CA2203878C

CA2203878C - Certain substituted benzylamine derivatives; a new class of neuropeptide y1 specific ligands

Info

Publication number: CA2203878C
Application number: CA002203878A
Authority: CA
Inventors: John M. Peterson; Charles A. Blum; Guolin Cai; Alan J. Hutchison
Original assignee: Pfizer Corp SRL
Current assignee: Pfizer Corp SRL
Priority date: 1994-11-07
Filing date: 1995-11-07
Publication date: 2002-06-25
Anticipated expiration: 2015-11-07
Also published as: NO972091D0; FI971931A0; AU4231996A; PL321136A1; MX9703349A; BR9509610A; AU692977B2; NO972091L; HUT78089A; SK57097A3; WO1996014307A1; KR970707101A; FI971931L; JP2001520625A; CZ137297A3; CA2203878A1; JP3386814B2; NZ297211A

Abstract

Disclosed are compounds of the formulas: wherein Ar is optimally substituted aryl; B is O, S, NR5 or CR5R6; n is 1, 2 or 3; m is 2,3 or 4; W, X, Y and T are each hydrogen or substituent; R1 and R2 are each hydrogen or alkyl; R3 and R4 are each hydrogen, alkyl or alkoxy; R5 is alkyl or aryl; R6 is hydrogen or substituent; and A is hydrogen or substituent. These compounds bind to neuropeptide Y1 (NPY1) reptor and are useful for treating eating disorders such as obesity and bulimia as well as cardiovascular diseases such as hypertension.

Description

Certain Substituted Benzylamine Derivatives;
A New Class of Neuropeptide Y1 Specific Ligands Field of the Invention 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.
Descrintion of the Related Art 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 animal studies have shown that activation of Neutopeptide Y
1 receptors is relaxed to vasoconstriction, Wahlestedt et aL. Regul. Peptides, ~: 307-318 (1986), McCauley and Westfall. J. Pharmacol. Exp. Ther. ~: 863-868 ( 1992), and Grundemar et al., Br. J. Pharcnacol.
jQ~: 45-50 (1992); and to stimulation of consummatory behavior, Flood and Motley, Peptides,1Q:
963-966 (1989). Leibowitz and Alexander. Peptides, ~: 1251-1260 (1991), and Stanley et al., Peptides,1,'~: 581-587 (1992).
Grundemar and Hakanson, TIPS. 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 pmcein will reduce hyperoension and appetite in animals.

SUMMARY OF THF INVFrr~rm~r Compounds that interact with NPY 1 receptors and inhibit the activity of Neuropeptide Y at those receptors are uxful in treating caring 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 arc useful in treating feeding disorders such as obesity and bulimia as well as certain cardiovascular diseaxs such as esxntial 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 embodirrxnt of the invention is directed to a compound of Formula I:
R~
f~H2)~
W , R3 Rt T
(cH2)J Ar A
I
where Ar is an aryl group B is sulfur, oxygen, a substituted nitrogen atom, or a mono- or disubstituted carbon atom;
n is 1. 2, or 3;
m is 2, 3, or 4;

WO 96/14307 PCT/TJS95~14472 W. X, Y, and T are the same or different and represent hydrogen, halogen, hydroxy, straight or branched chain lower allcyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms;
R1 and R2 independently represent hydrogen, or straight or branched chain lower alkyl having I-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.

BRIEF DFS _Rltrrtn~r nc 'tH nt! a wr~rr Figure 1 shows reprexntative substituted benzylamines of the prexnt invention.

The novel compounds encompassed by the instant invention can be described by general formula I:
Ra ~CH2)n w _ ~ R2 Y ~ T
(~H2)J Ar A
I
where Ar is an aryl group preferably selected from the group consisting of phenyl, 2-, 3-, or 4-pyridyl, 2-or 3-thienyl, 2-, 4- or 5-pyrimidyl, each of which is optionally mono- or disubstitutod with halogen, hydroxy, or straight or branched chain lower alkyl having 1-6 carbon atoms;
B is sulfur, oxygen, N(RS) or C(R5)(R6);
n is 1, 2, or 3;
mis2,3.or4;
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 1 and R2 are the same or different and represent hydrogen, or straight or branched chain lower allryl having 1-6 carbon atoms;
R3 and R4 are the same or different and represent hydrogen, straight or braachod chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms;

