TWI296618B - Novel 4,5-dihydro-1h-pyrazole derivatives having cb1-antagonistic activity - Google Patents

Description

1296618 A7 B7 V. INSTRUCTIONS (1) The present invention relates to a novel group of 4,5-dihydro-1H-pyrazole derivatives, a process for preparing such compounds, and containing one or more of these compounds as a main component Pharmaceutical composition. The above 4,5-dihydro-1H-pyrazole is a potent cannabis class (CBQ receptor antagonist which can be used to treat diseases involving cannabis. Cannabis is found in Indian cannabis Cannabis sativa and has been used as a medicament for centuries. (Mechoulam, R. & Feigenbaum, JJ Prog. Med. Chem. 1987, 24, 159). However, in the past few decades, research in the cannabis field has been on cannabinoid receptors and their (endogenous) The agonists and antagonists reveal key information. The discovery of two different subtypes of cannabinoid receptors (CB1 & CB2) and subsequent asexual reproduction stimulate novel cannabinoid receptor antagonists (Munro, S. et al., Nature 1993) , 365, 61. Matsuda, LA· and Bonner, TI Cannabis Receptor, Pertwee, R.G_ Ed. 1995, 117, Academic Press, London. In addition, pharmaceutical companies have become interested in treating diseases related to cannabis. Development of Cannabis Drugs for Diseases (Consroe, P. Neurobiology 1998, 5, 534. Pop, E. Cuir. Opin. In CPNS Investigational Drugs 1999, 1, 587, Greenberg, D_A· Drug News Perspect· 1999, 12 , 458· Pertwee, RG·, neurotic Advances in Physical Science 2001, 63, 569). To date, several 〇61 receptor antagonists are known. Sanofi reveals its diaryl p-prediction as a selective CB 丨 receptor antagonist. Is SR-141716A (Dutta, AK et al, Med. Chem. Res. 1994, 5, 54. Lan, R et al, j. Med. Chem. 1999, 42, 769. Nakamura-Palacios, Ε·Μ. Human, CNS Drug Rev· 1999, 5, 43). CP-272871 is like SR 14 17 16A is pyrazole-4 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1296618 A7 B7 Five Inventive Note (2) Derivatives, but lower in effect than SRI417 16A and lower CBi receptor subtype selectivity (Meschler, JP et al, Pharmacol 2000, 60, 1315). Aminoalkyl W嗓 is disclosed as A CBi receptor antagonist. A representative example is i〇d〇pravadoline (AM-63 0), which was introduced in 1995. AM_63 0 is a moderately active CBi receptor antagonist, but sometimes acts as a weak local agonist (Hosohata) , K. et al., Life Sc. 1997, 61, PL115). Researchers from Eli Lilly described aryl-aryl thiol-substituted benzofurans as selective CBi receptor antagonists (eg, LY-320135) (Felder, CC et al, J. Pharmacol. Exp. Ther. 1998, 284,291). 3 -Acetyl·5,5'-biphenylmethylenedione is described as a cannabinoid receptor, indicated as a cannabinoid antagonist (Kanyonyo, Μ. et al., Biorg. Med·Chem. Lett· 1999, 9, 2233). Aventis Pharma claims a diarylmethylene nitrogen analog as a CB! receptor antagonist (Mignani, S. et al., patent FR 2783246, 2000; Chem. Abstr. 2000, 132, 236982). Sanofi-Synthelabo claims tricyclic pyrazole as a CB! antagonist (Barth, F. et al., Chem. Abstr. 2001, 134, 340504). Many CBi receptor antagonists have been reported as in vitro inverse agonists (Landsman, R.S. et al., Eur. J. Pharmacol. 1997, 34, Rl). Review publications provide a good perspective in the field of cannabis research (Mechoulam, R. et al., Prog. Med. Chem. 1998, 35, 199. Lambert, DM Curr. Med. Chem. 1999, 6, 635. Mechoulam, R. et al. Man, Eur. J. Pharmacol. 1998, 359, 1· Williamson, EM and Evans, FJ Drugs 2000, 60, 1303. Pertwee, RG Addiction Biology 2000, 5? 37. Robson, P. Br. J. Psychiatry 2001, 178, 107. Pertwee, RG Prog.

