More applications determined for treating fragile X mental retardation of Puli

文档序号：1745376 发布日期：2019-11-26 浏览：39次中文

阅读说明：本技术 普利多匹定用于治疗脆性x综合征的应用 (More applications determined for treating fragile X mental retardation of Puli ) 是由迈克尔·海登马哈茂德·阿卜杜勒侯赛因·普拉迪于 2018-01-18 设计创作，主要内容包括：本发明提供一种用于治疗患有脆性X综合征(FXS)或FXS相关疾病的受试者的方法,包括定期向受试者施用包括对治疗所述受试者有效的量的普利多匹定的药物组合物。(The present invention provides a kind of method for treating the subject with fragile X mental retardation (FXS) or FXS related disease, includes the more fixed pharmaceutical compositions of Puli effectively measured to the treatment subject including periodically applying to subject.)

1. a kind of method of subject of the treatment with fragile X mental retardation (FXS), including periodically drug is applied to the subject Composition, described pharmaceutical composition include that Puli more effectively measured to the treatment subject determine.

2. according to the method described in claim 1, wherein, the subject also suffers from autism spectrum disorder (ASD).

3. method described in any one of -2 according to claim 1, wherein the Puli of the amount more can be effectively reduced surely The severity of one or more symptoms of FXS in the subject.

4. according to the method described in claim 3, wherein, one or more symptoms be selected from by cognitive disorder, hypoevolutism, Social and behavioral problem, anxiety, hyperactivity hyperkinesia behavior, gastrointestinal function and epilepsy group to hypersensitivity, the change of stimulus to the sense organ At group in.

5. according to the method described in claim 4, wherein, the symptom is cognitive disorder, and the cognitive disorder is intelligence Disability or learning disability.

6. according to the method described in claim 4, wherein, the symptom is hypoevolutism, the hypoevolutism is to speak and language The hypoevolutism of speech.

7. method described in any one of -6 according to claim 1, wherein apply 10-315mg Puli to the patient daily More fixed.

8. method described in any one of -7 according to claim 1, wherein daily to the patient apply 10mg, 22.5mg, 45mg, 67.5mg, 90mg, 100mg, 112.5mg, 125mg, 135mg, 150mg, 180mg, 200mg, 250mg or 315mg are general Benefit is fixed.

9. according to the method described in claim 8, wherein, the Puli of the amount more it is fixed with 10mg, 22.5mg, 45mg, 67.5mg, 90mg, 100mg, 112.5mg, 125mg, 135mg, 150mg, 180mg, 200mg, 250mg or 315mg Puli more Fixed unit dose application.

10. according to the method described in claim 9, wherein, the unit dose once-a-day administration.

11. according to the method described in claim 9, wherein, the unit dose daily administration is more than primary.

12. according to the method described in claim 9, wherein, the unit dose daily administration is twice.

13. method described in any one of -12 according to claim 1, wherein the subject has super on X chromosome Cross 200 CGG repetitive sequences.

14. method described in any one of -13 according to claim 1, wherein less than 18 years old of the subject.

15. method described in any one of -14 according to claim 1, wherein the subject is male.

16. method described in any one of -14 according to claim 1, wherein the subject is women.

17. method described in any one of -16 according to claim 1, wherein the regular application is to be administered orally.

18. method described in any one of -17 according to claim 1, wherein the subject is human experimenter.

19. method described in any one of -18 according to claim 1, wherein more of the Puli is Puli more and determines salt surely The form of hydrochlorate.

20. method described in any one of -19 according to claim 1 further includes application second medicament, the second medicament choosing Free carbamazepine, valproic acid, double valproic acids, lithium carbonate, Gabapentin, Lamotrigine, Topiramate, Tiagabine, sabril, Phenobarbital, primidone mysoline, phenytoinum naticum, methylphenidate, dextroamphetamine, L- acetylcarnitine, Venlafaxine, Nefazodone, gold Rigid alkanamine, folic acid, clonidine, guanfacine, Prozac, Sertraline, Citalopram, Paxil, Fluvoxamine, Risperidone, quinoline In the group that sulphur is flat, Olanzapine, Trazodone and epiphysin form.

21. Puli more are scheduled on for treating the application in the subject with fragile X mental retardation (FXS).

22. the Puli more applications being scheduled in drug of the preparation for treating the subject with fragile X mental retardation (FXS).

23. one kind includes more pharmaceutical compositions determined for treating fragile X mental retardation (FXS) of a effective amount of Puli.

24. a kind of including more fixed pharmaceutical compositions of Puli, described pharmaceutical composition suffers from fragile X mental retardation for treating (FXS) subject.

25. a kind of packet, comprising:

It a) include more fixed pharmaceutical compositions of a certain amount of Puli；With

B) for the specification using subject of the described pharmaceutical composition treatment with fragile X mental retardation (FXS).

