U.S. patent application number 11/687964 was filed with the patent office on 2007-07-12 for pharmaceutical uses for alpha2delta ligands.
This patent application is currently assigned to WARNER-LAMBERT COMPANY LLC. Invention is credited to David James Dooley, Charles Price Taylor, Jr., Andrew John Thorpe, Fong Wang, David Juergen Wustrow.
Application Number | 20070161706 11/687964 |
Document ID | / |
Family ID | 32595199 |
Filed Date | 2007-07-12 |
United States Patent
Application |
20070161706 |
Kind Code |
A1 |
Dooley; David James ; et
al. |
July 12, 2007 |
PHARMACEUTICAL USES FOR ALPHA2DELTA LIGANDS
Abstract
The invention relates to a method of treating central nervous
system disorders and other disorders by administering an
alpha2delta ligand such as, for example, a compound of the formula
##STR1## or a pharmaceutically acceptable salt thereof, wherein
R.sub.1 is hydrogen or straight or branched lower alkyl, and n is
an integer of from 4 to 6.
Inventors: |
Dooley; David James; (South
Lyon, MI) ; Taylor, Jr.; Charles Price; (Chelsea,
MI) ; Thorpe; Andrew John; (Whitmore Lake, MI)
; Wang; Fong; (Ann Arbor, MI) ; Wustrow; David
Juergen; (Ann Arbor, MI) |
Correspondence
Address: |
WARNER-LAMBERT COMPANY
2800 PLYMOUTH RD
ANN ARBOR
MI
48105
US
|
Assignee: |
WARNER-LAMBERT COMPANY LLC
2800 Plymouth Road
Ann Arbor
MI
48105
|
Family ID: |
32595199 |
Appl. No.: |
11/687964 |
Filed: |
March 19, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11675389 |
Feb 15, 2007 |
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11687964 |
Mar 19, 2007 |
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10731605 |
Dec 9, 2003 |
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11675389 |
Feb 15, 2007 |
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60433491 |
Dec 13, 2002 |
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Current U.S.
Class: |
514/561 |
Current CPC
Class: |
A61P 25/08 20180101;
A61K 31/16 20130101; A61K 31/18 20130101; A61K 31/4245 20130101;
A61K 31/20 20130101; A61K 31/433 20130101; A61P 15/08 20180101;
A61P 9/10 20180101; A61K 31/197 20130101; A61P 21/02 20180101; A61P
43/00 20180101; A61P 15/10 20180101; A61K 31/198 20130101; A61P
25/24 20180101; A61P 17/06 20180101; A61P 25/00 20180101; A61P 9/00
20180101; A61P 25/04 20180101; A61K 31/401 20130101; A61K 31/662
20130101; A61K 31/195 20130101; A61P 3/06 20180101; A61P 19/02
20180101; A61P 25/14 20180101; A61P 5/00 20180101; A61P 37/00
20180101; A61P 11/00 20180101; A61P 13/10 20180101; A61K 45/06
20130101; A61P 25/18 20180101; A61P 29/00 20180101; A61K 31/41
20130101; A61K 31/00 20130101; A61P 9/06 20180101; A61K 31/4015
20130101; A61P 25/20 20180101; A61P 25/28 20180101; A61P 11/14
20180101; A61K 31/185 20130101; A61P 17/00 20180101; A61P 13/00
20180101; A61P 15/00 20180101; A61P 1/00 20180101; A61P 31/18
20180101; A61P 35/00 20180101 |
Class at
Publication: |
514/561 |
International
Class: |
A61K 31/195 20060101
A61K031/195 |
Claims
1-19. (canceled)
20. A method of treating a disorder or condition selected from mood
disorders, such as depression, or more particularly, depressive
disorders, for example, major depressive disorder, severe unipolar
recurrent major depressive episodes, dysthymic disorder, depressive
neurosis and neurotic depression, melancholic depression including
anorexia, weight loss, insomnia, early morning waking or
psychomotor retardation, atypical depression (or reactive
depression) including increased appetite, hypersomnia, psychomotor
agitation or irritability; treatment resistant depression; seasonal
affective disorder and pediatric depression; premenstrual syndrome,
premenstrual dysphoric disorder, hot flashes, bipolar disorders or
manic depression, for example, bipolar I disorder, bipolar II
disorder and cyclothymic disorder; seasonal affective disorder,
conduct disorder and disruptive behavior disorder; stress related
somatic disorders and anxiety disorders, such as panic disorder
with or without agoraphobia, agoraphobia without history of panic
disorder, specific phobias (e.g., specific animal phobias), social
anxiety disorder, social phobia, obsessive-compulsive disorder,
stress disorders including post-traumatic stress disorder and acute
stress disorder, and generalized anxiety disorder in a mammal,
comprising administering to a mammal in need of such treatment a
therapeutically effective amount of an alpha2delta ligand or a
pharmaceutically acceptable salt thereof.
21. A method of treating a disorder or condition selected from the
group consisting of borderline personality disorder; schizophrenia
and other psychotic disorders, for example, schizophreniform
disorders, schizoaffective disorders, delusional disorders, brief
psychotic disorders, shared psychotic disorders, psychotic
disorders due to a general medical condition, psychotic disorders
with delusions or hallucinations, substance induced psychotic
disorder, psychotic episodes of anxiety, anxiety associated with
psychosis, psychotic mood disorders such as severe major depressive
disorder; mood disorders associated with psychotic disorders such
as acute mania and depression associated with bipolar disorder,
mood disorders associated with schizophrenia; and behavioral
disturbances associated with mental retardation in a mammal,
comprising administering to a mammal in need of such treatment a
therapeutically effective amount of an alpha2delta ligand or a
pharmaceutically acceptable salt thereof.
22. A method according to claim 20, wherein the alpha2delta ligand
is gabapentin.
23. A method according to claim 20, wherein the alpha2delta ligand
is pregabalin.
24. A method according to claim 20, wherein the alpha2delta ligand
is a compound of the formula X ##STR27## or a pharmaceutically
acceptable salt thereof, wherein R.sup.1 is hydrogen or
(C.sub.1-C.sub.3)alkyl optionally substituted with from one to five
fluorine atoms; R.sub.2 is hydrogen or (C.sub.1-C.sub.3)alkyl
optionally substituted with from one to five fluorine atoms;
R.sub.3 is (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl,
(C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.3)alkyl, phenyl,
phenyl-(C.sub.1-C.sub.3)alkyl, pyridyl,
pyridyl-(C.sub.1-C.sub.3)alkyl, phenyl-N(H)--, or pyridyl-N(H)--,
wherein each of the foregoing alkyl moieties can be optionally
substituted with from one to five fluorine atoms, preferably with
from zero to three fluorine atoms, and wherein said phenyl and said
pyridyl and the phenyl and pyridyl moieties of said
phenyl-(C.sub.1-C.sub.3)alkyl and said
pyridyl-(C.sub.1-C.sub.3)alkyl, respectively, can be optionally
substituted with from one to three substituents, preferably with
from zero to two substituents, independently selected from chloro,
fluoro, amino, nitro, cyano, (C.sub.1-C.sub.3)alkylamino,
(C.sub.1-C.sub.3)alkyl optionally substituted with from one to
three fluorine atoms and (C.sub.1-C.sub.3)alkoxy optionally
substituted with from one to three fluorine atoms; with the proviso
that when R.sub.1 is hydrogen, R.sub.2 is not hydrogen.
25. A method according to claim 21, wherein the alpha2delta ligand
is gabapentin.
26. A method according to claim 21, wherein the alpha2delta ligand
is pregabalin.
27. A method according to claim 21, wherein the alpha2delta ligand
is a compound of the formula X ##STR28## or a pharmaceutically
acceptable salt thereof, wherein R.sup.1 is hydrogen or
(C.sub.1-C.sub.3)alkyl optionally substituted with from one to five
fluorine atoms; R.sub.2 is hydrogen or (C.sub.1-C.sub.3)alkyl
optionally substituted with from one to five fluorine atoms;
R.sub.3 is (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl,
(C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.3)alkyl, phenyl,
phenyl-(C.sub.1-C.sub.3)alkyl, pyridyl,
pyridyl-(C.sub.1-C.sub.3)alkyl, phenyl-N(H)--, or pyridyl-N(H)--,
wherein each of the foregoing alkyl moieties can be optionally
substituted with from one to five fluorine atoms, preferably with
from zero to three fluorine atoms, and wherein said phenyl and said
pyridyl and the phenyl and pyridyl moieties of said
phenyl-(C.sub.1-C.sub.3)alkyl and said
pyridyl-(C.sub.1-C.sub.3)alkyl, respectively, can be optionally
substituted with from one to three substituents, preferably with
from zero to two substituents, independently selected from chloro,
fluoro, amino, nitro, cyano, (C.sub.1-C.sub.3)alkylamino,
(C.sub.1-C.sub.3)alkyl optionally substituted with from one to
three fluorine atoms and (C.sub.1-C.sub.3)alkoxy optionally
substituted with from one to three fluorine atoms; with the proviso
that when R.sup.1 is hydrogen, R.sub.2 is not hydrogen.
Description
[0001] This application claims priority from U.S. Provisional
Application 60/425,219 filed Nov. 8, 2002; the entire contents of
which are hereby incorporated herein by reference.
[0002] This invention relates to methods of treating various
central nervous system and other disorders by administering a
compound that exhibits activity as an alpha2delta ligand
(.alpha.2.delta. ligand). Such compounds have affinity for the
.alpha.2.delta. subunit of a calcium channel. Such compounds have
also been referred to in the literature as gamma-aminobutyric acid
(GABA) analogs.
BACKGROUND OF THE INVENTION
[0003] Several alpha2delta ligands are known. Gabapentin, a cyclic
alpha2delta ligand, is now commercially available (Neurontin.RTM.,
Warner-Lambert Company) and extensively used clinically for
treatment of epilepsy and neuropathic pain. Such cyclic alpha2delta
ligands are described in U.S. Pat. No. 4,024,175, which issued on
May 17, 1977, and U.S. Pat. No. 4,087,544, which issued on May 2,
1978. Other series of alpha2delta ligands are described in U.S.
Pat. No. 5,563,175, which issued on Oct. 8, 1996, U.S. Pat. No.
6,316,638, which issued on Nov. 13, 2001, US Provisional Patent
Application 60/353,632, which was filed on Jan. 31, 2002, European
Patent Application EP 1112253, which was published on Jul. 4, 2001,
PCT Patent Application WO 99/08671, which was published on Feb. 25,
1999, and PCT Patent Application WO 99/61424, which was published
on Dec. 2, 1999. These patents and applications are incorporated
herein by reference in their entireties.
SUMMARY OF THE INVENTION
[0004] This invention relates to a method of treating a disorder or
condition selected from faintness attacks, epilepsy, asphyxia,
general anoxia, hypoxia, spinal cord trauma, traumatic brain
injury, head trauma, cerebral ischemia, stroke (including
thromboembolic stroke, focal ischemia, global ischemia, transient
cerebral ischemia attacks and other cerebral vascular problems
accompanied by cerebral ischemia such as in patients undergoing
carotid endarterectomy or other vascular surgical procedures in
general or diagnostic vascular surgical procedures such as
angiography), cramp caused by thiosemicarbazide, cardiazole cramp,
and cerebral vascular disorders due to acute or chronic
cerebrovascular damage such as cerebral infarction, subarachnoid
haemorrhage or cerebral oedema in a mammal, comprising
administering to a mammal in need of such treatment a
therapeutically effective amount of an alpha2delta ligand or a
pharmaceutically acceptable salt thereof.
[0005] This invention also relates to a method of treating a
disorder or condition selected from the group consisting of
neurocardiac disorders such as neurocardiac syncope, neurogenic
syncope, hypersensitive Carotid sinus, neurovascular syndrome and
arrythmias including arrythmias secondary to gastrointestinal
disturbances in a mammal, comprising administering to a mammal in
need of such treatment a therapeutically effective amount of an
alpha2delta ligand or a pharmaceutically acceptable salt
thereof.
[0006] This invention also relates to a method of treating a
disorder or condition selected from acute pain, chronic pain, pain
resulting from soft tissue and peripheral damage such as acute
trauma; postherpetic neuralgia, occipital neuralgia, trigeminal
neuralgia, segmental or intercostal neuralgia and other neuralgias;
pain associated with osteoarthritis and rheumatoid arthritis;
musculo-skeletal pain such as pain associated with strains, sprains
and trauma such as broken bones; spinal pain, central nervous
system pain such as pain due to spinal cord or brain stem damage;
lower back pain, sciatica, dental pain, myofascial pain syndromes,
episiotomy pain, gout pain, and pain resulting from burns; deep and
visceral pain, such as heart pain; muscle pain, eye pain,
inflammatory pain, orofacial pain, for example, odontalgia;
abdominal pain, and gynecological pain, for example, dysmenorrhoea,
labour pain and pain associated with endometriosis; somatogenic
pain; pain associated with nerve and root damage, such as pain
associated with peripheral nerve disorders, for example, nerve
entrapment and brachial plexus avulsions; pain associated with limb
amputation, tic douloureux, neuroma, or vasculitis; diabetic
neurapathy, chemotherapy-induced-neuropathy, acute herpetic and
postherpetic neuralgia; atypical facial pain, neuropathic lower
back pain, and arachnoiditis, trigeminal neuralgia, occipital
neuralgia, segmental or intercostal neuralgia, HIV related
neuralgias and AIDS related neuralgias and other neuralgias;
allodynia, hyperalgesia, burn pain, idiopathic pain, pain caused by
chemotherapy; occipital neuralgia, psychogenic pain, brachial
plexus avulsion, pain associated with restless legs syndrome; pain
associated with gallstones; pain caused by chronic alcoholism or
hypothyroidism or uremia or vitamin deficiencies; neuropathic and
non-neuropathic pain associated with carcinoma, often referred to
as cancer pain, phantom limb pain, functional abdominal pain,
headache, including migraine with aura, migraine without aura and
other vascular headaches, acute or chronic tension headache, sinus
headache and cluster headache; temperomandibular pain and maxillary
sinus pain; pain resulting from ankylosing spondylitis; pain caused
by increased bladder contractions; post operative pain, scar pain,
and chronic non-neuropathic pain such as pain associated with HIV,
anthralgia, vasculitis and fibromyalgia in a mammal, comprising
administering to a mammal in need of such treatment a
therapeutically effective amount of an alpha2delta ligand or a
pharmaceutically acceptable salt thereof.
[0007] This invention also relates to a method of treating a
disorder or condition selected from mood disorders, such as
depression, or more particularly, depressive disorders, for
example, major depressive disorder, severe unipolar recurrent major
depressive episodes, dysthymic disorder, depressive neurosis and
neurotic depression, melancholic depression including anorexia,
weight loss, insomnia, early morning waking or psychomotor
retardation, atypical depression (or reactive depression) including
increased appetite, hypersomnia, psychomotor agitation or
irritability; treatment resistant depression; seasonal affective
disorder and pediatric depression; premenstrual syndrome,
premenstrual dysphoric disorder, hot flashes, bipolar disorders or
manic depression, for example, bipolar I disorder, bipolar II
disorder and cyclothymic disorder; seasonal affective disorder,
conduct disorder and disruptive behavior disorder; stress related
somatic disorders and anxiety disorders, such as panic disorder
with or without agoraphobia, agoraphobia without history of panic
disorder, specific phobias (e.g., specific animal phobias), social
anxiety disorder, social phobia, obsessive-compulsive disorder,
stress disorders including post-traumatic stress disorder and acute
stress disorder, and generalized anxiety disorder in a mammal,
comprising administering to a mammal in need of such treatment a
therapeutically effective amount of an alpha2delta ligand or a
pharmaceutically acceptable salt thereof.
[0008] This invention also relates to a method of treating a
disorder or condition selected from the group consisting of
borderline personality disorder; schizophrenia and other psychotic
disorders, for example, schizophreniform disorders, schizoaffective
disorders, delusional disorders, brief psychotic disorders, shared
psychotic disorders, psychotic disorders due to a general medical
condition, psychotic disorders with delusions or hallucinations,
substance induced psychotic disorder, psychotic episodes of
anxiety, anxiety associated with psychosis, psychotic mood
disorders such as severe major depressive disorder; mood disorders
associated with psychotic disorders such as acute mania and
depression associated with bipolar disorder, mood disorders
associated with schizophrenia; and behavioral disturbances
associated with mental retardation in a mammal, comprising
administering to a mammal in need of such treatment a
therapeutically effective amount of an alpha2delta ligand or a
pharmaceutically acceptable salt thereof.
[0009] This invention also relates to a method of treating a
disorder or condition selected from the group consisting of sleep
disorders such as insomnia (e.g., primary insomnia including
psychophysiological and idiopathic insomnia, secondary insomnia
including insomnia secondary to restless legs syndrome, Parkinson's
disease or another chronic disorder, and transient insomnia),
somnambulism, sleep deprivation, REM sleep disorders, sleep apnea,
hypersomnia, parasomnias, sleep-wake cycle disorders, jet lag,
narcolepsy, sleep disorders associated with shift work or irregular
work schedules, deficient sleep quality due to a decrease in slow
wave sleep caused by medications or other sources, and other sleep
disorders in a mammal, comprising administering to a mammal in need
of such treatment a therapeutically effective amount of an
alpha2delta ligand or a pharmaceutically acceptable salt
thereof.
[0010] This invention also relates to a method of increasing slow
wave sleep and increasing growth hormone secretion in a human
subject comprising administering to a human subject in need of such
treatment a therapeutically effective amount of an alpha2delta
ligand or a pharmaceutically acceptable salt thereof.
[0011] This invention also relates to a method of treating a
disorder or condition selected from the group consisting of
respiratory diseases, particularly those associated with excess
mucus secretion, such as chronic obstructive airways disease,
bronchopneumonia, chronic bronchitis, cystic fibrosis, adult
respiratory distress syndrome, and bronchospasm; cough, whooping
cough, angiotensin converting enzyme (ACE) induced cough, pulmonary
tuberculosis, allergies such as eczema and rhinitis; contact
dermatitis, atopic dermatitis, urticaria, and other eczematoid
dermatitis; itching, hemodialysis associated itching; inflammatory
diseases such as inflammatory bowel disease, psoriasis,
osteoarthritis, cartilage damage (e.g., cartilage damage resulting
from physical activity or osteoarthritis), rheumatoid arthritis,
psoriatic arthritis, asthma, pruritis and sunburn; and
hypersensitivity disorders such as poison ivy in a mammal,
comprising administering to a mammal in need of such treatment a
therapeutically effective amount of an alpha2delta ligand or a
pharmaceutically acceptable salt thereof.
[0012] This invention also relates to a method of treating a
disorder or condition selected from the group consisting of
neurodegenerative disorders, such as Parkinson's disease (PD),
Huntington's disease (HD) and Alzheimer's disease (AD); delerium,
dementias (e.g., senile dementia of the Alzheimer's type, senile
dementia, vascular dementia, HIV-1 associated dementia, AIDS
dementia complex (ADC), dementias due to head trauma, Parkinson's
disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob
disease, or due to multiple etiologies), amnestic disorders, other
cognitive or memory disorders, and behavioral symptoms of dementia
in a mammal, comprising administering to a mammal in need of such
treatment a therapeutically effective amount of an alpha2delta
ligand or a pharmaceutically acceptable salt thereof.
