CN101568342A - Treatment for multiple myeloma - Google Patents
Treatment for multiple myeloma Download PDFInfo
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- CN101568342A CN101568342A CNA2007800478308A CN200780047830A CN101568342A CN 101568342 A CN101568342 A CN 101568342A CN A2007800478308 A CNA2007800478308 A CN A2007800478308A CN 200780047830 A CN200780047830 A CN 200780047830A CN 101568342 A CN101568342 A CN 101568342A
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Abstract
The present invention provides methods of treating a subject suffering from multiple myeloma comprising administering to the subject an effect amount of a compound according to Formula I.
Description
Related application
The application requires on November 27th, 2006 to submit to, and application number is No.60/861,120 U.S. Provisional Application, and submitted on February 28th, 2007, application number is No.60/904, the rights and interests of 138 U.S. Provisional Application.Whole instructions of above-mentioned application are included in herein as a reference.
Background technology
Multiple myeloma belongs to plasmacytic cancer.Plasma cell is the immune system cell in the bone marrow, the antibody of its can create antagonism disease and infection.In the advancing of disease process, genetic abnormality can appear, and this just produces malignant plasma cell or multiple myeloma cells.These cells pass blood flow and accumulate in the bone marrow, and health tissues is produced nonvolatil injury.Because a lot of organs may be subjected to the influence of multiple myeloma, so symptom and performance are different.Common symptom comprises: infringement, the calcium content of bone is higher, renal failure, anemia and immunity are impaired.Myeloma cell's fast breeding and the release of IL-6 cause the damage of bone, and IL-6 also claims OAF, and it stimulates osteoclast to destroy bone.The destruction of bone can cause that also the calcium content in the blood flow raises, and this situation also claims hypercalcemia.Because the myeloma cell extrudes normal cell in the bone marrow, so can damage the generation of normal hemocyte.The minimizing of white blood cell count can increase infected risk, and erythrocytic minimizing then can cause anemia.Hematoblastic minimizing can prevent normal blood coagulation.In addition, the excessive M albumen and the light chain protein of myeloma cell's generation can make blood thicken.These albumen also cause damage to kidney, and weaken their function.When the myeloma cell thickened blood, the kidney circulation can go wrong.In addition, the too high work that makes the kidney over loading of blood calcium causes the discharge capacity of calcium to reduce, and voided volume increases, and might dewater.
Multiple myeloma is except non-Hodgkin lymphomas (non-Hodgkin ' s lymphoma), modal leukemia.Account for 1% of all cancers greatly, all cancer the dead's 2%.So far, can't cure this disease and the back can not recurred in long-time fully.Therefore, be necessary for multiple myeloma and seek a kind of new Therapeutic Method.
Summary of the invention
The present invention relates to a kind of Therapeutic Method of suffering from the patient of multiple myeloma.This method comprises the chemical compound shown in general formula I or its pharmaceutically acceptable salt that gives patient's effective dose.Multiple myeloma in the treatment can be in following any period, kind and morbid state.
General formula I
The present invention is based on such discovery (embodiment 1) of propagation that the chemical compound shown in the general formula I can suppress the quantity of many myeloma cell lines to small part.When with these compounds for treating myeloma patients' myeloma cell, these chemical compounds also have inhibitory action to constitutional myeloma cell's survival, but do not influence the survival (embodiment 4) of other medullary cell.When with ten thousand Mactra sulcatria Deshayess (Velcade) or melphalan (melphalan) coupling, these chemical compounds demonstrate additive effect (embodiment 3) to myeloma cell's propagation.
Description of drawings
What use in embodiment and the accompanying drawing is compd A: 1-(4-{4-[4-(4-chloro-phenyl)-pyrimidine-2--amino]-benzoyl }-piperazine-1-yl)-ethyl ketone.
Compd A
Fig. 1 is a block diagram, and the expression compd A is to 14 myeloma cell line inhibition of proliferation effect (IC among Figure 1A
50Represent IC among Figure 1B with μ M
90Represent with μ M).
Fig. 2 is a curve chart, and the apoptotic temporal correlation through the XG-12 cell of compd A treatment is induced in expression among the figure.
Fig. 3 is a curve chart, and the concentration of expression compd A increases the inhibitory action to the XG-3 cell proliferation among the figure, and wherein chemical compound does not add Velcade, and chemical compound adds Velcade, and concentration is for inducing 10% (IC
10) XG-3 cell inhibitory effect and chemical compound add Velcade, concentration is for inducing 50% (IC50) XG-3 cell inhibitory effect.
Fig. 4 is a curve chart, and the concentration of expression compd A increases the inhibitory action to the XG-12 cell proliferation among the figure, and wherein chemical compound does not add melphalan, and chemical compound adds melphalan, and concentration is for inducing 10% (IC
10) XG-12 cell inhibitory effect and chemical compound add melphalan, concentration is for inducing 50% (IC50) XG-12 cell inhibitory effect.
Fig. 5 is a block diagram, and the expression compd A is to taking from 5 CD138 that suffer from the patient of multiple myeloma of new diagnosis
+The action effect of constitutional myeloma cell's stripped survival.
Fig. 6 is a block diagram, and the expression compd A is to taking from the action effect of stripped survival of non-myeloma medullary cell that 5 of new diagnosis suffer from the patient of multiple myeloma.
Fig. 7 is a block diagram, and the expression compd A is to taking from 5 CD34 that suffer from the patient of multiple myeloma of new diagnosis
+The action effect of the stripped survival of hemopoietic forebody cell.
Fig. 8 is a block diagram, and the expression compd A is to the patient's of the multiple myeloma of taking from 5 recurrences CD138
+The action effect of constitutional myeloma cell's stripped survival.
Fig. 9 is a block diagram, and the expression compd A is to the action effect of the stripped survival of the patient's of the multiple myeloma of 5 recurrences non-myeloma medullary cell.
Figure 10 is a block diagram, and the expression compd A is to the patient's of the multiple myeloma of 5 recurrences CD34
+The action effect of the stripped survival of hemopoietic forebody cell.
The specific embodiment
" aryl " is meant the unsaturated aromatic carbocyclic that contains 6-14 carbon atom, can be a ring (as phenyl ring) or multi-ring (as naphthalene nucleus).Preferably, aryl comprises phenyl, naphthyl, phenanthryl or the like.
" alkylaryl " is meant that at least one the alkyl hydrogen atom on the alkyl replaces with aromatic yl group, as benzyl ,-(CH
2)
2Phenyl ,-(CH
2)
3Phenyl ,-CH (phenyl)
2Or the like.
" alkyl " is meant straight or branched, and saturated or undersaturated alkyl contains the ring-type or the acyclic hydrocarbon of 1-10 carbon atom, though " low alkyl group " or " C
1-C
6-alkyl " have identical implication, but only be to contain 1-6 carbon atom.Representational saturated straight chained alkyl comprises methyl, ethyl, n-pro-pyl, normal-butyl, n-pentyl, n-hexyl or the like; And saturated branched alkyl comprises isopropyl, sec-butyl, isobutyl group, the tert-butyl group, isopentyl or the like.Undersaturated alkyl contains two keys or triple bond (also referring to " thiazolinyl " or " alkynyl " respectively) at least between adjacent carbon atom.Representational straight chain and branched-chain alkenyl comprise vinyl, acrylic, 1-butylene base, crotyl, isobutyl group, 1-pentenyl, pentenyl, 3-methyl-1-butene base, 2-methyl-2-butene base, 2,3-dimethyl, crotyl or the like; And a representational straight chain and an alkynyl group comprise acetenyl, propinyl, ethyl acetylene base, 2-butyne base, 1-pentynyl, valerylene base, 3-methyl isophthalic acid-butynyl or the like.Representational saturated " cycloalkyl " comprises cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl or the like; And undersaturated cycloalkyl comprises cyclopentenyl and cyclohexenyl group or the like.Herein, the cycloalkanes base class also is referred to as " carbocyclic ring " and is, comprises the bicyclo-and three ring systems that contain 8-14 carbon atom, for example condenses the cycloalkyl (as Pentamethylene. or cyclohexane extraction) of one or more aromatic rings (as phenyl) or non-aromatic carbocyclic ring (as cyclohexane extraction).
" alkoxyl " be meant-O-(alkyl) or-O-aryl, for example methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, amoxy or the like.
" C
2-C
6-thiazolinyl " be meant alkenyl group, preferably contain 2-6 carbon atom, and contain the alkenyl group of 1-2 the unsaturated position of thiazolinyl.Preferable alkenyl group comprises vinyl (CH=CH
2), positive 2-acrylic, (CH
2CH=CH
2) or the like.
" C
2-C
6-alkynyl " be meant alkynyl group, preferably contain 2-6 carbon atom and have the alkynyl group of the unsaturated position of 1-2 alkynyl, preferable alkynyl group comprises acetenyl (C ≡ CH), propinyl (CH
2C ≡ CH) or the like.
" halogen " is meant fluorine, chlorine, bromine or iodine atom.
" ketone " is meant carbonyl (being C=O).
" heteroaryl " is meant the 5-10 membered aromatic heterocycle, and it has at least one hetero atom that is selected from nitrogen, oxygen and sulfur, and contains at least one carbon atom, comprises monocycle and bicyclic ring system.Representational heteroaryl comprises: pyridine radicals, furyl, benzofuranyl, thiophenyl, benzothienyl, quinolyl, pyrrole radicals, indyl, oxazolyl, benzoxazolyl, imidazole radicals, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidine radicals, pyrazinyl, triazine radical, cinnolines base (cinnolinyl), phenanthrene give repeated exhortations base (phthalazinyl) and quinazolyl.
" assorted alkylaryl " be meant and contain the alkyl that at least one alkyl hydrogen atom is replaced by heteroaryl moieties, for example, and-CH
2-pyridine radicals ,-CH
2-pyrimidine radicals or the like.
