AU692977B2

AU692977B2 - Certain substituted benzylamine derivatives; a new class of neuropeptide Y1 specific ligands

Info

Publication number: AU692977B2
Application number: AU42319/96A
Authority: AU
Inventors: Charles A Blum; Guolin Cai; Alan Hutchison; John M Peterson
Original assignee: Pfizer Inc
Current assignee: Pfizer Inc
Priority date: 1994-11-07
Filing date: 1995-11-07
Publication date: 1998-06-18
Anticipated expiration: 2015-11-07
Also published as: HUT78089A; NO972091D0; SK57097A3; MX9703349A; KR970707101A; CA2203878A1; CA2203878C; CZ137297A3; FI971931A0; NO972091L; JP3386814B2; PL321136A1; BR9509610A; AU4231996A; NZ297211A; FI971931A; WO1996014307A1; JP2001520625A

Description

WO 96/1007 WO 9614307PCTUS95/14472 Certain Substituted Benzylamine Derivatives; A New Class of Neuropeptide Y1 Specific Ligands BACKGROUND OF THE INVENTION Oded plte nention This invention relates to certain substituted benzylamine derivatives which selectively bind to human Neuropeptide Y1 (NPY1) receptors. This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds and compositions in treating feeding disorders and certain cardiovascular diseases.

Neuropeptide Y, a peptide first isolated in 1982, is widely distributed in the central and peripheral neurons and is responsible for a multitude of biological effects in the brain and the periphery. Various animl studies have shown that activation of Neuropeptide Yl receptors is related to vasoconstiction, Wahlestedt et al., Regul. Peptides, 1l: 307-318 (1986), McCauley and Westfall, J. Pharmacol. Exp. Ther. ZU~: 863-868 (1992), and Grundemar et al., Br. J. Pharmacol.

.1f. 45-5O (1992); and to stimulation of consummatory behavior, Flood and Morley, Peptides, IQ: 963-966 (1989), Leibowitz and Alexander, Peptides, IZ: 1251-1260 (1991), and Stanley et al., Peptides, 581-587 (1992).

Grundemar and Hakanson, TiPSY May 1994 [Vol. 15], 153-159, state that, in animals, Neuropeptide Y is a powerful stimuli of food intake, and an inducer of vasoconstriction leading to hypertension. They further point out that low levels of Neuropeptide Y is associated with loss of appetite. These reports clearly indicate that compouds that inhibit the activity of this protein will reduce hypertension and appetite in animals.

WO 96/14307 PCT/US95/14472 SUMMARY OF TH INVE NTION Compounds that interact with NPY1 receptors and inhibit the activity of Neuropeptide Y at those receptors are useful in treating 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 which selectively bind to Neuropeptide Y1 (NPY1) receptors. Such compounds are useful in treating feeding disorders such as obesity and bulimia as well as certain cardiovascular diseases such as essential hypertension.

The invention also provides pharmaceutical compositions comprising compounds of Formula I. The invention thus further relates to the use of such compounds and compositons in the treatment of eating as well as certain cardiovascular diseases. Accordingly, a broad embodiment of the invention is directed to a compound of Formula I:

R

4 (CH2)n W

R

3

R

1 XH R Y T CH2) Ar

A

I

where Ar is an aryl group B is sulfur, oxygen, a substituted nitrogen atom, or a mono- or disubstituted carbon atom; nis 1, 2, or 3; m is 2,3, or 4; I WO 96/14307 PCTIJS95/14472 W, X, Y, and T are the same or different and represent hydrogen, halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; R and R2 independently represent hydrogen, or straight or branched chain lower alkyl having 1-6 carbon atoms; and R3 and R4 are the same or different and represent hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms.

These compounds are highly selective partial agonists or antagonists at human NPY1 receptors and are useful in the diagnosis and treatment of feeding disorders such as obesity and bulimia as well as certain cardiovascular diseases such as essential hypertension and congestive heart failure.