[0013] This invention also relates to a method of treating a
disorder or condition selected from the group consisting of Down's
syndrome; Sjogren's syndrome, hypertension, hematopoiesis,
postoperative neuroma, benign prostatic hypertrophy, periodontal
disease, hemorrhoids and anal fissures, infertility, reflex
sympathetic dystrophy, hepatitis, tenalgia attendant to
hyperlipidemia, vasodilation, fibrosing and collagen diseases such
as scleroderma and eosinophilic fascioliasis; and vasospastic
diseases such as angina, migraine and Reynaud's disease in a
mammal, comprising administering to a mammal in need of such
treatment a therapeutically effective amount of an alpha2delta
ligand or a pharmaceutically acceptable salt thereof.
[0014] This invention also relates to a method of treating a
disorder or condition selected from the group consisting of
ophthalmic diseases such as dry eye syndrome, conjunctivitis,
vernal conjunctivitis, and the like; and ophthalmic conditions
associated with cell proliferation such as proliferative
vitreoretinopathy in a mammal, comprising administering to a mammal
in need of such treatment a therapeutically effective amount of an
alpha2delta ligand or a pharmaceutically acceptable salt
thereof.
[0015] This invention also relates to a method of treating a
disorder or condition selected from the group consisting of autism,
attention deficit hyperactivity disorder (ADHD), angiogenesis
(i.e., use for the inhibition of angiogenesis), Reiter's syndrome
and anthropathies in a mammal, comprising administering to a mammal
in need of such treatment a therapeutically effective amount of an
alpha2delta ligand or a pharmaceutically acceptable salt
thereof.
[0016] This invention also relates to a method of treating a
disorder or condition selected from the group consisting of
substance-related disorders arising from the use of alcohol,
amphetamines (or amphetamine-like substances) caffeine, cannabis,
cocaine, hallucinogens, inhalants and aerosol propellants,
nicotine, opioids, phenylglycidine derivatives, sedatives,
hypnotics, and anxiolytics, which substance-related disorders
include dependence and abuse, intoxication, withdrawal,
intoxication delerium and withdrawal delerium; and addiction
disorders involving addictions to behaviors (e.g., addictions to
gambling and other addictive behaviors) in a mammal, comprising
administering to a mammal in need of such treatment a
therapeutically effective amount of an alpha2delta ligand or a
pharmaceutically acceptable salt thereof.
[0017] This invention also relates to a method of treating a
disorder or condition selected from the group consisting of Down's
syndrome; demyelinating diseases such as multiple sclerosis (MS)
and amylolateral sclerosis (ALS) in a mammal, comprising
administering to a mammal in need of such treatment a
therapeutically effective amount of an alpha2delta ligand or a
pharmaceutically acceptable salt thereof.
[0018] This invention also relates to a method of treating a
disorder or condition selected from the group consisting of
pervasive development disorder, fibromyalgia, human
immunodeficiency virus (HIV) infections; HIV encephalopathy;
dissociative disorders such as body dysmorphic disorders; eating
disorder such as anorexia and bulimia; ulcerative colitis; Crohn's
disease; irritable bowel syndrome; chronic pancreatitis, chronic
fatigue syndrome; sudden infant death syndrome (SIDS); overactive
bladder; lower urinary tract symptoms of overactive bladder;
chronic cystitis; chemotherapy induced cystitis; cough, angiotensin
converting enzyme (ACE) induced cough, itch, hiccups, premenstrual
syndrome, premenstrual dysphoric disorder, amenorrheic disorders
such as desmenorrhea; reflex sympathetic dystrophy such as
shoulder/hand syndrome; plasma extravasation resulting from
cytokine chemotherapy; disorders of bladder function such as
chronic cystitis, bladder detrusor hyper-reflexia, inflammation of
the urinary tract and urinary incontinence, including urinary urge
incontinence, overactive bladder, stress incontinence and mixed
incontinence; fibrosing and collagen diseases such as scleroderma
and eosinophilic fascioliasis; blood flow disorders caused by
vasodilation and vasospastic diseases such as angina and Reynaud's
disease; sexual dysfunctions including premature ejaculation and
male erectile dysfunction in a mammal, comprising administering to
a mammal in need of such treatment a therapeutically effective
amount of an alpha2delta ligand or a pharmaceutically acceptable
salt thereof.
[0019] This invention also relates to a method of treating a
disorder or condition selected from the group consisting of
movement disorders such as primary movement disorders, akinesias,
dyskinesias (e.g., familial paroxysmal dyskinesia, tardive
dyskinesia, tremor, chorea, myoclonus, tics and other dyskinesias)
spasticities, Tourette's syndrome, Scott syndrome, palsys (e.g.,
Bell's palsy, cerebral palsy, birth palsy, brachial palsy, wasting
palsy, ischemic palsy, progressive bulbar palsy and other palsys),
akinetic-rigid syndrome; extra-pyramidal movement disorders such as
medication-induced movement disorders, for example,
neuroleptic-induced Parkinsonism, neuroleptic malignant syndrome,
neuroleptic-induced acute dystonia, neuroleptic-induced acute
akathisia, neuroleptic-induced tardive dyskinesia and
medication-induced postural tremour; restless legs syndrome and
movement disorders associated with Parkinson's disease or
Huntington's disease in a mammal, comprising administering to a
mammal in need of such treatment a therapeutically effective amount
of an alpha2delta ligand or a pharmaceutically acceptable salt
thereof.
[0020] This invention also relates to a method of treating a
disorder or condition selected from the group consisting of
mastalgia syndromes, motion sickness, systemic lupus erythematosis
and immune dysfunctions (e.g., stress induced immune dysfunctions
such as idiopathic immune dysfunctions, post infection immune
dysfunctions, post lumpectomy immune dysfunctions, porcine stress
syndrome, bovine shipping fever, equine paroxysmal fibrillation,
confinement dysfunction in chicken, sheering stress in sheep, and
human-animal interaction stress in dogs) in a mammal, comprising
administering to a mammal in need of such treatment a
therapeutically effective amount of an alpha2delta ligand or a
pharmaceutically acceptable salt thereof.
[0021] This invention also relates to a method of treating a
disorder or condition selected from the group consisting of
gastrointestinal (GI) disorders, including inflammatory
gastrointestinal disorders such as inflammation bowel disease,
disorders caused by helicobacter pylon and diseases of the GI tract
such as gastritis, proctitis, gastroduodenal ulcers, peptic ulcers,
dyspepsia, disorders associated with the neuronal control of
viscera, ulcerative colitis, Crohn's disease, irritable bowel
syndrome and emesis, including post operative nausea and post
operative vomiting, and including acute, delayed or anticipatory
emesis (emesis includes emesis induced by chemotherapy, radiation,
toxins, viral or bacterial infections, pregnancy, vestibular
disorders, for example, motion sickness, vertigo, dizziness and
Meniere's disease, surgery, migraine, variations in intercranial
pressure, gastro-oesophageal reflux disease, acid indigestion, over
indulgence in food or drink, acid stomach, waterbrash or
regurgitation, heartburn, for example, episodic, nocturnal or
meal-induced heartburn, and dyspepsia) in a mammal, comprising
administering to a mammal in need of such treatment a
therapeutically effective amount of an alpha2delta ligand or a
pharmaceutically acceptable salt thereof.
[0022] This invention also relates to a method of treating a
disorder or condition selected from the group consisting of
neoplasms, including breast tumours, gastric carcinomas, gastric
lymphomas, neuroganglioblastomas and small cell carcinomas such as
small cell lung cancer in a mammal, comprising administering to a
mammal in need of such treatment a therapeutically effective amount
of an alpha2delta ligand or a pharmaceutically acceptable salt
thereof.
[0023] The foregoing methods are also referred to herein,
collectively, as the "invention methods".
[0024] Preferred embodiments of the invention methods utilize an
alpha2delta ligand that is a cyclic amino acid compound of Formula
I ##STR2## wherein R.sub.1 is hydrogen or lower alkyl and n is an
integer of from 4 to 6, and the pharmaceutically acceptable salts
thereof. An especially preferred embodiment utilizes a compound of
Formula I where R.sub.1 is hydrogen and n is 5, which compound is
1-(aminomethyl)-cyclohexane acetic acid, known generically as
gabapentin. Other preferred alpha2delta ligands, or a
pharmaceutically acceptable salt thereof, are compounds of Formula
I wherein the cyclic ring is substituted, for example with alkyl
such as methyl or ethyl. Typical of such compounds include
(1-aminomethyl-3-methylcyclohexyl) acetic acid,
(1-aminomethyl-3-methylcyclopentyl) acetic acid, and
(1-aminomethyl-3,4-dimethylcyclopentyl) acetic acid.
[0025] The cyclic amino acids of Formula I and methods of
synthesizing them are described in U.S. Pat. Nos. 4,024,175 and
4,087,544, which are both incorporated herein by reference in their
entireties.
[0026] In other preferred embodiments, the invention methods
utilize an alpha2delta ligand of Formula II ##STR3## or a
pharmaceutically acceptable salt thereof, wherein: [0027] R.sub.1
is a straight or branched unsubstituted alkyl of from 1 to 6 carbon
atoms, unsubstituted phenyl, or unsubstituted cycloalkyl of from 3
to 6 carbon atoms; [0028] R.sub.2 is hydrogen or methyl; and [0029]
R.sub.3 is hydrogen, methyl, or carboxyl.
[0030] Diastereomers and enantiomers of compounds of Formula II can
be utilized in the invention methods.
[0031] Preferred embodiments of the invention methods utilize a
compound of Formula II that is 3-aminomethyl-5-methyl-hexanoic acid
or, especially, (S)-3-(aminomethyl)-5-methylhexanoic acid, which is
known generically as pregabalin.
[0032] Other preferred embodiments of the invention methods utilize
a compound of Formula II that is 3-(1-aminoethyl)-5-methylheptanoic
acid or 3-(1-aminoethyl)-5-methylhexanoic acid.
[0033] Alpha2delta ligands having the Formula II, and the synthesis
of such compounds, are described in U.S. Pat. No. 5,563,175, which
is incorporated herein by reference in its entirety.
[0034] Other preferred embodiments of the invention methods utilize
an alpha2delta ligand that is a compound of the Formula III, IIIC,
IIIF, IIIG, or IIIH ##STR4## or a pharmaceutically acceptable salt
thereof wherein: [0035] n is an integer of from 0 to 2; [0036] m is
an integer of from 0 to 3; [0037] R is sulfonamide, [0038] amide,
[0039] phosphonic acid, [0040] heterocycle, [0041] sulfonic acid,
or [0042] hydroxamic acid; [0043] with the proviso that R can not
be sulfonic acid when m is 2 and n is 1; [0044] R.sub.1 to R.sub.14
are each independently selected from hydrogen or straight or
branched alkyl of from 1 to 6 carbons, unsubstituted or substituted
benzyl or phenyl which substituents are selected from halogen,
alkyl, alkoxy, hydroxy, carboxy, carboalkoxy, trifluoromethyl, and
nitro; [0045] A' is a bridged ring selected from ##STR5## wherein
[0046] is the point of attachment; [0047] Z.sub.1 to Z.sub.4 are
each independently selected from hydrogen and methyl; [0048] o is
an integer of from 1 to 4; and [0049] p is an integer of from 0 to
2.
[0050] Other preferred embodiments of the invention methods utilize
a compound selected from the following compounds of the Formula
III, IIIC, IIIF, IIIG, or IIIH and their pharmaceutically
acceptable salts: [0051]
(1-Aminomethyl-cyclohexylmethyl)-phosphonic acid; [0052] (1R-trans)
(1-Aminomethyl-3-methyl-cyclohexylmethyl)-phosphonic acid; [0053]
(trans) (1-Aminomethyl-3,4-dimethyl-cyclopentylmethyl)-phosphonic
acid; [0054] (1R-trans)
(1-Aminomethyl-3-methyl-cyclopentylmethyl)-phosphonic acid; [0055]
(1S-cis) (1-Aminomethyl-3-methyl-cyclopentylmethyl)-phosphonic
acid; [0056] (1S-trans)
(1-Aminomethyl-3-methyl-cyclopentylmethyl)-phosphonic acid; [0057]
(1R-cis) (1-Aminomethyl-3-methyl-cyclopentylmethyl)-phosphonic
acid; [0058] (1.alpha.,3.alpha.,4.alpha.)
(1-Aminomethyl-3,4-dimethyl-cyclopentylmethyl)-phosphonic acid;
[0059] (1.alpha.,3.beta.,4.beta.)
(1-Aminomethyl-3,4-dimethyl-cyclopentylmethyl)-phosphonic acid;
[0060] (R)
(1-Aminomethyl-3,3-dimethyl-cyclopentylmethyl)-phosphonic acid;
[0061] (S)
(1-Aminomethyl-3,3-dimethyl-cyclopentylmethyl)-phosphonic acid;
[0062] (1-Aminomethyl-3,3-dimethyl-cyclobutylmethyl)-phosphonic
acid; [0063] 2-(1-Aminomethyl-cyclohexyl)-N-hydroxy-acetamide;
[0064]
(1S-trans)2-(1-Aminomethyl-3-methyl-cyclohexyl)-N-hydroxy-acetamide;
[0065]
(trans)2-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-N-hydroxy-aceta-
mide; [0066]
