AU2294592A - Sigma receptor ligands and the use thereof - Google Patents

Sigma receptor ligands and the use thereof

Info

Publication number
AU2294592A
AU2294592A AU22945/92A AU2294592A AU2294592A AU 2294592 A AU2294592 A AU 2294592A AU 22945/92 A AU22945/92 A AU 22945/92A AU 2294592 A AU2294592 A AU 2294592A AU 2294592 A AU2294592 A AU 2294592A
Authority
AU
Australia
Prior art keywords
alkyl
aryl
heteroaryl
substituted
phenyl
Prior art date
Legal status (The legal status 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 status listed.)
Granted
Application number
AU22945/92A
Other versions
AU676993B2 (en
Inventor
Richard A Glennon
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Virginia Commonwealth University
Original Assignee
Virginia Commonwealth University
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 Virginia Commonwealth University filed Critical Virginia Commonwealth University
Publication of AU2294592A publication Critical patent/AU2294592A/en
Application granted granted Critical
Publication of AU676993B2 publication Critical patent/AU676993B2/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C211/03—Monoamines
    • C07C211/08—Monoamines containing alkyl groups having a different number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/16—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings other than six-membered aromatic rings
    • C07C211/17—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings other than six-membered aromatic rings containing only non-condensed rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/28—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by unsaturated carbon chains
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/29—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/30—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system formed by two rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
    • C07C211/41—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems
    • C07C211/42—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems with six-membered aromatic rings being part of the condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
    • C07C215/52—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—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
    • C07C217/04—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
    • C07C217/06—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
    • 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
    • C07C217/16—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 the six-membered aromatic ring or condensed ring system containing that ring not being further substituted
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/60—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C219/10—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to an acyclic carbon atom of a carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C219/12—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
    • C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/033—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
    • C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/108—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/12—One of the condensed rings being a six-membered aromatic ring the other ring being at least seven-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes

Description

SIGMA RECEPTOR LIGANDS AND THE USE THEREOF
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. 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. Su, T., J. Pharmacol. Exp Ther. 223:284 (1982); Tarn, 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. 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.
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 neuroleptic agents bind at [3H]NANM-Iabelled 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 sigma- sites 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. Tarn, S.W. and Cook, L., Proc. Nat. Acad. Sci. (USA) 81:5618 (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 N-alkyl substituents, e.g., benzyl or phenethyl.
Largent, B.L. et at., MoI. Pharmacol. 32:772-784 (1987), disclose a study of the structural determinants of sigma receptor affinity. In particular, 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.
Sharkey, J. et al., Eur. J. Pharmacol. 149:171-174 (1988), studied the sigma receptor binding activity of cocaine-related compounds. The 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., J. 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)). There 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 phenylalkylamines. 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 4- positions 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, 2- thienyl, 3-methyl-2-phenol, 3-pyridyl, 6-methyl-2-pyridyl, 4-chlorophenyl, 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-chlorobenzylamine, N-(1-phenyl-2-propyl)-4-methylbenzyl-amine, and N-(1-phenyl-2-propyl)-4-methoxybenzylamine.
Boissier, J.R. et al., Chem. Abstr. 67:21527a (1967), disclose amphetamine derivatives of the Formula (II):
wherein R1 is hydrogen, 4-Cl, 3-Cl, or 3-CF3 and R2 is 2-chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 3-CF3-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.
Osbond, J.M. et al., Chem. Abstr. 69:51816c (1968), disclose N,N-bis-(omega-phenylalkyl)amines having the Formula
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 p-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 p-chloro amphetamines having the following
Formula (IV):
wherein R1 is 2-butanone-3-yl, 2-hydroxybutane-3-yl, 1-hydroxybutane-3-yl, or acetate.
Fuller, R.W. et al., J. Pharm. Pharmacol. 25:828-829
(1973), disclose lipid-soluble derivatives of amphetamine comprising 2-chloro, 3-chloro, 4-chloro, and beta, beta-difluoro amphetamine, and the effect thereof on amphetamine levels in the brain.
Fuller, R.W. et al., Neuropharmacology 14:739-746 (1975), disclose 4-chloroamphetamine, 4-bromoamphetamine, and 4- fluoroamphetamine 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 ethanolamine-N-methyl transf erase.
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-isopropyl-2-phenylethylamine.
Johansson, A.M. et al., J. Med. Chem. 30:602-611 (1987), disclose N-substituted 2-aminotetralins of the Formula (VI):
wherein R1 is OH or OMe and R2 and R3 are H or C1-C4 lower alkyl. These compounds were tested for dopamine receptor agonist and antagonist activities. Hacksell, U. et al., J. Med. Chem. 22:1469-1475 (1979), disclose N-alkylated-2-aminotetralins of the Formula (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):
These compounds reportedly have dopamine-receptor stimulating activity.
McDermed, J.D. et al.. J. Med. Chem. 18:362-367 (1975), disclose N-alkyl aminotetralins of the Formula (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):
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 N,N-di substituted 2-aminotetralins of the Formula (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) tetralinderivatives of the Formula (XIV):
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-HT1A receptor site.
Beecroft, R.A. et al., Tetrahedron 41:3853-3865 (1985), disclose N,N-disubstituted piperazines having the Formulae (XV)- (XVIII):
Fuller, R.W. et al., J. Pharmacol. EXP. Therapeut.218:636- 641 (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. 29:201-204 (1980), disclose the comparative effects on 5- hydroxyindole concentration in rat brain by p-chloroamphetamine and 1-(p-chlorophenol)piperazine having the following Formulae (XXI) and (XXII):
Boissier, J. et al . , Chem. Abstr. 61 : 10691c, di scl ose disubstituted piperazines having the Formula (XXIII) :
wherein R1 and R2 are aryl and X is a straight or branched chain alkylene of C1-C3. 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):
wherein R = H or methoxy and R1 = H, o-ethylphenyl, or p-chlorophenyl.
Ruschig, H et al., Chem. Abstr. 53:3253e, disclose a large series of N,N-disubstituted piperazines including 1-benzyl-4-(3-chloro-4-methylphenyl)piperazine.
Shvedov, V.I. et al., Chem. Abstr. 73:11806q (1970), disclose 4-(R2CH2-CH2 substituted)-1-phenyl-piperazines wherein R2 is phenyl, 2-naphthyloxy, 3-indolyl, 2-methyl-3-indolyl or 2- benzimidazolyl.
Popov, D., Chem. Abstr. 67:54102m (1967), disclose disubstituted piperazines of the Formula (XXV):
wherein 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.
Glennon, R.A et al., J. Med. Chem. 31:1968-1971 (1988), disclose various N,N-disubstituted piperazines having the Formulae (XXVI) -(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 N,N-disubstituted piperazines of the Formula (XXX):
wherein R1 is phenyl or o-methoxyphenyl and R2 is 2,4-dichlorophenyl, o-, 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 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-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, 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.
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 human a therapeutically effective amount of a compound selected from the Formulae (XXXI) and (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 ligands.
Surprisingly, 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-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 sigma-2 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.
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):
wherein:
Ar is aryl or heteroaryl wherein aryl or heteroaryl can be substituted by hydrogen, halogen such as chloro, fluoro, bromo, iodo, CF3, C1 -C6 alkoxy, C2-C6 dialkoxymethyl, C1 -C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1 -C6 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, C1 -C6 alkylthio, C1 -C6 alkylsulfonyl, C1 -C6 haloalkylsulfonyl, C1 -C6 alkyl - sulfinyl, C1 -C6 haloalkylsulfinyl, arylthio, C1 -C6 haloalkoxy, amino, C1 -C6 alkyl amino, C2-C15 di alkylamino, hydroxy, carbamoyl , C1-C6 N-alkyl carbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro and C2-C15 dialkylsulfamoyl;
R is hydrogen or C1-C6 alkyl;
R1 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, hydroxy, amino, C1-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 -H H-, wherein p is 1-3;
X is -(CH2)q-, wherein q is 1-6;
-(CH2)r-C≡C-(CH2)r-, wherein each r is 0-3 independently; -(CH2)r-CH=CH-(CH2)r-;
-(CH2)r-Y-(CH2)r-, wherein Y is O or S; or
C1-C6 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, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dial kyl aminoal kyl, carboxy, carboxamido, C1- C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkyl sul fonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkyl carbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro, C2-C15 dialkylsulfamoyl 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): wherein T is a cycloalkyl group or Ar as described above, n, R, and R , 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-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,
N-(3-(1-naphthyl)propyl)-1-phenylisopropylamine, N-(3-(2-naphthyl)propyl)-1-phenylisopropylamine, N-(3-phenyl-2-propyn-1-yl)-1-phenylisopropylamine, N-(3-phenylpropyl)-3-(4-hydroxyphenyl)isopropylamine, N-(3-phenylpropyl)-3-(4-methoxyphenyl)isopropylamine, N-(3-phenylpropyl)-3-(3-bromophenyl)isopropylamine, N-(3-phenylpropyl)-3-(4-bromophenyl)isopropylamine, N-(3-phenylpropyl)-3-(3,4-dichlorophenyl)isopropylamine, N-(3-phenylpropyl)-3-(4-iodophenyl)isopropylamine, N-(3-phenylpropyl)-3-(3-trifluoromethyl-phenyl)isopropylamine, N-(2-phenethyl)-N-methyl- 1-phenylisopropyl-amine, N-(3-phenylpropyl)-1-phenylpropan-1-one-2-amine, N-(2-indane)-3-phenylisopropylamine, N-(2-indane)-3-phenylpropylamine, N,N-di-((3-phenyl)propyl)amine, N-(2-(1-naphthyl)ethyl)-1-phenylisopropylamine, N-(2-(2-naphthyl)ethyl)-1-phenylisopropylamine, N-(2-(1-naphthyl)propyl)-1-phenylisopropylamine, N-(2-(2-naphthyl)propyl)-1-phenylisopropylamine, N-(3-phenylpropyl)-1-phenyl-2-pentylamine, N-(3-phenylbutyl)-1-phenyl-2-butylamine, N,N-di-(2-ethylphenyl)methylamine, N,N-dibenzylamine, N-(3-phenylpropyl)-N-(6-phenylhexyl)amine,N-(3-phenylpropyl)-N-(5-phenylpentyl)amine,N-propyl-N-methyl-5-phenylpentylamine, N-methyl-N-(3-phenylpropyl)-1-isopropylamine, N-methyl-N-(3-methyl-2-butenyl)-1-isopropylamine, N-methyl-N-(3-methylbutyl)-1-isopropylamine, N- methyl-N-(3-phenylbutyl)-1-phenyl-2-pentylamine, N-propyl-N-(3- phenyl)propyl)-1-phenyl-2-propylamine, N-benzyl-N-(3- phenyl)propyl)-1-phenyl-2-propylamine, N-phenyl-(5- phenyl)pentylamine, N-methyl-N-(3-phenyl)propyl-5- phenylpentylamine, N-(2-(o-methylphenyl)ethyl)-5- phenylpentylamine, N-(2-(m-methylphenyl)ethyl)-5- phenylpentylamine , N-(2-(p-methylpheny!)ethyl)-5- phenylpentylamine N-benzyl-5-phenylpentylamine, N-benzyl-N- methyl-5-phenylpentylamine, N-(2-(3-hydroxyphenyl)ethyl)-5- phenylpentylamine, N-(2-(2-hydroxyphenyl)ethyl)-5- phenylpentylamine N, N'-diethyl-2-(diphenylacetoxy) ethylamine, N,N'-diethyl-2-(fluorenecarboxy)ethylamine, N,N-Dimethyl-5- phenylpentylamine, N-Benzyl-N-(3-phenylpropyl)-1-phenyl-2- propylamine, N-Benzyl-N-methyl-5-phenylpentylamine, N-Benzyl-5- phenylpentylamine, and N-(2-phenethyl)-N-methyl pentyl 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):
wherein Ar, n, p, R, R1, X and Z are as defined above; and
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):
wherein X and Z are as defined above and V is N or -CM-, wherein M is hydrogen, C1-C6 alkyl, C1-C6 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, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialklcarbamoyl, nitro and C2-C15 dialkylsulfamoyl; 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):
wherein R2, 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):
wherein R2, M, X and Z are as defined above;
U is selected from the group consisting of hydrogen, halogen such as chloro, fluoro, bromo, iodo; CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 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, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkyl carbamoyl, nitro and C2-C15 dialkylsulfamoyl;
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):
wherein:
R3 is selected from the group consisting of C1 -C6 alkyl, C1 -C6 alkenyl, C2-C6 dialkoxymethyl, C3-C15 dialkylaminoalkyl, 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) 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)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) :
wherein:
R4 is hydrogen or an aryl group substituted with a group selected from the group consisting of C1-C6 alkyl, C1-C6 alkenyl, C2-C6 dialkoxymethyl, C3-C15 dialkylaminoalkyl, aralkyl, C3-C6 cycloalkyl, aroyl, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl;
R 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.
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
N-(2-phenethyl)-4-hydroxy-4-t-butylpiperidine, N-(5-(4- chlorophenyl)-5-pentanon-1-yl)piperidine,N-(5-(4-chlorophenyl}- 5-pentanon-1-yl)-4-phenylpiperidine, N-(5-(4-methoxyphenyl)-5- pentanon-1-yl)piperidine, N-(5-(4-methoxyphenyl)-5-pentanon-1-yl)-4-phenylpiperidine, N-(5-(4-methoxyphenyl)pentyl)-4-phenylpiperidine, N-(5-phenyl-5-pentanon-1-yl)-4-phenylpiperidine N-(5-(4-chlorophenyl)pentyl)-4-phenylpiperidine, N-(5-(3-methoxyphenyl)-5-pentanon-1-yl)piperidine, N-(5-(3-chlorophenyl)-5-pentanon-1-yl)piperidine, N-(5-(3-chlorophenyl)-5-pentanon-1-yl)-4-phenylpiperidine, N-(5-(3-methoxyphenyl)-5-pentanon-1-yl)- 4-phenylpiperidine , N-(4-(4-fluorophenyl)-4-butanon-1-yl)piperidine, 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-1-yl)-4-(3-chlorophenyl)-4-hydroxypiperidine, 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-fluorophenyl)piperidine , 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-fluorophenyl)-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-dichlorophenyl)-5-pentanon-1-yl)-4-(chlorophenyl)- piperidine, N-(5-cyclopentylpentan-5-on-1-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) :
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-(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):
wherein R4, R5, 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):
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. Other 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):
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)
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-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.
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) wherein X1 is -(CH2)r-C≡C-(CH2)r-, wherein each r is 0-3 independently;
-(CH2)r-CH=CH-(CH2)r-;
-(CH2)r-Y-(CH2)r-, wherein Y is O or S; or
C.-C6 alkyl (wherein Z is hydrogen);
and R2, V, X, and Z are defined as above.
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):
wherein R5 and R6 are independently a C1-8 al kyl group, R7 is hydrogen or a C1-8 al kyl group substituted by an aryl acetoxy group, and 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.