WO 96114307 PGT/I1S95/14472.
RS reprexnts 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 1-6 carbon atoms: and A and Rb are the same or different and repttxnt 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, phenoxy, 2- 3-, 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, 2-. 3-, or 4-pytzdyl, phenoxy, 2-, 3-, or 4-pyridyloxy, carboxyl, carboatkoxy, carboxamido, mono or dialkylcarboxamido, amino, or mono or dialkylamino.
Preferred 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 R 1-R4 are hydrogen. Particularly, preferred compounds or Formula I are thox 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:
~o R3 R~

N
~Ar A
where Ip Ar is phenyl, 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, 2-, 4-or 5-pyrimidyl, each of which is optionally mono- or disubstituted with halogen, hydroxyl, or straight or branched chain lower alkyl having 1-6 carbon atoms;
A, W, X, Y and T are the same or different and represent hydrogen, halogen, hydroxyl, straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms, benzyloxy, methoxymethoxy or ethoxymethoxy; or A and Y together form methylenedioxy;
R1 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; and R9 represents hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, methoxy or phenyl.
In one embodiment, the compounds of Formula IA are those in which Ar is as defined above other than phenyl, 2-chlorophenyl, 2-methoxyphenyl, 2-ethoxyphenyl, 2,3-dimethylphenyl or 2-hydroxyphenyl when A, W, X, Y and T are each hydrogen, R1 and R2 are each hydrogen, R3 and R4 are each hydrogen and Rg is hydrogen.
The invention further encompasses compounds of Formula II:

A
~N~Ar IN
X v where A and X independently represent alkoxy and Ar represents phenyl, pyrimidinyl, 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 BI:
III
Re where X and A independently represent alkoxy and R~ and Rg are different and represent hydrogen or fluorine.
The invention further encompasses compounds of Formula IV:
~N~Ar IV
where X represents hydroxy and Ar represents phenyl, pytimidinyl, or pyridyl.

The invention further encompasses compounds of Formula V:
~N~Ar IJJ
V
where X represents alkoxy and Ar represents phenyl, pyrirtvdinyl, or pyridyl.
Prefemeci compounds of Formula V are those where X is methoxy, ethoxy, isopropoxy, or butoxy, and Ar represents phenyl. Particularly preferred compounds of Formula V are those where X is metltoxymethoxy or ethoxymethoxy.
The invention also includes compounds of Formula YI:
Ar yI
when X t~epresents alkoxy, R9 is alkyl, and Ar represents phenyl, pyrimidinyl, or pyridyL
Preferred compounds of Formula VI are those where X is methoxy, ethoxy, isopmpoxy, or butoxy, Rg is allryl, anti Ar represents phenyl. Particularly prefertzd compounds of Formula VI
are those where X is methoxy, ethoxy, isopropoxy, or butoxy, R9 is methyl, and Ar represents phenyl. Other particularly preferred compounds of Formula VI are those when X
is nxthoxymethoxy or ethoxymethoxy, R9 is methyl, and Ar ttpresents phenyl.

The invention also encompasses compounds of Formula VII:
O ~N~Ar O
VII
where Ar reprexnts optionally substituted phenyl, pyrimidinyl, or pyridyl.
Preferred compounds of Formula Ar represents phenyl, pyrimidinyl, or pyridyl.
Representative compounds of the prexnt invention, which are encompassed by Formula I-VII, include, but are not limited to the compounds in Figure I and their phatmaoeutically acceptable salts. Non-toxic pharmaceutically acceptable salts include salts of acids such as hydrochloric, phosphoric, hydrobmmic, sulfuric, sulfinic, formic, toluene sulfonic, hydmiodic, acetic and the like. Thox skilled in the art will recognize a wide variety of non-toxic phartnaoeudcally acceptable addition salts.
The invention also relaxes to compounds of formula VIII:

N
Y T
Ar A
where / r7 Ar is phenyl, 2-. 3-, or 4-pyridyl. 2- or 3-thienyl, 2-, 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;
A, X, Y, and T are the same or different and represent hydrogen, halogen, hydmxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; and Rg 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-VIII. Those skilled in the art will recognize various synthetic methodologies which may be employed to pam non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I.
The invention encompasses both diasteriomers of the compounds having 1,4-substitution on the cyclohexane ring. Le, the invention encompasses both cis-, and traps-1,4-cyclohexanes.
Preferred compounds of the invention having 1,4-substitution on the cyclohexane ring are those where the nitrogen atom fom~ing the pipaazitx 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-1-piperazinyl-4-alkyl or phenyl-cyclohexanes.
By "aryl" and "Ar" is meant an aromatic carbocyclic group having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensed rings in which at least one is aromatic. (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), which can optionally be unsubstituted or substituted with e.g.. halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, aryl, hetemaryl, and hydroxy.
~/

WO 96114307 P~'-T/US95/14472 By "alkyl" and "lower 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 fmm 1-6 carbon atoms.
By "halogen" is meant fluorine, chlorine, bromine and iodine.
By 2-, 3-, and 4-pryidyloxy is meant groups of the following formulas respectively:
N
/ ~ /
The pharmaceutical utility of compounds of this invention is indicated by the following assay for human NPY 1 receptor activity.
The procedure used is similar to that described by Gordon et al. (J.
Neurochem. 55:506-513. 1990). SK-N-MC cells wen purchased from ATCC (Rockville, MD). Cells were maintained at 37oC and SR6 C02 in Dulbecco's modifiod essential media (DMEM) with L-glutamine and 110 mg/L sodium pyruvate, which was supplemented with 1096 fetal bovine serum and 25 mM HEPES (pH 7.3). 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 aspiraoed. To begin the assay, binding buffer consisting of serum-free DMEM
containing 0.596 bovine serum albumin, 0.196 bacitracin and 0.1 mM
phenylmethylsulfonylfluoride was added to each well. The cells and the binding buffer preincubated for 30 minutes at room temperature, at which point the drug dilution and [125nPYY
(NEN-DuPont: 50000 -75000 cpm -- 50 pM) were added to yield a final volume of 250 u1.
Nonspecific binding was defined with 1 mM NPY (porcine or human, Bachem California). After ?i a 3 hour incubation at room temperature, the plates were then put on ice and ttie wells were aspirated. The cells were washed 4-6 dines with 0.5 rnl of ice-cold DPBS. A
dilute solution of TritonX-100 ( 19b) was then added to each well. After approximately 1 hour at room temperature, an aliquot from each well was transferred to a 12x75 mm tesuube, and the amount of~[l~Ij was quanticated on a gamma counter with an efficiency of 80-8596 (Genesys 5000.
Laboratory Technologies). IC50 values were calculated with the non-linear curve fitting pmgram RSJl (88N
Software Products Corp., Cambridge, MA). The binding characteristics for compounds of this invention arc shown in Table 1.
TABLE I
('nmnound Numberl 9 0.137 I3 (cis isomer) 0.067 18 (cis isomer) 0.075 20 (cis isorra) 0.076 21 (traps isomer) 0.525 29 (cis isomer) 0.039 I Compound numbers relate to compounds shown in Fgttre I.
Compounds 13, 18. 20 and 29 are particularly preferred embodiments of the prexnt invention because of their potency in binding oo human NPY1 toctptors.
The compounds of general formula I may be administered orally. topically.
pareaterally.
by inhalation or spray or rcctally in dosage unit formulations containing conventional non-toxic pharmaceutically acctptable carriers, adjuvants and vehicles. The term parenneral as used herein includes subcutaneous injections, intravenous, intramttxtttar, incrasternal 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 Trade-mark WO 96/14307 PtrT7US95/14472 formula I may be prexnt in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The phannaoeutical 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 ux 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 xlected from the group consisting of sweetening agents, flavoring agents, coloring agents and prexrving 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 tray be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for acample, 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 hereby provide a sustained action over a longer period. For example, a time delay manorial such as glyceryi monosterate or glyc;ayl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with as 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 meditun, for exatnpk 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, for example sodium carboxymethylcellulox, methylcellulox, hydmpropylmethylcellulox, soditun alginate.
polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a 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 monooleace, 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 pant or cetyl alcohol. Sweetening agents such as those set forth above, anti 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 atachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring 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 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 may 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 art 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 oltic acid find use in the prepaisoion 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 parenteraUy in a sterile medium.
The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advaatageousiy, adjuvants such as local anaesthetics, preservatives and buffering agents can be dissolved in the vehicle.
Dosage levels of the ordtr of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the oreatrnent of the above-indicated conditions (about 0.5 mg tn about 7 g per patient per day). 'The amount of active ingredient that may be combined with the carrier 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 1 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 con~ination and the severity of the particular disease undergoing therapy.
As well known in the art, the pharmaceutical compositions may be put in commercial packages for practical use. Such commercial packages often include written matters which describe instructions that the pharmaceutical compositions should or can be used for the purposes described in this specification.
An illustration of the prepared 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.

