How to Treat Neuropathy

Abstract

A method for treating a neurological disorder (such as levodopa-induced dyskinesia) by administering a combination of Compound 1 and fesoterodine.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 283,140, ​​filed November 24, 2021, and U.S. Provisional Application No. 63 / 416,745, filed October 17, 2022, each of which is incorporated by reference for all purposes. [Background technology]

[0002] background Neurological disorders are currently the leading cause of disability worldwide. Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects movement. Parkinson's disease is the most common movement disorder and the fastest growing neurological disorder. In 2016, the global prevalence of Parkinson's disease was 6,062,893 cases, with 3.2 million disability-adjusted life years (DALYs) and 211,296 deaths. This is significantly higher than the prevalence reported in 1990, when the global PD population was 2.5 million. In the United States, in 2017, it was estimated that there were 1 million individuals diagnosed with Parkinson's disease. As the population ages, further substantial increases in PD diagnoses are predicted. In the United States alone, the PD prevalence in 2037 is projected to exceed 1.6 million.

[0003]

[0003] Motor symptoms resulting from loss of striatal dopamine (DA) in PD are routinely treated with levodopa (L-dopa) therapy. Long-term levodopa therapy leads to the development of abnormal involuntary movements called levodopa-induced dyskinesia (LID). Current treatment options for LID are limited and have many side effects. New methods of treating dyskinesias, including LID, in Parkinson's disease patients are needed. Summary of the Invention [Problem to be solved by the invention]

[0004]

[0004] The present disclosure provides methods of treating neurological disorders such as dyskinesia (including LID). [Means for solving the problem]

[0005] Disclosure Summary In embodiments, the present disclosure provides a method of treating a neuropathy in a patient in need thereof, the method comprising: (a) a therapeutically effective amount of Compound 1, or a pharma- ceutically acceptable salt thereof, and (b) a therapeutically effective amount of fesoterodine or a pharma- ceutically acceptable salt thereof. The method includes administering

[0006]

[0006] In an embodiment, the neurological disorder is dyskinesia.

[0007]

[0007] In an embodiment, the dyskinesia is levodopa-induced dyskinesia.

[0008]

[0008] In an embodiment, the patient is diagnosed with Parkinson's disease.

[0009]

[0009] In an embodiment, the patient is being treated for schizophrenia.

[0010] In embodiments, the neurological disorder is Alzheimer's disease psychosis, Parkinson's disease psychosis, dementia-related psychosis, dementia with Lewy bodies, schizophrenia (acute and maintained), brief psychotic disorder or acute delirium.

[0011]

[0011] In an embodiment, about 5 mg to about 800 mg of Compound 1 or a pharma- ceutically acceptable salt thereof is administered to a patient. In an embodiment, about 20 mg to about 80 mg of Compound 1 or a pharma- ceutically acceptable salt thereof is administered to a patient. In an embodiment, about 60 mg of Compound 1 or a pharma- ceutically acceptable salt thereof is administered to a patient.

[0012]

[0012] In an embodiment, administration provides a therapeutically effective steady state plasma concentration of Compound 1. In an embodiment, the therapeutically effective steady state plasma concentration of Compound 1 is about 100 ng / mL to 2500 ng / mL. In an embodiment, the therapeutically effective steady state plasma concentration of Compound 1 is about 600 ng / mL.

[0013]

[0013] In an embodiment, Compound 1 or a pharma- ceutically acceptable salt thereof is administered once a day. In an embodiment, Compound 1 or a pharma- ceutically acceptable salt thereof is administered twice a day. In an embodiment, Compound 1 or a pharma- ceutically acceptable salt thereof is administered three times a day.

[0014] In an embodiment, about 1 mg to about 50 mg of fesoterodine or a pharma- ceutically acceptable salt thereof is administered to a patient. In an embodiment, about 8 mg of fesoterodine or a pharma- ceutically acceptable salt thereof is administered. In an embodiment, about 24 mg of fesoterodine or a pharma- ceutically acceptable salt thereof is administered.

[0015] In embodiments, administration provides a therapeutically effective steady state plasma concentration of desfesoterodine (i.e., an amount sufficient to reduce peripheral side effects associated with administration of Compound 1). In embodiments, the therapeutically effective steady state plasma concentration of fesoterodine is from about 5 ng / mL to about 30 ng / mL.

[0016] In an embodiment, fesoterodine or a pharma- ceutically acceptable salt thereof is administered once daily. In an embodiment, fesoterodine or a pharma- ceutically acceptable salt thereof is administered twice daily. In an embodiment, fesoterodine or a pharma- ceutically acceptable salt thereof is administered three times daily.

[0017] In an embodiment, Compound 1 and fesoterodine are administered in separate pharmaceutical compositions.

[0018] In an embodiment, Compound 1 and fesoterodine are administered orally.

[0019] In an embodiment, the patient is administered Compound 1 at least 1 hour after the patient is administered fesoterodine.

[0020] In an embodiment, administration provides a plasma concentration ratio of Compound 1 to desfesoterodine of about 10:1 to about 1000:1. In an embodiment, administration provides a plasma concentration ratio of Compound 1 to desfesoterodine of 100:1.

[0021] In an embodiment, the dose and administration schedule of fesoterodine is selected to reduce the peripheral side effects of administering Compound 1 to a patient. [Brief description of the drawings]

[0022] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1]

[0022] As described in Example 7, the change (mL) from baseline saliva production after administration of different doses of Compound 1 (1 mg, 3 mg, 10 mg, 20 mg, and 40 mg) is shown. [Diagram 2]

[0023] 1 shows the change from baseline saliva production (mL) following administration of Compound 1 alone (40 mg) and in combination with fesoterodine fumarate (8 mg) (40 mg), as described in Example 7. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] Detailed Description of the Invention definition

[0024] Throughout this disclosure, various patents, patent applications, and publications (including non-patent publications) are referenced. The disclosures of these patents, patent applications, and publications in their entireties are incorporated by reference into this disclosure for all purposes in order to more fully describe the state of the art as known to those skilled in the art as of the date of this disclosure. This disclosure applies in the event of any inconsistency between the cited patents, patent applications, and publications and this disclosure.

[0024]

[0025] For convenience, certain terms used in the specification, examples, and claims are collected here. Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0025]

[0026] The term "about", when immediately preceding a numerical value, refers to a range (e.g., ±10% of that value). For example, "about 50" can refer to 45 to 55, "about 25,000" can refer to 22,500 to 27,500, etc., unless the context of this disclosure indicates otherwise or is inconsistent with such an interpretation. For example, in a list of numerical values ​​such as "about 49, about 50, about 55, ...", "about 50" refers to less than half the interval between the preceding and following values, e.g., a range extending from more than 49.5 to less than 52.5. Furthermore, the phrase "less than" an "about" value or "greater than" an "about" value should be understood in light of the definition of the term "about" provided herein. Similarly, the term "about" when preceding a series of numerical values ​​or a range of values ​​(e.g., "about 10, 20, 30" or "about 10 to 30") refers to all values ​​in the series, or to the end points of the range, respectively.

[0026]

[0027] As used herein, the term "Compound 1" refers to a compound having the following structural formula: [ka] refers to 1-(3-methyl-[1,2,4]oxadiazol-5-yl)-(1R,5R)-3-aza-bicyclo[3.1.0]hexane,

[0027]

[0028] As used herein, the phrase "pharmacologically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0028]

[0029] The term "therapeutically effective amount" refers to an amount of a compound or pharmaceutical composition described herein sufficient to achieve the intended use, including but not limited to disease treatment, as exemplified below. For example, an effective amount of Compound 1 is the amount required to reduce at least one symptom of dyskinesia in a patient. An effective amount of fesoterodine is the amount required to reduce at least one side effect associated with administration of Compound 1, including, for example, salivation, lacrimation, urination, defecation, gastrointestinal distress and vomiting, diarrhea, miosis, bronchorrhea, bronchospasm, relaxation, and sweating. The therapeutically effective amount may vary depending on the intended use (in vitro or in vivo), or the subject and disease state to be treated, such as the subject's weight and age, the severity of the disease state, the mode of administration, etc., which can be readily determined by one of ordinary skill in the art. The specific dose will vary depending, for example, on the dosing regimen to be followed, the timing of administration, the tissue to which it is administered, and the physical delivery system through which it is delivered.

