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Title:
ARYL SUBSTITUTED NAPHTHALENE, BENZOXEPINE, BENZAZEPINE, BENZOCYCLOHEPTENE DERIVATIVES
Document Type and Number:
WIPO Patent Application WO/1988/008836
Kind Code:
A2
Abstract:
Certain aryl substituted naphthalene, benzoxepine, benzazepine and benzocycloheptene derivatives are disclosed. The compounds are useful in treating hyperproliferative skin disease, allergic reactions and inflammation.

Inventors:
Shih, Neng-yang Mangiaracina Pietro Green Michael J.
Ganguly, Ashit Kumar
Application Number:
PCT/US1988/001524
Publication Date:
November 17, 1988
Filing Date:
May 13, 1988
Export Citation:
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Assignee:
SCHERING CORPORATION SHIH, Neng-Yang MANGIARACINA, Pietro GREEN, Michael, J
Ganguly, Ashit Kumar
International Classes:
A61K31/05; A61K31/047; A61K31/085; A61K31/09; A61K31/12; A61K31/135; A61K31/15; A61K31/16; A61K31/165; A61K31/175; A61K31/325; A61K31/335; A61K31/357; A61K31/385; A61K31/44; A61K31/4402; A61K31/4418; A61K31/55; A61P29/00; A61P37/08; A61P43/00; C07C39/14; C07C43/21; C07C43/215; C07C43/23; C07C45/00; C07C45/29; C07C45/46; C07C45/51; C07C45/62; C07C45/64; C07C45/65; C07C45/66; C07C45/68; C07C45/69; C07C49/747; C07C49/755; C07C49/757; C07C49/84; C07C69/157; C07C69/757; C07C233/06; C07C251/20; C07C251/44; C07C251/66; C07C251/84; C07C271/12; C07C323/17; C07C323/22; C07D213/50; C07D223/16; C07D313/08; C07D317/72; C07D339/06; (IPC1-7): C07C49/755; C07C49/747; C07C49/757; C07C125/077; C07C13/00; C07C109/16; C07C133/02; C07C9/14; C07C103/38; C07C69/12; C07C69/757; C07C43/20; C07C149/32; C07D223/16
Foreign References:
US3274213A1966-09-20
CH477401A1969-08-31
US3247253A1966-04-19
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Description:
- / - ARYL SUBSTITUTED NAPHTHALENE , BENZOXEPINE, BENZAZEPINE , BENZOCYCLOHEPTENE DERIVATIVES

BACKGROUND OF THE INVENTION

The present invention relates to certain aryl substituted naphthalene, benzoxepine, benzazepine and benzocycloheptene derivatives.

SUMMARY OF THE INVENTION The present invention relates to a compound having the structural formula I:

wherein F represents:

or a pharmaceutically acceptable salt or solvate thereof, wherein: the dotted line ( ) represents an optional double bond, T being absent in formula la, R 7 and R^° being absent in Ic when the dotted line represents a double bond;

A represents an aryl or an aromatic heterocylic group;

M represents -CR 7 R 8 , -0- or -NR 9 ;

N represents H or A;

T and are the same or different and each represents H, alkyl, alkenyl, Q, -OR 5 , -S-alkyl> -SQ, -CH 2 Q, -0(CH 2 ) n Q, halo, -C(0)R 6 , -CH 2 OR 5 , -0(CH 2 ) n C00R 6 or -C(0)0R 6 ;

D represents H, alkyl, -SR 5 , -C(0)R 5 ;

U, V and Z are the same or different and each represents a group selected from H, alkyl, -OR , -SR , -0(CH 2 ) n Q, -C(0)R 6 , -CH 2 OR 5 , -0(CH 2 ) n C00R 6 or halo;

Q represents phenyl or substituted phenyl; n is 1 to 8;

R 1 , R 2 and R 3 are the same or different and each represents H, alkyl, cycloalkylalkyl, alkenyl or alkynyl, which alkyl, alkenyl or alkynyl group may optionally be substituted with a group Q, -OR 6 , -SR , halo or -N(R 6 ) 2 , with the proviso that OH or NH 2 are not

directly bonded to the carbon atom of a carbon-carbon double or triple bond, and that in compounds of formula la and lb, R 1 and R 2 cannot both be H;

R 4 represents H, OH, N(R 6 ) 2 , -NR 6 (COR 6 ) or -SQ; in addition, R and R together with the carbon atom of the ring t to which they are attached may represent a spirocarbocyclic ring having from 3 to 6 carbon atoms; in addition, R 3 and R together may represent a carbonyl oxygen, =S, =N-OR 5 , =N-N(R 6 ) 2 , =N-NHC(0)R 6 ,

=N-NH(S0 )R 6 , =N-NHC(0)NH , 0 0 or ϊx S with the proviso

that R and R do not represent H when the dotted line represents a double bond; each R 5 independently represents H, alkyl,- alkanoyl (the alkyl portion of which may optionally be substituted with halo, -OR 6 , -SR 6 or a group Q) , -C(0)-Q, -C(0)-N(R 6 ) 2 or -C(0)-OR 6 ; each R 6 independently represents H, alkyl ' or Q; and

R 7' and Rft° are the same or different and each represent H or alkyl, alkynyl, alkenyl, -OR , Q , -S-alkyl, -SQ, -CH 2 Q, -COOR 6 or -C(0)R 6 .

R 9 represents H, alkyl or -C(0)R 6 ;

R 10 and R 11 are the same or different and each represent H, alkyl or alkenyl; in addition, R 10 and R 11 together may represent a carbonyl, =S, =N-OR 5 , =N-N(R 6 ) 2 , =N-NHC(O)R 6 , =N- NH(S0 2 )R 6 or =N-NHC(0)NH 2 .

In a preferred embodiment the compound is of formula la.

W is preferably H, OR 5 or alkyl. R 1 and R 2 are preferably each independently H or alkyl. U, V and Z are preferably each independently H or OR . A is preferably aryl, e.g., phenyl or phenyl substituted with 1 or 2

substituents each independently selected from H, alkyl or

OR.- . R and R 4 together preferably represent a carbonyl oxygen, =N-OR =N-0(CO)R 6 , =N-NH(CO)R 6 , =N-N(R 6 ) 2'

A preferred subgenus of compounds is represented by the structural formula Ig

wherein R- 1 - and R ώ are the same or different and each is selected from H or alkyl; R 3 is H or alkyl and R is H or OH, or R 3 and R together represent a carbonyl oxygen or =N-OR , wherein R 6 is H, alkyl, phenyl or substituted phenyl; E, G, K, L and P are the same or different and each is selected from hydroxy, alkoxy, alkanoyloxy or dialkylcarbamoyloxy; J represents H, hydroxy, alkoxy, alkanoyloxy or dialkylcarbamoyloxy; or a pharmaceutically acceptable salt of such a compound.

Another preferred group of compounds is represented by the structural formula Ih

1 9 wherein R and R^ is alkyl;

R 5 is H or alkanoyl;

E, G, U, V and Z are the same or different and each is H, OH or alkoxy;

T and W are the same or different and each is H, alkyl or alkenyl.

A third preferred group of compounds are those of formula Ic, Id or Ie wherein

A is H, phenyl, substituted phenyl or

M is -CH 2 -, -OH or -NH-;

U, V, Z are the same or different and each is H, OH, alkoxy;

R and R ώ are the same or different and each is H or alkyl;

R 10 and R 11 represent H, -OH, -N(R 6 ) 2 -NR 6 (COR 6 ) or R 10 and R 11 together represent a carbonyl oxygen, =N-OH or =N-Oalkyl; and N, T and W are as defined above.

The compounds of the invention may be formulated into pharmaceutical compositions with a pharmaceutically acceptable carrier. The compounds may be used to treat mammals suffering from hyper- proliferative skin disease (such as psoriasis) , allergic reactions and/or inflammation by administering an effective amount for such purpose to the mammal. Compounds of formula I wherein R and R together

represent =N-OR 6 or =N-NH(CQ)R β also inhibit platelet activating factor (PAF) and are thus particularly useful in treating diseases such as allergies, inflammation, etc., mediated by PAF.

DETAILED DESCRIPTION OF THE INVENTION

When utilized herein, the terms listed below have the following scope, unless otherwise indicated: halo-represents fluoro, chloro or bromo; alkyl (including the alkyl portion of alkoxy, alkanoyl, alkanoyloxy or cycloalkylalkyl) - represents straight and branched carbon chains and, unless otherwise specified, contains from 1 to 10 carbon atoms; carbonyl oxygen - represents a group =0;

0

II alkanoyl - represents a group alkyl-C-; alkenyl - represents straight and branched carbon chains having at least one carbon to carbon double bond and, unless otherwise specified, contains from 3 to 6 carbon atoms; alkynyl - represents straight and branched carbon chains having at least one carbon to carbon triple bond and, unless otherwise specified, contains from 3 to 6 carbon atoms; cycloalkyl - (including the cycloalkyl portion of cycloalkylalkyl) represents a saturated carbocyclic ring having from 3 to 7 carbon atoms, e.g., cyclohexyl; spirocarbocyclic ring - represents a saturated cycloalkyl ring having from 3 to 7 carbon atoms and having one carbon atom thereof common to the ring t in formula la or lb; aryl - represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one benzene ring, with all ' available substitutable carbon atoms thereof being intended as possible points of attachment. More preferably, aryl is phenyl or substituted phenyl;

substituted phenyl - represents phenyl substituted with up to 3 substituents U, V and/or Z as defined above or with a group selected from -0(C0)-0- or -OCH 2 0- via adjacent carbon atoms of the phenyl ring. Preferably, the substituents are independently selected from hydroxy, alkoxy, alkanoyloxy or dialkylcarbamoyloxy; and aromatic heterocyclic - represents cyclic groups having at least one 0, S and/or N in the ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the aromatic heterocyclic groups preferably containing from 2 to 14 carbon atoms, e.g., 2-, 3- or 4-pyridyl, 2- or 3- furyl, 2- or 3-thienyl, 2-, 4- or 5-thiazolyl, 2- or 4- imidazolyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, 3- or 4-pyridazinyl, 3-, 5- or 6-[1,2,4-triazinyl] , 2- , 3-, 4-, 5-, 6- or 7-benzofuranyl, 2-, 3-, 4-, 5-, 6- or 7- indolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, etc., with all available substitutable carbon atoms thereof being intended as a possible point of attachment.

Also, the lines drawn into the rings as in formulas la, lb, and Ic above are intended to indicate that the substituent group may be on any available position on such ring.

Compounds of the invention of formulas la and lb can exist in unsolvated as well as solvated forms, including hydrated forms, e.g., hemihydrate. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms for purposes of this invention.

Certain compounds of the invention may exist in isomeric forms. The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures.

Certain compounds of the invention also form pharmaceutically acceptable salts with organic and inorganic acids, e.g., compounds having basic nitrogen atoms. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well know to those in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for purposes of the invention.

Certain compounds of the invention will be acidic in nature, e.g. those compounds wherein U, V or Z is OH. These compounds may form pharmaceutically acceptable salts. Examples of such salts are the sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.

The compounds of formula la and lb can be prepared by the processes A-H described below. In these processes the substituents R 1 , R 2 , R 3 , R 4 / A, T, U, V, Z, and W are as defined above, unless otherwise indicated.

A. To prepare a compound of formula I wherein R 3 and R 4 together represent a carbonyl oxygen, T represents H, and W is as defined above excluding halogen, a compound of formula II may be reacted with a base such as aqueous NaOH, etc:

II III

This reaction can be performed at any suitable tempera¬ ture depending upon the base (e.g., with NaOH elevated temperature of from about 50°C to about 70°C may be employed) and may be run in an inert solvent such as tetrahydrofuran (THF) .

The compounds of III may be converted to other compounds of formula I (e.g., compounds of formulas IV, IVa, Va, VI, VII, IX, X and XI below) by various techniques as illustrated below. For example, a compound of formula III may be hydrogenated to prepare a compound of formula IV:

hydrogenating

III agent v

IV

This reaction may be performed under conventional conditions for hydrogenation of olefinic double bond, e.g., by hydrogenation. with palladium on activated carbon as a catalyst.

If W in formula IV is H, the groups W 1 and W 2 can be introduced as described below. For example, a compound of formula IVa may be reacted with a compound of the formula W ^--^ an <3 base to prepare a compound of formula Va:

wherein L 1 is a leaving group such as chloro, bromo or iodo, and represents alkyl, halo, -(CO)R , CH 2 Q, (CO)OR 6 or -CH 2 OR . This reaction can be performed with a base such as NaH or lithium diisopropylamide in THF.

A compound of formula IVa may also be reacted with lead tetraacetate to produce a compound of formula " VI which may be hydrolyzed and then reacted with a compound R 5 L 2 or QCH 2 L 2 or R 6 00C(CH 2 ) n -L 2 .

IVa + Pb(OOCCH 3 ) 4

I

R β

wherein W 2 represents OR 5 , 0(CH 2 % n Q, 0(CH 2 v n COOR 6 or

0 (CO) R and L 2 .represents a leaving group such as bromo or iodo.

To prepare a compound of the invention of formula IX, a compound of formula IV is reacted with a compound TL 3 in the presence of base:

IV IX

wherein L 3 is a leaving group such as bromo or iodo.

The compound of formula IX may be hydrogenated to form a compound of the invention of formula X:

IX hydrogenating agent V

X

The compound of formula IX may also be reacted with a compound of the formula R 3 M to prepare a compound of formul

XI wherein M represents a metal or metal salt such as Li, MgBr, Ti C l 3 (when R 3 = CH 3 ) , NaBH 4 (when R 3 =H ) , etc.

The compounds of formula II may be prepared from known materials. For example, a compound of formula XII may be reacted with a halogenating agent such as S0C1 2 or (COCl) 2 to form the corresponding acid halide of formula XIII which is then reacted with a compound ' A -M a wherein M a represents copper, cadmium, etc., or alternatively with the compound "AH" in the presence of a Lewis acid, e.g., AICI3, to produce a compound of formula XIV:

XII XIII

XIV

Compounds of formula XIV can be alternatively prepared by reacting a compound of formula XXXX with a compound of formula XXXI in the presence of base, such as NaH, in an organic polar solvent, such as DMF. Compounds XXXX can be prepared by following the literature procedure, see Tetrahedron, 31, 1219 (1975) .

