CN101378751A - Tuberous sclerosis treatment - Google Patents

Tuberous sclerosis treatment Download PDF

Info

Publication number
CN101378751A
CN101378751A CNA2007800043024A CN200780004302A CN101378751A CN 101378751 A CN101378751 A CN 101378751A CN A2007800043024 A CNA2007800043024 A CN A2007800043024A CN 200780004302 A CN200780004302 A CN 200780004302A CN 101378751 A CN101378751 A CN 101378751A
Authority
CN
China
Prior art keywords
chemical compound
purposes
treatment
epiloia
plyability
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CNA2007800043024A
Other languages
Chinese (zh)
Other versions
CN101378751B (en
Inventor
W·贝格
J·贝内代托
I·埃尔莫特
H·莱恩
D·勒布沃尔
W·塞勒斯
M·斯图姆
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
Original Assignee
Novartis AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=36100930&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CN101378751(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from GB0603568A external-priority patent/GB0603568D0/en
Priority claimed from GB0604593A external-priority patent/GB0604593D0/en
Priority claimed from GB0605760A external-priority patent/GB0605760D0/en
Priority claimed from GB0609698A external-priority patent/GB0609698D0/en
Priority claimed from PCT/EP2007/000818 external-priority patent/WO2007088034A2/en
Priority to CN201310425110.8A priority Critical patent/CN104000818B/en
Application filed by Novartis AG filed Critical Novartis AG
Publication of CN101378751A publication Critical patent/CN101378751A/en
Publication of CN101378751B publication Critical patent/CN101378751B/en
Application granted granted Critical
Ceased legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Rapamycin derivatives for use in the treatment of neurocutaneous disorders.

