Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases
AssigneeNPS Pharmaceuticals, Inc.
InventorsAlan L. Mueller, Manuel F. Balandrin, Bradford C. VanWagenen, Eric G. DelMar, Scott T. Moe, Linda D. Artman, Robert M. Barmore
Life of this patent
Estimating the term…
Abstract
Method and compositions for treating a patient having a neurological disease or disorder, such as stroke, head trauma, spinal cord injury, epilepsy, anxiety, or neurodegenerative diseases such as Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, or amyotrophic lateral sclerosis (ALS).
Claims185
A compound having the formula:
- ##STR117## wherein:
- each X is independently selected from the group consisting of meta-fluoro, meta-chloro, ortho-methoxy, and ortho-methyl;
- and R.sup.1 is methyl, and R.sup.2 is --H;
- or R.sup.1 and R.sup.2 are both --H;
- or R.sup.2 is methyl, and R.sup.1 is --H;
- or R.sup.1 and R.sup.2 together are --(CH.sub.2)n--;
- R.sup.3 is either --H or methyl;
- and
- n is an integer from 1 to 6;
- except for compounds wherein:
- R.sup.3 is --H, and each X is meta-chloro, or each X is meta-fluoro, or one X is meta-fluoro and one X is meta-chloro.
A compound having the following formula:
- ##STR118## wherein:
- each X is independently selected from the group consisting of meta-fluoro, meta-chloro, ortho-methoxy, and ortho-methyl;
- and R.sup.1 is methyl, and R.sup.2 is H;
- or R.sup.1 and R.sup.2 are both --H;
- or R.sup.2 is methyl, and R.sup.1 is --H;
- or R.sup.1 and R.sup.2 together are --(CH.sub.2)n--;
- R.sup.3 is either --H or methyl;
- and n is an integer from 1 to 6.
A compound selected from the group consisting of:
- ##STR119##
A compound having a chemical structure selected from the group consisting of
A compound having the chemical structure
A compound having the chemical structure
A compound having the chemical structure
A compound having the chemical structure
A compound having the chemical structure
A pharmaceutical composition, adapted for the treatment of a neurological disease or disorder, comprising a compound having the following formula:
- wherein:
- R.sup.1 and R.sup.5 are independently selected from the group consisting of --H, alkyl, hydroxyalkyl, --OH, --O-alkyl, and --O-acyl;
- R.sup.2 and R.sup.6 are independently selected from the group consisting of --H, alkyl, and hydroxyalkyl;
- or R.sup.1 and R.sup.2 together are --(CH.sub.2)n--;
- R.sup.3 is selected from the group consisting of --H, alkyl and 2-hydroxyethyl;
- n is an integer from 1 to 6;
- each X is independently in the meta- or ortho- position and is independently selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, O-alkyl, and O-acyl;
- m is independently an integer from 0 to 5;
- and pharmaceutically acceptable salts thereof, in a pharmaceutically acceptable carrier.
A pharmaceutical composition comprising a compound selected from the group consisting of ##STR123## and pharmaceutically acceptable salts thereof, in a pharmaceutically acceptable carrier.
A pharmaceutical composition having the following formula:
- ##STR126## wherein:
- (X)m is independently selected from the group consisting of meta-fluoro, meta-chloro, ortho-methoxy, and ortho-methyl;
- and R.sup.1 is methyl, and R.sup.2 is --H;
- or R.sup.1 and R.sup.2 are both --H;
- or R.sup.2 is methyl and R.sup.1 is H;
- or R.sup.1 and R.sup.2 together are --(CH.sub.2)n--;
- R.sup.3 is either --H or methyl;
- and n is an integer from 1 to 6, and pharmaceutically acceptable salts thereof, in a pharmaceutically acceptable carrier.
A pharmaceutical composition comprising a compound having the chemical structure:
- ##STR127## or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.
A pharmaceutical composition comprising a compound having the chemical structure:
- ##STR128## or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.
A pharmaceutical composition comprising a compound having the chemical structure:
- ##STR129## or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.