Neurobiol. 2001,63,569. Goya,P and Jagerovic,N. Exp. -5- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1296618 V. Description of invention (3) A7 B7

〇Pin. Ther. Patent 2000, H), 1 529. Pertwee, R G Gut 2〇〇1 48, 859). The novel 4,5-dihydro-1H-pyrazole derivative, its prodrug structure and its salts have been found to be effective and selective for the cannabis-CB! receptor. Presented in formula (I), its mutual variation

0) wherein -R and the card independently represent a phenyl, pyrenyl or pyridyl group, the group of which may be substituted with 2, 3 or 4 substituents Y which may be the same or different from the group cy alkyl or alkane Oxyl, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amine, mono or dialkyl (Ci2)-amino, single or two-compartment (CL2 )--Amine-based, (Cl-3). Acryl base, dimethylsulfanylamine, Ci.3. alkoxycarbyl, carboxyl, trifluoromethylsulfonyl, cyano, amine Methyl, thiol and ethenyl, or R and/or ] represents naphthyl, -R2 represents hydrogen, hydroxy, Cl-3-alkoxy, ethoxylated or propyloxy, -R3 Represents a hydrogen atom or a branched or unbranched Cl 8 alkyl or alkyl group, the alkyl or cycloalkyl group may be substituted with a hydroxyl group, -R4 represents a Cm branched or unbranched heteroalkyl group, a Cs·8 non-aromatic heterocycloalkyl group or C4-1() non-aromatic heterocycloalkyl-alkyl group, the group may contain one or more heteroatoms from a group (〇, N, S) or -S〇2_ group, the branch or not -6-

Binding

Line h 1296618 A7 B7 V. Description of the invention (4) Branched heteroalkyl, C3-8 non-aromatic heterocycloalkyl or C4-1G non-aromatic heterocycloalkyl-alkyl ketone, trifluoromethyl, Cu alkyl, hydroxy, amine, monoalkylamino, or dialkylamino or fluorine atom substituted, or R4 represents an amine group, a hydroxyl group, a phenoxy group or a benzyloxy group or r4 represents a Cw alkoxy group, C3.8 alkenyl, 〇5.8 cyclinyl or c6-9 cycloalkenylalkyl, the group may contain a sulfur, nitrogen or oxygen atom, a keto group or a -S〇2- group, the alkoxy group, an alkenyl group and The cycloalkyl group may be substituted with a hydroxy group, a trifluoromethyl group, an amine group, a monoalkylamino group or a dialkylamino group or a fluorine atom, or R4 represents a C2·5 alkyl group, the alkyl group containing a fluorine atom, or a 4 representing Imidazolyl, benzyl, pyridylmethyl, amphetamine or psecyl, or R4 represents substituted phenyl, benzyl, pyridyl, psecenyl, pyridylmethyl or benzene Isopropylamine ethyl, wherein the aromatic ring may be substituted with 1, 2 or 3 substituents γ, wherein Y has the meaning defined above, or when R3 is fluorene or methyl, R4 represents NR6r7 group, wherein -R0 and R? For the same or different And represents C24 alkyl, Gw trifluoroalkyl or R6 represents methyl, but the limitation is that R7 represents a Cm alkyl group, or R6 and R7 (together with a nitrogen atom bonded thereto) form 4 to 8 a saturated or unsaturated heterocyclic moiety of a ring atom which may contain an oxygen or sulfur atom or a keto group or a -S〇2 group or an additional nitrogen atom, and a saturated or unsaturated heterocyclic moiety may be a CN4 alkyl group. Substituting, or -R3 and R4 (together with a nitrogen atom bonded thereto) form a saturated or unsaturated, monocyclic or bicyclic heterocyclic moiety having 4 to 1 ring atoms, the heterocyclic moiety may contain - Or a plurality of atoms derived from a (〇, N, s) group or a _ group or a s〇2_ group, which may be a CN4 alkyl group, a base group, a phenyl group, a phenyl group, a butyl group, an amine group, Single-base amide-based thiol, dimethyl-based ketone, single-burning basic paper scale applicable to China National Standard (CNS) A4 specification (210X297 public) 1296618 A7 B7 V. Description of invention (5) Amine-based, primary-based Amino, amine alkyl, nitrogen pdanyl, p butyl group, peak bite or 7? hydrogen-1H-azepine, β R5 represents benzyl, phenyl, thienyl or pyridyl, Substituted with 1, 2, 3 or 4 substituents γ, wherein γ has the meaning defined above, which may be the same or different, or Rs represents a Cl-8 branched or unbranched alkyl group, a c3-8 alkenyl group, a Cno ring Alkyl, c:3,bicycloalkyl, C3, tricycloalkane or c58 cycloalkenyl or Han 5 represents a sulphate. The soil is less present at the center of the palmarity (in 4,5-dihydro-1H-pyridyl) The C4 position of the azole moiety is in the compound of the formula (1). The present invention relates to a racemate, a mixture of diastereomers and a specific compound of the formula (1) of the compound of the formula (1) at 4, 5 - Dihydro-1H-P has an absolute stereo configuration than the c4 position of the olfactory moiety, as shown in formula (1a).

