JP2008508316A - Treatment of benign prostatic hyperplasia - Google Patents

Abstract

Methods are provided for treating or preventing benign prostatic hyperplasia (BPH) by administration of lonidamine or a lonidamine analog. Unit dosage forms of lonidamine or lonidamine analogs useful for such treatment and prevention are also provided. Also provided are pharmaceutical compositions useful for the treatment of BPH, including sustained release formulations. In one embodiment, the formulation is administered orally and allows for once daily administration of a therapeutically effective dose of the compound.

Description

(Cross-reference of related applications)
This application is filed in U.S. Provisional Patent Application No. 60 / 592,833 (filed July 29, 2004) and provisional patent application 60 / 661,067 (filed March 11, 2005). Claiming priority under section (e), the entire contents of these applications are hereby incorporated by reference.

(Field of Invention)
The present invention relates to the treatment and prevention of benign prostatic hyperplasia and has applications in the pharmaceutical and related fields, including but not limited to chemistry, medicinal chemistry and molecular biology.

(Background of the Invention)
Benign prostatic hyperplasia (BPH) is a disease in which prostate epithelial cells proliferate abnormally and obstruct urine flow, affecting more than 10 million adult men in the United States, and all other countries around the world Then more than millions of people are affected. Until relatively recent years, surgical intervention has been the only treatment for this disease. And even today, surgery is the last treatment measure and almost necessarily relies on when other treatments are ineffective or no longer effective. Prostate surgery and recovery from it is painful and the surgery itself may not be effective and poses a risk of serious side effects. See Non-Patent Document 1 for a recent review (a full citation is provided below).

Only two classes of drugs are currently available to treat the symptoms of BPH. One class includes compounds that inhibit the production of the active form of testosterone (dihydrotestosterone, or DHT). The use of this class of drugs can cause decreased libido and decreased muscle mass and tension in men and is associated with an increased incidence of advanced prostate cancer. Furthermore, this treatment is limited by a very long delay (months) between the initial administration of this drug and a significant reduction in prostate size in the patient. The second class of drugs currently used for BPH, alpha adrenergic blockers, act by relaxing smooth muscle and allowing urine to pass more freely through the urethra. This class of drugs reduces symptoms more quickly than the first class of drugs, but this does not reduce the size of the prostate or prevent it from growing larger, which is ultimately Can lead to significant surgical intervention.
Barry et al., “Measuring the Symptoms and health impact of benign prophylactic hyperplasma and its treatments”, BENIGN PROSTATIC HYPERT , 2001

  Thus, there is a significant unmet need for drugs that can treat the disease state underlying BPH without serious side effects. The present invention satisfies this need.

(Summary of the Invention)
The present invention provides methods and compositions for treating BPH in a human subject by administration of lonidamine or a lonidamine analog to the human subject. Also provided are pharmaceutical compositions useful for the treatment of BPH, including sustained release formulations. In one embodiment, the formulation is administered orally and allows for once daily administration of a therapeutically effective dose of the compound.

(Detailed description of the invention)
(1. Definition)
The following definitions are provided to help the reader. Unless defined otherwise, all terms of technology, labeling and other scientific or medical terms or technical terms used herein have the meaning normally understood by those skilled in the chemical and pharmaceutical fields. Is intended. In some cases, terms with commonly understood meanings are defined herein for clarity and / or easy reference, and including such definitions in the present specification is It should not be construed as representing a substantial difference from what is commonly understood in the art.

  As used herein, “treating” a condition or patient refers to taking steps to obtain beneficial or desired results for the patient, including clinical results. For the purposes of the present invention, beneficial or desired clinical results include reduction or amelioration of one or more symptoms of BPH, reduction of the degree of disease, delay or slowing of disease progression, disease status Examples include, but are not limited to, improvements, mitigation or stabilization, and other beneficial results described below.

  As used herein, “reducing” symptoms (and the grammatical equivalents of this phrase) means reducing the severity or frequency of symptoms, or eliminating symptoms.

  As used herein, “administering” a drug to a subject or “administering” a drug to a subject (and grammatical equivalents of this phrase) includes direct administration (including self-administration). And both indirect administration (including drug prescription). For example, as used herein, a physician instructing a patient to self-administer the drug and / or providing the patient with a prescription for the drug is administering the drug to the patient.

  As used herein, “symptom manifestation” of BPH refers to symptoms, signs, anatomical conditions (eg, prostate size), physiological conditions (eg, PSA) specific to a subject with BPH. Level), or report (eg, AUASI score).

  As used herein, a “therapeutically effective amount” of a drug is a therapeutic effect (eg, one or more manifestations of BPH) that is intended in that subject when administered to a subject having BPH. Reduction, improvement, mitigation or elimination). A complete therapeutic effect does not necessarily occur with a single dose administration but can only occur after a series of dose administrations. Thus, a therapeutically effective amount can be administered by one or more administrations.

  As used herein, a “prophylactically effective amount” of a drug prevents or delays the intended preventive effect (eg, the occurrence (or recurrence) of a disease or symptom) when administered to a subject. Or the amount of a drug that reduces the likelihood of the occurrence (or recurrence) of a disease or condition. A complete prophylactic effect does not necessarily occur with the administration of one dose, but can only occur after administration of a series of doses. Thus, a prophylactically effective amount can be administered by one or more administrations.

  As used herein, “TID” and “QD” have their conventional meanings “3 times a day” and “once a day”, respectively.

  As used herein, “alkyl” refers to a monovalent alkane (hydrocarbon) -derived radical containing 1 to 15 carbon atoms. It can be linear, branched or cyclic and can be unsubstituted or substituted with substituents including but not limited to hydroxyl, halide, alkoxyl and nitrile. Alkoxy groups that can be used include, but are not limited to, methoxy. Exemplary linear or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl.

  As used herein, “aryl” refers to a moiety that includes one or more monocyclic or fused ring aromatic systems. Such moieties include any moiety that includes one or more monocyclic or bicyclic fused ring aromatic systems, including but not limited to phenyl and naphthyl. An aryl group can be unsubstituted or substituted with substituents as listed for a particular substituted aryl.

As used herein, “heteroaryl” is a monocyclic aromatic group having 5 or 6 ring atoms, or a fused ring bicyclic aromatic having 8 to 10 atoms. An aromatic group in which the ring atoms are C, O, S, SO, SO ₂ or N, and at least one of the ring atoms is a heteroatom (ie, O, S, SO, SO ₂ or N). . A heteroaryl group can be unsubstituted or substituted with substituents as listed for a particular substituted heteroaryl. Examples of monocyclic aromatic heteroaryl groups include, but are not limited to, pyridyl. Examples of bicyclic fused ring heteroaryl groups include indazolyl, pyrrolopyrimidinyl, indolizinyl, pyrazolopyridinyl, triazolopyridinyl, pyrazolopyrimidinyl, triazolopyrimidinyl, pyrrolotriazinyl, pyrazolotriazinyl , Triazotriazinyl, pyrazolotetrazinyl, hexaaza-indenyl, and heptaaza-indenyl. Unless otherwise indicated, the arrangement of the heteroatoms in the ring can be any arrangement allowed by the binding properties of the constituent ring atoms.

As used herein, the terms “heterocycloalkyl” and “heterocyclyl” are not at least partially aromatic and one or more of the carbon atoms in the ring system is O, S, SO, A monocyclic or fused-ring polycyclic cycloalkyl group substituted by a heteroatom selected from SO ₂ or N. Examples of heterocyclyl groups include, but are not limited to, piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydroimidazo [4,5-c] pyridinyl, imidazolinyl, piperazinyl, pyrrolidin-2-oneyl, and piperidin-2-oneyl. Not.

  As used herein, “cycloalkyl” refers to a monocyclic or fused-ring polycyclic group that is at least partially non-aromatic and whose ring atoms are carbon.

  As used herein, “heterocycloalkenyl” means one or more of the carbon ring atoms is replaced by a heteroatom, the ring system is at least partially non-aromatic, and the ring system Refers to a monocyclic or fused-ring polycyclic group containing at least one carbon-carbon double bond.

(2. Benign prostatic hyperplasia and the effects of lonidamine and lonidamine analogs)
The present invention provides compositions and methods useful for the treatment of benign prostatic hyperplasia (BPH). In particular, the present invention relates to the use of lonidamine (LND) for the treatment or prevention of BPH. Furthermore, the invention relates to the use of lonidamine analogues for the treatment or prevention of BPH. To assist in understanding the present invention, a brief discussion of the characteristics of BPH (also referred to as benign prostatic hyperplasia) and lonidamine and its bioactive analogs is provided below.

  BPH is involved in cell overgrowth (hyperplasia) in the prostate, resulting in enlargement of the prostate resulting in a reduction in urinary symptoms and urinary tract disease. The prostate contains secretory epithelial cells in the connective tissue and smooth muscle stroma (see Barry, 2003 for a more detailed description of prostate anatomy), and BPH is involved in hyperplasia of epithelial components To do. The secretory epithelial component in normal prostate is striking in that the level of zinc in this tissue is very high compared to other normal tissues. The result of high zinc levels is that through the mechanism for zinc inhibition of the enzyme m-aconitase, energy production and oxidative phosphorylation via the tricarboxylic acid (TCA) cycle is substantially reduced in the glandular epithelium, thereby This tissue is much more dependent on glycolysis than other organs and tissues as an energy source. Zinc inhibition of m-aconidase (an important enzyme in the TCA cycle) results in at least substantial reduction of the TCA cycle in prostate epithelial cells, and possibly almost complete blockade. Another physiological consequence of zinc-based inhibition of m-aconidase is the diversion of citrate from the TCA cycle, which allows the prostate to use large amounts of citrate in the semen that the sperm uses as an energy source. It is possible to secrete into. See generally, Costello, 1999; Costello et al., 2000; Costello and Franklin, 2000.