A pharmaceutical composition comprising a compound having the chemical structure:
- ##STR130## or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.
A pharmaceutical composition comprising a compound having the chemical structure:
- ##STR131## or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.
A composition comprising a compound having a chemical structure selected from the group consisting of ##STR132## or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.
A composition comprising a compound having a chemical structure selected from the group consisting of ##STR133## or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.
A pharmaceutical composition adapted to provide neuroprotection to a patient, comprising a compound having the following formula:
- ##STR134## wherein:
- R.sup.1 and R.sup.5 are independently selected from the group consisting of --H, alkyl, hydroxyalkyl, --OH, --O-alkyl, and --O-acyl;
- R.sup.2 and R.sup.6 are independently selected from the group consisting of --H, alkyl, and hydroxyalkyl;
- and R.sup.1 and R.sup.2 together are --(CH.sub.2)n--;
- R.sup.3 is selected from the group consisting of --H, alkyl and 2-hydroxyethyl;
- n is an integer from 1 to 6;
- each X is independently in the meta- or ortho-3position and is independen5 tly selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, O-alkyl, and O-acyl;
- m is independently an integer from 0 to 5;
- and pharmaceutically acceptable salts thereof, in a pharmaceutically acceptable carrier.
A pharmaceutical composition adapted to provide neuroprotection to a patient, comprising a compound selected from the group consisting of ##STR138## and pharmaceutically acceptable salts thereof, in a pharmaceutically acceptable carrier.
A method for treating a patient having a neurological disease or disorder, comprising administering a compound having the formula wherein:
- NR.sup.3 R.sup.3 is selected from the group consisting of --NH.sub.2 and --NH-methyl;
- (X)m is independently selected from the group consisting of meta-fluoro, meta-chloro, ortho-methoxy, and ortho-methyl;
- and
- R.sup.1 is methyl, and R.sup.2, R.sup.5, and R.sup.6 are --H;
- or R.sup.2 is methyl, and R.sup.1, R.sup.5, and R.sup.6 are --H;
- or R.sup.1, R.sup.2, R.sup.5, and R.sup.6 are --H;
- and pharmaceutically acceptable salts thereof.
A method for treating a patient having a neurological disease or disorder, comprising administering a compound having the structure of Formula IV or V:
- ##STR140## wherein n is an integer from 1 to 6;
- X is independently selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl;
- R.sup.3 is independently selected from the group consisting of --H and alkyl;
- and m is independently an integer from 0 to 5 or pharmaceutically acceptable salt thereof.
A method for treating a patient having a neurological disease or disorder comprising administering a compound having the structure of Formulas VI or VII:
- ##STR141## wherein n is an integer from 1 to 6;
- X is independently selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl;
- R.sup.3 is independently selected from the group consisting of --H and alkyl;
- R.sup.4 is selected from the group consisting of alkyl and cycloalkyl;
- and m is independently an integer from 0 to 5.
A method for treating a patient having a neurological disease or disorder comprising administering a compound selected from the group consisting of ##STR142## or pharmaceutically acceptable salt thereof.
A method for treating a patient having a neurological disease or disorder, comprising administering a compound having the following formula:
- ##STR148## wherein:
- each R.sup.3 is independently selected from the group consisting of --H, alkyl, and 2-hydroxyethyl;
- n is an integer from 1 to 6;
- each X is independently selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl;
- m is independently an integer from 0 to 5;
- and pharmaceutically acceptable salts thereof.
A method for treating a patient having a neurological disease or disorder, comprising administering a compound having the formula:
- wherein n is an integer from 1 to 6;
- each X is independently selected from the group consisting of--H, --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl;
- R.sup.3 is selected from the group consisting of --H and alkyl;
- and m is independently an integer from 0 to 5, and pharmaceutically acceptable salts thereof.
A method for treating a patient having a neurological disease or disorder, comprising administering a compound having the formula:
- ##STR150## and pharmaceutically acceptable salts thereof.
A method for treating a patient having Parkinson's disease, comprising administering a compound selected from the group consisting of:
- ##STR151## 107.
