WO1992021678A1 - LIPOXYGENASE INHIBITING PYRROLO [1,2a]INDOLE COMPOUNDS - Google Patents

Abstract

Pyrrolo[1,2-a]indole hydroxyurea/hydroxamate compounds, pharmaceutical compositions containing said compounds and their use as inhibitors of oxygenated polyunsaturated fatty acid metabolism.

Description

LICPOXYGENASE INEIIBITING PYRROLO [1,2a]INDOLE COMPOUNDS

FIELD OF INVENTION 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 INVENTION

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 various 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 5,12-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 leukotiienes 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 leukotiienes 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 thus remains a need 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 leukotiienes and prostaglandins. SUMMARY OF THE INVENTION

This invention relates to a compound of the Formula (I)

wherein

one of R₁ and R₂ is hydrogen and the other is

R is hydrogen, a pharmaceutically acceptable cation, aroyl or C_1-12 alkanoyl;

D is oxygen or sulfur;

W is CY₁Y₂(CH₂)s;

Y₁ is hydrogen or (C_1-2)alkyl;

s is a number having a value of 0 or 1;

R₄ is NR₅R₆; (C_1-6)alkyl; halosubstituted (C_1-6)alkyl; hydroxysubstituted-(C_1-6)alkyl; (C_2-6)alkenyl; aryl or heteroaryl optionally substituted by halogen, (C_1-6)alkyl, halosubstituted (C_1-6)alkyl, hydroxyl, or (C_1-6)alkoxy;

R₅ is H or (C_1-6)alkyl; R₆ is H; (C_1-6)alkyl; aryl; aryl(C_1-6)alkyl; heteroaryl; alkyl substituted by halogen or hydroxyl; aryl or heteroaryl optionally substituted by a substituent selected from the group consisting of halo, nitro, cyano, (C_1-12)alkyl, (C₁_ 6)alkoxy, halosubstituted (C_1-6)alkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthio, alkylsulphonyl, or alkylsulfinyl; or

R₅ and R₆ may together form a ring having 5 to 7 ring atoms, which ring atoms may optionally include a further heteroatom selected from oxygen, sulfur or nitrogen;

R₃, R₇ and R₈ are independent substituent groups which when combined with the parent ring system have a lipophilicity value from about 2.5 to about 50; or a pharmaceutically acceptable salt thereof.

The compounds of Formula (I) are useful for inhibiting the formation of oxygenated polyunsaturated fatty acids (hereinafter OPUFA).

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

This invention also relates to a method of treating an OPUFA mediated disease in an animal in need thereof which comprises administering to such animal, including humans, an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

More specifically this invention relates to a method of treating a lipoxygenase pathway mediated disease in an animal, including humans, 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.

This invention also relates to a method of treating analgesia in an animal in need thereof, including humans, which comprises administering to such animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. This invention also relates to a method of treating an OPUFA mediated disease in an animal in need thereof which comprises administering to such animal, including humans, an effective amount of a compound of formula (II) (a hydroxylamine precursor of a compound of formula (I), hereinafter defined) or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

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, methods of treating an OPUFA mediated disease, specifically a 5-lipoxygenase pathway mediated disease comprising

administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The compounds of formula (I) have been found to be useful in inhibiting the enzymes involved in tile oxygenated polyunsaturated fatty acid pathway which includes the metabolism of arachidonic acid, in an animal, including humans, in need thereof.

The lipophilicity value, as used herein, provides a quantitative treatment of the effect of structure on the reactivity or ability of the compounds of formula (I) and (II) to act as OPUFA inhibitors. It has been found that compounds of formula (I) and (II) which have certain combinations of substituents R₃, R₇ and R₈ which raise the lipophilicity value of the parent compound (in which each of R₃, R₇ and R₈ is hydrogen and s is 0) above the value of 2.5 calculated for the parent compound are active as OPUFA inhibitors. It is however appreciated that there may be some isolated instances where the particular combination of substituents R₃, R₇ and R₈ may raise the lipophilicity value above 2.5 but neverthe less result in compounds which are not OPUFA inhibitors. It is believed that such compounds will be those in which the R₃ substituent is physically too large and accordingly reults in steric hinderance of the R₁or R₂ substituent. It is however further believed that the skilled man will be alert to such a possibility. Furthermore, such compounds in which the lipophilicity value is calulated to be above 2.5 but which are not OPUFA inhibitors are outside the scope of this invention. The lipophilicity values, or Log P, for the present invention may be readily calculated using the CLOGP Program which is readily available from

MedChem Project, Pomona College, Claremont, California, United States and described by Leo in Comprehensive Medicinal Chemistry.4, 295-319, ed. Hansch, C, Sammes, P., Taylor J.; Pergammon Press (1990). This program calculates a lipophilicity value CLOGP. In this particular case, the CLOGP value of the parent compound varies from 2.5 (for R₃=R₇=R₈=H and s=0) to 3.3 (for R₃=R₇=R₈=H and s=1). The effect of changing the R₃, R₇ and R₈ moieties may then be calculated to determine if the substitution has increased or decreased the lipophilicity relative to the parent. For the purpose of these calculations, the lipophilicity of the R₁/R₂/Y₁ groups is not included and each is considered only as hydrogen. Preferably, the lipophilicity value for the R₃, R₇ and R₈ moieties in combination with the parent ring is in the range from about 2.5 to about 50, more preferably from about 2.8 to about 25, even more preferably from about 3.0 to about 15 and most preferably from about 3.3 to about 9. Representative examples are shown in Table A below for compounds of formula (I) wherein W is CH₂ and s is 0.

Preferably R₃, R₇ and R₈ is each independently selected from the group consisting of hydrogen, halogen, (C_1-10)alkyl, (C_1-10)alkoxy, NR₉R₁₀, (CH₂)_m- Ar-(X)y, O(CH₂)_mAr-(X)v, or S(CH₂)_m-Ar-(X)v; or R_3, R₇ and R₈ may also be a protected amine functionality, such as an N-acyl or sulfonyl amide;

wherein m is a number having a value of 0 to 4; preferably m is 0 to 2;

v is a number having a value of 1 or 2; preferably v is 1;

R₉ and R₁₀ are independently selected from hydrogen, (C_1-10)alkyl,

halosubstituted(C_1-6)alkyl, (C_5-8)cycloalkyl, (C_2-10)alkenyl, aryl(C_1-6)alkoxy, or R₉ and R₁₀ may together form a saturated or unsaturated ring having 5 to

7 ring atoms, which ring atoms may optionally include a further heteroatom selected from oxygen, sulfur or nitrogen;

Ar is a member selected from the group consisting of phenyl, naphthyl, quinolyl, isoquinolyl, pyridyl, furanyl, imidazoyl, benzimidazoyl, triazolyl, oxazolyl, isoxazolyl, thiazole, or thienyl;

Xis a member selected from the group consisting of hydrogen, halogen,

(C_1-10)alkyl, (C_5-8) cycloalkyl, (C_2-10)alkenyl, hydroxy, (CHY₃)_tcarboxy,

(C_1-10)aloxy, S(O)_r -, (C_1-10)alkyl, halosubstituted(C_1-10)alkyl,

hydroxysubstituted(C_1-10)alkyl, (CHY₂)_tN(R₅)₂, or cyano;

r is a number having a value of 0, 1 or 2;

Y₃ is hydrogen or (C_1-3)alkyl;

t is a number having a value of 0 or 1.

A preferred embodiment of the present invention is where R₃ is selected from hydrogen, halogen, (C_1-6)alkoxy, C_1-6 )alkyl or a derivative of the alkylaryl moieties ((CH₂)_m-Ar-(X )_v, O(CH₂)_mAr-(X)_v, or S(CH₂)_m-Ar-(X)_v), where the polymethylene chain (CH₂)m is of sufficent length to avoid a potential problem of steric hindrance. More preferably, R₃ is hydrogen or flourine. A more preferred embodiment of the present invention is where the (X)_v groups are hydrogen, alkoxy, halo, and CF₃, preferably in the 4-position. When X is (CHY₃)_tN(R₅)₂ the R₅ group is independently selected from hydrogen or a

(C_1-6)alkyl, giving an unsubstituted, mono- or di-substituted amine

component. The v term is preferably 1. If the Ar ring is disubstituted, preferably one of the X moieties is alkyl, alkoxy, halo, or CF₃.

Specific R₃, R₇ and Re groups of interest are halogen, alkoxy, phenethyl, benzyloxy, aryloxy and substituted derivatives thereof. Specifically such groups are halogen, such as chloro and flouro; halo substituted aryl and aryloxy derivatives, such as 4-chlorobenzyloxy, 4-flurophenoxy, methoxy, phenoxy, benzyloxy, 4-methoxybenzyloxy, 2-phenylethyl, 2-quinoylmethoxy, and 2-naphthylmethoxy. The term "protected amine" as used herein for the R₃, R₇ and Re moieties refers to those standardly used in the art as a non-strongly basic amine, such as those having a pKa above 7. The term "N-acyl amide", as used herein, includes such groups as, but is not limited to, formamide, acetamide, N-acetyl, and N-benzoyl. The term "sulfonylamide", as used herein, includes such groups as, but is not limited to, N-methanesulfonamide.

A further preferred embodiment of the present invention is where D is oxygen. Preferably R₄ is NR₅R₆ or (C_1-6)alkyl.

Preferably R₅ is aryl or arylalkyl and R₆ is phenyl or hydrogen. More preferably, R₅ and R₆ are independently hydrogen or alkyl.

A preferred ring placement for the R₇ moiety, when for instance R₈ is hydrogen and s is 0, is the 7-position. A preferred disubstitution for the R₇ and R₈ moieties also includes a 7-position substitution. For all compounds herein, R' is preferably hydrogen or a pharmaceutically acceptable cation.

Specific examples of hydroxyurea compounds of formula (I) include the following:

N-{1-(2,3-Dihydro-1H-pyrrolo[1,2-a]indolyl)}-N-hydroxyurea;

N-{1-(7-Benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indolyl)}-N-hydroxyurea;

N-{1-(2,3-Dihydro-7-isopropyl-9-methyl-1H-pyrrolo[1,2-a]indolyl)}-N-hydroxyurea;

N-{1-(7-Chloro-2,3-dihydro-1H-pyrrolo[1,2-a]indolyl)}-N-hydroxyurea;

N-{1-(2,3-Dihydro-7-ethyl-1H-pyrrolo[1,2-a]indolyl)}-N-hydroxyurea;

N-{1-(2,3-Dihydro-7-phenoxy-1H-pyrrolo[1,2-a]indolyl)}-N-hydroxyurea; or

N-{1-(2,3-Dihydro-9-methyl-7-phenoxy-1H-pyrrolo[1,2-a]indolyl)}-N-hydroxyurea.

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, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, and the like.

The term "alkenyl" is used herein at all occurrences to mean a 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-1-propenyl, 1-butenyl, 2-butenyl and the like.

The term "aralkyl" is used herein to mean Ar(C_1-4)alkyl, wherein Ar is as defined for formula (I).

The term "aroyl" is used herein to mean ArC(O)-, wherein Ar is as defined for formula (I), including, but not limited to, phenyl, 1- or 2-naphthyl and the like. The term "alkanoyl" is used herein to mean alkylC(O)-, 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 any lipoxygenase enzyme, such as but not limited to, 5-, 8-, 11-, 12-, or 15- lipoxygenase enzymes. 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-HETE,12-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) have also been found to be useful for inhibition of the OPUFA pathway and in the treatment of analgesia.

