Classifications

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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • 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
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
  • C07D207/24—Oxygen or sulfur atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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, directly attached to ring carbon atoms
  • C07D211/74—Oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
  • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
  • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings 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
  • C07D223/12—Nitrogen atoms not forming part of a nitro radical
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
  • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
  • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
  • C07D267/02—Seven-membered rings
  • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
  • C07D267/10—Seven-membered rings having the hetero atoms in positions 1 and 4 not condensed with other rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/10—Spiro-condensed systems

Definitions

• the present invention relates to a idino derivative compounds, pharmaceutical compositions containing these novel compounds, and to their use in therapy, in particular their use as nitric oxide synthase inhibitors.
• endothelium-derived relaxing factor a labile humoral factor termed endothelium-derived relaxing factor (EDRF) .
• NO nitric oxide
• NO is the active component of amyl nitrite, glyceryl trinitrate and other nitrovasodilators.
• EDRF endothelium-derived relaxing factor
• NO is the endogenous stimulator of the soluble guanylate cyclase and is involved in a number of biological actions in addition to endothelium-dependent relaxation including cytotoxicity of phagocytic cells and cell-to-cell communicatior. in the central nervous system (see Moncada et al ⁇ Biochemical Pharmacology. 38. 1709-1715 (1989) and Moncada et al. Pharmacological Reviews. 43. 109-142 (1991) .
• L-arginine analogue L-N-monomethyl-arginine
• L-NMMA L-N-monomethyl-arginine
• the therapeutic use of certain other NO synthase inhibitors apart from L-NMMA for the same purpose has also been proposed in WO 91/04024 and in EP-A- 0446699.
• the NO released by the constitutive enzymes acts as a transduction mechanism underlying several physiological responses.
• the NO produced by the inducible enzyme is a cytotoxic molecule for tumor cells and invading microorganisms. 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 inducible NO synthase.
• autoimmune and/or inflammatory conditions affecting the joints for example arthritis, inflammatory bowel disease, cardiovascular ischemia, diabetes, hyperalgesia (allodynia) , cerebral ischemia (both focal ischemia, thrombotic stroke and global ischemia, secondary to cardiac arrest) , and other CNS disorders mediated by NO, including opiate tolerance in patients needing protracted opiate analgesics, benzodiazepine tolerance in patients taking benzodiazepines, and other addictive behaviors for example nicotine and eating disorder.
• inflammatory conditions affecting the joints for example arthritis, inflammatory bowel disease, cardiovascular ischemia, diabetes, hyperalgesia (allodynia) , cerebral ischemia (both focal ischemia, thrombotic stroke and global ischemia, secondary to cardiac arrest) , and other CNS disorders mediated by NO, including opiate tolerance in patients needing protracted opiate analgesics, benzodiazepine tolerance in patients taking benzodiazepines, and other addictive behaviors for example nicotine and
• autoimmune diseases and/or inflammatory conditions such as those affecting the joints, for example arthritis or ARDS or inflammatory bowel disease, or asthma, cardiovascular ischemia, congestive heart failure, myocarditis, artherosclerosis, migraine, reflux esophagitis, diarrhea, irritable bowel syndrome, cystic fibrosis, emphysema, and diabetes.
• Use of such a non-selective NO synthase inhibitor requires that great care be taken in order to avoid the potentially serious consequences of over-inhibition of the constitutive NO-synthase including hypertension and possible thrombosis and tissue damage.
• L-NMMA for the treatment of toxic shock it has been recommended that the patient must be subject to continuous blood pressure monitoring throughout the treatment.
• NO synthase inhibitors which are selective in the sense that they inhibit the inducible NO synthase to a considerably greater extent than the constitutive isoforms of NO synthase would be of even greater therapeutic benefit and easier to use.
• W094/12165, WO94/14780, WO93/13055, EP0446699A1 and U.S. Patent No. 5,132,453 disclose compounds that inhibit nitric oxide synthesis and preferentially inhibit the inducible isoform of nitric oxide synthase. The disclosures of which are hereby incorporated by reference in their entirety as if written herein.
• novel amidino derivatives are provided.
• novel inhibitor compounds can be represented by the following chemical formula (I) :
• R 1 is selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, alkyloxy, thioalkoxy, cycloalkyl, heterocyclyl, and aryl, which may optionally be substituted by lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aryl, hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro, amino, alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, acylamino, carboxy. carboxyalkyl, CONR ⁇ R 11 , S(0)R 10 , 3(0)2R 10 , SO2NR 10 R 11 ,
• R 2 hydrogen, lower alkyl, aryl, heterocyclyl
• R 3 hydrogen, lower alkyl, aryl, heterocyclyl
• R 4 hydrogen, lower alkyl, aryl, heterocyclyl
• R ⁇ , R6, R 7 are independently selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, heterocyclyl, hydroxy, lower alkoxy, thiol, lower thioalkoxy, halogen, nitro, amino, alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, acylamino, carboxyl, carboalkoxy, carboaryloxy, carboarylalkyloxy, cyano, aminocarbonylalkoxy, aminocarbonylamino, aminocarbonylaminoalkyl, haloalkyl,
• substitutions may be optionally substituted with one or more of the following: lower alkyl, amino, alkylamino, dialkylamino, aminoalkyl, aminoacyl, carboxyl, carboalkoxy, carboaryloxy, carboalkylaryloxy, hydroxy, lower alkoxy;
• R 1 when R 1 is lower alkyl, lower alkenyl, or lower alkynyl, R 1 cannot be optionally substituted by cycloalkyl, heterocyclyl, and aryl, unless one A, or B is NR 2 , 0, S, SO, S02;
• X, A, and B may be selected from NR 2 , NR 3 , NR 4 respectively, or 0, S, SO, or S02;
• R 1 , R 5 , R ⁇ and R 7 can be alkyl, alkoxy, cycloalkyl or cycloalkoxy at the 5-position;
• R 1 , R 5 , R ⁇ and R 7 are an alkyl, cycloalkyl or aryl group at the 5-position, then none of the remaining R 1 , R ⁇ , R ⁇ and R 7 can be a cyano, substituted amino, alkoxy or thioalkoxy at the 5-position;
• the present invention is directed to inhibiting nitric oxide synthesis in a subject in need of such inhibition or treatment by administering a compound of Formula (I) which preferentially inhibits the inducible isoform of nitric oxide synthase over the constitutive isoform of nitric oxide synthase, in a nitric oxide synthesis inhibiting amount to such subject.
• the invention further relates to a pharmaceutical composition comprising a compound from Formula (I) .
