JP2011503045A - Use of CRTH2 antagonistic compounds - Google Patents

Abstract

【選択図】なしThe present invention relates to compounds of general formula (I) for treating allergic conditions, wherein R1, R2, R3, R4 and R5 are as defined herein, the treatment comprising By pulse therapy comprising a first period administered to the patient and a second period of at least 7 days in which the compound is administered to the patient in a reduced amount. In one embodiment of the invention, the allergen is present or suspected to be present during treatment and the compound of general formula (I) is at least 50% effective during the second period of the treatment cycle. Or a pharmacologically acceptable salt, hydrate, solvate or complex thereof is provided which retains
[Chemical 3]

[Selection figure] None

Description

  The present invention relates to the use of CRTH2 antagonist compounds for pulse therapy of allergic conditions.

Allergic conditions are more common across developed countries in as much as 10% of the world's population and are affected by one or more of allergic asthma, allergic rhinitis, atopic dermatitis and other allergic conditions. Numerous classes of compounds have been suggested for the treatment of these conditions, one of those recently developed is the use of CRTH2 antagonists, which are prostaglandins that act at the CRTH2 receptor. Inhibits the action of agonists such as gin D ₂ (PGD ₂ ).

PGD ₂ is an eicosanoid, a class of chemical mediators synthesized by cells that respond to local tissue damage, normal or hormonal stimulation, or via cell activation pathways. Eicosanoids bind to specific cell surface receptors on a wide range of tissues throughout the body and mediate various actions in those tissues. PGD ₂ is known to be produced by mast cells, macrophages, and Th2 lymphocytes, and is detected at high concentrations in the airways of asthmatic patients administered with antigen (Non-patent Document 1). Infusion of PGD _{2 into} the respiratory tract causes many characteristics of asthmatic reactions including bronchoconstriction (Non-patent document 2; Non-patent document 3) and eosinophil accumulation (Non-patent document 4).

The potential of PGD ₂ to elicit an inflammatory response has been confirmed by the use of transgenic mice that overexpress human PGD ₂ synthase, which exhibits excessive eosinophilic lung inflammation and Th2 cytokine production against antigen (Non-Patent Literature). 5).

The first receptor specific for PGD _{2 that} was discovered was the DP ₁ receptor associated with increased intracellular levels of cAMP. However, PGD ₂ is through an interaction with a G protein-coupled receptor called CRTH2 (a chemoattractant receptor homologous molecule expressed in Th2 cells) expressed by Th2 lymphocytes, eosinophils and basophils. It is thought to mediate many of its inflammatory activities (Non-patent Document 6 and Patent Document 1 and Patent Document 2 and Bauer et al., Patent Document 3). Effect of PGD ₂ on the activation of Th2 lymphocytes and eosinophils is so obvious to be mediated through CRTH2. This is because selective CRTH2 are agonists 13,14 dihydro-15-keto -PGD ₂ (DK-PGD ₂₎ and 15R- methyl -PGD ₂ is obtained induce this reaction, the action of PGD _2, the anti-CRTH2 This is because it is blocked by an antibody (Non-patent document 6; Non-patent document 7). In contrast, the selective DP agonist BW245C does not promote the migration of Th2 lymphocytes or eosinophils (Non-Patent Document 6; Non-Patent Document 8). Based on this evidence, antagonism of PGD ₂ at the CRTH2 receptor is associated with asthma (including allergic asthma), food allergies, acute and chronic urticaria, perennial allergic rhinitis, seasonal allergic rhinitis, atopic Alternative approaches for treating inflammatory components of Th2-dependent allergic diseases such as dermatitis, contact hypersensitivity (including contact dermatitis) and conjunctivitis, especially allergic conjunctivitis.

  Documents discussing the use of CRTH2 antagonists for the treatment of Th2-dependent allergic diseases include Patent Literature 4, Patent Literature 5, Patent Literature 6, Patent Literature 7, Patent Literature 8, Patent Literature 9, Patent Literature 10, Patent Document 11, Patent Document 12, Patent Document 13, Patent Document 14, Patent Document 15, and Patent Document 16.

  Other compounds in combination with CRTH2 and TP receptor antagonists are known, an example of such a compound is ramatroban, which is the nasal mucosa of guinea pigs (9), the respiratory tract of mice (non-patent literature). 10) and mouse skin (Non-Patent Document 11) have been shown to reduce allergic inflammation. Ramatroban has also been shown to reduce the symptoms of perennial allergic rhinitis in human subjects (12). Analogs of ramatroban that are inactive at TP but retain CRTH2 antagonistic activity are effective in reducing airway eosinophils and mucus cell hyperplasia in a model of allergic asthma in mice (13) . Uller et al. Concluded that the effectiveness of the allergic asthma model results from blockade of the CRTH2 receptor rather than inhibition of TP.

  Although there is sufficient evidence that CRTH2 antagonists are effective in treating allergic asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis and other allergic conditions, we have The surprising discovery that these compounds have a longer lasting effect than previously thought, thereby being useful for preventing or reducing the symptoms of allergic conditions for long periods after dosing Did.

European Patent EP0851030 European Patent EP-A-1211513 European Patent EP-A-1170594 International Publication No. WO-A-03 / 066046 International Publication WO-A-03 / 066047 Specification International Publication WO-A-03 / 097042 Specification International Publication WO-A-03 / 097598 Specification International Publication WO-A-03 / 101981 Specification International Publication WO-A-03 / 101961 Specification International Publication WO-A-2004 / 007451 Specification International Publication WO-A-2005 / 018171 International Publication WO-A-2005 / 094816 International Publication WO-A-2005 / 044260 Specification International Publication WO-A-2005 / 040112 Specification International Publication WO-A-2005 / 040114 Specification International Publication WO2006 / 095183 Specification

Murray et al. Engl. J. et al. Med. 315, p800-804, 1986 Hardy et al. Engl. J. et al. Med. 311, p209-213, 1984 Sampson et al., Thorax 52, p513-518, 1997 Emery et al. Appl. Physiol. 67, p959-962, 1989 Fujitani et al. Immunol. 168, p443-449, 2002 Hirai et al. Exp. Med. 193, p255-261, 2001 Monneret et al., J. MoI. Pharmacol. Exp. Ther. 304, p349-355, 2003 Gervais et al. Allergy Clin. Immunol. 108, p982-988, 2001 Narita et al., Int Arch Allergy Immunol, 109, p161-166, 1996 Nagai et al., Prostaglandins, 50, 75-87, 1995. Takeshita et al., Int. Immunol. 16, p947-959, 2004 Terada et al., Allergor. Int. 47, p59-67, 1998 Uller et al., Respir Res, 8, 16, 2007

（式中、
Ｒ^１はＣ_１−Ｃ_６アルキルであり、
Ｒ^２はハロゲンであり、
Ｒ^３はハロ、ＯＨ、ＣＮ、Ｒ^６、ＣＯＲ^６、ＣＨ_２Ｒ^６、ＯＲ^６、ＳＲ^６、ＳＯ_２Ｒ^６またはＳＯ_２ＹＲ^６から選択される１つ以上の置換基で必要に応じて置換されたアリールまたはヘテロアリールであり、
Ｒ^６はＣ_１−Ｃ_６アルキル、Ｃ_３−Ｃ_８シクロアルキル、ヘテロシクリル、アリールまたはヘテロアリールであり、それらのうちのいずれかは、ハロ、ＯＨ、ＣＮ、ＮＯ_２、Ｃ_１−Ｃ_６アルキルまたはＯ（Ｃ_１−Ｃ_６アルキル）から選択される１つ以上の置換基で必要に応じて置換され得、
ＹはＮＨまたは直鎖もしくは分枝Ｃ_１−Ｃ_４アルキレン鎖であり、
Ｒ^４はＨまたはＣ_１−Ｃ_４アルキルであり、
Ｒ^５は水素、Ｃ_１−Ｃ_６アルキル、アリール、（ＣＨ_２）_ｍＯＣ（＝Ｏ）Ｃ_１−Ｃ_６アルキル、（（ＣＨ_２）_ｍＯ）_ｎＣＨ_２ＣＨ_２Ｘ、（ＣＨ_２）_ｍＮ（Ｒ^７）_２またはＣＨ（（ＣＨ_２）_ｍＯ（Ｃ＝Ｏ）Ｒ^８）_２であり、
ｍは１または２であり、
ｎは１〜４であり、
ＸはＯＲ^７またはＮ（Ｒ^７）_２であり、
Ｒ^７は水素またはメチルであり、
Ｒ^８はＣ_１−Ｃ_１８アルキルである）
またはその薬理学的に許容可能な塩、水和物、溶媒和物もしくは錯体であって、
その処置は、
ａ．一般式（Ｉ）の化合物が患者に投与される第１の期間、
ｂ．一般式（Ｉ）の化合物が減少した量で患者に投与される、少なくとも７日の第２の期間、
を含む少なくとも１回の処置サイクルを含み、
アレルゲンが、処置の間にわたって存在するか、または存在する疑いがあり、一般式（Ｉ）の化合物が、処置サイクルの第２の期間、少なくとも５０％のその有効性を保持する、一般式（Ｉ）の化合物、またはその薬理学的に許容可能な塩、水和物、溶媒和物もしくは錯体が提供される。 Accordingly, in a first aspect of the invention, a compound of general formula (I) for treating an allergic condition induced by the presence of an allergen to which a patient is sensitive

(Where
R ¹ is C ₁ -C ₆ alkyl;
R ² is halogen,
R ³ is one or more substituents selected from halo, OH, CN, R ⁶ , COR ⁶ , CH ₂ R ⁶ , OR ⁶ , SR ⁶ , SO ₂ R ⁶ or SO ₂ YR ⁶ , as required. Substituted aryl or heteroaryl,
R ⁶ is C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl, any of which is halo, OH, CN, NO ₂ , C ₁ -C ₆ alkyl or O (C ₁ -C ₆ alkyl) 1 or more can be optionally substituted with substituents selected from,
Y is NH or a linear or branched C ₁ -C ₄ alkylene chain;
R ⁴ is H or C ₁ -C ₄ alkyl;
R ⁵ is hydrogen, C ₁ -C ₆ alkyl, aryl, (CH ₂ ) _m OC (═O) C ₁ -C ₆ alkyl, ((CH ₂ ) _m O) _n CH ₂ CH ₂ X, (CH ₂ ) _m N (R ⁷ ) ₂ or CH ((CH ₂ ) _m O (C═O) R ⁸ ) ₂ ,
m is 1 or 2,
n is 1 to 4,
X is OR ⁷ or N (R ⁷ ) ₂ ;
R ⁷ is hydrogen or methyl;
R ⁸ is C ₁ -C ₁₈ alkyl)
Or a pharmaceutically acceptable salt, hydrate, solvate or complex thereof,
The treatment is
a. A first period during which the compound of general formula (I) is administered to the patient;
b. A second period of at least 7 days, wherein the compound of general formula (I) is administered to the patient in a reduced amount;
Comprising at least one treatment cycle comprising
The allergen is present during or suspected of being present during treatment and the compound of general formula (I) retains its efficacy at least 50% during the second period of the treatment cycle. compounds of), or a pharmaceutically acceptable salt, hydrate, solvate or complex is provided.

  This is particularly advantageous for conditions such as allergic rhinitis, allergic conjunctivitis, or allergic asthma, and the drug is used to suppress those symptoms during the period the patient is suffering from symptoms, As before, it must be inoculated at least once a day and more frequently. In the present invention, treatment is done as usual during the first period of the treatment cycle, but during the second period, a greatly reduced dose of the compound of general formula (I) may be inoculated. In parts, the dose may be reduced to 0 for the second period of the treatment cycle. This means that in cases where the hay fever season is a condition such as allergic rhinitis that lasts for weeks or months, the patient may only need to be vaccinated during that season. .

