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(12) Patent Application Publication (10) Pub. No.: US 2009/0318437 A1 Gaeta Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2009/0318437 A1 Gaeta Et Al US 20090318437A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0318437 A1 Gaeta et al. (43) Pub. Date: Dec. 24, 2009 (54) SUBSTITUTED PYRAZOLO15-APYRIDINE (60) Provisional application No. 60/811,604, filed on Jun. COMPOUNDS AND THER METHODS OF 6, 2006. USE (76) Inventors: Federico C.A. Gaeta, Mountain Publication Classification View, CA (US); Matthew Gross, (51) Int. Cl. Vallejo, CA (US); Kirk W. A63L/437 (2006.01) Johnson, Moraga, CA (US) C07D 47L/04 (2006.01) Correspondence Address: C07D 413/14 (2006.01) King & Spalding LLP A 6LX 3/5.377 (2006.01) P.O. BOX 889 A6IP II/06 (2006.01) Belmont, CA 94002-0889 (US) (52) U.S. Cl. ...................... 514/233.2:546/121; 544/127; (21) Appl. No.: 12/482,307 514/3OO (22) Filed: Jun. 10, 2009 Related U.S. Application Data (57) ABSTRACT (62) Division of application No. 1 1/810,885, filed on Jun. 6, The present invention is directed to substituted pyrazolo 1.5- 2007, now Pat. No. 7,585,875. apyridines and related methods for their synthesis and use. Patent Application Publication Dec. 24, 2009 Sheet 1 of 2 US 2009/0318437 A1 log threshold withdrawal (mg x 10) s s t | yme as w (s (f) pouseul emerpum 909 Y Patent Application Publication Dec. 24, 2009 Sheet 2 of 2 US 2009/0318437 A1 s o O O war C SSm S.t c) is . E E C C a S. & S. is 25 &(2 52 > w- we t : : log threshold withdrawal (mg x 10) N CN N. CN N. w w w w E O CN L5 9 law. -C CN | O CO to wr (N st ven ve (f) pouseuu eme publM%09 US 2009/0318437 A1 Dec. 24, 2009 SUBSTITUTED PYRAZOLO15-APYRIDINE are well-known. It is believed that the compounds described COMPOUNDS AND THER METHODS OF herein provide one or more advantages over currently existing USE therapies. CROSS REFERENCE TO RELATED SUMMARY APPLICATIONS 0007. The present invention is generally directed to sub 0001. This application is a division of U.S. patent appli stituted pyrazolo 1.5-alpyridine compounds. The com cation Ser. No. 1 1/810,885, filed Jun. 6, 2007, which claims pounds of the invention are particularly useful in the treat the benefit of priority to U.S. Provisional Application No. ment of conditions such as neuropathic pain and migraine, 60/811,604, filed Jun. 6, 2006, the content of which is hereby among others. expressly incorporated herein by reference in its entirety. 0008. In one aspect, provided herein are 2,3,6-substituted pyrazolo 1.5-alpyridine compounds having the following FIELD Structure: 0002 The present invention relates generally to substi tuted pyrazolo 1.5-alpyridine compounds and compositions thereof, as well as methods for making and using Such com pounds, among others. BACKGROUND 0003 Ibudilast (3-isobutyryl-2-isopropylpyrazolo 1.5-a pyridine) is a small molecule drug that has been used for many years in Japan and Korea for the treatment of bronchial 0009. The compounds of the invention possess one or asthma as well as for treatment of cerebrovascular disorders more substituents as described in greater detail below at one Such as post-stroke dizziness. It is sold in these countries or more of ring positions 2, 3, and 6. That is to say, a com under the tradename, Ketas(R). Marketed indications for ibudi pound of the invention may possess a single Substituent at last in Japan include its use as a vasodilator, for treating position 2, a single Substituent at position 3, or a single Sub allergy, eye tissue regeneration, ocular disease, and treatment stituent at position 6. Alternatively, a compound of the inven of allergic ophthalmic disease (Thompson Current Drug tion may be 2,3-disubstituted, 2,6-disubstituted, or 3,6-dis Reports). Its use in the treatment of both chronic brain inf ubstituted. Further, a compound of the invention may be arction (ClinicalTrials.gov) and multiple sclerosis (News. 2,3,6-trisubstituted. Medical.Net: Pharmaceutical News, 2 Aug. 2005) is currently 0010. In one particular embodiment, a compound in accor being explored in separate, ongoing clinical trials. dance with structure I is di-substituted at ring positions 2 and 0004. The mechanisms of action of ibudilast have been 3 widely explored. Its role as a non-selective inhibitor of cyclic nucleotide phosphodiesterase (PDE) has been described 0011 Referring to structure I above, each of R. RandR (Fujimoto, T., et al., J. of Neuroimmunology, 95 (1999) generally corresponds to the following, where: 35-92). Additionally, ibudilast has been reported to act as an I0012 R is independently Horan organic radical selected LTD4 antagonist, an anti-inflammatory, a PAF antagonist, from the group consisting of alkyl, Substituted alkyl, aryl, and a vasodilatatory agent (Thompson Current Drug Substituted aryl, alkenyl, Substituted alkenyl, alkynyl, Substi Reports). Ibudilast is also thought to exert a neuroprotective tuted alkynyl, hydroxy, sulfhydryl, alkoxy, substituted role in the central nervous system of mammals, presumably alkoxy, aryloxy, Substituted aryloxy, carbamoyloxy, thio via Suppression of the activation of glial cells (Mizuno et al. alkyl, substituted thioalkyl, carbamoylthio, thioaryl, substi (2004) Neuropharmacology 46: 404-411). New uses for tuted thioaryl, amino, and carbamoylamino; ibudilast continue to be explored. 