CA2120134A1 - Derivatives of cyclic phenolic thioethers as inhibitors or stimulators of superoxide generation - Google Patents

Derivatives of cyclic phenolic thioethers as inhibitors or stimulators of superoxide generation

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Publication number
CA2120134A1
CA2120134A1 CA002120134A CA2120134A CA2120134A1 CA 2120134 A1 CA2120134 A1 CA 2120134A1 CA 002120134 A CA002120134 A CA 002120134A CA 2120134 A CA2120134 A CA 2120134A CA 2120134 A1 CA2120134 A1 CA 2120134A1
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Prior art keywords
alkyl
thio
phenyl
hydrogen
carbon atoms
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CA002120134A
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French (fr)
Inventor
Richard August Mueller
Richard Allen Partis
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GD Searle LLC
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C323/17—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/20—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/22—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered

Abstract

The present invention relates to compounds of formula (I) and the pharmaceutically acceptable salts thereof wherein R1, R2 and R10 are the same or different and independently represent alkyl, alkoxy, hydroxy, phenyl, halogen, trifluoromethyl, cyano, or hydrogen; q is 0 or 1; R3 represents hydrogen, alkyl, alkoxy, or hydroxy; X represents O, S or (CH2)m wherein m is an integer from 0 to 4; A represents O or S(O)n wherein n is 0, 1, or 2;
Alk1 is straight or branched chain alkyl having 1 to 6 carbon atoms; p is 0 or 1; and R represents: (a) alkyl; (b) OH; (c) OR4 wherein R4 is alkyl of 1 to 6 carbon atoms; (d) NR5R6 wherein R5 is hydrogen or alkyl, and R6 is hydrogen, alkyl, alkoxyalkyl, heterocyclealkyl, substituted heterocyclealkyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, or Alk-NR8R9 wherein Alk is alkyl of 1 to 10 carbon atoms and R8 and R9 each independently are hydrogen or alkyl; or NR5R6 together form a heterocyclic ring which may optionally be substituted; or (e) (CH2)tCOOR7 wherein t is an integer from 1 to 4 and r7 is hydrogen or alkyl of 1 to 4 carbon atoms. The compounds are inhibitors or stimulators of superoxide generation.

Description

5DERI~ATI~ES OF CYCLIC PHENOLIC THIOETHERS AS lNHIBlTORS
OR STlMULA~ORS OF SUPEROXIDE GENERATION
Back~round of the Invention 1. Field of the Invention 10The present invention relates to cyclic phenolic thioethers and more particularly relates to the novel compounds of Formula I which are inhibitors or stimulators of superoxide generation and may also inhibit cyclooxygenase and/or 5-lipoxygena~e. The compounds of the present invention which stimulate superoxide generation may be useful as adjunctive `~
therapeutic agents in the treatment of infections.
Other compounds of the present invention which inhibit superoxide generation may be useful in the therapeutic or prophylactic treatment of disease conditions which are mediated wholly or partly by superoxide generation such as adult respiratory distress syndrome, superoxide mediated inflammatory or allergic conditions, and other medical conditions which are caused by or aggravated by 25 superoxide. `
The compounds of Formula I which inhibit cyclooxygenase or 5-lipoxygenase are useful, for -example, as anti-inflammatory and/or anti-allergy agents and in the treatment of hypersensitivity --30 reactions, psoriasis, asthma, and related disorders and ``
conditions in which physiologically active agents formed in the arachidonic acid metabolic pathway are involved. Compounds of the present invention may be useful in treating inflammatory and allergic conditions such as arthritis, asthma, and psoriasis.
2. Background Information Recently, oxygen radicals have been implicated in the pathogenesis of many diseases. This implication is reflected by the many conferences devoted to this topic, books on the subject of free radicals and disease, and the appearance of two new specialized WO93/1~87 PCT/US92/09560 -~
212013~ -2-journals: Free Radical Research Communications, and Free Radical Bioloav and Medicine.
Much is known about the physicochemical properties of the various oxygen radicals, but knowledge of their overall importance in the initiation and amplification of human disease is limited. Some clinical conditions in which oxygen radicals are thought to be involved are discussed in Cross, C. E., et al., "Oxygen Radicals and Human Disease," ANN. INT. MED., 107:526-545 (1987) (see Table 1, p. S27) and Ward, P. A., et al., "Oxygen Radicals, Inflammation, and Tissue Injury," FREE
RADICAL BIOLOGY & MEDICINE, 5:403-408 (1988). Among the clinical conditions in which oxygen radicals are -~
thought to be involved are, for example, inflammatory~
immune injury, autoimmune diseases, ischemia-reflow states, aging disorders, cancer, cigarette-smoke effects, emphysema, acute respiratory distress syndrome (ARDS), atherosclerosis, rheumatoid arthritis, senile `i dementia, cataractogenesis, retinopathy of prematurity, radiation injury and contact dermatitis.
Oxygen radicals are capable of reversibly or irreversibly damaging compounds of all biochemical classes, including nucleic acids, protein and free amino acids, lipids and lipoproteins, carbohydrates, and connective tissue macromolecules. These species may have an impact on such cell activities as membrane function, metabolism, and gene expression. Oxygen radicals are formed in tissues by many processes (see Cross, et al., p. 528, Table 2). These are believed to be both endogenous, such as mitochondrial, microsomal and chloroplast electron transport chains; oxidant enzymes such as xanthine oxidase, indoleamine dioxygenase, tryptophan dioxygenase, galactose oxidase, cyclooxygenase, lipoxygenase, and monoamine oxidase;
phagocytic cells such as neutrophils, monocytes and macrophages, eosinophils, and endothelial cells; and WO 93tlO087 PCI/USg2/09560 212013~
.

antioxidation reactions; and exogenous, such as redox-cycling substances, drug oxidations, cigarette smoke, ionizing radiation, sunlight, heat shock and substances that oxidize glutathione. They may be involved in the action of toxins such as para~uat, cigarette smoke, and quinone antitumor drugs.
Those compounds of the present invention which inhibit superoxide generation may be useful in the treatment of diseases mediated by superoxide generation.
There are also some conditions in which the generation of superoxide may be desirable. Those compounds of the present invention which stimulate superoxide generation may be useful in the adjunctive therapy of microbial infections. See Goodman and Gilman's, The Pharmacological Basis of Therapeutics (7th Edition, 1985) p. 660-673; P. A. Ward, et. al., "Oxygen Radicals, Inflammation and Tissue Injury, n FREE
RADICAL BIOLOGY & MEDICINE~ 5: 403-408 (1988); and C.
E. Cross, et. al., "Oxygen Radicals and Human Disease~U; ANN. INT. MED. ~ 107: 526-54S (1987) .
Generation of reactive oxygen species is a critical event in successful host defense against invading organisms. Both neutrophils and macrophages rely on a 2S variety of oxidants to damage bacterial constituents (see V. L. Shepherd, "The role of the respiratory burst of phagocytes in host defense," SEMIN. RESPIR. INFECT.
(Vnited States) Jun. 1986, 1(2) p. 99-106.
It is well recognized that arachidonic acid, an essential unsaturated fatty acid, is enzymatically oxygenated to various products, including, prostaglandins, thromboxanes, the 5-, 11-, 12- and 15-hydroxyeicosatetraenoic acids (HETEs, DIHETEs) and hydroperoxyeicosatetraenoic acids (HPETEs) and the leukotrienes, all of which have potent physiological effects.

212013'1 _4_ ~

Those compounds of the present invention which inhibit cyclooxygenase inhibit the synthesis of prostaglandins via the cyclooxygenase pathway of arachidonic acid metabolism. These prostaglandin 5 synthetase inhibitors may exhibit anti-inflammatory, ;
anti-pyretic and analgesic activity, and are useful in the treatment of inflammatory conditions such as arthritis.
The leukotrienes, which are produced via the 5-lipoxygenase pathway, are the major contributors to the onset of the symptoms of asthma, and mediators for immediate hypersensitivity reactions, inflammation and other aller~ic responses.
Leukotrienes are found in inflammatory exudates and are involved in the process of cellular invasion during inflammation. The term "leukotrienes" is used as a generic term to describe a class of substances, -such as slow-reacting substance (SRS) which is an --important mediator in asthma and other hypersensitivity reactions. Immunologically generated SRS is usually referred to as slow-reacting substance of anaphylaxis (SRS-A). SRS-A consists of leukotrienes (LT) known as ~, B4, C4, D4, and E4. LTC4 is at least lOo times more potent than histamine in causing long lasting bronchoconstricting effects. The leukotrienes also increase vascular permeability and cause decreased cardiac output and impaired ventricular contraction.
LTB4 may be an important mediator of inflammation in, for example, inflammatory bowel disease.
Chemotaxis is a reaction by which the direction of migration of cells is determined by substances in their environment. It is one of the major processes bringing leukocytes from the blood to an inflammatory site, whether the inflammation is caused by an infectious agent, allergic challenge, or other pro-inflammatory stimuli. LTB4 is not only chemotactic for neutrophils WO93/10087 PCT/US92/Og560 ` 21~013~

and monocytes, but is also highly active in stimulating eosinophil locomotion. LTB4 also stimulates calcium influx and aggregation of polymorphonuclear leukocytes and LTB4 may, thus, play an important role in mediating S both acute and chronic inflammation.
Rheumatoid spondylitis is characterized by an acute neutrophil flareup in the joint which is associated with elevated levels of LTB4. LTB4 is also present in gouty effusions, and exposure to urate crystals is known to stimulate LTB4 production ~y neutrophils. Accordingly, those compounds of the present invention which inhibit 5-lipoxygenase through inhibition of neutrophil attraction and activation in arthritic joints should reduce the protease and oxidative burden believed responsible for joint destruction in arthritic diseases.
Prior to the recognition of the significance of -the arachidonic acid metabolism pathway in allergic reactions and inflammation, the search for effective therapeutic agents was based primarily on those agents which treated the symptoms of allergy and inflammation.
There has since been an effort to develop new drugs which selectively block the formation of the mediators of these conditions, and the present invention provides new chemical entities which are inhibitors of the arachidonic acid pathway and are useful in the treatment of asthma, rheumatoid arthritis, osteoarthritis, psoriasis, and other allergic, hypersensitivity, and inflammatory conditions. Further 30 examples of inflammatory conditions or diseases with an inflammatory or immune system component are disclosed in, for example, the Merck Manual of Diagnosis and Therapy, 15th Edition (1987) which is incorporated herein by reference.
Various thioether compounds have been described previously. For example, U.S. 4,711,903 and its WO93/10087 . - PCT/US92/09560 -6- ;
continuation-in-part, 4,755,524 disclose compounds of .~:
the formula R1 ~_~ (~m HC~ 5--~AIn--(B)--(C)p~

wherein: R~ and R2 are the same or different and independently represent tert-alkyl or phenyl; A
represents methylene or methylene substituted by alkyl, ~:~
dialkyl or hydroxy, provided that when A includes ::
hydroxymethylene, the hydroxymethylene group is not adjacent to a heteroatom; B represents sulfur, sulfoxide, sulfcne, oxygen, -NH- or nitrogen substituted by alkyl, phenyl, benzyl, substituted phenyl or substituted benzyl; C represents methylene or methylene substituted by alkyl; R3 represents CO2H, C2- ~.
alkyl or a tetrazole group; m is 0 or 1, n is 2, 3 or 4 .
and p is l, 2 or 3; and the pharmaceutically acceptable salts thereof~ The compounds are specific inhibitors of 5-lipoxygenase and are useful in the treatment of local and systematic inflammation, allergy and hypersensi ivity reactions and other disorders in which agen~s formed in the 5-lipoxygenase metabolic pathway are involved.

WO g3/10087 2 1 2 0 1 3 ~ Pcr/usg2/ogs60 ; ~ :

U.S. 4,621,098 and its equivalent, European Patent Application Publication No. 0131221 disclose compounds of the formula )n t Ar O A S- R

in which Ar is phenyl or phenyl substituted by one to three of varied substituents, for example, alkyl, -~
alkoxy, hydroxy, etc.; Q is oxygen, sulfur or an NH
group; A is straight or branched chain, optionally substituted, alkylene, and R is hydrogen or straight or lS branched alkyl, optiona}ly ~ubstituted by alkoxy, hydroxyl, carboxyl, alkoxycarbonyl, etc.; and n is 0, 1 or 2. The disclo~ed compounds are indicated to have anti-inflammatory and anti-allergic properties through inhibition of undefined anaphylactic and anaphylactoid reactions, although no test d~ta are provided. The preferred compounds are stated to be those in which Q
represents oxygen and n is 0 without mention of any preference among the numerous possible substituents for R or substituted phenyl as Ar. In contrast to the invention disclosed in the foregoing publication, the compounds of the present invention all have cycloalkyl ~t the position corresponding to A as well as having di(tertiary)-alkyl or diphenyl groups as substituents on the phenol moiety corresponding to the substituted 30 Ar group in the above publication which, as described therein, may or may not comprise a phenol.
- U.S. Patent Nos. 4,029,812, 4,076,841 and 4,078,084 disclose compounds of the formula WO93/10087 ; PCT/US92~09560 C(CH~)3 (CH~3 R~

H~ ~ S - CH--CN

C(CH3h comprising 2-(3,5-di-tert -butyl-4-hydroxy-phenyl) thio carboxamides. The compounds are indicated to be useful in lowering serum cholesterol and triglyceride levels.
A series of thioethers, useful as, for example, polyfunctional antioxidants for polymers, and ~`
biologically active substances, obtained by the nucleophilic addition of thiols, including 3,5-di-tert-butyl-4-hydroxythio-phenol, and hydrogen sulfide to acrylate derivatives have been described. See Medvedev et al., Khimiya; Khimicheskaya Tekhnologiya, Volume 20, (1977), pp. 568-574. The compounds resulting from the foregoing process have the general formulas RS(CH2)~X
and S(CH2CH2X) 2 in which R is 3,5-di-tert-butyl-4-hydroxyphenyl and X represents, for example, -C--N, NH2, CH(OH)CH2Cl, OH, COCl and various carboxy, carboxylate and amide functions. Compounds of formula I according to the present invention or 5-lipoxygenase activity for structurally related compounds are not disclosed.
U.S. Patent No. 4,~53,803 discloses cholesterol-lowering phenoxyalkanoic acid esters of the formula R Al ~y_ I COZ
X ~ k WO93/10087 PCT/US92/OgS60 21201~

wherein, when Y is sulfur, X is hydrogen, benzyl, benzyloxy or benzylthio or substituted derivatives thereof; R is hydrogen, halogen, hydroxy, alkyl or alkoxy, Al and A2 are hydrogen or alkyl and Z is amine or azacyclohydrocarbonyloxy.
JP 49116035 discloses a process for making compounds of the formula 1-Bu ~ R3 R4 HOy--S I Cl O

U
wherein Rl, R2, R3 and R4 are hydrogen, alkyl or aryl groups, and Rl and R2 can be combined to form a cycloalkyl group. The compounds are said to be useful as drug intermediates, agricultural chemicals, :~ antioxidants and industrial chemicals. Specifically disclosed is a compound of the formula t-\u )=\ ""
HO~

t-Bu OH~ ~
CA 107:197783q discloses dialkylphenol derivatives of the formula H0~ ~ H2)~

WO93/10087 ~ PCT/US92/09560 212013~ -lO-wherein Rl, R2 = alkyl; A = alkylene, S, So; Y =
alkoxyimino, o; Z = alkylene,O; n = 1, 2; 2-3 satrd. or unsatd. The compounds are said to be useful as modifiers for biosynthesis of prostaglandins and leukotrienes and hypolipemics (no data).
These compounds differ structurally from the compounds claimed in the present application which have ;
a carboxylic acid or ester moiety attached to the cycloalkyl ring through A-(CH2)p or through A-(CH2)p-C(0)-(CH2), and which do not have an alkoxyimino or =0 attached to the cycloalkyl ring.
EP0293900 discloses 5-lipoxygenase inhibiting compounds of the formula R~ -HO~ X Y--CO2R3 where R3 and Y together are ~ I
(CH2)n and n is 2 or 3. These compounds differ structurally from the claimed compounds. They have a lactone structure (i. e., a dihydro-furanone or dihydro-pyranone) attached to the phenylthio and lack a carboxylic acid or ester moiety attatched to the heterocyclic ring through A-(CH2)p or through A-(CH2)p-C(O)--(cH2)~

WO93/10087 2 1 2 0 1 3 ~ PCT/US92/09560 Katsumi, et al., CHEM. PHARM. BULL. 34(4):1619-1627(1986) discloses 3,5-di-tert-butyl-4-hydroxystyrenes. Some of the compounds disclosed had anti-inflammatory activity and some inhibited 5-lipoxygenase. Only one compound (Compound 3, Table I.)had S attached to the 3,5-di-tert-butyl-4-hydroxyphenol. It has the following structure:

(CH3)3C

HO~S~

(CH3)3C

This compound differs structurally from the claimed compounds. It has a butyrolactone (i.e., a dihydro-2(3H)-fur~none) attached to the thio and lacks a carboxylic acid or ester moiety attatched to the heterocyclic ring through A-(CH2)p or through A-(CH2)p-C(O)-(CH2)t. At the bottom of page 1621 the authors indicate that insertion of the thio group resulted in a loss of anti-inflammatory activity.

U. S. 4,801,611 discloses 5-lipoxygenase inhibitors of the formula HO ~ SCH2CH2~3 R/

W093/~7 PCT/US92/~560 i .

212013~ -12-where Rl and R~ are tert-alkyl and R3 can be R6~,~R7 ~

V - ~ :
H
where R~ and R7 are C,4 alkyl.

These compounds differ structurally from the compounds of the present invention. Compound (c) has a dialkyl-1,3-dioxanyl group attached to the phenylthio through an alkylene bridge whereas compound (d) has a 4-hydroxy-2-pyranone attached to the phenylthio through an alkylene bridge. Neither compound has a carboxylic acid or ester moiety attatched to the cycloalkyl ring through A- (CH2) p orlthrough A-(CH2)p-C(0)-(CH2), as do the compounds of the pre~ent invention, and both compound have an alkylene bridge inserted between the phenylthio and the heterocyclic ring.

