WO1993000313A2 - Sigma receptor ligands and the use thereof - Google Patents
Sigma receptor ligands and the use thereof Download PDFInfo
- Publication number
- WO1993000313A2 WO1993000313A2 PCT/US1992/005330 US9205330W WO9300313A2 WO 1993000313 A2 WO1993000313 A2 WO 1993000313A2 US 9205330 W US9205330 W US 9205330W WO 9300313 A2 WO9300313 A2 WO 9300313A2
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- alkyl
- aryl
- heteroaryl
- substituted
- phenyl
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- 0 **C1Cc2c(*)cccc2CC1 Chemical compound **C1Cc2c(*)cccc2CC1 0.000 description 7
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- 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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Definitions
- the invention is in the field of medicinal chemistry.
- 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.
- 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. 11:37-40 (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.
- 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. Tarn, 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.
- 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).
- certain neuroleptic agents such as haloperidol, produce their antipsychotic effects by both a sigma and DA mechanism. Tarn, S.W. and Cook, L., Proc. Nat. Acad. Sci. (USA) 81:5618 (1984).
- [ 3 H]haloperidol, in combination with spiperone is now commonly used to label sigma sites in radioligand binding studies.
- 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 N-alkyl substituents, e.g., benzyl or phenethyl.
- Largent et ai . 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.
- Aldous F.A.B., J. Med. Chem. 17:1100-1111 (1974), discloses a structure-activity study of psychotomimetic phenylalkylamines.
- Aldous et al. also disclose a number of halo, methyl, and methoxy substituted amphetamines.
- X is methyl, CF 3 , 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-chlorobenzylamine, N-(1-phenyl-2-propyl)-4-methylbenzyl-amine, and N-(1-phenyl-2-propyl)-4-methoxybenzylamine.
- R 1 is hydrogen, 4-Cl, 3-Cl, or 3-CF 3 and R 2 is 2-chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 3-CF 3 -phenyl, 4-tolyl, 4-methoxyphenyl, phenyl, 2-furyl, 2-tetrahydrofuryl, 2-thienyl, or 3-thienyl. Reportedly, these compounds were tested for anorexigenic activity in rats and dogs.
- R 1 , R 2 , and R 3 are hydrogen, chloro, CF 3 , or methoxy.
- R 1 is 2-butanone-3-yl, 2-hydroxybutane-3-yl, 1-hydroxybutane-3-yl, or acetate.
- 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 ethanolamine-N-methyl transf erase.
- R 1 is OH or OMe and R 2 and R 3 are H or C 1 -C 4 lower alkyl.
- R 1 is OH or OMe
- R 2 and R 3 are H or C 1 -C 4 lower alkyl.
- R 1 is OH or OMe
- R 2 is lower alkyl
- R 3 is lower alkyl or phenethyl.
- These compounds reportedly have dopamine-receptor stimulating activity.
- McDermed et al. disclose two compounds of the Formula (XI) and (XII):
- These compounds are reportedly dopamine receptor agonists.
- 2-aminotetralin is a conformationally restricted analog of amphetamine which is about one-half as effective as racemic amphetamine.
- R is H, OMe, or OBz;
- R 1 is H, Me, or n-Pr; and
- R 2 is H, n-propyl, benzyl, phenethyl, or phenpropyl.
- R 1 and R 2 are aryl and X is a straight or branched chain alkylene of C 1 -C 3 .
- the compounds are reportedly adrenolytics, hypotensors, potentiators of barbiturates, and depressants of the central nervous system.
- Roessler, Chem Abstr. 61:13328g disclose piperazine derivatives of the Formula (XXIV):
- R is tolyl, p-methoxyphenyl, m-ethoxyphenyl, beta-naphthyl, m-or p-carboxyl phenyl, 3,4-dimethoxyphenyl, 5-hydrindenyl, p-chloro-phenyl, p-bromophenyl, p-iodophenyl, 3,4-dichlorophenyl, and m- or p-nitrophenyl.
- R 1 is phenyl or o-methoxyphenyl and R 2 is 2,4-dichlorophenyl, o-, m- or p- methoxyphenyl, 3,4-dimethoxyphenyl, or m-tolyl. These compounds are reported to be antihypertensive agents.