The present invention also relates to a form of administration wherein the E isomer, the 2 isomer, and the t compound of the compound of formula (1) are formed into a suitable method suitable for the use of auxiliary substances and/or liquid or solid carrier materials. ▲Because of the effective CB1 anti-active activity, the compound according to the present invention is suitable for treating psychiatric diseases such as psychosis, anxiety, depression, and lack of attention. The paper scale is suitable for the gg standard (CNS) Α 4 specifications ((10) X tear public love 1296618 A7 B7 V. Description of invention (6), memory impairment, cognitive impairment, loss of appetite, obesity, addiction, sensuality, drug addiction and neurological diseases such as neurodegenerative diseases, dementia, lack of tension, muscle spasm , tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Hardington's disease, Torrede's syndrome, cerebral ischemia, stroke, skull and Brain trauma, spinal cord injury, neuroinflammatory disease, thrombocytopenia, viral encephalitis, myelin-learning-related diseases, and diseases used to treat pain, including neuropathic pain, and other diseases involving cannabinoid conduction, including treatment of septicemia Shock, glaucoma, cancer, diabetes, vomiting, nausea, asthma, respiratory disease, gastrointestinal disease, stomach ulcers, diarrhea, and cardiovascular disease. The affinity of the compounds of the invention for the cannabinoid CB! receptor is determined using a membrane preparation of Chinese voles ovary (CHO) cells, wherein the human cannabis CB! receptor is stably associated with [3H]CP-5 5,940 as a radioligand. Transfer the infection. After the newly prepared cell membrane preparation was incubated with or without the addition of the compound of the present invention with [3H]-ligand, the separation of the bond from the free ligand was carried out by filtration on a glass fiber filter. The radioactivity on the filter is determined by liquid scintillation counting. The cannabinoid CBi antagonistic activity of the compounds of the present invention is determined by functional studies of CHO cells stably expressed using the human cannabis CB! receptor. Adenine Nuclear cyclases were stimulated with forskolin and quantified by quantitative accumulation of cyclic AMP. The concomitant activation of CBi receptors by CB receptor agonists (e.g., CP-55, 940 or (R)-WIN-55, 212-2) can reduce the accumulation of forskolin c guidance of cAMP in a concentration-dependent manner. This CBi receptor intermediate response can be antagonized by a CB! receptor antagonist such as a compound of the invention. -9- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) binding

Line 1296618 A7 B7 V. INSTRUCTIONS (7) Intermediates of formula (II) (see below) can be obtained according to known methods, for example: a) Franccotte, E.; Tong, Z. Chem. Abstr. 126, 213598 b) Rempfler, H. and Kunz, W. Chem. Abstr. 113, 40432; c) Rempfler, H. and Kunz, W. Chem. Abstr. 107, 217473. Intermediates having the formula (111) wherein R2 represents hydrogen can be obtained according to known methods, for example: a) EP 0021506; b) DE 2529689; c) Grosscurt, AC et al., J. Agric. Food Chem. 1979,27,(2), 406 ° An intermediate having the formula (111) (wherein 112 represents a hydroxyl group) can be obtained by reacting a compound of the formula (II) with hydrazine or hydrazine hydrate to obtain (π) 丨 J ϊ This reaction, preferably carried out in an organic solvent such as ethanol, gives a compound of formula (III).

η — i Suitable synthetic routes for the compounds of the invention are as follows: Synthesis route A1 Step 1: Reaction of a compound of formula (III) with a thioisocyanate derivative of formula (IV),

NCS 0 十〇(IV) r5 -10- This paper scale applies to Chinese national standards (CNSfA4 specification (210X 297 mm) 1296618 A7 B7 5. Inventive Note (8) It is best to carry out in an organic solvent such as acetonitrile. There is obtained a thioisocyanate derivative of the formula (V): wherein R, Ri, 112 and 115 have the above meanings for the compound (I).

Step 2: A compound having the formula (1) can be obtained by reacting a compound of the formula (V) with a compound R3R4NH in the presence of a mercury (II) salt such as HgCl2. This reaction is preferably carried out in the presence of an organic solvent such as acetonitrile. Synthetic route A2 Step 1 • Compound with formula (III)

Reaction of Ri with a carboxylic acid transductive derivative of formula (VI) HN""0R8 0=S=0 (VI)

Rs wherein R8 represents a lower alkyl group, for example, a methyl group. This reaction is preferably carried out in an organic solvent such as 1,4-dioxane, and 4,5- having the formula (VII) wherein R, R!, R2 and R5 have the above meanings for the compound (I) can be obtained. Dihydropyrazole-1-carboxylic acid decylamine derivative. This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1296618 A7 B7 V. Description of invention (10) Synthetic route A3 Step "_·· Compound with formula (III)

R

Reaction of Ri r2 (ill) with a bisiminoimine carbonate derivative of the formula (IX) R10 τ 0 = S = 0 (IX) wherein Rio represents a Ci3 alkyl group. This reaction is preferably carried out in an organic solvent such as acetonitrile or toluene to give a carboxylic acid having the formula (X) wherein r, r2 & r5 have the above meaning for the compound (I) and wherein R1G represents a Cl.3 alkyl group. Acid imine thioester derivatives.

