WO2010019856A1

WO2010019856A1 - Methods and kits for treatings stroke and other neurological conditions

Info

Publication number: WO2010019856A1
Application number: PCT/US2009/053839
Authority: WO
Inventors: Seth Finklestein; Marc Charette; John L. Neumeyer; Ross J. Baldessarini
Original assignee: The Mclean Hospital Corporation; Neurocyte Pharmaceuticals, Inc.
Priority date: 2008-08-15
Filing date: 2009-08-14
Publication date: 2010-02-18

Abstract

The invention features methods and kits for treating stroke and related conditions in a subject by administering R(-)- 11 -O-valeryl-N-n- propylnoraporphine or an analogue thereof.

Description

PATENT

ATTORNEY DOCKET NO. 04843/170WO2

Methods and Kits for Treating Stroke and Other Neurological Conditions

Background of the Invention

The invention relates to the treatment of stroke and other neurological conditions.

Stroke is the third leading cause of death and disability in the U.S., with an incidence of over 700,000 cases per year, and a prevalence of over 5 million. The majority of strokes are ischemic, due to thromboembolic occlusion of a cerebral artery (85% of cases); the remainder are due to intracerebral hemorrhage (15% of cases). Stroke generally causes focal damage to the brain, resulting in motor, sensory, cognitive, memory, visual, coordination, gait and other neurological deficits, depending on the size and location of focal brain injury. Although damaged brain regions do not regenerate after stroke, some degree of spontaneous neurological recovery can occur, due to structural and functional reorganization of remaining intact brain tissue.

Stroke generally presents as the abrupt onset of focal neurologic deficit. The deficit may remain fixed, it may improve or progressively worsen, leading usually to irreversible neuronal damage at the core of the ischemic focus, whereas neuronal dysfunction in the penumbra may be treatable and or reversible. Prolonged periods of ischemia result in tissue necrosis. Cerebral edema follows and progresses over the subsequent 2 to 5 days. If the region of the infarction is large, the edema may produce considerable mass effect with all of its attendant consequences.

There are three general approaches to treat stroke: prevention, acute treatment, and recovery-promoting treatments. These treatments are given before stroke, in minutes to hours after stroke, and days to weeks after stroke, respectively. Preventitive treatments address stroke risk factors (hypertension, hyperlipidemia, diabetes, etc.), whereas acute stroke treatments address PATENT

ATTORNEY DOCKET NO. 04843/170WO2 vascular occlusion and its immediate consequences to the brain (e.g., thrombolytics and neuroprotective treatments). Stroke recovery-promoting treatments promote repair and reorganization of the damaged brain.

Traumatic brain injury (TBI) is also one of the most serious reasons for hospital admission and disability in modem society. Clinical experience suggests that TBI may be classified into primary damage occurring immediately after injury, and secondary damage, which occurs during several days post injury. Current therapy of TBI is either surgical or else mainly symptomatic. Brain injury can also occur when the brain is globally deprived of oxygen. Anoxic-ischemic brain injuries occur when the brain receives little or no oxygen, such as with a cardiac arrest victim or a near-drowning victim. Anoxic-ischemic brain injuries may result from airway obstruction, near- drowning, throat swelling, choking, strangulation, crush injuries to the chest, electrical shock, lightening strike, trauma to the head or neck, blood loss, shock, vascular disruption, heart attack, arteriovenous malformation, aneurysm, intracranial surgery, intracranial tumor, infectious disease, meningitis, metabolic disorders, hepatic encephalopathy, uremic encephalopathy, seizure disorders, lead poisoning, carbon monoxide poisoning, cardiac arrest, coronary artery bypass graft (CABG) surgery, and other conditions. Other neurological conditions resulting in brain injury include

Alzheimer's Disease, Huntington's Disease, amyotrophic lateral sclerosis , multiple sclerosis , brain infections, and brain tumors. In all of these conditions, brain cells (including neurons) die from a number of diverse causes. Treatments that promote brain cell (neuronal) survival and neurological recovery are also likely to promote recovery in these other conditions as well.

Stroke and other types of brain injuries result in neurological abnormalities, including motor, sensory, cognitive, memory, visual, coordination, gait, and other deficits. Such deficits may result in significant PATENT

ATTORNEY DOCKET NO. 04843/170 WO2 handicap, disability and lost quality of life. Thus, there is a great need for a novel treatment for the neurological deficits that result from stroke and related conditions.

Summary of the Invention

The invention features methods and kits for treating stroke and other neurological conditions in a subject by administering R(-)-l 1 -O-valeryl-N-H- propylnoraporphine or an analogue thereof.

In a first aspect, the invention features a method of treating a subject suffering from stroke by administering to the subject an effective amount of a compound selected from i?(-)-l l-O-valeryl-N-«-propylnoraporphine and analogues thereof, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is administered in an amount effective to aid recovery of motor, sensory, cognitive, memory, visual, coordination, or gait deficits resulting from the stroke. In other embodiments, the compound is administered within six months, four months, three months, two months, one month, 14 days, 7 days, 3 days, 2 days, or one day following said stroke. In still other embodiments, the compound is administered for a period of from 7 to 180 days, 1 to 180 days, 1 to 120 days, 1 to 90 days, 1 to 60 days, 1 to 30 days, 7 to 120 days, 7 to 90 days, 7 to 60 days, 7 to 30 days, 14 to 180 days, 14 to 120 days, 14 to 90 days, 14 to 60 days, 14 to 30 days, 21 to 180 days, 30 to 180 days, 60 to 180 days, or 90 to 180 days to aid recovery of motor, sensory, cognitive, memory, visual, coordination, or gait deficits resulting from the stroke. In certain embodiments, the method includes ameliorating stroke, or the symptoms of stroke, in a subject displaying symptoms of stroke by administering the compound to the subject within 24 hours, 12 hours, 8 hours, 6 hours, 5 hours, 4 hours, 90 minutes, 1 hour, 45 minutes, 30 minutes, or 15 minutes of said stroke. PATENT

ATTORNEY DOCKET NO. 04843/170WO2

The invention further features a method of treating a subject suffering from a traumatic brain injury by administering to the subject an effective amount of a compound selected from R(-)-l 1-O-valeryl-N-H- propylnoraporphine and analogues thereof, or a pharmaceutically acceptable salt thereof.

The invention also features a method of treating a subject suffering from an anoxic-ischemic brain injury by administering to the subject an effective amount of a compound selected from R(-)-l l-O-valeryl-N-«- propylnoraporphine and analogues thereof, or a pharmaceutically acceptable salt thereof.

The invention features a method of treating a subject suffering from a non-traumatic brain injury selected from Alzheimer's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, brain hemorrhage, brain infections, and brain tumor by administering to the subject an effective amount of a compound selected from R(-)- 11 -O-valeryl-N-rø- propylnoraporphine and analogues thereof, or a pharmaceutically acceptable salt thereof. In certain embodiments, the non-traumatic brain injury is Alzheimer's disease and the compound is administered chronically throughout the life of the subject. In an embodiment of any of the above aspects, the compound is administered in an amount effective to aid neurological recovery.

The invention further features a method of aiding recovery of cognitive function following brain injury in a subject by administering to the subject an effective amount of a compound selected from R(-)-l l-O-valeryl-N-«- propylnoraporphine and analogues thereof, or a pharmaceutically acceptable salt thereof. In certain embodiments, the brain injury is a consequence of a stroke, traumatic brain injury, non-traumatic brain injury, or anoxic-ischemic brain injury. PATENT

ATTORNEY DOCKET NO. 04843/170WO2

The invention features a method of aiding neurological recovery following brain injury in a subject by administering to the subject an effective amount of a compound selected from R(-)-l 1-O-valeryl-N-w- propylnoraporphine and analogues thereof, or a pharmaceutically acceptable salt thereof. In certain embodiments the brain injury is a consequence of a stroke, traumatic brain injury, non-traumatic brain injury, anoxic-ischemic brain injury, or other neurological conditions. In other embodiments, the compound is administered in an amount effective to aid recovery of motor, sensory, cognitive, memory, visual, coordination, or gait deficits resulting from brain injury.

