CN100584818C - Treatment of CNS disorders with trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine and its formamide - Google Patents
Treatment of CNS disorders with trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine and its formamide Download PDFInfo
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Abstract
Treatment of CNS disorders with (1R,4S)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine; and (1S,4R)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine is disclosed. A process for preparing 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine is also disclosed. The process includes the preparation of all four isomers of N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide, which are also useful.
Description
Technical field
The present invention relates to use (1R, 4S)-trans 4-(3, the 4-dichlorophenyl)-1,2,3,4-tetrahydrochysene-naphthalidine; (1S, 4R)-trans-4-(3, the 4-dichlorophenyl)-1,2,3,4-tetrahydrochysene-naphthalidine and N-[4-(3, the 4-dichlorophenyl)-1,2,3,4-naphthane-1-yl] method of four kinds of isomer treatment central nervous system (CNS) illnesss of methane amide.
Background technology
The clinician generally acknowledges the difference between the central nervous system disease, and mental disorder is had multiple classification schemes.By the Diagnostic and StatisticalManual of Mental Disorders that American Psychiatric Association publishes, Fourth Ed., (this paper is to call " DSM-IV-TR in the following text for Text Revision
TM"))) the standard diagnostics system that provides the technician to rely on, the document is incorporated herein for referencial use.According to DSM-IV-TR
TMFramework, Axis I CNS illness comprises: the illness of childhood diagnosis (for example attention shortage disease or " ADD " and attention deficit/how moving obstacle or " ADHD "))) and the illness diagnosed of Adulthood.The Adulthood CNS illness of diagnosis comprises (1) schizophrenia and psychosis; (2) cognitive disorder; (3) mood disorder; (4) illness relevant with anxiety; (5) eating disorder; (6) illness relevant with drug habit; (7) personality disorder; And in (8) this framework " illness that does not comprise as yet ".
The present invention is interested especially to be DSM-IV-TR
TMThe Adulthood illness of classification (1) to (7) and the sexual dysfunction that belongs to (8) class usually.The mood disorder of special concern comprises dysthymia disorders, seasonal affective disorder and bipolar disorder.The illness relevant with anxiety of special concern is agoraphobia, generalized anxiety disorder, phobic anxiety, obsession (OCD), paranoid fears, acute stress disorder, posttraumatic stress disorder, premenstrual tension syndrome, social phobia, chronic fatigue syndrome, premenopause, climacteric and male climacteric.
Usually psychosis is as schizoid treatment, for example, very different with the treatment of mood disorder.Psychosis D
2Antagonist, as olanzapine (" typical case " and " atypia " antipsychotic drug) treatment, mood disorder is then with suppressing neurone to monoamine, the especially pharmacological agent of serotonin (5-HT), norepinephrine (NE) and Dopamine HCL (DA) reuptake.
The conventional treatment medicine that is used for mood disorder includes but not limited to selectivity serotonin reuptake inhibitor (SSRI ' s), comprises fluoxetine, citalopram, nefazodone, fluvoxamine, paroxetine and Sertraline.
Sertraline, its chemistry is by name, and (1S, 4S)-cis-4-(3, the 4-dichlorophenyl)-1,2,3,4-tetrahydrochysene-N-methyl isophthalic acid-naphthylamines is used for the treatment of dysthymia disorders by American National food and Drug Administration's approval, can trade(brand)name
(NY USA) obtains for Pfizer Inc., NY.In people experimenter, proved that Sertraline is metabolized to that (1S, 4S)-cis-4-(3, the 4-dichlorophenyl)-1,2,3,4-tetrahydrochysene-naphthalidine is also referred to as Desmethylsertraline or falls Sertraline.Desmethylsertraline is described to people such as " not remarkable to the contribution that the serotonin of Sertraline can act on " Ronfield, Clinical Pharmacokinetcs, 32:22-30 (1997).From people such as Hamelin, Clinical Pharmacology﹠amp; Therapeutics, people such as 60:512 (1996) and Serebruany, Pharmacological Research, it is " non-activity on the neuroscience " that the report of 43:453-461 (2001) points out to fall Sertraline.As if these describe observed result in the serotonin inductive syndrome of carrying out in the body be based in the mouse model and the ptosis, yet on the basis of vitro data, primary Pfizer research report prompting Desmethylsertraline is a kind of selectivity serotonin uptake inhibitor.People such as Koe, JPET, 226:686-700 (1983).People such as Sanchez, Cellular and Molecular Neurobiology, 19:467 (1999) is although infer that the Desmethylsertraline effect is lower, and it may work in the result of treatment of Sertraline, does not support this theory but have evidence in the present document.
The initial clinical use of Sertraline is the treatment dysthymia disorders.In addition, United States Patent (USP) 4,981; 870 open and claimed Sertraline and Desmethylsertralines, and (1R, 4S)-trans-4-(3; the 4-dichlorophenyl)-1,2,3; 4-tetrahydrochysene-N-methyl isophthalic acid-naphthylamines and (1S; 4R)-trans-4-(3, the 4-dichlorophenyl)-1,2; 3,4-tetrahydrochysene-N-methyl isophthalic acid-naphthylamines is used for the treatment of the purposes of psychosis, psoriasis, rheumatoid arthritis and inflammation.People such as Welch, J.Med.Chem., 27:1508-1515 (1984) have described trans-4-(3, the 4-dichlorophenyl)-1,2,3,4-tetrahydrochysene-N-methyl isophthalic acid-naphthylamines single (1S, 4R) and (1R, 4S) the acceptor pharmacology of enantiomorph.
