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WO1996014842A1 - Heterocycles a substitutions utilises en tant qu'inhibiteurs de la synthetase d'oxyde nitrique - Google Patents

Heterocycles a substitutions utilises en tant qu'inhibiteurs de la synthetase d'oxyde nitrique Download PDF

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Publication number
WO1996014842A1
WO1996014842A1 PCT/US1995/014512 US9514512W WO9614842A1 WO 1996014842 A1 WO1996014842 A1 WO 1996014842A1 US 9514512 W US9514512 W US 9514512W WO 9614842 A1 WO9614842 A1 WO 9614842A1
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WO
WIPO (PCT)
Prior art keywords
amino
hydrogen
optionally
group
thiazine
Prior art date
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PCT/US1995/014512
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English (en)
Inventor
Shrenik K. Shah
Stephan K. Grant
Malcolm Maccoss
Kothandaraman Shankaran
Hongbo Qi
Ravindra N. Guthikonda
Original Assignee
Merck & Co., Inc.
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Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU41496/96A priority Critical patent/AU4149696A/en
Publication of WO1996014842A1 publication Critical patent/WO1996014842A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/18—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
    • C07D279/06—1,3-Thiazines; Hydrogenated 1,3-thiazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
    • C07D279/08—1,3-Thiazines; Hydrogenated 1,3-thiazines condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • This application is directed to inhibitors of Nitric oxide synthase, and in particular thiazolines and thiazines.
  • 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 tr- 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 ++ /calmoduIin dependent enzyme located in the endothelium (ecNOS or NOS 3), that releases NO in response to receptor or physical stimulation
  • a constitutive, Ca ++ /calmodulin dependent enzyme located in the brain (ncNOS or NOS 1) and elsewhere, that releases
  • 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.
  • 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 Utters, 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. 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).
  • 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.
  • 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
  • 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).
  • a yet further aspect of the present invention provides thiazine and thiazolone derivatives or salts thereof in the manufacture of a medicament for use in cytokine or cytokine-inducing therapy, as an adjuvant to short term l o 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, 0 IL-2 therapy such as in 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, inflammatory sequelae of viral infections, myocarditis, heart failure, atherosclerosis, arthritis, rheumatoid 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
  • Compounds of Formula I are also usful in the treatment of hypoxia, hyperbaric oxygen convulsions and toxicity, dementia, Sydenham's chorea, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, mulitple sclerosis, Korsakoff s disease, imbecility related to l o cerebral vessel disorder, NO mediated cerebral trauma and related sequelae, ischemic brain edema, sleeping disorders, schizophrenia, depression, pre-menstrual syndrome (PMS), anxiety, drug addiction, pain, migraine, immune complex disease, as immunosupressive agents, acute allograft rejection, infections caused by invasive microorganisms
  • PMS pre-menstrual syndrome
  • n O, 1, 2, 3 or 4
  • X is selected from C2, O, S and NH
  • Rl, R2 and R3 are each independently selected from the group consisting of
  • hetero C5-i ⁇ cycloalkyl wherein the hetero C5-l ⁇ cycloalkyl optionally contains 1 or 2 heteroatoms selected from S, 0 and N,
  • aryl selected from phenyl or naphthyl
  • heteroaryl wherein heteroaryl is selected from the group consisting of:
  • R6 is selected from hydrogen, phenyl, cyclohexyl or Ci-6alkyl, each of (b) to (m) being optionally mono or di- substituted the substituents being independently selected from (l) hydroxy,
  • R7 is selected from hydrogen, phenyl, cyclohexyl or Cl-6alkyl
  • halo selected from F, Cl, Br and I
  • halo selected from F, Cl, Br and I
  • phenyl optionally mono or di-substituted with hydroxy, halo, Ci-4alkyl, or Ci-4alkoxy, (c) -CONR8R9, where R8 and R9 are each independently hydrogen, phenyl, cyclohexyl or Ci-6alkyl, said Cl-6alkyl optionally substituted by
  • halo selected from F, Cl, Br and I
  • n 0, 1, 2, 3 or 4
  • X is selected from O, S and NH
  • Rl, R2 and R3 are each independently selected from the group consisting of
  • hetero C5 or C6 cycloalkyl wherein the hetero C5 or C6 cycloalkyl optionally contains 1 heteroatom selected from S,
  • aryl selected from phenyl or naphthyl
  • heteroaryl wherein heteroaryl is selected from the group consisting of:
  • halo selected from F, Cl, Br and I
  • halo selected from F, Cl, Br and I
  • X is selected from O, S and NH, Rl and R2 are each independently selected from the group consisting of
  • R4 is selected from the group consisting of
  • R5 is selected from the group consisting of
  • any variable e.g. Rl, R2, R3, R4, R5, 6, R7, R8, Ra, Rb, k, n, p etc.