In one embodiment of any of the above aspects, the compound is administered to the subject in an average daily dose of between 0.25 and 25 mg/kg/day, 0.75 and 20 mg/kg/day, 0.75 and 5 mg/kg/day, 1.5 and 25 mg/kg/day, 1.5 and 5 mg/kg/day, 2.5 and 20 mg/kg/day, 2.5 and 5 mg/kg/day, 3 and 20 mg/kg/day, or 3 and 10 mg/kg/day.

In another embodiment of any of the above aspects, the compound is administered daily for a period of 1 to 180 days, 1 to 120 days, 1 to 90 days, 1 to 60 days, 1 to 30 days, 1 to 15 days, 1 to 7 days, or 1 to 5 days.

In still another embodiment of any of the above aspects, the compound is administered orally, intravenously, or subcutaneously.

In yet another embodiment of any of the above aspects, the methods further includes the administration of an effective amount of an anti-emetic agent (e.g., nicotine, lobclinc sulfate, pipamazine, oxypendyl hydrochloride, ondansetron, buclizine hydrochloride, cyclizine hydrochloride, dimcnhydrinate, scopolamine, metopimazine, benzauinamine hydrochloride or diphenidol hydrochloride).

In a related aspect the invention features a kit including: (i) a pharmaceutical composition including a pharmaceutically acceptable excipient and a compound selected from R(-)-l l-O-valeryl-N-rc-propylnoraporphine and PATENT

ATTORNEY DOCKET NO. 04843/170WO2 analogues thereof, or a pharmaceutically acceptable salt thereof; and (ii) instructions for administering the compound to a subject for the treatment of stroke. In certain embodiments, the kit further includes instructions for administering the compound to a subject to aid recovery of motor, sensory, cognitive, memory, visual, coordination, or gait deficits resulting from the stroke. In other embodiments, the kit includes instructions for administering said compound to the subject within six months, four months, three months, two months, one month, two weeks, one week, 5 days, 3 days, 2 days, or 1 day after the stroke. The invention further features a kit including: (i) a pharmaceutical composition including a pharmaceutically acceptable excipient and a compound selected from i?(-)-l 1-O-valeryl-N-rc-propylnoraporphine and analogues thereof, or a pharmaceutically acceptable salt thereof; and (ii) instructions for administering the compound to a subject for the treatment of a traumatic brain injury.

The invention also features a kit including: (i) a pharmaceutical composition including a pharmaceutically acceptable excipient and a compound selected from R(-)-l l-O-valeryl-N-«-propylnoraporphine and analogues thereof, or a pharmaceutically acceptable salt thereof; and (ii) instructions for administering the compound to a subject for the treatment of an anoxic- ischemic brain injury.

The invention features a kit including: (i) a pharmaceutical composition including a pharmaceutically acceptable excipient and a compound selected from R(-)- 11 -O-valeryl-N-π-propylnoraporphine and analogues thereof, or a pharmaceutically acceptable salt thereof; and (ii) instructions for administering the compound to a subject for the treatment of a non-traumatic brain injury selected from Alzheimer's disease, Huntington's disease, multiple sclerosis, PATENT

ATTORNEY DOCKET NO. 04843/170WO2 amyotrophic lateral sclerosis, brain hemorrhage, brain infections, and brain tumor. In certain embodiments, the non-traumatic brain injury is Alzheimer's disease.

The invention further features a kit including: (i) a pharmaceutical composition including a pharmaceutically acceptable excipient and a compound selected from /?(-)- 1 l-O-valeryl-N-«-propylnoraporphine and analogues thereof, or a pharmaceutically acceptable salt thereof; and (ii) instructions for administering the compound for aiding recovery of cognitive function following brain injury in a subject. In certain embodiments, the brain injury is a consequence of a stroke, traumatic brain injury, non-traumatic brain injury, or anoxic-ischemic brain injury.

The invention features a kit including: (i) a pharmaceutical composition including a pharmaceutically acceptable excipient and a compound selected from i?(-)-l 1-O-valeryl-N-rø-propylnoraporphine and analogues thereof, or a pharmaceutically acceptable salt thereof; and (ii) instructions for administering the compound to aid neurological recovery following brain injury in a subject. In certain embodiments, the brain injury is a consequence of a stroke, traumatic brain injury, non-traumatic brain injury, or anoxic-ischemic brain injury. In other embodiments, the kit includes instructions for administering the compound to a subject to aid recovery of motor, sensory, cognitive, memory, visual, coordination, or gait deficits resulting from brain injury.

In an embodiment of any of the above kits, the kit includes instructions for administering daily from 2.5 to 1,200 mg, 2.5 to 1,000 mg, 5 to 1,000 mg, 10 to 1,000 mg, 25 to 1,000 mg, 50 to 1,000 mg, 50 to 800 mg, 100 to 1,000 mg, 100 to 700 mg, 200 to 1 ,000 mg, 200 to 800 mg, 200 to 700 mg, 200 to 500 mg, 300 to 1,000 mg, 300 to 800 mg, 300 to 600 mg, 400 to 1,000 mg, 400 to 800 mg, or 400 to 600 mg of the compound to the subject. PATENT

ATTORNEY DOCKET NO. 04843/170WO2

In another embodiment of any of the above kits, the pharmaceutical composition is formulated for oral administration, intravenous administration, or subcutaneous administration.

In one embodiment of any of the above methods or kits, the compound is R(-)- 1 1 -O-valcryl-N-n-propylnorapoφhine or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above methods or kits, the compound is an analogue of the formula:

wherein Y₁ is C(O)-R₃ or fatty acid acyl; X₁ is H, F, OH, or OCH₃; R₁ is CH₃, CH₂CH₃, CH₂CH₂CH₃, CH₂CH₂=CH₂, or cyclopropylmethyl; R₂ is H, CH₃, or OCH₃; and R₃ is ethyl, ^-propyl, isopropyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl, w-butyl, /sø-butyl, sec-butyl, tert-butyl, vinyl, allyl, 2- cyclopropyl- 1 -ethenyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-l- propenyl, 2-methyl-2-propenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2- butynyl, or 3-butynyl, or a pharmaceutically acceptable salt thereof. In particular embodiments, the compound has the above formula wherein Y₁ is fatty acid acyl; Xj is H; R₁ is CH₂CH₂CH₃; and R₂ is H. In still other embodiments, the compound is an analogue selected from R(-)-l l-O- isobutyryl-N-rø-propylnoraporphine, R(-)- 11 -O-butyryl-N-rø- propylnoraporphine, R(-)-\ l-O-isovaleryl-N-«-propylnoraporphine, R( -)-10- methyl-1 1-O-butyryl-N-ft-propylnoraporphine, /?(-)- 10-methyl- 1 l-O- isovaleryl-N-rz-propylnoraporphine, R(-)- 10-methyl- 11 -O-valeryl-N-rø- propylnoraporphine, /?(-)- 10-methoxy-l 1-O-isobutyryl-N-rø- PATENT

ATTORNEY DOCKET NO. 04843/170WO2 propylnoraporphine, R(-)- 10-methoxy- 11 -O-butyryl-N-rø-propylnoraporphine, /?(-)- 10-methoxy- 11 -O-isovaleryl-N-rc-propylnoraporphine, /?(-)- 10-methoxy- 11-O-valeryl-N-w-propylnoraporphine, i?(-)-2-fluoro-l l-O-isobutyryl-N-77- propylnoraporphine, i?(-)-2-fluoro- 1 l-O-butyryl-N-«-propylnoraporphine, R(- )-2-fluoro-l 1-O-isovaleryl-N-w-propylnoraporphine, and R(-)-2-fluoro- 1 l-O- valeryl-N-«-propylnoraporphine.

