Patent Application
20080015231
The following are hypothetical examples of useful compounds:
A compound of the formula
or a pharmaceutically acceptable salt thereof, or a prodrug thereof;
wherein a dashed line represents the presence or absence of a bond;
A is —(CH2)6—, cis —CH2CH═CH—(CH2)3—, or —CH2C≡C—(CH2)3—, wherein 1 or 2 carbon atoms may be replaced by S or O; or A is —(CH2)m—Ar—(CH2)o— wherein Ar is interarylene or heterointerarylene, the sum of m and o is 1, 2, 3, or 4, and wherein one CH2 may be replaced by S or O;
or a pharmaceutically acceptable salt thereof, or a prodrug thereof;
wherein a dashed line represents the presence or absence of a bond;
A is —(CH2)6—, cis —CH2CH═CH—(CH2)3—, or —CH2C≡C—(CH2)3—, wherein 1 or 2 carbon atoms may be replaced by S or O; or A is —(CH2)m—Ar—(CH2)o— wherein Ar is interarylene or heterointerarylene, the sum of m and o is 1, 2, 3, or 4, and wherein one CH2 may be replaced by S or O;
The compound according to compound example 1 wherein Y is selected from CO2R2, CON(R2)2, CON(OR2)R2, CON(CH2CH2OH)2, CONH(CH2CH2OH), CH2OH, P(O)(OH)2, CONHSO2R2, SO2N(R2)2, SO2NHR2,
wherein R2 is independently H, C1-C6 alkyl, unsubstituted phenyl, or unsubstituted biphenyl.
The compound according to compound example 1 or 3 of the formula
or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
The compound according to compound example 1 or 3, wherein said compound has the formula
or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
The compound according to compound example 1 or 3, wherein said compound has the formula
or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
The compound according to any one of compound examples 1 to 6 wherein A is (3-methylphenoxy)methyl.
The compound according to any one of compound examples 1 to 6 wherein A is (4-but-2-ynyloxy)methyl.
The compound according to any one of compound examples 1 to 6 wherein A is 2-(2-ethylthio)thiazol-4-yl.
The compound according to any one of compound examples 1 to 6 wherein A is 2-(3-propyl)thiazol-5-yl.
The compound according to any one of compound examples 1 to 6 wherein A is 3-(methoxymethyl)phenyl.
The compound according to any one of compound examples 1 to 6 wherein A is 3-(3-propyl)phenyl.
The compound according to any one of compound examples 1 to 6 wherein A is 3-methylphenethyl.
The compound according to any one of compound examples 1 to 6 wherein A is 4-(2-ethyl)phenyl.
The compound according to any one of compound examples 1 to 6 wherein A is 4-phenethyl.
The compound according to any one of compound examples 1 to 6 wherein A is 4-methoxybutyl.
The compound according to any one of compound examples 1 to 6 wherein A is 5-(methoxymethyl)furan-2-yl.
The compound according to any one of compound examples 1 to 6 wherein A is 5-(methoxymethyl)thiophen-2-yl.
The compound according to any one of compound examples 1 to 6 wherein A is 5-(3-propyl)furan-2-yl.
The compound according to any one of compound examples 1 to 6 wherein A is 5-(3-propyl)thiophen-2-yl.
The compound according to any one of compound examples 1 to 6 wherein A is 6-hexyl.
The compound according to any one of compound examples 1 to 6 wherein A is (Z)-6-hex-4-enyl.
The compound according to any one of compound examples 1, 3, 4 and 7 to 22, wherein said compound has the formula
or a pharmaceutically acceptable salt thereof or a prodrug thereof.
The compound according to any one of compound examples 1, 3, and 7 to 22, wherein said compound has the formula
or a pharmaceutically acceptable salt thereof or a prodrug thereof.
The compound according to any one of compound examples 1, 3, and 6 to 22, wherein said compound has the formula
or a pharmaceutically acceptable salt thereof or a prodrug thereof.
The compound according to any one of compound examples 1, 3, and 6 to 22, wherein said compound has the formula
or a pharmaceutically acceptable salt thereof or a prodrug thereof.
The compound according to any one of compound examples 1, 3, and 6 to 22, wherein said compound has the formula
or a pharmaceutically acceptable salt thereof or a prodrug thereof.
The compound according to any one of compound examples 1, 3, and 6 to 22, wherein said compound has the formula
or a pharmaceutically acceptable salt thereof or a prodrug thereof.
The compound according to any one of compound examples 1 to 3, and 7 to 22 wherein U1 is O.
The compound according to any one of compound examples 1 to 3, and 7 to 22 wherein U1 is S.
The compound according to any one of compound examples 1 to 3, and 7 to 22 wherein U1 is F.
The compound according to any one of compound examples 1 to 3, and 7 to 22 wherein U1 is Cl.
The compound according to any one of compound examples 1 to 3, and 7 to 22 wherein U1 is Br.
The compound according to any one of compound examples 1 to 3, and 7 to 22 wherein U1 is I.
The compound according to any one of compound examples 1 to 3, and 7 to 22 wherein U1 is CN.
The compound according to any one of compound examples 1 to 3, and 7 to 22 wherein U1 is O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.
The compound according to any one of compound examples 1 to 3, 7 to 22, and 29 to 36, wherein J1 is hydrogen.
The compound according to any one of compound examples 1 to 3, 7 to 22, and 29 to 36, wherein J1 is F.
The compound according to any one of compound examples 1 to 3, 7 to 22, and 29 to 36, wherein J1 is Cl.