[0029]

[0030] As used herein, the term "therapeutic effect" refers to a desired or beneficial effect provided by a method and / or composition. For example, a method for treating dyskinesia provides a therapeutic effect if the method reduces at least one symptom of dyskinesia in a patient.

[0030]

[0031] The term "treating" as used herein with respect to a patient refers to improving at least one symptom of the patient's disorder (e.g., dyskinesia). Treatment can improve or at least partially ameliorate the disorder.

[0031] Methods of the Disclosure

[0032] Parkinson's disease (PD) results in major motor symptoms including tremor, rigidity, bradykinesia (slow movements) and postural instability (balance problems). Motor symptoms resulting from the loss of striatal dopamine (DA) in PD continue to be best alleviated with levodopa (L-dopa) treatment. Levodopa, which is biosynthetically converted to dopamine via aromatic L-amino acid decarboxylase (AADC), is commonly given to increase dopamine levels in PD patients.

[0032]

[0033] Long-term levodopa therapy leads to the development of abnormal involuntary movements, called levodopa-induced dyskinesia (LID), which can develop as early as a few months after treatment and affect the majority of patients after 5-10 years of L-dopa therapy. Levodopa-induced dyskinesia can involve a variety of movement disorders, including chorea, dystonia, ballismus, myoclonus, and akathisia, and ultimately result in disability associated with a significant increase in the costs of treatment.

[0033]

[0034] Treatment options for LID are scarce. To date, the only approved pharmacological therapy, the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist amantadine, has shown variable efficacy and its use is associated with tolerability issues.

[0034]

[0035] The present disclosure provides a method for treating levodopa-induced dyskinesia (LID) by administering a therapeutically effective amount of Compound 1 (an M1 / M4 receptor agonist). As described in this example (see Example 4), administration of Compound 1 provides a reduction in LID symptoms determined using a standard LID disease model. Compound 1 is therefore useful for treating dyskinesia (including LID). However, muscarinic receptor agonists (such as Compound 1) exhibit undesirable peripheral cholinergic effects.

[0035]

[0036] Fesoterodine is a non-selective antimuscarinic prodrug of 5-hydroxymethyltolterodine (5-HMT) with affinity for the M1, M2, M3, M4, and M5 muscarinic receptors that is used in the methods of the disclosure to reduce the peripheral cholinergic effects of administration of Compound 1.

[0036]

[0037] In embodiments, fesoterodine reduces side effects associated with administration of Compound 1. In embodiments, the method of treating dyskinesia reduces side effects associated with administration of Compound 1, including, but not limited to, salivation, lacrimation, urination, defecation, gastrointestinal distress and vomiting, diarrhea, miosis, bronchorrhea, bronchospasm, relaxation, and sweating. In embodiments, the disclosed method reduces peripheral side effects associated with administration of Compound 1. In embodiments, the disclosed method reduces central side effects associated with administration of Compound 1, such as headache, confusion, and drowsiness.

[0037]

[0038] The present disclosure provides methods of administering a muscarinic receptor agonist (e.g., Compound 1) in combination with a peripherally acting anticholinergic (e.g., fesoterodine) to provide a method of effectively treating dyskinesias with reduced peripheral cholinergic efficacy.

[0038]

[0039] In embodiments, the present disclosure provides a method of treating dyskinesia in a patient in need thereof, the method comprising: (a) a therapeutically effective amount of Compound 1, or a pharma- ceutically acceptable salt thereof, and (b) a therapeutically effective amount of fesoterodine or a pharma- ceutically acceptable salt thereof. The method includes administering

[0039]

[0040] In an embodiment, the dyskinesia is levodopa-induced dyskinesia.

[0040]

[0041] In an embodiment, the patient has been diagnosed with Parkinson's disease.

[0041]

[0042] In embodiments, the present disclosure provides a method of treating Alzheimer's disease psychosis, Parkinson's disease psychosis, dementia-related psychosis, dementia with Lewy bodies, schizophrenia (acute and maintained), brief psychotic disorder, or acute delirium in a patient in need thereof, the method comprising: (a) a therapeutically effective amount of Compound 1, or a pharma- ceutically acceptable salt thereof, and (b) a therapeutically effective amount of fesoterodine or a pharma- ceutically acceptable salt thereof. The method includes administering

[0042]

[0043] In an embodiment, the patient is being treated for schizophrenia. In an embodiment, the patient is being treated for acute schizophrenia.

[0043]

[0044] In an embodiment, about 5 mg to about 300 mg of Compound 1 or a pharma- ceutically acceptable salt thereof is administered to a patient. In an embodiment, about 5 mg to about 800 mg, for example, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 22 mg, about 24 mg, about 26 mg, about 28 mg, about 30 mg, about 32 mg, about 34 mg, about 36 mg, about 38 mg, about 40 mg, about 42 mg, about 44 mg, about 46 mg, about 48 mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg , about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 3 00mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440 mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, About 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, or about 800 mg (including all values ​​and ranges therebetween) of Compound 1 or a pharma- ceutically acceptable salt thereof is administered to the patient. In an embodiment, about 20 mg to about 80 mg of Compound 1 or a pharma- ceutically acceptable salt thereof is administered to the patient. In an embodiment, about 20 mg to about 60 mg of Compound 1 or a pharma- ceutically acceptable salt thereof is administered to the patient.

[0044]

[0045] In embodiments, the amount of the compound is about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 22 mg, about 24 mg, about 26 mg, about 28 mg, about 30 mg, about 32 mg, about 34 mg, about 36 mg, about 38 mg, about 40 mg, about 42 mg, about 44 mg, about 46 mg, about 48 mg, about 50 ... 5mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 1 60mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg , about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570m g, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, or about 800 mg of Compound 1 or a pharma- ceutically acceptable salt thereof is administered to the patient. In an embodiment, about 40 mg of Compound 1 or a pharma- ceutically acceptable salt thereof is administered to the patient. In an embodiment, about 60 mg of Compound 1 or a pharma- ceutically acceptable salt thereof is administered to the patient. In an embodiment, about 80 mg of Compound 1 or a pharma- ceutically acceptable salt thereof is administered to the patient.

[0045]

[0046] In an embodiment, about 0.05 mg / kg to about 8 mg / kg, for example, about 0.05 mg / kg, about 0.10 mg / kg, about 0.15 mg / kg, about 0.20 mg / kg, about 0.25 mg / kg, about 0.30 mg / kg, about 0.35 mg / kg, about 0.40 mg / kg, about 0.45 mg / kg, about 0.50 mg / kg, about 0.55 mg / kg, about 0.60 mg / kg, about 0.65 mg / kg, about 0.70mg / kg, about 0.75mg / kg, about 0.80mg / kg, about 0.85mg / kg, about 0.90mg / kg, about 0.95mg / kg, about 1.00mg / kg, about 1.2 0mg / kg, approx. 1.40mg / kg, approx. 1.60mg / kg, approx. 1.80mg / kg, approx. 2.00mg / kg, approx. 2.20mg / kg, approx. 2.40mg / kg, approx. 2.60mg / kg, approx. 2 .80mg / kg, approx. 3.00mg / kg, approx. 3.20mg / kg, approx. 3.40mg / kg, approx. 3.60mg / kg, approx. 3.80mg / kg, approx. 4.00mg / kg, approx. 4.20mg / kg , about 4.40mg / kg, about 4.60mg / kg, about 4.80mg / kg, about 5.00mg / kg, about 5.20mg / kg, about 5.40mg / kg, about 5.60mg / kg, about 5.80mg / kg, about 6.00 mg / kg, about 6.20 mg / kg, about 6.40 mg / kg, about 6.60 mg / kg, about 6.80 mg / kg, about 7.00 mg / kg, about 7.20 mg / kg, about 7.40 mg / kg, about 7.60 mg / kg, about 7.80 mg / kg, or about 8.00 mg / kg (including all values ​​and ranges therebetween) of Compound 1 or a pharma- ceutically acceptable salt thereof is administered to the patient.

