WO1995002575A1 - 5-lipoxygenase inhibitors - Google Patents

Abstract

Hydroxyurea compounds comprising halo substituted 1, 2, 3, 4-tetrahydronaphthalene, and indane derivatives, pharmaceutical compositions and their use as OPUFA and 5-lipoxygenase pathway inhibitors.

Description

5-LIPOXYGENASE INHIBITORS

FIELD OF INNENTION

This invention relates to novel compounds, pharmaceutical compositions and methods for inhibiting oxygenated polyunsaturated fatty acid metabolism and disease states caused thereby. Specifically inhibited is the lipoxygenase enzyme pathway of arachidonic acid metabolism in an animal.

BACKGROUND OF THE INNENTION

The metabolism of arachidonic acid occurs by many pathways. One route of metabolism is via the cyclooxygenase (CO) mediated pathway which produces PGH2 which is in turn metabolized to the prostanoids (PGE2, TxA2, and prostacyclin). These products are produced by yarious cells including polymorphonuclear leukocytes, mast cells and monocytes. Another route is by the lipoxygenase mediated pathway which oxidizes arachidonic acid initially to 5-hydroperoxy-eicosatetraenoic acid (5-HPETE) which is further metabolized to LTA4_> the precursor to the peptidoleukotrienes (LTC4, LTD4, and LTE4) and LTB4. Additionally 5-HPETE is converted to 5-hydroxyeicosatetraenoic acid (5- HETE).

Lipoxygenases are classified according to the position in the arachidonic acid which is oxygenated. Platelets metabolize arachidonic acid to 12-HETE, while polymorphonuclear leukocytes (PMNs) contain 5 and 15 lipoxygenases. It is known that 12-HETE and 5J2- diHETE are chemotactic for human neutrophils and eosinophils, and may augment the inflammation process. 5-HPETE is known to be a precursor to the peptidylleukotrienes, formerly known as slow reacting substance of anaphylaxis (SRS-A) and LTB4. The SRS family of molecules, such as leukotrienes C4 and D4 have been shown to be potent bronchoconstrictors. LTB4 has been shown to be a potent chemotatic for PMNs. The products of the 5-lipoxygenase pathway are believed to play an important role in initiating and maintaining the inflammatory response of asthma, allergy, arthritis, psoriasis, and inflammatory bowel disease. It is believed that blockage of this enzyme will interrupt the various pathways involved in these disease states and as such inhibitors should be useful in treating a variety of inflammatory diseases, such as those inumerated above. The absence of selective inhibitors of lipoxygenase, as opposed to cyclooxygenase, which are active in vivo has prevented adequate investigation of the role of leukotrienes in inflammation.

The arachidonic acid oxygenated products, as noted above, have been identified as mediators of various inflammatory conditions. The various inflammatory disease states caused by these mediators and many other conditions, as discussed herein, are all conditions in which an oxygenated polyunsaturated fatty acid metabolite inhibitor, such as a 5-LO inhibitor, would be indicated.

There remains a need for treatment, in this field, for compounds which are capable of inhibiting the oxygenation of arachidonic acid by inhibition of enzymes such as lipoxygenase, specifically 5-lipoxygenase (5-LO) thereby preventing the formation of various leukotrienes and prostaglandins.

SUMMARY OF THE INVENTION

This invention relates to compounds of the Formula (I)

FORMULA (I) wherein

R3 is hydrogen, a pharmaceutically acceptable cation, aroyl or a C1J2 alkanoyl; B is oxygen or sulfur;

R4 is NR5R6, alkyl \. . halosubstituted alkyl ι_6, hydroxy substituted alkyl -β, alkenyl 2-6. aryl or heteroaryl optionally substituted by halogen, alkyl 1-6, halosubstituted alkyl 1-6, hydroxyl, or alkoxy i-6; R5 is H or alkyli-6;

R^ is H, alkylj.^, aiyl, arylalkyl ι_6, heteroaryl, alkyl substituted by halogen or hydroxyl, aryl or heteroaryl optionally substituted by a member selected from the group consisting of halo, nitro, cyano, alkylj.^. alkoxy \. , halosubstituted alkyli-6, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthio, alkylsulphonyl, or alkylsulfinyl; or R5 and R6 may together form a ring having 5 to 7 members, which members may be optionally replaced by a heteroatom selected from oxygen, sulfur or nitrogen; W is CH₂(CH2)_s; s is a number having a value of 0 or 1 ; R1 is a member selected from the group consisting of (CH2)_m-Ar-(X)v. O(CH2)m^Ar-(X)v, or S(CH₂)_m-Ar-(X)_v; m is a number having a value of 0 to 3; v is a number having a value of 1 to 3;

Ar is a member selected from the group consisting of phenyl or naphthyl;

X is halogen or halosubstituted alkyl; provided that when s is 1, and Ri is

O(CH2)_mAr-(X)v, and Ar is phenyl, and v is 1, and m is 0 or 1, then X is not 4- chloro; and when s is 0 or 1, and Ri is O(CH2)_mAr-(X)_v, and Ar is phenyl, and m is

0, and v is 1, then X is not 4-fluoro; or the pharmaceutically acceptable salts thereof.

This invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and an effective, non-toxic 5-lipoxygenase pathway inhibiting amount of a compound of the Formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

This invention also relates to a method of treating an oxygenated polyunsaturated fatty acid (hereinafter OPUFA) mediated disease in an animal in need thereof which comprises administering to such animal, an effective amount of a compound of Formula (I) or pharmaceutically acceptable salts thereof.

More specifically this invention relates to a method of treating a lipoxygenase pathway mediated disease in an animal in need thereof which comprises administering to such animal an effective, non-toxic lipoxygenase pathway inhibiting amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INNENTION

This invention relates to compounds of Formula (I) as described above, pharmaceutical compositions comprising a pharmaceutically acceptable carrier or diluent and a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and methods of treating an OPUFA mediated disease, specifically a 5-lipoxygenase pathway mediated disease comprising administration of a compound of Formula (I) and salts thereof.

The compounds of Formula (I) have been found to be useful in inhibiting the enzymes involved in the oxygenated polyunsaturated fatty acid pathway which includes the metabolism of arachidonic acid, in an animal, including humans, in need thereof. The compounds of Formula (I) have oral activity and are therefore useful for the treatment of various inflammatory disease states. This invention further relates to a method of treating analgesia in an animal in need thereof, which comprisies administering to such animal an effective, analgesia inhibiting amount of a compound of Formula (I). The compounds of Formula (I) possess unexpectedly, superior therapeutic profiles for treatment of OPUFA mediated disesases over the corresponding unsubstituted benzyloxy derivative. The specific requirement that the Ar (X)_v moiety in the Ri term possesses at least one fluorine, preferably two fluorines demonstrates improved activity in whole blood, and improved activity in the whole animal. Data for the compounds of Formula (I) is presented in Tables I in the Methods Section described herein. Additionally, the compounds of Formula (I) also possess unexpectedly improved solubility over the corresponding unsubstituted benzyloxy derivative.

Specific Ri groups of interest are the substituted (CH2)m-Ar-(X)_v derivatives, in particular phenylethyl, and substituted O(CH2)m-Ar-(X)_v derivatives, in particular benzyloxy. A preferred embodiment of the present invention is where Rj is selected from O(CH2)m-Ar-(X)v, m is a number having a value of 1 ; and v is a number having a value of 1 to 2.

Specific (X) substitutents include, but are not limited to, 4-fluoro, 2-fluoro; 2,6-di- fluoro, 2,4-difluoro, 2, 5-difluoro and 2,3-di-fluoro moieities; 4-trifluoromethyl, 3- trifluoromethyl, and 2-trifluoromethyl; 2-, 3- and 4- chloro; 2,6-dichloro, 2,4-dichloro, 2, 5-dichloro and 2,3-dichloro; and the mixed fluoro- chloro derivatives such as 2-chloro-6- fluoro. Preferred are the 2,6-difluoro, the 2- and 4-fluoro derivatives, and the 3- trifluoromethyl and 4-trifluromethyl. More preferred are the 2,6-difluoro, and the 2- and 4- fluoro derivatives.

A further preferred embodiment of the present invention is where B is oxygen.

A preferred embodiment of this invention is where s is 0, yielding the indane series. A preferred ring placement when W is CH2(CH2)s and s is 1 is on the 5- or 6- position of the benzene ring, more preferably the 6-position; and when s is 0 the preferred position is the 5- or 6-position, more preferably the 5-position.

Preferred R4 substituent groups are NR5R6 and the alkyl hydroxamate derivatives. Preferred R6 substitutions when R is aryl or arylalkyl are phenyl or benzyl. A more preferred embodiment is where R5 and R6 are independently hydrogen or alkyl. Most preferably R5 and R6 are independently hydrogen.

When R4 is other than a NR5R6 moiety yielding a hydroxamate derivative, R₄ is preferrably alkyl, more preferably an alkyl have 1-6 carbon atoms, such as methyl, ethyl, n- propyl, isopropyl or t-butyl, all optionally substituted. R3 is preferably hydrogen or a pharmaceutically acceptable cation.

As the hydroxamates and hydroxyureas disclosed herein are made thru a common intermediate, a hydroxylamine deriviatives of Formula (II), similarly the preferred intermediates of Formula (II) correpond to the same W, Ri, s, m, v, Ar, X as indicated above for Formula (I) compounds. Further, the N-hydroxy acetamide derivatives of the corresponding hydroxylamines made herein correpond to the same W, Ri, s, m, v, Ar, X as indicated above for Formula (I) compounds are also considered a preferred embodiment of this invention. Some preferred hydroxyurea compounds of Formula (I) compounds which are themselves within the scope of the present invention include the following:

N- 1 -[5-(2,6-Difluorobenzyloxy)indanyl]-N-hydroxyurea; N-l-[5-(4-Trifluoromethylbenzyloxy)indanyl]-N-hydroxyurea;

N- 1 -[5-(4-Fluorobenzyloxy)indanyl] -N-hydroxyurea;

N-l-[5-(3-Trifluoromethylbenzyloxy)indanyl]-N-hydroxyurea;

N-l-[5-(2-Chloro-6-fluorobenzyloxy)indanyl]-N-hydroxyurea.