Description

Tuberous sclerosis treatment
The application relates to treatment and prevents neural skin barrier, such as neural skin barrier by plyability epiloia (TSC) mediation, and tuberous sclerosis and for example such as the method for the tuberous sclerosis by the mediation of 1 type neurofibromatosis.
Neural skin barrier used herein comprises by plyability epiloia (TSC) disorder mediated, for example tuberous sclerosis and associated disorders and 1 type neurofibromatosis and associated disorders.
1 type neurofibromatosis (NF1) and plyability epiloia (TSC) have been represented two kinds of neural skin barrier, and the individual tumorigenic frequency of wherein being encroached on increases.
TSC is an autosomal dominant disorder, it is characterized in that general the optimum hamartoma of property, epilepsy, mental retardation and autism.TSC is relevant with sudden change among tumor suppressor gene TSC1 and the TSC2.The sudden change of these two kinds of genes in any causes the clinical manifestation of TSC.Common clinical symptoms comprises epilepsy, mental retardation, autism, renal failure, facial angiofibroma and cardia rhabdomyoma, and in addition, manyly be subjected to infringement individual, be meant in the bone (phalanx) with toe to have cyst sample zone especially in some bony areas.The characteristic skin lesion comprises clear-cut zone (hypopigmentation) that the colour of skin that may take place goes down and the relative little pale red tuberosity that may begin about 4 years old the time to occur on buccal and nose in the infancy stage process.The infringement of these pale reds is final to be enlarged, fusion each other (fusions) and develop into the wart sample and show (sebaceous adenoma).Extra skin lesion also may take place, and comprises the coffee-like ＂ zone (caf) of flat ＂ that cutaneous pigmentation increases; Around the fingernail or its optimum fibrous tubercle (fibroma) that occurs down; Or the ＂ excipuliform ＂ of coarse protuberance damages (shagreen patch) on waist.
Although it is neuropathic that the many features among the TSC are actually, renal dysfunction is the common feature of this disease.Approximately renal angiomyolipoma (AML) takes place in the TSC patient of 70-80%.Three kinds of xenogenesis benign tumors that different cell types are formed that AML serves as reasons and comprises smooth muscle, blood vessel and adipose cell.Also there is the evidence of the destructive form with the pneumonopathy that is called LAM (LAM) in TSC patient.LAM is unique and rare capsule lung (lung) disease, and it mainly encroaches on the preceding women of menopause.Passing in time, the myocyte blocks air-flow, blood and lymph fluid arrival and leaves lung, thereby prevents the remainder of lung oxygen supply to health.Common asymptomatic tumor of kidney can also find in having the patient of LAM, for example clinical symptoms be dyspnea (dysapnea), chronic cough, stridulate, pneumothorax and chest pain.These symptoms take place when the LAM cell migration is gone into lung and worsen, and cause capsule essence to be destroyed and the respiratory failure of carrying out property.(sporadic LAM) takes place or as the Secondary cases disease of TSC (TSC-LAM) takes place in the disease independently of can be used as LAM.AML is the symptom of LAM (50% patient occurs) and TSC (70% patient occurs), and does not have radiology, morphology or the genetic difference between AMLs between these two kinds of obstacles.
The tuberous sclerosis gene mutation is LAM (lymphyangioleiomyomatosis) reason (LAM) according to reports.In the women's who has LAM from 4 angiomyoliopma cell and LAM cell, these sudden changes have been found.These sudden changes are not present in normal lung, kidney or the hemocyte, show that these women with LAM do not have the heredopathia tuberous sclerosis.Identify that genetic association between this tuberous sclerosis and the sporadic LAM is the important step in the LAM research.(for example, referring to ＂ Mutations in the tuberous sclerosis complexgene TSC2 are a cause of sporatic lymphyangioleiomyomatosis ＂; Carsillo, Astrinidis and Henske; PNAS 2000 97:6085-90).
Subependymal giant cell astrocytoma (SEGA) takes place in part TSC patient, and they are general asymptomatic slow tumor progression, blocks up to ventricle takes place, thereby causes life-threatening acute hydrocephalus.Because the position, deep of these tumors, so excision is difficulty and relevant with tangible sickness rate usually.
1 type neurofibromatosis (NF1, von Recklinghaus disease) is one of modal genetic block of people's apoplexy due to endogenous wind.NF1 causes because of the sudden change in the NFL gene.NF1 influences many other parts of skin, brain, eye, kidney and health.NF1 is characterised in that at nervous system, muscle, growth in bone and the skin changes, wherein spread all over whole health and form neurofibroma (optimum and malignant tumor/lump), particularly in skin and brain: the performance of NF1 comprises nerve fiber neoplasia (optimum and malignant tumor/lump, glioma, vision track glioma for example, such as the rudimentary glioma that spreads all over whole health, particularly at skin, brain, the vision track, bone, in the cutaneous pigmentation transitional region, for example be called ' pigmentation spots (coffee-like birthmark) of coffee milk pigment ' speckle, osteopathia, deficiency of learning ability, the bone marrow malignant tumor, complication in hypertension and the several organs system.Also relate to skoliosis (rachiocamposis).Glioma (primary brain tumor) begins in brain or myeloid tissue.They can not diffuse to other zone of health, but can spread in nervous system.Glioma can be benign (slowly growth) or virulent (growth fast).Gliomatous type for example comprises:
-astrocytoma, in being called Astrocytic brain cell the beginning and can in the major part of brain, take place (and the chance in spinal cord; They are most commonly used to the major part brain of brain;
-ependymoma, it begins in ependyma, promptly is arranged in the cell of the passage in the brain, wherein protects the special-purpose fluid (being called cerebrospinal fluid) of brain to form and store.They are rare glioma and can find any position in brain or spinal column, but major part is found in the major part brain of brain;
-oligodendroglioma, their primary brain tumors for beginning in being called the brain cell of oligodendroglia, described oligodendroglia provide support and the nutrition to the cell of transmission impulsion.This tumor sees brain usually;
-mixed glioma, they are more than one type brain cells, comprise spider cell, the cerebroma of the cell of ependymocyte and/or oligodendroglia.The position of modal mixed glioma is at the major part brain of brain.Be similar to other glioma, they can diffuse to the other parts of brain.
Rudimentary glioma is slowly growth.Senior (pernicious) glioma is grown more fast.IV level glioma is called glioblastoma multiforme, and neurofibromatosis also comprises malignant peripheral nerve sheath tumor (MPNST) (performance is also referred to as neurofibroma and schwann's cell tumor), and it is the pernicious homologue to optimum soft tissue neoplasms.Have neurofibromatosis for example the patient of NF1 class pernicious schwann's cell tumor of this class or nerve sarcoma take place more at an early age.
Surprisingly, have been found that some rapamycin derivative is effective to tuberous sclerosis and NF-1 model, and this compounds is easy to treat neural skin barrier, the individual tumorigenic frequency of wherein being encroached on increases, such as tuberous sclerosis and 1 type neurofibromatosis, comprise associated disorders.
Provide among the present invention in one aspect:
1.1 be used for the treatment of the chemical compound of the following formula of neural skin barrier,
Figure A200780004302D00081
The chemical compound that for example comprises following formula,
Figure A200780004302D00082
Wherein
R 1Be CH 3Or C 3-6Alkynyl,
R 2For H ,-CH 2-CH 2-OH or-CH 2-CH 2-O-(C 1-8) alkyl, for example-CH 2-CH 2-O-CH 2-CH 3,
And
X is=O, (H, H) or (H, OH),
Condition is to be=O and R as X 1Be CH 3The time, R 2Not H,
Or compd A BT578, also called after zotarolimus for example, Compound C CI779, also called after temsirolimus for example, compd A P23573 (from Ariad), for example 40-(dimethyl phosphino-)-rapamycin, or chemical compound TAFA-93 (from Isotechnika).
The present invention further provides in aspect several:
1.2a the chemical compound of formula I, wherein R 1, R 2With X as above-mentioned definition; Compd A BT578; Or chemical compound TAFA-93;
They are used for the treatment of by plyability epiloia disorder mediated, induce by plyability epiloia disorder mediated and degenerate, treat symptom with the disease association that mediates by the plyability epiloia, treatment is passed through relevant obstacle of plyability epiloia disorder mediated and/or inhibition or control by plyability epiloia disorder mediated, for example, wherein comprise tuberous sclerosis by plyability epiloia disorder mediated, renal angiomyolipoma (ALM), LAM (LAM), following and/or the giant cell astrocytoma (SEGA) of ependyma.
1.2b the chemical compound of formula I, wherein R 1, R 2With X as above-mentioned definition; Or compd A BT578; Compound C CI779; Compd A P23573; Or chemical compound TAFA-93;
They are used for the treatment of 1 type neurofibromatosis (NF1), are used to induce by the NF1 disorder mediated degenerate, and are used for the treatment of the symptom relevant with NF1 and/or are used for suppressing or the NF1 disorder mediated is passed through in control.
The preferred chemical compound of formula I comprises:
40-O-(2-ethoxy)-rapamycin, and/or
The 32-deoxidation is for rapamycin, and/or
16-penta-2-alkynyloxy base-32-deoxidation is for rapamycin, and/or
16-penta-2-alkynyloxy base-32 (S or R)-dihydro-rapamycin, and/or
16-penta-2-alkynyloxy base-32 (S or R)-dihydro-40-O-(2-ethoxy)-rapamycin, such as
40-O-(2-ethoxy)-rapamycin and/or 32-deoxidation be for rapamycin,
For example 40-O-(2-ethoxy)-rapamycin is also referred to as the title everolimus.
The chemical compound of formula I comprises biolimus, and such as biolimus-9, it is the chemical compound of formula I, wherein R 1Be methyl, X is=O and R 2For-CH 2-CH 2-O-CH 2-CH 3
The chemical compound of compd A BT578, TAFA-93 and formula I, wherein R 1, R 2With X as above-mentioned definition, go back called after ＂ TSC-chemical compound of the present invention ＂ in this article.
The chemical compound of compd A BT578, CCI779, AP223573, TAFA-93 and formula I, wherein R 1, R 2With X as above-mentioned definition, go back called after ＂ NF1-chemical compound of the present invention ＂ in this article.
The present invention provides in others:
1.3a treatment comprises the TSC-chemical compound of the present invention to the individual administering therapeutic effective dose that these needs are arranged by the method for plyability epiloia disorder mediated.
1.4a induce the method for degenerating, comprise TSC-chemical compound of the present invention to the individual administering therapeutic effective dose that these needs are arranged by plyability epiloia disorder mediated.
1.5a the method for the symptom that treatment is relevant with passing through plyability epiloia disorder mediated comprises the TSC-chemical compound of the present invention to the individual administering therapeutic effective dose that these needs are arranged.
1.6a treatment comprises the TSC-chemical compound of the present invention to the individual administering therapeutic effective dose that these needs are arranged by the method for the relevant obstacle of plyability epiloia disorder mediated.
1.7a inhibition or control comprise the TSC-chemical compound of the present invention to the individual administering therapeutic effective dose that these needs are arranged by the method for plyability epiloia disorder mediated.
The present invention provides in others:
1.3b treat the method for the obstacle of 1 type neurofibromatosis (NF1), comprise NF1-chemical compound of the present invention to the individual administering therapeutic effective dose that these needs are arranged.
1.4b induce the method for degenerating, comprise NF1-chemical compound of the present invention to the individual administering therapeutic effective dose that these needs are arranged by the NF1 disorder mediated.
1.5b treat the method for the symptom relevant, comprise NF1-chemical compound of the present invention to the individual administering therapeutic effective dose that these needs are arranged with NF1.
1.6b inhibition or control comprise the NF1-chemical compound of the present invention to the individual administering therapeutic effective dose that these needs are arranged by the method for NF1 disorder mediated.
The present invention provides in one aspect of the method:
1.8 be used for as at above-mentioned 1.1,1.2a to 1.7a or the purposes of 1.2b to 1.6b or any chemical compound of method, chemical compound wherein of the present invention be 40-O-(2-ethoxy)-rapamycin, 32-deoxidation for rapamycin, 16-penta-2-alkynyloxy base-32-deoxidation for rapamycin, 16-penta-2-alkynyloxy base-32 (S or R)-dihydro-rapamycin or 16-penta-2-alkynyloxy base-32 (S or R)-dihydro-40-O-(2-ethoxy)-rapamycin;
Such as 40-O-(2-ethoxy)-rapamycin or 32-deoxidation for rapamycin,
40-O-(2-ethoxy)-rapamycin (for example this paper goes back called after ＂ compd A ＂) for example.
The present invention provides in aspect preferred:
2.1 be used for as above-mentioned 1.1,1.8 and 1.2a to 1.7a as shown in purposes or any chemical compound of method, it is used for the treatment of tuberous sclerosis.
2.2 be used for as above-mentioned 1.1,1.8 and 1.2a to 1.7a as shown in purposes or any chemical compound of method, it is used for the treatment of renal angiomyolipoma (ALM).
2.3 be used for as above-mentioned 1.1,1.8 and 1.2a to 1.7a as shown in purposes or any chemical compound of method, it is used for the treatment of LAM (LAM).
2.4 be used for as above-mentioned 1.1,1.8 and 1.2a to 1.7a as shown in purposes or any chemical compound of method, it is used for the treatment of acute hydrocephalus, for example the acute hydrocephalus that causes because of subependymal giant cell astrocytoma (SEGA).
The present invention provides in aspect extra:
3.1a that preparation is used for is above-mentioned 1.1,1.8, the TSC-chemical compound of the present invention in the medicine of any methods of 1.2a to 1.7a or 2.1 to 2.4 definition or purposes, for example comprises preferred aspect as defined above.
3.2a TSC-chemical compound of the present invention is used for purposes in the medicine of any methods of above-mentioned 1.1,1.8,1.2a to 1.7a or 2.1 to 2.4 definition or purposes in preparation, for example comprises preferred aspect as defined above.
The present invention provides in aspect extra:
3.1b preparation be used for above-mentioned 1.1,1.8 or the medicine of any method that defines of 1.2b to 1.7b or purposes in NF1-chemical compound of the present invention, for example comprise preferred aspect as defined above.
3.2b NF1-chemical compound of the present invention preparation be used for above-mentioned 1.1,1.8 or the medicine of any method that defines of 1.2b to 1.7b or purposes in purposes, for example comprise preferred aspect as defined above.
Any chemical compound of the present invention, for example comprise any method or purposes that are used for above-mentioned 1.1,1.8,1.2a to 1.7a or 2.1 to 2.4 definition or TSC-chemical compound and the NF1 chemical compound that is used for preparing the medicine that defines as above-mentioned 3.1a, 3.2a, 3.1b or 3.2b, for example comprise preferred aspect as defined above, preferably use with pharmaceutical compositions.
The present invention provides in one aspect of the method:
4.1a pharmaceutical composition, it comprises TSC-chemical compound of the present invention and at least a pharmaceutically acceptable excipient, for example appropriate carriers and/or diluent for example comprise filler, binding agent, disintegrating agent, flowing regulator, lubricant, saccharide or sweeting agent, spice, antiseptic, stabilizing agent, wetting agent and/or emulsifying agent, solubilizing agent, are used to regulate the salt and/or the buffer agent of osmotic pressure;
That this pharmaceutical composition is used for is above-mentioned 1.1,1.8, any method or the purposes of 1.2a to 1.7a or 2.1 to 2.4 definition, for example comprises preferred aspect as defined above.
For example and be used for preparing the medicine that above-mentioned 3.1a and 3.2a define.
4.1b pharmaceutical composition, it comprises NF1-chemical compound of the present invention and at least a pharmaceutically acceptable excipient, for example appropriate carriers and/or diluent for example comprise filler, binding agent, disintegrating agent, flowing regulator, lubricant, saccharide or sweeting agent, spice, antiseptic, stabilizing agent, wetting agent and/or emulsifying agent, solubilizing agent, are used to regulate the salt and/or the buffer agent of osmotic pressure;
This pharmaceutical composition is used for above-mentioned 1.1,1.8 or 1.2b to the 1.6b any method or the purposes that define, for example comprises preferred aspect as defined above.
For example and be used for preparing the medicine that above-mentioned 3.1b and 3.2b define.
Any chemical compound of the present invention, for example comprise TSC-chemical compound and NF1-chemical compound can be separately or and one or more, at least a second kind of drug substance united and is used for any method provided by the invention, any purposes and any pharmaceutical composition.
The present invention provides in others:
5.1a be used for for example comprising preferred aspect as defined above as above-mentioned 1.1,1.8,1.2a to 1.7a or the TSC-chemical compound of the present invention of 2.1 to 2.4 defined any methods or purposes and the combination of at least a second kind of drug substance.
5.2a be used for the drug regimen that comprises chemical compound of the present invention and at least a second kind of drug substance, for example comprise preferred aspect as defined above as above-mentioned 1.1,1.8,1.2a to 1.7a or 2.1 to 2.4 defined any methods or purposes.
5.3a be used for the pharmaceutical composition that comprises TSC-chemical compound of the present invention and at least a second kind of drug substance and one or more pharmaceutically acceptable excipient, for example comprise preferred aspect as defined above as above-mentioned 1.1,1.8,1.2a to 1.7a or 2.1 to 2.4 defined any methods or purposes.
5.4a be used for being used for purposes with the medicine of second kind of drug substance combination in preparation, for example comprise preferred aspect as defined above as the TSC-chemical compound of the present invention of above-mentioned 1.1,1.8,1.2a to 1.7a or 2.1 to 2.4 defined any methods or purposes.
5.5a be used for preparing TSC-chemical compound of the present invention medicine and at least a second kind of drug substance combination, for example comprise preferred aspect as defined above as above-mentioned 1.1,1.8,1.2a to 1.7a or 2.1 to 2.4 defined any methods or purposes.
5.6a as any method of definition among above-mentioned 1.1,1.8, the 1.2a to 1.7a or 2.1 to 2.4, for example comprise preferred aspect as defined above, comprise simultaneously or TSC-chemical compound of the present invention and at least a second kind of drug substance of common administering therapeutic effective dose successively, for example with the form of drug regimen or compositions.
5.7a as defined method among the above-mentioned 5.6a, its discontinuous is used TSC-chemical compound of the present invention.The present invention provides in others:
5.1b be used for for example comprising preferred aspect as defined above as above-mentioned 1.1,1.8 or the NF1-chemical compound of the present invention of defined any method of 1.2b to 1.6b or purposes and the combination of at least a second kind of drug substance.
5.2b be used for the drug regimen that comprises NF1-chemical compound of the present invention and at least a second kind of drug substance, for example comprise preferred aspect as defined above as above-mentioned 1.1,1.8, defined any method of 1.2b to 1.6b or purposes.
5.3b be used for for example comprising preferred aspect as defined above as above-mentioned 1.1,1.8 or the pharmaceutical composition that comprises NF1-chemical compound of the present invention and at least a second kind of drug substance and one or more pharmaceutically acceptable excipient of defined any method of 1.2b to 1.6b or purposes.
5.4b be used for as above-mentioned 1.1,1.8 or the NF1-chemical compound of the present invention of defined any method of 1.2b to 1.6b or purposes be used for purposes with the medicine of second kind of drug substance combination in preparation, for example comprise preferred aspect as defined above.
5.5b be used for preparing as above-mentioned 1.1,1.8 or the NF1-chemical compound of the present invention medicine and at least a second kind of drug substance combination of defined any method of 1.2b to 1.6b or purposes, for example comprise preferred aspect as defined above.
5.6b as above-mentioned 1.1,1.8 or 1.2b to 1.6b in any method of defining, for example comprise preferred aspect as defined above, comprise simultaneously or NF1-chemical compound of the present invention and at least a second kind of drug substance of common administering therapeutic effective dose successively, for example with the form of drug regimen or compositions.
5.7b as defined method among the above-mentioned 5.6b, its discontinuous is used NF1-chemical compound of the present invention.
Combination comprises: fixed combination, and chemical compound wherein of the present invention and at least a second kind of drug substance are in identical preparation; Medicine box wherein will be provided in the same packing at the The compounds of this invention in the different preparations and at least a second kind of drug substance, for example wherein have the description that is used for using jointly; Combination is wherein packed chemical compound of the present invention and at least a second kind of drug substance respectively freely, is used for simultaneously or the description of using successively but provide;
Chemical compound for example wherein of the present invention is TSC-chemical compound or NF1-chemical compound.
The present invention provides in one aspect of the method:
5.8a drug packages, first kind of drug substance and at least a second kind of drug substance that it is included as TSC-chemical compound of the present invention also comprise and are used for co-administered description;
5.9a drug packages, it comprises TSC-chemical compound of the present invention, also comprises and at least a second kind of description that drug substance is co-administered;
5.10a drug packages, it comprises at least a second kind of drug substance, also comprises and the co-administered description of TSC-chemical compound of the present invention;
They are used for above-mentioned 1.1,1.8,1.2a to 1.7a, or any method or purposes in 2.1 to 2.4, for example comprise as above-mentioned defined preferred aspect.
The present invention provides in one aspect of the method:
5.8b drug packages, first kind of drug substance and at least a second kind of drug substance that it is included as NF1-chemical compound of the present invention also comprise and are used for co-administered description;
5.9b drug packages, it comprises NF1-chemical compound of the present invention, also comprises and at least a second kind of description that drug substance is co-administered;
5.10b drug packages, it comprises at least a second kind of drug substance, also comprises and the co-administered description of NF1-chemical compound of the present invention;
They are used for above-mentioned 1.1,1.8 or any method or the purposes of 1.2b to 1.6b, for example comprise as above-mentioned defined preferred aspect.
Use the treatment of combination of the present invention that the improvement of comparing with single therapy can be provided.
The present invention provides in one aspect of the method:
5.11a drug regimen, it comprises a certain amount of TSC-chemical compound of the present invention and a certain amount of second kind of drug substance, and wherein said consumption is suitable for producing synergistic therapeutic action;
5.12a improve the method that the treatment of TSC-chemical compound of the present invention is used, comprise jointly and using, for example while or The compounds of this invention and second kind of drug substance of administering therapeutic effective dose successively;
5.13a improve the method that the treatment of second kind of drug substance is used, comprise jointly and using, for example while or TSC-chemical compound of the present invention and second kind of drug substance of administering therapeutic effective dose successively;
They are used for above-mentioned 1.1,1.8,1.2a to 1.7a or 2.1 to 2.4 defined any method or purposes.
The present invention provides in one aspect of the method:
5.11b drug regimen, it comprises a certain amount of NF1-chemical compound of the present invention and a certain amount of second kind of drug substance, and wherein said consumption is suitable for producing synergistic therapeutic action;
5.12b improve the method that the treatment of NF1-chemical compound of the present invention is used, comprise jointly and using, for example while or The compounds of this invention and second kind of drug substance of administering therapeutic effective dose successively.
5.13b improve the method that the treatment of second kind of drug substance is used, comprise jointly and using, for example while or NF1-chemical compound of the present invention and second kind of drug substance of administering therapeutic effective dose successively.
They are used for above-mentioned 1.1,1.8,1.2a to 1.7a, or defined any method or purposes in 2.1 to 2.4.
In the drug regimen or method that in above-mentioned 5.11a to 5.13a, defines, the activity of TSC-chemical compound of the present invention or second kind of drug substance is compared with single therapy and can be enhanced, when for example above-mentioned 1.1,1.8 when being used for, 1.2a to 1.7a or 2.1 to 2.4 defined any methods or purposes, for example combined therapy can produce synergism and maybe can overcome resistance to TSC-chemical compound of the present invention or chemotherapeutics.
In the drug regimen or method that in above-mentioned 5.11b to 5.13b, defines, the activity of NF1-chemical compound of the present invention or second kind of drug substance is compared with single therapy and can be enhanced, for example when being used for above-mentioned 1.1,1.8 or when defined any method of 1.2b to 1.6b or purposes, for example combined therapy can produce synergism and maybe can overcome resistance to NF1-chemical compound of the present invention or chemotherapeutics.
As (medicine) combination of the compositions pointed out among the 5.1a to 5.13a, it comprises:
A) for first kind of activating agent of TSC-chemical compound of the present invention; With
B) as second kind of drug substance of the common activating agent that uses, it is for for example as mentioned or hereinafter defined chemotherapeutics.
As (medicine) combination of the compositions pointed out among the 5.1b to 5.13b, it comprises:
A) for first kind of activating agent of NF1-chemical compound of the present invention; With
B) as second kind of drug substance of the common activating agent that uses, it is for for example as mentioned or hereinafter defined chemotherapeutics.
Treatment provided by the invention comprises prevention (prevention).Obstacle used herein comprises disease.
With regard to this class treatment, suitable dosage changes according to for example chemical property of compound used therefor and the character and the different of seriousness of pharmacokinetic data, individual host, method of application and the disease of being treated certainly.Yet generally speaking, for than large mammals, for example philtrum obtains gratifying effect, and specified every day, dosage comprised following scope:
-Yue 0.0001g is to about 1.5g, such as 0.001g to 1.5g;
-Yue 0.001mg/kg body weight is to about 20mg/kg body weight, such as the 0.01mg/kg body weight to the 20mg/kg body weight,
For example, use with the fractionated dose that reaches 4 every day.
In method provided by the invention, purposes, combination, drug regimen or pharmaceutical composition, if it is suitable, can be for example to become known for the dosage of The compounds of this invention, for example through intestinal, for example by oral or by parenteral administration chemical compound of the present invention, both can be the TSC-chemical compound, also can be the NF1-chemical compound.For example can use everolimus, for example by oral, dosage is at 0.1mg to 15mg, such as 0.1mg to 10mg.For example 0.1mg, 0.25mg, 0.5mg, 0.75mg, 1mg, 2.5mg, 5mg or 10mg, more preferably 0.5mg to 10mg is for example with the form of (can disperse) sheet; The solid dispersion form that for example comprises everolimus; For example dosage can comprise and reaches 70mg weekly, and for example 10 to 70mg, such as 30 to 50mg, and e.e., this depends on the disease of being treated.Can for example use other rapamycin derivative of the present invention in a similar way, both can be the TSC-chemical compound, also can be the NF1 chemical compound with similar dosage range.
If suitable, can in conjoint therapy, use second kind of drug substance, for example according to the method for routine, for example according to the specified similar mode of indication of using of the concrete medicine of single therapy.
Can use second kind of drug substance used herein by any conventional route, for example by intestinal, for example comprise nose, suck, rectum, Orally administered; Parenteral for example comprises infusion, transdermal (by the intact skin diffusion) in intravenous, intra-arterial, intramuscular, intracardiac, subcutaneous, the bone, strides mucosa (by the mucosa diffusion), sucks and use; By the part; For example comprise in epidermis, intranasal, the trachea and using; Intraperitoneal (infusion or injection abdominal cavity); (epidural) (injecting or be infused into epidural space) on the dura mater; In the sheath (injecting or be infused into cerebrospinal fluid); In the vitreous body (using) by eye; Or, for example be used for local delivery, for example support by medical apparatus and instruments;
For example with the form of coating or non-coated tablet, capsule, (injectable) solution, infusion solution, solid solution, suspension, dispersion, solid dispersion; For example with the form of ampoule, bottle, the form of cream, gel, paste, suction powder, foam, tincture, lip pomade, drop, spray or the form of suppository.
Can be with the form or the free form of pharmaceutically acceptable salt; Choose wantonly and use second kind of drug substance used herein with solvate form thereof.
Can according to, for example with as the conventional similar mode of method, for example prepare pharmaceutical composition of the present invention by mixing, granulation, coating, dissolving or freeze drying process.Unit dosage forms can comprise, and for example about 0.1mg is to about 1500mg, such as 1mg about 1000mg extremely.
If suitable, for example according to for example with as conventional or provide compositions that comprises the present invention's combination and the pharmaceutical composition that comprises second kind of drug substance as described herein to similar method as described in the pharmaceutical composition of the present invention as this paper.
Treatment comprises that by the method for the disease of plyability epiloia mediation treatment is individual defective Tsc approach result's disease.
＂ defective Tsc approach ＂ comprises the Tsc approach that produces biological agent of regulating, and this biological agent produces harmful effect to the cell or tissue in the Tsc approach.For example show in the disease of tuberous sclerosis with phenotype, heredity, biochemistry and branch submode.If suitable, for example according to identifying defective Tsc approach as the method for routine.
Tuberous sclerosis is included in the dysfunction that is actually nerve and renal insufficiency.For example comprise epilepsy, mental retardation, autism, renal failure, facial angiofibroma and cardia rhabdomyoma with the symptom and the disease of tuberous sclerosis disease association; In some bony areas, be meant in the bone (phalanx) with toe to have cyst sample zone especially; The characteristic skin lesion, comprise the clear-cut zone (hypopigmentation) that the colour of skin goes down, the relative little pale red tuberosity that may on buccal and nose, occur, pale reds infringement is final enlarges for these, fusion each other (fusion) and develop into wart sample outward appearance (sebaceous adenoma); The coffee-like ＂ zone (caf) of the flat ＂ that cutaneous pigmentation increases; For example around the fingernail or its optimum fibrous tubercle (fibroma) that occurs down; Or the ＂ excipuliform ＂ of coarse protuberance damages (shagreen patch) on waist; Relate to that the cell size increases the organ that causes or body part enlarges or the hypertrophy of undue growth because of forming, for example comprise right ventricular hypertrophy, hypertrophic cardiomyopathy, benign prostatauxe; Renal angiomyolipoma (AML); For example in the xenogenesis benign tumor, show,, comprise the xenogenesis benign tumor that smooth muscle, blood vessel and adipose cell are formed for example by three kinds of different cell types; The destructive form of pneumonopathy, such as LAM (LAM), blocking-up air-flow, blood and lymph fluid arrive and leave lung, the tumor of kidney relevant with LAM, dyspnea, chronic cough is stridulated, pneumothorax and chest pain, capsule essence is destroyed, the respiratory failure of carrying out property.
Second kind of drug substance ＂ of term ＂ used herein means any chemotherapeutics of non-The compounds of this invention, both can be the TSC-chemical compound, also can be the NF1-chemical compound.
For example, second kind of drug substance used herein comprise, for example anticarcinogen, antiinflammatory and/or immunosuppressant and/or antianaphylaxis medicine, antipruritic, astringent, local anesthetic.
For example, with regard to TSC-chemical compound of the present invention, second kind of drug substance used herein comprises, for example be used for the treatment of and medicine, such as being used for the treatment of tuberous sclerosis, renal angiomyolipoma (ALM), LAM (LAM), ependyma time and/or giant cell astrocytoma (SEGA) and/or associated symptom and/or the medicine of obstacle by the relevant symptom of plyability epiloia disorder mediated;
For example, with regard to NF1-chemical compound of the present invention, second kind of drug substance used herein comprise, for example is used for the treatment of NF1 and/or associated obstacle and/or the medicine of symptom with regard to NF1-chemical compound of the present invention.
Be easy to as and any chemical compound of the present invention, for example be easy to be used for of the present inventionly both can be the TSC-chemical compound, also can comprise for NF1-combination of compounds companion's anticarcinogen:
I. steroid; Prednisone for example.
Ii. adenosine-kinases-inhibitor; Its targeting, minimizing or suppress nuclear base, nucleoside, nucleotide and nucleic acid metabolism such as 5-iodine tubercidin (lodotubercidin), are also referred to as 7H-pyrrolo-[2,3-d] pyrimidine-4-amine, 5-iodo-7-β-D-ribofuranosyl-(9Cl).
Iii. adjuvant; The chemical compound that it is strengthened 5-FU-TS key and targeting, minimizing or suppresses alkali phosphatase is such as formyl tetrahydrofolic acid, levamisole.
Iv. adrenal cortex antagonist; The periphery metabolism of its targeting, minimizing or inhibition adrenal cortex activity and change corticosteroid causes 17-hydroxyl corticosteroid to reduce, such as mitotane.
The v.AKT approach restrainer; Chemical compound such as targeting, minimizing or inhibition Akt is also referred to as protein kinase B (PKB), such as deguelin, is also referred to as two [1] .alpha.-5:6-benzopyrans [3 of 3H-, 4-b:6 ', 5 '-e] pyrans-7 (7aH)-ketone, 13,13a-dihydro-9,10-dimethoxy-3, the 3-dimethyl-, (7aS, 13aS)-(9Cl); And triciribine, be also referred to as 1,4,5,6,8-pentaaza acenaphthylene-3-amine, 1,5-dihydro-5-methyl isophthalic acid-β-D-ribofuranosyl-(9Cl).
Vi. alkylating agent; It causes the DNA alkylation and causes and dna molecular fracture and double-stranded crosslinked, disturbs dna replication dna and rna transcription thus, such as chlorambucil, chlormethine, cyclophosphamide, ifosfamide, melphalan, estramustine; Nitrosoureas is such as carmustine, fotemustine, lomustine, streptozocin (streptozotocin, STZ), BCNU; Gliadel; Dacarbazine, chlormethine, hydrochloride form for example, procarbazine, hydrochloride form for example, thiophene is for group, temozolomide, chlormethine, mitomycin, altretamine, busulfan, estramustine, uracil mustard.Can be with at for example trade mark
Figure A200780004302D00191
The form of following sale is used cyclophosphamide; Ifosfamide is The temozolomide is
Figure A200780004302D00193
Chlormethine is Estramustine is
Figure A200780004302D00195
Streptozocin is
Figure A200780004302D00196
Vii. angiogenesis inhibitor; Its targeting, minimizing or inhibition neovascularity produce, for example targeting methionine aminopeptidase-2 (MetAP-2), macrophage inflammatory protein-1 (MIP-1 α), CCL5, TGF-β, lipoxygenase, cyclo-oxygenase and topoisomerase; Or indirect targeting p21, p53, CDK2 and collagen protein synthesis, for example comprise fumagillin, be also referred to as 2,4,6, the 8-tetradecendioic acid, one [(3R, 4S, 5S, 6R)-5-methoxyl group-4-[(2R, 3R)-2-methyl-3-(3-methyl-2-butene base) Oxyranyle]-1-oxaspiro [2.5] suffering-6-yl] ester, (2E, 4E, 6E, 8E)-(9CI); Shikonin is also referred to as 1, the 4-naphthalenedione, and 5, the 8-dihydroxy-2-[(1R)-1-hydroxy-4-methyl-3-pentenyl]-(9CI); Tranilast is also referred to as benzoic acid, 2-[[3-(3, the 4-Dimethoxyphenyl)-1-oxo-2-acrylic] amino]-(9Cl); Ursolic acid; Suramin; The bengamide or derivatives thereof, thalidomide, TNP-470.
Viii. antiandrogen; It blocks the androgenic effect in adrenal gland and testis source, and these androgens stimulate normal and malignant prostate tissue growth, such as nilutamide; Bicalutamide Can for example as disclosed in the US4636505, prepare them.
Ix. antiestrogen; Its antagonism is in the estrogenic effect of estrogen receptor level, for example comprise aromatase inhibitor, it suppresses estrogen production, for example respectively substrate androstenedione and testosterone are changed into estrone and estradiol, for example comprise atamestane, exemestane, formestane, aminoglutethimide, roglethimide, (.+-.)-Pyridoglutethimide, trilostane, testolactone, ketoconazole (ketokonazole), vorozole, fadrozole, Anastrozole, letrozole, toremifene; Bicalutamide; Flutamide; Tamoxifen, Tamoxifen Citrate; Tamoxifen; Fulvestrant; Raloxifene, RALOXIFENE HCL.For example, can be with for example
Figure A200780004302D00202
The form of selling is used tamoxifen; And conduct
Figure A200780004302D00203
The RALOXIFENE HCL of selling.Can as disclosing among the US4659516, prepare fulvestrant and conduct
Figure A200780004302D00204
Sell.
X. hypercalcemia medicine; It is used for the treatment of hypercalcemia, such as Ganite (Fujisawa). (III) hydrate; And Pamidronate Disodium.
Xi. antimetabolite; It suppresses or destroys DNA and synthesize, and causes cell death, such as the 6-mercaptopurine; Cytosine arabinoside; Fludarabine; Flexuridine; Fluorouracil; 5-fluorouracil (5-FU), floxuridine (5-FUdR), capecitabine; Raltitrexed; Methotrexate; Cladribine; Gemcitabine; Gemcitabine hydrochloride; Thioguanine; The 6-thioguanine, hydroxyurea; DNA goes-methylating agent, such as U-18496 and decitabine; Edatrexate; Antifol is such as pemetrexed.For example, can be with the sale form, such as
Figure A200780004302D00205
With
Figure A200780004302D00206
Use capecitabine and gemcitabine.
Xii. apoptosis inducers; Normal chain of events in its inducing cell causes its death, for example the chain mammal inhibitor of the X-of selective induction apoptosis protein XIAP or for example decrement regulate BCL-xL; Such as ethanol, 2-[[3-(2, the 3-dichlorophenoxy) propyl group] amino]-(9Cl); Gamlogic acid; Embelin is also referred to as 2,5-cyclohexadiene-1,4-diketone, 2,5-dihydroxy-3-hendecyl; Arsenic trioxide
The xiii.aurora inhibitors of kinases; Its targeting, minimizing or suppress late stage, all modes from the cell cycle at the G2/M outpost of the tax office all by the mitosis outpost of the tax office and late period mitosis; Such as binucleine 2, be also referred to as methanimidamide, N '-[1-(3-chloro-4-fluorophenyl)-4-cyano group-1H-pyrazoles-5-yl]-N, the N-dimethyl-(9CI).
Xiv.Bruton tyrosine kinase (BTK) inhibitor; Its targeting, minimizing or inhibition people and Mus B cell development; Such as terreic acid.
Xv. calcineurin inhibitor; Its targeting, minimizing or suppressor T cell activated channel such as cypermethrin, are also referred to as cyclopropane-carboxylic acid, 3-(2, the 2-dichloroethylene)-2, and the 2-dimethyl-, cyano group (3-Phenoxyphenyl) methyl ester (9Cl); Decis is also referred to as cyclopropane-carboxylic acid, 3-(2, the 2-dibromo vinyl)-2, and the 2-dimethyl-(S)-cyano group (3-Phenoxyphenyl) methyl ester, (1R, 3R)-(9Cl); Fenvalerate is also referred to as phenylacetic acid, 4-chloro-α-(1-Methylethyl)-and, cyano group (3-Phenoxyphenyl) methyl ester (9Cl); With tyrphostin 8; But do not comprise ciclosporin or FK506.
The xvi.CaM kinase ii inhibitors; Its targeting, minimizing or inhibition CaM kinases; These kinases constitute enzyme relevant on gang's structure, comprise phosphorylase kinase, myosin light chain kinase and CaM kinases I-IV; Such as 5-isoquinolin sulfonic acid, 4-[(2S)-2-[(5-isoquinolyl sulfonyl) methylamino]-3-oxo-3-(4-phenyl-peiperazinyl) propyl group] phenyl ester (9CI); Benzsulfamide, N-[2-[[[3-(4-chlorphenyl)-2-acrylic] methyl] amino] methyl] phenyl]-N-(2-ethoxy)-4-methoxyl group-(9Cl).
Xvii.CD45 tyrosine-phosphatase inhibitor; Its targeting, minimizing or the dephosphorylation that suppresses on Src-family albumen-tyrosine kinase are regulated the pTyr residue, and this helps to treat various inflammatories and dysimmunity; Such as phosphonic acids, [[2-(4-bromine phenoxy group)-5-nitrobenzophenone] methylol]-(9Cl).
The xviii.CDC25 inhibitors of phosphatases; The kinases of the dephosphorylation cyclin dependent of overexpression in its targeting, minimizing or the inhibition tumor; Such as 1,4-naphthalenedione, 2,3-two [(2-ethoxy) sulfo-]-(9Cl).
The xix.CHK inhibitors of kinases; The overexpression of its targeting, minimizing or inhibition anti-apoptotic protein B cl-2; Such as debromohymenialdisine.The target of CHK inhibitors of kinases is CHK1 and/or CHK2.
Xx. be used to regulate the controlling agent of genistein, olomoucine (olomucine) and/or tyrphostin; Such as daidzein, be also referred to as 4H-1-.alpha.-5:6-benzopyran-4-ketone, 7-hydroxyl-3-(4-hydroxy phenyl)-(9Cl); Different-olomoucine and tyrphostin 1.
Xxi. cyclooxygenase-2 inhibitor; For example, comprise the Cox-2 inhibitor; Its targeting, minimizing or inhibitory enzyme cox-2 (cyclo-oxygenase-2); Such as the 1H-indole-3-acetamide, 1-(4-chlorobenzene formacyl)-5-methoxyl group-2-methyl-N-(2-phenylethyl)-(9Cl); 2-virtue aminophenyl acetic acid and derivant, for example celecoxib that the 5-alkyl replaces
Figure A200780004302D00221
Rofecoxib
Figure A200780004302D00222
Etoricoxib, valdecoxib; Or 5-alkyl-2-virtue aminophenyl acetic acid, for example 5-methyl-2-(2 '-chloro-6 '-fluoroanilino) phenylacetic acid, Prexige; And celecoxib.
The xxii.cRAF inhibitors of kinases; Its targeting, minimizing or the inductive E-of inhibition TNF select the up regulation of albumen and blood vessel adhesion molecule-1; Such as 3-(3,5-two bromo-4-hydroxyl benzals)-5-iodo-1,3-Indolin-2-one; And Benzoylamide, 3-(dimethylamino)-N-[3-[(4-hydroxy benzoyl) amino]-the 4-aminomethyl phenyl]-(9Cl).The Raf kinases plays an important role in cell differentiation, propagation and apoptosis as extracellular signal-regulated kinase.The target of cRAF inhibitors of kinases includes, but are not limited to RAF1.
Xxiii. the inhibitors of kinases of cyclin dependent; Its targeting, reduce or be suppressed at the kinases of the cyclin dependent that works in the mammalian cell periodic adjustment; Such as N9-isopropyl-olomoucine; Olomoucine; Purvalanol B is also referred to as benzoic acid, 2-chloro-4-[[2-[[(1R)-1-(methylol)-2-methyl-propyl] amino]-9-(1-Methylethyl)-9H-purine-6-yl] amino]-(9CI); Roascovitine; Indirubin is also referred to as the 2H-indol-2-one, 3-(1,3-dihydro-3-oxo-2H-indole-2-base subunit)-1, and the 3-dihydro-(9CI); Kenpaullone is also referred to as also [3,2-d] [1] benzazepines-6 (5H)-ketone of indole, 9-bromo-7, and the 12-dihydro-(9CI); Purvalanol A is also referred to as the 1-butanols, the 2-[[6-[(3-chlorphenyl) amino]-9-(1-Methylethyl)-9H-purine-2-yl] amino]-the 3-methyl-, (2R)-(9CI); Indirubin-3 '-monoxime.The cell cycle progress is subjected to a series of successive event conditioning, comprises kinases (Cdks) and the activation of cyclin and the inactivation subsequently of cyclin dependent.Cdks is gang's serine/threonine kinase, and they are by forming active different dimerization complex in conjunction with its regulator subunit cyclin.The example of the inhibitors of kinases target of cyclin dependent includes, but are not limited to CDK, AHR, CDK1, CDK2, CDK5, CDK4/6, GSK3 β and ERK.
Xxiv. cystatin; Its targeting, reduce or be suppressed at that mammalian cell upgrades and apoptosis in the cysteine proteinase that plays a crucial role; Such as 4-morpholine Methanamide, N-[(1S)-3-fluoro-2-oxo-1-(2-phenylethyl) propyl group] amino]-2-oxo-1-(phenyl methyl) ethyl]-(9Cl).
The xxv.DNA intercalator; It is in conjunction with DNA and suppress DNA, RNA and protein synthesis; Such as plicamycin, dactinomycin.
The xxvi.DNA chain interrupts agent; It causes the DNA chain to cut off and causes the synthetic inhibition of DNA, and RNA and protein synthesis suppress; Such as bleomycin.
Xxvii.E3 ligase inhibitor; Its targeting, minimizing or inhibition E3 ligase, this enzyme suppresses ubiquitin chain and is transferred to protein, and they degrade labelling in proteasome; Such as N-((3,3,3-three fluoro-2-trifluoromethyls) propiono) sulfanilamide.
Xxviii. endocrine hormone; It mainly causes the hormone among the male to suppress by hypophysis is worked, net effect is that testosterone is reduced to the castration level; In the women, ovarioestrogen and androgen are synthetic to be suppressed; Such as leuprorelin; Megestrol, megestrol acetate.
Xxix. targeting, the epidermal growth factor family of minimizing or inhibition receptor tyrosine kinase is (as the EGFR of homodimer or heterodimer, ErbB2, ErbB3, ErbB4) active chemical compound, such as suppressing EGF receptor tyrosine kinase family, EGF receptor for example, ErbB2, ErbB3 and ErbB4 or in conjunction with the member's of EGF or EGF-associated ligands chemical compound, protein or antibody, and those general and concrete chemical compounds that disclose in WO9702266 particularly, protein or monoclonal antibody, for example embodiment 39, EP0564409, WO9903854, EP0520722, EP0566226, EP0787722, EP0837063, US5747498, WO9810767, WO9730034, WO9749688, the chemical compound that discloses among WO9738983 and the especially WO9630347, the chemical compound that for example is called CP358774, WO9633980 for example is called the chemical compound of ZD1839; And WO9503283, for example be called the chemical compound of ZM105180, for example comprise Herceptin
Figure A200780004302D00241
Cetuximab, Iressa, OSI-774, CI-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3,7H-pyrrolo--[2,3-d] pyrimidine derivatives, for example be disclosed among the WO03013541 erlotinib, gefitinib.Can be with the sale form, for example
Figure A200780004302D00242
Use Erlotinib, and gefitinib is
Figure A200780004302D00243
The human monoclonal antibodies of anti-epidermal growth factor receptor comprises ABX-EGFR.
Xxx.EGFR, PDGFR tyrosine kinase inhibitor; Such as the EGFR inhibitors of kinases, comprise tyrphostin 23, tyrphostin 25, tyrphostin 47, tyrphostin 51 and tyrphostin AG825; The 2-acrylamide, 2-cyano group-3-(3, the 4-dihydroxy phenyl)-N-phenyl-(2E)-(9Cl); Tyrphostin Ag1478; Lavendustin A; 3-pyridine acetonitrile, α-[(3, the 5-Dichlorobenzene base) methylene]-, (α Z)-(9Cl); The example of EGFR, PDGFR tyrosine kinase inhibitor for example comprises tyrphostin 46.The PDGFR tyrosine kinase inhibitor comprises tyrphostin 46.The target of EGFR inhibitors of kinases comprises guanylate cyclase (GC-C) HER2, EGFR, PTK and tubulin.
Xxxi. farnesyl transferase inhibitor; Its targeting, minimizing or inhibition Ras albumen; Such as a-hydroxyl farnesyl-phosphonic acids; Butanoic acid, 2-[[(2S)-2-[[(2S, 3S)-2-[[(2R)-2-amino-3-sulfydryl propyl group] amino]-the 3-methyl amyl] the oxygen base]-1-oxo-3-phenyl propyl] amino]-4-(methyl sulphonyl)-, 1-methyl ethyl ester, (2S)-(9cl); Manumycin A; L-744,832 or DK8G557, tipifarnib (R115777), SCH66336 (farnesol protein transferase inhibitor), BMS-214662,
The xxxii.Flk-1 inhibitors of kinases; Its targeting, minimizing or inhibition Flk-1 tyrosine kinase activity; Such as the 2-acrylamide, 2-cyano group-3-[4-hydroxyl-3, two (1-Methylethyl) phenyl of 5-]-N-(3-phenyl propyl)-(2E)-(9Cl).The target of Flk-1 inhibitors of kinases includes, but are not limited to KDR.
Xxxiii. glycogen synthase kinase-3 (GSK3) inhibitor; Its targeting, minimizing or inhibition glycogen synthase kinase-3 (GSK3); Such as indirubin-3 '-monoxime.Glycogen synthase kinase-3 (GSK-3; Protein tau kinases I) is the serine/threonine protein kitase of the omnipresence expression of high conservative, it relates to the signal transduction cascade of many cells process, for the verified not cell function on the same group of adjusting that relates to, comprise that protein synthesis, cell proliferation, cell differentiation, microtubule assemble/separate assembling and apoptotic protein kinase.
Xxxiv. histone deacetylase (HDAC) inhibitor; Its inhibition of histone deacetylase and have antiproliferative activity; Such as the chemical compound that is disclosed among the WO0222577, N-hydroxyl-3-[4-[[(2-ethoxy especially) [2-(1H-indol-3-yl) ethyl]-amino] methyl] phenyl]-2E-2-acrylamide and N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl)-ethyl]-amino] methyl] phenyl]-2E-2-acrylamide and pharmaceutically acceptable salt thereof; Octanedioyl aniline hydroxamic acid (SAHA); [4-(2-amino-phenyl amino formoxyl)-benzyl]-anginin-3-base methyl ester and derivant thereof; Butanoic acid, pyroxamide, Trichostatin A, oxamflatin, apicidin, depsipeptide; Depudecin; Trapoxin, HC toxin, be also referred to as ring [L-alanyl-D-alanyl-( S, 2S)--amino--oxo oxirane caprylyl-D-prolyl] (9CI); Phenylbutyrate sodium, octanedioyl be two-hydroxamic acid; Trichostatin A, BMS-27275, pyroxamide, FR-901228, valproic acid.
The xxxv.HSP90 inhibitor; The intrinsic ATPase activity of its targeting, minimizing or inhibition HSP90; By the degraded of ubiquitin proteasome pathway, targeting, minimizing or inhibition HSP90 prescription on individual diagnosis person albumen.The active chemical compound of intrinsic ATPase of targeting, minimizing or inhibition HSP90 especially suppresses the active chemical compound of ATPase, protein or the antibody of HSP90, for example, 17-allyl amino, 17-de-methoxy geldanamycin (17AAG), geldanamycin derivant; Other geldanamycin-related compound; Radicicol and hdac inhibitor.Other example of HSP90 inhibitor comprises geldanamycin, 17-de-methoxy-17-(2-acrylic amino)-(9Cl).The possible indirect target of HSP90 inhibitor comprises FLT3, BCR-ABL, CHK1, CYP3A5 *3 and/or NQ01 *2.
Xxxvi.I-κ B-alpha kinase inhibitor (IKK); Its targeting, minimizing or inhibition NF-κ B, such as the 2-acrylonitrile, the 3-[(4-aminomethyl phenyl) sulfonyl]-(2E)-(9Cl).
Xxxvii. insulin receptor tyrosine kinase inhibitor; It regulates phosphatidyl-inositol 3-kinase, microtubule-associated protein and the kinase whose activity of S6; Such as hydroxyl-2-naphthyl methyl phosphonic acids, LY294002.
Terminal kinases (JNK) inhibitors of kinases of xxxviii.c-Jun N-; Its targeting, minimizing or the terminal kinases of inhibition Jun N-; Such as pyrazole anthrone and/or epigallocatechin gallate (EGCG).The terminal kinases (JNK) of Jun N-, promptly the protein kinase of serine orientation relates to the phosphorylation of c-Jun and ATF2 and activation and plays an important role in metabolism, growth, cell differentiation and apoptosis.The target of JNK inhibitors of kinases includes, but are not limited to DNMT.
Xxxix microtubule bonding agent; It works to mitosis and the necessary microtubule reticulated structure of karyostasis cell function by destroying; Such as vinblastine, vinblastine sulfate; Vinca alkaloids is such as vincristine, vincristine sulfate; Vindesine; Vinorelbine; Taxanes is such as docetaxel; Paclitaxel; Discodermolides; Colchicine, Epothilones and derivant thereof, for example epothilone B or derivatives thereof.The paclitaxel conduct
