Gamma amino butyric and acid analogs

Details Gamma amino butyric and acid analogs Gamma amino butyric and acid analogs

2001-04-13

2003-09-30

Rotman, Alan L. (Department: 1625)

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

Organic compounds

Carboxylic acids and salts thereof

C562S443000, C562S553000, C562S567000, C562S571000, C562S568000, C514S385000, C514S585000, C514S561000

Reexamination Certificate

active

06627771

ABSTRACT:

BACKGROUND
Compounds of formula
wherein R
1
is hydrogen or a lower alkyl radical and n is 4, 5, or 6 are known in U.S. Pat. No. 4,024,175 and its divisional U.S. Pat. No. 4,087,544. The uses disclosed are: protective effect against cramp induced by thiosemicarbazide; protective action against cardiazole cramp; the cerebral diseases, epilepsy, faintness attacks, hypokinesia, and cranial traumas; and improvement in cerebral functions. The compounds are useful in geriatric patients. The patents are hereby incorporated by reference.
Compounds of formula
wherein R
1
is a straight or branched alkyl group having from 1 to 6 carbon atoms, phenyl, or cycloalkyl having from 3 to 6 carbon atoms; R
2
is hydrogen or methyl; and R
3
is hydrogen, methyl, or carboxyl are known in U.S. Pat. No. 5,563,175 and various divisionals. These patents are hereby incorporated by reference.
Compounds of formula
wherein R and R
1
are hydrogen or lower alkyl, and R
2
is
are known in U.S. Pat. Application No. 60/059900 filed Sep. 24, 1997, now abandoned and PCT/US97/17997 filed Oct. 7, 1997. This is also incorporated by reference.
SUMMARY OF THE INVENTION
The instant invention is compounds of Formula 1 below.
Preferred are compounds of Formula 1 wherein n is zero and R is hydrogen or methyl.
Especially preferred are 4-amino-3-cyclopentyl-butyric acid, (R)-4-amino-3-cyclopentyl-butyric acid, and (S)-4-amino-3-cyclopentyl-butyric acid.
Pharmaceutical composition containing one or more compounds of Formula 1 are part of the inventions.
The compounds are useful in the treatment of epilepsy, faintness attacks, hypokinesia, cranial disorders, neurodegeneration disorders, depression, anxiety, panic, pain, neuropathological disorders, treating gastrointestinal damage and inflammation.
DETAILED DESCRIPTION OF THE INVENTION
The instant invention is for certain compounds which exhibit improved activity in models of pain and epilepsy over those in U.S. Ser. No. 06/059900 now abandoned.
The compounds of the invention are those of Formula I
or a pharmaceutically acceptable salt thereof wherein:
R
1
is hydrogen or lower alkyl;
R is hydrogen or methyl;
n
1
is an integer of from 0 to 1; and
n
2
is an integer of from 0 to 3.
Since amino acids are amphoteric, pharmacologically compatible salts can be salts of appropriate inorganic or organic acids, for example, hydrochloric, sulphuric, phosphoric, acetic, oxalic, lactic, citric, malic, salicylic, malonic, maleic, succinic, methanesulfonic acid, and ascorbic. Starting from corresponding hydroxides or carbonates, salts with alkali metals or alkaline earth metals, for example, sodium, potassium, magnesium, or calcium are formed. Salts with quaternary ammonium ions can also be prepared with, for example, the tetramethyl-ammonium ion. The carboxyl group of the amino acids can be esterified by known means.
Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
The terms used to define the invention are as described below.
The term “alkyl” is a straight or branched group of from 1 to 4 carbon atoms including but not limited to methyl, ethyl, propyl, n-propyl, isopropyl, butyl, 2-butyl, and tert-butyl.
Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
Certain of the compounds of the present invention possess one or more chiral centers and each center may exist in the R(D) or S(L) configuration. The present invention includes all enantiomeric and epimeric forms as well as the appropriate mixtures thereof.
The radioligand binding assay using [
3
H]gabapentin and the &agr;
2&dgr;
subunit derived from porcine brain tissue was used (“The Novel Anti-convulsant Drug, Gabapentin, Binds to the &agr;
2
&dgr; Subunit of a Calcium Channel”, Gee N. S., et al.,
J. Biol. Chem.,
1996;271(10):5768-5776).
The compounds of the invention show good binding affinity to the &agr;
2&dgr;
subunit. Gabapentin (Neurontin®) is about 0.10 to 0.12 &mgr;M in this assay. Since the compounds of the instant invention also bind to the subunit, they are expected to exhibit pharmacologic properties comparable to gabapentin. For example, as agents for convulsions, anxiety, and pain.
TABLE 1

