Methods for Using Rapamycin Analogues in the Treatment of Neurological Disorders
The present invention provides methods for treatment of neurological disorders or complications due to stroke or head injury; benign or malignant neoplastic disease, carcinomas and adenocarcinomas; proliferative disorders; and inflammatory disorders, comprising administering a compound as described herein to a subject in need thereof, and a pharmaceutically acceptable carrier, within a therapeutic window that is from about 4 hours to 24 hours, or longer, for example at least 4, 6, 9, 12, 15, 18, 21 or 24 hours, or longer, after the onset of the neurological, proliferative, or inflammatory disorder or a symptom thereof. In some embodiments, the compounds of the following structure, wherein R 1 , R 2 , R 4 , R 4′ , R 6 , R 7 , and R 15 are as defined herein:
1 . A method of treating a neurological disorder comprising administering to a subject in need thereof a compound of Formula I, and a pharmaceutically acceptable carrier, where the compound of Formula I has the structure:
wherein:
R 1 and R 2 are different, independent groups and are selected from OR 3 and N(R 3′ )(R 3″ ); or
R 1 and R 2 are different, are connected through a single bond, and are selected from O and NR 3 ;
R 3 , R 3′ , and R 3″ , are independently selected from H, C 1-6 alkyl, substituted C 1-6 alkyl, C 3-8 cycloalkyl, substituted C 3-8 cycloalkyl, C 6-20 aryl, optionally substituted C 6-20 aryl, heteroaryl, and substituted heteroaryl;
R 4 and R 4′ are:
(a) independently selected from H, OH, O(C 1-6 alkyl), O(substituted C 1-6 alkyl), O(acyl), O(C 6-20 aryl), O(substituted aryl), and halogen; or
(b) taken together to form a double bond to O;
R 5 , R 6 , and R 7 are independently selected H, OH, and OCH 3 ;
R 8 and R 9 are connected through a (i) single bond and are CH 2 or (ii) double bond and are CH;
R 15 is selected from C═O, CHOH, and CH 2 ; and
n is 1 or 2;
or a pharmaceutically acceptable salt thereof;
wherein said compound is administered to said subject at least 4 hours after the onset of said disorder or a symptom thereof.
2 . A method of claim 1 , wherein brain function is substantially restored to where it was before the onset of the neurological disorder.
3 . A method of claim 1 , wherein ischemia associated with the neurological disorder is reversed.
4 . A method of claim 1 , wherein the neurological disorder is a brain disorder selected from complications due to stroke, head trauma, spinal cord injury or traumatic brain injury.
5 . The method of claim 1 , wherein R 1 is O, R 2 is NR 3 .
6 . The method of claim 1 , wherein R 1 is OR 3 and R 2 is N(R 3′ )(NR 3″ ).
7 . The method of claim 1 , wherein R 3 , R 3′ or R 3″ , is a C 6-20 aryl or optionally substituted C 6-20 aryl.
8 . The method of claim 7 , wherein said C 6-20 aryl or optionally substituted C 6-20 aryl is of the structure:
wherein:
R 10 , R 11 , R 12 , R 13 , and R 14 are independently selected from H, C 1-6 alkyl, substituted C 1-6 alkyl, C 6-20 aryl, optionally substituted C 6-20 aryl, heteroaryl, substituted heteroaryl, halogen, acyl, OH, O(C 1-6 alkyl), O(substituted C 1-6 alkyl), O(C 6-20 aryl), O(substituted aryl), O(acyl), NH 2 , NH(C 1-6 alkyl), NH(substituted C 1-6 alkyl), NH(C 6-20 aryl), NH(substituted aryl), and NH(acyl).
9 . The method of claim 1 , wherein R 4 or R 4′ is OH.
10 . The method of claim 1 , wherein R 4 or R 4′ is O(acyl).