In another aspect, the invention features a pharmaceutical composition formulated for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, lozenge, etc.), the unit dosage form including a pharmaceutically acceptable excipient and from 50 mg to 900 mg, 50 mg to 750 mg, 100 mg to 900 mg, 100 mg to 750 mg, 100 mg to 500 mg, 200 mg to 900 mg, 200 mg to 750 mg, 200 mg to 500 mg, 300 mg to 900 mg, 300 mg to 750 mg, 400 mg to 900 mg, or 400 mg to 600 mg of R( -)-l 1-O-valeryl-N-rø-propylnoraporphine or a pharmaceutically acceptable salt thereof. As used herein, the term "stroke" refers to a clinical event involving thrombotic or embolic occlusion of a blood vessel supplying the brain, or a brain hemorrhage. Occlusion or hemorrhage can involve brain arteries or veins. Typically, stroke is manifest by the abrupt onset of a focal neurologic deficit. The term "ischemic stroke" refers to stroke characterized by localized tissue anemia due to obstruction of the inflow of arterial blood. Ischemic stroke is usually caused by atherothrombosis or embolism of a major cerebral artery, but may also be caused by coagulation disorders or nonatheromatous vascular disease. As used herein, "treating" stroke includes administration of a compound of the present invention, or a pharmaceutically acceptable salt thereof, for the purpose of (1) preventing stroke, (2) inhibiting stroke or the symptoms of stroke in a subject that is experiencing or displaying the pathology or symptomatology of stroke (i.e., arresting further development of the pathology and/or symptomatology), (3) ameliorating stroke or the symptoms of stroke in a subject that is experiencing or displaying the pathology or PATENT

ATTORNEY DOCKET NO. 04843/170WO2 symptomatology of stroke (i.e., reversing the pathology and/or symptomatology), and/or (4) enhancing functional recovery following stroke or reducing hospitalization following stroke. Thus, the methods and kits of the invention can be used for preventing, treating, eradicating, ameliorating or otherwise reducing the severity of stroke. The methods and kits can be used to treat acute stroke (e.g., therapy beginning within 3 hours of a stroke event), as well as for stroke recovery (e.g., therapy beginning at least 8 hours following a stroke event).

The term "brain injury" is a general term used to refer to a condition that results in central nervous system damage, irrespective of its pathophysiological basis. Among the most frequent origins of a "brain injury" are stroke and traumatic brain injury (TBI).

As used herein, the term "traumatic brain injury" and "TBl" refer to traumatic injuries to the brain which occur when physical trauma causes brain damage. For example, TBI can result from a closed head injury or a penetrating head injury.

As used herein, the term "non-traumatic brain injury" refers to brain injuries that do not involve ischemia or external mechanical force (e.g. stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, brain hemorrhage, brain infections, brain tumor, among others).

As used herein, the term "anoxic-ischemic brain injury" refers to deprivation of oxygen supply to brain tissue resulting in compromised brain function and includes cerebral hypoxia. For example, anoxic-ischemic brain injury includes focal cerebral ischemia, global cerebral ischemia, hypoxic hypoxia (i.e., limited oxygen in the environment causes reduced brain function, such as with divers, aviators, mountain climbers, and fire fighters, all of whom are at risk for this kind of cerebral hypoxia), obstructions in the lungs (e.g., hypoxia resulting from choking, strangulation, the crushing of the windpipe, PATENT

ATTORNEY DOCKET NO. 04843/170WO2 and severe asthma), hypemic hypoxia (i.e., reduced brain function is caused by inadequate oxygen in the blood despite adequate environmental oxygen, as with anemia and carbon monoxide poisoning), and ischemic hypoxia (e.g., hypoxia is caused by inadequate blood flow to the brain, such as with stroke, shock, heart attacks, and by conditions exerting pressure on the brain an impede absorption of oxygen, such as cerebral edema, brain hemorrhages, and hydrocephalus).

The term "administration" or "administering" refers to a method of giving a dosage of a pharmaceutical composition to a patient, where the method is, e.g., oral, topical, transdermal, by inhalation, intravenous, intraperitoneal, intracerebroventricular, intrathecal, or intramuscular. The preferred method of administration can vary depending on various factors, e.g., the components of the pharmaceutical composition, site of administration, and severity of the symptoms being treated. As used herein, the terms "an amount effective" and "effective amount" refer to the amount ofR(-)-l l-O-valeryl-N-w-propylnoraporphine, analogue thereof, or pharmaceutically acceptable salt thereof, required to treat a condition associated with brain injury. The effective amount used to practice the invention for therapeutic treatment of conditions caused by, or contributed to by, brain injury can vary depending upon the manner of administration, the age, body weight, and general health of the subject. Ultimately, the attending physician will decide the appropriate amount and dosage regimen. Such amount is referred to as an "effective" amount.

By "aiding cognitive function" is meant using the methods of the invention to improve memory, communication, attention, perception, recognition, planning, or related skills in a subject having impaired cognitive function as a result of a brain injury in comparison to a subject suffering a brain injury of the same severity and type but left untreated. PATENT

ATTORNEY DOCKET NO. 04843/170WO2

By "aiding neurological recovery" is meant using the methods of the invention to ameliorate neurological abnormalities, such as motor, sensory, cognitive, memory, visual, coordination, and gait deficits in a subject having such neurological deficits as a result of a brain injury in comparison to a subject suffering a brain injury of the same severity and type but left untreated.

By "average daily dose" is meant the administered dose of R(-)-l 1-0- valeryl-N-/2-propylnorapoφhine, or an analogue thereof, per unit time. The average daily dose is calculated from the instructed regimen. For example, oral dosing of 10 mg twice weekly is an average daily dose of 2.87 mg/day (i.e., 20 mg/7 days). For regimens of indefinite intervals, the average daily dose is calculated from the average of the high and low values. For example, a regimen that calls for 150 mg over seven to ten days has an average daily dose of 18.2 mg/day ((150 mg/7 days + 150 mg/10 days)/2).

By "subject" is meant any mammal (e.g., a human). Other animals that can be treated using the methods and kits of the invention include horses, dogs, cats, pigs, goats, rabbits, hamsters, and monkeys.

As used herein, the term "treating" refers to administering a pharmaceutical composition for prophylactic and/or therapeutic purposes. To "prevent disease" refers to prophylactic treatment of a patient who is not yet ill, but who is susceptible to, or otherwise at risk of, a particular disease. To "treat disease" or use for "therapeutic treatment" refers to administering treatment to a patient already suffering from a disease to ameliorate the disease and improve the patient's condition. Thus, in the claims and embodiments, treating is the administration to a mammal either for therapeutic or prophylactic purposes. The pharmaceutical compositions of the invention include /?(-)- 11 -O- valeryl-N-rø-propylnoraporphine, or an analogue thereof, having a substantially R(-) enantiomeric configuration. This configuration refers to the stereochemical orientation of the fused ring system (i.e., the only stereocenter in R(-)-\ 1-O-valeryl-N-rø-propylnoraporphine). A pharmaceutical having a PATENT

ATTORNEY DOCKET NO. 04843/170WO2 substantially R(-) enantiomeric configuration is one having an enantiomeric excess in the R(-) configuration of at least 70%, 80%, 90%, 95%, 97%, 98%, 99%, or 99.5%.

As used herein, the term "analogue" or "analogues" refers to compounds of any of formulas I-I V, or a pharmaceutically acceptable salt or solvate thereof.