WO 96/14307 PCTUS95/14472 -RE D E IIQN OFTHE IR WN Figure I shows representative substituted benmylarnines of the present invention.

I _C WO 96/14307 PCT/US95/14472 DETAILED DESCRIPTION OF THE INVENTQN The novel compounds encompassed by the instant invention can be described by general formula I: R4

(CH

2 )n W R 3

R

1 X R2 Y T Ar

CH

2 )m

A

I

where Ar is an aryl group preferably selected from the group consisting of phenyl, or 4-pyridyl, 2or 3-thienyl, 4- or 5-pyrimidyl, each of which is optionally mono- or disubstituted with halogen, hydroxy, or straight or branched chain lower alkyl having 1-6 carbon atoms; B is sulfur, oxygen, N(R5) or C(R5)(R6); n is 1, 2, or 3; m is 2, 3, or 4; W, X, Y, and T are the same or different and represent hydrogen, halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; R I and R2 are the same or different and represent hydrogen, or straight or branched chain lower alkyl having 1-6 carbon atoms; R3 and R4 are the same or different and represent hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms;

K-

I

PCTUS95/14472 WO 96/14307 represents straight or branched chain lower alkyl having 1-6 carbon atoms, phenyl. or 4-pyridyl, or phenyl, or 4-pyridyl straight or branched chain lower alkyl having 1-6 carbon atoms; and A and R6 are the same or different and represent hydrogen, hydroxyl, amino, straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms, phenyl, or 4-pyridyl, phenoxy, 2- or 4- pyridyloxy, or -(CH2)p-A'-(CH2)q-B' where 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 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms, phenyl, or 4-pyridyl, phenoxy, or 4-pyridyloxy, carboxyl, carboalkoxy, carboxamido, mono or diaikylcarboxamido, amino, or mono or dialkylamino.

Prefer-d compounds according to Formula I are those where Ar is optionally substituted phenyl, pyrimidinyl or pyridyl, B is carbon optionally substituted with phenyl or alkyl, and W, X, Y, A, T, and R1-R4 are hydrogen. Particularly, preferred compounds or Formula I are those where Ar is phenyl, pyrimidinyl or pyridyl, B is carbon optionally substituted with phenyl or alkyl, and W, X, Y, A, T, and R1-R4 are hydrogen.

The invention also relates to compounds of formula IA: where Ar is phenyl, 3- or 4-pyridyl, 2- or 3-thienyl, 4- or 5-pyrimidyl, each of which is optionally mono- or disubstituted with halogen, hydroxy, lower alkoxy or lower alkyl; A, W, X, Y, and T are the same or different and represent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy;

R

1 and R 2 are the same or different and represent hydrogen, or lower alkyl;

R

3 and R 4 are the same or different and represent hydrogen, lower alkyl, or lower alkoxy; and

R

5 represents hydrogen, lower alkyl, or phenyl; and with the proviso that if W, X, Y, A, T, R 1

R

2

R

3

R

4 and R 5 are all hydrogen; then Ar must be an aromatic group other than phenyl, o-chlorophenyl, o-methoxyphenyl, o-ethoxypilenyl, o-hydroxyphenyl or 2, 3 xylyl.

15 The invention further encompasses compounds of Formula II: *o .:o S e IN:LIBAA14985;SSC WO 96/14307PC/S/147 PCrfUS95/14472 where A and X independently represent alkoxy and Ar represents phenyl, pyrin-udinyl, or pyridyl.

Preferred compounds of Formula II are those where X and A are methoxy, ethoxy, isopropoxy, or butoxy, and Ar represents phenyl, pyrimidinyl, or pyridyl.

The invention further includes compounds of Formula Ml: X" N in where X and A independently represent alkoxy and R7 and RP8 are different and represent hydrogen or fluorine.

The invention further encompasses compounds of Formula IV: where X represents hydroxy and Ar represents phenyl, pyrimidinyl, or pyridyl.

