EP2219645A2 - Utilisation de composés antagonistes de crth2 - Google Patents

Utilisation de composés antagonistes de crth2

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Publication number
EP2219645A2
EP2219645A2 EP08851028A EP08851028A EP2219645A2 EP 2219645 A2 EP2219645 A2 EP 2219645A2 EP 08851028 A EP08851028 A EP 08851028A EP 08851028 A EP08851028 A EP 08851028A EP 2219645 A2 EP2219645 A2 EP 2219645A2
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EP
European Patent Office
Prior art keywords
methyl
fluoro
acetic acid
indol
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP08851028A
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German (de)
English (en)
Inventor
Michael George Hunter
Eric Roy Pettipher
Colin Michael Perkins
Mark Anthony Payton
Luzheng Xue
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Atopix Therapeutics Ltd
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Oxagen Ltd
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Publication of EP2219645A2 publication Critical patent/EP2219645A2/fr
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the use of CRTH2 antagonist compounds for the pulsed treatment of allergic conditions.
  • Allergic conditions are becoming more common throughout the developed world with as much as 10% of the world's population being affected by one or more of allergic asthma, allergic rhinitis, atopic dermatitis and other allergic conditions. Numerous classes of compound have been suggested for the treatment of these conditions, with one of the more recent developments being the use of CRTH2 antagonists, which inhibit the action of agonists such as prostaglandin D 2 (PGD 2 ) acting at the CRTH2 receptor.
  • PPD 2 prostaglandin D 2
  • PGD 2 is an eicosanoid, a class of chemical mediator synthesised by cells in response to local tissue damage, normal stimuli or hormonal stimuli or via cellular activation pathways. Eicosanoids bind to specific cell surface receptors on a wide variety of tissues throughout the body and mediate various effects in these tissues. PGD 2 is known to be produced by mast cells, macrophages and Th2 lymphocytes and has been detected in high concentrations in the airways of asthmatic patients challenged with antigen (Murray et al, (1986), N. Engl. J. Med. 315: 800-804). Instillation of PGD 2 into airways can provoke many features of the asthmatic response including bronchoconstriction (Hardy et al, (1984) N.
  • the first receptor specific for PGD 2 to be discovered was the DPi receptor which is linked to elevation of the intracellular levels of cAMP.
  • PGD 2 is thought to mediate much of its proinflammatory activity through interaction with a G protein- coupled receptor termed CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) which is expressed by Th2 lymphocytes, eosinophils and basophils (Hirai et al, (2001) J. Exp. Med. 193: 255-261, and EPO851O3O and EP-A- 1211513 and Bauer et al, EP-A-1170594).
  • CRTH2 chemoattractant receptor-homologous molecule expressed on Th2 cells
  • the selective DP agonist BW245C does not promote migration of Th2 lymphocytes or eosinophils (Hirai et al, 2001; Gervais et al, (2001) J. Allergy Clin. Immunol. 108: 982-988).
  • antagonising PGD 2 at the CRTH2 receptor is an attractive approach to treat the inflammatory component of Th2-dependent allergic diseases such as asthma (including allergic asthma), food allergies, acute and chronic urticaria, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity (including contact dermatitis) and conjunctivitis, especially allergic conjunctivitis.
  • Documents which discuss the use of CRTH2 antagonists for the treatment of Th2- dependent allergic diseases include WO-A-03/066046, WO-A-03/066047, WO-A- 03/097042, WO-A-03/097598, WO-A-03/101981, WO-A-03/101961, WO-A- 2004/007451, WO-A-2005/019171, WO-A-2005/094816, WO-A-2005/044260, WO-A-2005/040112, WO-A-2005/040114 and WO2006/095183.
  • ramatroban which has been shown to reduce allergic inflammation in the guinea pig nasal mucosa (Narita et al, Im Arch Allergy Immunol 1996;109: 161-166), mouse airways (Nagai et al, Prostaglandins 1995;50:75-87) and mouse skin (Takeshita et al, Int. Immunol. 2004,16:947-959).
  • Ramatroban has also shown to reduce symptoms of perennial allergic rhinitis in human subjects (Terada et al, Allergol. Int. 1998; 47: 59-67).
  • CRTH2 antagonists are effective in treating allergic asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis and other allergic conditions, the inventors have now made the surprising discovery that these compounds have an effect which is much longer lasting than previously thought and are thus useful preventing or reducing the symptoms of the allergic condition for a prolonged period of time after dosing.
