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AU2017201162B2 - Compounds and methods of treating ocular disorders - Google Patents
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AU2017201162B2 - Compounds and methods of treating ocular disorders - Google Patents

Compounds and methods of treating ocular disorders Download PDF

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AU2017201162B2
AU2017201162B2 AU2017201162A AU2017201162A AU2017201162B2 AU 2017201162 B2 AU2017201162 B2 AU 2017201162B2 AU 2017201162 A AU2017201162 A AU 2017201162A AU 2017201162 A AU2017201162 A AU 2017201162A AU 2017201162 B2 AU2017201162 B2 AU 2017201162B2
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Prior art keywords
aminomethyl
acid
methyl
hexanoic acid
phenoxy
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AU2017201162A1 (en
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Marcin Golczak
Akiko Maeda
Krzysztof Palczewski
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Case Western Reserve University
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Case Western Reserve University
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Abstract

Abstract: A method of treating an ocular disorder in a subject associated with aberrant all-trans-retinal clearance in the retina, the method comprising administering to the subject a therapeutically effective amount of a primary amine compound of formula: wherein R1 is an aliphatic and/or aromatic compound; the primary amine compound upon administration to the subject forming a reversible Schiff-base with the all-trans-retinal or its metabolite in-chiding A2E and retinal dimer without adversely affecting normal retinoid cycle performance; the primary amine compound when administered to a Rdh8-'- Abca4-,- mouse increasing the optical coherence tomography score of the mouse to at least about 2.5 and increasing II-ds-retinal amount at least about 30% in comparison to untreated control animal, wherein the primary amine compound is not a local anesthetic, which includes an aromatic amine, that demonstrates sodium channel blockade when administered to the subject. 2218156v1

Description

The invention is further illustrated by the following example, which is not intended to limit the scope of the claims.
EXAMPLE 1
FORMATION OF SCHIFF BASE BETWEEN RETINAL AND SELECTED AMINES [00134] We tested 5 FDA approved drugs containing primary amino groups to determine if they react with the aldehyde group of all-z/'ms-RAI. to form conjugates (Schiff-base) under the physiological conditions of the eye. The five FDA approved drugs included Potaba,
Paser, Seromycin, Cuprimine, and Lyrica.
[00135] Formation of conjugates (Schiff-base) between retinal and primary amine compounds containing amino group (putative drugs) is the key mechanism to control
-692017201162 21 Feb 2017 all-trans-RAL levels in the retina and prevent retina degeneration. Stability of these conjugates is an important factor that can determine biological activity of the drugs. To standardize conditions of Schiff-base formation all reactions were performed in 90% ethanol in water buffered with 0.1 M phosphate buffer, pH 7.0. Stock solution of retinal was made up freshly in ethanol. Its final concentration was determined spectrophotometricaly at 380 nm (ε = 42,880). All procedures were earned out in the dark. Schiff base formation was initiated by addition of retinal stock solution to a 2 molar excess of tested amine dissolved in the reaction buffer. The reaction mixture was incubated for 1 h in room temperature. Steady-state rate of Schiff-base formation was obtained from absorbance changes at 380 and 440 nm (510 nm for aromatic amines) corresponding to free retinal and protonated Schiff base, respectively. To investigate stability of the given retinal conjugates a mixture of HPLC purified Schiff base of selected compound and phosphatidylocholine was dried down in SpeedVac. Then, Schiff-hase and lipids were overlaid with 0.1 M phosphate buffer and sonicated immediately to form liposomes. The samples were extracted with hexane following 30 min incubated in room temperature. The breakdown of Schiff-base was monitored by HPLC detection of free retinal extracted from the reaction mixture.
[00136] Figs. 3-5 illustrate UV/Vis spectra for the FDA approved drugs. FDA approved drugs that were active readily formed a Schiff base with all/ran.s-RAI. as evidenced by a substantial differential between spectra of unprotonated and protonated Schiff base.
Whereas, compounds that were inactive did not readily form a Schiff Base with all-trans-RAL and showed little differential in the spectra. Of the FDA approved drugs tested, Paser, Seromycin, and Lyrica readily formed stable Schiff-bases with all-Zrans-RAL. In contrast, Potaba and Curprimine did not readily form stable Schiff-bases with all-transRAL.
EXAMPLE 2 [00137] We tested 20 FDA approved drugs containing primary amino groups to determine if they react with the aldehyde group of all -//vw.s-RAl. to reduce its toxic levels in the eye after exposure to light and prevent its condensation into toxic conjugates. The FDA approved drugs included Flumadine, Nameda, Potaba, Dapsone, Paser, Luvox, Seromycin, Aminohippurate Sodium, Cuprimine, Januvia, Primaxin T.M., Prinivil, Sulfamylon, Lxforge, Stalevo, Sodium Diuril, Lyrica, Asacol, Tamiflu, or Rilutek. For these experiments, we used
-702017201162 21 Feb 2017
ABCA4 /RDI187 mice as models for Stargardt’s disease and AMD. We employed analytical methods for determining the pharmacodynamics and pharmacokinetics of candidate drags including: HPLC/MS/MS for analysis of retinoids and histological sections and OCT for assessment of retinal pathology. The relative amount of retinoids and their composition strongly correlates with the health status of the retina. FDA approved drags were determined effective in treating retinal degeneration if upon administration to ABCAfi' /RDllfi mice, the mice showed optical coherence tomography score of at least about 2.5 and the drag increased 1 l-r/.s-retinal amount at least about 30% in comparison to untreated control animal. Methodologies for performing the analysis on ABCAfi/RDflfi' mice is described below.
ANIMALS [00138] /ri/AYOnice were generated and genotyped as previously described in J. Biol. Chem. 280, 188-18832 (2005). Abcafi' mice also were generated by standard procedures (Ingenious Targeting, Inc., Stony Brook, NY). The targeting vector was constructed by replacing exon 1 with the neo cassette as described by Cell, 98 13-23 (1999). No Immunoreactivity against ABCA4 was detected in eye extracts from these mice by Immunocytochemistry or Immunoblottmg. Abcci4z mice were maintained with either pigmented 129Sv/Ev or C57BL/6 mixed backgrounds, and their siblings were used for most experiments. Rdh8'Abca4 ^ mice were established by crossbreeding Ahead' mice with Rdh8~'~ mice. Genotyping or mice was carried out by PCR with primers ABCR1 (5'gcccagtggtcgatctgtctagc-3') d ABCR2 (5'-cacaaaggccgctaggaccacg-3’) for wild type (WT) (619 bp) and A0 (5'-ccacagcacacatcagcatttctcc-3') and NI (5'-tgcgaggccagaggccacttgtgtagc3') for targeted deletion (455 bp). PCR products were cloned and sequenced to verify their identities. Rdh8'/'Abca4'/' mice were fertile and showed no obvious developmental abnormalities.
EXTRACTION AND HPLC ANALYSIS OF NON-POLAR RETINOIDS [00139] All experimental procedures related to extraction, derivatization, and separation of retinoids from dissected mouse eyes were carried out under dim red light. Two whole mouse eyes were homogenized in 1 ml of 50 mM phosphate buffer, pH 7.0, containing 50% ethanol and 10 mM NILOI I. Ice-cold methanol (1 ml) was added to the homogenates 20 min
-712017201162 21 Feb 2017 after incubation at room temperature (RT), non-polar retinoids were extracted twice with 4 ml of hexane. The organic phase was collected, dried down in a SpeedVac and re-solubilized in 0.3 ml of hexane. Three main classes of retinoids (retinyl esters, retinal oximes, and retinols) as well as their geometrical isomers was separated in single run by normal phase HPTC by using an Agilent Si, 5 pm, 4.5 x 250 mm column and a stepwise gradient of ethylacetate in hexane (0.5% for 15 min, and 6% for up to 60 min) at a flow rate of 1.4 ml/min (Fig. 6). Retinoids were detected at 325 nm (retinyl esters and retinols) and 350 nm (retinyl oximes) with a diode array detector. Those of interest were quantified based on the areas under their peaks calculated with the help of HP Chcmstation A.03.03 software and compared with areas calculated based on known amounts of synthetic standards plotted as a standard curve.
MASS SPECTROMETRY OF RETINOIDS [00140] A complementary technique, mass spectrometry, was used to detect, identify, and quantify retinoids and their derivatives in eye tissue. The conjugated polyene chain of retinoids contributes to relatively strong light absorption at UV and visible wavelengths.
Thus, absorbance spectra provided information about the number of conjugated double bonds. Moreover, slight differences in wavelengths of maximum absorbance and shapes of the spectra permitted precise identification of retinoid isomers. However, a limitation of this method is the low selectivity of its UV-Vis absorbance, which mandates carefully designed chromatographic conditions and precise identification of the compounds being analyzed.
This analysis can become especially challenging when multiple geometric isomers of retinoids at low abundance (less than 3 pmols/eye) or unidentified compounds are present. Thus, we used an alternative technique, mass spectrometry combined with high performance liquid chromatography (LC-MS) to address this issue. Mass spectra of retinoids was acquired by using a LXQ high throughput linear ion trap mass spectrometer (Thermo Scientific, Waltham, MA) connected with an Agilent 1100 HPLC system and interfaced with an atmospheric pressure chemical ionization (APCI) source. The APCI source in a positive ionization mode is chosen for LC-MS methodology because of its wide dynamic range and capacity to operate at the high flow rates required for HPLC retinoid separation. The greatest advantage of LC-MS is its sensitivity that reaches the limits of retinoid detection and quantification in the 10 to 50 fmol and 20 to 200 fmol ranges, respectively. Moreover, this
-722017201162 21 Feb 2017
LXQ instrument has capability to perform MSn analyses that provide definitive structural identification.