WO 96/14307 PTLSi/47 PCTICS95/14472 The hiwention further encompasses compounds of Formnula V:

N.N

V

where X represents alkoxy and Ar represents phenyl, pyriinidnyl, or pyr.idyl.

Preferred compounds of Formula V are those where X is methoxy, ethoxy, isopropoxy, or buioxy, and Ar represents phenyl. Particularly preferred compounds of Formula V are those where X is methoxymethoxy or ethoxymnethoxy.

The invention also includes compounds of Formula VI: where X represents alkoxy, R9 is alkyl, and Ar represents phenyl, pyrirnidinyl, or pyridyL1 Preferred compounds of Formula VI are those where X is metboxy, ethoxy, isopropoxy, or butoxy, R9 is alkyl, and Ar represents phenyl. Particularly preferred compounds of Formula VI are those- where X is methoxy, ethoxy, isopropoxy, or butoxy, Ro, is methyl, and Ar represents pheiiyl. Other particularly preferred compounds of Formula VI are those where X is methorymethoxy or ethoxyniethoxy, R9 is methyl, and Ar represents phenyl.

WO 96/14307 WO 9614307PCTIUS95/14472 The invention also encompasses compounds of Formula VII: 0

~N

VII

where Ar rvpresents optionally substituted phenyl, pyrimidinyl, or pyridyl.

Preferred compounds of Formula Ar reprnfents phenyl, pyrimidinyl, or pyridyl.

Representative compounds of the present invention, wuhich are encompassed by Formula I- \rfLj include, but are not limited to the compounds in Figure I and their pharmaceutically acceptable salts. Non-toxic pharmnaceuticay acceptable salts include salts of acids such as hydrochloric, phosphoric, hydrobrn-mic, sulfuric, sullinic, formic, toluene sulfonic, hydroiodic, acetic and the like. T7hose skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.

The L12-4 don also relates to compounds of formula VT,.

Y T Ar

VII

wh&"C WO 96/14307 PCV2US95/14472 Ar is phenyl, or 4-pyridyl, 2- or 3-thienyi, 4- or 5-pyrimidyl, each of which is optionally mono- or disubstituted with halogen, hydroxy, or sa-aight or branched chain lower alkcyl having 1-6 carbon atoms; A, X, Y, and T are the same or different and represent hydrogen, halogen. hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; and R9 represents hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, or phenyl.

The present invention also encompasses the acylated prodrugs of the compounds of Formula I-VflJ. Those skilled in the art will recognize various synthetic methodologies which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula L.

The invention encompasses both diasteriomers of the compounds having 1,4-substitution on the cyclohexane ring. L~e, the invention encompasses both cis-, and trans-i ,4-cyclohexanes.

Preferred compoands of the invention having 1 ,4-substitutiojn on the cyclehexane ring are those where the nitrogen atom forming the piperazine ring 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 such substitution are those that are cis- l-piperazinylb4-alkyl or phenyl- By "aryl" aid "Ar" is meant an aromatic carbocyclic group having a single ring phenyl), multiple rings biphenyl), rr multiple condensed rings in which at least one is aromatic, 1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthyl), which can optionally be unsubstituted or substituted with haLogon, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, aryl, heteroaryl, and hydroxy.

WO 96/14307 PCT/US95/14472 By "alkyl" and ":ower alkyl" is meant straight and branched chain alkyl groups having from 1-6 carbon atoms.

By "lower alkoxy" and "alkoxy" is meant straight and branched chain alkoxy groups having from 1-6 carbon atoms.

By "halogen" is meant fluorine, chlorine, bromine and iodine.

By and 4-pryidyloxy is meant groups of the following formulas respectively: The pharmaceutical utility of compounds of this invention is indicated by the following assay for human NPY1 receptor activity.

