recrystallized from Et2O: hexane obtaining of 1.46 g (72%) of crystals of yellowish-brown color, melting point 170,5 - 172,5oC.

1H-NMR (CD Cl3d 4,07 (Shir. D. J 6 Hz, 1H), 5,24 (Shir. D. J 6 Hz, 1H), 7,16 7,58 (m, 14N); MS 405 (M+; PKatitration of 6.6.

Analysis for C22H16ClN3OS:

Calculated WITH 65,10; N. OF 3.97; N 10,35;

Denon

1-/(4-Nitrophenyl) aminocarbonyl/-4,5-diphenyl-3-pyrazolidinone (500 mg, 1,24 mmol) is dissolved in 50 ml of EtOH and hydrogenizing 5 palladium carbon (500 mg) under hydrogen pressure of 60 pounds per square inch (4,219 kg/cm2) overnight at room temperature. The mixture is filtered to remove the catalyst, the solvent is removed in vacuum and the product emit chromatography (0-50% gradient of EtOAc: hexane) 125 kg (27%) of a solid.

1H-NMR (CDCl3d of 3.97 (d, J 6 Hz, 1H), 5,50 (d, J 6 Hz, 1H), return of 6.58 (d, J 10 Hz, 2H), return of 6.58 (d, J 10 Hz, 2H), of 6.96 (d, J 10 Hz, 2H), 7,2 7,5 (m, 10H); MS 372 (M+); PKatitration 4,5, 8,1.

Analysis for C22H20N4O2:

Calculated SN 70,95; N 5,41; N 15,04;

Found, 70,65; N 5,42; N 14,75.

Example 11.

1-/(4-Bromophenyl)aminocarbonyl/2-(0-tert-BUTYLCARBAMATE)-4,5-diphenyl-3-pyrazolidinone and 1/(4-bromophenyl)-aminocarbonyl/3-(0-tert-BUTYLCARBAMATE)-4,5-diphenyl-2-pyrazolin.

To a suspension of 1/(4-bromophenyl) aminocarbonyl/- 4,5-diphenyl-3-pyrazolidinone (2.0 g, 4.6 mmol) in 30 ml of absolute EtO added a solution of KOH (1.1 EQ. ) in absolute EtOH and tert-butylbromide (5 ml). After stirring for 3 days. appears sediment CVG. The mixture is diluted with water, extracted with Et2O, satama. Nonshared mixture of two products emit chromatography (0-25% gradient of EtOAc: hexane) in the form of 1.3 g (52% ) of a foam containing a 3:2 ratio of N-alkyl 0-alkilirovanny products (first and second specified in the header of the product, respectively).

1H-NMR (CDCl3)N-alkilirovanny: d 1,53 (S. 96), of 3.96 (d, J 19 Hz, 1H), 4,06 (C. 1H) and 4.65 (D. J 10 Hz, 1H), 5,95 (s, 1H), 7.23 percent - 7,46 (m, 14N), 9.70 (s, 1H), 0 alkilirovanny: d 1,53 (s, N), 4,18 (D. J 7 Hz, 1H), 4,67 (s, 2H), of 5.40 (d, J 7 Hz, 1H), 7.23 percent 7,46 (m, 14N), 7,74 (s, 1H); MS 549, 551 (M+for Br isotopes).

Analysis for C28H28BrN3O4:

Calculated WITH 61,10; N 5,13; N 7,63;

Found, 60,94; N Is 4.93; N A 7.85.

Example 12.

1-/(4-Bromophenyl) aminocarbonyl /2-carboxymethyl/-4,5-diphenyl-3-pyrazolidinone 1-/4-bromophenyl) aminocarbonyl/-3-carboxymethyl - 4,5 diphenyl-2-pyrazolin

Regioisomeric mixture of complex tert-butyl ester from example 11 /mix of 3: 2 N - 0-alkilirovanny/ (500 mg, of 0.91 mmol) dissolved in 30 ml of CH2Cl2and 5 ml triperoxonane acid. After 4 h of conducting thin-layer chromatography (CH2Cl2) is the disappearance of the starting materials. The solvent is removed in vacuo and a mixture of two products emit chromatography (0-100% gradient Et OAc: hexane) 180 mg (40%responsible, specified in the header/ when conducting NMR.

