AU606034B2 - 2-substituted -1- naphthols as 5-lipogenase inhibitors - Google Patents

Description

*this Jist day of- Ma f P/00/011 -_IAUS~AI~ Q 3 3 ~PATENTS ACT 1952-1973Fom1 COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE Class: Int. Cl: tn Loded 111 DitU d 1(So Ap. opleteo Speication-Lodged Published::I Related Ar:cMelbtudn PublsTOd BEGE COPLTE BSUAPPLICAN .,oeadArt:~pia eaae oae a imntn tt f eaae 19898, United States of' America.

Actual Inventor: DOUGLAS GUY BATT Address for Service: Care of': JAMES M. LAWRIE CO., Patent Attorneys of' 72 Willsrnere Road, K-1w, 3101, Victoria, Australia.

Complete Specification for the invention entitled: 2-SUBSTITUTED-i1-NAPHTHOLS AS LIPOXYGENASE INHIBITORS The following statement is a full description of this invention, including the best method of performing it known to me:-* 'Note :The description Is to be typed in double spacing, pica type face, in an area not exceeding 250 mm In depth and 160 mm in width, on tough white paper of good quality and it is to be Inserted Inside this form.

1 1710/7E3-L C.J.TnommaN.Commonwealth Govrnment Prntecranber Title BP-6291-A 2-Substituted-1-Naphthols as Inhibitors Backgiround of the Invention Field of Invention: This invention relates to 2-substituted-inaphthols, and processes for their preparation, pharmaceutical compositions containing them and pharmaceutical methods using them.

Prior Art: U. S. Patent 3,998,966 issued December 21.

1976 to Fried and Harrison discloses 6-substituted 2-naphthyl acetic acid derivatives with antiinflammatory. analgesic. antipyretic and antipruritic 15 activity.

U. S. Patent 3,969,415 issued July 13, 1976 to E. G. Galantay discloses antiinflammatory 1-(2naphthyl)-2.3--butandien-l-ols of the formula 3 1 'R

C--C=C=C,

j~ 1 '2 R wherein R is H, Fl. Ci. Br, C C alkyl. C-Cakxy C C -alkylthio or difluoromethoxy. R I is H orC C 14 2 3 414 alkyl. R is H or CH 3 ana R and R are independently H or C 1 -C 4 alkyl provided that at least one of R 3 and 4. 2 sees R is H when R is CH 3 U. S. Patent 4.442.392 issued January 17. 1984 to A. C. Goudie discloses antiinflammatory naphthyl compounds of the formula CH 2CH 2-CH-CH3 12

O-CO-R

wherein R is chioro or methoxy and R 2 is methyl.

ethyl. benzyl. 2-methoxyethyi. phenyl. 4-methoxyphenyl or aminomethyl.Y 1 -2- European Patent Application 0082005 filed December 13, 1982 by Nelson et al., discloses antiinflammatory naphthoxyalkylamines of the formula (Y)a

O(CH

2 b x 0 wherein Y is halo, alkoxy, or alkyl; a is 0 or 1; b is an integer from 2-12 with the proviso that if b is 2 1 or 3, a cannot be 0; and x is selected from -OH, OR 1

NH

2

NHR

1 NR2 -N and -NHCONHR 2 in which CH CH OH 1 1 each R is independently alkyl or phenyl or in -NR, 1 2 j *i 15 both R together are alkylene; and R is cycloalkyl or phenyl.

European Patent Application 0036502 filed February 25, 1981 by G. Wurm discloses naphthoquinones of the formula 0 -CH R I II OH 0 5 wherein R is methyl, ethyl, propyl, isopropyl, or tertiary butyl. These compounds are disclosed as prostaglandin synthetase inhibitors, useful in the treatment of allergy and anaphylactic shock.

European Patent Application 0127726 filed SJanuary 27, 1984 by Slapke et al.. discloses aromatic hydroxamic acid derivatives as inhibitors useful in the treatment of asthma. Included is the compound having the formula

OH

CON-OH

H

s i, 1 u.i.l- -3- U. K. Patent 2055097 issued February 25, 1981 to Terao et al. discloses quinone derivatives of the O formula

O

R C H 3 2

R

R*

R

0 CH 3

CH

3 wherein a-B means a saturated bond or double bond; each R independently of one another is a methyl or methoxy group, or two R's taken together repersent a -CH=CH-CH=CH- group; n is 0-9; R 2 is H or OH when a- is saturated, R is H when a-B is a double bond; when a-8 is a double bond or when R is OH, R is COOH.

a -(CH )mOH group or -(CH2)m-C(CH3) 2 group when a-B

S*OH

is a saturated bond and R2 is H, R 1 is hydroxymethyl or -(CH 2

-C(CH

3 2 m 1 to 3. These compounds are

OH

active as bronchodilators useful in the treatment of asthma.

G. Xi et al. in Yaoxue Xuebao 15, 548 (1980) discloses the synthesis of antiasthmatic quinones of 25 the formula (CH 2

COOH

OH

0 where n 4-8. A number of alkyl naphthols are disclosed as intermediates.

-3- 1 A number of references discloite l-naphthol as a lipoxygenase inhibitor, including T. Nakadate et al., Gann. 75. 214 (1984); J. Van Wauwe and J. Goossens, Prostaglandiing., 26, 725 (1983); and R. V. Panganamala et al., Prostagilandins, 14. 261 (1977).

M. Shiraishi and S. Tereo in J. Chem. Soc.

Perkin Trans.- 1. 1591 (1983) disclose ethylenic and acetylenic quinones which inhibit A number of references disclose 2-alkyl-lnaphthols as intermediates in the preparation of other chemical compounds inxcluding N. S. Narasimhan and R. S. Mali. Tetrahedron, 31. 1005 (1975); Newman et al., J. Orci. Chem. 43, 524 (1978); B. Miller and W. Lin,~ J. Org. Chem. 43. 4441 (1978); K. A. Parker 15 and J. L. Kalimerton. Tetrahedron Letters, 14. 1197 (1979); D. W. Cameron et al., Aust J. Chem, 35. 1481 (1982); P. Barua et al., Chem Ind. 303 (1984); 9T. Kometani et al., J. Org. Chem.. 48. 2630 (1983); 9T. Zhong and M. Huang, Hua Hseuh Hseuh Pao. 39, 229 (1981); C. Pac et al., Synthesis'. 589 (1978); 1. A.

*'*Akhtar and J. J. McCullough in J. Org. Chem.. 46. 1447 iii R. Alonso Cermona et al., An. Quim.. Ser. C.

78. 9 (1982); 1. M. Andreeva et al., Khim. Geterotsiki. Soedin. 2. 181 (1983): D. Berney and K. Schuh.

Helv. Chim. Acta. 62. 1268 (1979); S. P. S3tarkov, Izv.

I Vyssh. Uchebn. Zaved.. Khim. Khim. Tekhriol. 20. 1099 (1977); M. R. Saidi. Indian J. Chem., 474 (1982); L. Z. Oblasova and G. D. Kharlampovich Khim. Pro-St.

(MgScowj. 10. 776 (1977): F. T. Sher and G. A. Berchtold, J. Org. Chem. 42. 2569 (1977); M. Mully et al., Helv. Chim. Acta. 58. 610 (1975); T. R. Kasturi and R. Sivaramakrishnan, Proc. Indian Acad. Sci.. 86, 309 (1977) and T. Hirashima et.. in Japanese Patent No.

V 7010339 issued April 14, 1970.

A number of references disclose 2-benzyl-lnaphthol as a chemical entity, such as B. Miller and W. Lin, J. Org. Chem, 44, 887 (1979) and Z. Aizenshtat et al., J. Org. Chem, 42. 2386 (1977).

SUMMARY OF THE INVENTION According to the present invention there are provided pharmaceutical compositions containing 2-substituted-l-naphthols of Formula and pharmaceutical methods for using them.

OH

3 R4

(I)

R 2 R1 15 wherein 1.

R is H, CH 3 Br, Cl, OH, OCH 3 0C H

C

17 18 19 20 CR COOR *CONR R ,phenyl, 12)(R 13 -NHC lower alkyl, S(O) lower alkyl where pis 0,1 or 2, SO 2 NH 2 *or -NHSO 2lower alkyl optionally substituted 9999 with F; 2 3 R and R independently are H. CH 3 V C 2

HSI

OCH. or OC H R 4is straight-chain or branched alkyl of 1-12 carbons C straight-chain or bra~nched alkynyl of 2-12 straight-chain or branched alkenyl of 2-12 carbons, cycloalkyl or cycloalkenyl of 5-7 carbons.

CH -C=EC-(CH)R 5 where m is 1 4.

22 CH=CH-(CH 2 nR where n is 0 3 and the olefinic bond has either the Z or E configuration I m 7Qjjjjjj2 -6- A-fl 6 or CH-R 7 12l

R

A is a chain of 2-6 methylene groups optionally substituted at any one of the methylene carbons by a. group R r Ris C-C 7 cycloalkyl, phenyl,.COOR R is C -C 7 cycloalkyl, phenyl, COOR 12 13 CON(R CN, CH(COOR) 1010 11 9 2 C(R )C3R9. P(O)(OR9 2- S(O) wR where w is 0 -2 with the proviso that if w=1then R 9 is not H; SC(NH)NH 2 N(R 12)(R 13 OR OC(O)R Cl. Br. or I;

.~R

7 is C-C 0 cyclvraJ,'kyl, 3 a 14 .9 9

R

16

R

9 *where X is S. 0, or NR 10 and Y is CH or N;

R

8 is C-C 4 alkyl, C 5 C cycloalkyl, or phenyl;

R

9

R

10 and Rl' are independently H orC C 49 alkyl; R 1 and R 1 independently are H. C C- C alkyl, or Rl is H. C C lky. OR O-phenyl OCH 2 COOR.

that if wis 1lthen R is not H;j -6- At"

R

1 5 and R 1 6 are independently H, C0-C4 alkyl, OR 9 0-benzyl, F, or C1; 17 R is lower alkyl, pyridyl, thienyl, furyl, or phenyl optionally substituted with C1, Br, F, CH or R is H or lower alkyl;

R

19 and R 2 0 independently are H or lower alkyl, or taken together are (CH2)4_5; and R is H, lower alkyl, pyridyl, thienyl, furyl; D:r F4 7 P-1 G ilHTT or a pharmaceutically suitable salt thereof.

Pharmaceutical compositions preferred for their genase activity contain a compound of Formula where: R 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 -CC-(CH2) R 5 where m is 3 and R 5 is COOR 9 or phenyl;

CH=CH-(CH

2 )nR5 where n is 0 2, the olefinic bond has either the Z or E configuration, and R 9 is COOR or phenyl; 6 A-R or

CH

2 R7; where 6 7 A, R and R are as defined above, preferably A is a chain of 2-6 unsubstituted methylene groups; 7 tq IJ 7 jj -8- 4 4 6606 66 6 0 66 .44044

S

*6 4* 006

S.

06 0 g.e 6 4.

6 4 4590 6 @4 6 4 04 A 6.

6 646 6 *6 5 4 4460 6 9 12 13 R is phenyl, COOR CON(R )(RI CN, 9 10 11 9 9 CH(COOR C(R )OR P(O)(OR 2 S(0) wR 9 Sc(N)2 N(R 12 )R13) 9 9 OR OC(O)R Cl. Br, or I; R 7is as defined above except that X is 1restricted to S. 0, or N-CH 3 R is as defined above except for 0-phenyl.

O-benzyl. and OCH 2COOR 9 16 29 R and R are independently H, OR F. or Cl; and 9 10 11 12 13 w, R R *R *R and R are as defined above.

Specifically preferred for their lipoxygenase inhibitozy activity are: a. methyl 7 -(l-hydroxy-2-naphthyl.....heptynoate 15 b. ethyl 5-(l-hydroxy-2-naphthyl)-4pentenoate, Z isomer c. ethyl 3 -(l-hydroxy-2-naphthyl)-propenoate, E isomer d. 2-(2-propenyl)-l-naphthol e. ethyl 3 -Cl-hydroxy-2-naphthyl)-propanoate f. ethyl 5-(l-hydroxy-2-naphthyl)-pentanoate g. 2-(5-methylhexyl)1..naphthol h. diethyl 3 -(l-hydroxy-2-naphthyl)propyl]propanedioate i. 2-Cphenylmethyl)-l-naphthol j. 2 3 -fluorophenylme hy).l-.naphthol k. 2 3 4 1. 2-(2-furylmethyl)-l..naphthol MI. 2 3 4 -dimethoxypheyl)methyll.naphthol n. 2 -(2-thienylmethyl)l-.naphthol o. 2

-C

3 -chlorophenylmethyl)-lnaphthol p. 2 4 -ethoxyphenylmethyl)-l-naphthol q. 2 4 -bromophenylmethyl)..l.naphthol r. 5.

8 -dimethyl-2-(phenylmeth.yl....1naphthol Also provided in the inventioa are novel 2-substituted-l-naphthols within Formula which are defined by Formula (II).

-a- -9- 3

OH

R

wherein R is H. CH 3 Br, Cl. OC 2

H

5 0 COR17 18 19 COOR *CONR R phenyl, lover alkyl, where p is 0. 1 or 2.

IF 13 110 j -NHC lower alkyl, SO NH 2 cl 2 2 0

-NHSO

2 lower alkyl optionally substituted .*..with F; a2 3 R and R independently are H. CH 3 C H.

R

4 CH 0. or C H Ot R. is straight-chain or branched alkynyl of I: 2-12 carbons, C -C 7 cycloalkenyl.

CH

2

-C:EC-(CH

2

),R

5 where m is 1-4.

*.aCH=CH-(H) R where n is 1(C 3 and the a,2 n olefinic bond has either the Z or E configuration.

6.

4 A-R *or

CHR

7 121

R

A is a chain of 2-6 methylene groups;

R

5 is C -C 7 cycloalkyl. phenyl.) COOR 6.

R is C 3

-C

6 alkenyl. C C cycloalkyl.

CH(COOR

1 119 9 C(R )OR9. P(O)(OR ~2S(O)wR 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

1

OR

9 Cl. Br. or I: is C 3

-C

8 cycloalkyl.

-9- I OR 9 R Ri where X is S, 0, or NR 10 and Y is CH or N;

R

9 R 10 and R 1are independently H or 01l-0c4 alkyl; R 12 and R 13 independently are H, 0 1- O4 alkyl, or together 14are (OH 2 4 5 99 1 sC1- alkyl, OR 9 0-phenyl, OCH 2OOOR O-benzyl,

OOOR

9 CF 3 01, Br, I, N(R 12

)(R

13 or S(O) wR 9 where w is 0 2 with the proviso that if w is 1 *9 *then R 9 is not H; and

R

15 and R 1 6 are independently H, C1-0 alkyl, OR(, O-benzyl, F or 01;

R

17 is lower alkyl, pyridyl, thienyl, furyl, or phenyl optionally substituted with Cl, Br, F, OH 3or 18OH R is H or lower alkyl; R9and R 0independently are H or lower alkyl, or taken **together are (OH 2 45 and to R 2 1 is H; -jc if R1, R2, and R3 are all H, then R 4 is not 4-clhlorophenylnethyl, 4-rnethylphenylmethyl, or 2-furylmethyl; if R 2 or R 3 is 6-oOH, then R 4 is not 4-chlorophenylnethyl or 4-methylphenylmethyl; 10 1 4 3. if R is C1 then R is not 4-aminophenylmethyl; and 4. R4is not CH CH CN.

