CN101107240B - Anethole dithiolethione and other dithiolethiones for the treatment of conditions associated with dysfunction of monoamine neurotransmission - Google Patents
Anethole dithiolethione and other dithiolethiones for the treatment of conditions associated with dysfunction of monoamine neurotransmission Download PDFInfo
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- WVLHGCRWEHCIOT-UHFFFAOYSA-N C(C1)NCCN1c1cccc2c1OCCO2 Chemical compound C(C1)NCCN1c1cccc2c1OCCO2 WVLHGCRWEHCIOT-UHFFFAOYSA-N 0.000 description 1
- QBCPCKKWZGQFNP-UHFFFAOYSA-N CSC(SSC1=S)=C1c1ccccc1 Chemical compound CSC(SSC1=S)=C1c1ccccc1 QBCPCKKWZGQFNP-UHFFFAOYSA-N 0.000 description 1
- WFKOCLPRUVHUKN-UHFFFAOYSA-N CSSC(SSC1=S)=C1c1ccccc1 Chemical compound CSSC(SSC1=S)=C1c1ccccc1 WFKOCLPRUVHUKN-UHFFFAOYSA-N 0.000 description 1
- LIFRJANWIHVHNR-UHFFFAOYSA-N Cc(cc1)ccc1OCCN1CCOCCC1 Chemical compound Cc(cc1)ccc1OCCN1CCOCCC1 LIFRJANWIHVHNR-UHFFFAOYSA-N 0.000 description 1
- UQRHAYODRWWMPB-UHFFFAOYSA-N S=C1SSC(N(CC2)CCN2c2c3OCCOc3ccc2)=C1c1ccccc1 Chemical compound S=C1SSC(N(CC2)CCN2c2c3OCCOc3ccc2)=C1c1ccccc1 UQRHAYODRWWMPB-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- 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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
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- A—HUMAN NECESSITIES
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- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
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- A—HUMAN NECESSITIES
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- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
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- 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
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- A—HUMAN NECESSITIES
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- 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
- A61P25/22—Anxiolytics
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- 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]
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
- C07D339/02—Five-membered rings
- C07D339/04—Five-membered rings having the hetero atoms in positions 1 and 2, e.g. lipoic acid
Abstract
The invention relates to dithiolethiones derivatives as monoamino oxidase inhibitors, in particular MAO-B inhibitors, to methods for the preparation of these compounds and to novel intermediates useful for the synthesis of said dithiolethiones derivatives. The invention also relates to the use of a compound disclosed herein for the manufacture of a medicament giving a beneficial effect. In embodiments of the invention specific compounds disclosed herein are used for the manufacture of a medicament useful in the treatment, amelioration or prevention of conditions associated with dysfunction ofmonoamine neurotransmission. The compounds have the general formula (1) wherein the symbols have the meanings given in the specification.
Description
The present invention relates to as oxidase inhibitor, dithia cyclopentenes thioketones class (dithiolethiones) derivative of MAO-B inhibitor particularly, the preparation method of these compounds is used for the new intermediate of synthetic described dithia cyclopentenes thio-ketone derivative.The invention still further relates to compound disclosed herein and be used to prepare the purposes of the medicament that gives beneficial effect.Herein disclosed is a kind of beneficial effect or this effect is apparent to those skilled in the art from the general knowledge of this specification sheets and this area.The invention still further relates to compound of the present invention and be used to prepare the purposes of the medicament of treatment or preventing disease or illness.More particularly, the present invention relates to a kind ofly be used for the treatment of disclosed herein or from the new purposes of the general knowledge of this specification sheets and this area disease apparent to those skilled in the art or illness.In embodiments of the invention, particular compound disclosed herein is used for preparing at treatment, improvement or the prevention illness useful medicament relevant with the dysfunction of monoamine neurotransmission.
Plastosome flavo-enzyme monoamine oxidase (MAO; EC 1.4.3.4) inhibitor can cause that norepinephrine, suprarenin, Dopamine HCL, tryptamines and the serotonin level in brain and other tissue raises, and therefore can cause by they multiple pharmacological effects that influence mediated to these neurotransmitters.
Present available MAO inhibitor for example L-L-deprenyl, mofegiline, rasagiline, lazabemide has multiple side effect, comprises psychotic (delirium, illusion, excitement), cardiovascular (orthostatic hypotension, hypertension) and neurologic (calm, abnormal motion).
The objective of the invention is to develop new MAO inhibitor, on the structure with can obtain at present those are irrelevant, and side effect is little.
WO 98/27970 discloses 1, and 2-dithia cyclopentenes-3-thioketones class is used for the treatment of the purposes of the cytoclasis that disease that oxygen radical causes or prevention oxygen radical cause.WO01/09118 discloses the dithia cyclopentenes thione compounds that is used for the treatment of neurological disorder and is used for memory.It is said that (DAAO, E.C.1.4.3.3), this enzyme Stereoselective is sloughed the amino acid whose amino of D-to these compounds inhibition D-amino-acid oxidase, produces hydrogen peroxide-a kind of reactive oxygen species thus.Never show that dithia cyclopentenes thioketones class suppresses monoamine oxidase, this is a kind of diverse enzyme.
