2-Substituted-1-naphthols as 5-lipoxygenase inhibitors

Claim 2

A pharmaceutical composition comprising a suitable pharmaceutical carrier and a lipoxygenase inhibiting amount of a compound having the formula: wherein R 1 is H. CH 3 , Br. Cl, OH. OCH 3 , OC 2 H 5 , COR 17 . COOR 18 . CONR 19 R 20 , phenyl, -N(R 12 )(R 13 ), -NHC lower alkyl. S(O) p lower alkyl where p is 0, 1 or 2, SO 2 NH 2 , or -NHSO 2 lower alkyl optionally substituted with F: R 2 and R 3 independently are H. CH 3 . C 2 H 5 , OCH 3 , or OC 2 H 5 ; R 4 is straight-chain or branched alkyl of 1-12 carbons. straight-chain or branched alkenyl of 2-12 carbons, straight-chain or branched alkynyl of 2-12 carbons, cycloalkyl or cycloalkenyl of 5-7 carbons. CH 2 -C≡C-(CH 2 ) m R 5 where m is 1 - 4 , CH=CH-(CH 2 ) n R 5 where n is 0 - 3 and the olefinic bond has either the Z or E configuration A-R 6 , or A is a chain of 2-6 methylene groups optionally substituted at any one of the methylene carbons by a group R : R 5 is C 5 -C 7 cycloalkyl, phenyl, COOR 9 ; R 6 is C 5 -C 7 cycloalkyl, phenyl. COOR . CON ( R 12 )( R 13 ) . CN . CH(COOR 9 )2. C(R 10 )(R 11 )OR 9 . P(O)(OR 9 )2. S(O) w R 9 where w is 0 - 2 with the proviso that if w = 1 then R 9 is not H. SC(NH)NH 2. N(R 12 )(R 13 ). OR 9, OC(O)R 9 . Cl. Br, or I: R 7 is C 3 -C 8 cycloalkyl where X is S. O, or NR 10 , and Y is CH or N: R 8 is C 1 -C 4 alkyl, C 5 -C 7 cycloalkyl, or phenyl: R 9 , R 10 , and R 11 are independently H or C 1 -C 4 alkyl: R 12 and R 13 independently are H, C 1 -C 4 alkyl, or together are (CH 2 )4-5; R 14 is H. C 1 -C 4 alkyl, OR 9 , O-phenyl. OCH 2 COOR 9 , O-benzyl. COOR 9 , CF 3 , Cl, Br, I, N(R 12 )(R 13 ) or S(O) w R 9 where w is 0 - 2 with the proviso that if w is 1 then R 9 is not H: and R 15 and R 16 are independently H. C 1 -C 4 alkyl, OR 9 , O-benzyl. F, or Cl. R 17 is lower alkyl, phenyl, optionally monosubstituted with Cl. Br. F. CH 3 , CH 3 0. pyridyl, thienyl or furyl: R 18 is H or lower alkyl: R 19 and R 20 independently are H or lower alkyl, or taken together are (CH 2 ) 4-5 ; and R 21 is H, lower alkyl, phenyl. optionally monosubstituted with Cl. Br, F, CH 3 , CH 3 O, pyridyl, thienyl,' or furyl: or a pharmaceutically suitable salt thereof.

Claim 3

The composition of Claim 1 wherein R 4 is straight-chain or branched alkyl of 1-6 carbons. allyl optionally substituted on the double bond carbons with methyl or ethyl groups, cycloalkyl or cycloalkenyl of 5-6 carbons; CH 2 -C-C-(CH 2 ) R 5 where m is 3 and 2 R 5 is COOR 9 or phenyl, CH=CH-(CH 2 ) n R 5 where n is 0 - 2, the olefinic bond has either the Z or E 5 9 configuration, and R 5 is COOR 9 , or phenyl. A-R 6 , or CH 2 - R 7 . where 7 A. R 6 , and R are as defined in Claim 1. 3. The composition of Claim 2 wherein A is a chain of 2-6 unsubstituted methylene groups: R 6 is phenyl. COOR 9 , CON(R 12 )(R 13 ). CN. CH(COOR 9 ) 2 . C(R 10 )(R 11 )OR 9 . P(O)(OR 9 ) 2 , S(O) w R 9, SC(NH)NH 2 , N(R 12 )(R 13 ), OR 9 . OC(O)R 9 . Cl. Br, or I: R 7 is as defined in Claim 1 except that X is S, O, or N-CH 3 ; R 14 is as defined in Claim 1 except for O-phenyl. O-benzyl, and OCH 2 COOR 9 : R 15 and R 16 are independently H, OR 9 , F, or Cl: and w, R 9 , R 10 . R 11 . R 12 and R 13 are as defined in Claim 1.

