WO1996018617A1 - Pyridines 2-acylaminees substitutees utilisees comme inhibiteurs de synthase d'oxyde d'azote - Google Patents

Pyridines 2-acylaminees substitutees utilisees comme inhibiteurs de synthase d'oxyde d'azote Download PDF

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WO1996018617A1
WO1996018617A1 PCT/US1995/016158 US9516158W WO9618617A1 WO 1996018617 A1 WO1996018617 A1 WO 1996018617A1 US 9516158 W US9516158 W US 9516158W WO 9618617 A1 WO9618617 A1 WO 9618617A1
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group
phenyl
aryl
naphthyl
amino
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PCT/US1995/016158
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English (en)
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Ravindra K. Guthikonda
William K. Hagmann
Malcolm Maccoss
Shrenik K. Shah
Philippe L. Durette
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Merck & Co., Inc.
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Priority to US08/836,863 priority Critical patent/US5908842A/en
Priority to AU45158/96A priority patent/AU4515896A/en
Publication of WO1996018617A1 publication Critical patent/WO1996018617A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with 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
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl

Definitions

  • This application is directed to inhibitors of nitric oxide synthase, and in particular 2-acylamino-pyridines.
  • 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.
  • 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, 02 and NADPH are co- substrates while FMN, FAD and tetrahydrobiopterin are co-factors.
  • 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 (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 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 has 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.
  • NOS 1 and NOS 3 act 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 Letters, 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- ⁇ ), interleukin- 1 ⁇ (IL- 1 ⁇ ), tumor necrosis factor (TNF- ⁇ ) and LPS (lipopolysaccharide). Once induced, iNOS expression continues over a prolonged period of time. The enzyme does not require exogenous calmodulin for activity.
  • cytokines such as gamma interferon (IFN- ⁇ ), interleukin- 1 ⁇ (IL- 1 ⁇ ), tumor necrosis factor (TNF- ⁇ ) and 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). 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).
  • 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). 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 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 1 diabetes
  • Compounds of Formula I are also useful 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 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 which produce NO, radiocontrast induced renal failure and for preventing or reversing tolerance to opiates and diazepines.
  • PMS pre-menstrual syndrome
  • Rl, R2, R3 and R4 are each independently selected from the group consisting of (a) hydrogen,
  • halo where halo is selected from fluoro, chloro, bromo, and iodo, (i) trifluoromethyl, (j) Cl-I2alkyl, (k) C2-12alkenyl, (1) C2-12alkynyl, (m) Cl-12alkoxy, (n) Cl-l2alkylcarbonyl,
  • Ci-i2alkoxycarbonyl (p) C 1 - 12alkylaminocarbonyl, (q) mono- and di-C l - 12alkylamino, (r) Cl-l2alkylthio, (s) aryl, where aryl is selected from phenyl and naphthyl,
  • aryloxy where aryl is selected from phenyl and naphthyl
  • arylthio where aryl is selected from phenyl and naphthyl
  • arylCl-6alkyl where aryl is selected from phenyl and naphthyl