Have now found that unexpectedly dithia cyclopentenes thioketones class suppresses to derive from the MAO-B activity in the cell extract of rat striatum astroglia cell of cultivation effectively, and does not observe the active remarkably influenced to MAO-A.The present invention relates to the compound of general formula (1)
Wherein:
-R
1And R
2Identical or different; and represent hydrogen, alkyl, alkenyl, alkynyl, aryl, fluorine, chlorine, bromine, hydroxyl, alkoxyl group, alkenyloxy, aryloxy, acyloxy, amino, alkylamino, dialkyl amido, arylamino, sulfo-, alkylthio, arylthio, cyano group, nitro, acyl group, amido, alkyl amido, dialkyl group amido, perhaps
-R
1And R
2Can form with the carbon atom that they connected and contain 0,1 or 2 heteroatomic 5-or 6-unit's aromatic nucleus or non-aromatic ring that is selected from nitrogen, oxygen or sulphur, for example furans, thiophene, pyrroles, oxazole, thiazole, imidazoles, pyrazoles, isoxazole, isothiazole, 1,2,3-oxadiazole, 1,2,3-triazole, 1,3,4-thiadiazoles, pyridine, pyridazine, pyrimidine or pyrazine ring
-R
1And R
2Itself can have and be selected from other following substituting group: hydrogen, alkyl, alkenyl, alkynyl, aryl, fluorine, chlorine, bromine, hydroxyl, alkoxyl group, aminoalkoxy, morpholine-4-base-alkoxyl group, piperidines-1-base-alkoxyl group, alkenyloxy, aryloxy, acyloxy, amino, alkylamino, dialkyl amido, arylamino, sulfo-, alkylthio, arylthio, cyano group, oxo, nitro, acyl group, amido, alkyl amido or dialkyl group amido
And tautomer, steric isomer and N-oxide compound, and described formula (1) compound and tautomer, steric isomer and the acceptable salt of the pharmacology of N-oxide compound, hydrate and solvate are used to prepare the purposes of the pharmaceutical composition of treatment, improvement or the prevention illness relevant with the dysfunction of monoamine neurotransmission.
The present invention be more particularly directed to the purposes of the compound of general formula (1), wherein R
1And R
2Identical or different, and represent hydrogen, alkyl or aryl, they are chosen wantonly and are substituted with one or more following atom or groups of being selected from: hydrogen, alkyl, aryl, fluorine, chlorine, bromine, hydroxyl, alkoxyl group, aryloxy, amino, alkylamino, dialkyl amido, sulfo-, oxo or nitro.
More particularly the present invention relates to 5-(p-methoxyphenyl)-3H-1,2-dithia cyclopentenes-3-thioketones (methyl allylphenol dithia cyclopentenes thioketones, ADT), 3H-1,2-dithia cyclopentenes-3-thioketones (D3T) and 4-methyl-5-(2-pyrazinyl)-3H-1, the purposes of 2-dithia cyclopentenes-3-thioketones (oltipraz):
Be more preferably 5-(p-methoxyphenyl)-3H-1, the purposes of 2-dithia cyclopentenes-3-thioketones, it is a methyl allylphenol dithia cyclopentenes thioketones (ADT), 3H-1,2-dithia cyclopentenes-a kind of lipophilic of 3-thioketones (D3T), the analogue of replacement, decades are clinical does not notice any serious adverse effects (Christen as choleretic and sialagogue, M-O., MethodsEnzymol., 252,316-323,1995).
The present invention relates to the compound of formula (1) on the other hand:
Wherein:
-R
1Be optional phenyl and the R that replaces
2Represent S-CH
2One of-(4-methyl-phenyl) or following group:
Wherein n has value 2,3,4 or 5, and R
3Be hydrogen or alkyl (C
1-3), perhaps
-R
1Be 4-hexyloxy phenyl, R
2Be hydrogen, perhaps
-R
1Be the phenyl that replaces, R
2Represent SH, perhaps following group:
-R
1Be hydrogen, R
2Representative-CH=CH-4-(diethylamino phenyl) ,-CH=CH-(2-quinolyl) or following group:
Wherein n has and the identical implication that provides above, and R
4And R
5Represent alkyl (C independently
1-3), perhaps form saturated 5-or 6-unit ring with the nitrogen-atoms that they connected, the optional heteroatoms that contains one or more N of being selected from, O or S of described ring, perhaps
-R
1Be alkyl (C
1-3), R
2Be 1-(2,3-dihydro-1,4-Ben Bing dioxin-5-yl) piperazine-4-base, perhaps
-R
1Be cyano group, R
2Be group-NH-C (O)-NH-phenyl, phenyl is optional in this group is substituted, perhaps
-R
1Be-SO
2CH
3, R
2Represent amino,
And tautomer, steric isomer and N-oxide compound, and the acceptable salt of pharmacology, hydrate and the solvate of the compound of described formula (1) and tautomer, steric isomer and N-oxide compound.
The present invention relates to have the racemoid of the compound of (1), the mixture and the single steric isomer of diastereomer.Abbreviation ' alkyl ' is meant C when describing substituting group
1-3-alkyl, ' alkenyl ' is meant C
1-3-alkenyl, ' alkynyl ' is meant C
1-3-alkynyl, ' acyl group ' is meant alkyl (C
1-3) carbonyl, aryl carbonyl or arylalkyl (C
1-3) carbonyl, and ' aryl ' is meant furyl, thienyl, pyrryl oxazolyl, thiazolyl, imidazolyl, pyrazolyl isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, 1,3,5-triazynyl, phenyl, indazolyl, indyl, the indolizine base, pseudoindoyl, benzo [b] furyl, benzo [b] thienyl, (2,3-dihydro-1,4-Ben Bing dioxin-5-yl), benzimidazolyl-, benzothiazolyl, purine radicals, quinolynyl, isoquinolyl (isochinolyl), quinolyl (chinolyl), 2 base (phtalazinyl), quinazolyl, quinoxalinyl, 1, the 8-phthalazinyl, pteridyl, naphthyl or camomile cyclic group, preferred phenyl or (2,3-dihydro-1,4-Ben Bing dioxin-5-yl).' alkyl (C
1-3) ' be meant ' methyl, ethyl, n-propyl or sec.-propyl ', ' alkyl (C
1-4) ' be meant ' methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, 2-butyl, isobutyl-or 2-methyl-n-propyl '.' randomly being substituted ' be meant a group can by or be not selected from following one or more groups and further replaced: alkyl; alkenyl; alkynyl; aryl; fluorine; chlorine; bromine; hydroxyl; alkoxyl group; alkenyloxy; aryloxy; acyloxy; amino; alkylamino; dialkyl amido; arylamino; sulfo-; alkylthio; arylthio; cyano group; oxo; nitro; acyl group; amido; alkyl amido; the dialkyl group amido; carboxyl, perhaps two optional substituting groups can form with the carbon atom that they connected and contain 0; 1 or 2 is selected from nitrogen; the heteroatomic 5-of oxygen or sulphur or 6-unit's aromatic nucleus or non-aromatic ring.Optional substituting group itself can have other optional substituting group.The preferred optional substituting group comprises C
1-3Alkyl is methyl, ethyl and trifluoromethyl, fluorine, chlorine, bromine, hydroxyl, C for example
1-3Alkoxyl group is methoxyl group, oxyethyl group and trifluoromethoxy and amino for example.