26. one kind to the subject with fragile X mental retardation (FXS) for being allocated or for comprehensive to fragile X is suffered from The subject of sign (FXS) treats packet used in being allocated, and the treatment includes:

A) one or more unit doses, each unit dose includes a certain amount of Puli more fixed, wherein in the list The Puli more fixed amounts in the dosage of position can effectively treat the subject after being applied to the subject, and

B) it is used for its finished pharmaceutical container, the container to contain one or more unit doses, and the container also contains It or include the label used that the packet is guided in treating the subject.

27. a kind of packet, comprising:

A) the first pharmaceutical composition, including a certain amount of Puli more fixed and pharmaceutically acceptable carriers；

B) the second pharmaceutical composition, including a certain amount of carbamazepine, valproic acid, double valproic acids, lithium carbonate, Gabapentin, drawing Not triazine, Topiramate, Tiagabine, sabril, phenobarbital, primidone mysoline, phenytoinum naticum, methylphenidate, dextroamphetamine, L- Acetylcarnitine, Venlafaxine, Nefazodone, amantadine, folic acid, clonidine, guanfacine, Prozac, Sertraline, western phthalein are general Orchid, Paxil, Fluvoxamine, Risperidone, Quetiapine, Olanzapine, Trazodone or epiphysin and pharmaceutically acceptable load Body；With

C) for first pharmaceutical composition and second pharmaceutical composition to be used to treat with fragile X mental retardation together (FXS) specification of subject.

28. a kind of packet, comprising:

A) the first pharmaceutical composition, including a certain amount of Puli more fixed and pharmaceutically acceptable carriers；

C) for first pharmaceutical composition and second pharmaceutical composition to be used to treat with fragile X mental retardation together (FXS) specification of subject.

29. one kind to the subject with fragile X mental retardation (FXS) for being allocated or for comprehensive to fragile X is suffered from The subject of sign (FXS) treats packet used in being allocated, and the treatment includes:

A) one or more unit doses, each unit dose include:

I. determine for a certain amount of Puli more, and

Ii. a certain amount of second medicament, selected from by carbamazepine, valproic acid, double valproic acids, lithium carbonate, Gabapentin, Rameau Triazine, Topiramate, Tiagabine, sabril, phenobarbital, primidone mysoline, phenytoinum naticum, methylphenidate, dextroamphetamine, L- second Acylcarnitine, Venlafaxine, Nefazodone, amantadine, folic acid, clonidine, guanfacine, Prozac, Sertraline, Citalopram, In the group that Paxil, Fluvoxamine, Risperidone, Quetiapine, Olanzapine, Trazodone and epiphysin form,

B) wherein, the Puli in the unit dose more fixed and respective amounts of the second medicament are to described tested Person can effectively treat the subject when applying together, and

C) it is used for its finished pharmaceutical container, the container to contain one or more unit doses, and the container also contains It or include the label used that the packet is guided in treating the subject.

30. one kind to the subject with fragile X mental retardation (FXS) for being allocated or for comprehensive to fragile X is suffered from The subject of sign (FXS) treats packet used in being allocated, and the treatment includes:

A) one or more unit doses, each unit dose include:

I. determine for a certain amount of Puli more, and

Ii. a certain amount of one or more second medicaments are selected from by carbamazepine, valproic acid, double valproic acids, lithium carbonate, add Bar spray fourth, Lamotrigine, Topiramate, Tiagabine, sabril, phenobarbital, primidone mysoline, phenytoinum naticum, methylphenidate, dextrorotation peace His non-life, L- acetylcarnitine, Venlafaxine, Nefazodone, amantadine, folic acid, clonidine, guanfacine, Prozac, sertraline In the group that woods, Citalopram, Paxil, Fluvoxamine, Risperidone, Quetiapine, Olanzapine, Trazodone and epiphysin form,

B) wherein, one or more respective amounts of second medicament in the unit dose are to subject's phase The subject can be effectively treated when with application, and

Background technique

Fragile X is comprehensiveSign

Fragile X mental retardation (FXS) is the change of the most common form and autism spectrum disorder (ASD) of heredity intelligent disability Body (Yu and Berry-Kravis, 2014).FXS is in the 5 ' UTR as FMR1 gene caused by the amplification of CGG repetitive sequence, Its specific supermethylation, silencing and forfeiture for causing FMR1 albumen (FMRP) to express.

Fragile X correlation tremor/ataxia syndrome (FXTAS) is an example of FXS associated disease, is served as reasons The neurodegenerative disease of adult onset caused by CGG repetitive sequence expands in preceding prominent region (55-200) in FMR1 gene. Main clinical characteristics of the FXTAS in elderly men include the motion problems of cerebellar gait incoordination and action tremor (Leehey 2009)。

Still lack effective treatment method.For FXS and its related disease, there is still a need for new effective treatment methods.