Prostate epithelial cells rely solely on glycolysis (anaerobic metabolism) because other normal cells in the body do not accumulate zinc to a level that inhibits citrate metabolism. The present invention relates in part to the discovery of the sensitivity of these cells to the drug lonidamine, wherein lonidamine is administered to treat or prevent BPH in humans, as described herein. enable. Lonidamine is the generic name 1- (2,4-dichlorobenzyl) -1H-indazole-3-carboxylic acid, and in the medical literature it is 1-[(2,4-dichlorophenyl) methyl] -1H-indazole. It is also referred to as -3-carboxylic acid, AF1890, diclondazolinic acid (DICA) and Doridamine ^™ (ACRAF; Rome, Italy). See FIG. Lonidamine was first identified as an anti-spermatogenic agent and was later used in the treatment of breast cancer, cervical cancer, lung cancer and prostate cancer in several European countries. See Silverestrini, 1981; Gatto et al., 2002. The mechanism of action of lonidamine in spermatogenesis and cancer is not fully understood. However, the anticancer properties of lonidamine are due, at least in part, to lonidamine-mediated mitochondrial membrane disruption, thereby reducing the activity of hexokinase bound to mitochondria, and ATP via glycolytic pathways and oxidative phosphorylation Interfere with production. See Floridi et al., 1981, Fanciuli et al., 1996, and references numbered 15-22 therein; and Gatto, 2002. See also Kaplan, 2000. Without intending to be bound by a specific mechanism for the effect of lonidamine in benign prostatic hyperplasia, lonidamine inhibits glycolysis and / or inhibits already reduced mitochondrial function in prostate epithelial cells, It is thought that the energy of these cells is depleted compared to normal cells of the body. Without intending to be bound by a specific mechanism, due to energy deficiency, many hyperplastic epithelial cells are destroyed or epithelial cell size is reduced, resulting in prostate The size is reduced, thereby reducing the condition and its clinical course.

  Thus, administration of lonidamine to a human subject diagnosed with BPH or exhibiting symptoms of BPH may benefit from a reduction in the severity or frequency of one or more symptoms, a decrease in the size of the prostate or the rate of expansion. , Improved perceived quality of life, and recovery of other symptoms of BPH to a more normal state). Furthermore, administration of lonidamine to a human subject in need of prophylaxis against BPH provides benefits such as a reduction in the likelihood that BPH or BPH-related symptoms will appear, recur or progress in the subject. Still further, administration of a lonidamine analog to a human subject is similarly effective in treating and preventing BPH. In another embodiment, administration of lonidamine or an analog thereof to a human subject as described herein can be effective in the treatment of acute urinary retention. These and other aspects of the invention are discussed in more detail below. Section 3 below lists certain lonidamine analogs useful for the treatment and prevention of BPH. Section 4 relates to the synthesis and form of lonidamine and lonidamine analogs. Section 5 describes that administration of lonidamine and lonidamine analogs to the patient population provides benefits. Section 6 describes the method of administration of lonidamine (eg, dosage, route of administration, schedule of administration, and duration of administration). Section 7 describes a combination therapy where lonidamine or an analog is administered in combination with another drug or therapy. Section 8 describes exemplary dosage forms. Section 9 describes monitoring of PSA levels in subjects treated with lonidamine or lonidamine analogs. Section 10 provides examples of the use and effect of lonidamine. The following description is organized into sections for convenience only, and the disclosure found in any systematic section is applicable to any aspect of the invention.

(3. Lonidamine analog)
As mentioned above, in addition to lonidamine, various compounds related to lonidamine are useful for the treatment and prevention of BPH. Useful compounds are generally structurally similar to lonidamine, are biologically equivalent to lonidamine, or are pharmacophores of lonidamine, and are also discussed below. As such, it has a biological activity similar to that of lonidamine. Such compounds may be referred to as “biologically active lonidamine analogs”, “lonidamine analogs”, or in some cases, simply “analogs”.

  (Structural properties of lonidamine analogues) Suitable in part for use in the treatment or prevention of BPH, based in part on lonidamine and related compounds known to have pharmacological activity similar to that of lonidamine Certain lonidamine analogs, including novel analogs provided by the present invention, have the formula:

により記載され、ここで、Ｒ_１、Ｒ_２、Ｘ、Ｙ、ｎ、および

Where R ₁ , R ₂ , X, Y, n, and

は、以下に定義される：
Ｒ_１は、−ＣＯＯＨまたは−ＣＯＯＨ基の誘導体または生物学的等価物を表す。Ｒ_１は、通常は、式−ＣＯＯＨの酸性基；式−ＣＯＮＲ_３Ｒ_４のアミド（ここで、Ｒ_３およびＲ_４は、独立にアルキルまたは水素であり得、水素が好ましい）；式−ＣＯＮＨＮＲ_６Ｒ_７のヒドラジド（ここで、Ｒ_６およびＲ_７は、一般的には、−Ｈまたは−ＣＨ_３である）；式−ＣＯＯＲ_５の置換エステル（ここで、Ｒ_５は、投与後に被験体内で、容易に加水分解される残基であり、一般的に、一つ以上のヒドロキシル基で置換された直鎖または分枝鎖のアルキル基であり、より通常には、一つ以上のヒドロキシル基で置換された直鎖または分枝鎖のメチル基、エチル基、またはプロピル基であり、さらにより通常には、一つのヒドロキシル基で置換されたエチル基、または、二つのヒドロキシル基で置換された直鎖もしくは分枝鎖のプロピル基であり、そして、最も通常には、−ＣＨ_２ＣＨ_２ＯＨ、−ＣＨ_２ＣＨ（ＯＨ）ＣＨ_２ＯＨ、または−ＣＨ_２（ＣＨ_２ＯＨ）_２である）から選択される。Ｒ^１はまた、式−ＣＯＯ⁻のカルボン酸アニオンであり得、この場合、ロニダミンまたはロニダミンアナログは、対イオンであるＺ^＋と結合し、ここで、Ｚ^＋は、薬学的に受容可能なカチオンである。

Is defined as:
R ₁ represents —COOH or a derivative of a —COOH group or a biological equivalent. R ₁ is usually an acidic group of formula —COOH; an amide of formula —CONR ₃ R ₄ where R ₃ and R ₄ can independently be alkyl or hydrogen, preferably hydrogen; ₆ R ₇ hydrazide (where R ₆ and R ₇ are generally —H or —CH ₃ ); a substituted ester of formula —COOR ₅ where R ₅ is A residue that is easily hydrolyzed, generally a linear or branched alkyl group substituted with one or more hydroxyl groups, and more usually one or more hydroxyl groups. A linear or branched methyl group, ethyl group, or propyl group substituted with, and more usually, an ethyl group substituted with one hydroxyl group, or substituted with two hydroxyl groups Straight or branched A propyl group, and, most _typically, -CH ₂ CH ₂ OH, is selected from _{-CH 2 CH (OH) CH 2} OH or _-CH 2, _(CH 2 _OH) is _2). R ¹ also has the formula -COO ^- be a carboxylic acid anion, in this case, lonidamine or lonidamine analogue is combined with Z ⁺ is a counterion, wherein, Z ⁺ is a pharmaceutically acceptable It is a cation.

R ₂ represents a substituted or unsubstituted aryl group or heteroaryl group. Usually R ₂ is a substituted aryl group; more usually a substituted phenyl group; and even more usually halo and alkyl substituents (especially —Cl, —Br, —I, CF ₃ and one independently selected from -CH ₃ substituents), a phenyl group substituted by two or three, substituents. When R ₂ is a substituted phenyl group, R ₂ is usually —Cl, —Br, —I, CF ₃ or —CH ₃ , monosubstituted phenyl substituted at the 2-position, 3-position or 4-position; And dichlorophenyl, dibromophenyl, dimethylphenyl, or phenyl disubstituted with chloro and methyl substituted at the 3-position or 2-position and 4-position; or 2,4,5 trichlorophenyl. When R ₂ is a substituted phenyl group, R ₂ is more usually 2,4-dichlorophenyl or 4-chloro-2-methylphenyl.

X represents a linear or branched, saturated or unsaturated hydrocarbon bonding group. When X is a saturated hydrocarbon linking group, X is usually a linear linking group, usually X has the formula (CH ₂ ) _p —, where p is 1, 2 Or equal to 3. When X is a saturated hydrocarbon linking group, X is most usually a methylene group, — (CH ₂ ) —. When X is an unsaturated hydrocarbon linking group, X is usually a straight chain linking group, most usually-(CH = CH)-.

Y represents a moiety of the formula —CHR ₇ —, wherein R ₇ is hydrogen or a linear or branched alkyl group, more usually R ₇ is hydrogen or a linear alkyl group. Yes, and more usually R ₇ is hydrogen, methyl, ethyl, or n-propyl, even more usually R ₇ is hydrogen or methyl, and most usually R ₇ is Hydrogen (ie, Y is most usually —CH ₂ —).

  n is 0, or most usually 1.

は、コア環系であり、一般的には、アリール環系、ヘテロアリール環系、シクロアルキル環系またはヘテロシクリル環系であり得る。Ａｒコア環系は、通常は、２つの融合環を含む。融合環は、一般的に、４員環、５員環、６員環、７員環または８員環であり得、より通常には、５員環または６員環である。コア環系は、最も通常には、融合５員環および融合６員環である。融合環原子は、一般的には、任意の原子であり得るが、通常は、炭素またはヘテロ原子であり、より通常には、炭素族原子および窒素族原子であり、そして、さらにより通常には、炭素および窒素である。コア環系における炭素原子の数は、通常７である。コア環系は、通常２個のヘテロ原子を含み、好ましいヘテロ原子は、窒素である。一般的に、一つ以上の融合環が、芳香族環であり得る。コア環系が、融合５員環および融合６員環である場合、コア環系は、両方の融合環にわたる芳香族環である。融合５員環系および融合６員環系は、最も通常には、インダゾールである。

Is a core ring system and can generally be an aryl ring system, a heteroaryl ring system, a cycloalkyl ring system or a heterocyclyl ring system. The Ar core ring system usually comprises two fused rings. The fused ring may generally be a 4-membered, 5-membered, 6-membered, 7-membered or 8-membered ring, more usually a 5-membered or 6-membered ring. The core ring system is most usually a fused 5-membered ring and a fused 6-membered ring. The fused ring atom can generally be any atom, but is usually a carbon or heteroatom, more usually a carbon and nitrogen group atom, and even more usually. , Carbon and nitrogen. The number of carbon atoms in the core ring system is usually 7. The core ring system usually contains 2 heteroatoms, with the preferred heteroatom being nitrogen. Generally, one or more fused rings can be an aromatic ring. Where the core ring system is a fused 5-membered ring and a fused 6-membered ring, the core ring system is an aromatic ring spanning both fused rings. The fused 5-membered ring system and the fused 6-membered ring system are most commonly indazole.

