3-heteroarylalkyl substituted gaba analogs

Details 3-heteroarylalkyl substituted gaba analogs 3-heteroarylalkyl substituted gaba analogs

2001-11-21

2004-03-23

McKane, Joseph K. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06710190

ABSTRACT:

COMPOUNDS OF FORMULA
 
wherein R
1
is hydrogen or a lower alkyl radical and n is 4, 5, or 6 are known in U.S. Pat. No. 4,024,175 and its divisional U.S. Pat. No. 4,087,544. The uses disclosed are: protective effect against cramp induced by thiosemicarbazide; protective action against cardiazole cramp; the cerebral diseases, epilepsy, faintness attacks, hypokinesia, and cranial traumas; and improvement in cerebral functions. The compounds are useful in geriatric patients. The patents are hereby incorporated by reference.
SUMMARY OF THE INVENTION
The instant invention is a compound of Formula I and II
wherein A, X, Y, Z, W, and n are as described below.
The compounds of the invention and their pharmaceutically acceptable salts and the prodrugs of the compounds, are useful in the treatment of epilepsy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, neuropathological disorders, gastrointestinal disorders such as irritable bowel syndrome (IBS), and inflammation, especially arthritis.
The invention is also a pharmaceutical composition of a compound of Formula I or II.
The invention also includes novel intermediates useful in the preparation of the final products.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the invention are those of Formula I and II
or a pharmaceutically acceptable salt thereof wherein:
In Formula I, A is O, S, or NR wherein R is hydrogen, straight or branched alkyl of from 1 to 6 carbon atoms, cycloalkyl of from 3 to 8 carbon atoms, phenyl or benzyl;
In Formula II, A is N;
X, Y, Z and W are each independently hydrogen, straight or branched alkyl of from 1 to 6 carbon atoms;
cycloalkyl of from 3 to 8 carbon atoms, alkoxy, phenyl, benzyl, or halogen; and
n is an integer of from 1 to 4.
Preferred compounds are those of Formula I and II wherein Formula I and II are
Other preferred compounds are those of Formula I wherein A is oxygen.
Other preferred compounds are those of Formula I wherein A is sulfur.
Other preferred compounds are those of Formula I wherein A is NR.
When A is N, preferred compounds can also be those of Formula II.
More preferred compounds are selected from:
3-Aminomethyl-4-thiophen-2-yl-butyric acid;
3-Aminomethyl-4-thiophen-3-yl-butyric acid;
3-Aminomethyl-4-furan-2-yl-butyric acid;
3-Aminomethyl-4-furan-3-yl-butyric acid;
3-Aminomethyl-4-pyrrole-2-yl-butyric acid;
3-Aminomethyl-4-pyrrole-3-yl-butyric acid; and
3-Aminomethyl-4-pyrrole-1-yl-butyric acid;
The term lower alkyl is a straight or branched group of from 1 to 6 carbons including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, except as where otherwise stated.
The benzyl and phenyl groups may be unsubstituted or substituted by from 1 to 3 substituents selected from hydroxy, carboxy, carboalkoxy, halogen, CF
3
, nitro, alkyl, and alkoxy. Preferred are alkyl
Cycloalkyl is cyclic carbon group of from 3 to 8 atoms.
Alkoxy is a straight or branched group of from 1 to 4 carbons attached to the remainder of the molecule by an oxygen.
Halogen is chlorine, fluorine, bromine, or iodine.
The prodrugs of the compounds include, but are not limited to esters, amides, and carbamates.
Since amino acids are amphoteric, pharmacologically compatible salts of appropriate inorganic or organic acids, for example, hydrochloric, sulphuric, phosphoric, acetic, oxalic, lactic, citric, malic, salicylic, malonic, maleic, succinic, methanesulfonic acid, and ascorbic. Starting from corresponding hydroxides or carbonates, salts with alkali metals or alkaline earth metals, for example, sodium, potassium, magnesium, or calcium are formed. Salts with quaternary ammonium ions can also be prepared with, for example, the tetramethyl-ammonium ion. The carboxyl group of the amino acids can be esterfied by known means.
Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
Certain of the compounds of the present invention possess one or more chiral centers and each center may exist in the R(D) or S(L) configuration. The present invention includes all enantiomeric and epimeric forms as well as the appropriate mixtures thereof.
METHODS AND MATERIALS
Animals
Male Sprague-Dawley rats (180-250 g) were obtained from Bantin and Kingman, (Hull, U.K.). Animals were housed in groups of 6 to 10 under a 12 hour light/dark cycle (lights on at 7 hours, 0 minutes) with food and water ad libitum.
Carrageenan-induced Thermal Hyperalgesia in the Rat
Thermal hyperalgesia was assessed using the rat plantar test (Ugo Basile, Italy) following a modified method of Hargreaves, et al., 1988. Rats were habituated to the apparatus which consisted of three individual perspex boxes on an elevated glass table. A mobile radiant heat source located under the table was focused onto the desired paw and paw withdrawal latencies (PWL) recorded. PWL were taken 3 times for both hind paws of each animal, the mean of which represented baselines for right and left hind paws. At least 5 minutes were allowed between each PWL for an animal. The apparatus was calibrated to give a PWL of approximately 10 seconds. There was an automatic cutoff point of 20 seconds to prevent tissue damage. After baseline PWLs were determined, animals received an intraplantar injection of carrageenan (100 &mgr;L of 20 mg/mL) into the right hind paw. PWLs were reassessed following the same protocol as above 2-hour post-carrageenan (this time point represented the start of peak hyperalgesia) to ascertain that hyperalgesia had developed. Test compounds were administered orally (in a volume of 1 mL/kg) at 2.5 hours after carrageenan. PWLs were reassessed at various times after drug administration.
A Model of Anticonvulsant Efficacy and Protocol for DBA2 Test: Prevention of Audiogenic Seizures in DBA/2 Mice
Methods
All procedures were carried out in compliance with the NIH Guide for the Care and Use of Laboratory Animals under a protocol approved by the Parke-Davis Animal Use Committee. Male DBA/2 mice, 3 to 4 weeks old, were obtained from Jackson Laboratories, Bar Harbour, Me. Immediately before anticonvulsant testing, mice were placed upon a wire mesh, 4 inches square suspended from a steel rod. The square was slowly inverted through 180 degrees and mice observed for 30 seconds. Any mouse falling from the wire mesh was scored as ataxic.
Mice were placed into an enclosed acrylic plastic chamber (21 cm height, approximately 30 cm diameter) with a high-frequency speaker (4 cm diameter) in the center of the top lid. An audio signal generator (Protek model B-180) was used to produce a continuous sinusoidal tone that was swept linearly in frequency between 8 kHz and 16 kHz once each 10 msec. The average sound pressure level (SPL) during stimulation was approximately 100 dB at the floor of the chamber. Mice were placed within the chamber and allowed to acclimatize for 1 minute. DBA/2 mice in the vehicle-treated group responded to the sound stimulus (applied until tonic extension occurred, or for a maximum of 60 seconds) with a characteristic seizure sequence consisting of wild running followed by clonic seizures, and later by tonic extension, and finally by respiratory arrest and death in 80% or more of the mice. In vehicle-treated mice, the entire sequence of seizures to respiratory arrest lasts approximately 15 to 20 seconds.
The incidence of all the seizure phases in the drug-treated and vehicle-treated mice was recorded, and the occurrence of tonic seizures were used for calculating anticonvulsant ED
50
values by probit analysis. Mice were used only once for testing at each dose point. Groups of DBA/2 mice (n=5-10 per dose) were tested for sound-induced seizure responses 2 hours (previously determined time of peak effect) after given drug orally. All drugs in the present study were dissolved in distilled water and gi

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