US 2014O135361A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0135361 A1 Lin et al. (43) Pub. Date: May 15, 2014 (54) ANT-ALLERGY (57) ABSTRACT BENZOCYCLOHEPTATHOPHENE The present invention provides inhibitors of allergy, and aller DERVATIVES gic reactions specifically compounds of the present invention are described by the following chemical Formula I: (76) Inventors: Tongjun Lin, Fuzhou City (CN); Jun XIN, Dartmouth (CA) Formula I (21) Appl. No.: 14/129,766 (22) PCT Filed: Jun. 27, 2012 (86) PCT NO.: PCT/CN2012/077591 S371 (c)(1), (2), (4) Date: Dec. 27, 2013 Related U.S. Application Data (60) Provisional application No. 61/502,066, filed on Jun. 28, 2011. ls R-R3 Publication Classification A method for treating an allergic reaction, or allergy diseases (51) Int. C. or disorders includes administering a therapeutically effec CO7D 409/4 (2006.01) tive composition comprising a compound of Formula I or a (52) U.S. C. pharmaceutically acceptable salt, Solvate or prodrug thereof CPC .................................... C07D409/14 (2013.01) and a pharmaceutically acceptable carrier, vehicle or excipi USPC ........................................... 514/318; 546/194 ent to a subject in need thereof. Patent Application Publication May 15, 2014 Sheet 1 of 4 US 2014/O135361 A1 FIG 1A Day 1 Day 3 Day 2 Measurement of Anti-DNPlgE DNFB tissue swelling | V | V | V | {A. 2 Compound A(1 mg/kg. p.O.) Ketotifen (1 mg/kg. p.o.) FIG. 1B Earswelling Foot swelling S. w- & . E C 3. 3. &. 5CD 9d d as 2 O s % s s p s E & E & Š H Šiš. H Š w W Š & sgs & s SS S SSS C S CS& FIG. 2A Collecting ear tissue Anti-DNPlgE (30 min after injection (24 hrs before DNP-Evan's blue of DNP) injection of DNP) Compound A(1 mg/kg. p.o.) Ketotifen (1 mg/kg. p.o.) Patent Application Publication May 15, 2014 Sheet 2 of 4 US 2014/O135361 A1 FIG. 2B Evan's blue dye leakage FIG. 3A Anti-DNPlgE(24 hrs before SS measurementitement Oof application of DNFB) tissue swelling 3 hrs after application of DNFB Compound A(1 mg/kg. p.o.) Ketotifen (1 mg/kg. p.o.) Patent Application Publication May 15, 2014 Sheet 3 of 4 US 2014/O135361 A1 FIG. 3B d o Weight of ear O 2 gas$* Earswelling d) 2is 88 & - 13% Š SE(6 E so 5, 2 six s 9 :8:, . d 9 S is |. S. S. ii. s. gk- is ls. SSSS & sixxYMYYYY Ye'O Untreated Ketotifen Compound -- Untreated Ketotifen Compound A es s g CD2 & Foot swelling wa8 E S.S. s. Weicht9 Of foot E C. S g 5 of 338. w- E 3& r O 5 SE8 - $8 SS f a wa&-8 S sis. & Š aša 5. Untreated Ketotifen Compound Untreated Ketotifen Compound A FIG. 4 E 880 a. Š s S. 3: s s 1 Š Š S Š S S . Š S. S. O ( ). I 19 OG Ketotifen (uM) Compound A (uM) Patent Application Publication May 15, 2014 Sheet 4 of 4 US 2014/O135361 A1 FIG. 5 3ts - Ketotifen e Compound A S. 2000 1500 St O Xava Vava Va a o 5 it an US 2014/O 135361 A1 May 15, 2014 ANT-ALLERGY they need to be administered 3 to 4 times a day. Second, they BENZOCYCLOHEPTATHOPHENE are highly lipophilic and easily cross the blood-brain barrier DERVATIVES causing a major side effect of sedation. Thus, major efforts have been made to improve H1 antihistamine agents by BACKGROUND reducing their side effects on central nervous system and by 0001. The statements in this section merely provide back enhancing the duration of drug effect. ground information related to the present disclosure and may 0007 Accordingly, there is a need for newer anti-allergy not constitute prior art. agents aimed at improved efficacy and reduced side effects. 0002 Allergy is a complex disease. Multiple immune cells and inflammatory mediators contribute to the initiation and SUMMARY manifestation of allergic diseases. In addition to the blockade 0008. The following only summarizes certain aspects of of histamine H1 receptor, the anti-inflammatory effects have the invention and is not intended to be limiting in nature. increasingly been recognized to play an important role in the These aspects and other aspects and embodiments are management of allergic diseases. The anti-inflammatory described more fully below. All references cited in this speci effects include stabilization of mast cells (to prevent mediator fication are hereby incorporated by reference in their entirety. release), blockade of lipid mediators such as platelet-activat In the event of a discrepancy between the express disclosure ing factor (PAF) and leukotrienes, inhibition of adhesion of this specification and the references incorporated by refer molecules, and inhibition of eosinophils and CD4 T cells. ence, the express disclosure of this specification shall control. 