CN101336226A

CN101336226A - Substituted phenethylamines with serotoninergic and/or norepinephrinergic activity

Info

Publication number: CN101336226A
Application number: CNA200680052184XA
Authority: CN
Inventors: T·G·甘特; S·萨沙
Original assignee: Auspex Pharmaceuticals Inc
Current assignee: Auspex Pharmaceuticals Inc
Priority date: 2005-12-01
Filing date: 2006-11-30
Publication date: 2008-12-31
Anticipated expiration: 2026-11-30
Also published as: CN101336226B; ZA200805687B

Abstract

Chemical syntheses and medical uses of novel inhibitors of the uptake of monoamine neurotransmitters and pharmaceutically acceptable salts and prodrugs thereof, for the treatment and/or management of psychotropic disorders, anxiety disorder, generalized anxiety disorder, depression, post-traumatic stress disorder, obsessive-compulsive disorder, panic disorder, hot flashes, senile dementia, migraine, hepatopulmonary syndrome, chronic pain, nociceptive pain, neuropathic pain, painful diabetic retinopathy, bipolar depression, obstructive sleep apnea, psychiatric disorders, premenstrual dysphoric disorder, social phobia, social anxiety disorder, urinary incontinence, anorexia, bulimia nervosa, obesity, ischemia, head injury, calcium overload in brain cells, drug dependence, and/or premature ejaculation are described.

Description

Phenylethylamine with serotonin energy activity and/or the active replacement of norepinephrine energy

The cross reference of related application

[0001] the application requires the name of application on December 1st, 2005 to be called the U.S. Provisional Patent Application 60/741 of " SUBSTITUTEDPHENETHYLAMINES WITH SEROTONINERGIC AND/ORNOREPINEPHRINERGIC ACTIVITY ", No. 315, be called the U.S. Provisional Patent Application 60/841 of " SUBSTITUTED PHENETHYLAMINESWITH SEROTONINERGIC AND/OR NOREPINEPHRINERGIC ACTIVITY " with the name of on August 30th, 2006 application, No. 366 right of priority, these two applications all are incorporated herein by reference.

Technical field

[0002] the present invention relates to inhibitor and pharmacologically acceptable salts and its prodrug that the monoamine neurotransmitter absorbs, its chemosynthesis and this compounds are being used for the treatment of and/or are handling insane (psychotropic disorder), anxiety disorder, generalized anxiety disorder, dysthymia disorders, posttraumatic stress disorder, obsession, Phobias, hectic fever (hot flashes), senile dementia, migraine, liver lung syndromes, chronic pain, nociceptive pain, neurogenic pain, the pain diabetic retinopathy, the two-phase depression, obstructive sleep apnea, mental disorder, premenstrual dysphoric disorder, social phobia, social anxiety disorder, the urinary incontinence, apositia, bulimia nervosa, obesity, ischemic, head injury (head injury), the brain cell calcium overload, medicinal use in pharmacological dependence and/or the premature ejaculation.

Background technology

[0003] to decompose or help dissolving to be absorbed into the chemical substance and the nutritive substance of blood in order to attempt, human body has been expressed various enzymes (for example, the cytochrome P with described chemical substance and nutritive substance reaction ₄₅₀Enzyme or CYP, esterase, proteolytic enzyme, reductase enzyme, desaturase etc.) to produce new intermediate or metabolite.The metabolic reaction that some of medical compounds is the most general relates to hydrocarbon (C-H) key is oxidized to carbon-oxygen (C-O) key or carbon-to-carbon (C-C) π-key.The metabolite of gained can be stable or unsettled under physiological condition, and can have different basically pharmacokinetics, pharmacodynamics, acute and long term toxicity character (profile) with respect to parent compound.For most drug, described oxygenizement and finally causes every day repeatedly or the administration of high per daily dose normally fast.Therefore, the needs that have obvious and urgent this type of medicine of improvement.

[0004] chemical kinetics is the research to speed of reaction.In chemistry, activation energy E _ActIt is the energy that must apply system in order to cause specific chemical reaction.In other words, it is to make the particular chemical reaction that required minimum energy take place.If two suitably towards molecule have minimum essential energy, then will between them, react.In this process, the out-shell electron of each molecule will produce repulsion.Overcome this repulsion and need intake (being activation energy): be i.e. the translation energy of each molecule, vibrational energy and rotation energy; Described energy is produced by the heat energy of system.If can obtain enough energy, molecule just can obtain to cause the rearrangement of key and form novel substance the degree of approach (proximity) and towards.

[0005] relation of activation energy and speed of reaction can be quantized by the Arrhenius equation, and it has been described has enough molecules that can overcome the energy of energy barrier---and be that energy equals activation energy E at least _ActMolecule---part changes k=Ae exponentially with the activation and the ratio of heat energy ^-Eact/RTIn this equation, RT is the mean vol of the heat energy of molecule when having specified temp T, and wherein R is a molecular gas constant, and k is a reaction rate constants, A (frequency factor) is the specific constant for each reaction, and it depends on that molecule will be with the correct probability towards collision.

[0006] transition state in the reaction is that transient state along reaction path is (10 ^-14Second order of magnitude), during this period, original key extends to its limit.According to definition, the activation energy E of reaction _ActIt is the required energy of transition state that reaches this reaction.The reaction that relates to a plurality of steps must have a plurality of transition states.In this case, the activation energy of reaction equals the energy difference between reactant and the least stable transition state.In case reached transition state, thereby molecule can restore and forms the primary reactant again or form new key and produce product.Because two kinds of approach, forward and restore, all cause the release of energy, therefore described two minutes (dichotomy) is possible.Catalyzer causes the activation energy of transition state to promote reaction process by reduction.Enzyme is the example that reduces the biological catalyst that reaches specific transitions attitude institute energy requirement.

[0007] hydrocarbon key is covalent chemical bond in essence.Have similar electronegative atom and share its some valence electron when two, form described key when making described atom maintain together reactive force thereby produced.This reactive force or bonding strength can be quantized, and are expressed as the units of energy, and be same, and the covalent linkage between the various atoms can be according in order to destroy key or to separate two atoms and must classify to the energy size that key applies.

[0008] bonding strength is directly proportional with the absolute value of the ground state vibrational energy of key.This vibrational energy is also referred to as the residual vibration energy, and it depends on the quality of the atom that forms key.The absolute value of residual vibration energy increases along with the increase of one of atom that forms key or both quality.Because the quality of deuterium (D) is the twice of hydrogen (H), so the C-D key is stronger than corresponding C-H key.Compound with C-D key is at H ₂Ad infinitum stable usually among the O, and be widely used in Isotope Research.If c h bond is in the rate determining step of chemical reaction (promptly have the highest transition state can step) fracture, then deuterium will cause the reduction of speed of reaction to the replacement of this hydrogen, thereby reaction process will be slowed down.This phenomenon be called the deuterium kinetic isotope effect (Deuterium Kinetic Isotope Effect, DKIE), its can about 1 (the plain effect of No Parity) to very large numerical example as 50 or bigger scope in.This means when deuterium replaces hydrogen slow 50 times or more times of reaction meeting.High DKIE value can be partly that it is the result of uncertainty principle owing to be called the phenomenon of tunnel effect.Tunnel effect is owing to the small volume of hydrogen atom, and produces owing to the transition state that relates to proton can form under the situation that lacks required activation energy sometimes.Deuterium is bigger, and the probability that produces above-mentioned phenomenon statistically is much smaller.Replace stronger key with tritium replacement hydrogen even formation than deuterium, and produce bigger in number isotopic effect.

[0009] deuterium (D) was found by Urey in 1932, and it is the stable and inactive isotropic substance of hydrogen.It is the first kind of isotropic substance that comes out with pure isolated in form from its element, and quality is the twice of hydrogen, take up an area of hydrogen (in this usage, being meant all hydrogen isotopes) on the ball total mass about 0.02%.When two deuteriums combine with an oxygen, form water-d2 (D ₂O or " heavy water ").D ₂The outward appearance of O and taste and H ₂O is similar, but has different physical propertiess.It solidifies under 3.79 ℃ 101.41 ℃ of boilings down.Its thermal capacitance, Heat of fusion, vaporization heat and entropy all are higher than H ₂O.It also has higher viscosity, but is not so good as H as solvent ₂O is effective.

[0010] tritium (T) is the radio isotope of hydrogen, and it is used for scientific research, fusion reactor, neutron producer and radiopharmaceuticals.Tritium is mixed meeting produce the light source that continues with phosphorescent substance (phosphor), this is a kind of technology of generally using in wrist-watch, compasses, rifle scope and outlet sign.It 1934 by Rutherford, Oliphant and Harteck find, and as Millikan's rays and H ₂Natural generation in upper atmosphere during molecular reaction.Tritium is to have 2 neutrons and nucleidic mass near 3 hydrogen atom in nucleus.It exists so that extremely low concentration is natural in environment, is the liquid T as colorless and odorless the most at large ₂O exists.Tritium decay slowly (transformation period=12.3 year) and emission can not penetrate the outer field low energy beta particle of human skin.The main harm that isotropic substance is relevant is to expose in the body therewith, yet it must just can be caused significant health threat by huge uptake.

[0011] when with pure D ₂When O gave rodent, it was absorbed easily and reaches equilibrium level, described equilibrium level be generally the animal picked-up concentration about 80 percent.The amount that causes the required deuterium of toxicity is very high.When 0 to similar 15% the body moisture content by D ₂When O replaces, animal or health, but can not put on weight with contrast (being untreated) group equally soon.15 to 20%D ₂During O, animal becomes and is easy to excitement.20 to 25%D ₂During O, it is excited that animal becomes, to such an extent as to when they are upset, enter frequent spasticity.Skin injury, claw and mouth and nose ulcer and tail necrosis appear.The animal aggressiveness as rich as Croesus that also becomes; It is almost out of control that buck becomes.At 30%D ₂During O, feed of animal refusal and stupor.Their body weight sharply descends and its metabolic rate is reduced to far below normal value, takes place dead when 30 to 35% replacements.Unless previous body weight more than 30 percent because D ₂O and losing, otherwise these influences are reversible.Research also shows D ₂The application of O can delay the growth of cancer cell, and improves the cytotoxicity of some antineoplastic agent.

[0012] deuterate of medicine had before obtained proof to improve pharmacokinetics (PK), pharmacodynamics (PD) and toxicity character in the medicine of some kind.For example, DKIE is used as the liver toxicity that reduces fluothane, infer its be by the restricted activity component for example the generation of trifluoroacetyl chloride realize.Yet this method may not be suitable for all medicament categories.For example, deuterium mixes and can cause metabolism conversion (metabolic switching), itself in addition can produce and have faster from activation I phase enzyme (activatingPhase I enzyme) (cytochrome P for example ₄₅₀The oxidisability intermediate of dissociation rate 3A4) (off-rate).The notion of metabolism conversion shows, when xenogenesis thing (xenogens) during by I phase enzyme chelating (sequester), can chemical reaction (for example oxidizing reaction) before momently with various conformations in conjunction with and recombine (rebind).This judgement has obtained the support of the miscellaneous character of the huge relatively size of binding site in many I phase enzymes and many metabolic reactions.The metabolism conversion can cause the known metabolite of different ratios and new metabolite potentially.This new metabolisming property can cause more or less toxicity.This hidden danger (pitfall) is unconspicuous, and so far also not to the priori (priori) of the sufficient prediction of any medicament categories.

[0013] according to conjecture, Venlafaxine (

) drug effect mainly be because its absorption again that suppresses serotonin in neuronal cell also suppresses the resorbent ability of norepinephrine potentially.The latter it is said and only has an effect when high dosage.Described medicine is sold with the form of 50/50 racemic mixture of R-and S-enantiomorph.Broad research the mechanism of action of this medicine.

Venlafaxine

[0014] benefit of this medicine and defective were also discussed widely.In these defectives some can be traced back to the relevant phenomenon of some metabolism.Venlafaxine is multiple metabolite by oxidisability and conjugation Degradation and Transformation in vivo, wherein at least 48 kinds of existing document records.Main metabolite comprises and causing in oxygen and/or nitrogen center demethylation and cyclohexyl ring hydroxylated many I phases metabolism and the important II phase metabolism that comprises the glucoside acidifying of hydroxylated metabolite.Because described medicine is comprised the cytochrome P of CYP 2C19 and 2D6 ₄₅₀The isozyme metabolism of expressing polymorphically, and because it can be used as the inhibitor of CYP2D6, so its application in the compound medication must be complicated, and the potential side effect is arranged.These CYP relate to many usually and the metabolism of the Venlafaxine medicine of writing out a prescription simultaneously.This phenomenon has increased between the patient difference for the compound medication.For the example of the active demand that improves be delivered, at CYP2D6 allelotrope or lack observed patient's differences among " slow inactivation " (poor metabolizer) patient that CYP2D6 expresses fully with defective.These patients can not be converted into Venlafaxine the metabolite O-desmethylvenlafaxine (O-desmethylvenlafaxine) of its equal usefulness.With respect to most of serotonin reuptake inhibithors, Venlafaxine also has short shortcoming of transformation period.The transformation period of Venlafaxine in human body is about 5 hours, and the Ti of its active metabolite _{/ 2}Be about 11 hours.Because its pharmacology transformation period is 5-11 hour, if medicine is stopped using suddenly, the patient who then takes Venlafaxine has the material risk of suffering from SRI withdrawal symptom (SRIdiscontinuation symptoms).In addition, in order to overcome short defective of its transformation period, described medicine must be taken 2 times (BID) or 3 times (TID) every day, and this has increased the possibility that the patient does not comply with (incompliance) and drug withdrawal (discontinuance).Transformation period 〉=24 of most of other serotonin reuptake inhibithors (SRIs) hour.For this compounds, most of clinicians think that 24-72 hour transformation period is an ideal.Therefore, for the monoamine reuptake inhibithors for example the improvement of the exploitation of paroxetine (paroxetine) have obviously and exigence.

Summary of the invention

[0015] herein disclosed is the compound of formula 1:

Formula 1

Or the mixture of the mixture of the mixture of its single enantiomer, (+)-enantiomorph and (-)-enantiomorph, about 90 weight % or higher (-)-enantiomorph and about 10 weight % or lower (+)-enantiomorph, about 90 weight % or higher (+)-enantiomorph and about 10 weight % or lower (-)-enantiomorph, independent diastereomer, mixture or its pharmacologically acceptable salts, solvate or the prodrug of diastereomer, wherein:

R ₁, R ₂, R ₃, R ₄, R ₅, R ₆, R ₇, R ₈, R ₉, R ₁₀, R ₁₁, R ₁₂, R ₁₃, R ₁₄, R ₁₅, R ₁₆, R ₁₇And R ₁₈Be independently selected from hydrogen and deuterium;

R ₁₉, R ₂₀And R ₂₁Be independently selected from-CH ₃,-CH ₂D ,-CHD ₂With-CD ₃

Condition is that the compound of formula 1 comprises at least one D atom; And condition is that deuterium enriched degree is at least about 1% in the compound of formula 1.

[0016] this paper also discloses pharmaceutical composition, described pharmaceutical composition comprises formula 1 compound, the single enantiomer of formula 1 compound, the mixture of (+)-enantiomorph and (-)-enantiomorph, the mixture of about 90 weight % or higher (-)-enantiomorph and about 10 weight % or lower (+)-enantiomorph, the mixture of about 90 weight % or higher (+)-enantiomorph and about 10 weight % or lower (-)-enantiomorph, the independent diastereomer of formula 1 compound, the mixture of diastereomer, or its pharmacy acceptable salt, solvate or prodrug, and pharmaceutically acceptable carrier.

[0017] in addition, herein disclosed is and bring out, adjust and/or regulate the resorbent method of monoamine neurotransmitter that comprises serotonin and/or norepinephrine.

[0018] in addition, herein disclosed is the method for treatment mammalian object, described mammalian object has, under a cloud have or tend to have disease or illness, for example is selected from anxiety disorder, generalized anxiety disorder, dysthymia disorders, posttraumatic stress disorder, obsession, Phobias, hectic fever, senile dementia, migraine, liver lung syndromes, chronic pain, nociceptive pain, neurogenic pain, the pain diabetic retinopathy, the two-phase depression, obstructive sleep apnea, mental disorder, premenstrual dysphoric disorder, social phobia, social anxiety disorder, the urinary incontinence, apositia, bulimia nervosa, obesity, ischemic, head injury, the brain cell calcium overload, the disease of pharmacological dependence and/or premature ejaculation or illness.

Embodiment

[0019] some monoamine reuptake inhibithors is known in this area, and provides herein.Venlafaxine (

) be exactly a kind of this compounds.The hydrocarbon key of Venlafaxine comprises the natural distributed of hydrogen isotope, promptly ¹H or protium (about 99.9844%), ²H or deuterium (about 0.0156%) and ³H or tritium are (per 10 ¹⁸In the scope of about 0.5 to 67 the tritium atom of individual protium atom).With respect to the compound with natural horizontal deuterium, the increase that deuterium mixes level causes detectable kinetic isotope effect (KIE), and it can influence pharmacokinetics, pharmacology and/or the toxicology parameter of described monoamine reuptake inhibithors.The new analogue that designs and synthesize described monoamine reuptake inhibithors by chemically modified has been described in aspects more of the present invention disclosed herein, and described conditioning agent and/or be used for the new way of hydrocarbon key derivative of the precursor of synthetic described conditioning agent.The suitable modification that makes some hydrocarbon key become carbon deuterium key may produce with the monoamine reuptake inhibithors of heterotope enrichment and compare, and has the novel monoamine reuptake inhibithors that unexpected and non-obvious pharmacokinetics, pharmacology and toxicology character are improved.The present invention relies on wisdom and successfully chemical kinetics is applied to medicinal design.The deuterium level of mixing of The compounds of this invention is significantly higher than natural horizontal, and is enough to cause at least a substantive improvement the described herein.

[0020] makes that the information of the PD might advisably deuterium be used to solve Venlafaxine and absorption, distribution, metabolism, drainage and toxicology (ADMET) defective is known.For example, a plurality of sites on the cyclohexyl ring of present known N-methyl group, single O-methyl and Venlafaxine are cytochrome P ₄₅₀Metabolic site.The toxicity of the metabolite of all generations all is unknown.In addition, because the CYP that expresses polymorphically for example 2C19 and 2D6 oxidation Venlafaxine, and because Venlafaxine suppresses the CYP2D6 that expresses polymorphically, therefore stop this interaction will reduce difference between the patient, reduce the interaction of drug-drug, increase T _1/2, reduce necessary C _Max, and improve some other ADMET parameters.For example the transformation period of the parent drug of Venlafaxine is in 3-7 hour scope.The metabolite of its equal usefulness, the transformation period average out to of O-demethylation Venlafaxine 11 hours.Can use multiple deuterate scheme a) to change the ratio of active metabolite, b) reduce or eliminate unwanted metabolite, c) increase the transformation period and/or the d of parent drug) increase the transformation period of active metabolite and for the compound medication produces more efficient drug and safer medicine, no matter and whether the compound medication is intentionally.Can suppress the resorbent level of norepinephrine in order to reach, usually the Venlafaxine of administered with high dose prescription.Unfortunately, high dosage is also related with hypertension.Because these phenomenons by medicine contact rather than the contact of pharmacology target, therefore theoretically, thereby can allow reducing C by increasing the transformation period _MaxScope in administration, thereby and can avoid causing and cause hypertensive mechanism and these two kinds of phenomenons are separated.Further illustrate this point, known Venlafaxine demonstrates linear kinetics at the low side (75mg/ days) of dosage range, and demonstrating nonlinear kinetics in high-end (about 400mg/ days) of dosage range, this is because purge mechanism (clearance mechanism) saturated.This non-linear generation rising and the Venlafaxine dose response curve of non-flat forms.The deuterate approach has the metabolic great potential of slowing down by before saturated mechanism, thereby allows to manifest in whole dosage range (it also can reduce by the present invention) linear, more predictable ADMET response.This has caused the difference between the patient of the type that can cause the hypertension effect still less.

[0021] deuterate analogue of the present invention has the benefit of the medicine that keeps the heterotope enrichment uniquely, significantly increases transformation period (T simultaneously _1/2), reduce the maximum plasma concentration (C of subliminal dose (MED) _MaxThereby), reduce effective dose and reduce the relevant toxicity of non-mechanism and/or reduce the potentiality of the possibility of drug-drug interactions.Because the being easy to get property in the cheapness of deuteration agents source and the potentiality of previously mentioned reduction therapeutic dose, so these medicines also have the great potential of reduce cost (COG).The inventor finds, separately the deuterate of (methylenedioxy) base section and/or the deuterate of (methylenedioxy) base section add be found since the deuterate in metabolism conversion and unsettled other sites for realizing that some purpose disclosed herein is effective.

[0022] thereby, on the one hand, the invention provides compound with structural formula 1:

Formula 1

[0023] compound of the present invention has the benefit of the monoamine reuptake inhibithors that keeps the heterotope enrichment uniquely, significantly changes transformation period (T simultaneously _1/2), reduce the maximum plasma concentration (C of subliminal dose (MED) _MaxThereby), reduce effective dose and reduce the relevant toxicity of non-mechanism and/or reduce the potentiality of the possibility of drug-drug interactions.Compare with the monoamine reuptake inhibithors of heterotope enrichment, owing to have the potentiality that reduce therapeutic dose, so these medicines also have the potentiality of reduce cost (COG).In a word, the present invention has significantly improved the many aspects of ADMET of the monoamine reuptake inhibithors of heterotope enrichment.

[0024] in certain embodiments, medicine of the present invention will make the patient be exposed to the most about 0.000005% D ₂O (also can be expressed as about 0.00001%DHO).This amount is the D of naturally occurring background level in the circulation ₂The sub-fraction of O (or DHO).When all C-D keys of deuterium enriched medicine will obtain this maximum exposure limits during all by metabolism.Yet because DKIE, before described deuterium enriched medicine was drained from object, the C-D key of most of (even not being whole) deuterium enriched medicine will can be by metabolism.Therefore, the patient is for D ₂The actual exposed of O will be much smaller than above-mentioned greatest limit.Discuss as mentioned, in animal, demonstrate and cause toxic D ₂The O level will be much larger than because the greatest limit of the exposure of deuterium enriched medicine.Therefore, deuterium enriched compound of the present invention can not cause any extra toxicity because of using deuterium.

