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IE922112A1 - Sigma receptor ligands and the use thereof - Google Patents

Sigma receptor ligands and the use thereof

Info

Publication number
IE922112A1
IE922112A1 IE211292A IE922112A IE922112A1 IE 922112 A1 IE922112 A1 IE 922112A1 IE 211292 A IE211292 A IE 211292A IE 922112 A IE922112 A IE 922112A IE 922112 A1 IE922112 A1 IE 922112A1
Authority
IE
Ireland
Prior art keywords
alkyl
phenyl
aryl
heteroaryl
substituted
Prior art date
Application number
IE211292A
Inventor
Richard A Glennon
Original Assignee
Univ Virginia Commonwealth
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US07/894,771 external-priority patent/US6057371A/en
Application filed by Univ Virginia Commonwealth filed Critical Univ Virginia Commonwealth
Publication of IE922112A1 publication Critical patent/IE922112A1/en

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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
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    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
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Abstract

The invention relates to methods for the treatment of central nervous system disorders, gastrointestinal disorders, drug abuse, angina, migraine, hypertension and depression by administering a pharmaceutical composition comprising an effective amount of certain sigma receptor ligands to a patient in need of such treatment. The invention further relates to novel sigma receptor ligands having high binding to the sigma receptor and pharmaceutical compositions thereof. Unexpectedly, certain of the sigma receptor ligands of the present invention have selectivity for the sigma receptor over the DA, PCP and 5-HT1A receptors.

Description

Title of the Invention SIGMA RECEPTOR LIGANDS AND THE USE THEREOF - ΙΑ 10 Field of the Invention The invention is in the field of medicinal chemistry. In particular, the invention relates to new compounds having high binding to the sigma receptor and pharmaceutical compositions thereof. These sigma receptor ligands are useful for the treatment of central nervous system disorders.
Background of the Invention Brain sigma receptors are the subject of intense investigation in light of the fact that sigma receptors bind many psychotropic drugs (Sonders et al.. Trends Neurosci. 14:37-40 (1988)). Moreover, certain sigma receptor ligands have antipsychotic activity which suggests that sigma receptor active compounds may be used for the treatment of schizophrenia (Largent et al., Eur. J. Pharmacol. 11:345-347 (1988).
Certain neuroleptic (i.e. antipsychotic) agents bind with very high affinity at sigma sites. Su, T., J. Pharmacol. Exp Ther. 223:284 (1982); Tam, S.W., Proc. Nat. Acad. Sci (USA) 80:6703 (1983). One agent with very high affinity for sigma sites (Ki ca 1 nM; i.e., approximately 100-fold higher affinity than N-allyl normetrazocine (NANM)) is the neuroleptic agent haloperidol. Tam, S.W. et al., Proc. Nat. Acad. Sci (USA) 81:5618 (1984). Sigma-opiates, such as NANM, bind with low affinity at typical opiate receptors but bind with significant affinity at PCP receptors.
Current neuroleptic agents are thought to produce their effects via a dopaminergic (DA) mechanism; they display very high affinities for DA binding sites. However, not all of the potent -2neuroleptic agents bind at [3H]NANM-labelled sigma sites, nor do the sigma-opiates bind at DA sites. This has led to the suggestion that the sites labelled by [3H]NANM be termed sigmasites and not sigma-opiate sites (i.e., it may simply be coincidental that the sigma opiates possess an opiate-like chemical structure). In addition, there has been speculation that agents with high affinity for sigma sites may either (a) produce psychotic effects (if they behave as agonists), or (b) produce antipsychotic effects (if they behave as antagonists).
It has further been speculated that certain neuroleptic agents, such as haloperidol, produce their antipsychotic effects by both a sigma and DA mechanism. Tam, S.W. and Cook, I., Proc. Nat. Acad. Sci. (USA) §1:5618 (1984). In fact, [3H]haloperidol, in combination with spiperone (an agent with high affinity for DA sites and essentially no affinity for sigma sites) is now commonly used to label sigma sites in radioligand binding studies.
A number of researchers have studied the structure-activity relationship of sigma ligands. For example, Manallack, D.T. et al., Eur. J. Pharmacol. 144:231-235 (1987), disclose a receptor model for the phencyclidine and sigma binding sites. Manallack et al. disclose that in a recent SAR study (Largent et al., in press), sigma site affinity was shown to be enhanced by large Nalkyl substituents, e.g., benzyl or phenethyl.
Largent, B.L. et al., Mol. Pharmacol. 32:772-784 (1987), disclose a study of the structural determinants of sigma receptor affinity. In particular, Largent et al. teach that several piperidine and piperazine derivatives have sigma receptor activity. Largent et al. also disclose that affinity for the sigma receptor is markedly influenced by the N-alkyl substituents, with more lipophilic substituents affording greater affinity for the sigma receptor binding sites.
Sharkey, J. et al., Eur. J. Pharmacol. 149:171-174 (1988), studied the sigma receptor binding activity of cocaine-related compounds. -3The literature contains a number of suggestions that the sigma receptor is not a single, homogeneous binding site. Bowen, W.D. et al.. Eur. J. Pharm. 163:309-318 (1989), disclose that the effect of U.V. radiation on sigma receptor binding depended on the radioligand used to assay for it. It was also demonstrated that the binding characteristics of several sigma ligands were different in membranes from certain cell lines than in guinea pig brain membranes. (Hellewell, S.B. and Bowen, W.D., Brain Res. 527:224-253 (1990); Wu, X.-Z. et al.. J. Pharmacol. Exp. Ther. 257:351-359 (1991)). At least two groups have reported significantly different pharmacology for sigma receptors when using different radioligands to label these sites. (Itzhak, Y. et al., J. Pharmacol. Exp. Ther. 257:141-148 (1991); Karbon, E.W. et al.. Eur, J, Pharm. 93:21-27 (1991)). In addition, [3H]DTG binding was found to have two components in guinea pig membranes (Rothman, R.B. et al.. Mol. Pharm. 39:222-232 (1991)). An overlap of sigma sites with some of the multiple sites labeled by [3H]dextromethorphan has also been described (Musacchio, J.M. et al.. Life Sci. 45:1721-1732 (1989)).
Hellewell and Bowen, Brain Res. 527:224-253 (1990), were the first to define the characteristics of the two putative sigma receptor substypes, named sigma-1 and sigma-2. The primary pharmacological distinction between these tow sites is the affinity of the (+) isomers of the benzomorphan opiates for the binding sites. These compounds, such as (+)SKF 10,047 and (+)pentazocine show nearly two orders of magnitude higher affinity for the sigma-1 site compared to the sigma-2 site. The (-) isomers of the benzomethorphans show little selectivity between these two sites. Other distinctions noted between the two sites are a preponderance of the sigma-2 sites in cell lines such as NCB-20, PC12 and NG108-15 cells (Hellewell, S.B. and Bowen, W.D., Brain Res. 527:224-253 (1990); Wu, X.-Z. et al.. .k Pharmacol. Exp. Ther. 257:351-359 (1991); Georg, A. and Friedl, A., J. Pharmacol. Exp. Ther. 259:479-483 (1991); Quirion, R. et al., Trends in Pharmacological Sciences 13:85-86 (1992)). -4There has been considerable research on amphetamine and amphetamine derivatives. For example, Aldous, F.A.B., J. Med.
Chem. 17:1100-1111 (1974), discloses a structure-activity study of psychotomimetic phenyl alkyl amines. Aldous et al. also disclose a number of halo, methyl, and methoxy substituted amphetamines.
Fuller, R.W. et al.. J. Med. Chem. 14:322-325 (1971), disclose amphetamine derivatives substituted on the 3- and 4positions of the aromatic ring with one or more chloro, fluoro, alkyl, phenoxy, alkoxy and hydroxy substituents.
Foye, W.O. et al.. J. Pharm. Sci. 68:591-595 (1979), disclose heterocyclic analogues of amphetamine having 2-furyl, 2thienyl, 3-methyl-2-phenol, 3-pyridyl, 6-methyl-2-pyridyl, 4chlorophenyl, and 1-naphthyl rings.
Boissier, J.R. et al.. Chem. Abstr. 66:46195h (1967), disclose N-benzyl amphetamine derivatives of the Formula (I): wherein X is methyl, CF3, methoxy, or a halogen and R is hydrogen or methyl. These compounds reportedly have anoretic activity and low toxicity. Particular compounds disclosed by Boissier et al. include N- (1 -phenyl -2-propyl) -4 -chi orobenzyl ami ne, N- (1 -phenyl -2 propyl)-4-methylbenzyl-amine, and N-(l-phenyl-2-propyl)-4methoxybenzylami ne.
Boissier, J.R. et al.. Chem. Abstr. 67:21527a (1967), disclose amphetamine derivatives of the Formula (II): CH3 (II) -5wherein R1 is hydrogen, 4-C1, 3-CI, or 3-CF3 and R2 is 2chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 3-CF3-phenyl, 4tolyl, 4-methoxyphenyl, phenyl, 2-furyl, 2-tetrahydrofuryl, 2thienyl, or 3-thienyl. Reportedly, these compounds were tested for anorexigenic activity in rats and dogs.
Osbond, J.M. et al.. Chem. Abstr. 69:51816c (1968), disclose N,N-bis-(omega-phenylalkyl)amines having the Formula (HI): wherein R1, R2, and R3 are hydrogen, chloro, CF3, or methoxy.
Gosztonyi, T. et al.. J. Label. Comp. Radiopharm. 8:293-303 (1977), disclose the preparation of N-substituted omega-haloalkyl derivatives of £-chloro amphetamine. Also disclosed, is the corresponding omega-hydroxyalkyl amine.
Coutts, R.T. et al.. Can. J. Microbiol. 26:844-848 (1980), disclose N-substituted β-chloro amphetamines having the following Formula (IV): (IV) wherein R1 is 2-butanone-3-yl, 2-hydroxybutane-3-yl, 1hydroxybutane-3-yl, or acetate.
Fuller, R.W. et al., J. Pharm. Pharmacol. £5:828-829 (1973), disclose lipid-soluble derivatives of amphetamine comprising 2-chloro, 3-chloro, 4-chloro, and beta, beta-difluoroIE 922112 -6amphetamine, and the effect thereof on amphetamine levels in the brain.
Fuller, R.W. et al.. Neuropharmacoloqy 14/.739-746 (1975), disclose 4-chloroamphetamine, 4-bromoamphetamine, and 4fluoroamphetamine and the effect thereof on serotonin metabolism.
Conde, S. et al., J. Med. Chem. 21:978-981 (1978), disclose thiophene analogues of chloroamphetamine having the following Formula (V): wherein X, Y, and Z are chloro or hydrogen, and the effect thereof on serotonin levels in the brain.
Lukovits, I., Int. J. Quantum. Chem. 20:429-438 (1981), discloses various halo, methyl, and methoxy ring-substituted amphetamines, and the inhibitory potencies thereof on phenyl ethanol amine-N-methyl transferase.
Law, B., J. Chromatoq. 407:1-18 (1987), discloses amphetamine analogues comprising 1-methyl-2-(2'naphthyl)ethylamine, N-isopropyl-2-{2'-naphthyl)ethylamine, and N-i sopropyl-2-phenylethyl ami ne.
Johansson, A.M. et al.. J. Med. Chem. 30:602-611 (1987), disclose N-substituted 2-aminotetralins of the Formula (VI): F1 (VI) kr2r3 wherein R1 is OH or OMe and R2 and R3 are H or C,-C4 lower alkyl. 35 These compounds were tested for dopamine receptor agonist and antagonist activities. -7Hacksell, U. et al.. J. Med. Chem. £2:1469-1475 (1979), disclose N-alkylated-2-aminotetralins of the Formula (VII): (VII) wherein R1 is OH or OMe, R2 is lower alkyl, and R3 is lower alkyl or phenethyl. In particular, Hacksell et al. ^disclose two aminotetralins of the Formulae (VIII) and (IX): OCH15 N n-Pr '3)2-Pfa (VIII) n-Pr (CH2)3-Ph These compounds reportedly have dopamine-receptor stimulating activity.
McDermed, J.D. et al.. J. Med. Chem. 28:362-367 (1975), disclose N-alkyl aminotetralins of the Formula (X): CO.
NR^R2 (X) wherein R1 and R2 is one of a large number or alkyl, heteroalkyl, and alkaryl groups. In particular, McDermed et al. disclose two compounds of the Formula (XI) and (XII): -Ph These compounds are reportedly dopamine receptor agonists.
Glennon, R.A. et al.. Pharmacol. Biochem. Behav. 21:895-901 (1984), disclose that 2-aminotetralin is a conformationally restricted analog of amphetamine which is about one-half as effective as racemic amphetamine.
Beaulieu, M. et al.. Eur. J. Pharmacol. 105:15-21 (1984), disclose Ν,Ν-disubstituted 2-aminotetralins of the Formula (XIII): son H H SO « C, K, so C,H, CjH, SO C,H, SO 5-H C,H, C, 5-H C»Hj CKj-CH,-© 5Λ OK K K 5.6 OH C.H, CjH, (XIII) These compounds are reportedly potent D-2 dopamine receptor agonists.
Naiman, N. et al.. J. Med. Chem. 32 :253-256 (1989), disclose 2-(alkylamino)tetralin derivatives of the Formula (XIV): (XIV) NRTr2 wherein R is H, OMe, or OBz; R1 is H, Me, or n-Pr; and R2 is H, n-propyl, benzyl, phenethyl, or phenpropyl. These compounds reportedly bind to the 5-HTu receptor site.
Beecroft, R.A.~ et al.. Tetrahedron 41:3853-3865 (1985), disclose Ν,Ν-disubstituted piperazines having the Formulae (XV)(XVIII): (XV) (XVI) (XVII) «here Ar - 1.2-Wephth/l or S-AflthryJ •»«4 Ζ « tt.Z-Ofte or (XVIII) Fuller, R.W. et al., J. Pharmacol. Exp. Therapeut. 218:636641 (1981), disclose substituted piperazines having the following Formulae (XIX) and (XX): which reportedly act as serotonin agonists and inhibit serotonin uptake or serotonin oxidation.’ Fuller, R.W. et al.. Res. Commun. Chem. Pathol. Pharmacol. £9:201-204 (1980), disclose the comparative effects on 5hydroxyindole concentration in rat brain by p-chloroamphetamine and l-(p-chlorophenol)piperazine having the following Formulae (XXI) and (XXII): (XXI) (XXII) Boissier, J. et al., Chem. Abstr. 61:10691c, disclose di substituted piperazines having the Formula (XXIII): R-'-X-N N-R2 (XXIII) wherein R1 and R2 are aryl and X is a straight or branched chain alkylene of C,-C3. The compounds are reportedly adrenolytics, hypotensors, potentiators of barbiturates, and depressants of the central nervous system. -11Roessler, Chem Abstr. 61:13328g, disclose piperazine derivatives of the Formula (XXIV): (XXIV) wherein R * H or methoxy and R1 « H, o-ethylphenyl, or pchlorophenyl.
Ruschig, H et al.. Chem. Abstr. 53:3253e, disclose a large series of N,N-disubstituted piperazines including 1-benzyl-4-(3chloro-4-methylphenyl)piperazine.
Shvedov, V.I. et al.. Chem. Abstr. 73:11806ο (1970), disclose 4-(R2CH2-CH2 substituted)-1-phenyl-piperazines wherein R2 is phenyl, 2-naphthyloxy, 3-indolyl, 2-methyl-3-indolyl or 2benzimidazolyl.
Popov, 0., Chem. Abstr. £7:54102m (1967), disclose disubstituted piperazines of the Formula (XXV): (XXV) wherein R is tolyl, fi-methoxyphenyl, m-ethoxyphenyl, betanaphthyl, jn-or β-carboxylphenyl, 3,4-dimethoxyphenyl, 5hydrindenyl, p-chloro-phenyl, £-bromophenyl, p-iodophenyl, 3,4dichlorophenyl, and m- or £-nitrophenyl.
Glennon, R.A et al.. J. Ned. Chem. 31:1968-1971 (1988), disclose various N,N-disubstituted piperazines having the Formulae (XXVI)-(XXIX): (XXVI) (XXVII) (XXVIII) (XXIX) These compounds reportedly have high affinity for the 5-HT1A serotonin binding site.
Prasad, R.N et al.. J, Med. Chem. 11:1144-1150 (1968), disclose Ν,Ν-disubstituted piperazines of the Formula (XXX): R1-N N-CH \_t R2 (XXX) «4 -13wherein R1 is phenyl or o-metboxypbenyl and R2 is 2,4dichlorophenyl, p-, m- or p- methoxyphenyl, 3,4-dimethoxyphenyl, or m-tolyl. These compounds are reported to be antihypertensive agents.
Despite the development of the above-mentioned derivatives, a need continues to exist for new sigma receptor ligands and for methods for the treatment of central nervous system disorders.
Summary of the Invention The invention relates to the discovery that certain phenyl alkyl-amine, aminotetralin, piperazine, piperidine and related derivatives have high binding to the sigma receptor and, unexpectedly, low binding for the PCP, DA and 5-HT1A receptors.
Thus, the sigma receptor ligands of the present invention can be used for the treatment of central nervous system disorders and drug abuse without the side effects of traditional neuroleptic agents which also bind to the DA and 5-HT1A receptors.
The invention also relates to the discovery that certain phenylalkyl-amines, aminotetralins, piperazines, piperidines and related derivatives have selective binding for the sigma-1 binding site while others have selective binding to the sigma-2 binding site. Compounds which bind to the sigma-1 binding site are useful in treating gastrointestinal disorders, and are not associated with dystonic effects which are associated with binding to the sigma-2 binding site. In contrast, compouds which selectively bind to the sigma-2 binding site may block calcium channels. Thus, such calcium channel blocking sigma-2 receptor ligands may be used to treat psychosis, angina, migrane and hypertension.
The sigma receptor ligands of the present invention may also be employed in methods of treating or preventing depression.
In particular, the invention relates to methods of treating a human being suffering from central nervous system disorders, drug abuse, gastrointestinal disorders, hypertension, migrane, angina and depression, which comprises administering to said -14human a therapeutically effective amount of a compound selected from the Formulae (XXXI) and (XXXII): (XXXI) R2 (XXXII) wherein said compound exhibits high binding activity with respect to the sigma receptor.
The invention also relates to certain novel sigma receptor ligands defined by Formulae (XXXI) and (XXXII) as well as pharmaceutical compositions comprising these novel sigma receptor igands.
Surprisingly, the present inventor has discovered that certain N-substituted phenyl alkyl amines, although seemingly related to amphetamine, have activities which are, in fact, very much unlike amphetamine. Instead, the N-substituted phenyl alkyl amines have high affinity to the sigma receptors and low affinity to the DA and PCP receptors. In addition, certain of the sigma receptor ligands of the present invention have unexpectedly low affinity for the 5-HT1A receptor. In addition, certain of the sigma receptor ligands of the present invention are highly selective for the sigma-1 binding site over the sigma2 binding site. The discovery of such ligands having high affinity for the sigma receptors, in particular the sigma-1 receptor, and low affinity for other such receptors allows for the treatment of psychosis, drug abuse, gastrointestinal disorders, and depression, and other conditions without untoward side effects. In contrast, compounds which are selective for the sigma-2 receptor are useful for the treatment of psychosis, hypertension, migrane and angina. -1510 Description of the Preferred Embodiments The invention relates to a method of treating a human being suffering from central nervous system disorders, drug abuse, gastrointestinal disorders, hypertension, migrane, angina and depression, which comprises administering to said human a therapeutically effective amount of a compound having the Formula (XXXI): R1 (XXXI) wherein: Ar is aryl or heteroaryl wherein aryl or heteroaryl can be substituted by hydrogen, halogen such as chloro, fluoro, bromo, iodo, CF3, C^Cg alkoxy, C2-C6 dial koxymethyl, C^-Cg alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C^Cg haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, an aryl ring fused to a substituted benzene ring, a substituted aryl ring fused to a benzene ring, a heteroaryl ring fused to a benzene ring, a substituted heteroaryl ring fused to a benzene ring, C3-C6 heterocycloalkyl, a C3-C6 heterocycloalkyl ring fused to a benzene ring, C.,-C6 alkylthio, 0,-Cg alkylsulfonyl, C^Cg haloalkylsulfonyl, C^Cg alkylsulfinyl, 0,-Cg haloalkylsulfinyl, arylthio, 0,-Cg haloalkoxy, amino, C,-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, -16C^Cg N-alkyl carbamoyl, C2-C15 Ν,Ν-dialkylcarbamoyl, nitro and C2-C15 di alkyl sulfamoyl; R is hydrogen or -C6 alkyl; R1 is independently selected from the group consisting of hydrogen, Cj-Cg alkyl, hydroxy, amino, C.,-C6 alkylamino or «0 (a double bonded oxygen); or R and R1 together form a morpholino ring; n is 0-5; W is -(CH2)p- or -Η H-, wherein p is 1-3; X is -(CH2)q-, wherein q is 1-6; -(CH2)r-CeC-(CH2)r-, wherein each r is 0-3 independently; -(CH2)r-CH«CH-(CH2)r-; Ϊ -(CH2)r-C-(CH2)r-; -(CH2)r-Y-(CH2)r-, wherein Y is 0 or S; or C^Cg alkyl (wherein Z is hydrogen); Z is hydrogen, aryl, an aryl-substituted carboxylic acid group, heteroaryl or cycloalkyl, wherein aryl, heteroaryl and cycloalkyl can be substituted by hydrogen, halogen such as chloro, fluoro, bromo, iodo; Cf3, C-pCg alkoxy, C2-C6 dialkoxymethyl, C^Cg alkyl, cyano, C3-C15 di alkyl ami noalkyl, carboxy, carboxamido, C.,C6 haloalkyl, Cj-Cg haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C^Cg alkylthio, C.,-Cg alkylsulfonyl, C1-C6 haloalkyl sulfonyl, C^Cg alkylsulfinyl, C^-Cg haloalkyl sulfinyl, arylthio, C.,-C6 haloalkoxy, amino, Cj-Cg alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, Cj-Cg N-alkylcarbamoyl, C2-C15 N,N-dialkyl30 carbamoyl, nitro, C2-C15 di alkyl sulfamoyl or an ortho methylene dioxy group; wherein said compound exhibits high binding activity with respect to the sigma receptors.
The invention also relates to methods of treating central nervous system disorders, drug abuse, gastrointestinal disorders, hypertension, migrane, angina and depression, using compounds having the Formula (XXXIII): -17R R I I T— (CH)n-N-X-Z (XXXIII) N-(3-phenylpropyl)-3-(3N-(3-phenylpropyl)-3-(4N-(3-phenylpropyl)-3-(3,4N-(3-phenylpropyl )-3-(4N-(3-phenylpropyl)-3-(3wherein T is a cycloalkyl group or Ar as described above, n, R, and R1, X and Z are defined above; wherein said compound exhibits high binding activity with respect to the sigma receptors.
Especially preferred compounds within the scope of Formula (XXXIII) include N-phenethyl-l-phenyl-isopropylamine, Nphenylpropyl-1-phenyl isopropylamine, N-(2-phenoxyethyl)-1phenyli sopropy1 amine, N-(3-phenyl-3-propanon-l-yl)-lphenylisopropylamine, N-(4-phenylbutyl)-l-phenylisopropylamine, N-(3-(1-naphthyl) propyl )-1-phenyl isopropylamine, N-(3-(2naphthyl)propyl)-l-phenylisopropylamine, N-(3-phenyl-2-propyn-lyl)-l-phenylisopropylamine, N-(3-phenyl propyl)-3-(4hydroxyphenyl)i sopropy1 amine, N-(3-phenylpropyl)-3-(4methoxyphenyl) isopropylamine, bromophenyl)isopropylamine, bromophenyl)isopropylamine, dichlorophenyl)isopropylamine, iodopheny1)isopropylamine, tri f 1 uoromethyl -phenyl) i sopropyl amine, N-(2-phenethyl) -N-methyl 1 -phenyli sopropyl-amine, N-(3-phenyl propyl )-1-phenyl propan-1-one2-amine, N-(2-indane)-3-phenylisopropylamine, N-(2-indane)-3phenylpropyl amine, N,N-di-({3-phenyl)propyl)amine, N-(2-(lnaphthyl)ethyl)-l-phenylisopropylamine,N-(2-(2-naphthyl)ethyl) 1 - phenyli sopropylamine, N-(2-(l-naphthyl)propy1)-1phenylisopropylamine, N-(2-(2-naphthyl)propyl)-lphenyl i sopropylami ne, N-(3-phenyl propyl) -1-phenyl -2-pentyl ami ne, N-(3-phenylbutyl)-l-phenyl-2-butylamine, N,N-di-(2-ethyl phenylJmethylamine, Ν,Ν-dibenzylamine, N-(3-phenylpropyl)-N-(6phenylhexyl) amine,N-(3-phenylpropyl)-N-(5-phenylpentyl) amine,Npropyl-N-methyl-5-phenylpentyl amine, N-methyl-N-(3-phenylpropyl)1 - isopropyl amine, N-methyl-N-(3-methyl-2-butenyl)-1isopropylamine, N-methyl-N-(3-methylbutyl)-l-isopropylamine, N35 -ιβio phenyl pentyl amine, phenyl pentyl amine, phenyl pentyl amine, methyl-N-(3-phenylbutyl )-1-phenyl-2-pentylamine, N-propyl-N-(3phenyl)propyl)-1-phenyl-2-propylamine, N-benzyl -N- (3phenyl)propyl)-l-phenyl-2-propyl amine, N-phenyl-(5phenyl)pentyl amine, N-methyl-N-(3-phenyl)propyl-5N-(2-(o-methylphenyl)ethy1)-5N -(2-(m-methylphenyl)ethyl)-5N -(2 -(p-methylphenyl)ethyl)-5phenylpentylamine, N-benzyl-5-phenylpentylamine, N-benzyl-Nmethyl-5-phenylpentyl amine, N-(2-(3-hydroxyphenyl)ethyl)-5phenylpentylamine, N- (2 -(2-hydroxyphenyl)ethyl) - 5phenylpentyl amine, N,N' -diethyl-2-(diphenylacetoxy)ethyl amine, N,N'-diethyl-2-(fluorenecarboxy)ethylamine, N,N-Dimethyl-5phenylpentyl amine, N-Benzyl -N-(3-phenylpropyl)-1-phenyl-2propylamine, N-Benzyl-N-methyl-5-phenylpentylamine, N-Benzyl-5phenylpentyl amine, and N-(2-phenethyl)-N-methylpentyl amine.
The invention also relates to methods of treating central nervous system disorders, drug abuse, gastrointestinal disorders, hypertension, migrane, angina and depression, with compounds related to Formula (XXXII) where W is -(CH2)p- having the Formula (XXXIV): (XXXIV) wherein said compound exhibits high binding activity with respect to the sigma receptors.
The invention also relates to methods of treating central nervous system disorders, drug abuse, gastrointestinal disorders, hypertension, migrane, angina and depression, with compounds of the Formula (XXXII): (XXXII) wherein X and Z are as defined above and V is N or -CM-, wherein M is hydrogen, C^Cg alkyl, C^Cg alkoxy, hydroxy, fluoro, chloro, bromo, trifluoromethyl, or represents one half of a double bond (with the neighboring endocyclic carbon); R2 is independently selected from the group consisting of hydrogen, chloro, fluoro, bromo, iodo, CF3, (q-Cg alkoxy, C2-C6 di alkoxymethyl, C^-Οθ alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C,-C6 haloalkyl, C^Cg haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, Cj-Cg alkylthio, Cj-Cg alkylsulfonyl, ί,-Cg haloalkyl sulfonyl, C.,-C6 alkylsulfinyl, C^Cg haloalkyl sulfinyl, arylthio, C^Cg haloalkoxy, amino, C.,-C6 alkylamino, dialkylamino, hydroxy, carbamoyl, C^Cg Nalkylcarbamoyl, C2-C15 Ν,Ν-dialklcarbamoyl, nitro and C2-C15 di alkyl sulfamoyl; and wherein said compound exhibits high binding activity with respect to the sigma receptors.
Preferably, the invention relates to the treatment of central nervous system disorders, drug abuse, gastrointestinal disorders, hypertension, migrane, angina and depression, with a piperidine derivative having Formula (XXXV): (XXXV) wherein R , X and Z are as defined above.
The invention also relates to the treatment of central nervous system disorders, drug abuse, gastrointestinal disorders, hypertension, migrane, angina and depression, with compounds having the Formula (XXXIX): (XXXIX) wherein R2, Μ, X and Z are as defined above; U is selected from the group consisting of hydrogen, halogen such as chloro, fluoro, bromo, iodo; CF3, Ο,-Cg alkoxy, C2-C6 dialkoxymethyl, C^Cg alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C.,-Cg haloalkyl, C^-Cg haloal kylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-Cg acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, an aryl ring fused to a substituted benzene ring, a substituted aryl ring fused to a benzene ring, a heteroaryl ring fused to a benzene ring, a substituted heteroaryl ring fused to a benzene ring, C3C6 heterocycloalkyl, a C3-C6 heterocycloalkyl ring fused to a benzene ring, C^Cg alkylthio, C^Cg alkylsulfonyl, C^Cg haloalkylsulfonyl, C.,-C6 alkylsulfinyl, C^-Cg haloalkyl sulfinyl, arylthio, Cj-Cg haloalkoxy, amino, Cj-Cg alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C,-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkyl carbamoyl, nitro and C2-C15 di alkyl sulfamoyl; wherein said compound exhibits high binding activity with respect to the sigma receptors.
The invention also relates to a method of treating a human being suffering from central nervous system disorders, drug abuse, gastrointestinal disorders, hypertension, migrane, angina and depression, which comprises administering to said human a therapeutically effective amount of a compound of the Formula (XXXVa): (XXXVa) wherein: R3 is selected from the group consisting of C^-Cg alkyl, C^Cg alkenyl, C2-C6 dialkoxymethyl, C3-C15 di alkyl aminoal kyl, aralkyl, C3-C6 cycloalkyl, aroyl, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl; and X, Y and Z are defined above, wherein said compound exhibits a high binding activity with respect to the sigma receptors.
Especially preferred compounds within the scope of Formula (XXXVa) include N-methyl -N'-(4-phenyl-3-(E)butenyl)piperazine, Nmethyl-N'-(4-phenyl-3-(Z)butenyl)-piperazine,N-methyl-N'-(4-(3trifuoromethylphenyl )-3-(Z)butenyl) piperazine, N-methyl-N'-(4phenylbutyl)piperazine, N-benzyl-Ν'-(4-phthalimidobutyl) piperazine, N-(2-methoxyphenyl)-N'-(4-phthalimidobutyl) piperazine, N-(5-phenylpentyl)-4-benzylpiperidine, N-(5phenylpentyl)-4-benzyl-4-hydroxy-piperidine, N-benzyl-N'-(5phenyl)pentylpiperazine and N,N'-di-(5-phenyl)pentylpiperazine.
