Uses of aminopyrazole compounds

Abstract

The present invention provides the use of compounds of formula (I), being JAK inhibitors, for the treatment of JAK-1 mediated diseases such as atopic dermatitis and allergic dermatitis in young animals.

Description

[Technical field]

[0001] The present invention relates to compounds for use in the treatment of JAK-1 mediated diseases in an animal, such as, for example, atopic or allergic dermatitis. [Background technology]

[0002] Allergic diseases are one of the most serious problems in pets such as dogs, cats and horses. The symptoms of such diseases affect the health and quality of life of pets.

[0003] The potential factors involved in allergic diseases are numerous and poorly understood. These diseases are associated with an allergic reaction, a disorder or disease caused by the interaction of the immune system with a substance foreign to the body. This foreign substance is called an "allergen." Common allergens include aeroallergens such as pollen, dust, and mold, dust mite proteins, and injected saliva from insect bites.

[0004] The mammalian Janus Kinase (JAK) family of non-receptor tyrosine kinases has four members: JAK-1, JAK-2, JAK-3, and TYK-2. The JAK family is involved in intracellular signal transduction from over 70 different cytokines. Cytokines bind to receptors on the cell surface, resulting in receptor dimerization and subsequent activation / phosphorylation of JAK tyrosine kinases. Specific tyrosine residues on the receptor are then phosphorylated by activated JAKs and serve as docking sites for STAT proteins. STATs are phosphorylated by JAKs, dimerize, and then translocate to the nucleus, where they bind to specific DNA elements to activate gene transcription. JAK-1 signals in conjunction with all JAK isoforms in a cytokine-dependent manner.

[0005] JAKs are essential for multiple physiological functions, as evidenced by studies using genetically engineered mouse models lacking specific JAKs (K. Ghoreschi, A. Laurence, JJ O'Shea, Immunol. Rev. 228, 273(2009)) and by the identification of mutations in JAK enzymes associated with human disease (JJ O'Shea, M. Pesu, DC Borie, PSC Hangelian, Nat. Rev. Drug Discov. 3, 555(2004)). (Y. Minegishiet al, Immunity. 25, 745(2006)).

[0006] These mouse and human genetic data have implicated the Jak / STAT pathway in a variety of diseases and disorders, including, but not limited to, hyperproliferative diseases and cancers such as leukemia and lymphoma, transplant rejection, asthma, chronic obstructive pulmonary disease, allergies, rheumatoid arthritis, allergic and atopic dermatitis, type I diabetes, and immune and inflammatory disorders such as amyotrophic lateral sclerosis and multiple sclerosis.

[0007] In recent years, the role of mammalian Janus kinases (JAKs) in the pathophysiology of allergy has been studied and understood. Apoquel®, a commercially available JAK inhibitor, is a veterinary drug containing oclacitinib maleate as its active ingredient, and is approved for the suppression of pruritus associated with atopic dermatitis and the suppression of atopic dermatitis in dogs. Oclacitinib is a partially selective JAK-1 inhibitor.

[0008] JAK inhibitors can block the function of various cytokines that depend on JAK enzyme activity. Many of these cytokines play a role in the pathophysiology of allergic skin diseases / canine atopic dermatitis. While some of these cytokines are proinflammatory or have been implicated in allergic reactions / pruritus, these and other cytokines provoke a broad range of responses in various cell types. For example, many JAK-dependent cytokines are important components of host defense or play a role in normal hematopoiesis.

[0009] Thus, while JAK inhibitors may be useful in diseases such as atopic dermatitis that involve dysregulated cytokine signaling, there may be a wide range of other non-targeted effects (e.g., undesirable effects on host defense, hematopoiesis, etc.).

[0010] Known veterinary JAK-1 mediated diseases of importance include, for example, allergic diseases or conditions of the skin, gastrointestinal tract and respiratory tract, including allergic reactions, allergic dermatitis, atopic dermatitis, eczema, summer rash, hives, wheezing, inflammatory airway disease, recurrent airway obstruction, airway hyperresponsiveness, chronic obstructive pulmonary disease, inflammatory processes of autoimmune origin, and inflammatory diseases of non-human animals, particularly companion animals.

[0011] Many JAK-1 mediated diseases include diseases or disorders characterized by pruritic symptoms, i.e., an intense itchy sensation that causes the urge to rub or scratch the skin to relieve the itch. Animals typically demonstrate the itch sensation clinically by scratching. However, it can also be manifested by licking, sucking, biting, chewing, rubbing, or rolling.

[0012] When pruritus is uncontrolled, especially if it persists for a long period of time, secondary skin disorders often complicate treatment.

[0013] The skin condition resulting from pruritus in animals can be, for example, alopecia, scaling and hyperpigmentation, erythema, hyperpigmentation, scaling, crusting, papules and pustules. In young dogs (or older dogs with a long history of disease since developing the disease as a young animal), it can present as a chronic or chronic recurrent pyoderma.

