TW200902523A - Salt forms of an alkyl sulfonamide NPY Y5 receptor ligand, and methods for their preparation - Google Patents

Abstract

[(Methylethyl)sulfonyl](trans-4-{[(4-(2-pyridyl)(1,3-thiazol-2-yl))amino]methyl}cyclohexyl)amide in the form of its acid addition salts and solvates hereof, methods for the preparation thereof and pharmaceutical compositions thereof.

Description

200902523 IX. Description of the invention: [Technical field to which the invention pertains] The present invention relates to (mercaptoethyl)sulfonyl (trans-4_{[(4 gas 2_„pyridyl)) The 2-acid))amino]methyl}cyclohexyl)guanidinic acid addition salt form is a ligand for the neuropeptide Υ 5 receptor and is used to treat mood disorders (eg depression) And anxiety (such as obesity), and methods of manufacture. [Prior Art] (methylethyl)sulfonyl (trans-4-{[(4-(2-pyridyl))) 3-thiazol-2-yl))amino]methyl}cyclohexyl)guanamine has the following structure:

(Free base oxime) The compound of formula I is disclosed in its copending application PCT Application No. US06/024043 (filed on June 21, 2006) and belongs to a series of bases. A guanamine derivative which is a ligand for the neuropeptide γ Y 5 receptor and is used for the treatment of mood disorders such as depression, anxiety and obesity. The neuropeptide Υ (NPY) system is expressed in the peripheral and middle sacral nervous system of 36 amino acid neuropeptides. This peptide is a member of the pancreatic peptide steroid family, which also includes pancreatic p〇lypeptide (PP) and peptide YY (PYY). In addition, the biological effect of ΝΡΥ is regulated by its interaction with the receptor, which belongs to the superfamily of G-protein-coupled receptors, 200902523. Currently, five subtypes of NPY receptors have been selected: Y1 (D.

Larhammar et al., J. Biol. Chem., 1992, 267, 10935-10938); Y2 (C. Gerald et al., ed. 61〇1 (: 116111., 1995, 270, 26758-26761); Y4 (J Bard et al, J. Biol. Chem., 1995, 270, 26762-26765); Y5 (c. Gerald et al, J. Biol. Chem., 1995, 270 '2675 8-26761); and y6 (P Gregor et al., J. Biol. Chem., 1996, 271, 27776-27781. All of these receptor subtypes are expressed in several species 'except for the y6 subtypes, which have been shown to be small and Rabbits, but not rats and primates. Based on pharmacological data, γ3 subtypes have been proposed. However, the Y3 subtype has not yet been selected and its presence remains to be fully established. NPY exerts several physiological effects. On the basis of animal research, it is clear that there is a helpful relationship between Νργ and its stylistics for disorders such as depression, anxiety and obesity. For example, Νργ expression is proven to be sensitive to energy status when given Another important ability to reduce energy consumption and sputum is to stimulate food intake s. Kaira People, End〇cr. Rev. '1999,20,68-100) .NPY Y5 receptor has also been shown to be responsible for the Department of receptor sub-types caused by food intake of NPY (c.

Gerald et al, Nature, 1996, 382, 168-171). In addition, the link between NPY and mood disorders such as depression and anxiety is established in the literature. For example, rats suffering from chronic mild stress exhibit symptoms of amnesia (characteristics of clinical depression) (ρ·wiUner et al., Eur. J. Pharmac〇1, 1997, 34〇, 121132); they are also in the thalamus 200902523 The lower part contains elevated levels of NPY mRNA, accompanied by a decrease in the hippocampus. (V. Sergeyev et al., pSyCh〇pharmacology, 2005, 178, 115-124). Behavioral changes associated with chronic mild stress are reversed by a variety of anti-accounts (P. Willner et al., Eur. J. Pharmacol., 1997, 34, 121-132). In an antidepressant therapy study, rats treated with citalopram showed an increased degree of Νργ receptor binding in the hippocampus without altering NPY-like immune activity (H. Husum et al.

Neuropsychopharmacology, 2001 '2, 183-191); conversely, electroporation produces an increased degree of NPY immunological activity without altering the binding of the NPY receptor. These findings suggest that abnormal levels of NPY play a role in depression and that agents that modulate NP Y and/or NP Y receptor function (especially at the edge of the brain) are used to treat depression. Υ5 is expressed in the sputum receptor at the edge of the brain (Μ. Wolak et al, J. Comp. Neurol., 2003 '22 '285-311; and K. Nichol et al, J. Neurosci., 1999, 19 ' 1 〇295_10304). According to this, a drug system capable of regulating the function of the γ5 receptor is thus predicted to be used for the treatment of depression. An animal model of anxiety has also revealed an abnormal degree. In one example, rats separated from the mother showed anatomy of anxiety and sorrow throughout adulthood (R. Huot et al., Psychopharmacology, 2001, 158 '366-73); they also contained an increase in the hypothalamus. Such as NPY immunological activity' is accompanied by a decrease in the immune activity in the hippocampus and cortical regions (p ·

