TW200815378A - Chemical compound - Google Patents

Abstract

Novel crystalline forms of the compound (trans-4-{4-[({5-[(3,4-difluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]phenyl}cyclohexyl) acetic acid are provided, together with processes for the manufacture of such forms, pharmaceutical compositions comprising them and the use of such forms in medical treatment.

Description

200815378 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to a novel crystalline compound, and more particularly to the following formula (1) (anti-_4_{4_[({5_[(3, a novel crystalline form of 4_difluorophenyl)amino], _ 1,3,4-oxadiazole _ 2 _yl}carbonyl)amino]phenyl}cyclohexyl)acetic acid, the compound is ethyl hydrazide c 〇A (Ethyl Acetylase A): an inhibitor of dimercaptopurine = oil hydrazine-transferase (DGAT1) activity. The present invention is also directed to a method for producing the crystal forms, a pharmaceutical composition comprising the crystal forms, and a use of the S-crystal form in medical treatment. (I) [Prior Art] The oxadiazole containing a compound which inhibits DGAT1 is described in the international application PCT/GB2005/004726. The compound of formula (1) is exemplified in

The application (example 541 of International Application PCT/GB2005/004726; WO 2006/064 189), and obtained as a crystalline solid after recrystallization from acetic acid, is hereinafter referred to as Form 1. The X-ray powder diffraction pattern of Form 1 is shown in Figure 2A and the thermal data of the acetic acid solvate of Form 1 is shown in Figure 2Β. It has now been surprisingly and unexpectedly discovered that the agent of Formula (I) can be in other crystalline forms. Preparation, hereinafter referred to as Form 2 and Form 3. The polymorphic forms may have different solubilities and/or stability and/or bioavailability and/or different impurity distributions (eg, trace impurities due to manufacturing and/or separation processes) and / 121165.doc 200815378 or ease of handling, Micronization and/or formation of the crystalline form of the tablet. SUMMARY OF THE INVENTION _ /. It has a peak value. According to the present invention, the crystal form (morphology 2) of (1) is provided at 2, 21.4 and 22.7. The ray powder diffraction pattern is placed. It has a theoretical value. According to the present invention, the crystalline form (10) of (1) is provided 2), and at (4) 6.8, 21.4 and 22.7. The riding line of the powder is diffracted. Ο Ο In the invention, the crystal form (form 2) of (1) is provided, which has a peak case. ·, 9.3, 16.8, 21.4 and 22.7. The follow-up powder diffraction pattern according to the present invention 'provides the crystalline form of (1) (Form 2), and (4) the present invention provides the crystalline form of (1) (morphology 2 16,. 16,. 17^ l8i^ i86 7 23.3, 25.9 And the X-ray powder diffraction pattern at 29.2. The X-ray powder diffraction pattern of Form 2 is shown in the figure. The comparison between Form 丄 and Form 2 is shown in Figure 3 and the thermal data of Form 2 is shown in ( Form 2 in an anhydrous form. According to the present invention, there is provided a crystalline form (Form 2) of (1) having an X-ray powder diffraction pattern substantially as shown in Fig. 1. According to the present invention, a crystalline form of (1) is also provided. (Form 3), which has a ray-ray powder diffraction pattern having peaks at 2Θ8·4, 13′′, and 16·7. According to the present invention, a crystalline form (Form 3) of (1) having a value of m is also provided. 8·4, 13·8, 16.7, 21·6, and 24·3. X-ray powder 121165.doc 200815378 End diffraction pattern. According to the present invention, the crystal form (formation) of (1) 3), which has peaks at 2Θ = 4·8, 5.6, 7 η 〇·〇, 8.4, 13·8, 16·7, 19·5, 20·0, 21·6^ X-ray powder diffraction pattern at 24·3°. The X-ray powder diffraction pattern of Kaishen 3 is shown in Figure $ and the morphology of Figure 3. The material is shown in Figure 6 (form 3 in anhydrous form) According to the present invention, there is also provided a crystalline form (morphology 3) of (1) having an x-ray powder diffraction pattern as shown in Fig. 5 on a large carcass. Table 1, Table 2 and Table 3 respectively show the form 2, the form 1 and the main peak of Form 3 0 According to the present invention, Form 2 and Form 3 are substantially free of other crystal forms and amorphous forms of Compound (1). It should be understood that the term, substantially free of other crystal forms and amorphous forms, Means that the desired crystalline form contains less than 50%, preferably less than 20%, more preferably less than 1%, more preferably less than 5% of any other form of compound (I) 〇 1 / by the substance of the sa The sample was adhered to a Siemens single crystal silicon (SSC) wafer adhesive sheet and the sample was developed into a thin layer by means of a slide to determine the diffraction pattern of the xenon ray powder. The sample was rotated at 30 rpm (to improve count statistics). And use the Bruker D5 000 powder X-ray diffractometer (Bruker AXS, Banner • Lane Coventry CV4 9 GH) is irradiated with x-rays generated by a copper elongated focusing tube operating at 4 〇 kV and 40 mA at a wavelength of 1.5406 angstroms (A). The collimated X-ray source is passed through an automatic set to V 2 0 Variable divergence slits, and direct the reflected radiation through the 2 mm backscattering slit and the 〇·2 mm detector slit. The sample is made in the Θ-Θ mode in the range of 2 to 40 degrees 2Θ. 2 I21165.doc 200815378 Degree 2Θ1 exposure for 1 second (continuous scan mode). The appliance is equipped with a flash meter as a detector. The control and data acquisition is done by means of the Dell 〇ptiplex 686 NT 4.0 Workstation with Diffrac+ software. Those skilled in the art recognize that a two-line powder diffraction pattern with multiple measurement errors is obtained depending on the measurement conditions (such as the equipment used, sample preparation, or machine). In detail, it is known that the diffraction pattern of the ray-ray powder fluctuates according to the conditions of the measurement and the sample preparation. For example, those skilled in the art will appreciate that the relative peak intensities can be affected by, for example, grains having a size greater than 3' 微米 microns and a non-single aspect ratio that can affect sample analysis. Those skilled in the art will also recognize that the position of the reflection can be affected by the accuracy of the sample in the diffractometer and the zero correction of the diffractometer. #品的面面度 can also have a small impact. Rhyme, those skilled in the art will understand that the diffraction pattern data presented in this article is not considered absolute (for more information on Beixin, signing Jenkins, R and Snyder, RL, Intr〇ducti〇n than χ·