Summary of the invention
Have now found that (1R, 4S)-trans-4-(3, the 4-dichlorophenyl)-1,2,3,4-tetrahydrochysene-naphthalidine (P) and (1S, 4R)-trans-4-(3, the 4-dichlorophenyl)-1,2,3,4-tetrahydrochysene-naphthalidine (Q) is useful by the CNS associated conditions of the active mediation of monoamine to treatment, compare with current treatment standard, the side effect of its generation reduces.Medicable CNS illness includes but not limited to mood disorder (for example dysthymia disorders), anxiety illness (for example OCD), dystropy (for example ADD and ADHD), eating disorder, drug abuse and sexual dysfunction.These compounds are also useful to prevention of migraine.
Compound P and Q are expressed from the next:
On the one hand, the present invention relates to a kind of method of the CNS of treatment illness, it comprises P or the Q that treats significant quantity, or their pharmacologically acceptable salts.
On the other hand, the present invention relates to the trans-4-(3, the 4-dichlorophenyl)-1,2,3 of formula (PQ), 4-tetrahydrochysene-naphthalidine.
On the one hand, the present invention relates to be used to prepare 4-(3, the 4-dichlorophenyl)-1,2,3 again, the method for 4-tetrahydrochysene-naphthalidine, it comprises:
(a) make 4-(3, the 4-dichlorophenyl)-3,4-dihydro-1-naphthalenone and excessive formic acid and formamide obtain N-[4-(3, the 4-dichlorophenyl)-1,2,3,4-naphthane-1-yl] methane amide; With
(b) with aqueous acid this N-[4-of hydrolysis (3, the 4-dichlorophenyl)-1,2,3,4-naphthane-1-yl] methane amide, thus obtain 4-(3, the 4-dichlorophenyl)-1,2,3,4-tetrahydrochysene-naphthalidine.
Again on the one hand, the present invention relates to P, Q, its mixture or its pharmacologically acceptable salts and the D that treats significant quantity
2Antagonist or its pharmacologically acceptable salts one are used from the purposes of preparation treatment people's psychotic medicine.Preferred this D
2Antagonist is an olanzapine.
Again on the one hand, the present invention relates to P, Q, its mixture or its pharmacologically acceptable salts and be used from the purposes that people's psychotic medicine is treated in preparation with the typical antipsychotic drug for the treatment of significant quantity or its pharmacologically acceptable salts one.
Again on the one hand, the present invention relates to P, Q, its mixture or its pharmacologically acceptable salts and be used from the purposes that people's psychotic medicine is treated in preparation with the atypical antipsychotic agents for the treatment of significant quantity or its pharmacologically acceptable salts one.
Again on the one hand, the present invention relates to be selected from P, Q, P and Q mixture, with and atypical antipsychotic agents or its pharmacologically acceptable salts one of the compound of pharmacologically acceptable salts and the treatment significant quantity purposes that is used from preparation treatment people's psychotic medicine.
Embodiment
The invention provides several embodiments of the method that is used for the treatment of one or more CNS illnesss.This method comprises and gives pure P or pure Q, perhaps their mixture.Give arbitrary compound or their any combination, comprise the racemic mixture of trans-isomer(ide), obtain curative effect widely and avoid with norepinephrine, serotonin and Dopamine Receptors between the uneven relevant side effect of activity distribution.
The preparation of compound of the present invention explanation in following route 1 and additional description the thereof.
Route 1
Compound at route 1
R is
R wherein
1, R
2And R
3Be alkyl independently of one another.In the preferred embodiment of this compound, R is the tertiary butyl.
Intermediate N [4-(3, the 4-dichlorophenyl)-1,2,3,4-naphthane-1-yl] methane amide in synthetic shown in the route 1 exists with four kinds of stereoisomer forms:
When N-[4-(3, the 4-dichlorophenyl)-1,2,3,4-naphthane-1-yl] when methane amide was synthesized by non-stereoselectivity by the achirality raw material, all four kinds of isomer all can generate.Rely on chemistry and physical difference, can be easily by being racemize cis diastereomer and the trans diastereomer of racemize with this mixture separation such as recrystallization or the chromatography on the achirality medium.
Trans diastereomer, below with E representative, be 1: 1 mixture of A and B.When the E hydrolysis, generate PQ; When the A hydrolysis, generate P; When the B hydrolysis, generate Q.The cis diastereomer, below with F representative, be 1: 1 mixture of C and D.
E＝A+B F＝C+D
The diagram of racemize used herein, ambiscalemic and scalemic or enantiomerism pure compound is taken from Maehr, J.Chem.Ed., and 62:114-120 (1985): real and empty wedge shape is used to represent the absolute configuration of chiral atom; Wavy line represents not have the issuable any stereochemistry connotation of key of its representative; Solid line and thick dashed line are the shown relative configuration of expression but do not mean the geometric description symbol of any absolute stereo chemistry; Wedge shape and dotted line or dotted line are represented the different pure compound of the uncertain mapping of absolute configuration.
Therefore, above-mentioned formula PQ represents to have the single isomer P of trans relative configuration and any mixture of Q jointly.The mixture of most convenient obviously is 1: 1 a racemoid.When using single enantiomer, preferably the required enantiomorph that comprises of this mixture is greater than 90%, more preferably greater than 95%, most preferably greater than 98%.This percentage ratio refers to the optical purity of this single enantiomer.
According to the present invention, N-[4-(3, the 4-dichlorophenyl)-1,2,3 that also can the treatment significant quantity, 4-naphthane-1-yl] methane amide needs the people that treats, and described compound can be pure isomer or any or all of mixture of A, B, C and D.
Include but not limited to the treatable illness of compound of the present invention: dysthymia disorders, bipolar disorder, chronic fatigue syndrome, seasonal affective disorder, agoraphobia, generalized anxiety disorder, phobic anxiety, obsession (OCD), paranoid fears, acute stress disorder, social phobia, posttraumatic stress disorder, premenstrual tension syndrome, premenopause, climacteric and male climacteric.
For example, dysthymia disorders is a feature with emotional change and extremely sad or pessimistic worry.Symptom comprises that insomnia, anorexia, CNS go down and the forfeiture of drive, enthusiasm, sexual desire.