  • cycloalkyl wherein the cycloalkyl is a 5- to 10-membered monocyclic ring which optionally contains 1 or 2 heteroatoms selected from S, O, and N
  • heteroaryl wherein heteroaryl is selected from the group consisting of: (1) pyridyl,
  • halo selected from fluoro, chloro, bromo, and iodo
  • R2, or R2 and R3 or R3 and R4 including the optional substituents present thereon may be joined together to form a 5- to 10-membered saturated or unsaturated ring containing 0, 1 or 2 heteroatoms which together with the atoms to which Rl and R2, or R2 and R3 or R3 and R4 are attached there is formed a bicyclic ring according to Formulae (Ila-IIc), the heteroatoms being selected from the group consisting of O, S and N,
  • arylcarbonyl wherein the aryl group is selected from phenyl and naphthyl
  • heteroarylcarbonyl wherein heteroaryl is selected from the group consisting of:
  • aryloxycarbonyl wherein the aryl group is selected from phenyl an naphthyl
  • heteroarylCl-6alkoxycarbonyl wherein the heteroaryl group is defined ⁇ as above in item (g),
  • arylaminocarbonyl wherein the aryl group is selected from phenyl and naphthyl
  • arylaminosulfonyl wherein the aryl group is selected from phenyl and naphthyl
  • aryl wherein the aryl group is selected from phenyl and naphthyl
  • R6 and R7 may be joined together to form a 5- to 10-membered monocylic ring containing 0, 1 or 2 heteroatoms, the heteroatoms being selected from the group of S, O, and N,
  • halo selected from fluoro, chloro, bromo, and iodo
  • Rl, R2, R3 and R4 are each independently selected from the group consisting of
  • R2, or R2 and R3 or R3 and R4 including the optional substituents present thereon may be joined together to form a 5-, 6- or 7-membered saturated monocyclic ring containing 0, 1 or 2 heteroatoms which together with the atoms to which Rl and R2, or R2 and R3 or R3 and R4 are attached there is formed a bicyclic ring according to Formulae (Ila-IIc), the heteroatoms being selected from the group consisting of O, S and N,
  • aryl wherein the aryl group is selected from phenyl
  • R and R7 may be joined together to form a 5-, 6- or 7-membered ring containing 0 to 2 heteroatoms, the heteroatoms being elected from the group of oxygen, sulfur and nitrogen,
  • halo selected from fluoro, chloro, bromo, and iodo
  • Rl, R2, R3 and R4 are each independently selected from the group consisting of
  • Rl and R2, or R2 and R3 or R3 and R4 including the optional substituents present thereon may be joined together to form a 5, 6 or 7-membered unsaturated monocyclic ring containing 0, 1 or 2 heteroatoms which together with the atoms to which Rl and R2, or R2 and R3 or R3 and R4 are attached there is formed a bicyclic ring according to Formulae (Ila-IIc), the heteroatoms being selected from the group consisting of O, S and N,
  • R5 is selected from the group consisting of
  • each of (b) to (f) being optionally mono- or di- substituted, the substituents being independently selected from (1) hydroxy,
  • halo selected from fluoro, chloro, and bromo.
  • Formulae Ila, lib and lie are selected from the group consisting of
  • Rl, R2, R3 and R4 are each independently selected from the group consisting of
  • aryl wherein the aryl group is selected from phenyl
  • each of (b) to (f) being optionally mono- or di- substituted, the substituents being independently selected from
  • 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.
  • Cl-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 but is not limited to, pyridyl, pyrrolyl, furanyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuranyl, isobenzofuryl, benzothienyl, pyrazolyl, pyridazinyl, indolyl, isoindolyl, purinyl, carboxazolyl, isoxazolyl, thiazolyl, triazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, benzthiazolyl and benzoxazolyl.