0013 R is independently Horan organic radical selected 0005. An analog of ibudilast, KC-764 (2-methyl-3-(1,4,5, from the group consisting of alkyl, Substituted alkyl, aryl, 6-tetrahydronicotinoyl)pyrazolo(1.5-a)pyridine, developed Substituted aryl, alkenyl, Substituted alkenyl, alkynyl, and by Kyorin Pharmaceutical Co., has been reported to possess substituted alkynyl; and antiplatelet and antithrombotic activity (Momo, K., et al., I0014 R is independently Horan organic radical selected Arzneimittelforschung, 1992, January 42(1), 32-9). KC-764 from the group consisting of hydroxy, Sulfhydryl, alkoxy, possesses a chemical structure that differs from ibudilast in aryloxy, thioalkyl, thioaryl, amino, halogen, alkyl, alkenyl, the Substituents at the 2- and 3-ring positions. Interestingly, its alkynyl, aryl, cyano, carboxyl, and carboxamido. Illustrative reported therapeutic use, primarily as an antiplatelet agent, carboxamido moieties include both linear amido moieties as differs significantly from that of the parent compound, ibudi well as lactams, morpholinamides, tetrahydroquinolineam last. ides, tetrahydroisoquinolineamides, coumarinamides, and 0006. The applicants have surprisingly discovered that the like. certain compounds belonging to the Substituted pyrazolol, 00.15 Preferably, a substituted pyrazolo 1.5-alpyridine 5-alpyridine family are useful in the treatment of conditions compound of the invention corresponding to structure I above Such as neuropathic pain. Additionally, such compounds are is one where when R is isopropyl and R is 2-methylpropan useful for treating one or more of the following: inflammatory 1-one, then R is not H (i.e., is an organic radical other than conditions, opiate withdrawal and taxol-induced neuropathy, hydrogen). as well as for antiviral therapy, among others. The shortcom 0016. In one embodiment of the invention, R is lower ings of current therapeutic approaches in each of these areas alkyl, Substituted lower alkyl, amino, aryl, or Substituted aryl. US 2009/0318437 A1 Dec. 24, 2009 0017. In yet a further embodiment, R is phenyl or substi pyridine ring, a pyrazole ring, a pyrimidine ring, a pyridazine tuted phenyl. ring, an imidazole, a 1H-imidazole-2-(3H)-thione, a thiazole, 0018. In a preferred embodiment, R is lower alkyl or a thiazole-2(5H)-imine, and the like, including substituted mono-substituted lower alkyl. versions thereof. 0019. In a particular embodiment, R is isopropyl or 2-hy droxypropan-2-yl. 0028. For example, in one embodiment, R corresponds to 0020. In yet another embodiment, R is phenyl or mono structure II above, where C is unsaturated, and C, taken substituted phenyl. together with X, Y, and Ro, forms a 3-pyridin-4-yl substitu 0021. In yet another embodiment, R is a phenyl ring pos ent, while R is isopropyl. sessing either a single halogen or alkoxy Substituent. Pre 0029. In yet another embodiment, R corresponds to struc ferred R. Substituents include 4-halo phenyl groups such 4-fluorophenyl, 4-chlorophenyl, and 4-iodophenyl, as well as ture II above, where C is unsaturated, and C, taken together 4-alkoxy phenyl Substituents. with X, Y, and Ro, forms a Substituted pyrimidine ring having 0022. In another embodiment, R is Hand R is isopropyl. a substituent at the 2-position of the pyrimidinering, while R. 0023. In yet another embodiment, R possesses the struc is isopropyl. In a particular embodiment thereof, the Substitu ture: ent at the 2-position of the pyrimidine ring is an isopropy lamino group. Preferably, the pyrimidine ring is attached to the core pyrazolo 1.5-alpyridine ring at its 4 position. II X 0030. In yet another embodiment, R corresponds to struc ture II above, where C is unsaturated, and C, taken together -y with X, Y, and Ro, forms a 1H-imidazole-2-(3H)-thione, / while R is isopropyl. R10 0031. In an alternative embodiment, R corresponds to where structure II above, where C is unsaturated, and C, taken together with X, Y, and Ro, forms a thiazole-2(5H)-imine, while R is isopropyl. 0032. In yet a further embodiment, a substituted pyrazolo 1.5-apyridine compound of the invention possesses the fol lowing generalized structure: represents the pyrazolo 1.5-alpyridine ring system, and the carbon atom shown in structure II above is covalently attached to ring carbon 3, and C can be saturated or unsatur III ated. 21 NN- N V 0024. In the event that C in structure II is saturated, X and Y are each independently selected from the group consisting N1S of-H or an organic radical selected from the group consist ing of hydroxyl, amino, alkoxy, cyano, halo, Sulfhydryl, thio alkyl, lower alkyl, and substituted lower alkyl.
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