WO g3/10087Pcr/uss2/oss60 SUMMARY OF THE INVENTION
It is, therefore, a primary object of the present invention to provide novel cyclic phenolic thioethers pharmaceutical compositions containing them and methods of using them, as well as intermediates for producing them. The novel cyclic phenolic thioethers of the present invention are compounds of the formula ~ ~ tCH2)q - S ~ ~ - (A~1)p - C - R

R2 , (I) and the pharmaceutically acceptable salts thereof wherein Rl, R2 and Rl are the same or different and independently represent alkyl, alkoxy, hydroxy, phenyl, halogen, trifluoromethyl, cyano, nitro, alkylthio or hydrogen with the proviso that when Rl and R2 are 3,5-di-tert-butyl, Rl is not 4-hydroxy; q is 0 or 1; R3 represents hydrogen, alkyl, alkoxy, or hydroxy; X
represents O, S or (CH2)1D wherein m is an integer from 0 to 4; A represents O or S(O) D wherein n is 0, 1, or 2;
Alkl is straight or branched chain alkyl having 1 to 6 carbon atoms; p is o or l; y is 0, 1 or 2; and R
represents:
(a) alkyl;
(b) OH;
(c) oR4 wherein R4 is alkyl of 1 to 6 carbon atoms;
(d) NR5R6 wherein R5 is hydrogen or alkyl, and R6 is hydrogen, alkyl, alkoxyalkyl, heterocyclealkyl, substituted heterocyclealkyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, or Alk-NR8R9 wherein Alk is alkyl of 1 to 10 carbon atoms and R~ and R9 each independently are hydrogen or alkyl; or NR~6 together form a heterocyclic ring which may optionally be substituted; or (e) (CH2)tCooR7 wherein t is an integer from 1 to 4 lo and R7 is hydrogen or alkyl of 1 to 4 carbon atoms.
It is a further object of the present invention to provide methods for stimulating or inhibiting superoxide generation and to provide methods for treating conditions mediated by products of the arachidonic acid metabolic pathway and for promoting anti-inflammatory and/or anti-allergic effects in mammals in need thereof by the administration of preselected dosages of compounds of the present invention or pharmaceutically acceptable salts thereof in appropriate non-toxic pharmaceutical dosage forms or compositions. Some compounds of the present invention may inhibit 5-lipoxygenase and/or cyclooxygenase.
Those compounds which inhibit both 5-lipoxygenase and cyclooxygenase have an advantage when administered to patients who are sensitive or allergic to cyclooxygenase inhibitors since the 5-lipoxygenase inhibiting activity may have a mitigating effact on the patient's sensitivity to cyclooxygenase inhibitors.
This mitigating effect may also make compounds which inhibit both 5-lipoxygenase and cyclooxygenase useful for co-administration with cyclooxygenase inhibitors.
Another object of the present invention is to provide dosage unit forms adapted for, e.g., oral, topical, and/or parenteral administration and useful in the stimulation or inhibition of superoxide generation WO93/10087 2 1 2 0 1 3 4 PCT/USg2/09560 ~,`,``;i "

and in the treatment, management and mitigation of inflammation, allergies, psoriasis and hypersensitivity reactions and related disorders and conditions in which physiologically active agents formed in the arachidonic acid metabolic pathway are involved.
Those compounds of the present invention which inhibit superoxide generation may be useful in the therapeutic or prophylactic treatment of disease conditions which are mediated wholly or partly,by superoxide generation such as adult respiratory distress syndrome, superoxide mediated inflammatory or allergic conditions, and other medical conditions which ' are caused by or aggravated by superoxide.
Those compounds of Formula I which are stimulators of superoxide generation in neutrophils may be useful in the therapeutic or prophylactic treatment of disease conditions in which superoxide generation is an important factor.
Although it has been speculated that 5-lipoxygenase may be involved in superoxide generation,the ability of some compounds, which inhibit S-lipoxygenase, to stimulate superoxide generation in neutrophils while others inhibit superoxide generation indicates that superoxide generation is not governed by 5-lipoxygenase. Thus the activity of the compounds of Formula I in stimulating or inhibiting superoxide generation is not related to the ability to inhibit 5-lipoxygenase. Compounds which do not inhibit s-lipoxygenase may still act as inhibitors or stimulators of superoxide generation. In general those compounds of Formula I which are carboxylic acids inhibit superoxide generation and those compounds which are esters or heterocycle alkyl amides stimulate superoxide generation. Compounds of Formula I which are readily hydrolyzable to the carboxylic acid upon oral administration may also act as prodrugs which would be WO g3/lOQ87 , PCr/USg2/09560 212013~ -16-converted to superoxide inhibitors by stomach acid, blood, liver, or other organs. In addition some compounds of Formula I may inhibit 5-lipoxygenase and/or cyclooxygenase.
The present invention provides a method by which neutrophil activation and the generation of superoxide anions are accomplished utilizing compounds of Formula I having the ability to stimulate superoxide generation. Accordingly these compounds of Formula I
are useful in the design and testing of anti-inflammatory properties of other pharmacologically active agents.
The ability to produce superoxide which may itself be microbicidal or which is then converted to toxic oxidants such as H2O2,-OH, and singlet oxygen is important to the phagocytic ~illing mechanisms which enable neutrophils and macrophages to kill bacteria and parasites through phagocytosis.
Therefore, compounds of Formula I which stimulate superoxide generation may be useful in the adjunctive therapy of microbial infections. The compounds may also be useful in treating conditions such as Chediak-Higashi Syndrome in which the patient's macrophages and polymorphs are only wea~ly active causing the patients to suffer from recurring infections involving organisms with normally low pathogenicity. Compounds of Formula I which stimulate superoxide generation may also be useful in the adjunctive therapy of patients whose immune systems have been weakened or impaired by disease or by chemot~erapy or radiation therapy and who are more subject to microbial infections.

WO93/1~87 2 I 2 01 3 4 PCT/US92/09560 DETAILED DESCRIPTION OF THE ~REFERRED ~BO~IMENTS
These and other similar objects, advantages and features are accomplished according to the products, compositions and methods of the invention comprising compounds of the formula Rl ~~

~_ _~(CHz~q--S~A--(CH2)"--O--R

X' R3 tIa) and the pharmaceutically acceptable salts thereof 15 wherein Rl, R2 and Rl are the same or different and ~:
independently represent alkyl, alkoxy, hydroxy, phenyl, halogen, trifluoromethyl, cyano or hydrogen; q is 0 or -1; R3 represents hydrogen, alkyl, alkoxy, or hydroxy; X
represents O, S or (CH2)m wherein m is 1 to 4; A
represents O or S()n wherein n is 0, 1, or 2; p is an integer from 0 to 4; and R represents:
(a) alkyl;
(b) QH;
(c) oR4 wherein R4 is alkyl of 1 to 6 carbon atoms;
(d) NR5R6 wherein ~5 is hydrogen or alkyl, and R6 is hydrogen, alkyl, alkoxyalkyl, heterocyclealkyl, substituted heterocyclealkyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, or Alk-NR8R9 wherein Alk is alkyl of 1 to 10 carbon atoms and R8 and R9 each independently are hydrogen or alkyl; or NR5R6 together form a heterocyclic ring which may optionally be substituted; or . . ~

(e) (CH2)tCOOR7 wherein t is an integer from 1 to 4 and R7 is hydrogen or alkyl of 1 to 4 carbon atcms.
Included in the present invention are compounds of the formula R1 :
O
R10~/=\ 11 lO~S~A--~CH2)p--C--R

R2 ~ \ (Ib) X R3 :

15 and the pharmaceutically acceptable calts thereof :
wherein Rl, R2 and Rl are the same or different and independently represent tert-alkyl of 4 to 10 carbon atoms, phenyl, balogen or hydrogen; R3 represents ~;
hydrogen or alkyl of 1 to 4 carbon atoms; X represents O, S or (CH2)~ wherein m is 1 or 2; A represents O or S () n wherein n is 0, 1, or 2; p is an integer from 0 to 4; and R represents:
(a) alkyl of 1 to 4 carbon atoms;
(b) OH;
(c) oR4 wherein R4 is alkyl of 1 to 4 carbon atoms;
(d) NR5R6 wherein R5 is hydrogen or alkyl, and R6 is hydrogen, alkyl, alkoxyalkyl, heterocyclealkyl, substituted heterocyclealkyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, or Alk-NR8R9 wherein Alk is straight or branched chain alkyl of 1 to 6 carbon atoms and R8 and R9 each independently are hydrogen or alkyl of 1 to 4 carbon atoms; or NR5R6 together form a 212013~

--lg--heterocyclic ring which may optionally be substituted; or (e) (CH2)tCooR7 wherein t is an integer from l to 4 and R7 is hydrogen or alkyl of l to 4 carbon atoms.

Included in the present invention are compounds of the formula ~S~;A--(CH2)p--C--R

and the pharmaceutically acceptable salts thereof wherein R1 and R2 are the same or different and independently represent tert-butyl, phenyl, halogen or hydrogen; R3 represents hydrogen or alkyl of l to 4 carbon atoms; X represents O or (CH2)m wherein m is l or 2; A represents O or S; p is O or ~; and R represents:
(a) OH;
(b~ oR4 wherein R4 is alkyl of l to 4 carbon atoms; or (c3 NR~R6 wherein R5 is hydrogen or alkyl of 1 to 4 carbon atoms and R6 is hydrogen, alkyl of l to 4 carbon atoms, alkoxyalkyl wherein the alkyl 30 moieties each have l to 6 carbon atoms, heterocyclealkyl wherein the alkyl moiety has 1 to 4 carbon atoms, or Alk-NR8R9 wherein Alk is straight or branched chain alkyl of l to 6 carbon atoms and R8 and R9 are each independently hydrogen or alkyl of l to 4 carbon atoms; or NR~6 together form a W093/1~87 ; PCT/US92/09560 ,j. . .
212013~ :

heterocyclic ring which may optionally be substituted.
:.

Included in the present invention are compounds of the formula Rl :~

R2~S~A--(CHz)p--C--R
X~R3 lS (IIa) and the pharmaceutically acceptable salts thereof wherein Rl and R2 are the same or different and independently represent tert-butyl, phenyl, or hydrogen; R3 represents hydrogen or alkyl of l to 4 carbon atoms; X represents O or (CH2)m wherein m is 1 or 2; A represents O or S; p is O or l; and R represents:
(a) OH;
(b) oR4 wherein R4 is alkyl of l to 4 carbon atoms; or (c) NR5R6 wherein R5 is hydrogen or alkyl of l to 4 carbon atoms and R6 is hydrogen, alkyl~of 1 to 4 carbon atoms, alkoxyalkyl wherein the alkyl moieties each have l to 6 carbon atoms, heterocyclealkyl wherein the alkyl moiety has l to 4 carbon atoms, or Alk-NR~R9 wherein Alk is straight or branched chain alkyl of l to 6 carbon atoms and R8 and R9 are each independently hydrogen or alkyl of l to 4 carbon atoms; or NR~6 together form a heterocyclic ring which may optionally be : substituted.

WO 93/100~ 2 i20 13 ~ PCT/US92/09560 :

Also included in the present invention are novel intermediates of the Formula III

}~CH2)q S~Z

(III) wherein Rl, R2, R3, Rl, q, y and X, are defined as in Formula I, and Z represents hydroxy, halogen, sulfonate ester, or perfluoroacyl ester.
The compounds of Formula ITI are useful as intermediates for making compounds of Formula I.
In addition the present invention,includes intermediate compounds of the Formula XV ;

R~ R' ~1)~

~_ ~(CH2)q S ;~

R

wherein Rl, R2, R3, Rl, q, y and X are defined as above.
These compounds are useful as intermediates for making compounds of Formula I.

2 1 2 0 ~ 22-The present invention includes compounds of the formula IV:

R' ~ . O

~S~_<A CH2 C n F~2 ~X~

(IV) wherein R1 and R2 are the same or different and independently represent tert-butyl, phenyl or hydrogen;
15 X is ( CH2) m wherein m is 2, A is S or O; and R iæ:
(a) OH;
(b) O* wherein R4 is alkyl of l to 4 carbon atoms; or ( C ) NR~R6 wherein R5 is hydrogen or alkyl of 1 to 4 carbon atoms and R6 is alkyl of l to 4 carbon atoms; alkoxyalkyl; heterocyclealkyl wherein the alkyl moiety has l to 4 carbon atoms;
phenyl; substituted phenyl having one or more substituents selected from the group consisting of alkyl, hydroxy, alkoxy, halogen, alkylamino, dialkylamino, phenyl, and alkyl carbonyl; or Alk-NR~R9 wherein Alk - is straight or branched chain alkyl of l to 4 carbon atoms and R~ and R9 are each independently hydrogen or alkyl of l to 4 carbon atoms;
and the pharmaceutIcally acceptable salts thereof.
Included in the present invention are compounds of formula IV wherein R~ and R2 are both tert-butyl; X is (CH2)m wherein m is 2; A is S or O; and R is:
(a) OH;

W093~tO087 PCT/US92/09560 2 1 ~ O 1 3 Li (b) oR4 wherein R4 is alkyl of 1 to 2 carbon atoms; or tC) NR~6 wherein Rs alkyl of 1 to 4 carbon atoms and R6 is alkoxyalkyl, heterocyclealkyl wherein the alkyl moiety has 1 to 4 carbon atoms, phenyl, substituted phenyl, or Alk-NR8R9 wherein Alk is alkyl cf 1 to 4 carbon atoms and R8 and R9 are alkyl of 1 to 4 carbon atoms;
and the pharmaceutically acceptable salts thereof.
Compounds of the present invention can possess one or more asymmetric atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or nonracemic mixtures thereof.
The optical isomers can be obtained by resolution of the racemic mixtures by conventional processes.
Included in the family of compounds of the present invention are all isomeric forms thereof, including diastereoisomers, geometric isomers~ equatorial or axial isomers, conformers, tautomers, and their pharmaceutically acceptable salts.
The term "tert-alkyl" as used herein in reference :
to Rl and R2 refers to branched chain alkyl moieties of from about 4 to about 10 carbon atoms having a tertiary carbon atom attached to the phenyl ring substituted by Rl and R2. Examples of such groups are tert-butyl, i.e., l,l-dimethylethyl, l,l-dimethylpropyl, l-methyl-1-(ethyl)pentyl, l,l-diethylpropyl, l-ethyl-1-tpropyl)butyl and the like.
30 The term "alkyl" defines straight or branched chain monovalent hydrocarbon radica-s having between about 1 to 10 carbon atoms including, for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, sec-butyl, isobutyl, pentyl, l-methylbutyl, isopentyl, 35 neopentyl, hexyl, octyl, nonyl, decyl, etc. .

WO93/10087 PCT/USg2/095~

The term "alkoxyalkyl" refers to alkoxyalkyl moieties in which the alkyl moieties are straight or branched chain alkyl of 1 to 6 carbon atoms.
The terms "heterocycle" and "heterocyclic ring" as used herein refer to aromatic or nonaromatic heterocyclic rings which contain one or more heteroatoms and include but are not limited to pyridine, piperazine, piperidine, pyrrolidine, pipecoline, dioxolane, furfuryl, thiopene, tetrahydrofurfuryl, morpholine, azabicycloalkyl, e.g., 3-azabicyclo~3,2,2]nonane, azatricycloalkyl, 1,2,3,4-tetrahydroisoquinoline, 5,6,11,12-tetrahydrodibenztb,f~azocine, iminostilbene, and the ; like which may optionally be substituted with one or more substituents selected from alkyl, phenyl, substituted phenyl, phenylalkyl, heterocycle, cycloalkyl, halogen, hydroxy, nitro, trifluoromethyl and lower alkoxy.
The terms "substituted phenyl" and "substituted phenylalkyl" as used herein refer to phenyl or phenylalkyl moieties in which the phenyl ring is substituted by one or more substituents selected from ~-alkyl, hydroxy, alkoxy, halogen, alkylamino, dialkylamino, cycloalkyl, phenyl, substituted phenyl, trifluoromethyl, nitro, alkylthio, and alkyl carbonyl.
The term "cycloalkyl" refers to cycloalkyl rings of 3 to 10 carbon atoms and includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantane, norbornane and the like which may optionally be substituted by 1 or more substituents selected from alkyl, hydroxy, alkoxy, and halogen.
The term "halogen" refers to chlorine, bromine, fluorine, and iodine.
The expression "pharmaceutically acceptable salts"
is intended to include those salts capable of being wo g3,l~8, 2 1 2 ~ 1 3 ~ PCT/US92/09560 formed with the compounds of the present invention, e.g., when R represents OH, NR~6 when R6 is Alk-NR8R9 or heterocyclealkyl without materially altering the covalent chemical structure thereof. Such salts include inorganic and organic base or acid addition salts, such as sodium, potassium, calcium, ammonium, alkylammonium, quaternary ammonium, triethanolamine, lysine, hydrochloride, hydrobromide, phosphate, citrate, etc. well known to those skilled in the art.
The foregoing salts are prepared in the conventional mannAer by neutralization of the compounds of formula I
with the desired base or acid.
The compounds of the present invention can be administered to a patient in such oral dosage forms as tablets, capsu~es, pilIs, powders, granules, elixirs, or syrups as well as aerosols for inhalation.
Likewise, administration may be effected intravascularly, subcutaneously, topically, or intramuscularly using dosage forms known to those of ordinary skill in the pharmaceutical arts. In general, the preferred form of administration is oral. An effective but non-toxic amount of the compound is employed in treatment. The dosage regimen utilizing the present compounds is selected in accordance with a variety of factors including the type, age, weight, sex, and medical condition of the patient; the severity of the condition to be ameliorated; and the route of administration. A physician of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, treat or arrest the progress of the condition. For those conditions in - which it is desirable to inhibit superoxide generation or for those conditions in which it is desirable to stimulate superoxide generation the effective amount for administration is ordinarily that amount which is required to assure that the mammalian neutrophils W~93/1 ~ 7 PCT/US92/09560 involved in the generation of superoxide will be exposed to a sufficient concentration of drug to either inhibit superoxide generation or stimulate superoxide generation as the case may be.
Dosages of the compounds of the present invention, will range generally between O.l mg/kg/day to about lO0 mg/kg/day and preferably between about O.S mg/kg of body weight per day to about 50 mg/kg of body weight per day when administered to patients suffering from inflammation or allergic or hypersensitivity reactions.
In general, a unit dose form of the compounds of the invention will contain from about 1.75 to about ?S0 mg of compound. The compound may be administered in divided dosages, e.g. two or more times daily. The compounds may also be administered transdermally or topically to treat proliferative skin conditions such - as psoriasis. The daily dosage may be administered in a single dose or in equal divided doses three or four times daily.
Unit dosage forms such as tablets and capsules can contain any suitable, predetermined, therapeutically effective amount of one or more active agent and a pharmaceutically acceptable carrier or diluent.
Generally speaking, solid oral unit dosage forms and other unit dosage forms of the compounds of this invention which inhibit cyclooxy~genase and/or 5-lipoxygenase will contain from l.75 to 750 mg per tablet of drug as the effective 5-lipoxygenase and/or cyclooxygenase inhibiting amount of the compound.
In the case of acute allergic or hypersensitivity reactions, it is generally preferable to administer the initial dosage via-the parenteral route and continue parenteral administration until the patient is stabilized, and can be maintained, if necessary, on oral dosing.