" Heterocyclylalkyl " or " heterocycle " is meant the heterocycle that contains the 5-10 carbon atom.Be specially 5-7 unit's monocycle or 7-10 unit dicyclo, saturated or undersaturated heterocycle or aromatic ring, and contain 1-4 hetero atom, described hetero atom is independently selected from nitrogen, oxygen and sulfur, wherein hetero atom nitrogen and sulfur can be at random oxidized, and hetero atom nitrogen can also comprise dicyclo at random by quaternized, and wherein above-mentioned arbitrarily heterocycle and phenyl ring condense.Heterocycle can the combination by hetero atom arbitrarily or carbon atom.Heterocycle comprises the heteroaryl of above definition.Therefore, except above those heteroaryls of enumerating, heterocycle also comprises: morpholinyl, pyrrolidone-base, pyrrolidinyl, piperidyl, piperazinyl, hydantoin base, valerolactam base, epoxy ethyl, oxa-cyclobutyl (oxetanyl), tetrahydrofuran base, THP trtrahydropyranyl, tetrahydrochysene pyrindine base (tetrahydropyrindinyl), tetrahydro-pyrimidine base (tetrahydroprimidinyl), tetrahydrochysene thiophenyl, tetrahydro thiapyran base, tetrahydro-pyrimidine base, tetrahydrochysene thiophenyl, tetrahydro thiapyran base or the like.
" alkyl heterocycle alkyl " is meant the heterocyclically substituted alkyl of at least one alkyl hydrogen atom, for example 2-(1-pyrrolidinyl) ethyl, 4-morpholinyl methyl, (1-methyl-4-piperidyl) methyl or the like.
Term used herein " replacement " is meant that wherein at least one hydrogen atom in above-mentioned any group (being alkyl, aryl, alkylaryl, heterocyclic radical and Heterocyclylalkyl) is substituted the base displacement.Under the substituent situation of ketone (" C (=O) "), two hydrogen atoms are all replaced.Substituent group comprises halogen, hydroxyl, alkyl, the alkyl heterocycle alkyl of the Heterocyclylalkyl of the aryl alkyl of the aryl of the alkyl of replacement (as the aminoalkyl of haloalkyl, list-or all-replace, alkoxyalkyl or the like), aryl, replacement, aryl alkyl, replacement, Heterocyclylalkyl, replacement, alkyl heterocycle alkyl, replacement ,-NR
aR
b,-NR
aC (=O) R
b,-NR
aC (=O) NR
aR
b,-NR
aC (=O) OR
b-NR
aSO
2R
b,-OR
a,-C (=O) R
a,-C (=O) OR
a,-C (=O) NR
aR
b,-OC (=O) R
a,-OC (=O) OR
a,-OC (=O) NR
aR
b,-NR
aSO
2R
b, perhaps as general formula Y-Z-R
aShown group, alkane 2 basis (alkanediyl) or straight key that in the formula, Y is alkane 2 basis (alkanediyl), replace, Z be-O-,-S-, S (=O)-,-S (=O)
2-,-N (R
b)-,-C (=O)-,-C (=O) O-,-OC (=O)-,-N (R
b) C (=O)-,-C (=O) N (R
b)-or straight key, wherein R
aAnd R
bIdentical or different, and be independently selected from the alkyl heterocycle alkyl of Heterocyclylalkyl, alkyl heterocycle alkyl or replacement of alkylaryl, Heterocyclylalkyl, the replacement of aryl, alkylaryl, the replacement of alkyl (comprising haloalkyl), aryl, the replacement of hydrogen, amino, alkyl, replacement, perhaps R wherein
aAnd R
bForm the heterocycle of heterocycle or replacement with their bonded nitrogen-atoms.
" haloalkyl " is meant one or more hydrogen atoms by the metathetical alkyl of halogen, for example-and CF
3
" hydroxy alkyl " is meant one or more hydrogen atoms by the metathetical alkyl of hydroxyl, for example-and CH
2OH.
" sulfonyl " is meant " SO
2-R " group, wherein R is selected from H, aryl, heteroaryl, C
1-C
6The C that-alkyl, halogen replace
1-C
6-alkyl (as-SO
2-CF
3Group), C
2-C
6-thiazolinyl, C
2-C
6-alkynyl, C
3-C
8-cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, C
1-C
6-alkylaryl, C
1-C
6-miscellaneous alkyl aryl, C
2-C
6-alkene aryl, C
2-C
6-thiazolinyl heteroaryl, C
2-C
6-a alkynyl aryl, C
2-C
6-alkynyl heteroaryl, C
1-C
6-alkyl-cycloalkyl or C
1-C
6-alkyl heterocycle alkyl.
" sulfinyl " is meant " S (O)-R " group, and wherein R is selected from H, C
1-C
6The C that-alkyl, halogen replace
1-C
6-alkyl (as-SO
2-CF
3Group), C
2-C
6-thiazolinyl, C
2-C
6-alkynyl, C
3-C
8-cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, C
1-C
6-alkylaryl, C
1-C
6-miscellaneous alkyl aryl, C
2-C
6-alkenyl aryl, C
2-C
6-thiazolinyl heteroaryl, C
2-C
6-alkynyl aryl, C
2-C
6-alkynyl heteroaryl, C
1-C
6-alkyl-cycloalkyl or C
1-C
6-alkyl heterocycle alkyl.
" sulfane base " is meant " S-R " group, and wherein R is selected from H, C
1-C
6The C that-alkyl, halogen replace
1-C
6-alkyl (as-SO
2-CF
3Group), C
2-C
6-thiazolinyl, C
2-C
6-alkynyl, C
3-C
8-cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, C
1-C
6-alkylaryl, C
1-C
6-miscellaneous alkyl aryl, C
2-C
6-alkenyl aryl, C
2-C
6-thiazolinyl heteroaryl, C
2-C
6-alkynyl aryl, C
2-C
6-alkynyl heteroaryl, C
1-C
6Assorted alkyl of-alkyl or C
1-C
6-alkyl heterocycle alkyl.Preferred sulfane base group comprises methyl sulfane base, ethyl sulfane base etc.
" carboxyl " is meant-COOH.
" amino " is meant-NRR ' group, and wherein each R, R ' are hydrogen or C independently
1-C
6-alkyl, aryl, heteroaryl, C
1-C
6-alkylaryl, C
1-C
6-miscellaneous alkyl aryl, cycloalkyl or Heterocyclylalkyl, wherein R reaches the nitrogen-atoms that links to each other with them with R ' and can form the assorted naphthenic ring of 3-8 unit arbitrarily.
" ammonium " is meant the group-N of positively charged
+RR ' R ", wherein each R, R ', R " all be C independently
1-C
6-alkyl, C
1-C
6-alkylaryl, C
1-C
6-miscellaneous alkyl aryl, cycloalkyl or Heterocyclylalkyl, and wherein R and R ', and the nitrogen-atoms that links to each other with them can form the assorted naphthenic ring of 3-8-unit arbitrarily.
" HCl " is meant the hydrochlorate by their the described chemical compound of chemical constitution.
" nitrogenous non-aromatic heterocyclic " is meant morpholinyl, thio-morpholinyl, pyrrolidone-base, pyrrolidinyl, piperidyl, homopiperidinyl, piperazinyl, high piperazinyl, hydantoin base, tetrahydrochysene piperidyl, tetrahydro-pyrimidine base, oxazolidinyl (oxazolidinyl), thiazolidinyl, indyl, isoindolyl, tetrahydric quinoline group, tetrahydro isoquinolyl etc.
" pharmaceutically acceptable salt or complex " is meant the salt or the complex of chemical compound disclosed herein.The example of these salt includes but not limited to the salt with mineral acid (example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, nitric acid etc.) formation; With the salt that forms with organic acid, as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannin, Palmic acid, alginic acid, polyglutamic acid, LOMAR PWA EINECS 246-676-2, pyrovinic acid, naphthalenedisulfonic acid and Poly Gal A Galacturonan; And the salt that forms with basic amino acid, as lysine or arginine.
In addition, can be by comprising the salt of carboxylic acid or other acidic functionality with the preparation of suitable alkali reaction.This pharmaceutically acceptable salt can be with providing pharmaceutically acceptable cationic alkali to prepare, comprise alkali metal salt (especially sodium and potassium), alkali salt (especially calcium and magnesium), aluminum salt and ammonium salt, and make with physiologically-acceptable organic alkali, trimethylamine for example, triethylamine, morpholine, pyridine, piperidines, picoline, dicyclohexylamine, N, N '-dibenzyl-ethylenediamin, 2 hydroxy ethylamine, three-(2-hydroxyethyl) amine, procaine, the dibenzyl piperidines, N-benzyl-β-phenethylamine, dehydroabietylamine (dehydroabietylamine), N, N '-two dehydroabietylamine, glycosamine, the N-methylglucosamine, trimethylpyridine, quinine, quinoline and basic amino acid are as lysine and arginine.
The present invention relates to a kind of Therapeutic Method of suffering from the patient of multiple myeloma, this method comprises chemical compound shown in general formula I and the pharmaceutically acceptable salt thereof that gives patient's effective dose.
Multiple myeloma is plasmacytic cancer.Multiple myeloma be in which phase can utilize the world by stages system (ISS) determine.ISS is based on result to two blood counts to assess: β
2-microglobulin (β
2-M) and albumin, in the factor of a plurality of tests, the two best embodies the sign in early stage of multiple myeloma together.According to the world of myeloma system by stages, determine that the standard of different times is:
The I phase: β
2-M＜3.5mg/dL and albumin 〉=3.5g/dL
The II phase: β
2-M＜3.5mg/dL or β
2-M 3.5-5.5mg/dL, and albumin＜3.5g/dL (neither I phase neither III phase)
The III phase: β
2-M＞5.5mg/d
Multiple myeloma patients is classified as the class in a few class myeloma usually.Multiple myeloma can be asymptomatic also can be Symptomatic.Asymptomatic myeloma patient does not have the impaired or symptom appearance of relevant organ or tissue.The infringement of the organ or tissue relevant with myeloma comprises hypercalcemia, impaired renal function, anemia and bone injury.Asymptomatic myeloma comprises SMM (SMM), painless property multiple myeloma (IMM) and I phase multiple myeloma.SMM is characterised in that the plasma cell that increases a little in m protein in the bone marrow and the bone marrow.Painless property multiple myeloma is characterised in that the plasma cell that quantity increases in a spot of m protein in the bone marrow or the bone marrow.