Preferred for their lipoxygenase activity are those novel compounds of Formula (II) where: 4 R is cycloalkenyl of 5-6 carbons; CC(CH )mR 5where m is 3 and R 5is COOR 9 or phenyl; CH4CH-(CH 5 where n is 2. 2, the 2)n olefinic bond has either the Z or E configuration and R 5is COOR 9or phenyl; 6 A-R or CH -R;whrA.R and R 7 are as 0 02 defined above, preferably 00A is a chain of 2-6 unsubstituted methylene ~.,groups; R is CON(R )R 3 CN, CII(COOR )2 1.2 13 29, 1

SC(NH)NH-

2 C ),OR C, Dr. orn: R is as defined above except that X is restricted to S. 0, or N-CH 3 .o Is as defined above except for 0-phenyl, O-benzylo and OCH R and R are independently H, OR 00 0 F, or Cl;, andt 9 10 11 2 13 W, R R~ R U and R 1 are as defined above.

Specifically preferred novel compounds are the same ones specifically preferred for their lipoxygenase activity except compounds c, d. e, f, g and i.

As used herein, the term "lower alkyll" means a straight chain or a branched-chain alkyl of 1 to 4 carbon atoms.

-12.- N(R OR Cl. Br, or I; R is C 3

-C

8 cycloalkyl.

/3

I

-12- DETAILED DESCRIPTION OF THE INVENTION The novel compounds of Formula (II) may be prepared using the reactions and techniques described in this section. The reactions are usually performed in a solvent appropriate to the reagents and materials employed, and suitable for the transformation being effected. Unless stated otherwise, the reactions are performed at temperatures between -78° and the boiling point of the solvent used, as appropriate for a reasonable rate of reaction and the stability of the reagents, solvents, and products involved.

Throughout the following section, the preparation of certain compounds of Formula (II) by 15 the methods described will require that functional S groups on the starting materials be protected, by the use of standard protecting groups reported in the chemical literature. These cases will be readily recognized by one skilled in the art. Examples of 20 suitable protecting groups include benzyl ethers, .4 methyl ethers, and methoxymethyl ethers to protect hydroxyl groups, ketals and acetals to protect carbonyl groups, and trialkyl orthoesters to protect .1 esters. The choice of protecting groups is affected by the type of transformations to be performed upon the protected material, as well as the types of functionality elsewhere in the molecule which must be stable to the conditions used to remove the protecting group after it has served its pu"pose. A review of protecting group chemistry is T. W. Greene, h "Protective Groups in Organic synthesis" (John Wiley and Sons, 1981). In the cases where a protecting group is required, this group must often be removed in a separate step after performing those steps of the synthetic route with which the unprotected functionality is not compatible.

-12- 1~ *eve

S..

*of* g o* 6 6S* *6 *6

S.

6 *6

S

0 *00 S -13- Throughout the following section, not all compounds of Formula (II) falling into a given class may necessarily be prepared by all methods described for that class. Substituents on the starting materials may be incompatible with some of the reaction conditions required in some of the methods described.

Such restrictions in the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art.

Alternative methods described in the following section may then be used to prepare such compounds.

Throughout the following section, the letter "Z" in the Formulas represents the portion of R which is not already included in the formula, or the portion of R 4 not involved in the manipulations illustrated in the Schemes. The letters "Pr" represent a protecting group for the naphthol hydroxyl which is suitable for the transformations being illustrated, and which may be removed under conditions which will not affect the remainder of the compound. Examples of such protected hydroxyl groups are methyl, benzyl.

methoxymethyl, and trialkylsilyl ethers. The choice of a suitable protecting group will be apparent to one skilled in the art.

25 Compounds of Formula (II) where R 4 is an alkynyl group attached to the naphthalene ring through a methylene group may be prepared by the route shown in Scheme 1. A suitable l-(protected hydroxy)-2naphthaldehyde (III) may be treated with an alkynyl organometallic reagent such as an organolithium reagent to provide the intermediate alcohol This intermediate compound may be converted to the intermediate protected naphthol using standard methods of hydroxyl group removal, for instance by treatment with a trialkylsilane in the -13- LIPOXYGENASE INHIBITORS The following statement is a full description of this invention, including the best method of performing it known to me:-' 'Note: The description is to be typed in double spacing, pica type face, in an area not exceeding 250 mm in depth and 160 mm in width, on tough white paper of good quality and it is to be inserted inside this form.

11710/76-L C.J.TIOMPSON, Commonwalth Government Printer.Canberra 1. -14presence of an acid reagent such as boron trifluoride etherate. An example of this reductive dehydroxylation method is described by J. L. Fry et al.. Tetrahedron Letters. 2995 (1976). The protecting group of may then be removed using appropriate techniques to provide the desired (II).

SCHEME 1 3 OPr 3 O P r OH R R 2 R 2

R

R R1 R R1 .91 (III) (IV) S3 OPr

R

(II)

2 0 2 R 1

(V)

S. Compounds of Formula (II) where R 4 is an Salkynyl group attached to the naphthalene ring through one of the acetylenic carbons may be prepared as shown in Scheme 2. A suitable l-(protected hydroxyl)- 2-bromonaphthalene (VI) may be treated with a 1-alkyne in the presence of a suitable catalyst such as a palladium salt, for instance as reported by W. B.

SAustin et al.. J. Org. Chem. 46, 2280 (1981), to provide the intermediate protected alkynyl naphthol S(VII). Alternatively, a suitable l-(protected hydroxy)-2-naphthaldehyde (III) may be treated with tetrabromomethane and triphenylphosphine to provide the intermediate acetylenic compound (VIII). This -14- -41 zL uJCzZY., z-mernoxyetnylo phenyl- 4-methoxYPhenyl or aminomethyl.

I

intermediate may then be treated with a strong base such as n-butyllithium anid an electrophilic reagent such as an alkyl halide to provide the intermediate (VII). (This method of forming substituted acetylenes is reported by E. J. Corey and P. L. Fuchs, Tetrahedron Letters, 3769 (1972).) The protecting group of (VII) may then be removed using appropriate techniques to provide the desired (II).

Compounds of Formula (II) where R 4is CH 2 -CC- (CH 2 mR 5may be prepared by the route shown in Scheme 1.

6 ee s* '0 0O 00*S SCHEME 2: r z-c BrSC=C >1 i r) (vr) (VI 1) .CHO 3 (VI 11) (XXX) -2fl r' a -16- Compounds of Formula (II) where R 4 is a cycloalkenyl group may be prepared as shown in Scheme 3. A suitable protected 1-naphthol (IX) may be treated with a strong base such as n-butyllithium to provide the organolithium intermediate An example of this transformation is reported by D. A.

Shirley and C. F. Cheng. J. Organometallic Chem. 251 (1969). The organolithium derivative may then be treated with a suitable ketone, such as cyclopentanone, cyclohexanone, or cycloheptanone. to provide the intermediate tertiary alcohol The intermediate (XI) may be converted to the intermediate cycloolefin (XII) by dehydration using standard methods such as treatment with an acid. e.g..

15 hydrochloric acid or e-toluenesulfonic acid. The protecting group of (XII) may then be removed using appropriate techniques to provide the desired (II).

SCHEME 3:

S

55 see o g 0 6000 *0 *C S OPr OH 6 (xI)

(IX)

(II)

(XII)

-16-

U

-17- Compounds of Formula (II) where R 4 is 5

CH=CH-(CH

2 )nR may be prepared by the route shown in Scheme 4. A suitable l-(protected hydroxy)-2naphthaldehyde (III) may be treated with a reagent such as an alkylidene triarylphosEphorane (XIII) or the anion of a dialkyl alkylphosphonate (XIV) (the Wittig reaction) to provide the protected intermediate (XV), which may be obtained as either the Z or the E isomer, or as a mixture of the two. The protecting group may be removed using appropriate techniques to provide the desired (II).

Compounds of Formula (II) where R 4 is CH=CH-(CH nR may also be prepared by an 2 n alternative route also shown in Scheme 4. An organolithium derivative prepared from a suitable protected 1-naphthol may be treated with an aldehyde ZCH 2 CHO. The intermediate alcohol (XVI) may then be dehydrated using standard methods such as treatment with an acid, hydrochloric acid or S 20 E-toluenesulfonic acid. The resulting intermediate (XV) may then be deprotected using appropriate techniques to provide the desired (II).

o** 2 1 5-17- 1 -18- SCHEME 4: 0 (11) 0 OPr Ar 3 P-Z (XIII) or 9 (R o) 2 (XIV)

(XV)

(i i r) moo*** 0 0 *060 0 0

CHO

3 OPr OH R 2 MX (XVI) Compounds of Formula (II) where R 4 is CH 2 -R 7may be prepared by the method illustrated in Scheme 1.

Compounds of Formula (II) where R 4 is CH 2 -R 7 may also be prepared by the method illustrated in Scheme 5. A suitable naphthol (XVII) may be treated with a suitable carboxylic acid derivative. such as the free acid, acid halide. or anhydride, in the presence of a suitable acid catalyst (the Friedel-Crafts reaction). Examples of this type Chen, Yaoxue Xuebao 15, 548 (1980), and by G. Faway and L. F. Fieser, J. Amer. Chem. Soc. 72. 996 (1950).

The intermediate ketone (XVIII) may be converted to the desired (II) by standard methods, for instance by treatment with amalgamated zinc in the presence of hydrochloric acid (the Clemmensen reduction technique), or by conversion of the naphthol hydroxyl group to an ethyl carbonate followed by treatment with et al., Arzneimittel-Forschung 34, 652 (1984).

SCHEME .1 1 R I -19- R

R

:of reaction are reported by G. Xi X. Guo, and R.

R R The intermediate(XVII) (XVIII Compounds of Formula (II) where R 4 is 7 7 be prepared by the method shown in Scheme 6. A suitable 1-tetralone (XIX) may be treated with an aryl or heteroaryl aldehyde in the presence of a base such as potassium hydroxide or potassium t-butoxide in an alcoholic solvent. If the base/solvent combination is SCHEME 35 potassium t-butoxide and t-butanol, the 1-19su e -n ((II) 0 or heteroaryl aldehyde in the presence of a base such as potassium hydroxide or potassium t-butoxide in an alcoholic solvent. If the base/solvent combination is 35 potassium t-butoxide and t-butanol, the

I

-19- 1 i I y 4 2-arylmethyl-l-naphthol where R is

CH

2 -R 7 is obtained after workup with aqueous acid. If the base/solvent combination is potassium hydroxide and ethanol, an intermediate benzylidene tetralone (XX) is isolated, as reported by Z. Aizenshtat. M. Hausmann, Y. Pickholtz, D. Tal, and 0 J. Blum, J. Orq. Chem. 42, 2386 (1977). This intermediate may then be treated with potassium 4 t-butoxide in t-butanol to provide (II) where R is

CH

2 R after workup with aqueous acid, as reported by D. H. R. Barton, J. H. Bateson, S. C. Datta, and P.

D. Magnus, J. Chem. Soc., Perkin Trans. I, 503 (1976).

S* SCHEME 6: I 3 O 3 O

R

4 7 20 2 2 e

(II)

4 Compounds of Formula (II) where R is 21 7 CH(R )R may be prepared by the methods shown in Scheme 7. An organolithium derivative prepared from a suitable protected 1-naphthol may be treated with a ketone to provide the tertiary alcohol (XXI) after aqueous workup. Alternatively, a ketone (XXII) prepared by protection of the hydroxyl group of 7 -21a ketone (XVIII). where Z is either Ror R may be treated with an organometallic reagent ZIM, where Z' is R 7(if Zis R 21)orR 21(ifZ isR 7).

and M is a metal such as lithium or magnesium halide.

The intermediate (XXI) resulting from either of these reactions may be converted to the intermediate (XXIII) using standard methods of reductive dehydroxylation.

Rem~oval of the protecting group from (XXIII) will then provide the desired (II).

SCHEME 7: OPr R7 0 a* go*6 R 2 1 (LullI

(II)

Li j 0 R 7 ,WR 21

R

3 QPr OH I

R

2 1 1 R 2R1 So 5*S*

(XXI)

OPr 0

ZIN

R2

(XXII)

-21- -22- Compounds of Formula (II) where R 4 is A-R 6 may be prepared by the routes shown in Schemes 1 or Compounds of Formula (II) where R 4 is A-R 6 may also be prepared from certain compounds of Formula 4 (II) having an olefinic group for R (which may be prepared according to the routes shown in Scheme 4).

Reduction of the multiple bond may be performed using standard methods, for instance treatment with hydrogen in the presence of a catalyst such as palladium on charcoal.

Compounds of Formula (II) where R 4 is A-R 6 may also be prepared by the route shown in Scheme 8.

An organolithium derivative prepared from a oo suitable protected 1-naphthol may be treated with an alkylating agent such as an alkyl halide to •provide the intermediate (XXIV). The resulting intermediate may then be deprotected using appropriate S techniques to provide the desired (II).

SCHEME 8: R3 OP r 3 O P r Li

A-R

Br-A-R 6 22 (II)

R

2 1 R R1 R R

(XXIV)

Compounds of Formula (II) where R is

(CH

2 3 -OH may be prepared by the route shown in Scheme 9. The allyl ether of a suitable 1-naphthol (XXV) may be converted to the 2-allyl-l-naphthol (XXVI) by thermal rearrangement, for instance as described by K. A. Parker and J. L. Kallmerten, STetrahedron Letters, 1197 (1979). The intermediate (XXVI) may then be converted to a protected form -22-

I

4_.

-9- ,s n -23- (XXVII), and converted to the protected hydroxyl compound (XXVIII) by treatment with borane-tetrahydrofuran complex followed by a standard oxidative workup. Deprotection of (XXVIII) will then provide the desired (II).

Compounds of Formula (II) where R 4 is

(CH

2 )nOH, where n is 2-6, may also be prepared from the corresponding compounds of Formula (II) where R is (CH 2 )n-R where R is a carboxylic acid, carboxylic ester, or aldehyde, by treatment with a reducing agent such as lithium aluminum hydride.

*n C 0

S.

6 06

S.