WO93/1~87 2 1 2 0 1 ~ PCT/US92/09560 -27- :

In the case of psoriasis and other skin conditions, it may be preferred to apply a topical preparation of a compound of this invention to the affected area three or four times daily.
In treating asthma and arthritis with a compound of this invention, the compounds may be administered either on a chronic basis, or as symptoms appear.
However, in the case of arthritis and other inflammatory conditions which can lead to deterioration of joints and malformations, it is generally preferable to administer the active agent on a chronic basis.
When the compounds of this invention are co-administered with one or more cyclooxygenase inhibitors, they may conveniently be administered in a unit dosage form or may be administered separately.
When the patient is allergic or hypersensitive to the cyclooxygenase inhibitor, it is preferred to initiate therapy with a compound of this invention prior to administration of the cyclooxygenase inhibitor.
A typical tablet of this invention can have the following compositions:

_ .
Ingredient Mg/tablet Active ingredient lO0 Starch, U.S.P~ 57 Lactose, U.S.P. 73 Talc, U.S.P. g Stearic acid 12 ~
In the pharmaceutical compositions and methods of the present invention, at least one of the active .

compounds of the invention or a pharmaceutically acceptable salt thereof will typically be administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as "carrier" materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups, and the like, and consistent with conventional pharmaceutical practices. For instance, for oral administration in the form of tablets or capsules, the active drug component may be combined with any oral non-toxic pharmaceutically acceptable inert carrier such as sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol and the like; for oral administration in liquid form, the active drug component may be combined with any oral non-toxic pharmaceutically acceptable inert carrier such as ethanol and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated in the mixture. Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol, and waxes. Lubricants for use in these dosage forms include boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, guar gum, and the like.
The compounds of the invention are prepared from readily available starting materials by any of the following alternate processes in a conventional manner~
The following reaction schemes describe methods which can be employed for preparing the compounds of formula I, including starting materials, intermediates, and r~action conditions.
As shown in part (l) of Scheme A, a mercaptan (V) can be reacted with an oxabicyclo compound (VI) to give the intermediate (III) which may then be reacted with a monohaloacid or protected monohaloacid in a base or alternatively with a thiol acid in an acid to obtain a product acid of type (VII). Epoxides of type (VI) are W093/10087 2 1 2 0 1 ~ ~ PCT/USg2/OgS60 readily prepared by oxidation of a double bond with peroxides such as m-chloro-perbenzoic acid, peracetic acid, pertrifluoroacetic acids, hydrogen peroxide, t-butyl hydroperoxide and the like. Base induced cyclization of halohydrins, obtained by treatment of double bonds with mineral acids, also produces epoxides. In addition, epoxides can be uRed as starting materials for the preparation of halohydrins which can also be used to produce compounds of type TII, following reaction with, for example, a mercaptan.
Most bases can be used for the preparation of III, for example, hydroxides, tert-amines, heterocyclic ~mines, dimethylaminopyridines, hydrides, lithium alkyls, lithium amides and the like, since the thiolate anion is an exceptional nucleophile. Non-nucleophilic bases are preferred for the conversion of III into VII in the presence of an electrophilic reagent such as a substituted halo alkyl group.
Epoxides of Formula VI can be converted into thio~poxides (the sulfur analog) by, for example, the method described by E. E. Van Tamelin, Oraanic Svnthesis Collected Volume 4, p. 232 (1963).
Thioepoxides can be used in place of epoxides allowing the order of addition of substituents to be varied, especially in the case where A is sulfur.
Compound III may also be converted into VII via conversion into a halo compound tScheme C), an activated ester (Scheme C) or acid catalysis (Scheme A). In the first case, treatment of the hydroxy compound with hydrochloric, hydrobromic, hydriodic or hydrofluoric acid, preferably at reflux temperatures, converts it into the corresponding halo compound.
Displacement of the halogen ISN2) with a mercaptan under basic conditions (as shown in Scheme B) provides compound XIII.

W093/l0087 PCT/US92/09560 212013~ 30 The alcohols III or ~I may be converted into activated esters such as those of toluene sulfonic acid (tosylates), methane sulfonic acid (mesylates), trifluoromethane sulfonic acid triflates) and trifluoroacetic acid. Displacement of the activated ester (SN2) with a mercaptan under basic conditions (see above) provides compound VII. Both this method and that outlined above utilizing a halo intermediate have the advantage that the stereochemistry at the carbon bearing the functional group may be inverted thus allowing control (selection) of the stereochemistry of the product.
Treatment of alcohols III or XI with a mercaptan in the presence of an acid (Scheme A, B, C) should provide the corresponding sulfide, e.g., VII or XIII.
Mineral acids, organic acids and Lewis acids are suitable for this reaction. Non-nucleophilic acids are preferred and include, for example, trifluoroacetic acid, toluene sulfonic acid, perfluorobutyric acid, triflic acid, phosphoric acid, sulfuric acid, boron - trifloride, aluminum chloride and the like.
-~ Conversion of a carboxylic acid such as VII, XI or XII into an ester or an amide is accomplished by standard means. The carboxylic acid may be treated ~ 25 with the appropriate alcohol with or without added solvent in the presence of an acid (see above) to provide the product ester. A salt of the carboxylic acid may be prepared by treatment with a base (see above) and the salt then treated with an electrophilic group with displacement of, for example, a halide, tosylate and the like. An alternative method of preparation is conversion of the carboxylic acid into an activate carbonyl function such as an acid halide, mixed anhydride or activated ester followed by treatment with an appropriate alcohol or amine. Acid halides can be made by mixing, for example, thionyl WO93/1~87 PCT/US92/09560 212013~
-31-~

chloride, thionyl bromide, phosphorus trichloride, phosphorus pentabromide, oxalyl chloride and the like with the acid. Nixed anhydrides with, e.g., isobutyl chloroformate, are prepared in the standard manner with the acid being treated with isobutyl chloroformate in the presence of a base or from a preformed carboxylate salt. The same type of salt, either prepared in the reaction or preformed, can be treated with for example, N-chlorosuccinimide, to form the succinimide activated ester. Treatment of either of these intermediates with the appropriate amine, alcohol, mercaptan or electrophile will provide the compounds of this invention.
The conversion of the alcohols/mercaptans III, XI, XVI, XVII and the like into compounds of, for example, X, is accomplished in the same manner as the synthesis of the other esters outlined above. In this case, the appropriate alcohol/mercaptan is repreæented as outlined above and the acylating agent can be an acid halide or anhydride.
Scheme C illustrates yet another method for the preparation of the intermediates and compounds of this invention. An alpha-halo ketone, substituted or unsubstituted, is treated with a oxygen or sulfur nucleophile generated as described above. The valuable intermediate, XV, is reduced directly with, for example, a hydride reducing agent such as sodium borohydride, lithium aluminum hydride, sodium cyano borohydride and the like or borane, to provide the alcohols III and XI. The use of these intermediates for the preparation of compounds VII, VIII, XIV and X
is discussed above. Conversion of ketone XV into a thioketone is readily accomplished using reagents such as phosphorus pentasulfide or 2,4-bis(4-methoxyphenyl)-35 1,3-dithia-2,4-diphosphetane-2,4-disulfide ~Lawesson's Reagent). Reduction of the thioketone as discussed WOQ3~10087 . PCT/US92/09560 21201~4 -32-above for the ketones provides the mercaptan analogs of III and XI and it is used similarly.
The sulfone and sulfoxide compounds of the present invention are readily prepared by oxidation of the sulfides with, for example, m-chloroperoxybenzoic acid or sodium metaperiodate.

SCHEME A
(1) . .

~CH2)q--SH . ~ Elæ ~(CH2)--S~OH

(V) (Vl)1 ~ ) HAS(CdH2)PCOH
Cl(CH~pCOH
Basc ~CH2)--S~A-(CH2)"-O~Rt R10~A-(CH2)p~H

1)Cx~y1chlonde 2) HNR~6 RlO~(CH2)q--S~A~CH2)p CNR5R6 ax) (2) ~ (RCOkO ~ (CH2)q--~ A10CR

R=aky1~(CH~COOR7 :

wo g3/l0087 2 1 2 0 1 3 i PCI~/US92/09560 SCHEME B

,~ HS(CH2)pCOORHO ~S (CH2)pCOOR

X X

VI
~. ., HCI

Cl~ S (CH2)pCOOR

X XII

Base - -~, R10~rlR' ~_ ~(CH2)q--SH

;~ R2 ~1~
_~(CH2)q --- S~ ~S-- ~CH2)pCOOR

R2 ~ ~
X

xm ~: ~

WO g3/10087 PCl/US92/09560 SCHEME C

~J~Br H~
X~R3 x~R3 III, ~:
H3C~S02cl H(~l J _ ~

~AE ~H3 ~AE

Rcducdon XD~
:~ XII.
;H xvm ~,AE
;~: :: x~R3 XVI, xvn E = --(CH2)q{~ , (CH2)p--COH . H, ~2 ll - (CH2)p--COH

R3= alkyl, H A= S, O

WO 93/10087 21 2 0 I 3 I P~/US92/0g560 --3 ~

BIOLOGICAL EVALUATIONS
The. compounds of the invention are evaluated with respect to superoxide modulating activity according to the following assay procedure:

Human neutrophil superoxide qeneration:

Superoxide generation by formyl-methionyl-leucyl-phenylalanine (FMLP)-stimulated neutrophils was quantitated by the reduction of cytochrome C

(Badwey, J. A., Curnutte, J. T. and Karnovsky, M.

L., cis-Polyunsaturated fatty acids induce high levels of superoxide production by human neutrophils. J. Biol. Chem. 256: 12640-12643, 1981.) To 5 million neutrophils in 2.85 ml of Krebs-Rinqer phosphate buffer, pH 7.2, 50 ul of inhibitor (in 10% DMSOtbuffer), and 50 ul ferricytochrome C (5 ~M, stock) were added and preincubated for 3 minutes at 37 C. Absorption measurements at 550 nm were recorded at start of preincubation. Fifty ul ~MLP (6 uM, stock) was added to initiate reaction. A plateau was reached within 3 minutes and this reading minus the initial reading (before addition of FMLP) was used to calculate nanomoles of superoxide generated based on a molar extinction coefficient of 2.1 x 104 cm-~mole~~.

Isolation of human neutro~hils: Human neutrophils were isolated from freshly drawn blood of healthy donors. Two ml of 5% dextran (MW 200,000-30Q,000) in saline was added to 10 ml aliquots of blood, mixed and pla~ed upright for 45 min. at 37 C.

Approx. 8-10 ml of the plasma-white cell suspension from the dextran sedimentation was layered on 3 ml of Ficol-paque in a 15 ml tube and centrifuged at 400 g for 30 min. The supernate, WO93/1~87 ~ ! PCT/US92/09560 . .

containing plasma and platelets, was discarded by aspiration, and ~he pellet, containing predominantly neutrophils, was resuspended in 1 ml saline. The suspension was transferred to a clean tube, and pooled with other aliquots of blood treated similarly. The pooled suspension was centrifuged at 350 g for 5 min. and supernate discarded. The pellet was resuspended in 5 ml of 0.05% NaCl with a plastic Pasteur pipette. for 25 seconds to lyse contaminating red cells, then 5 ml of 1.75% NaCl added to regain isotonicity. The red cell lysing procedure was repeated, the cells suspended in appropriate buffer (depending on assay) and counted.
The compounds of the present invention evaluated with respect to cyclooxygenase inhibition according to the following assay procedure.
Inhibition of Shee~ Seminal Vesicle Microsome Cyclooxyaenase.
The assay was based on oxygen consumption during conversion of arachidonic acid to prostaglandin G~
catalyzed by cyclooxygenase Biochem. 11:3276-3285 (1972). Lyophilized ovine microsome (approx. 1 mg) suspended in 2.9 ml Tris-HCl buffer, pH 8.2, containing 0.7 mM phenol were used as æource of arachidonate cyclooxygenase. The inhibitor, 50 ~1 in DMSO, was added and the mixture preincubated for 5 minutes at 37C. Fifty ~1 of arachidonic acid (final conc. 50 ~M) was added to start the reaction. The slopes of the initial rates of oxygen uptake, in the presence and absence of inhibitor, were compared to W093/10087 2 l2 nl 3 ~ PCT/US92/09 determine reaction inhibition. Percent inhibition was computed using the following formula:
- I.S.* (control) - I.S. ~inhib.) X lO0 % Inhib. = I. S. (Control) *I.S. = initial slope.

The compounds of the invention are evaluated with respect to 5-lipoxygenase inhibition according to the following assay procedure.
Inhibition of 5~ oxvaenase. in vitro:
The lO0,000 x g supernatant fraction of Rat Basophilic Leukemia Cell Homogenate (RBL-l) serves as a 5-lipoxygenase enzyme source. The enzyme is incubated with ~ C)-arachidonic acid and Ca++ in the presence and absence of test compound. The product of 5-lipoxygenase, 5-hydroxyeicosatetraenoic acid (5-HETE), is separated by thin-layer chromatography and measured by radioactivity. A compound inhibiting 5-HETE synthesis by 30% or more is considered active at that concentration. Initial screening doses are 1 x 104M. When the compound inhibits more than 50% of 5-HETE synthesis at lO~M, that compound is tested at multiple dose levels to determine the IC50 value (inhibitory concentration to inhibit 50%).

212013~ -38-For comparison the compound of Formula XX, a known 5-lipoxygenase inhibitor described in U.S.
4,755,524 was used.

~/ c~
_~S~OU~U~OH (XX~

~ 2S*-~[3,5-bis(l,1-dimethylethyl)-4-hydroxyphenyl]thio]-lR*-methylpropoxy~acetic acid WO g3/10087 2 1 2 0 1 3 I PCr/US92/09s60 -39- ~ , .

The results with respect to certain compounds of the present invention are set forth in Table I below.

.
Compound5-Lipoxyg-na-e FMLP InducedCyclooxygon~-e Exampl~Inhibition SuperoxideInhibition ¦ Number IC~ ~M) Gen~rationIC~(~M) r Stimulation lO~M, lOO~M, l 167~ ~ control Inhibition 100 IC50 ~ l l~M 3 1 Stimulated 45~
7 at lO~M InhibitionInactive at at lOqM IC~ ~ 50~M 100 ~M
Stimulat~d 2 5~
11 at lO~h Inhibition 2 9 at lO~M IC~ - 4 8~M
Inhibitnd 21 3~ Inhibition ~t lO`'M IC50 ~ 2 8,uM 64 0 Inhibit~d 14 9 at 105M
~ Stimulation~
16 100 lO~M, 25~M, 50~M, 100~ > control l _ Inhibition 25- L 17 >100 IC~D~3 4~uM 3 8 4 9 InhLb~tion ~ ~ IC~

The compound of Formula XX inhibited both superoxide generation and 5-lipoxygenase whereas the compound of Example 16 inhibited 5-lipoxygenase and WO93/1~87 PCT/US92/~560 stimulated superoxide generation. This data indicates that superoxide generation is not dependent on 5-lipoxygenase and that the a~ility of a compound to inhibit 5-lipoxygenase is not related to its ability to simulate superoxide generation.
The compound of Example 7, which has no substituents on the phenyl ring ti.e., Rl and R2 = H) did not inhibit either 5-lipoxygenase or cyclooxygenase but did inhibit superoxide generation.
Complement C5a induced superoxide generation may also be stimulated or inhibited by compounds of the present invention.
Chronic adiuvant-induced polYarthritis test.
Rats t50-70 gm] were weighed, ear tagged and intradermally inoculated in the tail base with 2.0 mg of heat killed M. butyricum suspended in 0.05 ml of white paraffin oil [n = 12-15 per group]. Compounds were intragastrically administered beginning on the day of inoculation and continued for 18 days. Each daily dose was split [dose volume = 0.5 ml/100 gm] and given approximately 7 hours apart. Animals were weighed every 3 days and the dose adjusted accordingly. On day 19 animals were sacrificed by inhalation of CO2, weighed, and total hind paw volume was measured by the displacement of water with a plethysmometer (Ugo Basile, Varese, Italy). A group of age-matched naive rats were included. These rats, designated "normal", were not inoculated with adjuvant or gavaged with vehicle.
Statistical Analysis: For individual experiments, the paw volume/body weight ratios for each dose were compared to the ratio for the vehicle treated control group by a two-tailed Dunnett's t-test (p < 0.05). The Dunnett's test was preceded by a Bartlett's test of variance homogeneity across the dose groups. If the Bartlett's test was significant an appropriate variance WO93/10087 2 1 2 0 1 3 ~ PCT/USg2/09560 .

stabilizing transformation was applied to the data and the Dunnett's test performed on the transformed data.
-Chronic Adiuvant-Induced Polvarthritis Minimum dose to result in a statistically significant reduction tp < 0.05] in the paw volume/body weight ratio Compound Example No. ~ose ~mg/kg/day] % Inhibition~
Ex. 5 25 64.4 ~x. l7 25 ~ 50 % Inhibition in the paw volume to body weight ratio.
% Inhibition = tl-tcompound treated - normal) + (vehicle treated - normal)]J x 100 `::
~` While the invention has been described and illustrated with reference to certain preferred embodiments thereof, those skilled in the art will appreciate that various changes, modifications, and substitutions can be made therein without departing from the spirit of the invention. For example, effective dosages other than the preferred ranges set forth hereinabove may be applicable as a consequence of variations in the responsiveness of the mammal treated, severity of condition treated, dosage related adverse effects, if any, observed and analogous considerations.
Likewise, the specific pharmacological responses ~ observed may vary depending upon the particular active compounds selected or whether different active compounds are used-in combination or in the presence of suitable pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in results are contemplated in accordance with the objects and W093/1~87 PCT~US92~09560 212013~ -42-practices of the present invention. It is intended, therefore, that the invention be limited only by the scope of the claims which follow.
The following non-limiting examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand and appreciate that known variations of the conditions and procedures in the following preparative methods can be utilized. All temperatures are degrees Celsius unless otherwise noted. Melting points were determined on a Thomas-Hoover melting point apparatus or by DSC and are uncorrected.

212.013~

,, ~ ..
~ Example 1 O-t3,5-bis(1,1-dimethylethyl)phenyl]
dimethylcarbamothioate y \
>=/ CH, ~\

Potassium hexylmethyl disilane (15% by weight in toluene, 260 ml, 0.169 moles) was added by syringe to a solution of 3,5-di-tert-butylphenol ~34.8 g, 0.169 moles) in tetrahydrofuran (S00 ml).
After 30 minutes, a solution of dimethylthiocarbamoyl chloride (24.7 g, 0.20 moles) in tetrahydrofuran (50 ml) was added over 10 minutes. The reaction mixture was stirred at room temperature for 30 minutes then at 50C for 1.5 hours. After cooling to room temperature, the reaction mixture was poured into cold (0C) water (100 ml) containing potassium hydroxide (30 g). The mixture was extracted twice with 1000 ml of ethyl ether. The combined ethyl ether extracts were dried over sodium sulfate, filtered and concentrated with a rotary evaporator to give the crude product as a yellow oil. The title product was purified by chromatography on silica gel and used directly in the next Example 2.

WO93/10087 PCT/USg2/09560 212013~
Example 2 3,5-bis(l,l-dimethylethyl)benzenethiol ~SH
~J
/\

The compound of Example 1 (42 g, 0.143 moles) was heated to 300C in a round bottom flask with a heating mantle for 2 hours. After cooling to room temperature the material was dissolved in ethylene glycol (100 ml).
A solution of potassium hydroxide (12.0 g, 0.214 moles) in water (20 ml) was added and the reaction mixture was heated to 123C for 3.5 hrs. After stirring at room temperature for 20 hours, the reaction mixture was cooled to 0C with an ice bath, and 10% hydrochloric acid was added sl~wly to adjust the pH to 2Ø The reaction mixture was extracted twice with 100 ml of ethyl acetate. The combined ethyl acetate extracts were washed with brine (100 ml), dried over sodium sulfate, filtered and concentrated to an oil. The title product was purified by silica gel chromatography and recrystallized from pentane, m.p. ca. 58C. The structure assignment was supported by NMR, infrared spectroscopy and elemental analysis.

Analysis calculated for: C~4H~S (m.w.= 222.4):
Theory: C, 75.61; H, 9.71; S, 14.42.
Found: C, 75.55; H, 10.07; S, 14.34.