Research shows as if the raising of raising, the especially noradrenaline levels of monoamine level alleviates the symptom relevant with above-mentioned illness in the body.Therefore, believe that compound of the present invention provides their therapeutic activity by the re-uptake of blocking norepinephrine, serotonin and Dopamine HCL simultaneously.
Except their useful result of treatment, compound of the present invention provides the additional benefits of one or more side effects of avoiding relevant with conventional mood disorder treatment.These side effects comprise that for example, insomnia, mastalgia, weight increase, extrapyramidal symptom, serum prolactin antagonist level improve, sexual dysfunction (comprising hyposexuality, ejaculation dysfunction and anorgasmia).
Compound of the present invention is to the treatment disruptive behavior disorder, and also effective as attention shortage disease (ADD) and attention deficit/move obstacle (ADHD), described disease and its are as DSM-IV-TR more
TMIn the connotation unanimity of generally acknowledging that provides.These illnesss are defined as influencing a people's behavior, cause the inappropriate action in study and social circumstances.Though disruptive behavior disorder is mainly in childhood, also may take place in the Adulthood.
Term ADD used herein comprises the moving obstacle (ADHD) of attention shortage disease and attention deficit/how, and with its at DSM-IV-TR
TMIn defined generally acknowledged connotation consistent the use.Therefore, term attention shortage disease used herein comprises ADHD:DSM-IV-TR
TMClassification 314.xx (comprising 314.01,314.00 and 314.9); Conduct disorder: DSM-IV-TR
TMClassification 312.xx (comprise 312.81,312.82 and 312.89, and the 312.9-disruptive behavior disorder); And oppositional defiant disorder: DSM-IV-TR
TMClassification 313.81.Those skilled in the art will recognize that pathological state is had other nomenclature, nosonomy and categorizing system, and these systems develop along with medical science applied progress.
Ritalin (
Novartis Pharmaceuticals Corporation, EastHanover, NJ USA) is the common medicament selection that treats and/or prevents ADD.Tricyclics (for example imipramine), caffeine, Dextroamphetamine and other psychostimulant (for example pemoline) are the selections that slightly is worse than Ritalin.Decreased growth when the common side effect of Ritalin comprises somnopathy, depression or sadness, headache, stomachache, appetite stimulator, elevation of blood pressure and lasting high dosage.Therefore, the alternative method of treatment or prevention attention shortage disease will have very big benefit.Because compound of the present invention has strong dopaminergic component, they not only provide the effective treatment to disruptive behavior disorder, and avoid the many side effect relevant with conventional treatment.
When using with above-mentioned illness, term " treatment " means improvement, prevention or the alleviation of symptom relevant with these illnesss and/or influence, and the preventive administration that comprises Compound P or Q, its mixture or their pharmacologically acceptable salts is with the possibility or the seriousness of remarkable this illness of minimizing.
It is also effective that compound of the present invention advances to drink obstacle for treatment.Eating disorder is defined as a people's appetite or the illness of food habits or the illness of inappropriate build profile.Eating disorder includes but not limited to anorexia nervosa, bulimia nervosa, obesity and emaciation.
Compound of the present invention is also effective for the treatment functional disorders of brain.Term functional disorders of brain used herein comprises and relates to amential functional disorders of brain that the example can be senile dementia, dementia of the Alzheimer type, memory loss, amnesia/amnestic syndrome, epilepsy, consciousness disturbance, stupor, attention reduction, speech disorder, Parkinson's disease and autism.
The compound of formula P and Q is also effective for the treatment of the sexual dysfunction of masculinity and femininity.Such illness comprises, for example, and erective dysfunction and the orgasm disorder relevant with the clitoris obstacle.
Compound of the present invention is abused at medicine, comprises that for example the habituation of Cocaine, heroine, Nicotine, alcohol, anxiolytic and soporific, hemp, Amphetamine, halluoinogen, phenylcyclidine, volatile solvent and volatility nitrite is also useful.Nicotine addiction comprises the nicotine addiction of all form known, the nicotine addiction that is caused by cigarette, cigar and/or tobacco pipe smoking for example, and the habituation that is caused by chewing tobacco.In this respect because they have activity as norepinephrine and dopamine uptake inhibitor, compound of the present invention with Bupropion (
GlaxoSmithKline, ResearchTriangle, NC, USA) similar mode is by reducing the serious hope effect that Nicotine is stimulated.Yet, being better than Bupropion therapeutic activity part and being, compound of the present invention provides other serotonin energy component.
Compound of the present invention is also effective for prevention of migraine.
The big young pathbreaker of the prevention of the compound of formula A-F, P or Q or therapeutic dose is along with the character of the illness that will treat and severity and route of administration and change.Dosage, and possibility administration frequency also will change according to age, body weight and the reaction of single patient.Usually, total every day of the dosage of compound of the present invention be every day about 25mg to about 1000mg every day, preferred every day, about 100mg was to about 600mg every day, once or divide administration several times.
For children, age greater than 65 years old the patient and the patient of renal function and liver dysfunction, further low dosage is at first accepted in recommendation, and dosage is definite based on individuality response and blood levels titration.Sometimes it may be necessary adopting the dosage that exceeds these scopes, and this is clearly to those skilled in the art.And, it is noted that clinician or treatment doctor how to know in conjunction with patient's individual reaction interrupt, adjustment or stopped treatment.
Can adopt any suitable route of administration.In for example oral, rectum, the nose and injection (comprising subcutaneous, intramuscular and vein) approach all can adopt.Formulation can comprise tablet, lozenge, dispersion agent, suspensoid, solution, capsule and patch.
Pharmaceutical composition of the present invention comprises formula A-F, P or the simplification compound of Q or the mixture of these compounds as activeconstituents, or the pharmacologically acceptable salts of P or Q, and pharmaceutically acceptable carrier and other optional therapeutic component.