A method for treating stroke, comprising administering a compound having the formula:
A method for treating a patient having a neurological disease or disorder comprising administering a hydrochloride salt of a compound having the formula:
A method for treating a patient having Parkinson's disease, comprising administering a hydrochloride salt selected from the group consisting of:
A method for treating stroke, comprising administering a hydrochloride salt of a compound having the formula:
A method for treating a patient having a neurological disease or disorder, comprising administering the compound of Formula I:
- wherein:
- R.sup.1 and R.sup.5 are independently selected from the group consisting of --H, alkyl, hydroxyalkyl, --OH, --O-alkyl, and --O-acyl;
- R.sup.2 and R.sup.6 are independently selected from the group consisting of --H, alkyl, and hydroxyalkyl;
- or R.sup.1 and R.sup.2 together are --(CH.sub.2).sub.n -- or --(CH.sub.2).sub.n --N(R.sup.3)--;
- R.sup.3 is independently selected from the group consisting of --H, alkyl and 2-hydroxyethyl;
- n is an integer from 1 to 6;
- R.sup.4 is selected from the group consisting of alkyl, cycloalkyl, and ##STR152## X is independently selected from the group consisting of --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl;
- m is independently an integer from 1 to 5;
- Y is --NR.sup.3 R.sup.3, except when R.sup.1 and R.sup.2 together are --(CH.sub.2)n --N(R.sup.3)--, then Y is --H;
- and pharmaceutically acceptable salts thereof.
A method for treating a patient having a neurological disease or disorder, comprising administering the compound of Formula I:
- ##STR154## wherein:
- R.sup.1 and R.sup.5 are independently selected from the group consisting of --H, alkyl, hydroxyalkyl, --OH, --O-alkyl, and --O-acyl;
- R.sup.2 and R.sup.6 are independently selected from the group consisting of --H, alkyl, and hydroxyalkyl;
- or R.sup.1 and R.sup.2 together are --(CH.sub.2).sub.n -- or --(CH.sub.2).sub.n --N(R.sup.3)--;
- R.sup.3 is independently selected from the group consisting of --H, alkyl and 2-hydroxyethyl;
- n is an integer from 1 to 6;
- R.sup.4 is selected from the group consisting of alkyl, cycloalkyl, and ##STR155## X is independently selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl, provided that at least one X is present and is not H;
- m is independently an integer from 0 to 5;
- Y is --NR.sup.3 R.sup.3, except when R.sup.1 and R.sup.2 together are --(CH.sub.2)n--N(R.sup.3)--, then Y is --H;
- and pharmaceutically acceptable salts thereof.
A method for treating a patient having a neurological disease or disorder, comprising administering a compound having the following formula:
- ##STR157## wherein:
- R.sup.1 and R.sup.5 are independently selected from the group consisting of --H, alkyl, hydroxyalkyl, --OH, --O-alkyl, and --O-acyl;
- R.sup.2 and R.sup.6 are independently selected from the group consisting of --H, alkyl, and hydroxyalkyl;
- each R.sup.3 is independently selected from the group consisting of --H, alkyl and 2-hydroxyethyl;
- each X is independently selected from the group consisting of --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl;
- m is independently an integer from 1 to 5;
- and pharmaceutically acceptable salts thereof.
A method for treating a patient having a neurological disease or disorder, comprising administering a compound having the following formula:
- ##STR158## wherein:
- each R.sup.3 is independently selected from the group consisting of --H, alkyl and 2-hydroxyethyl;
- n is an integer from 1 to 6;
- each X is independently selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl;
- m is independently an integer from 0 to 5;
- and pharmaceutically acceptable salts thereof.