Multiple myeloma patients also shows as their morbid state.Determine morbid state as follows: whether the patient receives treatment, if receive treatment, the result how about.The patient of new diagnosis is the patient who suffers from myeloma individually, has also accepted treatment.The patient who receives treatment is divided into following a few class:
Reactive disorder: refer to myeloma that treatment is responded.M albumen reduces at least 50%.
Stable disease: be meant the myeloma (being that the proteic reduction of M is not to 50%) that treatment is not had response, but do not make progress (further worsening).
Progressivity disease: the active myeloma (be that M albumen increases, then organ degenerates or tissue damaged) of making a comment or criticism and worsening.In most of the cases, recurrent and/or refractory disease can be thought the progressivity disease.
The disease of recurrence: referring to has the myeloma disease that responds but began again afterwards to worsen to treatment at first.After initial therapy or treatment subsequently, can the patient of having recurred be classified further.
Stubborn disease: refer to initial therapy is not had the myeloma of response, and the myeloma that treatment is not subsequently had the recurrence of response.Under last a kind of situation here, myeloma also can be considered to recurrent and stubborn disease.
The invention provides the patient's who suffers from multiple myeloma Therapeutic Method, this method comprises the chemical compound shown in general formula I or its pharmaceutically acceptable salt that gives patient's effective dose.Subject multiple myeloma can be in aforesaid any period, classification and disease condition.
The method according to this invention, the chemical compound of general formula I or its pharmaceutically acceptable salt can use separately, also can be used to reduce the therapeutic agent coupling of the symptom of one or more multiple myelomas with at least a other.The chemical compound of general formula I or its pharmaceutically acceptable salt can with therapeutic agent administration simultaneously, it can be the identical compositions of a part or with the chemical compound that comprises general formula I or its pharmaceutically acceptable salt compositions inequality.Perhaps, the chemical compound of general formula I or its pharmaceutically acceptable salt can give before or after other therapeutic agent giving.The chemical compound of general formula I or its pharmaceutically acceptable salt can be by giving administration with the identical or different route of administration of other therapeutic agent.This therapeutic agent can be chemotherapeutics, supportive therapeutic agent or its combination.
" chemotherapeutics " used herein is to the deleterious medicament of cancer cell.The example that can be used for chemotherapeutics of the present invention comprise bortezomib (
Millennium), melphalan (melphalan), prednisone (predisone), vincristine (vincristine), Ka Mositing (carmustine), cyclophosphamide (cyclophosphamide), dexamethasone (dexamathasone), Thalidomide (thalidomine), amycin (doxorubicin), cisplatin (cisplatin), etoposide (etoposide) and cytosine arabinoside (cytarabine).In a specific embodiment, the chemical compound of general formula I or its pharmaceutically acceptable salt and bortezomib
Coupling.In another specific embodiment, the chemical compound of general formula I or its pharmaceutically acceptable salt and melphalan coupling.
" supportive therapeutic agent " is a kind of symptom that alleviates multiple myeloma and medicament of complication of being mainly used in.The example of supportive therapeutic agent includes but not limited to bisphosphate, somatomedin, antibiotic, diuretic and analgesic.
Antibiotic example comprises sulphonamides; penicillin is (as benzylpenicillin; P-hydroxybenzyl penicillin; the pentenyl penicillin; the N-penicillin K; penicillin Vl phenoxymethylpenicillin; phenethicillin; methicillin (Methicillin); oxazacillin (Oxacillin); cloxacillin (Cloxacillin); dicloxacillin (Dicloxacillin); flucloxacillin (Flucloxacillino); nafthicillin (Nafcillin); ampicillin (Ampicillin); amoxicillin (Amoxicillin); cyclacillin (Cyclacillin); Carbenicillin (Carbenicillin); carry card XiLin (Ticarcillin); piperacillin (Piperacillin); azlocillin (Azlocillin); mezlocillin (Meczlocillin); mecillinam (Mecillinam); methylene amine penicillin (Amdinocillin)); cephalosporin (Cephalosporin) and derivant thereof (cefalotin (Cephalothin) for example; cefapirin (Cephapirin); CEC (Cephacetrile); cefazolin sodium (Cephazolin); cephalexin (Cephalexin); cephalo fixed (Cephandine); cefadroxil (Cefadroxil); cefamandole (Cefamandol); cefuroxime (Cefuroxime); ceforanide (Ceforanide); cefoxitin (Cefocitin); cefotetan (Cefotetan); cefaclor (Cefaclor); cefotaxime (Cefptaxime); ceftizoxime (Ceftizoxime); ceftriaxone (Ceftrioxone); ceftazidime (Ceftazidime); latamoxef (Moxalactam); cefoperazone (Cefoperazone); cefixime (Cefixime); ceftibuten (Ceftibuten) and cefprozil (Cefprozil)) the oxolinic acid; amifloxacin (Amifloxacin); temafloxacin (Temafloxacin); nalidixan; minaline; ciprofloxacin (Ciprofloxacin); cinoxacin (Cinoxacin); norfloxacin (Norfloxacin); pefloxacin (Perfloxacin); rosoxacin (Rosaxacin); ofloxacin (Ofloxacin); enoxacin (Enoxacin); pipemidic acid; sulbactam (Sulbactam); clavulanic acid; the Beta-bromo penicillanic acid; β-chloro penicillanic acid; 6-acetyl group methylene-penicillanic acid cefoxazole; sultamicillin; the hydration formaldehyde ester of mecillinam and sulbactam (Formaldehyde Hudrate Ester of Adinocillin andSulbactam); Tazobactam Sodium (Tazobactam); aztreonam (Aztreonam); sulfazecin (Sulfazethin); different sulfazecin (Isosulfazethin); nocardin (Norcardicins); between-carboxyl phenyl phenyl acetyl aminomethyl phosphate ester; duomycin; oxytetracycline; tetracycline; demeclocycline; doxycycline; methacycline and minocycline.
The example of bisphosphate comprises: Etidronic Acid ester (Didronel), ammonia hydroxyl bisphosphate (Aredia), bisphosphonates (Fosamax), risedronic acid ester (Actonel), Zometa (Zometa), ibandronic acid ester (Boniva).
The example of diuretic comprises thiazine derivative, for example amiloride, chlorothiazide, hydrodiuril, methyl chlorothiazide and chlortalidone (chlorothalidon).
The example of somatomedin comprises granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), M-CSF (M-CSF), multiset G-CSF, erythropoietin, thrombopoietin, oncostatin M and interleukin.
Analgesic comprises opium (as morphine), cox 2 inhibitor is (as rofecoxib (Rofecoxib), penta ground former times cloth (Valdecoxib) and celecoxib (Celecoxib)), Salicylate is (as aspirin, Choline magnesium trisalicylate, salsalate, diflunisal (difunisal) and sodium salicylate), propanoic derivatives is (as fenoprofen calcium, ibuprofen, ketoprofen, naproxen and naproxen sodium), ethychlozate derivative is (as indomethacin, sulindac (sulfindac), support degree (etodalac) and Tolmetin (tometin)), fragrant that acid (as mefenamic acid and meclofenamic acid), benzothiazine derivative or former times health class (as meloxicam (mobic) or piroxicam (piroxicam)) or pyridylacetic acid (as ketorolac).
" treatment " used herein comprises partly or realizes one or more following results substantially: the degree that partially or completely palliates a disease, improve clinical symptoms or with the index of disease association, the progress that postpones, suppresses or ward off disease; Perhaps partially or completely postpone, suppress or stop sick sending out or advancing of disease.
" patient " refers to mammal, especially refers to the people, but also can be the animal that needs veterinary treatment, for example companion animals (as Canis familiaris L., cat etc.), farm-animals (as cattle, sheep, pig, horse etc.) and laboratory animal (as rat, mice, Cavia porcellus etc.).
The Therapeutic Method of the multiple myeloma that the patient suffers from comprises the chemical compound that gives patient's effective dose, i.e. anilino-pyrimidine derivant shown in general formula (I).
Disclosed described chemical compound among the WO 02/46171 (Signal drugmaker), this patent has been described autoimmune disease, inflammatory diseases, cardiovascular disease, infectious disease, apoplexy or treatment for cancer particularly.
