US20220016092A1 - Methods for treating symptoms and disorders associated with lysosomal storage diseases - Google Patents

Methods for treating symptoms and disorders associated with lysosomal storage diseases Download PDF

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US20220016092A1
US20220016092A1 US17/428,505 US202017428505A US2022016092A1 US 20220016092 A1 US20220016092 A1 US 20220016092A1 US 202017428505 A US202017428505 A US 202017428505A US 2022016092 A1 US2022016092 A1 US 2022016092A1
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quinuclidin
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Nigel Patrick Somerville CRAWFORD
Tanya Zaremba FISCHER
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Genzyme Corp
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
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    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
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    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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    • C12Y302/00—Hydrolases acting on glycosyl compounds, i.e. glycosylases (3.2)
    • C12Y302/01—Glycosidases, i.e. enzymes hydrolysing O- and S-glycosyl compounds (3.2.1)
    • C12Y302/01045—Glucosylceramidase (3.2.1.45), i.e. beta-glucocerebrosidase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • This invention relates to methods for treating or preventing particular symptoms and disorders which are associated with lysosomal storage diseases using quinuclidine compounds of formula (I), optionally in combination with enzyme replacement therapy.
  • This includes supranuclear gaze palsies, including horizontal and vertical saccadic gaze palsies, and cognitive deficits or gait disorders, such as in a patient having Gaucher disease or Niemann-Pick disease Type C.
  • Lysosomal storage diseases are a group of about 50 rare inherited metabolic diseases caused by defects in lysosomal function.
  • patients with an LSD accumulate harmful levels of a substrate (i.e., material stored) in lysosomes due to a deficiency or defect in an enzyme responsible for metabolizing the substrate, or due to a deficiency in an enzymatic activator required for proper enzymatic function.
  • Most LSDs are caused by a single enzymatic defect or deficiency, usually for an enzyme involved in the metabolism of lipids or glycoproteins.
  • Some of the more common LSDs include Gaucher disease, Fabry disease and Niemann-Pick disease (type C).
  • Gaucher, Fabry and Niemann-Pick are examples of sphingolipidoses. Each of these diseases are associated with a constellation of symptoms which are directly or indirectly caused by the underlying genetic defects. As a result, it is often difficult to predict which symptoms or disorders associated with these can be effectively treated with different treatment methods. Symptoms which are common across several LSDs include alterations in saccadic eye movements, cognitive dysfunction, and gait disorders, such as ataxia. These symptoms are particularly common in Gaucher disease (e.g., type 3) and in Neiman-Pick disease (type C).
  • saccades Several functional classes of eye movements exist, including saccades, smooth pursuit, optokinetic nystagmus (OKN), vestibular reflexes, and vergence, each controlled by distinct cortical, brainstem and cerebellar supranuclear networks. Failure of brainstem supranuclear saccade centers results in supranuclear gaze palsy, also called saccadic gaze palsy. “Supranuclear” refers to the location of the defect being superior to the relevant cranial nerve nuclei in the midbrain of the brainstem (oculomoter nerve, trochlear nerve) or the pons of the brainstem (abducens nerve). The oculomoter, trochlear and abducens nerves are the only cranial nerves controlling the small muscles which move the eye, and lesions to the nerves themselves do not result in conjugate gaze palsies.
  • Oculomoter nerve trochlear nerve
  • abducens nerves are the only
  • Saccades are quick, simultaneous movements of both eyes between two or more phases of fixation in the same direction. Saccades are in contrast to smooth pursuit movements, in which the eyes move smoothly without jumps, usually while tracking objects in the visual field. Saccades serve as a mechanism for visual fixation, rapid eye movement, and the fast phase of optokinetic nystagmus. Saccades are controlled cortically by the frontal eye fields region of the frontal cortex, or subcortically by the superior colliculus (a region of the midbrain). Saccades are particularly important during reading and when scanning the immediate surroundings. Because the high-resolution region of the retina, the fovea, is very small (about 1-2 degrees of vision wide), saccadic eye movement is critical in resolving small objects in the field of view. Skilled readers move their eyes during reading on the average of every 250 milliseconds, and during each saccade, lasting 20-40 milliseconds, the gaze target moves across 7-9 characters on average (range 1-20 characters).
  • the peak angular speed of the eye during a saccade can reach up to 900 degrees per second in humans. Saccades in response to an unexpected stimulus normally take only about 200 milliseconds to initiate, and they last from about 20 milliseconds to 200 milliseconds depending upon amplitude.
  • the amplitude of a saccade is the angular distance the eye travels during the eye movement.
  • Head-fixed saccades can have amplitudes up to 90 degrees, but under most condition, any shift of gaze larger than 20 degrees is accompanied by head movement. During these gaze saccades, the eye first undergoes saccade to shift the gaze to the target, and the head follows more slowly while the eyes maintain focus on the target.
  • VOR vestibulo-ocular reflex
  • Saccadic gaze palsy may result in the slowing of saccades either horizontally, vertically, or both, and may be either with or without range limitations. Whether horizontal or vertical saccadic palsy exists depends on the exact region of the brain involved in pathology.
  • Gaucher disease is a rare, autosomal recessive, lysosomal storage disease.
  • GD patients have a mutation in the GBA1 gene which encodes glucosylceramidase (GC), also known as beta-glucocerebrosidase.
  • GC glucosylceramidase
  • This enzyme is responsible for breaking down glycosphingolipids into their components, such as breaking down glucosylceramide (GLC; also known as glucocerebroside) into glucose and ceramide.
  • GLC glucosylceramide
  • Monocytes and macrophages have a particularly high content of lysosomes containing GLC, and in GD patients these cells become enlarged and accumulate toxic concentrations of GLC.
  • Gaucher cells accumulate in several organs, including the bone, bone marrow, spleen, liver, lung and brain. Systemically, this results in splenomegaly, hepatomegaly, anemia, thrombocytopenia, leukopenia, osteopenia, osteonecrosis, and other pathologic abnormalities.
  • Type 1 Gaucher disease non-neuronopathic GD
  • GD-1 non-neuronopathic GD
  • the GC enzyme retains some functionality, and there is no neurological involvement.
  • Type-2 GD is acute neuronopathic GD, with diagnosis during infancy, severe neurological involvement and death usually within the first two years of life. The GC enzyme in a Type-2 patient is more severely compromised in function compared to in GD-1.
  • Type-3 GD is chronic neuronopathic GD, with diagnosis during childhood, gradually worsening neurological involvement, and life expectancy usually not more than 30 years.
  • Symptoms of GD-3 include spleen and liver abnormalities, fatigue, bleeding, seizures and supranuclear gaze palsy.
  • the neurological manifestations in GD-3 patients gradually develops over the course of the disease.
  • One of the more debilitating features is gaze palsy, which is a defect in the neuronal pathways controlling saccadic eye movement.
  • gaze palsy is a defect in the neuronal pathways controlling saccadic eye movement.
  • the disease progresses to complete horizontal saccadic palsy along with varying degrees of vertical saccadic palsy.
  • the VOR may also be impaired in GD-3 patients.
  • GD-1 and GD-3 are limited to recombinant enzyme replacement therapy (ERT) using imiglucerase, velaglucerase, or taliglucerase, and substrate reduction therapy (SRT) using miglustat or eliglustat.
  • ERT enzyme replacement therapy
  • SRT substrate reduction therapy
  • Imiglucerase the leading treatment regimen, is a recombinant version of human GC, made in Chinese hamster ovary cells and administered by slow intravenous injection (typically over 1-2 hours) every 1-2 weeks. It has been available since 1998 in the U.S.
  • Velaglucerase is another recombinant human GC analog, this one made in a fibrosarcoma cell line, and it was FDA-approved in 2010. Taliglucerase is similar, made using genetically modified carrot plant root cells, and has been approved since 2012. These treatments all require IV administration in a hospital or other medical setting and the recombinant enzymes do not cross the blood-brain barrier, and therefore, are not capable of treating the neurological symptoms of GD. Thus, while these ERT regimes have proven effective in treating GD-1 patients, in GD-3 patients they are only effective in treating the non-neurological symptoms of the disease.
  • Substrate-reduction therapy is an alternative approach to treating GD.
  • the goal of this therapy is to reduce the accumulation of GLC by inhibiting the enzyme which is responsible for synthesizing GLC.
  • Glucosylceramide synthase also known as UDP-glucose ceramide synthase, is the enzyme which catalyzes the initial glycosylation step of ceramide to form glucosylceramide.
  • GCS inhibitors have been proposed for the treatment of a variety of diseases, including glycolipid storage diseases and lysosomal storage diseases, including Gaucher disease. See for example, WO 2005/068426 (Actelion Pharm. Ltd.).
  • Miglustat Zavesca
  • Miglustat is an iminoglucose GCS inhibitor. It is an N-alkylated iminosugar and acts as a reversible competitive inhibitor of GCS, binding in the enzyme's active site. While it was developed to treat the neuronopathic forms of GD, GD-2 and GD-3, the FDA has only approved it for the treatment of patients with mild to moderate GD-1, and only as a second-line therapy (patients must be unable to receive ERT treatment).