WOg3/100~ PCT/US92/09560 .`-``` 212013t~

Example 3 trans-2-tl3,5-bis(l,l-dimethylethyl) phenyl~thio~cyclohexanol X
- ~ ~s~

_~ OH
/ \

3,5-Bis(l,l-dimethylethyl)benzenethiol (Example 2) (5.0 g, 0.0225 moles) was added to freshly prepared sodium ethoxide (0.0230 moles) in absolute ethyl `~ alcohol (50 ml). After stirring for 1 hour, cyclohexene oxide (2.2 g; 0.0225 moles) was added by syringe over 5 minutes, and the reaction mixture was ~-~ stirred for 60 hours at room temperature.
Water (100 ml) was added, and the reaction mixture waæ
extracted twice with 75ml of ethyl acetate. The combined ethyl acetate extracts were washed with brine (50 ml) dried over sodium sulfate, filtered and concentrated to give the product as a yellow solid which was recrystallized from cold pentane. The structure assignment was supported by NMR spectroscopy.
The title compound was used in Example 4.

WO93/10087 PCT/US92/Og560 212013~

ExamPle 4 Methyl trans-[[2-t~3,5-bis(l,l-dimethylethyl) phenyl~thio]cyclohexyl)thio]acetate S >~
~S \/
S~COOCH3 \

Methyl thioglycolate (2.65 g, 0.025 moles) was added by syringe to a solution of trans-2-t~3,5-bis(l,l-dimethylethyl)phenyl]thio]cyclohexancl (5.0 g., 0.025 moles) in methylene chloride (10 ml).
After stirring the reaction mixture for 15 minutes, trifluoroacetic acid (10 ml) was added by syringe, and the reaction mixture was stirred for 20 hours at room temperature. The reaction mixture was poured into cold water (100 ml). After stirring for 30 minutes, the mixture was extracted with ethyl acetate. The aqueous layer was washed with ethyl acetate (50 ml). The combined ethyl acetate extracts were washed twice with 75 ml of water, dried over sodium sulfate, filtered and concentrated to give the crude product as an oil. The title compound was purified by silica gel chromatography and dried in a vacuum oven at 60C for 3 hours. The structure assignment was supported by NMR, infrared spectroscopy, ~nd elemental analysis.

Analysis calculated for: C23H36O2S2 (m.w.= 408.66):
Theory: C, 67.60; H, 8.88; S, 15.69.
Found: C, 67.62; H, 9.13; S, 15.58.

Example 5 trans-[t2-~[3,5-bis(1,1-dimethylethyl)phenyl]
thio]cyclohexyl]thio~acetic acid ~< I~
~s~J
~ g~COOH

lQ
Water was added to a solution of the compound of Example 4 (9.2 g, 0.0255 moles) in methyl alcohol (lOO ml) until the solution became cloudy.
Lithium hydroxide hydrate (1.75 g, 0.0675 moles) was added, and the reaction mixture was stirred at room temperature. Periodically, water was added to make the solution cloudy. After 6 hours, the solution was made acidic with 10% hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract was dried over sodium sulfate, filtered, and concentrated to give the crude product as an oil. The product was purified by silica gel chromatography. The structure assignment was supported by NMR and elemental analysis.

Analysis calculated for: CnH~S202 (m.w.= 394.63):
Theory: C, 66.96; H, 8.68; S, 16.25.
Found: C, 66.92; H, 8.80; S, 16.00.

WOg3~10087 . PCT/US92/09~0 ".~, Exam~le 6 ~r3na-2-(phenylthio)cyclOhexan ~
~: ~s~

OH

Thiophenol (2.14g, 0.0194 mole) was added to freshly prepared sodium ethoxide (sodium, 0.45 g) in ethanol (30 ml). After several minutes, cyclohexene oxide was added, and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture : 15 was concentrated with a gentle flow of nitrogen gas.
The residue was dissolved in diethyl ether (75 ml) and washed with lN hydrochloric acid (19 ml). The diethyl ether was washed three ti~es with 50 ml of 5~ sodium carbonate, once with 0.5N hydrochloric acid (50 ml) and once with brine (25 ml), dried over anhydrous magnesium sulphate, filtered and concentrated with a rotary ~ evaporator to give the product as an oil. The ¦ , structure was supported by NMR and infrared spectroscopy.

' : ' WO93/10087 2 1 2 0 1 3 ~ PCT/US92/09560 Exam~le 7 trans-~ r 2-(phenylthio)cyclohexyl~thio~acetic acid ~ s ~
S~COOH

Mercaptoacetic acid (0.44 g, 0.0048 mole) was added to a cold solution of the compound of Example 6 (1.0 g 0.0048 mole) in methylene chloride (5 ml) containinq trifluoracetic acid (3.5 ml). The reacticn mixture was stirred at room temperature for 20 hours.
The reaction mixture was concentrated to an oil with a rotary evaporator. The residue was dissolved in diethyl ether (50 ml), washed three times with 20ml of 5% sodium bicarbonate, followed by lN hydrochloric acid (10 ml) and water (20 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to a colorless oil with a rotary evaporator. The product was purified by silica gel chromatography. The ætructure was supported by NMR, infrared spectroscopy and elemental analysis.

Analysis calculated for: C~4HI8S207 (m.w.= 282.44):
Theory: C, 59.54; H, 6.42; 5, 22.70.
Found: C, 59.36; H, 6.57; S, 22.43.

W093/1~87 PCT/US92/095~

ExamDle 8 0-t3-(1,1-dimethylethyl)phenyl~dimethylearbamothioate ~ 1I N/

meta-t-Butyl phenol (30.0 g, 0.20 mole) was added to water (140 ml) eontaining potassium hydroxide (11.2 g, 0.20 mole) and stored at 0C for 20 hours.
Dimethyl thioearbamoyl chloride (32.8 g, 0.265 mole) was added as a solution in tetrahydrofuran (60 ml) to the eold solution with stirring. The iee bath was - removed, and the turbid solution was stirred for 15 minutes. To this mixture was added 10% potassium hydroxide (75 ml). The reaetion mixture was extraeted three times with 125 ml of benzene. The eombined l~-benzene extraets were washed with brine (75 ml) and eoncentrated in a rotary evaporator to give the erude ;~
produet as an oil. The product was purified by silica gel chromatography. The structure was supported by N~.

W093/10087 2 1 % O 1 3 ~ PCT/US92/09560 -51- - ;

Example 9 3~ dimethylethyl)benzenethiol .
\/

/~_SH

Starting w~th 0-~3-(1,1-dimethylethyl)phenyl]
dimethylcarbamothioate and following the procedure described in Example 2, the title compound was obtained.

Example 10 trans-2-~t3-(l~l-dimethylethyl)phenyl]thio]cyclohexan OH

Using the method of Example 6 and substituting 3-(1,1-dimethylethyl)benzenethiol for thiophenol, the title compound was o~tained.

WO93/1 ~ 7 PCT/US92/09560 , 21~ 0 13~ -52-Example 11 trans-[t2-tt3-(1,1-dimethylethyl)phenyl~thio]
-cyclohexyl]thio)acetic acid ~ ~ ~:`
~s~~J '`~
S~COOH

Trifluoracetic acid (lo ml) was added to a solution of the compound of Example 10 (3.6 g, 0.0136 mole) in methylene chloride (5 ml) with :~
stirring. After several minutes, methyl thioglycolate ;i (1.59 g, 0.015 mole) was added, and the reaction mixture was stirred for 30 minutes. The reaction mixture was poured into methanol (50 ml) containing lithium hydroxide hydrate (12.6 g, 0.30 mole).
Water (125 ml) was slowly added to the mixture and then the mixture was extracted with diethyl ether (100 ml). ~-The aqueous phase was acidified with concentrated hydrochloric acid and extracted twice with 100 ml of diethyl ether. The combined diethyl ether extracts were washed with water (30 ml), 5% sodium bicarbonate (50 ml) and brine (50 ml), dried over anhydrous ::
magnesium sulfate, filtered and concentrated with a rotary evaporator to give the crude product as an oil.
The product was purified by silica gel chromatography.
The structure was supported by NMR, infrared spectroscopy, and elemental analysis.

Analysis calculated for: C~8H26S202 (m.w.= 338.52):
Theory: C, 63.87; H, 7.74; S, 18.94.
Found: C, 64.00; H, 8.02; S, 19.10.

..

W093~1~W~ 2 1 2 0 1 3 4 PCT/US92/09~
i Example 12 [l,l'-biphenyll-3-yl dimethylcarbamoate ~
CH~
' '.

Using the method of Example 8 and substituting : 10 meta-phenyl phenol for meta-t-butyl phenol the title compound was prepared. The structure was supported by ;
' N~
.; ~
Example 13 3-tl,l'-biphenyl~thiol r\, .
~ ''.
~SH

Starting with [l,l'-biphenyl]-3-yl dimethylcarbamoate and using the procedure described in Example 2, the title compound was obtained.

WO93/10~87 PCT/US92/09560 212~13~

Example 14 trans-2-~(t~ biphenyl]-3-yl)thio3cyclohexanol 6~ :
S ~5 OH

Starting with 3-[1,1'-biphenyl]thiol and ~ollowing the procedure described in Example 3 gave the title compound.

Example 15 trans-~t2-[([1,1'-biphenyl~-3-yl)thio]
cyclohexyl]thio]acetic acid /.s=\ ;~:

S ;OOH

Starting with trans-2-[(~1,1'-biphenyl]-3-yl)thio]cyclohexanol and using the method described in Example 11 gave the title compound. The structure was supported by NMR, infrared spectroscopy and elemental analysis.
Analysis calculated for: C20H22S202 ~m.w.= 358.51):
Theory: C, 67.00; H, 6.18; S, 17.89.
Found: C, 66.-94; H, 6.30; S, 18.07.

WO g3/10087 2 1 2 0 1 3 4 PCT/US92/09560 ;-, Example 16 trans-2-t[2-tt3,5-bis(l,l-dimethylethyl)phenyl]thio]
cyclohexyl]thio]-N-methyl-N-(2-pyridinylethyl)acetamide ~S--~ O N~
~/ S~J¦~N~J

CH, Oxalyl chloride (0.19 g, 0.0015 moles) was added - by syringe to a cold (10C) solution of trans-tt2- `
~t3,5-bis(1,l-dimethylethyl)phenyllthio]cyclohexyl~-thio]acetic acid (Example 5) ~0.55 g, 0.0014 moles) in benzene (50 ml). The cold bath was removed and the reaction mixture was stirred at room temperature for -~ 20 hours. The reaction mixture was concentrated to an oil using a rotary evaporator. The oil was dissolved in toluene (50 ml) and concentrated to an oil. The process was repeated using tetrahydrofuran (25 ml) instead of toluene. The residue was dissolved in tetrahydrofuran (S0 ml). To this solution was added 2-(2-methylaminoethyl)pyridine (0.19 g, 0.0014 moles) and triethylamine (0.22 g) and the reaction mixture was stirred at room temperature for 48 hours. The white solid precipitate was removed by filtration and washed with ethyl acetate (25 ml). The filtrate was concentrated to give the crude product as an oil. The product was purified by silica gel chromatography and dried in vacuo at 100~C for 1 hour to give the title ~; -7 PCT/US92/ ~ 60 compound. The structure assignment was supported by NMR, infrared spectroscopy and elemental analysis~

Analysis calculated for: C~HUN202S2 (m.w.= 512.83):
. 5 Theory: C, 70.26; H, 8.65; S, 5.46.
Found: C, 69.95; H, 8.76; S, 5.43.

WO 93/1~ 2 1 2 0 1 3 ~ PCT/US92~09560 . . .

Fxample 17 trans-tt2-tt3,5-bis(l,l-dimethylethyl)phenyl]
thio]cyclohexylloxy~acetic acid ~s~O

Sodium hydride (0.33 g, 0.0138 mole) was added to a solution of trans-2-[t3,5-bis(l,l-dimethylethyl)phenyl]thio]cyclohexanol (3.4 g, 0.0106 mole) in tetrahydrofur~n (50 ml) at 0C. After stirring the reaction mixture for 1.5 hr, the tetrahydrofuran was removed by rotary evaporation.
Dimethyl sulfoxide (75 ml) was added followed by chloroacetic acid sodium salt (1.48 g, 0.0127 mole) and ; the reaction mixture was stirred at room temperature for 10 days. Water (100 ml) was added dropwise to the mixture followed by 10% hydrochloric acid (10 ml). The product was extracted twice with 200 ml of ethyl acetate. The combined ethyl acetate extracts were washed twice with 200 ml of water, dried over anhydrous sodium sulfate, filtered, and concentrated. The product was purified by chromatography on si~ica gel.
The structure was supported by NMR and elemental analysis (378.6 + 1/4 mole H20).

Analysis calculated for: C22H~03S + 1/4 mole H20:
Theory: C, 68.98; H, 9.08; S, 8.37.
Found: C, 69.12; N, 9.21; S, 8.27.

:

WOg3/1~87 PCT/US92/09560 212013~ -58-Exam~le 18 3,6-dioxabicyclot3.1.0]hexane O :

2,5-Dihydrofuran (DHF) (13.2 g, 0.188 mole) was added by syringe to a solution containing 3-chloroperoxybenzoic acid (29.1 g, 0.198, mole) and trifluorocetic acid (0.5 ml~ in methylene chloride (500 ml). After stirring at room temperature for 20 hours, the white solid was removed by filtration.
The filtrate was washed with a solution of sodium carbonate (100 ml, saturated). The organic phase was stirred with solid sodium carbonate and sodium thiosulf~te for 20 minutes and filtered. The product was purified by low pressure distillation (41C/5mmHg).
The structure was supported by NMR.

WO93/10087 rcT/us92/o956o 212013~
_59_ Example 19 trans-4-tt3,5-bis(l,l-dimethylethyl)-phenyl~thio~tetrahydro-3-furanol s ~ ~

,~ ~

3,5-Bis(l,1-dimethylethyl)benzenethiol (0.0078 mole) and the compound of Example 18 (0.0074 mole) are added to a degassed (Argon) solution of 50% sodium hydroxide (5 ml) and isopropyl alcohol (50 ml). The reaction is heated to reflux for 24 hours. The reaction is cooled to room temperature and poured into water (125 ml). The solution is made acidic with lN hydrochloric acid and extracted 3 times with 100 ml of diethyl ether. The combined diethyl ether extracts are dried over anhydrous magnesium sulfate, filtered and concentrated with a rotary evaporator. The product is purified by silica gel chromatography.

WO93/10087 PCT/US92/09~

21201 3ll -60-Exam~le 20 trans-4-t[3,5-bis(~,l-dimethylethyl)-phenyl]thio]tetrahydro-3-furanol, aeetate S~5~`0~ ~

~ ~ ..

The eompound of Example 19 (0.0062 mole) is added to aeetic anhydride (20 ml). Triethylamine (0.0062 mole) is added, and the reaetion mixture is stirred for 3 hours. Additional triethylamine (0.3 ml) is added, and the reaetion mixture is stirred for 2 hours. The reaetion mixture is eoneentrated to an oil with a gentle flow of nitrogen gas. The residue is dissolved in diethyl ether (75 ml), washed twice with 50 ml of 0.25N hydroehlorie aeid and onee with ~5 ml of brine, dried over anhydrous magnesium sulfate, filtered 20 and eoncentrated with a gentle flow of nitrogen gas. ~-The produet is purified by siliea gel ehromatography.

Example 21 butanedioic acid, ~g~-mono~4-~L3,5-bis(l,l-dimethylethyl)4-hydroxyphenyl]thio~tetrahydro-3-furanyl]ester 5. ~
~ o ~s~

~ O

Succinic anhydride (0.0185 mole) and triethylamine (0.0185 mole) are added to a solution of tetrahydrofuran (THF) (50 ml) containing the compound of Example 19 (0.0092 mole). The reaction mixture is ~tirred for 3 days and then concentrated to an oil with a gentle flow of nitrogen gas. The residue is dissolved in diethyl ether. The solution is washed twice with 50 ml of water and once with 20 ml of lN hydrochloric acid, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil with a rotary evaporator. The product is purified by silica gel chromatography.

W093/t~87 PCT/US92/Og5~

212013~ -62-Example 22 trans-2-~t2-t(tl,l'-biphenyl~-3-yl)thio~cyclo-hexyl~thi~]-N- (2,6-dimethylphenyl)acetamide NH

Oxalyl chloride (18mg, 0.000142 mole) was added to a solution of trans-2-t(tl,l'-biphenyl]-3-- yl)thio~cyclohexanol(24 mg, 0.000071 mole) in toluene `
(25ml) and stirred magnetically for 20 hours at room temperature. The solution was concentrated to an oil.
The oil was dissolved in toluene (25ml) and concentrated to an oil. The oil was dissolved in ethyl ether (50ml) to which were added 2,6-dimethylaniline (8.6mg, 0.000071 mole) and triethylamine (0.3 ml). The mixture was stirred at room temperature for three hours, filtered and concentrated to an oil. The product was purified by silica gel chromatography. The structure was supported by NMR.
Analysis calculated for ~8H31NOS2-0.25M H20:
Theory: C, 72.14; H, 6.81; N, 3.00.
Found: C, 72.21; H, 7.00; N, 2.94.

W093/10087 2 1 2 0 1 3 ~ Pcrtusg2/ogs60 Example 23 trans-2-tt2-~[3,5-bis(l,l-dimethylethyl)phenyl]thio~-cyclohexyl]thio]-N-[3-(dimethylamino)propyl]-N-methylacetamide ~ ~ I ~ N - C
CH

Oxalyl chloride (55mg, 0.00043 mole) was added to a solution of t~ans-tt2-[t3,5-bis(l,l-dimethylethyl)phenyl]thio]cyclohexyl]thio~acetic acid (85 mg, 0.000215 mole) in toluene (50 ml) and was stirred at room temperature for 20 hours. The solution was concentrated to an oil. The oil was redissolved in toluene (50 ml) and concentrated to an oil. The oil was dissolved in ethyl ether (75 ml) to which were added N,N,N'-trimethyl-1,3-propane diamine (19.5 mg, 0.000215 mole) and triethylamine (0.5 ml). After stirring at room temperature for 3 hours the mixture was filtered and concentrated to an oil. The product was purified by silica gel chromatography. The structure was supported by NMR.
Analysis calculated for C28H48N2OS2 0-5M H2O
Theory: C, 67.02; H, 9.84; N, 5.58.
Found: C, 67.08; H, 9.82; N, 5.57.

W093/10087 : PCT/US92/09560 212013~
Example 24 trans-2-~2-~3,5-bis(l,l-dimethylethyl)phenyl]thio]
cyclohexyllthio~-N-~4-(dimethylamino)butyl]acetamide ~ ~ _ ~N ~ < CH3 .10 By following the method of Example 23 and substituting 4-dimethylaminobutylamine for N,N,N'-trimethyl-1,3-propanediamine, the title compound was prepared. The struc~ure was supported by NMR. ;
: 15 Analysis calculated for C28H48N20S2:
Theory: C, 68.24; H, 9.82; N, 5.68.
Found: C, 67.84; H, 9.9~; N, 5.68.
.~

. . , Example 25 trans-2-[t2-tt3,5-bis(l,1-dimethylethyl)phenyllthio]
cyclohexyl]thio]-N-(2-methoxyethyl)acetamide S .~.
3 \,CH3 /~
H3C~ ~ ~OCH3 H

By following the method of Example 23 and substituting 2-methoxyethylamine for N,N,N'-trimethyl-1,3-propanediamine, the title compound was prepared.
The structure was supported by NMR.
Analysis calculated for C~H4,NO2S2: ;~
Theory: C, 66.47; H, 9.15; N, 3.10:
Found: C, 66.12; H, 9.28; N, 3.04.