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

wherein:

' one ofR'₁ and R'₂ is hydrogen and the other is

;

B' is hydrogen, benzyl, optionally substituted benzyl , Si(R_x)3, C(O)R_5', C(OX)R_5', CH₂OCH₂CH₂Si(Rx)₃, (Cι.₃)alkoxy(Cι)alkyl, (C_{1- 3})alkoxy(C₂)alkoxy(C₁)alkyl, or tetrahydropyranyl;

A is hydrogen or C(O)OR_Z;

R_z is benzyl, Si(R_x)₃, t-butyl, or CH₂OCH₂CH₂Si(Rx)₃;

R_5' is C_1-6 alkyl, aryl, or aralkyl;

R_x is independently selected from alkyl or aryl;

the remaining variables W, R'₃, R'₇, and R'₈, are as defined above for formula

(I) for the corresponding non-hyphenated variables;

or a salt, in particular, a pharmaceutically acceptable salt, thereof.

Preferred B' substituent groups are tetrahydropyranyl; -CH₂OCH₃ (B' is (C_1-3)alkoxy(C₁)alkyl); -CH₂OCH₂CH₂Si(CH₃)₃ (B' is CH₂OCH₂CH₂Si(Rx)₃), -CH₂OCH₂CH₂OCH₃ when (B' is (C_1-3)alkoxy(C₂)alkoxy(C₁)alkyl); C(O)R_5' and C(OX)R_5' with R_5' as (C_1-6) alkyl, specifically methyl, t-butyl, or phenyl group or benzyl (R_5' is aralkyl). When B' is an optionally substituted benzyl, the substituent groups are selected from (C_1-6)alkoxy or (C_1-6)alkyl.

Specific examples of hydroxylamines of formula (II) include:

N-{1-(2,3-Dihydro-1H-pyrrolo[1,2-a]indolyl)}-N-hydroxyamine;

N-{1-(7-Benzyloxy-2,3-dmydro-1H-pyrrolo[1,2-a]indolyl)}-N-hydroxyamine;

N-{1-(2,3-Dihydro-7-isopropyl-9-methyl-1H-pyrrolo[1,2-a]indolyl)}-N-hydroxyamine;

N-{1-(7-CMoro-2,3-dmydro-1H-pyrrolo[1,2-a]indolyl)}-N-hyclroxyamine;

N-{1-(2,3-Dihydro-7-ethyl-1H-pyrrolo[1,2-a]mdolyl)}-N-hyodroxyamine;

N-{1-(2,3-Dmydro-7-phenoxy-1H-pyrr rolo[1,2-a]mdolyl)}-N-hydroxyamine; and

N-{1-(2,3-Dihydro-9-methyl-7-phenoxy-1H-pyrrolo[1,2-a]indolyl)}-N-hydroxyamine. The compounds of formula (I) maybe readily obtained from the corresponding compounds of formula (II) by anology with procedures well known to those skilled in the art, such as those described by Summers et al in U.S. Patent no. 4,873,259, issued October 10, 1989, pages 7-11 whose disclosure is

incorporated by reference herein. Several different synthetic schemes may be used to prepare the compounds of this invention and are described in greater detail below. Although these schemes when illustrated utilize only one particular compound, it will be seen from the working examples that other compounds of this invention can be prepared in the same manner using the appropriate starting materials readily available to one skilled in the art.

In general, a compound of formula (I) may be obtained by a process which comprises treating a compound of formula (II) with a reagent capable of transforming a hydroxylamine [-NH(OH)] functional group into a hydroxyurea [-N(OH)CON-] or a hydroxamic acid derivative [-N(OH)CO-]. Suitable such reagents are well known in the art and include trimethyl isocyanate, alkali metal cyanate, phosgene or a phosgene equivalent followed by ammonia or an amine (for a hydroxyurea) or an acylating agent such as an acyl chloride or an acid anhydride(for a hydroxyamic acid derivative).

In more detail, the synthetic pathways described below illustrate how compounds of this invention, wherein R₂ is H, s is 0 and A is hydrogen, may be prepared. Suitable processes include:

A. treating a compound of formula (II) as described above, wherein B' is hydrogen, with:

(i) trimethylsilyl isocyanate (TMSNCO), followed by work up with

ammonium chloride to yield a hydroxyurea compound of formula (I) wherein R₁ is N(OH)CONH₂;

(ii) sodium or potassium cyanate in an acidic solution to yield a hydroxyurea compound of formula (I) wherein Ri is N(OH)CONH₂;

(iii) gaseous HCl, 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 intermediate; which intermediate is then reacted with aqueous ammonia or a substituted amine to yield an optionally

substituted hydroxyurea compound of formula (I); (iv) 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 hydroxamic acid derivative of formula (I) wherein R₁ is N(OH)COCH₃; or

(v) 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 of a hydroxamic acid derivative of formula (I) ;

B. treating a compound of formula (II) as described above, wherein B' 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 a formula (I) compound, which is then deprotected, for instance by hydrogenation or with ethane thiol in the presence of aluminium

trichloride, to yield a hydroxamic acid derivative of formula (I);

(ii) trimethylsilyl isocyanate as in step A above, to yield a protected

hydroxyurea which is then deprotected, for instance by hydrogenation or with ethane thiol in the presence of aluminium trichloride, to yield a hydroxyurea compound of formula (I);

(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 intermediate, which intermediate is then reacted with aqueous ammonia, or a substituted amine; to form a protected hydroxyurea which is then deprotected, for instance by hydrogenation or with ethane thiol in the presence of aluminium trichloride, to yield a hydroxyurea compound of formula (I); or

(iv) sodium or potassium cyanate in an acidic solution which is then

deprotected, for instance by hydrogenation or with ethane thiol in the presence of aluminium trichloride, to yield a hydroxyurea compound of formula (I);

C. reacting a compound of formula (II) as described above, wherein B' is Si(Rχ)₃, or CH₂OCH₂CH₂Si(Rx)₃ with:

(i) sodium or potassium cyanate in an acidic solution to form a protected hydroxyurea which is then deprotected using anhydrous fluoride (R_4'N+)F-, or mildly acidic conditions, to yield a hydroxyurea compound of formula (I); the R_4' term in (R_4'N⁺)F- as used herein is definded as R_4' being a (C_1-6 )alkyl or phenyl moiety or combinations thereof; (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 intermediate, which intermediate is then reacted with aqueous ammonia, or a substituted amine, to form a protected hydroxyurea which is then deprotected using anhydrous fluoride (R_4'N⁺)F- or mildly acidic conditions; to yield a hydroxyurea compound of formula (I);

(iii) trimethylsilyl isocyanate followed by deprotection with anhydrous fluoride (R_4'N+)F- or under mildly acidic conditions; to yield a hydroxyurea compound of formula (I); or

(iv) acetyl chloride in organic solvent followed by deprotection with an anhydrous fluoride [(R_4'N⁺)F-] or under mildly acidic conditions, to yield a hydroxyamic acid derivative of formula (I); or D. reacting a compound of formula (II) as described above, wherein B' is tetrahydropyranyl, (C_1-3)alkoxy(C1)alkyl, or (C_1-3)alkoxy(C₂)alkoxy(C₁)alkyl, with:

(i) sodium or potassium cyanate in an acidic solution, followed by

deprotection with a mild acid treatment, such as pyridinium 4- toulenesulphonate in methanol or dilute HCl to yield a hydroxyurea

compound of formula (I);

(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 intermediate, which intermediate is then treated with aqueous ammonia or a substituted amine, followed by deprotection with a mild acid treatment, such as pyridinium 4-toulenesulphonate in methanol or dilute HCl; to yield a hydroxyurea

compound of formula (I);

(iii) with trimethylsilyl isocyanate, followed by deprotection with a mild acid treatment, such as pyridinium para-toulenesulphonate in metiianol or dilute HCl, to yield a hydroxyurea compound of formula (I);

(iv) with acetyl chloride in organic solvent followed by deprotection with a mild acid treatement, such as pyridinium 4-toulenesulphonate in methanol or dilute HCl, to yield a hydroxyurea compound of formula (I); or

E. reacting a compound of formula (II) as described above, wherein B' is t-butyloxycarbonyl with: (i) sodium or potassium cyanate in an acidic solution, followed by

deprotection with trifluroracetic acid, trimethylsilyltrifilate with 2,6-lutidine, or anhydrous ether HCl, to yield a hydroxyurea compound of formula (I); (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 intermediate, which intermediate is then treated with aqueous ammonia, or a substituted amine, followed by deprotection by treatment with trifluroracetic acid,

trimethylsilyltrifilate with 2,6-lutidine, or with anhydrous ether HCl, to yield a hydroxyurea compound of formula (I);

(iii) with trimethylsilyl isocyanate, followed by deprotection, for instance by treatment with ethane thiol in the presence of aluminium trichloride, trifluroracetic acid, trimethylsilyltrifilate with 2,6-lutidine, or anhydrous ether HCl, to yield a hydroxyurea compound of formula (I); or

(iv) with acetyl chloride in organic solvent followed by deprotection for instance by treatment with ethane thiol in the presence of aluminium trichloride, trifluroracetic acid, trimethylsilyltrifilate with 2,6-lutidine, or anhydrous ether HCl; to yield a hydroxyamic acid derivative of formula (I); or F. reacting a compound of formula (II) as described above, wherein B' is an alkanoyl or aroyl group with:

(i) sodium or potassium cyanate in an acidic solution followed by deprotection with a suitable base, such as potassium carbonate; to yield a hydroxyurea compound of formula (I);

(ii) with trimethylsilyl isocyanate, followed by deprotection with a suitable base, such as potassium carbonate, to yield a hydroxyurea compound of formula (I); or

(iii) with acetyl chloride in organic solvent, followed by deprotection by treatment with a suitable base, such as potassium carbonate, to yield an example of a hydroxyamic acid derivative of formula (I).