The compound according to any one of compound examples 1 to 3, 7 to 22, and 29 to 36, wherein J1 is Br.
The compound according to any one of compound examples 1 to 3, 7 to 22, and 29 to 36, wherein J1 is I.
The compound according to any one of compound examples 1 to 3, 7 to 22, and 29 to 36, wherein J1 is O.
The compound according to any one of compound examples 1 to 3, 7 to 22, and 29 to 36, wherein J1 is OH.
The compound according to any one of compound examples 1 to 3, 7 to 22, and 29 to 36, wherein J1 is CN.
The compound according to any one of compound examples 1 to 3, 7 to 22, and 29 to 36, wherein J1 is O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.
The compound according to any one of compound examples 1 to 3, 7 to 22, and 29 to 36, wherein J1 is alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms.
The compound according to any one of compound examples 1 to 3, 7 to 22, and 29 to 36, wherein J1 is CF3.
The compound according to any one of compound examples 1 to 3, 7 to 22, and 29 to 47 wherein J2 is hydrogen.
The compound according to any one of compound examples 1 to 3, 7 to 22, and 29 to 47 wherein J2 is F.
The compound according to any one of compound examples 1 to 3, 7 to 22, and 29 to 47 wherein J2 is Cl.
The compound according to any one of compound examples 1 to 3, 7 to 22, and 29 to 47 wherein J2 is Br.
The compound according to any one of compound examples 1 to 3, 7 to 22, and 29 to 47 wherein J2 is I.
The compound according to any one of compound examples 1 to 3, 7 to 22, and 29 to 47 wherein J2 is CN.
The compound according to any one of compound examples 1 to 3, 7 to 22, and 29 to 47 wherein J2 is O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.
The compound according to any one of compound examples 1 to 3, 7 to 22, and 29 to 47 wherein J2 is alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms.
The compound according to any one of compound examples 1 to 3, 7 to 22, and 29 to 47 wherein J2 is CF3.
The compound according to any one of compound examples 1 to 56 wherein B is substituted or unsubstituted phenyl.
The compound according to any one of compound examples 1 to 56 wherein B is substituted or unsubstituted thienyl.
The compound according to any one of compound examples 1 to 56 wherein B is substituted or unsubstituted naphthyl.
The compound according to any one of compound examples 1 to 56 wherein B is substituted or unsubstituted furyl.
The compound according to any one of compound examples 1 to 56 wherein B is substituted or unsubstituted pyridinyl.
The compound according to any one of compound examples 1 to 56 wherein B is substituted or unsubstituted benzothienyl.
The compound according to any one of compound examples 1 to 56 wherein B is substituted or unsubstituted indanyl.
The compound according to any one of compound examples 1 to 56 wherein B is substituted or unsubstituted tetralonyl.
The compound according to any one of compound examples 1 to 56 wherein B has 1, 2, 3, 4, or 5 substituents, wherein each substituent has one or more carbon, fluorine, chlorine, bromine, or oxygen atoms; and wherein all substituents taken together consist of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9 fluorine atoms; 0, 1, 2 or 3 chlorine atoms, 0, 1, 2 or 3 bromine atoms, and 0, 1, 2 or 3 oxygen atoms.
The compound according to any one of compound examples 1 to 56 wherein B has a substituent of the formula CaHbOc; wherein a is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9, b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19; and c is 0, 1, 2, or 3.
The compound according to any one of compound examples 1 to 56 wherein B has 1, 2, 3, or 4 alkyl substituents having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
The compound according to any one of compound examples 1 to 56 wherein B has a hydroxyalkyl substituent having 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and 1 or 2 hydroxy moieties.
The compound according to any one of compound examples 1 to 56 wherein B has an alkyl substituent having 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
The compound according to any one of compound examples 1 to 56 wherein B has 1, 2, 3, or 4 halogen substituents.
The compound according to any one of compound examples 1 to 56 wherein B has 1, 2, 3, or 4 chloro substituents.
The compound according to any one of compound examples 1 to 56 wherein B has 1 chloro substituent.
The compound according to any one of compound examples 1 to 56 wherein B has 2 chloro substituents.
The compound according to any one of compound examples 1 to 56 wherein B has 1, 2, 3, or 4 trifluoromethyl substituents.
The compound according to any one of compound examples 1 to 56 wherein B has 1, 2, or 3 trifluoromethyl substituents.
The compound according to any one of compound examples 1 to 56 wherein B has 1 trifluoromethyl substituent.
The compound according to any one of compound examples 1 to 56 wherein B has 2 trifluoromethyl substituents.
The compound according to any one of compound examples 1 to 56 wherein B has a hydroxyl substituent.
The compound according to any one of compound examples 1 to 57 wherein B is unsubstituted phenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 3,5-dichlorophenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 3,5-di(trifluoromethyl)phenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 2-chlorophenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 3-chlorophenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 4-chlorophenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 3-(trifluoromethyl)phenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 3-isopropylphenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 3-tert-butylphenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 3-hydroxyphenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 3-methoxyphenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 3-(benzoyloxy)phenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 2,3-dimethylphenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 3,4-dimethylphenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 2,4-dimethylphenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 2,5-dimethylphenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 3,5-dimethylphenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 2,6-dimethylphenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 3-(hydroxymethyl)phenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 3-(1-hydroxyethyl)phenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 3-(1-hydroxy-2-methylpropyl)phenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 2-(hydroxymethyl)phenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 4-(hydroxymethyl)-3,5-dimethylphenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 4-(methoxymethyl)-3,5-dimethylphenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 3-(1-hydroxybutyl)phenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 4-(1-methoxybutyl)phenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 4-(1-hydroxybutyl)phenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 4-(2-hydroxyethyl)phenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 3-(2-hydroxyethyl)phenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 2-(2-hydroxyethyl)phenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 4-(2-hydroxyethyl)-3,5-dimethylphenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 3-(1-hydroxyhexyl)phenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 3-(acetoxymethyl)-5-chlorophenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 1-oxo-2,3-dihydro-1H-inden-4-yl.