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), R = hydrogen). 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. In particular, the invention relates to compounds having the Formula (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-C-≡C-(CH2)r-, wherein each r is 0-3 independently; -(CH2)r-CH=CH-(CH2)r-;
-(CH2) r-γ-(CH2) r-, wherein Y is O or S; or
C1 -C6 al kyl (wherein Z is hydrogen);
wherein said compound exhibits high binding activity with respect to the sigma reteptors.
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):
wherein T, n, R, R1, and Z are defined above, and
X is -(CH2)q-, wherein q is 3-6;
-(CH2)r-C≡C-(CH2)r-, wherein each r is 0-3 independently; -(CH2)r-CH=CH-(CH2)r-;
-(CH2)r-Y-(CH2)r-, wherein Y is O or S; or C1 -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 (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):
wherein R2, V and Z are as defined above;
X is -(CH2)r-C≡C-(CH2)r-, wherein r is 0-3;
-(CH2)r-CH=CH-(CH2)r-;
-(CH2)r-Y-(CH2)r-, wherein Y is O or S; or
C1 -C6 al kyl (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):
wherein R2 and Z are as defined above;
X is -(CH2)r-C≡C-(CH2)r-, wherein each r is 0-3 independently;
-(CH2)r-CH=CH-(CH2)r-;
-(CH2)r-Y-(CH2)r-, wherein Y is O or S; or
C1-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 (XXXV) also have unexpectedly high binding to the sigma receptors (see
Example 2).
The invention also relates to compounds which are related to the Formula XXXII and having the Formula (XXXIX):
wherein R2, M, X and Z are as defined above;
U is selected from the group consisting of hydrogen, halogen such as chloro, fluoro, bromo, iodo; CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 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, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkyl sul fonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro and C2-C15 dialkylsulfamoyl; wherein said compound exhibits high binding activity with respect to the sigma receptors.
The invention also relates to a compound of the Formula (XXXVa) :
wherein:
R3 is selected from the group consisting of C1-C6 alkyl, C1-C6 alkenyl, C2-C6 dialkoxymethyl, C3-C15 dial kyl ami noal kyl, aralkyl, C3-C6 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) :
wherein:
R4 is hydrogen or an aryl group substituted with a group selected from the group consisting of C1-C6 alkyl, C1-C6 alkenyl, C2-C6 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 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 (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):
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 C1-C6 alkyl; R2 is independently selected from the group consisting of hydrogen, chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dial kyl ami noal kyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkyl- sulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkyl-amino, dialkylamino, hydroxy, carbamoyl, C1-C6 N- alkylcarbamoyl, C2-C15 N,N-dialklcarbamoylo nitro and C2-C15 dialkylsulfamoyl;
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):
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):
wherein Ar, X and Z are defined above;
wherein said compound exhibits high binding activity with respect to the sigma receptors. Also as derivatives of compound XXXIII, this invention is concerned with a compound having the Formula (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)
wherein X is -(CH2)r-C≡C-(CH2)r-, wherein each r is 0-3 independently;
-(CH2)r-CH=CH-(CH2)r-;
-(CH2)r-Y-(CH2)r-, wherein Y is O or S; or
C1-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):
wherein R5 and R6 are independently a C1-C6 alkyl group, R7 is hydrogen or a C1-8 alkyl substituted by an arylacetoxy or arylcarboxy group, and 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 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 C1-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. diphenylacetoxy and fluorenecarboxy groups. Typical alkaryl groups include the above-listed aryl groups substituted by one or more C1 -C6 alkyl groups.
Typical aralkyl groups include a C1 -C6 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 C1 -C6 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 C1 -C6 alkyl groups substituted by phenyl, naphthyl, phenanthryl, and anthracyl groups.
Typical C2-C6 alkenyl groups include vinyl, allyl, 2-butenyl, 2-pentenyl, and 2-hexenyl groups.
Typical C2-C6 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 C1 -C6 alkoxy groups substituted by phenyl, naphthyl, phenanthyl, and anthracyl groups.
Typical substituted aryl groups include the above-listed aryl groups substituted by halo, hydroxy, C1 -C6 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, C1 -C6 alkyl and the like. Typical C5-C6 heterocycloalkyl groups include tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholino and pyrrol idinyl 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 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. 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., Mol. 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 angina. 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-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)piperιdine, N-(4-phenylbutyl)phenethylamine, Di-N-[3-(2'-naphthyl)propyl-N-methylamine, N-(4-phenylbutyl)-benzylamine, N-(5-phenylpentyl)-(4-phenyl)butylamine, N-(5-phenylpentyl)benzylamine,N-(4-phenylbutyl)-N'-benzylpiperazine, N-4(4-phenylbutyl)-N'-benzoylpiperazine, N-(3-phenylpropyl)-1-(p-ethoxyphenyl)-2-propylamine,N-(5-phenylpentyl)phenethylamine, N-(7-phenylheptyl)benzylamine,N-(7-phenylheptyl)phenethylamine,N-(5-cyclohexylpentyl)benzylamine, N-(4-phenylbutyl)-1-phenyl-2-butylamine, N-(4-phenyl-3(E)-butenyl)-N'-methylpiperazine, N-(4-phenyl-3(Z)-butenyl)-N'-methylpiperazine, N-(4-(3-trifluoromethyl)-3-(Z)-butenyl)-N-methylpiperazine, N-(4-phenyl)-N'-methylpiperazine, N-(5-phenylpentyl)-3-phenylpropylamine, N-methyl-N-propyl-5-phenylpentylamine, N-Methyl-N-(3-phenylpropyl)-1-phenylisopropylamine, N-(5-phenylpentyl)piperidine, N,N-Dimethyl-5-phenylpentylamine, 5-cyclohexylpentylamine,N-methyl-5-cyclohexylpentylamine, N,N-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 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. Surprisingly, 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 5- HT1A receptors. By the term "low affinity" is intended a binding affinity of >100 nM, more preferably, >1000 nM in a DA, PCP or 5- HT1A 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 reduce 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, 3H, 11C, 14C, 18F, 125I and 131I. 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.
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. 14:322- 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. et al., J.Pharm. Pharmacol. 25:828-829 (1973); Fuller, R.W. et al., Neuropharmacology 14:739-746 (1975); Conde, S. et al., J. Med. Chem. 21:978-981 (1978); Lukovits, I. et al., Int. J. Quantum Chem. 20:429-438 (1981); and Law, B., J. 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 14C-labelled starting material. 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).
Alternatively, where the starting compound comprises a carbonyl group, the compound having the Formula (XXXXIV) may be reduced with, for example, AlH3, 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. Examples of 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.
Alternatively, where 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) .
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):
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-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. 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 limited.
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. In 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 pyrrol idone. If desired, 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. For this purpose, 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. 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-sol ubl e form, for exampl e, water-sol ubl e sal ts . In additi on , 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. 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 H2O were removed under reduced pressure with warming to give a crude solid, which was recrystallized several times from MeOH and MEK to give 1.6 g (80%) of colorless crystals, mp 215-217°C. METHOD B: R(-)-N-(Cyclopropylmethyl)-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-(α-methylphenylethyl)-2- cyclopropylcarboxamide (1.5 g, 74 mmol) in anhyd. Et2O (20 mL). The mixture was heated at reflux overnight, cooled to 0°C and H2O (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 H2O (5 mL). After the inorganic precipitate was removed by filtration, the Et2O solution was dried (anhyd. Na2SO4) and treated with a solution of maleic acid (1.5 g in absolute EtOH (10 mL). The product was collected by filtration, washed with Et2O 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)-1-(4-bromophenyl)-2-aminopropane Hydrochloride. AlH3 was prepared by the addition of AlCl3 (0.07g, 0.5 mmol) to a suspension of LiAlH4 (0.064 g, 1.7 mmol) in Et2O (50 mL) at 0°C under a nitrogen atmosphere. A solution of N-hydrocinnamoyl-1-(4-bromophenyl)-2-aminopropane (100 mg, 0.29 mmol) in dry Et2O (10 mL) was added in a drop wise manner, to the AlH3 solution at 0°C. After the addition was complete, the mixture was allowed to stir for 0.5 h at the same temperature. Excess AlH3 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 H2O (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/Et2O (4×) to give 20 mg (19%) of a finely divided powder: mp 176-178°C.
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. 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 H2O and the solution was extracted with Et2O. The H2O portion was separated, the H2O 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-1-phenyl-2-aminopropane Hydrochloride. To a mixture of R(-)-amphetamine 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 Et2O. 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-aminopropane Hydrochloride. In a 5-mL 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 20 h. The reaction mixture was cooled, washed repeatedly with Et2O 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.
METHOD G: R(-)-N-(3-Phenyl-3-oxopropyl)-1-phenyl-2-aminopropane Hydrochloride. A mixture of R(-)-amphetamine hydrochloride (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 H2O (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 H2O 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 146- 147°C. METHOD H: (+)-α-[N-(3-phenylpropyl)amino]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 EtOH/Et20 to give 2.34 g (55%) of needles: mp 211-213°C.
An ice-cooled mixture of CH2Cl2 (20 mL) and pyridine (0.8 g, 10 mmol) was treated with dry CrO3 (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 CH2Cl2 (5 mL) was added to the pyridine-CrO3 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. Na2SO4 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 (2×) to give 150 mg (40%) of the hydrochloride salt: mp 154-155°C (solidified and melted again at 170-172°C). METHOD I : N-Benzyl -2-phenyl morphol ine Hydrochloride. To a solution of N-(2-hydroxyethyl)-N-(benzoylmethyl)-benzylamine hydrochloride (0.50 g, 1.6 mmol) and MeOH (5 mL) at 5ºC 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 H2O (1 ml) was added to the mixture and the solvents removed by warming under reduced pressure. Water (6 mL) and Et2O (12 mL) were added to the reaction mixture; the ether layer was removed and the Et2O 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 H2O and excess HCl afforded the crude product hydrochloride. Recrystallization from acetone gave colorless crystals of the amine hydrochloride 0.38 g (77%), mp 140-143ºC.
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 H2O and excess HCl were removed by warming under reduced pressure to give 40 mg of the crude, tan product, mp 201- 205ºC. Two recrystallizations from acetone gave 21 mg (66%) of the substituted morpholine hydrochloride as colorless crystals, mp 211-212ºC.
METHOD J: 1-(4-Phenylbutyl)-4-(4-chlorophenyl)-1,2,5,6-tetrahydropyridine 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, 4-phenylaminobutane (0.58 g, 4 mmol), paraformaldehyde (0.36 g) and 4-chloro-σ-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 H2O (10 mL), extracted with hexane and the aqueous layer made basic with Na2CO3. The crude product was extracted into hexane, dried over anhyd. K2CO3, and the solvent removed by evaporation. The crude free base was recrystallized from H2O-MeOH to give the purified free base (mp 87-90°C) which was dissolved in EtOH and treated with an Et2O solution of maleic acid to give the maleate salt. Recrystallization from EtOH-Et2O 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-Et2O to give 200 mg (88% yield) of the hydrobromide salt, mp 159-160°C.
METHOD L: 1-(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 1-(3-chlorophenyl)-4-(3-phenylpropionyljpiperazine (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.