Claim 4

The composition of Claim 1 wherein the compound is selected from methyl 7-(1-hydroxy-2-naphthyl)-5-heptynoate; ethyl 5-(1-hydroxy-2-naphthyl)-4-pentenoate, Z isomer; ethyl 3(-1-hydroxy-2-naphthyl)-propenoate, E isomer; 2-(2-propenyl)-1-naphthol; ethyl 3-(1-hydroxy-2-naphthyl)-propanoate; ethyl 5-(1-hydroxy-2-naphthyl)-pentanoate; 2-(5-methylhexyl)-1-naphtol; diethyl [3-(1-hydroxy-2-naphthyl)propyl]propane- dioate; 2-(phenylmethyl)-1-naphthol; 2-(3-fluorophenylmethyl)-1-naphthol; 2-/ (3,4,5-trimethoxyphenyl)methyl]-1-naphthol; 2-(2-furylmethyl)-1-naphthol; 2-[(3,4-dimethoxyphenyl)methyl]-1-naphthol; 2-(2-thienylmethyl)-1-naphthol; 2-(3-chlorophenylmethyl)-1-naphthol; 2-(4-ethoxyphenylmethyl)-1-naphthol; 2-(4-bromophenylmethyl)-1-naphthol, and 5,8-dimethyl-2-(phenylmethyl)-1-naphthol.

Claim 5

A compound having the formula: wherein R 1 is H. CH 3 , Br. Cl. OH. OC 2 H 5 , COR 17 , COOR 18 , CONR 19 R 20 , p henYl. -N(R 12 )(R 13 ). lower alkyl, S(O) p lower alkyl where p os 0. 1, or 2. SO 2 NH 2 . or -NHSO 2 lower alkyl optionally substituted with F: R 2 and R 3 independently are H, CH 3 ,C 2 H 5 , CH 3 O, or C 2 H 5 O; R 4 is straight-chain or branched alkynyl of 2-12 carbons. C 5 -C 7 cycloalkenyl. CH 2 -C≡C-(CH 2 ) m R 5 where m is 1 - 4. CH=CH-(CH 2 ) n R where n is 1 - 3 and the olefinic bond has either the Z or E configuration. A-R 6 , or A is a chain of 2-6 methylene groups: R 5 is C 5 -C 7 cycloalkyl, phenyl. COOR 9 ; R 6 is C 3 -C 6 alkenyl. C 5 -C 7 cycloalkyl. CON(R 12 )(R 13 ). CN, CH(COOR 9 ) 2 . C(R 10 )(R 11 )OR 9 . P(O)(OR 9 ) 2 . S(O) w R 9 where w is 0 - 2 with the proviso that if w is 1 then R 9 is not H. SC(NH)NH 2 . N(R 12 )(R 13 ). OR 9 . Cl. Br, or I: R 7 is C 3 -C 8 cycloalkyl. where X is S. O, or NR 10 , and Y is CH or N: R 9 , R 10 , and R are independently H or C 1 -C 4 alkyl: R 12 and R 13 independently are H. C 1 -C 4 alkyl, or together are (CH 2 ) 4-5 ; R 14 is C 1 -C 4 alkyl, OR 9 ' O-phenyl. OCH 2 COOR 9 , O-benzyl, COOR 9 , CF 3 , Cl, Br, I, N(R 12 )(R 13 ), or S(O) w R 9 where w is 0 - 2 with the proviso that if w is 1 then R 9 is not H: and R 15 and R 16 are independently H. C 1 -C 4 alkyl, OR 9 , O-benzyl, F or Cl: R 17 is lower alkyl, phenyl optionally monosubstituted with Cl. Br. F. CH 3 , CH 3 0. pyridyl., thienyl or furyl; R 18 is H or lower alkyl R 19 and R 20 independently are H or lower alkyl, or taken together are(CH 2 ) 4-5 : and R 21 is H, lower alkyl, phenyl, optionally monosubstituted with Cl, Br. F. CH 3 . CH 3 O, pyridyl. thienyl, or furyl: subject to the following provisos: 1 . if R 1 . R 2 , and R 3 are all H, then R 4 is not 4-chlorophenylmethyl. 4-methylphenylmethyl, or 2-furylmethyl: 2 . if R 2 or R 3 is 6-OCH 3 , then R 4 is not 4-chlorophenylmethyl or 4-methylphenylmethyl: 3 . if R 1 is Cl then R 4 is not 4-aminophenylmethyl: and 4 . R 4 is not CH 2 CH 2 CN. 6 . A compound of Claim 5 wherein R 4 is cycloalkenyl of 5-6 carbons: CH 2 -C≡C-(CH 2 ) m R 5 where m is 3 and R 5 is COOR 9 or phenyl; CH=CH-(CH 2 ) n R 5 where n is 1 - 2, the olefinic bond has either the Z or E configuration and R 5 is COOR 9 or phenyl: A-R 6 ; or CH 2 -R 7 ; where A, R 6 and R 7 are as defined in Claim 5 .

Claim 6

7 . A compound of Claim 6 wherein A is a chain of 2-6 unsubstituted methylene groups; R 6 is CON(R 12 )(R 13 ). CN. CH(COOR 9 ) 2 , C(R 10 )(R 11 )OR 9 . P(O)(OR 9 ) 2 . S(O) w R 9 , SC(NH)NH 2 , N(R 12 )(R 13 ), OR 9 . C1. Br, or I: R 7 is as defined in Claim 5 except that X is S . O, or N-CH 3 : R 14 is as defined in Claim 5 except for O-phenyl. O-benzyl, and OCH 2 COOR 9 ; R15 and R16 are independently H, OR 9 , F. or Cl: and w, R 9 , R 10 , R 11 R 12 and R 13 are as defined in Claim 5.