  More particularly, lonidamine analogs for use according to the methods of the present invention, and certain novel analogs provided by the present invention include the following formula:

のアナログが挙げられ、ここで、Ｒ_１、Ｒ_２、Ｘ、Ｙおよびｎは、一般的には上記の通りであるか、好ましいバージョンにおいては、
Ｒ_２は、−Ｃｌ、−Ｂｒ、−Ｉまたは−ＣＨ_３、２位、３位または４位で置換された一置換フェニル；２位および３位または２位および４位で置換された、ジクロロフェニル、ジブロモフェニル、ジメチルフェニルまたはクロロおよびメチルで二置換されたフェニル；または２，４，５トリクロロフェニルであり；
Ｙは、−（ＣＨ_２）−であり；そして、
ｎは、０であり、かつ、Ｒ_１は、−ＣＯＯＨ、−ＣＯＮＨ_２、−ＣＯＮＨＮＨ_２、−ＣＯＮＨＮ（ＣＨ_３）_２、−ＣＨ_２ＣＨ_２ＯＨ、−ＣＨ_２ＣＨ（ＯＨ）ＣＨ_２ＯＨ、もしくはＣＨ_２（ＣＨ_２ＯＨ）_２であるか；または
ｎは、１であり、Ｒ_１は、−ＣＯＯＨであり、かつ、Ｘは、−ＣＨ＝ＣＨ−である。

In which R ₁ , R ₂ , X, Y and n are generally as described above, or in preferred versions,
R ₂ is —Cl, —Br, —I or —CH ₃ , monosubstituted phenyl substituted at the 2-position, 3-position or 4-position; dichlorophenyl substituted at the 2-position and 3-position or 2-position and 4-position , Dibromophenyl, dimethylphenyl or phenyl disubstituted by chloro and methyl; or 2,4,5 trichlorophenyl;
Y is — (CH ₂ ) —; and
n is 0, and R ₁ is —COOH, —CONH ₂ , —CONHNH ₂ , —CONHN (CH ₃ ) ₂ , —CH ₂ CH ₂ OH, —CH ₂ CH (OH) CH ₂ OH, Or CH ₂ (CH ₂ OH) ₂ ; or n is 1, R ₁ is —COOH, and X is —CH═CH—.

  In one embodiment, the lonidamine analog is a 1,3-substituted indazole (eg, 1-halobenzyl-1H-indazole). In another embodiment, the lonidamine analog is 3-substituted 1-benzyl-1H-indazole. In another embodiment, the lonidamine analog is a 1-substituted indazole-3-carboxylic acid (eg, 1-halobenzyl-1H-indazole-3 carboxylic acid).

Biological equivalents Further, lonidamine analogs that can be used in the treatment methods of the present invention include the biological equivalents and pharmacophores of lonidamine and the analogs described herein. A biological equivalent is a well-known means for predicting the biological activity of a compound, based on the premise that compounds with similar size, morphology and electron density can have similar biological activity. It is. To form a biological equivalent of a given molecule, one or more atoms or groups are substituted with a known biologically equivalent substituent for that atom or group. Known biologically equivalent substituents, for example, -F, _-OH, -NH 2, compatibility -Cl and -CH _3; compatibility -Br and _-i-C 3 _{H 7;} - compatibility I and _{-t-C 4 H 9; -O} -, - S -, - NH -, - CH 2 and -Se- compatibility; -N =, - CH =, and -P = compatibility Phenyl group and pyridyl group compatibility; -C = C- and -S- compatibility (eg, benzene and thiophene); unsaturated carbon (R ₁ -C (= R compatibility ₃₎ -R ₂₎ aromatic nitrogen _(R 1 -N for _(R 3) -R _2); and -CO -, - SO- and -SO ₂ - compatibility and the like of. These examples are not intended to limit the scope of biologically equivalent equivalents, and one skilled in the art can identify other biologically equivalent substitutions known in the art. See, for example, Patani and LaVoe, 1996; and Burger, 1991.

  (Pharmacophores) In addition to the lonidamine analogs described herein, the lonidamine analogs that can be used in the methods of the invention are generally lonidamine and any pharmacophore of the above lonidamine analogs. possible. In many cases, an appropriate quantitative prediction of the binding capacity of a known molecule can be made based on the spatial arrangement of a small number of atoms or functional groups in the molecule. Such an arrangement is called a pharmacophore, and once a pharmacophore in a molecule is identified, this information can be used to identify other molecules that contain the same or similar pharmacophore. . Such methods are well known to those of ordinary skill in the medicinal chemistry field and the structural information described herein identifies the pharmacophore of lonidamine analogs associated with the treatment of lonidamine and BPH. As such, one of skill in the art can identify other LND analogs that include pharmacophores and are therefore useful for treating BPH. An example of a program that can be used to perform pharmacophore related searches is the 3D pharmacophore search program from Chemical Computing Group (see http://www.chemcomp.com/fdept/prodinfo.htm). .

For lonidamine analogs of particular interest, see tolnidamine (1- (4-chloro-2-methylbenzyl) -1H-indazole-3-carboxylic acid, AF1923); Ansari et al., 1998; Corsi et al., 1976. That. Tornidamine (TND) differs from lonidamine by the presence of a methyl substituent instead of a chlorine substituent at the 2-position of the benzyl group. Other analogs of lonidamine with biological activity are described in the following publication: US Patent No. 3, entitled “Substituted 1-Benzyl-1H-Indazole-3-Carboxylic Acids and Derivatives Thereof” 895, 026; Corsi et al., 1976, “1-Halobenzyl-1H-Indazole-3-Carboxylic Acids. A New Class of Antigenetic Agents, 1988: Journal of Medicine 78, Journal of Medicine 78, Journal of Medicine 78. Research n the Study of Indazole Carb xylic Acids ", Chemotherapy 27: 9-20; Lobl et al., 1981," Effects of Lonidamine (AF 1890) and its analogues on follicle-stimulating hormone, luteinizing hormone, testosterone and rat androgen binding protein concentrations in the rat and rhesus monkey. " , Chemotherapy 27: 61-76; U.S. Pat. No. 6,001,865 entitled “3-Substituted 1-Benzyl-1H-Individual Derivatives As Antigenic Agents”. And Cheng et al., 2001, "Two new male contraceptives exert their effects by depleting germ cells prematurely from the testis", Biol Reprod. 65: 449-61 (which describes AF-2364 and AF-2785 and other compounds). The structures of lonidamine (I, R = Cl), tornidamine (I, R = CH ₃ ), AF-2364 (II) and AF-2785 (III) are shown below.

（ロニダミンアナログの機能的特徴）本発明での使用に適切なロニダミンアナログは、ヒト、非ヒト霊長類、または他の哺乳動物に投与した場合に、前立腺上皮細胞の細胞エネルギー代謝を妨害するアナログである。薬学の分野で通常であるように、化合物（例えば、ロニダミン）の全ての構造的アナログが薬理学的に活性であるわけではない。活性な形態は、親化合物の活性についてアナログを慣用的にスクリーニングすることによって同定され得る。種々のアッセイおよび試験が、ロニダミンアナログの薬理学的活性を評価するために使用され得、これには、本明細書中において以下およびそれ以外で記載されるようなインビトロアッセイ、ヒト、非ヒト霊長類および他の哺乳動物における前立腺機能（クエン酸産生およびＡＴＰ産生を含む）のインビボアッセイ、ヒト、非ヒト霊長類および他の哺乳動物における前立腺の大きさのインビボアッセイ、ならびに／あるいは臨床的研究が挙げられる。

Functional Characteristics of Lonidamine Analogs A lonidamine analog suitable for use in the present invention interferes with cellular energy metabolism of prostate epithelial cells when administered to humans, non-human primates, or other mammals. It is analog. As is usual in the pharmaceutical field, not all structural analogs of compounds (eg, lonidamine) are pharmacologically active. Active forms can be identified by routine screening of analogs for the activity of the parent compound. A variety of assays and tests can be used to assess the pharmacological activity of lonidamine analogs, including in vitro assays, human, non-human as described herein below and elsewhere. In vivo assays of prostate function (including citrate production and ATP production) in primates and other mammals, in vivo assays of prostate size in humans, non-human primates and other mammals, and / or clinical studies Is mentioned.

  Apoptosis assay in cell lines Lonidamine induces apoptosis in cell lines derived from human prostate cells. The induction of apoptosis was significantly greater in LNCaP cells (ATCC number CLR-1740), citrate-producing prostate cell lines than in PC3 cells (ATCC number CLR-1435), citrated prostate cell lines, and lonidamine Consistent with the sensitivity of citrate-producing prostate cells to metabolic inhibitors such as In some embodiments of the invention where a lonidamine analog is used for the treatment or prevention of BPH or its manifestation, an analog with similar apoptosis-inducing activity is selected. Thus, in some embodiments of the invention, a lonidamine analog that induces apoptosis (enhances caspase 3 activity) in citrate producing prostate cells (eg, LNCaP cells) is administered to treat BPH. To do. In some embodiments of the invention, lonidamine analogs that induce apoptosis in LNCaP cells to a significantly higher degree than in PC3 cells are administered to treat BPH. In some embodiments of the invention, induction of apoptosis by lonidamine analogs is assayed at the analog concentration where the difference in the level of apoptosis in the two cell lines, LNCaP cells and PC3 cells, is greatest (provided that this The concentration of the analog used in the assay is 1 mM or less) at least about 2 times greater in LNCaP cells than in PC3 cells (sometimes at least about 3 times, at least about 4 times, or at least about 10 times) large).

  Apoptosis assay in primary cell cultures Lonidamine induces apoptosis in primary cultures of human prostate epithelial cells. Induction of apoptosis is significantly higher in primary cultures of prostate epithelial cells than in primary cultures of human prostate stromal cells, consistent with the sensitivity of citrate-producing prostate cells to metabolic inhibitors such as lonidamine. In some embodiments of the invention in which a lonidamine analog is administered for the treatment or prevention of BPH or its manifestation, an analog having apoptosis-inducing activity similar to lonidamine is selected. Thus, in some embodiments of the invention, lonidamine analogs that induce apoptosis in prostate epithelial cells are administered to treat BPH. In some embodiments of the present invention, a lonidamine analog is used that induces apoptosis in primary cultures of prostate epithelial cells to a significantly higher extent than in primary cultures of human prostate stromal cells. In some embodiments of the invention, the lonidamine analog does not significantly induce apoptosis in stromal cells. In some embodiments of the invention, induction of apoptosis by a lonidamine analog is assayed at the concentration of the analog that has the greatest difference in the level of apoptosis in the two cell lines, epithelial cells and stromal cells, provided that If the concentration of analog used in the assay does not exceed 1 mM), it is at least 2 times greater in epithelial cells (sometimes at least 4 times, sometimes at least 10 times, and sometimes at least 20 times greater) in stromal cells .

  HIF-1α expression assay Lonidamine reduces HIF-1α expression / accumulation (measured in the nuclear fraction) to approximately one-half at 200 micromolar concentrations in cells cultured under hypoxic conditions. , Decreased to below 1/5 (and below 1/10) at higher lonidamine concentrations. Accordingly, in some embodiments of the invention, the lonidamine analog is at least about 2 minutes in LNCaP cells cultured under hypoxic conditions compared to a culture in the absence of such lonidamine analog. Decrease HIF-1α expression (prevent HIF-1α accumulation) by at least about 1/5, at least about 1/5, or at least about 1/10.

