CN101612401B - Combinations comprising an antidiarrheal agent and an epothilone or an epothilone derivative - Google Patents
Combinations comprising an antidiarrheal agent and an epothilone or an epothilone derivative Download PDFInfo
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- CN101612401B CN101612401B CN2009101609016A CN200910160901A CN101612401B CN 101612401 B CN101612401 B CN 101612401B CN 2009101609016 A CN2009101609016 A CN 2009101609016A CN 200910160901 A CN200910160901 A CN 200910160901A CN 101612401 B CN101612401 B CN 101612401B
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Abstract
Epothilone derivatives are co-administered with an antidiarrheal agent, e.g., a DPP-IV inhibitor, in the treatment of a proliferative disease.
Description
Dividing an application of the application's Chinese patent application 02806845.9 that is entitled as " comprising the combination of diarrhea and Epothilones or epothilone derivate " that to be the inventor submit on March 18th, 2002.
The present invention relates to comprise (a) diarrhea, the drug regimen of Epothilones (epothilone) derivant of dipeptidyl peptidase-IV (DPP-IV) inhibitor, (b) general formula I and optional at least a pharmaceutically useful carrier particularly, described combination is used for simultaneously, uses respectively or continuously, especially for treatment proliferative disease, especially entity tumor disease; The invention still further relates to the pharmaceutical composition that comprises this combination, this combination be used to prepare the medicine that is used for treating proliferative disease purposes, comprise this combination as combination preparation, be used for using simultaneously, respectively or the commodity bundle that uses continuously or product and treatment homoiothermic animal, especially Ren Lei method.
People such as Bollag are at " cancer research (Cancer Research) ", and nineteen ninety-five, the 55th rolls up, and has at first described the microtubule Stabilization of Epothilones compounds in the 2325-33 page or leaf.Different types of tumors is especially used other chemotherapeutics, particularly TAXOL
TMThe suitable therapeutic scheme of the tumor of failing to respond to any medical treatment is addressed in WO99/43320.
The present invention relates to a kind of combination that is used for while, difference or uses continuously, as combination preparation or pharmaceutical composition, described combination comprises (a) diarrhea and (b) epothilone derivate and the optional at least a pharmaceutically useful carrier of general formula I, wherein active component (a) and (b) in various situations the form with free form or officinal salt exist
Wherein, compd A is represented oxygen or NR
N, R wherein
NBe hydrogen or low alkyl group, R is hydrogen or low alkyl group, and Z is oxygen or a key.
Wherein A represents that oxygen, R are that hydrogen and Z are that the compound of Formula I of oxygen is called as Epothilones A;
Wherein A represents that oxygen, R are that methyl and Z are that the compound of Formula I of oxygen is called as epothilone B;
Wherein A represents that oxygen, R are that hydrogen and Z are that the compound of Formula I of a key is called as Epothilone C (-)-Deoxyepothilone A;
Wherein A represents that oxygen, R are that methyl and Z are that the compound of Formula I of a key is called as epothilone d.
Term used herein " combination preparation ", refer in particular to " component bag " (kit ofparts) in some sense, i.e. COMBINATION OF THE INVENTION (a) and (b) administration independently of one another or by using (containing not commensurability COMBINATION OF THE INVENTION (a) and (b)) different fixed combination administration as defined above, i.e. while or in different time point administrations.Therefore, the component in the component bag can for example be used simultaneously or alternately be used in chronological order, that is to say that any component in the component bag is at different time points, be applied at identical or different interval.The total amount ratio of COMBINATION OF THE INVENTION that is applied in combination preparation (a) and COMBINATION OF THE INVENTION (b) can change, for example needs or the satisfied needs of being suffered from the single patient of the diarrheal order of severity based on the patient to satisfy patient subgroups to be treated.
The present invention relates to a kind of combination preparation especially, and it comprises the diarrhea of (a) one or more unit dosage forms and (b) epothilone derivate of the general formula I of one or more unit dosage forms, particularly epothilone B.
Using diarrhea is in order to prevent, control or eliminate relevant with using of Epothilones, especially epothilone B often diarrhoea.Therefore, the present invention also relates to prevent or control the diarrheal method relevant with the epothilone derivate of using general formula I, it comprises diarrhea from effective dose to the patient who accepts the epothilone derivate treatment that use.
Term " entity tumor " refers in particular to breast carcinoma, ovarian cancer, colon cancer and common gastrointestinal cancer, cervical cancer, pulmonary carcinoma, particularly small cell lung cancer and nonsmall-cell lung cancer, incidence cancer, bladder cancer, carcinoma of prostate or Kaposi sarcoma.This combination not only can suppress entity tumor but also can suppress the growth of liquid tumor (liquid tumors), in addition, according to tumor type and employed concrete combination, gross tumor volume is dwindled.Combination disclosed herein also is suitable for the transfer diffusion of prophylaxis of tumours and the growth or the progress of small transfer.