N-l-[5-(2-Ruorobenzyloxy)indanyl]-N-hydroxyurea; N-l-[5-(3,4-Difluorobenzyloxy)indanyl]-N-hydroxyurea;

N- 1 -[5-(2,5-Difluorobenzyloxy)indanyl]-N-hydroxyurea;

N-l-[5-(3,5-bisTrifluoromethylbenzyloxy)indanyl]-N-hydroxyurea;

N-l-[5-(2,4-Difluorobenzyloxy)indanyl]-N-hydroxyurea;

N-l-[5-(2-Trifluoromethylbenzyloxy)indanyl]-N-hydroxyurea; ,

Preferred hydroxyureas of Formula (I) are

N- 1 -[5-(2,6-Difluorobenzyloxy)indanyl]-N-hydroxyurea;

N-l-[5-(4-Trifluoromethylbenzyloxy)indanyl]-N-hydroxyurea;

N- 1 -[5-(4-Ruorobenzyloxy)indanyl]-N-hydroxyurea; N- l-[5-(3-Trifluoromethylbenzyloxy)indanyl]-N-hydroxyurea; and

N-l-[5-(2-Chloro-6-fluorobenzyloxy)indanyl]-N-hydroxyurea.

Most preferred hydroxyureas of Formula (I) are:

N- l-[5-(2,6-Difluorobenzyloxy)indanyl]-N-hydroxyurea; and N-l-[5-(4-Fluorobenzyloxy)indanyl]-N-hydroxyurea.

Another aspect of the present invention is the chiral pair of entaniomers, (+) N-l-[5- (3-benzyloxy)indanyl]-N-hydroxyurea; and (-) N-l-[5-(3-benzyloxy)indanyl]-N- hydroxyurea which have been found to have unexpected activity as a 5-lipoxygenase inhibitor as compared to the parent racemate as disclosed in Adams et al., WO 91/14674.

The terms "aryl" or "heteroaryl" are used herein at all occurrences to mean substituted and unsubstituted aromatic ring(s) or ring systems containing from 5 to 16 carbon atoms, which may include bi- or tri-cyclic systems and may include, but are not limited to heteroatoms selected from O, N, or S. Representative examples include, but are not limited to, phenyl, naphthyl, pyridyl, quinolinyl, thiazinyl, and furanyl.

The terms "lower alkyl" or "alkyl" are used herein at all occurrences to mean straight or branched chain radical of 1 to 10 carbon atoms, unless the chain length is limited thereto, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.

The term "alkenyl" is used herein at all occurrences to mean straight or branched chain radical of 2-10 carbon atoms,unless the chain length is limited thereto, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl and the like.

The term "aralkyl" is used herein to mean C1.4 Ar, wherein Ar is as defined in Formula (I).

The term "aroyl" is used herein to mean - C(O) Ar, wherein Ar is Aryl or Aryl alkyl as defined in Formula (I), or herein, including, but not limited to phenyl, benzyl, 1- or 2- naphthyl and the like.

The term "alkanoyl" is used herein to mean -C(O)Ci -io_. wherein alkyl is as defined above, including but not limited to methyl, ethyl, isopropyl, n-butyl, t-butyl, and the like.

The term "cycloalkyl" is used herein to mean cyclic radicals, preferably of 3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.

The term "halo" or "halogen" are used interchangeably herein to mean radicals derived from the elements fluorine, chlorine, bromine, and iodine.

The term "lipoxygenase" is used herein to mean 5-, 12-, or 15- lipoxygenase, preferably 5-lipoxygenase. By the term "OPUFA mediated disease or disease state" is meant any disease state which is mediated (or modulated) by oxidized polyunsaturated fatty acids, specifically the arachidonic acid metabolic pathway. The oxidation of arachidonic acid by such enzymes as the lipoxygenase enzymes is specifically targeted by the present invention. Such enzymes include, but are not limited to, 5-LO, 12-LO, and 15-LO; which produce the following mediators, including but not limited to, LTB4, LTC4, LTD4, 5,12-diHETE, 5-HPETE, 12-

HPETE, 15-HPETE, 5-HETEJ2-HETE and 15-HETE.

By the term "OPUFA interfering amount" is meant an effective amount of a compound of Formula (I) or (II) which shows a reduction of the in vivo levels of an oxgyenated polyunsaturated fatty acid, preferably an arachidonic acid metabolite.

The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds are contemplated to be within the scope of the present invention.

Useful intermediates of the present invention are the novel hydroxylamine derivatives of Formula (II) as represented by the formula below.

The compounds of Formula (II) are represented by the structure:

wherein R'2 is

R'3 is hydrogen, benzyl, optionally substituted benzyl , Si(R_x)3, C(O)R5', C(O)OR5', CH2OCH2CH2Si(CH3)3, Cι alkyl-Ci-3alkoxy, CιalkylC2alkoxyCi-3alkoxy, or tetrahydropyranyl ; A is hydrogen or C(O)OR_Z;

R_z is benzyl, Si(R_x)3, t-butyl, or CH2OCH2CH2Si(Rx)3; Ry is C 1-6 alkyl, aryl, or aralkyl; R_x is independently selected from alkyl or aryl; R'ι is defined as Ri in Formula (I), and the remaining variables W, Ar, X, m, s, and v are as defined above for Formula (I).

Preferred R'3 substituent groups are tetrahydropyranyl; CH2OCH3 when R'3 is CialkylCi-3alkoxy; CH2OCH2CH2Si(CH )3 , CH2OCH2CH2OCH3 when R^*3 is CιalkylC2alkoxyCi-3alkoxy; C(O)R5⁽ and C(O)OR5' with R5' as a Ci-6 alkyl, specifically methyl, t-butyl, or phenyl.group and benzyl when R5 is an aralkyl group. When R3 is an optionally substituted benzyl the substituent groups are selected from C1 -6 alkoxy or Ci-6 alkyl.

The hydroxylamine derivatives of Formula II are easily converted to the compounds of Formula (I) wherein R4 is NHR5R6 or a hydroxamate derivative using art known proceedures. Various illustrative methods to prepare compounds of Formula (I) are given in U.S. Patent Summers et al., 4,873,259, issued October 10, 1989, pages 7-11, and Adams et al., WO 91/14674, published 3 October 1991 whose disclosures in their entirety are incorporated by reference herein.

The present compounds of Formula (I) can be prepared by art-recognized procedures from known compounds. Several different synthetic schemes can be used to prepare the compounds of this invention and are described in greater detail below. Many starting materials are readily available, such as the 1,2,3,4-tetrahydronaphthalene derivatives, and as can be seen from the working examples, that other compounds of this invention can be prepared in the same manner using the appropriate starting materials, such as 6-methoxy-l-tetralone, 6-methoxy-2-tetralone, 5-hydroxy-2-tetralone, 7-methoxy-2- tetralone, or 5-methoxy-indan-l-one.

As a general summary of the synthetic pathways described in greater detail below the compounds of Formula (I) and (II) can be produced by the following means:

A. reacting a compound of Formula (II) as described above, wherein R'3 is hydrogen,

(i) with trimethylsilyl isocyanate (TMSNCO), followed by work up with ammonium chloride to yield a hydroxyurea derivative of a Formula (I) compound wherein R4 is NH₂; or

(ii) with sodium or potassium cyanate in an acidic solution to yield a hydroxyurea derivative of a Formula (I) compound wherein R4 is NH2; or

(iii) with gaseous HC1, followed by treatment with phosgene or a phosgene equivalent, resulting in the corresponding carbamoyl chloride intermediate; or an alkylchloroformate, such as ethyl chloroformate, resulting in the corresponding carbamate; which is reacted with aqueous ammonia, or a substituted amine to yield an optionally substituted hydroxyurea derivative of a Formula (I) compound; or

(iv) with acetyl chloride and organic solvent, such as triethylamine, to yield the N,O-diacetate derivative followed by hydrolysis with an alkali hydroxide, such as lithium hydroxide, to yield a compound of Formula (I) wherein R4 is other than NR5R6; or

(v) with an acylating agent, such as acetic anhydride in the presence of a base, such as pyridine, followed by hydrolysis with an alkali hydroxide, such as lithium hydroxide, to yield a compound of Formula (I) wherein R4 is a hydroxamic acid derivative; or

B. reacting a compound of Formula (II) as described above, wherein R'3 is a benzyl, substituted benzyl or a benzyl carbonate protecting group, with

(i) acetyl chloride in an organic solvent to yield a protected hydroxamic acid derivative of Formula (I) compounds, which is then deprotected, optionally by hydrogenation or with ethane thiol in the presence of aluminium trichloride, to yield a compound of Formula (I) wherein R4 is other than NR5R6; or

(ii) trimethylsilyl isocyanate as in step A above, to yield protected hydroxyurea derivatives of Formula (I) compounds which is then deprotected, optionally by hydrogenated with ethane thiol in the presence of aluminium trichloride, to yield a compound of Formula (I); or (iii) phosgene or a phosgene equivalent, resulting in the corresponding carbamoyl chloride intermediate; or an alkylchloroformate, such as ethyl chloroformate, resulting in the corresponding carbamate, which is reacted with aqueous ammonia, or a substituted amine; which is then deprotected, optionally by hydrogenation or with ethane thiol in the presence of aluminium trichloride, to yield a compound of Formula (I); or

(iv) sodium or potassium cyanate in an acidic solution which is then deprotected, optionally by hydrogenation or with ethane thiol in the presence of aluminium trichloride, to yield a compound of Formula (I); or