  The effect of lonidamine on HIF-1α expression in prostate cells appears to be more pronounced in LNCaP cells than in PC3 cells cultured under hypoxic conditions (oxygen levels <0.1%). Some lonidamine analogs useful for the treatment of BPH according to the present invention have similar effects.

  (Hexokinase activity) As discussed above, although not intended to be bound by any particular mechanism, the effect of lonidamine on the prostate is at least due to its effect on mitochondrial and mitochondrial hexokinase activity in secretory epithelial cells. Can be mediated in part. Accordingly, some lonidamine analogs useful in the present invention have hexokinase inhibitory activity that is as high as or higher than lonidamine. Assays for hexokinase activity are known in the art. See Fanciuli et al., 1996, and Floridi et al., 1981.

  (Anti-spermatogenic activity) Similarly, the anti-spermatogenic activity of lonidamine is thought to result, at least in part, from the energy decay (inhibition of energy production) effect in germ cells. Some lonidamine analogs useful in the present invention have antispermatogenic activity as high as or higher than lonidamine. Assays for anti-spermatogenic activity are known in the art. See, eg, Grima et al., 2001; Lohiya et al., 1991.

  In addition to in vitro assays, lonidamine analogs can be evaluated in vivo for suitability for use in the methods of the invention. For example, without limitation, suitable assays include measurement of prostate function and activity.

  In vivo measurement of prostate function The effect of a compound on prostate function (especially respiration) can be assessed by monitoring prostate tissue metabolism following administration of the compound. Some lonidamine analogs useful in the present invention detectably reduce ATP production, citrate production, and / or lactate production by the prostate in animals, including humans, non-human primates and other mammals. To do. ATP, citrate, and / or lactate levels can be monitored directly and / or indirectly in vivo using magnetic resonance spectroscopy (MRS) or other method techniques. See, for example, Narayan and Kurhanewicz, 1992; Kurhanewicz et al., 1991; Thomas et al., 1990 for MRS assays that can be applied for this purpose.

  In vivo measurement of prostate size. The effect of a compound on prostate size can be determined using standard methods (eg, ultrasonography or rectal palpation for humans, and ultrasound and / or organ weight comparison in animals). ) Can be evaluated after administration of the compound. Assays can be performed in humans, or more generally healthy non-human animals or other animal models of monkeys, dogs, rats or BPH (Jeyaraj et al., 2000; Lee et al., 1998; Mariotti et al., 1982). See Some lonidamine analogs useful in the present invention detectably reduce prostate size in such assays and animal models.

  Clinical Trials Clinical trials (e.g., clinical trials described for lonidamine in the examples below) can be used to evaluate the therapeutic effects of lonidamine analogs.

  The activity of the lonidamine analog of interest in any of the above assays, models and tests can be compared to the activity of lonidamine to provide guidance and other information regarding dosing schedules for the compound. In general, lonidamine analogs that have higher activity in biological activity per mg than lonidamine are of particular interest.

(4. Synthesis and form of lonidamine and lonidamine analogs)
Lonidamine and lonidamine analogs and lonidamine derivatives can be prepared using well-known synthetic methods and the present disclosure. The synthesis of lonidamine is described in US Pat. No. 3,895,026 and German Patent 2,310,031. Synthesis of exemplary lonidamine analogs, including tolnidamine (TND), has been described in the art (eg, Corsi et al., 1976, “1-Halobenzyl-1H-Indazole-3-Carboxylic Acids. A New). Class of Antispermatogenic Agents ", Journal of Medicinal Chemistry 19: 778-83; Cheng et al., 2001," Two new male contraceptives exert their effects by depleting germ cells prematurely from the testis ", Biol Reprod.65: 449-61; Silvestrini, 981, "Basic and Applied Research in the Study of Indazole Carboxylic Acids", Chemotherapy 27: 9-20; Lobl et al., 1981, "Effects of Lonidamine (AF 1890) and its analogues on follicle-stimulating hormone, luteinizing hormone, testosterone and rat and binding binding proteins in the rat and rhesus monkey ", Chemotherapy 27: 61-76; and U.S. Patent Nos. 3,895,026 and 6,001,865. Of course, the lonidamine analogs useful in the practice of the present invention are not limited to analogs for the specific structures provided in this disclosure or cited references, and the above compounds are exemplified by It is understood that the lonidamine analogs useful in the methods of the present invention are analogs as described herein or in the pharmaceutical and patent literature, provided that the invention is not limited thereto. Those skilled in the art, guided by the disclosure of the present invention, can synthesize novel analogs suitable for use according to the present invention using conventional methods of medicinal chemistry and the present disclosure.Lonidamine useful in the practice of the present invention And methods for the synthesis of lonidamine analogs (indazole derivatives) are described in US Provisional Patent Application No. 60/5769. No. 8 described in (June 20, 2004 filed) and U.S. Provisional Patent Application No. 60 / 588,694 (July 15, 2004 filed), both applications are incorporated herein by reference.

  In certain embodiments, lonidamine or a lonidamine analog is provided in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include acid addition salts and base salts. Salts with bases are, for example, alkali metal salts or alkaline earth metal salts (for example sodium, potassium, calcium or magnesium salts), or ammonium salts (for example ammonia or suitable organic amines (for example diethylamine, diamine). -(2-hydroxyethyl) -amine or tri- (2-hydroxyethyl) -amine)). Suitable acids for forming acid addition salts are, for example, inorganic acids (eg hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid), or organic acids (eg organic sulfonic acids (eg benzene) Sulfonic acid, 4-toluenesulfonic acid or methanesulfonic acid) and organic carboxylic acids (eg acetic acid, lactic acid, palmitic acid, stearic acid, malic acid, maleic acid, fumaric acid, tartaric acid, ascorbic acid or citric acid)) .

  Administration of esters, amides and prodrug derivatives of lonidamine and lonidamine analogs, as well as administration of polymorphic, enantiomeric, tautomeric, solvates, hydrates, etc., in the practice of the invention (For example, see US Pat. No. 6,146,658 for general information on the preparation of such derivatives derived from the compound of interest). Examples of prodrug forms of lonidamine and lonidamine analogs are described in US Provisional Patent Application No. 60 / 257,026 (invention title “Tertiary amine prodrugs of lonidamine and analogs”; filed July 8, 2004). It is incorporated by reference in the book.

(5. Patients who benefit from the administration of lonidamine)
The present invention allows administration of lonidamine to men affected or susceptible to BPH can be therapeutically effective. Thus, in one aspect of the invention, lonidamine or a lonidamine analog is administered to a subject in need of treatment for BPH. In one embodiment, the subject in need of treatment is a human male who does not have cancer. As used herein, a “subject in need of treatment for BPH” is a man diagnosed with BPH. BPH can be diagnosed using methods and criteria known in the art. The most common test is intrarectal palpation, in which the physician determines whether the prostate is of normal size and stiffness. Other diagnostic assays include urine flow rate tests, determination of residual urine volume after urination (eg, by abdominal pulsation, residual drainage, X-ray urography or ultrasonography), American Urological Association Symptom Index (AUASI). Barry et al., 1992) or International Prostate Symptom Score (IPSS; Barry et al., 2001) recording of moderate or severe symptoms, and other tests known in the art.

  Desired clinical outcomes of BPH treatment include alleviation or recovery of one or more symptoms of BPH (see below), reduction in prostate size (see below), baseline measurements prior to initiation of therapy Serum PSA with decreased AUSISI or IPSS score compared to (eg, 3 or more (eg, 5 or more), AUSISI or IPSS score of less than 8, at least about 20% (eg, at least about 40%)) (As discussed below, a temporary rise in serum PSA can occur upon initial administration of lonidamine or a lonidamine analog), less than 4 (eg, less than 2) serum PSA, urodynamic parameters And other desirable results that are recognized by the treating physician to indicate a decrease in the severity of BPH in the subject. Evaluation of response to treatment can be performed at any time after the first administration of the drug, for example, evaluation can be about 30 days, about 60 days or about 90 days after the start of treatment. Alternatively, the evaluation can be performed about 6 days, about 12 days, about 18 days, about 24 days, or a few months after the start of treatment, or less than about 30 days after the end of the treatment process. About 30 days, about 60 days, or about 90 days.

  In a related aspect, lonidamine or a lonidamine analog is administered to a human subject exhibiting symptoms associated with BPH to reduce the frequency or severity of the symptoms. As used herein, “BPH related symptoms” refers to any one or more of the following symptoms: (1) Urinary urgency, (2) Terminal urine instillation, (3 ) Frequent urination, (4) nocturia, (5) weak / slow urine flow, (6) sensation that the bladder is not completely empty, (7) intermittent urination, (8) strength, (9) urination Disability, (10) hematuria, (11) acute urinary retention, (12) urinary tract infection, and (13) incontinence. In addition, there is an association between BPH and erectile dysfunction. Thus, in one embodiment of the invention, lonidamine or a lonidamine analog is administered to treat erectile dysfunction. Administration of lonidamine or a lonidamine analog according to the methods of the invention typically results in a reduction or elimination of the severity of one or more of these symptoms; usually, a reduction or elimination of the severity of all of these symptoms. And can result in the elimination of all these symptoms.

  In another related aspect, lonidamine or a lonidamine analog is administered to reduce prostate size in a human subject in need of prostate size reduction. As used herein, a “human subject in need of prostate size reduction” is (1) imaging (eg, ultrasonography, magnetic resonance imaging) or (2) digital rectal An enlarged prostate as determined by examination or (3) one or more signs or symptoms that result directly or indirectly from urethral compression by the prostate, including, for example, the symptoms of BPH discussed herein A man with Reduction of serum PSA (prostate specific antigen) is also a useful surrogate for prostate volume reduction. Varying from individual to individual, enlarged prostates are often over 30, 40, or 50 grams in size. The degree of prostate size reduction varies from subject to subject due to many factors, including the degree of enlargement at the start of treatment, but is typically at least about the size of the prostate. A 10% volume reduction, more often at least about 25% reduction, sometimes at least about 40% reduction, and sometimes even more than 40% reduction is observed. This reduction can be determined by imaging or other methods. Serum PSA also serves as a useful substitute for prostate volume in some instances.