*s S

C

5 .666 *0

S

*6 0* 6 s e S SCHEME 9: (XXV) (XXVI) (XXVII)

(II)

(XXVIII)

Compounds of Formula (II) may also be prepared from other compounds of Formula (II) by functional group interconversions which are well known to those skilled in the art. Examples of such functional group interconversions are given herein.

-23- I -10 -24- Compounds of Formula (II) where R 4 contains 10 11 the group C(R )OH may be prepared from the corresponding compounds where this group is replaced by a carboxylic ester or carboxylic acid, as shown in Scheme 10. The ester or acid (XXIX) may be treated with an appropriate organometallic reagent such as an 0 alkyllithium or alkylmagnesium halide to provide the desired compound (XXX). where R and R are the same. If R 1 and R are different, the corresponding compound (XXX) may be prepared by treating the ester or carboxylic acid (XXIX) with an appropriate organometallic reagent to provide the intermediate alkyl ketone (XXXI). Treatment of this intermediate with either a reducing agent such as 1 15 sodium borohydride or with a second organometallic j reagent will then provide the desired compound (XXX).

SCHEME 3 OH 3 OH 0 20 R R l

CR

COOR

9

CR

i10 R 1 R 1 R R (XXIX) (XXXI) 11 1 1 3 OH SR OH OH 1 0 11 10 11 N R (IF R R

R

2 1 I

R

(XXX)

-24r Compounds of Formula (II) where R 4 contains a

C

3

-C

6 alkylene group may be prepared from compounds of Formula (XXX) by dehydration using standard techniques.

Compounds of Formula (II) where R 4 contains an aliphatic halogen atom may be prepared from the Scorresponding alcohol using standard procedures.

Compounds of this type may also be converted into compounds with a different halogen using standard procedures.

Compounds of Formula (II) where R 4 contains an aliphatic nitrile, malonic ester, phosphonic ester, sulfide, amine, ether, or SC(NI)NH 2 group may be prepared from the corresponding compound containing a 15 suitable leaving group such as Cl, Br, I, methanesulfonate, toluenesulfonate, or trifluoromethanesulfonate by treatment with an appropriate nucleophilic reagent such as sodium cyanide, diethyl sodiomalonate, triethyl phosphite.

20 potassium thiomethylate, sodium ethoxide, thiourea, etc. (Sulfonate leaving groups may be prepared by treatment of the corresponding alcohol with the apropriate sulfonyl chloride or sulfonic anhydride in *o the presence of a base such as triethylamine or pyridine.) In the case where R 4 contains SH, thiourea may be used as the nucleophile, in which case basic hydrolysis of the intermediate isothiourea provides the thiol. In the case where R 4 contains

NH

2 sodium azide may be used as tho nucleophile, in which case catalytic hydrogenation of the intermediate azide provides the primary amine.

Compounds of Formula (II) where R 4 contains an ether or sulfide group may be prepared by treatment of the corresponding alcohol or thiol (in which the -26naphthol hydroxyl has been suitably protected) with a strong base such as sodium hydride, followed by treatment with an appropriate alkylating agent such as methyl iodide or ethyl iodide, and removal of the protecting group.

Compounds of Formula (II) where R 4 contains a carboxylic ester may be prepared from the corresponding compound where R 4 contains a halogen such as Br or C1 and the naphthol has been suitably protected, by conversion to the corresponding organolithium or organomagnesium halide and allowing this intermediate to react with a dialkyl carbonate to provide the corresponding ester, followed by deprotectiun. The corresponding carboxylic acid may be prepared by allowing the organometallic intermediate to react with carbon dioxide, followed by deprotection.

Compounds of Formula (II) where R is Cl or Br may be prepared from the corresponding compound (II) where R l is H, by treatment with chlorine or bromine in a suitable solvent such as acetic acid, optionally in the presence of a suitable catalyst. In some cases, it may be preferable to mask the naphthol i hydroxyl group prior to reaction with bromine or chlorine, in which case depcotection is required to provide the desired product (II).

Compounds of Formula (11) where R is C(pO)R 7 may be prepared from compounds of Formula (II) where R 1 is hydrogen by treatment with a suitable acylating reagent such as an acid chloride, acid anhydride, or mixed anhydride, in the presence of a catalyst such as aluminum chloride or zinc chloride (the Friedel-Crafts reaction). In some cases, it may be preferable to mask the naphthol hydroxyl group prior to reaction with the acylating reagent, in which -26choie inwihcs dpoet i eurdt

J

-27case deprotection is required to provide the desired In some cases, the hydroxyl group will react 9 with the acylating agent in the course of the acylation reaction to provide the corresponding ester of the desired in which case hydrolysis of the ester provides the desired (II).

Compounds of Formula (II) where R 1 is C(=0)R 7 may also be prepared from compounds of Formula (II) where R 1 is hydrogen by the route shown in Scheme 11. The hydroxyl group of (II) may be protected to provide (XXXIII). The intermediate (XXXIII) may then be treated with bromine in a suitable solvent such as acetic acid to provide (XXXIV). This intermediate may then be converted to 15 an organometallic intermediate (XXXV) such as the corresponding organomagnesium halide or the corresponding organolithium reagent using standard chemical techniques. The organometallic intermediate may then be treated with with a suitable aldehyde 17 R -CHO to provide (XXXVI), which may then be oxidized to the corresponding ketone (XXXVII), using reagents such as pyridinium chlorochromate, Jones reagent, or other standard oxidizing agents. Removal of the protecting group on the hydroxyl group using suitable techniques then provides the desired (II).

S* -27- -14- 717

I

-28- OP r

R

4

T

(11) (R H) (XxxIII) (XXZ IV) 000.

*0 0 00 so*,) p0 4 0 R 3 OPr4

R

1 7 7

CHO

R

2

NO

1 7

(XXAVI)

(Xxxv)

N

3 OPr 4 Rt 0 R 17 (11) (XV I) -28- -29- Compounds of Formula (II) where R 1 is COOR 8 may be prepared from organometallic intermediates of Formula (XXXV) with a carboxylating agent such as carbon dioxide, a dialkyl carbonate, or an alkyl chloroformate. Removal of the protecting group on the hydroxyl using suitable techniques then provides the desired (II).

Compounds of Formula (II) where R is phenyl may be prepared by treatment of intermediates of Formula (XXXIV) with an appropriate arylmagnesium halide, in the presence of a suitable transition metal catalyst such as 1,3-bis-(diphenylphosphino)propane i. nickel (II) chloride, followed by removal of the protecting group on the hydroxyl using suitable 15 techniques.

Compounds of Formula (II) wherein R is S(0) R or SO2NH 2 may be prepared by treatment of w compounds of Formula (XXXIII) with chlorosulfonic acid to provide the corresponding sulfonyl chloride, followed by standard functional group manipulations, well known to one skilled in the art, to convert the sulfonyl chloride to the desired group S(0) x R or SO NH 2 Removal of the hydroxyl protecting group will then provide the desired (II).

Compounds of Formula (II) wherein R 1 is NR2 R may be prepared from compounds of Formula (XXXIII) by reaction with a suitable nitrating agent in a suitable solvent, such as fuming nitric acid in acetic acid. The intermediate nitro derivative may then be converted to the compound of Formula (II) wherein R 1 is NH 2 by standard techniques of nitro group reduction, such as catalytic hydrogenation.

-Standard functional group manipulations well known to one skilled in the art can then be used to convert the primary amine to other desired substituents

NRR

1 3 NHC(=O)alkyl, or NHSO 2 alkyl.

-29- -16- Compounds of Formula (II) containing ester functional groups may be converted to the corresponding compounds containing carboxylic acid groups by acidic or basic hydrolysis using standard conditions. Carboxylic acids may be converted to esters, and esters may be converted to esters of different alcohols, using standard techniques, for instance, by treatment with a catalytic amount of a strong acid such as sulfuric acid in the appropriate alcohol as solvent, optionally with an inert cosolvent to improve solubility of the starting material.

Compounds of Formula (II) containing an amide functional group attached through the carbonyl carbon may be prepared from the corresponding compounds oo, 15 containing a carboxylic acid functional group by protecting the naphthol hydroxyl group, converting the carboxylic acid to an acid chloride using standard o techniques, and allowing the acid chloride to react with ammonia or an appropriate amine. Deprotection of 20 the hydroxyl group then provides the desired (II).

OO,, Compounds of Formula (II) containing sulfoxide or sulfone functional groups may be prepared from the corresponding sulfides by protecting the naphthol hydroxyl group and treating with an oxidizing agent such as m-chloroperoxybenzoic acid or any of a number of other oxidants, followed by removal of the protecting group.

Starting materials for the synthetic routes described above, such as 1-naphthols, protected 1-naphthols, and 1-tetralones, are either commercially available, are described in the chemical literature, or may be prepared from known compounds by routes described in the chemical literature.

In particular, protected 2-formyl-l-naphthols of Formula (III) may be prepared from a suitably base such as n-butyllithium, followed by treatment with a formylating agent such as NN-dimethylformamidei as described by N. S. Narasimhan. R. S. Mali.

-31and M. V. Barve, Synthesis, 906 (1979). Alternatively, a 1-hydroxy 2-naphthoic acid may be converted to the 0 naphthyl ether carboxylic ester using standard techniques, and the ester moiety converted to an aldehyde group, again using standard techniques.

The compounds of this invention and their preparation are illustrated further in the following Examples. All temperatures are in degrees Centigrade and parts and percentages by volume. In these Exam- 0. ples, unless otherwise indicated; the reactions were 15 performed under an atmosphere of dry nitrogen; "isolation by extraction" refers to the liquid-liquid extrac- 0 tion of a water-containing mixture with an indicated .solvent, followed by drying the organic phase over magnesium sulfate,filtering, and evaporation of the solvent under reduced pressure; chromatography refers to the method of medium-pressure column chromatography described by W. C. Still, M. Kahn. and A. Mitra, J. Orq. Chem. 43, 2923 (1978).

o 0 EXAMPLE 1 PART A: Methyl 7-(l-benzyloxy-2-naphthyl)- A solution of 1,,l1-trimethoxy-5-hexyne (3.90 g, 0.023 mole) in dry tetrahydrofuran (50 mL) was stirred at -78° and treated with n-butyllithium (1.6 M in hexane; 15 mL, 0.024 mole). The solution was Sstirred for 30 minutes, then treated with a solution of l-benzyloxy-2-naphthaldehyde (4.25 g, 0.016 mole) in dry tetrahydrofuran (12 mL). The reaction mixture -31- -19was allowed to warm to room temperature, stirred for 4 hours, and poured into water. The crude product was isolated by extraction with ether and chromatographed with 3:1 ether/hexane. This afforded the title compound (6.15 g, 97%) as an oil.

PART B: Methyl 7-(l-benzyloxy-2-naphthyl)-5-heptynoate To a solution of boron trifluoride etherate mL. 0.041 mole) in methylene chloride (150 mL) at 00, triethylsilane (20 mL, 0.126 mole) was added, followed by a solution of methyl 7-(l-benzyloxy-2- (5.00 g, 0.013 mole) in methylene chloride (20 mL). The mixture was -32- S, stirred for 30 minutes then poured into saturated e4 15 aqueous potassium carbonate. The crude product was isolated by extraction with ether, and chromatographed g o" with 1:1 ether/hexane. This provided the title compound (2.42 g, 50%) as an oil.

20 PART C: Methyl 7-(l-hydroxy-2-naphthyl)-5-heptynoate A solution of anethiol (12.0 mL, 0.162 mole) and boron trifluoride etherate (6.0 mol 0.049 mole) was stirred at room temperature. A solution of methyl 7-(1-benzyloxy-2-naphthyl)-5-heptynoate (20.05 g 0.006 mole) in methylene chloride (8 mL) was added, *and the mixture was stirred for 1.5 hours, then poured Sinto water. The crude product was isolated by extraction with ether, and chromatographed with 2:1 ether/hexane. The title compound (1.09 g, 71%) was obtained as a colorless oil. Mass spectrum: m/z 282.

The compounds of Example 1, as well as other compounds which can be prepared by the procedure of Example 1. are shown in Table 1.

-32t.1 -19li -33- TABLE 1

OH

(CH 2 mR 2 1 1 2 Ex. m R R 2

R

5 Yield MP(OC) 1 3 H H COOCH 3 71 (oil) a C2H50 -33 2 2 H 6-C 2

H

5 0 3 3 C2H50 H cyclohexyl 15 4 2 H 6-CH30 CH(CH 3 2

O

a. mass spec m/z 282 EXAMPLE PART A: 2-(l-Hydroxycyclohexyl)-l-methoxymethoxy-naphthalene A solution of l-methoxymethoxy-naphthalene (3.76 g, 0.020 mole) in dry ether (40 mL) was treated with n-butyllithium (1.6 M in hexane; 25.0 mL. 0.040 mole) at room temperature over a period of 15 minutes.

After stirring for an additional 1.5 hours, a solution fees of cyclohexanone (4.90 g. 0.050 mole) in ether (15 mL) was added and the resulting mixture was stirred at room temperature for 2 hours. It was then quenched with saturated aqueous ammonium chloride and the crude product was isolated by extraction with ether. Chromatography with 9:1 hexane/ethyl acetate provided the title compound as a colorless oil (3.30 g. 58%).

-33- -34- PART B: 2-Cyclohexenyl-l-naphthol A solution of the product of Part A (3.30 g, 0.012 mole) in ethanol (100 mL) and 1.0 N hydrochloric acid (100 mL) was stirred at room temperature for hours. The ethanol was removed under reduced pressure, and the crude product was isolated by extraction with ethyl acetate. Chromatography with 95:5 hexane/ethyl acetate provided a white solid which was recrystallized (hexane) to give the title compound (1.59 g, 62%) as white crystals, mp 82-83°.

The compound of Example 5, as well as other compounds which can be prepared by the procedure of Example 5, are shown in Table 2.

11 ii *1 I oee* o *o o* *l o*« ooo* o *g TABLE 2

OH

Example

R

R

4 Yield MP(°C)

H

6-CH3 0 o cyclohexenyl cyclopentenyl cycloheptenyl 82-83

N(CH

2 4

H

EXAMPLE 8 Ethyl 4-(l-hydroxy-2-naphthyl)-3-butenoate, E isomer A suspension of sodium hydride (60% in mineral oil; 1.94 g, 0.049 mole) in dry tetrahydrofuran -34- (XXII) I -21- 2-naphthaldehyde (2.00 g, 0.009 mole) and 2-carboxyethyl-triphenylphosphonium bromide(prepared by the procedure of H. S. Corey, J. R. D. McCormick, and g, 0.023 mole) in dry dimethyl sulfoxide (15 mL) was added over 20 minutes. The mixture was allowed to warm to room temperature over 1.25 hours, then stirred at room temperature for 30 minutes. 1.0 N hydrochloric acid (10 mL) was added dropwise, followed by stirring for an additional 20 minutes. The crude material was isolated by extraction with ethyl acetate and dissolved in absolute ethanol (200 mL), treated with 0 drops of concentrated sulfuric acid, and heated at 15 reflux for 6 hours. The cooled solution was diluted with water, and the crude product isolated by extraca btion with ethyl acetate. The resulting oil was chromatographed with 9:1 petroleum ether/ether, to p provide a solid which was recrystallized (hexane) to give the title compound (0.35 g, 15%) as a tan solid, i mp 83-84°.

s EXAMPLES 9 AND j Ethyl 5-(l-hydroxy-2-naphthyl)-4-pentenoate, E and Z isomer A mixture of potassium t-butoxide (2.10 g, 0.019 mole) and 4-carbethoxypropyl-triphenylphosphonium bromide (prepared according to the procedure of P. E.