  • Eliglustat is also a GCS inhibitor, and it is an analogue of the ceremide. It has only been FDA-approved for treatment of the systemic symptoms in GD-1 patients.
  • NPC Niemann-Pick Disease Type C
  • NPC1 is a membrane protein which mediates intracellular trafficking of cholesterol to post-lysosomal destinations. Specifically, NPC1 acts in concert with NPC2 to promote the egress of cholesterol from the endosomal/lysosomal compartment. Unesterified cholesterol that has been released from low density lipoproteins in the lumen of the late endosomes/lysosomes is transferred by NPC2 to the cholesterol-binding pocket of NPC1.
  • NPC Newcastle disease virus
  • GM2-gangliosidoses such as Tay Sachs disease, Sandhoff disease and AB variant GM2 gangliosidosis.
  • GM2 gangliosidoses are, similar to Gaucher disease, lysosomal storage diseases marked by genetic defects in glycosphingolipid metabolism. GM2 gangliosidoses are marked by defects in the enzyme hexosaminidase A and/or its co-factor GM2 activator protein, which are responsible for the breakdown of GM2 to GM3. GM2 and GM3 are related gangliosides which are part of the same metabolic pathway in glucosylceramide is degraded to ceramide.
  • GM3 is made by a stepwise process that begins with the conversion of ceramide to glucosylceramide (by GLC), followed by conversion to a galactosyl-glucosylceramide, followed by conversion to GM3 (N-acetyl-a-neuraminidyl-galactosyl-glucosylceramide), followed by conversion to GM2 (N-acetyl-galactosyl N-acetyl-a-neuraminidyl-galactosyl-glucosylceramide).
  • GLC galactosyl-glucosylceramide
  • GM3 N-acetyl-a-neuraminidyl-galactosyl-glucosylceramide
  • GM2 N-acetyl-galactosyl N-acetyl-a-neuraminidyl-galactosyl-glucosylceramide.
  • the quinuclidine compounds described herein have activity as inhibitors of the enzyme glucosylceramide synthase (GCS). These compounds have been disclosed as generally being useful in the treatment lysosomal storage diseases such as Fabry disease, Gaucher disease and Niemann-Pick disease. See, e.g., WO 2012/129084 and U.S. 2016/0361301.
  • GCS glucosylceramide synthase
  • the present invention relates to a quinuclidine compound (Compound 1) according to formula (I),
  • the present application provides a method for treating or preventing supranuclear gaze palsies, including horizontal and vertical saccadic gaze palsies, in a subject in need thereof, the method comprising administering to the subject an effective amount of a quinuclidine compound as described herein, e.g., a compound according to Formula I.
  • the present application further provides use of the quinuclidine compounds described herein, for the treatment or prevention of supranuclear gaze palsies, including horizontal and vertical saccadic gaze palsies, and/or for the manufacture of a medicament for the treatment or prevention of supranuclear gaze palsies, including horizontal and vertical saccadic gaze palsies.
  • FIGS. 1 and 2 show horizontal saccadic eye movement measured in five patients as described in Example 5 ( FIG. 1 shows patients 1-3 and FIG. 2 shows patients 4-5). Saccade amplitude and peak velocity are measured when a target moves horizontally either 15° (grey dots) or 30° (black dots) from the center position in either a leftward or rightward direction. Movements of the eye to the right are represented by positive peak velocities and movement to the left by negative peak velocities. The grey shaded area on each plot represents the normal range of peak velocities at any given amplitude.
  • the phrase “in a method of treating or preventing” is meant to be equivalent to the phrase “in the treatment or prevention of” (such as in the phrase “in the treatment or prevention of supranuclear gaze palsies”).
  • compositions and methods are intended to mean that the compositions and methods include the recited elements, but not excluding others.
  • Consisting essentially of when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives and the like.
  • Consisting of shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the compositions of this invention or process steps to produce a composition or achieve an intended result. Embodiments defined by each of these transition terms are within the scope of this invention. Use of the term “comprising” herein is intended to encompass “consisting essentially of” and “consisting of”.
  • a “subject,” “individual” or “patient” is used interchangeably herein, and refers to a vertebrate, such as a mammal.
  • Mammals include, but are not limited to, murines, rats, rabbit, simians, bovines, ovine, porcine, canines, felines, farm animals, sport animals, pets, equines, primates, and humans.
  • the mammals include horses, dogs, and cats.
  • the mammal is a human, e.g., a human suffering from a particular disease or disorder, such as Gaucher disease (e.g., GD-3) or Niemann-Pick disease Type C.
  • administering is defined herein as a means of providing an agent or a composition containing the agent to a subject in a manner that results in the agent being inside the subject's body.
  • Such an administration can be by any route including, without limitation, oral, transdermal (e.g. vagina, rectum, oral mucosa), by injection (e.g. subcutaneous, intravenous, parenterally, intraperitoneally, into the CNS), or by inhalation (e.g. oral or nasal).
  • Pharmaceutical preparations are, of course, given by forms suitable for each administration route.
  • Treating” or “treatment” of a disease generally includes: (1) inhibiting the disease, i.e. arresting or reducing the development of the disease or its clinical symptoms; and/or (2) relieving the disease, i.e. causing regression of the disease or its clinical symptoms.
  • treating and “treatment” also refer to either a reversal of the supranuclear gaze palsy or a stabilization of the supranuclear gaze palsy.
  • diseases and disorders described herein are progressive disorders—in the absence of treatment, the supranuclear gaze palsies will continue to deteriorate until complete palsy (i.e., paralysis) results.
  • complete palsy i.e., paralysis
  • Treatment thus embraces both a slowing of this progressive deterioration (e.g., stabilization), as well as reversal of this progressive deterioration (e.g., improvement.
  • Preventing or “prevention” of a disease generally includes causing the clinical symptoms of the disease not to develop in a patient that may be predisposed to the disease but does not yet experience or display symptoms of the disease.
  • preventing also embraces the prevention of development of a supranuclear gaze palsy in a patient suspected of having or diagnosed as having a disease or disorder described herein. Because the diseases and disorders described herein are progressive disorders, different signs and symptoms may manifest progressively as the disease advances. Thus, for example, a patient may be diagnosed with GD-3 or NPC before supranuclear gaze palsy begins developing. In such a patient, the methods of treatment described herein may be effective in preventing the supranuclear gaze palsy from developing.
  • palsy is synonymous with “paralysis” and includes any degree of loss of motor function of one or more skeletal muscles. As used herein, the term “palsy” thus embraces both complete palsy, i.e., complete paralysis, as well as partial palsy. Complete palsy means that a muscle or group of muscles, for example the extraocular muscles, have lost the ability to contract. As such, the effected eye or eyes may be unable to move. Partial palsy may be manifested as an inhibition of movement, a slowing of movement, or other defects in movement. These may include a loss of range of motion.
  • palsy includes ophthalmoparesis and/or ophthalmoplegia.
  • the term embraces both weakness and paralysis of the extraocular muscles.
  • the extraocular muscles include any one or more of the superior recti, inferior recti, medial recti, lateral recti, inferior oblique and superior oblique muscles of the eye.
  • Weakness and/or paralysis may include one or more of horizontal movement, vertical movement or rotational movement.
  • the term “suffering” as it relates to the term “treatment” refers to a patient or individual who has been diagnosed with the disease.
  • the term “suffering” as it relates to the term “prevention” refers to a patient or individual who is predisposed to the disease.
  • a patient may also be referred to being “at risk of suffering” from a disease because of a history of disease in their family lineage or because of the presence of genetic mutations associated with the disease.
  • a patient at risk of a disease has not yet developed all or some of the characteristic pathologies of the disease.
  • an “effective amount” or “therapeutically effective amount” is an amount sufficient to effect beneficial or desired results.
  • An effective amount can be administered in one or more administrations, applications or dosages. Such delivery is dependent on a number of variables including the time period for which the individual dosage unit is to be used, the bioavailability of the therapeutic agent, and the route of administration. It is understood, however, that specific dose levels of the therapeutic agents of the present invention for any particular subject depends upon a variety of factors including, for example, the activity of the specific compound employed, the age, body weight, general health, sex, and diet of the subject, the time of administration, the rate of excretion, the drug combination, and the severity of the particular disorder being treated and form of administration. Treatment dosages generally may be titrated to optimize safety and efficacy.
  • dosage-effect relationships from in vitro and/or in vivo tests initially can provide useful guidance on the proper doses for patient administration.
  • one will desire to administer an amount of the compound that is effective to achieve a serum level commensurate with the concentrations found to be effective in vitro. Determination of these parameters is well within the skill of the art. These considerations, as well as effective formulations and administration procedures are well known in the art and are described in standard textbooks. Consistent with this definition, as used herein, the term “therapeutically effective amount” is an amount sufficient to treat (e.g. improve) one or more symptoms associated with a disease or disorder described herein (e.g., in any of Method 1 et seq., or Method 4 et seq.) ex vivo, in vitro or in vivo.
  • the term “pharmaceutically acceptable excipient” encompasses any of the standard pharmaceutical excipients, including carriers such as a phosphate buffered saline solution, water, and emulsions, such as an oil/water or water/oil emulsion, and various types of wetting agents.
