EP0723438A1 - Derives substitues de l'uree et de l'isothiouree utilises comme inhibiteurs de l'oxyde nitrique synthase - Google Patents

Derives substitues de l'uree et de l'isothiouree utilises comme inhibiteurs de l'oxyde nitrique synthase

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Publication number
EP0723438A1
EP0723438A1 EP94927761A EP94927761A EP0723438A1 EP 0723438 A1 EP0723438 A1 EP 0723438A1 EP 94927761 A EP94927761 A EP 94927761A EP 94927761 A EP94927761 A EP 94927761A EP 0723438 A1 EP0723438 A1 EP 0723438A1
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EP
European Patent Office
Prior art keywords
ethyl
isothiourea
phenyl
group
lysine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP94927761A
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German (de)
English (en)
Inventor
Jeffrey Alan Oplinger
Barry George Shearer
Eric Cleveland Bigham
Eric Steven Furfine
Edward Patrick Garvey
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Wellcome Foundation Ltd
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Wellcome Foundation Ltd
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Priority to EP94927761A priority Critical patent/EP0723438A1/fr
Publication of EP0723438A1 publication Critical patent/EP0723438A1/fr
Ceased legal-status Critical Current

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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
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/70—Compounds containing any of the groups, e.g. isoureas
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/30—Isothioureas
    • C07C335/32—Isothioureas having sulfur atoms of isothiourea groups bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/18—Nitrogen atoms

Definitions

  • the present invention relates to N-substituted urea derivatives, to methods for their manufacture, to pharmaceutical compositions containing them and to their use in therapy, in particular their use as inhibitors of nitric oxide synthase, and in particular neuronal nitric oxide synthase.
  • endothelium-derived relaxing factor a labile humoral factor termed endothelium-derived relaxing factor (EDRF).
  • NO nitric oxide
  • 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 communication in the central nervous system (see Moncada et al, Biochemical Pharmacology, 23, 1709- 1715 (1989) and Moncada et al, Pharmacological reviews, 42, 109-142 (1991)). It is now thought that excess NO production may be involved in a number of conditions, particularly conditions which involve systemic hypotension such as toxic shock and therapy with certain cytokines.
  • the NO released by the constitutive enzyme acts as a transduction mechanism underlying several physiological responses.
  • the function of the NO produced by the inducible enzyme is as a cytotoxic molecule for tumour 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 synthesised by the inducible NO synthase.
  • NO synthesis plays an important part in the pathology of a range of diseases of the nervous system, eg. ischemia.
  • non-selective inhibitors of NO synthases cause profound changes in blood pressure and blood flow, including cerebral blood flow.
  • ischemic injury inherently reduces the blood supply to the brain and any further decrease in blood flow caused by a non-selective NO synthase inhibitor would have a deleterious effect, potentially opposing any beneficial effect of decreased NO production within the brain.
  • studies of middle cerebral artery occlusion in both rats and mice have demonstrated a substantial protection effect of low doses of NO synthase inhibitors (see for example Nowicki et al, Eur. J Pharmacol., 1991. 204.
  • NO synthase inhibitors which are selective in the sense that they inhibit one NO synthase enzyme to a considerably greater extent compared to one or more of the other enzymes would be of even greater therapeutic benefit and much easier to use.
  • urea derivatives when used herein means "isothiourea derivatives" and “isourea derivatives”.
  • the present invention provides the use of an N-substituted urea derivative or a salt, ester or amide thereof, other than N-(2,6-dimethylphenyl)-5,6- dihydro-4H-l,3-thiazin-2-amine, for the manufacture of a medicament for the treatment of a condition where there is an advantage in inhibiting the neuronal NO synthase enzyme with less inhibition of the endothelial or inducible NO synthase enzymes.
  • the present invention provides a method of treatment of a condition where there is an advantage in inhibiting the neuronal NO synthase enzyme with less inhibition of the endothelial or inducible NO synthase enzyme comprising administering to a mammal in need thereof a therapeutically effective amount of an N- substituted urea derivative or a salt, ester or amide thereof, other than N-(2,6- dimethylphenyl)-5,6-dihydro-4H- 1 ,3-thiazin-2-amine.