- the invention relates to the discovery that certain phenylalkyl-amine, aminotetralin, piperazine, piperidine and related derivatives have high binding to the sigma receptor and, unexpectedly, low binding for the PCP, DA and 5-HT 1A receptors.
- 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-HT 1A 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.
- compouds which selectively bind to the sigma-2 binding site may block calcium channels.
- such calcium channel blocking sigma-2 receptor ligands may be used to treat psychosis, angi na , migrane and hypertensi on .
- the sigma receptor ligands of the present invention may also be employed in methods of treating or preventing depression.
- 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 human a therapeutically effective amount of a compound selected from the Formulae (XXXI) and (XXXII):
- 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 ligands.
- the present inventor has discovered that certain N-substituted phenylalkylamines, although seemingly related to amphetamine, have activities which are, in fact, very much unlike amphetamine. Instead, the N-substituted phenylalkylamines 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-HT 1A receptor. In addition, certain of the sigma receptor ligands of the present invention are highly selective for the sigma-1 binding site over the sigma-2 binding site.
- 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):
- Ar is aryl or heteroaryl wherein aryl or heteroaryl can be substituted by hydrogen, halogen such as chloro, fluoro, bromo, iodo, CF 3 , C 1 -C 6 alkoxy, C 2 -C 6 dialkoxymethyl, C 1 -C 6 alkyl, cyano, C 3 - C15 dialkylaminoalkyl, carboxy, carboxamido, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 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
- R is hydrogen or C 1 -C 6 alkyl
- R and R 1 together form a morpholino ring
- n 0-5;
- W is -(CH 2 ) p - or -H H-, wherein p is 1-3;
- X is -(CH 2 ) q -, wherein q is 1-6;
- 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; CF 3 , C 1 -C 6 alkoxy, C 2 -C 6 dialkoxymethyl, C 1 -C 6 alkyl, cyano, C 3 -C 15 dial kyl aminoal kyl, carboxy, carboxamido, C 1 - C 6 haloalkyl, C 1 -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 6 heterocycloalkyl,
- 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): wherein T is a cycloalkyl group or Ar as described above, n, R, and R , X and Z are defined above;
- Especially preferred compounds within the scope of Formula (XXXIII) include N-phenethyl-1-phenyl-isopropylamine, N-phenylpropyl-1-phenylisopropylamine, N-(2-phenoxyethyl)-1-phenylisopropylamine, N-(3-phenyl-3-propanon-l-yl)-l-phenylisopropylamine, N-(4-phenylbutyl)-1-phenylisopropylamine,
- 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 -(CH 2 ) p - having the Formula (XXXIV):
- 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):
- X and Z are as defined above and V is N or -CM-, wherein M is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, fluoro, chloro, bromo, trifluoromethyl, or represents one half of a double bond (with the neighboring endocyclic carbon);
- R 2 is independently selected from the group consisting of hydrogen, chloro, fluoro, bromo, iodo, CF 3 , C 1 -C 6 alkoxy, C 2 -C 6 dialkoxymethyl, C 1 -C 6 alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C 1 -C 6 haloalkyl, C 1 -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 6 heterocycloalkyl, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkylsulfonyl, C 1 -C
- 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):
- R 2 , 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):
- R 2 , M, X and Z are as defined above;
- U is selected from the group consisting of hydrogen, halogen such as chloro, fluoro, bromo, iodo; CF 3 , C 1 -C 6 alkoxy, C 2 -C 6 dialkoxymethyl, C 1 -C 6 alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 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 hetero
- 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):
- R 3 is selected from the group consisting of C 1 -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; and X, Y and Z are defined above,
- Especially preferred compounds within the scope of Formula (XXXVa) includeN-methyl-N'-(4-phenyl-3-(E)butenyl)piperazine, N-methyl-N'-(4-phenyl-3-(Z)butenyl)-piperazine, N-methyl-N'-(4-(3-trifuoromethylphenyl)-3-(Z)butenyl)piperazine, N-methyl-N'-(4-phenylbutyl)piperazine, N-benzyl-N'-(4-phthalimidobutyl)-piperazine, N-(2-methoxyphenyl)-N'-(4-phthalimidobutyl)-piperazine, N-(5-phenylpentyl)-4-benzylpiperidine, N-(5-phenylpentyl)-4-benzyl-4-hydroxy-piperidine, N-benzyl-N'-(5-phenyl)pentyl
- 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) :
- R 4 is hydrogen or an aryl group substituted with a group selected from the group consisting of C 1 -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;
- R is hydrogen or hydroxy
- Examples of compounds having Formula (XXXVb) include but are not limited to N-(5-phenylpentyl)piperidine, N-(8- phenylheptyl)piperidine, N-(5-(4-methoxyphenyl)pentyl)piperidine, N- (3-phenylpropyl)piperidine, N-(5-cyclohexyl)pentylpiperidine N-benzyl piperidine, N-(2-phenethyl)-4-hydroxy-4-phenyl 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) :
- An example of a compound having Formula XXXVc is N-(5-phenyl)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):
- R 4 , R 5 , X and Z are defined above, and 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):
- a 1-8;
- b is 1-8;
- R is as defined above;
- 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):
- R, R 2 , a and b as defined above, may be the same or different;
- Cy is C 3 -C 8 cycloalkyl and Ar, R 1 , n, R, X, and Z are defined as above.