[0046]

[0047] In an embodiment, the method of the present disclosure provides a therapeutically effective plasma concentration of Compound 1, as measured by the steady state plasma concentration of Compound 1 in a patient. In an embodiment, the therapeutically effective steady state plasma concentration of Compound 1 is from about 200 ng / mL to about 1500 ng / mL. In an embodiment, the therapeutically effective steady state plasma concentration of Compound 1 is from about 100 ng / mL to about 2500 ng / mL, e.g., about 100 ng / mL, about 110 ng / mL, about 120 ng / mL, about 130 ng / mL, about 140 ng / mL, about 150 ng / mL, about 160 ng / mL, about 170 ng / mL, about 280 ng / mL, about 190 ng / mL, about 200 ng / mL, about 210 ng / mL, about 220 ng / mL, about 230 ng / mL, about 240 ng / mL, about 250 ng / mL, about 260 ng / mL, about 280 ng / mL, about 290 ng / mL, about 300 ng / mL, about 310 ng / mL, about 320 ng / mL, about 330 ng / mL, about 340 ng / mL, about 350 ng / mL, about 360 ng / mL, about 370 ng / mL, about 380 ng / mL, about 390 ng / mL, about 400 ng / mL, about 410 ng / mL, about 420 ng / mL, about 430 ng / mL, about 440 ng / mL, about 450 ng / mL, about 460 ng / mL, about 470 ng / mL, about 480 ng / mL, about 490 ng / mL, 0ng / mL, approximately 270ng / mL, approximately 280ng / mL, approximately 290ng / mL, approximately 300ng / mL, approximately 310ng / mL, approximately 320ng / mL, approximately 330ng / mL, approximately 340ng / mL, approximately 350ng / mL, approximately 360ng / mL, approximately 3 70ng / mL, approximately 380ng / mL, approximately 390ng / mL, approximately 400ng / mL, approximately 410ng / mL, approximately 420ng / mL, approximately 430ng / mL, approximately 440ng / mL, approximately 450ng / mL, approximately 460ng / mL, approximately 470ng / mL, approximately 4 80ng / mL, approximately 490ng / mL, approximately 500ng / mL, approximately 510ng / mL, approximately 520ng / mL, approximately 530ng / mL, approximately 540ng / mL, approximately 550ng / mL, approximately 560ng / mL, approximately 570ng / mL, approximately 580ng / mL, approximately 590ng / mL, approximately 600ng / mL, approximately 610ng / mL, approximately 620ng / mL, approximately 630ng / mL, approximately 640ng / mL, approximately 650ng / mL, approximately 660ng / mL, approximately 670ng / mL, approximately 680ng / mL, approximately 690ng / mL, approximately 700ng / mL, approximately 710ng / mL, approximately 720ng / mL, approximately 730ng / mL, approximately 740ng / mL, approximately 750ng / mL, approximately 760ng / mL, approximately 770ng / mL, approximately 780ng / mL, approximately 790ng / mL, approximately 800ng / mL, Approximately 810ng / mL, approximately 820ng / mL, approximately 830ng / mL, approximately 840ng / mL, approximately 850ng / mL, approximately 860ng / mL, approximately 870ng / mL, approximately 880ng / mL, approximately 890ng / mL, approximately 900ng / mL, approximately 910ng / mL,Approximately 920ng / mL, approximately 930ng / mL, approximately 940ng / mL, approximately 950ng / mL, approximately 960ng / mL, approximately 970ng / mL, approximately 980ng / mL, approximately 990ng / mL, approximately 1000ng / mL, approximately 1050ng / mL, approximately 1100ng / m L, approximately 1150ng / mL, approximately 1200ng / mL, approximately 1250ng / mL, approximately 1300ng / mL, approximately 1350ng / mL, approximately 1400ng / mL, approximately 1450ng / mL, approximately 1500ng / mL, approximately 1550ng / mL, approximately 1600ng / mL , about 1650ng / mL, about 1700ng / mL, about 1750ng / mL, about 1800ng / mL, about 1850ng / mL, about 1900ng / mL, about 1950ng / mL, or about 2000ng / mL, about 2050ng / mL, about 2100ng / mL, about 2150ng / mL, about 2200ng / mL, about 2250ng / mL, about 2300ng / mL, about 2350ng / mL, about 2400ng / mL, about 2450ng / mL, or about 2500ng / mL (including all values ​​and ranges therebetween). In an embodiment, the therapeutically effective steady state plasma concentration of Compound 1 is about 500ng / mL to 1000ng / mL. In an embodiment, the therapeutically effective steady state plasma concentration of Compound 1 is about 600ng / mL.

[0047]

[0048] In an embodiment, the disclosed method includes measuring the mean maximum blood concentration (C maxIn embodiments, the disclosed methods provide a therapeutically effective plasma concentration of Compound 1, as measured by a 100 ng / mL to 2500 ng / mL, e.g., about 400 ng / mL, about 410 ng / mL, about 420 ng / mL, about 430 ng / mL, about 440 ng / mL, about 450 ng / mL, about 460 ng / mL, about 470 ng / mL, about 480 ng / mL, about 490 ng / mL, about 500 ng / mL, about 510 ng / mL, about 520 ng / mL, about 530 ng / mL, about 540 ng / mL, about 550 ng / mL, about 560 ng / mL, about 570 ng / mL, about 580 ng / mL, about 590 ng / mL, or about 600 ng / mL. L, about 600ng / mL, about 610ng / mL, about 620ng / mL, about 630ng / mL, about 640ng / mL, about 650ng / mL, about 660ng / mL, about 670ng / mL, about 680ng / mL, about 690ng / mL, about 700ng / mL, about 710ng / m L, about 720ng / mL, about 730ng / mL, about 740ng / mL, about 750ng / mL, about 760ng / mL, about 770ng / mL, about 780ng / mL, about 790ng / mL, about 800ng / mL, about 810ng / mL, about 820ng / mL, about 830ng / mL , about 840ng / mL, about 850ng / mL, about 860ng / mL, about 870ng / mL, about 880ng / mL, about 890ng / mL, about 900ng / mL, about 910ng / mL, about 920ng / mL, about 930ng / mL, about 940ng / mL, about 950ng / mL , about 960ng / mL, about 970ng / mL, about 980ng / mL, about 990ng / mL, about 1000ng / mL, about 1050ng / mL, about 1100ng / mL, about 1150ng / mL, about 1200ng / mL, about 1250ng / mL, about 1300ng / mL, about 13 50ng / mL, about 1400ng / mL, about 1450ng / mL, about 1500ng / mL, about 1550ng / mL, about 1600ng / mL, about 1650ng / mL, about 1700ng / mL, about 1750ng / mL, about 1800ng / mL, about 1850ng / mL, about 1900ng / mL, about 1950ng / mL, or about 2000ng / mL, about 2050ng / mL, about 2100ng / mL, about 2150ng / mL, about 2200ng / mL, about 2250ng / mL, about 2300ng / mL, about 2350ng / mL, about 2400ng / mL,Mean maximum plasma concentrations (C, max In an embodiment, the method of the present disclosure provides a C of about 2500 ng / mL of Compound 1. max In an embodiment, the method of the present disclosure provides a C of about 1000 ng / mL of Compound 1. max In an embodiment, the method of the present disclosure provides a C of Compound 1 of about 400 ng / mL. max to provide.

