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Last Updated: March 29, 2024

Claims for Patent: 9,951,042


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Summary for Patent: 9,951,042
Title:Polymorphic form of [5-fluoro-3-({2-[(4-fluorobenzene) sulfonyl] pyridin-3-yl}methyl)-2-methylindol-1-yl]-acetic acid
Abstract: The invention relates to a polymorphic form of [5-fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methyli- ndol-1-yl]-acetic acid which has higher solubility than other forms and is therefore useful for preparing stable pharmaceutical formulations.
Inventor(s): Hilfiker; Rolf (Kaiseraugst, CH), Grosse-Sender; Katja (Kaiseraugst, CH)
Assignee: ATOPIX THERAPEUTICS LIMITED (London, GB)
Application Number:15/308,290
Patent Claims:1. A polymorphic form of [5-fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methyli- ndol-1-yl]-acetic acid (Compound 1), characterised in that it gives an FT-Raman spectrum which is characterised by peaks at 3068.+-.2 cm.sup.-1, 3054.+-.2 cm.sup.-1, 2976.+-.2 cm.sup.-1, 1582.+-.2 cm.sup.-1, 1427.+-.2 cm.sup.-1, 1298.+-.2 cm.sup.-1, 1213.+-.2 cm.sup.-1, 1190.+-.2 cm.sup.-1, 1164.+-.2 cm.sup.-1, 1060.+-.2 cm.sup.-1, 956.+-.2 cm.sup.-1, 927.+-.2 cm.sup.-1, 834.+-.2 cm.sup.-1, 700.+-.2 cm.sup.-1, 502.+-.2 cm.sup.-1, 421.+-.2 cm.sup.-1, 401.+-.2 cm.sup.-1, 388.+-.2 cm.sup.-1, 363.+-.2 cm.sup.-1, 353.+-.2 cm.sup.-1, 301.+-.2 cm.sup.-1, 208.+-.2 cm.sup.-1, 116.+-.2 cm.sup.-1.

2. The polymorphic form of Compound 1 of claim 1 which comprises not more than 2% of other forms of Compound 1.

3. The polymorphic form of Compound 1 of claim 1 which comprises not more than 0.1% by weight of solvent.

4. A process for the preparation of the polymorphic form of Compound 1 of claim 1 comprising: (a). suspending [5-fluoro-3-({2-[(4-fluorobenzene)sulfonyl] pyridin-3-yl}methyl)-2-methylindol-1-yl]-acetic acid in methylethylketone; (b). stirring the suspension at a temperature of about 15 to 25.degree. C. for 15 to 30 days; and (c). isolating and drying the solid [5-fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-m- ethylindol-1-yl]-acetic acid.

5. The process of claim 4, further comprising: (d). dissolving the product of (c) in methyl ethyl ketone at an elevated temperature of from about 65 to 80.degree. C. to obtain a saturated solution; (e). partially evaporating the solvent; (f). stirring the mixture for 20-36 hours such that crystallisation takes place; and (g). isolating the crystalline Compound 1.

6. The process of claim 5, further comprising: (h). preparing a saturated solution of Compound 1 in methylethylketone at an elevated temperature of about 65-80.degree. C.; (i). seeding the solution with the crystalline product of (g); (j). allowing crystallisation to take place; and (k). isolating the crystalline product.

7. The process of claim 6 comprising repeating (h) to (k) using the product of (k) as the seed crystals for (i).

8. A method for the treatment of a CRTH2-mediated disease or condition selected from the group consisting of asthma, asthma exacerbations, chronic obstructive pulmonary disease, allergic rhinitis conjunctivitis, nasal polyps, atopic dermatitis, contact hypersensitivity (including contact dermatitis), eosinophilic cough, eosinophilic bronchitis, eosinophilic gastroenteritis, eosinophilic esophagitis, food allergies, inflammatory bowel disease, ulcerative colitis, Crohn's disease, mastocytosis, urticaria, hypereosinophilic syndrome, hyper IgE syndrome, fibrotic diseases, Churg-Strauss syndrome, and multiple sclerosis, comprising administering to a patient in need of such treatment an effective amount of the polymorphic form of Compound 1 of claim 1.

9. A method for the treatment of asthma exacerbations induced by respiratory syncytial virus or rhinovirus, comprising administering to a patient in need of such treatment an effective amount of the polymorphic form of Compound 1 of claim 1.

10. A pharmaceutical or veterinary composition comprising the polymorphic form of Compound 1 of claim 1 and a pharmaceutically or veterinarily acceptable excipient.

11. The composition of claim 10 further comprising one or more additional active agents useful in the treatment of diseases and conditions mediated by PGD.sub.2 or other agonists at the CRTH2 receptor.

