CN1738616A - Combination therapies for the treatment of cancer - Google Patents

Combination therapies for the treatment of cancer Download PDF

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CN1738616A
CN1738616A CN 200480002263 CN200480002263A CN1738616A CN 1738616 A CN1738616 A CN 1738616A CN 200480002263 CN200480002263 CN 200480002263 CN 200480002263 A CN200480002263 A CN 200480002263A CN 1738616 A CN1738616 A CN 1738616A
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lonidamine
treatment
bph
described method
analog
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G·提马思
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Molecular Templates Inc
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Threshold Pharmaceuticals Inc
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Abstract

A method for treatment or prophylaxis of benign prostatic hyperplasia by administration of lonidarrine or a lonidamine analog is provided. Also provided are unit dosage forms of lonidamine or an analog, useful for such treatment and prophylaxis.

Description

The treatment of benign prostatic hyperplasia
The cross reference of related application
[0001] the application requires the rights and interests of following U.S. Provisional Application: U.S. Provisional Application 60/496, No. 163 (proposition on August 18th, 2003), 60/488, No. 265 (proposition on July 18th, 2003), 60/472, No. 907 (proposition on May 22nd, 2003), 60/460, No. 012 (proposition on April 2nd, 2003), 60/458, No. 846 (proposition on March 28th, 2003), 60/458, No. 665 (proposition on March 28th, 2003), 60/458, No. 663 (proposition on March 28th, 2003), 60/442, No. 344 (proposition on January 23rd, 2003), with 60/441, No. 110 (proposition on January 17th, 2003), each application is incorporated at this with its full content, as a reference, be used for all propositions.
Technical field
[0002] the present invention relates to treatment and the prevention of benign prostatic hyperplasia (benign prostatic hyperplasia), be applied to medical domain and association area, comprise chemical field, medicinal chemistry field and biology field.
Background technology
[0003] benign prostatic hyperplasia (benign prostatic hyperplasia (BPH)), a kind of prostate epithelial cell misgrowth and the disease of blocking urine stream, torment the U.S. and surpassing 1,000 ten thousand adult male and other geographic other millions of adult males of going up all over the world.Up to recent relatively, surgical intervention (surgical intervention) is unique Therapeutic Method of this disease, and even in today, operation is the treatment of last resort; When other treatment is not effectively, when perhaps ceasing to have effect, almost invariably depend on operation.Operation on prostate and its recovery are painful, and operation itself may not be effectively, and have constituted the risk that produces serious side effects.To summary in the near future, referring to Barry, 2001 (complete quoting is provided at hereinafter).
[0004] present, only two class medicines are the treatments that can be applied to the BPH symptom.One class medicine comprises the chemical compound of the generation of the activity form (dihydrotestosterone or DHT) that suppresses testosterone.The medicine of using this apoplexy due to endogenous wind can cause the forfeiture of male's sexual anesthesia and muscle masses forfeiture and tone, and increases relevant with the incidence rate of height carcinoma of prostate (high grade prostate cancer).In addition, this therapy is subject to the obviously very long delay (several months) between the reduction of prostate size that gives this medicine and patient first.Be used to the second class medicine of BPH at present, promptly alpha antiadrenergic agent works by relaxing smooth muscle, thereby allows urine to pass through urethra more unobstructedly.Though this type of medicine is than first kind medicine mitigation symptoms more promptly, it does not reduce prostatic size, prevents that perhaps prostate from becoming bigger, and this can cause final surgical intervention.
[0005] therefore, exist the medicine that the underlying diseases state that can treat BPH do not had serious adverse significantly, unsatisfied demand.The present invention has satisfied this demand.
Summary of the invention
[0006] the invention provides method and composition, be used for treating BPH, implement by the analog that gives lonidamine (lonidamine) or a kind of lonidamine to this object in human subjects.Also provide the useful pharmaceutical composition of BPH treatment, comprised slow releasing preparation (sustainedrelease formulations).In one embodiment, said preparation is that per os is given, and allows the mode of taking once a day of the treatment effective dose of this chemical compound.
The accompanying drawing summary
[0007] Fig. 1 shown lonidamine (I, R=Cl), tolnidamine (tolnidamine) (I, R=CH 3), the structure of AF-2364 (II) and AF-2785 (III).
[0008] Fig. 2 has shown under normal oxygen and anoxybiotic situation and lonidamine when existing and not existing, the expression of the HIF-1 α in the LNCaP cell.Fig. 2 A has shown the analysis result that adopts the nucleus extract to carry out.Fig. 2 B and 2C have shown the analysis result that adopts full cell extract.[0009] Fig. 3 has shown under normal oxygen and anoxybiotic situation and lonidamine when existing and not existing, the expression of the HIF-1 α in the PC-3 cell.Fig. 3 A has shown the analysis of application cell nuclear extract.Fig. 3 B and 3C have shown the analysis of using full cell extract.
[00010] Fig. 4 has shown in LNCaP cell (Fig. 4 A) and PC-3 cell (Fig. 4 B), the inductive apoptosis of lonidamine (or programmed cell death, apoptosis).
[00011] Fig. 5 has shown in prostate epithelial cell, the inductive apoptosis of lonidamine.
[00012] Fig. 6 has shown in prostate epithelial cell among (Fig. 6 A) and prostate stromal cell (Fig. 6 B), the inductive apoptosis of lonidamine.
[00013] Fig. 7 has shown the influence of the lonidamine of 0-600 μ M to HIE-1 α and other protein expression, measures with the full cell extract that gets the LNCaP cell of cultivating under the comfortable anaerobic environment.
[00014] Fig. 8 has shown the influence of the lonidamine of 0-600 μ M to HIF-1 α and other protein expression, measures with the nucleus extract that gets the LNCaP cell of cultivating under the comfortable anaerobic environment.
Detailed Description Of The Invention
1. definition
[00015] provides following definition, to help the reader.If there is not other to limit, in all technical terms, symbol and other science or the medical terminology or the proper noun of this application, intention have chemistry and medical domain the technical staff the general implication of understanding.In some cases, term with implication of generally being understood, be defined at this, be used for distinct and/or be used to make things convenient for reference, and the content that this definition comprised herein, should necessarily not be interpreted as, the definition of this term of generally being understood in the field is compared therewith, has represented a kind of substantial difference.
[00016] as being employed at this, " treatment " a kind of state or a patient (" treating " acondition or patient) are meant, take steps to comprise clinical effectiveness to obtain result useful or that wish.For purpose of the present invention, clinical effectiveness useful or that wish comprises, but be not limited to, the alleviation of one or more symptom of BPH or improvement, alleviating of disease degree, the delay of disease process or slow down, the improvement of morbid state, mitigation or other useful result stable and that be described below.
[00017] as being employed at this, " alleviating " of a symptom or a plurality of symptoms (" reduction " of a symptom or symptoms) (with the phraseological equal composition of this phrase) means, the order of severity of this symptom (a plurality of symptom) or the reduction of occurrence frequency, the perhaps elimination of this symptom (a plurality of symptom).
[00018] as being employed at this, " give " " giving " (" administering " or " administration of " a drug to a subject) (with the phraseological equal composition of this phrase) of medicine or medicine to object, both comprised directly and having given, comprise from giving, comprise indirectly again giving, comprise the behavior of writing a prescription.For example, as being employed at this, the doctor indicates the patient from giving medicine and/or offering patient's drug prescription, is to give medicine to this patient.
[00019] as being employed at this, symptom, sign, anatomic status that " performance (manifestation) " of BPH is meant the object of suffering from BPH are (for example, prostatic size), physiological status (for example, PSA level) or report (for example, AUASI scoring) feature.
[00020] as being employed at this, " the treatment effective dose " of medicine (a " therapeutically effectiveamount " of a drug) is meant the amount of medicine, when with this when the experimenter who suffers from BPH gives, the therapeutic effect that will have intention, for example, in this experimenter, the alleviation of one of BPH performance or a plurality of performances, improve, alleviate or eliminate.By giving of a dosage, whole therapeutic effect not necessarily take place, and whole therapeutic effect can only take place after a series of dosage give.Therefore, the treatment effective dose can be through once or multiple dosing behavior and being given.
[00021] as being employed at this, " the prevention effective dose " of medicine (a " prophylacticallyeffective amount " of a drug) is meant the amount of medicine, when with this when the experimenter gives, the preventive effect that will have intention, for example, prevent or postpone the generation (perhaps taking place again) of disease or symptom, perhaps reduce the probability that (perhaps taking place) takes place again for disease or symptom.By giving of a dosage, whole preventive effects not necessarily take place, and whole preventive effects can occur over just after a series of dosage give.Therefore, the prevention effective dose can through once or multiple dosing be given.
[00022] as being employed at this, " TID " and " QD " has its common meaning, is respectively " every day three times (three timese a day) " and " (once daily) once a day ".
[00023] as being employed at this, " alkyl (alkyl) " be meant monovalent, by the deutero-base of alkane (Hydrocarbon), contain from 1 to 15 carbon atom.It can be straight chain, side chain or cyclic, can be unsubstituted or is substituted group and replaces, and substituted radical includes but not limited to hydroxyl, halogenide, alkoxyl and nitrile.The alkoxy base that can be employed includes but not limited to methoxyl group.The alkyl group of illustrative straight chain or side chain comprises methyl, ethyl, propyl group, isopropyl, butyl and the tert-butyl group (t-butyl).
[00024] as being employed at this, " aryl (aryl) " is meant the monocycle aroma system that contains one or more or the part of fused rings aroma system.Such part comprises any part of the monocycle aroma system that contains one or more or the fragrant system of bicyclic condensed cyclophane, includes, but are not limited to phenyl and naphthyl.Aromatic yl group can be unsubstituted, or replaces with substituted radical, as being replaced at the listed substituted radical of specific substituted aryl.
[00025] as being employed at this, " heteroaryl (heteroaryl) " is meant the monocyclic aromatic group with 5 or 6 annular atomses, perhaps has 8 fused rings Bicyclic groups to 10 atoms, and therein, annular atoms is C, O, S, SO, SO 2Perhaps N, and in the annular atoms at least one be hetero atom, i.e. O, S, SO, SO 2Perhaps N.Heteroaryl groups can be unsubstituted, perhaps for the heteroaryl of special replacement, by as listed substituted radical replace.The example of monocyclic aromatic series heteroaryl groups includes but not limited to pyridine radicals.The example of the heteroaryl groups of bicyclic condensed ring includes but not limited to indyl, pyrrolo-pyrimidine radicals (pyrrolopyrymidinyl), indolizine base, pyrazoline pyridine radicals, tripyrrole quinoline pyridine radicals, pyrazoline pyrimidine radicals, tripyrrole quinoline pyrimidine radicals, pyrrolo-triazine base, pyrazoline triazine radical, tripyrrole quinoline triazine radical, pyrazoline tetrazine base, six indyls and seven indyls.As do not have other explanation, and the arrangement of hetero atom in ring can be any arrangement, its bonding performance by the makeup ring atom allows.
[00026] as being employed at this, term " Heterocyclylalkyl (heterocycloalkyl) " and " heterocyclic radical (heterocyclyl) " are meant monocyclic cycloalkyl group or fused rings polycyclic naphthene base group, at least a portion wherein is not aromatic, and therein, in ring system, one or more of carbon atom is selected from O, S, SO, SO 2Perhaps the hetero atom of N substitutes.The example of heterocyclic radical group includes but not limited to that piperidyl, morpholinyl, pyrrolidinyl, tetrahydrofuran base, imidazolidine be [4,5-c] pyridine radicals, imidazolinyl, piperazinyl, pyrrolidin-2-one base also, and piperidines-2-ketone group.