EXAMPLE 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 × g for 20 minutes at 4°C. The supernatant was centrifuged at 20,000 × 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 × 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 × 75 mm polystyrene test tubes were added 0.8 ml of diluted membrane suspension, 0.1 ml of [3H]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 spectrometry 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 % polyethylenamine).
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 × 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 CaCl2, 1 mM MgCl2, pH 7.4 at 37 °C).
The binding assays were conducted with 100 uL of [3H]SCH-23390 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). The results of these binding assays appear in Table 4.
Results
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. EXAMPLE 3 5-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.
Table 5
5- HT1A
Compound No. IC50 (nM) ±SEM(n) Ratio 5-HT1A/σ
1 115.00 12.00(2) 4
2 90.30 28.83(3) 12
3 1776.33 579.30(3) .20
4 4052.50 372.50(2) 5.9
5 1500.00 100.00(2) .88
6 3781.50 3458.50(2) 31
7 2475.00 95.00(2) 40
8 43.65 1.85(2) .92
9 122.00 6.00(2) 2
10 212.00 31.00(2) 22
11 104.30 16.70(2) 11
12 131.58 39.31(4) 56
13 288.00 62.00(2) 2
14 154.50 35.50(2) 5.4
15 30.70 3.43(3) 2
16 44.8 2.5(2) 2.4
17 87.80 12.20(2) 13
18 588.50 68.50(2) 54
19 114.23 12.43(3) 7.6
20 108.05 10.95(2) 17
21 195.50 14.50(2) 21
22 202.00 47.00(2) 13
23 105.75 13.25(2) 25
24 955.50 33.50(2) 1.4
25 753,00 135.00(2) 7.3
26 10000 (1) 3.5
27 6514.00 874.00(2) 200
28 2442.50 342.50(2) .05
29 15515.00 5515.00(2) 3.1
30 54999.50 44999.50(2) 2.6
31 19.30 4.20(2) .92
32 8.73 0.46(2) .80
33 51.60 2.30(2) 2.6
34 6650.00 710.00(2) 2.6
35 10360.00 360.00(2) 40
36 1626.67 378.17(3) 239
37 20.30 4.70(2) 2.6
38 107.75 27.25(2) 25
39 89.60 0.10(2) 75
40 2965.00 585.00(2) 970
41 34.67 9.09(3) 7.6
42 572.50 134.50(2) 110
43 1112.33 162.85*3) 50
44 277.67 33.52(3) 40
45 594.00 67.68(3) 100
46 21.47 3.60(3) 3 Table 5 (Cont. )
5-HT1A
Compound No. IC50 (nM) ±SEM(n) Ratio 5-HT1 A/σ
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 [3H]DTG AND 5HT-1A BINDING ASSAYS
Further sigma receptor binding assays against [3H]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.
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 selectivity for the sigma receptors. For example, it has been determined that the α-methyl group on N-(3-phenylpropyl)iso- propylamine (Ki = 22 nM) is not required for high binding to the sigma receptor. The corresponding des-methyl compound N-(3- phenylpropyl)-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 phenylalkyl 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 phenylpentylamine 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-5-phenylpentylamine, 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 phenylpentylamines may be replaced by a cyclohexyl ring with retention (and an increase) of affinity. Table 7
Phenyl-(CH2)x-NH-(CH2)y-Phenyl
x y Ki (nM)
1 1 175
1 4 13
1 5 2.0
1 7 3.6
*
2 3 19
2 4 5.
2 5 2.
2 7 4.
3 3 14
3 4 7.0
3 5 1.8
3 6 2.6
4 4 6.7
4 5 2.5
5 1 2.0
5 2 2.4
5 3 1.8
5 4 2.5
* = des-methyl N-(3-phenylpropyl)isopropylphenylamine
With regard to sigma selectivity over 5-HT1A, the unsubstituted phenyl derivative N-(3-phenylpropyl)-1-isopropylamine (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 benzyl ic 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 α-methyl group of cmp. #1 (R(-)) seems to enhance 5-HT1A affinity. The optical isomers 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 48- fold selectivity. Similar results were obtained with the isomers of N-(2-ethylphenyl)isopropylamine (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)-1-(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 alkyl chain that separates the amine from its aromatic (phenyl-B) substituent has little influence on affinity (e.g., compare 76,
77, 89, and 111; 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 phenylethyl amines and the phenylpentyl amines may utilize different aromatic binding sites. These results prompted a further investigation of 5-phenylpentylamine derivatives as sigma l igands .
76 n = 1
77 n = 2
89 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 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.
EXPERIMENTAL:
Synthesis: Proton magnetic resonance spectra were obtained on JEOL FX90Q or QE 300 (300 MHz) spectrometers with tetramethyl si lane 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-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 Et3N (1.7g, 8.1 mmol) in dry methylene chloride (50 ml) under N2, 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 (MgSO4). Solvent was removed in vacuo to afford an oil which was crystallized from MeOH-H2O
(4.1g, 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,
5 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 H2O 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 Et2O, dried (MgSO4) 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 recrystallized MeOH/EtOAc; mp
223-224°C (see Table 8). Method B:
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 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 × 20 mL). The combined filtrate and washings were evaporated under reduced pressure and the residue taken up in CHCl3 (30 mL). The chloroform solution was washed with H2O (30 mL) and dried (Na2SO4). Solvent was removed in vacuo to obtain an oil which was shown by IR (C=O, 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 dropwi se 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 0ºC 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 Et2O (50 mL and dried (MgSO4). Solvent was removed under reduced pressure to obtain an oil (350 mg, 75%). The oil was converted to the oxalate salt (white crystals) and recrystallized from MeOH/Et2O solution; mp 139-140°C (see Table 8).
Method C:
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 CHCl3. The combined filtrates were evaporated to dryness under reduced pressure and the residue partitioned between Et2O (30 mL) and 10% NaOH solution (20 mL). The ethereal fraction was washed with H2O (10 mL) and dried (Na2SO4). A saturated solution of oxalic acid in anhydrous Et2O was added to obtain a white solid which was recrystallized from iPrOH/Et2O (0.4g, 12%); mp 101-102°C (see Table 8).
Method D:
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 Et2O (3 × 25 mL). The ethereal solution, which contained the expected product, was washed with 10% NaOH (30 mL), then water (10 mL) and dried (MgSO4). 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-Cyclohexylpropyl)-3-phenylpropylamine Hydrochloride (92). 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 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 1N HCl solution (20 mL). The precipitate was collected by filtration and washed thoroughly with anhydrous Et2O (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).
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 Et2O to afford the desired compound (100 mg, 42%); mp 151-153ºC (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 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 Et2O (20 mL); the aqueous portion was basified with 10% NaOH and extracted with Et2O (20 mL). The Et2O 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:
5-Cyclohexylpentylamine Hydrogen Oxalate (126). A solution of cyclohexanepentanoic acid (2 g, 10.9 mmol) in SOCl2 (8 mL) was heated on a steam bath for 3 h. The SOCl2 was removed under vacuum. Chloroform (2 × 10 mL) was added and reevaporated to give the crude acid chloride as a yellow liquid. A saturated solution 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 (MgSO4). Recrystallization from aqueous MeOH gave 5-cycl ohexyl val eramide (1.1g, 55%); mp 121-122°C (reported mp 122-123ºC) (Katsellson and Dubinin, Compt . Rend. Acad. Sci . U.R. S.S. [N.S.] 4:405 (1936); Chem. Abstr. 3i:3449 (1937)). A suspension of the amide (183 mg, 1 mmol) in anhydrous Et2O (9 mL) was slowly added to a stirred suspension of LiAlH4 (114 mg, 3 mmol) in Et2O (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 0°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 Et2O (3 ×8 mL). The combined Et2O solution was dried over anhydrous K2CO3 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.G., et a l ., J. Am. Chew. Soc. 79:2844 (1957)). A solution of the free base in anhydrous Et2O 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 Et2O; mp 164ºC (see Table 8).
Radioligand Binding. The σ binding assay was conducted using guinea pig (Taconic) brain membranes and [3H]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 μl [3H]DTG (1-2 nM final concentration) and 50 μl 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%. Non-specific binding was measured in the presence of 10 μM haloperidol.
Microanalytical
Data
Calculated/Found
C H N
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
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
172 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
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
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
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
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
70.36 12.01 4.57
24 71.21 12.11 4.37
71.27 12.04 4.33
RESULTS and DISCUSSION
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). 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 136 where the 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 (131; 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)pentyl amines, the primary amine 126 (Ki = 200 nM), the N-monomethyl amine 127 (Ki 10 nM), and the N,N-dimethyl amine 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 151 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 151, 89, 111 and 76). That is, affinity is independent of the length of the alkyl chain that separates the phenyl-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 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. Interestingly, 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. 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.
EXAMPLE 7 Discrimination between the Sigma-1 and Sigma-2 Binding Sites
Materials
[3H](+)pentazocine (35 Ci/mmol) was generously provided by 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 83:8784-8788 (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 μg of guinea pig membranes in a final volume of 500 μl of 50 mM TRIS-HCl, pH 8.0. Non-specific binding was determined in the presence of 10 μM 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 μg 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 μM 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. Data Analysis
Equilibrium binding data were analyzed by least squares nonlinear regression techniques as described by Fischer, J.B. and Schonbrunn, A., J. Biol. Chem. 263:2008-2816 (1988). Two site binding curves were fit to an equation describing the sum of two independent sites with Hill slopes of 1. Affinity constants (Ki) values were calculated from IC50 values using the Cheng-Prussoff equation (Cheng, Y.-C. and Prusoff, W.H., Biochem. Pharm. 22:3099-3108 (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.
EXAMPLE 8 Structure-Activity Analysis with Regard to Sigma-1
As shown in Table 12, compound 1 binds with an IC50 value of 10.8 nM at sigma-1. Substitution on the phenyl A ring has essentially no effect on binding.
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 2- naphthyl 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)).
Increasing 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 α-methyl group has little effect on sigma-1 binding. (Compare compound no. 1 to compound no. 87 (Table 14)).
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).
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-5- phenylpentylamine, IC50=0.29 nM). However, 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).
Reduction of the phenyl-A ring of cmp. no. 77 (N-benzyl-5- phenylpentylamine, IC5O=0.32) has little effect on sigma-1 binding affinity (cmp. #94, N-benzyl-5-cyclohexylpentylamine, IC50=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).
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. # 112, sigma-2/sigma-1 selectivity of 137), N-benzyl-7-phenylheptylamine (cmp. # 90, sigma-2/sigma-1 selectivity of 126), N-(5-phenyl)pentylpiperidine (cmp. # 124, sigma-2/sigma-1 selectivity of 100), and N,N-dimethyl-5- phenylpentylamine (cmp. # 125, sigma-2/sigma-1 selectivity of 96).
EXAMPLE 9 Structure-Activity Analysis with Regard to Sigma-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).
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)-1-(1-naphthyl)-2- isopropylamine, and #17, N-(3-phenylpropyl)-1-(2-naphthyl)-2- isopropylamine, 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-2- isopropylamine, and #1, N-(3-(2-naphthyl)propyl)-1-phenyl-2- isopropylamine, which have binding affinities of 280 and 260 nM, respectively.) Removal of the α-methyl group of cmp. # 1 has essentially no effect (IC50 of cmp. no. 87, N-(3-phenylpropyl)-2- phenethylamine, = 90 nM). Increasing the phenyl-B chain length from 3 to 4 also has little effect (IC50 of cmp. 71, N-(4- phenylbutyl)-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.
Removal of the phenyl-B ring results in a reduction in sigma-2 affinity. (Compare cmp. 111, N-(3-phenylpropyl)-5- phenylpentylamine, with N-methyl-N-propyl-5-phenylpentylamine, IC50=40 nM).
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).
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 (67)