- Examples of compounds having Formula LII include 5-cyclohexylpentylamine, N-methyl-5-cyclohexylpentylamine, N,N-Dimethyl-5-cyclohexylpentylamine, N-cyclohexylmethyl-5-cyclohexyl-n-pentylamine, and N-cyclohexylmethyl-N-methyl-5-cyclohexyl-n-pentylamine.
- X 1 is -(CH 2 ) r -C ⁇ C-(CH 2 ) r -, wherein each r is 0-3 independently;
- R 2 , V, X, and Z are defined as above.
- R 5 and R 6 are independently a C 1-8 al kyl group
- R 7 is hydrogen or a C 1-8 al kyl group substituted by an aryl acetoxy group
- X is as defined above.
- examples of such compounds include but are not l imited to N, N' -diethyl -2- (diphenyl acetoxy) ethyl ami ne and N , N ' -d i ethyl -2 - (9 - fluorenylcarboxy)ethyl amine.
- Such compounds include N,N-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 ligands and pharmaceutical compositions comprising the novel sigma receptor ligands.
- the invention relates to compounds having the Formula (XXXI):
- X is -(CH 2 ) q -, wherein q is 3-6;
- 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).
- q is 5.
- the invention also relates to sigma receptor ligands having the Formula (XXXIII):
- T, n, R, R 1 , and Z are defined above, and
- X is -(CH 2 ) q -, wherein q is 3-6;
- 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 2 , V and Z are as defined above;
- X is -(CH 2 ) r -C ⁇ C-(CH 2 ) r -, wherein r is 0-3;
- the invention also relates to compounds of the Formula (XXXV):
- R 2 and Z are as defined above;
- X is -(CH 2 ) r -C ⁇ C-(CH 2 ) r -, wherein each r is 0-3 independently;
- the invention also relates to compounds which are related to the Formula XXXII and having the Formula (XXXIX):
- R 2 , M, X and Z are as defined above;
- U is selected from the group consisting of hydrogen, halogen such as chloro, fluoro, bromo, iodo; CF 3 , C 1 -C 6 alkoxy, C 2 -C 6 dialkoxymethyl, C 1 -C 6 alkyl, cyano, C 3 -C 15 dialkylaminoalkyl, carboxy, carboxamido, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkylthio, allyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, aralkoxy, C 2 -C 6 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 hetero
- the invention also relates to a compound of the Formula (XXXVa) :
- R 3 is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 2 -C 6 dialkoxymethyl, C 3 -C 15 dial kyl ami noal kyl, aralkyl, C 3 -C 6 cycloalkyl, aroyl, C 2 -C 6 acyl, aryl, substituted aryl, alkaryl, substituted alkaryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, C 3 -C 6 heterocycloalkyl; and X, Y and Z are defined above,
- the invention also relates to a compound of the Formula (XXXVb) :
- R 4 is hydrogen or an aryl group substituted with a group selected from the group consisting of C 1 -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;
- R 5 is hydrogen or hydroxy
- the invention also relates to a compound of the Formula (XXXVc):
- the invention also relates to a tropane derivative of the Formula (XXXVd):
- R 4 , R 5 , X and Z are defined above, and
- the invention also relates to a compound of the Formula (XXXVI):
- a 1-8;
- b is 1-8;
- R is hydrogen or C 1 -C 6 alkyl
- R 2 is independently selected from the group consisting of hydrogen, chloro, fluoro, bromo, iodo, CF 3 , C 1 -C 6 alkoxy, C 2 -C 6 dialkoxymethyl, C 1 -C 6 alkyl, cyano, C 3 -C 15 dial kyl ami noal kyl, carboxy, carboxamido, C 1 -C 6 haloalkyl, C 1 -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 6 heterocycloalkyl, C 1 -C 6 alkylthio, C 1 -C 6 alkyl- sulfonyl, C 1 -
- the invention also relates to naphthyl derivatives within the scope of Formula (XXXI) having Formula (XXXVII):
- R, R 1 , a and b as defined above, may be the same or different;
- the invention also relates to morpholino derivatives having Formula (XXXVIII):
- Cy is C 3 -C 8 cycloalkyl and Ar, R 1 , n, R, X, and Z are defined as above.
