WO1997016430A1 - Hexahydro-5-imino-1,4-heteroazepine derivatives as inhibitors of nitric oxide synthases - Google Patents

Hexahydro-5-imino-1,4-heteroazepine derivatives as inhibitors of nitric oxide synthases Download PDF

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WO1997016430A1
WO1997016430A1 PCT/US1996/017447 US9617447W WO9716430A1 WO 1997016430 A1 WO1997016430 A1 WO 1997016430A1 US 9617447 W US9617447 W US 9617447W WO 9716430 A1 WO9716430 A1 WO 9716430A1
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aryl
phenyl
group
hydrogen
mono
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PCT/US1996/017447
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French (fr)
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Charles G. Caldwell
William K. Hagmann
Malcolm Maccoss
Shrenik K. Shah
Kothandaraman Shankaran
Karla L. Furman
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Merck & Co., Inc.
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Priority claimed from GBGB9605162.8A external-priority patent/GB9605162D0/en
Priority claimed from GBGB9605700.5A external-priority patent/GB9605700D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to CA002234641A priority Critical patent/CA2234641A1/en
Priority to AU75287/96A priority patent/AU700078B2/en
Priority to EP96937836A priority patent/EP0861238A4/en
Publication of WO1997016430A1 publication Critical patent/WO1997016430A1/en

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Definitions

  • This application is directed to inhibitors of nitric oxide synthase, and in particular cyclic amidines.
  • nitric oxide a reactive, inorganic radical gas as a molecule contributing to important physiological and pathological processes is one of the major biological revelations of recent times.
  • This molecule is produced under a variety of physiological and pathological conditions by cells mediating vital biological functions. Examples include endothelial cells lining the blood vessels; nitric oxide derived from these cells relaxes smooth muscle and regulates blood pressure and has significant effects on the function of circulating blood cells such as platelets and neutrophils as well as on smooth muscle, both of the blood vessels and also of other organs such as the airways.
  • nitric oxide serves as a neurotransmitter in non- adrenergic non-cholinergic neurons.
  • nitric oxide appears to be produced in small amounts on an intermittent basis in response to various endogenous molecular signals.
  • nitric oxide can be synthesized in much larger amounts on a protracted basis. Its production is induced by exogenous or endogenous inflammatory stimuli, notably endotoxin and cytokines elaborated by cells of the host defense system in response to infectious and inflammatory stimuli. This induced production results in prolonged nitric oxide release which contributes both to host defense processes such as the killing of bacteria and viruses as well as pathology associated with acute and chronic inflammation in a wide variety of diseases.
  • nitric oxide synthases which utilize the amino acid arginine and molecular oxygen as co-substrates has provided an understanding of the biochemistry of this molecule and provides distinct pharmacological targets for the inhibition of the synthesis of this mediator, which should provide significant beneficial effects in a wide variety of diseases.
  • Nitric oxide and L-citrulline are formed from L-arginine via the dioxygenase activity of specific nitric oxide synthases (NOSs) in mammalian cells.
  • NOSs specific nitric oxide synthases
  • L-arginine, ⁇ 2 and NADPH are cosubstrates while FMN, FAD and tetrahydrobiopterin are cofactors.
  • NOSs fall into two distinct classes, constitutive NOS (cNOS) and inducible NOS (iNOS) . Two constitutive NOSs have been identified. They are:
  • a constitutive, Ca ++ /calmodulin dependent enzyme located in the endothelium and elsewhere (ecNOS or NOS 3), that releases NO in response to receptor or physical stimulation,
  • the third isoform identified is inducible NOS (iNOS or NOS 2): (iii) a Ca ++ independent enzyme which is induced after activation of vascular smooth muscle, macrophages, endothelial cells, and a large number of other cells by endotoxin and cytokines. Once expressed, this inducible NO synthase produces NO in relatively large amounts for long periods of time.
  • Spectral studies of both the mouse macrophage iNOS and rat brain ncNOS have shown that these enzymes (which have been classified as P-450-like enzymes from their CO-difference spectra) contain a heme moiety.
  • the structural similarity between NOS and the P-450/flavoprotein complex suggests that the NOS reaction mechanism may be similar to P-450 hydroxylation and/or peroxidation.
  • NOS belongs to a class of flavohemeproteins which contain both heme and flavin binding regions within a single protein in contrast to the multiprotein NADPH oxidase or Cytochrome P-450/NADPH Cyt c reductase complexes.
  • NOS 3 acts as an autocoid mediating a number of physiological responses.
  • Two distinct cDNAs accounting for the activity of NOS 1 and NOS 3 in man have been cloned, one for NOS 1 (Nakane et. al, FEBS ⁇ Letters, 316, 175-182, 1993) which is present in the brain and a number of peripheral tissues, the other for an enzyme present in endothelium
  • NOS 3 Marsden et. al, FEBS tters, 307, 287-293, 1992. This latter enzyme is critical for production of NO to maintain vasorelaxation.
  • a second class of enzyme, iNOS or NOS 2 has been cloned from human liver (Geller et. al, PNAS, 90, 3491-5, 1993), and identified in more than a dozen other cells and tissues, including smooth muscle cells, chondrocytes, the kidney and airways.
  • this enzyme is induced upon exposure to cytokines such as gamma interferon (IFN- ⁇ ), interleukin- l ⁇ (IL-l ⁇ ), tumor necrosis factor (TNF- ⁇ ) and LPS (lipopolysaccharide).
  • cytokines such as gamma interferon (IFN- ⁇ ), interleukin- l ⁇ (IL-l ⁇ ), tumor necrosis factor (TNF- ⁇ ) and LPS (lipopolysaccharide).
  • IFN- ⁇ gamma interferon
  • IL-l ⁇ interleukin- l ⁇
  • TNF- ⁇ tumor necrosis factor
  • LPS lipopolysaccharide
  • Endothelium derived relaxation factor has been shown to be produced by NOS 3 (Moncada et. al, Pharmacol. Reviews, 43, 109-142, 1991). Studies with substrate analog inhibitors of NOS have shown a role for NO in regulating blood pressure in animals and blood flow in man, a function attributed to NOS 3. A transgenic mouse deficient in functional NOS 3 was shown to be hypertensive, thus validating the role of NO synthesis by NOS 3 in the regulation of blood pressure (Huang et al, Nature, 377, 239-242, 1995).
  • NO has also been shown to be an effector of the cytotoxic effects of activated macrophages (Nathan, FASEB J., 6, 3051-64, 1992) for fighting tumour cells and invading microorganisms (Wright et al, Card. Res., 26 ,48-57, 1992 and Moncada et al., Pharmacological Review, 43, 109-142, 1991). It also appears that the adverse effects of excess NO production, in particular pathological vasodilation and tissue damage, may result largely from the effects of NO synthesized by the NOS 2.
  • NO generated by NOS 2 has been implicated in the pathogenesis of inflammatory diseases.
  • hypotension induced by LPS or TNF- ⁇ can be reversed by NOS inhibitors and reinitiated by L-arginine (Kilbourn et. al, PNAS, 87, 3629- 32, 1990).
  • Conditions which lead to cytokine-induced hypotension include septic shock, hemodialysis (Beasley and Brenner, Kidney Int., 42, Suppl., 38, S96--S100, 1992) and IL-2 therapy in cancer patients (Hibbs et. al, J. Clin. Invest., 89, 867-77, 1992).
  • NOS 2 is implicated in these responses, and thus the possibility exists that a NOS inhibitor would be effective in ameliorating cytokine-induced hypotension.
  • Recent studies in animal models have suggested a role for NO in the pathogenesis of inflammation and pain and NOS inhibitors have been shown to have beneficial effects on some aspects of the inflammation and tissue changes seen in models of inflammatory bowel disease, (Miller et. al, J. Pharmacol Exp. Ther., 264, 11-16, 1990) and cerebral ischemia and arthritis (Ialenti et. al, Br. J. Pharmacol ., 110, 701-6, 1993; Stevanovic- Racic et al, Arth. & Rheum., 37, 1062-9, 1994).
  • transgenic mice deficient in NOS 1 show diminished cerebral ischemia (Huang et. al, Science, 265, 1883-5, 1994) and transgenic mice deficient in NOS 2 exhibit enhanced survivability in a model of LPS-induced shock (MacMicking et al Cell 81, 641-650, 1995) and Wei et al. Nature 375, 408-411, 1995)). Further conditions where there is an advantage in inhibiting
  • NO production from L-arginine include therapy with cytokines such as TNF, IL-1 and IL-2 or therapy with cytokine-inducing agents, for example 5, 6-dimethylxanthenone acetic acid, and as an adjuvant to short term immunosuppression in transplant therapy.
  • cytokines such as TNF, IL-1 and IL-2
  • cytokine-inducing agents for example 5, 6-dimethylxanthenone acetic acid
  • compounds which inhibit NO synthesis may be of use in reducing the NO concentration in patients suffering from inflammatory conditions in which an excess of NO contributes to the pathophysiology of the condition, for example adult respiratory distress syndrome (ARDS) and myocarditis.
  • ARDS adult respiratory distress syndrome
  • myocarditis myocarditis
  • an NO synthase enzyme may be involved in the degeneration of cartilage which takes place in autoimmune and/or inflammatory conditions such as arthritis, rheumatoid arthritis, chronic bowel disease and systemic lupus erythematosis (SLE). It is also thought that an NO synthase enzyme may be involved in insulin- dependent diabetes mellitus. Therefore, a yet further aspect of the present invention provides cyclic amidine derivatives or salts thereof in the manufacture of a medicament for use in cytokine or cytokine-inducing therapy, as an adjuvant to short term immunosuppression in transplant therapy, for the treatment of patients suffering from inflammatory conditions in which an excess of NO contributes to the pathophysiology of the condition.
  • nitric oxide synthase mediated diseases and disorders including neurodegenerative disorders, disorders of gastrointestinal motility and inflammation.
  • diseases and disorders include hypotension, septic shock, toxic shock syndrome, hemodialysis, IL-2 therapy such as in in cancer patients, cachexia, immunosuppression - 6 -
  • autoimmune and/or inflammatory indications including sunburn, eczema or psoriasis and respiratory conditions such as bronchitis, asthma, oxidant-induced lung injury and acute respiratory distress (ARDS), glomerulonephritis, restenosis, inflammatory sequelae of viral infections, myocarditis, heart failure, atherosclerosis, osteoarthritis, rheumatoid arthritis, septic arthritis, chronic or inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosis (SLE), ocular conditions such as ocular hypertension, retinitis and uveitis, type 1 diabetes, insulin- dependent diabetes mellitus and cystic fibrosis.
  • ARDS oxidant-induced lung injury and acute respiratory distress
  • glomerulonephritis glomerulonephritis
  • restenosis inflammatory sequelae of viral infections
  • myocarditis heart failure
  • atherosclerosis osteo
  • Compounds of Formula I are also usful in the treatment of hypoxia, hyperbaric oxygen convulsions and toxicity, dementia, Alzheimer's disease, Sydenham's chorea, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, epilepsy, Korsakoff s disease, imbecility related to cerebral vessel disorder, NO mediated cerebral trauma and related sequelae, ischemic brain edema (stroke), sleeping disorders, eating disorders such as anorexia, schizophrenia, depression, pre-menstrual syndrome (PMS), urinary incontinence, anxiety, drug and alcohol addiction, pain, migraine, emesis, tumor growth, immune complex disease, as immunosupressive agents, acute allograft rejection, infections caused by invasive microorganisms which produce NO and for preventing or reversing tolerance to opiates and diazepines.
  • ALS amyotrophic lateral sclerosis
  • epilepsy Korsakoff s disease
  • side a or side b has a double bond
  • X is selected from O, S(0) m , NH, and NR6, wherein R ⁇ is selected from Cl-l2alkyl, Cl-l2alkyl-carbonyl, C 1 - 12alkyloxy-carbonyl, C 1 - 12alkylamino-carbonyl Cl-l2alkyl-sulfonyl and Cl-l2alkylamino-sulfonyl wherein said Cl-12alkyl group being optionally mono or di- substituted by substituents being independently selected phenyl, Ci-6alkoxy, amino, and halo; m is 0, 1 or 2;
  • Rl, R2, R3 and R4 are each independently selected from the group consisting of
  • hetero C5-l()cycloalkyl wherein the hetero C5-l()cycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O and N, (1) aryl, selected from phenyl or naphthyl, (m) heteroaryl, wherein heteroaryl is selected from the group consisting of:
  • aryl-S(0)2NH where aryl is selected from phenyl and naphthyl
  • aryl-C(O) where aryl is selected from phenyl, naphthyl, pyridyl, thienyl, thiazolyl, oxazolyl, imidazolyl, and triazolyl
  • R7 is selected from hydrogen, phenyl, benzyl, cyclohexyl or Ci-6alkyl,
  • each of (b) to (y) being optionally mono or di- substituted, the substituents being independently selected from
  • halo selected from F, Cl, Br and I
  • hetero C5- 1 Ocycloalkyl wherein the hetero C5-l ⁇ cycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O and N,
  • aryl selected from phenyl or naphthyl
  • heteroaryl wherein heteroaryl is selected from the group consisting of: (a) imidazolyl,
  • R2, 3 an R4 including the optional substituents present thereon reside on the same carbon atom of Formula I, or two of the group Rl , R2, R3 and R4 including the optional substituents present thereon reside on adjacent atoms of Formula I
  • said two members may optionally be joined, such that together with the carbon atom to which they are attached there is formed a saturated or unsaturated monocyclic ring of 5, 6 or 7 atoms, said monocyclic ring optionally containing up to three hetero atoms selected from N, O or S, or when a member of the group Rl, R2, R3 and R4 including the optional substituents present thereon resides on an atom adjacent to the N on which R6 resides, said member may optionally be joined with R6, such that together with the N on which R6 resides and the carbon on which said member resides there is formed a saturated or unsaturated monocyclic heterocycle of 5, 6 or 7 atoms, said monocycle optionally containing up to three hetero atoms selected from
  • halo selected from F, Cl, Br and I
  • hetero C5-l ⁇ cycloalkyl wherein the heteroC5-iocycloalkyl optionally contains 1 or
  • aryl selected from phenyl or naphthyl, (g) cyclohexyl.
  • Rl, R2, R3 and R4 are each independently selected from the group consisting of
  • aryl where aryl is phenyl and naphthyl
  • aryloxy where aryl is phenyl and naphthyl
  • cycloalkyl wherein the cycloalkyi is a 5-, 6-, or 7-membered monocyclic ring which optionally contains 1 or 2 heteroatoms selected from S, O, and N, and
  • heteroaryl wherein heteroaryl is selected from the group consisting of:
  • R6R7N-S02-NH-C( 0)-, wherein R6 and R7 are independendy selected from the group consisting of
  • each of (b) to (e) being mono- or di- substituted, the substituents being independently selected from (1) hydroxy, (2) Cl-3alkoxy,
  • halo selected from fluoro, chloro, bromo, and iodo, (10) oxo, and
  • Rl, R2, R3 and R4 are each independently selected from the group consisting of
  • R5 is selected from the group consisting of
  • R6R7N-S02-NH-C( 0)-, optionally mono or di-substituted, wherein R6 and R7 are independently selected from the group consisting of
  • halo selected from fluoro, chloro, and bromo.
  • alkyl is defined to include linear, branched, and cyclic structures, with Cl-6alkyl including methyl, ethyl, propyl, 2-propyl, s- and t-butyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Ci-6alkoxy is intended to include alkoxy groups of from 1 to 6 carbon atoms of a straight, branched, or cyclic configuration. Examples of lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like.
  • Cl-6 alkylthio is intended to include alkylthio groups of from 1 to 6 carbon atoms of a straight, branched or cyclic configuration.
  • Examples of lower alkylthio groups include methylthio, propylthio, isopropylthio, cycloheptylthio, etc.
  • the propylthio group signifies -SCH2CH2CH3.
  • Heteroaryl includes furan, benzofuran, thiophene, py ⁇ ole, indole, isoxazole, isothiazole, pyrazole, oxazole, benzoxazole, thiazole, imidazole, benzimidazole, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,3- triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,3,4-triazole, 1,2,5- oxadiazole, 1,2,5-thiadiazole, pyridine, quinoline, isoquinoline, pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,4,5- tetrazine, tetrazole. and the like.
  • the compounds of the instant invention are useful in the treatment of a number of NOS implicated diseases.
  • NOS implicated diseases The implication of these diseases is well documented in the literature.
  • psoriasis see Ruzicka et. al, J. Invest. Derm., 103: 397 (1994) or Kolb-Bachofen et. al, Lancet, 344: 139 (1994) or Bull, et al., J. Invest. Derm., 103:435(1994); with regard to uveitis, see Mandia et.
  • compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt, thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic bases and organic bases. Salts derived from inorganic acids include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N_- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine.
  • basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N_- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpho
  • lysine methylglucar ⁇ ine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • compositions containing the active ingredient of the instant invention may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethyl-cellulose, methylcellulose, hydroxy- propylmethycellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene- oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • dispersing or wetting agents may be a naturally-occurring phosphatide, for example le
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p- hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy beans, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • compositions may also be administered in the form of a suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • topical use creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula I are employed. (For purposes of this application, topical application shall include mouth washes and gargles.)
  • Dosage levels of the order of from about 0.01 mg to about 140 mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day.
  • inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day, preferably 2.5 mg to 1 g per patient per day.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
  • Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
  • NOS activity is measured as the formation of L-[2,3,4,5- 3H]Citrulline from L- r 2,3A5- 3 H] Arginine.
  • the incubation buffer 100 uL contained; 100 mM TES, pH 7.5, 5 uM FAD, 5 uM FMN, 10 uM BH4, 0.5 mM NADPH, 0.5 mM DTT, 0.5 mg/mL BSA, 2 mM CaC12, 10 ug/mL cahnodulin (bovine), 1 uM L-Arg, 0.2 uCi L-[2,3,4,5- 3 H]Arg, and the inhibitor in aqueous DMSO (max. 5 %).
  • the reaction is initiated by addition of enzyme.
  • Illustrative of the utility of the compounds of Formula I is the ability of such compounds to inhibit NO synthase as shown in Table 1 and as measured by the assay described above:
  • the compounds of the present invention can be prepared according to the following methods.
  • Reaction conditions a) H 2 40 psi, Pd(OH)_>/C, EtOH, HOAc, 4 hr; b) (t-C 4 H9 ⁇ 2C) 2 O, NaCl, NaOH, CHCI 3 , reflux, 4hr; c) (CH3)3OBF 4j CH 2 C
  • hexahydro-l-(phenylmethyl)-(5/7)- l,4-diazepin-5-one A (prepared as described by T. Irikura, CAS 84:31153r, 83: 179149u) is reacted under hydrogen atmosphere at 40 psi in the presence of palladium hydroxide catalyst in ethanol and acetic acid to give hexahydro-5//-l,4-diazepin-5-one B as the acetic acid salt.
  • Reaction conditions a) NH 2 OH - HCl, NaOH, EtOH; b) n-BuLi, TsCl; Et 3 N, aq. dioxane; c) Lawesson's reagent, tol, 90°C; d) Me 3 OBF 4 , iPr 2 NEt, CH 2 CI 2 ; NH 4 CI, EtOH, reflux
  • 1,4-Oxa- and thiazepine analogs are prepared by methodology outiine in Scheme 3.