  • the present invention provides the use of a N-substituted urea derivative or salt, ester or amide thereof, other than N-(2,6-dimethylphenyl)-5,6- dihydro-4H-l,3-t_ ⁇ iazin-2-amine for the manufacture of a medicament for the treatment of a disease of the nervous system due to over production of the neuronal nitric oxide synthase enzyme.
  • diseases include cerebral ischemia, CNS trauma, epilepsy, AIDS dementia, chronic neurodegenerative disease and chronic pain, and conditions in which non-adrenergic non-cholinergic nerve may be implicated such as priapism, obesity and hyperphagia, particularly cerebral ischemia.
  • the N-substituted urea derivative is an N- substituted isothiourea derivative, other than N-(2,6-dimethylphenyl)-5,6-dihydro-4H- l,3-tl ⁇ az_n-2-amine, preferably an N,S-disubstituted isothiourea derivative.
  • the N-substituted urea derivative is an N- substituted isourea, preferably an N,O-disubstituted isourea derivative.
  • Preferred urea derivatives include those of the formula (I)
  • Q is oxygen or sulphur
  • R! is hydrogen or Ci _g hydrocarbyl
  • R2 is a mono- or bicyclic heterocyclic ring system, a C ⁇ . ⁇ Q hydrocarbyl group which may optionally contain an oxygen atom, a group S(O) n wherein n is 0, 1 or 2, or a group NR ⁇ wherein R- is hydrogen or a C ⁇ . ⁇ aliphatic group,each group R2 optionally being substituted by one to five groups independently selected from
  • Rl may be linked to the imino nitrogen to form a monocyclic heterocyclic ring; with the exception of N-(2,6-dimethylphenyl)-5,6-dihydro-4H-l,3-thiazin-2-amine.
  • a preferred group of compounds are those of formula (I) with the proviso that when Q is sulphur and R ⁇ is hydrogen or C ⁇ _5 alkyl, R ⁇ is not an ornithine or lysine derivative optionally substituted by a Cj.g alkyl group on either the ⁇ -, ⁇ - or ⁇ -carbon atoms, or a tautomer thereof.
  • One embodiment of the present invention provides compounds of formula (I) as hereinbefore defined with the proviso that R s not linked to the imino nitrogen to form a monocyclic heterocyclic ring.
  • Q is oxygen
  • Q is sulphur
  • Rl is hydrogen, C1.4 alkyl, C2-.5 alkenyl or benzyl; preferably R ⁇ is C ⁇ _4 alkyl for example ethyl;
  • R ⁇ is a 5- or 6- membered heterocyclic ring or a 9- or 10-membered bicyclic heterocyclic ring, a phenyl ring, or a C2-8 alkyl chain which optionally contains a group S(O) n as hereinbefore defined, or a C2.4 alkyl chain which contains a phenylene ring, each group R ⁇ optionally being substituted by one to five groups independently selected from (i) a C ⁇ _4 alkyl group optionally substituted by one to three fluoro atoms:
  • R1 may be linked to the imino nitrogen in the compound of formula (I) to form a thiazole or thiazoline ring.
  • Formula (I) includes compounds of formulae (I A) to (IF)
  • Z is oxygen or sulphur; Rl is as hereinbefore defined; X is a C2-9 hydrocarbyl group which may optionally contain an oxygen atom, a group S(O) n as hereinbefore defined, or a group NR ⁇ as hereinbefore defined; T is a C g hydrocarbyl group optionally containing a 5- or 6-membered heterocyclic ring, or T is a C2-.4 hydrocarbyl group containing a phenylene ring; and Ar is a mono- or bicyclic aromatic ring system optionally substituted by one to five groups selected from
  • R* is a C ⁇ _ hydrocarbyl group, preferably a Cj_4 alkyl group, e.g. ethyl.
  • X is a C2-6 hydrocarbyl group and preferably a C3.5 alkylene or alkenylene group.