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:
wherein:
Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, wherein the substituent is selected from the group consisting of chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2- C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkyl carbamoyl, nitro, C2-C15 dialkylsulfamoyl;
R is hydrogen or C1-C6 alkyl;
R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, fluoro, chloro, bromo and =0; or
R and R1 together form a morpholino, piperazinyl or piperidinyl ring;
n is 0-5;
W is -(CH2) - or -H H-, wherein p is 1-3;
X is -(CH2)q-, wherein q is 1-6;
-(CH2)r-C≡C-(CH2)r-. -(CH2)r-CH=CH-(CH2)r-;
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y is O or S; or
C1-C6 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, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1- C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl , C2-C15 N,N-dialkylcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or an ortho methylene-dioxy group;
wherein said compound exhibits high binding activity with respect to the sigma receptor.
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:
wherein: Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, wherein the substituent is selected from the group consisting of chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2- C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-al kyl carbamoyl, C2-C15
N,N-dialkylcarbamoyl, nitro, C2-C15 dialkylsulfamoyl;
R is hydrogen or C1-C6 alkyl;
R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, fluoro, chloro, bromo and =0; or
R and R1 together form a morpholino, piperazinyl or piperidinyl ring;
n is 0-5;
W is -(CH2)p- or -H H-, wherein p is 1-3;
X is -(CH2)q-, wherein q is 1-6;
-(CH2)r-C-C-(CH2)P-,
-(CH2)r-CH=CH-(CH2)r-;
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y is O or S; or
C1-C6 alkyl (wherein Z is hydrogen);
Z is cycloalkyl or an aryl-substituted carboxylic acid group, wherein Z may be substituted by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N, N-dialkylcarbamoyl, nitro, C2- C15 dialkylsulfamoyl or an ortho methylene-dioxy group;
wherein said compound exhibits high binding activity with respect to the sigma receptor.
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 amount of a compound of the formula: wherein:
R is hydrogen or C1-C6 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, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro, C2-C15 dialkylsulfamoyl , and an ortho methyl enedioxy group;
R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, fluoro, bromo, chloro, iodo and =0; or R and R1 together form a morpholino, piperazinyl or piperidinyl ring;
n is 0-5;
X is -(CH2)q -, wherein q is 1-6;
-(CH2)r-C≡-C-(CH2)r-, wherein r is 0-3;
-(CH2)r-CH=CH-(CH2)r-;
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y is 0 or S; or
C1-C6 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, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro, C2-C15 dialkylsulfamoyl, or an ortho methylene-dioxy group;
wherein said compound exhibits high binding activity with respect to the sigma receptor.
4. The method of claim 3, wherein said compound is selected from the group consisting of N-phenethyl-1-phenylisopropylamine, N-(3-phenylpropyl)-1-phenyl-isopropylamine,
N-(2-phenoxy)ethyl)-1-phenylisopropylamine, N-(3-phenyl-3-propanon-1-yl)-1-phenylisopropylamine, N-(4-phenylbutyl)-1-phenylisopropylamine, N-(3-(1-naphthyl)propyl)-1-phenyl-isopropylamine,N-(3-(2-naphthyl)propyl)-1-phenylisopropylamine, N-methyl-N-(3-(2-naphthyl)propyl)-1-phenylisopropylamine, N-(3-phenyl-2-propyn-1-yl)-1-phenyl-isopropylamine, N-(3-phenyl-propyl)-1-(4-hydroxyphenyl)isopropylamine, N-(3-phenylpropyl)-1-(4-methoxyphenyl)isopropylamine, N-(3-phenylpropyl)-1-(3-bromophenyl)isopropylamine, N-(3-phenylpropyl)-1-(4-bromophenyl)isopropylamine, N-(3-phenylpropyl)-1-(3,4-dichlorophenyl)isopropylamine, N-(3-phenylpropyl)-1-(4-iodophenylisopropyl)-amine, N-(3-phenylpropyl)-1-(3-trifluoromethyl- phenyl)isopropylamine, N-(2-phenethyl)-N-methyl-1-phenyl- isopropylamine, N-(3-phenylpropyl)-1-phenylpropan-1-one-2-amine, N-(2-indanyl)-3-phenylpropylamimne, N,N-di-(3-phenylpropyl)amine, N-(2-(1-naphthyl)ethyl)-1-phenylisopropylamine, N-(2-(2- naphthyl)ethyl)-1-phenylisopropylamine, N-(2-(1-naphthyl)propyl)- 1-phenylisopropylamine, N-(2-(2-naphthyl)propyl)-1-phenylisopropylamine, N-(4-phenylbutyl)-1-(2,5-dimethoxyphenyl)iso- propylamine, N-(4-phenylbutyl)-1-(4-bromo-2,5-dimethoxyphenyl)- isopropylamine, N-methyl-N-(4-phenylbutyl)-1-phenylisopropylamine, N-methyl-N-(5-phenylpentyl)-1-phenylisopropylamine,N-(3- phenylpropyl)-1-(4-ethoxyphenyl)isopropyl-amine, N-(3-phenylpropyl)-1-(4-propylphenyl)isopropylamine, N-(3-phenylpropyl)-1- (4-benzoxyphenyl)isopropylamine, N-methyl-N-(3-phenylpropyl)-1- (4-propylphenyl)isopropylamine, N-(3-phenylpropyl)-1-phenyl-2- pentylamine, N-(4-phenylbutyl)-1-phenyl-2-pentylamine, N,N-di-(2- ethylphenyl)methylamine, N,N-dibenzylamine, N-(3-phenylpropyl)-N- (6-phenylhexyl)amine, N-(3-phenylpropyl)-N-(5-phenylpentyl)amine, N-propyl-N-methyl-5-phenylpentylamine, N-methyl-N-(3-phenyl- propyl)-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)-1-phenyl-2- pentylamine, N-methyl-N-(3-methylbutyl)-1-isopropylamine, N-methyl-N-(3-phenylbutyl)-1-phenyl-2-pentylamine, N-propyl-N-(3- phenyl)propyl)-1-phenyl-2-propylamine, N-benzyl-N-(3-phenyl)-propyl)-1-phenyl-2-propylamine, N-phenyl-(5-phenyl)pentylamine, N-methyl-N-(3-phenyl)propyl-5-phenylpentylamine, N-(2-(o-methyl¬phenyl)ethyl)-5-phenylpentylamine, N-(2-(m-methylphenyl)ethyl)-5-phenylpentylamine, N-(2-(p-methylphenyl)ethyl)-5-phenylpentylamine, N-benzyl-5-phenylpentylamine, N-benzyl-N-methyl-5-phenylpentylamine,N-(2-(3-hydroxyphenyl)ethyl)-5-phenylpentylamine, N-(2-(2-hydroxyphenyl)ethyl)-5-phenylpentylamine, N,N'-diethyl-2-(diphenylacetoxy)ethylamine, N,N '-diethyl-2-(9-fluorenecarboxy)-ethylamine, N,N-Dimethyl-5-phenylpentylamine, N-Benzyl-N-(3-phenylpropyl)-1-phenyl-2-propylamine, N-Benzyl-N-methyl-5-phenylpentylamine, N-Benzyl-5-phenylpentylamine, and N-(2-phenethyl)-N-methylpentylamine.
5. 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 is hydrogen or C1-C6 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, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro, C2-C15 dialkylsulfamoyl, and an ortho methyl enedioxy group;
R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, fluoro, bromo, chloro, iodo and =0; or R and R together form a morpholino, piperazinyl or piperidinyl ring;
n is 0-5;
X is -(CH2)q -, wherein q is 1-6;
-(CH2)r-C≡C-(CH2)r-, wherein r is 0-3;
-(CH2)r-CH-=CH-(CH2)r-;
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y is O or S; or
C1-C6 alkyl (wherein Z is hydrogen); Z is cycloalkyl or an aryl-substituted carboxylic acid group wherein Z may be substituted by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy,
C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N, N-dialkylcarbamoyl, nitro, C2- C15 dialkylsulfamoyl, or an ortho methyl ene-dioxy group;
wherein said compound exhibits high binding activity with respect to the sigma receptor.
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)-1-(4- propylphenyl)isopropylamine, N-(3-phenylpropyl)-1-(4-benzoxyphenyl)isopropylamine, N-methyl-N-(3-phenylpropyl)-1-(4-propylphenyl)isopropylamine, N-(3-phenylpropyl)-1-phenyl-2-pentylamine, N-(4-phenylbutyl)-1-phenyl-2-pentylamine, N,N-di-(2-ethylphenyl)methylamine, N,N-dibenzylamine, N-(3-phenylpropyl)-N- (6-phenylhexyl)amine, N-(3-phenylpropyl)-N-(5-phenylpentyl)amine, 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-phenylisopropyl amine, N-methyl-N-(3-phenylpropyl)-1-phenyl-2-pentylamine, N-methyl-N-(3-methylbutyl)-1-isopropylamine, N-methyl-N-(3-phenylbutyl)-1-phenyl-2-pentylamine, N-propyl-N-(3-phenyl)propyl)-1-phenyl-2-propylamine, N-benzyl-N-(3-phenyl)-propyl)-1-phenyl-2-propylamine, N-phenyl-(5-phenyl)pentylamine, N-methyl-N-(3-phenyl)propyl-5-phenylpentylamine, N-(2-(o-methylphenyl)ethyl)-5-phenylpentylamine, N-(2-(m-methylphenyl)ethyl)-5-phenylpentylamine, N-(2-(p-methylphenyl)ethyl)-5-phenylpentyl amine, N-benzyl-5-phenylpentylamine, N-benzyl-N-methyl-5-phenylpentyl amine, N-(2-(3-hydroxyphenyl)ethyl)-5-phenylpentylamine, N-(2-(2-hydroxyphenyl)ethyl)-5-phenylpentylamine, N,N'-diethyl-2-(diphenylacetoxy)ethylamine, N,N'-diethyl-2-(9-fluorenecarboxy)-ethylamine, N,N-Dimethyl-5-phenylpentylamine, N-Benzyl-N-(3-phenylpropyl)-1-phenyl-2-propylamine, N-Benzyl-N-methyl-5-phenylpentylamine,N-Benzyl-5-phenylpentylamine, N-(2-phenethyl)-N-methylpentylamine, N-(5-phenylpentyl)-4-benzylpiperidine andN-(5-phenylpentyl)-4-benzyl-4-hydroxy-piperidine.
7. 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 hydrogen or C1 -C6 alkyl;
Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, wherein the substituent is selected from the group consisting of chloro, fluoro, bromo, iodo, CF3, C1 -C6 alkoxy, C2-C6 dialkoxymethyl, C1 -C6 alkyl, cyano, C3-C15 di alkyl aminoal kyl , carboxy, carboxamido, C1 -C6 haloalkyl, C1 -C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1 -C6 alkylthio, C1 -C6 alkylsulfonyl, C1 -C6 haloalkylsulfonyl, C1 -C6 alkylsulfinyl, C1 -C6 haloalkylsulfinyl, arylthio, C1 -C6 haloalkoxy, amino, C1 -C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro and C2-C15 dialkylsulfamoyl;
R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, fluoro, chloro, bromo, iodo and =0; or R and R1 together form a morpholino, piperazinyl or piperidinyl ring;
n is 1-3;
p is 1-3;
X is -(CH2)q -, wherein q is 1-6,
-(CH2)r-C≡ C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-,
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y is 0 or S; or
C1 -C6 alkyl;
Z is hydrogen, cycloalkyl, aryl or heteroaryl wherein Z may be substituted by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dial kyl ami noal kyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methylenedioxy;
wherein said compound exhibits a high binding activity with respect to the sigma receptor.
8. The method of claim 7, wherein said compound is selected from the group consisting of N-(2-indanyl)-1-phenylisopropylamine, N-(2-indanyl)-3-phenylpropylamine, N-(4,5-benzocycloheptyl)-1-phenylisopropylamine, N-(3,4-benzocycloheptyl)-3-(phenyl)propylamine, N-(4,5-benzocycloheptyl)-3- phenylpropylamine, N-(3,4-benzocyclohexyl)-1-phenylisopropylamine and N-3,4-benzocyclohexyl-3-phenylpropylamine.
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:
wherein:
R is hydrogen or C1-C6 alkyl;
Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, wherein the substituent is selected from the group consisting of chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 di alkyl ami noal kyl , carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro and C2-C15 dialkylsulfamoyl;
R is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, fluoro, chloro, bromo, iodo and =0; or R and R1 together form a morpholino, piperazinyl or piperidinyl ring;
n is 1-3;
p is 1-3;
X is -(CH2)q-, wherein q is 1-6, -(CH2)r-C≡C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-,
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y is O or S; or
C1 -C6 alkyl;
Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1- C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-al kyl carbamoyl, C2-C15 N, N-dialkylcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methyl enedioxy; wherein said compound exhibits a high binding activity with respect to the sigma receptor.
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:
R2 is selected from the group consisting of hydrogen, chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro and C2-C15 dialkylsulfamoyl;
X is -(CH2)-, wherein q is 1-6,
-(CH2)r-C≡C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-,
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y is O or S; or
C1-C6 alkyl (wherein Z is hydrogen);
Z is cycloalkyl, aryl or heteroaryl wherein Z may be substituted by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkyl-amino, dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N, N-dialklcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methyl enedioxy;
V is N or CM, wherein M is hydrogen, C1-C6 alkyl, C1-C6 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.
11. The method of claim 10, wherein V is N, said compound having the formula
12. The method of claim 11, wherein said compound is selected from the group consisting of N-(3-trifluoromethyl- phenyl)-N'-phenethylpiperazine, N-(3-trifluoromethylphenyl)-N'- (4-phenylbutyl)piperazine, N-(3-chlorophenyl)-N'-benzylpiperazine, N-(3-chlorophenyl)-N'-(3-phenylpropyl)piperazine, N-(3- chlorophenyl)-N'-phenethylpiperazine, N-phenyl-N'-(3-phenylpropyl)piperazine, N-phenyl-N'-(3-phenylbutyl)piperazine, N-(2- naphthyl)-N'-(3-phenylpropyl)-piperazine, N-phenyl-N'-(3-(2- naphthyl)propyl)-piperazine, N-phenyl-N'-propylpiperazine, N-(4- chlorophenyl)-N'-(3-phenylpropyl)piperazine, N-benzyl-N'-(4- phenylbutyl)-piperazine, N-phenyl-N'-(4-phthalimidobutyl)- piperazine, and N-phenyl-N'-(5-phthalimidopentyl)piperazine.
13. The method of claim 11, wherein V is CM, said compound having the formula
14. The method of claim 13, wherein said compound is selected from the group consisting of N-phenethyl-4-phenylpiperidine, N-phenethyl-4-phenyl-4-hydroxypiperidine,N-(3-phenylpropyl)-4-phenylpiperidine, N-(3-phenylpropyl)-4-phenyl-4-hydroxypiperidine, N-(5-phenylpentyl)-4-phenylpiperidine, N-(4-phenylbutyl)-4-phenylpiperidine, N-(3-phenylpropyl)-4-(4-chlorophenyl)-1,2,5,6-tetrahydropyridine, N-(4-phenylbutyl)-4-(4-chlorophenyl)-1,2,5,6-tetrahydropyridine, N-(5-phenylpentyl)-4- benzylpiperidine and N-(5-phenylpentyl)-4-benzyl-4-hydroxypiperidine.
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:
R2 is selected from the group consisting of hydrogen, chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro and C2-C15 dialkylsulfamoyl;
X is -(CH2)-, wherein q is 1-6,
-(CH2)r-C≡C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-,
wherein each r is independently 0,-3 and wherein Y is O or S; or
C1-C6 alkyl (wherein Z is hydrogen);
Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1- C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkyl-amino, dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N, N-dialklcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methylenedioxy;
V is N or CM, wherein M is hydrogen, C1-C6 alkyl, C1-C6 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.
16. The method of claim 15, wherein V is N, said compound having the formula
17. The method of claim 15, wherein V is CM, said compound having the formula
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:
wherein:
R3 is selected from the group consisting of C1-C6 alkyl, C1-C6 alkenyl, C2-C6 dialkoxymethyl, C3-C15 dialkylaminoalkyl, aralkyl, C3-C6 cycloalkyl, aroyl, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl; X is -(CH2)q -, wherein q is 1-6,
-(CH2)r-C≡C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-,
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y is O or S; or
C1-C6 alkyl (wherein Z is hydrogen);
Z is cycloalkyl, aryl or heteroaryl wherein Z may be substituted by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkyl-amino, dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialklcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methyl enedioxy;