  • a ketone derivative A is converted to its corresponding oxime B by reaction with hydroxylamine in ethanol.
  • Ring expansion of B via a Beckmann rearrangement of the O-tosyl- oxime formed by reaction of B with with butyl lithium and p-toluenesulfonyl chloride gives hexahydro-l,4-heteroazepin-5-one £,.
  • X S
  • the amide in Q is converted to the thioamide D by reaction with Lawesson's reagent.
  • More highly substituted hexahydro-5-imino-l,4- heteroazepines may be prepared according to methodology outlined in Scheme 4.
  • Diester A is cyclized via a Dieckmann condensation to keto- ester B.
  • B Treatment of B with a strong base such as sodium hydride followed by addition of an alkylating agent such as n-propyl iodide will give E (where R2 is hydrogen and R3 is n-propyl).
  • keto- ester B may be oxidized by manganese dioxide to form the ⁇ , ⁇ - unsaturated keto-ester C.
  • a substituent R2 is introduced via a Michael reaction with an organo-cuprate reagent to form D.
  • Reaction conditions a) (t-C 4 H9O) 2 CO, NaHCO 3 , CH 2 CI 2 ; b) Ph 3 P, (i-C 3 H7 ⁇ 2 C)2N2, THF; c) HS(CH2) 2 CO 2 H, CsCO 3 , DMF; d) HCl, EtOAc; e) 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide,
  • More highly substituted hexahydro-5-imino- 1 ,4- heteroazepines may also be prepared according to methodology outlined in Scheme 5. Briefly, the amine functionality in aminoalcohol A is protected to give B. Mitsunobu conditions will cyclize B to form aziridine Q. The aziridine ring in Q is opened with ⁇ -mercaptopropionic acid followed by treatment with hydrochloric acid in ethyl acetate to yield amino acid D. Reaction of D under standard peptide bond forming reactions gives lactam E. Reaction with Lawesson's reagent gives the thiolactam F which is converted to 5-imino-l,4-thiazepine Q_by previously described conditions.
  • Step A Hexahvdro-(5/T,- 1.4-diazepine-5-one acetic acid salt.
  • l-Benzylhexahydro-(5 )-l,4-diazepine-5-one (1.5 g, 7.34 mmol) was dissolved in 12 mL of ethanol and 6 mL of acetic acid. After addition of 150 mg of 20% palladium hydroxide on carbon, the mixture was shaken under 40 psi of hydrogen for 4 h. The resulting mixture was centrifuged and the supematant was filtered through a 0.45 micron membrane filter. The catalyst was washed with ethanol (3 x 10 mL), and the combined filtrate was concentrated in vacuo to give a yellow oil which began to crystallize.
  • Step B 1 -(ferf-ButoxycarbonyDhexahvdro-fS/fl- 1.4-diazepin-5-one.
  • Step C l-(?grr-Butoxycarbonyl -2.3.6.7-tetrahvdro-5-methoxy-f IH)- 1 ,4-diazepine.
  • Trimethyloxonium tetrafluoroborate (Meerwein's salt) (141 mg, 0.94 mmol) was added in one portion to a solution of l-(tert- butoxycarbonyl)hexahydro-(5 )-l,4-diazepin-5-one (200 mg, 0.94 mmol) in 2.0 mL of anhydrous methylene chloride. The mixture was stirred overnight at room temperature. The reaction mixture was partitioned between 10 mL of saturated aqueous sodium bicarbonate and 20 mL of ethyl acetate. The organic layer was separated and the aqueous layer was extracted with 3 x 10 mL of ethyl acetate.
  • Step D 1 -(fe -Butoxycarbonyl hexahvdro-5-imino-( 1 H)- 1.4- diazepine hydrochloride .
  • Step E Hexahvdro-5-Imino-( IH)- 1 ,4-diazepine dihydrochloride.
  • Step B Tetrahvdro-(2/ifi- 1 ,4-thiazepin-5-one
  • Step D Hexahydro-5-imino- 1 ,4-thiazepine hydrochloride
  • step A tetrahydropyran-4-one was converted to 4-oximino-tetrahydropyran.
  • Step B Tetrahvdro-(2HV 1.4-oxazepin-5-one
  • step B 4-oximino- tetrahydropyran was converted to tetrahydro-(2//)-l,4-oxazepin-5-one.
  • step D tetrahydro-(2H) 1, oxazepin-5-one was reacted with Meerwien's salt and ammonium chloride to form hexahydro-5-imino-l//-l,4-oxazepine, hydrochloride.
  • Step A Tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester.
  • Step B 3-Propyl-tetrahvdrothiopyran-4-one-3-carboxylic acid, allyl ester.
  • Step C 3-Propyl-tetrahydrothiopyran-4-one.
  • Step D 4-Oximino-3-propyl-tetrahvdrothiopyran.
  • step A 3-propyl- tetrahydrothiopyran-4-one was reacted with hydroxylamine hydrochloride to form 4-oximino-3-propyl-tetrahydrothiopyran and was used directly in the subsequent reaction.
  • Step E Tetrahvdro-3-propyl-(2 f)- 1 ,4-thiazepin-5-one and tetrahvdro-6-propyl-(2 D- 1.4-thiazepin-5-one.
  • step B 4-o ⁇ immo-3- propyl-tetrahydrothiopyran was converted to a 3: 1 mixture of tetrahydro- 3- ⁇ ropyl-(2/7)-l,4-thiazepin-5-one and tetrahydro-6-propyl-(2//)-l,4- thiazepin-5-one.
  • Step F Tetrahvdro-3-propyl-(2/f)- 1 ,4-thiazepin-5-thione.
  • step C the mixture of tetrahydro-3-propyl-(2 - 1 ,4-thiazepin-5-one and tetrahydro-6-propyl- (2H)-l,4-thiazepin-5-one was reacted with Lawesson's reagent to yield the corresponding thioamides.
  • the 3-n-propyl isomer was isolated and purified by flash column chromatography on silica gel eluted with methylene chloride : hexanes (1:1) to yield tetfahydro-3-propyl-(2i/)-l,4- thiazepin-5-thione as a single compound.
  • Step G Hexahvdro-5-imino-3-propyl- 1 ,4-thiazepine hydrochloride.
  • step D tetrahydro-3- propyl-(2 )-l,4-thiazepin-5-thione was reacted with Meerwein's salt and ammonium chloride to yield hexahydro-5-imino-3-propyl-l,4-thiazepine, hydrochloride.
  • Step A 2.3-Dihydrothiopyran-4-one-3-carboxylic acid, allyl ester.
  • Step B 2-Methyl-tetrahvdrothiopyran-4-one-3-carboxylic acid, allyl ester.
  • Step D Hexahydro-5-imino-7-methyl-1.4-thiazepine hydrochloride.
  • Hexahydro-5-imino-2-methyl- 1 ,4-thiazepine hydrochloride was prepared according to the procedures described in Example 6.
  • step B the 6- positional isomer was separated from the 3-positional isomer (see Example 9) as its respective thioamide by flash column chromatography
  • step D reaction with Meerwein's salt and ammonium chloride as described in Example 2, step D gave hexahydro-5-imino-6-(3-methyl-2- n-butenyl)- 1 ,4-thiazepine hydrochloride.
  • step B the 3- positional isomer was separated from the 6-positional isomer (see Example 8) by flash column chromatography as its respective thioamide. Subsequently, reaction with Meerwein's salt and ammomum chloride as described in Example 2, step D gave hexahydro-5-imino-3-(3-methyl-2- n-butenyl)- 1 ,4-thiazepine hydrochloride.
  • step B the 6-positional isomer was separated from the 3-positional isomer (see Example 11) as its respective thioamide by flash column chromatography . Subsequently, reaction with Meerwein's salt and ammonium chloride as described in Example 2, step D gave hexahydro-5-i ⁇ no-6-(2-methyl-propyl)-l,4-thiazepine hydrochloride.
  • step B the 3-positional isomer was separated from the 6-positional isomer (see Example 13) as its respective thioamide by flash column chromatography . Subsequently, reaction with Meerwein's salt and ammonium chloride as described in Example 2, step D gave hexahydro-5-imino-3-methyl-l,4-thiazepine hydrochloride.
  • step B the 3-positional isomer was separated from the 6-positional isomer as its respective thioamide by flash column chromatography . Subsequently, reaction with Meerwein's salt and ammonium chloride as described in Example 2, step D gave hexahydro- 5-imino-3-ethyl- 1 ,4-thiazepine hydrochloride.
  • step B the 3-positional isomer was separated from the 6-positional isomer as its respective thioamide by flash column chromatography . Subsequently, reaction with Meerwein's salt and ammonium chloride as described in Example 2, step D gave hexahydro- 5-imino-3-butyl- 1 ,4-thiazepine, hydrochloride.
  • iH NMR 500 MHz, CD3OD: ⁇ 3.90 (m, IH), 3.23 (m, IH), 3.02 (m,
  • step B the 3-positional isomer was separated from the 6-positional isomer as its respective thioamide by flash column chromatography . Subsequently, reaction with Meerwein's salt and ammonium chloride as described in Example 2, step D gave hexahydro-5-imino-3-(2-methyl-3-propenyl)-l,4-thiazepine hydrochloride.
  • (+)-frfln5-Decahvdro-4-imino-benzorbl-1.4-thiazepine acetic acid salt (+)-frfln5-Decahvdro-4-imino-benzorbl-1.4-thiazepine acetic acid salt.
  • Step B ( ⁇ V7-(fgrt-ButoxycarponylV7-aza-bicvclo-14.1.01- cycloheptane
  • Step C ( ⁇ frQ «.y-2-amino-l-12-(carboxy)ethylthio1-cyclohexane hydrochloride
  • Step D ( ⁇ r. s-Decahydro-4-oxo-benzolbl-1.4-thiazepine
  • reaction mixture After stirring for an additional 5 mins., the reaction mixture was warmed to room temperature and stirred ovemight at the same temperature. The following day the reaction mixture was diluted with water and extracted with methylene chloride. The solvent layer was washed with brine, dried and evaporated to give the cmde which was purified by silica column and eluted with hexane/ethylacetate (7 : 3 + 5% methanol) to give 0.102 g (55%) of ( ⁇ )- f r ⁇ ns-decahydro-4-oxo-benzo[b]- 1 ,4-thiazepane as white solid.
  • Step E ( ⁇ Vfr ⁇ n -Decahvdro-4-thioxo-benzolbl-1.4-thiazepine
  • Step F ( ⁇ ran.s-Decahvdro-4-imino-benzorbl- 1.4-thiazepine acetic acid salt.
  • ( ⁇ )- ran5-decahydr ⁇ -4-thioxo-benzo[b]-l,4-thiazepane 25 mg, 0.12 mmol
  • trimethyloxonium tetrafluoroborate Meerwein's salt
  • Step A Tetrahvdro-3(S)-propyl-(2 D- 1.4-thiazepine-5-thione
  • the title compound was prepared employing the procedure in Example 17, Steps A to E and starting from L-norvalinol instead of ( ⁇ )-trans-2- aminocy clohexanol .
  • Step B Hexahvdro-5-imino-3(S Vpropyl- 1 ,4-thiazepine acetic acid salt
  • the cmde compound was then purified by column chromatography and eluted with acetonitrile : water : acetic acid (90:5:5) giving 31.5 mg of hexahydro-5-imino-3(S)- ⁇ ropyl-l,4-thiazepine acetic acid salt.
  • Step B Hexahvdro-5-imino-3(RVpropyl- 1.4-thiazepine acetic salt
  • step B tetrahydro-3(R)-propyl-(2 /)-l,4- thiaze ⁇ ine-5-thione (40 mg, 0.21 mmol) was converted to 37.4 mg of hexahydro-5-imino-3(R)-propyl-l,4-thiazepine acetic acid salt.

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Abstract

Disclosed herein are compounds of Formula (I) and pharmaceutically acceptable salts thereof which have been found useful in the treatment of nitric oxide synthase mediated diseases and disorders, including neurodegenerative disorders, disorders of gastrointestinal motility and inflammation. These diseases and disorders include hypotension, septic shock, toxic shock syndrome, hemodialysis, IL-2 therapy such as in cancer patients, cachexia, immunosuppression such as in transplant therapy, autoimmune and/or inflammatory indications including sunburn, eczema or psoriasis and respiratory conditions such as bronchitis, asthma, oxidant-induced lung injury and acute respiratory distress (ARDS), glomerulonephritis, restenosis, inflammatory sequelae of viral infections, myocarditis, heart failure, atherosclerosis, osteoarthritis, rheumatoid arthritis, septic arthritis, chronic or inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosis (SLE), ocular conditions such as ocular hypertension, retinitis and uveitis, type 1 diabetes, insulin-dependent diabetes mellitus and cystic fibrosis.

Description

TITLE OF THE INVENTION
HEXAHYDRO-5-IMINO-l,4-HETEROAZEPINE DERIVAΗVES AS INHIBITORS OF NITRIC OXIDE SYNTHASES
BACKGROUND OF THE INVENTION
This application is directed to inhibitors of nitric oxide synthase, and in particular cyclic amidines.
Nitric Oxide in Biology.
The emergence of nitric oxide (NO), a reactive, inorganic radical gas as a molecule contributing to important physiological and pathological processes is one of the major biological revelations of recent times. This molecule is produced under a variety of physiological and pathological conditions by cells mediating vital biological functions. Examples include endothelial cells lining the blood vessels; nitric oxide derived from these cells relaxes smooth muscle and regulates blood pressure and has significant effects on the function of circulating blood cells such as platelets and neutrophils as well as on smooth muscle, both of the blood vessels and also of other organs such as the airways. In the brain and elsewhere nitric oxide serves as a neurotransmitter in non- adrenergic non-cholinergic neurons. In these instances nitric oxide appears to be produced in small amounts on an intermittent basis in response to various endogenous molecular signals. In the immune system nitric oxide can be synthesized in much larger amounts on a protracted basis. Its production is induced by exogenous or endogenous inflammatory stimuli, notably endotoxin and cytokines elaborated by cells of the host defense system in response to infectious and inflammatory stimuli. This induced production results in prolonged nitric oxide release which contributes both to host defense processes such as the killing of bacteria and viruses as well as pathology associated with acute and chronic inflammation in a wide variety of diseases. The discovery that nitric oxide production is mediated by a unique series of three closely related enzymes, named nitric oxide synthases, which utilize the amino acid arginine and molecular oxygen as co-substrates has provided an understanding of the biochemistry of this molecule and provides distinct pharmacological targets for the inhibition of the synthesis of this mediator, which should provide significant beneficial effects in a wide variety of diseases.
Nitric Oxide Svnthases
Nitric oxide and L-citrulline are formed from L-arginine via the dioxygenase activity of specific nitric oxide synthases (NOSs) in mammalian cells. In this reaction, L-arginine, θ2 and NADPH are cosubstrates while FMN, FAD and tetrahydrobiopterin are cofactors. NOSs fall into two distinct classes, constitutive NOS (cNOS) and inducible NOS (iNOS) . Two constitutive NOSs have been identified. They are:
(i) a constitutive, Ca++/calmodulin dependent enzyme, located in the endothelium and elsewhere (ecNOS or NOS 3), that releases NO in response to receptor or physical stimulation,
(ii) a constitutive, Ca++/calmodulin dependent enzyme, located in the brain (ncNOS or NOS 1) and elsewhere, that releases
NO in response to receptor or physical stimulation,
The third isoform identified is inducible NOS (iNOS or NOS 2): (iii) a Ca++ independent enzyme which is induced after activation of vascular smooth muscle, macrophages, endothelial cells, and a large number of other cells by endotoxin and cytokines. Once expressed, this inducible NO synthase produces NO in relatively large amounts for long periods of time.
Spectral studies of both the mouse macrophage iNOS and rat brain ncNOS have shown that these enzymes (which have been classified as P-450-like enzymes from their CO-difference spectra) contain a heme moiety. The structural similarity between NOS and the P-450/flavoprotein complex suggests that the NOS reaction mechanism may be similar to P-450 hydroxylation and/or peroxidation. This indicates that NOS belongs to a class of flavohemeproteins which contain both heme and flavin binding regions within a single protein in contrast to the multiprotein NADPH oxidase or Cytochrome P-450/NADPH Cyt c reductase complexes.
Distinct Functions of NO Produced by Different Nitric Oxide Synthases. The NO released by the constitutive enzymes (NOS 1 and
NOS 3) acts as an autocoid mediating a number of physiological responses. Two distinct cDNAs accounting for the activity of NOS 1 and NOS 3 in man have been cloned, one for NOS 1 (Nakane et. al, FEBS βLetters, 316, 175-182, 1993) which is present in the brain and a number of peripheral tissues, the other for an enzyme present in endothelium
(NOS 3) (Marsden et. al, FEBS tters, 307, 287-293, 1992). This latter enzyme is critical for production of NO to maintain vasorelaxation. A second class of enzyme, iNOS or NOS 2, has been cloned from human liver (Geller et. al, PNAS, 90, 3491-5, 1993), and identified in more than a dozen other cells and tissues, including smooth muscle cells, chondrocytes, the kidney and airways. As with its counterpart from the murine macrophage, this enzyme is induced upon exposure to cytokines such as gamma interferon (IFN-γ), interleukin- lβ (IL-lβ), tumor necrosis factor (TNF-α) and LPS (lipopolysaccharide). Once induced, iNOS expression continues over a prolonged period of time. The enzyme does not require exogenous calmodulin for activity.
Endothelium derived relaxation factor (EDRF) has been shown to be produced by NOS 3 (Moncada et. al, Pharmacol. Reviews, 43, 109-142, 1991). Studies with substrate analog inhibitors of NOS have shown a role for NO in regulating blood pressure in animals and blood flow in man, a function attributed to NOS 3. A transgenic mouse deficient in functional NOS 3 was shown to be hypertensive, thus validating the role of NO synthesis by NOS 3 in the regulation of blood pressure (Huang et al, Nature, 377, 239-242, 1995). NO has also been shown to be an effector of the cytotoxic effects of activated macrophages (Nathan, FASEB J., 6, 3051-64, 1992) for fighting tumour cells and invading microorganisms (Wright et al, Card. Res., 26 ,48-57, 1992 and Moncada et al., Pharmacological Review, 43, 109-142, 1991). It also appears that the adverse effects of excess NO production, in particular pathological vasodilation and tissue damage, may result largely from the effects of NO synthesized by the NOS 2.