Jimenez-Vasquez et al, Brain Res. Dev., 2001, 26, 149-152; H. Husum and A. Mathe, Neuropsychopharmacology, 2002, 27 '756-64; and H. Husum et al, Neurosci Lett., 2002 ,333, 200902523 1 2 7 -1 3 Ο ). In the second paradigm, rats in a feared situation showed increased behavior of anxious anxiety; they also contained an increased degree of NPY' in the hypothalamus, the tonsils and the nucleus with a decrease in the frontal cortex. Behavioral changes resulting from fearful situations can be reversed by treatment with anti-anxiety medications. In a study of a fearful situation, both anxious behavior and altered Νργ expression were reversed by treatment with diazepam (r. Kysiak et al., Neuropeptides '2000, 34, 148-57). These findings further suggest that NPY plays a role in anxiety disorders and that the agents that regulate Νργ and/or NPY receptor function (especially at the edge of the brain) are used to treat anxiety. Y5 is expressed in the NPY receptor at the edge of the brain (m. Wolak et al, J. Comp. Neurol., 2003, 22, 285-3 1 1 ; and κ· Nichol et al, J, Neurosci, 1999, 19 , 10295-10304). Accordingly, an agent capable of modulating the function of the Y 5 receptor is thus predicted to be useful for treating anxiety. In our laboratory, the decyl ruthenium derivative disclosed in the PCT application US06/024043, which is also incorporated by reference, has been evaluated in an animal model for predicting anti-depression activity. It has been found that these compounds produce effects similar to those observed with known antidepressants. The compound of formula I is now developed by H. Lundbeck A/S as a putative antidepressant and anxiolytic. Many teams have hypothesized various selective NPY Y5 small molecule ligands for the treatment of these disorders. In addition to maintaining appropriate medical elements to advance clinically, compounds should have advantageous ADME properties such as metabolic stability. The issue of drug-drug interaction and toxicity should also be noted. The metabolic stability of the drug can be predicted by 200902523 by its clearance rate in liver microsomes. In addition, cytochrome P450s (CYPs) play a role in metabolism, and inhibition of CYP can be used to predict the potential risk of drug-drug interaction toxicity. In addition, the current treatment for anxiety, anxiety and obesity is on the market. However, many patients do not respond to current treatment. Therefore, there is still a need for alternative treatment methods. After the positive evaluation of the animal model, the compound of formula J has recently been selected for clinical evaluation. However, the free base form of the guanidine compound has a very low water dissolution rate and also appears to exist in different polymorphic forms, which require extensive characterization before the clinical development schedule can be initiated. Thus, it has been apparent for the well-defined 'preferred salt form of the compound of formula J, which has an improved water dissolution rate and all suitable characteristics for pharmaceutical formulation. It has now been discovered that a crystalline salt form of a compound of the formula having an improved water dissolution rate can be formed with both a wide range of organic and inorganic acids. SUMMARY OF THE INVENTION The compounds of formula I are precipitated as solids with hydrochloric acid, hydrobromic acid, oxalic acid, plant toluenesulfonic acid, phosphoric acid and sulfuric acid salts. Several other acids such as methanesulfonic acid, methane phosphoric acid, potassium hydrogen sulfate, tartaric acid and malonic acid have also been tried, but their salts have not crystallized and precipitated as oils. Initially, all salts were analyzed by CHN, TGA, DSC and X-rays. If these results show the correct composition (CHN) and the material appears to be crystalline (X-ray), its solubility in water is also measured. Solubility in water is established by adding salt of i 0 2 〇 mg to [200902523 water]. The suspension was protected from light and kept for a few hours. The suspension is then centrifuged and the pH in the suspension is measured. ^ Solubility is measured by HPLC and calculated as a free test with respect to a compound of formula t. Samples were prepared by taking the amount of 2_1 supernatant and diluting the chest with a mobile phase prior to analysis. The remainder of the solution was kept in the mix and the pH of the supernatant was measured after another 5 days. The hydrochloride salt of the compound of formula I, the hydrobromide salt, the oxalate salt, the p-toluene salt acid salt, and the sulfate salt, have similar or improved water dissolution rates compared to the corresponding free tests. . All of these salts are crystallized, except for oxalate, which is evaluated by powder enthalpy diffraction and is only partially crystalline. However, in some cases, the acid can form both ^ 1 : ! and 2: : test) salts, potting method β μ,,, 八 depends on the reaction conditions, such as dihydrochloride, and some salts Showing multiple patterns. Solvents (e.g., hydrates) of acid addition salts under certain conditions can be precipitated from a solvent system containing water. In general, the separated salts do not appear to be hygroscopic. However, some salts are slightly unstable when heated and are evaluated by thermogravimetric analysis (Thermo is his heart-(T), TGA). In general, hydrogen citrate seems to be most suitable for the development of advanced pharmaceuticals because it is crystalline and exhibits an improved rate of water dissolution, with τ (iv). (d) It appears that & and also appears to be non-according to the invention in one of the sulfhydryl groups (trans-4-{[(4-(2-cyclohexyl)))). (ethylidene)pyridyl)(1,3-then-2-yl))amino]methyl} 10 200902523 In a particular embodiment, the acid addition salt comprises an equimolar amount (methyl b) Base) continuation of the base (trans _4-{[(4-(2-. than bite)) (1,3-° stopper β sit-2-yl)) amino]methyl}cyclohexyl) decylamine And acid. In a particular embodiment, the acid is selected from the group consisting of hydrobromic acid, hydrochloric acid, sulfuric acid, oxalic acid, phosphoric acid, and household-toluenesulfonic acid. In a further embodiment, the acid addition salt is selected from the solid form of hydrobromide 'hydrochloride, hydrogen sulfate, oxalate, phosphate and toluene, sulfonate, such as amorphous or crystalline. form. In a more specific embodiment, the invention relates to a crystalline form of (mercaptoethyl)sulfonyl (trans--4-{[(4-(2-pyridyl)(ι,3-thiazol-2-yl))) An acid addition salt of an amine] mercapto}cyclohexyl)guanamine selected from the group consisting of hydrobromide, hydrochloride, hydrogen sulfate 'oxalate' phosphate and toluenesulfonate. In another embodiment, the invention relates to a solid form of (methylethyl')sulfonyl (trans-4-U(4-(2-pyridyl)(1,3-thiazol-2-yl)) a hydrobromide salt of an amino]methyl}decyl)decylamine, for example in the form of an amorphous or crystalline form. In a particular embodiment, the invention relates to a crystalline form of (methylethyl)sulfonyl (trans-4-{[(4-(2-pyridyl))(1,3-thiazole-2-yl)) a hydrobromide salt of amino]methyl}cyclohexyl)guanamine. Another aspect of the invention relates to a pharmaceutical composition comprising a (methylethyl) continuation base (trans-M[(4-(2-pyridyl)(1,3n2_&))))) } Cyclohexyl) guanamine acid addition salt selected from hydrobromide, hydrochloride 'hydrogen sulfate, ¥acid phosphate, and broad benzene sulfonate, and one or more pharmaceuticals Acceptable carrier or diluent. The aspect of the present invention relates to (methylethyl) stone «base (trans-4-200902523 {[(4-(2 -ntt〇^Aw| - amine group for acid addition salt)" The salt of cyclohexyl, the bismuth oxalate, the (tetra) acid salt, the emotional imbalance of ammonium sulphate, the heart of the medicinal composition of the ancient genus of the treatment of the ancient medicinal composition. Further aspects of the invention relate to The coating of the base {[(4-(2-pyridyl 1)) (trans-4-indolyl) (1,3-thiazole-2-yl))amino]carboxylic acid addition salt, 1 coat Has been based on 醯fe^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ The invention relates to a pharmaceutical composition for treating an individual suffering from obesity. The invention also provides a method for treating an individual suffering from a syndrome, and adjusting the suffering individual, VIII, ° to the individual therapeutically effective amount (methyl acetylation # _ /ΓΜ r? Lu ^ 丞 ethyl) sulphate (trans-4-indolyl) (1,3-thiazole-2-yl))amino] acid addition oxime, 1 M f ^ 』T丞}J Yijiji) The attack of guanamine is remote from hydrobromide, guanidine hydrochloride , salt, phosphoric acid _β '^ thioindole salt, oxalic acid % θ 义 salt, and less tosylate salt. The present invention also provides a method for treating an obese person comprising Ha 駚 駚, * 叶 古 古 古 古 古, ί[(4 (2 π is more than two effective amounts of (mercaptoethyl) sulfonyl (trans-4-(5)) + sylvestrein, acid addition salt, It is selected from hydrobromide, hydrochloric acid _, ^ soil ^ l 'sulphate nitrogen salt, oxalic acid l-acid salt, and plant tosylate. - In a special embodiment of the invention. System human. In another specific example of this narrative, 俜 子 人 ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, In the other specific (four), the emotional disorder is anxiety. 200902523 In one embodiment of the present invention, the 'acid addition salt-type hydrogen desert acid salt. Another specific embodiment of the present invention. In the examples, 'acid addition salt hydrochloride. In a further embodiment of the invention, the acid addition salt is hydrogen sulfate. More in the present invention In one embodiment, the acid addition salt system oxalate. In another embodiment, the acid addition salt phosphate. In another embodiment, the acid addition salt toluenesulfonate. Acid addition salts also include solvates such as hydrates and polymorphic forms.