In formula I, Y₁ is C(O)-R₃, C(O)-O-R₃, C(O)-NR₃R₄, P(O)(OH)-O-R₃, C(S)- R₃, C(S)-O-R₃, C(S)-NR₃R₄, or fatty acid acyl; X₁ is H, F, Cl, Br, I, OH, OCH₃, or OC(O)-R₅; R₁ is H, C₁^ alkyl, C_2^1 alkenyl, or C₂^ alkynyl; R₂ is H, CH₃, or OCH₃; each of R₃ and R₄ is, independently, selected from II, C₁ _₁₂ alkyl, C₂-_I2 alkenyl, C₂_₁₂ alkynyl, C₂-₆ heterocyclyl, C₆^₂ aryl, C₇_₁₄ alkaryl, C₃ _₁₀ alkheterocyclyl, and C]_₇ heteroalkyl, or R₃ and R₄ together form a heterocyclic ring containing at least one nitrogen atom; and R₅ is C₁^ alkyl, C₂-^ alkenyl, or C₂^ alkynyl. Desirably, R₁ is H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH₂CH₂=CH₂, or cyclopropylmethyl. Compounds of formula I include those described by formulas II or a pharmaceutically acceptable salt or solvate thereof.

In formula II, X₁ is H, F, Cl, Br_; I, OH, or OCH₃; R, is CH₃, CH₂CH₃, CH₂CH₂CH₃, CH₂CH₂=CH₂, or cyclopropylmethyl; R₂ is H, CH₃, or OCH₃; and PATENT

ATTORNEY DOCKET NO. 04843/170WO2

R₃ is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl, rø-butyl, wø-butyl, sec-butyl, tert-butyl, vinyl, allyl, 2- cyclopropyl-1-ethenyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-l- propenyl, 2-methyl-2-propenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2- butynyl, or 3-butynyl. Compounds of formula II include R(-)- 11 -O-acetyl-N-rø- propylnoraporphine, /?(-)- 1 l-O-propionyl-N-«-propylnorapθφhine, R(-)-l 1-0- isobutyryl-N-rø-propylnorapoφhine, i?(-)-l 1-O-butyryl-N-n- propylnoraporphine, /?(-)- 1 l-O-isovaleryl-N-w-propylnoraporphine, R(-)-lO- methyl-1 l-O-acetyl-N-rø-propylnoraporphine, /?(-)-! 0-methyl-l 1-O-propionyl- N-«-propylnoraporphine, R(-)- 10-methyl- 11 -O-isobutyryl-N-rø- propylnorapoφhine, R(-)- 10-methyl- 11 -O-butyryl-N-π-propylnoraporphine, R(-)- 10-methyl- 11 -O-isovaleryl-N-rø-propylnoraporphine, R(-)- 10-methyl- 11- O-valeryl-N-f2-propylnoraporphine, R(-)- 10-methoxy- 1 1 -O-acetyl-N-?7- propylnoraporphine, i?(-)- 10-methoxy- 1 l-O-propionyl-N-^- propylnoraporphine, R(-)- 10-methoxy- 11 -O-isobutyryl-N-rø- propylnoraporphine, /?(-)- 10-methoxy- 1 1 -O-butyryl-N-/ϊ-propylnorapoφhine, R(-)- 10-methoxy- 1 1 -O-isovaleryl-N-π-propylnorapoφhine, R(-)- 10-methoxy- 1 l-O-valeryl-N-/?-propylnorapoφhine, i?(-)-2-fluoro-l l-O-acetyl-N-«- propylnorapoφhine, i?(-)-2-fluoro- 11 -O-propionyl-N-rø-propylnorapoφhine, i?(-)-2-fluoro- 11 -O-isobutyryl-N-«-propylnorapoφhine, i?(-)-2-fluoro- 11 -O- butyryl-N-π-propylnorapoφhine, i?(-)-2-fluoro- 11 -O-isovaleryl-N-«- propylnorapoφhine, and 7?(-)-2-fluoro-l l-O-valeryl-N-?7-propylnorapoφhine. Compounds of formula I include those described by formulas III or a pharmaceutically acceptable salt or solvate thereof. PATENT

ATTORNEY DOCKET NO. 04843/170WO2

In formula III, X₁ is H, F, Cl, Br, I, OH, or OCH₃; R₁ is CH₃, CH₂CH₃, CH₂CH₂CH₃, CH₂CH₂=CH₂, or cyclopropylmethyl; R₂ is H, CH₃, or OCH₃; and R₃ is H, methyl, ethyl, ^-propyl, isopropyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, vinyl, allyl, 2- cyclopropyl-1-ethenyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-l- propenyl, 2-methyl-2-propenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2- butynyl, or 3-butynyl. Compounds of formula III include R(-)-l l-O- methylcarbamoyl-N-rø-propylnorapoφhine, R(-)- 11 -O-ethylcarbamoyl-N-fl- propylnoraporphine, /?(-)- 1 1 -O-isopropylcarbamoyl-N-tt-propylnoraporphine, R(-)-l 1-O-rø-propylcarbamoyl-N-n-propylnorapoφhine, /?(-)- 1 l-O- isobutylcarbamoyl-N-^-propylnoraporphine, R(-)- 11 -O-n-butylcarbamoyl-N-rc- propylnoraporphine, i?(-)-l 0-methyl- 11-O-methylcarbamoyl-N-rø- propylnoraporphine, R(-)- 10-methyl- 1 l-O-ethylcarbamoyl-N-/7- propylnoraporphine, R(-)- 10-methyl- 11 -O-isopropylcarbamoyl-N-rø- propylnoraporphine, R(-)- 10-methyl- 11 -O-n-propylcarbamoyl-N-rc- propylnoraporphine, R(-)-l 0-methyl- 1 l-O-isobutylcarbamoyl-N-«- propylnoraporphine, R(-)-l 0-methyl- 1 l-O-n-butylcarbamoyl-N-?7- propylnorapoφhine, 7?(-)-10-methoxy-l 1 -O-methylcarbamoyl-N-n- propylnorapoφhine, R(-)- 10-methoxy- 11 -O-ethylcarbamoyl-N-«- propylnorapoφhine, R(-)- 10-methoxy- 1 1 -O-isopropylcarbamoyl-N-rø- propylnorapoφhine, R(-)-10-methoxy-l 1 -O-n-propylcarbamoyl-N-rc- propylnorapoφhine, 7?(-)-10-methoxy-l 1 -O-isobutylcarbamoyl-N-^- propylnorapoφhine, i?(-)-10-methoxy-l 1-O-n-butylcarbamoyl-N-n- PATENT

ATTORNEY DOCKET NO. 04843/170WO2 propylnoraporphine, i?(-)-2-fluoro-l 1 -O-methylcarbamoyl-N-w- propylnoraporphine, /?(-)-2-fluoro-l 1-O-ethylcarbamoyl-N-rø- propylnoraporphine, R(-)-2-fluoro- 1 l-O-isopropylcarbamoyl-N-rø- propylnoraporphine, i?(-)-2-fluoro-l 1 -O-rø-propylcarbamoyl-N-rc- propylnoraporphine, R(-)-2-fluoro- 11 -O-isobutylcarbamoyl-N-rø- propylnoraporphine, and R(-)-2-fluoro- 1 l-O-«-butylcarbamoyl-N-«- propylnoraporphine. Analogues further include compounds of formula IV, or a pharmaceutically acceptable salt or solvate thereof.

In formula IV₅ X₂ is F, Cl, Br, I, OH, OCH₃, or OC(O)-R₁₃; R₁₁ is H, C₁^ alkyl, C₂_₄ alkenyl, or C₂_₄ alkynyl; R₁₂ is H, CH₃, or OCH₃; and R₁₃ is C_1-4 alkyl, C₂^ alkenyl, or C₂^ alkynyl.

Analogues of /?(-)- 11-O-valeryl-N-rø-propylnoraporphine can be prepared as described in PCT Publication No. WO/2005/099702, published October 27, 2005.

