Piperidine derivatives having anxiolytic effect

Details Piperidine derivatives having anxiolytic effect Piperidine derivatives having anxiolytic effect

1999-09-07

2001-03-27

Huang, Evelyn Mei (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S278000, C514S299000, C514S320000, C514S321000, C514S322000, C514S323000, C514S324000

Reexamination Certificate

active

06207677

ABSTRACT:

The present invention relates to a class of piperidine compounds having anxiolytic effect, and potently binding to the sigma receptors and therefore being useful in the treatment of psychic and neurologic disorders.
Various related compounds are known from the prior art.
So, U.S. Pat. Nos. 3,686,186 and 3,745,165 disclose spiro[phthalan-1,4′-piperidine] and spiro[isochroman-3,4′-piperidine] compounds optionally having a benzyl substituent at the piperidine N-atom. The phthalan compounds are said to be useful as antidepressants as indicated by their ability to reverse reserpine hypothermia, whereas the isochromane compounds are stated to be useful as hypotriglyceridemics.
German Offenlegungsschrift No. 2,458,176 and the corresponding U.S. Pat. No. 3,985,889 generically describe inter alia 1,3-dihydrospiro[isobenzofuran-1,4 -piperidine] or 1,3-dihydrospiro[isobenzofuran-1,3′-pyrrolidine] compounds substituted at the ring N-atom with lower alkyl, cycloalkyl or phenyl(C
2-4
)alkyl and optionally having an oxo group attached to the furan ring. The compounds are alleged to be useful as tranquilizers as demonstrated by their ability to display effects on behaviour and reflex depression and on muscle relaxation, and they are claimed also to be useful in the treatment of pain as demonstrated in the 2-phenyl-1,4-quinone induced writhing assay in mice. However, only pharmacological data for one such compound without an oxo substituent in the furan ring, i.e. the compound 1,3-dihydro-1′-methyl-spiro[isobenzofuran-1,4′-piperidine], are presented, and only four such compounds having a substituent different from methyl on the piperidine N-atom are specifically disclosed, i.e. 1′-cyclopropylmethyl-, 1′-[3-(4-fluoro-benzoyl)propyl]-, 1′-[4,4-bis(4-fluorophenyl)butyl]- and 1′-acetyl-1,3-dihydrospiro[iso-benzofuran-1,4′-piperidine]. No indication of effect on sigma-receptors is given.
Japanese patent publication JP Kokai 55 143,980 generically describes inter alia a very broad class of spiro[chromane-piperidine] compounds which are optionally substituted at the piperidine N-atom with an alkyl, cycloalkyl, allyl, aryl, aralkyl, or arylcycloalkyl group and optionally substituted in the chromane ring with an oxo group. However, with respect to such spirochromane compounds having no oxo substituent in the chromane ring only compounds having a methyl, phenyl or benzyl group at the piperidine N-atom are specifically disclosed. These compounds are claimed to possess antiallergic activity and no suggestion of activity in the central nervous system is given.
European patent publication No EP 0 414 289 A1 generically describes a class of 1,2,3,4-tetrahydro-spiro[naphthalene-1,4′-piperidine] and 1,4-dihydro-spiro[naphthalene-1,4′-piperidine] derivatives substituted at the piperidine N-atom with a “hydrocarbon” and aleged to have selective sigma receptor antagonistic activity. The term “hydrocarbon” as defined in said patent covers all possible straight chained, cyclic, heterocyclic etc. groups; however, only compounds having benzyl, phenethyl, cycloalkylmethyl, furyl- or thienylmethyl or lower alkyl or alkenyl as the “hydrocarbon”. substituent at the piperidine nitrogen atom being specifically disclosed. The compounds are stated to displace tritiated di-tolyl guanidine (DTG) from sigma sites with potencies better than 200 nM. As a particularly preferred compound is mentioned 1′-benzyl-1,2,3,4-tetrahydro-spiro[naphthalene-1,4′-piperidine]. European patent publication No EP 0 445 974 A2 generically describes the corresponding spiro[indane-1,4′-piperidine) and spiro[benzocycloheptene-5,4′-piperidine] derivatives. Again the compounds are only stated to displace tritiated ditolyl guanidine (DTG) from sigma sites with potencies better than 200 nM