Ray Powder Diffractometry, J〇hn Wiley & s_, l996). Therefore, it should be understood that the crystal form of the compound (1) is not limited to the crystal which provides the same diffraction pattern of the X-ray powder diffraction pattern as the X-ray powder diffraction pattern shown in FIGS. 1 and 5, respectively, and is provided with Any crystal of the x-ray powder diffraction pattern having substantially the same x-ray powder diffraction pattern as shown in Fig. 5 is within the scope of the invention. Form 2 and Form 3 can also be analyzed by other techniques known in the art such as differential scanning calorimetry (1) sc) and thermogravimetric analysis (TGA), such as H^ne, G. W. H. et al. (1996),

Springer, the standard method described in Berlin, is identified by the standard method 121165.doc 200815378. It should be understood that the DSC start/peak temperature value and the TGA weight loss value may be slightly different for different machines or different samples, and thus the values quoted in the thermal trace are not considered absolute. The technique used is described in more detail below * Description ° • Differential scanning calorimetry was performed using the analytical instrument Mettler DSC820e. Usually '1' in the temperature range from 25 ° C to 325. Constant 〇/min plus 0 heat rate to heat less than 5 mg of material contained in a 40 μΐ aluminum pan fitted with a perforated lid. A purge gas with nitrogen was used with a flow rate of 1 〇〇 ml/min. Thermogravimetric analysis was performed using an analytical instrument: Mettler TG851. It is usually 1 Torr in the temperature range of 25 ° C to 325 ° C. Constant heating rate of 〇 / min Heats the substance between 3 ^ and ]^ mg contained in 70 μΐ al〇x (alumina). Use a purge gas with helium _ flow rate of 5 〇 ml / min. Form 2 and Form 3 can be crystallized as described in the accompanying examples. Accordingly, in another aspect of the present invention, there is provided a process for producing a crystalline form 2 of the compound of the formula (1), which comprises preparing and isolating the compound (I) from water and methanol, and then agitating the solid in water. The suspension is suspended (e.g., for 1-5 days, such as 3 days) and the solid obtained is isolated (e.g., by filtration, optionally with water, and dried). - In another aspect of the invention, there is provided a process for the manufacture of a knot 2 of a compound of formula (1) which comprises mixing a suspension of compound (I) in water. In another aspect of the invention, there is provided a process for the manufacture of crystalline Form 3 of a compound of formula (1) which comprises stirring at elevated temperatures (e.g., 3 Torr to 〇, especially at about 50 ° C). Compound (1) form 丨 and form 2 mixed in acetonitrile 121165.doc •10- 200815378 (for example, U days, such as 3 days), and separate the obtained solids (for example, -k depending on the situation, wash the strip with a suitable solvent And dry). According to another feature of the invention, there is provided a novel crystalline form of the compound of formula (I) which can be obtained by any of the methods or examples disclosed herein. According to another sorrow of the present invention, a pharmaceutical composition comprising Form 2 or Form 3 as defined above and a pharmaceutically acceptable excipient or carrier is provided. Ο

The composition of the present invention may be in a form suitable for oral administration (for example, in the form of a lozenge, an A ^ J sputum, a hard or soft capsule, an aqueous or oily suspension, a guide L, 'night, ', Dispersible powder or granules, syrup or elixir), topical use (eg $5丨喜^月, 孝人s, gel or aqueous or oily solution or county float), 叨人#心彤弋), Slave (for example, in the form of a fine powder or liquid aerosol / "" human-injected (for example, in the form of a fine powder) or parenteral (for example, in the form of a sputum) Sterile aqueous or oily solutions for internal, subcutaneous, intramuscular or intramuscular administration. 4 σ — 乂 or 壬 for suppository suppositories. 习 物 物 物 物 物 物The agent, the coloring agent, the sweetener, the fragrance and/or the anti-corrosive agent include an inert dilution; a suitable medically acceptable substance such as a powder; a lubricant, such as...", each "binder, agent" , such as (four) stupid: stearic acid or talc; preservative soil armor vinegar or vinegar Stupid formic acid; and antioxidant 121165.doc 200815378, such as ascorbic acid. The tablet formulation may be uncoated or coated to improve its disintegration in the gastrointestinal tract and subsequent absorption of the active ingredient, == The conventionally applied coating agent and the procedure J1, which are well known in each case in terms of its stability and/or appearance, may be in the form of a hard gelatin capsule, which is used in the art for oral use. The active ingredient is mixed with a solid diluent such as calcium carbonate, calcium phosphate or kaolin (ka〇iiW; or in the form of a soft gelatin capsule/eight, /, 肀 active