3
Ring
System L
&agr;
2
&dgr;
Pain Model
DBA2 Mouse
Vogel
Subst.
Spacer
size
Binding
Assay
% MPE
Model
Conflict
Example
R
n
1
n
2
IC
50
(mM)
IC
50
(&mgr;M)
1 Hour
2 Hour
% Protected
% of CI-1008
 1
H
0
0
0.733
0 1, 2 hr
 2
H
0
1
1.5
0.645
−1.7
−12.1
 0 1 Hr @ 30 m/k
2.48
40 2 Hr @ 30 m/k
 3
H
0
2
0.464
0.133
73.8
27.7
40 1 Hr
35.4
40 2 Hr
4R+
H
0
2
0.198
0.108
36
13.7
60 1 Hr
52
40 2 Hr
5S−
H
0
2
0.476
0.145
35
24
 0 1 Hr
0
 0 2 Hr
 6
H
1
0
1.87
0.626
2.3
−3.4
20 2 Hr
5.11
 7
H
1
1
2.6
0.317
1.5
−3.4
20 2 Hr
2.96
 8
H
1
2
4.64
3.18
 0 1 Hr
−8.3
 0 2 Hr
 9
H
1
3
5.5
4.87
10
Me
0
0
0.599
ca 10
−4.3
−9.1
0 1, 2 Hr
−8.13
11
Me
0
1
0.074
>10
4.2
3.1
0 1, 2 Hr
7.05
12
Me
1
1
0.105
0.8
−4.2
−5.2
0 1, 2 Hr
0.3
13
Me
1
2
1.04
>10
As can be seen in the above table, the R isomer of Example 4 is especially active in preventing convulsions, as an antihyperalgesic and as an antianxiety agent.
The compounds of the invention are related to Neurontin®, a marketed drug effective in the treatment of epilepsy. Neurontin®is 1-(aminomethyl)-cyclohexaneacetic acid of structural formula
The compounds of the invention are also expected to be useful in the treatment of epilepsy.
The present invention also relates to therapeutic use of the compounds of the mimetic as agents for neurodegenerative disorders.
Such neurodegenerative disorders are, for example, Alzheimer's disease, Huntington's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, and epilepsy.
The present invention also covers treating neurodegenerative disorders termed acute brain injury. These include but are not limited to: stroke, head trauma, and asphyxia.
Stroke refers to a cerebral vascular disease and may also be referred to as a cerebral vascular incident (CVA) and includes acute thromboembolic stroke. Stroke includes both focal and global ischemia. Also, included are transient cerebral ischemic attacks and other cerebral vascular problems accompanied by cerebral ischemia such as in a patient undergoing carotid endarterectomy specifically or other cerebrovascular or vascular surgical procedures in general, or diagnostic vascular procedures including cerebral angiography and the like.
Pain refers to acute as well as chronic pain.
Acute pain is usually short-lived and is associated with hyperactivity of the sympathetic nervous system. Examples are postoperative pain and allodynia.
Chronic pain is usually defined as pain persisting from 3 to 6 months and includes somatogenic pains and psychogenic pains. Other pain is nociceptive.
Still other pain is caused by injury or infection of peripheral sensory nerves. It includes, but is not limited to pain from peripheral nerve trauma, herpes virus infection, diabetes mellitus, causalgia, plexus avulsion, neuroma, limb amputation, and vasculitis. Neuropathic pain is also caused by nerve damage from chronic alcoholism, human immunodeficiency virus infection, hypothyroidism, uremia, or vitamin deficiencies. Neuropathic pain includes, but is not limited to pain caused by nerve injury such as, for example, the pain diabetics suffer from.
Psychogenic pain is that which occurs without an organic origin such as low back pain, atypical facial pain, and chronic headache.
Other types of pain are: inflammatory pain, osteoarthritic pain, trigeminal neuralgia, cancer

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