Structure by the definite active medicine of Code Number, common name or trade name can be taken from the standard directories " Merck index " of current edition or take from the data base, for example " international monopoly " data base (for example IMSWorld company).Therefore its corresponding contents is hereby incorporated by.
Should know: mention COMBINATION OF THE INVENTION (a) and (b) mean and also comprise pharmaceutically useful salt.If these COMBINATION OF THE INVENTION (a) and (b) have for example at least one basic center, they just can form acid-addition salts.If desired, also can form the acid-addition salts that has extra basic center.Have the COMBINATION OF THE INVENTION (a) of acidic-group (for example COOH) and (b) also can form salt with alkali.COMBINATION OF THE INVENTION (a) or (b) or its pharmaceutically useful salt also can use maybe can comprise and be used for crystalline other solvent with the form of hydrate.
Especially, patent and patent application WO 93/10121, US 6194181, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO 00/31247 disclose extensively and particularly wherein that A represents oxygen or NR
N, R wherein
NBe hydrogen or low alkyl group, R be hydrogen or low alkyl group and Z be an oxygen or a key general formula I epothilone derivate and be used to prepare the method for this epothilone derivate, in each case, it is disclosed in compound claim in particular, and the final products of embodiment of therefore working, theme, pharmaceutical preparation and the described claim of final products are introduced into the application as a reference.What equally also comprise has wherein disclosed corresponding stereoisomer and corresponding crystal variant, for example solvate and a polymorph.
The scheme 21 of WO 99/02514 (the 31st, 32 page) and embodiment 3 (48-50 page or leaf) disclose the conversion of epothilone B to corresponding lactam.Different compound of Formula I with epothilone B also can be finished similarly to the conversion of corresponding lactam.The epothilone derivate of corresponding general formula I (R wherein
NBe low alkyl group) can be with R wherein
NFor the epothilone derivate of hydrogen is raw material, prepares by methods known in the art such as standard reductive alkylation reaction.
The epothilone derivate of general formula I, particularly epothilone B, the composition that can be used as disclosed pharmaceutical composition among the WO 99/39694 is applied.
In a specific embodiment, epothilone derivate is a compound of Formula I, and wherein A represents oxygen or NR
N, R wherein
NBe hydrogen or low alkyl group, R is that hydrogen or low alkyl group and Z are oxygen or a key.
In the epothilone derivate of general formula I, preferred A represents oxygen, and R is a low alkyl group, ethyl or most preferably be methyl for example, and Z is preferably oxygen.
Diarrhea and their dosage regimen are known for those skilled in the art.The diarrhea that is suitable in the method and composition of the present invention includes but not limited to that natural opioid drug is (as tinctura opii, paregoric and codeine), synthetic opioid drug is (as diphenoxylate, difenoxin and loperamide), basic bismuth salicylate, Lanreotide (lanreotide), vapreotide (vapreotide) and octreotide, the motilin antagonist, cyclooxygenase inhibitor 2 such as celecoxib (celecoxib), glutamine, neurosedyn and traditional diarrhea such as Kaolin, pectin, berberine and poisonous fungus bases medicine.In one embodiment of the invention, diarrhea is selected from codeine, tinctura opii, paregoric, diphenoxylate, difenoxin and loperamide.In another embodiment of the invention, diarrhea is selected from Lanreotide, vapreotide and octreotide.In these three kinds of chemical compounds, particularly preferably be octreotide.Octreotide and acetate thereof can be by US 4,395, and the method described in 403 obtains and uses, and perhaps for example with as US 5,538, the form of its acetate described in 739 or embonate obtains or use.Especially, octreotide can be being SANDOSTATIN as trade mark
TMAnd SANDOSTATINLAR
TMCommodity be applied to the patient.
Employed diarrhea also can be the DPP-IV inhibitor among the present invention.The DPP-IV inhibitor is known in the art and can be used for treating diabetes.The dosage regimen of its treatment diabetes is well known by persons skilled in the art.Yet, in the present invention, DPP-IV inhibitor performance prevention and/or relevant with the using epothilone derivate often diarrheal effect of control.
DPP-IV is the reason that causes the GLP-1 inactivation.More particularly, DPP-IV can produce the physiological effect that therefore the GLP-1 receptor antagonist has also shortened GLP-1.GLP-1 is main pancreas insulin secretion stimulus object and the elimination of glucose is had direct beneficial effect.
The DPP-IV inhibitor can be peptide or non-peptide compound.Preferred non-peptide class DPP-IV inhibitor.