Puli more fixed (Pridopidine)

Puli more fixed (4- [3- (methyl sulphonyl) phenyl] -1- Propyl-piperidin) (being once called as ACR16) are a kind of opening The drug for being used to treat Huntington's chorea (Huntington ' s disease) of hair.Puli more have been demonstrated surely by right Hyperactivity hyperkinesia inhibit or enhanced hypoactivity to adjust motor activity.Puli more fixed neuroprotection performance quilts Think the high-affinity (S1R, in conjunction with IC50~100nM) for being attributed to it to σ -1 receptor (sigma-1receptor), and it is general The fixed locomotor activity of benefit may mainly by its to the low-affinities of d2 dopamine receptor (D2R) (in conjunction with IC50~10 μM), Antagonistic activity mediates (Ponten 2010).More low-affinities shown surely with the micro-molar range of other receptors of Puli In conjunction with.

S1R is endoplasmic reticulum (ER) chaperone, participates in the cell differentiation in brain, neural plasticity, neuroprotection and recognizes Know function.Recently, the transcription group of rat striatum is analysis shows that Puli more fixed treatment activation BDNF, Dopamine receptor_1 (D1R), glucocorticoid receptor (GR) and serine-threonine kinase protein kinase B (Akt)/phosphoinositide 3-kinase (PI3K) expression of approach, it is known that these are expressed the plasticity for promoting neurons and survival ability and are damaged in HD.In addition, Determine gene expression profile and show for Puli more to knock in the anti-of HD disease gene express spectra in (Q175KI) HD mouse model in Q175 Rotary-die type (Geva 2016).Determine for Puli more also to enhance neuroprotection in Human Neuroblastoma Cell Line in a manner of S1R dependence The secretion (Geva 2016) of property brain-derived neurotrophic factor (BDNF).

Summary of the invention

The present invention provides the methods of subject of the treatment with fragile X mental retardation (FXS) a kind of, including periodically to tested Person's application includes more fixed pharmaceutical compositions of Puli of the effectively amount for the treatment of subject.

It is fixed the present invention also provides Puli more, it is used to treat the subject for suffering from FXS.

The present invention also provides the purposes that Puli more are used to prepare the drug for treating the subject for suffering from FXS surely.

The present invention also provides it is a kind of include more fixed pharmaceutical compositions of a effective amount of Puli for treating FXS.

The present invention also provides a kind of including more fixed pharmaceutical compositions of Puli, is used to treat tested with FXS Person.

The present invention also provides a kind of packets, comprising:

It a) include more fixed pharmaceutical compositions of a certain amount of Puli；With

B) for the specification using subject of the described pharmaceutical composition treatment with FXS.

The present invention also provides it is a kind of for be allocated to the subject with FXS or for FXS by Examination person treats packet used in being allocated comprising:

A) one or more unit doses, each unit dose includes a certain amount of Puli more fixed, wherein in institute State the Puli more in unit dose it is fixed it is described it is a certain amount of can effectively be treated after being applied to the subject it is described Subject, and

B) it is used for its finished pharmaceutical container, the container to include one or more unit doses, and the container is also Contain or includes the label used for guiding the packet in treating the subject.

The present invention also provides a kind of packets, comprising:

A) the first pharmaceutical composition, including a certain amount of Puli more fixed and pharmaceutically acceptable carriers；

B) the second pharmaceutical composition, including a certain amount of carbamazepine, valproic acid, double valproic acids, lithium carbonate plus bar spray Fourth, Lamotrigine, Topiramate, Tiagabine, sabril, phenobarbital, primidone mysoline, phenytoinum naticum, methylphenidate, dextrorotation An Feita Life, L- acetylcarnitine, Venlafaxine, Nefazodone, amantadine, folic acid, clonidine, guanfacine, Prozac, Sertraline, west Phthalein Pulan, Paxil, Fluvoxamine, Risperidone, Quetiapine, Olanzapine, Trazodone or epiphysin and pharmaceutically acceptable Carrier；With

C) for first pharmaceutical composition and second pharmaceutical composition are used to together to treat with FXS by The specification of examination person.

The present invention also provides a kind of packets, comprising:

A) the first pharmaceutical composition, including a certain amount of Puli more fixed and pharmaceutically acceptable carriers；

C) for first pharmaceutical composition and second pharmaceutical composition are used to together to treat with FXS by The specification of examination person.