NO generated by NOS 2 has been implicated in the pathogenesis of inflammatory diseases. In experimental animals hypotension induced by LPS or TNF-α can be reversed by NOS inhibitors and reinitiated by L-arginine (Kilbourn et. al, PNAS, 87, 3629- 32, 1990). Conditions which lead to cytokine-induced hypotension include septic shock, hemodialysis (Beasley and Brenner, Kidney Int., 42, Suppl., 38, S96--S100, 1992) and IL-2 therapy in cancer patients (Hibbs et. al, J. Clin. Invest., 89, 867-77, 1992). NOS 2 is implicated in these responses, and thus the possibility exists that a NOS inhibitor would be effective in ameliorating cytokine-induced hypotension. Recent studies in animal models have suggested a role for NO in the pathogenesis of inflammation and pain and NOS inhibitors have been shown to have beneficial effects on some aspects of the inflammation and tissue changes seen in models of inflammatory bowel disease, (Miller et. al, J. Pharmacol Exp. Ther., 264, 11-16, 1990) and cerebral ischemia and arthritis (Ialenti et. al, Br. J. Pharmacol ., 110, 701-6, 1993; Stevanovic- Racic et al, Arth. & Rheum., 37, 1062-9, 1994). Moreover transgenic mice deficient in NOS 1 show diminished cerebral ischemia (Huang et. al, Science, 265, 1883-5, 1994) and transgenic mice deficient in NOS 2 exhibit enhanced survivability in a model of LPS-induced shock (MacMicking et al Cell 81, 641-650, 1995) and Wei et al. Nature 375, 408-411, 1995)). Further conditions where there is an advantage in inhibiting
NO production from L-arginine include therapy with cytokines such as TNF, IL-1 and IL-2 or therapy with cytokine-inducing agents, for example 5, 6-dimethylxanthenone acetic acid, and as an adjuvant to short term immunosuppression in transplant therapy. In addition, compounds which inhibit NO synthesis may be of use in reducing the NO concentration in patients suffering from inflammatory conditions in which an excess of NO contributes to the pathophysiology of the condition, for example adult respiratory distress syndrome (ARDS) and myocarditis.
There is also evidence that an NO synthase enzyme may be involved in the degeneration of cartilage which takes place in autoimmune and/or inflammatory conditions such as arthritis, rheumatoid arthritis, chronic bowel disease and systemic lupus erythematosis (SLE). It is also thought that an NO synthase enzyme may be involved in insulin- dependent diabetes mellitus. Therefore, a yet further aspect of the present invention provides cyclic amidine derivatives or salts thereof in the manufacture of a medicament for use in cytokine or cytokine-inducing therapy, as an adjuvant to short term immunosuppression in transplant therapy, for the treatment of patients suffering from inflammatory conditions in which an excess of NO contributes to the pathophysiology of the condition.
SUMMARY OF THE INVENTION
The invention disclosed herein encompasses compounds of Formula I
Figure imgf000007_0001
I
and pharmaceutically acceptable salts thereof which have been found useful in the treatment of nitric oxide synthase mediated diseases and disorders, including neurodegenerative disorders, disorders of gastrointestinal motility and inflammation. These diseases and disorders include hypotension, septic shock, toxic shock syndrome, hemodialysis, IL-2 therapy such as in in cancer patients, cachexia, immunosuppression - 6 -
such as in transplant therapy, autoimmune and/or inflammatory indications including sunburn, eczema or psoriasis and respiratory conditions such as bronchitis, asthma, oxidant-induced lung injury and acute respiratory distress (ARDS), glomerulonephritis, restenosis, inflammatory sequelae of viral infections, myocarditis, heart failure, atherosclerosis, osteoarthritis, rheumatoid arthritis, septic arthritis, chronic or inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosis (SLE), ocular conditions such as ocular hypertension, retinitis and uveitis, type 1 diabetes, insulin- dependent diabetes mellitus and cystic fibrosis. Compounds of Formula I are also usful in the treatment of hypoxia, hyperbaric oxygen convulsions and toxicity, dementia, Alzheimer's disease, Sydenham's chorea, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, epilepsy, Korsakoff s disease, imbecility related to cerebral vessel disorder, NO mediated cerebral trauma and related sequelae, ischemic brain edema (stroke), sleeping disorders, eating disorders such as anorexia, schizophrenia, depression, pre-menstrual syndrome (PMS), urinary incontinence, anxiety, drug and alcohol addiction, pain, migraine, emesis, tumor growth, immune complex disease, as immunosupressive agents, acute allograft rejection, infections caused by invasive microorganisms which produce NO and for preventing or reversing tolerance to opiates and diazepines.
DETAILED DESCRIPTION OF THE INVENTION
The invention disclosed herein encompasses compounds of Formula I
Figure imgf000008_0001
I or a pharmaceutically acceptable salt thereof wherein: side a or side b has a double bond, X is selected from O, S(0)m, NH, and NR6, wherein Rβ is selected from Cl-l2alkyl, Cl-l2alkyl-carbonyl, C 1 - 12alkyloxy-carbonyl, C 1 - 12alkylamino-carbonyl Cl-l2alkyl-sulfonyl and Cl-l2alkylamino-sulfonyl wherein said Cl-12alkyl group being optionally mono or di- substituted by substituents being independently selected phenyl, Ci-6alkoxy, amino, and halo; m is 0, 1 or 2;
Rl, R2, R3 and R4 are each independently selected from the group consisting of
(a) hydrogen,
(b) Cl-l2alkoxy,
(c) Ci-I2alkyl-S(0)k wherein k is 0, 1 or 2,
(d) mono C 1 - 12alkylamino, (e) (di-C l-l2alkyl)amino,
(f) Cl-l2alkylcarbonyl,
(g) Cl-l2alkyl, (h) C2-12alkenyl, (i) C2-12alkynyl, (j) C5-10cycloalkyl,
(k) hetero C5-l()cycloalkyl, wherein the hetero C5-l()cycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O and N, (1) aryl, selected from phenyl or naphthyl, (m) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) benzimidazolyl,
(2) benzofuranyl,
(3) benzooxazolyl, (4) furanyl,
(5) imidazolyl,
(6) indolyl,
(7) isooxazolyl,
(8) isothiazolyl, (9) oxadiazolyl,
(10) oxazolyl,
(11) pyrazinyl,
(12) pyrazolyl, (13) pyridyl,
(14) pyrimidyl,
(15) pyrrolyl,
(17) isoquinolyl,
(18) tetrazolyl, (19) thiadiazolyl,
(20) thiazolyl,
(21) thienyl, and
(22) triazolyl, (n) Cl-I2alkyl-C(0)NH, (o) Cl-l2alkoxy-C(0)NH,
(p) Cl-12alkylamino-C(0)NH, (q) Cl-I2alkyl-S(0)2NH, (r) Cl-l2alkylamino-C(0), (s) Cl-l2alkylamino-S(0)2, (t) aryl-C(0)NH where aryl is selected from phenyl, naphthyl, pyridyl, thienyl, thiazolyl, oxazolyl, imidazolyl, and triazolyl, (u) aryloxy-C(0)NH where aryl is selected from phenyl, naphthyl, and pyridyl, (v) phenylamino-C(0)NH,
(w) aryl-S(0)2NH where aryl is selected from phenyl and naphthyl, (x) aryl-C(O) where aryl is selected from phenyl, naphthyl, pyridyl, thienyl, thiazolyl, oxazolyl, imidazolyl, and triazolyl,
(y) phenylamino-S(0)2, (z) hydroxy,
(aa) amino,
(ab) oxo, (ac) C(0)OR7, R7 is selected from hydrogen, phenyl, benzyl, cyclohexyl or Ci-6alkyl,
each of (b) to (y) being optionally mono or di- substituted, the substituents being independently selected from
(1) hydroxy,
(2) -C(0)OH,
(3) -NR7R8, where R8 is selected from hydrogen, phenyl, benzyl, cyclohexyl or Cl-6alkyl, (4) -NR7C(0)R8,
(6) -NR7C(0)NHR8,
(5) -NR7C(0)ORo. ,where R9 is selected from phenyl, benzyl, cyclohexyl or Cl-6alkyl,
(7) -NR7S(0)2R9, (8) -OR7,
(9) -C(0)OR9,
(10) -C(0)NR7R8,
(11) -C(0)R7,
(12) -S(0)kR7. (13) -S(0)2NR7R8,
(14) halo selected from F, Cl, Br and I,
(15) -CF3,
(16) C(=NR7)-NHR8,
(17) hetero C5- 1 Ocycloalkyl,wherein the hetero C5-lθcycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O and N,
(18) aryl, selected from phenyl or naphthyl,
(19) heteroaryl, wherein heteroaryl is selected from the group consisting of: (a) imidazolyl,
(b) isooxazolyl,
(c) isothiazolyl,
(d) oxadiazolyl,
(e) oxazolyl, (f) pyridyl,
(g) tetrazolyl,
(h) thiazolyl,
(i) thienyl, and
(j) triazolyl,
or when two members of the group 1, R2, 3 an R4 including the optional substituents present thereon reside on the same carbon atom of Formula I, or two of the group Rl , R2, R3 and R4 including the optional substituents present thereon reside on adjacent atoms of Formula I, said two members may optionally be joined, such that together with the carbon atom to which they are attached there is formed a saturated or unsaturated monocyclic ring of 5, 6 or 7 atoms, said monocyclic ring optionally containing up to three hetero atoms selected from N, O or S, or when a member of the group Rl, R2, R3 and R4 including the optional substituents present thereon resides on an atom adjacent to the N on which R6 resides, said member may optionally be joined with R6, such that together with the N on which R6 resides and the carbon on which said member resides there is formed a saturated or unsaturated monocyclic heterocycle of 5, 6 or 7 atoms, said monocycle optionally containing up to three hetero atoms selected from N, O or S, elected from the group consisting of
(a) hydrogen,
(b) linear and branched C 1 - 12alkyl, optionally mono or di¬ substituted, the substituents being independently selected from (1) hydroxy,
(2) carboxy,
(3) -NR7R8,
(4) -OR7,
(5) -C(0)OR7, (6) -S(0)kR7.
(7) halo selected from F, Cl, Br and I,
(8) -CF3,
(9) phenyl, optionally mono or di-substituted with hydroxy, halo, C 1 -4alkyl, or C l -4alkoxy ,
(c) -C(O)NRl0Rl 1, where Rio and Rl l are each independently hydrogen, phenyl, cyclohexyl, -S(0)2NR7 g or optionally substituted Cl-6alkyl, wherein the substituent is selected from (1) -NR12R13, wherein R12 and R13 are each independently H, Cl-6alkyl, phenyl or benzyl,
(2) -OR12,
(3) -C(0)ORi2,
(4) -S(0)kRl2, where k is 0, 1 or 2, (5) halo selected from F, Cl, Br and I,
(6) optionally substituted aryl wherein aryl and aryl substituents are as defined above,
(7) optionally substituted heteroaryl wherein heteroaryl and heteroaryl substituents are as defined above,
(8) optionally substituted Cs-iocycloalkyl wherein cycloalkyi and cycloalkyi substituents are as defined above,
(9) hetero C5-lθcycloalkyl, wherein the heteroC5-iocycloalkyl optionally contains 1 or
2 heteroatoms selected from S, O and N,
(d) -C(0)Rn,
(e) -C(0)0RH,
(f) aryl, selected from phenyl or naphthyl, (g) cyclohexyl.
Within this embodiment there is a genus of compounds wherein Rl, R2, R3 and R4 are each independently selected from the group consisting of
(a) hydrogen,
(b) hydroxy, (c) amino,
(d) cyano,
(e) fluoro, chloro, bromo, and iodo,
(f) trifluoromethyl,
(g) Ci-6alkyl, (h) Ci-6alkoxy,
(i) Cl-6alkylthio,
(j) C l _6alkylcarbonyl,
(k) mono- and di-Cl-6alkylamino,
(1) aryl, where aryl is phenyl and naphthyl, (m) aryloxy, where aryl is phenyl and naphthyl,
(n) cycloalkyl,wherein the cycloalkyi is a 5-, 6-, or 7-membered monocyclic ring which optionally contains 1 or 2 heteroatoms selected from S, O, and N, and
(o) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) pyridyl,
(2) furanyl,
(3) thienyl,
(4) pyrazinyl, (5) pyrimidyl,
(6) thiazolyl, and
(7) triazolyl, each of (g) to (o) being optionally mono- or di- substituted, the substituents being independently selected from (1) hydroxy,
(2) Cl-4alkyl,
(3) Ci-3alkoxy,
(4) amino,
(5) mono- and di-C 1 -6alkylamino, (6) carboxyl,
(7) Cl-3alkylthio,
(8) Cl-3alkyl-S(0)k- , where k is 1 or 2,
(9) Cl-4alkoxycarbonyl, (10) halo selected from fluoro, chloro, bromo, and iodo,
(11 ) oχo; n
(12) amidino,
elected from the group consisting of
(a) hydrogen,
(b) Cl-6alkylcarbonyl,
(c) arylcarbonyi, wherein the aryl group is phenyl,
(d) arylcarbonyl-aminocarbonyl, wherein the aryl group is phenyl and naphthyl,
(e) R6R7N-S02-NH-C(=0)-, wherein R6 and R7 are independendy selected from the group consisting of
(1) hydrogen,
(2) Cl-6alkyl, (3) aryl, wherein the aryl group is selected from phenyl, and (4) R6 and R7 may be joined together to form a 5-, 6- or 7-membered ring containing 0, 1 or 2 heteroatoms, the heteroatoms being elected from the group of oxygen, sulfur and nitrogen,
each of (b) to (e) being mono- or di- substituted, the substituents being independently selected from (1) hydroxy, (2) Cl-3alkoxy,
(3) amino,
(4) mono- and di-C 1 -6alky lamino,
(5) carboxyl,
(6) Cl-3alkylthio, (7) Cl-3alkyl-S(0)k- , where k is 1 or 2,
(8) Ci-4alkoxycarbonyl,
(9) halo selected from fluoro, chloro, bromo, and iodo, (10) oxo, and
(11) amidino.
Within this genus there is a class of compounds wherein Rl, R2, R3 and R4 are each independently selected from the group consisting of
(a) hydrogen,
(b) hydroxy,
(c) amino,
(d) cyano, (e) fluoro, chloro or bromo,
(f) trifluoromethyl,
(g) Ci-4alkyl, (h) Cl-4alkoxy,
(i) Cl-4alkylthio, and (j) mono- and di-Cl-4alkylamino,
R5 is selected from the group consisting of
(a) hydrogen
(b) R6R7N-S02-NH-C(=0)-, optionally mono or di-substituted, wherein R6 and R7 are independently selected from the group consisting of
(1) hydrogen,
(2) Cl-4alkyl, and
(3) aryl, wherein the aryl group is phenyl, and said substituents are independently selected from
(1) hydroxy,
(2) Ci-3alkoxy,
(3) amino,
(4) mono- and di-C 1 -6alkylamino, (5) carboxyl, (6) Cl-3alkylthio, and
(7) halo selected from fluoro, chloro, and bromo.
Within this class there is a sub-class of compounds wherein wherein
R is hydrogen or methyl; R4 is hydrogen or methyl; Rl and R3 are each independently selected from (a) hydrogen,
(b) methyl, ethyl, propyl or butyl,
(c) chloro,
(d) -CN, and
(e) -CF3; and R5 is hydrogen.
Illustrating the invention are:
(a) hexahydro-5-imino-( 1 )- 1 ,4-diazepine dihydrochloride,
(b) hexahydro-5-imino-l,4-thiazepine hydrochloride (c) hexahydro-5-imino-l,4-oxazepine hydrochloride,
(d) hexahydro-5-imino-3-propyl- 1 ,4-thiazepine hydrochloride,
(e) hexahydro-5-imino-6-propyl- 1 ,4-thiazepine hydrochloride, (f) hexahydro-5-imino-7-methyl-l,4-thiazepine hydrochloride, (g) hexahydro-5-imino-2-methyl- 1 ,4-thiazepine hydrochloride, (h) hexahydro-5-imino-6-(3-methyl-2-n-butenyl)- 1 ,4- thiazepine hydrochloride,
(i) hexahydro-5-imino-3-(3-methyl-2-n-butenyl)- 1 ,4- thiazepine hydrochloride, (j) hexahydro-5-imino-6-(2-methyl-propyl)- 1 ,4- thiazepine hydrochloride, (k) hexahydro-5-imino-3-(2-methyl-propyl)- 1 ,4- thiazepine hydrochloride, (1) hexahydro-5-imino-6-methyl- 1 ,4-thiazepine hydrochloride, (m) hexahydro-5-imino-3-methyl-l,4-thiazepine hydrochloride, (n) hexabydro-5-imino- -ethy1-l ,4-tbiazepine hydrochloride, (o) hexahydro-5-imino-3-butyl- 1 ,4-thiazepine hydrochloride,
(p) hexahydro-5-imino-3-(2-methyl-3-propenyl)- 1 ,4- thiazepine hydrochloride, (q) (±)-frøns-decahydro-4-imino-benzo[b]- 1 ,4-thiazepine acetic acid salt., (r) hexahydro-5-imino-3(S)-propyl-l,4-thiazepine acetic acid salt, (s) hexahydro-5-imino-3(R)-propyl-l,4-thiazepine acetic acid salt, (t) hexahydro-5-imino- 1 -methyl-( 1 H)- 1 ,4-diazepine hydrochloride, and pharmaceutically acceptable salts thereof.
For purposes of this specification alkyl is defined to include linear, branched, and cyclic structures, with Cl-6alkyl including methyl, ethyl, propyl, 2-propyl, s- and t-butyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Similarly, Ci-6alkoxy is intended to include alkoxy groups of from 1 to 6 carbon atoms of a straight, branched, or cyclic configuration. Examples of lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like. Likewise, Cl-6 alkylthio is intended to include alkylthio groups of from 1 to 6 carbon atoms of a straight, branched or cyclic configuration. Examples of lower alkylthio groups include methylthio, propylthio, isopropylthio, cycloheptylthio, etc. By way of illustration, the propylthio group signifies -SCH2CH2CH3. Heteroaryl includes furan, benzofuran, thiophene, pyπole, indole, isoxazole, isothiazole, pyrazole, oxazole, benzoxazole, thiazole, imidazole, benzimidazole, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,3- triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,3,4-triazole, 1,2,5- oxadiazole, 1,2,5-thiadiazole, pyridine, quinoline, isoquinoline, pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,4,5- tetrazine, tetrazole. and the like.
As appreciated by those of skill in the art, the depiction
Figure imgf000019_0001
is intented to indicate that substituents Rl, R2, R3 and R4 may each independently reside at any available position on the ring structure of figure I.