V is N or CM, wherein M is hydrogen, C1-C6 alkyl, C1-C6 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. 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-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, andN-(5-phenylpentyl)-4-benzyl-4-hydroxy-piperidine.
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:
wherein:
R3 is selected from the group consisting of C1-C6 alkyl, C1-C6 alkenyl, C2-C8 dialkoxymethyl, C3-C15 dialkylaminoalkyl, aralkyl, C3-C6 cycloalkyl, aroyl, C2-C6 acyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, C3-C6heterocycloalkyl;
X is -(CH2)q -, wherein q is 1-6,
-(CH2)r-C≡C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-,
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y is 0 or S; or
C1-C6 alkyl (wherein Z is hydrogen);
Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 di alkyl ami noal kyl , carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfinyl , C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkyl-amino, dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialklcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methyl enedioxy;
V is N or CM, wherein M is hydrogen, C1-C6 alkyl, C1-C6 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.
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:
R4 is hydrogen or an aryl group substituted with a group selected from the group consisting of C1-C6 alkyl, C1-C6 alkenyl, C2-C6 dialkoxymethyl, C3-C15 dialkylaminoalkyl, aralkyl, C3-C6 cycloalkyl, aroyl, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl;
R is hydrogen or hydroxy;
X is -(CH2)q -, wherein q is 1-6,
-(CH2)r-C=C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-,
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y is 0 or S; or C1-C6 alkyl (wherein Z is hydrogen);
Z is cycloalkyl, aryl or heteroaryl wherein Z may be substituted by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 di alkyl ami noal kyl , carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkyl-amino, dialkylamino, hydroxy, carbamoyl, C1-C6 N- alkylcarbamoyl, C2-C15 N, N-dialklcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methylenedioxy;
wherein said compound exhibits a high binding activity with respect to the sigma receptors.
22. The method of claim 21, wherein said compound is selected from the group consisting of N-(5-phenylpentyl)- piperidine, N-(8-phenylheptyl)piperidine, N-(5-(4-methoxyphenyl)pentyl)piperidine, N-(3-phenylpropyl)piperidine,N- (5-cyclohexyl)pentylpiperidine, N-benzylpiperidine, N-(2-phenethyl)-4-hydroxy-4-phenylpiperidine, N-(2-phenethyl)-4-hydroxy-4-t-butylpiperidine,N-(5-(4-chlorophenyl)-5-pentanon-1-yl)piperidine, N-(5-(4-chlorophenyl)-5-pentanon-1-yl)-4-phenylpiperidine,N-(5-(4-methoxyphenyl)-5-pentanon-1-yl)piperidine, N- (5-(4-methoxyphenyl)-5-pentanon-1-yl)-4-phenylpiperidine, N-(5- (4-methoxyphenyl)pentyl)-4-phenylpiperidine, N-(5-phenyl-5-pentanon-1-yl)-4-phenylpiperidine, N-(5-(4-chlorophenyl)-pentyl)-4-phenylpiperidine, N-(5-(3-methoxyphenyl)-5-pentanon-1-yl)piperidine,N-(5-(3-chlorophenyl)-5-pentanon-1-yl)piperidine,
N-(5-(3-chlorophenyl)-5-pentanon-1-yl)-4-phenylpiperidine, N-(5-(3-methoxyphenyl)-5-pentanon-1-yl)-4-phenylpiperidine, N-(4-(4-f1uorophenyl)-4-butanon-1-yl)piperidine, 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-1-yl)-4-(3-chlorophenyl)-4-hydroxypiperidine, 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-fluorophenyl)-piperidine, 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-fluorophenyl)-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-dichlorophenyl)-5-pentanon-1-yl)-4-(chlorophenyl)-piperidine, N-(5-cyclopentylpentan-5-on-1-yl)piperidine and N-(5-(3,4-methylenedioxyphenyl)penta-2,4-dienyl)piperidine.
23. 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 having the formula:
wherein,
X is -(CH2)q -, wherein q is 1-6,
-(CH2)r-C≡C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-,
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y is O or S; or
C1-C6 alkyl (wherein Z is hydrogen);
Z is cycloalkyl, aryl or heteroaryl wherein Z may be substituted by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsul fonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkyl-amino, dialkylamino, hydroxy, carbamoyl, C1-C6 N- alkylcarbamoyl, C2-C15 N,N-dialklcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methyl enedioxy;
wherein said compound exhibits a high binding activity with respect to the sigma receptors.
24. The method of claim 23, wherein said compound is N- (5-phenyl)pentyl-3-azabicyclo[3.2.2]nonane.
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,
R4 is hydrogen or an aryl group substituted with a group selected from the group consisting of C1-C6 alkyl, C1-C6 alkenyl, C2-C6 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;
X is -(CH2)q -, wherein q is 1-6,
-(CH2)r-C≡C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-,
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y is O or S; or
C1-C6 alkyl (wherein Z is hydrogen);
Z is cycloalkyl, aryl or heteroaryl wherein Z may be substituted by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkyl- sul fonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkyl-amino, dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialklcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methylenedioxy;
wherein said compound exhibits a high binding activity with respect to the sigma receptors.
26. The method of claim 25, wherein said compound is N- (5-phenyl)pentyl-4-phenyltropan-4-ol.
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:
wherein
a is 1-8;
b is 1-8; R is hydrogen or C1-C6 alkyl;
R2 is independently selected from the group consisting of hydrogen, chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkyl- sul fonyl, C1-C6 hal oal kyl sul fonyl , C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, dialkylamino, hydroxy, carbamoyl, C1-C6 N- alkylcarbamoyl, C2-C15 N, N-dialklcarbamoyl, nitro and C2-C15 dialkylsulfamoyl;
wherein said compound exhibits high binding activity with respect to the sigma receptor.
28. The method of claim 27 wherein said compound is selected from the group consisting of N-(4-phenylbutyl)phenethyl- amine, N-(4-phenylbutyl)-3-phenylpropylamine, N-(4-phenylbutyl)- 4-phenylbutylamine, N-(4-phenylbutyl)benzylamine, N-(4-phenylbutyl)-5-phenylpentylamine, N-(5-phenylpentyl)benzylamine, N-(3-phenylpropyl)phenethylamine, N-(5-phenylpentyl)phenethylamine, N-(7-phenylheptyl)benzylamine, N-(7-phenylheptyl)-phenethylamine, N-methyl-N-(2-phenethyl)-1-phenylisopropylamine, N-methyl-N-(5-phenylpentyl)-1-phenylisopropylamine, N-methyl-N- (3-phenylpropyl)-1-(4-propylphenyl)isopropylamine, N-phenyl-(5-phenyl)pentylamine, N-methyl-N-(3-phenylpropyl)-5-phenylpentylamine, N-benzyl-N-methyl-5-phenylpentylamine, N-(2-(o-methoxyphenyl)ethyl)-5-phenylpentylamine, N-(2-(m-methoxyphenyl)ethyl)-5-phenylpentylamine, N-(2-(p-methoxyphenyl)ethyl)- 5-phenylpentylamine, N-benzyl-5-phenylpentylamine, N-(2-(m-hydroxyphenyl)ethyl)-5-phenylpentylamine, and N-(2-(o-hydroxyphenyl)ethyl)-5-phenylpentylamine.
29. 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
a is 1-8;
b is 1-8;
R is hydrogen or C1-C6 alkyl;
R2 is independently selected from the group consisting of hydrogen, chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkyl-amino, dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialklcarbamoyl, nitro and C2-C15 dialkylsulfamoyl; and
wherein said compound exhibits high binding activity with respect to the sigma receptor.
30. The method of claim 29, wherein said compound is N-(3-phenyl propyl)-2-(2-naphthyl)ethylamine.
31. 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;
Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, wherein the substituent is selected from the group consisting of chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2- C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15
N,N-dialkylcarbamoyl, nitro and C2-C15 dialkylsulfamoyl;
X is -(CH2)q -, wherein q is 1-6,
-(CH2)r-C≡C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-,
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y is O or S; or
C1-C6 alkyl;
Z is hydrogen, cycloalkyl, aryl or heteroaryl wherein Z may be substituted by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methylenedioxy; wherein said compound exhibits high binding activity with respect to the sigma receptor.
32. 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:
wherein;
Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, wherein the substituent is selected from the group consisting of chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro and C2-C15 dialkylsulfamoyl;
X is -(CH2)q -, wherein q is 1-6,
-(CH2)r-C≡C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-,
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y is O or S; or
C1-C6 alkyl;
Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1- C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methyl enedioxy; wherein said compound exhibits high binding activity with respect to the sigma receptor.
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 amount of a compound having the formula:
wherein n is 0-5;
Cy is C3-C8 cycloalkyl;
R is hydrogen or C1-C6 alkyl;
R1 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, fluoro, chloro, bromo, iodo and =0;
X is -(CH2)q -, wherein q is 1-6;
-(CH2)r-C≡C-(CH2)r-, wherein r is 0-3;
-(CH2)r-CH=CH-(CH2)r-;
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y is O or S; or
C1-C6 alkyl (wherein Z is hydrogen); and
Z is hydrogen, cycloalkyl, aryl or heteroaryl wherein Z may be substituted by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy,
C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkyl sul fonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methylenedioxy;
wherein said compound exhibits high binding activity with respect to the sigma receptor.
34. The method of claim 33, wherein said compound is selected from the group consisting of N-(3-cyclohexylpropyl)-3-phenylpropylamine, N-cyclohexylmethyl-3-phenylpropylamine, N-(5-cyclohexylpentyl)benzylamine, 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.
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 having the formula:
wherein n is 0-5;
Cy is C3-C8 cycloalkyl;
R is hydrogen or C1-C6 alkyl;
R1 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, fluoro, chloro, bromo, iodo and =0;
X is -(CH2)q -, wherein q is 1-6;
-(CH2)r-C≡C-(CH2)r-, wherein r is 0-3;
-(CH2)r-CH=CH-(CH2)r-;
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y is 0 or S; or
C1-C6 alkyl (wherein Z is hydrogen); and
Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1- C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cyclo- alkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 hal oalkylsul fonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methylenedioxy; wherein said compound exhibits high binding activity with respect to the sigma receptor.
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 is -(CH2)r-C≡C-(CH2)r-, wherein each r is 0-3 independently;
-(CH2)r-CH=CH-(CH2)r-;
-(CH2)r-Y-(CH2)r-, wherein Y is O or S; or
C1-C6 alkyl (wherein Z is hydrogen);
R2 is independently selected from the group consisting of hydrogen, chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 al kyl - sulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkyl-amino, dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialklcarbamoyl, nitro and C2-C15 dialkylsulfamoyl;
V is N or CM, wherein M is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, fluoro, chloro, bromo, trifluoromethyl, hydroxy or one half of a double bond with the neighboring endocyclic carbon;
X is -(CH2)q-, wherein q is 1-6;
-(CH2)r-C≡C-(CH2)r-, wherein r is 0-3;
-(CH2)r-CH=CH-(CH2)r-;
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y is O or S; or
C1-C6 alkyl (wherein Z is hydrogen); and
Z is hydrogen, cycloalkyl, aryl or heteroaryl wherein Z may be substituted by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy,
C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro and C2-C15 dialkylsulfamoyl;
wherein said compound exhibits high binding activity with respect to the sigma receptor.
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:
wherein X1 is -(CH2)r-C≡C-(CH2)r-, wherein each r is 0-3 independently;
-(CH2)r-CH=CH-(CH2)r-;
-(CH2)r-Y-(CH2)r-, wherein Y is 0 or S; or
C1-C6 alkyl (wherein Z is hydrogen);
R2 is independently selected from the group consisting of hydrogen, chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkyl-amino, dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialklcarbamoyl, nitro and C2-C15 dialkylsulfamoyl;
V is N or CM, wherein M is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, fluoro, chloro, bromo, trifluoromethyl, hydroxy or one half of a double bond with the neighboring endocyclic carbon;
X is -(CH2)q -, wherein q is 1-6;
-(CH2)r-(=C-(CH2)r-, wherein r is 0-3;
-(CH2)r-CH=CH-(CH2)r-;
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y is O or S; or
C1-C6 alkyl (wherein Z is hydrogen); and
Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro and C2-C15 dialkylsulfamoyl;
wherein said compound exhibits high binding activity with respect to the sigma receptor.
38. 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 having the formula:
wherein R5 and R6 are independently a C1-8 alkyl group;
R7 is hydrogen or a C1-8 alkyl group substituted by an arylacetoxy or aryl carboxy group; and
X is -(CH2)q -, wherein q is 1-6;
-(CH2)r-C≡C-(CH2)r-, wherein r is 0-3;
-(CH2)r-CH=CH-(CH2)r-; -(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y is O or S; or
C1-C6 alkyl (wherein R7 is hydrogen);
wherein said compound exhibits a high binding activity with respect to the sigma receptors.
39. The method of claim 38, wherein said compound is selected from the group consisting of N,N-dimethyl-n-hexylamine, N-methyl-N-propylhexylamine, N,N'-diethyl-2- (diphenylacetoxy)ethylamine, and N,N'-diethyl-2-(9- fluorenecarboxy)ethylamine.
40. A method of treating or preventing a central nervous system disorder, angina, migrane or hypertension, comprising administering to an animal an effective amount of a compound selected from the group consisting of N-phenyl-N'-(3-(1- phthalimido)propyl)piperazine, N-(4-(1-phthalimido)butyl)-N'-(o- methoxylphenyl)piperazine, and N-phenyl-N'-(4-(1- phthalimido)butyl)piperazine.
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.
42. 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, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N, N-dialkylcarbamoyl, nitro and C2-C15 dialkylsulfamoyl;
R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, fluoro, chloro, bromo, iodo and =0; or
R and R1 together form a morpholino ring;
n is 0-5;
W is -(CH2)p - or -H H-, wherein p is 1-3;
X is -(CH2)q -, wherein q is 3-6;
-(CH2)r-C≡C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-; or
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y is O or S;
Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfinyl , C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl , nitro and C2-C15 dialkylsulfamoyl; with the proviso that when W is -H H-, R and R 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.
43. A compound of the formula:
wherein:
R is hydrogen or C1-C6 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, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy,
C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkyl- sul fonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N- alkylcarbamoyl, C2-C15 N, N-dialkylcarbamoyl, nitro and C2-C15 dialkylsulfamoyl;
R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, fluoro, chloro, bromo, iodo and =0;
n is 0-5;
X is -(CH2)q -, wherein q is 3-6;
-(CH2)r-C≡C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-; or
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y is O or S; Z is cycloalkyl, an aryl carboxy, or an arylacetoxy group, wherein Z may be substituted by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy,
C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkyl sul fonyl , C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methylene dioxy;
with the proviso that when R and R1 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.
44. A compound selected from the group consisting of N-(3-phenylpropyl)-1-(4-propyl-phenyl)-isopropylamine, N-(3-phenylpropyl)-1-(4-benzoxyphenyl)-isopropylamine, N-methyl-N-(3-phenylpropyl)-1-(4-propylphenyl)-isopropylamine, N-(3-phenylpropyl)-1-phenyl-2-pentylamine, N-(4-phenylbutyl)-1-phenyl-2-pentylamine, N-(3-phenylpropyl)-N-(6-phenylhexyl)amine, N-(3-phenylpropyl)-N-(5-phenylpentyl)amine, N-propyl-N-methyl-5-phenylpentylamine, N-methyl-N-(3-phenylpropyl)-1-phenylisopropylamine, N-methyl-N-(3-methyl-2-butenyl)-1-phenylisopropylamine, N-methyl-N-(3-methylbutyl)-1-phenylisopropylamine, N-methyl-N-(3-phenylpropyl)-1-phenyl-2-pentylamine, N-methyl-N-(3-methylbutyl)-1-isopropylamine, N-methyl-N-(3-phenylbutyl)-1-phenyl-2-pentylamine, N-propyl-N-(3-phenyl)propyl)-1-phenyl-2-propylamine, N-benzyl-N-(3-phenyl)-propyl)-1-phenyl-2-propylamine, N-phenyl-(5-phenyl)pentylamine, N-methyl-N-(3-phenyl)propyl-5-phenylpentylamine, N-(2-(o-methylphenyl)ethyl)-5-phenylpentylamine, N-(2-(m-methylphenyl)ethyl)-5-phenylpentylamine, N-(2-(p-methylphenyl)ethyl)-5-phenylpentylamine, 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-phenylpentylamine, N,N'-diethyl-2-(diphenylacetoxy)ethylamine, N,N'-diethyl-2-(9- fluorenecarboxy)ethylamine, N,N-Dimethyl-5-phenylpentylamine, N- Benzyl-N-(3-phenylpropyl)-1-phenyl-2-propylamine, N-Benzyl-N- methyl-5-phenylpentylamine, N-Benzyl-5-phenylpentylamine, and N- (2-phenethyl)-N-methylpentylamine.
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, CF3, C1-C6 alkoxy, C2- C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methyl enedioxy;
R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, fluoro, chloro, bromo, iodo and =0; or R and R1 together form a morpholino ring;
n is 1-3; p is 1-3;
X is -(CH2)q -, wherein q is 1-6,
-(CH2)r-(=C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-, or
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-1 and wherein Y is 0 or S;
Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-al kyl carbamoyl , C2-C15 N,N-dialkylcarbamoyl, nitro and C2-C15 dialkylsulfamoyl;
wherein said compound exhibits high binding activity with respect to the sigma receptor.
46. A compound of the formula:
wherein:
R2 is selected from the group consisting of hydrogen, chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro and C2-C15 dialkylsulfamoyl;
X is -(CH2)-, wherein q is 1-6,
-(CH2)r-C≡C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-,
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y is O or S; or
C1-C6 alkyl (wherein Z is hydrogen);
Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C8 heterocycloalkyl, C1-C6 alkylthio, C1-C6 al kyl sul fonyl , C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkyl-amino, dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialklcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methyl enedioxy;
V is N or CM, wherein M is hydrogen, C1-C6 alkyl, C1-C6 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.
47. The compound claim 46, wherein V is N, said compound having the formula
48. A compound selected from the group consisting of N-(3-trifluoromethylphenyl)-N'-(4-phenylbutyl)piperazine, N-(3-chlorophenyl)-N'-benzylpiperazine, N-(3-chlorophenyl)-N'-(3-phenylpropyl)piperazine, N-phenyl-N'-(3-phenylpropyl)piperazine, N-phenyl-N'-(3-phenylbutyl)piperazine, N-(2-naphthyl)-N'-(3-phenylpropyl)-piperazine, N-phenyl-N'-(3-(2-naphthyl)propyl)-piperazine, N-phenyl-N'-propylpiperazine, N-(4-chlorophenyl)-N'-(3-phenylpropyl)piperazine, N-benzyl-N'-(4-phenylbutyl)-piperazine,N-phenyl-N'-(4-phthalimidobutyl)piperazine, N-phenyl-N'-(5-phthalimidopentyl)piperazine, N-(5-phenylpentyl)-4-benzylpiperidine and N-(5-phenylpentyl)-4-benzyl-4-hydroxypiperidine.
49. The compound of claim 46, wherein V is CM, said compound having the formula
50. A compound of the formula:
wherein:
R3 is selected from the group consisting of C1-C6 alkyl, C1-C6 alkenyl, C2-C6 dialkoxymethyl, C3-C15 dialkylaminoalkyl, aralkyl, C3-C6 cycloalkyl, aroyl, C2-C6 acyl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl;
X is -(CH2)q-, wherein q is 1-6,
-(CH2)r-C≡C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-,
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y is O or S; or
C1-C6 alkyl (wherein Z is hydrogen);
Z is cycloalkyl, aryl or heteroaryl wherein Z may be substituted by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkyl-amino, dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialklcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methylenedioxy;
V is N or CM, wherein M is hydrogen, C1-C6 alkyl, C1-C6 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.
51. The compound of claim 50 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-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, and N-(5-phenylpentyl)-4-benzyl-4-hydroxy-piperidine.
52. A compound selected from the group consisting of N-
(3-trifluoromethylphenyl)-N'-(4-phenylbutyl)piperazine, N-(3-chlorophenyl)-N'-(3-phenylpropyl)piperazine, N-phenyl-N'-(3-phenylpropyl)piperazine, N-phenyl-N'-(3-phenylbutyl)piperazine, N-naphthyl-N'-(3-phenylpropyl)-piperazine, N-phenyl-N'-(3-naphthylpropyl)piperazine, N-phenyl-N'-propylpiperazine, N-(4-chlorophenyl)-N'-(3-phenylpropyl)piperazine, N-benzyl-N'-(4-phenylbutyl)piperazine, N-phenyl-N'-(4-phthalimidobutyl)-piperazine, N-phenyl-N'-(5-phthalimidopentyl)piperazine, N-(5-phenylpentyl)-4-benzylpiperidineandN-(5-phenylpentyl)-4-benzyl-4-hydroxy-piperidine..
53. A compound having the formula
wherein
R2 is selected from the group consisting of hydrogen, chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro and C2-C15 dialkylsulfamoyl;
X is -(CH2)r-C≡C-(CH2)r-, -(CH2)r-CH=CH-(CH2)r-, or
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and
Y is O or S;
Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1- C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkyl-amino, dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialklcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methylenedioxy;
wherein said compound exhibits a high binding activity with respect to the sigma receptor.
54. A compound of the formula:
wherein:
R4 is hydrogen or an aryl group substituted with a group selected from the group consisting of C1-C6 alkyl, C1-C6 alkenyl, C2-C6 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;
X is -(CH2) -, wherein q is 1-6,
-(CH2)r-C≡C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-,
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y is O or S; or
C1-C6 alkyl (wherein Z is hydrogen);
Z is cycloalkyl, aryl or heteroaryl wherein Z may be substituted by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkyl- sul fonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkyl-amino, dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialklcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methyl enedioxy;
wherein said compound exhibits a high binding activity with respect to the sigma receptors.
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-(3-phenylpropyl)piperidine, N-(5-cyclohexyl)pentylpiperidine
N-benzylpiperidine, N-(2-phenethyl)-4-hydroxy-4-phenylpiperidine N-(2-phenethyl)-4-hydroxy-4-t-butylpiperidine, N-(5-(4-chlorophenyl)-5-pentanon-1-yl)piperidine, N-(5-(4-chlorophenyl)-5-pentanon-1-yl)-4-phenylpiperidine, N-(5-(4-methoxyphenyl)-5-pentanon-1-yl)piperidine, N-(5-(4-methoxyphenyl)-5-pentanon-1-yl)-4-phenylpiperidine, N-(5-(4-methoxyphenyl)pentyl)-4-phenylpiperidine, N-(5-phenyl-5-pentanon-1-yl)-4-phenylpiperidine N-(5-(4-chlorophenyl)pentyl)-4-phenylpiperidine, N-(5-(3-methoxyphenyl)-5-pentanon-1-yl)piperidine, N-(5-(3-chlorophenyl)-5-pentanon-1-yl)piperidine, N-(5-(3-chlorophenyl)-5-pentanon-1-yl)-4-phenylpiperidine, N-(5-(3-methoxyphenyl)-5-pentanon-1-yl)- 4-phenylpiperidine, N-(4-(4-fluorophenyl)-4-butanon-1- yl)piperidine, 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-1-yl)-4-(3-chlorophenyl)-4- hydroxypiperidine, 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-fluorophenyl)piperidine, 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-fluorophenyl)-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-dichlorophenyl)-5-pentanon-1-yl)-4-(chlorophenyl)-piperidine, N-(5- cyclopentylpentan-5-on-1-yl)piperidine, N-(5-(3,4-methylenedioxyphenyl)penta-2,4-dienyl)piperidine, N-phenyl-(5- phenyl)pentylamine, N-methyl-N-(3-phenylpropyl)-5- phenylpentylamine, N-benzyl-N-methyl-5-phenylpentylamine, N-(2- (o-methoxyphenyl)ethyl)-5-phenylpentylamine, N-(2-(m-methoxyphenyl)ethyl)-5-phenylpentylamine, N-(2-(p-methoxyphenyl)ethyl)-5-phenylpentylamine, N-benzyl-5-phenylpentylamine, N-(2-(m-hydroxyphenyl)ethyl)-5-phenylpentylamine, and N-(2-(o-hydroxyphenyl)ethyl)-5-phenylpentylamine.
56. A compound having the formula:
wherein,
X is -(CH2)q -, wherein q is 1-6,
-(CH2)r-C≡C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-,
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y is O or S; or
C1-C6 alkyl (wherein Z is hydrogen);
Z is cycloalkyl, aryl or heteroaryl wherein Z may be substituted by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkyl-amino, dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialklcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methyl enedioxy;
wherein said compound exhibits a high binding activity with respect to the sigma receptors.
57. N-(5-phenyl)pentyl-3-azabicyclo[3.2.2]nonane, a compound of claim 56.
58. A tropane derivative having the formula:
wherein,
R4 is hydrogen or an aryl group substituted with a group selected from the group consisting of C1-C6 alkyl, C1-C6 alkenyl, C2-C6 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;
X is -(CH2)q -, wherein q is 1-6,
-(CH2)r-C≡C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-,
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y is O or S; or
C1-C6 alkyl (wherein Z is hydrogen);
Z is cycloalkyl, aryl or heteroaryl wherein Z may be substituted by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkyl- sulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkyl-amino, dialkylamino, hydroxy, carbamoyl, C1-C8 N- alkylcarbamoyl, C2-C15 N,N-dialklcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methyl enedioxy;
wherein said compound exhibits a high binding activity with respect to the sigma receptors.
59. N-(5-phenyl)pentyl-4-phenyltropan-4-ol, a compound of claim 58.
60. A compound having the formula:
wherein; Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, wherein the substituent is selected from the group consisting of chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, Ca-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N, N-dialkylcarbamoyl, nitro and C2-C15 dialkylsulfamoyl;
X is -(CH2)q -, wherein q is 1-6,
-(CH2)r-C≡C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-,
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y is O or S; or
C1-C6 alkyl;
Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl , carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl , nitro or C2-C15 dialkylsulfamoyl;
wherein said compound exhibits high binding activity with respect to the sigma receptor.
61. A compound of the formula
wherein n is 0-5;
Cy is C3-C8 cycloalkyl; and
R1 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, fluoro, chloro, bromo, iodo and =0;
R is hydrogen or C1-C6 alkyl;
X is -(CH2) -, wherein q is 1-6;
-(CH2)r-C≡C-(CH2)r-, wherein r is 0-3;
-(CH2)r-CH=CH-(CH2)r-;
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y is O or S; or
C1-C6 alkyl (wherein Z is hydrogen); and
Z is cyclolkyl which may substituted by chloro, fluoro, bromo, iodo, CF3 C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano,
C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methyl enedioxy.
62. A compound selected from the group consisting of N-cyclohexylmethyl-3-phenyl propyl amine, N-(5-cyclohexylpentyl)benzylamine, 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.
63. A compound of the formula
wherein X1 is -(CH2)r-C≡C-(CH2)r-, wherein each r is 0-3 independently;
-(CH2)r-CH=CH-(CH2)r-;
-(CH2)r-Y-(CH2)r-, wherein Y is 0 or S; or
C1-C6 alkyl (wherein Z is hydrogen);
R2 is independently selected from the group consisting of hydrogen, chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkyl-amino, dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialklcarbamoyl, nitro and C2-C15 dialkylsulfamoyl;
V is N or CM, wherein M is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, fluoro, chloro, bromo, trifluoromethyl, hydroxy or one half of a double bond with the neighboring endocyclic carbon;
X is -(CH2)q-, wherein q is 1-6;
-(CH2)r-C≡C-(CH2)r-, wherein r is 0-3;
-(CH2)r-CH=CH-(CH2)r-; -(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y is O or S; or
C1-C6 alkyl (wherein Z is hydrogen); and
Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1- C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro and C2-C15 dialkylsulfamoyl.
64. A compound having the formula: wherein R5 and R6 are independently a C1-8 alkyl group;
R7 is hydrogen or a C1-8 alkyl group substituted by an arylacetoxy or arylcarboxy group; and
X is -(CH2)q-, wherein q is 1-6;
-(CH2)r-C≡C-(CH2)r-, wherein r is 0-3;
-(CH2)r-CH=CH-(CH2)r-;
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y is O or S; or
C1-C6 alkyl (wherein R7 is hydrogen);
wherein said compound exhibits a high binding activity with respect to the sigma receptors.
65. The compound claim 64 selected from the group consisting of N,N-dimethyl-n-hexylamine, N-methyl-N- propylhexyl amine,N,N'-diethyl-2-(diphenylacetoxy)ethylamine, and N,N'-diethyl-2-(9-fluorenecarboxy)ethylamine.
66. A compound selected from the group consisting of N-phenyl-N'-(3-(l-phthalimido)propyl)piperazine, N-(4-(1-phthalimido)butyl)-N'-(o-methoxylphenyl)piperazine, andN-phenyl-N'-(4-(1-phthalimido)butyl)piperazine.
67. A pharmaceutical composition comprising a 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.
AU22945/92A 1991-06-27 1992-06-26 Sigma receptor ligands and the use thereof Ceased AU676993B2 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US72017391A 1991-06-27 1991-06-27
US720173 1991-06-27
US894771 1992-06-10
US07/894,771 US6057371A (en) 1989-12-28 1992-06-10 Sigma receptor ligands and the use thereof
PCT/US1992/005330 WO1993000313A2 (en) 1991-06-27 1992-06-26 Sigma receptor ligands and the use thereof