Term " its pharmacologically acceptable salts " refers to comprise mineral acid and organic acid, the salt of preparation by the acceptable non-toxic acid of pharmacy.Form pharmacologically acceptable salts with amine of the present invention, and the exemplary acids that can be used for composition of the present invention is acetate, Phenylsulfonic acid, phenylformic acid, isethionic acid, camphorsulfonic acid, citric acid, vinyl sulfonic acid, fumaric acid, glyconic acid, L-glutamic acid, Hydrogen bromide, hydrochloric acid, lactic acid, toxilic acid, oxysuccinic acid, amygdalic acid, methylsulfonic acid, glactaric acid, nitric acid, piperazine acid (pamoic acid), pantothenic acid, phosphoric acid, succsinic acid, sulfuric acid, tosic acid and tartrate.Hydrochloride is particularly preferred.
The composition that is suitable for oral, rectum and administered parenterally is contained in the present invention.Preferred route of administration is oral.These compositions can be easily exist with the form of unit dosage form, and can be by known any method preparation in the pharmaceutical field.Preferred unit dosage form preparation is to contain activeconstituents or its suitable preparation partly for the treatment of effective dose.
Composition of the present invention also comprises pharmaceutically acceptable carrier.According to the route of administration of desiring to take, for example oral or parenteral (comprising intravenously), carrier can adopt various ways.In the composition of preparation oral dosage form, can use any useful drug media, at oral liquid, comprise under the situation of suspensoid, elixir and solution, as water, ethylene glycol, oil, alcohols, correctives, sanitas and tinting material.Under the situation of solid orally ingestible such as powder, capsule and capsule sheet, can use carrier such as starch, sugar, Microcrystalline Cellulose, thinner, granulating agent, lubricant, tackiness agent and disintegrating agent, solid orally ingestible is than liquid preparation more preferably.Owing to be easy to administration, preferred solid orally ingestible is tablet or capsule.If desired, tablet can carry out dressing by the moisture or non-water technology of standard.Also can adopt oral and the parenteral sustained release forms.
Oral syrup and other oral liquid are well-known to those skilled in the art, and the ordinary method for preparing them sees the pharmacy textbook of any standard, for example
Remington:The Science and Practice of PharmacyIn.The 19th edition complete preparation that has described syrup (1503-1505 page or leaf) and other oral liquid in detail of the 86th chapter that is entitled as " Solutions, Emulsions, Suspensions and Extracts " of Remington.
Similarly, delayed release preparation is also known by the people in the art, and the 94th chapter that same document is entitled as " Sustained-Release Drug Delivery Systems " has been described oral and more common types (1660-1675 page or leaf) the parenteral delayed release dosage forms.The associated viscera of these chapters and sections is incorporated herein for referencial use.Because compare with conventional oral dosage form, controlled release form reduces peak serum concentration, so they are providing the treatment plasma concentration, avoids the side effect aspect relevant with the high peak serum concentration that adopts regular dosage form to take place to be particularly useful simultaneously.
[4-(3 for 2-methyl-propane-2--sulfinic acid, the 4-dichlorophenyl)-1,2,3,4-tetrahydrochysene-naphthalene-y-yl]-acid amides (Tetralone an intermediate of Sertraline uncle butane-sulfinic acid imines (tetralone t-butanesulfinimine)) synthetic: to 4-((3, the 4-dichlorophenyl)-3, add (R)-uncle butane sulfinyl amine ((R)-t-butanesulfinamide (5.2g) and Ti (OEt) in the 4-dihydro-solution of 1-naphthalenone (12g) in tetrahydrofuran (THF) (40mL)
4Solution in ethanol (85mL 20%).Reaction mixture is heated to 60 ℃ continues 13 hours.Make reaction mixture be cooled to room temperature, and under agitation with in its impouring salts solution (100mL).Suspension is added in the ethyl acetate (300mL) then, and stirred 10 minutes.Filtering suspension liquid, and filtrate is concentrated into about 50mL.Add the 100mL ethyl acetate, separate organic phase, concentrate and obtain thick reaction mixture.Final product is by carefully carrying out the flash distillation column chromatography with ethyl acetate and hexane (3: 7 to 1: 1) and isolating from crude product, obtain about 3 gram raw ketones, and (1R, 4S)-4-(3, the 4-dichlorophenyl)-3,4-dihydro-1-naphthalenone uncle butane-sulfinic acid imines (2.5g, first product), the latter is an oily matter, and it places after fixing.
1H NMR(CDCl
3)δ1.33(S，9H)，2.10-2.20(m，1H)，2.28-2.38(m，1H)，2.88-2.98(m，1H)，3.34-3.44(m，1H)，4.12-4.24(m，1H)，6.84-6.88(m，2H)，7.20(s，1H)，7.25-7.40(m，3H)，8.22-8.28(m，1H)。Separate another product (1R, 4R)-4-(3, the 4-dichlorophenyl)-3,4-dihydro-1-naphthalenone uncle butane-sulfinic acid imines (3.0g, second product, low R
f), it is an oily matter, places after fixing.
1H NMR(CDCl
3)δ1.34(S，9H)，2.05-2.18(m，1H)，2.28-2.38(m，1H)，3.15-3.25(m，2H)，4.16-4.22(m，1H)，6.84-6.88(m，2H)，7.20(s，1H)，7.25-7.40(m，3H)，8.22-8.28(m，1H)。
(R)-4-(3, the 4-dichlorophenyl)-3,4-dihydro-1-naphthalenone synthetic: under the room temperature with (1R, 4R)-4-(3, the 4-dichlorophenyl)-3,4-dihydro-1-naphthalenone uncle butane-sulfinic acid imines (3.0g, second product) is dissolved among methyl alcohol (20mL) and the dense HCl (4mL).Reaction mixture is at room temperature stirred, obtain suspension.With its filtration, and use the hexane wash solid, obtain the 1.2g product.With ChiralPak AS 10 μ m, 4.6 * 250mm, hexane/IPA (90: 10), UV 220nm, record enantiomeric purity＞99.3% by the HPLC analysis.