The prodrug of above-claimed cpd also within the scope of the invention.Prodrug is non-activity own, but can change into the therapeutical agent of one or more activated metabolites.Prodrug is the bioreversible derivative that is used to overcome the drug molecule of some obstacles that utilize the parent drug molecule.These obstacles include but not limited to metabolism before the solubleness, perviousness, stability, whole body and target restriction (Medicinal Chemistry:Principles and Practice, 1994, ISBN0-85186-494-5, Ed.:F.D.King, p.215; J.Stella, " Prodrugsas therapeutics ",
Expert Opin.Ther.Patents,
14(3), 277-280,2004; P.Ettmayer etc., " Lessons learned from marketed andinvestigational prodrugs ", J.Med.Chem., 47,2393-2404,2004).The present invention includes prodrug, promptly when be administered to the compound that the man-hour energy metabolism becomes to have the compound of formula (1) by known approach arbitrarily.More specifically, this relates to the compound with primary amino or secondary amino group or oh group.Such compound can with organic acid reaction, generation has the compound of formula (1), wherein exist in the additional group that can easily remove after using, such as but not limited to amidine, enamine, Mannich base, hydroxyl-methylene derivatives, O-(acyloxy methene amido manthanoate) derivative, carbamate, ester, acid amides or enamine ketone (enaminone).
The N-oxide compound of above-claimed cpd also within the scope of the invention.Tertiary amine meeting or can not produce the N-oxide metabolites.The degree that the N-oxidation takes place can be from trace to being close to quantitative conversion.The N-oxide compound may more have activity or still less active than the tertiary amine of their correspondences.Though can easily the N-oxide compound be reduced into the tertiary amine of their correspondences by chemical mode, this takes place with different degree in human body.Some N-oxide compounds can experience almost quantitative reduction and transform, and become corresponding tertiary amine, and in other cases, conversion is the only reaction of trace, perhaps even does not fully exist.(M.H.Bickel：“The?pharmacology?and?Biochemistry?ofN-oxides”，
Pharmacological?Reviews，
21(4)，325-355，1969)。
The synthetic general aspect
Factor known to those skilled in the art is depended in the selection of specific synthesis program; the consistency of the reagent of functional group and use for example; use the possibility of blocking group, catalyzer, activation and coupling reagent and be present in final structure feature in the prepared final compound.
Medicinal acceptable salt
Medicinal acceptable salt can use standard operation well known in the art to obtain, and for example passes through compound of the present invention and suitable acid, and for example the mineral acid example hydrochloric acid perhaps mixes with organic acid.
Pharmaceutical preparation
By usual method, use auxiliary material, for example the liquid or solid carrier can be made the form that is suitable for administration with compound of the present invention.Ground in can intestines, per os ground, stomach other places (intramuscular ground or intravenously ground), rectum ground or partly (outer land used) use pharmaceutical composition of the present invention.Can use them with solution, powder, tablet, capsule (comprising microcapsule), ointment (emulsion or gel) or the form of suppository.The suitable vehicle that is used for such preparation is liquid or solid weighting agent and filler, solvent, emulsifying agent, lubricant, correctives, tinting material and/or a buffer substance conventional in the pharmacy.The auxiliary material commonly used that can mention is for example Oils,glyceridic,cod-liver, Trisun Oil R 80, peanut oil or sesame oil, a polyoxyethylene glycol and solvent sterilized water and monohydroxy-alcohol or polyvalent alcohol glycerine for example for example of magnesiumcarbonate, titanium dioxide, lactose, N.F,USP MANNITOL and other carbohydrate or sugar alcohol, talcum, milk-protein, gelatin, starch, Mierocrystalline cellulose and derivative thereof, animal and plant oil.
Usually, compound of the present invention is used as pharmaceutical composition, described pharmaceutical composition is an important and new embodiment of the present invention, because have compound, particular compound disclosed herein more specifically.The type of operable pharmaceutical composition includes but not limited to tablet, masticable tablet, capsule, solution, parenteral solution, suppository, suspension and other type disclosed herein or that those skilled in the art can understand from the general knowledge of specification sheets and this area.In embodiments of the invention, provide drug packages or test kit, it comprises one or more containers that one or more compositions of pharmaceutical composition of the present invention are housed.Such container can be with various written materials, working instructions for example, or the letter of information of the form of the statutory regulation of production, use or the sale of management medicament production, this letter of information can reflect the approval for production, application or the sales department of people or animal doctor's administration.