[00027] as being employed at this, " cycloalkyl (cycloalkyl) " is meant monocyclic groups or the multi-ring group of fused rings, and its at least a portion is not aromatic; And therein, annular atoms is a carbon.
[00028] is meant monocyclic groups or the multi-ring group of fused rings as be employed " heterocycloalkenyl (heterocycloalkenyl) " at this, wherein one or more in the carboatomic ring atom substituted by hetero atom, loop systems is not aromatic at least in part, and loop systems contains at least one carbon-to-carbon double bond.
2. the effect of benign prostatic hyperplasia and lonidamine and lonidamine analog
[00029] the invention provides compositions useful in the treatment of benign prostatic hyperplasia (BPH) and method.Particularly, the present invention relates to the application of lonidamine (lonidamine (LND)), be used for treatment or the prevention of BPH.In addition, the present invention relates to the application of lonidamine analog, be used for treatment or the prevention of BPH.In order to help to understand the present invention, the short discussion to the character of BPH (being also referred to as benign prostatic hyperplasia) and lonidamine and bioactive analogue thereof is provided as follows.
[00030] BPH relates to the undue growth (hypertrophy) of the cell in the prostate, causes prostatic increase, and causes urethral symptom and disease down.Prostate contains secretory epithelial cells, be arranged in the substrate (more detailed description of dissecting for prostate, referring to Barry, 2003) of connective tissue and smooth muscle, and BPH relates to the hypertrophy of epithelial components.In normal prostate, the epithelial components of secreted is significant, and reason is, compares with other normal structure, and the level of the zinc in this tissue is very high.A consequence of high zinc level is, by relating to m-aconitase (mitochondrion-aconitase, m-aconitase) zinc suppresses mechanism, in secretory epithelium, energy generation via tricarboxylic acid cycle (TCA) and oxidative phosphorylation is reduced significantly, cause this tissue to be compared with tissue, rely on glycolysis more as energy source with other organ.A key enzyme in the TCA circulation, the zinc inhibitory action of m-aconitase causes the substantial at least reduction of TCA circulation in the prostate epithelial cell, and perhaps one is close to blocking-up completely.Inhibiting another physiology consequence based on zinc of m-aconitase is to make citric acid depart from TCA circulation, and this makes prostate can secrete a large amount of citric acids to go in the seminal fluid, and citric acid is used as energy source by sperm.Referring to, usually, Costello, 1999; Costello et al., 2000; Costello and Franklin, 2000.[00031] do not reach the zinc that suppresses the metabolic level of citric acid because intravital other normal cell does not accumulate, prostate epithelial cell is to depend on glycolysis (anaerobic metabolism) uniquely.The present invention partly relates to the sensitivity of these cells of discovery to the medicine lonidamine, and this allows to give lonidamine, and is as the described herein, so that treat in the mankind or prevention BPH.Lonidamine is 1-(2, the 4-Dichlorobenzene base)-1H-indole-3-carboxylic acid's common name, and in medical literature, also be called as 1-[(2,4-Dichlorobenzene base) methyl]-the 1H-indole-3-carboxylic acid, AF1890, diclondazolic acid (DICA) and Doridamina TMReferring to Fig. 1.Lonidamine at first is confirmed as anti-spermatogenesis agent (antispermatogenic agent), and subsequently in several countries in Europe, is used to treat breast carcinoma, cervical cancer, pulmonary carcinoma and carcinoma of prostate.Referring to Silvestrini, 1981; Gatto et al., 2002.The mechanism of action of lonidamine in anti-spermatogenesis and cancer may do not understood fully.Yet, it was suggested, the anticancer character of lonidamine part at least is because the disintegrate of the mitochondrial membrane of lonidamine mediation causes the bonded hexokinase activity of mitochondrion to reduce, and disturbs the ATP that is undertaken by glycolytic pathway and oxidative phosphorylation approach to produce.Referring to, Floridi et al., 1981, Fanciulli et al., 1996 and be numbered the list of references of 15-22 herein; And Gatto, 2002.Also referring to Kaplan, 2000.Effect for lonidamine in the benign prostatic hyperplasia, be not intended to be subject to special mechanism, it is believed that lonidamine suppresses the glycolysis in the prostate epithelial cell and/or damages the mitochondrial function that had reduced already, thereby, with respect to intravital other normal cell, make these cell generation energy hunger.Be not intended to be subject to special mechanism, think, because the shortage of energy, enough hypertrophy epithelial cells are destroyed, perhaps otherwise since the cell size be reduced so that reduced prostatic size, thereby alleviated disease shape and its clinical consequences.
[00032] therefore, to being diagnosed as BPH or having shown that the human patients of BPH symptom gives lonidamine, following benefit is provided, as the order of severity of one or more symptom or the minimizing of occurrence frequency, prostatic size or the minimizing that increases speed, other performance of the raising of perceptible quality of life and BPH is to the more transformation of normal condition.Further, give lonidamine, following benefit is provided,, the appearance of BPH, occur or the reduction of the probability of progress again as in the experimenter to the human experimenter of needs preventions BPH.Further, giving the analog of lonidamine to the human experimenter, for treatment and the prevention of BPH, also is similarly effective.In another embodiment, give lonidamine or its analog to the human experimenter, as described here, can be effective in the treatment of acute urinary retention.These aspects of the present invention and others are described below in more detail.The 3rd following joint has been described some lonidamine analog, is used for treatment and the prevention of BPH.The 4th joint relates to the synthetic and form of lonidamine and analog thereof.The 5th joint has been described patient group, to this patient group, lonidamine and lonidamine analog benefit is provided.The 6th joint has been described the method that lonidamine gives (dosage of for example, using, approach, dosage regimen and persistent period).The 7th the joint conjoint therapy has been described, therein, lonidamine or a kind of analog with another kind of medicine or therapy use in conjunction.The 8th joint has been described exemplary dosage form.The 9th joint provides the application of lonidamine and the embodiment of effect.Only be purpose for convenience, following description is organized by trifle; In the trifle of any one establishment, being seen disclosure is applicable to any one aspect of the present invention.
3. lonidamine analog
[00033] as putting down in writing in the above, except lonidamine, the various chemical compound relevant with lonidamine for treatment and the prevention of BPH, is useful.Useful chemical compound is normally structurally similar to lonidamine, or the bioisoster of lonidamine (bioisosteres), or the pharmacophoric group of lonidamine (pharmacophores), as described below, and have the biological activity similar, also as discussing below to the biological activity of lonidamine.This compounds can be called as " bioactive lonidamine analog (bioactive lonidamine analogs) ", " lonidamine analog (lonidamineanalogs) ", perhaps, in some cases, be called as " analog (analogs) " simply.
[00034] The architectural characteristic of lonidamine analog.Partly, based on lonidamine and known structure with related compound of the pharmaceutical active similar to the pharmaceutical active of lonidamine, certain lonidamine analog, comprise by novel analogue provided by the present invention, be fit to be applied in the treatment (treatment) or prevention (prophalaxis) of BPH, describe by following formula
Figure A20048000226300141
R wherein 1, R 2, X, Y, n and
Figure A20048000226300142
Be defined as follows:
[00035] R 1Representative-COOH, perhaps-derivant or the bioisoster of COOH group.R 1Usually be selected from the acidic-group of formula-COOH; Formula-CONR 3R 4Amide, R wherein 3And R 4Can be alkyl or hydrogen independently, be preferably hydrogen; Formula-CONHNR 6R 7Hydrazides, R wherein 6And R 7Normally-H or-CH 3Formula-COOR 5The replacement ester, R 5Be one at the residue that in the experimenter, is hydrolyzed easily after the administration, and the alkyl group of straight chain or side chain is normally replaced by one or more oh group, more frequently, be methyl, ethyl or the propyl group of straight chain or side chain, replaced, further more frequently by one or more oh group, it is ethyl group, replaced by an oh group, or the propyl group of straight chain or side chain, replaced by two oh groups, and the most frequently, be-CH 2CH 2OH ,-CH 2CH (OH) CH 2OH, perhaps-CH 2(CH 2OH) 2R 1Also can be formula-COO -The carboxylate anion, in the case, lonidamine or lonidamine analog will with counter ion counterionsl gegenions Z +In conjunction with, Z wherein +It is pharmaceutically acceptable cation.
[00036] R 2Represent substituted or unsubstituted aromatic yl group or heteroaryl groups.Normally, R 2Being the aromatic yl group that replaces, more frequently, is the phenyl group that replaces, further more frequently, by one, two or three phenyl groups that substituent group replaces, described substituent group is independently selected from halogen substituent group and alkyl substituent, in particular-Cl ,-Br ,-I, CF 3With-CH 3Substituent group.Work as R 2When being the phenyl group that replaces, R 2Normally-Cl ,-Br ,-I, CF 3Perhaps-CH 3, the phenyl of monosubstitution is substituted at 2,3 or 4; The phenyl that dichloro, dibromo, dimethyl or chlorine and methyl double-basis replace, 2 and 3 on the throne, perhaps 2 and 4 are substituted; Perhaps 2,4,5 trichlorophenyl.Work as R 2When being the phenyl group that replaces, R 2More frequent is 2,4-Dichlorobenzene base or 4-chloro-2-aminomethyl phenyl.
[00037] X represents straight chain or side chain, saturated or unsaturated hydrocarbon linking group.When X was saturated hydrocarbon linking group, X is the linking group of straight chain normally, and normally, X has formula-(CH 2) p-, p equals 1,2 or 3.When X was saturated hydrocarbon linking group, X was methylene group the most frequently ,-(CH 2)-.When X was unsaturated hydrocarbon linking group, X often was the linking group of straight chain, be the most frequently-(CH=CH)-.
[00038] Y represents Shi-CHR 7-shown in part, R wherein 7Be the alkyl group of hydrogen or straight chain or the alkyl group of side chain, more frequently, R 7Be the alkyl group of hydrogen or straight chain, further frequently, R 7Be hydrogen, methyl, ethyl or n-pro-pyl, further frequently, R 7Be hydrogen or methyl and the most frequently, R 7Be that (that is, Y is-CH hydrogen the most frequently 2-).
[00039] n is 0, perhaps the most frequently, is 1.
[00040]
Figure A20048000226300151
Being core loop systems (core ring system), can be aryl, heteroaryl, cycloalkyl or heterocyclic ring system usually.Ar core loop systems contains 2 condensed rings usually.Condensed ring can be 4-, 5-, 6-, 7-usually, and perhaps 8-unit encircles, and more frequent is 5-or 6-unit ring.The core ring is condensed 5-unit's ring and condensed 6-unit ring the most frequently.Condensed annular atoms can be any atom usually, often is carbon atom or hetero atom, is carbon and nitrogen family atom and further frequently more frequently, is carbon and nitrogen.The number of the carbon atom in the core loop systems normally 7.The core loop systems contains 2 hetero atoms usually, and wherein preferred hetero atom is a nitrogen.Normally, in the fused rings or more a plurality of can be aromatic.When the core loop systems was condensed 5 yuan of rings and condensed 6 yuan of rings, the core loop systems all was aromatic usually on two fused rings.Condensed 5 yuan of rings and condensed 6 yuan of loop systems are indole the most normally.