A method for treating a patient having a neurological disease or disorder, comprising administering a compound having the formula ##STR159## wherein:
- R.sup.1 and R.sup.5 are independently selected from the group consisting of --H, alkyl, hydroxyalkyl, --OH, --O-alkyl, and --O-acyl;
- R.sup.2 and R.sup.6 are independently selected from the group consisting of --H, alkyl, and hydroxyalkyl;
- or R.sup.1 and R.sup.2 together are --(CH.sub.2).sub.n --;
- each R.sup.3 is independently selected from the group consisting of --H, alkyl, and 2-hydroxyethyl;
- n is an integer from 1 to 6;
- R.sup.4 is alkyl;
- X is selected from the group consisting of --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl;
- m is independently an integer from 0 to 5;
- and pharmaceutically acceptable salts thereof.
A method for treating a patient having a neurological disease or disorder, comprising administering a compound having the formula wherein:
- each R.sup.3 is independently selected from the group consisting of --H, alkyl, and 2-hydroxyethyl;
- n is an integer from 1 to 6;
- each X is independently selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl;
- m is independently an integer from 0 to 5;
- and pharmaceutically acceptable salts thereof.
A method for treating a patient having a neurological disease or disorder, comprising administering a compound having the following formula:
- ##STR162## wherein:
- R.sup.1 and R.sup.5 are independently selected from the group consisting of --H, alkyl, hydroxyalkyl, --OH, --O-alkyl, and --O-acyl;
- R.sup.2 and R.sup.6 are independently selected from the group consisting of --H, alkyl, and hydroxyalkyl,
- each R.sup.3 is independently selected from the group consisting of --H, alkyl and 2-hydroxyethyl;
- n is an integer from 1 to 6;
- (X)m is independently selected from the group consisting of meta-fluoro, metachloro, ortho-methoxy, and ortho-methyl;
- and pharmaceutically acceptable salts thereof.
A method for providing neuroprotection to a patient comprising administering a compound having the following formula:
- ##STR163## wherein:
- R.sup.1 and R.sup.5 are independently selected from the group consisting of --H, alkyl, hydroxyalkyl, --OH, --O-alkyl, and --O-acyl;
- R.sup.2 and R.sup.6 are independently selected from the group consisting of --H, alkyl, and hydroxyalkyl;
- each R.sup.3 is independently selected from the group consisting of --H, alkyl and 2-hydroxyethyl;
- n is an integer from 1 to 6;
- each X is independently selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl;
- m is independently an integer from 0 to 5;
- and pharmaceutically acceptable salts thereof.
A method for providing neuroprotection to a patient comprising administering a compound having the formula:
- wherein:
- N R.sup.3 R.sup.3 is selected from the group consisting of --NH.sub.2 and --NH-methyl;
- (X)m is independently selected from the group consisting of meta-fluoro, metachloro, ortho-methoxy, and ortho-methyl;
- and
- R.sup.1 is methyl, and R.sup.2, R.sup.5, and R.sup.6 are --H;
- or R.sup.2 is methyl, and R.sup.1, R.sup.5, and R.sup.6 are --H;
- or R.sup.1, R.sup.2, R.sup.5, and R.sup.6 are --H;
- and pharmaceutically acceptable salts thereof.
A method for providing neuroprotection to a patient having a neurological disease or disorder, comprising administering a compound having the formula:
- ##STR166## wherein:
- R.sup.1 and R.sup.5 are independently selected from the group consisting of --H, alkyl, hydroxyalkyl, --OH, --O-alkyl, and --O-acyl;
- R.sup.2 and R.sup.6 are independently selected from the group consisting of --H, alkyl, and hydroxyalkyl;
- or R.sup.1 and R.sup.2 together are --(CH.sub.2).sub.n --;
- each R.sup.3 is independently selected from the group consisting of --H, alkyl, and 2-hydroxyethyl;
- n is an integer from 1 to 6;
- R.sup.4 is alkyl;
- X is selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl;
- m is independently an integer from 0 to 5;
- and pharmaceutically acceptable salts thereof.
A method for providing neuroprotection to a patient comprising administering a compound having the formula:
- wherein n is an integer from 1 to 6;
- each X is independently selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl;
- R.sup.3 is selected from the group consisting of --H and alkyl;
- and m is independently an integer from 0 to 5 or pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.