  In a related aspect, lonidamine or a lonidamine analog is administered to a subject at a serum PSA level greater than 2 ng / ml. PSA is only secreted by prostate epithelial cells. In men with BPH, higher PSA levels suggest a relatively higher ratio of epithelial cell proliferation to stromal cell proliferation than men with lower PSA levels. The present invention provides a number of diagnostic methods suitable for use in determining patients who should respond favorably to treatment with lonidamine or lonidamine analogs. Thus, lonidamine treatment can provide a therapeutic benefit to subjects with PSA levels greater than 2 ng / ml. Thus, by identifying subjects with serum PSA values greater than 2 ng / ml, subjects who are expected to benefit most significantly from treatment according to the present invention are selected in the male population with BPH. obtain. In one embodiment of the invention, the subject has a PSA level greater than about 4 ng / ml. In one embodiment, subjects selected for treatment with lonidamine or a lonidamine analog are less than about 10 ng / ml because higher PSA levels are also and more probably associated with prostate cancer than BPH. PSA level of

  In one aspect of the invention, lonidamine or a lonidamine analog is administered to a subject that benefits from prevention of BPH. In one example, a “subject benefiting from prevention of BPH” previously had surgery, transurethral microwave thermotherapy, transurethral needle ablation, transurethral electrovapor therapy, laser treatment, balloon dilatation, prostate urethral stent, Men who have been treated with BPH by medication or other therapy and are not currently diagnosed with BPH or exhibit symptoms of BPH. In another example, a subject who benefits from BPH prevention is a male who has an increased risk of developing BPH due to age (eg, above 40, above 50, above 60). , Or men older than 70). In another example, a subject benefiting from prevention of BPH may be asymptomatic or have a sufficiently mild symptom to make no clear diagnosis of BPH, but elevated serum PSA levels (eg, PSA> 2 ng / ml, or in some cases> 4 ng / ml).

  Thus, in some cases, the subject to whom lonidamine is administered according to the methods of the invention is a man who has been previously treated with BPH, while in other cases, the subject has been previously treated with BPH. No men. Similarly, it is clear that any reference herein to the administration of lonidamine applies equally to the administration of a biologically active lonidamine analog.

  In one embodiment of the invention, a subject in need of treatment or prevention of BPH is also not in the treatment of cancer or has no cancer. In related embodiments, the subject in need of treatment or prevention of BPH has not been diagnosed as having cancer. In one embodiment, the subject in need of treatment or prevention of BPH does not have cancer. In one embodiment, the subject in need of treatment has a cancer other than prostate cancer but does not have prostate cancer. As used herein, “cancer” has its usual medical meaning and is generally a malignant tumor (head cancer) characterized by clonality, autonomy, regression and metastasis. Cervical cancer, prostate and breast cancer, leukemia and lymphoma) (see Mendelsohn, 1991).

  In one embodiment, the present invention provides a method of treating BPH in a patient by administering lonidamine to the patient. In a related embodiment, the invention provides a method for treating BPH comprising: (a) administering lonidamine to a patient diagnosed with BPH; and (b) one or more of BPH Determining whether the onset of symptoms is reduced in this patient. In one embodiment, the invention includes (a) diagnosing BPH in a patient, (b) administering lonidamine to the patient, and (c) one or more symptoms of BPH being reduced in the patient. A method for treating BPH is provided by determining whether or not. In one embodiment, the present invention provides a method of treating BPH in a patient by administering a lonidamine analog to the patient. In a related embodiment, the present invention provides a method for treating BPH comprising the steps of: (a) administering a lonidamine analog to a patient diagnosed with BPH; and (b) BPH. Determining whether one or more episodes are reduced in the patient. In one embodiment, the invention comprises (a) diagnosing BPH in a patient, (b) administering a lonidamine analog to the patient, and (c) reducing one or more symptoms of BPH in the patient. A method for treating BPH is provided by determining whether to do so. In the foregoing embodiments, optionally, the patient has not been diagnosed with or is not being treated for cancer; optionally, has a PSA of 2 ng / ml or less; or, as appropriate Has a PSA greater than 2 ng / ml and less than 10 ng / ml.

  In another aspect, the present invention provides a method involving promoting the use of lonidamine or a lonidamine analog, and b) selling the lonidamine or lonidamine analog to an individual for use in the treatment of BPH. To do. In one embodiment, this advertising step refers to a trademark identifying a lonidamine product (or lonidamine analog product), and the lonidamine (or analog) sold in step (b) is identified by the same trademark. Individuals sold with lonidamine include corporations (businesses) and the like, and “the process of selling BPH to individuals for use for the treatment of BPH” is distributed to patients for the treatment of BPH, for example It is understood to include a process of selling to a medical facility.

  In another embodiment, the present invention provides a method of treating acute urinary retention in a human by administering lonidamine or a lonidamine analog to a human in need of such treatment. Since acute urinary retention may be a symptom of BPH, this embodiment of the invention is diagnosed as having acute urinary retention but having BPH when lonidamine or a lonidamine analog is first administered. Applicable to any subject that has not.

(6. Dosage, route, schedule and duration of administration)
Various routes and dosing schedules are suitable for administration of lonidamine and lonidamine analogs according to the present invention.

  The preferred mode of delivery of lonidamine and lonidamine analogs to the patient is oral delivery. Preferred dosage forms for oral administration are pills, tablets, capsules, caplets and the like, especially when formulated for sustained release. Other forms suitable for oral administration include troches, elixirs, suspensions, syrups, wafers, lozenges and the like. Other modes of administration are also contemplated, including parenteral routes, inhalation sprays, transdermal routes, rectal routes, intraprostatic injection (eg, of lonidamine-containing microparticles) and other routes. Can be mentioned. Lonidamine and lonidamine analogs can be formulated into suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles suitable for each route of administration. In one embodiment, the dosage form is a 150 mg unit dosage form marketed in Italy by ACRAF for the treatment of cancer under the trade name Doridamina. Doridamin is lonidamine 150 mg; starch 87 mg; granule cellulose 55 mg; lactose 40 mg; carboxymethyl sodium starch 15 mg; hydroxypropyl methylcellulose 11 mg; precipitated silica 4.5 mg; magnesium stearate 3.5 mg; titanium dioxide 0.4 mg; Contains 0.4 mg. Another formulation is lonidamine 150 mg (intragranular), 87 mg corn starch (intragranular), 40 mg lactose (intragranular), 3 mg colloidal silicon dioxide (intragranular), 1.5 mg colloidal silicon dioxide (extragranular), 55 mg microcrystalline cellulose (extragranular), 15 mg sodium starch glycolate (extragranular), 3.5 mg magnesium stearate (extragranular), 9 mg hydroxypropyl methylcellulose (extragranular), 10.9 mg OPADRY white (coating). .

  The dose, schedule and duration of administration of lonidamine and lonidamine analogs depend on various factors, including the age, weight and health status of the subject, if any, the severity of BPH symptoms. , Subject medical history, concomitant treatment, therapeutic purpose (eg, treatment or prevention), mode of drug administration, formulation used, patient response to the drug, and the like. For purposes of illustration and not limitation, three general categories of dosing for the administration of lonidamine and lonidamine analogs can be described: high dose, low dose, and intermediate dose. For example, the standard lonidamine dose used for the treatment of cancer for which lonidamine is approved in several European countries is 150 mg by oral TID over about 30 days.

  Low dose Low dose is contemplated for the treatment and prevention of BPH. Exemplary low doses of lonidamine or lonidamine analogs range from 1 to 300 mg / day (total daily dosage), more often from 5 to 300 mg / day, or sometimes from 5 to 70 mg / day. Dosages include but are not limited to these. Other exemplary low dose ranges are 1-25 mg / day, 20-45 mg / day, 40-65 mg / day, 40-70 mg / day, 50-100 mg / day, 80-100 mg / day, 50-200 mg / day. , And 50-300 mg / day. In one embodiment, the low dose is 150 mg and is administered orally once per day; the Doridamina unit dose form can be used in this embodiment. In another embodiment, the low dose is 75 mg, administered orally once or twice daily. The Doridamina unit dosage form can be used in this embodiment by dividing it into two equal parts.

  As indicated, the daily dosage recommended herein can be divided, for example, for 2, 3, 4 administrations per day. In one embodiment, the drug is formulated for administration once per day. In one embodiment, the drug is frequently formulated for less than one administration per day. In another embodiment, a modified release form of the drug is used.

  Administration of low doses of lonidamine may be once a day, once every other day, with a 5-day dosing for 2 days, and other schedules, selected by the administering physician according to the teachings herein.

  The advantage of the low dose schedule of the present invention is that it limits undesirable side effects (mainly myalgia and testicular pain), although this dose has been reported with higher doses of lonidamine, usually mild. Simultaneously with exclusion, it can continue to be administered for weeks to months.

  A low dose schedule may be used for treatment or prevention. In one embodiment, the low dosage form is used for higher, maintenance doses after the initial sensitizing or loading dose.

  High Dose In another embodiment, BPH is treated according to the methods of the invention by administering a higher dose of lonidamine or a lonidamine analog to a BPH patient (usually over a shorter period than a lower dose). Exemplary high doses include total daily doses greater than 0.5 g (eg, 0.5-5 g / day, 0.5-3 g / day, 0.5-1 g / day, and 1-3 g / day). Day, or doses in the range of higher doses). The daily dosage can be divided, for example, into 2, 3 or 4 administrations per day. In one embodiment, the drug is formulated for administration once per day, or frequently less than once per day. In one embodiment, a modified release form of the drug is used. Alternatively, herein the high dose is once per week, once every two weeks, or once a month (eg, 0.5-5 g / dose) or by the administering physician herein. May be administered by other schedules selected according to the teachings of

  A high dose schedule may be used for treatment or prevention. In one embodiment, the high dose is administered in combination with or after surgery for BPH or other non-drug treatment.

  Intermediate dose In another embodiment, BPH is treated according to the methods of the invention by administering lonidamine or a lonidamine analog to a BPH patient at an intermediate dose between a high dose and a low dose. Exemplary intermediate doses include doses greater than 300 mg / day and less than 500 mg / day (eg, doses in the range of> 300-400 mg / day or 400 <500 mg / day (eg, 450 mg / day)). However, it is not limited to these. The daily dosage can be divided, for example, into 2, 3 or 4 administrations per day. In one embodiment, the drug is formulated for administration once per day, or frequently less than once per day. In one embodiment, a modified release form of the drug is used. Alternatively, this intermediate dose may be determined once at a time, once a week, once every two weeks, or once a month (eg, 300-500 mg / dose) or other determined by the administering physician. It can be administered on a schedule. In one embodiment, the daily dosage is 150 mg of lonidamine or a lonidamine analog and is taken three times a day. In one embodiment, 150 mg of lonidamine or a lonidamine analog is administered once a day for 28 days. In other embodiments, lonidamine or a lonidamine analog is administered at a dose of 5 mg, 25 mg, 50 mg, 75 mg or 100 mg per day for 4 to 26 weeks or longer.

  An intermediate dose schedule may be used for treatment or prevention. In one embodiment, the intermediate dose is administered in combination with or after surgery for BPH or other non-drug treatment.

