MXPA97003349A - Specific ligands of the neuropeptide - Google Patents

Abstract

The present invention relates to a compound, characterized in that it is selected from the group consisting of both diastereoisomers of 1- (3-methoxyphenyl) -1- (4-phenylpiperazin-1-yl) -4-methyl-cyclohexane, both diastereoisomers of 1- (3-ethoxyphenyl) -1- (4-phenylpiperazin-1-yl) -4-methyl-cyclohexane, both diastereoisomers of 1- (3-ethoxyphenyl) -1- (4-phenylpiperazin-1-yl) - 4-ethyl-cyclohexane, both diastereoisomers of 1- (3-isopropoxyphenyl) -1- (4-phenylpiperazin-1-yl) -4-methyl-cyclohexane; 4- (3-ethoxyphenyl-4- (4-phenylpiperazine-1) -il) -tetrahi dropirano, and 4- (3-ethoxyphenyl) -4- (4-phenylpiperazin-1-yl) -tetrahi drotiopira

Description

t TRQN? FRPFCTFTG.OS OF NEUROPEPTIDE Yl BACKGROUND OF THE INVENTION Field of the Invention This invention relates to certain substituted benzylamine derivatives that selectively bind to human neuropeptide Yl receptors (NPY1). This invention also relates to pharmaceutical compositions comprising such compounds. Furthermore, the invention relates to the use of such compounds and compositions in the treatment of eating disorders and certain cardiovascular diseases.

Description of the Prior Art Neuropeptide Y, a peptide or first isolated in 1982, is widely de-distributed in neurons of the central and peripheral nervous system and is responsible for a multitude of biological effects in the brain and periphery. Several animal studies have shown that the activation of Neuropeptide Ya receptors. is related to vasoconstriction, tated et al., Regul. Peptides, 13: 307-318 (1986), tlcCauley and Uestfall, .1. Pharmacol. Exp. Ther. 261: 863: 868 (1992) and Grundemar et. al., Br. 3. Pharmacol. 105: 45-50 (1992); and for stimulating consumer behavior, Flood and Tlorley, Peptides, M: 963,966 (1989), Leibowitz and Fllexander, Pept des, _ 12: 1251-1260 and Stanley et. al., Peptides, j_3: 481-587 (1992. Grundernar ant] Hakanson, TiP, Hayo 1994 (vol., 15) .153-159, rewrite that, in animals, Neuropepri do Y or? a powerful Stress and food intake and an inducer of vasoconstriction leading to hypertension also indicate that low levels of Neuropeptides are associated with loss of appetite, and studies clearly indicate that compounds that inhibit activity. of this protein reduce n hypertension and appetite in anima loo.

BRIEF DESCRIPTION OF THE INVENTION Compounds that interact with NPY1 receptors and inhibit the activity of Neuropeptide Y in these receptors are useful in the treatment of eating disorders such as, for example, obesity and bulimia, and certain cardiovascular diseases, such as, for example, hypertension. This invention provides novel compounds of Formula I that selectively bind to the receptors of Neuropeptides Yi (NPYl). Such compounds are useful in the treatment of eating disorders such as obesity and bulimia, as well as certain cardiovascular diseases such as essential hypertension. The invention also provides f-armaceutic compositions comprising compounds of Formula I. The invention thus also relates to the use of compounds and compositions in the treatment of food foci, as well as cardiovascular diseases. . Accordingly, a general embodiment of the invention is directed to a Formula I compound: I wherein ar is an aryl group B is sulfur, oxygen, a substituted nitrogen atom, or a mono- or disubstituted carbon atom; or represents a group of formula wherein Rrn and Rn independently represent a lower alkyl; or Rm and Rn together with the carbon atom to which they are attached form a 3, 4, 5, 6 or 7 optionally substituted linkage carboacelic ring substituted by halogen, hydroxy, lower alkyl or lower alkoxy; n is 1, 2 or J; rn is 2, 3 or 4; ), X, Y and T are the same or different, and represent hydrogen, halogen, hadroxy, straight or branched chain lower alkyl: having less than 6 carbon atoms or straight or branched chain lower akoxy having 1 ah tomos de cartono; and Ri J R_ independently represent hydrogen or straight or branched chain lower alkyl having from 1 to 6 carbon atoms; and R3 and R4 are the same or different and represent hydrogen or straight or branched chain lower alkyl having from 1 to 5 carbon atoms or straight or branched chain lower alkoxy having from 1 to 6 carbon atoms. These compounds are highly selective partial agonists or antagonists of human NPY1 receptors and are useful in the diagnosis and treatment of eating disorders such as obesity and bulirni, as well as certain cardiovascular diseases such as essential hypertension and congestive heart failure.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 represents representative substituted benzylamms of the present invention.

