RU2821362C2 - Lta4h inhibitors for treating purulent hydradenitis - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to methods of treating purulent hydradenitis, specifically to the use of an LTA4H inhibitor for treating or preventing purulent hydradenitis in a patient in need of such treatment. Said LTA4H inhibitor is (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2 H-tetrazol-2-yl)butanoic acid or a pharmaceutically acceptable salt thereof; or said LTA4H inhibitor is a crystalline form (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid in its free form, where said crystalline form is characterized by a powder X-ray diffraction pattern containing characteristic peaks at 2θ at 22.6 ± 0.2 °2θ, 24.1 ± 0.2 °2θ and 26.3 ± 0.2 °2θ measured at temperature of approximately 25 °C, and at x-ray wavelength λ of 1.5418 Å. Invention also relates to use of a pharmaceutical composition based on said compound or its crystalline form.

EFFECT: treatment with said compound or its crystalline form of purulent hydradenitis.

10 cl, 17 dwg, 2 tbl, 8 ex

Description

Field of technology to which the invention relates

The present invention relates to methods of treating hidradenitis suppurativa using leukotriene A4 hydrolase (LTA4H) inhibitors.

BACKGROUND OF THE INVENTION

Hidradenitis suppurativa (HS) (also called acne inversus or Verneuil's disease) is a chronic, relapsing inflammatory disease characterized by deep-seated nodules, fistulous tracts, and abscesses that lead to fibrosis in the axillary, inguinal, breast, and anogenital areas. (Revuz and Jemec (2016) Dermatol Clin 34:1-5; Jemec GB. (2012) N Engl J Med 366:158-64). It is associated with severe pain and comorbidities, including metabolic, psychiatric, and autoimmune disorders, as well as an increased risk of skin cancer. (Revuz (2016); Shlyankevich et al. (2014) J Am Acad Dermatol 71:1144-50; Kohorst et al. (2015) J Am Acad Dermatol 73:S27-35; Wolkenstein et al. (2007) J Am Acad Dermatol 56:621-3).

Published prevalence rates of HS range from <1% to 4% of the population. [Shlyankevich et al. (2014); Cosmatos et al. (2013) J Am Acad Dermatol 68:412-9; Davis et al. (2015) Skin Appendage Disord 1:65–73; Revuz et al. (2008) J Am Acad Dermatol 59:596–601; McMillan K (2014) Am J Epidemiol 179:1477–83; Garg et al. (2017) J Am Acad Dermatol, 77(1):118-122; Jemec et al. (1996) J Am Acad Dermatol 35:191-4]. However, true prevalence is difficult to establish because HS is rarely diagnosed and estimates vary depending on study design, population, and geographic location. [Miller et al. (2016) Dermatol Clin 34:7-16]. Although the National Institutes of Health (NIH) does not classify HS as a rare disease, experts generally estimate that the prevalence of the disease is <1% of the United States (US) population. [Cosmatos et al. (2013); Genetic and Rare Diseases Information Center. National Institutes of Health. Hidradenitis suppurativa. Available at: //rarediseases.info.nih.gov/diseases/6658/hidradenitis-suppurativa. Accessed March 20, 2017; Gulliver et al. (2016) Rev Endocr Metab Disord 17:343–51; Garg et al. 2007].

Current treatment for HS is the use of topical and/or systemic antibiotics, hormonal interventions, retinoids and, in some cases, immunosuppressants, biologics such as the tumor necrosis factor [TNF] inhibitor monoclonal antibody adalimumab, which is the only approved drug for HS, and often, as a last resort, extensive surgical removal. [Gulliver et al. (2016); Zouboulis et al. (2015) J Eur Acad Dermatol Venereol 29:619-4414-16; Kimball et al. (2016) N Engl J Med 375:422–34]. Because the lesions are painful, patients often require analgesics and pain relief.

However, symptom control and lesion resolution are not consistent among treatments, and randomized controlled clinical trials providing evidence are lacking for most treatments, with only adalimumab approved. Although antibiotic therapy is used as a long-term treatment for months or even years, antibiotic therapy may thus lead to the development of antibiotic resistance. Oral treatment with retinoids raises concerns about teratogenicity in sexually active populations that are predominantly female. Moreover, the effectiveness of anti-inflammatory drugs such as dapsone, fumarates, and cyclosporine is based on small diagnostic studies with variable results, and these molecules are not used systematically. Because of these conflicting findings and the severity of HS disease, patients with HS utilize health care in high-cost settings (eg, emergency department and hospital care) at a higher rate than patients with other chronic inflammatory skin conditions. (Khalsa et al. (2016) J Am Acad Dermatol 73:609-14; Kirby et al. (2014) JAMA Dermatol 150:937-44). Because there is no medical treatment for HS and the disease is physically and psychologically debilitating, there is a clear unmet need to provide safe and effective long-term treatment options for patients with HS, particularly oral treatments.

BRIEF DESCRIPTION OF THE PRESENT INVENTION

Although the pathogenesis of HS is still incompletely understood, this chronic skin disease is characterized by a large number of neutrophils and macrophages in the inflammatory lesions of HS. It is obvious that neutrophils and macrophages are key factors in the pathological mechanism of hidradenitis suppurativa [Shah et al (2017), “The critical role of macrophages in the pathogenesis of hidradenitis suppurativa.” Inflamm. Res. 66(11): 931-945; [Lima et al (2016), “Keratinocytes and neutrophils are important sources of proinflammatory molecules in hidradenitis suppurativa.” Br. J. Dermatol. 174: 514-21; Neutrophils and macrophages are the main producers and target cells of the lipid inflammatory mediator leukotriene B4 (LTB4) and the anti-inflammatory pro-resolving mediator lipoxin A4 (LXA4) (Serhan et al 2008, “Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators." Nat. Rev. p. 349-61). The pro-inflammatory lipid mediator LTB4 is one of the most effective chemotactic molecules for neutrophils and monocytes, and can stimulate and activate both neutrophils and macrophages [Marc Peters-Golden and William R Henderson (2007) “Leukotrienes”, N Engl J Med 357: 1841-1854]. Application of LTB4 to healthy skin induces the migration of IL-17+ neutrophils involved in the pathological mechanism of HS [Lima et al (2016), “Keratinocytes and neutrophils are important sources of proinflammatory molecules in hidradenitis suppurativa.” Br. J. Dermatol. 174: 514-21.], formation of neutrophilic abscesses and hyperproliferation of keratinocytes. [Hendriks et al (2014) “Cutaneous application of leukotriene B4 as an in vivo model of psoriasis-like skin inflammation: an immunohistological study,” Skin Pharmacol Physiol 27 (3):120-6. The relevance of LTB4 has been clinically demonstrated for the related skin pathology inflammatory acne (Zouboulis et al 2003, “A new concept for acne therapy: a pilot study with zileuton, an oral 5-lipoxygenase inhibitor. Arch Dermatol” p. 668-70) .

Self-performed lipidomic analysis of HS biopsies showed a strong increase in the level of the lipid mediator LTB4 in the lesional skin of HS patients compared with healthy skin. In addition, leukocytes in the lesions were predominant, and they showed strong expression of 5-lipoxygenase and intracellular localization of this enzyme on the perinuclear membrane, which is a clear sign of activation of the 5-lipoxygenase pathway leading to the production of LTB4. (Christmas et al 1999, “Differential localization of 5- and 15-lipoxygenases to the nuclear envelope in RAW macrophages.” J. Biol. Chem. p. 25594-8). Transcriptomic analysis of the lesions showed overexpression of the 5-lipoxygenase pathway genes ALOX5 and LTA4H, two enzymes responsible for the biosynthesis of LTB4 from arachidonic acid [Marc Peters-Golden and William R Henderson (2007) “Leukotrienes”, N Engl J Med 357:1841-1854 ]. Inhibition of the terminal and rate-limiting enzyme LTA4H of the 5-lipoxygenase pathway can prevent the biosynthesis of pro-inflammatory LTB4 but maintain or even increase the biosynthesis of anti-inflammatory LXA4. Additionally, increasing LXA4 levels may influence fibrosis in addition to the anti-inflammatory effect of the drug ( et al. 2011, “Lipoxin A4 and benzo-lipoxin A4 attenuate experimental renal fibrosis.” FASEB J.p. 2967-79).

The compounds described herein inhibit LTA4H and thereby prevent the biosynthesis of the pro-inflammatory leukotriene B4 (LTB4) but increase the formation of the anti-inflammatory pro-inflammatory lipoxin A4 (LXA4). Both lipid mediators are known to play important roles in coordinating neutrophilic inflammation. Inhibition of LTA4H represents a significant mechanism for the treatment of neutrophil-mediated inflammatory conditions.

It is therefore an object of the present invention to provide a new method of treating or preventing hidradenitis suppurativa (HS) in a subject in need thereof, comprising administering to said subject an effective amount of a leukotriene A4 hydrolase inhibitor (LTA4H).

More specifically, the present invention relates to a method of treating or preventing hidradenitis suppurativa in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (I):

(I),

Where

R1 represents OH or NH ₂ ;

Y is O, S or CH ₂ ;

X1, X2, X3 and X4 represent N; or

X1, X2, X3 and X4 are selected from N, NH, C, CH and O, provided that at least two of X1, X2, X3 or X4 are N or NH;

R2 is C ₁ -C ₆ alkyl, optionally substituted with phenyl; C ₃ -C ₆ cycloalkyl; phenyl, optionally substituted with halogen, cyano, C ₁ -C ₆ alkyl, optionally substituted with halogen, C ₁ -C ₆ alkoxy or a 5-6 membered heteroaryl ring containing from 1 to 3 heteroatoms selected from N, O and S; or a 5-10 membered mono- or bicyclic heteroaryl containing from 1 to 4 heteroatoms selected from N, O and S, wherein said heteroaryl is optionally substituted with halogen, cyano or C ₁ -C ₆ alkyl, optionally substituted with halogen; or a pharmaceutically acceptable salt thereof.

The present invention further provides a method of treating or preventing HS in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of an LTA4H inhibitor with one or more therapeutic agents.

In another aspect of the present invention, the present invention provides an LTA4H inhibitor for use in the treatment and/or prevention of HS in a patient in need of such treatment and/or prevention. More specifically, the present invention relates to a compound of formula (I) as described above, for use in the treatment and/or prevention of HS in a patient in need of such treatment and/or prevention.

The present invention further relates to combinations of an LTA4H inhibitor with one or more additional therapeutic agents for use in the treatment or prevention of HS in a patient in need of such treatment and/or prevention.

BRIEF DESCRIPTION OF GRAPHIC MATERIALS

Figure 1 shows an illustrative XRPD spectrum for the crystalline form ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl) -2H -tetrazol- 2-yl)butanoic acid in its free form, designated herein as Form B, with the X-axis denoting degrees 2θ (2-theta) and the Y-axis denoting relative intensity.

Figure 2 shows exemplary DSC results for the free form ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl) -2H -tetrazol- 2-yl)butanoic acid, referred to herein as Form B.

Figure 3 presents illustrative TGA results for the free form ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl) -2H -tetrazol- 2-yl)butanoic acid, referred to herein as Form B.

More detailed lists of XRPD peaks for each of the B forms are presented in Table 1 below, which also provides % relative intensity values (I/I ₀ x 100). It should be understood that there is natural variability in X-ray powder diffraction spectra or X-ray powder diffraction patterns with respect to the values measured in degrees 2θ (°2θ), resulting, for example, from instrument error (including differences between instruments). In this regard, it should be understood that there is a 2θ component of up to ±0.2° variability in XRPD peak measurements and, however, such peak values will also be considered representative of the particular solid form of the crystalline substances described herein. It should also be understood that other measured values from XRPD experiments and DSC/TGA experiments, such as relative intensity and water content, may vary as a result of, for example, sample acquisition and/or storage conditions and/or environmental conditions, and the measured values will also be considered characteristic of the particular solid form of the crystalline substances described herein.

Figure 4 shows the analysis of lesions in patients with HS by immunohistochemical examination using H&E staining.

Figure 5 shows immunohistochemical analysis of biopsies of HS-affected skin.

Figure 6 is an illustrative micrograph showing 5-lipoxygenase localized to the nuclear membrane in a multinucleated CD68+ giant cell.

Figure 7 shows LC-MS/MS analysis of lipids from biopsies of HS-affected skin and skin from healthy volunteers for LTB4 content.

Figure 8 shows the LC-MS/MS analysis of lipids from biopsies of HS-affected skin and skin from healthy volunteers for 5-HETE content.

Figure 9 shows transcriptomic analysis for HS-affected skin biopsies compared to healthy skin biopsies.

Figure 10 shows the inhibition by the compound of Example 1 of the biosynthesis of pro-inflammatory LTB4 in skin biopsies from HS patients as measured by LC-MS/MS.

Figure 11 shows the inhibition by the compound of an embodiment of 3D biosynthesis of pro-inflammatory LTB4 in skin biopsies from HS patients as measured by LC-MS/MS.

Figure 12 shows the inhibition of LTB4 release from ex-vivo stimulated blood in mice treated with 3 mg/kg or 10 mg/kg ( S )-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl) -2H -tetrazol-2-yl)butanoic acid (the compound according to Embodiment 3D).

Figure 13 shows mean plasma concentration versus time profiles following a single oral administration of ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl )-2 H -tetrazol-2-yl)butanoic acid (compounds from Example 1) at different doses.

Figure 14 shows the mean plasma concentration versus time profile after repeated oral administration of ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl ) -2H -tetrazol-2-yl)butanoic acid (compound of Example 1) at different doses (Figure 14a: day 1; Figure 14b: day 12).

Figure 15 shows the concentration of LTB4 in ex-vivo stimulated blood after oral administration of ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)- 2 H -tetrazol-2-yl)butanoic acid (the compound of Example 1) at the measured concentration of the compound of Example 1 in blood plasma (PK/PD relationship).

Figure 16 shows the change in LTB4 from baseline (inhibition in blood) after repeated oral administration of ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy) phenyl) -2H -tetrazol-2-yl)butanoic acid (the compound of Example 1) at different doses, measured at different times (days) after the first dose.

Figure 17 shows the inhibition of LTB4 in skin and plasma following oral administration of ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2 H -tetrazol-2-yl)butanoic acid (compounds from example 1).

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “C ₁ -C ₆ alkyl” refers to a fully saturated branched or straight-chain hydrocarbon moiety containing up to 6 carbon atoms. Unless otherwise stated, it refers to hydrocarbon moieties containing 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms. Illustrative examples of alkyl include, but are not limited to, methyl, ethyl, n -propyl, iso -propyl, n -butyl, sec -butyl, iso -butyl, tert -butyl, n -pentyl, isopentyl, neopentyl and n -hexyl, and the like.

As used herein, the term “C ₁ -C ₆ alkoxy” refers to alkyl-O-, where alkyl is defined herein above. Illustrative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, t -butoxy, pentyloxy, hexyloxy, cyclopropyloxy, cyclohexyloxy, and the like. Typically, alkoxy groups contain from about 1 to 6 carbon atoms, from 1 to 4 carbon atoms or 1 to 2 carbon atoms.

As used herein, the term “C ₁ -C ₆ alkyl, optionally substituted with halogen” refers to C ₁ -C ₆ alkyl, as defined above, which may be substituted with one or more halogen atoms. Examples include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, and 1-bromomethyl-2-bromoethyl.

As used herein, the term “di-C _1-6 alkylamino” refers to a moiety of the formula -N(R _a )-R _a , wherein each R _a is a C _1-6 alkyl, which may be identical or different as defined above .

As used herein, the term “C ₃ -C ₆ cycloalkyl” refers to saturated monocyclic hydrocarbon groups of 3-6 carbon atoms. A cycloalkyl may also be referred to as a carbocyclic ring and vice versa, with the additional indication of the number of carbon atoms present. Unless otherwise specified, cycloalkyl refers to cyclic hydrocarbon groups containing 3 to 6 ring carbon atoms or 3 to 4 ring carbon atoms. Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

As used herein, the term “halogen” or “halo” refers to fluorine, chlorine, bromine and iodine.

As used herein, the term “heteroaryl” refers to a 5-14 membered monocyclic or bicyclic or tricyclic aromatic ring system containing from 1 to 8 heteroatoms. Typically, heteroaryl is a 5-10 membered ring system containing from 1 to 4 heteroatoms selected from N, S or O (e.g. 5-7-membered monocycle or 8-10-membered bicycle) or 5-7-membered ring system. Preferably, the term “heteroaryl” includes a 5-7 membered monocycle. Typical heteroaryl groups include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3- or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4- or 5-pyrazinyl, 2-pyrazinyl, and 2-, 4- or 5-pyrimidinyl.

The term “heteroaryl” also refers to a group in which the heteroaromatic ring is fused to one or more aryl, cycloaliphatic or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7- or 8-indolizinyl, 1-, 3-, 4-, 5-, 6- or 7-isoindolyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 4-, 5-, 6-, 7- or 8-purinyl , 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1- , 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl, 2-, 3-, 4-, 5- or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 6 - or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-4aH-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6- , 7- or 8-carbzaolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8- or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7- , 8-, 9- or 10-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, 1-, 2-, 4-, 5- , 6-, 7-, 8- or 9-perimidinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9- or 10-phenatrolinyl, 1-, 2-, 3-, 4- , 6-, 7-, 8- or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenothiazinyl, 1-, 2-, 3- , 4-, 6-, 7-, 8-, 9- or 10-phenoxazinyl, 2-, 3-, 4-, 5-, 6- or l-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-benzisoquinilinyl, 2-, 3-, 4- or thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10 - or 11-7H-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5-, 6- or 7-2H-furo[3,2-b]pyranyl, 2-, 3-, 4-, 5-, 7- or 8-5H-pyrido[2,3-d]-o-oxazinyl, 1-, 3- or 5-1H-pyrazolo[4,3-d]-oxazolyl, 2-, 4- or 5-4H-imidazo[4,5-d]-thiazolyl, 3-, 5- or 8-pyrazino[2,3-d]-pyridazinyl, 2-, 3-, 5- or 6 -imidazo[2,1-b]-thiazolyl, 1-, 3-, 6-, 7-, 8- or 9-furo[3,4-c]-cinnolinyl, 1-, 2-, 3-, 4 -, 5-, 6-, 8-, 9-, 10- or 11-4H-pyrido[2,3-c]-carbazolyl, 2-, 3-, 6-, or 7-imidazo[1,2- b][1,2,4]-triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 2-, 4-, 5-, 6- or 7- benzimidazolyl, 2-, 4-, 4-, 5-, 6- or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-benzoxapinyl, 2-, 4 -, 5-, 6-, 7- or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-1H-pyrrolo[1, 2-b][2]-benzazapinyl. Typical linked heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl , 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6- or 7-benzo[b]thienyl, 2-, 4-, 5 -, 6- or 7-benzoxazolyl, 2-, 4-, 5-, 6- or 7-benzimidazolyl and 2-, 4-, 5-, 6- or 7-benzothiazolyl.

Substituted heteroaryl is a heteroaryl group containing one or more substituents.