  • R 1 is C 1 -C 6 alkyl
  • R 2 is halogen
  • R 3 is aryl or heteroaryl optionally substituted with 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 ;
  • R 6 is C 1 -C 6 alkyl, C 3 -Cg cycloalkyl, heterocyclyl, aryl or heteroaryl, any of which may optionally be substituted with one or more substituents selected from halo, OH, CN, NO 2 , C 1 -C 6 alkyl or 0(C 1 -C 6 alkyl); and Y is NH or a straight or branched C 1 -C 4 alkylene chain;
  • R 4 is H or C 1 -C 4 alkyl
  • m is 1 or 2;
  • n is 1-4;
  • X is OR 7 or N(R 7 ) 2 ;
  • R 7 is hydrogen or methyl
  • R 8 is C 1 -C 18 alkyl
  • the treatment comprises at least one treatment cycle which comprises: a. a first period during which the compound of general formula (I) is administered to the patient; and b. a second period of at least seven days during which the compound of general formula (I) is administered to the patient in a reduced amount; wherein the allergen is present or suspected to be present throughout the treatment and wherein the compound of general formula (I) retains at least 50% of its effectiveness during the second period of the treatment cycle.
  • the invention arises from observations made in the course of a double blind crossover study of a CRTH2 antagonist of general formula (I) in human subjects with allergic rhinitis.
  • the study compared two groups of patients. The first patient group was treated daily with the CRTH2 antagonist for 8 consecutive days, then had no treatment for 3 weeks, then had daily treatment with placebo for 8 consecutive days. The second patient group was treated with placebo for 8 consecutive days, then had no treatment for 3 weeks, then had daily treatment with the CRTH2 antagonist of general formula (I) for 8 consecutive days.
  • the study showed that in the first treatment period, patients treated with the CRTH2 antagonist of general formula (I) displayed fewer symptoms of allergic rhinitis than patients treated with a placebo and this result was expected by the inventors.
  • the first patient group which was being treated with placebo, still retained a reduction in symptoms, the results being comparable with those of the second patient group which was being treated with the CRTH2 antagonist of general formula (I) at that time.
  • These patients also displayed fewer symptoms than they had displayed in an initial screening before treatment with either CRTH2 antagonist or placebo.
  • CRTH2 antagonists such as the compounds of general formula (I) as defined above have a prolonged effect on the allergic response and that, therefore, these compounds are of use in a pulsed method for the treatment of an allergic condition which is induced by the presence of an allergen to which the patient is sensitive, the method comprising administering to a patient over at least one treatment cycle a CRTH2 antagonist compound of general formula (I), wherein the said treatment cycle comprises: a. a first period during which a compound of general formula (I) is administered to the patient; and b.
  • the invention also provides the use of a CRTH2 antagonist compound of general formula (I) in the preparation of an agent for the treatment of an allergic condition which is induced by the presence of an allergen to which the patient is sensitive, wherein the treatment comprises at least one treatment cycle which comprises: a. a first period during which the compound of general formula (I) is administered to the patient; and b.
  • CRTH2 antagonist compounds such as the compounds of general formula (I) in the treatment of allergic conditions is not completely clear but the inventors speculate that it may be related to a previously unknown effect of CRTH2 antagonists on Th2 cells.
  • PGD 2 plays an important role to play in Th2 cell survival by preventing the apoptosis of Th2 cells and their subsequent clearance from the allergic tissue.
  • CRTH2 antagonists are able to block the effect of CRTH2 and induce apoptosis of Th2 cells.
  • Th2 lymphocytes take part in the cascade leading to an allergic reaction as described by various authors, including Pettipher et al, Nature Reviews, 6 (April 2007), 313-325.
  • the immune response in allergy begins with the presentation of allergens to antigen presenting cells which internalise the antigens and cause them to be expressed on the cell surface. This initiates a cascade of events leading to the production of IgE, which binds to high affinity receptors on mast cells leaving its allergen-specific site available for interaction with allergen.
  • mast cell-bound IgE Upon re-exposure to the same allergen, cross-linking of mast cell-bound IgE initiates the production of a number of factors, including PGD 2 by the mast cells, which in turn leads to the recruitment and activation of Th2 cells via the interaction of PGD 2 with the CRTH2 receptor.
  • the activated Th2 cells produce various cytokines including IL4, IL5 and IL13.
  • IL4 causes the production of further IgE by B cells.
  • the inventors have postulated that the apoptotic effect of CRTH2 antagonists on Th2 lymphocytes interrupts the cascade by promoting apoptosis and clearance of Th2 cells which leads to a reduction in the levels of the Th2 cytokines IL4, IL5 or IL13.
  • the reduction in IL4 and IL 13 production would lead to a decrease in the production of IgE by the B-lymphocytes. Therefore it appears that the immune system would not be able to respond to an allergen by increased production of IgE. This would lead to a significantly decreased immune response to an allergen until such time as the Th2 cell population is replenished.
