TWI301128B - 4,5-dihydro-1H-pyrazole derivatives having CB1-antagonistic activity - Google Patents

Description

1301128 V. Description of invention (1) Zhang J new 4'5_ dihydro_1H,. The derivative groups were prepared to prepare their pharmaceutical compositions. As a active ingredient, i pyrazole is an effective cannabinoid-1 (CB!) receptor antagonist for therapeutic and neurological disorders. Cannabisoid (Cannabinoid) is found in Indian cannabis (CannaMs)

In Sa t i va L·), it has been used as a medicament for centuries (Mechoulam, R·; Feigenbaum, j.j. Pr〇g Med·(3)(4)·1 9 8 7, 2 4, 1 5 9). However, in the past few decades alone, the study of cannabis-like areas has shown no major information on cannabinoid receptors and their (endogenous) agonists and antagonists. The discovery and subsequent selection of two different subtypes of cannabinoid receptors (CBi & CBS) stimulated the study of novel cannabinoid receptor antagonists (Munr〇, S.; Thomas, KL; Abu-Shaar, M. Nature 1993, 365, 61 oMatsuda, LA·; Bonner, Τ· I. Cannabinoid Receptor, Pert wee, R·G·Editor, 1 9 9 5, 117, Academy Press “London”. In addition, pharmaceutical companies have become more interested in developing cannabis drugs for the treatment of diseases associated with cannabis-like disorders. The CB! receptor is widely distributed in the brain and combined with the CB2 receptor terminal distribution, making the CBi receptor a highly promising CNS-guided drug discovery molecular marker in both the mental and neurological disorders (Consroe, P· Neurobiology Of Disease 1998, 5, 534· Pop, Cur· Curr· Opin· In CPNS Investigational Drugs 1999, 1, 587. Greenberg, DA· Drug News Perspect· 1 9 99, 12, 458). To date, it has been known that three different known CBi receptor antagonists, ISanof i, reveal their diarylpyrryl

Page 9 1301128 V. INSTRUCTIONS (2) - The azole congener acts as a selective CBi receptor antagonist. A representative example is 31^-1 4 1 71 6 A, which is currently undergoing Phase II clinical investigators of mental disorders (Du 11 a, AK; Sard, H.; Ryan, W.; Razdan, RK; Compton, DR; Martin, BR Med. Chem. Res. 1 994, 5, 54. Lan, R. ; Liu, Q. ; Fan, P. ; Lin, S. ; Fernando, SR ; McCallion, D. ; Pertwee, R. ; Makriyannis, A. J. Med. Chem. 1999, 42, 769 o Nakamura-Palacios, EM; Moerschbaecher, JM; Barker, LA CNS Drug Rev·1 999, 5, 43). Aminoalkyl hydrazines have been disclosed as CBi receptor antagonists. A representative example is I 〇 d 〇 p r a v a d ο 1 i n e (A Μ - 6 3 0 ), which was introduced in 1959. AM-630 is a CBi receptor antagonist, but sometimes it is a weak partial agonist (Η 〇 s 〇 h a t a, K · ; Q u 〇 c k, R. Μ.;

Hosohata, Y.; Burkey, T. H.; Makriyannis, A.; Consroe, P.; Roeske, W. R.; Yamamura, H.l. Life Sciences ’ 1 9 9 7, 61, PL115). More recently, a study by El i Li 1 ly describes aryl-arylindenyl substituted benzofurans as selective CBi receptor antagonists (eg LY-320135) (Felder, CC·; Joyce, Κ·Ε· Briley, EJ; Glass, M.; Mackie, KP; Fahey, KJ; Cullinan, GJ; Hunden, DC; Johnson, DW; Chaney, M.0.; Koppel, GA; Brownstein, MJ Pharmacol·Exp· Ther· 1 9 98, 28 4, 291). Recently, 3-carbolyl-5,5'-diphenylimidedione has been described as a cannabinoid receptor ligand which is shown to be a cannabinoid antagonist (K any ο ny 〇t Μ · ; G 〇vaerts ,S,J,;

Hermans, E·; Poupaert, J.H·,? Lambert, D.M. Bi〇rg.

1301128 V. Description of invention (3) -

Med.Chem· Lett· 1999, 9, 2233). Interestingly, many CBi receptor antagonists have been reported to be endogenous agonists in vitro (L andsma η, RS; Burkey, TH; Consroe, P.; Roeske, WR; Yamamura, Η·1·Eur·J. Pharmacol. 1 9 97, 334, Rl). Recent Review k A good overview of current status in the field of cannabis research (M e c h o u 1 a m, R.;

Hanus, L. ; Fride, E. Prog. Med. Chem. 1 998, 3 5, 199, Lambert, DM Curr. Med. Chem. 1 9 9 9, 6, 6 3 5. Mechoulam, R, ; Fride, E. ; Di Marzo, V. Eur. J. Pharmacol. 1 9 98,3 5 9,1) Now, the novel 4,5-dihydro-1H-pyrazole derivatives of formula (I) have been unexpectedly discovered. Its prodrugs, their tautomers and their salts:

a (1)丨 Bb I r3

- R and the heart are the same or different and represent a phenyl, thienyl or anthracenyl group which may be substituted with hydrazine, 2 or 3 substituents γ, which may be the same or different and are selected from the group consisting of Ch - Anthracy or alkoxy, trans, halogen, trifluoromethyl, difluorodecylthio, trifluoromethoxy, nitro, amine, mono- or dialkyl (CM)-amine, single or Dialkyl (U-decylamine, (C13)-alkylsulfonyl, dimethylsulfonylamino, C13-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, amine Sulfhydryl, amine sulfonyl and ethenyl' or R and/or Ri represent naphthyl, -