Preferably, the present invention uses the DPP-IV inhibitor, it is at WO 98/19998, DE 19616486A1, extensively and particularly disclosed among WO 00/34241 and the WO 95/15309, in various situations, it is disclosed in the compound claim especially, and the final products of embodiment of therefore working, theme, pharmaceutical preparation and the described claim of final products are hereby incorporated by.The embodiment 3 of WO 98/19998 and the embodiment 1 of WO 00/34241 disclose DPP728 and LAF237 respectively particularly." diabetes (Diabetes) ", 1998,47:1253-1258 is described particularly to the DPP-IV inhibitor of general formula VI (seeing below) preferably.DPP728 can be according to the preparation of the method described in the 20th page of WO98/19998.
People such as H.U.Demuth are at " enzyme suppress magazine (J.Enzyme Inhibition) ", in 1998 the 2nd volume 129-142 pages or leaves, especially N-peptidyl-O-aroyl azanol and the preparation thereof to for example general formula VII or VIIa (seeing below) is described in the 130-132 page or leaf.
Unless indicate in addition in the disclosure, the organic group that is defined as " rudimentary " contains and is no more than 7, preferably is no more than 4 carbon atoms, and following statement has following given implication:
Halogen is preferably represented fluorine, chlorine or bromine.
If do not specialize, low alkyl group is preferably ethyl or methyl more preferably.(C
1-8) alkyl is side chain or preferably unbranched alkyl, preferred low alkyl group, for example methyl or ethyl.
Low-grade alkylidene is preferably methylene, ethylidene or propylidene.It can be unsubstituted or replace, for example be replaced by hydroxyl.
Lower alkoxy is preferably methoxy or ethoxy.(C
2-4) alkoxyl is for example ethyoxyl or propoxyl group.
Cycloalkyl is for example C
3-C
12Cycloalkyl, preferred cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl or ring decyl; Or bicyclic alkyl such as bicycloheptyl.Cycloalkenyl group is preferably 1-cyclohexenyl group, 2-cyclohexenyl group, 3-cyclohexenyl group, 1-cyclopentenyl or 1-cyclopentenyl.
(C
1-3) hydroxy alkyl is for example 3-hydroxypropyl, 1-hydroxyethyl or hydroxymethyl.
C unsubstituted or that replaced by one or two low alkyl group
4-C
6-alkylideneimino is for example pyrrolidinyl, methylpyrrole alkyl, piperidino, 2-piperidyl, 3-piperidyl, 2-methyl isophthalic acid-piperidyl or hexamethyleneimino.Preferably, C
4-C
6-alkylideneimino is a piperidino.
Optional as defined above substituted [3.1.1] bicyclic carbocyclic partly be preferably optional 6 by the dibasic dicyclo of methyl [3.1.1] heptan-2-base, or optional 2 by a methyl and 6 by 2 methyl trisubstituted dicyclo [3.1.1] heptan-3-base altogether.Optional as defined above substituted [2.2.1] bicyclic carbocyclic partly is preferably dicyclo [2.2.1] heptan-2-base.
Aryl preferably includes 6 to 12 carbon atoms and is for example phenyl, tolyl or naphthyl, and described each aryl all can be replaced by for example low alkyl group or halogen.
Term " heteroaryl " refers to aromatic heterocyclic radical, for example be selected from pyrrolidinyl, pyrrole radicals, pyrazolyl, oxetanes (oxetanyl), pyrazolinyl, imidazole radicals, imidazolinyl, imidazolidinyl oxazolyl oxazolidinyl isoxazoline-3-yl isoxazolyl, thiazolyl, thiadiazolyl group, thiazolidinyl, isothiazolyl, the isothiazole alkyl, furyl, tetrahydrofuran base, thienyl oxadiazole base, piperidyl, piperazinyl, azacyclo-heptantriene (azepinyl), the 4-piperidyl, pyridine radicals, pyrazinyl, pyrimidine radicals, pyridazinyl, THP trtrahydropyranyl, morpholinyl, the thiomorpholine base, thiomorpholine base sulfoxide, thiomorpholine base sulfone, 1, the 3-dioxolanes, indyl, benzothiazolyl benzoxazolyl, benzothienyl, quininuclidinyl, quinolyl, tetrahydro isoquinolyl, isoquinolyl, benzimidazolyl, benzopyranyl, indolizine base (indolizinyl), benzofuranyl, chromonyl, the coumarin base, benzopyranyl, the cinnolines base, quinoxalinyl, indazolyl, pyrrolopyridinyl, the two hydrogen benzisothiazole bases of furo pyridine radicals, two hydrogen isoindolyls, two hydrogen quinazolyls and tetrahydro quinazoline base.