If it is desired that R 1 and/or R 2 represent alkyl, -CH 2 - alkenyl or -CH 2 -alkynyl groups, they can be introduced into the compounds of formula XIV by reaction in succession with compounds of the formulas R la L , and R 2a L in the presence of base such as NaH or lithium diisopropylamide:

XVIa wherein L represents a leaving group such as bromo or iodo and R la and R 2a each independently represent alkyl, -CH -alkenyl or -CH -alkynyl groups. The order of the reactions with R la L 4 and R 2a L 3 may be reversed. ,-

The -CH 2 -alkenyl groups described above may be converted to alkenyl (R or R ) groups having the carbon- carbon double bond alpha relative to the carbon atom to which such groups are attached by treatment with iron carbonyl, e.g., Fe(C0) 5 .

The compound of formula XVI may be reacted with a compound of the formula L (CO)CH 2 W in the presence of a Lewis acid to produce a compound of formula II:

II

XVI

wherein L 4 is a leaving group such as chloro.

As an alternative method for making compounds of formula III wherein W represents OR 5 or 0CH 2 Q, a compound of formula IVa may be reacted with isoamylnitrile in ethanol and HCl to produce a compound of formula XVII:

XVII

If it is desired that W represent 0R 5a (wherein R 5a represents R 5 other than H) or OCH 2 Q, the compound of formula XVII is reacted with a compound of the formula R d L 6 in the presence of a base such as NaH, wherein R d represents R 5a or CH 2 Q and L° represents a leaving group such as bromo or iodo:

XVII - R V base.

XVIII

B. A compound of formula XIX may be reacted with a strong acid such as polyphosphoric acid to form a compound of formula IVa:

wherein R e represents an alkyl group such as methyl or ethyl. The compound of formula IVa may then be treated as discussed above to produce other compounds within the scope of formula I.

Compound IVa can be converted to compound Ilia by treatment with an appropriate oxidizing agent such as 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) :

This reaction may be performed at about room temperature, using an appropriate solvent, e.g., CH 2 C1 2 or THF.

The compounds of formula XIX may be prepared by reducing a compound of formula XX to the corresponding aldehyde, e.g., by reaction with lithium aluminum hydride and then with an oxidizing agent such as pyridium dichromate:

XX XXa

0 0 (I

The aldehyde XXa is then reacted with (C 2 H 5 0) P-CH -C-OR e in the presence of a base such as NaH to form a compound of formula XXI, which is then reacted with a compound of the formula ALi in the presence of Cul and BF3 to form a c

XXI

ALi

XIX

Cu

BP .3

The last reaction may be performed at low temperature, e.g., from about -78°C to about 0°C in an inert solvent such as THF.

Alternatively, the aldehyde of formula XXa can be prepared by reacting the alcohol of formula XXII with a compound HL 6 such as HBr, HCl, etc., to form a compound of formula XXIII, which is then reacted with Li in the presence of dimethylformamide (DMF) :

wherein R 2a is alkyl and L 6 is a leaving group such as chloro, bromo, etc.

A compound of formula XIX may alternatively be prepared by reacting a compound of formula XXIII with a compound of formula XXIV and Li dispersed in THF:

XXIII

wherein L° is as defined above.

C. A compound of formula XXV may be reacted with a strong acid such as trifluoroacetic acid to form a compound of formula XXVI:

wherein R ,2b u represents the precursor of the group R .

The -compound of formula XXVI may be oxidized to the corresponding keto compound of formula IVa, e.g., by reaction with chromic anhydride or DDQ.

oxidizing

XXVI agent V

IVa

The keto compound of formula IVa may be substituted with W, T and other R and R groups as described above.

The compounds of formula XXV may be prepared by reacting a compound of the formula XXVII with a compound H-(CO)-A in the presence of base to form a compound of formula XXVIII, which is then reacted with a compound XXIX where M represents, e.g., Li or MgBr, in the presence of a copper halide or copper cyanide to give a compound of formula XXIV, which is reduced, for example, by hydrazine in the presence of base at elevated temperature, e.g., about 130°-170°C, to generate the compound of formula XXV where =CH-R 2a represents =R :

XXVIII

XXIV D. A compound of formula Ilia may be prepared by reacting a compound of the formula XXX with a strong acid:

XXX

Ilia

The compound of formula Ilia may then be hydrogenated to produce a compound of formula IVa which may then be reacted to provide appropriate other , T, R and R substituents as described above.

A compound of formula XXX may be prepared by reacting a compound of formula XVI above with Br g-C≡C-OC 2 H 5 :

XVI + BrMg-C≡C-OC 2 H 5 XXX

E. A compound of formula IVa may be prepared by reacting a compound of the formula XXXI with A 2 -M in the presence of Ni(acac) 2 wherein acac is acetylacetonate:

XXXI IVa wherein M is a metal such as Zn.

The compound of formula XXXI may be prepared by reacting a compound of formula XXa above with BrMgC≡C-OC 2 H5 to produce a compound of formula XXXII which is then treated with strong acid such as trifluoroacetic acid to provide XXXI.

XXXII

XXXI

F. To prepare compounds of formula lb, a compound of formula XXXIII is reacted with base and a compound of the formula L 7 A, to produce a compound of formula XXXIV. The base is a hindered strong base such as Lithium cyclohexyisopropylamide, and L' is a leaving group such as bromo or iodo. Compounds of formula lb may also be prepared from a compound of formula XXXIII with a base and L'A in the presence of Ni(COD) 2 wherein COD is σyclooctadiene.

XXXIV

XXXIII

The compounds of formula XXXIII may be prepared by reacting a compound of formula XXXI above with D-M:

XXXI XXXII

0 wherein D represents alkyl, SR or -C-R 5 while M is Zn, Li or Ni, respectively.

G. Alternatively, a compound of formula XXXIV may be prepared by a compound of formula XXXV with D 2 -M in the presence of Ni (acac) 2 when D is alkyl or with DM when D is (CO)R 5 :

XXXV XXXIV wherein M is Zn and Ni, respectively.

To prepare a compound of formula XXXV, a compound of formula XXa above may be reacted with a compound of XXXVI to produce XXXVII, which under basic conditions may convert to a compound of formula XXXV:

XXa XXXVII

base XXXV q wherein L° is a leaving group such as chloro.

Alternatively, a compound of formula XXV can be prepared by oxidation of a compound of formula XXXIVa, for example use DDQ (dichlorodicyanoquinone) as oxidizing agent.

Compounds of formula XXXIVa can be prepared from XXXIIIa by literature procedure ( JACS, 13658 (1971)). XXIIa in term can be prepared from XXXI by simple hydrogenation.

where L is a leaving group such as bromo or iodo.

H. To prepare compounds of formula XXXVIII wherein R 3 and R 4 together represent =N-OR , =N-N(R 6 ) 2 , =N-NH(CO)R β , =N-NH(S0 2 )R 6 or =N-NH(CO)NH 2 , a compound of formula IX is reacted with an appropriate compound of the formula NH 2 -MM, where MM is OR 6 , -N(R 6 ) 2 , -NH(CO)R 6 , -NH(S0 2 )R 6 or -NH(CO)NH 2 , by conventional techniques e.g., reflux in ethanol or 1-butanol.

Alternatively compounds of formula XXXVIIIa, where MM=OH may be prepared by reaction of compounds of formula XXXIX with a strong base and TL. The strong base, for example, is n-butyl lithium. L is a leaving group such as chloro, bromo or iodo.

A compound of formula XXXIX may be prepared by reacting a compound of formula XXXXII with a strong base and WL.

where L is a leaving group such as chloro, bromo or iodo.

T Too pprreeppaarree ccoommppoouunnddss wwhheerreeiinn RR aanndd RR ttoogether represent =N-0(CO)R 6 , XXXXII, aa compound of formula XXXXXXVVIIIa may be reacted with R 6 (CO)L in the presence of base

XXXVIIIa

where L is a leaving group, such as chloro.

To prepare compounds wherein R is H and R- are NH(CO)R 6 , XXXXVI, a compound of formula XXXXII may be reacted with R (C0)C1 in the presence of base. Compound XXXXIV in term can be prepared from XXXXV by NaBH 4 reduction in the presence of Lewis acid, for example TiCL/i .

Cσmpounds of formula lb wherein R 3 and R 4 represent substituents other than carbonyl can be prepared from a compound of formula XXXIV in the same manner as described above in section A with regard to compounds of formula la.

The compounds of formula Ic, Id and Ie can be prepared by the processes described below. In these processes substituents R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R. , A,M,N,T,U,V,Z and W are as defined above unless otherwise indicated.

To prepare the compounds of formula Ic wherein M is oxygen and R 10 and R 11 together represent a carbonyl oxygen, a compound of formula IVa may be reacted with a oxidizing agent such as meta-chloroperbenzoic acid or hydrogen peroxide in acetic acid

This reaction can be performed at any suitable temperature from -10° to room temperature and may be run in an inert solvent such as methylene chloride.

The compounds of formula \» may be converted to other compounds of Ic by various procedures as illustrated below. For example, a compound of formula L, may be reacted with a compound of the formula WL and base to prepare a compound of formula:

L + L,

wherein L is a leaving group such as chloro, bromo or -iodo, and W represents alkyl, halo, -(CO)R 6 or -CH 2 OR . This reaction can be performed with a base such as sodium hydride or lithium diisopropylamide in an appropriate solvent, such as tetrahydrofuran.

To prepare a compound of the invention of formula LII a compound of formula LI is reacted with a compound, TL, in the presence of base, such as sodium hydride, potassium hydride, lithium diisopropylamide:

wherein L is a leaving group such as chloro, bromo or iodo.

To prepare a compound of the formula LIII, a compound of formula L is reacted with cyclopentadienyl titanium:

Llll

This reaction can be performed at any suitable temperature, such as 0°C to room temperature, in an organic solvent, e.g., methylene chloride or THF (see JACS, 102, 3270 (1980) .

The compound of formula LIII may hydrogenated to form the compound of formula LIV:

The sulfur compound of the formula LV may be prepared by reacting a compound of formula with phosphorous pentasulfide:

This reaction can be performed in an organic solvent, such as toluene, at the boiling point of the solvent.

To prepare the compound of formula Ic wherein M is oxygen and R 10 and R-*- 1 are both H, a compound of formula L is reacted with a reducing agent, e.g. lithium aluminum hydride, to afford a compound of formula LVI:

This compound is cyclized by reaction with diethyl azodicarboxylate and triphenyl phosphine in an appropriate solvent, THF, at room temperature:

\ ΪI

To prepare compounds of formula Ic where M is -NH- and R 10 and R 11 together represent a carbonyl oxygen, a compound of the formula LVIII may be reacted with methanesulfonyl chloride in pyridine to form the compound of a LIX:

The compound of formula may then be rearranged to a compound of formula LX by treatment under acidic conditions, for example aqueous hydrochloric acid in an organic solvent such as tetrahydrofuran, or passing the compound of formula over silica gel.

The sulfur compound of formula.LXI may be prepared by reacting a compound of formula LX with phosphorous pentasulfide

To prepare a compound of formula Ic wherein M is -CH 2 - and R 1 and R 11 together represent a carbonyl oxygen, a compound of the formula IVa may be reacted with t imethylsilyl diazomethane in the presence of boron trifluoride to afford:

The reaction can be performed at a suitable temperature, e.g. between -78°C to 0°C, and may be run in an inert solvent such as methylene chloride. The compounds of formula LXII and LXIII may be isolated by conventional techniques, such as chromatography.

To prepare a compound of Ic wherein M is CR 7Rft, R 10 , and R 11 together represent a carbonyl oxygen, a compound of the formula LXIII is reacted with a compound R'L and a base, e.g. sodium hydride or lithium diisopropylamide:

L-XtV where L is a leaving group such as brome or iodo.

Reaction of a compound of formula LXIV with a compound R°L in the presence of base as above affords the compound of formula ^

To prepare compounds of the formula Ic wherein M is -NH- and R 1 and R 1 are both hydrogen, a compound of the formula LIX may be reacted with a reducing agent, such as diisopropylaluminu hydride and lithium aluminum hydride, in an inert organic solvent, for example toluene

To prepare compounds of formula Ic wherein M is -NH- and R is alkyl, a compound of formula LIX may be reacted with (R^ 3 ) 3 A1 and diisobutylaluminum hydride:

v n\

This reaction may be performed in a inert organic solvent, such as toluene or methylene chloride.

To prepare a compound of the formula LXVIX, a compound of the formula LXVII may be reacted with an acid chloride in pyridine at a temperature of from about 0°C to

To prepare compounds of formula Ic where M is -NH- and R 13 and R14 are alkyl, allyl, a compound of formula LXVI is reacted with (R 10 ) 3 A1 and R 14 MgBr:

References for the ring expansions of methoximer are Pure and Appl. Chem., Vol. 55, No. 11, 1853 (1983) and Angew. Chem. Int. Ed. Eng. 24, 668 (1985).

To prepare a compound of the formula LXXI, a compound of formula LXVI is reacted with trimethylsilyl diazomethane in the presence of borontrifluoride

This reaction may be performed in methylene chloride at low temperature, such as -78°C.

The compound of formula LXXI may be reacted with a compound of formula WL and base, such as sodium hydride, potassium hydride, to prepare a compound of formula LXXII:

Lχy\\ where L is a leaving group such as chloro, bromo or iodo.

The compound of formula LXXII may be further reacted with a compound TL in the presence of base to prepare a compound of formula LXXIV:

Lxxni where L is a leaving group as noted above.

Compound LXXII can be converted to compound LXXIV by treatment with an appropriate oxidizing agent such as 2,3-dichloro -5, 6-dicyano-l , 4-benzoquinone (DDQ)

L.TO

To prepare compounds of the formula LXXV wherein R and R together represent = N-OR , = N- N(R 6 ) 2 , = N-NH(CO)R 6 , = N-NH(S0 2 )R 6 or = N-NH(CO)NH 2 , a compound of formula LXXI11 is reacted with an appropriate compound of the formula NH 2 ~MM, where MM is OR 6 , -N(R 6 ) 2 , -NH(CO)R 6 , -NH(S0 2 )R 6 or -NH(CO)NH 2 , by conventional techniques, e.g. reflux in ethanol or 1-butanol:

Nttl K

« f tΛV

To prepare a compound of formula LXXVII, a compound of the formula LXXVI is reacted with trimethylsilyl -chloride in the presence of a base, such as potassium hydride:

This compound of formula LXXVII is reacted with palladium acetate and 1, -benzoquinone in acetonitrile to afford the compound of formula LXXVIII:

Lxy u

The compound of formula LXXIX is prepared by reacting a compound of formula LXXVIII with a compound A- Met wherein Met is Li or MgBr- in the presence of CuCN or Cul:

Lxtfvm

To prepare compounds of the invention of formula Ic or Id wherein R 10 and R 1 together represent = N-OR 6 , = N-N(R 6 )2, = N-NH(C0)R 6 , = N-NH(S0 2 >-R 6 or = N- NH(C0)NH 2 . a compound of the formula Ic or Id wherein R 10 and R together represent a carbonyl oxygen is reacted with an appropriate compound of the formula NH 2 -MM, where MM is OR 6 , -N(R 6 ) 2 ,-NH(CO)R 6 , -NH(CO)NH 2 , by conventional techniques, e.g. reflux in ethanol or 1-butanol

NH λ MM

LXU

To prepare compounds of the invention- Ic, who the dotted line represents a double bond, a compound of p formula LXII is reacted with' R°Met in the presence of p

CeCl3 to give a compound of formula LXXXII, where R is alkyl, alkenyl, Q or -CH 2 Q and Met is Li or MgBr:

XXX \ .