Illustrative ofthe situation wherein two members of Rl, R2, R3 and R4 are joined together to form a ring or one member is joined together with R6 to form a ring include the following:
Figure imgf000019_0002
Figure imgf000020_0001
As outlined in the summary of the invention, the compounds of the instant invention are useful in the treatment of a number of NOS implicated diseases. The implication of these diseases is well documented in the literature. For example, with regard to psoriasis, see Ruzicka et. al, J. Invest. Derm., 103: 397 (1994) or Kolb-Bachofen et. al, Lancet, 344: 139 (1994) or Bull, et al., J. Invest. Derm., 103:435(1994); with regard to uveitis, see Mandia et. al, Invest Opthalmol., 35: 3673-89 (1994); with regard to type 1 diabetes, see Eisieik & Leijersfam, Diabetes & Metabolism, 20: 116-22 (1994) or Kroncke et. al, BBRC, 175: 752-8 (1991) or Welsh et. al, Endocrinol, 129: 3167-73 (1991); with regard to septic shock, see Petros et. al, Lancet,335: 1557-8 (1991),Thiemermann & Vane, Eur. J. Pharmacol., 211: 172-82 (1992), or Evans et. al, Infec. Imm., 60: 4133-9 (1992), or Schilling et. al, Intensive Care Med., 19: 227-231 (1993); with regards to pain, see Moore et. al, Brit. J. Pharmacol., 702: 198-202 (1991), or Moore et. al, Brit. J. Pharmacol., 108: 296-97 (1992) or Meller et. al, Europ. J. Pharmacol, 214: 93-6 (1992) or Lee et. al, NeuroReport, 3: 841-4 (1992); with regard to migraine, see Olesen et. al, ΗPS, 75: 149- 153 (1994); with regard to rheumatoid arthritis, see Kaurs & Halliwell, FEBS Letters, 350: 9-12 (1994); with regard to osteoarthritis, see Stadler et. al, J. Immunol, 147: 3915-20 (1991); with regard to inflammatory bowel disease, see Miller et. al, Lancet, 34: 465-66 (1993) or Miller et. al, J. Pharmacol. Exp. Ther., 264: 11-16 (1993); with regard to asthma, see Hamid et. al, Lancet, 342: 1510-13 (1993) or Kharitonov, et. al, Lancet, 343: 133-5 (1994); with regard to Immune complex diseases, see Mulligan et. al, Br. J. Pharmacol., 707: 1159-62 (1992); with regard to multiple sclerosis, see Koprowski et. al, PNAS, 90: 3024-7 (1993); with regard to ischemic brain edema, see Nagafuji et. al, Neurosci., 147: 159- 62 (1992) or Buisson et. al, Br. J. Pharmacol., 706: 766-67 (1992) or Trifiletti et. al, Europ. J. Pharmacol, 218: 197-8 (1992); with regard to toxic shock syndrome, see Zembowicz & Vane, PNAS, 89: 2051-55 (1992); with regard to heart failure, see Winlaw et. al, Lancet, 344: 373- 4 (1 94); with regard to ulcerative colitis, see Boughton-Smith et. al, Lancet 342: 338-40 (1993); and with regard to atherosclerosis, see White et. al, PNAS, 91: 1044-8 (1994); with regard to glomerulonephritis, see Miihl et. al, Br. J. Pharmcol, 112: 1-8 (1994); with regard to paget's disease and osteoporosis, see Lowick et. al, J. Clin. Invest, 93: 1465-72 (1994) or Evans et al, Clin. Orthopaedics & Related Res., 312: 275-294 (1995); with regard to inflammatory sequelae of viral infections, see Koprowski et. al, PNAS, 90: 3024-7 (1993); with regard to retinitis, see Goureau et. al, BBRC, 186: 854-9 (1992); with regard to oxidant induced lung injury, see Berisha et. al, PNAS, 91, 744-9 (1994); with regard to eczema, see Ruzica, et al., J. Invest. Derm., 103, 395(1994); with regard to acute allograft rejection, see Devlin, J. et al., Transplantation, 58, 592- 595 (1994); with regard to infection caused by invasive microorganisms which produce NO, see Chen, Y. and Rosazza, J.P.N., Biochem. Biophys. Res. Comm., 203: 1251-1258(1994); and with regard to tumor growth, see Jenkins et al, PNAS, 92, 4392-4396 (1995).
The pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt, thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic bases and organic bases. Salts derived from inorganic acids include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N_- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine. lysine, methylglucarπine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
It will be understood that in the discussion of methods of treatment which follows, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
The pharmaceutical compositions containing the active ingredient of the instant invention may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Patent 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethyl-cellulose, methylcellulose, hydroxy- propylmethycellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene- oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p- hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy beans, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Compounds of formula I may also be administered in the form of a suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula I are employed. (For purposes of this application, topical application shall include mouth washes and gargles.)
Dosage levels of the order of from about 0.01 mg to about 140 mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day. For example, inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day, preferably 2.5 mg to 1 g per patient per day.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
Assay Protocol for NOS activity
NOS activity is measured as the formation of L-[2,3,4,5- 3H]Citrulline from L-r2,3A5-3H] Arginine. The incubation buffer (100 uL) contained; 100 mM TES, pH 7.5, 5 uM FAD, 5 uM FMN, 10 uM BH4, 0.5 mM NADPH, 0.5 mM DTT, 0.5 mg/mL BSA, 2 mM CaC12, 10 ug/mL cahnodulin (bovine), 1 uM L-Arg, 0.2 uCi L-[2,3,4,5-3H]Arg, and the inhibitor in aqueous DMSO (max. 5 %). The reaction is initiated by addition of enzyme. Incubations are performed at room temperature for 30 minutes and stopped by the addition of an equal volume of quenching buffer consisting of 200 mM sodium citrate, pH 2.2, 0.02% sodium azide. Reaction products are separated by passing through a cation exchange resin and quantitated as cpm by scintillation counting. Percent inhibition is calculated relative to enzyme incubated without inhibitor according to: % inhibition = 100 x (cpm L-[2,3,4,5-3H]Cit with inhibitor / cpm L- [2,3,4,5-3H]Cit without inhibitor).
Illustrative of the utility of the compounds of Formula I is the ability of such compounds to inhibit NO synthase as shown in Table 1 and as measured by the assay described above:
Table 1. Inhibition of Nitric Oxide Synthase Isozymes
Example iNOS ecNOS ncNOS
Number (ICso, uM) (ICso, uM) (ICso, uM)
1 >50 >50 >50
2 <10 >10 <10
3 <50 <50 <10
4 <1 <50 <10
5 >50 >50 >50
6 <10 <10 <1
7 <10 <10 <1
8 >50 >50 >50
9 <1 >50 <50
10 <50 >50 >50
11 <1 >50 <10
12 >50 <50 <10
13 <1 <10 <10
14 <1 <50 <10
15 <1 >50 <10
16 <1 <50 <10
17 >50 >50 >50
18 <1 <10 <1
19 <10 <50 <10
20 <50 >50 >50
Methods of Synthesis
The compounds of the present invention can be prepared according to the following methods.
Figure imgf000028_0001
Reaction conditions: a) H240 psi, Pd(OH)_>/C, EtOH, HOAc, 4 hr; b) (t-C4H9θ2C)2O, NaCl, NaOH, CHCI3, reflux, 4hr; c) (CH3)3OBF4j CH2 C|2. T, overnight; d) NH4CI, EtOH, reflux, 4 hr; e) HCl, ethyl acetate,' RT, overnight.
As shown in Scheme 1, hexahydro-l-(phenylmethyl)-(5/7)- l,4-diazepin-5-one A (prepared as described by T. Irikura, CAS 84:31153r, 83: 179149u) is reacted under hydrogen atmosphere at 40 psi in the presence of palladium hydroxide catalyst in ethanol and acetic acid to give hexahydro-5//-l,4-diazepin-5-one B as the acetic acid salt. Reaction with di-t-butyl dicarbonate in the presence of sodium chloride and sodium hydroxide gives l-(f^rf-butyloxycarbonyl)-hexahydro-(5/7)- l,4-diazepin-5-one C. The imino ether D is formed from Q by reaction with Meerwein's salt (trimethyloxonium fluoroborate). The amidine E is obtained by reaction of D with ammonium chloride in refluxing ethanol. The amine protecting group in E is removed by reaction with hydrogen chloride in ethyl acetate to give the desired amidine F as the dihydrochloride salt.
Scheme 2
Figure imgf000029_0001
Reaction conditions: a) NH3, HgCI2, THF
An alternative preparation of the amidine functionality is shown in Scheme 2. A thioamide A is reacted directly with ammonia in the presence of mercuric chloride to give the 5-imino-l,4-diazepine B.
Scheme 3
Figure imgf000030_0001
Reaction conditions: a) NH2OH - HCl, NaOH, EtOH; b) n-BuLi, TsCl; Et3N, aq. dioxane; c) Lawesson's reagent, tol, 90°C; d) Me3OBF4, iPr2NEt, CH2CI2; NH4CI, EtOH, reflux
1,4-Oxa- and thiazepine analogs are prepared by methodology outiine in Scheme 3. A ketone derivative A is converted to its corresponding oxime B by reaction with hydroxylamine in ethanol. Ring expansion of B via a Beckmann rearrangement of the O-tosyl- oxime formed by reaction of B with with butyl lithium and p-toluenesulfonyl chloride gives hexahydro-l,4-heteroazepin-5-one £,. When X = S, the amide in Q is converted to the thioamide D by reaction with Lawesson's reagent. Reaction of D with Meerwein's salt to form the imino-thioether followed by reaction with ammonium chloride gives the hexahydro-5-imino-l,4-heteroazepine E. Alternatively, when X = O in Q, reaction with Meerwein's salt followed by ammonium chloride gives E directly. Scheme 4
Figure imgf000031_0001
React on con tons: a) NaOR, Et20; b) Mnθ2, CHCI3, reflux; c) CU2I2, (R2)Li, CH3SCH3; d) NaH, (R3)X, DMF; e) when R = allyl, (Ph3P)4Pd(0), moφholine, THF; f) H2NOH - HCl, NaOH, EtOH; g) n-BuLi, TsCl, EtjO; Et3N, aq. dioxane; h) Lawesson's reagent; separate positional isomers; i) Me3OBF , iPrcNEt, CH2CI2; NH4CI, EtOH.
More highly substituted hexahydro-5-imino-l,4- heteroazepines may be prepared according to methodology outlined in Scheme 4. Diester A is cyclized via a Dieckmann condensation to keto- ester B. Treatment of B with a strong base such as sodium hydride followed by addition of an alkylating agent such as n-propyl iodide will give E (where R2 is hydrogen and R3 is n-propyl). Alternatively, keto- ester B may be oxidized by manganese dioxide to form the α,β- unsaturated keto-ester C. A substituent R2 is introduced via a Michael reaction with an organo-cuprate reagent to form D. Alkylation of D with (R3)X in the presence of a strong base will form E R2 and R3 are not hydrogen). Deesterification-decarboxylation of E will form F. By procedures outlined in Scheme 3, F is converted to amides H and I via Beckmann rearrangement of oxime _. Since the Beckmann rearrangement can occur with migration to either side of the oxime, the two amides H and I may be formed. These amides H and I may be separated chromatographically at this point or, alternatively, may be subsequently converted to their respective thioamides by reaction with Lawesson's reagent and then separated. Reaction of the thioamides from H and I with Meerwein's salt followed by treatment with ammonium chloride will give substituted hexahydro-5-imino-l,4-heteroazepines J and K. When X is nitrogen, a appropriate amine protecting group (eg., r/-butyloxycarbonyl) may be employed in the reaction sequence.
Scheme 5
Figure imgf000033_0001
Figure imgf000033_0002
Reaction conditions: a) (t-C4H9O)2CO, NaHCO3, CH2CI2; b) Ph3P, (i-C3H7θ2C)2N2, THF; c) HS(CH2)2CO2H, CsCO3, DMF; d) HCl, EtOAc; e) 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide,
1 -hydroxy-7-azabenzotriazole, N-methylmoφholine; f) Lawesson's reagent, tol, 90°C; g) Me3OBF4, (i-C3H7)2NC2H5, CH CI ; h) NH4CI, EtOH, reflux
More highly substituted hexahydro-5-imino- 1 ,4- heteroazepines may also be prepared according to methodology outlined in Scheme 5. Briefly, the amine functionality in aminoalcohol A is protected to give B. Mitsunobu conditions will cyclize B to form aziridine Q. The aziridine ring in Q is opened with β-mercaptopropionic acid followed by treatment with hydrochloric acid in ethyl acetate to yield amino acid D. Reaction of D under standard peptide bond forming reactions gives lactam E. Reaction with Lawesson's reagent gives the thiolactam F which is converted to 5-imino-l,4-thiazepine Q_by previously described conditions.
The invention will now be illustrated by the following non- lirπiHng exam le*: in which, unl s stated otherwise*
all operations were carried out at room or ambient temperature, that is, at a temperature in the range 18-25°C; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 pascals: 4.5-30 mm. Hg) with a bath temperature of up to 60°C; the course of reactions was followed by thin layer chromatography (TLC) and reaction times are given for illustration only; melting points are uncorrected and 'd' indicates decomposition; the melting points given are those obtained for the materials prepared as described; polymoφhism may result in isolation of materials with different melting points in some preparations; the structure and purity of all final products were assured by at least one of the following techniques: TLC, mass spectrometry, nuclear magnetic resonance (NMR) spectrometry or microanalytical data; yields are given for illustration only; when given, NMR data is in the form of delta (δ) values for major diagnostic protons, given in parts per million (ppm) relative to tetramethy lsilane (TMS) as intemal standard, determined at 400 MHz or 500 MHz using the indicated solvent; conventional abbreviations used for signal shape are: s. singlet; d. doublet; t. triplet; m. multiplet; br. broad; etc.: in addition "Ar" signifies an aromatic signal; chemical symbols have their usual meanings; the following abbreviations have also been used v (volume), w (weight), b.p. (boiling point), m.p. (melting point), L (liter(s)), mL (milliliters), g (gram(s)), mg (milligrams(s)), mol (moles), mmol (millimoles), eq (equivalent(s)).
EXAMPLE 1
Figure imgf000035_0001
Hexahvdro-5-imino-( 1 H)- 1.4-diazepine dihydrochloride.
Step A: Hexahvdro-(5/T,- 1.4-diazepine-5-one acetic acid salt.
l-Benzylhexahydro-(5 )-l,4-diazepine-5-one (1.5 g, 7.34 mmol) was dissolved in 12 mL of ethanol and 6 mL of acetic acid. After addition of 150 mg of 20% palladium hydroxide on carbon, the mixture was shaken under 40 psi of hydrogen for 4 h. The resulting mixture was centrifuged and the supematant was filtered through a 0.45 micron membrane filter. The catalyst was washed with ethanol (3 x 10 mL), and the combined filtrate was concentrated in vacuo to give a yellow oil which began to crystallize. Swirling with 2 mL of methanol and 1 mL of ethyl acetate facilitated the crystallization, and evaporation of the solvent in vacuo gave 1.23 g (96%) of hexahydro-(5//)-l,4-diazepin-5-one acetic acid salt as light yellow crystals.
iH NMR (400 MHz, CD3OD): δ 3.44-3.40 (m, 2H), 3.19-3.15 (m, 2H), 3.15-3.11 (m, 2H), 2.74-2.70 ( m, 2H), 1.94 (s, 3H). Mass spectrum: m/z = 115 (M+l, 100%).
Step B : 1 -(ferf-ButoxycarbonyDhexahvdro-fS/fl- 1.4-diazepin-5-one.
A mixture of hexahydro-(5//)-l,4-diazepin-5-one acetic acid salt (200 mg, 1.15 mmol), di-tert-butyldicarbonate (277 mg, 1.27 mmol) and sodium chloride (460 mg, 7.93 mmol) in 2.0 mL of chloroform was stirred and 2.5 N aqueous sodium hydroxide (460 uL, 1.15 mmol) was added. The mixture was heated to reflux for 4 h, and then extracted with 3x10 mL of ethyl acetate. The combined ethyl acetate extracts were dried over anhydrous sodium sulfate, decanted and evaporated in vacuo to give 219 mg (89%) of l-(terf-butoxycarbonyl)hexahydro-(5 )-l»4-diazepin- 5-one as a white solid.
iH NMR (400 MHz, CD3OD): δ 3.60-3.53 (m, 4H), 3.28-3.25 (m, 2H),
2.61-2.56 (m, 2H), 1.47 (s, 9H).
Mass spectrum: m/z = 21 (M+1. 100%)
Anal, calcd for C10HI8N2O3: C, 56.32; H, 8.04; N, 13.14. Found: C,
55.92; H, 8.48; N, 13.00.
Step C: l-(?grr-Butoxycarbonyl -2.3.6.7-tetrahvdro-5-methoxy-f IH)- 1 ,4-diazepine.
Trimethyloxonium tetrafluoroborate (Meerwein's salt) (141 mg, 0.94 mmol) was added in one portion to a solution of l-(tert- butoxycarbonyl)hexahydro-(5 )-l,4-diazepin-5-one (200 mg, 0.94 mmol) in 2.0 mL of anhydrous methylene chloride. The mixture was stirred overnight at room temperature. The reaction mixture was partitioned between 10 mL of saturated aqueous sodium bicarbonate and 20 mL of ethyl acetate. The organic layer was separated and the aqueous layer was extracted with 3 x 10 mL of ethyl acetate. The combined ethyl acetate layers were washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the organic solution was concentrated in vacuo to give 180 mg (85%) of 1 -(terf-butoxycarbonyl)-2,3,6,7-tetrahydro-5-methoxy- (l )-l,4-diazepine as a yellow liquid.
Η NMR(400 MHz, CD3OD): δ 3.58 (s, 3H), 3.53-3.45 (m, 6H), 2.63- 2.59 (m, 2H), 1.46 (s, 9H). Mass spectrum: m/z = 129.
Step D: 1 -(fe -Butoxycarbonyl hexahvdro-5-imino-( 1 H)- 1.4- diazepine hydrochloride . A mixture of l-(tert-butoxycarbonyl)-2,3,6,7-tetrahydro-5-methoxy-(l /)- 1,4-diazepine (170 mg, 0.75 mmol) and ammonium chloride (40.1 mg, 0.75 mmol) in 2.0 mL of anhydrous ethanol was refluxed for 3 h. The solvent was then removed in vacuo and residue was triturated with 3 x 10 mL of ether to give 174 mg of l-(terf-butoxycarbonyl)-hexahydro-5- imino-(li )-l,4-diazepine hydrochloride as a light yellow solid.
Η NMR (400 MHz,CD3θD): δ 3.71-3.65 (m, 2H), 3.63-3.57 (m, 2H), 3.55-3.50 (m, 2H), 2.90-2.86 (m, 2H), 1.47 (s, 9H). Mass spectrum: rn z = 214 (M+l, 100%).
Step E: Hexahvdro-5-Imino-( IH)- 1 ,4-diazepine dihydrochloride.
Hydrogen chloride gas (2.0 g, 55 mmol) was bubbled into 15 mL of ethyl acetate at 0 C over 3 min. l-(terϊ-Butoxycarbonyl)-5-iminohexahydro-
(l /)-l,4-diazepine hydrochloride (85 mg, 0.34 mmol ) was added and mixture was stirred at room ovemight. Removal of solvent and hydrogen chloride in vacuo gave 60 mg (95%) of hexahydro-5-imino-(l /)"1.4- diazepine dihydrochloride as a yellow solid.
iH NMR (400 MHz, CD3OD): δ 3.84-3.80 (m, 2H), 3.55-3.50 (m, 2H),
3.43-3.39 (m, 2H), 3.21-3.16 (m, 2H).
Mass spectrum: m z = 114 (M - 2HC1 + 1, 100%).
Anal, calcd for C5H13N3CI2: C, 32.27; H, 7.04; N, 22.58; Cl, 38.10. Found: C, 32.09; H, 7.04; N, 21.67; Cl, 38.05.
Figure imgf000037_0001
l Hexahydro-5-imino- 1.4-thiazepine hydrochloride
Step A: 4-Oximino-tetrahydrothiopyran
To a stirring solution of solution of tetrahydrothiopyran-4-one (4.9 g, 42.1 mmol) and hydroxylamine hydrochloride (5.9 g. 84 mmol) in 35 mL of ethanol at 0 °C was added a solution of sodium hydroxide (3.38 g, 84.5 mmol) dissolved in 13 mL water. The reaction mixture was warmed to room temperature and stirred for an additional 2 h. The ethanol was removed in vacuo and the aqueous solution extracted with ether (2 X 250 mL). The etheral layer was washed with with water, saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated to give crude oxime which was recrystallized from hexane/ether to give 4. 66 g of 4-oximino-tetrahydrothiopyran.
iH NMR (500 MHz, CDC13): δ 9.43 (brs, IH), 2.86 (m, 2H), 2.78(m, 2H), 2.73 (m, 2H), 2.56 (m, 2H).