[00041] more specifically, the lonidamine analog that the method according to this invention is used and by novel analog more provided by the invention comprises the analog shown in the following structural formula:
Figure A20048000226300161
R wherein 1, R 2, X, Y and n usually as mentioned above, perhaps, in a kind of preferred pattern,
R 2Be-Cl ,-Br ,-I or-CH 3, the phenyl of monosubstitution is substituted at 2,3 or 4; Dichloro, dibromo, dimethyl, perhaps the phenyl of chlorine and methyl double-basis replacement is substituted and is substituted at 2 and 4 at 2 and 3; Perhaps 2,4,5 trichlorophenyl;
Y is-(CH 2)-; With
N is 0, and R 1Be-COOH-CONH 2,-CONHNH 2,-CONHN (CH 3) 2,-CH 2CH 2OH ,-CH 2CH (OH) CH 2OH, perhaps CH 2(CH 2OH) 2Perhaps
N is 1, R 1Be-COOH and X be-CH=CH-.
[00042] in one embodiment, the lonidamine analog is 1, and the indole that 3-replaces is as 1-halogenophenyl-1H-indole.In another embodiment, the lonidamine analog is 1-phenyl-1H-indole that 3-replaces.In another embodiment, the lonidamine analog is 1-replacement-indole-3-carboxylic acid, as 1-halogenophenyl-1H-indole-3-carboxylic acid.
[00043] BioisosterIn addition, the lonidamine analog that can use in Therapeutic Method of the present invention comprises the bioisoster and the pharmacophoric group of lonidamine described here and analog.The bioisostere principle is the bioactive useful tool of predictive compound, and it is based on following prerequisite: the chemical compound with similar size, shape and electron density can have similar biological activity.In order to form the bioisoster of given molecule, people use at row's alternatives such as the known organisms of an atom or group, replace this one or more atom or group.Row's alternatives such as known biology comprise, for example ,-F ,-OH ,-NH 2,-Cl and-CH 3Interchangeability;-Br and-i-C 3H 7Interchangeability;-I and-t-C 4H 9Interchangeability;-O-,-S-,-NH-,-CH 2, and-interchangeability of Se-;-N=,-CH=and-interchangeability of P=(in cyclic or acyclic part); The interchangeability of phenyl and pyridine radicals group;-C=C-and-interchangeability (for example, benzene and thiophene) of S-; Aromatic nitrogen (R 1-N (R 3)-R 2) to undersaturated carbon (R 1-C (=R 3)-R 2) interchangeability; With-CO-,-SO-and-SO 2-interchangeability.These examples are not the scopes of equivalents such as row such as restriction biology etc., and those skilled in the art can determine in this field row's alternatives such as known other biology.Referring to, for example, Patani and La Voie, 1996; And Burger, 1991.
[00044] Pharmacophoric group.Except lonidamine analog described herein, can use lonidamine analog in the method for the invention, can be any pharmacophoric group of above-described lonidamine and lonidamine analog usually.Frequently, can carry out the reasonable quantitative forecast of the binding ability of a known molecular, be based on the spatial arrangements of a small amount of atom in this molecule or functional group and carry out.This arrangement is called as a pharmacophoric group, in case and a pharmacophoric group or a plurality of pharmacophoric group in the molecule identified that this information can be used to identify other molecule that contains identical or similar pharmacophoric group.The method is known the those of ordinary skill in the pharmaceutical chemistry field, and, because the structural information described in this application has identified the lonidamine of relevant BPH treatment and the pharmacophoric group of lonidamine analog, those skilled in the art can identify that other contains the LND analog of pharmacophoric group, also therefore is used for the treatment of among the BPH.The example of the program that can obtain of the pharmacophoric group search of being correlated with is 3D pharmacophoric group program (3D Pharmacophore search), from the Chemical ComputingGroup (referring to http://www.chemcomp.com/fdept/prodinfo.htm).
[00045] valuable especially a kind of lonidamine analog be tolnidamine (tolnidamine) (1-(4-chloro-2-aminomethyl phenyl)-1H-indole-3-carboxylic acid, AF1923); Referring to Ansari et al., 1998; Corsi et al., 1976.Tolnidamine (TND) is different with lonidamine, is on 2 of phenyl group, to have methyl substituents, rather than chlorine substituent.Other lonidamine analog of biologically active, in following publication, be described: United States Patent (USP) 3,895, No. 026, exercise question be " Substituted 1-Benzyl-1H-Indazole-3-CarboxylicAcids and Derivatives Thereof; " Corsi et al., 1976, " 1-Halobenzyl-1H-Indazole-3-Carboxylic Acids.A New Class ofAntispermatogenic Agents, " Journal of Medicinal Chemistry 19:778-83; Silvestrini, 1981, " Basic and Applied Research n the Study of IndazoleCarboxylic Acids, " Chemotherapy 27:9-20; Lobl et al., 1981, " Effects ofLonidamine (AF 1890) and its analogues on follicle-stimulating hormone; luteinizing hormone; testosterone and rat androgen binding proteinconcentrations in the rat and rhesus monkey, " Chemotherapy 27:61-76; United States Patent (USP) 6,001, No. 865, exercise question is " 3-Substituted 1-Benzyl-1H-IndazoleDerivatives As Antifertility Agents "; With Cheng et al., 2001, " Two new malecontraceptives exert their effects by depleting germ cells prematurely fromthe testis; " Biol Reprod.65:449-61, it has described AF-2364 and AF-2785 and other chemical compound (referring to Fig. 1).
[00046] The functional characteristic of lonidamine analog.The lonidamine analog that is suitable for using in the present invention is these materials, when when the mankind, non-human primate or other mammal give, disturbs the cellular energy metabolism of prostate epithelial cell.As the common finding in pharmaceutical technology, not that each analog of a chemical compound (for example, lonidamine) all has pharmacological activity.Whether have the activity of parent compound by routine screening analog, can the identified activity form.Can use various analyses and experiment, pharmacological activity with evaluation lonidamine analog, comprise analyzed in vitro, as this paper hereinafter with other local described those analyzed in vitro, the body inner analysis of the mankind, non-human primate and other mammiferous prostate function (comprising that citric acid produces and ATP produces), the body inner analysis of human, inhuman Primate and other mammiferous prostate size, and/or clinical research.
[00047] Apoptosis research in the cell line.As shown in embodiment 3, in the cell line that is derived from the human benign prostatic cell, lonidamine has been induced apoptosis.(ATCC NO.CLR-1435) compares with the PC3 cell, apoptosis induction in LNCaP cell (ATCC NO.CLR-1740) is obviously more, this is consistent to the susceptibility (susceptibility) of metabolic antagonist such as lonidamine with the prostatic cell that produces citric acid, wherein the PC3 cell is a kind of prostate derived cell system of oxidation citric acid, and the LNCaP cell is a kind of prostate derived cell system that produces citric acid.In some embodiments of the present invention, wherein a kind of lonidamine analog is used to the treatment or the prevention of BPH or its performance, and a kind of have the active analog of similar apoptosis induction and be selected.Therefore, in some embodiments of the present invention, a kind of analog of lonidamine is given with treatment BPH, and described analog is cell death inducing (activity of raising caspase-3 (cysteine proteinase-3)) in the prostatic cell of citric acid-generations such as LNCaP cell.In some embodiments of the present invention, a kind of analog of lonidamine is given with treatment BPH, and described analog apoptosis-induced degree in the LNCaP cell enlarges markedly in the PC3 cell.In some embodiments of the present invention, in the LNCaP cell by the inductive apoptosis of lonidamine analog, apoptosis-induced than in the PC3 cell, about greatly at least 2 times (and, sometimes be about greatly at least 3 times, about greatly at least 4 times, perhaps about greatly at least 10 times); When analyzing, the concentration of analog is concentration like this, and promptly the difference of the level of apoptosis in two kinds of cell lines is maximum (as long as the concentration of the analog of using in analysis is to be not more than 1mM).
[00048] Apoptosis analysis in the primary cell culture.As shown in the embodiment 3, lonidamine has been induced apoptosis in the primary culture of human prostatic epithelial cell.Apoptosis induction in the epithelioglandular primary culture in prostatitis, the apoptosis induction in the primary culture of human prostate stromal cell is big significantly, and this is consistent to the sensitivity of metabolic antagonist such as lonidamine with citric acid generation cell.In some embodiments of the present invention, that a kind of lonidamine analog process of application is used for the treatment or the prevention of BPH or its performance, select a kind of active lonidamine analog of the apoptosis induction similar that has to lonidamine.Therefore, in some embodiments of the present invention, give a kind of lonidamine analog apoptosis-induced in prostate epithelial cell, with treatment BPH.In some embodiments of the present invention, use a kind of lonidamine analog, it is apoptosis-induced degree in the epithelioglandular primary culture in prostatitis, and compares in the primary culture of human prostate stromal cell, has reached obviously bigger degree.In some embodiments of the present invention, the lonidamine analog is apoptosis-induced indistinctively in stromal cell.In some embodiments of the present invention, and in stromal cell, compare, in epithelial cell by the accent of lonidamine analog die induce big at least 2 times (with, sometimes, be big 4 times at least, be big 10 times sometimes at least, and, be big 20 times sometimes at least); When analyzing under this concentration of analog, the difference of the level of apoptosis in two kinds of cell lines is maximum (as long as the concentration of the analog of using in this analysis is to be not more than 1mM).
[00049] The HIF-1 alpha expression is analyzedAs shown in the embodiment 2, in the cultured cells, when concentration was 200 micromoles, lonidamine made HIF-1 alpha expression/accumulation (measuring in nuclear components) reduce almost 2 times under anoxia condition; And under higher lonidamine concentration, lonidamine reduces more than 5 times (that is, greater than 10 times) HIF-alpha expression/accumulation.Therefore, in some embodiments of the present invention, cultivation when not existing with lonidamine is compared, in the LNCaP cell of under anoxia condition, cultivating, energy dissipation agent (energolytic agent) makes the expression (preventing the accumulation of HIF-1 α) of HIF-1 α reduce about at least 2 times, at least about 5 times, perhaps about at least 10 times.
[00050] in the accompanying drawing corresponding to embodiment 2, lonidamine seems more obvious in the PC3 cell at LNCaP cell ratio to the influence of the HIF-1 alpha expression in the prostatic cell, and wherein cell is cultivated (oxygen level＜0.1%) under anoxia condition.Some lonidamine analog according to of the present invention, useful to BPH treatment may have similar effect.
[00051] these result of experiment are not to set up mechanism or the specificity that suppresses HIF-1 α by lonidamine clearly.Lonidamine can be fully to the influence of HIF-1 alpha levels, perhaps partly owing to the common inhibition of protein synthesis, and by Floridi et al., 1985 described lonidamine activity.Lonidamine also can be fully to the influence of HIF-1 alpha levels, the perhaps influence that partly owing to lonidamine mitochondrial oxygen is utilized.Hagen et al.2003, report HIF-1 α is that composing type is synthetic, but is degraded in the presence of oxygen.Under anaerobic conditions, the mitochondrial respiratory effect that causes by lonidamine suppresses to have reduced mitochondrial oxygen consumption, is possible.Conversely, this may should cause the oxygen dependence enzyme, and the activity of prolyl hydrolytic enzyme increases, and this enzyme works in HIF-1 α degraded path.
[00052] Hexokinase activityAs discussed above and be not intended to be subject to concrete mechanism, lonidamine may be regulated prostatic effect, at least in part, by it to the effect of mitochondrion in the secreting type epithelial cell and mitochondrion hexokinase and regulate.Therefore, it is active that some useful lonidamine analog have the hexokinase inhibition among the present invention, active same strong, perhaps stronger than lonidamine with the inhibition of lonidamine.Analysis to hexokinase activity is known in this field.Referring to Fanciulli et al., 1996 and Floridi et al., 1981.