Sonnet, J. Orq. Chem. 34, 1147 (1964); 8.40 g, 0.018 mole) in dry tetrahydrofuran (15 mL) was stirred at After 45 minutes, a solution of 1-methoxymethoxy- 2-naphthaldehyde (2.00 g, 0.009 mole) in dry tetrahydrofuran (7.5 mL) was added over 10 minutes. The resulting mixture was stirred at 0° for 2 hours, then was poured into water. The crude material was isolated -22ii k~

A

IV :S.

I

1 -36by extraction with ethyl acetate and chromatographed with 10% ether/petroleum ether, then was dissolved in absolute ethanol (200 mL), treated with 3 drops of sulfuric acid, and heated at reflux for 18 hours.

After cooling, the solution was diluted with water and the crude product mixture isolated by extraction with etiyl acetate. This was chromatographed with 85:15 petroleum ether/ether to provide two different solids.

The first one to elute was recrystallized (hexane) to 10 provide the Z isomer of the title compound (0.43 g, 17%) as a pale yellow solid, mp 75-77°. The second solid was recrystallized (hexane) to provide the E isomer (0.23 g, as a white solid, mp 63-640 The compounds of Examples 8-10. along with other compounds which can be prepared using the procedures of Examples 8-10, are shown in Table 3.

TABLE 3

(CH

2 )nR Ex. R 1 8 H 9 H

H

11

CH

3

R

2

R

5 n Z/E Yield H COOC 2

H

5 H COOC2H 5 H COOC 2H H cyclohexyl 1 E 15

MP(°C)

83-84 63-64 75-77 2 E 2 Z 17 2 Z 2 Z 12 N(CH 3 2 H phenyl -36- -23- 1 i -37- EXAMPLE 13 PART A: 2-(1',1'-Diphenyl-l'-hydroxy)methyl-l-methoxynaphthalene A mixture of l-methoxynaphthalene (7.9 g, 0.05 mole) and cyclohexane (20 mL) was added to a solution of n-butyllithium (1.6 M in hexane; 31 mL 0.05 mole) and N,N,N .N -tetramethylethylenediamine (5.8 g.

0.05 mole) in cyclohexane (10 mL). The solution was stirred at room temperature for 2 hours, when a solution of benzophenone (9.1 g, 0.05 mole) in cyclohexane (10 mL) was added. The resulting mixture was stirred overnight and poured into water. The crude product was isolated by extraction with ether, and chromatographed with 19:1 hexane/ethyl acetate.

15 The resulting product was triturated with petroleum ether to provide the title compound (6.13 g, 36%) as a gat*e: "white powder, mp 123-124.5.

PART B: 2-(1',1'-Diphenylmethyl)-1-methoxynaphthalene A mixture of boron trifluoride etherate (8.08 g, 0.057 mole) and methylene chloride (150 mL) was Sg* stirred at 00. Triethylsilane (14.56 g, 0.125 mole) was added, followed by a solution of the product of I Part A (4.50 g, 0.013 mole) in methylene chloride mL). The mixture was stirred at 00 for 30 minutes and Spoured into saturated aqueous potassium carbonate.

i: The crude product was isolated by extraction with ether, and triturated with petroleum ether to provide the title compound (4.20 g, 100%) as a white powder, mp 119-121°.

PART C: 2-(l'.l'-Diphenylmethyl)-l-naphthol A mixture of boron tribromide (1.0 M in methylene chloride: 10 mL, 10 mmole) in methylene chloride (75 mL) was stirred at A solution of -37-

(XXX)

-24- -38the product of Part B (2.5 g, 7.7 mmole) was added, and the mixture stirred for 1 hour at -780. The reaction was then warmed to room temperature, stirred for 5 hours, and poured carefully into water. The crude product was isolated by extraction with ether, and chromatographed with 19:1 hexane/ethyl acetate.

The resulting solid was triturated with petroleum ether to provide the title compound (1.06 g, 44%) as a white powder, mp 87-89°.

EXAMPLE 14 PART A: 2-(l l -Cyclohexyl-l'-hydroxy)-methyl-l-methoxynaphthalene A solution of cyclohexylmagnesium chloride 15 M in ether; 10 mL, 0.02 mole) in dry ether (10 mL) was stirred at 00. A solution of l-methoxy-2-naphthaldehyde (1.88 g, 0.01 mole) in dry ether (15 mL) was added dropwise, and the mixture allowed to warm to room temperature. After stirring for 1 hour, the mixture was poured into 1.0 N hydrochloric acid (100 mL). The crude product was isolated by ether extraction and chromatographed with 19:1 toluene-ethyl acetate to provide the title product (1.7 g, 65%) as a pale yellow glass.

PART B: 2-Cyclohexylmethyl-l-methoxynaphthalene Using the procedure of Example 13, Part B, the product of Part A was converted in 77% yield to the title compound, a pale yellow oil. Mass spectrum: m/z 254.

PART C: 2-Cyclohexylmethyl-l-naphthol Using the procedure of Example 13, Part C, the product of Part B was converted in 15% yield to the title compound, a pale orange solid, mp 53-56°.

-38- 1 Usng he poceureof Eampe 1. Pat C th p.- -39- The compounds of Examples 13 and 14, along with other compounds which were or can be prepared using the procedure of one of these Examples are shown in Table 4.

TABLE 4 OH R7 2

CH-R

2 R 2 0 0 0 to

EX*

N. R 13 H 14 H

H

11

H

SCH

3

CH

3

H

H

CH 3

H

R 2

R

7 H C 6 H 5 H cyclohexyl H

C

6 H 5 H C 6 H 5 6-CH 3 3,4-(CH 3

O)

2

C

6

H

3 Ii 3-pyridyl H C 6

UH

5 5.7-(CU 3 2 4-(CH 3 0)C 6

H

4 1 C 6% 5.8-(H 3 )2 C 6

HS

S-CH

3 0 CUH p~radyl H 4-PC 6

H

4 6-C 2 H 3. 4b(CH 3

O)

2

C

6 1 3 R 21 C 6

UH

5

H

CU 3 C 2 H 5

CH

3

CHU

3

CHU

3 CH 3 3- YtELD% 44 1.5 85 81, (oil)b MP K C), 87-89 53-56 0 24 HI

UH

4 -FC 6

H

4

CH

3 at. Mass spectrum: h. Mass spectrum rn/z m248 mza262 w309 I_ EXAMPLE 26 2-(3-Pyridylmethyl)-l-naphthol A solution of 1-tetralone (5.85 g. 0.040 mole) and pyridine-3-carboxaldehyde (4.28 g. 0.40 mol) in t-butanol (400 mL) was treated with potassium t-butoxide (8.98 g, 0.080 mol) and the resulting mixture heated at reflux for 16 hours. After cooling to room temperature, the solution was poured into stirred 1.0 N hydrochluoic acid, and the pH of the resulting mixture was adjusted to 7.0 with 10% aqueous sodium hydroxide.

After isolation by extraction with ethyl acetate.

the crude product was recrystallized (benzene) to provide the title compound (4.86 g, 52%) as a tan 15 solid, mp 170-1720.

EXAMPLE 27 O: 2-(2-Hdroxyphenylmethyl)-l-naphthol A solution of 1-tetralone (5.85 g, 0.040 mole) and salicylaldehyde (4.88 g, 0.040 mole) in t-butanol (400 mL) was treated with potassium t-butoxide (17.6g, 0.160 mole) and heated at reflux for 16 hours. After cooling to room temperature, the solution was poured iNto stirred 1.0 N hydrochloric acid. After isolation by extraction with ethyl acetate, the crude product was chromatographed with 4:1 petroleum ether/ether, to provide a tan solid. This was recrystallized (cyclohexane/chloroform) to give the title compound as white i needles (5.24 g, mp 124-125°.

The compounds of Examples 26 and 27, along with other compounds which were and can be prepared using the procedures of Examples 26 and 27, are shown in Table S.

-41- TABLE Off

R

2 R1 7 2 Ex. R 7R 1 R 2 YIELD MP(OC) 26 3-Pyridyl H H 52 170-172 27 2-HOC 6 H 4 H H 52 124-125 gs28 4-CH OC H H H 57 80-81 06,0 3 6 4 a 06 go 15 29 2-CHOC 6H 4H H 66 89-90 4-(C 6 H 5 CH 2 O)C 6

H

4 H H 35 88-89 a a 31 3-CH 0C 6 H H H 36 55-57 .00 3p se2 32 3BC6 H4 H H 55 81-83 :.33 3-(C 6 H 5 CH 2 O)C 6 H 4 H H 29 54-57 *Go 34 2-BrC 6

H

4 H H 65857 3-FC H 4 H H 48 64-65 25 36 4-CH 3

SC

6 H 4 H H 59 82-83 it37 3,4,5-(CH 0) C H 2 H H 52 121-122 .38 2.4-(CH 3

OCH

3 H H 53 76-77 39 3,4-(C H CH 2

OCH

3 H H 31 60-61 40 3-(c 6 H 5 )C 6

H

4 H H 50 50-52 41 2,3-(CH 0) C H 3 H H 35 140-141 42 3.4-(CH 0) c H1 H H 27 106-107 43 2.4,6-(CHO)cH H H 17 104-105 351 44 2-Thienyl H H so 55-57 -41- -28- -42- TABLE (Cont inued) So S 0* 55005 5

S

55* 9* S S *05 0 5* S S 5.55 *5

S

*5 *5 S S See S

S.

S S 0*S* Ex.

46 47 48 4 51 52 15 53 54 55 56 5 58 59 60 61 62 63 64 66 67 68 t-CH 3 Pyrrol-2-yl 2-Pyridyl 4-(CH 3 2

NC

6

H

4 3-CF 3C 6H4 2-CH 3O-1-Naphthyl 3.4 (C1) 2

C

6 H 3 4-Pyr idyl 3-ClC 6H4 4-C 2H 5OC6 H4 2-CIC 6H4 5- (CH 3 O0) 3

C

6 H 2 2-IC 6HR 2-FC 6H4 4-FC 6H4 4-BrC 6H4 2-CH 3

C

6 H 4 3,5-(CH 3

O)

2 C6H 3 3-CH 3

C

6 H 4 5-CH 3 Furan-2-yl 2-(OCH 2 COOH)C 6 H 4 1-HO- 2-Naphthyl 4-HOC 6 H 4 (HO) 2 C 6 H 3 YIELD HMIC) 59 85-87 23 67-68 12 125-127 52 85-86 77 159-161 54 89-90 50 157-158 58 75-76 62 72-74 79 83-84 27 153-155 62 81-82 66 75-75 56 74-75 40 100-101 71 69-70 65 81-82 39 65-67 55 48-49 39 37-39 36 130-133 27 172-173 23 127-129 6 136-139 -42- -29- -43- IABtF (Continued) Ex.

Os S 5* 0 0

S.

S

S

SO

S

S..

S.

0 S SOS 0 0* 0 0S06

S.

S S

S.

00 5 69 71 72 73 74 15 75 76 77 78 79 80 81 82 83 84 7

R

2-naphthyl 1-naphthyl C 6H CH-C 3.4- (CH 3 O0) 2 C 6 H 4 3.4-Cl 2 6 H 4 3-pyriyl 3-CM SC 6H4 1 2 R R

H

H

CHM

3

H

H

H

H

CM 3 CH 3 CH 3

CHM

3 CH 3 CH 3

H

CH 3

H

H

5. 7- (CH 3 2 5- (CM 3 0) 7- (CH 3 O0) 5. 8- (CHM 3 2 89-91 132-134 78 101-102 116-117 54-55 90-92 YIELD% MPj!C) 5- (CM 3 5- (CH 3 O0)

(CH

3 O0) 2 5 8- (CM 3 2

H

5.7-(CH 3 2 goo@ EXAMPLE 86 2- (3-Hydroxyphenylmethyl) -l-naphthol The compound of Example 33 (7.0 g. 0.02 mole) was combined with 10% palladium/charcoal (0.70 g) and ethanol (100 mL) in a pressure bottle. The container was pressurized with hydrogen at 50 psi and agitated -43- U- -m I -44at room temperature for 16 hours. It was then vented, and the reaction mixture was filtered and the catalyst rinsed with additional ethanol. The combined filtrates were evaporated, and the residue was chromatographed with 8:2 petroleum ether/ether to provide an off-white solid. This was recrystallized (carbon tetrachloride) to give the title compound (3.94 g, 77%) as a white solid, mp 100-101°.

EXAMPLE 87 PART A: 2-(2-Bromophenylmethyl)-l-benzyloxynaphthalene A mixture of the compound of Example 34 (6.0 g, 0.019 mole), benzyl bromide (3.4 mL, 0.029 mole), o potassium carbonate (5.3 g. 0.038 mole), and acetone 15 (100 mL) was heated at reflux for 19 hours. The cooled solution was filtered and the filtrate was evaporated. The resulting oil was heated at 1400/0.5 S*o mm to remove residual benzyl bromide, then was *chromatographed with 3:1 hexane-toluene to provide the title compound (7.2 g, 94%) as a colorless oil.

So. PART B: 2-(2-Carbethoxyphenylmethyl)-l-benzyloxyo naphthalene A solution of the product of Part A (3.00 g.

0.007 mole) in dry tetrahydrofuran (15 mL) was added to dried magnesium chips (0.22 g, 0.009 mole). A crystal of iodine was added and the mixture heated at reflux for 2 hours, then cooled to room temperature.

Diethyl carbonate (4.5 mL, 0.037 mole) was added, stirring was continued for 16 hours, and the mixture was then poured into 1.0 N hydrochloric acid. After isolation by extraction with ether, the crude product was chromatographed with 9:1 petroleum ether/ether, to provide the title compound (0.60 g, 20%) as an oil.

-44i -r 1 01 1 PART C: 2-(2-Carbethoxyphenylmethyl)-l-naphthol The product of Part B (0.60 g, 0.0015 mole) was Shydrogenated in ethanol by the procedure of Example 86.

Recrystallization of the crude product (hexane/ether) provided the title compound (0.33 g, 71%) as a waxy solid, mp 86-88°.

