WO2001007028A2

WO2001007028A2 - The use of retinoid receptor antagonists in the treatment of prostate carcinoma

Info

Publication number: WO2001007028A2
Application number: PCT/US2000/019849
Authority: WO
Inventors: Roshantha A. Chandraratna; Geoffrey Brown
Original assignee: Allergan Sales, Inc.
Priority date: 1999-07-23
Filing date: 2000-07-21
Publication date: 2001-02-01
Also published as: WO2001007028A3; AU6228000A

Abstract

The present invention relates to methods for treating prostate cancer comprising administering a therapeutically effective amount of a retinoid receptor antagonist. In addition, the present invention provides methods of inhibiting the growth of a prostate carcinoma cell or tumor, the method comprising contacting the cell or tumor with an effective amount of a retinoid receptor antagonist.

Description

THE USE OF RETINOID RECEPTOR ANTAGONISTS IN THE TREATMENT OF PROSTATE CARCINOMA

This application claims priority to Provisional Patent Application

60/145,287, filed July 23, 1999, which is incorporated by reference herein.

Background of the Invention

Prostate cancer is a serious condition that affects increasing numbers of men worldwide. About one-third of all men have at least some cancerous prostatic cells at age 50, with the incidence increasing to as many as 90 percent of men at age 90. In the United States alone, about 40,000 men die each year from prostate cancer.

Prostate cancer is a sex hormone dependent cancer; that is, the growth of the cancer is promoted by male hormones (e.g., androgens such as testosterone and dihydrotestosterone). Removal of the testes (castration) was for many years the standard method of preventing the secretion of male hormones by the gonads, as a means for reducing growth of the cancer. More recently, secretion of male hormones has been perturbed by chemical means by interfering with production of luteinizing hormone (LH), which regulates the synthesis of male hormones. Luteinizing hormone releasing hormone (LHRH) is a natural hormone produced by the hypothalamus that interacts with luteinizing hormone releasing hormone receptor (LHRH-R) in the pituitary to stimulate production of LH. To decrease LH production, superagonists of the luteinizing hormone releasing hormone receptor (LHRH-R), such as leuprolide and goserelin, have been used. However, such LHRH-R superagonists initially act to stimulate LH release and only after prolonged treatment act to desensitize LHRH-R such that LH is no longer produced. The initial stimulation of LH production by the superagonist leads to an initial surge in the production of male hormones such that the initial response to superagonist therapy is aggravation, rather than amelioration, of the patient's condition (e.g., tumor growth increases). This phenomenon, known as the "flare reaction", can last for two to four weeks. Additionally, each successive administration of the superagonist can cause a small LH surge (known as the "acute-on chronic" phenomenon) that again can worsen the condition. The "flare reaction" prohibits the use of LHRH-R superagonists in the treatment of late stage prostatic cancer patients where the cancer has metastasized to the spinal cord, since the initial stimulation of cancer growth would cause nerve trunk compression and damage. To ensure that a candidate patient for superagonist therapy does not have spinal cord metastasis, additional diagnostic tests must be conducted, such as magnetic resonance imaging or a spinal CAT scan, which adds to the cost of superagonist therapy.

One approach that has been taken to avoid the "flare reaction" has been to combine administration of an LHRH-R superagonist with an antiandrogen, such as flutamide, known as total androgen ablation therapy (AAT). Hormonal therapy with an LHRH-R superagonist in combination with an antiandrogen has been used as a pre-treatment prior to radical prostatectomy, known as neoadjuvant therapy. The use of antiandrogens, however, is associated with serious hepatic and gastrointestinal side effects.

Retinoids, synthetic and natural analogs of retinoic acid exhibit potent growth inhibitory and cell differentiation activities which account for their beneficial effects in cancer in ex vivo and in vivo models. These simple molecules with pleiotropic effects have shown potential as therapeutic agents for the treatment of cancer whether alone or in combination with other agents. Retinoids regulate the growth of various cell types by directly modulating the expression of responsive genes through nuclear retinoid receptors (RARs and RXRs), which are ligand dependent transcription factors. The translocation of RARα in acute pro-myelocytic leukemia, decreased expression of RARβ and reduced activity of the RARβ promoter in various tumors and cancer cell lines, and restoration of retinoid sensitivity to cancer cells by RAR expression vector transfection, are all indicative of the direct involvement of RAR malfunction in the process of tumorigenesis and also suggest a role of RARs as ligand dependant tumor suppressors. However, the current use of retinoids in cancer is limited because of their associated toxicities and lack of efficacy at tolerated doses.

Accordingly, more effective methods for treating prostate cancer are needed.

Summary of the Invention

The present invention provides a method for treating prostate cancer in a patient in need of such treatment, the method comprising administering a therapeutically effective amount of a retinoid receptor antagonist. The present invention also provides a method of inhibiting the growth of a prostate carcinoma cell or tumor, the method comprising contacting the cell or tumor with an effective amount of a retinoid receptor antagonist.

The present invention further provides a method for treating prostate cancer comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a retinoid receptor antagonist and a pharmaceutically acceptable carrier or excipient.

In another embodiment, the present invention provides a method of inhibiting the growth of a prostate carcinoma cell or tumor, the method comprising contacting the cell or tumor with an effective amount of a pharmaceutical composition comprising a retinoid receptor antagonist and a pharmaceutically acceptable carrier or excipient.

In a preferred embodiment, the antagonist is an RAR antagonist, preferably an RARαβγ antagonist. According to another preferred embodiment, the antagonist is an RARα selective antagonist. Brief Description of the Drawings

Figure 1 shows the relative activities of retinoid receptor selective compounds on clonogenicity of serum free-grown LNCaP prostate carcinoma cells.

Figure 2 shows that RAR antagonism inhibits the clonogenicity of serum free-grown prostate carcinoma cells. Figure 3 shows the relative potency of RAR antagonists against carcinoma cell lines.

Figure 4 shows the influence of RAR antagonism on the growth of bulk cultures of LNCaP prostate carcinoma cells. Figure 5 shows that AGN 310 is not effective in inhibiting growth of

HL60 cells.

Figure 6 shows the effect of serum on the growth inhibitory effects of RAR antagonists against LNCaP prostate carcinoma cells.

Figure 7 shows the effect of serum on the growth inhibitory effects of RAR antagonists against PC-3 prostate carcinoma cells.

Figure 8 shows the effect of RARα agonists on LNCaP prostate carcinoma cells.

Figure 9 shows the effect of RARα agonists on PC-3 prostate carcinoma cells. Figure 10 shows that an RARβγ agonist does not interfere with the growth inhibitory effects of an RARαβγ antagonist against LNCaP prostate carcinoma cells.

Figure 11 shows that an RARβγ agonist does not interfere with the growth inhibitory effects of RAR antagonists against PC-3 prostate carcinoma cells.

Detailed Description of the Invention

The present invention provides a method of treating prostate carcinomas comprising the use of retinoid receptor antagonists. At the molecular level retinoids exert their biological effects through two families of nuclear receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which belong to the superfamily of steroid/thyroid/vitamin D3 nuclear receptors. RARs and RXRs are ligand-dependent transcription factors which regulate gene expression in two different ways: (a) they upregulate the expression of genes by binding to the RA-responsive elements (RAREs) present in their promoters or (b) they down-regulate the expression of genes by antagonizing the enhancer action of certain other transcription factors, such as API. The distinct isotypes of RARs (α, β and γ) and RXRs (α, β and γ) are encoded by three separate genes. Each RAR isotype is further expressed as several isoforms differing in their N- terminal A region, which are generated by alternative splicing and/or by differential usage of two promotors. RARα is expressed as two main isoforms (αl and α2). RARβ as four isoforms (βl, β2, β3 and β4) and RARγ as two main isoforms (γl and γ2). RARs are believed to function exclusively in vivo as RAR-RXR heterodimers.