DETECTION AND QUANTIFICATION OF RETINAL AMINE CONDENSATION
PRODUCTS IN MOUSE EYE [00141] Eyes of mice treated with compounds containing primary amines were homogenized in Tris/HCl buffer, pH 9.0, in 50% methanol and extracted with hexane or ethyl acetate depending of the polarity, dried down and resuspended in acetonitrile. After centrifugation, extracted compounds in the supernatant were separated by reverse phase HPLC chromatography (Agilent Zorbax Eclipse XBD C18, 5 pm, 4.6 x 150 mm column) with a linear gradient of water in acetonitrile (50 - 100%) for 20 min at a fixed flow rate of 1.5 ml/rnin. Retinal conjugates were detected and identified with a LXQ mass spectrometer equipped with an APCI source. MS scans were recorded in a SIM mode for each individual compound (Fig. 7 M3). The identity of detected adducts will be confirmed based on their MS2 spectra. Amounts of retinal-amine conjugates will be quantified with the aid of isotopically labeled synthetic standards added prior to extraction.
ULTRA-HIGH RESOLUTION SPECTRAL-DOMAIN OPTICAL COHERENCE
TOMOGRAPHY (SD-OCT) IMAGING [00142] Although analytical and histological methods provide exhaustive characterization of retina, they cannot be performed in vivo. To reduce the number of sacrificed animals and time required for analysis, SD-OCT from Bioptigen (Research Triangle Park, NC) was employed for in vivo imaging of mouse retinas. Bioptigen OCT systems utilize a narrow single-mode beam from a wide bandwidth light source to probe the structure of retina at a higher resolution (2.0 pm) than normal OCT systems. Mice were anesthetized by intraperitoneal (IP) injection of 20 pl/g bw of 6 mg/ml ketamine and 0.44 mg/ml xylazine diluted with 10 mM sodium phosphate, pH 7.2, containing 100 mM NaCl. Pupils were dilated with 1% tropicamide. In vivo SD-OCT images were obtained from both eyes. Four pictures acquired in a B-scan mode were used to construct the final averaged images (Fig. 8). SD-OCT imaging enabled us to identify early pathological changes in the retina and monitor progression or amelioration/prevention of pathological lesions quantitatively under various therapeutic regimens in the same live animal at a resolution
2017201162 21 Feb 2017
-73comparable to that obtained by current histopathological methods that employ cross sections of the retina.
GRADING WITH OCT [00143] In vivo retinal structures of RdhE^Abcafo' mice arc imaged by SD-OCT 7 days after 10,000 lux illumination for 30 min at 4 weeks of age. Fig. 9 illustrates RdhA'Ahrafo mouse without light shows healthy retina, whereas light with 10,000 lux for 30 min cause severe retinal degeneration (left panel). Preventive effects of compounds in retinal morphology are indicated as OCT score (right panel).
Score 5: no retinal degeneration
Score 4: regional retinal degeneration (less than 1000 pm width)
Score 3: widely observed retinal degeneration (more than 1000 pm width) with reflection of ELM
Score 2: widely observed retinal degeneration (more than 1000 pm width) without reflection of ELM
Score 1: severe retinal degeneration without reflection from photoreceptors as well as light exposed RdhS'^Abcafo mice (see left panel)
RESULTS [00144] The following Table lists the OCT score and 11 cis-retinal area of ABCA47' /RDIIif treated with Flumadine, Nameda, Potaba, Dapsone, Paser, Luvox, Seromycin, Aminohippurate Sodium, Cuprimine, Januvia, Primaxin I.M., Prinivil, Sulfamylon, Exforge, Stalevo, Sodium Diuril, Lyrica, Asacol, Tamiflu, or Rilutek. As noted in the Table, ABCA4'f'/RDH8'/' mice treated with either Flumadine, Dapsone, Paser, Luvox, Seromycin, Januvia, Sulfamylon, Exforgc, Sodium Diuril, Lyrica, Asacol, or Rilutek had a optical coherence tomography score of at least about 2.5 and the drug increased 11 -cis-retinal amount at least about 30% in comparison to untreated control animal and were effective in treating retinal degeneration in the mice. It is noted that the three FDA approved drags that readily formed Schiff bases in Example 1 with all-iraras-RAL under simulated physiological conditions had a optical coherence tomography score of at least about 2.5, increased 1 l -cL-relinal amount at least about 30% in comparison to untreated control animal, and were effective in treating retinal degeneration in the mice. In contrast, the two FDA approved
-74drugs that did not readily formed Schiff bases in Example 1 with all-Zrans-RAL under simulated physiological conditions had an optical coherence tomography score below 2.5, did not increase 11-cA-retinal amount at least about 30% in comparison to untreated control animal, and were ineffective in treating retinal degeneration in the mice.
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TABLE
Score OCT llcRAL (area)
1 Flumadine >2.5 135.3
2 Nameda 1.7 97.6
3 Potaba 2.3 90.6
4 Dapsone >2.5 156.5
5 Paser >2.5 151.9
6 Luvox >2.5 175.5
7 Seromycin >2.5 159.9
8 Aminohippurate Sodium 1 109.4
9 Cuprimine 1.7 118.5
10 Januvia >2.5 126.8
11 Primaxin I.M. 1.7 108.1
12 Prinivil 2.0 132.7
13 Sulfamylon >2.5 166.1
14 Exforge >2.5 173.8
15 Stalcvo 1.3 86.7
16 Sodium Diuril >2.5 139.7
17 Lyric a >2.5 166.5
18 Asacol >2.5 140.2
19 Tamiflu 1.3 87.3
20 Rilutek >2.5 158.2
21 No Treatment 1 88.2

Claims (6)

1/9
Fig. 1
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1. A method of treating a retinal disorder associated with aberrant all-trans-retinal clearance in the retina in a subject, comprising administering to the subject a therapeutically effective amount of a primary amine compound comprising the formula:
2017201162 06 Jul2018
R2 r4 or a pharmaceutically acceptable salt thereof, wherein:
R2 is hydrogen or (Ci-Ce) straight or branched unsubstituted alkyl;
R3 is (Ci-C8) straight or branched unsubstituted alkyl or alkyl substituted with fluoro, (C2-C8) straight or branched alkenyl, (C3-C7) cycioaikyl, (C1-C6) alkoxy, -alkylcycloalkyl, alkylalkoxy, OH, -alkylphenyl, -alkylphenoxy, phenyl, or phenyl subsituted with fluor, chloro, or methoxy; and
R4 is hydrogen or (C1-C6) straight or branched unsubstituted alkyl.