The term "compressed depression" refers to a disease or disorder such as sorrow, including major or severe depression, anxiety with anxiety symptoms, and has a manual for diagnosis and statistics by DSM IV (mental disorder ( Diagnostic and Statistical manual of Mental Disorders), the fourth edition of '2〇〇〇' defines the form of anxiety disorder or related anxiety disorders and other diseases associated with depression. The term used herein, anxiety, refers to disorders such as panic disorder, ph〇bias, obsessive-compulsive disorder, post-traumatic stress disorde U, Ucute stress disorder), a wide range of γ, , ',,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, The term "beta" obese, as used herein, means obesity, as defined in the International Classification of Diseases ninth bc Ding (ICD-9-CM) code 278.00, ie "restricted, as excessively tired or more body The increase in mass body weight exceeds the results of bone and physiologically necessary body fat. In adults, the 3〇13 200902523 Index (BMI) is considered obese; 60 million Americans are seen For obesity, it is equivalent to one in every three adults. The use of "obesity" in this also includes morbid obesity (M〇rbid)

Obesity, AHA clinical code ICD-9-CM 278.01) is diagnosed when the patient weighs two or more times the ideal weight, when the patient is 100 pounds or more more than the ideal weight, or when the BMI is 40 or more. Six million Americans are considered morbidly obese. The term "mole," means, with an equal number of moles, is used herein. For example, 1 molar base + 1 mole acid represents an equimolar mixture. As used herein, the term "stoichiometric," means the quantitative relationship between a reactant (eg, an acid or a base) in a chemical reaction (eg, formation of a salt). The term "acid addition salt" is used herein. By means of a salt formed by the reaction of all or part of the hydrogen ions of an acid with a positively charged group (for example, an ammonium ion) to form a triethylamine: see oxalic acid and the like. three

Awkward argon triethyl hydride (1:13⁄4 button) acid addition salt, further including all possibilities

Use the nouns in this, acid addition to learn the salt of Ϊ. The above examples illustrate the reaction of 1 with 1 molar acid), but with an amine or a base, which can form a non-equal 3 14 200902523