O EXAMPLE 88 PART A: 2-(3-Bromophenylmethyl)-l-(t-butyldimethylsilyloxy)-naphthalene A mixture of the compound of Example 32 (7.38 g, 0.024 mole), t-butyldimethylsilyl chloride (4.36 g.

0.029 mole), and imidazole (4.08 g, 0.060 mole) in N.N-dimethylformamide (20 mL) was stirred at room 15 temperature. After 17 hours, the reaction mixture was poured into saturated aqueous sodium bicarbonate, and the crude product isolated by extraction with ether as

S*

a white, waxy solid (10.1 g, mp 72-74°.

PART B: 2-(3-Carbethoxyphenylmethyl)-l-(t-butyldi- *methylsilyloxy)naphthalene The product of Part A was converted to the corresponding ethyl ester using the procedure of Part B of Example 87. The title compound was obtained as a 25 colorless oil in 52% yield.

PART C: 2-(3-Carbethoxyphenylmethyl)-l-naphthol A solution of the product of Part B (1.00 g, 0.002 mole) in a mixture of absolute ethanol (50 mL) and 1.0 N hydrochloric acid (50mL) was heated at reflux for 5 hours. The mixture was cooled to room temperature and the crude product isolated by extraction with ethyl acetate. This material was chromatographed with 4:1 petroleum ether/ether, and the resulting solid recrystallized (hexane) to provide -46the title compound (0.38 g. 62%) as white crystals.

mp 86-870 EXAMPLE 89 2-(2-Carbethoxymethoxyphenylmethyl)-l-naphthol A mixture of the compound of Example 65 (3.60 g, 0.012 mole), ethanol (100 mL), and sulfuric acid (0.25 mL) was heated at reflux for 4 hours. It was cooled to room temperature, then to 00, and the title compound was collected by filtration as a tan powder (2.68 g, mp 124-1250 EXAMPLE 0 PART A: 2-(4-Methylthiophenylmethyl)-l-(t-butyldimethylsilyloxy)naphthalene SThe title compound was prepared from the compound of Example 36 using the procedure of Part A of Example 88. It was obtained as a colorless oil in quantitative yield.

PART B: 2-(4-methylsulfonylphenylmethyl)-l-(tbutyldimethylsilyloxy)-naphthalene *A solution of the product of Part A (2.00 g, S0.005 mole) in glacial acetic acid (25 mL) was treated with solid sodium perborate (1.81 g, 0.011 mole) and was stirred at room temperature for 20 hours. The OPP mixture was poured into water and the crude product isolated by extraction with ether. This material was chromatographed with 7:3 petroleum ether/ether and recrystallized (hexane) to provide the title compound (1.38 g. 63%) as white crystals, mp 109-1100.

PART C: 2-(4-Methylsulfonylphenylmethyl)-l-naphthol A mixture of the product from Part B (1.18 g, 0.003 mole), ethanol (50 mL) and 1.0 N hydrochloric -46- -33- -47acid (50 mL) was heated at reflux for 3 hours and Scooled to room temperature The crude product was isolated by extraction with ethyl acetate, and recrystallized (cyclohexane/benzene) to provide the title compound (0.75 g, 80%) as white needles, mp 144-1450.

EXAMPLE 91 4-Bromo-2-(phenylmethyl)-l-naphthol A solution of 2-(phenylmethyl)-l-naphthol (1.00 g, 4.3 mmole) in acetic acid (20 mL) was stirred at room temperature. A solution of bromine (0.7 g. 4.3 mmole) in acetic acid (6 mL) was added dropwise over S4 10 minutes. The mixture was stirred for another 15 minutes, then poured into water. The resulting solid S* was collected by filtration and recrystallized (cyclohexane) to provide the title compound (1.21 g, 88%) as off-white needles, mp 123-125.

EXAMPLE 92 4-Benzoyl-2-(phenylmethyl)-l-naphthol A mixture of aluminum chloride (1.25 g, 9.4 mmole) in methylene chloride (25 mL) was stirred at 00 *and treated dropwise with benzoyl chloride (1.1 mL, 9.4 mmole) and stirred for 5 minutes. A solution of S2-(phenylmethyl)-l-naphthol (2.0 g, 8.5 mmole) in methylene chloride (6 mL) was added dropwise over minutes, and stirring was continued at 0° for 3 hours. The mixture was poured into 1.0 N hydrochloric acid, and the crude product was isolated by extraction with methylene chloride. Recrystallization from toluene provided the title compound (1.15 g, 40%) as pale yelow crystals, mp 152-1550 -47- -34- I -48- EXAMPLE 93 PART A: 4-Acetyl-2-(phenylmethyl)-l-acetoxynaphthalene A mixture of aluminum chloride (5.02 g. 0.038 mole) in methylene chloride (50 mL) was stirred at 00 and treated dropwise with acetyl chloride (2.7 mL, 0.038 mole). After stirring the mixture for minutes, a solution of 2-(phenylmethyl)-l-naphthol (4.00 g, 0.017 mole) in methylene chloride (10 mL) was added dropwise and stirring continued at 00 for 4 hours. The mixture was warmed to room temperature and stirred for 17 hours, then poured into 1.0 N hydrochloric acid. The crude product was isolated by extraction with methylene chloride, and chromatographed (98:2 toluene/ethyl acetate). The 15 resulting material was recrystallized (isopropanol) to provide the title compound (1.52 g, 32%) as white needles, mp 118-1200.

'0o PART B: 4-Acetyl-2-(phenylmethyl)-l-naphthol A solution of the compound prepared according to Part A (1.90 g, 6.0 mmole) and concentrated sulfuric acid (1.0 mL) in ethanol (150 mL) was heated at reflux for 24 hours, cooled, and poured into water. The resulting solid was collected by filtration and goo recrystallized (toluene) to provide the title compound (1.40 g, 84%) as a white solid, mp 139-1410.

**OS

EXAMPLE 94 PART A: 2-(Phenylmethyl)-l-methoxynaphthalene A mixture of 2-phenylmethyl-l-naphthol (40.0 g, 0.17 mole), methyl iodide (36.4 g, 0.26 mole), potassium carbonate (35.9 g, 0.26 mole) and acetone (1000 mL) was heated at reflux with stirring for 17 hours, then cooled and filtered. The acetone was removed under vacuum, and the residue was dissolved in -48- -3b- -49ethyl acetate, washed with water and brine, dried over magnesium sulfate and concentrated. The residual oil was distilled in a short-path distillation apparatus at approximately 160-1800/0.2 torr to provide the title compound (41.5 g, 98%) as an off-white solid, mp 56-59.

PART B: 4-Bromo-2-(phenylmethyl)-l-methoxynaphthalene A solution of the compound of Part A (20.5 g, 0.083 mole) in acetic acid (400 mL) was stirred at room.temperature and treated dropwise with a solution of bromine (13.2 g. 0.083 mole) in acetic acid (125 mL). After the mixture was stirred for an additional 15 minutes, it was diluted with water, and the crude 15 product isolated by extraction with methylene i chloride. This material was distilled at 155-1600/0.2 .o torr to provide the title compound (23.25 g, 86%) as a viscous yellow oil.

PART C: 4-(C-Hydroxy-a-(2-thienyl)-methyl)-2- 4 m(phenylmethyl)-1-methoxynaphthalene A solution of the compound of Part B (2.00 g, 6.1 mmole) in dry tetrahydrofuran (20 mL) was stirred eat -780 and treated dropwise with n-butyllithium (1.55 M in hexane; 4.4 mL, 6.7 mmole). The mixture was stirred at -780 for one hour. then treated If: dropwise with a solution of thiophene-2-carboxaldehyde (0.75 g, 6.7 mmole) in dry tetrahydrofuran (10 mL).

After stirring for 15 minutes, saturated aqueous ammonium chloride was added and the crude product isolated by extraction with methylene chloride. This material was chromatographed (85:15 hexane/ethyl acetate) and triturated in hexane to provide the title compound (1.90 g, 86%) as a white crystalline solid, mp 122-1240 -49i i*

IA

*1~ -36i PART D: 4-(2-Thienylcarbonyl)-2-(phenylmethyl)-lmethoxvnaDhthalene

S

S..

5 0

S

S

S S

S.

5.

S S

S.

A solution of the compound of Part C (1.50 g.

4.2 mmole) in methylene chloride (90 mL) was treated with pyridinium chlorochromate (2.28 g, 10.6 mmole) and stirred at room temperature for 1.5 hours. The mixture was filtered through florisil and concentrated under vacuum to provide the crude product. This was recrystallized (hexane/1-chlorobutane) to provide the title compound (1.17 g. 79%) as a white solid, mp 111-113°.

PART E. 4-(2-Thienylcarbonyl)-2-(phenylmethyl)-lnaphthol A mixture of the compound of Part D g. 1.6 mmole) and pyridine hydrochloride (3.48 g, 0.03 mole) was heated at 1900 for 3 hours. The cooled reaction mass was then partitioned between methylene chloride and 1.0 N hydrochloric acid, and the organic phase was 20 dried over magnesium sulfate and concentrated under vacuum. The residue was recrystallized (hexane/l-chlorobutane) to provide the title compound (0.50 g. 89%) as a pale yellow solid, mp 150-152°.

EXAMPLE PART A: 3-(Phenylmethyl)-4-methoxy-l-naphthoic acid A solution of the compound of Example 94 Part B (5.00 g. 0.015 mole) in dry tetrahydrofuran (50 mL) was cooled to -78° and treated dropwise with n-butyllithium (1.55 M in hexane: 10.9 mL, 0.017 mole). The mixture was stirred at -78° for minutes, and a stream of gaseous carbon dioxide was directed onto the surface of the stirred solution.

The cooling bath was removed from the reaction vessel and the addition of carbon dioxide was continued for L I i -51minutes. The mixture was then poured into 1.0 N hydrochloric acid, and the crude product isolated by extraction with methylene chloride. This was recrystallized (methylcyclohexane) to provide the title compound (4.0 g, 90%) as a pale yellow solid, mp 146-148.

PART B: 3-(Phenylmethyl)-4-hydroxy-l-naphthoic acid Using the procedure of Example 13 Part C. the compound of Part A was converted to the title compound, which was recrystallized (acetonitrile) to provide a tan solid mp 203-206° (decomposes).

.EXAMPLE 96 15 3-(Phenylmethyl)-4-hydroxy-l-naphthoic acid ethyl ester 9 9 A solution of the compound of Example 95 (2.55 g, 9.2 mmole) and concentrated sulfuric acid (3 drops) in ethanol (125 mL) was heated at reflux for hours. The mixture was cooled and diluted with water, and the crude product was isolated by extraction with ethyl acetate. This was chromatographed (9:1 hexane/ethyl acetate) and recrystallized (hexane) to provide the title compound (1.74 g, 62%) as white needles, mp 79-80.

EXAMPLE 97 PART A: 3-(Phenylmethyl)-4-methoxy-l-naphthamide A mixture of the compound of Example 95 Part A (3.00 g, 10.3 mmole), oxalyl chloride (6.50 g, 0.051 mole) and benzene (30 mL) was stirred at room temperature for 20 hours, and concentrated under vacuum. The residue was dissolved in dry tetrahydrofuran (30 mL) and added dropwise with stirring to aqueous ammonia which was cooled on an ice/acetone bath. Stirring was continued for 6 -51- -52hours, while the reaction mixture was allowed to warm to room temperature. The ammonia and tetrahydrofuran O were then removed under vacuum, and the product was isolated by extraction with ethyl acetate and methylene chloride. After recrystallization (isopropanol), the title product was obtained (2.69 g, 87%) as white needles, mp 199-201°.

PART B: 3-(Phenylmethyl)-4-hydroxy-l-naphthamide Using the procedure of Example 94 Part E, the compound of Part A was converted to the title compound, which was obtained in 56% yield as a white solid (mp 219-2200 dec.) after recrystallization from toluene.

S* EXAMPLE 98 PART A: 4-Phenyl-2-(phenylmethyl)-l-methoxynaphthalene A solution of the compound of Example 94 Part B i (5.00 g, 15.3 mmole) and bis-(1,3-diphenylphosphino)propane nickel(II) chloride (0.40 g, 0.74 mmole) in dry ether was stirred at 00. Phenylmagnesium chloride S. (2.0 M in ether; 9.5 mL, 19.0 mmole) was added j dropwise, and the mixture was stirred at room temperature for 2 hours. The mixture was then poured j 25 into 1.0 N hydrochloric acid, and the crude product was isolated by extraction with methylene chloride.

This was chromatographed to provide the title product (4.26 g. 86%) as a white solid. A small sample recrystallized from hexane melted at 103-1050.

PART B: 4-Phenyl-2-(phenylmethyl)-l-naphthol Using the procedure of Example 13 Part C, the compound of Part A was convertea to the title compound, which was obtained as a white solid (73% yield, mp 132-134°) after recrystallization from methylcyclohexane.

-52- EXAMPLE 99 PART A: 4-Methoxv-3- (Rhenylmethyl)-naphthalenesulfonic acid The product of Example 94 Part A (3.0g, 0.012 mole) was added in portions to concentrated sulfuric acid at, -100. The mixture was stirred at for 2 hours and poured into water. sodium bicarbonate was added, and the u.-ude product was isolated by extraction with ethyl acetate. The title compound (2.0g, was obtained as a brown oil after chromatography (1:1 hexane/ethyl acetate: then 99.:1 ethyl acetate/acetic acid;4 then methanol).

.4 PART B: 4-M4etbox-3-(Phenylinethyl)-nahthalene-ll ~sulfonvi chloride A mixture of the product of Part A (1.80g. inmolo), thionyl chloride (3.OmL), and N.N-diinethylformamide (1 drop) was heated at reflux for one hour.

4* The excoss thionyl chloride was removed at reduced pressure to provide the title compound (2.3g) as a 9' brown oil, which was used without further purification.

PART C: A-2.ethxy-phenylMgethjl) -naphtha Iengt-- 2S A solution of the product of Part B (4,65g, 0.013 tiole) in tetrahydrofuran was added dropwise to a solution or uooUs ammonia (281. 125m1). After minute&, the solvent was removed at reduced pressure.

and the aqueous residue was acidified. The crude product was isolated by ftxtraction with ethyl.

acatote. Chromatography heXane/ethyl acetate) and recrystallization (1-chiorobutane) provided the title compound (1.0q, 461) as a white solid. mp -54- PART D: 4-Aminosulfonyl-2-(Dhenylmethyl)-l-naphthol Usinlg the procedure of Example 13. Part C, the product of Part C was converted in 85% yield to the title compound, Tap 167=1680.

The compounds of Examples 86-99. along with other compounds which were or can be prepared using one of the methods described in Examples 86-99 or in the general synthetic discussions are shown in Table 6.

TABLE 6 *gom

C

a c #1o CH 2 R 7 Ex.