As-sa for aHuman NPY1 receptor binding activity The procedure used is similar to that described by Gordon et al. Neurochem. 55:506- 513, 1990). SiC-N-MC cells were purchased from ATCC (Rockville, MD). Cells were maintained at 37 0 C and 5% C02 in Dulbecco's modified essential media (DMEM) with Lglutamine and 110 mg/L sodium pyruvate, which was supplemented with 10% fetal bovine serum and 25 mM HEPES (pH The binding assay was performed in 24-well plates (Falcon) when the cells were confluent Taking care to not disturb the cells on the bottom of the wells, the media was aspirated, and 0.5 ml of Dulbecco's phosphate buffered saline (DPBS) with calcium and magnesium were added to each well. The DPBS was aspirated and an additional aliquot of DPBS was added and aspirated. To begin the assay, binding buffer consisting of serum-free DMEM containing 0.5% bovine serum albumin, 0.1% bacitracin and 0.1 mM phenylmethylsulfonylfluoride was added to each well. The cells and the binding buffer prejncubated for 30 minutes at room te ture, at which point the drug dilution and 12 5 ]pyy (NEN-DuPont: 50000 -75000 cpm 50 pM) were added to yield a final volume of 250 ul.

Nonspecific binding was defined with I mM NPY (porcine or human, Bachem California). After WO 96/14307 PCT/US95/14472 a 3 hour incubation at room temperature, the plates were then put on ice and the wells were aspir.ted. The cells were washed 4-6 times with 0.5 ml of ice-cold DPBS. A dilute solution of Triton X-100 was then added to each well. After approximately 1 hour at room temerature, an aliquot from each well was transferred to a 12x75 mm testtube, and the amount of [1251] was quantitated on a gamma counter with an efficiency of 80-85% (Genesys 5000, Laboratory Technologies). IC50 values were calculated with the non-linear curve fitting program RS/1 (BBN Software Products Corp., Cambridge, MA). The binding characteristics for compounds of this invention are shown in Table 1.

TABLE I Complnn Num rICHjm 9 0.137 13 (cis isomer) 0.067 18 (cis isomer) 0.075 (cis isomer) 0.076 21 (trans isomer) 0.525 29 (cis isomer) 0.039 1 Compound numbers relate to compounds shown in Figure L Compounds 13, 18, 20 and 29 are particularly preferred embodiments of the present invention because of their potency in binding to human NPY1 receptors.

The compounds of general formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of general formula I and a pharmaceutically acceptable carrier. One or more compounds of general WO 96/14307 PCT/VS5/14472 formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, frr example sodium carboxymethylcelulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a WO 96/14307 PMUS95/14472 naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example 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 may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as, liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturallyoccurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters WO 96/14307 10CIM895/1411471.

with ethylene oxide, for example polyoxyethylene sorbitan monoleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension nay be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compounds of general formula I may also be administered 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 the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

Compounds of general formula I may be administered parenterally in a sterile medium.

The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anaesthetics, preservatives and buffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that may be combined with the carrier PC1IMS95/1,147 WO 96/14307 materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about I mg to about 500 mg of an active ingredient.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

An illustration of the preparation of compounds of the present invention is given in Scheme I. Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present invention.