[0014] The prevalence of atopic dermatitis is estimated at 10% of the total dog population. Globally, approximately 4.5 million dogs suffer from this chronic, lifelong disease, and incidence appears to be on the rise. The most frequently observed clinical sign is intense pruritus, which has a significant impact on the quality of life of both the animal and its owner. Its diagnosis is clinical, based on the history and characteristic clinical signs associated with the exclusion of other pruritic skin diseases. Breed and sex bias has been suspected, but it may vary significantly depending on geographic region.

[0015] Allergic dermatitis presents with multiple skin reaction patterns, all of which may be caused by environmental, food and / or insect allergens, as well as other diseases. Allergic dermatitis is thought to be caused by an abnormal response of the immune system to substances that do not elicit a reaction in healthy cats or dogs. The most consistent feature of allergic dermatitis is chronic recurrent pruritus. The potential factors involved in allergic dermatitis are numerous and poorly understood.

[0016] Current treatments depend on the severity, duration and owner preference of clinical symptoms and include allergen-specific immunotherapy and antipruritic medications such as glucocorticoids and cyclosporine. Immunosuppressants such as glucocorticoids and cyclosporine are generally effective, but long-term use often causes undesirable adverse effects. Although these drugs are effective, they have significant side effects that prevent long-term use. For example, they suppress the animal's immune system, which can lead to infections. Corticosteroids can also cause osteoporosis, endocrine problems and cataracts in dogs and cats, as well as other non-human animals. In addition, corticosteroids tend to cause animals to eat, drink and urinate frequently, which may be undesirable for pet owners.

[0017] Immunotherapy is effective in some patients but requires frequent injections and clinical improvement may not be seen for six to nine months.

[0018] Recently approved products known as Janus kinase (JAK) inhibitors, or JAK inhibitors, are also available for the treatment of atopic dermatitis.

[0019] The JAK-1 enzyme is involved in the signal transduction and transduction of pro-inflammatory, pro-allergic, and pro-pruritic cytokines associated with atopic dermatitis.

[0020] Administration of oclacitinib to dogs with allergic or atopic dermatitis rapidly improves pruritus and reduces lesion size [Cosgrove et al., Vet. Derm. (2013), 24:479;Cosgrove et al., Vet. Derm. (2013), 24:587]. Further increases in doses of oclacitinib result in decreases in hematocrit, hemoglobin, and reticulocyte counts, likely due to JAK-2 inhibition [FOI Summary NADA 141-345;Gonzales et al., J. Vet. Pharmacol. Therapeut. (2014), 37:317].

[0021] Taken together, these data strongly suggest that inhibition of JAK-1 may be an effective treatment for allergic and atopic dermatitis.

[0022] Because atopic dermatitis in dogs and cats is often a chronic condition, these safety and side effect issues result in a large unmet medical need for safe and effective long-term treatments.

[0023] Alternative JAK inhibitors are known. WO2013 / 041042 discloses pyrazolecarboxamidines as Janus kinase inhibitors useful for the treatment of rheumatoid arthritis, asthma, COPD and cancer. The disclosed compounds are represented by the formula: [ka]

[0024] WO2013 / 040863 discloses substituted cycloalkylnitrile pyrazole carboxamides that are Janus kinase 1 inhibitors useful for the treatment of, for example, asthma, obstructive airways disease, arthritis, emphysema, cancer, myasthenia gravis, Graves' disease and Alzheimer's disease.

[0025] WO2014 / 146490 discloses that substituted 2-(3-amino-4-oxo-4,5-dihydropyrazolo(4,3-c)pyridin-1-yl)-cyclobutanecarbonitrile compounds are Janus kinase inhibitors.

[0026] WO2018 / 108969 discloses compounds that are selective Janus-1 kinase (JAK) inhibitors and are therefore useful in the treatment of JAK-mediated diseases such as atopic dermatitis, arthritis and cancer. Specifically, 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxamide as a compound of formula (I) is disclosed.

[0027] Apoquel® is an animal drug containing oclacitinib as an active ingredient, approved for the treatment of pruritus associated with atopic dermatitis and for the treatment of atopic dermatitis in dogs at least 12 months of age (see FOI Summary for NADA 141-345, May 14, 2013). See also U.S. Patent Nos. 6,890,929, 7,687,507, 8,133,899, and 8,987,283. [Prior art documents] [Patent documents]

[0028] [Patent Document 1] WO2013 / 041042 [Patent Document 2] WO2013 / 040863 [Patent Document 3] WO2014 / 146490 [Patent Document 4] WO2018 / 108969 [Patent Document 5] U.S. Patent No. 6,890,929 [Patent Document 6] U.S. Patent No. 7,687,507 [Patent Document 7] U.S. Patent No. 8,133,899 [Patent Document 8] U.S. Patent No. 8,987,283 [Non-patent literature]