The present invention also provides it is a kind of for be allocated to the subject with FXS or for FXS by Examination person treats packet used in being allocated comprising:

A) one or more unit doses, each such unit dose include:

I) determine for a certain amount of Puli more, and

Ii) a certain amount of second medicament, selected from by carbamazepine, valproic acid, double valproic acids, lithium carbonate, Gabapentin, Lamotrigine, Topiramate, Tiagabine, sabril, phenobarbital, primidone mysoline, phenytoinum naticum, methylphenidate, dextroamphetamine, L- acetylcarnitine, Venlafaxine, Nefazodone, amantadine, folic acid, clonidine, guanfacine, Prozac, Sertraline, western phthalein are general In the group that orchid, Paxil, Fluvoxamine, Risperidone, Quetiapine, Olanzapine, Trazodone and epiphysin form,

Wherein, the Puli in the unit dose more fixed and respective amounts of the second medicament to it is described by It is effective to the subject is treated when examination person applies together, and

The present invention also provides it is a kind of for be allocated to the subject with FXS or for FXS by Examination person treats packet used in being allocated comprising:

A) one or more unit doses, each unit dose include:

I) determine for a certain amount of Puli more, and

Ii) a certain amount of one or more second medicaments, selected from by carbamazepine, valproic acid, double valproic acids, carbonic acid Lithium, Gabapentin, Lamotrigine, Topiramate, Tiagabine, sabril, phenobarbital, primidone mysoline, phenytoinum naticum, methylphenidate, Dextroamphetamine, L- acetylcarnitine, Venlafaxine, Nefazodone, amantadine, folic acid, clonidine, guanfacine, Prozac, What Sertraline, Citalopram, Paxil, Fluvoxamine, Risperidone, Quetiapine, Olanzapine, Trazodone and epiphysin formed Group kind,

Wherein, the Puli in the unit dose more fixed and one or more respective amounts of second medicament Subject can be effectively treated when applying together to the subject, and

Detailed description of the invention

Figure 1A -1B.The FXS hESC for lacking FMRP expression maintains versatility.(1A-1B) versatility marker is in FXS Expression in hESC, such as by shown in immunocytochemistry (1A) and qRT-PCR (1B).FMRP (1A) is had no in FXS hESC Or FMR1mRNA (1B).In fig. ib, horizontal the 4th column from left to right by each control and FXS hESC of FMR1 indicates, and And it can't detect FMR1 (i.e. there is no the 4th columns in FXC hESC) in FXS hESC.

Fig. 2A -2C.FXS hESC can effectively be divided into mature neuron.(2A-2C) FXS hESC can be effectively Be divided into the neuron of excitability characteristic and inhibition characteristic, as MAP2, Tuj-1, GABA and NeuN albumen (2A) and MAP2, (2B) shown in the expression of VGLUT2, GAD67, SYP and SYN mRNA.At the 21st day of differentiation, about 80% cell was nerve First characteristic (2C).

Fig. 3 A and 3B.After FXS hESC neuron differentiation, FMR1 keeps silent.In neural progenitor cell (NPC) or from FXS The table of FMR1mRNA (3A) or FMRP (protein encoded by FMR1 gene) (3B) are not observed in the neuron of hESC differentiation It reaches.

Fig. 4 A-4C.People's FXS neuron shows neurite outgrowth defect.

(4A) depicts the neural process (bright field) of control neuron and FXS neuron at the 7th day.

(4B) compared with compareing neuron (top data), the neurite lengths (bottom data) in FXS are reduced.

(4C) compared with compareing neuron (top data), the neural process branch point (bottom data) in FXS is reduced.

Fig. 5.Puli more fixed treatments improve the neurite outgrowth in mankind FXS neuron.It was commented within 8 days time cycles Estimate the growth of the neural process of control cell and the neuron derived from 1uM, 5uM or the FXS hESC of carrier (DMSO) processing.In Under two kinds of proof loads, the Puli more fixed neural process defects improved in mankind FXS neuron.

Fig. 6 A-6C.The science of heredity inactivation and pharmacology inactivation of S1R eliminate neurite outgrowth in FXS neuron by general The improvement that benefit mediates surely.Effective inactivation and the loss of its protein product of S1R gene are confirmed by western blot method (Fig. 6 A).It eliminates in the FXS neuron that S1R is deactivated (S1RKO) and is seen in the FXS neuron handled surely at more with Puli The improvement (Fig. 6 B) that the neural process observed increases.NE-100, which is co-administered, has blocked Puli more to determine to neural in FXS neuron Uprush raw effect (Fig. 6 C).

Specific embodiment

The present invention provides the method for subject of the treatment with fragile X mental retardation (FXS) or FXS associated disease, including fixed Phase includes effectively treating more fixed pharmaceutical compositions of Puli of the amount of subject to subject's application.

Puli more additionally provided for treating the subject for suffering from FXS are fixed.

It additionally provides Puli more and is used to prepare answering for the drug used in subject of the treatment with FXS surely With.

Puli more are additionally provided to determine or comprising more fixed pharmaceutical compositions of a effective amount of Puli for treating answering for FXS With.

In one embodiment, subject also suffers from autism spectrum disorder (ASD).In some embodiments, by Examination person suffers from FXTAS.