WO 96/14307 pCT/US95/14472 Scheme I
R, R
R' KCN ' i I R, + ~ (CHz~ Nx (CHzk~ A
p (CHZnnJ NC N
A
(cH~, J
u~s_ g Re i (CHz~ Rt (cHa.~' Rz . w N
A
N C ~ A (CIi~ J
(CHz~n J x ~ / T
E
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 sulfur, oxygen NRS or CRSR6 n is l, 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;

R 1 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, 2, 3, or 4 pyridyl, or phenyl, 2, 3, or 4 pyridyl straight or branched chain lower alkyl having 1-6 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 awms, 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' where p represents.0-5 and q represents 1-5 and A' is a direct bond oxygen or sulfur and B' is hydrogen, straight or breached 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 dialkylcarboxamido, 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 I-Phenylpiperazine (11.3 mL, 12 g, 75 mmol) was suspended in 100 mL water. The pH
was adjusted to 3 using 1096 HCI. Cyclohexanone (7.8 mL. 7.4 g, 75 mmol) was added followed by KCN (5 g, 75 mmol). 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 rccrystalliud from ethanol to give 14.5 g of 1-Cyano- 1-(4-phenylpiperarin-I-yl)-cyclohexane as a white solid (73 9fo yield), mp = 133-135 °C.
~~'~l 1-Cyano-1-(4-phenylpiperazin-1-yl)-cyclohexane (300 mg, 1.1 mmol) was dissolved in 10 mL ether under N2 at room temperawre. Phenyl magnesium bromide (4 mL of a 3 M ether solution) was added and the reaction mixture stirred 15 hours. The mixture was diluted with 10 mL ether, transferred to a separatory funnel, washed 1 X 10 mL saurratod NH4C1 solution, then exa~acted 3 X 10 mL 5 96 HCl solution. The acidic extracts were basifiod using concentrated 2a NH40H solution then extracted 3 X 15 mL ether. The organic extracts were filtered through a silica gel pad thea concentrated to afford 280 mg of the free base of the desired compound as a white solid (80 R6 yield). This material was dissolved in 5 mL ethyl acetate.
Ethyl acetate saturated with HCl (5 mL) was added. 1-Phenyl-1-(4-phenyl-piperazin-1-yl)-cyclohexane dihydrochloride (Compound 1 ) which precipitated out of solution (88 mg) was collected by filtration , washod with ethyl acetate and dried in vacuo.
The following compounds were prepared essentially according to the procedure described in Examples I-II:
a) 1-(3-Methoxyphenyl)-1-(4-phenylpiperazin-1-yl)-cyclohexane dihydrochloride (Compound 2).
b) 1-(3-Methoxyphenyl~l-{4-(2-pyrimidinyl~piptrazin-1-yl]~yclohexaae dihydrochloride (Compound 3).
c) 1-(3-Methoxyphenyl}-1-[4-(2-pyridinyl)-pipetazin-I-yl]-cyclohexane dihydrochloride (Compound 4).
d) 1-(3-Methoxypheayl)-1-[4-(2-tluomphenyl~piperaan-1-yl]~yclohexane dihydrochloride (Compound ~.
e) I-(3-Methoxypheayl~l-[4-(4-fluoropheayl}-piperazin-1-yl]-cyclohexaae dihydrochloride (Compound ~.
Zr WO 96/14307 PCTIUS951144~2 1-(3-Hydroxyphenyl)-l-(4-phenylpiperazin-1-yl)-cyclohexane dihydrochloride (Compound 7).
g) 1-(3. 5-Dimethoxyphenyl)-1-(4-phenyipiperazin-1-yl)~yclohexane dihydrochloride S (Compound 8).
h) 1-(3-Ethoxyphenyl)-1-(4-phenylpiperazin-1-yl)-cyclohexane dihydrochloride (Compound 9).
~ i) 1-(3-Methoxyphenyl)-1-(4-phenylpiperazin-1-yl)-4~-phenyl~yclohexane dihydrochloride (cis isomer: Compound 10, traps isomer: Compound 11).
j) 1-(3-n-Butoxyphenyl)-1-(4-phenylpiperazin-1-yl)-cyclohexane dihydrochloride (Compound 12).
k) 1-(3-Methoxyphenyl)-1-(4-phenylpipaarin-1-yl)-4-methyl-cyclohexane dihydrochloride (cis isomer. Compound 13, traps isomer: Compound 14).
1) 1-(4-Methoxyphenyl)-1-(4-phenylpiperazin-1-yl)-cyclohexane dihydrochloride (Compound 15).
m) 1-(2-Methoxyphenyl)-1-(4-phcnylpipetazin-1-yl)-cyclohexane dihydrochloride (Compound 16).
n) 1-(3.4-Methenodioxyphenyl~l-(4-phenylpiperazin-1-yl)-cyclobexane dihydrochloride (Compound 1'n.