  • any variable e.g. Rl, R2, R3, R4, R5, 6, R7, R8, Ra, Rb, k, n, p etc.
  • compounds of Formula I include those wherein there is a double bond at side a or b such as shown in Ia and lb or tautomeric forms thereof
  • p is 0, 1, or 2 and n is defined as above and wherein the second ring may contain up to three hetero atoms selected from N, O or S
  • p is 0, 1, or 2 and wherein the second ring may contain up to three hetero atoms selected from N, O or S
  • 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.
  • C 1-6 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, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, 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, pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,4,5-tetrazine, and the like.
  • the compounds of the instant invention are useful for 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 containing the active ingredient 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.
  • l o 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
  • 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 20 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
  • 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.
  • excipients are suspending agents, for example sodium carboxymethyl-cellulose, methylcellulose, hydroxy-
  • 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 l o 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
  • 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
  • compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granule 1- suitable for preparation of an aqueous suspension by the addition of wat provide the active
  • 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.
  • Suitable 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
  • 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.
  • l o
  • 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
  • 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-[2,3,4,5-3H]Arginine.
  • the incubation buffer 100 30 ⁇ L contained; 100 mM TES, pH 7.5, 5 ⁇ M FAD, 5 ⁇ M FMN, 10 ⁇ M BH4, 0.5 mM NADPH, 0.5 mM DTT, 0.5 mg/mL BSA, 2 mM CaC12, 10 ⁇ g/mL calmodulin (bovine), 1 ⁇ M L-Arg, 0.2 ⁇ Ci L-[2,3,4,5- 3 H]Arg, and the inhibitor in aqueous DMSO (max. 5 %).
  • the reaction is initiated by addition of enzyme.
  • the aminoalkyl halides starting materials are commercially available or they can be prepared by the methods known to those skilled in the art.
  • the amine substrate for the displacement reaction may contain a different leaving group such as a mesylate or a tosylate which are prepared fron the corresponding alcohol using the methods described in March J. Advanced Organic Chemistry, 3rd ed., John Wiley & Sons, New York, p. 444 (1985).
  • the amine is first reacted with an acylating agent such as an alkyl, aryl or acyl isothiocyanate and the resulting thiourea is cyclized upon heating with or without a base 5 catalyst. If an acylisothiocyanate is used (Example 19) a 2- acylaminothiazine product is obtained.
  • Path c of scheme 1 shows a third way for forming the desired ring structures.
  • the aminoalcohol, halide or other l o suitable derivative is reacted with carbon disulfide to form the heterocyclic ring system with a thiocarbonyl group.
  • Methylation and displacement of the resulting methylthio group with ammonia or an amine gives the desired 2-amino substituted heterocycle.
  • the 2-aminothiazoline (and other rings) prepared by methods shown in schemes 1 or 2 can be further modified, for example by acylation (scheme 3).
  • acylation Scheme 3
  • reaction of 2-Amino-5,6-dihydro-4H-l,3- thiazine with an acid chloride or anhydride optionally in the presence of a base gives a 2-acylamino analog.
  • Other acylation procedures as described in March J., Advanced Organic Chemistry, 3rd ed., John Wiley & Sons, New York, (1985) may also be used. If an isocyanate or an isothiocyanate (Example 12) is used for acylation, the product is a urea or a thiourea.
  • ureas or a thioureas can also be prepared by reacting the amino compound with phosgene, thiophosgene, or other carbonyl tranfer reagents such as carbonyldiimidazole or thiocarbonyldiimidazole followed by reaction with another amine (Example 15) .