1H-NMR (CDCl3) N-alkilirovanny: d 4.09 to (d, J 2 Hz, 1H), 4,10 (d, J 19 Hz, 1H), and 4.68 (d, J 19 Hz, 1H), of 5.83 (d, J 2 Hz, 1H), 7,20 7,50 (m, 14N), the remaining 9.08 (s, 1H); 0 alkilirovanny: d 4,19 (d, J 5 Hz, 1H), a 4.83 (AB kV, J 16 Hz, Dv 30 Hz, 2H), 5,46 (d, J 5 Hz, 1H), 7,20 is 7.50 (m, 14N) of 7.75 (s, 1H), MS 493, 495 (M+for Br isotopes); PKatitration of 4.8.

Analysis for C24H20BrN3O4:

Calculated, With A 58.3; H 4,08; N Of 8.50; Found, 58,59; N Is 4.03; N 8,24.

N - and 0 alkylated products are separated by chromatography on obsevatory column waters WITH18using a mixture of 30 to 40% of CH3CN: N2O, buffered with use of 0.3 to 0.5% NH4O A. C. Leading faction of the first shoulder strap evaporated, lyophilized, then take in CH2Cl2, washed twice 1 N. Hcl solution, then the solvent is removed in vacuum and then the solvent is removed in vacuum to obtain 28 mg of 0-alkylated product:

1H-NMR (CDCl3): 4,19 (d, J 7 Hz, 1H), 4,84 (Avcv, J 17 Hz,Dv 25 Hz, 2H), of 5.45 (d, J 7 Hz, 1H), 6,39 (Shir. s, 1H), 7,20 - 7,40 (m, 14N), 7,70 (C. 1H).

The last faction twice periprosthetic, then processed in a similar fashion to obtain 8 mg alkylated product:

1Mr. YAM is tx2">

Example 13.

1-/(4-Triptoreline) aminocarbonyl/-3-methoxy - 4,5 - diphenyl-2-pyrazolin

A solution of 1/(4-triptoreline) aminocarbonyl/ -4,5-diphenyl-3-pyrazolidinone (740 mg, of 1.74 mmol) and KOH (122 mg, 88% purity, 1.1 EQ.) in 30 ml of absolute EtOH is treated with iodomethane (5 ml) and stirred over night. The mixture is diluted with water, extracted twice CH2Cl2and the combined extracts washed with water, dried in the presence of sodium sulphate and evaporated in vacuum. The product distinguish chromatography (0 to 15% gradient of EtOAc: hexane) in the form of 61 mg (8%) of a solid.

1H-NMR (CDCl3): d 4,0 (s, 3H), 4,11 (d, J 6 Hz, 1H), 5,48 (d, J 6 Hz, 1H), 7,2-7,74 m (m, 14N), of 8.09 (s, 1H) MS 439 (M+.

There are also 1-/(4-triptoreline) aminocarbonyl/-2 methyl-4,5-diphenyl-3-pyrazolidinone accordingly, the product obtained by the method of example 1 from 2-methyl-4,5-diphenyl-3-pyrazolidinone and 4-triftormetilfullerenov.

Example 14.

1-(Indole-2-carbonyl)-4,5-diphenyl-3-pyrazolidinone

Indole-2-carboxylic acid (1.35 g, scored 8.38 mmol) oxalyl-chloride (4 ml) and DMF (3 drops) was added in this order to 50 ml of toluene and stirred until gas evolution and obtain a homogeneous solution (20 min). The solvent is removed in vacuo,50 ml of CH2Cl2and 5 ml of pyridine. After stirring overnight the solution was washed with 1 N. Hcl solution, dried in the presence of sodium sulfate and the solvent is removed in vacuum. The residual solid was stirred with CH2Cl2, filtered and recrystallized from DMF: N2O to obtain 1.42 g (44%) of a solid white color, melting point 248-250oC.

