The present invention provides compounds that block calcium channels having the Formula I shown below.

The present invention relates to compounds that act to block calcium channels; methods of using the compounds to treat stroke, cerebral ischemia, pain, head trauma or epilepsy; and to pharmaceutical compositions that contain the compounds of the present invention.
The entry of excessive amounts of calcium ions into neurons following an ischemic episode or other neuronal trauma has been well documented. Uncontrolled high concentrations of calcium in neurons initiates a cascade of biochemical events that disrupts normal cellular processes. Among these events are the activation of proteases and lipases, breakdown of neuronal membranes and the formation of free radicals, which may ultimately lead to cell death. Several types of calcium channels have been discovered and called the L, N, P, Q, R, and T types. Each type possesses distinct structural features, functional properties and cellular/subcellular distributions. Type selective calcium channel blockers have been identified. For example, SNX-111 has been shown to be a selective N-type calcium channel blocker and has demonstrated activity in a number of models of ischemia and pain (Bowersox S. S., et al., Drug News and Perspective, 1994:7:261-268 and references cited therein). The compounds of the present invention are calcium channel blockers that can block N-type calcium channels and can be used to treat stroke, pain, cerebral ischemia, head trauma, and epilepsy.
The present invention provides compounds having the Formula I
wherein
each m is independently 1 to 3;
each n is independently 0 to 3;
each Ra and Rb is independently hydrogen, C1-C6alkyl, or Ra and Rb together with the carbon atom to which they are bonded form a C3-C6cycloalkyl
R5 is C1-C6alkyl, xe2x80x94(CH2)m-heteroaryl, xe2x80x94(CH2)m-substituted heteroaryl, xe2x80x94(CH2)m-phenyl, or xe2x80x94(CH2)-substituted phenyl;
R2 is hydrogen, C1-C8alkenyl, C3-C8cycloalkenyl, phenyl, substituted phenyl, C1-C8alkyl, substituted C1-C8alkyl, xe2x80x94(CH2)msubstituted C3-C8cycloalkyl, xe2x80x94(CH2)m-C3-C8cycloalkyl, C3-C8cycloalkyl, substituted C3-C8cycloalkyl, xe2x80x94(CH2)m-phenyl, or xe2x80x94(CH2)m substituted phenyl;
R3 is hydrogen, C1-C6alkyl, or C2-C6alkenyl;
Q is aryl, heteroaryl, substituted heteroaryl, C3-C8cycloalkyl, substituted C3-C8cycloalkyl, C1-C6alkyl, substituted C1-C6alkyl, hydrogen, C3-C8heterocycloalkyl, C3-C8 substituted heterocycloalkyl, or substituted aryl;
V is xe2x80x94O(CH2)nxe2x80x94, xe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94Oxe2x80x94,
or xe2x80x94(CH2)nxe2x80x94Oxe2x80x94;
R4 is hydrogen,
C1-C6alkyl, C2-C8alkenyl, C3-C8cycloalkenyl, C3-C8 substituted cycloalkenyl, xe2x80x94(CH2)m-phenyl, xe2x80x94(CH2)m-heteroaryl, xe2x80x94(CH2)m-substituted heteroaryl, xe2x80x94(CH2)m-substituted phenyl, C3-C8cycloalkyl, or C3-C8 substituted cycloalkyl;
or R3 and R4 together with the nitrogen atom to which they are bonded can form a 5-7 membered ring that can contain one or more heteroatom;
and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
In a preferred embodiment of the compounds of Formula I, V is xe2x80x94OCH2xe2x80x94 or CH2CH2, and Q is phenyl.
In another preferred embodiment of the compounds of Formula I, X is
and Z is
In another preferred embodiment of the compounds of Formula I, R3 and R4 are both hydrogen.
In another preferred embodiment of the compounds of Formula I, R3 is hydrogen and R4 is
In another preferred embodiment of the compounds of Formula I, V is xe2x80x94OCH2xe2x80x94;
Q is phenyl;
Z is
R3 is hydrogen;
R4 is
R2 is C2-C8cycloalkenyl, C2-C8alkyl, or C2-C8alkenyl; and
R5 is C1-C8alkyl.
In another preferred embodiment of the compounds of Formula I, Z is
and X is
In still another preferred embodiment of the compounds of Formula I, R5 is isobutyl, 3-methylbutyl, 2-methylbutyl, xe2x80x94CH2-pyridyl, or xe2x80x94CH2-imidazolyl.
In a preferred embodiment of the compounds of Formula I, R2 is 3-methyl-but-2-enyl, or 3-methylbutyl, 2-methylpropyl, methyl, CH2-cyclohexyl, n-butyl, or cyclohexyl.
In another preferred embodiment of the compounds of Formula I, V is xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94CH2xe2x80x94CH2, or xe2x80x94NHxe2x80x94CH2;
Q is pyridyl, phenyl, cyclohexyl, or C1-C8alkyl.
In a most preferred embodiment, the compounds of Formula I are:
(S)-Azepane-1-carboxylic acid (1-{2-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-1,1-dimethyl-ethylcarbamoyl}-3-methyl-butyl)-amide;
[S-(R*,R*)]-Azepane-1-carboxylic acid (1-{2-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-1-methyl-ethylcarbamoyl}-3-methyl-butyl)-amide;
(S)-Azepane-1-carboxylic acid (1-{2-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-ethylcarbamoyl}-3-methyl-butyl)-amide;
(S)-Azepane-1-carboxylic acid (1-{3-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-propylcarbamoyl}-3-methyl-butyl)-amide;
(S)-Azepane-1-carboxylic acid (1-{4-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidine-1-carbonyl}-3-methyl-butyl)-amide;
(S)-Azepane-1-carboxylic acid (1-{2-[(4-benzyloxy-phenyl)-cyclohex-2-enyl-amino]-ethylcarbamoyl}-3-methyl-butyl)-amide;
(S)-Azepane-1-carboxylic acid (1-{2-[benzyl-(4-benzyloxy-phenyl)-amino]-ethylcarbamoyl}-3-methyl-butyl)-amide;
(S)-Azepane-1-carboxylic acid (1-{2-[(4-benzyloxy-phenyl)-cyclohex-2-enyl-amino]-1,1-dimethyl-ethylcarbamoyl}-3-methyl-butyl)-amide;
(S)-2-Dimethylamino-4-methyl-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-1,1-dimethyl-ethyl}-amide;
(S)-4-Methyl-2-[methyl-(3-methyl-but-2-enyl)-amino]-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-1,1-dimethyl-ethyl}-amide;
(S)-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-1,1-dimethyl-ethyl}-amide;
(S)-2-(Cyclohex-2-enyl-methyl-amino)-4-methyl-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-1,1-dimethyl-ethyl}-amide;
(S)-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-1,1-dimethyl-ethyl}-amide;
[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-1,1-methyl-ethyl}-amide;
[S-(R*,R*)]-4-Methyl-2-(3-methyl-but-2-enylamino)-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-1-methyl-ethyl}-amide;
[S-(R*,R*)]-4-Methyl-2-(3-methyl-butylamino)-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-1-methyl-ethyl}-amide;
(S)-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid {2-[(4-benzyloxy-phenyl)-cyclohex-2-enyl-amino]-1,1-dimethyl-ethyl}-amide;
[S-(R*,R*)]-2-[Bis-(3-methyl-butyl)-amino]-4-methyl-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-1,1-methyl-ethyl}-amide; and
[S-(R*,R*)]-2-{Bis]-(3-methyl-but-2-enylamino)-4-methyl-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-1,1-methyl-ethyl}-amide.
In a most preferred embodiment, the compounds of Formula I are:
2-Amino-4-methyl-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-1,1-dimethyl-ethyl}-amide;
2-Benzylamino-4-methyl-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-1,1-dimethyl-ethyl}-amide;
4-Methyl-2-(3-methyl-butylamino)-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-1,1-dimethyl-ethyl}-amide;
2-(Cyclohexylmethyl-amino)-4-methyl-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-1,1-dimethyl-ethyl}-amide;
2-Dimethylamino-4-methyl-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-1,1-dimethyl-ethyl}-amide;
1-{4-[(4-Benzyloxy-phenyl)-(3-methyl-butyl)-amino]-piperidin-1-yl}-2-isopropylamino-4-methyl-pentan-1-one;
2-Benzylamino-1-{4-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
1-{4-[(4-Benzyloxy-phenyl)-(3-methyl-butyl)-amino]-piperidin-1-yl}-4-methyl-2-(3-methyl-butylamino)-pentan-1-one;
1-{4-[(4-Benzyloxy-phenyl)-(3-methyl-butyl)-amino]-piperidin-1-yl}-2-cyclohexylamino-4-methyl-pentan-1-one;
1-{4-[(4-Benzyloxy-phenyl)-(3-methyl-butyl)-amino]-piperidin-1-yl}-2-dimethylamino-4-methyl-pentan-1-one;
2-Isopropylamino-4-methyl-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-ethyl}-amide;
4-Methyl-2-(3-methyl-butylamino)-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-ethyl}-amide;
2-Cyclohexylamino-4-methyl-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-ethyl}-amide;
2-Isopropylamino-4-methyl-pentanoic acid {3-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-propyl}-amide;
4-Methyl-2-(3-methyl-butylamino)-pentanoic acid {3-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-propyl}-amide;
2-Cyclohexylamino-4-methyl-pentanoic acid {3-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-propyl}-amide;
Azepane-1-carboxylic acid (1-{4-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-piperidine-1-carbonyl}-3-methyl-butyl)-amide;
Azepane-1-carboxylic acid (1-{4-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-piperidine-1-carbonyl}-2-methyl-butyl)-amide;
Azepane-1-carboxylic acid (1-{4-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-piperidine-1-carbonyl}-2-methyl-propyl)-amide;
Azepane-1-carboxylic acid (1-{4-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-piperidine-1-carbonyl}-2-pyridin-2-yl-ethyl)-amide;
Azepane-1-carboxylic acid (1-{4-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-piperidine-1-carbonyl}-2-pyridin-4-yl-ethyl)-amide;
Azepane-1-carboxylic acid [1-{4-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-piperidine-1-carbonyl}-2-(3H-imidazol-4-yl)-ethyl]-amide;
Azepane-1-carboxylic acid (1-{2-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-1,1-dimethyl-ethylcarbamoyl}-3-methyl-butyl)-amide;
Azepane-1-carboxylic acid (1-{2-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-1,1-dimethyl-ethylcarbamoyl}-2-methyl-butyl)-amide;
Azepane-1-carboxylic acid (1-{2-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-1,1-dimethyl-ethylcarbamoyl}-2-methyl-propyl)-amide;
Azepane-1-carboxylic acid (1-{2-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-1,1-dimethyl-ethylcarbamoyl}-2-pyridin-2-yl-ethyl)-amide;
Azepane-1-carboxylic acid (1-{2-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-1,1-dimethyl-ethylcarbamoyl}-2-pyridin-4-yl-ethyl)-amide;
Azepane-1-carboxylic acid [1-{2-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-1,1-dimethyl-ethylcarbamoyl}-2-(3H-imidazol-4-yl)-ethyl]-amide;
Azepane-1-carboxylic acid [1-({2-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-1,1-dimethyl-ethylamino}-methyl)-3-methyl-butyl]-amide;
Azepane-1-carboxylic acid (1-{4-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-piperidin-1-yl-methyl}-3-methyl-butyl)-amide;
