This invention relates to non-steroidal compounds that are modulators (i.e. agonists and antagonists) of androgen receptors, and to methods for the making and use of such compounds.
Intracellular receptors (IRs) form a class of structurally-related genetic regulators scientists have named xe2x80x9cligand dependent transcription factors.xe2x80x9d R. M. Evans, Science, 240:889 (1988). Steroid receptors are a recognized subset of the IRs, including the progesterone receptor (PR), androgen receptor (AR), estrogen receptor (ER), glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). Regulation of a gene by such factors requires both the IR itself and a corresponding ligand which has the ability to selectively bind to the IR in a way that affects gene transcription.
Ligands to the IRs can include low molecular weight native molecules, such as the hormones progesterone, estrogen and testosterone, as well as synthetic derivative compounds such as methoxyprogesterone acetate, diethylstilbesterol and 19-nortestosterone. These ligands, when present in the fluid surrounding a cell, pass through the outer cell membrane by passive diffusion and bind to specific IR proteins to create a ligand/receptor complex. This complex then translocates to the cell""s nucleus, where it binds to a specific gene or genes present in the cell""s DNA. Once bound to this regard, a compound which binds an IR and mimics the effect of the native ligand is referred to as an xe2x80x9cagonistxe2x80x9d, while a compound that inhibits the effect of the native ligand is called an xe2x80x9cantagonist.xe2x80x9d
Ligands to the steroid receptors are known to play an important role in health of both women and men. For example, the native female ligand, progesterone, as well as synthetic analogues, such as norgestrel (18-homonorethisterone) and norethisterone (17xcex1-ethinyl-19-nortestosterone), are used in birth control formulations, typically in combination with the female hormone estrogen or synthetic estrogen analogues, as effective modulators of both PR and ER. On the other hand, antagonists to PR are potentially useful in treating chronic disorders, such as certain hormone dependent cancers of the breast, ovaries, and uterus, and in treating non-malignant conditions such as uterine fibroids and endometriosis, a leading cause of infertility in women. Similarly, AR antagonists, such as cyproterone acetate and flutamide have proved useful in the treatment of prostatic hyperplasia and cancer of the prostate.
The effectiveness of known modulators of steroid receptors is often tempered by their undesired side-effect profile, particularly during long-term administration. For example, the effectiveness of progesterone and estrogen agonists, such as norgestrel and diethylstilbesterol respectively, as female birth control agents must be weighed against the increased risk of breast cancer and heart disease to women taking such agents. Similarly, the progesterone antagonist, mifepristone (RU486), if administered for chronic indications, such as uterine fibroids, endometriosis and certain hormone-dependent cancers, could lead to homeostatic imbalances in a patient due to its inherent cross-reactivity as a GR antagonist. Accordingly, identification of compounds which have good specificity for one or more steroid receptors, but which have reduced or no cross-reactivity for other steroid or intracellular receptors, would be of significant value in the treatment of male and female hormone responsive diseases.
A group of quinoline analogs having an adjacent polynucleic ring system of the indene or fluorene series or an adjacent polynucleic heterocyclic ring system with substituents having a nonionic character have been described as photoconductive reducing agents, stabilizers, laser dyes and antioxidants. See e.g., U.S. Pat. Nos. 3,798,031; 3,830,647; 3,832,171; 3,928,686; 3,979,394; 4,943,502 and 5,147,844 as well as Soviet Patent No. 555,119; R. L. Atkins et al., J. Org. Chem., 43:1975 (1978), E. R. Bissell et al., J. Org. Chem., 45:2283 (1980), and G. N. Gromova et al., Khim. Prom-st., 43:97 (Moscow, 1967). Further, a group of quinoline derivatives was recently described as modulators of steroid receptors. See, e.g., WO 96/19458, published Jun. 27, 1996. A recent paper describes the synthesis and biological activity of the pyridone-containing precursors to the present series of molecules. See, e.g., L. G. Hamann, et al., J. Med. Chem., 41:623 (1998).
The present invention is directed to compounds, pharmaceutical compositions, and methods for modulating processes mediated by androgen receptors (AR). More particularly, the invention relates to non-steroidal compounds and compositions which are high affinity, high specificity agonists, partial agonists (i.e., partial activators and/or tissue-specific activators) and antagonists for androgen receptors. Also provided are methods of making such compounds and pharmaceutical compositions, as well as critical intermediates used in their synthesis.
These and various other advantages and features of novelty which characterize the invention are pointed out with particularity in the claims annexed hereto and forming a part hereof. However, for a better understanding of the invention, its advantages, and objects obtained for its use, reference should be made to the accompanying drawings and descriptive matter, in which there is illustrated and described preferred embodiments of the invention.
As used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise. Furthermore, in an effort to maintain consistency in the naming of compounds of similar structure but differing substituents, the compounds described herein are named according to the following general guidelines. The numbering system for the location of substituents on such compounds is also provided.
The term xe2x80x9calkylxe2x80x9d refers to an optionally substituted straight-chain or branched-chain hydrocarbon radical having from 1 to about 10 carbon atoms, more preferably from 1 to about 6 carbon atoms, and most preferably from 1 to about 4 carbon atoms. Examples of alkyl radical include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, octyl and the like.