R

N O—S^〇 Rs

Ri r2 (X) 5 - R10 Alternatively, the compound having the formula (x) may be a compound of the formula (v) and the compound Ri〇-X (wherein X represents a leaving group such as a moth group, and Rio has the above pair (X) ) -13- This paper size is obtained by the Chinese National Standard (CNS) A4 specification (210 X 297 public) 1296618 A7 ___ B7 V. The invention description ("Sisi thinking") is obtained. The reaction of the compound of x) with the compound r3r4nh is preferably carried out in an organic solvent such as methanol to give a compound of the formula (1). The preparation of the compound is exemplified by the following examples: Example 1 3-(4-chlorophenyl)-indole, ·((4_Chlorophenyl) fluorenyl)_N(hexahydropyridine small group)· 4- + yl-4,5-one wind-ΙΗ-ρ ratio Jun·1-acid acid adenine Α ·· ; 3-. 4-(4-chlorophenylphenyl·4,5-dihydro-m-pyrazole (3 39 g, 13.2 mmol) added to n-((4-chlorophenyl) decyl)amine A mixture of methyl formate (CAS: 3 4543-04-9) (2.99 g, 12.0 mmol) and pyridine (4 mL) in 1,4-dioxane (20 mL) Stir at °c for 4 hours. After concentration in vacuo, the residue was dissolved in dichloromethane. It was continuously washed with 1 N HCl and water, dried over anhydrous Na 2 SO 4 and concentrated in vacuo to a volume of 20 mL. Methyl-tert-butyl ether (6 〇mL) was added and the solution was concentrated to a volume of 20 mL. It was collected by filtration and recrystallized from methyl-tert-butyl ether to give 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4-phenyl-4,5- Dihydro-1H-pyrazole-1-carboxylic acid decylamine (4.75 g, 76% yield). Melting point: 211-214 〇 C. Part B: 3-(4-chlorophenyl)-N- (4 -Chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H.pyrazole-1-carboxylic acid decylamine (1.42 g, 3.00 mmol) and phosphorus pentachloride (卩( : 15) (0.63 §, 3.03 mmol) of a mixture of chlorobenzene (15 1111 Torr) at reflux temperature for 1 hour. After concentration in vacuo, 3-(4-chlorophenyl)-N- ((4-Chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-carboxylic acid imine oxime chloride suspended in dry dichloromethane (30 mL) with丨-Amino hexahydro-14- This paper scale applies to China National Standard (CNS) A4 specification (210X 297 metric tons)

Binding

1296618 A7 __B7___ V. Description of the invention (12) Pyridine (1.08 mL, 10.0 mmol) reaction. After stirring at room temperature for 16 hours, the mixture was washed twice with water and concentrated in vacuo. The residue is recrystallized from methyl-tert-butyl ether (MTBE) to give pure 3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-N-(hexahydropyridine) 1-yl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxylic acid hydrazine (0.57 g, 34% yield). Melting point: 213-214 ° C. MS ESI+: 556 (MH+). All 57 compounds having the formula (XI) were prepared in a similar manner to the synthesis of Example 1. It is shown in Table 1 and List 1.

Binding Table 1 Example Rs r4 Ru Melting Point (°C) MS ESI+ (MH+) Salt 2 Η Hexahydro ρ Ratio -1-Base F 189-190 540 3 Η ρ 咯 淀 -1 -1 -1 Cl 190-195 542 4 Η Pyrrolidin-1-yl F 526 5 Η Essence-1·yl Cl 197-199 6 顺 cis/trans-2,6-dimercaptohexahydropyridin-1-yl Cl 110-146 7 Η 2,2,2-Trifluoroethylamino group Cl 149-151 -15- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm)