  • SCHEME 3
  • ⁇ __c. 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 (miHigrams(s)), mol (moles), mmol (millimoles), eq (equivalent(s)).
  • Mass Spectrum m/e 275,159,145, 142, 129, 117.
  • Mass Spectrum m/e 303, 170, 159, 145, 143, 118, 102(M+1).
  • Mass Spectrum m/e 337, 292, 207, 191, 177, 159.
  • Step B 2-Benzoylamino-4H-3.1-benzothiazine.
  • Step A Na-(t-ButoxycarbonylV5-(2-thiazolinyl)amino-norvaline t- butyl ester.
  • Step B 5-(2-Thiazolin vDamino-norvaline hy drochloride .
  • HC1 gas was passed through 2 mL EtOAc at 0 "C until it was saturated.
  • This solution (2 mL) was added to 54 mg (0.144 mmol) of N 3 - (t-butoxycarbonyl)-5-(2-thiazolinyl)amino-norvaline t-butyl ester (from step A) and the mixture was stirred overnight. A white solid was formed. The mixture was diluted with Et2 ⁇ , the solid was filtered, washed with Et2 ⁇ and dried to isolate 26 mg (71%) of the title compound.
  • Step A 5-CS )-2-Thioxo-3-thia- 1 -aza-bicyclof 3.3 ,0)octane.
  • Step B 5-(SV2-Imino-3-thia-l-aza-bicvclo(3.3.0 octane.
  • Step C 3-Methanesulfonyloxy-2-methyl-butylamine hydrochloride.
  • Step D 2- Amino-cis-5.6-dimethyl-5.6-dihydro-4H- 1 ,3-thiazine. methanesulfonic acid salt
  • the suspension was heated to reflux for 2 h then cooled in ice bath and quenched by sequencially adding 0.48 mL of water, 0.48 mL of 15% NaOH solution and 1.5 mL of water. The mixmre was stirred for 0.5 h to allow the aluminium salts to coagulate. The solution was filtered through Na2S ⁇ 4 and the solid was rinsed with Et2 ⁇ . The combined filtrate was concentrated to yield 0.54 g of the title product as an oil which was used in the next step without purification.
  • Step C 2-Amino-trans-4.5-dimethyl-5.6-dihvdro-4H-L3-thiazine. methane sulfonic acid salt
  • the title compound was prepared from the threo isomer of 3-t-butyloxyamino-2-methyl-l-butanol by the method described in Example 26 steps C and D.
  • Example 30 The title compound was synthesized from erythro 3-t- butyloxyamino-2-methyl-l-butanol (Example 30, step B) according to the procedure of Example 26 steps C and D.
  • Step A trans- l-Amino-2-hydroxymethyl-cyclohexane hvdrochloride
  • the title compound was prepared fron ethyl cyclohexanone- 2-carboxylate by the method described in Example 31 step A.
  • Step B 4-Amino-3-thia-5-aza-trans-bicyclo(4.4.0Vdec-4-ene. methane sulfonic acid salt
  • This compound was prepared from trans- l-amino-2- hydroxymethyl-cyclohexane hydrochloride by the procedure of Example 26 steps C and D.
  • the title compound was prepared from l(R)-2(S)-l-amino- 2-hydroxymethyl-cyclohexane by the method of Example 26 steps C and D.
  • the title compound was prepared from l(S)-2(R)-l-amino- 2-hydroxymethyl-cyclohexane by the method of Example 26 steps C and D.
  • the compounds of Examples 35-38 were synthssized by the method of Example 26 steps C and D starting with the appropriate aminoalcohol.