[0048]

[0049] In an embodiment, the methods of the present disclosure include determining the mean minimum plasma concentration (C minIn embodiments, the disclosed method provides a therapeutically effective plasma concentration of Compound 1, as measured by 200 ng / mL to about 1000 ng / mL, e.g., about 200 ng / mL, about 210 ng / mL, about 220 ng / mL, about 230 ng / mL, about 240 ng / mL, about 250 ng / mL, about 260 ng / mL, about 270 ng / mL, about 280 ng / mL, about 290 ng / mL, about 300 ng / mL, about 310 ng / mL, about 320 ng / mL, about 330 ng / mL, about 340 ng / mL, about 350 ng / mL, about 360 ng / mL, about 370 ng / mL, Approximately 380ng / mL, approximately 390ng / mL, approximately 400ng / mL, approximately 410ng / mL, approximately 420ng / mL, approximately 430ng / mL, approximately 440ng / mL, approximately 450ng / mL, approximately 460ng / mL, approximately 470ng / mL, approximately 480ng / mL, approximately 490ng / mL, approximately 500ng / mL, approximately 510ng / mL, approximately 520ng / mL, approximately 530ng / mL, approximately 540ng / mL, approximately 550ng / mL, approximately 560ng / mL, approximately 570ng / mL, approximately 580ng / mL, approximately 590ng / mL, approximately 6 00ng / mL, approximately 610ng / mL, approximately 620ng / mL, approximately 630ng / mL, approximately 640ng / mL, approximately 650ng / mL, approximately 660ng / mL, approximately 670ng / mL, approximately 680ng / mL, approximately 690ng / mL, approximately 700ng / mL, approximately 7 10ng / mL, approximately 720ng / mL, approximately 730ng / mL, approximately 740ng / mL, approximately 750ng / mL, approximately 760ng / mL, approximately 770ng / mL, approximately 780ng / mL, approximately 790ng / mL, approximately 800ng / mL, approximately 810ng / mL, approximately 82

[0036] Mean minimum plasma concentrations (C) of Compound 1 of about 0 ng / mL, about 830 ng / mL, about 840 ng / mL, about 850 ng / mL, about 860 ng / mL, about 870 ng / mL, about 880 ng / mL, about 890 ng / mL, about 900 ng / mL, about 910 ng / mL, about 920 ng / mL, about 930 ng / mL, about 940 ng / mL, about 950 ng / mL, about 960 ng / mL, about 970 ng / mL, about 980 ng / mL, about 990 ng / mL, or about 1000 ng / mL (including all values ​​and ranges therebetween). min ) is provided.

[0049]

[0050] In embodiments, the dose and administration schedule of fesoterodine is selected to reduce the peripheral side effects of administering Compound 1 to a patient being treated for a neuropathy. In embodiments, the dose and administration schedule of fesoterodine is selected to reduce the peripheral side effects of administering Compound 1 to a patient being treated for dyskinesia (e.g., LID).

[0050]

[0051] In an embodiment, about 1 mg to about 20 mg of fesoterodine or a pharma- ceutically acceptable salt thereof is administered to a patient. In an embodiment, about 1 mg to about 50 mg, for example, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg , about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, or about 50 mg of fesoterodine or a pharma- ceutically acceptable salt thereof (including all values ​​and ranges therebetween) is administered to the patient. In an embodiment, about 3 mg of fesoterodine or a pharma- ceutically acceptable salt thereof is administered. In an embodiment, about 4 mg of fesoterodine or a pharma- ceutically acceptable salt thereof is administered. In an embodiment, about 6 mg of fesoterodine or a pharma- ceutically acceptable salt thereof is administered. In an embodiment, about 8 mg of fesoterodine or a pharma- ceutically acceptable salt thereof is administered. In an embodiment, about 24 mg of fesoterodine or a pharma- ceutically acceptable salt thereof is administered.

[0051]

[0052] In an embodiment, about 0.01 mg / kg to about 0.602 mg / kg, for example, about 0.010 mg / kg, about 0.011 mg / kg, about 0.012 mg / kg, about 0.013 mg / kg, about 0.015 mg / kg, about 0.016 mg / kg, about 0.018 mg / kg, about 0.019 mg / kg, about 0.021 mg / kg, about 0.024 mg / kg, kg, about 0.026mg / kg, about 0.029mg / kg, about 0.031mg / kg, about 0.035mg / kg, about 0.038mg / kg, about 0.042mg / kg, about 0.046mg / kg, about 0.051mg / kg, about 0.056mg / kg, about 0.061mg / kg, about 0.067mg / kg, about 0.074mg / kg, about 0.081

[0043] In one embodiment, the patient is administered about 0.090 mg / kg, about 0.098 mg / kg, about 0.108 mg / kg, about 0.119 mg / kg, about 0.131 mg / kg, about 0.144 mg / kg, about 0.159 mg / kg, about 0.174 mg / kg, about 0.192 mg / kg, about 0.211 mg / kg, about 0.232 mg / kg, about 0.255 mg / kg, about 0.281 mg / kg, about 0.309 mg / kg, about 0.340 mg / kg, about 0.374 mg / kg, about 0.411 mg / kg, about 0.453 mg / kg, about 0.498 mg / kg, about 0.548 mg / kg, about 0.602 mg / kg (including all values ​​and ranges therebetween) of fesoterodine or a pharma- ceutically acceptable salt thereof.

[0052]

[0053] In an embodiment, Compound 1 or a pharma- ceutically acceptable salt thereof and Fesoterodine or a pharma- ceutically acceptable salt thereof are in a ratio of about 2:1 to 50:1, for example, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 11:1, about 12:1, about 13:1, about 14:1, about 15:1, about 16:1, about 17:1, about 18:1, about 19:1, about 20:1, about 21:1, about 22:1, about 23:1, about 24:1, The patient is administered a weight ratio of compound 1 to fesoterodine of about 25:1, about 26:1, about 27:1, about 28:1, about 29:1, about 30:1, about 31:1, about 32:1, about 33:1, about 34:1, about 35:1, about 36:1, about 37:1, about 38:1, about 39:1, about 40:1, about 41:1, about 42:1, about 43:1, about 44:1, about 45:1, about 46:1, about 47:1, about 48:1, about 49:1 to about 50:1, including all values ​​and ranges therein. In embodiments, compound 1 or a pharma- ceutically acceptable salt thereof, and fesoterodine or a pharma- ceutically acceptable salt thereof are administered to the patient in a weight ratio of compound 1 to fesoterodine of about 2:1 to 30:1. In an embodiment, Compound 1, or a pharma- ceutically acceptable salt thereof, and Fesoterodine, or a pharma- ceutically acceptable salt thereof, are administered to a patient in a ratio of Compound 1 to Fesoterodine of about 5:1 to 15:1.

[0053]

[0054] In an embodiment, fesoterodine is administered in a sustained release composition.

[0054]

[0055] In an embodiment, administration provides a therapeutically effective steady state plasma concentration of desfesoterodine (ie, an amount sufficient to reduce peripheral or CNS side effects associated with administration of Compound 1).

[0055]

[0056] In embodiments, the disclosed methods provide a therapeutically effective plasma concentration of desfesoterodine (i.e., a metabolite of fesoterodine) as measured by the patient's steady state plasma concentration of desfesoterodine. In embodiments, the disclosed methods provide a therapeutically effective steady state plasma concentration of desfesoterodine of about 50 ng / mL to about 20 ng / mL. In embodiments, the disclosed methods provide a therapeutically effective steady state plasma concentration of desfesoterodine of about 0.1 ng / mL to about 30 ng / mL.In an embodiment, the method of the present disclosure provides a method for determining a concentration of 1000 mg / mL to about 50 pg / mL, e.g., about 50 pg / mL, about 60 pg / mL, 70 pg / mL, about 80 pg / mL, about 90 pg / mL, about 0.1 ng / mL, about 0.2 ng / mL, about 0.3 ng / mL, about 0.4 ng / mL, about 0.5 ng / mL, about 0.6 ng / mL, about 0.7 ng / mL, about 0.8 ng / mL, about 0.9 ng / mL, about 1.0 ng / mL, about 1.5 ng / mL, about 2.0 ng / mL, about 2.5 ng / mL, about 3.0ng / mL, approximately 3.5ng / mL, approximately 4.0ng / mL, approximately 4.5ng / mL, approximately 5.0ng / mL, approximately 5.5ng / mL, approximately 6.0ng / mL, approximately 6.5ng / mL, approximately 7.0ng / mL, approximately 7.5ng / mL, approximately 8.0ng / mL, approximately 8.5ng / mL, approximately 9.0ng / mL, approximately 9.5ng / mL, approximately 10.0ng / mL, approximately 10.5ng / mL, approximately 11.0ng / mL, approximately 11.5ng / mL, approximately 12.0ng / mL, approximately 12.5ng / mL, approximately 13.0ng / mL, approximately 13.5ng / mL, approximately 14.0ng / mL, approximately 14.5ng / mL, approximately 15.0ng / mL, approximately 15.5ng / mL, approximately 16.0ng / mL, approximately 16.5ng / mL, approximately 17.0ng / mL, approximately 17.5ng / mL, approximately 18. 0ng / mL, approximately 18.5ng / mL, approximately 19.0ng / mL, approximately 19.5ng / mL, approximately 20.0ng / mL, approximately 20.5ng / mL, approximately 21.0ng / mL, approximately 21.5ng / mL, approximately 22.0ng / mL, approximately 22.5ng / mL, approximately In an embodiment, administration provides a therapeutically effective steady state plasma concentration of desfesoterodine of about 5 ng / mL to about 10 ng / mL, inclusive of all values ​​and ranges therebetween.