13C NMR (125 MHz, CDCI3): δ 158.24, 33.94, 29.75, 28.38, 26.78.
Step B : Tetrahvdro-(2/ifi- 1 ,4-thiazepin-5-one
To a solution of 4-oximino-tetrahydrothiopyran (1.0 g, 7.6 mmol) in 20 mL of dry ether under nitrogen atmosphere at 0 °C was added n-butyllithium (5.0 mL of a 1.6 M solution in hexane, 8.0 mmol). The resulting white suspension was stirred at 0 °C for one hour at which point a solution of p-toluenesulfonyl chloride (1.52 g, 8.0 mmol) in 10 mL ether was added and the reaction mixture stirred for 4 h at 5 °C. The solvent was removed in vacuo and then the residue was treated with 20 mL of 70% dioxane containing five drops of triethylamine and stirred for 24 h at room temperature. The solvent was removed in vacuo and the residue was extracted with methylene chloride. The methylene chloride layer was washed with water, saturated sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and the product purified by flash column chromatography on silica gel eluted with hexane/ethyl acetate (7 :3) to give 0.13 g of hexahydro-(l )-l,4- thiazepin-5-one.
Η NMR (500 MHz, CDCI3): δ 6.92 (brs, IH), 3.61 (m, 2H), 2.92(m, 2H), 2.74 (m, 2H), 2.70 (m, 2H). C NMR (125 MHZ. CDC13 ): δ 177.76, 45.88, 40.95, 31 54: 24 61.
Step C: Tetrahydro-(2 D-1.4-thiazepin-5-thione
To a solution of tetrahydro-(2 /)-l,4-thiazepin-5-one (0.335 g, 2 mmol) in 5 mL of dry toluene was added Lawesson's reagent [2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulfide] (0.971 g , 2.4 mmol) and the mixture was stirred at 90°C for 30 mins. Evaporation of the solvent in vacuo followed by purification by flash column chromatography on silica gel eluted with methylene chloride : ethyl acetate (19 : 1) gave 0. 365 g of tetrahydro-(2 )-l,4-thiazepin-5- thione.
iH NMR (500 MHz, CDCI3): δ 9.19 (brs, IH), 3.80 (m, 2H), 3.44 (m, 2H), 2.78 (m, 2H), 2.71 (m, 2H). 13C NMR (125 MHZ, CDCI3 ): δ 208.90, 50.39, 49.02, 29.54, 25.86.
Step D: Hexahydro-5-imino- 1 ,4-thiazepine hydrochloride
To a solution of tetrahydro-(2 )-l»4-thiazepin-5-thione (90 mg, 0.5 mmol) in 2 mL of dry methylene chloride at room temperature was added trimethyloxonium tetrafluoroborate (Meerwein's salt) (88 mg, 0.6 mmol) followed by diisopropylethylamine (77 mg, 0.6 mmol). The resulting mixture was stirred at room temperatere for 2 h. The methylene chloride layer was washed with water, saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give the crude imino-ether which was subsequently treated with ammonium chloride (0. 017 g) in 3 mL of ethanol and heated at 80 °C for 15 h. Evaporation of ethanol followed by trituration of the oil with ethyl acetate and ether gave 53 mg of hexahydro-5-imino-l,4-thiazepine hydrochloride as a white solid.
Η NMR (500 MHz, D2θ): δ 3.81 ( m, 2H), 3.11 (m, 2H), 2.84 (m, 2H),
2.76 (m, 2H).
13 NMR (125 MHz, D2θ): δ 46.88. 35.52, 28.84, 23.74.
Mass spectrum: m/z = 131 (M+l).
EXAMPLE 3
Figure imgf000040_0001
Hexahvdro-5-imino- 1 ,4-oxazepine hydrochloride.
Step A: 4-Qximino-tetrahydropyran
Employing the procedure described in Example 2, step A, tetrahydropyran-4-one was converted to 4-oximino-tetrahydropyran.
W NMR (500 MHz, CDCI3): δ 3.82 (m, 2H), 3.77 (m, 2H), 2.68 (m, 2H), 2.39 (m, 2H).
Step B : Tetrahvdro-(2HV 1.4-oxazepin-5-one
Employing the procedure in Example 2, step B, 4-oximino- tetrahydropyran was converted to tetrahydro-(2//)-l,4-oxazepin-5-one. Η NMR (500 MHz, CDCI3): δ 7.07 (brs, IH), 3.79 (m, 2H), 3.75(m,
2H), 3.34 (m, 2H), 2.69 (m, 2H).
13C NMR (125 MHZ, CDCI3): δ 177.94, 71.61, 65.52, 44.74, 41.01.
Step C: Hexahydro-5-imino-1.4-oxazepine. hydrochloride
Employing the procedure in Example 2, step D, tetrahydro-(2H) 1, oxazepin-5-one was reacted with Meerwien's salt and ammonium chloride to form hexahydro-5-imino-l//-l,4-oxazepine, hydrochloride.
iH NMR (500 MHz, D2O): δ 3.89 ( m, 2H), 3.80 (m, 2H), 3.60 (m, 2H),
2.96 (m, 2H).
13C NMR (125 MHz, D20): δ 69.54, 64.92, 46.12, 35.42. MS: m/z =
115.1 (M+).
Figure imgf000041_0001
Hexahvdro-5-imino-3-propyl- 1.4-thiazepine hydrochloride.
Step A: Tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester.
A mixmre of 3,3'-thiodipropionic acid (17.82 g, 10 mmol), allyl alcohol (20.4 mL, 30 mmol) and p-toluenesulfonic acid (0.750 g) in 100 mL of toluene was refluxed for 8 h in a Dean-Stark apparatus to azeotropically remove water. The reaction mixmre was quenched with saturated solution of sodium bicarbonate and the toluene layer was separated and washed with samrated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and gave approximately 20 g of crude 3,3'-thiodipropionic acid, diallyl ester. This material was sufficiently pure by NMR and was used in the subsequent reaction.
To a mixture of sodium hydride (60% in oil, 1.6 g, 38.7 mmol) in 10 mL of dry ether at room temperamre was added allyl alcohol (2 25g, 38.7 mmol) in a dropwise manner. The resultant mixture was stirred for 15 min. A solution of 3,3'-thiodipropionic acid, diallyl ester (5.0 g, 19.3 mmol) in 10 mL ether was slowly added and the mixture refluxed for 5 h. The reaction was cooled to room temperature and then quenched with water and the pH adjusted to 4 with IN HCl. The ether layer was separated and the aqueous layer was extracted with ether (2 X 100 mL). The combined etheral layer was washed with sautrated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue purified by flash column chromatography on silica gel eluted with hexane : ether (9 :1) to give 2.57 g of tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester.
Ή NMR (500 MHz, CDCI3): δ 12.48 (s, IH), 5.95 (m, IH), 5.35 (m, 2H), 4.68 (m, 2H), 3.38 (s, 2H), 2.78 (t, J = 6 Hz, 2H), 2.60 (t, J = 6.1 Hz, 2H).
1 C NMR (125 MHZ, CDCI3): δ 172. 80, 131.91, 118.48, 65.32, 30.95, 24.75, 23.58.
Step B: 3-Propyl-tetrahvdrothiopyran-4-one-3-carboxylic acid, allyl ester.
A solution of tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester (1.0 g, 5 mmol) in 1 mL of dimethylformamide was added to a stirred mixture of sodium hydride (60% in oil, 0.22 g, 5.5 mmol) and 1-iodopropane (0.934 g, 5.5 mmol) in 2.5 mL of dimethylformamide at 0 °C. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with water and extracted with ether. The etheral layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and the residue purified by flash column chromatography on silica gel eluted with hexane : ether (19 :1) to give 0.277 g of 3-propyl- tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester.
iH NMR (500 MHz. CDC13): δ 5.93 (m. IH), 5.27-5.38 (m, 2U\ 4.70(m, 2H), 3.33-2.73 (m, 6H), 1.96-1.20(m, 4H), 0.93 (t, J = 6.3 Hz, 3H). 13C NMR (125 MHZ, CDCI3): δ 205.44, 170.83, 131.36, 119.10, 66.05, 63.14, 43.33, 38.66, 36.66, 30.93, 18.01, 14.48.
Step C: 3-Propyl-tetrahydrothiopyran-4-one.
To a stirred solution of 3-propyl-tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester (0.272 g, 1.1 mmol) in 5.0 mL dry tetrahydrofuran at room temperature was successively added morpholine (0.979 g, 1.12 mmol) followed by tetrakis(tιiphenylphosphine)palladium(0) (0.064 g, 0.055 mmol). Stirring was continued until the thin layer chromatography indicated the completion of reaction at which point the reaction mixmre was evaporated and the crude product was purified by flash column chromatography on silica gel eluted eluted with hexane : ether (19 :1) to give 0.163 g of 3-propyl-tetrahydrothiopyran-4-one.
iH NMR (500 MHz, CDCI3): δ 3.02-2.94 (m, 7H), 1.88-1.29 (m, 4H), 0.93 (t, J = 7.1 Hz, 3H).
13C NMR (125 MHZ, CDCI3): δ 210.61, 52.77, 43.82, 35.92, 31.58, 31.06, 20.19, 14.13.
Step D: 4-Oximino-3-propyl-tetrahvdrothiopyran.
Employing the procedure described in Example 2, step A, 3-propyl- tetrahydrothiopyran-4-one was reacted with hydroxylamine hydrochloride to form 4-oximino-3-propyl-tetrahydrothiopyran and was used directly in the subsequent reaction.
Step E: Tetrahvdro-3-propyl-(2 f)- 1 ,4-thiazepin-5-one and tetrahvdro-6-propyl-(2 D- 1.4-thiazepin-5-one.
Employing the procedure described in Example 2, step B, 4-oχimmo-3- propyl-tetrahydrothiopyran was converted to a 3: 1 mixture of tetrahydro- 3-ρropyl-(2/7)-l,4-thiazepin-5-one and tetrahydro-6-propyl-(2//)-l,4- thiazepin-5-one.
Step F: Tetrahvdro-3-propyl-(2/f)- 1 ,4-thiazepin-5-thione.
Employing the procedure described in Example 2, step C, the mixture of tetrahydro-3-propyl-(2 - 1 ,4-thiazepin-5-one and tetrahydro-6-propyl- (2H)-l,4-thiazepin-5-one was reacted with Lawesson's reagent to yield the corresponding thioamides. The 3-n-propyl isomer was isolated and purified by flash column chromatography on silica gel eluted with methylene chloride : hexanes (1:1) to yield tetfahydro-3-propyl-(2i/)-l,4- thiazepin-5-thione as a single compound.
iH NMR (500 MHz, CDC13): δ 8.06 (brs, IH), 3.95 (m, IH), 3.58 (m, IH), 3.30 (m, IH), 2.85 (m, IH), 2.73 (m, 2H), 2.56(m, IH), 1,71-1.42 (m, 4H), 0.97 (t, J = 7.3 Hz, 3H). 13C NMR (125 MHZ, CDCI3): δ 208.08, 61.95, 48.61, 37.70, 34.41, 25.75, 19.24, 13.68.
Step G: Hexahvdro-5-imino-3-propyl- 1 ,4-thiazepine hydrochloride.
Employing the procedure described in Example 2, step D, tetrahydro-3- propyl-(2 )-l,4-thiazepin-5-thione was reacted with Meerwein's salt and ammonium chloride to yield hexahydro-5-imino-3-propyl-l,4-thiazepine, hydrochloride. Η NMR (500 MHz, CD3OD): δ 3.93 ( m, 2H), 3.23-2.62 (m, 6H), 1.68- 1.47(m, 4H), 0.98 (t, 3H, J = 7 Hz).
13C NMR (125 MHZ, CD3OD): δ 170.96, 58.65, 36.54, 34.99, 34.10, 23.36, 18.87, 12.68. MS: m/z = 173.1 (M+l).
Figure imgf000045_0001
Hexahvdro-5-imino-6-propyl- 1.4-thiazepine hydrochloride.
The 6-propyl thioamide isomer isolated from Example 4, Step F was reacted with Meerwein's salt and ammonium chloride according to the procedure described in Example 2, Step D to yield hexahydro-5-imino-6- propyl- 1 ,4-thiazepine, hydrochloride.
Η NMR (500 MHz, CD3OD) 3.75 (m, 2H), 3.18 (m, IH), 2.95 (dd, IH), 2.82 (m, IH), 2.73 (m, 2H), 1.87 (m, 2H), 1.50 (m, IH), 1.39 (m, IH), 0.99 (t, 3H). Mass spectrum: m/z = 173 (M+l)
EXAMPLE 6
Figure imgf000045_0002
HCl Hexahvdro-5-imino-7-methyl- 1 ,4-thiazepine hydrochloride.
Step A: 2.3-Dihydrothiopyran-4-one-3-carboxylic acid, allyl ester.
To a solution of tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester (Exampl 4 step A) (2.3 g, 1 1.5 mmol) in 100 ml , ry chloroform at room temperature was added activated manganese dioxide (10 g, 115 mmol) and the resulting mixture was refluxed for 5 h. The reaction mixmre was filtered and evaporated. The the remaining residue was purified by flash column chromatography on silica gel eluted with hexane : ethyl acetate (7 :3) to give 2,3-dihydrothiopyran-4-one-3-carboxylic acid, allyl ester (0.988 g).
iH NMR (500 MHz, CDCI3): δ 8.49 (s, IH), 5.97 (m, iH), 5.41-5.25 (m, 2H), 4.70 (m, 2H), 3.29 (m, 2H), 2.82 (m, 2H).
1 C NMR (125 MHZ, CDCI3): δ 189.26, 162.68, 156.42, 131.97, 125.20, 118.61, 65.75, 37.83, 27.29.
Step B: 2-Methyl-tetrahvdrothiopyran-4-one-3-carboxylic acid, allyl ester.
To a stirring solution of methyl cuprate in dimethylsulfide (prepared from 1.05 g copper (I) iodide / 4.0 mL dimethylsulfide and 4.0 mL methyllithium/ether at -78 °C) at -78 °C was added a solution of 2,3- dihydrothiopyran-4-one-3-carboxylic acid, allyl ester (0.910 g, 4.6 mmol) in dimethylsulfide (5 mL). The resulting yellow-colored solution was sitrred for 30 min. at the same temperature. The reaction mixmre was quenched with a saturated solution of ammonium chloride and ammonia solution and then warmed to room temperamre for and 1 h. The reaction mixmre was added to ether (100 mL) and the etheral layer washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the product purified by flash column chromatography on silica gel eluted with hexane : ether (4 : 1) to give 2-methyl-tetrahydrothioρyran-4-one-3-carboxylic acid, allyl ester (0.794 g) as a 7:3 mixture of enol : keto tautomers.
Η NMR (500 MHz, CDCI3): δ 12.67 (s, IH), 5.94 (m, IH), 5.35-5.27 (m, 2H), 4.70 (m, 2H), 3.09-2.50(m, 6H), 1.52 (d, J = 6.9 Hz, 3H).
13C NMR (125 MHZ, CDCI3): δ 173. 02, 131.86, 119.50, 66.71, 65.33, 42.66, 30.76, 23.95, 20.02.
Step C: 2-Methyl-tetrahvdrothiopyran-4-one
Employing the procedure described in Example 4, step C, 2-methyl- tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester was decarboxylated to form 2-methyl-tetrahydrothiopyran-4-one.
Step D: Hexahydro-5-imino-7-methyl-1.4-thiazepine hydrochloride.
Employing the procedures described in Example 4, steps D through G,
2-methyl-tetrahydrothiopyran-4-one was converted to hexahydro-5- imino-7-methyl- 1 ,4-thiazepine, hydrochloride
iH NMR (500 MHz, D2O): δ 3.78 (d, IH, J = 15 Hz), 3.62 (dd, IH, J =
15, 7 Hz), 3.05 (m, 2H), 2.87 (m, 2H), 2.10 (m, IH), 1.21 (d, 3H, J = 7
Hz).
13C NMR (125 MHz, CD3OD): δ 51.87, 36.76, 34.73, 22.12, 17.34. Mass spectrum: /z = 145.1 (M+l).
and hexahydro-5-imino-2-methyl-l,4-thiazepine hydrochloride (see Example 7).
EXAMPLE 7
Figure imgf000048_0001
Hexahydro-5-imiiio-2-methyl-i .4-ιiιiazepine hydrochioride.
Hexahydro-5-imino-2-methyl- 1 ,4-thiazepine hydrochloride was prepared according to the procedures described in Example 6.
iH NMR (500 MHz, CD3OD): δ 3.80 (ABq, 2H), 3.30 (m, IH), 3.12 (m, 2H), 2.80 (ABq, 2H), 1.39 (d, 3H, J = 7 Hz). 13C NMR (125 MHz, CD3OD) δ 46.62, 42.25, 32.51, 28.01, 20.26. Mass spectrum: m/z = 145.2 (M+l).
Figure imgf000048_0002
Hexahydro-5-imino-6-(3-methyl-2-n-butenyD- 1.4-thiazepine hydrochloride.
Employing the procedures described in Example 4, but substituting l-bromo-3-methyl-2-n-butene for 1-iodopropane in step B, the 6- positional isomer was separated from the 3-positional isomer (see Example 9) as its respective thioamide by flash column chromatography Subsequently, reaction with Meerwein's salt and ammonium chloride as described in Example 2, step D gave hexahydro-5-imino-6-(3-methyl-2- n-butenyl)- 1 ,4-thiazepine hydrochloride.
Η NMR (500 MHz, CD3OD): δ 5.10 (m, IH), 4.15, (m, IH), 3.79 (m, IH), 1.75 (s, 3H), 1.71 (s, 3H).
Mass spectrum: m/z = 199.2 (M+l).
Figure imgf000049_0001
Hexahvdro-5-imino-3-(3-methyl-2-n-butenylV 1.4-thiazepine hydrochloride.
Employing the procedures described in Example 4, but substituting l-bromo-3-methyl-2-n-butene for 1-iodopropane in step B, the 3- positional isomer was separated from the 6-positional isomer (see Example 8) by flash column chromatography as its respective thioamide. Subsequently, reaction with Meerwein's salt and ammomum chloride as described in Example 2, step D gave hexahydro-5-imino-3-(3-methyl-2- n-butenyl)- 1 ,4-thiazepine hydrochloride.
iH NMR (500 MHz, CD3OD): δ 5.17 (br t, IH), 3.96 (ABq, 2H), 3.22 (m, IH), 3.09 (m, IH), 2.45 (m, 2H), 1.75 (s, 3H), 1.70 (s, 3H).
13C NMR (125 MHZ, CD3OD) δ 118.04, 59.14, 35.09, 33.38, 32.93,
24.63, 23.36, 16.81.