Pharmacological method
The active mensuration of MAO
Use neonate rat striatum astroglia cell as MAO-A and MAO-B activated source (Carlo et al., Brain Res 711,175-183,1996).As described astroglia cell is cultivated (Langeveld et al., Neurosci.Lett.192,13-16,1995).In 5%CO
2/ 95% air and 37 ℃ were cultivated down after 1 week, and cell is through trysinization and containing in the ice-cold 25mM Tris-HCl damping fluid (pH=7.4) of 1mM EDTA and carry out sonication.Afterwards, with the gained lysate 10,000g and 4 ℃ centrifugal 5 minutes down, and the separatory that waits that takes out the supernatant liquor part uses Amplex Red MAO mensuration test kit (Molecular Probes, Leiden, The Nether lands) measure the MAO activity, this mensuration is based on Zhou and the described method (Anal.Biochem.253 of Panchuk-Voloshina, 169-174,1997).Measure according to manufacturer's explanation.In brief, before adding substrate, with sample incubation 30 minutes in 96 orifice plates with medicine or solvent (cumulative volume is 50 μ l).Afterwards, add 50 μ l contain 2U/ml horseradish peroxidase (HRP), to tyrasamine HCl (2mM, the two substrate (Youdim and Finberg of MAO A and MAO B, Biochem.Pharmacol., 41,155-162,1991) and the Amplex Red reagent of Amplex red (10mM).Under these conditions, in the HRP linked reaction,, Amplex red is transformed into the fluorescence resorufin through the MAO-of tyrasamine catalyzed oxidation.In order to measure the MAO activity, at fluorescence microplate reader (BMG Labtechnologies GmbH, Germany) in, use excited under 544nm and launches under 595nm, continued to measure in 30 minutes the time-dependent manner increase of resorufin formation under room temperature with 2 minute timed interval.In this time limit, find that the fluorescence increase is linear.For calculation result, the relative background reading of data (promptly under the situation that does not have MAO substrate tyrasamine) is proofreaied and correct, and represents with the increase of any flat fluorescent/min.Use BSA as the standard test protein content according to the method (Anal.Biochem.72,248-254,1976) of Bradfordetal..Use one-way analysis of variance (ANOVA) to check the statistics between organizing to compare by Newman-Keuls post-hoc then.It is remarkable that P value＜0.01 is considered to.
CEREP (Paris, France), according to J.L.Salach,
Arch.Biochem. Biophys.,
192, the MAO-B that 128,1979 described schemes are measured compd A 1-D6 suppresses active.
Under methyl allylphenol dithia cyclopentenes thioketones and the dosage of relevant dithia cyclopentenes thioketones class in the scope of 0.1-100mg/kg activity is arranged after oral, and their selectivity suppress monoamine oxidase-B to make that they are particularly useful for treating because of main monoaminergic system disorder and causes or can be through operating spirit and/or the neurological disorder that these systems treat, described obstacle is selected from: mood disorder, for example bipolar disorder I, bipolar disorder II and one pole dysthymia disorders such as mild depression, seasonal affective disorder, postpartum depression, dysthymia and severe depression; Anxiety disorder comprises panic disorder (have or do not have agoraphobia), social phobia, the obsession chronic tic or the schizotypal disorder of not coexistence (have or), posttraumatic stress disorder and generalized-anxiety disorder; The obstacle that material is relevant comprises material application obstacle (for example rely on and abuse) and material inductive obstacle (for example material de-addiction); Attention deficit and disruptive behavior disorder be distractibility hyperkinetic syndrome and narcolepsy for example; Impulse control disorder is pathological gambling for example; Eating disorder is anorexia nervosa and bulimia nervosa for example; Tic disorder is tourette's syndrome for example; Restless legs syndrome; With cognition and/or memory defects is the obstacle for example alzheimer's disease, Parkinson's disease and AIDS is dull-witted and/or the mental disorder of coexistence and neural rehabilitation (brain injury after the wound), other CNS obstacle pain of epilepsy, mongolism, Huntington's disease, several forms for example of feature, comprises headache, atypical facial pain, pain obstacle and chronic pain syndrome; Amyotrophic lateral sclerosis and sexual dysfunction; The obstacle of brain or peripheral vascular system comprises primary, kidney vascular, pulmonary artery and ocular hypertension, thrombosis, myocardial infarction and cerebrovascular apoplexy; The non-vascular smooth muscle disorders comprises sphincter muscle and smooth muscle spasm and vesical dysfunction in obstruction of the air passage, asthma or another respiratory system obstacle and gastrointestinal peristalsis obstacle, hemorrhoid (hemorroids), the gi tract.And the MAO inhibitor can resist premature labor and lax at term chien shih birth canal, can be used for lax urinary tract and is used for passing through of urinary stone disease, and can be used for alleviating smooth muscle contraction and spasm.
Preferably, compound of the present invention is used for the treatment of mood disorder, bipolar disorder I, bipolar disorder II, one pole dysthymia disorders, mild depression, seasonal affective disorder, postpartum depression, dysthymia, severe depression, anxiety disorder, panic disorder, social phobia, obsession, posttraumatic stress disorder, generalized-anxiety disorder, obstacle, material that material is relevant are used obstacle, material inductive obstacle, material de-addiction, attention deficit and disruptive behavior disorder, distractibility hyperkinetic syndrome, narcolepsy; Sphincter muscle and smooth muscle spasm and vesical dysfunction in impulse control disorder, pathological gambling, eating disorder, anorexia nervosa, bulimia nervosa, tic disorder, tourette's syndrome, restless legs syndrome, pain, headache, atypical facial pain, pain obstacle and chronic pain syndrome, sexual dysfunction, obstruction of the air passage, asthma, gastrointestinal peristalsis obstacle, hemorrhoid (hemorroids), the gi tract.
Dosage
Measure the effectiveness of compound of the present invention as mentioned above as the inhibitor of MAO-B.By the effectiveness of given formula (1) compound determination, people can the estimation theory subliminal dose.During the twice of the inhibition constant that equals to measure in compound concentrations, this enzyme of 100% may be suppressed by this compound.Suppose desirable bioavailability, this concentration is transformed into mg compound/kg patient, obtain theoretical subliminal dose.Pharmacokinetics, pharmacodynamics and other Consideration can make the DM of actual administration to higher or lower value.The dosage that makes things convenient for administration is 0.001-1000mg/kg, preferred 0.1-100mg/kg weight in patients.
Treatment
Term used herein " treatment " is meant any treatment to the preferred people's of Mammals illness or disease, and comprise: (1) but prevent this disease or illness is to take place in the ill object may easily suffering from this disease N, (2) suppress this disease or illness, promptly stop its development, (3) alleviate this disease or illness, even this illness disappears, perhaps (4) alleviate the illness that this disease causes, even the symptom of this disease stops.