  • 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.
  • 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.
  • 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 gly eery 1 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-propylmethy- cellulose, 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
  • 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.
  • preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • flavoring agents such as sucrose, saccharin or aspartame.
  • 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.
  • 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.
  • 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.
  • these compounds are prepared by the Chitchibabin reaction involving the reaction of a substituted pyridine derivative with sodium amide or sodium amide in the presence of a substituted amine to yield a 2-aminopyridine derivative.
  • This methodology is amenable to a broad range of substitutents.
  • the pyridine and substituted amine starting materials are commercially available or they can be prepared by the methods known to those skilled in the art.
  • 2-halopyridines can be reacted with ammonia or substituted amines in the presence of copper (II) sulfate to form the 2-aminopyridine derivative.
  • the preparation of a variety of 2-halopyridine derivatives has been reviewed (see H. E. Mertel in The Chemistry of Heterocyclic Compounds, Pyridine and Its Derivatives, Part 2 E. Klingsberg, ed.; Interscience, NY, 1962, Ch. VI, pp. 299-419).
  • a recent publication describes new methodology for the preparation of highly functionalized 2-halopyridine derivatives (see P. Rocca et al, J. Org. Chem. 1993, 58, 7832-7838).
  • N'-(aminosulfonyl)-ureas C were prepared following methodology described by Karady et al. in Heterocycles, 1979, 12, 815-818 and illustrated in Scheme 6.
  • the appropriately substituted 2- aminopyridine A is reacted with chlorosulfonyl isocyanate in the presence of an organic base, such as triethylamine and diisopropylethylamine, to afford the intermediate thiatriazene B.
  • an organic base such as triethylamine and diisopropylethylamine
  • the title compound was synthesized according to the procedure in Example 2 by employing 2-amino-4,6-dimethylpyridine instead of 2-amino-4-methylpyridine.
  • Example 8 The title compound was synthesized according to the procedure in Example 8 by employing 4-bromophenyl isothiocyanate instead of phenyl isothiocyanate and 2-aminopyridine instead of 4-methyl-2-aminopyridine.
  • Benzoyl isocyanate (147 mg, 1 mmol) was added dropwise to a suspension of 2-amino-4-methylpyridine (108 mg, 1 mmol) in ether (10 mL) at room temperature. A precipitate formed instantaneously. After stirring 4 hours at room temperature, solid was filtered and washed with ether twice. The resulting white solid was dried in vacuo to give title compound (105 mg).
  • Step A N-(2-(4-Methylpyridyl))-N'-(((S)-4-t-butoxycarbonylamino- 4-t-butoxycarbonyl)-n-butyl -thiourea.
  • Step B N-(2-(4-MethylpyridynVN'-(((SV4-amino-4-carboxy)-n- butyP-thiourea.
  • NOS activity is measured as the formation of L-[2,3,4,5- 3H]Citrulline from L-[2,3,4,5- 3 H]Arginine.
  • the incubation buffer 100 ⁇ 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-aArg, 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.
  • 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 Human Inducible Nitric Oxide Synthase by