[00053] The activity of anti-spermatogenesisSimilarly, it is believed that the anti-spermatogenesis activity of lonidamine, at least in part, is because the energy dissipation effect (energolyticeffects) in the sexual cell.Some useful in the present invention lonidamine analog have anti-spermatogenetic activity, and are active same strong, perhaps strong than lonidamine with the anti-spermatogenesis of lonidamine.The active analysis of antagonism spermatogenesis is known in this field.Referring to Grima et al., 2001; Lohiya et al., 1991.
[00054] except analyzed in vitro, the energy dissipation agent can be estimated in vivo, is used for the purposes of the method for the invention.As an example and unrestricted, suitable analysis comprises prostate function and active mensuration.
[00055] Measure in the body of prostate functionA kind of chemical compound to the influence of prostate function and, particularly, to respiratory influence, can be by giving after this chemical compound, monitoring prostata tissue metabolism and being evaluated.Some useful in the present invention lonidamine analog will reduce the generation of the prostatic ATP of animal (comprising the mankind, inhuman Primate, perhaps other mammal), citric acid and/or lactic acid with detecting.Adopt magnetic resonance spectrum (magnetic response spectroscopy (MRS)) or other method, ATP, citric acid and/or lactate level can directly be monitored and/or indirect monitoring in vivo.Analyze for the MRS that can be used for this purpose, for example, referring to, Narayan and Kurhanewicz, 1992; Kurhanewicz et al., 1991; Thomas et al., 1990.
[00056] The body inner analysis of prostate sizeThe application standard method (for example, be used for human ultrasonography or rectal touch inspection and, be used for the ultrasonography of animal and/or organ weight relatively), after giving a kind of chemical compound, can evaluate of the influence of this chemical compound to the prostate size.Analysis can be the mankind, perhaps, more frequently in the non-human animal of health or monkey, Canis familiaris L., rat or other animal model at BPH operation (referring to Jeyaraj et al., 2000; Lee et al., 1998; Mariotti et al., 1982).In this alanysis and animal model, some useful in the present invention lonidamine analog can reduce the prostate size with detecting.
[00057] Clinical trial.Clinical trial as the clinical experiment about lonidamine described in the embodiment hereinafter, can be used to evaluate the therapeutic effect of lonidamine analog.
[00058] can be with the activity of a valuable lonidamine analog in aforementioned any analysis, compare with the activity of lonidamine, with provide be fit to this chemical compound medicine time table guidance, and out of Memory.Normally, compare with lonidamine, every milligram of lonidamine analog with stronger biologic activity is valuable especially.
4. lonidamine and lonidamine analog synthesizes and form
[00059] can be by the synthetic method of knowing, preparation lonidamine and lonidamine analog and derivant.Synthesizing of lonidamine, be described in No. 2,310,031, No. 026 and the Deutsche Bundespatent at United States Patent (USP) 3,895.Representational lonidamine analog, comprise tolnidamine (TND), in this field, be described (referring to, for example, Corsi et al., 1976, " 1-Halobenzyl-1H-Indazole-3-Carboxylic Acids.A New Class of AntispermatogenicAgents ", Journal of Medicinal Chemistry 19:778-83; Chenget al., 2001, " Two new male contraceptives exert their effects by depleting germ cellsprematurely from the testis " Biol Reprod.65:449-61; Silvestrini, 1981, " Basic and Applied Research in the Study of Indazole Carboxylic Acids " Chemotherapy 27:9-20; Lobl et al., 1981, " " Effects of Lonidamine (AF1890) and its analogues on follicle-stimulating hormone, luteinizinghormone, testosterone and rat androgen binding protein concentrations inthe rat and rhesus monkey " " Chemotherapy 27:61-76; U.S.Patent Nos.3,895,026 and 6,001,865) .).Certainly, should be understood that, useful lonidamine analog is not limited to provide the analog of concrete structure in the disclosure or the list of references quoted in practice of the present invention, and above-described chemical compound provides in order to the present invention to be described illustratively, rather than restriction the present invention.Useful in the method for the invention lonidamine analog is not limited to those present analog described here, and perhaps those are at other local analog of describing of pharmacy and patent documentation, and this also is clearly.Common technical operation personnel after being instructed by present disclosure, can use the conventional method of medicinal chemistry, the synthetic new analog that is suitable for the application according to the present invention.
The analog of lonidamine or a kind of lonidamine is provided with the form of pharmaceutically acceptable salt [00060] in some embodiments.Pharmaceutically acceptable salt (pharmaceuticallyacceptable salts) comprises, uses acid-addition salts, and with the salt of alkali addition.Salt with the alkali addition is, for example, alkali metal salt or alkali salt such as sodium salt, potassium salt, calcium salt or magnesium salt, perhaps ammonium salt is as having those salt of ammonia or suitable organic amine, such as diethylamine, two-(2-ethoxy)-amine or three-(2-ethoxy)-amine.Be used to form the suitable acid of acid-addition salts, for example, it is mineral acid, for example hydrochloric acid, hydrobromic acid, sulphuric acid or phosphoric acid, or organic acid, organic sulfonic acid for example is such as benzenesulfonic acid, 4-toluenesulfonic acid or Loprazolam, and organic carboxyl acid, such as acetic acid, lactic acid, Palmic acid, stearic acid, malic acid, maleic acid, Fumaric acid, tartaric acid, ascorbic acid or citric acid.
[00061] gives ester, amide and the prodrug derivatives of lonidamine and its analog, also be (for the general information of this derivant of preparation from compound of interest in practice of the present invention, referring to United States Patent (USP) 6,146, No. 658), as give polymorph form, enantiomeric forms, tautomeric forms, solvate, hydrate, and analog.
5. give the patient that lonidamine provides benefit
[00062] the invention provides to suffering that BPH torments or to the male lonidamine that gives of BPH susceptible, this to give in treatment be effective.Correspondingly, in one aspect of the invention, give lonidamine or a kind of lonidamine analog to the experimenter who needs the BPH treatment.In one embodiment, needing the experimenter of treatment is a human male, and it does not suffer from cancer.As using at this, " experimenter (a subject in need oftreatment for BPH) who needs treatment " is the man that a diagnosis suffers from BPH.BPH uses method as known in the art and standard is diagnosed.Prevailing check is the rectal touch inspection, and in this was checked, the doctor determined whether prostate is normal size and hardness.Other diagnostic analysis comprises the test of urine flow rate, the mensuration of residual urine volume (for example after urinating, vibration by abdominal part, the drain of residual urine, X-ray urography (X-ray urogramography), perhaps ultrasonography), American Urologic Association Symptom Index (AUASI; Barryet al., 1992) or International Prostate Symptom Score (IPSS; Barry et al., 2001) the moderate symptom in or serious symptoms scoring and known other test in this field.
[00063] to the clinical effectiveness of the hope of BPH treatment, includes but not limited to: the alleviation of one or more symptom of BPH or improve (referring to following); The minimizing of prostate size (referring to following); Compare with the baseline measures before the begin treatment, AUASI or IPSS scoring reduce (for example, reducing 3 minutes or more, such as reducing 5 minutes or more), and AUASI or IPSS scoring are less than 8; The minimizing of blood-serum P SA is reduced by at least approximately 20%, as is reduced by at least approximately 40%, and blood-serum P SA is less than 4, as less than 2; The result of the improvement of urodynamics parameter and other hope, these results are treated the sign that the doctor approves that the order of severity of conduct expression experimenter's BPH reduces.Evaluation to therapeutic response can be carried out in any time after giving this medicine first.For example, when behind begin treatment about 30 days, about 60 days or about 90 days, estimate.Estimate when alternatively, can be behind begin treatment about 6 months, 12 months, 18 months, 24 months or more months.Additionally, can be after one section treatment finishes be less than about 30 days, estimate when about 30 days, about 60 days or about 90 days.
[00064], gives lonidamine or a kind of lonidamine analog to showing the related indication human experimenter of BPH, with the occurrence frequency and the order of severity that reduces this symptom at a related aspect.As using at this, " BPH related symptoms (a symptom associated withBPH) " be meant in the following symptom any one or a plurality of: (1) urgent micturition; (2) terminal dribbling of urine; (3) frequent micturition; (4) nocturia; (5) subtract/urine flows slowly; (6) insufficient emptying sense; (7) urine interrupts; (8) urine distortion; (9) dysuria; (10) hematuria; (11) acute urinary retention; (12) urinary tract infection; (13) urinary incontinence.The method according to this invention gives lonidamine or lonidamine analog, typically cause in these symptoms one or more the order of severity reduction or eliminate; Normally, perhaps cause the reduction of the order of severity of all these symptoms, perhaps eliminate; And usually, cause the elimination of all these symptoms.
[00065], gives lonidamine or a kind of lonidamine analog, with the human experimenter's that need to reduce this kind minimizing prostatic size at another related aspect.As using at this, " needing to reduce the experimenter (a subject in need of reduction ofprostate size) of prostatic size " is the prostatic male with increase, the prostate that increases is determined with following method: (1) imaging (for example, ultrasonography, nuclear magnetic resonance) or (2) directly or one or more sign or symptom (for example, comprising BPH symptom discussed herein) of causing by prostate compressing urethra indirectly.The minimizing of blood-serum P SA (prostate specific antigen (prostatespecific antigen)) also is the useful representative that prostate volume reduces.Although different between individuality, the prostate of increase often surpasses 30 grams, 40 grams or 50 grams in size.The minimizing degree of prostate size, will be from experimenter to experimenter and change, because some factors, be included in the increase degree of treatment when initial, but can typically be reduced to about at least 10% volume, be reduced by at least about 25% volume more frequently, be reduced by at least about 40% volume sometimes, sometimes that be reduced by at least about 50% volume and observe the prostate size sometimes even surpass 50% minimizing.This minimizing can be determined by imaging or other method.In some cases, blood-serum P SA also can be used as the useful of prostate volume and substitutes, and is used.
[00066], gives lonidamine or a kind of lonidamine analog greater than the experimenter of 2ng/ml to Serum PSA level at a related aspect.PSA is only by prostatic epithelial cell secretion.For the man who suffers from BPH, higher PSA level is pointed out out, compares relative higher ratio of existence between epithelial cell proliferation and Interstitial cell propagation with the man with low PSA level.The invention provides some diagnostic methods, be suitable for being applied to definite patient that the treatment of lonidamine or a kind of analog is played response energetically.Therefore, lonidamine treatment can provide the treatment benefit greater than the experimenter of 2ng/ml to the PSA level.Thereby, can from the male crowd who suffers from BPH, select expection according to the experimenter that treatment of the present invention significantly is benefited, be to be tested and appraised the experimenter of blood-serum P SA value greater than 2ng/ml.In one embodiment of the present invention, the experimenter has the PSA level greater than about 4ng/ml.Because higher PSA level is also relevant with carcinoma of prostate, and perhaps relevant with carcinoma of prostate more nearly, rather than relevant with BPH.In one embodiment, be selected for the experimenter of lonidamine or a kind of analogue treatment, have PSA level less than about 10ng/ml.