  • C 1 -C 6 alkyl refers to a straight or branched saturated hydrocarbon chain having one to six carbon atoms and optionally substituted with one or more halo substituents or with one or more C 3 -O 7 cycloalkyl groups.
  • 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” have similar meanings except that they contain from one to four and from one to eighteen carbon atoms respectively.
  • C 3 -C 7 cycloalkyl refers to a saturated 3 to 7 membered carbocyclic ring. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • C 1 -C 4 alkylene in the context of the present specification refers to a disubstituted straight or branched saturated hydrocarbon chain having one to four carbon atoms.
  • halo refers to fluoro, chloro, bromo or iodo.
  • aryl in the context of the present specification refers to an aromatic ring system having from 5 to 14 ring carbon atoms and containing up to three rings. Examples of aryl groups are benzene and naphthalene.
  • heteroaryl in the context of the specification refers to a ring system with aromatic character having from 5 to 14 ring atoms, at least one of which is a heteroatom selected from N, O and S, and containing up to three rings. Where a heteroaryl group contains more than one ring, not all rings must be fully aromatic in character. Rings which are not fully aromatic may be substituted with one or more oxo groups.
  • heteroaryl groups include pyrrole, thiophene, thiazole, pyridine, pyrimidine, indole, benzofuran, benzimidazole, tetrahydroquinoline, indoline, quinoline, isoquinoline, quinoxaline, imidazo[l,2-a]pyridine, pyrazolo[l,5- a]pyridine, 2,3-dihydro-l-benzothiopyrane and 2,3-dihydro-l ⁇ 6 -benzothiopyran-l,l- dione.
  • heterocyclyl in the context of the specification refers to a saturated ring system having from 4 to 8 ring atoms, at least one of which is a heteroatom selected from N, O and S and which may be optionally substituted by one or more oxo groups.
  • heterocyclyl groups include azetidinyl, piperidinyl; tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, thiomorpholinyl, 1,1-dioxo-l ⁇ - thiomorpholinyl, morpholinyl, pyrrolyl, piperizinyl, azepanyl, 1,4-diazepanyl, 1,4- oxazepanyl and azocanyl.
  • Appropriate pharmaceutically and veterinarily acceptable salts of the compounds of general formula (I) include basic addition salts such as sodium, potassium, calcium, aluminium, zinc, magnesium and other metal salts as well as choline, diethanolamine, ethanolamine, ethyl diamine, megulmine and other well known basic addition salts as summarised in J. Med. Chem., 50, 6665-6672 (2007) and/or known to those skilled in the art.
  • pharmaceutically or veterinarily acceptable salts may also include salts of organic acids, especially carboxylic acids, including but not limited to acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, pamoate, pectinate, 3-phenylpropionate, picrate, pivalate, proprionate, tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate, organic sulfonic acids such as methanesulfonate, ethanesulfonate, 2-hydroxyethane sulfonate, camphorsulfonate, 2-naphthalate,
  • Salts which are not pharmaceutically or veterinarily acceptable may still be valuable as intermediates.
  • Prodrugs are any covalently bonded compounds which release the active parent drug according to general formula (I) in vivo.
  • X is OR 7 or N(R 7 ) 2 ;
  • R 7 is hydrogen or methyl
  • R 8 is C 1 -C 18 alkyl.
  • a chiral centre or another form of isomeric centre is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereoisomers, are intended to be covered herein.
  • Compounds of the invention containing a chiral centre may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone.
  • administered in combination with refers to the co-administration of a CRTH2 antagonist with another drug wherein the administration may be simultaneous, sequential or separate.
  • allergic condition refers to a condition in which the atopic state of a patient is increased above that of subject who does not have an allergic condition. This may be characterised by the presence in the circulation or tissues of a patient of increased numbers of cells reactive to allergens, and by the presence of IgE which binds specifically to an allergen to which the patient is sensitive.
  • the IgE may be circulating or bound, for example to the surface of mast cells and basophils.
  • references herein to a patient being "sensitive" to an allergen mean that when the patient is exposed to the allergen, an allergic response is induced such that the patient will display symptoms of inflammation arising from the production of substances such as histamine, prostaglandin D 2 and tryptase by mast cells and basophils when the allergen binds to IgE expressed on their surfaces.
  • References to "the treatment of an allergic condition” refer to the reduction or removal of the inflammatory symptoms which arise from the exposure of a patient to an allergen to which the patient is sensitive.
  • references herein to an antigen being present or suspected to be present thoughout the treatment cycle are intended to mean that the antigen may be present in the patient's environment either constantly or intermittently and in varying amounts.
  • the pollen to which they are sensitive may be present in the environment throughout the hay fever season but the amount of pollen in the environment may vary depending on the weather, the time of day and other conditions.
  • a patient may suspect that the allergen is present in the environment, even if no tests are carried out to confirm this.