(1S-cis)2-(1-Aminomethyl-3-methyl-cyclopentyl)-N-hydroxy-acetamide;
[0067]
(1R-trans)2-(1-Aminomethyl-3-methyl-cyclopentyl)-N-hydroxy-acetam-
ide; [0068]
(1R-cis)2-(1-Aminomethyl-3-methyl-cyclopentyl)-N-hydroxy-acetamide;
[0069]
(1S-trans)2-(1-Aminomethyl-3-methyl-cyclopentyl)-N-hydroxy-acetam-
ide; [0070]
(1.alpha.,3.alpha.,4.alpha.)2-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-N--
hydroxy-acetamide; [0071]
(1.alpha.,3.beta.,4.beta.)2-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-N-hy-
droxy-acetamide; [0072]
(S)2-(1-Aminomethyl-3,3-dimethyl-cyclopentyl)-N-hydroxy-acetamide;
[0073]
(R)2-(1-Aminomethyl-3,3-dimethyl-cyclopentyl)-N-hydroxy-acetamide-
; [0074]
2-(1-Aminomethyl-3,3-dimethyl-cyclobutyl)-N-hydroxy-acetamide;
[0075] N-[2-(1-Aminomethyl-cyclohexyl)-ethyl]-methanesulfonamide;
[0076]
(1S-cis)N-[2-(1-Aminomethyl-3-methyl-cyclohexyl)-ethyl]-methanesu-
lfonamide; [0077]
(trans)N-[2-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-ethyl]-methanesulfon-
amide; [0078]
(1S-cis)N-[2-(1-Aminomethyl-3-methyl-cyclopentyl)-ethyl]-methanesulfonami-
de; [0079]
(1R-trans)N-[2-(1-Aminomethyl-3-methyl-cyclopentyl)-ethyl]-methanesulfona-
mide; [0080]
(1R-cis)N-[2-(1-Aminomethyl-3-methyl-cyclopentyl)-ethyl]-methanesulfonami-
de; [0081]
(1S-cis)N-[2-(1-Aminomethyl-3-methyl-cyclopentyl)-ethyl]-methanesulfonami-
de; [0082]
(1.alpha.,3.alpha.,4.alpha.)N-[2-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-
-ethyl]-methanesulfonamide; [0083]
(1.alpha.,3.beta.,4.beta.)N-[2-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-e-
thyl]-methanesulfonamide; [0084]
(S)N-[2-(1-Aminomethyl-3,3-dimethyl-cyclopentyl)-ethyl]-methanesulfonamid-
e; [0085]
(R)N-[2-(1-Aminomethyl-3,3-dimethyl-cyclopentyl)-ethyl]-methanesulfonamid-
e; [0086]
N-[2-(1-Aminomethyl-3,3-dimethyl-cyclobutyl)-ethyl]-methanesulfonamide;
[0087]
(1S-cis)3-(1-Aminomethyl-3-methyl-cyclohexylmethyl)-4H-[1,2,4]oxa-
diazol-5-one; [0088]
(trans)3-(1-Aminomethyl-3,4-dimethyl-cyclopentylmethyl)-4H-[1,2,4]oxadiaz-
ol-5-one; [0089]
(1S-cis)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl)-4H-[1,2,4]oxadiazol--
5-one; [0090]
(1R-trans)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl)-4H-[1,2,4]oxadiazo-
l-5-one; [0091]
(1R-cis)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl)-4H-[1,2,4]oxadiazol--
5-one; [0092]
(1S-trans)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl)-4H-[1,2,4]oxadiazo-
l-5-one; [0093]
(1.alpha.,3.alpha.,4.alpha.)3-(1-Aminomethyl-3,4-dimethyl-cyclopentylmeth-
yl)-4H-[1,2,4]oxadiazol-5-one; [0094]
(1.alpha.,3.beta.,4.beta.)3-(1-Aminomethyl-3,4-dimethyl-cyclopentylmethyl-
)-4H-[1,2,4]oxadiazol-5-one; [0095]
(S)3-(1-Aminomethyl-3,3-dimethyl-cyclopentyl
methyl)-4H-[1,2,4]oxadiazol-5-one; [0096]
(R)3-(1-Aminomethyl-3,3-dimethyl-cyclopentyl
methyl)-4H-[1,2,4]oxadiazol-5-one; [0097]
3-(1-Aminomethyl-3,3-dimethyl-cyclobutylmethyl)-4H-[1,2,4]oxadiazol-5-one-
; [0098]
3-(1-Aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazole-5-thion- e;
[0099]
(1S-cis)3-(1-Aminomethyl-3-methyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazole--
5-thione; [0100] (trans)3-(1-Aminomethyl-3,4-dimethyl-cyclopentyl
methyl)-4H-[1,2,4]oxadiazole-5-thione; [0101]
(1S-cis)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl)-4H-[1,2,4]oxadiazole-
-5-thione; [0102]
(1R-trans)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl
-4H-[1,2,4]oxadiazole-5-thione; [0103]
(1R-cis)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl)-4H-[1,2,4]oxadiazole-
-5-thione; [0104]
(1S-trans)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl
)-4H-[1,2,4]oxadiazole-5-thione; [0105]
(1.alpha.,3.alpha.,4.alpha.)3-(1-Aminomethyl-3,4-dimethyl-cyclopentylmeth-
yl)-4H-[1,2,4]oxadiazole-5-thione; [0106]
(1.alpha.,3.beta.,4.beta.)3-(1-Aminomethyl-3,4-dimethyl-cyclopentylmethyl-
)-4H-[1,2,4]oxadiazole-5-thione; [0107]
(S)3-(1-Aminomethyl-3,3-dimethyl-cyclopentyl
methyl)-4H-[1,2,4]oxadiazole-5-thione; [0108]
(R)3-(1-Aminomethyl-3,3-dimethyl-cyclopentyl
methyl)-4H-[1,2,4]oxadiazole-5-thione; [0109]
3-(1-Aminomethyl-3,3-dimethyl-cyclobutylmethyl)-4H-[1,2,4]oxadiazole-5-th-
ione; [0110] C-[1-(1H-Tetrazol-5-ylmethyl)-cyclohexyl]-methylamine;
[0111]
(1S-cis)C-[3-Methyl-1-(1H-tetrazol-5-ylmethyl)-cyclohexyl]-methyl-
amine; [0112]
(trans)C-[3,4-Dimethyl-1-(1H-tetrazol-5-ylmethyl)-cyclopentyl]-methylamin-
e; [0113]
(1S-cis)C-[3-Methyl-1-(1H-tetrazol-5-ylmethyl)-cyclopentyl]-methylamine;
[0114]
(1R-trans)C-[3-Methyl-1-(1H-tetrazol-5-ylmethyl)-cyclopentyl]-met-
hylamine; [0115]
(1R-cis)C-[3-Methyl-1-(1H-tetrazol-5-ylmethyl)-cyclopentyl]-methylamine;
[0116]
(1S-trans)C-[3-Methyl-1-(1H-tetrazol-5-ylmethyl)-cyclopentyl]-met-
hylamine; [0117]
(1.alpha.,3.alpha.,4.alpha.)C-[3,4-Dimethyl-1-(1H-tetrazol-5-ylmethyl)-cy-
clopentyl]-methylamine; [0118]
(1.alpha.,3.beta.,4.beta.)C-[3,4-Dimethyl-1-(1H-tetrazol-5-ylmethyl)-cycl-
opentyl]-methylamine; [0119]
(S)C-[3,3-Dimethyl-1-(1H-tetrazol-5-ylmethyl)-cyclopentyl]-methylamine;
[0120]
(R)C-[3,3-Dimethyl-1-(1H-tetrazol-5-ylmethyl)-cyclopentyl]-methyl-
amine; [0121]
C-[3,3-Dimethyl-1-(1H-tetrazol-5-ylmethyl)-cyclobutyl]-methylamine;
[0122] N-[2-(1-Aminomethyl-cyclohexyl)-ethyl]-C, C,C-trifl
uoro-methanesulfonamide; [0123]
(1S-cis)N-[2-(1-Aminomethyl-3-methyl-cyclohexyl)-ethyl]-C,C,C-trifluoro-m-
ethanesulfonamide; [0124]
(trans)N-[2-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-ethyl]-C,C,C-trifluo-
ro-methanesulfonamide; [0125]
(1R-cis)N-[2-(1-Aminomethyl-3-methyl-cyclopentyl)-ethyl]-C,C,C-trifluoro--
methanesulfonamide; [0126]
(1S-trans)N-[2-(1-Aminomethyl-3-methyl-cyclopentyl)-ethyl]-C,C,C-trifluor-
o-methanesulfonamide; [0127]
(1S-cis)N-[2-(1-Aminomethyl-3-methyl-cyclopentyl)-ethyl]-C,C,C-trifluoro--
methanesulfonamide; [0128]
(1R-trans)N-[2-(1-Aminomethyl-3-methyl-cyclopentyl)-ethyl]-C,C,C-trifluor-
o-methanesulfonamide; [0129]
(1.alpha.,3.alpha.,4.alpha.)N-[2-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-
-ethyl]-C,C,C-trifluoro-methanesulfonamide; [0130]
(1.alpha.,3.beta.,4.beta.)N-[2-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-e-
thyl]-C,C,C-trifluoro-methanesulfonamide; [0131]
(S)N-[2-(1-Aminomethyl-3,3-dimethyl-cyclopentyl)-ethyl]-C,C,C-trifluoro-m-
ethanesulfonamide; [0132]
(R)N-[2-(1-Aminomethyl-3,3-dimethyl-cyclopentyl)-ethyl]-C,C,C-trifluoro-m-
ethanesulfonamide; [0133]
N-[2-(1-Aminomethyl-3,3-dimethyl-cyclobutyl)-ethyl]-C,C,C-trifluoro-metha-
nesulfonamide; [0134]
3-(1-Aminomethyl-cyclohexylmethyl)-4H-[1,2,4]thiadiazol-5-one;
[0135]
(1S-cis)3-(1-Aminomethyl-3-methyl-cyclohexylmethyl)-4H-[1,2,4]thiadiazol--
5-one; [0136]
(trans)3-(1-Aminomethyl-3,4-dimethyl-cyclopentylmethyl)-4H-[1,2,4]thiadia-
zol-5-one; [0137]
(1R-cis)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl)-4H-[1,2,4]thiadiazol-
-5-one; [0138]
(1S-trans)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl
)-4H-[1,2,4]thiadiazol-5-one; [0139]
(1S-cis)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl)-4H-[1,2,4]thiadiazol-
-5-one; [0140]
(1R-trans)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl)-4H-[1,2,4]thiadiaz-
ol-5-one; [0141]
(1.alpha.,3.alpha.,4.alpha.)3-(1-Aminomethyl-3,4-dimethyl-cyclopentylmeth-
yl)-4H-[1,2,4]thiadiazol-5-one; [0142]
(1.alpha.,3.beta.,4.beta.)3-(1-Aminomethyl-3,4-dimethyl-cyclopentylmethyl-
)-4H-[1,2,4]thiadiazol-5-one; [0143]
(S)3-(1-Aminomethyl-3,3-dimethyl-cyclopentyl
methyl)-4H-[1,2,4]thiadiazol-5-one; [0144]
(R)3-(1-Aminomethyl-3,3-dimethyl-cyclopentyl
methyl)-4H-[1,2,4]thiadiazol-5-one; [0145]
3-(1-Aminomethyl-3,3-dimethyl-cyclobutylmethyl)-4H-[1,2,4]thiadiazol-5-on-
e; [0146]
C-[1-(2-Oxo-2,3-dihydro-2.lamda..sup.4-[1,2,3,5]oxathiadiazol-4-ylmethyl)
-cyclohexyl]-methylamine; [0147]
(1S-cis)C-[3-Methyl-1-(2-oxo-2,3-dihydro-2.lamda..sup.4-[1,2,3,5]oxathiad-
iazol-4-ylmethyl)-cyclohexyl]-methylamine; [0148]
(trans)C-[3,4-Dimethyl-1-(2-oxo-2,3-dihydro-2.lamda..sup.4-[1,2,3,5]oxath-
iadiazol-4-ylmethyl)-cyclopentyl]-methylamine; [0149]
(1S-cis)C-[3-Methyl-1-(2-oxo-2,3-dihydro-2.lamda..sup.4-[1,2,3,5]oxathiad-
iazol-4-ylmethyl)-cyclopentyl]-methylamine; [0150]
(1R-trans)C-[3-Methyl-1-(2-oxo-2,3-dihydro-2.lamda..sup.4-[1,2,3,5]oxathi-
adiazol-4-ylmethyl)-cyclopentyl]-methylamine; [0151]
(1R-cis)C-[3-Methyl-1-(2-oxo-2,3-dihydro-2.lamda..sup.4-[1,2,3,5]oxathiad-
iazol-4-ylmethyl)-cyclopentyl]-methylamine; [0152]
(1S-trans)C-[3-Methyl-1-(2-oxo-2,3-dihydro-2.lamda..sup.4-[1,2,3,5]oxathi-
adiazol-4-ylmethyl)-cyclopentyl]-methylamine; [0153]
(1.alpha.,3.alpha.,4.alpha.)C-[3,4-Dimethyl-1-(2-oxo-2,3-dihydro-2.lamda.-
.sup.4-[1,2,3,5]oxathiadiazol-4-ylmethyl)-cyclopentyl]-methylamine;
[0154]
(1.alpha.,3.beta.,4.beta.)C-[3,4-Dimethyl-1-(2-oxo-2,3-dihydro-2.-
lamda..sup.4-[1,2,3,5]oxathiadiazol-4-ylmethyl)-cyclopentyl]-methylamine;
[0155]
(S)C-[3,3-Dimethyl-1-(2-oxo-2,3-dihydro-2.lamda..sup.4-[1,2,3,5]o-
xathiadiazol-4-ylmethyl)-cyclopentyl]-methylamine; [0156]
(R)C-[3,3-Dimethyl-1-(2-oxo-2,3-dihydro-2.lamda..sup.4-[1,2,3,5]oxathiadi-
azol-4-ylmethyl)-cyclopentyl]-methylamine; [0157]
C-[3,3-Dimethyl-1-(2-oxo-2,3-dihydro-2.lamda..sup.4-[1,2,3,5]oxathiadiazo-
l-4-ylmethyl)-cyclobutyl]-methylamine; [0158]
(1-Aminomethyl-cyclohexyl)-methanesulfonamide; [0159] (1R-trans)
(1-Aminomethyl-3-methyl-cyclohexyl)-methanesulfonamide; [0160]
(trans)
(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-methanesulfonamide; [0161]
(1S-trans) (1-Aminomethyl-3-methyl-cyclopentyl)-methanesulfonamide;
[0162] (1R-cis)
(1-Aminomethyl-3-methyl-cyclopentyl)-methanesulfonamide; [0163]
(1R-trans) (1-Aminomethyl-3-methyl-cyclopentyl
)-methanesulfonamide; [0164] (1S-cis)
(1-Aminomethyl-3-methyl-cyclopentyl)-methanesulfonamide; [0165]
(1.alpha.,3.beta.,4.beta.)
(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-methanesulfonamide; [0166]
(1.alpha.,3.beta.,4.beta.)
(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-methanesulfonamide; [0167]
(R) (1-Aminomethyl-3,3-dimethyl-cyclopentyl)-methanesulfonamide;
[0168] (S)
(1-Aminomethyl-3,3-dimethyl-cyclopentyl)-methanesulfonamide; [0169]
(1-Aminomethyl-3,3-dimethyl-cyclobutyl)-methanesulfonamide; [0170]
(1-Aminomethyl-cyclohexyl)-methanesulfonic acid; [0171] (1R-trans)
(1-Aminomethyl-3-methyl-cyclohexyl)-methanesulfonic acid; [0172]
(trans) (1-Aminomethyl-3,4-dimethyl-cyclopentyl)-methanesulfonic
acid; [0173] (1S-trans)
(1-Aminomethyl-3-methyl-cyclopentyl)-methanesulfonic acid; [0174]
(1S-cis) (1-Aminomethyl-3-methyl-cyclopentyl)-methanesulfonic acid;
[0175] (1R-trans)
(1-Aminomethyl-3-methyl-cyclopentyl)-methanesulfonic acid; [0176]
(1R-cis) (1-Aminomethyl-3-methyl-cyclopentyl)-methanesulfonic acid;
[0177] (1.alpha.,3.beta.,4.beta.)
(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-methanesulfonic acid;
[0178] (1.alpha.,3.alpha.,4.alpha.)
(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-methanesulfonic acid;
[0179] (R) (1-Aminomethyl-3,3-dimethyl-cyclopentyl)-methanesulfonic
acid; [0180] (S)
(1-Aminomethyl-3,3-dimethyl-cyclopentyl)-methanesulfonic acid;
[0181] (1-Aminomethyl-3,3-dimethyl-cyclobutyl)-methanesulfonic
acid; [0182] (1-Aminomethyl-cyclopentylmethyl)-phosphonic acid;
[0183] 2-(1-Aminomethyl-cyclopentyl)-N-hydroxy-acetamide; [0184]
N-[2-(1-Aminomethyl-cyclopentyl)-ethyl]-methanesulfonamide; [0185]
3-(1-Aminomethyl-cyclopentylmethyl)-4H-[1,2,4]oxadiazol-5-one;
[0186]
3-(1-Aminomethyl-cyclopentylmethyl)-4H-[1,2,4]oxadiazole-5-thione;
[0187] C-[1-(1H-Tetrazol-5-ylmethyl)-cyclopentyl]-methylamine;
[0188]
N-[2-(1-Aminomethyl-cyclopentyl)-ethyl]-C,C,C-trifluoro-methanesulfonamid-
e; [0189]
3-(1-Aminomethyl-cyclopentylmethyl)-4H-[1,2,4]thiadiazol-5-one;
[0190]
C-[1-(2-Oxo-2,3-dihydro-2.lamda..sup.4-[1,2,3,5]oxathiadiazol-4-ylmethyl
)-cyclopentyl]-methylamine; [0191]
(1-Aminomethyl-cyclopentyl)-methanesulfonamide; [0192]
(1-Aminomethyl-cyclopentyl)-methanesulfonic acid; [0193]
(9-Aminomethyl-bicyclo[3.3.1]non-9-ylmethyl)-phosphonic acid;
[0194]
2-(9-Aminomethyl-bicyclo[3.3.1]non-9-yl)-N-hydroxy-acetamide;
[0195]
N-[2-(9-Aminomethyl-bicyclo[3.3.1]non-9-yl)-ethyl]-methanesulfonamide;
[0196] 3-(9-Aminomethyl-bicyclo[3.3.1]non-9-ylmethyl)-4H-[1
,2,4]oxadiazol-5-one; [0197]
3-(9-Aminomethyl-bicyclo[3.3.1]non-9-ylmethyl)-4H-[1,2,4]oxadiazole-5-thi-
one; [0198]
C-[9-(1H-Tetrazol-5-ylmethyl)-bicyclo[3.3.1]non-9-yl]-methylamine;
[0199]
N-[2-(9-Aminomethyl-bicyclo[3.3.1]non-9-yl)-ethyl]-C,C,C-trifluor-
o-methanesulfonamide; [0200]
3-(9-Aminomethyl-bicyclo[3.3.1]non-9-ylmethyl)-4H-[1,2,4]thiadiazol-5-one-
; [0201]
C-[9-(2-Oxo-2,3-dihydro-2.lamda..sup.4-[1,2,3,5]oxathiadiazol-4-
-ylmethyl )-bicyclo[3.3.1]non-9-yl]-methylamine; [0202]
(9-Aminomethyl-bicyclo[3.3.1]non-9-yl)-methanesulfonamide; [0203]
(9-Aminomethyl-bicyclo[3.3.1]non-9-yl)-methanesulfonic acid; [0204]
(2-Aminomethyl-adamantan-2-ylmethyl)-phosphonic acid; [0205]
2-(2-Aminomethyl-adamantan-2-yl)-N-hydroxy-acetamide; [0206]
N-[2-(2-Aminomethyl-adamantan-2-yl)-ethyl]-methanesulfonamide;
[0207]
3-(2-Aminomethyl-adamantan-2-ylmethyl)-4H-[1,2,4]oxadiazol-5-one;
[0208]