R-isomer 8.23min, S-isomer 12.25min.
1H NMR(CDCl
3)δ2.20-2.32(m，1H)，2.42-2.53(m，1H)2.57-2.78(m，2H)，4.28(dd＝4.6，8.1Hz，1H)，6.95(dd，J＝2.1，7.6Hz，2H)，7.23(d J＝2.0Hz，1H)，7.37-50(m，3H)，8.13(d，J＝7.6Hz，1H)。[α]=-66 ° (c=1, acetone).
(S)-and 4-(3, the 4-dichlorophenyl)-3,4-dihydro-1-naphthalenone synthetic: adopt aforesaid method, from (1R, 4S)-4-(3, the 4-dichlorophenyl)-3,4-dihydro-1-naphthalenone uncle butane-sulfinic acid imines begins.Obtain the 1.7g product (＞99%, ee).[α]=+ 62 ° (c=1, acetone).
1H NMR spectrum is identical with its enantiomorph.
(1S, 4R) and (1R, 4R)-N-[4-(3, the 4-dichlorophenyl)-1,2,3,4-tetrahydrochysene-naphthalene-1-yl]-methane amide synthetic: to (S)-4-(3, the 4-dichlorophenyl)-3, add formic acid (3mL) and methane amide (3mL) in 4-dihydro-1-naphthalenone (1.2g).Reaction mixture is heated to 160-165 ℃ continues 15 hours in nitrogen atmosphere.Make reaction mixture be cooled to room temperature, slowly pour out solvent.Use ethyl acetate: hexane (3: 7 to 1: 1) makes residual solid by the flash distillation post, obtain (1R, 4R)-methane amide (400mg, first spot) and (1S, 4R)-methane amide (360mg).First product [(1R, 4R)-isomer]
1H NMR:(CDCl
3) δ 1.80-2.10 (m, 3H), 2.10-2.20 (m, 1H), 4.00-4.10 (m, 1H), 5.22-5.30 (m, 1H), 6.10-6.20 (m, 1H), 6.80-6.90 (m, 1H), 6.90-6.96 (m, 1H), 7.10-7.40 (m, 5H), 8.22 (s, 1H).M
+320。Second product [(1S, 4R)-isomer]
1H NMR: δ 1.64-1.90 (m, 2H), 2.10-2.28 (m, 2H), 4.10 (m, 1H), 5.38-5.42 (m, 1H), 5.82-6.05 (m, 1H), 6.80-6.90 (m, 2H), 7.10-40 (m, 5H), 8.28 (s, 1H).Mass spectrum: M
+320.
(1S, 4R)-trans-4-(3, the 4-dichlorophenyl)-1,2,3,4-tetrahydrochysene-naphthalidine HCl's is synthetic: with (1S, 4R) methane amide (about 300mg) is dissolved in the methyl alcohol (5mL), adds 6N HCl (6mL) subsequently.Reaction mixture is heated to 80 ℃ continues 2 hours.Make reaction mixture be cooled to room temperature and continue 1 hour, and solid collected by filtration.It is used acetone (3mL) washing, dry product (280mg) the ChiralPak AD 10 μ m that obtain, 4.6 * 250mm, hexane/IPA/DEA (99: 1: 0.1), UV 220nm records enantiomeric purity＞99.8% by the HPLC analysis.
(1R, 4S)-isomer 11.00min, (1S, 4R)-isomer 11.70min.[α]=-51 ° (C=1, methyl alcohol).
1H NMR (CD
3OD) δ 1.86-1.97 (m, 2H), 2.20-2.42 (m, 2H), 4.30 (wide s, 1H), 4.67 (wide s, 1H), 4.87 (s, 3H), 6.95-6.99 (m, 2H), 7.18 (s, 1H), 7.28-7.50 (m, m, 4H).M
+293。
(1R, 4S)-trans-4-(3, the 4-dichlorophenyl)-1,2,3,4-tetrahydrochysene-naphthalidine HCl's is synthetic: with HCl hydrolysis (1R, 4S) methane amide and obtain it similarly.With ChiralPak AD 10 μ m, 4.6 * 250mm, hexane/IPA/DEA (99: 1: 0.1), UV 220nm, the product ee that analyzes based on HPLC is＞99.8%, (1R, 4S)-isomer 11.00min, (1S, 4R)-isomer 11.70min.
(1R, 4R)-cis-4-(3, the 4-dichlorophenyl)-1,2,3,4-tetrahydrochysene-naphthalidine HCl's is synthetic: with HCl hydrolysis (1R, 4R) methane amide and obtain it similarly.With ChiralPak AD 10 μ m, 4.6 * 250mm, hexane/IPA/DES (99: 1: 0.1), UV 220nm, analyzing the enantiomeric purity that records by HPLC is＞96.8%, (1R, 4R)-isomer 11.84min, (1S, 4S)-isomer 9.80min.
1H NMR(CD
3OD)δ1.96-2.26(m，4H)，4.14-4.22(m，1H)，4.54-4.63(m，1H)，4.87(s，3H)，7.88-7.94(m，1H)，7.18-7.20(m，1H)，7.30-7.50(m，5H)。Mass spectrum M
+292.
(1S, 4S)-cis-4-(3, the 4-dichlorophenyl)-1,2,3,4-tetrahydrochysene-naphthalidine HCl's is synthetic: from (1S 4S) obtains it like the benzamide type.Analyzing the product ee that records by HPLC is 98.5%.
1H NMR spectrum is identical with enantiomorph.Mass spectrum M
+292.
Tested compound of the present invention respectively from the synaptosome of rat whole brain, hypothalamus or striatum preparation to the restraining effect of the functional picked-up of serotonin (5-HT), norepinephrine (NE) or Dopamine HCL (DA).Parallel two parts of test compounds under 10 μ M at first suppress 〉=50% if observe picked-up, then further under 10 different concns parallel two parts of tests they, to obtain complete inhibition curve.IC
50Value (concentration that suppresses control activity 50%) records by the inhibition curve is carried out non-linear regression, and is listed as follows.