The invention also relates to a method of treating a human being suffering from central nervous system disorders, drug abuse, gastrointestinal disorders, hypertension, migrane, angina and depression, which comprises administering to said human a therapeutically effective amount of a compound of the Formula (XXXVb): N-X-Z (XXXVb) -22wherein: R4 is hydrogen or an aryl group substituted with a group selected from the group consisting of C^-Cg alkyl, Cj-Cg alkenyl, C2-Cg dialkoxymethyl, C3-C15 dialkylaminoalkyl, aralkyl, C3-C6 cycloalkyl, aroyl, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl; R5 is hydrogen or hydroxy; and X, Y and 1 are defined above, wherein said compound exhibits a high binding activity with 10 respect to the sigma receptors.
Examples of compounds having Formula (XXXVb) include but are not limited to N-(5-phenylpentyl)piperidine, N-(8phenylheptyl)piperidine, N-(5-(4-methoxyphenyl)pentyl)piperidine, N-(3-phenylpropyl)pi peridine, N-(5-cyclohexyl) pentyl pi peri dine N-benzylpi peridine, N-(2-phenethyl )-4-hydroxy-4-phenyl pi peri dine N-(2-phenethyl)-4-hydroxy-4-t-butylpiperidine, N-(5-(4chlorophenyl)-5-pentanon-l -yl) pi peri dine, N-(5-(4-chlorophenyl) 5-pentanon-l-yl)-4-phenyl piperidine, N-(5-(4-methoxyphenyl)-5pentanon-l-yl) pi peridine, N-(5-(4-methoxyphenyl)-5-pentanon-120 yl )-4-phenylpiperidine, N-(5-(4-methoxyphenyl)pentyl)-4phenylpiperidine, N-(5-phenyl-5-pentanon-l-yl)-4-phenylpi peri dine N-(5-(4-chlorophenyl) pentyl)-4-phenylpi peridine, N-(5-(3methoxyphenyl)-5-pentanon-l-yl)piperidine, N-(5-(3-chlorophenyl)5-pentanon-l-yl) pi peridine, N-(5-(3-chlorophenyl) - 5-pentanon-l25 yl )-4-phenylpiperidine,N-(5-(3-methoxyphenyl)-5-pentanon-l-yl) 4-phenylpiperidine, N-(4-(4-fluorophenyl)-4-butanon-lyl) pi peridine, N-(5-(4-fluorophenyl)-5-pentanon-1-yl) piperidine N-(5-(4-fluorophenyl)-5-pentanon-l-yl)-4-phenylpiperidine,N-(5(4-fluorophenyl)-5-pentanon-1-yl )-4-(3-chlorophenyl)-430 hydroxypiperidine, N-(5-(4-chlorophenyl)-5-pentanon-l-yl)-4-(4fluorophenyl)-1,2,3,6-terahydropyridine, N-(5-(4-chlorophenyl)-5pentanon-l-yl)-4-(4-fluorophenyl)piperidine, N-(5 - (4chlorophenyl)-5-pentanon-1-yl)-4-(4-fluorophenyl)-1,2,3,6terahydropyridine, N-(5-(4-chiorophenyl)-5-pentanon-1-yl)-4-(435 fluorophenyl)-piperidine, N-(5-(4-chlorophenyl)-5-pentanon-1-yl)IE 922112 -234-(chloropheny1)-1,2,3,6-terahydropyridine, N-(5-(4chlorophenyl)-5-pentanon-l-yl)-4-(chlorophenyl) piperidine N - (5- (3,4-dichlorophenyl)-5-pentanon-l-yl)-4-(chlorophenyl) piperidine, N-(5-cyclopentylpentan-5-on-l-yl)piperidine and N-(5-(3,4-methylenedioxyphenyl)penta-2,4-dienyl) piperidine.
The invention also relates to a method of treating a human being suffering from central nervous system disorders, drug abuse, gastrointestinal disorders, hypertension, migrane, angina and depression, which comprises administering to said human a therapeutically effective amount of a compound of the Formula (XXXVc): N-X-Z (XXXVc) wherein X and Z are defined above, wherein said compound exhibits a high binding activity with respect to the sigma receptors.
An example of a compound having Formula XXXVc is N-(5phenyl) pentyl-3-azabicyclo[3.2.2]nonane.
The invention also relates to a method of treating a human being suffering from central nervous system disorders, drug abuse, gastrointestinal disorders, hypertension, migrane, angina and depression, which comprises administering to said human a therapeutically effective amount of a tropane derivative of the Formula (XXXVd): (XXXVd) wherein said compound exhibits a high binding activity with respect to the sigma receptors.
An example of compounds having Formula (XXXVd) include N(5-phenyl)pentyl-4-phenyltropan-4-ol.
The invention also relates to the treatment of central nervous system disorders, drug abuse, gastrointestinal disorders, hypertension, migrane, angina and depression, by administering a compound related to those of Formula XXXIII and having the Formula (XXXVI): -2415 (XXXVI) R2 wherein a is 1-8; b is 1-8; R is as defined above; wherein said compound exhibits high binding activity with respect to the sigma receptors.
Preferably, compounds which are useful for the treatment of central nervous system disorders, drug abuse, gastrointestinal disorders, hypertension, migrane, angina and depression, and which are within the scope of Formula (XXXI) are naphthyl derivatives having Formula (XXXVII): wherein R, R2, a ’and b, as defined above, may be the same or different; wherein said compound exhibits high binding activity with respect to the sigma receptors. -25Other compounds useful for the treatment of central nervous system disorders, drug abuse, gastrointestinal disorders, hypertension, migrane, angina and depression, include morpholino derivatives having Formula (XXXVIII): CHp / \ ch9 I I Ar-CH-CH2-N-X-Z (XXXVIII) wherein Ar, X and Z are defined above; wherein said compound exhibits high binding activity with respect to the sigma receptors.
Other compounds useful for the treatment of central nervous system disorders, drug abuse, gastrointestinal disorders, hypertension, migrane, angina and depression, include cycloalkyl derivatives having Formula (LII) R1 R I I Cy-(CH)n -N-X-Z (LII) wherein Cy is C3-C8 cycloalkyl and Ar, R1, n, R, X, and Z are defined as above. Examples of compounds having Formula LII include 5 - cy c I o hexy 1 pe n ty 1 am i n e , N-methyl-5cyclohexylpentyl ami ne, N,N-Dimethyl -5-cyclohexylpentyl ami ne, N-cyclohexyImethyI-5-cyclohexyl-n-pentylamine, and Ncyclohexylmethy1-N-methyl - 5-cyclohexyl-n-pentyl amine.
Other compounds useful for the treatment of central nervous system disorders, drug abuse, gastrointestinal disorders, hypertension, migrane, angina and depression, includes compounds of the Formula (LIII) (LIII) ΙΕ 922112 -26wherein X1 is -(CH2)r-CeC-(CH2)r-, wherein each r is 0-3 independently; - (CH2)r-CH-CH-(CH2)r-; I -(CH2)r-C-(CH2)r-; -(CH2)r-Y-(CH2)r-, wherein Y is 0 or S; or -C6 alkyl (wherein Z is hydrogen); and R2, V, X, and Z are defined as above. 1C Other compounds useful for the treatment of central nervous system disorders, drug abuse, gastrointestinal disorders, hypertension, migrane, angina and depression, includes compounds of the Formula (LIV): R6 I 7 R5-N-X-R7 (LIV) wherein R and R are independently a C^g alkyl group, R is 20 hydrogen or a C^g alkyl group substituted by an aryl acetoxy group, and X is as defined above. Examples of such compounds include but are not limited to N,N'-diethyl-2(diphenylacetoxy)ethyl amine and N,N'-diethyl-2-(9fluorenylcarboxy)ethyl amine.
The invention is also related to the discovery that the aryl rings of compounds having Formula (LIV) may be missing, and that the compounds still retain high binding to the sigma receptor (Formula (LIV), R7 * hydrogen). Such compounds include Ν,Ν-dimethyl-n-hexylamine and N-methyl-N-propylhexyl-amine.
The sigma receptor ligands of the present invention may exist in racemic form or in the optically active stereoisomeric form. Most preferably, the compounds exist in the S-(+) form.
The invention also relates to certain novel sigma receptor 35 ligands and pharmaceutical compositions comprising the novel sigma receptor ligands. In particular, the invention relates to compounds having the Formula (XXXI): iO -27R R I CH-N-X-Z (XXXI) wherein Ar n, R, R1, W and Z are as defined above and X is -(CH2)q-, wherein q is 3-6; -(CH2)r-Cs£-(CH2)r-, wherein each r is 0-3 independently; -(CH2)r-CH=CH-(CH2)r-; I! -(CH2)r-C-(CH2)r-; -(CH2)r-Y-(CH2)r-, wherein Y is 0 or S; or C-,-C6 alkyl (wherein Z is hydrogen); wherein said compound exhibits high binding activity with respect to the sigma receptors.
Sigma receptor ligands having the above Formula (XXXI) wherein q is 3-6 have unexpectedly high binding to the sigma receptors (see Example 2, below). Preferably, q is 5.
The invention also relates to sigma receptor ligands having the Formula (XXXIII): R1 R T— (CH)n-N-X-Z (XXXIII) wherein T, n, R, R1, and Z are defined above, and X is -(CH2)q-, wherein q is 3-6; -(CH2)r-CaC-(CH2)r-, wherein each r is 0-3 independently; -(CH2)r-CH=CH-(CH2)r-; S -(CH2)r-C-(CH2)r-; -(CH2)r-Y-(CH2)r-, wherein Y is O or S; or -28Cj-Cg alkyl (wherein Z is hydrogen); wherein said compound exhibits high binding activity with respect to the sigma receptors.
Sigma receptor ligands having the above Formula (XXXV) wherein q is 3-6 also have unexpectedly high binding to the sigma receptors (see Example 2). Most preferably, q is 5.
The invention also relates to compounds of the Formula (XXXII): R' (XXXII) wherein R2, V and Z are as defined above; X is -(CH2)r-(X-(CH2)r-, wherein r is 0-3; -(CH2)r-CH=CH-(CH2)r-; -(CH2)r-C-(CH2)r-; -(CH2)r-Y-(CH2)r-, wherein Y is 0 or S; or C^Cg alkyl (wherein Z is hydrogen); wherein said compound exhibits high binding activity with respect to the sigma receptors.
Sigma receptor ligands having the above Formula (XXXII) wherein q is 3-6 also have unexpectedly high binding to the sigma receptors (see Example 2).
The invention also relates to compounds of the Formula (XXXV): N-X-Z (XXXV) -29wherein R2 and Z are as defined above; X is -(CH2)r-CsC-(CH2)r-, wherein each r is 0-3 independently; -(CH2)r-CH=CH-(CH2)r-; I -(CH2)r-C-(CH2)r-; -(CH2)r-Y-(CH2)r-, wherein Y is 0 or S; or C^Cg alkyl (wherein Z is hydrogen); wherein said compound exhibits high binding activity with respect to the sigma receptors.
Sigma receptor ligands having the above Formula (XXXV) also have unexpectedly high binding to the sigma receptors (see Example 2).
The invention also relates to compounds which are related 15 to the Formula XXXII and having the Formula (XXXIX): (XXXIX) wherein R2, Μ, X and Z are as defined above; U is selected from the group consisting of hydrogen, halogen such as chloro, fluoro, bromo, iodo; CF3, C^Cg alkoxy, C2-C6 dialkoxymethyl, C^Cg alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C^Cg haloalkyl, £q-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, an aryl ring fused to a substituted benzene ring, a substituted aryl ring fused to a benzene ring, a heteroaryl ring fused to a benzene ring, a substituted heteroaryl ring fused to a benzene ring, C3C6 heterocycloalkyl, a C3-C6 heterocycloalkyl ring fused to a benzene ring, C^Cg alkylthio, 0,-Cg alkylsulfonyl, Cj-Cg haloalkyl sulfonyl, C^Cg alkylsulfinyl, Cj-Cg haloalkylsulfinyl, arylthio, C.,-C6 haloalkoxy, amino, C^Cg alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, Cj-Cg N-alkylcarbamoyl, C2-C15 Ν,Ν-dialkylcarbamoyl, nitro and C2-C15 dial kylsulfamoyl; wherein said compound exhibits high binding activity with respect to the sigma receptors.
The invention also relates to a compound of the Formula (XXXVa): (XXXVa) wherein: R3 is selected from the group consisting of Cj-Cg alkyl, C^Cg alkenyl, C2-C6 dialkoxymethyl, C3-C15 dialkylaminoalkyl, aralkyl, C3-Cg cycloalkyl, aroyl, C2-C6 acyl, aryl, substituted aryl, alkaryl, substituted alkaryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl; and X, Y and Z are defined above, wherein said compound exhibits a high binding activity with respect to the sigma receptors.
The invention also relates to a compound of the Formula (XXXVb): N-X-Z (XXXVb) wherein: R4 is hydrogen or an aryl group substituted with a group selected from the group consisting of C^Cg alkyl, C.,-Cg alkenyl, C2-C6 di alkoxymethyl, C3-C15 dialkylaminoalkyl, aralkyl, C3-Cg cycloalkyl, aroyl, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl; R5 is hydrogen or hydroxy; and X, Y and Z are defined above, wherein said compound exhibits a high binding activity with respect to the sigma receptors. -31The invention also relates to a compound of the Formula (XXXVc): (XXXVc) wherein X and Y are defined above, wherein said compound exhibits a high binding activity with respect to the sigma receptors.
The invention also relates to a tropane derivative of the Formula (XXXVd): (XXXVd) wherein R4, R5, X and Z are defined above, and wherein said compound exhibits a high binding activity with respect to the sigma receptors·.
The invention also relates to a compound of the Formula (XXXVI): wherein a is 1-8; b is 1-8; R is hydrogen or ί,-ίθ alkyl; -32R2 is independently selected from the group consisting of hydrogen, chloro, fluoro, bromo, iodo, CF3, C^Cg alkoxy, C2-C6 dialkoxymethyl, C^-Cg alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C^Cg haloalkyl, C^Cg haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-Ce carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C^Cg alkylthio, C-pCg alkylsulfonyl, C^-Cg haloalkylsulfonyl, C^Cg alkylsulfinyl, C^Cg haloalkylsulfinyl, arylthio, C.,-C6 haloalkoxy, amino, C.,-C6 iO alkyl-amino, dialkylamino, hydroxy, carbamoyl, C^Cg Nalkylcarbamoyl, C2-C15 Ν,Ν-dialklcarbamoyl, nitro and C2-C15 di alkyl sulfamoyl; wherein said compound exhibits high binding activity with respect to the sigma receptors.
The invention also relates to naphthyl derivatives within the scope of Formula (XXXI) having Formula (XXXVII): (XXXVII) R1 wherein R, R1, a and b, as defined above, may be the same or different; wherein said compound exhibits high binding activity with respect to the sigma receptors.
The invention also relates to morpholino derivatives having Formula (XXXVIII): CH, / \ CH, Ar-CH-CH-L x-z (XXXVIII) wherein Ar, X and Z are defined above; wherein said compound exhibits high binding activity with respect to the sigma receptors. -33Also as derivatives of compound XXXIII, this invention is concerned with a compound having the Formula (LII) R1 R I I Cy- (CH)n -N-X-Z (LII) wherein Cy is C3-C8 cycloalkyl and Ar, R1, n, R, X, and Z are defined as above.
Compounds derived from the Formula XXXII are also an aspect of the present invention. These compounds include a compound of the Formula (LIII) R20 (LIII) wherein X1 is -(CH2)r-Cs£-(CH2)r-, wherein each r is 0-3 independently; -(CH2)r-CH=CH-(CH2)r-; Ii -(CH2)r-C-(CH2)r-; -(CH2)r-Y-(CH2)r-, wherein Y is 0 or S; or C-|-C6 alkyl (wherein Z is hydrogen); and R2, V, X, and Z are defined as above.
The invention also relates to compounds having the Formula (LIV): R R5 and R6 are independently a CV8 alkyl group, R7 is hydrogen or a Cj.g alkyl substituted by an aryl acetoxy or arylcarboxy group, and X is as defined above. Examples of compounds having Formula LIV include Ν,Ν-dimethyl-n-hexylamine, N-methyl-N-propylhexylamine, N,N'-diethyl-240 -34(di phenylacetoxy)ethylamine, N,Ν'- diethyl- 2 (fluorenecarboxy)ethyl amine, N,N-diethyl-2(diphenylacetoxyjethylamine and Ν,Ν-diethyl-2-(9f1uorenylcarboxy)ethyl ami ne.
The compounds of the invention have high binding to the sigma receptors. The sigma receptors include both the sigma-1 and sigma-2 subtypes. See Hellewell, S.B. and Bowen, W.D., Brain Res. 527:224-253 (1990); and Wu, X.-Z. et al.. J, Pharmacol. Exp. Ther. 257:351-359 (1991). A sigma receptor binding assay which quantitates the binding affinity of a putative ligand for both sigma sites (against 3H-DTG, which labels both sites with about equal affinity) is disclosed by Weber et al.. Proc. Natl. Acad. Sci (USA) 83:8784-8788 (1986). Alternatively, [3H]pentozocine may be used to selectively label the sigma-1 binding site in a binding assay. A mixture of [3H]DTG and unlabeled (+)pentazocine is used to selectively label the sigma-2 site in a binding assay. The present invention is also directed to certain ligands which are selective for the sigma-1 and sigma-2 receptors. The discovery of such ligands which are selective for one of the two sigma receptor subtypes may be an important factor in identifying compounds which are efficacious in treating central nervous system disorders with minimal side effects.
Typical C,-C6 alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl and hexyl groups.
Typical C3.8 cycloakyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
Typical C2-C6 carboxylic acyl groups include acetyl, propanoyl, i-propanoyl, butanoyl, s-butanoyl, pentanoyl and hexanoyl groups.
Typical aryl groups include phenyl, naphthyl, phenanthryl, anthracyl and fluorene groups.
Typical aryl-substituted carboxylic acid groups include the above-mentioned carboxylic acyl groups substituted by one or more aryl groups, e.g. di phenylacetoxy and fluorenecarboxy groups. -35Typical alkaryl groups include the above-listed aryl groups substituted by one or more Cj-Cg alkyl groups.
Typical aralkyl groups include a 0,-Cg alkyl group substituted by one of the above-listed aryl groups, e.g. phenethyl, phenyl propyl, phenyl butyl, phenyl pentyl and phenyl hexyl groups as well as the branched chain isomers· thereof.
Typical -C6 alkoxycarbonyl groups include carbonyl substituted by methoxy, ethoxy, propanoxy, i-propanoxy, nbutanoxy, t-butanoxy, i-butanoxy, pentanoxy, and hexanoxy groups.
Typical aralkyl groups include the above-listed Cj-Cg alkyl groups substituted by phenyl, naphthyl, phenanthryl, and anthracyl groups.
Typical C2-C6 alkenyl groups include vinyl, allyl, 2butenyl, 2-pentenyl, and 2-hexenyl groups.
Typical C2-C6 alkynyl groups include acetynyl and propargyl groups.
Typical halo groups include fluorine, chlorine, bromine and iodine.
Typical aroyl groups include carbonyl substituted by phenyl, naphthyl, phenanthryl, and anthracyl groups.
Typical aralkanoyl groups include carbonyl substituted by the above-listed aralkyl groups.
Typical aralkoxy groups include the above listed C^Cg alkoxy groups substituted by phenyl, naphthyl, phenanthyl, and anthracyl groups.
Typical substituted aryl groups include the above-listed aryl groups substituted by halo, hydroxy, -C6 alkoxy, amino, and the like.
Typical heteroaryl groups include furyl, thienyl, pyrrolyl, 30 thiazolyl, pyridyl, pyrimidinyl, pyrizinyl, oxazolyl and phthalimido groups which may be fused to a benzene ring.
Typical substituted heteroaryl groups include the abovelisted heteroaryl groups substituted by halo, C^Cg alkyl and the like. -36Typical C5-C6 heterocycloalkyl groups include tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholino and pyrrolidinyl groups.
Under the binding activity studies, an IC50 value of at most about 100 nM, preferably at most about 25 nM, more preferably at most 10 nM, most preferably at most 1 nM indicates a high binding affinity with respect to the sigma receptor binding sites. In the present application, the term high affinity” is intended to mean a compound which exhibits an IC50 of less than 100 nM in a sigma receptor binding assay, preferably against 3H-DTG as disclosed by Weber et al.. Proc. Natl. Acad. Sci (USA) 83:8784-8788 (1986), which measures the binding affinity of compounds toward both the sigma-1 and sigma-2 sites. Especially preferred sigma ligands exhibit IC50 values of less than about 25 nM, more preferably less than about 10 nM, most preferably less than about 1 nH against 3H-DTG.
The inventor has unexpectedly discovered that certain of the sigma receptor ligand of the present invention exhibit enhanced selectivity to the sigma-1 binding site while other of the sigma receptor ligands exhibit enhanced selectivity to the sigma-2 binding site. Selective binding to the sigma-1 binding site is associated with various gastrointestinal effects, inhibition of contraction of the guinea pig ileum, and inhibition of acetylcholine-induced phosphoinositide response. In contrast, compounds which exhibit selective binding to the sigma-2 receptor are associated with dystonia and may block calcium channels. See Quiron et al., Trends Pharm. Sci. 13:85-86 (1992); Rothman et al.. Hoi. Pharmacol. 39:222-232 (1991). Thus, the compounds of the present invention which are selective for the sigma-1 receptor may be used for, in addition to the treament of psychosis, the treatment or prevention of gastrointestinal disorders such as emesis, colitis and the like, without any untoward dystonia. In addition, the compounds of the present invention which are selective for the sigma-2 receptor may be used for treating psychosis and conditions which are ameliorated by calcium channel blockers, e.g. hypertension, migrane and -37angina. Compounds which are selective for the sigma-2 receptor are known to produce dystonia. However, antagonists of the sigma-2 receptor are expected to be effective in treating hypertension, migrane and angina without dystonic side effects.
Preferably, compounds which are selective for the sigma-1 receptor compared to the sigma-2 receptor have an IC50 ratio of sigma-l/sigma-2 of less than about 0.1 (see Table 10). Such compounds include, but are not limited to (+) N-(1-phenyl-2propyl}-4-phenylbutylamine, R(-) N-(1-phenyl-2-propyl)-3-(210 naphthylJpropylamine, (+) N-[l-(l'-Naphthyl)-2-propyl]-3phenylpropylamine, 4-Hydroxy-4-phenyl-1-(3phenylpropyl) pi peri dine, N-(4-phenyl butyl) phenethyl amine, Di-N[3-(2'-naphthyl) propyl-N-methylami ne, N-(4-phenyl butyl) benzylamine, N-(5-phenylpentyl)-(4-phenyl)butylamine, N-(515 phenyl pentyl) benzyl amine,N-(4-phenylbutyl)-N'-benzyl piperazine, N-4(4-phenylbutyl)-N'-benzoyl piperazine, N-(3-phenylpropyl)-1 -(pethoxyphenyl)-2-propylami ne,N-(5-phenyl pentyl) phenethyl amine,N(7-phenylheptyl)benzyl amine,N-(7-phenyl heptyl)phenethylamine,N(5-cyclohexyl pentyl) benzyl amine, N-(4-phenyl butyl) -1-phenyl-220 butylamine, N-(4-phenyl-3(E)-butenyl)-N'-methyl piperazine, N-(4phenyl -3(Z)-butenyl)-N'-methylpiperazine, N-(4-(3-trifluoromethyl )-3-(Z)-butenyl)-N-methylpiperazine, N-(4-phenyl)-N'methylpiperazine, N-(5-phenylpentyl)-3-phenylpropylamine, Nmethyl-N-propyl-5-phenylpentylamine, N-Methyl-N-(3-phenylpropyl)25 1-phenylisopropylamine, N-(5-phenylpentylJpiperidine, N,NDimethyl-5-phenylpentylamine, 5-cyclohexylpentylamine, N-methyl5-cyclohexylpentylamine, Ν,Ν-Dimethyl -5-cyclohexylpentylamine, and N-Benzyl-N-methyl-5-phenylpentylamine.
Preferably, compounds which are selective for the sigma-2 receptor compared to the sigma-1 receptor have a ratio of sigmal/sigma-2 of greater than about 10 (see Table 10). Such compounds include, but are not limited to N-phenyl-N'-(3-(1phthalimido)propyl)-piperazine, and N-(4-phthalimido)butyl-N'phenylpiperazine. N-(5-phthalimi do)pentyl-N'-phenyl piperazine i s also expected to be highly selective for sigma-2. -38Surprisingly, the inventor has also discovered that the sigma receptor ligands of the present invention exhibit low affinity to the DA and PCP receptors. In addition, certain of the sigma receptor ligands of the present invention also exhibit low affinity for the 5-HT1A receptor. Thus, the sigma receptor ligands of the present invention may be used for the treatment of central nervous system disorders without the untoward side effects associated with unwanted binding at the DA, PCP and/or 5HT1A receptors. By the term low affinity is intended a binding affinity of >100 nM, more preferably, >1000 nM in a DA, PCP or 5HT1A binding assay. Especially preferred sigma receptor ligands have high binding to the sigma receptor and low binding to the DA, PCP and/or 5-HT1A receptors, as defined herein.
By the term central nervous system disorder is intended both psychiatric and movement dysfunctions. The selective sigma ligands of the present invention may be used to treat psychiatric disorders including psychoses, such as schizophrenia and related disorders, mania with psychotic features, major depression with psychotic features, organic psychotic disorders and other idiopathic psychotic disorders, in addition to anxiety disorders and depression. The term schizophrenia is intended to include any of a group of severe emotional disorders, usually of psychotic proportions, characterized by misinterpretation and retreat from reality, delusions, hallucinations, ambivalence, inappropriate affect, and withdrawn, bizarre, or regressive behavior. See Dorland's Illustrated Medical Dictionary. 26th edition, W.B. Saunders Company, Philadelphia, Pa., pp. 1171 (1981). The sigma receptor ligands of the present invention can also be used in treating movement disorders such as Parkinson's disease, tardive dyskinesia, and dystonias. See J.M. Walker et al., Pharmacol, Rev. 42:355-402 (1990), the disclosure of which is fully incorporated by reference herein.
The sigma receptor ligands of the present invention are also useful for the treatment of drug abuse. In this aspect of the invention, the compounds of the invention are administered to an individual to ameliorate symptoms of drug withdrawal or to -39reduce craving for the drug, e.g. cocaine, heroin, PCP and hallucinogens.
As discussed above, the sigma receptor ligands of the present invention are highly selective for the sigma receptor and show low affinity for the DA and PCP receptors. Certain specific sigma receptor ligands of the present invention also bind with low affinity to 5-HT1A receptors. Thus, in addition to the treatment of central nervous system disorders, the sigma selective ligands of the present invention may also be used as a pharmacological tool in an animal model for the screening of potential sigma receptor agents.
The sigma receptor ligands of the present invention may also be radiolabelled with, for example, 3K, 11C, 14C, 18F, 125I and 1311. In their radiolabelled form, the sigma receptor ligands of the present invention may be used for audoradiography studies of the sigma receptor sites in tissue, especially neuronal tissue.
The sigma receptor ligands of the present invention may be prepared by general methods of synthesis as disclosed in Example 1. For example, a sigma receptor ligand having Formula (XXXX) may be prepared by reductive amination of a compound having Formula (XXXXI) with an aldehyde having Formula (XXXXII) according to Scheme I outlined below. -40Scheme I Ar R1 (CH)n II -N-H + H-(-C-)-Z (XXXXI) R1 (XXXXII) iH] lN-(-CH2)-Z W (XXXX) The starting compound having Formula (XXXXI), where W = -H H-, may be prepared by general methods of organic synthesis. For general methods of preparing compounds of Formula (XXXXI), reference is made to Fuller, R.W. et al., J. Med. Chem. 14:322325 (1971); Foye, W.0. et al.. J. Pharm. Sci 68:591-595 .(1979); Bossier, J.R. et al.. Chem. Abstr. 66:46195h and 67:21527a (1967); Aldous, F.A.B., J. Med. Chem. 27.:1100-1113 (1974); Fuller, R.W. et al., J.Pharm. Pharmacol. £5:828-829 (1973); Fuller, R.W. et al., Neuropharmacoloqy 14:739-746 (1975); Conde, S. et al, J. Med. Chem. 21:978-981 (1978); Lukovits, I. et al..
Int. J. Quantum Chem. £0:429-438 (1981); and Law, B., 2_ Chromatoq. 407:1-18 (1987), the disclosures of which are incorporated by reference herein in their entirety. The radiolabelled derivatives having Formula (XXXX) may be prepared by, for example, using a tritiated reducing agent to perform the reductive amination or by utilizing a materi al.
C-labelled starting Alternatively, where R is H, an N-substituted carboxamide of Formula (XXXXIII) may be reduced, for example, with LiAlH4 to give the N,N-disubstituted sigma receptor ligand having the Formula (XXXX), below (see Scheme II).
Scheme II R1 (XXXX) Alternatively, where the starting compound comprises a carbonyl group, the compound having the Formula (XXXXIV) may be reduced with, for example, A1H3, diborane.-methyl sulfide or other standard carbonyl reducing reagent to give the sigma receptor ligand having Formula (XXXX) according to Scheme III. -42Scheme III R1 (XXXXIV) R1 Ar N-(-CH2-)-Z (XXXX) The sigma receptor ligands having Formula (XXXI) may be prepared by nucleophilic displacement of an electrophile (E) by the amino derivative (XXXXV) as outlined in Scheme IV. Examples of electrophiles which may be used for this purpose include halides such as Cl, Br, or I, tosylate or mesylate. -43Scheme IV (XXXXV) R1 (XXXI) Morpholino derivatives having the Formula (XXXXVI) may be prepared by reduction of a compound of the Formula (XXXXVII) with, for example, sodium borohydride to give the ring-closed morpholino derivative (XXXXVI) according to Scheme V.
Scheme V , H r1-c-ch2ch2ch2-oh CH? XCH, N-X-Z (XXXXVII) ·> R -CH-CH2-N-X-Z Alternatively, where the sigma receptor ligand comprises a tetrahydropyridine ring (Formula (XXXXVIII)), the tetrahydropyridine ring may be constructed by reaction of a 2arylpropene derivative (Formula (XXXXIX)) with an alkyl amine (XXXXVI) (Formula (L)) and para-formaldehyde in the presence of orthophosphoric acid (Scheme VI).
Scheme VI -44CH, Ar-C + NH2-X-Z + (CH20)x -> Ar-C u CH, C h V/ N-X-Z (XXXXIX) (L) (XXXXVIII) Reduction of the double bond of the compound having Formula (XXXXVIII) with, for example, hydrogen and a hydrogenation catalyst such as Pd/C or Pt gives the corresponding piperidine having Formula (LI): Scheme VII Ar-C r~\ C f \_/ N-X-Z IH1 Ar-C N-X-Z (XXXXVIII) (LI) Also included within the scope of the present invention are the optical isomers of the compounds of the invention. The optical isomers may be separated by classical resolution techniques by, for example, formation of a salt of the amino group with an optically active acid. A particularly preferred acid for this purpose is (+)-di-fi-toluoyl-D-tartaric acid. The resulting diastereoisomeric salt may then be separated by crystallization, chromatography, or by taking advantage of the differing solubilities of the two diastereoisomeric salts. The -45free base may then be isolated by treatment with a base such as aqueous ammonia and extraction with an organic solvent.