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2. A method of treating a retinal disorder associated with aberrant all-trans-retinal clearance in the retina in a subject, comprising administering to the subject a therapeutically effective amount of a primary amine compound selected from the group consisting of: 3-Aminomethyl-5methylhexanoic acid; 3-Aminomethyl-5-methylheptanoic acid; 3-Aminomethyl-5-methyloctanoic acid; 3-Aminomethyl-5-methyl-nonanoic acid; 3-Aminomethyl-5-methyl-decanoic acid; 3-Aminomethyl-5-methyl-undecanoic acid; 3-Aminomethyl-5-methyl-dodecanoic acid; 3Aminomethyl-5-methyl-tridecanoic acid; 3-Aminomethyl-5-cyclopiOpyl-hexanoic acid; 3Aminomethyl-5-cyclobutyl-hexanoic acid; 3-Aminomethyl-5-cyclopentyl-hexanoic acid; 3Aminomethyl-5-cyclohexyl-hexanoic acid; 3-Aminomethyl-5-trifluoromethyl-hexanoic acid; 3Aminomethyl-5-phenyl-hexanoic acid; 3-Aminomethyl-5-(2-chloiOphenyl)-hexanoic acid; 3Aminomethyl-5-(3-chlorophenyl)-hexanoic acid; 3-Aminomethyl-5-(4-chlorophenyl)-hexanoic acid; 3-Aminomethyl-5-(2-methoxyphenyl)-hexanoic acid; 3-Aminomethyl-5-(3methoxyphenylj-hexanoic acid; 3-Aminomethyl-5-(4-methoxyphenyl)-hexanoic acid; 3Aminomethyl-5-(phenylmethyl)-hexanoic acid; (S)-3-(Aminomethyl)-5-methylhexanoic acid;
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-76(R)-3-(Aminomethyl)-5-methylhexanoic acid; (3R,4S)-3-Aminomethyl-4,5-dimethyl-hexanoic acid; 3-Aniinomethyl-4,5-dimethyl-hexanoic acid; (3R,4S)-3-Aminomethyl-4,5-dimethylhexanoic acid MP; (38,4S)-3-Aminomethyl-4,5-dimethyl-hexanoic acid; (3R,4R)-3Aminomethyl-4,5-dimethyl-hexanoic acid MP; 3-Aminomethyl-4-isopropyl-hexanoic acid; 3Aminomethyl-4-isopropyl-heptanoic acid; 3-Aminomethyl-4-isopropyl-octanoic acid; 3Aminomethyl-4-isopropyl-nonanoic acid; 3-Aminomethyl-4-isopropyl-decanoic acid; 3Aminomethyl-4-phenyl-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-5-methoxy-hexanoic acid; (3S,5S)-3-AminomethyP5-ethoxy-hexanoic acid; (3S,5S)-3-Aminomethyl-5-propoxyhexanoic acid; (3S,5S)-3-Aminomethyl-5-isopropoxy-hexanoic acid; (3S,5S)-3-Aminomethyl-5 tert-butoxy-hexanoic acid; (3S,5S)-3-Aminomethyl-5-fluoromethoxy-hexanoic acid; (3S,5S)-3Aminomethyl-5-(2-fluoro-ethoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(3,3,3-trifluoropropoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-phenoxy-hexanoic acid; (3S,5S)-3Aminomethyl-5-(4-chloro-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(3-chlorophenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(2-chloro-phenoxy)-hexanoic acid; (3S,5S)· 3-Aminomethyl-5-(4-fluoro-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(3-fluorophenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(2-fluoro-phenoxy)-hexanoic acid; (3S,5S)3-Aminomethyl-5-(4-methoxy-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(3-methoxyphenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(2-methoxy-phenoxy)-hexanoic acid;
(35.55) -3-Aminomethyl-5-(4-nitro-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(3-nitro phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(2-nitro-phenoxy)-hexanoic acid; (3S,5S)-3 Aminomethyl-6-hydroxy-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-methoxy-5methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-ethoxy-5-methyl-hexanoic acid; (3S,5S)-3Aminomethyl-5-methyl-6-propoxy-hexanoic acid; (3S,5S)-3-Aminomethyl-6-isopropoxy-5methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-tert-butoxy-5-methyl-hexanoic acid; (3S,5S)3-Aminomethyl-6-fluoromethoxy-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(2-fluoro ethoxy)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-6-(3,3,3-trifluoiO-propoxy)· hexanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-6-phenoxy-hexanoic acid; (3S,5S)-3Aminomethyl-6-(4-chloro-phenoxy)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(3chloro-phenoxy)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(2-chloro-phenoxy)-5methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(4-fluoro-phenoxy)-5-methyl-hexanoic acid;
(35.55) -3-Aminomethyl-6-(3-fluoro-phenoxy)-5-methyl-hexanoic acid; (3S,5S)-3179867765 vl
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-ΊΊ Aminomethyl-6-(2-fluoro-phenoxy)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(4methoxy-phenoxy)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(3-methoxy-phenoxy)-5methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(2-niethoxy-phenoxy)-5-methyl-hexanoic acid;
(35.55) -3-Aminomethyl-5-methyl 6-(4-trifluoromethyl-phenoxy)-hexanoic acid; (3S,5S)-3Aminomethyl-5-methyl 6-(3-trifluoromethyl-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl5-methyl 6-(2-trifluoromethyl-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-methyl 6-(4nitro-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-methyl 6-(3-nitro-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-methyl 6-(2-nitro-phenoxy)-hexanoic acid; (3S,5S)-3Aminomethyl-6-benzyloxy-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-7-hydroxy-5methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-7-methoxy-5-methyl-heptanoic acid; (3S,5S)-3Aminomethyl-7-ethoxy-5-methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-7-propoxyheptanoic acid; (3S,5S)-3-Aminomethyl-7-isopropoxy-5-methyl-heptanoic acid; (3S,5S)-3Aminomethyl-7-tert-butoxy-5-methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-7-fluoiOmethoxy5-methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-7-(2-fluoiO-ethoxy)-5-methyl-heptanoic acid;
(35.55) -3-Aminomethyl-5-methyl-7-(3,3,3-trifluoro-piOpoxy)-heptanoic acid; (3S,5S)-3Aminomethyl-7-benzyloxy-5-methyl-heptanoic acid; (38,5S)-3-Aminomethyl-5-methyl-7phenoxy-heptanoic acid; (3S,5S)-3-Aminomethyl-7-(4-chloiO-phenoxy)-5-methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-7-(3-chloro-phenoxy)-5-methyl-heptanoic acid; (3S,5S)-3Aminomethyl-7-(2-chloro-phenoxy)-5-methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-7-(4fluoro-phenoxy)-5-methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-7-(3-fluoro-phenoxy)-5methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-7-(2-fluoro-phenoxy)-5-methyl-heptanoic acid;
(35.55) -3-Aminomethyl-7-(4-methoxy-phenoxy)-5-methyl-heptanoic acid; (3S,5S)-3Aminomethyl-7-(3-methoxy-phenoxy)-5-methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-7-(2methoxy-phenoxy)-5-methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-7-(4trifluoromethyl-phenoxy)-heptanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-7-(3trifluoromethyl-phenoxy)-heptanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-7-(2trifluoromethyl-phenoxy)-heptanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-7-(4-nitrophenoxy)-heptanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-7-(3-nitro-phenoxy)-heptanoic acid;
(35.55) -3-Aminomethyl-5-methyl-7-(2-nitro-phenoxy)-heptanoic acid; (3S,5S)-3-Aminomethyl5-methyl-6-phenyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(4-chloiO-phenyl)-5-methylhexanoic acid; (3S,5S)-3-Aminomethyl-6-(3-chloro-phenyl)-5-methyl-hexanoic acid; (3S,5S)-3179867765vl
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-78Aminomethyl-6-(2-chloro-phenyl)-5-methyl-hexanoic acid; (3 S,5S)-3-Aminomethyl-6-(4methoxy-phenyl)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(3-methoxy-phenyl)-5methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(2-methoxy-phenyl)-5-methyl-hexanoic acid;
(3S,5S)-3-Aminomethyl-6-(4-fluoro-phenyl)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl6-(3-fluoro-phenyl)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(2-fluoro-phenyl)-5methyl-hexanoic acid; (3S,5R)-3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid; (3S,5R)-3Aminomethyl-7-(4-chloiO-phenyl)-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-7-(3chloro-phenyl)-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-7-(2-chloro-phenyl)-5-methylheptanoic acid; (3S,5R)-3-Aminomethyl-7-(4-methoxy-phenyl)-5-methyl-heptanoic acid;
(3S,5R)-3-Aminomethyl-7-(3-methoxy-phenyl)-5-methyl-heptanoic acid; (3 S,5R)-3Aminomethyl-7-(2-methoxy-phenyl)-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-7-(4fluoro-phenyl)-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-7-(3-fluoro-phenyl)-5-methylheptanoic acid; (3S,5R)-3-Aminomethyl-7-(2-fluoro-phenyl)-5-methyl-heptanoic acid; (3S,5R)3-Aminomethyl-5-methyl-oct-7-enoic acid; (3S,5R)-3-Aminomethyl-5-niethyl-non-8-enoic acid; (E)-(3S,5S)-3-Aminomethyl-5-methyl-oct-6-enoic acid; (Z)-(3S,5S)-3-Aminomethyl-5-methyloct-6-enoic acid; (Z)-(3S,5S)-3-Aminomethyl-5-niethyl-non-6-enoic acid; (E)-(3S,5S)-3Aminomethyl-5-methyl-non-6-enoic acid; (E)-(3S,5R)-3-Aminomethyl-5-methyl-non-7-enoic acid; (Z)-(3S,5R)-3-Aminomethyl-5-methyl-non-7-enoic acid; (Z)-(3S,5R)-3-Aminomethyl-5methyl-dec-7-enoic acid; (E)-(3S,5R)-3-Aminomethyl-5-methyl-undec-7-enoic acid; (3S,5S)-3Aminomethyl-5,6,6-trimethyl-heptanoic acid; (3S,5S)-3-Aminomethyl-5,6-dimethyl-heptanoic acid; (3S,5S)-3-Ammomethyl-5-cyclopropyl-hexanoic acid; (3S,5S)-3-Aminomethyl-5cyclobutyl-hexanoic acid; (3S,5S)-3-Aminomethyl-5-cyclopentyl-hexanoic acid; (3S,5S)-3Aminomethyl-5-cyclohexyl-hexanoic acid; (3S,5R)-3-AminomethyI-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-5-niethyl-octanoic acid; (3S,5R)-3-Aminomethyl-5-methyl-nonanoic acid; (3S,5R)-3-Aminomethyl-5-methyl-decanoic acid; (3S,5R)-3-Aminomethyl-5-methylundecanoic acid; (3S,5R)-3-Aminomethyl-5-methyl-dodecanoic acid; (3S,5R)-3-Aminomethyl5,9-dimethyl-decanoic acid; (3S,5R)-3-Aminomethyl-5,7-dimethyl-octanoic acid; (3S,5R)-3Aminomethyl-5,8-dimethyl-nonanoic acid; (3S,5R)-3-Aminomethyl-6-cyclopropyl-5-methylhexanoic acid; (3S,5R)-3-Aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid; (3S,5R)-3Aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid; (3S,5R)-3-Aminomethyl-6-cyclohexyl-5methyl-hexanoic acid; (3S,5R)-3-Aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;
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-79(3S,5R)-3-Aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-7cyclopentyl-5-niethyl-heptanoic acid; (3S,5R)-3-Aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-8-cyclopropyl-5-methyl-octanoic acid; (3S,5R)-3-Aminomethyl8-cyclobutyl-5-methyl-octanoic acid; (3S,5R)-3-Aminomethyl-8-cyclopentyl-5-methyl-octanoic acid; (3S,5R)-3-Aminomethyl-8-cyclohexyl-5-methyl-octanoic acid; (3S,5S)-3-Aminomethyl-6fluoro-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-7-fluoro-5-niethyl-heptanoic acid; (3S,5R)-3-Aminoniethyl-8-fluoro-5-methyl-octanoic acid; (3S,5R)-3-Aminomethyl-9-fluoro-5methyl-nonanoic acid; (3S,5S)-3-Aminomethyl-7,7,7-trifluoiO-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-8,8,8-trifluoro-5-methyl-octanoic acid; (3S,5R)-3-Aminomethyl-5methyl-8-phenyl-octanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-6-phenyl-hexanoic acid; (3S,5R)-3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid; and pharmaceutically acceptable salts thereof.