I I, I PC'r1US95/14472 WO 96/14307 Scheme I F4 R4 R3R KCN R

R

(CI1 2 )n +A C 2 )nN 0 A

(CH

2 )m' W MgBr

IR

4 R T R3

(CH

2 )n CN CH)n (CH2)M where A is ArN or ArCH where Ar is phenyl, 2, 3, or 4 pyridyl, 2 or 3 thienyl, 2, 4 or 5 pyrimidyl either unsubstituted or mono or disubstituted with halogen, hydroxy, or straight or branched chain lower alkyl having 1-6 carbon atoms; B is sulfuar, oxygen NR5 or CRSR6 n is 1, 2, or 3; mis2,3,or4; W, X,Y, Z, T are the same or different and represent hydrogen, halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; PC3Y0S95114472 WO 96/14307 RI and R2 are the same or different and represent hydrogen, or straight or branched chain lower alkyl having 1-6 carbon atoms; R3 and R4 are the same or different and represent hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; represents straight or branched chain lower alkyl having 1-6 carbon atoms, phenyl, 2, 3, or 4 pyridyl, or phenyl, 2, 3, or 4 pyridyl straight or branched chain lower alkyl having 6 carbon atoms; E and R6 are the same or different and represent hydrogen, hydroxyl, amino, straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms, phenyl, 2, 3, or 4 pyridyl, phenyloxy, 2, 3, or 4 pyridyloxy, or -(CH2)p-A'-(CH2)q-B' whe p represents.0-5 and q represents 1-5 and A' is a direct bond, oxygen or sulfur and B' is hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms, phenyl, 2. 3, or 4 pyridyl, phenyloxy, 2, 3, or 4 pyridyloxy, carboxyl, carboalkoxy, unsubstituted, mono or dy, rboxamido, amino, or mono or dialkylamino.

The invention is illustrated, further by the following examples which are not to be construed as limiting the invention in scope or spirit to the specific procedures and compounds described in them.

WO 9( ?A4307 PTU9I47 PCr/VS95/J4472 1~auw1~J 1-Phenylpiperazfie (11.3 m.L, 12 g, 75 imol) was suspended in 100 niL water. The pH was adjusted to 3 using 10% HC1. Cyclohexanone (7.8 niL, 7.4 g, 75 rnmol) was added followed by KCN (5 g, 75 nina!). The mixture was stirred 15 hours at room temperature during which time the product solidified. The product was collected by filtration, washed with water, then recrystallized from etaotw~ give 14.5 g of I1-Cyano- 1-(4-phenylpiperazin-1I-yl)-.cyclohexane as a white solid (73 yield), nrip 133-135 TC.

Emud" I-Cyano-l-(4-phenylpiperazin-1-yl)-,ycohexane (300 mig, 1.1 nimol) was dissolved in 10 m.L ether under N2 at room temperature. Phienyl magnesium bromide (4 niL of a 3 M ether solution) was added and the reactior mixture stirred 15 hours. The mture was diluted with m.L ether, transferred to a separatory funnel, washed 1 X 10 niL saturated NH4CI solution, then extracted 3 X 10 m.L 5 Ha solution. The acidic extracts were basified using concentrated WO 96/14307 4 PPXIY1$95/Z4472 solution then extracted 3 X 15 ml, ether. The organic extracts were filtered through a silica gel pad then concentrated to afford 280 mg of the free base of the desired compound as a white solid (80 yield). This material was dissolved in 5 ml, ethyl acetate. Ethyl acetate saturated with HCI (5 mrL) was added. 1-Phenyl-l -(4-phenyl-piperazin- I-yl)-cyclohexane dihydrochloride (Compound 1) which precipitated out of solution (88 mg) was collected by filtration washed with ethyl acetate and dried in vacuo.

The following compounds were prepared essentially according to the procedure described in Examples I-II: a) I -(3-Methoxyphenyl)- 1 -(4-phenylpiperazin- 1-yl)-cyclohexane dihydrochioride (Compound 2).

b) 1-(3-Methoxyphenyl)- l-t4-(2-pyimidinyl)-piperazin-1 -yl]-cyclohexane dihydrochloride (Compound 3).

c) 1-(3-Methoxyphenyl)- 1 -[4-(2-pyridinyl)-pipeazin-1 -yl]-cyclohexane dihyrochloride (Compound 4).

d) 1-(3-Methoxyphenyl)- -[4-(2-fluorophenyl)-piperazin- 1-yl]-cyclohexane dihydrochioride (Compound e) 1-(3-Mczthoxyphenyl)- 1-[4-(4-fluorophenyl)-pipemzin- -yl]-cyclohexane dihydrochioride (Compound 6).