A compound of formula (II) wherein R₂ is H may be produced by a process which comprises: A. reacting a compound of Formula (III):

wherein R"₆ is =O; and R₃, R'₇, R'₈. and W are as defined for formula (II); with hydroxylamine in solvent to yield the corresponding oxime offormula (IV):

wherein R"₇ is =N-OH; and R'₃, R'₇, R'₈ and W are as defined for formula (II); which is then reduced with a suitable reducing agent capable of reducing an oxime to a hydroxyamine, for instance a borane complex such as borane pyridine, borane trimethylamine or borane tetrahydrofuran, sodium

cyanoborohydride or phenyldimethylsilane in trifluroacetic acid; to yield the corresponding hydroxylamine offormula (II); or

B. reacting a compound offormula (V):

wherein R'₉ is a leaving group, such as a halogen, tosylate, mesylate or a triflate moiety; and R'₃, R'₇, R'₈ and W are as defined for formula (II);

with Z-furfulaldehyde oxime and base to yield the corresponding nitrone of which is then hydroylzed to yield the corresponding hydroxylamine offormula (II);

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

wherein R'₁₀ is OH; and R'₃, R'₇, R'₈ and W are as defined for formula (II); with a protected hydroxylamine, such as N,O-bis(t-butyloxycarbonyl)-hydroxylamine or N,O-bis(bisbenzyloxycarbonyl)-hydroxylamine, and triphenylphosophine/ diethyldiazodicarboxylate to produce an intermediate which is then deprotected as desired, such as by treatment with

hydrogenation when N,O-bis(t-butyloxycarbonyl)-hydroxylamine is used or by acid, to yield the corresponding hydroxylamine 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. the steps of:

(i) reacting a homochiral oxazolidione of Formula (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 form the corresponding acid chloride intermediate of Formula (VII)

(ii) reacting the formula (VII) adduct with a racemic compound offormula (I) or a suitably protected compound of formula (II), in a chlorinated hydrocarbon or etheral solvent and base, to yield the corresponding diastereoisomric adducts which are then separated by conventional methods such as

chromatography or fractional crystallisation; (iii) cleaving each of the adducts under basic conditions to yield the individual entantiomers of the formula (I) or (II) compound;

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 then

deprotected, by for instance hydrogenation or treatment with acid, to yield a hydroxylamine of formula (II); or reacting the corresponding optically active halo or sulfonate, with a hydroxylamine which may be optionally protected, in the presence of a base such as triethylamine or pyridine; to yield a

hydroxylamine of formula (II);

which optically active hydroxylamine may then be converted under any of the various pathways described herein to yield optically active compounds of formula (I);

C. the steps of:

(i) reacting an optically active amine of formula (VIII):

wherein R' ₁₁ is NH₂; and R'₃, R'₇, R'₈ and W are as defined for formula (II); with 4-methoxybenzaldehyde in trhnethylamine;

(ii) oxidizing the intermediate of step (i) to yield the corresponding

oxaziridine;

(iii) reacting the oxaziridine of step (ii) under acid conditions to yield a hydroxylamine salts of formula (II);

which optically active hydroxylamine may then be converted under any of the various pathways described herein to yield an optically active compound of formula (I);

D. reacting the optically active amine of Formula (IX) as described above with dimethyldioxirane or a peracid, such as benzoyl peroxide, to yield a protected optically active hydroxylamine of Formula (II), which may then be optionally deprotected to yield a final compound of Formula (II); which optically active hydroxyamine may then be converted under any of the various pathways described herein to yield an optically active compound of formula (I);

An optically active amine of formula (VIII) may be obtained by reacting an optically active alcohol of formula (V) with diphenylphosphoryl azide and triphenylphosphine / diethyldiazodicarboxylate (DEAD) to form an optically active azide intermediate which may then be reduced to give the desired product.

A hydroxyurea compound of formula (I) may be prepared according to the synthetic route shown in Scheme la below :

In Scheme la, compound la is treated with a strong base, such as NaH, and an acrylate ester, for example ethyl acrylate, in a solvent, such as dry toluene, to yield the intermediate Dieckmann cyclization adduct which need not be purified. Hydrolysis of the ester and decarboxylation may be accomplished in a single step by heating the intermediate keto-ester in an acidic solution, for example glacial acetic acid, to produce lb. Compound 1b is then converted to the corresponding oxime 1c by addition of hydroxylarnine hydrochloride in a solvent, such as pyridine and heated for about 30 minutes to about 2 hours. The oxime 1c is reduced to the corresponding hydroxylamine 1d by addition of a borane/pyridine complex to which is added, after stirring, an acidic solution, preferably 6N HCl. Borane dimethylsulfide in tetrahydrofuran may also be used. Addition of an alkali metal hydroxide, such as NaOH, and extraction into an organic solvent , for example diethyl ether or CH₂Cl₂, yields the hydroxylamine 1d. This hydroxylamine is converted to the corresponding hydroxyurea le by addition of trimethysilylisocyanate and heating followed by an aqueous/organic workup. It will be appreciated that the R₆ term in the chemical intermediate R₆CH=CHC(O)OR moiety results in a chiral center and is represented as such in the formulae used herein.

A hydroxyurea of formula (I) wherein s=2 may be obtained according to the synthesis shown in Scheme Ib:

Alkylation of the indole la is performed under basic conditions in the presence of an omega halobutyrate, such as ethyl 4-bromobutyrate, to form If.

Dieckmann eyclization may be effected under a variety of conditions, including alcoholic base, such as sodium ethoxide at or near ambient temperature or using strong amide bases (for example, lithium diisopropyl amide, potassium bis(trimethylsilyl)amide) in inert solvents (for example, tetrahydrofuran, diethyl ether, or other ethereal solvents) at lower temperatures (-70 to 0ºC) to produce after isolation and decarboxylation, 1g. The conversion of 1g to a compound of formula (I) or (II) (1i to 1j) follows the same protocol used in Scheme la.

Hydroxamic acid derivatives of formula (I) may be obtained from intermediate 1d. This is converted to a diacetate intermediate by addition of an acylating agent, such as acetyl chloride (about 2 equivalents), in the presence of triethylamine (about 3 equivalents) in methylene chloride for about 30 minutes. Acetic anhydride in the presence of other bases such as pyridine may be used as an alternative acylating agent The O-acetate moiety is removed by hydrolysis with an alkali metal hydroxide, such as lithium hydroxide, to yield the corresponding hydroxamic acid of formula (I). The oxime 1d or an O-protected derivative thereof, such as the acetate, may also be reduced by borane-trimethylamine, borane-tetrahydrofuran, sodium cyanoborohydride in methanol, or other borane compounds.

Another synthetic route to prepare certain of the compounds of Formula (I) is described in Scheme II, illustrated below for when one of R₇ or R₈ is hydrogen:

The hydroxytetralone derivative 2 is modified to contain an active leaving group, such as the triflate indicated in 7. Other acceptable leaving groups are the bromides, chlorides, iodides, tosylates, and mesylates. Using a bidentate Pd (II) catalyst, such as PdCl₂ (dppf) or Pd(PPh₃)₄, or any other acceptable coupling agent, and a tris(phenethyl)-borane derivative, using the method of Sukuki (A. Suzuki et al, J Amer Chem Soc, Ill, 314-321, 1989) results in the addition of the appropriate R7/R8 group, to yield the corresponding tetralone compound 8. The above cited procedure is especially useful for the

preparation of compounds in which the R₇/R₈ group is an alkyl group. The use of other organometallics, such as alkylzinc, -lithium, -tin or -aluminum reagents may also be useful when R₇/R₈ is an alkyl group (see references cited in Suzuki paper). Additional ways of coupling using a palladium catalysis and an organoborane (A. Suzuki , Pure & Appl. Chem.. 57, 1749-1758, 1985), organozinc (R. Keenan et al, Syn. Commun., 19, 793-798, 1989), or organotin (J. K. Stille, Angew. Chem. Int. Ed., 25, 508-524, 1986) compound may also be useful in this process step when R₃ is an aryl or olefinic group. Also

potentially useful when R₇/R₈ is an alkyl, aryl, or olefinic group is the copper mediated coupling of an aryl trifalte, such as 7, using the procedure of

McMurry (J. E. McMurry et al, Tetrahedron Letters, 24, 2723-2726, 1983). The ketone 8 is converted to the hydhroxylamine 9 by reaction with

hydroxylamine, and subsequently reduced with borane in pyridine and hydrochloric acid. The hydroxylamine 9 is converted into the corresponding hydroxyurea 10 by the method outlined in Scheme I. The hydroxylamine 9 may also be converted into the corresponding hydroxamic acid derivative by the method outlined above for Scheme I.

A hydroxyurea compound of formula (I) wherein R₄ is NR₅R₆ and the corresponding amine NHR₅R₆is a substituted amine or cyclic amine , maybe prepared by treating a hydroxylamine hydrochloride of formula (II) firstly with phosgene to yield an acyl chloride intermediate which may then be treated with the appropriate amine to yield the compound of formula (I). An alkyl chloroformate, such as ethyl chloroformate, may be used in place of phosgene in which case the resulting R₁ term of formula (I) will determine the reaction time and temperature needed for the reaction to proceed, i.e. at 0º C or below or, if slow, at an elevated temperatures of 100º-200º C in the appropriate solvent.

The preparation of a hydroxyurea of formula (I) when -OB' is a protecting group, as opposed to a 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, to give a protected

hydroxylamine intermediate which is then 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 -OB' group. Deprotection of the hydroxyl may be by hydrogenation with H₂/Pd/C when B' is benzyl, by mild acid treatment, such pyridinium 4-toluenesulphonate in refluxing methanol or dilute HCl when B' is

tetrahydropyranyl, by a suitable base, such as potassium carbonate when B' is an alkanoyl or aroyl group, by use of anhydrous fluoride (R_4'N⁺)F- when B' is Si(R_x)₃, or by treatment with trifluoroacetic acid, trimethylsilyltrifilate with 2,6-lutidine, or anhydrous ether HCl when B' 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, whose disclosure is herein incorporated by reference.

A protected hydroxylamine of formula (I) may be obtained by treating the correponding compound of formula (II) in which the hydroxylamine moiety is replaced by an activated leaving group X such as chloro, bromo, mesylate or tosylate, with a protected hydroxylamine NH₂OB' in which B' is for instance benzyl or tetrahydropyranyl, with heating and in an appropriate solvent. The protected hydroxylamine may then be deprotected using the standard removal conditions for the protecting group employed, to yield the free hydroxylamine offormula (II). The protected intermediate may also used as outlined above to prepare the O-protected hydroxyurea and then deprotected to yield the final compound of formula (I). Similarly, the above noted process may also be used to make a starting amine compound by use of NH₃ or azide and a suitable reduction step, all well known to those skilled in the art.

The starting compounds for the preparation of the hydroxylamine and amine intermediates described above, in which the hydroxylamine or amine moiety is replaced by an activated leaving group, as hereinbefore defined, may be readily obtained from the corresponding ketone or hydroxyl precursors by procedures well known in the art. Thus, when X is halo, the starting compound may be prepared from the corresponding mesylate or toyslate derivative by reaction thereof with lithium chloride or bromide in acetone.

The benzylic sulfonates are highly reactive and are therefore in most cases are used as non-isolated intermediates. Alternatively, the halo compound may be obtained directly from the alcohol by a number of art known procedures. The mesylate or tosylate derivatives may in turn be prepared from the

corresponding alcohol by the treatment thereof with mesyl or tosyl chloride in the presence of an appropriate base, for example pyridine or triethylamine, with or without additional solvent. The alcohol may be obtained from the corresponding ketone by the reduction thereof with a suitable reducing agent, such as sodium borohydride or lithium aluminum hydride.

Selected examples of protected hydroxylamines of formula (II) may also be obtained by treating the corresponding alcohol with a protected

hydroxylamine, such as O-benzyl hydroxylamine or O-t-butyldiphenylsilyl hydroxylamine under solvolytic conditions, for example in the presence of trifluoroacetic acid. The protected intermediate may then be deprotected, using the standard removal conditions for the protecting group employed, to yield a free hydroxylamine of formula (II). The protected intermediate may also be converted first to the protected urea and then to a final compound of formula (I) as discussed above.