Claim 7

The compounds of Claim 5 selected from methyl 7-(1-hydroxy-2-naphthyl)-5-heptynoate; ethyl 5-(1-hydroxy-2-naphthyl)-4-pentenoate, Z isomer; diethyl [3(1-hydroxy -2-naphthyl)propyl]propanedioate 2-(3-fluorophenylmethyl)-1-naphthol; 2-[(3,4,5-trimethoxyphenyl)methyl)-1-naphthol; 2-(2-furylmethyl)-1-naphthol; 2-[(3,4-dimethoxyphenyl)methyl)-1-naphthol]; 2-(2-thienylmethyl)-1-naphthol; 2-(3-chlorophenylmethyl)-1-naphthol; 2-(4-ethoxyphenylmethyl)-1-naphthol; 2-(4-bromophenylmethyl)-1-naphthol; and 5,8-dimethyl-2-(phenylmethyl)-1-naphthol.

Claim 8

9 . A compound of Claim 7 wherein R 4 is AR 6 , where A and R are as defined in Claim 5 ..

Claim 9

10 . A compound of Claim 7 wherein R 4 is cycloalkenyl of 5-6 carbon atoms.

Claim 10

A compound of Claim 7 'wherein R 4 is CH 2 R 7 where R 7 is as defined in Claim 5.

Claim 11

1 2 . A process for preparing a compound of Claim 9 comprising (a) treating a protected 1-naphthol of the formula where R 2 and R 3 are as defined in Claim 5 and Pr is a protecting group such as methoxymethyl sequentially with a strong base such as n-butyllithium and then with a α,ω-bromochloroalkane: (b) treating the product of step (a) with an appropriate nucleophile such as CN. - I, Br. Cl. - N 3 . - OR 9 , SR 9 , P(OR 9 ) 3 , - CH(COOR 9 ) 2 , NH 2 C(S)NH 2 ; and (c) treating the product of step (b) with an acid such as hydrochloric acid.

Claim 12

13 . A process for preparing a compound of Claim 10 comprising (a) treating a protected 1-naphthol of the formula where R 2 and R 3 are as defined in Claim 7 and Pr is a protecting group such as methoxymethyl sequentially with a strong base such as n-butyllithium and then with cyclopentanone, cyclohexanone or cycloheptanone: and (b) treating the product of step (a) with an acid such as hydrochloric acid or p-toluenesulfonic acid.

Claim 13

14 . A process for preparing a compound of Claim 11 comprising (a) treating a mixture of a tetralone of the formula where R 2 and R 3 are as defined in Claim 5 and R 1 is H or CH 3 and an aryl or heteroaryl aldehyde R CHO where R is defined in Claim 5 in t-butanol with potassium t-butoxide, and optionally: (b) when R 1 = H treating a solution of the product of step (a) in acetic acid with chlorine or bromine.

Claim 14

15 . A process for preparing a compound of Claim 5 comprising: (a) treating a protected 1-naphtol of the formula where R 2 , and R 3 are as defined in Claim 5 and Pr is a protecting group such as methyl, sequentially with a strong base such as n-butyllithium and then with a ketone R 7 CR 21 ; (b) treating the product of step (a) with a reducing agent such as triethylsilane/boron trifluoride: and (c) treating the product of step (b) with a demethylating agent such as boron tribromide or pyridine hydrochloride.

Claim 15

16 . A process for preparing a compound of Claim 5 comprising: (a) treating a 1-naphthol of the formula with an acylating agent such as acid chloride in the presence of a catalyst such as aluminum chloride: and (b) treating the product of step (a) with a reducing agent such as zinc in an acid such as hydrochloric acid.

Claim 16

17 . A process for preparing a compound of Claim 5 where comprising: (a) treating a protected 1-naphthol of the formula where R . R . R and R are as defined in Claim 5 and Pr is a protecting group such as methyl with a brominating agent such as bromine in a suitable solvent such as acetic acid: (b) treating the product of step (a) sequentially with a strong base such as n-butyllithium and then with an electrophilic reagent such as a dialkyl carbonate, alkyl chlorofumate, carbon dioxide, or an aldehyde: (c) optionally treating the product of part (b) with an oxidizing agent such as pyridinium chlorochromate, if the electrophilic reagent used in part (b) is an aldehyde : and (d) treating the product of part (c) with a demethylating agent such as pyridine hydrochloride.

Claim 17

A process for preparing a compound of Claim 5 where comprising: treating a 1-naphthol of the formula where R 2 , R 3 , R 7 and R 21 are as defined in Claim 5 . with an acylating agent such as an acid chloride in the presence of a catalyst such as aluminum chloride: optionally followed by treatment of the product with an acid such as sulfuric acid in a solvent such as ethanol.