Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-04-03
2001-01-09
Richter, Johann (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C562S433000, C562S435000, C562S441000, C562S442000, C562S444000, C562S451000, C562S456000, C562S458000, C514S226200, C514S229800, C514S297000, C514S437000, C514S454000, C514S561000, C514S567000, C540S479000, C540S587000, C544S058100, C544S058200, C544S102000, C546S104000, C549S026000, C549S027000, C549S388000
Reexamination Certificate
active
06172058
ABSTRACT:
This invention relates to novel chemical compounds and their use as pharmaceuticals.
It is well known that excitatory neurotransmission in the mammalian central nervous system is primarily mediated by the amino acid, L-glutamate, acting on ionotropic and metabotropic receptors.
Certain cyclopropyl glycine derivatives are described as having useful properties in modulating the activity of such receptors as, for example, in U.S. Pat. No. 4,959,493 (Suntory Ltd) WO 96/07405 (Eli Lilly & Company) and WO 95/15940 (University of Bristol).
The present invention provides a compound of the formula:
in which R
1
is C
1-10
alkyl, C
2-10
alkenyl, C
2-10
alkynyl, C
3-10
cycloalkyl, C
3-10
cycloalkyl-C
1-10
alkyl, C
3-10
cycloalkyl-C
2-10
alkenyl, C
3-10
cycloalky-C
2-10
alkynyl, optionally substituted phenyl-C
1-10
alkyl, optionally substituted phenyl-C
2-10
alkenyl, optionally substituted phenyl-C
2-10
alkynyl, optionally substituted naphthyl, optionally substituted naphthyl-C
1-10
alkyl, C
1-10
alkoxy-C
1-10
alkyl, C
3-10
cycloalkoxy-C
1-10
alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl-C
1-10
alkyl, optionally substituted phenyl fused to C
5-10
cycloalkyl, optionally substituted tricyclic, optionally substituted tricyclic-C
1-10
alkyl, or [optionally substituted phenyl(CH
2
)
n
]
2
-C
1-10
alkyl, where n is 0 or 1 to 4, and
R
2
is hydrogen or one of the values for R
1
; or a salt or ester thereof.
The compounds of the invention have been found to be active in tests indicative of their use in the treatment of diseases of the central nervous system such as neurological diseases, for example neurodegenerative diseases, and as antipsychotic, anticonvulsant, analgesic and anti-emetic agents.
It will be appreciated that the compounds of formula (I) contain at least four asymmetric carbon atoms, three being in the cyclopropane ring and one being at the &agr;-carbon of the amino acid group. Accordingly, the compounds of the invention may exist in and be isolated in the form of diastereomeric pairs and individual enantiomers.
In the above general formula, a C
1-10
alkyl group can be straight or branched chain, such as, for example, methyl, ethyl, propyl, isopropyl, butyl and isobutyl, and is referably methyl or ethyl. A C
2-10
alkenyl group includes, or example, vinyl, prop-2-enyl, but-3-enyl, pent-4-enyl and isopropenyl, and an alkenyl group can contain more than one double bond and, in addition, one or more triple bonds. A preferred alkenyl group is of the formula R′—CH=CH— where R′ is C
1-4
alkyl. A C
2-10
alkynyl group includes, for example, prop-2-ynyl, but-3-ynyl, pent-4-ynyl and oct-7-ynyl, and is preferably of the formula R′C═C- where R′ is C
1-4
alkyl. A C
3-10
cycloalkyl group is preferably, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and these groups may optionally be substituted by one or two C
1-4
alkyl, for example methyl, substituents, or can be a bicyclo-system as, for example, bicyclooctane or adamantyl. Furthermore, the cycloalkyl group may be fused with phenyl or heterocyclyl.
In the above general formula, an optionally substituted phenyl or optionally substituted naphthyl is optionally substituted with, for example, one or more substituents, preferably 1 to 3 substituents, selected from C
1-4
alkyl, especially methyl, C
1-4
alkoxy, especially methoxy and ethoxy, carboxy, hydroxy, cyano, halo, especially bromo, chloro and fluoro, trifluoromethyl, nitro, amino, C
1-4
acylamino, C
1-4
alkylthio, optionally substituted phenyl and phenoxy. An optionally substituted phenyl-C
1-10
alkyl group is one such group linked through an alkylene chain, for example, phenyl-(CH
2
)n where n is 1 to 10, and a most preferred example is benzyl. An optionally substituted phenyl-C
2-10
alkenyl is one such phenyl group linked through an alkenylene chain derived from an alkenyl group as defined above, and preferably of the formula phenyl-(CH
2
)
n
CH═CH—where n is 1 to 4. An optionally substituted phenyl-C
2-10
alkynyl group is an optionally substituted phenyl group linked through an alkynylene chain derived from an alkynyl group as defined above, and preferably of the formula phenyl-(CH
2
)
n
C═C— where n is 1 to 4.