[0025] " deuterium enriched degree " be meant molecule to locating point on the per-cent that mixes of the deuterium of instead of hydrogen atom.For example, 1% deuterium enriched degree means that in given sample, the specific site of 1% molecule is occupied by deuterium.Because it is about 0.0156% that naturally occurring deuterium is distributed as, the deuterium enriched degree in the starting material synthetic compound that uses non-enrichment is about 0.0156%.In certain embodiments, the deuterium enriched degree in the The compounds of this invention is greater than 10%.In other embodiments, the deuterium enriched degree in the The compounds of this invention is greater than 20%.In other embodiments, the deuterium enriched degree in the The compounds of this invention is greater than 50%.In certain embodiments, the deuterium enriched degree in the The compounds of this invention is greater than 70%.In certain embodiments, the deuterium enriched degree in the The compounds of this invention is greater than 90%.

[0026] " isotope enrichment " be meant molecule to locating point on the more not general isotropic substance of a certain element substitute the more general isotopic per-cent that mixes of this element." the heterotope enrichment " is meant wherein various isotopic per-cents and the essentially identical molecule of naturally occurring per-cent.

[0027] in certain embodiments, formula 1 compound comprises (+)-enantiomorph of (-)-enantiomorph of about 60 weight % or higher compound and about 40 weight % or lower compound.In certain embodiments, formula 1 compound comprises (+)-enantiomorph of (-)-enantiomorph of about 70 weight % or higher compound and about 30 weight % or lower compound.In certain embodiments, formula 1 compound comprises (+)-enantiomorph of (-)-enantiomorph of about 80 weight % or higher compound and about 20 weight % or lower compound.In certain embodiments, formula 1 compound comprises (+)-enantiomorph of (-)-enantiomorph of about 90 weight % or higher compound and about 10 weight % or lower compound.In certain embodiments, formula 1 compound comprises (+)-enantiomorph of (-)-enantiomorph of about 95 weight % or higher compound and about 5 weight % or lower compound.In certain embodiments, formula 1 compound comprises (+)-enantiomorph of (-)-enantiomorph of about 99 weight % or higher compound and about 1 weight % or lower compound.

[0028] in certain other embodiments, formula 1 compound comprises (-)-enantiomorph of (+)-enantiomorph of about 60 weight % or higher compound and about 40 weight % or lower compound.In certain embodiments, formula 1 compound comprises (-)-enantiomorph of (+)-enantiomorph of about 70 weight % or higher compound and about 30 weight % or lower compound.In certain embodiments, formula 1 compound comprises (-)-enantiomorph of (+)-enantiomorph of about 80 weight % or higher compound and about 20 weight % or lower compound.In certain embodiments, formula 1 compound comprises (-)-enantiomorph of (+)-enantiomorph of about 90 weight % or higher compound and about 10 weight % or lower compound.In certain embodiments, formula 1 compound comprises about 95% or (+)-enantiomorph of higher compound and about 5% or (-)-enantiomorph of lower compound.In certain embodiments, formula 1 compound comprises about 99% or (-)-enantiomorph of (+)-enantiomorph of higher compound and about 1 weight % or lower compound.

[0029] in certain embodiments, R ₁Be hydrogen.In other embodiments, R ₂Be hydrogen.In certain embodiments, R ₃Be hydrogen.In other embodiments, R ₄Be hydrogen.In other embodiments, R ₅Be hydrogen.In other embodiments, R ₆Be hydrogen.In other embodiments, R ₇Be hydrogen.In other embodiments, R ₈Be hydrogen.In other embodiments, R ₉Be hydrogen.In other embodiments, R ₁₀Be hydrogen.In other embodiments, R ₁₁Be hydrogen.In certain embodiments, R ₁₂Be hydrogen.In other embodiments, R ₁₃Be hydrogen.In other embodiments, R ₁₄Be hydrogen.In other embodiments, R ₁₅Be hydrogen.In other embodiments, R ₁₆Be hydrogen.In other embodiments, R ₁₇Be hydrogen.In other embodiments, R ₁₈Be hydrogen.

[0030] in certain embodiments, R ₁It is deuterium.In other embodiments, R ₂It is deuterium.In certain embodiments, R ₃It is deuterium.In other embodiments, R ₄It is deuterium.In other embodiments, R ₅It is deuterium.In other embodiments, R ₆It is deuterium.In other embodiments, R ₇It is deuterium.In other embodiments, R ₈It is deuterium.In other embodiments, R ₉It is deuterium.In other embodiments, R ₁₀It is deuterium.In other embodiments, R ₁₁It is deuterium.In certain embodiments, R ₁₂It is deuterium.In other embodiments, R ₁₃It is deuterium.In other embodiments, R ₁₄It is deuterium.In other embodiments, R ₁₅Be deuterium, in other embodiments, R ₁₆It is deuterium.In other embodiments, R ₁₇It is deuterium.In other embodiments, R ₁₈It is deuterium.

[0031] in certain embodiments, R ₁Not hydrogen.In other embodiments, R ₂Not hydrogen.In certain embodiments, R ₃Not hydrogen.In other embodiments, R ₄Not hydrogen.In other embodiments, R ₅Not hydrogen.In other embodiments, R ₆Not hydrogen.In other embodiments, R ₇Not hydrogen.In other embodiments, R ₈Not hydrogen.In other embodiments, R ₉Not hydrogen.In other embodiments, R ₁₀Not hydrogen.In other embodiments, R ₁₁Not hydrogen.In certain embodiments, R ₁₂Not hydrogen.In other embodiments, R ₁₃Not hydrogen.In other embodiments, R ₁₄Not hydrogen.In other embodiments, R ₁₅Not hydrogen.In other embodiments, R ₁₆Not hydrogen.In other embodiments, R ₁₇Not hydrogen.In other embodiments, R ₁₈Not hydrogen.

[0032] in certain embodiments, R ₁It or not deuterium.In other embodiments, R ₂It or not deuterium.In certain embodiments, R ₃It or not deuterium.In other embodiments, R ₄It or not deuterium.In other embodiments, R ₅It or not deuterium.In other embodiments, R ₆It or not deuterium.In other embodiments, R ₇It or not deuterium.In other embodiments, R ₈It or not deuterium.In other embodiments, R ₉It or not deuterium.In other embodiments, R ₁₀It or not deuterium.In other embodiments, R ₁₁It or not deuterium.In certain embodiments, R ₁₂It or not deuterium.In other embodiments, R ₁₃It or not deuterium.In other embodiments, R ₁₄It or not deuterium.In other embodiments, R ₁₅It or not deuterium.In other embodiments, R ₁₆It or not deuterium.In other embodiments, R ₁₇It or not deuterium.In other embodiments, R ₁₈Not hydrogen.

[0033] in other embodiments, R ₁₉Be-CH ₃In other embodiments, R ₂₀Be-CH ₃In other embodiments, R ₂₁Be-CH ₃

[0034] in other embodiments, R ₁₉Be-CD ₃In other embodiments, R ₂₀Be-CD ₃In other embodiments, R ₂₁Be-CD ₃

[0035] in other embodiments, R ₁₉Be not-CH ₃In other embodiments, R ₂₀Be not-CH ₃In other embodiments, R ₂₁Be not-CH ₃

[0036] in other embodiments, R ₁₉Be not-CD ₃In other embodiments, R ₂₀Be not-CD ₃In other embodiments, R ₂₁Be not-CD ₃

[0037] in another embodiment of the present invention, provide and be used in the intestines, venoclysis, oral, parenteral, the pharmaceutical composition of part and/or dosing eyes, described pharmaceutical composition are included in pharmacy acceptable auxiliary (vehicle), carrier (carrier), thinner, or formula 1 compound in vehicle or its combination, the single enantiomer of formula 1 compound, the mixture of (+)-enantiomorph and (-)-enantiomorph, the mixture of about 90 weight % or higher (-)-enantiomorph and about 10 weight % or lower (+)-enantiomorph, the mixture of about 90 weight % or higher (+)-enantiomorph and about 10 weight % or lower (-)-enantiomorph, the independent diastereomer of formula 1 compound, the mixture of diastereomer, or its pharmacologically acceptable salts, at least a in solvate or the prodrug.

[0038] in another embodiment of the present invention, the pharmaceutical composition that is used for the treatment of the illness that relates to the resorbent inhibition of monoamine is provided, and described pharmaceutical composition is included in the pharmacy acceptable auxiliary, carrier, thinner, formula 1 compound in vehicle or its combination, the single enantiomer of formula 1 compound, the mixture of (+)-enantiomorph and (-)-enantiomorph, the mixture of about 90 weight % or higher (-)-enantiomorph and about 10 weight % or lower (+)-enantiomorph, the mixture of about 90 weight % or higher (+)-enantiomorph and about 10 weight % or lower (-)-enantiomorph, the independent diastereomer of formula 1 compound, the mixture of diastereomer, or its pharmacologically acceptable salts, at least a in solvate or the prodrug.

[0039] in another embodiment of the present invention, provide the adjusting monoamine resorbent method, described method is used formula 1 compound or composition, the single enantiomer of formula 1 compound, the mixture of (+)-enantiomorph and (-)-enantiomorph, the mixture of about 90 weight % or higher (-)-enantiomorph and about 10 weight % or lower (+)-enantiomorph, the mixture of about 90 weight % or higher (+)-enantiomorph and about 10 weight % or lower (-)-enantiomorph, the independent diastereomer of formula 1 compound, the mixture of diastereomer, or its pharmacologically acceptable salts, in solvate or the prodrug one or more.

[0040] in another embodiment of the present invention, provide formula 1 compound with one of following structure:

Or the mixture of the mixture of the mixture of its single enantiomer, (+)-enantiomorph and (-)-enantiomorph, about 90 weight % or higher (-)-enantiomorph and about 10 weight % or lower (+)-enantiomorph, about 90 weight % or higher (+)-enantiomorph and about 10 weight % or lower (-)-enantiomorph, independent diastereomer, mixture or its pharmacologically acceptable salts, solvate or the prodrug of diastereomer.

[0041] the invention is intended to comprise all isotropic substances of all atoms that appear in the The compounds of this invention.Isotropic substance comprises that those ordination number are identical but atom that total mass number is different.As general example rather than restriction, the isotropic substance of hydrogen comprises deuterium (D) and tritium (T).The isotropic substance of carbon comprises ¹³C and ¹⁴C.The isotropic substance of sulphur comprises ³²S, ³³S, ³⁴S and ³⁶S.The isotropic substance of nitrogen comprises ¹⁴N and ¹⁵N.The isotropic substance of oxygen comprises ¹⁶O, ¹⁷O and ¹⁸O.

[0042] hydrogen isotope can be incorporated in the organic molecule by the synthetic technology of using deuteration agents, mix thus than being scheduled to, and/or be incorporated in the organic molecule by switching technology, wherein mix than determining by equilibrium conditions, and can be according to the reaction conditions alterable height.Wherein tritium or deuterium synthetic technology direct and that insert specifically high tritium or D abundance can be produced, but the restriction of required chemical can be subjected to by tritiate or deuteration agents with known isotopic content.In addition, the fierce degree according to the building-up reactions that adopts can change the molecule that is labeled.On the other hand, switching technology may produce less tritium or deuterium mixes, and usually isotropic substance can be distributed on a plurality of sites of molecule, but has the advantage that does not need independent synthesis step, and it is less to destroy the possibility of structure of the molecule that is labeled.

[0043] in another aspect of this invention in, the treatment mammalian object is provided, people's method particularly, described mammalian object is under a cloud to be had or tends to have resorbent disease of the monoamine of relating to or illness, and described method comprises formula 1 compound to the mammalian object drug treatment significant quantity of needs, the single enantiomer of formula 1 compound, the mixture of (+)-enantiomorph and (-)-enantiomorph, the mixture of about 90 weight % or higher (-)-enantiomorph and about 10 weight % or lower (+)-enantiomorph, the mixture of about 90 weight % or higher (+)-enantiomorph and about 10 weight % or lower (-)-enantiomorph, the independent diastereomer of formula 1 compound, the mixture of diastereomer, or its pharmacologically acceptable salts, solvate or prodrug.

[0044] in certain embodiments, dosing step in the aforesaid method comprises the The compounds of this invention of administration in some composition, for example, independent tablet, pill, capsule, be used for intravenous independent solution, independent drinkable solution, independent dragee preparation or obedient agent etc., wherein the amount of administration be about 0.5 milligram to 400 milligrams every day total dose.

[0045] in another aspect of this invention in, provide and be used for the treatment of mammalian object, people's method particularly, described mammalian object is under a cloud to be had or tends to have resorbent disease of the monoamine of relating to or illness, described method comprises the monoamine reuptake inhibithors to the mammalian object drug treatment significant quantity of needs, described monoamine reuptake inhibithors comprises formula 1 compound, the single enantiomer of formula 1 compound, the mixture of (+)-enantiomorph and (-)-enantiomorph, the mixture of about 90 weight % or higher (-)-enantiomorph and about 10 weight % or lower (+)-enantiomorph, the mixture of about 90 weight % or higher (+)-enantiomorph and about 10 weight % or lower (-)-enantiomorph, the independent diastereomer of formula 1 compound, the mixture of diastereomer, or its pharmacologically acceptable salts, at least a in solvate or the prodrug, compare with the compound of heterotope enrichment with realization, in the process of the above-mentioned disease of treatment, reduce described compound or the interindividual variation of its metabolite in blood plasma level.

[0046] in certain embodiments, compare with the compound of heterotope enrichment, The compounds of this invention or the interindividual variation of its metabolite in blood plasma level have reduced greater than about 5%.In other embodiments, compare with the compound of heterotope enrichment, The compounds of this invention or the interindividual variation of its metabolite in blood plasma level have reduced greater than about 10%.In other embodiments, compare with the compound of heterotope enrichment, The compounds of this invention or the interindividual variation of its metabolite in blood plasma level have reduced greater than about 20%.In other embodiments, compare with the compound of heterotope enrichment, The compounds of this invention or the interindividual variation of its metabolite in blood plasma level have reduced greater than about 30%.In other embodiments, compare with the compound of heterotope enrichment, The compounds of this invention or the interindividual variation of its metabolite in blood plasma level have reduced greater than about 40%.In other embodiments, compare with the compound of heterotope enrichment, The compounds of this invention or the interindividual variation of its metabolite in blood plasma level have reduced greater than about 50%.At Rapid Communications in Mass Spectrometry 2005,19 (14), measure by the method described in the 1943-1950 by people such as Li for the blood plasma level of The compounds of this invention or its metabolite, and it all is incorporated herein by reference at this.

[0047] in another aspect of this invention in, provide and be used for the treatment of mammalian object, people's method particularly, described mammalian object is under a cloud to be had or tends to have resorbent disease of the monoamine of relating to or illness, described method comprises the monoamine reuptake inhibithors to the mammalian object drug treatment significant quantity of needs, described monoamine reuptake inhibithors comprises formula 1 compound, the single enantiomer of formula 1 compound, the mixture of (+)-enantiomorph and (-)-enantiomorph, the mixture of about 90 weight % or higher (-)-enantiomorph and about 10 weight % or lower (+)-enantiomorph, the mixture of about 90 weight % or higher (+)-enantiomorph and about 10 weight % or lower (-)-enantiomorph, the independent diastereomer of formula 1 compound, the mixture of diastereomer, or its pharmacologically acceptable salts, at least a in solvate or the prodrug, compare with the compound of heterotope enrichment realizing, increase every dose unit described compound average plasma levels or reduce the average plasma levels of at least a metabolite of the described compound of every dose unit.

[0048] in certain embodiments, compare with the compound of heterotope enrichment, the average plasma levels of The compounds of this invention has increased greater than about 5%.In other embodiments, compare with the compound of heterotope enrichment, the average plasma levels of The compounds of this invention has increased greater than about 10%.In other embodiments, compare with the compound of heterotope enrichment, the average plasma levels of The compounds of this invention has increased greater than about 20%.In other embodiments, compare with the compound of heterotope enrichment, the average plasma levels of The compounds of this invention has increased greater than about 30%.In other embodiments, compare with the compound of heterotope enrichment, the average plasma levels of The compounds of this invention has increased greater than about 40%.In other embodiments, compare with the compound of heterotope enrichment, the average plasma levels of The compounds of this invention has increased greater than about 50%.

[0049] in certain embodiments, compare with the compound of heterotope enrichment, the average plasma levels of the metabolite of The compounds of this invention has reduced greater than about 5%.In other embodiments, compare with the compound of heterotope enrichment, the average plasma levels of the metabolite of The compounds of this invention has reduced greater than about 10%.In other embodiments, compare with the compound of heterotope enrichment, the average plasma levels of the metabolite of The compounds of this invention has reduced greater than about 20%.In other embodiments, compare with the compound of heterotope enrichment, the average plasma levels of the metabolite of The compounds of this invention has reduced greater than about 30%.In other embodiments, compare with the compound of heterotope enrichment, the average plasma levels of the metabolite of The compounds of this invention has reduced greater than about 40%.In other embodiments, compare with the compound of heterotope enrichment, the average plasma levels of the metabolite of The compounds of this invention has reduced greater than about 50%.

[0050] at RapidCommunications in Mass Spectrometry 2005,19 (14), measure by the described method of 1943-1950 by people such as Li for the blood plasma level of The compounds of this invention or its metabolite, and it all is incorporated herein by reference at this.

[0051] in another aspect of this invention in, provide and be used for the treatment of mammalian object, people's method particularly, described mammalian object is under a cloud to be had or tends to have resorbent disease of the monoamine of relating to or illness, described method comprises the monoamine reuptake inhibithors to the mammalian object drug treatment significant quantity of needs, described monoamine reuptake inhibithors comprises formula 1 compound, the single enantiomer of formula 1 compound, the mixture of (+)-enantiomorph and (-)-enantiomorph, the mixture of about 90 weight % or higher (-)-enantiomorph and about 10 weight % or lower (+)-enantiomorph, the mixture of about 90 weight % or higher (+)-enantiomorph and about 10 weight % or lower (-)-enantiomorph, the independent diastereomer of formula 1 compound, the mixture of diastereomer, or its pharmacologically acceptable salts, at least a in solvate or the prodrug, compare with the compound of heterotope enrichment realizing, during above-mentioned treatment of diseases, reduce mammalian object at least a cytochrome P ₄₅₀The inhibition of isotype (isoform) and/or by at least a cytochrome P in the mammalian object ₄₅₀The metabolism of isotype.Cytochrome P in the mammalian object ₄₅₀The example of isotype comprises CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, CYP51 etc.

[0052] in certain embodiments, compare, by The compounds of this invention pair cell pigment P with the compound of heterotope enrichment ₄₅₀The inhibition of isotype reduces greater than about 5%.In other embodiments, compare, by The compounds of this invention pair cell pigment P with the compound of heterotope enrichment ₄₅₀The inhibition of isotype reduces greater than about 10%.In other embodiments, compare, by The compounds of this invention pair cell pigment P with the compound of heterotope enrichment ₄₅₀The inhibition of isotype reduces greater than about 20%.In other embodiments, compare, by The compounds of this invention pair cell pigment P with the compound of heterotope enrichment ₄₅₀The inhibition of isotype reduces greater than about 30%.In other embodiments, compare, by The compounds of this invention pair cell pigment P with the compound of heterotope enrichment ₄₅₀The inhibition of isotype reduces greater than about 40%.In other embodiments, compare, by The compounds of this invention pair cell pigment P with the compound of heterotope enrichment ₄₅₀The inhibition of isotype reduces greater than about 50%.

[0053] cytochrome P ₄₅₀At British Journal ofClinical Pharmacology 2000,49 (4), the method described in the 343-351 is measured by people such as Ko in the inhibition of isotype, and it all is incorporated herein by reference at this.

[0054] in another aspect of this invention in, provide and be used for the treatment of mammalian object, people's method particularly, described mammalian object is under a cloud to be had or tends to have resorbent disease of the monoamine of relating to or illness, described method comprises the monoamine reuptake inhibithors to the mammalian object drug treatment significant quantity of needs, described monoamine reuptake inhibithors comprises formula 1 compound, the single enantiomer of formula 1 compound, the mixture of (+)-enantiomorph and (-)-enantiomorph, the mixture of about 90 weight % or higher (-)-enantiomorph and about 10 weight % or lower (+)-enantiomorph, the mixture of about 90 weight % or higher (+)-enantiomorph and about 10 weight % or lower (-)-enantiomorph, the independent diastereomer of formula 1 compound, the mixture of diastereomer, or its pharmacologically acceptable salts, at least a in solvate or the prodrug, compare with the compound of heterotope enrichment with realization, during above-mentioned treatment of diseases, reduce via at least a cytochrome P of expressing polymorphically in the mammalian object ₄₅₀The metabolism of isotype.The cytochrome P of expressing polymorphically in the mammalian object ₄₅₀The example of isotype comprises CYP2C8, CYP2C9, CYP2C19 and CYP2D6.

[0055] in certain embodiments, compare cytochrome P with the compound of heterotope enrichment ₄₅₀Isotype reduces greater than about 5% the metabolism of The compounds of this invention.In other embodiments, compare cytochrome P with the compound of heterotope enrichment ₄₅₀Isotype reduces greater than about 10% the metabolism of The compounds of this invention.In other embodiments, compare cytochrome P with the compound of heterotope enrichment ₄₅₀Isotype reduces greater than about 20% the metabolism of The compounds of this invention.In other embodiments, compare cytochrome P with the compound of heterotope enrichment ₄₅₀Isotype reduces greater than about 30% the metabolism of The compounds of this invention.In other embodiments, compare cytochrome P with the compound of heterotope enrichment ₄₅₀Isotype reduces greater than about 40% the metabolism of The compounds of this invention.In other embodiments, compare cytochrome P with the compound of heterotope enrichment ₄₅₀Isotype reduces greater than about 50% the metabolism of The compounds of this invention.

[0056] cytochrome P ₄₅₀The metabolic activity of isotype is measured by following embodiment 14 described methods.

[0057] in another embodiment of the present invention, provide and be used for the treatment of mammalian object, people's method particularly, described mammalian object is under a cloud to be had or tends to have resorbent disease of the monoamine of relating to or symptom, described method comprises the monoamine reuptake inhibithors to the mammalian object drug treatment significant quantity of needs, described monoamine reuptake inhibithors comprises formula 1 compound, the single enantiomer of formula 1 compound, the mixture of (+)-enantiomorph and (-)-enantiomorph, the mixture of about 90 weight % or higher (-)-enantiomorph and about 10 weight % or lower (+)-enantiomorph, the mixture of about 90 weight % or higher (+)-enantiomorph and about 10 weight % or lower (-)-enantiomorph, the independent diastereomer of formula 1 compound, the mixture of diastereomer, or its pharmacologically acceptable salts, at least a in solvate or the prodrug, to realize the comparing level of raising source of students (biogenic) monoamine with the compound of heterotope enrichment.