Azepane-1-carboxylic acid [1-(1-{[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-methyl}-cyclobutylcarbamoyl)-3-methyl-butyl]-amide;
Azepane-1-carboxylic acid (1-{4-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-cyclohexylcarbamoyl}-3-methyl-butyl)-amide;
Azepane-1-carboxylic acid (1-{3-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-piperidine-1-carbonyl}-3-methyl-butyl)-amide;
Azepane-1-carboxylic acid (1-{3-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-pyrrolidine-1-carbonyl}-3-methyl-butyl)-amide;
Azepane-1-carboxylic acid (1-{2-[(4-benzyloxy-phenyl)-isobutyl-amino]-1,1-dimethyl-ethylcarbamoyl}-3-methyl-butyl)-amide;
Azepane-1-carboxylic acid (1-{2-[(4-benzyloxy-phenyl)-methyl-amino]-1,1-dimethyl-ethylcarbamoyl}-3-methyl-butyl)-amide;
Azepane-1-carboxylic acid (1-{2-[(4-benzyloxy-phenyl)-cyclohexylmethyl-amino]-1,1-dimethyl-ethylcarbamoyl}-3-methyl-butyl)-amide;
Azepane-1-carboxylic acid (1-{2-[(4-benzyloxy-phenyl)-cyclohexyl-amino]-1,1-dimethyl-ethylcarbamoyl}-3-methyl-butyl)-amide;
Azepane-1-carboxylic acid (1-{2-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-1,1-dimethyl-ethylcarbamoyl}-3-methyl-butyl)-amide;
Azepane-1-carboxylic acid (1-{2-[(4-benzyloxy-phenyl)-butyl-amino]-1,1-dimethyl-ethylcarbamoyl}-3-methyl-butyl)-amide;
Azepane-1-carboxylic acid (1-{4-[(4-benzyloxy-phenyl)-isobutyl-amino]-piperidine-1-carbonyl}-3-methyl-butyl)-amide;
Azepane-1-carboxylic acid (1-{4-[(4-benzyloxy-phenyl)-methyl-amino]-piperidine-1-carbonyl}-3-methyl-butyl)-amide;
Azepane-1-carboxylic acid (1-{4-[(4-benzyloxy-phenyl)-cyclohexylmethyl-amino]-piperidine-1-carbonyl}-3-methyl-butyl)-amide;
Azepane-1-carboxylic acid (1-{4-[(4-benzyloxy-phenyl)-cyclohexyl-amino]-piperidine-1-carbonyl)-3-methyl-butyl)-amide;
Azepane-1-carboxylic acid (1-{4-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-piperidine-1-carbonyl}-3-methyl-butyl)-amide;
Azepane-1-carboxylic acid (1-{4-[(4-benzyloxy-phenyl)-butyl-amino]-piperidine-1-carbonyl}-3-methyl-butyl)-amide;
Azepane-1-carboxylic acid [3-methyl-1-(4-{(3-methyl-butyl)-[4-(pyridin-2-yl-methoxy)-phenyl]-amino}-piperidine-1-carbonyl)-butyl]-amide;
Azepane-1-carboxylic acid [3-methyl-1-(4-{(3-methyl-butyl)-[4-(pyridin-3-yl-methoxy)-phenyl]-amino}-piperidine-1-carbonyl)-butyl]-amide;
Azepane-1-carboxylic acid [3-methyl-1-(4-{(3-methyl-butyl)-[4-(pyridin-4-ylmethoxy)-phenyl]-amino}-piperidine-1-carbonyl)-butyl]-amide;
Azepane-1-carboxylic acid (3-methyl-1-{4-[(3-methyl-butyl)-(4-phenylethynyl-phenyl)-amino]-piperidine-1-carbonyl}-butyl)-amide;
Azepane-1-carboxylic acid (1-{4-[[4-(2-cyclohexyl-ethyl)-phenyl]-(3-methyl-butyl)-amino]-piperidine-1-carbonyl}-3-methyl-butyl)-amide;
Azepane-1-carboxylic acid (1-{4-[{4-[2-(1-hydroxy-cyclohexyl)-ethyl]-phenyl}-(3-methyl-butyl)-amino]-piperidine-1-carbonyl}-3-methyl-butyl)-amide;
Azepane-1-carboxylic acid (1-{4-[[4-(3,3-dimethyl-butyl)-phenyl]-(3-methyl-butyl)-amino]-piperidine-1-carbonyl}-3-methyl-butyl)-amide;
Azepane-1-carboxylic acid [3-methyl-1-(4-{(3-methyl-butyl)-[4-(2-piperidin-1-yl-ethyl)-phenyl]-amino}-piperidine-1-carbonyl)-butyl]-amide;
Azepane-1-carboxylic acid [3-methyl-1-(4-{(3-methyl-butyl)-[4-(2-piperidin-1-yl-ethyl)-phenyl]-amino}-piperidine-1-carbonyl)-butyl]-amide;
Azepane-1-carboxylic acid (1-{4-[(2-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-piperidine-1-carbonyl}-3-methyl-butyl)-amide; Azepane-1-carboxylic acid (3-methyl-1-{4-[(3-methyl-butyl)-(4-phenoxy-phenyl)-amino]-piperidine-1-carbonyl}-butyl)-amide;
Azepane-1-carboxylic acid (1-{4-[(4-benzyl-phenyl)-(3-methyl-butyl)-amino]-piperidine-1-carbonyl}-3-methyl-butyl)-amide;
Azepane-1-carboxylic acid [1-(4-{[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-methyl}-piperidine-1-carbonyl)-3-methyl-butyl]-amide;
Azepane-1-carboxylic acid [1-(1,1-dimethyl-2-{(3-methyl-butyl)-[4-(pyridin-2-ylmethoxy)-phenyl]-amino}-ethylcarbamoyl)-3-methyl-butyl]-amide;
Azepane-1-carboxylic acid [1-(1,1-dimethyl-2-{(3-methyl-butyl)-[4-(pyridin-3-ylmethoxy)-phenyl]-amino}-ethylcarbamoyl)-3-methyl-butyl]-amide;
Azepane-1-carboxylic acid [1-(1,1-dimethyl-2-{(3-methyl-butyl)-[4-(pyridin-4-ylmethoxy)-phenyl]-amino}-ethylcarbamoyl)-3-methyl-butyl]-amide;
Azepane-1-carboxylic acid (1-{1,1-dimethyl-2-[(3-methyl-butyl)-(4-phenethyl-phenyl)-amino]-ethylcarbamoyl}-3-methyl-butyl)-amide;
Azepane-1-carboxylic acid (1-{1,1-dimethyl-2-[(3-methyl-butyl)-(4-phenylethynyl-phenyl)-amino]-ethylcarbamoyl}-3-methyl-butyl)-amide;
Azepane-1-carboxylic acid (1-{2-[[4-(2-cyclohexyl-ethyl)-phenyl]-(3-methyl-butyl)-amino]-1,1-dimethyl-ethylcarbamoyl}-3-methyl-butyl)-amide;
Azepane-1-carboxylic acid (1-{2-[{4-[2-(1-hydroxy-cyclohexyl)-ethyl]-phenyl}-(3-methyl-butyl)-amino]-1,1-dimethyl-ethylcarbamoyl}-3-methyl-butyl)-amide;
Azepane-1-carboxylic acid (1-{2-[[4-(3,3-dimethyl-butyl)-phenyl]-(3-methyl-butyl)-amino]-1,1-dimethyl-ethylcarbamoyl}-3-methyl-butyl)-amide;
Azepane-1-carboxylic acid [1-(1,1-dimethyl-2-{(3-methyl-butyl)-[4-(2-piperidin-1-yl-ethyl)-phenyl]-amino }-ethylcarbamoyl)-3-methyl-butyl]-amide;
Azepane-1-carboxylic acid (1-{2-[(3-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-1,1-dimethyl-ethylcarbamoyl}-3-methyl-butyl)-amide; and
Azepane-1-carboxylic acid (1-{2-[(2-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-1,1-dimethyl-ethylcarbamoyl}-3-methyl-butyl)-amide.
Also provided by the present invention is a pharmaceutical composition comprising a compound of Formula I.
Also provided is a method of blocking calcium channels, the method comprising administering to a patient in need of calcium channel blocking, a therapeutically effective amount of a compound of Formula I to block calcium channels.
In a preferred embodiment of the method of blocking calcium channels, the calcium channels are N-type calcium channels.
Also provided is a method of blocking N-type calcium channels, the method comprising administering to a patient in need of N-type calcium channel blocking a therapeutically effective amount of a compound of Formula I to block N-type calcium channels.
Also provided is a method of treating stroke, the method comprising administering to a patient having a stroke a therapeutically effective amount of a compound of Formula I.
Also provided is a method of preventing a stroke, the method comprising administering to a patient at risk of having a stroke a therapeutically effective amount of a compound of Formula I.
Also provided is a method of treating cerebral ischemia, the method comprising administering to a patient having cerebral ischemia a therapeutically effective amount of a compound of Formula I.
Also provided is a method of treating head trauma, the method comprising administering to a patient having head trauma a therapeutically effective amount of a compound of Formula I.
Also provided is a method of treating epilepsy, the method comprising administering to a patient having epilepsy a therapeutically effective amount of a compound of Formula I.
Also provided is a method of treating pain, the method comprising administering to a patient having pain a therapeutically effective amount of a compound of Formula I.
Also provided is a compound of Formula I wherein
R5 is 2-methylpropyl;
Z is
and
X is
Also provided is a compound of Formula I wherein
R3 and R4 are each independently hydrogen, or
and
R2 is xe2x80x94CH2phenyl, C1-C8 alkenyl, or C1-C8 alkyl.
Also provided is a compound of Formula I wherein
R3 and R4 are hydrogen;
R5 is 2-methyl propyl;
Z is xe2x80x94CH2xe2x80x94 or
and
X is
Also provided is a compound of Formula I wherein
R3 and R4 are hydrogen;
R5 is 2-methyl propyl;
Z is xe2x80x94CH2xe2x80x94 or
X is
R2 is C1-C8 alkyl, or C1-C8 alkenyl;
V is OCH2xe2x80x94, xe2x80x94(CH2)nxe2x80x94; and
Q is phenyl, substituted phenyl, C3-C8 cycloalkyl, and C1-C6 alkyl.
Also provided is a compound of Formula I wherein R2 is
xe2x80x94Oxe2x80x94CH2xe2x80x94 substituted phenyl, xe2x80x94CH2CH2-phenyl, or xe2x80x94CH2CH2-substituted phenyl.
Also provided are the compounds:
(S)-2-Amino-1-{4-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(R)-2-Amino-1-{4-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-2-Amino-1-{4-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-3-methyl-pentan-1-one;
(S)-1-{4-[(4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-2-dimethylamino-4-methyl-pentan-1-one;
(S)-1-{4-[(4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-2-isopropylamino-4-methyl-pentan-1-one;
(S)-1-{4-[(4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-4-methyl-2-(3-methyl-butylamino)-pentan-1-one;
(S)-1-{4-[(4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-2-cyclohexylamino-4-methyl-pentan-1-one;
(S)-1-{4-[(4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-4-methyl-2-[(1H-pyrrol-2-ylmethyl)-amino]-pentan-1-one;
(S)-Azepane-1-carboxylic acid {I-[4-(4-benzyloxy-phenylamino)-piperidine-1-carbonyl]-3-methyl-butyl}-amide;
(S)-Azepane-1-carboxylic acid (1-{4-[(4-benzyloxy-phenyl)-2-methylbutyl-amino]-piperidine-1-carbonyl}-3-methyl-butyl)-amide;
(S)-Azepane-1-carboxylic acid (1-{4-[(4-benzyloxy-phenyl)-ethyl-amino]-piperidine-1-carbonyl}-3-methyl-butyl)-amide;
(S)-Azepane-1-carboxylic acid (1-{4-[benzyl-(4-benzyloxy-phenyl)-amino]-piperidine-1-carbonyl}-3-methyl-butyl)-amide;
Azepane-1-carboxylic acid (1-{4-[(4-benzyloxy-phenyl)-(3-hydroxy-butyl)-amino]-piperidine-1-carbonyl}-3-methyl-butyl)-amide;
(S)-{4-[(1-{2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoyl}-piperidin-4-yl)-(3-methyl-but-2-enyl)-amino]-phenyl}-carbamic acid benzyl ester;
(S)-{4-[(1-{2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoyl}-piperidin-4-yl)-(3-methyl-butyl)-amino]-phenyl}-carbamic acid benzyl ester;
(S)-Azepane-1-carboxylic acid (1-{4-[(4-amino-phenyl)-(3-methyl-butyl)-amino]-piperidine-1-carbonyl}-3-methyl-butyl)-amide;
(S)-Azepane-1-carboxylic acid (1-{4-[[4-(3,3-dimethyl-butylamino)-phenyl]-(3-methyl-butyl)-amino]-piperidine-1-carbonyl}-3-methyl-butyl)-amide;
(S)-Azepane-1-carboxylic acid (1-{4-[[4-(Cyclohexylmethyl-amino)-phenyl]-(3-methyl-butyl)-amino]-piperidine-1-carbonyl}-3-methyl-butyl)-amide;
(S)-Azepane-1-carboxylic acid (1-{4-[[4-(3-hydroxy-butylamino)-phenyl]-(3-methyl-butyl)-amino]-piperidine-1-carbonyl}-3-methyl-butyl)-amide;
(S)-Azepane-1-carboxylic acid (1-{4-[(4-benzylamino-phenyl)-(3-methyl-butyl)-amino]-piperidine-1-carbonyl}-3-methyl-butyl)-amide;
