Patent Application
20070249596
The present invention relates to the use of Abnormal Cannabidiols as ocular hypotensives. These therapeutic agents are represented by compounds having the formula I or I′, above.
In one embodiment of the invention, the compound is selected from the group consisting of abnormal Cannabidiols and analogues thereof represented by formula II
wherein Q is selected from the group consisting of
A particularly preferred group represented by Q is menthadiene or
In this class of compounds, preferably, R is selected from the group consisting of hydrogen, methyl, bromo and chloro and R1 is selected from the group consisting of hydrogen, methyl and chloro.
Compounds of this type may be prepared by condensation of a cyclic alkene or cyclic alcohol with a suitably substituted benzene-1,3-diol. The reaction is catalysed by an acid such as oxalic acid dihydrate or p-toluenesulphonic acid. The reaction is carried out in a solvent or mixture of solvents such as toluene, diethyl ether or dichloromethane. A mixture of the two isomers is obtained and the desired product is separated by chromatography. The reaction scheme is illustrated below.
The synthesis of the starting materials is well known.
The mechanism of the reaction is the result of the formation of a carbocation by elimination of OH or a starting material containing a functional group such as acetate which can also be eliminated to give the carbocation can be used.
In another embodiment of the invention the compound is tetrahydropyridine represented by formula III
These tetrahydropyridine compounds may be synthesized according to the following reaction scheme wherein Me is methyl, Bu is butyl and iPr is isopropyl.
In a further embodiment of the invention, the compound is a piperidinedione represented by the formula IV
These compounds may be synthesized according to the following reaction scheme wherein Et is ethyl, THF is tetrahydrofuran and DMF is dimethyl formamide.
Compounds of formula I′ wherein Y and Y1 are keto are known as piperidine-2,4-diones and may be synthesized as described by H. Nishino, et al., Teterahedron 2005, 11107-11124. The corresponding cyclohexane-1,3 diones may be prepared as described in EP 291114 and EP 310186. Compounds of formula I′ wherein Y is keto and Y1 is hydroxyl are known as 4-hydroxypyridin-2-ones and may be prepared as described by Castillo, et al. in Bull. Soc. Chim. Fr. 1982, 257-261.
The compounds wherein Y═Y1=hydroxyl may be prepared by dehydrogenation of the corresponding cyclohexane-1,3 diones by the method described by E. D. Berymann, et a., JACS, 1953, 3226. Compounds of formula I′ wherein both of Z is N, Y is oxo and Y1 is hydroxyl may be prepared as described in WO 2005/007632 and J. Het. Chem. 1989, 169-176.
In all of the above formulae, as well as in those provided hereinafter, the straight lines represent bonds. Where there is no symbol for the atoms between the bonds, the appropriate carbon-containing radical is to be inferred.
Pharmaceutical compositions may be prepared by combining a therapeutically effective amount of at least one compound according to the present invention, as an active ingredient, with conventional ophthalmically acceptable pharmaceutical excipients, and by preparation of unit dosage forms suitable for topical ocular use. The therapeutically efficient amount typically is between about 0.0001 and about 5% (w/v), preferably about 0.001 to about 1.0% (w/v) in liquid formulations.
For ophthalmic application, preferably solutions are prepared using a physiological saline solution as a major vehicle. The pH of such ophthalmic solutions should preferably be maintained between 4.5 and 8.0 with an appropriate buffer system, a neutral pH being preferred but not essential. The formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.
Preferred preservatives that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate. A preferred surfactant is, for example, Tween 80. Likewise, various preferred vehicles may be used in the ophthalmic preparations of the present invention. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.
Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.
Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.
In a similar vein, an ophthalmically acceptable antioxidant for use in the present invention includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
Other excipient components which may be included in the ophthalmic preparations are chelating agents. The preferred chelating agent is edentate disodium, although other chelating agents may also be used in place or in conjunction with it.
The ingredients are usually used in the following amounts:
The actual dose of the active compounds of the present invention depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.
The ophthalmic formulations of the present invention are conveniently packaged in forms suitable for metered application, such as in containers equipped with a dropper, to facilitate application to the eye. Containers suitable for dropwise application are usually made of suitable inert, non-toxic plastic material, and generally contain between about 0.5 and about 15 ml solution. One package may contain one or more unit doses.
Especially preservative-free solutions are often formulated in non-resealable containers containing up to about ten, preferably up to about five unit doses, where a typical unit dose is from one to about 8 drops, preferably one to about 3 drops. The volume of one drop usually is about 20-35 μl.
The compounds disclosed herein for use in the method of this invention, i.e. the treatment of glaucoma or elevated intraocular pressure, may also be used in combination with other drugs useful for the treatment of glaucoma or elevated intraocular pressure.
