Amines as pharmaceutical agents

Details Amines as pharmaceutical agents Amines as pharmaceutical agents

2000-04-04

2003-02-18

Gerstl, Robert (Department: 1628)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S360000, C514S361000, C514S381000, C548S122000, C548S129000, C548S132000, C548S254000

Reexamination Certificate

active

06521650

ABSTRACT:

BACKGROUND OF THE INVENTION
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.
SUMMARY OF THE INVENTION
The compounds of the instant invention are novel amines and their pharmaceutically acceptable salts useful in a variety of disorders. The disorders include: epilepsy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, neuropathological disorders, inflammation, and gastrointestinal disorders.
The compounds of the invention are those of formulas 1A and 1B below.
Preferred compounds are those of formulas 1A and 1B wherein R is a sulfonamide selected from —NHSO
2
R
15
or —SO
2
NHR
15
wherein R
15
is straight or branched alkyl or trifluoromethyl.
Especially preferred are:
4-Methyl-2-(1H-tetrazol-5-ylmethyl)-pentylamine;
3-(2-Aminomethyl-4-methyl-pentyl )-4H-[1,2,4]oxadiazole-5-thione, HCl;
3-(2-Aminomethyl-4-methyl-pentyl)-4H-[1,2,4]oxadiazole-5-one, HCl;
(2-Aminomethyl-4-methyl-pentyl)-phosphonic acid;
3-(3-Amino-2-cyclopentyl-propyl)-4H-[1,2,4]oxadiazol-5-one;
3-(3-Amino-2-cyclopentyl-propyl)-4H-[1,2,4]thiadiazol-5-one;
2-Cyclopentyl-3-(2-oxo-2,3-dihydro-2&lgr;
4
-[1,2,3,5]oxathiadiazol-4-yl)-propylamine;
3-(3-Amino-2-cyclobutyl-propyl)-4H-[1,2,4]oxadiazol-5-one;
3-(3-Amino-2-cyclobutyl-propyl)-4H-[1,2,4]thiadiazol-5-one; and
2-Cyclobutyl-3-(2-oxo-2,3-dihydro-2&lgr;
4
-[1,2,3,5]oxathiadiazol-4-yl)-propylamine.
Other preferred compounds are those of formulas 1A and 1B wherein R is a phosphonic acid, —PO
3
H
2
.
Other preferred compounds are those of Formulas 1A and 1B wherein
Especially preferred are:
DETAILED DESCRIPTION OF THE INVENTION
The amines of the instant invention are compounds of formula 1A and 1B and the pharmaceutically acceptable salts thereof.
The compounds of the invention are those of formula
or a pharmaceutically acceptable salt thereof wherein:
n is an integer of from 0 to 2;
R is sulfonamide,
amide,
phosphonic acid,
heterocycle,
sulfonic acid, or
hydroxamic acid;
A is hydrogen or methyl; and
 straight or branched alkyl of from 1 to 11 carbons, or —(CH
2
)
1-4
—Y—(CH
2
)
0-4
-phenyl wherein Y is —O—, —S—, —NR′
3
wherein R′
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.
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.
Sulfonamides are those of formula —NHSO
2
R
15
or —SO
2
NHR
15
wherein R
15
is a straight or branched alkyl group of from 1 to 6 carbons or a trifluoromethyl.
Amides are compounds of formula —NHCOR
12
wherein R
12
is straight or branched alkyl of from 1 to 6 carbons, benzyl, and phenyl.
Phosphonic acids are —PO
3
H
2
.
Sulfonic acids are —SO
3
H.
Hydroxamic acid is
Heterocycles are groups of from 1 to 2 rings, with from 1 to 6 heteroatoms selected from oxygen, nitrogen, and sulfur.
Preferred heterocycles are
The term alkyl is a straight or branched group of from 1 to 11 carbon atoms including but not limited to methyl, ethyl, propyl, n-propyl, isopropyl, butyl, 2-butyl, tert-butyl, pentyl, hexyl, and n-hexyl, heptyl, octyl, nonyl, decyl, and undecyl except as where otherwise stated.
The cycloalkyl groups are from 3 to 8 carbons and are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl unless otherwise stated.
The benzyl and phenyl groups may be unsubstituted or substituted by from 1 to 3 substituents selected from hydroxy, carboxy, carboalkoxy, halogen, CF
3
, nitro, alkyl, and alkoxy. Preferred are halogens.
Alkoxy is as defined above for alkyl.
Halogen is fluorine, chlorine, and bromine and preferred are fluorine and chlorine.
Carboalkoxy is —COOalkyl wherein alkyl is as described above. Preferred are carbomethoxy and carboethoxy.
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 a &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

Vogel
&agr;2&dgr;
Pain Model
Conflict
DBA2
Assay
% MPE
% of
% Protection
R
IC
50
(&mgr;M)
1 Hr
2 Hr
CI-1008
1 Hr
2 Hr
2.47
0
0
0.0
0
0

>10
0
0

1.52

PO
3
H
2
>10
0
0
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
Preferred novel gabapentin and isobutyl-GABA analogs, their derivatives, and pharmaceutically acceptable salts are useful in the treatment of a variety of disorders including epilepsy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, and neuropathological disorders. The compounds are of the general formula:
a pharmaceutically acceptable salt thereof or a prodrug thereof, where n=0,1,2, m=0,1,2,3, and R can be sulfonamides of the general formula —NHSO
2
R
1
or —SO
2
NHR
1
where R
1
is H or C
1
-C
4
straight or branched chain alkyl or trifluoromethyl. R may also be an amide of the general formula —NHCOR
1
. Or R may also be a phosphonic acid —PO
3
H
2
(Lipinski C. A.,
Ann. Rep

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