Figure A200780004302D00261
Sell; Docetaxel is Vinblastine sulfate is VINBLASTIN
Figure A200780004302D00263
With vincristine sulfate be
Figure A200780004302D00264
The paclitaxel and the various paclitaxel dosage form that also comprise common name.The general type of paclitaxel includes, but are not limited to betaxolol hydrochloride.The various dosage forms of paclitaxel include, but are not limited to conduct
Figure A200780004302D00265
Figure A200780004302D00266
The albumin nanoparticle paclitaxel of selling.For example, can as disclosing, US5010099 obtain Discodermolide.Also comprise epothilone derivate, they are disclosed among US6194181, WO98/0121, WO9825929, WO9808849, WO9943653, WO9822461 and the WO0031247.Especially preferred Epothilones A and/or B.
Xl. mitogen-activated protein(MAP) (MAP) kinases-inhibitor; Its targeting, minimizing or inhibition mitogen-activated protein(MAP), such as benzsulfamide, N-[2-[[[3-(4-chlorphenyl)-2-acrylic] methyl] amino] methyl] phenyl]-N-(2-ethoxy)-4-methoxyl group-(9Cl).Mitogen-activated protein(MAP) (MAP) kinases is gang's protein serine/threonine kinase, they be activated as to the reaction of various born of the same parents' external stimuluss and mediation from cell surface to nuclear signal transduction.They regulate several physiology and pathological cells phenomenon, comprise inflammation, apoptotic cell death, oncogenic transformation, tumor cell intrusion and transfer.
The xli.MDM2 inhibitor; The interaction of its targeting, minimizing or inhibition MDM2 and p53 tumor suppressor gene; Such as trans-4-iodine, 4 '-boryl-chalcone derivative.
The xlii.MEK inhibitor; The kinase activity of its targeting, minimizing or inhibition map kinase MEK; Such as
Figure A200780004302D00268
(toluenesulfonic acid Sorafenib), succinonitrile, two [amino [2-aminophenyl] sulfo-] methylene]-(9Cl).The target of mek inhibitor includes, but are not limited to ERK.The indirect target of mek inhibitor includes, but are not limited to cyclin D1.
Xliii: matrix metallo-proteinase inhibitor (MMP) inhibitor; Its targeting, minimizing or suppress an albuminoid enzyme, their selective hydrolysis polypeptide keys, comprise and relate to enzyme MMP-2 and the MMP-9 that promotes tumor structures surrounding disappearance and help tumor growth, blood vessel generation and shift, such as actinonin, be also referred to as succinamide, N-4-hydroxy-n 1-[(1S)-1-[[(2S)-and 2-(methylol)-1-pyrrolidinyl] carbonyl]-the 2-methyl-propyl]-the 2-amyl group-, (2R)-(9CI); Epigallocatechin gallate (EGCG); Plain peptide and the non--plain inhibitor peptides of intending intended of collagen protein; Tetracycline derivant, for example plain inhibitor peptides batimastat of intending of hydroxamate; And oral available analog Marimastat, prinomastat, metastat, Neovastat, tanomastat, TAA211, BMS-279251, BAY12-9566, MMI270B or AAJ996.The target of MMP inhibitor includes, but are not limited to the polypeptide deformylase.
Xliv.NGFR tyrosine-kinases-inhibitor; Its targeting, minimizing or inhibition nerve growth factor dependency p140 C-trkTyrosine phosphorus acylase; Such as tyrphostin AG 879.The target of NGFR tyrosine-kinases-inhibitor includes, but are not limited to HER2, FLK1, FAK, TrkA and/or TrkC.Target suppresses the RAF1 expression indirectly.
The xlv.p38MAP inhibitors of kinases comprises the SAPK2/p38 inhibitors of kinases;
Its targeting, minimizing or suppress for MAPK family member's p38-MAPK, such as phenol, 4-[4-(4-fluorophenyl)-5-(4-pyridine radicals)-1H-imidazoles-2-yl]-(9Cl).The example of SAPK2/p38 inhibitors of kinases includes, but are not limited to Benzoylamide, 3-(dimethylamino)-N-[3-[(4-hydroxy benzoyl) amino]-the 4-aminomethyl phenyl]-(9Cl).The MAPK family member is by the activatory serine/threonine kinase of the phosphorylation of tyrosine and threonine residues.This kinases is thought that by many cellular stress and inflammatory stimulus phosphorylation and activation described cellular stress and inflammatory stimulus relate to adjusting important cell effect such as apoptosis and inflammatory reaction.
The xlvi.p56 tyrosine kinase inhibitor; Its targeting, minimizing or suppress the p56 tyrosine kinase, it is the enzyme for the crucial lymph sample-specificity src family tyrosine kinase of T-cell development and activation; Such as damnacanthal, be also referred to as 2-anthracene aldehyde, 9,10-dihydro-3-hydroxyl-1 methoxyl group-9, the 10-dioxo-(9Cl), tyrphostin 46.The target of p56 tyrosine kinase inhibitor includes, but are not limited to Lck.The cytoplasmic structure territory of Lck and CD4, CD8 and the beta chain of IL-2 receptor combine and think that they relate to the earliest period step of the T-cell activation of TCR-mediation.
The xlvii.PDGFR tyrosine kinase inhibitor; The activity of its targeting, minimizing or inhibition C-kit receptor tyrosine kinase (part of PDGFR family), the activity such as targeting, minimizing or inhibition c-Kit receptor tyrosine kinase family especially suppresses the c-Kit receptor.The example of PDGFR tyrosine kinase inhibitor target includes, but are not limited to PDGFR, FLT3 and/or c-KIT; Such as tyrphostin AG1296; Tyrphostin 9; 1,3-butadiene-1,1,3-three cyanogen, 2-amino-4-(1H-indole-5-yl)-(9Cl); The N-phenyl-2-pyrimidine-amine derivatives, for example imatinib,
Figure A200780004302D00281
PDGF is regulating normal cell and various disease states, such as playing a crucial role in the cell proliferation in cancer, atherosclerosis and the fibrotic conditions, chemotaxis and the survival.PDGF family forms (PDGF-AA, PDGF-BB, PDGF-AB, PDGF-CC and PDGF-DD) by the dimerization isotype, and they are by bringing into play its cytosis in conjunction with two kinds of receptor tyrosine kinases separably.PDGFR-α and PDGFR-β have respectively～and 170 and the molecular weight of 180kDa.
Xlviii. phosphatidyl-inositol 3-kinase inhibitor; Its targeting, minimizing or inhibition PI 3-kinases; Such as wortmannin, be also referred to as 3H-furo [4,3,2-de] indeno [4,5-h]-2-.alpha.-5:6-benzopyran-3,6, the 9-triketone, 11-(acetoxyl group)-1,6b, 7,8,9a, 10,11,11b-octahydro-1-(methoxy)-9a, the 11b-dimethyl-, (1S, 6bR, 9aS, 11R, 11bR)-(9CI); 8-phenyl-2-(morpholine-4-yl)-chromene-4-ketone; Quercetin, the Quercetin dihydrate.Confirmed that the PI3-kinase activity increases as the reaction to many hormones and factors stimulated growth thing, comprise insulin, platelet derived growth factor, insulin like growth factor, epidermal growth factor, colony stimulating factor and hepatocyte growth factor, and relate to the process relevant with conversion with the cell growth.The example of phosphatidyl-inositol 3-kinase inhibitor target includes, but are not limited to Pi3K.
Xlix. inhibitors of phosphatases; Its targeting, minimizing or inhibition phosphatase; Such as Cantharidic acid.; Cantharidin; With the L-leucyl amine, N-[4-(2-carboxy vinyl) benzoyl] glycyl-L-α-Gu Anxianji-(E)-(9Cl).Phosphatase is removed phosphoryl and protein is returned to its original dephosphorylation state.Therefore, phosphorylation-dephosphorylation cycle can be regarded as molecule " switch ".
L. platinum activating agent; It comprises platinum and crosslinked inhibition DNA synthesizes in dna molecular interchain and the chain by forming; Such as carboplatin; Cisplatin; Oxaliplatin; Cisplatin; Husky platinum and platinum activating agent are such as ZD0473.Carboplatin can be used with the form of for example selling, for example
Figure A200780004302D00291
And oxaliplatin, for
Figure A200780004302D00292
Li. protein phosphatase inhibitor comprises PP1 and PP2 inhibitor and tyrosine phosphatase inhibitors; Its targeting, minimizing or Profilin phosphatase.The example of PP1 and PP2A inhibitor comprises Cantharidic acid. and/or cantharidin.The example of tyrosine phosphatase inhibitors includes, but are not limited to L-P-bromine tetramisole oxalates; 2 (5H)-furanones, 4-hydroxyl-5-(methylol)-3-(1-oxo cetyl)-, (5R)-(9Cl); And benzylphosphonic acid.
Term used herein " PP1 or PP2 inhibitor " relates to targeting, minimizing or suppresses the chemical compound of Ser/Thr phosphoprotein phosphatase.Comprise that the I type phosphatase of PP1 can be known as two kinds of heat-stable proteins inhibition of inhibitor-1 (I-1) and inhibitor-2 (I-2).They preferably make phosphorylase kinase subunit dephosphorylation.II type phosphatase is divided into autonomous activity (PP2A), CA again 2+-dependency (PP2B) and Mg 2+The phosphatase of-dependency (PP2C) class.
Term used herein " tyrosine phosphatase inhibitors " relates to targeting, minimizing or suppresses the chemical compound of tyrosine phosphatase.Protein-tyrosine-phosphatase (PTPs) is for adding the member in the phosphatase family relatively in the recent period to.They have removed phosphate group from proteinic phosphorylated tyrosine residue.PTPs shows different architectural features and plays an important role in regulating cell proliferation, differentiation, cell adhesion and mobility and cytoskeleton function.The example of tyrosine phosphatase inhibitors target includes, but are not limited to alkali phosphatase (ALP), heparanase, PTPase and/or prostanoic acid (prostatic acid) phosphatase.
Lii.PKC inhibitor and PKC δ inhibitors of kinases: term used herein " pkc inhibitor " relates to the chemical compound of targeting, minimizing or Profilin kinase c and isozyme thereof.Protein kinase C (PKC), promptly a kind of omnipresence phospholipid-dependent enzyme relates to the signal transduction relevant with cell proliferation, differentiation and apoptosis.The example of pkc inhibitor target includes, but are not limited to MAPK and/or NF-κ B.The example of pkc inhibitor includes, but are not limited to 1-H-pyrrolo--2,5-diketone, 3-[1-[3-(dimethylamino) propyl group]-the 1H-indol-3-yl]-4-(1H-indol-3-yl)-(9Cl); Two indyl maleimide IX; Sphingol, it is known as 4-octadecylene-1, the 3-glycol, 2-amino-, (2S, 3R, 4E)-(9CI); Star shaped spore native, it is known as 9,13-epoxy-1H, 9H-two indole also [1,2,3-gh:3 ', 2 ', 1 '-lm] pyrrolo-[3,4-j] [1,7] benzo two azonines-1-ketone, the star shaped spore native derivant, such as being disclosed among the EP0296110, midostaurin for example; 2,3,10,11,12,13-six hydrogen-10-methoxyl group-9-methyl isophthalic acid 1-(methylamino)-, (9S, 10R, 11R, 13R)-(9CI); Tyrphostin 51; And hypericin, be also referred to as phenanthro-[1,10,9,8-opqra] perylene-7,14-diketone, 1,3,4,6,8,13-hexahydroxy-10, the 11-dimethyl-, stereoisomer (6CI, 7CI, 8CI, 9CI), UCN-01, Safingol, BAY43-9006, bryostatin 1, perifosine; Llmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196.Term used herein " PKC δ inhibitors of kinases " relates to its targeting, minimizing or suppresses the chemical compound of the δ isozyme of PKC.The δ isozyme is common PKC isozyme and is Ca 2+-dependent.The example of PKC δ inhibitors of kinases includes, but are not limited to kamalin, is also referred to as 2-propylene-1-ketone; 1-[6-[(3-acetyl group-2,4,6-trihydroxy-5-aminomethyl phenyl) methyl]-5; 7-dihydroxy-2,2-dimethyl-2H-1-benzofuran-8-yl]-the 3-phenyl-, (2E)-(9CI).
Liii. polyamine synthetic inhibitor; Its targeting, minimizing or inhibition polyamine class spermidine; Such as DMFO, be also referred to as (-)-the 2-Er Fujiajiniaoansuan; N1, N12-diethyl spermine 4HCl.Polyamine class spermidine and spermine on cell proliferation have crucial importance, though its accurate mechanism of action it be unclear that.Tumor cell has the polyamine balance that increases the change that is reflected by biosynthetic enzyme activity increase and polyamine storehouse.
Liv. proteasome inhibitor; Its targeting, minimizing or Profilin enzyme body are such as Aclacnomycin A; Gliotoxin; PS-341; MLN341; Bortezomib; Ten thousand Mactra sulcatria Deshayess.The example of proteasome inhibitor target includes, but are not limited to produce nadph oxidase, NF-κ B and/or the farnesyl tranfering enzyme of O (2) (-)-generation, busy cattle based transferase I.
The lv.PTP1B inhibitor; Its targeting, minimizing or inhibition PTP1B, protein tyrosine kinase inhibitor; Such as the L-leucyl amine, N-[4-(2-carboxy vinyl) benzoyl] glycyl-L-α-Gu Anxianji-, (E)-(9Cl).
Lvi. protein tyrosine kinase inhibitor comprises SRC family tyrosine kinase inhibitor; The Syk tyrosine kinase inhibitor; With JAK-2 and/or JAK-3 tyrosine kinase inhibitor;
Term used herein " protein tyrosine kinase inhibitor " relates to the chemical compound of targeting, minimizing or Profilin tyrosine kinase.Protein tyrosine kinase (PTKs) plays a crucial role in regulating cell proliferation, differentiation, metabolism, migration and survival.They are categorized as receptor PTKs and non--receptor PTKs.Receptor PTKs comprises and has the single polypeptide chain of striding the film sections.The born of the same parents outer end of this sections comprises high affinity part-binding structural domain, and the kytoplasm end comprises catalytic core and regulate sequence.The example of the target of tyrosine kinase inhibitor includes, but are not limited to ERK1, ERK2, Bruton tyrosine kinase (Btk), JAK2, ERK 1/2, PDGFR and/or FLT3.The example of target includes, but are not limited to TNF α, NO, PGE2, IRAK, iNOS, ICAM-1 and/or E-and selects albumen indirectly.The example of tyrosine kinase inhibitor includes, but are not limited to tyrphostin AG 126; Tyrphostin Ag 1288; Tyrphostin Ag 1295; Geldanamycin; And genistein.
Non--receptor tyrosine kinase comprises the member in Src, Tec, JAK, Fes, Abl, FAK, Csk and the Syk family.They are positioned at kytoplasm and nuclear.They show different kinases adjusting, substrate phosphorylation and function.These kinases imbalances are also relevant with several human body diseases.
Term used herein " SRC family tyrosine kinase inhibitor " relates to targeting, minimizing or suppresses the chemical compound of SRC.The example of SRC family tyrosine kinase inhibitor includes, but are not limited to PP1, is also referred to as 1H-pyrazolo [3,4-d] pyrimidine-4-amine, 1-(1, the 1-dimethyl ethyl)-3-(1-naphthyl)-(9CI); And PP2, be also referred to as 1H-pyrazolo [3,4-d] pyrimidine-4-amine, 3-(4-chlorphenyl)-1-(1, the 1-dimethyl ethyl)-(9CI).
Term used herein " Syk tyrosine kinase inhibitor " relates to targeting, minimizing or suppresses the chemical compound of Syk.The example of the target of Syk tyrosine kinase inhibitor includes, but are not limited to Syk, STAT3 and/or STAT5.The example of Syk tyrosine kinase inhibitor includes, but are not limited to four hydroxyl trans-stilbens, is also referred to as 1, the 2-Benzenediol, 4-[(1E)-2-(3, the 5-dihydroxy phenyl) vinyl]-(9CI).
Term used herein " Janus (JAK-2 and/or JAK-3) tyrosine kinase inhibitor " relates to targeting, minimizing or suppresses the chemical compound of janus tyrosine kinase.Confirm that the Janus tyrosine kinase inhibitor is the antileukemia with antithrombotic formation, antiallergic and immunosuppressive properties.The target of JAK-2 and/or JAK-3 tyrosine kinase inhibitor includes, but are not limited to JAK2, JAK3, STAT3.The example of the indirect target of JAK-2 and/or JAK-3 tyrosine kinase inhibitor includes, but are not limited to CDK2.The example of JAK-2 and/or JAK-3 tyrosine kinase inhibitor includes, but are not limited to tyrphostin AG490; With 2-naphthyl vinyl ketone.The active chemical compound of targeting, minimizing or inhibition c-Abl family member and gene fusion product thereof for example comprises PD180970; AG957; Or NSC680410.
Lvii. retinoid; Its targeting, minimizing or inhibition retinoid dependency receptor; Such as isotretinoin, dimension a acid.
The lviii.RNA polymerase II extends inhibitor; The nuclear and the kytoplasm p70S6 kinases of insulin-stimulation in its targeting, minimizing or the inhibition Chinese hamster ovary celI; Targeting, minimizing or inhibition depend on the rna plymerase ii of casein kinase i I and transcribe; And targeting, minimizing or inhibition bovine oocyte germinal vesicle breakdown; Such as 5,6-two chloro-1-β-D-ribofuranosyl benzimidazole.
Lvix. serine/threonine kinase inhibitor; Suppress serine/threonine kinase; Such as 2-aminopurine, be also referred to as 1H-purine-2-amine (9Cl).The example of the target of serine/threonine kinase inhibitor includes, but are not limited to dsRNA-deopendent protein kinase (PKR).The example of the indirect target of serine/threonine kinase inhibitor includes, but are not limited to MCP-1, NF-κ B, elF2 α, COX2, RANTES, IL8, CYP2A5, IGF-1, CYP2B1, CYP2B2, CYP2H1, ALAS-1, HIF-1, erythropoietin and/or CYP1A1.
Lx. sterin biosynthesis inhibitor; It suppresses steroid, such as the biosynthesis of cholesterol; Such as terbinadine.The example of the target of sterin biosynthesis inhibitor includes, but are not limited to squalene epoxidase and CYP2D6.
Lxi. topoisomerase enzyme inhibitor; Comprise topoisomerase I inhibitor and topoisomerase II inhibitor.The example of topoisomerase I inhibitor includes, but are not limited to hycamtin, gimatecan, irinotecan, camptothecine (camptothecan) and analog thereof, 9-nitrocamptothecin and macromole camptothecine conjugates PNU-166148 (chemical compound of called after A1 in WO9917804); The 10-hydroxycamptothecine acetate; Etoposide; Idarubicin hydrochloride; Irinotecan hydrochloride; Teniposide; Hycamtin, topotecan hydrochloride; Doxorubicin; Epirubicin, epirubicin hydrochloride; Mitoxantrone, mitoxantrone hydrochloride; Daunorubicin, daunorubicin hydrochloride, dasatinib (BMS-354825).For example, can for example exist with the form of selling Use irinotecan under the trade mark.Can for example exist with the form of selling Give hycamtin under the trade mark.Term ＂ topoisomerase II inhibitor ＂ used herein includes, but are not limited to the anthracene nucleus class, such as doxorubicin, comprises Liposomal formulation, for example