EP Application No. EP-A2-0 431 943 relates to a further extremely broad class of spiropiperidine compounds substituted at the piperidine N-atom. Said compounds are alleged to be useful as antiarrhythmics and for impaired cardiac pump function.
Said application exemplifies several compounds, the majority of which contain an oxo and/or a sulfonylamino substituent in the spiro cyclic ring system. Of the remainder compounds, the main part has another polar substituent, such as nitro, amino, a fused imidazo group etc. attached to the spiro nucleus and/or they have some polar substituents, such as sulfonylamino, nitro, amino, etc. in the substituent on the piperidine N-atom. Furthermore some of the compounds have heteroaryl alkyl substituents on the piperidine N-atom, whereas only a very few of those compounds exemplified do not have such substituents, i.e. a couple of 6-methoxy-spiro[2H-1-benzopyran-2,4′-piperidines] having a phenylsubstituent on the piperidine N-atom and a few spiro[3H-1-benzopyran-3,4′-piperidine]'s having a benzyl, phenethyl, hexyl or heptyl substituent on the piperidine N-atom. No suggestion or indication of effect of the compounds on the sigma receptors is given.
U.S. Pat. No. 4,420,485 discloses 1′-[3-(6-fluoro-1,2-benzoisoxazol-3-yl)propyl]spiro[benzofuran-2(H),4′-piperidines3 optionally having one or two substituents in the benzofuran ring. The compounds are claimed to be useful as antihypertensives. No mention or suggestion of effects in the treatment of psychic or neurological disorders is given.
German Offenlegungsschrift No 28 27 874 corresponding to U.S. Pat. No. 4,251,538 generically discloses a class of 3-[4-(4-phenyl-piperidin-1-yl)-butyl]- or 3-(4-(4-phenyl-tetrahydropyridyl-1-yl)-butyl]indole derivatives optionally substituted in the indole, piperidinyl or tetrahydropyridyl and/or phenyl groups. The compounds are said to show dopamine agonist effects and serotonin reuptake inhibiting effects in the central nervous system, and accordingly to be useful in the treatment of Parkinson's disease and depression. However, no documentation for such effects is given in the specification, no pharmacological data at all being given, and certainly no indication or suggestion of effect on the sigma receptor is given.
Furthermore, the majority of the compounds listed in the specification, of which obviously only a few have actually been prepared, are tetrahydropyridyl compounds and/or they have an oxo substituent in the butyl chain. Only a few piperidyl compounds without an oxo substituent in the butyl chain are mentioned, i.e. 3-[4-(4-phenyl-1-piperidyl)-butyl]-indole and the 1-methyl-, 1-phenyl- and 2-methyl-derivatives thereof as well as derivatives thereof substituted with halogen, methyl or trifluoromethyl in the 4-phenyl substituent on the piperidyl group thereof. With respect to physical data only melting point for one such compounds is given.
International Patent Application No WO 91/09594 published on Jul. 11, 1991 relates i.a. to sigma receptor ligands being 4-phenyl-piperidine compounds and having an optionally substituted “heteroaryl”-alkyl, -alkenyl, -alkynyl, -alkoxy or -alkoxy-alkyl substituent on the piperidine N-atom. The term “heteroaryl”-alkyl is defined by mention of a very broad class of such substituents. However only four N-substituted 4-phenyl-piperidine compounds are specifically disclosed which are all 1-(phenyl-lower alkyl)-4-phenyl-piperidines and only four compounds having a “heteroaryl”-alkyl substituent are specifically mentioned, which are all piperazine (and not piperidine) compounds. The compounds are stated to be antipsychotics.
From studies of the biology and function of sigma receptors, evidence has been presented that sigma receptor ligands may be useful in the treatment of psychosis and movement disorders, such as dystonia and tardive dyskinesia, and motor disturbances associated with Huntington's chorea or Tourette's syndrome and in Parkinson's disease (Walker, J. M. et al.,
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