3-(2-Aminomethyl-adamantan-2-ylmethyl)-4H-[1,2,4]oxadiazole-5-thione;
[0209] C-[2-(1H-Tetrazol-5-yl methyl)-adamantan-2-yl]-methylamine;
[0210] N-[2-(2-Aminomethyl-adamantan-2-yl
)-ethyl]-C,C,C-trifluoro-methanesulfonamide; [0211]
3-(2-Aminomethyl-adamantan-2-ylmethyl)-4H-[1,2,4]thiadiazol-5-one;
[0212]
C-[2-(2-Oxo-2,3-dihydro-2.lamda..sup.4-[1,2,3,5]oxathiadiazol-4-y-
lmethyl )-adamantan-2-yl]-methylamine; [0213]
(2-Aminomethyl-adamantan-2-yl)-methanesulfonamide; [0214]
(2-Aminomethyl-adamantan-2-yl)-methanesulfonic acid; [0215]
(1-Aminomethyl-cycloheptylmethyl)-phosphonic acid; [0216]
2-(1-Aminomethyl-cycloheptyl)-N-hydroxy-acetamide; [0217]
N-[2-(1-Aminomethyl-cycloheptyl)-ethyl]-methanesulfonamide; [0218]
3-(1-Aminomethyl-cycloheptylmethyl)-4H-[1,2,4]oxadiazole-5-thione;
[0219]
N-[2-(1-Aminomethyl-cycloheptyl)-ethyl]-C,C,C-trifluoro-methanesu-
lfonamide; [0220]
C-[1-(2-Oxo-2,3-dihydro-2|4-[1,2,3,5]oxathiadiazol-4-ylmethyl)-cyclohepty-
l]-methylamine; [0221]
(1-Aminomethyl-cycloheptyl)-methanesulfonamide; [0222]
(1-Aminomethyl-cycloheptyl)-methanesulfonic acid; [0223]
(1.alpha.,3.alpha.,4.alpha.)-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-ace-
tic acid; [0224]
(1.alpha.,3.alpha.,4.alpha.)-(1-Aminomethyl-3,4-diethyl-cyclopentyl)-acet-
ic acid; [0225]
(1.alpha.,3.alpha.,4.alpha.)-(1-Aminomethyl-3,4-diisopropyl-cyclopentyl)--
acetic acid; [0226]
[1R-(1.alpha.,3.alpha.,4.alpha.)]-(1-Aminomethyl-3-ethyl-4-methyl-cyclope-
ntyl)-acetic acid; [0227]
[1S-(1.alpha.,3.alpha.,4.alpha.)]-(1-Aminomethyl-3-isopropyl-4-methyl-cyc-
lopentyl)-acetic acid; [0228]
[1R-(1.alpha.,3.alpha.,4.alpha.)]-(1-Aminomethyl-3-isopropyl-4-methyl-cyc-
lopentyl)-acetic acid; [0229] [1S-(1.alpha.,3.alpha.,4
.alpha.)]-(1-Aminomethyl-3-ethyl-4-isopropyl-cyclopentyl)-acetic
acid; [0230]
[1R-(1.alpha.,3.alpha.,4.alpha.)]-(1-Aminomethyl-3-ethyl-4-isopro-
pyl-cyclopentyl)-acetic acid; [0231]
[1S-(1.alpha.,3.alpha.,4.alpha.)]-(1-Aminomethyl-3-tert-butyl-4-methyl-cy-
clopentyl)-acetic acid; [0232]
[1R-(1.alpha.,3.alpha.,4.alpha.)]-(1-Aminomethyl-3-tert-butyl-4-methyl-cy-
clopentyl)-acetic acid; [0233]
[1S-(1.alpha.,3.alpha.,4.alpha.)]-(1-Aminomethyl-3-tert-butyl-4-ethyl-cyc-
lopentyl)-acetic acid; [0234]
[1R-(1.alpha.,3.alpha.,4.alpha.)]-(1-Aminomethyl-3-tert-butyl-4-ethyl-cyc-
lopentyl)-acetic acid; [0235]
[1S-(1.alpha.,3.alpha.,4.alpha.)]-(1-Aminomethyl-3-tert-butyl-4-isopropyl-
-cyclopentyl)-acetic acid; [0236]
[1R-(1.alpha.,3.alpha.,4.alpha.)]-(1-Aminomethyl-3-tert-butyl-4-isopropyl-
-cyclopentyl)-acetic acid; [0237]
(1.alpha.,3.alpha.,4.alpha.)-(1-Aminomethyl-3,4-di-tert-butyl-cyclopentyl-
)-acetic acid; [0238]
[1S-(1.alpha.,3.alpha.,4.alpha.)]-(1-Aminomethyl-3-methyl-4-phenyl-cyclop-
entyl)-acetic acid; [0239]
[1R-(1.alpha.,3.alpha.,4.alpha.)]-(1-Aminomethyl-3-methyl-4-phenyl-cyclop-
entyl)-acetic acid; [0240]
[1S-(1.alpha.,3.alpha.,4.alpha.)]-(1-Aminomethyl-3-benzyl-4-methyl-cyclop-
entyl)-acetic acid; [0241]
[1R-(1.alpha.,3.alpha.,4.alpha.)]-(1-Aminomethyl-3-benzyl-4-methyl-cyclop-
entyl)-acetic acid; [0242]
(1S-cis)-(1-Aminomethyl-3-methyl-cyclopentyl)-acetic acid; [0243]
(1S-cis)-(1-Aminomethyl-3-ethyl-cyclopentyl)-acetic acid; [0244]
(1S-cis)-(1-Aminomethyl-3-isopropyl-cyclopentyl)-acetic acid;
[0245] (1S-cis)-(1-Aminomethyl-3-tert-butyl-cyclopentyl)-acetic
acid; [0246] (1S-cis)-(1-Aminomethyl-3-phenyl-cyclopentyl)-acetic
acid; [0247] (1S-cis)-(1-Aminomethyl-3-benzyl-cyclopentyl)-acetic
acid; [0248] (1R-cis)-(1-Aminomethyl-3-methyl-cyclopentyl)-acetic
acid; [0249] (1R-cis)-(1-Aminomethyl-3-ethyl-cyclopentyl)-acetic
acid; [0250] (1R-cis)-(1-Aminomethyl-3isopropyl-cyclopentyl)-acetic
acid; [0251]
(1R-cis)-(1-Aminomethyl-3-tert-butyl-cyclopentyl)-acetic acid;
[0252] (1R-cis)-(1-Aminomethyl-3-phenyl-cyclopentyl)-acetic acid;
[0253] (1R-cis)-(1-Aminomethyl-3-benzyl-cyclopentyl)-acetic acid;
[0254] (S)-(1-Aminomethyl-3,3-dimethyl-cyclopentyl)-acetic acid;
[0255] (S)-(1-Aminomethyl-3,3-diethyl-cyclopentyl)-acetic acid;
[0256] (1-Aminomethyl-3,3,4,4-tetramethyl-cyclopentyl)-acetic acid;
[0257] (1-Aminomethyl-3,3,4,4-tetraethyl-cyclopentyl)-acetic acid;
[0258]
(1.alpha.,3.beta.,4.beta.)-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-aceti-
c acid; [0259]
(1.alpha.,3.beta.,4.beta.)-(1-Aminomethyl-3,4-diethyl-cyclopentyl)-acetic
acid; [0260]
(1.alpha.,3.beta.,4.beta.)-(1-Aminomethyl-3,4-diisopropyl-cyclopentyl)-ac-
etic acid; [0261]
[1R-(1.alpha.,3.beta.,4.beta.)]-(1-Aminomethyl-3-ethyl-4-methyl-cyclopent-
yl)-acetic acid; [0262]
[1S-(1.alpha.,3.beta.,4.beta.)]-(1-Aminomethyl-3-ethyl-4-methyl-cyclopent-
yl)-acetic acid; [0263]
[1R-(1.alpha.,3.beta.,4.beta.)]-(1-Aminomethyl-3-isopropyl-4-methyl-cyclo-
pentyl)-acetic acid; [0264]
[1S-(1.alpha.,3.beta.,4.beta.)]-(1-Aminomethyl-3-isopropyl-4-methyl-cyclo-
pentyl)-acetic acid; [0265]
[1R-(1.alpha.,3.beta.,4.beta.)]-(1-Aminomethyl-3-ethyl-4-isopropyl-cyclop-
entyl)-acetic acid; [0266]
[1S-(1.alpha.,3.beta.,4.beta.)]-(1-Aminomethyl-3-ethyl-4-isopropyl-cyclop-
entyl)-acetic acid; [0267]
[1R-(1.alpha.,3.beta.,4.beta.)]-(1-Aminomethyl-3-tert-butyl-4-methyl-cycl-
opentyl)-acetic acid; [0268]
[1S-(1.alpha.,3.beta.,4.beta.)]-(1-Aminomethyl-3-tert-butyl-4-methyl-cycl-
opentyl)-acetic acid; [0269]
[1R-(1.alpha.,3.beta.,4.beta.)]-(1-Aminomethyl-3-tert-butyl-4-ethyl-cyclo-
pentyl)-acetic acid; [0270]
[1S-(1.alpha.,3.beta.,4.beta.)]-(1-Aminomethyl-3-tert-butyl-4-ethyl-cyclo-
pentyl)-acetic acid; [0271]
[1R-(1.alpha.,3.beta.,4.beta.)]-(1-Aminomethyl-3-tert-butyl-4-isopropyl-c-
yclopentyl)-acetic acid; [0272]
[1S-(1.alpha.,3.beta.,4.beta.)]-(1-Aminomethyl-3-tert-butyl-4-isopropyl-c-
yclopentyl)-acetic acid; [0273]
(1.alpha.,3.beta.,4.beta.)-(1-Aminomethyl-3,4-di-tert-butyl-cyclopentyl)--
acetic acid; [0274]
[1R-(1.alpha.,3.beta.,4.beta.)]-(1-Aminomethyl-3-methyl-4-phenyl-cyclopen-
tyl)-acetic acid; [0275]
[1S-(1.alpha.,3.beta.,4.beta.)]-(1-Aminomethyl-3-methyl-4-phenyl-cyclopen-
tyl)-acetic acid; [0276]
[1R-(1.alpha.,3.beta.,4.beta.)]-(1-Aminomethyl-3-benzyl-4-methyl-cyclopen-
tyl)-acetic acid; [0277]
[1S-(1.alpha.,3.beta.,4.beta.)]-(1-Aminomethyl-3-benzyl-4-methyl-cyclopen-
tyl)-acetic acid; [0278]
(1R-trans)-(1-Aminomethyl-3-methyl-cyclopentyl)-acetic acid; [0279]
(1R-trans)-(1-Aminomethyl-3-ethyl-cyclopentyl)-acetic acid; [0280]
(1R-trans)-(1-Aminomethyl-3-isopropyl-cyclopentyl)-acetic acid;
[0281] (1R-trans)-(1-Aminomethyl-3-tert-butyl-cyclopentyl)-acetic
acid; [0282] (1R-trans)-(1-Aminomethyl-3-phenyl-cyclopentyl)-acetic
acid; [0283] (1R-trans)-(1-Aminomethyl-3-benzyl-cyclopentyl)-acetic
acid; [0284] (1S-trans)-(1-Aminomethyl-3-methyl-cyclopentyl)-acetic
acid; [0285] (1S-trans)-(1-Aminomethyl-3-ethyl-cyclopentyl)-acetic
acid; [0286]
(1S-trans)-(1-Aminomethyl-3-isopropyl-cyclopentyl)-acetic acid;
[0287] (1S-trans)-(1-Aminomethyl-3-tert-butyl-cyclopentyl)-acetic
acid; [0288] (1S-trans)-(1-Aminomethyl-3-phenyl-cyclopentyl)-acetic
acid; [0289] (1S-trans)-(1-Aminomethyl-3-benzyl-cyclopentyl)-acetic
acid; [0290] (R)-(1-Aminomethyl-3,3-dimethyl-cyclopentyl)-acetic
acid; [0291] (R)-(1-Aminomethyl-3,3-diethyl-cyclopentyl)-acetic
acid; [0292] cis-(1-Aminomethyl-3-methyl-cyclobutyl)-acetic acid;
[0293] cis-(1-Aminomethyl-3-ethyl-cyclobutyl)-acetic acid; [0294]
cis-(1-Aminomethyl-3-isopropyl-cyclobutyl)-acetic acid; [0295]
cis-(1-Aminomethyl-3-tert-butyl-cyclobutyl)-acetic acid; [0296]
cis-(1-Aminomethyl-3-phenyl-cyclobutyl)-acetic acid; [0297]
cis-(1-Aminomethyl-3-benzyl-cyclobutyl)-acetic acid; [0298]
trans-(1-Aminomethyl-3-methyl-cyclobutyl)-acetic acid; [0299]
trans-(1-Aminomethyl-3-ethyl-cyclobutyl)-acetic acid; [0300]
trans-(1-Aminomethyl-3-isopropyl-cyclobutyl)-acetic acid; [0301]
trans-(1-Aminomethyl-3-tert-butyl-cyclobutyl)-acetic acid; [0302]
trans-(1-Aminomethyl-3-phenyl-cyclobutyl)-acetic acid; [0303]
trans-(1-Aminomethyl-3-benzyl-cyclobutyl)-acetic acid; [0304]
cis-(1-Aminomethyl-3-ethyl-3-methyl-cyclobutyl)-acetic acid; [0305]
cis-(1-Aminomethyl-3-isopropyl-3-methyl-cyclobutyl)-acetic acid;
[0306] cis-(1-Aminomethyl-3-tert-butyl-3-methyl-cyclobutyl)-acetic
acid; [0307]
cis-(1-Aminomethyl-3-methyl-3-phenyl-cyclobutyl)-acetic acid;
[0308] cis-(1-Aminomethyl-3-benzyl-3-methyl-cyclobutyl)-acetic
acid; [0309]
trans-(1-Aminomethyl-3-ethyl-3-methyl-cyclobutyl)-acetic acid;
[0310] trans-(1-Aminomethyl-3-isopropyl-3-methyl-cyclobutyl)-acetic
acid; [0311]
trans-(1-Aminomethyl-3-tert-butyl-3-methyl-cyclobutyl)-acetic acid;
[0312] trans-(1-Aminomethyl-3-methyl-3-phenyl-cyclobutyl)-acetic
acid; [0313]
trans-(1-Aminomethyl-3-benzyl-3-methyl-cyclobutyl)-acetic acid;
[0314] cis-(1-Aminomethyl-3-ethyl-3-isopropyl-cyclobutyl)-acetic
acid; [0315]
cis-(1-Aminomethyl-3-tert-butyl-3-ethyl-cyclobutyl)-acetic acid;
[0316] cis-(1-Aminomethyl-3-ethyl-3-phenyl-cyclobutyl)-acetic acid;
[0317] cis-(1-Aminomethyl-3-benzyl-3-ethyl-cyclobutyl)-acetic acid;
[0318] trans-(1-Aminomethyl-3-ethyl-3-isopropyl-cyclobutyl)-acetic
acid; [0319]
trans-(1-Aminomethyl-3-tert-butyl-3-ethyl-cyclobutyl)-acetic acid;
[0320] trans-(1-Aminomethyl-3-ethyl-3-phenyl-cyclobutyl)-acetic
acid; [0321]
trans-(1-Aminomethyl-3-benzyl-3-ethyl-cyclobutyl)-acetic acid;
[0322]
cis-(1-Aminomethyl-3-tert-butyl-3-isopropyl-cyclobutyl)-acetic
acid; [0323]
cis-(1-Aminomethyl-3-isopropyl-3-phenyl-cyclobutyl)-acetic acid;
[0324] trans-(1-Aminomethyl-3-benzyl-3-isopropyl-cyclobutyl)-acetic
acid; [0325]
cis-(1-Aminomethyl-3-tert-butyl-3-phenyl-cyclobutyl)-acetic acid;
[0326]
trans-(1-Aminomethyl-3-benzyl-3-tert-butyl-cyclobutyl)-acetic acid;
[0327]
trans-(1-Aminomethyl-3-tert-butyl-3-isopropyl-cyclobutyl)-acetic
acid; [0328]
trans-(1-Aminomethyl-3-isopropyl-3-phenyl-cyclobutyl)-acetic acid;
[0329] cis-(1-Aminomethyl-3-benzyl-3-isopropyl-cyclobutyl)-acetic
acid; [0330]
trans-(1-Aminomethyl-3-tert-butyl-3-phenyl-cyclobutyl)-acetic acid;
[0331] cis-(1-Aminomethyl-3-benzyl-3-tert-butyl-cyclobutyl)-acetic
acid; [0332] (1-Aminomethyl-3,3-dimethyl-cyclobutyl)-acetic acid;
[0333] (1-Aminomethyl-3,3-diethyl-cyclobutyl)-acetic acid; [0334]
(1-Aminomethyl-3,3-diisopropyl-cyclobutyl)-acetic acid; [0335]
(1-Aminomethyl-3,3-di-tert-butyl-cyclobutyl)-acetic acid; [0336]
(1-Aminomethyl-3,3-diphenyl-cyclobutyl)-acetic acid; [0337]
(1-Aminomethyl-3,3-dibenzyl-cyclobutyl)-acetic acid; [0338]
(1-Aminomethyl-2,2,4,4-tetramethyl-cyclobutyl)-acetic acid; [0339]
(1-Aminomethyl-2,2,3,3,4,4-hexamethyl-cyclobutyl)-acetic acid;
[0340] (R)-(1-Aminomethyl-2,2-dimethyl-cyclobutyl)-acetic acid;
[0341] (S)-(1-Aminomethyl-2,2-dimethyl-cyclobutyl)-acetic acid;
[0342] (1R-cis)-(1-Aminomethyl-2-methyl-cyclobutyl)-acetic acid;
[0343]
[1R-(1.alpha.,2.alpha.,3.alpha.)]-(1-Aminomethyl-2,3-dimethyl-cyclobutyl)-
-acetic acid; [0344]
(1.alpha.,2.alpha.,4.alpha.)-(1-Aminomethyl-2,4-dimethyl-cyclobutyl)-acet-
ic acid; [0345]
[1R-(1.alpha.,2.alpha.,3.beta.)]-(1-Aminomethyl-2,3-dimethyl-cyclobutyl)--
acetic acid; [0346]
(1.alpha.,2.alpha.,4.beta.)-(1-Aminomethyl-2,4-dimethyl-cyclobutyl)-aceti-
c acid; [0347]
(1S-trans)-(1-Aminomethyl-2-methyl-cyclobutyl)-acetic acid; [0348]
[1S-(1.alpha.,2.beta.,3.beta.)]-(1-Aminomethyl-2,3-dimethyl-cyclobutyl)-a-
cetic acid; [0349]
(1.alpha.,2.beta.,3.beta.)-(1-Aminomethyl-2,4-dimethyl-cyclobutyl)-acetic
acid; [0350]
[1S-(1.alpha.,2.beta.,3.alpha.)]-(1-Aminomethyl-2,3-dimethyl-cyclobutyl)--
acetic acid; [0351]
(1.alpha.,2.beta.,4.alpha.)-(1-Aminomethyl-2,4-dimethyl-cyclobutyl)-aceti-
c acid; [0352]
(1R-trans)-(1-Aminomethyl-2-methyl-cyclobutyl)-acetic acid; [0353]
[1R-(1.alpha.,2.beta.,3.beta.)]-(1-Aminomethyl-2,3-dimethyl-cyclobutyl)-a-
cetic acid; [0354]
[1R-(1.alpha.,2.beta.,4.beta.)]-(1-Aminomethyl-2-ethyl-4-methyl-cyclobuty-
l)-acetic acid; [0355]
[1R-(1.alpha.,2.beta.,3.alpha.)]-(1-Aminomethyl-2,3-dimethyl-cyclobutyl)--
acetic acid; [0356]
(1.alpha.,2.beta.,4.alpha.)-(1-Aminomethyl-2,4-dimethyl-cyclobutyl)-aceti-
c acid; [0357] (1S-cis)-(1-Aminomethyl-2-methyl-cyclobutyl)-acetic
acid; [0358]
[1S-(1.alpha.,2.alpha.,3.alpha.)]-(1-Aminomethyl-2,3-dimethyl-cy-
clobutyl)-acetic acid; [0359]
[1S-(1.alpha.,2.alpha.,3.alpha.)]-(1-Aminomethyl-2,4-dimethyl-cyclobutyl)-
-acetic acid; [0360]
[1S-(1.alpha.,2.beta.,3.alpha.)]-(1-Aminomethyl-2,3-dimethyl-cyclobutyl)--
acetic acid; [0361]
(1.alpha.,2.alpha.,4.beta.)-(1-Aminomethyl-2,4-dimethyl-cyclopentyl)-acet-
ic acid; [0362] (3S,
4S)-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid; [0363]
(3R, 4R)-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid;
[0364] (3S, 4S)-(1-Aminomethyl-3,4-diethyl-cyclopentyl)-acetic
acid; [0365] (3R,
4R)-(1-Aminomethyl-3,4-diethyl-cyclopentyl)-acetic acid; [0366]
(3S, 4S)-(1-Aminomethyl-3,4-diisopropyl-cyclopentyl)-acetic acid;
[0367] (3R, 4R)-(1-Aminomethyl-3,4-diisopropyl-cyclopentyl)-acetic
acid; [0368] (3S,
4S)-(1-Aminomethyl-3,4-di-tert-butyl-cyclopentyl)-acetic acid;
[0369] (3R,
4R)-(1-Aminomethyl-3,4-di-tert-butyl-cyclopentyl)-acetic acid;
[0370] (3S, 4S)-(1-Aminomethyl-3,4-diphenyl-cyclopentyl)-acetic
acid; [0371] (3R,
4R)-(1-Aminomethyl-3,4-diphenyl-cyclopentyl)-acetic acid; [0372]