  • T is Cj.g hydrocarbyl containing a 5- or 6-membered heterocyclic ring; or a C2.4 hydrocarbyl group containing a phenylene ring.
  • Ar is phenyl optionally substituted by one to three substituents which may be the same or different and are selected from C 4 alkyl or C3.6 cycloalkyl groups each optionally substituted by one to three halo atoms; C1.4 alkoxy groups; hydroxy groups, benzyloxy groups; halo atoms; CO2R ⁇ groups wherein R ⁇ is hydrogen or C j _4 alkyl; groups NR ⁇ R 7 wherein R ⁇ and R 7 are independently selected from hydrogen or Cj_4 alkyl.
  • Ar is phenyl substituted by one or two substituents, preferably one substituent.
  • Ar is phenyl substituted by C 1.3 alkoxy, hydroxy, benzyloxy, halo atoms or C ⁇ _4 alkyl optionally substituted by one to three fluoro atoms, C1.3 alkoxy, hydroxy, benzyloxy, or halo atoms.
  • One preferred embodiment of the present invention includes compounds of formula (IA) wherein X is a C2.9 hydrocarbyl group which contains an oxygen atom, a group S(O) n or NR3 wherein n and R ⁇ are as hereinbefore defined, and compounds of formulae (IB) to (IF) as hereinbefore defined.
  • Suitable compounds of the formula (I) include:
  • hydrocarbyl group is meant a group that contains only carbon and hydrogen atoms and may contain double and/or triple bonds and which may be cyclic or aromatic in nature.
  • An oxygen atom, or a group S(O) n or NR ⁇ as hereinbefore defined, may optionally intersperse the carbon atoms in the hydrocarbyl chain.
  • aliphatic is meant an alkyl, alkenyl, alkynyl or cycloalkyl group.
  • alkyl, alkenyl and alkynyl are intended to include both straight and branched chain variants.
  • heterocyclic ring a cyclic compound containing one to three heteroatoms selected from oxygen, sulphur and nitrogen, and preferably nitrogen and sulphur.
  • the compounds of formula (I) may include a number of asymmetric centres in the molecule depending on the precise meaning of the various groups and the present invention is intended to include all possible isomers.
  • Certain compounds of formula (I) have also been found to have activity against the inducible NO synthase enzyme and may be of use in the treatment of 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 therapy with cytokine- inducing agents such as 5,6-dimethylxanthenone acetic acid, as an adjuvant to short term immunosuppression in transplant therapy, and in the treatment of autoimmune and or inflammatory conditions affecting the joints, for example arthritis.
  • cytokines such as TNF, IL-1 and IL-2
  • cytokine- inducing agents such as 5,6-dimethylxanthenone acetic acid
  • the present invention further provides the use of a compound of formula (I) other than 5-methyl-2-(2-thiazolylamino)phenol and S-ethyl-N-phenylisothiourea for the manufacture of a medicament for the treatment of a condition requiring inhibition of the inducible NO synthase enzyme.
  • the present invention provides a N-substituted urea derivative of formula (I) other than S-ethyl-N-phenylisothiourea, S-ethyl-N-(2-chlorophenyl) isothiourea, S-ethyl-N-(2-trifluoromethylphenyl)isothiourea, 2-propenylthiourea, N- (2,6-dimethylphenyl)-5,6-dihydro-4H-l,3-thiazin-2-amine and 5-methyl-2-(2- thiazolyl amino)phenol, or a pharmaceutically acceptable salt, ester or amide thereof for use in medicine.