The compound of formula LXXXII can be reacted with pyridine and POCI3 in an organic solvent, e.g. benzene at a temperature of 0°C-to room temperature to give a compoun

L XXU

L X*< t

In the above processes, it is many times desirable and/or necessary to protect certain groups from reaction, e.g., the groups in column 1 of the following table. Conventional protecting groups are operable. Preferred protecting groups appear in column 2 of the table.

Of course other protecting groups well known in the art may be used. After the reaction or reactions, the protecting groups may be removed by standard procedures well known, in the art.

The compounds of formula la and lb may also be converted to other compounds of the invention by methods conventional in the art. For example, certain U, V and/or Z substituents may be changed to other U, V and/or Z substituents within the scope of the invention. In one such method, a U, V or Z OH group may be converted to a -0(CH ) n Q group by treatment with a compound L -(CH 2 ) n Q group in the presence of base wherein L 9 is a leaving group such as bromo or iodo. Also, a compound of formula la or lb wherein and D represent OH may be converted to acetyloxy groups by treatment with acetic anhydride.

The compounds of this invention can be used to treat allergies and a preferred use is for treating allergic chronic obstructive lung diseases. Chronic obstructive lung disease as used herein means disease conditions in which the passage of air into and out of the lungs is obstructed or diminished such as is the case in asthma, bronchitis and the like.

The anti-allergy method of this invention is identified by tests which measure a compound's inhibition of leukotriene release in sensitized guinea pigs. Sensitized guinea pigs are killed by a blow to the head and the lungs removed and cleaned of visible connective tissue, trachea and large blood vessels. The lungs from individual animals are sliced into fragments approximately 1 mm in thickness using a Mcllwain tissue chopper and then washed with oxygenated Tyrode's buffer. Weighed aliquots (approximately 400 mg wet weight) of lung are transferred into vials containing 2 ml of fresh Tyrode's solution (containing 10 mM cysteine) and incubated in the presence or absence of test compound

for 12 min at 37°C. The tissues are then challenged with 20 vg ovalbumin/ml (final concentration) and incubated, for 15 min. To measure leukotriene release, an aliquot of supernatant fluid is extracted with 4 volumes of 100% ethanol. After removal of the precipitated protein, the clear fluid is dried under a stream of N 2 gas. The leukotriene content is measured by a radioimmunoassay using [^HJLTC^ and antiserum obtained from New England Nuclear. The cross-reactivity of the antiserum for LTD 4 is 55%. Percent inhibition of lekotriene release is calculated by comparing for each lung the release in the presence of the test compound to that in the absence of test compound. Representative compounds of the invention at a relative dose of 50 M of tissue are found to inhibit leukotriene release in the test procedure as indicated below in Table 1:

Table 1 - Inhibition of SRS-A Itelease from Antigen-Challenged, Sensitized Guinea Pig Lung

equals Dose %

R 3 R 4 JL (3 JP ^ double bond tm Inhibition ω =o 0CH 3 OCH3 H OCH3 OCH 3 yes 50 55 a m =o OH OH H OH OH yes 50 77 ω =0 OCH3 OCH3 OH OCH3 OCH3 yes 50 24

H =0 OH OH OH OH OH yes 50 81 c =0 OCH3 OCH3 H OCH3 OCH3 no 50 62 C IO

00 m = OH OH H OH OH no 50 67

=0 QAc 1 Cftc 1 H Cftc 1 Cftc 1 no 50 48

=o Cftc 1 Cftc 1 QAC 1 Cftc 1 Cftc 1 no 50 26

=0 Cftc 1 Cftc 1 H Cftc 1 Cftc 1 yes 50 48

H,H OCH3 OCH3 H OCH3 OCH^ no 50 5

1 2 3 x AcO = acetyloxy; AcO trans to 3-(3,4-diacetyloxyphenyl) ; J AcO cis to 3-(3 f 4-diacetyloxyphenyl).

AcO = acetyloxy; 2 AcO trans to 3-(3,4-diacetyloxyρhenyl) f 3 AcO cis to 3-(3,4-diacetyloxyphenyl) ; 4 Expected to have activity at higher dose.

1 Expected to have activity at higher dose.

Table 1 (cont'd)

R 3 R 4 _P M Inhibition

The anti-allergy method of this invention is identified by tests which measure a compound's inhibition of anaphylactic bronchospams in sensitized guinea pigs having antigen-induced SRS-A mediated broncho- constriction. Allergic bronchospams was measured in actively sensitized guinea pigs by a modification of the procedure of Konzett and Rossler, Arch. Exptl. Pathol. Pharmakol., 194, pp. 71-74 (1940). Male Hartley guinea pigs were sensitized with 5 mg ovalbumin injected ip and 5 mg injected sc in 1 ml saline on day 1 and 5 mg ovalbumin injected ip on day 4. The sensitized animals were used 3-4 weeks later. To measure anaphylactic bronchospasm, sensitized guinea pigs were fasted overnight and the following morning were anesthetized with 0.9 ml/kp ip dialurethane. The trachea and jugular vein were cannulated and the animals were ventilated by a Harvard rodent respirator. A side arm to the tracheal cannula. was connected to a Harvard pressure transducer to obtain a continuous measure of intratracheal pressure. An increase in intratracheal pressure was taken as a measure of bronchoconstriction. Each guinea pig was injected iv with 1 mg/kg propranolol, 5 g/kg indomethacin and 2 mg/kg mepyramine given together in a volume of 1 mg/kg. Fifteen minutes later, the animals were challenged with antigen (0.5 per cent ovalbumin) delivered as an aerosol generated from a DeVilbiss Model 65 ultrasonic nebulizer and delivered through the tracheal cannula for 30 seconds. Bronchoconstriction was measured as the peak increase in intratracheal pressure occurring within 15 minutes after antigen challenge. Representative compounds of the invention at a dose of 50 mg/kg were found to " inhibit anaphylactic bronchospasms in such test procedure as indicated below in Table 2:

Table 2 - Inhibition of Anaphylactic Bronchospasms

equals Dose %

J £ L ^ J_ R 3 ,R 4 double bond (πpk) 1 Inhibition c CMe CMe CMe CMe H =0 yes 10 36 w OH OH OH OH H =o yes 10

C 17 -D

OH OH OH OH OH =0 yes 10 26

CMe OMe CMe CMe H O no 10 0 2

C I -I 0(CO)NMe 2 O(00)Mte 2 O(00)Mte 2 0(CO)Mte 2 H =0 yes 10 10 C m I

Cftc OAc Cftc OAc H =0 yes 10 7

X OMe OMe CMe CMe H =N-OH no 10 50 m CMe OMe αie CMe CH 3 =o yes 10 24

OMe CMe CMe CMe H =N-NH(CO)NH 2 no 10 20

CMe OMe OMe CMe H =N-OH yes 10 o 2

OMe CMe OH . CMe H =N-OH no 10 o 2

CMe OMe CM ., CMe H =N-0(CO) fc Bu no 10 20

OMe CMe OC 2 H 5 CMe H =N-OH no 3 25 by iv administration; Expected to have activity at higher dose.

x_ ' (πpk) Inhibition

0 H 10 56 By iv administration; Expected to have activity at higher dose.

Based on the above test procedure and results, the compounds are effective non-adrenergic, non- anticholinergic, antianaphylactic agents. The compounds may be administered by any conventional mode of administration for treatment of allergic reactions employing an effective amount of a compound of formula I for such mode. For example, when administered orally, appropriate doses are from about 1-100 mg/kg of body weight; when administered parenterally, e.g., intravenously, the compounds may be administered at dosages of from about 0.1-10 mg/kg body weight; when administered by inhalation (aerosol or nebulizer) the compounds may be administered at dosages of from about 0.1-20 mg per puff, one to four puffs may be taken every 4 hours .

The compounds of this invention inhibit 5- lipoxygenase activity, which inhibitory activity has been associated with anti-inflammatory activity. The compounds of the invention are thus useful for the treatment of inflammation, arthritis, bursitis, tendonitis, gout and other inflammatory conditions. The 5-lipoxygenase inhibitory activity of the compounds of the invention may be demonstrated by the procedure described below:

5-Lipoxygenase Assay

The IL-3-dependent murine mast cell clone, MC- 9, was used to test the effects of representative compounds of the invention on lipoxygenase activity. The MC-9 cell line was grown in suspension culture (0.4 to 1.2 x 10 6 cells/ml) in RPMI 1640 medium (Gibco) with 10% fetal bovine serum (Hyclone) and 2-5% conconavalin-A conditioned supernatant (Musch et . al . , (1985) Prostagandins 29, 405-4307. Cells were harvested, washed twice by centrifugation, and resuspended in a Ca -free

HEPES buffer (25mM HEPES, 125mM NaCl, 2.5mM KC1, 0.7mM MgCl 2 , 0.5mM EGTA and lOmM glucose at pH 7.4).

MC-9 cells (0.39 ml at 7.5 x 10 6 cells/ml) were preincubated with dimethylsulfoxide (DMSO) vehicle with or without test compound (1 ul) for 4 minutes then incubated for 5 minutes with [ 14C] arachidonic acid

(Amersham, 59 Ci/mole) at a 9 uM final concentration, and

A23187 (Calbiochem) at a 1 uM final concentration was added in 10 ul of water:ethanol (9:1). The reaction was stopped by addition of methanol (0.4 ml), and cellular debris was removed by centrifugation. Aliquots (250 ul) of the incubations were run on a Waters two pump HPLC system fitted with a Waters C18, 10 u 8 x 100 mm u-

Bondapak radial compression column and C18 "Guard Pak".

The column was initially eluted at 3 ml/min with water:methanol:acetic acid (67:33:0.08) containing 1 mM

EDTA adjusted to pH 6.0 with ammonium, hydroxide (Pump

A). At 4 minutes, a linear gradient to reach 100% methanol (Pump B) at 9 minutes was established. Between

13 and 14 minutes, methanol was exchanged for the initial eluting solvent and by 19 minutes the column had been reequilibrated for the next sample. The effluent was analyzed by a continuous flow radioactivity monitor

(model ROMONA-D) interfaced with a Hewlett Packard Lab

Automation System for quantitation of radioactive products. These were predominantly leukotriene C (LTC^) which eluted at 6 minutes, and 5-hydroxyeicosatetraenoic acid (5-HETE) which eluted at 11 minutes (Musch et. al. , supra) . The results with and without test compound were used to calculate percent inhibition of LTC^ and 5-HETE production for representative compounds of the invention as shown in Table 3 below:

Table 3 - 5-Lipoxyqenase Assay

1 AcO = acetyloxy; Expected to have activity at a higher dose; 3 Hc-9 cell; No measurement taken.

5-Lipoxygenase Assay with Human Neutrophils

Human polymorphonuclear leukocytes (neutrophils) were obtained from normal healthy volunteers by venipuncture and collected with heparin anticoagulant. Neutrophils were isolated by Dextran/ Ficol sedimentation as described (Billah et al., J. Biol. Chem. 260, 6899-6906 (1985)). In brief, 30 ml of blood was mixed with 5 ml of dextran (Sigma) solution and kept at 37 C for 30 min. The upper white cell-rich layer was removed and 10 ml was layered on 9 ml of Ficol-Paque solution (Pharmacia) and centrifuged at 280xg for 10 min. at 5 C. The supernatant was removed and the neutrophil pellet was resuspended in HEPES buffer containing 25mM N- 2-hydroxyethylpiperazine-N -2-ethanesulfonic acid HEPES, 125mM NaCl, 2.5mM KC1, 0.7mM MgCl 2 , 0.5mM and lOmM glucose at pH 7.4. The red cells in the suspension were lysed by hypotonic shock. The neutrophils were washed by centrifugation in HEPES buffer two times and finally resuspended at a concentration of 20X10 cells/ml in the presence of 1 mM CaCl .

Neutrophils (0.2 ml of suspension) were preincubated with dimethylsulfoxide (DMSO) vehicle with or without test compound (1 ul) for 4 minutes then incubated for 5 minutes with [ C] arachidonic acid (Amersham, 59 Ci/mole) at a 9 uM final " concentration, and the calcium ionophore A23187 (Calbiochem) at a 1 uM final concentration. These stimulants were added in 10 ul of water:ethanol (9:1). The reaction was stopped by addition of methanol (0.4 ml), and cellular debris was removed by centrifugation. Aliquots (100 ul) of the incubations were run on a Waters two pump HPLC system fitted with a DuPont Zorbax ODS, 5u, 4 x 80 cm Reliance Cartridge column and C18 "Guard Pak". The column was initially eluted at 2 l/min with 80% of the mixture water:methanol:acetic acid (46:54:0.08) containing 1 mM

EDTA adjusted to pH 6.0 with ammonium hydroxide (Pump A) and 20% methanol (Pump B). At 10 minutes, a linear gradient to reach 100% methanol (Pump B) at 27 minutes was established. Between 27 and 28 minutes, methanol was exchanged for the initial eluting solvent and by 35 minutes the column had been reequilibrated for the next sample. The effluent was analyzed by a continuous flow radioactivity monitor (model ROMONA-D) interfaced with a Hewlett Packard Lab Automation System for quantitation of radioactive products. These were predominantly leukotriene B^ (LTB^) which eluted at 7 minutes, and 5- hydroxyeicosatetraenoic acid (5-HETE) which eluted at 20 minutes. The results with and without test compound were used to calculate percent inhibition of LTB, and 5-HETE production for representative compounds of the invention as shown in Table 4 below:

Table 4 - 5-Lipoxygenase Assay With Human Neutrophils

ω l

X 0 OH Ul

0 in OCH3 OCHq H OCHq OCH, H =N-NH-C-g no 15 OCH, OCH, H OCHq OCH H . =N-NH(CO)NH 2 1 τ 50 ' no 15 2 3 0

- . OCH, OCH, CH, OCH q OCH^ H =N-OH no 15 31_ 2

OCHq OCHq H OCHq OCHq H =N-NH(CO)CH 3 no 15

OCHq OCHq H OCHq OCHq H =N-OH s 15 0 °? o 3 ye 3 9

OCHq OCHq CHO OCHq OCHq H =0 no 15 16 0

OCH q OCHq H OCHq OCHq H =N-O(C0)CH, no 15 13. . OCK OCH^ H ocai OCH, OCH, =0 J no 15 0 3 0 3

Hunan FMN; Expected to have activity at higher dose; No measurement taken.