In another embodiment, more fixed amounts of Puli can be effectively reduced one of subject or a variety of FXS The severity of symptom.In another embodiment, more fixed amounts of Puli can be effectively reduced one of subject or The severity of a variety of FXTAS symptoms.

In one embodiment, one or more symptoms of FXS are selected from by cognitive disorder, hypoevolutism, social activity and row For problem, anxiety, enliven excessive behavior, to the group of gastrointestinal function and the epilepsy composition of hypersensitivity, the change of stimulus to the sense organ In.In another embodiment, symptom is cognitive disorder, and the cognitive disorder is intelligence disability or learning disability.Another In one embodiment, symptom is hypoevolutism, and hypoevolutism is the hypoevolutism spoken with language.

One of elderly men or a variety of FXTAS symptoms include trembling with cerebellar gait incoordination and motility Dyskinesia.

In some embodiments, treatment method, composition and application include with FXS or FXS associated disease by Restore neurite outgrowth in examination person.

In one embodiment, 10-315mg Puli more are applied to patient daily to determine.In another embodiment, 22.5-315mg Puli more are applied to patient daily to determine.In one embodiment, more fixed amounts of the Puli of application are - 90mg/ days 20mg/ days.In one embodiment, more fixed amounts of the Puli of application are -225mg/ days 90mg/ days.One In a embodiment, more fixed amounts of the Puli of application are -225mg/ days 180mg/ days.In another embodiment, daily To patient apply 10mg, 22.5mg, 45mg, 67.5mg, 90mg, 100mg, 112.5mg, 125mg, 135mg, 150mg, 180mg, 200mg, 250mg or 315mg Puli more fixed.In one embodiment, more fixed amounts of the Puli of application are 45mg/ days. In one embodiment, more fixed amounts of the Puli of application are 90mg/ days.In one embodiment, the Puli of application is more Fixed amount is 180mg/ days.In one embodiment, more fixed amounts of the Puli of application are 225mg/ days.

In one embodiment, more fixed amounts of Puli by 10mg, 22.5mg, 45mg, 67.5mg, 90mg, More fixed unit doses of 100mg, 112.5mg, 125mg, 135mg, 150mg, 180mg, 200mg, 250mg or 315mg Puli It is administered.

In one embodiment, daily administration of unit doses is primary.

In one embodiment, daily administration of unit doses is more than primary.In another embodiment, application daily Unit dose is twice.

In one embodiment, Puli more are the Puli more forms for determining hydrochloride surely.

In one embodiment, subject has more than 200 CGG repetitive sequences on X chromosome.

In one embodiment, subject has about 50-200 CGG repetitive sequence and is suffered from X chromosome FXTAS。

In one embodiment, subject was less than 18 years old.In one embodiment, subject is male.At other In embodiment, subject is women.In one embodiment, subject is human patients.

In one embodiment, the mode periodically applied is oral.

The present invention provides the methods of subject of the treatment with FXS a kind of, including periodically include one to subject's application Quantitative more fixed pharmaceutical compositions of Puli, and further include application second medicament, second medicament are selected from by carbamazepine, the third penta Sour, double valproic acids, lithium carbonate, Gabapentin, Lamotrigine, Topiramate, Tiagabine, sabril, phenobarbital, Pu Li meter Ketone, phenytoinum naticum, methylphenidate, dextroamphetamine, L- acetylcarnitine, Venlafaxine, Nefazodone, amantadine, folic acid, cola Fixed, guanfacine, Prozac, Sertraline, Citalopram, Paxil, Fluvoxamine, Risperidone, Quetiapine, Olanzapine, bent azoles In the group of ketone and epiphysin composition.

The present invention also provides Puli more for treating the subject for suffering from FXS are fixed.

Puli more the present invention also provides the drug being used to prepare for treating the subject for suffering from FXS are fixed.

The present invention also provides include more fixed pharmaceutical compositions of a effective amount of Puli for treating FXS.

The present invention also provides include for treat suffer from FXS subject more fixed pharmaceutical compositions of Puli.

The present invention also provides a kind of packets, comprising:

It a) include more fixed pharmaceutical compositions of a certain amount of Puli；With

B) specification for the subject using medicine composite for curing with FXS.

The present invention also provides it is a kind of for be allocated to the subject with FXS or for FXS by Examination person treats packet used in being allocated comprising:

A) one or more unit doses, each unit dose includes a certain amount of Puli more fixed, wherein in institute The Puli more fixed amounts stated in unit dose can effectively treat subject after being applied to subject, and

B) it is used for its finished pharmaceutical container, the container to include one or more unit doses, and the container also contains It or include the label used that the packet is guided in treatment subject.

The present invention also provides a kind of packets, comprising:

A) the first pharmaceutical composition, including a certain amount of Puli more fixed and pharmaceutically acceptable carriers；

C) for being used to treat saying for the subject with FXS together for the first pharmaceutical composition and the second pharmaceutical composition Bright book.