Another synthetic pathway which may be used to obtain a hydroxylamine of formula (II) and which may also used to prepare optically active

intermediates, if the optically active alcohol derivative is used as a starting material, is illustrated in Scheme III below:

The starting material 11 is treated with N,O-bis-(t-butyloxycarbonyl)-hydroxylamine and triphenylphosprjine/diethyldiazodicarboxylate (DEAD), to form the intermediate 12 which is then treated with an appropriate acid, such as trifluroacetic acid or hydrochloric acid, to produce the free hydroxylamines of formula (II). The optically active alcohol 11 may be prepared by

enantioselective reduction of the corresponding ketone precursor with an appropriate reducing agent (M. Kawasaki et. al., Chem. Pharm. Bull,, 33, 52-60, 1985 or D. Mathre et. al., J. Org. Chem., 56, 751-762 and references cited therein). The thus obtained optically active alcohol may also be converted to the corresponding optically active halo or sulfonate compound (see D. Mathre, supra). Such steps as noted above are obviously useful as well to make the racemic mixture.

The (optically active) alcohol starting material 11 may also be treated with diphenylphosphoryl azide and triphenylphosphine/diethyldiazodicarboxylate (DEAD) to form the (optically active) azide which may then be reduced to the corresponding (optically active) amine 13.

An additional route for preparing optically active compounds of formula (I) is detailed in Scheme IV below:

The sequence starts with an optically active amine 13, obtained through a variety of methods including the classical methods of preparing salts with chiral acids, such as camphor sulfonic acids, such techniques being readily apparent to those skilled in the art. The requisite racemic amine can be prepared from the alcohol 11 or activated derivatives thereof, by the methods previously outlined above, substituting ammonia for (un)substituted

hydroxylamines. One available review for resolving racemic compounds is by R.M. Secor, Chem. Rev., 63, 197,1963. The starting material 13 is either the pure "R" or a pure "S" configuration which is then reacted with 4-methoxybenzaldehdye in triethylamine to form the intermediate 14. This may then be oxidized by a variety of agents, such as MCPBA (metachloroperbenzoic acid), MPP (monoperoxyphthalate) or MMPP

(magnesium monoperoxyphthalate) to yield the oxaziridine derivative 15 which under acidic conditions then yields the hydroxylamine salt 16. The general procedure can be found in Polanski et al, Tetrahedron Letters., 28, 2453-2456, 1974. Alternatively, the optically active amine 13 may be converted directly to the chiral hydroxylamine 16 using dimethyldioxirane (Danishesky, et.al. J. Org. Chem., vol . 55, p1981-1983, 1990) or a peracid anhydride, such as benzoyl peroxide (R.M. Coates et al, J. Org. Chem., 55, 3464-3474, 1990).

An additional method for obtaining the homochiral hydroxyureas of formula (II) is to form diastereomeric adducts of the hydroxyureas or hydroxamic acid derivatives which may then be separated by a variety of commonly used techniques, including flash chromatography and HPLC. This approach is illustrated in Scheme V for resolution of a racemic mixture.

The hydroxyurea is reacted with the N-chlorocarbonyl derivative of a homochiral oxazolidinone, for example 4-(phenylmethyl)-2-oxazolidinone (see Org. Syn. John Wiley & Sons, Inc., 68, 77 for preparation). Addition of this to a solution containing the hydroxyurea in a chlorinated hydrocarbon or etheral solvent, preferably CH₂CI₂, and a base (either an amine base such as trialkylamine or pyridine or a solid alkali metal carbonate, such as potassium or calcium, but most preferably triethylamine) affords the diastereomeric adducts 17A and 17B. Chromatography or other physical methods are employed to separate these adducts which are then cleaved under basic conditions, for example using an alkali metal hydroperoxide, such as lithium, in an aqueous-etheral solvent (THF, glyme, digylme, ethyl ether ) at about -20 to about 50°C, preferably from about -5°C to about room temperature, more preferably from about 0°C to about 15°C to yield the individual enantiomers of the hydroxyurea . The N-chlorocarbonyl derivative may be obtained by treating the

oxazolidinone firstiy with a base in an anhydrous solvent, preferrably

NaH/toluene at reflux and then adding to this solution,when cooled, phosgene or a phosgene equivalent, such as phosgene trimer or carbonyl diimidazole. Suitably the temperature will be about -30 to about 0°C for use with phosgene and about 20ºC to about 200 ºC for a phosgene equivalent. The thus formed intermediate, for example when phosgene is used, a chloro carbamate [acid chloride], may be isolated.

Additional 4-substituted chiral oxazolidinones which may also be used are optionally substituted (R groups) aryl, arylmethyl, heteroaryl, or

heteroarylmethyl wherein the substituents include, but are not limited to, mono or disubstituted alkyl, halo, alkoxy, cyano, or any other protected amino, alcohol, carboxy, or sulfur (regardless of oxidation state). Additionally R can be an alkyl moiety of greater than 2 carbons, preferably longer, such as t-butyl or iso-propyl, which may be optionally substituted as well. Representative examples of the aryl and heteroaryl groups include, but are not limited to, phenyl, naphthyl, pyrrolyl, thienyl, thiazinyl and furanyl. These

oxazolidinones are prepared from the chiral amino alcohols which are readily available from reduction of the chiral amino acids by the general procedure of Evans (Org. Syn., John Wiley & Sons, Inc. 68, 77 and references cited therein) which are incorporated by reference herein. Compounds of formula (I) in which R₁ is hydrogen and R₂ is a hydroxyurea or a hydroxamic acid moiety may be prepared from a precursor prepared by the 1,2-carbonyl transposition of the ketone group in the 1-ketone intermediate to the 2-position (Scheme VI). Many such 1,2-carbonyl transposition procedures are known (see Tetrahedron, 39, 345, 1983 for review). A particularly useful and general procedure is the reduction, dehydration, hydroboration-oxidation sequence ( see Kirkiacharian, B.S.et al, Synthesis. 815, 1990, for

hydroboration-oxidation).

Scheme VI

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, non-toxic 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, ethanesulfonate, 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, unexpectedly that the compounds of formula (I) possess analgesic activity, using the phenylbenzoquinone writhing test. It has further been found that the compounds offormula (I) do not appear to inhibit prostaglandin production in vitro and are therefore selective 5-lipoxygenase inhibitors. Test data presented in this specification is consistent with the premise that the mechanism of analgesic activity of the compounds of this invention is distinct and independent of the mechanism of action commonly associated with cyclooxygenase inhibitors. 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 leukotiienes, has broadened the interest in these products as mediators of inflammation [see O'Flaherty, Lab. Invest., 47, 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., Scie nce, 225, 743-745, 1984], together with known LTC₄ and LTD₄-mediated increase in capillary permeability [see Simmons et al., Biochem. Pharmacol., 32, 1353-1359, 1983, Vane et al.,

Prostaglandins, 21, 637-647, 1981, and Camp et al., Br. J. Pharmacol., 80,

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., 35, 2447-2456, 1976, Higgs et al., Brit. Bull., 39, 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 osteoarthritis, 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 andRainsford, 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. Dis., 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, 19, February 19, 1983]. The promising effect on psoriasis of benoxaprofen [see Allen et al., Brit. J.

Dermatol., 109, 126-129, 1983], a compound with in 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 infarction 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., 262, No. 22, 10438-40, 1987, see also Xu et al., J. Neurochemistry, 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., Denzlinger 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 Distress

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, glomerulonephritis, and immune complex disease [see Kadison et al., "Vasculitis: Mechanism of Vessel Damage" in Inflammation: Basic Principles and Clinical Correlates, 703-718, Ed. Gallin et al, Raven Press, N.Y., N.Y., 1988]. 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 Dermatology, Vol. III, 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, D., 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 H., J. Ocular Pharma, 4, 43-49, 1988; and Verbey N.L. et al., Current Eye 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 (II) ("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 tile 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 a compound of formula (I) (hereinafter referred to as 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 of formula (I) 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 carriers) 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 tile 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 compounds of formula (I) 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 0.1 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. 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).

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-lipoxygenase pathway. The route of administration may be oral, parenteral, by inhalation or topical.

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 both 5-lipoxygenase and algesia treatment.

It will be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of a formula (I) or (IT) compound 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. 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. SYNTHESIS EXAMPLES

Example 1 - N-{1-(2,3-Dihydro-1H-pyrrolo[1,2-a]indolyl)}-N- hydroxyurea 2,3-Dihydro-1H-pyrrolo[1,2-a]indole-1-one. To a suspension of sodium hydride (2.65 grams (hereinafter g) of 60% dispersion in mineral oil, 66 milimoles (hereinafter mmol)) in toluene (550 milliliters (hereinafter mL)) was added ethyl 2-indolecarboxylate (10.00 g, 53 mmol). The resulting mixture was stirred for 15 min, at which time ethyl acrylate (6.3 mL, 58 mmol) was added. The mixture was heated at reflux for 60 min, and additional ethyl acrylate (0.5 mL, 4.6 mmol) was added. Heating was continued for 1h, at which time additional sodium hydride (1.5 g of 60% dispersion in mineral oil, 37.5 mmol) and ethyl acrylate (1.0 mL, 9.2 mmol) were added. The resulting mixture was heated at reflux for an additional 4 h and allowed to cool to room temperature. Ethanol was added to the reaction mixture, followed by saturated aqueous NH₄CI. The pH was made acidic by the addition of 5% HCl, and the mixture was extracted with CH₂CI₂. The organic extract was washed with saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was dissolved in acetic acid (750 mL) containing H₂O (40 mL). The resulting mixture was heated at reflux for 14 h, then allowed to cool to room

temperature. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in CH₂CI₂ and washed successively with aqueous NaHCO₃ and saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with a solvent gradient of 10 - 100% EtOAc/ hexanes to provide the title compound (8.00 g, 89%).

¹H NMR (CDCI₃) : d 7.74 (apparent dd, 1H); 7.41 - 7.30 (m, 2H); 7.19 (apparent dt, 1H); 6.97 (s, 1H); 4.34 (t, 2H); 3.14 (t, 2H). 2,3-Dihydro-1H-pyrrolo[1,2-a]indol-1-one, oxime. To a solution of 2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one (8.00 g, 47 mmol) in pyridine (100 mL) was added hydroxylamine hydrochloride (6.50 g, 94 mmol). The resulting mixture was stirred overnight at room temperature, then concentrated under reduced pressure. Water was added to the residue, and the solid which formed was collected by filtration to provide the title compound (8.70 g, 100%) as a mixture of diastereomers.

¹H NMR (CDCl₃) : d 7.72 and 7.66 (2 br d, 1H); 7.37 - 7.10 (m, 3H); 7.09 and 6.71 (2s, 1H); 4.32 and 4.30 (2 overlapping t, 2H); 3.50 and 3.43 (2t, 2H).

N-{1-(2,3-Dihydro-1H-pyrrolo[1,2-a]indolyl)}-N-hydroxyaumine. To a solution of 2,3-dihydro- 1H-pyrrolo[1,2-a]indol-1-one, oxime (5.00 g, 26.8 mmol) in 1 : 2 EtOH/ THF (180 mL) at 0°C was added BH₃ pyridine (18.0 mL, 0.178 mol). To the resulting solution was added over 1 h, 3 N HCl (180 mL), and the mixture was allowed to warm to room temperature. After stirring at room

temperature for 45 min, 3 N HCl (40 mL) was added. The reaction mixture was stirred at room temperature for an additional 25 min, then quenched by the addition of solid Na₂CO₃. The mixture was extracted with Et₂O, and the organic extract was washed with saturated aqueous NaCl. The solvent was removed under reduced pressure, and the solid which formeα was collected by filtration and washed with Et₂O. The material was purified by flash

chromatography, eluting first with 5 : 1 EtOAc/ hexanes, followed by 3 : 1 EtOAc/ hexanes and finally with 50 : 1 CHCI₃/ MeOH to provide the title compound (1.5 g, 50% based on unreacted starting material).