A heterocyclic group is a cyclic group of one or more rings containing one or more hetero atoms, and can be aromatic or non-aromatic. A substituted heterocyclyl group can be substituted with one or more substituents, preferably 1 to 3 substituents, as defined for substituted phenyl. An aromatic heterocyclic group includes a 5 to 7 membered ring containing one to four heteroatoms selected from oxygen, sulfur and nitrogen, and can be fused with a benzene ring or a 5 to 6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen. Examples are thienyl, furyl, oxazolyl, isoxazolyl, thiazoyl, isothiazolyl, imidazolyl, benzofuryl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzothiazolyl and indolyl.
A non-aromatic heterocyclic group includes a 4 to 7 membered ring containing one or two heteroatoms selected from oxygen, sulphur and nitrogen, for example, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholinyl, or thiomorpholinyl.
An optionally substituted tricyclic group comprising three fused rings which can optionally be substituted with one or more substituents, for example, 1 to 3 substituents as defined for substituted phenyl. The fused rings can be aromatic or non-aromatic and can contain, for example, one or two heteroatoms selected from oxygen, sulphur and nitrogen. A preferred tricyclic group is of the formula
where Z is
or
and Y is —O—, —S—, —SO—, —SO
2
—, —CH═CH—,—(CH
2
)
p
— where p is 1, 2 or 3. A particularly preferred example is 9-xanthyl. An optionally substituted tricyclic-C
1-10
alkyl group is one such group attached to a C
1-10
alkyl, and a particularly preferred example is 9-xanthylmethyl.
Preferred examples of R
1
and R
2
are C
1-10
alkyl, C
3-10
cycloalkyl-C
1-10
alkyl, optionally substituted phenyl-C
1-10
alkyl, C
1-10
alkoxy-C
1-10
alkyl, optionally substituted heterocyclyl-C
1-10
alkyl, optionally substituted phenyl fused to C
5-10
cycloalkyl and [optionally substituted phenyl(CH
2
)
n
]
2
-C
1-10
alkyl.
Especially preferred examples are C
1-10
alkyl, C
3-10
cycloalkyl-C
1-4
alkyl, phenyl-C
1-4
alkyl, diphenyl C
1-4
alkyl, C
1-4
alkoxy-C
1-4
alkyl, and 9-xanthyl-C
1-4
alkyl, and particularly preferred instances of R
1
and R
2
are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, butoxyethyl, benzyl, phenethyl, diphenylmethyl, diphenylethyl and 9-xanthylmethyl.
A further preferred group of compounds is one of formula (I) in which R
1
is C
1-6
alkyl and R
2
is 9-xanthylmethyl.
A particularly preferred group is where R2 is H or xanthylmethyl. As mentioned above, the compounds of formula (I) can exist in enantiomeric forms and there are at least four chiral centres in the molecule. Substituents at the 1 and 2 position can be in both cis and trans relationship, the trans form being preferred. Thus, a preferred group of compounds has the following structure:
Furthermore, the amino acid moiety preferably has the natural amino configuration.
The present invention includes pharmaceutically acceptable salts of the formula (I) compounds. These salts can exist in conjunction with the acidic or basic portion of the molecule and can exist as acid addition, primary, secondary, tertiary, or quaternary ammonium, alkali metal, or alkaline earth metal salts. Generally, the acid addition salts are prepared by the reaction of an acid with a compound of formula (I). The alkali metal and alkaline earth metal salts are generally prepared by the reaction of the hydroxide form of the desired metal salt with a compound of formula (I).
It is, of course, possible to prepare salts of the compounds of the invention and such salts are included in the invention. Acid
Cano Ivan Collado
Ruiz Angel Maz{acute over (o)}n
Tercero Concepci{acute over (o)}n Pedregal
Anderson Arvie J.
Davis Brian J.
Harvey Suzanne M.
Hay Martin A.
Lilly, SA
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