FreshPatents.com Logo
stats FreshPatents Stats
2 views for this patent on FreshPatents.com
2012: 2 views
Updated: December 09 2014
newTOP 200 Companies filing patents this week


Advertise Here
Promote your product, service and ideas.

    Free Services  

  • MONITOR KEYWORDS
  • Enter keywords & we'll notify you when a new patent matches your request (weekly update).

  • ORGANIZER
  • Save & organize patents so you can view them later.

  • RSS rss
  • Create custom RSS feeds. Track keywords without receiving email.

  • ARCHIVE
  • View the last few months of your Keyword emails.

  • COMPANY DIRECTORY
  • Patents sorted by company.

Your Message Here

Follow us on Twitter
twitter icon@FreshPatents

Substituted indolealkanoic acids

last patentdownload pdfdownload imgimage previewnext patent

20120270912 patent thumbnailZoom

Substituted indolealkanoic acids


Disclosed are substituted indolealkanoic acids useful in the treatment of chronic complications arising from diabetes mellitus. Also disclosed are pharmaceutical compositions containing the compounds and methods of treatment employing the compounds, as well as methods for their synthesis.

Inventors: Michael Lee Jones, David Gunn, John Howard Jones, Michael C. Van Zandt
USPTO Applicaton #: #20120270912 - Class: 514367 (USPTO) - 10/25/12 - Class 514 
Drug, Bio-affecting And Body Treating Compositions > Designated Organic Active Ingredient Containing (doai) >Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai >Five-membered Hetero Ring Containing At Least One Nitrogen Ring Atom (e.g., 1,2,3-triazoles, Etc.) >1,3,4-thiadiazoles (including Hydrogenated) >Polycyclo Ring System Having The Thiazole Ring As One Of The Cyclos >Bicyclo Ring System Having The Thiazole Ring As One Of The Cyclos



view organizer monitor keywords


The Patent Description & Claims data below is from USPTO Patent Application 20120270912, Substituted indolealkanoic acids.

last patentpdficondownload pdfimage previewnext patent

This application is a continuation of application Ser. No. 12/701,967, filed on Feb. 8, 2010, which is a divisional of application Ser. No. 11/999,524, filed on Dec. 4, 2007, now U.S. Pat. No. 7,659,269, which is a continuation of application Ser. No. 11/531,151, filed on Sep. 12, 2006, now U.S. Pat. No. 7,304,079, which is a continuation of application Ser. No. 10/832,724, filed on Apr. 27, 2004, now U.S. Pat. No. 7,105,514, which is a continuation of application Ser. No. 10/185,863, filed on Jun. 28, 2002, now U.S. Pat. No. 6,730,794, which is a continuation of application Ser. No. 09/818,808, filed on Mar. 27, 2001, now U.S. Pat. No. 6,426,344, which is a continuation of application Ser. No. 09/282,280, filed on Mar. 31, 1999, now U.S. Pat. No. 6,214,991, which claims priority from application Ser. No. 60/080,143, filed Mar. 31, 1998.

BACKGROUND OF INVENTION

The use of aldose reductase inhibitors (ARIs) for the treatment of diabetic complications is well known. The complications arise from elevated levels of glucose in tissues such as the nerve, kidney, retina and lens that enters the polyol pathway and is converted to sorbitol via aldose reductase. Because sorbitol does not easily cross cell membranes, it accumulates inside certain cells resulting in changes in osmotic pressure, alterations in the redox state of pyridine nucleotides (i.e. increased NADH/NAD+ ratio) and depleted intracellular levels of myoinositol. These biochemical changes, which have been linked to diabetic complications, can be controlled by inhibitors of aldose reductase.