ϋ Mix with water or oil such as peanut oil, liquid paraffin or eucalyptus oil. Aqueous suspensions generally contain the active ingredient in the form of a fine powder together with or in a plurality of suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl: thiol cellulose, & sodium alginate, polyvinylpyrrole Acridine, gum tragacanth and a: gum acacia; dispersant or wetting agent, such as lecithin, or condensation products of alkylene oxides with fatty acids (such as polyoxyethylene stearate or propylene and long a condensation product of a chain aliphatic alcohol (e.g., heptahexylethyl oxysterol) '$ oxyethylene with a partial ester derived from a fatty acid and a hexitol: a product (such as polyoxyethylene sorbitan monooleate) a condensation product of an ethylene oxide 2 long-chain aliphatic alcohol (for example, hepta-ethyloxyhexadecanol) or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (= such as polyoxygen) Ethylene sorbitol monooleate), or a condensation product of ethylene oxide with a partial ester derived from fat S and hexitol anhydride (for example, polyethylene sorbitan monooleic acid). The aqueous suspension may also contain One or more preservatives (such as ethyl p-hydroxybenzoate) Ester or propylparaben), antioxidant (10) such as ascorbic acid), coloring agents, fragrances and/or sweeteners (such as sucrose, saccharin or aspartame). 121165.doc -12- 200815378 May: by the active ingredient suspended in vegetable oil (such as peanut oil, eucalyptus oil suspension = ^ or coconut oil) or mineral oil (such as liquid stone insect a) to prepare the text. The oily suspensions may also contain thickening agents, such as bees, hard :::. A sweetener such as those listed above may be added: and a flavoring agent to provide a savoury oral formulation. The compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for the preparation of aqueous suspensions by the addition of water usually contain the active ingredient together with dispersing or wetting agents, suspending agents and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by the above-mentioned reagents. Other excipients such as sweeteners, fragrances, and coloring agents may also be present. u The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil such as eucalyptus oil or peanut oil, or a mineral oil such as liquid stone butterfly, or a mixture of any of these oils. Suitable emulsifiers can be, for example, naturally occurring gums such as acacia or tragacanth; naturally occurring phospholipids such as large and lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (eg dehydrated sorbus) a sugar alcohol monooleate) and a chelating product of such partial esters with ethylene oxide (such as polyoxyethylene sorbitan monooleate). The lotion also contains sweeteners, fragrances and preservatives. The mash and tincture may be formulated with a sweetener such as glycerin, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, a prophylactic, a fragrance and/or a coloring agent. @医分-, γ f W composition can also be in the form of a sterile injectable aqueous or oily suspension. It can be used according to known procedures using the appropriate fractions mentioned above, monthly or wet 121 l65 <j〇c -13 - 200815378 Injectable preparations may also be formulated in one or more of sterile injectables and suspensions. Sterile is a non-toxic parenterally acceptable diluent or solvent solution or suspension, for example, a solution in butanediol for use in an inhaled administration which is configured to dispense the active ingredient into liquid droplets. . A propellant propellant can be used' and the ingredients are conveniently formulated. It may be in the form of a conventional dusting aerosol to form an aerosol containing a finely powdered solid or a conventional aerosol device such as a volatile fluorinated hydrocarbon or hydrocarbon to distribute the quantitative activity.

更多 For more information on formulations, the reader is referred to Medicinal Chemistry Volume 5, Chapter 25 2 (Heart_ Hansch;

Chairman of Editorial Board), Pergamon press and

Particle size reduction for improvement of 〇raj bioavailability 〇f hydrophobic drugs: G.G· Liversidge, K.C.

Cundy, International J. Pharmaceutics, 125 (1995), 91-97 (the relevant portions of which are incorporated herein by reference). The amount of active ingredient combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host being treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 5 mg to 2 g of active ingredient in admixture with appropriate and suitable amounts of excipients in the total composition. The weight can vary from about 5% to about 98%. The unit dosage form will generally contain from about 1 mg to about 500 mg of the active ingredient. For more information on routes of administration and dosage regimens, the reader is referred to the Comprehensive Medicinal Chemistry Volume 5, Chapter 25.3 (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990 〇121165.doc -14-200815378: According to the invention Alternatively, Form 2 or Form 3 in a method for treating a human or animal body by therapy as defined above or below is provided. The compound of the present invention was found to have an inhibitory activity and was therefore concerned with its effect on monoglyceride synthesis and/or weight loss and/or blood glucose lowering. Information on the role of DGAT1 is contained in our international application WO2005/044250 and references therein. Ο 另一 Another feature of the invention is the use of Form 2 or Form 3 of the medicament. Appropriate Form 2 or Form 3 is used as an agent for a warm-blooded animal (such as human: a broad-spectrum inhibitory effect. Specifically, Form I 2 or Form = used as a blood-borne animal (such as a human) for diabetes and disease. According to the invention - it is used in conjunction with: Form 2 or Form 3 for the treatment of Ik for inhibiting the activity of 1 in a warm-blooded animal such as a human. At ±, it is used in & morphological 2 or morphological 3 and / or obesity drugs: D treatment of warm-blooded animals (such as human coffee = = Ming's other side), providing form 2 or form 3 And a pharmaceutical composition for excipients or carriers of blood-stricken animals for inhibiting DGAT1 activity in warm animals (such as humans). 另In addition, the invention provides a form 2 or a form 3 and pharmaceutical compositions of medically acceptable agents or carriers for warm-blooded animals (such as butterfly diabetes and/or obesity. The "Month of the Moon - Characteristics" is provided for the temperature required for this treatment. Blood 121165.doc -15 - 200815378 Animals (such as humans) A method of inhibiting DGAT1 activity comprising administering an effective amount or form 3 to the animal. According to another feature of the invention, there is provided a method of treating a warm-blooded animal in need of such treatment (such as A method of diabetes and/or obesity in humans comprising administering to the animal an effective amount of Form 2 or Form 3 as defined above or below. - As described above, therapeutically or prophylactically treating a particular disease condition Desirable: The size will necessarily vary depending on the host treated, the route of administration, and the severity of the disease being treated. Preferably, a daily dose in the range of (10) mg/kg is used. However, the daily dose will be inevitable. The host treated, the particular route of administration, and the severity of the condition being treated vary. Thus the 'optimal dose can be determined by the physician treating any particular patient. As noted above, the compounds defined herein are of interest to inhibit DGAT1 active