Table 4 (cont'd)

equals Dose % Inhibition

R 3 /R 4 double bond im 5-HETE LTB

H OH OCH, =0 no 15 0 2 _3 H OH OCH, =N-0H no 15 42 __3 CH 2 -CH-CH 2 0CH 3 OCH, =0 no 15 __3 o 2 H H OCH, =N-OMe no 15 74 __3 H OCH, OCH, =N-NH 2 no 15 35 __3

0

H OCH, OCH, =N-0-C- fc C 4 H 9 no 15 0 2 _3 H OCH, OCH, H, NH(CO)CH 3 no 15 0 2 4 2 H OCH, OCH, H, NH 2 no 15 0 2 0 I C0 2 C 2 H 5 OCH- OCH, O no 15 69 89 H OCH3 OCH, H, S 0 Cl no 15 36 __3 H H OCH, O no 15 42 __3 H H OCH, =0 yes 15 79 __3 H OCH 3 H =0 no 15 23 __3 H OCH, H =0 yes 15 28 __3

Human FMN

2 Expected to have acti.vi.ty at hi.gher dose.

Table 4 (cont'd)

equals Dose % Inhibition

E_ G_ £ £ IK R 3 /R 4 double bond im 5-HETE LTB

OCH3 OCH3 OCH3 OCH3 H =0 yes 15 0 2 0 2

H OH OH OH H = no 15 23 __3

OH OH OH OH H =0 yes 15 11 __3

OCH3 OCH3 OCH3 OCH3 OCH3 =0 yes 15 7 2 I 2

OH OH OH OH H =N-OH no 15 57 __3

Dose % Inhibition

A B (μn) 5-HETE LTB

C 6 H 5 H 15 64 — 3

CH 2 -0-OCH 3 H 15 86 — 3

CH 2 -0-OCH 3 CH 2 - OCH 3 15 88 — 3

1 Human PMN

7 . . . ώ Expected to have activity at higher dose. 3

In the treatment of inflammation, the active compounds of this invention can be administered in conventional unit dosage forms such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, suppositories, mechanical delivery devices, e.g., transdermal, and the like. The compounds of this invention may be administered at doses of about 0.5 to about 50 mg/kg, preferably, from about 1 to about 20 mg/kg, of body weight per day. Preferably, the total dosages are administered 2-4 divided doses per day.

The compounds of formula la or lb are useful in the treatment of hyperproliferative skin disease, e.g., psoriasis, in mammals, e.g., humans, which may be demonstrated by their 5-lipoxygenase inhibitory activity as discussed above or by the Arachidonic Acid Mouse Ear Test as described below.

Arachidonic Acid

Mouse Ear Test,

Materials and Methods

Charles River, female, CD, (SD) BR mice, 6 weeks old, are caged 8/group and allowed to acclimate 1-3 weeks prior to use.

Arachidonic acid (AA) is dissolved in reagent grade acetone (2 mg/.Ol ml) and stored at -20°C for a maximum of 1 week prior to use. Inflammatory reactions are induced by applying 10 ml of AA to both surfaces of one ear (4 gm total) .

Test drugs are dissolved in either reagent grade acetone or aqueous ethanol (only if insoluble in acetone) at the same doses selected by Opas e_t ^ al. , Fed. Proc. 43, Abstract 2983, p. 1927 (1984) and Young et al. , J. Invest. Dermatol. 82, pp. 367-371 (1984). These doses are employed to ensure maximum responses and to overcome any- difference in topical absorption which could occur with any drug applied in an aqueous ethanol vehicle. The

test drug is applied 30 minutes prior to challenge with AA.

The severity of the inflammation is measured as a function of increased ear weight. A 6 mm punch biopsy is removed 1 hour after AA challenge and weighed to the nearest 0.1 mg. Mean ± standard error and all possible comparisons are made via Duncan's Multiple Range Statistic.

The compounds 3-(3,4-dihydroxyphenyl)-2,6,8- trihydroxy-4,4-dimethyl-l(4_H)-naphthalenone; 3-(3,4- dimethoxyphenyl)-6,8-dimethoxy-4,4-dimethyl-3,4-dihydro- 1(2 )-naphthalenone; 3-(3,4-dihydroxyphenyl)-8-hydroxy-6- methoxy-4,4-dimethy1-1(4JH)-naphthalenone; and 3-(3,4- dihydroxyphenyl)-6,8-dihydroxy-4,4-dimethyl-l(4£)- . naphthalenone and the trisodium salt of 3 (3,4-dihydroxy- phenyl) -6,8-dihydroxy-4,4-dimethyl-l(4j3) -naphthalenone provided 68%, 50%, 65%, 60% and 90% inhibition, respectively, at 1 mg/ear, in the above test procedure.

As a result of the administration of a compound of formula la or lb, a remission of the symptoms of the psoriatic patient, in most cases, can be expected. Thus, one affected by psoriasis can expect a decrease in scaling, erythema, size of the plaques, pruritus and other symptoms associated with psoriasis. The dosage of medicament and the length of time required for success¬ fully treating each individual psoriatic patient may vary, but those skilled in the art of medicine will be able to recognize these variations and adjust the course of .therapy accordingly.

When administered for the treatment of hyperproliferative skin disease, the compounds may be administered topically, orally, rectally or parenterally. When administered topically, the amount of compound administered varies widely with the amount of skin being treated, as well as with the concentration of active ingredient applied to the affected area. When

administered orally, the compounds of formula I are effective for the treatment of hyperproliferative skin disease at doses ranging from about 0.1 mg to about 100. mg, which may be administered in divided doses. When administered rectally, the compounds of formula I may be administered in doses ranging from about 0.1 mg to about 1000 mg. When administered parenterally, the compounds of formula I are effective for the treatment of hyperproliferative skin disease in doses ranging from about 0.1 mg/kg body weight to about 10 mg/kg body weight which may be administered in divided doses.

Included within the invention are preparations for topical application to the skin whereby the compounds having structural formula I are effective in the treatment and control of skin diseases characterized by rapid rates of cell proliferation and/or abnormal cell proliferation, e.g., psoriasis.

In a preferred method of treating hyperpro¬ liferative skin diseases, a pharmaceutical formulation comprising a compound of formula la or lb, (usually in concentrations in the range of from about 0.1 percent to about 10 percent, preferably from about 1 percent to about 5 percent) together with a non-toxic, pharma¬ ceutically acceptable topical carrier, is applied several times daily to the affected skin until the condition has improved. Topical applications may then be continued at less frequent intervals (e.g. once a day) to control mitosis in order to prevent return of severe disease conditions.

For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and supposito ies. A solid carrier can be one or more

substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders or tablet disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active compound. In the tablet the active compound is mixed with carrier having the necessary binding properties in suitable proportions, and compacted in the shape and size desired. The powders and tablets preferably contain from 5 to about 70 percent of the active ingredient. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethyl-cellulose, a low melting wax, cocoa butter and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component (with or without other carriers) is surrounded by carrier, which is thus in association with it. Similarly, cachets are included. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.

For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.

Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. Liquid preparations can also be formulated in solution in polyethylene glycol and/or propylene glycol, which may contain water. Aqueous

solutions suitable for oral use can be prepared by adding the active component in water and adding suitable colorants, flavors, stabilizing, sweetening, solubilizing and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, i.e., natural or synthetic gums, resins, methylcellulose, sodium carboxy ethylcellulose and other well-known suspending agents.

Formulations for topical application, e.g., for use in treating hyperproliferative skin diseases, may include the above liquid forms, creams, aerosols, sprays, dusts, powders, lotions and ointments which are prepared by combining an active ingredient according to this inventions with conventional pharmaceutical diluents and carriers commonly used in topical dry, liquid, cream and aerosol formulations. Ointment and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Such bases may, thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as peanut oil or castor oil. Thickening agents which may be used according to the nature -of-the base include soft paraffin, aluminum stearate, cetostearyl alcohol, propylene glycol, polyethylene glycols, woolfat, hydrogenated lanolin, beeswax, etc.

Lotions may be formulations with an aqueous or oily base and will, in general, also include-one or more of the following, namely, stabilizing agents, emulsifying agents, dispersing agents, suspending agents, thickening agents, coloring agents, perfumes and the like.

Powders may be formed with the aid of any suitable powder base, e.g., talc, lactose, starch, etc. Drops may be formulated with an aqueous base or non- aqueous base also comprising one or more dispersing agents, suspending agents, solubilizing agents, etc.

The topical pharmaceutical compositions according to the invention may also include one or more preservatives or bacteriostatic agents, e.g., methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chlorides, etc.

The topical pharmaceutical compositions according to the invention may also contain other active ingredients such as antimicrobial agents, particularly antibiotics, anesthetics, analgesics and antipruritic agents.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions. These particular solid form preparations are most conveniently provided in unit dose form and as such are used to provide a single liquid dosage unit. Alternatively, sufficient solid may be provided so that after conversion to liquid form, multiple individual liquid doses may be obtained by measuring predetermined volumes of the liquid form preparation as with a syringe, teaspoon or other volumetric container. When multiple liquid doses are so prepared, it is preferred to maintain the unused portion of said liquid doses at low temperature (i.e., under refrigeration) in order to retard possible decompo¬ sition. The solid form preparations intended to be converted to liquid form may contain, in addition to the active material, flavorants, colorants, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like. The solvent utilized for preparing the liquid form preparation may be water, isotonic water, ethanol, glycerine, propylene glycol and the like as well as mixtures thereof. Naturally, the solvent utilized will be

chosen with regard to the route of administration, for example, liquid preparations containing large amounts of ethanol are not suitable for parenteral use.

Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, for example, packeted tablets, capsules and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet or tablet itself or it can be the appropriate number of any of these in packaged form.

The dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated and the particular compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.

The following examples are intended to illustrate, but not to limit, the present invention.

EXAMPLE 1

1A

A. To a flask equipped with a rubber septum, a condenser with N 2 inlet and a dropping funnel was introduced 109 ml of 3.0 N methyl magnesium bromide by syringe. A solution of 30 g of methyl 3,5- dimethoxybenzoate in 80 ml of anhydrous ether was added to the stirred Grignard solution through the dropping funnel over 40 minutes under N 2 at room temperature. During the addition the reaction mixture started to reflux gently. After the addition the resulting mixture was stirred for another hour. It was then cooled to -10°C and quenched slowly by adding saturated aqueous NH4CI solution. The organic layer was separated, the aqueous layer was extracted with ethyl ether and the combined organic layers were washed with brine, dried over anhydrous MgSO^ and concentrated to give 30.50 g of oil which crystallized on standing. The product was purified by column chromatography on Si0 2 (eluting solvents 2:1 CH 2 Cl 2 /hexane, then CH 2 C1 2 , and then gradient up to 15% ether in CH2CI2) to give pure product 1A above, 28.8 g (96% yield), m.p. 52.5-54°C.

IB

B. Into a flask equipped with a nitrogen inlet, a rubber septum, and a drying tube was introduced a solution of 30 g of the product A above in 150 ml of anhydrous CH 2 C1 2 and 19.6 g of anhydrous MgS0 4 was added. The stirred mixture was cooled in an ice water bath, then dry HBr gas was bubbled in for 55 minutes at 0°C (until HBr was escaping through the drying tube) . The reaction mixture was filtered and the filtrate was concentrated in vacuum to give an oil which solidified at -78°C- to give the compound of formula IB above. The product IB was thermally unstable and moisture sensitive and was maintained under nitrogen and at low temperature.

3+Li(dispersion)

C. To a flask equipped with a nitrogen inlet, an addition funnel, and a rubber septum were added 1.22 g of

Li dispersion and 5 ml of anhydrous hexane. The mixture was stirred for a few minutes and then was allowed to stand until all the Li floated on the top of the solution. The bottom clear hexane was removed by pipette, then 5 ml of dry tetrahydrofuran (THF) was added. The mixture was then cooled to -20°C, a solution of 3.42 g of product IB above and 1.83 g of 3,4- dimethoxy-benzaldehyde in- 20 ml of dry THF were added dropwise from an addition funnel over 30 minutes. The resulting reaction mixture was stirred for another 20 minutes then cooled to -78°C, and quenched slowly by addition of 30 ml of saturated aqueous NH^Cl solution. The reaction mixture was allowed to warm up to room temperature with stirring until it gave a clear yellow solution. Two layers were separated. The bottom aqueous layer was extracted with ethyl ether. The combined organic layers were washed with brine, dried over anhydrous Na 2 S0 4 and concentrated to give a crude product which was separated by preparative TLC (5% ether in CH 2 C1 2 ) to give 2.3 g of the desired product of formula IC above as an oil, which was used as such in step D below.

.

D. To a solution of 49 mg of product IC above in 0.5 ml of anhydrous dimethylformamide (DMF) cooled at 0°C were added 4 equivalents (213 g) of pyridinium dichromate

(PDC) under N 2 . The mixture was then stirred at 0°C for 6 hours, 500 ml of water were added, and the resulting

mixutre was extracted with ethyl ether (3 x 5 ml) . The ether extracts were concentrated and the residue was purified by preparative TLC (eluting solvent: CH 2 C1 2 ) to give 37 mg of the desired compound of formula ID above, m.p. 99-100°C.