1H-NMR (d6DMSO): d 3,82 (s, 1H), 5,86 (s, 1H), 6,95 - to 7.6 (m, 10H), 11,84 (Shir. C. 1H), MS 381 (M+); PKatitration of 6.75.

Analysis for C24H19N3O2:

Calculated With 75,57; N 5,02; N 11,02; Found, 75,38; N To 5.21; N 10,99.

Examples 15 135 summarized below in table. 1. The connection of each example identifies with reference to structural formula, anticipating each group of examples. The method of obtaining each connection is specified with reference to the ways And 0, which are given in the above examples 1 to 9. Phenyl groups on the ring pyrazolidinone compounds of examples 1 to 67 and 74 109 are in the TRANS position.

Note to tables:

(a) includes other purification methods such as chromatography (chrom), poroshkovaya and precipitation, as indicated. If given solvent, the compound was purified perekrestenko;

b) after recrystallization from EtOAc: hexane;

(C) purified by extraction in 1H. NaOH solution, followed by acidification 1H. solution l and extraction in an organic solvent (Et2O or tOAc). Evaporation of the solvent allows to obtain a material homogeneous in TLC and have satisfactory purity;

d) obtained using S-(-)-a-methylbenzenesulfonate;

e) all of the patterns are splitting i.e. obvious after visual examination of the graph, and reflect a combination of true protonproton magnetic relations, as well as multipletness, due to the presence of a mixture of two diastereomers;

f) obtained using R-(+)-a-methylbenzenesulfonate;

g) is obtained using (4-bromo-a-methylbenzenesulfonate;

h) obtained using (R)-(-)-1-(1-naphthyl)-utilizationof.

Example 138.

1-[2(2-naphthyl) aminothiazolyl]-4,5-diphenyl-3-pyrazolidinone(Method G).

2-Aminonaphthalene (2,95 g of 20.6 mmol) was dissolved in 230 ml l3in nitrogen atmosphere. Add 11.5 ml triethylamine, 8,35 g of 82.5 mmol, 4,00 EQ.) and the mixture is cooled in an ice bath. Add thiophosgene (3,30 ml of 43.3 mmol, 2 EQ. ) dissolved in 90 ml Cl3slowly for hours Mixing The (CHCl3) phase. The organic phase is separated, washed with water and two times with 1 n Hcl, then passed dropwise through Na2SO4removal of water and evaporated in vacuum to obtain 4,29,

(> 100%) of brown oil, which solidified. NMR shows the desired 2-naphthylisocyanate and impurities,1H NMR (CDCl3) 7,30 a 7.85 (m, 7H).

4,5 Diphenyl-3-pyrazolidinone (1,00 g, 4.20 mmol) dissolved in 10 ml of THF under nitrogen atmosphere and add a solution of crude 2-naphthylisocyanate (obtained above: 0,93 g, 5.0 mmol, 1.2 EQ.) in 10 ml THF. After stirring overnight, TLC showed the unreacted pyrazolidine, was added 2-naphthylisocyanate (0.39 g, 0.50 EQ.) in THF. After stirring for another 1 h, TLC still showed a certain amount of pyrazolidinone. After removal of the solvent in vacuo the residue was partially purified on two successive silikagelevye columns (EtOAc: hexane with 0.5% SPLA). The obtained product is dissolved in l3and extracted three times with buffer solution pH 10. The combined aqueous extracts acidified to 1.0 N. Hcl and then extracted three times with the use of Et2O. the Organic extracts are combined to miss dropwise via Na2SO4to remove the water and upari is eduru extraction is repeated (using everywhere CH2Cl2as the organic phase) to give 311 mg (17) pale yellow foamy product:

1H NMR (CDCl3d 4,11 (D. J 5Hz, 1H, 5,73 (d, J 5Hz, 1H), 7,26 7,56 (m, 13), to 7.67 of 7.82 (m, 4H), MS: 423 (M+) titration PKa5,8.

