Amino heterocycles useful as pharmaceutical agents

Details Amino heterocycles useful as pharmaceutical agents Amino heterocycles useful as pharmaceutical agents

2001-11-30

2002-08-20

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S381000, C548S132000, C548S254000

Reexamination Certificate

active

06436974

ABSTRACT:

SUMMARY OF THE INVENTION
The instant invention is a compound of Formula I
wherein R
1
, R
2
, and Het are as defined below.
Preferred compounds of the invention as those of Formula I wherein R
1
and R
2
are each independently hydrogen or a straight or branched alkyl of from 3 to 8 carbon atoms; and Het is
Other preferred compounds of the invention are those of Formula I wherein R
1
and R
2
are taken together with the carbon to which they are attached to form a carbocyclic ring of from 3 to 8 carbon atoms; and Het is
Still other preferred compounds of the invention are those of Formula I wherein R
1
and R
2
are each independently hydrogen or a straight or branched alkyl of from 3 to 8 carbon atoms; and Het is
Still other preferred compounds of the invention are those of Formula I wherein R
1
and R
2
are taken together with the carbon atom to which they are attached to form a carbocyclic ring of from 3 to 8 carbon atoms; and Het is
More preferred compounds are selected from:
trans 3-(4-Isobutyl-pyrrolidin-3-yl)-4H-[1,2,4]oxadiazol-5-one;
cis 3-(4-Isobutyl-pyrrolidin-3-yl)-4H-[1,2,4]oxadiazol-5-one;
trans 5-(4-Isobutyl-pyrrolidin-3-yl)-1H-tetrazole;
cis 5-(4-Isobutyl-pyrrolidin-3-yl)-1H-tetrazole;
3-(2-Aza-spiro[4.5]dec-4-yl)-4H-[1,2,4]oxadiazol-5-one; and
4-(1H-Tetrazol-5-yl)-2-aza-spiro[4.5]decane.
The instant invention is also pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds of Formula I and a pharmaceutically acceptable carrier.
The compounds of the invention are agents in the treatment of epilepsy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, neuropathological disorders, and sleep disorders.
DETAILED DESCRIPTION OF THE INVENTION
The instant invention is a novel series of amino heterocycles of Formula I
or a pharmaceutically acceptable salt thereof wherein:
R
1
and R
2
are each independently hydrogen or a straight or branched alkyl of from 3 to 8 carbon atoms; or
R
1
and R
2
are taken together to form a carbocyclic ring of from 3 to 8 carbon atoms;
Het is
Since amino acids are amphoteric, pharmacologically compatible salts can be 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 esterified 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.
The terms used to define the invention are as described below.
The term alkyl is a straight or branched group of from 3 to 8 carbon atoms including but not limited to propyl, n-propyl, isopropyl, butyl, 2-butyl, tert-butyl, pentyl, hexyl, and n-hexyl, heptyl, and octyl except as where otherwise stated.
The cycloalkyl groups are from 3 to 8 carbons and are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl unless otherwise stated.
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.
The radioligand binding assay using [
3
H]gabapentin and the &agr;
2
&dgr; subunit derived from porcine brain tissue was used (“The Novel Anti-convulsant Drug, Gabapentin, Binds to the &agr;
2
&dgr; Subunit of a Calcium Channel,” Gee N.S., et al.,
J. Biol. Chem
., 1996;271(10):5768-5776).
The compounds of the invention show good binding affinity to the &agr;
2
&dgr; subunit. Gabapentin (Neurontin®) is about 0.10 to 0.12 &mgr;M in this assay. Since the compounds of the instant invention also bind to the subunit, they are expected to exhibit pharmacologic properties comparable to gabapentin. For example, as agents for anxiety and pain.
Biological Activity
Binding to the &agr;
2
&dgr; subunit for the final products are expected to be in the range of >10 &mgr;M to 43 nM. In the carageenan induced hyperalgesia model, maximal possible effects observed ranged from inactivity to 83% of the maximal possible effect. When compared to the activity of a reference agent, in this case pregabalin, activities were observed in the Vogel conflict assay of 0% to 53% of the activity of the standard.
The compounds of the invention will treat disorders, for example, Alzheimer's disease, Huntington's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, epilepsy, and pain.
Pain refers to acute as well as chronic pain.
Acute pain is usually short-lived and is associated with hyperactivity of the sympathetic nervous system. Examples are postoperative pain and allodynia.
Chronic pain is usually defined as pain persisting from 3 to 6 months and includes somatogenic pains and psychogenic pains. Other pain is nociceptive.
Still other pain is caused by injury or infection of peripheral sensory nerves. It includes, but is not limited to pain from peripheral nerve trauma, herpes virus infection, diabetes mellitus, causalgia, plexus avulsion, neuroma, limb amputation, and vasculitis. Neuropathic pain is also caused by nerve damage from chronic alcoholism, human immunodeficiency virus infection, hypothyroidism, uremia, or vitamin deficiencies. Neuropathic pain includes, but is not limited to pain caused by nerve injury such as, for example, the pain diabetics suffer from.
Psychogenic pain is that which occurs without an organic origin such as low back pain, atypical facial pain, and chronic headache.
Other types of pain are: inflammatory pain, osteoarthritic pain, trigeminal neuralgia, cancer pain, diabetic neuropathy, restless leg syndrome, acute herpetic and postherpetic neuralgia, causalgia, brachial plexus avulsion, occipital neuralgia, gout, phantom limb, burn, and other forms of neuralgia, neuropathic and idiopathic pain syndrome.
Other incidents are head trauma, spinal cord trauma, or injury from general anoxia, hypoxia, hypoglycemia, and hypotension as well as similar injuries seen during procedures from embole, hyperfusion, and hypoxia.
The compounds of the instant invention will be useful in gastrointestinal disorders, for example, irritable bowel syndrome (IBS).
The instant invention would be useful in a range of incidents, for example, during cardiac bypass surgery, in incidents of intracranial hemorrhage, in perinatal asphyxia, in cardiac arrest, and status epilepticus.
A skilled physician will be able to determine the appropriate situation in which subjects are susceptible to or at risk of, for example, stroke as well as suffering from stroke for administration by methods of the present invention.
The compounds of the invention are also expected to be useful in the treatment of depression. Depression can be the result of organic disease, secondary to stress associated with personal loss, or idiopathic in origin. There is a strong tendency for familial occurrence of some forms of depression suggesting a mechanistic cause for at least some forms of depression. The diagnosis of depression is made primarily by quantification of alterations in patients'mood. These evaluations of mood are generally perf

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