C. reacting a compound of Formula (II) as described above, wherein R'3 is Si(R_x)3, or CH₂OCH₂CH₂Si(Rx)₃ with

(i) sodium or potassium cyanate in an acidic solution and deprotected by use of anhydrous fluoride (R_₄'N⁺)F-, (wherein R4' is a suitable alkyl or aryl derivative) or under mildly acidic conditions, to yield the corresponding compounds of Formula (I); or

(ii) phosgene or a phosgene equivalent, resulting in the corresponding carbamoyl chloride intermediate; or an alkylchloroformate, such as ethyl chloroformate, resulting in the corresponding carbamate, which is reacted with aqueous ammonia, or a substituted amine; which is deprotected by use of anhydrous fluoride (R_4'N+)F-, or under mildly acidic conditions; to yield the corresponding compounds of Formula (I); or

(iii) trimethylsilyl isocyanate and deprotected by use of anhydrous fluoride (R4-N⁺)F-, or under mildly acidic conditions; to yield the corresponding compounds of Formula (I); or (iv) acetyl chloride in organic solvent which is then deprotected by use of anhydrous fluoride ((R4-N⁺)F-, or under mildly acidic conditions, to yield the corresponding compounds of Formula (I); or

D. reacting a compound of Formula (II) as described above, wherein R'3 is tetrahydropyranyl, C 1 alkyl-C 1 -3alkoxy, or C 1 alkylC2alkoxyC 1.3-ιlkoxy, with

(i) sodium or potassium cyanate in an acidic solution, and deprotected by a mild acid treatment, such as pyridinium para-toulenesulphonate in methanol or dilute HCl to yield the corresponding compounds of Formula (I); or

(ii) phosgene or a phosgene equivalent, resulting in the corresponding carbamoyl chloride intermediate; or an alkylchloroformate, such as ethyl chloroformate, resulting in the corresponding carbamate, which is reacted with aqueous ammonia, or a substituted amine; and deprotected by a mild acid treatment, such as pyridinium para-toulenesulphonate in methanol or dilute HCl; to yield the corresponding compounds of Formula (I); or

(iii) with trimethylsilyl isocyanate, then deprotected by a mild acid treatment, such as pyridinium para-toulenesulphonate in methanol or dilute HCl; to yield the corresponding compounds of Formula (I); or (iv) with acetyl chloride in organic solvent which is then deprotected by a mild acid treatement, such as pyridinium para-toulenesulphonate in methanol or dilute HCl to yield the corresponding compounds of Formula (I); or

E. reacting a compound of Formula (II) as described above, wherein R'3 is t-butyloxycarbonyl with

(i) sodium or potassium cyanate in an acidic solution, and deprotected by treatment with trifluroracetic acid, trimethylsilyltrifilate with 2,6-lutidine, or with anhydrous ether HCl; or (ii) phosgene or a phosgene equivalent, resulting in the corresponding carbamoyl chloride intermediate; or an alkylchloroformate, such as ethyl chloroformate, resulting in the corresponding carbamate, which is reacted with aqueous ammonia, or a substituted amine; and deprotected by treatment with trifluroracetic acid, trimethylsilyltrifilate with 2,6-lutidine, or with anhydrous ether HCl; to yield the corresponding compounds of Formula (I); or (iii) with trimethylsilyl isocyanate and then deprotected, optionally with ethane thiol in the presence of aluminium trichloride by treatment with trifluroracetic acid, trimethylsilyltrifilate with 2,6-lutidine, or anhydrous ether HCl; to yield the corresponding compounds of Formula (I); or

(iv) with acetyl chloride in organic solvent which is then deprotected, optionally with ethane thiol in the presence of aluminium trichloride; or by treatment with trifluroracetic acid, trimethylsilyltrifilate with 2,6-lutidine, or anhydrous ether HCl to yield the corresponding compounds of Formula (I); or

F. reacting a compound of Formula (II) as described above, wherein R'3 is an alkanoyl or aroyl with

(i) sodium or potassium cyanate in an acidic solution and deprotected with a suitable base, such as potassium carbonate; to yield the corresponding compounds of Formula (I); or

(ii) with trimethylsilyl isocyanate and deprotected with a suitable base, such as potassium carbonate; to yield the corresponding compounds of Formula (I); or (iii) with acetyl chloride in organic solvent which is then deprotected by treatment with a suitable base, such as potassium carbonate; to yield the corresponding compounds of Formula (I).

The compounds of Formula (II) can also be produced by a process which comprises A. reacting a compound of Formula (IE)

wherein

W, R'ι, s, m, v, Ar, and s are as defined for Formula (II); with hydroxylamine in a suitable solvent to yield the corresponding oxime derivative of

Formula (IV)

wherein

W, R'ι, m, v, Ar, and S are as defined for Formula (II); which is then reduced with borane pyridine complex, borane trimethylamine, or borane tetrahydrofuran or other borane complexes, to yield the hydroxylamine derviatives of Formula (II); or

B. reacting a compound of Formula (IV) as defined above with sodium cyanoborohydride or phenyldimethylsilane in anhydride in trifluroacetic acid to yield the hydroxylamine derviatives of Formula (II); or

C. reacting a compound of Formula (V)

wherein X is a leaving group, such as a halogen, tosylate, mesylate or a triflate moiety; W, R'ι, s, m, v, and Ar are as defined for Formula (II); with Z-furfulaldehyde oxime and base to yield the corresponding nitrone which is hydroylzed to yield the corresponding hydroxylamine derviatives of Formula (II);

D. reacting a compound of Formula (V) as described above, with a protected hydroxylamine to yield the corresponding protected hydroxylamine of Formula (II); or

E. reacting a compound of the Formula (VI)

wherein

W, R'ι, s, m, v, and Ar are as defined for Formula (II) as described above; with a protected hydroxylamine, such as N,O-bis(t-butyloxycarbonyl)-hydroxylamine) or bisbenzyloxycarbonyl, and triphenylphosophine/ diethyldiazodicarboxylate to produce an intermediate which is treated with acid to yield the hydroxylamines of Formula (II).

The homochiral compounds of Formula (I), as well as the homochiral intermediates of Formula (II) can be prepared by a process which comprises A. (i) reacting a homochiral oxazolidione of Formula (A)

O

\_y

^*'R (A) wherein R is an optionally substituted aryl, arylmethyl, heteroaryl, or heteroarylmethyl; with phosgene or a phosgene equivalent and a base in anhydrous solvent to yield to form the corresponding acid chloride intermediate of Formula (VII)

O O

R (VII)

(ii) reacting the Formula (VII) adduct with a chloronated hydrocarbon or etheral solvent and base to yield the corresponding diastereomers of the Formula

(iii) separating diastereomers by chromatography or selective crystallization (iv) cleaving the adducts under basic conditions to yield the individual entantiomers of the Formula (II) compounds; or B. reacting an optically active alcohol of Formula (VI) as defined above, with N,O- bis(t-butyloxycarbonyl)hydroxylamine) and triphenylphosophine/ diethyldiazodicarboxylate to produce an intermediate which is treated with acid to yield the hydroxylamines of Formula (II); or reacting the corresponding optically active halo or sulfonates of Formula (VI), which may be optionally protected with a base, such as triethylamine, or pyridine; are then optionally deprotected to yield the formula (II) compounds, which are optionally reacted under any of the various pathways described herein to yield optically active final compounds of Formula (I); or

C. (i) reacting an optically active amine of Formula (VHI)

wherein W, R'ι, s, m, v, and Ar are as defined for Formula (II); with 4-methoxybenzaldehyde in trimethylamine;

(ii) oxidizing the intermediate of step (i) to yield the corresponding oxaziridine; (iii) reacting the oxaziridine of step (ii) under acid conditions to yield the hy¬ droxylamine salts of Formula (II) compounds; and then optionally reacting under the various pathways described herein to yield optically active final compounds of Formula (I).

D. resolving a mixture of protected or non protected enantiomeric hydroxylamines of Formula (Ha)

([R*NHOZ]) (Ha) wherein

R* is ^{π 1} DO and * is the chiral carbon attached to the NHOZ moiety;

Z is hydrogen or a hydroxyl protecting group m, W, s, v, R'l, X, and Ar as are defined for Formula (I) or (II) as appropriate; by first treating the mixture of enantiomers of the formula (Ha) with a substantially chirally pure entanuomer of a homochiral organic acid HA*. Examples of suitable homochiral organic acids HA* include mild organic acids selected from amongst the homochiral acids conventionally used as resolving agents for racemic amines, for instance a dibasic acid such as (+)/L- or (-)/D-tartaric acid or a derivative thereof such as dibenzoyl- D- or L-tartaric acid or, more preferably, a monobasic acid such as (S)-(+)- or (R)-(-)- mandelic acid [C6H5CH(OH)CO2H]. Mono derivatives of tartaric acid (or other dibasic acids) such as the mono esters or amides may also be used, similarly the mandelate dervatives may also be used. Stronger organic acids such as camphorsulphonic acid should preferably be avoided. Suitable homochiral organic acids are readily available from the normal commercial suppliers. The organic acid should be a substantially pure homochiral entantiomer. It is preferable that the organic acid be at least 95% pure or better, more preferably 97% or better, most preferably better than 99% pure. A preferred chiral acid is (S)-(+)- or (R)-(-)- mandelic acid [C6H5CH(OH)CO2H] to form a mixture of diasteriomeric acid addition salt salts. The acid addition salts are then separated by conventional means well known to those of skill in the art to yield the desired diasteriomeric acid addition salt

The term "hydroxyl protecting group" is used herein to describe those groups well known in the art which may used to protect a hydroxyl group and which may be added to and removed from the substrate molecule without disturbing the remainder of the molecule. Suitable examples thereof are given in "Protecting Groups in Organic Chemistry", Greene T. W., Wiley, New York, 1981. Prefered values for the hydroxyl protecting group Z include optionally substituted benzyl, methyl(Ci-3)alkoxy, methylethoxy(Ci-3)alkoxy, lower alkoxycarbonyl, tetrahydropyranyl, lower alkanoyl, aroyl, trialkylsilyl and trialkylsilyl- ethoxymethyl.