Alternatively, the optical isomers may be prepared by resolution of the starting amine used to prepare the sigma ligand.
Also included within the scope of the present invention are the non-toxic pharmaceutically acceptable salts of the compounds of the invention. Acid addition salts are formed by mixing a solution of the sigma ligand of the invention with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, and the like.
In the methods of treatment of the present invention, the pharmaceutical compositions may comprise the sigma receptor ligand at a unit dose level of about 0.01 to about 500 mg/kg of body weight, or an equivalent amount of the pharmaceutically acceptable salt thereof, on a regimen of 1-4 times per day. Of course, it is understood that the exact treatment level will depend upon the case history of the animal, e.g., human being, that is treated. The precise treatment level can be determined by one of ordinary skill in the art without undue experimentation.
The pharmaceutical compositions of the invention may be administered to any animal which may experience the beneficial effects of the compounds of the invention. Foremost among such animals are humans, although the invention is not intended to be so 1imited.
The pharmaceutical compositions of the present invention may be administered by any means that achieve their intended purpose. For example, administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, or buccal routes. Alternatively, or concurrently, administration may be by the oral route. The dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired. -46In addition to the sigma receptor ligands, the new pharmaceutical preparations may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Preferably, the preparations, particularly those preparations which can be administered orally and which can be used for the preferred type of administration, such as tablets, dragees, and capsules, and also preparations which can be administered rectally, such as suppositories, as well as suitable solutions for administration by injection or orally, are present at a concentration of from about 0.01 to 99 percent, together with the excipient.
The pharmaceutical preparations of the present invention are manufactured in a manner which is itself known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the sigma ligand with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
Suitable excipients are, in particular, fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, disintegrating agents may be added such as the abovementioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are, above all, flowregulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Dragee cores are -47provided with suitable coatings which, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropymethyl-cellulose phthalate, are used. Dye stuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules can contain the active compounds in the form of granules which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin. In addition, stabilizers may be added.
Possible pharmaceutical preparations which can be used rectally include, for example, suppositories, which consist of a combination of one or more of the active compounds with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons. In addition, it is also possible to use gelatin rectal capsules which consist of a combination of the active compounds with a base. Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.
Suitable formulations for parenteral administration include aqueous solutions of the sigma ligands in water-soluble form, for example, water-soluble salts. In addition, suspensions of the active compounds as appropriate oily injection suspensions may be administered. Suitable lipophilic solvents or vehicles include -48fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension include, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, the suspension may also contain stabilizers.
The following examples are illustrative, but not limiting, of the method and compositions of the present invention. Other suitable modifications and adaptations of the sigma receptor ligands as well as the variety of conditions and parameters normally encountered in clinical therapy and which are obvious to those skilled in the art are within the spirit and scope of the invention.
Examples EXAMPLE 1 PREPARATION OF SIGMA RECEPTOR LIGANDS The sigma receptor ligands listed in Tables 1, 2 and 3 were synthesized according to one of twelve synthetic procedures (Methods A-L) disclosed immediately below.
METHODS METHOD A: R(-)-N-(3-Phenylpropyl )-1-phenyl-2-aminopropane Hydrochloride. A mixture of hydrocinnamaldehyde (1.11 g, 8.2 mmol) and R(-)-amphetamine (0.94 g, 7.0 mmol) in MeOH (20 mL) was hydrogenated over Pt/C 5% (0.2 g) at room temperature until the theoretical amount of hydrogen was absorbed. The methanolic solution of the base was separated from the catalyst by filtration and was treated with 10% HCl until the mixture was strongly acidic. The MeOH and H20 were removed under reduced pressure with warming to give a crude solid, which was recrystal 1 ized several times from MeOH and MEK to give 1.6 g (80%) of colorless crystals, mp 215-217*C. -49METHOD B: R(-)-N-(Cyclopropyl methyl )-1-phenyl -2-aminopropane Maleate. To a suspension of LiAlH4 (1.49 g, 38 mmoL) in anhyd. ether (50 mL) was added a solution of N-(σ-methylphenyl ethyl )-2cyclopropylcarboxamide (1.5 g, 74 mmol) in anhyd. Et20 (20 mL).
The mixture was heated at reflux overnight, cooled to 0*C and H20 (2.5 mL) was added in a drop wise manner. This was followed by the addition of 2N NaOH solution (2.5 mL) and then H20 (5 mL). After the inorganic precipitate was removed by filtration, the Et20 solution was dried (anhyd. Na2S04) and treated with a solution of maleic acid (1.5 g in absolute EtOH (10 mL). The product was collected by filtration, washed with Et20 and recrystallized from 2-PrOH/Et2O (3x) to afford 1.3 g (59%) of fine crystals: mp 162-163’C.
METHOD C: N-(3-Phenylpropyl)-l-(4-bromophenyl)-2-aminopropane Hydrochloride. A1H3 was prepared by the addition of A1C13 (0.07g, 0.5 mmol) to a suspension of LiAlH4 (0.064 g, 1.7 mmol) in Et20 (50 mL) at 0*C under a nitrogen atmosphere. A solution of N-hydrocinnamoyl-l-(4-bromophenyl)-2-aminopropane (100 mg, 0.29 mmol) in dry Et20 (10 mL) was added in a drop wise manner, to the A1H3 solution at 0*C. After the addition was complete, the mixture was allowed to stir for 0.5 h at the same temperature. Excess A1H3 was decomposed by the addition of crushed ice (1 g) followed by 15% NaOH solution (2 ml). The mixture was filtered and the organic portion was separated, washed with H20 (20, 10, 5 mL), dried (anhyd. MgSO4) and treated with sufficient HCl gas until precipitation was complete. The precipitate was collected by filtration and recrystallized from Et0H/Et20 (4x) to give 20 mg (19%) of a finely divided powder: mp 176-178*C.
METHOD 0: N- (3-Phenyl propyl )-1-(3-tri f1uoromethylphenyl )-2aminopropane Hydrochloride. A mixture of 1-(3trifluoromethylphenyl)-2-propanone (102 mg, 0.50 mmol), 3-phenyl35 1-propylamine (86 mg, 0.64 mmol), glacial acetic acid (8 mg, 0.13 mmol), and MeOH (2 mL) was allowed to stir at room temperature for 0.5 h. To this mixture was added over a 4-h period sodium -50borohydride (19 mg, 0.50 mmol) and the mixture was allowed to stir at room temperature for 20 h. The solvents were removed by warming under reduced pressure to give a small amount of an oil which was cooled and treated with 10% HCl. The crude product separated as a white solid, 122 mg (68%), mp 135-145’C. The crystals were dissolved in H20 and the solution was extracted with Et2O. The H20 portion was separated, the H20 was evaporated, and the crystals reformed; recrystallization from acetone gave 66 mg (37%) of colorless crystals, mp 167-169’C.
METHOD E: R(-)-N-Benzyl-l-phenyl-2-aminopropane Hydrochloride. To a mixture of R(-)-ampbetamine sulfate (0.633 g, 3.4 mmol), benzaldehyde (0.547 g, 5.2 mmol), MeOH (3 mL), and glacial acetic acid (0.5 g) was added sodium cyanoborohydride (0.263 g, 4.0 mmol) at room temperature over a 1-h period. During this addition, the pH was maintained at pH 5.5-6.0 by the addition of additional glacial acetic acid (0.25 g). After stirring 20 h at room temperature, the MeOH was removed by warming under reduced pressure. The residue was treated with an excess of 10% NaOH and the product extracted into Et20. The product was then extracted into an excess of 10% HCl solution; the aqueous layer was decanted and the water was removed by warming under reduced pressure to give the crude product, 0.5 g (56%), mp 170-174’C. After several recrystallizations from MeOH-MEK, the colorless crystals weighed 0.46 g (51%), mp 173-175’C.
METHOD F: R( -) -N-(2-Phenoxyethyl)-1-phenyl - 2-ami nopropane Hydrochloride. In a 5-tnL reaction vial was placed R(-)amphetamine (0.288 g, 2.1 mmol) and 2-phenoxyethyl chloride (0.335 g, 2.1 mmol). The vial was sealed and heated at 95*C for h. The reaction mixture was cooled, washed repeatedly with Et2O to give the crude product which melted at 155-160‘C. Recrystall ization (3x) using MeOH and MEK gave colorless crystals that weighed 50 mg (8%), mp 178-179’C.
METHOD G: R(-)-N-(3-Phenyl-3-oxopropyl)-1-phenyl -2-aminopropane Hydrochloride. A mixture of R(-)-amphetamine hydrochloride -51(0.259 g, 1.5 mmol), acetophenone (0.635 g, 5.3 mmol), paraformaldehyde (87 mg), MeOH (1.2 mL), and cone. HCl (1 drop) was placed in a 5-mL reaction vial, stirred, and heated at 65‘C for 24 h. After removing the solvent using reduced pressure and warming, the reaction mixture (which became partially solid) was dissolved in H20 (5 mL) and was extracted twice with hexane (10 mL). The aqueous portion was made basic with 10% NaOH and the product extracted into hexane (10 mL). The product was then extracted into a 10% HCl solution and the H20 and excess HCl were removed with warming under reduced pressure to form the crude solid, mp 135-144‘C. Repeated recrystallizations using MEK and acetone gave 50 mg (11% yield) of colorless crystals, mp 146147’C.
METHOD H: (+)-o-[N-(3-phenylpropyl) ami no]propiophenone Hydrochloride. A mixture of hydrocinnamaldehyde (2 g, 15 mmoL) and norephedrine (2.18 g, 14.4 mmol) in EtOH (100 mL) was hydrogenated over a catalytic amount of Pd/C 10%, at room temperature. A hydrogen uptake slightly in excess of theory was obtained. The suspension was filtered and the filtrate was treated with 2N HCl (30 mL). The acid solution was evaporated to give a residual solid, which was recrystallized twice from Et0H/Et20 to give 2.34 g (55%) of needles: mp 211-213‘C.
An ice-cooled mixture of CH2C12 (20 mL) and pyridine (0.8 g, 10 mmol) was treated with dry Cr03 (0.5 g, 5 mmol), which was added in portions within a 30-min period. The purple-brown mixture was stirred at room temperature for 2 h. A solution of the amino alcohol prepared above (0.23 g, 1.24 mmol) in CH2C12 (5 mL) was added to the pyridine-Cr03 mixture all at once with vigorous stirring. After 15 min, the yellow organic layer was decanted from the black, sticky precipitate and extracted with 5% NaOH (100 mL). The organic portion was filtered through a bed of anhyd. Na2S04 and evaporated to dryness. The oily residue was treated with cone. HCl (5 mL), warmed, and the mixture was evaporated to dryness. The solid residue was recrystallized from 2-PrOH/Et2O (2x) to give 150 mg (40%) of the hydrochloride salt: mp 154-155'C (solidified and melted again at 170-172*C). -52METHOD I: N-Benzyl-2-phenylmorpholine Hydrochloride. To a solution of N-(2-hydroxyethyl)-N-(benzoylmethyl)-benzylamine hydrochloride (0.50 g, 1.6 mmol) and MeOH (5 mL) at 5*C was added with stirring over 4 h sodium borohydride (0.213 g, 5.6 mmol).
The reaction was allowed to warm to room temperature over 18 h; an additional amount of sodium borohydride (70 mg, 1.8 mmol) was added, and the reaction was stirred for an additional 24 h. A small amount of H20 (1 ml) was added to the mixture and the solvents removed by warming under reduced pressure. Water (6 mL) and Et20 (12 mL) were added to the reaction mixture; the ether layer was removed and the Et20 evaporated under reduced pressure to give the crude liquid product as the free base (0.42 g). Treatment of the free base with cold cone. HCl (1 mL) followed by warming under reduced pressure to remove the H20 and excess HCl afforded the crude product hydrochloride. Recrystallization from acetone gave colorless crystals of the amine hydrochloride 0.38 g (77%), mp 140-143‘C.
A portion of these crystals (35 mg, 0.11 mmol) was heated at 125*C with cone. HCl (0.17 g) in a sealed reaction vial for 1.25 h. The H20 and excess HCl were removed by warming under reduced pressure to give 40 mg of the crude, tan product, mp 201205‘C. Two recrystallizations from acetone gave 21 mg (66%) of the substituted morpholine hydrochloride as colorless crystals, mp 211-212‘C.
METHOD J: l-(4-Phenylbutyl)-4-(4-chlorophenyl)-l,2,5,6tetrahydropyridine Maleate. To a stirred mixture of glacial acetic acid (1.9 g, 31.7 mmol) and acetic anhydride (0.4 g, 4 mmol) was added slowly (85%) orthophosphoric acid (0.43 g, 4 mmol). After the exothermic reaction had subsided, 4phenylaminobutane (0.58 g, 4 mmol), paraformaldehyde (0.36 g) and 4-chloro-o-methylstyrene (0.62 g, 4 mmol) were added. The reaction mixture was stirred at 115*C for 4 h then allowed to stand at room temperature for 2 days. The mixture was diluted with H20 (10 mL), extracted with hexane and the aqueous layer made basic with Na2C03. The crude product was extracted into -53hexane, dried over anhyd. K2C03, and the solvent removed by evaporation. The crude free base was recrystallized from H20MeOH to give the purified free base (mp 87-90’C) which was dissolved in EtOH and treated with an Et20 solution of maleic acid to give the maleate salt. Recrystallization from Et0H-Et20 gave 0.6 g (35% yield) of fine crystals, mp 162-164’C.
METHOD K: N- (3 -Pheny1 propyl )-1-(4-hydroxyphenyl)-2-ami nopropane Hydrobromide. A suspension of the free base of N-(310 phenylpropyl)-l-(4-methoxyphenyl)-2-aminopropane (200 mg, 0.63 mmol) in 48% HBr was heated at reflux for 6 h. The mixture was filtered while hot and the filtrate allowed to cool to room temperature to give crystals. The crystals were collected by filtration and recrystallized from Et0H-Et20 to give 200 mg (88% yield) of the hydrobromide salt, mp 159-160’C.
METHOD L: l-(3-Chlorophenyl)-4-(3-phenylpropyl)piperazine Hydrochloride. To a stirred solution of diborane:dimethyl sulfide complex (2M) in THF (30 ml) was added drop wise a solution of dry THF (25 mL) and l-(3-chlorophenyl)-4-(3phenylpropionyl)piperazine (1.28 g, 3.86 mmol). The reaction mixture was stirred at room temperature for 18 h, quenched by the addition of MeOH-HCl (25 mL), and the solvents removed under reduced pressure. Additional MeOH was added and removed under reduced pressure to give a tan solid. This was dried for 18 h under vacuum then recrystallized from MEK to give 0.9 g (67%) of colorless crystals, mp 168-169’C. -54Table Τι Prepertlte 0/ Seme Serlet I Ceepeund».
*» AA-55 H CHj ‘(CHjIj-Ph t(*) A HCl 18G146 54 Hit C^Hj^ClH -55fteeeyatttlItatlon aolventt «thyl acetate (*), «ettenltHt· abaolute ethanol (t), 2-propanot (I), 2-butanone (K), «ethanol CX <3 C. o cr «. o. «3 0 0 «30-** © •HO. © M HI .© © w w table ?i Propertied of Additional Serie· t Compound·.
Or) r) ^°) * i u » < < 4$et footnote a, tabla 1. bSae footnote b, table 1. • elller}ture (Chew, AbstiN 49t7812 (1955)), wp 201*202‘C. dfhere ere other way· In whleh the Serie· I compound» mlpht have been prepared then the method ahown. -57table ϊι aropertle* of terlaa II Compound». tIterature (Chem, Abatr, ££*12026), mp 20S«207‘C. 'lltermturm (J, Med, Chew, 9i1$) (1966)), mp 214*216*G.
There »re other waye In which th· tariei 11 compound· might have been prepared than the method ahown, -58EXAMPLE 2 SIGMA, PCP AND DOPAMINE RECEPTOR BINDING ASSAYS Methods Sigma receptor binding assays using guinea pig brain membrane homogenates and the radioligand [3H]DTG were conducted as described by Weber et al.. P.N.A.S. (USA) 83:8784-8788 (1986) which indicates binding to both the sigma-1 and sigma-2 sites. Briefly, frozen whole guinea-pig brains (Biotrol, Indianapolis, IN) were homogenized in 10 volumes (w/v) of ice-cold 320 mM sucrose using a Brinkman polytron. The homogenate was centrifuged at 1,000 x g for 20 minutes at 4*C. The supernatant was centrifuged at 20,000 x g for 20 minutes at 4*C. The resulting pellet was resuspended in 10 initial volumes of 50 mM Tris/HCl buffer at pH 7.4 and centrifuged at 20,000 x g for 20 minutes at 4*C. The resulting pellet was resuspended in 5 initial volumes ice-cold 50mM Tris/Hcl (pH .4), and the final volume was adjusted to yield a protein concentration of 3 mg/ml. Aliquots of 20-ml were stored at -70*C until used, with no detectable loss of binding.
For [3H]DTG binding assays, the frozen membrane suspensions were thawed and diluted 1:3 in 50 mM Tris/HCl (pH 7.4). To 12 x mm polystyrene test tubes were added 0.8 ml of diluted membrane suspension, 0.1 ml of [ H]DTG (Dupont/NEN) to yield a final concentration of 1.4 nM, and 0.1 ml of unlabelled drugs or buffer. The protein concentration in the 1-ml final incubation volume was 800 ug/ml, corresponding to 32 mg of brain tissue (original wet weight) and to a tissue concentration within the linear range for specific binding. Non-specific binding was defined as that remaining in the presence of 10 uM haloperidol. Incubations were terminated after 90 minutes at room temperature by addition of 4 ml of ice-cold 50mM Tris/HCl (pH 7.4) and rapid filtration of the membrane suspension through Whatman GF/B glass-fiber filters under vacuum, using a 48-well cell harvester (Brandel). The filters were washed 2 times with 4 ml of 50 mM Tris/HCl (pH 7.4). Each filter was suspended in 10 ml Cytoscint (ICI), and radioactivity was measured by liquid scintillation -59spectrometry at a counting efficiency of approximately 50%. IC50 values were determined by non-linear regression analyis.
PCP receptor binding assays against 3H-MK-801 were conducted as described by Keana et al.. Proc. Natl. Acad. Sci (USA) 86:5631-5635 (1989); Keana et al.. Life Sciences 43:965-973 (1988). For (+) 3H-MK-801 binding, 1 nM of radioligand was incubated with about 100 ug of thawed rat brain membrane protein for 4 hr at room temperature. The assays were carried out in 5 mM Tris/acetate and were stopped by rapid filtration through Whatman GF/B or Schleicher & Schuell no. 32 glass fiber filters (presoaked in 0.05 % polyethyl enamine).
Dopamine DI and D2 receptor binding assays were performed as described by Billard et al.. Life Sci. 35:1885-1893 (1984) using [3H]SCH-23390 for the DI receptors and [3H]domperidone for the D2 receptors (Baudry et al.. Arch. Pharmacol. 308:231-237 (1979).
Rat striatal membranes were prepared from frozen tissue by Poltron homogenization in 25 volumes of ice cold Tris-EDTA buffer (50 mM Tris-HCl, 1 mM EDTA, pH 7.4 at 4*C). The homogenate was centrifuged at 48,000 x g for 10 min. at 4’C, and the pellet was resuspended in 25 volumes of the same buffer. This suspension was then incubated at 37’C for 15 min., followed by recentrifugation as before. The resulting pellet was resuspended in 267 volumes of assay buffer (50 nW Tris-HCl, 120 mM NaCl, 5 mM KC1, 2 mM CaCl2, 1 mM MgCl2, pH 7.4 at 37 ’C).
The binding assays were conducted with 100 uL of [3H]SCH23390 or [3H]domperidone (to give about 1 nM final), 100 uL of buffer or drug solution, and 800 uL of membrane suspension (to give about 250 ug of striatal membrane protein per assay). The tubes were incubated at 37*C for 60 min. The assays were stopped by rapid filtration over Schleicher & Schuell #32 or Whatman GF/B glass fiber filters (presoaked in 0.5% polyethyleneimine for [3H]domperidone binding), followed by two 3 mL washes of ice cold buffer using a Brandel cell harvester. After vigorous shaking, the filter disks were counted at 52% efficiency in 5 mL of Cytoscint (ICN). -60The results of these binding assays appear in Table 4 -61TA8LE 4 # GTPOK) ISO- SIGMA SIGMA n 01 02 PCP 8.65/10-6 1.25x1ο-6 2 >10-5 R- H NCH X'’ 0 4 H NCH2CH3 R- 6.85xl0-7 2.50x10® 2 o 5 R- 1.705xl0-6 I.65xl0-8 2 NHCH2CH2CH3 >105 >105 -62GMOUM) ISO- SIGM ffR ICSO (M) SIGM n S.EJt PCP ICSO (M) /Ό HN RR- Hn—0 1.22xl0'7 1.65x10-® 2 €.24χ1<Γβ 9.00χ309 2 4.71x10-® 5.75xl0-9 2 .84x10-® 7.45xl0-9 2 9.69xl09 δ.ΙΟκΗΓ10 2 >10*5 9.00x10-® >10-5 >10-® >10-5 -63ί CQf«XK) ISO- SIGMA SIGMA n 01 02 PCP HER ICSO (M) S.EJt ICSO (irt) ICSO (M) (n) HN R- 9.15x1ο-9 2.75xl09 2 >10-5 HN R- 2.35x1ο-9 653χ10·1θ 4 >10- +/- 1.22xl0'7 2.50χΗΓ9 2 >10 2.85x10® 5.20X10-9 2 >10 r5 . < 6 44>xl0-8 1.21xl0'9 4 >10 1.68 >10*5 (2) +3.6 (2) COTCUO ISO- SIGW SIGM4 n t€R ICSO (M) S.EJt 02 pcp ICSO ((«, ICSO (M) (n) 1.82x10*3 2.65x10-® 6.60x10-® 1.79x10-® Ι.ΟβχΙΟ-8 0.00 I.«93xI0‘8 2.95xl0-9 >105 >10’s >10'5 >10 9.32 >10’5 (2) ±4.5 (3) OCH 20 3 +/5.17x10-® 1.02x10-® n=3. >10'5 • · -65GWROW ISO- SIGMA SIGMA n MER ICSO (M) S.EJt 02 PCP ICSO (Ψ) ICSO (M) (n) V9.11x10-3 C.lSxlO10 2 >10 rS & H 1.597xl0-8 4.64x1θ'9 4 >10 3.81 >10-5 (2) ±9.7 (3) V- 4.HM0-9 2.05χ1(Γ1θ 2 >10'5 cr +/ 6.91x10-7 1.39X10-7 2 >10-5 H 1.01x10-7 4.43x10-® 2 Λ ΊΟ >10 r5 • · ISO- SIGW SIGN* n KR IC50 -66CMUN) PCP ICSO (M) 2^8χ10*7 3.26x10-® 2.0QX10-9 2 2.05X10-9 2 NH.
R4.80χ10-5 0.00 2 >10-S >10*5 >10-5 NH.
R4.95x1ο-6 5.00x10-® 2 >10-5 nh2 R- 2.10x10-5 2.00x10-® MO'5 ISO- SIO4A SIGMA n HER IC5O (M) S.E.K -67compound PCP ICSO (K) 31 ^θ8*10*8 ό 6.50xl010 2 >105 • Ρ-0 χΓ 2.67xl09 2 >105 Cl 5.60xl09 2 >105 ΙΉ . ,,,. 4.00x10® 2 >10535 ^^0 +/ 2*59xi°7 1.90x10® 2 >105 □ t COMPOUND ISO- MER SIGMA ICSO SIGtt S.EJi n 01 02 ICSO (iM) PCP IC50 (M) (n) e^SxlO-9 1.5QxMr10 2 S.OOtxlO-6 >10-5 4.30xl0-9 2-lOxlO-9 2 o >10-5 1.20/10-9 2.0040-10 2 >i5 OH 3.18x10*° 3-0x10 ,-10 3.06xl0~q 3.4x10^7 5 >10 1 -9 . . u 2i (2) ± (3) >10 ,-5 The second set oi numbers represent a second lot. i CQMUJND ISO- ICR SIGMA ICSO (M) SIGMA S.CM. n 01 02 ICSO (iM) PCP ICSO (n) 4.52x10? .59x10’ .2QxlO’9 2.7x10*° 5 2.06x10’ 2 1 2-00x10'!° 2 >10 (2) 1.92 ±.19 (3) >10'5 >10-5 SW 2.27x10-® o 2-lQxlO-9 2 >10’5 «« arpouro iso- sio-w FER ICSO (K) -706.95X10-9 SIGMA S.EJt n 01 02 IC50 (ifl) (n) 7.50x10*1° 2 PCP ICSO (M) >10-5 2.70X10-9 2.00x10-1° >10-5 ISO- SIGMV SIGM HER ICSO (M) S.EJt -71# coraio « 01 02 ICSO (tM) PCP ICSO (H) .158 1.028 (2) >105 «· -72Results As can be seen in Table 4, the sigma receptor ligands of the present invention exhibit very high binding with respect to the sigma receptors and very low binding with respect to the PCP and DA receptors. Therefore, these sigma receptor ligands can be used for the treatment of mental illness without the extrapyramidal side effects of traditional neuroleptic agents caused by binding to the DA receptor. iu EXAMPLE 3 S-HT1A BINDING ASSAYS The sigma receptor ligands listed above (nos. 1-51) were further tested for binding at the 5-HT1A receptor using the method of Peroutka, S.J., J. Neurochem. 47:529-540 (1986). The results appear in Table 5. -73Table 5 -HT1A Compound No. IC50 (nN) iSEM(n) Ratio 1 115.00 12.00(2) 2 90.30 28.83(3) 3 1776.33 579.30(3) 4 4052.50 372.50(2) 5 1500.00 100.00(2) 6 3781.50 3458.50(2) 7 2475.00 95.00(2) 8 43.65 1.85(2) 9 122.00 6.00(2) 10 212.00 31.00(2) 11 104.30 16.70(2) 12 131.58 39.31(4) 13 288.00 62.00(2) 14 154.50 35.50(2) 15 30.70 3.43(3) 16 44.8 2.5(2) 17 87.80 12.20(2) 18 588.50 68.50(2) 19 114.23 12.43(3) 20 108.05 10.95(2) 21 195.50 14.50(2) 22 202.00 47.00(2) 23 105.75 13.25(2) 24 955.50 33.50(2) 25 753,00 135.00(2) 26 10000 (1) 27 6514.00 874.00(2) 28 2442.50 342.50(2) 29 15515.00 5515.00(2) 30 54999.50 44999.50(2) 31 19.30 4.20(2) 32 8.73 0.46(2) 33 51.60 2.30(2) 34 6650.00 710.00(2) 35 10360.00 360.00(2) 36 1626.67 378.17(3) 37 20.30 4.70(2) 38 107.75 27.25(2) 39 89.60 0.10(2) 40 2965.00 585.00(2) 41 34.67 9.09(3) 42 572.50 134.50(2) 43 1112.33 162.85*3) 44 277.67 33.52(3) 45 594.00 67.68(3) 46 21.47 3.60(3) -ΗΤ1Λ/σ .20 .9 .88 .92 .4 2 2.4 13 54 7.6 17 1.4 7.3 3.5 200 .05 3.1 2.6 .92 .80 2.6 2.6 40 239 2.6 25 75 970 7.6 110 100 -74IE 922112 Table 5 (Cont.) Compound No. 5-HT JCso-lntli1A±SEM(n) Ratio 5-HT 47 9.23 1.58(2) 1.6 48 6.30 0.74(2) 2.3 49 312.67 27.38(3) 30 50 281.67 69.00(3) 94 EXAMPLE 4 FURTHER i3H1DTG AND 5HT-1A BINDING ASSAYS Further sigma receptor binding assays against [ H]DTG and 5HT-1A binding assays were conducted according to the procedure outlined in the previous examples. The results of these further studies are listed in Table 6. -75TABLE 6 COMPOUND NH NH SIGMA IC50 (nM) 5HT-1A (nM) MEAN SEM (n) MEAN SEM(n) 11891.00 399.00(2) HO /^X 10901.50 1198.50(2) JP 11815.00 1815.00(2) ci 6393.67 4426.77(3) 4 TABLE 6 (Cont.) SIGMA IC50 (nM) # COMPOUND MEAN SEM (n) 5HT-1A (nM) MEAN SEM(n) 1190.50 159.50(2) , 6069.00 251.00(2) 2054.50 14.50(2) 575.50 98.50(2) TABLE 6 (Cont.) SIGMA IC50 (nM) COMPOUND MEAN SEM (n) 5HT-1A (nM) MEAN SEM(n) -NH 14850.00 4850.00(2) 11625.00 1625.00(2) 763.33 352.86(3) 784.00 17.00(2) 182.00 30.00(2) TABLE 6 (Cont.) SIGMA IC50 (nM) COMPOUND MEAN SEM (n) 5HT-1A (nM) MEAN SEM(n) 1320.00 158.46(3) 891.00 181.56(3) 3885.75 1466.82(4) a · TABLE 6 (Cont.) SIGMA IC50 (nM) COMPOUND MEAN SEM (n) 5HT-1A (nM) MEAN SEM(n) NH -795.68 2.19(2) 225.33 57.50(3) 92(2) 11.30 3.25(3) ·♦ TABLE 6 (Cont.) SIGMA IC50 (nM) COMPOUND MEAN SEM (n) 5HT-1A (nM) MEAN SEM(n) 2.65 0.63(2) 119.00 (1) 2.07 0.50(3) 759.00 (1) c 3 ·01 0-23(2) 98.40 (1) CPO^fXj)2.25 1.14(3) 173.00 (1) 130.10 18.16(3) TABLE 6 (Cont.) SIGMA IC50 (nM) COMPOUND MEAN SEM (n) 5HT-IA (nM) MEAN SEM(n) -815 • 4 TABLE 6 (Cont.) SIGMA IC50 (nM) COMPOUND MEAN SEM (n) 5HT-1A (nM) MEAN SEM(n) -8286 1.12(2) 502.00 (1) 21.83 2.86(3) 67.40 (1) 3208.00 148.00(2) TAESLE 6 (Cont.) SIGMA IC50 (nM) f COMPOUND MEAN SEM (n) 5HT-1A (nM) MEAN SEM(n) MH HH 4.02 0.27(4) -8307 0.52(4) 0.28(4) 0.05(4) 732.50 111.50(2) 26.30 1.10(2) 596.50 2.50(2) 5549.50119.50(2) 5HT-1A (nM) MEAN SEM(n) -84COMPOUND TABLE 6 (Cont.) SIGMA IC50 (nM) MEAN SEM (n) 2.23 0.84(2) TABLE 6 (Cont.) SIGMA IC50 (nM) 5HT-1A « COMPOUND MEAN SEM (n) MEAN -85(nM) SEM(n) .70 1.20(2) 101 TABLE 6 (Cont.) SIGMA IC50 (nM) 5HT# COMPOUND MEAN SEM (n) MEAN -86(nM) SEM(n) 75.20 36.80(2) (El V 76.15 17.05(2) (Z) y v 565.50(2) TABLE 6 (Cont.) 5HT-1A (nM) MEAN SEM( -8710 COMPOUND SIGMA IC50 (nM) MEAN SEM (n) 8.65(2) 107 ,000.00 0.00(2) TABLE 6 (Cont.) SIGMA IC50 (nM) 5HT-1A COMPOUND MEAN SEM (n) MEAN 109 184.50 12.50(2) -88(nM) SEM(n) 22.20(2) 22.10(2) ·· 5HT-1A (nM) MEAN SEM(n) -89TABLE 6 (Cont.) SIGMA IC50 (nM) # COMPOUND MEAN SEM (n) 112 •^s., 2.65 0.41(3) 8243.00 685.00(2) 113 S(+) 2.22 0.32(3) 2148.00105.00(2) 114 S(+) 6.71 1.07(3) 34000 24,000(2) TABLE 6 (Cont.) 5HT-1A (nM) MEAN SEM(n) COMPOUND -90SIGMA IC$0 (nM) MEAN SEM (n) 20000 10000(2) 8.28(2) 0.14(3) 781.50 258.50(2) « · 5HT-1A (nM) MEAN SEM(n) -91TABLE 6 (Cont.) SIGMA IC50 (nM) ί COMPOUND MEAN SEM (n) 1967.00 394.00(2) « · TABLE 6 (Cont.) SIGMA IC50 (nM) 5HT-1A (nM) # COMPOUND MEAN SEM (n) MEAN SEM(n) 125 I I 38.83 9.05(2) HH 126 219.33 7.45(3) TABLE 6 (Cont.) SIGMA IC50 (nM) 5HT-1A (nM) # COMPOUND MEAN SEM (n) MEAN SEM(n) _ -93127 NH J 10.57 1.28(3) TABLE 6 (Cont.) SIGMA IC50 (nM) 5HT-1A (nM) # COMPOUND MEAN SER (n) MEAN SEM(n _ -94• r· 131 46.90 15.45(3) TABLE 6 (Cont.) SIGMA IC50 (nM) 5HT-1A (nM) # COMPOUND MEAN SEM (n) MEAN SEM(n -95134 S(+) 198.77 74.48(3) -- 136 1.78 1.32(3) TABLE 6 (Cont.) -96SIGMA IC50 (nM) 5HT-1A (nM) COMPOUND MEAN SER (n) MEAN SEM(n) 137 1.11 0.52(3) 140 69.03 13.28(4) -45 -97TABLE 6 (Cont.) 5HT-1A (nM) MEAN SEM( # COMPOUND SIGMA IC50 (nM) MEAN SER (n) TABLE 6 (Cont.) SIGMA IC50 (nM) 5HT-1A (nM) f COMPOUND MEAN SER (n) MEAN SEM( _ iC -98147 117.3 63.05(3) -15 OH 149 21.48 2.24(4) TABLE 6 (Cont.) -99SIGMA IC50 (nM) 5HT-1A (nM) COMPOUND MEAN SEM (n) MEAN SEM(n) 150 0.24(3) 151 1.39 0.10(3) -100TABLE 6 (Cont.) SIGMA IC50 (nM) 5HT-1A (nM) COMPOUND MEAN SER (n) MEAN SEM(n) 1866 113(3) OK 155 TABLE 6 (Cont.) 5HT-1A (nM) MEAN SEM(n) -101COMPOUND SIGMA IC50 (nM) MEAN SER (n) 6113 2790(2) 159 1.30 0.27(3) o TABLE 6 (Cont.) SIGMA IC50 (nM) 5HT-1A (nM) # COMPOUND MEAN SER (n) MEAN SEM(n) _ TABLE 6 (Cont.) SIGMA IC50 (nM) 5HT-1A (nM) # COMPOUND MEAN SEM (n) MEAN SEM(n) _ -104TABLE 6 (Cont.) SIGMA IC50 (nM) 5HT-1A (nM) # COMPOUND MEAN SER (n) MEAN SEM(n) 166 169 22.80 2.30(2) TABLE 6 (Cont.) -105# COMPOUND SIGMA IC50 (nM) 5HT-1A (nM) MEAN SER (n) MEAN SEM(n) TABLE 6 (Cont.) SIGMA IC50 (nM) 5HT-1A (nM) # COMPOUND MEAN SER (n) MEAN SEM(n) _ -106it· TABLE 6 (Cont.) SIGMA IC50 (nM) 5HT-1A (nM) # COMPOUND MEAN SER (n) MEAN SEM( _ -10710 TABLE 6 (Cont.) 5HT-1A (nM) MEAN SEM(n) COMPOUND -108SIGMA IC50 (nM) MEAN SEM (n) TABLE 6 (Cont.) 5HT-1A (nM) MEAN SEM( COMPOUND -109SIGMA IC50 (nM) MEAN SEM (n) TABLE 6 (Cont.) SIGMA IC50 (nM) 5HT# COMPOUND MEAN SEM (n) MEAN -110(nM) SEM(n) ch2ch3 TABLE 6 (Cont.) 5HT-1A (nM) MEAN SEM(n) # COMPOUND -111SIGMA IC50 (nM) MEAN SEM (n) EXAMPLE 5 STRUCTURE-ACTIVITY RELATIONSHIP OF THE SIGMA RECEPTOR LIGANDS The binding data reproduced in Tables 4-6 allows the identification of groups of compounds having high binding and -112selectivity for the sigma receptors, for example, it has been determined that the σ-methyl group on N-(3-phenylpropyl)isopropylamine (Ki - 22 nM) is not required for high binding to the sigma receptor. The corresponding des-methyl compound N-(3phenylpropyl)-2-phenethylamine binds with comparable affinity (Ki « 19 nM). This des-methyl compound possesses two carbon atoms between the phenyl ring and the terminal amine and, on the other side of the molecule, possesses three carbon atoms between the amine and the second phenyl ring (see Table 7; x 2, y 3). A systematic comparison of phenyl alkyl amine derivatives with varrying x and y values is shown in Table 7.