  • formula (I) other than S-ethyl-N-phenylisothiourea, S-ethyl-N-(2-chlorophenyl) isothiourea, S-ethyl-N-(2-trifluoromethylphenyl)isothiourea, 2-
  • the present invention also provides a N-substituted urea derivative of formula (I) or a salt, ester or amide thereof, with the proviso that:
  • R! is methyl, R ⁇ is not a phenyl ring substituted by 3-chloro, 2-ethyl, 2-chloro-5-trifluoromethyl, 3-trifiuoromethyl, 3-methyl, 3-bromo, 4- nitro, 4-chloro, 3,4-dichloro or CO2H; or R 2 is not a group 5-chloro-2- pyridyl;
  • R! is ethyl, R 2 is not a phenyl ring or a phenyl ring substituted by 4- methoxy, 2-chloro, 4-hydroxy, 2-methoxy, 4-methyl. 2-trifluoromethyl or 3-trifluoromethyl; or
  • the present invention includes N-substituted urea derivatives in the form of salts, esters or amides, 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, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic, oxalic, fumaric, maleic, oxaloacetic, methanesulphonic, ethanesulphonic, p-toluenesulphonic, benzenesulphonic and isethionic acids.
  • Salts of N-substituted urea derivatives can be made by reacting the appropriate compound in the form of the free base with the appropriate acid.
  • Esters are pharmaceutically acceptable esters, for example Cj_4 alkyl esters.
  • treatment of a patient is intended to include prophylaxis.
  • the present invention provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt, ester or amide thereof, other than S-ethyl-N-phenylisothiourea, S-ethyl-N-(2- chlorophenyl)isothiourea, S-ethyl-N-(2-trifluoro methylphenyl)isothiourea, 2- propenyl thiourea, N-(2,6-clr ⁇ ethylphenyl)-5,6-dihydro-4H-l,3-thiazin-2-amine and 5-methyl-2-(2-thiazolylamino)phenol, together with one or more pharmaceutically acceptable carriers therefor and optionally one or more other therapeutic ingredients.
  • the carrier(s) must be "acceptable" in the sense of being compatible with the other
  • the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, 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, ester or amide thereof ("active ingredient”) with the carrier which constitutes one or more accessory ingredients.
  • active ingredient a pharmaceutically acceptable salt, ester or amide thereof
  • 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 anti-oxidants, 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 (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example, saline, or 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 flavoured 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.
  • 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 flavouring agents.
  • the compounds of the invention may be administered orally or via injection at a dose of from 0.1 to 500mg/kg per day.
  • the dose range for adult humans is generally from 5mg to 35g/day, preferably 5mg to 2g/day and most preferably lOmg to lg/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 5mg to 500mg, usually around 10mg to 200mg.
  • 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.
  • the invention further includes a process for the preparation of the novel compounds of formula (I), analagous to those known in the art for preparing N-substituted ureas.
  • R 2 is as hereinbefore defined, with a compound having a thiocarbonyl group, followed if necessary by hydrolysis to give a compound of formula (I) wherein R* is hydrogen or a tautomer thereof, and thereafter the optional conversion to a compound of formula (I) wherein R is other than hydrogen by alkylation of the sulphur atom of the isothiourea.
  • the coupling reaction may be carried out between a compound of formula (II) and a compound having a thiocarbonyl group, for example thiophosgene followed by ammonia as described in Tet. Lett. 1991, 21 (7) 875-878 or a compound of formula (II) and an isothiocyanate, such as benzoyl isothiocyanate.
  • a polar solvent such as dichloromethane, chloroform, ethanol or acetone at a non-extreme temperature of from -78°C to 200°C, for example -5°C to 100°C and preferably room temperature.
  • the intermediate thiourea e.g.
  • benzoylthiourea may be hydro lysed in a polar solvent such as 10% sodium hydroxide solution at a non- extreme temperature of from -20°C to 200°C, such as the refluxing solvent temperature.
  • the alkylation is generally carried out using a compound of formula R -L, wherein Rl is as hereinbefore defined other than hydrogen and L is a suitable leaving group.
  • Suitable leaving groups include a halo atom, for example iodo.
  • R 2 is as hereinbefore defined, followed by deprotection where necessary.
  • the acid catalysed addition is suitably carried out using the alcohol (Rl-OH or water) as the solvent, at a non-extreme temperature of 0°C to 100°C, and preferably room temperature, in the presence of an acid, e.g. hydrochloric acid, conveniently in solution in ether.