DETAILED DESCRIPTION OF THE INVENTION The new compounds included by the present invention can be described by the general formula. I: wherein Ar is an aryl group preferably selected from the group consisting of phenyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl, 2-? - or 5-pyrirnidyl, each of which is optionally mono- or disubstituted with halogen, hydroxy or straight-chain, or branched lower alkyl having 1 to 6 carbon atoms; B is sulfur, oxygen (s) or C (Re) (Re); or B represents a formula group optionally substituted with hydroxy halogen, lower alkyl or lower alkoxy; n is 1, 2 or 3; rn is 2, 3 or 4; Ul, X, Y and T are the same or different, and represent hydrogen, hydroxy, straight or branched chain lower alkyl having 6 carbon atoms or straight or branched chain lower alkoxy having from 1 to 6 carbon atoms; R1 and R2 are the same or different and represent hydrogen or straight or branched chain lower alkyl having from 1 to 6 carbon atoms; 3 and are the same or different and represent hydrogen, straight or branched chain lower alkyl having 1 to 6 carbon atoms or straight or branched chain lower alkoxy having 1 to 6 6 carbon atoms; R5 represents straight or branched chain lower alkyl having from 1 to 6 carbon atoms, phenyl, optionally substituted benzyloxy, 2-, 3- or 4-p? Pd? L or feml, 2-, 3- or 4-p? Pd l (straight or branched chain lower alkyl having from 1 to 6 carbon atoms); and A and Re are the same or different and represent hydrogen, hydroxyl, ammo, straight or branched chain lower alkyl having from 1 to 6 carbon atoms, straight or branched chain lower alkoxy having from 1 to 6 carbon atoms, phenyl, 2-, 3- or 4-p? pd? lo, phenoxy, 2-, 3-or 4-p? r? d? lox? or (CH2) P -A'- (CH2) -B ', where p is 0-5, q is 1-5 and 0' is a direct bond, oxygen or sulfur B 'is hydrogen, lower alkyl of chain 1 ineaL or branched having 1 6 carbon atoms, straight or branched chain lower alkoxy having from 1 to 6 carbon atoms, fem, 2-, 3- or 4-pyridol, phenoxy, 2-3 or 4-p? r? d? lcx? , carboxyl, carboalkoxy, carboxaride, mono- or dialkylcarboxarnide, arnino or mono- or dialkylamino. Preferred compounds according to the formula r are those in which r is phenyl, pyrimidinyl or optionally substituted p, B is optionally carbon optionally with femlo or alkyl and W, X, Y, A, T and Ri a R4 are hydrogen. In particular, the preferred compounds of Formula I are those in which Ar is pyrimidinyl phenyl or pipdyl, B is carbon optionally substituted with phenone or alkyl and U, X, Y, A, T and Ri to R "are hydrogen. The invention also relates to Formula IR compounds: IA in which flr os fon? what, 2--, '! - or 4- pin di lo,? - o 3 - l íoni lo, 2-, 4- or 5- ?? ? rn? 1 What, each do what? _. What is this or c? onal mont or mono- or di-substituted with halogen, hydroxy or lower alkyl with straight or branched chain that has not carbon; A, J, X, Y and T are the same or different, and represent hydrogen, halogen, hydroxyl, lower alkyl, straight chain J > rain iii each having 1 to 6 carbon atoms or linear or branched endone alkoxy having from 1? f) to 6 carbon atoms; Ri and R2 are the same or different and represent hydrogen or lower alkyl of straight or branched chain having 1 to 2 carbon atoms; R3 and R4 are the same or dLferent.es and represent Lb hydrogen, lower alkyl "straight or branched chain having 1 to 6 carbon atoms or straight or branched chain lower alkoxy having from 1 to B carbon atoms; and R9 represents hydrogen, to the straight or branched chain lower uyl having from 1 to 6 carbon atoms or phenyl. The invention includes adc v-. The comps of Formula El: n wherein A and X represent the formula independently and alkoxy and Ar represents f-enyl, ?? pmi di ni lo or pipdilo. 10 Compounds 1 ', etherido':, of formula .11. sor. to uello ':, in which X and A are methoxy, otoxy, isopropoxy or butoxy and Ar represents femlo, pi rimi di ni Lo o |) ii'i? Lo. The invention also includes the compounds of Formula GEI: m wherein X and A represent the independent urine alkoxy and R? Y. Re are different and represent hydrogen and f l or. The invention also includes the compounds of Formula IV: L IV wherein X represents hydroxy and Ar represents phenyl, pyrirnidinyl or pyridyl. The invention additionally includes the compounds of Formula V: wherein X represents alkoxy and Ar represents phenyl, pyrirnidinyl or pira di lo. Preferred compounds of Formula V are those in which X is methoxy, ethoxy, isopropoxy or butoxy and flr has phenyl. Particularly preferred compounds of formula V are those in which X is rnetoxyethoxy or ethoxy-methoxy. The invention further includes the compounds of Formula VI: VI in which X r -presents femio, pipmidini lo or pipdilo. Preferred compounds of Formula VI are those in which X is ethoxy, ethoxy, isopropoxy or butoxy, R is alkyl and Ar represents phenyl. Particularly preferred compounds of Formula VT are those in which X is rnetoxy, ethoxy, isopropoxy or butoxy, R9 is methyl and Ar represents femlo. Other particularly preferred compounds of Formula VI are those in which X is rnetoxynetoxy or ethoxymethoxy, R9 is methyl and flr represents phenyl. The invention also includes the compounds of Formula VII: vp in which Ar represents optionally substituted phenyl, pyrirnidinyl or pipdyl. Preferred compounds of Formula Ar represent phenyl, pyrimidinyl or pyridyl. The compounds represented by the present invention, which are included in Formulas I-VII, include, but are not limited to, the compounds of Figure 1 and their pharmaceutically acceptable salts. Nontoxic pharmaceutically acceptable salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulphonic, formic, toluene, sulphonic, iodohydric, acetic and the like. Those skilled in the art will recognize a wide range of pharmaceutically acceptable non-toxic addition salts. The invention also relates to the compounds of Formula VIII: v eT that Ar is phenyl, 2-, 3- or 4-p? pd? lo, 2- or 3-t? emlo, 2-, 4- or 5-?? ± pm? d? it, each of which is optionally mono- or disubstituted with halothane, hydroxy or straight-chain or branched inner alkyl having 6 carbon atoms; R9 represents hydrogen, straight or branched chain lower alkyl having 1 to 6 carbon atoms or phenyl. The present invention also includes pro-drugs acylated from the compounds of Formulas T to VÍII. Those skilled in the art will recognize various synthetic methodologies that can be employed to prepare pharmaceutically acceptable non-toxic addition salts and acylated prodrugs of the compounds included in Formula I. The invention includes the diastereoisomers of the compounds having a 1.4 substitution. on the cyclohexane ring. That is, the invention includes both cis- and trans-1,4-c-clohexanes. Preferred compounds of the invention having 1,4-substitution on the cyclohexane ring are those in which the nitrogen atom which forms the ring of piperazine and the alkyl or phenyl group in the 4-position of the cyclohexane ring are "cis" with respect to each other. Thus, Preferred compounds of the invention having said substitution are those which are c? S-l-p ?? erac? N? L-4-al? L or phe nyl-cyclohexanes. By "aral" and "Ar" is meant an aromatic carbocyclic group having a single ring (eg phenyl), several rings (eg biphenyl) or several fused rings in which at least one is aromatic, (eg 1, 2, 3, -tetrahydronyl, naphthyl, antiplo or fenantyl), which may optionally be unsubstituted or substituted with, eg, halogen, lower alkyl, lower alkoxy, taoalquiLo inferior, tp fluorornet i lo, aciLoxi inferior, aplo, heteroaplo and hydroxy. By "alkyl" and "lower alkyl" it is meant to represent straight or branched chain alkyl groups having from 1 to b carbon atoms. By "lower alkoxy" and "alkoxy" it is intended to represent straight-chain or modified groups having 1 to 6 carbon atoms. By "halogen" is meant fluorine, chlorine, bromine and iodine. For 2-, 3- and 4-p? Pd? Lox? you want to present groups of the following formulas, respectively: The pharmaceutical utility of the compounds of this invention is indicated by the following assay of human NPYl receptor activity.