Mass spectrum: m/z = 199.2 (M+l). EXAMPLE 10
Figure imgf000050_0001
Hexahvdro-5-imino-6-(2-methyl-propy - 1 ,4-thiazepine hydrochloride
Employing the procedures described in Example 4, but substituting isobutyl iodide for 1-iodopropane in step B, the 6-positional isomer was separated from the 3-positional isomer (see Example 11) as its respective thioamide by flash column chromatography . Subsequently, reaction with Meerwein's salt and ammonium chloride as described in Example 2, step D gave hexahydro-5-iπύno-6-(2-methyl-propyl)-l,4-thiazepine hydrochloride.
iH NMR (500 MHz, CD3OD): δ 3.77 (t, 2H), 3.25 (m, IH), 2.95 (d of d,
IH), 2.83 (m, IH), 2.73 (m, 2H), 1.87 (m, IH), 1.70 (m, 2H), 1.01 (d,
Figure imgf000050_0002
Mass spectrum: m/z = 187.2
Figure imgf000050_0003
Hexahvdro-5-imino-3-(2-methyl-propylV 1.4-thiazepine hydrochloride Employing the procedures described in Example 4, but substitutmg isobutyl iodide for 1-iodopropane in step B, the 3-positional isomer was separated from the 6-positional isomer (see Example 10) as its respective thioamide by flash column chromatography . Subsequently, reaction with Meerwein's salt and ammonium chloride as described in Example 2, step T gave he,χahydro-5-imino-3-(?,-metby1-prony1)-1 ,4-thi 7epine hydrochloride.
iH NMR (500 MHz, CD3OD): δ 3.95 (m, IH), 3.25 (m, IH), 3.10 (m, IH), 2.87 (m, IH), 2.80 (m, IH), 2.73 (d, IH), 2.65 (d of d, IH), 1.76 (m, IH), 1.69 (m, IH), 1.5 (m, IH), 0.98 (t, 6H) Mass spectrum: m/z = 187.2
EXAMPLE 12
Figure imgf000051_0001
Hexahvdro-5-imino-6-methyl-l ,4-thiazepine hydrochloride.
Employing the procedures described in Example 4, but substituting methyl iodide for 1-iodopropane in step B, the 6-positional isomer was separated from the 3-positional isomer (see Example 13) as its respective thioamide by flash column chromatography . Subsequently, reaction with Meerwein's salt and ammonium chloride as described in Example 2, step D gave hexahydro-5-imino-6-methyl-l,4-thiazepine hydrochloride. iH NMR (500 MHz, CD3OD): δ 3.78 (t, 2H), 3.4 (m, IH), 2.82 (m, 2H), 2.72 (m, 2H), 1.42 (d, 3H) Mass spectrum: m/z = 145.0
EXAMPLE 13
Figure imgf000052_0001
Hexahydro-5-imino-3-methyl- 1.4-thiazepine hydrochloride.
Employing the procedures described in Example 4, but substituting methyl iodide for 1-iodopropane in step B, the 3-positional isomer was separated from the 6-positional isomer (see Example 13) as its respective thioamide by flash column chromatography . Subsequently, reaction with Meerwein's salt and ammonium chloride as described in Example 2, step D gave hexahydro-5-imino-3-methyl-l,4-thiazepine hydrochloride.
iH NMR (500 MHz, CD3OD): δ 4.07 (m, IH), 3.19 (m, IH), 3.04 (m, IH), 2.80 (m, 2H), 2.69 (m, 2H), 11.39 (d, 3H) Mass spectrum: m/z = 145.1
Figure imgf000052_0002
HCl Hexahvdro-5-imino-3-ethyl- 1 ,4-thiazepine hydrochloride.
Employing the procedures described in Example 4, but substituting ethyl iodide for 1-iodopropane in step B, the 3-positional isomer was separated from the 6-positional isomer as its respective thioamide by flash column chromatography . Subsequently, reaction with Meerwein's salt and ammonium chloride as described in Example 2, step D gave hexahydro- 5-imino-3-ethyl- 1 ,4-thiazepine hydrochloride.
iH NMR (500 MHz, CD3OD): δ 3.87 (m, IH), 3.23 (m, IH), 3.06 (m, IH), 2.80 (m, 2H), 2.64 (d of d, 2H), 1.75 (m, 2H), 1.04 (t, 3H). Mass spectrum: m/z = 159.1
EXAMPLE 15
Figure imgf000053_0001
Hexahydro-5-imino-3-butyl- 1 ,4-thiazepine. hydrochloride.
Employing the procedures described in Example 4, but substituting butyl iodide for 1-iodopropane in step B, the 3-positional isomer was separated from the 6-positional isomer as its respective thioamide by flash column chromatography . Subsequently, reaction with Meerwein's salt and ammonium chloride as described in Example 2, step D gave hexahydro- 5-imino-3-butyl- 1 ,4-thiazepine, hydrochloride. iH NMR (500 MHz, CD3OD): δ 3.90 (m, IH), 3.23 (m, IH), 3.02 (m,
IH), 2.80 (m, 2H), 2.63 (d of d, IH), 1.70 (m, 3H), 1.40 (m, 4H), 0.94 (t,
3H).
Mass spectrum: m/z = 187.2
Figure imgf000054_0001
Hexahvdro-5-imino-3-(2-methyl-3-propenyD- 1.4-thiazepine hydrochloride.
Employing the procedures described in Example 4, but substituting 3- bromo-2-methylpropene for 1-iodopropane in step B, the 3-positional isomer was separated from the 6-positional isomer as its respective thioamide by flash column chromatography . Subsequently, reaction with Meerwein's salt and ammonium chloride as described in Example 2, step D gave hexahydro-5-imino-3-(2-methyl-3-propenyl)-l,4-thiazepine hydrochloride.
iH NMR (500 MHz, CD3OD): δ 4.85 (s, IH), 4.75 (s, IH), 4.13 (m, IH), 3.28 (m, IH), 3.12 (m, IH), 2.88 (m, IH), 2.82 (m, IH), 2.78 (d, IH), 2.66 (d of d, IH), 2.45 (m, 2H), 1.78 (s, 3H). Mass spectrum: m/z = 185.1
EXAMPLE 17
Figure imgf000055_0001
(+)-frfln5-Decahvdro-4-imino-benzorbl-1.4-thiazepine acetic acid salt.
Step A: (± ran.?-2-(terf-ButoxycarbonylaminoVcyclohexanol
To a vigoursly stirring solution of trans-2-aminocyclohexanol hydrochloride (5.5 g, 36 mmol) in 100 mL methylene chloride and saturated sodium bicarbonate solution (1:1) at 0 °C was added όi-tert- butylcarbonate (13.09 g, 60 mmol). The resulting heterogeneous mixmre was warmed to the room temperature and stiπed overnight. The methylene chloride layer was washed with brine, dried and evoporated. The solid obtained was triturated with hexane and filtered to give 5.86 g (96%) of (±)-frans-2-N-(tert-butoxycarbonyl)-cyclohexanol.
iH NMR (500 MHz, CDCI3): δ 4.61(brs, IH), 3.27 (m, IH), 2.73 (brs,
IH), 2.02-1.69 (m, 4H), 1,45 (s, 9H), 1.42-1.09(m, 4H).
13c NMR (125 MHz, CDCI3): δ 75.42, 56.62, 34.22, 31.84, 28.43,
27.48, 24.78, 24.11.
Step B: (±V7-(fgrt-ButoxycarponylV7-aza-bicvclo-14.1.01- cycloheptane
To a stirring mixmre of (±)-ι*røn.s-2-N-(terf-butoxycarbonyl)- cyclohexanol ( 4.08 g, 20 mmol) and triphenylphosphine (10.49 g, 40 mmol) in 50 mL of tetrahydrofuran at 0 °C was slowly added diisopropyl azodicarboxylate (8.08 g, 40 mmol). The reaction mixture was warmed to the room temperamre and stirred until the TLC indicated the disappearence of the starting alcohol ( appro. 2- 4 hrs). The tetrahydrofuran was evaparated in vacuo and the cmde product was passed through a silica gel column and eluted with hexane/methylene chloride (1:1) to give 3.18 g (85%) of the desired i±)-l-(tert- butoxycarbonyl)-7-aza-bicyclo-[4.1.0]-cycloheptane as an oil.
JH NMR (500 MHz, CDCI3): δ 2.55 (m, 2H), 1.93-1.75 (m, 4H), 1.45 (s, 9H), 1.44-1.21(m, 4H). 13C NMR (125 MHz. CDCI3): δ 80.62. 36.96. 28.04, 23.80, 19.93.
Step C: (± frQ«.y-2-amino-l-12-(carboxy)ethylthio1-cyclohexane hydrochloride
£±)-7-(fgrf-Butoxycarbonyl)-7-aza-bicyclo-[4.1.0]- cycloheptane (0.5 g, 2.68 mmol) was dissolved in 2 mL dimethylformamide and β-mercaptopropionic acid (0.318 g, 3 mmol). After the addition of cesium carbonate (1.95 g, 6 mmol), the mixture was stirred at 60 °C until the TLC indicated the full consumption of starting material (appro. 4 hrs). The reaction mixture was diluted with water, the pH was adjusted to 4 (with 2.4 M HCl) and finally extracted with methylene chloride. The solvent layer was washed with brine, dried and evaporated to give the crade (±)-frαn5-2-(tert-butocycarbonylamino)-l-[2-(carboxy)ethylthio]- cyclohexane, which was not purified but taken to the next stage. The cmde from the above was dissolved in 10 ml ethyl acetate samrated with hydrogen chloride and stir at room temperature. The white precipitate that resulted was filtered and dried under vacuo yielding 0.636 g of (±)-ι*rαn5-2-amino-l-[2-(carboxy)ethylthio]-cyclohexane.
iH NMR (500 MHz, D2θ): δ 3.20 (m, IH), 2.81-2.65 (m, 3H), 2.24 (m, 2H), 1.79-1.2 (m, 8H).
Step D: (± r. s-Decahydro-4-oxo-benzolbl-1.4-thiazepine
To (±)-j*rans-2-amino- 1 -[2-(carboxy)ethylthio]-cyclohexane hydrochloride (0.240 g, 1 mmol) dissolved in 2 mL of dimethylformaamide at 0 °C was successively added l-ethyl-3-(3- dimethylaminopropyl) carbodiimide (0.356 g, 1.2 mmol), l-hydroxy-7- azabenzotriazole (0.164 g, 1.2 mmol) and then finally N- methylmorpholine (0.252 g, 2.5 mmol). After stirring for an additional 5 mins., the reaction mixture was warmed to room temperature and stirred ovemight at the same temperature. The following day the reaction mixture was diluted with water and extracted with methylene chloride. The solvent layer was washed with brine, dried and evaporated to give the cmde which was purified by silica column and eluted with hexane/ethylacetate (7 : 3 + 5% methanol) to give 0.102 g (55%) of (±)- f rαns-decahydro-4-oxo-benzo[b]- 1 ,4-thiazepane as white solid.
iH NMR (500 MHz, CDC13): δ 5.66 (s, IH), 3.46 (m, IH), 2.98-2.64 (m, 5H), 2.05-1.74 (m, 4H), 1.39-1.21 (m, 4H). 13c NMR (125 MHz, CDCI3): δ 175.94, 58.07, 46.78, 40.50, 33.77, 31.70, 25.32, 24,67, 24.52.
Step E: (±Vfrøn -Decahvdro-4-thioxo-benzolbl-1.4-thiazepine
To a solution of (±)-/ran5-decahydrc>-4-oxo-benzo[b]-l,4-thiazepane (0.100 g, 0.54 mmol) in 5 mL of dry toluene was added Lawesson's reagent [2,4-bis(4-methoxyphenyl)- 1 ,3-dithia-2,4-diphosphetane-2,4- disulfide] (0. 328 g, 0.81 mmol) and the mixture was stiπed at 90 °C for 30 mins. Evaporation of the solvent in vacuo followed by purification by flash column chromatography on sihca gel eluted with methylene chloride : ethyl acetate (19 : 1) gave 0. 083 g (77%) of (±)-trans- decahydro-4-thioxo-benzo[b]- 1 ,4-thiazepine.
iH NMR (500 MHz, CDCI3): δ 7.70 (brs, IH), 3.72 (m, IH), 3.65 (m, IH), 3.23 (m, IH), 2.96 (m, IH), 2.77-2.65 (m, 2H), 2.14-1.25 (m, 8H). 13C NMR (125 MHZ, CDCI3 ): δ 63.26, 48.42, 44.43, 33.73, 31.41, 26.45, 25.06, 24.31.
Step F: (± ran.s-Decahvdro-4-imino-benzorbl- 1.4-thiazepine acetic acid salt. To a solution of (±)- ran5-decahydrσ-4-thioxo-benzo[b]-l,4-thiazepane (25 mg, 0.12 mmol) in 2 mL of dry methylene chloride at room temperature was added trimethyloxonium tetrafluoroborate (Meerwein's salt) (24 mg, 0.16 mmol). The resulting mixture was stirred at room temperatere overnight. The reaction mixmre was quenched with saturated solution of sodium bicarbonate solution and stir for 5 mins The methylene chloride layer was washed with water, samrated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give the cmde imino-ether which was subsequently treated with ammonium chloride (14 mg) in 4 mL of ethanol and heated at 80 °C for 4 h. Evaporation of ethanol followed by purification by column chromatography and elution with acetonitrile : water : acetic acid (90:5:5) gave 21.8 mg (±)-rrαn5-decahydro-4-imino- benzo[b]-l,4-thiazepine acetic acid salt.
H NMR (500 MHz, D2θ): δ 3.68 (m, IH), 3.64 (m, IH), 3.26-2.83 (m, 4H), 2.06-1.23 (m, 8H).
13C NMR (125 MHZ, CDC13 ): δ 58.72, 45.32, 33.96, 31.85, 31,76, 25.00, 23.95, 21.47.
Mass spectrum: m/z = 185.1 (M+)
EXAMPLE 18
Figure imgf000058_0001
H CHsCOϋH
Hexahydro-5-imino-3(SVpropyl-1.4-thiazepine. acetic acid salt
Step A: Tetrahvdro-3(S)-propyl-(2 D- 1.4-thiazepine-5-thione The title compound was prepared employing the procedure in Example 17, Steps A to E and starting from L-norvalinol instead of (±)-trans-2- aminocy clohexanol .
Step B: Hexahvdro-5-imino-3(S Vpropyl- 1 ,4-thiazepine acetic acid salt
To a solution of tefrahydro-3(S)-propyl-(2iζ/)-l,4-thiazepine-5-thione (42 mg, 0.22 mmol) in 5 mL tetrahydrofuran and saturated with ammonia gas at 60 °C was added mercuric chloride (73.3 mg, 0.27 mmol). The stream of ammonia gas was bubbled for another 10 mins. at the same temperamre. After stirring for 2 h, the reaction mixture was filtered and the filtrate was evaporated. The cmde compound was then purified by column chromatography and eluted with acetonitrile : water : acetic acid (90:5:5) giving 31.5 mg of hexahydro-5-imino-3(S)-ρropyl-l,4-thiazepine acetic acid salt.
iH NMR (500 MHz, CD3OD): δ 3.93 ( m, IH), 3.30-2.61 (m, 6H), 1.72- 1.40 (m, 4H), 0.97 (t, 3H, J = 7.3 Hz).
13c NMR (125 MHZ, CD3OD): δ 58.58, 36.42, 34.95, 34.09, 23.33,
18.87, 12.61.
Mass spectrum: m/z = 173.1 (M+l).
EXAMPLE 19
Figure imgf000059_0001
Hexahvdro-5-imino-3(RVpropyl-1.4-thiazepine acetic acid salt Step A: Tetrahvdro-3(R)-propyl-(2/f .4-thiazepine-5-thione
The title compound was prepared employing the procedure in Example 17, Steps A-E and starting from D-norvalinol instead of (±)-trans-2- aminocyclohexanol.
Step B : Hexahvdro-5-imino-3(RVpropyl- 1.4-thiazepine acetic salt
Employing the procedure 19, step B, tetrahydro-3(R)-propyl-(2 /)-l,4- thiazeρine-5-thione (40 mg, 0.21 mmol) was converted to 37.4 mg of hexahydro-5-imino-3(R)-propyl-l,4-thiazepine acetic acid salt.
iH NMR (500 MHz, CD3OD): d 3.93 ( m, IH), 3.29-3.02 (m, 2H), 2.87- 2.61 (m, 4H), 1.73-1.41 (m, 4H), 0.97 (t, 3H, J = 7.3 Hz). 13c NMR (125 MHZ, CD3OD): d 58.60, 36.43, 34.96, 34.10, 23.35, 18.87, 12.63. Mass spectrum: m/z = 173.1 (M+l).
EXAMPLE 20
Figure imgf000060_0001
Hexahvdro-5-imino- 1 -methyl- IH- 1.4-diazepine hydrochloride.
Employing the method of Foloppe et al (M.P. Foloppe, S. Rault, and M. Robba, Tetrahedron .Lett. 1992.21, 2803-2804), a solution of hexahydro- l-methyl-(5#)-l,4-diazepin-5-thione (R. Guryn, Polish J. Chem. 1987. £i, 259-262) (100 mg, 0.694 mmol) in tetrahydrofuran (5.0 mL) was warmed in a 55 °C oil bath as ammonia was bubbled into the solution. Mercuric chloride (207 mg, 0.764 mmol) was added in one portion, and the mixture quickly became black. After 20 min, the introduction of ammonia was discontinued and the mixture was stiπed at room temperature for 1 h. The mixture was then centrifuged and the supematant was decanted. The pellet was resuspended in tetrahydrofuran (3 mL) , the mixmre was centrifuged, and the supernatant was decanted. This was repeated with 2 x 3 mL of tetrahydrofuran and then 3 x 3 mL of methanol. The methanol extracts were combined, filtered through a 0.45 micron membrane, and evaporated to give 131 mg of white solid. Based on the combustion analysis for carbon, this material contained 92 mg (82% yield) of hexahydro-5-iι no-l-methyl-(l#)-l,4-diazepine hydrochloride salt.
iH NMR (400 MHz, CD3OD): δ 3.56-3.52 (m, 2H), 2.88 (dd, 2H, J = 6 Hz, 3 Hz), 2.79-2.71 (m, 2H), 2.71-2.63 (m, 2H), 2.43 (s, 3H). Mass spectrum: mlz = 128 (M - HCl + 1). Anal, calc'd. for C6H14N3CM.23 NH4CI: C, 31.1; H, 8.40; N, 25.5;
Cl. 34.1. Found: C, 31.08; H, 8.16; N, 23.41; Cl, 34.06.