U The compounds of the invention are useful for preventing, delaying or treating a variety of diseases including diabetes (more specifically, 'type 2 diabetes (T2DM)) and complications caused by it (such as retinopathy, neuropathy and nephropathy), glucose Tolerance to abnormality (IGT), conditions of impaired fasting glucose, metabolic acidosis, snoring, metabolic disorders, arthritis, osteoporosis, obesity, and obesity-related conditions (including peripheral vascular disease (including intermittent) Insufficiency), heart failure and certain cardiomyopathy, myocardial ischemia, cerebral ischemia and reperfusion 'hyperlipidemia, atherosclerosis, infertility and polycystic ovary disease' The compounds can also be applied to muscle weakness, skin diseases (such as acne), Alzheimer's disease (Alzheimer's disease), various immune-regulating diseases (such as psoriasis), HIV infection, inflammatory bowel syndrome and inflammatory |21165 .doc -16- 200815378 Enteropathy (such as Crohn's disease (C h , ftnsdlsease) and ulcerative colitis). _ _ 'The compound of the present invention is concerned with preventing, delaying or treating diabetes and / or obesity and / or obesity-related disorders. Her compounds are used to prevent, delay or treat diabetes: = a sad, the present invention The compound is used to prevent, delay or treat obesity. In another aspect, the a system of the invention is used to prevent, delay or treat obesity-related disorders.抑制 The inhibition of m-test described herein can be in the form of a single therapy: with - or a variety of other substances and/or therapies used in the treatment of indications. The combination therapy can be achieved by a gentleman who is administered by the individual components of the treatment, either sequentially or separately. Simultaneous therapy The seat τ is in the form of a tablet or an isolated tablet. For example, the combination therapy ~,, ', have a dish> σ therapy metabolic syndrome [疋义 for abdominal obesity (such as the human body and ^ f specific cut point measurement waist circumference) plus the following Any two of them: ancient sputum ^ diglycerin g blood (> 5 〇 mg / dl; 1.7 mmol / l); low HDLc (to Ding% alternative and Lu, < 4 〇 mg /dl or <1.03 mmol/1; and for the preparation of the product for the female! · born and έ, <5〇mg/dUiu 29mm〇i / i) or low ancestral (high-density lipoprotein) treatment; Gao Jin Press (give >i3〇 with Hg, make disaster with Hg) or treatment of high blood pressure; and hyperglycemia (fasting blood glucose 2100 mg/dl or 5 6 # , ^ or abnormal glucose tolerance or pre-diabetes Hlnternationd Diabetes aeration & input from IAS/NCEP] These combination therapies may include the following main categories: 1) Anti-obesity therapy, such as by weighting the effects of body intake, nutrient absorption or energy expenditure They are intimate, such as Roche (Rlistat), 121165.doc -17· 200815378, sibutramine and similar agents. 2) insulin secretagogues, including sulfonylureas (eg, glibenclamide, glipizide), dietary glucose regulators (eg, repaglinide, nateglinide) 3) an agent that improves incretin action (eg, dipeptidyl peptidase IV inhibitor, and GLP-1 agonist); 4) includes PPARy agonist (eg, pioglitazone (pi〇gHtaz〇ne) and Insulin sensitizers and combinations of PPARa and PPARy activities; 5) agents that regulate hepatic glucose balance (eg metformin, fructose), 6-bisphosphatase inhibitors, liver a sugar phosphorylase inhibitor, a glyco-synthase kinase inhibitor, a glucokinase activator); 6) an agent designed to reduce intestinal glucose absorption (eg, acarbose); 7) prevent renal resorption of glucose Agent (Sglt inhibitor); U 8) an agent designed to treat complications of long-term hyperglycemia (eg, aldose reductase inhibitor); 9) anti-dyslipidemic agents, such as HMG-CoA reductase inhibitors (eg Statins); PPARa An agonist (fiber acid g, such as gemfibrozil), bile acid spacer (cholestyramine); cholesterol absorption inhibitor (phytosterol, synthetic inhibitor); bile acid absorption inhibitor (IBATi) and nicotinic acid and analogues (nicotinic acid and sustained release formulations); 10) antihypertensive agents such as beta blockers (eg, atenolol, indeui); ACE Inhibitors (eg lisinopril 121165.doc -18- 200815378 (llSln〇Pnl)); calcium antagonists (eg nifedipine); angiotensin receptor antagonists (eg candesartan) )), alpha antagonists and diuretics (such as oral benzoic acid (chemical (7) "(6) heart), benzamidine Sigma); 11) hemostasis agents, such as antithrombotic agents, fibrinolytic activators and 'antiplatelets Thrombin antagonist; factor Xa inhibitor; factor Vila, scatter 1 9 丨 anti-blood], plate (eg aspirin, clopidogrel); anticoagulant ( Heparin and low molecular weight analogues, hirudin and warfarin; 12) antagonizing glycemic The agent of the action; and 1 3) 'Schothone' such as a non-steroidal anti-inflammatory drug (such as aspirin) and a steroid anti-inflammatory agent (such as cortisone). The utility of the compound form of the present invention can be as follows Assays to demonstrate: Human enzyme assays identify in vitro assays for DGAT1 inhibitors using human DGAT1 as an enzyme source in insect cell membranes (proc. Natl. Acad. Sci. 1998, 95, U 13018-13023). Briefly, sf9 cells were infected with recombinant baculovirus containing the human DGAT1 coding sequence and collected 48 h later. The cells were lysed by ultrasonic treatment and the membrane was separated by centrifugation at 28000 rpm for 1 h at zrc with a 41% sucrose gradient. The membrane fractions of the interphase are collected, washed and stored in liquid nitrogen. The sDGAT1 activity was examined by modifying the method described by Coleman (method of Enzymology 1992, 209, 98-102). 1-10 μΜ of the compound was incubated with 0. 4 pg of membrane protein, 5 mM MgC 2 and 100 μM of 1,2-dioleic acid-π-glycerol in a plastic tube at a total assay volume of 2 (10) y. By adding i21165.doc -19- 200815378 under the quotation of 30 public servants. The d ‘μΜ final concentration makes the reaction start and at room temperature. Add 1·5 mL 2-呙醢: 盎, bite:

The addition of 14C oily Kiev enzyme A (30 compounds of formula (1) and the corresponding pharmaceutically acceptable acid salts to inhibit dgati can be further confirmed by using the following whole cell assays] and ]): 1) measuring three of 3T3 cells Acid Glycerate Synthesis Mouse adipocyte 3T3 cells were cultured to confluence in a 6-well plate in medium containing newborn bovine serum, by containing 丨〇% fetal bovine serum, 1 Kg/mL insulin, 〇·25 μΜ The cells were induced to grow in the medium of dexamethasone and 〇5 mM isobutylmethylxanthine. After 48 h, the cells were cultured in a medium containing 10% fetal bovine serum and 丨μ§/ηιηί insulin. Maintain for another 4-6 days. For the experiment, the medium was changed to serum-free medium and the cells were pre-incubated with the compound dissolved in DMSO (final concentration 0.1%) for 30 minutes by adding in each well.脂肪·25 mM sodium acetate plus 1 pCi/mL 14C-sodium acetate for a further 2 h to measure re-fatogenesis (J. Biol Chem., 1976, 251, 6462-6464). Washed in physiological saline and dissolved in 1% sodium lauryl sulfate. Aliquots were removed for protein detection using the protein evaluation kit (pabio) based on the Lowry method (J. Biol. Chem., 1951, 193, 265-275). According to Coleman's method (Enzymology, 1992) , 209, 98-104, method 121165.doc -20- 200815378) using heptane: propan-2-ol: water (80:20:2) mixture, followed by aliquots of water and heptane Extract into the organic phase. Collect the organic phase and evaporate the solvent under a stream of nitrogen. Dissolve the extract in isohexane:acetic acid (99.1) and use according to the method of Silversand and Haux (1997) • LichrosPher diol_5, 4x250 mm column and dissident Alkyl·acetic acid (99:1) ^ and isohexane:propanol: acetic acid (85:15:1) gradient solvent system, flow rate of _ml/min 经由 via normal phase high performance liquid chromatography (HpLC) Separation of lipid tannins. Incorporation of radiolabels in triglyceride fractions using Radi〇matic Flo_one detection (Packard) attached to an HPLC machine. 2) Measurement of triglyceride synthesis in MCF7 cells Human mammary epithelial (MCF7) cells in a 6-well plate containing fetal bovine serum The medium was incubated to the fusion. For the experiment, the medium was changed to serum-free medium and the cells were pre-incubated with the compound dissolved in DM s (final concentration 〇·1%) for 30 minutes. Re-fat production was measured by adding 5 μM of sodium acetate ϋ plus 3 PCi/mL 14c-sodium acetate per well for 3 h (J. Biol Chem., 1976, 251, 6462-6464). The cells were washed in phosphate buffered saline and dissolved in 1% sodium dodecyl sulfate. Aliquots were removed for protein detection using the Protein Evaluation Kit (Perbi(R)) based on the Lowry method (J. Bi〇1. chem, 1951 • 193, 265-275). According to the method of Coleman (Enzymology, 1992, 209, 98-104), a mixture of heptane·propan-2-ol·water (80:2〇··2), followed by water and heptane is used. The fractions were extracted into the organic phase. The organic phase was collected and the solvent was evaporated under a stream of nitrogen. The extract was dissolved in isohexane:acetic acid 12ll65.doc -2]- 200815378 (99:1) and Lichrospher diol was used according to the method of SiWersand and Haux (J. Chr〇mat·b, 1997, 703, 7-14) -5,4x250 mm column and iso-burning acetic acid (99:1) and iso-burn: propan-2-ol: acetic acid (μ:.:}) gradient solvent system, flow rate of 1 ml / min via normal phase High performance liquid chromatography (HPLC) separates the lipids. The radiolabel was incorporated into the triglyceride fraction using a Radiomatic Flo-one detector (Packard) attached to the hplC machine. [Embodiment] The present invention will now be described by way of the following examples. EXAMPLES The invention will now be illustrated by the following examples, unless otherwise specified: (1) temperature is provided in degrees Celsius (C); operation is carried out at room temperature or ambient temperature, i.e., at a temperature in the range of 18-25 °C. And operating under an inert gas atmosphere such as argon; (11) drying the organic solution with anhydrous magnesium sulfate; at a reduced pressure (6〇〇_4〇〇〇Pa; 4.5-30 mmHg) up to 6 (TC bath Evaporation of the solvent using a rotary evaporator; (π〇 chromatography means flash chromatography on tannin; when referring to Biotage cartridges, it means by Biotage, a division of Dyax Corp., 1500 Avon

A filter cartridge containing KP-SIL M cerium oxide (60 A, particle size 32-63 mM) supplied by Street Extended, Charlottesville, VA 22902, USA; (iv) In general, the reaction process is followed by tlc and reaction Time is provided for the purpose of illustration only; 121165.doc -22- 200815378 ) Rates are provided for the purpose of illustration only and are not necessarily the same yields that can be obtained by careful processing; if more substances are required, repeat (4) When provided, unless otherwise specified, (9) is determined by using 氖 氖 风 风 _ 除非 除非 除非 除非 除非 400 400 400 400 400 400 400 400 400 400 400 400 400 Million parts (4) is the secret form of the unit that provides the main diagnostic protons relative to tetramethyl zebra (TMS); thus showing peak multiplicity: s, singlet; d, doublet; (5), double Double peak of the peak; dt, three Cao Lu 夕 cone tongue 丨 long · one double peak, dm, double peak of multiple peaks; t' triplet; q, quadruple peak; m, multiple peak; heart, broad peak; (vn) chemical paying has its ordinary meaning; use unit and symbol; (viii) solvent ratio to body Provide unit: volume (v/v) terminology; (iv) record mass spectrum (MS) (loop) on a Micr〇mass piatf〇rm Lc equipped with HP 110; unless otherwise specified The mass ions are (MH+); (X) on a system containing a Waters 996 photodiode array detector and MiC_ass ZMD Ms (10) 279 lc: with Ph(10)menex8 Gemini 5u C18 u〇A 50x2 mm tube Column and at a flow rate of 1 μm/mm with a gradient of 5% (water/acetonitrile (i:l) + i% citric acid) and from 95% acetonitrile (the rest (95 〇%) is water) The first 4 minutes of dissolution was recorded to record LCMS (liquid chromatography/mass spectrometry), and unless otherwise specified, when the HPLC residence time is reported, the residence time of hydrazine is in minutes in this system. Unless otherwise specified, otherwise the mass ion referred to is (MH+); (X1) when the phase separation filter cartridge is stated, it is used by Argonaut J21165.doc -23- 200815378

Technologies, New Road, Hengoed, Mid Glamorgan, CF82 8AU, ISOLUTE Phase Separator 70 ml tube supplied by United Kingdom, (xii) When referring to SiliCycle cartridge, it means SiliCycle Chemical Division, 1200 Ave St -Jean-Baptiste, Suite 114, Quebec City, Quebec, G2E 5E8, CANADA supplied with ultra-purified silicone (particle size 230-400 mesh, 40-63 μηι micropore size) filter cartridge; (xiii) when referring to Isco For Companion, use the Combi flash comp anion chromatograph supplied by 1800111 (: Address Teledyne ISOC Inc, 4700 Superior Street, Lincoln, NE 68504, USA; (xiv) when referring to microwave, it means by Biotage , Dyax Corp., 1500 Avon Street Extended, Charlottesville, VA 22902, US A supplied Biotage Initiator sixty or Smith Creator microwave; (xv) when referring to GCMS, is equipped with an AOC 20i autosampler and Gas chromatography-mass spectrometry was performed on a QP-2010 GC-MS system controlled by 'GCMS solutions' software (version 2.0, supplied by Shimadzu, Milton Keynes, MK12 5RE, UK); GC column was DB-5MS, 25 m long, 0.32 mm inner diameter, film thickness of 0·52 μηι supplied by J & W Scientific, Folsom, CA, USA; (xvi) When referring to filters, cartridges, Genevac EZ-2plus supplied by Genevac Limited, The Soveriegn Centre, Farthing Road, Ipswich, IP1 5AP, UK; (xvii) When referring to palm chromatography, it is generally used 20 μηι Merck 50 mm Chiralpak AD column (by Chiral Technologies Europe, 121165.doc -24- 200815378