For the treatment of glaucoma or elevated intraocular pressure, combination treatment with the following classes of drugs are contemplated: β-Blockers (or β-adrenergic antagonists) including carteolol, levobunolol, metipranolol, timolol hemihydrate, timolol maleate, β1-selective antagonists such as betaxolol, and the like, or pharmaceutically acceptable salts or prodrugs thereof;
Adrenergic Agonists including
non-selective adrenergic agonists such as epinephrine borate, epinephrine hydrochloride, and dipivefrin, and the like, or pharmaceutically acceptable salts or prodrugs thereof; and
α2-selective adrenergic agonists such as apraclonidine, brimonidine, and the like, or pharmaceutically acceptable salts or prodrugs thereof;
Carbonic Anhydrase Inhibitors including acetazolamide, dichlorphenamide, methazolamide, brinzolamide, dorzolamide, and the like, or pharmaceutically acceptable salts or prodrugs thereof;
Cholinergic Agonists including
direct acting cholinergic agonists such as carbachol, pilocarpine hydrochloride, pilocarpine nitrate, pilocarpine, and the like, or pharmaceutically acceptable salts or prodrugs thereof;
chlolinesterase inhibitors such as demecarium, echothiophate, physostigmine, and the like, or pharmaceutically acceptable salts or prodrugs thereof;
Glutamate Antagonists such as memantine, amantadine, rimantadine, nitroglycerin, dextrophan, detromethorphan, CGS-19755, dihydropyridines, verapamil, emopamil, benzothiazepines, bepridil, diphenylbutylpiperidines, diphenylpiperazines, HOE 166 and related drugs, fluspirilene, eliprodil, ifenprodil, CP-101,606, tibalosine, 2309BT, and 840S, flunarizine, nicardipine, nifedimpine, nimodipine, barnidipine, lidoflazine, prenylamine lactate, amiloride, and the like, or pharmaceutically acceptable salts or prodrugs thereof;
Prostamides such as bimatoprost, or pharmaceutically acceptable salts or prodrugs thereof; and
Prostaglandins including travoprost, UFO-21, chloprostenol, fluprostenol, 13,14-dihydro-chloprostenol, isopropyl unoprostone, latanoprost and the like.
The invention is further illustrated by the following non-limiting Examples.
Intraocular pressure was measured by applanation pneumatonometry in conscious animals. The test compound was administered topically to one eye while vehicle was given to the fellow eye in a masked fashion. Ocular normotensive Beagle dogs (males, females) were dosed once daily for five days. Laser-induced unilaterally ocular hypertensive Cynomolgus monkeys (females) were dosed once daily for 4 days. Student's paired t-test was used for statistical comparisons. Differences were considered statistically significant if the P-value is less than 0.05.
The results are shown in the Figures.
The figures show the change from baseline IOP of Monkey dosed with 0.1% of the active compound versus time.
Abnormal Cannabidiol receptor activity may be measured in accordance with the procedure disclosed in (Wagner J A et al., Hypertension 33 [part II], 429 (1999); Járai Z et al., PNAS 96, 14136 (1999), which is hereby incorporated by reference in its entirety.
(4R)-1-Methyl-4-isoprenylcyclohex-2-ene-1-ol (300 mg, 2 mmoles) was dissolved in toluene (20 ml) and 5-methylresorcinol (248 mg, 2 mmoles) was added in diethyl ether (5 ml). Oxalic acid dihydrate (252 mg, 2 mmoles) was added and the reaction mixture heated with stirring at 80° for 5 hours. The reaction mixture was allowed to cool and diluted with diethyl ether (30 ml). The ether solution was washed twice with aqueous sodium bicarbonate and dried over anhydrous magnesium sulphate. The solvents were evaporated under reduced pressure to give the crude product as a brown oil (800 mg). The product was purified using a silica column eluted with ethyl acetate:isohexane 1:9 going to ethyl acetate: isohexane 2:8.
The product was isolated as a yellow gum (106 mg)
The named compound is prepared according to the method described in Example 3 except that resorcinol is substituted for 5-methylresorcinol.
1H NMR (300 MHz, CDCl3) 6.2 (M, 2H), 6.1 (S, 1H), 5.55 (M, 1H), 4.7 (M, H), 4.55 (S, 1H), 4.5 (M, 1H), 3.55 (M, 1H), 2.5 (M, 1H), 2.2 (M, 2H), 2.15(S,3H), 1.85(M,2H), 1.8(S,3H), 1.6(S,3H)
Also prepared in a similar manner were
1H NMR (300 MHz, CDCl3) 6.4 (M, 1H), 6.3 (M, 1H), 6.25 (S, 1H), 5.6 (M, 1H), 4.7 (brS, 1H), 4.65 (M, 1H), 4.4 (M, 1H), 4.0 (M, 1H), 2.5 (M, 1H), 2.25 (M, 1H), 2.15 (M, 1H), 1.85 (M, 2H), 1.8 (S, 3H), 1.6 (S, 3H)
1H NMR (300 MHz, CDCl3) 6.15 (brS, 1H), 6.0 (M, 2H), 5.6 (M, 1H), 4.65 (brS, 1H), 4.5(M, 1H), 4.35 (M, 1H), 3.95(M, 1H), 3.7(S,3H), 2.4(M, 1H), 2.25 (1H, M), 2.1 (M, 1H), 1.8 (M, 2H), 1.8 (S, 3H), 1.65 (S, 3H)
1H NMR (300 MHz, CDCl3) 6.0 (brS, 2H), 5.55 (M, 1H), 4.7 (M, 1H), 4.6(M, 1H), 3.8 (M, 1H), 3.75 (S, 3H), 2.4 (M, 1H), 2.2 (M, 1H), 2.1 (M, 1H), 1.8 (S, 3H), 1.8 (M, 2H)
4-Chlororesorcinol (350 mg, 2.4 mmoles) was dissolved in toluene (30 ml) and diethyl ether (20 ml) and p-toluenesulphonic acid (91 mg, 0.48 mmoles) was added.