Comprise its pharmaceutically acceptable salt in the described chemical compound of general formula (I), each substituent definition is as follows:
R
1Be randomly to be independently selected from R with 1-4
7Aryl that substituent group replaced or heteroaryl;
R
2Be hydrogen;
R
3Be hydrogen or low alkyl group;
R
4Be independently selected from the group of forming by following in each case: halogen, hydroxyl, low alkyl group and lower alkoxy; Wherein n is the integer of 0-4;
R
5And R
6Identical or inequality, and be independently selected from the group of forming by following group :-R
8,
-(CH
2)
aC(＝O)R
9、-(CH
2)
aC(＝O)OR
9、-(CH
2)
aC(＝O)NR
9R
10、
-(CH
2)
aC(＝O)NR
9(CH
2)
bC(＝O)R
10、-(CH
2)
aNR
9C(＝O)R
10、
-(CH
2)
aNR
11C (=O) NR
9R
10,-(CH
2)
aNR
9R
10,-(CH
2)
aOR
9,-(CH
2)
aSO
cR
9Or
-(CH
2)
aSO
2NR
9R
10And R
5And R
6Form the heterocycle of heterocycle or replacement with their bonded nitrogen-atoms;
R
7Under each situation, be independently selected from the group of forming by following group: halogen, hydroxyl, cyano group, nitro, carboxyl, alkyl, alkoxyl, haloalkyl, acyloxy, sulfane base alkyl, sulfinyl alkyl, sulfonyl alkyl, hydroxy alkyl, aryl, the aryl of replacement, alkylaryl, the alkylaryl of replacement, Heterocyclylalkyl, the alkyl heterocycle alkyl of the Heterocyclylalkyl of replacement, alkyl heterocycle alkyl, replacement ,-C (=O) OR
8,-OC (=O) R
8,-C (=O) NR
8R
9,-C (=O) NR
8OR
9,-SO
CR
8,-SO
CNR
8R
9,-NR
8SO
CR
9,-NR
8R
9,-NR
8C (=O) R
9,-NR
8C (=O) (CH
2)
bOR
9,-NR
8C (=O) (CH
2)
bR
9,-O (CH
2)
bNR
8R
9Be fused to replacement or unsubstituted phenyl on replacement or unsubstituted Heterocyclylalkyl;
R
8, R
9, R
10And R
11Identical or inequality, and be independently selected from the group of forming by following group in each case: the alkyl heterocycle alkyl of the Heterocyclylalkyl of the alkylaryl of the aryl of the alkyl of hydrogen, alkyl, replacement, aryl, replacement, alkylaryl, replacement, Heterocyclylalkyl, replacement, alkyl heterocycle alkyl and replacement;
Perhaps R
8And R
9Form the heterocycle of heterocycle or replacement with their bonded carbon atoms;
A and b are identical or different, and are independently selected from each case by 1,2,3 and 4 groups of forming 0; And
C is 0,1 or 2 in each case.
In one embodiment of the invention, R
1Be replace or unsubstituted aryl or heteroaryl.Work as R
1When being substituted, replace with one or more following substituent groups that limit.Preferably, when replacing, R
1With halogen, sulfonyl or sulfonamide substitutions.
In another embodiment of the present invention, R
1Be selected from the group of forming by following group: replace or unsubstituted aryl, furyl, benzofuranyl, thiophenyl, benzothienyl, quinolyl, pyrrole radicals, indyl, oxazolyl, benzoxazolyl, imidazole radicals, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidine radicals, pyrazinyl, triazine radical, cinnolines base, phthalazinyl and quinazolyl.
In another embodiment of the present invention, R
1Be that replace or unsubstituted aryl, preferably that replace or unsubstituted phenyl.Work as R
1When being the aryl that replaces, this aryl replaces with one or more following substituent groups that limit.
Preferably, work as R
1When being the aryl that replaces, it uses halogen, sulfonyl or sulfonamide substitutions.
In another embodiment of the present invention, R
5And R
6Form nitrogenous nonaromatic heterocycles replacement or unsubstituted with their bonded nitrogen-atoms, preferably that replace or unsubstituted morpholinyl, replace or unsubstituted thio-morpholinyl, replace or unsubstituted pyrrolidone-base, replace or unsubstituted pyrrolidinyl, replace or unsubstituted piperidyl, replace or unsubstituted homopiperidinyl, replace or unsubstituted piperazinyl, replace or unsubstituted high piperazinyl, replace or unsubstituted hydantoin base, replace or unsubstituted tetrahydro pyridyl, replace or unsubstituted tetrahydro-pyrimidine base, replace or do not replace the De oxazolidinyl, replace or unsubstituted thiazolidinyl, replace or unsubstituted indolinyl, replace or unsubstituted iso-dihydro-indole-group, replace or unsubstituted tetrahydric quinoline group or replacement or unsubstituted tetrahydro isoquinolyl.
Work as R
5And R
6The nitrogen-atoms that links to each other with them forms piperazinyl replacement or unsubstituted, replacement or unsubstituted piperidyl or replacement or unsubstituted morpholinyl, and the morpholinyl of the piperazinyl of described replacement, the piperidyl of replacement or replacement replaces with one or more following substituent groups that limit.
Preferably, when replacing, substituent group is alkyl, amino, alkyl amino, alkyl ether, acyl group, pyrrolidinyl or piperidyl.
In one embodiment of the invention, R
2, R
3And R
4Be hydrogen, the chemical compound of this invention has the structure of general formula (II):
In the further specific embodiment of the present invention, R
1Be at random to use R
7The phenyl that replaces, it has the structure of general formula (III):
In further embodiment of the invention, R
7In the para-position of phenyl ring, shown in general formula (IV):
In further embodiment of the invention, the anilino-pyrimidine derivant is a compd A: 1-(4-{4-[4-(4-chloro-phenyl)-pyrimidine-2--amino]-benzoyl }-piperazine-1-yl)-ethyl ketone.
Compd A
In another embodiment, the present invention is by structural formula (I), (II), (III) or chemical compound or its pharmaceutically acceptable salt (IV), and condition is to get rid of compd A or its pharmaceutically acceptable salt.
The method preparation of the chemical compound of general formula I-IV and compd A by describing among the WO 02/46171A2 (Signal drugmaker).Its full content is included in herein for your guidance.
In one embodiment, accepting radiotherapy with the chemical compound of general formula I or the treatment of its pharmaceutically acceptable salt or with the patient of other medicament coupling treatment separately.In another embodiment, just preparing to accept stem cell transplantation with the chemical compound of general formula I or the treatment of its pharmaceutically acceptable salt or with the patient of other medicament coupling treatment separately.Separately or chemical compound or its pharmaceutically acceptable salt A of the general formula I that is used in combination with other therapeutic agent can be used as inductive treatment, load with ameliorate tumor before stem cell transplantation.In another embodiment, accepting stem cell transplantation with the chemical compound of general formula I or the treatment of its pharmaceutically acceptable salt or with the patient of other medicament coupling treatment separately.
When the chemical compound of general formula I or its pharmaceutically acceptable salt with the structure name or when describing, should be appreciated that the solvate of chemical compound and hydrate are also included within." solvate " is meant crystal habit, and wherein in crystallization process, solvent molecule is incorporated in the lattice.Hold the solvent that the thinner thing can comprise water or non-water, for example ethanol, isopropyl alcohol, DMSO, acetic acid, ethanolamine and ethyl acetate.Solvate, wherein water is the solvent molecule of incorporating lattice into, typically refers to " hydrate ".Hydrate comprises stoichiometric hydrate and the compositions that contains the water of variable.
In addition, the present invention also provides pharmaceutical composition, and it comprises as the chemical compound of the general formula I of effective ingredient or its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier.
" pharmaceutical composition " refers to the inert fraction of one or more effective ingredient and one or more composition carriers, and following any product: by the direct or indirect chemical combination of any two or more effective ingredient, complexation or the product that is polymerized, perhaps directly or indirectly decompose the product that forms, perhaps the product that forms by the reaction or the interaction of direct or indirect other type of ground warp of one or more compositions by one or more compositions.Certainly, pharmaceutical composition of the present invention comprises any compositions of making via mixing chemical compound of the present invention and pharmaceutically acceptable carrier.
Compositions comprises the compositions that is suitable for following administering mode: oral, rectally, topical, parenteral (comprising subcutaneous administration, muscle administration and intravenously administrable), ophthalmic administration (medicament for the eyes), pulmonary administration (nose or oral cavity suck) or nasal administration, but in any given case, optimal route of administration depends on the character of the state of an illness of treatment and the character of the order of severity and effective ingredient.They can be that form with unit dose exists easily, and any method preparation that can be known by pharmaceutical field.
In actual applications, the chemical compound of general formula I can be according to traditional pharmacy complex technique and pharmaceutically acceptable carrier combinations resulting mixture as effective ingredient.Carrier can be taked various ways, and this depends on the form of the preparation of administration, as oral or parenteral (comprising intravenously administrable).In the preparation of oral formulations, for example under the situation of oral liquid formulations, during as suspension, elixir and solution, can use any useful drug media, for example water, ethylene glycol, oil, ethanol, aromatic, antiseptic, coloring agent or the like; Perhaps for example under the situation of powder, hard and soft capsule and tablet, can use carrier, for example starch, sugar, microcrystalline Cellulose, diluent, granulation agent, lubricant, binding agent, disintegrating agent or the like at oral solid formulation; These carriers are used for solid orally ingestible more, and are not used in liquid preparation.
Owing to be convenient to administration, tablet and capsule are best oral dosage unit form, have wherein obviously used solid pharmaceutical carriers in this case.If needs are arranged, the water of tablet available standards or non-water technology coating.This compositions and preparation comprise 0.1% reactive compound at least.Certainly, the percentage ratio of reactive compound in these compositionss can change, and is generally between the about 2%-60% of per unit (weight).The content of the reactive compound in this medicative compositions is wanted to access effective dose.The reactive compound of general formula I also can be by giving with for example liquid drops or spray nasal cavity.
Tablet, pill, capsule or the like can contain binding agent, for example Tragacanth, Radix Acaciae senegalis, corn starch or gelatin; Excipient such as calcium hydrogen phosphate; Disintegrating agent such as corn starch, potato starch, alginic acid; Lubricant such as magnesium stearate; And sweeting agent such as sucrose, lactose or glucide.When dosage form was capsule, except the material of above-mentioned class, it can also comprise liquid-carrier, as fatty oil.
The profile that various other materials can be used as coating or modify dosage unit.For example, tablet can carry out coating with Lac, sugar or its combination.Syrup or elixir also contain sucrose as sweeting agent, as the methyl parahydroxybenzoate and the propyl p-hydroxybenzoate of antiseptic, dyestuff and flavoring agent such as cherry-flavored or orange flavor except containing active component.
The chemical compound of general formula (I) also can be through parenteral.The solution of reactive compound or suspension can suitably mix in water with surfactant such as hydroxyl-propyl cellulose.Also can in oil, make dispersant by glycerol, liquid macrogol and composition thereof.These preparations have comprised antiseptic, grow under normal storage and service condition to prevent microorganism.