[0058] in certain embodiments, the level of source of students monoamine has improved greater than about 5%.In other embodiments, the level of source of students monoamine has improved greater than about 10%.In other embodiments, the level of source of students monoamine has improved greater than about 20%.In other embodiments, the level of source of students monoamine has improved greater than about 30%.In other embodiments, the level of source of students monoamine has improved greater than about 40%.In other embodiments, the level of source of students monoamine has improved greater than about 50%.

[0059] at Rapid Communications in MassSpectrometry 2005,19 (14), measure by the method described in the 1943-1950 by people such as Li for the level of source of students monoamine, and it all is incorporated herein by reference at this.

[0060] in another aspect of this invention in, provide and be used for the treatment of mammalian object, people's method particularly, described mammalian object is under a cloud to be had or tends to have resorbent disease of the monoamine of relating to or illness, described method comprises the monoamine reuptake inhibithors to the mammalian object drug treatment significant quantity of needs, described monoamine reuptake inhibithors comprises formula 1 compound, the single enantiomer of formula 1 compound, the mixture of (+)-enantiomorph and (-)-enantiomorph, the mixture of about 90 weight % or higher (-)-enantiomorph and about 10 weight % or lower (+)-enantiomorph, the mixture of about 90 weight % or higher (+)-enantiomorph and about 10 weight % or lower (-)-enantiomorph, the independent diastereomer of formula 1 compound, the mixture of diastereomer, or its pharmacologically acceptable salts, at least a in solvate or the prodrug is to realize comparing with the compound of heterotope enrichment the clinical effectiveness of improvement.The example of the clinical effectiveness that improves includes but not limited to, quickens rehabilitation during treating, quicken sx speed, improves patient's conformability and/or reduces substance abuse Withrawal symptom (substance abusewithdrawal symptomology).

[0061] in another aspect of this invention in, provide and be used for the treatment of mammalian object, people's method particularly, described mammalian object is under a cloud to be had or tends to have resorbent disease of the monoamine of relating to or illness, described method comprises the monoamine reuptake inhibithors to the mammalian object drug treatment significant quantity of needs, described monoamine reuptake inhibithors comprises formula 1 compound, the single enantiomer of formula 1 compound, the mixture of (+)-enantiomorph and (-)-enantiomorph, the mixture of about 90 weight % or higher (-)-enantiomorph and about 10 weight % or lower (+)-enantiomorph, the mixture of about 90 weight % or higher (+)-enantiomorph and about 10 weight % or lower (-)-enantiomorph, the independent diastereomer of formula 1 compound, the mixture of diastereomer, or its pharmacologically acceptable salts, at least a in solvate or the prodrug, condition is that described formula 1 compound comprises at least one D atom, and condition is that deuterium enriched degree is at least about 1% in described formula 1 compound.

[0062] in certain embodiments, relate to resorbent disease of monoamine or illness and be selected from anxiety disorder, generalized anxiety disorder, dysthymia disorders, posttraumatic stress disorder, obsession, Phobias, hectic fever, senile dementia, migraine, liver lung syndromes, chronic pain, nociceptive pain, neurogenic pain, the pain diabetic retinopathy, the two-phase depression, obstructive sleep apnea, mental disorder, premenstrual dysphoric disorder, social phobia, social anxiety disorder, the urinary incontinence, apositia, bulimia nervosa, obesity, ischemic, head injury, the brain cell calcium overload, pharmacological dependence and premature ejaculation.

[0063] in another aspect of this invention in, the oral many units that are used for the treatment of drug addiction tablet medicine composition is provided, described pharmaceutical composition comprises first composition and second composition.In certain embodiments, first composition comprises at least a in the mixture of independent diastereomer, diastereomer of mixture, formula 1 compound of the mixture of the mixture of single enantiomer, (+)-enantiomorph and (-)-enantiomorph of formula 1 compound, formula 1 compound, about 90 weight % or higher (-)-enantiomorph and about 10 weight % or lower (+)-enantiomorph, about 90 weight % or higher (+)-enantiomorph and about 10 weight % or lower (-)-enantiomorph or its pharmacologically acceptable salts, solvate or the prodrug.In certain embodiments, second composition comprises one or more OPIOIDS antagonists (opioid antagonist).In some embodiments in these embodiments, the OPIOIDS antagonist is selected from Nalmefene, naloxone and TREXUPONT etc.In other embodiments, described drug addiction is selected from the habituation to tobacco, alcohol, hemp and Cocaine.In certain embodiments, first composition is separated with second composition by the coatings (coating layer) that covers first composition and second composition.This type of Drug coating is known to those skilled in the art.

[0064] in another aspect of this invention in, the method of treatment Mammals drug addiction is provided, described method comprises the composition that the Mammals administration is comprised first composition and second composition, wherein first composition comprises formula 1 compound, the single enantiomer of formula 1 compound, the mixture of (+)-enantiomorph and (-)-enantiomorph, the mixture of about 90 weight % or higher (-)-enantiomorph and about 10 weight % or lower (+)-enantiomorph, the mixture of about 90 weight % or higher (+)-enantiomorph and about 10 weight % or lower (-)-enantiomorph, the independent diastereomer of formula 1 compound, the mixture of diastereomer, or its pharmacologically acceptable salts, at least a in solvate or the prodrug, second composition comprises one or more OPIOIDS antagonists.In some embodiments in these embodiments, the OPIOIDS antagonist is selected from Nalmefene, naloxone and TREXUPONT etc.In other embodiments, described drug addiction is selected from the habituation to tobacco, alcohol, hemp and Cocaine.In other embodiments, compare with the analogue of the heterotope enrichment of first composition, first composition can cause the addicted clinical effectiveness of the medicine of improvement (for example, quickening rehabilitation, acceleration sx, raising patient's conformability and/or minimizing substance abuse Withrawal symptom during treating).

[0065] in certain embodiments, dosing step comprises almost administration first composition and second composition simultaneously.But these embodiments comprise those the wherein situation of two kinds of compounds in the composition of same administration, promptly contain independent tablet, pill or the capsule of two kinds of compounds simultaneously or are used for intravenous independent solution or independent drinkable solution or the independent dragee preparation or the situation of ointment.But described embodiment also comprise those wherein each compound in the composition of independent administration, but the patient is instructed the situation of almost taking described independent composition simultaneously, take another kind after promptly taking a kind of pill at once, or the situation of after a kind of compound of injection, at once injecting another kind of compound.In certain embodiments, the patient before the intravenous formulations of a kind of compound of infusion, the intravenous formulations of the another kind of compound of infusion.In these embodiments, infusion can carry out for some time, for example several minutes, half an hour or one hour or longer.Even passed through for some time at interval between infusion initial next time in the initial sum of an infusion, if but twice venoclysis be once then another time carry out, then this administration is considered in the scope of the present disclosure almost simultaneously.

[0066] in other embodiments, dosing step comprises a kind of in administration first composition and second composition, the another kind in administration first composition and second composition then.In these embodiments, can comprise the composition of one of described compound earlier to patient's administration, then over time, several minutes or after several hours, administration comprises another composition of another kind of compound.These embodiments are included in routine equally or comprise the composition of one of described compound continuously to patient's administration, and described patient accepts to comprise another compound compositions discontinuously simultaneously.In other embodiments, can for example pass through Vein Tube (IV line) infusion compound continuously to the whole two kinds of compounds of patient's administration on routine or continuous foundation.

[0067] in another aspect of this invention in, the effervesce formulation is provided, described effervesce formulation comprises first composition and second composition and the acceptable vehicle of one or more pharmacy randomly, wherein said first composition is one or more effervescent excipient, and second composition is formula 1 compound, the single enantiomer of formula 1 compound, the mixture of (+)-enantiomorph and (-)-enantiomorph, the mixture of about 90 weight % or higher (-)-enantiomorph and about 10 weight % or lower (+)-enantiomorph, the mixture of about 90 weight % or higher (+)-enantiomorph and about 10 weight % or lower (-)-enantiomorph, the independent diastereomer of formula 1 compound, the mixture of diastereomer, or its pharmacologically acceptable salts, at least a in solvate or the prodrug.

[0068] in another aspect of this invention in, slowly-releasing (extended release) pharmaceutical dosage form is provided, and described slow releasing pharmaceutical formulation comprises formula 1 compound, the single enantiomer of formula 1 compound, the mixture of (+)-enantiomorph and (-)-enantiomorph, the mixture of about 90 weight % or higher (-)-enantiomorph and about 10 weight % or lower (+)-enantiomorph, the mixture of about 90 weight % or higher (+)-enantiomorph and about 10 weight % or lower (-)-enantiomorph, the independent diastereomer of formula 1 compound, the mixture of diastereomer, or its pharmacologically acceptable salts, at least a in solvate or the prodrug, hydrophilic or hydrophobic matrix, water-soluble separate layer, enteric coating and the acceptable vehicle of one or more pharmacy randomly.

[0069] in another aspect of this invention in, the enteric coated drug formulation is provided, described enteric pharmaceutical dosage form comprises formula 1 compound, the single enantiomer of formula 1 compound, the mixture of (+)-enantiomorph and (-)-enantiomorph, the mixture of about 90 weight % or higher (-)-enantiomorph and about 10 weight % or lower (+)-enantiomorph, the mixture of about 90 weight % or higher (+)-enantiomorph and about 10 weight % or lower (-)-enantiomorph, the independent diastereomer of formula 1 compound, the mixture of diastereomer, or its pharmacologically acceptable salts, at least a in solvate or the prodrug, rupturable semi-permeable membranes and one or more expandable substance, wherein said formulation has instant inhibitor release portion and at least one time-delay inhibitor release portion, and can be with 0.1 to the described compound of the discontinuous release of form of at least two successive pulses that reaches 24 hours the timed interval.

[0070] in another aspect of this invention in, the stable pharmaceutical dosage form that is used to be administered orally to mammalian object is provided, described pharmaceutical dosage form comprises formula 1 compound, the single enantiomer of formula 1 compound, the mixture of (+)-enantiomorph and (-)-enantiomorph, the mixture of about 90 weight % or higher (-)-enantiomorph and about 10 weight % or lower (+)-enantiomorph, the mixture of about 90 weight % or higher (+)-enantiomorph and about 10 weight % or lower (-)-enantiomorph, the independent diastereomer of formula 1 compound, the mixture of diastereomer, or its pharmacologically acceptable salts, at least a in solvate or the prodrug, and one or more pharmacy adjuvants randomly, described adjuvant is encapsulated into the intermediate reaction layer, and described intermediate reaction layer comprises by alkali and partly neutralizes and have the polymer laminar material of resistant to gastric juice of cation exchange capacity (CEC) and the skin of resistant to gastric juice.

[0071] except as otherwise noted; when replacement is considered to " randomly replacing "; its implication is; substituting group is can be by separately and be independently selected from the group that one or more groups of following radicals replace: hydrogen; deuterium; alkyl; cycloalkyl; aryl; heteroaryl; heterocycle; hydroxyl; alkoxyl group; aryloxy; sulfydryl; alkylthio; arylthio; cyano group; halogen; carbonyl; thiocarbonyl group; O-formamyl (O-carbamyl); the N-formamyl; O-thiocarbamoyl (O-thiocarbamyl); the N-thiocarbamoyl; C-amino; N-amino; the S-sulfonamido; the N-sulfonamido; the C-carboxyl; the O-carboxyl; the isocyanide acyl group; thiocyano; the isocyanide sulfenyl; nitro; silyl; three halogen methylsulfonyl and amino, comprise single replace and disubstituted amino group with and shielded derivative.The blocking group that can form above-mentioned substituent protectiveness derivative is known to those skilled in the art, the example can find in the literature, for example Greene and Wuts, Protective Group in OrganicSynthesis, the third edition, John Wiley﹠amp; Sons, New York, NY, 1999, it all is incorporated herein by reference at this.

[0072] form of any rational tautomer that can generally acknowledge with those skilled in the art according to compound of the present invention exists or exists with the form of the mixture of this type of tautomer.Term " tautomer " or " tautomerism " are meant a kind of of two or more constitutional isomers, and described constitutional isomer is present in the equilibrium state, and are converted into another kind of isomer from a kind of isomer easily.The example comprises keto-enol tautomerism style such as acetone/propylene-2-alcohol etc., ring-chain tautomerism style such as glucose/2,3,4,5,6-penta hydroxy group-hexanal etc.Compound as herein described can have one or more tautomers, and therefore comprises multiple isomer.The described isomeric forms of all of these compounds all is included in the present invention clearly.

[0073] can comprise one or more asymmetric atoms according to compound of the present invention, and therefore can exist with the form of racemoid and racemic mixture, single enantiomer, non-enantiomer mixture or independent diastereomer.Term " steric isomer " is meant to have same molecular amount, chemical constitution and structure mutually, but the different compound of the gathering of atom (group).That is to say, some identical chemical part in the space towards difference, therefore, when it is pure, have the planar ability of rotatory polarization light.Yet the optics rotation of some pure stereoisomers is very little, to such an extent as to can not detect with present surveying instrument.Compound described herein can have one or more asymmetric atoms, therefore comprises multiple steric isomer.All described isomeric forms of these compounds all comprise within the scope of the invention clearly.

[0074] each solid (stereogenic) carbon or sulphur can be R or S configuration.Although the particular compound that exemplifies among the application may be described as specific configuration, have at any given chiral centre that opposite stereochemical compound or its mixture also be envisioned.When in derivative of the present invention, finding chiral centre, be construed as the present invention and comprise all possible steric isomer.

[0075] term " optically pure compound " or " optically pure isomer " are meant the independent steric isomer of chipal compounds, no matter and the configuration of described compound how.

[0076] term " homogeneous in fact " is meant the set of molecule, wherein at least about 80%, preferably at least about 90%, be independent compound or its independent steric isomer or the set that refers to molecule more preferably at least about 95% molecule, wherein at least about 80%, preferably at least about 90%, more preferably replaced (for example, deuterate) fully in described position at least about 95% molecule.

[0077] term used herein " connection " means stable covalent linkage, and some preferred tie point is conspicuous for those skilled in the art.

[0078] term " optional " or " randomly " are meant incident or the situation described subsequently take place or do not take place, and this description comprises the situation that situation that described incident or situation take place and described incident or situation do not take place.Under described linguistic context, sentence " the randomly alkyl group of Qu Daiing " is meant that alkyl can be substituted also and can be substituted, and this description comprises the alkyl group of replacement, also comprises the unsubstituted alkyl group.

[0079] compound of term " significant quantity " is meant and required effect is provided but does not have toxicity or have the compound of acceptable toxic q.s.This amount depends on ethnic group, age and the physical qualification of object according to object and different, the severity of the disease of being treated, and the specific compound of use, its administering mode, or the like.Suitable significant quantity can be determined by those of ordinary skills.

[0080] term " pharmacy is acceptable " is meant and is not biologically or other aspects not desired compounds, additive or composition.For example, additive or composition can be administered to object with The compounds of this invention, and can not cause any biological impact of not expecting or with any other interaction between component in the mode do not expected and the pharmaceutical composition that comprises it.

[0081] term " pharmacologically acceptable salts " comprises hydrochloride, hydrobromate, hydriodate, hydrofluoride, vitriol, Citrate trianion, maleate, acetate, lactic acid salt, nicotinate, succinate, oxalate, phosphoric acid salt, malonate, salicylate, phenylacetate, stearate, pyridinium salt, ammonium salt, piperazine salt, the diethyl amine salt, the nicotinoyl amine salt, formate, urea salt (urea salt), sodium salt, sylvite, calcium salt, magnesium salts, zinc salt, lithium salts, cinnamate, methylamino-salt, mesylate, picrate, tartrate, triethylamine salt, dimethylamine salt, Tutofusin tris salt etc.Other pharmacologically acceptable salts are known to those skilled in the art.

[0082] when using in conjunction with The compounds of this invention, term " cause (elicit, eliciting) ", " conditioning agent (modulator, regulator) ", " regulating (modulate, modulating, regulate or regulating) " activity are meant and can be used as for example compound of agonist, inverse agonist (inverse agonist), inhibitor or the antagonist of 5-hydroxytryptamine receptor of a certain specific enzyme or acceptor.

[0083] term " medicine ", " therapeutical agent ", " chemotherapeutics " are meant in treatment disease or medical conditions the compound or multiple compound and the pharmacy acceptable composition thereof that are administered to mammalian object as prophylactic agent or curative.Described compound can via oral preparations, inhalation, venoclysis, ocular administration, preparation capable of permeating skin or by drug administration by injection to object.

[0084] term " object " is meant animal, preferred mammal, and optimum is chosen, and it is the target of treatment, observation or test.Mammals is optional from mouse, rat, hamster, gerbil jird, rabbit, cavy, dog, cat, sheep, goat, milk cow, horse, giraffe, duckbill platypus, and primates is monkey, chimpanzee and ape and the mankind for example.

[0085] term " treatment significant quantity " is used to represent that active compound or medicament cause the specified biology or the amount of medical response.This reaction can appear at by investigator, animal doctor, doctor or other clinicians and seek in the tissue, system (animal that comprises the people) of (seek).

[0086] term " treatment (treating, treatment, therapy) " or " (therapeutic) of treatment " not necessarily mean losing fully of nociception (nociception).Can think treatment to any sign of not expecting of disease or any alleviation to any degree of symptom, for example those relate to the resorbent disease of monoamine, anxiety disorder to described disease, generalized anxiety disorder, dysthymia disorders, posttraumatic stress disorder, obsession, Phobias, hectic fever, senile dementia, migraine, liver lung syndromes, chronic pain, nociceptive pain, neurogenic pain, the pain diabetic retinopathy, the two-phase depression, obstructive sleep apnea, mental disorder, premenstrual dysphoric disorder, social phobia, social anxiety disorder, the urinary incontinence, apositia, bulimia nervosa, obesity, ischemic, head injury, the brain cell calcium overload, the subclass of pharmacological dependence and/or premature ejaculation or these illnesss (subset).In addition, treatment can comprise the behavior of the overall comfortable or presentation sensation that may worsen the patient.

[0087] term " Lewis acid " is meant the molecule that can accept not shared electron pair, and it is conspicuous to those of ordinary skills.The definition of " Lewis acid " includes but not limited to: boron trifluoride, boron trifluoride-ether complex, boron trifluoride-tetrahydrofuran complex, boron trifluoride-methyl tertbutyl ether complexes, boron trifluoride-dibutyl ether complex compound, the boron trifluoride dihydrate, boron trifluoride-oxalic acid complex compound, boron trifluoride-dimethyl sulphide ether complexes, boron trichloride, boron trichloride-dimethyl sulphide ether complexes, boron tribromide, boron tribromide-dimethyl sulphide ether complexes, triiodide boron, trimethyl borate, triethyl borate, trimethyl aluminium, triethyl aluminum, aluminum chloride, aluminum chloride-tetrahydrofuran complex, alchlor, titanium tetrachloride, titanium tetrabromide, titanium iodide, purity titanium tetraethoxide, tetraisopropoxy titanium, trifluoromethanesulfonic acid scandium (III), trifluoromethanesulfonic acid yttrium (III), Ytterbiumtriflate (III), trifluoromethanesulfonic acid lanthanum (III), zinc chloride (II), zinc bromide (II), zinc iodide (II), trifluoromethanesulfonic acid zinc (II), zinc sulfate (II), sal epsom, lithium perchlorate, copper trifluoromethanesulfcomposite (II), Tetrafluoroboric acid copper (II) etc.Some Lewis acid can have the optically pure ligand that is connected to the electron acceptor(EA) atom, reaches as following document as described in all reference of wherein being quoted: Corey, E.J.Angewandte Chemie, international version (2002), 41 (10), 1650-1667; Aspinall, H.C.Chemical Reviews (Washington, DC special zone) (2002), 102 (6), 1807-1850; Groger, H.Chemistry-A EuropeanJournal (2001), 7 (24), 5246-5251; Davies, H.M.L.Chemtracts (2001), 14 (11), 642-645; Wan, Y.Chemtracts (2001), 14 (11), 610-615; Kim, Y.H.Accountsof Chemical Research (2001), 34 (12), 955-962; Seebach, D.AngewandteChemie, international version (2001), 40 (1), 92-138; Blaser, H.U.Applied Catalysis, A:General (2001), 221 (1-2), 119-143; Yet, L.Angewandte Chemie, international version (2001), 40 (5), 875-877; Jorgensen, K.A.Angewandte Chemie, international version (2000), 39 (20), 3558-3588; Dias, L.C.Current Organic Chemistry (2000), 4 (3), 305-342; Spindler, F.Enantiomer (1999), 4 (6), 557-568; Fodor, K.Enantiomer (1999), 4 (6), 497-511; Shimizu, K.D.; ComprehensiveAsymmetric Catalysis I-III (1999), 3,1389-1399; Kagan, H.B.ComprehensiveAsymmetric Catalysis I-III (1999), 1,9-30; Mikami, K.Lewis AcidReagents (1999), 93-136.Described Lewis acid can be used by those skilled in the art, to prepare optically pure compound from the achirality starting material.

[0088] term " acylating agent " is meant the molecule that the alkyl-carbonyl or the aryl carbonyl group of alkyl-carbonyl, replacement can be converted to another molecule.The definition of " acylating agent " includes but not limited to, ethyl acetate; vinyl-acetic ester; propionate; vinyl butyrate; methylvinyl acetate; acetate 1-vinyl ethyl ether ester; the butyric acid trichloro ethyl ester; the butyric acid trifluoro ethyl ester; the lauric acid trifluoro ethyl ester; Thioctic Acid S-ethyl ester (S-ethyl thiooctanoate); di-acetyl monoxime acetic ester (biacetyl monooxime acetate); diacetyl oxide; Acetyl Chloride 98Min.; succinyl oxide; diketene; the diallyl carbonic ether; carbonic acid fourth-3-alkenyl esters cyanomethyl ester (carbonic acid but-3-enyl ester cyanomethyl ester); amino acid etc.