The experiment condition that monoamine uptake is measured
The functional picked-up of serotonin is measured
The sign of serotonin picked-up is carried out in employing from the isolating synaptosome of male Wistar rat cortex in the sucrose damping fluid of 0.32M.Test compounds and [
3H] serotonin (0.1 μ Ci/ point) existed down, made the serotonin of synaptosome (100 μ g albumen/point) picked-up labelled with radioisotope in deep hole in 37 ℃ of following incubations 15 minutes.
Containing 25mM NaHCO
3, 11mM glucose and 50 μ M xitix the Krebs damping fluid of pH7.4 in prepare synaptosome and [
3H] serotonin.Before incubation, give this incubation buffering liquid oxygenation 5 minutes.Will be substantially to impinging upon 4 ℃ of following incubations 15 minutes to avoid any picked-up.Behind this incubation, filter by " unifilter 96 hole GFB Packard plates " and stop picked-up, with containing 25mM NaHCO
3Krebs damping fluid flushing with remove free [
3H] serotonin.Use then and use scintillation solution microscint 0, the microplate scintillometer Topcount of Packard, Packard measures the radiant that is retained in the synaptosome on the unifilter corresponding to picked-up.
Reference substance is an imipramine, 10
-11M to 10
-5Test reference substance under 10 concentration in the M scope, to obtain IC
50Value.Referring to Perovics and M ü ller, " Pharmacologicalprofile of hypericum extract:effect on serotonin uptake by postsynapticreceptors; " Arzeim.Forsch./Drug Res., 45:1145-1148 (1995).
The functional picked-up of Dopamine HCL is measured
Be used in Cerep and in 0.32M sucrose damping fluid, carry out the sign of dopamine uptake from the isolating synaptosome of male Wistar rat striatum.Test compounds and [
3H]-Dopamine HCL (0.1 μ Ci/ point) existence was following, made the Dopamine HCL of synaptosome (20 μ g albumen/point) picked-up labelled with radioisotope in 37 ℃ of following incubations 15 minutes.Experiment is carried out in deep hole.Synaptosome and [
3H]-Dopamine HCL containing 25mM NaHCO
3, 11mM glucose and 50 μ M xitix the Krebs damping fluid of pH 7.4 in prepare.Before incubation, give this incubation buffering liquid oxygenation 5 minutes.Will be substantially to impinging upon 4 ℃ of following incubations 15 minutes to avoid any picked-up.Behind this incubation, filter by " unifilter 96 hole GFB Packard plates " and stop picked-up, with containing 25mM NaHCO
3Krebs damping fluid flushing with remove free [
3H]-Dopamine HCL.Use then and use scintillation solution microscint 0, the microplate scintillometer Topcount of Packard, Packard measures the radiant that is retained in the synaptosome on the unifilter corresponding to picked-up.Reference substance is GRB12909,10
-11M to 10
-6Test reference substance under 8 concentration in the M scope, to obtain IC
50Value.Referring to people such as Jankowsky, " Characterization ofsodium-dependent[
3H] GBR-12935 binding in brain:a radioligand forselective labeling of the dopamine transport complex, " J.Neurochem, 46:1272-1276 (1986).
The functional picked-up of norepinephrine is measured
Be used in Cerep and in 0.32M sucrose damping fluid, carry out the sign of norepinephrine uptake from the isolating synaptosome of male Wistar rat hypothalamus.The test compound and [
3H]-norepinephrine (0.1 μ Ci/ point) existence was following, made the norepinephrine of synaptosome (100 μ g albumen/point) picked-up labelled with radioisotope in 37 ℃ of following incubations 20 minutes.Experiment is carried out in deep hole.
Synaptosome and [
3H] norepinephrine containing 25mM NaHCO
3, 11mM glucose and 50 μ M xitix the Krebs damping fluid of pH 7.4 in prepare.Before incubation, give this incubation buffering liquid oxygenation 5 minutes.Will be substantially to impinging upon 4 ℃ of following incubations 20 minutes to avoid any picked-up.Behind this incubation, filter by " unifilter 96 hole GFB Packard plates " and stop picked-up, with containing 25mM NaHCO
3Krebs damping fluid flushing with remove free [
3H]-norepinephrine.Use then and use scintillation solution microscint 0, the microplate scintillometer Topcount of Packard, Packard measures the radiant that is retained in the synaptosome on the unifilter corresponding to picked-up.
Reference substance is an imipramine, 10
-11M to 10
-5The test reference substance is to obtain IC under 13 concentration in the M scope
50Value.Referring to Perovics and M ü ller, " Pharmacological profileof hypericum extract:effect on serotonin uptake by postsynapticreceptors; " Arzeim.Forsch./DrugRes., 45:1145-1148 (1995).The result that monoamine uptake is measured provides in table 1.
Table 1
The IC of compound of the present invention in functional monoamine uptake is measured
50Value (μ M)
| 5-HT | NE | DA | |
| Sertraline | 0.0016 | 0.31 | 0.048 |
| P | 0.0077 | 0.0096 | 0.0064 |
| Q | 0.088 | 0.035 | 0.019 |
| P+Q | 0.041 | 0.0088 | 0.0071 |
| Imipramine (standard) | 0.054/0.051 | - | - |
| Protriptyline (standard) | - | 0.0036 | - |
| GBR 12909 (standard) | - | - | 0.0028/0.0051/0.0034 |
/ independent repeatedly measurement
-＜50% suppresses
As shown in table 1, P renders a service the similar inhibition of neuron picked-up demonstration of NE, DA and 5HT with Q.At present, treatment people's the method for affective disorder is that selectivity suppresses single monoamine uptake mechanism or to two double inhibition of these molecule targets.The impartial neuron picked-up that suppresses NE, DA and 5HT provides the level by improving all monoamines in the brain simultaneously and has used identical dosage range to need not the ability that the independent medicine of titration is more effectively treated affective disorder and eating disorder for the clinician.At present with the CNS illness (for example OCD, ADD, ADHD, sexual dysfunction and drug abuse) of dopaminergic, norepinephrine or the treatment of blended DA-NE uptake inhibitor, the impartial neuron picked-up that suppresses NE, DA and 5HT provides by adding the more effectively treatment that serotonin can act on for those.