In the generic descriptions of compounds used in the methods and kits of the invention, the number of atoms of a particular type in a substituent group is generally given as a range, e.g., an alkyl group containing from 1 to 4 carbon atoms or C_1-4 alkyl. Reference to such a range is intended to include specific references to groups having each of the integer number of atoms within the specified range. For example, an alkyl group from 1 to 4 carbon atoms includes each of C₁, C₂, C₃, and C₄. A Ci_₎₂ heteroalkyl, for example, includes from 1 to 12 carbon atoms in addition to one or more heteroatoms. Other numbers of atoms and other types of atoms may be indicated in a similar manner. PATENT

ATTORNEY DOCKET NO. 04843/170 WO2

As used herein, the terms "alkyl" and the prefix "alk-" are inclusive of both straight- chain and branched- chain groups and of cyclic groups, i.e., cycloalkyl. Cyclic groups can be monocyclic or polycyclic and preferably have from 3 to 6 ring carbon atoms, inclusive. Exemplary cyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

By "C₁^ alkyl" is meant a branched or unbranched hydrocarbon group having from 1 to 4 carbon atoms. A C₁^ alkyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups. C₁^ alkyls include, without limitation, methyl, ethyl, n- propyl, isopropyl, cyclopropyl, cyclopropylmethyl, rc-butyl, /so-butyl, sec-butyl, tert-butyl, and cyclobutyl.

By "C₁^₁₂ alkyl" is meant a branched or unbranched hydrocarbon group having from 1 to 12 carbon atoms. A C^_n alkyl may be substituted or unsubstituted, may optionally include monocyclic or polycyclic rings, and includes the C₁^ alkyls above.

By "C₂-₄ alkenyl" is meant a branched or unbranched hydrocarbon group containing one or more double bonds and having from 2 to 4 carbon atoms. A C₂^ alkenyl may optionally include monocyclic or polycyclic rings, in which each ring desirably has from three to six members. The C₂^ alkenyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups. C₂^ alkenyls include, without limitation, vinyl, allyl, 2-cyclopropyl-l-ethenyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl- 1-propenyl, and 2-methyl-2-propenyl.

By "C₂-₁₂ alkenyl" is meant a branched or unbranched hydrocarbon group containing one or more double bonds and having from 2 to 12 carbon PATENT

ATTORNEY DOCKET NO. 04843/170WO2 atoms. A C₂_₁₂ alkenyl may be substituted or unsubstituted, may optionally include monocyclic or polycyclic rings, and includes the C₂^ alkenyls above.

By "C₂^ alkynyl" is meant a branched or unbranched hydrocarbon group containing one or more triple bonds and having from 2 to 4 carbon atoms. A C₂^ alkynyl may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has five or six members. The C₂_₄ alkynyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxy, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups. C_2^t alkynyls include, without limitation, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl.

By "C₂_i₂ alkynyl" is meant a branched or unbranched hydrocarbon group containing one or more triple bonds and having from 2 to 12 carbon atoms. A C₂_i₂ alkynyl may be substituted or unsubstituted, may optionally include monocyclic or polycyclic rings, and includes C₂^ alkynyls above.

By "C₂_₆ heterocyclyl" is meant a stable 5- to 7-membcrcd monocyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of 2 to 6 carbon atoms and 1 , 2, 3 or 4 heteroatoms independently selected from N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxy, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be covalently attached via any heteroatom or carbon atom which results in a stable structure, e.g., an imidazolinyl ring may be linked at either of the ring-carbon atom positions or at PATENT

ATTORNEY DOCKET NO. 04843/170WO2 the nitrogen atom. A nitrogen atom in the heterocycle may optionally be quaternized. Preferably when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. Heterocycles include, without limitation, lH-indazole, 2-pyrrolidonyl, 2H,6H- 1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H- quinolizinyl, 6H-l,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, moφholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-l,2,5-thiadiazinyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5- triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred 5 to 10 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, PATENT

ATTORNEY DOCKET NO. 04843/170WO2 thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, lH-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and isoquinolinyl. Preferred 5 to 6 membered heterocycles include, without limitation, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl.

By "C_<5_i₂ aryl" is meant an aromatic group having a ring system comprised of carbon atoms with conjugated π electrons (e.g., phenyl). The aryl group has from 6 to 12 carbon atoms. Aryl groups may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has five or six members. The aryl group may be substituted or unsubstituted. Exemplary substituents include alkyl, hydroxy, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, fluoroalkyl, carboxyl, hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, monosubstituted amino, disubstituted amino, and quaternary amino groups.

By "C₇_₁₄ alkaryl" is meant an alkyl substituted by an aryl group (e.g., benzyl, phenethyl, or 3,4-dichlorophenethyl) having from 7 to 14 carbon atoms.

By "C₃_₁₀ alkheterocyclyl" is meant an alkyl substituted heterocyclic group having from 3 to 10 carbon atoms in addition to one or more heteroatoms (e.g., 3-furanylmethyl, 2-furanylmethyl, 3-tetrahydrofuranylmethyl, or 2- tetrahydrofuranylmethyl).

By "C]_₇ heteroalkyl" is meant a branched or unbranched alkyl, alkenyl, or alkynyl group having from 1 to 7 carbon atoms in addition to 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O, S, and P. Heteroalkyls include, without limitation, tertiary amines, secondary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates, hydrazones, imines, phosphodiesters, phosphoramidates, sulfonamides, and disulfides. A heteroalkyl may optionally include monocyclic, bicyclic, or tricyclic rings, in PATENT

ATTORNEY DOCKET NO. 04843/170WO2 which each ring desirably has three to six members. The heteroalkyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, hydroxyalkyl, carboxyalkyl, and carboxyl groups. Examples of C]_₇ heteroalkyls include, without limitation, methoxymethyl and ethoxyethyl.

By "halide" is meant bromine, chlorine, iodine, or fluorine.

By "fluoroalkyl" is meant an alkyl group that is substituted with a fluorine atom. By "perfluoroalkyl" is meant an alkyl group consisting of only carbon and fluorine atoms.

By "carboxyalkyl" is meant a chemical moiety with the formula -(R)-COOH, wherein R is selected from C_1-._? alkyl, C₂_₇ alkenyl, C₂_₇ alkynyl, C₂_₆ heterocyclyl, C^₁₂ aryl, C₇_₁₄ alkaryl, C₃_₁₀ alkheterocyclyl, or Cj_₇ heteroalkyl.

By "hydroxyalkyl" is meant a chemical moiety with the formula -(R)- OH, wherein R is selected from C^₇ alkyl, C₂_₇ alkenyl, C₂_₇ alkynyl, C₂^ heterocyclyl,

C₆-_I2 aryl, C₇_₁₄ alkaryl, C₃_₁₀ alkheterocyclyl, or C]_₇ heteroalkyl. By "alkoxy" is meant a chemical substituent of the formula -OR, wherein R is selected from C]_₇ alkyl, C₂^₇ alkenyl, C₂^₇ alkynyl, C₂_₆ heterocyclyl, C₆^₂ aryl, C₇__H alkaryl, C₃_₁₀ alkheterocyclyl, or C]_₇ heteroalkyl.

By "aryloxy" is meant a chemical substituent of the formula -OR, wherein R is a C₆^₂ aryl group. By "alkylthio" is meant a chemical substituent of the formula -SR, wherein R is selected from C₁._? alkyl, C₂_₇ alkenyl, C₂_₇ alkynyl, C₂_₆ heterocyclyl, C₆-_{J 2} aryl, C₇__H alkaryl, C₃_i₀ alkheterocyclyl, or C]_₇ heteroalkyl.

By "arylthio" is meant a chemical substituent of the formula -SR, wherein R is a C₆^₂ aryl group. PATENT

ATTORNEY DOCKET NO. 04843/170WO2

By "quaternary amino" is meant a chemical substituent of the formula -(R)-N(R')(R")(R'")⁺, wherein R, R', R", and R'" are each independently an alkyl, alkenyl, alkynyl, or aryl group. R may be an alkyl group linking the quaternary amino nitrogen atom, as a substituent, to another moiety. The nitrogen atom, N, is covalently attached to four carbon atoms of alkyl and/or aryl groups, resulting in a positive charge at the nitrogen atom.