The present invention relates to the use of any retinoid receptor antagonist presently known in the art, or subsequently developed, in practicing the claimed methods. The synthesis of exemplary receptor antagonists is described, by way of example only, in U.S. patent nos. 5,877,207; 5,514,825; 5,648,514; 5,728,846; 5,739,338; 5,760,276; 5,776,699; 5,773,594; 5,763,635; and 5,808.124 and U.S.S.N. 08/840,040 and 08/845,019, incorporated herein by reference in their entireties. In a preferred method, the antagonist is an RAR antagonist, and more preferably an RARαβγ antagonist. However, antagonists with activity specific for a particular isotype and/or isoform or a combination thereof may also be used in the present methods. Thus, antagonists specific for RARα, β, γ or combinations thereof, may be used. Such receptor isotype specific antagonists may be preferred in order to reduce any side effects associated with the use of non-specific antagonists.

As used herein, "agonist" means a compound that will stimulate the ligand-mediated transactivational activity of the specified retinoid receptor.

As used herein, "antagonist" means a compound that will inhibit or block the ligand-mediated transactivational activity of the specified retinoid receptor.

As used herein, "inverse agonist" means a compound that will decrease a basal level of transactivational activity of the specified retinoid receptor, wherein the basal level is that amount of transactivational activity observed in the absence of added agonist. As used herein, the term "selective" means that a given ligand demonstrates at least about a 10 fold greater binding affinity, as indicated by, for example, K value, (dissociation constant) for one receptor subtype than for another receptor subtype. As used herein, the term "specific" means that a given ligand demonstrates at least about a 500 fold greater binding affinity, and more preferably at least about a 1000 fold greater binding affinity, for a one receptor subtype than for another receptor subtype.

In a preferred method of treatment, the antagonist is a compound of formula (I):

(I)

(R₃)o

^, X₂ X X,

wherein X is S, SO, SO₂, O, NR,, [C(R,)₂ ]„ where each Ri is independently or together H or alkyl of 1 to 6 carbons, and n is 1 or 2; or X is absent;

Xi is absent and X₂ is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; provided that at least X is present, or Xi and X are each C; are optionally present bonds; each R₂ is independently or together hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons, NH , NRiH, N(R ₂, N(R,)COR,, NRιCON(R,)₂ or OCOR,; each R₃ is independently or together hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br or I; m is an integer having the value of 0-3; o is an integer having the value of 0-3 ;

Z is -C≡C-, -N=N-, -N=CR,-, -CRι=N,

where n' is an integer having the value 0-5, -CO-NRi-, -CS-NR , -NRi-CO, -NRjCS-, -COO-, -OCO-; or

-CSO-; -OCS-;

Y is a phenyl or naphthyl group, or heteroaryl selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R groups, or when Z is -(CRι=CRι)_n - and n' is 3, 4 or 5 then Y represents a direct valence bond between said -(CRι=CRι)_n' group and B;

A is (CH₂)_q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;

B is hydrogen, COOH, COOR₈, CONR₉Rι₀, -CH₂OH, CH₂ORn, CH₂OCOR_π, CHO, CH(OR_[2)₂, CHOR₁₃O, -COR₇, CR₇(OR_!2)₂, CR₇OR₁₃O, or tri-lower alkylsilyl, where R₇ is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R₈ is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or Rg is phenyl or lower alkylphenyl, R₉ and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, Rn is lower alkyl, phenyl or lower alkylphenyl, Rι is lower alkyl, and Rn is divalent alkyl radical of 2-5 carbons; and

Rι₄ is (Rι₅)_r-phenyl, (Rι₅)_r-naphthyl, or (Rι₅)_r-heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of O, S and N, r is an integer having the values of 0-6, and

Ris is independently H, F, Cl, Br, I, NO₂, N(R₈)₂, N(R₈)COR₈, NR₈ CON(R₈)₂, OH, OCORs, OR₈, CN, an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a trialkylsilyl or (trialkylsilyl)oxy group where the alkyl groups independently have 1 to 6 carbons; or a pharmaceutically acceptable salt or ester thereof. According to one embodiment, X is present and Xi is absent, providing compounds of formula (la):

X^{'' '} x₂

In another embodiment, X is absent and Xj and X₂ are C, providing compounds of formula (lb):

(lb)

(R₃)o

In yet a further particularly preferred embodiment, X is present and Xi and X are C, providing compounds of formula (Ic):

In preferred embodiments of formulas I, la, lb and Ic, Y is phenyl and Rj₄ is (Ri₅)_r-phenyl, where preferably the bond between Rι₄ and the heterocyclic moiety comprising X allows for free rotation of the Rι₄ group. In a further embodiment, r is 1 and R_{i 5} is COOH. According to a preferred embodiment, the antagonist is AGN 310, whose structure is set forth below. In another preferred embodiment, the antagonist is AGN 301, whose structure is also set forth below. Further specific antagonists within the scope of formula (I), method of synthesis as well as definitions of terminology used to define compounds of formula (I), are more fully described in U.S. 5,776,699. Structures of specific compounds, antagonists as well as agonists, referenced in this disclosure are set forth below:

OOH

^ ,COOH

O

¥

Br 310 AGN 194574

COOH o ,COOH

,N -

- N^'

01 AGN 194431

COOH 04 AGN 194078

65 AGN 195153 C0₂Et

XOOH

N

X

'^ ^ O 190168

AGN 190299

^ COOH

COOH

N 193109 AGN 191 183 (TTNPB)

COOH

Λ O

GN 194175 COOH

AGN 195393

where,

AGN 310 is an RAR antagonist;

AGN 301 is an RARα selective antagonist;

AGN 204 is an RXR agonist; AGN 365 is an RARα selective agonist;

AGN 574 is an RARα specific antagonist;

AGN 431 is an RARβγ selective antagonist;

AGN 078 is an RARα specific agonist;

AGN 153 is an RARα selective agonist; AGN 168 is an RARβγ selective agonist;

AGN 109 is an RAR antagonist;

AGN 175 is an RAR antagonist;

AGN 299 is an RARβγ selective agonist;

AGN 183 (TTNPB) is an RAR agonist; and AGN 393 is an RXR antagonist.

Further examples of compounds which may be used in practicing the present invention include compounds of formulas (II) through (V):

R₁₄-X'-Y₁(R₂R^, ₃)-Z-Y(R₂)-A-B (II)

where X' is O, S, SO, S0₂, N, NR₃ or C(R₃)₂; or -X'-R₁₄ is -C(Rι₄)H₂ or - C(Rι₄)-(CH₂)_nH where n is 1-6;

Yi is phenyl, naphthyl or heteroaryl selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl, naphthyl and heteroaryl groups being optionally substituted with one R'₃ and one or two R₂ groups;

R'₃ is H, (Ci-Cio) alkyl, 1-adamantyl, 2-tetrahydropyranoxy, trialkylsilanyl and trialkylsilanyloxy where alkyl comprises 1 to 6 carbons, alkoxy and alkylthio where alkyl comprises 1 to 10 carbons, or OCH O(C[. ₆)alkyl; and Z, Y, A, B, R₂, R₃ and R_]4 are as defined above; where preferred embodiments include compounds of formula (Ila): R 14 B

A

X' Y

R,

(Ila)

(R₂ 2)^m ₃

where m is 0-2; where further preferred embodiments include compounds of formula (lib):

B

R 14 Y

R,

(lib)

where preferably R'₃ is alkyl; and where additional embodiments include compounds of formula (lie):

R ^,ι

B

Y

X'

R, (lie)