Line 1296618 A7 B7 V. Description of the invention (14 31 Η _ 2-aminooxyethyl C1 532 32 Η 2_(dimethylamino) ethoxy C1 201 560 33 Η 2 · (diethylamino) B Oxygen C1 210 588 34 Η 2·(Methoxy)ethyl C1 99-102 35 ch3 2-(ethoxycarbonyl)ethyl C1 157-158 573 36 Η 2-Hydroxyethyl F 501 37 Η 2- Hydroxyethyl C1 517 38 Η 2-Hydroxy-2-methylpropyl C1 39 Η 3-Hydroxypropyl C1 129-132 40 ch3 Hydroxy C1 208-211 41 Η Methoxy cf3 178-180 42 Η 2-Fluoro Base Cl 100-103 43 Η 2-Fluoroethyl cf3 132-134 List 1 44· 3-(4-Chlorophenyl)_N_methoxy, _((3-methylphenyl)sulfonyl) _4-Phenyl-4,5-monohydro-1H-oxime-1. Oreoside. Melting point: 151-152 ° C. 45. 3-(4-Chlorophenyl) N-methoxy- Ν,-((2·Methylphenyl)sulfonylphenyl-4,5-dihydro-1Η-pyrazole-1-carboxylic acid oxime. Melting point: 145-146 ° C. 46· 3-(4 -chlorophenyl)·Ν·methoxy-N'-((2,4,5-sfluorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1- Barium carboxylate. Melting point: 160-162 ° C. 47. 3-(5-Gasporin-2-yl)-N'-((4-chlorobenzene) Base sulfonyl)-N-methoxy-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxylic acid hydrazine. Melting point: 180-181 ° C. 48· Ν'-( (4·Chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-N-methoxy-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxylic acid hydrazine Melting point: 201-203 ° C. ___-17-_ _ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1296618 A7 ___B7 V. Description of invention (15) 49.3- (4-Chlorine Phenyl)卞'_(^4_chlorophenyl)sulfonyl)_yimethoxy_4_(3·(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazole β1 · Barium carboxylate. Melting point: 80-83〇C 〇50· 3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonylmethoxy_4<2, difluoro Phenyl)-4,5-dihydro-1H-pyrazole-1-carboxylic acid oxime. Melting point: 174-177 Ό. 51· 3-(4-chlorophenyl)-Ν'-((4-chlorophenyl) Sulfosyl)-indole (2-fluoroethyl (2,6-difluorophenyl)-4,5-dihydro-indoleazole-carboxylic acid hydrazine. Melting point: 153-1553⁄4. 52· 3-(4-Chlorophenyl)-indole,-((4·chlorophenyl)sulfonyl)_ν_(2·fluoroethyl)_4_(3·fluorophenyl)-4,5-dihydro -1H-pyrazole-1-carboxylic acid hydrazine. Melting point: 13 (rc. 53· 3-(4-chlorophenyl)-indole-(2·fluoroethyl)-heart (3-fluorophenyl)-N,-((4-(trifluoromethyl)) Phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxylic acid oxime. Melting point: 155 〇C. 54.3- (4-chlorophenyl)-;^'-((4- Chlorophenyl)sulfonyl)-4_(3-fluorophenyl)-;^-(methoxy)-4,5-dihydro-1H-pyrazole-1-carboxylic acid hydrazine. Amorphous. 3-(4-Chlorophenyl)-4-(3-fluorophenyl)-indole (methoxy)_N, gas (4彳 trifluoromethyl)) (bristol)-4,5-di Hydrogen is more than 唆-1-acid bismuth. Melting point: >260〇C 0 56· 3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-(2-fluorophenyl)-N-(A Oxy)-4,5-dihydro-1H.pyrazole·1_acid oxime. Melting point: 162-164 ° C. 57. 3-(4-Chlorophenyl)-4-(2-fluorophenyl)-N-(methoxy)-N,-((4-(trifluoromethyl)methyl) 3⁄4) -4,5-Dinitro-1H-P is more than sulphur-1. Melting point: 147-149〇C. In a similar manner, 29 compounds having the formula (ΧΠ) were prepared. It is shown on -18- This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1296618 A7 B7 V. Invention description (16) Table 2 and Table 2. Table 2

Example Rn Rl 2 Melting point (°C) MS ESI + (MH+) salt form 58 Cl 1,2,3,4-tetrahydroisoindoline-2-yl 589 59 F 1,2,3,4-tetrahydroisoquine啉-2-yl 573 60 F p 洛 bite-1 -yl 511 61 Cl morpholin-4-yl 543 62 F 〃林林-4 -yl 527 63 Cl 氮口旦-1 -基200-202 513 64 F Nitrogen-1 -yl 497 65 Cl 4-hydroxyhexahydropyridin-1-yl 112-117 66 Cl 3-hydroxyhexahydropyridin-1-yl 218-222 67 Cl 4-(hydroxymethyl)hexahydro Pyridine-1·yl 185-188 68 Cl 1,1-dioxythiomorpholin-4-yl 120 591 69 Cl 4-methylhexahydropyrrol-1-yl 556 70 Cl [1,4'] -Double Hexapyridine-1'-based 260 624

Binding gas-19- This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1296618 A7 B7 V. Description of invention (20) by racemic 3-(4-chlorophenyl)-N'-( Separation of (4-chlorophenyl)sulfonyl)-N-methoxy-4-phenyl-4,5-dihydro-lH-p than 嗓-1-deoxalate by palm chromatography For the palmitic stationary phase: Chiralpak AD), (-)-(4S)-3-(4-chlorophenyl)-Ν'·((4-chlorophenyl)sulfonyl)- N-methoxy-4-phenyl-4,5-dihydro-lH-p ratio jun-1-deoxalate ([a25D] = -165°, c = 0.01, MeOH) 〇 mobile phase system from ethanol Composed of.