[0056]

[0057] In an embodiment, Compound 1 or a pharma- ceutically acceptable salt thereof is administered once a day. In an embodiment, Compound 1 or a pharma- ceutically acceptable salt thereof is administered twice a day. In an embodiment, Compound 1 or a pharma- ceutically acceptable salt thereof is administered three times a day.

[0057]

[0058] In an embodiment, fesoterodine or a pharma- ceutically acceptable salt thereof is administered once daily. In an embodiment, fesoterodine or a pharma- ceutically acceptable salt thereof is administered twice daily. In an embodiment, fesoterodine or a pharma- ceutically acceptable salt thereof is administered three times daily.

[0058]

[0059] In an embodiment, Compound 1 and Fesoterodine are administered orally.In an embodiment, Compound 1 is administered orally.In an embodiment, Fesoterodine is administered orally.

[0059]

[0060] In an embodiment, Compound 1 and Fesoterodine are administered intravenously. In an embodiment, Compound 1 is administered intravenously. In an embodiment, Fesoterodine is administered intravenously.

[0060]

[0061] In embodiments, the present patent provides for administering fesoterodine and compound 1 according to a dosing schedule that minimizes side effects associated with compound 1. In embodiments, the patient is administered compound 1 about 1 hour to about 10 hours after the patient is administered fesoterodine. In embodiments, the patient is administered compound 1 about 5 minutes to about 10 hours, e.g., about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, or about 10 hours (including all values ​​and ranges therebetween) after the patient is administered fesoterodine. In embodiments, the patient is administered compound 1 at least 1 hour after the patient is administered fesoterodine. In an embodiment, the patient is administered Compound 1 about 4 hours after the patient is administered fesoterodine.

[0061]

[0062] In embodiments, the methods of the disclosure provide a plasma concentration ratio of Compound 1 to desfesoterodine of about 10:1 to about 1000:1. In an embodiment, the method of the present disclosure provides a method for the production of a cyclooxygenase (CDS) mixture having a CDS ratio of about 1:1 to about 1000:1, e.g., about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 11:1, about 12:1, about 13:1, about 14:1, about 15:1, about 16:1, about 17:1, about 18:1, about 19:1, about 20:1, about 21:1, about 22:1, about 23:1, about 24:1, about 25:1, about 26:1, about 27:1, about 28:1, about 29:1, about 30:1, about 31:1, about 32:1, about 33:1, about 34:1, about 35:1, about 36:1, about 37:1, about 38:1, about 39:1, about 40:1, about 41:1, about 42:1, about 43:1, about 44:1, about 45:1, about 46:1, about 47:1, about 48:1, about 49:1, about 50:1, about 51:1, about 52:1, about 53:1, about 54:1, about 55:1, about 56:1, about 57:1, about 58:1, about 59:1, about 60:1, about 61:1, about 62:1, about 63:1, about 64:1, about 65:1, about 66:1, about 67:1, about 68:1, about 69:1, about 70:1, about 71:1, about 72:1, about 73:1, about 74:1, about 75:1, about 76:1, about 77:1, about 78:1, about 79:1, about 80:1, about 81:1, about 82:1, about 83:1, about 84:1, about 85:1, about 86:1, about 87:1, about 88:1, about 89:1, about 90:1, about 91:1, about 92:1, about 93:1, about 94:1, about 95:1, about 96:1, about 97:1, about 98:1, about 99:1, about 100:1, about 110:1, about 120:1, about 130:1, about 140:1, about 150:1, about 160:1, about 170:1, about 180:1, about 190:1, about 200:1, about 210:1, about 2 20:1, about 230:1, about 240:1, about 250:1, about 260:1, about 270:1, about 280:1, about 290:1, about 300:1, about 310:1, about 320:1, about 330:1, about 340:1, about 350:1, about 360:1, about 370:1, about 380:1, about 390:1, about 400:1, about 410:1, about 420:1, about 430:1, about 440:1, about 450:1, about 460:1, about 470:1, about 480:1, about 490:1, about 500:1, about 550:1, about 600:1, about 650:1, about 700:1, about 750:1,In some embodiments, administration provides a plasma concentration ratio of Compound 1 to desfesoterodine of about 800:1, about 850:1, about 900:1, about 950:1, about 1000:1 (including all values ​​and ranges therebetween). In some embodiments, administration provides a plasma concentration ratio of Compound 1 to desfesoterodine of about 100:1. In some embodiments, administration provides a plasma concentration ratio of Compound 1 to desfesoterodine of about 470:1.

[0062]

[0063] In an embodiment, Compound 1 and fesoterodine are administered in the same pharmaceutical composition. In an embodiment, Compound 1 and fesoterodine are administered as separate pharmaceutical compositions.

[0063]

[0064] In an embodiment, the fesoterodine or a pharma- ceutically acceptable salt thereof comprises fesoterodine fumarate.

[0064] Pharmaceutical preparations

[0065] The methods of the present disclosure can employ a variety of formulations for administration to a patient, e.g., a human, in unit dosage forms such as tablets, capsules, films, orally disintegrating tablets, pills, powders, granules, sterile parenteral solutions or suspensions (e.g., intramuscular (IM), subcutaneous (SC) and intravenous (IV)), transdermal patches, and oral solutions or suspensions, as well as oil-water emulsions.

[0065]

[0066] Oral pharmaceutical dosage forms can be either solid or liquid. Solid dosage forms can be tablets, capsules, granules, films (e.g. buccal films) and bulk powders. Types of oral tablets include compressed chewable lozenges and tablets, which can be enteric coated, sugar coated or film coated. Capsules can be hard or soft gelatin capsules, while granules and powders can be provided in non-effervescent or effervescent form and in combination with other ingredients known to those skilled in the art. In some embodiments, the oral dosage form can include an orally disintegrating tablet. In some embodiments, the oral dosage form is one or more oral sustained release tablets.

[0066]

[0067] In embodiments, pharmaceutical preparations may include one or more pharma- ceutically acceptable excipients or adjuvants. Pharmaceutically acceptable excipients and adjuvants are added to compositions or preparations for various purposes. In embodiments, pharmaceutical preparations may include pharma- ceutically acceptable carriers. In embodiments, pharma- ceutically acceptable carriers include pharma- ceutically acceptable excipients, binders, and / or diluents. In embodiments, suitable pharma- ceutically acceptable excipients include, but are not limited to, water, salt solution, alcohol, polyethylene glycol, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, and polyvinylpyrrolidone.

[0067]

[0068] In embodiments, the disclosure provides pharmaceutical compositions comprising Compound 1 and one or more pharma- ceutically acceptable carriers or excipients.

[0068]

[0069] In embodiments, the present disclosure provides a pharmaceutical composition comprising fesoterodine and one or more pharma- ceutically acceptable carriers or excipients.

[0069]

[0070] In embodiments, the disclosure provides a pharmaceutical composition comprising Compound 1, fesoterodine, and one or more pharma- ceutically acceptable carriers or excipients.