o) 1-(3-Ethoxyphenyl)-1-(4-phenylpiperazin-1-y1~4-methyl-cyclohexane dihydrochioride (cis isomer. Compound 18, traps isomer: Compound 19).
p) 1-(3-Ethoxyphenyl~l-(4-phenylpiperazin-1-yl)-4-ethyl-cyclohexane dihydrochloride (cis isomer: Compound 20, traps isomer: Compound 21).
1-(3-Isopropoxyphenyl~ l-(4-phenylpiperazin-1-yl)-4-methyl~yclohexane dihydrochioride (cis isomer: Compound 22, traps isomer: Compound 23).
r) 1-(3-Methoxyphenylrl-(4-phenylpipQaan-1-yl)-3-methyl- cyclohexane dihydrochloride (cis isomer: Compound 24, traps isomer: Compound 25).
s) 1-(3-Benzyioxyphenyl)-1-(4-phenyipiperazin-1-yl)-cyclohexane dihydrochloride (Compound 26).
t) 4-(3-Ethoxyphenyl)-4-(4-phenylpiperazin-1-yl)-tetrahydropyran dihydrochloride (Compound 27).
u) 4-(3-Ethoxyphenyi}-4.-(4-phenylpiperarin-1-yl~tstrahydrothiopytan dihydrochioride (Compound 28).
v) I-(3-Methoxyrtxthoxyphenylrl-(4-phenylpiperaiin-1-y1~4-methyl-cyclohexane dihydrochloride (cis isomer: Compound 29, traps isomer: Compound 30).

w) 1-(3-Ethoxymethoxyphenyl)-1-(4-phenylpiperazin-1-yl)-4-methyl-cyclohexane dihydrochloride (cis isomer: Compound 31, craps isomer: Compound 32).
x) 1-(3-Ethoxyphenylrl-(4-phenylpiperazin-1-yl)-4-methoxy-cyclohexane dihydrochloride (cis isomer: Compound 33, traps isomer. Compound 34).
The invention and the manner and process of making and using it, are now described in such full, clear, concise and exact terms 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 describes preferred embodiments 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 the subject matter regarded as invention, the following claims conclude this specification.
2~

Claims

CLAIMS:

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:
Ar is phenyl, 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, 2-, 4- or 5-pyrimidyl, each of which is optionally mono- or disubstituted with substituents independently selected from the group consisting of halogen, hydroxyl, and 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, hydroxyl, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms;

R1 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;
R5 represents straight or branched chain lower alkyl having 1-6 carbon atoms, phenyl, 2-, 3-, or 4-pyridyl, phenyl-alkyl, or, 2-, 3-, or 4-pyridyl-alkyl, in which the alkyl in the phenyl-alkyl or the 2-, 3- or 4-pyridyl-alkyl is a straight or branched chain lower alkyl having 1-6 carbon atoms; and A and R6 are the same or different and represent:
(i) 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, phenoxy, 2- 3-, or 4-pyridyloxy, or (ii) -(CH2)p-A'-(CH2)q-B' in which p is 0-5, q is 1-5, 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, phenoxy, 2-, 3-, or 4-pyridyloxy, carboxyl, alkoxycarbonyl having 1-6 carbon atoms in the alkoxy moiety, aminocarbonyl, mono- or di-alkylaminocarbonyl having 1-6 carbon atoms in each alkyl, amino or mono- or dialkylamino having 1-6 carbon atoms in each alkyl.

2. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:
Ar is phenyl, 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, 2-, 4- or 5-pyrimidyl, each of which is optionally mono- or disubstituted with substituents independently selected from the group consisting of halogen, hydroxyl, and straight or branched chain lower alkyl having 1-6 carbon atoms;
A, W, X, Y and T are the same or different and represent hydrogen, halogen, hydroxyl, straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms, benzyloxy, methoxymethoxy or ethoxymethoxy; or A and Y together form methylenedioxy;

R1 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; and Rg represents hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, methoxy or phenyl, with the proviso that Ar is as defined above, other than phenyl, 2-chlorophenyl, 2-methoxyphenyl, 2-ethoxyphenyl, 2,3-dimethylphenyl or 2-hydroxyphenyl when A, W, X, Y and T are each hydrogen, R1 and R2 are each hydrogen, R3 and R4 are each hydrogen and Rg is hydrogen.

3. The compound or salt according to claim 2, wherein A is straight or branched chain lower alkoxy having 1-6 carbon atoms.

4. The compound or salt according to claim 2 or 3, wherein W, X, Y and T are each hydrogen, R1 and R2 are each hydrogen and R3 and R4 are each hydrogen.

5. 1-(3-Methoxyphenyl)-1-(4-phenylpiperazin-1-yl)cyclohexane or a pharmaceutically acceptable salt thereof.

6. 1-(3-Methoxyphenyl)-1-[4-(2-pyrimidinyl)-piperazin-1-yl]cyclohexane or a pharmaceutically acceptable salt thereof.

7. 1-(3-Methoxyphenyl)-1-[4-(2-pyridinyl)-piperazin-1-yl]cyclohexane or a pharmaceutically acceptable salt thereof.

8. 1-(3-Methoxyphenyl)-1-[4-(2-fluorophenyl)-piperazin-1-yl]cyclohexane or a pharmaceutically acceptable salt thereof.

9. 1-(3-Methoxyphenyl)-1-[4-(4-fluorophenyl)-piperazin-1-yl]cyclohexane or a pharmaceutically acceptable salt thereof.

10. 1-(3-Hydroxyphenyl)-1-(4-phenylpiperazin-1-yl)cyclohexane or a pharmaceutically acceptable salt thereof.

11. 1-(3,5-Dimethoxyphenyl)-1-(4-phenylpiperazin-1-yl)cyclohexane or a pharmaceutically acceptable salt thereof.

12. 1-(3-Ethoxyphenyl)-1-(4-phenylpiperazin-1-yl)cyclohexane or a pharmaceutically acceptable salt thereof.

13. 1-(3-Methoxyphenyl)-1-(4-phenylpiperazin-1-yl)-4-phenylcyclohexane or a pharmaceutically acceptable salt thereof.

14. 1-(3-n-Butoxyphenyl)-1-(4-phenylpiperazin-1-yl)cyclohexane or a pharmaceutically acceptable salt thereof.

15. 1-(3-Methoxyphenyl)-1-(4-phenylpiperazin-1-yl)-4-methylcyclohexane or a pharmaceutically acceptable salt thereof.

16. 1-(4-Methoxyphenyl)-1-(4-phenylpiperazin-1-yl)cyclohexane or a pharmaceutically acceptable salt thereof.

17. 1-(2-Methoxyphenyl)-1-(4-phenylpiperazin-1-yl)cyclohexane or a pharmaceutically acceptable salt thereof.

28a

18. 1-(3,4-Methenedioxyphenyl)-1-(4-phenylpiperazin-1-yl)cyclohexane or a pharmaceutically acceptable salt thereof.

19. 1-(3-Ethoxyphenyl)-1-(4-phenylpiperazin-1-yl)-4-methylcyclohexane or a pharmaceutically acceptable salt thereof.

28b

20. 1-(3-Ethoxyphenyl)-1-(4-phenylpiperazin-1-yl)-4-ethylcyclohexane or a pharmaceutically acceptable salt thereof.

21. 1-(3-Isopropoxyphenyl)-1-(4-phenylpiperazin-1-yl)-4-methylcyclohexane or a pharmaceutically acceptable salt thereof.

