Method of synthesis of pyrrole amides

Details Method of synthesis of pyrrole amides Method of synthesis of pyrrole amides

1999-01-19

2001-07-17

Lambkin, Deborah C. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S492000, C549S467000

Reexamination Certificate

active

06262272

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates a method for synthesis of novel fused pyrrolecarboxamides which selectively bind to GABAa receptors. This invention also relates to chemical intermediates for synthesis of such compounds. Compounds which bind to GABAa receptors are useful in treating anxiety, sleep and seizure disorders, and overdoses of benzodiazepine-type drugs, and enhancing alertness.
2. Description of the Related Art
&ggr;-Aminobutric acid (GABA) is regarded as one of the major inhibitory amino acid transmitters in the mammalian brain. Over 30 years have elapsed since its presence in the brain was demonstrated (Roberts & Frankel, J. Biol. Chem 187: 55-63, 1950; Udenfriend, J. Biol. Chem. 187:65-69, 1950). Since that time, an enormous amount of effort has been devoted to implicating GABA in the etiology of seizure disorders, sleep, anxiety and cognition (Tallman and Gallager, Ann. Rev. Neuroscience 8: 21-44, 1985). Widely, although unequally, distributed through the mammalian brain, GABA is said to be a transmitter at approximately 30% of the synapses in the brain. In most regions of the brain, GABA is associated with local inhibitory neurons and only in two regions is GABA associated with longer projections. GABA mediates many of its actions through a complex of proteins localized both on cell bodies and nerve endings; these are called GABAa receptors. Postsynaptic responses to GABA are mediated through alterations in chloride conductance that generally, although not invariably, lead to hyperpolarization of the cell. Recent investigations have indicated that the complex of proteins associated with postsynaptic GABA responses is a major site of action for a number of structurally unrelated compounds capable of modifying postsynaptic responses to GABA. Depending on the mode of interaction, these compounds are capable of producing a spectrum of activities (either sedative, anxiolytic, and anticonvulsant, or wakefulness, seizures, and anxiety).
1,4-Benzodiazepines continue to be among the most widely used drugs in the world. Principal among the benzodiazepines marketed are chlordiazepoxide, diazepam, flurazepam, and triazolam. These compounds are widely used as anxiolytics, sedative-hypnotics, muscle relaxants, and anticonvulsants. A number of these compounds are extremely potent drugs; such pofency indicates a site of action with a high affinity and specificty for individual receptors. Early electrophysiological studies indicated that a major action of benzodiazepines was enhancement of GABAergic inhibition. The benzodiazepines were capable of enhancing presynaptic inhibition of a monosynaptic ventral root reflex, a GABA-mediated event (schmidt et al., 1967, Arch. Exp. Path. Pharmakol. 258: 69-82). All subsequent electrophysiological studies (reviewed in Tallman et al. 1980, Science 207: 274-81, Haefley et al., 1981, Handb. Exptl. Pharmacol. 33: 95-102) have generally confirmed this finding, and by the mid-1970s, there was a general consensus among electrophysiologists that the benzodiazepines could enhance the actions of GABA.
With the discovery of the “receptor” for the benzodiazepines and the subsequent definition of the nature of the interaction between GABA and the benzodiazepines, it appears that the behaviorally important interactions of the benzodiazepines with different neurotransmitter systems are due in a large part to the enhanced ability of GABA itself to modify these systems. Each modified system, in turn, may be associated with the expression of a behavior.