(4R)-1-Methyl-4-isoprenylcyclohex-2-ene-1-ol (500 mg, 3 mmoles) in toluene (10 ml) was added and the reaction mixture was stirred at room temperature for 6 hours. Diluted with diethyl ether (30 ml) and washed twice with aqueous sodium bicarbonate. Dried over anhydrous magnesium sulphate and the solvent was evaporated under reduced pressure to give a yellow gum (800 mg). Purified using a silica column eluted with ethyl acetate:isohexane 9:1 going to ethyl acetate:isohexane 8:2. The product was isolated as a yellow gum (95 mg)
1H NMR (300 MHz, CDCl3) 6.9 (S, 1H), 6.5 (S, 1H), 5.5 (S, 1H), 5.45 (M, 1H), 5.35 (S, 1H), 4.7 (M, 1H), 4.6 (M, 1H), 3.35 (M, 1H), 2.2 (M, 3H), 1.8(M,3H), 1.75(M,2H), 1.6(S,3H)
This compound was prepared as described in JACS, 1953, 2341.
Resorcinol (2.2 g, 0.02 moles) was mixed with cyclohexanol (1 g, 0.01 moles) and zinc (II) chloride (0.48 g, 0.0035 moles) and the reaction mixture heated to 150° with stirring. After heating 2 hours, the reaction mixture was allowed to cool and then dissolved in ethyl acetate. Washed with water and dried over anhydrous magnesium sulphate. The solvent was evaporated to give a brown oil (3.0 g). Excess resorcinol was evaporated by heating in a Kugelrohr oven under reduced pressure (200°, 2 mmHg). Purified using a silica column eluted with ethyl acetate: isohexane 2:8 to give the product as a yellow oil (0.5 g). Trituration with isohexane gave the product as a white solid (0.2 g).
1H NMR (300 MHz, CDCl3) 7.0 (D, 1H J=8 Hz), 6.4 (M, 1H), 6.3 (M, 1H), 4.7(S, 1H), 4.55(S, 1H), 2.7(M, 1H), 1.8(M,5H), 1.4(M,5H)
The synthesis of 4R-Isoprenyl-1-methylcyclohex-2-enol was carried out as described in WO2004096740.
(+)-Limonene oxide (13.2 g, 0.087 moles) was dissolved in ethanol (40 ml) and lithium chloride (5.9 g, 0.14 moles) was added with stirring. Morpholine (11.4 g, 0.13 moles) was added and the reaction mixture was heated at 60° for 48 hours. The solvent was evaporated under reduced pressure and the residue taken up in dichloromethane. Washed with water. Extracted into 2M hydrochloric acid and washed with dichloromethane. Basified to pH 10 by addition of 2M sodium hydroxide. Extracted with diethyl ether and washed with water. Dried over anhydrous magnesium sulphate and evaporated the solvent under reduced pressure to give the product as a yellow oil (10.3 g)
1H NMR (300 MHz, CDCl3) 4.95 (M, 1H), 4.85 (M, 1H), 3.7 (M, 4H), 2.75 (M, 2H), 2.5 (M, 4H), 2.1 (M, 1H), 1.95 (M, 1H), 1.75 (S, 3H), 1.6 (M, 4H), 1.2 (S, 3H)
4-Isoprenyl-1-methyl-2-morpholin-4-yl-cyclohexanol (17.7 g, 0.074 moles) was dissolved in ethanol (100 ml) and 35% hydrogen peroxide (37 ml, 0.325 moles) was added. Heated with stirring at 50° for 6 hours. 5% palladium on carbon (100 mg) was added in order to decompose the excess peroxide. Stirred at room temperature for 3 hours. (Peroxide test papers gave a negative result.)
Filtered through a pad of HiFlo to remove the palladium on carbon and the solvent was evaporated under reduced pressure to give the product as a yellow oil (22.2 g).
1H NMR (300 MHz, CDCl3) 5.5 (M, 1H), 4.85 (M, 1H), 4.5 (M, 2H), 3.7 (M, 4H), 3.4 (M, 3H), 2.95 (M, 1H), 2.65 (M, 1H), 2.25 (M, 1H), 2.0 (M, 1H), 1.85 (M, 1H), 1.75 (M, 1H), 1.75 (S, 3H), 1.55 (M, 1H), 1.55 (S, 3H)
4-Isoprenyl-1-methyl-2-morpholin-4-yl-cyclohexanol (4.6 g, 0.018 moles) was dissolved in toluene (80 ml) and silica (1.1 g) was added. The reaction mixture was heated to reflux with stirring. Water generated in the reaction was removed using Dean and Stark apparatus. After refluxing overnight, the silica was removed by filtration and the filtrate evaporated under reduced pressure to give a brown oil
(4.0 g). Dissolved in dichloromethane and washed with 2M hydrochloric acid. Washed with water and dried over anhydrous magnesium sulphate. The solvent was removed by evaporation under reduced pressure to give the product as a brown oil (1.3 g).