¹H NMR (CDCI₃) : d 7.59 (br d, 1H); 7.28 (br d, 1H); 7.17 (dt, 1H); 7.09 (dt, 1H); 6.39 (s, 1H); 4.69 (dd, 1H); 4.21 - 4.02 (m, 2H); 2.90 - 2.75 (m, 1H); 2.65 - 2.53 (m, 1H). N-{1-(2,3-Dihydro-1H-pyrrolor[1,2-alindolyl)}-N-hydroxyurea. To a solution of N-{1-(2,3-dihydro-1H-pyrrolo[1,2-a]mdolyl)}-N-hydroxyamine (1.30 g, 6.9 mmol) in THF (80 mL) was added trimethylsilylisocyanate (2.0 mL, 15.0 mmol). The resulting mixture was heated at reflux for 1.5 h, then allowed to cool to room temperature. The mixture was partitioned between aqueous NH₄CI and EtOAc, and the organic extract was washed with saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with a solvent gradient of 2 - 4% MeOH/CHCI₃. The title compound was recrystallized from EtOH to give white needles (900 mg, 56%). m.p. 190 - 192°C (dec)

1H NMR (DMSO-d₆) : d 9.20 (s, 1H); 7.46 (d, 1H); 7.28 (d, 1H); 7.03

(apparent t, 1H); 6.96 (apparent t, 1H); 6.49 (br s, 2H); 6.11 (s, 1H); 5.71 (dd, 1H); 4.10 (m, 1H); 4.03 (m, 1H); 2.78 (m, 1H); 2.56 (m, 1H).

¹³C NMR(DMSO-d₆) : d 161.4, 142.5, 132.3, 132.0, 120.1, 120.0, 118.5, 109.4, 92.6, 55.3, 42.4, 30.7.

CIMS (NH₃); m/z (rel. int.) : 232 [(M+1)+; 5], 216 (17), 173 (64), 156 (100). Anal. Calc. for C₁₂H₁₃N₃O₂ : C 62.33, H 5.67, N 18.17; found : C 62.01, H 5.52, N 17.97.

Example 2 - N-{1-(7-Benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indolyl)}- N-hydroxyurea 7-Benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indole-1-one. To a solution of ethyl 5-benzyloxy-2-indolecarboxylate (6.7 g, 23 mmol) in toluene (235 mL) was added sodium hydride (1.2 g of 60% dispersion in mineral oil), followed by ethyl acrylate (1.6 mL, 25 mmol). The mixture was heated at reflux for 1 h, and additional ethyl acrylate (0.3 mL, 3 mmol) was added. Heating was continued for 1 h, at which time additional sodium hydride (0.8 g of 60% dispersion in mineral oil, 20 mmol) and ethyl acrylate (0.5 mL, 5 mmol) were added. The resulting mixture was heated at reflux for an additional 4 h and allowed to cool to room temperature. Ethanol was added to the reaction mixture, followed by saturated aqueous NH₄CI, and the mixture was

extracted with CH₂CI₂. The organic extract was washed with saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was dissolved in acetic acid (300 mL) containing H₂O (17 mL). The resulting mixture was heated at reflux for 15 h, then allowed to cool to room

temperature. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in CH₂CI₂ and washed successively with aqueous NaHCO₃ and saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with a solvent gradient of 10 - 100% EtOAc/ hexanes to provide the title compound (3.9 g, 63%).

1H NMR (CDCI₃) : d 7.52 - 7.10 (m, 8H); 6.91 (s, 1H); 5.11 (s, 2H); 4.39 (t, 2H); 3.20 (t, 2H). 7-Benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indole-1-one. oxime. To a solution of 7-benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one (3.90 g, 14.1 mmol) in pyridine (50 mL) was added hydroxylamine hydrochloride (1.80 g, 27.9 mmol). The resulting mixture was stirred overnight at room temperature, then concentrated under reduced pressure. Water was added to the residue, and the solid which formed was collected by filtration to provide the title

compound (1.8 g, 22%) as a mixture of diastereomers.

1H NMR (CDCl₃) : d 7.39 - 6.82 (m, 8H); 6.85 and 6.50 (2s, 1H); 4.99 (s,

2H); 4.17 and 4.15 (2 overlapping t, 2H); 3.35 and 3.25 (br t and m, 2H).

N-{1-(7-Benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indolyl})-N-hydroxyamine. To a suspension of 7-benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one (2.00 g, 6.8 mmol) in EtOH (15 mL) was added BH₃pyridine (2.3 mL, 22.0 mmol). To the resulting mixture was added over 2.5 h, 20% ethanolic HCl (10 mL). The reaction mixture was stirred an additional 30 min at room temperature. The reaction was quenched by the addition of solid Na₂CO_3, and the mixture was extracted with EtOAc. The organic extract was washed with saturated aqueous NaCl, and the solvent was removed in vacuo to provide the title compound (1.20 g, 60%).

N-{1-(7-Benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indolyl})-N-hydroxyurea. To a solution of N-{1-(7-benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indolyl)}-N-hydroxyamine (1.00 g, 3.4 mmol) in THF (60 mL) was added

trimethylsilylisocyanate (1.0 mL, 7.4 mmol). The resulting mixture was heated at reflux for 2 h, then allowed to cool to room temperature. The mixture was partitioned between aqueous NH₄CI and EtOAc, and the organic extract was washed with saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with a solvent gradient of 20 - 100% EtOAc/ hexanes, followed by 4% MeOH/ CHCI₃. Recrystallization of the solid from EtOH provided the title compound. m.p. 200°C (dec)

1H NMR (DMSO-d₆) : d 9.17 (s, 1H); 7.44 (d, 2H); 7.36 (t, 2H); 7.29 (t, 1H); 7.20 (d, 1H); 7.07 (d, 1H); 6.77 (dd, 1H); 6.48 (br s, 2H); 6.01 (s, 1H); 5.68 (dd, 1H); 5.06 (s, 2H); 4.00 (m, 1H); 3.92 (m, 1H); 2.70 (m, 1H); 2.49 (m, 1H).

CIMS (NH₃); m/z (rel. int.): 338 [(M+H)⁺; 64], 295 (43), 279 (21), 262 (31), 78 (100). Anal. Calc. for C₁₉H₁₉N₃O₃ : C 67.64, H 5.68, N 12.46; found : C 67.06, H 5.71, N 11.71.

Example 3 - N-{1-(2,3-Dihydro-7-isopropyl-9-methyl- 1H-pyrrolo- [1,2-a]indoIyl)}-N-hydroxyurea

2,3-Dihydro-7-isopropyl-9-methyl-1H-pyrrolo[1,2-a]indol-1-one. To a solution of ethyl 5-isopropyl-3-methyl-2-indolecarboxylate (2.00 g, 8.1 mmol) in toluene (85 mL) was added sodium hydride (0.43 g of 60% dispersion in mineral oil, 10.2 mmol). The resulting suspension was stirred for several min, at which time ethyl acrylate (0.95 mL, 9.0 mmol) was added. The mixture was heated at reflux, and after 30 min, additional toluene (70 mL) was added. After refluxing for 1 h, additional ethyl acrylate (0.08 mL, 0.7 mmol) was added. After refluxing for another h, additional sodium hydride (0.3 g of 60% dispersion in mineral oil, 7.5 mmol) and ethyl acrylate (0.16 mL, 1.5 mmol) were added successively. The resulting mixture was heated at reflux overnight and allowed to cool to room temperature. Ethanol was added to the reaction mixture, which was then poured into 3 N HCl and extracted with CH₂CI₂. The organic extract was washed with H₂O and saturated aqueous NaCl and dried. The solvent was removed in vacuo, and the residue was dissolved in acetic acid (110 mL) containing H₂O (6 mL). The resulting mixture was heated at reflux overnight, then allowed to cool to room

temperature. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in CH₂CI₂ and washed successively with aqueous NaHC03 and saturated aqueous NaCl. The solvent was removed in vacuo to provide the title compound (1.6 g, 86%).

¹HNMR (CDCI₃) : d 7.51 (br s, 1H); 7.29 (m, 2H); 4.30 (t, 2H); 3.15 (t, 2H); 3.04 (septet, 1H); 2.55 (s, 3H); 1.32 (d, 6H).

2,3-Dihydro-7-isopropyl-9-methyl-1H-pyrrolo[1,2-a]indol-1-one,oxime. To a solution of 2,3-dihydro-7-isopropyl-9-methyl-1H-pyrrolo[1,2-a]indol-1-one (1.60 g, 7.0 mmol) in pyridine (20 mL) was added hydroxylamine hydrochloride (0.91 g, 14.1 mmol). The resulting mixture was stirred for 42 h at room temperature, then concentrated under reduced pressure. Water was added to the residue. The solid which formed was collected by nitration and

recrystallized from EtOAc to provide the title compound (1.35 g, 79%). ¹H NMR (CDCI₃) : d 7.42 (br s, 1H); 7.21 (d, 1H); 7.12 (dd, 1H); 4.21 (t, 2H); 3.49 (t, 2H); 3.04 (septet, 1H); 2.48 (s, 3H); 1.59 (br, 1H); 1.32 (d, 6H).

N-{1-(2,3-Dihydro-7-isopropyl-9-methyl-1H-pyrrolo[1,2-a]indolyl)}-N-hydroxyamine To a solution of 2,3-dihydro-7-isopropyl-9-methyl-1H- pyrrolo[1,2-a]indol-1-one, oxime (0.75 g, 3.1 mmol) in 1 : 2 EtOH/THF (22.5 mL) containing a trace of methyl orange was added BH₃ pyridine (4.5 mL, 46.4 mmol). To the resulting mixture was added over 1 h, 3 N HCl (45 mL), and the mixture was stirred overnight at room temperature. Three N HCl (10 mL) was added, and the mixture was stirred for 10 min. Solid Na₂CO3 was added, and the mixture was extracted with Et₂O. The organic extract was washed with saturated aqueous NaCl and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with a solvent gradient of 0 - 5% MeOH/ CH₂CI₂ to provide the title compound (110 mg, 15%).

¹H NMR (CDCI₃) : d 7.38 (d, 1H); 7.17 (d, 1H); 7.09 (dd, 1H); 4.64 (dd, 1H); 4.10 - 3.94 (m, 2H); 3.05 (septet, 1H); 2.79 - 2.52 (m, 2H); 2.33 (s, 3H); 1.34 (d, 6H).