[0089] term " nucleophilic reagent (nucleophile, nucleophilic reagent) " is meant to have the electronegative of not shared electron pair or neutral molecule, and it is conspicuous for those of ordinary skills equally.The definition of " nucleophile " includes but not limited to: water, the alkane hydroxyl, the alkoxyl group negatively charged ion, the virtue hydroxyl, the aryloxy negatively charged ion, alkyl sulfhydryl, the alkylthio negatively charged ion, aryl mercaptan, the arylthio negatively charged ion, ammonia, alkylamine, arylamines, the alkylamine negatively charged ion, the arylamines negatively charged ion, hydrazine, alkyl hydrazine, the aryl hydrazine, the alkyl-carbonyl hydrazine, the aryl carbonyl hydrazine, the hydrazine negatively charged ion, the alkyl hydrazine negatively charged ion, aryl hydrazine negatively charged ion, alkyl-carbonyl hydrazine negatively charged ion, aryl carbonyl hydrazine negatively charged ion, prussiate, trinitride, hydride, the alkyl negatively charged ion, aryl negatively charged ion etc.

[0090] term " electrophilic reagent (electrophile, electrophilic reagent) " be meant have the price asked electronic shell (open valence shell) or the electron rich reactant is had a gravitational positively charged or the neutral molecule, it will be apparent to those skilled in the art equally.The definition of " electrophilic material " includes but not limited to: oxonium ion (hydronium), acylium cation (acylium), Lewis acid be boron trifluoride etc. for example, and halogen is Br for example ₂Deng, carbocation is tertiary butyl positively charged ion etc. for example, and diazomethane, trimethyl silyl diazomethane, haloalkane be methyl iodide, three deuterium methyl iodide (CD for example ₃I), bromotoluene etc., trifluoromethane sulfonic acid alkane ester (alkyl triflate) is trifluoromethane sulfonic acid methyl esters (methyltriflate) etc. for example, alkyl sulfonic ester, for example toluenesulphonic acids ethyl ester, butyl methyl sulfonate, methyl-sulfate, six deuterium methyl-sulfate ((CD ₃) ₂SO ₄) etc.; acyl halide is Acetyl Chloride 98Min., benzoyl bromide etc. for example; acid anhydrides; for example diacetyl oxide, succinyl oxide, maleic anhydride etc.; isocyanic ester is methyl isocyanate, phenylcarbimide etc. for example; chloro-formic ester is methyl-chloroformate, Vinyl chloroformate, chloroformic acid benzyl ester etc. for example; sulfonic acid halide is Methanesulfonyl chloride, Tosyl chloride etc. for example; silyl halides is trimethylchlorosilane, TERT-BUTYL DIMETHYL CHLORO SILANE etc., phosphoryl halogenide chlorine dimethyl phosphate etc. for example for example, and alpha-beta-beta-unsaturated carbonyl compounds is propenal, methyl vinyl ketone, phenylacrolein etc. for example.

[0091] term " leavings group " (leaving group, LG) is meant that being replaced the back at it by nucleophilic reagent is stable any atom (or atomic group) at its negatively charged ion or neutral form, and it will be apparent to those skilled in the art.The definition of " leavings group " includes but not limited to: water, methyl alcohol, ethanol, muriate, bromide, iodide, methanesulfonate, tosylate, trifluoromethanesulfonic acid root, acetate moiety, trichoroacetic acid(TCA) root, benzoate anion etc.

[0092] term " oxygenant " is meant that any energy increases the atom reagent of the oxidation state of hydrogen, carbon, nitrogen, sulphur, phosphorus etc. for example the starting material by adding oxygen to atom or removing de-electronation from atom, and it is conspicuous for those of ordinary skills equally.The definition of " oxygenant " includes but not limited to: perosmic anhydride, ruthenium tetroxide, ruthenium trichloride, potassium permanganate, metachloroperbenzoic acid, hydrogen peroxide, dimethyldioxirane etc.

[0093] term " metal ligand " refer to have not the electron pair shared and can with atoms metal coordinate molecule, it is conspicuous for those of ordinary skills equally.The definition of " metal ligand " includes but not limited to: water, alkoxyl group negatively charged ion, alkylthio negatively charged ion, ammonia, trialkylamine, triarylamine, trialkyl phosphine, triaryl phosphine, prussiate, trinitride etc.

[0094] term " reductive agent " is meant any energy by adding hydrogen to atom, or adds electronics or remove deoxidation and reduce the reagent of the oxidation state of the atom the starting material from atom to atom, and it will be apparent to those skilled in the art equally.The definition of " reductive agent " includes but not limited to: borine-dimethyl sulphide ether complexes, 9-boron dicyclo [3.3.1.] nonane (9-BBN) of mixing, adjacent benzene dioxy borine, lithium borohydride, the boron lithium deuteride LiD, sodium borohydride, boron deuterate sodium, sodium borohydride-methyl alcohol complex compound, POTASSIUM BOROHYDRIDE, the hydroxyl sodium borohydride, lithium triethylborohydride, the normal-butyl lithium borohydride, sodium cyanoborohydride, cyano group boron deuterate sodium, hydroboration calcium (II), lithium aluminum hydride, deuterate aluminium lithium, diisobutyl aluminium hydride, the normal-butyl diisobutyl aluminium hydride, two methoxyethoxy sodium aluminum hydrides (sodium bis-methoxyethoxyaluminum hydride), triethoxyl silane, diethoxymethyl silane, lithium hydride, lithium, sodium, hydrogen Ni/B (hydrogen Ni/B) etc.Some acid reagent and Lewis acid reagent have improved the activity of reductive agent.The example of described acid reagent comprises: acetate, methylsulphonic acid, hydrochloric acid etc.The example of described Lewis acid reagent comprises: trimethoxy borine, triethoxy borine, aluminum chloride, lithium chloride, vanadium trichloride, two luxuriant titanium dichloride (dicyclopentadienyl titanium dichloride), cesium fluoride, Potassium monofluoride, zinc chloride (II), zinc bromide (II), zinc iodide (II) etc.

[0095] term " coupling agent " be meant any can the activating carboxy acid carbonyl and help to form the reagent of ester bond or amido linkage.The definition of " coupling agent " includes but not limited to: Acetyl Chloride 98Min., Vinyl chloroformate, dicyclohexylcarbodiimide (DCC), DIC (DIC), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI), N-hydroxybenzotriazole (HOBT), N-hydroxy-succinamide (HOSu), the 4-nitrophenol, Pentafluorophenol, 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea Tetrafluoroboric acid ester (TBTU), O-benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HBTU), benzotriazole-1-base-oxygen-three-(dimethylamino)-Phosphonium phosphofluoric acid esters (BOP), benzotriazole-1-base-oxygen-three-Bi coughs up Wan Ji Phosphonium phosphofluoric acid ester, bromo tripyrrole Wan Ji Phosphonium phosphofluoric acid ester, 2-(5-norbornene-2, the 3-dicarbonyl imide)-1,1,3,3-tetramethyl-urea Tetrafluoroboric acid ester (TNTU), O-(N-succinimido)-1,1,3,3-tetramethyl-urea Tetrafluoroboric acid ester (TSTU), tetramethyl-fluoro carbonamidine phosphofluoric acid ester etc.

[0096] term " removable protecting group " or " protecting group " are meant when being bonded to functional group for example when the Sauerstoffatom of hydroxyl or carboxyl or amino nitrogen-atoms; can prevent to react in these functional groups; and described protecting group can be removed by the chemistry or the enzymatic step of routine, to recover any group of (reestablish) described functional group.The concrete removable protecting group of using is not crucial.

[0097] definition of " hydroxyl protecting group " includes but not limited to:

A) methyl, the tertiary butyl, allyl group, propargyl, rubigan, p-methoxyphenyl, p-nitrophenyl, 2, the 4-dinitrophenyl, 2,3,5,6-tetrafluoro-4-(trifluoromethyl) phenyl, methoxymethyl, methylthiomethyl, (phenyl dimetylsilyl) methoxymethyl, benzyloxymethyl, to methoxyl group-benzyloxymethyl, to the nitro benzyloxymethyl, adjacent nitro benzyloxymethyl, (4-methoxyl group phenoxy group) methyl, methyl guaiacol and 4 (guaiacolmethyl), the tert.-butoxy methyl, 4-pentenyl oxygen ylmethyl, the t-butyldimethylsilyloxy ylmethyl, 2,3-dimethyl-2-butyl dimethylsilane oxygen ylmethyl (thexyldimethylsiloxymethyl), tert-butyl diphenyl siloxy-methyl, 2-methoxy ethoxy methyl, 2,2,2-trichlorine ethoxyl methyl, two (2-chloroethoxy) methyl, 2-(trimethyl silyl) ethoxyl methyl, peppermint oxygen ylmethyl, the 1-ethoxyethyl group, 1-(2-chloroethoxy) ethyl, 1-[2-(trimethyl silyl) oxyethyl group] ethyl, 1-methyl isophthalic acid-ethoxyethyl group, 1-methyl isophthalic acid-benzyloxy ethyl, 1-methyl isophthalic acid-benzyloxy-2-fluoro ethyl, 1-methyl isophthalic acid-phenoxy group ethyl, 2,2,2-three chloroethyls, 1-two anisyls-2,2,2-three chloroethyls, 1,1,1,3,3,3-hexafluoro-2-propyloxy phenyl base, 2-trimethyl silyl ethyl, 2-(benzylthio-) ethyl, 2-(phenyl selenyl) ethyl, THP trtrahydropyranyl, 3-bromine THP trtrahydropyranyl, tetrahydro thiapyran base (tetrahydrothiopyranyl), 1-methoxyl group cyclohexyl, 4-methoxyl group THP trtrahydropyranyl, 4-methoxyl group tetrahydro thiapyran base, 4-methoxyl group THP trtrahydropyranyl S, the S-dioxide, 1-[(2-chloro-4-methyl) phenyl]-4-methoxyl group piperidin-4-yl, 1-(2-fluorophenyl)-4-methoxyl group piperidin-4-yl, 1,4-diox-2-base, tetrahydrofuran base, tetrahydro-thienyl etc.;

B) benzyl, the 2-nitrobenzyl, the 2-trifluoromethyl benzyl, the 4-methoxy-benzyl, the 4-nitrobenzyl, 4-benzyl chloride base, the 4-bromobenzyl, the 4-cyanobenzyl, the 4-phenylbenzyl, 4-amido benzyl, 4-azido-benzyl, 4-(methyl sulfinyl) benzyl, 2, the 4-dimethoxy-benzyl, 4-azido--3-benzyl chloride base, 3, the 4-dimethoxy-benzyl, 2, the 6-dichloro benzyl, 2, the 6-difluorobenzyl, 1-pyrenyl methyl, Biphenylmethyl, 4,4 '-the dinitrobenzene diphenyl-methyl, 5-benzocyclohepta base, trityl group (trityl), the Alpha-Naphthyl diphenyl methyl, (4-p-methoxy-phenyl)-phenylbenzene-methyl, two-(p-methoxyphenyl)-phenyl methyl, three-(p-methoxyphenyl) methyl, 4-(4 '-the bromobenzene acyloxy)-phenyl diphenyl methyl (4-(4 ' bromophenacyloxy)-phenyldiphenylmethyl), 4,4 ', 4 " three (4; 5-dichloro phthalimido phenyl) methyl; 4; 4 '; 4 "-three (stem tuber glycosyl oxygen base phenyl) methyl (4,4 '; 4 "-tris (levulinoyloxyphenyl) methyl), 4,4 '-dimethoxy-3 " [N-(imidazolyl methyl)] trityl; 4; 4 '-dimethoxy-3 " [N-(imidazolyl ethyl) formamyl] trityl, 1, two (the 4-p-methoxy-phenyls)-1 of 1-'-the pyrenyl methyl, 4-(17-four benzo [a, c, g, i] the fluorenyl methyl)-4,4 '-dimethoxytrityl, the 9-anthryl, 9-(9-phenyl) oxa-anthryl, 9-(9-phenyl-10-oxo) anthryl etc.;

C) trimethyl silyl, triethylsilyl, the triisopropyl silyl, dimethyl sec.-propyl silyl, diethyl sec.-propyl silyl, dimethyl hexyl silyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, the tribenzyl silyl, three-p-Xylol base silyl, the triphenyl silyl, the diphenyl methyl silyl, two-tertiary butyl methyl-silicane base, three (trimethyl silyl) silyl, (2-hydroxystyrene based) dimetylsilyl, (2-hydroxystyrene based) di-isopropyl silyl, tertiary butyl p-methoxy-phenyl silyl, tert.-butoxy diphenylmethyl silylation etc.;

D)-C (O) R ₃₀, R wherein ₃₀Be selected from following groups: the alkyl of alkyl, replacement, aryl, more specifically, R ₃₀=hydrogen, methyl, ethyl, the tertiary butyl, adamantyl, crot(on)yl, chloromethyl, dichloromethyl, trichloromethyl, trifluoromethyl, methoxymethyl, the triphenyl methoxymethyl, phenoxymethyl, 4-chlorophenoxy methyl, phenyl methyl, diphenyl methyl, 4-methoxyl group crot(on)yl, the 3-phenyl propyl, the 4-pentenyl, 4-oxo amyl group (4-oxopentyl), 4,4-(ethylene sulfo-) amyl group, two (4-p-methoxy-phenyl) the hydroxymethyl phenoxy groups of 5-[3-]-4-oxo amyl group, phenyl, the 4-aminomethyl phenyl, the 4-nitrophenyl, the 4-fluorophenyl, the 4-chloro-phenyl-, the 4-p-methoxy-phenyl, the 4-phenyl, 2,4, the 6-trimethylphenyl, Alpha-Naphthyl, benzoyl etc.;

E)-C (O) OR ₃₀, R wherein ₃₀Be selected from following groups: the alkyl of alkyl, replacement, aryl, more specifically, R ₃₀=methyl; methoxymethyl; 9-fluorenyl methyl; ethyl; 2; 2; the 2-trichloromethyl; 1; 1-dimethyl-2; 2; 2-three chloroethyls; 2-(trimethyl silyl) ethyl; 2-(phenyl sulfonyl) ethyl; isobutyl-; the tertiary butyl; vinyl; allyl group; the 4-nitrophenyl; benzyl; the 2-nitrobenzyl; the 4-nitrobenzyl; the 4-methoxy-benzyl; 2; the 4-dimethoxy-benzyl; 3; the 4-dimethoxy-benzyl; 2-(methyl sulfo-methoxyl group) ethyl; 2-dansyl ethyl (2-dansenyl ethyl); 2-(4-nitrophenyl) ethyl; 2-(2, the 4-dinitrophenyl) ethyl; 2-cyanogen-1-phenylethyl; benzylthio-; 4-oxyethyl group-1-naphthyl etc.Other examples of hydroxyl protecting group provide in above-mentioned Greene and Wutts.

[0098] definition of " amino protecting group " includes but not limited to:

2-methyl thio-ethyl, 2-methyl sulphonyl ethyl, 2-(p-toluenesulfonyl) ethyl, [2-(1, the 3-dithienyl)] ([2-(1 for methyl, 3-dithianyl)] methyl), 4-methylbenzene sulfenyl, 2,4-dimethyl benzene sulfenyl, 2-phosphorus base ethyl, 1-methyl isophthalic acid-(triphenyl phosphorus base) ethyl, 1,1-dimethyl-2-cyanoethyl, 2-dansyl ethyl, 2-(4-nitrophenyl) ethyl, 4-phenyl acetoxyl group benzyl, 4-nitrine benzyl, 4-nitrine methoxy-benzyl, m-chloro is to the acyloxy benzyl, to (dihydroxyl boryl) benzyl, 5-benzoisoxazole ylmethyl, 2-(trifluoromethyl)-6-chromone ylmethyl (2-(trifluoromethyl)-6-chromonytmethyl), the m-nitro base, 3, the 5-dimethoxy-benzyl, 1-methyl isophthalic acid-(3, the 5-Dimethoxyphenyl) ethyl, adjacent nitrobenzyl, Alpha-Methyl nitro piperonyl, 3,4-dimethoxy-6-nitrobenzyl, the N-benzenesulfinyl, N-ortho-nitrophenyl sulfinyl, N-2,4-dinitrobenzene sulfinyl, N-pentachlorobenzene sulfinyl, N-2-nitro-4-anisole sulfinyl, N-trityl group sulfinyl, N-1-(2,2,2-three fluoro-1,1-biphenyl) ethyl sulfinyl, N-3-nitro-2-pyridine sulfinyl, the N-p-toluenesulfonyl, the N-benzenesulfonyl, N-2,3,6-trimethylammonium-4-anisole alkylsulfonyl, N-2,4,6-trimethoxy benzenesulfonyl, N-2,6-dimethyl-4-anisole alkylsulfonyl, N-pentamethylbenzene alkylsulfonyl, N-2,3,5,6-tetramethyl--4-anisole alkylsulfonyl etc.;

-C (O) OR ₃₀, R wherein ₃₀Be selected from following groups: the alkyl of alkyl, replacement, aryl, more specifically, R ₃₀=methyl, ethyl, 9-fluorenyl methyl, 9-(2-sulfo group) fluorenyl methyl.9-(2; the 7-dibromo) fluorenyl methyl; 17-four benzo [a; c; g; i] the fluorenyl methyl; 2-chloro-3-indenyl methyl; benzo [f] indenes-3-ylmethyl; 2; 7-two-tertiary butyl-[9-(10; 10-dioxo-10; 10; 10; 10-tetrahydrochysene sulfo-xanthenyl)] methyl (2; 7-di-t-butyl-[9-(10; 10-dioxo-10; 10; 10; 10-tetrahydrothloxanthyl)] methyl); 1; 1-dioxo benzo [b] thiophene-2-ylmethyl; 2; 2; 2-three chloroethyls; 2-trimethyl silyl ethyl; the 2-phenylethyl; 1-(1-adamantyl)-1-methylethyl; the 2-chloroethyl; 1; 1-dimethyl-2-haloethyl; 1; 1-dimethyl-2; 2-two bromotrifluoromethanes; 1; 1-dimethyl-2; 2; 2-three chloroethyls; 1-methyl isophthalic acid-(4-phenylbenzene) ethyl; 1-(35-two-tert-butyl-phenyl)-1-methylethyl; 2-(2 '-pyridyl) ethyl; 2-(4 '-pyridyl) ethyl; 2; 2-pair (4 '-nitrophenyl) ethyl; N-(2-valeryl amino)-1; the 1-dimethyl ethyl; the 2-[(2-nitrophenyl) two sulphur]-the 1-phenylethyl; the tertiary butyl; the 1-adamantyl; the 2-adamantyl; vinyl; allyl group; 1-sec.-propyl allyl group; cinnamyl; 4-nitro cinnamyl; 3-(3-pyridyl) third-2-thiazolinyl; the 8-quinolyl; N-hydroxy piperidine base; alkyl two sulphur; benzyl; to methoxy-benzyl; to nitrobenzyl; to bromobenzyl; p-chlorobenzyl; 2, the 4-dichloro benzyl; 4-methyl sulfinyl benzyl; 9-anthryl methyl; diphenyl methyl; tert-pentyl; thiocarbamate S-benzyl ester; butynyl; to cyanobenzyl; cyclobutyl.Cyclohexyl, cyclopentyl.The cyclopropyl methyl; to oxy-benzyl in the last of the ten Heavenly stems; the di-isopropyl methyl; 2; 2-dimethoxy carbonyl ethenyl; o-(N; N '-dimethylformamide base) benzyl; 1-dimethyl-3-(N; N '-dimethylformamide base) propyl group; 1; the 1-alkynyl dimethyl; two (2-pyridyl) methyl; the 2-furyl methyl; 2-iodine ethyl; isobornyl; isobutyl-; different nicotinoyl; to (p '-the p-methoxy-phenyl azo) benzyl; 1-methyl cyclobutyl; the 1-methylcyclohexyl; 1-methyl isophthalic acid-cyclopropyl methyl; 1-methyl isophthalic acid-(to the phenylazo phenyl) ethyl; 1-methyl isophthalic acid-phenylethyl; 1-methyl isophthalic acid-4 '-the pyridyl ethyl; phenyl; to (phenylazo) benzyl; 2; 4; the 6-trimethylphenyl; 4-(trimethyl ammonium) benzyl; 2; 4,6-trimethyl benzyl etc.Other examples of amino protecting group provide in above-mentioned Greene and Wutts.

[0099] definition of " carboxyl-protecting group " includes but not limited to:

2-N-(morpholino) ethyl, choline, methyl, methoxy ethyl, 9-fluorenyl methyl, methoxymethyl, methylthiomethyl, THP trtrahydropyranyl, tetrahydrofuran base, methoxy ethoxy methyl, 2-(trimethyl silyl) ethoxyl methyl, benzyloxymethyl, oxy acid methyl neopentyl, phenyl acetoxy-methyl, triisopropyl silyl methyl, cyanogen methyl, hydroxyacetone, to bromobenzene formyl methyl.The Alpha-Methyl phenacyl; to the methoxybenzoyl methyl; Er Benyitongji; the formamido group methyl; to nitrogen benzide formamido group-methyl; N-phthalimido methyl; (methoxy ethoxy) ethyl; 2; 2; 2-three chloroethyls; the 2-fluoro ethyl; the 2-chloroethyl; the 2-bromotrifluoromethane; 2-iodine ethyl; the 4-chlorobutyl; 5-chlorine amyl group; 2-(trimethyl silyl) ethyl; 2-methyl thio-ethyl; 1; 3-dithienyl-2-methyl (1; 3-dithianyl-2-methyl); 2-(p-nitrophenyl sulfinyl) ethyl; 2-(p-toluenesulfonyl) ethyl; 2-(2 '-pyridyl) ethyl; 2-(p-methoxyphenyl) ethyl; 2-(diphenylphosphino) ethyl; 1-methyl isophthalic acid-phenylethyl; 2-(4-ethanoyl-2-nitrophenyl) ethyl; the 2-cyanoethyl; heptyl; the tertiary butyl; 3-methyl-3-amyl group; bicyclic methyl propyl; 2; 4-dimethyl-3-amyl group; cyclopentyl; cyclohexyl; allyl group; methylallyl (methallyl); 2-methyl fourth-3-alkene-2-base; 3-methyl fourth-2-(prenyl) (3-methylbut-2-(prenyl)); 3-butene-1-Ji; 4-(trimethyl silyl)-2-butylene-1-base; cinnamyl; the Alpha-Methyl cinnamyl; propargyl; phenyl; 2; the 6-3,5-dimethylphenyl; 2; the 6-diisopropyl phenyl; 2; 6-two-tertiary butyl-4-aminomethyl phenyl; 2; 6-two-tertiary butyl-4-p-methoxy-phenyl; to (methyl sulphur) phenyl; pentafluorophenyl group; benzyl; trityl group; diphenyl methyl; two (ortho-nitrophenyl base) methyl; 9-anthryl methyl; 2-(9; the 10-dioxo) anthryl methyl; 5-dibenzo suberyl; 1-pyrenyl methyl; 2-(trifluoromethyl)-6-chromone ylmethyl (2-(trifluoromethyl)-6-chromonylmethyl); 2; 4; the 6-trimethyl benzyl; to bromobenzyl; adjacent nitrobenzyl; to nitrobenzyl; to methoxy-benzyl; 2; the 6-dimethoxy-benzyl; 4-(methyl sulfinyl) benzyl; 4-sulfo group benzyl; 4-nitrine methoxy-benzyl; 4-{N-[1-(4; 4-dimethyl-2; 6-dioxo cyclohexylene)-and the 3-methyl butyl] amino } benzyl; piperonyl; the 4-picolyl; trimethyl silyl; triethylsilyl; t-butyldimethylsilyl, the sec.-propyl dimetylsilyl; the phenyl dimetylsilyl; two-tertiary butyl methyl-silicane base; triisopropyl silyl etc.Other examples of carboxyl-protecting group provide in above-mentioned Greene and Wutts.