R'₃ compounds of formula (III):

where R₂ is as described above and additionally preferably Cι-C₆ alkenyl, and X and Rj₄ are as described above; compounds of formula (IV):

R ι₄ (^R2)m (R₂)₀

B

R,

^ ,Y

(IV)

X ^. ^\ ^ R₂

wherein X is S, SO, SO₂, O, NR,, [C(Rι)₂ ]„, -C(Rι)₂-NR,-, -C(Rι)₂-S-, -

C(Rj)₂-0- or -C(Rι)₂-(Rι)₂-. where R,, R₂, R₃, R₎₄, Z, Y, A, B, m and o are as described above; where preferred embodiments include compounds of formula

COOH

(IVa)

R,

X

R

(IVa):

and compounds of formula (V):

,B

.A

,Y

,N. R₂

(V)

where Z, Y, A, B and R are as described above. As discussed above, any compound or agent having retinoid receptor antagonist activity may be used. Means for determining antagonist activity of a given agent or compound are known in the art. For example, a holoreceptor transactivation assay and a ligand binding assay which measure the antagonist agonist like activity of the compounds of the invention, or their ability to bind to the several retinoid receptor subtypes, respectively, are described in published PCT Application No. WO 93/11755 (particularly on pages 30-33 and 37-41) published on Jun. 24, 1993, the specification of which is also incorporated herein by reference. A pharmaceutically acceptable salt may be prepared for any compound in this invention having a functionality capable of forming a salt, for example an acid functionality. A pharmaceutically acceptable salt is any salt which retains the activity of the parent compound and does not impart any deleterious or untoward effect on the subject to which it is administered and in the context in which it is administered.

Pharmaceutically acceptable salts may be derived from organic or inorganic bases. The salt may be a mono or polyvalent ion. Of particular interest are the inorganic ions, sodium, potassium, calcium, and magnesium. Organic salts may be made with amines, particularly ammonium salts such as mono-, di- and trialkyl amines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar molecules. Where there is a nitrogen sufficiently basic as to be capable of forming acid addition salts, such may be formed with any inorganic or organic acids or alkylating agent such as methyl iodide. In such cases, preferred salts are those formed with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid. Any of a number of simple organic acids such as mono-, di- or tri-acid may also be used.

Some of the compounds of the present invention may have trans and cis (E and Z) isomers. In addition, the compounds of the present invention may contain one or more chiral centers and therefore may exist in enantiomeric and diastereomeric forms. Still further oxime and related compounds of the present invention may exist in syn and anti isomeric forms. The scope of the present invention is intended to cover all such isomers per se, as well as mixtures of cis and trans isomers, mixtures of syn and anti isomers, mixtures of diastereomers and racemic mixtures of enantiomers (optical isomers) as well. In the present application when no specific mention is made of the configuration (cis, trans, syn or anti or R or S) of a compound (or of an asymmetric carbon) then a mixture of such isomers, or either one of the isomers is intended. In a similar vein, when in the chemical structural formulas of this application a straight line representing a valence bond is drawn to an asymmetric carbon, then isomers of both R and S configuration, as well as their mixtures are intended. Defined stereochemistry about an asymmetric carbon is indicated in the formulas (where applicable) by a solid triangle showing β- configuraαon, or by a hashed line showing α-confϊgurauon.

The present invention also provides pharmaceutical compositions comprising one or more compounds of the invention together with a pharmaceutically acceptable diluent or excipient. Preferably such compositions are in unit dosage forms such as tablets, pills, capsules (including sustained- release or delayed-release formulations), powders, granules, elixirs, tinctures, syrups and emulsions, sterile parenteral solutions or suspensions, aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral (e.g., intravenous, intramuscular or subcutaneous), intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation, and may be formulated in an appropriate manner and in accordance with accepted practices such as those disclosed in Remington 's Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co., Easton PA, 1990. Alternatively, the compositions may be in sustained-release form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. The present invention also contemplates providing suitable topical formulations for administration to, e.g. eye or skin or mucosa. For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, pharmaceutically acceptable oils, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, flavoring agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate. magnesium stearate. sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

For preparing solid compositions such as tablets, the active ingredient is mixed with a suitable pharmaceutical excipient. e.g., such as the ones described above, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. By the term "homogeneous" is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. The solid preformulation composition may then be subdivided into unit dosage forms of the type described above containing from 0.1 to about 50 mg of the active ingredient of the present invention. The tablets or pills of the present composition may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner core containing the active compound and an outer layer as a coating surrounding the core. The outer coating may be an enteric layer which serves to resist disintegration in the stomach and permits the inner core to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with conventional materials such as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the present compositions may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical carriers. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose or polyvinyl-pyrrolidone. Other dispersing agents which may be employed include glycerin and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired. The compositions can also be formulated as an ophthalmic solution or suspension formation, i.e., eye drops, for ocular administration.

The term "subject," as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

The term "therapeutically effective amount" as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated.

Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses two, three or four times daily. Furthermore, compounds for the present invention may be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to persons skilled in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound employed. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the disease or disorder which is being treated.

The daily dosage of retinoid receptor antagonists or reverse agonists may vary over a wide range from 0.01 to 100 mg per adult human per day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0 or 50.0 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. A unit dose typically contains from about 0.001 mg to about 50 mg of the active ingredient, preferably from about 1 mg to about 10 mg of active ingredient. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0001 mg/kg to about 25 mg/kg of body weight per day. Preferably, the range is from about 0.001 to 10 mg/kg of body weight per day, and especially from about 0.001 mg/kg to 1 mg/kg of body weight per day. The compounds may be administered on a regimen of 1 to 4 times per day.

The invention is disclosed in further detail in the following examples which are not in any way intended to limit the scope of the invention as claimed.

Examples Example 1

Compounds were screened for activity using three cell lines, LNCaP,

PC-3 and DU145, including both serum-grown cells and cells that had been maintained in serum free conditions for 2 years. Activity was measured using a plate clonogenic assay and confirmed by analysis of the effects on bulk cultures of lines. The compounds tested in the initial screens are as follows:

Table 1. Compounds tested for activity against prostate carcinoma cell lines

Receptor selectivity Compound

Agonists

RARα AGN 078, 365, 153

RARβγ AGN 168, 299

RXR AGN 204

Antagonists

RARαβγ AGN 109, 310

RARα AGN 301

5 All of the compounds were screened at 100 nM in three separate experiments, against each of the three lines grown in serum and serum free conditions. Cells were seeded at 400 (serum) and 1500 (serum free) per plate and colonies enumerated at day 9 (serum) and day 14 (serum free). A representative screen outcome is shown in Figure 1, where: 10 1 : no agent

2: all trans retinoic acid: 3: AGN 168 4: AGN 299 5: AGN 310 15 6: AGN 204

7: AGN 078 8: AGN 365 9: AGN 153 10: AGN 301 20 Data are mean +/- SE of values from the 3 separate experiments.

Data obtained are summarized in Figure 2. The broken line represents

ATRA at 100 nM. Compounds with the same receptor selectivity had similar growth inhibitory activity and the data was therefore pooled (RXR agonist

(AGN 204); RARα agonists (AGN 078, 153, 365); RARβγ agonists (AGN 168,

25 299) and RARαβγ (AGN 310) and RARα (AGN 301) antagonists. An exception to this is that the RARαβγ antagonist AGN 310 was observed to be growth inhibitory, whereas AGN 109 was inactive.