WO 90/14307 CY 95142 PMAIS95/14,172 0 1 -(3-Hydroxyphenyl)" I-(4-phenylpiperazin- I -y',)-cyclohcxane dihydrochloride (Compound 7).

g) 1 5-Dimethoxyphenyl)- 1-(4-phenylpiperazin- 1-yl)-cyclohexane dihydrochioride (Compound 8).

h) 1 -(3-Ethoxyphenyl)- 1-(4-phenylpiperazin- 1-yl)-cyclohexane dihyUdrAOchloride (Compound 9).

i) 1-(3-Methoxyphenyl)- 1-(4-phenylpiperazin- 1-yi)-4phenyl-cyclei-exane dihydrochloride (cis isomer:- Compound 10, trans isomer. Compound 11).

j) 1 -(3-n-Butoxyphenyl)- 1-(4-phenylpiperazin- 1-yI)-cyclohexane dihydrochioride (Compound 12).

k) 1 -(3-Methoxyphenyl)- 1-(4-phenylpiperazin- 1 -yl)-4-mcthyl-cyclohexane dihydrochoride (cis isorw Compound 13, trans isomer Compound 14).

1) 1-(4-Meth ,xypheny1)- 1-(4-phenylpiperazin-1-yl)-cyclohexane dihydrochioride (Compound m) 1-(2-Metkhoxyphenyl)- 1-(4-phenylpiperazini-1 -yl)-cyclohexane dihydrochioride (Compound 16).

n) 1 -(3,4-Methenedioxyphenyl)- 1 -(4-phenylpiperazin- 1 -yi)-cyclohexane dihydrochoride (Compound 17).

I gl WO 96/14307PC/95147 PCf/VS9S/J4472 o) I -(3-Ethoxvphenyr, -t-phenylpiperazin- I -yi)-4methyl-cyclohexane dihydrochioride (cis isomer: Compound 18, trans isomer: Compound 19).

p) 1 -(3-Ethoxyphenyl)- 1 -(4-phenylpiperazin- 1 -yi)-4-ethyl-cyclohexane dihydrochioride (cis isomer: Compound 20, trims isomer: Compound 21).

q) I -(3-Isopropoxyphenyl). 1 -(4-phenylpilh-razin- I -yl)- 4 tthyI-cyclohcxane dihydrochiori'de (cis isomer: Compound 22, trans isomer: Compound 23).

r) 1 -(3-Mlethoxyphenyl)- 1-(4-phenylpiperazin-.1 -yl)-3-methyl- cyclohexane dihydrochloride (cis isomer: Compk,*..- 24,, trans isomer Compound s) 1-(3-Benzyloxyphenyl)- 1-(4-phenylpiperazin- 1-yl)-cyclohcxane dihydrochioride (Compound 26).

t) 4-(3-Ethoxyphenyl)-4-(4-phenylpiperazin- l-yl)-tetm"iydropyran dihydrochloride (Compound 27).

u) 4-(3-Ethoxyphenyl)-4-(4-phenylpiperazin- 1-yI)-tetrahydrothiopyran dihydrochioride (Compound 28).

v) 1-(3-Methoxymethoxynhenyl)- 1-(4-phenylpiperazin- fl-yI)-4methyl-cyclohexane dihydrochioride (cis isomer: Compound 29, trans isomer Compound WO 96/14307 PTU9147 PCT/US95/14472 w) I -(3-Ethoxy- ,o xyphenyl)- 1 -(4-phenylpiperazin. I -yl)-4.-methyl-cyclohcxane dihydrchloride (cis isomer: Compound 3 1, trans isomer: Compound 32).

x) 1-(3-Ethoxyphenyl)- l.(4-phenylpip-razin- 1 -yl)4-methoxy-cyclohexane dihydrochloride (cis isomer: Compound 33, trans isomer: Compound 34).