As shown in Table 7, the increase of x from 2 to 3 resulted in the retention of affinity. Interestingly, the total carbon chain length does not appear to be critical for high binding to the sigma receptor. The highest affinity agents are those where either x or y = 5. Thus, a phenyl pentyl amine is optimal while the length of the chain on the other side of the molecule appears to be inconsequential.
Since a carbon length of five atoms is optimal for high binding, and if the substituents on the other side of the molecule are relatively less important, then the second phenyl ring may not be important. Therefore, N-methyl-N-propyl-5phenylpentylamine, a des-phenyl analog, was prepared and found to bind with high affinity (Ki = 2.2 nM).
Where x and y = 3, it has also been found that replacement of one of the phenyl rings with a cyclohexyl ring (Ki = 2.5 nM) resulted in a nearly six-fold increase in affinity. Furthermore, the cyclohexyl analog N-benzyl-(5-cyclohexyl)pentylamine, where the cyclohexyl group is separated from the amine by five carbon atoms, also binds with high affinity (Ki = 1.3 nM).
Taken together, these data suggest that (a) phenylpentylamines bind with high affinity to the sigma receptor, (b) that the nature of the amine substituent is relatively unimportant, and (c) that the phenyl ring of the phenyl pentyl amines may be replaced by a cyclohexyl ring with retention (and an increase) of affinity. -113Table 7 Phenyl -(CH2)χ-NH-(CH2)y-Phenyl x y Ki (nM) 1 175 4 13 2.0 7 3.6 2* 3 19 4 5.5 2.4 7 4.1 3 14 4 7.0 1.8 6 2.6 4 6.7 2.5 1 2.0 2 2.4 3 1.8 4 2.5 * = des-methyl N-(3-phenyl propyl) i sopropyl phenyl ami ne With regard to sigma selectivity over 5-HT1A, the unsubstituted phenyl derivative N-(3-phenylpropyl)-lisopropylamine (cmp. no. 1) exhibits only a 4-fold selectivity for sigma receptors. Aromatic substitution enhances affinity for sigma receptors whereas 5-HT1A affinity remains relatively constant. Consequently, these aromatic substituted derivatives bind with a relatively low, but constant selectivity. Next, the effect of terminal amine modification was examined where the aromatic portion was held constant as a phenyl group. Replacement of the benzylic methylene group of cmp. #1 by an oxygen atom, carbonyl group, or sp-hybridized carbon atom (cmps. 8, 9 and 25) gave little effect. Removal of the σ-methyl group of cmp. #1 (R{-)) seems to enhance 5-HT1A affinity. The optical -114isomers of cmp. #1 bind at sigma receptors with comparable affinity; however, the S(+) isomer binds at 5-HT1A receptors with only one-tenth the affinity of its antipode resulting in a 48fold selectivity. Similar results were obtained with the isomers of N-(2-ethylphenyl) isopropyl amine (cmp. #7). N-Monomethylation (e.g. cmps. 45 and 69) also seems to enhance sigma affinity and selectivity. To further substantiate this finding, N-methyl-N(3-propylphenyl)-l-(4-n-propylphenyl)-isopropylamine was prepared and found to have the highest and most selective affinity for the sigma receptor.
EXAMPLE 6 Further Structure-Activity Studies of 5-Pentylamine Derivatives With N-substituted 5-phenylpentylamines, the length of 15 alkyl chain that separates the amine from its aromatic (phenyl-B) substituent has little influence on affinity (e.g., compare 76, 77, 89, and Hl; Ki = 2.0-2.7 nM). It seems unlikely that the phenylethylamines and phenylpentyl amines bind in exactly the same manner at the sigma receptors due to the difference in chain length. In order to account for the binding of these compounds, the phenylethylamines and the phenyl pentyl amines may utilize different aromatic binding sites. These results prompted a further investigation of 5-phenylpentylamine derivatives as sigma 1igands. n = 1 r> σ 2 69 n = 3 111 n = 4 CHEMISTRY: The compounds in Table 10 were synthesized by one of the methods described (A-H). Most of the compounds were prepared in two or three steps using either acylation and reduction of the -115intermediate amide or direct alkylation procedures. The amides were prepared either from the acyl halide and an amine or directly using ethyl chloroformate, an appropriate acid and an amine. Subsequent reduction by lithium aluminum hydride afforded the target amines. Following this procedure, the benzyl protected analog of compound 135 was obtained and subsequent hydrogenolysis produced the desired compound Compounds 136 and 152 were obtained by methylating the corresponding secondary amines using Eschweiler-Clark reductive alkylation procedure.
Compounds 173 and 172 were prepared by 0-demethylation of 144 and 145 respectively, using concentrated hydrobromic acid solution. Other target compounds prepared either by direct alkylation (method C) or by reductive alkylation (method E), using suitable aldehydes and appropriate amines.
EXPERIMENTAL: Synthesis: Proton magnetic resonance spectra were obtained on JEOL FX90Q or QE 300 (300 MHz) spectrometers with tetramethylsilane as internal standard. All spectra are consistent with the assigned structures. Melting points were determined on a Thomas Hoover apparatus and are uncorrected. Elemental analyses were performed by Atlantic Microlab and determined values are within 0.4% of calculated values.
Method A: N-Cyclohexylmethyl-5-cyclohexylpentyl ami ne Hydrochlori de (151). A solution of ethyl chloroformate (1.8g, 8.2 mmol) in methylene chloride (25 mL) was added in a dropwise manner to a stirred ice-cooled solution of cyclohexanepentanoic acid (3g, 8.1 mmol) and Et3N (1.7g, 8.1 mmol) in dry methylene chloride (50 ml) under N2, over 10 min. Stirring was continued for 30 min. and cyclohexylmethylamine (1.8g, 8.1 mmol) in methylene chloride (25 ml) was added dropwise over 5 mins. Stirring was allowed to continue for an additional 3 h after which the reaction mixture was washed water (50 mL) and dried (MgS04). Solvent was removed -116in vacuo to afford an oil which was crystallized from MeOH-H2O (4.lg, 91%); mp 69-72*C. A solution of the amide (3.8g, 14 mmol) in THF (50mL) was added dropwise to a suspension of LiAlH4 (2.6g, eq) in THF (100 mL). The reaction mixture was heated under reflux in a stream of N2 for 20 h. Excess LiAlH4 was decomposed by the gentle addition of H20 and 10% NaOH solution; Solid matter was removed by filtration and solvent was removed in vacuo to obtain an oily residue. The residue was taken up in Et20, dried (MgS04) and solvent was removed under reduced pressure to afford an oil (3.0 g, 80%). The hydrochloride salt, obtained by the addition saturated solution of ethereal HCl to an ethereal solution of 151 (free base), was recrystal 1ized MeOH/EtOAc; mp 223-224’C (see Table 8).
Method B: N-Methyl-N-hexyl-2-phenylethylamine Hydrogen Oxalate (130). A solution of hexanoyl chloride (lg, 7.4 mmol) in THF (40 mL) was added in a dropwise manner to a stirred solution of N-methyl-2phenylethylamine (lg, 7.4 mmol) and Et3N (2.3 g, 20 mmol) in THF (100 mL) cooled to 0’C. The reaction mixture was allowed to stir overnight (20 h) after which the triethylamine salt was removed by filtration and washed with THF (2 x 20 mL). The combined filtrate and washings were evaporated under reduced pressure and the residue taken up in CHC13 (30 mL). The chloroform solution was washed with H20 (30 mL) and dried (Na2SO4). Solvent was removed in vacuo to obtain an oil which was shown by IR (C=0, 1644cm'1) to be an amide (1.5g, 87%). A solution of the amide (0.5g, 2.1 mmol) in dry THF (60 mL) was added dropwise to a suspension of LiAlH4 (0.41g, 11 mmol) in THF(40 mL) under a stream of N2. The mixture was stirred overnight, cooled to 0’C and the reaction mixture was quenched by cautious addition of water and 15% NaOH solution. Solids were removed by filtration. The filtrate was evaporated to dryness under reduced pressure and the residue was taken up in Et20 (50 mL and dried (MgS04).
Solvent was removed under reduced pressure to obtain an oil (350 mg, 75%). The oil was converted to the oxalate salt (white -117crystals) and recrystallized from Me0H/Et20 solution; mp 139140*C (see Table 8).
Method C: N-Methyl-N-propylhexyl amine Hydrogen Oxalate (131). A stirred mixture of N-methylpropylamine {1.2g, 13.7 mmol), 1-bromohexane (3.4g, 20.5 mmol) and potassium carbonate (3.8g, 27 mmol) in 1,2dimethoxyethane (DME) (8 mL) was heated under reflux for 24 h and allowed to cool to room temperature. The solid material was removed by filtration and washed several times with CHC13. The combined filtrates were evaporated to dryness under reduced pressure and the residue partitioned between Et20 (30 mL) and 10% NaOH solution (20 mL). The ethereal fraction was washed with H20 (10 mL) and dried (Na2S04). A saturated solution of oxalic acid in anhydrous Et20 was added to obtain a white solid which was recrystallized from iPr0H/Et20 (0.4g, 12%); mp 101-102’C (see Table 8).
Method D: N-Methyl -N-cyclohexylmethyl-5-cyclohexylpentyl amine Hydrochloride (152). A mixture of 151 [CNS#?] (0.5g, 1.9 mmol), formic acid (l.lg, 23 mmol) and formaldehyde solution (37%) (1.85g, 23 mmol) was heated at about 100'C for 22 h and allowed to cool to room temperature. A 3N HCl solution (10 mL) was added and the solution extracted with Et20 (3 x 25 mL). The ethereal solution, which contained the expected product, was washed with 10% NaOH (30 mL), then water (10 mL) and dried (MgS04). A saturated ethereal HCl solution was added, solvent removed in vacuo, and the residue recrystallized from MeOH-EtOAc (370mg, 61%); mp 162-163*C (see Table 8).
Method E: N-(3-Cyclohexy1propyl)-3-phenylpropyl amine Hydrochloride (92). A solution of 3-phenyl propylamine (0.65 g, 5 mmol) and 335 cyclohexylpropionaldehyde (0.75 g, 5.4 mmol) in MeOH (40 mL) was hydrogenated in a Parr bottle containing 10% Pd/C (0.3 g) until -118sufficient H2 was taken up (40 min). The catalyst was removed by filtration; the filtrate was concentrated to about 10 ml under reduced pressure and added to IN HCl solution (20 mL). The precipitate was collected by filtration and washed thoroughly with anhydrous Et20 (3 x 10 mL). Recrystallization from 2butanone afforded the desired compound as white shiny plates (0.75 g, 53%); mp 203-205‘C (see Table 8).
Method F: N-[2-(3-hydroxyphenyl)ethyl)-5-phenylpentylamine Hydrobromide (172). A mixture of 145 (free base) (0.19 g, 0.65 mmol) and hydrobromic acid solution (48%) (0.22 mL, 1.3 mmol) was heated at reflux for 2 h and solvent was removed in vacuo. The solid residue was recrystallized from MeOH/anhydrous Et20 to afford the desired compound (100 mg, 42%); mp 151-153*C (see Table 8).
Method G: N-Phenyl-5-phenylpentylamine Hydrogen Oxalate (135). A mixture of N-benzyl-N-phenyl-5-phenylpentylamine (0.89 g, 2.5 mmol) in EtOH (20 mL) and 10% Pd/C (0.1 g) was hydrogenated at 50 psi for about h. The catalyst was removed by filtration and the filtrate was evaporated to dryness under reduced pressure. The residue was partitioned between 10% HCl solution (20 mL) and Et20 (20 mL); the aqueous portion was basified with 10% NaOH and extracted with Et20 (20 mL). The Et20 portion was dried (MgSO4) and solvent was removed in vacuo to afford an oil (0.3 g, 49%). The oxalate salt was prepared by the addition of a saturated solution of oxalic acid and subsequently recrystallized from EtOAc; mp 133-134‘C (see Table 8).
Method H: -Cyclohexylpentyl amine Hydrogen Oxalate (126). A solution of cyclohexanepentanoic acid (2 g, 10.9 mmol) in SOC12 (8 mL) was heated on a steam bath for 3 h. The SOC12 was removed under vacuum. Chloroform (2 x 10 mL) was added and reevaporated to give the crude acid chloride as a yellow liquid. A saturated -119solution of ammonia in dry THF (ammonia gas bubbled through 10 mL of THF for 5 min), was slowly added to a solution of the acid chloride in dry THF (50 mL) while cooling in an ice bath. The reaction mixture was allowed to stir at room temperature for 3 h and was then concentrated to half of its volume and poured onto water (100 mL). The solid was removed by filtration, washed with water and dried (MgS04). Recrystallization from aqueous MeOH gave 5-cyclohexylvaleramide (l.lg, 55%); mp 121-122’C (reported mp 122-123’C) (Katsellson and Dubinin, Compt. Rend. Acad. Sci.
U.R.S.S. [N.S.] 4:405 (1936); Chem. Abstr. 31:3449 (1937)). A suspension of the amide (183 mg, 1 mmol) in anhydrous Et20 (9 mL) was slowly added to a stirred suspension of LiAlH4 (114 mg, 3 mmol) in Et20 (15 mL). After addition was complete, the mixture was heated at reflux for 2 h and then allowed to stir overnight at room temperature. The reaction mixture was cooled to O’C and excess LiAlH4 was decomposed by successive addition of water (2 mL), 2N NaOH (2 mL) and water (5 mL). After stirring vigorously for 20 min, the mixture was filtered and the inorganic residue was washed with warm Et20 (3x8 mL). The combined Et20 solution was dried over anhydrous K2C03 and evaporated to dryness. The residue was distilled under reduced pressure to yield a clear oil (99 mg, 59%); bp 30-36’C (0.35 mm), Lit. bp 108-113’C (15 nm) (Skinner, C.6., et al., J. Am. Chem. Soc. 79:2844 (1957)). A solution of the free base in anhydrous Et20 was added to a solution of oxalic acid (52 mg) in anhydrous Et2O (8 mL) with continuous shaking. The precipitated solid was recrystallized from MeOH/anhydrous Et20; mp 164’C (see Table 8).
Radioligand Binding. The σ binding assay was conducted using guinea pig (Taconic) brain membranes and [ H]di-o-tolylguanidine (DTG) as radioligand. Briefly, membranes (P2 microsomal fraction) were diluted 1:3 with 50 mM Tris HCl (pH 7.4) and 0.4 mL was combined with 50 pi [3H]DTG (1-2 nM final concentration) and 50 pi of competing drug or buffer. After 90 min at room temperature, incubation was terminated by rapid filtration under vacuum through Whatman GF/B glass fiber filters using a Brandel 48-well cell harvester. Filters were washed three times with 5 mL of cold Tris HCl buffer and each filter was suspended in 5 mL of Cytoscint (ICN Biomedical). Radioactivity was measured by liquid scintillation spectrometry at a counting efficiency of 50%. Non5 specific binding was measured in the presence of 10 μΜ haloperidol. -120Microanalytical Data Calculated/Found C H N 10 152 70.56 7.61 3.92 70.43 7.59 3.93 136 71.66 8.11 3.63 71.37 8.08 3.59 144 71.94 8.45 4.20 15 71.88 8.49 4.19 8 67.54 7.29 3.75 67.47 7.33 3.69 145 71.94 8.45 4.20 71.87 8.49 4.21 20 122 62.02 7.12 3.81 62.01 7.22 3.81 146 71.18 8.48 4.15 71.23 8.46 4.17 135 68.90 7.06 4.23 25 68.52 7.22 4.23 112 65.99 8.80 4.53 65.82 8.75 4.51 130 65.99 8.80 4.53 65.92 8.79 4.57 30 131 58.27 10.19 5.66 58.20 10.17 5.66 193 73.06 10.22 4.75 72.95 10.23 4.74 92 73.06 10.22 4.73 72.96 10.22 4.77 126 58.10 9.76 5.23 5 58.18 9.77 5.22 127 61.60 9.97 5.12 61.51 9.96 5.12 128 62.71 10.16 4.92 62.69 10.17 4.87 10 125 63.94 8.19 5.10 64.03 8.24 4.98 94 73.06 10.22 4.73 73.12 10.27 4.78 23 70.55 12.01 4.57 15 70.36 12.01 4.57 £4 71.21 12.11 4.37 71.27 12.04 4.33 TABLE 8. Physicochemical properties of new sigma receptor ligands Compd Method Recryst. Solv. Mp <“C) Yield1 Formula 152 A PrOHZEtOAc 140-141 49C19H:5NC2H2°4 135 D PrOH 141-142 73 c,,h,9n.c,h,o< 144 A MEK 115 37 C^H^NO.HCI 173 B MEK 173-174 2 ο19η,?νο.ο,η,ο4 145 A MeOH/El,O 160 40 Ο,0Η,7ΝΟ.Ηα 172 F MeOH/Ει,Ο 151-153 39 Cj9H,5NO.HBrb 146 A MeOH/EbO 233-235 33 C,0H;1NO.HClb 135 G EtOAc 133-134 35 c17h21n.c,h,o/ 112 E EtOAc 130-131 24 c,5h,5n.c,h:o4 130 B McOH/EtiO 139-140 65 c]5h,,n.c,h,o4 131 C iPrOll/EbO 101-102 12 CinH2?N.C2H;04 93 A iPrOH/EbO 17M73 39 CjglLqN.HCl 92 E MEK 203-205 53 C,gH,9N.HCJ 126 H MeOH/Et,O 164 48cnH23NC2H2°4d 127 B MeOH 191 28C12H25NC2H2°4 128 B MeOH 152 25 CnH27N.C-,H204 125 B MeOH 163 43 Οι,Η,,Ν.^)^ 94 A iPrOH/EtiO 184-185 34 c18h,9n.hci 151 A MeOH/ EtOAc 223-224 73CisH35NHCie 152 D MeOH/ EtOAc 162-163 61 C19H37N.HCle (a) No attempt was made to optimize yields. Yields are overall % yields. (b) Crystallized with 0.2 moles of H-O. (c) Crystallized with 0.1 moles of H-,O. (d) Crystallized with 0.5 moles of H-,0. (e) Crystallized with 0.25 moles of H-,0.
RESULTS and DISCUSSION Binding data are shown in Table 9. N-Methylation of Nsubstituted phenylethylamines typically doubles and aromatic substitution at the 3- and 4-position has essentially no effect on sigma receptor affinity. N-Methylation of 151 and 111 (i.e., 152 and 136, respectively) doubles affinity (Table 9). Incorporation of phenolic or methoxy groups at the 3- and 4-positions (145, 172, and 146) has little effect on affinity, whereas the 2-hydroxy derivative 8 binds with about 7-fold lower affinity than its unsubstituted parent 89 (Ki = 2.4 nM).
Excision of the N-alkyl chain separating the amine from phenyl-B, to afford the aniline derivative 135 (Ki = 12 nM), reduces affinity by only 6-fold; this decrease in affinity may reflect a decrease in the basicity of the amine.
The above results (i.e., lack of influence of chain length and aromatic substitution on sigma affinity) suggest that the aromatic amine substituent plays only a small role in binding, and that it may be possible to replace the phenyl-B ring with a non-aromatic group. Indeed, compound 122, which may be viewed either as either an N-methyl analog of 89 where the phenyl-B group has been replaced by methyl, or as an analog of T36 where -123the phenyl group has been eliminated, binds with high affinity (Ki * 2.4 nM). Interestingly, the phenyl-A ring can also be replaced by a methyl group (130; Ki = 3.8 nM) with little reduction in affinity. Replacement of both phenyl groups by methyl (Hl; Ki - 45 nM) results in a significant reduction in affinity. Apparently, either phenyl-A or phenyl-B can be replaced by a methyl group; however, replacement of both results in decreased affinity.
Because both phenyl groups are unnecessary for binding, we examined several additional compounds bearing a single phenyl.
Compound 93, the phenyl-B reduced analog of 151, binds with twice the affinity (Ki = 1.2 nM) of 151· Compound 92 (Ki = 2.4 nM), an analog of 93 where the position of the amine has been shifted, also binds with high affinity.
Examination of three simple 5-(cyclohexyl)pentylamines, the primary amine 126 (Ki = 200 nM), the N-monomethylamine 127 (Ki 10 nM), and the N,N-dimethylamine 128 (Ki = 2.6 nM), reveals that tertiary amines are most favorable for binding. The affinity of the latter compound 128, was compared with the aromatic analog 125 (Ki = 35 nM), revealing that reduction results in about a 10-fold increase in affinity. However, reduction of the phenyl-A ring of 151 (94; Ki = 3.4 nM) results in essentially no change in affinity. This may be related to the fact that 128 and 125 are tertiary amines whereas 94 is a secondary amine; nevertheless, it is apparent from these results that both phenyl-A and phenyl-B can replaced with a cyclohexyl group. The final two compounds examined, 151 and 152, possess two cyclohexyl shortened or lengthened without adverse effect on sigma receptor affinity (e.g., see compounds Hi, 89, Hi and 76)· That is, affinity is independent of the length of the alkyl chain that separates the -124phenyl-B ring from the amine. To account for these observations, the sigma receptors may possess at last two distinct aromatic binding sites: one that utilizes the phenyl-B ring of phenylethylamines, and one that utilizes the phenyl-A ring of the phenylpentylamines. The phenyl-B ring of 151, §2, 111 and 76 is unnecessary for binding; it can be replaced by a small alkyl group (e.g. UL2.) or with a cyclohexyl group (e.g. Hl) with retention of affinity. Interestingly, the phenyl-A ring can also be replaced with a methyl or cyclohexyl group (e.g., 130 and 94, respectively) with little change in affinity. Had only one of the phenyl groups been replaceable by methyl (or cyclohexyl) without loss of affinity, this would have provided direct evidence for the two distinct sites on sigma receptors. Nevertheless, in as much as compounds such as 151 and 152 bind with high affinity, it would appear that, independent of mode of binding, an aromatic moiety is not a requirement for high affinity.
Table 9 Sigma receptor binding data.* X-(CH2)5-N(RHCH2)n-Y X R n Y Ki nM (SEM) 77 Phenyl H 1 Phenyl 2.0 89 Phenyl H 2 Phenyl 2.4 111 Phenyl H 3 Phenyl 2.7 76 Phenyl H 4 Phenyl 2.5 137 Phenyl Me 1 Phenyl 1.0(+0.4) 136 Phenyl Me 3 Phenyl 1.6( + 1.2) 144 Phenyl H 2 2-OMe Phenyl 4.0(+0.9) 173 Phenyl H 2 2-OH Phenyl 15.6(+4.1) 145 Phenyl H 2 3-OMe Phenyl 1.5(+0.4) 172 Phenyl H 2 3-OH Phenvl 6.8(±0.9) 146 Phenyl H 2 4-OMe Phenyl 2.2(+0.3) 135 Phenyl H 0 Phenyl 12.2(+4.0) 112 Phenyl Me 2 Methyl 2.4(+0.4) 130 Methyl Me 2 Phenyl 3.8(+0.1) 131 Methyl Me 2 Methyl 45( + 14) 93 Phenyl H 1 Cyclohexyl 1.2(+0.0) 126 Cyclohexyl H 0 H 200( + 7) 127 Cyclohexyl H 0 Methyl 10( + 1) 128 Cyclohexyl Me 0 Methyl 2.6(+0.7) 125 Phenyl Me 0 Methyl 35( + 8) 94 Cyclohexyl H 1 Phenyl 3.4(+0.3) 151 Cyclohexyl H 1 Cyclohexyl 1.2(+0.1) 152 Cyclohexyl Me 1 Cvclohexvl 1.6(+0.2) -126EXAMPLE 7 Discrimination between the Siqma-1 and Siqma-2 Binding Sites Materials [ H](+)pentazocine (35 Ci/mmol) was generously provided by 5 Dr. Steven Hunt of DuPont/NEN. [3H]DTG was purchased from DuPont/NEN. (+)Pentazocine was obtained from the NIDA Research Technology Branch, Division of Research. Guinea pig whole membrane preparations (P2 microsomal fraction) were obtained and used as described by Weber, E. et al.. Proc.Natl.Acad.Sci 23:8784-8788 (1986).
Sigma-1 binding assay ([3H](+)pentazocine) The sigma-1 selective binding assay was performed using [3H](+)pentazocine as the radioligand (3-4 nM final concentration unless otherwise specified) and approximately 100 pg of guinea pig membranes in a final volume of 500 μ} of 50 mM TRIS-HC1, pH 8.0. Non-specific binding was determined in the presence of 10 μΜ haloperidol. For the standard equilibrium assay, the mixtures were incubated for 4-5 hours at 37°C, quenched with 4 ml of ice cold incubation buffer and rapidly filtered over Whatman GF/B fiber filters, followed by three 4 ml rinses with additional ice cold incubation buffer. The radioactivity on the filters was determined by scintillation spectrometry at an efficiency of about 50 % using Cytoscint (ICN) scintillation fluid.