Figure A200780004302D00331
Daunorubicin comprises Liposomal formulation, for example Epirubicin, idarubicin and Nemorubicin; Anthraquinone class mitoxantrone and losoxantrone; With podophyllotoxin etoposide and teniposide.Teniposide with
Figure A200780004302D00333
Sell; Teniposide is with VM26-
Figure A200780004302D00334
Sell; Doxorubicin with Or
Figure A200780004302D00336
Sell; Epirubicin with Idarubicin with
Figure A200780004302D00338
Sell; With mitoxantrone with Sell.
The lxii.VEGFR tyrosine kinase inhibitor; Its targeting, minimizing and/or suppress known relating to and regulate angiogenesis factor and cytokine normal and that pathologic vessels takes place.Play primary and requisite effect in VEGF family (VEGF-A, VEGF-B, VEGF-C, VEGF-D) and the many aspects of corresponding receptor tyrosine kinase [VEGFR-1 (Flt-1), VEGFR-2 (Flk-1, KDR) and VEGFR-3 (Flt-4)] in regulating blood vessel generation and lymph vessels generating process thereof.The example of VEGFR tyrosine kinase inhibitor comprises 3-(4-dimethylamino benzal)-2-dihydroindolone.Targeting, minimizing or the active chemical compound of inhibition VEGFR be chemical compound, protein or antibody especially, they suppress vegf receptor tyrosine kinase, suppress vegf receptor or in conjunction with VEGF and particularly those generally and specifically are disclosed in the chemical compound among the WO9835958, protein or monoclonal antibody, 1-(4-chloroanilino)-4-(4-pyridylmethyl) phthalazines or its pharmaceutically acceptable salt for example, for example succinate or in WO0009495, WO0027820, WO0059509, WO9811223, WO0027819 and EP0769947 those; For example as M.Prewett etc. at Cancer Research 59 (1999) 5209-5218, F.Yuan etc. are at Proc.Natl.Acad.Sci.USA, vol.93, pp.14765-14770, Dec.1996, Z.Zhu etc. are at Cancer Res.58, and 1998,3209-3214 and J.Mordenti etc. are at Toxicologic Pathology, Vol.27, no.1, pp14-21, those described in 1999; At described in WO0037502 and the WO9410202 those; M.S.O ' Reilly etc. are at Cell79, and 1994, the described angiostatin of 315-328; M.S.O ' Reilly etc. are at Cell88, and 1997, the endostatin described in the 277-285; The ortho-aminobenzoic acid amide-type; ZD4190; ZD6474; SU5416; SU6668; Or anti-VEGF antibodies or anti-VEGF receptor antibody, for example RhuMab (shellfish is cut down the pearl monoclonal antibody).So-called antibody means complete monoclonal antibody, polyclonal antibody, by the multi-specificity antibody that at least 2 kinds of complete antibodies and antibody fragment form, need only them and show required biological activity.The example of VEGF-R2 inhibitor for example comprises axitinib,
Lxiii. gonadorelin agonist, such as 1: PN: WO02056903 PAGE: 25 claimed protein, goserelin, goserelin acetate,
Lxiv. the chemical compound of inducing cell atomization, such as dimension a acid, α-, γ-or 8-tocopherol or α-, γ-or 8-tocotrienol,
Lxv. diphosphate for example comprises etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic Acid, ibandronic acid, risedronic acid and zoledronic acid,
Lxvi. prevent the heparanase inhibitors of Heparan sulfate degraded, PI-88 for example,
Lxvii. biological response modifier, preferred lymphokine or interferon, interferon-ALPHA for example,
Lxviii. telomerase inhibitor, telomestatin for example,
Lxix. regulator is such as the inhibitor of catechol O-methyltransferase, for example entacapone.
Lxx:ispinesib, permetrexed
Figure A200780004302D00341
Sutent (SU11248), diethylstilbestrol (DES), BMS224818 (LEA29Y),
Lxxi somatostatin or somatostatin analogue, such as octreotide (
Figure A200780004302D00342
Or Sandostatin
Figure A200780004302D00343
Lxxii. growth hormone receptor antagonist is such as pegvisomant, filgrastim or Pei Feisi booth or interferon-ALPHA.
With such as the treatment of anticarcinogen shown in this article associating can with radiotherapy combined.
For example being easy to be used for anti-inflammatory agent and/or the immunomodulator that is easy to be used for The compounds of this invention (both can be the TSC-chemical compound, and also can be the NF1-chemical compound) coupling of the present invention for example comprises:
The regulator of-calcineurin, for example inhibitor, for example ciclosporin A, FK 506;
-have the ascosin of immunosuppressive properties, for example ABT-281, an ASM981;
-corticosteroid; Cyclophosphamide; Imuran; Leflunomide; Mizoribine;
-Mycophenolic Acid or salt; Mycophenolate mofetil sodium for example;
-15-deoxyspergualine or immunosuppressant congener, its analog or derivant;
The regulator of-bcr-abl tyrosine kinase activity, for example inhibitor;
The regulator of-c-kit receptor tyrosine kinase activity, for example inhibitor;
The regulator of-pdgf receptor tyrosine kinase activity, for example inhibitor, for example Gleevec (imatinib);
The regulator of-p38 MAP kinase activity, inhibitor for example,
The regulator of-VEGF receptor tyrosine kinase activity, inhibitor for example,
The active regulator of-PKC, inhibitor for example, for example as be disclosed among WO0238561 or the WO0382859, for example embodiment 56 or 70 chemical compound;
The regulator of-JAK3 kinase activity, inhibitor for example, N-benzyl-3 for example, 4-dihydroxy-benzal-cyanoacetamide alpha-cyano-(3, the 4-dihydroxy)-] N-benzyl cinnamamide (tyrphostin AG490), prodigiosin 25-C (PNU156804), [4-(4 '-hydroxy phenyl)-amino-6, the 7-dimethoxyquinazoline] (WHI-P131), [4-(3 '-bromo-4 '-hydroxy phenyl)-amino-6, the 7-dimethoxyquinazoline] (WHI-P154), [4-(3 ', 5 '-two bromo-4 '-hydroxy phenyl)-amino-6, the 7-dimethoxyquinazoline] WHI-P97, KRX-211,3-{ (3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-amino]-piperidines-1-yl }-3-oxo-propionitrile, it is free form or pharmaceutically acceptable salt form, one-citrate (being also referred to as CP-690,550) or be disclosed in chemical compound among WO2004052359 or the WO2005066156 for example;
-regulator, for example S1P receptor active agonist or regulator, for example FTY720 chooses phosphorylation or its analog wantonly, for example choose 2-amino-2-[4-(3-benzyloxy the thiophenyl)-2-chlorphenyl of phosphorylation wantonly] ethyl-1, ammediol or 1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxy imido grpup)-ethyl]-2-ethyl-benzyl }-azetidine-3-formic acid or its pharmaceutically acceptable salt;
-immunosuppressant monoclonal antibody, for example monoclonal antibody-leukocyte receptors, for example Blys/BAFF receptor, MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86, IL-12 receptor, IL-17 receptor, IL-23 receptor or its part;
-other immunomodulatory compounds, the binding molecule of for example recombinating, its have the CTLA4 ectodomain to small part or its mutant, for example the outer part of the born of the same parents at least of CTLA4 or its connection non--mutant of CTLA4 protein sequence, for example CTLA4Ig (for example called after ATCC68629) or its mutant, for example LEA29Y;
The active regulator of-adhesion molecule, inhibitor for example, for example LFA-1 antagonist, ICAM-1 or-3 antagonisies, VCAM-4 antagonist or VLA-4 antagonist,
The active regulator of-CCR9, antagonist for example,
The active regulator of-MIF, inhibitor for example,
-5-aminosalicylic acid (5-ASA) medicine, such as sulfasalazine,
Figure A200780004302D00361
Figure A200780004302D00362
Figure A200780004302D00363
Figure A200780004302D00364
Figure A200780004302D00365
Figure A200780004302D00366
Figure A200780004302D00367
The medicine that for example contains mesalazine; For example with the mesalazine of heparin combination;
The regulator of-TNF alpha active, for example inhibitor for example comprises the antibody in conjunction with TNF α, for example infliximab
Figure A200780004302D00368
Thalidomide, lenalidomide,
-discharge nitric oxide production nonsteroid anti-inflammatory drugs (NSAIDs), for example comprise the medicine that NO is provided (CINOD) that suppresses COX;
-phosphodiesterase, the active regulator of PDE4B for example, such as inhibitor,
The active regulator of-Caspase, inhibitor for example,
-G protein-coupled receptor GPBAR1 regulator, agonist for example,
The active regulator of-ceramide kinase, inhibitor for example,
-' multi-functional antiinflammatory ' medicine (MFAIDs), cPLA2 (phoshpholipase) A2 (cPLA2) inhibitor for example is such as the film grappling PLA 2 inhibitors that is connected with glycosaminoglycan;
-antibiotic, such as penicillins, cephalosporins, erythromycin series, Tetracyclines, sulfonamides, such as sulfadiazine, sulfafurazole; The sulfone class is such as dapsone; Pleuromutilin, fluoroquinolones, metronidazole for example, quinolones is such as ciprofloxacin; Levofloxacin; Probiotic bacteria and fungal component, Lactobacillus (Lactobacillus) for example, lactobacillus reuteri (Lactobacillus reuteri);
-antiviral agents is such as ribavirin (ribivirin), vidarabine, acyclovir, ganciclovir, zanamivir, oseltamivir phosphate, famciclovir, atazanavir, amantadine, didanosine, Sustiva, phosphine formic acid, indinavir, lamivudine, Nai Fennawei, Li Tuonawei, Saquinavir, stavudine, valaciclovir, valganciclovir, zidovudine.
For example be easy to be used for of the present invention be easy to be used for The compounds of this invention (both can be the TSC-chemical compound, also can be the NF1-chemical compound) anti-inflammatory agent of coupling comprises, non-steroidal anti-inflammatory drug (NSAIDs) for example, such as propanoic derivatives (alminoprofen benoxaprofen, the acid of cloth Lip river, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid is with tioxaprofen), acetogenin (indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, Isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin and zomepirac), fenamic acid derivatives (flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acid derivatives (diflunisal and flufenisal), former times health class (isoxicam, piroxicam, sudoxicam and tenoxicam), salicylic acid salt (aspirin, sulfasalazine) and pyrazoline ketone (azapropazone, benzpiperilone (bezpiperylon), feprazone, mofebutazone, oxyphenbutazone, Phenylbutazone); Cyclo-oxygenase-2 (COX-2) inhibitor is such as celecoxib; IV type phosphodiesterase (PDE-IV) inhibitor; Chemokine receptor anagonists, especially CCR-1, CCR-2 and CCR-3; Pravastatin, such as HMG-CoA reductase inhibitor (lovastatin, simvastatin and pravastatin, fluvastatin, atorvastatin and other statins), sequestering agent (colestyramine and colestipol), nicotinic acid, fenofibric acid derivant (gemfibrozil, clofibrat, fenofibrate and bezafibrate) and probucol; Anticholinergic is such as muscarine antagonist (ipratropium bromide); Other chemical compound, such as theophylline, sulfasalazine and aminosallcylic acid class, for example 5-aminosalicylic acid and prodrug thereof, antirheumatic.
For example being easy to be used for the antiallergic agent that is easy to be used for The compounds of this invention (both can be the TSC-chemical compound, and also can be the NF1-chemical compound) coupling of the present invention for example comprises:
Antihistaminic (H1-histamine antagonist), bromopheniramine for example, chlorphenamine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine, alimemazine, azatadine, Cyproheptadine, antazoline, the pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine, fexofenadine, descarboethoxyloratadine and on-steroidal antiasthmatics, such as β 2-agonist (terbutaline, orciprenaline, fenoterol, isoetarine, albuterol, bitolterol, albuterol and pirbuterol), theophylline, sodium cromoglicate, atropine, ipratropium bromide, leukotriene antagonist (zafirlukast, montelukast, pranlukast, iralukast, the pobilukast, SKB-106,203), leukotriene biosynthesis inhibitor (zileuton, BAY-1005); Bronchodilator, antiasthmatics (mast cell stabilizers).
For example being easy to be used for the anesthetics that is easy to be used for The compounds of this invention (both can be the TSC-chemical compound, and also can be the NF1-chemical compound) coupling of the present invention for example comprises: ethanol for example, bupivacaine, chloroprocaine, chirocaine, lignocaine, mepivacaine, procaine, ropivacaine, tetracaine, desflurane, isoflurane, ketamine, propofol, Sevoflurane, codeine, fentanyl, hydromorphone, marcaine, Pethidine, methadone, morphine, oxycodone, remifentanil, sufentanil, butorphanol, nalbuphine, tramadol, benzocaine, cincaine, ethyl chloride, lignocaine and phenazopyridine.
For example be easy to be used for of the present invention be easy to be used for The compounds of this invention (both can be the TSC-chemical compound, also can be the NF1-chemical compound) antipruritic of coupling for example comprises: menthol, Camphora, oatmeal bath, pramocaine, Calamine Lotion, doxepin, chlorphenamine, Cyproheptadine, hydrochloride form for example, sulfapyridine, aluminum acetate (aluminium acetate), hydroxyzine, for example hydrochloride form or pamoic acid salt form
Figure A200780004302D00381
Fexofenadine, TRK-820, terfenadine, Burrow solution, unna's boot, tar Emulsion.
For example be easy to be used for of the present invention be easy to be used for The compounds of this invention (both can be the TSC-chemical compound, also can be the NF1-chemical compound) astringent of coupling for example comprises: Alumen, oatmeal, Hamamelis virginiana, utmost point cold water and rubbing alcohol, for example surgical spirit; The astringent preparation comprises silver nitrate, zinc oxide, zinc sulfate, Burow solution, Benzoinum tincture, plant material, such as tannin and gallic acid.
In every kind of situation of patent application of specifying citation or science open source literature, the theme that will be referred to described chemical compound is introduced the application as a reference, the crystal modification thing that for example comprises the chemical compound of its pharmaceutically acceptable salt, corresponding racemate, diastereomer, enantiomer, tautomeride and corresponding above-mentioned disclosure equally, if exist, for example be solvate, hydrate and the polymorph that wherein discloses.Prepare respectively described in can describing as the documents of citation or product and use chemical compound as the active component in the present invention's combination.Also have the combination of aforesaid two or more independent active component in the scope of the invention, promptly the drug regimen in the scope of the invention can comprise three kinds of active components or active component more than three kinds.In addition, first kind of activating agent is not to be identical component with common activating agent.
The structure of the drug substance of being differentiated by code, common name or trade name can be taken from the Internet, practical version of manual of standards ＂ The Merck Index ＂ or data base, for example Patents International, for example IMS World Publications or above-mentioned and following open source literature.Its content corresponding is incorporated herein by reference.
The activity that can following confirmation be used for the chemical compound of the inventive method:
Generate MEF cell line, wherein lacked Tsc1 or Tsc2 and had remarkable reduction by the signal conduction of Akt.Can observe the Akt activation and reduce, comprise the reaction of serum, PDGF, EGF, insulin and IGF1 as to all stimulus object.Follow the trail of the basis that descends as signal conduction, and find that PDGFR α and PDGFR β level continue to descend because of transcribing/translate to reduce in Tsc1 or Tsc2 null cell the PDGF reaction.In addition, short-term or long-term transfection cause the Akt phosphorylation and stimulate the reaction that increases as to many somatomedin the overexpression of PDGFR α.In addition, the stably express in the naked or Tsc1 null cell system causes the tumor growth in vivo in the Subcutaneous tumor model to strengthen to PDGFR α at Tsc2, shows that it is crucial that this decrement is adjusted in the optimum relatively character of the tumor of determining to occur among the TSC patient.
The signal conduction downstream of also observing all serum, PDGF, EGF, insulin and IGF1 becomes to lack also minimizing in the cell of PDGFR α and PDGFR β at genetic modification, shows the phase mutual interference in these receptors.
Can seek and visit Tsc 1 or signal in the Tsc 2 naked MEFss conduction of conduct to the reaction of IGF1 and compd A.Wortmannin can be used as IGF1 inhibitor (inibtor).
Can use the MTT algoscopy in triplicate cell hole, estimate with the uniform density bed board Tsc1-/-and Tsc2-/-and the growth of matched group MEF cell line in serum.For without any the growth under the stimulation situation, growth response is calibrated every kind of cell line respectively.
Can alleged occurrence Tsc1 naked and cellular control unit system to the powerful growth response of serum, but these cell lines stimulate IGF1 and almost do not have growth response and compd A all significantly to reduce growth under all conditions and blocked any growth response of cell to IGF1.
Can also use compd A in the mouse model of Tsc, to carry out therapeutic test (research in 1 month).First kind of test Tsc1+/-carry out in the mice, wherein have the sex influence that tumor is grown, make and only study female mice.Second kind of test Tsc2+/-carry out in the mice, wherein use carcinogen ENU so that strengthen and the tumor quickened in kidney forms speed.
Can confirm compd A reduce Tsc1+/-mice and Tsc2+/-have remarkable effect in the tumor of mice middle kidney regulating liver-QI.
Can lack in cell or animal (mice) model at NF1, for example according to measuring the neurofibromatosis activity with mode like TSC shortage cell or animal (mice) model class.Compd A shows activity in corresponding mensuration.