[00067] in one aspect of the invention, benefit from the experimenter that BPH prevents, give lonidamine or a kind of lonidamine analog to meeting.In an example, " can benefit from the experimenter (a subject who would benefit from prophylaxis of BPH) of BPH prevention " is the male, the electrified art of underwent operative treatment in the past, transurethral microwave thermotherapy, transurethral needle ablation, per urethra, laser therapy, balloon dilation, prostate-urethra rack, Drug therapy or other treatment and treat BPH, and do not suffered from BPH or performance BPH symptom at present by diagnosis.In another embodiment, the experimenter that can benefit from BPH prevention is the male since the age relation be in the increase risk of generation BPH (for example, greater than 40 years old, greater than 50 years old, greater than 60 years old or greater than 70 years old male).In another embodiment, the experimenter that can benefit from the BPH prevention is the male, it is asymptomatic, perhaps have very slight symptom, so that cannot descend the diagnosis of BPH clearly, but its Serum PSA level with rising (for example, PSA＞2ng/ml, perhaps, in some cases,＞4ng/ml).
[00068] therefore, in some cases, the experimenter who gives lonidamine according to the inventive method is the male who has accepted the BPH treatment in the past, and in other cases, the experimenter does not accept the male that BPH treats before being.Similarly, be noted that in this joint and refer to any content that gives lonidamine, equally, be applicable to give biological activity lonidamine analog.
[00069] In one embodiment of the present invention, need the experimenter of treatment or prevention BPH, neither also be in simultaneously in the treatment of cancer, perhaps neither suffer from cancer.In a kind of relevant embodiment, the experimenter of needs treatment or prevention BPH never is diagnosed as suffers from cancer.In one embodiment, need the experimenter of treatment or prevention BPH not suffer from cancer.In one embodiment, it is not the cancer of carcinoma of prostate that the experimenter who needs BPH to treat suffers from a kind of, but does not suffer from carcinoma of prostate.As applied here, " cancer (cancer) " has its common medical significance, and refer to that malignant tumor (comprises head cancer, neck cancer, carcinoma of prostate and chest cancer, leukemia and lymphoma), usually be feature (referring to Mendelsohn, 1991) with clonality (clonality), autonomy (autonomy), anaplasia (anaplasia) and transfer (metastasis).
[00070] in one embodiment, the invention provides a kind of method of in the patient, treating BPH, implement by give lonidamine to this patient.In a kind of relevant embodiment, the invention provides the method for a kind of BPH of treatment, comprise that (a) gives lonidamine and determine in described patient (b) whether a performance or a plurality of performance of BPH are lowered to the patient who is diagnosed as BPH.In one embodiment, the invention provides the method for a kind of BPH of being used for the treatment of, in a patient, diagnose out BPH, (b) give lonidamine to this patient by (a), determine in described patient (c) whether a performance or a plurality of performance of BPH are lowered.In one embodiment, the invention provides a kind of method of in the patient, treating BPH, implement by give the lonidamine analog to this patient.In a kind of relevant embodiment, the invention provides the method for a kind of BPH of treatment, comprise that patient that (a) suffers from from BPH to diagnosis gives the lonidamine analog and (b) determines in described patient whether a performance or a plurality of performance of BPH are lowered.In one embodiment, the invention provides the method for a kind of BPH of treatment, in a patient, diagnose BPH, (b) give the lonidamine analog to this patient by (a), determine in described patient (c) whether a performance or a plurality of performance of BPH are lowered.In aforesaid embodiment, randomly, the experimenter is not diagnosed as cancer, perhaps is in the treatment for cancer; Randomly, have less than 2ng/ml or equal the PSA of 2ng/ml, randomly have greater than 2ng/ml with less than the PSA of 10ng/ml.
[00071] on the other hand, the invention provides a kind of method, need the purposes of (a) advertisement lonidamine or a kind of lonidamine analog, be used for the treatment of BPH, (b) sell lonidamine or a kind of lonidamine analog, to be used for the therapeutic use of BPH to individuality.In one embodiment, a trade mark has been mentioned in this advertisement, and this has indicated a kind of lonidamine product, and the lonidamine of selling in step (b) is distinguished by this same trade mark.Should be understood that, the individuality that lonidamine is sold to comprises legal person (company) and similar individuality, and " selling the therapeutic use that lonidamine is used for BPH " to individuality comprise to, for example, medical institutions sell lonidamine, are used for the treatment of BPH to sell to the patient.
[00072] in another embodiment, the invention provides the method for treatment acute urinary retention in the mankind, implement by the analog that gives lonidamine or a kind of lonidamine to this people.Because acute urinary retention can be the symptom of BPH, this embodiment of the present invention is applicable to any individuality, and described individuality suffers from acute urinary retention when giving lonidamine or lonidamine analog first, do not suffer from BPH but be diagnosed as.
6. the dosage that gives, approach, timetable and persistent period
[00073] according to the present invention, various approach and dosage time are suitable for giving of lonidamine and lonidamine analog.
[00074] a kind ofly carrying the optimal way of lonidamine and lonidamine analog to the patient, is to carry through the oral cavity.The preferred dose form that per os gives is pill, tablet, capsule, capsule sheet and analog, particularly is mixed with to be used for spacetabs type.Be used for other suitable form that per os gives and comprise, contain tablet (troches), elixir (elixirs), suspension, syrup, fast-release tablet (wafers), lozenge and analog.Also expect other the mode that gives, comprised intestinal give, spray injection (microparticle that for example, comprises lonidamine) and other path in suction, percutaneous, rectum, the prostate outward.Lonidamine and lonidamine analog can be formulated to the proper dosage unit formulation, and it contains conventional nontoxic pharmaceutically acceptable carrier, accessory drugs and excipient, is applicable to each path that gives.In one embodiment, dosage form is the 150mg unit dosage form of selling with trade mark Doridamina by name in Italy.
[00075] lonidamine and lonidamine the analog dosage, timetable and the persistent period that give, will depend on various factors, comprise experimenter's age, body weight and health status; The order of severity of BPH symptom, if any; The medical history that also comprises the experimenter, therapeutic alliance, therapeutic goal (for example, treatment or prevention) gives the mode of medicine, applied preparation, the patient is to the reaction and the similar factor of medicine.Be used for illustrating illustratively rather than limiting that the dosage regimen that is used for three kinds of common species of lonidamine and the administration of lonidamine analog can be described to: high dose administration, low dosage administration and middle dosed administration.Ratified the cancer that lonidamine is used for the treatment of some specific types in a few countries in Europe, as a reference, the standard lonidamine dosage that is used for the treatment of cancer of these specific types is 150mg, and is oral every day three times, continues about 30 days.
[00076] The low dosage administration.The low dosage administration is used for treatment and the prevention of BPH by expection.The exemplary low dosage of lonidamine or a kind of lonidamine analog comprises, is not restrictive, and the interior dosage (accumulated dose every day) of 1-300mg scope every day is more frequently in the scope of 1-300mg/ day, perhaps sometimes in the scope of 5-70mg/ day.Other representational low dosage scope comprises, 1-25mg/ day, 20-45mg/ day, 40-65mg/ day, 40-70mg/ day, 50-100mg/ day, 50-200mg/ day and 50-300mg/ day.In one embodiment, low dosage is 150mg, and oral administration is used once a day; The Doridamina unit dosage form can be applied in the present embodiment.In another embodiment, low dosage is 75mg, and every day, twice per os was given; By the Doridamina unit dosage form being divided into two equal parts, can be applied in the present embodiment.
[00077] as by being put down in writing, the every day of this recommendation dosage can be divided into, for example, take every day for 2 times, 3 times or 4 times.In one embodiment, medicine is given for being used for once a day by preparation.In one embodiment, medicine by preparation for using to be less than once every day.In another embodiment, use the releasing pattern of a kind of improvement of this medicine.
[00078] to give can be once a day to the lonidamine low dosage, the next day once, used in 5th, stopped using and give in 2nd by the table At All Other Times that the doctor who gives determines.
[00079] low dosage arrangement of time of the present invention advantage is, this dosage can be continued to give several weeks to the several months, usually is side effect (mainly being myalgia and testicular pain) due to the higher dosage of slight, the lonidamine that is in the news though limit or eliminated unnecessary simultaneously.
[00080] the low dosage arrangement of time can be used to treatment or prevention.In one embodiment, the low dosage form is used to, at higher initial dose, startup dosage or after loading dosage, as maintenance dose.
[00081] high dose administration.In another embodiment,,, treat BPH by give the lonidamine of higher dosage or a kind of analog of lonidamine (compare with low dosage, usually continue) to BPH patient than short-term according to the inventive method.Representational high dose comprises, is not restrictive, and every day, accumulated dose was greater than 0.5g, as the dosage in 0.5-5g/ day, 0.5-3g/ day, 0.5-1g/ day and 1-3g/ daily range, perhaps higher dosage.Every day, dosage can be divided into, and for example, give every day for 2 times, 3 times or 4 times.In one embodiment, medicine is given for being used for once a day by preparation, perhaps is less than once a day to give.In another embodiment, use a kind of improvement releasing pattern of this medicine.As another selection, high dose can be disposable, weekly, whenever biweekly or once be given on the basis of (for example, 0.5-5g/ gives) in every month, perhaps to be given by giving the determined table At All Other Times of doctor.
[00082] the high dose arrangement of time can be used to treatment or prevention.In one embodiment, high dose is co-administered with the operative treatment or the non-drug therapy that are used for BPH, perhaps uses after operative treatment that is used for BPH or non-drug therapy.
[00083] Middle dosed administration.In another embodiment, according to the inventive method, by giving the analog of lonidamine or a kind of lonidamine with middle dosage to BPH patient, treatment BPH, described in the middle of dosage be between high dose and the low dosage.The example of dosage comprises in the middle of representational, without limits, and greater than 300mg/ day and less than the dosage of 500mg/ day, as the dosage in the scope of＞300-400 or 400＜500 (for example, 450mg/ day).Every day, dosage can be divided into, and for example, give every day for 2 times, 3 times or 4 times.In one embodiment, medicine is given for being used for once a day by preparation, perhaps is less than once a day to give.In one embodiment, the improvement releasing pattern of this medicine is employed.As another selection, dosage can perhaps be given with the table of being determined by the doctor who gives At All Other Times once, once in a week, whenever biweekly or once be given on the basis of (for example, 300-500mg/ gives) in every month in the middle of this.In one embodiment, every day, dosage was, the analog 150mg of lonidamine or a kind of lonidamine takes three every day.
[00084] the dosage arrangement of time can be used to treatment trouble or prevention in the middle of.In one embodiment, a kind of in the middle of dosage be used for the operative treatment of BPH or non-drug therapy and unite and give, perhaps after operative treatment that is used for BPH or non-drug therapy, give.
[00085] should be realized that, these dosage arrangements of time are to be used for illustrative explanation, rather than be used for limiting, and the dosage timetable can change in therapeutic process, for example, according to reaction or a kind of application with lonidamine analog of with lonidamine significantly different activity/dose curve of patient to treatment.
[00086] Persistent period.In treatment and prophylactic applications, lonidamine or lonidamine analog can once give by coverlet one, perhaps can reach some months or several years during in repeatedly give.In one embodiment of the present invention, give lonidamine or a kind of analog, only to sx or disappearance, and stop treatment thereafter, unless or reappear up to symptom to Symptomatic (for example, just experiencing dysuria) BPH patient.When symptom reappeared, lonidamine or lonidamine analog were restarted to give.In another embodiment, treatment continues after transference cure, and perhaps treatment is reduced to acceptable target level, continues for some time at least, as a week, two weeks, one month or some months.In another embodiment, give medicine to Symptomatic experimenter, with development or the generation (for example, prophylactically administration) again that prevents symptom.