  These dosing schedules are exemplary and not limiting, and the dosing schedule is based on the patient's response to the treatment or use of a lonidamine analog having an activity / dose profile that differs significantly from that of, for example, lonidamine. It is understood that it can change during the process.

  Duration In therapeutic and prophylactic applications, lonidamine or lonidamine analogs can be administered once or several times over a period of months to years. In one embodiment of the invention, lonidamine or an analog is administered to symptomatic (eg, experiencing difficulties in urination) BPH patients only until the symptoms are alleviated or eliminated, and then the treatment is If it does not recur or until the symptoms reappear, it is discontinued. When symptoms reappear, lonidamine or analog administration is resumed. In another embodiment, treatment is continued for at least a period of time (eg, 1 week, 2 weeks, 1 month or months) even after symptoms disappear or decrease to an acceptable target level. In another embodiment, the drug can be administered to an asymptomatic subject to prevent the occurrence or recurrence of symptoms (ie, administered prophylactically).

(7. Combination of treatments)
Lonidamine and lonidamine analogs can be administered to BPH patients in combination with other drugs or procedures intended to treat BPH, can relieve symptoms of BPH, or the effects of lonidamine or lonidamine analogs. It can be enhanced or provide other therapeutic benefits. Administration of “combined” drugs includes concurrent administration (both drug administration to a patient over a period of time (eg, administration of lonidamine and tamsulosin every other day for a month), simultaneous administration (where the drugs are Almost simultaneously (eg, administered within about a few minutes to several hours of each other)) and co-formation (wherein the drugs are suitable for oral, parenteral or other administration) Exemplary agents for administration in combination with lonidamine or lonidamine analogs include zinc, alpha blockers, 5-alpha-reductase inhibitors, urinary incontinence And, but not limited to, plant extracts, combined with lonidamine or lonidamine analogs Other agents for combined administration include other metabolic inhibitors (including but not limited to other hexokinase inhibitors and other inhibitors of glycolysis, including 2-deoxy-D-glucose). , But not limited to), and inhibitors of HIF-1α (direct or indirect).

  Zinc As discussed above, high concentrations of zinc in prostate secretory epithelial cells inhibit m-aconitase and increase its tissue dependence on glycolysis for energy production. In accordance with the methods of the present invention, in some patients, zinc (eg, zinc chloride, zinc gluconate, zinc sulfate, zinc acetate, zinc aspartate, zinc citrate, zinc glycerate, zinc oxide, zinc picolinate, etc.) It may be beneficial to co-administer with the drug composition of the present invention to maximize the efficacy of the treatment. By way of example and not limitation, 15-300 mg / day of zinc can be administered for this purpose, typically 30-50 mg / day being administered.

  Alpha-adrenergic blockers Alpha-blockers alleviate some symptoms of BPH without curing the underlying disease. These drugs work by relaxing muscles in the bladder neck and in the prostate, reducing pressure on the urethra. Exemplary alpha-blockers include doxazosin (Cardura), terazosin (Hytrin), tamsulosin (Flomax), alfuzosin (Xatral), and prazosin (Hypovase). In one embodiment of the invention, the α-blocker is administered in combination with lonidamine or a lonidamine analog to treat BPH. In another embodiment, the alpha-blocker is a lower (amount) or less frequent (e.g., not daily) than a "standard" dosage (the dosage indicated for subjects without lonidamine administration) Every other day, administered in combination with lonidamine or a lonidamine analog.

  5-α-Reductase Inhibitors 5-α-reductase inhibitors inhibit the conversion of testosterone into dihydrotestosterone 2 (DHT), an androgen that contributes to prostate swelling. An exemplary 5-α-reductase inhibitor is finasteride (Proscar). Another exemplary 5-α-reductase inhibitor is Avodart® (dusteride). In one embodiment of the invention, the 5-α-reductase inhibitor is administered in combination with lonidamine to treat BPH. In another embodiment, the 5-α-reductase inhibitor is administered at a lower dose (amount) or less frequently (eg, daily) than a “standard” dose (the dose indicated for subjects without lonidamine administration). But every other day) in combination with lonidamine (or lonidamine analog).

  (Treatment for urinary incontinence) Treatment for urinary incontinence includes α-adrenergic agonists (eg, pseudoephedrine hydrochloride (Sudafed) and phenylpropanolamine); anticholinergic agents (eg, dicyclomine hydrochloride (eg, Bentyl), and hyoscyamine sulfate (Levsin SL, Levsin, Levsinex, Cystospaz-M, Levbid)); and antispasmodic (darifenacin) (Enablex), solifenacin succinate Tolterodine L-tartrate (Detrol and De) rol LA), and trospium (Sanctura)) can be mentioned.

  Glycolytic and mitochondrial function inhibitors Glycolytic inhibitors (eg, 2-deoxy-D-glucose, and compounds that inhibit glucose transport), mitochondrial function inhibitors, mitochondrial toxins, and hexokinase inhibitors (eg, 3-bromopyr) Bate and its analogs) can also be used in combination with lonidamine or lonidamine analogs to treat BPH. Such inhibitors are known in the art and are described in PCT Patent Publication No. WO 01/82926 (published Nov. 8, 2001); US Pat. No. 6,670,330; No. 6,218,435; No. 5,824,665; No. 5,652,273; and No. 5,643,883; U.S. Patent Application Publication No. 20030072814; No. 20020077300; No. 200200335071; / 754239 is included. Such inhibitors can be administered in combination with lonidamine or lonidamine analogs for therapeutic benefit in the treatment of BPH.

  Plants Saw Palmetto (Serenoa repens) or extracts thereof, or Pygeum Africanum or extracts thereof, can be administered in combination with lonidamine or a lonidamine analog for therapeutic benefit in the treatment of BPH.

  Procedure In addition, lonidamine or a lonidamine analog can be administered in combination with or prior to the procedure for the treatment of BPH, including surgery (transurethral resection of the prostate; Urethral incision; or open prostatectomy), laser treatment, transurethral microwave hyperthermia, balloon dilation, placement of urethral prostate stent, transurethral needle ablation, transurethral electrical transpiration of the prostate Or other non-drug therapies.

(8. Dosage form)
Unit Dosage Forms The compounds used in the methods of the invention are formulated in compositions suitable for therapeutic administration. In one embodiment, the method of the invention is practiced with unit dosage form of lonidamine, marketed as Doridamina (by ACRAF) in Italy. New dosage forms of lonidamine are also provided by the present invention. For example, the present invention provides lonidamine unit dosage pharmaceutical formulations (including tablets, capsules, caplets and pills) that are suitable for oral administration, and in various embodiments, the lower limit is (in mg). Including amounts of lonidamine in a range limited by 1, 5, 10, and 50 and an upper limit of 10, 20, 40, 50, 70 and 100, where the upper limit is in mg and is greater than the lower limit, Convenient for certain low dose schedules. In another embodiment, the unit dosage form has a lower limit (in mg) of 200, 300, 500 or 1000 and an upper limit of 500, 1000, 3000 or 5000 (where the upper limit is greater than the lower limit and is in mg) In particular, it is convenient for high dose schedules. In still other embodiments, the formulation comprises between 100 mg and 200 mg of compound (eg, 150 mg), between 200 mg and 5000 mg, between 200 mg and 1000 mg, or between 500 mg and 1000 mg. Including. The lonidamine analog can be similarly formulated. Specific purpose dosage forms include 5, 25, 50, 100 or 150 mg of lonidamine.

  In addition to lonidamine and / or lonidamine analogs, the solid unit dosage forms of the present invention generally comprise a pharmaceutically acceptable carrier. As used herein, “pharmaceutically acceptable carrier” refers to a solid or liquid filler, diluent, or encapsulating material (eg, excipients, fillers, binders and pharmaceuticals). Including other ingredients commonly used in typical preparations), including but not limited to those described below. Methods for drug formulation are generally well known in the art, and the descriptions herein are exemplary and not limiting. See, for example, Ansel et al., 1999; Marshall, 1979.

  Suitable hydrophilic binders for use in the formulations of the present invention include copolyvidone (crosslinked polyvinyl pyrrolidone), polyvinyl pyrrolidone, polyethylene glycol, sucrose, dextrose, corn syrup, polysaccharides (acacia, guar, and Alginate), gelatin and cellulose derivatives (including HPMC, HPC and sodium carboxymethylcellulose).

  Water soluble diluents suitable for use in the formulations of the present invention include sugars (lactose, sucrose, and dextrose), polysaccharides (dextrates and maltodextrins), polyols (mannitol, xylitol, and sorbitol), and A cyclodextrin is mentioned. Non-water soluble diluents suitable for use in the formulations of the present invention include calcium phosphate, calcium sulfate, starch, modified starch, and microcrystalline cellulose.

  Surfactants suitable for use in the formulations of the present invention include ionic and nonionic surfactants, or wetting agents (eg, ethoxylated castor oil, polyglycolized glycerides, acetylated monoglycerides, Examples include sorbitan fatty acid esters, poloxamers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene derivatives, monoglycerides or ethoxylated derivatives thereof, sodium lauryl sulfate, lecithin, alcohols, and phospholipids.

  Suitable disintegrants for use in the formulations of the present invention include starch, clay, cellulose, alginate, gum, cross-linked polymer (PVP, sodium carboxymethylcellulose), sodium glycolate starch, low substituted hydroxypropylcellulose, and soy Examples include polysaccharides. Preferred disintegrants include modified cellulose gum (eg, cross-linked sodium carboxymethyl cellulose).

  Lubricants and glidants suitable for use in the formulations of the present invention include talc, magnesium stearate, calcium stearate, stearic acid, colloidal silicon dioxide, magnesium carbonate, magnesium oxide, silicic acid Calcium, microcrystalline cellulose, starch, mineral oil, wax, glyceryl behenate, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, sodium lauryl sulfate, sodium stearyl fumarate, and hydrogenated vegetable oils. Preferred lubricants include magnesium stearate and talc and combinations thereof.

  Preferred ranges of total weight for tablets or capsules can be about 40 mg to 2 g, about 100 mg to 1000 mg, and about 300 mg to 750 mg.

  Sustained Release Form Furthermore, the present invention provides a unit dosage form that is a sustained release formulation of lonidamine or a lonidamine analog, once a day at a frequency that is sometimes preferred to the patient for multiple day dosing. Allows (or less) oral dosing. Such sustained release formulations of the present invention (including tablets, capsules, caplets and pills) typically contain between 1 mg and 3 g of active compound, and various alternative embodiments are conventional Oral unit dose (eg, lower limit (in mg) 1, 5, 10, and 50 and upper limit 10, 20, 40, 50, 70 and 100 (where the upper limit is greater than the lower limit and is in mg) A limited range of drug amounts), including those described above, and is particularly advantageous for certain low or intermediate dose schedules. In another embodiment, the unit dosage form has a lower limit (in mg) of 200, 300, 500, 750 or 1000 and an upper limit of 500, 1000, 2000, 3000 or 5000 (where the upper limit is greater than the lower limit, the amount of drug in a range limited by (in mg).