  • a patient would conventionally take medication as a precautionary measure if it was suspected that pollen may be present, as might occur, for example, during the hay fever season.
  • the term "effectiveness" as applied to the compounds of general formula (I) refers to the reduction of the allergic response in the patient.
  • the patient will experience a reduction of at least 30% in symptoms, suitably at least 40% and with increasing order of suitability, at least 50%, at least 60%, at least 70% at least 80% and, in the most favourable cases, at least a 90% reduction in symptoms.
  • rhinitis and conjunctivitis assessment may be carried out, for example in a Vienna Challenge Chamber experiment, which is well known to those of skill in this art and in which patients carry out self-assessment and scoring of their symptoms on a scale of 0 to 3.
  • Separate scores may be given for eye symptoms, nasal symptoms (including nasal obstruction, nasal itch, sneeze and rhinorrhea) and other symptoms.
  • the symptom score for each patient is subjective, if a sufficient number of patients is used, the total scores are meaningful.
  • other clinical trials may be designed and the measurement of reduction in symptoms may either be carried out by a subjective method such as self assessment by patients or, alternatively, may be made by an objective measurement.
  • asthma symptoms may be quantified using measurements of lung function such as forced expiratory volume in one second (FEVi) or peak expiratory flow rate (PEF) or using the Juniper quality of life scale.
  • FEVi forced expiratory volume in one second
  • PEF peak expiratory flow rate
  • Juniper quality of life scale The severity of atopic dermatitis symptoms can be assessed using the scoring atopic dermatitis (SCORAD) or six area six sign atopic dermatitis (SASSAD) systems.
  • SCORAD scoring atopic dermatitis
  • SASSAD six area six sign atopic dermatitis
  • the compound of general formula (I) retains at least 50% of its effectiveness, but it is more suitable that the compound of general formula (I) retains at least 60% of its effectiveness and, in increasing order of suitability, 70%, 80% and 90% of its effectiveness.
  • the amount of compound of general formula (I) administered to the patient during the second period of the treatment cycle is reduced compared with the amount administered during the first period.
  • the daily dose of compound of general formula (I) administered during the second period of the treatment cycle will be not greater than 50% of the daily dose administered during the first period. However, it may be less than this, for example not greater than 40%, not greater than 30%, not greater than 20% or not greater than 10% of the daily dose of compound of general formula (I) administered during the first period.
  • administration of the CRTH2 antagonist compound will be discontinued altogether during the second period of the treatment cycle.
  • the daily dose with be zero and no compound of general formula (I) will be administered to the patient. This is a particularly advantageous result as period during which the medication is necessary will be considerably shorter than for conventional medications, which has positive implications both for the general well being of the patient and the cost of the treatment.
  • the second period of the treatment cycle lasts for at least 7 days. However, it may last for longer periods, for example at least 14 days and it has been observed that the drug may retain at least 50% of its effectiveness during second periods lasting at least 21 days, at least 28 days and, in some cases, in excess of 35 days even when the dose of compound is reduced to zero during the second period of the treatment cycle.
  • the first period of the treatment cycle during which the CRTH2 antagonist is administered may be chosen such that it comprises a period of days that provides the maximum biological response to the compound in the patient. In general, this period may be from two to 8 days, during which time the drug may be administered from one to three times a day. It is particularly suitable however that the CRTH2 antagonist is administered to the patient once daily as this helps to increase patient compliance.
  • one treatment cycle may not be sufficient to last for the whole time over which treatment is required and therefore the treatment may include one or more further treatment cycles. This is often the case with conditions such as seasonal allergic rhinitis, where the hay fever season may last for several months.
  • CRTH2 antagonists such as the compounds of general formula (I) are useful in treating any allergic condition but they are particularly useful in the pulsed treatment of conditions such as asthma (including allergic asthma), food allergies, acute and chronic urticaria, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity (including contact dermatitis) and conjunctivitis, especially allergic conjunctivitis.
  • the CRTH2 antagonists of general formula (I) are indole- 1 -acetic acid derivatives and are some of the compounds and analogues thereof described in WO2005/044260, WO2005/094816 and WO2006/095183, WO2008/012511 and UK patent application Nos 0800874.0, filed 18 January 2008; 0801132.2, filed 22 January 2008; 0801671.9, filed 30 January 2008; 0801131.4, filed 22 January 2008; 0801672.7, filed 30 January 2008; and 0801674.3, filed 30 January 2008.
  • the indole- 1-acetic acid derivatives of general formula (I) as defined above are described in detail in these documents.
  • the compound of general formula (I) is a CRTH2 antagonist in which R 5 is hydrogen.
  • X is OR 7 or N(R 7 ) 2 ;
  • R 7 is hydrogen or methyl
  • R 8 is Ci-C 18 alkyl.