As used herein, the term “heterocyclyl” refers to a heterocyclic group that is saturated or partially saturated, and is preferably a monocyclic or polycyclic ring (in the case of a polycyclic ring, in particular a bicyclic, tricyclic or spirocyclic ring); and contains from 3 to 24, more preferably from 4 to 16, most preferably from 5 to 10, and most preferably 5 or 6 ring atoms; where one or more, preferably one to four, especially one or two ring atoms are a heteroatom (the remaining ring atoms are therefore carbon atoms). The linking ring (ie the ring connected to the molecule) preferably contains from 4 to 12, especially from 5 to 7 ring atoms. The term heterocyclyl excludes heteroaryl. A heterocyclic group may be attached to a heteroatom or carbon atom. Heterocyclyl may include fused or bridged rings, as well as spirocyclic rings. Examples of heterocycles include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, etc.

A substituted heterocyclyl is a heterocyclyl group independently substituted with 1-4, such as one, or two, or three, or four substituents.

As used herein, the term “aryl” refers to an aromatic hydrocarbon group containing 6-20 carbon atoms in the ring portion. Typically, aryl is monocyclic, bicyclic or tricyclic aryl containing 6-20 carbon atoms. In addition, the term "aryl" as used herein refers to an aromatic substituent, which may be a single aromatic ring or multiple aromatic rings coupled to each other. Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl.

Substituted aryl is an aryl group substituted with 1-5 (such as one, or two, or three) substituents independently selected from the group consisting of hydroxyl, thiol, cyano, nitro, C₁-C₄-alkyl, C₁-C₄-alkenyl, C₁-C₄-alkynyl, C₁-C₄-alkoxy, C₁-C₄-thioalkyl, C₁-C₄-alkenyloxy, C₁-C₄-alkynyloxy, halogen, C₁-C₄-alkylcarbonyl, carboxy, C₁-C₄-alkoxycarbonyl, amino, C₁-C₄-alkylamino, di-C₁-C₄-alkylamino, C₁-C₄-alkylaminocarbonyl, di-C₁-C₄-alkylaminocarbonyl, C₁-C₄-alkylcarbonylamino, C₁-C₄-alkylcarbonyl(C₁-C₄-alkyl)amino, sulfonyl, sulfamoyl, alkylsulfamoyl, C₁-C₄-alkylaminosulfonyl, where each of the above hydrocarbon groups (for example, alkyl, alkenyl, alkynyl, alkoxy radicals) may be further substituted by one or more radicals, independently selected in each case from halogen, hydroxyl or C₁-C₄-alkoxy groups.

As used herein, the terms “about” and “substantially” indicate with respect to characteristics such as endotherms, endothermic peak, ectotherms, baseline offsets, etc. that their values may vary. With respect to X-ray diffraction peak positions, the terms “about” or “substantially” mean that the typical variability in peak position and intensity is taken into account. For example, one of ordinary skill in the art will appreciate that the (2θ) peak positions will exhibit some variability between devices, typically up to 0.2°. Sometimes variability can be greater than 0.2° depending on differences in device calibration. In addition, one skilled in the art will appreciate that relative peak intensity values will exhibit inter-device variability, as well as variability due to degree of crystallinity, preferred orientation, surface of the resulting sample, and other factors known to those skilled in the art, and should be considered solely as qualitative indicators. In the case of DSC, the change in observed temperature values will depend on the rate of temperature change, as well as the sample acquisition technique and the specific instrument used. Therefore, the endotherm/melting point values given herein related to DSC/TGA thermograms may vary by ±5°C (and are also considered to be representative of the particular crystalline form described herein). When used in the context of other specifications such as percentage by weight (% by weight), reaction temperatures, the term “about” indicates a deviation of ±5%.

As used herein, the expression “substantially pure phase,” when used in relation to any crystalline form of a compound of Formula I, means a compound having a phase purity of greater than about 90% by weight, including greater than about 90, 91, 92, 93, 94, 95, 96, 97, 98 and about 99% by weight, and including equal to about 100% by weight of the compound of Formula I, based on the weight of the anhydrous compound. The term “pure phase” or “phase purity” as used herein refers to phase uniformity with respect to a particular solid form of a compound of formula I and does not necessarily imply a high degree of chemical purity unless expressly indicated thereto. Phase purity can be determined according to methods known in the art, e.g., using XRPD, to perform quantitative phase analysis using one or more approaches known in the art, e.g., using an external standard method, direct linear comparisons ( peak) characteristics that relate to different phases in specific spectra, or by using an internal standard method. However, quantification of phase purity using XRPD can be complicated by the presence of amorphous material. Accordingly, other methods that can be used to determine phase purity include, for example, solid state NMR spectroscopy, Raman spectroscopy and/or infrared spectroscopy. One skilled in the art will readily understand such methods and how to employ such additional (or alternative) methods for determining phase purity.

As used herein, the terms “salt” or “salts” refer to the acid addition or base addition salt of a compound for use in the method of the present invention. “Salts” include, in particular, “pharmaceutically acceptable salts”. The term “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compounds of the present invention and which are generally not biologically or otherwise undesirable. In many cases, the compounds for use in the method of the present invention are capable of forming acidic and/or basic salts due to the presence of amino and/or carboxyl groups or the like.

Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids, e.g. acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, Odide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulfate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, stearate, succinate, subsalicylate, tartrate, tosylate and trifluoroacetate salts.

Inorganic acids from which salts can be prepared include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can be prepared include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, etc. Pharmaceutically acceptable base addition salts can be formed using inorganic and organic bases.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table of elements. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

Pharmaceutically acceptable salts for use in the present invention can be synthesized from the basic or acid moiety using conventional chemical methods. Typically, such salts can be prepared by reacting the free acid forms of such compounds with a stoichiometric amount of a suitable base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.) or by reacting the free base forms of such compounds with stoichiometric amount of a suitable acid. Such reactions are typically carried out in water or an organic solvent or a mixture of both. It is generally desirable to use a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile when practical. Listings of additional suitable salts can be found, for example, in “Remington's Pharmaceutical Sciences , ” 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Any formula given herein also implies the presence of unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds are characterized by the structures depicted in the formulas given herein, except that one or more atoms are replaced by an atom having the selected atomic mass or mass number. Examples of isotopes that may be included in the compounds (i.e., the LTA4H inhibitor described herein) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl, ¹²⁵ I, respectively. The present invention includes various isotopically labeled compounds as defined herein, for example, compounds in which radioactive isotopes are present, such as ³ H and ¹⁴ C, or compounds in which non-radioactive isotopes are present, such as ² H and ¹³ C Such isotope-labeled compounds are useful in metabolic studies (using ¹⁴ C), reaction kinetic studies (eg using ² H or ³ H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography. tomography (SPECT), including analyzes of drug or substrate distribution in tissues, or during radiation therapy of patients. In particular, the ¹⁸ F labeled compound may be particularly useful for PET or SPECT studies. Isotopically labeled compounds of formula (I) generally can be prepared by conventional techniques known to those skilled in the art, or by methods similar to those described in the accompanying examples and methods of preparation, using suitable isotopically labeled reagents in place of the unlabeled reagent used previously.

In addition, substitution with heavier isotopes, particularly deuterium (i.e., ^2H or D), may provide certain therapeutic benefits due to greater metabolic stability, such as increased in vivo half-life, or reduced dosage requirements, or improvement regarding the therapeutic index. It should be understood that deuterium is considered in this context as a substitute for the compound of formula (I). The concentration of such a heavier isotope, specifically deuterium, can be determined by means of an isotope enrichment factor. As used herein, the term "isotopic enrichment factor" means the ratio of the abundance of an isotope to the natural occurrence of that isotope. Where the substituent in a compound of the present invention is specified deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (incorporation of 52.5% deuterium for each designated deuterium atom), at least 4000 ( injection of 60% deuterium), at least 4500 (injection of 67.5% deuterium), at least 5000 (injection of 75% deuterium), at least 5500 (injection of 82.5% deuterium), at least 6000 (injection of 90 % deuterium), at least 6333.3 (injection of 95% deuterium), at least 6466.7 (injection of 97% deuterium), at least 6600 (injection of 99% deuterium) or at least 6633.3 (injection of 99 .5% deuterium).

Pharmaceutically acceptable solvates for use in the method of the present invention include those wherein the crystallization solvent may be replaced by an isotope, e.g. D₂O,d₆-acetone, d₆-DMSO.

Compounds for use in the method of the present invention, ie compounds of formula (I) which contain groups capable of acting as hydrogen bond donors and/or acceptors, may be capable of forming cocrystals with suitable cocrystal forming agents. Such cocrystals can be prepared from compounds of formula (I) by known cocrystal preparation procedures. Such procedures include grinding, heating, co-sublimation, co-melting or contacting in solution the compounds of formula (I) with an agent to form co-crystals under crystallization conditions and isolating the co-crystals thus formed. Suitable means for forming cocrystals include those described in WO 2004/078163. Therefore, the present invention further provides cocrystals containing a compound of formula (I) for use in the method of the present invention.

As used herein, the term “administration” with respect to a compound, eg, an LTA4H inhibitor (eg, a compound of Formula I or a specific compound described herein) or other means is used to mean delivery of the compound to a patient by any route.

As used herein, the term "pharmaceutically acceptable carrier" includes all possible solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g. antibacterial agents, antifungal agents), isotonicity agents, absorption retardants, salts, preservatives, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, coloring agents, etc. and their combinations that will be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Unless any conventional carrier is incompatible with the active ingredient, it is intended for use in therapeutic or pharmaceutical compositions.

The term "therapeutically effective amount" of a compound for use in the method of the present invention refers to the amount of said compound that will produce a biological or medical response in a subject, such as reducing or inhibiting the activity of an enzyme or protein, or reducing the severity of symptoms of HS, alleviating associated HS conditions, slow or delay disease progression in HS, or prevent HS. In one non-limiting embodiment, the term “therapeutically effective amount” refers to that amount of a compound that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit, prevent, and/or ameliorate the manifestations of the HS condition . In another non-limiting embodiment, the term “therapeutically effective amount” refers to that amount of a compound that, when administered to a cell or tissue or non-cellular biological material or environment, is effective to at least partially reduce or inhibit the activity of LTA4H; or partial or complete reduction or inhibition of LTA4H expression.

As used herein, the term “subject” refers to an animal. Typically the animal is a mammal. Subject also refers to, for example, primates (e.g. humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human. The term “subject” is used interchangeably with “patient” when referring to a person.

As used herein, the phrase “patient population” means a group of patients. In some embodiments of the disclosed methods, an LTA4H inhibitor (eg, a compound of Formula I, or a compound disclosed in WO2015/092740, or any compound described herein) is used to treat a population of patients with HS.

As used herein, the phrases “previously systemically treated for HS” and “treatment naïve” refer to a patient with HS who has not previously been treated for HS with a systemic agent, such as methotrexate, cyclosporine, or a biologic agent (such as for example, IL-12 and IL-23 blockers such as ustekinumab and guselkumab, or using TNF-alpha inhibitors such as infliximab, or using an IL-17 blocker such as secukinumab, ixekizumab and brodalumab). Systemic agents (i.e., agents administered orally, by injection, etc.) differ from locally acting agents (e.g., topical agents and phototherapy) in that systemic agents have a systemic (whole-body) effect when delivered to the patient . In some embodiments of the disclosed methods, regimens, uses, kits, and pharmaceutical compositions, the patient has not previously received systemic treatment for HS.

As used herein, the phrase “previously treated with a systemic agent for HS” is used to refer to a patient who has previously been treated for HS with a systemic agent. Such patients include those who have previously been treated with biologics such as IL-12 and IL-23 blockers such as ustekinumab and guselkumab, or with TNF-alpha inhibitors such as infliximab, or with an IL-17 blocker , such as secukinumab, ixekizumab and brodalumab, as well as those previously treated with non-biological agents, such as a systemic immunosuppressant or immunomodulators (for example, cyclosporine, methotrexate and cyclophosphamide), using systemic treatments, including retinoids ( such as isotretinoin), dapsone, metformin and an oral zinc-based treatment. In some embodiments of the present invention, the patient has previously been administered a systemic agent to treat HS. In some embodiments, the patient has previously been administered a systemic drug for HS (e.g., methotrexate, cyclosporine), but the patient has not previously been administered a systemic biological drug (i.e., a drug produced by a living organism, e.g., antibodies, decoy receptors, etc.). etc.) for the treatment of HS (eg, secukinumab, ustekinumab, ixekizumab, brodalumab, TNF-alpha inhibitors (etanercept, adalimumab, remicade, etc.). In this case, the patient is called “biologic naïve.” In In some embodiments, the patient is naïve to treatment with the biological agent.

As used herein, the terms “selected” and “selected” when used in relation to a patient mean that a particular patient is specifically selected from a larger group of patients based on the fact that the particular patient meets predetermined criteria. Likewise, “selective treatment” refers to the provision of treatment to a patient having a particular disease, wherein that patient is specifically selected from a larger group of patients based on the fact that the particular patient meets a predetermined criterion. Likewise, “selective administration” refers to the administration of a drug to a patient that is specifically selected from a larger group of patients based on the fact that the particular patient meets a predetermined criterion. By screening, selective treatment, and selective administration, we mean that the patient is provided with personalized therapy based on the patient's personal history (eg, previous therapeutic interventions, such as previous treatment with biologics), biology (eg, specific genetic markers) and/or manifestation (eg, failure to meet certain diagnostic criteria), rather than applying a standard treatment regimen based solely on the patient's membership in a larger group. Selection, as used in the context of this document, does not refer to randomly treating a patient who meets a particular criterion, but rather refers to an informed decision made regarding the administration of a drug to a patient based on the patient meeting a particular criterion. Thus, selective treatment/administration differs from standard treatment/administration, which provides delivery of a specific drug to all patients with a specific disease, regardless of their personal history, disease manifestations and/or biological characteristics. In some embodiments, a patient is selected for treatment based on the presence of HS.

As used herein, the term “suppress,” “suppress,” or “suppress” refers to a decrease in the severity or suppression of a condition, symptom, or disorder, or disease in question, or a significant decrease in the baseline activity level of a biological activity or process.

As used herein, the terms “treat,” “treat,” or “cure” any disease or disorder refer in one embodiment to reducing the severity of the disease or disorder (i.e., slowing, stopping, or reducing the development or progression of the disease or at least one of its clinical symptoms). In another embodiment, the expressions “treat,” “treat,” or “treat” refer to alleviating or reducing the severity of at least one physical parameter, including those that may not be felt by the patient. In yet another embodiment, “treat,” “treat,” or “treat” refers to modulating a disease or disorder either physically (eg, by stabilizing an overt symptom), or physiologically (e.g. by stabilizing a physical parameter), or using both. More specifically, the term “treating” HS disease refers to the treatment of lesions in patients with HS (by quantity or quality, or by reducing their volume and size), and/or to the treatment of abscesses and inflammatory nodules and/or draining fistulas in patients with HS, and/or to a decrease in the number of scars, and/or to a decrease in functional limitations associated with scarring. Treatment of HS disease also refers to partial reduction of pain, fatigue and/or itching associated with HS, reduction of pus discharge and odor associated with pus discharge, and/or improvement of quality of life, and/or reduction of disability patients with HS.

As used herein, the term “prevention” means delaying the onset, or development, or progression of a disease or disorder. More specifically, the term “preventing” HS disease means preventing exacerbations of HS and/or the appearance of new lesions; the implementation of the prevention of scarring and the implementation of the prevention of functional limitations associated with scarring, and/or, in particular, the implementation of the prevention of surgical interventions due to HS.

As used herein, a subject “needs” treatment if such subject would experience a biological, medical, or quality of life benefit as a result of such treatment.

As used herein, singular terms and similar terms used in the context of the present invention (particularly in the context of the claims) are to be construed to include both singular and plural forms unless otherwise specified herein. or it is clearly consistent with the context.

Any asymmetric atom (for example, carbon or the like) of the compound(s) for use in the method of the present invention may be in racemic or enantiomerically enriched form, for example in (R)-, (S)- or (R, S)-configurations. In certain embodiments, each asymmetric atom is characterized by at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least at least 95% enantiomeric excess or at least 99% enantiomeric excess in (R)- or (S)-configurations. Substituents on atoms with unsaturated double bonds may, if possible, be present in cis- (Z)- or trance- (E)-form.

Accordingly, a compound for use in the method of the present invention may be in the form of one of possible isomers, rotamers, atropisomers, tautomers, or mixtures thereof, for example, substantially pure geometric ( cis or trans ) isomers, diastereomers, optical isomers ( antipodes), racemates or mixtures thereof. For clarity, the term “possible isomers” will not include positional isomers.

Any resulting mixtures of isomers can be separated based on the physicochemical differences of the constituent components into pure or essentially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.

Any resulting racemates of final products or intermediates can be separated into optical antipodes by known methods, e.g. by separating their diastereomeric salts obtained with an optically active acid or base and isolating the optically active acid or base compounds. In particular, the basic fragment can thus be used to separate the compounds of the present invention into their optical antipodes, for example, by fractional crystallization of a salt formed with an optically active acid, for example tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O, O'-p-toluoyltartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be separated using chiral chromatography, e.g. high pressure liquid chromatography (HPLC) using a chiral stationary phase.

In addition, the compounds for use in the method of the present invention, including their salts, can also be obtained in the form of their hydrates or include other solvents used for their crystallization. The compounds for use in the method of the present invention may, by design, form solvates with pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to cover the use of the compounds as defined herein in both solvated and non-solvated form. The term "solvate" refers to a molecular complex of a compound for use in the method of the present invention (including pharmaceutically acceptable salts thereof) with one or more solvent molecules. Such solvent molecules are those widely used in the pharmaceutical field, which are known to be non-toxic to the recipient, e.g. water, ethanol, etc. The term "hydrate" refers to a complex where the solvent molecule is water.

Compounds for use in the method of the present invention include salts, hydrates, solvates and polymorphs thereof.

LTA4H inhibitors

In one embodiment number one, the present invention provides a method of treating or preventing HS in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of an LTA4H inhibitor.

In Embodiment 1A, the present invention provides a method of treating or preventing HS in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of an LTA4H inhibitor, as described in WO2014/164658.

In Embodiment 1B, the present invention provides a method of treating or preventing HS in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of an LTA4H inhibitor that is:

or a pharmaceutically acceptable salt thereof.

In Embodiment 1C, the present invention provides a method of treating or preventing HS in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of an LTA4H inhibitor that is 4-(((1S,4S)-5-(4-(4 -(oxazol-2-yl)phenoxy)benzyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)benzoic acid; or a pharmaceutically acceptable salt thereof.

In Embodiment 1D, the present invention provides a method of treating or preventing HS in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of an LTA4H inhibitor, which is acebilustat, also known as CTX 4430.

In embodiment two, the present invention provides a method of treating or preventing HS in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof:

(I),

Where

R1 represents OH or NH ₂ ;

Y is O, S or CH ₂ ;

X1, X2, X3 and X4 represent N; or

X1, X2, X3 and X4 are selected from N, NH, C, CH and O, provided that at least two of X1, X2, X3 or X4 are N or NH;

R2 is C ₁ -C ₆ alkyl, optionally substituted with phenyl; C ₃ -C ₆ cycloalkyl; phenyl, optionally substituted with halogen, cyano, C ₁ -C ₆ alkyl, optionally substituted with halogen, C ₁ -C ₆ alkoxy or a 5-6 membered heteroaryl ring containing from 1 to 3 heteroatoms selected from N, O and S; or a 5-10 membered mono- or bicyclic heteroaryl containing from 1 to 4 heteroatoms selected from N, O and S, wherein said heteroaryl is optionally substituted with halogen, cyano or C ₁ -C ₆ alkyl, optionally substituted with halogen; or a pharmaceutically acceptable salt thereof.