WOg3/1~87 PCT/US92/09~

212013~ -66-Example 26 2-tt4-(1,1-dimethylethyl)phenyl]thiolcyclohexanone ~ S ~

: To a solution of 2-chlorocyclohexanone (6.1g, 0.046 moles) in tetrahydrofuran (250 ml) cooled to +5C :
by an ice bath was added 4-t-butyl-thiophenol (6.6g, 0.040 moles). After stirring for 15 minutes, triethylamine (13 ml) was added. The ice bath was `
;~ removed and the mixture was stirred at room temperature ~:15 for 60 hours. The mixture was filtered to remove a white solid. The filtrate was concentrated to an oil, and the product was purified by silica gel chromatography to give a white solid which was `~
:recrystallized from hexane (DSC 64.25C). The 20 structure was supported by NMR and Ir. ~:
Analysis calculated for C~nOS (262.42): ~;
Th ory: C, 73.23; H, 8.45; S, 12.22.
Found: C, 73.12; H, 8.76; S, 12.19.

WO93/10087 PCT/US92/OgS60 ExamDle ~7 2-tt3,5-bis(~ dimethylethyl)phenyl]thio]cyclohexanone /~5~ ~

. '~
2-Chlorocyclohexanone (0.6g, 0.0045 moIes) was ~;
added to a cold (+5C) solution of 3,5-bis (1,1-dimethylethyl)benzenethiol (Example 2)(l.Og, 0.0045 moles) in tetrahydrofuran (50ml). The solution was stirred for 15 minutes. Triethylamine (1.25ml) was -added, the cold bath was removed and the mixture was stirred at room temperature for 20 hours and then at 50C for 2 hours. The mixture was cooled to room temperature and filtered to remove a white solid. The ~ filtrate was concentrated to an oil. The product was ;~ purified by silica gel chromatography to give a white solid which was recrystallized from hexane (DSC
81.49C). The structure was supported by NMR and Ir.
; Analysis calculated for CNH300S:
Theory: C, 75.42; H, 9.49; S, 10.07.
Found: C, 75.45; H, 9.72; S, 10.36.

WOg3/10087 PCT/US9~09560 21201~ l -68-Example 28 2-t[4-(1,1-dimethylethyl)phenyl~thio]cyclopentanone O ~:

~ S ~

By following the method of Example 26 and substituting 2-chloro~yclopentanone for 2-chlorocyclohexanone, the titled compound was obtained.
` The structure was supported by NMR and Ir.

ExamDle 29 152-(phenylthio)cyclohexanone ~ ~

By following the method of Example 26 and substituting thiophenol for 4-t-butylthiophenol the tilted compound was obtained. The structure was supported by NMR and Ir.

WO93/1~87 21 2 0 I 3 4 PCT/US92/Og ~

' -69 , Example 30 Starting with 2-bromothiophenol and following the ;~
procedure of Example 3 gives trans-2-t(2-bromophenyl)thio~cyclohexanol.
Starting with this compound and following the procedures described in Examples 4, 5, 16, 22, 23, and 25 respectively gives:
(a) methyl trans-t[2-t(2-bromophenyl)thiol-cyclohexyllthio~acetate;
(b) trans-tt2-t(2-bromophenyl)thio]cyclohexyll-thio~acetic acid;
(c) trans-tt2-t(2-bromophenyl)thio~-cyclohexyl]thio]-N-methyl-N-(2-pyridinylethyl) acetamide;
(d) trans-2-tt2-t(2-bromophenyl)thiol- -cyclohexyl]thio]-N-(2,6-dimethylphenyl)acetamide;
~- (e) trans-2-tt2-tt2-bromophenyl]thio]-cyclohexyl]thio]-N-t3-(dimethylamino)propyll-N-methylacetamide; and (f) trans-2-tt2-~2-bromophenyl]thio]-cyclohexyl~thio]-N-(2-methoxyethyl)acetamide.

212013~ _70_ Example 31 Starting with 3-bromothiophenol and following the procedure of Example 3 gives trans-2-t(3-bromophenyl)thio~cyclohexanol.
Starting with this compound and following the procedures described in Examples 4, 5, 16, 22, 23, and 25 respectively gives:
(a) methyl trans-t[2-t(3-bromophenyl)thiol-cyclohexyl~thio~acetate; :
(b) trans-tt2-~(3-bromophenyl)thio~cyclohexyl]-thio~acetic acid;
(c) trans-tt2-t(3-bromophenyl)thio~cyclohexyl]-thio~-N-methyl-N-(2-pyridinylethyl)acetamide;
(d) trans-2-tt2-t(3-bromophenyl)thio]-cyclohexyl~thio~-N-(2,6-dimethylphenyl)acetamide;
(e) trans-2-tt2-tt3-bromophenyl~thio~-cyclohexyl~thio~-N-[3-(dimethylamino)propyl]-N-methylacetamide; and ;
(f) trans-2-tt2-tt3-bromophenyl]thio]-cyclohexyl~thio~-N-(2-methoxyethyl)acetamide.

21~013~
_7~_ Exam~le 32 Starting with 4-bromothiophenol and following the proeedure of Example 3 gives trans-2-t(4-bromophenyl)thio]eyclohexanol.
Starting with this eompound and following the proeedures deseribed in Examples 4, 5, 16, 22, 23, and 25 respeetively gives:
(a) methyl trans-tt2-t(4-bromophenyl)thio~-eyelohexyl]thio~aeetate;
(b) trans-tt2-t(4-bromophenyl)thio~eyelohexyl]-thio)aeetie aeid;
(e) trans-2-tt2-t(4-bromophenyl)thio~eyclohexyl~-thio~-N-methyl-N-(2-pyridinylethyl)aeetamide;
(d) trans-2-tt2-t(4-bromophenyl)thio]-cyclohexyl]thio]-N-(2,6-dimethylphenyl)acetamide;
(e) trans-2-tt2-tt4-bromophenyl]thio~-eyelohexyl~thio]-N-t3-(dimethylamino)propyl]-N-methylaeetamide; and (f) trans-2-tt2-tt4-bromophenyllthio]- i:
eyelohexyl]thio]-N-(2-methoxyethyl)aeetamide.

212013~ -72-Exam~le 33 Starting with 2,5-dichlorobenzenethiol and following the procedure of Example 3 gives trans-2-[(2,5-dichlorophenyl)-thiolcyclohexanol.
Starting with this compound and following the procedures described in Examples 4, 5, 16, 22, 23, and 25 respectively gives:
(a) methyl trans-tt2-tt2,5-dichlorophenyl)thio~-cyclohexyl]thiolacetate;
(b) trans-tt2-t(2,5-dicholorophenyl)thio]
cyclohexyl]thio~acetic acid;
(c) trans-2-t[2-t(2,5-dichlorophenyl)thio]-cyclohexyl~thio]-N-methyl-N-(2-pyridinylethyl) acetamide;
(d) trans-2-tt2-[(2,5-dichlorophenyl)thiol-cyclohexyl]thio]-N-(2,6-dimethylphenyl)acetamide;
(e) trans-2-tt2-tt2,5-dichlorophenyllthio]-cyclohexyl]thio]-N-t3-(dimethylamino~propyl]-N-methylacetamide; and (f) trans-2-tt2-tt2,5-dichlorophenyl]thio]-cyclohexyl~thio~-N-(2-methoxyethyl)acetamide.

wo g3/10087 2 1 2 0 1 3 ll PCT/US92/09560 , . ' !- ~
-73~

ExamDle 34 Starting with 2-chlorothiophenol and following the procedure of Example 3 gives trans-2-t(2-chlorophenyl)thiolcyclohexanol.
Starting with this compound and following the procedures described in Examples 4, 5, 16, 22, 23, and 25 respectively gives:
(a) methyl trans-~t2-t(2-chlorophenyl)thio~-cyclohexyl]thiolacetate;
(b) trans-tt2-[(2-chlorophenyl)thio]-cyclohexyllthiolacetic acid;
(c) trans-t~2-t(2-chlorophenyl)thiolcyclohexyl~-thiol-N-methyl-N-(2-pyridinylethyl)acetamide;
(d) trans-2-tt2-t(2-chlorophenyl)thiol-cyclohexyl]thio~-N-(2,6-dimethylphenyl)acetamide;
(é) trans-2-tt2-tt2-chlorophenyllthio~-. cyclohexyl]thio]-N-t3-~dimetbylamino)propyl]-N-methylacetamide; and (f) trans-2-tt2-tt2-chlorophenyl]thio]-cyclohexyl]thio]-N-(2-methoxyethyl)acetamide.
.

WOs3/100~ PCTlUS92/09560 - Exam~le 35 Starting with 3-chlorothiophenol and following the procedure of Example 3 gives trans-2-t(3-chlorophenyl)thio~cyclohexanol.
S Starting with this compound and following the procedures described in Examples 4, 5, 16, 22, 23, and 25 respectively gi~es:
(a) methyl trans-tt2-[(3-chlorophenyl)thio~-cyclohexyl]thio~acetate;
(b) trans-~t2-[(3-chlorophenyl)thio~
cyclohexyl]thio~acetic acid;
(c) ~a~s-tt2-[(3-chlorophenyl)thio]-cyclohexyl~thio]N-methyl-N-(2-pyridinylethyl) acetamide;
lS (d) trans-2-tt2-t(3-ehlorophenyl)thiol-: cyclohexyl~thio]-N-(2,6-dimethylphenyl)acetamide;
(e) trans-2-tt2-[t3-chlorophenyl~thio]-cyclohexyl]thio]-N-t3-(dimethylamino)propyl]-N-methylacetamide; and (f) trans-2-[[2-~t3-chlorophenyl~thio]-cyclohexyl]thio]-N-(2-methoxyethyl)acetamide.

W093/lO0~ 2 1 2 0 1 3 ~ PCT/US92/09560 ;-Exam~le 36 Starting with 4-chlorothiophenol and following the procedure of Example 3 gives trans-2-t(4-chlorophenyl)thio~cyclohexanol.
Starting with this compound and following the procedures described in Examples 4, 5, 16, 22, 23, and 25 respectively gives:
(a) methyl trans-tt2-t(4-chlorophenyl)thio]-cyclohexyl]thio]acetate;
(b) trans-tt2-t(4-chlorophenyl)thio~-cyclohexyl~thiolacetic acid;
(c) trans-2-~t2-t(4-chlorophenyl)thio]-cyclohexyl]thio~-N-methyl-N-(2-pyridinylethyl) acetamide;
(d) trans-2-tt2-t(4-chlorophenyl)thio~-cyclohexyl]thiol-N-(2,6-dimethylphenyl)acetamide;
(e) trans-2-~t2-tt4-chlorophenyllthio~-cyclohexyl~thiol-N-t3-(dimethylamino)propyll-N-methylacetamide; and (f) trans-2-tt2-~[4-chloroph¢nyl]thiol-cyclohexyllthiol-N-(2-methoxyethyl)acetamide.

WO93/1~87 PCT/US92/09~0 2l~ 0~ 76-Example 37 Starting with 2,6-dichlorobenzenethiol and following the procedure of Example 3 gives trans-2-~(2,6-dichlorophenyl)thio~cyclohexanol.
S Starting with this compound and following the procedures described in Examples 4, 5, 16, 22, 23, and 25 respectively gives:
(a) methyl trans-t~2-t(2,6-dichlorophenyl)thiol-cyclohexyl]thiolacetate;
- 10 (b) trans-tt2-t(2,6-dicholorphenyl)thio~-cyclohexyl~thio~acetic acid;
(c) trans-2-t[2-t(2,6-dichlorophenyl)thio~-cyclohexyl]-thio]-N-methyl-N-(2-pyridinylethyl) acetamide;
(d) trans-2-t[2-t(2,6-dichlorophenyl)thio]- :
cyclohexyl~thio]-N-(2,6-dimethylphenyl)acetamide;
(e) trans-2-[[2-tt2,6-dichlorophenyl~thio]-cyclohexyl]thio]-N-t3-(dimethylamino)propyl~-N-methylacetamide; and (f) trans-2-tt2-t~2,6-dichlorophenyl~thio]
cyclohexyl~thio]-N-(2-methoxyethyl)acetamide.

WOg3/10087 PCT/US92~09 ~
212013~
,. . ~ .

Exam~le 38 Starting with 3,4-dichlorobenzenethiol and following the procedure of Example 3 gives trans-2-t(3,4-dichlorophenyl)-thio]cyclohexanol.
Starting with this compound and following the procedures described in Examples 4, 5, 16, 22, 23, and 25 respectively gives:
(a) methyl ~rans-t[2-~(3,4-dichlorophenyl)thiol-cyclohexyl~thio]acetate;
(b) trans-tt2-t(3,4-dicholorphenyl)thio]-cyclohexyllthio~acetic acid;
(c) trans-2-tt2-t(3,4-dichlorophenyl)thio]-cyclohexyll-thio]-N-methyl-N-(2-pyridinylethyl) acetamide;
(d) trans-2-tt2-t(3,4-dichlorophenyl?thio]-cyclohexyllthio]-N-(2,6-dimethylphenyl)acetamide;
: (e) trans-2-tt2-tt3,4-dichlorophenyl]thio]-cyclohexyl]thio]-N-t3-(dimethylamino)propyl]-N-methylacetamide; and (f) trans-2-1~2-t[3,4-dichlorophenyl]thio~-cyclohexyl]thio]-N-(2-methoxyethyl)acetamide.

WO g3/10087 PCr/USg2/09560 21201~ 4 -78-Example 39 Starting with 2,4-dimethylthiophenol and following the procedure of Example 3 gives trans-2-[(2,4-dimethylphenyl)-thio]cyclohexanol.
Startinq with this compound and following the procedures described in Examples 4, 5, 16, 22, 23, and 25 respectively gives:
(a) methyl trans-[~2-t(2,4-dimethylphenyl)thio~-cyclohexyllthio]acetate;
(b) trans-~t2-t(2,4-dimethylphenyl)thio~-cyclohexyl]thio]acetic acid;
(c) trans-2-tt2-t(2,4-dimethylphenyl)thio]-cyclohexyl~-thio]-N-methyl-N-(2-pyridinylethyl) acetamide;
(d) trans-2-[t2-[(2,4-dimethylphenyl)thiol-cyclohexyl~thio]-N-(2,6-dimethylphenyl)acetamide;
(e) trans-2-tt2-tt2,4-dimethylphenyl]thio]-cyclohexyl]thio]-N-t3-(dimethylamino)propyl]-N-: methylacetamide; and (f) trans-2-tt2-tt2,4-dimethylphenyl]thio~-cyclohexyl]thio]-N-(2-methoxyethyl)acetamide.

wo g3,l0087 2 1 2 0 1 ~ ~ PCT/US92/09560 Example 40 Starting with 2,5-dimethylthiophenol and following the procedure of Example 3 gives trans-2-~(2,5-dimethylphenyl)-thio~cyclohexanol.
Starting with this compound and following the procedures described in Examples 4, 5, 16, 22, 23, and 25 respectively gives:
(a) methyl trans-t~2-t(2,5-dimethylphenyl)thio]-cyclohexyl]thio~acetate;
(b) trans-~t2-t(2,5-dimethylphenyl)thio~- ;
cyclohexyl~thio]acetic acid;
(c) trans-2-tt2-t(2,5-dimethylphenyl)thio~-cyclohexyl]thio~-N-methyl-N-t2-pyridinylethyl) ~
acetamide; .
(d) trans-2-[t2-1(2,5-dimethylphenyl)thio~-cyclohexyl~thio~-N-(2,6-dimethylphenyl)acetamide;
(e) trans-2-tt2-tt2,5-dimethylphenyl~thio~-cyclohexyl~thio~-N-t3-(dimethylamino)propyl]-N-methylacetamide; and (f) trans-2-tt2-tt2,5-dimethylphenyl]thio]-cyclohexyl~thio~-N-(2-methoxyethyl)acetamide.

WO93/1~87 PCT/US92/09560 212013~ -80-Example 41 Startîng with 3,4-dimethylthiophenol and following the procedure of Example 3 gives trans-2-t(3,4-dimethylphenyl)-thio~cyclohexanol.
Starting with this compound and following the procedures described in Examples 4, 5, 16, 22, 23, and 25 respectively gives:
(a) methyl trans-~t2-~(3,4-dimethylphenyl)thio]-cyclohexyl~thio)acetate;
(b) trans-[t2-t(3,4-dimethylphenyl)thio~-cyclohexyl~thio~acetic acid;
(c) trans-2-tt2-[(3,4-dimethylphenyl)thio]- ~-cyclohexyl~thio]-N-methyl-N-(2-pyridinylethyl) acetamide;
(d) trans-2-tt2-t(3,4-dimethylphenyl)thio~- :
cyclohexyl~thio~-N-(2,6-dimethylphenyl)acetamide;
(e) trans-2-[[2-[[3,4-dimethylphenyl~thiol-cyclohexyl~thio~-N-t3-(dimethylamino)propyl~-N-methylacetamide; and (f) trans-2-t[2-[[3,4-dimethylphenyl~thio~- :
cyclohexyl~thio~-N-(2-methoxyethyl)acetamide.

W093~l0087 2 1 2 0 1 3 ~ PCT/US92/09 ~

i .

Exam~le 42 Starting with 4-fluorothiophenol and following the procedure of Example 3 gives ~rans-2-[(4- ;
fluorophenyl)thiolcyclohexanol. ~`
Starting with this compound and following the procedures described in Examples 4, 5, 16, 22, 23, and 25 respectively gives:
(a) methyl trans-tt2-~(4-fluorophenyl)thiol-cyclohexyllthio)acetate;
(b) trans-[t2-~(4-fluorophenyl)thiolcyclohexyll-thio~acetic acid;
(c) trans-tt2-t(4-fluorophenyl)thiolcyclohexyll-thiol-N-methyl-N-(2-pyridinylethyl) acetamide;
(d) trans-2-~[2-t(4-fluorophenyl)thio~-cyclohexyllthio]-N-(2,6-dimethylphenyl)~acetamide;
(e) trans-2-~t2-t[4-fluorophenyl]thio]-cyclohexyl~thiol-N-t3-(dimethylamino)propyl]-N-methylacetamide; and (f) trans-2-~[2-[[4-fluorophenyl~thio]-cyc}ohexyl~thio]-N-t2-methoxyethyl)acetamide.