• Conditions in which there is an advantage in inhibiting NO production from L-arginine in disorders mediated by nitric oxide including amongst others, systemic hypotension associated with septic and/or toxic shock induced by a wide variety of agents; therapy with cytokines such as TNF, IL-1 and IL-2; and as an adjuvant to short term immunosuppression in transplant therapy.
• autoimmune diseases and/or inflammatory conditions such as those affecting the joints, for example arthritis or inflammatory bowel disease, cardiovascular ischemia, diabetes, congestive heart failure, myocarditis, artherosclerosis, migraine, reflux esophagitis, diarrhea, irritable bowel syndrome, cystic fibrosis, emphysema, hyperalgesia (allodynia) cerebral ischemia (both focal ischemia, thrombotic stroke and global ischemia, secondary to cardiac arrest) and other CNS disorder mediated by NO, including opiate tolerance in patients needing protracted opiate analgesics, benzodiazepine tolerance in patients taking be ⁇ zodiazepines, and other addictive behaviors for example nicotine and eating disorder.
• inflammatory diseases and/or inflammatory conditions such as those affecting the joints, for example arthritis or inflammatory bowel disease, cardiovascular ischemia, diabetes, congestive heart failure, myocarditis, artherosclerosis, migraine, reflux esophagitis, diarrhea, irritable bowel
• the present invention includes compounds of formula (I) in the form of salts, in particular acid addition salts.
• Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable although salts of non- pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question.
• preferred salts include those formed from hydrochloric, hydrobromic, sulfuric, citric, tartaric, phosphoric, lactic, acetic, succinic, fumaric, maleic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, benzenesulfonic and the like. (See, for example, S. M. Berge et al. , Pharmaceutical Salts, J. Phar . Sci . , 1977, 66, 1-19.) Salts of the compounds of formula (I) can be made by reacting the appropriate compound in the form of the free base with the appropriate acid.
• the present invention provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients.
• the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• the formulations include those suitable for oral, inhalation, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular) , rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient.
• the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof ("active ingredient”) with the carrier which constitutes one or more accessory ingredients .
• the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
• Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
• the active ingredient may also be presented as a bolus, electuary or paste.
• a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
• Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
• the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
• Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents .
• the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline, • water-for-injection, immediately prior to use.
• Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
• Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter or polyethylene glycol.
• Formulations for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
• Formulations for inhalation administration where the active ingredient is inhaled into the lungs either as a mist or co- administered with an inert carrier agent.
• Preferred unit dosage formulations are those containing an effective dose, as hereinbelow recited, or an appropriate fraction thereof, of the active ingredient.
• formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
• the compounds of the invention may be administered orally or via injection at a dose of from 0.001 to 2500 mg/kg per day.
• the dose range for adult humans is generally from 0.005 mg to 10 g/day.
• Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
• the compounds of formula (I) are preferably administered orally or by injection (intravenous or subcutaneous) .
• the precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity. Also, the route of administration may vary depending on the condition and its severity.
• lower alkyl means an acyclic alkyl radical containing from 1 to about 10, preferably from 1 to about 8 carbon atoms and more preferably 1 to about 6 carbon atoms.
• examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like.
• lower alkenyl refers to an unsaturated acyclic hydrocarbon radical in so much as it contains at least one double bond. Such radicals containing from about 2 to about 10 carbon atoms, preferably from about 2 to about 8 carbon atoms and more preferably 2 to about 6 carbon atoms.
• suitable alkenyl radicals include propylenyl, buten-1-yl, isobutenyl, pentenylen-1-yl, 2-2-methylbuten-l-yl, 3- methylbuten-1-yl, hexen-1-yl, he ten-1-yl, and octen-1-yl, and the like.
• lower alkynyl refers to an unsaturated acyclic hydrocarbon radical in so much as it contains one or more triple bonds, such radicals containing about 2 to about 10 carbon atoms, preferably having from about 2 to about 8 carbon atoms and more preferably having 2 to about 6 carbon atoms.
• alkynyl radicals examples include ethynyl, propynyl, butyn-1- yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 3-methylbutyn-l-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, 3 , 3-dimethylbutyn-l-yl radicals and the like.
• alicyclic hydrocarbon or "cycloalkyl” means a aliphatic radical in a ring with 3 to about 10 carbon atoms, and preferably from 3 to about 6 carbon atoms.
• suitable alicyclic radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl and the like.
• aromatic hydrocarbon means aromatic radical with 4 to about 16 carbon atoms, preferably 6 to about 12 carbon atoms, more preferably 6 to about 10 carbon atoms.
• suitable aromatic hydrocarbon radicals include phenyl, naphthyi and the like.
• aryl as used herein means 5- and 6-membered single-aromatic radicals which may include from zero to four- heteroatoms.
• Representative aryls include phenyl, thienyl, furanyl, pyridinyl, (is)oxazoyl and the like.
• DCM dichloromethane
• DEAD means diethyl azodicarboxylate.
• DIBAL-H means diisobutylaluminum hydride.
• DMAP means dimethylaminopyridine.
• DMSO dimethylsulfoxide
• EDC means 1- (3-dimethylaminopropyl) -3- ethylcarbodiimide hydrochloride.
• heterocyclyl radical means a saturated or unsaturated cyclic hydrocarbon radical including aromatic systems with 4 to about 10 carbon atoms, preferably about 5 to about 6; wherein 1 to about 4 carbon atoms are replaced by nitrogen, oxygen, sulfur, or carbonyl.
• the "heterocyclic radical” may be fused to an aromatic hydrocarbon radical.
• Suitable examples include pyrrolyl, pyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, indolyl, thienyl, furanyl, tetrazolyl, 2- pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, 1, 3-dioxolanyl, 2- imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolinyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyi, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyrazin
• lower alkoxy means an alkyl ether radical wherein the term alkyl is as defined above and most preferably containing 1 to about 4 carbon atoms.
• suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
• lower thioalkoxy means an alkyl thioether radical wherein the term alkyl is as defined above and most preferably containing 1 to about 4 carbon atoms.
• suitable alkyl thioether radicals include thiomethoxy, thioethoxy, thio-n-propoxy, thio-i-propoxy, thio-n- butoxy, thio-iso-butoxy, thio-sec-butoxy, thio-tert-butoxy and the like.
• halogen means fluorine, chlorine, bromine or iodine.
• MCPBA means m-chloroperbenzoic acid.
• NMM N-methylmorpholine
• NMMO 4-methylmorpholine N-oxide
• prodrug refers to a compound that is made more active in vivo .
• sulfinyl means SO.
• sulfonyl means SO2.
• TEA means triethylamine
• TMSN 3 means azidotrimethylsilane.