Claims

WHAT IS CLAIMED IS:
1. A compound of Formula I
Figure imgf000062_0001
I or a pharmaceutically acceptable salt thereof wherein: side a or side b has a double bond,
X is selected from O, S(0)m, NH, and NR wherein R6 is selected from Cl-l2alkyl, C(0)Cl-l2alkyl, C(0)OCi-i2alkyl, C(0)NHCl-l2alkyl, S(0)2Cl-l2alky and
S(0)2NHCl_l2alkyl wherein said Cl-l2alkyl group being optionally mono or di- substimted by substiments being independently selected phenyl, Cl-6alkoxy, amino, and halo; m is 0, 1 or 2; Rl, R2, R3 and R4 are each independently selected from the group consisting of
(a) hydrogen,
(b) Cι_i2alkoxy,
(c) C l . I2alkyl-S(0)k wherein k is 0, 1 or 2, (d) mono Cl-i2alkylamino,
(e) (di-C 1.12alkyl)amino,
(f) C 1.12alkylcarbonyl,
(g) Ci-l2alkyl, (h) C2-12alkenyl, (i) C2-12alkynyl,
(j) C5- locycloalkyl,
(k) hetero C5- 1 θcycloalkyl,wherein the hetero C5- locycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O and N, (1) aryl, selected from phenyl or naphthyl, (m) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) benzimidazolyl,
(2) benzofuranyl,
(3) benzooxazolyl,
(4) furanyl,
(5) imidazolyl,
(6) indolyl,
(7) isooxazolyl,
(8) isothiazolyl,
(9) oxadiazolyl,
(10) oxazolyl,
(11) pyrazinyl,
(12) pyrazolyl,
(13) pyridyl,
(14) pyrimidyl,
(15) pyrrolyl,
(17) isoquinolyl,
(18) tetrazolyl,
(19) thiadiazolyl,
(20) thiazolyl,
(21) thienyl, and
(22) triazolyl,
(n) Cl-12alkyl-C(0)] MH,
(o) Cl-l2alkoxy-C(0)NH,
(P) Cl-l2alkylamino -C(0)NH,
(q) Cl-I2alkyl-S(0)2NH,
(r) Cl-l2alkylamino -C(O),
(s) Cl-l2alkylamino -S(0)2,
(t) aryl-C(0)NH where aryl is selected from phenyl, naphthyl, pyridyl, thienyl, thiazolyl, oxazolyl, imidazolyl, and triazolyl,
(u) aryloxy-C(0)NH where aryl is selected from phenyl, naphthyl, and pyridyl, (v) phenylamino-C(0)NH,
(w) aryl-S(0)2NH where aryl is selected from phenyl and naphthyl, (x) aryl-C(O) where aryl is selected from phenyl, naphthyl, pyridyl, thienyl, thiazolyl, oxazolyl, imidazolyl, and triazolyl, (y) phenylamino-S(0)2. (z) hydroxy, (aa) amino, (ab) oxo,
(ac) C(0)OR7, R7 is selected from hydrogen, phenyl, benzyl, cyclohexyl or Ci-6alkyl,
each of (b) to (y) being optionally mono or di- substimted, the substiments being independently selected from
(1) hydroxy,
(2) carboxy,
(3) -NR7R8, where R8 is selected from hydrogen, phenyl, benzyl, cyclohexyl or Cl-6alkyl, (4) -NR7C(0)R8
(6) -NR7C(0)NHR8,
(5) -NR7C(0)OR9, where R9 is selected from phenyl, benzyl, cyclohexyl or Cl-6alkyl,
(7) -NR7S(0)2R9, (8) -OR7,
(9) -C(0)OR9,
(10) -C(0)NR7R8, (11) -C(0)R7, (12) -S(0)kR7, (13) -S(0)2NR7R8,
(14) halo selected from F, Cl, Br and I,
(15) -trifluoromethyl, (16) -C(=NR7)-NHR8, (17) hetero C5-10cycloalkyl,wherein the hetero C5- lOcycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O and N,
(18) aryl, selected from phenyl or naphthyl, (19) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(a) imidazolyl,
(b) isooxazolyl,
(c) isothiazolyl, (d) oxadiazolyl,
(e) oxazolyl,
(f) pyridyl,
(g) tetrazolyl, (h) thiazolyl, (i) thienyl, and
(j) triazolyl,
or when two members of the group Rl, R2, R3 and R4 reside on the same carbon atom of Formula I, or two of the group Rl , R2, R3 and R4 reside on adjacent atoms of Formula I, said two members along with the optional substimtents thereon may optionally be joined, such that together with the carbon atom to which they are attached there is formed a samrated or unsaturated monocyclic ring of 5, 6 or 7 atoms, said monocyclic ring optionally containing up to three hetero atoms selected from N, O or S, or when a member of the group Rl, R2, R3 and R4 resides on an atom adjacent to the N on which R6 resides, said member may optionally be joined with R6 along with the optional substimtents thereon, such that together with the N on which
R6 resides and the carbon on which said member resides there is formed a samrated or unsaturated monocyclic heterocycle of 5, 6 or 7 atoms, said monocycle optionally containing up to three hetero atoms selected from N, O or S, elected from the group consisting of
(a) hydrogen,
(b) linear and branched C 1 - 12alkyl, optionally mono or di¬ substituted, the substituents being independently selected from
(1) hydroxy,
(2) carboxy,
(3) -NR7R8,
(4) -OR7, (5) -C(0)OR7,
(6) -S(0)kR7,
(7) halo selected from F, Cl, Br and I,
(8) trifluoromethyl,
(9) phenyl, optionally mono or di-substituted with hydroxy, halo, C l -4alky 1, or C l -4alkoxy ,
(c) -C(O)NRl0Rl 1 , where RlO and Rl l are each independently hydrogen, phenyl, cyclohexyl, -S(0)2NR7R or optionally substituted Cl-6alkyl, wherein said substituent is selected from ( 1 ) -NR 12R 13 , wherein R 12 and R 13 are each independently
H, Cl-6alkyl, phenyl or benzyl,
(2) -OR12,
(3) -C(0)ORi2,
(4) -S(0)kRl2, where m is 0, 1 or 2, (5) halo selected from F, Cl, Br and I,
(6) optionally substimted aryl wherein aryl and aryl substituents are as defined above,
(7) optionally substimted heteroaryl wherein heteroaryl and heteroaryl substituents are as defined above, (8) optionally substituted C5-10cycloalkyl wherein cycloalkyi and cycloalkyi substituents are as defined above, (9) hetero C5- locycloalkyl, wherein the hetero - όS -
CS- locycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O and N,
(d) -C(0)RH,
(e) -C(0)ORn, (f) aryl, selected from phenyl or naphthyl,
(g) cyclohexyl.
2. A compound according to Claim 1 wherein R 2» R3 and R4 are each independently selected from the group consisting of
(a) hydrogen,
(b) hydroxy,
(c) amino,
(d) cyano, (e) fluoro, chloro, bromo, and iodo,
(f) trifluoromethyl,
(g) Cl-6alkyl, (h) Ci-6alkoxy, (i) Cl-6alkylthio, (j) Cl-6alkylcarbonyl,
(k) mono- and di-C l-6alkylamino, (1) aryl, where aryl is phenyl and naphthyl, (m) aryloxy, where aryl is phenyl and naphthyl, (n) cycloalkyl,wherein the cycloalkyi is a 5-, 6-, or 7-membered monocyclic ring which optionally contains 1 or 2 heteroatoms selected from S, O, and N, and (o) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) pyridyl, (2) furanyl,
(3) thienyl,
(4) pyrazinyl,
(5) pyrimidyl,
(6) thiazolyl, and (7) triazolyl, each of (g) to (o) being optionally mono- or di- substituted, the substituents being independently selected from (1) hydroxy, (2) Cl-4alkyl,
(3) Cl-3alkoxy,
(4) amino,
(5) mono- and di-C 1 -6alkylamino,
(6) carboxyl, (7) Cl-3alkylthio,
(8) Cl-3alkyl-S(0)k- , where k is 1 or 2,
(9) Cl-4alkoxycarbonyl,
(10) halo selected from fluoro, chloro, bromo, and iodo, (11) oxo, and
(12) amidino,
elected from the group consisting of (a) hydrogen, (b) Cl-6alkylcarbonyl,
(c) aroyl, wherein the aroyl group is benzoyl,
(d) aroylaminocarbonyl, wherein the aroyl group is benzoyl and naphthoyl,
(e) R6R7N-S02-NH-C(=0)-, wherein R6 and R7 are independently selected from the group consisting of
(1) hydrogen,
(2) Cl-6alkyl,
(3) aryl, wherein the aryl group is selected from phenyl, and (4) R6 and R7 may be joined together to form a
5-, 6- or 7-membered ring containing 0, 1 or 2 heteroatoms, the heteroatoms being elected from the group of oxygen, sulfur and nitrogen, each of (b) to (e) being mono- or di- substimted, the substituents being independently selected from
(1) hydroxy,
(2) Ci-3alkoxy, (3) amino,
(4) mono- and di-Cl-6alkylamino,
(5 carboxvl.
(6) Cl-3alkylthio,
(7) C 1 -3alkyl-S(0)k- , where k is 1 or 2, (8) Ci-4alkoxycarbonyl,
(9) halo selected from fluoro, chloro, bromo, and iodo,
(10) oxo, and
(11) amidino.
3. A compound according to Claim 2 wherein Rl, R2, R3 and R4 are each independently selected from the group consisting of
(a) hydrogen, (b) hydroxy,
(c) amino,
(d) cyano,
(e) fluoro, chloro or bromo,
(f) trifluoromethyl, (g) Ci-4alkyl,
(h) Cl-4alkoxy,
(i) Cl-4alkylthio, and
(j ) mono- and di-C l -4alkylamino,
R5 is selected from the group consisting of
(a) hydrogen,
(b) R6R7N-S02-NH-C(=0)-, optionally mono or di-substituted, wherein R6 and R7 are independently selected from the group consisting of (1) hydrogen, (2) Cl-4alkyl, and
(3) aryl, wherein the aryl group is phenyl, and said substituents are independently selected from
(1) hydroxy, (2) Cl-3alkoxy,
(3) amino,
(4) mono- and di-Cl- 6alkylamino,
(5) carboxyl,
(6) Ci-3alkylthio, and (7) halo selected from fluoro, chloro, and bromo.
4. A compound according to Claim 3 wherein R2 is hydrogen or methyl; R4 is hydrogen or methyl; Rl and R3 are each independently selected from
(a) hydrogen,
(b) methyl, ethyl, propyl or butyl, (c) chloro,
(d) -CN, and
(e) -CF3; and R5 is hydrogen.
5. A compound according to Claim 1 wherein or a pharmaceutically acceptable salt thereof wherein: side a or side b has a double bond,
X is selected from O, S(0)m, NH, and NR6, wherein R6 is selected from Cl-l2alkyl, C(0)Cl-l2alkyl, C(0)OCi-l2alkyl, C(0)NHCl-l2alkyl, S(0)2Ci-i2alky and
S(0)2NHCi-i2alkyl wherein said Ci-l2alkyl group being optionally mono or di- substimted by substituents being independently selected phenyl, Cl-6alkoxy, amino, and halo; m is 0, 1 or 2, R2 are each independently selected from the group consisting of
(a) hydrogen,
(b) Cl-12alkoxy,
(c) C 1 - I2alkyl-S(0)k wherein k is 0, 1 or 2, (d) mono Ci-l2alkylamino,
(e) (di-C l .12alky l)amino,
(f) Ci -l2alkylcarbony1,
(g) Cl-l2alkyl, (h) C2-12alkenyl, (i) C2-12alkynyl,
(j) C5- locycloalkyl,
(k) hetero C5- 1 θcycloalkyl,wherein the hetero C5- locycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O and N, (1) aryl, selected from phenyl or naphthyl,
(m) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) benzimidazolyl,
(2) benzofuranyl, (3) benzooxazolyl,
(4) furanyl,
(5) imidazolyl,
(6) indolyl,
(7) isooxazolyl, (8) isothiazolyl,
(9) oxadiazolyl,
(10) oxazolyl,
(11) pyrazinyl,
(12) pyrazolyl, (13) pyridyl,
(14) pyrimidyl,
(15) pyπolyl,
(17) isoquinolyl,
(18) tetrazolyl, (19) thiadiazolyl,
(20) thiazolyl,
(21) thienyl, and
(22) triazolyl, (n) Cl-I2alkyl-C(0)NH,
(o) Cl-12alkoxy-C(0)NH, (p) C 1.1 ?alkylamino-C(0)NH, (q) Cl-I2alkyl-S(0)2NH, (r) Cl-I2alkylamino-C(0), (s) Cl-l2alkylamino-S(0)2,
(t) aryl-C(0)NH where aryl is selected from phenyl, naphthyl, pyridyl, thienyl, thiazolyl, oxazolyl, imidazolyl, and triazolyl, (u) aryloxy-C(0)NH where aryl is selected from phenyl, naphthyl, and pyridyl,
(v) phenylamino-C(0)NH, (w) aryl-S(0)2NH where aryl is selected from phenyl and naphthyl, (x) aryl-C(O) where aryl is selected from phenyl, naphthyl, pyridyl, thienyl, thiazolyl, oxazolyl, imidazolyl, and triazolyl, (y) phenylamino-S(0)2, (z) hydroxy, (aa) amino, (ab) oxo,
(ac) C(0)OR7, R7 is selected from hydrogen, phenyl, benzyl, cyclohexyl or Cl-6alkyl,
each of (b) to (y) being optionally mono or di- substituted, the substituents being independently selected from
(1) hydroxy,
(2) carboxy,
(3) -NR7R8, where R8 is selected from hydrogen, phenyl, benzyl, cyclohexyl or Cl-6alkyl, (4) -NR7C(0)R8
(6) -NR7C(0)NHR8,
(5) -NR7C(0)OR9,where R9 is selected from phenyl, benzyl, cyclohexyl or Cl-6alkyl (7) -NR7S(0)2R9,
(8) -OR7,
(9) -C(O)OR0,
(10) -C(0)NR7R8, (11) -C(0)R7, (12) -S(0)kR7,
(13) -S(0)2NR7R8,
(14) halo selected from F, Cl, Br and I,
(15) -trifluoromethyl,
(16) -C(=NR7)-NHR8, (17) hetero C5- 1 ocycloalkyl, wherein the hetero C5- lOcycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O and N,
(18) aryl, selected from phenyl or naphthyl,
(19) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(a) imidazolyl,
(b) isooxazolyl,
(c) isothiazolyl,
(d) oxadiazolyl, (e) oxazolyl,
(f) pyridyl,
(g) tetrazolyl, (h) thiazolyl, (i) thienyl, and (j) triazolyl,
R3 and R4 reside on the same carbon atom of Formula I, or reside on adjacent atoms of Formula I, and R3 and R4 are joined such that together with the carbon atom to which they are attached there is formed a saturated or unsaturated monocyclic ring of 5, 6 or 7 atoms, said monocyclic ring optionally containing up to three hetero atoms selected from N, O or S,
R5 is selected from the group consisting of (a) hydrogen,
(b) linear and branched C 1 - 12alkyl, optionally mono or di¬ substituted, the substituents being independently selected from
(1) hydroxy, (2) carboxy,
(3) -NR7R8,
(4) -OR7,
(5) -C(0)OR7,
(6) -S(0)kR7, (7) halo selected from F, Cl, Br and I,
(8) trifluoromethyl,
(9) phenyl, optionally mono or di-substituted with hydroxy, halo, Cl-4alkyl, or Cl-4alkoxy,
(c) -C(0)NRioRl 1 , where Rio and Rl 1 are each independently hydrogen, phenyl, cyclohexyl, -S(0)2NR7R8 or Cl-6alkyl, said Cl-6alkyl optionally substituted by
(1) -NR12R13, wherein Rl2 and R 13 are each independently
H, Cl-6alkyl, phenyl or benzyl,
(2) -OR12, (3) -C(0)ORl2,
(4) -S(0)kRl2, where m is 0, 1 or 2,
(5) halo selected from F, Cl, Br and I,
(6) optionally substituted aryl wherein aryl and aryl substituents are as defined above, (7) optionally substituted heteroaryl wherein heteroaryl and heteroaryl substituents are as defined above, (8) optionally substimted C5-10cycloalkyl wherein cycloalkyi and cycloalkyi substituents are as defined above, (9) hetero C5- locycloalkyl, wherein the hetero C5- locycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O and N, (d) -C(0)RH, (e) -C(0)ORl l,
(f) aryl, selected from phenyl or naphthyl,
(σ) cvrl hev l
6. A compound according to Claim 5 wherein Rl and R2 are each independently selected from the group consisting of
(a) hydrogen,
(b) hydroxy,
(c) amino,
(d) cyano, (e) fluoro, chloro, bromo, and iodo,
(f) trifluoromethyl,
(g) Ci-6alkyl, (h) Cl-6alkoxy,
(i) Cl-6alkylthio, (j) Cl-6alkylcarbonyl,
(k) mono- and di-C l_6alkylamino, (1) aryl, where aryl is phenyl and naphthyl, (m) aryloxy, where aryl is phenyl and naphthyl, (n) cycloalkyi, wherein the cycloalkyi is a 5-, 6-, or 7-membered monocyclic ring which optionally contains 1 or 2 heteroatoms selected from S, O, and N, and (o) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) pyridyl, (2) furanyl,
(3) thienyl,
(4) pyrazinyl,
(5) pyrimidyl,
(6) thiazolyl, and (7) triazolyl, each of (g) to (o) being optionally mono- or di- substituted, the substituents being independently selected from (1) hydroxy, (2) Cl-4alkyl,
(3) Ci-3alkoxy,
(4) amino,
(5) mono- and di-Cl-6alkylamino,
(6) carboxyl, (7) Ci-3alkylthio,
(8) C l-3alkyl-S(0)k- , where k is 1 or 2,
(9) Cl-4alkoxycarbonyl,
(10) halo selected from fluoro, chloro, bromo, and iodo, (11) oxo, and
(12) amidino, R3 and R4 reside on the same carbon atom of Formula I, or reside on adjacent atoms of Formula I, and R3 and R4 are joined, such that together with the carbon atom to which they are attached there is formed a saturated or unsaturated monocyclic ring of 5 or 6 atoms, said monocyclic ring optionally containing one or 2 hetero atoms selected from N, O or S, R5 is selected from the group consisting of
(a) hydrogen,
(b) Ci-6alkylcarbonyl, (c) aroyl, wherein the aroyl group is benzoyl,
(d) aroylaminocarbonyl, wherein the aroyl group is benzoyl and naphthoyl,
(e) R6R7N-S02-NH-C(=0)-, wherein R6 and R7 are independently selected from the group consisting of (1) hydrogen,
(2) Cl-6alkyl
(3) aryl, wherein die aryl group is selected from phenyl, and (4) R6 and R7 may be joined together to form a 5-, 6- or 7-membered ring containing 0, 1 or 2 heteroatoms, the heteroatoms being elected from the group of oxygen, sulfur and nitrogen,
each of (b) to (e) being mono- or di- substimted, the substituents being independently selected from
(1) hydroxy,
(2) Ci-3alkoxy, (3) amino,
(4) mono- and di-Cl-6alkylamino,
(5) carboxyl,
(6) Ci-3alkylthio,
(7) Cl-3alkyl-S(0)k- , where k is 1 or 2, (8) Cl-4alkoxycarbonyl,
(9) halo selected from fluoro, chloro, bromo, and iodo,
(10) oxo, and
(11) amidino.