  The present invention arises from observations made during a double blind cross-over study of CRTH2 antagonists of general formula (I) in human subjects suffering from allergic rhinitis. This study compared two groups of patients. The first group of patients was treated daily with a CRTH2 antagonist for 8 consecutive days, then untreated for 3 weeks, and then treated daily with placebo for 8 consecutive days. A second group of patients were treated with placebo for 8 consecutive days, then untreated for 3 weeks, and then treated daily with a CRTH2 antagonist of general formula (I) for 8 consecutive days. This study showed that, during the first treatment period, patients treated with a CRTH2 antagonist of general formula (I) exhibited fewer symptoms of allergic rhinitis than patients treated with placebo. Was expected by the inventor. Surprisingly, however, during the second treatment period, the first group of patients treated with placebo still had reduced symptoms, the result of which is the CRTH2 antagonism of general formula (I) at that time. Comparable to that of the second group of patients being treated with drugs. These patients also exhibited fewer symptoms than they exhibited in the initial screen prior to treatment with either CRTH2 antagonist or placebo.

Thus, CRTH2 antagonists such as the compounds of general formula (I) defined above appear to have a long-term effect on allergic reactions, whereby these compounds are allergens to which patients are sensitive. Wherein the method comprises administering to the patient a CRTH2 antagonist compound of general formula (I) for at least one treatment cycle, and treating the allergic condition induced by the presence of The treatment cycle is
a. A first period during which the compound of general formula (I) is administered to the patient;
b. A second period of at least 7 days, wherein the compound of general formula (I) is administered to the patient in a reduced amount;
The allergen is present or suspected to be present throughout the treatment and the compound of general formula (I) retains its effectiveness at least 50% during the second period of the treatment cycle.

The present invention also provides the use of a CRTH2 antagonist compound of general formula (I) in the preparation of a medicament for treating an allergic condition induced by the presence of an allergen to which a patient is sensitive, the treatment comprising:
a. A first period during which the compound of general formula (I) is administered to the patient;
b. Comprising at least one treatment cycle comprising a second period of at least 7 days, wherein the compound of general formula (I) is administered to the patient in a reduced amount;
The allergen is present or suspected to be present throughout the treatment and the compound of general formula (I) retains its effectiveness at least 50% during the second period of the treatment cycle.

  The reason for the long-term effect of CRTH2 antagonistic compounds such as compounds of general formula (I) in the treatment of allergic conditions is not completely clear, but the inventor has previously known CRTH2 antagonists for Th2 cells. It is speculated that it may be related to the effects that are not.

The inventor has discovered that PGD ₂ plays an important role in Th2 cell survival by preventing apoptosis of Th2 cells and by their subsequent clearance from allergic tissues. Furthermore, the present inventors have discovered that CRTH2 antagonists can block the action of CRTH2 and induce apoptosis of Th2 cells.

  The inventor believes that the long-term effect may be a result of the effects of CRTH2 antagonists on Th2 cell apoptosis.

Th2 lymphocytes involved in cascades leading to allergic reactions described by various authors are known, including Pettifer et al., Nature Reviews, 6 (April 2007), 313-325. The immune response in allergies begins with the presentation of allergens to antigen-presenting cells that internalize the antigens and express them on the cell surface. This initiates a cascade event that leads to the production of IgE binding to high-affinity receptors in mast cells, the state of that allergen-specific site available to interact with the allergen. Upon re-exposure to the same allergen, cross-linking of IgE bound to mast cells initiates the production of many factors, including PGD ₂ , by mast cells, and then through the interaction of PGD ₂ with the CRTH2 receptor. Leads to the recruitment and activation of Th2 cells. Activated Th2 cells produce a variety of cytokines including IL4, IL5 and IL13. IL4 then causes further IgE production by B cells.

  The inventor claims that the apoptotic effect of CRTH2 antagonists on Th2 lymphocytes blocks the cascade by promoting apoptosis and clearance of Th2 cells leading to decreased levels of Th2 cytokines, IL4, IL5 or IL13 is doing. The decrease in IL4 and IL13 production causes a decrease in IgE production by B lymphocytes. Thus, it appears that the immune system cannot respond to allergens due to increased production of IgE. This causes a significantly reduced immune response to the allergen until the Th2 cell population is replenished.

  Similarly, a decrease in IL5 causes reduced eosinophil migration and a decrease in IL13 causes reduced mucus production. This combination of factors also reduces allergic symptoms.

  However, even if this relationship proves inappropriate, the long-lasting effects of CRTH2 antagonists such as compounds of general formula (I) in reducing the symptoms of allergic conditions may exist in vivo. It should be noted that it is shown.

As used herein, “C ₁ -C ₆ alkyl” has 1 to 6 carbon atoms and is optionally required with one or more halo substituents or one or more C ₃ -C ₇ cycloalkyl groups. It refers to a linear or branched saturated hydrocarbon chain that is substituted accordingly. Examples include methyl, ethyl, n-propyl, isopropyl, t-butyl, n-hexyl, trifluoromethyl, 2-chloroethyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclobutyl and methylenecyclopentyl.

_"C 1 -C ₄ alkyl" and _"C 1 _{-C 18} alkyl", they, except that it has respectively 1 to 4, and 1 to 18 of carbon atoms, have the same meaning. C ₃ -C ₇ cycloalkyl, refers to a 3-7 membered carbocyclic ring saturated. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In the context of the present specification, the term “C ₁ -C ₄ alkylene” refers to a disubstituted straight or branched saturated hydrocarbon chain having 1 to 4 carbon atoms.

  As used herein, “halo” refers to fluoro, chloro, bromo or iodo.

  In the context of this specification, the term “aryl” refers to an aromatic ring system having from 5 to 14 ring carbon atoms and containing up to 3 rings. Examples of aryl groups are benzene and naphthalene.

In the context of the present specification, the term “heteroaryl” has 5 to 14 ring atoms, at least one of which is a heteroatom selected from N, O and S, up to 3 rings. An aromatic ring system is included. If the heteroaryl group contains more than one ring, not all rings must be fully aromatic. Rings that are not fully aromatic may be substituted with one or more oxo groups. Examples of heteroaryl groups include pyrrole, thiophene, thiazole, pyridine, pyrimidine, indole, benzofuran, benzimidazole, tetrahydroquinoline, indoline, quinoline, isoquinoline, quinoxaline, imidazo [1,2-a] pyridine, pyrazolo [1, 5-a] pyridine, 2,3-dihydro-1-benzothiopyran and 2,3-dihydro-1λ ⁶ -benzothiopyran-1,1-dione.

In the context of the present specification, the term “heterocyclyl” has 4 to 8 ring atoms, at least one of which is a heteroatom selected from N, O and S, optionally one or more A saturated ring system that may be substituted by an oxo group of Examples of heterocyclyl groups include azetidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, thiomorpholinyl, 1,1-dioxo-1λ ₆ -thiomorpholinyl, morpholinyl, pyrrolyl, piperidinyl, azepanyl, 1,4-diazepanyl, 1,4 -Oxazepanyl and azocanyl.

  Suitable pharmaceutically and veterinary acceptable salts of the compounds of general formula (I) include sodium, potassium, calcium, aluminum, zinc, magnesium and other metal salts and choline, diethanolamine, ethanolamine, ethyldiamine Base addition salts such as meglumine and J. Med. Chem. , 50, 6665-6672 (2007) and / or base addition salts known to those skilled in the art.

  Where appropriate, pharmaceutically or veterinary acceptable salts may also be organic acids, including but not limited to acetone, trifluoroacetone, lactate, gluconate, citrate, tartrate, maleate , Malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerin phosphate Salt (glycerophosphate), oxalate, heptanoate, hexanoate, fumarate, nicotinate, pamoate, pectinate, 3-phenylpropionate, picrine Acid salt, pivalate salt, propiate Carboxylic acids, including organic acids, tartrate, lactobionate, pivorate, camphorate, undecanoate and succinate, eg methanesulfonate, ethanesulfone Acid salts, 2-hydroxyethane sulfonate, camphorsulfonate, 2-naphthalene sulfonate, benzene sulfonate, p-chlorobenzene sulfonate and p-toluene sulfonate; and inorganic acids such as And salts of hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, hemisulfate, thiocyanate, persulfate, phosphoric acid and sulfonic acid.

  Salts that are not pharmaceutically or veterinarily acceptable may also be useful as intermediates.

Compounds of general formula (I) in which R ⁵ is hydrogen are active as CRTH2 antagonists.

Prodrugs are any covalently bonded compounds that release the active parent drug according to general formula (I) in vivo. Examples of prodrugs are: R ⁵ is C ₁ -C ₆ alkyl, aryl, (CH ₂ ) _m OC (═O) C ₁ -C ₆ alkyl, ((CH ₂ ) _m O) _n CH ₂ CH ₂ X , (CH ₂ ) _m N (R ⁷ ) ₂ or CH ((CH ₂ ) _m O (C═O) R ⁸ ) ₂ ;
m is 1 or 2;
n is 1 to 4;
X is OR ⁷ or N (R ⁷ ) ₂ ;
R ⁷ is hydrogen or methyl;
R ⁸ is C ₁ -C ₁₈ alkyl,
The compound of general formula (I) is mentioned.

  Where a chiral center or another form of isomeric center is present in a compound of the invention, all forms of such isomer (s), including enantiomers and diastereoisomers, are provided herein. Intended to be included. Compounds of the invention containing chiral centers can be used as racemic mixtures, enantiomerically enriched mixtures, or racemic mixtures can be separated using well-known techniques and individual enantiomers alone May be used.

  The term “administered in combination” refers to the co-administration of a CRTH2 antagonist and another drug, and the administration may be simultaneous, sequential or separate.

  In the context of the present invention, the term “allergic condition” refers to a condition in which the patient's atopic condition is higher than that of a subject who does not have an allergic condition. This can be characterized by the presence of an increased number of cells relative to the allergen in the patient's circulatory system or tissue and by the presence of IgE that specifically binds to the allergen to which the patient is sensitive. IgE can circulate or bind, for example, to the surface of mast cells and basophils.

As used herein, reference to a patient being “sensitive” to an allergen means that when the patient is exposed to the allergen, it binds to IgE expressed on the surface of mast cells and basophils. histamine by their mast cells and basophils, the patient resulting from the production of substances such as prostaglandin D ₂ and tryptase is meant that induced allergic reactions representing the symptoms of inflammation.

  Reference to “treatment of an allergic condition” refers to the reduction or elimination of inflammatory symptoms resulting from the patient's exposure to an allergen to which the patient is sensitive.

  As used herein, reference to an antigen being present or suspected of being present throughout a treatment cycle can mean that the antigen is present in varying amounts in the patient's environment, either constantly or intermittently. Is meant to mean that there is. For example, if a patient suffers from allergic rhinitis, pollen that the patient is sensitive to may be present in the environment during the hay fever season, but the amount of pollen in the environment is May vary depending on daytime and other conditions. In some cases, the patient may assume that the allergen is present in the environment without performing a test to confirm that the allergen is present in the environment. Again, in the case of allergic rhinitis, for example, if it is suspected that there may be pollen that may occur during the hay fever season, the patient is conventionally inoculated with medication as a preventive measure. However, according to the present invention, it is not necessary for the patient to be inoculated with a sufficient dose of the compound of general formula (I) during the second period of the treatment cycle, and often the general formula (I The compound of I) need not be administered during this second period.

  As applied to the compounds of general formula (I), the term “efficacy” refers to the reduction of allergic reactions in a patient. Usually, during the first period of a treatment cycle, patients will have at least 30% reduction in symptoms, preferably at least 40%, preferably in order of increasing, at least 50%, at least 60%, at least 70%, at least 80%, most preferably at least 90% reduction in symptoms.