The present invention also provides a kind of packets, comprising:

A) the first pharmaceutical composition, including a certain amount of Puli more fixed and pharmaceutically acceptable carriers；

C) for instructing to be used to treat with FXS together by first pharmaceutical composition and second pharmaceutical composition Subject specification.

The present invention also provides it is a kind of for be allocated to the subject with FXS or for FXS by Examination person treats packet used in being allocated comprising:

A) one or more unit doses, each unit dose include:

I) determine for a certain amount of Puli more, and

Wherein, the Puli in the unit dose more fixed and respective amounts of the second medicament to it is described by The subject is effectively treated when examination person applies together, and

The present invention also provides it is a kind of for be allocated to the subject with FXS or for FXS by Examination person treats packet used in being allocated comprising:

A) one or more unit doses, each such unit dose include:

I) determine for a certain amount of Puli more, and

Wherein, the Puli in the unit dose more it is fixed and described one in or the respective amount of a variety of second medicaments Subject is effectively treated when applying together to the subject, and

The combination of above embodiment is also within the scope of the invention." the second pharmaceutical composition " being mentioned above includes one Quantitative carbamazepine, valproic acid, double valproic acids, lithium carbonate, Gabapentin, Lamotrigine, Topiramate, Tiagabine, ammonia hexene Acid, phenobarbital, primidone mysoline, phenytoinum naticum, methylphenidate, dextroamphetamine, L- acetylcarnitine, Venlafaxine, Nefazodone, Amantadine, folic acid, clonidine, guanfacine, Prozac, Sertraline, Citalopram, Paxil, Fluvoxamine, Risperidone, Quetiapine, Olanzapine, Trazodone or epiphysin, or any combination thereof；And pharmaceutically acceptable carrier.

As described herein " second medicament " be selected from by carbamazepine, valproic acid, double valproic acids, lithium carbonate, Gabapentin, Lamotrigine, Topiramate, Tiagabine, sabril, phenobarbital, primidone mysoline, phenytoinum naticum, methylphenidate, dextroamphetamine, L- acetylcarnitine, Venlafaxine, Nefazodone, amantadine, folic acid, clonidine, guanfacine, Prozac, Sertraline, western phthalein are general Orchid, Paxil, Fluvoxamine, Risperidone, Quetiapine, Olanzapine, Trazodone and epiphysin and any combination thereof composition Group in, and optionally include pharmaceutically acceptable carrier.

For aforementioned embodiments, it is contemplated that each embodiment disclosed herein is suitable for other each disclosed embodiment party Formula.For example, the element recorded in method implementation can be used for pharmaceutical composition, packet and application implementation mode as described herein In, vice versa.

Term

As used herein, unless otherwise stated, each of following term should have definition described below.

Article " one (a) ", " one (an) " and "the" are non-limiting.For example, " this method " includes the phrase meaning Most definition extensively, can be more than one method.

As used herein, " applied to subject " be directed to subject give, distribute or drug application to alleviate, cure or Mitigate and disease, illness or health status (for example, pathological condition) relevant symptom.Oral administration is to apply the compounds of this invention Use a kind of mode of subject.

As used herein, " periodically application " means duplicate/periodic application separated by a period of time.Apply it Between period preferably remain unchanged every now and then.Periodically application may include such as once-a-day administration, daily administration twice, often Day application is three times, daily administration four times, application is primary weekly, apply weekly apply twice, weekly three times, application in one week four times Deng.

As used herein, refer to that Puli present in preparation is more with Puli more fixed " amounts " or " dosage " that milligram measures The milligram number of fixed (4- [3- (methyl sulphonyl) phenyl] -1- Propyl-piperidin), no matter which kind of form preparation is.For example, containing The unit dose of " 90mg Puli more fixed " means that the Puli more amounts for determining alkali are 90mg in preparation, and no matter which kind of shape preparation is Formula.Therefore, it in the presence of Puli more are determined in the form of salt, such as Puli more determine hydrochloride, due to the presence of salt, provides More weight for determining salt form necessary to dosage of 90mg Puli will be greater than 90mg.

As used herein, " unit dose " and " unit dosage forms " refers to single drug administration entity entity.

As used herein, in the context of several value or ranges, documented by " about " indicates or claimed numerical value or ± the 10% of range.

As used herein, such as realize that the quantity of " effective " meaning component in target is enough to generate controlling for instruction with effective quantity Reaction is treated, and is worked as in a manner of the disclosure in use, the not unsuitable side effect according to reasonable interests/Hazard ratio (such as toxicity, stimulation or allergic reaction).For example, the amount of effectively treatment cognitive defect.Specific effective quantity is according to being treated Particular condition, the physical condition of patient, the type for the mammal treated, the duration for the treatment of while the treatment of progress Property (if any) and used specific preparation and compound or derivatives thereof the factors such as structure and become Change.