[0070] Numbered embodiments: 1. A method for treating dyskinesia in a patient in need thereof, comprising: (a) a therapeutically effective amount of Compound 1, or a pharma- ceutically acceptable salt thereof, and (b) a therapeutically effective amount of fesoterodine or a pharma- ceutically acceptable salt thereof. The method of claim 1, further comprising administering 2. The method of embodiment 1, wherein the dyskinesia is levodopa-induced dyskinesia. 3. The method of embodiment 1 or embodiment 2, wherein the patient is diagnosed with Parkinson's disease. 4. A method for treating Alzheimer's disease psychosis, Parkinson's disease psychosis, dementia-related psychosis, dementia with Lewy bodies, schizophrenia (acute and maintained), brief psychotic disorder, or acute delirium in a patient in need thereof, comprising: (a) a therapeutically effective amount of Compound 1, or a pharma- ceutically acceptable salt thereof, and (b) a therapeutically effective amount of fesoterodine or a pharma- ceutically acceptable salt thereof. The method of claim 1, further comprising administering 5. The method of embodiment 4, wherein the patient is being treated for schizophrenia. 6. The method of embodiment 4 or embodiment 5, wherein the patient is being treated for Alzheimer's disease psychosis, Parkinson's disease psychosis, dementia-related psychosis, or dementia with Lewy bodies. 7. The method of any one of embodiments 1-6, wherein about 5 mg to about 800 mg of compound 1 or a pharma- ceutically acceptable salt thereof is administered to the patient. 7a. The method of any one of embodiments 1-6, wherein about 5 mg to about 300 mg of Compound 1 or a pharma- ceutically acceptable salt thereof is administered to the patient. 8. The method of embodiment 7, wherein about 20 mg to about 80 mg of compound 1 or a pharma- ceutically acceptable salt thereof is administered to the patient. 9. The method of embodiment 7, wherein about 60 mg of compound 1 or a pharma- ceutically acceptable salt thereof is administered to the patient. 10. The method of any one of embodiments 1-9, wherein administration provides a therapeutically effective steady-state plasma concentration of Compound 1. 11. The method of embodiment 10, wherein the therapeutically effective steady-state plasma concentration of compound 1 is from about 100 ng / mL to about 2500 ng / mL. 11a. The method of embodiment 10, wherein the therapeutically effective steady-state plasma concentration of compound 1 is from about 500 ng / mL to about 1000 ng / mL. 12. The method of embodiment 10, wherein the therapeutically effective steady-state plasma concentration of compound 1 is about 600 ng / mL. 13. The method of any one of embodiments 1-12, wherein about 1 mg to about 50 mg of fesoterodine or a pharma- ceutically acceptable salt thereof is administered to the patient. 13a. The method of any one of embodiments 1-12, wherein about 1 mg to about 20 mg of fesoterodine or a pharma- ceutically acceptable salt thereof is administered to the patient. 13b. The method of any one of embodiments 1-12, wherein about 4 mg of fesoterodine or a pharma- ceutically acceptable salt thereof is administered to the patient. 14. The method of embodiment 13, wherein about 8 mg of fesoterodine or a pharma- ceutically acceptable salt thereof is administered. 15. The method of embodiment 13, wherein about 24 mg of fesoterodine or a pharma- ceutically acceptable salt thereof is administered. 16. The method of any one of embodiments 1-15, wherein administration provides a therapeutically effective steady-state plasma concentration of desfesoterodine (i.e., an amount sufficient to reduce peripheral side effects associated with administration of Compound 1). 17. The method of embodiment 16, wherein the therapeutically effective steady-state plasma concentration is from about 5 ng / mL to about 30 ng / mL. 17a. The method of embodiment 16, wherein the therapeutically effective steady state plasma concentration is from about 5 ng / mL to about 10 ng / mL. 18. The method of any one of embodiments 1-17, wherein compound 1, or a pharma- ceutically acceptable salt thereof, is administered once a day. 19. The method of any one of embodiments 1-17, wherein compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily. 20. The method of any one of embodiments 1-17, wherein compound 1, or a pharma- ceutically acceptable salt thereof, is administered three times daily. 21. The method of any one of embodiments 1-20, wherein fesoterodine or a pharma- ceutically acceptable salt thereof is administered once a day. 22. The method of any one of embodiments 1-20, wherein fesoterodine or a pharma- ceutically acceptable salt thereof is administered twice daily. 23. The method of any one of embodiments 1-20, wherein fesoterodine or a pharma- ceutically acceptable salt thereof is administered three times a day. 24. The method of any one of embodiments 1-23, wherein compound 1 and fesoterodine are administered in separate pharmaceutical compositions. 25. The method of any one of embodiments 1-24, wherein compound 1 and fesoterodine are administered orally. 26. The method of any one of embodiments 1-25, wherein fesoterodine or a pharma- ceutically acceptable salt thereof is administered in a sustained release composition. 27. The method of any one of embodiments 1-26, wherein the patient is administered compound 1 at least 1 hour after the patient is administered fesoterodine. 28. The method of embodiment 27, wherein the patient is administered compound 1 about 4 hours after the patient is administered fesoterodine. 29. The method of any one of embodiments 1-28, wherein administration provides a plasma concentration ratio of compound 1 to desfesoterodine of about 10:1 to about 1000:1. 30. The method of any one of embodiments 1-28, wherein administration provides a plasma concentration ratio of compound 1 to desfesoterodine of about 100:1. 31. The method of any one of embodiments 1-26 or 29-30, wherein compound 1 and fesoterodine are administered in the same pharmaceutical composition. 32. Compound 1 has the formula: [ka] The method of any one of the preceding embodiments, comprising the hydrochloride salt of 33. The method of any one of embodiments 1-32, wherein the fesoterodine or a pharma- ceutically acceptable salt thereof comprises fesoterodine fumarate. 34. The method of any one of embodiments 1-33, wherein the dose and administration schedule of fesoterodine is selected to reduce peripheral side effects of administering Compound 1 to the patient. EXAMPLES

[0071]

[0071] The present invention will be further described by referring to the following examples. However, it should be noted that these examples are illustrative and should not be construed as limiting the scope of the present invention in any way.

[0072] Example 1: Effect of Compound 1 on amphetamine-induced hyperlocomotion

[0072] The hyperdopaminergic state underlying LID was modeled in naive male wild-type c57 / Bl6 mice by administration of d-amphetamine, a drug that rapidly increases synaptic dopamine levels.

[0073] A single dose of 3 mg / kg intraperitoneal (IP) d-amphetamine was administered to 32 male wild-type c57 / Bl6 mice approximately 8 weeks of age. The animals were then divided into three groups and co-administered with a single IP dose of either vehicle alone, 0.3 mg / kg Compound 1, or 1 mg / kg Compound 1. The locomotor behavior of the animals in an open field chamber (dimensions 44 cm x 44 cm x 20 cm) was monitored using a video tracking system (Noldus EthoVision v15). Over a 30-minute period, the identified average (mean) centimeters traveled (± standard deviation) were: 7500 cm (± 314.9) in the vehicle cohort Compound 1 0.3 mg / kg cohort: 5141 cm (±805.6) (p<0.5 one-way ANOVA followed by Tukey's multiple comparisons) Compound 1 1.0 mg / kg cohort: 2008 cm (±406.2) (p<0.001) It was.

[0074]

[0074] This study demonstrated that Compound 1 dose-dependently reversed hyperdopaminergic motor behavior. These data suggest that Compound 1 may have utility in treating psychiatric disorders such as schizophrenia, Alzheimer's disease and Parkinson's disease, as well as levodopa-induced dyskinesia.

[0075] Example 2: Dose-response effect of Compound 1 and Fesoterodine on saliva secretion

[0075] An in vivo primary pharmacological study was carried out to evaluate the dose-response antagonism of fesoterodine fumarate against compound 1-induced salivation in anesthetized male Sprague Dawley rats. Salivation was induced by intravenous administration of compound 1 at 1 mg / kg. Intravenous fesoterodine doses were administered at 0.0078 mg / mL, 0.0156 mg / mL, 0.0312 mg / mL, 0.0625 mg / mL, 0.125 mg / mL, 0.25 mg / mL, and 0.5 mg / mL. Fesoterodine was administered 10 minutes prior to administration of compound 1. All animals were normal and showed no clinical signs or behavioral abnormalities. Salivation was measured using oral dry swabs in anesthetized rats, and the calculated difference between the dry and wet swab weights represented the weight of saliva produced. Samples were collected at 10-minute intervals for 1 hour after administration.

[0076] Compound 1 showed a significant effect in increasing saliva secretion compared to the 0.9% saline vehicle control. Fesoterodine effects with Compound 1 showed a significant decrease in saliva secretion in a consistent dose-response manner, as summarized in Table 1.

[0077] [Table 1]

[0078] At the end of the study period, plasma samples were collected to measure exposure to Compound 1, fesoterodine fumarate, and the active metabolite of fesoterodine, 5-hydroxymethyltolterodine (5-HMT), also called desfesoterodine, as summarized in Table 2.