By "fatty acid acyl" is meant a chemical moiety with the formula R- C(O)-, wherein R is a partially-saturated straight- chain or branched hydrocarbon group having between 12 and 26 carbon atoms. Fatty acid acyls are derived from fatty acids including, without limitation, those occurring naturally in the brain. For example, fatty acids having 16 carbon atoms and 0, 1 or 2 double bonds (C 16:0; C 16:1 and C 16:2), those with 18 carbon atoms and 1, 2 or 3 double bonds (C18:l ; C18:2; and C18:3), those with 20 carbon atoms and 1, 2 or 4 double bonds (C20:l; C20:2; and C20:4) and those with 22 carbon atoms and 4, 5 or 6 double bonds (C22:4; C22:5 and C22:6). The fatty acids can be substituted or unsubstituted. Exemplary substituents include hydroxyl, halide, methyl, ethyl, propyl, isopropyl, butyl, and pentyl groups. Desirably, the fatty acid acyl is 4, 7, 10, 13, 16, 19 docosahexanoyl.

The invention features derivatives of /?(-)- 1 1 -hydroxy aporphines and their use for the treatment of stroke and other neurological conditions. The compounds can exhibit enhanced bioavailability and extended in vivo half lives in comparison to /?(-)-apomorphine ("apomorphine"). As a result, the compounds of the invention can be administered in a more convenient and less invasive manner than currently used for apomorphine therapy. Other features and advantages of the invention will be apparent from the following Drawings, Detailed Description, and the claims. PATENT

ATTORNEY DOCKET NO. 04843/170WO2

Brief Description of the Drawings

Figure 1 is a chart depicting the study design (e.g., handling, surgery, injections and sacrifice timetable) of R(-)-l 1-O-valeryl-N-w- propylnoraporphine in a rat stroke recovery model. Further details are provided in Example 1.

Figure 2 is a graph depicting the results of a forelimb placing test in undosed rats and rats dosed with R(-)-l 1-O-valeryl-N-rø-propylnoraporphine twice daily (BID) at 0.625mg/kg, 1.250 mg/kg, and 2.500 mg/kg (total daily dosing = 1.250, 2.500, or 5.000 mg/kg of body-weight, respectively) for a period of 7 days following stroke. (* ^<0.05; ** jcκθ.01, *** pO.OOl). These observations indicate a dose-dependent increase in favorable functional improvements compared with an inactive placebo-treatment condition.

Figure 3 is a graph depicting the results of a hindlimb placing test in undosed rats and rats dosed with R(—)-l 1-O-valeryl-N-rc-propylnoraporphine twice daily (BID) at 0.625mg/kg, 1.250 mg/kg, and 2.500 mg/kg (total daily dosing - 1.250, 2.500, or 5.000 mg/kg of body- weight, respectively) for a period of 7 days following stroke. (* /K0.05; ** /Kθ.01, *** /?<0.001). These observations indicate a dose-dependent increase in favorable functional improvements compared with an inactive placebo-treatment condition. Figure 4 is a graph depicting the results of body swing test in undosed rats and rats dosed with R(-)-\ l-O-valeryl-N-rø-propylnoraporphine twice daily (BID) at 0.625mg/kg, 1.250 mg/kg, and 2.500 mg/kg (total daily dosing = 1.250, 2.500, or 5.000 mg/kg of body-weight, respectively) for a period of 7 days following stroke. These observations indicate a trend toward a dose- dependent increase in favorable functional improvements compared with an inactive placebo-treatment condition.

Figure 5 is a graph depicting the changes in body weight for undosed rats and rats dosed with R(-)-l 1-O-valeryl-N-rø-propylnoraporphine twice daily (BID) at 0.625mg/kg, 1.250 mg/kg, and 2.500 mg/kg (total daily dosing = PATENT

ATTORNEY DOCKET NO. 04843/170WO2

1.250, 2.500, or 5.000 mg/kg of body- weight, respectively) for a period of 7 days following stroke. There were no significant differences among groups.

Detailed Description The invention features methods and kits for treating stroke and related conditions in a subject by administering R(-)- 11 -O-valeryl-N-n- propylnoraporphine or an analogue thereof.

Neurological Conditions Representative examples of conditions treatable using compounds of the present invention are as listed hereinabove, and include, but are not limited to, stroke, traumatic brain injury, anoxic-ischemic brain injury, or other conditions of non- traumatic brain injury, including Alzheimer's disease, Huntington's Disease, amyotrophic lateral sclerosis, multiple sclerosis, and brain infections and tumors. These conditions have in common loss of brain cells (esp. neurons), resulting in neurological dysfunction. All of these conditions can improve or recover to some degree, following treatment using the methods of the invention. Without being bound by any theory, it appears that following brain injury the compounds in the methods of the invention stimulate recovery pathways through activation of brain dopamine receptors. Although brain injury is not necessarily associated with a deficit of dopamine, or a deficit of activity at dopamine receptors, R(-)- 1 1 -0-valeryl-N-n-propylnoraporphine, and analogues thereof, can be administered following a stroke, or brain injury due to other neurological conditions, to reduce the loss of brain function and/or restore some lost brain function. Accordingly, the motor, sensory, cognitive, memory, visual, coordination or other neurological deficits of a subject having one of the above conditions and undergoing the therapy of the invention are improved in comparison to a subject suffering a condition of the same severity and type but left untreated. PATENT

ATTORNEY DOCKET NO. 04843/170WO2

Therapy

Formulations of R(-)-l l-O-valeryl-N-n-propylnoraporphine, and analogues thereof, may be in the form of liquid solutions or suspensions; for oral administration, formulations may be in the form of tablets or capsules; and for intranasal formulations, in the form of powders, nasal drops, or aerosols. Methods well known in the art for making formulations are found, for example, in "Remington: The Science and Practice of Pharmacy" (20th ed., editors: A.R. Gennaro AR., 2000, Philidelphia: Lippincott- Williams & Wilkins). Formulations for parenteral administration may, for example, contain excipients, sterile water, or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated napthalenes. Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds. Nanoparticulate formulations (e.g., biodegradable nanoparticles, solid lipid nanoparticles, liposomes) may be used to control the biodistribution of the compounds. Other potentially useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycolate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel. The concentration of the compound in the formulation will vary depending upon a number of factors, including the dosage of the drug to be administered, and the route of administration. The compound may be optionally administered as a pharmaceutically acceptable salt, such as a non-toxic acid addition salts or metal complexes that are commonly used in the pharmaceutical industry. Examples of acid addition salts include organic acids such as acetic, lactic, pamoic, maleic, citric, malic, ascorbic, succinic, benzoic, palmitic, suberic, salicylic, tartaric, PATENT

ATTORNEY DOCKET NO. 04843/170WO2 methanesulfonic, toluenesulfonic, or trifluoroacetic acids or the like; polymeric acids such as tannic acid, carboxymethyl cellulose, or the like; and inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid phosphoric acid, or the like. Metal complexes include calcium, zinc, iron, and the like. Administration of compounds in controlled release formulations is useful where the compound of formula I has: (i) a narrow therapeutic index (e.g., the difference between the plasma concentration leading to harmful side effects or toxic reactions and the plasma concentration leading to a therapeutic effect is small; generally, the therapeutic index (TI) is defined as the ratio of median lethal dose (LD₅₀) or median toxic dose (TD₅₀) to median effective dose (ED₅₀); (ii) a narrow absorption window in the gastro- intestinal tract; or (iii) a short biological half-life, so that frequent dosing during a day is required in order to sustain the plasma level at a therapeutic level.

Many strategies can be pursued to obtain controlled release in which the rate of release outweighs the rate of metabolism of the therapeutic compound. For example, controlled release can be obtained by the appropriate selection of formulation parameters and ingredients, including, for example, appropriate controlled release compositions and coatings. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticulate formulations, patches, and liposomes.

Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These cxcipients may be, for example, inert diluents or fillers (e.g., sucrose and sorbitol), lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc).

