Crystalline forms and process for preparing spiro-hydantoin compounds

Abstract

A process is provided for preparing spiro-hydantoin compounds of the formula IIwherein Z is N or CR4b; K and L are independently O or S; Ar is an optionally substituted aryl or heteroaryl; A2 is a linker, G′ is a linker; Q is a linker; and R2, R4a, R4c, and Rh are defined in the specification. The process optionally includes the enantiomeric separation of intermediates to allow preparation of enantiomers of the spiro-hydantoin compounds of formula II. Substituted spiro-hydantoin compounds may be prepared from the spiro-hydantoin compounds of formula II. The spiro-hydantoin compound of formula II and the substituted spiro-hydantoin compounds are useful in the treatment of immune or inflammatory diseases. Also, provided are products made by the instant inventive process and crystalline forms (prepared by any process) of the substituted spiro-hydantoin compound, 5-[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-ylmethyl]-thiophene-3-carboxylic acid, including solvates and salts thereof, as well as methods of use thereof. Crystalline forms of certain intermediates are provided.

Description

RELATED APPLICATIONS[0001]This application is a continuation of co-pending U.S. patent application Ser. No. 11 / 238,427, filed on Sep. 29, 2005, which claims the benefit of U.S. Provisional Application Nos. 60 / 615,292 filed on Oct. 1, 2004; 60 / 617,905 filed on Oct. 12, 2004; and 60 / 717,290 filed on Sep. 15, 2005, incorporated herein by reference in their entirety.FIELD OF INVENTION[0002]The present invention relates to a process for preparing spiro-hydantoin compounds and substituted spiro-hydantoin compounds. Also provided are crystalline forms of the substituted spiro-hydantoin compound, 5-[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-ylmethyl]-thiophene-3-carboxylic acid, including solvates and salts thereof as well as methods of use thereof. Crystalline forms of certain intermediates are also provided.BACKGROUND OF INVENTION[0003]A key event in an immune response involves the migration of leukocytes to a disease site. During an i...

AI Technical Summary

Benefits of technology

[0286]In addition, the inventive compounds may be used with agents that increase the levels of cAMP or cGMP in cells for a therapeutic benefit. For example, the compounds of the invention may have advantageous effects when used in combination with phosphodiesterase inhibitors, including PDE1 inhibitors (such as those described in Journal of Medicinal Chemistry, Vol. 40, pp. 2196-2210 [1997]), PDE2 inhibitors, PDE3 inhibitors (such as revizinone, pimobendan, or olprinone), PDE4 inhibitors (referenced above), PDE7 inhibitors, or other PDE inhibitors such as dipyridamole, cilostazol, sildenafil, denbutyline, theophylline (1,2-dimethylxanthine), ARIFLO™ (i.e., cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylic acid), arofyline, C-11294A, CDC-801, BAY-19-8004, cipamfylline, SCH351591, YM-976, PD-189659, mesiopram, pumafentrine, CDC-998, IC-485, and KW-4490.

[0287]In view of their usefulness in treating ischemia, the inventive compounds may be used in combination with agents for inhibiting F1F0-ATPase, including efrapeptin, oligomycin, autovertin B, azide, and compounds described in U.S. patent application Ser. No. 60 / 339,108, filed Dec. 10, 2001 and assigned to the present assignee; -alpha- or beta-adrenergic blockers (such as propranolol, nadolol, carvedilol, and prazosin), antianginal agents such as nitrates, for example, sodium nitrates, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, and nitrovasodilators; antiarrhythmic agents including Class I agents (such as propafenone); Class II agents (propranolol); Class III agents (such as sotalol, dofetilide, amiodarone, azimilide and ibutilide); Class IV agents (such as ditiazem and verapamil); K+ channel modulators such as IAch inhibitors and inhibitors of the Kv1 subfamily of K+ channel openers such as IKur inhibitors (e.g., compounds disclosed in U.S. application Ser. No. 09 / 729,731, filed Dec. 5, 2000); and gap-junction modulators such as connexions; anticoagulant or antithrombotic agents including aspirin, warfarin, ximelaglran, low molecular weight heparins (such as lovenox, enoxaparain, and dalteparin), anti-platelet agents such as GPlIb / GPIIIa blockers, (e.g., abciximab, eptifibatide, and tirofiban), thromboxane receptor antagonists (e.g., ifetroban), P2Y1 and P2Y12 antagonists (e.g., clopidogrel, ticlopidine, CS-747, and aspirin / clopidogrel combinations), and Factor Xa inhibitors (e.g., fondaprinux); and diuretics such as sodium-hydrogen exchange inhibitors, chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolintine, bumetanide, triamtrenene, and amiloride.

[0288]The inventive compounds may also be useful in combination with antiangiogenic agents, such as compounds that are inhibitors of VEGF receptors, or in conjunction with antitumor agents such as paclitaxel, adriamycin, epothilones, cisplatin, and carboplatin. Examples of anticancer and other cytotoxic agents that may be used in combination with the inventive compounds include the following: epothilone derivatives as found in German Patent No. 4138042.8; WO 97 / 19086, WO 98 / 22461, WO 98 / 25929, WO 98 / 38192, WO 99 / 01124, WO 99 / 02224, WO 99 / 02514, WO 99 / 03848, WO 99 / 07692, WO 99 / 27890, WO 99 / 28324, WO 99 / 43653, WO 99 / 54330, WO 99 / 54318, WO 99 / 54319, WO 99 / 65913, WO 99 / 67252, WO 99 / 67253 and WO 00 / 00485; cyclin dependent kinase inhibitors as found in WO 99 / 24416; and prenyl-protein transferase inhibitors as found in WO 97 / 30992 and WO 98 / 54966.

[0289]The combination of the inventive compounds with other therapeutic agents may prove to have additive and synergistic effects. The combination may be advantageous to increase the efficacy of the administration or decrease the dosage to reduce possible side-effects.

[0290]The above other therapeutic agents, when employed in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art. In the methods of the present invention, such other therapeutic agent(s) may be administered prior to, simultaneously with, or following the administration of the inventive compounds.

[0291]The present inventive compounds, including the substituted spiro-hydantoin compounds described in the examples herein, have been tested in assay(s) described below and have shown a measurable level of activity as inhibitors of LFA-1 and / or ICAM-1.AssaysH1-Hela Adhesion Assay

Problems solved by technology

However, there are recognized difficulties associated with the adaptation of the disclosed multistep synthesis for preparing such spiro-hydantoin compounds to larger scale, such as production in a pilot plant or on a manufacturing scale.

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