In the case of allergic rhinitis and conjunctivitis, the assessment can be performed, for example, in an experiment in an antigenic exposure chamber in Vienna, which is well known to those skilled in the art, and the patient can self-assess their symptoms. And scoring on a scale of 0-3. Separate scores may be given for ocular symptoms, nasal symptoms (nasal obstruction, nasal itching, sneezing and rhinorrhea) and other symptoms. The symptom score for each patient is subjective, but if a sufficient number of patients are used, the overall score is meaningful. For other allergic conditions, other clinical trials may be designed, and the measurement of symptom reduction may be performed by subjective methods such as patient self-assessment or by objective measurements Good. For example, asthma symptoms may be measured using pulmonary function measurements such as forced expiratory vital capacity (FEV ₁ ) or peak expiratory velocity (PEF) in 1 second, or using Juniper's quality of life scale. May be quantified. The severity of the symptoms of atopic dermatitis is determined by scoring atopic dermatitis (SCORAD) or six areas of six signs of atopic dermatitis (SSASAD). ) Can be evaluated using the system.

  As noted above, during the second period of the treatment cycle, the compound of general formula (I) retains its effectiveness of at least 50%, but more preferably the compound of general formula (I) is: It retains its effectiveness of at least 60%, preferably in order of increasing, 70%, 80% and 90%.

  As already indicated, the amount of the compound of general formula (I) administered to the patient during the second period of the treatment cycle is reduced compared to the amount administered during the first period. . Usually, the daily dose of the compound of general formula (I) administered during the second period of the treatment cycle is not more than 50% of the daily dose administered during the first period. However, it may be less than this. For example, no more than 40%, no more than 30%, no more than 20%, or no more than 10% of the daily dose of a compound of general formula (I) administered during the first period . In many cases, administration of the CRTH2 antagonist compound is completely stopped during the second period of the treatment cycle. Thus, in the second period of the treatment cycle, the daily dose is 0 and no compound of general formula (I) is administered to the patient. This yields advantageous results, especially since the duration of the medication is much shorter than for conventional medications, and has positive significance in both the patient's general health and treatment costs.

  The second period of the treatment cycle lasts at least 7 days. However, the compound dose may be zero for a longer period of time, eg, at least 14 days, and for a second period lasting at least 21 days, at least 28 days, in some cases during the second period of the treatment cycle. It is observed that the drug can retain at least 50% of its effectiveness even after 35 days.

  While the CRTH2 antagonist is administered, the first period of the treatment cycle may be selected to include several days that provide maximal biological response to the patient's compound. Usually this period may be 2-8 days, during which time the drug may be administered 1-3 times a day. However, it is particularly preferred that the CRTH2 antagonist is administered to the patient once a day because it helps to increase patient compliance.

  In some cases, a single treatment cycle may not be sufficient to continue for all periods where treatment is required, so that the treatment may include one or more additional treatment cycles. . This is often the case when related to conditions such as seasonal allergic rhinitis, where the hay fever season may last for months.

  Although CRTH2 antagonists such as compounds of general formula (I) are useful for treating any allergic condition, they are useful in treating asthma (including allergic asthma), food allergies, acute and chronic urticaria, year-round. It is particularly useful for pulse therapy of conditions such as allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity (including contact dermatitis) and conjunctivitis, especially allergic conjunctivitis.

  The CRTH2 antagonist of the general formula (I) is an indole-1-acetic acid derivative and is disclosed in International Publication WO2005 / 044260, International Publication WO2005 / 094816, International Publication WO2006 / 095183, International Publication WO2008 / 012511 and 20081. British Patent Application No. 0800874.0 filed on Jan. 18, 2008 / 081132.2 filed on Jan. 22, 2008, No. 081671.9 filed on Jan. 30, 2008; No. 0801131.4 filed on January 22, 2008; 0801672.7 filed on January 30, 2008; and 0801674.3 filed on January 30, 2008; And some of the analogs described therein. The above indole-1-acetic acid derivatives of general formula (I) are described in detail in these documents.

In one embodiment of the invention, the compound of general formula (I) is a CRTH2 antagonist wherein R ⁵ is hydrogen.

In an alternative embodiment of the invention, the compound of general formula (I) is a prodrug for a CRTH2 antagonist and R ⁵ is C ₁ -C ₆ alkyl, aryl, (CH ₂ ) _m OC (═O ) _C 1 -C _{6 alkyl, ((CH 2) m O} ) n CH 2 CH 2 X, (CH 2) m n (R 7) 2 or _{CH ((CH 2) m O} (C = O) R 8 ) ₂ ; where
m is 1 or 2;
n is 1 to 4;
X is OR ⁷ or N (R ⁷ ) ₂ ;
R ⁷ is hydrogen or methyl; and R ⁸ is C ₁ -C ₁₈ alkyl.

In suitable compounds of general formula (I), independently or in any combination,
R ¹ is fluoro;
R ² is C ₁ -C ₄ alkyl, especially methyl or ethyl, more particularly methyl;
R ⁴ is H or methyl; and R ³ is quinoline, quinoxaline, isoquinoline, thiazole, phenyl, naphthalene, thiophene, pyrrole or pyridine, any of which are optionally substituted as described above obtain.

In particularly preferred compounds, R ⁴ is H.

More typically, R ³ groups include optionally substituted quinoline, phenyl, naphthalene, thiophene, pyrrole or pyridine.

When R ³ is quinoline or isoquinoline, it is preferably unsubstituted or substituted with one or more halo substituents, especially fluoro.

When R ³ is phenyl, naphthalene, thiophene, pyrrole or pyridine, it is optionally substituted with one or more substituents, in particular OR ⁶ , SO ₂ R ⁶ or SO ₂ YR ⁶ (where R ^{And 6} and Y are as described above).

Typically, in this case, R ⁶ is C ₁ -C ₆ alkyl, a 4-6 membered cycloalkyl group, a 5 or 6 membered heterocyclyl group or phenyl, any of which are as described above. May be substituted.

When R ³ is pyridyl, it is most preferably a 3-pyridyl moiety.

In the more active compounds, if present, Y is CH ₂ moiety.

When R ³ is substituted with SO ₂ R ⁶ or SO ₂ YR ⁶ , the R ⁶ group is usually unsubstituted or substituted with one or more substituents selected from methyl and halo, especially chloro or fluoro Is done.

When R ³ is substituted with OR ⁶ , the R ⁶ group may be unsubstituted or selected from halo, cyano, C ₁ -C ₄ alkyl and O (C ₁ -C ₄ alkyl) It may be substituted with one or more substituents.