Binding

Line -23-This paper scale applies to China National Standard (CNS) Α4 specification (210X 297 mm)

Claims (1)

A8 B8 Announcement m Patent Application No. 129661^119796 Patent Application Serial No. (January 1997), Patent Application No. 1. A compound having the formula (1), o =: s = ok wherein R and R each independently represent a phenyl "sepeno, W phenyl or yl group, wherein the phenyl group may be substituted by a substituent 丫 which is selected from methyl, halogen or tri Fluoromethyl, ', R2 represents hydrogen, -R3 represents a hydrogen atom or a branched or unbranched Ci 4 alkyl group, -b represents a 〇2_10 branched or unbranched heteroalkyl group, cu non-aromatic heterocycloalkyl group or C4-1G a non-aromatic heterocycloalkyl-alkyl group which may contain one or more heteroatoms from a group (0, N, 8) or _8〇2_ group, the Cm branched or unbranched heteroalkyl group , Cw non-aromatic heterocycloalkyl or C4] non-aromatic heterocycloalkyl-alkyl may be keto, trifluoromethyl, Cw alkyl, hydroxy, amine, monoalkylamine, or dioxane The amino group or the fluorine atom is substituted by ' or R4 represents an amine group, a trans group, a phenoxy group or a benzyloxy group or R4 represents a Cw alkoxy group, a C:3·8 gal group, a C5-8 cyclyl group or a C: a hexacycloalkenyl group which may contain a sulfur, nitrogen or oxygen atom, a keto group or a -S〇2- group, and the alkoxy group, alkenyl group and cycloalkenyl group may be a hydroxyl group, a trifluoromethyl group or an amine group. Base, monoalkylamino or dialkylamine or fluorine atom 0301-970124.doc This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) A8 B8 C8 D8 1296618, the scope of patent application, or R4 represents CM alkyl, the alkyl group contains fluorine atom, or & Represents an imidazolidinyl group, a benzyl group, a pyridylmethyl group, an amphetamine ethyl group or a thiophene group, or R4 represents a substituted phenyl group, a benzyl group, a pyridinyl group, a phenanthrenyl group, a pyridylmethyl group or a benzene group. Isopropylamine ethyl, wherein the aromatic ring may be substituted with 1, 2 or 3 substituents, wherein γ has the meaning defined above, or when R3 is fluorene or methyl, I represents Nr0r7s, wherein -R6 and R7 are the same Or different, and represents a CL4 alkyl or Cw trifluoroalkyl group or R6 represents a methyl group 'but the limitation is that it represents a C2 4 alkyl group, or R6 and R7 (together with the nitrogen atom bonded thereto) form 4 to a saturated or unsaturated heterocyclic moiety of 8 ring atoms, the heterocyclic moiety may contain an oxygen or sulfur atom or a keto group or a -S〇2 group or an additional nitrogen atom, and the saturated or unsaturated heterocyclic moiety may be ffiCw Alkyl substitution, or -R3 and R4 (together with the nitrogen atom to which they are bonded) form a fullness of 4 to 10 ring atoms Or an unsaturated, monocyclic or bicyclic heterocyclic moiety which may contain one or more atoms from the (0, N, s) group or a keto group or a -s〇2 group, which may be Cl_4 Alkyl, hydroxyalkyl, phenyl, thienyl, pyridyl, amine, monoalkylaminoalkyl, dialkylaminoalkyl, monoalkylamino, dialkylamino, amin a base, an azide group, a pyrrolidinyl group, a piperidinyl group or a hexahydro-indolyl group, -R5 represents a phenyl group which may be substituted by a substituent γ, wherein 丫 has the meaning defined above, or R5 represents a Cw branch Or an unbranched alkyl group wherein the alkyl or aryl group has 1 to 4 carbon atoms, and tautomers, stereoisomers and salts thereof. Order 80301-970124.doc -2 - A8 1296618 $ D8 VI. Scope of Application 2. For the compound of claim 1 of the patent scope, it has the general formula (XI) Where: R3 r4 Rn Η hexanitro ρ ratio bite · 1 · yl Cl Η hexanitrogen 比 -1 -1 - base F Η ρ Bilo.