The use of aldose reductase inhibitors for the treatment of diabetic complications has been extensively reviewed, see: (a) Textbook of Diabetes, 2nd ed.; Pickup, J. C. and Williams, G. (Eds.); Blackwell Science, Boston, Mass. 1997; (b) Larson, E. R.; Lipinski, C. A. and Sarges, R., Medicinal Research Reviews, 1988, 8 (2), 159-198; (c) Dvornik, D. Aldose Reductase Inhibition. Porte, D. (ed), Biomedical Information Corp., New York, N.Y. Mc Graw Hill 1987; (d) Petrash, J. M., Tarle, I., Wilson, D. K. Quiocho. F. A. Perspectives in Diabetes, Aldose Reductase Catalysis and Crystalography: Insights From Recent Advances in Enzyme Structure and Function, Diabetes, 1994, 43, 955; (e) Aotsuka, T.; Abe, N.; Fukushima, K.; Ashizawa, N. and Yoshida, M., Bioorg. & Med. Chem. Letters, 1997, 7, 1677, (f), T., Nagaki, Y.; Ishii, A.; Konishi, Y.; Yago, H; Seishi, S.; Okukado, N.; Okamoto, K., J. Med. Chem., 1997, 40, 684; (g) Ashizawa, N.; Yoshida, M.; Sugiyama, Y.; Akaike, N.; Ohbayashi, S.; Aotsuka, T.; Abe, N.; Fukushima, K.; Matsuura, A, Jpn. J. Pharmacol. 1997, 73, 133; (h) Kador, P. F.; Sharpless, N. E., Molecular Pharmacology, 1983, 24, 521; (I) Kador, P. F.; Kinoshita, J. H.; Sharpless, N. E., J. Med. Chem. 1985, 28 (7), 841; (j) Hotta, N., Biomed. & Pharmacother. 1995, 5, 232; (k) Mylar, B.; Larson, E. R.; Beyer, T. A.; Zembrowski, W. J.; Aldinger, C. E.; Dee, F. D.; Siegel, T. W.; Singleton, D. H., J. Med. Chem. 1991, 34, 108; (l) Dvornik, D. Croatica Chemica Acta 1996, 69 (2), 613.

Previously described aldose reductase inhibitors most closely related to the present invention include those sighted in: (a) U.S. Pat. No. 5,700,819: 2-Substituted benzothiazole derivatives useful in the treatment of diabetic complications, (b) U.S. Pat. No. 4,868,301: Processes and intermediates for the preparation of oxophthalazinyl acetic acids having benzothiazole or other heterocyclic side chains, (c) U.S. Pat. No. 5,330,997: 1H-indazole-3-acetic acids as aldose reductase inhibitors, and (d) U.S. Pat. No. 5,236,945: 1H-indazole-3-acetic acids as aldose reductase inhibitors. Although many aldose reductase inhibitors have been extensively developed, none have demonstrated sufficient efficacy in human clinical trials without significant undesirable side effects. Thus no aldose reductase inhibitors are currently available as approved therapeutic agents in the United States; and consequently, there is still a significant need for new, efficacious and safe medications for the treatment of diabetic complications.

SUMMARY

OF THE INVENTION

This invention provides compounds that interact with and inhibit aldose reductase. Thus, in a broad aspect, the invention provides compounds of Formula I:

or pharmaceutically acceptable salts thereof wherein A is a C1-C4 alkylene group optionally substituted with C1-C2 alkyl or mono- or disubstituted with halogen, preferably fluoro or chloro; Z is a bond, O, S, C(O)NH, or C1-C3 alkylene optionally substituted with C1-C2 alkyl; R1 is hydrogen, alkyl having 1-6 carbon atoms, halogen, 2-, 3-, or 4-pyridyl, or phenyl, where the phenyl or pyridyl is optionally substituted with up to three groups selected from halogen, hydroxy, C1-C6 alkoxy, C1-C6 alkyl, nitro, amino, or mono- or di(C1-C6)alkylamino; R2, R3, R4 and R5 are each independently hydrogen, halogen, nitro, or an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens); OR7, SR7, S(O)R7, S(O)2(R7)2, C(O)N(R7)2, or N(R7)2, wherein each R7 is independently hydrogen, an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens) or benzyl, where the phenyl portion is optionally substituted with up to three groups independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, and mono- or di(C1-C6)alkylamino; phenyl or heteroaryl such as 2-, 3- or 4-imidazolyl or 2-, 3-, or 4-pyridyl, each of which phenyl or heteroaryl is optionally substituted with up to three groups independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, and mono- or di(C1-C6)alkylamino; phenoxy where the phenyl portion is optionally substituted with up to three groups independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, and mono- or di(C1-C6)alkylamino; or a group of the formula

where J is a bond, CH2, oxygen, or nitrogen; and each r is independently 2 or 3; R6 is hydroxy or a prodrug group; Ra is hydrogen, C1-C6 alkyl, fluoro, or trifluoromethyl; and Ar represents aryl or heteroaryl, each of which is optionally substituted with up to five groups.

In another aspect, the invention provides methods for preparing such compounds.