The compound according to any one of compound examples 1 to 57 wherein B is 1-hydroxy-2,3-dihydro-1H-inden-4-yl.
The compound according to any one of compound examples 1 to 57 wherein B is 5-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl.
The compound according to any one of compound examples 1 to 57 wherein B is 3-(1-hydroxy-2-phenylethyl)phenyl.
The compound according to any one of compound examples 1 to 57 wherein B is 4-(2-phenylpropan-2-yl)phenyl.
The compound according to any one of compound examples 1 to 56 wherein B is naphthalen-2-yl.
The compound according to any one of compound examples 1 to 56 wherein B is naphthalen-1-yl.
The compound according to any one of compound examples 1 to 56 wherein B is 4-chloronaphthalen-1-yl.
The compound according to any one of compound examples 1 to 3, 7 to 22, and 37 to 119 wherein U1 is hydrogen.
The compound according to any one of compound examples 1 to 3, 7 to 22, and 39 to 119 wherein U1 is OH.
A composition comprising a compound according to any one of compound examples 1 to 121, wherein said composition is a liquid which is ophthalmically acceptable.
Use of a compound according to any one of compound examples 1 to 121 in the manufacture of a medicament for the treatment of glaucoma or ocular hypertension in a mammal.
A medicament comprising a compound according to any one of compound examples 1 to 121, wherein said composition is a liquid which is ophthalmically acceptable.
A method comprising administering a compound according to any one of compound examples 1 to 121 to a mammal for the treatment of glaucoma or ocular hypertension.
A kit comprising a composition comprising compound according to any one of compound examples 1 to 121, a container, and instructions for administration of said composition to a mammal for the treatment of glaucoma or ocular hypertension.
“Treatment,” “treat,” or any other form of these words as used herein are intended to mean use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals.
H1-H64 are hypothetical examples of useful compounds.
DMSO (94 μL, 1.21 mmol) was added to a solution of oxalyl chloride (51 μL, 0.58 mmol) in CH2Cl2 (0.5 mL) at −78° C. After 15 min, a solution of alcohol 1 (250 mg, 0.485 mmol) in CH2Cl2 (1.0 mL+1.0 mL rinse) was added. After 15 min at −78° C., triethylamine (541 μL, 3.88 mmol) was added and the reaction was allowed to warm to room temperature. After 1 h at room temperature the reaction mixture was partitioned between saturated aqueous NaHCO3 (3 mL) and CH2Cl2 (5 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (2×5 mL). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification of the crude residue by flash column chromatography on silica gel (30% EtOAc/hexane) afforded 169 mg (68%) of aldehyde 2.
A solution of aldehyde 2 (169 mg, 0.33 mmol) in DMF (2 mL) was added to a mixture of potassium carbonate (99.99%, 227 mg, 1.65 mmol) and 3,5-dichlorophenylmethyltriphenylphosphonium chloride (see Cullen, et al., U.S. Pat. No. 5,536,725, 129 mg, 0.66 mmol) in DMF (1 mL) at 0° C. The mixture was allowed to warm to room temperature. After 18 h the reaction mixture was partitioned between water (10 mL) and EtOAc (10 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2×10 mL). The combined extracts were washed with brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification of the crude residue by flash column chromatography on silica gel (12 g, hexane→EtOAc, gradient) afforded 130 mg (73%) of alkene 3.
Palladium on carbon (10 wt. %, 2.5 mg) was added to a solution of alkene 3 (130 mg, 0.24 mmol) in EtOAc (5 mL). A hydrogen atmosphere was established by evacuating and refilling with hydrogen (10×) and the reaction mixture was stirred under a balloon of hydrogen for 3 h. The reaction mixture was filtered through celite, washing with EtOAc, and the filtrate was concentrated in vacuo to afford 110 mg (83%) of saturated compound 4.
Pyridinium p-toluenesulfonate (PPTs, 23 mg, 0.092 mmol) was added to a solution of 4 (110 mg, 0.20 mmol) in methanol (2.0 mL) at room temperature under nitrogen. The solution was heated at 40° C. for 18 h, then cooled and concentrated in vacuo. Purification of the crude residue by flash column chromatography on silica gel (12 g, hexane→EtOAc, gradient) afforded 59 mg (58%) of alcohol 5.
Lithium hydroxide (0.46 mL of a 1.0 M aqueous solution, 0.46 mmol) was added to a solution of ester 5 (54 mg, 0.12 mmol) in THF (0.5 mL). The solution was heated at 40° C. for 18 h, then cooled to room temperature. The mixture was partitioned between 10% HCl (5 mL) and EtOAc (5 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2×5 mL). The combined extracts were washed with brine (5 mL), dried (MgSO4), filtered and concentrated in vacuo to afford 44 mg (90%) of the title compound.