11 . The method of claim 10 , wherein said acyl is:
12 . The method of any one of claims 1 , wherein R 5 , R 6 , and R 7 are OCH 3 .
13 . The method of any one of claims 1 , wherein n is 2.
14 . The method of any one of claims 1 , wherein R 15 is C═O.
15 . The method of any one of claims 1 , wherein R 1 and R 2 are connected through a single bond; R 1 is O; R 2 is NR 3 ; R 3 is phenyl; R 4 is OH; R 5 , R 6 and R 7 are OCH 3 ; and R 8 and R 9 are HC═CH.
16 . The method of any one of claims 1 , wherein R 1 and R 2 are connected through a single bond; R 1 is O; R 2 is NR 3 ; R 3 is phenyl; R 4 is OH; R 5 , R 6 and R 7 are OCH 3 ; and R 8 and R 9 are H 2 C—CH 2 .
17 . The method of any one of claims 1 , wherein R 1 and R 2 are connected through a single bond; R 1 is O; R 2 is NR 3 ; R 4 is OH; R 5 , R 6 and R 7 are OCH 3 ; R 8 and R 9 are HC═CH or H 2 C—CH 2 ; and R 3 is selected from
18 . The method of any one of claims 1 , wherein R 1 and R 2 are connected through a single bond; R 1 is O; R 2 is NR 3 ; R 3 is phenyl; R 5 , R 6 and R 7 are OCH 3 ; R 8 and R 9 are HC═CH; and R 4 is
19 . The method of any one of claims 1 , wherein the compound of Formula I is selected from:
20 . The method of any one of claims 1 , wherein the compound of Formula I has the Formula Ia:
Ia
wherein:
R 1 and R 2 are different, independent groups and are selected from OH and N(R 3′ )(R 3″ ); or
R 1 and R 2 are different, are connected through a single bond, and are selected from O and NR 3 ;
R 3′ and R 3″ are independently selected from H, C 1-6 alkyl, substituted C 1-6 alkyl, C 3-8 cycloalkyl, substituted C 3-8 cycloalkyl, C 6-20 aryl, optionally substituted C 6-20 aryl, heteroaryl, and substituted heteroaryl;
R 8 and R 9 are connected through a (i) single bond and are CH 2 or (ii) a double bond and are CH; or a pharmaceutically acceptable salt thereof.
21 . The method of claim 1 , wherein the compound of Formula I has the Formula Ib:
wherein:
R is independently selected from H, C 1-6 alkyl, substituted C 1-6 alkyl, C 6-20 aryl, optionally substituted C 6-20 aryl, heteroaryl, substituted heteroaryl, halogen, acyl, OH, O(C 1-6 alkyl), O(substituted C 1-6 alkyl), O(C 6-20 aryl), O(substituted aryl), O(acyl), NH 2 , NH(C 1-6 alkyl), NH(substituted C 1-6 alkyl), NH(C 6-20 aryl), NH(substituted aryl), and NH(acyl); and
m is 1 to 5.
22 . The method of claim 1 , wherein said neurological disorder is selected from: venous cardiovascular thromboembolic disorders, thromboembolic disorders in the chambers of the heart, atherosclerosis, restenosis, peripheral arterial disease, coronary bypass grafting surgery, carotid artery disease, arteritis, ischemic heart disease, cardiac ischemia, ischemia, ischemic sudden death, transient ischemic attack, stroke, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, thrombosis, supraventricular arrhythmia, atrial arrhythmia, atrial flutter, and atrial fibrillation.
23 . The method of claim 1 , wherein the compound is administered to said subject at least 6 hours and can be at least 24 hours or longer after the onset of said disorder or symptom thereof.
24 . The method of claim 1 , wherein said compound of Formula I is prepared from norrapamycin, deoxorapamycin, or desmethylrapamycin starting material.
25 . The method of claim 24 wherein the deoxorapamycin is
26 . The method of claim 24 wherein the desmethylrapamycin is selected from