The compounds of the invention inhibit aldose reductase. Since aldose reductase is critical to the production of high levels of sorbitol in individuals with diabetes, inhibitors of aldose reductase are useful in preventing and/or treating various complications associated with diabetes. The compounds of the invention are therefore effective for the treatment of diabetic complications as a result of their ability to inhibit aldose reductase.

Thus, in another aspect, the invention provides methods for treating and/or preventing chronic complications associated with diabetes mellitus, including, for example, diabetic cataracts, retinopathy, nephropathy, and neuropathy.

In still another aspect, the invention provides pharmaceutical compositions containing compounds of Formula I.

DETAILED DESCRIPTION

OF THE INVENTION

The numbering system for the compounds of Formula I is as follows:

As noted above, the invention provides novel substituted indole alkanoic acids useful in treating and/or preventing complications associated with or arising from elevated levels of glucose in individuals suffering from diabetes mellitus. These compounds are represented by Formula I above.

In compounds of Formula I, the aryl and heteroaryl groups represented by Ar include: a phenyl group optionally substituted with up to 5 groups independently selected from halogen, an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens), nitro, OR7, SR7, S(O)R7, S(O)2R7 or N(R7)2 wherein R7 is hydrogen, an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens) or benzyl, where the phenyl portion is optionally substituted with up to three groups independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, and mono- or di(C1-C6)alkylamino, or the phenyl group may be condensed with benzo where the benzo is optionally substituted with one or two of halogen, cyano, nitro, trifluoromethyl, perfluoroethyl, trifluoroacetyl, or (C1-C6)alkanoyl, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, trifluoromethoxy, trifluoromethylthio, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl; a heterocyclic 5-membered ring having one nitrogen, oxygen or sulfur, two nitrogens one of which may be replaced by oxygen or sulfur, or three nitrogens one of which may be replaced by oxygen or sulfur, said heterocyclic 5-membered ring substituted by one or two fluoro, chloro, (C1-C6)alkyl or phenyl, or condensed with benzo, or substituted by one of pyridyl, furyl or thienyl, said phenyl or benzo optionally substituted by one of iodo, cyano, nitro, perfluoroethyl, trifluoroacetyl, or (C1-C6)alkanoyl, one or two of fluoro, chloro, bromo, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, trifluoromethoxy, trifluoromethylthio, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl or trifluoromethyl, or two fluoro or two trifluoromethyl with one hydroxy or one (C1-C6)alkoxy, or one or, preferably, two fluoro and one trifluoromethyl, or three fluoro, said pyridyl, furyl or thienyl optionally substituted in the 3-position by fluoro, chloro, bromo, (C1-C6)alkyl or (C1-C6)alkoxy; a heterocyclic 6-membered ring having one to three nitrogen atoms, or one or two nitrogen atoms and one oxygen or sulfur, said heterocyclic 6-membered ring substituted by one or two (C1-C6)alkyl or phenyl, or condensed with benzo, or substituted by one of pyridyl, furyl or thienyl, said phenyl or benzo optionally substituted by one of iodo or trifluoromethylthio, or one or two of fluoro, chloro, bromo, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl, or trifluoromethyl, and said pyridyl, furyl or thienyl optionally substituted in the 3-position by fluoro, chloro, (C1-C6)alkyl or (C1-C6)alkoxy; said benzo-condensed heterocyclic 5-membered or 6-membered rings optionally substituted in the heterocyclic 5-membered or 6-membered ring by one of fluoro, chloro, bromo, methoxy, or trifluoromethyl; oxazole or thiazole condensed with a 6-membered aromatic group containing one or two nitrogen atoms, with thiophene or with furane, each optionally substituted by one of fluoro, chloro, bromo, trifluoromethyl, methylthio or methylsulfinyl; imidazolopyridine or triazolopyridine optionally substituted by one of trifluoromethyl, trifluoromethylthio, bromo, or (C1-C6)alkoxy, or two of fluoro or chloro; thienothiophene or thienofuran optionally substituted by one of fluoro, chloro or trifluoromethyl; thienotriazole optionally substituted by one of chloro or trifluoromethyl; naphthothiazole; naphthoxazole; or thienoisothiazole.