(S)-Azepane-1-carboxylic acid {3-methyl-1-[4-((3-methyl-butyl)-{4-[(pyridin-2-ylmethyl)-amino]-phenyl}-amino)-piperidine-1-carbonyl]-butyl}-amide;
(S)-Azepane-1-carboxylic acid (1-{4-[[4-(4-dimethylamino-benzylamino)-phenyl]-(3-methyl-butyl)-amino]-piperidine-1-carbonyl}-3-methyl-butyl)-amide;
(S)-Azepane-1-carboxylic acid (1-{4-[[4-(4-hydroxy-benzylamino)-phenyl]-(3-methyl-butyl)-amino]-piperidine-1-carbonyl}-3-methyl-butyl)-amide;
(S)-Azepane-1-carboxylic acid (1-{4-[[4-(1-hydroxy-cyclohexylethynyl)-phenyl]-(3-methyl-but-2-enyl)-amino]-piperidine-1-carbonyl}-3-methyl-butyl)-amide;
(S)-2-Amino-1-{4-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S, R/S)-2-Amino-1-{3-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S,R/S)-Azepane-1-carboxylic acid (1-{3-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidine-1-carbonyl}-3-methyl-butyl)-amide;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amine;
(S)-2-Amino-1-{4-[(4-(4-fluorobenzyloxy)-phenyl)-(3-methyl-butyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-[4-(4-fluorobenzyloxy)-phenyl]-(3-methyl-butyl)-amine;
(S)-2-Amino-1-{4-[(4-phenethyl-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one; and
(S)-Azepane-1-carboxylic acid (1-{4-[(4-phenethyl-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidine-1-carbonyl}-3-methyl-butyl)-amide. Also provided are the compounds:
(S)-N1-{2-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-1,1-dimethyl-ethyl}-4-methyl-pentane-1,2-diamine;
(S)-2-Amino-4-methyl-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-1,1-dimethyl-ethyl}-amide;
(S)-N1-{2-[(4-Cyclohexylmethoxy-phenyl)-(3-methyl-butyl)-amino]-1,1-dimethyl-ethyl}-4-methyl-pentane-1,2-diamine;
(S)-2-Amino-4-methyl-pentanoic acid {2-[(4-cyclohexylmethoxy-phenyl)-(3-methyl-butyl)-amino]-1,1-dimethyl-ethyl}-amide;
(S)-N1-{2-[[4-(2-Cyclohexyl-ethyl)-phenyl]-(3-methyl-butyl)-amino]-1,1-dimethyl-ethyl}-4-methyl-pentane-1,2-diamine;
(S)-2-Amino-4-methyl-pentanoic acid {2-[[4-(2-cyclohexyl-ethyl)-phenyl]-(3-methyl-butyl)-amino]-1,1-dimethyl-ethyl}-amide;
(S)-N1-{2-[[4-(3,3-Dimethyl-butyl)-phenyl]-(3-methyl-butyl)-amino]-1,1-dimethyl-ethyl}-4-methyl-pentane-1,2-diamine;
(S)-2-Amino-4-methyl-pentanoic acid {2-[[4-(3,3-dimethyl-butyl)-phenyl]-(3-methyl-butyl)-amino]-1,1-dimethyl-ethyl}-amide;
(S)-N1-{2-[[4-(2,2-Dimethyl-propoxy)-phenyl]-(3-methyl-butyl)-amino]-1,1-dimethyl-ethyl}-4-methyl-pentane-1,2-diamine;
(S)-2-Amino-4-methyl-pentanoic acid {2-[[4-(2,2-dimethyl-propoxy)-phenyl]-(3-methyl-butyl)-amino]-1,1-dimethyl-ethyl}-amide;
(S)-N1-{2-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-1,1-dimethyl-ethyl}-4-methyl-pentane-1,2-diamine;
(S)-2-Amino-4-methyl-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-1,1-dimethyl-ethyl}-amide;
(S)-N1-{2-[(4-Cyclohexylmethoxy-phenyl)-(3-methyl-but-2-enyl)-amino]-1,1-dimethyl-ethyl}-4-methyl-pentane-1,2-diamine;
(S)-2-Amino-4-methyl-pentanoic acid {2-[(4-cyclohexylmethoxy-phenyl)-(3-methyl-but-2-enyl)-amino]1,1-dimethyl-ethyl}-amide;
(S)-N1-{2-[[4-(2-Cyclohexyl-ethyl)-phenyl]-(3-methyl-but-2-enyl)-amino]-1,1-dimethyl-ethyl}-4-methyl-pentane-1,2-diamine;
(S)-2-Amino-4-methyl-pentanoic acid {2-[[4-(2-cyclohexyl-ethyl)-phenyl]-(3-methyl-but-2-enyl)-amino]-1,1-dimethyl-ethyl}-amide;
(S)-N1-{2-[[4-(3,3-Dimethyl-butyl)-phenyl]-(3-methyl-but-2-enyl)-amino]-1,1-dimethyl-ethyl}-4-methyl-pentane-1,2-diamine;
(S)-2-Amino-4-methyl-pentanoic acid {2-[[4-(3,3-dimethyl-butyl)-phenyl]-(3-methyl-but-2-enyl)-amino]-1,1-dimethyl-ethyl}-amide;
(S)-N1-{2-[[4-(2,2-Dimethyl-propoxy)-phenyl]-(3-methyl-but-2-enyl)-amino]-1,1-dimethyl-ethyl}-4-methyl-pentane-1,2-diamine;
(S)-2-Amino-4-methyl-pentanoic acid {2-[[4-(2,2-dimethyl-propoxy)-phenyl]-(3-methyl-but-2-enyl)-amino]-1,1-dimethyl-ethyl}-amide;
(S)-N1-{2-[[4-(4-chloro-benzyloxy)-phenyl]-(3-methyl-butyl)-amino]-1,1-dimethyl-ethyl}-4-methyl-pentane-1,2-diamine;
(S)-2-Amino-4-methyl-pentanoic acid {2-[[4-(4-chloro-benzyloxy)-phenyl]-(3-methyl-butyl)-amino]-1,1-dimethyl-ethyl}-amide;
(S)-N1-{2-[[4-(4-Fluoro-benzyloxy)-phenyl]-(3-methyl-butyl)-amino]-1,1-dimethyl-ethyl}-4-methyl-pentane-1,2-diamine;
(S)-2-Amino-4-methyl-pentanoic acid {2-[[4-(4-fluoro-benzyloxy)-phenyl]-(3-methyl-butyl)-amino]-1,1-dimethyl-ethyl}-amide;
(S)-N1-{1,1-Dimethyl-2-[(3-methyl-butyl)-(4-phenethyl-phenyl)-amino]-ethyl}-4-methyl-pentane-1,2-diamine;
(S)-2-Amino-4-methyl-pentanoic acid {1,1-dimethyl-2-[(3-methyl-butyl)-(4-phenethyl-phenyl)-amino]-ethyl}-amide;
(S)-2-Amino-4-methyl-pentanoic acid {2-[{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-(3-methyl-butyl)-amino]-1,1-dimethyl-ethyl}-amide;
(S)-2-Amino-4-methyl-pentanoic acid {2-[{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-(3-methyl-butyl)-amino]-1,1-dimethyl-ethyl}-amide;
(S)-N1-{2-[[4-(4-Chloro-benzyloxy)-phenyl]-(3-methyl-but-2-enyl)-amino]-1,1-dimethyl-ethyl}-4-methyl-pentane-1,2-diamine;
(S)-2-Amino-4-methyl-pentanoic acid {2-[[4-(4-chloro-benzyloxy)-phenyl]-(3-methyl-but-2-enyl)-amino]-1,1-dimethyl-ethyl}-amide;
(S)-N1-{2-[[4-(4-Fluoro-benzyloxy)-phenyl]-(3-methyl-but-2-enyl)-amino]-1,1-dimethyl-ethyl}-4-methyl-pentane-1,2-diamine;
(S)-N1-{1,1-Dimethyl-2-[(3-methyl-but-2-enyl)-(4-phenethyl-phenyl)-amino]-ethyl}-4-methyl-pentane-1,2-diamine;
(S)-2-Amino-4-methyl-pentanoic acid {2-[[4-(4-fluoro-benzyloxy)-phenyl]-(3-methyl-but-2-enyl)-amino]-1,1-dimethyl-ethyl}-amide;
(S)-2-Amino-4-methyl-pentanoic acid {1,1-dimethyl-2-[(3-methyl-but-2-enyl)-(4-phenethyl-phenyl)-amino]-ethyl}-amide;
(S)-2-Amino-4-methyl-pentanoic acid {2-[{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-(3-methyl-but-2-enyl)-amino]-1,1-dimethyl-ethyl}-amide;
(S)-2-Amino-4-methyl-pentanoic acid {2-[{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-(3-methyl-but-2-enyl)-amino]-1,1-dimethyl-ethyl}-amide;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-(4-benzyloxy-phenyl)-(3-methyl-butyl)-amine;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-(4-cyclohexylmethoxy-phenyl)-(3-methyl-butyl)-amine;
(S)-2-Amino-1-{4-[(4-cyclohexylmethoxy-phenyl)-(3-methyl-butyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-[4-(2-cyclohexyl-ethyl)-phenyl]-(3-methyl-butyl)-amine;
(S)-2-Amino-1-{4-[[4-(2-cyclohexyl-ethyl)-phenyl]-(3-methyl-butyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-[4-(2,2-dimethyl-propoxy)-phenyl]-(3-methyl-butyl)-amine;
(S)-2-Amino-1-{4-[[4-(2,2-dimethyl-propoxy)-phenyl]-(3-methyl-butyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-[4-(3,3-dimethyl-butyl)-phenyl]-(3-methyl-butyl)-amine;
(S)-2-Amino-1-{4-[[4-(3,3-dimethyl-butyl)-phenyl]-(3-methyl-butyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amine;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-(4-cyclohexylmethoxy-phenyl)-(3-methyl-but-2-enyl)-amine;
(S)-2-Amino-1-{4-[(4-cyclohexylmethoxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-[4-(2-cyclohexyl-ethyl)-phenyl]-(3-methyl-but-2-enyl)-amine;
(S)-2-Amino-1-{4-[[4-(2-cyclohexyl-ethyl)-phenyl]-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-[4-(2,2-dimethyl-propoxy)-phenyl]-(3-methyl-but-2-enyl)-amine;
(S)-2-Amino-1-{4-[[4-(2,2-dimethyl-propoxy)-phenyl]-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-[4-(3,3-dimethyl-butyl)-phenyl]-(3-methyl-but-2-enyl)-amine;
(S)-2-Amino-1-{4-[[4-(3,3-dimethyl-butyl)-phenyl]-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-[4-(4-chloro-benzyloxy)-phenyl]-(3-methyl-but-2-enyl)-amine;
(S)-2-Amino-1-{4-[[4-(4-chloro-benzyloxy)-phenyl]-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-{4-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-(3-methyl-but-2-enyl)-amine;
(S)-2-Amino-1-{4-[{4-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-(3-methyl-but-2-enyl)-(4-phenethyl-phenyl)-amine;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-(3-methyl-but-2-enyl)-amine;
(S)-2-Amino-1-{4-[{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-[4-(4-chloro-benzyloxy)-phenyl]-(3-methyl-but-2-enyl)-amine;
(S)-2-Amino-1-{4-[[4-(4-chloro-benzyloxy)-phenyl]-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-{4-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-(3-methyl-butyl)-amine;
(S)-2-Amino-1-{4-[{4-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-(3-methyl-butyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-(3-methyl-butyl)-(4-phenethyl-phenyl)-amine;
(S)-2-Amino-4-methyl-1-{4-[(3-methyl-butyl)-(4-phenethyl-phenyl)-amino]-piperidin-1-yl}-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-(3-methyl-butyl)-amine;
(S)-2-Amino-1-{4-[{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-(3-methyl-butyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-3-yl]-(4-benzyloxy-phenyl)-(3-methyl-butyl)-amine;
(S)-2-Amino-1-{3-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-3-yl]-(4-cyclohexylmethoxy-phenyl)-(3-methyl-butyl)-amine;
(S)-2-Amino-1-{3-[(4-cyclohexylmethoxy-phenyl)-(3-methyl-butyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-3-yl]-[4-(2-cyclohexyl-ethyl)-phenyl]-(3-methyl-butyl)-amine;
(S)-2-Amino-1-{3-[[4-(2-cyclohexyl-ethyl)-phenyl]-(3-methyl-butyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-3-yl]-[4-(2,2-dimethyl-propoxy)-phenyl]-(3-methyl-butyl)-amine;
(S)-2-Amino-1-{3-[[4-(2,2-dimethyl-propoxy)-phenyl]-(3-methyl-butyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-3-yl]-[4-(3,3-dimethyl-butyl)-phenyl]-(3-methyl-butyl)-amine;
(S)-2-Amino-1-{3-[[4-(3,3-dimethyl-butyl)-phenyl]-(3-methyl-butyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-2-Amino-1-{3-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-3-yl]-(4-cyclohexylmethoxy-phenyl)-(3-methyl-but-2-enyl)-amine;
(S)-2-Amino-1-{3-[(4-cyclohexylmethoxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-3-yl]-[4-(2-cyclohexyl-ethyl)-phenyl]-(3-methyl-but-2-enyl)-amine;
(S)-2-Amino-1-{3-[[4-(2-cyclohexyl-ethyl)-phenyl]-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-3-yl]-[4-(2,2-dimethyl-propoxy)-phenyl]-(3-methyl-but-2-enyl)-amine;
(S)-2-Amino-1-{3-[[4-(2,2-dimethyl-propoxy)-phenyl]-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-2-Amino-1-{3-[[4-(3,3-dimethyl-butyl)-phenyl]-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-3-yl]-[4-(3,3-dimethyl-butyl)-phenyl]-(3-methyl-but-2-enyl)-amine;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-3-yl]-[4-(4-chloro-benzyloxy)-phenyl]-(3-methyl-but-2-enyl)-amine;
(S)-2-Amino-1-{3-[[4-(4-chloro-benzyloxy)-phenyl]-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-3-yl]-{4-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-(3-methyl-but-2-enyl)-amine;