  • R 1 is fluoro
  • R 2 is C 1 -C 4 alkyl, particularly methyl or ethyl but more especially methyl;
  • R 4 is H or methyl; and
  • R 3 is quinoline, quinoxaline, isoquinoline, thiazole, phenyl, naphthalene, thiophene, pyrrole or pyridine, any of which may optionally be substituted as set out above.
  • R 4 is H.
  • R 3 groups include optionally substituted quinoline, phenyl, naphthalene, thiophene, pyrrole or pyridine.
  • R 3 is quinoline or isoquinoline, it is suitably unsubstituted or substituted with one or more halo substituents, especially fluoro.
  • R 3 is phenyl, naphthalene, thiophene, pyrrole or pyridine, it may optionally have one or more substituents, with particularly suitable substituents including OR 6 , SO 2 R 0 or SO 2 YR 0 ; where R >6 0 and Y are as defined above.
  • R 6 is C 1 -C 6 alkyl, a 4- to 6-membered cycloalkyl group, a 5- or 6-membered heterocyclyl group or phenyl, any of which may be substituted as defined above.
  • R 3 is pyridyl it is most suitably a 3-pyridyl moiety.
  • Y when present, is a CH 2 moiety.
  • R 6 group is generally unsubstituted or substituted with one or more substituents chosen from methyl and halo, particularly chloro or fluoro.
  • group When group may be unsubstituted or substituted with one or more substituents chosen from halo, cyano, C 1 -C 4 alkyl and 0(Ci-C 4 alkyl).
  • Particularly suitable compounds of general formula (I) include: ⁇ 3-[l-(4-Chloro-phenyl)-ethyl]-5-fluoro-2-methyl-indol-l-yl ⁇ -acetic acid;
  • X is OR 7 or N(R 7 ) 2 ;
  • R 7 is hydrogen or methyl
  • R 8 is C 1 -C 18 alkyl.
  • the compounds of general formula (I) may be prepared according to methods set out in the prior art or methods analogous to those set out in the prior art, in particular WO2005/044260, WO2005/094816 and WO2006/095183, WO2008/012511 and UK patent application Nos 0800874.0, 0801132.2, 0801671.9, 0801131.4, 0801672.7 and 0801674.3.
  • the compound of general formula (I) may be combined with one or more additional agent which is of use in the treatment of these allergic conditions.
  • additional agent which is of use in the treatment of these allergic conditions.
  • agents include existing therapies for allergic and other inflammatory diseases including:
  • B 2 adrenoreceptor agonists such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate ,pirbuterol and indacaterol or methylxanthanines such as theophylline and aminophylline, mast cell stabilisers such as sodium cromoglycate or muscarinic receptor antagonists such as ipratropium and tiotropium; antihistamines, for example histamine H 1 receptor antagonists such as loratadine cetirizine, desloratadine, levocetirizine, fexofenadine, astemizole, azelastine and chlorpheniramine or H 4 receptor antagonists; (X 1 and ⁇ 2 adrenoreceptor agonists such as propylhexedrine phenylep
  • the CRTH2 antagonist of general formula (I) will generally be administered in a pharmaceutical formulation which may be a formulation suitable for oral, rectal, nasal, bronchial (inhaled), topical (including eye drops, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration and may be prepared by any methods well known in the art of pharmacy.
  • a pharmaceutical formulation which may be a formulation suitable for oral, rectal, nasal, bronchial (inhaled), topical (including eye drops, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration and may be prepared by any methods well known in the art of pharmacy.
  • compositions for oral, nasal, bronchial or topical administration.
  • the formulation may be prepared by bringing into association the above defined active agent with a carrier.
  • the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • Formulations for oral administration in the present invention may be presented as: discrete units such as capsules, sachets, tablets, which may be chewable tablets, or lozenges, each containing a predetermined amount of the active agent; as a powder or granules; as fine particles for sprinkling over food; as a solution or a suspension of the active agent in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water in oil liquid emulsion; or as a bolus etc.
  • the term "acceptable carrier” includes vehicles such as common excipients e.g. binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers, for example corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate, sodium stearate and other metallic stearates, glycerol stearate stearic acid, silicone fluid, talc waxes, oils and colloidal silica.
  • Flavouring agents such as peppermint, oil of wintergreen, cherry flavouring and the like can also be used. It may be desirable to
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active agent in a free flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active agent.
  • compositions suitable for oral administration include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active agent in a suitable liquid carrier.
  • CRTH2 antagonists such as compounds of general formula (I) may be made up into a cream, ointment, jelly, solution or suspension etc.
  • 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 text books of pharmaceutics such as the British Pharmacopoeia.