• treatment of a patient is intended to include prophylaxis.
• Compounds of the present invention can exist in geometric or stereoisomeric forms.
• the present invention contemplates all such compounds, including cis- and trans-geometric isomers, E- and Z-geometric isomers, R- and S-enantiomers, diastereomers, d- isomers, 1-isomers, the racemic mixtures thereof and other mixtures thereof, as falling within the scope of the invention.
• R H, alkyl, cycloalkyl, aryl, heterocycle
• R n H, alkyl, aryl, heterocycle
• R m and R n may be taken together to form a ring a) solvent (benzene); b) NH 2 OH, NaOAc, EtOH; c) PhS0 2 Cl, NaOH, H 2 0, acetone; d) Me 3 0*BF 4 -, CH 2 Cl 2 ; e) NH 4 C1, MeOH.
• Example 1 A 4.9 g (34.3 mmol) sample of the title material of Example 1 was added to a dropping funnel containing 6 mL of 80% H2SO4. After using a stirring rod to obtain a turbid solution, this mixture was added dropwise (10 min) to 5 mL of 80% H2SO4 stirred magnetically and maintained at 120 °C with an external oil bath. Within 5 minutes of the start of addition an exotherm was noted and the temperature of the reaction rose to 160 °C before cooling again to 120 °C. Ten minutes later the flask was removed from the bath and allowed to cool to room temperature. The product mixture was diluted with water (20 mL) and brought to pH 6 with concentrated NH4OH.
• Example 5 The Isomer-B product of Example 2 is reacted with trimethyloxonium tetrafluoroborate by the method of Example 3 to produce the title material.
• Example 5
• Example 3 The title product of Example 3 (0.30 g, 1.4 mmol) and 0.06 g (1.1 mmol) of ammonium chloride (NH4CI) were refluxed in 13 mL of methanol (MeOH) under a nitrogen atmosphere for 19 h. After cooling the reaction to room temperature, it was filtered, stripped of all solvent under reduced pressure, and partitioned between 15 mL of water and 7 mL of CH2CI2- The organic and aqueous phases were separated and the aqueous phase was washed with a 25 mL portion of EtOAc before it was lyophilized to provide 0.24 g (92%) of the white solid title material.
• NH4CI ammonium chloride
• Example 7 The product of Example 4 in MeOH is reacted with ammonium chloride by the method of Example 5 to generate the title material.
• Example 7 The product of Example 4 in MeOH is reacted with ammonium chloride by the method of Example 5 to generate the title material.
• Example 7 A sample of the product of Example 7 (7.5 g, 44.4 mmol) was converted to the title compound by the method of Example 2 using 11 mL of 80% H2SO4. The procedure produced 5.6 g (75%) of the title material as a pale yellow tacky solid.
• Example 8 The title product of Example 8 (845 mg, 5.0 mmol) was reacted with trimethyloxonium tetrafluoroborate (962 mg, 5.0 mmol) by the method of Example 3 to yield 815 mg (100%) of the title material.
• Example 9 The product of Example 9 (110 mg, 0.6 mmol) in 3.5 mL of MeOH was reacted with ammonium chloride (32 mg, 0.6 mmol) by the method of Example 5 to yield 90 mg (67%) of the title material.
• Tetrahydro-4H-pyran-4-one (5.0 g, 0.05 mole), hydroxylamine hydrochloride (5.2 g, 0.075 mole) and sodium acetate (13.6 g, 0.1 mole) were refluxed in ethanol (30 mL) /H2O (20 mL) overnight. Contents were allowed to cool and concentrated in vacuo to remove the ethanol. The aqueous solution left was extracted with CH2CI2 which was dried (MgS ⁇ 4) and concentrated in vacuo leaving the title material as a white solid (5.4 g) .
• Example 11 To the title material of Example 11 (5.4 g, 0.047 mole) in acetone (30 mL) at 0 'C was added IN sodium hydroxide. Benzene sulfonyl chloride (6 mL, 0.047 mole) in acetone (10 mL) was added dropwise with magnetic stirring. Contents were stirred "" . hours and concentrated in vacuo to remove the acetone. The aqueous solution was extracted with CH2CI2 (2 x 150 mL) , dried (MgS04) and concentrated in vacuo leaving an amber oil/solid (2.2 g) . The residue was crystallized from hexanes to give the title material as a white solid (1.37 g) .
• Example 12 The title material of Example 12 (960 mg, 0.008 mole) and trimethyloxonium tetrafluoroborate (1.5 g, 0.01 mole) were mixed in CH2CI2 (50 mL) and stirred 72 hours. Contents were concentrated in vacuo and the residue was dissolved in methanol (50 mL) . Anhydrous ammonia was bubbled through for 15 minutes. Contents were stoppered and stirred overnight. After concentrating in vacuo, the residue was partitioned between CH2CI2 and water. The aqueous layer was purified by C-18 reverse phase chromatography eluting with 100% H2O (0.05% TFA) to give the title material as a white solid (730 mg) .
• Tetrahydro-4H-pyran-4-one (5.0 g, 0.05 mole) and pyrrolidine (4.6 mL, 0.055 mole) were refluxed in benzene (50 mL) with a Dean Stark trap to collect water for 2 hours. Contents were concentrated in vacuo leaving a thick amber oil (7.6 g) which was distilled on a kugelrohr apparatus at 40 * C (0.1 mm) to give the title material as a clear colorless oil (5.9 g) .
• Example 14 The title material of Example 14 (23 g, 0.15 mole) and crotyl bromide (15.4 mL, 0.15 mole) were mixed in benzene (200 mL) and stirred 72 hours. Water (50 mL) was added and stirred 2 hours. The benzene layer was removed and the aqueous layer was extracted with EtOAc (150 mL) . The organic extracts were combined, dried (MgS04) and concentrated in vacuo leaving an oil
• Example 15 To the title material of Example 15 (13.0 g, 0.084 mole) and hydroxylamine hydrochloride (6.5 g, 0.093 mole) in methanol (100 mL) was added dropwise anhydrous pyridine (8.1 mL, 0.1 mole) in methanol (50 mL) . Contents were stirred overnight. Contents were concentrated in vacuo and the residue was partitioned between CH2CI2 and water. The CH2CI2 layer was dried (MgS04) and concentrated in vacuo leaving the title material as an oil (19.5 g) .