  • alcohol Rl-OH or water
  • an acid e.g. hydrochloric acid
  • Compounds of formula (III) may be prepared by the reaction of a compound of formula (II) as hereinbefore defined with a compound of formula L'-CN wherein L' is a leaving group, for example a halo atom such as bromo.
  • the reaction may be carried out in ether as a solvent at a non-extreme temperature of from -20°C to 100°C, suitably 0°C.
  • the thiazoline foam was taken up into a mixture of trifluoroacetic acid (9.5ml), water (0.5ml), thioanisole (0.5ml), phenol (0.75g) and 1 ,2-ethanediol (0.25ml) at 0°C.
  • the solution was stirred for two hours at 20°C and concentrated to a volume of 3ml.
  • the solution was rapidly stired and diethyl ether (50ml) was added.
  • the intermediate bis-thiourea (5.92g) was prepared from p-xylylenediamine (3.4G, 25mmol) as described in Example 5. To a solution of the bis-thiourea intermediate (1.27g, 5mmol) in dimethylformamide (25ml) was added iodomethane (2.5ml, 40mmol). The solution was stirred at 22°C for 72 hours, and the solvent was removed under reduced pressure to yield a crude, amber-coloured oil. The crude product was taken up into hot ethanol (40 mL) and treated with 160mL of ethyl acetate with scratching to induce crystallization.
  • N -Tertbutoxycarbonyl-L-thiocitrulline tert-butyl ester (Tett. Lett. (1991) 21(7), 875- 878) (4g, 12.0 mmol) was treated with 7.5 mL (120 mmol) iodomethane in 30 mL anhydrous acetonitrile at 20°C with stirring for 4 hours. The solution was concentrated to a yellow foam and stirred with a 0°C mixture of trifluoroacetic acid (30mL), phenol (2.25g), water (l.OmL), thioanisole (1.0 mL), and 1 ,2-ethanedithiol (0.5 mL) for 1.5 hours.
  • N 2 -tert-butoxycarbonyl-L-thiocitrulline tert-butyl ester (1.3g, 3.89 mmol) in 20mL anhydrous acetonitrile was stirred with 1.2 lg (7.75 mmol) iodoethane at 20°C for 60 hours.
  • the solution was concentrated to a tan-coloured foam (1.75g).
  • This crude solid was treated at 0°C with stirring for 2 hours with a solution of 14 mL trifluoroacetic acid, 2.25g phenol, 1.5mL thioanisole, 1.5mL water, and 0.75 mL 1,2-ethanedithiol. The mixture was partially concentrated and lOOmL diethylether was added.
  • N-S-fiminomethoxymethyD-L-ornithine dihvdrochloride A solution of 0.75 g (1.96 mmol) N 2 -(tert-butoxycarbonyl)-N5- (iminomethoxymethyl)-L-ornithine tert-butyl ester hydrochloride in 2 mL dioxane at 0°C was treated with 15 mL of 4N hydrochloric acid in dioxane solution. The solution was stirred overnight at 22 °C, concentrated to a crude paste, and freeze-dried from 8 mL of water.
  • the product was freeze- dried a second time to yield 0.53 g N ⁇ -(iminomethoxymethyl)-L-ornithine dihydrochloride.
  • the product analyzed solvated with an additional 0.2 molar hydrochloric acid. 0.1 molar water, and 0.3 molar dioxane.
  • N6-((ber_zyloxy)carbonyl)-N 2 -(tert-butoxycarbonyl)-L-lysine tert-butyl ester was hydrogenated at 20°C under 50 psi hydrogen in 100 mL ethyl acetate for 1 h.
  • the catalyst was removed by filtration through celite and the amine intermediate isolated without further purification as an oil (3.05g).
  • the amine intermediate was taken into 40mL ether and the solution added over 10 min to a solution of l.lg (10.1 mmol) of cyanogen bromide in 50 mL ether at 0°C.
  • N 2 -(tert-butoxycarbonyl)-N ⁇ -(cyano)-L-lysine tert-butyl ester was prepared 0.95 g (91%) N 2 -(tert-butoxycarbonyl)-N6- (iminomethoxymethyl)-L-lysine tert-butyl ester hydrochloride as a foamy- solid by the method described for the preparation of N -(tert-butoxycarbonyl)- N :> -(iminomethoxymethyl)-L-ornithine tert-butyl ester hydrochloride.