Preferred DPP-IV inhibitor is the represented N-of the general formula (I) of free form or acid-addition salts form (N '-glycyl that replaces)-2-Cyanopyrolidine,
Wherein R is:
A) R
1R
1aN (CH
2)
m-, wherein
R
1Replaced or disubstituted pyridine radicals of difference or pyrimidine radicals part by low alkyl group, lower alkoxy, halogen, trifluoromethyl, cyano group or nitro list for optional; Or optional the replacement by low alkyl group, lower alkoxy or halogen list or the disubstituted phenyl of difference;
R
1aBe hydrogen or (C
1-8) alkyl; With
M is 2 or 3;
B) choose wantonly at 1 quilt (C
1-3) mono-substituted (C of hydroxy alkyl
3-12) cycloalkyl;
C) R
2(CH
2)
n-, wherein
R
2Replaced by low alkyl group, lower alkoxy, halogen list or two respectively the replacement or trisubstd phenyl or choose wantonly on phenyl ring respectively for optional by the mono-substituted thiophenyl of methylol; Or be (C
1-8) alkyl, optional by (C
1-8) the alkyl list replaces or polysubstituted [3.1.1] bicyclic carbocyclic part, optional by low alkyl group, lower alkoxy or the replacement of halogen list or the disubstituted pyridine radicals of difference or naphthyl moiety, cyclohexene or adamantyl; With
N is 1 to 3; Perhaps
R
2Replaced by low alkyl group, lower alkoxy or halogen list or the disubstituted phenoxy group of difference for optional; With
N is 2 or 3;
D) (R
3)
2CH (CH
2)
2-, each R wherein
3Replaced by low alkyl group, lower alkoxy or halogen list or the disubstituted phenyl of difference for optional independently of one another;
E) R
4(CH
2)
P-R wherein
4Be 2-oxo-pyrrolidine base or (C
2-4) alkoxyl, and
P is 2 to 4;
F) choose wantonly at 1 quilt (C
1-3) the mono-substituted isopropyl of hydroxyalkyl;
G) R
5, R wherein
5Be indanyl, optional pyrrolidinyl or the piperidyl part, optional that is replaced by benzyl by (C
1-8) the alkyl list replaces or polysubstituted [2.2.1]-or [3.1.1] bicyclic carbocyclic part, adamantyl, or optional by hydroxyl, methylol or (optional replaced by low alkyl group, lower alkoxy or halogen list or disubstituted respectively) phenyl list replaces or polysubstituted (C respectively
1-8) alkyl;
H) adamantyl of Qu Daiing.
In an embodiment preferred of the present invention, the N-of free form or acid-addition salts form (N '-glycyl that replaces)-2-Cyanopyrolidine is by general formula (I) expression, wherein
R is R
1R
1aN (CH
2)
m-, wherein
R
1Replaced or disubstituted pyridine radicals of difference or pyrimidine radicals part by low alkyl group, lower alkoxy, halogen, trifluoromethyl, cyano group or nitro list for optional; Or optional the replacement by low alkyl group, lower alkoxy or halogen list or the disubstituted phenyl of difference;
R
1aBe hydrogen or (C
1-8) alkyl; With
M is 2 or 3.
More preferably, the N-of free form or acid-addition salts form (N '-glycyl that replaces)-2-Cyanopyrolidine is by general formula (I) expression, wherein
R is R
1R
1aN (CH
2)
m-, wherein
R
1Replaced by low alkyl group, lower alkoxy, halogen, trifluoromethyl, cyano group or nitro list or the disubstituted pyridine radicals part of difference for optional;
R
1aBe hydrogen or (C
1-8) alkyl; With
M is 2 or 3;
Most preferably, the N-of general formula I (N '-glycyl that replaces)-the 2-Cyanopyrolidine is (S)-1-{2-[5-cyanopyridine-2-yl] amino } ethyl-glycyl }-2-cyano group-pyrrolidine (DPP728) or (S)-1-[(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyano group-pyrrolidine (LAF237).