  • Pharmaceutical compositions also can include stabilizers and preservatives.
  • carriers, stabilizers and adjuvants see Remington's Pharmaceutical Sciences (20th ed., Mack Publishing Co. 2000).
  • prodrug means a pharmacological derivative of a parent drug molecule that requires biotransformation, either spontaneous or enzymatic, within the organism to release the active drug.
  • prodrugs are variations or derivatives of the quinuclidine compounds described herein that have groups cleavable under certain metabolic conditions, which when cleaved, become the quinuclidine compounds described herein, e.g. a compound of Formula I. Such prodrugs then are pharmaceutically active in vivo when they undergo solvolysis under physiological conditions or undergo enzymatic degradation.
  • Prodrug compounds herein may be called single, double, triple, etc., depending on the number of biotransformation steps required to release the active drug within the organism, and the number of functionalities present in a precursor-type form. Prodrug forms often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism.
  • Prodrugs commonly known in the art include well-known acid derivatives, such as, for example, esters prepared by reaction of acid compounds with a suitable alcohol, amides prepared by reaction of acid compounds with an amine, and basic groups reacted to form an acylated base derivative. Other prodrug derivatives may be combined with other features disclosed herein to enhance bioavailability. As such, those of skill in the art will appreciate that certain of the presently disclosed compounds having, for example, free amino or hydroxy groups can be converted into prodrugs.
  • Prodrugs include compounds having an amino acid residue, or a polypeptide chain of two or more (e.g.
  • amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone.
  • Prodrugs also include compounds having a carbonate, carbamate, amide or alkyl ester moiety covalently bonded to any of the above substituents disclosed herein.
  • pharmaceutically acceptable salt means a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable base addition salt of a currently disclosed compound that may be administered without any resultant substantial undesirable biological effect(s) or any resultant deleterious interaction(s) with any other component of a pharmaceutical composition in which it may be contained.
  • C 1-6 -alkyl means a saturated linear or branched free radical consisting essentially of 1 to 6 carbon atoms and a corresponding number of hydrogen atoms.
  • Exemplary C 1-6 -alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl.
  • Other C 1-6 -alkyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure.
  • C 1-3 -alkyl saturated linear or branched free radical consisting essentially of 1 to 3 (or 4) carbon atoms and a corresponding number of hydrogen atoms.
  • C 2-6 -alkenyl means an unsaturated linear or branched free radical consisting essentially of 2 to 6 carbon atoms and a corresponding number of hydrogen atoms, which free radical comprises at least one carbon-carbon double bond.
  • exemplary C 2-6 -alkenyl groups include ethenyl, prop-1-enyl, prop-2-enyl, isopropenyl, but-1-enyl, 2-methyl-prop-1-enyl, and 2-methyl-prop-2-enyl.
  • Other C 2-6 -alkenyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure.
  • C 2-6 -alkynyl means an unsaturated linear or branched free radical consisting essentially of 2 to 6 carbon atoms and a corresponding number of hydrogen atoms, which free radical comprises at least one carbon-carbon triple bond.
  • exemplary C 2-6 -alkynyl groups include ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, and 3-methyl-but-1-ynyl.
  • Other C 2-6 -alkynyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure.
  • C 1-6 -alkyloxy means a saturated linear or branched free radical consisting essentially of 1 to 6 carbon atoms (and a corresponding number of hydrogen atoms) and an oxygen atom.
  • a C 1-6 -alkyloxy group is attached via the oxygen atom.
  • Exemplary C 1-6 -alkyloxy groups include methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, and isobutyloxy.
  • Other C 1-6 -alkyloxy groups will be readily apparent to those of skill in the art given the benefit of the present disclosure.
  • C 1-3 -alkyloxy “C 1-4 -alkyloxy”, and the like, have an equivalent meaning, i.e. a saturated linear or branched free radical consisting essentially of 1 to 3 (or 4) carbon atoms (and a corresponding number of hydrogen atoms) and an oxygen atom, wherein the group is attached via the oxygen atom.
  • C 2-6 -alkenyloxy means an unsaturated linear or branched free radical consisting essentially of 2 to 6 carbon atoms (and a corresponding number of hydrogen atoms) and an oxygen atom, which free radical comprises at least one carbon-carbon double bond.
  • a C 2-6 -alkenyloxy group is attached via the oxygen atom.
  • An exemplary C 2-6 -alkenyloxy group is ethenyloxy; others will be readily apparent to those of skill in the art given the benefit of the present disclosure.
  • C 2-6 -alkynyloxy means an unsaturated linear or branched free radical consisting essentially of 2 to 6 carbon atoms (and a corresponding number of hydrogen atoms) and an oxygen atom, which free radical comprises at least one carbon-carbon triple bond.
  • a C 2-6 -alkenyloxy group is attached via the oxygen atom.
  • An exemplary C 2-6 -alkenyloxy group is ethynyloxy; others will be readily apparent to those of skill in the art given the benefit of the present disclosure.
  • heteroaryl means an aromatic free radical having 5 or 6 atoms (i.e. ring atoms) that form a ring, wherein 1 to 5 of the ring atoms are carbon and the remaining 1 to 5 ring atom(s) (i.e. hetero ring atom(s)) is selected independently from the group consisting of nitrogen, sulfur, and oxygen.
  • exemplary 5-membered heteroaryl groups include furyl, thienyl, thiazolyl (e.g.
  • heteroaryl groups include pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, and benzimidazolyl.
  • Other heteroaryl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure. In general, the heteroaryl group typically is attached to the main structure via a carbon atom. However, those of skill in the art will realize that certain other atoms, e.g. hetero ring atoms, can be attached to the main structure.
  • aryl means an aromatic free radical having 5 or 6 atoms (i.e. ring atoms) that form a ring, wherein all of the ring atoms are carbon.
  • An exemplary aryl group is a phenyl group.
  • aliphatic means a non-aromatic compound containing carbon and hydrogen atoms, e.g. containing 1 to 9 carbon atoms. Aliphatic compounds may be straight-chained or branched, may contain one or more ring structures, and may contain one or more carbon-carbon double bonds (provided that the compound does not contain an unsaturated ring structure having aromatic character). Examples of aliphatic compounds include ethane, propylene, cyclobutane, and cyclohexadiene.
  • cyano means a free radical having a carbon atom linked to a nitrogen atom via a triple bond. The cyano radical is attached via its carbon atom.
  • nitro means an —NO 2 radical which is attached via its nitrogen atom.
  • hydroxy and “hydroxyl” mean an —OH radical which is attached via its oxygen atom.
  • thio means an —SH radical which is attached via its sulfur atom.
  • amino means a free radical having a nitrogen atom and 1 or 2 hydrogen atoms.
  • amino generally refers to primary and secondary amines.
  • a tertiary amine is represented by the general formula RR′N—, wherein R and R′ are carbon radicals that may or may not be identical.
  • RR′N— a tertiary amine
  • the term “amino” generally may be used herein to describe a primary, secondary, or tertiary amine, and those of skill in the art will readily be able to ascertain the identification of which in view of the context in which this term is used in the present disclosure.
  • oxo means an oxygen radical which is attached via a double bond. Where an atom bonded to this oxygen is a carbon atom, the bond is a carbon-oxygen double bond which may be denoted as —(C ⁇ O)— and which may be referred to as a ketone.
  • compositions or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein.
  • the present disclosure relates to quinuclidine compounds for use in therapeutic methods relating to the treatment or prevention of the diseases and disorders discussed herein.
  • the invention relates to a quinuclidine compound (Compound 1) according to formula (I),
  • the present disclosure further relates to Compounds as follows:
  • any of Compounds 1 or 1.1-1.75 that are basic in nature are generally capable of forming a wide variety of different salts with various inorganic and/or organic acids.
  • such salts are generally pharmaceutically acceptable for administration to animals and humans, it is often desirable in practice to initially isolate a compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent, and subsequently convert the free base to a pharmaceutically acceptable acid addition salt.
  • the acid addition salts of the base compounds can be readily prepared using conventional techniques, e.g.
  • the base compound by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as, for example, methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained.
  • a suitable organic solvent such as, for example, methanol or ethanol.
  • the desired solid salt is obtained.
  • Presently disclosed compounds that are positively charged, e.g. containing a quaternary ammonium may also form salts with the anionic component of various inorganic and/or organic acids.
  • Acids which can be used to prepare pharmaceutically acceptable salts of quinuclidine compounds are those which can form non-toxic acid addition salts, e.g. salts containing pharmacologically acceptable anions, such as chloride, bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, malate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [i.e. 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts.
  • non-toxic acid addition salts e.g. salts containing pharmacologically acceptable anions, such as chloride, bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate,
  • Presently disclosed compounds that are acidic in nature are generally capable of forming a wide variety of different salts with various inorganic and/or organic bases.
  • such salts are generally pharmaceutically acceptable for administration to animals and humans, it is often desirable in practice to initially isolate a compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free acid compound by treatment with an acidic reagent, and subsequently convert the free acid to a pharmaceutically acceptable base addition salt.
  • These base addition salts can be readily prepared using conventional techniques, e.g.