More specific compounds of the invention are those of Formula I wherein Ar is optionally substituted benzothiazolyl, benzoxazolyl, isoquinolyl, benzothiophen-yl, benzofuran-yl or benzimidazolyl, or substituted oxadiazolyl or indolyl. Other more specific compounds are of Formula I those wherein Ra is trifluoromethyl, Z is a covalent bond or CH2, R6 is hydroxy, and each of R2-R5 are independently hydrogen, halogen, more preferably bromo or chloro, C1-C2 alkyl, phenoxy, benzyloxy, or C1-C2 alkoxy, and R1 is hydrogen or methyl.

Preferred compounds of the invention are those wherein Z is a covalent bond, R6 is hydroxy, Ar is optionally substituted benzothiazol-2-yl, benzothiazol-5-yl, benzoisothiazol-3-yl, benzoxazol-2-yl, 2-quinolyl, 2-quinoxalyl, oxazolo[4,5-b]pyridine-2-yl, benzothiophen-2-yl, benzofuran-2-yl, or thazolo[4,5-pyridine-2-y, thieno[2,3-b]pyridine-2-yl, imidazo[1,5-a]pyridine-2-yl, or indol-2-yl, or substituted 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, isothiazol-5-yl, isothiazol-4-yl, 1,3,4-oxadiazol-5-yl, 1,2,5-thiadiazol-3-yl, oxazol-2-yl, thiazol-2-yl, or thiazol-4-yl, R2-R5 are independently hydrogen, halogen, more preferably bromo or chloro, C1-C2 alkyl, phenoxy, benzyloxy or phenyl where each phenyl portion is optionally substituted with C1-C6 alkyl, halogen, C1-C6 alkoxy, hydroxy, amino or mono- or di(C1-C6)alkylamino Ra is hydrogen, fluoro or C1-C2 alkyl, and R1 is hydrogen or methyl.

Other preferred compounds are those wherein the methylene bridge connecting the indolyl group with Ar is located alpha with respect to a nitrogen atom in Ar, e.g. wherein Ar is benzoxazol-2-yl or 1,2,4-oxadiazol-3-yl mentioned above.

Other more specific compounds of the invention are those wherein Z is a covalent bond, R6 is hydroxy, Ra is hydrogen, Ar is optionally 4,5,6 or 7 benzo-substituted benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, or indolyl, or Ar is 2-benzothiazolyl substituted on benzo by one trifluoroacetyl or trifluoromethylthio, or one or two of fluoro chloro, bromo, hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, or one or, preferably, two fluoro and one trifluoromethyl, or two fluoro or two trifluoromethyl with one methoxy, or three fluoro, or by 6,7-benzo, and those wherein one of R2 and R3 is hydrogen, fluoro, chloro, bromo or methyl, and one of R4 and R5 is hydrogen, or chloro, bromo, methyl, isopropyl, methoxy, nitro or trifluoromethyl; or R3 and R4 is 5,6-difluoro, Ra is hydrogen; and those wherein Ar is optionally substituted benzothiazol-2-yl or quinoxalyl and R3 and R4 are each chloro, and R1 is hydrogen or methyl.

Further more specific compounds are those wherein Z is a covalent bond, R6 is hydroxy, Ar is optionally substituted benzothiazol-2-yl, R3 and R4 are hydrogen, and R5 is methyl; those wherein Z is a covalent bond, R6 is hydroxy, R3, R4 and R5 are hydrogen, chloro, fluoro, bromo or C1-C2 alkyl, Ra is hydrogen, and Ar is optionally 4,5,6 or 7 benzosubstituted benzothiazolyl-2-trifluoromethyl, benzoxazolyl-2-trifluoromethyl, benzimidazolyl-2-trifluoromethyl, benzofuran-2-trifluoromethyl, benzofuran-3-trifluoromethyl, benzothiophen-2-trifluoromethyl, benzothiophen-3-trifluoromethyl, indolyl-2-trifluoromethyl, or indolyl-3-trifluoromethyl; and those wherein Z is CH2, R6 is hydroxy, Ar is optionally substituted benzothiazol-2-yl, benzothiazol-5-yl, benzoisothiazol-3-yl, benzoxazol-2-yl, 2-quinolyl, 2-quinoxalyl, oxazolo[4,5-b]pyridine-2-yl, or thiazolo[4,5-b]pyridine-2-yl, or substituted 1,2,4-oxadiazol3-yl, 1,2,4-oxadiazol-5-yl, isothiazol-5-yl, isothiazol-4-yl, 1,3,4-oxadiazol-5-yl, 1,2,5-thiadiazol-3-yl, oxazol-2-yl, thiazol-2-yl, or thiazol-4-yl, and R3, R4 and R5 are independently hydrogen, chloro, fluoro, bromo, C2-C2 alkyl, or trifluoromethyl, and Ra is hydrogen.