7. therapeutic alliance (treatment combinations)
[00087] lonidamine and lonidamine analog can be united with other medicament or process therapy (procedures), be applied to BPH patient, described other medicament or method attempt to treat BPH, improve the symptom of BPH, strengthen the effect of lonidamine or lonidamine analog, the benefit of other treatment perhaps is provided.Comprising of " use in conjunction (in combination with) " medicament (agent), parallel giving (in one period, give two kinds of medicaments to the patient, as the next day in, give lonidamine and Tamsulosin (tamsulosin), continue 1 month); Give jointly (wherein, give medicament in about identical time, for example, to each other about a few minutes to several hours within) and preparation (wherein, medicament is combined or is mixed into the single dose form, be suitable for per os or intestinal gives outward) altogether.Unite the example of the representative medicaments that gives with lonidamine or lonidamine analog, include but not limited to zinc, alpha block agent, 5-alpha-reductase inhibitors and plant extract.Be used for uniting other medicament that gives with lonidamine or lonidamine analog, comprise other metabolic antagonist, include but not limited to other hexokinase inhibitor and glucolytic other inhibitor, include but not limited to a kind of direct inhibitor or the indirect inhibitor of 2-deoxy-D-glucose and HIF-1 α.
[00088] Zinc:As discussed above, the high zinc concentration in the prostatic secreted epithelial cell suppresses the m-aconitase, and this has increased this tissue to being used for the glucolytic dependency that energy generates.The method according to this invention, in some patients, (for example give zinc jointly, zinc chloride, zinc gluconate, zinc sulfate, zinc acetate, Aspartic acid zinc (zinc aspatate), zinc citrate, glyceric acid zinc, zinc oxide, selenium picolinate (zinc picolinate), or the like) and a kind of pharmaceutical composition of the present invention may be useful, with the usefulness of maximization treatment.For example, and not conduct restriction, the zinc that can give 15-300mg/ day is used for this purpose, typically, gives the zinc of 30-50mg/ day.
[00089] Alpha antiadrenergic agent.Some symptoms of BPH are alleviated in the alpha block agent, do not treat underlying diseases.These reagent are by the muscle of lax bladder neck and the muscle in the prostate, alleviate the pressure of urethra and work.Representational alpha block agent comprises doxazosin doxazosin (Cardura), terazosin terazosin (Hytrin), Tamsulosin tamsulosin (Flomax), alfuzosin alfuzosin (Xatral) and prazosin prazosin (Hypovase).In one embodiment of the present invention, a kind of alpha block agent united with lonidamine or a kind of lonidamine analog give, with treatment BPH.In another embodiment, unite with lonidamine (perhaps a kind of lonidamine analog), with the alpha block agent with " standard " dosage (when not existing lonidamine to give, pointed out to be used for experimenter's dosage) low dosage (consumption) or lower frequency are (for example, every other day, rather than every day) be given.
[00090] The 5-alpha-reductase inhibitors.The 5-alpha-reductase inhibitors suppresses the transformation (DHT) of testosterone to dihydrotestosterone 2, and dihydrotestosterone 2 is a kind of androgens that help prostate to increase.That sharp finasteride (Proscar) that gets of representational 5-alpha-reductase inhibitors right and wrong.In one embodiment of the present invention, 5-alpha-reductase inhibitors and lonidamine united give, with treatment BPH.In another embodiment, with the 5-alpha-reductase inhibitors with " standard " dosage (when not existing lonidamine to give, pointed out to be used for experimenter's dosage) low dosage (consumption) or low frequency are (for example, every other day, rather than every day), unite with lonidamine (perhaps a kind of lonidamine analog) and give.
[00091] Glycolysis depressant of functions and mitochondrial function inhibitor.Also can be with the chemical compound of glucolytic inhibitor such as 2-deoxy-D-glucose and inhibition glucose transport, the mitochondrial function inhibitor, the mitochondrion toxic agent, with hexokinase inhibitor such as acid of 3-bromacetone and its analog, unite with lonidamine or a kind of lonidamine analog and to give, with treatment BPH.Such inhibitor is known in this field, and comprises the inhibitor of those following document descriptions: PCT patent publications WO 01/82926 is disclosed in November 8 calendar year 2001; United States Patent (USP) 6,670,330,6,218,435,5,824,665,5,652,273 and 5,643, No. 883; No. 20030072814,20020077300 and 20020035071, U.S. Patent application publication; (on January 9th, 2004 submitted to United States Patent (USP) publication serial number 10/__; Lawyer's files numbering (attorney docket number) 54492-2000400), exercise question is " Treatment Of CancerWith 2-Deoxyglucose. ".These inhibitor can be united with lonidamine or a kind of lonidamine analog and given, to reach the treatment benefit in the BPH treatment.
[00092] Plant.Sawtooth palmetto (Saw Palmetto (Serenoa repens (Serenoa repens))) or its extract, perhaps African Fructus Ribis Alpestris (Pygeum Africanum) or its extract, can unite with lonidamine or lonidamine analog and give, so that pursue treatment benefit in the BPH treatment.
[00093] Process therapy (procedures).In addition, can be with lonidamine or a kind of lonidamine analog and the process therapy that is used for BPH treatment use in conjunction together, perhaps gave before the process therapy of BPH treatment, the process therapy that is used for the BPH treatment comprises, operation (transurethral prostatic resection; Per urethra prostate stereotomy; Perhaps open prostatectomy), laser therapy, transurethral microwave thermotherapy, balloon dilation, prostate-urethra rack are placed, prostatic per urethra electric gasifying art, perhaps other non-drug therapy method are melted in per urethra acupuncture.
8. dosage form (dosage forms)
[00094] Unit dosage form.The chemical compound that is used for the inventive method is to be suitable for the compositions that therapeutic gives by preparation.In one embodiment, put into practice method of the present invention with the lonidamine of unit dosage form, unit dosage form is sold with Doridamina (being provided by ACRAF) in Italy.The new dosage form of lonidamine also is provided.For example, the invention provides a kind of unit dose drug preparation of lonidamine, it is suitable for per os and gives (comprising tablet, capsule, capsule sheet and pill), and comprise, in various embodiments, a certain amount of lonidamine, (wherein by the upper limit of 1,5,10 and 50 lower limit (unit is mg) and 10,20,40,50,70 and 100, the unit of higher limit is mg, and is greater than lower limit) in institute's restricted portion, and be especially easily for some low dosage arrangement of time.In another embodiment, unit dosage form comprises a certain amount of medicine, (wherein by the upper limit of 200,300,500 or 1000 lower limit (unit is mg) and 500,1000,3000 or 5000, higher limit is greater than lower limit) in institute's restricted portion, and be especially easily for some high dose arrangement of time.In another embodiment, preparation contains the chemical compound of between 100mg to 200mg (for example 150mg), between 200mg to 5000mg, and between 200mg to 1000mg, the perhaps chemical compound between 500mg to 1000mg.The lonidamine analog can similarly be mixed with preparation.
[00095] except lonidamine and/or lonidamine analog, solid unit dose forms of the present invention contains pharmaceutically acceptable carrier usually.As using at this, " pharmaceutically acceptable carrier (pharmaceutically acceptable carrier) " is meant solid or liquid filling agent, diluent or encapsulated substance, comprise excipient for example, filler, binding agent and other composition commonly used in medication preparation, include but not limited to the material that those are described below.Be used for that the method for pharmaceutical preparation normally knows in this field, and description herein is to illustrate illustratively, rather than restrictive.Referring to, for example, Ansel et al., 1999; Marshal, 1979.
[00096] hydrophilic adhesive that is applicable to preparation of the present invention comprises, vinyl pyrrolidone/vinyl acetate co-polymer (copolyvidone (crospolyvinylpyrrolidone)), polyvinylpyrrolidone, Polyethylene Glycol, sucrose, dextrose, corn syrup, polysaccharide (comprising Radix Acaciae senegalis (acacia), guar gum (guar) and alginate), gelatin and cellulose derivative (comprising hydroxypropyl emthylcellulose (HPMC), hydroxypropyl cellulose (HPC) and sodium carboxymethyl cellulose).
[00097] is applicable to water-soluble diluent in the preparation of the present invention, comprises sugar (lactose, sucrose, dextrose), polysaccharide (dextrates (Dextrates) and maltodextrin), polyhydric alcohol (mannitol, xylitol and sorbitol), and cyclodextrin.The water-insoluble diluent that is applicable to preparation of the present invention comprises calcium phosphate, calcium sulfate, starch, modified starch and microcrystalline Cellulose.
[00098] surfactant that is applicable to preparation of the present invention comprises ionic surfactant and nonionic surfactant, perhaps wetting agent such as ethoxylated castor oil, polyglycolyzed glyceride, acetylated monoglycerides, sorbitan fatty acid ester, poloxamer (poloxalkol poloxamers), polyoxyethylene sorbitan fatty acid ester, polyoxyethylene deriv (derivefatives), nonoglycerides or its ethoxylated derivative, sodium lauryl sulphate, lecithin, ethanol and phospholipid.
[00099] disintegrating agent that is applicable to preparation of the present invention comprises starch, clay, cellulose, alginate, natural gum, crosslinked polymer (polyvinyl pyrrolidone (PVP), sodium carboxymethyl cellulose), sodium starch glycollate, low hydroxypropyl cellulose and the soy polysaccharides that replaces.Preferred disintegrating agent comprises modified cellulose natural gum, as cross-linking sodium carboxymethyl cellulose.
[00100] is applicable to that the lubricant of preparation of the present invention and fluidizer comprise Muscovitum, magnesium stearate, calcium stearate, stearic acid, silica sol, magnesium carbonate, magnesium oxide, calcium silicates, microcrystalline Cellulose, starch, mineral oil, wax, Glyceryl Behenate, Polyethylene Glycol, sodium benzoate, sodium acetate, sodium chloride, sodium lauryl sulphate, sodium stearyl fumarate and hydrogenated vegetable oil.Preferred lubricant comprises magnesium stearate and Muscovitum and their combination.
[00101] preferable range of tablet or capsular gross mass can be from about 40mg to 2g, from about 100mg to 1000mg with from about 300mg to 750mg (milligram).
[00100] The slow release form.In addition, the invention provides unit dosage form, it is the slow releasing preparation of lonidamine or a kind of lonidamine analog, and to allow (perhaps still less) oral administration once a day, this is a kind of sometimes through too much day administration and by the preferred frequency of patient.This slow release type preparation of the present invention (comprises tablet, capsule, capsule sheet and pill) usually comprise reactive compound, between 1mg to 3g, for various alternate embodiments, comprise that those are above-described, the scheme that is used for conventional oral dosage, for example the amount of medicine is limited among the scope, by 1,5,10 and 50 lower limit (unit is mg) and 10,20,40,50,70 and 100 the upper limit (wherein, higher limit is greater than lower limit) limit, and be especially easily for some low dosage arrangement of time or median dose arrangement of time.In another embodiment, unit dosage form comprises a certain amount of medicine, (wherein by the upper limit of 200,300,500,750 or 1000 lower limit (unit is mg) and 500,1000,2000,3000 or 5000, higher limit is greater than lower limit) in institute's restricted portion, and be especially easily for some high dose arrangement of time.
[00101] in one embodiment, lonidamine or a kind of lonidamine analog in the slow release type preparation (being also referred to as " improvement " or " controlled " releasing pattern) after giving, are released during greater than 6 hours, for example, and greater than 12 hours.In one embodiment, extended release preparation allows administration once a day, with the pharmacokinetics curve of acquisition with curve equivalence in treatment of lonidamine administration 150mg, three acquisitions every day.