3HCI tannic acid

"Jijing II Forged Freckle (2:13⁄4) The term used herein, proton solvent, means any solvent containing dissociable H+ such as hydrogen attached to oxygen in a hydroxyl group, or attached to :: Nitrogen on the base. Typical protic solvents are water, alcohols, primary amines and the like. Conversely, the ''aprotic solvent' does not contain dissociable H+. Typical aprotic solvents are ethers, esters, ketones, hydrocarbons and the like. A therapeutically effective amount of a compound for use herein, which means sufficient to be cured: to reduce or partially arrest the clinical manifestations of a given disease and the amount of complications of 2. A system that is sufficient to accomplish such a quantity is defined as a therapeutically effective amount. The effective amount for each purpose will depend on the severity of the disease or injury, as well as the weight and general condition of the individual. It is to be understood that the determination of the appropriate dose can be accomplished using routine experimentation by constructing a numerical matrix and different points in the test matrix, all within the general skill of the trained physician. The term "treating" as used herein refers to the management and care of a disease for the purpose of combating symptoms such as diseases or disorders. The term is intended to include the treatment of a given condition: a condition such as: administration of an active compound to alleviate symptoms or complications, L-late disease, progression of disease A, week or symptom, reduction or reduction Delayed symptoms and complications, and/or cure or eliminate of diseases, disorders or symptoms, and prevention of symptoms, among which prevention is understood as a disease for the purpose of fighting diseases, symptoms or disorders 15 200902523 Management and Care, & This includes administering the active compound to prevent attack or complications. However, prevention of disease (prevention) and _ (treatment of X) > _ two different aspects of the invention. The patient to be treated is preferably a mammal, especially a human. [Embodiment] Experimentality In the following, standard abbreviations are used. Examples of such abbreviations include _(Ν,Ν-dimethylcartoamine); TEA (triethylamine) (tetra), (:(dibutyl)carbonate) 4〇c~butoxy); Cbz( ; Oxygen base), DPPA (diphenyl-squaric acid azide); BzNCS (stupyl thiol isothiocyanate); Et2 oxime (diethyl ether); mtbe (methyl-butyl ether); EtOAc (ethyl acetate); THF (tetrahydrofuran); bribe (acetamidine) 'TFA (difluoroacetic acid); rt (room temperature); h (hours); and _ (minutes). In addition, in certain instances, the methods of preparing the compounds of the present invention are generally described by reference to representative agents such as bases or solvents. The particular reagents identified are representative but not inclusive and not The present invention is limited by the hydrazine mode. For example, a representative test includes, but is not limited to, K2C〇3' TEA or DIEA (diisopropylethylamine). The formation of an acid addition salt of the compound of Formula 1 Preferably 2 aprotic organic solvents or aprotic components containing aprotic components such as toluene, ^AC ' 2 -methyl-TMF ' n-heptane, acetone, 2-butanone and MTBE For example, the solvent mixture of Et〇H is used. The acid standard laboratory reagent is used · concentrated aqueous hydrochloric acid solution (about π%) 'accumulating hydrobromic acid aqueous solution (about 48% HBr), concentrated sulfuric acid (98% 16 200902523 H2so4 ), concentrated oxalic acid aqueous solution (85% H3p〇4) and reagent grade oxalic acid and p-toluene acid. The free test system of the compound of formula 1 is suspended in an organic solvent or solvent mixture & Μ =1 π Initially heated and heated to about 50_60. 〇. Related acid system Add during warming, or it will be present at the beginning. The reaction mixture will be homogenous at this time, and the system will remain at room temperature for 3 minutes to several hours (or overnight) until the Shen Temple appears to be completed. The sediment system is collected by filtration, washed and dried with a small amount of fresh solvent. General method: The anhydrous solvent is purchased from Aldnch Chemical C〇mpany and used in the received state. Measured on a Bruker Avance 400 spectrometer or 3 〇〇 MHz (Varian) with CDC13 'DMSO-d6 or CD3OD as solvent and tetramethyl hydrazine as internal standard (unless otherwise noted). Chemical shift (d) • expressed as pPm, the coupling constant (J) is expressed in Hz, and the split form is described as follows: s = singlet; d = doublet; t = triplet; q = quartet; br = broad; m = multiple peaks; dd = double sets of doublets; dt = two sets of triplets; td = three sets of doublets; dq = two sets of quadruple peaks. Unless otherwise noted, mass spectrograms were obtained from the use of electrospray ionization (ESMS, Micromass Platform Π or Quattro Micro). For LC-MS The following methods were used: Luna C18 column, 5% to 95. / 〇 methyl acetonitrile / H20 with 0.05% formic acid. Thin-layer chromatography (TLC) is based on Shi 60F254 pre-coated (0.25 mm, EM Separations Technologies) glass plate is used. Preparative TLC was carried out on a glass sheet pre-coated with 2 g (Analtech.). Shixi Rubber Column chromatography is carried out on Merck Silicone 60 (230-400 mesh). 17 200902523 The refining point is by differential screening > . Private scanning

Cal〇dmetry ’ DSC) was obtained, which was calibrated at 5 ° C/min using a ΤΑ-instrument DSC_Q1000 with a given melting point as the starting value. Approximately 2 mg of the sample was subjected to a nitrogen flow and heated in a slightly tight pot at 5 Torr/min. Thermo gravimetric analysis (TGA) was performed to estimate the solvent/water of the dry material. The content was measured using TA_ Instruments TGA-Q500. The 1-10 mg sample was heated in an open pot at 10 ° C / min under a nitrogen flow. The powder x-ray diffraction pattern was measured on a PANalytical X'Pert PRO X-ray diffractometer using CuKal radiation. Samples were measured in reflection mode using an X'celerator detector at 2q-range 5-40 °C. List of chemicals and 泺trans-4-(aminomethyl)cyclohexanecarboxylic acid, isopropylsulfonium chloride and 2-act-1-(2-pyridyl)eth-1-one bromate Provided by Sigma-Aldrich. 18 200902523 Preparation method of compound of formula i Scheme 1

HOOC

Nh2 trans-4-(amine sulfhydryl) cyclohexane carboxylic acid

HOOC

5*ui NH8oc

Cb2NM!