定1 -基 Cl Η 外匕洛 定定1 -Base F Η Nitrogen π平-1-yl Cl Η cis/trans-2,6-dimethylhexahydropyridin-1 -yl Cl Η 2 , 2,2·Trifluoroethylamino group Cl Η Third butoxy group Η 2-propoxy group 甲 methoxy group 甲 methoxy group F Η p lin 4 - group Cl Η 2- (? Porphyrin·4·yl)ethylCl Η 2-(hexanitro-p-r-butyr-1-yl)ethylCl Η 2-(ρ 比洛丁-1-yl)ethylCl Η 2-(dimethyl Amino) Ethyl F ch3 2-(Dimethylamino)ethyl Cl 80301-970124.doc - 3 - This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) A8 1296618 S D8 6. Patent application scope Η 2-(Dimethylamino)ethyl C1 Η 2-(methylamino)ethyl C1 Η 2·(ethylamino)ethyl C1 Η 3-(dimethylamine ))-2-methylpropan-2-yl C1 Η (N-methylpyrrolidin-2-yl)indenyl C1 Η (N-methylpyrrolidin-3-yl)methyl C1 Η 4 _ (p ratio嘻.1 -yl)butyl C1 Η 3 -(Molin-4-yl)propyl C1 Η 3-(didecylamino)propyl C1 €3 3-(dimethylamino)propyl Base F c2h5 2 -Aminoethyl C1 Η 3-(dimethylamino group Propyl F Η 3·(1Η-imidazole-1·yl)propyl C1 Η 2-Aminooxyethyl C1 Η 2-(Dimethylamino)ethoxy C1 Η 2-(diethylamino group Ethoxylated C1 Η 2·(Methoxy)ethyl C1 ch3 2-(ethyloxy)ethyl C1 Η 2-ylidylethyl F Η 2 -ylethyl C1 Η 2-hydroxy-2 Mercaptopropyl C1 Η 3 - propyl propyl C 1 ch 3 hydroxy C 1 甲 methoxy cf 3 Η 2-fluoroethyl Cl Η 2-oxyethyl CF 3 3. The compound of claim 1 has a pass Formula (XII) 80301-970124.doc - 4 - This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1296618 VI. Patent application scope Where: Rii Rl2 Cl l, 2,3,4·tetrahydroisoindoline_2·yl F 1,2,3,4-tetraaza-isosin 17-lin-2-yl F pbiol °-1 Base Cl 〃 林 - 4 - F F -4 - 4 - yl Cl Nitrogen 0 den-1 · Basis F Nitrogen-denier-1 -yl Cl 4 - via base six mice?淀1 -1 -1 -Cl3 -1,6-dioxythio-indolyl-1 -yl-Cl, 4-(hydroxymethyl)hexahydropyridin-1 -yl,Cl 1,1-dioxythiolan-4-yl Cl 4 -methyl six mouse? Ratio 0 well-1-yl Cl [1,4']_bishexahydropyridine-1'-yl Cl 3,5-cis-dimethylhexahydropyrrolidin-1-yl F 4 -methylhexanitro Ρ-pyridyl-1·yl F 3,5-cis-dimethylhexahydropyrrolidin-1-yl F [1,4']-bishexahydropyridine-1'-yl F 4 -methyl-1 ,4 -diazepine-1-yl Cl 1,4·diazehr-1-yl F 1,4·diazepine-1-yl Cl 2,6-cis-dimethylhexahydropyrrole- 1-based F 4-(didecylamino)hexahydropyridin-1-yl 80301-970124.doc - 5 - This paper size applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) A8 B8 C8 D8 1296618 VI. Patent application scope F hexa-nitrogen p whistle 1 -1 -yl C1 4 - (ρ ratio _ 4 -yl) hexanitro ptb -1-1 -yl C1 4-(2-dimethylamino group Ethyl) hexahydropyrazole-1-yl C1 4-(3-dimethylaminopropyl)hexahydropyrrole-1-yl C1 4-(3_propylidene)hexanitrogen p- 1-based C1 2,6-cis-dimethyl-4-methyl hexahydropyrazine-1-yl group 4. The compound of claim 1 having the formula (XIII) Where: R3 r4 Rl3 Η 3-(dimethylamino)propyl ch3 Η N-methyl hexazone? 〇定- 4-基i-C3H7 5. A compound according to claim 1 which is 3-(4-chlorophenyl)_N-methoxy-N'-((3-methylphenyl) , sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxylic acid hydrazine, 3-(4-chlorophenyl)-fluorene-methoxy-Ν'-(( 2-methylphenyl)sulfonyl)-4-phenyl-4,5-diox- lH-p ratio 13-sodium-1-antimonate '3-(4-chlorophenyl)-N- oxy-N'-((2,4,5-trifluorophenyl)sulfonyl)-4- -6 - 80301-970124.doc This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297) PCT) 1296618 •... - D8 VI. Patent Application Benzyl-4,5-dihydro-1H-pyrazole-1-carboxylic acid hydrazine, 3-(5-chloropyrimidin-2-yl)-N' -((4-Phenylphenyl)sulfonyl)·Ν-曱oxy-4-phenyl-4,5-dihydro-1Η-pyrazole-1-carboxylic acid hydrazine, Ν'-((4- Chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-fluorene-methoxy-4-phenyl-4,5-dihydro-1?