WO2003075922A1 - Inhibiteurs de la synthetase du monoxyde d'azote - Google Patents

Inhibiteurs de la synthetase du monoxyde d'azote Download PDF

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Publication number
WO2003075922A1
WO2003075922A1 PCT/JP2002/002392 JP0202392W WO03075922A1 WO 2003075922 A1 WO2003075922 A1 WO 2003075922A1 JP 0202392 W JP0202392 W JP 0202392W WO 03075922 A1 WO03075922 A1 WO 03075922A1
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synthase inhibitor
atom
amino
group
compound
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PCT/JP2002/002392
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English (en)
Japanese (ja)
Inventor
Hideo Terauchi
Shigeo Ueda
Motoharu Ido
Akihiro Yano
Masashi Matsumoto
Junichi Tsuji
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Dainippon Pharmaceutical Co., Ltd.
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Priority to AU2002238889A priority Critical patent/AU2002238889A1/en
Priority to PCT/JP2002/002392 priority patent/WO2003075922A1/fr
Publication of WO2003075922A1 publication Critical patent/WO2003075922A1/fr

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    • 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
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D277/38—Nitrogen atoms
    • C07D277/40—Unsubstituted amino or imino radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • 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

Definitions

  • the present invention relates to 2-aminothiazoline or oxazoline derivatives useful as nitric oxide synthase inhibitors.
  • nitric oxide is an endothelium-derived vasorelaxant in the vascular system (Moncada, S., et al., Pharmacol. Rev., 1991, 43, 109), and the nervous system. It is believed that they have important physiological activities as neurotransmitters (Edelman, GM, et al., Proc. Natl. Acad. Sci., USA., 1992, 89, 11651).
  • NO is considered to play a role as a biological defense factor due to bactericidal action (Nathan C.F., et al., Curr. Opin. Immunol., 1991, 3, 65).
  • NOs are produced by nitric oxide synthase (NOS) using L-arginine as a substrate.
  • NOS nitric oxide synthase
  • cNOS constitutive NOS
  • eNOS endothelial NOS
  • nervous NOS nervous NOS
  • nNOS neuroneuronal NOS: hereinafter abbreviated as “nNOS”), all of which are constantly expressed and are temporarily active depending on intracellular calcium that is increased by physiological stimulation. To produce small amounts of NO. The other is called inducible NOS (inducible NOS), and its expression is induced in various cells, including macrophages, by stimulation of endotoxins and various cytokines. Once induced, cNOS, unlike cNOS, produces persistent and large amounts of NO independent of intracellular calcium. Therefore, it has been reported that N ⁇ produced by iNOS causes various cell damages. For example, in septic endotoxinemia, excessive NO produced by iNOS can cause hypotensive shock. (Hollenberg, SM, et al., Circ.
  • NOS inhibitor a compound represented by the following general formula (a) is described in a patent gazette (WO 95/11231, JP-T-Hei 9-504028).
  • R 1 and R 2 represent a hydrogen atom, a lower alkyl group, etc.
  • R 3 represents a hydrogen atom, etc.
  • R 4 represents a hydrogen atom, etc.
  • X represents an oxygen atom, a sulfur atom, etc.
  • Means n means 0-7)
  • R 1 represents a hydrogen atom, etc.
  • R 5 , R 6 and R 7 represent C 1-10 -alkyl etc.
  • R 8 and R 9 represent a hydrogen atom etc.
  • X, A And B represent NR 2 , oxygen atom, sulfur atom, (CH 2 ) P, etc.
  • p represents 0-6, and R 2 represents hydrogen atom etc.
  • R 1 ′ means an alkyl having 1 to 6 carbon atoms
  • R 2 ′ and R 3 ′ represent a hydrogen atom, an alkyl having 1 to 3 carbon atoms, and the like, (4 means hydrogen atom, methyl, ethyl, etc.)
  • NOS has cNOS and iNOS, so N
  • an object of the present invention is to inhibit NOS, which has a high inhibitory activity and high selectivity for iNOS, which is useful for treating and / or preventing diseases caused by excessive NO production of iNOS. To provide an agent.
  • the present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found a compound having extremely strong inhibitory activity against iNOS and having high power and selectivity.
  • the present invention is useful for treating and / or preventing a disease caused by excessive NO production of iNOS, and more specifically, 2-aminothiazoline or a compound represented by the following general formula (I).
