Management of ophthalmologic disorders, including macular degeneration

• US 20060069078A1
• Filed: 08/08/2005
• Published: 03/30/2006
• Est. Priority Date: 02/17/2004
• Status: Active Grant

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Rando, Robert R.
• Granted Patent: US 7,566,808 B2
• Time in Patent Office: Days
• US Class Current: 514/183
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: C07B 2200/09 Geometrical isomers
• CPC Class Codes: C07C 211/45 Monoamines
• CPC Class Codes: C07C 217/86 to an acyclic carbon atom of a hydrocarbon radical containing six-membered aromatic rings
• CPC Class Codes: C07C 229/56 with amino and carboxyl groups bound in ortho-position
• CPC Class Codes: C07C 229/60 with amino and carboxyl groups bound in meta- or para- positions
• CPC Class Codes: C07C 233/05 having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 233/09 with carbon atoms of carboxamide groups bound to carbon atoms of an acyclic unsaturated carbon skeleton
• CPC Class Codes: C07C 233/25 having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 243/38 with acylating carboxyl groups bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 251/40 to carbon atoms of an unsaturated carbon skeleton
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2601/16 the ring being unsaturated
• CPC Class Codes: C07C 403/08 by hydroxy groups
• CPC Class Codes: C07C 403/10 by etherified hydroxy groups
• CPC Class Codes: C07C 403/12 by esterified hydroxy groups
• CPC Class Codes: C07C 403/16 not being part of —CHO groups
• CPC Class Codes: C07C 403/18 having side-chains substituted by nitrogen atoms
• CPC Class Codes: C07C 403/20 having side-chains substituted by carboxyl groups or halides, anhydrides, or (thio)esters thereof
• CPC Class Codes: C07C 43/15 containing only non-aromatic carbon-to-carbon double bonds
• CPC Class Codes: C07C 43/162 : containing rings other than six-membered aromatic rings
• CPC Class Codes: C07C 45/68 : by increase in the number of carbon atoms
• CPC Class Codes: C07C 49/203 : with only carbon-to-carbon double bonds as unsaturation
• CPC Class Codes: C07C 57/26 : containing rings other than six-membered aromatic rings
• CPC Class Codes: C07C 69/24 : esterified with monohydroxylic compounds
• CPC Class Codes: C07D 203/08 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 303/08 : with hydrocarbon radicals, substituted by halogen atoms, nitro radicals or nitroso radicals

Abstract

A drug may be used in the preparation of a medicament for the treatment or prevention of an ophthalmologic disorder, wherein the drug inihibits, antagonizes, or short-circuits the visual cycle at a step of the visual cycle that occurs outside a disc of a rod photoreceptor cell.

Claims

1-50. -50. (canceled)

51. A compound of formula I:

52. The compound of claim 51, wherein said compound is represented by formula Ia, Ib, Ic or Id:

65. The compound of claim 51, wherein said compound is represented by formula Ie, If, Ig, or Ih:

81. The compound of claim 51, wherein said compound is represented by IIa, IIb, IIc, or IId:

94. The compound of claim 51, wherein said compound is represented by IIe, IIf, IIg, or IIh:

112. The compound of claim 51, wherein said compound is represented by IIIa, IIIb, IIIc or IIId:

124. The compound of claim 51, wherein said compound is represented by IIIe, IIIf, IIIg, or IIIh:

282. A formulation comprising a compound defined by claim 51 and a second compound, different from the first compound, also as defined by claim 51.

296. A method for treating or preventing an ophthalmologic disease in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 51.

299. The method of claim 296, wherein the disease is macular degeneration or Stargardt'"'"'s disease.

53-64. -64. (canceled)

66-80. -80. (canceled)

82-93. -93. (canceled)

95-111. -111. (canceled)

113-123. -123. (canceled)

125-135. -135. (canceled)

136. A compound of formula IV:

199. The compound of claim 136, wherein said compound is represented by formula VIa or VIb:

203. The compound of claim 136, wherein said compound is represented by formula VIc, VId or VIe:

217. The compound of claim 136, wherein L has the formula VIIa:

218. The compound of claim 136, wherein said compound is represented by formula VIIb:

219. The compound of claim 136, wherein said compound is represented by formula VIIc:

223. The compound of claim 136, wherein said compound is represented by formula VIId:

227. The compound of claim 136, wherein said compound is represented by formula VIIe:

231. The compound of claim 136, wherein said compound is represented by formula VIIf:

297. A method for treating or preventing an ophthalmologic disease in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 136.

137-198. -198. (canceled)

200-202. -202. (canceled)

204-216. -216. (canceled)

220-222. -222. (canceled)

224-226. -226. (canceled)

228-230. -230. (canceled)

232-243. -243. (canceled)

244. A compound of formula VIII:

298. A method for treating or preventing an ophthalmologic disease in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 244.

245-261. -261. (canceled)

263-269. -269. (canceled)

271-281. -281. (canceled)

283. A method of identifying a drug for treating or preventing an ophthalmologic disorder, comprising:

administering a candidate drug to a subject having, or at risk for developing, the ophthalmologic disorder; and

measuring accumulation of a retinotoxic compound in the retinal pigment epithelium (RPE) of the subject;

wherein accumulation of the retinotoxic compound in the RPE in the presence of the candidate drug relative to the absence of the candidate drug indicates that the candidate drug is a drug for treating or preventing the ophthalmologic disorder.

285. The method of claim 283, wherein the ophthalmologic disorder comprises macular degeneration or Stargardt'"'"'s disease.

295. A method of identifying an agent for treating or preventing an ophthalmologic disorder, comprising performing at least two of the following assays:

(i) contacting an enzyme of the visual cycle with a test agent and determining whether the test agent binds to the enzyme of the visual cycle;

(ii) contacting retinal pigment epithelial membranes with a test agent and determining whether the test agent interferes with the visual cycle processing;

(iii) administering a test agent to an animal under dim light conditions;

keeping the animal in dim light conditions for an amount of time;

exposing the animal to bleaching light; and

conducting an in vivo b-wave corneal electroretinogram;

(iv) administering a test agent to an animal;

keeping the animal in dim light conditions for an amount of time;

exposing the animal to bleaching light; and

determining the extents of rhodopsin regeneration; and

(v) the method of claim 283,

wherein a positive result obtained in at least two of the above assays indicate that the test agent is an agent for treating or preventing an ophthalmologic disorder.

284. A method of identifying a drug for treating or preventing an ophthalmologic disorder, comprising:

contacting one or more cells representing an in vitro model of the visual cycle with the candidate drug; and

measuring accumulation of a visual cycle intermediate product in at least one cell;

wherein accumulation of the intermediate product in the presence of the candidate drug relative to the absence of the candidate drug indicates that the candidate drug is a drug for treating or preventing the ophthalmologic disorder.

286-294. -294. (canceled)