In another preferred embodiment, described DPP-IV inhibitor is selected from the chemical compound of general formula I I, III, IV and V free form or the acid-addition salts form:
A-B (general formula I I, G1 and G2 group)
Wherein B is
F is 1 or 2;
G is 0,1 or 2;
X is CH
2, O, S, SO, SO
2, NH or NR α
1, R α wherein
1Be low alkyl group (C
1To C
6);
-Y is-N ,-CH or-C=(when A-CO group quilt-CH=or-when CF=substitutes);
R α is H, CN, CHO, B (OH)
2, PO
3H or its ester, CC-R α
7, or CH=N-R α
8, R α wherein
7Be H, F, low alkyl group (C
1To C
6), CN, NO
2, OR α
9, CO
2R α
9Or COR α
9R α
9Be low alkyl group (C
1To C
6); R α
8Be Ph, OH, OR α
9, OCOR α
9Or OBn; A is connected on the Y;
Wherein, for G1 group chemical compound,
(a) when R α is hydrogen, A be carry the annular aliphatic side chain a-amino acid alpha-amido-carboxyl groups or have the beta-amino-carboxyl groups of following general formula,
Wherein h is 1 to 6, and in each case, described ring is all optional for undersaturated and/or exist hetero atom to replace;
(b) when R α be CN, CC-R α
7Or CH=N-R α
8The time, A is as defined group in (a), and in addition also can derive from any L-a-amino acid that has the lipotropy side chain;
(c) when R α be CHO or B (OH)
2The time, A be as (a) in defined beta-amino-carboxyl groups;
For G2 group chemical compound, R α is H, CN, C=C-R α
7Or-CH=N-R α
8, and A is
Wherein a is 1 to 5; D
1For-G-(CH
2)
b-(R α
4)
q-R α
3G is O, NH or NMe; B is 0 to 12; Q is 0 to 5; When G is not oxygen, D
2Be D
1R α
4Be Z-NH-(CH
2)
c-or NH-Z-(CH
2)
c-, wherein c be 1 to 12 and Z be CO, CH
2Or SO
2R α
3Be CO
2H or its ester, CONH
2, CONHNH
2, CONR α
5R α
6, CONHNR α
5R α
6, PO
3H or its ester, SO
3H, SO
2NH
2, SO
2NR α
5R α
6, OH, OR α
5, replacement or unsubstituted aryl or heteroaryl, NH
2, NR α
5R α
6, NHCO
2R α
5, NHSO
2NR α
5R α
6, NHCOR α
5, NH-SO
2R α
5, NH-CH (: NR α
5) NR α
5R α
6, NHCONHR α
5R α
6, sugar, CO-amino sugar, NHCO-amino sugar or-the NHCS-amino sugar; And R α
5With R α
6Be selected from hydrogen independently of one another and be no more than cycloalkyl, low alkyl group and the fluoro-alkyl of 8 atoms and be no more than aryl, heteroaryl and the miscellaneous alkyl aryl of 11 atoms, or R α
5With R α
6Can form a chain (C jointly
3To C
8); Perhaps A is
R α wherein
10Be H or Me, described ring can contain a plurality of hetero atoms, and E is J-(CH
2)
b-(R α
4)
q-R α
3, J is CO, CH
2Or SO
2, and a, b, q, R α
3With R α
4Be as defined group in (i); Perhaps A is
R α wherein
2Be H or Me, described ring can contain one or more hetero atoms, and L is (CH
2)
d-(CO)
r-(CH
2)
b-(R α
4)
q-R α 3 or (CH
2)
e-NR α
10-(CH
2)
b-(R α
4)
q-R α
3, wherein r is 0 or 1, and d is 0 to 4, and e is 2 to 4, and b, q, R α
3With R α
4Be as defined group in (i);
For G3 group chemical compound, each B can have any body defined above, and each A can be selected from structure (i) that any above G2 organizes (ii) or (iii), wherein the end group R α in the residue A
3By a shared group-ε-ω-ε-or-ε-ε-or-ω-replacement, and ε and ω are selected from CH independently of one another
2, O, NH, CO, S, SO
2, Ph and NHMe;
And in G2 and G3 group, have at least a methylene in the chain to be substituted by its bioisostere, perhaps any amide group or any amide group that is among the side chain A in G2 or G3 group chemical compound that connects A and B in G1, G2 or G3 group chemical compound can be substituted by the bioisostere of amide.
In another preferred embodiment, the DPP-IV inhibitor is the chemical compound of the general formula VI of free form or acid-addition salts form.
In another preferred embodiment, the DPP-IV inhibitor is N-peptidyl-O-aroyl azanol or its pharmaceutically useful salt.Aroyl is for example naphthyl carbonyl or benzoyl, and described benzoyl is unsubstituted or for example lower alkoxy, low alkyl group, halogen or preferred nitro list replacement or two replacement of quilt.Peptidyl-part preferably comprises 2 a-amino acids, for example glycine, alanine, leucine, phenylalanine, lysine or proline, and wherein the a-amino acid that directly is connected with the azanol nitrogen-atoms is preferably proline.
Preferably, N-peptidyl-O-aroyl azanol is the compound or pharmaceutically acceptable salt thereof of general formula VII,
Wherein
J is 0,1 or 2;
R ε
1The side chain of expression natural amino acid; With
R ε
2Expression lower alkoxy, low alkyl group, halogen or nitro.
In a highly preferred embodiment of the present invention, N-peptidyl-O-aroyl azanol is chemical compound or its pharmaceutically useful salt of general formula VIIa.
In a highly preferred embodiment, component (a) DPP-IV inhibitor is (S)-1-{2-[5-cyano group-pyridine-2-yl] amino } ethyl-glycyl }-2-cyano group-pyrrolidine (DPP728), component (b) epothilone derivate is an epothilone B.