  • Bases which can be used to prepare the pharmaceutically acceptable base addition salts of quinuclidine compounds are those which can form non-toxic base addition salts, e.g. salts containing pharmacologically acceptable cations, such as, alkali metal cations (e.g. potassium and sodium), alkaline earth metal cations (e.g. calcium and magnesium), ammonium or other water-soluble amine addition salts such as N-methylglucamine (meglumine), lower alkanolammonium, and other such bases of organic amines.
  • non-toxic base addition salts e.g. salts containing pharmacologically acceptable cations, such as, alkali metal cations (e.g. potassium and sodium), alkaline earth metal cations (e.g. calcium and magnesium), ammonium or other water-soluble amine addition salts such as N-methylglucamine (meglumine), lower alkanolammonium, and other such bases of organic amines.
  • the pharmaceutically acceptable salt is a succinate salt.
  • the pharmaceutically acceptable salt is a 2-hydroxysuccinate salt, e.g. an (S)-2-hydroxysuccinate salt.
  • the pharmaceutically acceptable salt is a hydrochloride salt (i.e. a salt with HCl).
  • the pharmaceutically acceptable salt is a malate salt.
  • the present disclosure further embraces prodrugs of the compounds 1 and 1.1-1.75.
  • the pharmaceutically acceptable prodrugs disclosed herein are derivatives of quinuclidine compounds which can be converted in vivo into the quinuclidine compounds described herein.
  • the prodrugs which may themselves have some activity, become pharmaceutically active in vivo when they undergo, for example, solvolysis under physiological conditions or enzymatic degradation. Methods for preparing prodrugs of compounds as described herein would be apparent to one of skill in the art based on the present disclosure.
  • the carbamate moiety of the quinuclidine compound is modified.
  • the carbamate moiety of the quinuclidine compound may be modified by the addition of water and/or one or two aliphatic alcohols.
  • the carbon-oxygen double bond of the carbamate moiety adopts what could be considered a hemiacetal or acetal functionality.
  • the carbamate moiety of the quinuclidine compound may be modified by the addition of an aliphatic diol such as 1,2-ethanediol.
  • one or more of the hydroxy, thio or amino groups on the quinuclidine compound are modified.
  • one or more of the hydroxy, thio and/or amino groups on the quinuclidine compound may be modified to form acid derivatives, e.g. esters, thioesters (or thiolesters) and/or amides.
  • the acid derivatives can be formed, for example, by reacting a quinuclidine compound which comprises one or more hydroxy, thio or amino groups with an acetylating agent.
  • acetylating agents include anhydrides such as acetic anhydride, acid chlorides such as benzyl chloride, and dicarbonates such as di-tert-butyl dicarbonate.
  • the present disclosure further embraces stereoisomers and mixture of stereoisomers of compounds 1 and 1.1-1.75.
  • Stereoisomers e.g. cis and trans isomers
  • optical isomers of a presently disclosed compound e.g. R- and S-enantiomers
  • racemic, diastereomeric and other mixtures of such isomers are within the scope of the present disclosure.
  • the quinuclidin-3-yl group of a quinuclidine compound as defined herein has the R-configuration. Accordingly, the quinuclidine compound may be selected from the group consisting of compounds of formulae (Ia) to (XIIa):
  • the quinuclidin-3-yl group of the quinuclidine compound as defined herein has the S-configuration. Accordingly, the quinuclidine compound may be selected from the group consisting of compounds of formulae (Ib) to (XIIb):
  • the quinuclidine compound is a compound of formula (Xb) or a pharmaceutically acceptable salt or prodrug thereof. In another embodiment the quinuclidine compound is a compound of formula (XIIb) or a pharmaceutically acceptable salt or prodrug thereof.
  • the quinuclidin-3-yl group of the quinuclidine compound as defined herein exists in a mixture of isomers having the R- and S-configurations.
  • the quinuclidine compound may be a mixture of compounds selected from the group consisting of compounds of formulae (Ia) and (Ib), (IIa) and (IIb), (IIIa) and (IIIb), (IVa) and (IVb), (Va) and (Vb), (VIa) and (VIb), (VIIa) and (VIIb), (VIIIa) and (VIIIb)), (IXa) and (IXb), (Xa) and (Xb), (XIa) and (XIb), and (XIIa) and (XIIb), and the pharmaceutically acceptable salts and prodrugs thereof.
  • the quinuclidine compound is present as a racemic mixture, e.g. the R- and S-isomers of the quinuclidin-3-yl group are present in about equal amounts. In another embodiment the quinuclidine compound is present as a mixture of isomers having the R- and S-configurations, wherein the R- and S-isomers are present in different amounts.
  • the S-isomer is present in an enantiomeric excess of at least about 5%, 10%, 25%, 40%, 70%, 80%, 90%, 95%, 97%, 98% or 99%, e.g. about 100%.
  • the R-isomer is present in an enantiomeric excess of at least about 5%, 10%, 25%, 40%, 70%, 80%, 90%, 95%, 97%, 98% or 99%, e.g. about 100%.
  • Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, all tautomers are within the scope of the present disclosure.
  • Atropisomers are also within the scope of the present disclosure. Atropisomers refer to compounds that can be separated into rotationally restricted isomers.
  • the present disclosure further embraces hydrates, solvates and polymorphs of Compound 1 and 1.1-1.75.
  • Pharmaceutically acceptable hydrates, solvates, and polymorphs, of the quinuclidine compounds described herein are within the scope of the present disclosure.
  • Quinuclidine compounds as described herein may be in an amorphous form and/or in one or more crystalline forms.
  • Isotopically-labeled compounds are also within the scope of the present disclosure.
  • an “isotopically-labeled compound” refers to a presently disclosed compound including pharmaceutical salts and prodrugs thereof, each as described herein, in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds presently disclosed include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • the quinuclidine compounds, and pharmaceutical compositions containing them, described herein are useful in therapy, in particular in the therapeutic treatment of supranuclear gaze palsies, including horizontal and vertical saccadic gaze palsies, neurological deficits, including dementia and gait disorders in a patient having a disease such as Gaucher disease.
  • Subjects to be treated according to the methods described herein include vertebrates, such as mammals. In particular embodiments the mammal is a human patient.
  • the present invention provides a method (Method 1) for treating or preventing supranuclear gaze palsies, including horizontal and vertical saccadic gaze palsies in a subject in need thereof, the method comprising administering to the subject an effective amount of a quinuclidine compound as described herein, e.g., a compound according to Formula I or any of II-XII, Ia-XIIa or Ib-XIIb, or any of Compounds 1 or 1.1 to 1.75.
  • a quinuclidine compound as described herein, e.g., a compound according to Formula I or any of II-XII, Ia-XIIa or Ib-XIIb, or any of Compounds 1 or 1.1 to 1.75.
  • a quinuclidine compound as described herein e.g., a compound according to Formula I or any of II-XII, Ia-XIIa or Ib-XIIb, or any of Compounds 1 or 1.1 to 1.75, for use in a method for treating or preventing supranuclear gaze palsies, including horizontal and vertical saccadic gaze palsies in a subject in need thereof, e.g., for use in Method 1 or any of 1.1-1.62.
  • a quinuclidine compound as described herein e.g., a compound according to Formula I or any of II-XII, Ia-XIIa or Ib-XIIb, or any of Compounds 1 or 1.1 to 1.75, in the manufacture of a medicament for use in a method of treating or preventing supranuclear gaze palsies, including horizontal and vertical saccadic gaze palsies in a subject in need thereof, e.g., in the manufacture of a medicament for use in Method 1 or any of 1.1-1.62.
  • a subject or subject is diagnosed with having a particular disease or disorder and is also diagnosed to have a particular genetic mutation, for example, one that is known to be a cause of the disease or disorder in question, although it often cannot be proven that a particular patient's disease or disorder is caused by the particular mutation that a person has been diagnosed with having.
  • diagnosis to have a particular genetic mutation means that a subject or patient has been tested, e.g., by DNA or RNA sequencing, protein profiling, or other suitable means, and found to have the mutation in question.
  • genetic diseases and disorders can have multiple genetic causes (e.g., mutations), and patients may have multiple mutations each of which may, under some circumstances, be sufficient to cause the disease or disorder, without it being subject to proof that a particular mutation causes a particular disease or disorder in a particular patient.
  • mutations e.g., mutations
  • the methods according to Method 1 et seq. may be beneficial for subjects who have been diagnosed with a lysosomal storage disease, such as Gaucher Type 3 or Niemann-Pick Type C, but who are not yet experiencing the ocular symptoms associated with the disease state.
  • the methods according to Method 1 et seq. may also be beneficial for subjects who are at risk of developing a lysosomal storage disease, such as Gaucher Type 3 or Niemann-Pick Type C, due to, for example, a mutation in the subject or the subject's family lineage known to cause such disease.
  • the subject has been diagnosed as being at risk of developing said disease or disorder, and the method prevents or delays the onset and/or development of the ocular symptoms of the disease or disorder (e.g., the supranuclear gaze palsy) in the subject.
  • the subject has been diagnosed as being at risk of developing said disease or disorder by virtue of having a mutation in a gene as described herein.