Page 11 1301128

2 represents hydrogen, thiol, alkoxy, ethoxylated or propionic acid, and VIII represents one of (i), (ii), (iii), (iv) or (v)

〇) (ii) (iii) (iv) (v) where

, ^ and 匕 each independently represent hydrogen or 匕 ^ branched or unbranched alkyl or hi cycloalkyl ' or R 4 represents acetamido or dimethylamino or 2, 2, 2 -trifluoroethyl or benzene Or pyridyl, but r5 represents hydrogen h represents gas or Ci_3 non-branched group ~Bb represents sulfonyl or carbonyl, I represents a stupid, thienyl or pyridyl group, which may be 1, 2 or 3 Substituent Y substitution, the substituents may be the same or different, or 匕 represents a Ci 8 branched or unbranched alkyl group, or a C 3-8 cycloalkyl group, or r 3 represents a naphthyl group which is highly potent of the cannabinoid CBi-receptor And selective antagonists.

Due to the potent CBi antagonistic activity, the compounds of the invention are useful for the treatment of psychotic disorders such as psychosis, anxiety, depression, inattention, dysregulation and irritability, obesity, neurological disorders such as dementia, dist ο nia, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Durre's complications, cerebral ischemia, and treatment of pain symptoms and other CNS diseases, including cannabinoid conduction, And treatment of gastrointestinal diseases and cardiovascular diseases. -f

Page 12 1301128 V. INSTRUCTIONS (5) The affinity of the compound of the present invention for the cannabinoid CBi-receptor is determined by the cell membrane preparation of the Chinese stagnation (CH0) cell, wherein the human cannabis CBi style is [3H ] CP-55, 940 most radioligands are properly transfected. With or without the addition of the compound of the present invention, the newly prepared cell membrane preparation was incubated with the [3H]-ligand, and then filtered on a glass fiber filter to carry out the separation and separation of the free ligand. The radioactivity on the filter paper was measured by a liquid flash counter. The cannabinoid CB1 antagonistic activity of the compound of the invention is determined using the function of CH0 cells in which the human cannabis CBi receptor is appropriately expressed. The adenosine % enzyme can be measured using f orskol in stimulation and quantitatively accumulated cyclic AMp. Co-survival of CBi receptors by CBi receptor agonists (such as CP-55, 94〇 or (R)-W] [N-55, 212-2) can inactivate forskolin-induced cAMP accumulation in a concentration-dependent manner. This CBi receptor modulating response can be antagonized by a CBi receptor antagonist such as a compound of the invention. There is at least one pair of palmarity centers in the compound of formula (I) ((4 position) at the 4,5-dihydro-hydrogen 1H-pyrazole moiety. The present invention relates to the racemate, non-formula of the compound of formula (1) Mixtures of Enantiomers and Individual Stereoisomers. The invention also relates to E isomers, z isomers and E/Z mixtures of the compounds of formula (I), wherein Aa has the definitions as defined above (〇 or (ii) The compound of the present invention can be formed into a form suitable for administration by a general method using an adjuvant substance and/or a liquid or solid carrier substance. The present invention having the formula (111) (hereinafter) (where & represents hydrogen) The compounds can be prepared according to known methods, for example: a) EP 〇〇21 5〇6; b) DE 2529689.

Suitable compounds of the compounds of the invention are as follows:

Page 13 1301128 V. INSTRUCTIONS (6) Synthetic Path A (for compounds of formula (I), wherein Aa has the definition of (i) or (i i above)). Step 1 of Path A Compound of formula (I I )

R 0>

Ri i (II) should be anti-complexed with amine άρ or an amine and the formula

1 2 R R ΝΙΗ where r2 represents a transradical. The reaction is preferably carried out in a polar solvent such as ethanol. The compound of the formula (I I I ) wherein R 2 represents a hydroxyl group and wherein R and the ratio are as defined above for the compound (I) are novel compounds. Step 2 of Route A The compound of formula (III) is reacted with a compound of formula (IVa) or a compound of formula (IVb), or a suitable salt thereof, in the presence of a base ΗΝγ^-r7 Νγ^-r7 H~R5 (IVa)- (IVb)

Page 14 1301128 V. Description of the invention (7) The reaction wherein R7 represents a low, money group, such as 2-methyl-2-thiosemiuret to give 4,5-dihydro-1H-pyrazole of formula (V) < - formazan derivatives

R2 Aa

R (V) wherein Aa is as defined herein above for (i) or (ii) θ . , /, and 11". A compound of the formula ("a" as defined herein (wherein or (ii), and wherein r, the ratio, and & are as defined above for the compound (I)) are novel compounds. The compound is reacted with a so-called deuteration agent. Examples of the deuteration agent are 1H D ratio σ sitting - 曱 vein and its salt (such as hydrochloride) and 3, $ dimethyl 一 1 Η-pyrazole-1 - 曱Ruthenium and its salts (such as nitrates), etc. This reaction gives the formazan derivative of formula (V). In addition, the compound of formula (III) is reacted with a so-called protected oximation agent. Ν-(Benzyloxycarbonyl 1Η__pyrazole-oxime-methylhydrazine, Ν-(2nd butoxy-yl)-1Η - π ratio Jun ~ A vein and ν, ν, _ bis (third-butoxycarbonyl) -1Η-pyrazole-1-oxime, etc. The reaction is deprotected to give the compound of formula (ν). Step 3 of the path The compound of formula (V) is substituted with the form s〇2X 4R3_c〇x (where the center is substituted) The reaction is the same as defined above, and X represents a compound of the im group. The reaction is preferably carried out in the presence of a base such as triethylamine in a protic solvent such as acetonitrile. ), wherein Bb represents a sulfonyl group or a carbonyl group respectively. Jin Cheng Lu" (a compound of the formula (1),: Aa in the boxing with the above (i) or (i i)

Page 15 1301128 V. Definition of invention (8)). Step 1 Compound of formula (111)

(111) is reacted with a thioisocyanate derivative of the formula (VI).