Embodiment 2A relates to the method of Embodiment 2, comprising administering to a subject a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof,

(II),

where the variables R1, R2 and Y have the values defined in embodiment 1.

Embodiment 2B relates to the method of Embodiment 2, comprising administering to a subject a therapeutically effective amount of a compound of formula (III) or a pharmaceutically acceptable salt thereof,

(III),

where the variables R1, R2 and Y have the values defined in embodiment 1.

Embodiment 2C relates to the method of Embodiment 2 comprising administering to a subject a therapeutically effective amount of a compound of formula (IV) or a pharmaceutically acceptable salt thereof,

(IV),

where the variables R1, R2 and Y have the values defined in embodiment 1.

Embodiment 2D relates to the method of Embodiment 2, comprising administering to a subject a therapeutically effective amount of a compound of formula (V) or a pharmaceutically acceptable salt thereof;

(V),

where the variables R1, R2 and Y have the values defined in embodiment 1.

Embodiment 2E of the present invention provides a method according to any of Embodiments 2 and 2A-2D, comprising administering to a subject a therapeutically effective amount of a compound of formula (I), (II), (III), (IV) or (V) or a pharmaceutically acceptable salt wherein Y is O; And

R2 represents phenyl, optionally substituted halogen, cyano, C ₁ -C ₆ alkyl, optionally substituted halogen, C ₁ -C ₆ alkoxy or a 5-6 membered heteroaryl ring containing from 1 to 3 heteroatoms selected from N, O and S; or

R2 is a 5-10 membered mono- or bicyclic heteroaryl containing from 1 to 4 heteroatoms selected from N, O and S, wherein said heteroaryl is optionally substituted with halogen, cyano or C ₁ -C ₆ alkyl, optionally substituted with halogen .

Embodiment 2F of the present invention provides a method according to any of Embodiments 2 and 2A-2D, comprising administering to a subject a therapeutically effective amount of a compound of formula (I), (II), (III), (IV) or (V) or a pharmaceutically acceptable salt wherein Y is CH ₂ ; And

R2 represents phenyl, optionally substituted halogen, cyano, C ₁ -C ₆ alkyl, optionally substituted halogen, C ₁ -C ₆ alkoxy or a 5-6 membered heteroaryl ring containing from 1 to 3 heteroatoms selected from N, O and S; or

R2 is a 5-10 membered mono- or bicyclic heteroaryl containing from 1 to 4 heteroatoms selected from N, O and S, wherein said heteroaryl is optionally substituted with cyano, halogen or C ₁ -C ₆ alkyl, optionally substituted with halogen .

Embodiment 2G of the present invention relates to a method in accordance with any of embodiments 2 and 2A-2D, comprising administering to a subject a therapeutically effective amount of a compound of formula (I), (II), (III), (IV) or (V) or a pharmaceutically acceptable salt; where Y represents O; And

R2 is C ₁ -C ₆ alkyl, optionally substituted with phenyl; or C ₃ -C ₆ cycloalkyl.

Embodiment 2H of the present invention relates to a method according to any of Embodiments 2 and 2A-2D, comprising administering to a subject a therapeutically effective amount of a compound of formula (I), (II), (III), (IV) or (V) or a pharmaceutically acceptable salt; where Y represents CH ₂ ; And

R2 is C ₁ -C ₆ alkyl, optionally substituted with phenyl; or C ₃ -C ₆ cycloalkyl.

Embodiment 2I relates to the method of any of Embodiments 2 and 2A-2H, comprising administering to a subject a therapeutically effective amount of a compound of formula (I), (II), (III), (IV) or (V) or a pharmaceutically acceptable compound thereof salt or a pharmaceutically acceptable salt thereof, wherein Y is attached to the phenyl moiety in the para position.

Embodiment 2J relates to the method of any of Embodiments 2 and 2A-2H, comprising administering to a subject a therapeutically effective amount of a compound of formula (I), (II), (III), (IV) or (V) or a pharmaceutically acceptable compound thereof salts where Y is attached to the phenyl moiety in the meta position.

Embodiment 2K relates to the method of any of Embodiments 2 and 2A-2J, comprising administering to a subject a therapeutically effective amount of a compound of formula (I), (II), (III), (IV) or (V) or a pharmaceutically acceptable compound thereof salts where R1 represents OH.

Embodiment 2L relates to the method of any of Embodiments 2 and 2A-2K, comprising administering to a subject a therapeutically effective amount of a compound of formula (I), (II), (III), (IV) or (V) or a pharmaceutically acceptable compound thereof salt; where the amino group is characterized by the ( R )-configuration.

Embodiment 2M relates to the method of any of Embodiments 2 and 2A-2K, comprising administering to a subject a therapeutically effective amount of a compound of formula (I), (II), (III), (IV) or (V) or a pharmaceutically acceptable compound thereof salt; where the amino group is characterized by the ( S ) configuration.

Embodiment 2N relates to the method of Embodiment 2 comprising administering to a subject a therapeutically effective amount of a compound of formula (I) and/or a pharmaceutically acceptable salt thereof, wherein the compound is disclosed in WO2015/092740 [patent attorney file number PAT056044-WO-PCT] ; i.e. the connection is selected from:

( R )-3-amino-4-(5-(4-(benzo[ d ]thiazol-2-yloxy)phenyl)-2H - tetrazol-2-yl)butanoic acid;

( R )-3-amino-4-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-2H - tetrazol-2-yl)butanoic acid;

( R )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H - tetrazol-2-yl)butanoic acid;

( R )-3-amino-4-(5-(4-(4-(oxazol-2-yl)-phenoxy)phenyl)-2H - tetrazol-2-yl)-butanoic acid;

( R )-3-amino-4-(5-(3-(4-chlorophenoxy)phenyl)-2H - tetrazol-2-yl)butanoic acid;

( R )-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H - tetrazol-2-yl)butanoic acid;

( R )-3-amino-4-(5-(4-(4-fluorophenoxy)phenyl)-2H - tetrazol-2-yl)butanoic acid;

( R )-3-amino-4-(5-(4-(3-chloro-4-fluorophenoxy)phenyl)-2H - tetrazol-2-yl)butanoic acid;

( R )-3-amino-4-(5-(4-( p -tolyloxy)phenyl)-2H - tetrazol-2-yl)butanoic acid;

( S )-3-amino-4-(5-(3-phenoxyphenyl) -2H -tetrazol-2-yl)butanoic acid;

( S )-3-amino-4-(5-(4-(benzo[ d ]thiazol-2-yloxy)phenyl)-2H - tetrazol-2-yl)butanoic acid;

( S )-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H - tetrazol-2-yl)butanoic acid;

( R )-3-amino-4-(5-(3-phenethoxyphenyl) -2H -tetrazol-2-yl)butanoic acid;

( R )-3-amino-4-(5-(4-phenethoxyphenyl) -2H -tetrazol-2-yl)butanoic acid;

( R )-3-amino-4-(5-(4-(benzyloxy)phenyl)-2H - tetrazol-2-yl)butanoic acid;

( R )-3-amino-4-(5-(3-(benzyloxy)phenyl)-2H - tetrazol-2-yl)butanoic acid;

( R )-3-amino-4-(5-(4-butoxyphenyl) -2H -tetrazol-2-yl)butanoic acid;

( R )-3-amino-4-(5-(4-(pentyloxy)phenyl)-2H - tetrazol-2-yl)butanoic acid;

( R )-3-amino-4-(5-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-2H - tetrazol-2-yl)butanoic acid;

( R )-3-amino-4-(5-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-2H - tetrazol-2-yl)butanoic acid;

( R )-3-amino-4-(5-(3-(benzo[ d ]thiazol-2-yloxy)phenyl)-2H - tetrazol-2-yl)butanoic acid;

( R )-3-amino-4-(5-(3-(3,5-difluorophenoxy)phenyl)-2H - tetrazol-2-yl)butanoic acid;

( S )-3-amino-4-(5-(4-( p -tolyloxy)phenyl)-2H - tetrazol-2-yl)butanoic acid;

( R )-3-amino-4-(5-(4-(4-fluorophenoxy)phenyl)-1,3,4-oxadiazol-2-yl)butanoic acid;

( R )-3-amino-4-(5-(4-(4-chlorophenoxy)phenyl)-1,3,4-oxadiazol-2-yl)butanoic acid;

( R )-3-amino-4-(3-(4-(4-chlorophenoxy)phenyl)-1,2,4-oxadiazol-5-yl)butanoic acid;

( R )-3-amino-4-(3-(4-(4-chlorophenoxy)phenyl)-1,2,4-oxadiazol-5-yl)butanamide;

( S )-3-amino-4-(4-(4-(4-chlorophenoxy)phenyl)-1H - pyrazol-1-yl)butanoic acid; And

( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H - tetrazol-2-yl)butanoic acid.

In Embodiment 3A, the present invention provides a method according to Embodiment 2, comprising administering to a subject a therapeutically effective amount of a compound of formula (I), wherein the compound is ( S )-3-amino-4-(5-(4-(( 5-chloro-3-fluoropyridin-2-yl)oxy)phenyl) -2H -tetrazol-2-yl)butanoic acid; or a pharmaceutically acceptable salt thereof.

In Embodiment 3B, the present invention provides a method according to Embodiment 2, comprising administering to a subject a therapeutically effective amount of a compound of formula (I), wherein the compound is ( R )-3-amino-4-(5-(4-phenethoxyphenyl) -2 H -tetrazol-2-yl)butanoic acid; or a pharmaceutically acceptable salt thereof.

In Embodiment 3C, the present invention provides a method according to Embodiment 2, comprising administering to a subject a therapeutically effective amount of a compound of formula (I), wherein the compound is ( R )-3-amino-4-(5-(4-(4 -chlorophenoxy)-phenyl) -2H- tetrazol-2-yl)butanoic acid; or a pharmaceutically acceptable salt thereof.

In Embodiment 3D, the present invention provides a method according to Embodiment 2, comprising administering to a subject a therapeutically effective amount of a compound of formula (I), wherein the compound is ( S )-3-amino-4-(5-(4-(4 -chlorophenoxy)-phenyl) -2H- tetrazol-2-yl)butanoic acid; or a pharmaceutically acceptable salt thereof.

Compounds of any of formulas (I)-(V) and compounds according to any of embodiments 2, 2A-2N, 3 and 3A-3C for use in the method of the present invention are disclosed in WO2015/092740, which is incorporated herein by links.

In Embodiment 3E, the present invention provides a method according to Embodiment 2, comprising administering to a subject a therapeutically effective amount of a compound of formula (I), wherein the compound is a crystalline form of ( S )-3-amino-4-(5-(4- ((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl) -2H -tetrazol-2-yl)butanoic acid in its free form (i.e., non-salt form); or a pharmaceutically acceptable salt thereof.

In Embodiment 3F, the present invention relates to the method according to Embodiment 21, wherein the crystalline form has at least one of the following characteristics:

(i) a powder X-ray diffraction pattern containing characteristic peaks expressed in 2θ with a 2θ value of 22.6 ± 0.2°, a 2θ value of 24.1 ± 0.2° and a 2θ value of 26.3 ± 0.2° , measured at a temperature of approximately 25°C and an x-ray wavelength, λ, of 1.5418 Å;

(ii) a powder X-ray diffraction pattern containing four or more 2θ values selected from the group consisting of a 2θ value of 11.3 ± 0.2°, a 2θ value of 12.8 ± 0.2°, a 2θ value of 15.2 ± 0.2°, 2θ value of 19.7 ± 0.2°, 2θ value of 20.0 ± 0.2°, 2θ value of 20.3 ± 0.2°, 2θ value of 21.0 ± 0, 2°, 2θ values of 22.6 ± 0.2°, 2θ values of 24.1 ± 0.2°, 2θ values of 24.4 ± 0.2°, 2θ values of 25.1 ± 0.2° , a 2θ value of 26.3 ± 0.2°, a 2θ value of 28.5 ± 0.2°, and a 2θ value of 30.0 ± 0.2°, measured at a temperature of approximately 25°C and at x-ray wavelength, λ, equal to 1.5418 Å;

(iii) a powder X-ray diffraction pattern containing five or more 2θ values selected from the group consisting of a 2θ value of 11.3 ± 0.2°, a 2θ value of 12.8 ± 0.2°, a 2θ value of 15.2 ± 0.2°, 2θ value of 19.7 ± 0.2°, 2θ value of 20.0 ± 0.2°, 2θ value of 20.3 ± 0.2°, 2θ value of 21.0 ± 0, 2°, 2θ values of 22.6 ± 0.2°, 2θ values of 24.1 ± 0.2°, 2θ values of 24.4 ± 0.2°, 2θ values of 25.1 ± 0.2° , a 2θ value of 26.3 ± 0.2°, a 2θ value of 28.5 ± 0.2°, and a 2θ value of 30.0 ± 0.2°, measured at a temperature of approximately 25°C and at x-ray wavelength, λ, equal to 1.5418 Å;

(iv) an X-ray diffraction spectrum substantially the same as that shown in FIG. 1 X-ray powder diffraction spectrum;

(v) a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in Figure 2; And

(vi) a thermogravimetric analysis (TGA) diagram essentially the same as that shown in Figure 3.

The crystal form according to embodiments 3D and 3E is disclosed in PAT058189-WO-PCT, which is PCT/CN2018/000278 filed 31 July 2018, which is incorporated herein by reference.

Methods of treatment and use of LTA4H inhibitors in HS

The disclosed LTA4H inhibitors (i.e., compounds of any of formulas (I) to (V) and compounds of any of embodiments 1, 2, 2A-2N, 3 and 3A-3E, or a pharmaceutically acceptable salt thereof) can be used in in vitro , ex vivo , or included in pharmaceutical compositions and administered in vivo for the treatment of patients with HS (eg human patients).

HS is a chronic inflammatory condition with scarring primarily affecting the intertriginous skin of the axillary, inguinal, inframammary, genitoanal, and perineal areas of the body. It is also called inverse acne. The diagnosis of HS is based on three diagnostic criteria: typical lesions (deeply located painful nodules, [unopened] boils in early primary lesions or abscesses, draining fistulas, overlapping scars and open comedones “blackheads” in secondary lesions); typical topography (axilla, groin, genitals, perineal and perianal areas, buttocks, infra- and intermammary areas; and chronic and recurrent nature (Margesson and Danby (2014) Best Practices and Res. Clin. Ob. And Gyn 28: 1013-1027). The physical grade of HS can be classified using Hurley's clinical staging shown below in Table 2 .

Stage I Only abscesses (single or multiple) without fistula tracts or scar formation (scarring) Stage II Abscesses (single or multiple) with burrow or scar formation, single or multiple, widely spaced lesions (e.g. > 10 cm apart) Stage III Diffuse or near-diffuse involvement or multiple connecting tracts or abscesses throughout the area

Table 2 . Stages of HS according to Hurley. In essence, a patient who has Hurley stage III may have stage III with dystrophic changes but with active stage I or II lesions.

HS consists of blocked follicles, ruptured ducts, and secondary inflammation. In patients, the follicular duct first becomes blocked, which over time leads to leakage from the duct and a horizontal rupture into the dermis. If the pilosebaceous follicle (FPSB) does not recover, follicle fragments stimulate three reactions that initiate the course of HS disease. The first is an inflammatory response triggered by the innate immune system, causing suppuration and tissue destruction and leading to foreign body reactions and extensive scarring. The second reaction results in the formation of epithelialized fistulas, which can develop from stem cells derived from a single FPSB that survive the destruction caused by the inflammatory response. The third reaction in most cases produces an invasive proliferative gelatinous mass consisting of a gel containing inflammatory cells and, presumably, the precursors of the epithelialized elements described above. (See Margesson and Danby (2014). As used herein, the phrase “slowing the progression of HS disease" means slowing the rate of development of any of the aspects of HS disease described above, particularly the inflammatory response. In some embodiments of the present invention, treatment with an LTA4H inhibitor slows progression of HS disease.

Recurrence of HS in a patient includes the development of papules, pustules or inflammatory nodules, pain and itching, abscesses, drainage, and any combination thereof. As used herein, the term “exacerbation of HS” (etc.) is defined as an increase in the number of abscesses and inflammatory nodules (AN) of at least 25% with a minimum increase of two times AN compared to baseline.

In some embodiments of the present invention, treatment in accordance with the disclosed methods with LTA4H inhibitors prevents exacerbations of HS, reduces the severity of exacerbations of HS, and/or reduces the frequency of exacerbations of HS. In some embodiments, if a population of patients with HS is treated in accordance with the disclosed methods, less than 5%, less than 10%, less than 15%, or less than 20% of patients experience an exacerbation during treatment, such as during the first 16 weeks of treatment.

As used herein, the phrase “reducing the severity of HS exacerbations”, etc., means reducing the severity of an HS exacerbation, such as reducing the number and/or size of abscesses and/or inflammatory nodules, reducing the intensity of a particular component of the exacerbation (for example, reducing the number, size, thickness and etc. abscesses and/or inflammatory nodules, reducing the degree of skin irritation (itching, pain, etc.) and/or reducing the length of time an exacerbation (or its component) persists.

As used herein, the phrase “reducing the incidence of HS flares” and the like means a reduction in the incidence of HS flares, such as a reduction in the number of abscesses and/or inflammatory nodules. With a decrease in the frequency of HS exacerbations, the patient will experience fewer relapses of HS. The frequency of exacerbations can be assessed by monitoring the patient over time to determine whether the frequency of exacerbations is decreasing.

As used herein, the phrase “preventing HS exacerbations” means eliminating future HS exacerbations and/or components of the exacerbation.

The effectiveness of treatment for HS can be assessed using various known methods and means that provide assessment of HS disease status and/or clinical response in HS. Some examples include, for example, Hurley Staging, Severity Scoring System (SAHS), Sartorius Score, Modified Sartorius Score, HS Physician Global Assessment (HS-PGA), Visual Analog Scale (VAS), or Numerical Rating skin-related pain score (NRS), skin disease quality of life index (DLQI), clinical response in HS based on the sum of abscesses and inflammatory nodules (HiSCR), HiSCR simplified scale, EuroQuol-5D (EQ5D), Hospital Anxiety and Depression Scale, Healthcare Resource Utilization, Hidradenitis Suppurativa Severity Index (HSSI), Work Productivity Index (WPI), Body Surface Area (BSA), Acne Inversus Severity Index (AISI), etc. (see e.g. , Deckers and Prens (2016) Drugs 76:215–229; Sartorius et al. (2009) Br. J Dermatol 161:831-39; Chiricozzi et al. (2015) Wounds 27(10):258–264). In some embodiments, the effectiveness of the method of the present invention disclosed herein can be assessed through the HS Physician Global Assessment (HS-PGA), Severity Assessment System (SAHS), Numerical Rating Scale (NRS), Disease Quality of Life Index skin (DLQI), clinical response in HS based on the sum of abscesses and inflammatory nodules (HiSCR), and/or HiSCR based on a simplified score. Preferably, the effectiveness of the treatment for HS disclosed herein can be assessed by clinical response in HS based on the sum of abscesses and inflammatory nodules (HiSCR) and/or HiSCR using a simplified score.