Esayo of the Human NPYl Receptor Binding Activity The procedure used is similar to that described by Gordon et al. (3. Neurochem .. 55: 106-513, 1990). K-N-MC cells were purchased from fiTCC (Rockville, ID). The cells were maintained at 37 ° C and CO2 < 5% in üulbecco modified essential medium (DMEIO with L -glutamine and 110 rng / 1 of sodium pyruvate, which is supplemented with 10% fetal bovine serum and 25 nM HEPF (pH 7.3). The binding was carried out in 24-well plates (Falcon) when the cells were placed on the bottom of the wells and 0.5 ml of Dulbecco's phosphate buffered saline solution (DPBS) with calcium and magnesium was added to each well. The DPBS was aspirated and an additional aliquot of DPBS was added and aspirated again To start the assay, each well was added tarnpon binding composed of serum free DMErl containing 0.5% bovine serum albumin, 0.1 bacitracin. % and phenol fluoride Imeti i ul fonilo 0.1% The cells and the binding buffer were preincubated for 30 minutes at room temperature, at which time drug and C125I-IPYY solution was added (NEN-DuPont: 50,000- 75,000 cprn approximately 50 pM) to provide a final volume of 250 ul. non-specific binding with NPY 1 rl (porcine or human, Bachern California). After an incubation of 3 hours at room temperature, the plates were placed on ice and the wells were aspirated. The cells were washed 4 to 6 times with 0.5 rnl of DPBS cooled with ice. A diluted solution of Tpton-X-100 IB (1%) was then added to each well. After about 1 hour at room temperature, an aliquot of each well was drawn to a test tube of 12 x 75 nm and the amount of C12S H was determined in a gamma counter with an efficiency of 85% BO (Genesys 5000, Laboratory Technologies). The IC50 values were calculated with the RS / 1 non-linear curve fitting program (BBN Software Products 3orp, Cambridge, HA). The binding characteristics for the compounds of this invention are presented in Table I.