- X is -(CH 2 ) r -C ⁇ C-(CH 2 ) r -, wherein each r is 0-3 independently;
- R 2 , V, X, and Z are defined as above.
- the invention also relates to compounds having the Formula
- R 5 and R 6 are independently a C 1 -C 6 alkyl group
- R 7 is hydrogen or a C 1-8 alkyl substituted by an arylacetoxy or arylcarboxy group
- X is as defined above.
- Examples of compounds having Formula LIV include N,N-dimethyl-n-hexylamine,
- N-methyl -N-propyl hexyl amine N,N' -diethyl -2- (diphenylacetoxy)ethylamine, N,N'-diethyl-2- (fluorenecarboxy)ethylamine, N,N-diethyl-2- (diphenylacetoxy)ethylamine and N,N-diethyl-2-(9- fluorenylcarboxy)ethylamine.
- 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 3 H-DTG, which labels both sites with about equal affinity) is disclosed by Weber et al., Proc. Natl. Acad. Sci (USA) 83:8784-8788 (1986).
- [ 3 H]pentozocine may be used to selectively label the sigma-1 binding site in a binding assay.
- a mixture of [ 3 H]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 1 -C 6 alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl and hexyl groups.
- Typical C 3-8 cycloakyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
- Typical C 2 -C 6 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. diphenylacetoxy and fluorenecarboxy groups.
- Typical alkaryl groups include the above-listed aryl groups substituted by one or more C 1 -C 6 alkyl groups.
- Typical aralkyl groups include a C 1 -C 6 alkyl group substituted by one of the above-listed aryl groups, e.g. phenethyl, phenylpropyl, phenylbutyl, phenylpentyl and phenylhexyl groups as well as the branched chain isomers thereof.
- Typical C 1 -C 6 alkoxycarbonyl groups include carbonyl substituted by methoxy, ethoxy, propanoxy, i-propanoxy, n-butanoxy, t-butanoxy, i-butanoxy, pentanoxy, and hexanoxy groups.
- Typical aralkyl groups include the above-listed C 1 -C 6 alkyl groups substituted by phenyl, naphthyl, phenanthryl, and anthracyl groups.
- Typical C 2 -C 6 alkenyl groups include vinyl, allyl, 2-butenyl, 2-pentenyl, and 2-hexenyl groups.
- Typical C 2 -C 6 alkynyl groups include acetynyl and propargyl groups.
- Typical halo groups include fl uorine, 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 1 -C 6 alkoxy groups substituted by phenyl, naphthyl, phenanthyl, and anthracyl groups.
- Typical substituted aryl groups include the above-listed aryl groups substituted by halo, hydroxy, C 1 -C 6 alkoxy, amino, and the like.
- Typical heteroaryl groups include furyl, thienyl, pyrrolyl, thiazolyl, pyridyl, pyrimidinyl, pyrizinyl, oxazolyl and phthalimido groups which may be fused to a benzene ring.
- Typical substituted heteroaryl groups include the above-listed heteroaryl groups substituted by halo, C 1 -C 6 alkyl and the like.