Particularly suitable compounds of the general formula (I) include
{3- [1- (4-Chloro-phenyl) -ethyl] -5-fluoro-2-methyl-indol-1-yl} -acetic acid;
{5-fluoro-2-methyl-3- [1- (4-trifluoromethyl-phenyl) -ethyl] -indol-1-yl} -acetic acid;
{3- [1- (4-tert-butyl-phenyl) -ethyl] -5-fluoro-2-methyl-indol-1-yl} -acetic acid;
{5-Fluoro-3- [1- (4-methanesulfonyl-phenyl) -ethyl] -2-methyl-indol-1-yl} -acetic acid;
[5-Fluoro-2-methyl-3- (1-naphthalen-2-yl-ethyl) -indol-1-yl] -acetic acid;
(5-Fluoro-2-methyl-3-quinolin-2-ylmethyl-indol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-naphthalen-2-ylmethyl-indol-1-yl) -acetic acid;
[5-Fluoro-3- (8-hydroxyquinolin-2-ylmethyl) -2-methyl-indol-1-yl] -acetic acid;
[5-fluoro-2-methyl-3- (quinoxalin-2-ylmethyl) indol-1-yl] -acetic acid;
[5-Fluoro-3- (4-methoxy-benzyl) -2-methyl-indol-1-yl] -acetic acid;
[5-fluoro-2-methyl-3- (1,3-thiazol-2-ylmethyl) indol-1-yl] -acetic acid;
[3- (4-Chloro-benzyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid;
[5-Fluoro-2-methyl-3- (4-trifluoromethyl-benzyl) -indol-1-yl] -acetic acid;
[5-fluoro-2-methyl-3- (4-tert-butyl-benzyl) -indol-1-yl] -acetic acid;
{5-fluoro-2-methyl-3-[(4-phenylphenyl) methyl] indol-1-yl} -acetic acid;
[5-Fluoro-3- (4-methanesulfonyl-benzyl) -2-methyl-indol-1-yl] -acetic acid;
{5-fluoro-3-[(6-fluoroquinolin-2-yl) methyl] -2-methylindol-1-yl} -acetic acid;
(2-methyl-3-quinolin-2-ylmethyl-indol-1-yl) -acetic acid;
(5-chloro-2-methyl-3-quinolin-2-ylmethyl-indol-1-yl) -acetic acid;
(3-{[1- (benzenesulfonyl) pyrrol-2-yl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
[5-fluoro-2-methyl-3-({1-[(4-methylbenzene) sulfonyl] pyrrol-2-yl} methyl) indol-1-yl] -acetic acid;
[3-({1-[(2,4-difluorobenzene) sulfonyl] pyrrol-2-yl} methyl) -5-fluoro-2-methylindol-1-yl] -acetic acid;
(3-{[2- (benzenesulfonyl) phenyl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
[3-({2-[(4-chlorobenzene) sulfonyl] phenyl} methyl) -5-fluoro-2-methylindol-1-yl] -acetic acid;
[5-Fluoro-3-({2-[(4-fluorobenzene) sulfonyl] phenyl} methyl) -2-methylindol-1-yl] -acetic acid;
(3-{[2- (benzenesulfonyl) pyridin-3-yl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
[5-Fluoro-3-({2-[(4-fluorobenzene) sulfonyl] pyridin-3-yl} methyl) -2-methylindol-1-yl] -acetic acid;
[3-({2-[(4-chlorobenzene) sulfonyl] pyridin-3-yl} methyl) -5-fluoro-2-methylindol-1-yl] -acetic acid;
2- (3- (4- (benzylsulfonyl) benzyl) -5-fluoro-2-methyl-indol-1-yl) -acetic acid;
2- (3- (4- (4-chlorobenzylsulfonyl) benzyl) -5-fluoro-2-methyl-indol-1-yl) -acetic acid;
2- (3- (3- (benzylsulfonyl) benzyl) -5-fluoro-2-methyl-indol-1-yl) -acetic acid;
2- (5-fluoro-3- (3- (4-fluorobenzylsulfonyl) benzyl) -2-methyl-indol-1-yl) -acetic acid;
2- (3- (2- (benzylsulfonyl) benzyl) -5-fluoro-2-methyl-indol-1-yl) -acetic acid;
2- (3- (4- (4-fluorobenzylsulfonyl) benzyl) -5-fluoro-2-methyl-indol-1-yl) -acetic acid;
2- (3- (2- (cyclohexylsulfonyl) benzyl) -5-fluoro-2-methyl-indol-1-yl) -acetic acid;
2- (5-fluoro-2-methyl-3- (2- (piperidin-1-ylsulfonyl) benzyl) -indol-1-yl) -acetic acid;
2- (3- (2- (cyclopentylsulfonyl) benzyl) -5-fluoro-2-methyl-indol-1-yl) -acetic acid;
2- (5-fluoro-2-methyl-3- (3- (piperidin-1-ylsulfonyl) benzyl) -indol-1-yl) -acetic acid;
2- (5-fluoro-2-methyl-3- (2- (pyrrolidin-1-ylsulfonyl) benzyl) -indol-1-yl) -acetic acid;
2- (3- (4- (cyclohexylsulfonyl) benzyl) -5-fluoro-2-methyl-indol-1-yl) -acetic acid;
2- (3- (4- (cyclopentylsulfonyl) benzyl) -5-fluoro-2-methyl-indol-1-yl) -acetic acid;
2- (3- (2- (cyclobutylsulfonyl) benzyl) -5-fluoro-2-methyl-indol-1-yl) -acetic acid;
2- (5-fluoro-2-methyl-3- (3- (pyrrolidin-1-ylsulfonyl) benzyl) -indol-1-yl) -acetic acid;
2- (5-fluoro-2-methyl-3- (4- (piperidin-1-ylsulfonyl) benzyl) -indol-1-yl) -acetic acid;
[5-fluoro-2-methyl-3- (2-phenoxybenzyl) -indol-1-yl] -acetic acid;
[5-Fluoro-2-methyl-3- (2- (4-methoxyphenoxy) benzyl) -indol-1-yl] -acetic acid;
[5-Fluoro-2-methyl-3- (2- (4-methoxyphenoxy) benzyl) -indol-1-yl] -acetic acid;
[5-Fluoro-2-methyl-3- (2- (2,4-dichlorophenoxy) benzyl) -indol-1-yl] -acetic acid;
[5-Fluoro-2-methyl-3- (2- (4-fluorophenoxy) benzyl) -indol-1-yl] -acetic acid;
[5-fluoro-2-methyl-3- (2- (3,4-difluorophenoxy) benzyl) -indol-1-yl] -acetic acid;
[5-fluoro-2-methyl-3- (2- (4-cyanophenoxy) benzyl) -indol-1-yl] -acetic acid;
[5-Fluoro-2-methyl-3- (2- (4-chlorophenoxy) benzyl) -indol-1-yl] -acetic acid;
[5-Fluoro-2-methyl-3- (2- (2-cyanophenoxy) benzyl) -indol-1-yl] -acetic acid;
(5-Fluoro-2-methyl-3-{[2- (4-methylphenoxy) pyridin-3-yl] methyl} indol-1-yl) -acetic acid;
{5-fluoro-3-[(3-methanesulfonylnaphthalen-2-yl) methyl] -2-methylindol-1-yl} -acetic acid;
{5-fluoro-3-[(1-methanesulfonylnaphthalen-2-yl) methyl] -2-methylindol-1-yl} -acetic acid;
{5-Fluoro-3-[(6-methanesulfonylnaphthalen-2-yl) methyl] -2-methylindol-1-yl} -acetic acid;
[5-fluoro-2-methyl-3- (quinolin-3-ylmethyl) indol-1-yl] -acetic acid;
[5-fluoro-2-methyl-3- (quinoxalin-6-ylmethyl) indol-1-yl] -acetic acid;
[5-fluoro-2-methyl-3- (quinolin-7-ylmethyl) indol-1-yl] -acetic acid;
{5-Fluoro-3-[(6-methanesulfonylquinolin-2-yl) methyl] -2-methylindol-1-yl} -acetic acid;
{5-fluoro-3-[(4-methanesulfonylquinolin-2-yl) methyl] -2-methylindol-1-yl} -acetic acid;
(5-Fluoro-2-methyl-3- {pyrazolo [1,5-a] pyridin-3-ylmethyl} indol-1-yl) -acetic acid;
(5-Fluoro-3- {imidazo [1,2-a] pyridin-2-ylmethyl} -2-methylindol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[2- (methylsulfanyl) phenyl] methyl} indol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[3- (methylsulfanyl) phenyl] methyl} indol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[4- (ethylsulfanyl) phenyl] methyl} indol-1-yl) -acetic acid;
(3-{[4- (ethylsulfanyl) phenyl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[4- (n-propylsulfanyl) phenyl] methyl} indol-1-yl) -acetic acid;
(5-fluoro-2-methyl-3-{[4- (i-propylsulfanyl) phenyl] methyl} indol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[4- (t-butylsulfanyl) phenyl] methyl} indol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[4- (pentan-3-ylsulfanyl) phenyl] methyl} indol-1-yl) -acetic acid;
[3-({4-[(cyclopropylmethyl) sulfanyl] phenyl} methyl) -5-fluoro-2-methylindol-1-yl] -acetic acid;
{3-[(4,4-Dimethyl-2,3-dihydro-1-benzothiopyran-6-yl) methyl] -5-fluoro-2-methylindol-1-yl} -acetic acid;
(3-{[2- (ethanesulfonyl) phenyl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[2- (propane-1-sulfonyl) phenyl] methyl} indol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[2- (propane-2-sulfonyl) phenyl] methyl} indol-1-yl) -acetic acid;
(3-{[2- (butane-1-sulfonyl) phenyl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
(3-{[2- (butane-2-sulfonyl) phenyl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[2- (2-methylpropane-2-sulfonyl) phenyl] methyl} indol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[2- (pentane-1-sulfonyl) phenyl] methyl} indol-1-yl) -acetic acid;
(3-{[2- (cyclopropylmethane) sulfonylphenyl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[2- (propylsulfamoyl) phenyl] methyl} indol-1-yl) -acetic acid;
(3-{[2- (butylsulfamoyl) phenyl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[3- (propylsulfamoyl) phenyl] methyl} indol-1-yl) -acetic acid;
(3-{[3- (butylsulfamoyl) phenyl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
(5-fluoro-2-methyl-3-{[4- (trifluoromethane) sulfonylphenyl] methyl} indol-1-yl) -acetic acid;
(3-{[4- (ethanesulfonyl) phenyl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[4- (propane-1-sulfonyl) phenyl] methyl} indol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[4- (propane-2-sulfonyl) phenyl] methyl} indol-1-yl) -acetic acid;
(3-{[4- (butane-1-sulfonyl) phenyl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[4- (2-methylpropane-2-sulfonyl) phenyl] methyl} indol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[4- (pentane-1-sulfonyl) phenyl] methyl} indol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[4- (pentan-3-ylsulfonyl) phenyl] methyl} indol-1-yl) -acetic acid;
[3-({4-[(cyclopropylmethyl) sulfonyl] phenyl} methyl) -5-fluoro-2-methylindol-1-yl] -acetic acid;
(5-Fluoro-2-methyl-3-{[4- (propylsulfamoyl) phenyl] methyl} indol-1-yl) -acetic acid;
(3-{[4- (butylsulfamoyl) phenyl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[4- (trifluoromethoxy) phenyl] methyl} indol-1-yl) -acetic acid;
(5-Fluoro-3-{[4-methanesulfonyl-3- (trifluoromethoxy) phenyl] methyl} -2-methylindol-1-yl) -acetic acid;
(5-Fluoro-3-{[4-methanesulfonyl-3- (trifluoromethoxy) phenyl] methyl} -2-methylindol-1-yl) -acetic acid;
{5-fluoro-3-[(5-methanesulfonylthiophen-2-yl) methyl] -2-methylindol-1-yl} -acetic acid;
{3-[(4,4-Dimethyl-1,1-dioxo-2,3-dihydro-1λ ⁶ -benzothiopyran-6-yl) methyl] -5-fluoro-2-methylindol-1-yl} -acetic acid ;
[3-({1-[(4-chlorobenzene) sulfonyl] pyrrol-2-yl} methyl) -5-fluoro-2-methylindol-1-yl] -acetic acid;
[5-Fluoro-3-({1-[(4-fluorobenzene) sulfonyl] pyrrol-2-yl} methyl) -2-methylindol-1-yl] -acetic acid;
[5-Fluoro-3-({1-[(4-methoxybenzene) sulfonyl] pyrrol-2-yl} methyl) -2-methylindol-1-yl] -acetic acid;
{3- [1- (2,4-dichloro-benzenesulfonyl) pyrrol-2-ylmethyl] -5-fluoro-2-methyl-indol-1-yl} -acetic acid;
[5-Fluoro-3-({1-[(4-methanesulfonylbenzene) sulfonyl] pyrrol-2-yl} methyl) -2-methylindol-1-yl] -acetic acid;
{5-fluoro-2-methyl-3-[(2-phenylphenyl) methyl] indol-1-yl} -acetic acid;
(3-{[1- (benzenesulfonyl) indol-2-yl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
(3-{[2- (4-chlorophenyl) phenyl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[2- (4-methylphenyl) phenyl] methyl} indol-1-yl) -acetic acid;
{5-fluoro-2-methyl-3-[(3-phenoxyphenyl) methyl] indol-1-yl} -acetic acid;
[5-Fluoro-3-({4-[(4-fluorophenyl) carbonyl] -1-methylpyrrol-2-yl} methyl) -2-methylindol-1-yl] -acetic acid;
{5-fluoro-2-methyl-3-[(6-{[3- (trifluoromethyl) phenyl] methyl} pyridin-3-yl) methyl] indol-1-yl} -acetic acid;
{5-fluoro-2-methyl-3-[(3-phenoxythiophen-2-yl) methyl] indol-1-yl} -acetic acid;
(3-{[2- (benzenesulfonyl) -1,3-thiazol-5-yl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
{3-[(1-benzylpyrazol-4-yl) methyl] -5-fluoro-2-methylindol-1-yl} -acetic acid;
(3-{[5- (4-chlorophenoxy) -1-methyl-3- (trifluoromethyl) pyrazol-4-yl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
[3-({5-[(4-chlorobenzene) sulfonyl] furan-2-yl} methyl) -5-fluoro-2-methylindol-1-yl] -acetic acid;
[3-({5-[(4-chlorobenzene) sulfonyl] thiophen-2-yl} methyl) -5-fluoro-2-methylindol-1-yl] -acetic acid;
[3-({3-[(4-chlorobenzene) sulfonyl] thiophen-2-yl} methyl) -5-fluoro-2-methylindol-1-yl] -acetic acid;
{3-[(2-benzylphenyl) methyl] -5-fluoro-2-methylindol-1-yl} -acetic acid;
Or C ₁ -C ₆ alkyl, aryl, (CH ₂ ) _m OC (═O) C ₁ -C ₆ alkyl, ((CH ₂ ) _m O) _n CH ₂ CH ₂ X, (CH ₂ ) _m N (R ⁷ ) ₂ or CH ((CH ₂ ) _m O (C═O) R ⁸ ) ₂ , an ester of any of the above, wherein
m is 1 or 2;
n is 1 to 4;
X is OR ⁷ or N (R ⁷ ) ₂ ;
R ⁷ is hydrogen or methyl;
R ⁸ is C ₁ -C ₁₈ alkyl,
Compounds.

  The compounds of the general formula (I) are those described in the prior art or those described in the prior art, in particular International Publication WO2005 / 044260, International Publication WO2005 / 094816, International Publication WO2006 / 095183, International Publication WO2008. / 012511 and UK patent applications 0800874.0, 0801132.2, 0801671.9, 0801131.4, 0801672.7 and 0801674.3 May be prepared according to methods.

The compounds of general formula (I) may be combined with one or more additional agents that are useful in the treatment of these allergic conditions. Examples of such drugs include
Suplatast tosylate and similar compounds;
Metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, mesylate bitolterol, B ₂ adrenergic receptor agonists such as pirbuterol and indacaterol, or theophylline and methylquinolinium Santa Nin such aminophylline , Mast cell stabilizers such as sodium cromoglycate, or muscarinic receptor antagonists such as ipratropium and tiotropium;
Antihistamines such as histamine H ₁ receptor antagonists or H ₄ receptor antagonists such as loratadine, cetirizine, desloratadine, levocetirizine, fexofenadine, astemizole, azelastine and chlorpheniramine;
Α ₁ and α ₂ adrenergic receptor agonists such as propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride and ethyl norepinephrine hydrochloride;
Corticosteroids such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, fluticasone furoate, mometasone furoate and ciclesonide;
Examples include existing therapies for allergies and other inflammatory diseases, including allergen immunotherapy drugs such as Grazax.

  CRTH2 antagonists of general formula (I) are usually oral, rectal, nasal, bronchial (inhalation), topical (including eye drops, buccal and sublingual), vaginal or parenteral (subcutaneous, intramuscular, It can be administered in a pharmaceutical formulation that can be a formulation suitable for administration (including intravenous and intradermal) and prepared by any method well known in the pharmaceutical arts.