Bb (VI)

I R3

The reaction is preferably carried out in the presence of an inert organic solvent such as acetonitrile. This reaction gives a thiocarbamine derivative of the formula (V11). The compound of the formula (v丨丨) wherein R, h, R2, Rs and Bb are as defined above for the compound (I) is a novel compound. ^ j=S (VII) ' 唧 丨 巳b

I R3 is the step of jf A1

r The compound is reacted with an amine in the presence of a mercury (1)) salt (such as Hgei2), and the compound of formula (I) has a broad Aa as defined in (i) or (ii) above. Human [reaction is good in polar organic solvent unloading acetonitrile Exist in the presence of ^^2 (a compound of formula (1), which is "same as (1) or (1) above)

Page 16 1301128 V. INSTRUCTIONS (9) Meaning) Step 1 of path A2 Formula (I I I) compound

Reaction of Ri r2 (ill) with an amino phthalate derivative of the formula (V I I I)

〇 HN human R7 巳b I (VIII) wherein R7 represents a lower alkyl group such as a methyl group. ^ The reaction is preferably carried out in an inert organic solvent such as 1,4-dioxane to give a compound of formula (IX), 4,5-dihydroindole ratio σ sit-1 -cartoamine derivative formula (ή) compound (wherein R, Ri, R2, R3 and Bb are as defined for the compound of the above formula (I)) are novel compounds. R, R2 IN h (IX) HN I Bb I r3 Step 2 of the route A2 Reaction of the compound of the formula (IX) with a halogenating agent (for example, PC15) (X) 4, 5-dihydropyrazole-1-methyl Bismuth halide derivative

Page 17 five

R

Ri r2 Bb I r3

R

Page 18 13〇1128, invention description (10) (X) wherein R8 represents a halogen atom such as gas κ ^ Τ 虱. This reaction is carried out less than pregnancy, such as fluorobenzene. In an inert organic solvent, the compound of formula U) (wherein R, &, and R, wherein R represents the above compound (I) atom) is a novel compound. The compound of formula (X) is reacted with an amine to define the definition of (i) or (ii). In the case of J 'U), in which the reaction of Aa is the same as above, it is preferably carried out in an inert state, a human AQ / i bathing agent such as dichloromethane. -^A_SJ^A_3 (Formula (Π化人## τ疋叫 meaning) σ, where Aa is as defined in (i) or (ii) above, step t 3 of the formula (III)

R1 R2

The oxime-feline carbonate derivative is reacted. ;9 N

1301128 V. INSTRUCTION DESCRIPTION (11) — wherein R9 represents a Ci_3 alkyl group. The reaction is preferably carried out in a polar organic solvent such as acetonitrile. This reaction gives an ester derivative of the formula (X I I).

j-s-R, (XII)

V

Bb I . r3 wherein R9 represents a Ch alkyl group. A compound of the formula (XI I) wherein R, h, R2, R3 and Bb are as defined above for the compound (I), and wherein the alkyl group represents a novel compound. Step 2 of Scheme A3 The compound of formula (X I I) is reacted with an amine to provide a compound of formula (I) wherein Aa is as defined above for (i) or (ii). The reaction is preferably carried out in a polar organic solvent such as decyl alcohol. Synthesis Path B (a compound of formula (I) wherein Aa is as defined above for (iii) or (iv)). Step 1 of Path B Compound of formula (I 11)

R

A, r2 . H (III) are respectively reacted with a compound of the formula (x m) or a compound of the formula (xi y)

Page 19 1301128 V. Description of invention (12)

Wherein Bb, R3 and hydrazine are as defined above, and Z represents a so-called leaving group. The reaction results in a compound of formula (I) wherein Aa is as defined above for (i i i) or (iv). Synthesis Path C (Compound of Formula (I), wherein Aa is as defined in (v) above) Step 1 of Formula C Formula (III) %^R2 H (III); respectively, with a derivative of formula (XV) , or the compound of formula (XVI)

Prot

(XV) (XVI) wherein R6 is the same as defined above, Z represents a so-called leaving group, and Prot represents a so-called protecting group such as a third-butoxycarbonyl group, a benzyloxycarbonyl group or the like. These reactions give compounds of formula (XV I I).

Page 20 1301128 V. Description of invention (13)

R

Ri R2 a Prot (XVII) ______________________ί where Aa is as defined in (v) above. A compound of the formula (XVII) wherein R, Ri, and the above compound (I) are defined, and wherein Aa is as defined in the above (v) and wherein Prot represents a so-called protecting group is a novel compound. Then according to known methods (see for example: T W. Greene, PGM Wuts '"Pr〇tective in ^ganiC Synthesis", Third Edition, J〇hn WUey & s〇ns, 丄Nc·, New York, 1999) rvx . ^ A ; in addition to the so-called protecting group, get the compound

IV), wherein Aa is the same as defined in the above macro (M) and the above compound (1). The compound of the formula (1) wherein R and Ri are defined is a novel compound. And the compound of the formula (V) of the above-mentioned (v) path C (where Aa is the same as ^ Λ 'Ρ ς η γ ^ (v) is defined) and is replaced by the case of '^ Κ 3 - Compound reaction of S02X or R3 -C0X (where r η library. 兮g at &&<%) and X is halogen). Preferably, the reaction is carried out in a protic solvent Γ in a base of #c; #^ Μ (e.g., acetonitrile) (e.g., triethylamine). The reaction is compounded into a butyl group. (I) 'wherein B b represents respectively, and the compound of the above formula (V) can be, t ^ ^ r ^ ^ ^ / formed from the compound of the formula R3-C00H, formed according to the π T generation S day, Or in the presence of so-called 八 下 丨丨 丨丨 Α丨 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Preparation of the following compounds