Potassium carbonate (99.99%, 216 mg, 1.56 mmol) and 3,5-dichlorophenylmethyltriphenylphosphonium chloride (see Cullen, et al., U.S. Pat. No. 5,536,725, 123 mg, 0.27 mmol) were added to a solution of aldehyde 7 (see, U.S. Provisional Patent Application No. 60/947,904, filed Jul. 3, 2007, incorporated by reference herein, 130 mg, 0.31 mmol) in DMF (3.1 mL) at room temperature. After 3 d, the reaction mixture was partitioned between water (10 mL) and EtOAc (10 mL). The phases were separated and the organic phase was washed with water (5×10 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification of the crude residue by chromatography on 4 g silica gel (hexane→EtOAc, gradient) afforded 100 mg (67%) of alkene 8a.
Palladium on carbon (10 wt. %, 2 mg) was added to a solution of alkene 8a (100 mg, 0.18 mmol) in EtOAc (5 mL). A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 18 h. The reaction mixture was filtered through celite, washing with EtOAc, and the filtrate was concentrated in vacuo to afford 100 mg (quant.) of saturated compound 9a.
In accordance with the procedures of Example 1, step 4, THP-ether 9a (100 mg, 0.18 mmol) was converted into 72 mg (85%) of alcohol 10a.
Lithium hydroxide (0.25 mL of a 1.0 M aqueous solution, 0.25 mmol) was added to a solution of ester 10a (30 mg, 0.063 mmol) in THF (0.32 mL). The mixture was stirred at room temperature for 18 h, acidified with 10% HCl (10 mL) and extracted with EtOAc (2×20 mL). The combined extracts were washed with brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification of the crude residue by chromatography on 4 g silica gel (CH2Cl2→10% MeOH/CH2Cl2, gradient) afforded 12 mg (40%) of the title compound (11a). 1H NMR (300 MHz, CDCl3) δ ppm 1.40-1.67 (m, 3H), 1.65-1.90 (m, 5H), 2.18 (dd, J=6.74, 5.57 Hz, 2H), 2.53-2.78 (m, 2H), 2.80-2.95 (m, 2H), 4.05 (q, J=6.93 Hz, 1H), 4.10-4.22 (m, 1H), 6.82 (d, J=3.81 Hz, 1H), 7.07 (d, J=1.76 Hz, 2H), 7.19 (t, J=1.90 Hz, 1H), 7.72 (d, J=3.81 Hz, 1H).
Palladium on carbon (10 wt. %, 1.4 mg) was added to a solution of alkene 8b (see U.S. Provisional Patent Application No. 60/947,904, 78 mg, 0.14 mmol) in EtOAc (3.5 mL). A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 2 d. The reaction mixture was filtered through celite, washing with EtOAc, and the filtrate was concentrated in vacuo to afford 71 mg (91%) of saturated compound 9b.
In accordance with the procedures of Example 1, step 4, THP-ether 9b (71 mg, 0.13 mmol) was converted into 31 mg (51%) of alcohol 10b.
Lithium hydroxide (0.26 mL of a 1.0 M aqueous solution, 0.26 mmol) was added to a solution of ester 10b (31 mg, 0.065 mmol) in THF (0.65 mL). The mixture was stirred at 40° C. for 3 d, cooled to room temperature, acidified with 1.0 N HCl (0.5 mL) and extracted with EtOAc (2×10 mL). The combined extracts were washed with brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification of the crude residue by chromatography on 4 g silica gel (CH2Cl2→10% MeOH/CH2Cl2, gradient) afforded 17 mg (56%) of the title compound (11b). 1H NMR (300 MHz, CDCl3) δ ppm 1.42-1.66 (m, 3H), 1.64-1.89 (m, 5H), 2.14-2.25 (m, 2H), 2.58-2.84 (m, 2H), 2.84-2.96 (m, 2H), 4.05 (q, J=6.55 Hz, 1H), 4.18 (q, J=5.37 Hz, 1H), 6.83 (d, J=3.81 Hz, 1H), 7.10 (s, 2H), 7.72 (d, J=3.81 Hz, 1H).
In accordance with the procedures of Example 2, step 2, alkene 12c (see U.S. Provisional Patent Application No. 60/947,904, 12 mg, 0.0026 mmol) was converted into 10 mg (83%) of alcohol 10c.
Lithium hydroxide (85 μL of a 1.0 M aqueous solution, 0.085 mmol) was added to a solution of ester 10c (10 mg, 0.021 mmol) in THF (0.1 mL). The mixture was stirred at 40° C. for 18 h, cooled to room temperature, acidified with 0.5 N HCl (2 mL) and extracted with CH2Cl2 (2×2 mL). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification of the crude residue by chromatography on 4 g silica gel (CH2Cl2→10% MeOH/CH2Cl2, gradient) afforded 3 mg (31%) of the title compound (11c). 1H NMR (300 MHz, CDCl3) δ ppm 1.19-1.37 (m, 2H), 1.42-1.65 (m, 4H), 1.67-1.88 (m, 2H), 2.10-2.23 (m, 2H), 2.50-2.78 (m, 2H), 2.84-2.93 (m, 2H), 3.97-4.09 (m, 1H), 4.10-4.20 (m, 1H), 4.65 (s, 2H), 6.82 (d, J=4.40 Hz, 1H), 7.08 (d, J=5.57 Hz, 2H), 7.18 (s, 1H), 7.70 (d, J=3.81 Hz, 1H).
Palladium on carbon (10 wt. %, 24 mg) was added to a solution of alkene 12d (see Allergan ROI 2007-011, incorporated by reference herein, 100 mg, 0.23 mmol) in EtOAc (5 mL). A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 3 d. The reaction mixture was filtered through celite, washing with EtOAc, and the filtrate was concentrated in vacuo to afford 75 mg (75%) of saturated compound 10d.