  Although the route of administration depends on the condition being treated, suitable compositions are formulated for oral, nasal, bronchial or topical administration.

  Formulations may be prepared by combining the active agent and a carrier described above. Typically, formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers or finely divided solid carriers or both, and if necessary shaping the formulation.

  Formulations for oral administration according to the invention are as separate units such as tablets or lozenges, each of which can be a capsule, sachet, chewable tablet each containing a predetermined amount of active agent; as a powder or granules; It may be present as fine particles for sprinkling; as a solvent or suspension of the active agent in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or water-in-oil liquid emulsion; or as a bolus.

  With respect to compositions for oral administration (eg, tablets and capsules), the term “acceptable carrier” includes common excipients such as syrups, acacia, gelatin, sorbitol, tragacanth , Polyvinylpyrrolidone (povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers such as corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, Dicalcium phosphate, sodium chloride and alginic acid; and magnesium stearate, sodium stearate and other metal stearates, glycerol stearate, Alin acid, silicone fluid, talc waxes, lubricants such as oils and colloidal silica. Flavoring agents such as peppermint, winter green oil and cherry flavoring agents may also be used. It may be desirable to add a colorant so that the dosage form can be easily identified. The tablets may also be coated by methods well known in the art.

  A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets are prepared by compressing the active agent into a free-flowing form such as powder or granules in a suitable machine, if necessary binders, lubricants, inert diluents, preservatives, surfactants They may be mixed using an agent or a dispersant. Molded tablets may be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Tablets may be coated or scored as necessary to formulate sustained or controlled release of the active agent.

  Other formulations suitable for oral administration include flavor bases, usually tablets containing active agent in sucrose and acacia or tragacanth; troches containing active agent in an inert base such as gelatin and glycine, or sucrose and acacia As well as mouthwashes containing the active agent in a suitable liquid carrier.

  For topical application to the skin, CRTH2 antagonists such as compounds of general formula (I) may be manufactured in creams, ointments, jellies, solutions or suspensions and the like. Cream or ointment formulations that may be used for the drug are conventional formulations well known in the art, for example as described in standard pharmaceutical textbooks such as British Pharmacopoeia.

  For topical application to the eye, CRTH2 antagonists such as compounds of general formula (I) may be manufactured in eye drop formulations. Suitable eye drop formulations are also well known in the art and are described in standard pharmaceutical textbooks such as British Pharmacopoeia.

  CRTH2 antagonists intended to reduce or eliminate symptoms of conditions such as allergic asthma, allergic conjunctivitis and allergic rhinitis are pharmacologically active, eg, in powder form or in solution or suspension drop form It may be administered to the respiratory tract by nasal, bronchial or buccal administration of an aerosol or spray capable of dispersing the ingredients. Pharmaceutical compositions having powder dispersion properties are typically liquid propellants having a boiling point below room temperature, and, if desired, liquid or solid nonionic or anionic surfactants and / or dilutions in addition to the active ingredient Additives such as agents. Pharmaceutical compositions in which the pharmacologically active ingredient is contained in solution additionally contain a suitable propellant and, if necessary, further solvents and / or stabilizers. Instead of a propellant, compressed air may be used, which can be manufactured as required by means of a suitable compression and expansion device.

  Parenteral formulations are usually sterilized.

Typically, oral dose of the compounds, so as to achieve a drug concentration in plasma at a concentration effective to inhibit PGD ₂ at the CRTH2 receptor, is about 0.01 - 100 / kg. The exact amount of a CRTH2 antagonist compound that is therapeutically effective, and the route by which such compound is optimally administered, will compare the blood level of the drug with the concentration required to have a therapeutic effect. Is easily determined by those skilled in the art.

  In formulations for topical administration such as eye drops, creams or ointments, the concentration of the active compound is typically about 0.1% to 1% w / w so that systemic exposure to the CRTH2 antagonist compound is limited. It is.

Since the mechanism of action appears as described above, a long-term effect on inflammatory symptoms of allergic conditions is observed with either CRTH2 antagonist. References discussing the use of CRTH2 antagonists for the treatment of Th2-dependent allergic diseases include International Publication WO-A-03 / 066606, International Publication WO-A-03 / 0666047, International Publication WO- A-03 / 097042, International Publication WO-A-03 / 097598, International Publication WO-A-03 / 101981, International Publication WO-A-03 / 101961, International Publication WO-A-2004 / 007451 International publication WO-A-2005 / 018171, International publication WO-A-2005 / 054322, International publication WO-A-2004 / 088984, International publication WO-A-2004 / 088985, International publication WO-A -2005/018529, International Publication WO-A-2006 / 005909, International Publication WO2006 / 21759, International Publication WO-A-2007 / 039736, International Publication WO-A-2007 / 052023, International Publication WO-A-2006 / 075139, International Publication WO-A-2007 / 068894, International Publication WO -A-2007138282, International Publication WO-A-2008 / 199917, International Publication WO-A-2008 / 113965, International Publication WO-A-2008 / 074966, International Publication WO-A-2008 / 078069, International Publication WO-A-2007 / 144625, International Publication WO-A-2007 / 028999, International Publication WO-A-2007 / 031747, International Publication WO-A-2006 / 136659, International Publication WO-A- 2006/111560, International Publication WO-A-2005 / 0948 6, International Publication WO-A-2005 / 040112, International Publication WO-A-2005 / 040114, International Publication WO-A-2004 / 096777, International Publication WO-A-2005 / 123731, International Publication WO -A-2006 / 125784, International Publication WO-A-2007 / 045867, International Publication WO-A-2006 / 034419, International Publication WO-A-2006 / 036994, International Publication WO-A-2007 / 022501 International Publication WO-A-2004 / 106302, International Publication WO-A-2004 / 032848, International Publication WO-A-2005 / 100321, International Publication WO-A-2006 / 091674, International Publication WO- A-2004 / 058164, International Publication WO-A-2005 / 007094, International Publication WO-A-2007 / 036743, International Publication WO-2004 / 035543, International Publication WO-A-2007 / 062797, International Publication WO-A-2007 / 062773, International Publication WO-A-2007 / No. 062678, International Publication WO-A-2007 / 062677, International Publication WO-A-2005 / 116001, International Publication WO-A-2005 / 115382, International Publication WO-A-2005 / 115374, International Publication WO -A-2006 / 111560, International Publication WO-A-2006 / 037982, International Publication WO-A-2006 / 056752, International Publication WO-A-2007 / 039741, International Publication WO-A-2005 / 073234 No., International Publication WO-A-2005 / 105727, International Publication W -A-2006 / 063763, International Publication No. WO-A-2006 / 125593 and International Publication No. WO-A-2006 / 125596, and the compounds described in these references are the presence of patient-sensitive allergens Useful for the treatment of allergic conditions induced by
a. A first period during which the CRTH2 antagonist compound is administered to the patient;
b. Comprising at least one treatment cycle comprising a second period of at least 7 days, wherein the compound of general formula (I) is administered to the patient in a reduced amount;
The allergen is present or suspected to be present throughout the treatment and the CRTH2 antagonist retains its efficacy at least 50% during the second period of the treatment cycle.

Some particularly suitable compounds are those that are similar to compounds of general formula (I), but the -CHR ³ R ⁴ moiety of general formula (I) is R ³ , SR ³ , SOR ³ or SO ₂ R ³ is substituted, where R ³ is as defined in general formula (I). An exemplary compound of this type is [5-fluoro-3- (4-chloro-benzenesulfonyl) -2-methyl-indol-1-yl] -acetic acid, which is disclosed in International Publication No. WO 2004/007451. Within the scope, tested in the apoptosis assay of Example 3 (below) and found to counteract the effective function of PGD ₂ with an IC ₅₀ of 204 ± 160 nM.

In the context of the present invention, a CRTH2 antagonist is a compound that binds to the CRTH2 receptor with a Ki of less than 1000 nM in a radiobinding assay described below and treated with PGD ₂ with an IC ₅₀ of less than 1000 nM. Inhibits a dose-dependent increase in intracellular Ca2 ⁺ mobilization in cells. Although any compound having CRTH2 antagonistic activity is suitable for use in reducing hypersensitivity to a subject's allergy, the CRTH2 antagonist is preferably a compound of general formula (I).

  The invention will now be described in more detail with reference to examples and drawings.

FIG. 2 is a series of plots showing the combined symptom scores of two groups of patients suffering from allergic rhinitis in a study comparing CRTH2 antagonists and placebo at each treatment period of 2 days and 8 days. FIG. 1A shows the combined nasal symptom scores for both groups of patients for administration with a CRTH2 antagonist. The plot shows that patients inoculated with a CRTH2 antagonist show reduced nasal symptoms in both the 2 day and 8 day treatment periods. FIG. 2 is a series of plots showing the combined symptom scores of two groups of patients suffering from allergic rhinitis in a study comparing CRTH2 antagonists and placebo at each treatment period of 2 days and 8 days. FIG. 1B shows the combined score for eye symptoms. The plot shows that patients receiving a CRTH2 antagonist show reduced ocular symptoms in both the 2 and 8 day treatment periods. A series of plots similar to those of FIG. 1, but the score for each patient group is shown separately. The plot also shows the screening response, which is the patient's response to the allergen before the start of the study. FIG. 2A shows all nasal symptoms for group A patients compared to the screening response score for the same group of patients. FIG. 2A is a plot showing the scores for nasal symptoms of Group A patients at 2 days for each treatment period. Group A patients were treated with a CRTH2 antagonist for 8 days, then untreated for 3 weeks, and then treated with placebo for 8 days. A series of plots similar to those of FIG. 1, but the score for each patient group is shown separately. The plot also shows the screening response, which is the patient's response to the allergen before the start of the study. FIG. 2B shows all nasal symptoms for Group A patients compared to the screening response score for the same group of patients. FIG. 2B shows nasal symptom scores for the same group of patients at 8 days. Group A patients were treated with a CRTH2 antagonist for 8 days, then untreated for 3 weeks, and then treated with placebo for 8 days. FIG. 2C is similar to FIGS. 2A and 2B, but shows scores for nasal symptoms from Group B patients 2 days after the treatment period, along with scores for screening responses for the same group of patients. Group B patients were treated with placebo for 8 days, then untreated for 3 weeks, and then treated with a CRTH2 antagonist for 8 days. FIG. 2D is similar to FIGS. 2A and 2B, but shows scores for nasal symptoms from Group B patients 8 days after the treatment period, along with screening response scores for the same group of patients. Group B patients were treated with placebo for 8 days, then untreated for 3 weeks, and then treated with a CRTH2 antagonist for 8 days. FIG. 3 is a plot showing the anti-apoptotic effect of PGD2 in human Th2 cells. Human Th2 cells were treated with 50 U / ml IL-2 or various concentrations of PGD ₂ in the absence of IL-2 for 16 hours. Cells were stained with Annexin V-PE / PI and then analyzed by FACSArray flow cytometry.

(Radiobinding assay for measurement of binding to CRTH2 receptor)
(material)
Calcium-3 dye was purchased from Molecular Devices (Wokingham, UK). Mono-poly resolving medium was obtained from Dainippon Pharmaceuticals (Osaka, Japan). Macs anti-CD16 microbeads were obtained from Miltenyi biotec (Bisley, Surrey). ChemoTx plates were purchased from Neuroprobe (Gaithesburg, MD). A 96-well plate coated with poly-D-lysine was obtained from Greiner (Gloesterster, UK). [ ³ H] PGD ₂ was obtained from Amersham Biosciences (Buckinghamshire, UK). [ ³ H] SQ29548 was purchased from Perkin Elmer Life Sciences (Buckinghamshire, UK). All other reagents were obtained from Sigma-Aldrich (Dorset, UK) unless otherwise indicated.