Table T Composition numbers CIso (uM) 9 0.137 13 (cis isomer) 0.067 18 (cis isomer) 0.075 20 (cis isomer) 0.07b 21 (trans isomer) 0.525 29 (c-isomer) 0.039 The numbers of Copyrims refer to the compounds shown in Figure I. Compounds 13, 18, 20 and 29 are particularly preferred embodiments of the present invention because of their potency in binding to human NPYl receptors. The compounds of general Formula I can be administered orally, topically, parenterally or by inhalation or spraying or rectally in one-dose formulations containing conventional non-toxic pharmaceutically acceptable diluents, adjuvants and vehicles. Parenteral term as used herein includes subcutaneous injections and infusion, infusion, intramuscular, or intra-nal infusion techniques. In addition, a pharmaceutical formulation comprising a compound of general formula I and a pharmaceutically acceptable carrier is provided. One or more compound 1 'of general formula I may be present in association with one or more non-toxic pharmaceutically acceptable vehicles and / or diluents and / or adjuvants and, as desired, other active ingredients. The pharmaceutical compounds containing compounds of general formula I may be in a form suitable for oral use, for example, co or pressed, tablets to dissolve in the mouth, tablets, aqueous and oily suspensions, powders or granules of epersables, emulsion. , hard or soft capsules or syrups or elixirs. Compositions intended for oral use can be prepared according to any method known in the art for poorer fabra on which compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and co-agents for provide pharmacologically suitable and palatable preparations. Tablets containing the active longrediene mixed with excipients can be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate.; granulation and disintegration agents, for example, corn starch or alginic acid; binding agents, for example, starch, gelatin or gum arabic and lubricating agents, for example, magnesium stearate, -ici or stearate or + alco "The tablets may be uncoated or these may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and provide this action a sustained action for a longer period of time. For example, a material can be used to delay the disintegration time such as glycemic monostearate or glycemic distearate. Formulations for oral use may also be presented as hard gelatin capsules in which the ingredient is either mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in the that the active ingredient is mixed with water or an oily medium, for example, peanut oil, liquid paraffin or olive oil. The aqueous suspensions contain active materials mixed with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, e.g., earboxi hl in the "iodide", hypochloride, dropropylphenolose, sodium algae, polyvinylpyrrolium, gum tragacanth and gum arabic; dispersing or wetting agent may be a phosphat ida is found in nature, for example, lecithin or condensation products of an alkylene oxide with fatty acids, for example, poly (oxyethylene stearate) or condensation products of an ethanedione oxide with long-chain aliphatic alcohols, example, hept decaeti lenoxicet anol or condensation products of ethylene oxide with partial ethers obtained from fatty acids and a hexitol such as poly (oxyethylene sorbitol monooleate) or condensation products of ethylene oxide with partial esters obtained from fatty acids and anhydrides of hexitol, for example, poly (ethylene sorbitan monooleate) The aqueous suspensions may contain one or more preservatives, or exemplifying, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions can be suspended by suspending the active ingredients in a vegetable oil, for example, peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil that is blunt to fine liquid. The oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetHo alcohol. Sweetening agents such as those described above and flavoring agents may be added to provide palatable oral preparations. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible powders and dispersible granules suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient mixed with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing and wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients may also be present, for example, sweetening, flavoring and coloring agents. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil, for example, olive oil or peanut oil, or a mineral oil, for example, liquid paraffin or mixture of the same. Suitable emulsifying agents may be natural gums, for example, gum arabic or tragacanth gum, natural phosphatides, for example, soybean seed, lecithin and partial esters or esters obtained from fatty acids and hexitol, anhydrides, for example, sorbitan monooleate and condensation products of said partial esters with ethylene oxide, for example poly (osethylene sorbitan monooleate). The emulsions may also contain sweetening and aromatizing agents before.

