Patent
Phenazine derivatives and uses thereof as potassium channel modulators
| العنوان: | Phenazine derivatives and uses thereof as potassium channel modulators |
|---|---|
| Patent Number: | 8,669,257 |
| تاريخ النشر: | March 11, 2014 |
| Appl. No: | 12/729083 |
| Application Filed: | March 22, 2010 |
| مستخلص: | The present invention provides compounds of Formula I: [chemical expression included] or a pharmaceutically acceptable salt thereof, wherein each of W, Q, R1, R2, R3, R4, R5, m, and n is as defined herein, pharmaceutically acceptable compositions thereof, and methods of using the same. |
| Inventors: | Liu, Jun O. (Clarksville, MD, US); Ren, Yunzhao (Timonium, MD, US); Pan, Fan (Baltimore, MD, US); Chong, Curtis R. (Honolulu, HI, US); Penner, Reinhold (Honolulu, HI, US); Behr, Jonathan R. (Cambridge, MA, US) |
| Assignees: | The Johns Hopkins University (Baltimore, MD, US) |
| Claim: | 1. A method for treating or lessening the severity of a disorder in a patient, wherein the disorder is selected from the group consisting of multiple sclerosis, plaque psoriasis, rheumatoid psoriasis, and vitiligo, wherein said method comprises administering to said patient a pharmaceutical composition consisting essentially of an effective amount of a compound of formula I: [chemical expression included] or a pharmaceutically acceptable salt thereof, wherein: W is ═O, ═N—, or ═C(R)—; R 1 is absent if W is ═O; or if W is ═N—, then R 1 is an optionally substituted group selected from C 1-6 aliphatic, C 3-7 cycloaliphatic, a 6-10 membered monocyclic or bicyclic aromatic carbocyclic ring, or a 5-10 membered monocyclic or bicyclic saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or if W is ═C(R)—, then R 1 is hydrogen or an optionally substituted group selected from C 1-6 aliphatic, C 3-7 cycloaliphatic, a 6-10 membered monocyclic or bicyclic aromatic carbocyclic ring, or a 5-10 membered monocyclic or bicyclic saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Q is —O—, —S—, —C(R) 2 —, or —N(R)—; each R is independently hydrogen or an optionally substituted C 1-6 aliphatic group, or: two R groups on the same nitrogen are taken together with the nitrogen atom to form a 4-7 membered saturated, partially unsaturated, or aromatic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 2 is an optionally substituted group selected from C 3-7 cycloaliphatic, a 6-10 membered monocyclic or bicyclic aromatic carbocyclic ring, or a 5-10 membered monocyclic or bicyclic saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 3 is an optionally substituted group selected from C 3-7 cycloaliphatic, a 6-10 membered monocyclic or bicyclic aromatic carbocyclic ring, or a 5-10 membered monocyclic or bicyclic saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; n is 0, 1, 2, 3, or 4; each R 4 is independently selected from halogen, CN, R, OR, SR, N(R) 2 , C(O)R, C(O)OR, C(O)N(R) 2 , N(R)C(O)R, OC(O)R, SO 2 R, SO 2 N(R) 2 , N(R)SO 2 R, or N(R)C(O)N(R) 2 ; m is 0, 1 or 2; and each R 5 is independently selected from halogen, CN, R, OR, SR, or N(R) 2; wherein each optionally substituted group is independently optionally substituted with halogen; —(CH 2) 0-4 R ∘ ; —(CH 2) 0-4 OR ∘ ; —O(CH 2) 0-4 R ∘ , —O—(CH 2) 0-4 C(O)OR ∘ ; —(CH 2) 0-4 CH(OR ∘) 2 ; —(CH 2) 0-4 SR ∘ ; —(CH 2) 0-4 Ph, which may be substituted with R ∘ ; —(CH 2) 0-4 O(CH 2) 0-1 Ph which may be substituted with R ∘ ; —CH═CHPh, which may be substituted with R ∘ ; (CH 2) 0-4 O(CH 2) 0-1 -pyridyl which may be substituted with R ∘ ; —NO 2 ; —CN; —N 3 ; —(CH 2) 0-4 N(R ∘) 2 ; —(CH 2) 0-4 N(R ∘)C(O)R ∘ ; —N(R ∘)C(S)R ∘ ; —(CH 2) 0-4 N(R ∘)C(O)NR ∘ 2 ; —N(R ∘)C(S)NR ∘ 2 ; —(CH 2) 0-4 N(R ∘)C(O)OR ∘ ; —N(R ∘)N(R ∘)C(O)R ∘ ; —N(R ∘)N(R ∘)C(O)NR ∘ 2 ; —N(R ∘)N(R ∘)C(O)OR ∘ ; —(CH 2) 0-4 C(O)R ∘ ; —C(S)R ∘ ; —(CH 2) 0-4 C(O)OR ∘ ; —(CH 2) 0-4 C(O)SR ∘ ; —(CH 2) 0-4 C(O)OSiR ∘ 3 ; —(CH 2) 0-4 OC(O)R ∘ ; —OC(O)(CH 2) 0-4 SR—, SC(S)SR ∘ ;—(CH 2) 0-4 SC(O)R ∘ ; —(CH 2) 0-4 C(O)NR ∘ 2 ; —C(S)NR ∘ 2 ; —C(S)SR ∘ ; —SC(S)SR ∘ , —(CH 2) 0-4 OC(O)NR ∘ 2 ; —C(O)N(OR ∘)R ∘ ; —C(O)C(O)R ∘ ; —C(O)CH 2 C(O)R ∘ ; —C(NOR ∘)R ∘ ; —(CH 2) 0-4 SSR ∘ ; —(CH 2) 0-4 S(O) 2 R ∘ ; —(CH 2) 0-4 S(O) 2 OR ∘ ; —(CH 2) 0-4 OS(O) 2 R ∘ ; —S(O) 2 NR ∘ 2 ; —(CH 2) 0-4 S(O)R ∘ ; —N(R ∘)S(O) 2 NR ∘ 2 ; —N(R ∘)S(O) 2 R ∘ ; —N(OR ∘)R ∘ ; —C(NH)NR ∘ 2 ;—P(O) 2 R ∘ ; —P(O)R ∘ 2 ; —OP(O)R ∘ 2 ; —OP(O)(OR ∘) 2 ; SiR ∘ 3 ; —(C 1-4 straight or branched alkylene)O—N(R ∘ 2 ; or —(C 1-4 straight or branched alkylene)C(O)O—N(R ∘ 2 , wherein each R ∘ may be substituted as defined below and is independently hydrogen, C 1-6 aliphatic, —CH 2 Ph, —O(CH 2) 0-1 Ph, —CH 2 —(5-6membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two independent occurrences of R ∘ , taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below; or each saturated carbon atom of an optionally substituted group is independently optionally substituted with ═O, ═S, ═NNR* 2 , ═NNHC(O)R* , ═NNHC(O)OR* , ═NNHS(O) 2 R* , ═NR* , ═NOR* , —O(C(R* 2)) 2-3 O, or S(C(R* 2)) 2-3 S—, wherein each independent occurrence of R* is selected from hydrogen, C 1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6 -membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: —O(CR* 2) 2-3 O—, wherein each independent occurrence of R* is selected from hydrogen, C 1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6 -membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur; R ∘ (or the ring formed by taking two independent occurrences of R ∘ together with their intervening atoms), is independently optionally substituted with halogen, —(CH 2) 0-2 R ● , (haloR ●), —(CH 2) 0-2 OH, —(CH 2) 0-2 OR ● , —(CH 2) 0-2 CH(OR ●) 2 ; —O(haloR ●), —CN, —N 3 , —(CH 2) 0-2 C(O)R ● ,—(CH 2) 0-2 C(O)OH, —(CH 2) 0-2 C(O)OR ● , —(CH 2) 0-2 SR ● , —(CH 2) 0-2 SH, —(CH 2) 0-2 NH 2 , —(CH 2) 0-2 NHR ● , —(CH 2) 0-2 NR ● 2 , —NO 2 , -SiR ● 3 , -OSiR ● 3 , —C(O)SR ● , —(C 1-4 straight or branched alkylene) C(O)OR ● , or —SSR ● wherein each R ● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C 1-4 aliphatic, —CH 2 Ph, —O(CH 2) 0-1 Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or a saturated carbon atom of R ∘ is optionally substituted with ═O or ═S; each R* is independently optionally substituted with halogen, —R ● , -(haloR ●), —OH, —OR ● , —O(haloR ●), —CN, —C(O)OH, —C(O)OR ● , —NH 2 , —NHR ● , —NR ● 2 , or —NO 2 , wherein each R ● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1-4 aliphatic, —CH 2 Ph, —O(CH 2) 0-1 Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each substitutable nitrogen of an optionally substituted group is independently optionally substituted with —R † , —NR † 2 , —C(O)R † , —C(O)OR † , —C(O)C(O)R † , —C(O)CH 2 C(O)R † , —S(O) 2 R † , —S(O) 2 NR † 2 , —C(S)NR † 2 , —C(NH)NR † 2 , or —N(R †)S(O) 2 R † ; wherein each R † is independently hydrogen, C 1-6 aliphatic which may be substituted as defined below, unsubstituted —OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R † , taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and each R † is independently optionally substituted with halogen, —R ● , -(haloR ●),—OH, —OR ● , —O(haloR ●), —CN, —C(O)OH, —C(O)OR ● , —NH 2 , —NHR ● , —NR ● 2 , or —NO 2 , wherein each R ● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1-4 aliphatic, —CH 2 Ph, —O(CH 2) 0-1 Ph, or a 5-6 -membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and a pharmaceutically acceptable carrier. |