• Example 16 To the title material of Example 16 (5.0 g, 0.03 mole) in acetone (30 mL) at 0 * C was added IN sodium hydroxide (30 mL) . Benzene sulfonyl chloride (3.8 mL, 0.03 mole) in acetone (10 mL) was added dropwise and after the reaction came, to room temperature, it was stirred overnight. The contents were concentrated in vacuo to remove acetone and the aqueous solution left was extracted with CH2CI2 (2 x 150 mL) . The CH2CI2 extracts were combined, dried (MgS04) , and concentrated in vacuo leaving an oil.
• Example 17 To the title material of Example 17 (612 mg, 3.6 mmol) in CH2CI2 (25 mL) was added trimethyloxonium tetrafluoroborate (540 mg, 3.6 mmol) and contents were stirred overnight. After concentrating in vacuo, the residue was dissolved in methanol (25 mL) and anhydrous ammonia was bubbled through the solution. Contents were stoppered and stirred 72 hours. Contents were concentrated in vacuo and the residue was purified by C-18 reverse phase chromatography eluting with a CH3CN/H 2 O gradient (0.05 % TFA) to give the title material as a white solid (404 mg) .
• Example 19 To the title material of Example 19 (9.2 g, 0.056 mole) in acetone (50 mL) at 0 "C was added dropwise IN sodium hydroxide. After stirring 5 minutes, benzene sulfonyl chloride (7.1 mL) ir acetone (5 mL) was added dropwise. Contents were stirred 72 hours, coming to room temperature. Contents were concentrated in vacuo to remove the acetone, the aqueous solution was made basic with IN sodium hydroxide and lyophilized leaving a solid. The solid was triturated with CH2CI2 and filtered. The CH2CI2 was concentrated in vacuo leaving the title material as a solid (4.9 g) .
• Example 14 The title compound of Example 14 is reacted with bromoethyl methyl ether by the method of Example 15 to generate the title compound.
• Example 22 The title compound of Example 22 is reacted with hydroxylamine by the method of Example 16 to generate the title compound.
• Example 23 The title compound of Example 23 is reacted with benzenesulfonyl chloride by the method of Example 17 to generate the title compounds.
• the isomers are separated by column chromatography.
• Example 24 The Isomer A of Example 24 is reacted with trimethyloxonium tetrafluoroborate in methylene chloride by the method of Example 3 to generate the title compound.
• the isomer B of Example 24 is reacted with trimethyloxonium tetrafluoroborate in methylene chloride by the method of Example 3 to generate the title compound.
• Example 25 The product of Example 25 is reacted with ammonium chloride in methanol by the method of Example 4 to generate the title compound.
• Example 26 The product of Example 26 is reacted with ammonium chloride in methanol by the method of Example 4 to generate the title compound.
• Example 29A Ethyl 3 , 3-dimethylacrylate (4.9 g, 38 mmol) was mixed with nitrohexane (5.0 g, 38 mmol), IM tetrabutylammoniu fluoride (in THF, 38 mL) and heated at 40 °C for 24 hours. The reaction mixture was diluted with diethyl ether, washed with brine, followed by water. Purification by chromatography on silica gel yielded the product, methyl 3,3- dimethyl-4-nitrononanoate (6.6 g, 67%) .
• Example 29 B) The product of Example 29 A (5.6 g, 24 mmol) in absolute MeOH was hydrogenated over RaNi at 55 * C and 60 psi for 24h. The reaction product was purified by column chromatography to yield 4, 4-dimethyl-5-pentylpyrrolidin-2-one (2.63 g, 60%).
• Example 29 C) The product of Example 29 B (2.63 g, 14.3 mmol) was treated with trimethyloxonium tetrafluoroborate (2.56 g, 17.4 mmol) in DCM (20 mL) by the method of Example 3, to yield 3, 4-dihydro-5- methoxy-3,3-dimethyl-2-pentyl-2H-pyrrole (2.0 g, 71%) .
• Example 29 A solution of the title product of Example 29 C (2.0 g, 10 mmol) in MeOH (30 mL) was reacted with ammonium chloride (529 mg, 9.9 mmol) by the method of Example 5 followed by chromatography on reverse phase HPLC.
• Example 30 Ethyl 4,4,4-trifluoro-3- (trifluromethyl)crotonate (9.0 g, 38 mmol) was mixed with nitrohexane (5.0 g, 38 mmol), potassium carbonate (5.3 g, 38 mmol) and Aliquat 336 (20 drops) . The mixture was sonicated at room temperature. When the reaction, monitored by G.C., was complete the mixture was acidified with HCl (1 N) and the aqueous phase extracted with ether. Purification by chromatography on silica gel yielded the product, methyl 4-nitro- 3,3-bis (trifluoromethyl)nonanoate (3 g, 21%) .
• Example 30 B The product of Example 30 A in absolute MeOH is hydrogenated over RaNi at 55 * C and 60 psi for 24h. The reaction product is purified by column chromatography to yield 5-pentyl-4,4- bis (trifluoromethyl)pyrrolidin-2-one.
• Example 30 C The product of Example 30 B is treated with trimethyloxonium tetrafluoroborate in DCM (20 mL) by the method of
• Example 30 A solution of the title product of Example 30 C in MeOH (30 mL) is reacted with ammonium chloride by the method of Example 5 followed by chromatography on reverse phase HPLC to generate the title material.
• Example 31 ethyl 2-imino-4-methyl-5-pentylpyrrolidine-3-carboxylate, monohydrochloride
• Example 31 B The product of Example 31 A in absolute EtOH is hydrogenated over RaNi at 55 * C and 60 psi for 24h.
• the reaction product is purified by column chromatography to yield ethyl 4- methyl-2-oxo-5-pentylpyrrolidine-3-carboxylate.
• Example 31 C The material 31 B is treated with trimethyloxonium tetrafluoroborate in DCM by the method of Example 3 , to yield ethyl 3 , 4-dihydro-5-methoxy-2-pentyl-2H-pyrrole-3-carboxylate.
• Example 31 A solution of the title product of Example 31 C in MeOH is reacted with ammonium chloride by the method of Example 5 followed by chromatography on reverse phase HPLC to generate title material.
• Example 32 A solution of the title product of Example 31 B in MeOH / 2N NaOH is stirred 6h followed by lyophilization. The resulting solid is dissolved in water and EtOAc containing benzylbromide added. The mixture is shaken in a separatory funnel. The organic solution is separated, dried and evaporated. The residue is purified by column chromatography to yield phenylmethyl 4-me_hyl-2-oxo-5-pentylpyrrolidine-3-carboxylate.
• Example 32 B The product of Example 32 A is treated with trimethyloxonium tetrafluoroborate in DCM by the method of Example 3, to yield phenylmethyl 3,4-dihydro-5-methoxy-3-methyl-2-pentyl- 2H-pyrrole-4-carboxylate.