C 2 H_MgBr + HC3C-0C.H ^ MgBrCΞC-OC H s

IE

E. ' To 445 ml of anhydrous THF was added 103.7 ml of 2.8 N ethyl ether solution of ethylmagnesium bromide (by syringe) under N 2 . To the stirred solution was then added 47 ml of ethyl ethyne ether solution dropwise over 1/2 hour. The resulting solution was stirred for another hour at room temperature, then a solution of 55.50.g of product ID above in 160 ml of anhydrous THF -was added over 30 minutes with warming to dissolve product ID. After the addition the resulting reaction mixture was stirred at room temperature for 10 hours. The reaction mixture was poured into 1000 ml of ice-water, the mixture was extracted with ethyl ether, the dark solution was filtered through Celite to give a clear two phase filtrate. The aqueous layer was extracted with ethyl ether. The combined ether layers were washed with brine, dried over anhydrous MgS0 4 in the presence of aHC>3 and concentrated. The residue was passed though a short column of Si 0 2 (using CH 2 ci 2 / e ther 2:1). After . concentration, the mixture gave 66.82 g of crude product

1E above which was used directly for next step (F below) without further purification.

IF

F. Anhydrous methylene chloride (1.3 1) was introduced under N 2 to a flask equipped with mechanical stirrer. An anhydrous CH 2 C1 2 solution (200 ml) of crude product IE above (66.82g) (previously azeotropically dried over anhydrous toluene) was added. Anhydrous MgS0 4 (29.14 g) was then added and the stirred mixture was cooled to -78°C. A solution of 49.7 mL of trifluoroacetic acid in 200 ml of anhydrous methylene chloride was added from a dropping funnel over 10 minutes. After an additional 15 minutes of-stirring at -78°C, the cooling .bath was removed, and the mixture was quenched with a 1/3 of a solution of 178.5 g of anhydrous K 2 Cθ3 in 1.95 L of distilled water. After 30 seconds of stirring, another 1/3 of the K 2 C0 3 solution was added and stirred for 30 seconds, and then the last 1/3 of the K 2 C0 3 solution was added. The mixture was stirred at room temperature until the internal temperature raised to about 0°C. The two layers were separated and the aqueous layer was extracted with 500 ml of ethyl acetate. The combined ethyl acetate extract and CH 2 C1 2 layer were dried over anhydrous MgSθ4/ filtered and concentrated._

The crude product IF was purified by flash chromatography on Si0 2 . The column was first eluted with CH 2 C1 2 until the non-polar side products were collected, then with a gradient of increasing ether content up to 30% ether in CH 2 C1 2 . This gave 41.0 g (59% yield) of desired product IF, m.p. 171-172°C.

EXAMPLE 2

sl

2A

A. In a two necked round bottom flask provided with reflux condenser and addition funnel, a CH3OH (15 ml) solution of 3,4-dimethoxy benzaldehyde (1.66 g) was added dropwise ^t room temperature over a period of two hours to solution of NaCN (0.588 g) and diethylamine hydrochloride (1.315 g) in 5 ml of water. After the addition, the solution was heated at 40°C for twenty hours, then cooled to room temperature. Water "(1.5 liters) was added and the resulting mixture was extracted several times with EtOAc. The combined extracts were washed with water and dried (Na 2 S0 ) . Evaporation of the solvent under reduced pressure gave 2.18 g (88%) of the product of formula 2A.

2G>

B. 3,5-dimethoxybenzyl alcohol (16.8 g; 0.1 mole) and triphenylphosphine (28 g; 0.12 moles) were refluxed in 100 ml of dry CC1 4 under 2 . After three hours, more C 6 H 5^ P (3.0 g) was added, and the mixture was refluxed overnight. After cooling to room temperature, the mixture was purified by flash chromatography (Si0 2 ) (10% EtOAc/Hexanes) yielding 17.6 g (94%) of product of formula 2B above.

OCH,

2C

C. The apparatus consisted of a dry three necked round bottom flask provided with two dry addition funnels. NaH (2.50 g) (60% oil dispersion) was washed three times under N 2 with Hexanes in the three necked flask. The NaH was then suspended in 20 ml of dry DMF. One of the addition funnels was charged with " 3,5- dimethoxy benzyl chloride of formula 2B (7.7 g; 41 mmoles ) dissolved in 30 ml of dry DMF.

The other addition funnel was charged with α- cyano-N,N-diethyl-3,5-dimethoxy-benzylamine of formula 2A (9.5 g; 38.3 mmoles) dissolved in 40 ml of dry DMF. The latter was added dropwise at room temperature to the suspension of NaH over a period of one hour. After the addition, the mixture was stirred for 3 1/2 hours, then the solution of 3,5-dimethoxybenzylchloride was added dropwise. After the solution, the mixture was stirred under N 2 overnight. The reaction was quenched by careful addition of 25 ml of CH,OH. The solvents were removwd using high vacuum at a bath temperature of 65°C. The

resulting paste was kept at that temperature for six hours, then cooled to room temperature. This paste was triturated with 6N aqueous HCl (200 ml) , then the mixture was heated at a bath temperature of 125°C for 3 1/2 hours.

The mixture was cooled to room temperature, diluted with water (200 ml) , and extracted with CH 2 C1 2 . The combined extracts were washed with water and dried ( a 2 Sθ ) . The reaction mixture was purified by flash chromatography (Si0 2 ) (15% EtOAc/Hexanes) yielding 9.30 g (76%) of product of formula 2C.

23

D. 3.2 g (10 mmoles) of the compound of formula 2C above dissolved in dry THF (45 ml) were added dropwise under N 2 to a stirred precooled (dry ice-acetone bath) 1 M THF solution of lithium bis (trimethylsilyl)amide (13 ml) over a period of one hour in a dry apparatus.

After the addition, the resulting yellow solution was stirred under N 2 for two hours at -78°C, then 0.93 ml (15 mmoles) of iodomethane was added in one portion. The solution was then let warm up and stirred at room temperature for 20 hours. The solution was cooled at -78°C and 17 ml (17 mmoles) of 1 M THF solution of lithium bis (trimethylsilyl)amide were added dropwise over a period of five minutes. After the addition, the solution ^ was stirred for three hours at 0°-5°C (ice bath). 2.5 ml of CH3I were then added in one portion. The solution was then warmed up and stirred at room

temperature overnight. The solution was then diluted with ethyl acetate (total volume = 300 ml) , washed with IN aqueous HCl, then with brine, then with water, and dried over anhydrous Na 2 S0 . The crude reaction mixture was filtered through Si0 2 (CH 2 C1 2 ) yielding 3.22 g of the title compound of formula 2 (92%) .

E. By following the same procedures of step E and step F in the EXAMPLE 1, a compound of formula 2D above was first converted to a compound of formula " 2E, and then consequently converted to a compound of formula 2F above. By following the same procedures from A to E of EXAMPLE 2, the following compounds in Table 4 were prepared.

Table 4

Product

Starting Materials Product of Invention m.p. °C

*mass spectrometry, m/e (M+l)

EXAMPLE 3

3A

150 g of product IF of Example 1 above was divided into two portions of 75 g. Each portion was hydrogenated in the presence of 7 g of 10% Pd on carbon at room temperature in 1400 ml of benzene and initial H 2 pressure of 60 psi. After six hours, the reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated. The residue (combined each 75 g portions) was purified by flash chromatography on Si0 2 . The column was eluted first with 40% ethylacetate/ hexane. After the less polar compound was collected, the column was eluted with ethylacetate to give-13,7 g of desired product 3A (91% yield) which was recrystallized from ethylacetate, m.p. 176-177°C.

By following the above hydrogenation procedure, the following were prepared, Table 5.

Table 5

Product

Starting Materials Product of Invention m.p. (°C) or MS* (m

*MS: mass spectrometry

EXAMPLE 4

A. To a suspension of 0.111 g of lithium dispersion (prewashed with hexane) in 1 ml of dry THF was added a solution of 0.444 g of methyl 3,4- dimethoxycinnamate and 0.259 g of 2-bromo-2-(3,5- dimethoxyphenyl)propane of formula IB in 1 ml of dry THF over 15 minutes at -20°C under nitrogen. The resulting mixture was stirred vigorously for another 50 minutes. It was diluted with ethyl ether and then quenched with a saturated aqueous ammonium chloride solution. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by preparative TLC (5% ether in CH 2 C1 2 ) to give 0.240 g (60% yield) of the desired product of formula 4A above, mass spectrometry; m/e 402 (M + ).

OCH.

4B

B. A solution of 0.1386 g of the compound of formula 4A above in 1.38 ml of THF, 1.38 ml of IN LiOH and 1 ml of methanol was stirred at room temperature under 2 overnight (15 hours), then the solvent was removed under vacuum. The residue was dissolved in 2 ml of water, which was then extracted with ethyl ether. The aqueous solution was then cooled in ice-water bath and acidified with 2N HCl to pH between 2 and 3. The resulting mixture was extracted with ethyl acetate. The ethyl acetate extracts were washed with brine, dried over anhydrous MgS0 4 and concentrated to give compound 4B above as a white solid, 0.106 g (79% yield), mass spectrometry, m/e 388 (M ).

C. To a solution of 83 mg of the compound of formula 4B above in 1.6 ml of dry methylene chloride was added 21 μl of oxalyl chloride and 1.3 μl of N,N- dimethylformamide at room temperature under 2 . The resulting solution was stirred for 10 minutes, then it was cooled to 0°C and 1 equivalent (28.5 mg) of anhydrous aluminum chloride was added. The resulting mixture was stirred at 0°C for 20 minutes then it was quenched by aqueous saturated sodium bicarbonate solution. The organic solution was separated, dried over MgS0 4 and concentrated. The crude product of formula 3A above, 0.75 mg (95% yield) was recrystallized from ethyl acetate to give pure product 3A, m.p. 175-176°C.

By the same procedure, starting from 2-chloro- 2-(3,4,5-trimethoxyphenyl) propane, 3-(3,4-dimethoxy- phenyl)-3,4-dihydro-6,7-,8-trimethoxy-4,4-dimethyl-l(2H) - naphthalenone was prepared, mass spectrometry m/e 401 (M+l) .

EXAMPLE 5

5A

A. 11.0 g of 3,5-dimethoxyphenylacetic acid was dissolved in CHCI3 (55 ml) in a dry flask. 10.0 ml of oxalyl chloride was added and the solution was refluxed until the evolution of HCl was ceased. The solvent and excess oxalyl chloride was removed first using vacuum, then high vacuum.

The resulting mixture was dissolved in veratrole (25 ml) and cooled in a ice bath in a three necked Morton flask provided of mechanical stirrer and dry reflux condenser with drying tube.

8.2 gm of AICI3 were added in portions over a period of 1 1/4 hours. After the addition, the reaction mixture was stirred in ice bath for three hours. The reaction was then quenched by careful addition of ice water. The mixture was extracted with ethyl ether/ethyl acetate (1:1) . The combined extracts were washed with water and dried over Na 2 S0 4 .

The reaction mixture was purified by column chromatography (Si0 2 ) (50% Hexanes/CHC^) yielding 10.5 g

(64%) of the compound of formula 5A above, which was recrystallized from CH3OH to provide pure compound 5A, m.p. = 70-71°C.

OCH.

ID

B. 15.0 g of NaH (50% oil dispersion) were washed three times with hexanes under Argon gas in a dry three necked Morton flask provided with dry reflux condenser and dry addition funnel containing 15.0 g of the compound of formula 5A above dissolved in 60 ml of 1,2- dimethoxyethane. The reflux condenser was provided of a rubber septum with a needle connected to an end valve.

After the washings, the NaH was suspended in 85 ml of 1,2-dimethoxyethane (DME) and cooled in ice bath. The starting material was added dropwise over a period of 1 1/2 hours. After the addition, the ρaste_was stirred in ice bath until the evolution of H 2 was ceased. 30 ml of CH I in 30 ml of DME were added slowly dropwise, then the paste was stirred in ice bath for one hour, then heated at 65-70°C overnight. After cooling at room temperature, 10 ml more of the. CH3I were added and the mixture was heated again at 65-70° for 24 hours. After cooling in ice bath, the reaction mixture was quenched by careful addition of water (100 ml) . The aqueous layer was separated and extracted with ether. The combined organic solutions were washed with water and dried over a 2 Sθ « The reaction mixture was used as such for the

next step C below, purified by column chromatography (Si0 2 ) (50% Hexanes/CHC1 3 ) .

An analytical sample of product ID above was obtained by recrystallization from CH3OH, m.p. = 99-100°C.

OCH.

ID

Alternative Step B

3.2 g (10 mmoles) of the compound of formula 5A above dissolved in dry THF (45 ml) were added dropwise under 2 to a stirred precooled (dry ice-acetone bath) 1 M THF solution of lithium bis (trimethylsilyl) amide (13 ml) over a period-of one hour in a dry apparatus.

After the addition, the resulting yellow solution was stirred under N 2 for two hours at -78°C, then 0.93 ml (15 mmoles) of iodomethane was added in one portion. The solution was then let warm up and stirred at room temperature for 20 hours. The solution was cooled at -78°C and 17 ml (17 mmoles) of 1 M THF solution of lithium bis (trimethylsilyl) amide were added dropwise over a period of five minutes. After the addition, the solution was stirred for three hours at 0°-5°C (ice bath) . 2.5 ml of CH3I were then added in one portion. The solution was then warmed up and stirred at room temperature overnight. The solution was then diluted with ethyl acetate (total volume = 300 ml) , washed with IN aqueous HCl, then with brine, then with water, and dried over anhydrous Na 2 Sθ4« The crude reaction mixture was filtered through Si0 2 (CH 2 C1 2 ) yielding 3.22 g of the title compound of formula ID (92%) .

C. 8.5 ml of acetyl chloride were added in one portion to 16.3 g of the compound of formula ID above dissolved in nitrobenzene (160 ml) in a dry three necked Morton flask provided of mechanical stirrers and of a dry reflux condenser with a drying tube. The dark solution was cooled in ice bath, then 15.0 g of AICI3 were added in portions over a period of two hours. After the addition, the black solution was stirred in ice bath for an additional 1 1/4 hour, then the reaction was quenched by careful addition of water. The organic layer was separated. The aqueous layer was extracted with ethyl acetate (EtOAc) . The combined organic solutions were washed with water and dried (Na 2 S0 4 ) .

The reaction mixture was partially purified by column chromatography (Si0 2 ) (CHCI3) . Two components were isolated. The less polar component was further purified by flash chromatography (Si0 2 ) (20% EtOAc/ Hexanes), yielding 3.6 g (20%) of the compound of formula 5C above, which was recrystallized from ethyl acetate/ hexane, m.p. 128-129°C.

The more polar component, which is the compound of formula 5B above (9.5 g) (52%), m.p. 104-106°C, was used as such for the reaction in step E below.

IF .