(S)-2-Amino-1-{3-[{4-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-3-yl]-(3-methyl-but-2-enyl)-(4-phenethyl-phenyl)-amine;
(S)-2-Amino-4-methyl-1-3-[(3-methyl-but-2-enyl)-(4-phenethyl-phenyl)-amino]-piperidin-1-yl}-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-3-yl]-{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-(3-methyl-but-2-enyl)-amine;
(S)-2-Amino-1-{3-[{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-3-yl]-[4-(4-chloro-benzyloxy)-phenyl]-(3-methyl-butyl)-amine;
(S)-2-Amino-1-{3-[[4-(4-chloro-benzyloxy)-phenyl]-(3-methyl-butyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-[-(2-Amino-4-methyl-pentyl)-piperidin-3-yl]-{4-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-(3-methyl-butyl)-amine;
(S)-2-Amino-1-{3-[{4-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-(3-methyl-butyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-3-yl]-(3-methyl-butyl)-(4-phenethyl-phenyl)-amine;
(S)-2-Amino-4-methyl-1-{3-[(3-methyl-butyl)-(4-phenethyl-phenyl)-amino]-piperidin-1-yl}-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-3-yl]-{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-(3-methyl-butyl)-amine;
(S)-2-Amino-1-{3-[{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-(3-methyl-butyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-pyrrolidin-3-yl]-(4-benzyloxy-phenyl)-(3-methyl-butyl)-amine;
(S)-2-Amino-1-[3-(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-pyrrolidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-pyrrolidin-3-yl]-(4-cyclohexylmethoxy-phenyl)-(3-methyl-butyl)-amine;
(S)-2-Amino-1-{3-[(4-cyclohexylmethoxy-phenyl)-(3-methyl-butyl)-amino]-pyrrolidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-pyrrolidin-3-yl]-[4-(2-cyclohexyl-ethyl)-phenyl]-(3-methyl-butyl)-amine;
(S)-2-Amino-1-{3-[[4-(2-cyclohexyl-ethyl)-phenyl]-(3-methyl-butyl)-amino]-pyrrolidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-pyrrolidin-3-yl]-[4-(2,2-dimethyl-propoxy)-phenyl]-(3-methyl-butyl)-amine;
(S)-2-Amino-1-{3-[[4-(2,2-dimethyl-propoxy)-phenyl]-(3-methyl-butyl)-amino]-pyrrolidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-pyrrolidin-3-yl]-[4-(3,3-dimethyl-butyl)-phenyl]-(3-methyl-butyl)-amine;
(S)-2-Amino-1-{3-[[4-(3,3-dimethyl-butyl)-phenyl]-(3-methyl-butyl)-amino]-pyrrolidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-pyrrolidin-3-yl]-(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amine;
(S)-2-Amino-1-[3-(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-pyrrolidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-pyrrolidin-3-yl]-(4-cyclohexylmethoxy-phenyl)-(3-methyl-but-2-enyl)-amine;
(S)-2-Amino-1-{3-[(4-cyclohexylmethoxy-phenyl)-(3-methyl-but-2-enyl)-amino]-pyrrolidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-pyrrolidin-3-yl]-[4-(2-cyclohexyl-ethyl)-phenyl]-(3-methyl-but-2-enyl)-amine;
(S)-2-Amino-1-{3-[[4-(2-cyclohexyl-ethyl)-phenyl]-(3-methyl-but-2-enyl)-amino]-pyrrolidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-pyrrolidin-3-yl]-[4-(2,2-dimethyl-propoxy)-phenyl]-(3-methyl-but-2-enyl)-amine;
(S)-2-Amino-1-{3-[[4-(2,2-dimethyl-propoxy)-phenyl]-(3-methyl-but-2-enyl)-amino]-pyrrolidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-pyrrolidin-3-yl]-[4-(3,3-dimethyl-butyl)-phenyl]-(3-methyl-but-2-enyl)-amine;
(S)-2-Amino-1-{3-[[4-(3,3-dimethyl-butyl)-phenyl]-(3-methyl-but-2-enyl)-amino]-pyrrolidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-pyrrolidin-3-yl]-[4-(4-chloro-benzyloxy)-phenyl]-(3-methyl-but-2-enyl)-amine;
(S)-2-Amino-1-{3-[[4-(4-chloro-benzyloxy)-phenyl]-(3-methyl-but-2-enyl)-amino]-pyrrolidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-pyrrolidin-3-yl]-{4-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-(3-methyl-but-2-enyl)-amine;
(S)-2-Amino-1-{3-[{4-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-(3-methyl-but-2-enyl)-amino]-pyrrolidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-pyrrolidin-3-yl]-(3-methyl-but-2-enyl)-(4-phenethyl-phenyl)-amine;
(S)-2-Amino-4-methyl 1-{3-[(3-methyl-but-2-enyl)-(4-phenethyl-phenyl)-amino]-pyrrolidin-1-yl}-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-pyrrolidin-3-yl]-{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-(3-methyl-but-2-enyl)-amine;
(S)-2-Amino-1-{3-[{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-(3-methyl-but-2-enyl)-amino]-pyrrolidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-pyrrolidin-3-yl]-[4-(4-chloro-benzyloxy)-phenyl]-(3-methyl-butyl)-amine;
(S)-2-Amino-1-{3-[[4-(4-chloro-benzyloxy)-phenyl]-(3-methyl-butyl)-amino]-pyrrolidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-pyrrolidin-3-yl]-{4-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-(3-methyl-butyl)-amine;
(S)-2-Amino-1-{3-[{4-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-(3-methyl-butyl)-amino]-pyrrolidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-pyrrolidin-3-yl]-(3-methyl-butyl)-(4-phenethyl-phenyl)-amine;
(S)-2-Amino-4-methyl-1-{3-[(3-methyl-butyl)-(4-phenethyl-phenyl)-amino]-pyrrolidin-1-yl}-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-pyrrolidin-3-yl]-{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-(3-methyl-butyl)-amine;
(S)-2-Amino-1-{3-[{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-(3-methyl-butyl)-amino]-pyrrolidin-1-yl}-4-methyl-pentan-1-one;
(S)-Benzoic acid 4-[[1-(2-amino-4-methyl-pentyl)-piperidin-3-yl]-(3-methyl-but-2-enyl)-amino]-phenyl ester;
(R)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-(4-benzyloxy-phenyl)-(3-methyl-butyl)-amine;
(R)-2-Amino-1-{4-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(R)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-(4-cyclohexylmethoxy-phenyl)-(3-methyl-butyl)-amine;
(R)-2-Amino-1-{4-[(4-cyclohexylmethoxy-phenyl)-(3-methyl-butyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(R)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-[4-(2-cyclohexyl-ethyl)-phenyl]-(3-methyl-butyl)-amine;
(R)-2-Amino-1-{4-[[4-(2-cyclohexyl-ethyl)-phenyl]-(3-methyl-butyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(R)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-[4-(2,2-dimethyl-propoxy)-phenyl]-(3-methyl-butyl)-amine;
(R)-2-Amino-1-{4-[[4-(2,2-dimethyl-propoxy)-phenyl]-(3-methyl-butyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(R)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-[4-(3,3-dimethyl-butyl)-phenyl]-(3-methyl-butyl)-amine;
(R)-2-Amino-1-{4-[[4-(3,3-dimethyl-butyl)-phenyl]-(3-methyl-butyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(R)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amine;
(R)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-[4-(2-cyclohexyl-ethyl)-phenyl]-(3-methyl-but-2-enyl)-amine;
(R)-2-Amino-1-{4-[[4-(2-cyclohexyl-ethyl)-phenyl]-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(R)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-[4-(3,3-dimethyl-butyl)-phenyl]-(3-methyl-but-2-enyl)-amine;
(R)-2-Amino-1-{4-[[4-(3,3-dimethyl-butyl)-phenyl]-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(R)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-[4-(4-chloro-benzyloxy)-phenyl]-(3-methyl-butyl)-amine;
(R)-2-Amino-1-{4-[[4-(4-chloro-benzyloxy)-phenyl]-(3-methyl-butyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(R)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-{4-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-(3-methyl-butyl)-amine;
(R)-2-Amino-1-{4-[{4-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(R)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-(3-methyl-but-2-enyl)-(4-phenethyl-phenyl)-amine;
(R)-2-Amino-4-methyl-1-{4-[(3-methyl-but-2-enyl)-(4-phenethyl-phenyl)-amino]-piperidin-1-yl}-pentan-1-one;
(R)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-(3-methyl-but-2-enyl)-amine;
(R)-2-Amino-1-{4-[{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(R)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-[4-(4-fluoro-benzyloxy)-phenyl]-(3-methyl-butyl)-amine;
(R)-2-Amino-1-{4-[[4-(4-fluoro-benzyloxy)-phenyl]-(3-methyl-butyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(R)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-{4-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-(3-methyl-butyl)-amine;
(R)-2-Amino-1-{4-[{4-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-(3-methyl-butyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(R)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-(3-methyl-butyl)-(4-phenethyl-phenyl)-amine;
(R)-2-Amino-4-methyl-1-{4-[(3-methyl-butyl)-(4-phenethyl-phenyl)-amino]-piperidin-1-yl}-pentan-1-one;
(R)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-(3-methyl-butyl)-amine;
(R)-2-Amino-1-{4-[{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-(3-methyl-butyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-3-methyl-pentyl)-piperidin-4-yl]-(4-benzyloxy-phenyl)-(3-methyl-butyl)-amine;
(S)-2-Amino-1-{4-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-piperidin-1-yl}-3-methyl-pentan-1-one;
(S)-[1-(2-Amino-3-methyl-pentyl)-piperidin-4-yl]-(4-cyclohexylmethoxy-phenyl)-(3-methyl-butyl)-amine;
(S)-2-Amino-1-{4-[(4-cyclohexylmethoxy-phenyl)-(3-methyl-butyl)-amino]-piperidin-1-yl}-3-methyl-pentan-1-one;
(S)-[1-(2-Amino-3-methyl-pentyl)-piperidin-4-yl]-[4-(2-cyclohexyl-ethyl)-phenyl]-(3-methyl-butyl)-amine;
(S)-2-Amino-1-{4-[[4-(2-cyclohexyl-ethyl)-phenyl]-(3-methyl-butyl)-amino]-piperidin-1-yl}-3-methyl-pentan-1-one;
(S)-[1-(2-Amino-3-methyl-pentyl)-piperidin-4-yl]-[4-(2,2-dimethyl-propoxy)-phenyl]-(3-methyl-butyl)-amine;
(S)-2-Amino-1-{4-[[4-(2,2-dimethyl-propoxy)-phenyl]-(3-methyl-butyl)-amino]-piperidin-1-yl}-3-methyl-pentan-1-one;
(S)-[1-(2-Amino-3-methyl-pentyl)-piperidin-4-yl]-[4-(3,3-dimethyl-butyl)-phenyl]-(3-methyl-butyl)-amine;
(S)-2-Amino-1-{4-[[4-(3,3-dimethyl-butyl)-phenyl]-(3-methyl-butyl)-amino]-piperidin-1-yl}-3-methyl-pentan-1-one;
(S)-[1-(2-Amino-3-methyl-pentyl)-piperidin-4-yl]-(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amine;
(S)-[1-(2-Amino-3-methyl-pentyl)-piperidin-4-yl]-[4-(4-fluorobenzyloxy)-phenyl]-(3-methyl-butyl)-amine;
(S)-2-Amino-1-{4-[(4-(4-fluorobenzyloxy)-phenyl)-(3-methyl-butyl)-amino]-piperidin-1-yl}-3-methyl-pentan-1-one;
(S)-[1-(2-Amino-3-methyl-pentyl)-piperidin-4-yl]-[4-(2-cyclohexyl-ethyl)-phenyl]-(3-methyl-but-2-enyl)-amine;
(S)-2-Amino-1-{4-[[4-(2-cyclohexyl-ethyl)-phenyl]-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-3-methyl-pentan-1-one;