1301128 V. Description of invention (14) —

Example I 3 -(4-Chlorophenyl)-4,5-dihydro-4-trans-yl-4-phenyl-1H-indole ratio at 25 ° C, 2-(4-gasbenzhydrazide The base 2-phenyl oxirane (112 g, 0.43 mol) was dissolved in ethanol (650 ml). To the resulting stirred solution was added Ν2Η4·Η20 (42 ml), and the formed 3-(4-chlorophenyl)-4,5-dihydro-4-hydroxy-4-phenyl-1 Η-pyrazole was slowly precipitated. After standing for 16 hours, the crystalline material was collected by filtration, washed sequentially with ethanol, water and ethanol, followed by dehydration to give 3-(4-chlorophenyl)-4,5-dihydro-4-hydroxy-4. - Stupid-1 Η-pyrazole (92 g, yield 78%), m.p.: 1 85 - 1 9 6 ° C.

Example II 3 -(4-Chlorophenyl)-4,5-dihydro-N-((4_Itphenyl)-S-basid)-4_phenyl-1H-D than 嗤-1_甲脉Part A: 3-(4-chlorophenyl)-4,5-dihydro-4-hydroxy-4-phenyl-1H-pyrazole (5. 13 g, 20.0 mmol), 2- The mixture of methyl-2-thiohypouronic acid iodate (5. 00 g, 23.0 mmol) and pyridine (10 ml) was heated at 110 ° C for 1 hour. After standing at room temperature overnight, diethyl ether was added, and the precipitate was collected by filtration. The precipitate was washed three times with diethyl ether to give a solid (9 g). Melting point: ~2 3 0 °C. This solid was dissolved in methylation (20 mL). 2N sodium hydroxide solution (12 ml) and water (200 ml) were sequentially added to the resulting solution. The precipitate formed was collected by filtration, washed twice with diethyl ether, and then with diethyl ether. The obtained solid was dried under vacuum to give 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 oxime-pyrazole-1-carboxamide (5.1 g, yield 88%) . Melting point: 1 87-1 89 °C. _ Part B: N,N-dimercapto-4-amine 吼2^(0·0 2 0g, 0·175 mmol

1301128 V. Inventive Note (15) ~ er) and triethylamine (1 ml) added to 3-(4-chlorophenyl)-4,5-diaza-4-phenyl-1H-pyrazole-1- A stirred mixture of formazan (0.50 g, 1.68 mmol) and 4-fluorophenylsulfonium chloride (0.34 g, 1.75 mmol). The resulting solution was stirred at room temperature for 30 minutes. After adding 2 N sodium hydroxide solution and extracting with ethyl acetate (40 mL), ethyl acetate layer was concentrated in vacuo. The crude residue was purified further by flash chromatography (EtOAc/EtOAc/EtOAc (EtOAc) Concentration in vacuo then to give the solid 3-(4-chlorophenyl)-4,5-dihydro-N-((4-fluorophenyl)-sutonyl)-4-phenyl-1H-D ratio . Sitting - Bujia 眯 (〇 · 55 grams, yield 72%). Melting point: 214-215 °C. The following compounds of formula (I) are prepared in a similar manner:

4,5-Dihydro-N-((4-ranylphenyl)-3-(4-decyloxyphenyl)-4-(4-methoxyphenyl)-1Η-pyrazole-1-pyrene脒, melting point: 155-1561 4,5-dihydro-3-(4-methoxyphenyl)-4-(4-methoxyphenyl)-N-(4-decyloxyphenyl)sulfonate Mercapto)-1Η-pyrazole-1-indole, melting point: 148-15(TC 3-(4-chlorophenyl)-4, 5-dihydro-4-phenyl-N-((2, 4 , 6-trimethylphenyl)sulfonyl)-1H-pyrazole-1-indole, melting point: 22 1 -2 22 °C 3-(4-chlorophenyl)-4,5-dihydro- N-((4-fluorophenyl)sulfonyl)-4-hydroxy-

4-phenyl-1H-pyrazole-1-indole, melting point: 2 27-228 °C Example III 3-(4-chlorophenyl)-4,5-dihydro-N-(l-naphthylquinone )-4-phenyl-1H-pyrazole-1-carboxamidine added triethylamine (1 ml) to 3-(4-chlorophenyl)-4,5-diaza-4-phenyl-1 hydrazine Pyrazole-1-oxime (0.75 g, _ 2. 50 mmol) and naphthoquinone chloride (0.4 ml, 2.70 mmol) of acetonitrile (5 ml) were stirred in the mixture.