E. A compound of formula 5B (5.0 g) above was refluxed for two days in 50 ml of THF and 25 ml of IN NaOH. After cooling to room temperature, the solution was diluted with water and the aqueous layer was separated and extracted with diethyl ether. The combined organic solutions were washed with water and dried over Na 2 S0 4 . The organic solution was purified by column chromatography (Si0 2 ) (10% ethyl acetate/CHCl 3 ) to yield 1.9 g (39%) of the product of formula IF above which was recrystallized twice from ethyl acetate/hexane, m.p. 171-172°C.

EXAMPLE 6

3A 5D

40.0 g of the compound of formula IF above were hydrogenerated at 55 psi using 9.35 g of 10% Pd/C in benzene ' (125 ml). After six hours, the reaction mixture was filtered through Celite^ and the filtrate was

purified by flash chromatography (Si0 2 ) . The column was eluted first with 40% ethyl acetate/hexane until the less polar component of the mixture was collected, then with 100% ethyl acetate until the more polar component was collected.

The more polar component was recrystallized from ethyl acetate/hexane yielding two crops (34.2 g and 3.0 g) (92%) of the compound of formula 3A, m.p. 175- 176°C. The less polar compound was recrystallized twice from ethyl acetate/hexanes to yield 0.86 g of a compound of formula 5D, m.p. 161-162°C.

EXAMPLE 7

7A 7B

A. 7.0 g of a 50% oil suspension of NaH was added in portions to precooled (ice bath) triethyl phosphonoacetate (60 ml) with stirring under N 2 in a dry apparatus.

The mixture was stirred in an ice bath until the formation of H 2 ceased. 5.0 g of the compound of formula 7A above was added in one portion and then the solution was heated at 120-125°C for 12 hours. The hot solution was then poured in ice water and extracted with CH 2 C1 2 (700 ml) . The combined extracts were washed with water and dried over Na 2 so 4 . After evaporation of the solvent, the excess reagent was distilled under high

vacuum. The resulting mixture was purified by flash chromatography (Si0 2 ) . The column was eluted first with 10% ethyl acetate/hexanes (2 gallons) , then with 15% ethyl acetate/hexanes yielding 5.0 g (82%) of product of formula 7B above which was used as such for step B below.

7C

B. The product of formula 7B above obtained from step A (5.0 g) was hydrogenated with 10% Pd/C (2.0 , g) in benzene (150 ml) at room temperature overnight at 50 psi of pressure. The catalyst was then filtered through Celite and washed with ethyl acetate. Evaporation of the filtrate gave 4.69 g (95%) of the compound of formula 7C, as an oil.

7D

C. 4.1 g of the compound of formula 7C from step B above and 50 g of polyphosphoric acid were mixed at 85- 90°C for two hours. Ice was then added to the red thick oil, then the resulting mixture was extracted with ethyl acetate. The combined extracts were washed with aqueous NaHC0 3 , then with water, and dried over Na 2 S0 4 . The reaction mixture (3.15 g) was purified by flash chromatography (Si0 ) . The column was eluted first with 15% ethyl acetate/ hexanes (2 liters) , then with ethyl

acetate. The product 2.9 g (80%) was recrystallized from ethyl acetate to provide a compound of formula 7D above, m.p. 134-135°C.

EXAMPLE 8

IB 8A

A. To a suspension of 92.5 mg of lithium dispersion (prewashed with hexane) in 1 ml of dry THF was added a solution of 0.259 g of the compound of formula IB above and 64.5 μl of dry DMF in 1 ml of dry THF over 17 minutes at -20°C. The resulting mixture was then stirred for 1 hour more at -15°C, then it was quenched with aqueous saturated ammonium chloride solution. The resulting solution was extracted with ethyl ether. The ether extracts were washed with brine, dried over MgS0 4 and concentrated. The residue was purified by preparative thin layer chromatography (CH 2 Cl2.) to give 0.142 g (82% yield) of the product of formula 8A above as an oil.

C 2 H 5 MgBr HC3C-0C 2 H 5 -

8B

B. Ethoxyacetylene (77.4 ul) was added to a solution of 0.3 ml of ethyl magnesium bromide (3M) in 2 ml of dry THF at room temperature. The resulting solution was stirred for 1 hour 15 minutes, then 0.123 g of the compound of formula 8A above was added by syringe. After 1 hour of stirring at room temperature, the resulting mixture was quenched by ice water and extracted with ethyl acetate. The organic layer was separated, dried over MgS0 4 and concentrated. The residue was purified by preparative thin layer chromatography (5% ether in CH 2 C1 2 ) to give 0.13 g of product of formula 8B above (79% yield), which was used as such in step C below.

8C

C. To a solution of 0.105 g of the compound of formula 8B above in 3.5 ml of anhydrous methylene chloride was added 68 mg of anhydrous magnesium sulfate. The resulting mixture was then cooled to -78°C and a solution of 116 ul of trifluoroacetic acid in 0.2 ml of dry methylene chloride was added by syringe. After 20 minutes of stirring at -78°C, the cooling bath was removed and the resulting mixture quenched right away with a solution of 417 mg of potassium carbonate in 4.5 ml of water. The two layers were separated. The aqueous layer was extracted with ether, the combined ether and methylene chloride solution were dried over MgS0 4 and

concentrated. The residue was purified by preparative thin layer chromatography (10% ether in CH 2 C1 2 ) to give 79.0 mg (90% yield) of the desired product of formula 8C above, mass spectometry, m/e 232 (M + ) .

EXAMPLE 9

9A

To a mixture of 0.24 ml of bromobenzene, 0.252 g of zinc bromide and 31 mg of lithium wire in 7 ml of anhydrous ether at 0°C under nitrogen was sonicated for 1 hr 55 min (temperature of ultrasonic bath raised from 0°C to 33°C) . The black mixture was cooled to 0°C, a solution of 0.13 g of compound 8C and 3.4 mg of Ni (acac) 2 in 3 ml of dry ether was added by cannula over 5 min. The reaction mixture was stirred for 20 min. at 0°C and 25 min at room temperature then it was quenched by aqueous amonium chloride solution. The resulting mixture was extracted with ethyl actate, the combined organic extracts were washed with brine, dried over MgSO^ and concentrated. The residue was purified by preparative TLC on silica gel (10% ether in CH 2 C1 2 ) to give 0.16 g (52% yield) of the desired product of formula 9A, mass spectrometry, m/e 310 (M + ) .

EXAMPLE 10

3A 10A

The compound of formula 3A above (0.8) g was suspended and stirred for ten minutes in 70 ml of absolute C 2 HrOH and 4 ml of concentrated HCl. 4.0 ml σf isoamylnitrate were added dropwise at room temperature over a period of ten minutes. The resulting solution was stirred at room temperature for 24 hours, then poured in water (400 ml) . The aqueous mixture was extracted with CHCI3 (total volume = 600 ml) . The combined. extracts were washed with aqueous NaHCθ3, then with water and dried over anhydrous Na 2 S0 for 24 hours. After filtration and evaporation of the solvent, the . ' reaction mixture was purified by column chromatography (Merck silica gel, grade 60) (25% Hexanes/CHC1 3 ) . The almost pure material (0.59 g) was further purified by preparative TLC using 40% ethyl ether/CHCl as eluent and ethyl acetate :CH 3 OH:CHCl3 (1:1:1) for the extraction. The pure material (0.36 g) (43%) was recrystallized from CHCl 3 /hexanes to provide the compound of formula 10A above, m.p. = 161-162°C.

EXAMPLE 11

Uft

The compound of formula 3A above (0.3 g, 0.81 mmoles) was dissolved in 10 ml of dry benzene in a dry flask provided with a dry reflux condenser. 0.72 g (1.62 mmoles) of PbfOAc)^ were added in three portions, each at three hour intervals. After each addition, the mixture was refluxed under N 2 . After the last addition, the mixture was refluxed overnight, then 0.3 g more of Pb (OAc) 4 were added and refluxed for another four hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with water, then with saturated aqueous NaHG^, then again with water and dried over Na 2 S0 . The reaction mixture (0.35 g) was purified by flash chromatography (Si0 2 ) (55% ethyl acetate/hexanes) to yield 0.13 g (37%) of the compound of formula 11A above which was recrystallized from ethyl acetate, m.p. 202-204°C.

EXAMPLE 12

I?ft

To a solution of 1.27 ml of 1.6M methyllithium cooled in ice water bath was added a solution of 0.5 g of the compound of formula 3A above in 4 ml of anhydrous 1,4-dioxane over 10 minutes. The resulting light yellow solution was stirred for 1.5 hours at 0°C, then it was quenched with water. The resulting solution was extracted with ethyl acetate, dried over sodium sulfate and concentrated. The residue was purified by preparative TLC (silica gel was deactivated with triethylamine; eluting solvents 1:1 CH 2 C1 2 / hexane) to give 0.150 g of the desired product of formula 12A (20% yield) , mass spectrometry, m/e 386 (M + ) .

EXAMPLE 13

13Q

To a solution of 2.1 g of a compound of formula 3A above in 20 ml of absolute C 2 H 5 OH and 30 ml of dry THF was added 0.4 g of Pd/C (10% Pd) . The mixture was hydrogenated at room temperature with vigorous stirring for 20 hours, then it was filtered through a pad of Celite . The filtrate was concentrated to give 2.1 g of product, which was purified by flash chromatography (solvent: 2:1 CH 2 Cl 2 /hexane, 4:1 CH 2 Cl 2 /hexane) to give 1.825 g of desired product of formula 13A above (90% yield) ,- mass spectrometry, m/e 356 (M + ) .

EXAMPLE 14

(4 ft

To a stirred solution of 0.8 g of the compound of formula 13A above in 2 ml of dry CH 2 C1 2 was added 18 ml of IN BBr 3 solution in CH 2 C1 2 over 10 minutes at -78°C under N . " The resulting solution was stirred for another 10 minutes at -78°C, then the cooling bath was removed and the mixture was stirred at room temperature for 48 hours. The solvent was evaporated under vacuum, the residue was cooled in an ice water bath, ice cold 3N NaOH solution was added slowly until the pH of the solution - was 9-10. The resulting homogeneous solution was acidified to pH 4 by addition of cold IN HCl. Ethyl acetate was added. The reaction mixture was shaken and separated. The organic solution was collected, washed with brine, dried over MgS0 and concentrated. The crude product was purified by flash chromatography on Si0 2 (2:1 CH 2 Cl 2 /ethyl acetate) and gave 0.570 g of pure product (85% yield) , which was recrystallized from acetone giving the compound of formula 14A above, mass spectσmetry, m/e 300 (M + ) .

By substituting as a starting material the compounds listed in the first column of Table 3 below for compound 13A above and employing basically the same procedure as in Example 14, the compounds listed in the second column of Table 6 were prepared.

TABLE 6

Product m.p.

Starting Material Product of Invention °C

ed)

a) Using BCI3 instead of BBr3 b) Reaction time 2 hours. c) Reaction mixture purified by C 18 -Reverse Phase-HPLC [CH 3 CN:H 2 0:HCOOH (50:50:1)] as mobile phase.

TABLE 6 (cont'd)

Product m.p.

Starting Material Product of Invention °C

* MS: mass spectrometry, m/e (M+l) . a) Using BCI3 instead of BB^. b) Reaction time 2 hours. c) Reaction mixture purified by C^g-Reverse Phase-HPLC

[CH 3 CN:H 2 0:HCOOH (50:50:1)] as mobile phase.

EXAMPLE 15

The compound of formula 14B above (0.7) g was stirred at room temperature with 5 ml of pyridine and 2 ml of acetic anhydride. After two days, the solvents were vacuumed off using high vacuum. The residue was purified using flash chromatography (Si0 2 ) (40% ethyl acetate/hexanes) to yield 0.7 g (65%) of the compound of formula 15A above as a white solid which was characterized by mass spectrometry, m/e 482 (M + ) .

Basically the same procedure was used to prepare 3-(3,4-diacetyloxyphenyl) -6,8-diacetyloxy-4,4- dimethyl-1 (4_H) -naphthalenone.

EXAMPLE 16

16A 16B

A mixture of Pb(OAc) (0.7 g) and the compound of formula 15A above (0.6 g) was refluxed under N 2 in dry benzene (6 ml) in a dry apparatus. After 16 hours, the mixture was cooled to room temperature, 0.7 g of Pb(OAc) 4 was added and the mixture refluxed again for 24 hours. Three more additions of Pb(OAc) at 12 hour intervals were made. After cooling to room temperature, the mixture was diluted with ethyl acetate (350 ml), washed with water and dried over a 2 S0 4 - Purification of the mixture by flash chromatography (Si0 2 , 35% ethyl acetate/hexanes) yielded 0.26 g (38%) of a racemic mixture of the compound of formula 16A above (which is the 2α, 33 compound), m.p. 202-204°C, and 60 mg (9%) of a racemic mixture of a compound of formula 16B above (which is the 2β, 3--£ compound), m.p. 92-95°C.

= EXAMPLE 17

Dimethylcarbamoyl chloride (0.81 ml, 8.8 mmoles) was added to a dry pyridine (1.1 ml, 14 mmoles) solution of the compound of formula 14C above (0.5 g, 1.6 mmoles) in a dry apparatus. The thick solution was heated at 40-42°C under N 2 overnight. After cooling to room temperature the thick mixture was transferred into a beaker containing ice and 18 ml in IN aqueous HCl. The precipitate formed was extracted in ethyl acetate (180

l) . The combined extracts were washed with water and dried. Purification by flash chromatography (Si0 2 ) (ethyl acetate) yielded 0.48 g (57%) of the compound of formula 17A, mass spectrometry, m/e 526 (M+l) .

EXAMPLE 18

2

18A

l,8-Diazatricyclo[5,4,0]undec-7-ene (0.15 ml) were added at room temperature to the compound.of formula 17A above (0.322 g, 0.61 mmoles) and 0.085 ml (0.92 mmoles) of dimethylcarbamoyl chloride. After stirring overnight under N 2 at room temperature, the thick paste was treated with cold IN aqueous HCl. The precipitate formed was extracted into ethyl acetate. The ethyl acetate solution was washed with water and dried over Na 2 S0 . Purification by flash chromatography (Si0 2 ) (ethyl acetate) yielded 0.251 g (68%) of the compound of formula 18A above, mass spectrophotometry, m/e 597 (M+l) .

EXAMPLE 19

3A 19A

A mixture of 2.0 g of the compound of formula 3A above, 0.564 g of hydroxylamine hydrochloride, and 0.732 g of anhydrous sodium acetate in 20 ml of absolute ethanol or n-butanol was refluxed for about 24 hours.. After cooling, the reaction mixture was filtered, the precipitate was washed with ethyl ether and dried under * vacuum to give 2 g (98%) of the compound of formula 19A above, mass spectrometry, m/e 386 (M+l) .