  • the present invention provides a method (Method 4) for treating or preventing cognitive dysfunction and/or gait abnormalities, including ataxia, associated with a lysosome storage disease, in a subject in need thereof, the method comprising administering to the subject an effective amount of a quinuclidine compound as described herein, e.g., a compound according to Formula I or any of II-XII, Ia-XIIa or Ib-XIIb, or any of Compounds 1 or 1.1 to 1.75.
  • a quinuclidine compound as described herein, e.g., a compound according to Formula I or any of II-XII, Ia-XIIa or Ib-XIIb, or any of Compounds 1 or 1.1 to 1.75.
  • a quinuclidine compound as described herein e.g., a compound according to Formula I or any of II-XII, Ia-XIIa or Ib-XIIb, or any of Compounds 1 or 1.1 to 1.75, for use in a method for treating or preventing cognitive dysfunction and/or gait abnormalities, including ataxia, associated with a lysosome storage disease, in a subject in need thereof, e.g., for use in Method 4 or any of 4.1-4.62.
  • a quinuclidine compound as described herein e.g., a compound according to Formula I or any of II-XII, Ia-XIIa or Ib-XIIb, or any of Compounds 1 or 1.1 to 1.75, in the manufacture of a medicament for use in a method of treating or preventing cognitive dysfunction and/or gait abnormalities, including ataxia, associated with a lysosome storage disease, in a subject in need thereof, e.g., in the manufacture of a medicament for use in Method 4 or any of 4.1-4.62.
  • a subject or subject is diagnosed with having a particular disease or disorder and is also diagnosed to have a particular genetic mutation, for example, one that is known to be a cause of the disease or disorder in question, although it often cannot be proven that a particular patient's disease or disorder is caused by the particular mutation that a person has been diagnosed with having.
  • diagnosis to have a particular genetic mutation means that a subject or patient has been tested, e.g., by DNA or RNA sequencing, protein profiling, or other suitable means, and found to have the mutation in question.
  • genetic diseases and disorders can have multiple genetic causes (e.g., mutations), and patients may have multiple mutations each of which may, under some circumstances, be sufficient to cause the disease or disorder, without it being subject to proof that a particular mutation causes a particular disease or disorder in a particular patient.
  • mutations e.g., mutations
  • the methods according to Method 4 et seq. may be beneficial for subjects who have been diagnosed with a lysosomal storage disease, such as Gaucher Type 3 or Niemann-Pick Type C, but who are not yet experiencing the cognitive and/or ataxic symptoms associated with the disease state.
  • the methods according to Method 4 et seq. may also be beneficial for subjects who are at risk of developing a lysosomal storage disease, such as Gaucher Type 3 or Niemann-Pick Type C, due to, for example, a mutation in the subject or the subject's family lineage known to cause such disease.
  • the subject has been diagnosed as being at risk of developing said disease or disorder, and the method prevents or delays the onset and/or development of the cognitive and/or ataxic symptoms of the disease or disorder (e.g., the supranuclear gaze palsy) in the subject.
  • the subject has been diagnosed as being at risk of developing said disease or disorder by virtue of having a mutation in a gene as described herein.
  • the present disclosure also provides pharmaceutical compositions comprising at least one quinuclidine compound as described herein and at least one pharmaceutically acceptable excipient, e.g. for use according to the methods disclosed herein.
  • the pharmaceutically acceptable excipient can be any such excipient known in the art including those described in, for example, Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985).
  • Pharmaceutical compositions of the compounds presently disclosed may be prepared by conventional means known in the art including, for example, mixing at least one presently disclosed compound with a pharmaceutically acceptable excipient.
  • the present disclosure provides a pharmaceutical dosage form comprising a quinuclidine compound as described herein and a pharmaceutically acceptable excipient, wherein the dosage form is formulated to provide, when administered (e.g. when administered orally), an amount of said compound sufficient to treat a disease or disorder described herein (e.g., in any of Method 1 et seq., or Method 4 et seq.).
  • a pharmaceutical composition or dosage form of the invention can include an agent and another carrier, e.g. compound or composition, inert or active, such as a detectable agent, label, adjuvant, diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant or the like.
  • Carriers also include pharmaceutical excipients and additives, for example, proteins, peptides, amino acids, lipids, and carbohydrates (e.g.
  • sugars including monosaccharides, di-, tri-, tetra-, and oligosaccharides; derivatized sugars such as alditols, aldonic acids, esterified sugars and the like; and polysaccharides or sugar polymers), which can be present singly or in combination, comprising alone or in combination 1 to 99.99% by weight or volume.
  • exemplary protein excipients include serum albumin such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like.
  • amino acid/antibody components which can also function in a buffering capacity, include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, and the like.
  • Carbohydrate excipients are also intended within the scope of this invention, examples of which include but are not limited to monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol) and myoinositol.
  • monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like
  • disaccharides such as lactose, sucrose
  • Carriers which may be used include a buffer or a pH adjusting agent; typically, the buffer is a salt prepared from an organic acid or base.
  • Representative buffers include organic acid salts such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid; Tris, tromethamine hydrochloride, or phosphate buffers.
  • Additional carriers include polymeric excipients/additives such as polyvinylpyrrolidones, ficolls (a polymeric sugar), dextrates (e.g.
  • cyclodextrins such as 2-hydroxypropyl- ⁇ -cyclodextrin
  • polyethylene glycols such as 2-hydroxypropyl- ⁇ -cyclodextrin
  • flavoring agents such as 2-hydroxypropyl- ⁇ -cyclodextrin
  • antimicrobial agents such as “STYPES”
  • sweeteners such as “STYPES”
  • antioxidants such as “TWEEN 20” and “TWEEN 80”
  • surfactants e.g. polysorbates such as “TWEEN 20” and “TWEEN 80”
  • lipids e.g. phospholipids, fatty acids
  • steroids e.g. cholesterol
  • chelating agents e.g. EDTA
  • compositions, and kits comprising said compositions, which contain at least one quinuclidine compound as described herein and at least one further pharmaceutically-active agent.
  • These pharmaceutical compositions and kits may be adapted to allow simultaneous, subsequent and/or separate administration of the quinuclidine compound and the further active agent.
  • the quinuclidine compound and the further active agent may be formulated in separate dosage forms, e.g. in separate tablets, capsules, lyophilizates or liquids, or they may be formulated in the same dosage form, e.g. in the same tablet, capsule, lyophilizate or liquid.
  • the quinuclidine compound and the further active agent are formulated in the same dosage form
  • the quinuclidine compound and the further active agent may be present substantially in admixture, e.g. within the core of a tablet, or they may be present substantially in discrete regions of the dosage form, e.g. in separate layers of the same tablet.
  • the pharmaceutical dosage form comprises a further agent which is capable of treating or preventing a supranuclear gaze palsy, e.g., in a patient having, diagnosed with or predisposed to a lysosomal storage disease, such as Gaucher Type 3 or Niemann-Pick Type C, or pain, e.g., in a patient having, diagnosed with or predisposed to a lysosomal storage disease, such as Fabry disease, as described herein.
  • a supranuclear gaze palsy e.g., in a patient having, diagnosed with or predisposed to a lysosomal storage disease, such as Gaucher Type 3 or Niemann-Pick Type C
  • pain e.g., in a patient having, diagnosed with or predisposed to a lysosomal storage disease, such as Fabry disease, as described herein.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising: (i) a quinuclidine compound as described herein; (ii) a further active agent; and (iii) a pharmaceutically acceptable excipient.
  • the further active agent is an agent which is capable of treating or preventing a supranuclear gaze palsy, a gait disorder or a cognitive dysfunction (e.g., dementia), e.g., in a patient having, diagnosed with or predisposed to a lysosomal storage disease, such as Gaucher Type 3 or Niemann-Pick Type C, as described herein.
  • a presently disclosed compound can be formulated as a pharmaceutical composition for oral, buccal, parenteral (e.g. intravenous, intramuscular or subcutaneous), topical, rectal or intranasal administration or in a form suitable for administration by inhalation or insufflation.
  • the quinuclidine compound or pharmaceutical composition is formulated for systemic administration, e.g. via a non-parenteral route.
  • the quinuclidine compound or pharmaceutical composition is formulated for oral administration, e.g. in solid form.
  • Such modes of administration and the methods for preparing appropriate pharmaceutical compositions are described, for example, in Gibaldi's Drug Delivery Systems in Pharmaceutical Care (1st ed., American Society of Health-System Pharmacists 2007).
  • the pharmaceutical compositions can be formulated so as to provide slow, extended, or controlled release of the active ingredient therein using, for example, hydroxypropyl methyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • the pharmaceutical compositions can also optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner, e.g. by using an enteric coating.
  • embedding compositions include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more pharmaceutically acceptable carriers, excipients, or diluents well known in the art (see, e.g., Remington's).
  • the compounds presently disclosed may be formulated for sustained delivery according to methods well known to those of ordinary skill in the art. Examples of such formulations can be found in U.S. Pat. Nos. 3,119,742; 3,492,397; 3,538,214; 4,060,598; and 4,173,626.