(S)-[1-(2-Amino-3-methyl-pentyl)-piperidin-4-yl]-[4-(3,3-dimethyl-butyl)-phenyl]-(3-methyl-but-2-enyl)-amine;
(S)-2-Amino-1-{4-[[4-(3,3-dimethyl-butyl)-phenyl]-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-3-methyl-pentan-1-one;
(S)-[1-(2-Amino-3-methyl-pentyl)-piperidin-4-yl]-[4-(4-chloro-benzyloxy)-phenyl]-(3-methyl-butyl)-amine;
(S)-2-Amino-1-{4-[[4-(4-chloro-benzyloxy)-phenyl]-(3-methyl-butyl)-amino]-piperidin-1-yl}-3-methyl-pentan-1-one;
(S)-[1-(2-Amino-3-methyl-pentyl)-piperidin-4-yl]-{4-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-(3-methyl-butyl)-amine;
(S)-2-Amino-1-{4-[{4-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-3-methyl-pentan-1-one;
(S)-[1-(2-Amino-3-methyl-pentyl)-piperidin-4-yl]-(3-methyl-but-2-enyl)-(4-phenethyl-phenyl)-amine;
(S)-2-Amino-3-methyl-1-{4-[(3-methyl-but-2-enyl)-(4-phenethyl-phenyl)-amino]-piperidin-1-yl}-pentan-1-one;
(S)-[1-(2-Amino-3-methyl-pentyl)-piperidin-4-yl]-{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-(3-methyl-but-2-enyl)-amine;
(S)-2-Amino-1-{4-[{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-3-methyl-pentan-1-one;
(S)-[1-(2-Amino-4-methyl-pentyl)-piperidin-4-yl]-[4-(4-fluoro-benzyloxy)-phenyl]-(3-methyl-butyl)-amine;
(S)-2-Amino-1-{4-[[4-(4-fluoro-benzyloxy)-phenyl]-(3-methyl-butyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one;
(S)-[1-(2-Amino-3-methyl-pentyl)-piperidin-4-yl]-{4-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-(3-methyl-butyl)-amine;
(S)-2-Amino-1-{4-[{4-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-(3-methyl-butyl)-amino]-piperidin-1-yl}-3-methyl-pentan-1-one;
(S)-[1-(2-Amino-3-methyl-pentyl)-piperidin-4-yl]-(3-methyl-butyl)-(4-phenethyl-phenyl)-amine;
(S)-2-Amino-3-methyl-1-{4-[(3-methyl-butyl)-(4-phenethyl-phenyl)-amino]-piperidin-1-yl}-pentan-1-one;
(S)-[1-(2-Amino-3-methyl-pentyl)-piperidin-4-yl]-{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-(3-methyl-butyl)-amine; and
(S)-2-Amino-1-{4-[{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-(3-methyl-butyl)-amino]-piperidin-1-yl}-3-methyl-pentan-1-one.
The present invention provides compounds having the Formula I
wherein
each m is independently 1 to 3;
each n is independently 0 to 3;
each Ra and Rb is independently hydrogen, C1-C6alkyl, or Ra and Rb together with the carbon atom to which they are bonded form a C3-C6cycloalkyl ring;
R5 is C1-C6alkyl, xe2x80x94(CH2)m-heteroaryl, xe2x80x94(CH2)m-substituted heteroaryl, xe2x80x94(CH2)m-phenyl, or xe2x80x94(CH2)-substituted phenyl;
R2 is hydrogen, C1-C8alkenyl, C3-C8cycloalkenyl, phenyl, substituted phenyl, C1-C8alkyl, substituted C1-C8alkyl, xe2x80x94(CH2)msubstituted C3-C8cycloalkyl, xe2x80x94(CH2)m-C3-C8cycloalkyl, C3-C8cycloalkyl, substituted C3-C8cycloalkyl, xe2x80x94(CH2)m-phenyl, or xe2x80x94(CH2)m substituted phenyl;
R3 is hydrogen, C1-C6alkyl, or C2-C6alkenyl;
Q is aryl, heteroaryl, substituted heteroaryl, C3-C8cycloalkyl, substituted C3-C8cycloalkyl, C1-C6alkyl, substituted C1-C6alkyl, hydrogen, C3-C8heterocycloalkyl, C3-C8 substituted heterocycloalkyl, or substituted aryl;
V is xe2x80x94O(CH2)nxe2x80x94, xe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94(CH2)n,
or xe2x80x94(CH2)nxe2x80x94Oxe2x80x94;
R4 is hydrogen,
C1-C6alkyl, C2-C8alkenyl, C3-C8cycloalkenyl, C3-C8 substituted cycloalkenyl, xe2x80x94(CH2)m-phenyl, xe2x80x94(CH2)m-heteroaryl, xe2x80x94(CH2)m-substituted heteroaryl, xe2x80x94(CH2)m-substituted phenyl, C3-C8cycloalkyl, or C3-C8 substituted cycloalkyl;
or R3 and R4 together with the nitrogen atom to which they are bonded can form a 5-7 membered ring that can contain one or more heteroatom;
and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
The term xe2x80x9calkylxe2x80x9d means a straight or branched chain hydrocarbon. Representative examples of alkyl groups are methyl, ethyl, propyl, isopropyl, isobutyl, butyl, tert-butyl, sec-butyl, pentyl, and hexyl.
The term xe2x80x9calkoxyxe2x80x9d means an alkyl group attached to an oxygen atom. Representative examples of alkoxy groups include methoxy, ethoxy, tert-butoxy, propoxy, and isobutoxy.
The term xe2x80x9chalogenxe2x80x9d includes chlorine, fluorine, bromine, and iodine.
The term xe2x80x9calkenylxe2x80x9d means a branched or straight chain hydrocarbon having one or more carbon-carbon double bond.
The term xe2x80x9carylxe2x80x9d means an aromatic hydrocarbon. Representative examples of aryl groups include phenyl and naphthyl.
The term xe2x80x9cheteroatomxe2x80x9d includes oxygen, nitrogen, and sulfur.
The term xe2x80x9cheteroarylxe2x80x9d means an aryl group wherein one or more carbon atom of the aromatic hydrocarbon has been replaced with a heteroatom. Examples of heteroaryl radicals include, but are not limited to, pyridyl, imidazolyl, pyrrolyl, thienyl, furyl, pyranyl, pyrimidinyl, pyridazinyl, indolyl, quinolyl, naphthyridinyl, and isoxazolyl.
The term xe2x80x9ccycloalkylxe2x80x9d means a cyclic hydrocarbon. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The term xe2x80x9cheterocycloalkylxe2x80x9d means a cycloalkyl group in which one or more carbon atom has been replaced by a heteroatom.
The term xe2x80x9ccycloalkenylxe2x80x9d means a cycloalkyl group having one or more carbon-carbon double or triple bond. Example includes cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclobutadiene, cyclopentadiene, and the like.
The symbol xe2x80x9cxe2x80x94xe2x80x9c means a bond.
The term xe2x80x9cpatientxe2x80x9d means all animals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, and pigs.
The term xe2x80x9csubstitutedxe2x80x9d means that the base organic radical has one or more substituents. For example, substituted cyclohexyl means a cyclohexyl radical that has one or more substituents. Substituents include, but are not limited to, halogen, C1-C8alkyl, xe2x80x94CN, CF3, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NHC1-C8alkyl, xe2x80x94N(C1-C8alkyl)2, xe2x80x94OC1-C8alkyl, and xe2x80x94OH. Particularly preferred substituents include, but are not limited to tert-butyl, methyl, chlorine, fluorine, bromine, xe2x80x94OCH3, xe2x80x94OCH2CH3, xe2x80x94OH, and xe2x80x94N(CH3)2.
The term xe2x80x9ccycloalkenylxe2x80x9d means a cycloalkyl group having at least one carbon-carbon double bond. Examples of cycloalkenyl groups include cyclopentene, cyclobutene, and cyclohexene.
The term xe2x80x9cheterocyclexe2x80x9d means a cycloalkyl group wherein one or more carbon atom is replaced with a heteroatom. Examples of heterocycles include, but are not limited to, pyrrolidinyl, piperidinyl, and piperazinyl.
Those skilled in the art are easily able to identify patients having a stroke or at risk of having a stroke; cerebral ischemia; head trauma; or epilepsy. For example, patients who are at risk of having a stroke include, but is not limited to patients having hypertension or undergoing major surgery.
A therapeutically effective amount is an amount of a compound of Formula I, that when administered to a patient, ameliorates a symptom of the disease.
The compounds of the present invention can be administered to a patient either alone or a part of a pharmaceutical composition. The compositions can be administered to patients either orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), intracistemally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments, or drops), or as a buccal or nasal spray.
Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (C) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.
Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
The term xe2x80x9cpharmaceutically acceptable salts, esters, amides, and prodrugsxe2x80x9d as used herein refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term xe2x80x9csaltsxe2x80x9d refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate and laurylsulphonate salts, and the like. These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. (See, for example, S. M. Berge, et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. Pharm. Sci., 1977;66:1-19 which is incorporated herein by reference.)
Examples of pharmaceutically acceptable, non-toxic esters of the compounds of this invention include C1-C6alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C5-C7cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. C1-C4alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods.
Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary C1-C6alkyl amines and secondary C1-C6dialkyl amines wherein the alkyl groups are straight or branched chain. In the case of secondary amines the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C1-C3alkyl primary amines, and C1-C2dialkyl secondary amines are preferred. Amides of the compounds of the invention may be prepared according to conventional methods.
The term xe2x80x9cprodrugxe2x80x9d refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, xe2x80x9cPro-drugs as Novel Delivery Systems,xe2x80x9d Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
The compounds of the present invention can exist in different stereoisomeric forms by virtue of the presence of asymmetric centers in the compounds. It is contemplated that all stereoisomeric forms of the compounds, as well as mixtures thereof including racemic mixtures, form part of this invention.
The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is preferable. The specific dosage used, however, can vary. For example, the dosage can depended on a numbers of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to those skilled in the art.
In addition, it is intended that the present invention cover compounds made either using standard organic synthetic techniques, including combinatorial chemistry or by biological methods, such as through metabolism.
The examples presented below are intended to illustrate particular embodiments of the invention and are not intended to limit the scope of the specification, including the claims, in any way.
The following abbreviations are used throughout this application:
General Procedure for the Preparation of Calcium Channel Blockers
Schemes III, IV, and V below illustrate the preparation of the compounds of the present invention (II). The preparation of intermediates (I) is illustrated in Schemes I and II.
Step I: The Preparation of Intermediate I
Step II: The Preparation of the Compounds of the Present Invention (II)
where each R and Y are appropriate molecular entities with regard to Formula I.