The following compounds in Table 7 are prepared by employing basically the same procedure as described- in Example 19, by either substituting of NH 2 OH to NH 2 R, or substituting of a starting material for compound 3A above.

Table 7

Starting Material NH R

3A NH 2 NH 2 'H 2 0

3A NH 2 -NH WC 426

Table 7 (cont'd)

EXAMPLE 20

To a mixture of 0.193 g of a compound of formula 19A above in 0.5 ml of anhydrous pyridine was added 71 ul of acetic anhydride at 0°C. After few minutes of stirring, the cooling bath was removed, and the reaction mixture was stirred at room temperature for overnight (18 h). The mixture was diluted with methylene chloride and then extracted with cold IN HCl solution. The organic layer was separated and then washed with water, brine, dried over anhydrous MgS0 4 , and concentrated to give 0.156 g (73% yield) of product of formula 20A above, mass spectrometry, m/e 428 (M+l).

By substitution of acetic anhydride with trimethyl acetyl chloride, a compound of formula 20B above can be prepared according to the same procedure for the conversion of a compound 19A to 20A.

EXAMPLE 21

rX \ r\

One half of 1.5 ml of n-BuLi (2.5 M solution in Hexanes) was added slowly dropwise under N 2 to a precooled (-78°C) suspension of a compound of formula 19A above (0.5 g; 1.3 mmoles) in 3.0 ml of dry THF. After the addition, the dry ice-acetone bath was replaced with an ice bath and the mixture was let warm up to 0°C. The second half of the n-Buli was then added also dropwise. After the addition, the solution was cooled back to -78°C and 0.15 ml of allyl bromide was added dropwise. The cooling bath was removed and the solution was let warm up and stirred at room temperature for one hour. After adding water, the solution was diluted with CH 2 C1 2 , washed with water, and dried (Na 2 SO^) . The reaction mixture was purified by flash chromatography (Si0 2 ) (30% EtOAc/Hexanes) yielding 370 mg (67%) of product of formula 21A, mass spectrometry, m/e 426 (M+l) .

EXAMPLE 22

A compound of formula 3A (3.7 g) dissolved ln dry THF:CH 2 C1 2 (1:1) (60 ml) was added slowly dropwise under N 2 to a precooled (-78°C) 1.0 Molar THF solution of lithium bis (trimethylsilyl) amide (15 ml) . After the addition, which lasted 90 minutes, the solution was stirred at -78°C for two hours, then 2.0 ml of CH3I were added in one portion. The solution was let warm up and stirred at room temperature overnight. After cooling in ice bath, the reaction was quenched by careful addition of water. The organic layer was separated. The aqueous layer was extracted several times with CH 2 C1 2 . The

σombined CH 2 C1 2 solutions were washed with water and dried (Na 2 S0 4 ) . The reaction mixture was purified by flash chromatography (Si0 2 ) (30% EtOAc/Hexanes) .

The product was recrystallized from EtOAc/Hexanes yielding 2.0 g of compound (52%) of formula 22A.

22B 22C 22D

Using the same procedure, by reaction of the same starting material of formula 3A with ethyl formate, ethyl chloroformate and allyl bromide gave a product of formula 22B (50% yield), 22C (18% yield) and 22D (58%) individually. Mass. spectrometry of 22B, m/e 398 (M + ) ; 22C, m/e 442 (M + ) ; 22C m/e 410 (M + ) .

EXAMPLE 23

23A

A compound of formula 22A (2.0 g; 5.2 mmole) was dissolved at 45°C in dry benzene (400 ml) in a dry apparatus. The solution was then cooled to room temperature and 2,3-dichloro-5,6-dicyario-l,4-benzoquinone (DDQ) (1.6 g) was added in one portion. The mixture was then heated at 85-90°C under 2 for 24 hours. After cooling to room temperature, the solid was filtered through "Celite". The "Celite" was washed with CH 2 Cl2 « The reaction mixture was partially purified by flash

chromatography (35% EtOAc/Hexanes) (Si0 2 ) . Another purification as before (Si0 2 ) (50% EtOAc/Hexanes) gave the product of formula 23A which was recrystallized from EtOAc/Hexanes (1.8 g) (94%), m.p. 183-186°C.

EXAMPLE 24

portion to a suspension of a compound of formula 3A (1.4 g; 3.8 mmoles) in 50 ml of absolute EtOH and 5 ml of dry THF. The mixture was then heated under N 2 for 5 hours at 60°C. The solution was then poured in ice water. The resulting white solid was extracted with EtOAc. The combined extracts were washed with water and dried (Na 2 S0 4 ) . The reaction mixture was purified by flash chromatography (Si0 ) (50% EtOAc/Hexanes) . The product of formula 5D was recrystallized from EtOAc/Hexanes (1.12 g) (80%) .

24A

B. N-(4-chlorophenylthio)succinimide (0.582 g) was added under N 2 £ n one portion to a solution of n-Bu 3 p (0.6 ml) in dry benzene (4.0 ml). After stirring for ten

minutes at room temperature, a compound of formula 5D (0.4 g) was added. The solution was stirred at room temperature for two days, then water was added. The organic layer was diluted with EtOAc, washed with water and dried (Na 2 S0 4 ) . The reaction mixture is purified twice by flash chromatography (Si0 2 ) (15% EtOAc/Hexanes) yielding 0.148 g (28%) of product of formula 24A, mass spectrometry, m/e 499 (M + ) .

EXAMPLE 25

A mixture of p-toluene sulfonic acid (5 mg) , ethylene glycol (0.26 ml), a compound of formula 3A (0.374 g; 1.0 mmole), and trimethyl ortoformate (0.53 ml) in dry benzene (1.3 ml) was heated at a bath temperature of 35-40°C in a dry apparatus consisting of a two necked flask with a Liebig condenser. A 14 m Hg vacuum was applied while heating. After 90 minutes, the bath temperature was raised to 80-85°C.

After two hours at that temperature, the resulting solid was cooled to room temperature and dissolved in EtOAc. The solution was washed first with saturated aqueous NaHCθ3, then with water and dried (Na S0 4 ) . The reaction mixture was purified by flash chromatography (Si0 2 ) (5%, 30%, 50% gradient CH 2 C1 2 /Hexanes) .

The product was recrystallized from EtOAc/Hexanes yielding 0.27 g (65%) of compound of formula 25A, m.p. 173-174°C.

EXAMPLE 26

26A To a solution of a compound of formula 3A (0.2 g) in 2.2 ml of dry methylene chloride was added 68 yl of

1,2-ethanedithiol and 30 yl of borontrifluoride etherate. The yellow solution was stirred at room temperature for overnight, a solution of 34 yl of 1,2- ethanedithol and 15 yl of borontrifluoride etherate was added. After 2 h of stirring, the reaction mixture -was quenched by 2 ml of 5% NaOH solution. The organic layer was separated, washed with water, brine, dried over gSO^ and concentrated. The residue was crystallized from

CH 2 Cl 2 /hexane to give a product of formula 26A (0.2 g;

83%), mass spectrometry, m/e 466 (M ).

EXAMPLE 27

A. To a solution of 2.14 ml of N-isopropyl-N- cycylhexylamine in 18 ml of anhydrous THF was added 5.16 ml of 2.5N of n-butyllithium at -78°C. The resulting solution was stirred at -25°C for 1/2 h, then recooled to -78°C. A solution of 0.702 g of a compound of formula 27 (prepared by. hydrogenation of a compound of formula 8C according to the procedure in Example 13) in 12 ml of

anhydrous THF was added dropwisely. The reaction mixture was stirred at -78°C for 1 h, then the reaction temperature was allowed to warm to -25°C. A solution of 0.853 ml of bromobenzene in 5 ml of anhydrous THF was added over 5 min, the reaction mixture was stirred at ambient temperature (-25° ~ r.t.) for 24 h, then it was quenched by aqueous saturated NH^Cl solution. After extraction with ethyl acetate, the organic extracts were washed with cold 10% HCl solution, then washed with brine, dried over anhydrous MgS0 4 , and concentrated. The residue was purified by preparative TLC (CH 2 C1 2 ) to give 0.58 g (62%) of a product of formula 27A, mass spectrometry m/e 311 (M+l).

π e>

B. To a solution of 0.38 g of a compound of formula 27A in 9 ml of 2:1 dimethoxyethane/ diisopropylamine was added 0.24g of sodium, a ide at room temperature under 2 . The mixture was stirred for 20 min at 25°C and 2 hr at 80°C. After cooling to 0°C, the reaction mixture was quenched by ice water, acidified by ice cold 2N HCl, extracted with methylene chloride. The organic layer was washed with saturated NaHC0 3 , dried over anhydrous MgS0 4 and concentrated. The residue was recrystallized from CH 2 Cl hexane to give 0.32 g (85%) of product of formula 27B, mass spectrometry m/e 310 (M ) .

EXAMPLE 28

28A

A. To a mixture of 0.199 g of sodium borohydride in 5 ml of anhydrous DMF was added under nitrogen 2.63 ml of IM TiCl 4 solution at 0°C. After 10 min of stirring, a solution of 0.5 g of methoxime of formula 19G in 5 ml of anhydrous DME was added dropwisely, the resulting mixture was stirred for 25 min at 0°C and for 3 h at room temperature. Ice water was added to quench the reaction, ethyl ether with extraction was used to remove the nonpolar material. The acidic aqueous solution was cooled and basified by IN NaOH solution at 0°C to pH 10, then it was extracted with EtOAC/CH 2 Cl 2 . The combined organic extracts were dried over anhydrous K 2 Cθ , evaporated. The residue was purified by preparative TLC (5% ether in CH 2 C1 2 ; Si0 2 deactivated with triethylamine) to give 0.335 g (72%) of a product of formula 28A, mass spectrometry m/e 372 (M+l) .

28B

B. To a solution of 0.235 g of compound 28A in 0.7 ml of dry pyridine was added 71 yl of acetic anhydride at 0°C. After 1/2 hour of stirring, the cooling bath was removed, the reaction mixture was stirred for 4 h at room temperature, then 100 yl of triethylamine were added, and continued stirring for another 2 hours. The mixture was diluted with CH 2 C1 2 and extracted three times with cold IN HCl solution. The organic layer was washed with water, brine, dried and concentrated. The residue was purified by flash chromatography on Si0 2 (CH C1 2 as eluting solvent; the polarity was increased gradually to 10% ether in CH 2 C1 2 ) to give 0.15 g (57%) of product of formula 28B, which was recrystallized from CH 2 C1 2 / • hexane. Mass spectrometry m/e 413 (M ).

EXAMPLE 29

3A 29A

A compound of formula 3A (1.0 g; 2.7 mmoles) was stirred at room temperature in 8.0 ml of glacial acetic acid and 1.5 ml (13.0 mmoles) of 30% aqueous H 2 0 2 . After twenty hours, the solution was poured in water and the solid formed was extracted with CH 2 ci 2 . The combined extracts were washed with water and dried (Na 2 S0 4 ). The reaction mixture was purified by flash chromatography. (20% EtOAc/Hexanes). The product 29A

was recrystallized from EtoAc/Hexanes. Yield: 0.64 g (61%) (m.p. = 168-169°C).

Using the same procedure 0.66 g of 3-(3,4- dimethoxyphenyl)-6,8-dimethoxy-2,4,4-trimethyl-dihydro- 1(4H_)-naphthalenone gave 0.28 g (41%) of 4-(3,4-dimethoxy phenyl)-4,5-dihydro-7,9-dimethoxy-3,5,5-trimethy1-1- benzoxepin-2 (3H)-one (m.p. = 163-165°C) (EtOAc/Hexanes).

EXAMPLE 30

30A

A dry THF (30 ml), solution of compound of formula 29A (1.5 g; 3.9 mmoles) was added under to a precooled (ice bath) slurry of LiAlH 4 (222 mg; 5.8 mmoles) in dry THF (3.0 ml). After the addition, the mixture was stirred in ice bath for two hours, -then the reaction was quenched by careful addition of saturated aqueous NH 4 C1. The organic layer was filtered. The slurry was washed several times with EtOAc. The combined washings were washed with water and dried (Na 2 S0 ) . The reaction mixture was purified by flash chromatography yielding 1.35 g (89%) of product of formula

303

B. Diethyl azodicarboxylate (0.36 ml; 2.29 mmoles) was added in small volumes over a period of 45 minutes under 2 to a dry THF (10 ml) solution of (CgH 5 ) 3 P (0.58 g; 2.21 mmoles) and a compound of formula 30A (0.72 g; 1.84 mmoles) . After the addition, the solution was stirred for one hour, then the solvent was evaporated under reduced pressure. The reaction mixture was purified by flash chromatography (20% EtOAc/Hexanes) (Si0 2 ) yielding 0.57 g (83%) of product of formula 30B.

. EXAMPLE 31

31A 3IB

BF .Et 0 (6.72 ml) was added via addition funnel over 30 minutes under 2 to a precooled . (-7.8°C) dry CH 2 C1 2 (70 ml) solution of a compound of formula 3A . (13.5 g) . After the addition, the solution was stirred at -78°C for one hour, then 50 ml of a CH 2 C1 2 solution of (CH 3 ) 3 SiCHN 2 (10% /W) was added over a period of 1 1/2 hours dropwise. The solution was stirred at that temperature for 2 1/2 hours, the cooling bath was then removed, and the reaction was quenched by slow addition of water. The mixture was stirred at room temperature for 1 1/2 hour, then the aqueous layer was separated. The organic layer was diluted with CH 2 C1 2 (400 ml) , washed with water, and dried (Na 2 S0 ) . The reaction mixture was purified by flash chromatography (Si0 2 ) (20% EtOAc/Hexanes) . The less polar product on Si0 2 TLC (35%

EtOAc/Hexanes) was identified as compound of formula 31B (1.5 g) (10.7%) .

The more polar product was recrystallized from EtOAc/hexanes and was found to be compound of formula 31A (48%) (m.p. = 144-146°C) .