The monoamine uptake result of compd A-F provides in table 3.
Table 3
The IC of methane amide A-F in functional monoamine uptake test
50Value (μ M)
| N-[4-(3, the 4-dichlorophenyl)-1,2,3,4-naphthane-1-yl] methane amide | 5-HT | NE | DA |
| (R, S/S, R) trans=E=A+B | 7.5 | 0.40 | 0.51 |
| (R, R/S, S) cis=F=C+D | ------ | 3.9 | 0.53 |
| Pacify non-its ketone (positive control) | 0.611 | 0.294 | |
| Sertraline (positive control) | 0.0016 | 0.31 | 0.048 |
| Imipramine (standard) | 0.054/0.051 | ||
| Protriptyline (standard) | 0.0036 | ||
| GBR 12909 (standard) | 0.0028/0.0051/0.0034 |
/ independent repeatedly measurement
The space is represented＜50% inhibition
As shown in table 3, diastereo-isomerism cis and trans N-[4-(3, the 4-dichlorophenyl)-1,2,3,4-naphthane-1-yl] methane amide demonstrates the effectiveness of the useful inhibition neuronal uptake Dopamine HCL of treatment.Trans diastereomer also demonstrates the effectiveness of the inhibition neuronal uptake norepinephrine of appropriateness.
Table 4
Behavior in mouse baffle in the test (R, S/S, R) N-[4-(3, the 4-dichlorophenyl)-1,2,3,4-naphthane-1-yl] influence (N=10) of methane amide (E) intraperitoneal administration
| Compound | Vehicle | Imipramine 10mg/kg | E 10mg/kg | E 50mg/kg |
| The motionless time length (second) | 188 183 167 199 174 158 124 157 179 222 | 64 28 156 98 0 0 63 30 56 116 | 50 59 162 131 22 167 58 135 122 164 | 0 15 0 98 34 59 25 63 0 15 |
| Mean value ± sem | 175 8 | 61 16 | 107 | 31 10 |
| Dunnett | P＜ 0.05 | * | * | * |
Vehicle=1% methylcellulose gum
* represent to have significant difference P＜0.05 (Dunnett check) with respect to vehicle
Illustrative drug preparation of the present invention comprises:
P (or other compounds of the present invention) and silicon-dioxide dry mixing are mixed, add the first step part croscarmellose, and the further dry mixing of mixture is mixed.Add Magnesium Stearate, dry mixing mixes, and makes mixture flow through drum-type compactor and shredder.The gained dried particles is mixed compressing tablet with its excess-three kind composition.
P, lactose and W-Gum is even according to the mixed of above demonstration, then Magnesium Stearate to be sneaked in the gained powder, the back employing conventional equipment that sieves is packed in the suitable big or small dimeric hard gelatin capsule.Other dosage if necessary changes the capsule size and suitable preparing by changing filling weight.
The pharmaceutical preparation of methane amide A-F can prepare in a similar fashion.
Claims (42)
1. the compound of formula PQ:
2. according to the compound of claim 1, it is the compound of formula P or Q:
3. pharmaceutical composition, it comprises the compound of pharmaceutically acceptable carrier and claim 1 or 2.
4. according to the pharmaceutical composition of claim 3, it is tablet or Capsule form.
5. the compound that is selected from down group is used to prepare the purposes of the medicine of the central nervous system disorders for the treatment of the people:
(a) (1R, 4S)-trans-4-(3, the 4-dichlorophenyl)-1,2,3,4-tetrahydrochysene-naphthalidine
(b) (1S, 4R)-trans-4-(3, the 4-dichlorophenyl)-1,2,3,4-tetrahydrochysene-naphthalidine
(c) mixture of P and Q; And
(d) its pharmacologically acceptable salts.
6. according to the purposes of claim 5, wherein this central nervous system disorders is a mood disorder.
7. according to the purposes of claim 6, wherein this mood disorder is a dysthymia disorders.
8. according to the purposes of claim 5, wherein this central nervous system disorders is the illness relevant with anxiety.
9. purposes according to Claim 8 should the illness relevant with anxiety be an obsession wherein.
10. according to the purposes of claim 5, wherein this central nervous system disorders is a disruptive behavior disorder.
11. according to the purposes of claim 10, wherein this disruptive behavior disorder is one of the moving obstacle of attention shortage disease and attention deficit/how.
12. according to the purposes of claim 5, wherein this central nervous system disorders is a sexual dysfunction.
13. according to the purposes of claim 5, wherein this central nervous system disorders is drug abuse.
14. according to the purposes of claim 5, wherein this central nervous system disorders is an eating disorder.
15. according to the purposes of claim 5, wherein this central nervous system disorders is a premenstrual tension syndrome.
16. the compound that is selected from down group is used to prepare the purposes of the migrainous medicine that prevents the people:
(a) (1R, 4S)-trans-4-(3, the 4-dichlorophenyl)-1,2,3,4-tetrahydrochysene-naphthalidine
(b) (1S, 4R)-trans-4-(3, the 4-dichlorophenyl)-1,2,3,4-tetrahydrochysene-naphthalidine
(c) mixture of P and Q; And
(d) its pharmacologically acceptable salts.