[0029] [Non-Patent Document 1] K. Ghoreschi, A. Laurence, JJ O′Shea, Immunol. Rev. 228, 273(2009) [Non-Patent Document 2] JJ O'Shea, M. Pesu, DC Borie, PSC hangelian, Nat. Rev. Drug Discov. 3, 555(2004) [Non-Patent Document 3] Y. Minegishiet al, Immunity. 25, 745(2006) [Non-Patent Document 4] Cosgrove et al., Vet. Derm. (2013), 24:479 [Non-Patent Document 5] Cosgrove et al., Vet. Derm. (2013), 24:587 [Non-Patent Document 6] FOI Summary NADA 141-345;Gonzales et al., J. Vet. Pharmacol. Therapeut. (2014), 37:317 [Non-Patent Document 7] FOI Summary for NADA 141-345, May 14, 2013 Summary of the Invention [Problem to be solved by the invention]

[0030] A margin of safety (MOS) study was conducted for Apoquel. This GLP study was conducted in young adult beagle dogs, approximately 6 months of age at study initiation. Oclacitinib was administered twice daily to dogs at 0, 1, 3, and 5 times the maximum exposure dose of 0.6 mg / kg. The planned duration of the study was 26 weeks. After 4 months of treatment, two dogs required euthanasia, and several dogs in the medium and high dose groups developed clinical demodicosis due to treatment-related immunosuppression. Two dogs died from infections secondary to immunosuppression, one of which died 28 days after discontinuation of oclacitinib maleate.

[0031] The trial was terminated early at 16 weeks.

[0032] The most severe adverse clinical effects were found to be in dogs less than 1 year of age. As a result of the effects observed in young dogs, the decision was made to limit its use to dogs over 1 year of age.

[0033] Thus, Apoquel, the only available JAK-1 inhibitor, is contraindicated for use in animals under 12 months of age.

[0034] Given the ongoing unmet need for safe and effective alternative treatments for atopic and allergic dermatitis in companion animals, particularly those under 12 months of age, it would be desirable to provide new effective and safe treatment options. [Means for solving the problem]

[0035] The present invention relates to a compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer thereof for use in the treatment of a JAK-1 mediated disease in a companion animal selected from dogs, cats and horses, comprising [ka] The present invention relates to a compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer thereof, comprising administering a therapeutically effective amount of such compound to an animal younger than 12 months of age.

[0036] Another embodiment is a pharmaceutical composition comprising a therapeutically effective dose of a compound of formula (I) and a pharma- ceutically acceptable carrier, for the uses indicated above. [ka]

[0037] Another aspect is a pharmaceutical composition for such use comprising a therapeutically effective dose of a compound of formula (I) as described above or a pharma- ceutically acceptable salt or stereoisomer thereof and a pharma- ceutically acceptable carrier.

[0038] In a specific embodiment, the disease is canine atopic or allergic dermatitis. [Brief description of the drawings]

[0039] [Figure 1A]Figure 1 shows the results of Compound 1 when tested in the IL-31-induced pruritus model. Figure 1A shows a comparison of Compound 1 with placebo and Apoquel. [Figure 1B] Figure 1 shows the results of Compound 1 when tested in the IL-31-induced pruritus model. Figure 1B shows the effect of three different doses of Compound 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0040] It is an object of the present invention to provide compounds that are effective and safe for the treatment of JAK-mediated diseases that can be effectively and safely administered to animals up to 12 months of age. The present invention addresses this need.

[0041] It is to be understood that the present invention is not limited to the exemplary methods or compositions disclosed herein. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the present invention only, and is not intended to be limiting.

[0042] Before describing the invention in detail, some terms used in the context of the invention are defined. In addition to these terms, other terms are defined elsewhere in this specification, as necessary.

[0043] Unless expressly defined otherwise herein, technical terms used herein have their art-recognized meanings.

[0044] As used in this specification and claims, the singular forms "a," "an," and "the" include the plural forms as well, unless the context clearly dictates otherwise.

[0045] As used herein, the term "comprising" means that the compositions and methods include the recited elements, but do not exclude other elements.

[0046] The present inventors have surprisingly found that compounds of formula (I) can be administered to young animals under the age of 12 months to treat JAK-1 mediated diseases in companion animals such as dogs, cats and horses, particularly dogs.

[0047] The compounds of formula (I) are described as JAK-1 inhibitors. The only commercially available veterinary product with such a mechanism of action is the product Apoquel, whose active ingredient is oclacitinib, which is approved for the suppression of atopic dermatitis-associated pruritus and the suppression of atopic dermatitis in dogs aged 12 months or older (see FOI Summary for NADA 141-345, May 14, 2013). See also U.S. Patent Nos. 6,890,929, 7,687,507, 8,133,899, and 8,987,283.