The pair of diastereoisomeric acid addition salts may be separated by any suitable means, for instance fractional crystallisation. A 1:1 ratio is preferable, although a 2:1 ratio may also be used. Suitable solvents include those normally used in acid addition salt formation, such as ethyl acetate, aceto nitrile, acetone, or an alcohol optionally with acetic acid, for instance methanol, ethanol or isopropanol, preferably methanol or ethanol, and more preferably methanol with acetic acid.

Preferably salt formation is carried out with efficient stirring and temperature control, so that, if a suitable solvent is choosen, fractional crystallisation may occur in a controlled fashion. Suitable bases include mild amine bases such as aqueous ammonium hydroxide. Suitable solvents include water.

The hydroxyureas of Formula (I) wherein R4 is NR5R6 is a substituted amine or cyclic amine can be prepared by reaction of the appropriately substituted hydroxylamine hydrochloride of Formula (II) with phosgene to yield the acyl chloride intermediate which is reacted with the appropriate amine to yield the compounds of Formula (I).

An alternative to the use of phosgene is an alkyl chloroformate, such as ethyl chloroformate, in which case the resulting R4 term of Formula (I) will determine the reaction time and temperature needed for the reaction to proceed, i.e. at O° C or below or, if slow at an elevated temperatures of 100°-200° C in the appropriate solvent. The preparation of the hydroxyureas of Formula (I) when -OR3 is a protecting group, as opposed to the free hydroxyl proceeds in a similiar manner. The protected hydroxylamine is reacted with phosgene or a phosgene equivalent, such as carbonyl diimidazole or phosgene trimer yielding a protected hydroxylamine intermediate which is reacted with an appropriate amine component (NHR5R6) to yield the protected hydroxyurea of Formula (I). Alternatively, the reaction of the protected hydroxylamine with trimethylsilyl isocyante or with sodium or potasium cyanate in an acidic solution as discussed above may be employed to prepare the protected hydroxyurea of Formula (I). This is followed by any means appropriate for the deprotection of the -OR3 group. Deprotection of the hydroxyl may be by hydrogenation with H2/Pd/C when R3 is benzyl , by mild acid treatment, such pyridinium para-toluenesulphonate in refluxing methanol or dilute HCl when R3 is tetrahydropyranyl , by a suitable base, such as potassium carbonate when R3 is an alkoyl or aroyl, by use of anhydrous fluoride (R'4N⁺)F^_ when B is Si(R_x)3, or by treatment with trifluoroacetic acid, trimethylsilyltrifilate with 2,6-lutidine, or anhydrous ether HCl when R3 is t-butyloxycarbonyl. In general, suitable protecting groups and methods for their removal will be found in T.W. Greene, Protective Groups in Organic Synthesis. Wiley, New York, 1981.

Pharmaceutically acceptable base addition salts and their preparation are well known to those skilled in pharmaceuticals. Pharmaceutically acceptable bases (cations) of the compounds of Formula (I) which are useful in the present invention include, but are not limited to nontoxic organic and inorganic bases, such as ammonium hydroxide, arginine, organic amines such as triethylamine, butylamine, piperazine and (trihydroxy)methylamine, nontoxic alkali metal and alkaline earth metal bases, such as potassium, sodium and calcium hydroxides. Pharmaceutically acceptable acid addition salts of the compounds of Formula

(I) which are useful in the present invention include, but are not limited to, maleate, fumarate, lactate, oxalate, methanesulfonate, ethane-sulfonate, benzenesulfonate, tartrate, citrate, hydrochloride, hydrobromide, sulfate and phosphate salts and such salts can be readily repared by known techniques to those skilled in the art.

METHOD OF TREATMENT

It has now been discovered that the compounds of Formula (I) are useful for treating disease states mediated by the 5-lipoxygenase pathway of arachidonic acid metabolism in an animal, including mammals, in need thereof. The discovery that the compounds of Formula (I) are inhibitors of the 5-lipoxygenase pathway is based on the effects of the compounds of

Formula (I) on the production of 5-lipoxygenase products in blood ex vivo and on the 5- lipoxygenase in vitro assays, some of which are described hereinafter. The 5-lipoxygenase pathway inhibitory action of the compounds of Formula (I) was confirmed by showing that they impaired the production of 5-lipoxygenase products such as leukotriene B4 production by RBL-1 cell supernatants. It has also been found that the compounds of Formula (I) do not appear to inhibit prostaglandin production in. vitro and are therefore selective 5- lipoxygenase inhibitors. Another aspect of the present invention is the use of the chiral pair of entiomers, (+)

N-l-[5-(3-benzyloxy)indanyl]-N-hydroxyurea; and (-) N-l-[5-(3-benzyloxy)indanyl]-N- hydroxyurea for their use in treating disease states mediated by the 5-Lipoxygenase pathway as enumerated above for compounds of Formula (I).

The pathophysiological role of arachidonic acid metabolites has been the focus of recent intensive studies. In addition to the well-described phlogistic activity (i.e. general inflammatory activity) of prostaglandins, the more recent description of similar activity for other eicosanoids, including the leukotrienes, has broadened the interest in these products as mediators of inflammation [See, O'Flaherty, Lab. Invest.. 42, 314-329 (1982)]. The reported discovery of potent chemotactic and algesic activity for LTB4 [see, Smith, Gen. Pharmacol..12, 211-216 (1981) and Levine et al., Science. 225. 743-745 (1984)], together with known LTC4 and LTD4-mediated increase in capillary permeability [see, Simmons et al., Biochem. Pharmacol..22, 1353-1359 (1983), Vane et al., Prostaglandins. 21, 637-647 (1981), and Camp et al., Br. J. Pharmacol.. £Q_, 497-502 (1983)], has led to their consideration as targets for pharmacological intervention in both the fluid and cellular phases of inflammatory diseases.

The pharmacology of several inflammatory model systems has attested to the effectiveness of corticosteroids in reducing the cellular infiltration. These results, and the observation that corticosteroids inhibit the generation of both cyclooxygenase and lipoxygenase products, suggest that such dual inhibitors may effectively reduce both the fluid and cellular phases of the inflammatory response since selective cyclooxygenase inhibitors do not reliably inhibit cell influx into inflammatory sites [See, Vinegar et al., Fed. Proc.25, 2447-2456 (1976), Higgs et al., Brit. Bull.. 2, 265-270 (1983), and Higgs et al., Prostaglandins. Leukotrienes and Medicine. 13. 89-92 (1984)]. Under optimal conditions, it is likely that an agent with preferential lipoxygenase inhibitory activity would not share the ulcerogenic liability of cyclooxygenase inhibitors or the toxicity of corticosteroids. This may suggest that the compounds of the present invention could be useful in treating diseases, such as osteoaithritis, where it is beneficial to limit ulcerogenic activity or steroidal side effects. [See Palmoski et al., "Benoxaprofen Stimulates Proteoglycan Synthesis in Normal Canine Knee Cartiledge in Vitro." Arthritis and Rheumatism 26. 771-774 (1983) and Rainsford, K.D.. Agents and Actions 21. 316-319 (1987).] Clinical data supports the enthusiasm for inhibitors of the 5-lipoxygenase pathway in a variety of inflammatory diseases in which granulocyte and/or monocyte infiltration is prominent. The reported demonstration of elevated levels of LTB4 in rheumatoid arthritic joint fluid [See, Davidson et al., Ann. Rheum. Pis.. 42, 677-679 (1983)] also suggests a contributing role for arachidonic acid metabolites in rheumatoid arthritis. Sulfasalazine, which is used for treatment of ulcerative colitis, has been reported to inhibit LTB4 and 5-

HETE production in vitro [See, Stenson et al., J. Clin. Invest.. 69, 494-497 (1982)]. The recently reported preliminary observation of efficacy, including remission, reported with sulfasalazine treatment of rheumatoid arthritic patients [See Neumann et al., Brit. Med. J.. 287, 1099- 1102 (1983)] illustrates the utility of inhibitors of the 5-lipoxygenase pathway in rheumatoid arthritis.

Additionally it has been reported that inflamed gastrointestinal mucosa from inflammatory bowel disease patients showed increased production of LTB4 [See, Sharon et al., Gastroenterol.. 84, 1306 (1983)], which suggests that sulfasalazine can be effective by virtue of inhibition of production of chemotactic eicosanoids (such as the 5-lipoxygenase pathway product known as LTB4). The observations serve to underscore utility of inhibitors of the 5-lipoxygenase pathway in inflammatory bowel disease.

Another area of utility for an inhibitor of the 5-lipoxygenase pathway is in the treatment of psoriasis. It was demonstrated that involved psoriatic skin had elevated levels of LTB4 [See, Brain et al., Lancet. J9, February 19, 1983]. The promising effect of benoxaprofen on psoriasis [See, Allen et al., Brit. J. Permatol.. 109, 126-129 (1983)], a compound with jn vitro lipoxygenase inhibitory activity lends support to the concept that inhibitors of the 5-lipoxygenase pathway can be useful in the treatment of psoriasis.

Lipoxygenase products have been identified in exudate fluids from gouty patients. This disorder is characterized by massive neutrophil infiltration during the acute inflammatory phases of the disease. Since a major 5-lipoxygenase product, LTB4, is produced by neutrophils, it follows that inhibition of the synthesis of LTB4 may block an amplification mechanism in gout.

Another area in which inhibitors of the 5-lipoxygenase product can have utility is in myocardial infarction. Studies in dogs with the dual inhibitor, BW755-C, demonstrated that the area of in arction following coronary occlusion was reduced, and such reduction was attributed to inhibition of leukocyte infiltration into the ischaemic tissue [See, Mullane et al., J. Pharmacol. Exp. Therap.. 228. 510-522 (1984)].

