Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-06-15
2002-07-09
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S575000
Reexamination Certificate
active
06417183
ABSTRACT:
The present invention relates to chemical compounds, in particular 1,4-diazacycloheptanes, to processes for their preparation and to chemical intermediates useful in such processes. The present invention further relates to 1,4-diazacycloheptanes, to pharmaceutical compositions containing them and to their use in methods of therapeutic treatment of animals including man, in particular in the treatment of neurological disorders.
Neurological disorders, for which the present compounds are useful, include stroke, head trauma, transient cerebral ischemic attack, and chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, diabetic neuropathy, amyotrophic lateral sclerosis, multiple sclerosis, vascular dementia and AIDS-related dementia.
The compounds useful in the present invention are believed to act by binding with the [
3
H]-emopamil binding site. Emopamil has classically been thought of as a neuroprotective agent whose efficacy is most likely derived from actions at either voltage-sensitive calcium channels (VSCC) or 5-HT
2
receptors. An apparent paradox to this logic is that verapamil, although chemically and pharmacologically very similar to emopamil, is not neuroprotective. While the lack of neuroprotective efficacy by verapamil was initially explained by lack of CNS penetration, recent studies suggest other factors may be involved (Keith et al., Br. J. Pharmacol. 113: 379-384, 1994).
[
3
H]-Emopamil binding defines a unique high affinity site that is not related to VSCC, is found in the brain, but is most prevalent in the liver (Moebius et al., Mol. Pharmacol. 43: 139-148, 1993). Moebius et al. have termed this the “anti-ischemic” binding site on the basis of high affinity displacement by several chemically disparate neuroprotective agents. In liver, the [
3
H]-emopamil binding site is localized to the endoplasmic reticulum.
Neuroprotective compounds are known, for example emopamil and ifenprodil, that exhibit high affinity for the [
3
H]-emopamil binding site. However these are not selective inhibitors and exhibit activity either at neuronal VSCC, the polyamine site of the NMDA receptor (N-Methyl-D-aspartate) and/or the sigma-1 binding site. We have now found a class of compounds that show selective action at the [
3
H]-emopamil binding site that are neuroprotective in global and focal models of cerebral ischemia without acting directly at either VSCC or NMDA receptors, and consequently exhibit fewer associated side effects than are conventionally seen with either emopamil (hypotension) or ifenprodil (behavioural manifestations). Such compounds are especially useful in treating neurodegeneration resulting from ischemia, for example in Alzheimer's disease, vascular dementia, Parkinson's disease, Huntington's disease and AIDS-related dementia. In another aspect such compounds are especially useful in treating stroke as they provide neuronal protection by preventing neuronal death in the penumbra region surrounding the core infarct. Accordingly the present invention provides the use of a compound which binds selectively to the [
3
H]-emopamil binding site for treating neurodegeneration resulting from ischemia.
Accordingly the present invention provides a compound of the formula (I):
wherein:
R is hydrogen, C
1-10
alkyl, C
3-8
cycloalkyl, C
3-8
cycloalkylC
1-6
alkyl, phenylC
1-6
alkyl or phenyl;
R
1
is C
1-6
alkyl, C
2-6
alkenyl, C
1-6
alkoxy, halo, hydroxy, C
1-6
alkanoyl, haloC
1-6
alkyl, cyano or nitro;
m is 0, 1 or 2;
R
2
is C
1-6
alkyl;
n is 1, 1 or 2;
wherein any phenyl ring is optionally substituted; p
1
or a pharmaceutically acceptable salt or in vivo hydrolysable ester, amide or carbanate thereof
Any phenyl ring in R may be optionally substituted, for example by up to five substituents, preferably up to three substituents which may be the same or different. Typical substituents include: hydroxy; C
1-6
alkoxy for example methoxy; mercapto; C
1-6
alkylthio for example methylthio; amino; C
1-6
alkylamino for example methylamino; di-(C
1-6
alkyl)amino for example dimethylamino; carboxy; carbamoyl; C
1-6
alkylcarbamoyl for example methylcarbamoyl; di-C
1-6
alkylcarbamoyl for example dimethylcarbamoyl; C
1-6
alkylsulphonyl for example methylsulphonyl; arylsulphonyl for example phenylsulphonyl; C
1-6
alkylaminosulphonyl for example methylaminosulphonyl; di-(C
1-6
alkyl)aminosulphonyl for example dimethylamino-sulphonyl; nitro; cyano; cyano-C
1-6
alkyl for example cyanomethyl; hydroxyC
1-6
alkyl for example hydroxymethyl; amino-C
1-6
alkyl for example aminoethyl; C
1-6
alkanoyl-amino for example acetamido; C
1-6
alkoxycarbonylamino for example methoxycarbonylamino; C
1-6
alkanoyl for example acetyl; C
1-6
alkanoyloxy for example acetoxy; C
1-6
alkyl for example methyl, ethyl, isopropyl or tert-butyl; halo for example fluoro, chloro or bromo; trifluoromethyl or trifluoromethoxy. In another aspect a further typical substituent for any phenyl group is phenylC
1-6
alkoxy.