The medicament forms that is suitable for injection comprises aseptic aqueous solution or dispersion liquid and prepares aseptic parenteral solution in real time or sterilized powder that dispersion liquid is used.Medicament forms under all situations all must be aseptic, and must have to a certain degree flowability be easy to the injection.It must be stablized under manufacturing and condition of storage, and must do anti-corrosion measure to prevent the pollution of microorganism such as antibacterial and fungus.Carrier can be solvent or disperse medium, contains for example water, ethanol, polyhydric alcohol (as glycerol, propylene glycol and liquid macrogol), suitable mixture and vegetable oil.
Can adopt any suitable route of administration to mammal especially people, so that the chemical compound of the present invention of effective dose to be provided.For example, can adopt oral, rectum, topical, parenteral, ophthalmic, pulmonary, nasal cavity or the like administering mode.Dosage form comprises tablet, lozenge, dispersant, suspension, solution, Emulsion, ointment, aerosol or the like.Preferably, the chemical compound of general formula I adopts oral administration.
Term " effective dose " is meant when giving chemical compound with the patient, can reach the amount of the chemical compound of effective clinical effectiveness." effectively clinical effectiveness " comprises and improves disease symptoms or symptom is taken a turn for the better to some extent; Prevent, suppress or postpone the recurrence of disease symptoms or disease itself and/or compare the life-span that can prolong the patient, perhaps prevent, suppress or postpone further developing of disease symptoms or disease itself with there not being treatment.Give the patient accurately the chemical compound (or other therapeutic agent) of amount depend on the type of disease and the order of severity of the state of an illness, and patient's self situation: as general health, age, sex, body weight with to the drug resistance of medicine.This also depends on severity extent, seriousness and the type of disease.The technical staff can determine proper dosage according to these or other factors.When giving other therapeutic agent jointly, " effective dose " of second medicament decided on the drug type of use.Effective dose can change along with administering mode.
The chemical compound of general formula I adopt day dosage from about 0.1 milligram to about 100 mg/kg the weight of animals, preferably divide single dose administration or every day 2-6 time dosed administration, or continue the form of release.Concerning most of larger animals, total daily dose is about 1.0 milligrams to about 1000 milligrams, preferably about 1 milligram to about 50 milligrams.For the adult of 70kg, total daily dose generally is approximately 7 milligrams to about 350 milligrams.Can adjust this dosage regimen, so that best therapeutic response to be provided.
By following embodiment the present invention is set forth, these embodiment are intended to limit the invention by any way.
Experimental section
1. cell line and cell proliferation test
Characterize and safeguard
In tying up to the hyclone (FCS) of RPMI640 and 10%, 3-4 angel myeloma cell goes down to posterity.For IL-6 independent cell system, when cultivating beginning, add the IL-6 (Abcys France) that 2ng/ml newly thaws.Each cell line has single phenotype and HLA feature, and these might periodically check their homogeneity.
Following cell line obtains at the B.Klein laboratory: XG-1, XG-2, XG-3, XG-4, XG-6, XG-7, XG-11, XG-12, XG-13, XG-14, XG-19, XG-20 (people 1994 such as Zhang; People such as Rebouissou 1998).
RPMI8226 and L363 cell line are bought from ATCC.
Cell proliferation test
In that to be exponential growth interim (when cell concentration is approximately 5x10
5Individual cell/ml, after cultivation is gone down to posterity the 3rd day) gather the myeloma cell.Cell is cleaned twice, in the FCS of RPMI1640 and 10%, cultivated 3 hours, clean again twice.Doing like this might scavenger cell binding growth factor (especially reconstitution cell IL-6).Then according to the doubling time, cell is inserted in the flat microwell plate in 96 holes with variable concentrations:
For cell line: XG-1, XG-7, in 100 μ l, be 5x10
3Individual cells/well;
For cell line: XG-2, XG-4, XG-6, XG-11, PRMI8226, L363, in 1000 μ l, be 10
4Individual cells/well;
For cell line: XG-3, XG-12, XG-13, XG-14, XG-19, XG-20, in 100 μ l, be 2x10
4Individual cells/well.
The culture medium of using is:
XG-1, XG-2, XG-3, XG-4, XG-6, XG-7, XG-11, XG-12, XG-13, XG-19, XG-20 cell use is PRMI1640,10% FCS and the IL-6 of 0.5ng/ml;
That the XG-14 cell uses is X-VIVO20 and 0.5ng/ml IL-6;
That RPMI8226 and L363 cell use is the FCS of PRMI1640 and 10%.
When cultivating beginning, in 100 μ l, add chemical compound, DMSO or the control medium of dilution.Three culture hole are with a kind of diluent of chemical compound, and test repeats (last six culture hole with a kind of diluted chemical compound liquid) twice.
Cell culture 4 days.Before cultivate finishing 8 hours, in the FCS of the RPMI1640 of 50 μ l and 10%, add the tritiated thymidine of 0.5 μ Ci.Then use the cell harvestor collecting cell, reuse β cell counter is determined the infiltration capacity of thymidine.
(corresponding to chemical compound is 1: DMSO group 333DMSO), the toxicity of inferring of mensuration DMSO to contain the highest DMSO concentration by adding.
The stock solution of preparation ten thousand Mactra sulcatria Deshayess (3mM) and dexamethasone (10mM) in DMSO.At FCS-VELCADE of RPMI1640 and 10% (1 μ M ultimate density) and DEX (10
-6The M ultimate density)-these chemical compounds of middle dilution and be used as the positive control that the myeloma cell breeds inhibition.
2. the apoptotic detection of myeloma cell line
Annexin-V (FITC-annexin-V, BoehringerMannheim) detection apoptotic cell with fluorescein isocyanates labelling.Annexin V is higher to the affinity of the phosphine acyl serine of the outside of the cytoplasma membrane of the cell of dying at accent.Clean cell, use the FITC-annexin-V labeled cell according to manufacturer recommendation, (CA USA) analyzes for Becton Dickinson, Moutain View with Cell Quest software on the FACScan flow cytometer again.
3. the mensuration of the cell cycle of myeloma cell line
The cell cycle distribution of cell line is through measuring with the flow spectrophotometry analysis of propidium iodide (PI) and bromodeoxyribouridine (BrdU) double staining.Before cultivate finishing 30 minutes add BrdU (10 μ M) in culture fluid, then centrifugal collecting cell cleans 2 times cell in phosphate buffer saline (PBS), then at room temperature, fixes 20 minutes in 70% ethanol.Clean after twice with PBS, cell is suspended in 50 μ L3N HCl and 0.5% polysorbas20 (Tween 20) again, and in the time of 20 ℃, cultivated 20 minutes, so that the DNA degeneration.Then use centrifugal recovery cell, be suspended in again in the sodium tetraborate of 250 μ L 10mM, carry out neutralization reaction, then clean 2 times with PBS, 0.05% polysorbas20 (Tween20), and with 20 μ L resist-BrdU-FITC cultivates (BD bioscience).After twice extra cleaning, make cell be suspended in again 500 μ L PBS, contain in 0.05% the polysorbas20 of 10 μ g/ml PI.On the FACScan flow cytometer, use Cell Quest software (Becton Dickinson) that the fluorescence of FL1-H (BrdU) and FL2-A (PI) is analyzed.
4. statistical analysis
To experiment each time, draw out the relation curve of the infiltration capacity (meansigma methods that in three culture hole, records) of average tritiated thymidine to the logarithm concentration of chemical compound.The curve index of coincidence that draws returns, and it is to use the concentration (3-4 kind concentration usually) of qualification inhibitory reaction to determine.
Use these regression curves, determined myeloma cell's propagation is produced 50% and 90% inhibiting concentration.
5. medullary cell
In 10 patients that suffer from multiple myeloma (patient of 5 new diagnosis and the patient of 5 recurrences) body, take out medullary cells, and with glucosan-cardiografin (ficoll hypaque) centrifugalize mononuclear cell.
Use in contrast culture medium, the DMSO of maximum concentration and the compd A of 3 kinds of concentration in the hyclone of RPMI1640 and 5%, myelomonocyte to be cultivated 5x10
5Individual cell/ml.Three kinds of concentration of compd A (1 μ M, 3.3 μ M and 10 μ M) are mean concentrations, and the suppression ratio of three kinds of concentration in 10 myeloma cell lines are measured is 10%, 50% or 90%.
At the 5th day, the number count of pair cell, and use the painted FACS of anti--CD138 monoclonal antibody to measure myeloma cell's percentage ratio and quantity.This just might measure the myeloma cell of survival, because lose among the myeloma cell of CD138 before apoptosis (Jourdan, people such as M. (1998) Br.J.Haematol., 100,637-648).CD34 hemopoietic ancestral's percentage ratio and quantity are also measured with anti--CD34 monoclonal antibody and FACS labelling.
The chemical compound of general formula I: 1-(4-{4-[4-(4-chlorphenyl)-pyrimidine-2--amino]-benzoyl-piperazine-1-yl)-ethyl ketone (compd A) with DMSO (σ chemicals) dilution so that obtain the stock solution of 3mM.Stock solution is divided equally, and stored for future use at-80 ℃.The chemical compound that thaws is heated to 37 ℃ simply in water-bath, and to be diluted to concentration in the FCS of RPMI 160 and 10% be 10 μ M.An amount of 10 μ M solution adding is contained in myeloma cell's the culture hole, to obtain the compd A of following concentration: 10 μ M, 3.33 μ M, 1.11 μ M, 0.37 μ M, 0.12 μ M, 0.04 μ M.As shown in Figure 1, compd A has the complete inhibition effect to the propagation of 13 cells among 14 people's the myeloma cell.
Embodiment 2 compd As are to myeloma cell's apoptosis induced with to the inhibitory action in myeloma cycle
Select two to compd A: (1-(4-{4-[4-(4-chlorphenyl)-pyrimidine-2--amino]-benzoyl }-piperazine-1-yl)-ethyl ketone) responsive myeloma cell (XG-3 and XG-12) studies.Be the effect of assessing compound A, annexin V combined to determine the percentage rate of apoptotic cell with apoptotic cell myeloma cell's survival.By calculating the interim cell percentage ratio of cell cycle S that adds BrdU-FITC, the influence of assessing compound A cell cycle.In four days culture period, use the compd A of IC10, IC50 and I90 dosage to measure apoptosis, cell cycle and the cell quantity of cell line every day respectively.