1H NMR (300 MHz, CDCl3) 5.7 (M, 2H), 4.8 (M, 2H), 2.7 (M, 1H), 1.8 (M,2H), 1.75(S,3H), 1.65(M,2H), 1.3(S,3H)
Experimental details for Synthesis of Tetrahydropyridines
To a stirred solution of 2,4-dimethoxybromobenzene (1) (0.5 g, 2.3 mmol) in diethyl ether (10 ml) cooled at −78° C. under nitrogen was added a solution of n-butyl lithium (1.0 ml, 2.5 mmol of 2.5M solution in hexane) drop wise. The mixture was stirred at −78° C. for 2 hours and then 1,4-dimethyl pyridinium iodide (2) (0.54 g, 2.5 mmol) was added as a solid. The resultant mixture was allowed to warm to room temperature and stirred at room temperature for 18 hours. The mixture was diluted with water (20 ml) and extracted with diethyl ether (2×15 ml). The combined organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated to yield 2-(2,4-dimethoxyphenyl)-1,4-dimethyl-1,2-dihydropyridine (4) (0.5 g, 93%) as a brown oil, 1H NMR CDCl3??1.7 (s, 3H), 2.7 (s, 3H), 3.8(s, 6H), 4.45 (dd, 1H, J=2,7) 4.85 (m, 1H), 5.4 (d, 1H, J=4), 6.05 (d, 1H, J=7), 6.45 (d, 1H, J=3), 6.55 (m, 1H), 7.5 (d, 1H, J=9).
By proceeding in a similar manner starting from 2,4-dimethoxybromobenzene (1) and 1-isopropyl-4-methyl pyridinium iodide (3), 2-(2,4-dimethoxyphenyl)-1-isopropyl-4-methyl-1,2-dihydropyidine (5) was prepared, 1H NMR CDCl3? (d, 6H J=7), 1.7 (s, 3H), 3.15 (m, 1H), 3.7 (s, 6H), 4.5 (d, 1H J=8), 4.8 (m,1H), 5.5(5, 1H J=5), 6.3 (d, 1H J=7), 6.45 (d, 1H J=2), 6.55 (m, 1H), 7.55 (d, 1H J=8).
To a stirred solution of 2-(2,4-dimethoxyphenyl)-1,4-dimethyl-1,2-dihydropyridine(4) (0.48 g, 2.06 mmol) in methanol (5 ml) at room temperature was added sodium borohydride (98 mg, 2.51 mmol), gas evolution commenced immediately, the resulting mixture was stirred for 3 hours. At this time the solvent was evaporated and the residue suspended in water (5 ml) and extracted with ethyl acetate (2×10 ml). The organic extract was then extracted with 2M hydrochloric acid (2×15 ml). The aqueous layer was basified with 2M sodium hydroxide and extracted with ethyl acetate (2×20 ml), the organic extract was dried over anhydrous magnesium sulphate, filtered and evaporated to yield 6-(2,4-dimethoxyphenyl)-1,4-dimethyl-1,2,3,6-tetrahydropyridine (6) (350 mg, 73%) as a yellow oil, 1H NMR CDCl3 δ?1.55 (s, 3H), 1.9 (m, 1H), 2.2 (s, 3H), 2.5(m, 2H), 2.95 (m, 1H), 3.8 (s, 6H), 4.1 (m, 1H), 5.2 (m, 1H), 6.5 (m, 2H), 7.3 (d, 1H J=4).
By proceeding in a similar manner starting from 2-(2,4-dimethoxyphenyl)-1-isopropyl-4-methyl-1,2-dihydropyidine (5), 6-(2,4-dimethoxyphenyl)-1-isopropyl-4-methyl-1,2,3,6-tetrahydropyridine (7) was prepared, 1H NMR CDCl3 δ 0.95 (d, 3H J=6), 1.05 (d, 3H J=6), 1.7 (s, 3H), 1.9 (m, 1H), 2.5 (m, 1H), 2.85 (m, 1H), 3.0 (m,1H), 3.8 (s, 6H), 4.6 (s, 1H), 5.2 (s, 1H), 6.45 (d, 1H J=3), 6.5 (dd, 1H J=3,8), 7.4 (d, 1H J=8).
To a stirred solution of 6-(2,4-dimethoxyphenyl)-1,4-dimethyl-1,2,3,6-tetrahydro-pyridine (6) (300 mg, 1.27 mmol) in dichloromethane (20 ml) cooled at 0° C. under nitrogen was added boron tribromide (3.1 ml, 3.18 mmol of 1.0M solution in dichloromethane), the resultant dark solution was allowed to warm to room temperature and stirred for 1 hour. The solution was poured onto ice and basified with sodium bicarbonate. The layers were separated and the aqueous layer was extracted with dichloromethane (20 ml), the combined organic layers were dried over anhydrous magnesium sulphate, filtered and evaporated to a gum (200 mg). The material was purified on a 10 g silica cartridge eluting with methanol/dichloromethane/ammonia (7:92:1) to yield 4-(1,4-dimethyl-1,2,5,6-tetrahydropyridin-2-yl)-benzene-1,3-diol (8) (93 mg, 35%) as a gum, 1H NMR D6-acetone ??1.67 (s, 3H), 1.97 (m,1H), 2.3 (s, 3H), 2.42 (m, 1H), 2.74 (m, 1H), 3.08 (m, 1H), 3.74 (s, 1H), 5.15 (s, 1H), 6.2 (d, 1H J=2), 6.27 (dd, 1H J=2,8), 6.82 (d, 1H J=8), 9.4 (bs, 2H).