Abstract: The present invention also provides methods of using the compounds of Formula I to treat stroke, cerebral ischemia, head trauma, or epilepsy and to pharmaceutical compositions that contain the compounds of Formula I.


A multilayer reflector useable to reflect or transmit light over the visible wavelength range includes optically thick constituent layers. The optical thickness of the constituent layers through the thickness of the reflector defines a layer thickness profile. The layers are arranged so that the thickness profile has a tailored non-uniform distribution, such as a graded distribution or a randomized distribution. The layers desirably have an optical thickness in a range from about one to five or one to ten design wavelengths. The reflector can be a polarizer, reflecting only one normally incident polarization state, or a mirror, reflecting two normally incident orthogonal polarization states.

Thin film multilayer reflectors suitable for reflecting visible or near-visible light are known. Such reflectors have long been made by evaporating thin films of different inorganic dielectric light-transmissive materials in succession on a glass substrate in a vacuum chamber. The different refractive indices of adjacent layers form tens or hundreds of interfaces, each of which reflects light by Fresnel reflection, and coherent constructive or destructive interference of reflected light components provides the reflector with its reflection and transmission properties. It is also know to make thin film multilayer reflectors by an extrusion process in which a multitude of alternating light-transmissive polymer materials are coextruded through a die, optionally passed through one or more layer multipliers, then cast onto a casting wheel or surface, and subsequently uniaxially or biaxially stretched. Such a technique can be used to make all-polymeric thin film reflective optical bodies, such as reflective polarizing films and reflective mirror films. See, for example, U.S. Pat. No. 5,486,949 (Schrenk et al.); U.S. Pat. No. 5,882,774 (Jonza et al.); U.S. Pat. No. 6,531,230 (Weber et al.); and U.S. Pat. No. 6,827,886 (Neavin et al.). In contrast to vacuum-coated inorganic dielectric thin film stacks, the multilayer reflectors made by polymer coextrusion techniques do not require a separate substrate for formation or handling.
Because of their reliance on coherent constructive or destructive interference of light from neighboring layer interfaces, and because such constructive or destructive interference is a strong function of the individual layer thicknesses, as well as other geometric factors, great care is typically needed to ensure that the layers are controlled to within a narrow tolerance of a design goal to ensure proper operation of the thin film interference device. As the physical size of the thin film device increases—such as for polymeric thin film reflective polarizers or broadband mirrors used in LCD devices, where the demand for larger screen sizes continues to grow—the need for such layer control can be even more important. Increasing the physical size of thin film reflective polarizers and mirrors that are manufactured in the form of thin, flexible all polymeric sheets or films also magnifies potential mechanical problems such as wrinkling, warping, and delamination.
Certain "thick film" multilayer reflectors are also known. These reflectors, which are generally associated with incoherent light reflection, are variously defined in the literature, for example, structures whose individual layers have an optical thickness of at least 0.45 micrometers, or structures whose individual layers have an average optical thickness of at least 5/4 times the average wavelength of light to be reflected. In any case, principles of incoherent light reflection inform the skilled artisan that, for most practical situations, thick film multilayer reflectors have peak reflectivities well below those achievable by their thin film counterparts, and thus the former are often considered inferior to the latter. Further, several references suggest that thick film multilayer stacks provide incoherent light reflection regardless of how thick the individual layers are, and that the layer thicknesses of a thick film multilayer stack have substantially no effect on such a stack's reflectivity.