Sigma-2 binding assay The sigma-2 selective binding assay was performed using about 2 nM [3H]DTG as the radioligand in the presence of 200 nM (+)pentazocine to block the sigma-1 sites, with 400 pg of guinea pig membranes in a total volume of 0.5 ml of 50 mM TRIS-HC1, pH 7.4. Non-specific binding was determined in the presence of 10 μΜ haloperidol. For the standard equilibrium assay, the mixtures were incubated for 30 min. at room temperature, then filtered and the radioactivity determined as described above. -127Data Analysis Equilibrium binding data were analyzed by least squares nonlinear regression techniques as described by Fischer, J.B. and Schonbrunn, A., J. Biol. Chem. ££3:2808-2816 (1988). Two site binding curves were fit to an equation describing the sum of two independent sites with Hill slopes of T. Affinity constants (KJ values were calculated from IC50 values using the Cheng-Prussoff equation (Cheng, Y.-C. and Prusoff, W.H., Biochem. Pharm, ££:3099-3108 (1973)). The results are reported in Table 10 for DTG, several lots of an N,N'-disubstituted guanidine, haloperidol and BMY-14802, as well as for certain of the compounds of the invention. For comparison, Table 11 shows the sigma-) 1 and sigma- 2 binding data for a number of other known compouds. 15 TABLE 10 SlQHA-t (a M) Kl VS. 3H-PEtfTAZOCIIC Sian-2 (a U) Kl vs. 3HDTG+Pc«T*20citc 20 cap. MEAN SH n MEAN SBI n S1/S2 Ratio N,Ν’-Di-(o-tolyl)guanidine 40.67 1 .67 3 52.39 4.14 4 Haloperidol 0.47 0.09 3 11.50 0.55 3 BMY-14802 271.00 52.00 2 132.60 43.86 3 1 R(-)N - (1-phenyl-2-propyl)-3phenylpropylamine 10.75 2.06 2 60.75 1 .85 2 10 ( + ) N·(1-phenyl-2-propyl)-4pEenylbutylamine 4.68 1 .26 3 53.20 6.00 2 11 R(-) N-(1-phenyl-2-propyl)-3(1-naphthylJpropylamine 8.60 1.40 2 280.00 31.00 2 12 R(-) N-(1-phenyl-2-propyl)-3(2-naphthyl)propylamine 5.73 1 .71 3 258.00 48.00 2 15 Di-(3-phenylpropyl,-amine 11.37 2.00 3 63.90 1 .37 3 16 ( + ) N-11 - (1 ’-Naphthyl)-2propylj-3-phenylpropylamine 9.25 0.75 2 152.00 14.00 2 17 (♦) N-[1 -(2’-Naphthyl)-2propyl)-3-phenylpropyiaaine 31 .00 13.00 2 222.00 82.00 2 18 N-(3-phenylpropyl)-1-(2naphthyl)-2-propylamine 25.70 6.30 2 15.13 2.61 3 20 ( + ) N-11 -(3’-Bromophenyl)-2propyl)-3-phenylpropylamine 9.65 2.35 2 26.15 10.35 2 21 (+, N-[1 -(4’-Bromophenyl)-2propylj-3-phenylpropylamine 11.97 2.85 3 39.13 9.20 4 22 ( + ) N-11 -(4’-Iodophenyl)-2- 17.67 3.64 3 76.03 6.29 4 propyl)-3-phenylpropylamine 0.776 0.041 2.044 0.177 0.088 0.31 0.022 .178 0.061 0.140 1.7 0.369 0.306 0.232 »>ΟΜ-1 (a H) 81«·»-2 (X N) S1/S2 Kl v*. 3H-Peitta2oc»e Ki «. 3H- Ratio OTG+Pemtazdciic eep. t MEAN sa n MEAN sai n 23 (♦) N-[1 -(3’-TrifluoroRethyl)2~propyl]-3-phenylpropylamine 8.75 4.05 4 20.85 3.48 4 0.420 32 1 -(3'-Chlorophenyl)-4-(2phenylethyl(piperazine 14.95 7.40 4 42 .'43 4.02 3 0.352 34 (♦) 1-Phenyl-2-aminopenxane 1177.00 415.64 3 10276.00 276.00 3 0.115 40 4-Hydroxy-4-phenyl-1-(3phenylpropyl(piperidine 0.66 0.36 3 9.20 2.07 3 0.074 40 4-Hydroxy-4-phenyl-1-(3phenylpropyl(piperidine 0.66 0.36 3 7.03 2.87 3 0.096 43 N-(3-phenylpropyl) -1-phenyl-2propylamine 51 .47 11 .44 3 37.50 11.02 3 1 .37 44 N-(4-phenylbutyl)·1-phenyl-2pcopylamine 19.43 4.96 3 35.80 3.34 3 .543 45 N-(5-phenylpentyl) -1-phenyl-2propylamine 0.68 0.21 4 18.47 2.27 3 .048 60 N-(2-Naphthyl(piperazine 219.87 60.75 3 5599.00 610.04 3 0.C39 64 N·Phenyl-N’-propylpiperazine 81 .60 13.29 3 538.00 42.00 3 0.152 70 Di-13 - (2 ’ -Naphthyl(propyl(amine -- -- 010000.00 0.00 2 71 N-(4-phenylbutyl(phenethylamine 2.60 0.31 4 118.67 14.99 3 0.C22 74 Di-N-13-(21-naphthyl) propyl-Nethylamine 29.98 11.06 3 460.75 165.40 4 0.065 75 N-(4-phenylbutyl(benzylamine 9.61 2.66 5 161.63 31 .37 3 0.059 76 N-(5-phenylpentyl)-(4phenyl(butylamine 0.48 0.05 2 66.00 5.00 2 0.007 77 N-(5-phenylpentyl)benzylamine 0.32 0.10 3 34.33 6.87 3 0.009 79 N-(4-phenylbutyl) - N ’ benzylpiperazine 0.17 0.02 4 6.99 1.14 3 0.024 60 N-4(4-phenylbutyl)-N‘benzoylpiperazine 71.63 2.51 3 965.00 65.00 2 0.074 63 N-(3-phenylpropyl) -1 -(pethoxyphenyl)-2-propylamine 3.36 0.30 2 33.50 0.50 2 0.101 87 N-(3- phenylpropyl(phenethylamine 11.27 0.97 2 90.10 37.90 2 0.125 69 N- (5- phenylpentyl(phenethylamine 0.17 0.00 2 14.60 5.31 2 0.012 90 N-(7-phenylheptyl)benzylamine 2.30 1 .00 2 36.47 9.44 3 0.060 91 N-(7- phenylheptyl(phenethylamine 1 .47 0.63 4 33.23 10.16 3 0.044 94 N-(5- cyclohexylpentyl(benzylamine 0.81 0.17 3 43.57 6.76 3 0.019 96 N-phenyl-N’·(3-(1 - phthalimido(propyl(piperazine 3100.33 1597.63 3 149.18 16.06 4 67.619 97 N-phenyl-Ν' -(4-1- phthalimido(butyl(piperazine 195.33 31.78 3 20.36 0.86 4 9.567 101 N-(4-phenylbutyl)-1-phenyl-2butylamine 2.70 0.60 2 104.10 12.90 2 0.026 103 N-(4-phenyl-3(E)-butenyl)-N’- 26.67 3.67 3 2544.67 699.93 3 0.011 methylpiperazine Sl«t-1 (Μ M) Slttft-2 (n M) S1/S2 KI VS. 3H-PCMTA2DCIIC Kt vs. 3H- Ratio DTG-PtKTAZOCINE cep. < MEAN SOI n MEAN SOI n 104 N-(4-phenyl-3(Z)-butenyl)-N’ethylpiperazine 28.67 6.67 3 1306.00 54.00 2 0.022 105 N-(4-(3-trifluoroeethyl)-3-(Z)butenyl)-N-»ethylpiperazine 1.50 0.26 3 176.53 53.26 3 0.008 106 N-(4-phenyl)-N'ethylpiperazine 19.33 3.93 3 898.80 180.96 5 0.022 111 N-(5-phenylpentyl)-3phenylpropylamine 0.28 0.03 3 9.84 4.58 3 0.029 112 N-aethyl-N-propyl-5phenylpentylanine 0.29 0.05 3 40.48 10.77 5 0.DC7 113 N-Methyl-N-(3-phenylpropyl) · 1 phenylisopropylamine 0.51 1 4.87 0.72 3 0.105 117 N-(5-phenylpentyl)-4benzylpipendine 0.58 0.26 3 2.78 0.33 3 0.210 120 N-(4-(1-phthalimido)butyl)-N’(o-«ethoxyphenyl)piperazine 511.67 115.79 3 76.57 24.14 3 6.683 124 N- (5-phenylpentyl)pipendine 0.46 0.01 3 49.90 8.87 • 0.010 125 N,N-Dimethyl-5- phenylpentylamine 10.45 1 .07 3 965.00 55.00 2 0.011 126 5-cyclohexylpentylamine 191.33 16.76 3 2554.00 64.00 2 0.075 127 N-methyl-5cyclohexylpentylamine 6.7B 0.92 4 346.00 29.00 2 0.020 128 N,N-Dimethyl-5- cyclohexylpentylamine 0.26 0.03 3 195.33 27.82 3 0.0C1 129 N-Benzyl-Ν’-(5-phenylpentyl) piperazine 0.41 0.04 2 11.32 1 .70 3 .036 134 N-Benzyl-N-(3-phenylpropyl)-1phenyl -2-propylamine 127.90 25.04 5 470.75 37.40 4 0.272 137 N-Benzyl-N-«ethyl-5phenylpentyl amine 0.19 0.04 2 12.55 0.15 2 0.015 140 N- (3 - phenyl propyl )pipendine 48.94 4.39 3 146.50 3.50 2 SlONA-1 ( N) BlOM-2 ( M) S1/S2 Kl VS. 3H-PEMTA2DCIIC Kl VS. 3H-0TG Ratio vPentazbciie -130TABLE 11 COMPOUND MEAN sat n MEAN sat n 5 (♦)3-PPP 47.67 1 .45 3 493.00 40.07 3 0.097 (-J3-PPP 312.33 17.89 3 1261.00 97.32 3 0.248 (♦(Butaclaaol 583.67 177.34 3 1399.67 B6.15 3 0.417 (- (Butaclaaol 69.33 14.89 3 3422.67 723.43 3 0.020 10 Chlorproaazine 336.00 23.56 4 714.00 201.00 2 0.471 Dextroaethorphan 522.00 239.06 3 14990.00 2653.32 3 0.035 Fluoxetine 56.75 8.8353 4 10000 0 3 Fluphenazine 31.67 7.62 3 67.33 6.50 4 0.470 Ifenprodil 5.63 0.64 3 2 .39 0.39 3 2 .444 15 (♦(Pentazocine 1 .60 0.09 4 906.33 27.39 3 0.002 (·(Pentazocine 114.00 20.30 3 242.33 8.97 3 0.470 Perphenazine 25.10 7.45 3 80.35 0.05 2 0.312 Praairacetas 10000.00 0.00 3 10000.00 1 1 .000 Beaoxipnde 312.00 36.58 4 1617.00 267.38 3 0.193 20 Riaoazole 1156.00 183.06 3 264.67 86.11 3 4 .368 (*)SKF 10047 148.00 19.09 3 16173.25 3447.26 4 0.009 (-)SKF 10047 364 0.00 625.19 3 9131.25 1574.11 4 0.399 Thioridazine 520.50 81.22 4 334.50 82.50 2 1 .556 Triflupenzine 561.25 135.80 4 160.50 47.50 2 3.497 25 Spiperone 10000.00 1 0 EXAMPLE 8 Structure-Activity Analvsis with Regard to : Siqma-1 As shown in Table 12, compound 1 binds with an IC 50 value of 10.8 nM at sigma-1. Substitution on the phenyl A ring has essentially no effect on binding.
N Table 12 Cmp.# X Isomer IC,n (nM) . 1 H R(-) 10.8 43 H S(+) 20 3-Br (i) 9.6 21 4-Br (i) 12.0 22 4-1 RU 17.7 23 3-CF^ i±) 8.8 83 4-OEt (±) 3.4 Replacement of the phenyl-A with 1-naphthyl has no effect on binding. (Compare compound no. 1 to compound no. 16 (Table 13)). However, replacement of the 1-naphthyl group with a 2naphthyl group reduces sigma-1 affinity about three fold. (Compare compound no. 16 to compound no. 17 (Table 13)). In addition, replacement of phenyl-B with 1-naphthyl or 2-naphthyl has little effect on binding. (Compare compound no. 1 to compound nos. 11 and 12 (Table 13)).
Table 13 Cmp._Structure_Siqma-1 IC50 (nM) -132Increasing the length of the N-phenyl-B alkyl chain of compound No. 1 from 3 to 4 methylene groups doubles affinity to the sigma-1 receptor. A further increase to 5 methylene groups substantially increases affinity. (Compare compound no. 1 to compound nos. 10 and 45 (Table 14)). Removal of the σ-methyl group has little effect on sigma-1 binding. (Compare compound no. 1 to compound no. 87 (Table 14)).
I H Table 14 Cmp. # n Isomer IC,n (nM) 1 R = CH, 3 R(-) 10.8 10 R = CH, 4 (±) 4.7 44 R = CH, 4 S(4) 45 R = CH, 5 S(+) .88 87 R = H 3 11.3 Holding the methylene groups linking the phenyl-B ring constant at four and removing the σ-methyl group does not affect substantially the affinity to sigma-1. (Compare cmp. nos. 71 and 10 (N-phenyl-A; n=2), which have binding affinities of 2.6 and 4.7 nM, respectively). Shortening the number of methylene groups linking the phenyl-A substituent to one decreases affinity. (Compare cmp. nos. 71 and 75, which have binding affinities of 2.6 and 9.6, respectively.) In contrast, increasing the number of methylene groups linking the phenyl-A ring to five increases affinity. (Compare cmp. nos. 71 and 76, which have binding affinities of 2.6 and 0.48 nM, respectively.) Since five methylenes between the phenyl-A ring and the amine is associated with high binding to sigma-1, a homologous series of related analogs were examined (Table 15).
Table 15 cmp. # n R IC,n (nM) 76 4 H 0.48 111 3 H 0.28 89 2 H 0.17 77 1 H 0.32 137 1 CH, 0.19 As is evident from Table 15, the length of the N-phenyl-B chain has little effect on binding to the sigma-1 site. In addition, elimination of the N-phenyl-B ring has little effect on sigma-1 receptor binding. (Cmp. #112, N-methyl-N-propyl-5phenylpentylamine, IC5O=0.29 nM). However, an increase in the phenyl-A chain length results in a decrease in affinity to sigma1 (compare cmp. nos. 90, N-benzyl-7-phenylheptylamine, and cmp. 91, N-phenethyl-7-phenylheptylamine which have binding affinities at sigma-1 of 2.3 and 1.5 nM, respectively).
Reduction of the phenyl-A ring of cmp. no. 77 (N-benzyl-5phenylpentyl amine, IC5O=0.32) has little effect on sigma-1 binding affinity (cmp. #94, N-benzyl-5-cyclohexylpentylamine, IC5O=0.81).
Removal of the aromatic phenyl-B ring of the A-ring cyclohexyl compounds is also well tolerated. However, the tertiary amines appear to have enhanced affinity compared to the primary and secondary amines (Table 16).
Table 16 Cmp. #_Structure_Siqma-1 IC50 (nM) 0.81 -13410 128 127 0.26 6.8 The most selective sigma-1 binding compound is N,Ndimethyl-5-cyclohexylpentylamine (cmp. # 128, sigma-2/sigma-l selectivity of 650). Other sigma-1 selective ligands include Nmethyl-5-cyclohexylpentylamine (cmp. # 127, sigma-2/sigma-l selectivity of 51), 5-cyclohexylpentyl-amine (cmp. # 126, sigma2/sigma-l selectivity of 13), N-methyl-N-propyl-5phenylpentyl amine (cmp. # 112, sigma-2/sigma-l selectivity of 137), N-benzyl-7-phenylheptylamine (cmp. # 90, sigma-2/sigma-l selectivity of 126), N-(5-phenyl)pentylpiperidine (cmp. # 124, sigma-2/sigma-l selectivity of 100), and Ν,Ν-dimethyl-5phenylpentylamine (cmp. # 125, sigma-2/sigma-1 selectivity of 96).
EXAMPLE 9 Structure-Activity Analysis with Regard to Siqma-2 Many alterations in structure do not improve the binding of the compounds of the present invention to the sigma-2 site. Compound #1 binds at the sigma-2 site with modest affinity (60 nM). Aromatic substitution in the phenyl-A ring has little effect on binding at sigma-2 (Table 17).
H Table 17 cmp. # X Isomer ICqn (nM) 1 H R1-) 60 43 H S(+) - . 20 3-Br (i) 26 21 4-Br t±) 39 22 4-1 R(-) 76 23 3-CF, (±) 21 83 4-OEt (±) 34 However, replacement of phenyl-A with a naphthyl ring decreases affinity to sigma-2 several fold. (Compare cmp. #1, IC50= 60 with cmp. # 16, N-(3-phenylpropyl)-l-(l-naphthyl)-2isopropylamine, and #17, N-(3-phenylpropyl)-l-(2-naphthyl )-2isopropylamine, which have binding affinities of 150 and 220 nM, respectively.) In addition, replacement of phenyl-B with a naphthyl ring reduces affinity about 4 fold. (Compare cmp. #1, IC50= 60 with cmp. # 11, N-(3-(1-naphthyl)propyl)-1-phenyl-2isopropylamine, and #1, N-(3-(2-naphthylJpropyl)-l-phenyl-2isopropylamine, which have binding affinities of 280 and 260 nM, respectively.) Removal of the σ-methyl group of cmp. # 1 has essentially no effect (IC50 of cmp. no. 87, N-(3-phenylpropyl)-2phenethylamine, = 90 nM). Increasing the phenyl-B chain length from 3 to 4 also has little effect (IC50 of cmp. 71, N-(4phenylbutyl)-2-phenethylamine = 120 nM). Decreasing the phenyl-A alkyl chain length by one methylene slightly decreases affinity (IC50 of cmp. # 75, N-(4-phenylbutyl)benzylamine, = 160 nM).
However, it is possible to improve binding affinity to sigma-2 by keeping the phenyl-B chain at 4 methylenes and increasing the phenyl-A chain to 5 methylenes to give a 3-fold increase in affinity (Table 18). An alkyl chain of n=3 appears to be optimal. In addition, N-methylation triples affinity. s'.
Table 18 cmp. # n R IC,n (nM) 76 4 H 48 111 3 H 9.8 89 2 H 15 77 1 H 34 37 1 CH, 12 Removal of the phenyl-B ring results in a reduction in 10 sigma-2 affinity. (Compare cmp. Ill, N-(3-phenylpropyl)-5phenyl pentyl amine, with N-methyl-N-propyl-5-phenylpentylamine, IC5O=40 nM).
The most selective sigma-2 ligand of the present invention is N-phenyl-N'-(3-(l-phthalimido)propyl)piperazine (cmp. #96) which has a sigma-l/sigma-2 ratio of 87. Other sigma-2 selective ligands include N - ( 4 - phtha 1imido)buty 1 - N ' - ( o methoxyphenyl)piperazine (cmp. #120; sigma-l/sigma-2 ratio of 7) and N-(4-phthalimidojbutyl-N'-phenylpiperazine (cmp. #97; sigmal/sigma-2 ratio of 10).
Having now fully described this invention, it will be understood by those of skill in the art that the same can be practiced within a wide range of equivalent conditions, formulations, structural variations and other parameters without affecting the scope of the invention or any embodiment thereof.

Claims (71)

  1. WHAT IS CLAIMED IS: 1. A method of treating a human being suffering from drug abuse, gastrointestinal disorder or depression, which comprises administering to said human a therapeutically effective amount of a compound of the formula: -13710 wherein: Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, wherein the substituent is selected from the group consisting of chloro, fluoro, bromo, iodo, CF 3 , C-|-C 6 alkoxy, C 2 C 6 di al koxymethyl, alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C-pCg haloalkyl, C 1 -C g haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C g acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, (j-Cg alkylthio, C^Cg alkylsulfonyl, C^Cg haloalkylsulfonyl, Cj-Cg al kyl sul finyl, C^Cg haloalkylsulfinyl, arylthio, 0,-Cg haloalkoxy, amino, C^Cg alkylamino, C 2 -C 15 dialkylamino, hydroxy, carbamoyl, C^Cg N-al kyl carbamoyl, C 2 -C 15 Ν,Ν-dialkylcarbamoyl, nitro, C 2 -C 15 dial kyl sulfamoyl; R is hydrogen or C^Cg alkyl; R 1 is selected from the group consisting of hydrogen, Cj-Cg alkyl, C-,-C 6 alkoxy, fluoro, chloro, bromo and =0; or R and R 1 together form a morpholino, piperazinyl or piperidinyl ring; n is 0-5; W is -(CH 2 ) p - or -Η H-, wherein p is 1-3; X is -(CH 2 ) q -, wherein q is 1-6; -(CH 2 ) r -(M-(CH 2 ) r -, -138-(CH 2 ) r -CH=CH-(CH 2 ) r -; II -(CH 2 ) r -C-(CH 2 ) r -; -(CH 2 ) r -Y-(CH 2 ) r -, wherein each r is independently 0-3 and wherein Y is 0 or S; or C-j-Cg alkyl (wherein Z is hydrogen); Z is hydrogen, cycloalkyl, aryl, an aryl-substituted carboxylic acid group, or heteroaryl wherein Z may be substituted by chloro, fluoro, bromo, iodo, CF 3 , C^-Cg alkoxy, C 2 -C 6 di al koxymethyl, C 6 alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C^Cg haloalkyl, C^-Cg haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, C^Cg alkylthio, C-,-C 6 al kyl sul fonyl, C^-Cg haloalkyl sulfonyl, C^Cg alkylsulfinyl, C.,-C 6 hal oal kyl sul f inyl, arylthio, C.,-Cg haloalkoxy, amino, C.,-C 6 alkylamino, C 2 -C 15 dialkylamino, hydroxy, carbamoyl, -C 6 N-al kylcarbamoyl, C 2 -C 15 Ν,Ν-dialkylcarbamoyl, nitro, C 2 -C 15 dialkylsulfamoyl or an ortho methylene-dioxy group; wherein said compound exhibits high binding activity with respect to the sigma receptor.
  2. 2. A method of treating a human being suffering from a central nervous system disorder, which comprises administering to said human a therapeutically effective amount of a compound of the formula: R 1 wherein: -139Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, wherein the substituent is selected from the group consisting of chloro, fluoro, bromo, iodo, CF 3 , C^Cg alkoxy, C 2 C 6 dialkoxymethyl, 0,-Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, 5 carboxy, carboxamido, C^Cg haloalkyl, C^Cg haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C g heterocycloalkyl, C^Cg alkylthio, C^Cg alkylsulfonyl, C^Cg haloalkylsulfonyl, Cj-Cg alkylsulfinyl, C^Cg haloal kyl sul finyl, 10 arylthio, C^Cg haloalkoxy, amino, C^Cg alkylamino, C 2 -C 15 dialkylamino, hydroxy, carbamoyl, C.,-Cg N-alkylcarbamoyl, C 2 -C 15 Ν,Ν-dialkylcarbamoyl, nitro, C 2 -C 15 dialkylsulfamoyl; R is hydrogen or C^Cg alkyl; R 1 is selected from the group consisting of hydrogen, C-|-C 6 15 alkyl, C^Cg alkoxy, fluoro, chloro, bromo and =0; or R and R 1 together form a morpholino, piperazinyl or piperidinyl ring; n is 0-5; W is -(CH 2 ) p - or -Η H-, wherein p is 1-3; 20 X is -(CH 2 ) q -, wherein q is 1-6; -(CH 2 ) r -C<-(CH 2 ) r -, -(CH p ) r -CH=CH-(CH 2 ) r -; II 25 -(CH 2 ) r -C-(CH 2 ) r -; -(CH 2 ) Γ -Y-(CH 2 ) r -, wherein each r is independently 0-3 and wherein Y is 0 or S; or Cj-Cg alkyl (wherein Z is hydrogen); Z is cycloalkyl or an aryl-substituted carboxylic acid group, 30 wherein Z may be substituted by chloro, fluoro, bromo, iodo, CF 3 , C-,-C 6 alkoxy, C 2 -C 6 dial koxymethyl, C 7 -C 6 alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C^Cg haloalkyl, C^Cg haloalkylthio, allyl, aralkyl, C 3 -C g cycloalkyl, aroyl, aralkoxy, C 2 -C 6 carboxylic acyl, aryl, substituted aryl, heteroaryl, 35 substituted heteroaryl, C 3 -C 6 heterocycloalkyl, C^Cg alkylthio, -C 6 alkylsulfonyl, C^Cg haloalkylsulfonyl, C-,-Οθ alkylsulfinyl, C,-C 6 haloalkylsulfinyl, arylthio, C^Cg haloalkoxy, -140amino, C 1 -C 6 alkylamino, C 2 -C 15 dialkylamino, hydroxy, carbamoyl, C-j-Cg N-al kyl carbamoyl, C 2 -C 15 Ν,Ν-dialkylcarbamoyl, nitro, C 2 C 15 di alkylsulfamoyl or an ortho methylene-dioxy group; wherein said compound exhibits high binding activity with 5 respect to the sigma receptor.
  3. 3. A method of treating a human being suffering from drug abuse, gastrointestinal disorder or depression, which comprises administering to said human a therapeutically effective 10 amount of a compound of the formula: R 1 R I I T— (CH) n -N-X-Z 15 wherein: R is hydrogen or C.,-C 6 alkyl; T is aryl, heteroaryl, substituted aryl, substituted heteroaryl, or cycloalkyl, wherein said substituent is selected 20 from the group consisting of chloro, fluoro, bromo, iodo, CF 3 , C-pCg alkoxy, C 2 -C 6 d ial koxymethyl, C^-Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C^Cg haloalkyl, C^Cg haloalkylthio, allyl, aralkyl, C 3 -C g cycloalkyl, aroyl, aralkoxy, C 2 -C 6 acyl, aryl, substituted aryl, heteroaryl, substituted 25 heteroaryl, C 3 -C g heterocycloalkyl, Cj-Cg alkylthio, -C 6 alkylsulfonyl, C^Cg haloalkylsulfonyl, -C 6 al kyl sul finyl, 0,-Cg haloalkylsulfinyl, arylthio, C-|-C 6 haloalkoxy, amino, C^Cg alkylamino, C 2 -C 15 dialkylamino, hydroxy, carbamoyl, C^Cg Nalkylcarbamoyl, C 2 -C 15 Ν,Ν-dialkylcarbamoyl, nitro, C 2 -C 15 dial30 kylsulfamoyl, and an ortho methylenedioxy group; R 1 is selected from the group consisting of hydrogen, -C 6 alkyl, -C 6 alkoxy, fluoro, bromo, chloro, iodo and =0; or R and R 1 together form a morpholino, piperazinyl or piperidinyl ring; 35 n is 0-5; X is -(CH 2 ) q -, wherein q is 1-6; -(CH 2 ) r -OC-(CH 2 ) r -, wherein r is 0-3; -(CH 2 ) r -CH=CH-(CH 2 ) r -; -141-{CH 2 ) r -C-(CH 2 ) r -; -(CH 2 ) r -Y-(CH 2 ) r -, wherein each r is independently 0-3 and 5 wherein Y is 0 or S; or C^Cg alkyl (wherein Z is hydrogen); Z is hydrogen, cycloalkyl, aryl, an aryl-substituted carboxylic acid group, or aryl wherein Z may be substituted by chloro, fluoro, bromo, iodo, CF 3 , C^Cg alkoxy, C 2 -C 6 dial koxymethyl, (^10 Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, 0,-Cg haloalkyl, C^Cg haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, C-,-C 6 alkylthio, C^Cg alkylsulfonyl, C,-C 6 15 haloalkyl sulfonyl, C^Cg al kyl sul f inyl, C^Cg haloalkylsulfinyl, arylthio, C^Cg haloalkoxy, amino, C^Cg alkylamino, C 2 -C 15 dialkylamino, hydroxy, carbamoyl, C^Cg N-alkyl carbamoyl, C 2 -C 15 Ν,Ν-dialkylcarbamoyl, nitro, C 2 -C 15 dial kylsulfamoyl, or an ortho methylene-dioxy group; 20 wherein said compound exhibits high binding activity with respect to the sigma receptor.