Yet another area in which inhibitors of lipid peroxidation involved in the OPUFA mediated can have utility is that generally refered as degenerative neurological disorders, such as Parkinson's disease. Another area is that of traumatic or ischemic injuries, such as stroke, brain or spinal cord injuries and inflammatory disease of the brain and spinal column. More specicially preferred disease states are the mycardial induced ischemic injuries and/or reperfusion injuries. [See, Braughler et al., Jour. Biol. Chem., Vol. 262, No. 22, ppl0438-40 (1987), see also Xu et al., J. Neurochemistrv. 55, 907-912 (1990); Asano et al., Molecular and Chemical Neuropathology. 10:101-133 (1989) and Bracken et al., NE. J. Med., 322:1405-1411 (1990)] Yet another area of utility for inhibitors of the 5-lipoxygenase pathway is in the area of prevention of rejection of organ transplants. [See, e.g., Foegh et al., Adv. Prostaglandin. Thromboxane. and Leukotriene Research.13, 209-217 (1983).]

Yet another utility for inhibitors of the 5-lipoxygenase pathway is in the treatment of tissue trauma. [See, e.g., Penzlinger et al. Science, 230 (4723), 330-332 (1985)]. Furthermore, another area of utility for inhibitors of the 5-lipoxygenase pathway is in the treatment of inflammatory reaction in the central nervous system, including multiple sclerosis. [See, e.g., Mackay et al., Clin. Exp. Immunology. 15, 471-482 (1973)].

Another area of utility for inhibitors of the 5-lipoxygenase pathway is in the treatment of asthma. [See, e.g., Ford-Hutchinson, J. Allergy Clin. Immunol.. 74, 437-440 (1984)]. Additionally another utility for inhibitors of the 5-lipoxygense pathway is in the treatment of Adult Respitory Pistress Syndrome. [ See, e.g., Pacitti et. al., Circ. Shock , 21. 155-168 (1987)]. Yet another utility for inhibitors of the 5-lipoxygenase pathway is in the treament of allergic rhinitis.

Another area of utility for inhibitors of the 5-lipoxygenase pathway is in the treatment of vasculitis, immune complex disease, immune complex nephritis, glomerulonephritis, and generally in renal diseases, such as ischemic renal failure, glycerol induced acute renal failure, aminonucleoside induced nephrosis, nephrotoxic nephritis, lupus nephritis, and obstructive nephropathy. [See Kadison et al., "Vasculitis: Mechanism of Vessel Pamage" in Inflammation: Basic Principles and Clinical Correlates.703-718, Ed. Gallin et al., Raven Press, N.Y., N.Y. (1988); see also Albrightson et al., Selective

Inhibiton of 5-LO Attenuates Golemular Nephritis in the Rat, Kidney Int'l, Vol. 45, pg 1301-1310; Spaethe, et al., J. Pharmacol. Exp. Ther.. 245, 1088-1094 (1988); Shibouta et al., Kidney Int'l, 39, 920-929; Spaethe et al., J. Pharmcol. Exp. Ther.. 248, 1308-1316 (1989); Terao, et al., Adv. Prostaglandin Thromboxane Leukotriene Res., 21 A, 173-176 (1991); Yared, et al., J. Am. Soc. Neprol.. 2, 45-56 (1991); Rahman et al., J. Clin.

Invest., 81, 1945-52 (1988b); Klausner et al., Am. J. Physiol, 256, F794-F802 (1989a)].

Another area of utility for inhibitors of the 5-lipoxygenase pathway is in the treatment of dermatitis. [See Pye et al., "Systemic Therapy" in Textbook of Permatology, Vol. in, 2501-2528, Ed. Rook et al., Blackwell Scientific Publications, Oxford, England (1986).]

Another area of utility for inhibitors of the 5-lipoxygenase pathway is in the treatment of atherosclerosis. Recent studies have shown that inhibition of oxidative modification of low density lipoprotein slows progression of atherosclerosis, and that inhibitors of lipoxygenase effectively inhibit cell-induced oxidative modification. [See Carew et al., Proc. Natl. Acad. Sci. USA. 84, 7725-7729, November 1987; and Steinberg, P.. Cholesterol and Cardiovascular Disease. 76. 3, 508-514 (1987).]

An additional area of utility for inhibitors of the 5-lipoxygenase pathway is in the opthamalogic area, in particular general inflammation of the corneal anterior and posterior segments due to disease or surgery such as in post surgical inflammation, uveitis, and allergic conjuntivitis. [See Rao N. et al. Arch. Ophathmal. 105 (3) 413-419 (1987); Chiou, L. and Chiou, G. J. Ocular Pharmacol. 1. 383-390 (1985); Bazan . J. Ocular Pharma. 4. 43-49 (1988); and Verbey N.L. et al.. Current Eve Research 7. 361-368 (1988).]

FORMULATION OF PHARMACEUTICAL COMPOSITIONS

The pharmaceutically effective compounds of this invention are administered in conventional dosage forms prepared by combining a compound of Formula (I) or the chiral compounds (+) N-l-[5-(3-benzyloxy)indanyl]-N-hydroxyurea; and (-) N-l-[5-(3- benzyloxy)indanyl]-N-hydroxyurea which for purposes herein will all be referred to as

"active ingredient" in an amount sufficient to produce 5-lipoxygenase pathway inhibiting activity with standard pharmaceutical carriers or diluents according to conventional procedures. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation. The pharmaceutical carrier employed may be, for example, either a solid or liquid.

Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25 mg. to about 1 g. When a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.

Preferably, each parenteral dosage unit will contain the active ingredient [i.e., the compound of Formula (I)] in an amount of from about 30 mg. to about 300 mg. Preferably, each oral dosage will contain the active ingredient in an amount of from about 50 mg to about 1000 mg.

The compounds of Formula (I) may also be administered topically to a mammal in need of the inhibition of the 5-lipoxygenase pathway of arachidonic acid metabolism. Thus, the compounds of Formula (I) may be administered topically in the treatment or prophylaxis of inflammation in an animal, including man and other mammals, and may be used in the relief or prophylaxis of 5-lipoxygenase pathway mediated diseases such as rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, inflamed joints, eczema, psoriasis or other inflammatory skin conditions such as sunburn; inflammatory eye conditions including conjunctivitis; pyresis, pain and other conditions associated with inflammation.

The amount of the active ingredient required for therapeutic effect on topical administration will, of course, vary with the compound chosen, the nature and severity of the inflammatory condition and the animal undergoing treatment, and is ultimately at the discretion of the physician. A suitable anti-inflammatory dose of an active ingredient is 1.5 mg to 500 mg for topical administration, the most preferred dosage being 1 mg to 100 mg, for example 5 to 25 mg administered two or three times daily.

By topical administration is meant non-systemic administration and includes the application of a compound externally to the epidermis, to the buccal cavity and instillation of such a compound into the ear, eye and nose, and where the compound does not significantly enter the blood stream. By systemic administration is meant oral, intravenous, intraperitoneal and intramuscular administration.

While it is possible for an active ingredient to be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation. The active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, e.g. from 1% to 2% by weight of the formulation although it may comprise as much as 10% w/w but preferably not in excess of 5% w/w and more preferably from 0.1% to 1% w/w of the formulation.

The topical formulations of the present invention, both for veterinary and for human medical use, comprise an active ingredient together with one or more acceptable carrier(s) therefor and optionally any other therapeutic ingredient(s). The carrier(s) must be

'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as: liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.

Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous or alcholic solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent. The resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100°C. for half an hour. Alternatively, the solution may be sterilized by filtration and transferred to the container by an aseptic technique. Examples of bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol. Lotions according to the present invention include those suitable for application to the skin or eye. An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops. Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.

Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy basis. The basis may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives, or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol. The formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic sulfactant such as sorbitan esters or polyoxyethylene derivatives thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.

The active ingredients may also be administered by inhalation. By "inhalation" is meant intranasal and oral inhalation administration. Appropriate dosage forms for such administration, such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques. The daily dosage amount of a compound of Formula (I) administered by inhalation is from about 0J mg to about 100 mg per day, preferably about 1 mg to about 10 mg per day.

This invention relates to a method of treating a disease state which is mediated by the 5-lipoxygenase pathway in an animal in need thereof, including humans and other mammals, which comprises administering to such animal an effective, 5-lipoxygenase pathway inhibiting amount of a Formula (I) compound.

By the term "treating" is meant either prophylactic or therapeutic therapy. By the term "mediated" is meant caused by or exacerbated by. Such Formula (I) compound can be administered to such mammal in a conventional dosage form prepared by combining the Formula (I) compound with a conventional pharmaceutically acceptable carrier or diluent according to known techniques. It will be recognized by one of skill in the art that the form and character of the pharmaceutically acceptable carrier or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables. The Formula (I) compound is administered to an animal in need of inhibition of the 5-lipoxygenase pathway in an amount sufficient to inhibit the 5-lipoxy¬ genase pathway. The route of administration may be oral, parenteral, by inhalation or topically.

The term parenteral as used herein includes intravenous, intramuscular, subcutaneous, intra-rectal, intravaginal or intraperitoneal administration. The subcutaneous and intramuscular forms of parenteral administration are generally preferred. The daily parenteral dosage regimen will preferably be from about 30 mg to about 300 mg per day. The daily oral dosage regimen will preferably be from about 100 mg to about 2000 mg per day for OPUFA and in particular 5-lipoxygenase treatment.

It will be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of the active ingredient will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular animal being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of the Formula (I) compound given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.

SYNTHESIS EXAMPLES Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following examples further illustrate the synthesis and use of the compounds of this invention. The following examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way.