The syrups and elixirs can be formulated with sweetening agents, for example, gil zero], propylene glycol, oorbitol or sucrose. Such formulations may also contain a demulcent, preservative or flavoring agents and colorants. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oily suspension. This suspension can be formulated according to the known art using the appropriate dispersing or wetting agents and suspending agents that have been cited above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a diluent or solvent p rent non-toxic acceptable ration, for example, a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Rmger solution and isotonic sodium chloride solution. On the other hand, normally sterile non-volatile oils are used as solvent or suspension medium. For this purpose any insipid non-volatile oil including synthetic mono- or diglycepils can be employed. In addition, fatty acids such as oleic acid can be used in the preparation of injectables. The compounds of general formula I can also be used. n Administer in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at rectal temperature and which therefore melts in the rectum to release the drug. Such materials are cocoa butter and Jileoles polietiien. The compounds of general formula I can be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle. Dosage levels of the order of about 0.1 mg to about 140 rng per kilogram of body weight per day are useful in the treatment of the above-mentioned disorders (about 0.5 mg to about 7 g per patient per day). The amount of ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending on the patient treated and the particular mode of administration. The unit dosage forms will generally contain from about 1 mg to about 500 grams of active ingredient. It will be understood, however, that the specific dosage level for a particular patient will depend on a number of factors including the activity of the specific compound employed, age, body weight, general health, sex, diet, acupuncture time, route of administration and rate of excretion, the combination of drugs and the severity of the particular disease that undergoes therapy. An illustration of the preparation of the compounds of the present invention is provided in Scheme I. Those skilled in the art will recognize that the starting materials ee may be modified and additional steps may be employed to produce the compounds included in the present invention. SCHEME I wherein A is ArN or ArCH, wherein Ar is phenyl, 2-, 3- or 4-pipdyl, 2- or 3-t? emlo, 2-, 4- or 5-?? pm? d? lo either unsubstituted or mono- or disubstituted with halogen, hydroxy or straight or branched chain lower alkyl having 6 carbon atoms; B is sulfur, oxygen, NR5 or CR5 Re; n is 1, 2 or 3; rn is 2, 3 or 4; Ul, X, Y, Z and T are the same or different, and represent hydrogen, halogen, hydroxy, straight or branched chain lower alkyl having 6 carbon or lower alkoxy straight or branched chain which has 1 to 6 carbon atoms; Ri and R2 are the same or different and represent hydrogen or straight or branched chain lower alkyl having from 1 to 6 carbon atoms; R3 and 4 are the same or different and represent hydrogen, straight or branched chain lower alkyl having 1 to 6 carbon atoms or lower chain alkoxy Linear or branched having 1 to 6 carbon atoms; Rs represents straight or branched chain lower alkyl having from 1 to 6 carbon atoms, femlo, 2-, 3-or 4-?? r? D? Lo or feml-, 2-, 3- or 4-p? r? dil (straight or branched chain lower alkyl having from 1 to 6 carbon atoms); and E and Re are the same or different and represent hydrogen, hydroxyl, a mo, straight or branched chain lower alkyl having from 1 to 6 carbon atoms, straight or branched chain lower alkoxy having from 1 to 6 carbon atoms , phenyl, 2-, 3- or 4-p? pd? lo, phenyloxy, 2-, 2b 3- or 4 - ?? pd lox? or - (CFte) p-A'- (CFte) q-B ', where p? -e? resen < at 0-5, q represents 1-5 and A 'is a direct bond, oxygen or sulfur and B' is hydrogen, straight or branched chain lower alkyl having from 1 to 6 carbon atoms, straight chain lower alkoxy or branched that has 1 ab carbon atoms, phenyl, 2-, 3- or 4-p? r? d? lo, phenyloxy, 2-, 3- or 4-?? r? d? lox ?, carbox lo, carboalkoxy, unsubstituted carboxarnide, ~ ono- or dialkylcarboxamido, amano or mono- or day Lqui Lamino. The invention is further illustrated by the following examples which do not limit the spirit or scope of the invention to the specific processes and compounds described therein.

EXAMPLE 1 It was suspended in 100 ml of water 1-phenylpiperazine (11.3 ml, 12 g, 75 mmol). The pH was adjusted to 3 using 10% HCl. Cyclohexanone (7.8 ml, 7.4 g, 75 ml) was added followed by KCN (5 g, 75 nmol). The mixture was stirred for 15 hours at room temperature, during which time the product solidified. The product was collected by filtration, washed with water and then recpstal hoisted in ethane L to give 14.5 g of l-ano-1- (4-phenol-peracol-l) -cyclohexane as a solid. white (73% yield), mp = 133-L35"0.

EXAMPLE II It was dissolved in 10 ml of ether under N2 at room temperature 1-cyano-1- (4-phenol-peracol-1-yl) -cyclohexane (300 mg, 1.1 mmol). Phenyl magnesium bromide (4 ml of a 3 rt ether solution) was added and the reaction mixture was stirred for 15 hours. The mixture was diluted with 10 ml of ether, transferred to a separatory funnel, washed once with 10 ml of saturated NH 4 Cl solution and then extracted 10 ml of a 5% HCl solution three times. The acid extracts were basified using concentrated NH 4 OH solution and then extracted three times with 15 rnl of ether. The organic extracts were filtered through a pad of silica gel and concentrated to provide 280 mg of the free base of the desired compound as a white solid (80% yield). This material was dissolved in 5 nl of ethyl acetate. Saturated ethyl acetate with HC] (5 mL) was added. 1-phenol-1- (4-t-enylpyrazole-1-yl) -richlohexane dihydrochloride was collected by filtration.

(Compound 1) which precipitated in the solution (88 mg), was washed with ethyl acetate and dried in vacuo.