N-{1-(2,3-Dihydro-7-isopropyl-9-methyl-1H-pyrrolo[1,2-a]indolvyl}-N- hydroxyurea. To a solution of N-{1-(2,3-dihydro-7-isopropyl-9-methyl-1H- pyrrolo[1,2-a]mdolyl)}-N-hydroxyamine (120 mg, 0.5 mmol) in THF (10 mL) was added trimethylsilylisocyanate (0.15 mL, 1.1 mmol). The resulting mixture was heated at reflux for 1.5 h, then allowed to cool to room

temperature. The mixture was partitioned between aqueous NH₄CI and EtOAc, and the organic extract was washed with saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 2% MeOH/ CHCI₃ to provide a crystalline solid (90 mg, 63%) which was recrystallized from EtOAc/ MeOH. m.p. 175 - 177°C (dec)

¹H NMR (DMSO-d₆) : d 9.03 (s, 1H); 7.14 (d, 1H); 7.07 (d, 1H); 6.83 (dd, 1H); 6.36 (br s, 2H); 5.68 (dd, 1H); 3.94 (m, 1H); 3.84 (m, 1H); 2.85 (m, 1H); 2.67 (m, 1H); 2.43 (m, 1H); 2.04 (s, 3H); 1.12 (d, 6H).

CIMS (NH₃); m/z (rel. int.) : 288 [(M+H)⁺, 47]; 272 (7), 245 (21); 229 (31); 227 (33); 214 (58); 212 (100). Example 4 - N-{1-(7-Chloro-2,3-dihydro-1H-pyrrolo[1,2-a]indolyl)}-N- hydroxyurea

7-Chloro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one. To a solution of ethyl 5- chloro-2-indolecarboxylate (5.00 g, 22.4 mmol) in toluene (230 mL) was added sodium hydride (1.20 g of 60% dispersion in mineral oil, 27.9 mmol). The resulting suspension was stirred for 10 min, at which time ethyl acrylate (2.66 mL, 24.6 mmol) was added. The mixture was heated at reflux for 70 min, and additional ethyl acrylate (0.2 mL, 1.9 mmol) was added. Heating was continued for 1 h, at which time additional sodium hydride (0.80 g of 60% dispersion in mineral oil, 20.0 mmol) and ethyl acrylate (0.4 mL, 3.7 mmol) were added. The resulting mixture was heated at reflux for an additional 4.5 h and allowed to cool to room temperature. Ethanol was added to the reaction mixture, followed by saturated aqueous NH₄CI. The pH was made acidic by the addition of 5% HCl, and the mixture was extracted with CH₂CI₂. The organic extract was washed with saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was dissolved in acetic acid (300 mL) containing H₂O (15 mL). The resulting mixture was heated at reflux for 13 h, then allowed to cool to room temperature. The reaction mixture was

concentrated under reduced pressure. The residue was dissolved in CH₂CI₂ and washed successively with aqueous NaHCO₃ and saturated aqueous NaCl.

The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with a solvent gradient of 33 - 100% EtOAc/ hexanes to provide the title compound (4.00 g, 87%).

1H NMR (CDCI₃) : d 7.73 (d, 1H); 7.37 (dd, 1H); 7.30 (dd, 1H); 6.92 (s, 1H);

4.44 (brt, 2H); 3.22 (br t, 2H).

7-Chloro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one, oxime. To a solution of 7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one (4.00 g, 19.5 mmol) in pyridine (40 mL) was added hydroxylamine hydrochloride (2.50 g, 39.0 mmol). The resulting mixture was stirred overnight at room temperature, then

concentrated under reduced pressure. Water was added to the residue, and the solid which formed was collected by filtration to provide the title

compound (3.69 g, 84%) as a mixture of diastereomers.

1HNMR (CDCl₃/MeOH-d₄) : d 7.63 and 7.48 (2d, 1H); 7.17 - 7.01 (m, 2H); 6.89 and 6.51 (2d, 1H); 4.19 and 4.16 (2 overlapping t, 2H); 3.37 and 3.28 (2t, 2H). N-{1-(7-Chloro-2,3-dihydro-1H-pyrrolo[1,2-a]indolyl)}-N-hydroxyurea To an ice-cold suspension of 7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one, oxime (2.00 g, 9.7 mmol) in EtOH (70 mL) was added BH₃·pyridine (7.00 mL, 68.0 mmol). To the resulting mixture was added over 1 h, 3 N HCl (70 mL), and the reaction mixture was allowed to warm to room temperature and stirred overnight. Analysis by thin layer chromatography indicated that the reaction was incomplete, so additional BH₃·pyridine (45 mL, 0.45 mol) was added, followed by 3 N HCl (165 mL) which was added dropwise overnight. After stirring at room temperature for 2 d, the reaction mixture was quenched by the addition of solid Na₂CO₃ and extracted with Et₂O. The organic extract was washed with saturated aqueous NaCl and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with 2% MeOH/ CHCI₃ to provide the title compound (1.6 g, 80%).

1H NMR (CDCl_3/MeOH-d₄) : d 7.41 (d, 1H); 7.05 (d, 1H); 6.97 (dd, 1H); 6.20 (s, 1H); 4.52 (dd, 1H); 4.09 - 3.85 (m, 2H); 2.78 - 2.61 (m, 1H), 2.54 -2.40 (m, 1H).

N-{1-(7-Chloro-2,3-dihydro-1H-pyrrolo[1,2-a]indolyl)}-N-hydroxyurea. To a solution of N-{1-(7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]indolyl)}-N-hydroxyamine (1.55 g, 7.5 mmol) in THF (60 mL) was added

trimethylsilylisocyanate (2.0 mL, 15.0 mmol). The resulting mixture was heated at reflux for 3 h, then allowed to cool to room temperature. The mixture was partitioned between aqueous NH₄CI and EtOAc, and the organic extract was washed with saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with

5% MeOH/ CHCI₃ and recrystallized from EtOH to provide the title compound _as white needles (1.00g, 55%). m.p. 186 - 189°C

¹H NMR (DMSO-d₆) : d 9.15 (s, 1H); 7.44 (dd, 1H); 7.26 (dd, 1H); 6.96 (dd, 1H); 6.42 (br s, 2H); 6.04 (s, 1H); 5.64 (m, 1H); 4.01 (m, 2H); 2.72 (m, 1H); 2.49 (m, 1H).

¹³C NMR (DMSO-d₆) : d 161.4, 144.5, 133.3, 130.5, 123.4, 119.7, 119.2, 110.9,

92.6, 55.4, 42.7, 30.7.

CIMS (NH₃); m/z (rel. int.) : 266 [(M+1)⁺; 9], 250 (12), 209 (16), 207 (49),

192 (64), 190 (100).

Anal. Calc. for C₁₂H₁₂CIN₃O₂ : C 54.25, H 4.55, N 15.82; found : C 54.18, H 4.79, N 15.76. Example 5 - N-{1-(2,3-Dihydro-7-ethyl-1H-pyrrolo[1,2-a]indolyl)}-N- hydroxyurea

7-Ethyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one. To a solution of ethyl 5- ethyl-2-indolecarboxylate (5.01 g, 23 mmol) in toluene (200 mL) was added sodium hydride (1.16 g of 60% dispersion in mineral oil, 29 mmol). The resulting suspension was stirred for several min, at which time ethyl acrylate (2.75 mL, 25 mmol) was added. The mixture was heated at reflux for 1 h, and additional ethyl acrylate (0.30 mL, 2.8 mmol) was added. After refluxing for 2 h, additional sodium hydride (0.5 g of 60% dispersion in mineral oil, 12.5 mmol) and ethyl acrylate (0.30 mL, 2.8 mmol) were added successively. The resulting mixture was heated at reflux for 4 h and allowed to cool to room temperature. Ethanol was added to the reaction mixture, which was then poured into 3 N HCl and extracted with CH₂CI₂. The organic extract was washed with H₂O and saturated aqueous NaCl and dried. The solvent was removed in vacuo, and the residue was dissolved in acetic acid (250 mL) containing H₂O (20 mL). The resulting mixture was heated at reflux for 17 h, then allowed to cool to room temperature and stirred for an additional 24 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in CH₂CI₂ and washed successively with aqueous NaHCO₃ and saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 1 : 1 CH₂CI₂/ hexanes and recrystallized from EtOAc/ hexanes (3.16 g, 69%).

1H NMR (CDCl₃) : d 7.55 (br s, 1H); 7.31 (br d, 1H); 7.21 (dd, 1H); 6.91 (s, 1H); 4.34 (t, 2H); 3.15 (t, 2H); 2.75 (q, 2H); 1.29 (t, 3H).

2.3-Dihydro-7-ethyl-1H-pyrrolo[1,2-a]indol-1-one. oxime. To a solution of 2,3-dihydro-7-ethyl-1H-pyrrolo[1,2-a]indol-1-one (3.16 g, 16 mmol) in pyridine (40 mL) was added hydroxylamine hydrochloride (2.19 g, 32 mmol). The resulting mixture was heated at 60°C for 0.5 h, then allowed to cool to room

temperature and concentrated under reduced pressure. The residue was allowed to stand at 0°C overnight. The solid which formed was collected by filtration and washed with EtOH (3.38 g, 99%).

1H NMR (CDCl₃) : d 7.31 (m, 1H); 7.10 (m, 1H); 6.96 and 6.92 (2 dd, 1H); 6.85 and 6.47 (2 br s, 1H); 4.10 (m, 2H); 3.31 and 3.21 (2 dd, 2H); 2.59 (2 overlapping q, 2H); 1.15 (2 overlapping t, 3H). N-{1-(2,3-Dihydro-7-ethyl-1H-pyrrolo[1,2-a]indolyl)}-N-hydroxyamine. To a solution of 2,3-dihydro-7-ethyl-1H-pyrrolo[1,2-a]indol-1-one, oxime (3.38 g, 15.8 mmol) in 25% THF/ EtOH (100 mL) was added BH₃·pyridine (25 mL, 0.25 mol), and the resulting mixture was allowed to stir at room temperature. After stirring for 0.5 h, 3 N HCl (125 mL) was added dropwise over 6 h. Ether was added to the reaction mixture, which was then cooled to 0°C. The pH was adjusted to basic by the addition of solid Na₂CO₃, and the organic phase was concentrated under reduced pressure. The residue was dissolved in EtOAc and washed successively with H₂O and saturated aqueous NaCl. The solvent was removed in vacuo to provide the title compound (0.52 g, 15%).

N-{1-(2,3-Dihydro-7-ethyl-1H-pyrrolo[1,2-a]indolyl)}-N-hydroxyurea. To a solution of N-{1-(2,3-dihydro-7-ethyl-1H-pyrrolo[1,2-a]indolyl)}-N-hydroxyamine (0.52 g, 2.4 mmol) in THF (3 mL) was added

trimethylsilylisocyanate (0.64 mL, 4.8 mmol). The resulting solution was heated at 60°C for 0.5 h, then allowed to cool and concentrated under reduced pressure. The residue was dissolved in EtOAC and washed successively with H2O and saturated aqueous NaCl. The solvent was removed in vacuo. The residue was triturated with Et₂O and purified by flash chromatography, eluting with a solvent gradient of 0 - 50 % MeOH/ CH₂Cl₂. The solid which was obtained was recrystallized from MeOH/ CH₂CI₂/ hexanes (91 mg, 15%). m.p. 209 - 210.5°C

1H NMR (DMSO-d₆) : d 9.16 (br s, 1H); 7.30 (br s, 1H); 7.20 (d, 1H); 6.90

(dd, 1H); 6.50 (br s, 2H); 6.04 (s, 1H); 5.70 (dd, 1H); 4.02 (m, 2H); 2.86 - 2.52 (m, 4H); 1.19 (t, 3H).

CMS (NH₃); m/z (rel. int.) : 260 [(M+H)⁺; 36], 244 (10), 217 (42), 201 (70),

186 (73), 184 (100).