As used herein, " treatment (treat) " or " treatment (treating) " include such as illness and/or disease (such as FXS or associated disease) induction inhibit, subside or stagnate, or alleviate, mitigate, compacting, inhibit, reduce the tight of disease or illness Weight degree, eliminates or substantially eliminates or improve the symptom of disease or illness.

As used herein, " inhibition " of the progression of disease of subject or disease complications is meant to prevent, delay or subtract The progression of disease and/or disease complications of few subject.This includes the progress for for example delaying one or more symptoms in subject, It include but is not limited to delay progress below: cognitive disorder, intelligence disability, learning disability (for example it is difficult to learning new technical ability), hair Educate slow (for example, cannot learn simultaneously to be seated with other children of the same age, walk or speak), social and behavioral problem (example Such as, carry out eye contact, anxiety, absent minded, hand shaking, perform without thinking and make a speech and very active), it is burnt Consider and hyperactivity hyperkinesia behavior, to the super quick, gastrointestinal function that changes of stimulus to the sense organ, self-closing symptom is (for example, from slight case Shyly, eye contact is bad, Social Anxiety clapping hands, stinging hand and retention speech (preservative into severe case Speech)), absent minded and hyperactivity hyperkinesia, conduct disorder (for example, irritability, aggressiveness and Self-injurious behavior), insane Epilepsy, compulsive behavior and the gastrointestinal function of change.

" symptom " relevant to FXS includes any clinical or laboratory performance relevant with FXS, and is not limited to subject It can feel or observe.The symptom of FXS include but is not limited to cognitive disorder, intelligence disability, learning disability (for example it is difficult to Learn new technical ability), it is hypoevolutism (for example, cannot learn simultaneously to be seated with other children of the same age, walk or speak), social With behavioral problem (for example, carry out eye contact, anxiety, absent minded, hand shaking, without thinking perform and make a speech and It is very active), anxiety and hyperactivity hyperkinesia behavior, the super quick, gastrointestinal function that changes to stimulus to the sense organ, self-closing symptom (for example, from In slight case it is shy, eye contact is bad, Social Anxiety clapping hands, stinging hand and retention speech into severe case), Absent minded and more dynamic, conduct disorder (for example, irritability, aggressiveness and Self-injurious behavior), epilepsy, compulsive behaviors and The gastrointestinal function of change.

As used herein, " subject with FXS " refers to the subject for being diagnosed with FXS.In an embodiment In, pass through FMR1DNA testing and diagnosing subject.In some embodiments, subject is diagnosed with FXS associated disease, example Such as FXTAS.

" pharmaceutically acceptable carrier " refers to suitable for people and/or animal and not according to reasonable interests/Hazard ratio And the carrier or excipient of unsuitable side effect (such as toxicity, stimulation or allergic reaction).It can be pharmaceutically acceptable Solvent, suspending agent or carrier, for the compounds of this invention to be delivered to subject.

As used herein, " Puli more fixed " refers to that Puli more are determined alkali or its pharmaceutically acceptable salt and derivative Object, such as Puli more fixed and salt of deuterium enriched form.Deuterium enriched Puli more fixed and the example of salt and preparation method thereof is shown in No.2013-0197031,2016-0166559 and 2016-0095847 disclosed in U. S. application, in whole disclosed in aforementioned three Appearance is incorporated by reference herein.In some embodiments, Puli more are pharmaceutically acceptable salt surely, such as HCl salt or tartrate.Preferably, in any embodiment as of the invention described herein, Puli more are its salt surely The form of hydrochlorate.

" deuterium enriched " means in a certain amount of compound, and the abundance of the deuterium at any related locus of compound is greater than The abundance of naturally occurring deuterium at the site.The naturally occurring distribution of deuterium is about 0.0156%.Therefore, " deuterium enriched " In compound, the abundance of the deuterium of any related locus is both greater than 0.0156%, and can be greater than 0.0156% to 100% Range.Deuterium enriched compound can obtain and with deuterium exchange hydrogen or by using described in deuterium enriched starting material synthesis Compound.

It is deuterium enriched to refer in the molecule in the incorporation hundred of the deuterium of given position substitution hydrogen when being used in combination with percentage Divide ratio.For example, meaning that in given sample 1% molecule contains deuterium in designated position deuterium enriched the 1% of given position.Deuterium is rich Collection can be used conventional method of analysis known to persons of ordinary skill in the art and determine, the method includes mass spectrography and nuclear-magnetism are total Spectroscopy.