  • the present invention relates to a NOS inhibitor comprising, as an active ingredient, an oxazoline derivative or a physiologically acceptable acid addition salt thereof (hereinafter, also referred to as “the compound of the present invention”).
  • R 1 and R 2 are the same or different and each represents a hydrogen atom or a lower alkyl group, and X represents an oxygen atom or a sulfur atom. However, R 1 and R 2 are not hydrogen atoms at the same time. "*" Indicates an asymmetric carbon atom when R 1 or R 2 is not a hydrogen atom.
  • R 1 and R 2 are identical or different, a methyl group or Echiru group wherein
  • the present invention also provides
  • R 1 ′ and R 2 are the same or different and represent a lower alkyl group.
  • R 1 ′ and R 2 ′ are not methyl groups at the same time. “*” Indicates an asymmetric carbon atom.)
  • R and R 2 ′′ are different and represent a lower alkyl group, and “*” represents an asymmetric carbon atom.
  • the 2-aminothiazoline or oxazoline derivative represented by the general formula (I) may be referred to as a 4,5-dihydro-1,3-thiazole (or oxazole) -12-ylamine derivative.
  • the compound of the present invention is preferably a compound represented by the general formula (I), wherein X is a sulfur atom in the general formula (I), and the carbon atoms at the 4-position and the 5-position are both R-type. Compound.
  • More preferred specific examples include the following compounds or their physiologically acceptable acid addition salts.
  • the compound of the present invention represented by the general formula (I) may form a physiologically acceptable acid addition salt.
  • the acid addition salt include hydrochloric acid, hydrobromic acid, hydroiodic acid, and sulfuric acid. , Phosphoric acid, nitric acid and other salts with inorganic acids, or acetic acid, oxalic acid, fumaric acid, maleic acid, malonic acid, lactic acid, malic acid, succinic acid, citric acid, tartaric acid, benzoic acid, methanesulfonic acid, p- Salts with organic acids such as toluene sulfonic acid are mentioned.
  • lower alkyl group means a linear or branched C1-6 alkyl group, and specific examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, and a —Butynole group, isobutyl group, sec-butynole group, tert-butynole group, n-pentyl group and the like. Among them, C 1-3 alkyl group is particularly preferable.
  • the configuration when one asymmetric carbon atom is present, the configuration is R type or S type. When two asymmetric carbon atoms are present, the configuration is There are RR type, RS type, SR type and SS type, and these optically active substances are all included in the compound of the present invention.
  • the compound represented by the general formula (I) may exist as an imino tautomer represented by the following formula ( ⁇ ), and these tautomers are also included in the compound of the present invention. included.
  • the compound represented by the general formula (I) or a physiologically acceptable acid addition salt thereof may exist as a hydrate or a solvate, and these compounds are also included in the compounds of the present invention. included.
  • the compound of the present invention represented by the general formula (I) can be produced by the following production method 1 or 2.
  • the compound of the present invention represented by the general formula (I) can be produced according to the following reaction formula.
  • X 1 represents a leaving group such as a halogen atom, p-toluenesulfonyloxy, and methanesulfonyloxy
  • RR 2 , X, and the symbol “*” are the same as described above.
  • II isothiocyanate or an isocyanate derivative
  • the reaction temperature varies depending on the type of the starting compound used and the like, but is usually from 10 to 150 ° C, preferably from 10 to 100 ° C.
  • the reaction time is usually about 30 minutes to 24 hours, preferably about 1 to 10 hours.
  • the compound (I ") of the present invention in which X is an oxygen atom in the general formula (I) can also be produced by the method shown in the following reaction formula.
  • the compound (1 ′′) of the present invention can be prepared by the method described in the literature (J. Org. Chem., 1996, 61, 4210; synthesized according to Angew. Chem. Int. Ed. Engl., 1987, 26, 1141).
  • the compound (III) can be produced by reacting a cyanogen halide with or without a base in a suitable solvent.