(3S, 4S)-(1-Aminomethyl-3,4-dibenzyl-cyclopentyl)-acetic acid;
[0373] (3R, 4R)-(1-Aminomethyl-3,4-diphenyl-cyclopentyl)-acetic
acid; [0374]
[1S-(1.alpha.,3.alpha.,4.beta.)]-(1-Aminomethyl-3-methyl-4-ethyl-cyclopen-
tyl)-acetic acid; [0375]
[1R-(1.alpha.,3.beta.,4.alpha.)]-(1-Aminomethyl-3-methyl-4-ethyl-cyclopen-
tyl)-acetic acid; [0376]
[1R-(1.alpha.,3.alpha.,4.beta.)]-(1-Aminomethyl-3-methyl-4-ethyl-cyclopen-
tyl)-acetic acid; [0377]
[1S-(1.alpha.,3.beta.,4.alpha.)]-(1-Aminomethyl-3-methyl-4-ethyl-cyclopen-
tyl)-acetic acid; [0378]
[1S-(1.alpha.,3.alpha.,4.beta.)]-(1-Aminomethyl-3-methyl-4-isopropyl-cycl-
opentyl)-acetic acid; [0379]
[1R-(1.alpha.,3.beta.,4.alpha.)]-(1-Aminomethyl-3-methyl-4-isopropyl-cycl-
opentyl)-acetic acid; [0380]
[1R-(1.alpha.,3.alpha.,4.beta.)]-(1-Aminomethyl-3-methyl-4-isopropyl-cycl-
opentyl)-acetic acid; [0381]
[1S-(1.alpha.,3.beta.,4.alpha.)]-(1-Aminomethyl-3-methyl-4-isopropyl-cycl-
opentyl)-acetic acid; [0382]
[1S-(1.alpha.,3.alpha.,4.beta.)]-(1-Aminomethyl-3-methyl-4-tert-butyl-cyc-
lopentyl)-acetic acid; [0383]
[1R-(1.alpha.,3.beta.,4.alpha.)]-(1-Aminomethyl-3-methyl-4-tert-butyl-cyc-
lopentyl)-acetic acid; [0384]
[1R-(1.alpha.,3.alpha.,4.beta.)]-(1-Aminomethyl-3-methyl-4-tert-butyl-cyc-
lopentyl)-acetic acid; [0385]
[1S-(1.alpha.,3.beta.,4.beta.)]-(1-Aminomethyl-3-methyl-4-tert-butyl-cycl-
opentyl)-acetic acid; [0386]
[1S-(1.alpha.,3.alpha.,4.beta.)]-(1-Aminomethyl-3-methyl-4-phenyl-cyclope-
ntyl)-acetic acid; [0387]
[1R-(1.alpha.,3.beta.,4.alpha.)]-(1-Aminomethyl-3-methyl-4-phenyl-cyclope-
ntyl)-acetic acid; [0388]
[1R-(1.alpha.,3.alpha.,4.beta.)]-(1-Aminomethyl-3-methyl-4-phenyl-cyclope-
ntyl)-acetic acid; [0389]
[1S-(1.alpha.,3.beta.,4.alpha.)]-(1-Aminomethyl-3-methyl-4-phenyl-cyclope-
ntyl)-acetic acid; [0390]
[1S-(1.alpha.,3.alpha.,4.beta.)]-(1-Aminomethyl-3-benzyl-4-methyl-cyclope-
ntyl)-acetic acid; [0391]
[1R-(1.alpha.,3.beta.,4.alpha.)]-(1-Aminomethyl-3-benzyl-4-methyl-cyclope-
ntyl)-acetic acid; [0392]
[1R-(1.alpha.,3.alpha.,4.beta.)]-(1-Aminomethyl-3-benzyl-4-methyl-cyclope-
ntyl)-acetic acid; [0393]
[1S-(1.alpha.,3.beta.,4.alpha.)]-(1-Aminomethyl-3-benzyl-4-methyl-cyclope-
ntyl)-acetic acid; [0394]
[1S-(1.alpha.,3.alpha.,4.beta.)]-(1-Aminomethyl-3-ethyl-4-isopropyl-cyclo-
pentyl)-acetic acid; [0395]
[1R-(1.alpha.,3.beta.,4.alpha.)]-(1-Aminomethyl-3-ethyl-4-isopropyl-cyclo-
pentyl)-acetic acid; [0396]
[1R-(1.alpha.,3.alpha.,4.beta.)]-(1-Aminomethyl-3-ethyl-4-isopropyl-cyclo-
pentyl)-acetic acid; [0397]
[1S-(1.alpha.,3.beta.,4.alpha.)]-(1-Aminomethyl-3-ethyl-4-isopropyl-cyclo-
pentyl)-acetic acid; [0398]
[1S-(1.alpha.,3.alpha.,4.beta.)]-(1-Aminomethyl-3-tert-butyl-4-ethyl-cycl-
opentyl)-acetic acid; [0399]
[1R-(1.alpha.,3.beta.,4.alpha.)]-(1-Aminomethyl-3-tert-butyl-4-ethyl-cycl-
opentyl)-acetic acid; [0400]
[1R-(1.alpha.,3.alpha.,4.beta.)]-(1-Aminomethyl-3-tert-butyl-4-ethyl-cycl-
opentyl)-acetic acid; [0401]
[1S-(1.alpha.,3.beta.,4.alpha.)]-(1-Aminomethyl-3-tert-butyl-4-ethyl-cycl-
opentyl)-acetic acid; [0402]
[1S-(1.alpha.,3.alpha.,4.beta.)]-(1-Aminomethyl-3-ethyl-4-phenyl-cyclopen-
tyl)-acetic acid; [0403]
[1R-(1.alpha.,3.beta.,4.alpha.)]-(1-Aminomethyl-3-ethyl-4-phenyl-cyclopen-
tyl)-acetic acid; [0404]
[1R-(1.alpha.,3.alpha.,4.beta.)]-(1-Aminomethyl-3-ethyl-4-phenyl-cyclopen-
tyl)-acetic acid; [0405]
[1S-(1.alpha.,3.beta.,4.alpha.)]-(1-Aminomethyl-3-ethyl-4-phenyl-cyclopen-
tyl)-acetic acid; [0406]
[1S-(1.alpha.,3.alpha.,4.beta.)]-(1-Aminomethyl-3-benzyl-4-ethyl-cyclopen-
tyl)-acetic acid; [0407]
[1R-(1.alpha.,3.beta.,4.alpha.)]-(1-Aminomethyl-3-benzyl-4-ethyl-cyclopen-
tyl)-acetic acid;
[0408]
[1R-(1.alpha.,3.alpha.,4.beta.)]-(1-Aminomethyl-3-benzyl-4-ethyl--
cyclopentyl)-acetic acid; [0409]
[1S-(1.alpha.,3.beta.,4.alpha.)]-(1-Aminomethyl-3-benzyl-4-ethyl-cyclopen-
tyl)-acetic acid; [0410]
[1S-(1.alpha.,3.alpha.,4.beta.)]-(1-Aminomethyl-3-tert-butyl-4-isopropyl--
cyclopentyl)-acetic acid; [0411]
[1R-(1.alpha.,3.beta.,4.alpha.)]-(1-Aminomethyl-3-tert-butyl-4-isopropyl--
cyclopentyl)-acetic acid; [0412]
[1R-(1.alpha.,3.alpha.,4.beta.)]-(1-Aminomethyl-3-tert-butyl-4-isopropyl--
cyclopentyl)-acetic acid; [0413]
[1S-(1.alpha.,3.beta.,4.alpha.)]-(1-Aminomethyl-3-tert-butyl-4-isopropyl--
cyclopentyl)-acetic acid; [0414]
[1S-(1.alpha.,3.alpha.,4.beta.)]-(1-Aminomethyl-3-isopropyl-4-phenyl-cycl-
opentyl)-acetic acid; [0415]
[1R-(1.alpha.,3.beta.,4.alpha.)]-(1-Aminomethyl-3-isopropyl-4-phenyl-cycl-
opentyl)-acetic acid; [0416]
[1R-(1.alpha.,3.alpha.,4.beta.)]-(1-Aminomethyl-3-isopropyl-4-phenyl-cycl-
opentyl)-acetic acid; [0417]
[1S-(1.alpha.,3.beta.,4.alpha.)]-(1-Aminomethyl-3-isopropyl-4-phenyl-cycl-
opentyl)-acetic acid; [0418]
[1S-(1.alpha.,3.alpha.,4.beta.)]-(1-Aminomethyl-3-benzyl-4-isopropyl-cycl-
opentyl)-acetic acid; [0419]
[1R-(1.alpha.,3.beta.,4.alpha.)]-(1-Aminomethyl-3-benzyl-4-isopropyl-cycl-
opentyl)-acetic acid; [0420]
[1R-(1.alpha.,3.alpha.,4.beta.)]-(1-Aminomethyl-3-benzyl-4-isopropyl-cycl-
opentyl)-acetic acid; [0421]
[1S-(1.alpha.,3.beta.,4.alpha.)]-(1-Aminomethyl-3-benzyl-4-isopropyl-cycl-
opentyl)-acetic acid; [0422]
[1S-(1.alpha.,3.alpha.,4.beta.)]-(1-Aminomethyl-3-tert-butyl-4-phenyl-cyc-
lopentyl)-acetic acid; [0423]
[1R-(1.alpha.,3.beta.,4.alpha.)]-(1-Aminomethyl-3-tert-butyl-4-phenyl-cyc-
lopentyl)-acetic acid; [0424]
[1R-(1.alpha.,3.alpha.,4.beta.)]-(1-Aminomethyl-3-tert-butyl-4-phenyl-cyc-
lopentyl)-acetic acid; [0425]
[1S-(1.alpha.,3.beta.,4.alpha.)]-(1-Aminomethyl-3-tert-butyl-4-phenyl-cyc-
lopentyl)-acetic acid; [0426]
[1R-(1.alpha.,3.alpha.,4.beta.)]-(1-Aminomethyl-3-benzyl-4-tert-butyl-cyc-
lopentyl)-acetic acid; [0427]
[1S-(1.alpha.,3.beta.,4.alpha.)]-(1-Aminomethyl-3-benzyl-4-tert-butyl-cyc-
lopentyl)-acetic acid; [0428]
[1S-(1.alpha.,3.alpha.,4.beta.)]-(1-Aminomethyl-3-benzyl-4-tert-butyl-cyc-
lopentyl)-acetic acid; [0429]
[1R-(1.alpha.,3.beta.,4.alpha.)]-(1-Aminomethyl-3-benzyl-4-tert-butyl-cyc-
lopentyl)-acetic acid; [0430]
[1S-(1.alpha.,3.alpha.,4.beta.)]-(1-Aminomethyl-3-benzyl-4-phenyl-cyclope-
ntyl)-acetic acid; [0431]
[1R-(1.alpha.,3.beta.,4.alpha.)]-(1-Aminomethyl-3-benzyl-4-phenyl-cyclope-
ntyl)-acetic acid; [0432]
[1R-(1.alpha.,3.alpha.,4.beta.)]-(1-Aminomethyl-3-benzyl-4-phenyl-cyclope-
ntyl)-acetic acid; [0433]
[1S-(1.alpha.,3.beta.,4.alpha.)]-(1-Aminomethyl-3-benzyl-4-phenyl-cyclope-
ntyl)-acetic acid; [0434]
(1R-cis)-(1-Aminomethyl-2-methyl-cyclopentyl)-acetic acid; [0435]
(1S-cis)-(1-Aminomethyl-2-methyl-cyclopentyl)-acetic acid; [0436]
(1R-trans)-(1-Aminomethyl-2-methyl-cyclopentyl)-acetic acid; [0437]
(1S-trans)-(1-Aminomethyl-2-methyl-cyclopentyl)-acetic acid; [0438]
(R)-(1-Aminomethyl-2,2-dimethyl-cyclopentyl)-acetic acid; [0439]
(S)-(1-Aminomethyl-2,2-dimethyl-cyclopentyl)-acetic acid; [0440]
(1-Aminomethyl-2,2,5,5-tetramethyl-cyclopentyl)-acetic acid; [0441]
(1.alpha.,2.beta.,5.beta.)-(1-Aminomethyl-2,5-dimethyl-cyclopentyl)-aceti-
c acid; [0442] (2R,
5R)-(1-Aminomethyl-2,5-dimethyl-cyclopentyl)-acetic acid; [0443]
(2S, 5S)-(1-Aminomethyl-2,5-dimethyl-cyclopentyl)-acetic acid;
[0444]
(1.alpha.,2.alpha.,5.alpha.)-(1-Aminomethyl-2,5-dimethyl-cyclopentyl)-ace-
tic acid; [0445]
[1R-(1.alpha.,2.alpha.,3.alpha.)]-(1-Aminomethyl-2,3-dimethyl-cyclopentyl-
)-acetic acid; [0446]
[1R-(1.alpha.,2.beta.,3.alpha.)]-(1-Aminomethyl-2,3-dimethyl-cyclopentyl)-
-acetic acid; [0447]
[1R-(1.alpha.,2.alpha.,3.beta.)]-(1-Aminomethyl-2,3-dimethyl-cyclopentyl)-
-acetic acid; [0448]
[1R-(1.alpha.,2.beta.,3.beta.)]-(1-Aminomethyl-2,3-dimethyl-cyclopentyl)--
acetic acid; [0449]
[1S-(1.alpha.,2.alpha.,3.alpha.)]-(1-Aminomethyl-2,3-dimethyl-cyclopentyl-
)-acetic acid; [0450]
[1S-(1.alpha.,2.beta.,3.alpha.)]-(1-Aminomethyl-2,3-dimethyl-cyclopentyl)-
-acetic acid; [0451]
[1S-(1.alpha.,2.alpha.,3.beta.)]-(1-Aminomethyl-2,3-dimethyl-cyclopentyl)-
-acetic acid; [0452]
[1S-(1.alpha.,2.beta.,3.beta.)]-(1-Aminomethyl-2,3-dimethyl-cyclopentyl)--
acetic acid; [0453]
[1R-(1.alpha.,2.alpha.,4.alpha.)]-(1-Aminomethyl-2,4-dimethyl-cyclopentyl-
)-acetic acid; [0454]
[1S-(1.alpha.,2.alpha.,4.alpha.)]-(1-Aminomethyl-2,4-dimethyl-cyclopentyl-
)-acetic acid; [0455]
[1R-(1.alpha.,2.alpha.,4.beta.)]-(1-Aminomethyl-2,4-dimethyl-cyclopentyl)-
-acetic acid; [0456]
[1S-(1.alpha.,2.alpha.,4.beta.)]-(1-Aminomethyl-2,4-dimethyl-cyclopentyl)-
-acetic acid; [0457]
[1R-(1.alpha.,2.beta.,4.alpha.)]-(1-Aminomethyl-2,4-dimethyl-cyclopentyl)-
-acetic acid; [0458]
[1S-(1.alpha.,2.beta.,4.alpha.)]-(1-Aminomethyl-2,4-dimethyl-cyclopentyl)-
-acetic acid; [0459]
[1R-(1.alpha.,2.beta.,4.beta.)]-(1-Aminomethyl-2,4-dimethyl-cyclopentyl)--
acetic acid; and [0460]
[1S-(1.alpha.,2.beta.,4.beta.)]-(1-Aminomethyl-2,4-dimethyl-cyclopentyl)--
acetic acid.
[0461] Other preferred embodiments of the invention methods utilize
a compound of the Formula III, IIIC, IIIF, IIIG, or IIIH, wherein R
is a sulfonamide selected from --NHSO.sub.2R.sup.15 or
--SO.sub.2NHR.sup.15 wherein R.sup.15 is straight or branched alkyl
or trifluoromethyl.
[0462] Other preferred embodiments of the invention methods utilize
a compound of the Formula III, IIIC, IIIF, IIIG, or IIIH that is
N-[2-(1-aminomethyl-cyclohexyl)-ethyl]-methanesulfonamide.
[0463] Other preferred embodiments of the invention methods utilize
a compound of the Formula III, IIIC, IIIF, IIIG, or IIIH, wherein R
is a phosphonic acid, --PO.sub.3H.sub.2.
[0464] Other preferred embodiment of the invention methods utilize
a compound of the Formula III, IIIC, IIIF, IIIG, or IIIH that is
(1-aminomethyl-cyclohexylmethyl)-phosphonic acid and
(2-aminomethyl-4-methyl-pentyl)-phosphonic acid.
[0465] Other preferred embodiments of the invention methods utilize
a compound of the Formula II, IIIC, IIIF, IIIG, or IIIH, wherein
other preferred compounds are those wherein R is a heterocycle
selected from: ##STR6##
[0466] Other preferred embodiments of the invention methods are
those that utilize a compound of the Formula III, IIIC, IIIF, IIIG,
or IIIH, that is
C-[1-(1H-tetrazol-5-ylmethyl)cyclohexyl]-methylamine or
4-methyl-2-(1H-tetrazol-5-ylmethyl)-pentylamine.
[0467] Especially preferred embodiments of the invention methods
utilize a compound of the Formula III, IIIC, IIIF, IIIG, or IIIH
wherein: [0468] m is an integer of from 0 to 2; [0469] p is an
integer of 2; and ##STR7##
[0470] Other more preferred embodiments of the invention methods
are those that utilize a compound of the Formula III, IIIC, IIIF,
IIIG, or IIIH that is
3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one, or a
pharmaceutically acceptable salt thereof.
[0471] Other more preferred embodiments of the invention methods
are those that utilize a compound of the Formula III, IIIC, IIIF,
IIIG, or IIIH that is
3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one
hydrochloride.
[0472] Other more preferred embodiments of the invention methods
are those that utilize a compound of the Formula III, IIIC, IIIF,
IIIG, or IIIH that is
3-(1-aminomethyl-cycloheptylmethyl)-4H-[1,2,4]oxadiazol-5-one, or a
pharmaceutically acceptable salt thereof.
[0473] Other more preferred embodiments of the invention methods
are those that utilize a compound of the Formula III, IIIC, IIIF,
IIIG, or IIIH that is
3-(1-aminomethyl-cycloheptylmethyl)-4H-[1,2,4]oxadiazol-5-one
hydrochloride.
[0474] Other more preferred embodiments of the invention methods
are those that utilizes a compound of the Formula III, IIIC, IIIF,
IIIG, or IIIH that is
C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, or a
pharmaceutically acceptable salt thereof.
[0475] Alpha2delta ligands of the Formulas III, IIIC, IIIF, IIIG,
and IIIH, and methods of synthesizing them, are described in PCT
Patent Application No. WO 99/31075, which is incorporated herein by
reference in its entirety.
[0476] Other preferred embodiments of the invention methods utilize
an alpha2delta ligand that is a compound of the Formula IV ##STR8##
or a pharmaceutically acceptable salt thereof wherein: [0477]
R.sup.1 is hydrogen, straight or branched alkyl of from 1 to 6
carbon atoms or phenyl; [0478] R.sup.2 is straight or branched
alkyl of from 1 to 8 carbon atoms, [0479] straight or branched
alkenyl of from 2 to 8 carbon atoms, [0480] cycloalkyl of from 3 to
7 carbon atoms, [0481] alkoxy of from 1 to 6 carbon atoms, [0482]
-alkylcycloalkyl, [0483] -alkylalkoxy, [0484] -alkyl OH [0485]
-alkylphenyl, [0486] -alkylphenoxy, [0487] -phenyl or substituted
phenyl; and [0488] R.sup.1 is straight or branched alkyl of from 1
to 6 carbon atoms or phenyl when R.sup.2 is methyl.
[0489] Other preferred embodiments of the invention methods are
those that employ a compound of Formula IV wherein R.sup.1 is
hydrogen, and R.sup.2 is alkyl.
[0490] Other preferred embodiments of the invention methods are
those that employ a compound of Formula IV wherein R.sup.1 is
methyl, and R.sup.2 is alkyl.
[0491] Other preferred embodiments of the invention methods are
those that employ a compound of Formula IV wherein R.sup.1 is
methyl, and R.sup.2 is methyl or ethyl.