• Example 32 C A solution of the title product of Example 32 B in MeOH is reacted with ammonium chloride by the method of Example 5 followed by chromatography on reverse phase HPLC to generate phenylmethyl 2-imino-4-methyl-5-pentyl-3-carboxylate.
• Example 32) A solution of product of Example 32 C in absolute MeOH is hydrogenated over Pd/C. The reaction product is purified by chromatography on reverse phase HPLC to generate title material.
• Example 33 A The ethyl 4,4,4-trifluoromethyl crotonate (10 mmol) and 2- (2-nitroethyl)-1,3-dioxolane (12 mmol) are reacted with, potassium carbonate (5 mmol) and Aliquat 336 (3 drops), by the method of Example 14. Purification by chromatography on silica gel yields ethyl ⁇ -nitro- ⁇ - (trifluoromethyl) -1,3-dioxolane-2- pentanoate.
• Example 33 B The product of Example 33 A in MeOH is hydrogenated over RaNi at 55'C and 60 psi for 6h.
• Example 33 C The product of Example 33 B is treated with di-t- butyldicarbonate and DMAP in THF and refluxed for 2 h. The solvent is removed and the product is purified by column chromatography to yield 1, 1-dimethylethyl 2- [ (1, 3-dioxolan-2-yl)methyl] -5-oxo-3- (trifluoromethyl)pyrrolidine-l-carboxylate.
• Example 33 D The product of Example 33 C with HMPA (1 equivalent) in THF at -70 * C is treated with Lithium hexamethyl disilazide (1.2 equivalents, IM in THF) . The solution is allowed to warm to -40 * C then cooled to -70 'C, and a solution of camphor sulfonyl oxaziridine in THF is added. The solution is stirred at -40 °C for 2h then quenched onto saturated NH4CI. The solution is then extracted with EtOAc. The organics are combined.
• Lithium hexamethyl disilazide 1.2 equivalents, IM in THF
• Example 33 E The product of Example 33 D is treated with NaH and benzylbromide in THF. The product is purified by column chromatography to yield 1, 1-dimethylethyl 2- [ (1,3-dioxolan-2- yl)methyl] -5-oxo-4- (phenylmethoxy) -3- (trifluoromethyl)pyrrolidine- 1-carboxylate.
• Example 33 F The product of Example 33 E in MeOH is treated with HCl (IN) to yield 5-oxo-4- (phenylmethoxy) -3- (trifluoromethyl)pyrrolidine-2-acetaldehyde which is used directly in the next step.
• Example 33 G To a solution of product of Example 33 F and Z- ⁇ - phosphonoglycine trimethyl ester in CH2CI2 is added DBU.
• Example 33 H The product of Example 33 G is hydrogenated with [Rh(COD) (R,R-DIPAMP) ] + BF4-. The solvent is removed and the product is purified by column chromatography to yield methyl 5-oxo- OC-[ [ (phenylmethoxy)carbonyl]amino] -4- (phenylmethoxy) -3- (trifluoromethyl)pyrrolidine-2-butanoate.
• Example 33 I The product of Example 33 H is treated with trimethyloxonium tetrafluoroborate in DCM by the method of Example 3, to yield methyl 3,4-dihydro-5-methoxy- ⁇ -
• Example 33 J A solution of the title product of Example 33 I in MeOH is reacted with ammonium chloride by the method of Example 5 followed by chromatography on reverse phase HPLC to yield methyl 5- imino- ⁇ - [ [ (phenylmethoxy)carbonyl]amino] -4- (phenylmethoxy) -3- (trifluoromethyl)pyrrolidine-2-butanoate, monohydrochloride.
• Example 33 The product of Example 33 J in absolute MeOH is hydrogenated over Pd/C for 24h. The reaction product is purified by chromatography on reverse phase HPLC to yield 33.
• Example 34 A solution of the title product of Example 33 I in MeOH is reacted with ammonium chloride by the method of Example 5 followed by chromatography on reverse phase HPLC to yield methyl 5- imino- ⁇ - [ [ (phenylmethoxy)carbonyl]amino] -4- (phenylmethoxy) -3- (trifluoromethyl)pyrrolidine-2-butano
• Example 34 A THF solution of hexahydro-4-methyl-7- (2- propenyl) -2H-azepin-2-one is treated with di-t-butyldicarbonate and dimethylaminopyridine (DMAP, 1 eq) to generate the Boc protected lactam, 1, 1-dimethylethyl hexahydro-4-methyl-2-oxo-7- (2-propenyl) -lH-azepine-1-carboxylate.
• DMAP di-t-butyldicarbonate and dimethylaminopyridine
• Example 34B To the product of Example 34 A above dissolved in THF and cooled to a low temperature is added hexamethylphosphoramide (HMPA, 1 eq) followed by lithium hexamethyldisilylazide (LHMDS, 1.1 eq) .
• HMPA hexamethylphosphoramide
• LHMDS lithium hexamethyldisilylazide
• Example 34 C A product or product mixture from Example 34 B above dissolved in DMF is treated with imidazole (2 eq) and t- butyldimethylsilyl chloride yielding 1, 1-dimethylethyl 3- [(1,1- dimethylethyl)dimethylsilyloxy]hexahydro-4-methyl-2-oxo-7-(2- propenyl) -lH-azepine-1-carboxylate.
• Example 34 D To a product or product mixture from Example 34 C above dissolved in acetonitrile and warmed to around 50 'C is added magnesium perchlorate [Mg(Cl ⁇ 4)2/ 0.2 eq] generating 3-
• Example 34 E The product or a product mixture from Example 34 D above is treated with trimethyloxonium tetrafluoroborate in CH2CI2 by the method of Example 3, to yield 6- [(1,1- dimethylethyDdimethylsilyloxy] -3,4,5, 6-tetrahydro-7-methoxy-5- methyl-2H-azepine.
• Example 34 F A solution of the title product or a product mixture of Example 34 E in MeOH is reacted with ammonium chloride by the method of Example 5 to generate 3- [(1,1- dimethy1ethyl)dimethylsilyloxy]hexahydro-4-methyl-7- (2-propenyl)- 2H-azepin-2-imine, monohydrochloride. This material is treated with a source of fluoride ion and the crude product chromatographed on reverse phase HPLC to yield the title material.
• Example 35 A A THF solution of 6-butyl-4-methylpiperidin-2-one is treated with di-t-butyldicarbonate and dimethylaminopyridine (DMAP, 1 eq) to generate the Boc protected lactam, 1,1- dimethylethyl 2-butyl-4-methyl-6-oxopiperidine-l-carboxylate.