6 87 11 89 H

H

91 Br 0 it 92 CC 6 H 5 0 93 CcIl 3 0 It 9 4 C Sjl* H 3-H0C 6 11 4 H 2-(c 2 H.00C)C 6

H

4 4 H 3-(C 2 HS00C)c 6 H 4 H 2- (OCH 2

COOC

2 H )C 6 11 4 H 4- (L"H 3 Bog) C 6 11 4 H

C

6

HS

YIELD%

77 71 MP (0C)- 100-101 86-88 62 06-87 66 124-125 144-145 123-125 152-155 H C 6 H 5 it

COS

5 HI

C

6 H 5 84 139-141 89 ISO-152 -54- Table 6 (continued) 96 97 98 99 lob)

COOH

COPOC 2H8 COMH 2 CH 3

H

H

H

5,a- (CH 3 2

CMA

CH-C

YIELD%.

68 62 56 73 85 203-206 (dec) 79-80 219-220 Wde) 132-1.34 16 7-16 8

V

V V *9

S

S 545 0 *0

S

S 555 S 90 V V 9 S VS S V *5VS 55 VV S V IV I 55 5 5 Vet S *9 S S 0 101 C 3-pyridy.

102 103 104 105 106 0 NHCCH 3 NiISO 2CH WHSO 2CF3 Cl 21% 99-101 0 11 107 CCH 2CH CH 0

HI

108 C 0 109 110 11.2 1.13 114 Br CON'HCH

C

3 CON (CH 3 2 C0NJCH 2

A

WICH 3 7-CM 0

H

H

H

3 ,A-(CH 3 O0) 2

C

6

H

3 3 4- (CH 3 O) 2 C 0 C 6 H CMd' C6$H 127. 208-210 r -56- Table 6 (continued) O Ex. Ex. 1 2 7 No. R R R YIELD% MP(oC) 115 SCH 3 H

C

6

H

116 COOCH 3 H C 6

H

EXAMPLE 117 PART A: Ethyl l-hydroxy-2-naphthalenepentanoate The title compound was prepared as reported by G. Xi, X. Guo, and R. Chen, Yaoxue Xuebao 15, 548 (1980).

PART B: 15 A solution of the product of Part A (2.00 g, 0.007 mole) in dry tetrahydrofuran (10 mL) was added dropwise to a mixture of lithium aluminum hydride \o (0.28 g. 0.007 mole) in dry tetrahydrofuran (20 mL) at 00. The mixture was heated at reflux for minutes, then cooled to room temperature. Water (0.28 mL). then 3.0 N aqueous sodium hydroxide (0.28 mL), then water (0.60 mL) were added, and the mixture was stirred at room temperature for 10 minutes, then filtered. The filtrate was diluted with water and extracted with ethyl acetate. The resulting material was chromatographed with 7:3 toluene/ethyl acetate to provide the title compound (1.10 g, 65%) as a waxy solid, mp 43-460.

EXAMPLE 118 PART A: 2-(2-Propenyl)-l-naphthol The title compound was prepared by the procedure of J. St. Pyrek, 0. Achmatowicz, and A. Zamojski, Tetrahedron 33. 673 (1977).

-56- 1 yfWdb L oDUL. A. -43m Ji -57- PART B: 2-(2-Propenyl)-l-benzyloxynaphthalene A mixture of the product of Part A (12.80 g, 0.070 mole), benzyl bromide (10.75 mL. 0.090 mole), and potassium carbonate (19.20 g. 0.139 mole) in acetone (150 mL) was heated at reflux for 3 hours.

The cooled solution was filtered and the filtrate O evaporated. The residual oil was distilled to provide the title compound (12.91 g, 68%) as a pale yellow liquid, bp 150-151° (0.1 torr).

PART C: 2-(3-Hydroxypropyl)-l-benzyloxynaphthalene A solution of borane (1.0 M in tetrahydrofuran; 100 mL, 0.100 mole) was treated at 00 with a solution of 2-methyl-2-butene (2.0 M in tetrahydrofuran; 100 15 mL, 0.200 mole) over 40 minutes, and the resulting solution stirred at 00 for 2 hours. A solution of j *2-(2-propenyl)-l-benzyloxynaphthalene (27.40 g, 0.100 mole) in dry tetrahydrofuran (50 mL) was added over *O9.

minutes, and stirring was continued for 40 minutes.

Water (4.0 mL) was then added, followed by 3.0 M aqueous sodium hydroxide (34 mL), followed by r aqueous hydrogen peroxide (34 mL). After the mixture S" was warmed to room temperature, it was extracted with ether. The residue was chromatographed with 1:1 ether/hexane and recrystallized (cyclohexane) to provide the title compound (16.10 g, 55%) as a white solid, mp 80-810.

PART D: 2-(3-Hydroxypropyl)-l-naphthol The product of Part C (1.00 g, 0.003 mole) was combined with 10% palladium/charcoal (0.20 g) and ethanol (35 mL) in a pressure bottle. The container was pressurized with hydrogen at 50 psi, and agitated at room temperature for 4 hours. It was then vented, and the reaction mixture was filtered and the catalyst -57- I -58rinsed with additional ethanol. The combined filtrates were evaporated, and the residue was recrystallized (cyclohexane) to give the title compound (0.52 g, 74%) as off-white crystals, mp 85-860.

EXAMPLE 119 2-(5-Hydroxy-5-methylhexyl)-l-naphthol A solution of the product of Example 117 Part A (2.00 g, 0.007 mole) in dry tetrahydrofuran (20 mL) was stirred at 00 and treated with aethyllithium M in ether: 20 mL, 0.030 mole) over 10 minutes. Stirring was continued for 1.25 hours at 00, then for hours at room temperature. The mixture was again cooled to 00, and treated with saturated ammonium S 15 chloride solution, then warmed to room temperature and extracted with ether. The crude product was recry- Sstallized (toluene) to give the title compound (1.70 g, 89%) as white crystals, mp 101-102°.

EXAMPLE 120 2-(5-Methyl-4-hexenyl)-1-naphthol A solution of the compound of Example 119 (0.45 g, 0.002 mole) and 2-toluenesulfonic acid 2 crystals) in toluene (20 mL) was heated at reflux with 25 azeotropic removal of water. After 18 hours, the cooled solution was washed with saturated aqueous sodium bicarbonate and evaporated to provide the title compound (0.45 g, 100%) as an oil; mass spectrum: m/z 240.

EXAMPLE 121 PART A: 2-(4-Chlorobutyryl)-l-naphthol A mixture of 1-naphthol (15.14 g, 0.105 mole), 4-chlorobutyric acid (9.90 mL, 0.100 mole), and boron trifluoride etherate (75 mL) was heated on a steam -58- -2 U -59bath for 4 hours. The mixture was then treated slowly j with 100 mL of water, and heating continued for minutes. The mixture was poured into water, stirred, and the solution decanted. The residue was triturated with water, then crystallized from ethanol to provide the title compound (9.50 g, 38%) as a pale green solid, mp 73-790 PART B: 2-(4-Chlorobutyl)-l-naphthol A mixture of granular zinc (6.50 g, 0.099 mole), mercury (II) chloride (0.2 concentrated hydrochloric acid (0.6 mL), and water (10 mL) was stirred at room temperature for 30 minutes, then washed with water by decantation. To the solid was added the 15 product of Part A (5.00 g, 0.020 mole), ethanol (125 mL), and concentrated hydrochloric acid (35 mL). The mixture was stirred at reflux overnight, cooled, and 'the supernatant was diluted with water. The crude I product was isolated by extraction with ethyl acetate and chromatographed with 98:2 hexane/ether. The title compound was obtained as a light brown oil (2.00 g, mass spectrum m/z 234, 236.

EXAMPLE 122 25 PART A: 2-(2-Propenyl)-l-t-butyldimethylsilyloxy- A mixture of 2-(2-propenyl)-l-naphthol (Example 118 Part A; 101.9 g, 0.550 mole), t-butyldimethylsilyl chloride (100.0 g, 0.660 mole), and imidazole (93.6 g, 1.375 mole) in N,N'-dimethylformamide was stirred at room temperature for 6.5 hours. It was then poured Sinto saturated aqueous sodium bicarbonate, and the crude product isolated by extraction with hexane. The residue was distilled at reduced pressure to provide the title compound (155.2 g, bp 135-1400 (0.1 torr).

-59- J3 u.uuj mole), ethanol (50 mL) and 1.0 N hydrocniorlc -46- PART B: 2-(3-Hydroxypropyl)-l-t-butyldimethylsilyloxy-naphthalene A solution of the product of Part A (29.80 g, 0.100 mole) in dry tetrahydrofuran was treated at 0° with borane (1.0 M in tetrahydrofuran; 38 mL, 0.038 mole) over 30 minutes. Water (7.0 mL) was added, followed by 3.0 N aqueous sodium hydroxide (14 mL), after which the reaction flask was again cooled to 00. 30% Aqueous hydrogen peroxide (14 mL) was added over 10 minutes, and the mixture was warmed to room temperature, stirred for 30 minutes, and heated to with a warm water bath. After 30 minutes, the cooled mixture was diluted with water, and the crude product extracted with ether. The residue was recrystallized 15 (cyclohexane) to provide the title compound (22.70 g, 72%) as a white solid, mp 91-93°.

s PART C: 2-(3-Bromopropyl)-l-t-butyldimethylsilyloxyo.

naphthalene A solution of the product of Part B (15.80 g, 0.050 mole) and carbon tetrabromide (33.10 g, 0.100 mole) in ether (150 mL) was treated at room temperature with a solution of triphenylphosphine (26.20 g, .0.100 mole) in ether (110 mL). After 2.75 hours, the mixture was filtered, and the filtrate was evaporated.

The residue was chromatographed with petroleum ether to provide the title compound (18.00 g. 95%) as a colorless oil.

PART D: 2-(3-Bromopropyl)-l-naphthol A solution of the product of Part C (2.60 g, 0.007 mole) in ethanol (50 mL) was mixed with 1.0 N aqueous hydrochloric acid (30 mL) and heated at reflux. After 3.5 hours, the mixture was cooled to room temperature, and diluted with water. The crude i M I -61product was isolated by extraction with methylene O chloride, and chromatographed with 9:1 hexane/ethyl to acetate provide an orange solid. This was recrystallized from hexane to give the title compound (0.51 g, 28%) as a tan solid, mp 53-55.

EXAMPLE 123 Part A: 3-(l-t-Butyldimethylsilyloxy-2-naphthyl)propylisothiourea hydrochloride A mixture of the product of Example 122 Part C (1.55 g, 0.004 mole), thiourea (0.31 g, 0.004 mole), and absolute ethanol (8.0 mL) was heated at reflux for 7 hours. The cooled solution was treated with water (5.0 mL), cooled to 00, and treated with concentrated 15 hydrochloric acid (5.0 mL). The precipitated solid was isolated by filtration, rinsed with water and air-dried to provide the title compound (1.45 g, 86%) as a white powder, mp 190-1940 S* PART B: 3-(l-Hydroxy-2-naphthyl)-propylisothiourea i. hydrochloride A mixture of the product of Part A (0.65 g, S 0.002 mole), ethanol (6 mL), and 1.0 N aqueous hydrochloric acid (10 mL) was heated at reflux for 25 2 hours. After cooling, the ethanol was removed by j evaporation at reduced pressure, and the solid collected by filtration and washed with water. The title compound was obtained (0.42 g, 84%) as a white powder, mp 184-188°.

EXAMPLE 124 2-(3-Mercaptopropyl)-l-naphthol A mixture of the product from Example 123 Part B (0.90 g, 0.002 mole), ethanol (4.0 mL). and 4.0 N aqueous sodium hydroxide (10.0 mL) was heated at -61- 3 £LhLV I t. ur VK..Y.LaUI -48- ;i

S

S

S*

5* 5 0 *9 -62reflux for 2 hours. The cooled solution was acidified with concentrated hydrochloric acid and extracted with methylene chloride. The crude product was chromatographed with 97:3 hexane/ethyl acetate to provide the title compound (0.50 g. 97%) as an orange oil. Mass spectrum: m/z 218.

EXAMPLE 125 2-[3-(N-Pyrrolidino)-propyll-l-naphthol hydrochloride A mixture of the product of Example 122 Part C (2.00 g, 0.005 mole), pyrrolidine (4.40 mL, 0.053 mole), potassium carbonate (1.10 g, 0.008 mole), and acetonitrile (20 mL) was heated at reflux for 16 hours. The cooled solution was filtered, and the filtrate chromatographed with 98:2 methylene chloride/methanol chloride to give a light tan oil.

This was dissolved in ether, treated with ethereal hydrogen chloride, and stirred at room temperature.

The precipitated solid was isolated by filtration, 20 washed with ether, washed further with a small amount of acetonitrile, and air-dried to provide the title compound (1.17 g, 76%) as a white powder, mp 198-2010.

EXAMPLE 126 2-(3-Aminopropyl)-l-naphthol hydrochloride A solution of the product of Example 122 Part C (2.00 g, 0.005 mole) in NN-dimethylformamide (3.4 mL) was added over a period of 5 minutes to a stirred suspension of sodium azide (0.41 g, 0.006 mole) in NN-dimethylformamide (4 mL) at 1050. After the mixture was stirred for 4 hours, it was cooled to room temperature, poured into water, and extracted with methylene chloride. The residue was stirred in a mixture of ethanol (100 mL) and 1.0 N hydrochloric acid (100 mL) at reflux for 2 hours. The cooled -62- .5 *eve

S

0 555.

I

L

i- I 1. L- i

I~

9 as 0* .9 C

C.

C

C*

9 CC* C

C

C

S

C.

C

C..

-63mixture was extracted with methylene chloride, and the crude product was hydrogenated using the procedure of Example 110 Part D in 17% chloroform/ethanol. The resulting material was boiled in acetonitrile, then isolated by filtration to provide the title compound (0.87 g, 73%) as a tan solid, mp 213-218° (decomposes).

EXAMPLE 127 PART A: 2-(4-Chlorobutyl)-l-methoxynaphthalene A solution of N.N.N',N'-tetramethylenediamine (18.12 mL, 0.120 mole) in cyclohexane (36 mL) was treated with n-butyllithium (1.55 M in hexane; 79.8 mL, 0.123 mole) at room temperature. A solution of l-methoxynaphthalene (17.4 mL. 0.120 mole) in cyclo- 15 hexane (20 mL) was added over 30 minutes, and the resulting solution was stirred for 1.5 hours. It was then cooled to 00, and l-bromo-4-chlorobutane (27.0 mL, 0.234 mole) was added over 15 minutes. The mixture was warmed to room temperature and stirred for 20 17 hours, then poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The crude product was chromatographed with 98:2 hexane/ether to provide the title compound (11.60 g, 39%) as a pale yellow oil.