- Typical C 5 -C 6 heterocycloalkyl groups include tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholino and pyrrol idinyl groups.
- an IC 50 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.
- the term "high affinity" is intended to mean a compound which exhibits an IC 50 of less than 100 nM in a sigma receptor binding assay, preferably against 3 H-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 IC 50 values of less than about 25 nM, more preferably less than about 10 nM, most preferably less than about 1 nM against H-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.
- compounds which exhibit selective binding to the sigma-2 receptor are associated with dystonia and may block calcium channels. See.
- 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.
- 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 angina.
- Compounds which are selective for the sigma-2 receptor are known to produce dystonia.
- antagonists of the sigma-2 receptor are expected to be effective in treating hypertension, migrane and angina without dystonic side effects.
- compounds which are selective for the sigma-1 receptor compared to the sigma-2 receptor have an IC 50 ratio of sigma-1/sigma-2 of less than about 0.1 (see Table 10).
- Such compounds include, but are not limited to (+) N-(1-phenyl-2-propyl)-4-phenylbutyl amine, R(-) N-(l-phenyl-2-propyl)-3-(2-naphthyl)propylamine, (+) N-[1-(1'-Naphthyl)-2-propyl]-3-phenylpropylamine, 4-Hydroxy-4-phenyl-1-(3-phenylpropyl)piper ⁇ dine, N-(4-phenylbutyl)phenethylamine, Di-N-[3-(2'-naphthyl)propyl-N-methylamine, N-(4-phenylbutyl)-benzylamine, N-(5-
- compounds which are selective for the sigma-2 receptor compared to the sigma-1 receptor have a ratio of sigma- 1/sigma-2 of greater than about 10 (see Table 10).
- Such compounds include, but are not limited to N-phenyl-N'-(3-(1-phthalimido)propyl)-piperazine, and N-(4-phthalimido)butyl-N'-phenylpiperazine.
- N-(5-phthalimido)pentyl-N'-phenylpiperazine is also expected to be highly selective for sigma-2.
- the inventor has also discovered that the sigma receptor ligands of the present invention exhibit low affinity to the DA and PCP receptors.
- certain of the sigma receptor ligands of the present invention also exhibit low affinity for the 5-HT 1A receptor.
- 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 5- HT 1A receptors.
- low affinity is intended a binding affinity of >100 nM, more preferably, >1000 nM in a DA, PCP or 5- HT 1A binding assay.
- Especially preferred sigma receptor ligands have high binding to the sigma receptor and low binding to the DA, PCP and/or 5-HT 1A receptors, as defined herein.
- 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.
- 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.
- 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, playful, or regressive behavior. See Dorland's Illustrated Medical Dictionary, 26th edition, W.B.
- 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.
- the compounds of the invention are administered to an individual to ameliorate symptoms of drug withdrawal or to reduce craving for the drug, e.g. ***e, heroin, PCP and hallucinogens.
- 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-HT 1A 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, 3 H, 11 C, 14 C, 18 F, 125 I and 131 I.
- 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.
- a sigma receptor ligand having Formula (XXXX) may be prepared by reductive amination of a compound having
- general methods of preparing compounds of Formula (XXXXI) reference is made to Fuller, R.W. et al., J. Med. Chem. 14:322- 325 (1971); Foye, W.O. 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. 17:1100-1111 (1974); Fuller, R.W.
- 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 14 C-labelled starting material.
- R is H
- an N-substituted carboxamide of Formula (XXXXIII) may be reduced, for example, with LiAlH 4 to give the N,N-disubstituted sigma receptor ligand having the Formula (XXXX), below (see Scheme II).
- the compound having the Formula (XXXXIV) may be reduced with, for example, AlH 3 , diborane:methyl sulfide or other standard carbonyl reducing reagent to give the sigma receptor ligand having Formula (XXXX) according to Scheme III.
- 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.
- electrophiles which may be used for this purpose include halides such as Cl , Br, or I, tosylate or mesylate.
- 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.
- the sigma receptor ligand comprises a tetrahydropyridine ring (Formula (XXXXVIII)
- the tetrahydropyridine ring may be constructed by reaction of a 2-arylpropene derivative (Formula (XXXXIX)) with an alkyl amine (Formula (L) ) and para-formaldehyde in the presence of orthophosphoric acid (Scheme VI) .