[0048] For Apoquel, margin of safety studies found that the most severe adverse clinical effects were observed in dogs under 1 year of age. Some of the side effects observed in young dogs (compared to adult dogs) may be due to differences in immune system capabilities. As a result of side effects observed in young dogs, it was decided that the use of Apoquel should be limited to dogs over 1 year of age.

[0049] Thus, Apoquel, the only available JAK-1 inhibitor, is contraindicated for use in children younger than 12 months of age.

[0050] Age is known to be an important factor when considering changes in animal health and disease phenotypes in general. Patient age can influence the course and progression of a disease and be important in determining the correct course of treatment.

[0051] Consequently, based on the available information, it would not be expected that JAK inhibitors would be successfully used in companion animals under 12 months of age.

[0052] However, signs of atopic dermatitis are already present in such young adult animals as under 12 months of age. The age at onset of atopic dermatitis in dogs is usually between 6 months and 3 years of age.

[0053] Dogs of this age often exhibit symptoms of pruritus associated with atopic syndrome, particularly atopic or allergic dermatitis.

[0054] It is therefore desirable to be able to treat animals under 12 months of age, especially those with skin symptoms (e.g. pruritus), at a young age and (already) when such symptoms develop.

[0055] This is of great importance in controlling the progression of such diseases: early treatment, on the one hand, prevents the worsening of symptoms at this age, and, on the other hand, prevents the appearance of secondary infections with pathogens that appear when the animal's skin barrier is destroyed by scratching.

[0056] Animals with atopic dermatitis are prone to secondary skin infections, ear infections and Malassezia (yeast) infections and often have sensitive skin. Skin infections, irritants and fleas can all exacerbate allergy symptoms and cause relapses even when under control.

[0057] Dogs with allergic dermatitis often have concurrent skin and ear infections. The skin of atopic dogs is generally overpopulated with Staphylococcus species, especially Staphylococcus pseudintermedius, which are commonly implicated in pyoderma. Studies have suggested that inflamed and atopic skin may favor the attachment of staphylococci, explaining the high abundance of this bacteria. These bacteria have also been implicated in hypersensitivity reactions, most commonly due to staphylococcal components or toxins acting as superantigens. Treatment often requires topical and / or systemic antimicrobial therapy.

[0058] As a result, pyoderma is often caused by pruritus that is not treated early enough.

[0059] Therefore, treatment of young animals, particularly dogs under 12 months of age, may be of great benefit in treating atopic and allergic dermatitis.

[0060] Surprisingly, it has been found that compounds of formula (I) can be administered to young animals, particularly dogs of about 6 to 12 months of age, as shown in Example 1, indicating that a safety margin has been established for therapeutically effective doses of compounds of formula (I).

[0061] Age is the age of the animal at the start of treatment and treatment continues beyond this age.

[0062] The compounds of formula (I) have been shown to effectively inhibit pruritus in pet animals.

[0063] Consequently, in one embodiment, the compounds of formula (I) are used to treat pruritus associated with allergic dermatitis in dogs, or to treat clinical symptoms of atopic dermatitis in companion animals, particularly dogs under the age of 12 months.

[0064] In one embodiment, the age of the treated animal is about 8-12 months.

[0065] The compounds of formula (I) can be used to suppress allergic dermatitis-associated pruritus and atopic dermatitis in pet animals, particularly dogs under the age of 12 months. In one embodiment, the animals to be treated are approximately 8 to 12 months old.

[0066] Accordingly, one of the objects of the present invention is the use of a compound of formula (I), or a pharmaceutical composition or veterinary product containing such a compound, for the manufacture of a medicament for the treatment of JAK-1 mediated atopic diseases in such young companion animals.

[0067] This is particularly useful in JAK-1 mediated diseases accompanied by pruritic symptoms such as atopic dermatitis, allergic dermatitis, eczema, or summer eczema (especially in horses).

[0068] In a particular embodiment, the disease is allergic dermatitis or atopic dermatitis. Preferably, the disease is canine or feline, especially canine atopic dermatitis.

[0069] In certain embodiments, compounds of formula (I) are used to treat clinical symptoms of atopic dermatitis in dogs.

[0070] In another embodiment, the compounds of formula (I) are used to treat pruritus associated with allergic dermatitis in dogs.

[0071] The compound for use in the present invention is a compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer thereof. [ka]

[0072] The compounds of formula (I) contain one or more asymmetric centers and may therefore occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers, and the present invention is intended to encompass all such isomeric forms of the compounds of formula I, either as single species or as mixtures thereof.

[0073] In a preferred embodiment, the compound of formula I is: [ka]

[0074] In one embodiment, the compounds of the invention are selective JAK-1 inhibitors versus JAK-2 and JAK-3. In one embodiment, the compounds of the invention are selective JAK-1 inhibitors versus JAK-2 or JAK-3. Determining the relative selectivity of a given compound for JAK1 inhibition can be done using the (JAK2 IC50 Value / JAK1 IC 50 The relative ratio of the JAK3 IC 50 Value / JAK1 IC 50 The relative ratio of the two values ​​is at least 500.