12. The composition of claim 11 wherein the additional active agent is selected from: other CRTH2 receptor antagonists; Suplatast tosylate and similar compounds; .beta.2 adrenoreceptor agonists such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, indacaterol, terbutaline, orciprenaline, bitolterol mesylate and pirbuterol or methylxanthines such as theophylline and aminophylline, mast cell stabilisers such as sodium cromoglycate or muscarinic receptor antagonists such as tiotropium; antihistamines, for example histamine H.sub.1 receptor antagonists such as loratadine, cetirizine, desloratadine, levocetirizine, fexofenadine, astemizole, azelastine and chlorpheniramine or H.sub.4 receptor antagonists; .alpha..sub.1 and .alpha..sub.2 adrenoreceptor agonists such as propylhexedrine phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride and ethylnorepinephrine hydrochloride; modulators of chemokine receptor function, for example CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C--C family) or CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C--X--C family) and CX.sub.3CR1 for the C--X.sub.3--C family; Leukotriene antagonists such as montelukast, pranlukast and zafirlukast leukotriene biosynthesis inhibitors such as 5-lipoxygenase inhibitors or 5-lipoxygenase activating protein (FLAP) inhibitors such as zileuton, ABT-761, fenleuton, tepoxalin, Abbott-79175, N-(5-substituted)-thiophene-2-alkylsolfonamides, 2,6-di-tert-butylphenol hydrazones, methoxytetrahydropyrans such as ZD2138, SB-210661, pyridinyl-substituted-2-cyanonaphthalene compounds such as L-739010, 2-cyanoquinoline compounds such as L-746,530, indole and quinoline compounds such as MK-591, MK-886 and BAY x 1005; Phosphdiesterase inhibitors, including PDE4 inhibitors such as roflumilast; anti-IgE antibody therapies such as omalizumab; anti-infectives such as fusidic acid (particularly for the treatment of atopic dermatitis); anti-fungals such as clotrimazole (particularly for the treatment of atopic dermatitis); immunosuppressants such as tacrolimus and particularly pimecrolimus in the case of inflammatory skin disease or alternatively FK-506, rapamycin, cyclosporine, azathioprine or methotrexate; Immunotherapy agents including allergen immunotherapy such as Grazax; corticosteroids such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate mometasone furoate and fluticasone furoate drugs which promote Th1 cytokine response such as interferons, TNF or GM-CSF; other antagonists of PGD.sub.2 acting at other receptors such as DP antagonists; drugs that modulate cytokine production such as inhibitors of TNF.alpha. converting enzyme (TACE) anti-TNF monoclonal antibodies, TNF receptor immunoglobulin molecules, inhibitors of other TNF isoforms, non-selective COX-1/COX-2 inhibitors such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefanamic acid, indomethacin, sulindac and apazone, pyrazolones such as phenylbutazone, salicilates such as aspirin; COX-2 inhibitors such as meloxicam, celecoxib, fofecoxib, valdecoxib and etoricoxib, low dose methotrexate, lefunomide, ciclesonide, hydroxychloroquine, d-penicillamine, auranofin or parenteral or oral gold; drugs that modulate the activity of Th2 cytokines IL-4 and IL-5 such as blocking monoclonal antibodies and soluble receptors for Th2 cytokines; PPAR-.gamma. agonists such as rosiglitazone; or with anti-RSV antibodies such as Synagis (palivizumab) and agents that may be used to treat rhinovirus infection in the future e.g. interferon-alpha, interferon-beta or other interferons.

13. A kit for the treatment of a disease or condition mediated by the action of PGD2 at the CRTH2 receptor comprising; (a) a first container comprising the polymorphic form of Compound 1; and (b) a second container comprising an additional agent useful in the treatment of diseases or conditions mediated by PGD2 or other agonists at the CRTH2 receptor, wherein the additional active agent is selected from the agents listed in claim 12.

14. The composition of claim 12 wherein the additional active agent is montelukast.

15. A process for the preparation of the pharmaceutical or veterinary composition of claim 10, comprising bringing into association the polymorphic form of Compound 1 and a pharmaceutically or veterinarily acceptable excipient.

16. A product comprising the polymorphic form of Compound 1 and one or more of the agents listed in claim 12 as a combined preparation for simultaneous, separate, or sequential use in the treatment of a disease or condition mediated by the action of PGD.sub.2 at the CRTH2 receptor.

Details for Patent 9,951,042

Applicant Tradename Biologic Ingredient Dosage Form BLA Approval Date Patent No. Expiredate
Swedish Orphan Biovitrum Ab (publ) SYNAGIS palivizumab For Injection 103770 06/19/1998 ⤷  Try a Trial 2034-05-02
Swedish Orphan Biovitrum Ab (publ) SYNAGIS palivizumab Injection 103770 07/23/2004 ⤷  Try a Trial 2034-05-02
Jubilant Hollisterstier Llc N/A positive skin test control-histamine Injection 103891 03/13/1924 ⤷  Try a Trial 2034-05-02
Genentech, Inc. XOLAIR omalizumab For Injection 103976 06/20/2003 ⤷  Try a Trial 2034-05-02
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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