As table 1 and shown in Figure 2, compd A is induced the apoptosis of myeloma cell line.Apoptosis and dosage and time correlation.As shown in table 1, compd A is also induced the minimizing of the interim cell quantity of the cell cycle S of myeloma cell line.
Table 1. was IC with concentration respectively at the 3rd day of cell culture
10, IC
50Or IC
90The XG-12 that handles of compd A or the percentage ratio of XG-3 myeloma cell line apoptotic cell, cell percentage ratio and cell quantity that S is interim.
Embodiment 3 compd As and ten thousand Mactra sulcatria Deshayess or melphalan are to myeloma cell's inhibition of proliferation
What use is to have shown to compd A: (1-(4-{4-[4-(4-chlorphenyl)-pyrimidine-2--amino]-benzoyl }-piperazine-1-yl)-ethyl ketone) the most responsive cell line (XG12 and XG3) and more insensitive cell line (XG7 and L363) studies.Determined myeloma cell line is produced 10% (IC
10) or 50% (IC
50) inhibiting concentration, its data are listed in the table 2.
Table 2. melphalan and ten thousand Mactra sulcatria Deshayess are to the inhibitory action of myeloma cell line.
Compd A and melphalan or ten thousand Mactra sulcatria Deshayess are united to be tested.The ever-increasing compd A of concentration (0,0.01,0.03,0.12,0.37,1.1,3.1,10,30 μ M) be used for individually 4 kinds of cell lines or with produce about 10% or 50% inhibiting ten thousand Mactra sulcatria Deshayess or melphalan coupling in 4 kinds of cell lines.
Table 3 and Figure 3 shows that and do not using ten thousand Mactra sulcatria Deshayess or during with ten thousand Mactra sulcatria Deshayes couplings produces the concentration of 50% or 90% inhibiting compd A to myeloma cell's propagation.When because to the concentration and the use of the inhibiting compd A of myeloma cell's proliferation-inducing 50% or 90% or do not use ten thousand Mactra sulcatria Deshayess similar, and when compd A and ten thousand Mactra sulcatria Deshayes couplings, can be observed additive effect.
Table 3. uses or when not using ten thousand Mactra sulcatria Deshayess, the inhibition effect of compd A.
(IC when the concentration fixed of continuous increase of the concentration of compd A and melphalan
10Or IC
50), also carried out similar coupling experimental study.Result of study is shown among table 4 and Fig. 4.When because to the concentration and the use of myeloma cell's proliferation-inducing 50% or 90% inhibiting compd A or do not use melphalan similar, and when compd A and melphalan coupling, can be observed additive effect.
Table 4. uses or when not using melphalan, the inhibition effect of compd A.
Embodiment 4 compd As are to constitutional myeloma cell, non-myeloma cell and CD34
+The influence of the survival of hematopoietic stem cell.
The myelomonocyte that myelomatosis multiplex philtrum from 5 new myelomatosis multiplex people that diagnose and 5 recurrences extracts was cultivated 5 days with the hyclone of culture medium and 10%.Cell is with 10
-6M dexamethasone, 1 μ M, ten thousand Mactra sulcatria Deshayess or mean concentration are IC
10, IC
50Or IC
90Compd A: (1-(4-{4-[4-(4-chlorphenyl)-pyrimidine-2--amino]-benzoyl-piperazine-1-yl)-ethyl ketone) cultivate.Cultivate when finishing the quantity of metering cell.Use is with the definite myeloma cell that can survive of the FACS of anti--CD138 labeling of monoclonal antibody, and use resists-the definite hematopoietic stem cell that can survive of CD34 monoclonal antibody.Compare with the contrast culture group of not using inhibitor, the result represents with the percentage ratio of the myeloma cell that can survive, non-myeloma cell or CD34 cell.
Shown in Fig. 5-10, compd A suppresses constitutional myeloma cell's survival, and does not influence the survival of other medullary cell, except some patients' hemopoietic precursor.
Though the present invention has been carried out detailed elaboration, it should be appreciated by those skilled in the art that outside the scope of invention that does not break away from subsidiary claims qualification, the present invention also has multiple variation in the form and details with reference to specific embodiment.
Claims (80)
1. Therapeutic Method of suffering from multiple myeloma patients, this method comprises the chemical compound shown in general formula I that gives patient's effective dose:
Or its pharmaceutically acceptable salt, in the formula:
R
1Be randomly to be independently selected from R with one to four
7Aryl that substituent group replaced or heteroaryl;
R
2Be hydrogen;
R
3Be hydrogen or low alkyl group;
R
4Be independently selected from the group of forming by following in each case: halogen, hydroxyl, low alkyl group and lower alkoxy; Wherein n is the integer of 0-4;
R
5And R
6Identical or inequality, and be independently selected from the group of forming by following group :-R
8,-(CH
2)
aC (=O) R
9,-(CH
2)
aC (=O) OR
9,-(CH
2)
aC (=O) NR
9R
10,-(CH
2)
aC (=O) NR
9(CH
2)
bC (=O) R
10,-(CH
2)
aNR
11C (=O) NR
9R
10,-(CH
2)
aNR
9R
10,-(CH
2)
aOR
9,-(CH
2)
aNR
9C (=O) R
10,-(CH
2)
aSO
cR
9And-(CH
2)
aSO
2NR
9R
10
Perhaps R
5And R
6Form the heterocycle that randomly replaces with their bonded nitrogen-atoms;
R
7Be independently selected from the group of forming by following group in each case: the alkyl heterocycle alkyl of the Heterocyclylalkyl of the alkylaryl of the aryl of halogen, hydroxyl, cyano group, nitro, carboxyl, alkyl, alkoxyl, haloalkyl, acyloxy, sulfane base alkyl, sulfinyl alkyl, sulfonyl alkyl, hydroxy alkyl, aryl, replacement, alkylaryl, replacement, Heterocyclylalkyl, replacement, alkyl heterocycle alkyl, replacement ,-C (=O) OR
8,-OC (=O) R
8,-C (=O) NR
8R
9,-C (=O) NR
8OR
9,-SO
CR
8,-SO
CNR
8R
9,-NR
8SO
CR
9-NR
8R
9,
-NR
8C (=O) R
9,-NR
8C (=O) (CH
2)
bOR
9,-NR
8C (=O) (CH
2)
bR
9,-O (CH
2)
bNR
8R
9With the Heterocyclylalkyl that is fused to phenyl;
R
8, R
9, R
10And R
11Identical or inequality, and all be independently selected from the group of forming by following group in each case: the alkyl heterocycle alkyl of the Heterocyclylalkyl of the alkylaryl of the aryl of the alkyl of hydrogen, alkyl, replacement, aryl, replacement, alkylaryl, replacement, Heterocyclylalkyl, replacement, alkyl heterocycle alkyl and replacement;
Perhaps R
8And R
9Form the heterocycle that randomly replaces with their bonded atoms;
A and b are identical or different, and all are independently selected from each case by 1,2,3 and 4 groups of forming 0; And
In each case, c is 0,1 or 2.
2. method according to claim 1 is characterized in that R
5And R
6Form the nitrogenous nonaromatic heterocycles that randomly replaces with their bonded nitrogen-atoms.
3. method according to claim 1 and 2, it is characterized in that nitrogenous nonaromatic heterocycles is selected from the group of being made up of following group: morpholinyl, thio-morpholinyl, pyrrolidone-base, pyrrolidinyl, piperidyl, homopiperidinyl, piperazinyl, high piperazinyl, hydantoin base, tetrahydro pyridyl, tetrahydro-pyrimidine base, oxazolidinyl, thiazolidinyl, indolinyl, iso-dihydro-indole-group, tetrahydric quinoline group and tetrahydro isoquinolyl.
4. according to any described method among the claim 1-3, it is characterized in that R
1Be aryl or heteroaryl.
5. according to any described method among the claim 1-4, it is characterized in that R
1Be selected from the group of forming by following group: aryl, furyl, benzofuranyl, thiophenyl, benzothienyl, quinolyl, pyrrole radicals, indyl, oxazolyl, benzoxazolyl, imidazole radicals, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidine radicals, pyrazinyl, triazine radical, cinnolines base, phthalazinyl and quinazolyl.
6. according to any described method among the claim 1-5, it is characterized in that R
1It is phenyl.
7. according to any described method among the claim 3-6, it is characterized in that nitrogenous heterocycle is a piperazinyl.
8. according to any described method among the claim 3-6, it is characterized in that nitrogenous heterocycle is a piperidyl.
9. according to any described method among the claim 3-6, it is characterized in that nitrogenous heterocycle is a morpholinyl.