  4. 4. The method of claim 3, wherein said compound is selected from the group consisting of N-phenethyl-1 25 phenyl isopropylamine, N-(3-phenylpropyl)-1-phenyl-isopropylamine, N-(2-phenoxy)ethyl)-1-phenylisopropylamine, N-(3-phenyl-3propanon-1-yl)-1-phenyli sopropylamine, N - (4-phenyl butyl )-1phenyli sopropylamine, N-(3-(l-naphthy1) propyl)-1-phenyli sopropyl amine,N-(3-(2-naphthyl)propyl) -1-phenyli sopropyl amine, 30 N-methyl-N-(3-(2-naphthyl)propyl) -1-phenylisopropyl amine, N-(3phenyl -2-propyn-l-yl)-1-phenyl -i sopropylami ne, N-(3-phenyl propyl )-1-(4-hydroxyphenyl) isopropyl amine,N-(3-phenylpropyl)-1(4-methoxyphenyl)i sopropylamine, N-(3-phenyl propyl )-1-(3bromophenyl)isopropylamine, N-(3-phenylpropy 1)-1-(435 bromophenyl)i sopropylami ne, N-(3-phenyl propyl) -1 -(3,4-di chi orophenyl)i sopropylamine, N-(3-phenylpropyl) -1 -(4-iodophenyl isopropyl)-amine, N-(3-phenylpropyl)-1-(3-trifluoromethylIE 922112 -142phenyl)isopropylamine, N-(2-phenethyl)-N-methyl-1-phenyl isopropylamine, N-(3-phenylpropyl)-1-phenylpropan-l-one-2-amine, N-(2-indanyl)-3-phenyl propyl amine,N,N-di-(3-phenylpropyl) amine, N-(2-(1-naphthyl)ethyl)-1-phenylisopropylamine, N-(2-(2naphthyl )ethyl)-1-pheny1 isopropylamine, N-(2 - (1- naphthyl) propyl) 1-phenyl isopropylamine, N- (2 - (2-naphthyl) propyl)-l-phenyl i sopropyl amine, N-(4-phenyl butyl)-1 -(2,5-dimethoxyphenyl)i sopropyl amine, N-(4-phenylbutyl)-l-(4-bromo-2,5-dimethoxyphenyl) isopropylamine, N-methyl-N-(4-phenylbutyl)-1-phenyl isopropyl amine, N-methyl-N-(5-phenylpentyl)-1-phenyli sopropylamine, N - (3phenylpropyl)-1-(4-ethoxyphenyl)isopropyl-amine, N-(3-phenylpropyl )-1-(4-propylphenyl)i sopropylamine, N-(3-phenylpropyl )-1(4-benzoxyphenyl)isopropylamine, N-methyl-N-(3-phenylpropyl )-1(4-propylphenyl)i sopropylamine, N- (3-phenylpropyl) -1-phenyl - 2pentyl amine,N-(4-phenylbutyl) -1-phenyl -2-pentylamine,N,N-di-(2ethylphenylJmethylami ne,N,N-di benzyl ami ne,N-(3 - phenyl propyl)-N(6-phenylhexyl) amine, N-(3-phenylpropyl)-N-(5-phenylpentyl)ami ne, N-propyl-N-methyl-5-phenylpentylamine, N-methyl-N-(3-phenylpropyl)-1-phenyl isopropyl amine,N-methyl-N-(3-methyl-2-butenyl) 1-phenyl iso-propyl amine, N-methyl-N-(3-methyl butyl) -1-pheny 1 isopropylamine, N-methyl-N-(3-phenylpropyl)-l-phenyl-2pentylamine, N-methyl-N-(3-methylbutyl)-l-isopropylamine, Nmethyl-N-(3-phenylbutyl)-1-phenyl-2-pentylamine, N-propyl-N-(3phenyl)propyl)-1-phenyl-2-propylamine, N-benzyl-N-(3-phenyl)propyl)-1-phenyl-2-propylamine, N-phenyl -(5-phenyl)pentyl amine, N-methyl-N-(3-phenyl) propyl-5-phenylpentylamine,N-(2-(o-methylphenyl)ethyl)-5-phenylpentyl amine, N-(2-(m-methylphenyl)ethyl )-5phenylpentyl amine, N-(2-(p-methylphenyl)ethyl)-5-phenyl pentyl amine, N-benzyl -5-phenylpentylamine, N-benzyl -N-methyl -5-phenyl pentyl amine,N-(2-(3-hydroxyphenyl)ethyl) - 5-phenylpentylamine,N(2-(2-hydroxyphenyl)ethyl)-5-phenylpentyl amine, N,N'-diethyl-2(diphenyl acetoxy)ethyl amine,N,N' - diethyl-2-(9-fluorenecarboxy)ethylamine, Ν,Ν-Dimethyl-5-phenylpentylamine, N-Benzyl-N-(3phenylpropyl)-1-pheny1-2-propylamine, N-Benzyl-N-methyl-5phenylpentylamine, N-Benzyl-5-phenylpentyl amine, and N-(2phenethyl)-N-methylpentylamine. -1435. A method of treating a human being suffering from a central nervous system disorder, which comprises administering to said human a therapeutically effective amount of a compound of the formula:
  5. 5. R 1 R I I T— (CH) n -N-X-Z 10 wherein: R is hydrogen or C-,-C 6 alkyl; T is aryl, heteroaryl, substituted aryl, substituted heteroaryl, or cycloalkyl, wherein said substituent is selected from the group consisting of chloro, fluoro, bromo, iodo, CF 3 , 15 ®1®6 alkoxy, C 2 -C 6 di al koxymethyl, C^Cg alkyl, cyano, C 3 -C 15 di alkyl ami noal kyl, carboxy, carboxamido, C^Cg haloalkyl, C^Cg haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, C-,-C 6 alkylthio, C-,-C 6 alkyl20 sulfonyl, C.,-C 6 haloalkylsulfonyl, ί,-Οθ alkylsulfinyl, C^-Cg haloalkylsulfinyl, arylthio, C^Cg haloalkoxy, amino, C.,-C 6 alkylamino, C 2 -C., 5 dialkylamino, hydroxy, carbamoyl, C.,-C 6 Nalkylcarbamoyl, C 2 -C 15 Ν,Ν-dialkylcarbamoyl, nitro, C 2 -C 15 dialkyl sul famoyl, and an ortho methylenedioxy group; 25 R 1 is selected from the group consisting of hydrogen, C^Cg alkyl, C^Cg alkoxy, fluoro, bromo, chloro, iodo and =0; or R and R 1 together form a morpholino, piperazinyl or piperidinyl ring; n is 0-5; 30 X is -(CH 2 ) q -, wherein q is 1-6; -(CH 2 ) r -O£-(CH 2 ) r -, wherein r is 0-3; -(CH 2 ) r -CH=CH-(CH 2 ) r -; II 35 -(CH 2 ) r -C-(CH 2 ) r -; -(CH 2 ) r -Y-(CH 2 ) r -, wherein each r is independently 0-3 and wherein Y is 0 or S; or C^Cg alkyl (wherein Z is hydrogen); -144Z is cycloalkyl or an aryl-substituted carboxylic acid group wherein Z may be substituted by chloro, fluoro, bromo, iodo, CF 3 , ί,-Cg alkoxy, C 2 -C 6 dialkoxymethyl, C-j-Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C.,-C 6 haloalkyl, C^Cg 5 haloalkylthio, allyl, aralkyl, C 3 -C g cycloalkyl, aroyl, aralkoxy, C 2 -Cg carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, C 1 -C 6 alkylthio, C^Cg alkylsulfonyl, C^Cg haloalkyl sulfonyl, C^Cg alkylsulfinyl, C^Cg haloalkylsulfinyl, arylthio, C^-Cg haloalkoxy, 10 amino, C^Cg alkylamino, C 2 -C 15 dialkylamino, hydroxy, carbamoyl, C^Cg N-alkylcarbamoyl, C 2 -C 15 Ν,Ν-dialkylcarbamoyl, nitro, C 2 C 15 di alkylsulfamoyl, or an ortho methylene-dioxy group; wherein said compound exhibits high binding activity with respect to the sigma receptor.
  6. 6. A method of treating a human being suffering from a central nervous system disorder, which comprises administering to said human a therapeutically effective amount of a compound selected from the group consisting of N-(3-phenyl-propyl)-l-(420 propyl phenyl) isopropyl amine, N-(3-phenyl propyl) -1 -(4-benzoxyphenyl)isopropylamine, N-methyl - N-(3-phenylpropyl )-1-(4propylphenyl)i sopropylamine, N - (3-phenylpropyl) -1-phenyl -2pentylamine,N-(4-phenyl butyl )-1-phenyl-2 - pentyl amine,N,N-di-(2ethylphenylJmethylamine,N,N-dibenzyl amine,N-(3-phenyl propyl)-N25 (6-phenylhexyl) ami ne, N-(3-phenylpropyl)-N-(5-phenyl pentyl) ami ne, N-propyl-N-methyl-5-phenylpentylamine, N-methyl-N-(3-phenylpropyl)-1-phenylisopropylamine, N-methyl-N-(3-methyl-2-butenyl)1-phenyliso-propylamine, N-methyl-N-(3-methylbutyl)-1-phenyl isopropylamine, N-methyl-N-(3-phenylpropyl)-l-phenyl-230 pentylamine, N-methyl-N-(3-methylbutyl)-l-isopropylamine, Nmethyl-N-(3-phenylbutyl)-1-phenyl -2-pentylamine, N-propyl-N-(3phenyl )propyl)-1-phenyl-2-propylamine, N-benzyl-N-(3-phenyl) propyl)-1-phenyl-2-propylamine, N-phenyl-(5-phenyl)pentyl amine, N-methyl-N-(3-phenyl)propyl-5-phenylpentylamine,N-(2-(o-methyl 35 phenyl)ethyl)-5-phenylpentylamine, N-(2-(m-methylphenyl)ethyl )-5phenylpentyl amine, N- (2- (p-methylphenyl)ethyl)-5-phenylpentyl IE 922112 amine, N-benzyl-5-phenylpentylamine, N-benzyl -N-methyl-5-phenylpentyl amine,N-(2-(3-hydroxyphenyl)ethyl)-5-phenylpentyl amine,N(2-(2-hydroxyphenyl)ethyl)-5-phenylpentyl amine, N,N'-diethyl-2(diphenylacetoxy)ethyl amine, N,N'-diethyl -2-(9-fluorenecarboxy)5 ethylamine, Ν,Ν-Dimethyl-5-phenylpentylamine, N-Benzyl-N-(3phenylpropyl) -1-phenyl-2-propyl amine, N-Benzyl-N-methyl-5phenylpentyl amine,N-Benzyl-5-phenylpentylamine,N-(2-phenethyl) N-methylpentyl amine, N- (5-phenylpentyl)-4-benzyl piperidine and N(5-phenylpentyl)-4-benzyl-4-hydroxy-piperidine. -1457. A method of treating a human being suffering from drug abuse, gastrointestinal disorder, or depression, which comprises administering to said human a therapeutically effective 15 amount of a compound of the formula: R 1 wherein: R is hydrogen or C.,-C 6 alkyl; Ar is aryl, heteroaryl, substituted aryl or substituted 30 heteroaryl, wherein the substituent is selected from the group consisting of chloro, fluoro, bromo, iodo, CF 3 , C 1 -C g alkoxy, C 2 C 6 dial koxymethyl, C^Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C 1 -C 6 haloalkyl, C^-Cg haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 acyl, 35 aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, C^-Cg alkylthio, Cj-Cg alkylsulfonyl, C^Cg haloalkylsulfonyl, C^Cg alkylsulfinyl, C 7 -C 6 haloalkylsulfinyl, arylthio, C^Cg haloalkoxy, amino, C^Cg alkylamino, C 2 -C 15 -146dialkylamino, hydroxy, carbamoyl, C-pCg N-al kylcarbamoyl, C 2 -C 15 Ν,Ν-dialkylcarbamoyl, nitro and C 2 -C 15 dial kylsulfamoyl; R 1 is selected from the group consisting of hydrogen, C-,-C 6 alkyl, C^Cg alkoxy, fluoro, chloro, bromo, iodo and =0; or 5 R and R 1 together form a morpholino, piperazinyl or piperidinyl ring; n is 1-3; p is 1-3; X is -(CH 2 ) q -, wherein q is 1-6, 10 -(CH 2 ) r -OC-(CH 2 ) r -, -(CH 2 ) r -CH=CH-(CH 2 ) r -, II -(CH 2 ) r -C-(CH 2 ) r -, 15 -(CH 2 ) r -Y-(CH 2 ) r -, wherein each r is independently 0-3 and wherein Y is 0 or S; or C-,-C 6 alkyl; Z is hydrogen, cycloalkyl, aryl or heteroaryl wherein Z may be substituted by chloro, fluoro, bromo, iodo, CF 3 , -C 6 alkoxy, 20 C 2 -C 6 dialkoxymethyl, C.,-C 6 alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C,-C 6 haloalkyl, C.,-C 6 haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -Cg carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, -C 6 alkylthio, 25 Ci-Cg alkylsulfonyl, ί,-Cg haloalkylsulfonyl, C.,-C 6 alkylsulfinyl, C^Cg haloalkylsulfinyl, arylthio, C^Cg haloalkoxy, amino, C^Cg alkylamino, C 2 -C 15 dialkylamino, hydroxy, carbamoyl, C^Cg N-al kyl carbamoyl, C 2 -C 15 Ν,Ν-dialkylcarbamoyl, nitro, C 2 C 15 di alkyl sulfamoyl or methylenedioxy; 30 wherein said compound exhibits a high binding activity with respect to the sigma receptor.
  7. 7.
  8. 8. The method of claim 7, wherein said compound is selected from the group consisting of N-(2-indanyl)-l35 phenyl isopropyl amine, N-(2-indanyl)-3-phenylpropylamine, N-(4,5benzocycloheptyl )-l-phenylisopropylamine, N-(3,4-benzocycloheptyl)-3-(phenyl)propyl amine, N-(4,5-benzocycloheptyl )-3IE 922112 -147phenyl propyl ami ne, N-(3,4-benzocycl ohexyl) -1-phenyli sopropylami ne and N-3,4-benzocyclohexyl-3-phenylpropylamine. 8.
  9. 9. A method of treating a human being suffering from a central nervous system disorder, which comprises administering to said human a therapeutically effective amount of a compound of the formula: R 1 wherein: 20 R is hydrogen or C^-Cg alkyl; Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, wherein the substituent is selected from the group consisting of chloro, fluoro, bromo, iodo, CF 3 , C^Cg alkoxy, C 2 C 6 di al koxymethyl, C^Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, 25 carboxy, carboxamido, haloalkyl, C n -C 6 haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C g acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, Cj-Cg alkylthio, C-j-Cg alkylsulfonyl, C-,-C 6 haloalkylsulfonyl, C.,-C 6 al kyl sul f i ny 1, C-,-C 6 haloalkylsulfinyl, 30 arylthio, C^Cg haloalkoxy, amino, C.,-Cg alkylamino, C 2 -C 15 dialkylamino, hydroxy, carbamoyl, Cj-Cg N-alkylcarbamoyl, C 2 -C 15 Ν,Ν-dialkylcarbamoyl, nitro and C 2 -C 15 dialkylsulfamoyl; R 1 is selected from the group consisting of hydrogen, C^Cg alkyl, Cj-Cg alkoxy, fluoro, chloro, bromo, iodo and =0; or 35 R and R 1 together form a morpholino, piperazinyl or piperidinyl ring; n is 1-3; p is 1-3; X is -(CH 2 ) -, wherein q is 1-6, -(CH 2 ) r -OC-(CH 2 ) r -, -(CH 2 ) r -CH=CH-(CH 2 ) r -, -14810 II -(CH 2 ) r -C-(CH 2 ) r -, -(CH 2 ) r -Y-(CH 2 ) r -, wherein each r is independently 0-3 and wherein Y is 0 or S; or C^Cg alkyl; Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo, CF 3 , C^-Cg alkoxy, C 2 -C 6 dial koxymethyl, C.,-C 6 alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C,C 6 haloalkyl, C-,-C 6 haloalkylthio, allyl, aralkyl, C 3 -C g cycloalkyl, aroyl, aralkoxy, C 2 -C 6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, C-|-Cg alkylthio, C^Cg al kyl sul fonyl, C^Cg haloalkyl sulfonyl, C.,-Cg alkylsulfinyl, C.,-C 6 haloalkylsulfinyl, arylthio, C.,-C 6 haloalkoxy, amino, C^Cg alkylamino, C 2 -C 15 dialkylamino, hydroxy, carbamoyl, C^Cg N-al kyl carbamoyl, C 2 -C 15 N,N-dialkylcarbamoyl, nitro, C 2 -C 15 di alkylsulfamoyl or methylenedioxy; wherein said compound exhibits a high binding activity with respect to the sigma receptor. 9.
  10. 10. A method of treating a human being suffering from drug abuse, gastrointestinal disorder, or depression, which comprises administering to said human a therapeutically effective amount of a compound of the formula: wherein: R is selected from the group consisting of hydrogen, chloro, fluoro, bromo, iodo, CF 3 , C.,-C 6 alkoxy, C 2 -C 6 dialkoxymethyl, C^Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, -149carboxamido, C^Cg haloalkyl, C-,-C 6 haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, C.,-C 6 alkylthio, C.,-C 6 alkylsulfonyl, C-,-C 6 5 hal oal kyl sul fonyl, C^Cg alkylsulfinyl, Cj-Cg haloalkylsulfinyl, arylthio, C-,-C 6 haloalkoxy, amino, C^Cg alkylamino, C 2 -C 15 dialkylamino, hydroxy, carbamoyl, C^-Cg N-alkylcarbamoyl, C 2 -C 15 Ν,Ν-dialkylcarbamoyl, nitro and C 2 -C 15 di alkylsulfamoyl; X is -(CH 2 )-, wherein q is 1-6, 10 -(CH 2 ) r -te£-(CH 2 ) r -, -(CH 2 ) r -CH=CH-(CH 2 ) r -, I 15 -(CH 2 ) r -C-(CH 2 ) r -, -(CH 2 ) Γ -Y-(CH 2 ) r -, wherein each r is independently 0-3 and wherein Y is 0 or S; or C^Cg alkyl (wherein Z is hydrogen); Z is cycloalkyl, aryl or heteroaryl wherein Z may be substituted 20 by chloro, fluoro, bromo, iodo, CF 3 , C^Cg alkoxy, C 2 -C 6 di al koxymethyl, C^Cg alkyl, cyano, C 3 -C 15 di alkyl ami noal kyl, carboxy, carboxamido, C^Cg haloalkyl, C 1 -C 6 haloalkylthio, allyl, aralkyl, C 3 -C g cycloalkyl, aroyl, aralkoxy, C 2 -C 6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted 25 heteroaryl, C 3 -C 6 heterocycloalkyl, Cj-Cg alkylthio, C-,-C 6 alkylsulfonyl, C.,-C 6 haloal kyl sul fonyl, C^Cg alkylsulfinyl, C^Cg haloalkylsulfinyl, arylthio, C^Cg haloalkoxy, amino, C.|-Cg alkyl-amino, dialkylamino, hydroxy, carbamoyl, ^-Cg Nalkylcarbamoyl, C 2 -C 15 Ν,Ν-dialklcarbamoyl, nitro, C 2 -C 15 30 di alkylsulfamoyl or methylenedioxy; V is N or CM, wherein M is hydrogen, C^Cg alkyl, C-,-C 6 alkoxy, hydroxy, fluoro, chloro, bromo or represents one half of a double bond with a neighboring endocyclic carbon; wherein said compound exhibits a high binding activity with 35 respect to the sigma receptor. 10.
  11. 11. The method of claim 10, wherein V is N, said compound having the formula 11.
  12. 12. The method of claim 11, wherein said compound is 10 selected from the group consisting of N-(3-trifluoromethylphenyl)-N'-phenethylpiperazine, N-(3-trifluoromethylphenyl)-N'(4-phenyl butyl)piperazine, N-(3-chlorophenyl)-N'-benzyl piperazine, N-(3-chlorophenyl)-N'-(3-phenylpropyl )piperazine, N-(3chlorophenyl)-N'-phenethylpiperazine, N-phenyl-N'-(3-phenyl15 propyl)piperazine, N-phenyl-N'-(3-phenylbutyl)piperazine, N-(2naphthyl)-N'-(3-phenylpropyl)-piperazine, N-phenyl-N'-(3-(2naphthyl)propyl)-piperazine, N-phenyl-N'-propylpiperazine, N-(4chlorophenyl)-N'-(3-phenyl propyl) piperazine, N-benzyl-Ν'-(4phenylbutyl)-piperazine, N-phenyl - Ν'-(4-phthalimidobutyl) 20 piperazine, and N-phenyl-N'-(5-phthalimidopentyl)piperazine. 12.
  13. 13. The method of claim 11, wherein V is CM, said compound having the formula 13.
  14. 14. The method of claim 13, wherein said compound is selected from the group consisting of N-phenethyl-435 phenyl piperidine,N-phenethyl-4-phenyl -4-hydroxypiperi dine,N-(3phenylpropyl)-4-phenyl piperidine,N-(3-phenylpropyl)-4-phenyl-4hydroxypiperidine, N-(5-phenylpentyl)-4-phenylpiperidine, N-(4phenylbutyl )-4-phenyl pi peri dine, N-(3-phenylpropyl )-4-(4chlorophenyl) -1,2,5,6-tetrahydropyridine, N-(4-phenylbutyl)-4-(440 chlorophenyl)-1,2,5,6-tetrahydropyridine, N-(5-phenylpentyl )-4922112 -151benzylpiperidine and N-(5-phenylpentyl )-4-benzyl-4-hydroxypiperidine. 14.
  15. 15. A method of treating a human being suffering from a central nervous system disorder, which comprises administering to said human a therapeutically effective amount of a compound of the formula: wherein: R 2 is selected from the group consisting of hydrogen, chloro, fluoro, bromo, iodo, CF 3 , C-,-C 6 alkoxy, C 2 -C 6 dialkoxymethyl, C^Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, Cj-Cg haloalkyl, C^Cg haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -Cg heterocycloalkyl, C 1 -C 6 alkylthio, C^Cg alkylsulfonyl, Cj-Cg haloalkylsulfonyl, C.,-C 6 al kyl sul f i nyl, C^Cg haloalkylsulfinyl, arylthio, C^Cg haloalkoxy, amino, C^Cg alkylamino, C 2 -C 15 dialkylamino, hydroxy, carbamoyl, C^Cg N-alkylcarbamoyl, C 2 -C 15 Ν,Ν-dialkylcarbamoyl, nitro and C 2 -C 15 dialkylsulfamoyl; X is -(CH 2 )-, wherein q is 1-6, -(CH 2 ) r -O€-(CH 2 ) r -, -(CH 2 ) r -CH=CH-(CH 2 ) Γ -, I -(CH 2 ) r -C-(CH 2 ) r -, -(CH 2 ) r -Y-(CH 2 ) r -, wherein each r is independently 0-3 and wherein Y is 0 or S; or -Cg alkyl (wherein Z is hydrogen); Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo, CF 3 , Cj-C 6 alkoxy, C 2 -C 6 dial koxymethyl, C^Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C,922112 -152C 6 haloalkyl, C^Cg haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, C^Cg alkylthio, C^Cg alkylsulfonyl, 0,-Cg haloalkyl sulfonyl, C.,-Cg alkylsulfinyl, Cj-Cg haloalkylsulfinyl, arylthio, C^Cg haloalkoxy, amino, C^Cg alkyl-amino, dialkylamino, hydroxy, carbamoyl, C.,-Cg N-alkylcarbamoyl, C 2 -C 15 Ν,Ν-dialklcarbamoyl, nitro, C 2' C 15 dialkylsulfamoyl or methylenedioxy; V is N or CM, wherein M is hydrogen, C^Cg alkyl, C-|-Cg alkoxy, hydroxy, fluoro, chloro, bromo or represents one half of a double bond with a neighboring endocyclic carbon; wherein said compound exhibits a high binding activity with respect to the sigma receptor. 15.
  16. 16. The method of claim 15, wherein V is N, said compound having the formula N-X-Z 16.
  17. 17. The method of claim 15, wherein V is CM, said compound having the formula CM N-X-Z 17.
  18. 18. A method of treating a human being suffering from drug abuse, gastrointestinal disorder, or depression, which comprises administering to said human a therapeutically effective amount of a compound of the formula: -153 N-X-Z wherein: R 3 is selected from the group consisting of C^Cg alkyl, C^Cg alkenyl, C 2 -C 6 dial koxymethyl, C 3 -C 15 dialkylaminoalkyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, C 2 -C 6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl; X is -(CH 2 ) q -, wherein q is 1-6, -(CH 2 ) r -(M-(CH 2 ) r -, -(CH 2 ) r -CH=CH-(CH 2 ) r -, II -(CH 2 ) r -C-(CH 2 ) r -, -(CH 2 ) r -Y-(CH 2 ) r -, wherein each r is independently 0-3 and wherein Y is O or S; or C^Cg alkyl (wherein Z is hydrogen); Z is cycloalkyl, aryl or heteroaryl wherein Z may be substituted by chloro, fluoro, bromo, iodo, CF 3 , C^Cg alkoxy, C 2 -C 6 dialkoxymethyl, -C 6 alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C.,-C 6 haloalkyl, C.,-C 6 haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C g heterocycloalkyl, C.,-C 6 alkylthio, C.,-C 6 alkylsulfonyl, C-|-C 6 hal oal kyl sul fonyl, C t -C 6 alkylsulfinyl, ϋ,-Cg hal oal kyl sulfinyl, arylthio, C^Cg haloalkoxy, amino, C^Cg alkyl-amino, dialkylamino, hydroxy, carbamoyl, C.,-Cg Nalkylcarbamoyl, C 2 -C 15 Ν,Ν-dialklcarbamoyl, nitro, C 2 -C 15 dialkylsulfamoyl or methylenedioxy; V is N or CM, wherein M is hydrogen, C^Cg alkyl, C^Cg alkoxy, hydroxy, fluoro, chloro, bromo or represents one half of a double bond with a neighboring endocyclic carbon; wherein said compound exhibits a high binding activity with respect to the sigma receptor. -15419.
  19. The method of claim 18, wherein said compound is selected from the group consisting of N-methyl-N'-(4-phenyl-3(E)butenyl)pipera-zine, N-methyl-N'-(4-phenyl-3-(Z)butenyl) piperazine, N-methyl - N'-(4-(3-tri fuoromethylphenyl )-3(Z)butenyl) piperazine, N-methyl - N' - (4-phenyl butyl) piperaz ine, Nbenzyl-N'-(4-phthalimidobutyl) piperazine, N-(2-methoxyphenyl)-N'(4-phthalimidobutyl)piperazine, N-(5-phenylpentyl)-4-benzylpiperidine,andN-(5-phenylpentyl)-4-benzyl-4-hydroxy-piperidine. 18.
  20. 20. A method of treating a human being suffering from a central nervous system disorder, which comprises administering to said human a therapeutically effective amount of a compound of the formula: N-X-Z wherein: o R is selected from the group consisting of C-,-C 6 alkyl, C.,-Cg alkenyl, C 2 -C g dialkoxymethyl, C 3 -C 15 dialkylaminoalkyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, C 2 -C 6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl; X is -(CH 2 ) q -, wherein q is 1-6, -(CH 2 ) r -(M-(CH 2 ) r -, -(CH 2 ) r -CH=CH-(CH 2 ) r -, -(CH 2 ) r -C-(CH 2 ) r -, -(CH 2 ) r -Y-(CH 2 ) r -, wherein each r is independently 0-3 and wherein Y is 0 or S; or C^Cg alkyl (wherein Z is hydrogen); Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo, CF 3 , C^Cg alkoxy, C 2 -C 6 dialkoxymethyl, Cj-Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C,C 6 haloalkyl, C r C 6 haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 carboxylic apyl, aryl, substituted -15510 aryl, heteroaryl, substituted heteroaryl, C 3 -C g heterocycloalkyl, -C 6 alkylthio, C-,-C 6 alkylsulfonyl, C-,-C 6 haloal kyl sul fonyl, C^Cg alkylsulfinyl, C^Cg haloalkylsulfinyl, arylthio, C^Cg haloalkoxy, amino, C^Cg alkyl-amino, dialkylamino, hydroxy, carbamoyl, 0,-Cg N-al kylcarbamoyl, C 2 -C 15 Ν,Ν-dialklcarbamoyl, nitro, C 2 -C 15 di alkylsulfamoyl or methylenedioxy; V is N or CM, wherein M is hydrogen, C-,-C 6 alkyl, C-,-C 6 alkoxy, hydroxy, fluoro, chloro, bromo or represents one half of a double bond with a neighboring endocyclic carbon; wherein said compound exhibits a high binding activity with respect to the sigma receptor. 19.
  21. 21. A method of treating a human being suffering from a central nervous system disorder, drug abuse, gastrointestinal disorder, or depression, which comprises administering to said human a therapeutically effective amount of a compound of the formula: wherein: R 4 is hydrogen or an aryl group substituted with a group selected from the group consisting of C^Cg alkyl, C^Cg alkenyl, C 2 -Cg dial koxymethyl, C 3 -C 15 dialkylaminoalkyl, aralkyl, C 3 -C g cycloalkyl, aroyl, C 2 -C 6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl; R 5 is hydrogen or hydroxy; X is -(CH 2 ) q -, wherein q is 1-6, -(CH 2 ) r -(M-(CH 2 ) r -, -(CH 2 ) r -CH=CH-(CH 2 ) r -, II -(CH 2 ) r -C-(CH 2 ) r -, -(CH 2 ) r -Y-(CH 2 ) r -, wherein each r is independently 0-3 and wherein Y is 0 or S; or , -156-C 6 alkyl (wherein Z is hydrogen); Z is cycloalkyl, aryl or heteroaryl wherein Z may be substituted by chloro, fluoro, bromo, iodo, CF 3 , C^Cg alkoxy, C 2 -C 6 dial koxymethyl, C^Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, 5 carboxy, carboxamido, C-,-C 6 haloalkyl, C-,-C 6 haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C g heterocycloalkyl, C^Cg alkylthio, C^Cg alkylsulfonyl, C^Cg haloalkylsulfonyl, C.,-C 6 al kyl sul finyl, C^Cg 10 haloalkylsulfinyl, arylthio, Cj-Cg haloalkoxy, amino, 0,-Cg alkyl-amino, dialkylamino, hydroxy, carbamoyl, f-j-Cg Ilal kyl carbamoyl, ^2^15 Ν,Ν-dialklcarbamoyl, nitro, dialkylsulfamoyl or methylenedioxy; wherein said compound exhibits a high binding activity with 15 respect to the sigma receptors. 20.
  22. 22. The method of claim 21, wherein said compound is selected from the group consisting of N-(5-phenylpentyl)piperidine, N-(8-phenyl heptyl ) pi per idine, N-(5-(420 methoxyphenyl) pentyl) piperidine, N-(3-phenylpropyl)piperidine,N(5-cyclohexylJpentylpiperidine, N-benzylpiperidine, N-(2phenethyl)-4-hydroxy-4-phenylpiperidine, N-(2-phenethyl )-4hydroxy-4-t-butylpi peridine, N-(5-(4-chlorophenyl)-5-pentanon-lyl )piperi dine, N-(5-(4-chlorophenyl)-5-pentanon-l-yl)-4-phenyl 25 piperidine,N-(5-(4-methoxyphenyl)-5-pentanon-1-yl)piperidine,N(5-(4-methoxyphenyl)-5-pentanon-l-yl)-4-phenylpiperidine, N-(5(4-methoxyphenyl) pentyl)-4-phenylpiperidine, N-(5-phenyl-5pentanon-1-yl)-4-phenylpiperidine, N-(5-(4-chlorophenyl)-pentyl)4-phenyl pi peridi ne, N-(5-(3-methoxyphenyl)-5-pentanon -130 yl) pi peri dine,N-(5-(3-chlorophenyl)-5-pentanon-l-yl) pi peri dine, N-(5-(3-chlorophenyl)-5-pentanon-l-yl)-4-phenylpiperidine,N- (5(3-methoxyphenyl)-5-pentanon-1-yl )-4-phenyl pi peridine, N-(4-(4f1uorophenyl)-4-butanon-1-yl)pi per i d ine, N-(5-(4-fluorophenyl)-5pentanon-1-yl)piperidine, N-(5-(4-fluorophenyl)-5-pentanon-1-yl)35 4-phenylpi peri di ne,N-(5 - (4-fluorophenyl)-5-pentanon-l -yl)-4-(3chlorophenyl)-4-hydroxypiperidine, N-(5-(4-chiorophenyl)-5IE 922112 -157pentanon-l-yl)-4-(4-f1uorophenyl)-1,2,3,6-terahydropyridine, N(5-(4-chlorophenyl)-5-pentanon-l-yl)-4-(4-fluorophenyl)piperidine, N-(5-(4-chlorophenyl) -5-pentanon-1-yl)-4-(4f luorophenyl)-1,2,3,6-terahydropyridine, N-(5-(4-chlorophenyl)-55 pentanon-l-yl)-4-(4-f1uorophenyl)-pi peridine, N-(5-(4, chlorophenyl )-5-pentanon-l-yl)-4-(chloropheny1)-1,2,3,6terahydropyridine, N-(5-(4-chlorophenyl)-5-pentanon-l-yl )-4(chl orophenyl)piperidine, N-(5-(3,4-dichlorophenyl)-5-pentanon-lyl )-4-(chiorophenyl)-pi peri dine, N-(5-cyclopentylpentan-5-on-l10 yl)piperidine and N-(5-(3,4-methylenedioxyphenyl)penta-2,4dienyl)piperidine. 21.