In some embodiments, a patient with HS achieves HiSCR in response to treatment for HS. In some embodiments, when treating a population of patients with HS according to the disclosed methods, at least 30%, at least 40%, at least 50%, at least 60%, or at least 70% achieve HiSCR by week 16 treatment.

In other embodiments, the effectiveness of an HS treatment disclosed herein can be measured by the difference between the response rate of treated patients (i.e., a patient who achieves a HiSCR response to treatment of an HS compound of the present invention) and the response rate responding patients receiving placebo by week 16 of treatment. In some embodiments, this difference in response rate as measured by HiSCR is at least 15%, at least 25%, at least 30%, or at least 35%.

The preferred treatment response scoring systems are HiSCR, HiSCR simplified score, NRS (especially NRS30), Severity Scoring System (SAHS), HS-PGA, number of inflammatory sites (number of abscesses, inflammatory nodules, and/or draining fistulas), and DLQI.

Hidradenitis suppurativa clinical response (HiSCR) is a measure of clinical response to treatment for HS. A HiSCR response to treatment (compared to baseline) is 1) at least a 50% reduction in abscesses and inflammatory nodules, while 2) the number of abscesses does not increase, and 3) the number of draining fistulas does not increase. As used herein, the terms “simplified HiSCR” or “sHiSCR” refer to a modified HiSCR that does not compare the number of abscesses with the number of abscesses at baseline when assessing lesion progression. In preferred embodiments, a patient with HS achieves HiSCR on a simplified scale in response to treatment for HS. In some embodiments, when treating a population of patients with HS according to the disclosed methods, at least 40%, at least 50%, at least 60%, or at least 70% achieve HiSCR on the simplified scale by week 16 of treatment.

Pain can be assessed using a Numeric Rating Scale (NRS). In some embodiments, a patient with HS achieves an improvement in the NRS in response to treatment for HS. NRS30 is defined as a decrease of at least 30% in pain intensity and a decrease of at least 1 unit from baseline in patient global assessment (PGA) of skin pain intensity from baseline in patients with a score of 3 or higher at baseline. In some embodiments, a patient with HS achieves NRS30 in response to treatment for HS. In some embodiments, when treating a population of patients with HS according to the disclosed methods, at least 25%, at least 30%, at least 40%, at least 50%, or at least 60% achieve NRS30 by week 16 treatment. In a preferred aspect of this embodiment, when treating a population of patients with HS according to the disclosed methods, at least 30% achieve NRS30 by week 16 of treatment. In some embodiments, in response to treatment in accordance with the claimed methods, the patient experiences a rapid decrease in pain intensity, as measured by VAS or NRS, as early as 1 week after initial dosing.

The severity scoring system (SAHS) is described in JAMA Dermatol 2018, 154(3): 330-335, Hassam et al. The severity of HS can be assessed using the SAHS scoring system, which examines the following items: the number of areas involved (left axillary, right axillary, left submammary, right submammary, intermammary or thoracic, abdominal, pubic, left inguinal, right inguinal, genital, perianal or perineal, left gluteal, right gluteal and others [eg neck, retroauricular]), number of inflammatory and/or painful lesions other than fistulas (ILOF) and number of fistulas. These physician-rated items were supplemented with 2 patient-reported items: Patients were asked to indicate the number of new boils or the number of existing boils that had become inflamed during the past 4 weeks and to rate the current pain severity (NRS) of the most symptomatic lesion during activities of daily living. (eg sitting, moving or working) on a numerical rating scale. The SAHS score is a composite score of all the information collected above. A mild case of HS is defined as a SAHS score of 4 or less. A moderate case of HS is defined as a SASH score of 5–8, and a severe case of HS is defined as a SASH score of 9 or higher.

In some embodiments, a patient with HS achieves an improvement in the SAHS score in response to treatment for HS. In some embodiments, a patient with HS achieves a reduction of at least one point from baseline on the SAHS score in response to treatment for HS. In other embodiments, a patient with HS achieves a reduction of at least two points or at least 3 points from baseline on the SAHS score in response to treatment for HS. Preferably, the SAHS score is at least 4 at baseline before LTA4H inhibitor treatment.

The DLQI is the most widely accepted measure of quality of life in dermatological diseases. It consists of questions regarding the impact of the skin disease on sensations and various aspects of daily life during the past week. Each question is scored from 0 (not at all) to 3 (very much). The maximum score is a total of 30 points, with 0-1 considered no effect, 2-5 small, 6-10 moderate, 11-20 very significant and 21-30 extremely significant effect on the patient's life. (Cm. Finlay and Khan (1994) Clin Exp Dermatol 19:210-16). In some embodiments, a patient with HS achieves improvement on the DLQI in response to treatment for HS.

In some embodiments, in response to treatment in accordance with the claimed methods, the patient experiences a rapid decrease in CRP levels, as measured by a standard CRP assay or a high sensitivity CRP assay (hsCRP), as early as 1 week after initial dosing. As used herein, the terms “C-reactive protein” and “CRP” refer to serum C-reactive protein, a protein in blood plasma often used as an indicator of the acute phase response to inflammation. The level of CRP in blood plasma can be presented in any concentration, for example mg/dL, nmol/L. CRP levels can be measured by a number of standard assays, such as radial immunodiffusion, electroimmunoassay, immunoturbidimetry, ELISA, turbidimetric methods, fluorescence polarization immunoassay and laser nephelometry. To test CRP levels, you can use a standard CRP test or a high-sensitivity CRP (hs-CRP) test (ie, a high-sensitivity test that can measure low levels of CRP in a sample using laser nephelometry). CRP test kits can be purchased from various companies, such as Calbiotech, Inc., Cayman Chemical, Roche Diagnostics Corporation, Abazyme, DADE Behring, Abnova Corporation, Aniara Corporation, Bio-Quant Inc., Siemens Healthcare Diagnostics, etc.

The Sartorius HS score (also called the HS score or HSS) is obtained by counting the involved areas, nodules, and fistulous tracts in a patient with HS. (Sartorius et al. (2003) Br J Dermatol 149:211-13). The Modified Sartorius HS score represents a revision of the original version of the HSS by introducing minor simplifications that have made its use more practical, such as fewer specific lesions to include in the score, changes in the number of points assigned to each dimension, etc. ( Sartorius et al (2009) Br J Dermatol 161:831-839). In some embodiments, a patient with HS achieves an improved modified Sartorius score for HS in response to treatment for HS.

The HS Physician Global Assessment (HS-PGA) is a 6-point rating scale (scores ranging from 0 to 5) based on the number of HS lesions (ie, abscesses, draining fistulas, inflammatory nodules, and noninflammatory nodules). (Kimball AB, Kerdel F, Adams D et al Adalimumab for the treatment of moderate to severe hidradenitis suppurativa: a parallel randomized trial. Ann Intern Med 2012; 157: 846-855). In some embodiments, a patient with HS achieves improved HS-PGA in response to treatment for HS. In some embodiments, a patient with HS achieves a reduction of at least 2 points from baseline on the HS-PGA scale in response to treatment for HS. Preferably, the HS-PGA score is at least 3 at baseline before LTA4H inhibitor treatment.

In some embodiments, if a population of HS patients is treated in accordance with the disclosed methods, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of patients who respond to treatment by week 16 (eg, patients achieving HiSCR or HiSCR simplified score by week 16) have a sustained response after completion of treatment (eg, 3 months or 6 months after completion of treatment or 12 months after completion of treatment). In another aspect of this embodiment, at least 40% of patients or at least 50% of patients who responded to treatment (eg, patients achieving HiSCR or HiSCR on a simplified scale, for example, by week 16) have a sustained response after completion of treatment (eg 3 months after completion of treatment). Preferably, at least 70% of patients who respond to treatment (eg, patients achieving HiSCR or HiSCR simplified score by week 16) have a sustained response after completion of treatment (eg, 3 months after completion of treatment). As used herein, the term “sustained” means that the result or goal (eg, reduction in pain, reduction in inflammation) is substantially maintained over the specified period of time.

Itching associated with the lesion can be assessed through a patient questionnaire. The patient is asked to rate the itching associated with the lesion from 0 (no itching) to 10 (worst possible itching). In some embodiments, if a population of patients with HS is treated in accordance with the disclosed methods, the pruritus score improves by at least 2 points, preferably by at least 3 points. Moreover, compared with the placebo group, the difference between the treatment group and the placebo group was at least 1 point.

Odor caused by drainage of the lesion can be assessed through a patient questionnaire. The patient is asked to rate the odor caused by draining the lesion from 1 (no odor), 2 (mild odor), 3 (moderate odor) to 4 (strong odor). In some embodiments, if a population of patients with HS is treated in accordance with the disclosed methods, the pruritus score improves by at least 1 point, preferably by at least 2 points. Moreover, compared with the placebo group, the difference between the treatment group and the placebo group was at least 1 point.

The impact of HS on ability to perform work can be assessed through patient questionnaires. The patient is asked to rate the extent to which HS affects the ability to perform work, from 1 (not at all), 2 (little), 3 (moderate), 4 (major) to 5 (unable to perform any work). In some embodiments, if the HS patient population is treated in accordance with the disclosed methods, the pruritus score improves by at least 1 point, preferably by at least 2 points. Moreover, compared with the placebo group, the difference between the treatment group and the placebo group was at least 1 point.

The LTA4H inhibitors disclosed herein can be used as a pharmaceutical composition and dosage form when combined with a pharmaceutically acceptable carrier. Such a composition may contain, in addition to the LTA4H inhibitor, carriers, various diluents, fillers, salts, buffers, stabilizers, solubilizers and other materials known in the art. The characteristics of the vehicle will depend on the route of administration. The pharmaceutical composition for use in the method of the present invention can be formulated for specific routes of administration, such as oral administration, parenteral administration and rectal administration, etc. Moreover, the pharmaceutical compositions for use in the method of the present invention can be prepared in solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories) or in liquid form (including without limitation solutions, suspensions or emulsions). Pharmaceutical compositions for use in the method of the present invention may be subjected to traditional pharmaceutical operations, such as sterilization, and/or may contain traditional inert diluents, lubricants or buffers, as well as auxiliary agents such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc. Pharmaceutical compositions and dosage forms for use in the present invention may contain one or more agents that reduce the rate at which a compound (i.e., the LTA4H inhibitor described herein) as an active ingredient will be degraded . Such agents, which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers or saline buffers, etc.

Typically, pharmaceutical compositions for use in the present invention are tablets or capsules containing the active ingredient together with

a) fillers, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine;

b) lubricants, for example, silicon dioxide, talc, stearic acid, its magnesium or calcium salt (eg magnesium stearate) and/or polyethylene glycol;

c) binders, for example magnesium aluminosilicate, starch paste, gelatin, tragacanth, methylcellulose, for example hydroxypropylmethylcellulose (HPMC or hypromellose), sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if necessary

d) leavening agents, for example crospovidone, types of starch, agar, alginic acid or its sodium salt or effervescent mixtures;

e) a glidant such as silica, colloidal anhydrous/colloidal silica and/or

f) absorbents, dyes, flavors and sweeteners.

Tablets can be either film-coated or enteric-coated according to methods known in the art.

Suitable compositions for oral administration include an effective amount of a compound of formula I (or a compound according to any of embodiments 1, 2, 2A-2N, 3 and 3A-3E) in the form of tablets, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions , hard or soft capsules, or syrups, or tinctures. Compositions intended for oral administration are prepared in accordance with any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavorings, colors and preservatives, with the goal of obtaining drugs that are pharmaceutically aesthetic and palatable. Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. Such excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thus provide sustained action over a longer period. For example, a delayed release material such as glyceryl monostearate or glyceryl distearate may be used. Oral formulations may be presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules where the active ingredient is mixed with water or an oily vehicle such as peanut oil, liquid paraffin or olive oil.

Suitable compositions for transdermal use contain an effective amount of a compound for use in the method of the present invention with a suitable carrier. Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to facilitate passage through the patient's skin. For example, transdermal devices are in the form of a dressing comprising a support member, a reservoir containing the compound, optionally with carriers, optionally a rate-controlled barrier for delivering the compound through the patient's skin at a controlled and predetermined rate over an extended period of time, and a means to attach the device to the skin.

In a preferred embodiment, a suitable composition is a composition for oral administration.

In preferred embodiments of the disclosed methods, routes of administration, and kits, an LTA4H inhibitor (e.g., a compound according to any of Embodiments 1, 2, 2A-2N, 3, and 3A-3E, or a pharmaceutically acceptable salt thereof) is included in a pharmaceutical composition, wherein said pharmaceutical composition additionally contains one or more fillers in an amount of 70-95% by weight, a leavening agent in an amount of 3-5% by weight and a binder in an amount of 2-3% by weight. In a specific aspect of this embodiment, the composition further comprises a lubricant in an amount of 1% by weight and a glidant in an amount of 0.5% by weight.

In some embodiments of the disclosed methods, routes of administration and kits, the pharmaceutical composition is presented in the form of a capsule or tablet. In some embodiments of the disclosed methods, routes of administration and kits, the pharmaceutical composition is presented in tablet form.

In some embodiments of the disclosed methods, routes of administration and kits, the pharmaceutical composition is presented in capsule form. In a specific aspect of this embodiment, the contents of the capsule contain a compound according to any of embodiments 1, 2, 2A-2N, 3 and 3A-3E, or a pharmaceutically acceptable salt thereof, a filler consisting of microcrystalline cellulose and mannitol, wherein the amount of filler is 70- 95% by weight of the total contents of the capsule, crospovidone in an amount of 3-5% by weight of the entire contents of the capsule, hypromellose in an amount of 2-3% by weight of the total contents of the capsule, magnesium stearate in an amount of approximately 1% by weight of the total contents of the capsule , silicon dioxide and colloidal silicon dioxide in an amount of approximately 0.5% by weight of the total contents of the capsule.

Pharmaceutical compositions for use in the disclosed methods may also contain additional therapeutic agents for treating the specific target disorder. For example, the pharmaceutical composition may also contain anti-inflammatory agents. Such additional factors and/or agents may be included in the pharmaceutical composition to obtain a synergistic effect with the LTA4H inhibitor described herein or to minimize side effects caused by the LTA4H inhibitor described herein.

Various therapies can be advantageously combined with the disclosed LTA4H inhibitors, such as compounds of any of formulas (I) to (V) or a compound of any of embodiments 1, 2, 2A-2N, 3 and 3A-3E, or pharmaceutically thereof acceptable salt during HS treatment.

Therefore, the LTA4H inhibitors of the present invention can be administered either simultaneously with one or more other therapeutic agents, or before or after their administration. LTA4H inhibitors for use in the method of the present invention can be administered separately from other agents through the same or a different route of administration or together with them in the same pharmaceutical composition.

In one embodiment, the present invention provides a method of treating or preventing HS in a subject, comprising administering to the subject a product containing a compound according to any of Formulas (I) to (V) (or a compound according to any of Embodiments 1, 2, 2A-2N , 3 and 3A-3E) or a pharmaceutically acceptable salt thereof and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy. Optionally, the pharmaceutical composition for use in the method of the present invention may contain a pharmaceutically acceptable excipient as described above.

The products provided as a combined preparation for use in the method of the present invention include a composition containing a compound according to any of formulas (I) to (V) (or a compound according to any of embodiments 1, 2, 2A-2N, 3 and 3A-3E) or a pharmaceutically acceptable salt thereof and other therapeutic agent(s) together in the same pharmaceutical composition, or a compound according to any of formulas (I) to (V) (or a compound according to any of embodiments 1, 2 , 2A-2N, 3 and 3A-3E) or a pharmaceutically acceptable salt thereof and other therapeutic agent(s) in separate form, for example in the form of a set.

In one embodiment, the present invention provides a kit for use in the method of the present invention, containing two or more separate pharmaceutical compositions, at least one of which contains a compound according to any of formulas (I) to (V) (or a compound according to any of embodiments 1, 2, 2A-2N, 3 and 3A-3E) or a pharmaceutically acceptable salt thereof. In one embodiment, the kit contains means for containing the compositions separately, such as a container, a divided bottle or a divided foil pouch. An example of such a set is blister packaging, usually used for packaging tablets, capsules, etc.

The kit of the present invention can be used to administer different dosage forms, for example, for oral and parenteral use, to administer individual compositions at different dosage intervals, or to titrate individual compositions against each other. To promote compliance with a treatment regimen, the kit of the present invention typically contains instructions for administration.

In the combination therapies of the present invention, the LTA4H inhibitor described herein and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, the LTA4H inhibitors described herein and another therapeutic agent may be combined into a combination therapy: (i) prior to distributing the combination drug to physicians (for example, in the case of a kit containing a compound for use in a method of the present invention and another therapeutic agent). means); (ii) by the physicians themselves (or under the direction of a physician) shortly before administration; (iii) by the patients themselves, for example during sequential administration of a compound (LTA4H inhibitor) and another therapeutic agent.

Accordingly, the present invention provides the use of a compound according to any of formulas (I) to (V) (or a compound according to any of Embodiments 1, 2, 2A-2N, 3 and 3A-3E) or a pharmaceutically acceptable salt thereof for treating or HS warnings where the drug is prepared for administration with another therapeutic agent. The present invention also provides for the use of another therapeutic agent for the treatment or prevention of HS, wherein the drug is administered with a compound according to any of formulas (I) to (V) (or a compound according to any of embodiments 1, 2, 2A-2N, 3 and 3A-3E) or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound according to any of formulas (I) to (V) (or a compound according to any one of embodiments 1, 2, 2A-2N, 3 and 3A-3E) or a pharmaceutically acceptable salt thereof for use in a method of treatment or HS warning, where the specified compound is obtained for administration with another therapeutic agent. The present invention also provides another therapeutic agent for use in a method of treating or preventing HS, wherein the other therapeutic agent is formulated for administration with a compound according to any of formulas (I) to (V) (or a compound according to any of embodiments 1, 2, 2A-2N, 3 and 3A-3E) or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound according to any of formulas (I) to (V) (or a compound according to any one of embodiments 1, 2, 2A-2N, 3 and 3A-3E) or a pharmaceutically acceptable salt thereof for use in a method of treatment or HS warning where the compound is administered with another therapeutic agent. The present invention also provides another therapeutic agent for use in a method of treating or preventing HS, wherein the other therapeutic agent is administered with a compound according to any of formulas (I) to (V) (or a compound according to any of embodiments 1, 2, 2A- 2N, 3 and 3A-3E) or a pharmaceutically acceptable salt thereof.

The present invention also provides the use of a compound according to any of formulas (I) to (V) (or a compound according to any of embodiments 1, 2, 2A-2N, 3 and 3A-3E) or a pharmaceutically acceptable salt thereof for the treatment and/or or prevention of HS in a patient requiring such treatment and/or prevention where the patient has previously (e.g. up to 24 hours before) was treated with another therapeutic agent. The present invention also provides for the use of another therapeutic agent for the treatment or prevention of HS in a patient in need thereof, where the patient has previously (eg, up to 24 hours previously) was treated with a compound according to any of formulas (I) to (V) (or a compound according to any of embodiments 1, 2, 2A-2N, 3 and 3A-3E) or a pharmaceutically acceptable salt thereof .

Such combination therapies include topical treatments (creams [non-steroidal or steroidal], rinses, antiseptics), systemic treatments (eg, biologics, antibiotics, or chemicals), antiseptics, photodynamic therapy, and surgery (laser, drainage or cutting, excision).

Examples of oral antibiotics are tetracyclines and rifampicin.