10. method according to claim 1 is characterized in that, the chemical compound of described treatment multiple myeloma comprises the chemical compound shown in general formula (II) of effective dose
Or its pharmaceutically acceptable salt, in the formula:
R
1Be randomly to be independently selected from R with 1-4
7Aryl that substituent group replaced or heteroaryl;
R
5And R
6Identical or different, and be independently selected from the group of forming by following group :-R
8,-(CH
2)
aC (=O) R
9,-(CH
2)
aC (=O) OR
9,-(CH
2)
aC (=O) NR
9R
10,-(CH
2)
aC (=O) NR
9(CH
2)
bC (=O) R
10,-(CH
2)
aSO
cR
9,-(CH
2)
aNR
9C (=O) R
10,-(CH
2)
aNR
11C (=O) NR
9R
10,-(CH
2)
aNR
9R
10,-(CH
2)
aOR
9With-(CH
2)
aSO
2NR
9R
10
Perhaps R
5And R
6Form the heterocycle of heterocycle or replacement with their bonded nitrogen-atoms;
R
7Be independently selected from the group of forming by following group in each case: the alkyl heterocycle alkyl of the Heterocyclylalkyl of the alkylaryl of the aryl of halogen, hydroxyl, cyano group, nitro, carboxyl, alkyl, alkoxyl, haloalkyl, acyloxy, sulfane base alkyl, sulfinyl alkyl, sulfonyl alkyl, hydroxy alkyl, aryl, replacement, alkylaryl, replacement, Heterocyclylalkyl, replacement, alkyl heterocycle alkyl, replacement ,-C (=O) OR
8,-NR
8R
9,-OC (=O) R
8,-C (=O) NR
8R
9,-C (=O) NR
8OR
9,-SO
CR
8,-SO
CNR
8R
9,-NR
8SO
CR
9,
-NR
8C (=O) R
9,-NR
8C (=O) (CH
2)
bOR
9,-NR
8C (=O) (CH
2)
bR
9,-O (CH
2)
bNR
8R
9With the Heterocyclylalkyl that is fused to phenyl;
R
8, R
9, R
10And R
11Identical or different, and all be independently selected from the group of forming by following group in each case: the alkyl heterocycle alkyl of the Heterocyclylalkyl of the alkylaryl of the aryl of the alkyl of hydrogen, alkyl, replacement, aryl, replacement, alkylaryl, replacement, Heterocyclylalkyl, replacement, alkyl heterocycle alkyl and replacement;
Perhaps R
8And R
9Form the heterocycle that randomly replaces with their bonded atoms;
A and b are identical or different, and all are independently selected from each case by 1,2,3 and 4 groups of forming 0; And
C is 0,1 or 2 in each case.
11. method according to claim 10 is characterized in that, R
5And R
6Form the nitrogenous nonaromatic heterocycles that randomly replaces with their bonded nitrogen-atoms.
12. according to claim 10 or 11 described methods, it is characterized in that nitrogenous nonaromatic heterocycles is selected from the group of being made up of following group: morpholinyl, thio-morpholinyl, pyrrolidone-base, pyrrolidinyl, piperidyl, homopiperidinyl, piperazinyl, high piperazinyl, hydantoin base, tetrahydro pyridyl, tetrahydro-pyrimidine base, oxazolidinyl, thiazolidinyl, indolinyl, iso-dihydro-indole-group, tetrahydric quinoline group and tetrahydro isoquinolyl.
13., it is characterized in that R according to any described method among the claim 10-12
1Be aryl or heteroaryl.
14., it is characterized in that R according to any described method among the claim 10-13
1Be selected from the group of forming by following group: aryl, furyl, benzofuranyl, thiophenyl, benzothienyl, quinolyl, pyrrole radicals, indyl, oxazolyl, benzoxazolyl, imidazole radicals, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidine radicals, pyrazinyl, triazine radical, cinnolines base, phthalazinyl and quinazolyl.
15., it is characterized in that R according to any described method among the claim 10-14
1It is phenyl.
16., it is characterized in that nitrogenous heterocycle is a piperazinyl according to any described method among the claim 11-15.
17., it is characterized in that nitrogenous heterocycle is a piperidyl according to any described method among the claim 11-15.
18., it is characterized in that nitrogenous heterocycle is a morpholinyl according to any described method among the claim 11-15.
19., it is characterized in that described is chemical compound shown in general formula (III) to treatment multiple myeloma compounds effective according to any described method among the claim 10-18:
20., it is characterized in that described is chemical compound shown in general formula (IV) to treatment multiple myeloma compounds effective according to any described method among the claim 10-18:
21. the patient treatment method of a multiple myeloma of suffering from, this method comprise the compd A that gives patient's effective dose: 1-(4-{4-[4-(4-chloro-phenyl)-pyrimidine-2--amino]-benzoyl-piperazine-1-yl)-ethyl ketone, its structural formula is as follows:
Perhaps its pharmaceutically acceptable salt.
22., it is characterized in that described multiple myeloma is an I phase multiple myeloma according to claim 1 or 21 described methods.
23., it is characterized in that described multiple myeloma is an II phase multiple myeloma according to claim 1 or 21 described methods.
24., it is characterized in that described multiple myeloma is an III phase multiple myeloma according to claim 1 or 21 described methods.
25., it is characterized in that described multiple myeloma is asymptomatic multiple myeloma according to claim 1 or 21 described methods.
26. method according to claim 25 is characterized in that, described asymptomatic multiple myeloma is a SMM.
27. method according to claim 25 is characterized in that, described asymptomatic myeloma is painless property multiple myeloma.
28., it is characterized in that described multiple myeloma is Symptomatic myeloma according to claim 1 or 21 described methods.
29., it is characterized in that described multiple myeloma is the multiple myeloma of new diagnosis according to claim 1 or 21 described methods.
30., it is characterized in that the reactive multiple myeloma of described multiple myeloma according to claim 1 or 21 described methods.
31., it is characterized in that described multiple myeloma is stable multiple myeloma according to claim 1 or 21 described methods.
32., it is characterized in that described multiple myeloma is carrying out a property multiple myeloma according to claim 1 or 21 described methods.
33., it is characterized in that described multiple myeloma is the multiple myeloma of recurrence according to claim 1 or 21 described methods.
34., it is characterized in that described multiple myeloma is the intractable multiple myeloma according to claim 1 or 21 described methods.
35. according to claim 1 or 21 described methods, it is characterized in that, described method further comprises at least a therapeutic agent that gives patient's effective dose, and this therapeutic agent is selected from the group of being made up of following: bortezomib (ten thousand Mactra sulcatria Deshayess), melphalan, prednisone, vincristine, Ka Mositing, cyclophosphamide, dexamethasone, Thalidomide, amycin, cisplatin, etoposide and cytosine arabinoside.
36. method according to claim 35 is characterized in that, described therapeutic agent is ten thousand Mactra sulcatria Deshayess.
37. method according to claim 35 is characterized in that, described therapeutic agent is a melphalan.
38., it is characterized in that the patient is just accepting radiotherapy according to claim 1 or 21 described methods.
39., it is characterized in that the patient prepares to carry out stem cell transplantation according to claim 1 or 21 described methods.
40., it is characterized in that the patient is just accepting stem cell transplantation according to claim 1 or 21 described methods.
41. a pharmaceutical composition for the treatment of the multiple myeloma that the patient suffers from, it comprises the chemical compound shown in general formula I:
Perhaps its pharmaceutically acceptable salt, in the formula:
R
1Be randomly to be independently selected from R with one to four
7Aryl that substituent group replaced or heteroaryl;
R
2Be hydrogen;
R
3Be hydrogen or low alkyl group;
R
4Be independently selected from the group of forming by following in each case: halogen, hydroxyl, low alkyl group and lower alkoxy; Wherein n is the integer of 0-4;
R
5And R
6Identical or inequality, and be independently selected from the group of forming by following group :-R
8,-(CH
2)
aC (=O) R
9,-(CH
2)
aC (=O) OR
9,-(CH
2)
aC (=O) NR
9R
10,-(CH
2)
aC (=O) NR
9(CH
2)
bC (=O) R
10,-(CH
2)
aNR
11C (=O) NR
9R
10,-(CH
2)
aNR
9R
10,-(CH
2)
aOR
9,-(CH
2)
aNR
9C (=O) R
10,-(CH
2)
aSO
cR
9And-(CH
2)
aSO
2NR
9R
10
Perhaps R
5And R
6Form the heterocycle that is randomly replaced with their bonded nitrogen-atoms;
R
7Be independently selected from the group of forming by following group in each case: the alkyl heterocycle alkyl of the Heterocyclylalkyl of the alkylaryl of the aryl of halogen, hydroxyl, cyano group, nitro, carboxyl, alkyl, alkoxyl, haloalkyl, acyloxy, sulfane base alkyl, sulfinyl alkyl, sulfonyl alkyl, hydroxy alkyl, aryl, replacement, alkylaryl, replacement, Heterocyclylalkyl, replacement, alkyl heterocycle alkyl, replacement ,-C (=O) OR
8,-OC (=O) R
8,-C (=O) NR
8R
9,-C (=O) NR
8OR
9,-SO
CR
8,-SO
CNR
8R
9,-NR
8SO
CR
9-NR
8R
9,-NR
8C (=O) R
9,-NR
8C (=O) (CH
2)
bOR
9,-NR
8C (=O) (CH
2)
bR
9,-O (CH
2)
bNR
8R
9With the Heterocyclylalkyl that is fused to phenyl;
R
8, R
9, R
10And R
11Identical or inequality, and all be independently selected from the group of forming by following group in each case: the alkyl heterocycle alkyl of the Heterocyclylalkyl of the alkylaryl of the aryl of the alkyl of hydrogen, alkyl, replacement, aryl, replacement, alkylaryl, replacement, Heterocyclylalkyl, replacement, alkyl heterocycle alkyl and replacement;
Perhaps R
8And R
9Form the heterocycle that randomly replaces with their bonded atoms;
A and b are identical or different, and all are independently selected from each case by 1,2,3 and 4 groups of forming 0; And
In each case, c is 0,1 or 2.
42., it is characterized in that R according to the described pharmaceutical composition of claim 41
5And R
6Form the nitrogenous aromatic heterocycle that randomly replaces with their bonded nitrogen-atoms.
43. according to claim 41 or 42 described pharmaceutical compositions, it is characterized in that nitrogenous nonaromatic heterocycles is selected from the group of being made up of following group: morpholinyl, thio-morpholinyl, pyrrolidone-base, pyrrolidinyl, piperidyl, homopiperidinyl, piperazinyl, high piperazinyl, hydantoin base, tetrahydro pyridyl, tetrahydro-pyrimidine base, oxazolidinyl, thiazolidinyl, indolinyl, iso-dihydro-indole-group, tetrahydric quinoline group and tetrahydro isoquinolyl.
44., it is characterized in that R1 is aryl or heteroaryl according to any described pharmaceutical composition among the claim 41-43.
45. according to any described pharmaceutical composition among the claim 41-44, it is characterized in that R1 is selected from the group of being made up of following group: aryl, furyl, benzofuranyl, thiophenyl, benzothienyl, quinolyl, pyrrole radicals, indyl, oxazolyl, benzoxazolyl, imidazole radicals, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidine radicals, pyrazinyl, triazine radical, cinnolines base, phthalazinyl and quinazolyl.