-pyrazole-1-carboxylic acid hydrazine, 3- (4-Chlorophenyl)-indole-((4-chlorophenyl)sulfonyl)-fluorenyl-methoxy-4-(3-(trifluoromethyl)phenyl)-4,5-di Hydrogen-111_pyrazole-1-carboxylic acid hydrazine, 3-(4-chlorophenyl)-N'-((4-hydrophenyl)sulfonyl)-N- Oxy-4-(2,6-difluorophenyl)-4,5-dihydro-1H-pyrazole·1·carboxylate, 3—(4-chlorophenyl)-Ν'-((4- Phenyl)sulfonyl)-indole-(2-fluoroethyl)-4-(2,6-difluorophenyl)-4,5-dihydro-1?-pyrazole-1-carboxylic acid hydrazine, 3 -(4-chlorophenyl)-N'-((4-phenylphenyl)sulfonyl)-indole-(2-fluoroethyl)-4-(3-fluorophenyl)-4,5-di Hydrogen-1H-pyrazole·1-carboxylic acid hydrazine, 3-(4-phenylphenyl)-fluorene-(2·fluoroethyl)-4-(3-fluorophenyl)-Ν'-((4- (Trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1Η-pyrazole-1-carboxylic acid hydrazine, 3-(4-chlorophenyl)-N'-((4-chloro Phenyl)sulfonyl)-4-(3-fluorophenyl)-indole-(methoxy)-4,5-dihydro-1indole-pyrazole-1-carboxylic acid hydrazine, 3-(4-chloro Phenyl)-4-(3-fluorophenyl)-indole-(methoxy)-indole-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro- 1H-pyrazole-1-carboxylic acid hydrazine, 3-(4-phenylphenyl)-N'-((4-phenylphenyl)sulfonyl)-4-(2-fluorophenyl)-N-( Methoxy)-4,5-diaza·1Η·ρ is ϋ -1-1· 叛 脉 ' 3-(4-chlorophenyl)-4-(2-fluorophenyl)-Ν_(oxime )-Ν'-((4-(Trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1Η-pyrazole-1 - Carboxylic acid hydrazine, 80301-970124.doc - 7 - This paper scale is applicable to China National Standard (CNS) Α4 specification (210 X 297 mm) 1296618 A8 B8 C8 D8, patent application scope N-[(3-(4_ Chlorophenyl)_4-(3_(trifluoromethyl)phenyl)_4,5-dihydro-1H_pyrazol-1-yl)(4-methylhexahydropyridin-yl)-indenyl] _4_Chlorobenzenesulfonamide, N-[(4-phenyl_3_(pyridine_3_yl)_455_dihydro] "pyrazole small group" ('mercaptohexahydropyrazine-i-yl) Methyl]_4_chlorobenzenesulfonamide, (_M4S)-3-(4-phenylphenyl)-N'-((4-phenylphenyl)sulfonyl)_N_methoxy-4-phenyl -4,5-Dihydro-111-pyrazole-1-carboxylic acid hydrazine. A pharmaceutical composition for treating a disease involving cannabinoid conduction, which comprises at least one pharmaceutically effective amount of a compound as claimed in claim 3, 4, or 5 as an active ingredient. 7. A compound of the formula No. 2, 3, 4 or 5 of the patent scope is used as a medicament. 8. Use of a compound of claim 2, 3, 4 or 5 of the scope of the patent application' for the preparation of a pharmaceutical composition for treating a disease involving cannabinoid conduction. 9. The use of the scope of claim 8 is characterized in that the disease is a psychiatric disease such as mental paralysis, anxiety, depression #, attention deficit, memory disorder, cognitive impairment, loss of appetite, obesity, Addiction, meat, addiction, and neurological diseases such as neurodegenerative diseases, dementia, lack of tension, muscle spasms, tremors, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Azheimer's disease Disease, epilepsy, Dytenton's disease, Torrede's syndrome, cerebral ischemia, stroke, cranial and brain trauma, spinal injury, neuroinflammatory disease, platelet sclerosis, viral encephalitis, Zhaoler loss Disease and used to treat pain, package (four)" 80301-970124.doc -8 - 8 8 8 8 A BCD 1296618 VI. The scope of patent application, and other diseases involving cannabinoid conduction, including treatment of septic shock, glaucoma, cancer, diabetes, 11 district vomiting, ° nausea, asthma, respiratory disease, gastrointestinal disease , stomach ulceration, diarrhea and heart disease. 80301-970124.doc - 9 - This paper size applies to China National Standard (CNS) A4 specification (210X297 mm)