[0075] In yet another embodiment, for a given compound, (JAK2 IC 50 Value / JAK1 IC 50 In another embodiment, the relative ratio of (JAK3 IC 50 Value / JAK1 IC 50 The relative ratio of the α, β, β and β values ​​is at least 500, or at least 750, or at least 1000.

[0076] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. When the compound of the present invention is basic, salts can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids.

[0077] It will be understood that unless otherwise indicated, a reference to a compound of formula (I) is meant to also include any stereoisomers or pharma- ceutically acceptable salts thereof.

[0078] The compounds of formula (I) may be used to treat JAK-1 mediated diseases in companion animals.

[0079] In one embodiment, the JAK-1 mediated disease is one that can be ameliorated by selective inhibition of the Janus kinase JAK-1 relative to JAK2 and JAK3.

[0080] Important known JAK-1 mediated diseases in animals include, for example, allergic diseases and conditions of the skin, gastrointestinal and respiratory tract, including allergic reactions, allergic dermatitis, atopic dermatitis, eczema, summer rash, hives, wheezing, inflammatory airway diseases, recurrent airway obstruction, airway hyperresponsiveness, chronic obstructive pulmonary disease, inflammatory processes of autoimmune origin, and inflammatory diseases in non-human animals, particularly companion animals.

[0081] In a particular embodiment, the JAK-1 mediated disease is allergic dermatitis or atopic dermatitis. Preferably, the disease is atopic dermatitis in companion animals, particularly dogs or cats, preferably dogs.

[0082] These diseases are related to allergic reactions. The term "allergic reaction" is defined herein as a disorder or disease caused by an interaction between the immune system and a substance foreign to the body. This foreign substance is called an "allergen." Common allergens include pollen, dust, mold, mite proteins, and aeroallergens such as injected saliva from insect bites. Atopic dermatitis is the second most common allergic skin condition in dogs after flea allergy.

[0083] Many JAK-1 mediated diseases include pruritus. Examples of JAK-1 mediated diseases include, but are not limited to, atopic dermatitis, allergic dermatitis, eczema, and summer eczema.

[0084] Pet animals suffering from atopic or allergic dermatitis often suffer from itching, hair loss, scaling of the skin due to deep scratching, frequent paw licking, and excessive tear production.

[0085] Pruritus is a sensation and is synonymous with itch. Animals commonly manifest the itch sensation clinically by scratching; however, it may also be manifested by licking, sucking, biting, chewing, rubbing, and rolling. If the itch remains uncontrolled, especially over a long period of time, secondary skin disorders often complicate treatment.

[0086] Skin lesions resulting from pruritus in animals include alopecia, scaling, hyperpigmentation, erythema, crusting, papules and pustules. In younger dogs (or older dogs with a long history of disease since onset in the younger animal), it may present as chronic or chronic relapsing pyoderma.

[0087] As shown in Example 2, the compound of formula (I) was found to effectively suppress pruritus.

[0088] Consequently, in one embodiment, the compounds of formula (I) can be used to treat pruritus associated with allergic dermatitis in dogs. The compounds of formula (I) can be used to treat clinical symptoms of atopic dermatitis in companion animals, particularly dogs.

[0089] The compounds of formula (I) may be used to treat or inhibit pruritus associated with allergic dermatitis and to inhibit atopic dermatitis in companion animals, particularly dogs under the age of 12 months.

[0090] Pet animals include dogs (e.g., pet dogs), cats (e.g., house cats), and equines (e.g., horses). It is preferred to treat dogs or cats, especially dogs.

[0091] Additionally, the terms "treat," "treating," or "treatment," as used herein, refer to any type of action that provides a modulatory effect, which may be beneficial and / or therapeutic, to an animal suffering from a condition, disorder, disease, or condition, including, for example, amelioration of symptoms (e.g., of one or more symptoms) in a subject, slowing the progression of the disorder, disease, or condition, and / or alteration of clinical parameters of the condition, disorder, disease, or condition, as would be well known in the art.

[0092] Furthermore, as used herein, the terms "prevent", "preventing" or "prevention" refer to any type of action that results in the absence, avoidance and / or delay of the onset and / or progression of a disease, disorder and / or clinical condition in an animal, and / or a reduction in the severity of the onset of a disease, disorder and / or clinical condition compared to that which would occur in the absence of the method of the invention. Prevention may be complete, such as a complete absence of a disease, disorder and / or clinical condition. Prevention may be partial, such that the onset and / or severity of the onset of a disease, disorder and / or clinical condition in an animal is less than that which would occur in the absence of the invention.

[0093] The term "treatment" in the present invention also includes the preventive aspects mentioned above.