In another highly preferred embodiment, component (a) DPP-IV inhibitor is (S)-1-[(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyano group-pyrrolidine (LAF237), component (b) epothilone derivate is an epothilone B.
The present invention relates to a kind of combination preparation especially, and it comprises the DPP-IV inhibitor of (a) one or more unit dosage forms and (b) epothilone derivate, the especially epothilone B of the general formula I of one or more unit form of medication.
A kind of combination will be called as combination of the present invention hereinafter, described combination comprise (a) diarrhea and (b) epothilone derivate of general formula I (wherein compd A is represented oxygen or NR
N, R wherein
NBe hydrogen or low alkyl group, R is hydrogen or low alkyl group, and Z is oxygen or a key) and optional at least a pharmaceutically useful adjuvant, active component wherein exists with the form of free form or officinal salt in various situations.
If in this not explanation in addition, when employed COMBINATION OF THE INVENTION in the combination of the present invention be with as the form of commercially available single medicine when being used, the information that is provided in can the package insert according to various marketed drugs is determined their dosage and administering mode, to obtain beneficial effect described herein.
Diarrhea is to use in the whole cycle or occur, use when needing in diarrhoea as a kind of preventive measure.
In an embodiment preferred of the present invention, study subject is accepted the epothilone derivate of general formula I once in a week, and lasting several weeks are 3 weeks for example, one week of drug withdrawal subsequently or several weeks; Diarrhea is used as preventive measure, and it is by using and continue to use in the whole cycle to the experimenter in advance before beginning to use epothilone derivate; Or do not use in advance and in the whole cycle, continue to use; Or under the optional situation of using diarrhea in advance, diarrhoea during treatment cycle, occurs, use when needing.For example, when epothilone derivate is used once in a week, continued for 3 weeks, drug withdrawal is during 1 week, the interval in then per 4 weeks will be used as one-period.
The effective dose of diarrhea is to be enough to prevent, control or eliminate the diarrheal amount relevant with using epothilone derivate.Especially, when diarrhoea is epothilone derivate, when particularly the dosage of epothilone B is xicity related, but described effective dose is the amount that can increase the amount of application of epothilone derivate.
Combination of the present invention can be combination preparation or pharmaceutical composition.
An object of the present invention is to provide a kind of pharmaceutical composition, it comprises the combination of the present invention to proliferative disease therapeutic alliance effective dose, promptly in this pharmaceutical composition, and COMBINATION OF THE INVENTION (a) and (b) in fixed combination, used together.
Can be according to pharmaceutical composition of the present invention with known method preparation itself, and be suitable in intestinal, being applied to mammal (homoiothermic animal) outside (as the oral or rectum) and intestinal, comprise the mankind.
Described new pharmaceutical composition comprises for example about 10% to about active component of 100%, preferred about 20% to about 60%.Be used in the intestinal or intestinal pharmaceutical preparation that use, that be used for therapeutic alliance is for example pharmaceutical preparation of those unit dosage forms outward,, also have injection in addition as sugar coated tablet, tablet, capsule or suppository.If do not particularly point out, these preparations are with known method preparation itself, for example by conventional mixing, granulation, sugar coating, dissolving or freeze-drying process preparation.Because essential effective dose can reach by using a plurality of dosage units, therefore the unit content of the COMBINATION OF THE INVENTION that is contained in every kind of dosage form of single dose need not to constitute effective dose.
Be used for the process of the compositions of peroral dosage form in preparation, can use any drug media commonly used as, for example water, ethylene glycol, oils, alcohols, flavouring agent, antiseptic, coloring agent; Or the preparation oral dosage form as, for example under the situation of powder agent, capsule or tablet, can use carrier such as starch, sugar, microcrystalline Cellulose, diluent, granulation agent (granulating agent), lubricant, binding agent, disintegrating agent etc., and solid orally ingestible is better than liquid preparation.Owing to be convenient to use, tablet and capsule have been represented best oral dosage form, in this case, obviously need to use solid pharmaceutical carriers.
Especially, the treatment effective dose of every kind of COMBINATION OF THE INVENTION of combination of the present invention can be used respectively, and promptly described component can be simultaneously or continuous administration in any order.For example, according to the method for treatment proliferative disease of the present invention can comprise with merge effective dose, preferably with cooperative effective quantity (for example with daily dose) corresponding to said amount simultaneously or in any order continuously (i) use first COMBINATION OF THE INVENTION of free or pharmaceutical acceptable salt and (ii) use and dissociate or second COMBINATION OF THE INVENTION of pharmaceutical acceptable salt.Each component of combination of the present invention can be used respectively or be used simultaneously with the form of gradation or single coupling in the different time during the treatment.A kind of medicine can for example be the preparation of using in intestinal and another kind can be used outside intestinal.In addition, term administering " also comprise and use those to be converted into the prodrug of the COMBINATION OF THE INVENTION of COMBINATION OF THE INVENTION itself in vivo.Therefore, will be understood that: the present invention comprises all these simultaneously or the scheme of alternating treatment, and should be correspondingly to term administering " make an explanation.