Vi

3(3⁄43⁄43⁄43) The compound of formula I can be synthesized according to the procedure described in Scheme 1. The compound of formula II is synthesized from commercially available trans-4-(aminomethyl)cyclohexanecarboxylic acid and subsequently converted to its Cbz-protected amine derivative to provide 19 200902523 for the formula m Compound. The 保护^ protects the substrate from being selectively removed. The amine of f is combined with isopropylsulfonium chloride to provide a product of formula V. The Boc substrate is then removed and the resulting amine ~, v: meso-indenyl isothiocyanate of formula IV is treated to provide a benzyl sigma species of formula VII. Formula VII

The 5 is then subjected to alkaline solvent solvolysis to provide a thiourea intermediate of 弋V. This intermediate product is then 盥J νπι, 昊_1-(2-pyridyl)ethyl i, which is compounded to give a free base. In the last step, the compound of formula I is converted to an acid addition salt, such as the hydrobromide salt of formula la. &quot;&quot; Experimental procedure: In the formula II, the trans-formation of _4-{[(t-butoxy) decylamino]methyl}cyclohexane retinoic acid: Boc2〇 (41·7 g ' 190 mmol) was added to a stirred biphasic solution containing trans-4-(aminoindenyl)cyclohexane succinic acid (25.0 g, ^59 mmol), NaHCO3 (20 g, 238 mmol), water (300 mL) & Et2〇 (200 mL) at rt. The pH of the solution was adjusted to pH 〜9·0 by adding an additional portion of the saturated NaHC〇3 aqueous solution. After stirring at rt for 24 hours, the layer phase was separated and the aqueous layer was acidified to pH 4.0 with 1 M aqueous HCl. The aqueous layer was extracted with EtOAc. The organic layer was separated and washed sequentially with water and brine. The organic layer was concentrated in vacuo and dried <RTI ID=0.0></RTI> to <RTI ID=0.0> β NMR (CDC13) δ 4.60 ( br s, 1Η) , 2.99 ( t, 2H, J = 6.4 Hz), 2.29-2.23 ( m, 3H) , 2.05 ( dd, 2H, J = 13.6 and 3.2 Hz), 20 200902523 1.84 ( dd ' 2H, J = 13.2 and 2.8 Hz), 1.44 ( s, 9H) , 1.42 (br m, 1H) , 0.97 ( dq , 2H , J = 25.6 , 12.4 and 3.2 Hz ). Intermediate product of formula III (tertiary butyl)-N-({trans-4-[(phenylmethoxy)indolyl]cyclohexyl}methyl)carboxamide: trans-4-{[( The third butoxy)nonylamino]hydrazino}cyclohexanecarboxylic acid (20.3 g '0.073 mol) was suspended in toluene (420 mL) and cooled to -10 ° C in a dry ice bath. DPPA (15. 8 mL, 0.073 mol) was added and the cooling system continued. TEA (1 5.3 mL, 0 11 mol) was added dropwise over 1 minute. The color of the solution changed from milky white to clear. The mixture was removed from the ice bath, heated to 10 ° C and then slowly heated to 70 ° C. After 15 hours, the nitrogen evolution was observed to end and the reaction mixture turned yellow. The mixture was cooled to 471 and benzoyl alcohol (22.8 mL, 0.220 mol) was added. The mixture was heated to 1 Torr. (3) Stirring overnight. The mixture was cooled to 50. (: and concentrated under vacuum to afford amber solid. The solid was treated with deionized water (400 mL) and EtOAc (150 mL). The layers were separated and the aqueous layer was extracted several times with EtOAc. The organic layer was combined, dried and concentrated under vacuum. The obtained solid was triturated in MTBE to afford white solid (17.8 g, 67%) The desired product. iH NMR (CDC13) δ 7.34-7.286 (m, 3H), 7.13 (d, 2H, J = 8_0 Hz), 6.78 (t, 1H, J = 6_0 Hz), 4.97 (s, 2H) '3.3-3.14(br'm,iH),2.73(t'lH,J=6.3 Hz), US ( d,2H ' J=l〇.6 Hz) , 1·64 ( d,2H,J=11.8 Hz), 21 200902523 1.35 ( s,6H) , 1.35-1.00 ( m,3H),0.87 ( q,2H,J=12.5 and 2.8 Hz). Intermediate NN-(trans _4_aminocyclohexane Alkyl)methyl(t-butoxy)carbamamine: 10 〇/〇 of Pd-c (0.20 g) is added to the (rt-butoxy)-N- ({reverse) A solution of the formula _4_[(phenylmethoxy)decylamino]cyclohexyl}methyl)oxime amine (2.0 g, 5.5 mol) in EtOAc / MeOH (1: The mixture was degassed and purged twice with %, and further stirred for 2 h at rt, quis. H2 gas. The mixture was filtered through celite and the cake was washed with EtOAc. Concentrated under vacuum to give the desired compound as a white solid (1 g, 91%). 丨H NMR (CDC13) δ 4.59 (br ' s ' 1 Η), 2.97 (t ' 2 Η, JT = 6.4 Hz) , 2.63-2.58 (m, 1H) ' 1.87( d' 2H' J=12.4 Hz), 1.75 ( d, 2H, J = 12.4 Hz), 1.44 ( s, 9H), 1.37 ( m, 1H), 96 ( m,4H). ESMS m/e : ( ( M + H) -55 ) + intermediate of the formula (2 -butoxy)-N-[(trans-4-{[(methylethyl))) Male group]amino)cyclohexyl)methyl] formamidine: isopropyl group ~ helium (6.2 mL '7.9 g, 5 6 mmo 1 ) is added to the stirred biphasic solution at rt. Ν-[(trans-4_Aminocyclohexyl)methyl](second butoxy)caraamine (10 g, 44 mmol), 1M aqueous NaOH (100 mL) and Et20 (100 mL). After stirring for 2 h, 22 200902523 white precipitate appeared. The precipitate was collected by filtration, washed with EtOAc and dried under vacuum to give the desired white solid product (9.5 g, 65%). . NMR NMR (CDC13) 54.58( br 1H) » 3.89( d&gt; 1H^ J = 8.0 Hz), 3.23 (septet,1H,J=4.4 Hz ) , 2.96 ( t,2H,J=6.4 Hz ), 2.61 ( m ,1H),2.09 ( d,2H,J=1 1.6 Hz) ' 1.89-1.74 ( m , 3H) ,1_44 ( s,9H) ,1.3 7 ( d,6H,J=6_8 Hz) ,1.22 (dq, 1H, J = 13.2 and 3.6 Hz), 1.09-1.00 (br m, 3H) 〇ESMS m/e : 279 ( ( M+H) -55 ) +. Intermediate product of formula VI [trans-4-(aminomethyl)cyclohexyl][(methylethyl)sulfonyl]amine: TFA (5 mL) is added to a stirred solution at rt. Containing (t-butoxy)-N-[(trans-4-{[(methylethyl)sulfonyl]amino}cyclohexyl) decyl]carbamamine (1.3 g, 3.9 mmol) and CH2C12 (45 mL). After 4 h, the solution was concentrated under vacuum and the residue was redissolved in CHC13. The CHC13 solution was washed with aq. EtOAc (aq. NMR (CDC13) δ 3.19-3.09 ( m, 2H) ' 2.82 ( dd, 2H, J = 13.6 and 7.2 Hz), 2.07 ( d, 2H, J = 13.6 Hz), 1.88 ( d, 2H, J = 6_0 Hz) &gt; 1.64-1.60 ( br m &gt; 2H) 5 1-51-1.30 ( m , 2H), 1.34 ( d, 6H, J = 6.8 Hz), 1.23-1.08 ( m, 3H). ESMS m/e : 235 ( M+H) +.