  • CRTH2 antagonists such as compounds of general formula (I) may be made up into an eye drop formulation.
  • Suitable eye drop formulations are also well known in the art and are described in standard text books of pharmaceutics such as the British Pharmacopoeia.
  • CRTH2 antagonists which are intended to reduce or remove the symptoms of conditions such as allergic asthma, allergic conjunctivitis and allergic rhinitis may be administered to the respiratory tract by nasal, bronchial or buccal administration of, for example, aerosols or sprays which can disperse the pharmacological active ingredient in the form of a powder or in the form of drops of a solution or suspension.
  • Pharmaceutical compositions with powder-dispersing properties usually contain, in addition to the active ingredient, a liquid propellant with a boiling point below room temperature and, if desired, adjuncts, such as liquid or solid non-ionic or anionic surfactants and/or diluents.
  • compositions in which the pharmacological active ingredient is in solution contain, in addition to this, a suitable propellant, and furthermore, if necessary, an additional solvent and/or a stabiliser.
  • a suitable propellant instead of the propellant, compressed air can also be used, it being possible for this to be produced as required by means of a suitable compression and expansion device.
  • Parenteral formulations will generally be sterile.
  • the oral dose of the compound will be about 0.01 to 100 mg/kg; so as to achieve a concentration of drug in the plasma at a concentration effective to inhibit PGD 2 at the CRTH2 receptor.
  • the precise amount of a compound of CRTH2 antagonist which is therapeutically effective, and the route by which such compound is best administered, is readily determined by one of ordinary skill in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect.
  • the concentration of active compound will typically be about 0.1%-1% w/w such that systemic exposure of the CRTH2 antagonist compound is limited.
  • CRTH2 antagonists for the treatment of Th2-dependent allergic diseases include WO-A-03/066046, WO-A- 03/066047, WO-A-03/097042, WO-A-03/097598, WO- A-03/101981, WO-A- 03/101961, WO-A-2004/007451, WO-A-2005/019171, WO-A-2005/054232, WO- A-2004/089884, WO-A-2004/089885, WO-A-2005/018529, WO-A-2006/005909, WO2006/021759, WO-A-2007/039736, WO-A-2007/052023, WO-A-2006/075139, WO-A-2007/068894, WO- A-2007138282,
  • a first period during which the CRTH2 antagonist compound is administered to the patient and b. a second period of at least seven days during which the compound of general formula (I) is administered to the patient in a reduced amount; wherein the allergen is present or suspected to be present throughout the treatment and wherein the CRTH2 antagonist retains at least 50% of its effectiveness during the second period of the treatment cycle.
  • Some particularly suitable compounds are compounds which are similar to the compounds of general formula (I) but in which the moiety -CHR 3 R 4 of general formula (I) is replaced by R 3 , SR 3 , SOR 3 or SO 2 R 3 , where R 3 is as defined for general formula (I).
  • An example compound of this type, [5-Fluoro-3-(4-chloro- benzenesulfonyl)-2-methyl-indol-l-yl]-acetic acid, which falls within the scope of WO 2004/007451 was tested in the apoptosis assay of Example 3 (below) and was found counter the rescuing function of PGD 2 with an IC 50 of 204 ⁇ 160 nM.
  • a CRTH2 antagonist is a compound which binds to the CRTH2 receptor with a Ki of less than 1000 nM in the radioligand binding assay described below and which inhibits the dose-dependent increase in intracellular Ca 2+ mobilisation in CHO/CRTH2 cells treated with PGD 2 with an IC 50 of less than 1000 nM.
  • the CRTH2 antagonist is suitably a compound of general formula (I).
  • Calcium-3 dye was purchased from Molecular Devices (Wokingham, UK). Mono- -poly resolving medium was obtained from Dainippon Pharmaceuticals (Osaka,
  • Macs anti-CD 16 microbeads were from Miltenyi biotec (Bisley, Surrey).
  • ChemoTx plates were purchased from Neuroprobe (Gaithesburg, MD). PoIy-D- lysine coated 96-well plates were obtained from Greiner (Gloucestershire, UK).
  • [ 3 H]PGD 2 was 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 stated.
  • Cell culture Chinese Hamster Ovary cells were transfected with CRTH2 receptors (CHO/CRTH2) and were maintained in culture in a humidified atmosphere at 37 0 C (5% CO 2 ) in Minimum Essential Medium (MEM) supplemented with 10% foetal bovine serum, 2 raM glutamine, and 1 mg ml '1 active G418. The cells were passaged every 2-3 days.
  • MEM Minimum Essential Medium
  • radioligand binding assay cells were prepared in triple-layer flasks or in 175 cm 2 square flasks (for membrane preparation).
  • calcium mobilisation assay cells were grown in a 96 well plate 24h prior to the assay at a density of 80,000 cells per well.