WOg3/1~87 PCT/US92/~560 21201~ l -82-Example 43 Starting with 4-hydroxythiophenol and following the procedure of Example 3 gives trans-2-t(4-hydroxyphenyl)thio~cyclohexanol. ~:
Starting with this compound and following the procedures described in Examples 4, 5, 16, 22, 23, and ~
25 respectively gives: ~:
(a) methyl trans-tt2-[(4-hydroxyphenyl)thio~-cyclohexyl~thio]acetate;
(b) trans-tt2-t(4-hydroxyphenyl)thio]-cyclohexyl]thio]acetic acid;
(c) trans-tt2-t(4-hydroxyphenyl)thio]-cyclohexyl]thio~-N-methyl-N-(2-pyridinylethyl) acetamide;
(d) trans-2-tt2-[(4-hydroxyphenyl)thio~-cyclohexyl]thio]-N-(2,6-dimethylphenyl)acetamide;
(e) trans-2-tt2-t[4-hydroxyphenyl]thiol-cyclohexyllthio]-N-t3-(dimethylamino)propyl~-N-methylacetamide; and (f) trans-2-tt2-tt4-hydroxyphenyl~thio~-cyclohexyl]thio]-N-(2-methoxyethyl)acetamide.

WOg3/10087 PCT/US92/09560 212013~ ~

Example 44 Starting with 2-isopropylthiophenol and following the procedure of Example 3 gives trans-2-[(2-isopropylphenyl)thio]cyclohexanol.
Starting with this compound and following the procedures described in Examples 4, 5, 16, 22, 23, and 25 respectively gives:
(a) methyl trans-~t2-t(2-isopropylphenyl)thio~-cyclohexyllthio~acetate;
(b) trans-tt2-t(2-isopropylphenyl)thio~-cyclohexyllthio]acetic acid;
(c) trans-2-tt2-t(2-isopropylphenyl)thio]
cyclohexyl]thio]-N-methyl-N-(2-pyridinylethyl) acetamide;
(d) trans-2-tt2-t(2-isopropylphenyl)thiol-cyclohexyl]thio]-N-(2,6-dimethylphenyl)acetamide;
(e) trans-2-tt2-tt2-isopropylphenyl]thio~-cyclohexyl~thio]-N-~3-(dimethylamino)propyl]-N-methylacetaMide; and (f) trans-2-tt2-tt2-isopropylphenyl~thio]-cyclohexyl]thio]-N-(2-methoxyethyl)acetamide.

Exam~le 4s Starting with 2-methoxybenzenethiol and following the procedure of Example 3 gives trans-2-~(2-methoxyphenyl)thio~cyclohexanol.
Starting with this compound and following the procedures described in Examples 4, 5, 16, 22, 23, and 25 respectively gives:
(a) methyl trans-~[2-t(2-methoxyphenyl)thio~-cyclohexyllthio~acetate;
(b) trans-[t2-t(2-methoxyphenyl)thio~-cyclohexyl]thio~acetic acid;
(c) trans-2-tt2-t(2-methoxyphenyl)thio]-cyclohexyl~thio]-N-methyl-N-(2-pyridinylethyl) acetamide;
(d) trans-2-tt2-t(2-methoxyphenyl)thio~-cyclohexyl~thio~-N-(2,6-dimethylphenyl)acetamide;
(e) trans-2-tt2-tt2-methoxyphenyl]thio~-cyclohexyl~thio]-N-t3-(dimethylamino)propyl~-N-methylacetamide; and (f) trans-2-tt2-tt2-methoxyphenyl]thio]-cyclohexyl~thio]-N-(2-methoxyethyl)acetamide.

WO93~10087 PCT/US92/09560 Example 46 Starting with 3-methoxybenzenethiol and following the procedure of Example 3 gives trans-2-t(3-methoxyphenyl)thio~cyclohexanol.
Starting with this compound and following the procedures described in Examples 4, 5, 16, 22, 23, and 2s respectively gives: :
(a) methyl trans-t[2-[(3-methoxyphenyl)thio~- -cyclohexyl]thio~acetate;
(b) trans-tt2-t(3-methoxyphenyl)thio~-cyclohexyl]thiolacetic acid;
(c) trans-tt2-t(3-methoxyphenyl)thio]-cyclohexyl]thio]-N-methyl-N-(2-pyridinylethyl)acetamide;
(d) trans-2-tt2-t(3-methoxyphenyl)thio~- -cyclohexyl]thio]-N-(2,6-dimethylphenyl)acetamide; ~:
(e) trans-2-tt2-tt3-methoxyphenyl]thio]- -~
cyclohexyl]thio]-N-t3-(dimethylamino)propyl~-N-methylacetamide; and ~.
(f) trans-2-tt2-t~3-methoxyphenyl]thio~-cyclohexyl]thio]-N-(2-methoxyethyl)acetamide.

WOg3/100X7 PCT/US92/09560 2120 13 ~ -86-Example 47 Starting with 4-methoxybenzenethiol and following the procedure of Example 3 gives trans-2-~(4-methoxyphenyl)thio]eyclohexanol.
Starting with this eompound and following the proeedures deseribed in Examples 4, 5, 16, 22, 23, and 25 respeetively gives:
(a) methyl trans-[t2-t(4-methoxyphenyl~thio~-cyclohexyllthio]aeetate;
(b) trans-tt2-t(4-methoxyphenyl)thio]
cyclohexyl]thio]aeetic aeid;
(e) trans-tt2-t(4-methoxyphenyl)thio]-eyelohexyl]thio]-N-methyl-N-t2-pyridinylethyl) aeetamide;
(d) trans-2-tt2-t(4-methoxyphenyl)thio~-eyelohexyl]thio~-N-(2,6-dimethylphenyl)aeetamide;
(e) trans-2-tt2-tt4-methoxyphenyl]thio}-cyciohexyl]thio]-N-t3-(dimethylamino)propyl]-N-methylaeetamide; and : 20 (f) trans-2-[[2-tt4-methoxyphenyl~thio]-eyelohexyl~thio]-N-(2-methoxyethyl)aeetamide.

wo g3/1~87 2 1 2 0 1 ~ I PCT/US92/09560 Example 48 ;~
Starting with o-thiocresol and following the procedure of Example 3 gives trans-2-t(2- .
methylphenyl)thio]cyclohexanol.
Starting with this compound and following the procedures described in Examples 4, 5, 16, 22, 23, and 25 respectively gives:
(a) methyl trans-tt2-t(2-methylphenyl)thio]-cyclohexyl]thio]acetate;
(b) trans-tt2-t(2-methylphenyl)thio]cyclohexyl]- :
thio]acetic acid;
(c) trans-2-t t2-t (2-methylphenyl)thio]-cyclohexyl]thio]-N-methyl-N-(2-pyridinylethyl) acetamide;
(d) trans-2-tt2-t(2-methylphenyl)thio]-~: cyclohexyl]thio]-N-(2,6-dimethylphenyl)acetamide;
(e) trans-2-tt2-tt2-methylphenyl]thio]-cyclohexyl]thio]-N-t3-(dimethylamino)propyl]-N-methylacetamide; and -:
(f) trans-2-tt2-tt2-methylphenyl~thio]-: cyclohexyl~thio]-N-(2-methoxyethyl)acetamide.

WO93/10087 PCT/USg2/095~

21201~ 88-ExamPle 49 Starting with p-thiocresol and following the procedure of Example 3 gives trans-2-t(4-methylphenyl)-thiolcyclohexanol.
Starting with this compound and following the procedures described in Examples 4, 5, 16, 22, 23, and 25 respectively gives:
(a) methyl trans-tt2-t(4-methylphenyl)thio3-cyclohexyl]thio]acetate;
(b) trans-~2-~(4-methylphenyl)thio cyclohexyl~thio]acet~c acid;
(c) trans-2-~2-~(4-methylphenyl)thio]-cyclohexyl]thio]-N-methyl-N-(2-pyridinylethyl) acetamide;
(d) trans-2-~t2-t(4-methylphenyl)thio]-cyclohexyl]thio]-N-(2,6-dimethylphenyl)acetamide;
(e) trans-2-~2-tt4-methylphenyl]thio]-cyclohexyl]thio]-N-~3-(dimethylamino)propyl]-N-methylacetamide; and (f) trans-2-tt2-t~4-methylphenyl]thio]-cyclohexyl]thio]-N-(2-methoxyethyl)acetamide.

W093/10087 2 1 2 0 1 3 ~ PCT/US92/09560 Example 50 :
Starting with 2-chlorobenzyl mercaptan and following the procedure of Example 3 gives trans-2-tt2-chlorophenyl)methyl]thio]cyclohexanol.
s Starting with this compound and following the . procedures described in Examples 4, 5, 16, 22, 23, and 25 respectively gives:
(a) methyl trans-tt2-tt(2-chlorophenyl)methyl3-thio~cyclohexyl]thio~acetate;
(b) trans-tt2-t[(2-chlorophenyl)methyl~thio~
cyclohexyl3thio3acetic acid;
(c) trans-[t2-tt(2-chlorophenyl)methyl~thio3-cyclohexyl3thio]-N-methyl-N-(2-pyridinylethyl) acetamide;
(d) trans-2-[t2-t[(2-chlorophenyl)methyl]thio~-cyclohexyl]thio3-N-(2,6-dimethylphenyl)acetamide;
(e) trans-2-tt2-[[2-chlorophenyl]thio]-cyclohexyl3thio3-N-t3-(dimethylamino)propyl3-N-methyl acetamide; and (f) trans-2-[t2-[[(2-chlorophenyl)methyl]thio3-cyclohexyl]thio]-N-(2-methoxyethyl)acetamide. :

WO93/1~87 PCT~US92/09560 212013~
Example 51 Starting with 4-chlorobenzyl mercaptan and following the procedure of Example 3 gives trans-2-tt(4-chlorophenyl)methyl]thio~cyclohexanol.
Starting with this compound and following the . procedures described in Examples 4, 5, 16, 22, 23, and 25 respectively gives:
(a) methyl trans-tt2-tt(4-chlorophenyl)methyl~-thio]cyclohexyl]thio~acetate;
(b) trans-tt2-tt(4-chlorophenyl)methyl]thio]-cyclohexyl~thiolacetic acid;
(c) trans-[t2-tt(4-chlorophenyl)methyl]thio]-cyclohexyl]thio]-N-methyl-N-(2-pyridinylethyl) acetamide; :
(d) trans-2-tt2-tt(4-chlorophenyl)methyl]thio]-cyclohexyl]thio~-N-(2,6-dimethylphenyl)acetamide;
(e) trans-2-tt2-tt4-chlorophenyl]thio]-cyclohexyl~thio]-N-[3-(dimethylamino)propyl]-N-methylacetamide; and .
(f) trans-2-tt2-tt(4-chlorophenyl)methyl]thio]-cyclohexyl]thio]-N-(2-methoxyethyl)acetamide.

WO93/1~87 2 1 2 0 1 3 ~ PCT/US92/09~

ExamDle 52 (a) trans-2-tt3,5-bis(l,1-dimethylethyl)phenyl~-thio~cyclohexanol (b) cis-2-tt3,5-bis(l,l-dimethylethyl)phenyl]-thio]cyclohexanol ~S~ ~ S~

Sodium borohydride (57 mg, 0.00l50 mole) was added to a solution of 2-tt3,5-bis(l,l-dimethylethyl)phenyllthio]
cyclohexanone (0.24 gm, 0.00075 mole) in methanol (10 ml) at room temperature. After 1.5 hrs. 10%
hydrochloric acid (0.5 ml) and water (15 ml) were added. The methanol was removed by rotary evaporator and the products were extracted into ethyl acetate.
The combined extracts were dried over sodium sulfate, - 20 filtered and concentrated to an oil. Thin layer chromatography (10% ethyl acetate-90% hexane) indicated two products. The lower Rf component (minor) corresponded to the product of Example 3. Silica gel chromatography (5% ethyl acetate-95% hexane) separated the two products. The NMR of the minor product was identical with that for Example 3. The NMR for the major product (higher Rf) corresponded to the "cis"
product.

WOg3/10087 PC~/US92/09560 212 0 1 3 ~ -92-Example 53 (a) 2-~t4-(1,1-dimethylethyl)phenyl]thio~-cycloheptanone O
10 ~S~

Following the method of Example 26 and 15 substituting 2-chlorocycloheptanone for 2- `
chlorocyclohexanone gives the title compound~
(b) 2-tt3,5-bis(1,l-dimethylethyl)phenyl]thio~-cyclooctanone ,:
O

Following the method of Example 27 and substituting 2-chlorocyclooctanone for 2-chlorocyclohexanone-gives the title compound.

WOg3/1~7 2 1 2 0 1 3 ~I PCT/US92/09560 -93- ~ .

Exam~le 54 (a) trans-2-[[4-(1,1-dimethylethyl)phenyl]thio]-cycloheptanol (b) c s-2-[t4-(1,1-dimethylethyl)phenyl]thio]-5 cycloheptanol ~:~

10 ~35~ ~s~?~

OH

Starting with 2-~14-(l,l(dimethylethyl)phenyl]-: thio]cycloheptanone and following the procedure described in Example 52 gives the title compounds.

21201 ')~ -94-Exam~le 55 (a) Methyl trans-[t2-tt4~ -dimethylethyl)-phenyl]thio]cycloheptyl]thio]acetate and trans-t~2-tt4-(l,l-dimethylethyl)phenyl]thio]cycloheptyl]thio] acetic acid 10 ~s~? ~s~
S COOCH3 S~_~CCC

Starting with trans-2-tt4~ -dimethylethyl)- ~;
phenyl]thio~cycloheptanol and following the procedures described in Examples 4 and 5 gives the title compounds.

~: :

: .

W093/~ ~ 7 2 1 2 Q 1 3 I PCT/US92/09560 Example 56 ~ rans-2-~t2-~1,1'-biphenyl]-3ylthio-cyclohexyl~-thiQ i -N- ( 2,6-dimethylphenyl)-N-ethyl acetamide s~
J~N~
C2H5 `:
' Following the procedure of Example 22 and substituting 2,6-dimethyl-N-ethylaniline for 2,6-dimethylaniline gives the title compound.

Exam~le 57 (a) trans-2-~3,5-bis(l,l-dimethylethyl)phenyl]-thio~cyclooctanol (b) c s-2-tt3,5-bis(l,l-dimethylethyl)phenyl]-: thio]cyclooctanol ~ 30 ~S$ ~SQ

Starting with 2-t[3,5-bis(l,l(dimethylethyl)-phenyllthio~cyclooctanone and following the procedure : 35 described in Example 52 gives the title compounds.

WOg3/10087 PCT/US92/O9S~O

212~ 96- ~

Exam~le S8 (a) Methyl trans-tr2-t[3,5-bis(l,l-dimethylethyl)phenyl]-thio~cyclooctyl]thio]acetate and trans-[t2-~t3,5-bis(l,l-dimethylethyl)phenyl]-thio~cyclooctyl]thio]acetic acid 1~ ~5~ ~S~
S~COOCH3 S~COOH

Starting with trans-2-[~3,5-bis(l,1-dimethylethyl)phenyl]thio]cyclooctanol and following the procedures described in Examples 4 and 5 gives the title compounds.

-97~

E~ample ss Substituting the compound listed in column A of Table 3 below for 3,5-bis(1,1-dimethylethyl)-benzenethiol and following the procedure of Example 19 and then substituting the resulting furanol for the cyclohexanol used in Example 17 and following the procedure of Example 17 gives the compound of the Formula XXX in which W is the moiety listed in the lo second column of Table 3 below.

w--S~ ' XXX ;' O~_~COOH

A W
20 (a) 2-bromothiophenol 2-bromophenyl (b) 3-bromothiophenol 3-bromophenyl (c) 4-bromothiophenol 4-bromophenyl (d) 2,5-dichlorobenzenethiol 2,5-dichlorophenyl (e) 2-chlorothiophenol 2-chlorophenyl 25 (f) 3-chlorothiophenol 3-chlorophenyl (g) 4-chlorothiophenol 4-chlorophenyl (h) 2,6-dichlorobenzenethiol 2,6-dichlorophenyl (i) 3,4-dichlorobenzenethiol 3,4-dichlorophenyl (j) 2,4-dimethylthiophenol 2,4-dimethylphenyl 30 (k) 2,5-dimethylthiophenol 2,5-dimethylphenyl (1) 3,4-dimethylthiophenol 3,4-dimethylphenyl (m) 2-chlorobenzyl mercaptan 2-chlorobenzyl (n) 4-chlorobenzyl mercaptan 4-chlorobenzyl (o) 4-fluorothiophenol 4-fluorophenyl 35 (p) 4-hydroxythiophenol 4-hydroxyphenyl (q) 2-isopropylthiophenol 2-isopropylphenyl wo g3/l0087 Pcr/usg2/o9s6o ::

212 0 1 3 l~ -98-(r) 2-methoxybenzenethiol 2-methoxyphenyl (s) 3-methoxybenzenethiol 3-methoxyphenyl (t) 4-methoxybenzenethiol 4-methoxyphenyl (u) o-thiocresol 2-methylphenyl 5 (v) p-thiocresol 4-methylphenyl WO93/10087 2 1 2 0 1~ ~ PCTIUS92/09560 _99 _ ~

Example 60 Following the procedure of Example 22 and substituting the aniline listed in column B of Table 4 below for 2,6-dimethylaniline gives the compound of S Formula XXXI in which Z is the moiety listed in the second column (Z) of Table 4 below.
~3 ~ ~ XXXI

N~-Z

: _ B Z
(a) 2-bromo-4-methylaniline 2-bromo-4-methylphenyl (b) 4-bromo-2-methylaniline 4-bromo-2-methylphenyl (c) 4-t-butylaniline 4-t-butylphenyl (d) 2-chloro-6-methylaniline 2-chloro-6-methylphenyl (e) 2,6-dibromo-4-methylaniline 2,6-dibromo-4-methylphenyl (f) 2,6-diethylaniline 2,6-diethylphenyl 25 (g) 2,6-difluoroaniline 2,6-difluorophenyl (h) 2,6-diisopropylaniline 2,6-diisopropylphenyl (i) 2,5-dimethoxyaniline 2,5-dimethoxyphenyl (j) 2,5-dimethylaniline 2,5-dimethylphenyl (k) 3,5-dimethylaniline 3,5-dimethylphenyl (1) 4,6-dimethyl-2-nitroaniline 4,6-dimethyl-2-nitrophenyl (m) 6-ethyl-o-toluidine 6-ethyl-o-phenyl (n) 4-hexylaniline 4-hexylphenyl (o) 4-hexyloxyaniline 4-hexyloxyphenyl 35 (p) 4-iodoaniline 4-iodophenyl WO g3/10087 , Pcr/uss2/oss60 212013~ -lOO-(q) 5-methoxy-2-methyl- 5-methoxy-2-methyl-4-nitroaniline 4-nitrophenyl (r) 3-(Dethylmercapto)aniline 3-(methylmercapto)-phenyl 5 (s) 4-octylaniline 4-octylphenyl (t) 2-propylaniline 2-propylphenyl (u) 3,5-bis(trifluoromethyl)- 3,5-bis(trifluoro-aniline methyl)phenyl (v) 2,4,6-trimethylaniline 2,4,6-trimethylphenyl Exam~le 61 Substituting the compound listed in column A of Table 3 above for 3,5-bis(l,1-dimethylethyl)-. benzenethiol and f,ollowing the procedure of Example 19 and then substituting the resulting furanol for the trans-2-t(tl,l'-biphenyl]-3-yl)thio~cyclohexanol used in Example 22 and also substituting the aniline listed in column B of Table 4 above for the 2,6-dimethylaniline used in Example 22 and following the procedure described in Example 22 gives the compound of formula XXXI(a) in which W is the moiety listed in the second column (w) of Table 3 above and Z is the moiety listed in the second column (Z) of Table 4 above.

w - S ~ 0 XXXI(a) ~NH--Z

WO g3/10087 2 1 2 0 1 3 ~ Pcr/usg2/ogs60 . .