- optical isomers of the compounds of the invention 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-p-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 free base may then be isolated by treatment with a base such as aqueous ammonia and extraction with an organic solvent.
- the optical isomers may be prepared by resolution of the starting amine used to prepare the sigma ligand.
- non-toxic pharmaceutically acceptable salts of the compounds of the invention are also included within the scope of the present 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.
- 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.
- 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.
- 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.
- compositions of the invention may be administered to any animal which may experience the beneficial effects of the compounds of the invention.
- animals Foremost among such animals are humans, although the invention is not intended to be so limited.
- compositions of the present invention may be administered by any means that achieve their intended purpose.
- administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, or buccal routes.
- 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.
- 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.
- 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.
- compositions 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.
- 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 pyrrol idone.
- 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,
- disintegrating agents may be added such as the above-mentioned 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, flow-regulating 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 provided with suitable coatings which, if desired, are resistant to gastric juices.
- concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrol idone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
- 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.
- the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin.
- 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.
- 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-sol ubl e form, for exampl e, water-sol ubl e sal ts .
- suspensi ons of the active compounds as appropriate oily injection suspensions may be administered.
- Suitable lipophilic solvents or vehicles include fatty 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.
- the suspension may also contain stabilizers.
- 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.
- RESULTS 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.
- AlH 3 was prepared by the addition of AlCl 3 (0.07g, 0.5 mmol) to a suspension of LiAlH 4 (0.064 g, 1.7 mmol) in Et 2 O (50 mL) at 0°C under a nitrogen atmosphere.
- METHOD D N-(3-Phenylpropyl)-1-(3-trifluoromethylphenyl)-2-aminopropane Hydrochloride.
- a mixture of 1-(3-trifluoromethylphenyl)-2-propanone (102 mg, 0.50 mmol), 3-phenyl-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 borohydride (19 mg, 0.50 mmol) and the mixture was allowed to stir at room temperature for 20 h.
- METHOD F R(-)-N-(2-Phenoxyethyl)-1-phenyl-2-aminopropane Hydrochloride.
- R(-)-amphetamine 0.288 g, 2.1 mmol
- 2-phenoxyethyl chloride 0.335 g, 2.1 mmol
- the vial was sealed and heated at 95°C for 20 h.
- the reaction mixture was cooled, washed repeatedly with Et 2 O to give the crude product which melted at 155-160°C. Recrystallization (3x) using MeOH and MEK gave colorless crystals that weighed 50 mg (8%), mp 178-179°C.
- 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 H 2 O (10 mL), extracted with hexane and the aqueous layer made basic with Na 2 CO 3 .
- the crude product was extracted into hexane, dried over anhyd. K 2 CO 3 , and the solvent removed by evaporation.
- the crude free base was recrystallized from H 2 O-MeOH to give the purified free base (mp 87-90°C) which was dissolved in EtOH and treated with an Et 2 O solution of maleic acid to give the maleate salt. Recrystallization from EtOH-Et 2 O gave 0.6 g (35% yield) of fine crystals, mp 162-164°C.
- METHOD K N-(3-Phenylpropyl)-1-(4-hydroxyphenyl)-2-aminopropane Hydrobromide.
- a suspension of the free base of N-(3-phenylpropyl)-1-(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 EtOH-Et 2 O to give 200 mg (88% yield) of the hydrobromide salt, mp 159-160°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 ⁇ 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.
- 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 spectrometry at a counting efficiency of approximately 50%.
- IC 50 values were determined by non-linear regression analyis.
- PCP receptor binding assays against 3 H-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).
- (+) 3 H-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 % polyethylenamine).
- 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 ⁇ 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.
- Tris-EDTA buffer 50 mM Tris-HCl, 1 mM EDTA, pH 7.4 at 4°C.
- the homogenate was centrifuged at 48,000 ⁇ 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 mM Tris-HCl, 120 mM NaCl, 5 mM KCl, 2 mM CaCl 2 , 1 mM MgCl 2 , pH 7.4 at 37 °C).
- assay buffer 50 mM Tris-HCl, 120 mM NaCl, 5 mM KCl, 2 mM CaCl 2 , 1 mM MgCl 2 , pH 7.4 at 37 °C).