• DMAP di-t-butyldicarbonate and dimethylaminopyridine
• Example 35 B To the product of Example 35 A above dissolved in THF and cooled to a low temperature is added hexamethylphosphoramide (HMPA, 1 eq) followed by lithium hexamethyldisilylazide (LHMDS, 1.1 eq) .
• HMPA hexamethylphosphoramide
• LHMDS lithium hexamethyldisilylazide
• Example 35 C A product or product mixture from Example 35 B above dissolved in DMF is treated with imidazole (2 eq) and t- butyldimethylsilyl chloride yielding 1, 1-dimethylethyl 6-butyl- 3- [ (1, 1-dimethylethyl)dime hylsilyloxy] -4-methyl-2- oxopiperidine-1-carboxylate.
• Example 35 D To a product or product mixture from Example 35 C above dissolved in acetonitrile and warmed to around 50 "C is added magnesium' perchlorate [Mg(Cl ⁇ 4)2- 0- 2 eq] generating 6- butyl-3- [ (1, 1-dimethylethyl)dimethylsilyloxy] -4-methylpiperidin-
• Example 35 E The product or a product mixture from Example 35 D above is treated with trimethyloxonium tetrafluoroborate in CH2CI2 by the method of Example 3, to yield 2-butyl-5- [ (1, 1- dimethylethyl)dimethylsilyloxy] -6-ethoxy-2,3,4,5-tetrahydro-4- methylpyridine.
• Example 35 F A solution of the title product or a product mixture of Example 35 E in MeOH is reacted with ammonium chloride by the method of Example 5 to generate 6-butyl-3- [ (1, 1- dimethylethyDdimethylsilyloxy] -4-methylpiperidin-2-imine. This material is treated with a source of fluoride ion and the crude product chromatographed on reverse phase HPLC to yield the title material.
• Example 37 B The product of Example 37 A was dissolved in 50 mL of acetone and 50 mL of 1 N sodium hydroxide at 0 °C.
• Benzenesulfonyl chloride (7.8 g, 44 mmol) was added over 5 min. The reaction mixture was allowed to warm up and stirred for 18 hrs until complete as determined by shift in HPLC retention time (Vydac C-18, linear gradient 5 % to 75 % acetonitrile/0.05 % TFA in water/0.05 % TFA over 20 min) . The solvent was removed by evaporation and the residue redissolved in 100 mL EtOAc, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and stripped of all solvent by evaporation.
• Example 37 C To the product of Example 37 B (3.3 mmol) in 10 mL CH2CI2 was added trimethyloxonium tetrafluoroborate (0.6 g, 4.0 mmol).
• Example 35 The product of Example 37 C was dissolved in 25 mL of methanol and refluxed with ammonium chloride for 3 hrs. The solvent was removed by evaporation and the residue oil was dissolved in 25 mL of EtOAc, washed with water, and stripped of all solvent under reduced pressure to produce the crude product.
• Example 38 A solution of 2, 4,4-trimethylcyclopentanone (5.5 g, 44 mmol) in 35 mL ethyl acetate/25 mL water was refluxed with hydroxylamine hydrochloride (4.6 g, 66 mmol) and sodium acetate trihydrate (10.8 g, 79 mmol) for 4 hrs under nitrogen. Removed solvent by evaporation, redissolved in 100 mL ethyl acetate and washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and then removed solvent to give 6.2 g of 2,4,4-trimethylcyclopentanone oxime as a white powder.
• FAB/MS: (MH + ) 142.
• Example 38 B The product of Example 38 A was dissolved in 50 mL acetone and 50 mL 1 N sodium hydroxide at 0 °C. Benzenesulfonyl chloride was then added (7.8 g, 44 mmol) over 5 min. The reaction mixture was allowed to warm up and stir for 18 hrs until complete, as determined by the shift in HPLC retention time (Vydac C-18, linear gradient 5 % to 75 % acetonitrile/0.05 % TFA in water/0.05 % TFA over 20 min).
• Example 38 C To the product of Example 38 B (5.3 mmol) in 15 mL CH2CI2 was added trimethyloxonium tetrafluoroborate (0.9 g, 6.0 mmol) . After stirring 18 hrs, the reaction mixture was diluted with an additional 15 mL of CH2CI2, washed with saturated aqueous potassium carbonate solution, dried over magnesium sulfate, and stripped of all solvent to give 0.69 g of 2,3, 4, 5-tetrahydro-6-methoxy-2,4, 4-trimethylpyridine as an oil.
• Example 38 The product of Example 38 C was dissolved in 25 mL of methanol and refluxed with ammonium chloride (0.25 g, 4.6 mmol) for 3 hrs.
• Example 39 A sample of the 3- (2-Buten-l-yl) -5-oxo- 2,3 ,4,5, 6,7-hexahydro-l,4-oxazepine product of Example 17 (6.6 g, 39 mmol), di-t-butyl dicarbonate (17.5 g, 80 mmol) and 4- dimethylaminopyridine (200 mg) were refluxed in anhydrous THF
• Example 39 B To the 4-N-Boc-3- (2-buten-l-yl) -5-oxo- 2, 3 , 4,5, 6,7-hexahydro-1, 4-oxazepine product of Example 39 A (3.1 g, 12 mmol) in anhydrous THF (60 mL) at -78 °C was added dropwise lithium bis (trimethylsilyl)amide (IM in THF, 12 mL) keeping the temperature below -70 °C. The contents were allowed to warm to -40 °C and then cooled back to -78 °C.
• IM lithium bis (trimethylsilyl)amide
• Example 39 C The 4-N-Boc-3- (2-buten-l-yl) -6-hydroxy-5-oxo- 2, 3,4, 5, 6,7-hexahydro-l,4-oxazepine product of Example 39 B (600 mg) , t-butyldiniethylsilyl chloride (2.0 g) , imidazole (1.6 g) and anhydrous THF (50 mL) were stirred overnight. The contents were partitioned between EtOAc and water. The EtOAc layer was dried over MgSU4 and concentrated in vacuo to generate an oil.
• Example 39 D The 4-N-Boc-3- (2-Buten-l-yl) -6- (t- butyldimethylsilyloxy) -5-oxo-2,3 ,4,5,6, 7-hexahydro-1,4-oxazepine product of Example 39 C (400 mg, 1 mmol) and magnesium perchlorate (45 mg) were heated at 50 °C in CH3CN (25 mL) for 3 hours. The contents were allowed to cool and were partitioned between EtOAc and water.