Non-limiting examples of topical HS treatment agents for use with the disclosed LTA4H inhibitors include benzoyl peroxide, topical steroid creams, topical aminoglycoside antibiotics such as clindamycin, gentamicin and erythromycin, resorcinol-based cream, iodine-based exfoliants and chlorhexidine.

Non-limiting examples of HS agents used in systemic treatment for use with disclosed LTA4H inhibitors include IL-17 antagonists (ixekizumab, brodalumab, secukinumab CJM112), as well as IL17A/F antagonists such as bimekizumab, or IL17C antagonists such as MOR106 , tumor necrosis factor alpha (TNF-alpha) blockers (such as Enbrel® (etanercept), Humira® (adalimumab), Remicade® (infliximab) and Simponi® (golimumab)), interleukin 12/23 blockers (such as Stelara® ( ustekinumab), tazocitinib and briakinumab), IL-23 blockers (such as guselkumab, tildrakizumab and risankizumab), p19 inhibitors, PDE4 inhibitors such as apremilast or Otezla®), complement pathway inhibitors such as factor B inhibitors (for example, the compounds disclosed in WO2015/009616, or LNP023, which is also known as 4-(( 2S , 4S )-4-ethoxy-1-((5-methoxy-7-methyl)-1H - indol-4-yl)methyl) piperidin-2-yl)benzoic acid), C5a inhibitors (IFX-001, CCX168, also known as avacopan), IL-1 antagonists (canakinumab, gevokizumab, rilonacept, anakinra, MaBp1 (XBiotech)), inflammasome inhibitors such as NLRP3 and NLRP5, CXCR1/2 inhibitors, IL-18 antagonists, IL-6 antagonists, IL-36 antagonists, CD20 antagonists, CTLA4 antagonists, IL-8 antagonists, B-cell depletors (particularly CD20 antagonists such as rituximab, and also BAFF-R and CD40 antagonists such as isqlimab (CFZ533)), IL-21 antagonists, IL-22 antagonists, VEGF antagonists, CXCL antagonists, MMP antagonists and defensin antagonists (eg decoy receptors, antagonistic antibodies, etc. ), as well as broad-spectrum oral JAK inhibitors or more specific TYK2 or JAK 1, JAK2 or JAK 3 inhibitors.

Additional HS treatments for use in combination with disclosed LTA4H inhibitors during the treatment of HS include retinoids such as acitretin (e.g. Soriatane ® ) and isotretinoin, immune suppressants (e.g. rapamycin, T-cell blockers [e.g. Amevive® (alefacept) ) and Raptiva® [efalizumab]), cyclosporine, methotrexate, mycophenolate mofetil, mycophenolic acid, leflunomide, tacrolimus, etc.), hydroxyurea (e.g. Hydrea®), sulfasalazine, 6-thioguanine, fumarates (e.g. dimethyl fumarate and fumaric esters acids), azathioprine, colchicine, alitretinoin, steroids, corticosteroids, certolizumab, mometasone, rosiglitazone, pioglitazone, botulinum toxin, triamcinolone, IFX-1 (InflaRx), LY-3041658 (Eli Lilly), TE-2232 (Immunwork), NSAID, inhibitors COX, prescription narcotics, ketoprofen, codeine, gabapentin, pregabalin, fentanyl, antibiotics (topical, oral, intravenous) (eg, clindamycin, rifampin, tetracycline, sarecycline, doxycycline, minocycline, lymecycline, trimethoprim-sulfamethoxazole, erythromycin, ceftriaxone, moxifloxacin, metronidazole, alone or in combinations), corticosteroid (injection or oral), antiandrogen/hormonal therapy (oral contraceptives, spironolactone, finasteride, dutasteride, progesterone IUD, cyproterone acetate, ethinyl estradiol , gestodene, norgestimate, desogestrel, drospirenone, spironolactone), triamcinolone acetonide, MEDI8968, hydroxychloroquine, dapsone, metformin, adapalene, azelaic acid and zinc.

Preferred combinations for use in the disclosed kits, methods and routes of administration include PDE4i and JAKi, as well as antibiotics (all for oral administration).

Examples of JAK inhibitors for use in combination are BMS986165, INCB054707, ruxolitinib, abrocitinib, tofacitinib and baricitinib. Other examples of JAK inhibitors are the compounds disclosed in WO2017/089985, WO2018/055550 and WO2018/055551.

One skilled in the art will be able to determine appropriate dosages of the above HS treatment agents for co-delivery with the disclosed LTA4H inhibitors.

An LTA4H inhibitor, such as a compound according to any of Embodiments 1, 2, 2A-2N, 3 and 3A-3E, or a pharmaceutically acceptable salt thereof, is conveniently administered orally. The duration of oral therapy using the pharmaceutical composition of the present invention will vary depending on the severity of the disease being treated, as well as the condition and individual response of each individual patient. The healthcare professional will decide the appropriate duration of oral therapy and timing of administration of the therapy using the pharmaceutical composition of the present invention. In some embodiments, the patient is treated with HS in accordance with the claimed methods for at least 16 weeks, at least 24 weeks, at least 36 weeks, at least 48 weeks, or at least 52 weeks. In some embodiments, the patient's HS is treated under long-term conditions.

In one embodiment, the pharmaceutical composition of the present invention for use in the prevention or treatment of HS may be provided in a single dosage of approximately 1-500 mg of active ingredient(s) for a subject weighing approximately 50-70 kg, or approximately 1-250 mg, or about 1-150 mg, or about 1-100 mg, or about 1-50 mg of active ingredients. The therapeutically effective dosage of the compound or pharmaceutical composition depends on the species of the subject, body weight, age and individual condition, severity of the disorder representing contrast-induced nephropathy. A physician, clinician, or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients needed to prevent, treat, or inhibit the progression of the disorder or disease.

The preferred formulation is a composition in capsule or tablet form containing from about 1 mg to about 160 mg of an LTA4H inhibitor or compound according to any of embodiments 1, 2, 2A-2N, 3 and 3A-3E or a pharmaceutically acceptable salt thereof, and one or more excipients independently selected from fillers, disintegrants, binders and optionally a lubricant and a glidant. In a preferred embodiment, the composition in capsule or tablet form contains from about 5 mg to about 80 mg of an LTA4H inhibitor or a compound according to any of Embodiments 1, 2, 2A-2N, 3 and 3A-3E or a pharmaceutically acceptable salt thereof and one or more excipients independently selected from fillers, disintegrants, binders and optionally a lubricant and a glidant. In yet another embodiment, the composition in capsule or tablet form contains about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, and about 50 mg of an LTA4H inhibitor or a compound according to any of the embodiments 1, 2, 2A-2N, 3 and 3A-3E or a pharmaceutically acceptable salt thereof and one or more excipients independently selected from fillers, disintegrants, binders and optionally a lubricant and glidant.

Disclosed herein are methods of treating hidradenitis suppurativa (HS) comprising daily oral administration to a patient in need thereof of a dose of from about 1 mg to about 160 mg, or from about 10 mg to about 100 mg, or from about 20 mg to about 60 mg. mg of LTA4H inhibitor (ie, the compound according to any of embodiments 1, 2, 2A-2N, 3 and 3A-3E or a pharmaceutically acceptable salt thereof). These doses may be administered to the patient using either a once-daily dosing schedule or a twice-daily dosing schedule. In another embodiment, the method comprises orally administering to a patient in need thereof a dose of from about 10 mg to about 30 mg of an LTA4H inhibitor (i.e., a compound according to any of Embodiments 1, 2, 2A-2N, 3, and 3A- 3E or a pharmaceutically acceptable salt thereof) administered twice daily (BID). In a preferred aspect of this embodiment, the method comprises orally administering a dose of approximately 20 mg of an LTA4H inhibitor (i.e., a compound of any of Embodiments 1, 2, 2A-2N, 3, and 3A-3E, or a pharmaceutically acceptable salt thereof) to the designated patient, administered twice daily (BID).

Disclosed herein are methods of treating hidradenitis suppurativa (HS), comprising orally administering to a patient in need thereof a daily dose of about 1 mg to about 160 mg, or about 10 mg to about 100 mg, or about 20 to about 60 mg. an LTA4H inhibitor, wherein the LTA4H inhibitor is ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl) -2H -tetrazole-2- yl)butanoic acid or a pharmaceutically acceptable salt thereof. In a preferred aspect of this embodiment, the method comprises orally administering a dose of from about 10 mg to about 30 mg ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy )phenyl) -2H -tetrazol-2-yl)butanoic acid or a pharmaceutically acceptable salt thereof to the specified patient, administered twice daily. In the most preferred aspect of this embodiment, the method comprises orally administering a dose of approximately 20 mg ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl ) -2H -tetrazol-2-yl)butanoic acid or a pharmaceutically acceptable salt thereof, as indicated to the patient, administered twice daily.

Disclosed herein are methods of treating hidradenitis suppurativa (HS), comprising orally administering to a patient in need thereof a daily dose of about 1 mg to about 160 mg, or about 10 mg to about 100 mg, or about 20 mg to about 60 mg. mg LTA4H inhibitor, where the LTA4H inhibitor is the crystalline form of ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl) -2H -tetrazole -2-yl)butanoic acid in its free form, as described herein. In a preferred aspect of this embodiment, the method comprises orally administering a dose of about 10 mg to about 30 mg of the crystalline form of ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl )oxy)phenyl) -2H -tetrazol-2-yl)butanoic acid, as described herein, to the designated patient, administered twice daily. In the most preferred aspect of this embodiment, the method comprises orally administering a dose of approximately 20 mg of the crystalline form of ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy )phenyl) -2H -tetrazol-2-yl)butanoic acid, as described herein, to the designated patient, administered twice daily.

Disclosed herein is an LTA4H inhibitor (i.e., a compound according to any of Embodiments 1, 2, 2A-2N, 3, and 3A-3E, or a pharmaceutically acceptable salt thereof) for use in the treatment of hidradenitis suppurativa (HS), wherein the inhibitor LTA4H is administered orally to a patient in need thereof at a daily dose of about 1 mg to about 160 mg, or about 4 mg to about 100 mg, or about 10 mg to about 100 mg, or about 20 mg to about 60 mg. , or from about 5 mg to about 80 mg (for example, about 20 mg, about 30 mg, about 40 mg, or about 80 mg). In a preferred aspect of this embodiment, an LTA4H inhibitor (e.g., a compound according to any of Embodiments 1, 2, 2A-2N, 3, and 3A-3E, or a pharmaceutically acceptable salt thereof) is administered orally to a patient in need thereof at a dose of about 5 mg QD to approximately 40 mg BID. In yet another preferred aspect of this embodiment, an LTA4H inhibitor (e.g., a compound according to any of Embodiments 1, 2, 2A-2N, 3, and 3A-3E, or a pharmaceutically acceptable salt thereof) is administered orally to a patient in need thereof at a dose from about 10 mg to about 30 mg twice daily (eg, about 10 mg BID, about 15 mg BID, preferably about 20 mg BID). In the most preferred aspect of this embodiment, an LTA4H inhibitor (eg, a compound according to any of Embodiments 1, 2, 2A-2N, 3, and 3A-3E, or a pharmaceutically acceptable salt thereof) is administered orally to a patient in need thereof at a dose approximately 20 mg twice daily.

Disclosed herein is an LTA4H inhibitor which is ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl) -2H -tetrazol- 2-yl)butanoic acid or a pharmaceutically acceptable salt thereof, for use in the treatment of hidradenitis suppurativa (HS), wherein LTA4H is administered orally to a patient in need thereof at a daily dose of about 1 mg to about 160 mg, or about 4 mg to about 100 mg, or about 10 mg to about 100 mg, or about 20 mg to about 60 mg, or about 5 mg to about 80 mg (e.g., about 20 mg, about 30 mg, about 40 mg, or about 80 mg). In a preferred aspect of this embodiment, ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl) -2H- tetrazol-2-yl) butanoic acid or a pharmaceutically acceptable salt thereof is administered orally to a patient in need thereof at a dose of about 5 mg QD to about 40 mg BID. In yet another preferred aspect of this embodiment, ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl) -2H -tetrazol-2- yl)butanoic acid or a pharmaceutically acceptable salt thereof is administered orally to a patient in need thereof at a dose of about 10 mg to about 30 mg twice daily (e.g., about 10 mg BID, about 15 mg BID, preferably about 20 mg BID) . In the most preferred embodiment, ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl) -2H- tetrazol-2-yl)butane the acid or a pharmaceutically acceptable salt thereof is administered orally to a patient in need thereof at a dose of approximately 20 mg twice daily.

Disclosed herein is an LTA4H inhibitor which is the crystalline form of ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl) -2H- tetrazol-2-yl)butanoic acid in its free form, as described herein, for use in the treatment of hidradenitis suppurativa (HS), wherein LTA4H is administered orally to a patient in need thereof at a daily dose of about 1 mg to about 160 mg , or about 4 mg to about 100 mg, or about 10 mg to about 100 mg, or about 20 mg to about 60 mg, or about 5 mg to about 80 mg (e.g., about 20 mg, about 30 mg , approximately 40 mg or approximately 80 mg). In a preferred aspect of this embodiment, the crystalline form of ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl) -2H -tetrazole-2- yl)butanoic acid in its free form, as described herein, is administered orally to a patient in need thereof at a dose of from about 10 mg QD to about 40 mg BID. In yet another preferred aspect of this embodiment, the crystalline form of ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl) -2H -tetrazol- 2-yl)butanoic acid in its free form, as described herein, is administered orally to a patient in need thereof at a dose of about 10 mg to about 30 mg twice daily (e.g., about 10 mg BID, about 15 mg BID, preferably approximately 20 mg BID). In a most preferred embodiment, the crystalline form is ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl) -2H- tetrazol-2-yl )butanoic acid in its free form, as described herein, is administered orally to a patient in need at a dose of approximately 20 mg twice daily.

In preferred embodiments of the disclosed methods, uses and kits, the dose of the LTA4H inhibitor is from about 10 mg to about 30 mg BID or about 20 mg BID.

In preferred embodiments of the disclosed methods, uses, and kits, the patient achieves a sustained response after one year of treatment, as measured by Hidradenitis Suppurativa Clinical Response (HiSCR) (Simplified Scale), Numerical Rating Scale (NRS), Physician Global Rating hidradenitis suppurativa (HS-PGA) or skin disease life quality index (DLQI).

In preferred embodiments of the disclosed methods, uses and kits, prior to treatment with an LTA4H inhibitor as described herein, the patient has previously been treated with a systemic agent for the treatment of HS. In preferred embodiments of the disclosed methods, uses, and kits, the systemic agent is selected from the group consisting of a topical treatment, an antibiotic, an immune suppressant, a TNF-alpha inhibitor, an IL-1 antagonist, and combinations thereof.

In some embodiments of the disclosed methods, uses, and kits, prior to treatment with LTA4H as described herein, the patient has not previously received treatment with a systemic agent or topical agent for the treatment of HS.

In one embodiment of the disclosed methods, uses, and kits, an LTA4H inhibitor as described herein (e.g., a compound according to any of Embodiments 1, 2, 2A-2N, 3, and 3A-3E, or a pharmaceutically acceptable salt thereof), administered in combination with at least one antibiotic, JAK inhibitor, TYK2 inhibitor, PDE4 inhibitor, or immunosuppressant.

In preferred embodiments of the disclosed methods, uses, and kits, the dosage of an LTA4H inhibitor as described herein (e.g., a compound of any of Embodiments 1, 2, 2A-2N, 3, and 3A-3E, or a pharmaceutically acceptable salt thereof) , ranges from about 10 mg to about 30 mg BID. In other preferred embodiments of the disclosed methods, uses, and kits, the dose of the LTA4H inhibitor (e.g., a compound according to any of Embodiments 1, 2, 2A-2N, 3, and 3A-3E, or a pharmaceutically acceptable salt thereof) is approximately 20 mg .

In preferred embodiments of the disclosed methods, uses, and kits, the patient has moderate to severe HS.

As used herein, the phrase “moderate to severe” refers to HS disease in which patients have greater than or equal to 3 active inflammatory lesions [i.e. e. deep inflammatory lesions, such as abscesses and/or inflammatory nodules], no more than 10 fistulas, and at least two anatomical areas must be involved in the HS lesions.

In preferred embodiments of the disclosed methods, uses and kits, the patient is an adult. In some embodiments of the disclosed methods, uses, and kits, the patient with HS is an adult with moderate to severe HS.

In some embodiments of the disclosed methods, uses, and kits, the patient is an adolescent patient (12 years of age or older). In some embodiments, the patient is an adolescent patient who has moderate to severe HS.

In some embodiments of the disclosed methods, uses, and kits, the patient has been diagnosed with HS for at least one year.

In some embodiments of the disclosed methods, uses and kits, the patient does not have extensive scarring as a result of HS (ie, less than 20 fistulas, either draining or non-draining, or less than 10 fistulas).

In some embodiments of the disclosed methods, uses, and kits, the patient has previously had an insufficient response to conventional systemic therapy for HS.

In preferred embodiments of the disclosed methods, uses, and kits, prior to treatment with an LTA4H inhibitor as described herein (e.g., compounds according to any of Embodiments 1, 2, 2A-2N, 3, and 3A-3E, or a pharmaceutical thereof acceptable salt), the patient has an HS-PGA score greater than or equal to 3.

In preferred embodiments of the disclosed methods, uses, and kits, the patient achieves a HiSCR (simplified scale) by week 16 of treatment.

In preferred embodiments of the disclosed methods, uses, and kits, the patient achieves NRS30 by week 16 of treatment.

In preferred embodiments of the disclosed methods, uses and kits, the patient experiences a reduction in HS flares by week 16 of treatment.

In preferred embodiments of the disclosed methods, uses, and kits, the patient achieves a score reduction that is less than or equal to 6, as measured by the DLQI, by week 16 of treatment.

In preferred embodiments, when the disclosed methods, uses, or kits are used to treat a population of patients with moderate to severe HS, at least 40% of said patients achieve HiSCR on a simplified scale by week 16 of treatment in response to the specified stage of administration.

In another preferred embodiment, when the disclosed methods, uses, or kits are used to treat a population of patients with moderate to severe HS, the difference between the response rate of patients (e.g., patients who achieve a HiSCR response to HS treatment) and the response rate of placebo-treated patients by week 16 of treatment is at least 15%, at least 25%, or at least 30%.

In preferred embodiments of the disclosed methods, uses and kits, the patient experiences a decrease in the modified Sartorius score, for example, after 16 weeks of treatment.

In preferred embodiments of the disclosed methods, uses and kits, the patient experiences improvement according to the DLQI, for example, after 16 weeks of treatment.

In preferred embodiments, when the disclosed methods, uses, or kits are used to treat a population of patients with moderate to severe HS, at least 25% (and preferably at least 30%) of those patients achieve a response , corresponding to NRS30, for example, by week 16 of treatment in response to the specified administration stage.

In preferred embodiments, when the disclosed methods, uses, or kits are used to treat a population of patients with moderate to severe HS, less than 15% of said patients experience an exacerbation of HS during treatment in response to said administration step ( for example, within 16 weeks of treatment).

In preferred embodiments of the disclosed methods, uses, and kits, the patient is further treated with at least one topical agent and at least one antiseptic in combination with an LTA4H inhibitor as described herein.