3. A method of treating a retinal disorder associated with aberrant all-trans-retinal clearance in the retina in a subject, comprising administering to the subject a therapeutically effective amount of a primary amine compound comprising the formula:
R2 R
4 or a pharmaceutically acceptable salt thereof, wherein:
R2 is hydrogen, (Οι-Οό) straight or branched alkyl, or phenyl, and R2 is (C1-C6) straight or branched alkyl or phenyl when R3 is methyl;
R3 is (Ci-Ce) straight or branched unsubstituted alkyl or alkyl substituted with fluoro, (C2-C8) straight or branched alkenyl, (C3-C7) eycloalkyl, (C1-C6) alkoxy, -alkylcycloalkyl, alkylalkoxy, OH, -alkylphenyl, -alkylphenoxy, phenyl, or phenyl subsituted with fluor, chloro, or methoxy; and
R4 is hydrogen.
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-804. A method of treating a retinal disorder associated with aberrant all-trans-retinal clearance in the retina in a subject, comprising administering to the subject a therapeutically effective amount of a primary amine compound selected from the group consisting of: 3-Aminomethyl-5methylhexanoic acid; 3-Aminomethyl-5-methylheptanoic acid; 3-Aminomethyl-5-methyloctanoic acid; 3-Aminomethyl-5-methyl-nonanoic acid; 3-Aminomethyl-5-methyl-decanoic acid; 3-Aminomethyl-5-methyl-undecanoic acid; 3-Aminomethyl-5-methyl-dodecanoic acid; 3Aminomethyl-5-methyl-tridecanoic acid; 3-Aminomethyl-5-cyclopropyl-hexanoic acid; 3Aminomethyl-5-cyclobutyl-hexanoic acid; 3-Aminomethyl-5-cyclopentyl-hexanoic acid; 3Aminomethyl-5-cyclohexyl-hexanoic acid; 3-Aminomethyl-5-trifluoiOmethyl-hexanoic acid; 3Aminomethyl-5-phenyl-hexanoic acid; 3-Aminomethyl-5-(2-chlorophenyl)-hexanoic acid; 3Aminomethyl-5-(3-chlorophenyl)-hexanoic acid; 3-Aminomethyl-5-(4-chlorophenyl)-hexanoic acid; 3-Aminomethyl-5-(2-methoxyphenyl)-hexanoic acid; 3-Aminomethyl-5-(3methoxyphenyl)-hexanoic acid; 3-Aminomethyl-5-(4-methoxyphenyl)-hexanoic acid; 3Aminomethyl-5-(phenylmethyl)-hexanoic acid; (S)-3-(Aminomethyl)-5-methylhexanoic acid; (R)-3-(Aminomethyl)-5-methylhexanoic acid; (3R,4S)-3-Aminomethyl-4,5-dimethyl-hexanoic acid; 3-Aminomethyl-4,5-dimethyl-hexanoic acid; (3R,4S)-3-Aminomethyl-4,5-dimethylhexanoic acid MP; (3S,4S)-3-Aminomethyl-4,5-dimethyl-hexanoic acid; (3R,4R)-3Aminomethyl-4,5-dimethyl-hexanoic acid MP; 3-Aminomethyl-4-isopropyl-hexanoic acid; 3Aminomethyl-4-isopropyl-heptanoic acid; 3-Aminomethyl-4-isopropyl-octanoic acid; 3Aminomethyl-4-isopropyl-nonanoic acid; 3-Aminomethyl-4-isopropyl-decanoic acid; 3Aminomethyl-4-phenyl-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-5-methoxy-hexanoic acid; (3S,5S)-3-Aminomethyl-5-ethoxy-hexanoic acid; (3S,5S)-3-Aminomethyl-5-propoxyhexanoic acid; (3S,5S)-3-Aminomethyl-5-isopropoxy-hexanoic acid; (3S,5S)-3-Aminomethyl-5tert-butoxy-hexanoic acid; (3S,5S)-3-Aminomethyl-5-fluoiOmethoxy-hexanoic acid; (3S,5S)-3Aminomethyl-5-(2-fluoro-ethoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(3,3,3-trifluoiOpropoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-phenoxy-hexanoic acid; (3S,5S)-3Aminomethyl-5-(4-chloro-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(3-chlorophenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(2-chloro-phenoxy)-hexanoic acid; (3S,5S)3-Aminomethyl-5-(4-fluoro-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(3-fluoiOphenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(2-fluoiO-phenoxy)-hexanoic acid; (3S,5S)3-Aminomethyl-5-(4-methoxy-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(3-methoxy179867765vl
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-81 phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(2-methoxy-phenoxy)-hexanoic acid;
(35.55) -3-Aminomethyl-5-(4-nitro-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(3-nitrophenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(2-nitro-phenoxy)-hexanoic acid; (3S,5S)-3Aminomethyl-6-hydroxy-5-methyl-hexanoic acid; (3 S,5S)-3-Aminomethyl-6-methoxy-5methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-ethoxy-5-methyl-hexanoic acid; (3S,5S)-3Aminomethyl-5-methyl-6-propoxy-hexanoic acid; (3S,5S)-3-Aminomethyl-6-isopropoxy-5methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-tert-butoxy-5-methyl-hexanoic acid; (3S,5S)3-Aminomethyl-6-fluoromethoxy-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(2-fluoroethoxy)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-6-(3,3,3-trifluoro-propoxy)hexanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-6-phenoxy-hexanoic acid; (3S,5S)-3Aminomethyl-6-(4-chloro-phenoxy)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(3chloro-phenoxy)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(2-chloro-phenoxy)-5methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(4-fluoro-phenoxy)-5-methyl-hexanoic acid;
(35.55) -3-Aminomethyl-6-(3-fluoro-phenoxy)-5-methyl-hexanoic acid; (3S,5S)-3Aminomethyl-6-(2-fluoro-phenoxy)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(4methoxy-phenoxy)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(3-methoxy-phenoxy)-5methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(2-methoxy-phenoxy)-5-methyl-hexanoic acid;
(35.55) -3-Aminomethyl-5-methyl 6-(4-trifluoromethyl-phenoxy)-hexanoic acid; (3S,5S)-3Aminomethyl-5-methyl 6-(3-trifluoromethyl-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl5-methyl 6-(2-trifluoromethyl-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-methyl 6-(4nitro-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-methyl 6-(3-nitro-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-methyl 6-(2-nitro-phenoxy)-hexanoic acid; (3S,5S)-3Aminomethyl-6-benzyloxy-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-7-hydroxy-5methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-7-methoxy-5-methyl-heptanoic acid; (3S,5S)-3Aminomethyl-7-ethoxy-5-methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-7-propoxyheptanoic acid; (3S,5S)-3-Aminomethyl-7-isopropoxy-5-methyl-heptanoic acid; (3S,5S)-3Aminomethyl-7-tert-butoxy-5-methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-7-fluoromethoxy5-methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-7-(2-fluoro-ethoxy)-5-methyl-heptanoic acid;
(35.55) -3-Aminomethyl-5-methyl-7-(3,3,3-trifluoiO-propoxy)-heptanoic acid; (3S,5S)-3Aminomethyl-7-benzyloxy-5-methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-7phenoxy-heptanoic acid; (3S,5S)-3-Aminomethyl-7-(4-chloiO-phenoxy)-5-methyl-heptanoic
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-82acid; (3S,5S)-3-Aminomethyl-7-(3-chloiO-phenoxy)-5-methyl-heptanoic acid; (3S,5S)-3Aminomethyl-7-(2-chloro-phenoxy)-5-methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-7-(4fluoro-phenoxy)-5-methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-7-(3-fluoro-phenoxy)-5methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-7-(2-fluoro-phenoxy)-5-methyl-heptanoic acid;
(35.55) -3-Aminomethyl-7-(4-methoxy-phenoxy)-5-methyl-heptanoic acid; (3S,5S)-3Aminomethyl-7-(3-methoxy-phenoxy)-5-methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-7-(2methoxy-phenoxy)-5-methyl-heptanoic acid; (3 S,5S)-3-Aminomethyl-5-methyl-7-(4trifluoromethyl-phenoxy)-heptanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-7-(3trifluoromethyl-phenoxy)-heptanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-7-(2trifluoromethyl-phenoxy)-heptanoic acid; (3 S,5S)-3-Aminomethyl-5-methyl-7-(4-nitrophenoxy)-heptanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-7-(3-nitro-phenoxy)-heptanoic acid;