By proceeding in a similar manner starting from 6-(2,4-dimethoxyphenyl)-1-isopropyl-4-methyl-1,2,3,6-tetrahydropyridine (7), 4-(1-isopropyl-4-methyl-1,2,5,6-tetra-hydropyridin-2-yl)-benzene-1,3-diol (9) was prepared, NMR D6-acetone δ 0.81 (d, 3H J=7), 0.98 (d, 3H J=7), 1.52 (s, 3H), 1.84 (m, 1H), 2.15(m, 1H), 2.29(m, 1H), 2.94 (m, 2H), 4.09 (s, 1H), 4.97 (s, 1H), 6.05 (d, 1H J=3), 6.11(dd, J=3,8), 6.68 (d, J=8), 9.6 (bs, 2H).
To a stirred solution of 4-picoline (2.5 g, 26.8 mmol) in acetonitrile (50 ml) was added isopropyl iodide (9.1 g, 53.6 mmol) drop wise, the resultant mixture was heated at 90° C. for 24 hours. After cooling the solvent was evaporated to give a red solid which on trituration with ethyl acetate yielded 1-isopropyl-4-methyl pyridinium iodide (6.01 g, 85%) as a cream solid, 1H NMR D6-DMSO δ?1.6 (d, 6H, J=7), 2.6 (s, 3H), 4.95 (m, 1H), 8.0 (d, 2H J=6), 9.05 (d, 2H J=6).
3-Chloroaniline (3.8 g, 0.03 moles) was dissolved in ethanol (5 ml) and ethyl acrylate (3.3 g, 0.033 moles) was added in ethanol (5 ml). Concentrated hydrochloric acid (1 ml) was added and the reaction mixture was heated at reflux for 48 hours. Evaporated to a low bulk and dissolved the residue in dichloromethane and water. Basified to pH 9 with aqueous ammonia and separated. Evaporated off the dichloromethane under reduced pressure to give the crude product as a yellow oil (5.4 g) Purified using a silica column eluted with isohexane:ethyl acetate 9:1 to give the required product (3.5 g, 51%) as a colourless oil.
1H NMR CDCl3 δ 1.30 (t, 3H, J=6.5 Hz), 2.65 (t, 2H, J=6 Hz), 3.45 (q, 2H J=6 Hz), 4.20 (q, 2H, J=6.5 Hz), 6.50 (m, 1H), 6.60 (m, 1H), 6.70 (m, 1H), 7.10 (m, 1H)
Ethyl 3-(3-Chlorophenylamino)propionate (3.5 g, 0.0154 moles) was dissolved in dichloromethane (40 ml) and ethyl malonyl chloride (2.55 g, 0.017 moles) was added dropwise in dichloromethane (10 ml) with stirring and cooling in order to keep the reaction temperature below 20°. Triethylamine (1.72 g, 0.017 moles) was added dropwise in dichloromethane (10 ml). The reaction temperature was kept below 20° by ice bath cooling. The reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight. Washed with 2M hydrochloric acid, water and sodium bicarbonate solution. Dried over anhydrous magnesium sulphate, filtered and evaporated to give the required product as an orange oil. (4.5 g, 86%)
1H NMR CDCl3 δ 1.25 (m, 6H), 2.65 (t, 2H, J=7 Hz), 3.20 (s, 2H), 4.10 (m, 4H), 7.15 (m, 1H), 7.30 (m, 1H), 7.40 (m, 2H)
Sodium (0.7 g, 0.029 moles) was dissolved in ethanol (90 ml) and N-(3-Chlorophenyl)-N-(2-ethoxycarbonyl-ethyl)-malonamic acid ethyl ester (4.5 g, 0.0132 moles) was added in ethanol (30 ml). The reaction mixture was heated at reflux overnight. The ethanol was evaporated off and the residue dissolved in water. Washed with diethyl ether and acidified to pH2 with concentrated sulphuric acid. Extracted with dichloromethane and the combined dichloromethane extracts were combined. Washed with water and dried over anhydrous magnesium sulphate. Filtered and evaporated to give the product as an orange oil (2.8 g, 72%)
1H NMR CDCl3 δ 1.40 (t, 3H, J=5 Hz), 2.85 (t, 2H, J=6 Hz), 3.85 (t, 2H J=6 Hz), 4.40 (q, 2H, J=5 Hz), 7.20 (m, 2H), 7.30 (m, 1H), 7.35 (m, 1H)
Ethyl 1-(3-chlorophenyl)piperidine-2,4-dione carboxylate (2.8 g, 0.0095 moles) was dissolved in acetonitrile (100 ml)/water (10 ml) and refluxed for 2 hours. Evaporated to a low bulk and dissolved in dichloromethane. Washed with water and dried over anhydrous magnesium sulphate. Filtered and evaporated to give the product as an orange oil (2.2 g). Purified using a silica column eluted with dichloromethane:ethyl acetate 9:1 to give the required product as a pale yellow gum (1.2 g, 59%)
1H NMR CDCl3 δ 2.80 (t, 2H, J=6 Hz), 3.55 (s, 2H), 4.05 (t, 2H, J=6 Hz), 7.20 (m, 1H), 7.30 (m, 1H), 7.35 (m, 1H), 7.40 (m, 1H)
Also prepared in a similar manner were
1H NMR CDCl3, ppm) δ 2.80 (t, 2H, J=6 Hz), 3.6 (s, 2H), 4.05 (t, 2H, J=6 Hz), 7.30 (m, 3H), 7.45 (m, 2H)
1H NMR (CDCl3, ppm) δ 2.40 (s, 3H), 2.80(t, 2H, J=6.5 Hz), 3.6 (s, 2H), 4.05 (t, 2H, J=6.5 Hz), 7.30 (m, 3H), 7.45 (m, 2H)
1H NMR CDCl3, ppm) δ 2.80 (t, 2H, J=6 Hz), 3.55 (s, 2H), 4.0 (t, 2H, J=6 Hz), 7.1 (m, 2H), 7.25 (m, 2H)
1H NMR (CDCl3, ppm) δ 2.80 (t, 2H, J=6 Hz), 3.58 (s, 2H), 4.04 (t, 2H, J=6 Hz), 6.68-6.83 (m, 1H), 6.84-6.99 (m, 2H).