-iJLjA N-({[(transmethylethyl))sulfonyl)amino}cyclohexyl)methyl] 23 200902523 Amino}thiomethyl)benzamide: Benzene Mercaptoisothiocyanate (1·6 g, 10 mmol) was added under a gas-atmospheric pressure [trans-4-(aminoindenyl)cyclohexyl][(methylethyl)-acid group] A solution of the amine (2.3 g, 10 mmol) in EtOAc. The reaction mixture was concentrated under vacuum and the resulting gum material was triturated with hexane to afford a pale yellow solid product (3.8 g - 96%). WNMMCDCIJ δ 10.86 ( s, 1H), 9. 〇 8 (s, 1 Η), 7.86 ( d, 1 Η, J = 4.0 Hz ), 7.64 ( dt, 1H, J = 5 6

f ^ U and 1.2 Hz), 7.54 - 7.49 (m, 3H), 4_18 (d, lH, J = 8.4 Hz), 3.59 (t, 2H, J = 6.0 Hz), 3.25 (septet, 1H, J = 4.0) Hz ), 2.14 ( dd, 2H, J = 7.2 and 2.4 Hz), 1.91 ( d, 2H, J = 6.4 Hz), 1.74 ( m ' 1H), 1.29 ( d, 6H, J = 1 2.8 Hz), 1.25 -1.12 ( m, 2H). ESMS m/e : 398 ( M+H) +. In the formula VIII ϋ ϋ (trans-4-{[(thiomethylamine)amino]methyl}cyclohexyl (methylhexyl) fluorenyl] decylamine: K2C〇3 ( 2.00g ' 14.5 mmol) is added to contain Ν-({[(trans-4-{[(methylethyl)sulfonyl)]amino]pyranyl) fluorenyl]amino}thiomethyl) phenylhydrazine A solution of the amine (3.8 g, 9.57 mmol) in MeOH (75 mL) and H20 (25 mL). The obtained turbid mixture was refluxed for 16 h, during which time the mixture turned into a clear homogeneous solution. Cooled and concentrated under vacuum to give a solid which was dissolved in acetone and filtered through a pad of alumina, followed by additional washing of the diatomaceous earth with acetone. Filter 24 200902523 was concentrated under vacuum to provide the desired light yellow Solid product (2.20 g, 79%). 4 NMR (CDC13) δ 6.98 (br s, 1H), 6.39-6.32 (br s' 2H), 3.50 (br s, 1H), 3_32 (m, 1H), 3.14 (m, 2H), 2.16-2.13 ( br m, 1H), 1.94-1.92 ( m, 2H), 1.82-1.79 (m, 2H), 1.52-1.36 (m, 2H), 1.38 (d, 6H, J =6.8 Hz ) , 1 _26-l _ 10 ( m,2H ) .ESMS m/e : 294 ( M+H ) [(methylethyl) valence] (trans-4_ {[(4-(2_ΒΛ)) (1,3-oxazol-2-yl))amino]methyl}cyclohexyl) decylamine : i N-[(trans-4-{[(methylethyl) fluorenyl)amino}cyclohexyl) fluorenyl]amino}thiomethyl) decylamine (〇_ 60 g, 2· 0 mmo 1 ) was added to 2_ bromo-1-(2-pyridyl)ethylidene hydrobromide (〇57 g, 2 〇mm〇1) M Et〇H (20 mL) at rt. The solution was stirred and then mEA (i 〇 5 to 6 〇 mmol) was added. The reaction mixture was heated under reflux for 4 h, cooled to hydrazine and concentrated in vacuo. The resulting residue was redissolved in CHC13 and sequentially washed with aqueous citric acid, water and brine. The organic layer was dried at Ν0 〇 4 and concentrated under vacuum. The crude product was purified by column chromatography (% EtOAc) eluted to afford the desired tan product (10 g). 1H NMR (CDC10 δ 8 5R r ”, S.58 (d, 1H, J = 4.8 Hz), 7.89 (dt, 1H, J=7.6 and 1.2 Hz), 7 71 ," ' 7.71 ( td,1H,J =7_8 and 2.0 Hz), 7.17 (td,1H,J=4 8 and ]〇u, δ and 12 Hz), 5.25 ( br s, 1H) ^ 3.85 ( d - IR , J=8.4) &gt; 3 2W κ , ( br m,1H ) , 3.18 25 200902523 (t,2H,J=6.4Hz) , 2.14 ( dt,2H,J=12.0 and 1.2 Hz), 2.19 ( br ' d ' 2H,J=12.8Hz) , 1.62 ( br, m, 3H) , 1.38 (d, 6H ' J 6.8 Hz), 1.25 ( dq, 2H, J = 12.8 and 1.6 Hz) LC-MS m/e ·· 395 ( M+H) + ; tR = 2.14 min. The acid addition salt of the compound of the formula I is a compound of the formula la (methylethyl)sulfonyl (trans-4-{[(4-(2-pyridyl))). 3-喽f': Ioxazol-2-yl))indenyl]methyl}cyclohexyl)decylamine, argon bromide: (mercaptoethyl)sulfonyl (trans-4-{[(4) -(2-Acridine)(1,3-thiazol-2-yl))amino]methyl}cyclohexyl)guanamine (1,0 g) was suspended in THF (7.5 mL) and EtOH (2_5) (M) was heated to 60 ° C. HBr (4 8% aq., 〇. 3 mL) in THF (2 mL) was added. The solution was obtained. After about 30 min of mixing at rt, the desired product was sedimented. The product was collected by filtration, washed with a small amount of pure solvent and dried under vacuum. Yield 1_10 gr, DSC Start at 180.7 ° C. The salt has a 1:1 (acid: base) stoichiometry and is considered to be crystalline by X-ray analysis. Elemental analysis (C, H, N) Calculated (45.47, 5.72, 1 1.79) (45.56, 5.95, 1 1.13) of the compound (methylethyl) of the formula lb (trans--4-{ [(4-(2-«)) Olfactory 26 200902523 