Analysis for C26H21N3OS: Calculated, 73,73; 5,00; N 9,92; Found, 73,75; N 5,13; N becomes 9.97.

Preparative example 1

(R)-a-Methylbenzyloxycarbonyl. (R)-a-Methylbenzylamine alcohol (4,34 g, 35.5 mmol) was dissolved in 120 ml of CH2Cl2in a nitrogen atmosphere and add pyridine (or 4.31 ml, 1.5 EQ.). The mixture is cooled in an ice bath and slowly add a solution of phenyl-chloroformate in 30 ml of CH2Cl2. Then remove the ice bath and stirring is continued overnight at room temperature. The mixture was partitioned between CH2Cl2and 1.0 N. Hcl, then the organic layer was separated, passed dropwise through Na2SO4to remove water and the solvent is removed in vacuum to obtain a 8.34 g of oil which is used without further purification (97% crude yield),1H NMR (CDCl3) d 1.69 in (D. J 7 Hz, 3H), of 5.83 (sq J 7 Hz, 1H), 7,14 7,46 (m, 10H), MS 242 (M+), []D=+119,6o, []385+428,8o(1,02, Meon).

Analysis for C15H14O3:

Vychislenii) oxycarbonyl]-TRANS-4,5-diphenyl-3-pyrazolidinone.

()-TRANS-4,5-Diphenyl-3-pyrazolidinone (8,13 g, 34,2 mmol.) dissolved in 150 ml of THF in a nitrogen atmosphere, cooled in an ice bath and add 1,43 g Pan (60% in mineral oil, the content of the hydride 0,86 g, 35,7 mmol, of 1.05 EQ.). The mixture is stirred for 15 min at the temperature of the ice bath and 30 min at room temperature. A solution of (R)-a-methylbenzyloxycarbonyl (preparative example 1) (8,25 g, to 34.4 mmol, 1.00 equiv.) in THF is then added dropwise within 10 min and the mixture is stirred for another 40 minutes After the separation between Et2O and 1.0 N. Hcl organic phase is separated and the aqueous phase is extracted a second time with Et2O. the Organic extracts are collected, passed by precapitalism through Na2SO4to remove water and evaporated to obtain 17,45 g crude product mixture contained in the title of the example. Pre-cleaning (without separation of diastereomers) are on two consecutive silikagelevye columns (EtOAc: hexane). Final purification and separation of diastereomers a and b complete by HPLC (Waters RCM 1,2,3 system 3, Packed metal chips speakers, Nova 18, each h mm, 6 m particles, the transmission rate of 45 ml/min (1100 p.s.i.)), UV detection at f 245 nm/1,0, eluent 64 Meon: N2O with 2.5% of the SPLA, download 50 60 mg/ who (which recyclist),and the third with a high content of diastereoisomer Century The first fractions of several experiments unite, evaporated and the residue lyophilized with getting diastereoisomer A. Processing the third faction of the various experiments in this way, get the diastereoisomer Century Purity of diastereomers a and b were determined on an analytical HPLC (column Nova 18, eluent 70% of Mean2O 10 SPLA at 1500 psi, UV detection at 254 nm, and typically was in the range of 95 to 100% of the Diastereoisomer A:

1H NMR (CDCl3) to 1.48 (d, J 8 Hz, 3H), 3,88 (d, J 6 Hz, 1H), of 5.34 (d, J 6 Hz, 1H), 5,81 (kV, J 8 Hz, 1H), 7,03 (m, 1H), 7,15 - 7,42 (m, 14N) 8,08 (sh. C. 1H), MS: 386 (M+), titration pKa8,7 []D-23,1o385-71,0o(0.99, and the Meon).

Analysis for C24H22N2O3:

Calculated WITH 74,59; N 5,74; N 7,25;

Found, With 74,52; N 5,97; N 7,24.