Thick film multilayer reflector with tailored layer thickness profile


An audio communication based electronic signature system and a method thereof are provided. The system includes: an audio smart key device including an interface module, a data processing module, a smart key module and a power module; and a terminal including an audio output interface, an audio input interface and an application unit. The interface module of the audio smart key device communicates with the terminal in the form of audio signal and it can perform operations of A/D conversion and modulation and demodulation on the audio signal. In the signing method, the terminal sends an audio signal including important data to the smart key device, the audio smart key device receives and decodes the audio signal, demodulates the decoded data and decrypts the demodulated data, signs the decrypted data, encodes, modulates and encrypts the signature result subsequently, sends the crypted result to the terminal, where the encrypted result is sent to the server for signature verification.

Development in telephone banking and online banking allows people to enjoy banking services at home. With social development and progress, banking requirements increasingly develop, such as inquiry, transfer, and payment at any time and any location. Both telephone banking and online banking cannot provide customers with desirable services at any time and any location due to some restrictions. The emergence of mobile phone banking leads to another way to provide electronic services to users. As an extension of the online banking, mobile phone banking brings great convenience to users, and therefore, mobile phone banking is expected to be popular with the wide use and technology development of mobile phones.
For the security of electronic transaction, the USB key plays a role of escort with the development of online banking. In mobile phone banking, a device supporting electronic signatures should be provided according to the electronic signature law to sign important electronic data. Traditionally, a SIM card or WAP technology functions as a USB key, or alternatively, a digital signature algorithm and a key is simply stored in a mobile phone. Compared with a USB key used on a computer, the security technologies in the prior art are weak, and therefore, a USB key is needed for mobile devices used for mobile phone banking. For example, some devices communicate data with a computer via a USB interface. Similar functionality can be applied to applications on mobile phones by practicing the solution of the present invention.

Audio communication based electronic signature system and method thereof


A printed wiring board having at least one connector includes a dielectric substrate that has, on a first face, a first ground plane, and on a second face, at least two transmission lines between which the connector and a footprint are mounted. The footprint includes a first element positioned between the two transmission lines under the connector. The first element forming with the first ground plane, a capacitive element and, at each extremity of the first element, second elements forming with the first element, a self-inductive and capacitive element. The second elements each extending by a second ground plane, the second ground planes which are connected to the first ground plane.

The present invention will be described by referring to a printed circuit board on which reception antenna are mounted but also the transmission/reception system, namely the "Front End Radio" circuit for wireless communication applications. However, it is obvious for a person skilled in the art that the present invention can be used on any printed circuit board requiring the use of test connectors.
Hence, as shown diagrammatically in FIG. 1 which shows a printed circuit board of the market on which an RF circuit (radiofrequency) is mounted, a test connector 1 is mounted on each of the printed lines 2 connecting a printed antenna such as antenna 3 to one of the inputs 4 of an RF circuit referenced 5. The test connectors that are in fact miniature connectors are automatically and definitively transferred on the printed circuit board, between the antennas and the RF circuit.
As shown in FIG. 2 of which the left-hand part relates to the operational mode and the right-hand part the test mode of a miniature connector, each connector comprises a mechanical switching system constituted mainly of two overlapping blades 10, 11, the blade 10 being offset on the RF circuit side input line whereas the blade 11 that overlaps the end of the blade 10 is an elastic blade offset and fixed to the output line on the antenna side.
The operation of such a connector is as follows. In operational mode, the two blades 10, 11 are in short-circuit and the transmission/reception signal (E/R) of the RF circuit is connected directly to the antenna in return for some insertion loss. In test mode, a coaxial probe referenced 12 in FIG. 2, equipped with a suitable adaptor, is plugged into the connector of the board. This has the effect of separating the blade 11 from the blade 10 by disconnecting in this manner the RF channel from the antenna channel and this enables the transmission/reception signal (E/R) of the RF circuit to be recovered in order for it to be measured.
Currently, the offset footprints of a test connector recommended by connector manufacturers have a shape such as the one shown in FIG. 3. Hence, in a more precise manner, on a part of the substrate 100 of the printed circuit board, the two metal feeder lines 101, 102 are realised. These two lines are found between two ground plane elements 103, 104. At the attachment site of the connector, each of the lines extends by a solder stud referenced 105, 106. Moreover, four solder studs 107 enable the connector to be attached to the board. A conductive material footprint 108 connects the two ground planes 103, 104 by passing between the solder studs.
As shown in FIG. 3, this footprint or pattern is connected by a metallised hole 109 to the lower ground plane of the printed board. Other metallised holes also connect the ground planes 103, 104 to the lower ground plane. The metallised holes enable the ground continuity to be provided between the lower and upper planes of the substrate.
The simulations conducted with test connectors of the market mounted on a footprint such as described with reference to FIG. 3, show that the transmission response (S21) is of the quasi low-pass type for the chosen operating band. Said response is due essentially to the form of the central parts of the connector that have been designed to meet two constraints, namely:                A mechanical constraint consisting in providing a perfect and reliable connection in operational mode of the two parts and a connection between the mobile part of the blades of the test connector in test mode.        Electrical constraints, namely to provide in particular in the operational mode, a perfect impedance matching to the access lines of characteristic impedance 50 ohms in the specified operating band.

Offset footprint of a connector on a printed board


Some of a plurality of frame images are made comparison object images for use in synthesizing a still image. Selecting one of the comparison object images as a comparison reference image and one as a target image, the comparison reference image and target image are compared, and a parameter is calculated. If the parameter does not meet a predetermined criterion, the target image is excluded from the comparison object images. Additionally, any number of frame images from among the plurality of frame images are set as comparison object images, and the aforementioned comparison is carried out until the total number of comparison object images and reference images serving as reference for synthesis is equal to or greater than a predetermined number. A synthesized image generating module 75 synthesizes the reference images and comparison object images whose total number is equal to or greater than the predetermined number, to generate a still image.

Conventionally a still image is created by capturing a single scene from video shot with a digital video camera or the like so that the still image has higher resolution than the frame images. Such a still image is created through a synthesis process that involves overlapping several frames contained in the video image.
For example, JP2000-244851A discloses a technique wherein a single frame image is selected as a reference image from among a number (n+1) of successive images, motion vectors for the other n frame images (processing-object-images) with respect to this reference image are calculated. and on the basis of the motion vectors, the (n+1) frame images are synthesized to produce a still image.
JP06-350974A discloses another technique for created a still image from interlacing video images, wherein one field is selected as a reference image from among a pair of interlacing fields, with the other filed being selected as a processing-object-image, then determining on a field-by-field basis whether the processing-object-image is suitable for synthesis, synthesizing them where determined to be appropriate. Typically, by increasing the number of frame images to be synthesized, it is possible to improve picture quality of the still image; however, it is not always the case that picture quality is improved by increasing the number of frame images to be synthesized. The reasons for this are described hereinbelow.
FIG. 1 is an illustration of a method for synthesizing a reference image and an object image for synthesis. At top in FIG. 1 are shown a reference image and an object image for synthesis, positioned so as to compensate for image shift. At bottom in FIG. 1 are shown positional relationships among pixels of the reference image, object image for synthesis, and synthesized image. At bottom in FIG. 1, "∘" symbols denote pixels of the reference image. "•" symbols denote pixels of the object image for synthesis. The hatched circles shown on the broken gridlines denote pixels of the synthesized image. In this drawing, resolution of the reference image and object image for synthesis are shown as being the same, with frame image resolution being increased by 1.5× in the x axis direction and y axis direction.
Here, pixel g1 of the synthesized image will be considered. This pixel g1 coincides with pixel t1 of the reference image. Here, on the basis of tone values of the four pixels s1-s4 of the object image for synthesis surrounding pixel g1, a tone value at the position of pixel g1 is calculated by a bilinear method, and this tone value is then averaged with the tone value of pixel t1 of the reference image to obtain a tone value for pixel g1.
A tone value for pixel g2 of the synthesized image is determined by the following procedure. On the basis of tone values of the four pixels t2-t5 of the reference image surrounding pixel g2, a tone value at the position of pixel g2 is calculated by a bilinear method. Next, on the basis of tone values of the four pixels s4-s7 of the object image for synthesis surrounding pixel g2, a tone value at the position of pixel g2 is calculated by a bilinear method. The two are then averaged to obtain a tone value for pixel g2.
Tone values for other pixels can be determined in the manner described above. Here, in order to facilitate understanding, the description assumes that resolution of the reference image and processing-object-image is the same; however, where reference image and processing-object-image resolutions are different, a similar process may be carried out after enlargement or reduction, as appropriate.
FIG. 2 is an illustration showing a synthesis method for use where there is zero image shift between a reference image and an object image for synthesis. At top in FIG. 2 are shown a reference image and an object image for synthesis, positioned so as to correct for shift. In this case, since shift is zero, the reference image and object image for synthesis overlap completely. At bottom in FIG. 2 are shown positional relationships among pixels of the reference image, object image for synthesis, and synthesized image. Since the reference image and object image for synthesis overlap in their entirety, the pixels of the reference image and those of the object image for synthesis are situated at the same locations.
A tone value for pixel g2 of the synthesized image is determined by the following procedure. First, on the basis of tone values of the four pixels t2-t5 of the reference image surrounding pixel g2, a tone value at the position of pixel g2 is calculated by a bilinear method. Next, on the basis of tone values of the four pixels s2-s5 of the object image for synthesis surrounding pixel g2, a tone value at the position of pixel g2 is calculated by a bilinear method. The two are then averaged to obtain a tone value for pixel g2.
Since tone values of pixels t2-t5 and tone values of pixels s2-s5 are the same values, the tone value at the position of pixel g2 calculated by bilinear method on the basis of pixels t2-t5 and the tone value at the position of pixel g2 calculated by bilinear method on the basis of pixels s2-s5 are identical values. That is, the average value thereof will also be the same as tone value at the position of pixel g2 calculated by bilinear method on the basis of pixels t2-t5, and tone value at the position of image g2 calculated by bilinear method on the basis of pixels s2-s5.
That is, where there is zero shift between a reference image and an object image for synthesis, carrying out the synthesis process will give a synthesis result that is no different from the original image. Similarly, where there is only a slight shift amount, there will be substantially no noticeable difference between the image resulting from synthesis and the original image. In such instances, the synthesis only increases the processing time, with no hope of substantial improvement in picture quality.