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Abstract

L'invention traite de composés de la formule (I) et de leurs sels, acceptables du point de vue pharmaceutique. Ces substances ont montré leur efficacité dans le traitement de maladies et de troubles induits par la synthétase de l'oxyde nitrique, des troubles neurodégénératifs notamment, ainsi que des troubles de la motilité gastro-intestinale ou des troubles de nature inflammatoire. Parmi ces maladies et ces troubles figurent l'hypotension, le choc septique, le syndrome de choc toxique, des désordres liés à l'hémodialyse, à la thérapie par l'IL-2 chez des patients atteints de cancer, la cachexie, l'immuno-dépression, dans des cas de thérapie de transplantation par exemple, des signes auto-immunes et /ou inflammatoires, y compris l'érythème solaire et le psoriasis et des affections respiratoires comme la bronchite, l'asthme, la détresse respiratoire aiguë, la myocardite, l'insuffisance cardiaque, l'artériosclérose, l'arthrite, la polyarthrite rhumatoïde, les affections intestinales chroniques ou inflammatoires, la rectolite hémorragique, le lupus érythémateux aigu disséminé, des troubles ophtalmiques tels que l'hypertonie oculaire et l'uvéite, le diabète du type 1, le diabète sucré insulinodépendant et la mucoviscidose. Des composés de la formule I sont également efficaces dans le traitement de l'hypoxie, des convulsions dues à l'absorption d'oxygène hyperbare et de désordres imputables à la toxicité de l'oxygène hyperbare, de la démence, de la chorée de Sydenham, de la maladie de Parkinson, de la maladie d'Huntington, de la sclérose latérale amyotrophique, de la sclérose en plaques, de la maladie de Korsakoff, de l'idiotie liée à des troubles cérébro-vasculaires, de l'oedème cérébral ischémique, des troubles du sommeil, de la schizophrénie, de la dépression, du syndrome prémenstruel, de l'anxiété, des algies, de la migraine, de la maladie des complexes immuns, en tant qu'agents immunodépresseurs et dans la prévention de la tolérance aux opiacés et aux diazépines ou pour le retour à celle-ci.
PCT/US1995/014512 1994-11-15 1995-11-13 Heterocycles a substitutions utilises en tant qu'inhibiteurs de la synthetase d'oxyde nitrique WO1996014842A1 (fr)

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EP0870763A1 (fr) * 1997-04-10 1998-10-14 Ono Pharmaceutical Co., Ltd. Derives condenses de la piperidine comme inhibiteur de synthese de monoxide d'azote
US5854234A (en) * 1993-10-21 1998-12-29 G. D. Searle & Co. Amidino dervatives useful as nitric oxide synthase inhibitors
US5872124A (en) * 1996-07-31 1999-02-16 Thomas Jefferson University Treatment of diseases of the central nervous system using uric acid as a scavenger of peroxynitrite
US5883251A (en) * 1995-04-20 1999-03-16 G. D. Searle & Co. Azepine derivatives useful as nitric oxide synthase inhibitors
US5945408A (en) * 1996-03-06 1999-08-31 G.D. Searle & Co. Hydroxyanidino derivatives useful as nitric oxide synthase inhibitors
US5958958A (en) * 1997-07-22 1999-09-28 G.D. Searle & Co. 1,2,4-oxa diazolino and 1,24-oxa diazolidion heterocycles as useful nitric oxide synthase inhibitors
EP1004317A1 (fr) * 1997-08-12 2000-05-31 Chugai Seiyaku Kabushiki Kaisha Remedes contre les maladies associees a la resorption osseuse
WO2000064904A1 (fr) * 1999-04-28 2000-11-02 Astrazeneca Ab Derives d'amidine 5,7-bicyclique utiles en tant qu'inhibiteurs de l'oxyde nitrique synthase