17. be selected from down the compound of group:
(a) (1R, 4S)-trans-4-(3, the 4-dichlorophenyl)-1,2,3,4-tetrahydrochysene-naphthalidine
(b) (1S, 4R)-trans-4-(3, the 4-dichlorophenyl)-1,2,3,4-tetrahydrochysene-naphthalidine
(c) mixture of P and Q; And
(d) its pharmacologically acceptable salts, with
(e) D of treatment significant quantity
2Antagonist or its pharmacologically acceptable salts one are used from the purposes of preparation treatment people's psychotic medicine.
18. according to the purposes of claim 17, this D wherein
2Antagonist is an olanzapine.
19. be selected from down the compound of group:
(a) (1R, 4S)-trans-4-(3, the 4-dichlorophenyl)-1,2,3,4-tetrahydrochysene-naphthalidine
(b) (1S, 4R)-trans-4-(3, the 4-dichlorophenyl)-1,2,3,4-tetrahydrochysene-naphthalidine
(c) mixture of P and Q; And
(d) its pharmacologically acceptable salts, with
(e) the typical antipsychotic drug of treatment significant quantity or its pharmacologically acceptable salts one are used from the purposes of preparation treatment people's psychotic medicine.
20. be selected from down the compound of group:
(a) (1R, 4S)-trans-4-(3, the 4-dichlorophenyl)-1,2,3,4-tetrahydrochysene-naphthalidine
(b) (1S, 4R)-trans-4-(3, the 4-dichlorophenyl)-1,2,3,4-tetrahydrochysene-naphthalidine
(c) mixture of P and Q; And
(d) its pharmacologically acceptable salts, with
(e) atypical antipsychotic agents of treatment significant quantity or its pharmacologically acceptable salts one are used from the purposes of preparation treatment people's psychotic medicine.
21. be used to prepare 4-(3, the 4-dichlorophenyl)-1,2,3, the method for 4-tetrahydrochysene-naphthalidine, this method comprises:
(a) make 4-(3, the 4-dichlorophenyl)-3,4-dihydro-1-naphthalenone and excessive formic acid and formamide obtain N-[4-(3, the 4-dichlorophenyl)-1,2,3,4-naphthane-1-yl] methane amide; And
(b) with aqueous acid this N-[4-of hydrolysis (3, the 4-dichlorophenyl)-1,2,3,4-naphthane-1-yl] methane amide, obtain 4-(3, the 4-dichlorophenyl)-1,2,3,4-tetrahydrochysene-naphthalidine.
22. the compound of following formula:
23. according to the compound of claim 22, it is the compound of formula E:
24. according to the compound of claim 22, it is the compound of formula F:
25. according to the compound of claim 22, it is the compound of formula A, B, C or D:
26. a pharmaceutical composition, it comprises pharmaceutically acceptable carrier and according to each compound of claim 22 to 25.
27. according to the pharmaceutical composition of claim 26, it is tablet or Capsule form.
(28.N-[4-3, the 4-dichlorophenyl)-1,2,3,4-naphthane-1-yl] methane amide is used to prepare the purposes of the medicine of the central nervous system disorders for the treatment of the people.
29., this N-[4-(3, the 4-dichlorophenyl)-1,2,3 wherein, 4-naphthane-1-yl according to the purposes of claim 28] methane amide is selected from:
(a) (1S, 4R)-N-[4-(3, the 4-dichlorophenyl)-1,2,3,4-naphthane-1-yl] methane amide
(b) (1R, 4S)-N-[4-(3, the 4-dichlorophenyl)-1,2,3,4-naphthane-1-yl] methane amide
(c) (1S, 4S)-N-[4-(3, the 4-dichlorophenyl)-1,2,3,4-naphthane-1-yl] methane amide
(d) (1R, 4S)-N-[4-(3, the 4-dichlorophenyl)-1,2,3,4-naphthane-1-yl] methane amide
(e) mixture of A and B; And
(f) mixture of C and D.
30. according to the purposes of claim 28, wherein this central nervous system disorders is a mood disorder.
31. according to the purposes of claim 30, wherein this mood disorder is a dysthymia disorders.
32. according to the purposes of claim 28, wherein this central nervous system disorders is the illness relevant with anxiety.
33., should the illness relevant be obsession wherein with anxiety according to the purposes of claim 32.
34. according to the purposes of claim 28, wherein this central nervous system disorders is a disruptive behavior disorder.
35. according to the purposes of claim 34, wherein this disruptive behavior disorder is one of the moving obstacle of attention shortage disease and attention deficit/how.
36. according to the purposes of claim 28, wherein this central nervous system disorders is a sexual dysfunction.
37. according to the purposes of claim 28, wherein this central nervous system disorders is drug abuse.
38. according to the purposes of claim 28, wherein this central nervous system disorders is an eating disorder.
39. according to the purposes of claim 28, wherein this central nervous system disorders is a premenstrual tension syndrome.
(40.N-[4-3, the 4-dichlorophenyl)-1,2,3,4-naphthane-1-yl] methane amide is used to prepare the purposes of the migrainous medicine that prevents the people.
41. according to the purposes of claim 40 this N-[4-(3, the 4-dichlorophenyl)-1,2,3 wherein, 4-naphthane-1-yl] methane amide is selected from down group:
(a) (1S, 4R)-N-[4-(3, the 4-dichlorophenyl)-1,2,3,4-naphthane-1-yl] methane amide
(b) (1R, 4S)-N-[4-(3, the 4-dichlorophenyl)-1,2,3,4-naphthane-1-yl] methane amide
(c) (1S, 4S)-N-[4-(3, the 4-dichlorophenyl)-1,2,3,4-naphthane-1-yl] methane amide
(d) (1R, 4R)-N-[4-(3, the 4-dichlorophenyl)-1,2,3,4-naphthane-1-yl] methane amide
(e) mixture of A and B; And
(f) mixture of C and D.
(42.N-[4-3, the 4-dichlorophenyl)-1,2,3,4-naphthane-1-yl] methane amide is used to prepare the purposes of the psychotic medicine for the treatment of the people.
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