0003 Allergic diseases have reached epidemic propor 0009. The invention comprises compounds of Formula I tions worldwide. Allergic diseases such as asthma, rhinitis or that inhibit histamine and allergic reactions and pharmaceu atopic dermatitis affect at least 8%–16% population with the tical compositions thereof. The invention is also directed to annual economic burden of 12.7, 1.2, and 3.8 billion dollars, methods of inhibiting allergic hypersensitivity and for treat respectively, in the United States and are a major health ing allergy, or allergic conditions or diseases in a subject in burden world-wide. The range of allergic diseases includes need thereof. rhinitis, sinusitis, conjunctivitis, asthma, dermatitis and food allergy. These diseases negatively impact the patient’s quality 0010. A first aspect of the invention provides a compound of life and impair their ability to perform in school or work of Formula I: place. Thus, allergic diseases result in significant Socio-eco nomic costs. 0004 Mast cells play a major role in allergy through secre Formula I tion of granule associated and newly synthesized mediators. They are distributed widely in the body and are especially abundant in skin or mucosa where they can interact with foreign materials such as allergens or pathogens. Mast cells possess a large number of high affinity IgE receptors on their Surface. Allergen binding to IgE receptors on mast cells ini tiates a cascade of signaling events leading to the production of potent inflammatory mediators including histamine, plate let-activating factor, IL-6 and many others. 0005 The role of histamine in the pathophysiology of allergic disorders has been well-recognized. Mast cells pro duce and store histamine in their granules. Upon allergen ls R-R3 activation, mast cells immediately (within seconds) release histamine into local tissues. Histamine exerts its effects in allergic diseases primarily through interacting with histamine 00.11 or a pharmaceutically acceptable salt, solvate or H1 receptors which are present in a variety of organs such as prodrug thereof, wherein nerve endings, blood vessel walls, and airway Smooth 0012 R is each independently Cs alkyl, Cs alkenyl, muscles. Histamine has broad biological effects. Depending Cs alkynyl, alkoxy, alkenoxy, Cao cycloalkyl, Cao het on the location where histamine is released, its biological erocycloalkyl, Cao aryl, Cao aralkyl, aralkyloxy, Cao het effects vary from mild discomfort of itch to life-threatening eroaryl, or Coheteroaralkyl, wherein each Cs alkyl, Cs bronchoconstriction. In the nose or skin, histamine induces alkenyl, C2-s alkynyl, alkoxy, alkenoxy, Cao cycloalkyl, vasodilation and increases vascular permeability leading to Cao heterocycloalkyl, Cao aryl, Cao aralkyl, aralkyloxy, edema and erythema. It stimulates the sensory nerve endings Coheteroaryl, or Coheteroaralkyl optionally including leading to itching or Sneezing. In the lung, histamine pro 1-3 substituents independently selected from Q or Q.: Vokes the bronchial Smooth muscle leading to bronchocon 0013 R is each independently, hydrogen, halo, OH, striction. —CN, NO. —N=O. —NHOQ, —OQ, SOQ, 0006 H1 antihistamine agents play a pivotal role in the —SOQ, —SON(Q) —SON(Q) —N(Q), —C(O) treatment of allergic diseases and are among the most pre OQ, —C(O)O. —C(O)N(O), —C(=NQ)NQ-, scribed medications in the world. Depending on their action —NQC(=NO)NQ-, —C(O)N(O)(OQ), —N(Q)C(O)- on the central nervous system, H1 antihistamines are classi Q, N(Q)C(O)N(O), N(Q)C(O)O-Q, N(Q) fied as first-generation and second-generation. In general, SOO. —N(Q)SOQ, Cisalkyl, C-salkenyl, Cs alkynyl, first-generation H1 antihistamines such as dexchlorphe alkoxy, alkenoxy, Cao cycloalkyl, Cao heterocycloalkyl, niramine, hydroxyZine, contain two features that limit their Cao aryl, Cao aralkyl, aralkyloxy, Cao heteroaryl, or Cao usage. One, they are rapidly absorbed and metabolized. Thus, heteroaralkyl, wherein each Cs alkyl, Cs alkenyl, Cs US 2014/O 135361 A1 May 15, 2014 alkynyl, alkoxy, alkenoxy, Cao cycloalkyl, Cao heterocy benzo-1,3-dioxolyl. pyridine-N-oxide, 1-piperidinyl, 2-pip cloalkyl, Cao aryl, Cao aralkyl, aralkyloxy, Cao het eridinyl, 3-piperidinyl, 4-piperidinyl, N-methyl-piperidinyl, eroaryl, or Coheteroaralkyl optionally Substituted with 1-3 N-ethyl-piperidinyl, N-propyl-piperidinyl, hexahydrothiopy Substituents independently selected from Q or Q.: ranyl, azepanyl, methylazepanyl, tetrahydropyranyl, pip 0014 each Q is independently hydrogen, Cs alkyl, Cs eridinylmethyl, pyridinyl, pyridinylmethyl, tetrahydrothi alkenyl, alkoxy, alkenoxy, Cao cycloalkyl, Cao aryl, Cao opyranyl, dioxolanylmethyl, dioxanylmethyl. N-isopropyl arylalkyl, aralkyloxy, Cao heterocyclic, or Cao heteroaryl piperidinyl, N-butyl-piperidinyl, N-pentyl-piperidinyl, ring, each optionally including 1-3 Substituents indepen N-hexylpiperidinyl, N-cyclohexyl-piperidinyl, N-acetyl-pip dently selected from Q.: eridinyl, or N-benzyl-piperidinyl. In some aspects, R is pyri 0015 each Q is halo, haloalkyl, oxo, oxime, azido, dine. amino, amido, cyano, ON, NO, CF.