[0079] [Table 2]

[0080] Based on the salivation and exposure data, a plasma concentration ratio of Compound 1:5-HMT of 100:1 attenuates the peripheral cholinergic activity of Compound 1-induced salivation.

[0081] Example 3: Pharmacokinetics and Drug Metabolism in Rats

[0079] An in vitro study was conducted to evaluate the pharmacokinetics of the combination of Compound 1 and fesoterodine.

[0082] Plasma concentration-time profiles were evaluated for the fesoterodine active metabolites desfesoterodine and Compound 1 in male Sprague Dawley rats following single intravenous doses of fesoterodine (0.25 mg / kg) and Compound 1 (0.5 mg / kg and 1.5 mg / kg) alone and single co-administration. Plasma exposure of desfesoterodine was similar following administration of fesoterodine alone and in combination with Compound 1. PK parameters of Compound 1 were comparable following administration of the 1.5 mg / kg dose alone and co-administration with fesoterodine (Table 3).

[0083]

[0081] The amount of the active metabolite desfesoterodine in Group 1 (fesoterodine 0.25 mg / kg) was quantifiable from 0.033 hours to 6 hours.

[0084]

[0082] The pharmacokinetics of compound 1 in group 2 (compound 1 1.5 mg / kg) showed a moderate plasma clearance of approximately 50% of normal hepatic blood flow in rats (55 mL / min / kg), a moderate Vss of approximately 2.4 times total body water (0.7 L / kg), and a terminal plasma elimination half-life of 0.83 hours.

[0085] Group 3 (compound 1 0.5 mg / kg coadministered with fesoterodine 0.25 mg / kg) active metabolite desfesoterodine concentrations were quantifiable from 0.033 hours to 6 hours. Compound 1 showed moderate plasma clearance of approximately 40% of normal hepatic blood flow (55 mL / min / kg) in rats, moderate Vss of approximately 3 times total body water (0.7 L / kg), and terminal plasma elimination half-life of 2.18 hours.

[0086] Group 4 (compound 1 1.5 mg / kg coadministered with fesoterodine 0.25 mg / kg) active metabolite desfesoterodine concentrations were quantifiable from 0.033 hours to 6 hours. Compound 1 showed moderate plasma clearance of approximately 42% of normal hepatic blood flow (55 mL / min / kg) in rats, moderate Vss of approximately 2.7 times total body water (0.7 L / kg), and terminal plasma elimination half-life of 1.24 hours.

[0087] [Table 3]

[0088] Example 4: Effect of Compound 1 on MPTP-induced dyskinesia

[0085] When discovered as a contaminant in heroin, the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was identified as a compound that selectively induces degeneration of dopaminergic neurons in the substantia nigra, causing users to develop clinical symptoms indistinguishable from PD. It is currently used to model the major parkinsonian motor phenotypes in non-human primates and subsequently the response to treatments such as L-dopa, including dyskinesias, and can therefore be used as a foundational model for LID. See Huat 2012. (Huot P, Johnston TH, Koprich JB, Fox SH, Brotchie JM. L-DOPA pharmacokinetics in the MPTP-lesioned macaque model of Parkinson's disease. Neuropharmacology. 2012 Oct; 63(5): 829-36.) The MPTP non-human primate model, which has both face validity and construct validity, is considered the animal model of PD motor symptoms with the greatest translational relevance.

[0089]

[0086] A study was conducted in seven female MPTP-lesioned cynomolgus monkeys, which received chronic repeated treatment with L-dopa and, in response, developed stable and reproducible dyskinesias that were choreic and dystonic in nature. Cynomolgus monkey behavior was evaluated after dose escalation for LID symptoms in each test animal with a single 1 mg / kg dose of Compound 1 or vehicle in combination with a high dose of L-dopa delivered as Madopar. "On-time" treatment effects and abnormal LID movements were evaluated 6 hours after administration of L-dopa. A single 1 mg / kg oral dose of Compound 1 or vehicle was administered simultaneously with L-dopa at the beginning of behavioral observations. All animals received all treatments in a crossover design with a minimum of 72 hours between repeated treatments in each animal. Treatment and LID behavior were scored by trained raters supervised by a neurologist in a blinded fashion using high-resolution video recordings and the Non-Human Primate Dyskinesia Rating Scale. See Fox 2012. (Fox SH, Johnston TH, Li Q, Brotchie J, Bezard E. A critique of available scales and presentation of the Non-Human Primate Dyskinesia Rating Scale. Mov Disord. 2012 Sep 15; 27(11): 1373-8.)

[0090] Compound 1 (1 mg / kg, PO) provided a significant antidyskinesia effect, reducing the median level of dyskinesia between 0 and 1 hour by 91% (median level 11 cf.1; vehicle cf. Compound 1, P<0.001). A strong reduction in LID was evident in 6 of 7 animals included in the final analysis. The median level of dyskinesia accumulated over the 0-2 hour period was reduced by 42%, resulting in levels that were non-impairing (median level 33 cf.19; vehicle cf. Compound 1, P=0.0156). This large reduction in peak effect dyskinesia was further evident as a beneficial reduction in the duration of "bad" on-times (on-times associated with impaired dyskinesias) (41% reduction) and a significant increase in the duration of "good" on-times (on-times associated with absent or only non-impairing dyskinesias) (143% increase). Compound 1 did not reduce the antiparkinsonian effects of L-dopa or the overall duration of on-time associated with L-dopa.

[0091]

[0088] These results from the MPTP-induced dyskinetic cynomolgus monkey study provide strong evidence of the therapeutic potential of Compound 1 for LID in PD patients.

[0092] Example 5: Pharmacokinetics of Compound 1 after oral administration to cynomolgus monkeys The following example characterized the pharmacokinetics (PK) of Compound 1 in cynomolgus monkeys after a single oral (PO) Compound 1 dose. Compound formulated as a solution in saline was administered by oral gavage at 0.3 mg / kg and 1 mg / kg. After administration, plasma was collected to characterize the PK profile of Compound 1. No adverse effects were observed during the study. The results are summarized in Table 4.

[0093] [Table 4]

[0094] Example 6: Clinical Observations and Pharmacokinetics of Compound 1 and Fesoterodine Compound 1 and fesoterodine fumarate were orally administered alone and in combination to male beagle dogs for clinical observations and plasma concentrations of Compound 1 and desoterodine. The study was conducted over a 7-day period and levels of Compound 1 and desfesoterodine (the active fesoterodine metabolite) were measured over a 24-hour period on days 1 and 7. Group 1: Compound 1 (1.5 mg / kg / day PO) Group 2: fesoterodine fumarate (3 mg / kg / day PO) Group 3: Compound 1 (1.5 mg / kg / day PO) and fesoterodine fumarate (3 mg / kg / day PO)

[0095]

[0091] As shown in Table 9, animals in groups 1, 2 and 3 were observed after administration. Group 1, treated with compound 1 alone, showed peripheral side effects. However, when treated with both compound 1 and fesoterodine (group 3), no peripheral side effects were observed. Group 3 showed only miosis. These data indicate that administration of fesoterodine fumarate substantially reduced the peripheral effects observed in subjects who received compound 1 alone (group 1) (group 3).

[0096] [Table 5]

[0097] [Table 6]

[0098] [Table 7]

[0099] [Table 8]

[0100] [Table 9]

[0101] [Table 10]

[0102] [Table 11]

[0103] [Table 12]

[0104] [Table 13]

[0105] Example 7: Oral administration of Compound 1 (single ascending doses) with or without administration of fesoterodine fumarate in healthy subjects.

[0092] Compound 1 was administered in a single ascending dose (SAD) study conducted in approximately 54 healthy adult volunteers to investigate the pharmacokinetics, safety, and tolerability of Compound 1. The study was conducted in two groups.

[0106] Group 1 evaluated multiple dose cohorts in which Compound 1 was administered in a single ascending dose (SAD) fashion to establish the maximum tolerated dose (MTD), using the doses listed in Table 10.

[0107] [Table 14]

[0108]

[0094] The MTD was established at the dose that produced mild to moderate cholinergic adverse effects. Cholinergic effects, including pupillometry and salivation, were monitored for each dose.

[0109] Group 2 evaluated the tolerability of Compound 1 at the MTD of Group 1 with or without fesoterodine fumarate coadministration. Subjects received 8 mg fesoterodine fumarate tablets or matching placebo tablets 4 hours prior to administration of 40 mg Compound 1.