Parc d'Innovation, Bd. Gonthier d'Andernach, 67404 Illkirch Cedex, France for the palmitic stationary phase), using MeCN/2-propanol/AcOH (90/10/0.1) as the dissolving agent, 80 mL/ The flow rate of min, the wavelength of 300 nm, was performed using a Gilson preparative HPLC instrument (200 ml head); (xviii) the melting point was determined using a Buchi 530 apparatus and was uncorrected; (xix) when equivalent (equiv) is mentioned , which is intended to mean the molar equivalent; (XX) The following abbreviations may be used below or in the method section above or below:

Et20 or diethyl ether (diethyl ether) DMF dimethyl decylamine DCM chloroformane DME 1,2-dimethoxyethane MeOH decyl alcohol EtOH ethanol H2 hydrazine TFA trifluoroacetic acid THF tetrahydro σ喃 DMSO 曱 曱 HO HOBt 1-hydroxybenzotriazole EDCI (EDAC) 1 -ethyl-3 - (3-diaminopropyl) carbodiimide hydrochloride DIPEA diisopropyl B Amine DEAD diethyl azodicarboxylate 121165.doc -25 - 200815378 Ο

EtOAc ethyl acetate NaHC03 sodium hydrogencarbonate Κ3Ρ〇4 potassium silicate PS polymer supported BINAP 2,2'-bis(diphenylphosphino, naphthalene Dppf Μ,-bis(diphenylphosphino)ferrocene Dba a subunit propyl propyl hydrazine with PS-CDI polymer supported carbonyl disporin CH3CN or MeCN acetonitrile h hour min min HATU aza benzotriazol-1-yl n, n, n', n'-tetrafene Base hexafluorophosphate NaOH sodium hydroxide AcOH acetic acid DMA dimethyl acetamide nBuLi n-butyl lithium MgS04 magnesium sulfate Na2S04 sodium sulphate CDCI3 oxime gas imitation CD3OD total oxime methanol Boc third butoxycarbonyl example 1 2(trans-4-{4-[({5-[(3,4-difluorophenyl)amino) 1,3,4-oxadiazol-2-yl}carbonyl)amino]phenyl] Cyclohexyl)acetic acid -26 - 121165.doc 200815378

HO

FF will add lithium hydroxide monohydrate (10 equivalents) in water (2.23 L per mole of intermediate 1) to (anti-4-{4-[({5-[(3,xin difluorobenzene) Methylamino) η,3,4-oxadiazol-2-yl}carbonyl)amino]phenyl}cyclohexyl)acetic acid methyl ester (intermediate;

1 when 1) in a stirred suspension of methanol (9·3 8 L per mole of intermediate 1). The reaction mixture was stirred at 30 ° C for 2 hours and then cooled to hydrazine. And acidified to pH 2 with concentrated hydrochloric acid (maintaining temperature at i〇t; below). The resulting white precipitate was filtered, washed with water and EtOAc then EtOAcjjjjjjjjjjjjjjj In about 28 ml), the suspension was then stirred for 3 days. The solid was then filtered off and washed with fresh water (slow filtration). The resulting white solid was dried to constant weight and analyzed in a high vacuum drying oven at 50 C (see Figure 丨, Figure 3 and Figure 4) Intermediate 1: (trans-4-{4-[({5](3,4-difluorophenyl)aminooxadiazole-2-yl}carbonyl)amine Methyl phenyl}cyclohexyl)acetate 3,4-monofluoroisothiocyanate (12 equivalents) is added to the [anti-[indolyl(ethyloxy)ethenyl]amino}phenyl) ring Methyl hexanoacetate (intermediate 2, fult) was taken up in a THF (about 53 liters per ounce of 2 liters) and the mixture was heated to 45 Torr and stirred for 2 hours. Add edac (i 2 equivalents) and heat the resulting mixture to 85 χ: and stir for 3 hours. Add water (about 4.3 liters per mole of intermediate 2). The precipitate was filtered off and washed with water then dried then evaporated Intermediate 2: [trans-4-(4_{[indolyl(ethyloxy)ethyl)amino)phenyl)cyclohexyl 121165.doc •27·200815378 base] decyl acetate

Me〇2C\ ' ! One technique 〇 i) 2-[4-(4-Phenylphenyl)cyclohexylene]acetic acid methyl vinegar

OMe 逐 Add phosphinyl triacetate (170 mL, (10) m〇1) dropwise to 6G%, 27.5 g, a(iv) in THF (3.5 L) cooled to 12 ° C in hydrogenated sodium (9) mineral oil Mix in the suspension. After the addition is complete, allow the reaction mixture to warm to ambient temperature and stir! h. In a separate vessel, N,N_tetramethylguanidine (144 mL, 1.14 mol) was added to 4_(4-diphenyl)cyclohexane (10) g, 0.95 mol) in thf〇2 L) The reaction mixture was allowed to give (8) h at ambient temperature. The squarylium acetate mixture was cooled to 10 C and the hydrazine solution was slowly added to control the temperature between 8 and 12 art until no residual exotherm was observed. The temperature was raised to ambient temperature and the reaction mixture was allowed to mix for 16 h. The mixture was partitioned between a chlorinated solution (2.4 L) and a dilute aqueous solution of ethyl acetate (2.4 L). The aqueous phase was separated and extracted with ethyl acetate (1.2 L). The organics were combined and washed with brine (2.sub.2L), dried (MgSO4) and concentrated in vacuo. The solid was slurried in a mixture of acetaminophen and hexagram (2:1; 47 〇mL), filtered and washed with a mixture of acetonitrile and iso- hexane (2·· 1 '· 24 〇mL) to obtain a white color. ^^(285 g5 94〇/〇)〇iH NMR δ 1.35-1.55 (2Η, m), 1.85- 2·05 (4H, called, 2.25·2, (2H, m), 2.65-2.75 ( 1H, m), 3.6〇121165.doc -28- 200815378 (3H,s),3·80 (1H,m),6.66 (2H,d),6.99 (2H,d),9·10 (1H, ii ) anti-2·[4_(4·hydroxyphenyl)cyclohexyl]methyl acetate