Generally, R1 in the specific compounds described above is hydrogen, halogen, preferably chloro or fluoro, C1-C6 alkyl, or phenyl optionally substituted with up to three groups independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, and mono- or di(C1-C6)alkylamino. Preferred R1 groups are hydrogen and methyl.

Preferred compounds of the invention include those where Ar in Formula I is substituted phenyl, i.e., compounds of Formula II:

wherein A is a C1-C4 alkylene group optionally substituted with C1-C2 alkyl; Z is a bond, or C1-C3 alkylene optionally substituted with C1-C2 alkyl; Ra is hydrogen, C1-C6 alkyl, chloro, bromo, fluoro, or trifluoromethyl; R1 is hydrogen, C1-C6 alkyl, fluoro, or phenyl optionally substituted with up to three groups independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, and mono- or di(C1-C6)alkylamino; R2, R3, R4 and R5 are each independently hydrogen, halogen, an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens), nitro, OR7, SR7, S(O)R7, S(O)2N(R7)2, C(O)N(R7)2, or N(R7)2, wherein each R7 is independently hydrogen, an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens) or benzyl, where the phenyl portion is optionally substituted with up to three groups independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, and mono- or di(C1-C6)alkylamino; phenyl or heteroaryl such as 2-, 3- or 4-imidazolyl or 2-, 3-, or 4-pyridyl, each of which phenyl or heteroaryl is optionally substituted with up to three groups independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, and mono- or di(C1-C6)alkylamino; phenoxy where the phenyl portion is optionally substituted with up to three groups independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, and mono- or di(C1-C6)alkylamino; or a group of the formula



Download full PDF for full patent description/claims.

Advertise on FreshPatents.com - Rates & Info


You can also Monitor Keywords and Search for tracking patents relating to this Substituted indolealkanoic acids patent application.
###
monitor keywords

Keyword Monitor How KEYWORD MONITOR works... a FREE service from FreshPatents
1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored.
3. Each week you receive an email with patent applications related to your keywords.  
Start now! - Receive info on patent apps like Substituted indolealkanoic acids or other areas of interest.
###


Previous Patent Application:
Pharmaceutical containing ppar-delta agonist
Next Patent Application:
Composition and method for controlling plant diseases
Industry Class:
Drug, bio-affecting and body treating compositions
Thank you for viewing the Substituted indolealkanoic acids patent info.
- - - Apple patents, Boeing patents, Google patents, IBM patents, Jabil patents, Coca Cola patents, Motorola patents

Results in 0.78154 seconds


Other interesting Freshpatents.com categories:
Amazon , Microsoft , IBM , Boeing Facebook

###

Data source: patent applications published in the public domain by the United States Patent and Trademark Office (USPTO). Information published here is for research/educational purposes only. FreshPatents is not affiliated with the USPTO, assignee companies, inventors, law firms or other assignees. Patent applications, documents and images may contain trademarks of the respective companies/authors. FreshPatents is not responsible for the accuracy, validity or otherwise contents of these public document patent application filings. When possible a complete PDF is provided, however, in some cases the presented document/images is an abstract or sampling of the full patent application for display purposes. FreshPatents.com Terms/Support
-g2-0.262
Key IP Translations - Patent Translations

     SHARE
  
           

stats Patent Info
Application #
US 20120270912 A1
Publish Date
10/25/2012
Document #
13534875
File Date
06/27/2012
USPTO Class
514367
Other USPTO Classes
548159, 548510, 514415
International Class
/
Drawings
0


Your Message Here(14K)



Follow us on Twitter
twitter icon@FreshPatents



Drug, Bio-affecting And Body Treating Compositions   Designated Organic Active Ingredient Containing (doai)   Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai   Five-membered Hetero Ring Containing At Least One Nitrogen Ring Atom (e.g., 1,2,3-triazoles, Etc.)   1,3,4-thiadiazoles (including Hydrogenated)   Polycyclo Ring System Having The Thiazole Ring As One Of The Cyclos   Bicyclo Ring System Having The Thiazole Ring As One Of The Cyclos