Formulations for oral use may also be provided as chewable tablets, or as hard gelatin capsules wherein the active ingredient is mixed with an inert PATENT

ATTORNEY DOCKET NO. 04843/170WO2 solid diluent, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium.

Formulations for oral use also include rapidly disintegrating or dissolving dosage forms, also known as fast dissolve, fast or rapid melt, and quick disintegrating dosage forms. These dosage forms dissolve or disintegrate rapidly in the patient's mouth without chewing or the need for water within a short time frame. Because of their ease of administration, such compositions are particularly useful for the specific needs of pediatrics, geriatrics, and for patients with dysphagia. The formulations can be administered to patients in therapeutically effective amounts. For example, an amount is administered which aids recovery of neurological function following brain injury. Typical dose ranges are from about 0.25 mg/kg to about 50 mg/kg of body- weight per day. Desirably, a dose of between 1 and 5 mg/kg of body weight, or 2 and 10 mg/kg of body weight, is administered daily in one or more doses. The exemplary dosage of drug to be administered is likely to depend on such variables as the type and extent of the condition, the overall health status of the particular patient, the formulation of the compound, and its route of administration. Standard clinical trials may be used to optimize the dose and dosing frequency for any particular compound.

The compounds of the invention may also be administered by a dose escalating method of acclimatization as described in U.S. Patent No. 5,994,363 thereby ameliorating potential adverse effects. Furthermore, potential adverse effects can be ameliorated by administering R(-)-l 1-hydroxyaporphine compounds in combination with an anti-emetic agent, such as nicotine, lobeline sulfate, pipamazine, oxypendyl hydrochloride, ondansetron, buclizine hydrochloride, cyclizine hydrochloride, dimenhydrinate, scopolamine, metopimazine, benzauinamine hydrochloride or diphenidol hydrochloride. PATENT

ATTORNEY DOCKET NO. 04843/170WO2

The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the methods and compounds claimed herein are performed, made, and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention.

Example 1. Efficacy of /?(-)- 11 -O-valeryl-N-rø-propylnoraporphine in an experimental model of stroke recovery in laboratory rats.

Surgical occlusion of the middle cerebral artery (Tamura model) was utilized to determine the effect of varying doses of /?(-)- 11-O-valeryl-N-rø- propylnoraporphine in alleviating the neurological deficit resulting from stroke demonstrated as sensorimotor skill performance. Behavioral assessment of compound-treated animals in comparison to control (vehicle-treated) animals was used for evaluating compound efficacy over a 14 day period.

Methods

Animal Preparation. Forty adult, male, Sprague-Dawley rats initially weighing 300^00 g, were used for the study. Animals were housed in a standard animal facility and fed with commercial rodent chow ad libitum. Extra animals were included to allow for proper randomization and mortality from the surgical procedures. All animals were housed and handled for behavioral assessment for 7 days prior to surgery for acclimation purposes. At the end of the training period, animals were randomized and assigned to different groups. Middle Cerebral Artery Occlusion (MCA occlusion). Focal cerebral infarcts were made by permanent occlusion of the proximal right middle cerebral artery (MCA). Male Sprague-Dawley rats (300^100 g) were anesthetized with l%-3% (vols.) isoflourane in N₂O/O₂ (2: 1). The temporalis muscle was bisected and reflected through an incision made midway between PATENT

ATTORNEY DOCKET NO. 04843/170WO2 the eye and the eardrum canal. The proximal MCA was exposed through a subtemporal craniectomy without removing the zygomatic arch and without transecting the facial nerve. The artery was then occluded by microbipolar coagulation from just proximal to the olfactory tract to the inferior cerebral vein, and transected. Body temperature was maintained at 37.5 ± TC throughout the entire procedure. Each rat received Cefazolin sodium intraperitoneally (i.p.; 40 mg/kg) and Buprenorphine subcutaneously (s.c; ~0.1 mg/kg) right after the surgery to control pain.

Dosing levels. The rats were divided into 4 groups of 10 each. Group 1, the control group, received only vehicle. Groups 2, 3, and 4 received doses of R(-)-l l-O-valeryl-N-rc-propylnoraporphine at 0.625, 1.250, or 2.500 mg/kg. Vehicle or R(-)- 11 -O-valeryl-N-w-propylnoraporphine at the above doses was administered twice daily intraperitoneally (BID, i.p.) for 7 days, starting 24 hours post MCA occlusion surgery (see Figure 1).

Behavioral Analysis

Two behavioral tests were performed: the limb placing and body swing tests. These tests were performed prior to MCA occlusion and on days 1, 3, 7, and 14 following the surgery (see Figure 1). Limb Placing. Limb placing tests include assessments of both forelimb and hindlimb placement. For the forelimb-placing test, the examiner ("blinded," or unaware of the treatment provided) held the rat close to a tabletop and scored the rat's ability to place the forelimb on the tabletop in response to whisker, visual, tactile, or proprioceptive stimulation. Similarly, for the hindlimb placing test, the examiner assessed the rat's ability to place the hindlimb on the tabletop in response to tactile and proprioceptive stimulation. Separate sub-scores were obtained for each mode of sensory input and added to give total scores (for the forelimb placing test: 0=normal, 12=maximally impaired; for the hindlimb placing test, scoring ranged from: 0=normal; PATENT

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6=maximally impaired). The results of the forelimb placing test for medicated and unmedicated (vehicle-treated) rats are provided in Figure 2. The results of the hindlimb placing test for medicated and unmedicated rats are provided in Figure 3. Body Swing Test. The rat was held approximately 1 inch from the base of its tail. It was then elevated to an inch above a surface of a table, and held in the vertical axis, defined as no more than ±10°, defined as no more than 10- degrees to either the left or right of vertical. A swing was recorded whenever the animal moved its head >10° out of the vertical axis to either side. Before attempting another swing, the animal must return to the vertical position for the next swing to be counted, and a total of 30 swings were counted. A normal animal typically has an equal number of swings to either side. Following focal stroke, the animals tend to swing to the contralateral side. The results of the body swing test for medicated and unmedicated rats are provided in Figure 4. Body Weight. Body weights were measured on days 1, 3, 7, and 14 following the stroke surgery (see Figure 1). Changes in body weight for both medicated and unmedicated (vehicle-treated) rats are shown in Figure 5.

Statistical Analysis. Behavioral scores and body weight were analyzed by two-way repeated measures analysis of variance (ANOVA; treatment- by- time) including all data for each test, followed by appropriate pairwise comparisons between groups. A two-tailed p value of <0.05 was considered a statistically significant difference.

Other Embodiments All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each independent publication or patent application was specifically and individually indicated to be incorporated by reference. PATENT

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While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims.

Other embodiments are within the claims. What is claimed is:

Claims

PATENT ATTORNEY DOCKET NO. 04843/170WO2CLAIMS

1. A method of treating a subject suffering from stroke, said method comprising administering to said subject an effective amount of a compound selected from R(-)-l l-O-valeryl-N-«-propylnoraporphine and analogues thereof, or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein compound is administered in an amount effective to aid recovery of motor, sensory, cognitive, memory, visual, coordination, or gait deficits resulting from said stroke.

3. The method of claim 2, wherein said compound is administered for a period of from 1 to 180 days after stroke.

4. The method of claim 1, comprising ameliorating stroke, or the symptoms of stroke, in a subject displaying symptoms of stroke by administering said compound to said subject within 24 hours of said stroke.

5. A method of treating a subject suffering from a traumatic brain injury, said method comprising administering to said subject an effective amount of a compound selected from /?(-)- 11 -O-valeryl-N-rø- propylnoraporphine and analogues thereof, or a pharmaceutically acceptable salt thereof.