In preferred embodiments of the disclosed methods, uses and kits, the patient is treated with an LTA4H inhibitor as described herein for at least 16 weeks, at least 24 weeks, at least 36 weeks, at least 48 weeks or at least 52 weeks. Most preferably, the patient is treated for at least 16 weeks.

In preferred embodiments of the disclosed methods, uses, and kits, the patient experiences a rapid reduction in pain, as measured by VAS or NRS, as early as one week after receiving the first dose of the LTA4H inhibitor.

In preferred embodiments of the disclosed methods, uses, and kits, the patient experiences a rapid decrease in CRP levels, as measured using a standard CRP assay, as early as one week after the first dose of the anti-IL-17 antibody or antigen-binding fragment thereof.

In preferred embodiments of the disclosed methods, embodiments and kits, the LTA4H inhibitor is ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)- 2 H -tetrazol-2-yl)butanoic acid or a pharmaceutically acceptable salt thereof.

In preferred embodiments of the present invention, the LTA4H inhibitor is the crystalline form of ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl) -2H- tetrazol-2-yl)butanoic acid in its free form (herein referred to as Form B).

In preferred embodiments, the LTA4H inhibitor is Form B, as described herein, presented as a substantially pure phase.

The aspects, advantageous features and preferred embodiments of the present invention, which are summarized in the following paragraphs, respectively alone or in combination, contribute to achieving the object of the present invention.

Claim 1. A method of treating or preventing hidradenitis suppurativa (HS), comprising administering to a subject in need thereof a therapeutically effective amount of an LTA4H inhibitor.

Claim 2. The method according to claim 1, wherein the LTA4H inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof:

(I),

Where

R1 represents OH or NH ₂ ;

Y represents O, S or CH ₂ ;

X1, X2, X3 and X4 represent N; or

X1, X2, X3 and X4 are selected from N, NH, C, CH and O, provided that at least two of X1, X2, X3 or X4 are N or NH;

R2 is C ₁ -C ₆ alkyl, optionally substituted with phenyl; C ₃ -C ₆ cycloalkyl; phenyl, optionally substituted with halogen, cyano, C ₁ -C ₆ alkyl, optionally substituted with halogen, C ₁ -C ₆ alkoxy or a 5-6 membered heteroaryl ring containing from 1 to 3 heteroatoms selected from N, O and S; or a 5-10 membered mono- or bicyclic heteroaryl containing from 1 to 4 heteroatoms selected from N, O and S, wherein said heteroaryl is optionally substituted with halogen, cyano or C ₁ -C ₆ alkyl, optionally substituted with halogen; or a pharmaceutically acceptable salt thereof.

Point 3. Method according to paragraphs. 1-2, where the LTA4H inhibitor is ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl) -2H -tetrazole-2 -yl)butanoic acid or a pharmaceutically acceptable salt thereof.

Claim 4. The method of any of the above claims, wherein the LTA4H inhibitor is contained in a pharmaceutical composition, wherein said pharmaceutical composition contains one or more pharmaceutically acceptable carriers, each independently selected from an excipient, a lubricant, a binder, a disintegrant and a glidant. .

Clause 5. The method according to claim 4, where the pharmaceutical composition is in the form of a tablet or capsule.

Claim 6. The method of any of the above, wherein the LTA4H inhibitor is administered at a daily dose of from about 10 mg to about 100 mg.

Claim 7. The method according to any of the above claims, wherein the LTA4H inhibitor is administered in combination with one or more therapeutic agents.

Clause 8. Method according to any one of paragraphs. 1-6, wherein the patient is further treated with at least one topical drug and at least one antiseptic in combination with an LTA4H inhibitor.

Clause 9. Method according to any one of paragraphs. 1-8, where before treatment with an LTA4H inhibitor, the patient had not previously been treated with a systemic agent or topical agent for the treatment of HS.

Claim 10. A method according to any of the above claims, wherein the patient is selected according to one of the following criteria:

a) the patient has moderate to severe HS;

b) before treatment with an LTA4H inhibitor, the patient has an HS-PGA score greater than or equal to 3;

c) before treatment with an LTA4H inhibitor, the patient has at least 3 inflammatory lesions; or

d) before treatment with an LTA4H inhibitor, the patient does not have extensive scarring (less than 10 fistulas) due to HS.

Item 11. A method according to any of the above items, wherein said patient achieves at least one of the following (for example, by week 16 of treatment):

a) HiSCR on a simplified scale;

b) reduction of exacerbations of HS;

c) NRS30;

d) a decrease in score that is less than or equal to 6, as measured by the DLQI; and/or

e) improvement according to DLQI.

Claim 12. A method as claimed in any one of the above, wherein when said method is used to treat a population of patients with moderate to severe HS, at least 40% of said patients achieve HiSCR on a simplified scale, for example, by week 16 of treatment.

Clause 13. Method according to any one of paragraphs. 1-11, wherein when the method is used to treat a population of patients with moderate to severe HS, at least 25% of said patients will achieve an NRS30 response, for example by week 16 of treatment.

Clause 14. Method according to any one of paragraphs. 1-11, wherein when this method is used to treat a population of patients with moderate to severe HS, less than 15% of these patients experience an exacerbation of HS during treatment, for example within 16 weeks of treatment.

Claim 15. The method of any of the above, wherein the patient is treated with an LTA4H inhibitor for at least 16 weeks.

Clause 16. Method according to any one of paragraphs. 1-11, wherein the patient exhibits at least one of the following as early as one week after the first dose of the LTA4H inhibitor:

a) rapid reduction in pain, as measured by VAS or NRS,

b) a rapid decrease in CRP levels, as measured by a standard CRP assay.

Claim 17. The method of any of the above claims, wherein said patient achieves a sustained response after completion of treatment (eg, 3 months after completion of treatment), as measured by the number of inflammatory lesions, by clinical response in hidradenitis suppurativa (HiSCR), digital rating scale (NRS), modified Sartorius HS score, hidradenitis suppurativa physician global assessment (HS-PGA), or skin disease life quality index (DLQI).

Clause 18. The method of claim 17, wherein said patient achieves a sustained response after completion of treatment (eg, 3 months after completion of treatment), as measured by the Simplified HiSCR (sHiSCR).

Claim 19. The method of any of the above, wherein the LTA4H inhibitor is administered at a dose of about 10 mg to about 30 mg twice daily.

Clause 20. An LTA4H inhibitor for use in the treatment and/or prevention of hidradenitis suppurativa (HS) in a patient in need of such treatment and/or prevention.

Claim 21. An LTA4H inhibitor for use according to claim 20, wherein said LTA4H inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof:

(I),

Where

R1 represents OH or NH ₂ ;

Y is O, S or CH ₂ ;

X1, X2, X3 and X4 represent N; or

X1, X2, X3 and X4 are selected from N, NH, C, CH and O, provided that at least two of X1, X2, X3 or X4 are N or NH;

R2 is C ₁ -C ₆ alkyl, optionally substituted with phenyl; C ₃ -C ₆ cycloalkyl; phenyl, optionally substituted with halogen, cyano, C ₁ -C ₆ alkyl, optionally substituted with halogen, C ₁ -C ₆ alkoxy or a 5-6 membered heteroaryl ring containing from 1 to 3 heteroatoms selected from N, O and S; or a 5-10 membered mono- or bicyclic heteroaryl containing from 1 to 4 heteroatoms selected from N, O and S, wherein said heteroaryl is optionally substituted with halogen, cyano or C ₁ -C ₆ alkyl, optionally substituted with halogen.

Clause 22. An LTA4H inhibitor for use according to claim 20 or claim 21, wherein said LTA4H inhibitor is ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridine-2- yl)oxy)phenyl) -2H -tetrazol-2-yl)butanoic acid or a pharmaceutically acceptable salt thereof.

Clause 23. LTA4H inhibitor for use according to any one of paragraphs. 20-22, wherein the LTA4H inhibitor is formulated in a pharmaceutical composition, wherein said pharmaceutical composition contains one or more pharmaceutically acceptable carriers, each independently selected from an excipient, a lubricant, a binder, a disintegrant and a glidant.

Claim 24. An LTA4H inhibitor for use according to claim 23, wherein the pharmaceutical composition is in the form of a tablet or capsule.

Clause 25. A pharmaceutical composition containing an LTA4H inhibitor, which is a compound of formula I or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, for use in the treatment and/or prevention of HS in a patient in need of such treatment and/or warning

Clause 26. LTA4H inhibitor for use according to any one of paragraphs. 20-24 or a pharmaceutical composition for use according to claim 25, wherein the LTA4H inhibitor is administered in a daily dose of from about 10 mg to about 100 mg.

Clause 27. LTA4H inhibitor for use according to any one of paragraphs. 20-24 and claim 26 or a pharmaceutical composition for use according to claim 25 or claim 26, wherein the LTA4H inhibitor or a pharmaceutical composition containing it is administered in combination with one or more second therapeutic agents.

Clause 28. A combination preparation containing a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more therapeutic agents, for use in the treatment and/or prevention of HS in a patient in need of such treatment and/or prevention.

Clause 29. LTA4H inhibitor for use according to any one of paragraphs. 20-24 and claim 26, a pharmaceutical composition for use according to any one of claim 25 and claim 26, wherein the patient is further treated with at least one topical drug and at least one antiseptic in combination with an LTA4H inhibitor .

Clause 30. LTA4H inhibitor for use according to any one of paragraphs. 20-24, 26, 27 and paragraph 29, pharmaceutical composition for use according to any one of paragraphs. 25-27 and claim 29 or the combination of claim 28 or claim 29, wherein prior to treatment with the LTA4H inhibitor, the patient has not previously been treated with a systemic agent or topical agent for the treatment of HS.

Clause 31. LTA4H inhibitor for use according to any one of paragraphs. 20-24, 26, 27 and paragraph 29, pharmaceutical composition for use according to any one of paragraphs. 25-27 and paragraph 29 or a combination according to paragraph 28 or paragraph 29, where the patient is selected in accordance with one of the following criteria:

a) the patient has moderate to severe HS;

b) before treatment with an LTA4H inhibitor, the patient has an HS-PGA score greater than or equal to 3;

c) before treatment with an LTA4H inhibitor, the patient has at least 3 inflammatory lesions; or

d) before treatment with an LTA4H inhibitor, the patient does not have extensive scarring (less than 10 fistulas) due to HS.

Clause 32. LTA4H inhibitor for use according to any one of paragraphs. 20-24, 26, 27 and pp. 29-31, pharmaceutical composition for use according to any one of paragraphs. 25-27 and pp. 29-31 or a combination according to any one of paragraphs. 27-31, wherein said patient achieves at least one of the following by week 16 of treatment:

a) HiSCR on a simplified scale;

b) reduction of exacerbations of HS;

c) NRS30;

d) a decrease in score that is less than or equal to 6, as measured by the DLQI; and/or

e) improvement according to DLQI.

Clause 33. LTA4H inhibitor for use according to any one of paragraphs. 20-24, 26, 27 and pp. 29-31, pharmaceutical composition for use according to any one of paragraphs. 25-27 and pp. 29-31 or a combination according to any one of paragraphs. 27-31, where by week 16 of treatment at least 40% of these patients achieve HiSCR on the simplified scale; or at least 25% of these patients achieve a response corresponding to NRS30; or less than 15% of these patients experience an exacerbation of HS.

Clause 34. LTA4H inhibitor for use according to any one of paragraphs. 20-24, 26, 27 and pp. 29-31, pharmaceutical composition for use according to any one of paragraphs. 25-27 and pp. 29-31 or a combination according to any one of paragraphs. 27-31, wherein the patient exhibits at least one of the following as early as one week after the first dose of the LTA4H inhibitor:

a) rapid reduction in pain as measured by VAS or NRS, and

b) a rapid decrease in CRP levels, as measured by a standard CRP assay.

Clause 35. LTA4H inhibitor for use according to any one of paragraphs. 20-24, 26, 27 and pp. 29-34, pharmaceutical composition for use according to any one of paragraphs. 25-27 and pp. 29-34 or a combination according to any one of paragraphs. 27-34, wherein said patient achieves a sustained response after completion of treatment (e.g., 3 months after completion of treatment), as measured by the number of inflammatory lesions, through the Hidradenitis Suppurativa Clinical Response (HiSCR), Numerical Rating Scale (NRS), Modified Sartorius HS score, Hidradenitis Suppurativa Physician Global Assessment (HS-PGA), or Skin Disease Life Quality Index (DLQI).

Claim 36. The LTA4H inhibitor, pharmaceutical composition or combination of claim 35, wherein said patient achieves a sustained response after completion of treatment, for example 3 months after completion of treatment, as measured by the Simplified HiSCR (sHiSCR).

Clause 37. LTA4H inhibitor for use according to any one of paragraphs. 20-24, 26, 27 and pp. 29-34, pharmaceutical composition for use according to any one of paragraphs. 25-27 and pp. 29-34 or a combination according to any one of paragraphs. 27-34, wherein the LTA4H inhibitor is administered at a dose of about 10 mg to about 30 mg twice daily.

general information

Details of one or more embodiments of the present invention are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described in the present invention may be used in practicing or testing the present invention, preferred methods and materials are described herein. Other features, objects and advantages of the present invention will be apparent from the description and claims. In the specification and the accompanying claims, the singular form includes references to the plural unless the context clearly dictates otherwise. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as would be commonly understood by one of ordinary skill in the art to which this invention relates. All patents and publications cited in this specification are incorporated herein by reference. The following examples are presented to more fully illustrate preferred embodiments of the present invention. These examples should in no way be construed as limiting the scope of the disclosed subject matter as defined in the appended claims.

EXAMPLES

Reduction

AE undesirable effect

AUC area under the curve

AUClast area under the plasma (or serum or blood) concentration versus time curve

from time zero to time point at which the concentration is quantifiable (mass x time/volume)

AUCtau area under the plasma (or serum or blood) concentration versus time curve

from time zero to the end of the tau dosing interval (mass x time/volume)

b.i.d. or BID twice a day

CI confidence interval

Cmax. maximum concentration after drug administration

Cmax, ss maximum concentration at equilibrium

ECG electrocardiogram

EoS end of study

PK pharmacokinetics

PD pharmacodynamics

q.d. or QD once daily

,ss in equilibrium

Tmax maximum length of time until maximum concentration is reached after drug administration

T1/2 terminal half-life

Example 1. ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2 H -Tetrazol-2-yl)butanoic acid (crystalline form B)

The compound of Example 29 described in WO2015/092740 (28 g, 35 mmol) and a solvent mixture containing 360 g of water and 40 g of THF were mixed together and stirred for 20 minutes. The mixture was filtered and the pH of the filtrate was adjusted to pH=5 using aqueous NaHCO ₃ solution. Stirring was continued for 18 hours, after which the mixture was filtered to obtain the free acid (Int-1) in a wet cake weighing 25.6 g, which was used to obtain Form B of the polymorph without further purification.

Weigh 505 mg of free acid (Int-1) in a 20 ml glass vial and add 6 ml of methanol. The suspension was heated to 50°C and stirred for 4 days using a magnetic stirrer. The suspension was cooled to room temperature and filtered. The recovered solid was dried at 40°C for 2.5 hours under vacuum. The white solid was analyzed by XRPD, DSC and TGA (Figures 1-3, respectively).

Alternative methods for preparing crystalline Form B are described in Patent Application No. PCT/CN2018/000278, filed July 31, 2018 (Patent Attorney File Number PAT058189-WO-PCT).

Powder X-ray diffraction

X-ray powder diffraction (XRPD) patterns were obtained using a Bruker Discovery D8 in reflection geometry (Figure 1). Powders were analyzed using a sample holder with a Si substrate and zero background. The radiation was Cu Kα (l=1.5418 Å). Diffraction patterns were obtained at 2-theta values ranging from 2° to 40°.

Table 1

X-ray powder diffraction data for crystal form B

Angle (°2-theta) Intensity (d value, angstrom) rel. intensity (%) 10.9 2863 23 11.3 5874 47 12.8 5903 48 15.2 3080 25 17.1 1900 15 19.7 6203 50 20.0 2950 24 20.3 4949 40 20.5 2602 21 21.0 2526 20 22.6 9030 73 24.1 12400 100 24.4 3104 25 25.1 7318 59 26.3 8074 65 28.5 5291 43 29.3 1891 15 30.0 2649 21 36.4 2085 17 39.1 1308 eleven

DSC:

Differential scanning calorimetry was performed for each crystalline form using a TA Instruments instrument (DSC 2500) (Figure 2). For each analysis, 2-4 mg of sample was placed in a T-zero aluminum crucible, which was closed with a lid with a hole for a needle. The heating rate was 10°C per minute over a temperature range of 30 to 300°C. Temperature values are given in degrees Celsius (°C), and enthalpy values are given in Joules per gram (J/g). The graphs show endothermic peaks pointing downwards. The endothermic melting peak (melting point) was estimated from the extrapolated melting onset temperature. The accuracy of the sample temperature measured by this method is approximately ±1°C, and the heat of fusion can be measured with a relative error of approximately ±5%.

Exemplary DSC results obtained using crystalline forms B are shown in Figure 2.

Form B: melting endotherm: _start temperature = 197.4°C (melting during decomposition)

Thermogravimetric Analysis (TGA):

TGA curves were obtained using a TA Instrument Q5000. 5-15 mg of sample was placed in an aluminum crucible and hermetically sealed. Immediately before analysis, an automated sampler punched a hole in the closed cup. Measurements for the TGA curve were carried out in the temperature range of 30-300°C with a step of 10°C/min. LoD (loss on drying) was calculated at temperatures ranging from 40°C to 150°C. A graph was made of the dependence of weight loss on the measured temperature of the sample. Temperature values are given in degrees Celsius (°C) and weight loss is given in %.

Exemplary TGA results obtained using crystalline forms B are shown in Figure 3.

Example 2.

Composition based on the compound from example 1 in capsule form

Ingredient Quantity per capsule (mg) Function 1 mg 5 mg 50 mg Contents of the capsule Connection from example 1 1.00 5.00 50.00 Active Ingredient Mannitol 98.75 104.75 145.95 Filler Cellulose, microcrystalline/microcrystalline cellulose 40.00 30.00 50.00 Filler Crospovidone 5.00 5.00 12.50 Baking powder Hypromellose 3.00 3.00 7.50 Binder Magnesium stearate ¹ 1.50 1.50 2.70 Lubricant Silicon dioxide, colloidal, anhydrous/colloidal silicon dioxide 0.75 0.75 1.35 Sliding agent Water, purified (bulk)/purified water ² --- --- --- Suspending agent/solvent Weight of capsule contents 150.00 150.00 270.00 - Capsule shell (theoretical weight) ³ 48.00 48.00 76.00 - Total capsule weight 198.00 198.00 346.00 - ¹ Plant origin ² Removed during processing ³ Capsule shell components are listed in the table below

Components of the shell of one capsule

Regulation (EU) 231/2012: Commission regulation (EU) establishing specifications for food additives. Capsules purchased from Lonza (now Capsugel)

Example 3 Analysis of skin biopsy samples from patients with HS indicates strong activation of the 5-lipoxygenase pathway in leukocytes from lesions

Neutrophils and macrophages, the main cellular targets of LTA4H inhibitors, are frequently found in HS lesions. Histological analysis of HS lesions by H&E staining demonstrated a large number of myeloid cells, such as neutrophils and macrophages, in the HS lesions of patients. Three-μm-thick paraffin sections were cut and stained with hematoxylin and eosin. Automated immunohistochemical staining for 5-lipoxygenase (clone: EP6072(2), Abcam, United Kingdom) and CD68 (clone KP-1, Dako, Denmark) was performed using a Ventana Discovery XT immunostainer (Roche Diagnostics, Switzerland). Isotype specific controls were used as negative controls. All biopsy samples were digitized using a ScanScope XT slide scanner (Aperio, Leica Biosystems, Switzerland) with a x40 objective.