[0100] definition of " sulfhydryl protected base " includes but not limited to:

I. alkyl, benzyl, 4-methoxy-benzyl, 2-hydroxybenzyl, 4-hydroxybenzyl, 2-acetoxyl group benzyl, 4-acetoxyl group benzyl, 4-nitrobenzyl, 2,4,6-trimethyl benzyl, 2,4,6-trimethoxy benzyl, 4-picolyl, 2-quinolyl methyl, 2-picolyl n-oxido, 9-anthryl methyl, 9-fluorenyl methyl, xanthenyl, ferrocenyl methyl etc.;

II. diphenyl methyl, two (4-p-methoxy-phenyl) methyl, 5-dibenzo suberyl, trityl group, phenylbenzene-4-pyridylmethyl, phenyl, 2,4-dinitrophenyl, the tertiary butyl, 1-adamantyl etc.;

III. methoxymethyl, isobutoxy methyl, benzyloxymethyl, 2-THP trtrahydropyranyl, benzylthio-methyl, thiophenyl methyl, acetylamino methyl, trimethyl-acetyl methyl, benzene carbon amide ylmethyl, allyloxy formamido group methyl, phenyl acetylamino methyl, phthalimido methyl, ethanoyl, carboxyl-, cyanogen methyl etc.;

IV. (2-nitro-1-phenyl) ethyl, 2-(2, the 4-dinitrophenyl) ethyl, 2-(4 '-pyridyl) ethyl, 2-cyanoethyl, 2-(trimethyl silyl) ethyl, 2, two (ethoxy carbonyl) ethyls of 2-, 1-(3-nitrophenyl)-2-benzoyl-ethyl, 2-phenyl sulfonyl ethyl, 1-(4-aminomethyl phenyl alkylsulfonyl)-2-methyl pro4-2-yl) etc.;

V. trimethyl silyl, triethylsilyl, the triisopropyl silyl, dimethyl sec.-propyl silyl, diethyl sec.-propyl silyl, dimethyl hexyl silyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, the tribenzyl silyl, three-p-Xylol base silyl, the triphenyl silyl, the diphenyl methyl silyl, two-tertiary butyl methyl-silicane base, three (trimethyl silyl) silyl, (2-hydroxystyrene based) dimetylsilyl, (2-hydroxystyrene based) di-isopropyl silyl, tertiary butyl p-methoxy-phenyl silyl, tert.-butoxy diphenylmethyl silylation etc.;

VI. benzoyl, trifluoroacetyl group, N-[[(4-xenyl) isopropoxy] carbonyl]-N-methyl-gamma-amino Thiobutyric acid ester, N-(tert-butoxycarbonyl)-N-methyl-gamma-amino Thiobutyric acid ester etc.;

VII.2,2,2-trichlorine ethoxy carbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, 4-methoxyl group benzyloxy base carbonyl etc.;

VIII.N-(ethylamino) carbonyl, N-(methoxymethyl amino) carbonyl etc.;

IX. ethylmercapto group, uncle's butylthio, thiophenyl, the thiophenyl of replacement etc.;

X. (dimethyl phosphino-) thioyl, (diphenylphosphino) thioyl etc.;

XI. sulfonate (or ester), alkoxy carbonyl sulfenyl, benzyloxycarbonyl sulfenyl, 3-nitro-2-pyridine sulfenyl etc.;

XII. three carbonyls [1,2,3,4,5-η]-2,4-cyclohexadiene-1-yl]-iron (1+) etc.Other examples of sulfhydryl protected base provide in above-mentioned Greene and Wutts.

[0101] term " amino acid " be meant any naturally occurring amino acid with and synthetic analogue and derivative.A-amino acid comprises and amino group bonded carbon atom, carboxylic group, hydrogen atom and the specific groups that is called " side chain ".Naturally occurring amino acid whose side chain is being known in the art, and it comprises, for example hydrogen (for example in glycine), alkyl is (for example at L-Ala, Xie Ansuan, leucine, Isoleucine, in the proline(Pro)), the alkyl that replaces (for example at Threonine, Serine, methionine(Met), halfcystine, aspartic acid, N, L-glutamic acid, glutamine, in arginine and the Methionin), arylalkyl (for example in phenylalanine), the arylalkyl of replacement (for example in tyrosine), heteroarylalkyl (for example at tryptophane, in the Histidine) etc.It will be understood by those skilled in the art that term " amino acid " can also comprise β-, γ-, δ-, omega-amino acid, etc.Alpha-non-natural amino acid also is known in this area, as at Natchus, and M.G.Organic Synthesis:Theory and Applications (2001), 5,89-196; Ager, D.J.Current Opinion in Drug Discovery﹠amp; Development (2001), 4 (6), 800; Reginato, G.Recent Research Developments in Organic Chemistry (2000), 4 (Pt.1), 351-359; Dougherty, D.A.Current Opinion in ChemicalBiology (2000), 4 (6), 645-652; Lesley, S.A.Drugs and the PharmaceuticalSciences (2000), 101 (Peptide and Protein Drug Analysis), 191-205; Pojitkov, A.E.Journal of Molecular Catalysis B:Enzymatic (2000), 10 (1-3), 47-55; Ager, D.J.Speciality Chemicals (1999), 19 (1), described in 10-12 and all reference of wherein being quoted.Described 20 kinds of amino acid whose steric isomers of routine (for example, D-amino acid), alpha-non-natural amino acid is α for example, and α-dibasic amino acid and other unconventional amino acid is the suitable composition of The compounds of this invention also.Unconventional amino acid whose example comprises: 4-oxyproline, 3-Methyl histidine, 5-oxylysine and other similar amino acid and imino-acid (for example, 4-oxyproline).

[0102] term " amino acid of N-protected " is meant that the nitrogen of amido functional group is combined with any amino acid of protecting group.This protecting group prevents that amido functional group from reacting, and can remove by the chemistry or the enzymatic step of routine, to recover described amido functional group.

[0103] term " amino acid of O-protection " is meant that the oxygen of carboxyl functional group is combined with any amino acid of protecting group.This protecting group prevents that carboxyl functional group from reacting, and can remove by the chemistry or the enzymatic step of routine, to recover described carboxyl functional group.The concrete protecting group of using is not crucial.

[0104] term " prodrug " is meant the medicament that is converted into parent drug in vivo.Because prodrug is than the easier administration of parent drug in some cases, so prodrug is normally useful.For example, they can pass through oral administration and biological effectively (bioavailable), and its parent drug then can not.Prodrug can also have the solubleness higher than parent drug in pharmaceutical composition.Can prodrug be converted into parent drug by various mechanism, comprise enzymic process and metabolism hydrolysis.Harper among the Progress in Drug Research 4:221-294 (1962) that edits referring to Jucker, " Drug Latentiation "; The Design of Biopharmaceutical Properties through Prodrugsand Analogs that E.B.Roche edits, Morozowich among the APHA Acad.Pharm.Sci. (1977) etc., " Application of Physical Organic Principles to Prodrug Design "; BioreversibleCarriers in Drug in Drug Design, Theory and Application, E.B.Roche, ed., APHAAcad.Pharm.Sci. (1987); Design of Prodrugs, H.Bundgaard, Elsevier (1985); " Prodrugapproaches to the improved delivery of peptide drag " such as Wang among Curr.Pharm.Design.5 (4): the 265-287 (1999); Pauletti etc. (1997) Improvement in peptide bioavailability:Peptidomimetics and Prodrug Strategies, Adv.Drug.Delivery Rev.27:235-256; Mizen etc. (1998) " The Use of Esters asProdrugs for oral Delivery of β-Lactam antibiotics, " Pharm.Biotech.11,345-365; Gaignault etc. (1996) " Designing Prodrugs and Bioprecursors I.CarrierProdrugs ", Pract.Med.Chem.671-696; Transport Processes in PharmaceuticalSystems, G.L.Amidon, P.I.Lee and E.M.Topp, Eds., Marcell Dekker, the Asgharnejad in (2000) p.185-218, " Improving oral Drug Transport "; Balant etc., " Prodrugs for the improvement of drug absorption via different routes ofadministration ", Eur.J.Drag Metab.Pharmacokinet, 15 (2): 143-53 (1990); Balimane and Sinko, " Involvement of multiple transporters in the oral absorptionof nucleoside analogues ", Adv.Drag Delivery Rev., 39 (1-3): 183-209 (1999); Browne, " Fosphenytoin (Cerebyx) ", Clin.Neuropharmacol.20 (1): 1-12 (1997); Bundgaard, " Bioreversible derivatization of drugs-principle and applicability toimprove the therapeutic effects of drugs ", Arch.Pharm.Chemi 86 (1): 1-39 (1979); Bundgaard H. " Improved drug delivery by the Prodrug approach ", Controlled Drag Delivery 17:179-96 (1987); Bundgaard H. " Prodrugs as ameans to improve the delivery of peptide drugs ", Ad v.Drug DeliveryRev.8 (1); 1-38 (1992); Fleisher etc. " Improved oral drug delivery:solubility limitationsovercome by the use of Prodrugs ", Adv.Drag Delivery Rev.19 (2): 115-130 (1996); Fleisher etc. " Design of Prodrugs for improved gastrointestinalabsorption by intestinal enzyme targeting ", Methods Enzymol.112 (DrugEnzyme Targeting, Pt.A): 360-81, (1985); Farquhar D etc., " BiologicallyReversible Phosphate-Protective Groups ", J.Pharm.Sci., 72 (3): 324-325 (1983); Freeman S etc., " Bioreversible Protection for the Phospho Group:ChemicalStability and Bioactivation of Di (4-acetoxy-benzyl) Methylphosphonate withCarboxyesterase; " J.Chem.Soc, Chem.Commun., 875-877 (1991); Friis and Bundgaard, " Prodrugs of phosphates and phosphonates:Novel lipophilicalpha-acyloxyalkyl ester derivatives of phosphate-or phosphonate containingdrugs masking the negative charges of these groups ", Eur.J.Pharm.Sci.4:49-59 (1996); Gangwar etc., " Pro-drug, molecular structure and percutaneousdelivery ", Des.Biopharm.Prop.Prodrugs Analogs, [Symp.] Meeting Date 1976,409-21. (1977); Nathwani and Wood, " Penicillins:a current Review of theirclinical pharmacology and therapeutic use ", Drugs 45 (6): 866-94 (1993); Sinhababu and Thakker, " Prodrugs of anticancer agents ", Adv.Drug Delivery Rev.19 (2): 241-273 (1996); Stella etc., " Prodrugs.Do they have advantages in clinicalpractice? ", Drugs 29 (5): 455-73 (1985); Tan etc., " Development and optimizationof anti-HIV nucleoside analogs and Prodrugs:A Review of their cellularpharmacology; structure-activity relationships and pharmacokinetics ", Adv.Drug Delivery Rev.39 (1-3): 117-151 (1999); Taylor, " Improved passive oraldrug delivery via prodrugs ", Adv.Drug Delivery Rev., 19 (2): 131-148 (1996); Valentino and Borchardt, " Prodrug strategies to enhance the intestinal absorptionof peptides ", Drug Discovery Today 2 (4): 148-155 (1997); Wiebe and Knaus, " Concepts for the design of anti-HIV nucleoside prodrugs for treating cephalicHIV infection ", Adv.Drug Delivery Re v.:39 (1-3): 63-80 (1999); Waller etc., " Prodrugs ", Br.J.Clin.Pharmac.28:497-507 (1989).

[0105] according to above-mentioned purpose of the present invention, according to the needs of the medicine of realizing being converted into the improvement that this paper proposes, all reagent that comprise hydrogen, hydride or proton usually of mentioning can comprise its partially or completely deuterated form (comprising deuterium or heavy hydride).

[0106] term " halogen ", " halogenide " or " halogen " comprises fluorine, chlorine, bromine and iodine.

[0107] term " alkyl " and " alkyl of replacement " can exchange, and comprise replacement with specified number of carbon atoms, randomly that replace and unsubstituted C ₁-C ₁₀Straight chain radical of saturated aliphatic hydrocarbyl group, replacement, randomly that replace and unsubstituted C ₂-C ₁₀Straight chain unsaturated aliphatic hydrocarbyl group, replacement, randomly that replace and unsubstituted C ₂-C ₁₀Side chain radical of saturated aliphatic hydrocarbyl group, replacement and unsubstituted C ₂-C ₁₀Side chain unsaturated aliphatic hydrocarbyl group, replacement, randomly that replace and unsubstituted C ₃-C ₈Ring-type radical of saturated aliphatic hydrocarbyl group, replacement, randomly that replace and unsubstituted C ₅-C ₈Ring-type unsaturated aliphatic hydrocarbyl group.For example, the definition of " alkyl " should include but not limited to: methyl (Me), three deuterium methyl (CD ₃), ethyl (Et), propyl group (Pr), butyl (Bu), amyl group, hexyl, heptyl, octyl group, nonyl, decyl, undecyl, vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, the nonene base, the decene base, undecenyl, sec.-propyl (i-Pr), isobutyl-(i-Bu), the tertiary butyl (t-Bu), sec-butyl (s-Bu), isopentyl, neo-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, the ring octyl group, cyclopentenyl, cyclohexenyl, cycloheptenyl, the cyclooctene base, the methyl cyclopropyl, the ethyl-cyclohexene base, the butenyl cyclopentyl, adamantyl, norcamphyl etc.Alkyl substituent be independently selected from hydrogen, deuterium, halogen ,-OH ,-SH ,-NH ₂,-CN ,-NO ₂,=O ,=CH ₂, trihalogenmethyl, formamyl, aryl C _0-10Alkyl, heteroaryl C _0-10Alkyl, C _1-10Alkoxyl group, aryl C _0-10Alkoxyl group, C _1-10Alkyl sulfenyl, aryl C _0-10Alkyl sulfenyl, C _1-10Alkylamino, aryl C _0-10Alkylamino, N-aryl-N-C _0-10Alkylamino, C _1-10Alkyl-carbonyl, aryl C _0-10Alkyl-carbonyl, C _1-10Alkyl carboxyl, aryl C _0-10Alkyl carboxyl, C _1-10Alkyl carbonylamino, aryl C _0-10Alkyl carbonylamino, tetrahydrofuran base, morpholinyl, piperazinyl, hydroxyl pyrethrum base (hydroxypyronyl) ,-C _0-10Alkyl COOR ₃₁With-C _0-10Alkyl CONR ₃₂R ₃₃, R wherein ₃₁, R ₃₂And R ₃₃Be independently selected from hydrogen, deuterium, alkyl, aryl, or R ₃₂And R ₃₃Connected nitrogen forms saturated rings or unsaturated loop systems together, and described loop systems comprises 3 to 8 carbon atoms and has the substituting group that at least one defines herein.

[0108] purpose of description according to the present invention, according to the improved needs of realizing that this paper proposes, " alkyl " group that all are mentioned or any group that comprises c h bond usually all can comprise its partially or completely deuterated form.

[0109] replacement with the carbon atom that specifies number of the definition as mentioned that connects by oxo bridge of term " alkoxyl group " (for example methoxyl group, oxyethyl group, propoxy-, allyloxy, cyclohexyloxy) expression or the unsubstituted alkyl group.The alkoxy base by the alkyl group connection of the alkyl group with the carbon atom that specifies number of definition as mentioned or replacement represented in term " alkoxyalkyl ".

[0110] replacement with the carbon atom that specifies number or the unsubstituted alkoxy base of definition as mentioned that connects by the carbonyl bridging of term " alkoxy carbonyl " (for example methoxycarbonyl, ethoxy carbonyl, tert-butoxycarbonyl, allyloxy carbonyl) expression.

[0111] replacement with the carbon atom that specifies number of the definition as mentioned that connects by sulphur bridge of term " alkyl sulfenyl " (for example methyl sulfenyl, ethyl sulfenyl, propyl group sulfenyl, cyclohexenyl sulfenyl etc.) expression or the unsubstituted alkyl group.The alkyl sulfenyl group that the alkyl group that term " alkyl sulfenyl alkyl " expression specifies number carbon atom by having of definition as mentioned or the alkyl group of replacement connect.

[0112] one or two replacement with the carbon atom that specifies number of the definition as mentioned that connects by the amine bridging of term " alkylamino " (for example methylamino, diethylamino, butyl amino, N-propyl group-N-hexyl amino, (2-cyclopentyl) propyl group amino, hexenyl amino etc.) expression or the unsubstituted alkyl group.Described replacement or the unsubstituted alkyl group can form saturated rings or unsaturated loop systems together by connected nitrogen, described loop systems comprises 3 to 10 carbon atoms and has the substituting group that at least one defines herein.Term " alkylamino alkyl " expression is by the alkylamino group replacement with the carbon atom that specifies number or that the unsubstituted alkyl group connects of definition as mentioned.

[0113] one or two replacement with the carbon atom that specifies number of the definition as mentioned that connects of term " alkyl diazanyl " (for example methyl diazanyl, diethyl diazanyl, butyl diazanyl, (2-cyclopentyl) propyl group diazanyl, hexanaphthene diazanyl etc.) the expression nitrogen-atoms by the hydrazine bridge or the unsubstituted alkyl group.Described replacement or the unsubstituted alkyl group can form saturated rings or unsaturated loop systems together by connected nitrogen, described loop systems comprises 3 to 10 carbon atoms and has the substituting group that at least one defines herein.Term " alkyl diazanyl alkyl " expression is by the alkyl diazanyl group replacement with the carbon atom that specifies number or that the unsubstituted alkyl group connects of definition as mentioned.

[0114] replacement with the carbon atom that specifies number of the definition as mentioned that connects by carbonyl group of term " alkyl-carbonyl " (for example encircling octyl group carbonyl, amyl group carbonyl, 3-hexenyl carbonyl etc.) expression or the unsubstituted alkyl group.Term " alkyl-carbonyl alkyl " expression is by the alkyl-carbonyl group replacement with the carbon atom that specifies number or that the unsubstituted alkyl group connects of definition as mentioned.

[0115] alkyl-carbonyl of definition as mentioned that wherein said carbonyl connects by oxygen again represented in term " alkyl carboxyl " (for example heptyl carboxyl, cyclopropyl carboxyl, 3-pentenyl carboxyl etc.).The alkyl carboxyl group that term " alkyl carboxyl alkyl " expression connects by the alkyl group with the carbon atom that specifies number that defines as mentioned.

[0116] alkyl-carbonyl of definition as mentioned represented in term " alkyl-carbonyl-amino " (for example hexyl carbonylamino, cyclopentylcarbonyl-amino methyl, methyl carbonylamino phenyl etc.), and wherein said carbonyl connects by the nitrogen-atoms of amino group again.Nitrogen groups self can substituted or unsubstituted alkyl or aromatic yl group replacement.Term " alkyl-carbonyl-amino alkyl " expression is by the alkyl-carbonyl-amino replacement with the carbon atom that specifies number or that unsubstituted alkyl connects of definition as mentioned.

[0117] the alkyl-carbonyl group of definition as mentioned represented in term " alkyl-carbonyl diazanyl " (for example ethyl carbonyl diazanyl, tertiary butyl carbonyl diazanyl etc.), and wherein said carbonyl connects by the nitrogen-atoms of diazanyl group again.

[0118] term " aryl " is illustrated in the not replacement that any ring position that can form stable covalent linkage covalently connects, single replacement or polysubstituted monocycle, many rings, diaryl aromatic group, some preferred tie point is conspicuous (for example 3-phenyl, 4-naphthyl etc.) for those skilled in the art.Aryl substituent be independently selected from hydrogen, deuterium, halogen ,-OH ,-SH ,-CN ,-NO ₂, trihalogenmethyl, hydroxyl pyrethrum base (hydroxypyronyl), C _1-10Alkyl, aryl C _0-10Alkyl, C _0-10Alkoxy C _0-10Alkyl, aryl C _0-10Alkoxy C _0-10Alkyl, C _0-10Alkyl sulfenyl C _0-10Alkyl, aryl C _0-10Alkyl sulfenyl C _0-10Alkyl, C _0-10Alkylamino C _0-10Alkyl, aryl C _0-10Alkylamino C _0-10Alkyl, N-aryl-N-C _0-10Alkylamino C _0-10Alkyl, C _1-10Alkyl-carbonyl C _0-10Alkyl, aryl C _0-10Alkyl-carbonyl C _0-10Alkyl, C _1-10Alkyl carboxyl C _0-10Alkyl, aryl C _0-10Alkyl carboxyl C _0-10Alkyl, C _1-10Alkyl-carbonyl-amino C _0-10Alkyl, aryl C _0-10Alkyl-carbonyl-amino C _0-10Alkyl ,-C _0-10Alkyl COOR ₃₁And C _0-10Alkyl CONR ₃₂R ₃₃, R wherein ₃₁, R ₃₂And R ₃₃Be independently selected from hydrogen, deuterium, alkyl, aryl, or R ₃₂And R ₃₃Connected nitrogen forms saturated rings or unsaturated loop systems together, and described loop systems comprises 3 to 8 carbon atoms and has the substituting group that at least one defines herein.

[0119] definition of " aryl " includes but not limited to: phenyl, five deuterium phenyl, xenyl, naphthyl, dihydro naphthyl, tetralyl, indenyl, indanyl, Azulene base (azulenyl), anthryl, phenanthryl, fluorenyl, pyrenyl etc.

[0120] term " arylalkyl " (for example (4-hydroxy phenyl) ethyl, (the amino naphthyl of 2-) hexenyl etc.) have the as mentioned aromatic yl group of definition replacement or that unsubstituted alkyl group connect that specify number carbon atom of expression by defining as mentioned.

[0121] term " aryl carbonyl " (for example 2-thio-phenyl carbonyl, 3-methoxyl group anthryl carbonyl etc.) expression is by the aromatic yl group of definition as mentioned of carbonyl group connection.