  • N 2 -(tert-butoxycarbonyl)-N ⁇ -(cyano)-L-lysine tert- butyl ester was prepared 1.5 g (75%) of foamy solid N -(tert-butoxycarbonyl)- N"-(ethoxyiminomethyl)-L-lysine tert-butyl ester hydrochloride by the method described for N 2 -(tert-butoxycarbonyl)-N ⁇ -(iminomethoxymethyl)-L- ornithine tert-butyl ester hydrochloride.
  • the crude material was purified by silica gel chromatography eluting with methanol/methylene chloride/ammonium hydroxide (5/95/0.5 to 15/85/0.5) to yield 5.28g (30%) of a thick, viscous yellow oil.
  • Amion and chorion were removed from fresh placenta, which was then rinsed with 0.9% NaCl.
  • the tissue was homogenized in a Waring blender in 3 volumes of HEDS buffer (20mM Hepes pH 7.8, 0.1 mM EDTA, 5 mM DTT, 0.2 M sucrose) plus 0.1 mM PMSF.
  • the homogenate was filtered through cheesecloth and then centrifuged at lOOOg for 20 min. The supernatant was recentrifuged at 27500g for 30 min. Solid ammonium sulfate was added to the supernatant to give 32% saturation.
  • Precipitated protein was pelleted at 25,000g and then redissolved in a minimal volume of HEDS buffer plus 0.1 mM PMSF, 1 O ⁇ g/ml leupeptin and soybean trypsin inhibitor, and 1 ⁇ g/ml pepstatin. The redissolved pellet was centrigued at 15000g for 10 min. To the supernatant was added 1/20 volume of 2',5' ADP agarose resin (Sigma), and the slurry was mixed slowly overnight. In morning, slurry was packed into a column. The resin was sequentially washed with HEDS, 0.5 M NaCl in HEDS, HEDS, and then NOS was eluted with lOmM NADPH in HEDS. The enzyme could be concentrated by ultrafiltration and quick frozen and stored at -70°C without loss in activity for at least 6 months.
  • NOS was assayed for the formation of citrulline following the procedure of Schmidt et al (PNAS 88 365-369 , 1991) with these modifications: 20 mM Hepes, pH 7.4, lO ⁇ g/ml calmodulin, 2.5 mM CaCl2 2.5 mM DTT, 125 ⁇ M NADPH lO ⁇ M H4 Biopterin, 0.5 mg/ml BSA, and 1 ⁇ M L-[14C] arginine (New England Nuclear). Linearity of NOS-catalyzed rate was confirmed prior to kinetic studies that used single time point determination of rate.
  • DLD-1 (ATCC No. CCL 221) were grown at 37°C, 5% C0 2 in RPMI 1640 medium supplemented with L-glutamin, penicillin, streptomycin, and 10% heat-inactivated fetal bovine serum. Cells were grown to confluency and then the following cocktail of cytokines were added: 100 units/ml interferon-gamma, 200 units/ml interleukin-6, 10 ng/ml tumor necrosis factor, and 0.5 ng/ml interleukin-l ⁇ .
  • citrulline was assayed as described above except that 10 ⁇ M FAD was included and calmodulin and CaC12 were excluded from the assay mix.
  • Human brain NOS Human brain NOS was prepared using variations of the procedures of Schmidt et al. (TNAS 88 365-369, 1991), Mayer et al. (Ted. Eur. Biochem. Soc. 288 187-191, 1991), and Bredt and Snyder, (PNAS 87 682-685, 1990). Briefly, frozen human brain (1050 gm) was homogenized in cold buffer A (50 mM HEPES, pH 7.5 (pH at RT) and 0.5 mM EDTA, 10 mM DTT, 3.6 L total volume) with a polytron. The mixture was centrifuged at 13,000g for 1 hour and the supernatant was removed (about 2050 ml).