  • Membranes were prepared either from CHO/CRTH2 cells. CHO cells grown to confluency were washed with PBS and detached using a Versene solution (15 ml per flask). When the cells were grown in 175 cm 2 square flask, they were collected by scrapping in PBS. The cell suspensions were centrifuged (1,700 rpm, 10 min, 4 0 C) and resuspended in 15 ml of buffer (IxHBSS, supplemented with 10 mM HEPES, pH 7.3). Cell suspensions were then homogenised using an Ultra Turrax at setting 4- 6 for 20 s.
  • the homogenate was centrifuged at 1,700 rpm for 10 min and the supernatant was collected and centrifuged at 20,000 rpm for Ih at 4°C. The resulting pellet was resuspended in buffer and stored at -80 0 C in aliquots of 200-500 ⁇ l.
  • the protein concentration was determined by the method of Bradford (1976), using bovine serum albumin as standard.
  • the platelets were washed by centrifugation at 600xg for 10 min and resuspended in ice-cold assay buffer (10 mM Tris-HCl, pH 7.4, 5 mM Glucose, 120 mM NaCl, 10 ⁇ M indomethacin) and directly centrifuged at 20,000 rpm for 30 min at 4 0 C. The resulting pellet was treated as described above.
  • Radioligand binding assays [ 3 H]PGD 2 (160 Ci/mmol) binding experiments were performed on membranes prepared as described above. Assays were performed in a final volume of 100 ⁇ l of buffer (1XHBSS/HEPES 10 mM, pH 7.3). Cell membranes (15 ⁇ g). Cell membranes 15mg were preincubated at room temperature with varying concentration of competing ligand for 15 min. [ 3 H]PGD 2 (mol, final concentration) was then added and the incubation continued for a further one hour at room temperature.
  • the reaction was terminated by the addition of 200 ⁇ l ice-cold assay buffer to each well, followed by rapid filtration through Whatman GF/B glass fibre filters using a Unifilter Cell harvester (PerkinElmer Life Sciences) and six washes of 300 ⁇ l of ice- cold buffer.
  • the Unifilter plates were dried at room temperature for at least Ih and the radioactivity retained on the filters was determined on a Beta Trilux counter (PerkinElmer Life Sciences), following addition of 40 ⁇ l of Optiphase Hi-Safe 3 (Wallac) liquid scintillation. Non specific binding was defined in the presence of 10 ⁇ M unlabelled PGD 2 .
  • the CRTH2 antagonists useful in the present invention may be selective for the CRTH2 receptor and in this case will not have high affinity for the DP 1 or TP receptors. Binding to the DPi receptor may be measured in a radioligand binding assay similar to the one described above for measurement of CRTH2 antagonist activity except that in the cell culture phase, the Chinese Hamster Ovary cells were transfected with DP 1 receptors (CHO/DP), rather than with CRTH2 receptors, and the CHO/DP cells were used to prepare the cell membranes.
  • DP 1 receptors CHO/DP
  • Ki at the DP 1 receptor may be at least 5 ⁇ M or even at least 10 ⁇ M.
  • TP receptor radioligand binding may be carried out on membranes prepared from platelets. 15-40 ⁇ g of protein were pre-incubated with varying concentrations of competing ligand for 15 min at room temperature in assay buffer (10 mM Tris-HCl, pH 7.4, 5 mM glucose, 120 mM NaCl, 10 ⁇ M indomethacin). [ 3 H]SQ29548 (38 Ci/mmol, 10 nM final concentration) was then added and the incubation continued for a further 30 min at room temperature.
  • the reaction was terminated by the addition of 200 ⁇ l ice-cold assay buffer to each well, followed by rapid filtration through Whatman GF/C glass fibre filters using a Unif ⁇ lter Cell harvester (PerkinElmer Life Sciences) followed with six washes of 300 ⁇ l of ice-cold buffer.
  • the radioactivity was determined as described for the CRTH2 and DP 1 receptors.
  • Ki at the TP receptor may be at least 5 ⁇ M or even at least 10 ⁇ M.
  • the most suitable compounds for use in the present invention are those in which the binding selectivity is greater than 200 fold for CRTH2 receptor, compared to DP 1 TP receptors.
  • CRTH2 antagonist activity can be measured by the calcium mobilisation assay as follows.
  • Cells were seeded onto poly-D-lysine coated 96-well plates at a density of 80,000 cells per well and incubated at 37°C overnight to allow the cells to adhere. Cells were washed twice with HBSS and incubated for Ih at 37°C in lOO ⁇ l HBSS and lOO ⁇ l calcium-3-dye (Molecular Devices), supplemented with 4mM probenecid. Changes in fluorescence were monitored over a 50s time course with agonist addition at 17s using a Flexstation (Molecular Devices).