Embodiment
Embodiment 1: material and method
Relate to the moisture-sensitive compound respond and all in dried nitrogen environment, carry out.Use tlc (TLC) to go up with the eluent monitoring reaction of indicating at the plastic sheet (Merck silica gel 60 F254) of coating silicon-dioxide.By UV-light (254nm) or I
2Make these compounds as seen.Flash chromatography is meant eluent shown in the use and Acros silica gel (0.030-0.075mm) purifying.Shown in measure in the solvent nuclear magnetic resonance spectrum (
1H NMR and
13C NMR, APT).Coupling constant J provides with Hz.The following symbolic representation of peak shape in the NMR spectrum: ' q ' (quartet), ' dq ' (two quartet), ' t ' (triplet), ' dt ' (two triplet), ' d ' (doublet), ' dd ' (double doublet), ' s ' (unimodal), ' b s ' (wide unimodal) and ' m ' (multiplet).
Embodiment 2: particular compound synthetic
Its synthetic particular compound is described below plans further to illustrate in more detail the present invention, and therefore in no case think and limit the scope of the invention.
Consider that from specification sheets of the present invention disclosed herein and practice other embodiment of the present invention will be conspicuous for a person skilled in the art.Therefore planning this specification sheets and embodiment only is considered as illustration, and true scope of the present invention and spirit are indicated by claims.
Compd A 1
The step I of option A .1
The sulphur of 32g (1mol) is joined among the DMF (N, dinethylformamide) of 150ml and and be close to dissolving up to sulphur to refluxing with the gained mixture heating up.Drip 2-(the positive hexyloxy phenyl of 4-)-propylene of 43.6g (200mmol).After adding is finished, continue to stir also heating, (tlc, eluent: toluene) tracking is reacted, and makes reaction arrive room temperature after 4 hours by TLC.Filter and the vaporising under vacuum reaction mixture, obtain resistates, make it through column chromatography (SiO
2, eluent: toluene).The fraction that contains product that merges is concentrated under vacuum.Resistates is recrystallization from hexanaphthene, obtains the required compound A1 of 5g (8.1%).Fusing point: 121 ℃.
Compd A 2
The step I of option A .2
In the ethanol solution that contains 2 equivalent sodium ethylates (NaOEt), add 1 normal 4-hydroxy acetophenone and 1 normal N-(2-chloroethyl) morpholine.Adding makes reaction mixture refluxed 5h after finishing, and stops heating then and at room temperature continues to stir 12h.Except that desolvating and resistates being absorbed in the hydrochloride aqueous solution (about 2N), back one solution washs with diethyl ether under the vacuum.Water layer extracts with diethyl ether afterwards with sodium hydroxide solution (about 2N) neutralization.With the organic moiety drying (Na that merges
2SO
4).Remove by filter siccative and under vacuum, remove and desolvate, obtain phenolic ether, be orange-yellow oil, productive rate 91%.
The step I i of option A .2(according to Thuillier etc., Bull.Chim.Soc., (1959) 1398)
To containing 2 normal trimethylacetic acid sodium (NaOC (CH
3)
2CH
2CH
3) the toluene of the cold no water yield in add the phenolic ether of 1 normal step I, and dissolve 1 normal dithiocarbonic anhydride.When adding is finished, reaction mixture is stirred 6h.Then add 1 normal glycol dibromide, continue to stir 12h afterwards.Reaction mixture reaches 7 with aqueous sodium hydroxide solution (about 2N) and water washing up to pH.Organic moiety is at Na
2SO
4Last dry.Remove by filter siccative and under vacuum, remove and desolvate, obtain pure 1, the orange crystallization of 3-dithiolan derivatives thing, productive rate is 70%.
The step I ii of option A .2
In backflow dimethylbenzene, use tetraphosphorus decasulfide (P
4S
10) the dithiolan derivatives thing of step I i was handled 15 minutes.Wash this suspension with the 1N aqueous sodium hydroxide washes after the cooling, add chloroform afterwards, the gained organic moiety is at Na
2SO
4Last dry.Remove by filter siccative and under vacuum, remove and desolvate, obtain resistates, through column chromatography (SiO
2, eluent: purifying diethyl ether/toluene 1/1), obtain required compound A2, be orange crystallization, productive rate 4%.Fusing point: 102 ℃.
1H-NMR(CDCl
3，δppm)：2.59(t，4H)、2.83(t，2H)、3.73(t，4H)、4.17(t，2H)、6.98(d，2H)、7.60(d，2H)、7.36(s，1H)。
Compound A-13 (reddish oil,
1H-NMR (CDCl
3, δ ppm): 1.49 (q, 2H), 1.67 (t, 4H), 2.63 (t, 4H), 2.97 (t, 2H), 4.24 (t, 2H), 7.00 (d, 2H), 7.38 (s, 1H), 7.60 (d, 2H)) are similar to compd A 2 described programs are made.
Compound B-11
The step I of option b .1
With 2 normal piperazines and 1 normal 5-methylthio group-4-phenyl-[1,2]-dithia cyclopentenes-3-thioketones (Grandin, A.et al., Bull.Soc.Chim.Fr., 11 (1968) 4555) be dissolved in the dehydrated alcohol, make reaction mixture reach reflux temperature afterwards.Under vacuum, remove after 7 days desolvate and resistates through chromatography (SiO
2, eluent: purifying 2% ethanol v/v in toluene).The fraction that contains product that to collect under vacuum concentrates, and resistates obtains orange crystallization by acetone recrystallization, productive rate 12%: compound B-11, fusing point: 174 ℃.
1H-NMR(CDCl
3，δppm)：2.97(t，4H)、3.44(t，4H)、4.23(m，4H)、6.42-6.76(m，3H)、7.34-7.49(m，5H)。
Compd B 2 (yellow crystal, 108 ℃ of fusing points,
1H-NMR (CDCl
3, δ ppm): 2.37 (s, 3H), 2.98 (t, 4H), 3.45 (t, 4H), 4.23 (m, 4H), 6.43-6.76 (m, 3H), 7.22-7.28 (m, 4H)) is similar to the described program of compound B-11 is made.