1301128 V. INSTRUCTIONS (16) .- The resulting mixture was stirred at room temperature for 1 hour. After adding 2N sodium hydroxide solution and extracting with ethyl acetate, ethyl acetate layer was concentrated in vacuo. The obtained crude residue was further purified by flash chromatography ( petroleum ether / diethyl ether = 3//1 (v/v), followed by ethyl acetate. Concentration in vacuo then afforded 3-(4-chlorophenyl)-4,5-dihydro-N-(1-naphthylphenyl)-4-phenyl-1H-pyrazole-1-carboxamide (0.94 Gram, yield 83%). Melting point: 206-207 °C. The following compound of the formula (丨) is prepared in a similar manner: 3-(4-chlorophenyl)-4,5-dihydro-4-indolyl 1-(2-pyridyl)-111-pyrazole-1 - Hey. Melting point: 11 8 ° C (decomposition). Example IV.; N1,N1-dimethyl-N2-((4-chlorophenyl)sulfonyl)-3-(4-phenylphenyl)-4,5-dihydro-4-phenyl-1H - Q is more than salivary-1 - formazan A · at the reflux temperature 'make 3 - (4- gas phenyl b 4,5-dihydro-4-phenyl-1P pyrazole (12 · 0 g, 46·8 millimoles), [(4-monophenyl)sulfonyl]dithio-branched dimethyl carbonate (CAS: 13〇68-1217) (9·2 gram, 31· Mix 1 mM and triethylamine (15 ml) in acetonitrile (2 mL) = heat for 20 hours. Add another portion of 3-(4-phenylphenyl)-4,5-dihydro- 4 Benzene, =H-pyrazole (1 2. gram, 46.8 mmol), and the resulting mixture was heated at reflux temperature for an additional 16 hours. After concentration in vacuo, di-methane was added to water. The resulting solution was washed twice and dehydrated with ΝΑδ〇4. After filtration and flashing in vacuo, the residue was purified by flash chromatography (diethyl ether/ petroleum ether = 1 / 1 (ν/νγ). Shaped solid 3' (4-chlorophenyl)_Ν一((4-cyclophenyl)sulfonyl)-4,5-dihydro-4-phenyl-pyridyl-pyrazole<-曱醯Iridium thiourate (丨2.5 g, yield, [(4-chlorophenyl)sulfonate]

Page 24

1301128 V. DESCRIPTION OF THE INVENTION (17) A dimethyl]dithioarylidene dimethyl carbonate is a standard. Part B: Di-decylamine (10 ml) and dichloromethane (75 ml) were added to 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4 , 5 -Dihydro-4-phenyl-1 Η-pyrazole-1_methionine thioxanthate (4. 20 g, 8. 30 mmol) sterol (75 ml) The mixture was stirred and the resulting solution was stirred at room temperature for 6 hours. Evaporation in vacuo and purification by flash chromatography (diethyl ether / petroleum ether = 1 / 1 (v/v), followed by diethyl ether) to give a solid which is recrystallized from diethyl ether to give Ν1, Ν1- Dimethyl-indole 2-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1Η-pyrazole-1-pyrene (2.63 g, yield 63%). Melting point: 182 °C. The following compound of formula (I) is prepared in a similar manner: N-methyl-Ν'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4, 5-dihydro 4-(3-Pyridinyl)-1Η-indazole-1-carboxamidine. Melting point: 10 Bu 105 °C. N-methyl-Ν'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4, 5-dihydro-4-(4-pyridyl)-1Η-pyridyl Oxazole-1-carboxamidine. Melting point: 112-115 °C. ^-\1-Dimethyl-indole-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-· 4,5-dihydro-4-hydroxy-4-phenyl -1H-pyrazole-1-carboxamidine. Melting point: No stereotype. 'N-Ethyl-Ν' - ((4-chlorophenyl)sulfonyl)-3 -(4-chlorophenyl)-4, 5-dihydro-4-hydroxy-4-phenyl-1 Η -pyrazole-1-indole. Melting point: 1 83- 1 85 °C. Example V - N-fluorenyl-Ν'-(3-(trifluoromethyl)benzimidyl)-3-(4-phenylphenyl)-4, 5-dihydro-4-yl-1H-吼ϋ 曱 曱 曱 :: 3 - (trifluoromethyl) benzhydryl isothiocyanate at 0 ° C

1301128 V. INSTRUCTIONS (18) 4U·』2/ '2〇. 〇 莫 尔 )) is added to 3-(4-chlorophenyl)-4,5-dihydro- _, and ί~1Η::ί (5. , 13 * '20. 〇 mmol) acetonitrile (8 〇 ml) in the mash, and the mixture was stirred for 1 hour. The yellow precipitate formed by filtration is collected to obtain 3 cf of the same portion of acetonitrile and a water-washed strip, and then vacuum-dried, abbreviated scorpion) - 4,5-dihydro- 4-phenyl-N-((3_3) Dunmethyl)-knowyl-1-anthracene-pyrazole-indole-thiocarbamide (8 26 g, yield 85%). Point hang 1 80- 1 82. . . ^部: Add ice-cold methylamine (5 ml) to 3-(4-chlorophenyl)-dihydro-4-phenyl-N-((3-trifluoromethyl)-benzhydryl) _ih-pyrazole _, = carbamide A. 88 g, 10. 〇 莫 ) 之 acetonitrile (5 〇 ml) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ After adding a solution containing HgC 12 (3.0 g, 1 1 mmol < 25 ml of acetonitrile, the resulting mixture was stirred for three hours. The hydrazine was removed by filtration on hyflo, the filtrate was collected and the MCi was concentrated in vacuo. After ethyl acetate and hydrazine·5 N NaOH, the ethyl acetate layer was collected, washed with saturated aqueous concentrated aqueous solution and dried over anhydrous Na.sub.2.sub.4, filtered and filtered in vacuo. (v/v)), obtained as a foamed N-gas N (3 (-fluoroindolyl)-brenyl)-3 -(4-chlorophenyl)- 4,5-di-hydroxy-1H-pyridyl Azole-1_ formazan (〇·99 g, yield 2〇%). Melting point: ...clearing °Rf (Shixijiao: two gas ablation/acetone=9/1 (v/v)) = 〇3 4[Vl ·Μ,甲τ基-Ν'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4, 5-di, 4-, phenyl-1H- Pyrazole-1-methacryl A portion: 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-111-pyrazole (3.39 ΐ3·2 mmol) is added to the N-((All-Phenylphenyl)sulfonyl)aminopurine