The diastereoisomer IN:

1H NMR (CDCl3)[]D: to 1.42 (d, J 7 Hz, 3H); 3,88 (d, J 5Hz, 1H), of 5.34 (s, 1H), 5,80 (kV, J 7 Hz, 1H), 7,14 the 7.43 (m, 15 NM), 8,30 (sh. C. 1H), MS (M+), titration PKa8,6, []385-18,7o-122,2o(from 1.01 Meon).

Analysis for C24H22N2O3:

Calculated WITH 74,59; N 5,74; N 7,25;

Found, 74,79; N. Of 5.84; N 7,22.

Preparative example 2.

(+)-TRANS-4,5-Diphenyl-3-pyrazolidinone. In thin-walled glass tube for hydrogenation download dieste is), 15.0 ml THF and 5% Pd/C catalyst (112 mg) and shaken in a Parr apparatus under hydrogen pressure of 50 psi for a 15.5 hours the Catalyst is filtered off using Celite, and washed with THF. The filtrate is evaporated in vacuum and obtain 134 mg (96%) of a white foamy product:

1H NMR (CDCl3) to 3.99 (d, J 11z, 1H), 4,66 (sh.with. 1H), 4,74 (d, J 11Hz, 1H), 7,20 7,39 (m, 10H), 8,63 (sh. C. 1H).

Preparative example 3.

(-)-TRANS-4,5-Diphenyl-3-pyrazolidinone. The diastereoisomer And 1 -[((R)a-methylbenzyl) oxycarbonyl] -TRANS-4,5-diphenyl-3-pyrazolidinone (from example 139A/V) (2,61 mg, 0,0677 mmol) is subjected to hydrogenolysis (17 ml THF, 128 mg 5% P VC) and treated similar to preparative example 2 and obtain 154 mg (96) white foamy product:

1H NMR (CDCl3d: 4,01 (d, J 11 Hz, 1H), to 4.38 (Shir. C. 1H), 5,81 (Shir. C. 1H), 7,1841 (m, 10H), []D= -76o, []385278o(1,08 Cl3).

Example 140.

(-)-TRANS-1-[(14-Bromophenyl) aminocarbonyl]-4,5 - diphenyl-3-pyrazolidinone.

(-)-TRANS-4,5-Diphenyl-3-pyrazolidone (from preparative example 2) 7,07 mg, 0,297 mmol) dissolved in 1.0 ml THF in a nitrogen atmosphere is treated with a solution of 4-bromonicotinate (67,9 mg, 0,343 mmol, 1.15 EQ.) 1.0 MD THF. The mixture is stirred for 45 minutes then the solvent is removed in wakoopa NMR data, there are admixtures. The product is dissolved in toluene and adding hexane until then, until the precipitate. The solvents were carefully removed by pipette and the remaining solid product is dried on a vacuum pump to obtain for 77.3 mg (60%) of a white solid product:

1H NMR (CDCl3), to 4.01 (d, J 7Hz, 1H), 5,52 (d, J 7z, 1H), 6,90 7,50 (m, 15 NM), at 8.60 (Shir. C. 1H), MS 436 437 (M+) for Br isotopes) []D= -38o, []365-293o(1,26, CHCl3).

Analysis for C22H18BrN3O2:

Calculated WITH 60,56; N 4,16; N 9,63;

Found, 61,43; N 4,29; N 9,58.

The content of the enantiomer (95,1), according to HPLC analysis diastereomeric purity of diastereoisomer In the previous example 139A/U.

Example 141.

(+)-TRANS-1-1-[(4-Bromophenyl) aminocarbonyl]-4,4-diphenyl-3-pyrazolidinone.