Lithium hydroxide (0.68 mL of a 1.0 M aqueous solution, 0.68 mmol) was added to a solution of ester 10d (75 mg, 0.17 mmol) in THF (0.7 mL). After 18 h at room temperature, the mixture was partitioned between 1.0 N HCl (20 mL) and CH2Cl2 (50 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (50 mL). The combined organic phase was washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification of the crude residue by chromatography on 12 g silica gel (CH2Cl2→20% MeOH/CH2Cl2, gradient) afforded 4 mg (6%) of the title compound (11d). 1H NMR (300 MHz, CDCl3) δ ppm 1.41-1.67 (m, 3H), 1.63-1.89 (m, 5H), 2.11-2.26 (m, 2H), 2.52-2.83 (m, 2H), 2.82-2.94 (m, 2H), 3.99-4.11 (m, 1H), 4.12-4.27 (m, 1H), 6.54-6.76 (m, 3H), 6.81 (d, J=2.93 Hz, 1H), 7.71 (d, J=2.93 Hz, 1H).
In accordance with the procedures of Example 2, step 2, alkene 12e (see U.S. Provisional Patent Application No. 60/947,904, 185 mg, 0.43 mmol) was converted into 160 mg (86%) of saturated compound 10e.
In accordance with the procedures of example 5, step 2, ester 10e (160 mg, 0.37 mmol) was converted into 120 mg (75%) of recovered 10e and 5 mg (3%) of the title compound (11e). 1H NMR (300 MHz, CDCl3) δ□ppm 1.44-1.65 (m, 4H), 1.69-1.87 (m, 6H), 2.17 (s, 3H), 2.28 (s, 3H), 2.47-2.75 (m, 2H), 2.86 (t, J=7.03 Hz, 2H), 4.04 (q, J=6.84 Hz, 1H), 4.09-4.21 (m, 1H), 6.82 (d, J=4.10 Hz, 4H), 7.71 (d, J=3.52 Hz, 1H).
Lithium aluminum hydride (44 μL of a 1.0 M solution in Et2O, 0.044 mmol) was added to a solution of ester 10a (21 mg, 0.044 mmol) in THF (0.15 mL) at 0° C. After 1 h at 0° C., the reaction mixture was allowed to warm to room temperature. After 18 h at room temperature, the reaction was quenched with water (0.1 mL) and 15% NaOH (0.1 mL). The resulting mixture was filtered through a pad of celite, washing with water (0.3 mL) and THF (5 mL). The filtrate was concentrated to dryness in vacuo. Purification of the crude residue by chromatography on 4 g silica gel (hexane→EtOAc, gradient) afforded 14 mg (71%) of the title compound (13). 1H NMR (300 MHz, CDCl3) δ ppm 1.41-1.67 (m, 5H), 1.64-1.88 (m, 6H), 2.16 (dd, J=6.74, 5.57 Hz, 2H), 2.53-2.77 (m, 2H), 2.81 (t, J=7.33 Hz, 2H), 4.05 (q, J=6.64 Hz, 1H), 4.16 (q, J=5.28 Hz, 1H), 4.75 (s, 2H), 6.63 (d, J=3.22 Hz, 1H), 6.82 (d, J=3.22 Hz, 1H), 7.07 (d, J=1.76 Hz, 1H), 7.20 (t, J=1.76 Hz, 1H).
Triphenylphosphine (120 mg, 0.46 mmol) and diisopropyl azodicarboxylate (DIAD, 67 μL, 0.35 mmol) were added to a solution of alcohol 14 (see U.S. Provisional Patent Application No. 60/947,904, 54 mg, 0.11 mmol) and 4-nitrobenzoic acid (57 mg, 0.34 mmol) in THF (4 mL) at room temperature. After 18 h at room temperature, the reaction was diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic phase was dried (MgSO4), filtered and concentrated in vacuo. Purification of the crude residue by chromatography on 4 g silica gel (hexanes→EtOAc, gradient) afforded 70 mg (99%) of the benzoate 15.
In accordance with the procedures of Example 2, step 2, alkene 15 (35 mg, 0.056 mmol) was converted into 6 mg (17%) of saturated compound 16.
Lithium hydroxide (0.30 mL of a 1.0 M aqueous solution, 0.30 mmol) was added to a solution of ester 16 (6 mg, 0.010 mmol) in THF (0.3 mL) in a 1 dram vial. The vial was sealed and the reaction mixture was heated at 40° C. for 18 h, then cooled to room temperature. The mixture was partitioned between 1.5 N HCl (3 mL) and EtOAc (5 mL). The phases were separated and the organic phase was washed with water (3 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification of the crude residue by flash column chromatography on silica gel (10% MeOH/CH2Cl2) afforded 4 mg (90%) of the title compound (17).