EXAMPLE III The following compounds were prepared practically according to the procedure described in Examples I and II. a) L- (3-methox-fem-l) -l- (4-phenol-1-yl-1-yl) -c-clohexane dihydrochloride (Compound 2). b) L- (3-rnetoxy? phen? 1) -i-T4- (2-piprnidiniDpiperaca n-1-? 11-cyclohexane dihydrochloride (Compound 3) c) D- (3-rnetoxy? ) -l- 4- (2-pipdinil) -? perac? nl-? l] -c? clohexane (Compound 4). d) l- (3-rnetoxy? phen? 1) -l-C4- (2-fluorophen? Dp? perac? n-1-yl-cyclohexane) dichlorohydrate (Compound 5) e) l- (3-) dihydrochloride methox? phen?) -1-C4-? -fluorophen? Dp? perac? n-1-? l] -c? elohexane (Compound 6). f) 1- (3-Ha droxy-phena) -1- (4 -femyl-1-yl) -c-clohexane dihydrochloride (Compound 7). g) L- (3,5-d? rnetox? feml) -1 - (- phenylpiperacm-L -? l) -c dichlorohydrate? Clohexane (Compound 8). h) 1- (3-ethoxy? phen? 1) -L- (4-phenyl? perac? n-1-? l) -c dichlorohydrate? Clohexane (Compound 9). i) 1- (3-rnetoxofen? 1) -1 - -fen? lp? perac? n-1-? L) -4-phenol-cyclohexane (cis isomer: Compound 10, trans isomer: Compound 11). j) L- (3-n-butox? phen? l) -1 - -femlpiperaci dihydrochloride. - 1 -yl) -ci clohexane (Compound 12). ) Dichloride of l- (3-me-oxy phenyl) -1- (phen? Lp? Erac? R-1-? L) -4-met? L-cyclohexane (isomer-or cis: Compound 13, trans isomer: Compound 14). 1) 1- (4-rnetox? Phenyi) -1- -phen? -peracm-1-yl) -4-c-clohexane dichloride (Compound L5). m) L- (2-rnetoxa phena 1) ~ 1 - (4-phen? lp? peracm-1-? l) -cyclohexane dihydrochloride (Compound 16). n) 1- (3, -Metenedioxy-phenyl-1) -1- (4-phenylpiperaz'-l-yl) -cyclohexane-dihydrochloride (Compound 17). o) Dichlorhydrate or 1- (3-ethoxyphenyl) -l- (-phenyl? perac? n-1-? i) -4-rnet? l-ca clohexane (cis isomer: Compound 18, trans isomer) : Compound 19). p) L- (3-ethoxy? phen? l) -1- (4-phen? lp? erac? n-1-? l) -4-et 1-c? clohexane dihydrochloride (cis isomer: Compound 20) , isomer t ans: Compound 21). q) It gives 1 ~ (3-isopropoxyphenyl) -1- (4-phenol-peracin-1-? l) -4-rnet? l-caclohexane hydrochloride (cis isomer: Compound 22, trans isomer: Compound 23). r) Dichloride time of 1- (-meto i eni L) -1 - (4-phenol-perac? n-1-? l) -3-? net? l-c? clohexane (cis isomer: Compound 24, trans isomer: Compound 25) ,. s) 1- (3-Methox ifenyl) -l- (4-phenyl? perac? n-1-? l) -cyclohexane dihydrochloride (Compound 26). t) 4- (3-ethoxyphenyl) -4- (-fen? lp? perac? n-1-? l) -tetraha dropirano dihydrochloride (Compound 27). u) 4 - (-ethoxy? eni L) -4- (4-t in? lp? perac? n-l-? l) -te < rahylthiopyran (Compound 28). v) It gives 1 - (3-rnetoxy-rnet-oxy-phenyl) -1- (4-fem-p-perac-n-1-yl) -4-met-l-c-clohexane hydrochloride (cis isomer: Compound 29, trans isomer: Compound 30). w) 1- (3-ethoxy? rnetox? phen? i) -1 - (4-phenol-perac? n-1-? l) -4-rnet? l-ca-clohexane (cis isomer: Compound 31, trans isomer: Compound 32). x) 1 - (3-ethoxy fem) -l- (4-fem lp ?? erac? n-1-? l) -4-rnetox dihydrochloride? -cyclohexane (cis isomer: Compound 33, trans isomer: Compound 34). z) l- (3 ~ ethoxy? phen? l) -l-f4- (4-h? dro to fem 1)? a peracm-1-? l] -4-met? i cycloexan (cis isomer: Compound 35) , trans isomer: Compound 36).

Compound 35 (aa) l-sp? roc? cloxane-4- (3-ethoxypol?) -4- (4-phen? lp? perac? n-l-? l) -c? clohexane (Compound 37).

Compound 37 bb) l- (3-ethoxy? phen? l) -l- (4-phenolpiperac? n-1-l) -4-hydroxy-cyclohexane (Compound 38).

Compound 38 ce) 1- (3-ethoxy enyl) -lE 4- (2,4-di-romophenyl) -α-γ-1-yl] -4-rnethyl-cyclohexane (cis-isomer: Compound 39, trans-isomer: Compound 40).

Compound 39 dd) 1- (3-ethoxy phenyl) -1- E 4- (pheny1pipe racin-1-i.) -2-methoxy-cyclohexane (cis isomer: Compound 41, trans isomer: Compound 42).

Compound 42 e) 1- (3-benzicloxifem 1) -l- (4-phen? lp? perac? n-1? L) -4-inet il-cyclohexane (cis isomer: Compound 43, trans isomer: Step 44 ).