Page 26 1301128 V. INSTRUCTIONS (20) -1 4,5-Dihydro-4-phenyl-1H-D is more than 嗤-1-methyl. Melting point: amorphous. N-propyl-Ν'-((4-fluorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 Η-pyrazole-1 - Hey. Melting point: 1 29- 1 38 °C. N-(2-propyl)-Ν'-((4-fluorophenyl)sulfonyl)-3-(4-chlorophenyl)-4, 5-dihydro-4-phenyl-1 Η- Pyrazole-1-carboxamidine. Melting point: 110-112 °C. N-fluorenyl-Ν'-((2-propyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 Η-D than saliva-1 - Hyperthyroidism. Melting point··No stereotype. Bu (2-propyl)-"-((4-chlorophenyl)sulfonyl)-3-(4-pyridyl)-4,5-dihydro-4-phenyl-1Η-D -1- A pulse. 'Solution point: no stereotype. \Ν-Ethyl-Ν'-mercapto-Ν'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl- 1H-pyrazole-1-carboxamidine. Melting point: 184 °C. N1-ethyl-N1-methyl-N2-((4-fluorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H'pyry Oxazole-1-carboxamidine. Melting point: 1 73- 1 76 °C. N^N1-dimethyl-N2-((4-(trifluoromethyl)phenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl- 1H-pyrazole-1-carboxamidine. Melting point: 195-1 9 6 〇C. \1^1-Dimethyl 12-((3-mercaptophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-indole ratio Saliva-1-曱 pulse. Melting point: 195 - 198 C. N1,N1-dimethyl-N2-((3-methoxyphenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyridyl Carbazole-1-oxime. Melting point: 204-20 6 〇C. N-ethyl-Ν'-((4-(phenyl)sulfonyl)-3-(4-chlorophenyl)-4, 5-dihydro-4-phenyl-sodium-I-indole. Melting point: amorphous. N-Dimethylamino-indole-((4-(phenylphenyl)sulfonyl)-3-(4-chlorophenyl)

1301128 V. Description of the Invention (21) ~ 4,5-Dihydro-4-phenyl-1H-pyrazole-1-carboxamidine. Melting point: 1 5 5- 1 5 9 °C. N-fluorenyl-Ν'-((4-(trifluoromethyl)phenyl)-retinyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1Η -pyrazole-1-carboxamidine. Melting point: amorphous. Ν',Ν'-dimercapto-Ν'-((2-methylphenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1Η -pyrazole-1-indole. Melting point: 148-151 °C. N-methyl-Ν'-((2,4-difluorophenyl)sulfonyl)-3-(4-chlorophenyl)-4, 5-dihydro-4-phenyl-1H-pyrazole -1- armor. Melting point: 85 °C. N-acetamido-Ν'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1Η-pyrazole- 1-曱脒. Melting point: amorphous. Ν-( 2, 2, 2 -trifluoroethyl)-Ν' - ((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4- Phenyl-1 Η - mouth ratio ° sitting 1-A pulse. Melting point: amorphous. Ν-(2-Pyridyl)-Ν'-((4-(phenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrene Oxazole-1-carboxamidine. Melting point: 1 42-1 46 °C. N-(4-Pyridyl)-Ν'-((4-(phenyl)sulfonyl)-3-(4-phenylphenyl)-4,5-dihydro-4-phenyl-1 Η- Pyrazole-1-pyrene. Melting point: 204-20 6Λ:. Ν-phenyl-Ν'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1- Hey. Melting point: 1 58- 1 60 ° C.

EXAMPLE VI I 3-(4-Phenylphenyl)-1-[3-((4-gasphenyl)-S-S-based) Butyl]-4,5-dihydro-4-phenyl-1H- Pyrazole 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (3.0 g, 11.7 mmol) added to 3-((4- Chlorophenyl)sulfonyl)butyric acid (1.85 g, 7.00 mmol), diisopropylethylamine (3 ml) and 1-ethyl-3-(3-dimethylaminopropyl) Mixing of carbodiimide hydrochloride (H. 50 g 15.7 mmol)

Page 29 1301128 V. INSTRUCTIONS (22) - The mixture is mixed and the resulting mixture is stirred at room temperature for 16 hours. After concentration in vacuo, the residue obtained was purified by flash chromatography (EtOAc/EtOAc/EtOAc (EtOAc) Base]-[3-((4-Chlorophenyl)sulfonyl)butanyl]-4,5-dihydro-4-phenyl-1H-pyrazole (3·69 g, yield 63%). Melting point: amorphous. In a similar manner, the following compound of formula (I) is prepared: 3[(4-chlorophenyl)-1 -[3-(phenylsulfonyl)propanyl]-4,5-dihydro- 4 Phenyl-1 Η-pyrazole. Melting point: i 22- 1 23 °c. ‘propionic acid group】-4,5-two

3;·(4_,stupyl)-1—[3-((4-chlorophenyl)sulfonyl)hydro-4-phenyl-1Η-pyrazole, melting point · 178 —丨81 Example VI II 3 -(4-chlorophenyl 4,5-dihydro-4-phenyl-1-pyrene phenylsulfonyl)ethyl]q Η-pyrazole dioxazite will contain 2-((3 one (three) Fluoromethyl)-benzene 5·50 mM acetonitrile (20 mM) ethyl chloride (1.5 g, yl)-4,5-dihydro+phenyl-1 Η|sitting (1 And /= added to acetonitrile (25 ml·g, 6.^0耄mol) containing 3_(4-gas benzene c〇Uidine (2 ml) and the solution was heated at reflux temperature for 16 hours, mixed in the mixture, The product was dissolved in ethyl acetate and concentrated under vacuum in vacuo. The residual B: layer was sequentially washed with 1N hydrochloric acid solution and carbon. The obtained acetic acid was purified by flash chromatography (petroleum ether / B' aqueous solution). Washing: oil, in the oil from the two two = 1/2 (V / V)) base -4,5 ~ dihydro-4-phenyl-l-[2- (( 3 r, L ° crystal, paid to 3_(4_ 虱 基) ethyl b 1H-吼. sit (0.52 g, yield =, Dun methyl) phenyl) _ Shihuang