(Method)
(Cell culture)
Chinese hamster ovary cells were transfected with CRTH2 receptor (CHO / CRTH2) and in a humid environment at 37 ° C. (5% CO ₂ ), 10% fetal calf serum, 2 mM glutamine, and 1 mg ml ⁻¹ Maintained in culture of minimal essential medium (MEM) supplemented with active G418. Cells were passaged every 2-3 days. For radioligand binding assays, cells were prepared in 3-layer flasks or 175 cm ² square flasks (for membrane preparation). For the calcium mobilization assay, cells were grown in 96-well plates 24 hours prior to the assay at a density of 80,000 cells per well.

(Preparation of cell membrane)
Membranes were prepared from either CHO / CRTH2 cells. CHO cells grown to confluency were washed with PBS and separated using Versene solution (15 ml per flask). Cells were grown in 175 cm ² square flasks and they were harvested by scraping into PBS. The cell suspension was centrifuged (1,700 rpm, 10 min, 4 ° C.) and resuspended in 15 ml buffer (1 × HBSS, supplemented with 10 mM HEPES, pH 7.3). The cell suspension was then homogenized for 20 seconds using an Ultra Turrax with a setting of 4-6. The homogenate was centrifuged at 1,700 rpm for 10 minutes and the supernatant was collected and centrifuged at 20,000 rpm for 1 hour at 4 ° C. The resulting pellet was resuspended in buffer and stored in 200-500 μl aliquots at −80 ° C. Protein concentration was measured by the method of Bradford (1976) using bovine serum albumin as a reference. Platelets are washed by centrifugation at 600 × g for 10 minutes and resuspended in ice-cold assay buffer (10 mM Tris-HCl, pH 7.4, 5 mM glucose, 120 mM NaCl, 10 μM indomethacin). Centrifuged directly at 20,000 rpm for 30 minutes at 4 ° C. The resulting pellet was processed as described above.

(Radioligand binding assay)
[ ³ H] PGD ₂ (160 Ci / mmol) binding experiments were performed on membranes prepared as described above. The assay was performed in 100 μl final volume of buffer (1 × HBSS / HEPES 10 mM, pH 7.3). Cell membrane (15 μg). 15 mg of cell membrane was preincubated for 15 minutes at room temperature with varying concentrations of competing ligand. [ ³ H] PGD ₂ (mol, final concentration) was then added and incubation continued for an additional hour at room temperature. The reaction was stopped by the addition of 200 μl ice-cold assay buffer to each well, followed by rapid filtration through a Whatman GF / B glass fiber filter using a Unifilter Cell harvester (PerkinElmer Life Science) and 300 μl of Wash 6 times with ice-cold buffer. Unifilter plates are dried for at least 1 hour at room temperature and the radioactivity retained on the filter is measured with a Beta Trilux counter (PerkinElmer Life Sciences) followed by 40 μl Optiphase Hi-Safe3 (Wallac) liquid scintillation. added. Nonspecific binding was defined in the presence of unlabeled PGD ₂ of 10 [mu] M.

  This assay is also described in Example 3 of WO 2005/044260. More suitably, a compound that is a CRTH2 antagonist has a Ki of less than 100 nM, typically less than 50 nM or even less than 20 nM.

CRTH2 antagonists useful in the present invention is obtained selective for CRTH2 receptor, in this case, no high affinity for DP ₁ or TP receptors. Binding to the DP ₁ receptor is the cell culture phase, Chinese hamster ovary cells are transfected with DP ₁ receptor (CHO / DP) rather than CRTH2 receptor, and CHO / DP cells prepare the cell membrane Can be measured in a radioligand binding assay similar to that described above for the determination of CRTH2 antagonistic activity.

Compounds that do not bind to the DP ₁ receptor have a Ki of 1 μM or greater in this assay. Indeed, for some compounds, the Ki of the DP ₁ receptor can be at least 5 μM or even at least 10 μM.

Radioligand binding of TP receptors can be performed on membranes prepared from platelets. 15-40 μg of protein is preincubated for 15 minutes at room temperature with varying concentrations of competing ligand in assay buffer (10 mM Tris-HCl, pH 7.4, 5 mM glucose, 120 mM NaCl, 10 μM indomethacin) did. [ ³ H] SQ29548 (38 Ci / mmol, 10 nM final concentration) was then added and incubation continued for an additional 30 minutes at room temperature. The reaction was stopped by adding 200 μl of ice-cold assay buffer to each well, followed by rapid filtration through a Whatman GF / C glass fiber filter using a Unifilter Cell harvester (PerkinElmer Life Science) and 300 μl of Washed 6 times with ice-cold buffer. It was measured as described for radioactivity CRTH2 and DP ₁ receptor.

  Compounds useful in the present invention that do not bind to the TP receptor have a Ki of 1 μM or greater in this assay. Indeed, for some compounds, the Ki of the TP receptor can be at least 5 μM or even at least 10 μM.

The most suitable compounds for use in the present invention are those that have a binding selectivity greater than 200-fold for the CRTH2 receptor relative to the DP ₁ TP receptor.

  CRTH2 antagonistic activity can be measured by a calcium mobilization assay as follows.

(Calcium mobilization assay for measurement of CRTH2 antagonistic activity)
Cells were seeded on poly-D-lysine coated 96-well plates at a density of 80,000 cells per well and incubated overnight at 37 ° C. to allow the cells to attach. The cells were washed twice with HBSS and incubated in 100 μl HBSS supplemented with 4 mM probenecid and 100 μl calcium-3-dye (Molecular Devices) for 1 hour at 37 ° C. Changes in fluorescence were monitored over a 50 second time course with agonist added at 17 seconds using a Flexstation (Molecular Devices).

(Effect of CRTH2 agonist on calcium mobilization in CHO-CRTH2 cells)
PGD ₂ causes a dose-dependent increase in intracellular Ca ²⁺ mobilization in CHO / CRTH2 cells and has an EC ₅₀ = 2.4 ± 0.5 nM (n = 3).

A CRTH2 antagonist compound suitably inhibits this effect with an IC ₅₀ of less than 1 μM, more preferably less than 500 nM, even more preferably less than 100 nM and typically less than 50 nM or even less than 20 nM.

  In the examples, the following test compounds were used.

Example 1-Study in an antigen-exposed room in Vienna (Vienna Challenge Chamber Study)
(Research design)
This study was conducted with a randomized, double-blind, placebo-controlled, double crossover evaluation of Compound 1 administered orally for 8 days. There was a one week screening period and a three week washout period between the two treatment periods. The study continued for one week after the last dose of study drug. The group of patients inoculated with study drug in the first treatment period and inoculated with placebo in the second period is designated Group A, while inoculated with placebo in the first treatment period and in the second treatment period. The group of patients vaccinated with study drug was designated as group B.

(Action plan and method)
Subjects underwent a complete screening assessment to determine a baseline response to allergen. This screening evaluation was performed one week before the start of dosing.

  Subjects began dosing with Compound 1 or placebo (visit 2 or visit 5) on day 1 of each treatment period of the study. Adverse events, all nasal symptom scores and concomitant medications were noted on the CRF. Subjects inoculated each dose (2 capsules in the morning and 2 capsules in the evening) as soon as breakfast and dinner were finished respectively.

Subjects reported back to the clinic on the second day of each treatment period for a 6 hour allergen dose. The following measured values were obtained.
-0-3 pre-doses, every nasal symptom score (TNSS) (obstruction, rhinorrhea, itching, sneezing) including each symptom scored on a classification scale every 15 minutes after 0-6 hours of dosing .
O Pre-administration of 0-3, ocular symptom scores (tears, itchy eyes, congested eyes) with each symptom scored on a classification scale every 15 minutes after 0-6 hours of administration.
• Other symptoms (cough, itchy itch, ear itch) including each symptom scored on a classification scale every 0 to 6 hours after dosing, 0 to 3 pre-doses.

  The subject reported back to the clinic on day 8 of each treatment period of 6 hours of allergen administration and repeated the measurements obtained on day 2.

  The last study visit was made once after the last dose of test substance in treatment period 2.

(result)
Group A subjects were inoculated with a CRTH2 antagonist for 8 days, followed by a 3-week washout and then a placebo for 8 days. This subject showed a reduced response to allergen after administration of the CRTH2 antagonist. This reduced response to allergen is still present after administration with placebo. Group B subjects were inoculated with placebo for 8 days, followed by a 3-week washout and then inoculated with a CRTH2 antagonist for 8 days.

  The results of the experiment are shown in FIGS. When the results of the two groups of patients are combined, the subject shows a 23% decrease in all nasal symptom scores after 2 days of CRTH2 antagonist dosing compared to placebo. This decrease increases to 37% after 8 days of dosing (FIG. 1A). All ocular symptom scores were also reduced in patients treated with CRTH2 antagonists, and subjects received a 45% reduction in all ocular symptom scores after 2 days of CRTH2 antagonist dosing compared to placebo Indicates. This response increases to 61% after 8 days of dosing (FIG. 1B).

  Then a diagram for the group of individual patients was obtained. Figures 2A and 2B show all nasal symptoms for each group A patient on days 2 and 8 of each study period compared to the screening response for those patients obtained at the start of the experiment. Shows the score. Figures 2C and 2D show comparable data for Group B.

  Subjects increased the expected response to allergens in placebo and showed a decreased response to allergens in TNSS after administration of CRTH2 antagonists.

  This result shows that the patients in Group B, first treated with placebo and then with Compound 1, responded as expected. Thus, as can be seen from FIGS. 2C and 2D, patients treated with placebo showed the same response as the baseline screening response obtained before the start of the experiment.

  However, the results were different for Group A patients. As shown in FIGS. 2A and 2B, 3-4 weeks after the last dose of Compound 1, patients treated with placebo still have nasal symptoms significantly lower than baseline values obtained before the start of the experiment. Had a score. This indicates that Compound 1 has a long-lasting effect in Group A patients and that this effect lasts longer than 4 weeks after the last treatment with Compound 1.

  This result shows that in this experiment in the antigen exposure room in Vienna, a 36% reduction in all nasal symptom scores (0-6 hours) was maintained for 22 days after the last dose of CRTH2 antagonist, A 38% reduction in all nasal symptom scores (0-6 hours) indicates a 28-day maintenance after the last dose of CRTH2 antagonist.

Example 2 Apoptosis Induction Test
Human Th2 cells were treated with 50 U / ml IL-2 or various concentrations of PGD ₂ in the absence of IL-2 for 16 hours. Cells were stained with Annexin V-PE / PI and then analyzed by FACSArray flow cytometry. The results are shown in FIG. 3, which indicates that PGD ₂ has an anti-apoptotic effect on human Th2 cells.

Human Th2 cells were treated with medium containing 100 nM PGD ₂ and various concentrations of CRTH2 antagonist compounds (compounds 1, 2, 3, 4 and 5) for 16 hours in the absence of IL-2. Cells were stained with Annexin V-PE / PI and then analyzed by FACSArray flow cytometry. The IC ₅₀ of compounds 1-5 for the effective function of PGD ₂ was calculated and found to be less than 100 nM in all cases.

The results of this experiment indicate that PGD2 has an anti-apoptotic effect on Th2 cells, while CRTH2 antagonists have a pro-apoptotic effect.