Generation of still image from a plurality of frame images


A throttle device provides a large number of small flow channels generally in parallel rather than a single flow path. The throttling device, a porous cartridge within a tube, may be porous metal, packed ferrous spheres or other particles, packed fibrous material, a plurality of smaller capillaries joined together in parallel, etc. The number and size of the channels provide proper pressure drop performance of the throttle, and flow is laminar with a Reynolds number less than 2,000. Vibrations are low. With certain refrigerant components, and small openings in the porous throttle device, refrigerant flow resistance increases until all flow ceases below selected and repeatable temperature levels. Thus, a temperature-dependent, variable on to off throttle device is provided without moving parts. This self adjusting throttle device can operate in parallel with a fixed throttle device.

This invention relates generally to a refrigerant flow control device in a closed cycle refrigeration system, and in particular to a flow controller or throttle device that provides rapid cool down and low vibration steady-state performance.
Every throttle cycle refrigerator incorporates a throttling device as a means for reducing the refrigerant pressure from the compressor discharge before the refrigerant flow enters the evaporator. However, accomplishing this pressure change is complicated by the fact that operating conditions are significantly different at start up of a warm system as compared to steady-state operation at desired loads and operating temperatures. For good overall performance, the throttling device should provide the desired vapor pressure in the evaporator under steady-state conditions and also during cool down.
For fast cool down, it is necessary that the refrigerant flow rate be higher than at steady state operating conditions. Thus at cool down, it is desirable that the return pressure to the compressor be high enough to provide sufficient flow rate through the system; compressor pumping capacity increases as the inlet refrigerant pressure to the compressor increases. Unfortunately, a fixed restrictor such as an orifice or capillary tube limits the compressor performance and refrigerant flow rate most just when maximum flow rate would be beneficial. This occurs because at start up the restrictor flows a refrigerant of low average density, that is more gaseous than liquid. Thus, the simplest means used for reducing the pressure of the refrigerant flow, that is, a fixed geometry restrictor such as a capillary tube or small orifice, which are simple in design and easy to manufacture, have low mass flow rates at start up and slow cool down if sized for subsequent steady-state performance.
To improve the cool down characteristic and thereby reduce the cool down time, many constructions of throttling devices have been proposed. For example there are U.S. Pat. Nos. 3,320,755; 3,257,823; 3,457,730, and British patents Nos. 1,164,276 and 1,297,132. Japanese patent No. 24498 (1970) is also of interest. These patents disclose various means for increasing the orifice size in the throttle device during cool down. This increase in orifice size is achieved, for instance, using a needle that is actuated by a gas filled bellows, or by using the difference in thermal expansion of different materials to move the needle relative to an orifice. These throttling devices incorporate many high precision parts, which result in high cost to manufacture and low reliability in performance of the whole device.
Further, in many applications of closed cycle refrigeration systems, vibration is a critical parameter to be controlled. The energy dissipated when refrigerant flow is throttled from high pressure to low pressure, as is required in a closed refrigeration cycle, is a major contributor to vibrations at the cold end of the system. Whereas the vibration induced by the throttle device may be subsequently damped and isolated by special constructions, which add to the complexity of the system at the cold end, elimination of the vibrations where they originate in the throttle device would be advantageous.
Preliminary investigations indicate that vibration as measured at the load interface for the closed cycle refrigeration system has a steady state component and a pulsating component when the system uses a capillary tube throttle. A multi-phase refrigerant, which was used in the investigations, having two liquid phases and one vapor phase flowing through the capillary throttle valve, produced an unacceptable pulsating flow due to the large density change as the refrigerant pressure drops from high pressure compressor discharge to low pressure at the cooler evaporator and the compressor inlet. Smaller diameter capillary tubes increase the refrigerant velocity in the tube for a given mass flow rate of refrigerant. It has been found that this high velocity tends to increase the steady state portion of the throttling vibration.
What is needed is a throttle device for a closed cycle refrigeration system that is simple in construction, provides rapid cool down and produces low vibration at the cold end especially at steady-state conditions.

Low vibration throttling device for throttle-cycle refrigerators


An electronic circuit according to the present invention has one or more circuit sections which operate according to a variable power supply voltage and a variable clock frequency. In the electronic circuit, active information related to load and/or processing time which changes in real time from a control processing section included in the circuit section is output and, based on the active information, a voltage/frequency setting section which sets values of a power supply voltage and clock frequency is provided. The electronic circuit further includes a voltage controller which controls the power supply voltage to be supplied to the circuit section based on the voltage value set by the voltage/frequency setting section and a clock frequency controller which controls the clock frequency to be supplied to the circuit section based on the frequency value set by the voltage/frequency setting section.

1. Field of the Invention
The present invention relates to an electronic circuit and an electronic device using the electronic circuit and, for example, relates to a mobile terminal such as a mobile phone.
2. Description of the Related Art
Conventionally, a plurality of IC chips (chipset) are incorporated in an electronic device such as a mobile terminal. An operating clock is supplied to the chipset. A high-speed clock is supplied to a circuit requiring high speed operation, and a low-speed clock is supplied to other different circuits. In the case where a further high-speed operation is required, a clock obtained by multiplying the frequency of a high-speed clock is used, in some cases.
Further, there is available a technique that changes a supply voltage in accordance with the clock frequency. For example, a battery-powered integrated circuit to which the above technique has been applied is described in Jpn. Pat. Appln. Laid-Open Publication No. 5-119876. This example selects a supply voltage according to a selection signal output from a processing circuit. When the frequency of an operating clock signal is high, a high supply voltage which is formed by serially connecting two batteries is selected; whereas the frequency of an operating clock signal is low, a low supply voltage which is formed by connecting two batteries in parallel is selected.
Further, an image processor to which the above technique has been applied is described in Jpn. Pat. Appln. Laid-Open Publication No. 2001-238190. This image processor controls a clock signal and a supply voltage to be supplied to a processing circuit in accordance with an operation mode. More specifically, under the control of a CPU in the image processor, the image processor loads image data at a resolution and frame rate specified in accordance with an operation mode, determines the minimum supply voltage and frequency of a clock signal at which the processor can function for each set mode, and controls the clock signal frequency and supply voltage value output from a clock generator and regulator.
However, there is still room for further improvement in order to reduce power consumption.

This patent is subject to a terminal disclaimer.

Electronic circuit and electronic device


Duty cycle adjustment circuitry includes a first stage, a second stage, and decoder circuitry. The first stage includes a first strength tuning circuit having first inverter branches, and a first fine tuning circuit having second inverter branches. The first strength tuning circuit and the first fine tuning circuit are coupled in parallel. The second stage includes a second strength tuning circuit having third inverter branches, and a second fine tuning circuit having fourth inverter branches. The second strength tuning circuit and the second fine tuning circuit are coupled in parallel. Further, the second stage is electrically coupled to the first stage. The decoder circuitry is electrically coupled to the first stage and the second stage. The decoder circuitry controls the first strength tuning circuit independently from the first fine tuning circuit to adjust the duty cycle of an input signal received by the duty cycle adjustment circuitry.

High speed input/output (I/O) devices having a duty cycle of substantially 50 percent improves timing margins of the I/O devices. In various instances, the I/O devices operate with twice the frequency rate to partially mitigate the need for clock duty cycle correction and to employ a duty cycle of 50 percent. Such a method only uses rising edges of a clock signal instead of both rising and falling edges of a clock signal for timing closure. However, such a method has higher power and worse timing budgets as compared to I/O devices that operate at lower frequency rates.
In a dual-data rate system, both the rising and falling edges of a clock signal are used to sample a data signal, improving the speed at which the I/O devices are able to operate. A duty cycle of about 50 percent on both clock signal and data signal aids in accommodating increasing data transfer frequencies. For example, at a data rate of 7500 megabits per second (Mbps), assuming a 50 percent of duty cycle, each bit of data is transferred with a 133 pico-second (ps) unit interval (UI). Further, each bit of data is sampled using the clock signal at the center of the data eye with 66.5 ps of timing margin in either direction. However, ensuring that acceptable timing margins are preserved due to process, voltage, and temperature (PVT) variations in semiconductor manufacturing processes is very challenging. Additionally, the data and clock signals are forwarded from between semiconductor chips through packages, board(s), and/or connectors. Even in an ideal PVT situation, current implementations that use both the rising and falling edges of a clock signal to sample a data signal result in a very little available timing margin, increasing sampling errors within the corresponding system.

Duty cycle adjustment circuit with independent range and step size control