Macrophages were identified by staining with anti-CD68 antibody. Co-staining with anti-5-lipoxygenase antibody demonstrated strong nuclear expression of the 5-lipoxygenase enzyme in myeloid cells found in the lesional skin of HS patients. Higher magnification images demonstrated expression of the enzyme 5-lipoxygenase on the nuclear membrane of many macrophages, a sign of activation of the pathway (Christmas et al., 1999 “Differential localization of 5- and 15-lipoxygenases to the nuclear envelope in RAW macrophages.” J. Biol Chem. p. 25594-8). Translocation of 5-lipoxygenase to the nuclear membrane activates the enzyme and produces its biosynthetic product LTA4, which is a substrate of LTA4H, which converts it to LTB4. (Figures 4, 5, 6)

Figure 4 . Lesion biopsy specimen obtained from a patient with HS. A paraffin section stained with hematoxylin and eosin demonstrated a mixed, severe inflammatory infiltrate containing large numbers of polymorphonuclear cells and macrophages (scale bar = 4 mm).

Figure 5 . Skin biopsy specimens with HS were immunohistochemically stained for 5-lipoxygenase. Staining demonstrated strong expression of 5-lipoxygenase in myeloid cells. The expression profile of 5-lipoxygenase was either diffuse in the nucleus (short arrows) or localized to the nuclear membrane (long arrows; scale bar represents 50 μm).

Figure 6 . Illustrative micrograph showing 5-lipoxygenase (brown) localized to the nuclear membrane in a multinucleated CD68+ giant cell (red, scale bar represents 30 μm).

Example 4. Lipidomic analysis of skin biopsy samples from patients with HS

Frozen human skin biopsy samples from healthy skin or extracted HS lesions (average 500 mg) were atomized using mechanical force (Covaris) and homogenized in 4 ml of deuterium-labeled internal standards containing methanol (ISTD) using a homogenizer (cycles of 2 ×20 sec at 5000 rpm, Precellys), maintained at low temperature. Samples were then stored at −20°C/45 min to allow protein precipitation and centrifuged at 13,000 rpm for 10 min at 4°C. Supernatants were then evaporated (Genevac) until completely dry and reconstituted in 70 μl methanol:water (50%/50%; v/v) followed by injection into the LC-MS/MS system. Calibration curves were de novo generated by serial dilutions of pure standards in methanol:water (50%/50%, v/v) containing the ISTD, and quantification was performed by comparing the peak area ratios of the metabolites to the ISTD in the samples compared to the calibration solutions.

Two analytical platforms were used to acquire data depending on instrument availability: 1) a Waters Class H UPLC system coupled to a Waters XevoTQS triple quadrupole mass spectrometer (QQQ), and 2) a Dionex Ultimate 3000RS UPLC coupled to a Sciex6500+ QQQ. Lipid separation was achieved using ACQUITY UPLC BEH C18, 1.7 μm, 2.1 × 50 mm, and CORTECS UPLC C18, 1.6 μm, 2.1 × 50 mm reverse phase columns heated to 40 °C, respectively. The flow rate was set to 0.180 mL/min and the mobile phase consisted of water-acetic acid (99.99/0.01; v/v) (A) and methanol-acetonitrile-acetic acid (B) (50/50 /0.01; volume/volume/volume). The eluent gradient was maintained at 45% of B for 2 min, then at 45-65% of B for 2-16 min, 65-100% for 16-19 min, and 100% of B for 19-22 min. From 23-30 min the column was re-equilibrated to initial conditions. Ionization was carried out using an ESI source, which operated in the mode for determining negatively charged ions. Fragmentation parameters were adjusted for each connection separately.

Manufacturer-specific software (TargetLyx for Waters and Analyst/Multiquant for Sciex data) was used for peak selection and quantitation. Further data processing, including imputation of missing values (replacement with the group mean), logarithmic transformation (base 2), correction for group effects (based on scaling by the mean for each sample), and group comparisons (empirical Bayes t tests) were performed in R (version 3.4.2) with the Metabolomics and NormalizeMets software packages (available from CRAN). (Anal. Chem., 2015, 87 (7), pp 3606-3615). (Figures 7 and 8)

Lipids were extracted from skin biopsy samples of 14 healthy patients and 16 HS patients and analyzed by LC-MS/MS.

Figure 7. The LTA4H product, LTB4, had increased levels in affected skin compared to unaffected skin (shown as log ₂ mean scaled concentrations [fmol/mg]).

Figure 8 . Levels of the 5S,6R DiHETE mediator of the 5-lipoxygenase pathway were also elevated, indicating strong activation of the 5-lipoxygenase pathway in HS lesions (depicted as log ₂ mean scaled concentrations [fmol/mg]). *** p < 0.001 using two-tailed unpaired t test.

Example 5: Transcriptomic Analysis of HS Skin Biopsy Samples Compared to Healthy Skin Biopsy Samples

Transcriptomic analysis of 18 HS skin biopsy samples compared with 8 healthy skin biopsy samples demonstrates increased transcriptomic regulation of 5-lipoxygenase pathway genes.

A homogenate was prepared from snap-frozen skin tissue using the recommended buffers from the Qiagen RNeasy mini kit. Total RNA from cells was extracted according to the manufacturer's protocol. cDNA from the samples was prepared from the same starting amount of RNA using the High capacity cDNA reverse Transcription Kit (Applied Biosystems). Samples were processed at CiToxLAB France on Affymetrix HG_U133_Plus2 microarrays. Normalized RMA data were analyzed using GeneSpring 11.5.1 (Agilent Technologies, Santa Clara, CA) and results were interpreted using Illumina BaseSpace Correlation Engine and Qiagen IPA software. Data were first subjected to standard QC controls using CiToxLAB and GeneSpring (PCA, hybridization controls). These were further filtered by expression levels to probe sets above the 20th percentile in 100% of samples in either condition before further analysis.

Lesional skin from HS patients showed increased levels of 5-lipoxygenase pathway genes, including LTA4H. LTA4H expression was high in both healthy and diseased skin (Figure 9).

Figure 9 shows the normalized expression level of the target genes. A significant increase in the expression levels of the 5-lipoxygenase genes ALOX5, ALOX5AP and LTA4H could be detected in samples from 18 HS patients compared to 8 control samples from healthy patients, indicating an increase in the level of LTB4 biosynthesis in accordance with lipidomics data. ***P<0.001;**P<0.01; * P < 0.05 using two-tailed unpaired t test.

Example 6 The compound of Example 1 and the compound of Embodiment 3D inhibit the biosynthesis of pro-inflammatory LTB4 in stimulated skin biopsy samples from HS patients

Skin biopsy samples from HS patients were cultured in cell culture medium for 2 hours in the presence or absence of 5 μM LTA4H inhibitors selected from the compound of Example 1 and the compound of Embodiment 3D. Biopsy samples were then stimulated for 2 h with 10 μg/ml ionophore to induce full activation of the 5-lipoxygenase pathway in inflammatory cells from the lesions. Skin biopsy samples were then collected and lipids were extracted and analyzed to obtain LTB4 by LC-MS/MS as described above. In stimulated skin biopsy samples with HS lesions, large amounts of the lipid mediator LTB4 were produced. Skin biopsy samples that were treated with the compound of Example 1 or the compound of Embodiment 3D exhibited virtually no LTB4 release. ( Figures 10 and 11 )

Lesional skin biopsies from HS patients were left untreated or fully ionophore stimulated to induce LTB4 biosynthesis in the presence or absence of an LTA4H inhibitor

Figure 10 : Compound 1 is the compound from Example 1;

Figure 11 : Connection 2 is a 3D embodiment

The presence of the LTA4H inhibitor completely suppressed the ability of biopsy samples from lesional skin of HS patients to produce LTB4. LTB4 amounts are presented in fmol/mg tissue. Shown are illustrative results obtained using one donor for one compound out of several tested.

Figure 12: Mice were treated with either vehicle at 3 mg/kg or Compound 2 at 10 mg/kg (Compound of Embodiment 3D). 22 hours after the last dose, blood was obtained diluted 1:3 and stimulated for 15 minutes ex-vivo with 10 mg/ml calcium ionophore to induce LTB4 formation. LTB4 release was quantified by LTB4 EIA and demonstrated greater than 90% LTB4 suppression in both treated groups. Shown are means of 4 mice per group +/- SEM.

Example 7 Clinical data from a first-in-human (FIH) trial

The compound of Example 1 was studied in the FIH study, designed to characterize its preliminary safety, tolerability and PK in adult healthy subjects. The study consisted of Part 1, Single Ascending Dose (SAD), and Part 2, Multiple Ascending Dose (MAD). The compound of Example 1 was administered orally as a single dose of QD or BID after meals or after fasting in a dose range of 5 mg to 2 times 100 mg. The compound of Example 1 was also administered orally in multiple doses after fasting for 12 days, ranging from 5 mg QD to 80 mg BID.

Part 1 (SAD)

Part 1 was a randomized, subject-blinded, partially investigator-blinded, placebo-controlled study of single oral ascending doses. The dose was administered either in one dose or in two doses 12 hours apart (N=69). Eight subjects were randomized in each cohort (except Cohort 7, which randomized seven subjects, and Cohort 9, which randomized six subjects) to receive either the compound of Example 1 or the matching placebo in a 6:2 ratio (active compound: placebo) for the trial nine dose levels.

Subjects were assigned to one of the following cohorts:

cohort 1: single 5 mg oral dose or matching placebo

cohort 2: single 10 mg oral dose or matching placebo

cohort 3: single 20 mg oral dose or matching placebo

cohort 4: single oral dose of 30 mg or matching placebo

cohort 5: single oral dose of 45 mg or matching placebo

cohort 6: single oral dose of 70 mg or matching placebo

Cohort 7: total oral dose of 140 mg or matching placebo, divided into two 70 mg doses given 12 hours apart

Cohort 8: total oral dose of 200 mg or matching placebo, divided into two 100 mg doses given 12 hours apart

Cohort 9: total oral dose of 80 mg or matching placebo, divided into two 40 mg doses given 12 hours apart

part 1: regimen (single ascending dose) (qd) - study overview

part 1: regimen (single ascending dose) (split dose once daily) - review of the study

Part 2 (MAD)

Part 2 was a randomized, blinded, partially blinded, placebo-controlled MAD study in which eight subjects were randomized into five cohorts to receive either the compound of Example 1 or a matching placebo in a 6:2 ratio (active ingredient: placebo).

Subjects were assigned to one of the following cohorts:

cohort 1: multiple (qd) oral daily dose of 5 mg or matching placebo

cohort 2: multiple (qd) oral daily dose of 15 mg or matching placebo

cohort 3: multiple oral daily doses of 20 mg or matching placebo administered twice daily (bid)

cohort 4: multiple oral daily dose of 40 mg or matching placebo administered twice daily (bid)

cohort 5: multiple oral daily dose of 80 mg or matching placebo administered twice daily (bid)

part 2: multiple ascending dose (qd) regimen - review of the study

part 2: multiple ascending dose regimen (bid) - review of the study

Human safety and tolerability

In Part 1 (single ascending dose, SAD) of the above study, healthy subjects received a single dose of the compound of Example 1 up to a maximum total daily dose of 200 mg (two 100 mg doses administered 12 hours apart). In Part 2 (multiple ascending dose, MAD) of the study, subjects received doses of no more than 80 mg BID for 12 days. No adverse events led to study termination. The highest doses in both arms were safe, and the maximum tolerated dose has not been established.

Some subjects treated with the compound of Example 1 or placebo in the SAD or MAD portions of this study experienced asymptomatic elevations in lipase levels. Three of the treated subjects (one from the SAD portion with the lowest dose of 5 mg, two from the MAD portion with the highest dose of 80 mg BID) and one subject treated with placebo experienced an increase in lipase levels. In three subjects with elevated lipase levels, the increased lipase level was accompanied by a moderate increase in amylase level (≤ 1.5 ULN). All subjects were asymptomatic and the events were transient, quickly returning to normal levels, while the subjects continued to receive the compound of Example 1. None of the significant physical examination, vital signs, or ECG findings were associated with the compound of Example 1.

Therefore, the compound of Example 1 was well tolerated in healthy subjects at doses not exceeding 80 mg bid (160 mg daily dose) for 12 days.

Human pharmacokinetic data

The pharmacokinetic behavior of the compound of Example 1 was evaluated in healthy subjects after single and multiple oral doses. The calculated PK parameters were standard parameters used to measure the time of action of a drug in the systemic circulation after receiving single or multiple doses of the compound of Example 1.

Part 1 (SAD)

The time profiles of the average concentration of the compound from Example 1 in blood plasma are shown in Figure 13.

After a single oral administration of the compound at a dose of 5, 10, 20, 30, 45, 70, twice at a dose of 70 (split dose, 2 identical doses administered 12 hours apart), twice at a dose of 100 (split dose) and two times at a dose of 40 mg (divided dosing), the plasma time of action of the compound of Example 1 increased with dose, and the median Tmax, ranging from 1 to 1.5 hours after dosing, indicated rapid absorption. After peak concentrations were reached, the initial peak plasma concentrations decreased very rapidly; at later time points, the rate of decline in concentrations slowed significantly and the mean apparent half-life (T1/2) ranged from 245 to 513 hours. With an increase in dose from 5 to 100 mg (i.e. 20-fold) Cmax. increased by 21.7 times; AUC0-24h increased 75-fold with a 40-fold increase in daily dose (from 5 mg to 100 mg bid). The percentage coefficient of variation (CV%) ranged from 18.5 to 41.4 for Cmax. and from 6.4 to 26.3 for AUC0-24h.

For a dose range of 5 mg to 2 times daily, 100 mg (40x) for AUC and 5 mg to 100 mg for Cmax. (20-fold) slope and corresponding 90% CI for Cmax. was 1.08 (1.01, 1.15), for AUClast the slope was 1.00 with 90% CI (0.957, 1.04), and for AUC0-24 the slope was 1.20 with 90% CI ( 1.15, 1.24). Dose proportionality across the entire dose range was demonstrated for AUClast, but not for Cmax. and AUC0-24h, where data indicate a slight, hyperproportional increase in duration of action with dose. However, for Cmax. and AUC0-24h PK can be considered dose proportional for no more than 4.50-fold and 2.57-fold dose increases, respectively.

Part 2 (MAD)

Average plasma compound concentration versus time profiles are shown in Figures 14a (day 1) and 14b (day 12).

Following oral administration of the first dose of the compound of Example 1 on day 1 for all dose groups (5 and 15 mg qd post-fasting; 20, 40 and 80 mg bid post-prandial), plasma concentration values of the compound of Example 1 increased in a dose-dependent manner with a median Tmax value ranging from 1 to 2.5 hours.

With an increase in the dose of the compound from Example 1 from 5 mg qd to 80 mg bid (i.e., 16-fold for the dosing interval), the Cmax values. and AUC at day 12 (AUC0-12h,ss for the 20, 40 and 80 mg bid cohorts and AUC0-24h,ss for the 5 and 15 mg qd cohorts) increased 17.9-fold and 20.9-fold, respectively. For the dose range from 5 to 80 mg (16-fold), the slope and corresponding 90% CI for Cmax,ss was 1.19 (1.08, 1.30), and for AUCtau,ss the coefficient was 1.07 with 90 % CI (1.01, 1.12). For both Cmax,ss and AUCtau,ss, dose proportionality was not demonstrated across the entire dose range. However, the PK for Cmax,ss and AUCtau can be considered dose proportional for no more than a 2.12- and 6.29-fold increase in dose, respectively. Dose proportionality criteria were met for AUCtau over the dose range of 5 mg qd to 40 mg bid. %CV ranged from 17.1 to 30.2% for Cmax. and from 11.7 to 18.1 for AUC0-24h.

Over the entire dose range studied, the Cmax,ss value was from 1.39 to 1.19 times higher than after a single dose (average Cmax (day 12)/Cmax (day 1)). For AUC (AUC0-12 and AUC0-24), mean ratios ranged from 2.08 to 1.27. This indicates a slight accumulation of the compound from Example 1 from Day 1 until equilibrium was reached. For the lowest dose of 5 mg qd, an average 2.1-fold accumulation to equilibrium was observed, but for all higher doses the accumulation was ≤ 1.4-fold. The small accumulation on day 1 of the bid regime (average Raccumulation, day 1, 1.09 to 1.29) suggests that the time until equilibrium is reached is short. In 4 of the 5 dose groups, morning predose concentration values were higher on day 3 compared to day 2, but the differences between concentration values were small. From day 3 to day 4, no consistent or significant increase in pre-dose morning concentrations was observed. This demonstrates that the equilibrium state is achieved quickly, i.e. around day 3.

For oral administration of BID doses of the compound of Example 1 after food administration, steady-state time of action is achieved within 3-4 days after dosing. At steady state, dose proportionality criteria were met for AUCtau from 5 mg QD to 40 mg BID.

Pharmacodynamic data for humans

Blood PD biomarker: leukotriene B4 (LTB4) in blood

Determination of leukotriene B4 (LTB4) in blood plasma ex vivo from stimulated whole blood

In animal models, the degree of LTB4 suppression in stimulated blood ex-vivo correlated well with the degree of therapeutic effect (Figure 10), in particular with a decrease in the number of neutrophils in inflamed tissues.

Determination of PD in peripheral blood from ex-vivo stimulated blood with LTB4 is predictive of therapeutic efficacy and is therefore suitable for monitoring target suppression in the FIH trial.

Figure 10: Mice were treated with either vehicle at 3 mg/kg or Compound 2 at 10 mg/kg. 22 hours after the last dose, blood was obtained diluted 1:3 and stimulated for 15 minutes ex-vivo with 10 mg/ml calcium ionophore to induce LTB4 formation. LTB4 release was quantified by LTB4 EIA and demonstrated greater than 90% LTB4 suppression in both treated groups. Shown are means of 4 mice per group +/- SEM.

Therefore, LTB4 concentrations were determined in plasma from stimulated whole blood ex-vivo by LC-MS/MS method.

Bioanalytical method for LTB4

Ex-vivo stimulation was performed at the clinical trial site according to the following procedure:

whole blood (500 μl) was stimulated for 30 min using calcium ionophore A23187. The blood plasma supernatant was then collected and frozen at -80°C for at least 24 hours before use.

Quantification of LTB4 by LC-MS/MS was performed as follows:

Human blood plasma was processed by organic precipitation followed by separation by reverse phase high performance liquid chromatography with detection by tandem mass spectrometry.

Chromatography:

reverse phase separation on Agilent Technologies 1290 Infinity HPLC and Zorbax SB-C18, Rapid Resolution HD 1.8 µm (100 × 2.1 mm) column at 60°C and flow rate 400 µl/min.

The total analytical time for the analysis is 11.0 minutes.

Revealing:

AB Sciex QTrap 5500 MS/MS Turbo Spray Ion Drive in negative ion detection mode.