Claims (15)

1. the following formula: compound that is used for the treatment of neural skin barrier,
Figure A200780004302C00021
Wherein
R 1Be CH 3Or C 3-6Alkynyl,
R 2For H ,-CH 2-CH 2-OH or-CH 2-CH 2-O-(C 1-8) alkyl, for example-CH 2-CH 2-O-CH 2-CH 3,
And
X is=O, (H, H) or (H, OH),
Condition is to be=O and R as X 1Be CH 3The time, R 2Be not H,
Or compd A BT578, Compound C CI779, compd A P23573 or chemical compound TAFA-93.
2. according to the chemical compound of the purposes of claim 1, wherein this chemical compound is selected from formula I chemical compound, compd A BT578 or the chemical compound TAFA-93 as definition in the claim 1, and wherein said purposes is selected from treatment by plyability epiloia disorder mediated, induce by plyability epiloia disorder mediated and degenerate, the symptom of treatment and disease association by plyability epiloia mediation, treatment is by the purposes in the relevant obstacle of plyability epiloia disorder mediated.
3. according to the chemical compound of claim 1, it is used for the treatment of 1 type neurofibromatosis (NF1), is used to induce by the NF1 disorder mediated degenerate, and is used for the treatment of the symptom relevant with NF1, and/or is used for suppressing or controlling by the NF1 disorder mediated.
4. be used for the treatment of plyability epiloia disorder mediated, induce plyability epiloia disorder mediated to degenerate, the symptom of the disease association of treatment and the mediation of plyability epiloia, the relevant obstacle of treatment plyability epiloia disorder mediated, and/or the method for inhibition or control plyability epiloia disorder mediated, wherein plyability epiloia disorder mediated is selected from tuberous sclerosis, renal angiomyolipoma (ALM), LAM (LAM), following and/or the giant cell astrocytoma (SEGAs) of ependyma, this method comprises the chemical compound according to claim 2 to the individual administering therapeutic effective dose that these needs are arranged.
5. treat 1 type neurofibromatosis (NF1), induce the NF1 disorder mediated to degenerate, be used for the treatment of the symptom relevant with NF1, and/or be used to suppress or control the method for NF1 disorder mediated, this method comprises the chemical compound according to claim 1 to the individual administering therapeutic effective dose that these needs are arranged.
6. as the chemical compound or the method for purposes as described in any one in the claim 1 to 5, wherein said chemical compound be selected from 40-O-(2-ethoxy)-rapamycin, 32-deoxidation for rapamycin, 16-penta-2-alkynyloxy base-32-deoxidation for rapamycin, 16-penta-2-alkynyloxy base-32 (S or R)-dihydro-rapamycin or 16-penta-2-alkynyloxy base-32 (S or R)-dihydro-40-O-(2-ethoxy)-rapamycin.
7. as the chemical compound or the method for purposes described in claim 1 or 6 any one, wherein said chemical compound is 40-O-(2-ethoxy)-rapamycin.
As in the claim 2,6 or 7 in any one defined chemical compound in preparation as defined in claim 2 purposes or as the purposes in the medicine in the method as defined in claim 4.
As in the claim 1,3,6 or 7 in any one defined chemical compound in preparation as defined in claim 3 purposes or as the purposes in the medicine in the method as defined in claim 5.
10. pharmaceutical composition, it comprises as any one defined chemical compound in the claim 2,6 or 7 and at least a pharmaceutically acceptable excipient, and this pharmaceutical composition is used for purposes as defined in claim 2 or is used for as defined in claim 4 method.
11. pharmaceutical composition, comprise as any one defined chemical compound in the claim 1,3,6 or 7 and at least a pharmaceutically acceptable excipient, this pharmaceutical composition is used for purposes as defined in claim 3 or is used for as defined in claim 5 method.
12., be used for purposes as defined in claim 2 or be used for as defined in claim 4 method as the combination of defined chemical compound and at least a second kind of drug substance in any one in the claim 1,2,6 or 7.
13., be used for purposes as defined in claim 3 or be used for as defined in claim 5 method as the combination of defined chemical compound and at least a second kind of drug substance in any one in the claim 1,3,6 or 7.
14. as in the claim 1,2,6 or 7 in any one defined chemical compound be used for purposes with the medicine of second kind of drug substance combination in preparation, this medicine is used for purposes as defined in claim 2 or is used for as defined in claim 4 method.
15. as in the claim 1,3,6 or 7 in any one defined chemical compound be used for purposes with the medicine of second kind of drug substance combination in preparation, this medicine is used for purposes as defined in claim 3 or is used for as defined in claim 5 method.
CN200780004302.4A 2006-02-02 2007-01-31 40-O-(2-ethoxy)-rapamycin is for preparing the purposes of medicine Ceased CN101378751B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201310425110.8A CN104000818B (en) 2006-02-02 2007-01-31 tuberous sclerosis treatment