EXAMPLE 1 (+/-)-N-l-r5-(4-FluorobenzvIoxy)indanvn-N-hvdroxyurea a 5-C4- fluorobenzyloxy^'.-1-indanone. To a solution of 5-hydroxy-l-indanone (1.02 g, 6.86 mmol) in dry DMF (15 mL) was added potassium carbonate (2.00 g, 17.15 mmol).

After stirring the mixture at room temperature for 10 min., 4-fluorobenzylbromide (1.6 mL, 10.28 mmol) was added and the resulting mixture was stirred at room temperature for 4 h. The mixture was poured into ice water and the product was extracted with EtOAc. The organic extract was dried over MgSO4. The solvent was removed in vαcuo and the residue was purified by flash chromatography, eluting with 25% EtOAc/Hexane to provide the desired product (1.09 g, 62% yield). 400 MHz iH NMR (CDCI3): 3 7.72 (d, 1H); 7.44 (m, 2H); 7.07 (m, 2H); 6.98 (m, 2H); 5.11 (s, 2H); 3.00 (t, 2H); 2.68 (t, 2H). b) 5-(4-fluorobenzyloxy -l-indanone oxime. To a solution of 5-(4- fluorobenzyloxy)-l-indanone (1.09 g, 4.25 mmol) in dry pyridine (15 mL) was added hydroxylamine hydrochloride (.44 g, 6.38 mmol). The resulting mixture was heated at 60°C for 1 h. The mixture was poured into ice water. The product was filtered, washed with water and dried in vacuo. The product (1J2 g, 97% yield) was used without further purification. 400 MHz *H NMR (CDCI3, MeOH-d4): 3 7.54 (d, 1H); 7.37 m, 2H); 7.02 (t, 2H); 6.82 (m, 2H); 4.99 (s, 2H); 2.96 (m, 2H); 2.90 (m, 2H). c) N-l-[5-(4-fluorobenzyloxy indanyl1-N-hvdroxyamine. To a solution of 5-(4- fluorobenzyloxyH-indanone oxime (1J2 g, 413 mmol) in ethanol (60 mL) was added borane-pyridine complex (2J mL, 20.7 mmol). The resulting mixture was stirred at room temperature for 30 min. Added dropwise over a period of 1 h. was 15% ethanolic HCl (6.9 mL). The mixture was stirred at room temperature 4 h. The reaction was quenched with saturated aqueous Na2CO3. Water was added until two phases formed. The organic phase was washed two times with water. The solvent was removed in vacuo and the residue was triturated with an ether/hexane solution. The desired hydroxyamine (0.66 g 59% yield) was recrystalized from EtOH/H2θ. 400 MHz 1H NMR (CDCI3, MeOH-d4): 97.38 (m, 2H); 7.28 (d, 1H); 7.05 (t, 2H); 6.83 (s, 1H); 6.79 (dd, 1H); 4.99 (s, 2H); 4.42 (m, 1H); 2.98 (m, 1H); 2.78 (m, 1H); 2.27 (m, 1H); 2.05 (m, 1H). d N- 1 -r5-(4-Fluorobenzyloxy')indanyll -N-hvdroxyurea. To a solution of N-l -[5- (4-fluoro)benzyloxy]-N-hydroxyamine (0.66 g, 2.42 mmol) in dry DMF (5 mL) was added acetic acid (0.20 mL, 3.63 mmol). The mixture was cooled to 0°C. Potassium cyanate (0.29 g, 3.63 mmol) dissolved in water (.5 mL) was added and the reaction mixture was stirred at 0°C for 20 min. The reaction mixture was diluted with water and the product was filtered and washed with water. Treatment with decolorizing carbon and purification by flash chromatography eluting with 2% MeOH/CH2Cl2 yielded a white residue what was recrystallized from EtOH/H2θ to give the desired hydroxyurea (0.65 g, 85% yield), m.p. 180 - 181⁰C.

EXAMPLE 2 (+/-)-N-l-r5-(2.6-Difluorobenzyloxy)indanyll-N-hvdroxyurea a) 5-(2.6-difluorobenzyloxy^')- 1-indanone. Following the procedure of Example la using 5-hydroxy- 1-indanone and a-bromo-2,6-difluorotoluene the desired indanone was obtained. 400 MHz *H NMR (CDCI3): d 7.71 (d, 1H); 7.38 (m, 1H); 7.05 (s, 1H); 6.99 (m, 3H); 5J9 (s, 2H); 3J0 (t, 2H); 2.70 (t, 2H). b) 5-(2,6-difluorobenzyloxy> 1-indanone oxime. Using the product of the proceeding reaction and following the procedure of example lb the titled oxime (92% yield) was obtained.400 MHz H NMR (CDCI3, MeOH-d4): d 7.53 (d, 1H); 7.29 (m, 1H); 6.90 (m, 4H); 5.06 (s, 2H); 2.98 (m, 2H); 2.90 (m, 2H). c) N- l-r5-(2,6-difluorobenzyloxy)]-N-hydroxyamine. Using the product of the proceeding reaction and following the procedure of example lc the titled hydroxyamine was obtained as a residue for which recrystallization from EtOH/MeOH was not successful. Instead, the product was purified by flash chromatography eluting with 2% MeOH/CH2θ2 yielding the desired hydroxyamine (76% yield). 400 MHz 1H NMR (CDCl, MeOH-d4): d 7.27 (m, IH); 6.88 (m, 3H); 6.80 (dd, IH); 5.04 (s, 2H); 4.42 (m, IH); 2.98 (m, IH); 2.80 (m, IH); 2.27 (m, IH); 2.05 (mJH). d¹) N- 1 -[5-(2,6-Difluorobenzyloxy^')indanyll-N-hydroxyurea. Using the product of the proceeding reaction and following the procedure of example Id the titled hydroxyurea was obtained (58% yield) was obtained, m.p. 157 - 158°C.

EXAMPLE 3 (+ -N-l-r5-(4-TrifIuoromethylbenzyloxy)indanvn-N- hydroxyurea a) 5-(4-trifluoromethylbenzyloxy)- 1 -indanone. Following the procedure of Example la using 5-hydroxy- 1-indanone and 4-trifluoromethylbenzyl bromide the desired product was obtained (44% yield). 400 MHz 1H NMR (CDCI3): 3 7.71 (d, IH); 7.68 (d, 2H); 7.56 (d, 2H); 6.98 (s, 2H); 5.21 (s, 2H); 3.09 (t, 2H); 2.68 (t, 2H). b) 5-(4-trifluoromethylbenzyloxy^")- 1-indanone oxime. Using the product of the proceeding reaction and following the procedure of example lb the titled oxime (76% yield) was obtained. 400 MHz *H NMR (CDCI3, MeOH-d4): d 7.70-7.55 (m, 5H); 6.92 (s, 2H);

5J5 (s, 2H); 3.03 (m, 2H); 2.99 (m, 2H). c) N- 1 -[5-(4-trifluoromethylbenzyloxy1-N-hydroxyamine. Using the product of the proceeding reaction and following the procedure of example lc the titled hydroxyamine was obtained (51% yield). 400 MHz 1H NMR (CDCI3, MeOH-d4): 97.61 (d, 2H); 7.53 (d, 2H); 7.30 (d, IH); 6.80 (m, 2H); 5.08 (s, 2H); 4.45 (m, IH); 3.00 (m, IH); 2.80 (m, IH);

2.30 (m, IH); 2.08 (m, IH). d) N-l-r5-(^'4-Trifluoromethylbenzyloxy)indanyl1-N-hydroxyurea. Using the product of the proceeding reaction and following the procedure of example Id the titled hydroxyurea was obtained (79% yield), m.p. 169 - 170°C.

EXAMPLE 4 (+/-)-N-l-r5-(3-Trifluoromethylbenzyloxy)indanvn-N- hydroxyurea a) 5-G-trifluoromethylbenzyloxy')- 1 -indanone. Following the procedure of Example la using 5-hydroxy- 1-indanone and 3-trifluoromethylbenzyl bromide the desired product was obtained (82% yield), m.p. 95-96°C. b) 5-G-trifluoromethylbenzyloxy',- 1-indanone oxime. Using the product of the proceeding reaction and following the procedure of example lb the titled oxime (94% yield) was obtained, m.p. 170-172°C. c) N- 1 -r5-(3-trifluoromethylbenzyloxyl-N-hvdroxyamine. Using the product of the proceeding reaction and following the procedure of example lc the titled hydroxyamine was obtained (62% yield), m.p. 114-115°C. d N-l-r5-(3-Trifluoromethylbenzyloxynndanyl1-N-hvdroxyurea. Using the product of the proceeding reaction and following the procedure of example Id the titled hydroxyurea was obtained (37% yield), m.p. 157 - 158°C.

The compounds of Examples 4 to 11 may be made by analagous processess to that of

Examples 1 to 4 using appropriate starling materials: Example 4 N-l-[5-(2-Trifluoromethylbenzyloxy)indanyl]-N-hydroxyurea

Example 5 N-l-[5-(2-Chloro-6-fluorobenzyloxy)indanyl]-N-hydroxyurea m.p. 149°C

Example 6 N-l-[5-(2-Trifluoromethylbenzyloxy)indanyl]-N-hydroxyurea

Example 7 N- 1 -[5-(2,4-Difluorobenzyloxy)indanyl]-N-hydroxyurea;

Example 8 N-l-[5-(2-Fluorobenzyloxy)indanyl]-N-hydroxyurea; Example 9 N-l-[5-(3,4-Difluorobenzyloxy)indanyl]-N-hydroxyurea;

Example 10 N-l-[5-(2,5-Difluorobenzyloxy)indanyl]-N-hydroxyurea;

Example 11 N- 1 -[5-(3,5-bisTrifluoromethylbenzyloxy)indanyl]-N-hydroxyurea.