[0122] term " aromatic yl alkyl carbonyl " (for example (2, the 3-Dimethoxyphenyl) propyl group carbonyl, (2-chloronaphthyl, methylnaphthyl) pentenyl-carbonyl etc.) the expression aromatic yl alkyl group of definition as mentioned, wherein said alkyl group connects by carbonyl again.

[0123] term " aryloxy " (for example phenoxy group, naphthyloxy, 3-methylphenoxy etc.) expression is by the aryl with the carbon atom that specifies number of definition as mentioned of oxo bridge connection or the aromatic yl group of replacement.Term " aryloxy alkyl " expression is by the aryloxy group of the replacement with the carbon atom that specifies number or the connection of unsubstituted alkyl group of definition as mentioned.

[0124] replacement with the carbon atom that specifies number or the unsubstituted aryloxy group of definition as mentioned that connect by the carbonyl bridging of term " aryloxycarbonyl " (for example phenyloxycarbonyl, naphthyloxy carbonyl) expression.

[0125] term " artyl sulfo " (for example phenyl sulfenyl, naphthyl sulfenyl, 3-bromophenyl sulfenyl etc.) expression is by the aryl with the carbon atom that specifies number of definition as mentioned of sulphur bridge connection or the aromatic yl group of replacement.Term " artyl sulfo alkyl " expression is by the alkyl sulfenyl group of the replacement with the carbon atom that specifies number or the connection of unsubstituted alkyl group of definition as mentioned.

[0126] one or two aromatic yl group of definition as mentioned of connecing by the amine bridging of term " arylamino " (for example phenyl amino, benzidino-, naphthyl amino, N-phenyl-N-naphthyl amino, o-methyl-phenyl-amino, p-methoxyphenyl amino etc.) expression with the carbon atom that specifies number.Term " arylamino alkyl " expression is by the arylamino group replacement with the carbon atom that specifies number or that the unsubstituted alkyl group connects of definition as mentioned.The aromatic yl group that term " aryl-alkyl amino " expression connects by the alkylamino group with the carbon atom that specifies number that defines as mentioned.An aryl with the carbon atom that specifies number of the definition as mentioned that term " N-aryl-N-alkylamino " (for example N-phenyl-N-methylamino, N-naphthyl-normal-butyl amino etc.) expression connects by the amine bridging independently and a replacement or the unsubstituted alkyl group.

[0127] one or two aromatic yl group of definition as mentioned of connecing by the hydrazine bridging of term " aryl diazanyl " (for example phenyl diazanyl, naphthyl diazanyl, 4-p-methoxy-phenyl diazanyl etc.) expression with the carbon atom that specifies number.Term " aryl diazanyl alkyl " expression is by the aryl diazanyl group replacement with the carbon atom that specifies number or that the unsubstituted alkyl amino group connects of definition as mentioned.The aromatic yl group that term " arylalkyl diazanyl " expression connects by the alkyl diazanyl group with the carbon atom that specifies number that defines as mentioned.Term " N-aryl-N-alkyl diazanyl " (for example N-phenyl-N-methyl diazanyl, N-naphthyl-N-butyl diazanyl etc.) expression independently the aryl with the carbon atom that specifies number of the definition as mentioned that connects of the amine atom by the hydrazine bridge and a replacement or the unsubstituted alkyl group.

[0128] the aryl carbonyl group of definition as mentioned represented in term " aryl carboxyl " (for example phenyl carboxyl, naphthyl carboxyl, 3-fluorophenyl carboxyl etc.), and wherein said carbonyl connects by oxo bridge again.Term " aryl carboxyalkyl " expression is by the aryl carboxylic group of the replacement with the carbon atom that specifies number or the connection of unsubstituted alkyl group of definition as mentioned.

[0129] the aryl carbonyl group of definition as mentioned represented in term " aryl-amino-carbonyl " (for example phenylcarbonyl group amino, naphthyl carbonyl amino, 2-aminomethyl phenyl carbonylamino etc.), and wherein said carbonyl connects by the nitrogen-atoms of amino group again.Nitrogen groups self can substituted or unsubstituted alkyl or aromatic yl group replacement.Term " aryl-amino-carbonyl alkyl " expression is by the aryl-amino-carbonyl replacement with the carbon atom that specifies number or that the unsubstituted alkyl group connects of definition as mentioned.Nitrogen groups self can substituted or unsubstituted alkyl or aromatic yl group replacement.

[0130] the aryl carbonyl group of definition as mentioned represented in term " aryl carbonyl diazanyl " (for example phenylcarbonyl group diazanyl, naphthyl carbonyl diazanyl etc.), and wherein carbonyl connects by the nitrogen-atoms of diazanyl group again.

[0131] term " heteroaryl ", " heterocycle " or " heterocyclic " is meant the unit price unsaturated group, described unit price unsaturated group has monocycle or a plurality of condensed ring, has 1 to 13 carbon atom and 1 to 10 heteroatoms that is selected from nitrogen, sulphur and oxygen in ring.Heteroaryl groups among the present invention can be randomly be selected from following substituent substituting group with 1 to 10 and replace: hydrogen, deuterium, halogen ,-OH ,-SH ,-CN ,-NO ₂, trihalogenmethyl, hydroxyl pyrethrum base (hydroxy), C _1-10Alkyl, aryl C _0-10Alkyl, C _0-10Alkoxy C _0-10Alkyl, aryl C _0-10Alkoxy C _0-10Alkyl, C _0-10Alkyl sulfenyl C _0-10Alkyl, aryl C _0-10Alkyl sulfenyl C _0-10Alkyl, C _0-10Alkylamino C _0-10Alkyl, aryl C _0-10Alkylamino C _0-10Alkyl, N-aryl-N-C _0-10Alkylamino C _0-10Alkyl, C _1-10Alkyl-carbonyl C _0-10Alkyl, aryl C _0-10Alkyl-carbonyl C _0-10Alkyl, C _1-10Alkyl carboxyl C _0-10Alkyl, aryl C _0-10Alkyl carboxyl C _0-10Alkyl, C _1-10Alkyl-carbonyl-amino C _0-10Alkyl, aryl C _0-10Alkyl-carbonyl-amino C _0-10Alkyl ,-C _0-10Alkyl COOR ₃₁And-C _0-10Alkyl CONR ₃₂R ₃₃, R wherein ₃₁, R ₃₂And R ₃₃Be independently selected from hydrogen, deuterium, alkyl, aryl, or R ₃₂And R ₃₃Connected nitrogen forms saturated rings or unsaturated loop systems together, and described loop systems comprises 3 to 8 carbon atoms and has the substituting group that at least one defines herein.

[0132] definition of " heteroaryl " includes but not limited to: thienyl, benzothienyl, isobenzo-thienyl, 2,3-dihydrobenzo thienyl, furyl, pyranyl, benzofuryl, isobenzofuran-base, 2, the 3-dihydro benzo furyl, pyrryl, pyrryl-2, the 5-diketone, the 3-pyrrolinyl, indyl, pseudoindoyl, the 3H-indyl, indolinyl, indyl (indolizinyl), indazolyl, phthalimide-based (phthalimidyl) (or pseudoindoyl-1, the 3-diketone), imidazolyl, the 2H-imidazolinyl, benzimidazolyl-, the deuterium benzimidazolyl-, two deuterium benzimidazolyl-s, three deuterium benzimidazolyl-s, four deuterium benzimidazolyl-s, pyridyl, the deuterium pyridyl, two deuterium pyridyl, three deuterium pyridyl, four deuterium pyridyl, pyrazinyl, pyridazinyl (pyradazinyl), pyrimidyl, triazinyl, quinolyl, isoquinolyl, 4H-quinoline piperazine base (4H-quinolizinyl), cinnolines base (cinnolinyl), phthalazinyl, quinazolyl, quinoxalinyl, 1,8-naphthyridinyl (1,8-naphthyridinyl), pteridyl (pteridinyl), carbazyl, acridyl, phenazinyl, phenothiazinyl Ben oxazinyl (phenoxazinyl), chromanyl, benzo dioxy base, piperonyl, purine radicals, pyrazolyl, triazolyl, tetrazyl, thiazolyl, isothiazolyl, benzothiazolyl oxazolyl isoxazolyl benzoxazolyl oxadiazole base, thiadiazolyl group (thiadiazolyl), pyrrolidyl-2, the 5-diketone, imidazolidyl-2, the 4-diketone, 2-sulfo-(thioxo)-imidazolidyl-4-ketone, imidazolidyl-2, the 4-dithione, thiazolidine base-2, the 4-diketone, 4-sulfo--thiazolidine base-2-ketone, piperazinyl-2, the 5-diketone, tetrahydrochysene-pyridazinyl-3, the 6-diketone, 1,2-dihydro-[1,2,4,5] tetrazine base-3,6-diketone (1,2-dihydro-[1,2,4,5] tetrazinyl-3,6-dione), [1,2,4,5] tetrazine base-3,6-diketone ([1,2,4,5] tetrazinanyl-3,6-dione), dihydro-pyrimidyl-2, the 4-diketone, pyrimidyl-2,4, the 6-triketone, 1H-pyrimidyl-2, the 4-diketone, 5-iodo-1H-pyrimidyl-2, the 4-diketone, 5-chloro-1H-pyrimidyl-2, the 4-diketone, 5-methyl isophthalic acid H-pyrimidyl-2, the 4-diketone, 5-sec.-propyl-1H-pyrimidyl-2, the 4-diketone, 5-proyl-1H-pyrimidyl-2, the 4-diketone, 5-Trifluoromethyl-1 H-pyrimidyl-2, the 4-diketone, 6-amino-9H-purine radicals, 2-amino-9H-purine radicals, 4-amino-1H-pyrimidyl-2-ketone, 4-amino-5-fluoro-1H-pyrimidyl-2-ketone, 4-amino-5-methyl isophthalic acid H-pyrimidyl-2-ketone, 2-amino-1,9-dihydro-purine radicals-6-ketone, 1,9-dihydro-purine radicals-6-ketone, 1H-[1,2,4] triazolyl-3-carboxylic acid amide, 2,6-diamino-N 6-cyclopropyl-9H-purine radicals, 2-amino-6-(4-p-methoxy-phenyl sulfane base)-9H-purine radicals, 5,6-two chloro-1H-benzimidazolyl-s, 2-sec.-propyl amino-5,6-two chloro-1H-benzimidazolyl-s, 2-bromo-5,6-two chloro-1H-benzimidazolyl-s, 5-methoxyl group-1H-benzimidazolyl-, the 3-ethylpyridine base, 5-methyl-2-phenyl-oxazolyls, 5-methyl-2-thiophene-2-base-oxazolyls, 2-furans-2-base-5-methyl-oxazolyls, 3-methyl-3H-quinazoline-4-one, 4-methyl-2H-phthalazines-1-ketone, 2-ethyl-6-methyl-3H-pyrimidin-4-one, 5-methoxyl group-3-methyl-3H-imidazoles [4,5-b] pyridine etc.For the application's purpose, term " heteroaryl ", " heterocycle " or " heterocyclic " do not comprise carbohydrate ring (being monose or oligosaccharides).

[0133] term " saturated heterocyclic " expression covalently is connected any ring position and can forms the unsubstituted of stable covalent linkage, single replacement and polysubstituted monocycle, many ring fillings heterocyclic group, some preferred tie point is conspicuous (for example piperidino, 4-piperazinyl, DBU etc.) for those skilled in the art.

[0134] saturated heterocyclic substituent be independently selected from halogen ,-OH ,-SH ,-CN ,-NO ₂, trihalogenmethyl, hydroxyl pyrethrum base (hydroxypyronyl), C _1-10Alkyl, aryl C _0-10Alkyl, C _0-10Alkoxy C _0-10Alkyl, aryl C _0-10Alkoxy C _0-10Alkyl, C _0-10Alkyl sulfenyl C _0-10Alkyl, aryl C _0-10Alkyl sulfenyl C _0-10Alkyl, C _0-10Alkylamino C _0-10Alkyl, aryl C _0-10Alkylamino C _0-10Alkyl, N-aryl-N-C _0-10Alkylamino C _0-10Alkyl, C _1-10Alkyl-carbonyl C _0-10Alkyl, aryl C _0-10Alkyl-carbonyl C _0-10Alkyl, C _1-10Alkyl carboxyl C _0-10Alkyl, aryl C _0-10Alkyl carboxyl C _0-10Alkyl, C _1-10Alkyl-carbonyl-amino C _0-10Alkyl, aryl C _0-10Alkyl-carbonyl-amino C _0-10Alkyl ,-C _0-10Alkyl COOR ₃₁And-C _0-10Alkyl CONR ₃₂R ₃₃, R wherein ₃₁, R ₃₂And R ₃₃Be independently selected from hydrogen, deuterium, alkyl, aryl, or R ₃₂And R ₃₃Connected nitrogen forms saturated rings or unsaturated loop systems together, and described loop systems comprises 3 to 8 carbon atoms and has the substituting group of at least one above-mentioned definition.

[0135] definition of saturated heterocyclic includes but not limited to: pyrrolidyl, pyrazolidyl, piperidyl, 1, the 4-alkyl dioxin (1,4-dioxanyl), morpholinyl, 1,4-dithienyl, thio-morpholinyl, piperazinyl, quinuclidinyl etc.

[0136] term " alpha-beta-unsaturated carbonyl " is meant and has the molecule that directly is connected the carbonyl group on two keys or the triple bond carbon, and it is conspicuous to those of ordinary skills.The definition of alpha-beta-unsaturated carbonyl includes but not limited to propenal, methyl vinyl ketone etc.

[0137] term " acetal " is meant to comprise and is connected directly to hydrogen atom (H ₁) carbon atom C ₁, the carbon atom (C that replaces ₂) and two Sauerstoffatom (O ₁And O ₂) molecule.These Sauerstoffatoms are connected to the carbon atom (C of other replacement again ₃And C ₄), it is conspicuous to those of ordinary skills.The definition of acetal includes but not limited to: 1, and 1-Propanal dimethyl acetal, 1,1-pair-allyloxy butane etc.

[0138] term " cyclic acetal " is meant acetal as defined above, wherein C ₃And C ₄Connected Sauerstoffatom encircles in conjunction with forming 5-to 10-unit by the alkyl bridge together, and it is conspicuous to those of ordinary skills.The definition of cyclic acetal includes but not limited to: 2-methyl-[1,3] dioxolane, the 2-ethyl-[1,3] diox, the 2-phenyl-[1,3] diox, 2-phenyl-six hydrogen-pyrans be [3,2-d] [1,3] Dioxins etc. also.

N=1 to 5

[0139] term " ketal " is meant and comprises directly and the carbon atom (C of two replacements ₂And C ₃) and two Sauerstoffatom (O ₁And O ₂) continuous carbon atom C ₁Molecule.These Sauerstoffatoms are connected to the carbon atom (C of other replacement again ₄And C ₅), it is conspicuous to those of ordinary skills.The definition of acetal includes but not limited to 2,2-dimethoxy-butane, 3,3-diethoxy-pentane etc.

[0140] term " cyclic ketal " is meant ketal as defined above, wherein C ₄And C ₅Connected Sauerstoffatom encircles in conjunction with forming 5-to 10-unit by the alkyl bridge together, and it is conspicuous to those of ordinary skills.The definition of cyclic acetal includes but not limited to 2,2,4, and 5-tetramethyl--[1,3] dioxolane, 2,2-diethyl-[1,3] Dioxepane, 2,2-dimethyl-six hydrogen-pyrans be [3,2-d] [1,3] Dioxins etc. also.

N=0 to 5

[0141] " C-carboxyl " group be meant-C (=O) or group, wherein R as defined herein.

[0142] " ethanoyl " group is meant-C (=O) CH ₃Group.

[0143] " haloform alkylsulfonyl " group is meant X ₃CS (=O) ₂-group, wherein X is a halogen.

[0144] " cyanogen " group is meant-the CN group.

[0145] " isocyanide acyl group " group is meant-the NCO group.

[0146] " thiocyano " group is meant-the CNS group.

[0147] " isothiocyano " group is meant-the NCS group.

[0148] " sulfinyl " group be meant-S (=O)-the R group, R as defined herein.

[0149] " S-sulfonamido " group be meant-S (=O) ₂NR group, R are as defined herein.

[0150] " N-sulfonamido " group be meant RS (=O) ₂NH-group, R are as defined herein.

[0151] " haloform sulfonamido " group is meant X ₃CS (=O) ₂The NR-group, X and R are as defined herein.

[0152] " O-formamyl " group be meant-OC (=O)-the NR group, R as defined herein.

[0153] " N-formamyl " group is meant ROC (=O) NH-group, R is for as defined herein.

[0154] " O-thiocarbamoyl " group be meant-OC (=S)-the NR group, R as defined herein.

[0155] " N-thiocarbamoyl " group is meant ROC (=S) NH-group, R as defined herein.

[0156] " C-amino " group be meant-C (=O)-NR ₂Group, R are as defined herein.

[0157] " N-amino " group is meant RC (=O) NH-group, R as defined herein.

[0158] term " perhaloalkyl radical " is meant the alkyl group that wherein all hydrogen atoms are all replaced by halogen atom.

[0159] term " pharmaceutical composition " is meant for example mixture of diluent or carrier of compound disclosed herein and other chemical ingredients.Described pharmaceutical composition helps compound to organic administration.There is multiple technology of giving drug compound this area, and that described technology includes but not limited to is oral, injection, aerosol, parenteral and topical.Pharmaceutical composition can also obtain by making compound and inorganic or organic acid reaction, and described inorganic or organic acid is hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic, ethane sulfonic acid, tosic acid, Whitfield's ointment etc. for example.

[0160] term " carrier " is limited with and helps compound and enter compound in the cell or tissue.For example, because dimethyl sulfoxide (DMSO) (DMSO) helps the absorption of many organic compound in the organic cell or tissue, so it often be the carrier of use.

[0161] term " thinner " limits the solution that can dissolve compound of interest and can stablize the biologically active form of described compound, and it is normally aqueous or partially aqueous.The salt that will be dissolved in the art in the buffered soln is used as thinner.A kind of buffered soln of frequent use is phosphate buffered saline buffer, and this is because it has simulated the salt condition of human blood.Because buffering salt can be controlled the pH of solution with lower concentration, so the buffered thinner changes the biologic activity of compound hardly.

[0162] before disclosure and description compound of the present invention, composition and method, it should be understood that, because it can change in the nature of things, therefore aspect of the present invention is not limited to concrete synthetic method, concrete pharmaceutical carrier or concrete pharmaceutical preparation or dosage regimen.Should also be understood that term used herein only is used to describe the purpose of particular, rather than be intended to limit the present invention.

[0163] unless should also be noted that in the context and clearly indicates in addition that the singulative that uses " (a, an) " and " described (the) " comprise the thing that refers to of plural number in specification sheets and claims.The mixture that comprises dinuclear aromatics when therefore, for example, mentioning " dinuclear aromatics "; Comprise the mixture of two or more described carriers etc. when mentioning " pharmaceutical carrier ".

[0164] by preparing some pharmacologically acceptable salts of the present invention with the acceptable alkaline purification of an amount of pharmacy novel cpd of the present invention.The acceptable alkali of representational pharmacy is ammonium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, ferrous hydroxide, zinc hydroxide, copper hydroxide, aluminium hydroxide, ironic hydroxide, isopropylamine, Trimethylamine, diethylamide, triethylamine, tripropylamine, thanomin, 2-dimethylaminoethanol, 2-DEAE diethylaminoethanol, Methionin, arginine, Histidine etc.Be reflected under about 0 ℃ to 100 ℃ temperature, preferably at room temperature, only at water or D ₂Carry out among the O, or at water or D ₂Carry out in the combination of O and inert and the immiscible organic solvent of water, or only in organic solvent, carry out.The mol ratio of the alkali of choice structure formula 1 compound and use is to provide for the required ratio of arbitrary concrete salt.For preparation example such as starting material ammonium salt, can be with acceptable alkaline purification formula 1 compound of pharmacy of about monovalent, with the generation neutral salt.When the preparation calcium salt, use the alkali of about half molar equivalent, with the generation neutral salt, and, will use the alkali of about 1/3rd molar equivalents for aluminium salt.

[0165] The compounds of this invention can be mixed with pharmaceutical composition easily, described pharmaceutical composition comprise one or more described compounds and as E.W.Martin at the pharmaceutically acceptable carrier described in the latest edition Remington ' sPharmaceutical Sciences (Mack Publ.Co., Easton Pa.).

[0166] although usually preferred oral or topical, The compounds of this invention can pass through oral administration, administered parenterally (for example intravenously administrable), by the intramuscular injection administration, by intraperitoneal injection administration, topical, transdermal administration etc.The dosage of active compound will depend on the object of treatment, the body weight of object, the mode of administration and prescription doctor's judgement certainly.Dosage will be in about 1 microgram scope of every kilogram of milligram every kilogram of every day every day to 100.

[0167] administering mode as required, described pharmaceutical composition can be the form of solid, semisolid or liquid dosage form, for example be tablet, suppository, pill, capsule, pulvis, liquid, suspensoid, washing lotion, ointment, gelifying agents etc. are preferably the form of the unit dosage that is applicable to the single-dose exact dosage desired.As mentioned above, described composition will comprise the selected medicine of significant quantity and the combination of pharmaceutical acceptable carrier, in addition, also can comprise other drug, pharmacy agent, carrier, adjuvant, thinner etc.

[0168] for solids composition, conventional nontoxicity solid carrier comprises the N.F,USP MANNITOL, lactose, starch, Magnesium Stearate, soluble saccharin, talcum, Mierocrystalline cellulose, glucose, sucrose, magnesiumcarbonate of pharmaceutical grade for example etc.But the liquid composition of administration can be for example by active compound described herein and optional pharmacy adjuvant are dissolved in vehicle, preparation such as dispersion, described vehicle for example is water, salt solution, the dextrose aqueous solution, glycerine, ethanol etc., thereby forms solution or suspensoid.If desired, the pharmaceutical composition for the treatment of administration also can comprise a spot of nontoxicity auxiliary substance for example wetting agent or emulsifying agent, pH buffer reagent etc., for example sodium acetate, sorbitan monolaurate, trolamine sodium acetate, triethanol amine oleate etc.To those skilled in the art, the practical methods for preparing described formulation is known or conspicuous; For example referring to Remington ' s PharmaceuticalSciences mentioned above.