Add 10% Pappy Carbon (50% water, damp, 6.9 mmol) to methyl 2-[4-(cardohydroxyphenyl)cyclohexylene]acetate (100 g, 0.41 m) in dry THF (400 mL) 〇l). The reaction mixture was heated at 3 Torr under a hydrogen atmosphere (2 bar). The mixture was filtered through celite to leave a solid, which was washed with THF (50 mL). The THF solution was concentrated in vacuo to leave a residue which was washed with ethyl acetate. The crude mixture was dissolved in hot ethyl acetate (丨〇〇 mL) and then cooled to ambient temperature. After cooling with ice water, EtOAc (EtOAc m. 1HNMR δl·02-1.17(2H,m), l·31-1.46 (2H5 m)5 1.66- 1.82 (5H? m)5 2.23 (2H5 d)? 2.28-2.38 (1H,m),3.63 (3H,s ), 6.66 (2H, d), 6.99 (2H, d), 9.10 (1H, s). Iii) trans-2-[4-(4-aminophenyl)cyclohexyl] decyl acetate

Ethyl 2-[4-(4-hydroxyphenyl)cyclohexyl]acetate (2·82 g, 114 mmol) and diisopropylethylamine (2 32 mL, 13.3 mmol) in DCM (40 121165. Doc -29- 200815378 The solution in the middle is cooled to the next generation and trifluoromethane is added to the helium gas (1M mL ' 13.3 mm〇1) for 30 minutes to keep the temperature below the generation. The reaction mixture is mixed under η: After 45 minutes and then warmed to irc. The mixture was stopped and the reaction mixture was allowed to stand for 16 hr. The mixture was poured into ice water (18 mL), and the layers were separated and the aqueous layer was extracted with DCM (7 mL). The mixture was treated with a solution of hydrogen peroxide (2 mL) (2 mL) and then brine (9 mL), dried (MgSO4) and concentrated in vacuo to leave the intermediates as a yellow solid. 4.59 §, rain %), which is used without further purification. Add the intermediate tri-floated pyruvate (12 g, 32 mm 〇1) to the carbonic acid (M.4 g, 44 mm 〇1) , palladium acetate (〇43 g,] 9 赖, BINAP (1.2 g, 1.9 mm〇l) and benzophenone imine (7 9 rainbow, 47 mmol) in a mixture of THF (200 mL). Stir and evacuate the container and use nitrogen 5 times. The stirred mixture was heated to reflux for 16 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to leave a residue. The residue was taken in diethyl ether (36 mL) and water (21 mL) The syrup was separated and the layers were separated and the aqueous layer was evaporated eluting with ethyl ether (3 EtOAc, EtOAc) The crude imine (21 g, 51 mmol) was dissolved in methanol (300 mL) and the solution was cooled to 4 ° C. A 1 Μ solution of hydrochloric acid (1 〇〇 mL) was slowly added to maintain the temperature. Below 7 ° C. The suspension was warmed to ambient temperature over 16 h. Methanol was removed in vacuo and the mixture was diluted with water (1 mL). The aqueous mixture was washed with diethyl ether (2×30 mL) and hydrogen The combined organic layer was washed with a 1 μ solution of chloric acid (2×3 0 mL). The aqueous layer of hydrated 121165.doc -30-200815378 was basified to pH 9 with a sodium carbonate aqueous solution to give a precipitate. Add ethyl acetate (3 x 2 〇〇 mL) and separate the layers. The combined organic layers are dried (MgS04) and in the true Concentrate in the air until a precipitate formed. The mixture was cooled, filtered and washed with EtOAc EtOAc (EtOAc) Purification by column chromatography using 10-50% gradient of Et EtOAc and EtOAc (EtOAc) . 111 hire 11 (〇〇 (: 13) 5 0.98-1.06 (211, 111), 1.33-1.42 (2H? m)? 1.72-1.81 (5H, m)? 2.16-2.18 (2H? m)? 2.28- 2 · 34 (1H, m) 5 3·61 (3H, s), 6·68 (2H, d) 5 6.96 (2H, d) W) ({4-[reverse-4_(2-曱oxy side) Oxyethyl)cyclohexyl]phenyl}amino) (oxy)-methyl acetate

Add chloro(oxooxy)acetic acid decyl ester (0·842 mL) to methyl 2-[4-(4-aminophenyl)cyclohexyl]acetate (174 〇 and pyridine (0·689) at 〇 °c (mL) in a stirred solution of DCM (50 mL). After the addition was completed, the mixture was warmed to ambient temperature and stirred for 64 hours. The solution was diluted with DCM (100 mL). Water (50 mL) and brine (50 mL) The title compound (2267 mg); NMR δ 7·60 (2H, d), 7.18 (2H, d), 3.83 (3H, s), 3.58 ( 3H, s), 2.58-35 (1H+DMSO, m), 2.21 (2H, d)5 1·75 (5H, m), 1.43 (2H, m), 1.12 (2H, m); MS m/e (MH)-332. 121165.doc -31 - 200815378 iV) Add hydrazine hydrate (G.361mL) to a decyloxy-l-ethyl)ethylhexyl]phenyl}amino)(trioxy)acetate (10) In the mixing solution in (10) (9) mL). The mixture is instructed for hours. The precipitate was taken up in 'Et 2 〇 and dried under vacuum overnight to give the title compound ( Intermediate 2' 1845 mg) as a solid; iH s. s. 44 (1H, S), 1 〇· 20 (1H, S), 7.70 lang, d), 7.21 (2H, sentence, 4.60 (2H, s), 3.60 (3H, s), 2.42 (1H, m), 1.79 (5Hj m), 1.45