As used herein, " combination " refers to the reagent set in being used to treat and being administered simultaneously or the same period applies. Be administered simultaneously refer to that application Puli more is fixed and the mixture of second compound (either homogeneous mixture, suspension, lotion, Or other physical combinations).In this case, which can be Puli more fixed and second compound mixtures or in sight The individual container that will be combined before application.The same period, which applies, to be referred to Puli more fixed and second compounds while being administered alone, or Add so that observing relative to Puli more fixed or individual the active of second compound in close enough time application Activity that is adding or preferably cooperateing with.

As used herein, " application (concomitant administration) together " or " concomitantly " application are meant Two kinds of medicaments are applied in the close enough time, so that the respective therapeutic effect of every kind of medicament overlaps.

As used herein, " additional " or " additional treatment " refers to by the set for the reagent for being used to treat, wherein receiving treatment Subject by the first therapeutic scheme of one or more different reagents, then start in addition to the first therapeutic scheme Second therapeutic scheme of one or more difference reagents, thus simultaneously all reagents used in non-treatment are all to start simultaneously at application 's.For example, applying Puli more fixed treatments to the patient for having received Donepezil treatment.

Dosage device as used herein may include single compound or the mixture of its compound.Dosage device can be by It is prepared as oral dosage form, such as tablet, capsule, pill, pulvis and granule.

Pharmaceutically acceptable salt

Reactive compound used in accordance with the present invention can be suitable for the arbitrary form for the application being intended to provide.Suitably Form includes pharmaceutically (i.e. physiologically) the acceptable salt and prodrug forms of the compounds of this invention.

" its salt " is the salt of the compounds of this invention, is modified by the hydrochlorate or alkali salt that prepare the compound.At this Aspect, term " pharmaceutically acceptable salt " refer to the inorganic of the relative nontoxic of the compounds of this invention suitable for medicinal usage and Organic acid addition salt or base addition salts.Pharmaceutically acceptable salt can be prepared by program that is known in the art and having described. A kind of method for preparing this salt is with inorganic alkali process the compound of the present invention.

The example of pharmaceutically acceptable salt includes but is not limited to nontoxic inorganic and organic acid addition salt, such as hydrochloric acid Salt, hydrobromate, nitrate, perchlorate, phosphate, sulfate, formates, acetate, aconate, ascorbate, Benzene sulfonate, benzoate, cinnamate, citrate, embonate, enanthate, fumarate, glutamate, glycolic Salt, lactate, maleate, malonate, mandelate, mesylate, naphthalene-2-sulfonic acid salt, phthalate, salicylic acid Ester, sorbate, stearate, succinate, tartrate, p-methyl benzenesulfonic acid ester etc..These salt can be by this field The method preparation known and described.

Pharmaceutical composition

Although compound used according to the invention can be applied with its primitive form, preferably (optionally by active constituent Ground is in the form of physiologically acceptable salt) with one or more adjuvants, excipient, carrier, buffer, diluent and/or Other conventional pharmaceutical auxiliary agents are concomitantly introduced into pharmaceutical composition.

In one embodiment, the present invention provide pharmaceutical composition comprising reactive compound or its can pharmaceutically connect Salt received or derivatives thereof and its one or more pharmaceutically acceptable carrier used, and optionally, this field is Know and used other treatment and/or prevention ingredient.Carrier must be " acceptable ", i.e. the other compositions of carrier and preparation It is compatible and harmless to its recipient.

Pharmaceutical composition of the invention can facilitate approach to apply by therapy needed for any be suitble to.Preferred application way Diameter includes that (especially with tablet, capsule, sugar-coat (drag é), powder or liquid form) and parenteral administration (spy is administered orally It is not skin, subcutaneous, muscle or intravenous injection).Those skilled in the art can be by using the standard for being suitable for required preparation Method and routine techniques prepare pharmaceutical composition of the invention.When needing, it can be used suitable for sustained release activity ingredient Composition.

Further details about preparation and application technique can be found in Remington's Pharmaceutical Science (the Maack publication of latest edition Co., Ltd, Easton, PA) (Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton,PA))。

Any range disclosed herein mean all 1 percent, 1/10th and graduation of whole numbers of units amount within the scope of this by The present invention provides and as the specific disclosure of a part of the invention.Thus, for example, " 10mg to 315.0mg " or " 10mg- 315.0mg " refer to 10.0mg, 10.1mg, 10.2mg ... 22.0,22.1mg, 22.2mg, 22.3mg, 22.4mg etc., highest Unit quantity up to 315.0mg is included in the present invention as embodiments of the present invention.

In this application, various publications are quoted with the first authors and Publication Year.These publications completely draw It is provided in " bibliography " part.The disclosure for the publication quoted in " bibliography " part is whole simultaneously by reference Enter in the application, so that the state of the art by the date of invention as described herein is described more fully with.

The present invention is better understood with reference to following " experimental detail ", but the person skilled in the art will easily understand, Specific experimental detail is only to explaination of the invention, and the present invention will be described more fully in claims.

Experimental detail

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