| Claim: | 2. The method according to claim 1 , wherein said compound is selected from the group consisting of formula I-a, formula I-b, formula I-c and formula I-d: [chemical expression included] or a pharmaceutically acceptable salt thereof. |
| Claim: | 3. The method according to claim 1 , wherein said compound is administered in one or more loading doses followed by one or more maintenance doses, wherein said one or more maintenance doses comprise less compound than said one or more loading doses. |
| Claim: | 4. The method of claim 1 , wherein the disorder is multiple sclerosis. |
| Claim: | 5. The method of claim 1 , wherein the disorder is plaque psoriasis, rheumatoid psoriasis, or vitiligo. |
| Claim: | 6. The method of claim 1 , wherein the compound is clofazimine. |
| Claim: | 7. The method according to claim 1 , wherein said compound is selected from the group consisting of: [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] or a pharmaceutically acceptable salt thereof. |
| Claim: | 8. The method according to claim 7 , wherein said compound is compound I-1, or a pharmaceutically acceptable salt thereof. |
| Current U.S. Class: | 514/250 |
| Patent References Cited: | 2948726 August 1960 Barry et al. 5763443 June 1998 Medlen et al. 2002/0006403 January 2002 Yu et al. |
| Other References: | Jordan, V. C. Nature Reviews: Drug Discovery, 2, 2003, 205. cited by examiner Hackam, et al. JAMA, 296(14), 2006, 1731-1732. cited by examiner Anderson R, et al. “Clofazimine and B669 inhibit the proliferative responses and Na+, K(+)-adenosine triphosphatase activity of human lymphocytes by a lysophospholipid-dependent mechanism.” Biochem Pharmacol. Dec. 3, 1993;46(11):2029-2038. cited by applicant Lee SJ, et al. “Treatment of chronic graft-versus-host disease with clofazimine.” Blood. Apr. 1, 1997;89(7):2298-2302. cited by applicant Bezerra EL, et al. “Double-blind, randomized, controlled clinical trial of clofazimine compared with chloroquine in patients with systemic lupus erythematosus.” Arthritis Rheum. Oct. 2005;52(10):3073-3078. cited by applicant Arbiser JL, et al. “Clofazimine: A Review of Its Medical Uses and Mechanisms of Action”. J Am Acad Dermatol. Feb. 1995;32(2 Pt 1):241-247. cited by applicant Reddy VM, et al. “Antimycobacterial activities of riminophenazines” J Antimicrobial Chem. May 1999; 43(5):615-623. cited by applicant O'Sullivan JF, et al. “Clofazimine analogues active against a clofazimine-resistant organism” J Med Chem. Mar. 1988;31(3):567-72. cited by applicant Twomey D, et al. “Some novel halogenated phenazine derivatives” J Heterocyclic Chem. 1986 US; 23(2):615-620. cited by applicant Ren YR, et al. “Clofazimine Inhibits Human Kv1.3 Potassium Channel by Perturbing Calcium Oscillation in T Lymphocytes” PloS One. Dec. 2008;3(12). cited by applicant |
| Primary Examiner: | Willis, Douglas M |
| Attorney, Agent or Firm: | Edwards Wildman Palmer LLP Corless, Peter F. |
| رقم الانضمام: | edspgr.08669257 |
| قاعدة البيانات: | USPTO Patent Grants |
| الوصف غير متاح. |