Claims (27)

Compounds of general formula (I) for treating allergic conditions induced by the presence of allergens to which the patient is sensitive

(Where
R ¹ is C ₁ -C ₆ alkyl;
R ² is halogen,
R ³ is one or more substituents selected from halo, OH, CN, R ⁶ , COR ⁶ , CH ₂ R ⁶ , OR ⁶ , SR ⁶ , SO ₂ R ⁶ or SO ₂ YR ⁶ as required. Substituted aryl or heteroaryl,
R ⁶ is C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl, any of which is halo, OH, CN, NO ₂ , C ₁ -C ₆ alkyl Or optionally substituted with one or more substituents selected from O (C ₁ -C ₆ alkyl);
Y is NH or a linear or branched C ₁ -C ₄ alkylene chain;
R ⁴ is H or C ₁ -C ₄ alkyl;
R ⁵ is hydrogen, C ₁ -C ₆ alkyl, aryl, (CH ₂ ) _m OC (═O) C ₁ -C ₆ alkyl, ((CH ₂ ) _m O) _n CH ₂ CH ₂ X, (CH ₂ ) _m N (R ⁷ ) ₂ or CH ((CH ₂ ) _m O (C═O) R ⁸ ) ₂ ,
m is 1 or 2,
n is 1 to 4,
X is OR ⁷ or N (R ⁷ ) ₂ ;
R ⁷ is hydrogen or methyl;
R ⁸ is C ₁ -C ₁₈ alkyl)
Or a pharmaceutically acceptable salt, hydrate, solvate or complex thereof,
The treatment is
a. A first period during which the compound of general formula (I) is administered to the patient;
b. A second period of at least 7 days, wherein said compound of general formula (I) is administered to said patient in a reduced amount;
Comprising at least one treatment cycle comprising
The allergen is present or suspected to exist throughout the treatment, and the compound of general formula (I) retains its efficacy at least 50% during the second period of the treatment cycle. , A compound of general formula (I), or a pharmaceutically acceptable salt, hydrate, solvate or complex thereof. A pulse therapy for treating an allergic condition induced by the presence of an allergen to which a patient is sensitive, said method comprising CRTH2 of the general formula (I) according to claim 1 over at least one treatment cycle. Administering an antagonist compound to said patient,
The treatment cycle is
a. A first period during which the compound of general formula (I) according to claim 1 is administered to the patient;
b. A second period of at least 7 days, wherein the compound of general formula (I) according to claim 1 is administered to said patient in a reduced amount;
The allergen is present or suspected to be present during the treatment, and the compound of general formula (I) according to claim 1 is at least 50% of that during the second period of the treatment cycle. Pulse therapy that retains its effectiveness. Use of a CRTH2 antagonist compound of general formula (I) according to claim 1 in the preparation of a medicament for treating an allergic condition induced by the presence of an allergen to which a patient is sensitive, said treatment comprising
a. A first period during which the compound of general formula (I) according to claim 1 is administered to the patient;
b. Comprising at least one treatment cycle comprising a second period of at least 7 days, wherein the compound of general formula (I) according to claim 1 is administered to said patient in a reduced amount,
The allergen is present or suspected to be present during the treatment, and the compound of general formula (I) according to claim 1 is present at least 50% of the second period of the treatment cycle. Use, preserving effectiveness.   4. The compound of claim 1, the method of claim 2, or the use of claim 3, wherein, during the first period of the treatment cycle, the patient undergoes a symptom reduction of at least 50%.   5. A compound, method or use according to any one of claims 1-4, wherein during the second period of the treatment cycle, the compound retains its efficacy of 80%.   6. A compound, method or use according to any one of claims 1 to 5, wherein administration of the CRTH2 antagonist compound is discontinued during the second period of the treatment cycle.   7. A compound, method or use according to any one of claims 1 to 6, wherein the second period of the treatment cycle lasts for at least 28 days.   8. A compound, method or use according to any one of claims 1 to 7, wherein the first period of the treatment cycle is 2 to 8 days.   9. A compound, method or use according to any one of claims 1 to 8, wherein in the first period of the treatment cycle, the compound is administered once a day.   10. A compound, method or use according to any one of claims 1 to 9, further comprising one or more additional treatment cycles.   Allergic conditions include asthma (including allergic asthma), food allergies, acute and chronic urticaria, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity (including contact dermatitis) ) Or conjunctivitis, in particular allergic conjunctivitis, compound, method or use according to any one of claims 1-10. In the compounds of general formula (I), R ⁵ is hydrogen, A compound according to any one of claims 1 to 11, use or method. In the compound of the general formula (I), R ⁵ is C ₁ -C ₆ alkyl, aryl, (CH ₂ ) _m OC (═O) C ₁ -C ₆ alkyl, ((CH ₂ ) _m O) _n CH _2. CH ₂ X, (CH ₂ ) _m N (R ⁷ ) ₂ or CH ((CH ₂ ) _m O (C═O) R ⁸ ) ₂
(Where
m is 1 or 2,
n is 1 to 4,
X is OR ⁷ or N (R ⁷ ) ₂ ;
R ⁷ is hydrogen or methyl;
R ⁸ is C ₁ -C ₁₈ alkyl)
The compound, use or method according to any one of claims 1 to 11, wherein In the compound of the general formula (I), independently or in any combination,
R ¹ is fluoro,
R ² is C ₁ -C ₄ alkyl, especially methyl or ethyl, more particularly methyl,
R ⁴ is H or methyl;
R ³ is quinoline, quinoxaline, isoquinoline, thiazole, phenyl, naphthalene, thiophene, pyrrole or pyridine, any of which can be optionally substituted as in claim 1, 14. A compound, use or method according to any one of 13. In the compounds of general formula (I), R ⁴ is H, A compound according to claim 14, use or method. In the compounds of formula (I), quinoline R ³ is substituted optionally, phenyl, naphthalene, thiophene, pyrrole or pyridine compound according to any one of claims 1 to 15, using Or the method. In said compound of general formula (I), R ³ is a quinoline or isoquinoline, or unsubstituted or substituted with one or more halo substituents The compound of claim 16, use or method. In the compound of the general formula (I), R ³ is phenyl, naphthalene, thiophene, pyrrole or pyridine, OR ⁶ , SO ₂ R ⁶ or SO ₂ YR ⁶ (wherein R ⁶ and Y are defined in claim 1) 17. A compound, use or method according to claim 16, optionally substituted with one or more substituents selected from: In the compounds of the general formula (I), R ⁶ is C ₁ -C ₆ alkyl, a 4-6 membered cycloalkyl group, a 5 or 6 membered heterocyclyl group or phenyl, any of which is claimed. 19. A compound, use or method according to claim 18, which can be substituted as defined in 1. In said compound of general formula (I), R ³ is a 3-pyridyl moiety, A compound according to claim 16, use or method. Wherein ^{R 3} is substituted with _SO 2 YR ^6, Y is CH ₂ moiety, A compound according to any one of claims 1 to 20, use or method. The R ³ is substituted with SO ₂ R ⁶ or SO ₂ YR ⁶ , and the R ⁶ group is unsubstituted or substituted with one or more substituents selected from methyl and halo. The compound, use or method of any one of -21. Said R ³ is substituted with OR ⁶ and said R ⁶ group is unsubstituted or one or more selected from halo, cyano, C ₁ -C ₄ alkyl and O (C ₁ -C ₄ alkyl) 21. A compound, use or method according to any one of claims 1 to 20, which is substituted with a substituent. The compound of the general formula (I) is
{3- [1- (4-Chloro-phenyl) -ethyl] -5-fluoro-2-methyl-indol-1-yl} -acetic acid;
{5-fluoro-2-methyl-3- [1- (4-trifluoromethyl-phenyl) -ethyl] -indol-1-yl} -acetic acid;
{3- [1- (4-tert-butyl-phenyl) -ethyl] -5-fluoro-2-methyl-indol-1-yl} -acetic acid;
{5-Fluoro-3- [1- (4-methanesulfonyl-phenyl) -ethyl] -2-methyl-indol-1-yl} -acetic acid;
[5-Fluoro-2-methyl-3- (1-naphthalen-2-yl-ethyl) -indol-1-yl] -acetic acid;
(5-Fluoro-2-methyl-3-quinolin-2-ylmethyl-indol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-naphthalen-2-ylmethyl-indol-1-yl) -acetic acid;
[5-Fluoro-3- (8-hydroxyquinolin-2-ylmethyl) -2-methyl-indol-1-yl] -acetic acid;
[5-fluoro-2-methyl-3- (quinoxalin-2-ylmethyl) indol-1-yl] -acetic acid;
[5-Fluoro-3- (4-methoxy-benzyl) -2-methyl-indol-1-yl] -acetic acid;
[5-fluoro-2-methyl-3- (1,3-thiazol-2-ylmethyl) indol-1-yl] -acetic acid;
[3- (4-Chloro-benzyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid;
[5-Fluoro-2-methyl-3- (4-trifluoromethyl-benzyl) -indol-1-yl] -acetic acid;
[5-fluoro-2-methyl-3- (4-tert-butyl-benzyl) -indol-1-yl] -acetic acid;
{5-fluoro-2-methyl-3-[(4-phenylphenyl) methyl] indol-1-yl} -acetic acid;
[5-Fluoro-3- (4-methanesulfonyl-benzyl) -2-methyl-indol-1-yl] -acetic acid;
{5-fluoro-3-[(6-fluoroquinolin-2-yl) methyl] -2-methylindol-1-yl} -acetic acid;
(2-methyl-3-quinolin-2-ylmethyl-indol-1-yl) -acetic acid;
(5-chloro-2-methyl-3-quinolin-2-ylmethyl-indol-1-yl) -acetic acid;
(3-{[1- (benzenesulfonyl) pyrrol-2-yl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
[5-fluoro-2-methyl-3-({1-[(4-methylbenzene) sulfonyl] pyrrol-2-yl} methyl) indol-1-yl] -acetic acid;
[3-({1-[(2,4-difluorobenzene) sulfonyl] pyrrol-2-yl} methyl) -5-fluoro-2-methylindol-1-yl] -acetic acid;
(3-{[2- (benzenesulfonyl) phenyl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
[3-({2-[(4-chlorobenzene) sulfonyl] phenyl} methyl) -5-fluoro-2-methylindol-1-yl] -acetic acid;
[5-Fluoro-3-({2-[(4-fluorobenzene) sulfonyl] phenyl} methyl) -2-methylindol-1-yl] -acetic acid;
(3-{[2- (benzenesulfonyl) pyridin-3-yl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
[5-Fluoro-3-({2-[(4-fluorobenzene) sulfonyl] pyridin-3-yl} methyl) -2-methylindol-1-yl] -acetic acid;
[3-({2-[(4-chlorobenzene) sulfonyl] pyridin-3-yl} methyl) -5-fluoro-2-methylindol-1-yl] -acetic acid;
2- (3- (4- (benzylsulfonyl) benzyl) -5-fluoro-2-methyl-indol-1-yl) -acetic acid;
2- (3- (4- (4-chlorobenzylsulfonyl) benzyl) -5-fluoro-2-methyl-indol-1-yl) -acetic acid;