• Example 39 The 3- (2-Buten-l-yl) -6- (t-butyldimethylsilyloxy) -5- oxo-2,3, 4, 5, 6,7-hexahydro-1,4-oxazepine product of Example 39 D (300 mg, 1 mmol) and Me3 ⁇ + BF4" (150 mg, 1 mmol) were stirred in CH2CI2 overnight. The contents were concentrated in vacuo, the residue dissolved in methanol, and anhydrous ammonia bubbled into the solution. The reaction was stoppered and stirred overnight. The contents were concentrated in vacuo leaving a yellow oil (366 mg) . The oil was purified by C-18 reverse phase chromatography eluting with a CH3CN/H2O to give the title products of this Example 39 (isomer A , 16 mg) and Example 40 (isomer B, 11 mg) as oils.
• Example 39 The crude product oil of Example 39 was purified by C-18 reverse phase chromatography eluting with a CH3CN/H2O to give the title products of Example 39 and title product of Example 40 (isomer B, 11 mg) .
• Example 18 The product of Example 18 (1.3 g, 4.6 mmole), 5% rhodium/carbon
• Example 43 C The 2-Nitroethyltetrahydropyran-4-one product of Example 43 B, hydroxylamine-O-sulfonic acid, and formic acid (98%) are refluxed for 0.5 hr. The contents are allowed to cool and concentrated in vacuo. The residue is partitioned between CH 2 Cl2 and water. The CH 2 Cl2 layer is dried over MgS0 4 and concentrated in vacuo. The residue is purified by C-18 reverse phase chromatography to give 3- (2-nitroethyl) -5-oxo-2,3,4, 5, 6,7- hexahydro-1,4-oxazepine.
• Example 43 D To the 3- (2-nitroethyl) -5-oxo-2,3,4, 5, 6, 7- hexahydro-1,4-oxazepine product of Example 43 C in CH2CI2 (25 mL) is added Me3 ⁇ + BF4 " and the contents are stirred overnight.
• Example 44 was prepared from Example 45e, iodomethane, and sodium hydride. The synthesis of Example 44 is completed in the manner described in Example 45.
• Example 45A To a stirring solution of methyl crotonate (3.28 g, 32.8 mmol) and nitromethane (1.08 g, 16.0 mmol) in 20 mL of CH 3 CN was added DBU (2.39 mL, 16.0 mL) . After 72 h, the reaction was concentrated under reduced pressure. The residue was taken up in EtOAc. The EtOAc solution was washed with 0.5 N HCl and brine, was dried over Na 2 S ⁇ 4 anhydrous, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to give 3.05 g.
• Example 45B,C Example 45A (34 g, 0.15 mol) was reduced under catalytic hydrogenation conditions using Raney Ni in MeOH. After heating the reaction mixture for 16 h at 55 °C, the solvent was removed under vacuum. The crude lactam was separated by column chromatography into the cis (45B) and trans (45C) lactam.
• Example 45D A stirring solution of Example 45B (20 g, 0.12 mol), (BocO) 2 0 (38.7 g, 0.18 mol), DMAP (14.4 g, 0.12 mol) in 500 mL of THF was heated at reflux for 3 h. After concentrating reaction under vacuum, the residue was taken up in EtOAc and washed with KHSO 4 and brine. The organic layer was dried over anhydrous Na 2 S0 4 , filtered, and stripped. The crude product was purified by column chromatography to yield 31 g.
• Example 45E To a stirring solution of Example 45D (2.7 g, 9.9 mmol) and HMPA (1.8 g, 10.0 mmol) in 15 mL of THF cooled to -70 'C was added lithium hexamethyldisilazide (1.7 g, 10.0 mmol) . After 20 min, the reaction was warmed to -40 'C and cooled again to -70 * C. To the stirring reaction was added (R) -(-)- (camphorsulphonyl)oxaziridine (2.4 g, 10.4 mmol) in 7 mL of THF. After stirring at -70 "C for 30 min, the reaction was warmed to -30 * C and stirred an additional 2.5 h.
• Example 45F To a solution of Example 45E (1.3 g) in CH2CI2 was added TFA (6 mL) . After 2 h, the reaction was concntrated under vacuum to give 0.85 g of product.
• Example 45G To a stirring solution of Example 45F (0.85 g, 4.6 mmol) and imidazole (0.35 g, 4.6 mmol) in 15 mL was added t-butyldimethylsilylchloride (0.70 g, 4.6 mmol) . After 18 h, the reaction mixture was concentrated under high vacuum. To the residue was added EtOAc. The organic layer was washed with KHCO 3 solution, H 2 O, and brine, dried over anhydrous Na 2 S ⁇ 4 , filtered, and stripped to yield 1.1 g of product.
• Example 45H A solution of Example 45G (1.1 g, 3.7 mmol) and trimethyloxonium tetrafluoroborate (0.6 g, 4.7 mmol) in 30 mL was stirred for 72 h at ambient temperature. After removing solvent under vacuum, the residue was dissolved in EtOAc. The organic layer was washed with KHCO 3 solution and brine, dried over anhydrous Na2S ⁇ 4 , filtered, and stripped to yield 1 g of product. ⁇ '
• Example 451 Example 45H (1 g) in MeOH was treated with NH 4 CI (0.3 g) under 12 Kbar of pressure. The reaction was concentrated under vacuum. The residue was taken up in CH2CI 2 , filtered, and stripped to give 0.8 g of product.
• Example 46 The synthesis and isolation of Example 46 was described i:
• Example 47A A suspension of ethyl 4, 4, 4-trifluorocrotonate (10.0 g, 59 mmol) , 1-nitrohexane (7.86 g, 60 mmol), K 2 C0 3 (4.1 g) , and Aliquot 336 ( 6 drops) was sonicated for 5 h. To the reaction was added Et 2 0 (200 mL) . The reaction mixture was filtered, extracted with brine, dried over Na 2 S0 4 (anhydrous) , filtered, and concentrated under reduced pressure to give a yellow liquid. The product was purified by column chromatography to give 13.8 g (77%) .
• Example 47B,C A solution of Example 47A (13.0 g) in MeOH was reduced under catalytic hydrogenation conditions (60 psi, 55 * C) using Raney nickel. The reaction was heated for 8 h to effect cyclization after reduction of the nitro group. After concentration of the reaction mixture under reduced pressure, the residue was purified by column chromatography to give 9.0 g of a light yellow liquid. A second column was run to separate the cis (47B) and trans lactam (47C) .
• the title product is prepared according to the procedure of Example 43, using ⁇ -nitrostyrene instead of l-acetyl-2- nitroethanol to afford the title product.
• Example 43 is allowed to react with 2-methoxypyrroline to afford the title product.
• Example 50 A) Example 43 is allowed to react with N-CBZ- dehydroalanine methyl ester to afford the protected title produc .