A sample from each subject and for each time point was obtained and analyzed in three aliquots. Aliquots one and two contained blood plasma from ex-vivo stimulated whole blood, while aliquot three contained blood plasma from unstimulated whole blood as a negative control. Samples with CV >25% for the first two aliquots and/or with detected values in aliquot three were excluded from the results.

LTB4 concentration data were calculated as the average concentration in aliquots one and two. The concentration in aliquot three was not included in the calculation. Change from baseline and percent suppression (percentage from baseline) were calculated for each biomarker. Baseline was the average of baseline and 1-day and 1-hour measurements.

To avoid missing values when calculating changes from baseline and percent suppression, values lower than LLOQ were replaced by 0.5 x LLOQ, and values above the upper limit of quantitation (ULOQ) were replaced by 1.5 x ULOQ.

Results:

results for the first SAD cohorts indicated that LTB4 release by stimulated blood cells remained at 25-50% of baseline after 24 hours at the 5 mg dose. Increased suppression was observed after 24 hours at the higher dose. Approximately 50% suppression at 24 hours post-dose was observed at the 10 mg dose and transient maximal suppression (>90%) after Cmax was reached. observed at a dose of 20 mg. (Figure 15)

Additional cohorts in SAD confirmed dose-dependent suppression of LTB4. Approximately 81%, 86%, and 89% suppression at 24 hours post-dose were observed at 30 mg, 45 mg, and 70 mg, respectively.

Steady-state data from cohorts 1–3 in the MAD portion support dose-dependent suppression of LTB4. Approximately 75%, 90%, and 99% inhibition were observed in samples collected pre-dose on day 9 (steady state) at 5 mg (Q.D.), 15 mg (Q.D.), and 20 mg (B.I.D.), respectively. (Figure 16)

Target suppression of 90-99% was maintained at doses of 15 mg (Q.D.) and 20 mg (B.I.D.) in the MAD portion of the study.

In conclusion, target inhibition of leukotriene A4 hydrolase at steady state assessed in ex-vivo blood samples averaged 75% at 5 mg QD, 90% at 15 mg QD, and 99% at 20 mg QD bid.

Blister content biomarker: blood leukotriene B4 (LTB4) in cantharidin-induced blister contents.

Cantharidin-induced skin blisters

To evaluate the PD effect of the compound of Example 1 on a potential target organ, skin blisters were induced on the arm of subjects in one selected SAD portion cohort and selected MAD portion cohorts.

In parts 1 and 2 of the clinical study (SAD and MAD), skin blisters were induced on the hand

subjects in the selected cohorts. To do this, 10 mm diameter filter paper discs soaked in a cantharidin solution (such as cantharon) were applied to the subject's arm, which induced the appearance of an epidermal blister, and the contents of the blister were collected approximately 24 hours (+/- 1 h) after application.

Blister content samples were collected on predose day 1 and predose day 2 in SAD cohort 4, and predose day 1 and predose day 9 in MAD cohorts 2–5.

Obtaining samples for the analysis of leukotrienes and lipoxin A4 in the contents of human blisters

Blister content samples were obtained frozen on dry ice and stored at -70°C or lower until analysis.

On the day of analysis, samples were removed from the freezer and immediately removed after

defrosting.

Procedure for Leukotrienes and Lipoxin A4 in Human Blister Contents

90 μL of blister contents (sample or QC sample) was spiked with 5 μL of IS-L-2 internal standard solution (deuterated leukotrienes and lipoxin at 50 ng/mL) and vortexed in a microcentrifuge tube. 90 μl of methanol with 0.1% formic acid was added. The mixture was then mixed by shaking for 5 minutes and sonicated on ice for 10 minutes. Samples were incubated at -20°C in a freezer for 40 minutes. Then

centrifuged at 16,000 rpm (27,500xg) at 4°C for 20 minutes. 160 μl of the supernatant was transferred to Millipore 5kDa MWCO filters. The MWCO filters were previously cleaned by centrifugation with 500 μl of a 1/1 methanol/water mixture passed through them. The loaded filters were centrifuged at 16,000 rpm (27,500xg) at 4°C for 40 minutes (or until all liquid was filtered out). 140 µl filtrate

transferred to glass HPLC vials, combined with 108 μL of water and vortexed briefly. If the content volume of the blisters was less than 90 μL, water was used to adjust the volume to 90 μL and the dilution factor was recorded.

High performance liquid chromatography

HPLC was performed using an Agilent UHPLC system equipped with 2 pumps, one UHPLC pump (model G4220B) for the analytical gradient and one quaternary pump (model G1311B) as the loading pump.

results

In Part 1 of the study, the contents of the blisters were assessed in the 30 mg treatment group, the sample was collected after 24 hours and the average concentration of the compound from Example 1 was found to be 4.67 ng/ml. Blister content concentrations were on average approximately twice as high as plasma concentrations at the same time and were only 14% of the corresponding blood concentrations.

In Part 2 of the study, wheal contents were analyzed in the 15 mg qd treated group and in the 20, 40 and 80 mg treated groups, with samples collected pre-dose on day 9 (blister contents). The mean concentrations of the compound from Example 1 increased at dose from 4.62 ng/ml at 15 mg qd to 233 ng/ml at 80 mg bid for blistered contents. Blister concentrations were similar to plasma concentrations, with blister/plasma ratios around 2.

LTB4 suppression in skin and plasma (% change from baseline) is shown in Figure 17. A daily dose of 40 mg (20 mg BID) demonstrates almost complete suppression of LTB4 in blood at steady state, and at the same dose 90% suppression of LTB4 was achieved in samples contents of human skin blisters, where the appearance of a skin blister was induced by topical application of cantharidin.

Example 8. Efficiency and safety ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2 H -tetrazol-2-yl)butanoic acid (form B) in adult patients with moderate to severe HS.

Details of the clinical trial design demonstrating the efficacy of ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2 H -tetrazole-2 are provided below -yl)butanoic acid compared with placebo.

Clinical trial design

Blinding of subjects and investigators allows for objective assessment of subjective data, such as HS lesion counts or overall HS-PGA scores, as well as adverse events.

A randomized, subject- and investigator-blinded, placebo-controlled, multicenter, parallel study was conducted to evaluate the efficacy, safety, and tolerability of several active treatment compounds, such as the compound of Example 1, in subjects with hidradenitis suppurativa (HS) of moderate to moderate severity. heavy. After a screening period of approximately 4 weeks, a treatment period of 16 weeks is planned, followed by a safety observation period of approximately 12 weeks. Subjects receive 20 mg of the compound from Example 1 BID p.o. or placebo BID p.o.

Subjects included in this study are adult men and women aged 18 to 65 years diagnosed with moderate to severe HS with recurrent lesions of inflammation for at least 12 months. The requirements for a subject to be included in the study are that they must have at least 3 lesions of inflammation. Baseline assessment can begin on day -7 with assessment completion on day -1 prior to treatment on day 1. All baseline safety assessment results must be available prior to dosing and meet eligibility criteria. Randomization is performed using the Interactive Randomization Technology (IRT) system.

The selected primary clinical endpoint was HiSCR simplified scale (clinical response in hidradenitis suppurativa) after 16 weeks of treatment.

On day 113 (week 17), after safety and other assessments have been completed, all subjects enter the follow-up period without administration of any drug. If medically warranted and if no potential safety concerns have been identified (after discussion with the sponsor), subjects may receive previously prohibited medications during this follow-up period.

Safety and efficacy assessments are performed at follow-up visits on day 141 (week 21) and day 197 (week 29). Pharmacokinetics (PK) and pharmacodynamics (PD) data are collected. Blinding is maintained for the investigator and subject until completion of the study. The final visit occurs on Day 197 (Week 29), which includes an end-of-study assessment followed by completion of study participation.

Approximately 45 subjects are randomized, with 30 receiving the active substance and 15 placebo. On Day 1, 20 mg of the compound of Example 1 or its corresponding placebo is provided to subjects at the study site. Personnel at the study site will instruct the subject on how to administer the medication (BID), including the need to drink fluids (preferably water) and take the medication during or shortly after the morning and evening meals. At study entry, drug administration and clinical assessments are performed, as well as PK, pharmacodynamics (PD) and necessary safety assessments. Subjects will be released from the study on the day of completion of all assessments, provided there are no safety concerns. Subjects return to the study site on Day 8 (Week 2), Day 15 (Week 3), and Day 29 (Week 5), and then at one-month intervals: Day 57 (Week 9), Day 85 (Week 13), and day 113 (week 17) respectively. During these visits, safety assessments and selected efficacy parameters are assessed and samples are collected for PK/PD analysis.

The primary objective is to demonstrate the preliminary efficacy of treatment with the compound of Example 1 in subjects with HS after 16 weeks of treatment compared to placebo. After the 16-week treatment period, a 12-week follow-up period begins to monitor the sustainability of the effect, which may persist or increase after 16 weeks of treatment.

A 2:1 randomization is planned based on the fact that preference is given to exposure to active substances while limiting subjects' exposure to placebo.

The study includes several clinical endpoints to better evaluate the data properties of the selected endpoints:

For this study, the simplified HiSCR was selected as the primary endpoint. Simplified HiSCR is defined as a 50% reduction in the total number of abscesses and inflammatory nodules without any increase in the number of draining fistulas.

Inflammatory lesions in HS will be considered as discrete lesions (inflammatory nodules, abscesses and draining fistulas) in typical anatomical areas. In addition to the scoring, a global rating scale (Hidradenitis Suppurativa Physician Global Assessment, or HS-PGA) will be used, as well as a composite score (Hidradenitis Suppurativa Severity Score, or SAHS).

Several patient-based treatment outcomes will be used, including the Skin Disease Life Quality Index (DLQI). Finally, because skin-related pain is the most important symptom from the subject's perspective, a Numerical Rating Scale (NRS) is included to assess pain.

Additional information about clinical assessments:

HS-PGA (Physician Global Assessment for Hidradenitis Suppurativa): The score will be used as a study objective to assess HS and has been implemented and described in Kimball AB, Kerdel F, Adams D, et al (2012) Adalimumab for the treatment of moderate to severe Hidradenitis suppurativa: a parallel randomized trial. Ann Intern Med;157:846-55.

The SAHS score is a composite score ( Hessam S, Scholl L, Sand M, et al (2018) A Novel Severity Assessment Scoring System for Hidradenitis Suppurativa. JAMA Dermatol;154(3):330-335) and will be obtained from the collected information on the number of inflammatory foci, the number of fistulas and the NRS pain rating scale. In addition, anatomical regions and new or aggravated existing boils will be collected in both cohorts.

Skin-related pain - NRS (Numerical Pain Rating Scale): The NRS for skin-related pain was used in the adalimumab studies ( Kimball et al. (2016) N Engl J Med 375:422-34) and will be used in the future , as pain associated with HS is the greatest burden to the patient ( Matusiak et al (2017) J Am Acad Dermatol;76:670-5). Pain associated with HS will be recorded on average over the last 24 hours and at worst (over the last 24 hours).

Other patient-based outcome measures (PROs) will include the Skin Disease Life Quality Index (DLQI) as a means of assessing dermatology-related quality of life (QoL), with validated scoring scales available in many countries and countries. languages. The patient's overall assessment is also included.

Study objectives and endpoints

Main goal(s) Endpoints corresponding to the main goal(s) Demonstrate the effectiveness of the compound of Example 1 compared to placebo in patients with moderate to severe hidradenitis suppurativa (HS) Proportion of patients achieving clinical response as assessed by HiSCR (HiSCR) clinical response after 16 weeks of treatment Secondary goal(s) Endpoints corresponding to secondary goal(s) To evaluate the safety and tolerability of the compound from Example 1 in patients with moderate to severe hidradenitis suppurativa (HS) Number and severity of AEs
Frequency of changes in laboratory safety parameters, vital signs, and ECG parameters
Physical examination and vital signs at baseline and periodically until the end-of-study visit Assess the effect of the compound of Example 1 compared to placebo on clinical outcome measures over time Hidradenitis Suppurativa Physician Global Assessment (HS-PGA) Over Time
Number of inflammatory nodules over time
Number of abscesses over time
Number of draining fistulas over time
Number of uninflamed nodules over time To evaluate the effect of the compound from Example 1 on reducing exacerbations of HS compared to the corresponding placebo Proportion of patients who experienced at least one exacerbation during 16 weeks of treatment
A flare is defined as an increase of at least 25% in the total number of abscesses and inflammatory nodules (AN count) with a minimum increase of 2 AN from baseline. Assess the effect of the compound of Example 1 compared with placebo on patient-reported treatment outcomes Skin Disease Life Quality Index (DLQI)
Patient's overall assessment
Proportion of patients achieving NRS30 after 16 weeks of treatment among patients with a baseline NRS skin pain level greater than or equal to 3
The number of new boils or existing boils that have appeared in the last four weeks.

Key inclusion criteria

Male and female subjects aged 18 to 65 years with clinically diagnosed HS for at least 12 months prior to screening

A total of at least 3 inflammatory lesions, i.e. abscesses and/or inflammatory nodules, and

no more than 10 fistulas, and

at least two anatomical sites must be involved in HS lesions

The minimum body weight of the subject must be 50 kg (inclusive)

Key exclusion criteria

Use of investigational medicinal products at the time of screening, or within 30 days of study entry, or within 5 half-lives of study entry, or until the expected pharmacodynamic effect returns to baseline, but not earlier than any of these ; or longer if required by local regulations.

Use of biological agents that block IL12 and IL23, such as ustekinumab or guselkumab, within the last 6 months before randomization/initiation of treatment.

Use of B-cell-targeting or B-cell-depleting biologics or similar drugs, such as rituximab or belilumab, for 12 months; for a patient who has previously received these drugs, the B cell count should be within the normal range.

Use of biological immunomodulatory agents other than the above (for example, adalimumab, secukinumab, etanercept, infliximab, etc.) 3 months before randomization/initiation of treatment or 5 half-lives (but not earlier than any of these).

Use of rituximab or belilumab for 12 months.

Use of any systemic treatment for HS within the last 4 weeks before randomization (eg, retinoids or other immunomodulatory therapies, eg methotrexate, cyclosporine A, corticosteroids).

Use of cyclophosphamide within the last 6 months.

Use of systemic antibiotics for the treatment of HS during the last week before randomization/initiation of treatment.

If spironolactone or other antiandrogens (finasteride, cyproterone acetate, etc.) are being used (for HS), only patients who have been on a fixed dose for the past 3 months and who plan to continue taking it during the study are eligible to participate.

Surgical treatment of HS in the last 4 weeks before randomization/initiation of treatment. Surgical treatment does not include occasional excisional biopsies.

Receiving a high bolus dose of any corticosteroid (>1 mg/kg) for 3 months.

Claims (17)

1. Use of an LTA4H inhibitor for the treatment or prevention of hidradenitis suppurativa in a patient in need of such treatment or prevention, wherein said LTA4H inhibitor is ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl) -2H -tetrazol-2-yl) butanoic acid or a pharmaceutically acceptable salt thereof; or said LTA4H inhibitor is the crystalline form of ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl) -2H- tetrazole-2- yl)butanoic acid in its free form, wherein said crystalline form is characterized by a powder X-ray diffraction pattern containing characteristic peaks at 2θ at 22.6±0.2°2θ, 24.1±0.2°2θ and 26.3±0, 2 °2θ, measured at a temperature of approximately 25°C, and at an X-ray wavelength, λ, of 2. The use of an LTA4H inhibitor according to claim 1, where the crystalline form is ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl) -2H -Tetrazol-2-yl)butanoic acid in its free form is characterized by the following X-ray powder diffraction, XRPD data: Angle, °2-theta Intensity, d value, angstrom Rel. intensity, % 10.9 2863 23 11.3 5874 47 12.8 5903 48 15.2 3080 25 17.1 1900 15 19.7 6203 50 20.0 2950 24 20.3 4949 40 20.5 2602 21 21.0 2526 20 22.6 9030 73 24.1 12400 100 24.4 3104 25 25.1 7318 59 26.3 8074 65 28.5 5291 43 29.3 1891 15 30.0 2649 21 36.4 2085 17 39.1 1308 eleven 3. Use of an LTA4H inhibitor according to claim 1 or 2, wherein the LTA4H inhibitor is contained in a pharmaceutical composition, wherein said pharmaceutical composition contains one or more pharmaceutically acceptable carriers, each independently selected from an excipient, a lubricant, a binder, a disintegrant and a substance, promoting sliding. 4. Use of an LTA4H inhibitor according to claim 3, where the pharmaceutical composition is in the form of a tablet or capsule. 5. Use of a pharmaceutical composition containing an LTA4H inhibitor, which is ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl) -2H -tetrazol-2-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, or the crystalline form of ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy )phenyl) -2H -tetrazol-2-yl)butanoic acid in its free form, wherein said crystalline form is characterized by a powder X-ray diffraction pattern containing characteristic peaks at 2θ at 22.6±0.2°2θ, 24.1±0 .2 °2θ and 26.3±0.2 °2θ, measured at a temperature of approximately 25°C, and at an X-ray wavelength λ of together with one or more pharmaceutically acceptable carriers, for the treatment or prevention of hidradenitis suppurativa in a patient in need of such treatment or prevention. 6. Use according to claim 5, where the crystalline form is ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl) -2H -tetrazole -2-yl)butanoic acid in its free form is characterized by the following X-ray powder diffraction, XRPD data: Angle, °2-theta Intensity, d value, angstrom Rel. intensity, % 10.9 2863 23 11.3 5874 47 12.8 5903 48 15.2 3080 25 17.1 1900 15 19.7 6203 50 20.0 2950 24 20.3 4949 40 20.5 2602 21 21.0 2526 20 22.6 9030 73 24.1 12400 100 24.4 3104 25 25.1 7318 59 26.3 8074 65 28.5 5291 43 29.3 1891 15 30.0 2649 21 36.4 2085 17 39.1 1308 eleven 7. Use of an LTA4H inhibitor according to any one of paragraphs. 1-4 or the use of a pharmaceutical composition according to any one of paragraphs. 5, 6, wherein the LTA4H inhibitor is administered at a daily dose of from about 10 mg to about 100 mg and where the term “about” indicates a deviation of ±5%. 8. Use of an LTA4H inhibitor according to any one of paragraphs. 1-4, 7 and 8, or the use of a pharmaceutical composition according to any one of paragraphs. 5-8, wherein prior to treatment with an LTA4H inhibitor, the patient had not previously been treated with a systemic agent or topical agent for the treatment of hidradenitis suppurativa. 9. Use of an LTA4H inhibitor according to any one of paragraphs. 1-4, 7 and 8, or the use of a pharmaceutical composition according to any one of paragraphs. 5-8, where the patient is selected according to one of the following criteria: a) the patient has moderate to severe hidradenitis suppurativa; b) before treatment with an LTA4H inhibitor, the patient has an HS-PGA score greater than or equal to 3; c) before treatment with an LTA4H inhibitor, the patient has at least 3 inflammatory lesions; or d) before treatment with an LTA4H inhibitor, the patient does not have extensive scarring (less than 10 fistulas) due to hidradenitis suppurativa. 10. The use of an LTA4H inhibitor according to any one of claims 1-4, 7 and 8, or the use of a pharmaceutical composition according to any one of claims. 5-8, wherein the LTA4H inhibitor is administered at a dose of from about 10 mg to about 30 mg twice daily and where the term "about" indicates a deviation of ±5%.

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