  23. 23. A method of treating a human being suffering from a central nervous system disorder, drug abuse, gastrointestinal 15 disorder, or depression, which comprises administering to said human a therapeutically effective amount of a compound having the formula: N-X-Z / wherein, X is -(CH 2 ) q -, wherein q is 1-6, -(CH 2 ) r -OC-(CH 2 ) r -, -(CH 2 ) r -CH=CH-(CH 2 ) r -, II -(CH 2 ) r -C-(CH 2 ) r -, -(CH 2 ) r -Y-(CH 2 ) p -, wherein each r is independently 0-3 and wherein Y is 0 or S; or C 7 -C 6 alkyl (wherein Z is hydrogen); Z is cycloalkyl, aryl or heteroaryl wherein Z may be substituted by chloro, fluoro, bromo, iodo, CF 3 , C^-Cg alkoxy, C 2 -C g di al koxymethyl, C^Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C.,-C 6 haloalkyl, , C 1 -C 6 haloalkylthio, -158allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, C.,-C 6 alkylthio, C^Cg alkylsulfonyl, (j-Cg haloalkyl sulfonyl, C^Cg alkylsulfinyl, C-,-C 6 5 haloalkylsulfinyl, arylthio, C^Cg haloalkoxy, amino, C^Cg alkyl-amino, dialkylamino, hydroxy, carbamoyl, C^Cg Nalkylcarbamoyl, C 2 -C 15 Ν,Ν-dialklcarbamoyl, nitro, C 2 -C 15 di alkylsulfamoyl or methylenedioxy; wherein said compound exhibits a high binding activity with 10 respect to the sigma receptors. 22.
  24. 24. The method of claim 23, wherein said compound is N(5-phenyl) pentyl-3-azabicyclo[3.2.2]nonane. 15
  25. 25. A method of treating a human being suffering from a central nervous system disorder, drug abuse, gastrointestinal disorder, or depression, which comprises administering to said human a therapeutically effective amount of a tropane derivative having the formula: wherein, R 4 is hydrogen or an aryl group substituted with a group 30 selected from the group consisting of C^Cg alkyl, C^Cg alkenyl, C 2 -Cg dialkoxymethyl, C 3 -C 15 dialkylaminoalkyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, C 2 -C 6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl; R 5 is hydrogen or hydroxy; 35 X is -(CH 2 ) q -, wherein q is 1-6, -(CH 2 ) r -C=£-(CH 2 ) p -, -(CH 2 ) r -CH=CH-(CH 2 ) r -, -1590 II -(CH 2 ) r -C-(CH 2 ) r -, -(CH 2 ) r -Y-(CH 2 ) r -, wherein each r is independently 0-3 and 5 wherein Y is 0 or S; or C^Cg alkyl (wherein Z is hydrogen); Z is cycloalkyl, aryl or heteroaryl wherein Z may be substituted by chloro, fluoro, bromo, iodo, CF 3 , C^-Cg alkoxy, C 2 -C 6 di al koxymethyl, C^Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, 10 carboxy, carboxamido, C^Cg haloalkyl, C^Cg haloalkylthio, allyl, aralkyl, C 3 -C g cycloalkyl, aroyl, aralkoxy, C 2 -C 6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, C 1 -C 6 alkylthio, C.,-C 6 alkylsulfonyl, C^Cg haloalkylsul fonyl, 0,-Cg alkylsulfinyl, Cj-Cg 15 haloalkylsulfinyl, arylthio, C^Cg haloalkoxy, amino, C^-Cg alkyl-amino, dialkylamino, hydroxy, carbamoyl, C^-Cg Nalkylcarbamoyl, C 2 -C 15 Ν,Ν-dialklcarbamoyl, nitro, C 2 -C 15 di alkylsulfamoyl or methylenedioxy; wherein said compound exhibits a high binding activity with 20 respect to the sigma receptors.
  26. 26. The method of claim 25, wherein said compound is N(5-phenyl)pentyl-4-phenyltropan-4-ol. 23. 25
  27. 27. A method of treating a human being suffering from drug abuse, gastrointestinal disorder, or depression, which comprises administering to said human a therapeutically effective amount of a compound of the formula: 30 R wherein a is 1-8; b is 1-8; -160R is hydrogen or -C 6 alkyl; o R is independently selected from the group consisting of hydrogen, chloro, fluoro, bromo, iodo, CF 3 , C-,-C 6 alkoxy, C 2 -C 6 di al koxymethyl, C.,-Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, 5 carboxy, carboxamido, C^Cg haloalkyl, C^Cg haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C g carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, C^Cg alkylthio, C-,-C 6 alkylsulfonyl, C^Cg hal oal kyl sul fonyl, C.,-C 6 alkylsulfinyl, 0,-Cg 10 haloalkylsulfinyl, arylthio, C^Cg haloalkoxy, amino, C^Cg alkylamino, dialkylamino, hydroxy, carbamoyl, -C 6 Nalkylcarbamoyl, C 2 -C 15 Ν,Ν-dialklcarbamoyl, nitro and C 2 -C 15 dialkylsulfamoyl; wherein said compound exhibits high binding activity with 15 respect to the sigma receptor. 24.
  28. 28. The method of claim 27 wherein said compound is selected from the group consisting of N-(4-phenylbutyl)phenethylamine, N-(4-phenylbutyl )-3-phenyl propyl amine, N-(4-phenylbutyl) 20 4-phenylbutylamine, N-(4-phenylbutyl)benzylamine, N-(4phenylbutyl)-5-phenyl pentyl amine, N-(5-phenylpentyl)benzyl amine, N-(3-phenylpropyl)phenethylamine, N-(5-phenylpentyl)phenethylamine, N-(7-phenylheptyl)benzylamine, N-(7-phenylheptyl) phenethyl amine, N-methyl -N-(2-phenethyl )-l-phenylisopropylamine, 25 N-methyl-N-(5-phenylpentyl) -1-phenyl i sopropylamine, N-methyl-N(3-phenylpropyl)-l-(4-propylphenyl)isopropylamine, N-phenyl-(5phenyl)pentyl amine, N-methyl-N-(3-phenylpropyl)-5-phenylpentyl amine, N-benzyl-N-methyl-5-phenyl pentyl amine, N-(2-(omethoxyphenyl)ethyl)-5-phenylpentylamine, N-(2-(m-methoxy30 phenyl)ethyl)-5-phenylpentylamine, N-(2-(p-methoxyphenyl)ethyl) 5-phenylpentylamine, N-benzyl-5-phenylpentylamine, N-(2-(mhydroxyphenyl)ethyl)-5-phenylpentyl amine, and N-(2-(ohydroxyphenyl)ethyl)-5-phenylpentylamine. 35 25.
  29. 29. A method of treating a human being suffering from drug abuse, gastrointestinal disorder, or depression, which -161comprises administering to said human a therapeutically effective amount of a compound having the Formula: R wherein 10 a is 1-8; b is 1-8; R is hydrogen or C.,-C 6 alkyl; R 2 is independently selected from the group consisting of hydrogen, chloro, fluoro, bromo, iodo, CF 3 , C^Cg alkoxy, C 2 -C 6 15 di al koxymethyl, C.,-C 6 alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C^Cg haloalkyl, C.,-Cg haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, C.,-C 6 alkylthio, C^Cg alkyl20 sulfonyl, C^Cg haloalkyl sul fonyl, C^-Cg al kyl sul f inyl, C^Cg haloalkylsulfinyl, arylthio, C^Cg haloalkoxy, amino, C^Cg alkyl-amino, dialkylamino, hydroxy, carbamoyl, C.,-C 6 Nalkylcarbamoyl, C 2 -C 15 Ν,Ν-dialklcarbamoyl, nitro and C 2 -C 15 dialkylsulfamoyl; and 25 wherein said compound exhibits high binding activity with respect to the sigma receptor. 26.
  30. 30. The method of claim 29, wherein said compound is N(3-phenylpropyl)-2-(2-naphthyl)ethyl amine. 27.
  31. 31. A method of treating a human being suffering from drug abuse, gastrointestinal disorder or depression, which comprises administering to said human a therapeutical ly effective amount of a compound having the formula: 35 CH 2 / \ 0 CH, Ar-CH-CH 2 -N-X-Z -162wherein; Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, wherein the substituent is selected from the group consisting of chloro, fluoro, bromo, iodo, CF 3 , C-,-C 6 alkoxy, C 2 C 6 dial koxymethyl, C^Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C-pCg haloalkyl, C^Cg haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, C^Cg alkylthio, C^Cg alkylsulfonyl, C^Cg hal oal kyl sul fonyl, C.,-C 6 alkylsulfinyl, ϋ,-Cg haloalkylsulfinyl, arylthio, C-pCg haloalkoxy, amino, C^Cg alkylamino, C 2 -C 15 dialkylamino, hydroxy, carbamoyl, C.,-C 6 N-al kyl carbamoyl, C 2 -C 15 Ν,Ν-dialkylcarbamoyl, nitro and C 2 -C 15 dialkylsulfamoyl; X is -(CH 2 ) q -, wherein q is 1-6, -(CH 2 ) r -(M-(CH 2 ) r -, - (CH 2 ) r -CH=CH-(CH 2 ) r -, II -(CH 2 ) r -C-(CH 2 ) r -, -(CH 2 ) r -Y-(CH 2 ) r -, wherein each r is independently 0-3 and wherein Y is 0 or S; or (q-Cg alkyl; Z is hydrogen, cycloalkyl, aryl or heteroaryl wherein Z may be substituted by chloro, fluoro, bromo, iodo, CF 3 , C^Cg alkoxy, C 2 -Cg dialkoxymethyl, -C g alkyl, cyano, L 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, Ο,-Cg haloalkyl, -C 6 haloalkylthio, allyl, aralkyl, C 3 -C g cycloalkyl, aroyl, aralkoxy, C 2 -Cg carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, C,-C 6 alkylthio, 0-,-Cg alkylsulfonyl, C-j-Cg hal oal kyl sul fonyl, C.,-C 6 alkylsulfinyl, C-|-Cg haloalkylsulfinyl, arylthio, C-pCg haloalkoxy, amino, C-pCg alkylamino, C 2 -C 15 dialkylamino, hydroxy, carbamoyl, C^Cg N-alkylcarbamoyl, C 2 -C 15 Ν,Ν-dialkylcarbamoyl, nitro, C 2 C 15 dialkylsulfamoyl or methylenedioxy; -163wherein said compound exhibits high binding activity with respect to the sigma receptor. 28.
  32. 32. A method of treating a human being suffering from a 5 central nervous system disorder, which comprises administering to said human a therapeutically effective amount of a compound having the formula: CH/ \ 10 0 CH ? I I Ar-CH-CH 2 -N-X-Z 15 wherein; Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, wherein the substituent is selected from the group consisting of chloro, fluoro, bromo, iodo, CF 3 , C.,-Cg alkoxy, C 2 C 6 di al koxymethyl, C^Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, 20 carboxy, carboxamido, ^-Cg haloalkyl, C^Cg haloalkylthio, allyl, aralkyl, C 3 -C g cycloalkyl, aroyl, aralkoxy, C 2 -C g acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, C-,-C g alkylthio, 0,-Cg alkylsulfonyl, C-,-C 6 haloal kyl sulfonyl, C.,-Cg alkylsulf inyl, C^-Cg haloalkylsulfinyl, 25 arylthio, C^Cg haloalkoxy, amino, C^Cg alkylamino, C 2 -C 15 dialkylamino, hydroxy, carbamoyl, C-,-C 6 N-al kyl carbamoyl, C 2 -C 15 Ν,Ν-dialkylcarbamoyl, nitro and C 2 -C 15 di alkylsulfamoyl; X is -(CH 2 ) q -, wherein q is 1-6, -(CH 2 ) r -OC-(CH 2 ) r -, 30 -(CH 2 ) r -CH=CH-(CH 2 ) r -, II -(CH 2 ) r -C-(CH 2 ) r -, -(CH 2 ) r -Y-(CH 2 ) r -, wherein each r is independently 0-3 and 35 wherein Y is 0 or S; or 0,-Cg alkyl; Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo, CF 3 , C^Cg alkoxy, C 2 -C g dial koxymethyl, Cj-Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C.,IE 922112 -164C 6 haloalkyl, C^Cg haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, C^-Cg alkylthio, C^Cg alkylsulfonyl, C^Cg haloalkyl sulfonyl, 5 C^Cg alkylsulfinyl, Cj-Cg haloalkylsulfinyl, arylthio, Cj-Cg haloalkoxy, amino, C^Cg alkylamino, C 2 -C 15 dialkylamino, hydroxy, carbamoyl, C^Cg N-alkylcarbamoyl, C 2 -C 15 Ν,Ν-dialkylcarbamoyl, nitro, C 2 -C 15 di alkylsulfamoyl or methylenedioxy; wherein said compound exhibits high binding activity with 10 respect to the sigma receptor. 29.
  33. 33. A method of treating a human being suffering from drug abuse, gastrointestinal disorder, or depression, which comprises administering to said human a therapeutically effective 15 amount of a compound having the formula: R 1 R I I Cy- (CH)—NH-X-Z 20 wherein n is 0-5; Cy is C 3 -C 8 cycloalkyl; R is hydrogen or C-,-C 6 alkyl; R 1 is independently selected from the group consisting of hydrogen, C-,-C 6 alkyl, C.,-C 6 alkoxy, fluoro, chloro, bromo, iodo 25 and =0; X is -(CH 2 ) q -, wherein q is 1-6; -(CH 2 ) r -fcC-(CH 2 ) r -, wherein r is 0-3; -(CH 2 ) r -CH=CH-(CH 2 ) r -; 30 II -(CH 2 ) r -C-(CH 2 ) r -; -(CH 2 ) Γ -Y-(CH 2 ) r -, wherein each r is independently 0-3 and wherein Y is 0 or S; or C^Cg alkyl (wherein Z is hydrogen); and 35 Z is hydrogen, cycloalkyl, aryl or heteroaryl wherein Z may be substituted by chloro, fluoro, bromo, iodo, CF 3 , C-,-C 6 alkoxy, C 2 -C 6 dialkoxymethyl, C^Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C.,-C 6 haloalkyl, C,-C 6 -165haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C e heterocycloalkyl, C.,-C 6 alkylthio, Cj-Cg alkylsulfonyl, 0,-Cg haloalkylsulfonyl, C^Cg alkyl5 sulfinyl, Cj-Cg haloalkylsulfinyl, arylthio, C^Cg haloalkoxy, amino, C-pCg alkylamino, C 2 -C 15 dialkylamino, hydroxy, carbamoyl, C^Cg N-alkylcarbamoyl, C 2 -C 15 Ν,Ν-dialkylcarbamoyl, nitro, C 2 C 15 dialkylsulfamoyl or methylenedioxy; wherein said compound exhibits high binding activity with 10 respect to the sigma receptor. 30.
  34. 34. The method of claim 33, wherein said compound is selected from the group consisting of N-(3-cyclohexylpropyl)-3phenylpropyl amine, N-cyclohexylmethyl -3-phenylpropylamine, N-(515 cyclohexylpentyl)benzyl amine, 5-cyclohexylpentylamine, N-methyl5-cyclohexylpentyl amine, Ν,Ν-Dimethyl-5-cyclohexylpentylamine, N-cyclohexylmethyl-5-cyclohexyl-n-pentylamine, and Ncyclohexylmethyl-N-methyl-5-cyclohexyl-n-pentylamine. 20
  35. 35. A method of treating a human being suffering from a central nervous system disorder, which comprises administering to said human a therapeutically effective amount of a compound R 1 R I I Cy—(CH) n —NH-X-Z Cy is C 3 -C g cycloalkyl; 30 R is hydrogen or C^Cg alkyl; R 1 is independently selected from the group consisting of hydrogen, Cj-Cg alkyl, C-,-C 6 alkoxy, fluoro, chloro, bromo, iodo and =0; X is -(CH 2 ) q -, wherein q is 1-6; 31. 35 -(CH 2 ) r -OC-(CH 2 ) p -, wherein r is 0-3; -(CH 2 ) r -CH=CH-(CH 2 ) r -; having the formula: wherein n is 0-5; -166ίο -(CH 2 ) r -C-(CH 2 ) r -; -(CH 2 ) Γ -Y-(CH 2 ) p -, wherein each r is independently 0-3 and wherein Y is 0 or S; or C.,-Cg alkyl (wherein Z is hydrogen); and Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo, CF 3 , C^Cg alkoxy, C 2 -C 6 dial koxymethyl, C^Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C^ C 6 haloalkyl, C^Cg haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, C-j-Cg alkylthio, C-,-C 6 alkylsulfonyl, C^Cg haloalkylsulfonyl, C^Cg alkylsulfinyl, 0,-Cg haloalkylsulfinyl, arylthio, C,-C 6 haloalkoxy, amino, ^-Cg alkylamino, C 2 -C 15 dialkylamino, hydroxy, carbamoyl, C^Cg N-al kylcarbamoyl, C 2 -C 15 N,N-dialkylcarbamoyl, nitro, C 2 -C 15 di alkylsulfamoyl or methylenedioxy; wherein said compound exhibits high binding activity with respect to the sigma receptor. 32.
  36. 36. A method of treating a human being suffering from drug abuse, gastrointestinal disorder or depression, which comprises administering to said human a therapeutically effective amount of a compound having the formula: wherein X 1 is -(CH 2 ) r -C=i-(CH 2 ) r -, wherein each r is 0-3 independently; -(CH 2 ) r -CH=CH-(CH 2 ) r -; II -(CH 2 ) r -C-(CH 2 ) r -; -(CH 2 ) r -Y-(CH 2 ) r -, wherein Y is 0 or S; or -Cg alkyl (wherein Z is hydrogen); R 2 is independently selected from the group consisting of hydrogen, chloro, fluoro, bromo, iodo, CF^, C-,-C 6 alkoxy, C 2 -C 6 -167dialkoxymethyl, C^Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C-,-C 6 haloalkyl, C^Cg haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted 5 heteroaryl, C 3 -C 6 heterocycloalkyl, C^-Cg alkylthio, C^Cg alkylsulfonyl, -C 6 hal oal kyl sul fonyl, C^Cg alkylsulfinyl, C^Cg haloalkylsulfinyl, arylthio, C^Cg haloalkoxy, amino, C^Cg alkyl-amino, dialkylamino, hydroxy, carbamoyl, C^Cg Nalkylcarbamoyl, C 2 -C 15 Ν,Ν-dialklcarbamoyl, nitro and C 2 -C 15 10 dialkylsulfamoyl; V is N or CM, wherein M is hydrogen, C^Cg alkyl, C-j-C 6 alkoxy, fluoro, chloro, bromo, trifluoromethyl, hydroxy or one half of a double bond with the neighboring endocyclic carbon; X is -(CH 2 ) q -, wherein q is 1-6; 15 -(CH 2 ) r -O€-(CH 2 ) p -, wherein r is 0-3; -(CH 2 ) r -CH=CH-(CH 2 ) r -; II 20 -(CH 2 ) r -C-(CH 2 ) r -; -(OH 2 ) r -Y-(CH 2 ) r -, wherein each r is independently 0-3 and wherein Y is 0 or S; or C-,-C 6 alkyl (wherein Z is hydrogen); and Z is hydrogen, cycloalkyl, aryl or heteroaryl wherein Z may be 25 substituted by chloro, fluoro, bromo, iodo, CF 3 , C-pCg alkoxy, C 2 -C 6 dialkoxymethyl, 0,-Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C^Cg haloalkyl, C^Cg haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 carboxylic acyl, aryl, substituted aryl, heteroaryl, 30 substituted heteroaryl, C 3 -C g heterocycloalkyl, C^Cg alkylthio, C-,-Cg al kyl sul fonyl, Cj-Cg haloalkylsul fonyl, C-j-Cg alkylsulfinyl, C^Cg haloalkylsulfinyl, arylthio, C^Cg haloalkoxy, amino, C^Cg alkylamino, C 2 -C 15 dialkyl amino, hydroxy, carbamoyl, Ci-Cg N-alkylcarbamoyl, C 2 -C 15 Ν,Ν-dialkylcarbamoyl, nitro and 35 C 2 -C 15 dialkylsulfamoyl; wherein said compound exhibits high binding activity with respect to the sigma receptor. 33.
  37. 37. A method of treating a human being suffering from a central nervous system disorder, which comprises administering to said human a therapeutically effective amount of a compound having the formula: -168- 10 wherein X 1 is - (CH 2 ) r -C=£-(CH 2 ) r -, wherein each r is 0-3 independently; -(CH 2 ) r -CH=CH-(CH 2 ) r -; II 15 -(CH 2 ) r -C-(CH 2 ) r -; -(CH 2 ) r -Y-(CH 2 ) r -, wherein Y is 0 or S; or C^Cg alkyl (wherein Z is hydrogen); R is independently selected from the group consisting of hydrogen, chloro, fluoro, bromo, iodo, CF 3 , C^Cg alkoxy, C 2 -C g 20 di al koxymethyl, C^Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C^-Cg haloalkyl, C^Cg haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C g carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, C^-Cg alkylthio, -C 6 alkyl 25 sulfonyl, C.,-C 6 haloalkylsulfonyl, C^Cg alkylsulfinyl, 0,-Cg haloalkylsulfinyl, arylthio, C-,-C 6 haloalkoxy, amino, C^Cg alkyl-amino, dialkylamino, hydroxy, carbamoyl, C^Cg Ilal kyl carbamoyl, C 2 -C 15 Ν,Ν-dialklcarbamoyl, nitro and C 2 -C 15 di alkylsulfamoyl; 30 V is N or CM, wherein M is hydrogen, C^Cg alkyl, C^Cg alkoxy, fluoro, chloro, bromo, trifluoromethyl, hydroxy or one half of a double bond with the neighboring endocyclic carbon; X is -(CH 2 ) q -, wherein q is 1-6; -(CH 2 ) r -Cs£-(CH 2 ) r -, wherein r is 0-3; -(CH 2 ) r -CH=CH-(CH p ) r -; -1690 I -(CH 2 ) r -C-(CH 2 ) r -; -(CH 2 ) r -Y-(CH 2 ) r -, wherein each r is independently 0-3 and wherein Y is 0 or S; or Cj-Cg alkyl (wherein Z is hydrogen); and 5 Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo, CF 3 , C-,-C 6 alkoxy, C 2 -C g di alkoxymethyl, C-,-C 6 alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C.,Cg haloalkyl, C.,-Cg haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 carboxylic acyl, aryl, substituted 10 aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloal kyl, C.|-Cg alkylthio, C^Cg alkylsulfonyl, C^Cg haloal kyl sul fonyl, C-pCg alkylsulfinyl, C^Cg haloalkylsulfinyl, arylthio, C^Cg haloalkoxy, amino, C.,-Cg alkylamino, C 2 -C 15 dialkylamino, hydroxy, carbamoyl, C^Cg N-alkylcarbamoyl, C 2 -C 15 N, N-d i al kyl15 carbamoyl, nitro and C 2 -C 15 dialkylsulfamoyl; wherein said compound exhibits high binding activity with respect to the sigma receptor. 34.
  38. 38. A method of treating a human being suffering from a 20 central nervous system disorder, drug abuse, gastrointestinal disorder or depression, which comprises administering to said human a therapeutically effective amount of a compound having the formula: 25 R 6 5 I 7 R -N-X-R 7 c e wherein R and R are independently a C 18 alkyl group; 30 R 7 is hydrogen or a C 1g alkyl group substituted by an aryl acetoxy or aryl carboxy group; and X is -(CH 2 ) q -, wherein q is 1-6; -(CH 2 ) r -OC-(CH 2 ) r -, wherein r is 0-3; -(CH 2 ) r -CH=CH-(CH 2 ) r -; -(CH 2 ) r -C-(CH 2 ) r -; -170-(CH 2 ) r -Y-(CH 2 ) r -, wherein each r is independently 0-3 and wherein Y is 0 or S; or C^Cg alkyl (wherein R 7 is hydrogen); wherein said compound exhibits a high binding activity with 5 respect to the sigma receptors. 35.
  39. 39. The method of claim 38, wherein said compound is selected from the group consisting of Ν,Ν-dimethyl-n-hexylamine, N-methyl-N-propylhexylamine, N,N'- diethyl - 210 (di phenyl acetoxy)ethyl amine, and N,N'-diethyl-2-(9f1uorenecarboxy)ethyl ami ne. 36.
  40. 40. A method of treating or preventing a central nervous system disorder, angina, migrane or hypertension, comprising 15 administering to an animal an effective amount of a compound selected from the group consisting of N-phenyl-N'-(3-(1phthalimi do)propyl)piperazine,N- (4-(1-phthalimido)butyl)-N'-(omethoxylphenyl)piperazine, and N-phenyl-N' - (4 - (1 phthalimido)butyl)piperazine. 37.
  41. 41. The method of any one of claims 1-3, 5-10, 15, 18, 20, 23, 25, 27, 29, 31, 32, 33, 35-38 and 40 wherein said compound is administered as part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier. 38.
  42. 42. A compound of the formula wherein: -171R is hydrogen or methyl; Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, wherein the substituent is selected from the group consisting of chloro, fluoro, bromo, iodo, CF 3 , ϋ-,-Οθ alkoxy, C 2 5 C 6 di al koxymethyl, C^Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C-|-C 6 haloalkyl, C^Cg haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C g heterocycloalkyl, C^-Cg alkylthio, Cj-Cg alkylsulfonyl, C^Cg 10 hal oal kyl sul fonyl, C^Cg al kyl sul f i nyl, C^Cg haloalkylsulfinyl, arylthio, C^Cg haloalkoxy, amino, C.,-C 6 alkylamino, C 2 -C 15 dialkylamino, hydroxy, carbamoyl, C.,-C 6 N-al kylcarbamoyl, C 2 -C 15 Ν,Ν-dialkylcarbamoyl, nitro and C 2 -C 15 dialkylsulfamoyl; R 1 is selected from the group consisting of hydrogen, C.,-Cg 15 alkyl, C-j-Cg alkoxy, fluoro, chloro, bromo, iodo and =0; or R and R 1 together form a morpholino ring; n is 0-5; W is -(CH 2 ) p - or -Η H-, wherein p is 1-3; X is -(CH 2 ) q -, wherein q is 3-6; 20 - (CH 2 ) r -OC-(CH 2 ) r -, -(CH 2 ) r -CH=CH-(CH 2 ) p -; II -(CH 2 ) r -C-(CH 2 ) r -; or 25 -(CH 2 ) r -Y-(CH 2 ) r -, wherein each r is independently 0-3 and wherein Y is 0 or S; Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo, CF 3 , C-,-C 6 alkoxy, C 2 -C g dial koxymethyl, C^Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C.,30 C 6 haloalkyl, C^Cg haloalkylthio, allyl, aralkyl, C 3 -C g cycloalkyl, aroyl, aralkoxy, C 2 -C 6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, C^Cg alkylthio, C-,-C 6 alkylsulfonyl, C^Cg hal oal kyl sul fonyl, C-|-Cg alkylsulfinyl, C.,-Cg haloalkylsulfinyl, arylthio, C^Cg 35 haloalkoxy, amino, C^Cg alkylamino, C 2 -C 15 dialkylamino, hydroxy, carbamoyl, C^Cg N-alkylcarbamoyl, C 2 -C 15 Ν,Ν-dialkylcarbamoyl, nitro and C 2 -C 15 dialkylsulfamoyl ; with the proviso that when W is -Η H-, R and R 1 are hydrogen and n is 0-2, then q is 4-6; wherein said compound exhibits high binding activity with respect to the sigma receptor. -17243.
  43. A compound of the formula: R R I I T—(CH) n -N-X-Z wherein: 15 R is hydrogen or C.,-C 6 alkyl; T is cycloalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl, wherein said substituent is selected from the group consisting of chloro, fluoro, bromo, iodo, CF 3 , C^Cg alkoxy, C 2 -C 6 di al koxymethyl, C^Cg alkyl, cyano, C 3 -C 15 20 dialkylaminoalkyl, carboxy, carboxamido, Cj-Cg haloalkyl, Cj-Cg haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, C.,-Cg alkylthio, C.,-Cg alkylsulfonyl, C^Cg haloalkylsulfonyl, C.,-Cg al kyl sul finyl, C^Cg 25 haloalkyl sul finyl, arylthio, C^Cg haloalkoxy, amino, Cj-Cg alkylamino, C 2 *C 15 dialkylamino, hydroxy, carbamoyl, C^Cg Nalkylcarbamoyl, C 2 -C 15 Ν,Ν-dialkylcarbamoyl, nitro and C 2 -C 15 dialkylsulfamoyl; R 1 is selected from the group consisting of hydrogen, C.,-C 6 30 alkyl, C.,-C 6 alkoxy, fluoro, chloro, bromo, iodo and =0; n is 0-5; X is -(CH 2 ) q -, wherein q is 3-6; -(CH 2 ) r -(M-(CH 2 ) r -, -(CH 2 ) r -CH=CH-(CH 2 ) r -; 35 II -(CH 2 ) r -C-(CH 2 ) r -; or -(CH 2 ) r -Y-(CH 2 ) r -, wherein each r is independently 0-3 and wherein Y is 0 or S; -17310 Z is cycloalkyl, an arylcarboxy, or an arylacetoxy group, wherein Z may be substituted by chloro, fluoro, bromo, iodo, CF 3 , -C 6 alkoxy, C 2 -C 6 dialkoxymethyl, C^-Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, ϋ,-Cg haloalkyl, C^Cg haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, Cj-Cg alkylthio, C r C 6 alkylsulfonyl, C^Cg haloalkylsulfonyl, C^Cg alkylsulfinyl, C^Cg haloalkylsulfinyl, arylthio, C^Cg haloalkoxy, amino, C^Cg alkylamino, C 2 -C 15 dialkylamino, hydroxy, carbamoyl, C^Cg N-al kylcarbamoyl, C 2 -C 15 Ν,Ν-dial kyl carbamoyl, nitro, C 2 C 15 di alkylsulfamoyl or methylene dioxy; with the proviso that when R and R 1 are hydrogen and n is 0-2, then q is 4-6; wherein said compound exhibits high binding activity with respect to the sigma receptor. phenyli sopropylami ne, phenyl isopropylamine,
  44. 44. A compound selected from the group consisting of N(3-phenylpropyl)-1-(4-propyl-phenyl)-isopropylamine, N-(3phenylpropyl)-1-(4-benzoxyphenyl)-isopropyl amine, N-methyl -N- (3phenylpropy1)-1-(4-propyl phenyl) -i sopropylami ne, N - (3phenylpropyl) -1-phenyl-2-pentylamine, N-(4-phenylbutyl) -1 -phenyl 2-pentylamine, N-(3-phenylpropyl)-N-(6-phenylhexyl)amine, N-(3phenylpropyl)-N-(5-phenylpentyl)amine, N-propyl-N-methyl-5phenylpentylamine, N-methyl-N-(3-phenylpropyl ) -1 N-methyl -N-(3-methyl-2-butenyl )-1N-methyl-N-(3-methylbutyl) -1-phenyl isopropylamine, N-methyl-N-(3-phenylpropyl) -1-phenyl-2pentylamine, N-methyl-N-(3-methylbutyl)-l-isopropy1amine, Nmethyl-N-(3-phenylbutyl)-l-phenyl-2-pentylamine, N-propyl-N-(3phenyl) propyl)-1-phenyl-2-propyl amine, N-benzyl-N-(3-phenyl) propyl)-1-phenyl-2-propylamine, N-phenyl - (5-phenyl)pentyl amine, N-methyl -N- (3-phenyl Jpropyl -5-phenylpentylamine, N- (2- (o-methyl phenyl)ethyl)-5-phenylpentyl amine, N-(2- (m-methylphenyl)ethy1 )-5phenylpentyl amine, N-(2-(p-methylphenyl) ethyl)-5-phenylpentyl amine, N-benzyl-5-phenylpentylamine, N-benzyl-N-methyl-535 -174phenyl pentyl amine, N-(2-(3-hydroxyphenyl) ethyl)-5-phenylpentylamine, N-(2-(2-hydroxyphenyl )ethyl )-5-phenylpentylamine, N,N'-diethyl-2-(diphenylacetoxy)ethyl amine, N,N'-diethyl - 2-(9fluorenecarboxy)ethylamine, Ν,Ν-Dimethyl-5-phenylpentylamine, NBenzyl-N-(3-phenylpropyl)-l-phenyl -2-propylamine, N-Benzyl-Nmethyl-5-phenylpentylamine, N-Benzyl-5-phenylpentylamine, and N(2-phenethyl)-N-methylpentyl amine.