Compd B 3 (red crystallization, fusing point 148-150 ℃ (decomposition)) is similar to the described program of compound B-11 is made.
Compound C 1
Scheme step I C.1
5-methyl-[1,2]-dithia cyclopentenes-3-thioketones of 1g (6.8mmol) is dissolved in the dehydrated alcohol of 50ml.Add 4-(the diethylamino)-phenyl aldehyde of 2.5g (14.1mmol) and the piperidines of 1ml then, in water-bath, reaction mixture is heated 2h afterwards.Under the vacuum reaction mixture is concentrated and resistates is placed in the refrigerator, form crystallization thus.With Crystallization Separation and by the Virahol recrystallization, obtain the required compound C1 of 1.5g (4.9mmol, 35%), fusing point: 130 ℃.Also referring to patent JP1319477.
Compound C 2 (TLC (SiO
2, eluent: toluene), Rf=0.36 is having in the presence of the raw material) be similar to Compound C 1 described program is made.
Compound D 1
Scheme step I D.1
The 1-bromo-2-phenyl-propane of 17.5g (87.9mmol) is dissolved among the DMF of 300ml, adds the sulphur of 14.1g (441mmol) afterwards.Reaction mixture refluxed is spent the night, at room temperature continue afterwards to stir a night again.Under vacuum, reaction mixture is concentrated, add the toluene of about 100ml afterwards, form crystallization, collect the latter and drying under vacuum.Productive rate: 13g (45.3mmol, 52%) contains the yellow solid of the dimethyl ammonium of 4-phenyl-5-sulfydryl-[1,2]-dithia cyclopentenes-3-thioketones.
Scheme step I i D.1
The iodide (to synthesizing of iodide, seeing below) of 3.5g (10.4mmol) are dissolved in the methyl alcohol of 40ml, add 3g (10.4mmol) (step I) dimethyl ammonium afterwards.The reaction mixture stirring is spent the night, concentrate under vacuum afterwards, resistates is through column chromatography (SiO
2, eluent: heptane/ethyl acetate 6/1).The fraction that will contain product concentrates, and obtains the reddish oil of 700mg (1.6mmol, 15%).
Scheme step I ii D.1
The product of the step I i of 700mg (1.6mmol) is dissolved in a small amount of methylene dichloride, adds a certain amount of 7N HCl (in Virahol) afterwards, causing ultimate density is about 3N.The reaction mixture stirring is spent the night, under vacuum, it is concentrated afterwards, obtain the orange solids that contains D1.HCl of 265mg, fusing point: 243 ℃.
Compound D 2 (fusing point: 96-101 ℃, with decomposing) is similar to Compound D 1 described program is made.Can prepare used iodide according to synthetic (referring to following) of the used iodide of preparation D1.
Compound d3 (fusing point: 82-87 ℃) is similar to Compound D 1 described program is made.Can be according to the used iodide of synthetic preparation of the used iodide of preparation D1.
Compound D 4 (fusing point: 65-70 ℃, with decomposing) is similar to Compound D 1 described program is made.Can be according to the used iodide of synthetic preparation of the used iodide of preparation D1.
Compound D 5 (fusing point: 65-72 ℃) is similar to Compound D 1 described program is made.Can be according to the used iodide of synthetic preparation of the used iodide of preparation D1.
Compound D 6 (fusing point: 134-135 ℃) is similar to Compound D 1 described program is made, so that Monobromoxylene is begun as alkylating agent.
Be used to prepare synthetic (scheme D.2) of the iodide of Compound D 1.
Scheme step I D.2
4-hydroxyl-2-butanone of 6.4g (72.6mmol) is dissolved in 1 of 250ml, in the 2-ethylene dichloride, adds the propargylamine of 5.5ml (80mmol) afterwards.Reaction mixture was stirred 10 minutes, it is cooled to 0 ℃ afterwards.NaBH (OAc) with 20g (94mmol)
3Portioning joins in the reaction mixture, continues to stir 48h, pours this mixture into saturated NaHCO afterwards
3In the aqueous solution.Back one aqueous solution extracts with DCM, obtains the required product of 3g after concentrating under vacuum.Water layer carries out the extraction second time with NaOH solution (33%, the aqueous solution) alkalization and saturated with NaCl (solid) with EtOAc.With the organic moiety drying (Na that merges
2SO
4) and under removing by filter siccative and vacuum, concentrate except that after desolvating, obtain the required product (being orange oil) of 7.6g (82%).Use it for step I i without being further purified.
Scheme step I i D.2
7.6g (59.8mmol) (step I) aminopropanol derivatives is dissolved among the DCM of 200ml, adds 9.2ml (～triethylamine 65mmol) and (Boc) of 14g (65mmol) afterwards
2O (Boc=tertbutyloxycarbonyl).The stirring of gained mixture is spent the night, under vacuum, it is concentrated afterwards and resistates is dissolved among the EtOAc once more.The saturated NaHCO of organic moiety
3(water) solution, water and salt water washing are afterwards at Na
2SO
4On be dried.Remove by filter siccative and under vacuum, concentrate to remove desolvate after, be separated to the brown oil of 13.7g (100%), contain the aminopropanol of N-Boc protection.
Scheme step I ii D.2
The triphenyl phosphine of 33g (126mmol) is dissolved among the 600ml DCM, adds the imidazoles of 19g (280mmol) afterwards, make the gained mixture reach 0 ℃.The drips of solution of 35.5g (140mmol) iodine in the DCM of 300ml (methylene dichloride) is added in this reaction mixture, continues afterwards to stir 10 minutes.Then, add the aminopropanol (deriving from step I i) of this N-Boc protection of the 8g (35mmol) among the DCM that is dissolved in 50ml, continue to stir 20 minutes down at 0 ℃.Make reaction mixture reach room temperature then and stir 16h.Reaction mixture is filtered, and filtrate concentrates with the salt water washing and under vacuum.Resistates is through short SiO
2Post " filtration " (eluent: heptane/EtOAc 6/1) is also concentrated under vacuum with elutriant, obtains the corresponding iodide of 5.1g (%), is light yellow oil.These iodide are used to prepare Compound D 1 (referring to scheme D.1).