1H NMR (CDCl3, ppm) δ 2.80 (t, 2H, J=6 Hz), 3.58 (s, 2H), 4.02 (t, 2H, J=6 Hz), 7.20-7.36 (m, 3H).
1H NMR (CDCl3, ppm) δ 2.41 (s, 3H), 2.75 (t, 2H, J=6 Hz), 3.62 (s, 2H), 4.44 (t, 2H, J=6 Hz), 6.94-7.02 (m, 1H), 7.72-7.79 (m, 1H), 8.25-8.36 (m, 1H).
Sodium (0.3 g, 0.013 moles) was dissolved in ethanol (50 ml) and 4-Fluorophenylacetone (2.0 g, 0.013 moles) was added in ethanol (10 ml). Ethyl acrylate (1.3 g, 0.013 moles) was and the reaction mixture was heated at reflux overnight. The reaction mixture was allowed to cool and evaporated under reduced pressure to give a brown gum. Dissolved in water and washed with diethyl ether. The aqueous layer was acidified to pH2 with conc. Hydrochloric acid and extracted with dichloromethane. The extracts were combined and washed with water. Dried over anhydrous magnesium sulphate and filtered. The filtrate was evaporated to give an orange oil. (1.7 g) This was purified using a silica column eluted with dichloromethane: ethyl acetate 8:2 and then dichloromethane:ethyl acetate 2:1 to give a colorless gum. (0.428 g) This was triturated with diethyl ether/isohexane to give 4-(4-Fluorophenyl)cyclohexane-1,3-dione (0.28 g) as a white solid.
1H NMR (CD3OD, ppm) δ 2.1 (m, 1H), 2.3 (m, 1H), 2.4 (m, 2H), 3.7 (m, 1H), 4.9 (s, 2H), 7.1 (m, 2H), 7.2 (m, 2H).
Also prepared in a similar manner
1H NMR (CD3OD, ppm) δ 2.15 (m, 1H), 2.3 (m, 3H), 3.7 (m, 1H), 4.9 (s, 2H), 7.2 (m, 3H), 7.3 (m, 2H).
To a mixture of aniline (1.86 g, 20 mmol) in concentrated hydrochloric acid (10 ml) and water (20 ml) at a temperature below 5° C. was added a solution of sodium nitrite (1.38 g, 20 mmol) in water (15 ml) drop wise. The resultant mixture was stirred for 15 minutes and then it was poured into a solution of dimethylacetonedicarboxylate (3.48 g, 20 mmol) and sodium acetate (12 g, 0.146 mol) in ethanol (12 ml) and water (40 ml) causing an immediate precipitation. The suspension was stirred for 1 hour and then extracted with ethyl acetate (3×125 ml). The combined organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated to yield 3-oxo-2-phenylhydrazono)pentanedioic acid dimethyl ester as a red oil (5.58 g, quantitative) consisting of a mixture of E and Z isomers about the hydrazone
1NMR CDCl3 δ{tilde over (□)}{tilde over (□)}{tilde over (□)}(singlets, 8H), 7.1-7.5 (m, 5H), 12.8 (s, 1H).
3-Oxo-2-phenylhydrazono)pentanedioic acid dimethyl ester (12.5 mmol) was dissolved in dichlorobenzene and heated at reflux for 24 hours and then allowed to cool to room temperature. The solvent was evaporated and the residue triturated with ether to give methyl 4-hydroxy-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylate a beige solid (2.4 g, 78%)
1H NMR CDCl3 δ 4.0 (s, 3H), 6.4 (s, 1H), 7.4-7.6 (m, 5H), 10.3 (s, 1H).