Using the same procedure:

(i) 3-(3,5-dimethoxyphenyl)-6i,8-dimethoxy-4,4- dimethyl-3,4-dihydro-l(2H_)-naphthalenone gave 8-(3,5- dimethoxyphenyl)-6,7,8,9-tetradydro-2,4-dimethoxy-9,9- dimethyl-5II-benzocyclohepten-5-one (44%) and 8-(3,5- dimethoxyphenyl)-5,7,8,9-tetrahydro-2,4-dimethoxy-9,9- dimethyl-6H-benzocyclohepten-6-one;

(ii) 3,4-dihydro-3-(3,4-dimethoxyphenyl)-4,4- dimethyl-8-methoxy-l(2lϊ)-naphthalenone gave 8-(3,4- . dimethoxyphenyl)-9,9-dimethyl-4-πtethoxy-6,7,8,9- tetrahydro-5j-benzp-cyclohepten-5-one (45%) and 8-(3,4- dimethoxyphenyl)-9,9-dimethyl-4-methόxy-5,7,8,9- tetrahydro-6ji-benzocyclohepten-6-one (14%) ;

(iii) a compound of formula 27 (Example 27) gave 6,7,8,9-tetrahydro-2,4-dimethoxy-9,9-dimethyl-5jI- benzocyclohepten-5-one (31C) .

EXAMPLE 32 - .-

32A

The compound of 32A was prepared from the compound of formula 31A according to the procedure described in Example 14, yield 28%. Mass spectrometry m/e 329 (M+l) .

EXAMPLE 33

33ft

A dry THF (1.8 ml) solution of the compound of formula 31A was added via syringe dropwise under N 2 to a precooled (-78°C) IM. THF solution of [ (CH3) 3 Si 2 ]NLi (2.4 ml; 2.4 mmoles) . After the addition, the solution was stirred at -78°C for three hours, then transferred via cannule into a dry THF (1.0 ml) solution of CgHgSSCgHg (250 g; 1.15 mmoles) at room temperature. After stirring for 20 hours at room temperature, two 0.2g aliquots of C HςSSC Hg were added at four hours intervals. After the second aliquot, the solution was stirred for two hours, then diluted with EtOAc, washed first with IN aqueous HCl, then with water, and dried (Na 2 S0 4 ) . the reaction mixture was purified by flash chromatography (Si0 2 ) (10% EtOAc/Hexanes) . The product of formula 33A (0.4g; 81%) was recrystallized from EtOAc/Hexanes (m.p. 194-196°C) .

EXAMPLE 34

Both compounds of formula 34A and 34B were prepared from the compound of formula 31A by using the same reagents and procedure detailed in Example 22. The trimethyl compound of formula 34A (76%) was recrystallized from EtoAc/Hexanes (m.p. = 146-147°C) . The tetramethyl product of formula 34B was obtained in 8% yield from the same reaction. Mass spectrometry; m/e 413 (M+l) .

EXAMPLE 35

35A The compound of formula 35A was obtained in 54% yield as a separable mixture of E and Z oximes, mass spectrometry m/e 400 (M +1 ) , from the compound of formula 31A using the same reagents and procedure detailed in Example 19.

EXAMPLE 36

UαOftc

36A 3tβ

A mixture of the compound of formula 31B (800 mg) , NH 2 OH HCl (360 mg) , and AcONa (600 mg) was stirred at room temperature for two hours in 3.0 ml of n-BuOH. The solvent was then removed using high vacuum. The residue was treated with water, taken in EtOAc, washed with water and dried (Na 2 S0 ) . The reaction mixture was purified by flash chromatography (Si0 2 ) (25% EtOAc/Hexanes) yielding the major oxime of formula 36B, (330 mg) (39%) (m/e = 400) (M+l) + , and the minor one. The letter was further purified by preparative TLC (Si0 2 ) (30% EtOAc/Hexanes) yielding 50 mg (6%) of oxime of formula 36A. Mass spectometry m/e 400 (M+l) .

EXAMPLE 37

31A 37A

CgHgSeCl (0.31 g; 1.6 mmoles) was- added in small portions under 2 over a period of 90 minutes to an EtOAc (9.0 ml) (predried over 3A° molecular sieves) solution of the compound of formula 31A (0.35 g; 0.91 mmoles) . When the solution became yellow, it was washed with water (3x2.5 ml), then 1.4 ml of THF and 0.22 ml of 30% H 2 0 2 were added in the order. The solution was then stirred for one hour, then diluted with EtOAc, washed with aqueous Na 2 Cθ3, then with water, and dried (Na 2 S0 4 ) . The reaction mixture was separated by flash chromatography (20% EtOAc/Hexanes) . The fraction containing the desired product of formula 37A which was further purified by preparative TLC (2 elutions with 40%

EtOAc/Hexanes) . Yield: 75 mg (21%) Mass spectrometry m/e 383 (M+l) .

EXAMPLE 38

38A

A. CeCl3 H 2° (480 mp) was dried in a two necked round bottom flask at 145° under high vacuum overnight. The solid was then cooled to room temperature and the flask was provided with rubber septa. Dry THF (4.0 ml) was added, the mixture was stirred at room temperature for two hours under N 2 , then cooled to_-78°C. Phenyllithium (1.2 ml) (2.0 Molar) was added dropwise and the mixture was stirred for 30 minutes. A THF (4.0 ml) solution of the compound of formula 31A (0.384 g; 1.0 mmoles) was added dropwise over a period of- 10- minutes. After the addition, the mixture was stirred at -78°C for four hours, then the reaction was quenched by addition of saturated aqueous NH 4 C1 at -78°C. The cooling bath was removed and the mixture let warm up to room temperature. The solid was filtered through "Celite," washed with EtOAc, and the filtrate dried over Na 2 S0 . The reaction mixture was purified by preparative TLC (Si0 2 ) (35% EtOAc/Hexanes) yielding 0.2 g (43%) of product of formula 38A. Mass spectometry m/e 445 (M- H 2 0+1) .

383 B. Dry Pyridine (1.0 ml) and P0C1 3 (0.4 ml) were added in the order to a precooled (ice bath) dry benzene

(3.0 ml) solution of the compound of formula 38A (0.11 g) . The resulting mixture was stirred in ice bath for two hours, then the reaction was quenched with water.

The mixture was extracted with CH 2 C1 2 . The combined extract were washed with water and dried (Na S0 4 ) . The reaction mixture was purified by preparative TLC (Si0 2 )

(20% EtOAc/Hexanes) yielding 86 mg (78%) of product of formula 38B. Mass spectrometry m/e 445 (M+l) .

EXAMPLE 39

A. To a mixture of 0.55g of potassium hydride in 3 mL of dry THF was added a solution of 0.992g of the compound of formula 31C in 4 mL of dry THF. The resulting mixture was vigorously stirred for 1 hr at room temperature under nitrogen. After cooling to -78°C, a solution of 0.836 mL of dry triethylamine was added, followed by 0.71 mL of trimethylsilyl chloride. After 15 min. of stirring, the cooling bath was removed .and the

reaction was quenched by ice cold 0.1N HCl solution and 12 mL of methylene chloride. The mixture was shaked, the organic layer was separated and washed with aqueous NaHCθ3 solution. After drying over anhydrous sodium sulfate, the solution was concentrated to give 1.164g of product of formula 39A (91% yield) , which was used directly in the next step.

39B

B.- To a mixture of 0.449g of palladium acetate and 0.216g of 1,4-benzoquinone in 11 mL of anhydrous acetonitrile was added at room temperature a solution of 1.164g of the compound of formula 39A in 3 ml of dry THF .for over 5 min. The resulting solution was stirred for 4.5 hours then 0.449g of palladium acetate were added. After 1.5 hours of stirring, the reaction mixture was quenched with water and then extracted with.EtOAc. The organic layer was separated, dried over MgS0 4 and concentrated. The residue was purified by flash chromatography on Si0 2 (CH 2 C1 2 ) to give 0.6g (61%) of a product of formula 39B.

3^

C. To a mixture of 0.229g of copper (I) iodide in 3 mL of dry ether at -78°C was added 1.4 mL of 1.7N phenyllithium. The resulting mixture was stirred at -30° for 1/2 h. then it was cooled to -78°C. TMSC1 (0.152 mL) was added, followed by a solution of 0.246g of the compound of formula 39B in 3 mL of 2:1 ether/THF (over 10 min.). The reaction mixture was stirred at -78°C for 20 min. and at -25-30°C for 40 minutes. Then the cooling bath was removed, the mixture was stirred for 15 min., then the reaction was quenched with saturated NH C1 solution. The mixture was stirred till the aqueous layer turned to deep blue. The organic layer was separated, the aqueous layer was extracted with EtOAc. The combined organic solution was concentrated, and the residue was dissolved in 2 mL of THF and 0.5 mL of IN HCl solution. The mixture was stirred at room temperature for 10 min., then it was neutralized with aqueous NaHCC^ solution and extracted with EtOAc. The EtOAc extracts were dried over MgS0 4 and concentrated. The residue was purified by preparative TLC (CH 2 C1 2 ) to give 0.21g (65%) of the product of formula 39C, mass spectrometry m/e 324 (M + ) .

D. To a mixture of 0.248g of copper (I) iodide in 0.191 mL of diethyl sulfide and 3 mL of dry ether was added 2-pyridyllithium (prepared by addition of 1.04 mL of 2.5N butyllithium to a solution of 0.248 mL of 2- bromopyridine in 2.5 mL of dry ether at -78°C) . After 20 min. of stirring at 0°C, a solution of 0.246g of the compound of formula 39B in 1 mL of dry THF was added

dropwisely. The reaction mixture was stirred for ^ hr. then a solution of NH OH/saturated NH Cl ' was added. The organic layer was separated, the aqueous layer was extracted with CH 2 C1 2 three times. The "combined organic solutions were washed with brine, dried over anhydrous Na 2 S0 , and concentrated. The residue was purified by preparative TLC (33% ethyl ether in CH 2 C1 2 ) to give 0.145g of the product of formula 39D, mass spectrometry m/e 326 (M +1 ) .

EXAMPLE 40

A. To a solution of 2 L of p-methoxybenzyl alcohol in 60 mL of dry CH 2 C1 2 was added 3.45 mL ; of triethylamine and 1.73 mL of methanesulfonyl chloride at -25°C. After ^ hr. of stirring, the mixture was filtered, the filtrate was concentrated under high vacuum. The residue was redissolved in 50 mL of dry DMF, 2.14g of Lil was then added at -10°C. The cooling bath was removed, and the reaction mixture was stirred at ambient temperature for 10 min. After diluting with CH 2 C1 2 , the mixture was washed with water four times, then with brine, dried over MgS0 , and concentrated to give 3.77g (95%) of p-methoxybenzyl iodide which was used directly for the next step.

40A B. To a mixture of 0.14g of potassium hydride in 1 mL of dry THF was added a solution of 0.248g of the compound of formula 31C in 1 mL of THF at room temperature. After 1.5 hrs. of stirring, a 0.37 mL of p- methoxybenzyl iodide and 1 mL of HMPA (hexamethyl- phosphormaide) were added. The reaction mixture was stirred for 2 hr. at room temperature and 3.5 hours at 85°C, then it was stirred for overnight (14 hrs.) at room temperature. After cooling to 0°C, the reaction mixture was quenched by aqueous saturated NH 4 C1 solution. The mixture was extracted with EtOAc, dried over MgS0 and concentrated. The residue was purified by preparative TLC (5% ether in CH 2 C1 2 ) to give 0.130g (35%) of a product of formula 40A, mass spectrometry m/e 368 (M + ) .

EXAMPLE 41

To a solution of O.lg of the compound of formula 19G in 2.5 mL of IN diisopropylaluminum hydride in toluene was added 9.5 mg of lithium aluminum hydride at 0°C. The resulting mixture was stirred at 0°C for 7

hours, and then the cooling bath was removed, and the mixture was stirred for ^ hour at ambient temperature. After recooled at 0°C, 0.2 mL of water were added to the reaction mixture. After ^ hour of stirring, 10 mL of EtOAc were added, the mixture was filtered through a pad of Celite . The filtrate was concentrated to give 87 mg (94%) of the product of formula 41A, mass spectrometry m/e 371 (M + ) . When the above reaction was carried in the absence of LiAlH (room temperature for 25 hours) , two products were isolated (4% ether in CH 2 C1 2 ) . They are 41A and 41B with 35% and 36% yield, respectively.

EXAMPLE 42

42A To a mixture of 1.575g of the compound of formula 19A in 15 mL of anhydrous pyridine was added 0.475 mL of methanesulfonyl chloride at 0°C. The resulting mixture was stirred for 35 min. at 0°C and 4.5 min. at room temperature, then it was diluted with 15 mL of CH 2 C1 2 . The resulting solution was washed four times with cold IN HCl solution, then with brine, dried over

MgS0 4 , and concentrated. The residue was purified by flash chromatography on Si0 2 (CH 2 C1 2 ; 5% ether in CH 2 C1 2 , 10% ether in CH 2 C1 2 , finally 20% ether in CH 2 C1 2 ) to give 0.55g (35%) of the product of formula 42A, mass spectrometry m/e 386_ (M+l) .

EXAMPLE 43

To a precooled (—78°C) IM THF of lithium bis(trimethylsilyl)amide (1.5 ml; 1.5 mmoles) was added a dry THF (5.0 mL) solution of compound of formula 31A (384 mg; 1.0 mmoles) under N 2 dropwise. After the addition, the solution was stirred at -78°C for two hours, allyl bromide (0.35 L) was added, then the cooling bath was removed. After stirring for another three hours, the solution was diluted with EtOAc, washed with 0.IN HCl, then with water and dried (Na 2 S0 4 ) . The reaction mixture was purified by flash chromatography (Si0 2 ) (15% EtOAc/Hexanes) yielding 83 mg (18%) of compound of formula 43B [Mass spectrometry, m/e 465 (M+l) ] and 230 mg (54%) of compound of formula 43A [mass spectrometry m/e 425 (M+l)].

ΞXAMPLE 44

31

A dry THF (10 mL) solution of compound of formula 31A (768 mg; 2.0 mmoles) was added slowly dropwise to a precooled (-78°C) IM THF solution of lithium bis (trimethylsilyl)amide (3.2 mL; 3.2 mmoles) under N . After the addition, the solution was stirred at -78°C for two hours, then 0.70 mL of paramethoxybenzyl iodide were added dropwise. After the addition, the solution was stirred at room temperature for three hours, then diluted with EtOAc, washed with O.lN HCl, then with water, and dried (Na 2 S0 4 ) . The reaction mixture was purified by flash chromatography (Si0 2 ; 25% EtOAc/Hexanes) yielding 340 mg (33%) of a compound of formula 44A [mass spectrometry, m/e 505 (M+l)].and a compound of formula 44B [mass spectrometry, m/e ] .