The compounds that were observed to be more active than all-trans retinoic acid against all of the three lines tested were the RARαβγ antagonist AGN 310 and the RARα specific antagonist AGN 301. Treatment with 100 nM of the RARαβγ antagonist resulted in survival of <1% of control plates and the same dose of the RARα-selective antagonist reduced colony formation to « 40% of control plates. Significant growth inhibitory activity was only observed when these agents were tested against cells grown under serum-free conditions. The RXR agonist AGN 204 showed some inhibitory activity against serum- grown and serum free-grown cells, but this was not substantially greater than that observed with all-trans retinoic acid. When the compounds were tested against serum free-grown LNCaP cells, in combination with one another, in a "checker-board" manner, growth inhibition greater than that resulting from treatment with the RARαβγ antagonist alone was not observed (see table below).

Table 2 - Growth inhibitory effects of combinations of agonists and antagonists on serum free-gown LNCaP prostate carcinoma cells (compounds at 1 x 10^"7 M)

Data are means of values from 3 separate experiments

A: AGN 168

B: AGN 299

C: AGN 310

D: AGN 204

E: AGN 078

F: all-trans retinoic acid: RAR agonist

Values are % survival

Example 2 AGN 310 and AGN 301. together with all-trans retinoic acid, were titrated against serum free-grown LNCaP, PC-3 and DU145 cells. Two-fold (high doses) and ten-fold (low doses) dilutions of ATRA and AGN310 and AGN 301 were used to inhibit clonogenic growth of serum free grown prostate carcinoma cell lines. Data are means of values from 3 separate experiments. As observed in the initial screens, the RARαβγ antagonist AGN 310 was observed to be 5 to 1 Ox more active than the RARα-specific antagonist AGN 301. Both of these compounds were more active than all-trans retinoic acid (see figure 3). IC₅₀ values (concentration of compound which inhibits growth by 50%)) for these three compounds against all three lines are given in the following table:

Table 3. IC50 values of agents of interest against prostate carcinoma cell lines RARα, β, γ RARβ, γ antagonist RARα antagonists ATRA antagonist (AGN 431 ) (AGN 301, 574)

(AGN 310)

LNCaP 17 nM 165nM 198 nM, 500 nM 590 nM

PC-3 16 nM n.d 245 nM, n.d 290 nM

DU145 50 nM n.d 205 nM, n.d 300 nM n.d. not determined

Activity of AGN 310 and AGN 301 against serum free-grown LNCaP cells has been confirmed in analyses of bulk liquid cultures (see Figure 4).

Cultures of serum free-grown LNCaP cells, seeded at 6 x 10⁵ cells/flask, were treated with AGN 310 (column 2) and AGN 301 (column 3), at 100 nM. Viable cells were enumerated after trypsinising the cultures at day 3. Control values are shown in column 1. Data are the mean +/- SE of values from 5 experiments. Example 3 Specificity of the growth inhibitory effect of RAR antagonism was investigated by testing the two compounds against serum free-grown HL60 (a promyeloid cell line) cells. Two assays were used. The effects on bulk cultures of HL60 cells seeded at their normal starting density of 2.5 x 10⁵ cell/ml, and at sub-optimal seeding densities of 1 and 0.5 x 10⁵ cell/ml were analyzed. At these two densities growth of HL60 cells is compromised. Compounds were also tested against single HL60 cells plated in microtitre wells. The RAR antagonists did not significantly affect the growth of HL60 cells in either of the two assays (see Figure 5; square = AGN 310; triangle = AGN 301; compounds tested at 100 nM). In the single cell cloning experiments, treatment with the RARαβγ antagonist AGN 310 resulted in a slight reduction in cloning efficiency (from 90% to 81%; the number of wells analyzed were 78 (control), 85 (AGN 310) and 68 (AGN 301)).

Example 4 To determine whether the serum free cell lines per se are sensitive to

RAR antagonists or a component of serum interferes with the growth inhibitory activity of compounds, the activity against serum free-grown cells plated in the presence and absence of 10 and 20%) fetal calf serum was determined. Experiments were undertaken using LNCaP and PC3 cells. Colony growth of LNCaP cells was moderately stimulated by plating the cells in serum conditions (up to 146%) of control serum free plated cells). Massive stimulation of PC3 colony formation was observed when these cells were plated in serum (up to 300%>). Treatment of serum free-grown LNCaP and PC3 cells with antagonists in the presence of serum blocked the capacity of the antagonists to inhibit colony formation (see figure 6; serum free-grown LNCaP cells in serum free medium (1), 10% FCS (2) and 20% FCS (3); AGN 310 at lOOnM against LNCaP cells in serum free medium (4), 10% FCS (5) and 20% FCS (6); AGN 301 against LNCaP cells in serum free medium (7), 10% FCS (8) and 20% FCS (9); colonies were enumerated at day 14 (n=3))(see figure 7; serum free-grown PC-3 cells in serum free medium (1) and 10% FCS (2); AGN 310 , at lOOnM, against PC-3 cells in serum free medium (3) and 10% FCS (4); and AGN 301 against PC-3 cells in serum free medium (5) and 10% FCS (6); colonies enumerated at day 14; n=3).

Example 5

An attempt to block growth inhibition of LNCaP and PC-3 cells was made, by antagonists AGN 310 and AGN 301 (at 100 nM), by co-addition of agonists. The agonists used were the RARα agonists AGN 194078 and AGN 195153 and the RARβγ agonist tazarotenic acid (all at concentrations of 100, 200 and 500 nM). These experiments were undertaken prior to knowledge of affinity constants for each of the agents. As predictable from the relative binding efficiencies of antagonists and agonists, blocking of growth inhibition by antagonists (see figures 8 - 1 1) was not achieved.

Figure 8 - LNCaP cells: AGN 310 and AGN 301 were tested at lOOnM for their ability to inhibit colony formation in the presence and absence of the RARα agonist AGN 194078 and AGN 195153. The agonists were used at 100 and 500 nM. The data obtained from the individual agonists and at each concentration were similar and therefore pooled. Columns are: 1 (no agent); 2 (RARα agonists alone); 3 (RARαβγ antagonist alone); 4 (RARαβγ antagonist & RARα agonists); 5 (RARα-s elective antagonist alone); and 6 (RARα-selective antagonist & RARα agonists). Colonies were enumerated at day 14; n=3. Figure 9 - PC-3 cells: AGN 310 and AGN 301 were tested at lOOnM for their ability to inhibit colony formation in the presence and absence of the RARα agonists AGN 194078 and AGN 195153. The agonists were used at 100, 200 and 500 nM. The data obtained from the individual agonists and at each concentration were similar and therefore pooled. Columns are: 1 (no agent); 2 (RARα agonists alone); 3 (RARαβγ antagonist alone); 4 (RARαβγ antagonist & RARα agonists); 5 (RARα-selective antagonist alone); and 6 (RARα-selective antagonist & RARα agonists). Colonies were enumerated at day 14; n=3.

Figure 10 - LNCaP cells: AGN 310 was tested at lOOnM for their ability to inhibit colony formation in the presence and absence of the RARβγ agonist AGN 190299. The agonist was used at 100 and 200 nM. Columns are: 1 (no agent); 2 (RARβγ agonist alone, 100 nM); 3 (RARβγ agonist alone, 200 nM); 4 (RARαβγ antagonist alone); 5 (RARαβγ antagonist & RARβγ agonist, 100 nM); 5 (RARαβγ antagonist & RARβγ agonist, 200 nM); and 6 (RARα-selective antagonist & RARα agonists). Colonies were enumerated at day 14; n=3.