Methyl 4-hydroxy-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylate (0.8 g, 3.24 mmol) was suspended in sodium hydroxide solution (20 ml of 2.0M) and heated at reflux for 1 hour. The mixture was allowed to cool to room temperature, acidified with 2M hydrochloric acid and extracted with ethyl acetate (3×15 ml). The combined organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated to yield 4-hydroxy-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylic acid as a yellow solid (0.6 g, 80%)
1H NMR CDCl3 δ 6.3 (s, 1H), 7.35-7.7 (m, 5H).
4-Hydroxy-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylic acid (400 mg, 1.72 mmol) was heated at 270° C. in a microwave for 3 minutes. The resultant black mixture was extracted into saturated sodium bicarbonate (15 ml). The sodium bicarbonate solution was acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3×15 ml). The combined organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated to a crude solid (300 mg). This was purified on a 10 g SPE cartridge eluting with dichloromethane/ethyl acetate (80:20 to 60:40) to yield 5-hydroxy-2-phenyl-2H-pyridazin-3-one (60 mg) as a beige solid
1H NMR D6 DMSO δ 6.05 (d, 1H, J=2.7 Hz), 7.4-7.6 (m, 5H), 7.85 (d, 1H, J=2.7 Hz), 11.6 (s, 1H).
The following compounds are also active in the method of the present invention:
The following synthesis is described in J. Het. Chem. 1989, 26, 169-176
4-Bromo-2-(3,5-difluorophenyl)-5-hydroxypyridazin-3-one (0.6 g, 1.98 mmoles) was dissolved in ethanol (50 ml) and 1M sodium hydroxide (4 ml) was added. 10% Palladium on carbon (0.15 g) was added and the flask was placed under an atmosphere of hydrogen (balloon) with stirring. The reaction mixture was stirred overnight at room temperature. Filtered off the catalyst using Hyflo and evaporated to dryness. Added 2M hydrochloric acid and extracted into ethyl acetate. Washed with water and dried over anhydrous magnesium sulphate. Filtered and evaporated the filtrate to give a white solid. Triturated with diethyl ether to give the product as a white solid. (0.32 g, 72%)
1H NMR DMSOd6 δ 12.2 (br s, 1H), 7.9 (d, 1H, J=3 Hz), 7.3 (m, 5H), 6.1 (d, 1H, J=3 Hz)
Also prepared in a similar manner
1H NMR DMSOd6 δ 11.8 (br s, 1H), 7.85 (d, 1H, J=2.5 Hz), 7.4 (m, 4H), 6.1 (d, 1H, J=2.5 Hz)
4,5-Dibromo-2-(3,5-difluorophenyl)pyridazin-3-one (1.5 g, 0.0041 moles) was suspended in ethanol (50 ml) and potassium hydroxide (0.8 g, 0.0123 moles) was added in water (8 ml). Refluxed for 4 hours with stirring. Evaporated to a low bulk and diluted with water. Acidified to pH2 with conc. hydrochloric acid and extracted with ethyl acetate. Washed with water and dried with anhydrous magnesium sulphate. Filtered and evaporated the filtrate to give an orange solid. Triturated with diethyl ether and dried in a desiccator to give the product as a cream solid. (0.7 g, 56%)
1H NMR DMSOd6 δ 12.5 (br s, 1H), 7.9 (s, 1H), 7.35 (m, 3H); 19F NMR δ 110
Also prepared in a similar manner
1H NMR DMSOd6 δ 7.9 (s, 1H), 7.5 (m, 3H); 19F NMR δ 117, 126
1H NMR DMSOd6 δ 7.9 (s, 1H), 7.8 (d, 1H, J=2.5 Hz), 7.7 (d, 1H, J=8.5 Hz), 7.6 (d,d, 1H, J=2.5, 8.5 Hz)
Mucobromic acid (2.8 g, 0.011 moles) was dissolved in ethanol (75 ml) and 3,5-difluorophenyl hydrazine hydrochloride (1.8 g, 0.01 moles) was added. After 30 minutes, triethylamine (1.4 ml, 0.01 moles) was added. The reaction mixture was stirred at room temperature for 3 hours. Evaporated to a low bulk and the residue was suspended in glacial acetic acid (80 ml). Refluxed with stirring overnight to give a brown solution. Evaporated to dryness and triturated with methanol to give the required product as a pale brown solid. (3.4 g, 93%)
1H NMR DMSOd6 δ 8.3 (s, 1H), 7.4 (m, 3H); 19F NMR δ 109
Also prepared in a similar manner
1H NMR DMSOd6 δ 7.9 (s, 1H), 7.45 (m, 1H), 7.4 (m, 2H)
1H NMR DMSOd6 δ 8.35 (s, 1H), 7.8 (m, 1H), 7.7(m,2H)
1H NMR DMSOd6 δ 8.35 (s, 1H), 7.5 (m, 3H)
2-(3,5-Dichlorophenyl)-5-methoxypyridazin-3-one (0.25 g, 0.92 mmoles) was suspended in ethanol (40 ml) and potassium hydroxide (0.12 g, 1.8 mmoles) was added in water (5 ml). Refluxed overnight with stirring to give a yellow solution. Evaporated to dryness and added 2M hydrochloric acid. Extracted with ethyl acetate (×2) and washed with water and dried over anhydrous magnesium sulphate. Filtered and evaporated to give a yellow solid. Triturated with dichloromethane to give a pale yellow solid. (0.1 g, 42%)
1H NMR DMSOd6 δ 7.75 (d, 1H, J=3 Hz), 7.6 (m, 2H), 7.5 (m, 1H), 6.25 (d, 1H, J=3 Hz)
Also prepared in a similar manner
1H NMR DMSOd6 δ 10.9 (br s, 1H), 7.7 (d, 1H, J=3 Hz), 7.4 (m, 1H), 7.35 (m, 1H), 7.3 (m, 1H), 6.2 (d, 1H, J=3 Hz)
4-Bromo-2-(3,5-dichlorophenyl)-5-methoxypyridazin-3-one (2.5 g, 0.0071 moles) was dissolved in THF (250 ml) and cooled to −50° under nitrogen. 1.6M n-Butyl lithium (6.7 ml, 0.011 moles) was added dropwise with stirring. Allowed to warm to −20° over 1 hour. Added 1 equivalent of 1.6M n-Butyl lithium (4.4 ml, 0.0071 moles) dropwise. Stirred at −20° for 30 minutes. Poured into ammonium chloride solution and stirred for 15 minutes. Extracted with EtOAc (×2) and washed with water. Dried over anhydrous magnesium sulphate, filtered and evaporated to give a brown solid. (3.0 g) Purified using MPLC (silica, eluted with dichloromethane: EtOAc 9:1) to give a yellow solid. (0.25 g, 13%) Not pure used directly in the next reaction.