Anal. Calc. for C₁₄H₁₇N₃O₂ : C 64.85, H 6.61, N 16.20; found : C 64.08, H 6.71, N 16.20.

Example 6 - N-{1-(2,3-Dihydro-7-phenoxy-1H-pyrrolo[1,2-a]indolyl)}-N-hydroxyurea

Ethyl 5-phenoxy-2-indolecarboxylate. To a suspension of 4-phenoxyaniline (26.6 g, 0.144 mol) in H₂O (90 mL) was added concentrated HCl (62 mL), with ice bath cooling. To the resulting mixture was added dropwise a solution of sodium nitrite (10.90 g, 0.158 mol) in H₂O (30 mL). The mixture was allowed to stir for 10 min and added to a cold solution containing 50% aqueous KOH (53 mL) and ethyl 2-methylacetoacetate (25.4 mL, 0.180 mol) in H₂O (300 mL). The resulting mixture was stirred rapidly for 20 min, then poured into Et₂O. The organic extract was washed with saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was dissolved in EtOH (300 mL). Hydrochloride gas was bubbled into the solution for 4 h, at which time, ice-H₂O was added. The solid which formed was collected by nitration and recrystallized from H₂O/ MeOH. The mother liquor was extracted with Et₂O, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography, eluting with 10% EtOAc/ hexanes to provide a solid which was combined with the recrystallized material. This was further purified by recrystallization from EtOAc/ hexanes to afford the title compound (12.0 g). An additional quantity was obtained by flash chromatography of the mother liquor (20.0 g total, 50%).

1H NMR (CDCI₃) : d 7.42 - 7.25 (m, 4H); 7.17 - 6.96 (m, 5H); 4.40 (q, 2H); 1.41 (t, 3H).

2,3-Dihydro-7-phenoxy-1H-pyrrolo[1,2-a]indol-1-one. To a suspension of ethyl 5-phenoxy-2-indolecarboxylate (11.70 g, 41.6 mmol) and sodium hydride (2.10 g of 60% dispersion in mineral oil, 52.0 mmol) in toluene (430 mL) was added ethyl acrylate (4.58 mL, 46.0 mmol). The resulting mixture was heated at reflux for 1 h, at which time additional ethyl acrylate (0.42 mL, 3.9 mmol) was added. After heating at reflux for 1 h more, sodium hydride (1.20 g of 60% dispersion in mineral oil, 30.0 mmol) and ethyl acrylate (0.85 mL, 7.9 mmol) were added. Heating was resumed for 4 h more. Ethanol was added to the reaction mixture, followed by saturated aqueous NH₄CI. The pH was made acidic by the addition of 5% HCl, and the mixture was extracted with CH₂CI₂. The organic extract was washed with saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was dissolved in acetic acid (550 mL) containing H₂O (30 mL). The resulting mixture was heated at reflux overnight, then allowed to cool. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in CH₂CI₂ and washed

successively with aqueous NaHCO₃ and saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was filtered through a pad of florisil and then purified by flash chromatography, eluting with 10% EtOAc/hexanes to provide the title compound (8.00 g, 73%).

¹HNMR(CDCl₃) : d 7.40 (dd, 1H); 7.36 - 7.25 (m, 3H); 7.15 (dd, 1H); 7.12 -6.96 (m, 3H); 6.91 (d, 1H); 4.40 (t, 2H); 3.20 (t, 2H). 2,3-Dihydro-7-phenoxy-1H-pyrrolo[ 1,2-a]indol-1-one, oxime. To a solution of 2,3-dihydro-7-phenoxy-1H-pyrrolo[1,2-a]indol-1-one (2.65 g, 10.0 mmol) in pyridine (30 mL) was added hydroxylamine hydrochloride (1.30 g, 20.0 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in H₂O and filtered. The solid was recrystallized from EtOH to afford the oxime (1.9 g, 68%) as a mixture of diastereomers.

¹H NMR (CDCI₃) : d 7.40 - 7.13 (m, 4H); 7.04 - 6.84 (m, 4H); 6.57 (s, 1H);

4.33 - 4.20 (m, 2H); 3.48 - 3.31 (m, 2H).

N-{1-(2,3-Dihydro-7-phenoxy-1H-pyrrolo[1,2-a]indolyl)}-N-hydroxyamine. To a suspension of 2,3-dihydro-7-phenoxy-1H-pyrrolo[1,2-a]indol-1-one, oxime (3.2 g, 11.5 mmol) in EtOH was added BH₃·pyridine (3.5 mL, 35.0 mmol).

Ethanolic 20% HCl (17 mL) was then added dropwise over 4 h. The solution was made basic by the addition of saturated aqueous Na2CO3, and the mixture was extracted with Et₂O. The organic extract was washed with saturated aqueous NaCl. The solvent was removed under reduced pressure, and the solid which formed was collected by filtration and washed with Et₂O. The material was purified by flash chromatography, eluting first with 1 : 2 EtOAc/ hexaxes, followed by 1 : 1 EtOAc/ hexanes to afford the hydroxyamine (3.0 g, 93%).

¹H NMR (MeOH-d₄) : d 7.29 - 7.20 (m, 3H); 7.12 (d, 1H); 6.98 (m, 1H); 6.90 -6.70 (m, 3H); 6.31 (s, 1H); 4.59 (dd, 1H); 4.22 - 4.01 (m, 2H); 2.90 - 2.74 (m, 1H); 2.69 - 2.56 (m, 1H).

N-{1-(2,3-Dihydro-7-phenoxy-1H-pyrrolo[1,2-a]indolyl)}-N-hydroxyurea. To a solution of N-{1-(2,3-dihydro-7 -phenoxy-1H-pyrrolo[1,2-a]indolyl)}-N-hydroxyamine (3.00 g, 10.7 mmol) in THF (150 mL) was added trimethylsilyl isocyanate (3.0 mL, 21.5 mmol). The resulting mixture was heated at reflux for 5 h, then allowed to cool. The mixture was partitioned between aqueous NH₄CI and EtOAc, and the organic extract was washed with saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 2% MeOH/ CHCI₃ to afford the title compound (1.8 g, 52%). m.p. 186 - 188°C (dec)

1H NMR (CDCI₃) : d 9.20 (s, 1H); 7.32 (d, 1H); 7.28 (m, 2H); 7.14 (s, 1H);

7.00 (apparent t, 1H); 6.86 (d, 1H); 6.80 (d, 1H); 6.48 (br s, 2H); 6.10 (s, 1H); 5.70 (br d, 1H); 4.10 (m, 2H); 2.81 (m, 1H); 2.61 (m, 1H). CIMS(NH₃), m/z (rel. int.) : 324 [(M+H)⁺, 14], 281 (24), 265 (54), 250 (80), 248 (100).

Anal. Calc. for C₁₈H₁₇N₃O₃ : C 66.86, H 5.30, N 13.00; found : C 67.28, H 5.61, N 12.56.

Example 7 - N-{1-(2,3-Dihydro-9-methyl-7-phenoxy-1H-pyrrolo- [1,2-a]indolyl)}-N-hydroxyurea

Ethyl 3-methyl-5-phenoxy-2-indolecarboxylate. To a mixture of 4- phenoxyaniline (15.03 g, 0.081 mol) in H₂O (65 mL) was added concentrated

HCl (34 mL). The resulting mixture was cooled to 0°C, and to this was added dropwise a solution of sodium nitrite (6.69 g, 0.097 mol) in H₂O (20 mL). The mixture was allowed to stir for 10 min and added to a cold solution containing 50% aqueous KOH (20 mL) and ethyl 2-ethylacetoacetate (14.0 mL, 0.099 mol) in H₂O (80 mL). The resulting mixture was allowed to stir for 20 min, then poured into Et₂O. The organic extract was washed successively with H₂O (2x) and saturated aqueous NaCl. Removal of the solvent in vacuo provided the title compound (3.66 g, 15%).

1H NMR (CDCl₃) : d 8.77 (br s, 1H); 7.29 (m, 4H); 7.10 - 6.93 (m, 4H); 4.42 (q, 2H); 2.53 (s, 3H); 1.42 (t, 3H). 2,3-Dihydro-9-methyl-7 phenoxy-1H-pyrrolo[1,2-a]indol-1-one. To a

suspension of ethyl 3-methyl-5-phenoxy-2-indolecarboxylate (3.66 g, 12.4 mmol) and sodium hydride (0.64 g of 60% dispersion in mineral oil, 14.9 mmol) in toluene (100 mL) was added ethyl acrylate (1.50 mL, 13.6 mmol). The resulting mixture was heated at reflux for 3 h, then allowed to cool. Ethanol was added, and the pH was adjusted to acidic with 3N HCl. The reaction mixture was extracted with CHCI₃, and the organic extract was washed successively with. H₂O (2x) and saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was dissolved in acetic acid (250 mL) containing H₂O (20 mL). The mixture was heated at reflux for 24 h, then allowed to cool. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in CH₂CI₂ and washed successively with aqueous NaHCO₃ and saturated aqueous NaCl. The solvent was removed in vacuo to provide the title compound (3.09 g, 90%).

1H NMR (CDCl₃) : d 7.30 (m, 4H); 7.15 - 6.94 (m, 4H); 4.33 (t, 3H); 3.17 (t, 2H); 2.49 (s, 3H). 2,3-Dihydro-9-methyl-7-phenoxy-1H-pyrrolo[1,2-a]indol-1-one, oxime. To a solution of 2,3-dihydro-9-methyl-7-phenoxy-1H-pyrrolo[1,2-a]indol-1-one (3.09 g, 11.2 mmol) in pyridine (100 mL) was added hydroxylamine hydrochloride (1.54 g, 22.3 mmol). The resulting mixture was heated at 60°C for 1 h, then allowed to cool. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from EtOH to afford the oxime (2.68 g, 82%).

1H NMR (CDCl₃) : d 7.34 - 7.20 (m, 4H); 7.05 - 6.91 (m, 4H); 4.26 (s, 1H); 4.20 (t, 2H); 3.45 (t, 2H); 2.40 (s, 3H).

N-{1-(2,3-Dihydro-9-methyl-7-phenoxy-1H-pyrrolo[1,2-a]indolyl)}-N-hydroxyamine. To a solution of 2,3-dihydro-9-methyl-7-phenoxy-1H-pyrrolo[1,2-a]indol-1-one, oxime (2.17 g, 7.43 mmol) in EtOH (20 mL) was added BH₃·pyridine (2.25 mL, 22.29 mmol), and the resulting mixture was cooled to 0°C. Ethanolic 6N HCl (10.6 mL) was added dropwise over 1 h, maintaining the temperature at 0°C. The reaction mixture was allowed to warm to room temperature and stirred for 5 h. The solution was made basic by the addition of saturated aqueous Na₂CO₃, and the solid which formed was collected by filtration and washed with H₂O to afford the hydroxyamine (1.25 g, 57%).