- the binding assays were conducted with 100 uL of [ 3 H]SCH-23390 or [ 3 H]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 [ 3 H]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).
- the results of these binding assays appear 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.
- EXAMPLE 3 5-HT 1A BINDING ASSAYS
- Table 7 A systematic comparison of phenylalkyl amine derivatives with varrying x and y values is shown in Table 7.
- N-methyl-N-propyl-5-phenylpentylamine a des-phenyl analog
- the unsubstituted phenyl derivative N-(3-phenylpropyl)-1-isopropylamine exhibits only a 4-fold selectivity for sigma receptors.
- Aromatic substitution enhances affinity for sigma receptors whereas 5-HT 1A affinity remains relatively constant. Consequently, these aromatic substituted derivatives bind with a relatively low, but constant selectivity.
- the effect of terminal amine modification was examined where the aromatic portion was held constant as a phenyl group. Replacement of the benzyl ic methylene group of cmp. #1 by an oxygen atom, carbonyl group, or sp-hybridized carbon atom (cmps.
- N-methyl-N- (3-propylphenyl)-1-(4-n-propylphenyl)-isopropylamine was prepared and found to have the highest and most selective affinity for the sigma receptor.
- 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 intermediate 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 O-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.
- N-Cyclohexylmethyl-5-cyclohexylpentylamine Hydrochloride (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 Et 3 N (1.7g, 8.1 mmol) in dry methylene chloride (50 ml) under N 2 , over 10 min. Stirring was continued for 30 min. and cyclohexylmethyl amine (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 (MgSO 4 ). Solvent was removed in vacuo to afford an oil which was crystallized from MeOH-H 2 O
- N-Methyl-N-hexyl-2-phenylethylamine Hydrogen Oxal ate 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-2- phenylethylamine (1g, 7.4 mmol) and Et 3 N (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 ⁇ 20 mL).
- N-Methyl-N-propylhexyl amine Hydrogen Oxalate 131.
- a stirred mixture of N-methyl propyl amine (1.2g, 13.7 mmol), 1-bromohexane (3.4g, 20.5 mmol) and potassium carbonate (3.8g, 27 mmol) in 1,2-dimethoxyethane (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 CHCl 3 . The combined filtrates were evaporated to dryness under reduced pressure and the residue partitioned between Et 2 O (30 mL) and 10% NaOH solution (20 mL).
- N-Methyl-N-cyclohexylmethyl-5-cyclohexylpentylamine Hydrochloride (152).
- a mixture of 151 [CNS#?] (0.5g, 1.9 mmol), formic acid (1.1g, 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 Et 2 O (3 ⁇ 25 mL).
- the ethereal solution, which contained the expected product, was washed with 10% NaOH (30 mL), then water (10 mL) and dried (MgSO 4 ).
- 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).
- N-(3-Cyclohexylpropyl)-3-phenylpropylamine Hydrochloride 912.
- a solution of 3-phenyl propylamine (0.65 g, 5 mmol) and 3-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 sufficient H 2 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 1N HCl solution (20 mL).
- the precipitate was collected by filtration and washed thoroughly with anhydrous Et 2 O (3 ⁇ 10 mL). Recrystallization from 2- butanone afforded the desired compound as white shiny plates (0.75 g, 53%); mp 203-205°C (see Table 8).
- 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 3 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 Et 2 O (20 mL); the aqueous portion was basified with 10% NaOH and extracted with Et 2 O (20 mL).
- the Et 2 O portion was dried (MgSO 4 ) 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).
- Radioligand Binding The ⁇ binding assay was conducted using guinea pig (Taconic) brain membranes and [ 3 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 ⁇ l [ 3 H]DTG (1-2 nM final concentration) and 50 ⁇ l 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.
- Binding data are shown in Table 9.
- N-Methylation of N- substituted 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.
- the sigma receptors may possess at last two distinct aromatic binding sites: one that utilizes the phenyl-B ring of phenylethyl amines, and one that utilizes the phenyl-A ring of the phenylpentyl amines.
- the phenyl-B ring of 151, 89, 111 and 76 is unnecessary for binding; it can be replaced by a small alkyl group (e.g. 112) or with a cyclohexyl group (e.g. 131) with retention of affinity.