[00102] being used for can be modified so that the example of the slow releasing preparation of the other medicines of Ying Yonging is in the present invention known in the art according to instruction herein, for example, is described in United States Patent (USP) 5,968,551; 5,266,331; 4,970,075; 5,549,912; 5,478,577; 5,472,712; 5,356,467; 5,286,493; 6,294,195; 6,143,353; 6,143,322; 6,129,933; 6,103,261; 6,077,533; 5,958,459; With 5,672, in No. 360.Slow releasing preparation is also in scientific literature, for example, the ORALSUSTAINED RELEASE FORMULATIONS:DESIGN ANDEVALUATION that is editing by A.Yacobi and E.Halperin-Walega, Pergamon Press, come into question in 1988, it has described various types of extended release preparation forms and mechanisms for drug release, and for example single unit (for example, the substrate tablet, coated tablet, capsule), many units (for example, granule, pearl, microcapsule), inert substrate, insoluble substrate, hydrophilic gel substrate (for example, biological adhesive, erosion property, non-erosion property) and ion exchange resin sustained-release dosage form.
[00103] in one embodiment, the invention provides the method for a kind of BPH of treatment, by patient to this treatment of needs, give a kind of spacetabs type tablet dose once a day, it contains therapeutic dose every day of lonidamine, from about 1mg to 2g, is present in the hydrophilic substrate.This substrate can, be used for for example and without limits, be selected from hydroxypropyl emthylcellulose (the approximately percentage by weight of 20-40%), lactose (5-15%), microcrystalline Cellulose (4-6%), and silicon dioxide (1-5%), the mean particle size scope that silicon dioxide has are from the 1-10 micron, usually scope is for from about 2 to 3 microns from 2-5 micron and the most frequent scope.
[00104] exemplary preferred slow releasing preparation of the present invention comprises preparation A and the B in the following table.
Preparation A B
(percentage by weight)
Lonidamine (pulverizing) 53.8 53.8
HPMC(Methocel?K15M，CR) 8 30
Methylcellulose (Methocel, K100L, CR) 18 0
Anydrous lactose 12.2 8.2
Microcrystalline Cellulose (Avicel PH101) 55
Silicon dioxide (1-10 micron, Syloid 244) 33
The total weight of table (with the gram expression) 11
[00105] slow release type preparation of the present invention can be the form of compressed tablets, it contains the immixture of lonidamine and the neutral pH dependency of part binding agent, this binding agent, when the pH scope of process stomach (typically～2) and small intestinal (typically～5.5), the medicine dissolution speed in the control aqueous media.
[00106] in pharmaceutical field, the material of many being known as " enteric " binding agent and coating materials has the pH dissolution properties of hope, is suitable for the purposes of slow releasing preparation of the present invention.This comprises phthalic acid derivatives, phthalic acid derivatives, hydroxy alkyl cellulose, alkylcellulose, cellulose acetate, acetic acid hydroxy alkyl cellulose, cellulose ether, acetic acid alkylcellulose as polyvinyl and copolymer, with its ester, polymer and copolymer and its part ester with low alkyl group acrylic acid and lower alkyl acrylate.
[00107] preferred pH dependency binder substance is a methacrylic acid copolymer.This copolymer is commercial available, obtains with the EudragitTML-100-55 of powder type from Rohm Pharma, and perhaps the L30D-55 with 30% dispersion in water obtains.Other pH dependency binder substance, it can be used separately or use in conjunction, comprise phthalic acid hydroxypropyl cellulose, Hydroxypropyl Methylcellulose Phathalate, cellulose acetate-phthalate, phthalic acid polyvinyl acetate, phthalic acid polyvinylpyrrolidone, and analog.One or more pH dependency binding agents occur in lasting liberation port oral dosage forms of the present invention, and the scope of amount is from about 1 to 20 percetage by weight, perhaps from about 5 to 12 percetages by weight, perhaps about 10%.
[00108] is included in pH dependency binding agent or viscosity-increasing agent in the slow releasing preparation of the present invention, comprise following material, as hydroxypropyl emthylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinylpyrrolidone, neutral poly-(methyl) acrylate, and analog.The scope of the amount of pH dependency binding agent is from 1 to 10 percetage by weight, perhaps from 1 to 3 percetage by weight, perhaps about 2%.
[00109] in some embodiments, slow releasing preparation of the present invention also contains one or more pharmaceutical excipients, mix with following material homogeneous: ranolazine ranolazine (Lonidamine lonidamine) and pH dependency binding agent, form agent, starch, gelatin, sugar, carboxymethyl cellulose and analog as non-pH dependency binding agent or film, and other useful pharmacy diluent such as lactose, mannitol, dried starch, microcrystalline Cellulose and analog, surfactant such as polyoxyethylene sorbitan esters, sorbitan ester and analog; With coloring agent and correctives.Also there are lubricant such as Muscovitum and magnesium stearate, and the tabletting adminicle.
[00110] extended release preparation of the present invention comprises commercial available, be applicable to the arbitrary substance of this preparation purposes, include but not limited to, cellulose, ethyl cellulose, methylcellulose, carboxymethyl cellulose, hydroxypropyl emthylcellulose, Hydroxypropyl Methylcellulose Phathalate, hydroxypropyl cellulose, microcrystalline Cellulose, sodium carboxymethyl cellulose, cellulose acetate-phthalate, O-phthalic vinegar polyvinyl acetate, polyvinylpyrrolidone, poly(ethylene oxide), Polyethylene Glycol, zein, alginate, Hydroxypropyl Methylcellulose Phathalate, methacrylic acid copolymer, crospovidone Crospovidone, the aeroge of silicon, pregelatinized Starch, corn starch, cross-linked carboxymethyl cellulose sodium, the glycolate Starch Sodium, candelilla wax, hard paraffin, Brazil wax, the ethylene glycol montan wax, white beeswax, Eudragit (polymethacrylates), Aquacoat (ethyl cellulose, cellulose acetate-phthalate), Carbopol (acrylic acid polyalken copolyether), and Macrogol (Polyethylene Glycol).
[00111] slow release type preparation of the present invention comprises the preparation of controlling its diffusion, and as those preparations, it is applied to:
(a) a kind of storage system, its Chinese medicine is encapsulated in the polymeric film capsule, and the diffusion of passing film by water to be to dissolve this medicine, and then drug diffusion goes out outside the device;
(b) a kind of monoblock type (substrate) system, its Chinese medicine is suspended in polymeric matrix, and spreads out by long path;
(c) microcapsule and coated granule system, its medium and small drug particles (the perhaps granule of medicine and polymer) to 1 micron is coated in the polymeric film, comprise following embodiment, wherein by the polymer coating granule with different releasing properties, these granules are carried in a capsule jointly;
(d) solvent-activation system, (for example, OROS), wherein penetrating agent and medicine are wrapped in the semipermeable membrane capsule, because osmotic gradient, water is drawn in the device, and the pressure that increases is evicted medicine from device by laser drill to comprise (i) osmotic pressure control device; (ii) a kind of hydrogel expansion system, its Chinese medicine is disperseed in polymer, and/or polymer is coated on the drug particles, and when contacting with water, polymer expands (in some embodiments, expansion is pH control, or enzymatic control), allow drug diffusion to go out this device; (iii) a kind of microporous film system, its Chinese medicine is encapsulated in the film, and film has a kind of composition, dissolving when this composition contacts with water (in some embodiments, dissolving is subjected to pH control, or controlled by enzyme), stay the hole like this on film, medicine is by this hole diffusion; (iv) a kind of wax-matrix system, its Chinese medicine and a kind of additional solvable composition are scattered in the wax, so, when this composition of water dissolution, allow medicine to diffuse out from this system; With
(e) depolymerization system comprises (i) bulk degraded, and its Chinese medicine is scattered in the polymeric matrices, and degraded betides in the polymer architecture with random fashion, makes drug release; (ii) surface erosion, its Chinese medicine is scattered in the polymeric matrices, and is transferred along with the erosion of polymer surfaces.
[00112] in one aspect, the invention provides the method for a kind of BPH of treatment, by giving the combination of oral medication of a unit dose, it is a slow release type preparation, contains the lonidamine of effective dose, as described above, and once a day.
9. embodiment
Embodiment 1
Clinical trial
[00113] the II phase dosage comparative study at random of enforcement lonidamine administration, wherein giving lonidamine is the treatment that is used for Symptomatic benign prostatic hyperplasia.The patient is 50 to 80 years old male, suffers from BPH, confirm by ultrasonic photograph, and blood-serum P SA＞2, and do not have the sign of carcinoma of prostate.Give lonidamine (150mg, tablet; The Doridamina preparation) 150mg, day three times, oral (middle dosage); Perhaps day once oral (low dosage) 8 weeks.The patient who accepts day three dosage took chemical compound 5 days and inactive 2 days, to help to comply with this programme.
[00114] by ultrasonic photograph, urine stream, AUASI scoring, PSA, adverse events and serum chemistry, the baseline of evaluate patient, the 30th day, the 60th day prostate volume, with the benefit that determines whether that in two dosage one provides significantly to be increased than another dosage, and measure the minimizing of the prostate size that treatment thus obtains.
Embodiment 2
Lonidamine reduces the expression of HIF-1 α in the prostate epithelial cell
[00115] present embodiment has shown in being derived from two kinds of cell lines of human benign prostatic cancer metastasis, and the lonidamine treatment is to the effect of HIF-1 alpha expression.LNCaP is that citric acid produces cell (ATTC No.CRL-1740), and PC3 is citric acid oxidation cell (ATTC No.CRL-1435).Referring to Franklin et al; 1995.Cell can be from (ATCC) P.O.Box 1549 of American type culture collection (American Type Culture Collection), Manassas, and VA 20108 USA obtain.
[00116] as shown in Figures 2 and 3, the lonidamine treatment reduces the proteic level of HIF-1 α, extracts in prepared product (NE) and the full cell extraction prepared product (WCE) at nucleus to be detected.Inhibition is a dose dependent, and is observed under normal oxygen (only PC3 cell) and anoxia (LNCaP cell and PC3 cell) situation.Under test condition, the lonidamine effect is special to the HIF-1 alpha subunit, and, except under 800 μ M concentration, under test condition, the protein level of actin, caspase 3, NF-κ B or I κ B α is not had can detected inhibitory action.Yet, lonidamine is in the news, generally Profilin matter is synthetic (referring to Floridi et al., see above), and the result who herein presents should not be interpreted as conclusion evidence, the proof lonidamine is a kind of specific inhibitor of HIF-1 α, perhaps the therapeutics effect of lonidamine in BPH treatment fully, or partly owing to its inhibitory action to the accumulation of the HIF-1 α in any cell category.