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU, 5.4 μL, 0.036 mmol) and 2-iodopropane (48 μL, 0.48 mmol) were added to a solution of acid 11c (11 mg, 0.024 mmol) in acetone (0.3 mL) at room temperature under nitrogen. After 3 days at room temperature, the reaction mixture was concentrated in vacuo. The residue was acidified with 1.0 N HCl (5 mL) extracted with EtOAc (10 mL). The organic phase was washed with brine (5 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on 3 g silica (10% MeOH/CH2Cl2, gradient) afforded 10 mg (83%) of the title compound (18). 1H NMR (500 MHz, CDCl3) δ□ppm 1.21-1.32 (m, 6H), 1.32 (s, 3H), 1.34 (s, 3H), 1.75-1.80 (m, 6H), 2.62 (ddd, J=13.91, 9.69, 6.72 Hz, 1H), 2.71 (td, J=9.35, 5.01 Hz, 1H), 2.84 (t, J=7.40 Hz, 2H), 4.03 (q, J=7.09 Hz, 1H), 4.08-4.18 (m, 1H), 4.65 (s, 2H), 5.17 (dt, J=12.47, 6.24 Hz, 1H), 6.77 (d, J=3.67 Hz, 1H), 7.08 (d, J=9.54 Hz, 2H), 7.18 (s, 1H), 7.60 (d, J=3.67 Hz, 1H).
The α-chain A may be modified may be varied by following or adapting procedures found in U.S. Provisional Patent Application No. 60/805,285, which is expressly incorporated by reference herein, wherein an analog of the Corey lactone is used as the precursor to a Wittig reaction to install all the atoms of the α-chain; other Wittig reactions and the preparation of the requisite phosphonates are described by Collect. Czech. Chem. Commun. 1994, 58, 138-148, and Collect. Czech. Chem. Commun. 1994, 59, 2533-2544. Alternatively, the intermediate Corey lactone analog may be reduced to the corresponding primary alcohol, which may then be manipulated by methods known in the art to compounds bearing a heteroatom at the 5th (by alkylation of the alcohol or the derived thiol), 4th (by lengthening the chain by one atom (e.g. by homologation via the corresponding aldehyde)) or 6th (by shortening the chain by one atom (e.g. by ozonolysis of an enol ether derived from the corresponding aldehyde)) atom from the acid terminus.
The α-chain A may be modified may be varied by following or adapting procedures found in U.S. patent application Ser. No. 11/764,929, filed Jun. 19, 2007, which is expressly incorporated by reference herein, wherein an analog of the Corey lactone is used as the precursor to a Wittig reaction to install all the atoms of the α-chain; other Wittig reactions and the preparation of the requisite phosphonates are described by Collect. Czech. Chem. Commun. 1994, 58, 138-148, and Collect. Czech. Chem. Commun. 1994, 59, 2533-2544. Alternatively, the intermediate Corey lactone analog may be reduced to the corresponding primary alcohol, which may then be manipulated by methods known in the art to compounds bearing a heteroatom at the 5th (by alkylation of the alcohol or the derived thiol), 4th (by lengthening the chain by one atom (e.g. by homologation via the corresponding aldehyde)) or 6th (by shortening the chain by one atom (e.g. by ozonolysis of an enol ether derived from the corresponding aldehyde)) atom from the acid terminus.
Different J1, J2, and U1 substituents may be obtained by following or adapting procedures found in the following documents, all of which are expressly incorporated by reference herein:
U.S. patent application Ser. No. 11/764,929;
U.S. patent application Ser. No. 11/738,307, filed on Apr. 20, 2007;
U.S. patent application Ser. No. 11/690,678, filed on May 23, 2007;
U.S. patent application Ser. No. 11/742,987 filed on May 1, 2007; and
U.S. patent application Ser. No. 11/747,478, filed on May 11, 2007.
Different substituted or unsubstituted aryl groups for B may be obtained by methods well known in the art. For example, this may be accomplished by preparing analogs to the Wittig reagent in step 2. These analogs may be prepared by the reaction of an aldehyde such as 2 with the anion of an aryl or heteroaryl methyl phosphonate, the latter being derived from the reaction of triphenylphosphine with the appropriate aryl or heteroaryl methyl halide (e.g., see Maryanoff, B. E., and Reitz, A. B., Chem. Rev. 1989, 89, 863-927 and references therein). The requisite aryl or heteroaryl methyl halide, if not commercially available may be prepared from commercially available aryl or heteroaryl methyl alcohols (by halogenation), aryl or heteroaryl halides (by one carbon homogation via the aryl or heteroaryl methyl alcohol), or aryl or heteroaryl carboxylate compounds (by reduction and halogenation). Different substituted or unsubstituted aryl groups for B may also be obtained by the obtaining an analog for compound 3 using the procedures described in U.S. Pat. No. 6,531,485, expressly incorporated herein by reference, (see, e.g. compound 1-4, Scheme 3, columns 23-24), and varying J1, J2, and U1 as described above. Alternatively, conjugate addition reactions, analogous to reactions in U.S. Pat. No. 6,531,485, of styryl halides could be used to introduce different substituted aryl or heteroaryl groups for B. The requisite styryl halides may be prepared from the corresponding alkyne (via hydrohalogenation) or other organometallic methods known in the art.
Competition binding experiments were performed in a medium containing Hank's balanced salt solution, Hepes 20 mM, pH 7.3, membranes (˜60 μg protein) or 2×105 cells from HEK 293 cells stably expressing human EP2 receptors, [3H]PGE2 (10 nM) and various concentrations of test compounds in a total volume of 300 μl. Reaction mixtures were incubated at 23° C. for 60 min, and were filtered over Whatman GF/B filters under vacuum. Filters were washed three times with 5 ml ice-cold buffer containing 50 mM Tris/HCl (pH 7.3). Non-specific binding was estimated in the presence of excess unlabeled PGE2 (10 μM). Binding data fitted to the binding model for a single class of binding sites, using nonlinear regression analysis. IC50 values thus obtained were converted to Ki using the equation of Ki=(IC50/(1+[L]/KD) where [L] represents PGE2 concentration (10 nM) and KD the dissociation constant for [3H]PGE2 at human EP2 receptors (40 nM).