Exam~le 62 transtt-2-[t3,5-bis(l,l-dimethylethyl)phenyl~-thio]cyclohexyl]thio]-N-(2,6-dimethylphenyl)acetamide C~CH3)3 f ~

Following the procedure of Example 22 and substituting trans-2-t~3,5-bis(l,l-dimethylethyl)phenyl~thio]-15 cyclohexanol for trans-2-[([1,1'-biphenyl]-3- :;
yl)]thio~cyclohexanol gives the title compound.

Example 63 C~:H3)3 ~ ~ XXXII

C~CH3)3 , Following the procedure of Example 22 and substituting trans-2-t[3,5-bis(l,l-dimethylethyl)- :
phenyl]thio]cyclohexanol for trans-2-t(tl,l'-biphenyl]- :
3-yl)]thio]cyclohexanol used therein and also substituting the aniline listed in column B of Table 4 above for 2,6-dimethylaniline gives the compound of Formula XXXII in which Z is the moiety listed in the second column of Table 4 above.

W093~87 PCT/US92/09560 2l~nl3 1 Exam~le 64 (a) Substituting the compound listed in column A
of Table 3 above for 3,5-bis(l,l-dimethylethyl)-benzenethiol and following the procedure of Example 3 and then substituting the resulting cyclohexanol for the trans-2-t~3,5-bis(l,1-dimethylethyl)phenyl]thio]-cyclohexanol used in Example 17 and following the procedure of Example 17 gives the compound of the Formula XXXIII(a) in which W is the moiety listed in the second column (W) of Table 3 above.

W - 5 ~ XXXIII(a) o ~ OH

(b) Substituting the compound listed in column A
of Table 3 above for 3,5-bis(l,l-dime~hylethyl)-: 20 benzenethiol and following the procedure of Example 3 and then substituting the resulting cyclohexanol for the trans-2-[t(l,l'-biphenyl)-3-yl~thio~cyclohexanol used in Example 22 and also substituting the aniline listed in column B of Table 4 above for the 2,6-dimethylaniline used in Example 22 and following the procedure described in Example 22 gives the compound of Formula XXXIII(b) in which W is the moiety listed in the second column (W) of Table 3 above and Z is the moiety listed in the second column (Z) of Table 4.

W -S ~ O XXXIII(b) ~1 NH--Z

WOg3/10087 PCT/US92/Og560 Exam~le 65 Substituting the compound listed in column A of Table 3 above for 3,5-bis(l,l-dimethylethyl) benzenethiol in Example 3 and also substituting cyclopentene oxide for cyclohexene oxide in Example 3 and then following Examples 3, 4 and 5 respectively gives the compounds of (a) Formula XXXIV, (b) Formula XXXV, and (c) Formula XXXVI below in which W is the moiety listed in the second column of Table 3 above.
10 Ex. 65(a) r\
w--S~
- XXXIV
Ex. 65(b) ~ .
~ >
W--S ~ XXXV
-Ex. 65(c) ~ XXXVI
W--S~
S~COOH

W093/10087 PCT~US92/09560 21~013~ -104-Example 66 Following the procedure of Example 23 and substituting the amine listed in column C of Table 5 below for N,N,N'-trimethyl-1,3-propane diamine gives the compound of Formula XXXVII below in which Y is the moiety listed in the second column (Y) of Table 5 below.

H3C~CH3 , H3C~ ~ ~ XXXVII

TABLE 5 ;~
C Y
(a) dimethylamine -N(CH3) 2 (b) diethylamine -N(C2Hs)2 (c) diisopropylamine -NtCH(CH3)2~2 .
(d) dibutylamine -Nt(CH2)3CH3]2 25 (e) dihexylamine -N ~ (CH2) 5CH3 ] 2 (f) diisobutylamine -NtCH2CH(CH3) 2] 2 (g) hexylamine -NH(CH2)sCH3 (h) butylamine -NH(CH2) 3CH3 (i) octylamine -NH ( CH2 ) ~CH3 30 (j) t-butylamine -NHC ( CH3) 3 (k) 3,3-dimethlbutylamine -NHCH2CH2C(CH3j 3 (1) dipentylamine ~ -N~(CH2) 4CH3 ] 2 (m) l-ethylpropylamine -NHCH(C2Hs) 2 (n) l-cyclohexylethylamine -NH t CH ( CH3 ) C6H,I ]
35 (o) methylphenylamine -NHt (CH3) C6H5~

WO93/10087 2 1 2 0 1 34 PCT/USg2/09560 Exam~le 67 (a) Substituting N,N-diethyl-1,4-pentane diamine for the N,N,N'-trimethyl-1,3-propane diamine of Example 23 and following the procedure described therein gives trans-2-tt2-t[3,5-bis(l,l-dimethylethyl)phenyl]thio]cyclohexyl~thio]-N-~4-diethylamino)pentyl]acetamide.
(b) Substituting 4-(2-aminoethyl)morpholine for the N,N,N'-trimethyl-1,3-propane diamine of Example 23 ::
and following the procedure described therein gives trans-2-tt2-~t3,5-bis(l,l-dimethylethyl)phenyl~thiol-cyclohexyllthio]-N-(4-morpholinylethyl)acetamide.
(c) Substituting 1-(2-aminoethyl)piperidine for the N,N,N'-trimethyl-1,3-propane diamine of Example 23 and following the procedure described therein gives trans-2-tt2-tt3,5-bis(l,l-dimethylethyl)phenyllthiol-cyclohexyllthiol-N-(l-piperidinylethyl)acetamide.
(d) Substituting 1-(2-aminoethyl)pyrrolidine for the N,N,N'-trimethyl-1,3-propane diamine of Example 23 and following the procedure described therein gives trans-2-t[2-tt3,5-bis(l,l-dimethylethyl)phenyllthio]-cyclohexyllthio~-N-(l-pyrrolidinylethyl)acetamide.
(e) Substituting 1-(3-aminopropyl)-2-methylpiperidine for the N,N,N'-trimethyl-1,3-propane diamine of Example 23 and following the procedure described therein gives trans-2-[[2-[~3,5-bis(l,l-dimethylethyl)phenyllthio~cyclohexyl]thio~-N-~(2-methylpiperidin-l-yl)propyllacetamide.
(f) Substituting N,N-diethyl-1,3-propane diamine for the N,N,N'-trimethyl-1,3-propane diamine of Example 23 and following the procedure described therein gives trans-2-[12-~[3,5-bis(l,l-dimethylethyl)-phenyl]thio]cyclohexyl~thio]-N-t3-(diethylamino)-propyl]acetamide.
(g) Substituting 4-diisopropylaminobutylamine for the N,N,N'-trimethyl-1,3-propane diamine of Example 23 WO93/1~87 PCT/USg2/OgS60 and following the procedure described therein gives trans-2-tt2-tt3,5-bis(l,1-dimethylethyl)phenyl]thio]-cyclohexyl~thio]-N-t4-(diisopropylamino)butyl]-acetamide.
(h) Substituting N,N-diethyl-N'methyl-1,3-diaminopropane for the N,N,N'-trimethyl-1,3-propane diamine of Example 23 and following the procedure described therein gives trans-2-[[2-[t3,5-bis(l,l-dimethylethyl)phenyl]thio]cyclohexyl]thio]-N-t3-(diethylamino)propyl]-N-methylacetamide.
(i) Substituting N,N-diethyl-N'-methyl-ethylenediamine for the N,N,N'-trimethyl-1,3-propane diamine of Example 23 and following the procedure described therein gives trans-2-[~2-tt3,5-bis(l,1-dimethylethyl)phenyl]thiolcyclohexyl]thio]-N-t(diethylamino)ethyll-N-methylacetamide.
(j) Substituting N,N,N'-trimethylethylenediamine for the N,N,N'-trimethyl-1,3-propane diamine of Example 23 and following the procedure described therein gives trans-2-t[2-tt3,5-bis(1,1-: dimethylethyl)phenyl~thio]cyclohexyl]thio]-N-t(dimethylamino)ethyl]-N-methylacetamide.

W093/10087 2 1 2 0 1 3 4 PCT/US92~09560 ; ~
' !

ExamDle 68 (a) Substituting 4-(ethylaminomethyl)pyridine for the.2-(2-methylaminoethyl)pyridine of Example 16 and following the procedure described therein gives trans-2-tt2-tt3,5-bis(l,l-dimethylethyl)phenyllthio]cyclo-. hexyl]thio~-N-ethyl-N-(4-pyridinylmethyl)acetamide.
(b) Substituting 2-(2-aminoethylamino)-5-nitropyridine for the 2-(2-methylaminoethyl)pyridine of Example 16 and following the procedure described 1~ therein gives trans-2-1t2-tt3,5-bis(l,l-dimethylethyl)phenyllthio3cyclohexyl]thiol-N-t[(5-nitropyridin-2-yl)amino~ethyl)acetamide.
(c) Substituting 2-(i-aminoethyl)-1-methylpyrrolidine for the 2-(2-methylaminoethyl)-pyridine of Example 16 and following the proceduredescribed therein gives trans-2-tt2-tt3,5-bis(l,l-dimethylethyl)phenyl~thiolcyclohexyllthio]-N-t(l-methylpyrrolidin-2-yl)ethyl]acetamide.
(d) Substituting 2-(2-aminoethyl)pyridine for the 2-(2-methylaminoethyl)pyridine of Example 16 and following the procedure described therein gives trans-2-t[2-tt3,5-bis(l,l-dimethylethyl)phenyl]thiol-cyclohexyllthiol-N-(2-pyridinylethyl)acetamide.
(e) Substituting 2-(aminomethyl)pyridine for the 2-(2-methylaminoethyl)pyridine of Example 16 and following the procedure described therein gives trans-2-~[2-[~3,5-bis(1,1-dimethylethyl)phenyl]thio]-cyclohexyl]thio]-N-(2-pyridinylmethyl)-acetamide.
(f) Substituting 3-(aminomethyl)pyridine for the 2-(2-methylaminoethyl)pyridine of Example 16 and following the procedure described therein giveæ trans-2-tt2-tt3,5-bis(l,l-dimethylethyl)phenyl]thio~-cyclohexyl~thio~-N-(3-pyridinylmethyl)-acetamide.
(g) Substituting 4-(aminomethyl)pyridine for the 2-(2-methylaminoethyl)pyridine of Example 16 and following the procedure described therein gives t~ans-2-~2-tt3,5-bis(l,l-dimethylethyl)phenyl]thio~- :
cyclohexyl]thio]-N-(4-pyridinylmethyl)-acetamide.
. (h) Substituting 2-aminomethyl-6-methylpyridine for the 2-(2-methylaminoethyl)pyridine of Example 16 and following the procedure described therein gives . trans-2-~t2-tt3,5-bis(l,l-dimethylethyl)phenyl]thio~-cyclohexyl]thio~-N-t(6-methylpyridine-2-yl)methyl~-acetamide.

WO g3/1~87 2 1 2 0 1 3 4 PCT/US92/09560 Example 69 (a) Substituting 3-methoxypropylamine for the 2-methoxyethylamine in Example 25 and following the procedure described therein gives trans-2-[t2-tt3,5-5 bis(l,l-dimethylethyl)phenyl]thio]cyclohexyl]thio]-N- `
(3-methoxypropyl)acetamide.
(b) Substituting 3-isopropoxypropylamine for the 2-methoxyethylamine in Example 25 and following the : procedure described therein gives trans-2-t[2-1~3,5-bis(l,l-dimethylethyl)phenyl]thio~cyclohexyl~thio]-N-(3-isopropoxypropyl)acetamide. .:
(c) Substituting 3-ethoxypropylamine for the 2-methoxyethylamine in Example 25 and following the -~
procedure described therein gives trans-2-~t2-t[3,5-bis(l,l-dimethylethyl)phenyl]thio~cyclohexyl]thio~-N-(3-ethoxypropyl)acetamide.
(d) Substituting 3-butoxypropylamine for the 2-methoxyethylamine in Example 25 and following the procedure described therein gives trans-2-tt2-tt3~5-bis(l,l-dimethylethyl)phenyl]thiolcyclohexyl~thio]-N-: (3-butoxypropyl)acetamide.
(e) Substituting 2-methylaminomethyl-1,3-dioxolane for the 2-methoxyethylamine in Example 25 and following the procedure described therein gives tranæ-25 2-tt2-tt3,5-bis(l,l-dimethylethyl)phenyl]thio~- :
cyclohexyl~thio~-N-methyl-N-(2-methyl-1,3-dioxolane)acetamide.
(f) Substituting furfurylamine for the 2-methoxyethylamine in Example 25 and following the procedure described therein gives trans-2-tt2-~t3,5-bis(1,1-dimethylethyl)phenyl]thio]cyclohexyl~thio~-N-(furfuryl)acetamide.
(g) Substituting 2-thiophenemethylamine for the 2-methoxyethylamine in Example 25 and following the procedure described therein gives trans-2-tt2-tt3,5-WO93/1~87 PCT/US92/09560 212013~

bis(l,l-dimethylethyl)phenyl~thioJcyclohexyl]thio]-N-(2-thiophenemethyl)acetamide.
(h) Substituting tetrahydrofurfuralamine for the 2-methoxyethylamine in Example 25 and following the procedure described therein gives trans-2-tt2-~[3,5-bis(l,l-dimethylethyl)phenyl]thio]cyclohexyl]thio]-N-(tetrahydrofurfuryl)acetamide.

WOg3/l~W~ PCT~US92/09560 -` 21201~

Example 70 (a) Substituting 2-trifluoromethylphenol for the meta-t-butyl phenol in Example 8 and following the procedures described in Examples 8, 9, 10, and 11 respectively gives trans-tt2-t(2-trifluoromethyl-phenyl)thio]cyclohexyllthio~acetic acid.
(b) Substituting 3-trifluoromethylphenol for the meta-t-butyl phenol in Example 8 and following the procedures described in Examples 8, 9, 10, and 11 - ~o respectively gives trans-tt2-1(3-trifluoromethyl-phenyl)thio~cyclohexyllthio~acetic acid.
- (c) Substituting 4-trifluoromethylphenol for the meta-t-butyl phenol in Example 8 and following the procedures described in Examples 8, 9, 10, and 11 respectively gives trans-[~2-t(4-trifluoromethyl-phenyl)thio]cyclohexyl]thiolacetic acid.
(d) Substituting 3,5-bis-(trifluoromethyl)phenol for the meta-t-butyl phenol in Example 8 and following the procedures described in Examples 8, 9, 10, and 11 respectively gives trans-~t2-~t3,5-bis(trifluoro-methyl)phenyl]thio~cyclohexyl]thiolacetic acid.

W093/10087 PCT/US92/09~

212013~ -112-Exam~le 71 By substituting the products of:
(a) Example 52(b);
(b) Example 54(a);
(c) Example 54(b);
(d) Example 57(a); and (e) Example 57(b) respectively for trans-2-tt3,5-bis(1,l-dimethyletbyl)phenyl]- ::
thio~cyclohexanol in Example 17 and following the procedure described therein, the following products are obtained:

(a) ~

~)~ (C~ ~}S~
O~COOH O~COOH

d) ~ } Q

O~COOH O~COOH
/\ /\

:: SUBSTITUTE SHEET

Claims (26)

What is claimed is:
1. A compound of the formula:

or a pharmaceutically acceptable salt thereof wherein R1, R2 and R10 are the same or different and independently represent alkyl, alkoxy, hydroxy, phenyl, halogen, trifluoromethyl, cyano, nitro or alkylthio, or hydrogen, with the proviso that when R1 and R2 are 3,5-di-tert-butyl, R10 is not 4-hydroxy; q is 0 or 1; R3 represents hydrogen, alkyl, alkoxy, or hydroxy; X
represents O, S or (CH2)m wherein m is an integer from 0 to 4; A represents O or S(O)n wherein n is 0, 1, or 2;
Alk1 is straight or branched chain alkyl having 1 to 6 carbon atoms; p is 0 or 1; y is 0, 1, or 2; and R
represents:
(a) alkyl with the proviso that, when A is oxygen, p is 0; q is 0; and R1, R2 and R10 are all hydrogen or are 2,4,6-trimethyl or R1 and R2 are 2,4-dinitro and R10 is hydrogen, or R1 and R2 are H and R10 is 4-chloro or 4-nitro or 4-methyl, then R is not methyl;
(b) OH;
(c) OR4 wherein R4 is alkyl of 1 to 6 carbon atoms;

(d) NR5R6 wherein R5 is hydrogen or alkyl, and R6 is hydrogen, alkyl, alkoxyalkyl, heterocyclealkyl, substituted heterocyclealkyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, or Alk-NR8R9 wherein Alk is alkyl of 1 to 10 carbon atoms and R8 and R9 each independently are hydrogen or alkyl; or NR5R6 together form a heterocyclic ring which may optionally be substituted; or (e) (CH2)1COOR7 wherein t is an integer from 1 to 4 and R7 is hydrogen or alkyl of 1 to 4 carbon atoms.
2. A compound according to Claim 1 of the formula or a pharmaceutically acceptable salt thereof wherein R1, R2 and R10 are the same or different and independently represent alkyl, alkoxy, phenyl, halogen, trifluoromethyl, cyano, or hydrogen; q is 0 or 1; R3 represents hydrogen, alkyl, alkoxy, or hydroxy; X
represents O, S or -(CH2)m wherein m is an integer from O
to 4; A represents O or S(O)n wherein n is 0, 1, or 2; p is an integer from o to 4; and R represents:

(a) alkyl with the proviso that when A is oxygen, p is 0, q is 0 and R1, R2 and R10 are all hydrogen or are 2,4,6-trimethyl, then R is not methyl;
(b) OH;
(c) OR4 wherein R4 is alkyl of 1 to 6 carbon atoms;
(d) NR5R6 wherein R5 is hydrogen or alkyl, and R6 is hydrogen, alkyl, alkoxyalkyl, heterocyclealkyl, substituted heterocyclealkyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, or Alk-NR3R9 wherein Alk is alkyl of 1 to 10 carbon atoms and R8 and R9 each independently are hydrogen or alkyl; or NR5R6 together form a heterocyclic ring which may optionally be substituted; or (e) (CH2)1COOR7 wherein t is an integer from 1 to 4 and R7 is hydrogen or alkyl of 1 to 4 carbon atoms.
3. A compound according to Claim 1 of the formula:

wherein R1, R2 and R10 are the same or different and independently represent tert-alkyl of 4 to 10 carbon atoms, phenyl, halogen, or hydrogen; R3 represents hydrogen or alkyl of 1 to 4 carbon atoms; X represents O, S or (CH2)m wherein m is 1 or 2; A represents O or S(O)n wherein n is 0, 1, or 2; p is an integer from 0 to 4; and R represents:
(a) alkyl of 1 to 4 carbon atoms with the proviso that when A is oxygen and p is 0, and R1, R2 and R10 are all hydrogen, then R is not methyl;
(b) OH;
(c) OR4 wherein R4 is alkyl of 1 to 4 carbon atoms;
(d) NR5R6 wherein R5 is hydrogen or alkyl, and R6 is hydrogen, alkyl, alkoxyalkyl, heterocyclealkyl, substituted heterocyclealkyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, or Alk-NR8R9 wherein Alk is straight or branched chain alkyl of 1 to 6 carbon atoms and R8 and R9 each independently are hydrogen or alkyl of 1 to 4 carbon atoms; or NR5R6 together form a heterocyclic ring which may optionally be substituted; or (e) (CH2)tCOOR7 wherein t is an integer from 1 to 4 and R7 is hydrogen or alkyl of 1 to 4 carbon atoms.
or a pharmaceutically acceptable salt thereof.
4. A compound according to Claim 1 of the formula wherein R1 and R2 are the same or different and independently represent tert-butyl, phenyl, halogen, or hydrogen; R3 represents hydrogen or alkyl of 1 to 4 carbon atoms; X represents o or (CH2)m wherein m is 1 or 2; p is 0 or 1; A
represents O or S; and R represents:
(a) OH;
(b) OR4 wherein R4 is alkyl of 1 to 4 carbon atoms; or (c) NR5R6 wherein R5 is hydrogen or alkyl of 1 to 4 carbon atoms and R6 is hydrogen, alkyl of 1 to 4 carbon atoms or heterocyclealkyl wherein the alkyl moiety has 1 to 4 carbon atoms, alkoxyalkyl, substituted phenyl, or Alk-NR8R9 wherein Alk is straight or branched chain alkyl of 1 to 6 carbon atoms and R8 and R9 are each independently hydrogen or alkyl of 1 to 4 carbon atoms; or NR5R6 together form a heterocyclic ring which may optionally be substituted;
or a pharmaceutically acceptable salt thereof.
5. A compound according to Claim 4 of the formula or a pharmaceutically acceptable salt thereof wherein R1 and R2 are the same or different and independently represent tert-butyl, phenyl, halogen or hydrogen; R3 represents hydrogen or alkyl of 1 to 4 carbon atoms;
X represents O or (CH2)m wherein m is 1 or 2; A
represents O or S; p is 0 or 1; and R represents:
(a) OH;
(b) OR4 wherein R4 is alkyl of 1 to 4 carbon atoms; or (c) NR5R6 wherein R5 is hydrogen or alkyl of 1 to 4 carbon atoms and R6 is hydrogen, alkyl of 1 to 4 carbon atoms, substituted phenyl, alkoxyalkyl wherein the alkyl moieties each have 1 to 6 carbon atoms, heterocyclealkyl wherein the alkyl moiety has 1 to 4 carbon atoms, or Alk-NR8R9 wherein Alk is straight or branched chain alkyl of 1 to 6 carbon atoms and R8 and R4 are each independently hydrogen or alkyl of 1 to 4 carbon atoms; or NR5R6 together form a heterocyclic ring which may optionally be substituted.
6. A compound according to Claim 5 of the formula (IV) wherein R1 and R2 are the same or different and independently represent tert-butyl, phenyl or hydrogen; X is (CH2)m wherein m is 2, A is S or O;
and R is:
(a) OH;
(b) OR4 wherein R4 is alkyl of 1 to 4 carbon atoms; or (c) NR5R6 wherein R5 is hydrogen or alkyl of 1 to 4 carbon atoms and R6 is alkoxyalkyl wherein the alkyl moieties each have 1 to 4 carbon atoms; heterocyclealkyl wherein the alkyl moiety has 1 to 4 carbon atoms; substituted phenyl having one or more substituents selected from the group consisting of alkyl, hydroxy, alkoxy, halogen, alkylamino, dialkylamino, phenyl, and alkyl carbonyl; or Alk-NR8R9 wherein Alk is straight or branched chain alkyl of 1 to 4 carbon atoms and R8 and R9 are each independently hydrogen or alkyl of 1 to 4 carbon atoms;
or a pharmaceutically acceptable salt thereof.
7. A compound according to Claim 6 wherein R1 and R2 are tert-butyl or phenyl; X is (CH2)m wherein m is 2; A is S or O; and R is:
OH;
OR4 wherein R4 is alkyl of 1 to 4 carbon atoms; or NR5R6 wherein R5 is alkyl of 1 to 4 carbon atoms and R6 is substituted phenyl, alkoxyalkyl wherein the alkyl moieties have 1 to 4 carbon atoms; pyridinylalkyl wherein the alkyl moiety has 1 to 4 carbon atoms; or Alk-NR8R9 wherein Alk is alkyl of 1 to 4 carbon atoms and R8 and R9 are hydrogen or alkyl of 1 to 4 carbon atoms;
or a pharmaceutically acceptable salt thereof.
8. A compound according to Claim 1 which is selected from the group consisting of methyl trans-[[2-[[3,5-bis(1,1-dimethylethyl) phenyl]thio]cyclohexyl]thio]acetate;

trans-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]thio]
cyclohexyl]thio]acetic acid;

trans-[[2-[[3-(1,1-dimethylethyl)phenyl]thio]
cyclohexyl]thio]acetic acid;

trans-[[2-[([1,1'-biphenyl]-3-yl)thio]cyclohexyl]
thio]acetic acid;

trans-2-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]
thio]cyclohexyl]thio]-N-methyl-N-(2-pyridinylethyl)acetamide;

trans-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]thio]
cyclohexyl]oxy]acetic acid;

trans-[[2-(phenylthio)cyclohexyl]thio]acetic acid;

trans-2-[[2-[[1,1'-biphenyl]-3-ylthio]cyclo-hexyl]thio]-N-(2,6-dimethylphenyl)acetamide;

trans-2-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]
thio]-cyclohexyl]thio]-N-[3-(dimethylamino) propyl]-N-methylacetamide;

trans-2-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]
thio]cyclohexyl]thio]-N-[4-(dimethylamino)butyl]
acetamide; and trans-2-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]-thio]cyclohexyl]thio]-N-(2-methoxyethyl)acetamide.
9. A pharmaceutical composition for use in inhibiting superoxide generation in a mammal which comprises an amount of a compound of the formula or a pharmaceutically acceptable salt thereof wherein R1, R2 and R10 are the same or different and independently represent alkyl, alkoxy, hydroxy, phenyl, halogen, trifluoromethyl, cyano, or hydrogen, with the proviso that when R1 and R2 are 3,5-di-tert-butyl, R10 is not 4-hydroxy; q is 0 or 1; R3 represents hydrogen, alkyl, alkoxy, or hydroxy; X represents O, S or (CH2)m wherein m is an integer from 0 to 4; A represents O or S(O)n wherein n is 0, 1, or 2; Alk1 is straight or branched chain alkyl having 1 to 6 carbon atoms;
y is 0, 1, or 2; and p is 0 or 1, which is effective to inhibit superoxide generation; and a pharmaceutically acceptable carrier.
10. A pharmaceutical composition according to Claim 9 for use in inhibiting superoxide generation in a mammal which comprises an amount of a compound of the formula wherein R1 and R2 are the same or different and independently represent tert-alkyl, phenyl, halogen or hydrogen; R3 represents hydrogen or alkyl of 1 to 4 carbon atoms; X represents O, S or (CH2)m wherein m is 1 or 2; A represents O or S(O) D
wherein n is 0, 1, or 2; and p is an integer from 0 to 4; or a pharmaceutically acceptable salt thereof, which is effective to inhibit superoxide generation; and a pharmaceutically acceptable carrier.
11. A pharmaceutical composition according to Claim 9 wherein said compound is selected from the group consisting of trans-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]-thio]cyclohexyl]thio]acetic acid;
trans-[[2-[[3-(1,1-dimethylethyl)phenyl]thio]
cyclohexyl]thio]acetic acid;
trans-[[2-[([1,1'-biphenyl]-3-yl)thio]cyclohexyl]
thio]acetic acid;
trans-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]-thio]cyclohexyl]oxy]acetic acid; and trans-[[2-(phenylthio)cyclohexyl]thio]acetic acid.
12. A pharmaceutical composition for use in stimulating superoxide generation in a mammal which comprises a compound of the formula or a pharmaceutically acceptable salt thereof wherein R1, R2 and R10 are the same or different and independently represent alkyl, alkoxy, hydroxy, phenyl, halogen, trifluoromethyl, cyano, or hydrogen, with the proviso that when R1 and R2 are 3,5-ditertbutyl, R10 is not 4-hydroxy; q is 0 or 1;
R3 represents hydrogen, alkyl, alkoxy, or hydroxy;
X represents O, S or (CH2)m wherein m is an integer from 0 to 4; A represents O or S(O)n wherein n is 0, 1, or 2; Alk1 is straight or branched chain alkyl having 1 to 6 carbon atoms; y is 0, 1, or 2;
p is 0 or 1; and R represents OR4 wherein R4 is alkyl of 1 to 6 carbon atoms; or NR5R6 wherein R5 is hydrogen or alkyl, and R6 is hydrogen, alkyl, alkoxyalkyl, heterocyclealkyl, substituted heterocyclealkyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, phenylalkyl, or substituted phenylalkyl, or Alk-NR8R9 wherein Alk is alkyl of 1 to 10 carbon atoms and R8 and R9 each independently are hydrogen or alkyl; or NR5R6 together form a heterocyclic ring which may optionally be substituted which is effective to stimulate superoxide generation and a pharmaceutically acceptable carrier.
13. A pharmaceutical composition according to Claim 12 for use in stimulating superoxide generation in a mammal which comprises an amount of a compound of the formula wherein R1 and R2 are the same or different and independently represent tert-alkyl, phenyl, or hydrogen; R3 represents hydrogen or alkyl of 1 to 4 carbon atoms; X represents O, S or (CH2)m wherein m is 1 or 2; A represents O or S(O)n wherein n is 0, 1, or 2; p is an integer from 0 to 4; and R
represents OR4 wherein R4 is alkyl of 1 to 4 carbon atoms; or NR5R6 wherein R5 is hydrogen or alkyl, and R6 is hydrogen, alkyl, alkoxyalkyl, heterocyclealkyl, substituted heterocyclealkyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl or Alk-NR8R9 wherein Alk is alkyl of 1 to 6 carbon atoms and R8 and R9 each independently are hydrogen or alkyl of 1 to 4 carbon atoms; or NR5R6 together form a heterocyclic ring which may optionally be substituted; or a pharmaceutically acceptable salt thereof, which is effective to stimulate superoxide generation and a pharmaceutically acceptable carrier.
14. A pharmaceutical composition according to Claim 13 wherein said compound is selected from the group consisting of trans-2-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]
thio]cyclohexyl]thio]-N-methyl-N-(2-pyridinylethyl)acetamide;

methyl trans-[[2-[[3,5-bis(1,1-dimethylethyl)-phenyl]thio]cyclohexyl]thio]acetate;

trans-2-[[2-[[1,1'-biphenyl]-3-ylthio]cyclo-hexyl]thio]-N-(2,6-dimethylphenyl)acetamide;

trans-2-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]
thio]-cyclohexyl]thio]-N-[3-(dimethylamino) propyl]-N-methylacetamide;

trans-2-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]
thio]cyclohexyl]thio]-N-[4-(dimethylamino)butyl]
acetamide; and trans-2-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]-thio]cyclohexyl]thio]-N-(2-methoxyethyl)acetamide.
15. A method of inhibiting superoxide generation in a mammal which comprises administering to a mammal in need of such treatment an amount of a compound of the formula or a pharmaceutically acceptable salt thereof wherein R1, R2 and R10 are the same or different and independently represent alkyl, alkoxy, hydroxy, phenyl, halogen, trifluoromethyl, cyano, or hydrogen, with the proviso that when R1 and R2 are 3,5-di-tert-butyl, R10 is not 4-hydroxy; t is 0 or 1; R3 represents hydrogen, alkyl, alkoxy, or hydroxy; X represents O, S or (CH2)m wherein m is an integer from 0 to 4; A represents O or S(O)n wherein n is 0, 1, or 2; Alk1 is straight or branched chain alkyl having 1 to 6 carbon atoms; y is 0, 1, or 2; and p is 0 or 1, which is effective to inhibit superoxide generation.
16. A method according to Claim 15 of inhibiting superoxide generation in a mammal which comprises administering to a mammal in need of such treatment an amount of a compound of the formula wherein R1 and R2 are the same or different and independently represent tert-alkyl, phenyl, or hydrogen; R3 represents hydrogen or alkyl of 1 to 4 carbon atoms; X represents O, S or (CH2)m wherein m is 1 or 2; A represents O or S(O)n wherein n is 0, 1, or 2; and p is an integer from 0 to 4; or a pharmaceutically acceptable salt thereof, which is effective to inhibit superoxide generation.
17. A method according to Claim 16 wherein said compound is selected from the group consisting of trans-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]-thio]cyclohexyl]thio]acetic acid;
trans-[[2-[[3-(1,1-dimethylethyl)phenyl]thio]
cyclohexyl]thio]acetic acid;
trans-[[2-[([1,1'-biphenyl]-3-yl)thio]cyclohexyl]
thio]acetic acid;
trans-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]-thio]-cyclohexyl]oxy]acetic acid; and trans-[[2-(phenylthio)cyclohexyl]thio]acetic acid.
18. A method of stimulating superoxide generation in a mammal which comprises administering to a mammal in need of such treatment an amount of a compound of the formula or a pharmaceutically acceptable salt thereof wherein R1, R2 and R10 are the same or different and independently represent alkyl, alkoxy, hydroxy, phenyl, halogen, trifluoromethyl, cyano, or hydrogen, with the proviso that when R1 and R2 are 3,5-di-tert-butyl, R10 is not 4-hydroxy; t is 0 or 1; R3 represents hydrogen, alkyl, alkoxy, or hydroxy; X represents O, S or (CH2)m wherein m is an integer from 0 to 4; A represents O or S(O)n wherein n is 0, 1, or 2; Alk1 is straight or branched chain alkyl having 1 to 6 carbon atoms;
and p is 0 or 1, and R represents OR4 wherein R4 is alkyl of 1 to 6 carbon atoms; y is 0, 1, or 2 or NR5R6 wherein R5 is hydrogen or alkyl, and R6 is hydrogen, alkyl, alkoxyalkyl, heterocyclealkyl, substituted heterocyclealkyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, phenylalkyl, or substituted phenylalkyl, or Alk-NR8R9 wherein Alk is alkyl of 1 to 10 carbon atoms and R8 and R9 each independently are hydrogen or alkyl; or NR5R6 together form a heterocyclic ring which may optionally be substituted which is effective to stimulate superoxide generation.
19. A method according to Claim 18 of stimulating superoxide generation in a mammal which comprises administering to a mammal in need of such treatment an amount of a compound of the formula wherein R1 and R2 are the same or different and independently represent tert-alkyl, phenyl, or hydrogen; R3 represents hydrogen or alkyl of 1 to 4 carbon atoms; X represents O, S or (CH2)m wherein m is 1 or 2; A represents O or S(O)n wherein n is 0, 1, or 2; p is an integer from 0 to 4; and R
represents OR4 wherein R4 is alkyl of 1 to 4 carbon atoms; NR5R6 wherein R5 is hydrogen or alkyl, and R6 is hydrogen, alkyl, alkoxyalkyl, heterocyclealkyl, substituted heterocyclealkyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, or Alk-NR8R9 wherein Alk is alkyl of 1 to 6 carbon atoms and R8 and R9 each independently are hydrogen or alkyl of 1 to 4 carbon atoms; or NR5R6 together form a heterocyclic ring which may optionally be substituted; or a pharmaceutically acceptable salt thereof, which is effective to stimulate superoxide generation.
20. A method according to Claim 18 wherein said compound is selected from the group consisting of trans-2-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]-thio]cyclohexyl]thio]-N-methyl-N-(2-pyridinylethyl)acetamide;

methyl trans-[[2-[[3,5-bis(1,1-dimethylethyl)-phenyl]thio]cyclohexyl]thio]acetate;

trans-2-[[2-[[1,1'-biphenyl]-3-ylthio]cyclo-hexyl]thio]-N-(2,6-dimethylphenyl)acetamide;

trans-2-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]
thio]-cyclohexyl]thio]-N-[3-(dimethylamino) propyl]-N-methylacetamide;

trans-2-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]
thio]cyclohexyl]thio]-N-[4-(dimethylamino)butyl]
acetamide; and trans-2-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]-thio]cyclohexyl]thio]-N-(2-methoxyethyl)acetamide.
21. A compound of the formula wherein R1, R2 and R10 are the same or different and independently represent alkyl, alkoxy, hydroxy, phenyl, halogen, trifluoromethyl, cyano, or hydrogen, with the proviso that when R1 and R2 are 3,5-di-tert-butyl, R10 is not 4-hydroxy; and when R1, R2 and R10 are all hydrogen, Z is not hydroxy or halogen; q is 0 or 1; y is 0, 1, or 2; R3 represents hydrogen, alkyl, alkoxy, or hydroxy; X represents O, S or (CH2)m wherein m is 0 to 4; and Z represents hydroxy, halogen, sulfate ester, or perfluoracyl ester.
22. A compound according to Claim 21 of the formula wherein R1 and R2 are the same or different and independently represent tert-alkyl, phenyl, halogen or hydrogen; R3 represents hydrogen or alkyl of 1 to 4 carbon atoms; q is 0 or 1; y is 0, 1, or 2; X represents O, S or (CH2)m wherein m is 1 or 2; and Z represents hydroxy, halogen, sulfate ester, or perfluoroacyl ester.
23. A compound according to Claim 22 which is selected from the group consisting of trans-2-[[3,5-bis(1,1-dimethylethyl)phenyl]thio]
cyclohexanol;

trans-2-[[3-(1,1-dimethylethyl)phenyl]thio]
cyclohexanol;

trans-2-[([1,1'-biphenyl]-3-yl)thio]cyclohexanol;

and cis-2-[[3,5-bis(1,1-dimethylethyl)phenyl]thio]
cyclohexanol.
24. A compound of the formula wherein R1, R2 and R10 are the same or different and independently represent alkyl, alkoxy, hydroxy, phenyl, halogen, trifluoromethyl, cyano, or hydrogen with the proviso that when R1 and R2 are 3,5-di-tert-butyl, R10 is not 4-hydroxy; q is 0 or 1; y is 0, 1, or 2; R3 represents hydrogen, alkyl, alkoxy, or hydroxy; and X
represents O, S or (CH2)m wherein m is 0 to 4.
25. A compound according to Claim 24 of the formula wherein R1 and R2 are the same or different and independently represent tert-alkyl, phenyl, halogen or hydrogen; R3 represents hydrogen or alkyl of 1 to 4 carbon atoms; q is 0 or 1; and y is 0, 1, or 2; and X represents O, S or (CH2)m wherein m is 1 or 2.
26. A compound according to Claim 24 which is selected from 2-[[4-(1,1-dimethylethyl)phenyl]thio]
cyclohexanone;

2-[[3,5-bis(1,1-dimethylethyl)phenyl]thio]
cyclohexanone;

2-[[4-(1,1-dimethylethyl)phenyl]thio]
cyclopentanone; and 2-(phenylthio)cyclohexanone.
CA002120134A 1991-11-18 1992-11-17 Derivatives of cyclic phenolic thioethers as inhibitors or stimulators of superoxide generation Abandoned CA2120134A1 (en)

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