22. 1-(3-Methoxyphenyl)-1-(4-phenylpiperazin-1-yl)-3-methylcyclohexane or a pharmaceutically acceptable salt thereof.

23. 1-(3-Benzyloxyphenyl)-1-(4-phenylpiperazin-1-yl)cyclohexane or a pharmaceutically acceptable salt thereof.

24. 4-(3-Ethoxyphenyl)-4-(4-phenylpiperazin-1-yl)tetrahydropyran or a pharmaceutically acceptable salt thereof.

25. 4-(3-Ethoxyphenyl)-4-(4-phenylpiperazin-1-yl)tetrahydrothiopyran or a pharmaceutically acceptable salt thereof.

26. 1-(3-Methoxymethoxyphenyl)-1-(4-phenylpiperazin-1-yl)-4-methylcyclohexane or a pharmaceutically acceptable salt thereof.

27. 1-(3-Ethoxymethoxyphenyl)-1-(4-phenylpiperazin-1-yl)-4-methylcyclohexane or a pharmaceutically acceptable salt thereof.

28. 1-(3-Ethoxyphenyl)-1-(4-phenylpiperazin-1-yl)-4-methoxycyclohexane or a pharmaceutically acceptable salt thereof.

29. The compound or salt according to claim 1, wherein:

B is sulfur, oxygen or C(R5)(R6) in which R5 is straight or branched chain lower alkyl having 1-6 carbon atoms or phenyl and R6 is hydrogen;
n is 2;
m is 2;
A is straight or branched chain lower alkoxy having 1-6 carbon atoms; and W, X, Y and T are each hydrogen.

30. The compound or salt according to claim 1 or 29, wherein:
Ar is phenyl, 2-,3- or 4-pyridyl, 2-pyrimidinyl or phenyl mono- or disubstituted with substituents independently selected from the group consisting of halogen, hydroxyl and straight or branched chain lower alkyl having 1-6 carbon atoms;
R1 and R2 are each hydrogen; and R3 and R4 are each hydrogen.

31. A pharmaceutical composition for treating an eating disorder or cardiovascular disease, which comprises;
(a) the compound or salt as defined in any one of claims 1 to 30 in an amount effective to treat such a disorder or disease, and (b) a pharmaceutically acceptable carrier, adjuvant or vehicle.

32. The pharmaceutical composition according to claim 31, which is for treating an eating disorder.

33. The pharmaceutical composition according to claim 32, wherein the eating disorder is obesity.

34. The pharmaceutical composition according to claim 32, wherein the eating disorder is bulimia.

35. The pharmaceutical composition according to claim 31, which is for treating a cardiovascular disease.

36. The pharmaceutical composition according to claim 35, wherein the cardiovascular disease is hypertension.

37. A pharmaceutical composition for treating an eating disorder or cardiovascular disease, which comprises:
(a) in an amount effective to treat such a disorder or disease, a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:
Ar is phenyl, 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, 2-, 4- or 5-pyrimidyl, each of which is optionally mono- or disubstituted with substituents independently selected from the group consisting of halogen, hydroxyl, and straight or branched chain lower alkyl having 1-6 carbon atoms;
A, W, X, Y and T are the same or different and represent hydrogen, halogen, hydroxyl, straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms, benzyloxy, methoxymethoxy or ethoxymethoxy; or A and Y together form methylenedioxy;
R1 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; and Rg represents hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, methoxy or phenyl, (b) a pharmaceutically acceptable carrier, adjuvant or vehicle.

38. The pharmaceutical composition according to claim 37, wherein the compound is 1-phenyl-1-(4-phenylpiperazin-1-yl)cyclohexane.

39. The pharmaceutical composition according to claim 37 or 38, which is for treating obesity or bulimia.

40. The pharmaceutical composition according to claim 37 or 38, which is for treating hypertension.

41. A commercial package which comprises the pharma-ceutical composition according to claim 31, 37 or 38 and a written matter which states that the pharmaceutical composition is to be used for treating an eating disorder or cardiovascular disease.

42. The commercial package according to claim 41, wherein the written matter states that the pharmaceutical composition is to be used for treating obesity or bulimia.

43. The commercial package according to claim 41, wherein the written matter states that the pharmaceutical composition is to be used for treating hypertension.