Compound 43 The invention and the form and procedure of its realization and use have been described with complete, clear, concise and exact terms to allow any person skilled in the art to which it belongs, to make use of it. It will be understood that the foregoing describes preferred embodiments of the present invention and that modifications may be made thereto without departing from the spirit or scope of the present invention as unmistakably described in the claims the subject matter relating to the invention, the following claims conclude this descriptive report.

Claims (1)

14 NOVELTY OF THE INVENTION CLAIMS 1. A compound of formula or the pharmaceutically acceptable salts thereof in which: Ar is female, 2-, 3- or 4-pyridyl, 2- or 3-time, 2-. 4- or 5-p? R? Rn? dilo, each of which is optionally mono- or disubstituted with halogen, hydroxy, or straight or branched chain lower alkyl having from 1 to 7 carbon atoms; B is sulfur, oxygen, N (Rs) or C (Rs) (Rd); or a group of formula optionally substituted with halogen, hydroxy, lower alkyl or lower alkoxy; n is 1, 2 or 3; m is 2, 3 or 5; Ib Ul; X Y and T are the same or different and represent hydrogen, halogen, hydroxy, branched linear branched chain alkyl having 1 to 6 carbon atoms or straight or branched chain lower oxy having 1 to carbon atoms; R1 and R2 are the same or different and represent hydrogen or straight or amine chain lower alkyl having from 1 to 6 carbon atoms or straight-chain or lower alkoxy having from 1 to 6 carbon atoms; R-5 represents straight or branched chain lower alkyl having from 1 to 6 carbon atoms, phenyl, 2-, 3-or 4-?? r? D? L? or feml-, 2-, 3- or 4-p? r? d? l (aiqui The lower linear or branched chain that has from 1 to 5 carbon atoms), - and A and Re are the same or different and represent hydrogen, hydroxyl, arnine, branched straight chain lower alkyl having 1 ab carbon atoms, branched straight chain lower aleoxy having from 1 to 6 carbon atoms, femlo, benzyloxy 2-, 3- or 4-p ? pd? lo, phenoxy, 2-, 3- or 4-p? pd? lox? or - (CH2) P -A '- (CH2) -, -B', wherein p is 0-5, q is 1-5 and A 'is a direct bond, oxygen or sulfur and B' is hydrogen, straight or branched chain lower alkyl having from 1 to 6 carbon atoms, straight or branched chain lower alkoxy having from 1 to 6 carbon atoms, 2-, 3- or 4-pyridyl, phenoxy, 2-, 3- or 4-pipdoyloxy, carboxyl, carboalkoxy, carboxarnido, mono- or Ib dialkylnoxycini or, amido, or mono- or dialqui lamí no. A compound of formula where = r is phenyl, 2-, 3- or 4-p? r? d? lo, 2- or 3-t? in? Lo, 2-, 4- or 5-p? pm? d? lo , each of which is optionally mono- or di-substituted with halogen, hydroxy or loweral or branched chain lower alkyl having 1 to 6 carbon atoms; , U, X, Y and T are the same or different and represent hydrogen, halogen, hydroxy, straight or branched chain lower alkyl having from 1 to 6 carbon atoms or lower alkoxy straight or branched chain having from L to 6 carbon atoms; R2 are the same or different and represent hydrogen, straight or branched chain lower alkyl having from 1 to S carbon atoms or straight or branched chain lower alkoxy having from 1 to 6 carbon atoms; and R9 represents hydrogen, straight or branched chain lower alkyl having from 1 to 6 carbon atoms or femlo. 3. A compound according to Claim 2, wherein A is lower alkoxy. 4. A compound according to claim 1 which is l-phenol-l- (4-phenylpa peracin-1-a1) -cyclohexane. 5. A compound according to claim 1 which is 1- (3-rnetox? In? L) -L- (4-phen? Lpi peraem-l?? L) -c-clohexane 6. A compound according to Claim 1 which is l- (3-methox-phena 1) -1-C4-- (2-p? R a i di ni 1) -pa peracm-l- i 1"J -cyclohexane 7. A compound of According to claim 1, which is l- (3-rnetox-phenyl) -l-C4- (2-p? r? d? n? l) - pipe rac? n-1-? LU-cyclohexane 8. A compound of according to Claim 1 which is l- (3-methox-phena 1) -lL-4- (2-fluorophenyl) -α-peracl-1-l-cyclohexane 9. A compound according to claim 1 which is l- (3-methoxa-phena) -1-C4- (4-fluoro-phena-1) -pa peracm-1-? l] -cyclohexane 10. A compound according to claim 1 which is 1- (3h? drox? phen?) -l- (4-phen? lp? perac? nl-? l) -cyclohexane 11. A compound according to the Reiva ndicacion l which is l- (3,5-dirnetox? fen? l) -l- (4-phenyl-p-erac-n-1 -yl) -coclohexane. 