[0094] A "therapeutically effective dose" or "therapeutically effective amount" refers to an amount of a compound or composition of the invention sufficient to produce a desired effect, which can be a therapeutic and / or beneficial effect, that is non-toxic to animals and sufficient to achieve the desired effect by alleviating the signs and symptoms associated with a disease or disorder.

[0095] For allergic diseases, such effects are, for example, reduction or elimination of the severity and / or frequency of symptoms, and / or amelioration or repair of damage (e.g., reduction, delay and / or prevention of inflammation), and / or reduction, suppression, alleviation, or prevention of lesions and / or itch in animals suffering from atopic or allergic dermatitis.

[0096] "Non-toxic" in this document means that at a particular dose, there are no severe side effects in treated animals, which means in particular that, if any side effects are observed, they are tolerable, e.g. the clinical or microscopic findings are temporary and resolve without the need for (long-term) treatment or other intervention, or show only minor changes (e.g. in hematological parameters).

[0097] Another important aspect of such chronic diseases is that treatment with therapeutically effective and non-toxic doses of the compounds of formula (I) that inhibit pruritus significantly improves the quality of life of the animal (and the pet owner). This is also important from an animal welfare perspective, since such chronic diseases result in continued discomfort for the animal. Particularly in young dogs, about 6-12 months of age, continued pruritus can interfere with mental and physical development and lead to undesirable behaviors in the animal, which can negatively impact the socialization of the young (canine) animal.

[0098] Surprisingly, therapeutically effective doses have been observed to be well tolerated and non-toxic in young dogs aged 12 months or less, a finding that is unexpected in light of reports of side effects observed in studies administering the commercially available JAK inhibitor Apoquel to young dogs, which caused severe side effects and is contraindicated in dogs under 12 months of age.

[0099] The therapeutically effective daily dose of the compound of formula (I) is about 0.1 mg / kg to about 6.0 mg / kg. In one embodiment, the therapeutically effective dose is about 0.25 mg / kg to about 3.0 mg / kg / day, preferably 0.5 to about 1.8 mg / kg / day or about 0.6 mg / kg to about 1.2 mg / kg, or 1 mg / kg.

[0100] Preferably, a therapeutically effective amount of a compound of formula (I) is administered orally to the animal, which has the advantage that administration does not require veterinary intervention and can be continued over an extended period of time.

[0101] Atopic or allergic dermatitis often requires lifelong treatment of the condition, and in many embodiments, treatment is continued continuously daily (as maintenance therapy) for weeks, if not the life of the animal.

[0102] Typically, treatment is continued with repeated daily administration for at least 14 consecutive days, if not longer, i.e., at least one month, preferably at least four months. In many embodiments, daily treatment is continued for at least one year, if not longer, i.e., five years, up to the remainder of the animal's life.

[0103] In one embodiment, administration is repeated daily for at least four months.

[0104] In another embodiment, the administration is repeated daily for at least one year.

[0105] The desired therapeutically effective dose may conveniently be presented in a single daily dose or as divided doses administered at appropriate intervals, for example, two, three, four or more times daily.

[0106] It should also be understood that the initial dosage administered may be increased above the upper levels above in order to rapidly achieve the desired plasma concentration, whereas the initial dosage may be less than optimal and the daily dosage gradually increased over the course of treatment depending on the particular circumstances.

[0107] The daily dose can also be administered in multiple doses, for example by dividing the daily dose into halves that are administered twice a day, about 12 hours apart.

[0108] In one embodiment, a dose of a compound of formula (I) is administered twice daily initially for 2-6 weeks, followed by once daily at the same dose as maintenance therapy.

[0109] In a preferred embodiment, a compound of formula (I) is administered orally twice daily for up to 14 days, preferably 2 weeks, followed by once daily administration as a maintenance therapy, which may last for 4 months, 1 year or more.

[0110] In another preferred embodiment, a therapeutically effective amount of a compound of formula (I) is administered orally twice daily for six weeks, followed by the same dose once daily as maintenance therapy.

[0111] In some embodiments, the compounds of formula (I) are administered in combination with one or more additional active ingredients, which may be, for example, an immunomodulatory agent, an anti-inflammatory agent, or an antibiotic.

[0112] The compounds of formula (I) can be administered in a pharma- ceutically acceptable form, either alone or in combination with one or more additional active ingredients that modulate the immune system of a mammal, or with anti-inflammatory agents, such as NSAIDs or anti-inflammatory steroids (e.g., prednisolone or dexamethasone). These agents can be administered as part of the same or separate dosage forms, via the same or different routes of administration, with the same or different dosing schedules, in accordance with standard pharmaceutical practice known to those skilled in the art.

[0113] Preferably, the compound of formula (I) is administered as a pharmaceutical composition. The term "composition", as in pharmaceutical composition, is intended to include a product that contains an active ingredient and an inactive ingredient that constitutes a carrier (a pharma- ceutical acceptable excipient), as well as any product that results directly or indirectly from the combination, complexation or aggregation, or dissociation of one or more of the ingredients, or any other type of reaction or interaction of one or more of the ingredients.