  • the reaction temperature varies depending on the type of the starting material to be used and the like, but is usually from 10 to 100 ° C, preferably from 0 to 70 ° C.
  • the reaction time is generally about 1-20 hours, preferably about 1-5 hours.
  • the base may be sodium acetate, sodium acetate, such as sodium acetate acetate, sodium hydrogen carbonate, sodium hydrogen carbonate, such as sodium hydrogen carbonate, or sodium carbonate.
  • sodium carbonate, potassium carbonate such as potassium carbonate and organic bases such as pyridine, triethylamine, diisopropylethylamine, and N-methylmorpholine.
  • Reactions used in the above Process 1 and 2 is usually carried out in a suitable solvent inert to the reaction.
  • a suitable solvent inert methanol, ethanol, isopropyl Nono 0 Nord, Arukonore such as tert- butanol
  • examples include acetone, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, dioxane, and water. These solvents may be used alone or as a mixed solvent of two or more.
  • the compound of the present invention produced by the above production method 1 or 2 can be isolated and purified by ordinary chemical operations such as chromatography and recrystallization.
  • the compound of the present invention represented by the general formula (I) can be obtained in the form of a free base or an acid addition salt, and both can be converted into each other by a usual method.
  • the compound (II) used in the production method 1 can be synthesized according to the method shown in the following reaction formula according to the method described in the literature. i) MsCI or PPh 3 ⁇ ⁇ 2
  • x 1 represents a leaving group such as a halogen atom, p-toluenesulfonyloxy, methanesulfonyloxy, etc.
  • Ri, R 2 , X and ⁇ * '' are the same as described above.
  • carbonate (Boc 2 ⁇ ) is allowed to act in a solvent in the presence or absence of a base to obtain a compound (IV) in which the amino group is protected, and then the compound (IV) Sulfonylation of the hydroxy group with tosinolectide or methanesulfonyl chloride, or nitrogenation with triphenylphosphine dihalogenide, followed by deprotection of the amino group under acidic conditions such as trifluoroacetic acid (TFA).
  • TFA trifluoroacetic acid
  • Test Example 1 Inhibitory activity on inducible NO synthase (iNOS)
  • Mouse macrophage cell line RAW264.7 (3-4x10 6 cells / culture dish) is carbon dioxide ink in D-MEM (Dulbecco-Minimum Essential Medium) medium containing 10% FBS (fetal calf serum). : The cells were cultured in the ⁇ . Next, LPS (lipopolysaccharide) and mouse IFN- ⁇ (interferon-gamma) were added to this medium to a final concentration of 0.2 ⁇ g Zm1 and 100 U / m1, respectively.
  • D-MEM Dulbecco-Minimum Essential Medium
  • FBS fetal calf serum
  • the crude enzyme preparation (701) contains 1 mM N ADPH (reduced nicotinamide adenine dinucleotide phosphate) in 5 OmM Tris-HCl buffer (pH 7.5) (20 ⁇ l), test compound (1 0 1), 1 0 ⁇ C i / m 1 L- [3 H] one arginine (20 ⁇ 1) and 5 Omm tris monohydrochloride buffer solution (p H7. 5) (80 1) was added, at 37 Incubated for 30 minutes.
  • N ADPH reduced nicotinamide adenine dinucleotide phosphate
  • Test Example 2 Inhibitory activity on rat brain-derived constitutive NO synthase (nNOS) (Preparation of crude DnNOS enzyme preparation)
  • nNOS nNOS nNOS nNOS nNOS nNOS nNOS nNOS nNOS nNOS nNOS nNOS nNOS nNOS nNOS nNOS nNOS nNOS nNOS nNOS nNOS nNOS nNOS nNOS nNOS nNOS nNOS nNOS was prepared by the following procedure. An untreated female Wistar rat (body weight 150-: L 70 g) was decapitated and the whole brain was quickly removed and mixed with 5 volumes of 0.1 mM PMS F (phenylmethylsulfonyl fluoride) on ice. 5 OmM HEP ES (N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid) buffer containing 12.5 mM 2-mercaptoethanol and 0.5 mM EDTA The mixture was homogenized by adding a liquid (pH 7.1
  • the compound of the present invention has an iNOS inhibitory activity equal to or higher than that of a known compound with respect to iNOS and also has excellent selectivity for iNOS. It is clear that there is.
  • the compound of the present invention has excellent iNOS inhibitory activity and high selectivity for iNOS, so that safe NOS for humans and mammals can be used. It is expected to be used as SP and harmful agent. Therefore, the NOS inhibitor of the present invention is useful for NO-induced diseases such as arteriosclerosis, myocarditis, cardiomyopathy, cerebral ischemic disorder, Alzheimer's disease, multiple sclerosis, sepsis, hypotension, rheumatoid arthritis, and deformation.