(35.55) -3-Aminomethyl-5-methyl-7-(2-nitro-phenoxy)-heptanoic acid; (3S,5S)-3-Aminomethyl5- methyl-6-phenyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(4-chloro-phenyl)-5-methylhexanoic acid; (3S,5S)-3-Aminomethyl-6-(3-chloro-phenyl)-5-methyl-hexanoic acid; (3S,5S)-3Aminomethyl-6-(2-chloro-phenyl)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(4niethoxy-phenyl)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(3-methoxy-phenyl)-5methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(2-methoxy-phenyl)-5-methyl-hexanoic acid;
(35.55) -3-Aminomethyl-6-(4-fluoro-phenyl)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl6- (3-fluoro-phenyl)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(2-fluoro-phenyl)-5methyl-hexanoic acid; (3S,5R)-3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid; (3S,5R)-3Ammomethyl-7-(4-chloro-phenyl)-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-7-(3chloro-phenyl)-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-7-(2-chloro-phenyl)-5-methylheptanoic acid; (3S,5R)-3-Aminomethyl-7-(4-methoxy-phenyl)-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-7-(3-methoxy-phenyl)-5-methyl-heptanoic acid; (3S,5R)-3Aminomethyl-7-(2-methoxy-phenyl)-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-7-(4fluoro-phenyl)-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-7-(3-fluoro-phenyl)-5-methylheptanoic acid; (3S,5R)-3-Aminomethyl-7-(2-fluoro-phenyl)-5-methyl-heptanoic acid; (3S,5R)3-Aminomethyl-5-methyl-oct-7-enoic acid; (3S,5R)-3-Aminomethyl-5-methyl-non-8-enoic acid; (E)-(3S,5S)-3-Aminomethyl-5-methyl-oct-6-enoic acid; (Z)-(3S,5S)-3-Aminomethyl-5-methyloct-6-enoic acid; (Z)-(3S,5S)-3-Aminomethyl-5-methyl-non-6-enoic acid; (E)-(3S,5S)-3Aminomethyl-5-methyl-non-6-enoic acid; (E)-(3S,5R)-3-Aminomethyl-5-methyl-non-7-enoic
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-83acid; (Z)-(38,5R)-3-Aminomethyl-5-methyl-non-7-enoic acid; (Z)-(3S,5R)-3-Aminomethyl~5methyl-dec-7-enoic acid; (E)-(3S,5R)-3-Aminomethyl-5-methyl-undec-7-enoic acid; (3S,5S)-3Aminomethyl-5,6,6-trimethyl-heptanoic acid; (3S,5S)-3-Aminomethyl-5,6-dimethyl-heptanoic acid; (3S,5S)-3-Aminomethyl-5-cyclopropyl-hexanoic acid; (3S,5S)-3-Aminomethyl-5cyclobutyl-hexanoic acid; (3S,5S)-3-Aminomethyl-5-cyclopentyl-hexanoic acid; (3S,5S)-3Aminomethyl-5-cyclohexyl-hexanoic acid; (3S,5R)-3-Aminomethyl-5-niethyl-heptanoic acid;
(3S,5R)-3-Aminomethyl-5-methyl-octanoic acid; (3S,5R)-3-Aminomethyl-5-methyl-nonanoic acid; (3S,5R)-3-Aminomethyl-5-methyl-decanoic acid; (3S,5R)-3-Aminomethyl-5-methylundecanoic acid; (38,5R)-3-Aminomethyl-5-methyl-dodecanoic acid; (3S,5R)-3-Aminomethyl5,9-dimethyl-decanoic acid; (3S,5R)-3-Aminomethyl-5,7-dimethyl-octanoic acid; (3S,5R)-3Aminomethyl-5,8-dimethyl-nonanoic acid; (3S,5R)-3-Aminomethyl-6-cyclopropyl-5-methylhexanoic acid; (3S,5R)-3-Aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid; (3S,5R)-3Aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid; (3S,5R)-3-Aminomethyl-6-cyclohexyl-5methyl-hexanoic acid; (3S,5R)-3-Aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid; (3S,5R)-3-Ammomethyl-7-cyclobutyl-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-7cyclopentyl-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-8-cyclopropyl-5-methyl-octanoic acid; (3S,5R)-3-Aminomethyl8-cyclobutyl-5-methyl-octanoic acid; (3S,5R)-3-Aminomethyl-8-cyclopentyl-5-methyl-octanoic acid; (3S,5R)-3-Aminomethyl-8-cyclohexyl-5-methyl-octanoic acid; (38,5S)-3-Aminomethyl-6fluoro-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-7-fluoro-5-methyl-heptanoic acid; (38,5R)-3-Aminomethyl-8-fluoro-5-methyl-octanoic acid; (3S,5R)-3-Aminomethyl-9-fluoro-5methyl-nonanoic acid; (3S,5S)-3-Aminomethyl-7,7,7-trifluoro-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-8,8,8-trifluoro-5-methyl-octanoic acid; (3S,5R)-3-Aminomethyl-5methyl-8-phenyl-octanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-6-phenyl-hexanoic acid; (3S,5R)-3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid; and pharmaceutically acceptable salts thereof.
5. The method of any one of claims 1-4, wherein the primary amine compound is selected from the group consisting of (R)-3-(Aminomethyl)-5-methylhexanoic acid and a racemic mixtures of (R)-3-(Aminomethyl)-5-methylhexanoic acid and (S)-3-(Aminomethyl)-5methylhexanoic acid.
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6. The method of any one of claims 1-4, wherein the primary amine compound administered to the subject includes less than about 1%, 10%, or 25% by weight (S)-3-(Aminomethyl)-5methylhexanoic acid and greater than about 99%, 90%, or 75% by weight (R)-3-(Aminomethyl)5-methylhexanoic acid.
7. The method of any one of claims 1-4, wherein the primary amine compound administered to the subject consists essentially of (R)-3-(Aminomethyl)-5-methylhexanoic acid.
8. The method of any one of claims 1-4, wherein the primary amine compound administered to the subject is (R)-3-(Aminomethyl)-5-methylhexanoic acid.
9. The method of any one of claims 1-8, wherein the primary amine compound is delivered to the subject by at least one of topical administration, systemic administration, intravitreal injection, and intraocular delivery.
10. The method of any one of claims 1-9, wherein the retinal disorder is selected from the group consisting of age-related macular degeneration, Stargardt’s disease and retinitis pigmentosa.
11. A method of treating a retinal disorder associated with aberrant all-trans-retinal clearance in the retina in a subject, comprising administering to the subject a therapeutically effective amount of a primary amine compound selected from the group consisting of (R)-3(Aminomethyl)-5-methylhexanoic acid, and a racemic mixture of (R)-3-(Aminomethyl)-5methylhexanoic acid and (S)-3-(Aminomethyl)-5-methylhexanoic acid.
12. The method of claim 11, wherein the racemic mixture includes less than about 1%, 10%, or 25% by weight (S)-3-(Aminomethyl)-5-methylhexanoic acid and greater than about 99%, 90%, or 75% by weight (R)-3-(Aminomethyl)-5-methylhexanoic acid.
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-8513. The method of claim 11, wherein the primary amine compound administered to the subject consists essentially of (R)-3-(Aminomethyl)-5-methylhexanoic acid.
14. The method of claim 11, wherein the primary amine compound administered to the subject is (R)-3-(Aminomethyl)-5-methylhexanoic acid.
15. The method of any one of claims 11-14, wherein the primary amine compound is delivered to the subject by at least one of topical administration, systemic administration, intravitreal injection, and intraocular delivery.
16. The method of any one of claims 11-15, wherein the retinal disorder is selected from the group consisting of age-related macular degeneration, Stargardt’s disease and retinitis pigmentosa.
17. Use of a therapeutically effective dose of a primary amine compound comprising the fonnula:
R2 r4 or a pharmaceutically acceptable salt thereof, wherein:
R2 is hydrogen or (Οι-Οό) straight or branched unsubstituted alkyl;
R3 is (Ci-Ce) straight or branched unsubstituted alkyl or alkyl substituted with fluoro, (C2-C8) straight or branched alkenyl, (C3-C7) cycloalkyi, (C1-C6) alkoxy, -alkylcycloalkyl, alkylalkoxy, OH, -alkylphenyl, -alkylphenoxy, phenyl or phenyl subsituted with fluor, chloro, or methoxy; and
R4 is hydrogen or (Ci-Cs) straight or branched unsubstituted alkyl; in the manufacture of a medicament for the treatment of a retinal disorder associated with aberrant all-trans-retinal clearance in the retina.