[0169] for oral administration, pulvis subtilis or granule can comprise thinner, dispersion agent and/or tensio-active agent, and may reside in water or the syrup, be present in capsule or the medicine bag (sachet) or be present in non-aqueous solution or the suspensoid with drying regime and (wherein can comprise suspension agent), be present in (wherein can comprise binding agent and lubricant) in the tablet or the suspensoid in water or syrup in.In office what is the need for when wanting also can comprise seasonings, sanitas, suspension agent, thickening material or emulsifying agent.Tablet and granula are the form of preferred oral administration, and it can be covered.

[0170] if use administered parenterally, then it is feature usually with the injection.Can prepare the injectable thing with conventionally form, described conventionally form is liquor or suspensoid for example, is applicable to the solid form, emulsion or the slowly-releasing delivery system that were used for liquor or suspensoid before injection.

[0171] the whole body administration can also be passed through through mucous membrane or transdermal route.For through mucous membrane or transdermal administration, in preparation, use the permeate agent that is applicable to barrier to be infiltrated.Described permeate agent is being known in the art, and it comprises cholate and the fusidic acid derivatives that for example is used for transmucosal administration.In addition, can use washing composition (detergent) to help infiltration.Mucosal can or for example use suppository by nasal spray (nasalspray).

[0172], medicament is mixed with ointment, ointment, ointment (salves), pulvis and gelifying agent for topical.In one aspect, the transdermal delivery agent can be DMSO.Transdermal delivery system can comprise for example patch.

[0173] comprises The compounds of this invention can adopt tablet, capsule, pulvis, suspensoid, solution, emulsion and ointment and ointment as the pharmaceutical composition of activeconstituents form, and can be used as parenteral (in the vein, intracutaneous, intramuscular, sheath etc.) injection, infiltration, topical application, at the injection of spinal cord place central authorities, oral, rectum, intravaginal and intranasal administration or be used for topical application.Described composition can be by preparing activeconstituents and the acceptable excipient composition of pharmacy that is generally used for this purpose.Described vehicle can comprise moisture or not water-containing solvent, stablizer, suspension agent, dispersion agent, wetting agent etc., and is known for the technician of pharmaceutical field.Described composition can also comprise for example polyoxyethylene glycol of the same additive that is fit to, and optional colorant, flavouring agent etc.

[0174] described pharmaceutical composition will preferably comprise the activeconstituents at least about 0.1 volume/weight %.Actual concentrations will depend on the route of administration of human subjects and selection.Usually, for above-mentioned application and indication, this concentration will be between about 0.1 and about 100%.The dosage of activeconstituents to be administered can also be changed between every day in about 1 microgram and about 100 milligrams of every kg body weight, preferably change between every day, most preferably change between every day in about 1 microgram and about 20 milligrams of every kg body weight in about 1 microgram and about 50 milligrams of every kg body weight.

[0175] desired dosage is preferably with the form existence of every day with one, two, three, four, five, six or more times sub-doses (sub-dose) of reasonable time interval administration.Described dosage or sub-doses can be with the form administrations of dose unit, every described dose unit comprises for example from 0.5 to 1500 milligram, preferably from 0.5 to 200 milligram, from 0.5 to 40 milligram activeconstituents most preferably, if patient's illness needs, mode as an alternative then, described dosage can be with the form administration of continuous infusion.

Embodiment

When [0176] using in this article, except as otherwise noted, following abbreviation has following implication: Me nail base (CH ₃-), Et refers to ethyl (CH ₃CH ₂-), i-Pr refers to sec.-propyl ((CH ₃) ₂CH ₂-), t-Bu or " tert-butyl " refer to the tertiary butyl ((CH ₃) ₃CH-), Ph refers to phenyl, and Bn refers to benzyl (PhCH ₂-), Bz refers to benzoyl (PhCO-), MOM nail oxygen ylmethyl, Ac refer to that ethanoyl, TMS refer to that trimethyl silyl, TBS refer to t-butyldimethylsilyl, Ms nail alkane alkylsulfonyl (CH ₃SO ₂-), Ts refers to tolysulfonyl (p-CH ₃PhSO ₂-), Tf refers to trifluoromethane sulfonyl group (CF ₃SO ₂-), TfO refers to trifluoro-methanyl sulfonate (ester) (CF ₃SO ₃-), D ₂O refers to water-d2, and DMF refers to N, and dinethylformamide, DCM refer to methylene dichloride (CH ₂Cl ₂), THF refers to tetrahydrofuran (THF), EtOAc refers to ethyl acetate, Et ₂O is meant ether, and MeCN refers to acetonitrile (CH ₃CN), NMP refers to the 1-N-N-methyl-2-2-pyrrolidone N-, and DMA refers to N, the N-N,N-DIMETHYLACETAMIDE, DMSO refers to dimethyl sulfoxide (DMSO), DCC refers to 1,3-dicyclohexyl two carbon imide, EDCI refer to 1-(3-dimethylaminopropyl)-3-ethyl carbon imide, and Boc refers to tertiary butyl carbonyl, Fmoc refers to 9-fluorenyl methoxy carbonyl, and TBAF refers to tetrabutyl ammonium fluoride, and TBAI refers to tetrabutylammonium iodide, TMEDA refers to N, N, N, N-tetramethyl-Edamine, Dess-Martin crosses iodine alkane (Dess-Martin periodinane) or Dess-Martin reagent refers to 1,1,1-triacetyl Oxy-1,1-dihydro-1,2-benzenesulfonyl-3 (1H)-ketone, DMAP refers to 4-N, the N-dimethyl aminopyridine, (i-Pr) ₂Net or DIEA or Hunig ' s alkali refer to N, N-diethyl isopropylamine, and DBU refers to 18-diazabicyclo [5.4.0] 11 carbon-7-alkene, (DHQ) ₂AQN refers to hydroquinine anthraquinone-1,4-two basic diether, (DHQ) ₂PHAL refers to hydroquinine phthalazines-1,4-two basic diether, (DHQ) ₂PYR refers to hydroquinine 2,5-biphenyl-46-pyrimidine two basic diether, (DHQD) ₂AQN refers to dihydrochinidin anthraquinone-14-two basic diether, (DHQD) ₂PHAL refers to dihydrochinidin phthalazines-14-two basic diether, (DHQD) ₂PYR refers to dihydrochinidin 2,5-biphenyl-4, and 6-pyrimidine two basic diether, LDA refers to LDA, LiTMP refers to 2,2,6,6-tetramethyl piperidine acid amides lithium, the n-BuLi butyllithium of making a comment or criticism, t-BuLi refers to tert-butyl lithium, and IBA refers to 1-hydroxyl-1,2-benzenesulfonyl-3 (1H)-ketone 1-oxide compound, OsO ₄Refer to perosmic anhydride, m-CPBA refers to metachloroperbenzoic acid, DMD refers to dimethyldioxirane, PDC refers to the dichromic acid pyridine, NMO refers to N-methylmorpholine-N-oxide compound, NaHMDS refers to sodium hexamethyldisilazide, LiHMDS refers to hexamethyl two silica-based amido lithiums, and HMPA refers to hexamethylphosphoramide, and TMSCl refers to trimethylsilyl chloride, TMSCN refers to trimethylsilyl cyanide, TBSCl refers to the tert-butyldimethylsilyl chloride thing, and TFA refers to trifluoroacetic acid, and TFAA refers to trifluoroacetic anhydride, AcOH refers to acetate, Ac ₂O refers to diacetyl oxide, and AcCl refers to Acetyl Chloride 98Min., and TsOH refers to tosic acid, and TsCl refers to Tosyl chloride, and MBHA refers to 4-methyldiphenyl methylamine, and BHA refers to benzhydryl amine, ZnCl ₂Refer to zinc dichloride (II), BF ₃Refer to boron trifluoride, Y (OTf) ₂Refer to trifluoromethanesulfonic acid yttrium (III), Cu (BF ₄) ₂Refer to Tetrafluoroboric acid copper (II), LAH refers to lithium aluminum hydride (LiAlH ₄), LAD refers to deuterate aluminium lithium, NaHCO ₃Refer to sodium bicarbonate, K ₂CO ₃Refer to salt of wormwood, NaOH refers to sodium hydroxide, and KOH refers to potassium hydroxide, and LiOH refers to lithium hydroxide, and HCl refers to hydrochloric acid, H ₂SO ₄Refer to sulfuric acid, MgSO ₄Refer to sal epsom, Na ₂SO ₄Refer to sodium sulfate. ¹H NMR refers to proton magnetic resonance (PMR), ¹³C NMR refers to 13C nuclear magnetic resonance, NOE is meant nuclear Overhauser effect (nuclear overhauser effect), and NOESY refers to examine Overhauser and exchange spectrum, and COSY refers to close spectrum with nuclear phase, HMQC refers to the heteronuclear multiplet quantum relevant (proton detected heteronuclear multiplet-quantumcoherence) of proton detection, HMBC refers to heteronuclear Multiple Bonds dependency, and s refers to singlet, br s finger beam singlet, d refers to doublet, br d finger beam doublet, t refers to triplet, q refers to quartet, dd refers to double doublet, m refers to multiplet, and ppm refers to ppm, and IR refers to infrared spectra, MS refers to mass spectrum, HRMS refers to high resolution mass spectrum, and EI refers to electronic impact, and FAB refers to fast atom bombardment(FAB), CI refers to chemi-ionization, HPLC refers to high performance liquid chromatography, and TLC refers to thin-layer chromatography, R _fRefer to retention factors, R _tRefer to retention time, GC refers to gas-chromatography, and min is minute, and h is hour, and Rt or RT are room temperature or envrionment temperature, and g is a gram, and mg is a milligram, and kg is a kilogram, and L rises, and mL is a milliliter, and mol is a mole, and mmol is a mmole.

[0177] for all following embodiment, can use the operation (work-up) and the purification process of standard, it will be conspicuous to those skilled in the art.Synthetic method of the present invention is shown in the scheme 1.Described scheme only is one of preparation approach of many obtainable documents, and it is intended to come the applicable chemical process of illustration by the use specific embodiment, and does not represent the scope of the invention.

Scheme 1

[0178] following non-restrictive example has illustrated that the inventor is used to implement the preferred method of the inventive method.

Embodiment 1:d ₉-2-(4-p-methoxy-phenyl)-acetate

[0179] can be according to the method for known references (2002,4 (5), 431-435, it all is incorporated herein by reference at this for Ouk etc., Green Chemistry), by making d ₆-(4-hydroxy phenyl)-acetate (1 equivalent, Cambridge Isotopes Laboratories), K ₂CO ₃(0.04 equivalent) and d ₆-methylcarbonate (1.25 equivalents, Cambridge Isotopes Laboratories) reacts down at 160 ℃ and prepares d until finishing ₉-(4-p-methoxy-phenyl)-acetate.

Embodiment 2:d ₁₅-2-(4-p-methoxy-phenyl)-N, N-dimethyl-ethanamide

[0180] by Yardley etc. at Journal of Medicinal Chemistry 1990,33 (10), the method for describing among the 2899-2905 prepares title compound, described document all is incorporated herein by reference at this.With d ₉The dichloromethane solution of-(4-p-methoxy-phenyl)-acetate (1 equivalent) is handled with oxalyl chloride (1.22 equivalent) and DMF (catalytic amount), at room temperature stirs then, all is converted into chloride of acid (acid chloride) until all acid.Under reduced pressure remove and desolvate, and with residue with the methylene dichloride dissolving and use d ₆-dimethyl amine hydrochloride (1 equivalent, Cambridge Isotopes Laboratories), ethyl diisopropyl amine (2.1 equivalent) and DMAP (0.2 equivalent) handle.The mixture stirring is spent the night.Under reduced pressure remove and desolvate, with thick residue silica gel chromatography.

Embodiment 3:d ₂₄-2-(1-hydroxy-cyclohexyl)-2-(4-p-methoxy-phenyl)-N, N-dimethyl-ethanamide

[0181] according to Yardley etc. at Journal of Medicinal Chemistry 1990,33 (10), the method for describing among the 2899-2905 prepares title compound.Under-78 ℃ with d ₁₅-2-(4-p-methoxy-phenyl)-N, the THF solution of N-dimethyl-ethanamide (1 equivalent) is handled with n-Butyl Lithium (1 equivalent).Mixture stirred 90 minutes down at-78 ℃; Add d ₁₀(1.2 equivalents, THF solution Sigma-Aldrich) are kept stirring until finishing to-pimelinketone.By adding D ₂O (2 equivalent) finishes reaction, and mixture is warmed to room temperature, under reduced pressure removes and desolvates, with thick residue silica gel chromatography.

Embodiment 4:d ₂₆-1-[2-dimethylamino-1-(4-p-methoxy-phenyl)-ethyl]-hexalin

[0182] according to Yardley etc. at Journal of Medicinal Chemistry 1990,33 (10), the method for describing among the 2899-2905 prepares title compound.Under 0 ℃ with d ₂₄-2-(1-hydroxy-cyclohexyl)-2-(4-p-methoxy-phenyl)-N, the THF solution of N-dimethyl-ethanamide (1 equivalent) dropwise join in the mixture of deuterate aluminium lithium (1.6 equivalent) and stir until finishing.Use D ₂O finishes reaction, and operates under standard conditions well known to those skilled in the art.Then mixture is filtered, and will precipitate for several times with the THF washing.With the filtrate evaporation after the combination, with residual from The suitable solvent recrystallization.

Embodiment 5:d ₃-4-(p-methoxy-phenyl)-acetonitrile

[0183] at ambient temperature, with d ₃-methyl iodide (8.70g, what 60mmol) join stirring comprises salt of wormwood (6.21g, (4.50g in acetone 30mmol) (30mL) solution, spends the night postcooling to envrionment temperature with mixture heating up to reflux temperature to (4-hydroxy phenyl)-acetonitrile 45mmol), filter, and concentrate, obtain thick product, by using the thick product of purification by flash chromatography of hexane-ethyl acetate, to obtain required product, the d of light yellow oily ₃-(4-p-methoxy-phenyl)-acetonitrile.

[0184] productive rate: 3.99g (89%). ¹H-NMR(CDCl ₃)δppm：3.67(s，2H)，6.88(d，2H，J＝8.7Hz)，7.22(d，2H，J＝8.7Hz)。

Embodiment 5:d ₃-(1-hydroxy-cyclohexyl)-(4-p-methoxy-phenyl)-acetonitrile

[0185] under 0 ℃ with four-normal-butyl monoammonium sulfate (0.10g, 0.29mmol) and 2NNaOH (1.2mL) add intensively stirred d successively ₃-(4-p-methoxy-phenyl)-acetonitrile (0.85g, 5.66mmol) in, and keep and stirred 30 minutes.Under 0-5 ℃, in 10 minutes, in this mixture, add pimelinketone (0.67g, 6.8mmol).Reaction mixture is warmed to envrionment temperature and continued violent stirring again 1 hour.Filter white precipitate, and water and hexane wash, required product obtained, white solid d3-(1-hydroxy-cyclohexyl)-(4-p-methoxy-phenyl)-acetonitrile.

[0186] productive rate: 1.28g (91%). ¹H-NMR(CDCl ₃)δppm：1.05-1.80(m，10H)，3.73(s，1H)，6.90(d，2H ₃?J＝8.7Hz)，7.27(d，2H，J＝8.7Hz)。

Embodiment 6:d ₃-1-[2-amino-1-(4-p-methoxy-phenyl)-ethyl]-hexalin

[0187] be furnished with Raney Ni catalyzer tube (cartridge) (eluent: the methanol solution of 2.0M ammonia, flow velocity: 1mL/min, temperature: 80 ℃, pressure: 80 the crust) H-Cube ^TM(Thales Nanotechnology, Budapest Hungary) go up reduction d to the continuous flow hydrogenator ₃(400.0mg 1.61mmol), obtains required product, the d of water white transparency oily to-(1-hydroxy-cyclohexyl)-(4-p-methoxy-phenyl)-acetonitrile ₃-1-[2-amino-1-(4-p-methoxy-phenyl)-ethyl]-hexalin.

[0188] productive rate: 280mg (69%). ¹H-NMR(CDCl ₃)δppm：1.05-1.80(m，10H)，2.59(br?s，2H)，2.68(t，1H，6.9Hz)，3.21(m，2H)，6.83(d，2H，J＝9.0Hz)，7.17(d，2H，J＝9.0Hz)。

Embodiment 7:d ₃-1-[2-dimethylamino-1-(4-p-methoxy-phenyl)-ethyl]-hexalin (d ₃-Venlafaxine)

[0189] under 80-90 ℃, with d ₃-1-[2-amino-1-(4-p-methoxy-phenyl)-ethyl]-hexalin (207mg, 0.82mmol), 37% formalin (0.3mL), formic acid (0.3mL) and water (2mL) stirred 12 hours, being concentrated into volume under vacuum is 1.5mL, dropwise add 20% aqueous sodium hydroxide solution so that it becomes alkalescence, and use ethyl acetate extraction.With the organic layer salt water washing that merges, dry (Na ₂SO ₄), filter and under vacuum, concentrate, obtain thick residue, with the described thick residue of silica gel chromatography (ethyl acetate-methanol-hydrogen ammonium oxide) purifying, to obtain required product, d ₃-1-[2-dimethylamino-1-(4-p-methoxy-phenyl)-ethyl]-hexalin.

[0190] productive rate: 24.4mg (11%). ¹H-NMR (methyl alcohol-d ₄) δ ppm:0.84-1.54 (m, 10H), 2.42 (s, 6H), 2.84-2.92 (m, 2H), 3.26-3.36 (m, 1H), 6.87 (d, 2H), 7.18 (d, 2H).

Embodiment 8:d ₉-1-[2-dimethylamino-1-(4-p-methoxy-phenyl)-ethyl]-hexalin (d ₉-Venlafaxine)

[0191] with d ₃-1-[2-amino-1-(4-p-methoxy-phenyl)-ethyl]-hexalin (0.126g, 0.5mmol), d ₂-formic acid (0.3mL) and d ₂-formaldehyde (the D of 20 weight % ₂O solution, D 0.25mL) ₂O (1.5mL) solution be heated to 100 ℃ 16 hours, be cooled to envrionment temperature, water (5mL) dilution neutralizes with 35% ammoniacal liquor, and uses ethyl acetate extraction.With the organic layer dried over sodium sulfate that merges, and under reduced pressure concentrate, obtain thick residue, with flash chromatography (ethyl acetate-methyl alcohol-NH ₄OH) the described thick residue of purifying is to obtain required product, the d of light yellow semi-solid ₉-1-[2-methylamino-1-(4-p-methoxy-phenyl)-ethyl]-hexalin.

[0192] productive rate: 0.024g (20%). ¹H-NMR(CDCl ₃)δppm：0.78-1.80(m，10H)，2.33(dd，1H，J＝12.0，3.3Hz)，2.96(dd，1H，J＝12.0，3.3Hz)，3.31(t，1H，J＝12.0Hz)，6.81(d，2H，J＝9.0Hz)，7.17(d，2H，J＝9.0Hz)。MS(m/z)：287(M+1)。

Embodiment 9:d ₁₄-(1-hydroxy-cyclohexyl)-(4-p-methoxy-phenyl)-acetonitrile

[0193] method as embodiment 5 prepares title compound, wherein uses d ₁₀-pimelinketone (Sigma-Aldrich) replaces pimelinketone and uses the D of 2N NaOD ₂O solution replaces the 2N NaOH aqueous solution.Final product is purifying by recrystallization from ethyl acetate-hexane.

[0194] productive rate (60%). ¹H-NMR(CDCl ₃)δppm：1.60(br?s，1H)，6.90(d，2H，J＝8.4Hz)，7.26(d，2H，J＝8.4Hz)。

Embodiment 10:d ₁₄-1-[2-amino-1-(4-p-methoxy-phenyl)-ethyl]-hexalin

[0195] be furnished with Raney Ni catalyzer tube (eluent: the methanol solution of 2.0M ammonia, flow velocity: 1mL/min, temperature: 80 ℃, pressure: 80 the crust) H-Cube ^TM(Thales Nanotechnology, Budapest Hungary) go up reduction d to the continuous flow hydrogenator ₁₄-(1-hydroxy-cyclohexyl)-(4-p-methoxy-phenyl)-acetonitrile (570.0mg, 2.21mmol), to obtain required product, the d of water white transparency oily ₁₄-1-[2-amino-1-(4-p-methoxy-phenyl)-ethyl]-hexalin.

[0196] productive rate: 530mg (92%). ¹H-NMR(CDCl ₃)δppm：2.62(br?s，3H)，3.21(dd，2H)，6.83(d，2H)，7.17(d，2H)。

Embodiment 11:d ₁₄-1-[2-dimethylamino-1-(4-p-methoxy-phenyl)-ethyl]-hexalin (d ₁₄-Venlafaxine)

[0197] at room temperature, with d ₁₄-1-[2-amino-1-(4-p-methoxy-phenyl)-ethyl]-hexalin (257.0mg, 0.98mmol), formic acid (0.334mL) and formaldehyde (37% the aqueous solution, water 0.146mL) (2.32mL) solution stirring 45 minutes.(37% the aqueous solution 0.146mL), to refluxing 17 hours, is cooled to room temperature with mixture heating up, with the ethyl acetate washing, transfers to alkalescence with 20% aqueous sodium hydroxide solution, and uses ethyl acetate extraction to add formaldehyde.With the organic fraction that the salt water washing merges, dry (Na ₂SO ₄), filter and concentrate, obtain thick residue, with column chromatography (ethyl acetate-methanol-hydrogen ammonium oxide) the thick residue of purifying, to obtain required product, the d of water white transparency oily ₁₄-1-[2-dimethylamino-1-(4-p-methoxy-phenyl)-ethyl]-hexalin.

[0198] productive rate: 154.4mg (54%), ¹H-NMR (methyl alcohol-d ₄) δ ppm:2.25 (s, 6H), 2.55 (d, 1H), 3.14 (d, 1H), 6.84 (d, 2H), 7.13 (d, 2H).

Embodiment 12:d ₂₀-1-[2-dimethylamino-1-(4-p-methoxy-phenyl)-ethyl]-hexalin (d ₂₀-Venlafaxine)

[0199] prepares title compound as method as described in the embodiment 8.