The effective dose of every kind of COMBINATION OF THE INVENTION using in the combination of the present invention can change according to the order of severity of employed particular compound or pharmaceutical composition, administering mode, the state of an illness of being treated, the state of an illness for the treatment of.Therefore, the dosage of combination of the present invention is according to comprising that route of administration and patient's the kidney and the multiple factor of liver function select.Internist, clinician or a veterinary who possesses conventional technical ability can easily determine the effective dose of the single-activity composition that prevention, control or prevention disease progression are required and leave prescription.Be in the concentration that makes epothilone derivate and can produce curative effect but do not occur in the process in the toxic scope,, need a dynamic (dynamical) dosage regimen that arrives target site based on active component in order to obtain optimum precision.This relates to distribution, balance and the elimination factor of active component.
If described homoiothermic animal is human, the dosage of compound of Formula I is preferably once in a week, and each about 0.25 to 75mg/m
2, preferred 0.5 to 50mg/m
2, be 2.5mg/m for example for the described dosage of adult patient
2, lasting 2 to 4 weeks are 3 weeks for example, drug withdrawal subsequently 6 to 8 days.
According to the dosage regimen of the diarrhea of having established, diarrhea is used for preferred 1 time/day to 4 times/day.
If use the DPP-IV inhibitor, it preferably is applied according to the known arrangement that is used for the treatment of diabetes.Preferably, described dosage is that 25mg/ day is to 1000mg/ day.
In addition, the present invention relates to treat the method for the homoiothermic animal of suffering from proliferative disease, described method comprises to animal uses a certain amount of combination of the present invention, and described amount is effectively to proliferative disease in treatment and can makes any diarrhoea minimizing relevant with using epothilone derivate.
In addition, the present invention relates to the purposes that combination of the present invention is used for the treatment of the purposes of proliferative disease and is used to prepare the medicine that is used for treating proliferative disease.
In addition, the invention provides a kind of commercial bag, it comprises the description that is used for using simultaneously, respectively or continuously described combination as the combination of the present invention of active component and in the process of treatment proliferative disease.
Following examples have been illustrated foregoing invention, but they and do not mean that from the restriction the present invention of any aspect.Also can determine the beneficial effect of combination of the present invention by known other experimental model of various equivalent modifications.
Embodiment 1: 1 human patients of suffering from proliferative disease has been carried out the treatment of the epothilone B in 6 cycles, wherein each cycle comprise once in a week, the Epothilones of 5 minutes intravenous injections or 15 minutes intravenous injection 2.5mg, continued for three weeks, ended subsequently 14 days.During whole treatment, described patient accepts the loperamide hydrochloride of 2mg/ day to 16mg/ day with control diarrhoea.
Embodiment 2: 1 human patients of suffering from proliferative disease has been carried out the treatment of the epothilone B in 6 cycles, wherein each cycle comprise once in a week, the epothilone B of 5 minutes intravenous injection 2.5mg, continued for three weeks, ended subsequently 14 days.When diarrhoea occurring, described patient can accept to be no more than the loperamide hydrochloride of 16mg/ day.
Embodiment 3: 1 human patients of suffering from proliferative disease has been carried out the treatment of the epothilone B in 6 cycles, wherein each cycle comprise once in a week, the epothilone B of 5 minutes intravenous injection 2.5mg, continued for three weeks, ended subsequently 14 days.During whole treatment, described patient accepts the DPP728 of 1 to 6 50mg/ daily dose with control diarrhoea.
Embodiment 4: 1 human patients of suffering from proliferative disease has been carried out the treatment of the epothilone B in 6 cycles, wherein each cycle comprise once in a week, the epothilone B of 5 minutes intravenous injection 2.5mg, continued for three weeks, ended subsequently 14 days.When diarrhoea occurring, described patient can accept to be no more than the DPP728 of 300mg/ day.
Embodiment 5: 1 human patients of suffering from proliferative disease has been carried out the treatment of the epothilone B in 6 cycles, and the epothilone B that wherein each cycle comprises once in a week, 15 minutes angular veins are injected 2.5mg continued for three weeks, ended subsequently 14 days.During whole treatment, described patient accepts the LAF237 of 1 to 6 50mg/ daily dose with control diarrhoea.
Embodiment 6: 1 human patients of suffering from proliferative disease has been carried out the treatment of the epothilone B in 6 cycles, and the epothilone B that wherein each cycle comprises once in a week, 5 minutes angular veins are injected 2.5mg continued for three weeks, ended subsequently 14 days.When diarrhoea occurring, described patient can accept to be no more than the LAF237 of 300mg/ day.