  • cold buffer A 50 mM HEPES, pH 7.5 (pH at RT) and 0.5 mM EDTA, 10 mM DTT, 3.6 L total volume
  • the mixture was thawed and passed through a 2',5' ADP-agarose column (0.4 g swelled in buffer A) at 4 ml/min.
  • the column was washed with 100ml buffer A. 200ml buffer A with 500 mM NaCl, 100ml Buffer A, then 30 ml buffer A with 5 mM NADPH.
  • To the enzyme eluted from the column was added glycerol to 15%, CaCl2 to 1 mM, tetrahydrobiopterin to lO ⁇ M, tween to 0.1% and FAD, FMN to 1 ⁇ M each.
  • the enzyme was then passed through a 1 ml calmodulin-agarose column which had been equilibrated in Buffer A, 15% glycerol and 1 mM CaCl2.
  • the column was washed with 15ml Buffer A, 15% glycerol and 1 mM CaC_2, 15 ml of Buffer A, 15% glycerol and 5 mM EDTA, and then enzyme activity was eluted with 3 ml of Buffer A, 15% glycerol and 5 mM EDTA, 1 M NaCl.
  • To the enzyme was added tetrahydrobiopterin to 10 ⁇ M, FAD and FMN to 1 ⁇ M, and tween to 0.1%.
  • the progress curve was an exponential decay followed by a linear steady state rate.
  • Inhibition constant was calculated by dividing the steady state inhibited rate by the control uninhibited rate; percent inhibition was then used to calculate the inhibition constant assuming competitive inhibition with respect to arginine.
  • alue obtained from measuring percent inhibition at three or more concentrations of inhibitor at a single time point and assuming competitive inhibition with respect to arginine.
  • the progress curve was an exponential decay of the rate. Value is a K ⁇ determined by measuring association and dissociation rate constants for the slow onset of inhibition, as previously described (Furfine, E.S., Harmon, M.F., Paith, J.E., and Garvey, E.P. (1993) Biochemistry 32, 8512-8517).

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Abstract

L'invention se rapporte à l'utilisation d'un dérivé de l'urée N-substitué dans la fabrication d'un médicament destiné au traitement d'une affection, en particulier de l'ischémie cérébrale, dans laquelle il y a un avantage à inhiber l'oxyde nitrique synthase; l'invention concerne également les formulations pharmaceutiques de ce dérivé, ainsi que des nouveaux dérivés de l'urée N-substitués et leurs procédés de préparation.
EP94927761A 1993-10-04 1994-10-03 Derives substitues de l'uree et de l'isothiouree utilises comme inhibiteurs de l'oxyde nitrique synthase Ceased EP0723438A1 (fr)

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US13179493A 1993-10-04 1993-10-04
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EP94303939 1994-06-01
PCT/GB1994/002138 WO1995009619A2 (fr) 1993-10-04 1994-10-03 Derives substitues de l'uree et de l'isothiouree utilises comme inhibiteurs de l'oxyde nitrique synthase
EP94927761A EP0723438A1 (fr) 1993-10-04 1994-10-03 Derives substitues de l'uree et de l'isothiouree utilises comme inhibiteurs de l'oxyde nitrique synthase

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ES2137512T3 (es) * 1994-05-07 1999-12-16 Astra Ab Derivados de amidina biciclicos como inhibidores de la sintetasa de oxido nitrico.