6. A method of treating a subject suffering from an anoxic-ischemic brain injury, said method comprising administering to said subject an effective amount of a compound selected from R(-)-l 1 -O-valeryl-N-rø- propylnoraporphine and analogues thereof, or a pharmaceutically acceptable salt thereof. ATTORNEY DOCKET NO. 04843/170WO2

7. A method of treating a subject suffering from a non-traumatic brain injury selected from Alzheimer's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, brain hemorrhage, brain infections, and brain tumor, said method comprising administering to said subject an effective amount of a compound selected from i?(-)-l 1-O-valeryl-N-w- propylnoraporphine and analogues thereof, or a pharmaceutically acceptable salt thereof.

8. The method of any of claims 1, 5, 6, or 7, wherein said compound is administered in an amount effective to aid neurological recovery.

9. A method of aiding recovery of cognitive function following brain injury in a subject, said method comprising administering to said subject an effective amount of a compound selected from i?(-)-l l-O-valeryl-N-«- propylnoraporphine and analogues thereof, or a pharmaceutically acceptable salt thereof.

10. The method of claim 9, wherein said brain injury is a consequence of a stroke, traumatic brain injury, anoxic-ischemic brain injury, or nontraumatic brain injury.

1 1. A method of aiding neurological recovery following brain injury in a subject, said method comprising administering to said subject an effective amount of a compound selected from R(-)-l 1-O-valeryl-N-rø- propylnoraporphine and analogues thereof, or a pharmaceutically acceptable salt thereof. PATENT

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12. The method of claim 11, wherein said brain injury is a consequence of a stroke, traumatic brain injury, anoxic-ischemic brain injury, or.non- traumatic brain injury.

13. The method of claim 11, wherein compound is administered in an amount effective to aid recovery of motor, sensory, cognitive, memory, visual, coordination, or gait deficits resulting from said brain injury.

14. The method according to any of claims 1-13, wherein said compound is administered to said subject in an average daily dose of between 0.25 mg/kg/day and 50 mg/kg/day.

15. The method of claim 14, wherein said compound is administered daily for a period of 1 to 180 days after brain injury.

16. The method of any of claims 1-15, wherein said compound is administered orally, intravenously, or subcutaneously.

17. The method of any of claims 1-16, further comprising the administration of an effective amount of an anti-emetic agent.

18. The method of claim 17, wherein said anti-emetic agent is nicotine, lobeline sulfate, pipamazine, oxypendyl hydrochloride, ondansetron, buclizine hydrochloride, cyclizine hydrochloride, dimenhydrinatc, scopolamine, metopimazine, benzauinamine hydrochloride or diphenidol hydrochloride. A

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19. A kit comprising:

(i) a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound selected from /?(-)- 11-O-valeryl-N-n- propylnoraporphine and analogues thereof, or a pharmaceutically acceptable salt thereof; and

(ii) instructions for administering said compound to a subject for the treatment of stroke.

20. The kit of claim 19, further comprising instructions for administering said compound to a subject to aid recovery of motor, sensory, cognitive, memory, visual, coordination, or gait deficits resulting from said stroke.

21. The kit of claim 19, further comprising instructions for administering said compound to said subject within six months after said stroke.

22. A kit comprising:

(i) a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound selected from R(-)- 11 -O-valeryl-N-«- propylnoraporphine and analogues thereof, or a pharmaceutically acceptable salt thereof; and

(ii) instructions for administering said compound to a subject for the treatment of a traumatic brain injury. ATTORNEY DOCKET NO. 04843/170WO2

23. A kit comprising:

(i) a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound selected from R(-)-l 1-O-valeryl-N-w- propylnoraporphine and analogues thereof, or a pharmaceutically acceptable salt thereof; and

(ii) instructions for administering said compound to a subject for the treatment of an anoxic-ischemic brain injury.

24. A kit comprising:

(i) a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound selected from R(-)-l 1-O-valeryl-N-n- propylnoraporphine and analogues thereof, or a pharmaceutically acceptable salt thereof; and

(ii) instructions for administering said compound to a subject for the treatment of a non-traumatic brain injury selected from Alzheimer's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, brain hemorrhage, brain infections, and brain tumor.

25. The kit of claim 24, wherein said non-traumatic brain injury is Alzheimer's disease.

26. A kit comprising:

(ii) instructions for administering said compound for aiding recovery of cognitive function following brain injury in a subject. ATTORNEY DOCKET NO. 04843/170WO2

27. The kit of claim 26, wherein said brain injury is a consequence of a stroke, traumatic brain injury, anoxic-ischemic brain injury, or non-traumatic brain injury.

28. A kit comprising:

(i) a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound selected from R(-)-l l-O-valeryl-N-«- propylnoraporphine and analogues thereof, or a pharmaceutically acceptable salt thereof; and

(ii) instructions for administering said compound to aid neurological recovery following brain injury in a subject.

29. The kit of claim 27, wherein said brain injury is a consequence of a stroke, traumatic brain injury, anoxic-ischemic brain injury, or non-traumatic brain injury.

30. The kit of claim 28 or 29, further comprising instructions for administering said compound to a subject to aid recovery of motor, sensory, cognitive, memory, visual, coordination, or gait deficits resulting from said brain injury.

31. The kit of any of claims 19-30, further comprising instructions for administering daily from 2.5 mg to 3,500 mg of said compound to said subject.

32. The kit of any of claims 19-30, wherein said pharmaceutical composition is formulated for oral administration, intravenous administration, or subcutaneous administration. PATENT

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33. The method or kit of any of the preceding claims, wherein said compound is R(-)-l l-O-valeryl-N-«-propylnoraporphine or a pharmaceutically acceptable salt thereof.

34. The method or kit of any of the preceding claims, wherein said compound is an analogue of the formula:

wherein

Y₁ is C(O)-R₃ or fatty acid acyl;

X₁ is H₅ F, OH, or OCH₃;

R₁ is CH₃, CH₂CH₃, CH₂CH₂CH₃, CH₂CH₂=CH₂, or cyclopropylmethyl;

R₂ is H, CH₃, or OCH₃; and

R₃ is ethyl, π-propyl, isopropyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, vinyl, allyl, 2- cyclopropyl-1-ethenyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-l- propenyl, 2-methyl-2-propenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2- butynyl, or 3-butynyl, or a pharmaceutically acceptable salt thereof.

35. The method of claim 34, wherein Y₁ is fatty acid acyl; X₁ is H; R₁ is CH₂CH₂CH₃; and R₂ is H. PATENT ATTORNEY DOCKET NO. 04843/170WO2

36. The method of claim 34, wherein said analogue is selected from R(- )-l 1-O-isobutyryl-N-rø-propylnoraporphine, R(-)-l 1 -O-butyryl-N-rc- propylnoraporphine, 7?(-)-l l-O-isovaleryl-N-«-propylnoraporphine, 7?(-)-10- memyl-11-O-butyryl-N-rc-propylnoraporphine, 7?(-)-10-methyl-l 1-0- isovaleryl-N-π-propylnoraporphine, R(-)- 10-methyl- 11 -O-valeryl-N-«- propylnoraporphine, R(-)-10-methoxy-l 1-O-isobutyryl-N-rø- propylnoraporphine, /?(-)- 10-methoxy- 11 -O-butyryl-N-^-propylnoraporphine, R(-)- 10-methoxy- 1 1 -O-isovaleryl-N-rø-propylnoraporphine, /?(-)- 10-methoxy-

1 l-O-valeryl-N-77-propylnoraporphine, R(-)-2-fluoro-l 1 -O-isobutyryl-N-«- propylnorapoφhine, R(-)-2-fluoro-l 1-O-butyryl-N-rø-propylnoraporphine, R(- )-2-fluoro-l l-O-isovaleryl-N-«-propylnoraporphine, and Z?(-)-2-fluoro- 1 l-O- valeryl-N-^-propylnoraporphine.

37. A pharmaceutical composition formulated for oral administration in unit dosage form, said unit dosage form comprising a pharmaceutically acceptable excipient and from 50 mg to 900 mg of /?(-)- 1 1-O-valeryl-N-rø- propylnoraporphine or a pharmaceutically acceptable salt thereof.