[0110] Results: Safety - In Group 1, 22 of 36 subjects (61.6%) who received any dose of Compound 1 observed a total of 95 treatment-emergent adverse events (TEAEs). Approximately 50.0%, 33.3%, 50.0%, 50.0%, 50.0%, 83.3%, and 100% of subjects in the 0 mg (placebo), 1 mg, 3 mg, 10 mg, 20 mg, 40 mg, and 60 mg treatment groups, respectively, reported TEAEs. No deaths or serious TEAEs were reported, and no subjects discontinued the study due to TEAEs. In Group 2, 100.0% of subjects who received Compound 1 + placebo reported a total of 9 TEAEs, and 83.3% of the 6 subjects who received Compound 1 + fesoterodine fumarate reported 20 TEAEs. No deaths, serious, or severe TEAEs were reported. No subjects discontinued due to TEAEs. The most common TEAEs in the placebo group were hypersalivation and dizziness. Dizziness and fainting dizziness were observed in the fesoterodine group.

[0111] Similar to those observed in actively treated subjects in the Group 1 cohort, all TEAEs were experienced on Day 1 (i.e., the day of dosing) in the Compound 1 + placebo treatment group in Group 2. Conversely, in the Compound 1 + fesoterodine fumarate treatment group, TEAEs in subjects developed at least one day after dosing (Days 2-5). The delayed onset of these TEAEs in this treatment group is due to administration of a sustained release formulation of fesoterodine fumarate prior to Compound 1 (i.e., consistent with muscarinic blockade).

[0112] Pharmacodynamics - In Group 1, increased salivation was observed with increasing doses of Compound 1, as shown in Figure 1. In Group 2, the increase in salivation observed following administration of Compound 1 was not observed in subjects pretreated with fesoterodine fumarate compared to placebo pretreated subjects (Figure 2), indicating successful blockade by fesoterodine of the peripheral muscarinic effects of Compound 1.

[0113] Pharmacokinetics - In Group 1, the concentration of Compound 1 in the CSF at 1 hour after dosing increased with increasing doses, being 19.15 ng / mL (Cohort 3-10 mg, N=1), 32.27 ng / mL mean (Cohort 4-20 mg, N=2), 50.30 ng / mL mean (Cohort 5-40 mg, N=2), and 59.15 ng / mL (Cohort 6-60 mg, N=1). In Group 2, the mean concentration of Compound 1 in the CSF at 1 hour after dosing was 43.29 ng / mL and 56.96 ng / mL when administered after fesoterodine fumarate. The mean desfesoterodine concentration in the CSF at 1 hour after Compound 1 dosing was 121.44 pg / mL, with a mean CSF ratio of Compound 1 to desfesoterodine of 469:1.

[0114] Conclusion: Compound 1 administration after single oral doses ranging from 1 mg to 40 mg was generally safe and well tolerated in healthy subjects, with 40 mg established as the MTD for Compound 1 when administered alone. Objective increases in salivation were observed with increasing doses of Compound 1. Overall, in group 2, pretreatment with sustained-release fesoterodine resulted in a delay in the onset of TEAEs after administration of Compound 1. Furthermore, pretreatment with fesoterodine nearly abolished both the subjective reports of hypersalivation and the objective increase in saliva volume observed with Compound 1, consistent with fesoterodine blocking the peripheral muscarinic effects of Compound 1. In this study, absorption of Compound 1 was generally rapid, with median tmax observed between 0.65 and 1.17 hours. Following co-administration of fesoterodine fumarate, compound 1 exposure was 30.0%, 29.0%, and 50.0% higher for AUC0-t, AUC0-inf, and Cmax, respectively, however only the increase in Cmax was considered statistically significant (p-value: 0.0347).

[0115] Incorporation by Reference

[0101] All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated by reference in their entirety for all purposes. However, the mention of any references, articles, publications, patents, patent publications, and patent applications cited herein is not, and should not be construed as, an admission or any form of suggestion that they constitute valid prior art or form part of the common general knowledge in any country in the world.

Claims

Claim 1 A method for treating schizophrenia or Alzheimer's psychosis in a patient in need thereof, comprising: (a) a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, and (b) a therapeutically effective amount of fesoterodine or a pharmaceutically acceptable salt thereof administered to the patient. Claim 2 The method according to claim 1, wherein the patient is undergoing treatment for schizophrenia. Claim 3 The method according to claim 1, wherein the patient is undergoing treatment for Alzheimer's psychosis. Claim 4 The method according to any one of claims 1 to 3, wherein about 5 mg to about 800 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient. Claim 5 The method according to claim 4, wherein about 20 mg to about 80 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient. Claim 6 The method according to claim 4, wherein about 60 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient. Claim 7 The method according to any one of claims 1 to 6, wherein the administration provides a therapeutically effective steady-state plasma concentration of Compound 1. Claim 8 The method according to claim 7, wherein the therapeutically effective steady-state plasma concentration of Compound 1 is about 100 ng / mL to about 2500 ng / mL. Claim 9 The method according to claim 7, wherein the therapeutically effective steady-state plasma concentration of Compound 1 is about 600 ng / mL. Claim 10 The method according to any one of claims 1 to 9, wherein about 1 mg to about 50 mg of fesoterodine or a pharmaceutically acceptable salt thereof is administered to the patient. Claim 11 The method according to claim 10, wherein about 8 mg of fesoterodine or a pharmaceutically acceptable salt thereof is administered. Claim 12 The method according to claim 10, wherein about 24 mg of fesoterodine or a pharmaceutically acceptable salt thereof is administered. Claim 13 The method according to any one of claims 1 to 12, wherein the administration provides a therapeutically effective steady-state plasma concentration of desfesoterodine (i.e., an amount sufficient to reduce peripheral side effects associated with the administration of Compound 1). Claim 14 The method according to claim 13, wherein the therapeutically effective steady-state plasma concentration of desfesoterodine is about 5 ng / mL to about 30 ng / mL. Claim 15 The method according to any one of claims 1 to 14, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered once daily. Claim 16 The method according to any one of claims 1 to 14, wherein the compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day.

17. The method according to any one of claims 1 to 14, wherein the compound 1 or a pharmaceutically acceptable salt thereof is administered three times a day.

18. The method according to any one of claims 1 to 17, wherein the fesoterodine or a pharmaceutically acceptable salt thereof is administered once a day.

19. The method according to any one of claims 1 to 17, wherein the fesoterodine or a pharmaceutically acceptable salt thereof is administered twice a day.

20. The method according to any one of claims 1 to 17, wherein the fesoterodine or a pharmaceutically acceptable salt thereof is administered three times a day.

21. The method according to any one of claims 1 to 20, wherein the compound 1 and fesoterodine are administered in separate pharmaceutical compositions.

22. The method according to any one of claims 1 to 21, wherein the compound 1 and fesoterodine are administered orally.

23. The method according to any one of claims 1 to 22, wherein the fesoterodine or a pharmaceutically acceptable salt thereof is administered in a sustained release composition.

24. The method according to any one of claims 1 to 23, wherein the patient is administered the compound 1 at least 1 hour after the patient is administered the fesoterodine.

25. The method according to claim 24, wherein the patient is administered the compound 1 approximately 4 hours after the patient is administered the fesoterodine.

26. The method according to any one of claims 1 to 25, wherein the administration provides a plasma concentration ratio of compound 1 to desfesoterodine of about 10:1 to about 1000:

1.

27. The method according to any one of claims 1 to 25, wherein the administration provides a plasma concentration ratio of compound 1 to desfesoterodine of about 100:

1.

28. The method according to any one of claims 1 to 23 or 26 to 27, wherein the compound 1 and fesoterodine are administered in the same pharmaceutical composition.

29. The compound 1 is of the formula: 【Chemical 1】 The method according to any one of claims 1 to 28, comprising a hydrochloride salt thereof.

30. The method according to any one of claims 1 to 29, wherein the fesoterodine or a pharmaceutically acceptable salt thereof comprises fesoterodine fumarate.

31. The method according to any one of claims 1 to 30, wherein the dosage and administration schedule of fesoterodine are selected to reduce the peripheral side effects of administering compound 1 to the patient.

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