EXAMPLE 12 and 13 (+)-N-l-(5-BenzvIoxy-2.3-dihvdroindanvn-N- hydroxyurea : and (-)-N-l-(Benxyloxy-2_<3-dihydroindanyl)-N-hvdroxyurea

The chiral compounds of Examples 12 and 13 may be made by the analagous process exemplified in WO 91/14674, published 3 October 1991, whose disclosure is hereby incorporated by reference, or by the methods disclosed herein, but using the appropriate indandyl starting materials. aUlRS. 4SVNJJ5-Benzyloxy-2.3.dihyroindanvD-N-(N'-4-benzyl-3- carboxyloxazolidin-2-onyl^'.urea. To a solution of N-l-(5-benzyloxy-2,3-dihydroindanyl)- N-hydroxyurea (3.97 g, 13.32 mmol) in CH2CI2 (100 mL) was added triethylamine (3.7 mL, 26.6 mmol), followed by (S)-4-benzyl-2-oxazolidinone-N-3-carboxylic acid chloride (4.76 g, 19.98 mmol). The resulting mixture was stirred at room temperature for 1 h, then washed successively with H2O and saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 1% MeOH/CH2θ2 to afford the title compound as a mixture of diastereomers (3.67 g, 55%). The diastereomers were separated by normal-phase HPLC (Crosfield silica gel column, 1 mL/min flow rate, 254 nm UV detector) eluting with 75:12.5:12.5:1 EtOAc/CH2Cl2/hexane/HCO2H. b) (+)-N-l-(5-Benzyloxy-2.3-dihydroindanyO-N-hydroxyurea. To a solution of one of the diasterioners obtained from the separation of (lRS,4S)-N-l-(5- Benzyloxy-2,3-dihydroindanyl)-N-(N'-4-benzyl-3-carboxyloxazoUdin-2-onyl)urea (2.58 g, 5J5 mmol) in ethanol (70 mL) was added lithium hydroxide monohydrate (.22 g, 5.23 mmol) dissolved in H2O (3 mL). After stirring at room temperature for 30 min, the mixture was diluted with water and the precipitate was filtered. Purification by flash chromatography (silica gel, 2%-5% MeOH/CH2θ2) and recrystalization from EtOH/H2θ afforded the title compound (.59 g 38.5%). m.p. 167 - 168°C. [a]D = +36.0° (MeOH). ^lH NMR (DMSO-d6): d 8.90 (s, IH), 7.50-7.30 (m, 5H), 7.00 (d, IH), 6.85 (s, IH), 6.80 (d, IH), 6.38 (m, IH), 2J5 (m, IH), 2.05 (m, IH). IR: 3460, 3340-3260, 1670. CIMS (NH3), m z (rel. int.): 316 [(m+NH4)+, 11], 223 (100). Anal. Calc. for C17H18N2O3: C 68.44, H 6.08, N 9.39; found C 68.09, H 6.05, N 9.29. c) (-)-N-l-(5-Benzyloxy-2_<3-dihydroindanyl)-N-hydroxyurea. The (-)- enantiomer was prepared in a similar fashion, except using the other diastereomer obtained from the separation of (lRS,4S)-N-l-(5-Benzyloxy-2,3-dihydroindanyl)-N-(N'-4-benzyl-3- carboxyloxazolidin-2-onyl)urea. m.p. 165.5 - 166.5°C. [a]p -39.2° (MeOH). ²H NMR (DMSO-d6): d 8.90 (s, IH), 7.50-7.30 (m, 5H), 7.00 (d, IH), 6.85 (s, IH), 6.80 (d, IH), 6.38 (s, 2H), 5.58 (t, IH), 5.05 (s, 2H), 2.90-2.80 (m, IH), 2.65 (m, IH), 2J5 (m,

IH), 2.05 (m, IH). IR: 3460, 33440-3260, 1670. CIMS (NH3), m z (rel. int.): 316 [(M+NH4)⁺, 11], 223 (100). Anal. Calc. for C17H18N2O3: C 68.44, H 6.08, N 9.39; found C 68.15, H 6.09, N 9.29.

EXAMPLE 14

COMPOSITION FOR ADMINISTRATION BY INHALATION For an aerosol container with a capacity of 15-20 ml: Mix 10 mg of a compound of Formula (I) with OJ-0.2% of a lubricating agent, such as Span 85 or oleic acid, and disperse such mixture in a propellant (c.a.), such as freon, preferably a combination of freon 114 and freon 12, and put into an appropriate aerosol container adapted for either intranasal or oral inhalation administration.

EXAMPLE 15 COMPOSITION FOR ADMINISTRATION BY INHALATION For an aerosol container with a capacity of 15-20 ml: Dissolve 10 mg of a compound of Formula (I) in ethanol (6-8 ml), add OJ-0.2% of a lubricating agent, such as Span 85 or oleic acid, and disperse such in a propellant (c.a.), such as freon, preferably a combination of freon 144 and freon 12, and put into an appropriate aerosol container adapted for either intranasal or oral inhalation administration.

UTILΠΎ EXAMPLES METHODS : For the in vitro experiments, compounds were dissolved at appropriate concentrations in ethanol or DMSO (dimethylsulfoxide) having a final concentration of less than or equal to 1.0%, and then diluted to their respective concentrations using the buffers indicated in the text. In experiments when mice were used they were Balb/c mice obtained from Charles River Breeding Laboratories, and within a single experiment the mice were age-matched. Their weight range was from 21 to 30 g. The test groups generally contained 3-6 animals.

5-LIPOXYGENASE ACTTVπΥ:

The 5-lipoxygenase (5-LO) was isolated from extracts of RBL-1 cells. The assay for assessing inhibition of the 5-LO activity was a continuous assay which monitored the consumption of oxygen (O2). The cell extract (100 ug) was preincubated with the inhibitor or its vehicle in 25 mM BisTris buffer (pH 7.0) that contained 1 mM EDTA, 1 mM ATP, 150 mM NaCl and 5% ethylene glycol for 2 minutes at 20°C (total volume 2.99 ml). Arachidonic acid (10 uM) and CaCl2 (2 mM) were added to start the reaction, and the decrease in O2 concentration followed with time using a Clark-type electrode and the Yellow Spring O2 monitor (type 53) (Yellow Springs, OH). The optimum velocity was calculated from the progress curves. All compounds were dissolved in ethanol with the final concentration of ethanol being 1% in the assay.

Drug-induced effects on enzyme activities are described as the concentration of drug causing a 50% inhibition of oxygen consumption (IC50).

EICOS ANOID PRODUCTION FROM HUMAN MONOCYTES IN VITRO

Human monocytes were prepared from leukosource packs supplied by the American Red Cross. The leukosource packs were fractionated by a two-step procedure described by F. Colatta et al. (J. Immunology 132:936, 1984) that uses sedimentation on Ficoll followed by sedimentation on Percoll. The monocyte fraction that results from this technique was composed of 80-90% monocytes with the remainder being neutrophils and lymphocytes. In addition, significant number of platelets are present.

The monocytes (10^ cells) were placed into polypropylene tubes and used as a suspended culture. The assay buffer consisted of RPMI 1640 buffer, 2 mM glutamine, 2.5 mM HEPES and 2 mM CaCl2 (total volume 0.475 ml). Compounds (0.005 ml) were added in DMSO, and the cells were preincubated for 10 minutes at 37°C with constant agitation. A23187 (2 uM) was used to stimulate the cells. After an additional 10 minutes, the buffer was collected by centrifugation (2500 xg for 15 minutes), and stored at -70°C until assayed. LTB4 production was measured by radioimmunassay which was performed according to the manufacturer's (Advanced Magnetics, Boston, MA) instructions. PGE2 was determined using an RIA kit supplied by New England Nuclear (Boston, MA). EX VTVO MOUSE BLOOD EICOSANOID ASSAY

Mice were pre-treated per os with vehicle or a test compound (dissolved in dimethylacetamide and diluted 1 to 10 with sesame oil) 30 minutes prior to removal of blood. The 5-lipoxygenase product LTB4, was extracted from whole blood following A23187 stimulation. Aliquots of pooled heparinized mouse blood (1 ml each aliquot) from male CD1 mice (Charles River) were placed into 4 ml polypropylene tubes. The tubes were preincubated for about five minutes at 37°C. A23187 (60 uM) was added to stimulate eicosanoid production. Several aliquots of blood were not stimulated and, thus, provided background levels for eicosanoid production. All tubes were incubated for about 30 minutes at 37°C. The blood samples were centrifuged at 400 xg for about 15 minutes, and the plasma recovered for extraction. One volume of chilled acetonitrile was added to all at 5°C. The supernatants were recovered and diluted with 1% formic acid:l% triethylamine to achieve a final concentration of 20% acetonitrile. These supernatants were then loaded onto the extraction cartridge that had been conditioned according to the Manufacturer's instructions (Solid Phase Extraction Columns, J. T. Baker, C18 3 ml size). The samples were washed with 3 ml of 1% formic acid:l% triethylamine, air dried, and then washed with 3 ml of petroleum ether. After air drying again, the samples were eluted with methyl formate. The eluents were concentrated under vacuum. The concentrates were resuspended in 30% acetonitrile buffered with 50 mM ammonium acetate (200 ul). The recovery of LTB4 was 60%. The 300 ul concentrates were assayed by radioreceptor assay for LTB4 by labortatory protocol-

DATA ANALYSIS AND STATISTICS

Mean values for groups were calculated and percent inhibition was determined between the vehicle control mean and test group. The ED50 was determined using linear regression analysis and was taken as the dose which resulted in a 50% inhibition of the vehicle control constriction response. Statistical analysis was done using Student's "t" test and a p<0.05 was considered statistically significant.