  • NO-induced diseases such as arteriosclerosis, myocarditis, cardiomyopathy, cerebral ischemic disorder, Alzheimer's disease, multiple sclerosis, sepsis, hypotension, rheumatoid arthritis, and deformation.
  • Osteoarthritis gastric ulcer, duodenal ulcer, ulcerative colitis, diabetes, glomerulonephritis, uvea It is useful as a prophylactic and / or therapeutic agent for inflammation, osteoporosis, pneumonia, hepatitis, ischemia-reperfusion injury, transplant rejection, pain, pruritus (itch) and the like.
  • the administration route of the compound of the present invention may be any of oral administration, parenteral administration and rectal administration, and the daily dose varies depending on the type of the compound, the administration method, the symptom-age of the patient, etc.
  • oral administration usually about 0.001 to 100 mg, more preferably about 0.01 to 50 mg per lkg body weight of human or mammal is divided into 1 to several portions.
  • parenteral administration such as intravenous injection, usually, for example, it may be administered to humans or mammals lkg body weight per about 1 ⁇ ⁇ ⁇ 1 0 ⁇ 8, preferably from about 1 0 g to 5 mg in further.
  • the compound of the present invention When the compound of the present invention is used for the above-mentioned pharmaceutical uses, it is usually administered in the form of a preparation prepared by mixing with a preparation carrier.
  • a preparation carrier a non-toxic substance which is commonly used in the pharmaceutical field and does not react with the compound of the present invention is used.
  • Dosage forms include tablets, capsules, granules, powders, syrups, suspensions, injections, suppositories, eye drops, ointments, liniments, inhalants and the like. These preparations are always It can be prepared according to the method. When used, liquid preparations may be in the form of solutions or suspensions in water or other suitable media. Tablets and granules may be coated by a well-known method.
  • aqueous solvents eg, distilled water, saline, Ringer's solution, etc.
  • tonicity agents eg, glucose, D-sorbitol, D-mannitol, salt
  • Sodium hydroxide e.g.
  • stabilizers eg, human serum albumin
  • preservatives eg, benzyl alcohol, chlorobutanol, methyl parahydroxybenzoate, propyl paraoxybenzoate, phenol
  • buffers eg, phosphorus Salt buffers, sodium acetate buffers, etc.
  • soothing agents eg, benzanolecone chloride, proforce hydrochloride, etc.
  • these preparations may contain other therapeutically valuable ingredients.
  • Me is a methyl group
  • Et is an ethyl group
  • n is a methyl group
  • Pr represents a normal propyl group
  • n-Bu represents a normal butyl group.
  • the symbols used as recrystallization solvents are E for getyl ether, T for toluene, AC for acetonitrile, CF for chromatoform, ET for ethanol, HX for n- hexane, and IP for isopropanol. .
  • s is a singlet
  • d is a doublet
  • td is a triplet
  • t is a triplet
  • q is a quadruple
  • (111 is a quintuple
  • , Br are broad
  • J means the binding constant.
  • Example 2 instead of (1, S, 2'R) -2'-amino-ethylpropylmethylsulfonate hydrochloride in Example 1, the corresponding (R, 2'R) _2 'obtained in Reference Example 2 (1) —Amino-ethylpropylmethylsulfonate hydrochloride, The reaction and treatment were carried out in the same manner as in Example 1, and the product was recrystallized from ethanol to obtain 0.23 g of the desired product. Melting point 193_ 195 ° C
  • Example 26 instead of (2R, 3R) -2-amino-3-pentanol in Example 26 the corresponding (2R, 3S) -2-amino-3-pentanol obtained in Reference Example 1 (1)
  • the reaction and treatment were carried out in the same manner as in Example 26 using 0.50 g, and crystallized from getyl ether to obtain 0.12 g of the desired product. Melting point 101-105 ° C
  • the NOS inhibitor of the present invention containing a 2-aminothiazoline or oxazoline derivative represented by the general formula (I) as an active ingredient has excellent iNOS inhibitory activity and i
  • NO-related diseases such as arteriosclerosis, myocarditis, cardiomyopathy, cerebral ischemic injury, Alzheimer's disease, Multiple sclerosis, sepsis, hypotension, rheumatoid arthritis, osteoarthritis, gastric ulcer, duodenal ulcer, ulcerative colitis, diabetes, glomerulonephritis, pud's meningitis, osteoporosis, pneumonia, hepatitis, ischemic reperfusion injury Useful as a prophylactic and / or therapeutic agent for transplant rejection, pain, pruritus (itch), etc.