[0114] Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of formula (I) and at least one pharma- ceutically acceptable excipient.

[0115] In various embodiments, the compound of formula (I) is formulated in unit dose form as a tablet or capsule. In some embodiments, the tablet or capsule is chewable. Furthermore, the texture and formulation of the unit dose form for cats is generally the same or substantially similar to that for dogs, although the unit dose form for cats may be available in smaller sizes and / or concentrations that are more suitable for smaller animals.

[0116] In one embodiment, the pharmaceutical composition for use in the present invention is a unit dose for oral administration, preferably a tablet containing a flavoring that is palatable to the intended companion animal.

[0117] In various embodiments, the compound of formula (I) is formulated into a composition that includes flavors that are palatable to the intended pet animal. For example, in some cases, formulations are provided that include flavors that are palatable to dogs. In other cases, formulations are provided that include flavors that are palatable to cats. Suitable flavors include beef, chicken, pork, fish, and turkey flavors, or other flavors used in dog and cat foods. In one embodiment, the flavor is a preparation that includes one or more of beef liver, chicken liver, pork liver, and turkey liver.

[0118] In one embodiment, the present invention provides an orally administered chewable, flavored pharmaceutical composition of a compound of formula (I) for the treatment of atopic dermatitis or allergic dermatitis in a pet animal, such as a dog or cat, preferably a dog. Preferably, such pet animal is under 12 months of age at the start of treatment.

[0119] The present invention also provides pharmaceutical formulations in the form of pastes and gels comprising a therapeutically effective amount of a compound of formula (i). In one embodiment, particularly suitable for administration to horses, a suitable dose is administered in the form of a paste to be applied to the gums and / or teeth of the horse. In another embodiment, particularly suitable for administration to cats, a suitable dose is administered in the form of a paste to be applied to the paws and / or fur of the cat.

[0120] Such pharmaceutical compositions may generally be prepared using standard pharmaceutical processes and equipment and may contain, in addition to a compound of formula (I), additional active ingredients, eg, as described above. EXAMPLES

[0121] In the examples below, compound 1 is 1-((3R,4S) or (3S,4R)-4-cyanotetrahydro-2H-pyran-3-yl)-3-((2-fluoro-6-methoxypyridin-4-yl)amino)-1H-pyrazole-4-carboxamide).

[0122] Example 1 A pilot target animal safety study was conducted.

[0123] The objective of this study was to provide margin of safety data for compound 1 administered orally to 8-month-old beagle dogs (at initiation of dosing) at 1, 3, and 5 times the maximum recommended commercial dose (0.6 mg / kg twice daily for 2 weeks and then once daily (BID) or 1.2 mg / kg once daily (SID)) for 4 months (112 consecutive days). The 2-week clinical challenge phase of the BID treatment regimen was extended to 6 weeks (3 times the proposed duration) in this study in accordance with VICH GL43.

[0124] The test article was the final formulation mixture of the investigational veterinary product filled into a gelatin capsule for administration. The control article was an empty gelatin capsule.

[0125] Additionally, a 4-month pilot targeted animal safety study was conducted in 6-month-old dogs, 3 males and 3 females per group, using doses of 0.6, 1.8, or 3.0 mg / kg twice daily for the first 6 weeks (loading phase), then reduced to once daily (BID), or a dose of 6.0 mg / kg once daily (SID) for the entire study period, compared to a control group ( Robertson, 2021 ).

[0126] All doses were well tolerated by male and female dogs and there were no changes in body weight, food consumption, ophthalmological examinations, electrocardiograms or blood pressure changes.

[0127] It can be concluded that compound 1 was administered orally daily at doses up to 5 times the maximum recommended commercial dose of 1.2 mg / kg (BID or SID administration) and was well tolerated in male and female 6-month-old beagle dogs. Minor clinical findings (e.g., interdigital cysts, conjunctivitis, gingivitis, diarrhea) were noted in overdosed animals. The cysts did not affect the overall function of the musculoskeletal system (lameness). Furthermore, the other findings mentioned above resolved with veterinary treatment. Conjunctivitis, gingivitis, diarrhea, as well as minor infections such as interdigital cysts, are commonly recurrent problems in large dog colonies and are often associated with environmental bacteria (Ledbetter et al., 2009; Kovacs et al., 2005; Saleh et al., 2016).

[0128] In summary, repeated overdoses of Compound 1 only increased susceptibility to minor infections associated with environmental bacteria (e.g., conjunctivitis, gingivitis, diarrhea, interdigital cysts). The maximum recommended commercial dose did not increase susceptibility to minor infections.

[0129] It is therefore concluded that Compound 1 is considered safe for use in young dogs.