7. A compound according to Claim 6 wherein Rl and R2 are each independently selected from the group consisting of
(a) hydrogen,
(b) hydroxy, (c) amino,
(d) cyano,
(e) fluoro, chloro or bromo,
(f) trifluoromethyl,
(g) Ci-4alkyl, (h) Ci-4alkoxy,
(i) Cl_4alkylthio, and (j) mono- and di-C l -4alkylamino, R3 and R4 reside on adjacent atoms of Formula I, and R3 and R4 are joined, such that together with the carbon atom to which they are attached there is formed a samrated or unsamrated monocyclic ring of 5 or 6 atoms, said monocyclic ring optionally containing one or 2 hetero atoms selected from N, O or S,
R5 is selected from the group consisting of
(a) hydrogen, (b) R6R7N-S02-NH-C(=0)-, optionally mono or di-substituted, wherein R6 and R7 are independently selected from the group consisting of
(1) hydrogen,
(2) Ci-4alkyl, and (3) aryl, wherein the aryl group is selected from phenyl, and said substituents are independently selected from
(1) hydroxy,
(2) Cl-3alkoxy, (3) amino,
(4) mono- and di-C l -6alkylamino,
(5) carboxyl,
(6) Cl-3alkylthio, and
(7) halo selected from fluoro, chloro, and bromo.
8. A compound according to Claim 7 wherein
Rl and R2 are each independently selected from (a) hydrogen,
(b) methyl, ethyl, propyl or butyl,
(c) chloro,
(d) -CN, and
(e) -CF3, R3 and R4 reside on adjacent atoms of Formula I, and R3 and R4 are joined, such that together with the carbon atom to which they are attached there is formed a saturated or unsamrated monocyclic ring of 5 or 6 atoms, said monocyclic ring optionally containing one or 2 hetero atoms selected from N, O or S, R5 is hydrogen.
9. A compound according to Claim 1 or a pharmaceutically acceptable salt thereof wherein: side a or side b has a double bond, X is NR6, wherein R6 is selected from Cl l2alkyl, C(0)Cl .I2alkyl, C(0)OCl-l2alkyl, C(0)NHCi-i2alkyl, S(0)2Ci-i2alky and S(0)2NHCl-12alkyl wherein said Cl-l2alkyl group being optionally mono or di- substituted by substituents being independently selected phenyl, Cl-6alkoxy, amino, and halo; m is 0, 1 or 2,
Rl, R2 and R3 are each independently selected from the group consisting of (a) hydrogen,
(b) Cl-l2alkoxy,
(c) Cl_l2alkyl-S(0)k wherein k is 0, 1 or 2,
(d) mono C 1- 12alkylamino,
(e) (di-Cl-l2alkyl)amino, (f) Ci-i2alkylcarbonyl,
(g) Cl-l2alkyl,
(h) C2-12alkenyl,
(i) C2-12alkynyl,
(j) C5- locycloalkyl, (k) hetero C5-lθcycloalkyl,wherein the hetero C5- locycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O and N,
(1) aryl, selected from phenyl or naphthyl,
(m) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) benzimidazolyl,
(2) benzofuranyl,
(3) benzooxazolyl,
(4) furanyl, (5) imidazolyl,
(6) indolyl,
(7) isooxazolyl,
(8) isothiazolyl, (9) oxadiazolyl,
(10) oxazolyl,
( ] ) pyrazinyl,
(12) pyrazolyl,
(13) pyridyl, (14) pyrimidyl,
(15) pyπolyl,
(17) isoquinolyl,
(18) tetrazolyl,
(19) thiadiazolyl, (20) thiazolyl,
(21) thienyl, and
(22) triazolyl, (n) Cl-12alkyl-C(0)NH,
(o) Cl-l2alkoxy-C(0)NH, (p) C 1 - 12alkylamino-C(0)NH,
(q) Cl-12alkyl-S(0)2NH, (r) Cl-l2alkylamino-C(0), (s) Cl-l2alkylamino-S(0)2,
(t) aryl-C(0)NH where aryl is selected from phenyl, naphthyl, pyridyl, thienyl, thiazolyl, oxazolyl, imidazolyl, and triazolyl, (u) aryloxy-C(0)NH where aryl is selected from phenyl, naphthyl, and pyridyl, (v) phenylamino-C(0)NH, (w) aryl-S(0)2NH where aryl is selected from phenyl and naphthyl, (x) aryl-C(O) where aryl is selected from phenyl, naphthyl, pyridyl, thienyl, thiazolyl, oxazolyl, imidazolyl, and triazolyl, (y) phenylamino-S(0)2,
(z) hydroxy,
(aa) amino,
(ab) oxo, (ac) C(0)OR7, R7 is selected from hydrogen, phenyl, benzyl, cyclohexyl or Ci-6alkyl,
each of (b) to (y) being optionally mono or di- substimted, the substituents being independently selected from (1) hydroxy,
(2) carboxy,
(3) -NR7R8, where R8 is selected from hydrogen, phenyl, benzyl, cyclohexyl or Ci-6alkyl,
(4) -NR7C(0)R8 (6) -NR7C(0)NHR8,
(5) -NR7C(0)OR9,where R9 is selected from phenyl, benzyl, cyclohexyl or Ci-6alkyl
(7) -NR7S(0)2R9,
(8) -OR7, (9) -C(0)OR9,
(10) -C(0)NR7R8,
(11) -C(0)R7,
(12) -S(0)kR7,
(13) -S(0)2NR7R8, (14) halo selected from F, Cl, Br and I,
(15) -trifluoromethyl,
(16) -C(=NR7)-NHR8,
(17) hetero C5-lθcycloalkyl,wherein the hetero C5- lOcycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O and N,
(18) aryl, selected from phenyl or naphthyl,
(19) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(a) imidazolyl, (b) isooxazolyl,
(c) isothiazolyl,
(d) oxadiazolyl,
(e) oxazolyl,
(f) pyridyl,
(g) tetrazolyl,
(h thiazolyl,
(i) thienyl, and
(i) triazolyl,
R4 resides on an atom adjacent to the N on which R6 resides, and R4 is joined with R6, such that together with the N on which R6 resides and the carbon on which said member resides there is formed a saturated or unsamrated monocyclic heterocycle of 5 or 6 atoms, said monocycle optionally containing one or 2 hetero atoms selected from N, O or S, R5 is selected from the group consisting of
(a) hydrogen,
(b) linear and branched C l - 12alkyl, optionally mono or di¬ substituted, the substiments being independently selected from
(1) hydroxy,
(2) carboxy,
(3) -NR7R8,
(4) -OR7, (5) -C(0)OR7,
(6) -S(0)kR7,
(7) halo selected from F, Cl, Br and I,
(8) trifluoromethyl,
(9) phenyl, optionally mono or di-substituted with hydroxy, halo, C 1 -4alkyl, or C 1 -4alkoxy ,
(c) -C(0)NRlθRl 1, where Rio and Rl 1 are each independently hydrogen, phenyl, cyclohexyl, -S(0)2NR7R8 or Cl-6alkyl, said Ci-6alkyl optionally substituted by (1) -NRi2Rl3, wherein R12 and R13 are each independently
H, Ci-6alkyl, phenyl or benzyl,
(2) -OR12,
(3) -C(0)0R12, (4) -S(0)kRl2, where m is 0, 1 or 2,
(5) halo selected from F, Cl, Br and I,
(6) optionally substituted aryl wherein aryl and aryl substituents are as defined above,
(7) optionally substituted heteroaryl wherein heteroaryl and heteroaryl substituents are as defined above,
(8) optionally substituted C5-10cycloalkyl wherein cycloalkyi and cycloalkyi substituents are as defined above,
(9) hetero C5- locycloalkyl, wherein the hetero C5- locycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O and N,
(e) -C(0)RH,
(f) -C(0)0RH,
(g) aryl, selected from phenyl or naphthyl, (h) cyclohexyl.
10. A compound according to Claim 9 wherein Rl, R2 and R3 are each independently selected from the group consisting of (a) hydrogen,
(b) hydroxy,
(c) amino,
(d) cyano,
(e) fluoro, chloro, bromo, and iodo, (f) trifluoromethyl,
(g) Cl-6alkyl,
(h) Ci-6alkoxy,
(i) Cl-6alkylthio,
(j) Cl-6alkylcarbonyl, (k) mono- and di-C l -6alkylamino, (1) aryl, where aryl is phenyl and naphthyl, (m) aryloxy, where aryl is phenyl and naphthyl, (n) cycloalkyl,wherein the cycloalkyi is a 5-, 6-, or 7-membered monocyclic ring which optionally contains 1 or 2 heteroatoms selected from S, O, and N, and (o) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) pyridyl, (2) furanyl,
(3) thienyl,
(4) pyrazinyl,
(5) pyrimidyl,
(6) thiazolyl, and (7) triazolyl, each of (g) to (o) being optionally mono- or di- substimted, the substituents being independently selected from
(1) hydroxy,
(2) Cl-4alkyl, (3) Ci-3alkoxy,
(4) amino,
(5) mono- and di-C l -6alkylamino,
(6) carboxyl,
(7) Ci-3alkylthio, (8) Cl-3alkyl-S(0)k- , where k is 1 or 2,
(9) Cl-4alkoxycarbonyl,
(10) halo selected from fluoro, chloro, bromo, and iodo,
(11) oxo, and (12) amidino,
R4 resides on an atom adjacent to the N on which R6 resides, and R4 is joined with R6, such that together with the N on which R6 resides and the carbon on which said member resides there is formed a saturated or unsamrated monocyclic heterocycle of 5 or 6 atoms, said monocycle optionally containing one or 2 hetero atoms selected from N, O or S, R5 is selected from the group consisting of (a) hydrogen, (b) Cl-6alkylcarbonyl,
(c) aroyl, wherein the aroyl group is benzoyl,
(d) aroylaminocarbonyl, wherein the aroyl group is benzoyl and naphthoyl,
(e) R6R7N-S02-NH-C(=0)-, wherein R6 and R7 are independently selected from the group consisting of
(1) hydrogen,
(2) Cl-6alkyl
(3) aryl, wherein the aryl group is selected from phenyl, and (4) R6 and R7 may be joined together to form a
5-, 6- or 7-membered ring containing 0, 1 or 2 heteroatoms, the heteroatoms being elected from the group of oxygen, sulfur and nitrogen,
each of (b) to (e) being mono- or di- substimted, the substituents being independently selected from
(1) hydroxy,
(2) Ci-3alkoxy,
(3) amino,
(4) mono- and di-Cl-6alkylamino,
(5) carboxyl,
(6) Cl-3alkylthio,
(7) Cl-3alkyl-S(0)k- , where k is 1 or 2,
(8) C 1 -4alkoxycarbonyl,
(9) halo selected from fluoro, chloro, bromo, and iodo,
(10) oxo, and
(11) amidino.
11. A compound according to Claim 10 wherein Rl, R2 and R3 are each independently selected from the group consisting of
(a) hydrogen,
(b) hydroxy, (c) amino,
(d) cyano,
(e) fluoro, chloro or bromo,
(f) trifluoromethyl,
(g) Cl-4alkyl, (h) Cl-4alkoxy,
(i) Cl-4alkylthio, and (j) mono- and di-Cl-4alkylamino, R4 resides on an atom adjacent to the N on which R6 resides, and R4 is joined with R6, such that together with the N on which R6 resides and the carbon on which said member resides there is formed a samrated or unsamrated monocyclic heterocycle of 5 or 6 atoms, said monocycle optionally containing one or 2 hetero atoms selected from N, O or S, R5 is selected from the group consisting of (a) hydrogen, (b) R6R7N-Sθ2-NH-C(=0)-, optionally mono or di-substituted, wherein R6 and R7 are independently selected from the group consisting of
(1) hydrogen,
(2) Ci-4alkyl, and (3) aryl, wherein the aryl group is selected from phenyl, and said substiments are independently selected from
(1) hydroxy,
(2) Cl-3alkoxy, (3) amino,
(4) mono- and di-C 1 -6alkylamino,
(5) carboxyl,
(6) Cl-3alkylthio, and (7) halo selected from fluoro, chloro, and bromo.
12. A compound according to Claim 11 wherein
Rl is hydrogen or methyl; R2 is hydrogen or methyl: R3 is selected from
(a) hydrogen, (b) methyl, ethyl, propyl or butyl,
(c) chloro,
(d) -CN, and
(e) -CF3,
R4 resides on an atom adjacent to the N on which R6 resides, and R4 is joined with R6, such that together with the N on which R6 resides and the carbon on which said member resides there is formed a saturated or unsamrated monocyclic heterocycle of 5 or 6 atoms, said monocycle optionally containing one or 2 hetero atoms selected from N, O or S; and R5 is hydrogen.
13. A compound according to Claim 1 selected from the group consisting of
(a) hexahydro-5-imino-( 1 H)- 1 ,4-diazepine dihydrochloride, (b) hexahydro-5-imino-l,4-thiazepine hydrochloride
(c) hexahydro-5-imino-l,4-oxazepine hydrochloride,
(d) hexahydro-5-imino-3-propyl- 1 ,4-thiazepine hydrochloride,
(e) hexahydro-5-imino-6-propyl- 1 ,4-thiazepine hydrochloride,
(f) hexahydro-5-imino-7-methyl- 1 ,4-thiazepine hydrochloride,
(g) hexahydro-5-imino-2-methyl- 1 ,4-thiazepine hydrochloride, (h) hexahydro-5-imino-6-(3-methyl-2-n-butenyl)- 1 ,4- thiazepine hydrochloride, (i) hexahydro-5-imino-3-(3-methyl-2-n-butenyl)- 1 ,4- thiazepine hydrochloride, (j) hexahydro-5-imino-6-(2-methyl-propyl)-l,4- thiazepine hydrochloride, (k) hexahydro-5-imino-3-(2-methy1-proρy1)-1 ,4- thiazepine hydrochloride, (1) hexahydro-5-imino-6-methyl- 1 ,4-thiazepine hydrochloride,
(m) hexahydro-5-imino-3-methyl- 1 ,4-thiazepine hydrochloride, (n) hexahydro-5-imino-3-ethyl- 1 ,4-thiazepine hydrochloride, (o) hexahydro-5-imino-3-butyl- 1 ,4-thiazepine hydrochloride, (p) hexahydro-5-imino-3-(2-methyl-3-propenyl)- 1 ,4- thiazepine hydrochloride, (q) (±)-frøws-decahydro-4-imino-benzo[b]- 1 ,4-thiazepine acetic acid salt.,
(r) hexahydro-5-imino-3(S)-propyl-l,4-thiazepine acetic acid salt, (s) hexahydro-5-imino-3(R)-propyl-l,4-thiazepine acetic acid salt, (t) hexahydro-5-imino-l-methyl-(l -l,4-diazepine hydrochloride, and pharmaceutically acceptable salts thereof.
14. A compound according to Claim 1 of the formula
Figure imgf000088_0001
wherein
R4 is selected from the group consisting of (a) hydrogen, (b) hydroxy,
(c) amino,
(d) cyano,
(e) fluoro, chloro, bromo, and iodo,
(f) trifluoromethyl, (g) Cl-6alkyl,
(h) Cl-6alkoxy, (i) Cl-6alkylthio, (j) Cl-6alkylcarbonyl, (k) mono- and di-C 1 -6alkylamino, (1) aryl, where aryl is phenyl and naphthyl,
(m) aryloxy, where aryl is phenyl and naphthyl, (n) cycloalkyl,wherein the cycloalkyi is a 5-, 6-, or 7-membered monocyclic ring which optionally contains 1 or 2 heteroatoms selected from S, O, and N, and (o) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) pyridyl,
(2) furanyl,
(3) thienyl, (4) pyrazinyl,
(5) pyrimidyl,
(6) thiazolyl, and
(7) triazolyl, each of (g) to (o) being optionally mono- or di- substimted, the substituents being independently selected from
(1) hydroxy,
(2) Cl-4alkyl,
(3) Cl-3alkoxy,
(4) amino, (5) mono- and di-Ci-6alkylamino,
(6) carboxyl,
(7) Ci-3alkylthio,
(8) Ci-3alkyl-S(0)k- , where k is 1 or 2, (9) Ci-4alkoxycarbonyl,
(10) halo selected from fluoro, chloro, bromo, and iodo,
(11) oxo, and
(12) amidino,
15. A compound according to Claim 14 wherein R4 is selected from the group consisting of
(a) hydrogen,
(b) hydroxy, (c) amino,
(d) cyano,
(e) fluoro, chloro or bromo,
(f) trifluoromethyl,
(g) Ci-4alkyl, (h) Ci-4alkoxy,
(i) C l _4alky lthio, and
(j) mono- and di-Cl-4alkylamino.
16. A pharmaceutical composition for treating a nitric oxide synthase mediated disease comprising a pharmaceutical carrier and a non¬ toxic effective amount of the compound according to Claim 1.
17. A method for inhibiting the activity of nitric oxide synthases comprising administering to a subject suffering from a nitric oxide synthase mediated disease, a non-toxic therapeutically effective amount of the compound of Claim 1.
18. A method for inhibiting the activity of nitric oxide synthases comprising administering to a subject suffering from a nitric oxide synthase mediated disease, a non-toxic therapeutically effective amount of the compound of Claim 13.
PCT/US1996/017447 1995-11-01 1996-10-28 Hexahydro-5-imino-1,4-heteroazepine derivatives as inhibitors of nitric oxide synthases WO1997016430A1 (en)

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WO2000064904A1 (en) * 1999-04-28 2000-11-02 Astrazeneca Ab 5,7-bicyclic amidine derivatives useful as nitric oxide synthase inhibitors
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US8202874B2 (en) 2008-06-26 2012-06-19 Mitsubishi Tanabe Pharma Corporation Substituted N-oxide pyrazine derivatives
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US8501728B2 (en) 2008-01-29 2013-08-06 Sanofi Substituted heteroarylamide oxazepinopyrimidone derivatives
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US9073914B2 (en) 2008-06-26 2015-07-07 Sanofi Substituted alkyl pyrimidin-4-one derivatives
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US5854234A (en) * 1993-10-21 1998-12-29 G. D. Searle & Co. Amidino dervatives useful as nitric oxide synthase inhibitors
US6046211A (en) * 1993-10-21 2000-04-04 G.D. Searle & Co. Amidino derivatives useful as nitric oxide synthase inhibitors
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US5981556A (en) * 1997-07-22 1999-11-09 G.D. Searle & Co. 1,3-diazolino and 1,3-diazolidino heterocycles as useful nitric oxide synthase inhibitors
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US6391887B1 (en) 1998-02-12 2002-05-21 Schering Aktiengesellschaft 3,4-Dihydroquinoline derivatives as nitrogen monoxide synthase (NOS) inhibitors
WO1999041240A1 (en) * 1998-02-12 1999-08-19 Schering Aktiengesellschaft 3,4-dihydroquinoline derivatives as nitrogen monoxide synthase (nos) inhibitors
US6489323B1 (en) 1998-06-10 2002-12-03 G.D. Searle & Co. Heterobicyclic and tricyclic nitric oxide synthase inhibitors
WO2000064904A1 (en) * 1999-04-28 2000-11-02 Astrazeneca Ab 5,7-bicyclic amidine derivatives useful as nitric oxide synthase inhibitors
US6344473B1 (en) 2000-08-07 2002-02-05 G.D. Searle & Co. Imidazoles useful as nitric oxide synthase inhibitors
US8507475B2 (en) 2008-01-29 2013-08-13 Sanofi Substituted heteroarylamide diazepinopyrimidone derivatives
US8507476B2 (en) 2008-01-29 2013-08-13 Sanofi Substituted arylamide diazepinopyrimidone derivatives
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US8507470B2 (en) 2008-01-29 2013-08-13 Sanofi Substituted arylamide oxazepinopyrimidone derivatives
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