HEK-293 cells stably expressing the human or feline FP receptor, or EP1, EP2, or EP4 receptors were washed with TME buffer, scraped from the bottom of the flasks, and homogenized for 30 sec using a Brinkman PT 10/35 polytron. TME buffer was added to achieve a final 40 ml volume in the centrifuge tubes (the composition of TME is 100 mM TRIS base, 20 mM MgCl2, 2M EDTA; 10N HCl is added to achieve a pH of 7.4).
The cell homogenate was centrifuged at 19000 r.p.m. for 20 min at 4° C. using a Beckman Ti-60 rotor. The resultant pellet was resuspended in TME buffer to give a final 1 mg/ml protein concentration, as determined by Biorad assay. Radioligand binding competition assays vs. [3H-]17-phenyl PGF2α (5 nM) were performed in a 100 μl volume for 60 min. Binding reactions were started by adding plasma membrane fraction. The reaction was terminated by the addition of 4 ml ice-cold TRIS-HCl buffer and rapid filtration through glass fiber GF/B filters using a Brandel cell harvester. The filters were washed 3 times with ice-cold buffer and oven dried for one hour.
[3H-] PGE2 (specific activity 180 Ci mmol) was used as the radioligand for EP receptors. [3H] 17-phenyl PGF2α was employed for FP receptor binding studies. Binding studies employing EP1, EP2, EP4 and FP receptors were performed in duplicate in at least three separate experiments. A 200 μl assay volume was used. Incubations were for 60 min at 25° C. and were terminated by the addition of 4 ml of ice-cold 50 mM TRIS-HCl, followed by rapid filtration through Whatman GF/B filters and three additional 4 ml washes in a cell harvester (Brandel). Competition studies were performed using a final concentration of 5 nM [3H]-PGE2, or 5 nM [3H] 17-phenyl PGF2α and non-specific binding determined with 10−5M of unlabeled PGE2, or 17-phenyl PGF2α, according to receptor subtype studied.
(a) Cell Culture
HEK-293(EBNA) cells, stably expressing one type or subtype of recombinant human prostaglandin receptors (prostaglandin receptors expressed: hDP/Gqs5; hEP1; hEP2/Gqs5; hEP3A/Gqi5; hEP4/Gqs5; hFP; hIP; hTP), were cultured in 100 mm culture dishes in high-glucose DMEM medium containing 10% fetal bovine serum, 2 mM l-glutamine, 250 μg/ml geneticin (G418) and 200 μg/ml hygromycin B as selection markers, and 100 units/ml penicillin G, 100 μg/ml streptomycin and 0.25 μg/ml amphotericin B.
(b) Calcium Signal Studies on the FLIPR™
Cells were seeded at a density of 5×104 cells per well in Biocoat® Poly-D-lysine-coated black-wall, clear-bottom 96-well plates (Becton-Dickinson) and allowed to attach overnight in an incubator at 37° C. Cells were then washed two times with HBSS-HEPES buffer (Hanks Balanced Salt Solution without bicarbonate and phenol red, 20 mM HEPES, pH 7.4) using a Denley Cellwash plate washer (Labsystems). After 45 minutes of dye-loading in the dark, using the calcium-sensitive dye Fluo-4 μM at a final concentration of 2 μM, plates were washed four times with HBSS-HEPES buffer to remove excess dye leaving 100 μl in each well. Plates were re-equilibrated to 37° C. for a few minutes.
Cells were excited with an Argon laser at 488 nm, and emission was measured through a 510-570 nm bandwidth emission filter (FLIPR™, Molecular Devices, Sunnyvale, Calif.). Drug solution was added in a 50 μl volume to each well to give the desired final concentration. The peak increase in fluorescence intensity was recorded for each well. On each plate, four wells each served as negative (HBSS-HEPES buffer) and positive controls (standard agonists: BW245C (hDP); PGE2 (hEP1; hEP2/Gqs5; hEP3A/Gqi5; hEP4/Gqs5); PGF2α (hFP); carbacyclin (hIP); U-46619 (hTP), depending on receptor). The peak fluorescence change in each drug-containing well was then expressed relative to the controls.
Compounds were tested in a high-throughput (HTS) or concentration-response (CoRe) format. In the HTS format, forty-four compounds per plate were examined in duplicates at a concentration of 10−5 M. To generate concentration-response curves, four compounds per plate were tested in duplicates in a concentration range between 10−5 and 10−11 M. The duplicate values were averaged. In either, HTS or CoRe format each compound was tested on at least 3 separate plates using cells from different passages to give an n≧3.
cAMP Assay
A 384-well drug plate was prepared to contain 6 test compounds, PGE2 and cAMP in 16 serial dilutions in triplicate, using a Biomek station. HEK-EBNA cells expressing a target PG receptor subtype (EP2 or EP4) were suspended in a stimulation buffer (HBSS, 0.1% BSA, 0.5 mM IBMX and 5 mM HEPES, pH 7.4) in a density of 104 cells/5 μl. The reaction was initiated by mixing 5 μL drug dilutions with 5 μl of HEK-EBNA cells in a well, carried out for 30 min at room temperature, and followed by the addition of 5 μl anti-cAMP acceptor beads in the control buffer with Tween-20 (25 mM NaCl, 0.03% Tween-20, 5 mM HEPES, pH7.4). After 30 min in the dark at room temperature, the mixtures were incubated with 15 μl biotinylated-cAMP/strepavidin donor beads in Lysis/Detection buffer (0.1% BSA, 0.3% Tween-20 and 5 mM HEPES, pH7.4) for 45 min at the room temperature. Fluorescence changes were read using a Fusion-alpha HT microplate reader.