The required corresponding iodide of preparation Compound D 2, D3, D4 and D5 can be according to the condition preparation described in synthetic (scheme D.2) of the iodide that are used to prepare D1.For Compound D 4 and D5, do not need protection and go to protect step (N-Boc), this is owing to there is methyl on nitrogen-atoms.
Embodiment 3: the preparation of compd A 1
For oral (p.o.) administration: in the solid chemical compound A1 of the aequum in Glass tubing (0.5-5mg), add some granulated glass spherees, by vortex with this solid abrasive 2 minutes.Add after the solution of 1% methylcellulose gum in the Poloxamer 188 of water and 2% (v/v) (Lutrol F68) of 1ml, this compound was suspended 10 minutes by vortex.With several NaOH aqueous solution (0.1N) with pH regulator to 7.Use the ultrasonic bath remaining particle in the suspension that further suspends.
For intraperitoneal (i.p.) administration: in the solid chemical compound A1 of the aequum in Glass tubing (0.5-15mg), add some granulated glass spherees, by vortex with this solid abrasive 2 minutes.Add after 1% methylcellulose gum and the solution of 5% N.F,USP MANNITOL in water of 1ml, this compound was suspended 10 minutes by vortex.At last with pH regulator to 7.
Embodiment 4: the pharmacology test result
In the cell extract that is obtained by neonate rat striatum astroglia cell, L-deprenyl (L-dep) and methyl allylphenol dithia cyclopentenes thioketones (ADT) are to the active influence of total monoamine oxidase (∑ MAO) (2 and 3 hurdle); L-dep, ADT and 3H-1,2-dithia cyclopentenes-3 thioketones (D3T) is to the active influence of monoamine oxidase-B (MAO-B) (4,5 and 6 hurdle); M and B 9302 (Clor) and ADT are to the active influence of monoamine oxidase A (MAO-A) (7 and 8 hurdle).Measure the influence of MAO activity and medicine as mentioned above to it.
Data represent with the percentage ratio that accounts for separately contrast, and are the mean value of the independent experiment that carries out in triplicate for 2-5 time.Under the situation that solvent (0.03%DMSO) only arranged, measure total MAO activity, measure the MAO-A activity measuring the MAO-B activity under the situation of the selectivity MAO-A inhibitor M and B 9302 that 0.1 μ M is arranged and having under the situation of selectivity MAO-B inhibitor L-deprenyl of 1 μ M.
Known astroglia cell is mainly expressed MAO-B (Thorpe et al., J.Histochem.Cytochem., 35,23-32,1987).Use non-selective substrate tyrasamine and selectivity MAO-B inhibitor L-deprenyl (Youdim and Finberg, Biochem.Pharmacol., 41,155-162,1991), find to form by MAO-B up to total astroglia cell MAO activity of 80%.Residue MAO activity under the situation of the L-deprenyl that maximum effective concentration is arranged (about 20%) is suppressed fully by bringing Selection In property MAO-A inhibitor M and B 9302.L-deprenyl suppresses total astroglia cell MAO activity, apparent IC in the concentration dependent mode
50Be about 0.04 μ M.Similarly, the ADT concentration dependent suppresses total MAO activity, apparent IC
50Be about 0.5 μ M, be issued to maximum effect (about 80% suppresses) in the concentration of 30 μ M.By the M and B 9302 selectivity with after blocking the MAO-A activity fully,,, observe identical concentration-effect relation with active the comparing of finding of the total MAO of inhibition for L-deprenyl and ADT.Under these conditions, promptly under the situation that has M and B 9302 to exist, D3T is observed similarly to the active concentration dependent blocking-up of MAO-B, apparent IC
50For about 20 μ M and maximum effective concentration are 300 μ M.When with the L-deprenyl selectivity with after blocking the MAO-B activity fully, do not detect ADT to the remarkable effect of the active statistics of MAO-A.
At CEREP (Paris, FRA), according to J.L.Salach,
Arch.Biochem. Biophys.,
192, the MAO-B of the compd A 1-D6 that 128,1979 described schemes are measured suppresses active
| Compound | MAO-B% suppresses, 10 -5Under the M |
| A1 | 100 |
| A2 | 81 |
| A3 | 83 |
| B1 | 65 |
| B2 | 74 |
| B3 | 54 |
| C1 | 52 |
| C2 | 56 |
| D1 | 25 |
| D2 | 100 |
| D3 | 95 |
| D4 | 81 |
| D5 | 75 |
| D6 | 71 |
Claims (6)
1. the compound of general formula (1):
Wherein:
-R
1Be optional through C
1-3Alkyl or C
1-3The phenyl that alkoxyl group replaces, R
2Represent S-CH
2One of-(4-methyl-phenyl) or following group:
Wherein n has value 2,3,4 or 5, R
3Be hydrogen or C
1-3Alkyl, aryl are phenyl or 2,3-dihydro-1, and 4-Ben Bing dioxin-5-base group, perhaps
-R
1Be 4-hexyloxy phenyl, R
2Be hydrogen, perhaps
-R
1Be optional through C
1-3Alkyl or C
1-6The phenyl that alkoxyl group replaces, R
2Represent SH, perhaps following group:
R
1Be hydrogen, R
2Representative-CH=CH-4-(diethylamino phenyl) ,-CH=CH-(2-quinolyl) or following group:
Wherein n has and the identical implication that provides above, and R
4And R
5Represent C independently
1-3Alkyl perhaps forms saturated 5-or 6-unit ring with the nitrogen-atoms that they connected, the optional heteroatoms that contains one or more N of being selected from, O or S of described ring, perhaps
-R
1Be C
1-3Alkyl, R
2Be 1-(2,3-dihydro-1,4-Ben Bing dioxin-5-base group) piperazine-4-base, perhaps
-R
1Be cyano group, R
2Be-NH-C (O)-NH-phenyl, perhaps
-R
1Be-SO
2CH
3, R
2Represent amino,
And the acceptable salt of pharmacology.