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-8618. Use of a therapeutically effective dose of a primary amine compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a retinal disorder associated with aberrant all-trans-retinal clearance in the retina, wherein the primary amine compound selected from the group consisting of: 3-Aminomethyl-5methylhexanoic acid; 3-Aminomethyl-5-methylheptanoic acid; 3-Aminomethyl-5-methyloctanoic acid; 3-Aminomethyl-5-methyl-nonanoic acid; 3-Aminomethyl-5-methyl-decanoic acid; 3-Aminomethyl-5-methyl-undecanoic acid; 3-Aminomethyl-5-methyl-dodecanoic acid; 3Aminomethyl-5-methyl-tridecanoic acid; 3-Aminomethyl-5-cyclopropyl-hexanoic acid; 3Aminomethyl-5-cyclobutyl-hexanoic acid; 3-Aminomethyl-5-cyclopentyl-hexanoic acid; 3Aminomethyl-5-cyclohexyl-hexanoic acid; 3-Aminomethyl-5-trifluoiOmethyl-hexanoic acid; 3Aminomethyl-5-phenyl-hexanoic acid; 3-Aminomethyl-5-(2-chlorophenyl)-hexanoic acid; 3Aminomethyl-5-(3-chlorophenyl)-hexanoic acid; 3-Aminomethyl-5-(4-chlorophenyl)-hexanoic acid; 3-Aminomethyl-5-(2-methoxyphenyl)-hexanoic acid; 3-Aminomethyl-5-(3methoxyphenyl)-hexanoic acid; 3-Aminomethyl-5-(4-methoxyphenyl)-hexanoic acid; 3Aminomethyl-5-(phenylmethyl)-hexanoic acid; (S)-3-(Aminomethyl)-5-methylhexanoic acid; (R)-3-(Aminomethyl)-5-methylhexanoic acid; (3R,4S)-3-Aminomethyl-4,5-dimethyl-hexanoic acid; 3-Aminomethyl-4,5-dimethyl-hexanoic acid; (3R,4S)-3-Aminomethyl-4,5-dimethylhexanoic acid MP; (3S,4S)-3-Aminomethyl-4,5-dimethyl-hexanoic acid; (3R,4R)-3Aminomethyl-4,5-dimethyl-hexanoic acid MP; 3-Aminomethyl-4-isopropyl-hexanoic acid; 3Aminomethyl-4-isopropyl-heptanoic acid; 3-Aminomethyl-4-isopropyl-octanoic acid; 3Aminomethyl-4-isopropyl-nonanoic acid; 3-Aminomethyl-4-isopropyl-decanoic acid; 3Aminomethyl-4-phenyl-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-5-methoxy-hexanoic acid; (3S,5S)-3-Aminomethyl-5-ethoxy-hexanoic acid; (3S,5S)-3-Aminomethyl-5-propoxyhexanoic acid; (3S,5S)-3-Aminomethyl-5-isopropoxy-hexanoic acid; (3S,5S)-3-Aminomethyl-5tert-butoxy-hexanoic acid; (3S,5S)-3-Aminomethyl-5-fluoromethoxy-hexanoic acid; (3S,5S)-3Aminomethyl-5-(2-fluoiO-ethoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(3,3,3-trifluoropropoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-phenoxy-hexanoic acid; (3S,5S)-3Aminomethyl-5-(4-chloro-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(3-chlorophenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(2-chloro-phenoxy)-hexanoic acid; (3S,5S)3-Aminomethyl-5-(4-fluoro-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(3-fluorophenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(2-fluoro-phenoxy)-hexanoic acid; (3S,5S)179867765vl
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-873-Aminomethyl-5-(4-methoxy-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(3-methoxyphenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(2-methoxy-phenoxy)-hexanoic acid;
(35.55) -3-Aminomethyl-5-(4-nitro-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(3-nitrophenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(2-nitro-phenoxy)-hexanoic acid; (3S,5S)-3Aminomethyl-6-hydroxy-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-methoxy-5methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-ethoxy-5-methyl-hexanoic acid; (3S,5S)-3Aminomethyl-5-methyl-6-propoxy-hexanoic acid; (3S,5S)-3-Aminomethyl-6-isopropoxy-5methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-tert-butoxy-5-methyl-hexanoic acid; (3S,5S)3-Aminomethyl-6-fluoromethoxy-5-methyl-hexanoic acid; (38,5S)-3-Aminomethyl-6-(2-fluoroethoxy)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-6-(3,3,3-trifluoro-propoxy)hexanoic acid; (38,5S)-3-Aminomethyl-5-methyl-6-phenoxy-hexanoic acid; (3S,5S)-3Aminomethyl-6-(4-chloro-phenoxy)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(3chloro-phenoxy)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(2-chloro-phenoxy)-5methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(4-fluoro-phenoxy)-5-methyl-hexanoic acid;
(35.55) -3-Aminomethyl-6-(3-fluoiO-phenoxy)-5-methyl-hexanoic acid; (3S,5S)-3Aminomethyl-6-(2-fluoro-phenoxy)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(4methoxy-phenoxy)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(3-methoxy-phenoxy)-5methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(2-methoxy-phenoxy)-5-methyl-hexanoic acid (35.55) -3-Aminomethyl-5-methyl 6-(4-trifluoromethyl-phenoxy)-hexanoic acid; (3S,5S)-3Aminomethyl-5-methyl 6-(3-trifluoromethyl-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl5-methyl 6-(2-trifluoromethyl-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-methyl 6-(4nitro-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-methyl 6-(3-nitro-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-methyl 6-(2-nitro-phenoxy)-hexanoic acid; (3S,5S)-3Aminomethyl-6-benzyloxy-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-7-hydroxy-5methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-7-methoxy-5-methyl-heptanoic acid; (3S,5S)-3Aminomethyl-7-ethoxy-5-methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-7-propoxyheptanoic acid; (3S,5S)-3-Aminomethyl-7-isopiOpoxy-5-methyl-heptanoic acid; (3S,5S)-3Aminomethyl-7-tert-butoxy-5-methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-7-fluoiOmethoxy 5-methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-7-(2-fluoiO-ethoxy)-5-methyl-heptanoic acid;
(35.55) -3-Aminomethyl-5-methyl-7-(3,3,3-trifluoiO-propoxy)-heptanoic acid; (3S,5S)-3Aminomethyl-7-benzyloxy-5-methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-7179867765vl
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-88phenoxy-heptanoic acid; (3S,5S)-3-Aminomethyl-7-(4-chloro-phenoxy)-5-methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-7-(3-chloro-phenoxy)-5-methyl-heptanoic acid; (3S,5S)-3Aminomethyl-7-(2-chloro-phenoxy)-5-methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-7-(4fluoro-phenoxy)-5-methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-7-(3-fluoro-phenoxy)-5methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-7-(2-fluoro-phenoxy)-5-methyl-heptanoic acid;
(35.55) -3-Aminomethyl-7-(4-methoxy-phenoxy)-5-methyl-heptanoic acid; (3S,5S)-3Aminomethyl-7-(3-methoxy-phenoxy)-5-methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-7-(2methoxy-phenoxy)-5-methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-7-(4trifluoromethyl-phenoxy)-heptanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-7-(3trifluoromethyl-phenoxy)-heptanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-7-(2trifluoromethyl-phenoxy)-heptanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-7-(4-nitrophenoxy)-heptanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-7-(3-nitro-phenoxy)-heptanoic acid;
(35.55) -3-Aminomethyl-5-methyl-7-(2-nitro-phenoxy)-heptanoic acid; (3S,5S)-3-Aminomethyl5- methyl-6-phenyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(4-chloro-phenyl)-5-methylhexanoic acid; (3S,5S)-3-Aminomethyl-6-(3-chloro-phenyl)-5-methyl-hexanoic acid; (3S,5S)-3Aminomethyl-6-(2-chloro-phenyl)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(4methoxy-phenyl)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(3-methoxy-phenyl)-5methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(2-methoxy-phenyl)-5-methyl-hexanoic acid;
(35.55) -3-Aminomethyl-6-(4-fluoro-phenyl)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl6- (3-fluoro-phenyl)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(2-fluoro-phenyl)-5methyl-hexanoic acid; (3S,5R)-3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid; (3S,5R)-3Aminomethyl-7-(4-chloro-phenyl)-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-7-(3chloro-phenyl)-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-7-(2-chloro-phenyl)-5-methylheptanoic acid; (3S,5R)-3-Aminomethyl-7-(4~methoxy-phenyl)-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-7-(3-methoxy-phenyl)-5-methyl-heptanoic acid; (3S,5R)-3Aminomethyl-7-(2-methoxy-phenyl)-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-7-(4fluoro-phenyl)-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-7-(3-fluoro-phenyl)-5-methylheptanoic acid; (3S,5R)-3-Aminomethyl-7-(2-fluoro-phenyl)-5-methyl-heptanoic acid; (3S,5R)3-Aminomethyl-5-methyl-oct-7-enoic acid; (3S,5R)-3-Aminomethyl-5-methyl-non-8-enoic acid; (E)-(3S,5S)-3-Aminomethyl-5-methyl-oct-6-enoic acid; (Z)-(3S,5S)-3-Aminomethyl-5-methyloct-6-enoic acid; (Z)-(3S,5S)-3-Aminomethyl-5-methyl-non-6-enoic acid; (E)-(3S,5S)-3179867765vl
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-89Aminomethyl-5-methyl-non-6-enoic acid; (E)-(3S,5R)-3-Aminomethyl-5-methyl-non-7-enoic acid; (Z)-(38,5R)-3-Aminomethyl-5-methyl-non-7-enoic acid; (Z)-(3S,5R)-3-Aminomethyl-5methyl-dec-7-enoic acid; (E)-(3S,5R)-3-Aminomethyl-5-methyl-undec-7-enoic acid; (3S,5S)-3Aminomethyl-5,6,6-trimethyl-heptanoic acid; (3S,5S)-3-Aminomethyl-5,6-dimethyl-heptanoic acid; (3S,5S)-3-Aminomethyl-5-cyclopropyl-hexanoic acid; (3S,5S)-3-Aminomethyl-5cyclobutyl-hexanoic acid; (3S,5S)-3-Aminomethyl-5-cyclopentyl-hexanoic acid; (3S,5S)-3Aminomethyl-5-cyclohexyl-hexanoic acid; (3S,5R)-3-Aminomethyl-5-methyl-heptanoic acid;
(3S,5R)-3-Aminomethyl-5-methyl-octanoic acid; (3S,5R)-3-Aminomethyl-5-methyl-nonanoic acid; (3S,5R)-3-Aminomethyl-5-methyl-decanoic acid; (3S,5R)-3-Aminomethyl-5-methylundecanoic acid; (3S,5R)-3-Aminomethyl-5-methyl-dodecanoic acid; (3S,5R)-3-Aminomethyl5,9-dimethyl-decanoic acid; (3S,5R)-3-Aminomethyl-5,7-dimethyl-octanoic acid; (3S,5R)-3Aminomethyl-5,8-dimethyl-nonanoic acid; (3S,5R)-3-Aminomethyl-6-cyclopropyl-5-methylhexanoic acid; (3S,5R)-3-Aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid; (3S,5R)-3Aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid; (3 S,5R)-3-Aminomethyl-6-cyclohexyl-5methyl-hexanoic acid; (3S,5R)-3-Aminomethyl-7-cyclopiOpyl-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-7cyclopentyl-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-8-cyclopropyl-5-methyl-octanoic acid; (3S,5R)-3-Aminomethyl8-cyclobutyl-5-methyl-octanoic acid; (3 S,5R)-3-Aminomethyl-8-cyclopentyl-5-methyl-octanoic acid; (3S,5R)-3-Aminomethyl-8-cyclohexyl-5-methyl-octanoic acid; (3S,5S)-3-Aminomethyl-6fluoro-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-7-fluoro-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-8-fluoro-5-methyl-octanoic acid; (3S,5R)-3-Aminomethyl-9-fluoro-5methyl-nonanoic acid; (3S,5S)-3-Aminomethyl-7,7,7-trifluoiO-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-8,8,8-trifluoiO-5-methyl-octanoic acid; (3S,5R)-3-Aminomethyl-5methyl-8-phenyl-octanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-6-phenyl-hexanoic acid; (3S,5R)-3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid; and pharmaceutically acceptable salts thereof.