1H NMR DMSOd6 δ 7.7 (d, 1H, J=3 Hz), 7.6 (d, 2H, J=2 Hz), 7.5 (d, 1H, J=2 Hz), 6.2 (d, 1H, J=3 Hz)
Also prepared in a similar manner
1H NMR DMSOd6 δ 7.95 (d, 1H, J=3 Hz), 7.75 (d, 1H, J=2.5 Hz), 7.7 (d, 1H, J=8 Hz), 7.6 (d, d, 1H, J=2.5, 8 Hz), 6.45 (d, 1H, J=3 Hz)
Sodium (0.28 g, 0.012 moles) was dissolved in methanol (100 ml) and a suspension of 4,5-Dibromo-2-(3,5-dichlorophenyl)pyridazin-3-one (4.0 g, 0.01 moles) in methanol (60 ml) was added. Refluxed overnight. Evaporated to dryness and added water. Filtered off the solid and dried in a dessicator. Triturated with ether and dried in a dessicator. (3.1 g, 89%)
1H NMR DMSOd6 δ 8.35 (s, 1H), 7.75 (m, 1H), 7.7 (m, 2H), 4.15 (s, 3H)
Also prepared in a similar manner
1H NMR DMSOd6 δ 8.35 (s, 1H), 7.8 (d, 1H, J=2.5 Hz), 7.7 (d, 1H, J=8.5 Hz), 7.65 (d of d, 1H, J=2.5, 8 Hz), 4.15 (s, 3H)
4,5-Dichloro-2-phenylpyridazin-3-one (2.4 g, 0.01 moles) was suspended in ethanol (50 ml) and potassium hydroxide (2.0 g, 0.03 moles) was added in water (20 ml). Refluxed for 4 hours. Evaporated to dryness and added water. Acidified to pH2 with c. hydrochloric acid. Filtered off the product as a buff solid and dried in a desiccator. (2.1 g) Took 0.5 g and dissolved in methanol, filtered and evaporated. Triturated with ether to give the product as a cream solid. (0.4 g, 76%)
1H NMR DMSOd6 δ 7.9, (s, 1H), 7.5 (m, 4H), 7.4 (m, 1H)
Mucochloric acid (9.3 g, 0.055 moles) was dissolved in ethanol (60 ml) and phenyl hydrazine (5.4 g, 0.05 moles) was added. The reaction mixture was stirred at room temperature for 2 hours. Evaporated to a low bulk and the residue was suspended in glacial acetic acid (60 ml). Refluxed with stirring for 3 hours. Evaporated to dryness and triturated with methanol to give the required product as a pale brown solid. (11.0 g, 91%)
1H NMR DMSOd6 δ 7.95 (s, 1H), 7.5 (m, 4H), 7.4 (m, 1H)
The following compounds have also been found to be effective in treating glaucoma or ocular hypertension according to the method of the present invention.
It is apparent to one of ordinary skill in the art that different pharmaceutical compositions may be prepared and used with substantially the same results. That is, other Abnormal Cannabidiols will effectively lower intraocular pressure in animals and are within the scope of the present invention. Also, the novel compounds of the present invention may be used in a method of providing neuroprotection to the eye of a mammal in a similar manner to the abnormal Cannabidiols of Published U.S. Patent Application 2005/0282912.
This is a Continuation-In-Part (CIP) based on, and claims the benefit of U.S. Ser. No. 11/409,868 filed Apr. 24, 2006; Ser. No. 11/409,570 filed Apr. 24, 2006, and Ser. No. 11/409,871 filed Apr. 24, 2006, and which are incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| Parent | 11409868 | Apr 2006 | US |
| Child | 11739183 | US | |
| Parent | 11409570 | Apr 2006 | US |
| Child | 11409868 | US | |
| Parent | 11409871 | Apr 2006 | US |
| Child | 11409570 | US |