Figure 1 1 - PC-3 cells: AGN 310 and AGN 301 were tested at lOOnM for their ability to inhibit colony formation in the presence and absence of the RARβγ agonist AGN 190299. The agonist was used at 100 and 200 nM. Columns are: 1 (no agent); 2 (RARβγ agonist alone, 100 nM); 3 (RARβγ agonist alone, 200 nM); 4 (RARαβγ antagonist alone); 5 (RARαβγ antagonist & RARβγ agonist, 100 nM); 6 (RARαβγ antagonist & RARβγ agonist, 200 nM); 7 (RARα-selective antagonist alone); 8 (RARα-selective antagonist & RARβγ agonist. 100 nM); and 9 (RARα-selective antagonist & RARβγ agonist, 200 nM). Colonies were enumerated at day 14; n=3.

Example 6

To confirm that antagonists of RAR are appropriately effective in cell model systems, we investigated their effects on ATRA-induced differentiation of HL60 cells to neutrophils. HL60 cells express RARα and treatment with 100 nM ATRA gave rise to 80%> neutrophils (displaying stimulated NBT reduction) within 5 days. AGN194310 (a pan-antagonist of RARs) and AGN194301 (an antagonist of RARα), used at 100 nM, prevented ATRA-induced neutrophil differentiation.

Example 7

In order to better acertain whether the observed growth inhibitory effects of the tested RAR antagonists exert their effects via the RAR receptor, we investigated whether the non-metabolized RAR agonist TTNPB can reverse AGN194310-mediated inhibition of LACaP, PC3 and DU145 colony formation in a clonogenic plate assay. LNCaP ITS⁺-grown (non-serum grown) cells were seeded into dishes, treated immediately with various concentrations of the compounds, followed by a change of medium with agents on day 3. Colonies were thereafter counted.

Treatment of cells with concentrations equal to or greater than 500 nM TTNPB inhibited colony formation by ITS⁺-grown LNCaP cells by > 50%. Treatment of these cells with 25 nM of the pan-antagonist AGN 194310 resulted in a 40%) inhibition of colony formation. Treatment of ITS⁺-grown LNCaP cells with 25 nM of the pan-antagonist AGN 194310, together with two-fold dilutions of TTNPB (from 62.5 nM to 1000 nM) resulted in a progressive blocking of the growth inhibitory effect of AGN 194310 with increasing TTNPB concentration. Also, the growth inhibitory effect of high concentrations of TTNPB alone was blocked by AGN 194310. It is therefore likely that both agents are exerting their effects via RAR.

Example 8

In order to determine the effect of RAR antagonism on the cell cycle of treated cells, Flask cultures of LACaP (serum free) cells were seeded. Then treated with 1 μM AGN 194310 or left untreated. Cells were harvested daily from the flasks, trypsinized, and polled with cells in suspension. The effect of AGN 194310 was determined as a percentage of the cells present in untreated flasks; treatment of cells with AGN 194310 resulted in an 80 ± 1 1 % reduction in cell number by day 3, as compared with untreated cell cultures. Analysis of cell cycle status, by propidium iodide labelling and flow cytometry, revealed a transient increase at day 1 in the proportion of Gi cells, from a value of 62 ± 4% for untreated cultures to a value of 71 ± 2%> for agent treated cultures There was a corresponding decrease in the proportion of cells in the S phase of cell cycle, from 22 ± 2% (control cultures) to 15 ± 3% (agent treated).

By day 3, a large proportion of antagonist-treated cells had detached from the flask and had undergone apoptosis, as shown by TdT end-labelling and FACS analysis. Values obtained for the percentages of apoptotic cells in agent-treated and untreated cultures were 20± 9% and 3 ± 1%, respectively. Thus, the data indicate that antagonist treatment results not only in a decease in cell division but an increase in cell death in prostate carcinoma cells.

Example 9

A serum component which may regulate the growth of LNCaP ITS⁺ cells is insulin-like growth factor- 1 (IGF- 1 ), which has been proposed to play an important role in controlling the growth of prostate carcinoma cells. We performed the following experiment to test whether the inhibitory effects of RAR antagonists were exerted via the same control location(s) as IGF-1.

LNCaP ITS+ cells were grown and exposed to the long R3 form of IGF- I at 2-fold dilutions between 0.1 and 100 ng/ml. IGF-1 did not block the inhibition of colony formation in the plate assay when LNCaP ITS⁺ cells were also treated with 100 nM of AGN194310. IGF-1 activity was verified by transferring FBS-grown cells of the breast carcinoma line MCF-7 to 10%o charcoal stripped serum. Transfer of flask cultures of these cells to charcoal stripped serum and the addition of 100 ng/ml of IGF- 1 caused an increase in viable cell numbers to 164±27 % of the number of cells present in control cultures grown in charcoal stripped serum in the absence of agent. In similar transfer experiments, IGF-1 stimulated the growth of LNCaP cells to a smaller extent; viable cell numbers were increased to 123±5 %.

Example 10

The RAR pan-antagonist AGN 194310 was tested against primary prostate carcinoma cells. Bulk cell cultures were taken from core biopsies of two patients suffering from prostate cancer. Cultures were established using a commercially available serum-free medium; cells were verified as being epithelial in nature and contained few contaminating fibroblasts-like cells. These cultures were treated on day 0 with either 10 nM or 100 nM AGN 194310, lOnM or 100 nM ATRA, or vehicle alone. Flask cultures of primary carcinoma cells were tested, at passages 2, for their sensitivities to 10 and 100 nM of the pan-antagonist of RARs AGN 194310 and of ATRA together with appropriate vehicle controls. Cell growth in vehicle treated cultures was similar to that observed in untreated cultures. No growth inhibition and a low level of grow were observed post-treatment of ATPrC and WBPrC cells with 100 nM ATRA; cells numbers were, respectively, 110% and 88%> of those observed in vehicle and untreated cultures (see Fig. 6). By contrast, treatment of both primary lines with 100 and lOnM of the pan-antagonist AGN 194310 resulted in good levels of growth inhibition. Post-treatment with 100 nM, the numbers of cells, at days 3 or 6, were reduced to 23% (ATPrC) and 37% (WBPrC) of those observed in vehicle treated and untreated cultures. When AGN194310 was used at a concentration of 10 nM; cell numbers were, respectively, reduced to 39% and 46% of those observed for vehicle and untreated cultures.

It will be understood that the preceding embodiments are intended to be exemplary only, and the claimed invention is not limited thereto.

Claims

We claim:

1. A method for treating prostate cancer in a patient in need of such treatment, the method comprising administering a therapeutically effective amount of a retinoid receptor antagonist.

2. A method according to claim 1, wherein said antagonist is an

RAR antagonist. 3. The method according to claim 2, wherein said antagonist is an

RARαβγ antagonist.

4. The method according to claim 2, wherein said antagonist is an RARα antagonist.

5. A method according to claim 1, wherein the antagonist is a compound of formula (I):

^R'4 (R₂)_{m Y}-^A ^'' z^

R₂ (i)

(R₃)o

X, x x,

wherein X is S, SO, S0₂, O, NR, or [C(Rι)₂ ]_n where each R, is independently H or alkyl of 1 to 6 carbons, and n is 1 or 2; or X is absent;

Xi is absent and X₂ is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; provided that at least X is present, or X] and X₂ are each C; is an optionally present bond; each R is independently or together hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons, NH₂, NRiH, N(Rι)₂, N(Ri)COR_!, NRiCON(Ri)₂ or OCOR,; each R₃ is independently or together hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br or I; m is an integer having the value of 0-3; o is an integer having the value of 0-3;

Z is -C≡C-, -N=N-, -N=CRι-, -CR,=N, -(CR^CR _n- where n' is an integer having the value 0-5,

-CONRi-,

-CSNR,-,

-NRiCO-,

-NRiCS-, -COO-,

-OCO-;

-CSO-;

-OCS-;

Y is a phenyl or naphthyl group, or heteroaryl selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R groups, or when Z is -(CRι=CRι)_n'- and n' is 3, 4 or 5 then Y represents a direct valence bond between said -(CRι=CRι)_n' group and B; A is (CH₂)_q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;