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Abstract

Cette invention concerne des composés de pyridine 2-acylaminée substituée et de leurs sels viables sur le plan pharmaceutique, lesquels composés peuvent être utilisés dans le traitement de maladies et de troubles dus à la synthase d'oxyde d'azote.
PCT/US1995/016158 1994-12-12 1995-12-08 Pyridines 2-acylaminees substitutees utilisees comme inhibiteurs de synthase d'oxyde d'azote WO1996018617A1 (fr)

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US08/836,863 US5908842A (en) 1995-12-08 1995-12-08 Substituted 2-acylamino-pyridines as inhibitors of nitric oxide synthase
AU45158/96A AU4515896A (en) 1994-12-12 1995-12-08 Substituted 2-acylamino-pyridines as inhibitors of nitric oxide synthase

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Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998000430A1 (fr) * 1996-06-27 1998-01-08 Schering Aktiengesellschaft Derives d'imidazol utiles comme inhibiteurs de la synthase de monoxyde d'azote
WO1999011621A2 (fr) * 1997-09-03 1999-03-11 American Home Products Corporation Thiouree elevant les niveaux de hdl-cholesterol s'averant utilies comme agents antiatherosclereux
US5962531A (en) * 1997-01-28 1999-10-05 Syntex (U.S.A.) Inc. 5-aroylnaphthalene derivatives as anti-inflammatory agents
WO1999052522A1 (fr) * 1998-04-15 1999-10-21 King's College, London University Protection du systeme nerveux a l'aide de bloquants des canaux sodiques
US6022884A (en) * 1997-11-07 2000-02-08 Amgen Inc. Substituted pyridine compounds and methods of use
WO2000027842A1 (fr) * 1998-11-05 2000-05-18 Astrazeneca Ab Composes
WO2000048591A1 (fr) * 1999-02-16 2000-08-24 Angiogene Pharmaceuticals Ltd. Combinaisons pour traiter les maladies faisant intervenir l'angiogenese
US6239142B1 (en) 1999-03-09 2001-05-29 Pharmacia & Upjohn Company 4-oxo-4,7-dihydro-thieno[2,3-b]pyridine-5carboxamides as antiviral agents
US6620810B2 (en) 2001-08-30 2003-09-16 Pharmacia & Upjohn Company 4-thioxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carboxamides as antiviral agents
WO2004087666A1 (fr) * 2003-03-31 2004-10-14 Astrazeneca Ab Nouveaux derives de 2-aminopyridine substituee en n
WO2004087665A1 (fr) * 2003-03-31 2004-10-14 Astrazeneca Ab Nouveaux derives de 2-aminopyridine substituee en 6
US6852731B2 (en) 2002-01-14 2005-02-08 Pfizer Antiviral compounds
US6861438B2 (en) 2002-01-14 2005-03-01 Pfizer Antiviral agents
US6878705B2 (en) 2002-01-14 2005-04-12 Pfizer 4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide antiviral agents
US6924283B2 (en) 2001-08-30 2005-08-02 Pfizer 4-thioxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carbothioamides as antiviral agents
WO2009046784A1 (fr) 2007-10-09 2009-04-16 Merck Patent Gmbh Dérivés de pyridine utiles comme activateurs de glucokinase
US7649004B2 (en) 2004-07-23 2010-01-19 Pfizer, Inc. Pyridine derivatives
US8134007B2 (en) 2007-05-03 2012-03-13 Pfizer Inc. Pyridine derivatives
US8686002B2 (en) 2005-08-21 2014-04-01 AbbVie Deutschland GmbH & Co. KG Heterocyclic compounds and their use as binding partners for 5-HT5 receptors
US9951069B1 (en) 2017-01-11 2018-04-24 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US10421756B2 (en) 2015-07-06 2019-09-24 Rodin Therapeutics, Inc. Heterobicyclic N-aminophenyl-amides as inhibitors of histone deacetylase
US10919902B2 (en) 2015-07-06 2021-02-16 Alkermes, Inc. Hetero-halo inhibitors of histone deacetylase
US11225475B2 (en) 2017-08-07 2022-01-18 Alkermes, Inc. Substituted pyridines as inhibitors of histone deacetylase
US11548867B2 (en) 2017-07-19 2023-01-10 Idea Ya Biosciences, Inc. Amido compounds as AhR modulators
WO2023176554A1 (fr) * 2022-03-14 2023-09-21 国立大学法人東北大学 Agent améliorant la fonction cognitive

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WO1994014780A1 (fr) * 1992-12-18 1994-07-07 The Wellcome Foundation Limited Derives de pyrimidine, de pyridine, de pteridinone et d'indazole utilises comme inhibiteurs enzymatiques

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CHEMICAL ABSTRACTS, Volume 98, No. 7, issued 14 February 1983, DAVE et al., "Synthesis and Biological Activity of Some Pyridylthioureas and Pyridopyrimidinethiones", page 607, Abstract No. 53822z; & INDIAN J. PHARM. SCIENCE, 1982, 44(4), 83-5, (Eng.). *