The invention and the manner and process of making and using it, are now described in such full. clear, concise c-ad exact ter-ins as to enable any person skilled in the art to which it pertains, to make and use 'the same. It is to be understood that the foregoing descrihb-,s preferred imbadiments of the present invention and that modifications may be made therein without departing from the spirit or scope of the present invention as set forth in the claims. To particularly point out and distinctly claim :he subjeect matter regarded as invention, the following claims conclude this specificafon.

Claims

1. A compound of the formula:

6-8 R4 (CH 2 )n W R R 1 X. R 2 Y T A, (CH2)m A or thepharmaceutically acceptable salts thereof wherein: Ar is phenyl, or 4-pyridyl, 2- or 3-thienyl, 4- or 5-pyrimidyl, each of which is optionally mono- or disubstituted with halogen, hydroxy, or straight or branched chain lower alkyl having 1-(6 carbon atoms; B is sulfur, oxygen, or C(R5)(R6); nis 1, 2, or 3; mis 2,3, or 4; W, X, Y, and T are the same or different and represent hydrogen, halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; R and R2 are the same or different and represent hydrogen, or straight or branched chain lower alkyl having 1-6 carbon atoms; R3 and R4 are the same or different and represent hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; RS represents straight or branched chain lower alkyl having 1-6 carbon atoms, phenyl, or 4-pyridyl, or phenyl, or 4-pyridyl straight or branched chain lower alkyl having 1-6 carbon atoms; and I 26 A and R 6 are the same or different and represent hydrogen, hydroxyl, amino, straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched lower alkoxy having 1-6 carbon atoms, phenyl, 3-, or 4-pyridyl, phenoxy, or 4-pyridyloxy or -(CH 2 )p-A'-(CH 2 where 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 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms, phenyl, or 4-pyridyl, phenoxy, 2-, or 4-pyridyloxy, carboxyl, carboalkoxy, carboxamido, mono or dialkylcarboxamido, amino, or mono or dialkylamino. 2. A compound of the formula: where Ar is phenyl, 3- or 4-pyridyl, 2- or 3-thienyl, 4- or 5-pyrimidyl, each of :which is optionally mono- or disubstituted with halogen, hydroxy, lower alkoxy or lower S: 15 alkyl; S. A, W, X, Y, and T are the same or different and represent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy; R 1 and R 2 are the same or different and reoresent hydrogen, or lower alkyl; R 3 and R 4 are the same or different and represent hydrogen, lower alkyl, or lower S 2o alkoxy; and R 5 represents hydrogen, lower alkyl, or phenyl; and with the proviso that if W, X, Y, A, T, R 1 R 2 R 3 R 4 and R 5 are all hydrogen; then Ar must be an aromatic group other than phenyl, o-chlorophenyl, o-methoxyphenyl, o-ethoxyphenyl, o-hydroxyphenyl or 2, 3- xylyl. 3. A compound according to Claim 2 wherein A is lower alkoxy. 4. A compound according to Claim 1 which is 1-(3-Methoxyphenyl)-1-(4- phenylpiperazin-l-yl)-cyclohexane. A compound according to Claim 1 which is l-(3-Methoxyphenyl)-l-[4-(2- pyrimidinyl)-piperazin-l-yl]-cyclohexane. 6. A compound according to Claim 1 which is 1-(3-Methoxyphenyl)-1-[4-(2- Spyridinyl)-piperazin-l-yl]-cyclohexane. (N:\LBAA4985SSC 27

7. A compound according to Claim 1 which is 1-(3-Methoxyphenyl)-1-[4-(2- fluorophenyl)-piperazin-1-yl]-cyclohexane.

8. A compound according to Claim 1 which is 1-(3-Methoxypheny])-1-{4-(4- fluorophenyl)-piperazin-1-yl]-cyclohexane.

9. A compound according to Claim 1 which is 1-(3-Hydroxyphenyl)-1-(4- pheniylpiperazin-1-yl)-cyclohexane. A compound according to Claim 1 which is 5-Dilnethoxyphenyi)-1-(4- pheniylpiperazin-1 -yl)-cyclohexane.