N-{1-(2,3-Dihydro-9-methyl-7-phenoxy-1H-pyrrolo[1,2-a]indolyl)}-N-hydroxyurea. To a solution of N-{1-(2,3-dihydro-9-methyl-7-phenoxy-1H-pyrrolo[1,2-a]indolyl)}-N-hydroxyamine (1.25 g, 4.25 mmol) in THF (20 mL) was added trimethylsilyl isocyanate (1.13 mL, 8.50 mmol). The resulting mixture was heated at 60°C for 1 h, then allowed to cool and was concentrated under reduced pressure. The residue was dissolved in EtOAc and washed successively with H₂O and saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was triturated with Et₂O and recrystallized from MeOH/ CH₂CI₂ to afford the title compound (602 mg, 42%). m.p. 187 - 188°C ¹H NMR (CDCI₃) : d 9.21 (s, 1H); 7.27 (m, 3H); 7.10 (d, 1H); 7.00 (br t, 1H); 6.87 (d, 2H); 6.78 (dd, 1H); 6.50 (s, 2H); 5.80 (dd, 1H); 4.08 (m, 1H); 3.96 (m, 1H); 2.78 (m, 1H); 2.56 (m, 1H); 2.16 (s, 3H).

CMS (NH₃), m/e (rel. int.) : 338 [(M+H)⁺, 9], 295 (12), 264 (60), 262 (100). Anal. Calc. for C₁₉H₁₉N₃O₃.1/8 H₂O : C 67.19, H 5.71, N 12.37; found : C 67.17, H 5.68, N 12.51. Example 8 - Capsule Composition

A pharmaceutical composition of this invention in the form of a capsule is prepared by filling a standard two-piece hard gelatin capsule with 50 mg. of a compound of formula (I), in powdered form, 110 mg. of lactose, 32 mg. of talc and 8 mg. of magnesium stearate.

Example 9 - Ointment Composition Compound of Formula (I) 1.0 g

White soft paraffin to 100.0 g

The compound of formula (I) is dispersed in a small volume of the vehicle and this dispersion is gradually incorporated into the bulk to produce a smooth, homogeneous product which is filled into collapsible metal tubes.

Example 10 - Topical Cream Composition

Compound of Formula (I) 1.0 g

Carbowax 20020.0 g

Lanolin Anhydrous 2.0 g

White Beeswax 2.5 g

Methyl hydroxybenzoate 0.1 g

Distilled Water to 100.0 g

The carbowax, beeswax and lanolin are heated together at 60°C and added to a solution of methyl hydroxybenzoate. Homogenization is achieved using high speed stirring and the temperature is allowed to fall to 50°C. The compound of formula (I) is added and dispersed throughout, and the composition is allowed to cool with slow speed stirring.

Example 11 - Topical Lotion Composition

Compound of Formula (I) 1.0 g

Sorbitan Monolaurate 0.6 g

Polysorbate 200.6 g

Cetostearyl Alcohol 1.2 g

Glycerin 6.0 g · Methyl Hydroxybenzoate 0.2 g

Purified Water B.P. to 100.00 ml

The methyl hydroxybenzoate and glycerin are dissolved in 70 ml of the water at 75°C. The sorbitan monolaurate, polysorbate 20 and cetostearyl alcohol are melted together at 75°C and added to the aqueous solution. The resulting emulsion is homogenized, allowed to cool with continuous stirring and the compound of formula (I) is added as a suspension in the remaining water. The whole suspension is stirred until homogenized.

Example 12 - 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 0.1-0.2% 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 13 - 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 0.1-0.2% 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.

UTILITY 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 CD1 mice obtained from Charles River Breeding Laboratories, and within a single experiment the mice were age-matched. Their weight range was from 25 to 42 g. The test groups generally contained 3-6 animals.

5-Lipoxygenase Activity

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 comsumption of oxygen (O₂). The cell extract (100 ug) was preincubated with the inhibitor or its vehicle in 25 mM Bis Tris 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 velodty 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).

Eicosanoid 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 (10⁶ 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 vivo 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:1% 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.

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

Mice were 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 was placed into individual 4 liter beakers. CD1 mice show a characteristic abdominal contraction/stretching response which consists of extending one or both of the bind limbs. These responses which occur at a variable frequency (not less than 1-2 seconds apart) were counted on a hand counter. The counting period was for 10 minutes following a 5 minute acclimation period. Results are based on the total number of constrictions observed during the 10 minute period.

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 is shown in Table I. The compounds tested displayed a range of inhibitory activity both in vitro and in vivo. On the RBL-1 supernatant 5-LO enzyme assay several

compounds showed activity in and around 1.0 uM IC₅₀. The compounds showed little, if any, potent inhibition of cyclooxygenase activity as indicated by production of the prostaglandin, PGE₂, i.e. see Table 2..

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 also seen in Table I, with the exception of the halo derivative, the compounds tested were shown to inhibit 5-LO activity ex vivo as well as in vitro. Several of these compounds also showed inhibition of LTB₄ production, per os. The analgetic activity of these compounds was tested using the phenylbenzoquinone-induced abdominal constriction assay. As seen in Table 1, several of these compounds possess mild analgetic activity. DISCUSSION AND CONCLUSION

The compounds shown herein inhibited 5-LO enzyme activity using isolated enzyme, whole cells and mouse blood, ex vivo. This inhibition of fatty acid oxygenase activity did not extend to cyclooxygenase and therefore, these selective 5-LO inhibitors would not be expected to have analgetic activity which is a property of cyclooxygenase inhibitors (Doherty, N.S. Mediators of the Pain of Inflammation. Annual Reports in Med. Chem. 22, 245-252, 1987). It was therefore surprising to find that many of these 5-LO inhibitors had significant and potent analgetic activity. This property enhances the utility of these inhibitors in diseases such as osteoarthritis were the clinical endpoint is pain (Moskowitz, R.W. Treatment of Osteoarthritis. In: Arthritis and Allied Conditions. Ed. D.J. McCarty. Lea and Febiger, Philadelphia, PA ,1181-1189, 1979).

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

1. A compound of the formula (I)

wherein

one of R₁ and R2 is hydrogen and the other is

R' is hydrogen, a pharmaceutically acceptable cation, aroyl or a C_1-12 alkanoyl;

D is oxygen or sulfur;

W is CY₁Y₂(CH₂)_s;

Y₁ is hydrogen or (C_1-2) alkyl;

s is a number having a value of 0 or 1;

R₄ is NR₅R₆; (C_1-6)alkyl; halosubstituted (C_1-6)alkyl; hydroxysubstituted- (C_1-6)alkyl; (C_2-6)alkenyl; aryl or heteroaryl optionally substituted by halogen,

(C_1-6)alkyl, halosubstituted(C_1-6)alkyl, hydroxyl, or (C_1-6)alkoxy;

R₅ is H or (C_1-6)alkyl;

R₆ is H; (C_1-6)alkyl; aryl; aryl(C_1-6)alkyl; heteroaryl; alkyl substituted by halog or hydroxyl; aryl or heteroaryl optionally substituted by a substituent selected from the group consisting of halo, nitro, cyano, (C_1-12)alkyl, (C_1-6)alkoxy, halosubstituted(C_1-6)alkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl dialkylaminocarbonyl, alkylthio, alkylsulphonyl, or alkylsulfinyl; or

R₅ and R₆ may together form a ring having 5 to 7 ring atoms, which ring atoms may optionally include a further heteroatom selected from oxygen, sulfur or nitrogen;

R₃, R₇ and R₈ are independent substituent groups which when combined with t parent ring system have a lipophilidty value from about 2.5 to about 50;

or a pharmaceutically acceptable salt thereof.

2. The compound according to Claim 1 wherein R₃, R₇ and R₈ is each

independently selected from the group consisting of hydrogen, halogen, (C₁- 1₀)alkyl, (C_1-10)alkoxy, NR₉R₁₀, (CH₂)_m-Ar-(X)_v, O(CH₂)_mAr-(X)_v, or S(CH₂)_m- Ar-(X)v; or R_3, R₇ and R₈ may also be a protected amine functionality;

wherein m is a number having a value of 0 to 4; preferably m is 0 to 2;

v is a number having a value of 1 or 2; preferably v is 1;

R₉ and R₁₀ are independently selected from hydrogen, (C_1-10)alkyl,

halosubstituted(C_1-6)alkyl, (C_5-8)cycloalkyl, (C_2-10)alkenyl, aryl(C_1-6)alkoxy, or R₉ and R₁₀ may together form a saturated or unsaturated ring having 5 to 7 ring atoms, which ring atoms may optionally include a further heteroatom selected from oxygen, sulfur or nitrogen;

Ar is a member selected from the group consisting of phenyl, naphthyl, quinolyl, isoquinolyl, pyridyl, furanyl, imidazoyl, benzimidazoyl, triazolyl, oxazolyl, isoxazolyl, thiazole, or thienyl;

X is a member selected from the group consisting of hydrogen, halogen,

(C_1-10)alkyl, (C_5-8)cydoalkyl, (C_2-10)alkenyl, hydroxy, (CHY₃)_tcarboxy,

(C_1-10)aloxy, S(O)_r -, (C_1-10)alkyl, halosubstituted(C_1-10)alkyl, hydroxy

substituted(C_1-10)alkyl, (CHY₂)_tN(R₅)₂, or cyano;

r is a number having a value of 0, 1 or 2;

Y₃ is hydrogen or (C_1-3)alkyl;

t is a number having a value of 0 or 1.

3. The compound according to Claim 2 wherein R₃ is hydrogen, halogen, or (C_1-6)alkyl

4. The compound according to Claim 3 wherein R₇ and R₈ are independently selected from the group consisting of hydrogen, alkyl, halo, O(CH₂)_m-Ar-(X)_v, or (CH₂)_m-Ar-(X)_v, and m is a number having a value of 0 to 2.

5. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier or diluent and a compound of of formula (I) as according to any one of Claims 1 to 4 or a pharmaceutically acceptable salt thereof.

6. A compound according to any one of claims 1 to 4 for use in therapy.

7. A compound of the formula (II):

wherein:

' one of R'₁ and R'₂ is hydrogen and the other is

;

B' is hydrogen, benzyl, optionally substituted benzyl , Si(R_x)₃, C(O)R₅', C(O)OR₅',

CH₂OCH₂CH₂Si(Rx)₃, (C_1-3)alkoxy(C₁)alkyl, (C_1-3)alkoxy(C₂)alkoxy(C₁)alkyl, or tetrahydropyranyl ;

A is hydrogen or C(O)OR_Z;

R_z is benzyl, Si(R_x)₃, t-butyl, or CH₂OCH₂CH₂Si(Rx)₃;

R₅' is C_1-6 alkyl, aryl, or aralkyl;

Rx is independently selected from alkyl or aryl;

R'₃, R'₇ and R'₈ are independent substituent groups which when combined with the parent ring system have a lipophilidty value in the range of about 2.5 to about 50; and

or a salt thereof.

8. A compound of formula (II) as defined in Claim 7 for use in therapy

9. A process for preparing a compound of formula (I) as defined in Claim 1 which process comprises treating a compound of formula (II) as defined in Claim 7 with a reagent capable of transforming a hydroxylamine [-NH(OH)] functional group into a hydroxyurea [-N(OH)CON-] or a hydroxamic acid derivative [-N(OH)CO-] and thereafter and if necessary removing any protecting group.

10. A process for preparing a homochiral compound of formula (I) as defined in Claim 1 which process comprises reacting a substantially racemic compound of formula (I) with a compound of formula (VII):

wherein R is an optionally substituted aryl, arylmethyl, heteroaryl, or heteroarylmethyl;

to form a mixture of diastereoisomeric adducts which are then separated and each of the adducts cleaved under basic conditions.