Exhibition competition 19 ° / 〇. Melting point: 118-119 °C 1301128 V. Description of the invention (23) ^ Preparation of 傜 > 3-(4-chlorophenyl)-fluorene in a similar manner, "Compound compound: BASE-1H-H ^ ·~( Phenyl sulphate) ethyl]- 4,5_: chloro- 4 benzene ^ ling point. U1 ° C. hair / 1 soil) 1 [2 - ((4 chlorophenyl) feldspar) B Base] - 4, 5 - dihydrogen - _ 1 - 1 - pyrazole, melting point · amorphous.

^(4_Chlorophenyl)-J^[2—((4-phenylphenyl)sulfonyl)ethyl]- 4,5-dihydro-4-yl-4-phenyl- 1 η-d Bizolium, refining point: 1 2 7 -1 2 8 °C. Example IX N-[2-(3-(4-Chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-yl)ethyl]- 3-(trifluoromethyl) Benzene amide A-containing 3-(4' chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole (5·00 g "9.5 mM") and N- (Third-butoxycarbonyl) azetidine (2 g, 14.0 mol) toluene (1 ml) was stirred at reflux temperature for 16 hours. After concentration in vacuo, the residue was purified by flash chromatography eluting eluting eluting After the vacuum "after shrinking", the oily residue left behind is crystallized from the second propyl test to obtain the bl [2 ((second-butyringo)-)ethyl]-3-(4-Teaching Beauty)- 4 5-Aza-4-benzene m sitting (1.91 g, 34%). From the mother m crystal:; to other amounts of crystal 1-[2-((T-butoxycarbonyl)amino)ethyl]_3-(4-indolyl)-4,5-dihydro- 4-phenyl-pyrazole (119 g). Part B·Addition of difluoroacetic acid (5 ml) to 1-[2-((t-butoxycarbonyl)amino)ethyl]-3-(4-indolyl)- 4, 5-di ^ λ_1Η_卩 ratio+ 1301128 V. Description of invention (24) __

The resulting solution was taken up at room temperature, and the residue was dissolved in ethyl acetate, and the residue was dried with magnesium sulfate and dried over magnesium sulfate. Ethyl acetate, ethyl acetate, "-(4-gas, vacuum concentration, to give oily 1-(2-amine gram, quantitative yield ^ soil) - 4'5-dihydro- 4-phenyl- 1H-pyrazole (1.44 er; diterpene: 3 persons; 7 fluoroindolyl) stupid sputum chlorine (〇. 35 ml, 2·18 mM ΐ Λ: .56 gyi 87 mM) and diisopropyl Ethylamine in acetonitrile ('liter) in a bath and the resulting solution was stirred at room temperature for 2 minutes. After concentration in vacuo, the residue was dissolved in ethyl acetate. Washing; heart, concentrated ethyl acetate layer under vacuum. The obtained oil was crystallized from a small amount of isopropyl scale to give crystals of N-[2-(3-(4-chlorophenyl)-4,5- Hydrogen-4-phenyl-1H-pyrazol-1-yl)ethyl]-(3-trifluoromethyl)benzenesulfonamide (0.44 g, yield 46%). Happiness: 94-96 ° C.

Example X () N-methyl-N _((4-Phenylphenyl)glycol) 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole -1-曱脒

Using Chiralpak AD, a 20 micron pair of palmar standard phase via racemic N-methyl-Ν'-((4-chlorophenyl)lithophyllin)-3-(4-phenylphenyl)-4,5 -Dihydro-4-phenyl-1-indole-pyrazole-1-indole (18 g, 0. 037 Mohr) was separated by palm chromatography to give (-)-indole-indenyl-indole- ((4-Phenylphenyl)-retinyl)-3-(4-chlorophenyl)-4,5-di-argon-4_phenyl-1Η-port ratio ° sitting-1-A pulse (7· 16 g '0.0147 Moore' ((a25D]= -150. , ς = 〇·〇1 , Me0H) (melting point: 1 69- 1 70. 〇. The mobile phase contains hexane/youol (8 0/20 ( ^/¥)) and 0.1〇/〇

Page 32 1301128 V. Inventive Note (25), a mixture of ammonium hydroxide (25% aqueous solution). The following optically pure compounds were prepared in a similar manner from the corresponding racemate: (i)-N-ethyl-Ν' _((4-chlorophenyl)sulfonyl)-3-(4-chlorobenzene Base)-4,5-dihydro-4-phenyl-1H-pyrazole-1-indole ([〇;25]>126.,c = (K〇i, ; melting point: 1 72- 1 75 °C. Static phase · chiral cel 0D. Mixture of hexane/2-propanol (85/15 (v/v)). Dimethylamino- Ν' _((4-chlorophenyl) sulfonate醯-)-3-(4-chlorobenzene chci3) mobile phase: (-)-N-yl)-4, 5-dihydro-4_phenyl-1H-pyrazole-1-methoxyindole ([u25d]= — 132 ° , c = 〇· 01, CHC13); melting point: 218-22 4 ° C. Static phase: Chiralcel 0D. Mobile phase: Geng Xuan / 2-propanol (85/15 (v/v)) (-)-N-Mercapto-N,-((4-(trifluoromethyl)phenyl)sulfonyl)-3-(4-chlorophenyl)-4, 5-dihydro-4 -Phenyl-pyrazole-oxime ([a25D] = -131 ° , c = 〇. 01, CHCU); Hyun: 1 57-1 ° C. Static phase: Chiralcel 〇 ^ OD. Mobile phase: G a mixture of alkane/2-propyl pure (85/1 5 (v/v)). (-)- N1,N1-dimercapto-N2-((2-methylphenyl)-carsonyl)-3-( 4 -Chlorophenyl)-4,5-dihydro-4_phenyl-1H-pyrazole-1 - hydrazine ([u25d] = - 88 °, c = 〇· 01, MeOH); Margin: amorphous. Static phase: Chiralpak AD. Mobile phase: ethanol. (-)-N-fluorenyl-N,-((2,4-difluorophenyl)glycosyl)-3-(4-chlorophenyl)-4, 5-Dihydro-4-phenyl-11^-pyrazole-1-pyrene ([02%]=-129°, c = 〇·〇1, MeOH); Hyun: amorphous. Static phase: ChiralPak AD. Mobile phase: sterol.