C/ / --XTX X JL ° Example 2: Form 3 (trans-4-{4-[({5_[(3,4-difluorophenyl)amino)]-diazol-2-yl}carbonyl Amino]phenyl}cyclohexyl)acetic acid (2H, m), 1.11 (2H, m); MS m/e MH+ 334 Oral Form 2 (as in Example 4 kg; about 2 mg) In a vial containing an electromagnetic stirrer. A small amount of morphological hydrazine was added as a seed crystal and acetonitrile (about mL) was added. The vial was sealed with a lid and placed on a 5 (heated plate (4) device for 3 days, always stirred. After 3 days, the vial was removed from the stirrer, the lid was removed, and any remaining solvent was evaporated. The obtained Form 3 solids were analyzed (see Figure 5 and Figure 6 and Table 3). The Form 1 material was prepared as follows: 2-[4-[4-[[5-[(3,4-difluorobenzene) was stirred with nitrogen) Amino]] 1 '3,4·-oxadihydro-2-carbonyl]amino]-phenyl]cyclohexyl]acetic acid decyl ester (see Example 1; 1 equivalent) suspended in furfuryl alcohol / tetrahydrofuran (14 A volume/7 volume) and a solution of hydrazine, plus a hydrazine hydroxide (10 equivalents) in water (5 vol). A yellow solution was formed 'heated to 3 (TC (1 hour later completed lc/ms). The mixture was cooled to 0 C and acidified to pH 2 with hydrochloric acid to keep the temperature below 1 s. A white precipitate formed which was filtered off and washed with water and methanol. The obtained product was dried under high vacuum at 50 ° C to give a white solid. The solid was slurried in water (50 vol) and stirred at ambient temperature for 24 hours and heated to 6 0 ° C for 2 hours and allowed to cool overnight. The solid was vacuum dried to give the product (THF 0.57 w / w). Table 1: X-ray diffraction pattern of Form 2 peak number 2 晶 relative spacing of lattice spacing ( >20%) 1 4.7 19.0 54 2 9.3 9.5 32 3 16.2 5.5 40 4 16.8 5.3 99 5 17.7 5.0 40 6 18.1 4.9 41 7 18.6 4.8 44 8 21.4 4.1 92 9 22.7 3.9 100 10 23.3 3.8 53 11 25.9 3.4 73 12 29.2 3.1 41 Ο Table 2: X-ray diffraction pattern of Form 1 Peak number 2Θ Relative spacing of lattice spacing (>20%) 1 5.1 17.4 19 2 7.8 11.4 100 3 14.8 6.0 36 4 16.5 5.4 30 5 22.1 4.0 52 121165 .doc •33- 200815378 Table 3: X-ray diffraction pattern of Form 3 Peak number 2Θ 1 4.8 1 2 5.6 3 7.0 A4 8.4 — 5 13.8 ~ 6 16.7 A 7 Γ 19.5 A 8 20.0 — 9 21.6 _ 10 24.3 [ Simple description of the schema]

Figure 1 shows an X-ray diffraction pattern of Form 2. Figure 2A shows a further ray diffraction pattern of the form. Figure 2B shows the thermal data for the acetic acid solvate of Form 1. Fig. 3 shows a comparison of the x-ray diffraction patterns of the form 1 (bottom) and the form 2 (top). Figure 4 shows the thermal data of Form 2 in anhydrous form. Back to the X-ray diffraction pattern that does not form evil. Figure 6 shows the thermal data of Form 3 in the absence of water. 121165.doc -34-

Claims (1)

200815378 X. Patent application scope: 1. Species (trans-4·Η-[({5-[(3,4-difluorophenyl)amino)oxadiazolyl}-yl)amino]phenyl} ring The crystalline form of hexyl)acetic acid has a peak at 2 Θ 6.8, 21.4 and 22.7. The ray powder diffraction pattern is placed. 2·. (Reverse-4-{4-[({5-[(3,4-difluorophenyl)amino]-U'4.~~-yl-2-yl}carbonyl)amino] The crystalline form of phenyl}cyclohexyl)acetic acid has peaks at 2Θ=4.7, 9.3, 16·8, 21.4 and 22 7 . Where it is: the laser powder diffraction pattern. 3. If you ask for it! Or 2 (reverse, heart {heart [(Bu [(3,4-difluorophenyl)amino), phenyl-on- 2 -yl}-amino)amino]phenyl}cyclohexyl)acetic acid ~ It has an X-ray powder diffraction pattern substantially as shown in FIG. 4. A (trans-4-{4-[({5-[(3,4-difluorophenyl)amino]-1,3,4-oxadiazole-2-yl) carbonyl) amine group Crystalline form of phenyl}cyclohexyl)acetic acid having peaks at 2 Θ = 8·4, 13.8 and 16.7. The ray powder diffraction pattern is placed. 5·如. (4) (trans-4-{4-[({5-[(3,4-diIphenyl)amine-based oxazole-quot; 2 = yl}carbonyl)amino]phenyl}cyclohexyl The crystalline form of acetic acid having peaks at m 8.4, 13.8, 16.7, 216 and 24 3 . The X-ray powder is diffracted at the pattern.士口月求项4 or 5(反·4-{4-[({5-[(3,4-difluorophenyl)amino] '4 heart-salt_2-yl}carbonyl)amino group The crystal form of phenyl}cyclohexyl)acetic acid has peaks at 2Θ=4·8, 5.6, 7.0, 8.4, 13.8, 16·7, 19·5, 2〇·〇, 21·6 and 243. At the same time, the ray powder is diffracted. 7. If the request item 4, 5 or 6 (reverse _4_{4_[({5_[(3,4_二说phenyl)amino]]] 121165 200815378 8. Oxadiazole_2-yl} number base The crystalline form of the amine]phenyl}cyclohexyl)acetate has an X-ray powder diffraction pattern substantially as shown in FIG. 9.10. 11. A pharmaceutical formulation comprising a mixture of a human of any one of claims 1 to 7 in association with a pharmaceutically acceptable adjuvant, diluent or carrier. A compound according to any one of claims 1 to 7, which is for use as a pharmaceutical. Use of a compound according to any one of claims 1 to 7 for the manufacture of a medicament for the treatment of a condition requiring or requiring inhibition of DGAT1. A method for treating or requiring a condition for inhibiting DGAT1, which is administered to a patient in need of such treatment, a therapeutically effective amount of a compound of any one of the above-mentioned items. , 121165