[0130] Example 2 A canine interleukin-31 (cIL-31)-induced pruritus model in beagle dogs was used to obtain information about the dose of compound 1 required to inhibit JAK1 signaling in vivo. The cIL-31-induced pruritus model is a relevant model of acute pruritus associated with atopic and allergic dermatitis in dogs. The degree of inhibition of cIL-31-induced pruritus by JAK inhibitors is predictive of inhibition of pruritus in patients with allergic or atopic dermatitis.

[0131] As a measure of JAK-1 inhibition in vivo, and by extension the expected clinical efficacy of compound 1, we evaluated compound 1 in relevant pharmacodynamic models and included clinical criteria. Canine interleukin-31 (cIL-31) has been demonstrated to be involved in the pruritus associated with atopic and allergic dermatitis in dogs [Gonzales et al., Vet Dermatol 2013;24:48], and IL-31 can activate JAK-1 and JAK-2 signaling molecules after binding to its receptor complex [Zhang et al., Cytokine & Growth Factor Reviews 19(2008) 347-356].

[0132] Administration of cIL-31 to beagle dogs produces a robust pruritic response that can be suppressed by prior treatment with the JAK inhibitor oclacitinib [Gonzales et al., Vet Dermatol 2016;27:34-e10].

[0133] A randomized, open-label, crossover study design was used to administer Compound 1 (1 mg / kg), Apoquel, or placebo 2 hours prior to cIL-31 challenge (approximate T max ) was orally administered to laboratory beagle dogs. The dogs were observed for 2 hours after cIL-31 challenge, and the time the animals exhibited pruritic behavior was recorded.

[0134] In this study, Compound 1 significantly inhibited cIL-31-induced pruritus to a similar extent as Apoquel. A second study using a randomized, open-label, crossover design evaluated several doses of Compound 1 (0.5, 0.1, and 0.05 mg / kg) and also included Apoquel® and placebo treatments.

[0135] Compound 1 significantly suppressed pruritus at a dose of 0.5 mg / kg, but not at doses of 0.1 mg and 0.05 mg / kg. The extent of the effect was similar for Compound 1 at 0.5 mg / kg and Apoquel (registered trademark). See Figures 1A and 1B.

Claims

1. A compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer of said compound for use in the treatment of a JAK-1 mediated disease in a companion animal selected from dogs, cats and horses: [Formula 1] And, A compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer thereof comprising administering to said animal less than 12 years of age a therapeutically effective amount of such compound.

2. 2. A compound for use according to claim 1, characterized in that the compound of formula (I) is: [Case 2]

3. The compound for use according to claim 1 or 2, characterized in that the animal is about 6 to 12 months old.

4. The compound for use according to any one of claims 1 to 3, characterized in that the animal is about 8 to 12 months old.

5. A compound for use according to any one of claims 1 to 4, characterized in that the animal is a dog.

6. A compound for use according to any one of claims 1 to 5, characterized in that the atopic disease is allergic dermatitis or atopic dermatitis.

7. 7. The compound for use according to claim 6, characterized in that said compound is used for the treatment of clinical symptoms of atopic dermatitis.

8. 7. The compound for use according to claim 6, characterized in that the compound is used for the treatment or inhibition of pruritus associated with allergic dermatitis.

9. The compound for use according to any one of claims 1 to 8, characterized in that said therapeutically effective dose of said compound is from about 0.1 mg / kg / day to about 6.0 mg / kg / day.

10. The compound for use according to claim 9, characterized in that said therapeutically effective dose is from about 0.25 mg / kg / day to about 3.0 mg / kg / day, preferably from 0.6 to about 1.8 mg / kg / day.

11. 10. The compound for use according to claim 9, wherein said therapeutically effective dose is from about 0.6 mg / kg / day to about 1.2 mg / kg / day.

12. The compound for use according to any one of claims 1 to 11, characterized in that said therapeutically effective dose is administered orally.

13. A compound for use according to any one of claims 1 to 12, characterized in that said administration is repeated daily for at least 4 months.

14. 14. The compound for use according to claim 13, characterized in that said administration is repeated daily for at least one year.

15. The compound for use according to any one of claims 1 to 14, characterized in that the dose of said compound is initially administered twice a day for 2 to 6 weeks, and then once a day.

16. The compound for use according to any one of claims 1 to 15, characterized in that the compound of formula (I) is administered in combination with one or more additional active ingredients.

17. 17. A compound for use according to claim 16, characterized in that such additional active ingredient is an immunomodulatory agent, an anti-inflammatory agent, or an antibiotic or antifungal agent.

18. A compound of formula (I) for use according to any one of claims 1 to 17: [C3] Or a pharmaceutical composition comprising a pharma- ceutically acceptable salt or stereoisomer of said compound.

19. The compound of formula (I) [C4] 19. The pharmaceutical composition for use according to claim 18, characterized in that it is

20. 20. A pharmaceutical composition for use according to claim 18 or 19, characterized in that the composition is a unit dosage form for oral administration, preferably a tablet containing a flavour that is palatable to the intended pet animal.

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