B is hydrogen, COOH, COOR₈, CONR₉Rι₀, -CH₂OH, CH₂OR_u,

CH₂OCOR_n, CHO, CH(ORι₂)₂, CHOR₁₃O, -COR₇, CR₇(OR₁₂)₂, CR₇OR_I3O, or tri-lower alkylsilyl, where R₇ is an alkyl, cycloalkyl or alkenyl group containing

1 to 5 carbons, R₈ is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R₈ is phenyl or lower alkylphenyl, R₉ and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, Rn is lower alkyl, phenyl or lower alkylphenyl, Rι₂ is lower alkyl, and Rn is divalent alkyl radical of 2-5 carbons; and Rι₄ is (Rι₅)_r-phenyl, (Rι₅)_r-naphthyl, or (Ri₅)_r-heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of O, S and N, r is an integer having the values of 0-6, and

R₁₅ is independently H, F, Cl, Br, I, NO₂, N(R₈)₂, N(R₈)COR₈, NR₈ CON(R₈)₂, OH, OCORs, OR₈, CN, an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a trialkylsilyl or (trialkylsilyl)oxy group where the alkyl groups independently have 1 to 6 carbons; or a pharmaceutically acceptable salt or ester thereof.

6. The method of claim 5, wherein X is present and Xi is absent.

7. The method of claim 6, wherein Y is phenyl and R)₄ is (Ri₅)_r- phenyl.

8. The method of claim 7, wherein r is 1 and R_{) 5} is COOH. 9. The method of claim 5, wherein X is absent and Xi and X are C.

10. The method of claim 9, wherein Y is phenyl and Rι is (Rι₅)_r- phenyl.

11. The method of claim 10, wherein r is 1 and R₁₅ is COOH.

12. The method of claim 5, wherein X is present and Xi and X₂ are C.

13. The method of claim 12, wherein Y is phenyl and R]₄ is (Rι₅)_r- phenyl.

14. The method of claim 13, wherein r is 1 and R₁₅ is COOH.

15. The method of claim 14, wherein the compound is COOH

16. The method of claim 14, wherein the compound is

COOH

O

I

O

Br

17. A method according to claim 1, wherein the antagonist is a compound of formula (II):

R,₄-X'-Y₁(R₂R'₃)-Z-Y(R₂)-A-B (II)

where Rι is (Ri5)_r-phenyl, (Ri₅)_r-naphthyl or (Rι₅)_r-heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of O, S and N, r is an integer having the value of 0-6, and

R₁₅ is independently H, F, Cl, Br, I, NO₂, N(R₈)₂, N(R₈)COR₈, NR₈ CON(R₈)₂, OH, OCOR₈, OR₈, CN, an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a trialkylsilyl or (trialkylsilyl)oxy group where the alkyl groups independently have 1 to 6 carbons; X' is O, S, SO, SO₂, N, NR₃ orC(R₃)₂; or -X'-R₁₄ is -C(R_i4)H₂ or - C(R,₄)-(CH₂)_nH where n is 1-6;

Yi is phenyl, naphthyl or heteroaryl selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl, naphthyl and heteroaryl groups being optionally substituted with one R'₃ and one or two R groups;

R is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons, NH₂, NRiH, N(R,)₂, N(R, CORι, NR,CON(R,)₂ or OCOR,; R'₃ is H, (Ci-Cio) alkyl, 1-adamantyl, 2-tetrahydropyranoxy, trialkylsilanyl and trialkylsilanyloxy where alkyl comprises 1 to 6 carbons, alkoxy and alkylthio where alkyl comprises 1 to 10 carbons, or OCH O(Cι_ _ό)alkyl;

Z is -C≡C-, -N=N-, -N=CR,-, -CR,=N, -(CR,=CRι)_n- where n' is an integer having the value 0-5,

-CONR,-,

-CSNR,-,

-NRiCO-,

-NR,CS-, -COO-,

-OCO-;

-CSO-;

-OCS-; where each Rj is independently or together H or alkyl of 1 to 6 carbons, and n is 1 or 2;

Y is a phenyl or naphthyl group, or heteroaryl selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R groups, or when Z is -(CRι=CRι)_n- and n' is 3, 4 or 5 then Y represents a direct valence bond between said -(CRι=CRι)_n' group and B; A is (CH₂)_q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds; and

B is hydrogen, COOH, COOR₈, CONR₉R₁₀, -CH₂OH, CH₂OR, ι, CH₂OCOR, ,, CHO, CH(ORι₂)₂, CHOR₁₃O, -COR₇, CR₇(ORι₂)₂, CR₇OR₁₃O, or tri-lower alkylsilyl, where R₇ is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, Rg is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R₈ is phenyl or lower alkylphenyl, R₉ and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, Rn is lower alkyl, phenyl or lower alkylphenyl, Rι₂ is lower alkyl, and Rn is divalent alkyl radical of 2-5 carbons; or a pharmaceutically acceptable salt or ester thereof. 18. The method according to claim 17, wherein the antagonist is a compound of formula (Ila):

R 14 B

Λ^'

X' .Y^'

R

(Ila)

where m is 0-2.

19. The method according to claim 18, wherein the antagonist is a compound of formula (lib):

.B

R A

14 Y

X'

R,

(lib)

R\

where R'₃ is alkyl. 20. A method according to claim 17, wherein the antagonist is a compound of formula (He):

R 15

,B

Y

X'

R, (He)

R\

21. A method according to claim 1, wherein the antagonist is a compound of formula (III):

wherein X is S, SO, SO₂, O, NR_t or [C(R,)₂ ]„ where each Ri is independently or together H or alkyl of 1 to 6 carbons, and n is 1 or 2;

R₂ is Ci-C_δ alkenyl; and

Rι₄ is (RisVphenyl, (Rι₅)_r-naphthyl, or (Rι₅)_r-heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of O, S and N, r is an integer having the values of 0-6, and

R,₅ is independently H, F, Cl, Br, I, NO₂, N(R₈)₂, N(R₈)COR₈, NR₈ CON(R₈)₂, OH, OCORs, OR₈, CN, an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a trialkylsilyl or (trialkylsilyl)oxy group where the alkyl groups independently have 1 to 6 carbons, where R₈ is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R₈ is phenyl or lower alkylphenyl; or a pharmaceutically acceptable salt or ester thereof.

22. A method according to claim 1, wherein the antagonist is a compound of the formula (IV):

^R'⁴ (R₂)_m (R₂)₀

R₃ . . ^' / '^a

Y

(IV)

X ^ , ^*- . . R₂

wherein X is S, SO, SO₂, O, NR [C(Rι)₂ ]„, -C(Rι)₂-NR , -C(Rι)₂-S-, - C(Rι)₂-O- or -C(Rι)₂-(Rι)₂-, where each Ri is independently or together H or alkyl of 1 to 6 carbons, and n is 1 or 2; each R₂ is independently or together hydrogen, lower alkyl of 1 to 6 carbons. F, Cl, Br, I, CF₃, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons, NH₂, NRiH, N(Rι) , N(Rι)CORι, NR,CON(Rι)₂ or OCORi ;

R₃ is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br or I; m is an integer having the value of 0-3 ; o is an integer having the value of 0-3 ;

Z is -C≡C-, -N=N-, -N=CR,-, -CR,=N, -(CRι=CRι)„- where n' is an integer having the value 0-5, -CONRi-, -CSNRi-, -NR,CO, -NRiCS-, -COO-,

-OCO-; -CSO-; -OCS-;

Y is a phenyl or naphthyl group, or heteroaryl selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R groups, or when Z is -(CRι=CRι)_n - and n' is 3, 4 or 5 then Y represents a direct valence bond between said -(CR|=CRι)_n- group and B;