  In one embodiment, the lonidamine or lonidamine analog in the sustained release formulation (also referred to as “modified” release form or “controlled” release form) is for a period greater than 6 hours (eg, greater than 12 hours) after administration. Released. In one embodiment, the sustained release formulation makes it possible to achieve a pharmacokinetic profile that is therapeutically comparable to dosing 150 mg of lonidamine three times a day, once a day.

  Examples of sustained release formulations of other drugs that can be modified according to the teachings herein that are useful in the present invention are well known in the art, eg, US Pat. No. 5,968,551; No. 5,266,331; No. 4,970,075; No. 5,549,912; No. 5,478,577; No. 5,472,712; No. 5,356,467 No. 5,286,493; No. 6,294,195; No. 6,143,353; No. 6,143,322; No. 6,129,933; No. 6 103,261; 6,077,533; 5,958,459; and 5,672,360. Sustained release formulations are also available in the scientific literature (eg, ORAL SUSTAINED RELEASE FORMULATIONS: DESIGN AND EVALUATION, A. Yacobi and E. Halperin-Walega, Ed., Pergamon Press, 1988). Morphology and drug release mechanism, eg, one unit (eg, matrix tablet, coated tablet, capsule), multiple units (eg, granules, beads, microcapsules), inert insoluble matrix, hydrophilic gel matrix (eg, biological Adhesive, corrosive, non-corrosive), and ion-exchange resin sustained release dosage forms).

  In one embodiment, the present invention administers a sustained release tablet dosage form comprising a daily therapeutic dose of about 1 mg to 2 g of lonidamine in a hydrophilic matrix to a patient in need of treatment for BPH once a day. Provides a method of treating BPH. The matrix is exemplary and not limiting: hydroxypropyl methylcellulose (about 20-40% by weight), lactose (5-15%), microcrystalline cellulose (4-6%), and 1-10 microns It may be selected from the group consisting of silicon dioxide (1-5%) having an average particle size in the range, often in the 2-5 micron range, most often in the range of about 2-3 microns.

Exemplary preferred sustained release formulations of the present invention include Formula A and Formula B in Table 1:
(Table 1)

本発明の徐放性処方物は、圧縮錠剤の形態であり得、この圧縮錠剤は、ロニダミン、ならびに胃（代表的には、約２）および腸（代表的には、約５．５）におけるｐＨ範囲にまたがる水性媒体中の薬物溶解速度を制御する、部分的に中和したｐＨ依存性結合剤の密な混合物を含む。

The sustained release formulations of the present invention can be in the form of compressed tablets, which are lonidamine and in the stomach (typically about 2) and intestine (typically about 5.5). Includes an intimate mixture of partially neutralized pH-dependent binders that control the rate of drug dissolution in aqueous media across the pH range.

  Many materials known in the pharmaceutical industry as “enteric” binders and enteric coatings have desirable pH solubility properties suitable for use in the sustained-release formulations of the present invention. These include phthalic acid derivatives (eg, vinyl polymers and copolymers, hydroxyalkyl cellulose, alkyl cellulose, cellulose acetate, hydroxyalkyl cellulose acetate, cellulose ether, alkyl cellulose acetate and esters thereof, and polymers and copolymers of lower alkyl acrylic acids and lower Alkyl acrylates, and phthalic acid derivatives of partial esters thereof).

A preferred pH dependent binder material is a methacrylic acid copolymer. Such copolymers are commercially available from Rohm Pharma as Eudragit ^™ L-100-55 as a powder or as L30D-55 as a 30% dispersion in water. Other pH-dependent binding materials that can be used alone or in combination include hydroxypropylcellulose phthalate, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, polyvinyl acetate phthalate, polyvinylpyrrolidone phthalate, and the like. The one or more pH dependent binders are present in the sustained release oral dosage form of the present invention in an amount ranging from about 1 to 20%, or 5 to 12%, or about 10%.

  The pH independent binder or thickener contained in the sustained release formulation of the present invention includes hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone, natural poly (meth) acrylate esters and the like. Substances. The pH independent binder is in an amount in the range of 1-10 wt% or 1-3 wt%, or about 2%.

  The sustained release formulations of the present invention may also include, in some embodiments, one or more pharmaceutical excipients (eg, non-pH) intimately mixed with lonidamine or a lonidamine analog and its pH dependent binder. Dependent binders or film formers, starches, gelatins, sugars, carboxymethylcellulose, etc.) and other useful pharmaceutical diluents (eg, lactose, mannitol, dry starch, microcrystalline cellulose, etc.) and surfactants (eg, , Polyoxyethylene sorbitan esters, sorbitan esters, etc.); and colorants and flavoring agents. Lubricants such as talc and magnesium stearate and tableting aids can also be used.

  The sustained release formulations of the present invention include any of the commercially available polymers suitable for use in such formulations, including but not limited to: cellulose, Ethylcellulose, methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylcellulose, microcrystalline cellulose, sodium carboxymethylcellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, polyvinylpyrrolidone, polyethylene oxide, polyethylene glycol, zein, alginate, Hypromellose phthalate, methacrylic acid copolymer, crospovidone, siri Aerogel, pregelatinized starch, corn starch, croscarmellose sodium, sodium starch glycolate, canderia wax, paraffin wax, carnauba wax, montan glycol wax, white wax, Eudragit (polymethacrylate), Aquacoat (ethylcellulose, cellulose acetate phthalate) ), Carbopol (acrylic acid polyalkene polyether copolymer), and Macrogol (polyethylene glycol).

The sustained release formulations of the present invention include formulations with controlled diffusion, which employ, for example:
(A) Reservoir system (where the drug is encapsulated in a polymer membrane and water diffuses through the membrane to dissolve the drug, which then diffuses out of the device) );
(B) a monolithic (matrix) system where the drug is suspended in a polymer matrix and diffuses out through a long pathway;
(C) Microencapsulated and coated granule system (where drug particles (or drug and polymer particles) on the order of 1 micron are coated on a polymer film, and particles coated with polymers having different release characteristics are contained in the capsule. Including embodiments delivered together);
(D) solvent activation system ((i) osmotic pressure control device (eg, OROS) (where osmotic agent and drug are encapsulated in a semi-permeable membrane and water is the device due to osmotic gradient) Drawn in and with increased pressure, the drug is forced out of the device through laser perforation; (ii) a hydrogel swelling system where the drug is dispersed in the polymer and / or the polymer is a drug particle And the polymer swells in contact with water (swelling is in some embodiments pH controlled or enzymatically controlled) and allows diffusion of the drug out of the device (Iii) a pore membrane system, wherein the drug is encapsulated in a membrane having components that dissolve in contact with water (in some embodiments, dissolution is H) or leave the pores in the membrane in which the drug diffuses); and (iv) the wax matrix system, where the drug and further soluble components are dispersed in the wax and the Resulting in the diffusion of the drug from the system when water dissolves the component)); and (e) a polymer degradation system ((i) a bulk degradation where the drug is a polymer Dispersed in the matrix, degradation occurs in a random manner throughout the polymer structure, allowing drug release; and (ii) surface erosion (where the drug is dispersed in the polymer matrix and the surface of the polymer is Delivered when eroded).

  In one aspect, the invention is a sustained release formulation comprising an effective amount of lonidamine (eg, as described above) to treat BPH by administering a unit dose oral pharmaceutical composition once per day. Provide a way.

(9. Example)
(Lonidamine treatment significantly reduces prostate volume and improves urinary flow in benign prostatic hyperplasia)
This example is a phase II open label study that evaluates the efficacy and safety of oral lonidamine (LND) treatment in subjects with symptomatic benign prostatic hyperplasia (BPH) by measuring the following baseline changes: The results are described: total prostate volume by transrectal ultrasound (TRUS), maximum flow rate in uroflowmetry (Q _max ), international prostate symptom score (I-PSS) and prostate specific antigen (PSA).

Thirty subjects with symptomatic BPH were given fluorescent LND once a day for 28 days (150 mg / day). Subjects were baseline, active treatment evaluation visit (14th day, 28th day), 4 weeks after treatment (day 56), 8 weeks after treatment (day 84), 12 weeks after treatment (day 112) and Six months after treatment (Day 200), prostate volume (by TRUS), _Qmax , I-PSS, serum chemistry and adverse events were evaluated.

(result)
Subjects experienced an average 11.2% (p <0.001) decrease in prostate volume on day 28, which was maintained until day 56 (average 12.0% decrease; p <0 .001). Q _max improved by an average of 3.2 mL / sec on day 28 (p = 0.002). The I-PSS score improved from 19.5 before treatment to 12.2 on day 28 (p <0.001). PSA decreased by 17.8% from baseline by day 28 (p = 0.001). LND was generally well tolerated and no moderate or severe adverse events were reported.

(Subject)
Between March and August 2004, 30 subjects were enrolled and given LND treatment. Have experienced lower urinary tract symptoms (LUTS) for at least 3 months, prostate volume greater than 30 cc as measured by TRUS, Q _max less than 15 mL / sec as measured by urofurometry, I-PSS greater than 13 Male subjects aged between 50 and 80 years of age when having a PSA greater than 1.0 ng / mL and being able to follow the treatment protocol and evaluation described above were desirable. Exclusion criteria included: treatment history of BPH other than alpha blockers; history of prostate surgery (excluding biopsy); uncontrolled diabetes mellitus (fasting blood glucose> 200 mg / dL); and prostate malignancy Current or past signs of disease; active heart disease, kidney disease, or liver disease manifested by creatinine greater than 1.8 mg / dL, ALT or AST greater than 2.5x (upper limit of normal), before study History of myocardial infarction, congestive heart failure, or unstable arrhythmia within 6 months. Alpha blocker treatment was not available during the study and for 14 days prior to the study. All subjects were given informed consent according to institutional guidelines. Subject characteristics are summarized in Table 2.