WO2001093867A1 (fr) * 2000-06-09 2001-12-13 Aventis Pharma S.A. Derives de 4,5-dihydro-thiazol-2-ylamine et leur utilisation comme inhibiteurs de no synthase
WO2001094325A1 (fr) * 2000-06-09 2001-12-13 Aventis Pharma S.A. Derives de 2-aminothiazoline et leur utilisation comme inhibiteurs de no-synthase
US6344473B1 (en) 2000-08-07 2002-02-05 G.D. Searle & Co. Imidazoles useful as nitric oxide synthase inhibitors
US6353006B1 (en) 1999-01-14 2002-03-05 Bayer Corporation Substituted 2-arylimino heterocycles and compositions containing them, for use as progesterone receptor binding agents
US6420566B2 (en) 2000-06-09 2002-07-16 Aventis Pharma S.A. Pharmaceutical compositions containing a 4, 5-dihydro-1, 3-thiazol-2-ylamine derivative, novel derivatives and preparation thereof
US6432947B1 (en) 1997-02-19 2002-08-13 Berlex Laboratories, Inc. N-heterocyclic derivatives as NOS inhibitors
US6433019B1 (en) 1998-01-30 2002-08-13 Sumitomo Pharmaceuticals Company, Limited Neurotrophic factor secretion promoters
US6451821B1 (en) 2000-06-09 2002-09-17 Aventis Pharma S.A. Use of 2-aminothiazoline derivatives as inhibitors of inducible no-synthase
US6489323B1 (en) 1998-06-10 2002-12-03 G.D. Searle & Co. Heterobicyclic and tricyclic nitric oxide synthase inhibitors
US6525051B2 (en) 2000-03-27 2003-02-25 Schering Aktiengesellschaft N-heterocyclic derivatives as NOS inhibitors
WO2003022309A1 (fr) * 2001-09-10 2003-03-20 Ono Pharmaceutical Co., Ltd. Remedes pour maladies allergiques
WO2003040115A1 (fr) * 2001-11-09 2003-05-15 Aventis Pharma S.A. Derives de 2-amino-thiazoline et leur utilisation comme inhibiteurs de no-synthase inductible
WO2003040142A1 (fr) * 2001-11-09 2003-05-15 Aventis Pharma S.A. Derives de 2-amino-4-heteroarylethyl thiazoline et leur utilisation comme inhibiteurs de no-synthase inductible
FR2832152A1 (fr) * 2001-11-09 2003-05-16 Aventis Pharma Sa Utilisation de derives de 2-amino-thiazoline comme inhibiteurs de no-synthase inductible
FR2832150A1 (fr) * 2001-11-09 2003-05-16 Aventis Pharma Sa Utilisation de derives de 2-amino-4-pyridylmethyl-thiazoline comme inhibiteurs de no-synthase inductible
FR2832151A1 (fr) * 2001-11-09 2003-05-16 Aventis Pharma Sa Utilisation de derives de 2-amino-4-heteroarylethyl-thiazoline comme inhibiteurs de no-synthase inductible
WO2003075922A1 (fr) * 2002-03-14 2003-09-18 Dainippon Pharmaceutical Co., Ltd. Inhibiteurs de la synthetase du monoxyde d'azote
WO2003039446A3 (fr) * 2001-11-09 2003-11-27 Aventis Pharma Sa Derives de 2-amino-4-pyridylmethyl-thiazoline et leur utilisation comme inhibiteurs de no-synthase inductible
US6982259B2 (en) 2002-04-30 2006-01-03 Schering Aktiengesellschaft N-heterocyclic derivatives as NOS inhibitors
WO2007049532A1 (fr) 2005-10-25 2007-05-03 Shionogi & Co., Ltd. Derive aminodihydrothiazine
WO2008133273A1 (fr) 2007-04-24 2008-11-06 Shionogi & Co., Ltd. Composition pharmaceutique pour le traitement de la maladie d'alzheimer
WO2008133274A1 (fr) 2007-04-24 2008-11-06 Shionogi & Co., Ltd. Dérivés d'aminodihydrothiazine substitués par des groupes cycliques
WO2009151098A1 (fr) 2008-06-13 2009-12-17 塩野義製薬株式会社 DÉRIVÉ HÉTÉROCYCLIQUE CONTENANT DU SOUFRE AYANT UNE ACTIVITÉ INHIBANT LA β-SÉCRÉTASE
US7648983B2 (en) 2008-05-02 2010-01-19 Eli Lilly And Company BACE inhibitors