(+)-TRANS-4,5-Diphenyl-3-pyrazolidinone (from preparative example 3) (82,9 mg, 0,348 mmol) dissolved in 1.0 ml THF in an argon atmosphere and treated with a solution of 4-bromonicotinate (with 76.8 mg, 0,388 mmol, 1,11 EQ.) in 1 ml of THF. The mixture is stirred for 30 min, then the solvent is removed in vacuum. The product is first purified by chromatographytandem (33 to 66% EtOAc: toluene gradient) and get to 51.6 mg of product which, according to NMR, is still prisutstvie2Cl2: toluene hexane. Carefully removed with a pipette solvents, dried on vacuum pump and get to 20.8 mg (14%) of white solid product:

1H NMR (CDCl3) was 4.02 (d, J 7 Hz, 1H)- 5,52 (d, J 7 Hz, 1H), 6,90 7,50 (m, 15 NM), at 8.60 (Shir. C. 1H) MS 435, 437 (M+, Br isotopes), []d+40o. []385+299o(0,88, Hcl3).

Analysis for C22H18BrN3O2:

Calculated With 60,56; N 4,16; N 9,63.

Found, 61,93, N 4,43, N 9,37.

The content of the enantiomer (100% ) according to the HPLC analysis diastereomeric purity of diastereoisomer As in the previous example 139A/U.

Example 142.

(+)-TRANS-1-(4-Chloro-3-triptoreline)- aminothiophenol/ 4,5-diphenyl-3-pyrazolidinone.

(+)-TRANS-4,5-Diphenyl-3-pyrazolidinone (from preparative example 2) (134 mg, 0,561 mmol) was dissolved in 8.0 ml of THF under nitrogen atmosphere and add a solution of 4-chloro-3-triftormetilfullerenov (137 mg, of 0.58 mmol, 1.03 EQ.) in 2 ml of THF. The mixture was stirred for 12 h and then the solvent is removed in vacuum. The residue is first cleaned for 2 consecutive silikagelevye columns (EtOAc: hexane with 0.5% SPLA). Partially purified product (155 mg) was dissolved in CH2With and extracted three times with buffer solution pH 10. Water extracts merge the cabins dropwise via Na2SO4removal of water and evaporated under vacuum obtaining of 93.5 g (35%) of a pale yellow foam:

1H NMR (CDCl3) 4,10 (d, J 5Hz, 1H), 5,74 (d, J 5Hz 1H), 7,35 of 7.60 (m, 15 NM), MS: 475 (M+). []D= +32o, []385-116o(1,06, l3.

Analysis for C23H17CF3N3OS:

Calculated WITH 58,05; N. OF 3.60; N 8,83;

Found: 5,86; N 3,79; N 8,69.

Enantiomeric output (98,6%), according to HPLC analysis diastereomeric purity of diastereoisomer In the previous example 139A/U.

Example 143.

(-)-TRANS-1[(4-Chloro-3-triptoreline) aminothiazolyl] -4,5-diphenyl-3-pyrazolidinone

(-)-TRANS-4,5-Diphenyl-3-pyrazolidinone (from preparative example 3) (147 mg, 0,617 mmol) was dissolved in 8.0 ml of THF under nitrogen atmosphere and treated with a solution of 4-chloro-3-triftormetilfullerenov (160 mg, 0,673 mmol, 1,09 EQ. ) in 3 ml THF. The mixture is stirred for 1.5 h and the solvent then removed in vacuum. The product was then purified as in example 142, except that the initial phase chromatography was carried out were excluded and the complete procedure of extraction was performed twice to obtain 145 mg (49%) of pale yellow foamy product.

1H NMR (CDCl3) to 4.14 (d, J 35 Hz, 1H) 5,74 (d, J 5Hz, 1H).