19. Use of a therapeutically effective dose of a primary amine compound comprising the formula:
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R2 R4 or a pharmaceutically acceptable salt thereof, wherein:
R2 is hydrogen, (Ci-Ce) straight or branched alkyl, or phenyl, and R2 is (C1-C6) straight or branched alkyl or phenyl when R3 is methyl;
R3 is (Ci-Cs) straight or branched unsubsituted alkyl or alkyl substituted with fluoro, (C2Cs) straight or branched alkenyl, (C3-C7) cycloalkyl, (Ci-Ce) alkoxy, -alkylcycloalkyl, alkylalkoxy, OH, -alkylphenyl, -alkylphenoxy, phenyl, or phenyl subsituted with fluor, chloro, or methoxy; and
R4 is hydrogen, in the manufacture of a medicament for the treatment of a retinal disorder associated with aberrant all-trans-retinal clearance in the retina.
20. Use of a therapeutically effective dose of a primary amine compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a retinal disorder associated with aberrant all-trans-retinal clearance in the retina, wherein the primary amine compound selected from the group consisting of: 3-Aminomethyl-5methylhexanoic acid; 3-Aminomethyl-5-methylheptanoic acid; 3-Aminomethyl-5-methyloctanoic acid; 3-Aminomethyl-5-methyl-nonanoic acid; 3-Aminomethyl-5-methyl-decanoic acid; 3-Aminomethyl-5-methyl-undecanoic acid; 3-Aminomethyl-5-methyl-dodecanoic acid; 3Aminomethyl-5-methyl-tridecanoic acid; 3-Aminomethyl-5-cyclopropyl-hexanoic acid; 3Aminomethyl-5-cyclobutyl-hexanoic acid; 3-Aminomethyl-5-cyclopentyl-hexanoic acid; 3Aminomethyl-5-cyclohexyl-hexanoic acid; 3-Aminomethyl-5-trifluoromethyl-hexanoic acid; 3Aminomethyl-5-phenyl-hexanoic acid; 3-Aminomethyl-5-(2-chlorophenyl)-hexanoic acid; 3Aminomethyl-5-(3-chlorophenyl)-hexanoic acid; 3-Aminomethyl-5-(4-chlorophenyl)-hexanoic acid; 3-Aminomethyl-5-(2-methoxyphenyl)-hexanoic acid; 3-Aminomethyl-5-(3methoxyphenyl)-hexanoic acid; 3-Aminomethyl-5-(4-methoxyphenyl)-hexanoic acid; 3Aminomethyl-5-(phenylmethyl)-hexanoic acid; (S)-3-(Aminomethyl)-5-methylhexanoic acid;
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-91 (R)-3-(Aminomethyl)-5-methylhexanoic acid; (3R,4S)-3-Aminomethyl-4,5-dimethyl-hexanoic acid; 3-Aminomethyl-4,5-dimethyl-hexanoic acid; (3R,4S)-3-Aminomethyl-4,5-dimethylhexanoic acid MP; (3S,4S)-3-Aminomethyl-4,5-dimethyl-hexanoic acid; (3R,4R)-3Aminomethyl-4,5-dimethyl-hexanoic acid MP; 3-Aminomethyl-4-isopropyl-hexanoic acid; 3Aminomethyl-4-isopiOpyl-heptanoic acid; 3-Aminomethyl-4-isopropyl-octanoic acid; 3Aminomethyl-4-isopropyl-nonanoic acid; 3-Aminomethyl-4-isopropyl-decanoic acid; 3Aminomethyl-4-phenyl-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-5-methoxy-hexanoic acid; (3S,5S)-3-Aminomethyl-5-ethoxy-hexanoic acid; (3S,5S)-3-Aminomethyl-5-propoxyhexanoic acid; (3S,5S)-3-Aminomethyl-5-isopropoxy-hexanoic acid; (3S,5S)-3-Aminomethyl-5 tert-butoxy-hexanoic acid; (3S,5S)-3-Aminomethyl-5-fluoromethoxy-hexanoic acid; (3S,5S)-3Aminomethyl-5-(2-fluoro-ethoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(3,3,3-trifluoropropoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-phenoxy-hexanoic acid; (3S,5S)-3Aminomethyl-5-(4-chloiO-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(3-chlorophenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(2-chloro-phenoxy)-hexanoic acid; (3S,5S)3-Aminomethyl-5-(4-fluoro-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(3-fluorophenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(2-fluoiO-phenoxy)-hexanoic acid; (3S,5S)3-Aminomethyl-5-(4-methoxy-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(3-methoxyphenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(2-methoxy-phenoxy)-hexanoic acid;
(35.55) -3-Aminomethyl-5-(4-nitro-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(3-nitro phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-(2-nitro-phenoxy)-hexanoic acid; (3S,5S)-3 Aminomethyl-6-hydiOxy-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-methoxy-5methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-ethoxy-5-methyl-hexanoic acid; (3S,5S)-3Aminomethyl-5-methyl-6-propoxy-hexanoic acid; (3S,5S)-3-Aminomethyl-6-isopropoxy-5methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-tert-butoxy-5-methyl-hexanoic acid; (3S,5S)3-Aminomethyl-6-fluoiOmethoxy-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(2-fluoro ethoxy)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-6-(3,3,3-trifluoro-propoxy)· hexanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-6-phenoxy-hexanoic acid; (3S,5S)-3Aminomethyl-6-(4-chloro-phenoxy)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(3chloro-phenoxy)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(2-chloro-phenoxy)-5methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(4-fluoro-phenoxy)-5-methyl-hexanoic acid;
(35.55) -3-Aminomethyl-6-(3-fluoro-phenoxy)-5-methyl-hexanoic acid; (3S,5S)-3179867765 vl
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-92Aminomethyl-6-(2-fluoro-phenoxy)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(4methoxy-phenoxy)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(3-methoxy-phenoxy)-5methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(2-methoxy-phenoxy)-5-methyl-hexanoic acid;
(35.55) -3-Aminomethyl-5-methyl 6-(4-trifluoromethyl-phenoxy)-hexanoic acid; (3S,5S)-3Aminomethyl-5-methyl 6-(3-trifluoromethyl-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl5-methyl 6-(2-trifluoromethyl-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-methyl 6-(4nitro-phenoxy)-hexanoic acid; (3S,5S)-3-Aminomethyl-5-methyl 6-(3-nitro-phenoxy)~hexanoic acid; (3S,5S)-3-Aminomethyl-5-methyl 6-(2-nitro-phenoxy)-hexanoic acid; (3S,5S)-3Aminomethyl-6-benzyloxy-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-7-hydroxy-5methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-7-methoxy-5-methyl-heptanoic acid; (3S,5S)-3Aminomethyl-7-ethoxy-5-methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-7-propoxyheptanoic acid; (3S,5S)-3-Aminomethyl-7-isopropoxy-5-methyl-heptanoic acid; (3S,5S)-3Aminomethyl-7-tert-butoxy-5-methyl-heptanoic acid; (3 S,5 S)-3 -Aminomethyl-7-fluoromethoxy5-methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-7-(2-fluoiO-ethoxy)-5-methyl-heptanoic acid;
(35.55) -3-Aminomethyl-5-methyl-7-(3,3,3-trifluoiO-propoxy)-heptanoic acid; (3S,5S)-3Aminomethyl-7-benzyloxy-5-methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-7phenoxy-heptanoic acid; (3S,5S)-3-Aminomethyl-7-(4-chloro-phenoxy)-5-methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-7-(3-chloro-phenoxy)-5-methyl-heptanoic acid; (3S,5S)-3Aminomethyl-7-(2-chloro-phenoxy)-5-methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-7-(4fluoro-phenoxy)-5-methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-7-(3-fluoro-phenoxy)-5methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-7-(2-fluoro-phenoxy)-5-methyl-heptanoic acid;
(35.55) -3-Aminomethyl-7-(4-methoxy-phenoxy)-5-methyl-heptanoic acid; (3S,5S)-3Aminomethyl-7-(3-methoxy-phenoxy)-5-methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-7-(2methoxy-phenoxy)-5-methyl-heptanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-7-(4trifluoromethyl-phenoxy)-heptanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-7-(3trifluoromethyl-phenoxy)-heptanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-7-(2trifluoromethyl-phenoxy)-heptanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-7-(4-nitrophenoxy)-heptanoic acid; (3S,5S)-3-Aminomethyl-5-methyl-7-(3-nitro-phenoxy)-heptanoic acid;