WO2010041964A1 (fr) * 2008-10-09 2010-04-15 Victoria Link Limited Procédés pour la préparation d'alcénylamines, de carbamates cycliques ou de dithiocarbamates, et d'aminoalcools ou d'aminothiols
TWI423970B (zh) * 2008-01-18 2014-01-21 Eisai R&D Man Co Ltd 經稠合之胺基二氫噻衍生物
US8703785B2 (en) 2008-10-22 2014-04-22 Shionogi & Co., Ltd. 2-aminopyrimidin-4-one and 2-aminopyridine derivatives both having BACE1-inhibiting activity
US8883779B2 (en) 2011-04-26 2014-11-11 Shinogi & Co., Ltd. Oxazine derivatives and a pharmaceutical composition for inhibiting BACE1 containing them
US8927721B2 (en) 2010-10-29 2015-01-06 Shionogi & Co., Ltd. Naphthyridine derivative
US8999980B2 (en) 2009-12-11 2015-04-07 Shionogi & Co., Ltd. Oxazine derivatives
US9018219B2 (en) 2010-10-29 2015-04-28 Shionogi & Co., Ltd. Fused aminodihydropyrimidine derivative
JP2016503785A (ja) * 2012-12-19 2016-02-08 ファイザー・インク 炭素環式および複素環式置換ヘキサヒドロピラノ［３，４−ｄ］［１，３］チアジン−２−アミン化合物
JP2016507580A (ja) * 2013-02-15 2016-03-10 ファイザー・インク 置換フェニルヘキサヒドロピラノ［３，４−ｄ］［１，３］チアジン−２−アミン化合物
JP2016507551A (ja) * 2013-02-13 2016-03-10 ファイザー・インク ヘテロアリール置換ヘキサヒドロピラノ［３，４−ｄ］［１，３］チアジン−２−アミン化合物
US9540359B2 (en) 2012-10-24 2017-01-10 Shionogi & Co., Ltd. Dihydrooxazine or oxazepine derivatives having BACE1 inhibitory activity
WO2019177142A1 (fr) * 2018-03-16 2019-09-19 脳科学香料株式会社 Agent prophylactique ou thérapeutique pour lésion hypoxique, lésion d'ischémie-reperfusion et inflammation, agent de protection de cellule pour la transplantation, et agent de bio-conservation

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US6448286B1 (en) 1993-10-21 2002-09-10 G.D. Searle & Co. Imino pyrrolidine derivatives useful as nitric oxide synthase inhibitors
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US5883251A (en) * 1995-04-20 1999-03-16 G. D. Searle & Co. Azepine derivatives useful as nitric oxide synthase inhibitors
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US9540359B2 (en) 2012-10-24 2017-01-10 Shionogi & Co., Ltd. Dihydrooxazine or oxazepine derivatives having BACE1 inhibitory activity
JP2016503785A (ja) * 2012-12-19 2016-02-08 ファイザー・インク 炭素環式および複素環式置換ヘキサヒドロピラノ［３，４−ｄ］［１，３］チアジン−２−アミン化合物
JP2016507551A (ja) * 2013-02-13 2016-03-10 ファイザー・インク ヘテロアリール置換ヘキサヒドロピラノ［３，４−ｄ］［１，３］チアジン−２−アミン化合物
JP2016507580A (ja) * 2013-02-15 2016-03-10 ファイザー・インク 置換フェニルヘキサヒドロピラノ［３，４−ｄ］［１，３］チアジン−２−アミン化合物
WO2019177142A1 (fr) * 2018-03-16 2019-09-19 脳科学香料株式会社 Agent prophylactique ou thérapeutique pour lésion hypoxique, lésion d'ischémie-reperfusion et inflammation, agent de protection de cellule pour la transplantation, et agent de bio-conservation
CN111918649A (zh) * 2018-03-16 2020-11-10 脑科学香料株式会社 缺氧障碍、缺血再灌注障碍或炎症的预防或治疗剂，移植用细胞保护剂，及生物体防腐剂
JPWO2019177142A1 (ja) * 2018-03-16 2021-07-08 脳科学香料株式会社 低酸素障害、虚血再灌流障害又は炎症の予防又は治療剤、移植用細胞保護剤、及び生体保存剤
US11590141B2 (en) 2018-03-16 2023-02-28 Scent Science International Inc. Prophylactic or therapeutic agent for hypoxic injury, ischemia-reperfusion injury and inflammation, cell protection agent for transplantation, and bio-preservation agent
CN111918649B (zh) * 2018-03-16 2024-07-30 脑科学香料株式会社 缺氧障碍、缺血再灌注障碍或炎症的预防或治疗剂，移植用细胞保护剂，及生物体防腐剂
US12076325B2 (en) 2018-03-16 2024-09-03 Scent Science International Inc. Prophylactic or therapeutic agent for hypoxic injury, ischaemia-reperfusion injury and inflammation, cell protection agent for transplantation, and bio-preservation agent

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