[0492] Other preferred embodiments of the invention methods are
those that employ a compound of Formula IV selected from: [0493]
3-Aminomethyl-5-methylheptanoic acid; [0494]
3-Aminomethyl-5-methyl-octanoic acid; [0495]
3-Aminomethyl-5-methyl-nonanoic acid; [0496]
3-Aminomethyl-5-methyl-decanoic acid; [0497]
3-Aminomethyl-5-methyl-undecanoic acid; [0498]
3-Aminomethyl-5-methyl-dodecanoic acid; [0499]
3-Aminomethyl-5-methyl-tridecanoic acid; [0500]
3-Aminomethyl-5-cyclopropyl-hexanoic acid; [0501]
3-Aminomethyl-5-cyclobutyl-hexanoic acid; [0502]
3-Aminomethyl-5-cyclopentyl-hexanoic acid; [0503]
3-Aminomethyl-5-cyclohexyl-hexanoic acid; [0504]
3-Aminomethyl-5-trifluoromethyl-hexanoic acid; [0505]
3-Aminomethyl-5-phenyl-hexanoic acid; [0506]
3-Aminomethyl-5-(2-chlorophenyl)-hexanoic acid; [0507]
3-Aminomethyl-5-(3-chlorophenyl)-hexanoic acid; [0508]
3-Aminomethyl-5-(4-chlorophenyl)-hexanoic acid; [0509]
3-Aminomethyl-5-(2-methoxyphenyl)-hexanoic acid; [0510]
3-Aminomethyl-5-(3-methoxyphenyl)-hexanoic acid; [0511]
3-Aminomethyl-5-(4-methoxyphenyl)-hexanoic acid; and [0512]
3-Aminomethyl-5-(phenylmethyl)-hexanoic acid. [0513]
(3R,4S)-3-Aminomethyl-4,5-dimethyl-hexanoic acid; [0514]
3-Aminomethyl-4,5-dimethyl-hexanoic acid; [0515]
(3R,4S)-3-Aminomethyl-4,5-dimethyl-hexanoic acid MP; [0516]
(3S,4S)-3-Aminomethyl-4,5-dimethyl-hexanoic acid; [0517]
(3R,4R)-3-Aminomethyl-4,5-dimethyl-hexanoic acid MP; [0518]
3-Aminomethyl-4-isopropyl-hexanoic acid; [0519]
3-Aminomethyl-4-isopropyl-heptanoic acid; [0520]
3-Aminomethyl-4-isopropyl-octanoic acid; [0521]
3-Aminomethyl-4-isopropyl-nonanoic acid; [0522]
3-Aminomethyl-4-isopropyl-decanoic acid; [0523]
3-Aminomethyl-4-phenyl-5-methyl-hexanoic acid; [0524]
(3S,5S)-3-Aminomethyl-5-methoxy-hexanoic acid; [0525] (3S
,5S)-3-Aminomethyl-5-ethoxy-hexanoic acid; [0526]
(3S,5S)-3-Aminomethyl-5-propoxy-hexanoic acid; [0527]
(3S,5S)-3-Aminomethyl-5-isopropoxy-hexanoic acid; [0528]
(3S,5S)-3-Aminomethyl-5-tert-butoxy-hexanoic acid; [0529]
(3S,5S)-3-Aminomethyl-5-fluoromethoxy-hexanoic acid; [0530]
(3S,5S)-3-Aminomethyl-5-(2-fluoro-ethoxy)-hexanoic acid; [0531] (3S
,5S)-3-Aminomethyl-5-(3,3,3-trifl uoro-propoxy)-hexanoic acid;
[0532] (3S,5S)-3-Aminomethyl-5-phenoxy-hexanoic acid; [0533]
(3S,5S)-3-Aminomethyl-5-(4-chloro-phenoxy)-hexanoic acid; [0534]
(3S,5S)-3-Aminomethyl-5-(3-chloro-phenoxy)-hexanoic acid; [0535]
(3S,5S)-3-Aminomethyl-5-(2-chloro-phenoxy)-hexanoic acid; [0536]
(3S,5S)-3-Aminomethyl-5-(4-fluoro-phenoxy)-hexanoic acid; [0537]
(3S,5S)-3-Aminomethyl-5-(3-fluoro-phenoxy)-hexanoic acid; [0538]
(3S,5S)-3-Aminomethyl-5-(2-fluoro-phenoxy)-hexanoic acid; [0539]
(3S,5S)-3-Aminomethyl-5-(4-methoxy-phenoxy)-hexanoic acid; [0540]
(3S,5S)-3-Aminomethyl-5-(3-methoxy-phenoxy)-hexanoic acid; [0541]
(3S,5S)-3-Aminomethyl-5-(2-methoxy-phenoxy)-hexanoic acid; [0542]
(3S,5S)-3-Aminomethyl-5-(4-nitro-phenoxy)-hexanoic acid; [0543]
(3S,5S)-3-Aminomethyl-5-(3-nitro-phenoxy)-hexanoic acid; [0544]
(3S,5S)-3-Aminomethyl-5-(2-nitro-phenoxy)-hexanoic acid; [0545]
(3S,5S)-3-Aminomethyl-6-hydroxy-5-methyl-hexanoic acid; [0546]
(3S,5S)-3-Aminomethyl-6-methoxy-5-methyl-hexanoic acid; [0547]
(3S,5S)-3-Aminomethyl-6-ethoxy-5-methyl-hexanoic acid; [0548]
(3S,5S)-3-Aminomethyl-5-methyl-6-propoxy-hexanoic acid; [0549]
(3S,5S)-3-Aminomethyl-6-isopropoxy-5-methyl-hexanoic acid; [0550]
(3S,5S)-3-Aminomethyl-6-tert-butoxy-5-methyl-hexanoic acid; [0551]
(3S,5S)-3-Aminomethyl-6-fluoromethoxy-5-methyl-hexanoic acid;
[0552] (3S,5S)-3-Aminomethyl-6-(2-fluoro-ethoxy)-5-methyl-hexanoic
acid; [0553]
(3S,5S)-3-Aminomethyl-5-methyl-6-(3,3,3-trifluoro-propoxy)-hexanoic
acid; [0554] (3S,5S)-3-Aminomethyl-5-methyl-6-phenoxy-hexanoic
acid; [0555]
(3S,5S)-3-Aminomethyl-6-(4-chloro-phenoxy)-5-methyl-hexanoic acid;
[0556] (3S,5S)-3-Aminomethyl-6-(3-chloro-phenoxy)-5-methyl-hexanoic
acid; [0557]
(3S,5S)-3-Aminomethyl-6-(2-chloro-phenoxy)-5-methyl-hexanoic acid;
[0558] (3S,5S)-3-Aminomethyl-6-(4-fluoro-phenoxy)-5-methyl-hexanoic
acid; [0559]
(3S,5S)-3-Aminomethyl-6-(3-fluoro-phenoxy)-5-methyl-hexanoic acid;
[0560] (3S,5S)-3-Aminomethyl-6-(2-fluoro-phenoxy)-5-methyl-hexanoic
acid; [0561]
(3S,5S)-3-Aminomethyl-6-(4-methoxy-phenoxy)-5-methyl-hexanoic acid;
[0562]
(3S,5S)-3-Aminomethyl-6-(3-methoxy-phenoxy)-5-methyl-hexanoic acid;
[0563] (3S
,5S)-3-Aminomethyl-6-(2-methoxy-phenoxy)-5-methyl-hexanoic acid;
[0564] (3S,5S)-3-Aminomethyl-5-methyl
6-(4-trifluoromethyl-phenoxy)-hexanoic acid; [0565] (3S
,5S)-3-Aminomethyl-5-methyl 6-(3-trifluoromethyl-phenoxy)-hexanoic
acid; [0566] (3S,5S)-3-Aminomethyl-5-methyl
6-(2-trifluoromethyl-phenoxy)-hexanoic acid; [0567]
(3S,5S)-3-Aminomethyl-5-methyl 6-(4-nitro-phenoxy)-hexanoic acid;
[0568] (3S,5S)-3-Aminomethyl-5-methyl 6-(3-nitro-phenoxy)-hexanoic
acid; [0569] (3S,5S)-3-Aminomethyl-5-methyl
6-(2-nitro-phenoxy)-hexanoic acid; [0570]
(3S,5S)-3-Aminomethyl-6-benzyloxy-5-methyl-hexanoic acid; [0571]
(3S,5S)-3-Aminomethyl-7-hydroxy-5-methyl-heptanoic acid; [0572]
(3S,5S)-3-Aminomethyl-7-methoxy-5-methyl-heptanoic acid; [0573]
(3S,5S)-3-Aminomethyl-7-ethoxy-5-methyl-heptanoic acid; [0574]
(3S,5S)-3-Aminomethyl-5-methyl-7-propoxy-heptanoic acid; [0575]
(3S,5S)-3-Aminomethyl-7-isopropoxy-5-methyl-heptanoic acid; [0576]
(3S,5S)-3-Aminomethyl-7-tert-butoxy-5-methyl-heptanoic acid; [0577]
(3S,5S)-3-Aminomethyl-7-fluoromethoxy-5-methyl-heptanoic acid;
[0578] (3S
,5S)-3-Aminomethyl-7-(2-fluoro-ethoxy)-5-methyl-heptanoic acid;
[0579] (3S
,5S)-3-Aminomethyl-5-methyl-7-(3,3,3-trifluoro-propoxy)-heptanoic
acid; [0580] (3S,5S)-3-Aminomethyl-7-benzyloxy-5-methyl-heptanoic
acid; [0581] (3S,5S)-3-Aminomethyl-5-methyl-7-phenoxy-heptanoic
acid; [0582]
(3S,5S)-3-Aminomethyl-7-(4-chloro-phenoxy)-5-methyl-heptanoic acid;
[0583]
(3S,5S)-3-Aminomethyl-7-(3-chloro-phenoxy)-5-methyl-heptanoic acid;
[0584]
(3S,5S)-3-Aminomethyl-7-(2-chloro-phenoxy)-5-methyl-heptanoic acid;
[0585]
(3S,5S)-3-Aminomethyl-7-(4-fluoro-phenoxy)-5-methyl-heptanoic acid;
[0586]
(3S,5S)-3-Aminomethyl-7-(3-fluoro-phenoxy)-5-methyl-heptanoic acid;
[0587]
(3S,5S)-3-Aminomethyl-7-(2-fluoro-phenoxy)-5-methyl-heptanoic acid;
[0588]
(3S,5S)-3-Aminomethyl-7-(4-methoxy-phenoxy)-5-methyl-heptanoic
acid; [0589] (3S,5S)-3-Aminomethyl-7-(3-
methoxy-phenoxy)-5-methyl-heptanoic acid; [0590]
(3S,5S)-3-Aminomethyl-7-(2- methoxy -phenoxy)-5-methyl-heptanoic
acid; [0591]
(3S,5S)-3-Aminomethyl-5-methyl-7-(4-trifluoromethyl-phenoxy)-heptanoic
acid; [0592]
(3S,5S)-3-Aminomethyl-5-methyl-7-(3-trifluoromethyl-phenoxy)-heptanoic
acid; [0593]
(3S,5S)-3-Aminomethyl-5-methyl-7-(2-trifluoromethyl-phenoxy)-heptanoic
acid; [0594]
(3S,5S)-3-Aminomethyl-5-methyl-7-(4-nitro-phenoxy)-heptanoic acid;
[0595] (3S,5S)-3-Aminomethyl-5-methyl-7-(3-nitro-phenoxy)-heptanoic
acid; [0596]
(3S,5S)-3-Aminomethyl-5-methyl-7-(2-nitro-phenoxy)-heptanoic acid;
[0597] (3S,5S)-3-Aminomethyl-5-methyl-6-phenyl-hexanoic acid;
[0598] (3S,5S)-3-Aminomethyl-6-(4-chloro-phenyl)-5-methyl-hexanoic
acid; [0599]
(3S,5S)-3-Aminomethyl-6-(3-chloro-phenyl)-5-methyl-hexanoic acid;
[0600] (3S,5S)-3-Aminomethyl-6-(2-chloro-phenyl)-5-methyl-hexanoic
acid; [0601]
(3S,5S)-3-Aminomethyl-6-(4-methoxy-phenyl)-5-methyl-hexanoic acid;
[0602] (3S,5S)-3-Aminomethyl-6-(3-methoxy-phenyl)-5-methyl-hexanoic
acid; [0603]
(3S,5S)-3-Aminomethyl-6-(2-methoxy-phenyl)-5-methyl-hexanoic acid;
[0604] (3S,5S)-3-Aminomethyl-6-(4-fluoro-phenyl)-5-methyl-hexanoic
acid; [0605]
(3S,5S)-3-Aminomethyl-6-(3-fluoro-phenyl)-5-methyl-hexanoic acid;
[0606] (3S,5S)-3-Aminomethyl-6-(2-fluoro-phenyl)-5-methyl-hexanoic
acid; [0607] (3S,5R)-3-Aminomethyl-5-methyl-7-phenyl-heptanoic
acid; [0608]
(3S,5R)-3-Aminomethyl-7-(4-chloro-phenyl)-5-methyl-heptanoic acid;
[0609] (3S,5R)-3-Aminomethyl-7-(3-chloro-phenyl)-5-methyl-heptanoic
acid; [0610]
(3S,5R)-3-Aminomethyl-7-(2-chloro-phenyl)-5-methyl-heptanoic acid;
[0611]
(3S,5R)-3-Aminomethyl-7-(4-methoxy-phenyl)-5-methyl-heptanoic acid;
[0612]
(3S,5R)-3-Aminomethyl-7-(3-methoxy-phenyl)-5-methyl-heptanoic acid;
[0613]
(3S,5R)-3-Aminomethyl-7-(2-methoxy-phenyl)-5-methyl-heptanoic acid;
[0614] (3S,5R)-3-Aminomethyl-7-(4-fluoro-phenyl)-5-methyl-heptanoic
acid; [0615]
(3S,5R)-3-Aminomethyl-7-(3-fluoro-phenyl)-5-methyl-heptanoic acid;
[0616] (3S,5R)-3-Aminomethyl-7-(2-fluoro-phenyl)-5-methyl-heptanoic
acid; [0617] (3S,5R)-3-Aminomethyl-5-methyl-oct-7-enoic acid;
[0618] (3S,5R)-3-Aminomethyl-5-methyl-non-8-enoic acid; [0619]
(E)-(3S,5S)-3-Aminomethyl-5-methyl-oct-6-enoic acid; [0620]
(Z)-(3S,5S)-3-Aminomethyl-5-methyl-oct-6-enoic acid; [0621]
(Z)-(3S,5S)-3-Aminomethyl-5-methyl-non-6-enoic acid; [0622]
(E)-(3S,5S)-3-Aminomethyl-5-methyl-non-6-enoic acid; [0623]
(E)-(3S,5R)-3-Aminomethyl-5-methyl-non-7-enoic acid; [0624]
(Z)-(3S,5R)-3-Aminomethyl-5-methyl-non-7-enoic acid; [0625]
(Z)-(3S,5R)-3-Aminomethyl-5-methyl-dec-7-enoic acid; [0626]
(E)-(3S,5R)-3-Aminomethyl-5-methyl-undec-7-enoic acid; [0627]
(3S,5S)-3-Aminomethyl-5,6, 6-trimethyl-heptanoic acid; [0628]
(3S,5S)-3-Aminomethyl-5,6-dimethyl-heptanoic acid; [0629]
(3S,5S)-3-Aminomethyl-5-cyclopropyl-hexanoic acid; [0630]
(3S,5S)-3-Aminomethyl-5-cyclobutyl-hexanoic acid; [0631]
(3S,5S)-3-Aminomethyl-5-cyclopentyl-hexanoic acid; [0632]
(3S,5S)-3-Aminomethyl-5-cyclohexyl-hexanoic acid; [0633]
(3S,5R)-3-Aminomethyl-5-methyl-heptanoic acid; [0634]
(3S,5R)-3-Aminomethyl-5-methyl-octanoic acid; [0635]
(3S,5R)-3-Aminomethyl-5-methyl-nonanoic acid; [0636]
(3S,5R)-3-Aminomethyl-5-methyl-decanoic acid; [0637]
(3S,5R)-3-Aminomethyl-5-methyl-undecanoic acid; [0638]
(3S,5R)-3-Aminomethyl-5-methyl-dodecanoic acid; [0639]
(3S,5R)-3-Aminomethyl-5,9-dimethyl-decanoic acid; [0640]
(3S,5R)-3-Aminomethyl-5,7-dimethyl-octanoic acid; [0641]
(3S,5R)-3-Aminomethyl-5,8-dimethyl-nonanoic acid; [0642]
(3S,5R)-3-Aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid; [0643]
(3S,5R)-3-Aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid; [0644]
(3S,5R)-3-Aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid; [0645]
(3S,5R)-3-Aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid; [0646]
(3S,5R)-3-Aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid; [0647]
(3S,5R)-3-Aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid; [0648]
(3S,5R)-3-Aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid; [0649]
(3S,5R)-3-Aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid; [0650]
(3S,5R)-3-Aminomethyl-8-cyclopropyl-5-methyl-octanoic acid; [0651]
(3S,5R)-3-Aminomethyl-8-cyclobutyl-5-methyl-octanoic acid; [0652]
(3S,5R)-3-Aminomethyl-8-cyclopentyl-5-methyl-octanoic acid; [0653]
(3S,5R)-3-Aminomethyl-8-cyclohexyl-5-methyl-octanoic acid; [0654]
(3S,5S)-3-Aminomethyl-6-fluoro-5-methyl-hexanoic acid; [0655]
(3S,5S)-3-Aminomethyl-7-fluoro-5-methyl-heptanoic acid; [0656]
(3S,5R)-3-Aminomethyl-8-fluoro-5-methyl-octanoic acid; [0657]
(3S,5R)-3-Aminomethyl-9-fluoro-5-methyl-nonanoic acid; [0658]
(3S,5S)-3-Aminomethyl-7,7,7-trifluoro-5-methyl-heptanoic acid;
[0659] (3S,5R)-3-Aminomethyl-8,8,8-trifluoro-5-methyl-octanoic
acid; [0660] (3S,5R)-3-Aminomethyl-5-methyl-8-phenyl-octanoic acid;
[0661] (3S,5S)-3-Aminomethyl-5-methyl-6-phenyl-hexanoic acid; and
[0662] (3S,5R)-3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid.
[0663] Alpha2delta ligands of the Formula IV, and methods of
synthesizing them are described in PCT Patent Application No. WO
00/76958, which is incorporated herein by reference in its
entirety.
[0664] Other preferred embodiments of the invention methods utilize
an alpha2delta ligand which is a compound of the Formula (IXA) or
(IXB) ##STR9## or a pharmaceutically acceptable salt thereof,
wherein: [0665] n is an integer of from 0 to 2; [0666] R is
sulfonamide, [0667] amide, [0668] phosphonic acid, [0669]
heterocycle, [0670] sulfonic acid, or [0671] hydroxamic acid;
[0672] A is hydrogen or methyl; and ##STR10## [0673] a straight or
branched alkyl of from 1 to 11 carbons, or [0674]
--(CH.sub.2).sub.1-4- Y--(CH.sub.2).sub.0-4-phenyl wherein Y is
--O--, --S--, --NR'.sub.3 wherein: [0675] R'.sub.3 is alkyl of from
1 to 6 carbons, cycloalkyl of from 3 to 8 carbons, benzyl or phenyl
wherein benzyl or phenyl can be unsubstituted or substituted with
from 1 to 3 substituents each independently selected from alkyl,
alkoxy, halogen, hydroxy, carboxy, carboalkoxy, trifluoromethyl,
and nitro.
[0676] Other preferred embodiments of the invention methods utilize
an alpha2delta ligand that is a compound of the Formula (IXA) or
(IXB), wherein R is a sulfonamide selected from
--NHSO.sub.2R.sup.15 and --SO.sub.2NHR.sup.15, wherein R.sup.15 is
straight or branched alkyl or trifluoromethyl.
[0677] Other preferred embodiments of the invention methods utilize
a compound of the Formula (IXA) or (IXB) selected from: [0678]
4-Methyl-2-(1H-tetrazol-5-ylmethyl)-pentylamine; [0679]
3-(2-Aminomethyl-4-methyl-pentyl)-4H-[1,2,4]oxadiazole-5-thione,
HCl; [0680] (2-Aminomethyl-4-methyl-pentyl)-phosphonic acid; [0681]
3-(3-Amino-2-cyclopentyl-propyl)-4H-[1,2,4]oxadiazol-5-one; [0682]
3-(3-Amino-2-cyclopentyl-propyl)-4H-[1,2,4]thiadiazol-5-one; [0683]
2-Cyclopentyl-3-(2-oxo-2,3-dihydro-2.lamda..sup.4-[1,2,3,5]oxathiadiazol--
4-yl)-propylamine; [0684]
3-(3-Amino-2-cyclobutyl-propyl)-4H-[1,2,4]oxadiazol-5-one; [0685]
3-(3-Amino-2-cyclobutyl-propyl)-4H-[1,2,4]thiadiazol-5-one; and
[0686]
2-Cyclobutyl-3-(2-oxo-2,3-dihydro-2.lamda..sup.4-[1,2,3,5]oxathiadiazol-4-
-yl)-propylamine.