(35.55) -3-Aminomethyl-5-methyl-7-(2-nitro-phenoxy)-heptanoic acid; (38,5S)-3-Aminomethyl5-methyl-6-phenyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(4-chloro-phenyl)-5-methylhexanoic acid; (3S,5S)-3-Aminomethyl-6-(3-chloro-phenyl)-5-methyl-hexanoic acid; (3S,5S)-3179867765 vl
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-93Aminomethyl-6-(2-chloro-phenyl)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(4methoxy-phenyl)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(3-methoxy-phenyl)-5methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(2-methoxy-phenyi)-5-methyl-hexanoic acid;
(3S,5S)-3-Aminomethyl-6-(4-fluoro-phenyl)-5-methyI-hexanoic acid; (3S,5S)-3-Aminomethyl6-(3-fluoro-phenyl)-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-6-(2-fluoro-phenyl)-5methyl-hexanoic acid; (3S,5R)-3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid; (3S,5R)-3Aminomethyl-7-(4-chloro-phenyl)-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-7-(3chloro-phenyl)-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-7-(2-chloro-phenyl)-5-methyIheptanoic acid; (3S,5R)-3-Aminomethyl-7-(4-methoxy-phenyl)-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-7-(3-methoxy-phenyl)-5-methyl~heptanoic acid; (3S,5R)-3Aminomethyl-7-(2-methoxy-phenyl)-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-7-(4fluoro-phenyl)-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-7-(3-fluoro-phenyl)-5-methylheptanoic acid; (3S,5R)-3-Aminomethyl-7-(2-fluoro-phenyl)-5-methyl-heptanoic acid; (3S,5R)3-Aminomethyl-5-methyl-oct-7-enoic acid; (3S,5R)-3-Aminomethyl-5-methyl-non-8-enoic acid; (E)-(3S,5S)-3-Aminomethyl-5-methyl-oct-6-enoic acid; (Z)-(3S,5S)-3-Aminomethyl-5-methyloct-6-enoic acid; (Z)-(3S,5S)-3-Aminomethyl-5-methyl-non-6-enoic acid; (E)-(3S,5S)-3Aminomethyl-5-methyl-non-6-enoic acid; (E)-(3S,5R)-3-Aminoniethyl-5-methyl-non-7-enoic acid; (Z)-(3S,5R)-3-Aminomethyl-5-methyl-non-7-enoic acid; (Z)-(3S,5R)-3-Aminomethyl-5methyl-dec-7-enoic acid; (E)-(3S,5R)-3-Aminomethyl-5-methyl-undec-7-enoic acid; (3S,5S)-3Aminomethyl-5,6,6-trimethyl-heptanoic acid; (3S,5S)-3-Aminomethyl-5,6-dimethyl-heptanoic acid; (3S,5S)-3-Aminomethyl-5-cyclopropyl-hexanoic acid; (3S,5S)-3-Aminomethyl-5cyclobutyl-hexanoic acid; (3S,5S)-3-Aminomethyl-5-cyclopentyl-hexanoic acid; (3S,5S)-3Aminomethyl-5-cyclohexyl-hexanoic acid; (3S,5R)-3-Aminomethyl-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-5-methyl-octanoic acid; (3S,5R)-3-Aminomethyl-5-methyl-nonanoic acid; (3S,5R)-3-Aminomethyi-5-methyl-decanoic acid; (3S,5R)-3-Aminomethyl-5-methylundecanoic acid; (3S,5R)-3-Aminomethyi-5-methyl-dodecanoic acid; (3S,5R)-3-Aminomethyl5,9-dimethyl-decanoic acid; (3S,5R)-3-Aminomethyl-5,7-dimethyI-octanoic acid; (3S,5R)-3Aminomethyl-5,8-dimethyl-nonanoic acid; (3S,5R)-3-Ammomethyl-6-cyclopropyl-5-methylhexanoic acid; (3S,5R)-3-Aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid; (3S,5R)-3Aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid; (3S,5R)-3-Aminomethyl-6-cyclohexyl-5methyl-hexanoic acid; (3S,5R)-3-Aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;
179867765vl 3735081vl
2017201162 06 Jul 2018
-94(38,5R)-3-Aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-7cyclopentyl-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-8-cyclopropyl-5-methyl-octanoic acid; (3S,5R)-3-Aminomethyl8-cyclobutyl-5-methyl-octanoic acid; (3S,5R)-3-Aminomethyl-8-cyclopentyl-5-niethyl-octanoic acid; (3S,5R)-3-Aminomethyl-8-cyclohexyl-5-methyl-octanoic acid; (3S,5S)-3-Aminomethyl-6fluoro-5-methyl-hexanoic acid; (3S,5S)-3-Aminomethyl-7-fluoro-5-methyl-heptanoic acid; (3S,5R)-3-Aminomethyl-8-fluoro-5-methyl-octanoic acid; (3S,5R)-3-Aminomethyl-9-fluoro-5methyl-nonanoic acid; (3S,5S)-3-Aminomethyl-7,7,7-trifluoiO-5-rnethyl-heptanoic acid; (3S,5R)-3-Aminomethyl-8,8,8-trifluoro-5-methyl-octanoic acid; (3S,5R)-3-Aminomethyl-5methyl-8-phenyl-octanoic acid; (3S,5S)-3~Aminomethyl-5-methyl-6-phenyl-hexanoie acid; (3S,5R)-3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid; and pharmaceutically acceptable salts thereof.
21. The use according to any one of claims 17-20, wherein the primary amine compound is selected from the group consisting of (R)-3-(Aminomethyl)-5-methylhexanoic acid and a racemic mixtures of (R)-3-(Aminomethyl)-5-methylhexanoic acid and (S)-3-(Aminomethyl)-5methylhexanoic acid.
22. The use according to any one of claims 17-21, wherein the primary amine compound includes less than about 1%, 10%, or 25% by weight (S)-3-(Aminomethyl)-5-methylhexanoic acid and greater than about 99%, 90%, or 75% by weight (R)-3-(Aminomethyl)-5methylhexanoic acid.
23. The use according to any one of claims 17-21, wherein the primary amine compound consists essentially of (R)-3-(Aminomethyl)-5-methylhexanoic acid.
24. The use according to any one of claims 17-21, wherein the primary amine compound is (R)-3-(Aminomethyl)-5-methylhexanoic acid.
25. Use of a therapeutically effective dose of a primary amine compound selected from the group consisting of (R)-3-(Aminomethyl)-5-methylhexanoic acid, and a racemic mixture of (R)179867765 vl
3735081vl
-953-(Aminomethyl)-5-methylhexanoic acid and (S)-3-(Aminomethyl)-5-methylhexanoic acid, in the manufacture of a medicament for the treatment of a retinal disorder associated with aberrant all-trans-retinal clearance in the retina.
26. The use according to any one of claims 17-25, wherein the retinal disorder is selected from the group consisting of age-related macular degeneration, Stargardt’s disease and retinitis pigmentosa.
2017201162 06 Jul2018
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2017201162 21 Feb 2017
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Time (min)
Fig. 6
2017201162 21 Feb 2017 r-j
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2017201162 21 Feb 2017
2017201162 21 Feb 2017
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2017201162 21 Feb 2017
CWRO19171WOORD SEQUENCE LISTING <110> CASE WESTERN RESERVE UNIVERSITY <120> COMPOUNDS AND METHODS OF TREATING OCULAR DISEASES <130> CWR-019171W0 ORD <150> 61/267,645 <151> 2009-12-08 <160> 4 <170> PatentIn version 3.5 <210> 1 <211 > 23 <212> DNA <213> Mus musculus <400> 1 gcccagtggt cgatctgtct age <210> 2 <211 > 22 <212> DNA <213> Mus musculus <400> 2 cacaaaggcc gctaggacca cg <210> 3 <211 > 25 <212> DNA <213> Mus musculus <400> 3 ccacagcaca catcagcatt tctcc <210> 4 <211 > 27 <212> DNA <213> Mus musculus <400> 4 tgcgaggcca gaggccactt gtgtagc
AU2017201162A 2009-12-08 2017-02-21 Compounds and methods of treating ocular disorders Ceased AU2017201162B2 (en)

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Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Gahlot et al, "Effect of penicillamine on the sensori-neural deafness of retinitis pigmentosa", The Journal of Laryngology & Otology (1977), Vol. 91, No. 12, Pages 1107-1111 *
Maeda et al, "Retinopathy in Mice Induced by Disrupted All-trans-retinal Clearance", Journal of Biological Chemistry (2008), Vol. 283, No. 39, Pages 26684-26693 *
Maeda et al, Investigative Ophthalmology & Visual Science (2009), Vol. 50, No. 10, Pages 4917-4925 *

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