WO1996006076A1 (fr) * 1994-08-18 1996-02-29 Chugai Seiyaku Kabushiki Kaisha Derives aminoacides exerçant une activite inhibitrice de la synthetase du monoxyde d'azote
GB9418912D0 (en) * 1994-09-20 1994-11-09 Fisons Corp Pharmaceutically active compounds
WO1996018607A1 (fr) * 1994-12-12 1996-06-20 Chugai Seiyaku Kabushiki Kaisha Derive d'aniline inhibant la synthase du monoxyde d'azote
TW397812B (en) * 1995-02-11 2000-07-11 Astra Ab Bicyclic isothiourea derivatives useful in therapy
US6140322A (en) * 1995-11-07 2000-10-31 Astra Aktiebolag Amidine and isothiourea derivatives as inhibitors of nitric oxide synthase
TW458978B (en) * 1995-11-07 2001-10-11 Astra Ab Amidine and isothiourea derivatives as inhibitors of nitric oxide synthase
US5929085A (en) * 1996-11-06 1999-07-27 Astra Aktiebolag Amidine and isothiourea derivatives, compositions containing them and their use as inhibitors of nitric oxide synthase
WO1998028257A1 (fr) 1996-12-24 1998-07-02 Chugai Seiyaku Kabushiki Kaisha Derives d'amine aromatiques ayant une action inhibitrice a l'egard des nos
SE9701681D0 (sv) 1997-05-05 1997-05-05 Astra Ab New compounds
US6166030A (en) * 1997-05-05 2000-12-26 Astra Aktiebolag Compounds
CA2366897C (fr) 1999-04-06 2009-11-17 Andrew B. Onderdonk Compositions immunomodulatrices et procedes d'utilisations connexe
CA2494323C (fr) * 2002-08-07 2011-01-25 Neuraxon Inc. Composes d'amino benzothiazole a activite inhibitrice de nos
US7186725B2 (en) 2003-01-03 2007-03-06 Genzyme Corporation Anti-inflammatory compositions and methods
ES2476027T3 (es) 2005-10-25 2014-07-11 Shionogi & Co., Ltd. Derivados de aminodihidrotriazina
WO2008133273A1 (fr) 2007-04-24 2008-11-06 Shionogi & Co., Ltd. Composition pharmaceutique pour le traitement de la maladie d'alzheimer
ES2476605T3 (es) 2007-04-24 2014-07-15 Shionogi & Co., Ltd. Derivados de aminohidrotiazina sustituidos con grupos cíclicos
AU2009258496B8 (en) 2008-06-13 2014-06-26 Shionogi & Co., Ltd. Sulfur-containing heterocyclic derivative having beta-secretase-inhibiting activity
JPWO2010047372A1 (ja) 2008-10-22 2012-03-22 塩野義製薬株式会社 Ｂａｃｅ１阻害活性を有する２−アミノピリミジン−４−オンおよび２−アミノピリジン誘導体
WO2010113848A1 (fr) 2009-03-31 2010-10-07 塩野義製薬株式会社 Dérivé isothiourée ou dérivé isourée ayant une activité inhibitrice de bace1
US8999980B2 (en) 2009-12-11 2015-04-07 Shionogi & Co., Ltd. Oxazine derivatives
EP2634188A4 (fr) 2010-10-29 2014-05-07 Shionogi & Co Dérivé d'aminodihydropyrimidine fusionnée
EP2634186A4 (fr) 2010-10-29 2014-03-26 Shionogi & Co Dérivé de naphtyridine
TW201247635A (en) 2011-04-26 2012-12-01 Shionogi & Co Oxazine derivatives and a pharmaceutical composition for inhibiting BAC1 containing them
RU2503450C1 (ru) * 2012-04-19 2014-01-10 Федеральное Государственное Бюджетное Учреждение "Медицинский Радиологический Научный Центр" Министерства Здравоохранения и Социального Развития Российской Федерации (ФГБУ МРНЦ Минздравсоцразвития России) Противоопухолевое средство
WO2014065434A1 (fr) 2012-10-24 2014-05-01 Shionogi & Co., Ltd. Dérivés de dihydrooxazine ou d'oxazépine ayant une activité inhibitrice de bace1
WO2016105448A1 (fr) * 2014-12-22 2016-06-30 Darryl Rideout Ligands du récepteur aux imidazolines de type 1 à utiliser en tant qu'agents thérapeutiques
RU2699558C2 (ru) * 2018-10-05 2019-09-06 Федеральное государственное бюджетное учреждение "Национальный медицинский исследовательский центр радиологии" Министерства здравоохранения Российской Федерации (ФГБУ "НМИЦ Радиологии" Минздрава России РФ) Средство для таргетной терапии злокачественных новообразований

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