Cited By (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998000430A1 (fr) * 1996-06-27 1998-01-08 Schering Aktiengesellschaft Derives d'imidazol utiles comme inhibiteurs de la synthase de monoxyde d'azote
US6150397A (en) * 1997-01-28 2000-11-21 Syntex (U.S.A.) Inc. 5-aroylnaphthalene derivatives as anti-inflammatory agents
US5962531A (en) * 1997-01-28 1999-10-05 Syntex (U.S.A.) Inc. 5-aroylnaphthalene derivatives as anti-inflammatory agents
WO1999011621A2 (fr) * 1997-09-03 1999-03-11 American Home Products Corporation Thiouree elevant les niveaux de hdl-cholesterol s'averant utilies comme agents antiatherosclereux
WO1999011621A3 (fr) * 1997-09-03 1999-07-01 American Home Prod Thiouree elevant les niveaux de hdl-cholesterol s'averant utilies comme agents antiatherosclereux
US6184237B1 (en) 1997-11-07 2001-02-06 Amgen Inc. Substituted pyridine compounds and methods of use
US6022884A (en) * 1997-11-07 2000-02-08 Amgen Inc. Substituted pyridine compounds and methods of use
US6333341B1 (en) 1997-11-07 2001-12-25 Amgen Inc. Substituted pyridine compounds and methods of use
US6458813B1 (en) 1997-11-07 2002-10-01 Amgen Inc. Substituted pyridine compounds and methods of use
WO1999052522A1 (fr) * 1998-04-15 1999-10-21 King's College, London University Protection du systeme nerveux a l'aide de bloquants des canaux sodiques
WO2000027842A1 (fr) * 1998-11-05 2000-05-18 Astrazeneca Ab Composes
WO2000048591A1 (fr) * 1999-02-16 2000-08-24 Angiogene Pharmaceuticals Ltd. Combinaisons pour traiter les maladies faisant intervenir l'angiogenese
US7087627B1 (en) 1999-02-16 2006-08-08 Angiogene Pharmaceuticals Ltd. Combinations for the treatment of diseases involving angiogenesis
US6239142B1 (en) 1999-03-09 2001-05-29 Pharmacia & Upjohn Company 4-oxo-4,7-dihydro-thieno[2,3-b]pyridine-5carboxamides as antiviral agents
US6495683B2 (en) 1999-03-09 2002-12-17 Pharmacia And Upjohn Company 4-oxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carboxamides as antiviral agents
US6924283B2 (en) 2001-08-30 2005-08-02 Pfizer 4-thioxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carbothioamides as antiviral agents
US6620810B2 (en) 2001-08-30 2003-09-16 Pharmacia & Upjohn Company 4-thioxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carboxamides as antiviral agents
US6852731B2 (en) 2002-01-14 2005-02-08 Pfizer Antiviral compounds
US6861438B2 (en) 2002-01-14 2005-03-01 Pfizer Antiviral agents
US6878705B2 (en) 2002-01-14 2005-04-12 Pfizer 4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide antiviral agents
WO2004087666A1 (fr) * 2003-03-31 2004-10-14 Astrazeneca Ab Nouveaux derives de 2-aminopyridine substituee en n
WO2004087665A1 (fr) * 2003-03-31 2004-10-14 Astrazeneca Ab Nouveaux derives de 2-aminopyridine substituee en 6
US7649004B2 (en) 2004-07-23 2010-01-19 Pfizer, Inc. Pyridine derivatives
US8686002B2 (en) 2005-08-21 2014-04-01 AbbVie Deutschland GmbH & Co. KG Heterocyclic compounds and their use as binding partners for 5-HT5 receptors
US8134007B2 (en) 2007-05-03 2012-03-13 Pfizer Inc. Pyridine derivatives
WO2009046784A1 (fr) 2007-10-09 2009-04-16 Merck Patent Gmbh Dérivés de pyridine utiles comme activateurs de glucokinase
US10919902B2 (en) 2015-07-06 2021-02-16 Alkermes, Inc. Hetero-halo inhibitors of histone deacetylase
US11858939B2 (en) 2015-07-06 2024-01-02 Alkermes, Inc. Hetero-halo inhibitors of histone deacetylase
US10421756B2 (en) 2015-07-06 2019-09-24 Rodin Therapeutics, Inc. Heterobicyclic N-aminophenyl-amides as inhibitors of histone deacetylase
US10519149B2 (en) 2017-01-11 2019-12-31 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US10793567B2 (en) 2017-01-11 2020-10-06 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US10696673B2 (en) 2017-01-11 2020-06-30 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US11225479B2 (en) 2017-01-11 2022-01-18 Alkermes, Inc. Bicyclic inhibitors of histone deacetylase
US11286256B2 (en) 2017-01-11 2022-03-29 Alkermes, Inc. Bicyclic inhibitors of histone deacetylase
US9951069B1 (en) 2017-01-11 2018-04-24 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US11987580B2 (en) 2017-01-11 2024-05-21 Alkermes, Inc. Bicyclic inhibitors of histone deacetylase
US11548867B2 (en) 2017-07-19 2023-01-10 Idea Ya Biosciences, Inc. Amido compounds as AhR modulators
US11225475B2 (en) 2017-08-07 2022-01-18 Alkermes, Inc. Substituted pyridines as inhibitors of histone deacetylase
US11912702B2 (en) 2017-08-07 2024-02-27 Alkermes, Inc. Substituted pyridines as inhibitors of histone deacetylase
WO2023176554A1 (fr) * 2022-03-14 2023-09-21 国立大学法人東北大学 Agent améliorant la fonction cognitive

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