[00117] MethodWith 5 * 10 5The density of individual cell is plated on cell in the culture dish, and then, (5%CO in 37 ℃ of incubators 2) kept 2 days.Before the analysis, with (37 ℃) RPMI-1640 culture fluid (ATCC No.30-2001 of preheating; 10mM HEPES; The 1mM Sodium Pyruvate; The 2mM L-glutaminate; 4500mg glucose/L; 1500mg sodium bicarbonate/L) cell is cleaned 2 times.Perhaps under normal oxygen or under anoxia (oxygen level＜0.1% (, in 37 ℃, when lonidamine does not exist or exists with variable concentrations, with 2ml culture fluid incubation cell 4 hours.In incubation latter stage, culture dish is placed on ice, and with cold PBS buffer (4 ℃) washed cell 2 times rapidly.For the nucleus extract, with buffer A (10mM Tris, pH7.5; 1.5mM MgCl 210mM KCl and protease inhibitor) and buffer C (0.5M NaCl; 20mM Tris pH7.5; 1.5mM MgCl 220% glycerol and protease inhibitor) cell lysis sequentially.The protease inhibitor that is used for this experiment is mixture (500mM AEBSF-HCl, 1mg/ml aprotinin Aprotinin, 1mME-64, the bright aprotinin Leupeptin of 500mM EDTA and 1mM of five kinds of albumen enzyme inhibitors; Calbiochem NO539131).For full cell lysate, use 150mM NaCl; 10mM Tris pH7.5; 10mM EDTA; 1% TritonX-100; 0.5% dexycholate; And protease inhibitor, cell lysis.Use the Bio-Rad analysis of protein, measure protein concentration.With the albumen application of sample of equivalent on the SDS-PAGE gel.Sample transfer is to pvdf membrane, and with the TBST closing membrane that contains 5% defatted milk powder, 4 ℃ are spent the night.Subsequently, with first antibody (HIF-1 α, HIF-1 β, and actin) and the link coupled second antibody incubation of alkali phosphatase film, each incubation 2 hours.For detecting the expression of caspase 3, NF-κ B, P65 and I κ B α, with the TBST closing membrane that contains 5% defatted milk powder, room temperature 1 hour, and by with 4 ℃ of incubations that spend the night of corresponding antibody, and and link coupled second temperature resistance of alkali phosphatase was educated detection protein 1 hour.Use colorimetric substrates, detect specific protein, and use NIH imaging system, the intensity of quantitative every kind of protein.
[00118] in the experiment of as above carrying out usually respectively, under being derived from anoxia condition in the cultured cells, in full cell extract of LNCaP (Fig. 7) or nucleus extract (Fig. 8), 0-600 μ M lonidamine is measured the influence of HIF-1 α and other protein expression.
Embodiment 3
Lonidamine produces cell death inducing in the cell at citric acid
[00119] in the cell that adopts lonidamine to handle whether apoptosis taking place in order to determine, has estimated the influence of lonidamine to the cell (PC3) of the cell (LNCaP) that produces citric acid and oxidation citric acid.As shown in FIG. 4, lonidamine produces inductive caspase3 activation in the cell (LNCaP) at citric acid, reaches than bigger degree in citric acid oxidation cell (PC3).The activation of caspase3 is a time dependence process (Fig. 5).
[00120] also detected lonidamine, in the primary culture of the primary culture of prostate epithelial cell (it accumulates citric acid) or prostate stromal cell (it does not accumulate citric acid), effect.As shown in FIG. 6, lonidamine is only in prostate epithelial cell, rely on mode, cell death inducing with dosage.In contrast, after handling, in the prostate stromal cell, do not observe apoptotic inducing with lonidamine.
Method
[00121] immunoblotting: described at embodiment 2, implement immunoblotting.In order to detect the expression of caspase3, with the TBST closing membrane that contains 5% defatted milk powder, room temperature 1 hour, and, by with 4 ℃ of caspase3 antibody spend the night incubation and and the link coupled second antibody incubation of alkali phosphatase 1 hour, detect caspase3 albumen.Use colorimetric substrates, detect special protein, and use the quantitative every kind of proteic intensity of NIH imaging system.
[00122] primary cell culture: the primary culture of human prostatic epithelial cell (Cambrex No.CC-2555), primary culture with human prostate stromal cell (Cambrex No.CC-2508), be from Cambrex Bio Science Rockland, Inc. (191 Thomaston Street, Rockland, Maine 04841) obtain.
[00123] apoptosis analysis: with 2 * 10 4The density of individual cells/well is plated on cell in 96 orifice plates, then, and (5%CO in 37 ℃ of incubators 2) kept 16 hours.Lonidamine is added each hole with different concentration, then, 37 ℃ of incubations 6 hours.For estimating the activity of caspase3, existing or not existing under the caspase3 inhibitor (Promega NoG5961), with homogenizing buffer and caspase3 substrate (Promega No G7791; PromegaCorporation, 2800 Woods Hollow Road, Madison WI USA 53711) join in each hole.Use the fluorescent screen reader, under exciting light 485nm and emission light 530nm, measure the fluorescence intensity that is cut substrate.
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Although the present invention is described in detail with reference to specific embodiment, person of skill in the art will appreciate that [00124] modification and improvement are within scope and spirit of the present invention, as illustrated in the following claims.At these all publications quoted and patent documentation (patent, disclosed patent application and undocumented patent application), incorporate into herein as a reference, pointed out to incorporate into herein as a reference particularly and respectively as each such publication or document.The quoting of publication and patent documentation is not that intention is made and a kind ofly admits that admit that any this class document is the prior art of being correlated with, this does not constitute admits the content of these documents or any of date yet.The present invention is described by the mode of written explanation and embodiment so far, person of skill in the art will appreciate that: the present invention can put into practice with various embodiment, and aforesaid description and embodiment are the purposes that is used for illustrative, rather than the restriction following claim.

Claims (44)

1. the method for a treatment benign prostatic hyperplasia (BPH) comprises the human subjects to this treatment of needs, treats the lonidamine or the lonidamine analog of effective dose.
2. a method that alleviates the symptom relevant with BPH comprises to the human subjects of this symptom of performance, gives lonidamine or lonidamine analog.
3. a method that reduces the prostate size in human subjects comprises the lonidamine or the lonidamine analog that give this object treatment effective dose.
4. a method that is used to prevent BPH comprises that the administration of human class object prevents the lonidamine or the lonidamine analog of effective dose.
5. the described method of each in the claim 1 to 4 comprises the lonidamine that gives effective dose.
6. the described method of each in the claim 1 to 4 comprises the tolnidamine that gives effective dose.
7. the described method of each in the claim 1 to 6, wherein said object is not diagnosed as cancer.
8. the described method of each in the claim 1 to 6, wherein said object is not in the treatment of cancer.
9. the described method of each in the claim 1 to 8, wherein said object has the blood-serum P SA greater than about 2ng/ml.
10. the described method of claim 9, wherein said object have less than the about blood-serum P SA of 10ng/ml.
11. the described method of each in the claim 1 to 10, wherein said object were once treated because of BPH in the past.
12. the described method of each in the claim 1 to 11, wherein said lonidamine or lonidamine analog are to give with uniting at other treatment of BPH.
13. the described method of claim 11, wherein said other treatment is a modus operandi.
14. the described method of claim 11, wherein said other treatment is:
A) give the alpha block agent; Perhaps
B) give 5-alpha-reductase inhibitors.
15. the described method of each in the claim 1 to 14, wherein lonidamine or lonidamine analog join together to give with zinc.
16. the described method of claim 5, wherein lonidamine continues at least five days at least once to be given every day.
17. the described method of claim 16, wherein lonidamine is to be given every day, at least 5 days weekly, in every month at least 3 week, continues at least 1 month.
18. the described method of claim 5 wherein is given in lonidamine 10 days in during 15 days at least.
19. the described method of claim 5, wherein lonidamine at least once is given weekly, continues at least 4 weeks.
20. the described method of each among the claim 16-19, wherein every day, dosage was between about 300mg at about 1mg.
21. the described method of claim 20, wherein said every day, dosage was at about 5mg with approximately between the 70mg.
22. the described method of each among the claim 16-19, wherein said every day, dosage was approximately between 500mg and about 5 grams.
23. the described method of claim 22, wherein said every day, dosage was approximately between 500mg and about 1 gram.
24. the described method of each among the claim 16-19, wherein said every day, dosage was about 450mg.
25. the described method of each among the claim 16-19, wherein said dosage is 150mg, and is oral, every day three times.
26. the described method of each among the claim 16-19, wherein lonidamine be with every day 150mg be given, continue 5 days; Then, be not given in lasting 2 days.
27. the described method of each among the claim 16-19, wherein, when comparing with the initial baseline before of treatment, described object
A) AUASI or IPSS scoring reduced by 3 fens at least, randomly reduced about at least 5 minutes;
B) prostate size reduces approximately at least 20%, randomly reduces about at least 40%; And/or
C) Serum PSA level reduce about at least 20%, randomly reduce about at least 40%,
When after treatment is initial, measured in the time of in the time of 60 days or after 60 days.
28. the described method of claim 20, wherein, when comparing with the initial baseline before of treatment, described object:
A) AUASI or IPSS scoring reduced by 3 fens at least, randomly reduced about at least 5 minutes;
B) prostate size reduces approximately at least 20%, randomly reduces about at least 40%; And/or
C) Serum PSA level reduce about at least 20%, randomly reduce about at least 40%,
When in the time of initial back 30 days, measuring in the time of perhaps after 30 days after treatment is initial in treatment.
29. a method for the treatment of BPH comprises that (a) diagnoses BPH in a patient, (b) gives lonidamine or lonidamine analog and (c) determines in described patient to this patient, one or more performance of BPH is alleviated.
30. a method for the treatment of BPH comprises that (a) gives lonidamine or lonidamine analog and (b) determine in described patient to the patient who is diagnosed as BPH, one or more performance of BPH is alleviated.
31. the combination of oral medication of a unit dose is used for the treatment of BPH, is included in the lonidamine between the 1mg to 70mg.
32. the combination of oral medication of a unit dose is used for the treatment of BPH, comprises 200 and the lonidamine of 1000mg.
33. the combination of oral medication of a unit dose, it is a slow releasing preparation, comprises the lonidamine from about 1mg to about 2000mg.
34. the described method of claim 5, wherein lonidamine is given with the unit dose combination of oral medication, and this unit dose combination of oral medication is a slow releasing preparation, comprises the lonidamine from about 1mg to about 2000mg.
35. lonidamine or lonidamine analog are used for purposes in the medicine of patient treatment or prevention benign prostatic hyperplasia in preparation.
36. the described purposes of claim 35, wherein said patient has the blood-serum P SA greater than 2ng/ml, and, randomly have blood-serum P SA less than about 10ng/ml.
37. the described purposes of each among the claim 35-36, wherein said lonidamine or lonidamine analog are the treatments that are used for BPH with another kind unites and gives.
38. the described purposes of each among the claim 35-37, wherein lonidamine is to be given with accumulated dose every day between 1mg and the 300mg.
39. the described purposes of claim 38, wherein said every day, dosage was at about 5mg with approximately between the 70mg.
40. the described purposes of each among the claim 35-37, wherein lonidamine is to be given with accumulated dose every day between 500mg and 1 gram.
41. the described purposes of each among the claim 35-37, wherein said every day, dosage was about 450mg.
42. the described purposes of each among the claim 35-39, wherein lonidamine is to be given with the frequency that is no more than once a day, and is given with the slow release form.
43. a method comprises that (a) advertisement lonidamine is used for the purposes of BPH treatment and (b) sells lonidamine and give individually, is used for the purposes of BPH treatment.
44. the described method of claim 43, wherein said advertisement are mentioned a trade mark, this trade mark is regarded as a kind of lonidamine product, and the lonidamine of being sold is distinguished by blanket brand.
CN 200480002263 2003-01-17 2004-01-16 Combination therapies for the treatment of cancer Pending CN1738616A (en)

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US44111003P 2003-01-17 2003-01-17
US60/441,110 2003-01-17
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US60/458,665 2003-03-28
US60/458,846 2003-03-28
US60/460,012 2003-04-02
US60/472,907 2003-05-22
US60/488,265 2003-07-18
US60/496,163 2003-08-18

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