[0200] productive rate (31%): ¹H-NMR (CDCl ₃) δ ppm:2.33 (d, 1H, J=12.6Hz), 3.30 (d, 1H, J=12.6Hz), 6.81 (d, 2H, J=9.0Hz), 7.05 (d, 2H, J=9.0Hz).MS(m/z)：298(M+1)。

Embodiment 13: external hepatomicrosome stability test

[0201] at 2%NaHCO ₃(2.2mM NADPH, 25.6mM 6-glucose 1-phosphate1-, every mL glucose-6-phosphate dehydrogenase of 6 units and 3.3mM MgCl ₂) in, in the hepatomicrosome albumen of 1mg/mL, carry out the hepatomicrosome stability test with NADPH-generation system.Test compound is formed in solution in 20% acetonitrile-water, and is added into test mixture (final experimental concentration: the every mL of 5 micrograms), and at 37 ℃ of following incubations.In test, the ultimate density of acetonitrile＜1%.In the time is 0,15,30,45 and 60 timesharing, takes out aliquots containig (50 μ L), and with ice-cold acetonitrile (200 μ L) dilution, with stopped reaction.Sample under 12000RPM centrifugal 10 minutes is with precipitating proteins.Supernatant liquor is transferred to micro-centrifuge tube, and stores the LC/MS/MS analysis of the degradation half life that is used for test compound.Thereby have been found that with the medicine of heterotope enrichment and compare that Shi Yan formula of the present invention (1) compound exhibits goes out degradation half life in this test increases by 10% or more.For example, compare d with the Venlafaxine of heterotope enrichment ₃-Venlafaxine, d ₉-Venlafaxine, d ₁₄-Venlafaxine and d ₂₀The degradation half life of-Venlafaxine has increased 50-300%.

Embodiment 14: end user's cytochrome P ₄₅₀The external metabolism of enzyme

[0202] use baculovirus expression system (BD Biosciences) from corresponding people cDNA express cell pigment P ₄₅₀Enzyme.Under 37 ℃, comprise 0.8 milligram of every ml protein, 1.3 mmole NADP with 0.25 milliliter ⁺, the reaction mixture of formula 1 compound of 3.3 mmole 6-glucose 1-phosphate1-s, 0.4U/mL glucose-6-phosphate dehydrogenase, 3.3 mmole magnesium chlorides and 0.2 mmole and compound or standard substance or reference substance incubation 20min in 100 mmole potassiumphosphates (pH 7.4) of corresponding heterotope enrichment.Behind the incubation, make reaction terminating by adding appropriate solvent (for example acetonitrile, 20% trichoroacetic acid(TCA), 94% acetonitrile/6% glacial acetic acid, 70% perchloric acid, 94% acetonitrile/6% Glacial acetic acid), and centrifugal (10,000g) 3 minutes.Supernatant liquor is analyzed with HPLC/MS/MS.

Cytochrome P ₄₅₀	Standard substance
Cytochrome P ₄₅₀	Standard substance	CYP1A2	Phenacetin
CYP2A6	Tonka bean camphor	CYP1A2	Phenacetin
CYP2A6	Tonka bean camphor	CYP2B6	[ ¹³C]-(S)-mephenytoin
CYP2C8	Taxol	CYP2B6	[ ¹³C]-(S)-mephenytoin
CYP2C8	Taxol	CYP2C9	Diclofenac
CYP2C19	[ ¹³C]-(S)-mephenytoin	CYP2C9	Diclofenac
CYP2C19	[ ¹³C]-(S)-mephenytoin	CYP2D6	(+/-)-bufuralol
CYP2E1	Chlorzoxazone	CYP2D6	(+/-)-bufuralol
CYP2E1	Chlorzoxazone	CYP3A4	Testosterone
CYP4A	[ ¹³C]-lauric acid	CYP3A4	Testosterone

Pharmacology

[0203] pharmacological property of the compound of formula 1 compound or its corresponding heterotope enrichment or standard substance or reference substance can be described as follows.Utilize Ki value that preferred exemplary compounds that following scintillation proximity assay (ScintillationProximity Assay, SPA) records shows for the serotonin transporter less than 1 micromole, be more preferably less than 500 nmoles.Referring to WO 2005/060949.In addition, use described SPA, with respect to norepinephrine and DAT, preferred exemplary compounds optionally suppresses at least 5 times of serotonin transporters.

Embodiment 15: the generation of the stable cell lines of expressing human Dopamine HCL, norepinephrine and serotonin transporter

[0204] molecule clone technology of use standard produces the stable cell lines of expressing human Dopamine HCL, norepinephrine and serotonin transporter.Use polymerase chain reaction (PCR) with separate and amplification from each of three kinds of full-length cDNAs in suitable cDNA library.Use reported sequence design data to be used for the PCR primer of following neurotransmitter transporter.The connection of use standard (ligation) technology for example among the pcDNA3.1 (Invitrogen), is used commercially available lipofectin reagent (Lipofectamine to mammalian expression vector with the PCR product cloning subsequently ^TM-Invitrogen) according to the operational manual cotransfection HEK293 cell of manufacturers.

[0205] people's DAT: GenBank M95167.Vandenbergh etc., Molecular Brain Research 1992,75,161-166, it all is incorporated herein by reference at this.

[0206] people's noradrenaline transporter body: GenBank M65105.Pacholczyk etc., Nature 1991,350,350-354, it all is incorporated herein by reference at this.

[0207] people's serotonin transporter: GenBank L05568.Ramamoorthy etc., Proceedings of the National Academy of Sciences of the USA 1993,90,2542-2546, it all is incorporated herein by reference at this.

Embodiment 16: the external SPA of noradrenaline transporter body is in conjunction with test

[0208] described experimental evidence Gobel etc. is at Journal of Pharmacological andToxicological Methods 1999,42 (4), and the method for describing among the 237-244 is carried out, and it all is incorporated herein by reference at this.The compound of formula 1 compound or corresponding heterotope enrichment is serotonin/noradrenaline reuptake inhibitor; Use is bonded to norepinephrine in the clone and absorbs the site again ³The H-nisoxetine is measured the avidity of part for the noradrenaline transporter body, the be encoded DNA transfection of people's noradrenaline transporter binding protein precursor of wherein said clone.

Film preparation

[0209] will from the cell paste (cell pastes) of the HEK-293 cell of people's noradrenaline transporter body of the cloning by expression of scale operation at the pH 7.4 of 4 times of volumes, comprise homogeneous among the 50 mmole Tris-HCl of 300 mmole NaCl and 5 mmole KCl.With centrifugal twice of homogenate (40,000g, 10 minutes, 4 ℃), wherein bead (pellet) is at for the first time centrifugal back Tris-HCl damping fluid resuspending that comprises mentioned reagent with 4 times of volumes, for the second time centrifugal back with 8 times of volume resuspending.The homogenate that centrifugal (100g, 10 minutes, 4 ℃) suspend keeps supernatant liquor and recentrifuge (40,000g, 20 minutes, 4 ℃).Bead is resuspending in the Tris-HCl damping fluid that contains mentioned reagent and 10 weight/volume % sucrose and 0.1 mmole phenylmethylsulfonyl fluoride (PMSF).Film preparation is divided into equal portions (1.0 milliliters) to store for future use under-80 ℃.(bicinchonicic acid, BCA) protein analysis test kit (can obtain from Pierce) is measured the protein concn of film preparation to use dihomocinchonine acid.

³The H-nisoxetine is in conjunction with test

Each hole of [0210] 96 hole microtiter plate be set to comprise 50 microlitres, 2 nmoles [the N-methyl- ³H]-hydrochloric acid nisoxetine (70-87 Ci/ mmole, available from NEN Life Science Products), 75 microlitres test damping fluid (comprise the 50 mmole Tris-HCl of 300 mmole NaCl and 5 mmole KCl, pH 7.4), formula 1 compound of 25 microlitres dilution or the compound of corresponding heterotope enrichment, test damping fluid (combination fully) or 10 micromole's desipramine hydrochlorides (non-specific binding), poly-(Vinyl toluene) (WGA PVT) SPA pearl (AmershamBiosciences RPNQ0001) (10 mg/ml) of 50 microlitre wheat germ agglutinins lining, 50 microlitre films (0.2 milligram albumen every milliliter).Before with Trilux scintillometer reading, at room temperature with microtiter plate incubation 10 hours.(Milton Keynes UK) analyzes, to obtain the K of every kind of test compounds the gained result for Multicalc, Packard with automatic spline-fitting program _iValue.

The external SPA of embodiment 17:5-hydroxy-tryptamine transporter is in conjunction with test

[0211] described experimental evidence Ramamoorthy etc. is at J.Biol.Chem.1998, and 273 (4), the method for describing among the 2458-2466 is carried out, and it all is incorporated herein by reference at this.With the compound of formula 1 compound or corresponding heterotope enrichment with [ ³H]-ability that citalopram is competed its binding site on the film of the people's serotonin transporter that comprises the clone stops the means of testing of the ability that serotonin absorbs via its special transporter as test compounds.

Film preparation

[0212] film preparation is similar substantially to the preparation of the above-mentioned film that comprises the noradrenaline transporter body.Film preparation is divided into equal portions (1.0 milliliters) to store for future use under-70 ℃.Use the protein concn of BCA analysis of protein kit measurement film preparation.

[ ³H]-citalopram is in conjunction with test

Each hole of [0213] 96 hole microtiter plate be set to comprise 50 microlitres, 2 nmoles [ ³H]-citalopram (60-86Ci/ mmole, Amersham Biosciences), the compound of formula 1 compound of 75 microlitres tests damping fluid (comprise the 50 mmole Tris-HCl of 150 mmole NaCl and 5 mmole KCl, pH 7.4), the dilution of 25 microlitres or corresponding heterotope enrichment, test damping fluid (fully in conjunction with) or 100 micromole's fluoxetines (non-specific binding), 50 microlitre WGA PVT SPA pearls (40 mg/ml), 50 microlitre film preparations (0.4 milligram albumen every milliliter).Before with Trilux scintillometer reading, at room temperature with microtiter plate incubation 10 hours.(Milton Keynes UK) analyzes, to obtain the K of every kind of test compounds the gained result for Multicalc, Packard with automatic spline-fitting program _i(nmole) value.

Embodiment 18: the external SPA of DAT is in conjunction with test

[0214] described experimental evidence Ramamoorthy etc. is at J.Biol.Chem.1998, and 273 (4), the method for describing among the 2458-2466 is carried out, and it all is incorporated herein by reference at this.With test compounds with [ ³H]-WIN35, the ability of 428 its binding sites on people's cytolemma of the people's DAT that comprises the clone of competition stops the means of testing of the ability of Dopamine HCL absorption via its special transporter as described test compounds.

Film preparation

[0215] basic identical with the film of the above-mentioned people's serotonin transporter that comprises the clone.

[ ³H]-WIN35,428 in conjunction with test

Each hole of [0216] 96 hole microtiter plate be set to comprise 50 microlitres, 4 nmoles [ ³H]-WIN35,428 (84-87 Ci/ mmoles, available from NEN Life Science Products), the compound of formula 1 compound of 5 microlitres tests damping fluid (comprise the 50 mmole Tris-HCl of 150 mmole NaCl and 5 mmole KCl, pH 7.4), the dilution of 25 microlitres or corresponding heterotope enrichment, test damping fluid (fully in conjunction with) or 100 micromole's nomifensines (non-specific binding), 50 microlitre WGAPVT SPA pearls (10 mg/ml), 50 microlitre film preparations (0.2 milligram albumen every milliliter).Before with Trilux scintillometer reading, at room temperature with microtiter plate incubation 120 minutes.(Milton Keynes UK) analyzes, to obtain the K of every kind of test compounds the gained result for Multicalc, Packard with automatic spline-fitting program _iValue.

Embodiment 19: to the in vivo test of rat behavior despair (behavioral despair)

[0217] described experimental evidence Porsolt etc. is at Archives Internationales dePharmacodynamie et de Therapie, and 1977,229 (2), the method for describing among the 327-336 is carried out, and it all is incorporated herein by reference at this.In to rat peritoneum, after the administration test compounds, animal was put into the aqueous cylinder of bag 6 minutes.Measured the dead time in the end 4 minutes.The dead time shortening shows that drug effect increases.

Although the present invention is described with reference to the foregoing description, should be appreciated that [0218] its modifications and variations contain within the spirit and scope of the present invention.Therefore, the present invention is only defined by the appended claims.

The reference of quoting: the disclosed content of each piece in the following reference all is incorporated herein by reference at this.

Patent documentation

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Claims

1. the compound of formula 1:

Formula 1

Or the mixture of the mixture of the mixture of its single enantiomer, (+)-enantiomorph and (-)-enantiomorph, about 90 weight % or higher (-)-enantiomorph and about 10 weight % or lower (+)-enantiomorph, about 90 weight % or higher (+)-enantiomorph and about 10 weight % or lower (-)-enantiomorph, independent diastereomer, mixture or its pharmacy acceptable salt, solvate or the prodrug of diastereomer, wherein:

R ₁₉, R ₂₀And R ₂₁Be independently selected from-CH ₃With-CD ₃

Condition is that the compound of formula 1 comprises at least one D atom; And

Condition is that deuterium enriched degree is at least about 1% in the compound of formula 1.

2. be selected from following compound:

Or the mixture of the mixture of the mixture of its single enantiomer, (+)-enantiomorph and (-)-enantiomorph, about 90 weight % or higher (-)-enantiomorph and about 10 weight % or lower (+)-enantiomorph, about 90 weight % or higher (+)-enantiomorph and about 10 weight % or lower (-)-enantiomorph, independent diastereomer, mixture or its pharmacy acceptable salt, solvate or the prodrug of diastereomer.

3. be selected from following compound:

4. pharmaceutical composition, described pharmaceutical composition comprises the compound as claimed in claim 1 for the treatment of significant quantity, or the single enantiomer of compound as claimed in claim 1, the mixture of (+) of compound as claimed in claim 1-enantiomorph and (-)-enantiomorph, the mixture of about 90 weight % of compound as claimed in claim 1 or higher (-)-enantiomorph and about 10 weight % or lower (+)-enantiomorph, the mixture of about 90 weight % of compound as claimed in claim 1 or higher (+)-enantiomorph and about 10 weight % or lower (-)-enantiomorph, the independent diastereomer of compound as claimed in claim 1, the mixture of the diastereomer of compound as claimed in claim 1, or its pharmacy acceptable salt, solvate or prodrug and pharmaceutically acceptable carrier.

5. that pharmaceutical composition as claimed in claim 4, wherein said composition are applicable to is oral, parenteral or intravenous infusion administration.

6. pharmaceutical composition as claimed in claim 5, wherein said oral administration comprises administration tablet or capsule.

7. pharmaceutical composition as claimed in claim 4, the compound of wherein said claim 1 is with 0.5 milligram to 400 milligrams total dose administration every day.

8. treat to suffer to relate to and absorb again or the disease of the illness that the monoamine acceptor is relevant or the mammiferous method of situation (condition) with monoamine, described method comprises formula 1 compound to described Mammals drug treatment significant quantity, and wherein said formula 1 compound has following structure:

Formula 1

R ₁₉, R ₂₀And R ₂₁Be independently selected from-CH ₃With-CD ₃

Condition is that the compound of described formula 1 comprises at least one D atom; And

Condition is that deuterium enriched degree is at least about 1% in the compound of described formula 1.

9. method as claimed in claim 8, wherein said monoamine disease or illness are selected from insane, anxiety disorder, generalized anxiety disorder, dysthymia disorders, posttraumatic stress disorder, obsession, Phobias, hectic fever, senile dementia, migraine, liver lung syndromes, chronic pain, nociceptive pain, neurogenic pain, the pain diabetic retinopathy, the two-phase depression, obstructive sleep apnea, mental disorder, premenstrual dysphoric disorder, social phobia, social anxiety disorder, the urinary incontinence, apositia, bulimia nervosa, obesity, ischemic, head injury, the brain cell calcium overload, pharmacological dependence and premature ejaculation.

10. method as claimed in claim 8 is wherein compared with the compound of heterotope enrichment, and the compound of described formula 1 has reduced described compound or the interindividual variation of its metabolite in blood plasma level.

11. method as claimed in claim 8 is wherein compared with the compound of heterotope enrichment, described formula 1 compound has increased the average plasma levels of the described compound of every dose unit.

12. method as claimed in claim 8 is wherein compared with the compound of heterotope enrichment, described formula 1 compound has reduced the average plasma levels of at least a metabolite of the described compound of every dose unit.

13. method as claimed in claim 8 is wherein compared with the compound of heterotope enrichment, described formula 1 compound has reduced its every dose unit by at least a cytochrome P of expressing polymorphically in the mammalian object ₄₅₀The metabolism of isotype.

14. method as claimed in claim 13, wherein said cytochrome P ₄₅₀Isotype is selected from CYP2C8, CYP2C9, CYP2C19 and CYP2D6.

15. method as claimed in claim 8 is wherein compared with the compound of heterotope enrichment, described formula 1 compound has reduced its every dose unit at least a cytochrome P in the mammalian object ₄₅₀The inhibition of isotype.

16. method as claimed in claim 15, wherein said cytochrome P ₄₅₀Isotype is selected from CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46 and CYP51.

17. method as claimed in claim 8 is wherein compared with the compound of heterotope enrichment, described formula 1 compound its every dose unit during described Mammals treatment causes the clinical effectiveness that improves.

18. method as claimed in claim 17, the clinical effectiveness of wherein said improvement are quickened rehabilitation, acceleration sx during being included in treatment, are improved the effect of patient's conformability and minimizing substance abuse Withrawal symptom.

19. the method for treatment Mammals drug addiction, described method comprises Combined Preparation first composition and second composition, and wherein said first composition comprises formula 1 compound for the treatment of significant quantity, and described second composition comprises the OPIOIDS antagonist for the treatment of significant quantity,

Wherein said formula 1 compound, i.e. composition A has following structure:

Formula 1

R ₁₉, R ₂₀And R ₂₁Be independently selected from-CH ₃With-CD ₃

Condition is that described formula 1 compound comprises at least one D atom; And

Condition is that deuterium enriched degree is at least about 1% in described formula 1 compound.

20. method as claimed in claim 19, wherein said OPIOIDS antagonist is selected from Nalmefene, TREXUPONT and naloxone.

21. method as claimed in claim 19, wherein said drug addiction are selected from tobacco addiction, alcohol addiction, hemp habituation and cocaine addiction.

22. method as claimed in claim 19, the administration after described second composition of administration of wherein said first composition.

23. method as claimed in claim 19, wherein said first composition and described second composition be administration simultaneously basically.

24. method as claimed in claim 19, the administration before described second composition of wherein said first composition.

25. method as claimed in claim 19 is wherein compared with the analogue of the heterotope enrichment of described first composition, described first composition causes the addicted clinical effectiveness of medicine that improves.

26. method as claimed in claim 25, the clinical effectiveness of wherein said improvement are quickened rehabilitation, acceleration sx during being included in treatment, are improved the effect of patient's conformability and minimizing substance abuse Withrawal symptom.

27. formula 1 compound preparation be used for the treatment of relate to that monoamine absorbs again or the medicine of the disease of the illness that the monoamine acceptor is relevant or situation in application, wherein said formula 1 compound has following structure:

Formula 1

R ₁₉, R ₂₀And R ₂₁Be independently selected from-CH ₃With-CD ₃

Condition is that described formula 1 compound contains and comprises a D atom; And

28. application as claimed in claim 27, wherein said monoamine disease or illness are selected from insane, anxiety disorder, generalized anxiety disorder, dysthymia disorders, posttraumatic stress disorder, obsession, Phobias, hectic fever, senile dementia, migraine, liver lung syndromes, chronic pain, nociceptive pain, neurogenic pain, the pain diabetic retinopathy, the two-phase depression, obstructive sleep apnea, mental disorder, premenstrual dysphoric disorder, social phobia, social anxiety disorder, the urinary incontinence, apositia, bulimia nervosa, obesity, ischemic, head injury, the brain cell calcium overload, pharmacological dependence and premature ejaculation.

29. application as claimed in claim 27 is wherein compared with the compound of heterotope enrichment, formula 1 compound has reduced described compound or the interindividual variation of its metabolite in blood plasma level.

30. application as claimed in claim 27 is wherein compared with the compound of heterotope enrichment, described formula 1 compound has increased the average plasma levels of the described compound of every dose unit.

31. application as claimed in claim 27 is wherein compared with the compound of heterotope enrichment, described formula 1 compound has reduced the average plasma levels of at least a metabolite of the described compound of every dose unit.

32. application as claimed in claim 27 is wherein compared with the compound of heterotope enrichment, described formula 1 compound has reduced its every dose unit by at least a cytochrome P of expressing polymorphically in the mammalian object ₄₅₀The metabolism of isotype.

33. application as claimed in claim 32, wherein said cytochrome P ₄₅₀Isotype is selected from CYP2C8, CYP2C9, CYP2C19 and CYP2D6.

34. application as claimed in claim 27 is wherein compared with the compound of heterotope enrichment, described formula 1 compound has reduced its every dose unit at least a cytochrome P in the mammalian object ₄₅₀The inhibition of isotype.

35. application as claimed in claim 34, wherein said cytochrome P ₄₅₀Isotype is selected from CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46 and CYP51.

36. application as claimed in claim 27 is wherein compared with the compound of heterotope enrichment, described formula 1 compound its every dose unit during described Mammals treatment causes the clinical effectiveness that improves.

37. application as claimed in claim 36, the clinical effectiveness of wherein said improvement are quickened rehabilitation during being included in treatment, quicken sx, are improved the effect in patient's conformability and the minimizing substance abuse Withrawal symptom.

38. formula 1 compound is used for the treatment of application in the medicine of drug addiction in preparation, described medicine comprises first composition and second composition, wherein said first composition comprises formula 1 compound for the treatment of significant quantity, and described second composition comprises the OPIOIDS antagonist for the treatment of significant quantity

Wherein said formula 1 compound has following structure:

Formula 1

R ₁₉, R ₂₀And R ₂₁Be independently selected from-CH ₃With-CD ₃

39. application as claimed in claim 38, wherein said OPIOIDS antagonist is selected from Nalmefene, naloxone and TREXUPONT.

40. application as claimed in claim 38, wherein said drug addiction are selected from tobacco addiction, alcohol addiction, hemp habituation and cocaine addiction.

41. application as claimed in claim 38, the administration after described second composition of administration of wherein said first composition.

42. application as claimed in claim 38, wherein said first composition and described second composition be administration simultaneously basically.

43. application as claimed in claim 38, the administration before described second composition of wherein said first composition.

44. application as claimed in claim 38 is wherein compared with the analogue of the heterotope enrichment of described first composition, described first composition causes the addicted clinical effectiveness of medicine that improves.

45. application as claimed in claim 44, the clinical effectiveness of wherein said improvement are quickened rehabilitation, acceleration sx during being included in treatment, are improved the effect of patient's conformability and minimizing substance abuse Withrawal symptom.