[0687] Other preferred embodiments of the invention methods utilize
a compound of the Formula (IXA) or (IXB), wherein R is a phosphonic
acid, --PO.sub.3H.sub.2.
[0688] Other preferred embodiments of the invention methods utilize
a compound of the Formula (IXA) or (IXB), wherein R is
##STR11##
[0689] Other preferred embodiments of the invention methods utilize
a compound of the Formula (IXA) or (IXB) wherein R is ##STR12##
[0690] Other preferred embodiments of the invention methods utilize
a compound of the Formula (IXA) or (IXB) that is
3-(2-aminomethyl-4-methyl-pentyl)-4H-[1,3,4]oxadiazol-5-one, or a
pharmaceutically acceptable salt thereof.
[0691] Other preferred embodiments of the invention methods utilize
a compound of the Formula (IXA) or (IXB) that is
3-(2-aminomethyl-4-methyl-pentyl)-4H-[1,2,4]oxadiazol-5-one
hydrochloride.
[0692] Alpha2delta ligands of the Formulas (IXA) and (IXB), and
methods of synthesizing them, are described in PCT Patent
Application No. WO 99/31074. This application is incorporated
herein by reference in its entirety.
[0693] Other preferred embodiments of the invention methods utilize
an alpha2delta ligand that is a compound of the Formula V, VI, VII,
or VIII ##STR13## or a pharmaceutically acceptable salt thereof,
wherein n is integer of from 1 to 4, where there are stereocenters,
each center may be independently R or S.
[0694] Other preferred embodiments of the invention methods utilize
a compound of the Formula V, VI, VII, or VIII, or a
pharmaceutically acceptable salt thereof, wherein n is an integer
of from 2 to 4.
[0695] Other preferred embodiments of the invention methods utilize
a compound of the Formula V or a pharmaceutically acceptable salt
thereof.
[0696] Other preferred embodiments of the invention methods utilize
a compound of the Formula V, VI, VII, or VIII, or a
pharmaceutically acceptable salt thereof, that is selected from the
following compounds and their pharmaceutically acceptable salts:
[0697] (1.alpha.,6.alpha.,8.beta.)
(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid; [0698]
(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid; [0699]
(2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid; [0700]
(2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid; [0701]
(3-Aminomethyl-bicyclo[3.2.0]hept-3-yl )-acetic acid; [0702]
(3-Aminomethyl-bicyclo[3.2.0]hept-3-yl )-acetic acid; [0703]
(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid; [0704]
(1.alpha.,5.beta.) (3-Aminomethyl-bicyclo[3.1.0]hex-3-yl)-acetic
acid, [0705] (1.alpha.,5.beta.)
(3-Aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, [0706]
(1.alpha.,5.beta.) (2-Aminomethyl-octahydro-pentalen-2-yl)-acetic
acid, [0707] (1.alpha.,6.beta.)
(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid, [0708]
(1.alpha.,7.beta.) (2-Aminomethyl-decahydro-azulen-2-yl)-acetic
acid, [0709] (1.alpha.,5.beta.)
(3-Aminomethyl-bicyclo[3.1.0]hex-3-yl)-acetic acid, [0710]
(1.alpha.,5.beta.) (3-Aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic
acid, [0711] (1.alpha.,5.beta.)
(2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid, [0712]
(1.alpha.,6.beta.) (2-Aminomethyl-octahydro-inden-2-yl)-acetic
acid, [0713] (1.alpha.,7.beta.)
(2-Aminomethyl-decahydro-azulen-2-yl)-acetic acid, [0714]
(1.alpha.,3.alpha.,5.alpha.)
(3-Aminomethyl-bicyclo[3.1.0]hex-3-yl)-acetic acid, [0715]
(1.alpha.,3.alpha.,5.alpha.)
(2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid, [0716]
(1.alpha.,6.alpha.,8.alpha.)
(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid, [0717]
(1.alpha.,7.alpha.,9.alpha.)
(2-Aminomethyl-decahydro-azulen-2-yl)-acetic acid, [0718]
(1.alpha.,3.beta.,5.alpha.)
(3-Aminomethyl-bicyclo[3.1.0]hex-3-yl)-acetic acid, [0719]
(1.alpha.,3.beta.,5.alpha.)
(3-Aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, [0720]
(1.alpha.,3.beta.,5.alpha.)
(2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid, [0721]
(1.alpha.,6.alpha.,8.beta.)
(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid, [0722]
(1.alpha.,7.alpha.,9.beta.)
(2-Aminomethyl-decahydro-azulen-2-yl)-acetic acid, [0723]
((1R,3R,6R)-3-Aminomethyl-bicyclo[4.1.0]hept-3-yl)-acetic acid,
[0724] ((1R,3S,6R)-3-Aminomethyl-bicyclo[4.1.0]hept-3-yl)-acetic
acid, [0725]
((1S,3S,6S)-3-Aminomethyl-bicyclo[4.1.0]hept-3-yl)-acetic acid,
[0726] ((1S,3R,6S)-3-Aminomethyl-bicyclo[4.1.0]hept-3-yl)-acetic
acid, [0727]
((1R,3R,6S)-3-Aminomethyl-bicyclo[4.2.0]oct-3-yl)-acetic acid,
[0728] ((1R,3S,6S)-3-Aminomethyl-bicyclo[4.2.0]oct-3-yl)-acetic
acid, [0729]
((1S,3S,6R)-3-Aminomethyl-bicyclo[4.2.0]oct-3-yl)-acetic acid,
[0730] ((1S,3R,6R)-3-Aminomethyl-bicyclo[4.2.0]oct-3-yl)-acetic
acid, [0731] ((3.alpha.R,5R,
7.alpha.S)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid, [0732]
((3.alpha.R,5S,
7.alpha.S)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid, [0733]
((3.alpha.S ,5S, 7.alpha.R)-5-Aminomethyl-octahydro-inden-5-yl
)-acetic acid, [0734] ((3.alpha.S
,5R,7.alpha.R)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid,
[0735]
((2R,4.alpha.S,8.alpha.R)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic
acid, [0736]
((2S,4.alpha.S,8.alpha.R)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic
acid, [0737]
((2S,4.alpha.R,8.alpha.S)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic
acid, [0738]
((2R,4.alpha.R,8.alpha.S)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic
acid, [0739]
((2R,4.alpha.S,9.alpha.R)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-
-acetic acid, [0740]
((2S,4.alpha.S,9.alpha.R)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-
-acetic acid, [0741]
((2S,4.alpha.R,9.alpha.S)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-
-acetic acid, [0742] ((2R,4.alpha.R,
9.alpha.S)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic
acid, [0743]
((1R,3R,6S)-3-Aminomethyl-bicyclo[4.1.0]hept-3-yl)-acetic acid,
[0744] ((1R,3S,6S)-3-Aminomethyl-bicyclo[4.1.0]hept-3-yl)-acetic
acid, [0745]
((1S,3S,6R)-3-Aminomethyl-bicyclo[4.1.0]hept-3-yl)-acetic acid,
[0746] ((1S,3R,6R)-3-Aminomethyl-bicyclo[4.1.0]hept-3-yl)-acetic
acid, [0747]
((1R,3R,6R)-3-Aminomethyl-bicyclo[4.2.0]oct-3-yl)-acetic acid,
[0748] ((1R,3S,6R)-3-Aminomethyl-bicyclo[4.2.0]oct-3-yl)-acetic
acid, [0749]
((1S,3S,6S)-3-Aminomethyl-bicyclo[4.2.0]oct-3-yl)-acetic acid,
[0750] ((1S,3R,6S)-3-Aminomethyl-bicyclo[4.2.0]oct-3-yl)-acetic
acid, [0751] ((3.alpha.R,5
R,7.alpha.R)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid,
[0752]
((3.alpha.R,5S,7.alpha.R)-5-Aminomethyl-octahydro-inden-5-yl)-acetic
acid, [0753]
((3.alpha.S,5S,7.alpha.S)-5-Aminomethyl-octahydro-inden-5-yl)-acetic
acid, [0754]
((3.alpha.S,5R,7.alpha.S)-5-Aminomethyl-octahydro-inden-5-yl
)-acetic acid, [0755] ((2R,4.alpha.,
8.alpha.R)-2-Aminomethyl-decahydro-naphthalen-2-yl )-acetic acid,
[0756]
((2S,4.alpha.S,8.alpha.R)-2-Aminomethyl-decahydro-naphthalen-2-yl)-aceti-
c acid, [0757]
((2S,4.alpha.R,8.alpha.S)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic
acid, [0758]
((2R,4.alpha.S,8.alpha.S)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic
acid, [0759]
((2R,4.alpha.R,9.alpha.R)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-
-acetic acid, [0760]
((2S,4.alpha.R,9.alpha.R)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-
-acetic acid, [0761]
((2S,4.alpha.S,9.alpha.S)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-
-acetic acid, and [0762]
((2R,4.alpha.S,9.alpha.S)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-
-acetic acid.
[0763] Other preferred embodiments of the invention methods utilize
an alpha2delta ligand of the Formula V, VI, VII, or VIII that is
(1.alpha.,3.alpha.,5.alpha.)
(3-aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, or a
pharmaceutically acceptable salt thereof.
[0764] Other preferred embodiments of the invention methods utilize
an alpha2delta ligand of the Formula V, VI, VII, or VIII that is
(1.alpha.,3.alpha.,5.alpha.)
(3-aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid
hydrochloride.
[0765] PCT Patent Application No. WO 01/28978, which is
incorporated herein by reference in its entirety, describes
alpha2delta ligands that are compounds of the Formulas V, VI, VII,
and VIII, and methods of synthesizing them.
[0766] Other preferred embodiments of the invention methods utilize
an alpha2delta ligand that is selected from the following compounds
and their pharmaceutically acceptable salts: [0767]
3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one;
[0768] (S,S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid;
[0769] (R,S)-3-aminomethyl-5-methyl-octanoic acid; [0770]
(S,R)-3-aminomethyl-5-methyl-octanoic acid; [0771]
(3-aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid; [0772]
(3-aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, wherein the
cyclobutyl ring is trans to the methylamine group; and [0773]
C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine.
[0774] These compounds can be prepared as described below or in PCT
Patent Application WO 99/21824, published May 6, 1999, PCT Patent
Application WO 00/76958, published Dec. 21, 2000, or PCT Patent
Application WO 01/28978, published Apr. 26, 2001. These
applications are incorporated herein by reference in their
entireties.
[0775] Other alpha2delta ligands that can be used in preferred
embodiments of the invention methods are described in PCT Patent
Application No. WO 99/31057, which is incorporated herein by
reference in its entirety. Such alpha2delta ligands are compounds
of the Formulas (XII) and (XIII) ##STR14## or a pharmaceutically
acceptable salt thereof wherein: [0776] n is an integer of from 0
to 2; [0777] R is sulfonamide, [0778] amide, [0779] phosphonic
acid, [0780] heterocycle, [0781] sulfonic acid, or [0782]
hydroxamic acid; and [0783] X is --O--, --S--, --S(O)--,
--S(O).sub.2--, or NR'.sub.1 wherein R'.sub.1 is hydrogen, straight
or branched alkyl of from 1 to 6 carbons, benzyl, --C(O)R'.sub.2
wherein R'.sub.2 is straight or branched alkyl of 1 to 6 carbons,
benzyl or phenyl or --CO.sub.2R'.sub.3 wherein R'.sub.3 is straight
or branched alkyl of from 1 to 6 carbons, or benzyl wherein the
benzyl or phenyl groups can be unsubstituted or substituted by from
1 to 3 substituents selected from halogen, trifluoromethyl, and
nitro.
[0784] Other alpha2delta ligands that may be utilized in preferred
embodiments of the invention methods are described, along with
methods of synthesizing them, in PCT Patent Application No. WO
98/17627, which is incorporated herein by reference in its
entirety. Such alpha2delta ligands are compounds of the formula
##STR15## or a pharmaceutically acceptable salt thereof wherein:
[0785] R is hydrogen or lower alkyl; [0786] R.sub.1 is hydrogen or
lower alkyl; ##STR16## [0787] a straight or branched alkyl of from
7 to 11 carbon atoms, or [0788]
--(CH.sub.2).sub.(1-4)-X--(CH.sub.2).sub.(0-4)-phenyl wherein
[0789] X is --O--, --S--, --NR.sub.3 wherein [0790] R.sub.3 is
alkyl of from 1 to 6 carbons, cycloalkyl of from 3 to 8 carbons,
benzyl or phenyl; [0791] wherein phenyl and benzyl can be
unsubstituted or substituted with from 1 to 3 substituents each
independently selected from alkyl, alkoxy, halogen, hydroxy,
carboxy, carboalkoxy, trifluoromethyl, amino, and nitro.
[0792] Other alpha2delta ligands that can be utilized in preferred
embodiments of the invention methods are described, along with
methods of synthesizing them, in PCT Patent Application No. WO
99/61424, which is incorporated herein by reference in its
entirety. Such alpha2delta ligands are compounds of the formulas
(1), (2), (3), (4), (5), (6), (7), and (8) ##STR17## and the
pharmaceutically acceptable salts and prodrugs of such compounds
wherein: [0793] R.sub.1 to R.sub.10 are each independently selected
from hydrogen or a straight or branched alkyl of from 1 to 6
carbons, benzyl, or phenyl; [0794] m is an integer of from 0 to 3;
[0795] n is an integer of from 1 to 2; [0796] o is an integer of
from 0 to 3; [0797] p is an integer of from 1 to 2; [0798] q is an
integer of from 0 to 2; [0799] r is an integer of from 1 to 2;
[0800] s is an integer of from 1 to 3; [0801] t is an integer of
from 0 to 2; and [0802] u is an integer of from 0 to 1.
[0803] Other alpha2delta ligands that can be utilized in preferred
embodiments of the invention methods are described, along with
methods of synthesizing them, in U.S. Provisional Patent
Application No. 60/368,413, filed on Mar. 28, 2002. Such
alpha2delta ligands are compounds of the formulas X, XA, XB, XI,
XIA, XIB and XB-1, as described below, and their pharmaceutically
acceptable salts.
[0804] Compounds of the formula X have the formula ##STR18##
wherein R.sub.1 is hydrogen or (C.sub.1-C.sub.3)alkyl optionally
substituted with from one to five fluorine atoms; [0805] R.sub.2 is
hydrogen or (C.sub.1-C.sub.3)alkyl optionally substituted with from
one to five fluorine atoms; [0806] R.sub.3 is
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl,
(C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.3)alkyl, phenyl,
phenyl-(C.sub.1-C.sub.3)alkyl, pyridyl,
pyridyl-(C.sub.1-C.sub.3)alkyl, phenyl-N(H)--, or pyridyl-N(H)--,
wherein each of the foregoing alkyl moieties can be optionally
substituted with from one to five fluorine atoms, preferably with
from zero to three fluorine atoms, and wherein said phenyl and said
pyridyl and the phenyl and pyridyl moieties of said
phenyl-(C.sub.1-C.sub.3)alkyl and said
pyridyl-(C.sub.1-C.sub.3)alkyl, respectively, can be optionally
substituted with from one to three substituents, preferably with
from zero to two substituents, independently selected from chloro,
fluoro, amino, nitro, cyano, (C.sub.1-C.sub.3)alkylamino,
(C.sub.1-C.sub.3)alkyl optionally substituted with from one to
three fluorine atoms and (C.sub.1-C.sub.3)alkoxy optionally
substituted with from one to three fluorine atoms; [0807] with the
proviso that when R.sub.1 is hydrogen, R.sub.2 is not hydrogen.
[0808] Compounds of the formula XI have the formula ##STR19##
wherein R.sub.1, R.sub.2, and R.sub.3 are defined as above in the
definition of compounds of the formula X.
[0809] Compounds of the formula XA have the formula ##STR20##
wherein R.sub.3 is defined as above in the definition of compounds
of the formula X.
[0810] Compounds of the formula XIA have the formula ##STR21##
wherein R.sub.3 is defined as above in the definition of compounds
of the formula X.
[0811] Compounds of the formula XIB have the formula ##STR22##
wherein R.sub.1, R.sub.2, and R.sub.3 are defined as above in the
definition of compounds of the formula X.
[0812] Compounds of the formula XB have the formula ##STR23##
wherein R.sub.1, R.sub.2, and R.sub.3 are defined as above in the
definition of compounds of the formula X.
[0813] Compounds of the formula XB-1 have the formula ##STR24##
wherein R.sub.3 is defined as above in the definition of compounds
of the formula X.
[0814] All U.S. patents and WO publications referenced above are
incorporated herein by reference in their entireties.
[0815] It should be appreciated that the terms "uses", "utilizes",
and "employs" are used interchangeably when describing an
embodiment of the present invention.
[0816] The phrase "lower alkyl" means a straight or branched alkyl
group or radical having from 1 to 6 carbon atoms, and includes
methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl,
tert-butyl, n-pentyl, n-hexyl, and the like.
[0817] The term "alkyl", as used herein, unless otherwise
indicated, includes saturated monovalent hydrocarbon radicals
having straight, branched or cyclic moieties or combinations
thereof. Examples of "alkyl" groups include, but are not limited
to, methyl, ethyl, propyl, isopropyl, butyl, iso- sec- and
tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and
the like.
[0818] The cycloalkyl groups are saturated monovalent carbocyclic
groups containing from 3 to 8 carbons and are selected from
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and
cyclooctyl, unless otherwise stated.
[0819] The benzyl and phenyl groups may be unsubstituted or
substituted by from 1 to 3 substituents selected from hydroxy,
amino, carboxy, carboalkoxy, halogen, CF.sub.3, nitro, alkyl, and
alkoxy. Preferred substituents are fluorine and chlorine.
[0820] Carboalkoxy is --COOalkyl wherein alkyl is as described
above. Preferred carboalokoxy groups are carbomathoxy and
carboethoxy.
[0821] The term "alkoxy", as used herein, unless otherwise
indicated, means "alkyl--O--", wherein "alkyl" is as defined above.
Examples of "alkoxy" groups include, but are not limited to,
methoxy, ethoxy, propoxy, butoxy and pentoxy.
[0822] The term "alkenyl", as used herein, unless otherwise
indicated, includes unsaturated hydrocarbon radicals having one or
more double bonds connecting two carbon atoms, wherein said
hydrocarbon radical may have straight, branched or cyclic moieties
or combinations thereof. Examples of "alkenyl" groups include, but
are not limited to, ethenyl, propenyl, butenyl, pentenyl, and
dimethylpentyl, and include E and Z forms where applicable.