2- (3- (3- (benzylsulfonyl) benzyl) -5-fluoro-2-methyl-indol-1-yl) -acetic acid;
2- (5-fluoro-3- (3- (4-fluorobenzylsulfonyl) benzyl) -2-methyl-indol-1-yl) -acetic acid;
2- (3- (2- (benzylsulfonyl) benzyl) -5-fluoro-2-methyl-indol-1-yl) -acetic acid;
2- (3- (4- (4-fluorobenzylsulfonyl) benzyl) -5-fluoro-2-methyl-indol-1-yl) -acetic acid;
2- (3- (2- (cyclohexylsulfonyl) benzyl) -5-fluoro-2-methyl-indol-1-yl) -acetic acid;
2- (5-fluoro-2-methyl-3- (2- (piperidin-1-ylsulfonyl) benzyl) -indol-1-yl) -acetic acid;
2- (3- (2- (cyclopentylsulfonyl) benzyl) -5-fluoro-2-methyl-indol-1-yl) -acetic acid;
2- (5-fluoro-2-methyl-3- (3- (piperidin-1-ylsulfonyl) benzyl) -indol-1-yl) -acetic acid;
2- (5-fluoro-2-methyl-3- (2- (pyrrolidin-1-ylsulfonyl) benzyl) -indol-1-yl) -acetic acid;
2- (3- (4- (cyclohexylsulfonyl) benzyl) -5-fluoro-2-methyl-indol-1-yl) -acetic acid;
2- (3- (4- (cyclopentylsulfonyl) benzyl) -5-fluoro-2-methyl-indol-1-yl) -acetic acid;
2- (3- (2- (cyclobutylsulfonyl) benzyl) -5-fluoro-2-methyl-indol-1-yl) -acetic acid;
2- (5-fluoro-2-methyl-3- (3- (pyrrolidin-1-ylsulfonyl) benzyl) -indol-1-yl) -acetic acid;
2- (5-fluoro-2-methyl-3- (4- (piperidin-1-ylsulfonyl) benzyl) -indol-1-yl) -acetic acid;
[5-fluoro-2-methyl-3- (2-phenoxybenzyl) -indol-1-yl] -acetic acid;
[5-Fluoro-2-methyl-3- (2- (4-methoxyphenoxy) benzyl) -indol-1-yl] -acetic acid;
[5-Fluoro-2-methyl-3- (2- (4-methoxyphenoxy) benzyl) -indol-1-yl] -acetic acid;
[5-Fluoro-2-methyl-3- (2- (2,4-dichlorophenoxy) benzyl) -indol-1-yl] -acetic acid;
[5-Fluoro-2-methyl-3- (2- (4-fluorophenoxy) benzyl) -indol-1-yl] -acetic acid;
[5-fluoro-2-methyl-3- (2- (3,4-difluorophenoxy) benzyl) -indol-1-yl] -acetic acid;
[5-fluoro-2-methyl-3- (2- (4-cyanophenoxy) benzyl) -indol-1-yl] -acetic acid;
[5-Fluoro-2-methyl-3- (2- (4-chlorophenoxy) benzyl) -indol-1-yl] -acetic acid;
[5-Fluoro-2-methyl-3- (2- (2-cyanophenoxy) benzyl) -indol-1-yl] -acetic acid;
(5-Fluoro-2-methyl-3-{[2- (4-methylphenoxy) pyridin-3-yl] methyl} indol-1-yl) -acetic acid;
{5-fluoro-3-[(3-methanesulfonylnaphthalen-2-yl) methyl] -2-methylindol-1-yl} -acetic acid;
{5-fluoro-3-[(1-methanesulfonylnaphthalen-2-yl) methyl] -2-methylindol-1-yl} -acetic acid;
{5-Fluoro-3-[(6-methanesulfonylnaphthalen-2-yl) methyl] -2-methylindol-1-yl} -acetic acid;
[5-fluoro-2-methyl-3- (quinolin-3-ylmethyl) indol-1-yl] -acetic acid;
[5-fluoro-2-methyl-3- (quinoxalin-6-ylmethyl) indol-1-yl] -acetic acid;
[5-fluoro-2-methyl-3- (quinolin-7-ylmethyl) indol-1-yl] -acetic acid;
{5-Fluoro-3-[(6-methanesulfonylquinolin-2-yl) methyl] -2-methylindol-1-yl} -acetic acid;
{5-fluoro-3-[(4-methanesulfonylquinolin-2-yl) methyl] -2-methylindol-1-yl} -acetic acid;
(5-Fluoro-2-methyl-3- {pyrazolo [1,5-a] pyridin-3-ylmethyl} indol-1-yl) -acetic acid;
(5-Fluoro-3- {imidazo [1,2-a] pyridin-2-ylmethyl} -2-methylindol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[2- (methylsulfanyl) phenyl] methyl} indol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[3- (methylsulfanyl) phenyl] methyl} indol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[4- (ethylsulfanyl) phenyl] methyl} indol-1-yl) -acetic acid;
(3-{[4- (ethylsulfanyl) phenyl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[4- (n-propylsulfanyl) phenyl] methyl} indol-1-yl) -acetic acid;
(5-fluoro-2-methyl-3-{[4- (i-propylsulfanyl) phenyl] methyl} indol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[4- (t-butylsulfanyl) phenyl] methyl} indol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[4- (pentan-3-ylsulfanyl) phenyl] methyl} indol-1-yl) -acetic acid;
[3-({4-[(cyclopropylmethyl) sulfanyl] phenyl} methyl) -5-fluoro-2-methylindol-1-yl] -acetic acid;
{3-[(4,4-Dimethyl-2,3-dihydro-1-benzothiopyran-6-yl) methyl] -5-fluoro-2-methylindol-1-yl} -acetic acid;
(3-{[2- (ethanesulfonyl) phenyl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[2- (propane-1-sulfonyl) phenyl] methyl} indol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[2- (propane-2-sulfonyl) phenyl] methyl} indol-1-yl) -acetic acid;
(3-{[2- (butane-1-sulfonyl) phenyl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
(3-{[2- (butane-2-sulfonyl) phenyl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[2- (2-methylpropane-2-sulfonyl) phenyl] methyl} indol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[2- (pentane-1-sulfonyl) phenyl] methyl} indol-1-yl) -acetic acid;
(3-{[2- (cyclopropylmethane) sulfonylphenyl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[2- (propylsulfamoyl) phenyl] methyl} indol-1-yl) -acetic acid;
(3-{[2- (butylsulfamoyl) phenyl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[3- (propylsulfamoyl) phenyl] methyl} indol-1-yl) -acetic acid;
(3-{[3- (butylsulfamoyl) phenyl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
(5-fluoro-2-methyl-3-{[4- (trifluoromethane) sulfonylphenyl] methyl} indol-1-yl) -acetic acid;
(3-{[4- (ethanesulfonyl) phenyl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[4- (propane-1-sulfonyl) phenyl] methyl} indol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[4- (propane-2-sulfonyl) phenyl] methyl} indol-1-yl) -acetic acid;
(3-{[4- (butane-1-sulfonyl) phenyl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[4- (2-methylpropane-2-sulfonyl) phenyl] methyl} indol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[4- (pentane-1-sulfonyl) phenyl] methyl} indol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[4- (pentan-3-ylsulfonyl) phenyl] methyl} indol-1-yl) -acetic acid;
[3-({4-[(cyclopropylmethyl) sulfonyl] phenyl} methyl) -5-fluoro-2-methylindol-1-yl] -acetic acid;
(5-Fluoro-2-methyl-3-{[4- (propylsulfamoyl) phenyl] methyl} indol-1-yl) -acetic acid;
(3-{[4- (butylsulfamoyl) phenyl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[4- (trifluoromethoxy) phenyl] methyl} indol-1-yl) -acetic acid;
(5-Fluoro-3-{[4-methanesulfonyl-3- (trifluoromethoxy) phenyl] methyl} -2-methylindol-1-yl) -acetic acid;
(5-Fluoro-3-{[4-methanesulfonyl-3- (trifluoromethoxy) phenyl] methyl} -2-methylindol-1-yl) -acetic acid;
{5-fluoro-3-[(5-methanesulfonylthiophen-2-yl) methyl] -2-methylindol-1-yl} -acetic acid;
{3-[(4,4-Dimethyl-1,1-dioxo-2,3-dihydro-1λ ⁶ -benzothiopyran-6-yl) methyl] -5-fluoro-2-methylindol-1-yl} -acetic acid ;
[3-({1-[(4-chlorobenzene) sulfonyl] pyrrol-2-yl} methyl) -5-fluoro-2-methylindol-1-yl] -acetic acid;
[5-Fluoro-3-({1-[(4-fluorobenzene) sulfonyl] pyrrol-2-yl} methyl) -2-methylindol-1-yl] -acetic acid;
[5-Fluoro-3-({1-[(4-methoxybenzene) sulfonyl] pyrrol-2-yl} methyl) -2-methylindol-1-yl] -acetic acid;
{3- [1- (2,4-dichloro-benzenesulfonyl) pyrrol-2-ylmethyl] -5-fluoro-2-methyl-indol-1-yl} -acetic acid;
[5-Fluoro-3-({1-[(4-methanesulfonylbenzene) sulfonyl] pyrrol-2-yl} methyl) -2-methylindol-1-yl] -acetic acid;
{5-fluoro-2-methyl-3-[(2-phenylphenyl) methyl] indol-1-yl} -acetic acid;
(3-{[1- (benzenesulfonyl) indol-2-yl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
(3-{[2- (4-chlorophenyl) phenyl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
(5-Fluoro-2-methyl-3-{[2- (4-methylphenyl) phenyl] methyl} indol-1-yl) -acetic acid;
{5-fluoro-2-methyl-3-[(3-phenoxyphenyl) methyl] indol-1-yl} -acetic acid;
[5-Fluoro-3-({4-[(4-fluorophenyl) carbonyl] -1-methylpyrrol-2-yl} methyl) -2-methylindol-1-yl] -acetic acid;
{5-fluoro-2-methyl-3-[(6-{[3- (trifluoromethyl) phenyl] methyl} pyridin-3-yl) methyl] indol-1-yl} -acetic acid;
{5-fluoro-2-methyl-3-[(3-phenoxythiophen-2-yl) methyl] indol-1-yl} -acetic acid;
(3-{[2- (benzenesulfonyl) -1,3-thiazol-5-yl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
{3-[(1-benzylpyrazol-4-yl) methyl] -5-fluoro-2-methylindol-1-yl} -acetic acid;
(3-{[5- (4-chlorophenoxy) -1-methyl-3- (trifluoromethyl) pyrazol-4-yl] methyl} -5-fluoro-2-methylindol-1-yl) -acetic acid;
[3-({5-[(4-chlorobenzene) sulfonyl] furan-2-yl} methyl) -5-fluoro-2-methylindol-1-yl] -acetic acid;
[3-({5-[(4-chlorobenzene) sulfonyl] thiophen-2-yl} methyl) -5-fluoro-2-methylindol-1-yl] -acetic acid;
[3-({3-[(4-chlorobenzene) sulfonyl] thiophen-2-yl} methyl) -5-fluoro-2-methylindol-1-yl] -acetic acid;
{3-[(2-benzylphenyl) methyl] -5-fluoro-2-methylindol-1-yl} -acetic acid;
Or C ₁ -C ₆ alkyl, aryl, (CH ₂ ) _m OC (═O) C ₁ -C ₆ alkyl, ((CH ₂ ) _m O) _n CH ₂ CH ₂ X, (CH ₂ ) _m N (R ⁷ ) ₂ or CH ((CH ₂ ) _m O (C═O) R ⁸ ) ₂ , an ester of any of the above, wherein
m is 1 or 2;
n is 1 to 4;
X is OR ⁷ or N (R ⁷ ) ₂ ;
R ⁷ is hydrogen or methyl;
R ⁸ is C ₁ -C ₁₈ alkyl,
11. A compound, use or method according to any one of claims 1-10.   25. A compound, use or method according to any one of claims 1 to 24, wherein said compound of general formula (I) is administered in combination with one or more further agents used for the treatment of said allergic conditions. . The additional agent is
Suplatast tosylate and similar compounds;
Metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, mesylate bitolterol, B ₂ adrenergic receptor agonists such as pirbuterol and indacaterol, or theophylline and methylquinolinium Santa Nin such aminophylline , Mast cell stabilizers such as sodium cromoglycate, or muscarinic receptor antagonists such as ipratropium and tiotropium;
Antihistamines such as histamine H ₁ receptor antagonists or H ₄ receptor antagonists such as loratadine, cetirizine, desloratadine, levocetirizine, fexofenadine, astemizole, azelastine and chlorpheniramine;
Α ₁ and α ₂ adrenergic receptor agonists such as propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride and ethyl norepinephrine hydrochloride;
Corticosteroids such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, fluticasone furoate, mometasone furoate and ciclesonide;
Allergen immunotherapy drugs such as Grazax,
26. A compound, use or method according to claim 25, selected from:   27. A compound, use or method according to any one of claims 1 to 26, wherein said compound of general formula (I) is administered via oral, nasal, bronchial or topical route.

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