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers, excipients, or diluents, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, microcrystalline cellulose, calcium phosphate and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, pregelatinized maize starch, polyvinyl pyrrolidone, hydroxypropyl methylcellulose, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, sodium starch glycolate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbon
  • compositions can also comprise buffering agents.
  • Solid compositions of a similar type can also be prepared using fillers in soft and hard-filled gelatin capsules, and excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet can be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets can be prepared using binders (for example, gelatin or hydroxypropyl methyl cellulose), lubricants, inert diluents, preservatives, disintegrants (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-actives, and/or dispersing agents.
  • Molded tablets can be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
  • the tablets and other solid dosage forms, such as dragees, capsules, pills, and granules can optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the art.
  • the pharmaceutical compositions are administered orally in a liquid form.
  • Liquid dosage forms for oral administration of an active ingredient include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • Liquid preparations for oral administration may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • the liquid dosage forms can contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (e.g. cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,
  • the liquid pharmaceutical compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents, and the like.
  • Suspensions in addition to the active ingredient(s) can contain suspending agents such as, but not limited to, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Suitable liquid preparations may be prepared by conventional means with a pharmaceutically acceptable additive(s) such as a suspending agent (e.g.
  • sorbitol syrup methyl cellulose or hydrogenated edible fats
  • emulsifying agent e.g. lecithin or acacia
  • non-aqueous vehicle e.g. almond oil, oily esters or ethyl alcohol
  • preservative e.g. methyl or propyl p-hydroxybenzoates or sorbic acid
  • the active ingredient(s) can also be administered as a bolus, electuary, or paste.
  • the composition may take the form of tablets or lozenges formulated in a conventional manner.
  • the pharmaceutical compositions are administered by non-oral means such as by topical application, transdermal application, injection, and the like.
  • the pharmaceutical compositions are administered parenterally by injection, infusion, or implantation (e.g. intravenous, intramuscular, intra-arterial, subcutaneous, and the like).
  • Presently disclosed compounds may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion.
  • Formulations for injection may be presented in unit dosage form, e.g. in ampules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain a formulating agent such as a suspending, stabilizing and/or dispersing agent recognized by those of skill in the art.
  • the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • compositions may be administered directly to the central nervous system. Accordingly, in certain embodiments the compositions are administered directly to the central nervous system so as to avoid the blood brain barrier.
  • the composition can be administered via direct spinal cord injection.
  • the composition is administered by intrathecal injection.
  • the composition is administered via intracerebroventricular injection.
  • the composition is administered into a cerebral lateral ventricle.
  • the composition is administered into both cerebral lateral ventricles.
  • the composition is administered via intrahippocampal injection.
  • the compositions may be administered in one injection or in multiple injections. In other embodiments, the composition is administered to more than one location (e.g. to two sites in the central nervous system).
  • the pharmaceutical compositions can be in the form of sterile injections.
  • the pharmaceutical compositions can be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • the active ingredient is dissolved or suspended in a parenterally acceptable liquid vehicle.
  • exemplary vehicles and solvents include, but are not limited to, water, water adjusted to a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1,3-butanediol, Ringer's solution and isotonic sodium chloride solution.
  • the pharmaceutical composition can also contain one or more preservatives, for example, methyl, ethyl or n-propyl p-hydroxybenzoate.
  • a dissolution enhancing or solubilizing agent can be added or the solvent can contain 10-60% w/w of propylene glycol or the like.
  • the pharmaceutical compositions can contain one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders, which can be reconstituted into sterile injectable solutions or dispersions just prior to use.
  • Such pharmaceutical compositions can contain antioxidants; buffers; bacteriostats; solutes, which render the formulation isotonic with the blood of the intended recipient; suspending agents; thickening agents; preservatives; and the like.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • Controlled release parenteral compositions can be in form of aqueous suspensions, microspheres, microcapsules, magnetic microspheres, oil solutions, oil suspensions, emulsions, or the active ingredient can be incorporated in biocompatible carrier(s), liposomes, nanoparticles, implants or infusion devices.
  • Materials for use in the preparation of microspheres and/or microcapsules include, but are not limited to, biodegradable/bioerodible polymers such as polyglactin, poly-(isobutyl cyanoacrylate), poly(2-hydroxyethyl-L-glutamine) and poly(lactic acid).
  • Biocompatible carriers which can be used when formulating a controlled release parenteral formulation include carbohydrates such as dextrans, proteins such as albumin, lipoproteins or antibodies.
  • Materials for use in implants can be non-biodegradable, e.g. polydimethylsiloxane, or biodegradable such as, e.g., poly(caprolactone), poly(lactic acid), poly(glycolic acid) or poly(ortho esters).
  • a presently disclosed compound may be formulated as an ointment or cream.
  • Presently disclosed compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • presently disclosed compounds may be conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurized container or nebulizer may contain a solution or suspension of the presently disclosed compound.
  • Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of a presently disclosed compound and a suitable powder base such as lactose or starch.
  • the agents and compositions described herein are administered in an effective amount or quantity sufficient to treat or prevent a supranuclear gaze palsy in a subject in need thereof.
  • the dose can be adjusted within this range based on, e.g., age, physical condition, body weight, sex, diet, time of administration, and other clinical factors. Determination of an effective amount is well within the capability of those skilled in the art.
  • the crude acyl azide was further dried via coevaporation with toluene and then taken up in toluene ( ⁇ 0.1 M).
  • the stirred solution was refluxed for 2-2.5 hours, cooled and treated with an alcohol component (1.25-2 equivalents).
  • the reaction was heated at reflux overnight and then concentrated.
  • the residue was taken up in either ethyl acetate or chloroform and washed with aqueous sodium carbonate, (Na 2 SO 4 ) and concentrated.
  • the crude product was purified by flash chromatography over silica using chloroform/methanol (less polar carbamates) or chloroform/methanol/ammonia (more polar carbamates) solvent gradients.
  • the organic layer was combined with a back-extract of the aqueous layer (ethyl acetate, 1 ⁇ 75 mL), dried (Na 2 SO 4 ) and concentrated.
  • the resulting amber oil was purified by flash chromatography using a hexane/ethyl acetate gradient to afford ethyl 2-(2-(4-fluorophenyl)thiazol-4-yl)acetate as a low melting, nearly colourless solid (13.58 g, 89%).
  • the resulting amber oil was purified by flash chromatography using a hexane/ethyl acetate gradient to afford 2-(5-bromothiophen-3-yl)propan-2-ol as a pale amber oil (8.05 g, 64%).
  • the resulting amber oil was purified by flash chromatography using a methylene chloride/methanol/ammonia gradient to afford a mixture of 2-(5-bromothiophen-3-yl)propan-2-amine and triphenylphosphine oxide ( ⁇ 70/30 ratio) as a viscous amber oil (1.32 g, 17%).
  • the resulting dirty yellow gum was purified by flash chromatography using a chloroform/methanol/ammonia gradient to afford quinuclidin-3-yl (1-(5-bromothiophen-3-yl)cyclopropyl)carbamate as an off-white solid (0.305 g, 49%).
  • a 3N RB flask was equipped with a thermometer, an addition funnel and a nitrogen inlet.
  • the flask was flushed with nitrogen and potassium tert-butoxide (MW 112.21, 75.4 mmol, 8.46 g, 4.0 equiv., white powder) was weighed out and added to the flask via a powder funnel followed by the addition of THF (60 mL).
  • Most of the potassium tert-butoxide dissolved to give a cloudy solution. This mixture was cooled in an ice-water bath to 0-2° C. (internal temperature).
  • the starting ester (MW 265.3, 18.85 mmol, 5.0 g, 1.0 equiv.) was dissolved in THF (18 mL+2 mL as rinse) and transferred to the addition funnel. This solution was added dropwise to the cooled mixture over a period of 25-30 min, keeping the internal temperature below 5° C. during the addition. The reaction mixture was cooled back to 0-2° C.
  • a solution of methyl iodide (MW 141.94, 47.13 mmol, 6.7 g, 2.5 equiv.) in THF (6 mL) was prepared and transferred to the addition funnel.
  • the flask containing the methyl iodide solution was then rinsed with THF (1.5 mL) which was then transferred to the addition funnel already containing the clear colorless solution of methyl iodide in THF.
  • This solution was added carefully dropwise to the dark brown reaction mixture over a period of 30-40 min, keeping the internal temperature below 10° C. at all times during the addition.
  • the slightly turbid mixture was stirred for an additional 1 h during which time the internal temperature dropped to 0-5° C.
  • the reaction mixture was quenched with the slow dropwise addition of 5.0M aqueous HCl (8 mL) over a period of 5-7 min. The internal temperature was maintained below 20° C.
  • Step 3 Formation of Hydroxamic Acid with NH 2 OH.HCl
  • the carboxylic acid (MW 265.3, 18.85 mmol, 5.0 g, 1.0 equiv.) was weighed and transferred to a 25 mL 1N RB flask under nitrogen. THF (5.0 mL) was added and the acid readily dissolved to give a clear dark yellow to brown solution. The solution was cooled to 0-2° C. (bath temperature) in an ice-bath and N, N′-carbonyldiimidazole (CDI; MW 162.15, 20.74 mmol, 3.36 g, 1.1 equiv.) was added slowly in small portions over a period of 10-15 minutes. The ice-bath was removed and the solution was stirred at room temperature for 1 h.