[0823] The term "aryl", as used herein, unless otherwise indicated,
includes an aromatic ring system with no heteroatoms, which can be
either unsubstituted or substituted with one, two or three
substituents selected from the group consisting of halo,
(C.sub.1-C.sub.4)alkyl optionally substituted with from one to
three fluorine atoms and (C.sub.1-C.sub.4)alkoxy optionally
substituted with from one to three fluorine atoms.
[0824] The term "aryloxy", as used herein, unless otherwise
indicated, means "aryl-O--", wherein "aryl" is as defined
above.
[0825] The term "heteroaryl", as used herein, unless otherwise
indicated, includes an aromatic heterocycle containing five or six
ring members, of which from 1 to 4 can be heteroatoms selected,
independently, from N, S and O, and which rings can be
unsubstituted, monosubstituted or disubstituted with substituents
selected, independently, from the group consisting of halo,
(C.sub.1-C.sub.4)alkyl, and (C.sub.1-C.sub.4)alkoxy, optionally
substituted with from one to three fluorine atoms.
[0826] The term "heteroaryloxy", as used herein, unless otherwise
indicated, means "heteroaryl-O", wherein heteroaryl is as defined
above.
[0827] The term "one or more substituents", as used herein, refers
to a number of substituents that equals from one to the maximum
number of substituents possible based on the number of available
bonding sites.
[0828] The terms "halo" and "halogen", as used herein, unless
otherwise indicated, include, fluoro, chloro, bromo and iodo.
[0829] The term "treating", as used herein, refers to reversing,
alleviating, inhibiting the progress of, or preventing the disorder
or condition to which such term applies, or preventing one or more
symptoms of such condition or disorder. The term "treatment", as
used herein, refers to the act of treating, as "treating" is
defined immediately above.
[0830] The term "methylene", as used herein, means
--CH.sub.2--.
[0831] The term "ethylene", as used herein, means
--CH.sub.2CH.sub.2--.
[0832] The term "propylene", as used herein, means
--CH.sub.2CH.sub.2CH.sub.2--.
[0833] "Halogen" or "halo" includes fluorine, chlorine, bromine,
and iodine.
[0834] Sulfonamides are those of formula --NHSO.sub.2R.sup.15 or
--SO.sub.2NHR.sup.15 wherein R.sup.15 is a straight or branched
alkyl group of from 1 to 6 carbons or a trifluoromethyl.
[0835] Amides are compounds of formula --NHCOR.sup.12 wherein
R.sup.12 is straight or branched alkyl of from 1 to 6 carbons,
benzyl, and phenyl.
[0836] Phosphonic acids are --PO.sub.3H.sub.2.
[0837] Sulfonic acids are --SO.sub.3H .
[0838] Hydroxamic acid is ##STR25##
[0839] Heterocycles are groups of from 1 to 2 rings, the monocyclic
rings having from 4 to 7 ring members and the bicyclic ring having
from 7 to 12 ring members, wherein sucg rings contain from 1 to 6
heteroatoms selected from oxygen, nitrogen, and sulfur, with the
proviso that there are no two adjacent ring members that are
oxygen.
[0840] Preferred heterocycles are ##STR26##
[0841] Compounds of formulas I--XI-B (i.e., compounds of the
formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XA, XB, XB-1, XI,
XIA, and XIB) may contain chiral centers and therefore may exist in
different enantiomeric and diastereomeric forms. Individual isomers
can be obtained by known methods, such as optical resolution,
optically selective reaction, or chromatographic separation in the
preparation of the final product or its intermediate. This
invention relates to all optical isomers and all stereoisomers of
compounds of the formulas I--XIB, both as racemic mixtures and as
individual enantiomers and diastereoismers of such compounds, and
mixtures thereof, and to all pharmaceutical compositions and
methods of treatment defined above that contain or employ them,
respectively. Individual enantiomers of the compounds of formula I
may have advantages, as compared with the racemic mixtures of these
compounds, in the treatment of various disorders or conditions.
[0842] In so far as the compounds of formulas I--XIB of this
invention are basic compounds, they are all capable of forming a
wide variety of different salts with various inorganic and organic
acids. Although such salts must be pharmaceutically acceptable for
administration to animals, it is often desirable in practice to
initially isolate the base compound from the reaction mixture as a
pharmaceutically unacceptable salt and then simply convert to the
free base compound by treatment with an alkaline reagent and
thereafter convert the free base to a pharmaceutically acceptable
acid addition salt. The acid addition salts of the base compounds
of this invention are readily prepared by treating the base
compound with a substantially equivalent amount of the chosen
mineral or organic acid in an aqueous solvent or in a suitable
organic solvent, such as methanol or ethanol. Upon careful
evaporation of the solvent, the desired solid salt is readily
obtained. The acids which are used to prepare the pharmaceutically
acceptable acid addition salts of the aforementioned base compounds
of this invention are those which form non-toxic acid addition
salts, i.e., salts containing pharmaceutically acceptable anions,
such as the hydrochloride, hydrobromide, hydroiodide, nitrate,
sulfate or bisulfate, phosphate or acid phosphate, acetate,
lactate, citrate or acid citrate, tartrate or bi-tartrate,
succinate, maleate, fumarate, gluconate, saccharate, benzoate,
methanesulfonate, ethanesulfonate, benzenesulfonate,
p-toluenesulfonate and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate))salts.
[0843] The present invention also includes isotopically labelled
compounds, which are identical to those recited in formulas I--XIB,
but for the fact that one or more atoms are replaced by an atom
having an atomic mass or mass number different from the atomic mass
or mass number usually found in nature. Examples of isotopes that
can be incorporated into compounds of the present invention include
isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,
sulfur, fluorine and chlorine, such as .sup.2H, .sup.3H, .sup.13C,
.sup.11C, .sup.14C, .sup.15N, .sup.18O, .sup.17O, .sup.31p,
.sup.32p, .sup.35S, .sup.18 F, and .sup.36CI, respectively.
Compounds of the present invention, prodrugs thereof, and
pharmaceutically acceptable salts of said compounds or of said
prodrugs which contain the aforementioned isotopes and/or other
isotopes of other atoms are within the scope of this invention.
Certain isotopically labelled compounds of the present invention,
for example those into which radioactive isotopes such as .sup.3H
and .sup.14C are incorporated, are useful in drug and/or substrate
tissue distribution assays. Tritiated, i.e., .sup.3H, and
carbon-14, i.e., .sup.14C, isotopes are particularly preferred for
their ease of preparation and detectability. Further, substitution
with heavier isotopes such as deuterium, i.e., .sup.2H, can afford
certain therapeutic advantages resulting from greater metabolic
stability, for example increased in vivo half-life or reduced
dosage requirements and, hence, may be preferred in some
circumstances.
DETAILED DESCRIPTION OF THE INVENTION
[0844] The degree of binding to the .alpha.2.delta. subunit can be
determined using the radioligand binding assay using [3H]gabapentin
and the .alpha.2.delta. subunit derived from porcine brain tissue,
as described by N. S. Gee et al., J. Biol. Chem., 1996,
271:5879-5776.
[0845] All that is required to practice the method of this
invention is to administer an alpha2delta ligand, or a
pharmaceutically acceptable salt thereof, in an amount that is
therapeutically effective to treat one or more of the disorders or
conditions referred to above. Such therapeutically effective amount
will generally be from about 1 to about 300 mg/kg of subject body
weight. Typical doses will be from about 10 to about 5000 mg/day
for an adult subject of normal weight. In a clinical setting,
regulatory agencies such as, for example, the Food and Drug
Administration ("FDA") in the U.S. may require a particular
therapeutically effective amount.
[0846] In determining what constitutes an effective amount or a
therapeutically effective amount of an alpha2delta ligand, or a
pharmaceutically acceptable salt thereof, for treating one or more
of the disorders or conditions referred to above according to the
invention method, a number of factors will generally be considered
by the medical practitioner or veterinarian in view of the
experience of the medical practitioner or veterinarian, published
clinical studies, the subject's age, sex, weight and general
condition, as well as the type and extent of the disorder or
condition being treated, and the use of other medications, if any,
by the subject. As such, the administered dose may fall within the
ranges or concentrations recited above, or may vary outside, i.e.,
either below or above, those ranges depending upon the requirements
of the individual subject, the severity of the condition being
treated, and the particular therapeutic formulation being employed.
Determination of a proper dose for a particular situation is within
the skill of the medical or veterinary arts. Generally, treatment
may be initiated using smaller dosages of the alpha2delta ligand
that are less than optimum for a particular subject. Thereafter,
the dosage can be increased by small increments until the optimum
effect under the circumstance is reached. For convenience, the
total daily dosage may be divided and administered in portions
during the day, if desired.
[0847] Pharmaceutical compositions of an alpha2delta ligand, or a
pharmaceutically acceptable salt thereof, are produced by
formulating the active compound in dosage unit form with a
pharmaceutical carrier. Some examples of dosage unit forms are
tablets, capsules, pills, powders, aqueous and nonaqueous oral
solutions and suspensions, and parenteral solutions packaged in
containers containing either one or some larger number of dosage
units and capable of being subdivided into individual doses.
[0848] Some examples of suitable pharmaceutical carriers, including
pharmaceutical diluents, are gelatin capsules; sugars such as
lactose and sucrose; starches such as corn starch and potato
starch; cellulose derivatives such as sodium carboxymethyl
cellulose, ethyl cellulose, methyl cellulose, and cellulose acetate
phthalate; gelatin; talc; stearic acid; magnesium stearate;
vegetable oils such as peanut oil, cottonseed oil, sesame oil,
olive oil, corn oil, and oil of theobroma; propylene glycol,
glycerin; sorbitol; polyethylene glycol; water; agar; alginic acid;
isotonic saline, and phosphate buffer solutions; as well as other
compatible substances normally used in pharmaceutical
formulations.
[0849] The compositions to be employed in the invention can also
contain other components such as coloring agents, flavoring agents,
and/or preservatives. These materials, if present, are usually used
in relatively small amounts. The compositions can, if desired, also
contain other therapeutic agents commonly employed to treat the
disorder or condition being treated.
[0850] The percentage of the active ingredients in the foregoing
compositions can be varied within wide limits, but for practical
purposes it is preferably present in a concentration of at least
10% in a solid composition and at least 2% in a primary liquid
composition. The most satisfactory compositions are those in which
a much higher proportion of the active ingredient is present, for
example, up to about 95%.
[0851] Preferred routes of administration of an alpha2delta ligand,
or a pharmaceutically acceptable salt thereof, are oral or
parenteral. For example, a useful intravenous dose is between 5 and
50 mg, and a useful oral dosage is between 20 and 800 mg.
[0852] The alpha2delta ligand, or a pharmaceutically acceptable
salt thereof, may be administered in any form. Preferably,
administration is in unit dosage form. A unit dosage form of the
alpha2delta ligand, or a pharmaceutically acceptable salt thereof,
to be used in this invention may also comprise other compounds
useful in the therapy of the disorder or condition for which the
alpha2delta ligand is being administered or a disorder or condition
that is secondary to the disorder or treatment for which the
alpha2delta ligand is being administered.
[0853] Some of the compounds utilized in a method of the present
invention are capable of further forming pharmaceutically
acceptable salts, including, but not limited to, acid addition
and/or base salts. The acid addition salts are formed from basic
compounds, whereas the base addition salts are formed from acidic
compounds. All of these forms are within the scope of the compounds
useful in the method of the present invention.
[0854] Pharmaceutically acceptable acid addition salts of the basic
compounds useful in the method of the present invention include
nontoxic salts derived from inorganic acids such as hydrochloric,
nitric, phosphoric, sulfuric, hydrobromic, hydroiodic,
hydrofluoric, phosphorous, and the like, as well nontoxic salts
derived from organic acids, such as aliphatic mono- and
dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy
alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and
aromatic sulfonic acids, etc. Such salts thus include sulfate,
pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate,
monohydrogenphosphate, dihydrogenphosphate, metaphosphate,
pyrophosphate, chloride, bromide, iodide, acetate,
trifluoroacetate, propionate, caprylate, isobutyrate, oxalate,
malonate, succinate, suberate, sebacate, fumarate, maleate,
mandelate, benzoate, chlorobenzoate, methylbenzoate,
dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate,
phenylacetate, citrate, lactate, malate, tartrate,
methanesulfonate, and the like. Also contemplated are salts of
amino acids such as arginate and the like and gluconate,
galacturonate (see, for example, Berge S. M. et al.,
"Pharmaceutical Salts," J. of Pharma. Sci., 1977;66:1).
[0855] An acid addition salt of a basic compound useful in the
method of the present invention is prepared by contacting the free
base form of the compound with a sufficient amount of a desired
acid to produce a nontoxic salt in the conventional manner. The
free base form of the compound may be regenerated by contacting the
acid addition salt so formed with a base, and isolating the free
base form of the compound in the conventional manner. The free base
forms of compounds prepared according to a process of the present
invention differ from their respective acid addition salt forms
somewhat in certain physical properties such as solubility, crystal
structure, hygroscopicity, and the like, but otherwise free base
forms of the compounds and their respective acid addition salt
forms are equivalent for purposes of the present invention.
[0856] A pharmaceutically acceptable base addition salt of an
acidic compound useful in the method of the present invention may
be prepared by contacting the free acid form of the compound with a
nontoxic metal cation such as an alkali or alkaline earth metal
cation, or an amine, especially an organic amine. Examples of
suitable metal cations include sodium cation (Na.sup.+), potassium
cation (K.sup.+), magnesium cation (Mg.sup.2+), calcium cation
(Ca.sup.2+), and the like. Examples of suitable amines are
N,N'-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, dicyclohexylamine, ethylenediamine,
N-methylglucamine, and procaine (see, for example, Berge, supra.,
1977).
[0857] A base addition salt of an acidic compound useful in the
method of the present invention may be prepared by contacting the
free acid form of the compound with a sufficient amount of a
desired base to produce the salt in the conventional manner. The
free acid form of the compound may be regenerated by contacting the
salt form so formed with an acid, and isolating the free acid of
the compound in the conventional manner. The free acid forms of the
compounds useful in the method of the present invention differ from
their respective salt forms somewhat in certain physical properties
such as solubility, crystal structure, hygroscopicity, and the
like, but otherwise the salts are equivalent to their respective
free acid for purposes of the present invention.
[0858] Certain of the compounds useful in the method 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.
[0859] Certain of the compounds useful in the method of the present
invention possess one or more chiral centers, and each center may
exist in the R or S configuration. A method of the present
invention may utilize any diastereomeric, enantiomeric, or epimeric
form of an alpha2delta ligand, or a pharmaceutically acceptable
salt thereof, as well as mixtures thereof.
[0860] Additionally, certain compounds useful in the method of the
present invention may exist as geometric isomers such as the
entgegen (E) and zusammen (Z) isomers of alkenyl groups. A method
of the present invention may utilize any cis, trans, syn, anti,
entgegen (E), or zusammen (Z) isomer of an alpha2delta ligand, or a
pharmaceutically acceptable salt thereof, as well as mixtures
thereof.
[0861] Certain compounds useful in the method of the present
invention can exist as two or more tautomeric forms. Tautomeric
forms of the compounds may interchange, for example, via
enolization/de-enolization and the like. A method of the present
invention may utilize any tautomeric form of an alpha2delta ligand,
or a pharmaceutically acceptable salt thereof, as well as mixtures
thereof.
[0862] The following examples illustrate the invention
pharmaceutical compositions containing an alpha2delta ligand, and a
pharmaceutically acceptable carrier, diluent, or excipient. The
examples are representative only, and are not to be construed as
limiting the invention in any respect.
FORMULATION EXAMPLE 1
[0863] TABLE-US-00001 Tablet Formulation: Amount Ingredient (mg)
3-(1-aminomethyl-cyclohexylmethyl)-4H- 25 [1,2,4]oxadiazol-5-one
hydrochloride Lactose 50 Cornstarch (for mix) 10 Cornstarch (paste)
10 Magnesium stearate (1%) 5 Total 100
[0864] 3-(1-Aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one
hydrochloride, lactose, and cornstarch (for mix) are blended to
uniformity. The cornstarch (for paste) is suspended in 200 mL of
water and heated with stirring to form a paste. The paste is used
to granulate the mixed powders. The wet granules are passed through
a No. 8 hand screen and dried at 80.degree. C. The dry granules are
lubricated with the 1% magnesium stearate and pressed into a
tablet. Such tablets can be administered to a human from one to
four times a day for treatment of ADHD.
FORMULATION EXAMPLE 2
Coated Tablets:
[0865] The tablets of Formulation Example 1 are coated in a
customary manner with a coating of sucrose, potato starch, talc,
tragacanth, and colorant.
FORMULATION EXAMPLE 3
Injection vials:
[0866] The pH of a solution of 500 g of gabapentin and 5 g of
disodium hydrogen phosphate is adjusted to pH 6.5 in 3 L of
double-distilled water using 2 M hydrochloric acid. The solution is
sterile filtered, and the filtrate is filled into injection vials,
lyophilized under sterile conditions, and aseptically sealed. Each
injection vial contains 25 mg of gabapentin.
FORMULATION EXAMPLE 4
Suppositories:
[0867] A mixture of 25 g of (1.alpha.,3.alpha.,5.alpha.)
(3-aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid hydrochloride,
100 g of soya lecithin, and 1400 g of cocoa butter is fused, poured
into molds, and allowed to cool. Each suppository contains 25 mg of
(1.alpha.,3.alpha.,5.alpha.)
(3-aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid
hydrochloride.
FORMULATION EXAMPLE 5
Solution:
[0868] A solution is prepared from 1 g of
3-(2-aminomethyl-4-methyl-pentyl)-4H-[1,2,4]-oxadiazol-5-one
hydrochloride, 9.38 g of NaH.sub.2PO.sub.412H.sub.2O, 28.48 g of
Na.sub.2HPO.sub.412H.sub.2O, and 0.1 g benzalkonium chloride in 940
mL of double-distilled water. The pH of the solution is adjusted to
pH 6.8 using 2 M hydrochloric acid. The solution is diluted to 1.0
L with double-distilled water, and sterilized by irradiation. A 25
mL volume of the solution contains 25 mg of
3-(2-aminomethyl-4-methyl-pentyl)-4H-[1,2,4]-oxadiazol-5-one
hydrochloride.
FORMULATION EXAMPLE 6
Ointment:
[0869] 500 mg of
3-(1-aminomethyl-cycloheptylmethyl)-4H-[1,2,4]oxadiazol-5-one
hydrochloride is mixed with 99.5 g of petroleum jelly under aseptic
conditions. A 5 g portion of the ointment contains 25 mg of
3-(1-aminomethyl-cycloheptylmethyl)-4H-[1,2,4]oxadiazol-5-one
hydrochloride.
FORMULATION EXAMPLE 7
Capsules:
[0870] 2 kg of
3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one
hydrochloride are filled into hard gelatin capsules in a customary
manner such that each capsule contains 25 mg of
3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one
hydrochloride.
FORMULATION EXAMPLE 8
Ampoules:
[0871] A solution of 2.5 kg of gabapentin is dissolved in 60 L of
double-distilled water. The solution is sterile filtered, and the
filtrate is filled into ampoules. The ampoules are lyophilized
under sterile conditions and aseptically sealed. Each ampoule
contains 25 mg of gabapentin.
[0872] Having described the invention method, various embodiments
of the invention are hereupon claimed.
* * * * *