Studies on the mechanistic nature of these interactions depended on the demonstration of a high-affinity benzodiazepine binding site (receptor). Such a receptor is present in the CNS of all vertebrates phylogenetically newer than the boney fishes (Squires & Braestrup 1977, Nature 166: 732-34, Mohler & Okada, 1977, Science 198: 854-51, Mohler & Okada, 1977, Br. J. Psychiatry 133. 261-68). By using tritiated diazepam, and a variety of other compounds, it has been demonstrated that these benzodiazepine binding sites fulfill many of the criteria of pharmacological receptors; binding to these sites in in vitro is rapid, reversible, stereospecific, and saturable. More importantly, highly significant correlations have been shown between the ability of benzodiazepines to displace diazepam from its binding site and activity in a number of animal behavioral tests predictive of benzodiazepine potency (Braestrup & Squires 1978, Br. J. Psychiatry 133: 261-68). The average therapeutic doses of these drugs in man also correlate with receptor potency (Tallman et al. 1980, Science 207: 274-281.
Certain fused pyrrolecarboxamides which are useful as GABA brain receptor ligands are disclosed in U.S. Pat. No. 5,484,944 which is hereby incorporated by reference. These compounds may be prepared by the scheme shown below.
wherein z is N—R or a carbon atom substituted with R groups; and W is an optionally substituted aromatic ring.
SUMMARY OF THE INVENTION
This invention provides a method for preparing a compound of the formula
wherein R
1
and R
2
are independently selected from hydrogen and C
1
-C
6
alkyl; and Ar is phenyl or heterocycle; or phenyl or heterocycle substituted with up to three substituents selected from C
1
-C
6
alkoxy, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
1
-C
6
perflouroalkyl, C
1
-C
6
alkoxy, C
1
-C
6
perfluoroalkoxy, F, Cl, Br, —O—(CH
2
)
k
—O—, or (CH
2
)
m
NR
1
R
2
; wherein
n is an integer selected from 0 to 2;
m is an integer selected from 0 to 6; and
k is an integer selected from 1 or 2;
which comprises:
1) Reacting a compound of the formula
with an excess of an acid chloride or anhydride in a reaction inert solvent containing an excess of an acid acceptor until reaction is complete;
2) Adding an equivalent amount of NH
2
—Ar to the solution of step 1 and holding until reaction is complete.
This invention also provides a method for preparing a compound of the formula
which comprises:
reacting a compound of formula II with an excess of an ammonium source in a reaction inert solvent at an elevated temperature until reaction is complete.
This invention also provides a method for preparing a compound of formula III wherein Ar is 2-fluoromethoxy phenyl, (4methyl-N-t-butylcarbamic ester)-amino methyl phenyl, 4-ethoxy phenyl or 4-methoxyphenyl, 4fluorophenyl, 4-pyridyl or 3-pyridyl, b-(2-hydroxyethoxy)-3-pyridyl, benzo[1,3] dioxol-5-yl. This invention also provides a method for preparing a compound of formula I wherein n is 2 and R
1
and R
2
are hydrogen; n is 1 and R
1
and R
2
are methyl; n is one and R
1
and R
2
are hydrogen; n is zero and R
1
and R
2
are hydrogen; and n is 1, R
1
is methyl and R
2
is hydrogen.
In another aspect this invention provides the compound of formula 1 which is 4-Oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]furan-3-carboxylic acid, 4-Oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]furan-3-carboxylic acid (2-fluoro-4-methoxy-phenyl)-amide, 6,6-Dimethyl-4-oxo-4,5,6,7-tetrahydro-benofuran-3-carboxylic acid (2-fluoro-4-methoxyphenyl)-amide, 4-[(4-Oxo-4,5,6,7-tetrahydro-benzofuran-3-carbonyl)-amino]-benzylmethyl-carbamic acid tert-butyl ester,
4-[(4-Oxo-4,5,6,7-tetrahydro-1H-indole-3-carbonyl)-amino]-benzyl-methyl-carbamic acid tert-butyl ester,
4-Oxo-5,6-dihydro-4H-cyclopenta[b]furan-3-carboxylic acid (4-ethoxy-phenyl)-amide,
4-Oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]furan-3-carboxylic acid benzo[1,3]dioxol-5-ylamide,
4-Oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]furan-3-carboxyric acid-(4-methoxy-phenyl)-amide,
6-Methyl-4-oxo-4,5,6,7-tetrahydro-benzofuran-3-carboxylic acid (4-fluoro-phenyl)-amide,
6-Methyl-4-oxo-4,5,6,7-tetrahydro-benzofuran-3-carboxylic acid pyridin-4-ylamide,
6-Methyl-4-oxo-4,5,6,7-tetrahydro-benzofuran-3-carboxylic acid pyridin-3-ylamide,
6-Methyl-4-oxo-4,5,6,7-tetrahydro-berzofuran-3-carboxylic acid [6-(2-hydroxy-ethoxy)-pyridin-3-yl]-amide, and
4-Oxo-4,5,6,7-tetrahydro1H-indole-3carboxylic acid (4-methylaminomethyl-phenyl)-a

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