The results of the binding and activity studies, presented in Table 1 below, demonstrate that the compounds disclosed herein are selective prostaglandin EP2 agonists, and are thus useful for the treatment of glaucoma, ocular hypertension, and other diseases or conditions.
U.S. Pat. No. 7,091,231 describes the methods used for these in vivo tests.
7-{(1R,2R,3R,5R)-5-Chloro-2-[2-(3,5-dichloro-phenyl)-ethyl]-3-hydroxy-cyclopentyl}-heptanoic acid (6) was tested in normotensive dogs at 0.01%, dosing once daily for 5 days. The maximum intraocular pressure (IOP) decrease from baseline was 3.6 mmHg (18%) at 102 h; the maximum ocular surface hyperemia (OSH) score was 0.8 at 74 h.
The composition of In vivo Example 1 may be used to reduce IOP in a person by administering the composition once a day to the person.
5-(3-((1R,2R,3R,5R)-5-chloro-2-(3,5-dichlorophenethyl)-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylic acid (11a) was tested in normotensive dogs multiple concentrations, dosing once daily for 5 days. At 0.01%, the maximum intraocular pressure (IOP) decrease from baseline was 8.8 mmHg (47%) at 28 h; the maximum ocular surface hyperemia (OSH) score was 2.5 at 26 h. At 0.001%, the maximum intraocular pressure (IOP) decrease from baseline was 6.2 mmHg (34%) at 54 h; the maximum ocular surface hyperemia (OSH) score was 1.8 at 50 h. At 0.0005%, the maximum intraocular pressure (IOP) decrease from baseline was 5.6 mmHg (36%) at 54 h; the maximum ocular surface hyperemia (OSH) score was 1.75 at 50 h. At 0.0001%, the maximum intraocular pressure (IOP) decrease from baseline was 3.6 mmHg (24%) at 76 h; the maximum ocular surface hyperemia (OSH) score was 0.8 at 74 h.
5-(3-((1R,2R,3R,5R)-5-chloro-2-(3,5-dichlorophenethyl)-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylic acid (11a) tested in laser-induced hypertensive monkeys, using one single day dose. At 0.01%, the maximum IOP decrease from baseline was 20.6 mmHg (55%) at 24 h.
The compositions of In vivo Example 3 may be used to reduce IOP in a person by administering the composition once a day to the person.
5-(3-((1R,2R,3R,5R)-5-chloro-2-(2-(2,6-dichloropyridin-4-yl)ethyl)-3-hydroxycyclopentyl)propyl)-thiophene-2-carboxylic acid (11b) was tested in normotensive dogs at 0.001%, dosing once daily for 4 days. The maximum intraocular pressure (IOP) decrease from baseline was 7.1 mmHg (36%) at 78 h; the maximum ocular surface hyperemia (OSH) score was 1.9 at 74 h. This compound was also tested in laser-induced hypertensive monkeys, using one single day dose. At 0.001%, the maximum IOP decrease from baseline was 12.6 mmHg (31%) at 24 h.
The compositions of In vivo Example 6 may be used to reduce IOP in a person by administering the composition once a day to the person.
5-(3-((1R,2R,3R,5R)-5-chloro-2-(3-chloro-5-(hydroxymethyl)phenethyl)-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylic acid (11c) was tested in normotensive dogs at 0.001%, dosing once daily for 5 days. The maximum intraocular pressure (IOP) decrease from baseline was 2.2 mmHg (12%) at 30 h; the maximum ocular surface hyperemia (OSH) score was 0.8 at 50 h.
The compositions of In vivo Example 8 may be used to reduce IOP in a person by administering the composition once a day to the person.
Isopropyl 5-(3-((1R,2R,3R,5R)-5-chloro-2-(3-chloro-5-(hydroxymethyl)phenethyl)-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylate (18) was tested in normotensive dogs at 0.001%, dosing once daily for 5 days. The maximum intraocular pressure (IOP) decrease from baseline was 2.8 mmHg (17%) at 4 h; the maximum ocular surface hyperemia (OSH) score was 0.9 at 26 h.
Isopropyl 5-(3-((1R,2R,3R,5R)-5-chloro-2-(3-chloro-5-(hydroxymethyl)phenethyl)-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylate (18) was also tested in laser-induced hypertensive monkeys, using one single day dose. At 0.001%, the maximum IOP decrease from baseline was 9.2 mmHg (24%) at 24 h.
The composition of In vivo Example 11 may be used to reduce IOP in a person by administering the composition once a day to the person.
The foregoing description details specific methods and compositions that can be employed to practice the present invention, and represents the best mode contemplated. However, it is apparent for one of ordinary skill in the art that further compounds with the desired pharmacological properties can be prepared in an analogous manner, and that the disclosed compounds can also be obtained from different starting compounds via different chemical reactions. Similarly, different pharmaceutical compositions may be prepared and used with substantially the same result. Thus, however detailed the foregoing may appear in text, it should not be construed as limiting the overall scope hereof; rather, the ambit of the present invention is to be governed only by the lawful construction of the claims.
This application claims the benefit of U.S. Provisional Application Ser. No. 60/806,947, filed Jul. 11, 2006, which is hereby incorporated by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 60806947 | Jul 2006 | US |