Applications Claiming Priority (11)

Application Number Priority Date Filing Date Title
GB0602123.2 2006-02-02
GB0602123A GB0602123D0 (en) 2006-02-02 2006-02-02 Organic compounds
GB0603568A GB0603568D0 (en) 2006-02-22 2006-02-22 Organic compounds
GB0603568.7 2006-02-22
GB0604593.4 2006-03-07
GB0604593A GB0604593D0 (en) 2006-03-07 2006-03-07 Organic compounds
GB0605760A GB0605760D0 (en) 2006-03-22 2006-03-22 Organic compounds
GB0605760.8 2006-03-22
GB0609698.6 2006-05-16
GB0609698A GB0609698D0 (en) 2006-05-16 2006-05-16 Organic compounds
PCT/EP2007/000818 WO2007088034A2 (en) 2006-02-02 2007-01-31 Tuberous sclerosis treatment

Related Child Applications (1)

Application Number Title Priority Date Filing Date
CN201310425110.8A Division CN104000818B (en) 2006-02-02 2007-01-31 tuberous sclerosis treatment

Publications (2)

Publication Number Publication Date
CN101378751A true CN101378751A (en) 2009-03-04
CN101378751B CN101378751B (en) 2016-06-01

Family

ID=36100930

Family Applications (1)

Application Number Title Priority Date Filing Date
CN200780004302.4A Ceased CN101378751B (en) 2006-02-02 2007-01-31 40-O-(2-ethoxy)-rapamycin is for preparing the purposes of medicine

Country Status (2)

Country Link
CN (1) CN101378751B (en)
GB (1) GB0602123D0 (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104530112A (en) * 2014-12-23 2015-04-22 连云港恒运医药科技有限公司 Method for preparing everolimus intermediate and ethylated impurities thereof
CN105163735A (en) * 2013-02-01 2015-12-16 格力尔罗格克斯股份有限公司 Compositions and methods for the treatment of neurodegenerative and other diseases
CN106061482A (en) * 2013-10-08 2016-10-26 拉姆医疗公司 Rapamycin for the treatment of lymphangioleiomyomatosis
CN106924269A (en) * 2016-04-19 2017-07-07 南京大学 The purposes of zoledronic acid
US11103449B2 (en) 2014-04-04 2021-08-31 AI Therapeutics, Inc. Inhalable rapamycin formulation for treating age-related conditions
US11491143B2 (en) 2014-10-07 2022-11-08 AI Therapeutics, Inc. Inhalable rapamycin formulation for the treatment of pulmonary hypertension

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2269603B1 (en) * 2001-02-19 2015-05-20 Novartis AG Treatment of breast tumors with a rapamycin derivative in combination with exemestane

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105163735A (en) * 2013-02-01 2015-12-16 格力尔罗格克斯股份有限公司 Compositions and methods for the treatment of neurodegenerative and other diseases
CN105163735B (en) * 2013-02-01 2018-12-11 格力尔罗格克斯股份有限公司 For treating the composition and method of neurodegenerative disease and other diseases
CN106061482A (en) * 2013-10-08 2016-10-26 拉姆医疗公司 Rapamycin for the treatment of lymphangioleiomyomatosis
US11123289B2 (en) 2013-10-08 2021-09-21 AI Therapeutics, Inc. Rapamycin for the treatment of lymphangioleiomyomatosis
US11744797B2 (en) 2013-10-08 2023-09-05 AI Therapeutics, Inc. Rapamycin for the treatment of lymphangioleiomyomatosis
US11103449B2 (en) 2014-04-04 2021-08-31 AI Therapeutics, Inc. Inhalable rapamycin formulation for treating age-related conditions
US11648199B2 (en) 2014-04-04 2023-05-16 Al Therapeutics, Inc. Inhalable rapamycin formulation for treating age-related conditions
US11491143B2 (en) 2014-10-07 2022-11-08 AI Therapeutics, Inc. Inhalable rapamycin formulation for the treatment of pulmonary hypertension
CN104530112A (en) * 2014-12-23 2015-04-22 连云港恒运医药科技有限公司 Method for preparing everolimus intermediate and ethylated impurities thereof
CN104530112B (en) * 2014-12-23 2018-01-09 连云港恒运药业有限公司 The preparation method of everolimus intermediate and its ethylization impurity
CN106924269A (en) * 2016-04-19 2017-07-07 南京大学 The purposes of zoledronic acid

Also Published As

Publication number Publication date
GB0602123D0 (en) 2006-03-15
CN101378751B (en) 2016-06-01

Similar Documents

Publication Publication Date Title
CN104000818B (en) tuberous sclerosis treatment
CN103446138A (en) Neuroendocrine tumor treatment using mtor inhibitors
CN101378751B (en) 40-O-(2-ethoxy)-rapamycin is for preparing the purposes of medicine
US20090012105A1 (en) Combination of Mtor Inhibitor and Antipolate Compound
CN101389337A (en) Rapamycin derivatives for treating neuroblastoma
CN101360496B (en) Neuroendocrine tumor treatment using mTOR inhibitors
AU2017218980B2 (en) Tuberous Sclerosis treatment
CN101374524A (en) Combination of mTOR inhibitor and antipolate compound
MX2008008944A (en) Combination of mtor inhibitor and antipolate compound
MX2008009880A (en) Tuberous sclerosis treatment

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C53 Correction of patent of invention or patent application
CB02 Change of applicant information

Address after: Basel, Switzerland

Applicant after: NOVARTIS AG

Address before: Basel, Switzerland

Applicant before: Novartis AG

COR Change of bibliographic data

Free format text: CORRECT: APPLICANT; FROM: NOVARTIS AG TO: NOVARTIS CO., LTD.

C14 Grant of patent or utility model
GR01 Patent grant
IW01 Full invalidation of patent right

Decision date of declaring invalidation: 20220407

Decision number of declaring invalidation: 54747

Granted publication date: 20160601

IW01 Full invalidation of patent right