PART B: Diethyl 4-(l-methoxy-2-naphthyl)butylphosphonate The product from Part A (5.00 g, 0.020 mole) was dissolved in acetone (50 mL) and treated with sodium iodide (6.00 g. 0.040 mole). The solution was heated at reflux for 3.5 hours, cooled to room temperature.

and extracted with methylene chloride. The resulting material was combined with triethyl phosphite (15 mL) and stirred at 1500 for 17 hours. After cooling, the excess triethyl phosphite was removed under reduced -63aj -64pressure, and the residue was chromatographed with J ethyl acetate to provide the title com~ound (3.90 g.

56%) as a pale yellow oil.

PART C: Diethyl 4-(l-hydroxy-2-naphthyl)butylphosphonate A solution of diethyl 4-(1-methoxy--2-naphthyl)butylphosphonate (5.50 g. 0.016 mole) in methylene chloride (80 mL) was stirred at -780, and trepted with boron tribromide (1.0 M in methylene chloride; 4 24.0 mL. 0.024 mole) over 20 minutes. Stirring was continued for 2 hours at this temperature, then at room temperature for 16 hours. Water (80 mL) was *added, and the mixture was extracted with ether. The 15 organic layer was extracted with N aqueous sodium hydroxide, the aqueous layer was aci.dified with con- 0 centrated hydrochloric acid, and the crude product isolated from this by extraction with ether. The residue was recrystallized (hexane) to provide the title compound (2.10 g. 40%) as a white solid, mp to0 EXAMPULE 128 09PART A: 2-(3-p-Toluenesulfonyloxypropyl)-l-benzyloxy- A solution of the product of Example 118 Part C 9 go 0.031 mole) In pyridine (150 mL) was stirred at 00 and treated with p-toluenesulfonyl chlorido (6.70 g, 0.iO35 mole), then stirred for 16 hours at room temperature. The solution was poured into water, and the mixture extracted with ethyl acetate. The resulting oil was chromatographed With 41 hexane/ether to provide tha title compound (3.20 q.

23t) as an oil, -64i_ PART B: 2-(4,4-bis-Carbethoxybutyl)-l-benzyloxynaphthalene Sodium (0.08 g, 0.004 mole) was dissolved in ethanol (5 mL) and the resulting solution was treated with diethyl malonate (0.51 mL, 0.004 mole) and stirred at room temperature for 10 minutes. A solution of O the product from Part A (1.00 g. 0.002 mole) in ethanol mL) was added, and the mixture was stirred at reflux for 3.5 hours. The cooled solution was poured into 1.0 N hydrochloric acid, and the crude product was isolated by extraction with ethyl acetate.This was chromatographed with 9:1 petroleum ether/ether to provide the title compound (0.70 g, 72%) as an oil.

15 PART C: 3-[(l-Hydroxy-2-naphthyl)propyl]propanedioic acid, diethyl ester Using the procedure of Example 118. Part D the product of Part B was converted in 84% yield to the title compound, an orangish oil. Mass spectrum: m/z 344.

EXAMPLE 129 l-Hydroxy-2-naphthalenebutyronitrile 2A mixture of the product of Example 122 Part C 25 (3.79 g. 0.010 mole), potassium cyanide (0.72 g, 0.011 mole), ethanol (15 mL) and water (2 mL) was heated at reflux for 20 hours. The cooled mixture was poured into water and extracted with ethyl acetate. The crude product was chLomatographed with 1:1 ether/ hexane and recrystallized (cyclohexane/toluene) to provide the title compound (0.73 g. 35%) as a white solid, mp 76-78°.

I

i -66- EXAMPLE 130 2-(3-Methoxypropyl)-l-naphthol A suspension of sodium hydride (60% in mineral oil; 0.28 g. 0.007 mole) in dry tetrahydrofuran (5 mL) was stirred at 00. A solution of the product of Example 122 Part B 12.00 g, 0.006 mole) was added slowly, and the mixture warmed to :oom temperature.

Methyl iodide (0.8 mL. 0.013 mole) was added, the mixture was stirred for 3 hours, then was poured into 1.0 N hydrochloric acid. The crude material was isolated by extraction with methylene chloride, dissolved in a mixture of methanol (20 mL) and 1.0 N hydrochloric acid (20 mL), and heated at reflux for 20 hours. The cooled solution was extracted with 15 methylene chloride, and the residue was chromatographed with 9:1 petroleum ether/ether to provide the title compound (0.90 g, 66%) as a colorless oil. Mass spectrum: m/z 216.

9 EXAMPLE 131 PART A: Ethyl l-benzyloxy-2-naphthalenepentanoate 4* Using the procedure of Example 87 Part A, the compound of Example 117 Part A was converted into the title compound, a pale yellow oil, in 100% yield.

PART B: 1-Benzyloxy-2-naphthalenepentanoic acid A mixture of the compound of Part A (6.10 g.

0.017 mole), ethanol (10 mL), and 1.0 N aqueous sodium hydroxide was heated at reflux for 17 hours and cooled to Concentrated hydrochloric acid was added until the mixture was acidic, then stirring was continued for 3 days. The crude product was isolated by filtration, dissolved in hot isopropanol, filtered and concentrated. The residue was recrystallized (cyclohexane-hexane) to yield the title compound (3.7 g, 65%) as a tan solid, mp 70-77°.

-66i ii i go 0 s

S

S.

0 *0 0 e bole *n S.

SO 0 50 goal .00 5 5 0 ,05O -67- PART C: l-Benzyloxy-2-naphthalenepentanamide A mixture of the product of Part B (1.00 g, mmole), oxalyl chloride (1.3 mL, 15.0 mmole) and benzene (10 mL) was stirred at room temperature for 16 hours. The mixture was concentrated under vacuum to provide a tan, viscous oil which was dissolved in dry tetrahydrofuran (8 mL) and added dropwise with stirring to aqueous ammonia 50 mL) at -120. The mixture was warmed to room temperature and stirred for 6 hours, then concentrated under vacuum to remove the ammonia and tetrahydrofuran. The crude product was isolated by extraction with ethyl acetate as a yellow glass (1.0 g, 100%).

PART D: l-Hydroxy-2-naphthalenepentanamide The compound of Part C (1.0 g, 3.0 mmole) was hydrogenated in ethanol by the procedure of Example 86. Recrystallization of the crude product (cyclohexane/ethylacetate) provided the title compound (0.35 g, 48%) as a white solid, mp 75-780.

EXAMPLE 132 l-(5-[l-Hydroxy-2-naphthyl]-l-oxopentyl)-pyrrolidine A mixture of the compound of Example 131 Part B 25 (1.00 g, 3.0 mmole), oxalyl chloride (1.3 mL, 15.0 mmole) and benzene (10 mL) wrs stirred at room temperature for 21 hours and concentrated under vacuum. The residue was dissolved in methylene chloride (10 mL) and added dropwise to a stirred solution of pyrrolidine (0.53 mL, 6.3 mmole) in methylene chloride (10 mL) at After 6.5 hours, the mixture was diluted with ether, washed with water and 1.0 N hydrochloric acid, then dried over magnesium sulfate and concentrated under vacuum. The crude material was hydrogenated using the procedure of -67- Li 1

Y

68- Example 86. Recrystallization of the crude product (ethyl acetate/ethanol) provided the title compound (0.63 g. 76%) as an off-white solid, nip 166-1600.

The compounds of Examples 117 to 132. as well as other compounds which can be prepared using one of the procedures described in Examples 117 to 132 or in the general synthetic discussion, are shown in Table 7.

TABLE 7 (CH 2 R 6 *e 0 :000 0 0 0 0 *060 0 0 *0 0 .00 fee* *S 00 ad so s* S *too Ex.

No.

117 118 20 119

R

1

H

H

H

120 3 H 121 122 123

H

H

H

H

H

H

H

H

H

H

H

R 6

OH

OH

C (CH 3 2 0OH CH=C(CH 3 2 Cl1 Br SC(NlF)NH 2 HC1

SH

N(CH 2 )4 4 OHCl NH 2 HCl P(O) (0C 2

H

5 2 CH( COOC 2 H 5 )~2

CN

OCH 3 74 89 100 43 28 84 97 76 73 40 84 35 66 85-86 101-102 (ol (oil)b 53-55 184-188 198-201 213-218 (d) 90-91 (oil) d 7 6-78 (oil) e YIELD% MP(0Q 65 43-46 124 125 126 127 128 129 130 131 4 H 132 4 H 133 3 CH 3 CONH 2 CON (CH 2 4 48 75-78 76 166-169 -68- -69- Table 7 Ccont'd) Ex.

No.

134 H 135 4 Br 136 3 C 6H5 137 4 CH 3 5 8- (CH 3 2

H

6-CH 3

H

R 6 CON (CH 3 2 cyclohexyl P(O)OCH 3 2 YIELD% MP( 0

CQ

11 SOCH 3 *0 0 @040 0 40 0@0*00 0 0@ 0@S 0* 000 3 @4 @0 0 0000 00 04 0 00 0* 0 0 0

I~

0 0 *@00 138 3 CCH 3 a. mass spec b. mass spec C. mass spec 20 d. mass spec e. mass spec M/z =240 m/z =234. 236 m/z =218 m/z =344 m/z =216 -69iii i_.i Dosage Forms The lipoxygenase inhibitors of this invention can be administered to treat inflammation, including but not limited to rheumatoid arthritis, dermatoses, allergy, chronic obstructive lung diseases such as asthma and bronchitis, or psoriasis. In addition, Sthe compounds of this invention may also be useful in the treatment of osteoarthritis. They may be administered by any means that produces contact of the active agent with the agent's site of action in the body of a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic *o agents or in a combination of therapeutic agents.

15 They can be administered alone, but are generally administered with a pharmaceutical carrier selected on 'the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage administered will, of cour vary depending upon known factors such as the ,tarmacodynamic characteristics of the particular agent, and its *mode and route of administration: age, health, and weight of the recipient; nature and extent of symptoms, 9 .kind of concurrent treatment, frequency of treatment, and the effect desired. U/sually a daily dosage of active ingredient can be about 0.1 to 100 milligrams per kilogram of body weight. Ordinarily 0.5 to and preferably 1 to 10 milligrams per kilogram per day given in divided doses 1 to 6 times a day or in sustained release form is effective to obtain desired results.

Dosage forms (compositions) suitable for internal administration contain from about 1 milligram to about 500 milligrams of active ingredient per unit. In these i pharmaceutical compositions the active ingredient will 1^a ia w^* 1

S

a r.

-71ordinarily be present in an amount of about 0.5 by weight based on the total weight of the composition.

The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. It can also be administered parenterally, in sterile liquid dosage forms, by inhalation in the form of a nasal spray or lung inhaler, or topically as an ointment, cream or lotion.

Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, sucrose mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

25 In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration contain the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid either alone or combined are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, -71-

U

*i 4.

4* 4 *r 4 4** o*4 a..

5 9 -72parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in this field.

Useful pharmaceutical dosage forms for administration of the compounds of this invention can be illustrated as follows: Capsules A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 50 milligrams of powdered active ingredient, 175 milligrams of lactose, 24 milligrams of talc, and 6 15 milligrams of magnesium stearate.

Soft Gelatin Capsules A mixture of active ingredient in soybean oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules 20 containing 50 milligrams of the active ingredient.

The capsules are washed in petroleum ether and dried.

Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit is milligrams of active ingredient, 6 milligrams of magnesium stearate, 70 milligrams of microcrystalline cellulose, 11 milligrams of cornstarch and 225 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

Injectable A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is sterilized by commonly used techniques.

-72c 1 -73- Suspension An aqueous suspension is prepared for oral administration so that each 5 milliliters contain milligrams of finely divided active ingredient, 200 milligrams of sodium carboxymethyl cellulose, 5 milligrams of sodium benzoate, 1.0 grams of sorbitol solution. and 0.025 milliliters of vanillin.

Nasal Spray An aqueous solution is prerared such that each 1 milliliter contains 10 milligrams of active ingredient, 1.8 pilligrams methylparaben, 0.2 milligrams propylparaben and 10 milligrams methylcellulose. The solution is dispensed into 1 milliliter vials.

Lung Inhaler A homogeneous mixture of the active ingredient in polysorbate 80 is prepared such that the final concentration of the active ingredient will be 10 milligrams per container and the final concentration of polysorbate 80 in the container will be 1% by weight.

S 20 The mixture is dispensed into each can, the valves are crimped onto the can and the required amount of dichlorotetrafluoroethane is added under pressure.

S.Topical Formulation An ointment for topical administration may be prepared by adding the active ingredient to a mixture of 48% by weight white petrolatum, 10% liquid petrolatum, 8% glycerol monostearate, 3% isopropyl myristate and 20% lanolin at 70 0 C. After thorough mixing, a warm solution of methyl and propyl parabens in water containing sodium acetone bisulfite is added such that the final concentrations of each paraben is 0.15%, of water is 8% and of sodium acetone bisulfite is The mixture is stirred until it has reached room temperature.

-73i II--

.I

i p

II:

I

p i ti e -74- Use The compounds of this invention have been shown to inhibit 5-lipoxygenase in an in vitro test system using rat basophilic leukemia (RBL-1) cells as the source of enzyme. The test method is a modification of the procedures developed by Jakschik et al (Prostaqlandins, 16, 733-748 (1978), Biochem, Biophys. Res.

Comm., 95, 103-110 (1980), 102, 624-629 (1981). The 10,000 xg supernatant from homogenized RBL-1 cells was incubated with drug in a pH 7.0 phosphate buffer for 14 five minutes. 1C-arachidonic acid was added to initiate the reaction which was allowed to continue at 37 0 C for two minutes. The reaction was stopped by freezing in a dry ice/ethanul slurry, and the 15 5-lipoxygenase products were separated from the substrate on silica gel columns. The amount of individual lipoxygenase products produced was determined and the percent inhibition calculated.

The enzyme 5-lipoxygenase catalyzes the first reaction in the biosynthesis of the potent biological mediators, the leukotrienes (LTB 4

LTC

4

LTD

4

LTE

4 from arachidonic acid. Collectively LTC 4

LTD

4 and

LTE

4 are the materials which used to be known as slow reacting substance of anaphylaxis (SRS-A) before they were chemically characterized as leukotrienes. LTC 4 and LTD 4 are extremely potent mediators of anaphylaxis and seem to be particularly effective at reducing the air flow in peripheral airways. In animal models, reduction of the synthesis of SRS-A leads to a reduction in the symptoms following an allergic challenge.

LTB

4 is a potent leukocyte chemotactic factor and aggregating agent. Polymorphonuclear leukocytes (PMN) are particularly sensitive to activation by LTB 4 Reduction of the synthesis of LTB 4 by blocking 5-lipoxygenase should reduce the influx of PMN to an -74i L-

II

1 4 Ui: inflamed site-either an arthritic joint or a psoriatic lesion. Elevated levels of LTB 4 have been found in both the synovial fluid of rheumatoid patients and in the plaque area of psoriasis patients. Thus a 5-lipoxygenase inhibitor, by reducing the production of these potent biological mediators, is useful for the treatment of inflammation, chronic obstructive lung diseases such as asthma and bronchitis, and skin diseases such as psoriasis.