Page 33 1301128

Page 34

Claims (1)

13011^(§01〇676〇 Patent Application Replacement of Chinese Patent Application (November 1996) 1 . A compound of formula (I), 1 2 RR wherein -R and R 1 are the same or different and represent a phenyl, pyrenyl or pyridyl group, and the yl group may be substituted with 1, 2 or 3 substituents γ, and the substituents may be the same or Different and selected from Ci·3·alkane or alkoxy, pixel or trifluoromethyl, —R 2 represents hydrogen or a radical, —Aa represents a radical (i), (π), 〇π), (iv) or (v) One of the N \R5 FI La produces N • ·--. (!) (Π) (iii) (iv) NH (v) wherein -R^ and R5 each independently represent a hydrogen alkyl group, or R4 represents an acetamide or a y-amine or 2,2,2-trifluoro Ethyl or phenyl or pyridyl, but] represents hydrogen, -R6 represents hydrogen or (^3 unbranched alkyl-B b represents sulfonyl or carbonyl, 3 methyl or phenyl) The group may have 1, 2 or 3 substituents or 3 represents C 8 ·8 alkyl, or R 3 represents a fluorenyl group, and a tautomer 70086-961127.doc 1301128 Its salt. 2. For the compound of formula (1) of the scope of patent application, straight-soil 'R' is phenyl, R2 is hydrogen, and Aa is base (1), wherein R4 is gas and L is methyl, and Bb is sulfonyl And I represents 4_chlorophenyl, and is abbreviated. 3 3. The compound of claim 2, which is characterized by a left-handed pair: isomer. A method for preparing a compound of the formula I, characterized in that (8) a compound is prepared by the following, wherein R, R1 - R3 are as defined in claim 1 of the patent application, and A a is as in the scope of claim J A compound of formula (i) or (ii) is defined, wherein a compound of formula (II) is reacted with a hydrazine or a hydrazine hydrate to give a compound of formula (I), a compound of formula (111) and formula (丨va). Or (丨vb) compound is reacted to give a compound of formula (V), a compound of formula (V) is reacted with a compound of formula R; 5-S〇2X or Rs-COX, wherein ruthenium is a functional element, or 2) is a formula (III) The compound is reacted with a thioisocyanate of the formula (VI) to give a compound of the formula (VII), the compound of the formula (VII) is further reacted with an amine in the presence of a mercury (π) salt, or 3) a compound of the formula (III) V 111) The compound is reacted to obtain a compound of the formula (IX), which is then reacted with a self-leveling agent to obtain a compound of the formula (X), which is then reacted with an amine, or 4) a compound of the formula (ΙΠ) (XI) reacting a compound to obtain a compound of the formula (xn), which is then reacted with an amine, or b) by reacting a compound of the formula (111) with a formula ( X Π I) or (XIV) compound reaction 70086-961127.doc -2 - 1301128 Preparation of a compound wherein R, R!-R3 and Bb are as defined in claim 1 and A a is as claimed Formula (iii) or (iv), or c), by reacting a compound of formula (ΠΙ) with a compound of formula (XV) or (XVI), to give a compound of formula (X v 11), wherein R , R丨_ R 3 and B b are both as defined in the patent application scope 1 and A a is based on the formula (V) of claim 1 and then deprotected to obtain the compound of formula (v) And reacting with a compound of the formula RkSC^X or R^COX (wherein X is a halogen) or with a compound of the formula R^COOH. 5 · a compound of the formula (111), Wherein R 2 represents a hydroxyl group, and wherein R and R I are as defined in the first claim of the patent application. 6. a compound of formula (V), Where A a is as defined in (i), (i i), or (v) of item 1 of the scope of application, and wherein R, R and R2 are as defined in item 1 of the scope of application. A compound of the formula (V Π )' 70086-961127.doc 1301128 (VII) wherein R, R I, R 2, R 3 and B b are as defined in the first paragraph of the patent application. 8. A compound of formula (IX), R HN I Bb I (IX) wherein R, R|, R2, R3 and Bb are as defined in the first item of the patent application. 9. A compound of formula (X), Wherein R, R 1 , R 2, R 3 and B b are as defined in the first item of the patent application, and wherein R 8 represents a halogen atom. 70086-961127.doc -4 - 1301128 10. Compound of formula (XII), N I Bb I Us-r9 (XII) wherein R, R 1 , R 2, R 3 and B b are as defined in the first item of the patent application, and wherein 119 represents C, _3 alkyl. 11. A compound of formula (XVII), (XVII) wherein R, R and R2 are as defined in claim 1 of the scope of the patent application, and wherein A a is as defined in claim 1 (v), and wherein Prot represents a third-butoxy group A protecting group for a carbonyl group and a fluorenyloxy group. 70086-961127.doc 5-