B is hydrogen, COOH, COOR₈, CONR₉R,₀, -CH₂OH, CH₂OR_u, CH₂OCORι ι, CHO, CH(OR,₂)₂, CHOR₁3O, -COR₇, CR₇(OR₁₂)₂, CR₇ORι₃O, or tri-lower alkylsilyl, where R is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R₈ is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or Rg is phenyl or lower alkylphenyl, R₉ and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, Rn is lower alkyl, phenyl or lower alkylphenyl, R₁₂ is lower alkyl, and Rι₃ is divalent alkyl radical of 2-5 carbons; and

Rι₄ is (Ri₅)_r-phenyl, (Rι₅)_r-naphthyl, or (Rι₅)_r-heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of O, S and N, r is an integer having the values of 0-6, and

R,₅ is independently H, F, Cl, Br, I, NO₂, N(R₈)₂, N(R₈)COR₈, NR₈ CON(R₈)₂, OH, OCORs, OR₈, CN. an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a trialkylsilyl or (trialkylsilyl)oxy group where the alkyl groups independently have 1 to 6 carbons; or a pharmaceutically acceptable salt or ester thereof.

23. A method according to claim 1 , wherein the antagonist is a compound of formula (V): B

Λ^'

,IS

R>

(V)

wherein Z is -C≡C-, -N=N-, -N=CR,-, -CRι=N, -(CRι=CRι)„- where n' is an integer having the value 0-5,

-CONRi-, -CSNR ,

-NRiCO,

-NRiCS-,

-COO-,

-OCO-; -CSO-;

-OCS-; where each Ri is independently or together H or alkyl of 1 to 6 carbons, and n is 1 or 2;

Y is a phenyl or naphthyl group, or heteroaryl selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R₂ groups, or when Z is -(CRι=CRι)_n- and n' is 3, 4 or 5 then Y represents a direct valence bond between said -(CRι=CRι)_n> group and B; A is (CH₂)_q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;

B is hydrogen, COOH, COOR₈, CONR₉R₁₀, -CH₂OH, CH₂ORn, CH₂OCORι ι, CHO, CH(ORi2)₂, CHOR13O, -COR7, CR₇(OR,₂)₂, CR₇OR₁₃O, or tri-lower alkylsilyl, where R₇ is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R₈ is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R₈ is phenyl or lower alkylphenyl, R and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, Rn is lower alkyl, phenyl or lower alkylphenyl, Rι₂ is lower alkyl, and Rn is divalent alkyl radical of 2-5 carbons; and

R₂ is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons, NH₂, NR,H, N(R,)₂, N(R,)COR,, NR,CON(R,)₂ or OCOR,; or a pharmaceutically acceptable salt or ester thereof.

24. A method of inhibiting the growth of a prostate carcinoma cell or tumor, the method comprising contacting said cell or tumor with an effective amount of a retinoid receptor antagonist.

25. A method according to claim 24, wherein said antagonist is an RAR antagonist.

26. The method according to claim 25, wherein said antagonist is an RARαβγ antagonist.

27. The method according to claim 25, wherein said antagonist is an RARα antagonist.

28. A method according to claim 24, wherein the antagonist is a compound of formula (I):

B

R₁₄ (R₂)_m Y

⁷ z ^' - \

-^ R₂ (I)

(R₃)o , x₂

X Xi

wherein X is S, SO, SO₂, O, NR, or [C(Rι)₂ ]_n where each Ri is independently or together H or alkyl of 1 to 6 carbons, and n is 1 or 2; or X is absent;

Xi is absent and X₂ is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃, fluoro substituted alkyl of 1 to 6 carbons. OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; provided that at least X is present, or Xi and X are each C; is an optionally present bond; each R₂ is independently or together hydrogen, lower alkyl of 1 to 6 carbons, F, Cl. Br, I, CF₃, fluoro substituted alkyl of 1 to 6 carbons. OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons, NH₂, NRiH, N(Rι)₂, N(Ri)CORi, NR,CON(Ri)₂ or OCOR,; each R₃ is independently or together hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br or I; m is an integer having the value of 0-3; o is an integer having the value of 0-3;

Z is -C≡C-, -N=N-, -N=CR,-, -CR,=N, -(CR,=CR,)_n- where n' is an integer having the value 0-5, -CONR,-, -CSNR,-, -NRiCO, -NR,CS-, -COO-, -OCO-; -CSO-; -OCS-;

Y is a phenyl or naphthyl group, or heteroaryl selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R₂ groups, or when Z is -(CRι=CRι)_n' - and n' is 3, 4 or 5 then Y represents a direct valence bond between said -(CRι=CRι)_n- group and B;

A is (CH₂)_q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds; B is hydrogen, COOH, COOR₈, CONR₉R,₀, -CH₂OH, CH₂OR, ,,

CH₂OCOR,ι, CHO, CH(OR,₂)₂, CHOR,₃O, -COR₇, CR₇(ORι₂)₂, CR₇OR,₃O, or tri-lower alkylsilyl, where R₇ is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R₈ is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R₈ is phenyl or lower alkylphenyl, R and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R, , is lower alkyl, phenyl or lower alkylphenyl, R,₂ is lower alkyl, and R,₃ is divalent alkyl radical of 2-5 carbons; and R_t is (Rι₅)_r-phenyl, (R,₅)_r-naphthyl, or (Rι₅)_r-heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of O, S and N, r is an integer having the values of 0-6, and

R,₅ is independently H, F, Cl, Br, I, NO₂, N(R₈)₂, N(R₈)COR₈, NR₈

CON(R₈)₂, OH, OCORs, OR₈, CN, an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a trialkylsilyl or (trialkylsilyl)oxy group where the alkyl groups independently have 1 to 6 carbons; or a pharmaceutically acceptable salt or ester thereof.

29. The method of claim 28, wherein X is present and X) is absent. 30. The method of claim 29, wherein Y is phenyl and Rι is (Ri₅)r- phenyl.

31. The method of claim 30, wherein r is 1 and R₁₅ is COOH.

32. The method of claim 28, wherein X is absent and X_\ and X₂ are C. 33. The method of claim 32, wherein Y is phenyl and R_[4 is (Rι₅)_r- phenyl.

34. The method of claim 33, wherein r is 1 and R₁₅ is COOH.

35. The method of claim 28, wherein X is present and X, and X₂ are C. 36. The method of claim 35, wherein Y is phenyl and R14 is (Rι₅)_r- phenyl.

37. The method of claim 36, wherein r is 1 and R1₅ is COOH.

38. The method of claim 37, wherein the compound is

COOH

9. The method of claim 37, wherein the compound is

COOH

O

o

Br

40. A method according to claim 24, wherein the antagonist is a compound of formula (II):

Rw-X'- Yi (R₂R'₃)-Z- Y(R₂)-A-B (II)

where R,₄ is (Rι₅)_r-phenyl, (Rι₅)_r-naphthyl or (R,₅)_r-heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of O, S and N, r is an integer having the value of 0-6, and

R,₅ is independently H, F, Cl, Br, I, NO₂, N(R₈)₂, N(R₈)COR₈, NR₈ CON(R₈)₂. OH, OCORs, OR₈, CN, an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a trialkylsilyl or (trialkylsilyl)oxy group where the alkyl groups independently have 1 to 6 carbons; X is O, S, SO, SO₂, N, NR₃ or C(R₃)₂; or -X'-R,₄ is -C(R,₄)H₂ or -

C(R,₄)-(CH₂)_nH where n is 1-6;

Y, is phenyl, naphthyl or heteroaryl selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl, naphthyl and heteroaryl groups being optionally substituted with one R'₃ and one or two R₂ groups;