- the phenyl-A ring can also be replaced with a methyl or cyclohexyl group (e.g., 13.0 and 94, respectively) with little change in affinity.
- a methyl or cyclohexyl group e.g. 13.0 and 94, respectively
- 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.
- Guinea pig whole membrane preparations (P2 microsomal fraction) were obtained and used as described by Weber, E. et al., Proc.Natl.Acad.Sci 83:8784-8788 (1986).
- the sigma-1 selective binding assay was performed using [ 3 H](+)pentazocine as the radioligand (3-4 nM final concentration unless otherwise specified) and approximately 100 ⁇ g of guinea pig membranes in a final volume of 500 ⁇ l of 50 mM TRIS-HCl, pH 8.0. Non-specific binding was determined in the presence of 10 ⁇ M haloperidol.
- 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.
- the sigma-2 selective binding assay was performed using about 2 nM [ 3 H]DTG as the radioligand in the presence of 200 nM (+)pentazocine to block the sigma-1 sites, with 400 ⁇ g of guinea pig membranes in a total volume of 0.5 ml of 50 mM TRIS-HCl, pH 7.4. Non-specific binding was determined in the presence of 10 ⁇ M haloperidol.
- the mixtures were incubated for 30 min. at room temperature, then filtered and the radioactivity determined as described above.
- Table 10 shows the results 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.
- Table 11 shows the sigma-1 and sigma- 2 binding data for a number of other known compouds.
- the length of the N-phenyl-B chain has little effect on binding to the sigma-1 site.
- elimination of the N-phenyl-B ring has little effect on sigma-1 receptor binding.
- an increase in the phenyl-Achain length results in a decrease in affinity to sigma- 1 (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).
- the most selective sigma-1 binding compound is N,N- dimethyl-5-cyclohexylpentyl amine (cmp. # 128, sigma-2/sigma-1 selectivity of 650).
- Other sigma-1 selective ligands include N- methyl -5-cyclohexylpentyl amine (cmp. # 127, sigma-2/sigma-1 selectivity of 51), 5-cyclohexylpentyl-amine (cmp. # 126, sigma- 2/sigma-1 selectivity of 13), N-methyl-N-propyl-5- phenylpentylamine (cmp.
- the most selective sigma-2 ligand of the present invention is N-phenyl-N'-(3-(1-phthalimido)propyl)piperazine (cmp. #96) which has a sigma-1/sigma-2 ratio of 87.
- Other sigma-2 selective ligands include N-(4-phthalimido)butyl-N'-(o- methoxyphenyl)piperazine (cmp. #120; sigma-l/sigma-2 ratio of 7) and N-(4-phthalimido)butyl-N'-phenylpiperazine (cmp. #97; sigma- 1/sigma-2 ratio of 10).
Abstract
Description
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FR2795724B1 (en) * | 1999-07-02 | 2002-12-13 | Sanofi Synthelabo | NOVEL BENZENE DERIVATIVES, A PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
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- 1992-06-26 EP EP92914789A patent/EP0591426A4/en not_active Withdrawn
- 1992-06-26 PT PT100639A patent/PT100639A/en not_active Application Discontinuation
- 1992-06-26 CA CA002111957A patent/CA2111957A1/en not_active Abandoned
- 1992-06-26 JP JP5501248A patent/JPH06509069A/en active Pending
- 1992-06-26 WO PCT/US1992/005330 patent/WO1993000313A2/en not_active Application Discontinuation
- 1992-06-26 AU AU22945/92A patent/AU676993B2/en not_active Ceased
- 1992-07-01 IE IE211292A patent/IE922112A1/en not_active Application Discontinuation
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Also Published As
Publication number | Publication date |
---|---|
EP0591426A4 (en) | 1996-08-21 |
JPH06509069A (en) | 1994-10-13 |
PT100639A (en) | 1993-09-30 |
WO1993000313A3 (en) | 1993-03-04 |
CA2111957A1 (en) | 1993-01-07 |
AU2294592A (en) | 1993-01-25 |
EP0591426A1 (en) | 1994-04-13 |
IE922112A1 (en) | 1992-12-30 |
AU676993B2 (en) | 1997-04-10 |
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