Claims (9)
1. one kind is used for while, difference or the continuous combination preparation that uses; It is composed as follows: (a) antidiarrheal agent and (b) Epothilones of general formula I; And optional at least a pharmaceutically useful carrier; Wherein said antidiarrheal agent is the antidiarrheal agent of prevention or the control diarrhoea relevant with the Epothilones of the general formula I of using free form or pharmaceutically acceptable salt form; And be dipeptidyl peptidase-IV inhibitor or synthetic opiates antidiarrheal agent; Active component (a) and (b) exist with the form of free form or pharmaceutically acceptable salt wherein
Wherein A represents oxygen or NR
N, R wherein
NBe hydrogen or C
1-7Alkyl, R are hydrogen or C
1-7Alkyl, and Z is oxygen or a key.
2. according to the combination preparation of claim 1, it contains the Epothilones of general formula I, and wherein A represents oxygen, and R is C
1-7Alkyl or hydrogen, and Z is oxygen or a key.
3. the purposes of diarrhea in the combination preparation of the Epothilones of the general formula I of preparation itself and free form or pharmaceutical acceptable salt, wherein said diarrhea is used to prevent or controls the relevant diarrhoea of Epothilones with general formula I from pharmaceutical acceptable salt to the patient that use free form or, and be dipeptidyl peptidase-iv inhibitor or synthetic opiates diarrhea
Wherein compd A is represented oxygen or NR
N, R wherein
NBe hydrogen or C
1-7Alkyl, R are hydrogen or C
1-7Alkyl, and Z is oxygen or a key.
4. the purposes of claim 3, wherein Epothilones is an epothilone B.
5. pharmaceutical composition, it comprises each combination preparation and at least a pharmaceutically useful carrier among the claim 1-2 of proliferative disease therapeutic alliance effective dose.
6. the purposes of each combination preparation among the claim 1-2, it is used to prepare the medicine that is used for treating proliferative disease.
7. the purposes of the combination preparation of the Epothilones of diarrhea and general formula I, it is used to prepare the medicine that is used for treating proliferative disease, wherein said diarrhea is prevention or the control diarrheal diarrhea relevant with the Epothilones of the general formula I of using free form or pharmaceutical acceptable salt, and be dipeptidyl peptidase-iv inhibitor or synthetic opiates diarrhea
Wherein compd A is represented oxygen or NR
N, R wherein
NBe hydrogen or C
1-7Alkyl, R are hydrogen or C
1-7Alkyl, and Z is oxygen or a key.
8. commodity bundle, it comprises (a) diarrhea and (b) Epothilones of general formula I,
Wherein compd A is represented oxygen or NR
N, R wherein
NBe hydrogen or C
1-7Alkyl, R are hydrogen or C
1-7Alkyl, and Z is oxygen or a key; Wherein said diarrhea is prevention or the control diarrheal diarrhea relevant with the Epothilones of the general formula I of using free form or pharmaceutical acceptable salt, and be dipeptidyl peptidase-iv inhibitor or synthetic opiates diarrhea, and the description that in the process of treatment proliferative disease, is used for using simultaneously, respectively or continuously described combination preparation.
9. combination preparation, it comprises the diarrhea of the one or more unit dosage forms of free form or pharmaceutical acceptable salt (a), wherein said diarrhea is prevention or the control diarrheal diarrhea relevant with the Epothilones of the general formula I of using free form or pharmaceutical acceptable salt, and be dipeptidyl peptidase-iv inhibitor or synthetic opiates diarrhea, (b) Epothilones of the general formula I of one or more unit dosage forms
Wherein compd A is represented oxygen or NRN, and wherein RN is hydrogen or C
1-7Alkyl, R are hydrogen or C
1-7Alkyl, and Z is oxygen or a key.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US27715301P | 2001-03-19 | 2001-03-19 | |
| US60/277,153 | 2001-03-19 | ||
| US27720701P | 2001-03-20 | 2001-03-20 | |
| US60/277,207 | 2001-03-20 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB028068459A Division CN100540001C (en) | 2001-03-19 | 2002-03-18 | Comprise the combination of diarrhea and Epothilones or epothilone derivate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101612401A CN101612401A (en) | 2009-12-30 |
| CN101612401B true CN101612401B (en) | 2011-01-12 |
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ID=34589864
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009101609016A Expired - Fee Related CN101612401B (en) | 2001-03-19 | 2002-03-18 | Combinations comprising an antidiarrheal agent and an epothilone or an epothilone derivative |
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| Country | Link |
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| CN (1) | CN101612401B (en) |
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| CN101612401A (en) | 2009-12-30 |
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