2. the compound with general formula (1) as claimed in claim 1:
Wherein:
-R
1Represent 4-hexyloxy phenyl, R
2Represent hydrogen,
-R
1Represent hydrogen, R
2Representative
-R
1Represent hydrogen, R
2Representative
-R
1Represent phenyl, R
2Representative
-R
1Represent the 4-aminomethyl phenyl, R
2Representative
-R
1Represent the 4-aminomethyl phenyl, R
2Represent the 4-Phenylpiperazinyl,
-R
1Represent hydrogen, R
2Representative-CH=CH-(4-diethylamino-phenyl),
-R
1Represent hydrogen, R
2Representative-CH=CH-(2-quinolyl),
-R
1Represent phenyl, R
2Representative-S (CH
2)
2CH (CH
3) the NH-2-proyl,
-R
1Represent phenyl, R
2Representative-S (CH
2)
3CH (CH
3) the NH-2-proyl,
-R
1Represent phenyl, R
2Representative-S (CH
2)
4CH (CH
3) the NH-2-proyl,
-R
1Represent phenyl, R
2Representative-S (CH
2)
4CH (CH
3) N (CH
3)-2-propynyl,
-R
1Represent phenyl, R
2Representative-S (CH
2)
3CH (CH
3) N (CH
3)-2-propynyl,
-R
1Represent phenyl, R
2Representative-S-CH
2-(4-aminomethyl phenyl).
3. pharmaceutical composition, except comprising medicinal acceptable carrier and/or at least a medicinal acceptable auxiliary substance, the compound or its salt of at least a claim 1 that also comprises pharmacological activity amount is as activeconstituents.
4. compound or its salt as claimed in claim 1 or 2 or 5-(p-methoxyphenyl)-3H-1,2-dithia cyclopentenes-3-thioketones, 3H-1,2-dithia cyclopentenes-3-thioketones or 4-methyl-5-(2-pyrazinyl)-3H-1,2-dithia cyclopentenes-3-thioketones are used for the preparation treatment, improve or the prevention mood disorder, bipolar disorder I, bipolar disorder II, the one pole dysthymia disorders, mild depression, seasonal affective disorder, postpartum depression, dysthymia, severe depression, anxiety disorder, panic disorder, social phobia, obsession, posttraumatic stress disorder, generalized-anxiety disorder, the illness that material is relevant, material is used obstacle, material inductive obstacle, the material de-addiction, attention deficit and disruptive behavior disorder, the distractibility hyperkinetic syndrome, narcolepsy; The purposes of the sphincter muscle in impulse control disorder, pathological gambling, eating disorder, anorexia nervosa, bulimia nervosa, tic disorder, tourette's syndrome, restless legs syndrome, pain, headache, atypical facial pain, pain obstacle and chronic pain syndrome, sexual dysfunction, obstruction of the air passage, asthma, gastrointestinal peristalsis obstacle, hemorrhoid (hemorroids), the gi tract and the pharmaceutical composition of smooth muscle spasm and vesical dysfunction.
5. purposes as claimed in claim 4, be characterised in that described compound is 5-(p-methoxyphenyl)-3H-1,2-dithia cyclopentenes-3-thioketones, 3H-1,2-dithia cyclopentenes-3-thioketones or 4-methyl-5-(2-pyrazinyl)-3H-1,2-dithia cyclopentenes-3-thioketones.
6. purposes as claimed in claim 4 is characterised in that described compound is 5-(p-methoxyphenyl)-3H-1,2-dithia cyclopentenes-3-thioketones.
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| EP05101405 | 2005-02-24 | ||
| PCT/EP2006/060060 WO2006089861A2 (en) | 2005-02-24 | 2006-02-17 | Anethole dithiolethione and other dithiolethiones for the treatment of conditions associated with dysfunction of monoamine neurotransmission |
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| KR (1) | KR20070117607A (en) |
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| CN102807557B (en) * | 2012-08-21 | 2015-02-04 | 苏州大学 | 3H-1,2-dithio-cyclopentene-3-thioketone compound and application thereof |
| KR101438415B1 (en) * | 2013-07-25 | 2014-09-17 | 동국대학교 경주캠퍼스 산학협력단 | Extract of Uncaria rhynchophylla for preventing or ameliorating the memory impairment |
| CN104788440B (en) * | 2015-04-03 | 2017-12-26 | 苏州大学 | Nicotinic acid derivates and its application |
| BR112019018495A2 (en) | 2017-03-07 | 2020-04-14 | Centre Hospitalier Univ Bordeaux | derivatives of desmethylanetola trithion for the treatment of diseases related to the mitochondrial production of reactive oxygen species (ero) |
| FR3063640B1 (en) * | 2017-03-07 | 2020-10-09 | Elodie Petitjean | TREATMENT OF PULMONARY FIBROSIS USING A SELECTIVE INHIBITOR OF THE PRODUCTION OF REACTIVE OXYGEN SPECIES OF MITOCHONDRIAL ORIGIN |
| MX2021003123A (en) * | 2018-09-18 | 2021-08-11 | St Ip Holding Ag | Rotomeric isomers of 4-alkyl-5-heteroaryl-3h-1,2- dithiole-3-thiones. |
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| JPH089611B2 (en) * | 1988-06-20 | 1996-01-31 | 三井東圧化学株式会社 | Novel 1,2-dithiole-3-thione derivative and immunomodulator containing the same as active ingredient |
| WO1998027970A2 (en) * | 1996-12-24 | 1998-07-02 | National Research Council Of Canada | Treatment of diseases or prevention of cellular damage caused by oxygen-containing free radicals |
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