11. A compound according to Claim 1 which is 1-(3-Ethoxyphenyl)-1-(4- phenylpiperazin-1 -yl)-cyclohexane.

12. A compound according to Claim 1 which is both diastereomers of 1-(3- Methoxyphenyl)-1-(4-phenylpiperazin-1-yl)-4-phenyl-cyclohexane.

13. A compound according to Claim 1 which is 1-(3-n-Butoxyphenyl)-1-(4- phenylpiperazin-1-yl)-cyclohexane.

14. A compound according to Claim 1 which is both diastereomers of 1-(3- Methoxyphenyl)-l-{4-phenylpiperazin-1-yl)-4-methyl-cyclohexane. A compound according to Claim 1 which is 1..(4-Methoxyphenyl)-1-(4- phenylpiperazin-1-yl)-cyclohexane.

16. A compound according to Claim 1 which is 1-(3,4-methenedioxyphenyl)-1-(4- phenylpiperazin-1-yl)-cyclohexane.

17. A compound according to Claim 1 which is both diastereomers of 1-(3- Ethoxyphenyl)-1-(4-phenylpiperazin-1-yl)-4-methyl-cyclohexane.

18. A compound according to Claim 1 which is both diastereomers of 1-(3- Ethoxyphenyl)-1 -(4-phenylpiperazin-1-yl)-4-ethyl-cyclohexane. 25 19. A compound according to Claim 1 which is both diastereoniers of 1-(3- Isopropoxyphenyl)-1-(4-phenylpiperazin-1-yl)-4-methyl-cyclohexane. A compound according to Claim 1 which is both diastereomers of 1-(3- Methoxyphenyl).-1-(4-phenylpiperazin-1-yl)-3-methyl-cyclohexane. 0 021. A compound according to Claim 1 which is 1-(3-Benzyloxyphenyl)-!.-(4- :00: 30 phenylpiperazin-1-yl)-cyclohexane dihydrochloride.

22. A compound according to Claim 1 which is 4-(3-Ethoxyphenyl)-4-(4- phenylpiperazin-1-yl)-tetrahydropyran.

23. 4-(3-ethioxyphenyl)-4-(4-phenylpiperazin-l.-yl)-tetrahydrothiopyran. 00 01(-hn~nprznl 0 24. Either diastereomer of 1-(3-methoxymethioxyphenyl)-1~-hnhprzn1 0 35yl)-4-methylcyclohexane. Either diastereomer of 1-(3-ethoxymethoxyphenyl)- 1-(4-phenylpiperazin-1-yl)- 4-methylcyclohexane.

26. Either diastereomer of 1-(3-ethoxyphenyl)-1 -(4-phenylpiperazin-1-yl)-4- methoxycyclohexane. 9' [INALIBAA149BB:KWW 28

27. A benzylamine derivative which selectively binds to human Neuropeptide Y1 receptors, substantially as hereinbefore described with reference to any one of the examples.

28. A pharmaceutical composition comprising an effective amount of at least one compound according to any one of claims 1 to 27, together with a pharmaceutically acceptable carrier, diluent or adjuvant therefor.

29. A method for the treatment or prophylaxis of feeding disorders in a mammal requiring said treatment or prophylaxis, which method comprises administering to said mammal an effective amount of at least one compound according to any one of claims 1 to 27, or of a composition according to claim 28. The method according to claim 29, wherein the disorder is obesity or bulimia.

31. A method for the treatment or prophylaxis of cardiovascular diseases in a mammal requiring said treatment or prophylaxis, which method comprises administering to said manunal an effective amount of at least one compound according to any one of claims 1 to 27, or of a composition according to claim 28.

32. The method according to claim 31, wherein the disease is hypertension or congestive heart failure. Dated 23 January, 1998 PFIZER INC. 20 Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON a o a a.« IN:\LIBAA)4985:KWW