R₂ is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃, fluoro substituted alkyl of 1 to 6 carbons, OH, SH. alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons, NH₂, NRiH, N(Rι)₂, N(Rι)CORι, NRιCON(Rι)₂ or OCORi; R'₃ is H, (Cι-C,o) alkyl, 1-adamantyl, 2-tetrahydropyranoxy, trialkylsilanyl and trialkylsilanyloxy where alkyl comprises 1 to 6 carbons, alkoxy and alkylthio where alkyl comprises 1 to 10 carbons, or OCH₂O(Cι. ₆)alkyl;

Z is -C≡C-, -N=N-, -N=CRι-, -CR,=N, -(CR,=CR,)_n- where n' is an integer having the value 0-5, -CONR,-,

-CSNR,-, -NR,CO-,

-NRiCS-,

-COO-,

-OCO-; -CSO-;

Y is a phenyl or naphthyl group, or heteroaryl selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R₂ groups, or when Z is -(CR,=CR,)_n"- and n' is 3, 4 or 5 then Y represents a direct valence bond between said -(CRι=CR,)_n' group and B; A is (CH₂)_q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds; and

B is hydrogen, COOH, COOR₈, CONR₉R₁₀, -CH₂OH, CH₂OR,,, CH₂OCOR, ι, CHO, CH(ORι₂)₂, CHOR13O, -COR₇, CR₇(OR,₂)₂, CR₇ORι₃O, or tri-lower alkylsilyl, where R₇ is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R₈ is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R₈ is phenyl or lower alkylphenyl, R₉ and R,₀ independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R,, is lower alkyl, phenyl or lower alkylphenyl, R,₂ is lower alkyl, and R,₃ is divalent alkyl radical of 2-5 carbons; or a pharmaceutically acceptable salt or ester thereof.

41. The method according to claim 40, wherein the antagonist is a compound of formula (Ila):

(Ila)

R (R₂ 2)

where m is 0-2.

42. The method according to claim 41, wherein the antagonist is a compound of formula (lib):

R₁₄ A ^B Y

X'^ , z R₂

(lib)

R'₃

where R'₃ is alkyl.

43. A method according to claim 40, wherein the antagonist is a compound of formula (lie):

44. A method according to claim 24, wherein the antagonist is a compound of formula (III):

^_\^/COOH

(III)

X R,

wherein X is S, SO, SO₂, O, NR, or [C(Rι)₂ ]_n where each Ri is independently or together H or alkyl of 1 to 6 carbons, and n is 1 or 2;

R₂ is C|-C₆ alkenyl; and

Rι₄ is (R₁₅)_r-phenyl, (Rι₅)_r-naphthyl, or (Ri₅)_r-heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of O, S and N, r is an integer having the values of 0-6, and Ris is independently H, F, Cl, Br, I, NO₂, N(R₈)₂, N(R₈)COR₈, NR₈

CON(R₈)₂, OH, OCORs, OR₈, CN, an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a trialkylsilyl or (trialkylsilyl)oxy group where the alkyl groups independently have 1 to 6 carbons, where R₈ is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R₈ is phenyl or lower alkylphenyl; or a pharmaceutically acceptable salt or ester thereof.

45. A method according to claim 24, wherein the antagonist is a compound of the formula (IV):

wherein X is S, SO, SO₂, O, NR,, [C(Rι)₂ ]„, -C(R,)₂-NR_r, -C(R,)₂-S-, - C(Rι)₂-0- or -C(Rι)₂-(Rι)₂- where each Ri is independently or together H or alkyl of 1 to 6 carbons, and n is 1 or 2; and each R₂ is independently or together hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons, NH₂, NR,H, N(Rι)₂, N(R,)CORi, NR,CON(R,)₂ or OCOR,;

R₃ is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br or I; m is an integer having the value of 0-3; o is an integer having the value of 0-3;

Z is -C≡C-, -N=N-, -N=CR,-, -CR,=N, -(CR,=CR,)_n- where n' is an integer having the value 0-5, -CONR,-, -CSNR,-, -NR,CO, -NR,CS-, -COO-,

-OCO-; -CSO-; -OCS-;

Y is a phenyl or naphthyl group, or heteroaryl selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R₂ groups, or when Z is -(CRι=CR,)_n' - and n' is 3, 4 or 5 then Y represents a direct valence bond between said -(CR,=CR,)_n' group and B;

B is hydrogen, COOH, COORs, CONR₉R,₀, -CH₂OH, CH₂OR,„ CH₂OCORn, CHO, CH(OR₁₂)₂, CHOR,₃O, -COR₇, CR₇(OR₁₂)₂, CR₇OR,₃O, or tri-lower alkylsilyl, where R₇ is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R₈ is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R₈ is phenyl or lower alkylphenyl, R and R,o independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R,, is lower alkyl, phenyl or lower alkylphenyl, R,₂ is lower alkyl, and R,₃ is divalent alkyl radical of 2-5 carbons; and

R,₄ is (R,₅)_r-phenyl, (R,5)_r-naphthyl, or (R,₅)_r-heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of O, S and N, r is an integer having the values of 0-6, and

R,₅ is independently H, F, Cl, Br, I, NO₂, N(R₈)₂, N(R₈)COR₈, NR₈ CON(R₈)₂, OH, OCORs, OR₈, CN, an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a trialkylsilyl or (trialkylsilyl)oxy group where the alkyl groups independently have 1 to 6 carbons; or a pharmaceutically acceptable salt or ester thereof.

46. A method according to claim 24, wherein the antagonist is a compound of formula (V):

,B

A

N

R,

(V)

wherein Z is -C≡C-, -N=N-, -N=CR,-, -CR,=N, -(CR^CR, - where n' is an integer having the value 0-5. -CONR,-,

-CSNR,-,

-NR,CO,

-NRiCS-,

-COO-, -OCO-;

-CSO-;

-OCS-; where each R, is independently or together H or alkyl of 1 to 6 carbons, and n is 1 or 2; Y is a phenyl or naphthyl group, or heteroaryl selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R₂ groups, or when Z is -(CRι=CR,)n'- and n' is 3, 4 or 5 then Y represents a direct valence bond between said -(CR,=CR,)_n' group and B;

A is (CH₂)_q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds; B is hydrogen, COOH. COOR₈, CONR₉R,₀, -CH₂OH, CH₂OR, ,, CH₂OCOR, ,, CHO, CH(OR,₂)₂, CHOR₁₃O, -COR₇, CR₇(OR,₂)₂, CR₇OR,₃O, or tri-lower alkylsilyl, where R₇ is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R₈ is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R₈ is phenyl or lower alkylphenyl, R₉ and R,o independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R, , is lower alkyl, phenyl or lower alkylphenyl, R,₂ is lower alkyl, and R,₃ is divalent alkyl radical of 2-5 carbons; and

R is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃, fluoro substituted alkyl of 1 to 6 carbons, OH, SH. alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons, NH₂, NR,H, N(R,)₂, N(R,)COR,, NR,CON(R,)₂ or OCOR,; or a pharmaceutically acceptable salt or ester thereof.

47. A method for treating prostate cancer in a patient in need of such treatment, the method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a retinoid receptor antagonist and a pharmaceutically acceptable carrier or excipient. 48. The method of claim 47, wherein said antagonist is an RAR antagonist.

49. A method of inhibiting the growth of a prostate carcinoma cell or tumor, the method comprising contacting said cell or tumor with an effective amount of a pharmaceutical composition comprising a retinoid receptor antagonist and a pharmaceutically acceptable carrier or excipient.

50. The method of claim 49, wherein said antagonist is an RAR antagonist.