12. A compound according to Claim 1 which is L- (3e ox? Phen?) -1 - (4-fem-piperac? N-11) - e / hex year. 13. A compound according to Claim 1 which is any of the two diastereomers of 1- (3-rneto if eml) -1- (4-phenylpiperaclin-yl) -cyclohexane. 14. A compound according to Claim 1 which is l- (3-n-t)? Tox? Fen? 1) -1- (4 ~ phen? Ipiper here n- 1 -i 1) -cyclohexane. 15. A compound according to Claim 1 which is any of the diastereoisorneros of l- (3-methox phen? L) -l- (4-phen? Lp? Perac? Nl-? L) - 4 -met Ll- Cycle ohe anus. 16. A compound according to claim 1 which is l- (4-rneto? Phen? L) -l- (4-femlp? Perac? N-l-l) -c? cl ohex anus. 17. A compound according to claim 1 which is l- (2-rnetox? Phen? L) -l- (-fena lp? Perac? N-1-? L) -cyclohexane. The compound according to claim 1 which is 1- (3,4-rnetenod? Ox? Fem 1) -1- (4-phenol piperazin-1-L) -cyclohexane. 19. A compound according to Claim L which is any of the two diastereomers of l- (3-ethoxyphenyl) -1-γ 4 -phenol? peracm-1-a 1) -4-met? l-c? cl ohe no. 20. A compound according to Claim 1 which is either of the two diastereomers of l- (3 ~ ethoxy? Phen? L) -l- (4-phen? Lpa perac? Nl-? L) -4-et? Lc Clohexane 21. A compound according to claim 1 which is any of the diastereomers of l- (3 ~ 3'-) i opropo i feni ".) -l - (4-fem 1 p ?? erac? -1-il) -4-? ne? lc clohexane .. 22. A compound according to Claim 1 which is which of the diastereomers of l - () -rnetoxifeml) -l- (4-phen? lp? pe ac? n-1- 1 L) -3-rne? ic? clohexane 23. A compound according to Claim L which is l- (3-benzyloxy eni 1) -L- < -fen? L ??? erac? R-1-? L) -ci elhex dichlorohydrate 24. A compound according to Claim 1 which is 4- (3-ethoxo-phenyl) -4- (4-phen? Lp? per-an-1-i-1) -tet hydropyr py = - 1 or 25. A compound according to Claim 1 which is 4- (3-ethoxyphene 1) -4- (4-phenylpiperazin-1-y1) -tetrahydro-ioanal 26. A compound according to claim 1 which is any of the diastereomers of l- (3-rneto irneto ifena 1) -l- (4-femlpí perací n-1 -11) - -met i] -cyclohexane 27. A compound according to Claim i which is any of the diastere isomers of 1 ~ (3-etoxi rnet oxifep i) -1- (4-phena-1-piperac-m-yl) -4-rnet-11-cyclohexane. 28. A compound according to Claim 1 which is any one of the diastere isomers of 1- (3-ethoxypheny1) -1-C4- (4-hydroxyphenyl) piperacm-1-ill. 4-rnet? Lc? Clohexane 29. A compound according to claim which is 30. A compound according to claim 1 which is l-esp? Roc? Elohexane-4- (3-ethoxy feni 1). ) -4 - ('+ -fen? Lp? Perac? R-1-? L) -cyclohexane 31. A compound according to Claim 1 which is 32. A compound according to Claim L which is l- (3-ethoxy? Phen? L) -l- (4-eny1 piperazine-1-y1) -4-hydroxycyclohexane. 33. A compound according to Claim 1 which is 34. A compound according to Claim 1 which is l- (3-etho? In? L) -1-1 * 4 - (2, 4-bromo-da-na-1) -piperacyl -111- 4 -met il- ci cl ohexano. 35. A compound according to Claim 1 which is A compound according to the Rei indication 1 which is l- (3-ethoxyphenyl) -1-C4 - (phenylpiperazin-1-yl) -2-rnetoxy-cyclohexane. 37. A compound according to Claim 1 which is 38. A compound according to claim 1 which is 1- (3-benzyl-phenyl) -l- (4-phenyl-peracm-1-11) -4-rnet i L-cyclohexane. LO 39. A compound according to Claim 1 40. The use of a compound of Claim 1, in the preparation of a composition for inhibiting the activity of L-neuropeptide Y at NPY1 receptors in a mammal in need of inhibition of neuropeptide Y activity, 41. The use of a compound of Claim 1, in the preparation of compositions for treating obesity, bulirnia and hypertension in a mammal in need of damage. 42. A pharmaceutical composition comprising an amount of a compound according to Claim 1, effective to inhibit NPY1 receptors and a pharmaceutically acceptable carrier. SUMMARY OF THE INVENTION This invention relates to compounds of formula and pharmaceutically acceptable salts thereof in which W, X, Y, fl and T represent organic or inorganic substituents, n is 1, 2 or 3, m is 2, 3 or 4, R to R are hydrogen or organic substituents and B is nitrogen, carbon, sulfur or oxygen useful in the diagnosis and treatment of food trophogens such as obesity and bulimia and cardiovascular diseases such as essential hypertension and congestive heart failure due to the binding of these compounds to the receptors of the body. neuropeptide human Yl. Figure 1 Compound 9 Compound 13 Compound 18 Compound 20 Compound 21 Compound 29 Pf / ycl * lmq * avc * lprn P97-368