  45. 45. A compound of the formula: wherein: R is hydrogen or methyl; Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, wherein the substituent is selected from the group consisting of chloro, fluoro, bromo, iodo, CF 3 , C^Cg alkoxy, C 2 C 6 di al koxymethyl, C^Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C.,-C 6 haloalkyl, C^-Cg haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, Cj-Cg alkylthio, C^-Cg alkylsulfonyl, C^Cg hal oal kyl sul fonyl, C^Cg alkylsulfinyl, C^Cg haloalkylsulfinyl, arylthio, C^Cg haloalkoxy, amino, -C g alkylamino, C 2 -C 15 dialkylamino, hydroxy, carbamoyl, -C 6 N-alkylcarbamoyl, C 2 -C 15 Ν,Ν-dialkylcarbamoyl, nitro, C 2 -C 15 dialkylsulfamoyl or methylenedioxy; R 1 is selected from the group consisting of hydrogen, C.,-C 6 alkyl, C.,-C 6 alkoxy, fluoro, chloro, bromo, iodo and =0; or R and R 1 together form a morpholino ring; n is 1-3; -175p is 1-3; X is -(CH 2 ) q -, wherein q is 1-6, -(CH 2 ) r -(=C-(CH 2 ) r -, -(CH 2 ) r -CH=CH-(CH 2 ) r -, 5 0 II -(CH 2 ) r -C-(CH 2 ) r -, or -(CH 2 ) Γ -Y-(CH 2 ) r -, wherein each r is independently 0-1 and wherein Y is 0 or S; 10 Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo, CF 3 , C^Cg alkoxy, C 2 -C 6 di al koxymethyl, C^Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C,Cg haloalkyl, C^Cg haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 carboxylic acyl, aryl, substituted 15 aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, C.,-Cg alkylthio, C^Cg al kyl sul fonyl, C^Cg haloal kyl sul fonyl, -C 6 alkylsulfinyl, C^Cg haloalkylsulfinyl, arylthio, C.,-C 6 haloalkoxy, amino, C^Cg alkylamino, C 2 -C 15 dialkylamino, hydroxy, carbamoyl, C^Cg N-al kylcarbamoyl, C 2 -C 15 N,N-dialkyl20 carbamoyl, nitro and C 2 -C 15 dialkylsulfamoyl; wherein said compound exhibits high binding activity with respect to the sigma receptor.
  46. 46. A compound of the formula: wherein: R 2 is selected from the group consisting of hydrogen, 35 chloro, fluoro, bromo, iodo, CF 3 , C^Cg alkoxy, C 2 -C g dialkoxymethyl, C^Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C^Cg haloalkyl, C^Cg haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 -17630 heterocycloalkyl, C^Cg alkylthio, C^Cg alkylsulfonyl, 0,-Cg haloalkylsulfonyl, C^Cg alkylsulfinyl, ί,-Cg haloalkylsulfinyl, arylthio, C^-Cg haloalkoxy, amino, Cj-Cg alkylamino, C 2 -C 15 dialkylamino, hydroxy, carbamoyl, C^Cg N-alkylcarbamoyl, C 2 -C 15 5 Ν,Ν-dialkylcarbamoyl, nitro and C 2 -C 15 dialkylsulfamoyl; X is -(CH 2 )-, wherein q is 1-6, -(CH 2 ) r -OC-(CH 2 ) r -, -(CH 2 ) r -CH=CH-(CH 2 ) r -, 10 0 II -(CH 2 ) r -C-(CH 2 ) r -, -(CH 2 ) r -Y-(CH 2 ) r -, wherein each r is independently 0-3 and wherein Y is 0 or S; or 15 -Cg alkyl (wherein Z is hydrogen); Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo, CF 3 , C^Cg alkoxy, C 2 -C 6 di al koxymethyl, C^Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C^ C 6 haloalkyl, C.,-C 6 haloalkylthio, allyl, aralkyl, C 3 -C 6 cyclo20 alkyl, aroyl, aralkoxy, C 2 -C g carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C g heterocycloalkyl, C.|-Cg alkylthio, C^Cg alkyl sul fonyl, Cj-Cg haloalkylsulfonyl, C^Cg alkylsulfinyl, C^Cg haloalkylsulfinyl, arylthio, C^Cg haloalkoxy, amino, C^Cg alkyl-amino, dialkylamino, hydroxy, 25 carbamoyl, C-,-C 6 N-alkylcarbamoyl, C 2 -C 15 Ν,Ν-dial klcarbamoyl, nitro, C 2 -C 15 di alkylsulfamoyl or methylenedioxy; V is N or CM, wherein M is hydrogen, C 7 -C 6 alkyl, C^Cg alkoxy, hydroxy, fluoro, chloro, bromo or represents one half of a double bond with a neighboring endocyclic carbon; wherein said compound exhibits a high binding activity with respect to the sigma receptor. -17747.
  47. The compound claim 46, wherein V is N, said compound having the formula N-X-Z
  48. 48. A compound selected from the group consisting of N(3-trifluoromethyl phenyl)-N'-(4-phenyl butyl) piperazine, N-(3chlorophenyl)-N'-benzyl piperazine, N-(3-chlorophenyl)-N'-(3 phenylpropyl)piperazine,N-phenyl-N'-(3-phenylpropyl)piperazine, N-phenyl-N'-(3-phenylbutyl)piperazine, N-(2-naphthyl)-N' -(3phenylpropyl)-piperazine, N-phenyl-N'-(3-(2-naphthyl)propyl )piperazine, N-phenyl-N'-propylpiperazine, N- (4-chlorophenyl)-N'(3-phenylpropyl)piperazine, N-benzyl-N'-(4-phenyl butyl) piperazine,N-phenyl-N'-(4-phthal imidobutyl)piperazine,N-phenylN' -(5-phthalimidopentyl)piperazine, N-(5-phenyl pentyl )-4benzylpiperidine and N-(5-phenylpentyl)-4-benzyl-4-hydroxypiperidine.
  49. 49. The compound of claim 46, wherein V is CM, said compound having the formula CM N-X-Z
  50. 50. A compound of the formula: R 3 -V N-X-Z 173wherein: R is selected from the group consisting of Cj-Οθ alkyl, C.,-C 6 alkenyl, C 2 -C 6 di al koxymethyl, C 3 -C 15 dialkylaminoalkyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, C 2 -C 6 acyl, heteroaryl, 5 substituted heteroaryl, C 3 -C 6 heterocycloalkyl; X is -(CH 2 ) q -, wherein q is 1-6, -(CH 2 ) r -(M-(CH 2 ) r -, -(CH 2 ) r -CH=CH-(CH 2 ) r -, 10 0 II -(CH 2 ) r -C-(CH 2 ) r -, -(CH 2 ) r -Y-(CH 2 ) r -, wherein each r is independently 0-3 and wherein Y is 0 or S; or 15 C-|~Cg alkyl (wherein Z is hydrogen); Z is cycloalkyl, aryl or heteroaryl wherein Z may be substituted by chloro, fluoro, bromo, iodo, CF 3 , C-,-C 6 alkoxy, C 2 -C 6 dialkoxymethyl, C.,-Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C^Cg haloalkyl, C.,-Cg haloalkylthio, 20 allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, C^Cg alkylthio, 0,-Cg alkylsulfonyl, ε,-Cg haloalkylsulfonyl, Cj-Cg al kyl sul finyl, C^Cg haloalkylsulfinyl, arylthio, Cj-Cg haloalkoxy, amino, C 1 -Cg 25 alkyl-amino, dialkylamino, hydroxy, carbamoyl, C^Cg FIal kyl carbamoyl, C 2 -C 15 Ν,Ν-dialklcarbamoyl, nitro, C 2 -C 15 dialkylsulfamoyl or methylenedioxy; V is N or CM, wherein M is hydrogen, Cj-Cg alkyl, C^Cg alkoxy, hydroxy, fluoro, chloro, bromo or represents one half of a double 30 bond with a neighboring endocyclic carbon; wherein said compound exhibits a high binding activity with respect to the sigma receptor.
  51. 51. The compound of claim 50 selected from the group 35 consisting of N-methyl-N'-(4-phenyl-3-(E)butenyl)pipera-zine, Nmethyl-N'-(4-phenyl-3-(Z)butenyl)-piperazine,N-methyl-N'-(4-(3trifuoromethylphenyl)-3-(Z)butenyl)piperazine, N-methyl-N'-(4phenylbutyl)piperazi ne, N-benzyl-N' -/4-phthalimidobutyl) 922112 -179piperazine, N- (2-methoxyphenyl) - N' - (4-phthalimidobutyl) piperazine, N-(5-phenylpentyl)-4-benzylpiperidine, and N-(5phenylpentyl)-4-benzyl-4-hydroxy-piperidine.
  52. 52. A compound selected from the group consisting of N(3-tri fluoromethyl phenyl)-Ν' -(4-phenylbutyl) piperazine, N - (3chlorophenyl)-Ν' - (3-phenylpropyl)piperazine, N-phenyl-N'-(3phenylpropyl) piperazine, N-phenyl-N'-(3-phenyl butyl) piperazine, N-naphthyl-N'-(3-phenyl propyl)-piperazine, N-phenyl-N'-(3naphthylpropyl)piperazine, N-phenyl-N'-propylpiperazine, N-(4chlorophenyl)-Ν' - (3-phenylpropyl)piperazine, N-benzyl-N'-(4phenylbutyl)piperazine, N-phenyl-N'-(4-phthalimidobutyl) piperazine, N-phenyl-N'-(5-phthalimidopentyl)piperazine, N-(5phenylpentyl) - 4-benzyl piperidineandN- (5-phenylpentyl) - 4-benzyl 4-hydroxy-piperidine..
  53. 53. A compound having the formula wherein R 2 is selected from the group consisting of hydrogen, chloro, fluoro, bromo, iodo, CF 3 , C.,-C 6 alkoxy, C 2 -C 6 dialkoxymethyl, 0,-Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C^Cg haloalkyl, Ο,-Cg haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, C.,-Cg alkylthio, C^Cg alkylsulfonyl, C^Cg haloal kyl sul fonyl, C^Cg alkylsulfinyl, C-,-C e haloalkylsulfinyl, arylthio, C^Cg haloalkoxy, amino, C^Cg alkylamino, C 2 -C 15 dialkylamino, hydroxy, carbamoyl, C.,-C 6 N-alkylcarbamoyl, C 2 -C 15 Ν,Ν-dialkylcarbamoyl, nitro and C 2 -C 15 di alkylsulfamoyl; X is -(CH 2 ) r -C<-(CH 2 ) r -, -180-(CH 2 ) r -CH=CH-(CH 2 ) r -, II -(CH 2 ) r -t-(CH 2 ) r -, or 5 -(CH 2 ) r -Y-(CH 2 ) r -, wherein each r is independently 0-3 and Y is 0 or S; Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo, CF 3 , C 1 -C 6 alkoxy, C 2 -C g di al koxymethyl, Cj-Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C,10 Cg haloalkyl, ϋ,-Cg haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C g carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, C^Cg alkylthio, C^Cg alkylsulfonyl, C.,-C 6 hal oal kyl sul fonyl, C-j-Cg alkylsulfinyl, C^Cg haloalkylsulfinyl, arylthio, C.,-Cg 15 haloalkoxy, amino, C^-Cg alkyl-amino, dialkylamino, hydroxy, carbamoyl, C.,-C 6 N-alkylcarbamoyl, C 2 -C 15 Ν,Ν-dialklcarbamoyl, nitro, C 2 -C 15 dialkylsulfamoyl or methylenedioxy; wherein said compound exhibits a high binding activity with respect to the sigma receptor.
  54. 54. A compound of the formula: wherein: R 4 selected is hydrogen or an aryl group substituted with a group from the group consisting of C^Cg alkyl, C^Cg alkenyl, C 2 -C 6 dialkoxymethyl, C 3 -C 15 dialkylaminoalkyl, aralkyl, C 3 -C g cycloalkyl, aroyl, C 2 -C 6 ac Y^» aryl, substituted aryl, 35 heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl; R 5 is hydrogen or hydroxy; X is -(CH 2 ) q -, wherein q is 1-6, -(CH 2 ) r -(M-(CH 2 ) r -, -(CH 2 ) r -CH=CH-(CH 2 ) r -, -ιβιο II -(CH 2 ) r -C-(CH 2 ) r -, -(CH 2 ) r -Y-(CH 2 ) r -, wherein each r is independently 0-3 and 5 wherein Y is 0 or S; or C^Cg alkyl (wherein Z is hydrogen); Z is cycloalkyl, aryl or heteroaryl wherein Z may be substituted by chloro, fluoro, bromo, iodo, CF 3 , C^Cg alkoxy, C 2 -C 6 d ial koxymethyl, C^Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, 10 carboxy, carboxamido, C^Cg haloalkyl, C^Cg haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, C^Cg alkylthio, C^Cg alkylsulfonyl, C.,-Cg hal oal kyl sul fonyl, (^-Cg alkylsulfinyl, (j-Cg 15 haloalkylsulfinyl, arylthio, ί,-Cg haloalkoxy, amino, C^Cg alkyl-amino, dialkylamino, hydroxy, carbamoyl, -C 6 Nalkylcarbamoyl, C 2 -C 15 Ν,Ν-dialklcarbamoyl, nitro, C 2 -C 15 dialkylsulfamoyl or methylenedioxy; wherein said compound exhibits a high binding activity with 20 respect to the sigma receptors.
  55. 55. The compound of claim 54 selected from the group consisting of N-(5-phenylpentyl)piperidine, N-(8-phenylheptyl)piperidine, N-(5-(4-methoxyphenyl)pentyl)piperidine, N-(325 phenylpropyl)piperidine, N-(5-cyclohexyl)pentylpiperidine N-benzylpiperidine,N-(2-phenethyl)-4-hydroxy-4-phenylpiperidine N-(2-phenethyl)-4-hydroxy-4-t-butyl piperidine, N - (5-(4chlorophenyl)-5-pentanon-l-yl) pi peridine, N-(5-(4-chlorophenyl) 5-pentanon-l-yl)-4-phenyl pi peri dine, N-(5-(4-methoxyphenyl )-530 pentanon-l-yl)piperidine, N-(5-(4-methoxyphenyl)-5-pentanon-lyl)-4-phenylpi peri dine, N-(5-(4-methoxyphenyl)pentyl )-4phenylpiperidine, N-(5-phenyl-5-pentanon-l-yl)-4-phenylpiperidine N-(5-(4-chlorophenyl)pentyl)-4-phenylpiperidine, N - (5-(3methoxyphenyl)-5-pentanon-l-yl)piperidine, N-(5-(3-chlorophenyl)35 5-pentanon-l-yl)piperidine, N-(5-(3-chlorophenyl) - 5-pentanon-1yl)-4-phenylpiperidine,N-(5-(3-methoxyphenyl)-5-pentanon-1-yl) IE 922112 -1824- phenylpiperidine, N-(4-(4-fluorophenyl)-4-butanon-lyl) pi peri dine, N-(5-(4-fluorophenyl)-5-pentanon-1-yl)piperidine N-(5-(4-fluorophenyl)-5-pentanon-1-yl)-4-phenylpiperidine, N-(5(4-fluorophenyl)-5-pentanon-l-yl)-4-(3-chlorophenyl)-45 hydroxypiperidine, N-(5-(4-chlorophenyl)-5-pentanon-1-yl)-4-(4fluorophenyl)-l,2,3,6-terahydropyridine, N-(5-(4-chlorophenyl)-5pentanon-1-yl)-4-(4-fluorophenyl) pi peri dine, N-(5-(4-chlorophenyl) -5-pentanon- 1-yl )-4 -( 4- fluorophenyl )-1,2,3,6-terahydropyridine, N-(5-(4-chlorophenyl)-5-pentanon-1-yl)-4-(4-fluoro10 phenyl)-piperidine, N-(5-(4-chlorophenyl)-5-pentanon-1-yl)-4(chlorophenyl )-1,2,3,6-terahydropyridine, N-(5-(4-chlorophenyl) 5- pentanon-1-yl)-4-(chlorophenyl)piperidine, N-(5-(3,4-dichiorophenyl )-5-pentanon-1-yl)-4-(chiorophenyl)-piperidine, N-(5cyclopentylpentan-5-on-l-yl)piperidine, N-(5-(3,4-methylene15 dioxyphenyl)penta-2,4-dieny1)piperidine, N-phenyl-(5phenyl)pentylamine, N-methyl-N-(3-phenylpropyl)-5phenylpentyl amine, N-benzyl-N-methyl-5-phenylpentylamine, N-(2(o-methoxyphenyl)ethy1)-5-phenylpentylamine, N- (2 -(mmethoxypheny1)ethyl)-5-phenylpentylamine, N- (2- (p20 methoxyphenyl)ethy1) - 5 - phenyl pentylamine, N-benzyl-5phenylpentylamine, N-(2-(m-hydroxyphenyl)ethyl)-5phenylpentylamine, and N-(2-(o-hydroxyphenyl)ethyl)-5phenylpentylamine. 25
  56. 56. A compound having the formula: wherein, 35 X is -(CH 2 ) q -, wherein q is 1-6, -(CH 2 ) r -(M-(CH 2 ) r -, - (CH 2 ) r -CH=CH-(CH 2 ) f -, -183-(CH 2 ) r -C-(CH 2 ) r -, -(CH 2 ) r -Y-(CH 2 ) r -, wherein each r is independently 0-3 and 5 wherein Y is 0 or S; or C^Cg alkyl (wherein Z is hydrogen); Z is cycloalkyl, aryl or heteroaryl wherein Z may be substituted by chloro, fluoro, bromo, iodo, CF 3 , Cj-Cg alkoxy, C 2 -C 6 di al koxymethyl, (^-Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, 10 carboxy, carboxamido, C 7 -C 6 haloalkyl, C^Cg haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, Cj-Cg alkylthio, C^-Cg alkylsulfonyl, i^-Cg haloalkylsulfonyl, Ο,-Cg alkylsulfinyl, C^Cg 15 haloalkylsulfinyl, arylthio, C^Cg haloalkoxy, amino, -C g alkyl-amino, dialkylamino, hydroxy, carbamoyl, C.,-C 6 Nal kyl carbamoyl, ^2^15 Ν,Ν-dial klcarbamoyl, nitro, C 2 -C 15 di alkylsulfamoyl or methylenedioxy; wherein said compound exhibits a high binding activity with 20 respect to the sigma receptors.
  57. 57. N-(5-phenyl)pentyl-3-azabicyclo[3.2.2]nonane, a compound of claim 56. 25
  58. 58. A tropane derivative having the formula: wherein, 35 R 4 is hydrogen or an aryl group substituted with a group selected from the group consisting of C 7 -C 6 alkyl, C 1 -C 6 alkenyl, C 2 -C 6 dialkoxymethyl, C 3 -C 15 dialkylaminoalkyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, C 2 -C 6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl; -184c R is hydrogen or hydroxy; X is -(CH 2 ) q -, wherein q is 1-6, -(CH 2 ) r -OC-(CH 2 ) r -, (CH 2 ) r -CH=CH-(CH 2 ) r -, II -(CH 2 ) r -C-(CH 2 ) r -, -(CH 2 ) r -Y-(CH 2 ) r -, wherein each r is independently 0-3 and wherein Y is 0 or S; or (q-Cg alkyl (wherein Z is hydrogen); Z is cycloalkyl, aryl or heteroaryl wherein Z may be substituted by chloro, fluoro, bromo, iodo, CF 3 , C^Cg alkoxy, C 2 -C 6 di al koxymethyl, C^Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, 0,-Cg haloalkyl, C^Cg haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, C,-C 6 alkylthio, C.,-C 6 alkylsulfonyl, C^Cg haloal kyl sul fonyl, C^Cg alkylsulfinyl, C-j-Cg haloalkylsulfinyl, arylthio, C^Cg haloalkoxy, amino, C^Cg alkyl-amino, dialkylamino, hydroxy, carbamoyl, C-pCg Nalkylcarbamoyl, C 2 -C 15 Ν,Ν-dialklcarbamoyl, nitro, C 2 -C 15 dialkylsulfamoyl or methylenedioxy; wherein said compound exhibits a high binding activity with respect to the sigma receptors.
  59. 59. N-(5-phenyl)pentyl-4-phenyltropan-4-ol, acompoundof claim 58.
  60. 60. A compound having the formula: CH, / \ 0 CHr Ar-CH-CH 2 -N-X-Z wherein; -185Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, wherein the substituent is selected from the group consisting of chloro, fluoro, bromo, iodo, CF 3 , 0,-Cg alkoxy, C 2 C 6 di al koxymethyl, C^Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, 5 carboxy, carboxamido, C^Cg haloalkyl, C^Cg haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, Cj-Cg alkylthio, C.,-C 6 alkylsulfonyl, C^Cg haloalkylsulfonyl, C-,-C 6 al kyl sul finyl, -C 6 haloalkylsulfinyl, 10 arylthio, C^Cg haloalkoxy, amino, C^Cg alkylamino, C 2 -C 15 dialkylamino, hydroxy, carbamoyl, C^Cg N-alkylcarbamoyl, C 2 -C 15 Ν,Ν-dialkylcarbamoyl, nitro and C 2 -C 15 dialkylsulfamoyl; X is -(CH 2 ) q -, wherein q is 1-6, -(CH 2 ) r -OC-(CH 2 ) r -, 15 -(CH 2 ) r -CH=CH-(CH 2 ) Γ -, II -(CH 2 ) r -C-{CH 2 ) r -, -(CH 2 ) Γ -Y-(CH 2 ) Γ -, wherein each r is independently 0-3 and 20 wherein Y is 0 or S; or -Cg alkyl; Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo, CF 3 , 0,-Cg alkoxy, C 2 -C 6 di al koxymethyl, Cj-Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C.,25 C 6 haloalkyl, C^Cg haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, Cj-Cg alkylthio, C^Cg alkylsulfonyl, C^Cg haloalkylsulfonyl, C-j-Cg alkylsulfinyl, C.,-C 6 haloalkylsulfinyl, arylthio, C^Cg 30 haloalkoxy, amino, C^Cg alkylamino, C 2 -C 15 dialkylamino, hydroxy, carbamoyl, C^Cg N-alkylcarbamoyl, C 2 -C 15 Ν,Ν-dialkylcarbamoyl, nitro or C 2 -C 15 dialkylsulfamoyl; wherein said compound exhibits high binding activity with respect to the sigma receptor. -18661.
  61. A compound of the formula R 1 R 5 I I Cy—(CH) n -NH-X-Z wherein n is 0-5; 10 Cy is Cg-C 8 cycloalkyl; and R 1 is independently selected from the group consisting of hydrogen, C^Cg alkyl, C^Cg alkoxy, fluoro, chloro, bromo, iodo and =0; R is hydrogen or C^Cg alkyl; 15 X is -(CH 2 ) q -, wherein q is 1-6; -(CH 2 ) r -C=€-(CH 2 ) r -, wherein r is 0-3; -(CH 2 ) r -CH-CH-(CH 2 ) r -; ί 20 -(CH 2 ) r -C-(CH 2 ) r -; -(CH 2 ) r -Y-(CH 2 ) r -, wherein each r is independently 0-3 and wherein Y is 0 or S; or C^Cg alkyl (wherein Z is hydrogen); and Z is cyclolkyl which may substituted by chloro, fluoro, bromo, 25 iodo, CF 3 C^Cg alkoxy, C 2 -C 6 di al koxymethyl, C^Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C.,-C 6 haloalkyl, Ο,-Cg haloalkylthio, allyl, aralkyl, C 3 -C g cycloalkyl, aroyl, aralkoxy, C 2 -C 6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl, 0,-Cg 30 alkylthio, C^Cg alkylsulfonyl, C^Cg hal oal kyl sul fonyl, C 1 -C 6 alkylsulfinyl, C^Cg haloalkylsulfinyl, arylthio, 0,-Cg haloalkoxy, amino, C^Cg alkylamino, C 2 -C 15 dialkylamino, hydroxy, carbamoyl, C^Cg N-alkylcarbamoyl, C 2 -C 15 Ν,Ν-dialkylcarbamoyl, nitro, C 2 -C 15 dialkylsulfamoyl or methylenedioxy.
  62. 62. A compound selected from the group consisting of Ncyclohexylmethyl - 3- phenylpropylamine, N- ( 5 cyclohexylpentyl)benzyl amine, 5-cyclohexylpentyl amine, N-methyl5-cyclohexylpentyl amine,N,N-Di methyl-5-cyclohexyl pentyl amine,NIE 922112 -187- cyclohexylmethyl-5-cyclohexyl-n-pentylamine, and Ncyclohexylmethyl-N-methyl-5-cyclohexyl-n-pentylamine.
  63. 63. A compound of the formula 5 χ!—V N-X-Z 10 wherein X 1 is - (CH 2 ) r -Cs£-(CH 2 ) r -, wherein each r is 0-3 independently; -(CH 2 ) r -CH=CH-(CH 2 ) r -; II 15 -(CH 2 ) r -C-(CH 2 ) r -; -(CH 2 ) Γ -Y-(CH 2 ) r -, wherein Y is 0 or S; or Cf-Cg alkyl (wherein Z is hydrogen); R 2 is independently selected from the group consisting of hydrogen, chloro, fluoro, bromo, iodo, CF 3 , C.,-C g alkoxy, C 2 -C 6 20 dial koxymethyl, C^Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C^Cg haloalkyl, C-^Cg haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C g heterocycloalkyl, C 7 -C 6 alkylthio, C^Cg alkyl25 sulfonyl, C^Cg haloalkylsulfonyl, C^Cg alkylsulfinyl, C-,-ίθ haloalkylsulfinyl, arylthio, C^Cg haloalkoxy, amino, C-j-C 6 alkyl-amino, dialkylamino, hydroxy, carbamoyl, C^Cg Nalkylcarbamoyl, Ν,Ν-dialklcarbamoyl, nitro and C^-C^ di alkyl sul famoyl; V is N or CM, wherein M is hydrogen, C-,-C g alkyl, C^Cg alkoxy, 30 fluoro, chloro, bromo, trifl uoromethyl, hydroxy or one half of a double bond with the neighboring endocyclic carbon; X is -(CH 2 ) q -, wherein q is 1-6; -(CH 2 ) r -O£-(CH 2 ) r -, wherein r is 0-3; -(CH 2 ) r -CH=CH-(CH 2 ) r -; -(CH 2 ) r -C-(CH 2 ) r -; -188-(CH 2 ) r -Y-(CH 2 ) r -, wherein each r is independently 0-3 and wherein Y is 0 or S; or C^Cg alkyl (wherein Z is hydrogen); and Z is cycloalkyl which may be substituted by chloro, fluoro, 5 bromo, iodo, CF 3 , C^Cg alkoxy, C 2 -C 6 di al koxymethyl, C^Cg alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C,C 6 haloalkyl, C.,-C 6 haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C g heterocycloalkyl, 10 0.,-Cg alkylthio, C^Cg alkylsulfonyl, C^-Cg hal oal kyl sul fonyl, (q-Cg alkylsulfinyl, C^-Cg haloalkylsulfinyl, arylthio, C.,-Cg haloalkoxy, amino, C.,-C 6 alkylamino, C 2 -C 15 dialkylamino, hydroxy, carbamoyl, C.,-C 6 N-alkylcarbamoyl, C 2 -C 15 Ν,Ν-dialkylcarbamoyl, nitro and C 2 -C 15 dialkylsulfamoyl.
  64. 64. A compound having the formula: R 6 5 I 7 20 R -N-X-R' wherein R and R are independently a C 18 alkyl group; R 7 is hydrogen or a C^g alkyl group substituted by an arylacetoxy or aryl carboxy group; and 25 X is -(CH 2 ) q -, wherein q is 1-6; -(CH 2 ) r -O£-(CH 2 ) r -, wherein r is 0-3; -(CH 2 ) r -CH=CH-(CH 2 ) r -; II 30 -(CH 2 ) r -C-(CH 2 ) r -; -(CH 2 ) r -Y-(CH 2 ) r -, wherein each r is independently 0-3 and wherein Y is 0 or S; or C.,-C 6 alkyl (wherein R 7 is hydrogen); wherein said compound exhibits a high binding activity with 35 respect to the sigma receptors.
  65. 65. The compound claim 64 selected from the group consisting of Ν,Ν-dimethyl-n-hexyl,amine, N-methyl-NIE 922112 -189propylhexyl amine,N,N'-diethyl - 2- (diphenyl acetoxy)ethyl amine, and N,N' -diethyl - 2-(9-fluorenecarboxy)ethyl amine.
  66. 66. A compound selected from the group consisting of N5 phenyl-N'-(3-(4-phthal imido)propyl)piperazine, N-(4-(lphthal imido)butyl)-N' -(o-methoxylphenyl )piperazine, andN-phenyl N'-(4-(1-phthalimido)butyl Jpiperazine.
  67. 67. A pharmaceutical composition comprising a 10 therapeutically effective amount of the compound of any one of claims 42-46, 48, 52-54, 56, 58 and 60-66 and a pharmaceutically acceptable carrier.
  68. 68. A compound as claimed in any one of claims 42, 39. 43, 45, 46, 50, 53, 54, 56, 58, 60, 61 , 63 or 64, substantially as hereinbefore described and exemplified.
  69. 69. A pharmaceutical composition according to claim 67, substantially as hereinbefore described.
  70. 70. A process for preparing a compound as claimed in any one of claims 42, 43, 45, 46, 50, 53, 54, 56, 58, 60, 61, 63 or 64, substantially as hereinbefore described and exemplified.
  71. 71 . A compound as claimed in any one of claims 42, 43, 45, 46, 50, 53, 54, 56, 58, 60, 61, 63 or 64, whenever prepared by a process claimed in claim 70.
IE211292A 1991-06-27 1992-07-01 Sigma receptor ligands and the use thereof IE922112A1 (en)

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