Publications (2)

Publication Number Publication Date
AU2294592A true AU2294592A (en) 1993-01-25
AU676993B2 AU676993B2 (en) 1997-04-10

Family

ID=27110210

Family Applications (1)

Application Number Title Priority Date Filing Date
AU22945/92A Ceased AU676993B2 (en) 1991-06-27 1992-06-26 Sigma receptor ligands and the use thereof

Country Status (7)

Country Link
EP (1) EP0591426A4 (en)
JP (1) JPH06509069A (en)
AU (1) AU676993B2 (en)
CA (1) CA2111957A1 (en)
IE (1) IE922112A1 (en)
PT (1) PT100639A (en)
WO (1) WO1993000313A2 (en)

Families Citing this family (76)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2060547B1 (en) * 1992-06-04 1995-06-16 Ferrer Int IMPROVEMENTS IN THE PURPOSE OF THE INVENTION PATENT N / 9201158 THAT REFERS TO "PROCEDURE FOR OBTAINING NEW DERIVATIVES OF 4-BENCILPIPERIDINE".
AU5833494A (en) * 1992-12-22 1994-07-19 Smithkline Beecham Plc Piperidine derivatives as calcium channel antagonists
WO1995000131A1 (en) * 1993-06-23 1995-01-05 Cambridge Neuroscience, Incorporated Sigma receptor ligands and the use thereof
AU667280B2 (en) * 1993-08-30 1996-03-14 Otsuka Pharmaceutical Co., Ltd. Benzylamine derivatives
GB9416571D0 (en) * 1994-08-16 1994-10-12 Battelle Memorial Institute Novel alkylamino derivatives as sigma 2 selective ligands
GB9510459D0 (en) 1995-05-24 1995-07-19 Zeneca Ltd Bicyclic amines
ZA9610741B (en) 1995-12-22 1997-06-24 Warner Lambert Co 4-Substituted piperidine analogs and their use as subtype selective nmda receptor antagonists
ZA9610736B (en) 1995-12-22 1997-06-27 Warner Lambert Co 2-Substituted piperidine analogs and their use as subtypeselective nmda receptor antagonists
ZA9610738B (en) 1995-12-22 1997-06-24 Warner Lambert Co Subtype selective nmda receptor ligands and the use thereof
ZA9610745B (en) * 1995-12-22 1997-06-24 Warner Lambert Co 4-Subsituted piperidine analogs and their use as subtype selective nmda receptor antagonists
WO1997030038A1 (en) * 1996-02-15 1997-08-21 Mitsubishi Chemical Corporation Diarylsultam derivatives
EP0901490B1 (en) * 1996-05-13 2004-04-07 Syngenta Limited Bicyclic amines as insecticides
HUP9601331A3 (en) * 1996-05-17 2000-06-28 Egyt Gyogyszervegyeszeti Gyar Piperazine- and homopiperazine-derivatives, process for producing them and pharmaceutical compositions containing them
GB9623944D0 (en) * 1996-11-15 1997-01-08 Zeneca Ltd Bicyclic amine derivatives
GB9624114D0 (en) * 1996-11-20 1997-01-08 Zeneca Ltd Pesticidal bicyclic amine derivatives
EA199900502A1 (en) 1996-11-26 2000-02-28 Зенека Лимитед 8-AZABICILO [3.2.1] OKTAN-, 8-AZABICYCLO [3.2.1] OKT-6-EN-, 9-AZABICYCLO [3.3.1] NONAN-, 9-AZA-3-OXABICYCLO [3.3.1] NONAN - AND 9-AZA-3-TIABICYCLO [3.3.1] NONANE DERIVATIVES, THEIR PRODUCTION AND THEIR APPLICATION AS INSECTICIDES
GB9624611D0 (en) 1996-11-26 1997-01-15 Zeneca Ltd Bicyclic amine compounds
WO1998037068A1 (en) 1997-02-21 1998-08-27 Bristol-Myers Squibb Company Benzoic acid derivatives and related compounds as antiarrhythmic agents
IL134363A0 (en) * 1997-10-24 2001-04-30 Warner Lambert Co Method for treating disease-related or drug-induced dyskinesias
US5919802A (en) * 1997-12-05 1999-07-06 Princeton University Methods of preventing and/or treating temporal lobe epilepsy
US6528529B1 (en) 1998-03-31 2003-03-04 Acadia Pharmaceuticals Inc. Compounds with activity on muscarinic receptors
CO5150201A1 (en) * 1998-09-07 2002-04-29 Hoffmann La Roche PIPERIDINE DERIVATIVES
EP1130018B1 (en) 1998-11-09 2007-01-17 Santen Pharmaceutical Co., Ltd. Drug dependence remedy
FR2794742B1 (en) * 1999-06-11 2005-06-03 Sanofi Synthelabo NOVEL BENZENE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
FR2795724B1 (en) * 1999-07-02 2002-12-13 Sanofi Synthelabo NOVEL BENZENE DERIVATIVES, A PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
US6875759B1 (en) 1999-07-21 2005-04-05 Kadmus Pharmaceuticals Substituted guanidines and the use thereof
EP1078630A1 (en) * 1999-08-27 2001-02-28 Warner-Lambert Company Use of sigma receptor agonists for the treatment of depression
USRE46117E1 (en) 1999-12-22 2016-08-23 Teva Pharmaceuticals International Gmbh Modulators of dopamine neurotransmission
SE9904723D0 (en) 1999-12-22 1999-12-22 Carlsson A Research Ab New modulators of dopamine neurotransmission II
SE9904724D0 (en) * 1999-12-22 1999-12-22 Carlsson A Research Ab New modulators of dopamine neurotransmission I
US7067539B2 (en) 2001-02-08 2006-06-27 Schering Corporation Cannabinoid receptor ligands
US7507767B2 (en) 2001-02-08 2009-03-24 Schering Corporation Cannabinoid receptor ligands
DE10334188B4 (en) 2003-07-26 2007-07-05 Schwarz Pharma Ag Use of rotigotine to treat depression
DE10361258A1 (en) 2003-12-24 2005-07-28 Schwarz Pharma Ag Use of substituted 2-aminotetralins for the preventive treatment of Parkinson's disease
DE102004014841B4 (en) 2004-03-24 2006-07-06 Schwarz Pharma Ag Use of rotigotine for the treatment and prevention of Parkinson-Plus syndrome
DE602005021641D1 (en) 2004-06-08 2010-07-15 Nsab, Filial Af Neurosearch Sweden Ab NEW DISUBSTITUTED PHENYLPIPERIDINES AND PIPERAZINES AS MODULATORS OF DOPAMINE NEUROTRANSMISSION
SE0401465D0 (en) 2004-06-08 2004-06-08 Carlsson A Research Ab New substituted piperdines as modulators of dopamine neurotransmission
US7851629B2 (en) 2004-06-08 2010-12-14 Nsab, Filial Af Neurosearch Sweden Ab, Sverige Disubstituted phenylpiperidines as modulators of dopamine and serotonin neurotransmission
NZ552409A (en) 2004-06-08 2010-04-30 Nsab Af Neurosearch Sweden Ab New disubstituted phenylpiperidines as modulators of dopamine and serotonin neurotransmission
US7951805B2 (en) 2004-09-20 2011-05-31 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as mediators of stearoyl-CoA desaturase
AR051202A1 (en) 2004-09-20 2006-12-27 Xenon Pharmaceuticals Inc HETEROCICLIC DERIVATIVES AND THEIR USE AS INHIBITORS OF ESTEAROIL-COA DESATURASA
CN101083994A (en) 2004-09-20 2007-12-05 泽农医药公司 Heterocyclic derivatives and their use as therapeutic agents
WO2006034315A2 (en) 2004-09-20 2006-03-30 Xenon Pharmaceuticals Inc. Heterocyclic derivatives for the treatment of diseases mediated by stearoyl-coa desaturase enzymes
CA2580845A1 (en) 2004-09-20 2006-03-30 Xenon Pharmaceuticals Inc. Pyridazine derivatives for inhibiting human stearoyl-coa-desaturase
MX2007003321A (en) 2004-09-20 2007-06-05 Xenon Pharmaceuticals Inc Heterocyclic derivatives and their use as therapeutic agents.
AU2005329423A1 (en) 2004-09-20 2006-09-28 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
WO2006040155A1 (en) 2004-10-13 2006-04-20 Neurosearch Sweden Ab Process for the synthesis of 4-(3-methanesulfonylphenyl)-1-n-propyl-piperidine
FR2882257B1 (en) * 2005-02-24 2007-04-20 Oreal CAPILLARY USE OF CYCLIC AMINE DERIVATIVES
BRPI0611187A2 (en) 2005-06-03 2010-08-24 Xenon Pharmaceuticals Inc amino thiazide derivatives as inhibitors of human stearoyl coa desaturase
SE529246C2 (en) 2005-10-13 2007-06-12 Neurosearch Sweden Ab New disubstituted phenyl-piperidines as modulators of dopamine neurotransmission
AU2006304787A1 (en) 2005-10-21 2007-04-26 Braincells, Inc. Modulation of neurogenesis by PDE inhibition
US20070112017A1 (en) 2005-10-31 2007-05-17 Braincells, Inc. Gaba receptor mediated modulation of neurogenesis
US20100216734A1 (en) 2006-03-08 2010-08-26 Braincells, Inc. Modulation of neurogenesis by nootropic agents
EP2021000A2 (en) 2006-05-09 2009-02-11 Braincells, Inc. Neurogenesis by modulating angiotensin
US20100184806A1 (en) 2006-09-19 2010-07-22 Braincells, Inc. Modulation of neurogenesis by ppar agents
PT2146961E (en) 2007-04-12 2014-04-30 Ivax Int Gmbh N-oxide and/or di-n-oxide derivatives of dopamine receptor stabilizers/modulators displaying improved cardiovascular side-effects profiles
US8592477B2 (en) 2007-11-28 2013-11-26 Ucb Pharma Gmbh Polymorphic form of rotigotine and process for production
DE102008035596A1 (en) * 2008-07-31 2010-02-04 Westfälische Wilhelms-Universität Münster Körperschaft des öffentlichen Rechts Derivatives of benzoannated nitrogen heterocycles
WO2010059711A1 (en) * 2008-11-18 2010-05-27 Wisconsin Alumni Research Foundation Sigma-1 receptor ligands and methods of use
WO2010099217A1 (en) 2009-02-25 2010-09-02 Braincells, Inc. Modulation of neurogenesis using d-cycloserine combinations
JP6173693B2 (en) * 2010-02-24 2017-08-02 リサーチ・トライアングル・インスティチュート Aryl piperazine opioid receptor antagonist
HUE029239T2 (en) 2011-11-08 2017-02-28 Actelion Pharmaceuticals Ltd 2- (1,2,3-triazol-2-yl) benzamide and 3-(1,2,3-triazol-2-yl) picolinamide derivatives as orexin receptor antagonists
US9012476B2 (en) 2011-12-08 2015-04-21 IVAX International GmbH Hydrobromide salt of pridopidine
CA2869145A1 (en) 2012-04-04 2013-10-10 IVAX International GmbH Pharmaceutical compositions for combination therapy
CN105073728A (en) 2013-03-15 2015-11-18 全球血液疗法股份有限公司 Compounds and uses thereof for the modulation of hemoglobin
EA201992707A1 (en) 2013-11-18 2020-06-30 Глобал Блад Терапьютикс, Инк. COMPOUNDS AND THEIR APPLICATIONS FOR HEMOGLOBIN MODULATION
WO2016067043A1 (en) 2014-10-31 2016-05-06 Indivior Uk Limited Dopamine d3 receptor antagonists compounds
MX2018005342A (en) 2015-11-02 2018-08-15 Janseen Pharmaceutica Nv [1,2,4]TRIAZOLO[1,5-a]PYRIMIDIN-7-YL COMPOUND.
US10668030B2 (en) 2016-04-21 2020-06-02 University Of Kentucky Research Foundation Vesicular monoamine transporter-2 ligands and their use in the treatment of psychostimulant abuse
JP7018944B2 (en) 2016-11-02 2022-02-14 ヤンセン ファーマシューティカ エヌ．ベー． [1,2,4] triazolo [1,5-a] pyrimidine compound as a PDE2 inhibitor
CA3041412A1 (en) 2016-11-02 2018-05-11 Janssen Pharmaceutica Nv [1,2,4]triazolo[1,5-a]pyrimidine derivatives as pde2 inhibitors
EP3535269B1 (en) 2016-11-02 2020-12-09 Janssen Pharmaceutica NV [1,2,4]triazolo[1,5-a]pyrimidine compounds as pde2 inhibitors
MX2020004283A (en) 2017-10-27 2021-10-21 Boehringer Ingelheim Int Pyridine carbonyl derivatives and therapeutic uses thereof as trpc6 inhibitors.
TWI767148B (en) 2018-10-10 2022-06-11 美商弗瑪治療公司 Inhibiting fatty acid synthase (fasn)
IL293592A (en) 2019-12-06 2022-08-01 Vertex Pharma Substituted tetrahydrofurans as modulators of sodium channels
EP4347031A1 (en) 2021-06-04 2024-04-10 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE8004002L (en) * 1980-05-29 1981-11-30 Arvidsson Folke Lars Erik THERAPEUTICALLY APPLICABLE TETRALIN DERIVATIVES
IL65501A (en) * 1981-05-08 1986-04-29 Astra Laekemedel Ab 1-alkyl-2-aminotetralin derivatives,process for their preparation and pharmaceutical compositions containing them
DE3719924A1 (en) * 1986-12-22 1988-06-30 Bayer Ag 8-SUBSTITUTED 2-AMINOTETRALINE
US4943428A (en) * 1987-07-10 1990-07-24 Wright State University Stimulation of serotonin-1A receptors in mammals to alleviate motion sickness and emesis induced by chemical agents
EP0476016B1 (en) * 1989-05-31 1998-10-28 PHARMACIA & UPJOHN COMPANY CNS active 8-heterocyclyl-2-aminotetralin derivatives
EP0507863A4 (en) * 1989-12-28 1993-07-07 Virginia Commonwealth University Sigma receptor ligands and the use thereof

Also Published As

Publication number Publication date
WO1993000313A3 (en) 1993-03-04
PT100639A (en) 1993-09-30
IE922112A1 (en) 1992-12-30
WO1993000313A2 (en) 1993-01-07
EP0591426A4 (en) 1996-08-21
CA2111957A1 (en) 1993-01-07
EP0591426A1 (en) 1994-04-13
JPH06509069A (en) 1994-10-13
AU676993B2 (en) 1997-04-10

Similar Documents

Publication Publication Date Title
AU676993B2 (en) Sigma receptor ligands and the use thereof
US6057371A (en) Sigma receptor ligands and the use thereof
US6087346A (en) Sigma receptor ligands and the use thereof
EP1874746B1 (en) Derivatives of 1-n-azacycloalkyl-3-phenoxypropane useful for the preparation of psychotropic medicaments
US6469010B1 (en) Medicament for the alleviation or treatment of symptom derived from the ischemic disease and compound useful thereof
JP3205343B2 (en) Diaryldiamine derivatives and their use as delta opioid (ant) -agonists
US20100016600A1 (en) N- and O-Substituted 4-[2-(Diphenylmethoxy)-Ethyl]-1-[(Phenyl)Methyl]Piperdine Analogs and Methods of Treating CNS Disorders Therewith
NZ198953A (en) (-)-n-methyl-3-(2-methylphenoxy)-3-phenylpropylamine,its salts and pharmaceutical formulations
IL106124A (en) N (hetero)-aryl-n (hetero)- tetralin-alkyl-piperazines having serotoninergic, dopaminergic and adrenergic activity
JP2620422B2 (en) Hexahydroazepine derivatives, their production methods and pharmaceutical compositions containing them
Heinzelman Physiologically active secondary amines. β-(o-Methoxyphenyl)-isopropyl-N-methylamine and related compounds
CA2631096A1 (en) Piperidine and piperazine derivatives
US7501453B2 (en) Cyclopropanes with central nervous system activity
CA2308151A1 (en) Biphenyl derivatives as pharmaceuticals
IE55261B1 (en) Enantiomers of substituted phenylpiperidines
JPS624250A (en) Benz-trisubstituted-2-aminotetraline
US7342133B2 (en) Substituted amino compounds as 5-HT/NA uptake inhibitors
WO2001025202A1 (en) Process for the preparation of paroxetine intermediate
CS268486B1 (en) Method of 2-(phenylthio) benzylamines and their hydrogen maleates preparation