  • CDI N, N′-carbonyldiimidazole
  • Step 3 continued: Conversion of hydroxamic acid to cyclic intermediate (not isolated)
  • the crude hydroxamic acid (MW 280.32, 5.1 g) was transferred to a 250 mL 1N RB flask with a nitrogen inlet. A stir bar was added followed by the addition of acetonitrile (50 mL). The solid was insoluble in acetonitrile. The yellow heterogeneous mixture was stirred for 2-3 minutes under nitrogen and CDI (MW 162.15, 20.74 mmol, 3.36 g, 1.1 equiv.) was added in a single portion at room temperature. No exotherm was observed. The solid immediately dissolved and the clear yellow solution was stirred at room temperature for 2-2.5 h. After 2-2.5 h, an aliquot was analyzed by HPLC and LC/MS which showed conversion of the hydroxamic acid to the desired cyclic intermediate.
  • the acetonitrile was then evaporated in vacuo to give the crude cyclic intermediate as reddish thick oil.
  • the oil was taken up in toluene (60 mL) and the reddish mixture was heated to reflux for 2 hours during which time, the cyclic intermediate released CO 2 and rearranged to the isocyanate (see below).
  • reaction mixture was cooled to 50-60° C. and (S)-(+)-quinuclidinol (MW 127.18, 28.28 mmol, 3.6 g, 1.5 equiv.) was added to the mixture as a solid in a single portion.
  • the mixture was re-heated to reflux for 18 h. After 18 h, an aliquot was analyzed by HPLC and LC/MS which showed complete conversion of the isocyanate to the desired product.
  • the reaction mixture was transferred to a separatory funnel and toluene (25 mL) was added. The mixture was washed with water (2 ⁇ 40 mL) and the water layers were separated.
  • the combined water layers were re-extracted with toluene (30 mL) and the water layer was discarded.
  • the combined toluene layers were extracted with 1N HCl (2 ⁇ 60 mL) and the toluene layer (containing the 0-acyl impurity) was discarded.
  • the combined HCl layers were transferred to a 500 mL Erlenmeyer flask equipped with a stir bar. This stirring clear yellow/reddish orange solution was basified to pH 10-12 by the dropwise addition of 50% w/w aqueous NaOH. The desired free base precipitated out of solution as a dirty yellow gummy solid which could trap the stir bar.
  • the beige to tan colored crude free base was weighed and re-crystallized from heptane/isopropyl acetate (3:1, 9.0 mL of solvent/g of crude free base). The appropriate amount of heptane/isopropyl acetate was added to the crude free base along with a stir bar and the mixture was heated to reflux for 10 min (free base was initially partially soluble but dissolved to give a clear reddish orange solution when heated to reflux). The heat source was removed and the mixture was allowed to cool to room temperature with stirring when a white precipitate formed.
  • Crystalline salts of (S)-Quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate may be formed from the free base prepared as described in Example 23.
  • the free base of (S)-Quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate (about 50 mmol) is dissolved IPA (140 ml) at room temperature and filtered. The filtrate is added into a 1 L r.b. flask which is equipped with an overhead stirrer and nitrogen in/outlet. L-malic acid (about 50 mmol) is dissolved in IPA (100+30 ml) at room temperature and filtered. The filtrate is added into the above 1 Liter flask. The resulting solution is stirred at room temperature (with or without seeding) under nitrogen for 4 to 24 hours. During this period of time crystals form. The product is collected by filtration and washed with a small amount of IPA (30 ml). The crystalline solid is dried in a vacuum oven at 55° C. for 72 hours to yield the desired malate salt.
  • Crystal forms of other salts e.g. acid addition salts with succinic acid or HCl, may be prepared in an analogous manner.
  • Inhibition of glucosylceramide synthase activity can be measured with one or more assays.
  • a first assay is a microsomal assay that directly measures the conversion of ceramide to glucosylceramide by HPLC. Microsomes are a source of glucosylceramide synthase activity in the microsomal assay.
  • a second assay is a cell based, phenotypic assay that monitors cell surface expression of the downstream lipid GM3 by antibody mediated immunofluorescence. Specific protocols are provided below.
  • An enzyme assay using microsomes as a source of glucosylceramide synthase activity Fluorescent ceramide substrate is delivered to membrane-bound enzyme as a complex with albumin. After reaction, ceramide and glucosylceramide are separated and quantitated by reverse-phase HPLC with fluorescence detection. Enzymatic activity is assessed using a fluorescent labeled substrate and microsomes as a source of glucosylceramide synthase.
  • C 6 -NBD-Ceramide is complexed with albumin for delivery to microsomes that are isolated according to the procedure described below. The final concentration of C 6 -NBD-Ceramide in the stock solution is 0.5 mM; the final concentration of BSA is 0.5 mM. Separation and quantitation of substrate and product (glucosylceramide) are achieved by reverse-phase HPLC with fluorescence detection.
  • Microsomes are isolated from A375 human melanoma cells. Eight to ten million cells are harvested by trypsinization and washed with ice cold PBS. Cells are resuspended in ice-cold lysis buffer containing protease inhibitors. Cell lysate is sonicated on ice using a probe sonicator. After sonication, the cell lysate is separated from debris by centrifugation at 10,000 g for 10 minutes at 4° C. The supernatant is removed and cleared by additional centrifugation at 100,000 g for 1 hour at 4° C. The pellet is then resuspended in the lysis buffer, aliquoted and stored at ⁇ 80° C. prior to use.
  • substrates at 2 ⁇ of their Km fluorescent ceramide and UDP-glucose, 3 ⁇ M and 4 ⁇ M respectively
  • microsomes (1:50 dilution) are combined 1:1 and incubated at room temperature for 1 hour in the dark on a plate shaker.
  • the reaction is stopped by the addition of 150 ⁇ L of 100 ⁇ M C 8 -ceramide in 50% aq. isopropanol; 10 ⁇ L of the final mix is analyzed on HPLC (with fluorescence detector).
  • the mobile phase is 1% formic acid added to 81% methanol/19% water with flow rate 0.5 mL/min.
  • NBD-C 6 -GluCer had a retention time of about 1.7 min and NBD-C 6 -Cer elutes from the column after about 2.1 min. Both peaks are separated from each other and the baseline and were integrated automatically by the HPLC software. The percent conversion of substrate to product is used as the readout for inhibitor testing.
  • Cell surface GM3 expression is determined by antibody mediated fluorescence.
  • Compounds are diluted in media and plated in 384 well plates in DMSO.
  • B16 and C32 cells are assayed at densities of 20,000 cells/ml and 62,500 cells/ml, respectively, per well.
  • Each titration curve contains 10 points that are assayed in duplicate on each test run.
  • the plates are incubated for 48 hours at 37° C., 5% CO2, and are then washed once with TBS.
  • results of certain exemplified compounds in these assays are presented in the Table below.
  • the results of the microsomal assays are expressed as “GCS IC 50 ”, which represents the concentration of the compound causing 50% inhibition of glucosylceramide synthase activity.
  • the results of the cell-based assays are expressed as “GM3 B16 IC 50 ” or “GM3 C32 IC 50 ” for the B16 assay and the C32 assay, respectively. These values represent the concentration of the compound causing 50% inhibition of GM3 expression on the cell surface.
  • Patients must have reached the following GD therapeutic goals: hemoglobin level of ⁇ 11.0 g/dL for females and ⁇ 12.0 g/dL for males; platelet count ⁇ 100 000/mm3; spleen volume ⁇ 10 multiples of normal (MN), or total splenectomy (provided the splenectomy occurred >3 years prior to randomization); liver volume ⁇ 1.5 MN; and no bone crisis and free of symptomatic bone disease such as bone pain attributable to osteonecrosis and/or pathological fractures within the last year.
  • Patients must have GD3 featuring oculomotor apraxia (supranuclear gaze palsy) characterized by a horizontal saccade abnormality.
  • Severity of interstitial lung disease was characterized by the percent of lung volume affect by ILD as measured by high-resolution CT in four lung regions (aortic arch, carina, lower zone L3, lower zone L4). Patients were rated as having severe ILD (51-100% of lung volume affected), moderate ILD (26-50% of lung volume affected), mild ILD (1-25% of lung volume affected) or normal (0% of lung volume showing ILD). All patients showed ILD at baseline, and 4 out of 5 patients showed regression of ILD after 26 weeks of treatment (patient 5 showed slight progression of ILD):
  • Patient 1 Patient 2
  • Patient 3 Patient 4
  • Screening 192 207 259* 313 149 Day 1 186* 192* n/a 307* 127* Week 4 203 243 247 239 154 Week 12 214 294 264 314 180 Week 26 264 236 248 267 173 % Change from +42% +23% ⁇ 4.3% ⁇ 13% +36% baseline to 26 weeks *indicates figure used as baseline
  • the mean PV of horizontal rightward 30° saccades was 77.7°/s (+/ ⁇ 16.4°/s) at baseline and 68.1°/min (+/ ⁇ 24.7°/s) at Week 26; and the mean PV of horizontal leftward 30° saccades was 58.7°/s (+/ ⁇ 21.5°/s) at baseline and 49.9°/s (+/ ⁇ 8.5°/s) at Week 26.