(Table 2)
Baseline characteristics of research subjects (n = 30)

（評価）
処置前評価は、以下を含んだ：研究開始前２週間に服用した医薬の記録；ナトリウム、カリウム、塩素、二酸化炭素、血中尿素窒素（ＢＵＮ）、クレアチニン、ＡＳＴおよびＡＬＴを含む血清化学パネル；ホルモンプロフィール（ＦＳＨ、ＬＨ、ＰＲＬ、テストステロン、遊離テストステロン）；前立腺体積のＴＲＵＳ測定；ＰＳＡ；ウロフロメトリー；およびＩ−ＰＳＳ。１４日目および２８日目に、前立腺体積、ＰＳＡ、ウロフロメトリー、有害事象および併用医薬評価について、被験体を評価した。２８日目にはまた、指による直腸検査、体温および生命徴候；血清化学の評価；ホルモンプロフィール；およびＩ−ＰＳＳを含む身体検査を被験体に受けさせた。５６日目にはまた、被験体を、前立腺体積およびウロフロメトリーについて評価した。８４日目に、被験体を、ウロフロメトリーについて評価した。１１２日目に、患者を、ウロフロメトリーについて評価した。２００日目に、被験体を、前立腺体積、ＰＳＡ、およびウロフロメトリーについて評価した。

(Evaluation)
Pre-treatment assessments included: records of medications taken 2 weeks prior to study initiation; serum chemistry panel including sodium, potassium, chlorine, carbon dioxide, blood urea nitrogen (BUN), creatinine, AST and ALT; Hormonal profiles (FSH, LH, PRL, testosterone, free testosterone); TRUS measurement of prostate volume; PSA; urofurometry; and I-PSS. On days 14 and 28, subjects were evaluated for prostate volume, PSA, urofluometry, adverse events, and concomitant medication evaluation. On day 28, subjects also underwent physical examination including digital rectal examination, body temperature and vital signs; assessment of serum chemistry; hormone profile; and I-PSS. On day 56, subjects were also evaluated for prostate volume and urofluometry. On day 84, subjects were evaluated for urofluometry. On day 112, patients were evaluated for urofluometry. On day 200, subjects were evaluated for prostate volume, PSA, and urofurometry.

  Thirty patients were evaluated at baseline, 29 patients were evaluated on day 28 (one dropped out due to hematuria), and 28 patients were evaluated on day 84 (one of the protocols) And dropped out due to disobedience), and 28 patients were evaluated on day 200 (voluntary withdrawal, unfollowable).

(Statistical analysis)
The primary efficacy endpoint was the change from baseline to day 28 in prostate volume, Q _max , I-PSS and PSA. Efficacy was analyzed by paired t-test of percent change in prostate volume and PSA and absolute change from baseline for Q _max and I-PSS. A non-parametric test was also performed to test the reliability of the results. All tests were two-sided and no adjustments were made for multiple tests. The missing data for days 14 and 28 was replaced using the final observations made in later procedures.

(result)
The oral LND once daily regimen was very tolerated and there were no significant treatment-related side effects. No occurrence of myalgia, testicular pain, sexual dysfunction or cardiovascular events was reported. One subject who experienced hematuria apparently unrelated to drug treatment discontinued LND treatment for safety reasons. One subject became unfollowable at 1 month. One subject exhibited clinically significantly higher ALT and AST values on day 28. Abdominal ultrasound was negative. ALT and AST returned to normal limits. No other clinically significant serum chemistry data were reported. Three subjects showed an increase above normal limits in FSH on day 28, and two subjects showed an increase in LH. Testosterone levels did not change significantly, but free testosterone levels decreased. However, none of the subjects fell below the lower normal limit on day 28.

(Prostate volume)
Average total prostate volume was significantly reduced during the treatment period. At the end of treatment (day 28), 16 (53%) subjects had a total prostate volume decrease of 10% or more, and 7 (23%) subjects had a total prostate volume decrease of 20% or more. Respectively. Prostate volume continued to decrease over 4 weeks after the subject stopped LND treatment. See Table 3, Table 4, Table 5, Table 6, and Table 7.

(PSA)
On day 14, PSA levels fell moderately on average 1.5% (95% CI: -14.1% to 11.2%), but on day 28, PSA levels averaged 17.8% (95% CI: −27.2% to −8.4%; p = 0.001). See Table 3 and Table 4.

(Urofurometry)
Subjects experienced a significant increase in Q _max by day 14, which lasted until days 28 and 56. At the end of the treatment, 12 (40%) subjects showed an improvement of more than 3 mL / sec from baseline Q _max and 7 (24%) showed an improvement of more than 5 mL / sec. Residual urine (volume after void) was significantly reduced from an average volume of 82.1 mL at baseline to 44.0 mL on day 14, 31.6 mL on day 28, and 34.8 mL on day 56. See Table 3 and Table 4.

(I-PSS)
Subjects' I-PSS symptom scores decreased from an average of 19.5 at baseline to 12.2 on day 28 (p <0.001). The decrease was consistent between subjects. See Table 3, Table 4 and Table 8.

(Commentary)
Subjects selected for this study will be targeted based on serum PSA> 1.0 ng / mL to have a higher degree of epithelial or glandular hyperplasia versus more interstitial hyperplasia Ensured to include subjects with. Dose levels were selected based on extensive clinical literature published for LND. To determine if the side effects observed in cancer patients are alleviated while maintaining the therapeutic activity of BPH, as well as to help enhance patient compliance, 150 mg p. o. The typical dose of TID was reduced to a regimen once a day. Interestingly, serum PSA levels declined gently on day 14, but then fell sharply on average day 28. This is probably related to prostate cell apoptosis due to interference with the citrate cycle. This magnitude and rate of response to compounds that affect prostate volume is unique in medical treatment of BPH.

(Table 3)
Summary of efficacy endpoints on days 14, 28, 56, 84, 112, and 200

（表４）
１４日目、２８日目、５６日目、８４日目、１１２日目および２００日目の効力終末点のまとめ

(Table 4)
Summary of efficacy endpoints on days 14, 28, 56, 84, 112, and 200

（表５）
基線と比較して総前立腺体積（ＴＰＶ）における少なくとも１０％もしくは少なくとも２０％の減少を有する患者

(Table 5)
Patients with at least 10% or at least 20% reduction in total prostate volume (TPV) compared to baseline

（表６）
総前立腺体積（ＴＰＶ）における改善を示す患者の割合（％）

(Table 6)
Percentage of patients showing improvement in total prostate volume (TPV)

（表７）
前立腺の移行帯体積における変化

(Table 7)
Changes in prostate transition zone volume

（表８）
研究開始２８日後のＩ−ＰＳＳにおける改善

(Table 8)
Improvement in I-PSS 28 days after the start of the study

（表９）
ホルモンプロフィールのまとめ

(Table 9)
Summary of hormone profiles

（中間結果）
１５人の患者について基線および１４日目に測定した中間結果を示す。１５人の被験体のうち、８人の被験体を２８日目でも測定した。８人の被験体のうち、７人の被験体を５６日目でも測定した。ここで、統計学的有意性は、ウイルコクソンの符号付き検定を用いて決定した。研究は続行中であったため、完了した研究の最終結果（上記）は、以下に示す結果からいくらか異なり得る。しかし、中間結果からの全体の傾向（前立腺の大きさの減少、尿流の増加およびＡＵＡＳＩの低下）は、維持されることが予測される。

(Intermediate result)
Shown are baseline results and intermediate results measured on day 14 for 15 patients. Of the 15 subjects, 8 subjects were also measured on day 28. Of the 8 subjects, 7 subjects were also measured on day 56. Here, statistical significance was determined using Wilcoxon signed test. Since the study was ongoing, the final results of the completed study (above) may differ somewhat from the results shown below. However, the overall trend from the interim results (decrease in prostate size, increase in urine flow and decrease in AUASI) is expected to be maintained.

  Table 10 shows changes in prostate volume in subjects treated with lonidamine compared to baseline.

  Urine flow was measured on days 0, 14, 28 and 56 for all individuals treated with lonidamine. The% increase from baseline in urine flow was 40.1% (p = 0.057; N = 13) on day 14, 52.2% (p = 0.016; N = 8) on day 28, and On day 56, it was 37.0% (p = 0.204; N = 7).

  Table 11 shows the AUA and PSA measured at baseline and day 28 from 8 individuals treated with lonidamine.

  (Table 10)

（表１１）

(Table 11)

これらの中間臨床試験結果は、ロニダミンのＢＰＨを有する個体への投与は、前立腺の大きさ、尿量、ＰＳＡレベルおよびＡＵＳＩスコアに顕著な変化をもたらし得ることを実証し、このことは、ＢＰＨの有意な治療効果と一致する。

These mid-clinical trial results demonstrate that administration of lonidamine to individuals with BPH can result in significant changes in prostate size, urine output, PSA levels and AUSI scores, which Consistent with significant therapeutic effects.

  (10. Cited references)

本発明を、特定の実施形態に関して詳細に記載したが、当業者は、変更および改良が随伴する特許請求の範囲に示すような本発明の範囲および精神内にあることを認識する。本明細書中に引用する全ての刊行物および特許文献（特許、公開された特許出願、および未公開の特許出願）を、そのような刊行物または文献の各々を、本明細書中に参考として援用されると詳細にかつ個々に示されるように、本明細書中に参考として援用する。刊行物および特許文献の引用は、このような文献のいずれかが、関連する先行技術であることの承認として意図されないし、その内容および日付に関するいかなる承認をも構成しない。記した詳細な説明および実施例の様式によって記載されている本発明について、当業者は、本発明が種々の実施形態で実施され得、前述の詳細な説明および実施例は例示の目的であり、随伴する特許請求の範囲を限定する目的ではないことを認識する。

Although the invention has been described in detail with respect to particular embodiments, those skilled in the art will recognize that changes and modifications are within the scope and spirit of the invention as set forth in the appended claims. All publications and patent documents (patents, published patent applications, and unpublished patent applications) cited herein are hereby incorporated by reference for each such publication or document. This application is hereby incorporated by reference as if set forth in detail and individually. Citation of publications and patent documents is not intended as an admission that any such document is pertinent prior art and does not constitute any approval as to its content and date. With respect to the present invention described in the detailed description and example forms set forth, those skilled in the art will recognize that the present invention may be implemented in various embodiments, and that the foregoing detailed description and examples are for illustrative purposes only; It will be appreciated that it is not intended to limit the scope of the appended claims.

Claims (5)

A method for treating benign prostatic hyperplasia (BPH) comprising administering a therapeutically effective amount of lonidamine or a lonidamine analog to a human subject in need of such treatment. . A method for reducing prostate size in a human subject comprising administering to the subject a therapeutically effective amount of lonidamine or a lonidamine analog. A method for the prevention of BPH comprising administering to a human subject a prophylactically effective amount of lonidamine or a lonidamine analog. A method for treating BPH, comprising: (a) diagnosing BPH in a patient; (b) administering lonidamine or a lonidamine analog to the patient; and (c) one or more manifestations of BPH Determining whether or not is reduced in the patient. A method for treating BPH, comprising: (a) administering lonidamine or a lonidamine analog to a patient diagnosed with BPH; and (b) reducing one or more symptoms of BPH in said patient. Determining whether or not.