Methods the effect using mouse membranes in accordance with the method of Chang and Lottie (Proc. Natl. Acad. Sc: 83: 4923 4926, 1986). Mice CE-1 male weighing 23 to 25 g killed by cervical dislocation, the brain was removed and placed in chilled on ice in 50 mm Tris buffer, pH 7.4. The tissue is homogenized in 100 volumes of Tris buffer using a Brinkman transmitter station or Tekmar Tissumizer and then centrifuged at 40,000 g for 10 minutes Precipitates after centrifugation resuspended in Tris buffer, centrifuged as above, and then resuspended in 100 volumes of the test buffer solution, pH 6.5 (20 mm 11 2-hydroxyethyl-piperazine-N'-2-econsultation (HEPES), 1 mm etilenglikoli (2-aminoethylamide ether-N,N,N',N'- tetraoxane acid) (GOSTA), 5 mm MgCl2, 130 mm NaCl and 0.25 mg/ml bacitracin). Analysis of the binding consists of 50 μl of the compound (or butene for total binding) or 50 μl of 125 1-CCK-8 sulfate (20 PM) (Amersham 1M-159), 200 μl of test buffer solution and 200 μl of the homogenate (80 to 120 μg protein). Samples incubated at room temperature (25oC) for 2 h, then filtered through glass fiber filters GF/B (soaked in wash buffer for 2 h before use) using a harvester cells Brandel with 48 holes, which is intended for receptor binding. The filtrate was washed with two razvykh tubes using an automatic gamma counter/quanta Micromedic 10/- 600.

Compounds are dissolved in dimethyl sulfoxide (DMSO) at a concentration of 10 mm and then diluted test buffer solution. The concentration of DMSO in the incubation is 0.1 or less, and does not affect the analysis at this level. Values IR50curves offset determined using concentrations of compounds and calculated using a computer program AL LF GG Delina, Munson and Rodbard (Am. J Phsiol 235: E97 E102, 1978). Nonspecific binding is defined as the substitution of radioligand 100 nm CCK 8 sulfate.

The pancreas.

Linking with peripheral CCK receptors type in the pancreas glands of rats carried out in accordance with the method of Chang and others (Mol. Pharmacol. 30: 212-217, 1986), using3N-1 364, 718. The pancreas receives from the rat Sprague-Dawley male weighing 150 200 after decapitate and freed from fat and connective tissue. The tissue is homogenized in 30 volumes of 50 mm Tris buffer, pH 7.4 and centrifuged at 40,000 g for 10 minutes Tissue residue washed with resuspending and centrifugation as described above. The final precipitate is suspended in 500 volumes of the test buffer solution (50 mm Tris-buffer, pH 7, 4, 5 mm MgCl2, 0.14 mg of bacitracin and 5 of Hecny fact, used for CCK binding to brain membranes. The third labeled L - 364, 718 (Dupont NeN, NET 971) is used as the ligand at a concentration of 0.4 - 0.6 mm. Samples incubated for one hour at room temperature and then filtered as described above for brain CCK receptor. Scintillation cocktail was added to the filtrate, which counted for radioactivity using an automatic liquid scintillation counter Micromedic Taurus.

Sample connection and get the values IR50determine as described above for experiments with CCK in the brain. Nonspecific binding is the amount that remains bound to the filters after addition of 100 nm L - 364,718.

The mucous membrane of the stomach.

The method used to gastrin binding to the mucous membrane of the stomach of the Guinea pig is similar to that described Takeuchi, Speira and Johnson (Am. J Phsiol. 237 (3), E 284-A, 199). The fundus of the stomach of the Guinea pig get from Hartley Guinea pigs male fields weighing 300-350 g, and the mucosa scraped the slide. The mucous membrane homogenized in 50 mm Tris buffer, pH 7.4, containing 1 mm phenylmethanesulfonyl, with ispolzovaniem resuspended and centrifuged again then the final precipitate is suspended in 100 ml of test buffer solution in the stomach one cavy with poluchenii protein concentrations of 200 to 300 µg/200 µl. Test buffer solution containing 50 mm Tris-buffer, pH 7, 4, 5 mm MgCl2, 0.14 mg/ml bacitracin and 1 µg/ml each of leupeptin, hemostasia, Aprotinin and pepstatin. The volumes of reagents for analysis correspond to those used for the binding of CCK with brain membranes. Radioactive ligand is 20 nM1251 gastrin 1 from Du Pont NeN (NEX 176). Samples incubated for 3 h at room temperature and filtered and counted as described for CCK binding to brain membranes. Sample compounds and get values IR50as described for receptor binding relative to CCK in the brain. Nonspecific binding was determined using 100 nm gastrin 1 (human synthetic, obtained from the Sigma chemical Co).