RESULTS

The effect of hydroxyurea compounds as inhibitors of 5-LO, and Human Whole Blood is shown in Table I. The compounds tested displayed a range of inhibitory activity both in vitro and in vivo. Examination of the activity of these compounds on human monocyte production of LTB4, in isoloated cases, corroborated the 5-LO inhibitory activity. None of the compounds tested showed potent inhibition of cyclooxygenase activity as indicated by production of the prostaglandin, PGE2. Evaluation of the in vivo 5-LO inhibitory activity of these compounds was done using mouse whole blood stimulated with calcium ionophore (A23187) ex vivo. As seen in Table I, those tested were shown to inhibit 5-LO activity ex vivo as well as in vitro. Several of these compounds also showed dose-related inhibition of LTB4 production as well. Evaluation of the in vivo 5-LO inhibitory activity of the compounds of Examples 12 and 13 was done using mouse whole blood stimulated with calcium ionophore (A23187) ex vivo. As seen in Table π, the chiral compound was shown to superior inhibition of 5-LO activity ex vivo as well as in vitro.

LTBA PRODUCΉON BY HUMAN WHOLE BLOOD

Heparinized human blood was collected by venipuncture. The blood was prewarmed (4.5ml of blood per sample) for 5 min at 37° C in a waterbath with constant agitation, then preincubated with the test compound or DMSO for an additional 5 minutes. A23187 (60μM) in 0.5ml autologous plasma was added and the blood incubated for 10 min at 37 °C. The reaction was stopped by placing the samples on ice followed by centrifugation at 2500 x g for 15 min at 4°C. The plasma was collected and combined with

2 ml of ice-cold acetonitrle. This mixture was centrifuged at 2500 x g for 15 min and the supemantant was added to 6 ml of ice-cold 1% formic acid. The sample was purified by solid phase extraction unsing a Ci8 column (J.T. Baker, Phillipsburg, NJ) and eluted with

3 ml of methyl formate. The methyl formate was dried under vacuum and the residue resuspended in 500μl of enzyme immunoassay (EIA) buffer. Leukotriene B4 was measured by EIA.

PHENYLBENZOOUINONE-INDUCED ABDOMINAL CONSTRICTION ASSAY

Phenylbenzoquinone (PBQ, Eastman Kodak Co., Rochester, NY) is dissolved in warm (50°C) ethanol and diluted with distilled water to a final concentration of 0.2 mg/ml. The solution is protected from light by a foil wrap and is administered intraperitoneally at a dose volume of 0.01 ml/gm.

Mice are pre-treated with vehicle or test compound (dissolved or suspended in 25% PEG 200) for about 15 minutes and then injected with PBQ, following which each mouse is placed into individual 4 liter beakers. CD1 mice show a characteristic abdominal contraction/stretching response which consists of extending one or both of the hind limbs. These responses which occur at a variable frequency (not less than 1-2 seconds apart) are counted on a hand counter. The counting period is for 10 minutes following a 5 minute acclimation period. Results are based on the total number of constrictions observed during the 10 minute period. TABLE I

Indane-based 5-LO Inhibitors

* Actual Examples from WO 91/14674

TABLE π

Indane-based 5-LO Inhibitors

5-LO LTB4 mouse ex vivo HWB cacld¹ IC50 % of control ED50

X log P UM @ 10mg/kg(ED₅o) UM

(+/-) OCH₂P h 3.1 0.78 - 85 (4 . 0 ) 0.64 chiral OCH₂Ph 3 J 0.62 0.9 0.15 chiral OCH₂Ph 3 J 0.88 1 .9 0.72

* Racemate Example from WO 91/14674

The above description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent Therefore the Examples herein are to be construed as merely illustrative and not a limitation of the scope of the present invention in any way. The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows.

Claims

What is claimed is:

1. A compound of the formula

FORMULA (T) wherein

R3 is hydrogen, a pharmaceutically acceptable cation, aroyl or a C1J2 alkanoyl; B is oxygen or sulfur;

R4 is NR5R , alkyl j_6, halosubstituted alkyl 1-6, hydroxy substituted alkyl ι_6, alkenyl2-6, aryl or heteroaryl optionally substituted by halogen, alkyl i-6, halosubstituted alkyl ι_6, hydroxyl, or alkoxy 1-6; R5 is H or alkyl 1-6; R6 is H, alkyl ι_6, aryl, arylalkyl 1- , heteroaryl, alkyl substituted by halogen or hydroxyl, aryl or heteroaryl optionally substituted by a member selected from the group consisting of halo, nitro, cyano, alkylι_i2, alkoxy ι_6, halosubstituted alkyli-6, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthio, alkylsulphonyl, or alkylsulfinyl; or R5 and R6 may together form a ring having 5 to 7 members, which members may be optionally replaced by a heteroatom selected from oxygen, sulfur or nitrogen; W is CH2(CH2)_s; s is 0 or an integer having a value of 1;

Ri is a member selected from the group consisting of (CH2)nrAr-(X)v, O(CH2)_mAr-(X)_v, or S(CH₂)m-Ar-(X)_v; m is 0 or an integer having a value of 1, 2 or 3; v is n integer having a value of 1, 2 or 3;

Ar is phenyl or naphthyl;

X is halogen or halosubstituted alkyl; provided that when s is 1, and Ri is O(CH2)m^Ar-(X)v, and Ar is phenyl, and v is 1, and m is 0 or 1, then X is not 4- chloro; and when s is 0 or 1, and Ri is O(CH2)_mAr-(X) , and Ar is phenyl, and m is 0, and v is 1, then X is not 4-fluoro; or the pharmaceutically acceptable salts thereof.

2. The compound according to Claim 1 wherein R4 is alkyl i.g, halosubstituted alkyl 1-6, hydroxy substituted alkyl i- , alkenyl 2-6, aryl or heteroaryl optionally substituted by halogen, alkyl 1-6, halosubstituted alkyli-6, hydroxyl, or alkoxy 1-6- or R4 is NR5R6.

3. The compound according to Claim 2 wherein R is O(CH2)m-Ar-(X)_v, or (CH2)m-Ar- (X)v; m is a number having a value of 0 to 2; and v is a number having a value of 1 or 2.

4. The compound according to Claim 3 wherein Ri is in the 5- or 6-position and Ar is phenyl.

5. The compound according to Claim 4 wherein R₄ is NR5R and R5 and R6 are independently selected from hydrogen or alkyl.

6. The compound according to Claim 5 wherein the m is 1 and the phenyl is substituted by flourine in the 2- position, 4- position; 2,6-difluoro, 2,4-difluoro, 3,4-difluoro, 2, 5- difluoro, 2-C1-6-F, 4-CF3, or 3-CF3.

7. The compound according to Claim 5 wherein s is 0 .

8. The compound according to Claim 7 wherein Ri is in the 5-position.

9. The compound according to claim 1 which is N-l-[5-(2,6-Difluorobenzyloxy)indanyl]-N-hydroxyurea;

N-l-[5-(4-Trifluoromethylbenzyloxy)indanyl]-N-hydroxyurea;

N-l-[5-(4-Fluorobenzyloxy)indanyl]-N-hydroxyurea;

N- 1 - [5-(3-Trifluoromethylbenzyloxy)indanyl]-N-hydroxyurea;

N- l-[5-(2-Chloro-6-fluorobenzyloxy)indanyl]-N-hydroxyurea; or pharmaceutically acceptable salts thereof.

10. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier or diluent and a compound according to Claim 1 or 9 or a pharmaceutically acceptable salt thereof.

11. A method of treating an OPUFA mediated disease in a mammal in need thereof, which process comprises administering to such mammal an effective OPFUA inhibiting amount of a compound according to any of Claims 1 to 9, or pharmaceutical salt thereof .

12 . The method according to Claim 11 wherein the enzyme 5-lipoxygenase is inhibited.

13. The method according to Claim 11 wherein s is 0, m is 1, B is oxgyen, Ri is the 5- position.

14. The method according to Claim 13 wherein the phenyl is substituted by flourine in the 2- position, 4- position; 2,6-difluoro, 2,4-difluoro, 3,4-difluoro, 2, 5-difluoro, 2-C1-6-F, 4-CF3, or 3-CF3.

15. The method according to Claim 12 wherein the lipoxygenase mediated disease is arthritis, rheumatoid arthritis, osteoarthritis, allergic rhinitis, psoriasis, dermatitis, ischemic induced myocardial injury, reperfusion injury, gout, asthma, adult respiratory distress syndrome, atherosclerosis, inflammatory bowel disease, stroke, renal disease, spinal cord injury or traumatic brain injury.

16. The method according to Claim 15 wherein the lipoxygenase mediated disease is asthma.

17. The method according to Claim 11 which is administered orally or by inhalation.

18. The method according to Claim 12 wherein the compound is N-l-[5-(2,6-Difluorobenzyloxy)indanyl]-N-hydroxyurea; N-l-[5-(4-Trifluoromethylbenzyloxy)indanyl]-N-hydroxyurea; N-l-[5-(4-Fluorobenzyloxy)indanyl]-N-hydroxyurea;

N-l-[5-(3-Trifluoromethylbenzyloxy)indanyl]-N-hydroxyurea; N- l-[5-(2-Chloro-6-fluorobenzyloxy)indanyl]-N-hydroxyurea; or pharmaceutically acceptable salts thereof.

19. The compound which is N-l-[5-(4-Fluorobenzyloxy)indanyl]-N-hydroxyurea, or a pharmaceutically acceptable salt thereof.

20. The compound which is N-l-[5-(2,6-Difluorobenzyloxy)indanyl]-N-hydroxyurea, or a pharmaceutically acceptable salt thereof.

21. The compound (+) N-l-[5-(3-benzyloxy)indanyl]-N-hydroxyurea or (-) N-l-[5-(3- benzyloxy)indanyl]-N-hydroxyurea, or a pharmaceutically acceptable salts thereof.

22. A pharmaceutical composition comprising an effective amount of (+) N- 1-[5-(3- benzyloxy)indanyl]-N-hydroxyurea or (-) N-l-[5-(3-benzyloxy)indanyl]-N-hydroxyurea and a pharmaceutically acceptable carrier or diluent.