Some of the 5-lipoxygenase inhibiting compounds of this invention were found to inhibit arachidonic acid-induced ear edema. This in vivo assay is a modification of the procedure described by Young et al.

Invest. Derm., 80, 48-52, 1983) and indicates a 15 specific use in the treatment of skin diseases such as psoriasis.

In addition, two of the 5-lipoxygenase inhibiting compounds of this invention were tested in vitro using sensitized guinea pig pulmonary parenchymal strips and 20 found to be active. This test utilizes procedures described by Fleish et al. Pharm. Exp. Therap., 221. 146-151, 1982) and Drazen et al. (Proc. Acad. of Sci. USA. 77, 4354-4358, 1980) and is indicative of anti-asthmatic potential.

9 a *9 a.

St 4r *9 4 9 9t 9* 9 9a*

Claims (1)

1. 76- The claims defining the invention are as follows:- 1. A pharmaceutical composition compneai a suitable pharmaceutical carrier and a lipoxygenase inhibiting amount of a compound having the formula: 011 5+ I K wherein R 1 is H, CH 3 Br, C1, OH, OCH 3 OC 2 H COR 1 7 COOR 1 8 CONR 1 9 R 2 0 phenyl, -N(R 1 2 -NHC lower alkyl, S(O)p lower alkyl I O 0 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, C 2 H 5 OCH3, or OC 2 R 4 is straight-chain or branched alkyl of 1-12 carbons (provided that when R 4 is CH 3 R 1 can not be OH), straight-chain or branched alkenyl of 2-12 carbons, straight-chain or branched alkynyl of 2-12 carbons, cycloalkyl or cydoalkenyl of 5-7 carbons, CH-C=C-(CH 2 R 5 where m is 1 4, CH=CH-(CH 2 )nR 5 where n is 0 3 and the olefinic bond has either the Z or E configuration A-R 6 or CHR 7 0 R 21 A is a chain of 2-6 methylene groups optionally substituted at any one of the methylene carbons by a group R8; /c 76- C 7 oycloakyl, phenyl, or cOOR 9 R is C5C7 cyloalkyll phenyl, NC0OR I CON(R 12 )(R 13 CN, CH(00R 9 C(R 1 )(r 1 ,)0R 9 P(O)(0R 9 2 S(O)WR 9 where w is 0-2 with the proviso that if w 1 then R 9 is not Hi, SC(NH)NH 2 N(R 1 )(R 1 OR 9 OQ(O)R 0L, Br, or 1; tE 7 R is G 0.8 cycloalkyl, R OR 9 1 R 9 *4 15g R9 vthero X in, 0, orNR 10 and Y ic Oilr N; R in 0 1 C, alkyl, C -cq eycloalkyl, or phonyl; R9 Rl Rnd) R n 1 are independently 11 or C 1 -0 aky; 12 1- 044..kyl and R 13 independently are It, C.0-C lkyl, or together are (ell 2)4 R in Ut 1-01 alkyl, OR o-pnnyl, OcI COOrP 0-benyl) COR F 3 0, Brt 1, N(R XR3) o SO) R9 where W iz 0 2 with the provico that it w ia I then R 9 in not H; and R 15an 1 6 are independently H, 01-C4 alkyl, OR, O-benzyl, P or 01; 17 i lower alkyl, pyridy, thienyl, furyl, or phenyl optAonally oubutttuted with C, Br, F, 0113 or oil 0; 1 YR in It or lower alkyl; 77 78 ft R 19 and R 20 independently are H or lower alkyl, or taken together are II(CH 2 and R 21 is H, lower alkyl, pyridyl, thienyl, or furyl; or a pharmaceutically suitable salt thereof. 4 2. 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 )mR 5 where m is 3 and R 5 is CO OR 9 or phenyl, CH=CH-(CH 2 )nR 5 where n is 0 2, the olefinic bond has either the Z or E configuration, and R 5 is CO OR 9 or phenyl, A-R 6 or CR 2 e 7 where 0 0 A, R 6 and R 7 are as defined in claim 1. The composition of claim 2 wherein A is a chain of 2-6 *aunsubstituted methylene groups; R 6 is phenyl, COOR 9 CON(R 1 2 3 CN, CH(COOR 9 )7 2 C(R' 0 ()(hOR 9 P(O)(0R 9 2 S(O)XR, SC(NH)NH, 4 N(R0 2 3 OR?, OC(O)R 9 Cl, Br, or I; R 7 is as defined in claim 1 except that X is S, 0, or N-CH3; jtR 14 is as defined in claim 1 except for 0-p henyl, O-benzyl, and OCH 2 COOR 9 0' 5 and k 16 are independently H, OR 9 F, or C1; and w R 9 kR 1 Rk 1 R 12 and 0~ 3 are as defined in claim 1. 0 -78 9, 65%) as a tan solid, MP 70-770- -66- -79- 4. The composition as claimed in Claim 1 wherein the compound is selected from the group consisting of; methyl 7-(1 heptynoate; ethyl -hydroxy.-2-naphthyl) -4- pentenoate, Z isomer; ethyl 3- (1-hydroxy-2-naphthyl) -propen- oate, E isomer; 2- (2-propenyl) -1-naphthol; ethyl 3- (1-hydroxy-2-naphthyl) -propan- oate; ethyl 5-(1-hydroxy-2 naphthyl)-pent- anoate; 2-C 5-methyjlhexyl) -1 -iaphthol; diethyl [3-Cl -hydroxy-2-naphthyl)propyl] -propanedioate; 2- (p1enylmethyl) -1 -naphtO'hol; 2-(3-fluorophenylmethyl)-1 -naphthol; (3,4,5-trimethoxyphenyl) methyl]-1- naphthol; 2- (2-f urylmethyl) -'I-naphthol; C3, 4-dimethoxyphenyl )methyl 3-1- naphthol; 2-C 2-thienylmethyl)-1 -naphthol; 2- C3-chlorophenyl-methyl) -1-naphthol; 2-C 4-ethoxyphenylmethyl) -1-naphthol; 2-C 4-bromophenylmethyl)-1 -naphthol; and 5 ,8-dimethyl-2-(phenylmethyl-1 S S 5055 S. S S .5 4 5. 5 S. S 14 naphthol. claimed in any one of the prece ms substan- tially as her ed with reference to the p I p -79- -67- SEli II II ~~mI i*iI* I r I A method of' treating inflammation, chronic obstruct- ive lung disease and/or psoriasis in a mammal which comprises administering to the mammal an effective amount of a compound as defined in any one of the preceding claims. compound having the formula: R 2 R wherein R 1 is H, OH 3 Br,' Cl, OH, 00C 2 H 5 1 COR 1 7 CO, 0R 18 COR 17 CR 18 C0NR 19 R 2 phenyl, *-NHC lower alkyl, S(O) plower alkyl .9 If 0 .9.80- h. 133 3 CH 3 H I -68- II -81- where p Os 0, 1, or 2, SO 2 NH 2 or -NHSO lower alkyl optionally substituted 2 with F; R2 and R3 independently are H. CH 3 C 2 H 5 CH30. or C 2 H 5 0 4 R is straight-chain or branched alkynyl of 2-12 carbons, C 5 -C 7 cycloalkenyl, 5 CH 2 -CEC-(CH 2 R where m is 1 4, CH=CH-(CH2 )nR where n is 1 3 and the olefinic bond has either the Z or E configuration, 6 A-R or CH-R 7 121 R A Is a chain of 2-6 methylene groups; 5 9 R is C5-C 7 cycloalkyl, phenyl, COOR R6 is C -C alkenyl. C -C7 cycloalkyl, 12 13 9 CON(R CN, CH(COOR 10 11 9 9 9 C(R 10 )OR P(0)(OR 9 2' S(0)wR where w is 0 2 with the proviso that if w is 1 then R is not H, SC(NH)NH 2 12 13 9 N(R2 OR C1, Br, or I; 7 R is C 3 -C 8 cycloalkyl, 14 9 R 1 OR, 815 1 6 R 9 4Y R 9 R9 ,or 10 where X is S, 0. or NR and Y is CH or N;: 9 10 11 R R and R are independently H or C 1 4 alkyl; -81- il_ ;-LYi -69- a q 4 *4* R 2and R3independently are H, 0 1-0C4 alkyl, or together 1are (OH 2 4 5 99 R is C 1 -C4 alkyl, OR 9 0-phenyl, OOH 2 000R 9 O-benzyl, COOR OF 3 Cl, Br, I, N(R 12 )(R 13 or S(O) wR 9 where w is 0-2 with the proviso that if w is 1 then R 9 is not H; and R 1 6 are independently H, C 1- O4 alkyl, OR 9 O-benzyl, F or Cl; R7is lower alkyl, pyridyl, thienyl, furyl, or phenyl 18optionally substituted with Cl, Br, F, OH 3 or 0113 0; R is H or lower alkyl; R 12 and R 20 independently are H or lower alkyl, or 21taken together are (OH 2 4 5 and R 2 is H; subject to the following provisos: 2. 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-oOH 3 then R 4 is not 4 4-chlorophenylmethyl or 4-methylphenyl.Athyl; 3. if R 1 is 01 then R 4 is not 4-aminophenylmethyl; and R 4 is not CH CH 2 ON. 7. A compound of claim 6 wherein R 4 is cycloalkenyl of 5-6 carbons; ICH -oCZ-(oH 2) R 5 where m is 3 and R is OOOR 9 or phenyl; H=OH-(OH 2) nR 5 where n is 1 2, the olefinic bond has either the Z or E configuration and R 6is 000R 9 or phenyl. A-R o CH -R ;whee 6and R7 are as defined in claim 6. .08. A compound of cl~aim 7 wherein A is a chain of 2-6 unsubstituted methylene groupa; R R 6 is OON(R 12 )(R 13 ow, oH(CooR 9 2 O(R 10 )(R 1 %oR 9 ,1 P(o)(oR 9 2 1 S(O) 2 R 9 So (NH)NH 2 N(R 12 )(R 13 OR 9 01, Br, or 1; 1 4.4 4 4 4.. 4 4 .4 82 R 7 is as defined in claim 6 except that X is S, 0, or 14N-OH 3 R 1 is as defined in claim 6 except for 0-phenyl, O-benzyl, and OCH 2 C00R9 R 15 and R 16 are independently H, OR 9 F, or Cl: and w, R 9 R 10 R 11 1R 12 and R 13 are as defined in claim 611 9. The compound as claimed in claim 6, selected from the group consisting of methyl 7-(1-hydroxy-2-naphthyl)-5- heptynoate; ethyl 5-(1-hydroxy-2-naphthyl)-4-pentenoate, Z isomer; diethyl -hydroxy-2-naphthyl)propyllpropanedioate; 2-(3-.fluorophenylmethyl)-1 -naphthol; (3,4,5-trimethoxyphenyl)m.thyl-2--naphthol; 2- (2-furylmethyl) -1-naphthol; (3,4-dimiethoxyphenyl)methyl]-2-naphthol; 2-(2-thienylmethyl)-l1-naphthol; 2- (3-chlorophenylmethyl) -1-naphthol; 2- (4-ethoxyphenylmethyl -1-naphthol; 2-(4-bromophenylmethyl)-1-naphthol; and 5,8-dimethyl-2-(phenylmethyl)-1-naphthol. A compound as claimed in claim 8 wherein R 4 is AR, where A and R 6 are as defined in claim 6. 11. A compound as claimed in cla~im 8 wherein R 4 is cyclo- alkenyl of 5-6 carbon atoms. 12. A compound of claim 8 wherein R 4 is CH 2 R 7 whereR 7 is as defined in claim 6. 13. A process for preparing a compound of claim Se comprising treating a protected 1-naphthol of the formula R 2 OPr 2 3 where R 2 and R 3 are as defined in claim 6 and Pr is a protecting group sequentially with a strong base and then Swith a c,w-bromochloroalkane; 83 -71- J! 1. I v -19 4' treating the product of step with an appropriate nucelophile selected from the group consisting of CN, Br, Cl, N 3 -OR 9 -SR 9 SR 9 P(OR 9 3 -CH(COOR 9 2 NH 2 C(S)NH 2 and treating the product of step with an acid. 14. A process for preparing a compound of claim 11 comprising treating a protected 1-naphthol of the formula OPr 2 R 2 3 4 where R and R are as defined in claim 9 and Pr is a protecting group sequentially with a strong base and then cyclopentanone, cyclohexanone or cycloheptanone; and treating the product of step with an acid. 15. A process for the preparing a compound of claim 12 comprising treating a mixture of a tetralone of the formula I R2-pU where R and R 3 are as defined in claim 6 and R 1 is H or CH 3 and an aryl or heteroaryl aldehyde R CHO where R is defined in claim 6 in t-butanol with potassium t-butoxide, and optionally; 1 when R H treating a solution of the product of S step in acetic acid with chlorine or bromine. 84 commonly usea tecnniques. -72- I 16. A process for preparing a compound of claim 6. comprising: treating a protected 1-naphthol of the formula OPr R R 2 where R and R are as defined in claim 6 and Pr is a protecting group sequentially with a strong 0 base and then with a ketone R7CR21; treating the product of step with a reducing agent; and treating the product of step with a demethylating agent. 15. 17. A process for preparing a compound of claim 6 comprising: treating a 1-naphthol of the formula OH 2. R. R *9* 0 9 9 9 3* with an acylating agent in the presence of a Friedel-Craft reaction catalyst; and treating the product of step with a reducing agent in an acid. 18. A process for preparing a compound of claim 6 where 0 1 17 R =C R comprising: treating a protected 1-naphthol of the formula OPr SCHR R21 R 2 85 Y -i ii _I where R 2 R 3 R and R 2 1 are as defined in claim 6 and Pr is a protecting group with a brominating agent in a suitable s lvent; treating the product of step sequentially with a strong base and then with an electrophilic reagent selected from the group consisting of a dialkyl carbonate, alkyl chlorofumate, carbon dioxide, or an aldehyde; optionally treating the product of part with an oxidizing agent, if the electrophilic reagent used in part is an aldehyde; and 1 17 where R =CR comprising: treating a 1-naph+hol of the formula OPr "N CHR R2 R E2 3 7 21 S* where R 2 R 3 R and R 21 are as defined in claim 6, with an acylating agent in the presence of a Friedel-Craft reaction catalyst; optionally followed by treatment of the product with an 1| acid in an alcoholic solvent. A process for preparing a compound as claimed in any one of claims 6 to 12, substantially as hereindescribed with reference to any one of the Examples. 21. A compound whenever produced by the process as claimed in claim DATED this 17 day of July 1989. E.I. DU PONT DE NEMOURS COMPANY t 'V By: SRgd. Pate Attorney 86 L ,1 ~Y i. I