46., it is characterized in that R according to any described pharmaceutical composition among the claim 41-45
1It is phenyl.
47., it is characterized in that nitrogenous heterocycle is a piperazinyl according to any described pharmaceutical composition among the claim 43-46.
48., it is characterized in that nitrogenous heterocycle is a piperidyl according to any described pharmaceutical composition among the claim 43-46.
49., it is characterized in that nitrogenous heterocycle is a morpholinyl according to any described pharmaceutical composition among the claim 43-46.
50., it is characterized in that the described chemical compound that is used for the treatment of multiple myeloma comprises the chemical compound shown in general formula (II) of effective dose according to the described pharmaceutical composition of claim 41:
Perhaps its pharmaceutically acceptable salt, in the formula:
R
1Be randomly to be independently selected from R with 1-4
7The substituent group aryl or the heteroaryl that replace;
R
5And R
6Identical or different, and be independently selected from the group of forming by following group :-R
8,-(CH
2)
aC (=O) R
9,-(CH
2)
aC (=O) OR
9,-(CH
2)
aC (=O) NR
9R
10,-(CH
2)
aC (=O) NR
9(CH
2)
bC (=O) R
10,-(CH
2)
aSO
cR
9,-(CH
2)
aNR
9C (=O) R
10,-(CH
2)
aNR
11C (=O) NR
9R
10,-(CH
2)
aNR
9R
10, (CH
2)
aOR
9With-(CH
2)
aSO
2NR
9R
10
Perhaps R
5And R
6Form the heterocycle of heterocycle or replacement with their bonded nitrogen-atoms;
R
7Be independently selected from the group of forming by following group in each case: the alkyl heterocycle alkyl of the Heterocyclylalkyl of the alkylaryl of the aryl of halogen, hydroxyl, cyano group, nitro, carboxyl, alkyl, alkoxyl, haloalkyl, acyloxy, sulfane base alkyl, sulfinyl alkyl, sulfonyl alkyl, hydroxy alkyl, aryl, replacement, alkylaryl, replacement, Heterocyclylalkyl, replacement, alkyl heterocycle alkyl, replacement ,-C (=O) OR
8,-NR
8R
9,-OC (=O) R
8,-C (=O) NR
8R
9,-C (=O) NR
8OR
9,-SO
CR
8,-SO
CNR
8R
9,-NR
8SO
CR
9,-NR
8C (=O) R
9,-NR
8C (=O) (CH
2)
bOR
9,-NR
8C (=O) (CH
2)
bR
9,-O (CH
2)
bNR
8R
9With the Heterocyclylalkyl that is fused to phenyl;
R
8, R
9, R
10And R
11Identical or inequality, and be independently selected from the group of forming by following group in each case: the alkyl heterocycle alkyl of the Heterocyclylalkyl of the alkylaryl of the aryl of the alkyl of hydrogen, alkyl, replacement, aryl, replacement, alkylaryl, replacement, Heterocyclylalkyl, replacement, alkyl heterocycle alkyl and replacement;
Perhaps R
8And R
9Form the heterocycle that randomly replaces with their bonded atoms;
A and b are identical or different, and are independently selected from each case by 1,2,3 and 4 groups of forming 0; And
In each case, c is 0,1 or 2.
51., it is characterized in that R according to the described pharmaceutical composition of claim 50
5And R
6Form the nitrogenous nonaromatic heterocycles that at random replaces with their bonded nitrogen-atoms.
52. according to claim 50 or 51 described pharmaceutical compositions, it is characterized in that described nitrogenous nonaromatic heterocycles is selected from the group of being made up of following group: morpholinyl, thio-morpholinyl, pyrrolidone-base, pyrrolidinyl, piperidyl, homopiperidinyl, piperazinyl, high piperazinyl, hydantoin base, tetrahydro pyridyl, tetrahydro-pyrimidine base, oxazolidinyl, thiazolidinyl, indolinyl, iso-dihydro-indole-group, tetrahydric quinoline group and tetrahydro isoquinolyl.
53., it is characterized in that R according to any described pharmaceutical composition among the claim 50-52
1Be aryl or heteroaryl.
54., it is characterized in that R according to any described pharmaceutical composition among the claim 50-53
1Be selected from the group of forming by following group: aryl, furyl, benzofuranyl, thiophenyl, benzothienyl, quinolyl, pyrrole radicals, indyl, oxazolyl, benzoxazolyl, imidazole radicals, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidine radicals, pyrazinyl, triazine radical, cinnolines base, phthalazinyl and quinazolyl.
55., it is characterized in that R according to any described pharmaceutical composition among the claim 50-54
1It is phenyl.
56., it is characterized in that nitrogenous heterocycle is a piperazinyl according to any described pharmaceutical composition among the claim 51-55.
57., it is characterized in that nitrogenous heterocycle is a piperidyl according to any described pharmaceutical composition among the claim 51-55.
58., it is characterized in that nitrogenous heterocycle is a morpholinyl according to any described pharmaceutical composition among the claim 51-55.
59., it is characterized in that described is chemical compound shown in general formula (III) to treatment multiple myeloma compounds effective according to any described pharmaceutical composition among the claim 50-58:
60., it is characterized in that described is chemical compound shown in general formula (IV) to treatment multiple myeloma compounds effective according to any described pharmaceutical composition among the claim 50-58:
61. a pharmaceutical composition for the treatment of the multiple myeloma that the patient suffers from, comprise the compd A shown in following structural formula that gives patient's effective dose: 1-(4-{4-[4-(4-chloro-phenyl)-pyrimidine-2--amino]-benzoyl-piperazine-1-yl)-ethyl ketone:
Or its pharmaceutically acceptable salt.
62., it is characterized in that described multiple myeloma is an I phase multiple myeloma according to claim 41 or 61 described pharmaceutical compositions.
63., it is characterized in that described multiple myeloma is an II phase multiple myeloma according to claim 41 or 61 described pharmaceutical compositions.
64., it is characterized in that described multiple myeloma is an III phase multiple myeloma according to claim 41 or 61 described pharmaceutical compositions.
65., it is characterized in that described multiple myeloma is asymptomatic multiple myeloma according to claim 41 or 61 described pharmaceutical compositions.
66., it is characterized in that described smoldering multiple myeloma is a SMM according to the described pharmaceutical composition of claim 65.
67., it is characterized in that described smoldering multiple myeloma is painless property multiple myeloma according to the described pharmaceutical composition of claim 65.
68., it is characterized in that described multiple myeloma is Symptomatic myeloma according to claim 41 or 61 described pharmaceutical compositions.
69., it is characterized in that described multiple myeloma is the multiple myeloma of new diagnosis according to claim 41 or 61 described pharmaceutical compositions.
70., it is characterized in that described multiple myeloma is reactive multiple myeloma according to claim 41 or 61 described pharmaceutical compositions.
71., it is characterized in that described multiple myeloma is stable multiple myeloma according to claim 41 or 61 described pharmaceutical compositions.
72., it is characterized in that described multiple myeloma is carrying out a property multiple myeloma according to claim 41 or 61 described pharmaceutical compositions.
73., it is characterized in that described multiple myeloma is the multiple myeloma of recurrence according to claim 41 or 61 described pharmaceutical compositions.
74., it is characterized in that described multiple myeloma is the intractable multiple myeloma according to claim 41 or 61 described pharmaceutical compositions.
75. according to claim 41 or 61 described pharmaceutical compositions, it is characterized in that, further comprise at least a therapeutic agent that gives patient's effective dose, this therapeutic agent is selected from the group of being made up of following: bortezomib (ten thousand Mactra sulcatria Deshayess), melphalan, prednisone, vincristine, Ka Mositing, cyclophosphamide, dexamethasone, Thalidomide, amycin, cisplatin, etoposide and cytosine arabinoside.
76., it is characterized in that described therapeutic agent is ten thousand Mactra sulcatria Deshayess as the described compositions of claim 75.
77., it is characterized in that described therapeutic agent is a melphalan as the described compositions of claim 75.
78., it is characterized in that this patient is just accepting radiotherapy as claim 41 or 61 described compositionss.
79., it is characterized in that this patient prepares to carry out stem cell transplantation as claim 41 or 61 described compositionss.
80., it is characterized in that this patient is accepting stem cell transplantation as claim 41 or 61 described compositionss.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US86112006P | 2006-11-27 | 2006-11-27 | |
| US60/861,120 | 2006-11-27 | ||
| US60/904,138 | 2007-02-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101568342A true CN101568342A (en) | 2009-10-28 |
Family
ID=41284118
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007800478308A Pending CN101568342A (en) | 2006-11-27 | 2007-11-27 | Treatment for multiple myeloma |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101568342A (en) |
| ZA (1) | ZA200903242B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103709172A (en) * | 2012-09-28 | 2014-04-09 | 江苏先声药物研究有限公司 | Substituted furan-piperidine derivative and application thereof |
| CN110891608A (en) * | 2017-07-26 | 2020-03-17 | 豪夫迈·罗氏有限公司 | Combination therapy with BET inhibitors and Bcl-2 inhibitors |
-
2007
- 2007-11-27 CN CNA2007800478308A patent/CN101568342A/en active Pending
- 2007-11-27 ZA ZA200903242A patent/ZA200903242B/en unknown
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103709172A (en) * | 2012-09-28 | 2014-04-09 | 江苏先声药物研究有限公司 | Substituted furan-piperidine derivative and application thereof |
| CN103709172B (en) * | 2012-09-28 | 2018-02-13 | 江苏先声药业有限公司 | Substituted furan and piperidine derivative and its application |
| CN110891608A (en) * | 2017-07-26 | 2020-03-17 | 豪夫迈·罗氏有限公司 | Combination therapy with BET inhibitors and Bcl-2 inhibitors |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200903242B (en) | 2010-08-25 |
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