oxazol-2-yl))amino]methyl}cyclohexyl) decylamine, decanoic acid: (mercaptoethyl) stellate base (trans-4-{[(4-(2- (比11)(1,3-11-deso-2-yl))amino]methyl}cyclohexyl)guanamine (3.0 g) was suspended in THF (15 mL) and EtOH (15 mL) And heated to 60 ° C. HC1 (app. 3 7% aq·, 0.6 mL) in THF (5 mL) was added over 2 min. A clear solution was obtained. When stirred overnight at rt, the desired product precipitated. The product was collected by filtration, washed with a small amount of neat solvent and dried under vacuum. f, ' produces 2.40 gr' DSC starting at 234.9 °C. This salt has a 1:1 (acid: test) stoichiometry and is considered to be crystalline by X-ray analysis. Elemental analysis (C, H, N) Calculated (50_03, 6.49, 12.80) Found (50.27, 6.32, 12.92) Compound of formula Ic (methylethyl)sulfonyl (trans-4-{ [(4-(2-Acridine)(1,3-oxazol-2-yl))amino]methyl}cyclohexyl)decylamine, hydrogen sulphate: (methylethyl)sulfonyl ( Trans-4-{[(4-(2-pyridyl)(1,3-thiazol-2-yl))amino]methyl}cyclohexyl)decylamine (3.0 g) was suspended in THF (1 5 mL) and EtOH (15 mL) and heated to 60 °C. H2S04 (98% '〇.42 mL) in THF (5 mL) was added. A clear solution was obtained. When stirred at rt overnight, the desired product precipitated. The product was collected by filtration, washed with a small amount of neat solvent and dried under vacuum. Produced 3.29 gr, DSC starts at 178.9 °C. This salt has a 1:1 (acid: base) stoichiometry and is considered to be crystalline by X-ray analysis. 27 200902523 Elemental analysis (C, Η, N) Calculated (43.78, 5.87, 1 1.08) Found (44.23, 5.83, 1 1.1 1) Compound of formula Id (methylhexyl)sulfonyl (reverse) -4-{[(4-(2-·*)pyridyl)(1,3-indol-2-yl)))yl]methyl}cyclohexyl) 3⁄4 slope, bis(p_toluene) ): (methylethyl) fluorenyl (trans-4-{[(4-(2-»-pyridyl)(l,3-thiazol-2-yl))amino]methyl}cyclohexyl The indoleamine (0.48 g) and anhydrous p-toluenesulfonic acid monohydrate (0.60 g) were suspended in THF (5 mL) and heated to 60 °C. A clear solution was obtained. When stirring at rt overnight, the desired product is Shen Dian. The product was collected by a transition, washed with a small amount of neat solvent and dried under vacuum. Produced 3.29 gr, DSC starts 204.81. This salt has a 2: 1 (acid: test) stoichiometry and is considered to be crystalline by X-ray analysis. Elemental analysis (C, H, N) Calculated (52.01, 5.73, 7.58) Found (51.38, 5_85, 7.29) Prepared in a similar manner: Formula Ie compounded you (methylethyl) sulfonate Base (trans_4_{[(4-(2-pyridyl)(1,3-indolyl-2-yl))amino]methyl}cyclohexyl)guanamine, oxalate: DSC starting 135_4. (: This salt has a 1: (acid: test) chemistry 28 200902523 Measure 'and is considered to be crystalline by χ ray analysis. Elemental analysis (C, H, N) Calculated (49.57, 5.82, 1 1.56) Found (49.30,5·87,1 1.39) bismuth (methylethyl)sulfonyl (trans-4-{[(4-(2-pyridyl))) 3 喽 bit-2-yl))amino]methyl}cyclohexyl) decylamine, phosphate: DSC starts η nc. This salt has i: 丄 (acid: base) stoichiometry' and by X-ray Analysis is considered to be crystalline. Analysis of elements (C, H, N) Calculated (43.80, 5 94J1 35) Found (43·47, 6.22, 10.63) Formulations The pharmaceutical formulations of the present invention may be subordinated BACKGROUND OF THE INVENTION Processes are prepared. For example, tablets can be compressed by mixing active agents, 'agents and/or diluents and then with conventional tableting machines: Examples of agents include · corn house powder, horse ring system Powder, t: adjuvant or diluted knee, lactose, gum, and the like. Usually: use = tartrate, any other adjuvant or diluent can be used, the first two k kinds of active ingredients. For the preparation of 1:1 compatible with the solution for injection, it can be dissolved in the injection solvent by using the ingredients and possible 29 200902523, 劁 — - part (preferably sterile water), 敕 solution To the desired volume, the solution is killed for ten nights and filled in a suitable ampoule or small official. Any suitable additives conventionally used in the art can be added, provided that they are compatible with Active ingredient.