In table. 15 below presents typical test results of CCK and gastrin binding to compounds in accordance with the invention.

7,35 of 7.60 (m, 15 H), MS (M+), []D-28o, []365+128 (1,15 l3).

Analysis for C23H17CIF3N3O:

Comparative data of biological tests listed in the following table. 16.

From the comparison of the data shows that the proposed compounds are more active.

Compounds showed low toxicity.

1. Derivatives of pyrazole of the General formula I

< / BR>
where L group C=O or COR4;

--- optional connection;

p is 0 or 1;

R and R1independently from each other hydrogen, C1- C6-alkyl, phenyl, benzyl, naphthyl, pyridyl or substituted phenyl having 1 or 2 substituent selected from the group consisting of C1- C6-alkoxy, halogen, trifloromethyl, cyano, carbamyl, phenyl, nitro, amino, C1WITH4-monoalkylamines, benzylamine, di-C1- C4-alkylamine;

R2hydrogen, C1WITH6-alkyl, carboxymethyl,1WITH4-alkoxycarbonylmethyl or a group of the formula

< / BR>
where t 1;

AND-NH;

Y is phenyl substituted by trifluoromethyl and/or halogen;

R4WITH1WITH6-alkyl, carboxymethyl or1- C4-alkoxycarbonylmethyl;

R3hydrogen or a group of the formula

< / BR>
or

< / BR>
where B is O or S;

X is halogen;

m is 0, 1 or 2;

n is 0 or 1;

Q-NH-, -N(C1WITH6-al hydrogen or C1WITH6-alkyl;

q is 0 or 1;

r is 0, 1 or 2;

R7hydrogen, C1WITH8-alkyl, pentafluorophenyl, pyridyl, tetrahydronaphthyl, indolyl, chinoline, phenyl, naphthyl, or phenyl or naphthyl, substituted by 1 or 2 substituents selected from the group consisting of C1WITH6-alkyl, C1WITH6-alkoxy, C1- C6-alkylthio, halogen, trifloromethyl, phenyl, phenoxy, phenyl-C1WITH4-alkoxy, C1WITH6alkanoyl, nitro, C1- C6-alkoxy, carbonyl, methylenedioxy,3WITH6-alkylene, amino, di-C1WITH4-alkylamino, or the group -(Q)n- R5mean 2-tetrahydroisoquinoline,

or their pharmaceutical acceptable salts, provided that at least one of the groups R or R1has a value other than hydrogen or C1WITH6-alkyl, and R or R1hydrogen when one of the groups R or R1phenyl, substituted phenyl group, provided that at least one of the groups R2and R3has a value other than hydrogen, and when R3a group of the formula

< / BR>
R2has a value different from a group of the formula

< / BR>
and when L is 0, p is 1, and when L COR4then p 0, and---- means with the CLASS="ptx2">

3. Connection PP.1 and 2, having the formula

< / BR>
where R, R1, R2and R3have the meanings given in paragraph 1.

4. Connection PP. 1 to 3, characterized in that R and R1phenyl or substituted phenyl, as defined in paragraph 1.

5. Connection PP. 1 to 4, characterized in that R2the hydrogen.

6. Connection PP. 1 to 6, characterized In that in the group of the formula

< / BR>
means oxygen, and X and m have the specified values.

7. Connection PP. 1 to 6, characterized in that in the group of the formula

[CH(R6)]q(CH2R7< / BR>
q and r are 0;

R7phenyl or phenyl with the substituents defined in paragraph 1.

8. Derivatives of pyrazole on p. 1 of General formula I

< / BR>
where L, R, R1, R2, R3and p have the meanings given in paragraph 1, with activity antagonists cholecystokinin or gastrin in warm-blooded vertebrates.

 

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