  • CRTH2 antagonist compounds inhibit this effect suitably with an IC 50 of less than l ⁇ M, more appropriately less than 500 nM still more suitably less than 100 nM and typically less than 50 nM or even less than 20 nM.
  • FIGURE 1 is a series of plots showing the combined symptom scores of two groups of patients with allergic rhinitis in a test comparing a CRTH2 antagonist with a placebo on Days 2 and 8 of each treatment period.
  • Figure IA shows the combined nasal symptom scores for both patient groups in response to challenge with a CRTH2 antagonist
  • Figure IB shows the combined scores for eye symptoms.
  • the plots show that patients taking the CRTH2 antagonist show reduced nasal and eye symptoms on both Day 2 and Day 8 of the treatment period.
  • FIGURE 2 is a series of plots similar to that of Figure 1 but where the scores for each patient group have been shown separately. The plots also show a screening response, which is the response of the patients to allergen before the beginning of the trial.
  • Figures 2A and 2B show the total nasal symptoms for patient group A compared with the screening response score for the same group of patients.
  • Figure 2A is plot showing the scores for nasal symptoms of patients in Group A on day 2 of each of the treatment periods while Figure 2B shows the nasal symptom scores for the same group of patients on day 8.
  • Patient group A was treated with CRTH2 antagonist for 8 days, then given no treatment for 3 weeks, then treated with placebo for 8 days.
  • Figures 2C and 2D are similar to Figures 2 A and 2B but show the scores for nasal symptoms from patients from patient group B on days 2 and 8 of the treatment periods together with the screening response score for the same group of patients.
  • Patient group B was treated with placebo for 8 days, then given no treatment for 3 weeks, then treated with CRTH2 antagonist for 8 days.
  • FIGURE 2 is a plot showing the anti-apoptotic effect of PGD2 in human Th2 cells.
  • Human Th2 cells were treated with 50U/ml IL-2 or various concentrations of PGD 2 in the absence of DL-2 for 16 hrs. The cells were stained with Annexin V-PE/PI and then analysed by FACSArray flow cytometer.
  • the study was a randomised, double blind, placebo controlled, two way crossover evaluation of Compound 1, given orally for eight days. There was a screening period of one week and a washout period of three weeks between the two treatment periods.
  • Subjects commenced dosing with Compound 1 or placebo on Day 1 (visit 2 or visit 5) of each treatment period of the study. Adverse events, total nasal symptom score and concomitant medications were noted in the CRF. Subjects took each dose (2 capsules in the morning and 2 capsules in the evening) as soon as they had finished breakfast and their evening meal respectively.
  • TNSS Total nasal symptom score
  • Eye symptom score watery eyes, itchy eyes, red eyes
  • each symptom scored on a categorical scale from 0 to 3 pre-challenge, every 15mins from 0 to 6h post-start of challenge
  • Subjects in Group A received a CRTH2 antagonist for 8 days, followed by a three week washout and then received placebo for 8 days. The subjects showed a reduced response to allergen after dosing with a CRTH2 antagonist. This reduced response to allergen was still present on dosing with placebo.
  • Subjects in Group B received placebo for 8 days, followed by a three week washout and then received a CRTH2 antagonist for 8 days.
  • the subjects mounted the expected response to allergen on placebo and showed a reduction in TNSS in response to allergen after dosing with the CRTH2 antagonist.
  • Human Th2 cells were treated with 50U/ml IL-2 or various concentrations of PGD 2 in the absence of IL-2 for 16 hrs. The cells were stained with Annexin V-PE/PI and then analysed by FACSArray flow cytometer. The results are illustrated in Figure 3, which shows that PGD 2 has an anti-apoptotic effect on human Th2 cells.
  • Human Th2 cells were treated in the absence of JL-2 with a medium containing 100 nM PGD 2 and various concentrations of CRTH2 antagonistic compounds (Compounds 1, 2, 3, 4 and 5) for 16 hrs. The cells were stained with Annexin V- PE/PI and then analysed by FACSArray flow cytometer. The IC 50 of Compounds 1 to 5 to the rescuing function of PGD 2 were calculated and found to be less than 10OnM in all cases.

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Abstract

L'invention concerne les composés de formule générale (I), dans laquelle R1, R2, R3, R4 et R5 sont tels que définis dans le présent document, destinés au traitement d'états allergiques, ledit traitement se faisant par thérapie pulsée qui se compose d'une première période au cours de laquelle le composé est administré au patient et une seconde période d'au moins sept jours au cours de laquelle le composé est administré au patient en quantité réduite.
EP08851028A 2007-11-13 2008-11-13 Utilisation de composés antagonistes de crth2 Ceased EP2219645A2 (fr)

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