Extracorporeal Methods The pharmaceutical properties of the compounds of Formula 1 are evaluated in the selected human NPY π receptor using the procedure disclosed in U.S. Patent No. 6, i24, 33i. The radioligated hip-bound membrane suspension is diluted in binding buffer, which supplements 〇1% bovine serum albumin to produce the optimal membrane protein concentration, so the uq-PYY membrane binding system is less than 10% in the analysis. Delivered into the sample (100,000 dpm/sample = 〇.〇8 ηΜ for competitive binding assays) 125ι ργγ and small molecule ligand competitors were also diluted to the desired concentration in the supplemental binding buffer. The sample was then prepared in a 96-well polypropylene microtiter plate by mixing 125; [_ρΥΥ, competing peptide or supplementation binding buffer (25 pL)' and finally 'membrane suspension (200 μΐ). The cells were incubated at 3 ° C for 120 minutes. The culture was stopped by filtration through Whatman gf/c; precaution (pre-coated with 1% polyethyleneimine and air dried before use), followed by 5 mL The ice-cold binding buffer was cleaned. Filter-trapped membranes were filled with MeltiLex solid scintillator (Wallax, Turku, Finland) and 125I-PYY was counted in a Wallac beta-dish reader. Or, the culture is in GF/C The tray (pre-coated with 1% polyethyleneimine and air dried before use) was then vacuum filtered and washed with 300 pL of ice-cold binding buffer three times 30 200902523. 50 μί UltimaGold (Packard) scintillation system It was added and counted 125 ΐ _ ρ γ in Wallac MicroBeta Trilux. Non-specific binding is defined by 300 Μ human ΡΥΥ. Specific binding in time course and competition studies is typically 8%; most non-specific binding lines Filter linkage. Combine data using nonlinear regression and statistical analysis available in the GraphPAD prism package (San Diego, Calif.) Use this procedure to radiolabel the ligand (labeled ργγ or replace the sacred partner) For example, 12 5 Τ士发0夕*\jp v \

The compound of the bottle, such as NpY, which binds to 5 hexagrams, binds to the selected human npy which is expressed in COS-7 cells. The membrane system of the Β* a 'huang human JNPY body is determined in vitro, and it is revealed to have human and large The 5 receptor binding affinities of the mice were in vitro pharmacological data charts of Κ1 = 15 and 〇·8ηΜ, respectively. Compared with other known drug targets, the compound showed a 5,000-fold selectivity for human Νργ5 and a further potent antagonist of human Νργ5 steroid in vitro with IC5G = 4.4 ηΜ. [Simple description of the diagram] [Explanation of main component symbols] Benefit 31

Claims (1)

200902523 X. Application for Patent Park: 1. (Methyl ethyl) sulfonyl group in the form of a sputum addition salt (trans _4_ {[(4 (2 t 匕疋))) _2 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Mercapto (trans-4-{[(4-(2-) ratio) (1,3-(2)-2-yl)amino)methyl}cyclohexyl) acid and acid. The acid addition salt according to any one of the claims, wherein the acid is selected from the group consisting of hydrogen desert acid 'hydrochloric acid' sulfuric acid, oxalic acid, acid and polytoluenesulfonic acid. 4. The acid addition salt according to any one of the claims, wherein the 5 Hai I addition salt is selected from the group consisting of hydrobromide, hydrochloride, hydrogen sulfate, oxalate 'phosphate and P-toluenesulfonate. '5' is an acid addition salt according to any one of the following claims, wherein an acid addition salt solvate, such as a hydrate. The acid addition salt according to any one of the above claims, which is in a solid form, such as an amorphous or crystalline form. An acid addition salt according to any one of the preceding claims, which is in crystalline form. The acid addition salt according to any one of the preceding claims, which is in solid form, wherein the acid addition salt is a hydrobromide salt. 9. A fluorenyl (sulfonylethyl) sulfonyl group in the form of ruthenium (trans-4-{ [(4-(2-) than butyl) (1,3-pyrazole-2-yl-l-amino) Methyl fluorenylcyclohexyl) guanamine hydrobromide. The use of the acid addition salt 32 200902523 according to any one of the preceding claims, which is a pharmaceutical product. An acid addition salt according to any one of the items of the scope of the patent application, and a pharmaceutically acceptable carrier and a diluent. 1 2. The pharmaceutical composition according to the scope of the patent application, wherein the acid addition A salt-based hydrobromide salt. The use of an acid addition salt or a solvate thereof according to any one of claims 1 to 3 for the manufacture of a medicament for treating an individual suffering from an emotional disorder Composition 14_ According to the application of the scope of claim 13, wherein the mood disorder is depression. 15. According to the application of the scope of claim 13, wherein the mood disorder is anxiety disorder. Use of an acid addition salt or a solvate thereof according to any one of items -9, A pharmaceutical composition for the treatment of an individual suffering from obesity. The use according to any one of claims 13 to 16, wherein the acid addition salt is a hydrobromide salt. The use of any one of clauses 13 to 7, wherein the solvate is a hydrate. The use of any one of claims 13 to 18 wherein the system is human. 2〇_ A method of treating an individual suffering from an emotional disorder, comprising administering to the individual a therapeutically effective amount of an acid addition salt, or a solvate thereof, according to any one of claims 31 200902523 of claim i. The method of claim 2, wherein the mood disorder is sorrow. 22. The method of claim 2, wherein the mood disorder is an anxiety disorder. An acid addition salt, or a solvate thereof, according to any one of claims 1 to 9 of the patent application, which comprises administering to the individual a therapeutically effective amount. 24_A method according to any one of claims 2 to 23. , Wherein the acid addition salt is a hydrobromide salt. I according to the scope of claims 2 to 24 of the solvate hydrate. - According to the scope of claims 2 to 25 of the patent system Θ &lt;万法' Η'1, schema: no 34