  • the normal range for 150 and 300 horizontal saccades has previously been reported as >200°/s and >400°/s (Bremova-Ertl et al, 2018).
  • HSEM measurements in each of the five patients are shown in FIGS. 1 and 2 . In summary, no clinically meaningful changes in HSEM were observed over the 26-week treatment period. As with HSEM, VSEM measurements were stable between baseline and week 26.
  • chitotriosidase (CHITO; an enzyme known to be elevated in GD patients) was measured in CSF and serum
  • GM3 a glycosphingolipid marker known to be elevated in GD patients
  • GPNMB glycoprotein nonmetastatic melanoma protein B
  • a second interim analysis was performed when the first 6 patients had reached 52-weeks of treatment, as described above in section (A). This analysis included Patients 1-5 as described in section (A), as well as new Patient 6. All six patients had L444P (1448T/C) homozygous Gaucher phenotype.
  • CSF of GD3 patients ceramide (the precursor of GL-1), chitotriosidase (CHITO), GM3, and GPNMB.
  • ceramide the precursor of GL-1
  • CHITO chitotriosidase
  • GPNMB GPNMB
  • the trail making test was used to evaluate cognitive function in the patients.
  • the TMT is one of the most widely used neuropsychological tests and is included in most test batteries.
  • the TMT is a diagnostic tool to assess general intelligence and cognitive dysfunctions (Tombaugh et al. [2004]; Cavaco et al. [2013]).
  • Part A of the TMT subjects are asked to connect a cluster of numbers in ascending order.
  • This task is a combination of visual search and general visual and motor processing speed.
  • Part B presents a sequence which alternates between numbers and letters. Subjects must actively switch between both categories when connecting them in ascending, but alternating order. Hence, this task is considered to include an executive function component since the subject must actively switch between categories while connecting the symbols (MacPherson et al. [2017]).
  • TMT-A evaluates mainly perceptual and psychomotor speed.
  • TMT-B assesses more specifically mental flexibility and shifting abilities.
  • TMT B minus TMT A score is used to remove the variance attributable to the graphomotor and visual scanning components of TMT A. This derived score reflects the unique task requirements of TMT B.
  • Neurological function- was further evaluated using functional magnetic resonance imaging (fMRI).
  • Patient 2 was excluded because no fMRI data was collected at the Week 52 session. Resting-state fMRI screening sessions were performed at baseline screening, Week 26, and Week 52 visits. Connectivity estimates from four subjects (Patients 1, 3, 4 and 5) were entered into second-level analyses as a “compliant” group. Patient 5 was isolated due to likely non-compliance with study medication, as described above. Analyses were performed as described elsewhere (Smith et al. [2009]).
  • compliant subjects demonstrate an enhanced connectivity between a more broadly distributed set of brain regions than the non-compliant subject, with increasing strength between posterior and anterior aspects as the most prominent feature.
  • compliant subjects demonstrate a widespread and robust strengthening of connections between occipital-parietal structures and frontal, temporal and limbic targets.
  • Connectivity changes in Patient 5 were more modest and restricted within spatially proximal structures.
  • enhanced connectivity between default mode and medial frontal networks is seen in every subject except Patient 5. This suggests signal within these disparate networks becomes more coherent, such that brain activity can be more efficiently transferred between cognitive reserve (posterior) and higher-order executive functions (anterior).
  • results are summarized in the table below. Spatial analysis of the connectivity between different anatomic regions of the brain is performed to define a correlation coefficient for regressed voxelwise mean intensity. The results show that connectivity between the default mode (resting) network and the executive function network increased in Patients 1, 3, 4 and 6, but decreased in Patient 5.
  • Compound 2 is also known as venglustat.
  • Study 1 was a 2-part single-center trial in healthy adult male volunteers. Part 1 was a double-blind, randomized, placebo-controlled sequential ascending single-dose study of Compound 2 for safety, tolerability, and PK. Part 2 was an open-label, single-cohort, randomized, 2-sequence, 2-period, 2-treatment crossover study of Compound 2 for PK with and without a high-fat meal.
  • Part 1 the subjects were randomized to receive 2, 5, 15, 25, 50, 100, or 150 mg of Compound 2 (L-malic salt form) or matching placebo on the morning of the first day after at least a 10-hour fast.
  • the subjects were randomized to receive a single oral dose of 5 mg Compound 2 either while fasting (at least 10 hours before and 4 hours after administration) or 30 minutes after a standardized high-fat breakfast ( ⁇ 815 kcal). After a 7-day washout period, participants were crossed over to the other condition.
  • Study 2 was a single-center, double-blind, randomized, placebo-controlled, sequential ascending repeated-dose study of the safety, tolerability, PK, and pharmacodynamics of Compound 2 in healthy adult male and female volunteers.
  • the study enrolled and randomized 36 healthy adults (19 men and 17 women) (n 9 each to group). The subjects were randomized to receive once-daily doses of Compound 2 at 5, 10, or 20 mg (provided as 5-mg capsules of the L-malic salt form) or placebo for 14 days after at least a 10-hour fast.
  • Blood was sampled for plasma concentrations of Compound 2 as follows: Day 1 at 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, and 16 hours post-dose; On Days 2-5, 8, 11, and 13, at 0 h; On Day 14, at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12 hours post-dose; On Days 15-17, at 24, 48, and 72 hours, respectively, after the Day 14 dose.
  • Urine samples were collected for analysis of Compound 2 concentrations on Day 1 (0 hours post-dose) and continuously on Day 14 from 0-24 hours post-dose.
  • Pharmacodynamic endpoints (plasma GL-1, GL-3, and GM3 concentrations) were assessed on Days 1-5, 8, 11, 13, and 14, at 0 hours post-dose; and on Day 15, at 24 hours after the Day 14 dose.
  • Plasma GL-1, GL-3, and GM3 in placebo recipients remained similar to baseline throughout, whereas plasma GL-1 and GM3 levels decreased from baseline time- and dose-dependently across the 3 Compound 2 dose groups, as shown in the following table (Point estimates of treatment ratios for glucosylceramide (GL-1), globotriaosylceramide (GL-3), and GM3 ganglioside (GM3) on Day 15 in the repeated ascending dose study):
  • GM3 Maximal sustained GM3 decreases occurred across all Compound 2 dose groups starting on Day 13. Mean Day 15 plasma GM3 levels were 42.7%, 49.4%, and 57.8% of baseline for the 5-, 10-, and 20-mg dose groups, respectively. GM3 was below the LLOQ at Day 15 in 1 and 2 subjects in the 10- and 20-mg dose groups, respectively.
  • Plasma GL-3 also decreased with time in all Compound 2 dose groups, but variable and low baseline GL-3 values relative to LLOQ limited mean calculated GL-3 reductions.
  • GL-3 values were below LLOQ in 1, 3, 1, and 6 subjects, respectively, at baseline and in 4, 9, 7, and 9 subjects, respectively, at Day 15.
  • Plasma samples were also analyzed for GL-3, lyso-GL-3, GL-1 and GM3 at baseline and weeks 12, 26, 52 and 156. Pain scores and abdominal symptoms were analyzed at baseline and weeks 12, 26, 52, 104 and 156 using the SF-36 scoring protocol.
  • SF-36 Short Form-36
  • gastrointestinal symptoms including abdominal pain, abdominal distention, and bowl movements, were assessed using a modified version of the inflammatory bowel severity scoring system.
  • Plasma and urine data are summarized in the table below:
  • patients receiving Compound 2 were matched with phase 3 study patients based on propensity scores using baseline variables of age, plasma GL-3, gender, UPCR ( ⁇ 500 mg/g versus 500-1000 mg/g versus >1000 mg/g), and eGFR ( ⁇ 80 versus ⁇ 80 mL/min/1.73m 2 ).
  • 11 patients receiving Compound 2 were matched to 19 patients for the placebo comparison and to 28 patients for the agalsidase beta comparison. All patients in all three groups were male and demonstrated elevated plasma GL-3, UPCR of ⁇ 500 mg/g, and eGFR ⁇ 80 mL/min/1.73 m 2 . Mean ages were similar across the three groups.
  • the fraction of the volume of endothelial cell cytoplasm occupied by GL-3 inclusions was estimated using point-counting of electron microscopic images by a masked reader. Images from at least 50 superficial endothelial cell capillaries were obtained using electron microscopy at 7500 ⁇ magnification. Two-sided t tests were used to evaluate differences between baseline and post-treatment values at each time point. The results are shown in the table below:

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US12060349B2 (en) 2012-09-11 2024-08-13 Genzyme Corporation Glucosylceramide synthase inhibitors
US12083115B2 (en) 2020-02-03 2024-09-10 Genzyme Corporation Methods for treating neurological symptoms associated with lysosomal storage diseases
US12527776B2 (en) 2019-02-04 2026-01-20 Genzyme Corporation Treatment of ciliopathies using inhibitors of glucosylceramide synthase (GCS)

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