• Example 50 Removal of the CBZ protecting group from Example 50 A by hydrogenation followed by acid hydrolysis affords the title produc .
• Example 55 Tetrahydropyran-4-one is allowed to react with o- nitrobenzyl bromide under basic conditions to give 2-(o- nitrobenzyl) tetrahydropyran-4-one.
• Example 55 B) The 2- (o-nitrobenzyl) tetrahydropyran-4-one product of Example 55 A is carried on as in Example 43c-d to give 3- (o-nitrobenzyl) -5-imino-2,3,4,5,6,7-hexahydro-l, 4- oxazepine.
• Example 55) The 3- (o-nitrobenzyl) -5-imino-2, 3 ,4, 5, 6,7- hexahydro-1, 4-oxazepine product of Example 55 A is reduced under hydrogen atmosphere utilizing platinum oxide catalyst to afford the title product.
• Example 60 The product of Example 43C is reacted as in Example 39 to afford 3- (2-nitroethyl)hexahydro-5-imino-1, - oxazepin-6-ol.
• Example 60 he product of Example 60 is reacted as in Example 49 to afford :he title compound.
• Example 62 3- (2-Nitro-l-phenylethyl) -6-hydroxy-5-imino- 2, 3 , 4, 5, 6,7-hexahydro-l, 4-oxazepine is reduced as in Example 43 to afford the title compound.
• Example 63 is synthesized and isolated from Example 47
• Example 64 is prepared from Example 47B in the manner described in Example 47.
• Example 65 is prepared from Example 47B in the manner described in Example 47.
• Example 66 is prepared from Example 45C in the manner described in Exaitrole 45.
• Example 67 is prepared from Example 45C in the manner described in Example 45.
• Example 72 is prepared from Example 45E and Boc 2 NH by Mitsunobu reaction conditions. The synthesis of Example 72 is completed in the manner described in Example 45.
• Example 80 A cis and trans-5- [ (1, 3-dioxolan-2-yl)methyl] -4- (methyl)pyrrolidin-2-one was prepared in the manner described in R. Ohrlein, W. Schwab, R. Ehrler, V. Jager, Synthesis 1986, 535-538) starting with 1, l-dimethoxy-3-nitropropane and methyl crotonate.
• Example 80 3,C Example 80 A was reduced under catalytic hydrogenation conditions using Raney Ni in MeOH. After heating the reaction mixture for 16 h at 55 °C, the solvent was removed under vacuum. The crude lactam was separated by column chromatography into the cis (80 B) and trans (80C) lactam.
• Example 80 D A stirring solution of Example 80 B ,
• Example 80 To a stirring solution of Example 80 D and HMPA in THF cooled to -70 °C is added lithium hexamethyldisilazide. After 20 min, the reaction is warmed to -40 * C and cooled again to -70 * C. To the stirring reaction is added (R) -(-)- (camphorsulphonyl)oxaziridine in THF. After stirring at -70 °C for 30 min, the reaction is warmed to -30 °C and stirred an additional 2.5 h. To the reaction is added saturated NH 4 CI solution followed by EtOAc. The organic layer is washed with brine, dried over anhydrous a 2 S0 4 , filtered, and stripped.
• Example 80 F To a stirring solution of Example 80 E in CHCi ⁇ is added H 2 O and TFA. After stirring for 2 h, the reaction mixture is concentrated under reduced pressure. The residue is dissolved in EtOAc. The organic layer is washed with a minimum of saturated NaHC0 3 , dried over MgS ⁇ 4, filtered, and concentrated under reduced pressure to recover crude aldehyde.
• Example 80 G To a sirring solution of Example 80 F in MeOH is added NaBH 3 CN. The reaction is maintained at pH 4 by the addition of HOAc. After stirring for three days, the reaction mixture is concentrated under vacuum. To the residue is added 1 N HCl and EtOAc.
• Example 80 H The product of Example 80 G is treated with trimethyloxonium tetrafluoroborate in CH2CI2 as described in Example 45.
• Example 80) A solution of the product of Example 80 H in MeOH is reacted with ammonium chloride by the method of Example 5 followed by chromatography on reverse phase HPLC to generate the title material.
• Nitric Oxide Synthase activity was measured by monitoring the conversion of [3H] -arginine to [3H] -citrulline (Bredt and Snyder, Proc. Natl. Acad. Sci. U.S.A.. 87 , 682-635, 1990 and Misko et al, Eur. J. Pharm.. 233 , 119-125, 1993) .
• Human inducible NOS * hiNOS human endotheliai constitutive NOS
• hecNOS human neuronal constitutive NOS
• hncNOS human neuronal constitutive NOS
• the cDNA for human inducible NOS (hiNOS) was isolated from a ⁇ cDNA library made from RNA extracted from a colon sample from a patient with ulcerative colitis.
• the cDNA for human endotheliai constitutive NOS (hecNOS) was isolated from a ⁇ cDNA library made from RNA extracted from human umbilical vein endotheliai cells (HUVEC) and the cDNA for human neuronal constitutive NOS (hncNOS) was isolated from a ⁇ cDNA library made from RNA extracted from human cerebellum obtained from a cadaver.
• the recombinant enzymes were expressed in Sf9 insect cells using a baculovirus vector (Rodi et al, in The Biology of Nitric Oxide. Pt. 4: Enzvmolo ⁇ v. Biochemistry and Immunology: Moncada, S., Feelisch, M. , 3usse, R. , Higgs, E. , Eds.; Portland Press Ltd.: London, 1995; pp 447- 450) . Enzyme activity was isolated from soluble cell extracts and partially purified by DEAE-Sepharose chromatography.
• calmodulin was included at a final concentration of 40-100 nM. Following incubation at 37° C for 15 minutes, the reaction was terminated by addition of 300 ⁇ L of cold stop buffer containing 10 mM EGTA, 100 mM H ⁇ PES, pH 5.5 and 1 mM citrulline. [3H] -Citrulline was separated by chromatography or. .owex ⁇ OW X-3 cation exchange resin and radioactivity determined with a liquid scintillation counter. Results are reported in Table I as the IC50 values of compounds for hiNOS, hecNC ⁇ and hncNOS. Compounds giving less than 50% inhibition at 10C ⁇ M were reported as having IC50 values of >100 ⁇ M and compounds giving greater than 50% inhibition at 100 ⁇ M were reported as having IC50 values of ⁇ 100 ⁇ M.
• hiNOS refers to human inducible NOS hecNOS refers to human endotheliai constitutive NOS hncNOS refers to human neuronal constitutive NOS

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