In one aspect the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable amide or carbamate thereof, wherein
R is hydrogen, C
1-6
alkyl, C
3-8
cycloalkyl, C
3-8
cycloalkylC
1-6
alkyl, phenylC
1-6
alkyl or phenyl;
R
1
is
C
1-6
alkyl, C
1-6
alkoxy, halo, hydroxy, haloC
1-6
alkyl, cyano or nitro; m is 0, 1 or 2; R
2
C
1-6
alkyl; and n is 0, 1 or 2; wherein any phenyl ring is optionally substituted.
Suitably R is hydrogen; C
1-10
alkyl for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl (n-pentyl or 3-methylbutyl) or 2-ethylheptyl; C
3-8
cycloalkyl for example cyclopropyl, cyclobutyl or cyclopentyl; C
3-8
cycloalkylC
1-6
alkyl for example cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl; phenylC
1-6
alkyl for example benzyl, 2-phenethyl or 3-phenylpropyl.
Favourably R is hydrogen or C
1-6
alkyl. In particular R is hydrogen or C
1-4
alkyl such as methyl, ethyl, isopropyl, n-propyl, n-butyl or isobutyl. In particular also R is C
5-6
alkyl for example 3-methylbutyl. Another particular value for R is phenylC
1-6
alkyl for example benzyl, 2-phenethyl or 3-phenylpropyl. In one aspect R is C
1-6
alkyl or phenylC
1-6
alkyl. Preferably R is methyl, 3-methylbutyl or 3-phenylpropyl. In one aspect R is C
1-6
alkyl or phenylC
1-6
alkyl.
Suitably R
1
is C
1-6
alkyl for example methyl, ethyl or propyl; C
2-6
alkenyl for example vinyl; C
1-6
alkoxy for example methoxy, ethoxy or propoxy; halo for example bromo, chloro or fluoro; hydroxy; C
1-6
alkanoyl for example formyl or acetyl; haloC
1-6
alkyl for example trifluoromethyl; cyano or nitro
In one aspect R
1
is C
1-6
alkyl, C
1-6
alkoxy, halo, hydroxy, haloC
1-6
alkyl, cyano or nitro.
Preferably R
1
is C
1-6
alkoxy for example methoxy or ethoxy or is halo for example bromo chloro or fluoro. In a particularly preferred aspect, m is one and R
1
is methoxy, for example at the 5-position or the 7-position of the 1,2,3,4-tetrahydronaphthalene ring system, most preferably at the 5-position. In another particularly preferred aspect, m is one and R
1
is bromo or fluoro, for example at the 6-position of the 1,2,3,4-tetrahydronaphthalene ring system.
In another preferred aspect m is zero.
Suitably R
2
is C
1-6
alkyl for example methyl or ethyl.
In a preferred aspect n is zero.
A particular class of preferred compounds is that of the formula (II):
wherein R
3
is hydrogen, or C
1-6
alkyl or pheny C
1-6
alkyl and R
4
is hydrogen or C
1-6
alkoxy. In one aspect R
3
is C
1-6
alkyl. In particular in the compounds of the formula (II), R
4
is hydrogen and R
3
is methyl, 3-methylbutyl or 3-phenylpropyl.
Particular compounds of the present invention include those of the Examples hereinafter; 4-(7-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine 1-methyl-4-(7-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine and 1-isopropyl-4-(5-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine
The compounds of the present invention possess a chiral centre at the 1-position
Keith Richard A
Simpson Thomas R
Warawa Edward J
Astrazenela UK Limited
Coleman Brenda
Mitchell Kenneth F.
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