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Abstract

La présente invention concerne des inhibiteurs de la synthétase du monoxyde d'azote (NOS) à base de dérivés 2-aminothiazoline ou oxazoline représentés par la formule générale (I), ou l'un de ses sels d'addition acides physiologiquement admis. Dans cette formule, R1 et R2 sont identiques ou différent, chacun étant hydrogène ou alkyle inférieur; X est oxygène ou soufre, auquel cas R1 et R2 sont atome d'hydrogène simultanément, chaque * étant un atome de carbone asymétrique si l'un des R1 ou R2 n'est pas hydrogène. Ces composés présentent sur les iNOS une activité inhibitrice très élevée, et ce, avec une haute sélectivité, ce qui les destine comme inhibiteurs des NOS avec peu d'effets secondaires.
PCT/JP2002/002392 2002-03-14 2002-03-14 Inhibiteurs de la synthetase du monoxyde d'azote WO2003075922A1 (fr)

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AU2002238889A AU2002238889A1 (en) 2002-03-14 2002-03-14 Nitrogen monoxide synthase inhibitors
PCT/JP2002/002392 WO2003075922A1 (fr) 2002-03-14 2002-03-14 Inhibiteurs de la synthetase du monoxyde d'azote

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009137340A1 (fr) * 2008-05-05 2009-11-12 Allergan, Inc. Agonistes d’alpha2b et d’alpha2c
CN111918649A (zh) * 2018-03-16 2020-11-10 脑科学香料株式会社 缺氧障碍、缺血再灌注障碍或炎症的预防或治疗剂，移植用细胞保护剂，及生物体防腐剂

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GB1448592A (en) * 1972-11-02 1976-09-08 Hoechst Ag Oxazolines and process for preparin' them
WO1995011231A1 (fr) * 1993-10-21 1995-04-27 G. D. Searle & Co. Derives amidino utiles en tant qu'inhibiteurs de la synthase de l'oxyde nitrique
WO1996014842A1 (fr) * 1994-11-15 1996-05-23 Merck & Co., Inc. Heterocycles a substitutions utilises en tant qu'inhibiteurs de la synthetase d'oxyde nitrique
WO2001094325A1 (fr) * 2000-06-09 2001-12-13 Aventis Pharma S.A. Derives de 2-aminothiazoline et leur utilisation comme inhibiteurs de no-synthase

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1448592A (en) * 1972-11-02 1976-09-08 Hoechst Ag Oxazolines and process for preparin' them
WO1995011231A1 (fr) * 1993-10-21 1995-04-27 G. D. Searle & Co. Derives amidino utiles en tant qu'inhibiteurs de la synthase de l'oxyde nitrique
WO1996014842A1 (fr) * 1994-11-15 1996-05-23 Merck & Co., Inc. Heterocycles a substitutions utilises en tant qu'inhibiteurs de la synthetase d'oxyde nitrique
WO2001094325A1 (fr) * 2000-06-09 2001-12-13 Aventis Pharma S.A. Derives de 2-aminothiazoline et leur utilisation comme inhibiteurs de no-synthase

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TIECCO MARCELLO ET AL.: "One-pot conversion of alkenes into oxazolines and oxazolidin-2-ones promoted by diphenyl diselenide", SYNTHETIC COMMUNICATIONS, vol. 27, no. 23, 1997, pages 4131 - 4140, XP002952198 *
WOHL RONALD E. ET AL.: "The stereochemistry of aziridine ring expansion reactions with sulfur nucleophiles to give thiazolidines and 2-amino-2-thiazolidines", J. ORG. CHEM., vol. 37, no. 26, 1972, pages 4401 - 4406, XP002159496 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009137340A1 (fr) * 2008-05-05 2009-11-12 Allergan, Inc. Agonistes d’alpha2b et d’alpha2c
US8080570B2 (en) 2008-05-05 2011-12-20 Allergan, Inc. α2B and α2C agonists
CN111918649A (zh) * 2018-03-16 2020-11-10 脑科学香料株式会社 缺氧障碍、缺血再灌注障碍或炎症的预防或治疗剂，移植用细胞保护剂，及生物体防腐剂
EP3766492A4 (fr) * 2018-03-16 2022-03-23 Scent Science International Inc. Agent prophylactique ou thérapeutique pour lésion hypoxique, lésion d'ischémie-reperfusion et inflammation, agent de protection de cellule pour la transplantation, et agent de bio-conservation
US11590141B2 (en) 2018-03-16 2023-02-28 Scent Science International Inc. Prophylactic or therapeutic agent for hypoxic injury, ischemia-reperfusion injury and inflammation, cell protection agent for transplantation, and bio-preservation agent
CN111918649B (zh) * 2018-03-16 2024-07-30 脑科学香料株式会社 缺氧障碍、缺血再灌注障碍或炎症的预防或治疗剂，移植用细胞保护剂，及生物体防腐剂
US12076325B2 (en) 2018-03-16 2024-09-03 Scent Science International Inc. Prophylactic or therapeutic agent for hypoxic injury, ischaemia-reperfusion injury and inflammation, cell protection agent for transplantation, and bio-preservation agent

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