The term xe2x80x9calkenylxe2x80x9d refers to a straight-chain or branched-chain hydrocarbon radical having one or more carbon-carbon double-bonds and having from 2 to about 10 carbon atoms, preferably from 2 to about 6 carbon atoms, and most preferably from 2 to about 4 carbon atoms. Preferred alkeny groups include allyl. Examples of alkenyl radicals include ethenyl, propenyl, 1,4-butadienyl and the like.
The term xe2x80x9callylxe2x80x9d refers to the radical H2Cxe2x95x90CHxe2x80x94CH2.
The term xe2x80x9calkynylxe2x80x9d refers to a straight-chain or branched-chain hydrocarbon radical having one or more carbon-carbon triple-bonds and having from 2 to about 10 carbon atoms, preferably from 2 to about 6 carbon atoms, and most preferably from 2 to about 4 carbon atoms. Examples of alkynyl radicals include ethynyl, propynyl, butynyl and the like.
The term xe2x80x9carylxe2x80x9d refers to optionally substituted aromatic ring systems. The term aryl includes monocyclic aromatic rings, polycyclic aromatic ring systems, and polyaromatic ring systems. The polyaromatic and polycyclic ring systems may contain from two to four, more preferably two to three, and most preferably two, rings. Preferred aryl groups include 5- or 6-membered aromatic ring systems.
The term xe2x80x9cheteroarylxe2x80x9d refers to optionally substituted aromatic ring systems having one or more heteroatoms such as, for example, oxygen, nitrogen and sulfur. The term heteroaryl may include five- or six-membered heterocyclic rings, polycyclic heteroaromatic ring systems, and polyheteroaromatic ring systems where the ring system has from two to four, more preferably two to three, and most preferably two, rings. The terms heterocyclic, polycyclic heteroaromatic, and polyheteroaromatic include ring systems containing optionally substituted heteroaromatic rings having more than one heteroatom as described above (e.g., a six membered ring with two nitrogens), including polyheterocyclic ring systems from two to four, more preferably two to three, and most preferably two, rings. Preferably, heteroaryl groups have from one to The term heteroaryl includes ring systems such as, for example, pyridine, quinoline, furan, thiophene, pyrrole, imidazole and pyrazole.
The term xe2x80x9calkoxyxe2x80x9d refers to an alkyl ether radical wherein the term alkyl is defined as above. Examples of alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
The term xe2x80x9caryloxyxe2x80x9d refers to an aryl ether radical wherein the term aryl is defined as above. Examples of aryloxy radicals include phenoxy, benzyloxy and the like.
The term xe2x80x9ccycloalkylxe2x80x9d refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl radical wherein each cyclic moiety has about 3 to about 8 carbon atoms. Examples of cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
The term xe2x80x9ccycloalkylalkylxe2x80x9d refers to an alkyl radical as defined above which is substituted by a cycloalkyl radical having from about 3 to about 8 carbon atoms.
The term xe2x80x9carylalkylxe2x80x9d refers to an alkyl radical as defined above in which one hydrogen atom is replaced by an aryl radical as defined above, such as, for example, benzyl, 2-phenylethyl and the like. Preferably, arylalkyl refers to arylmethyl.
The terms alkyl, alkenyl, and alkynyl include optionally substituted straight-chain, branched-chain, cyclic, saturated and/or unsaturated structures, and combinations thereof.
The terms cycloalkyl, allyl, aryl, arylalkyl, arylalkyl, heteroaryl, alkynyl, and alkenyl include optionally substituted cycloalkyl, allyl, aryl, arylalkyl, arylalkyl, heteroaryl, alkynyl, and alkenyl groups.
The terms haloalkyl, haloalkenyl and haloalkynyl include alkyl, alkenyl and alkynyl structures, as described above, that are substituted with one or more fluorines, chlorines, bromines or iodines, or with combinations thereof.
The terms heteroalkyl, heteroalkenyl and heteroalkynyl include optionally substituted alkyl, alkenyl and alkynyl structures, as described above, in which one or more skeletal atoms are oxygen, nitrogen, sulfur, or combinations thereof.
The substituents of an xe2x80x9coptionally substitutedxe2x80x9d structure include, for example, one or more, preferably 1 to 4, and more preferably 1 to 2 of the following preferred substitutents: alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl, cycloalkylalkyl, arylalkyl, amino, alkylamino, dialkylamino, F, Cl, Br, I, C1-C6 alkyl, OR2, NR13R14 and SR2.
An 8-pyridono[5,6-g]quinoline is represented by the following structure. 
An 9-pyrido[3,2-g]quinoline is represented by the following structure. 
Compounds of the present invention are represented as those having the formula: 
wherein:
R1 is hydrogen, C1-C6 alkyl, F, Cl, Br, I, NO2, OR2, NR13R14, or SR2;
R2 is hydrogen, C1-C6 alkyl or C1-C6 alkenyl, wherein the C1-C6 alkyl and C1-C6 alkenyl are optionally substituted with C1-C6 alkyl, arylalkyl or heteroaryl;
R3 and R4 each independently represent hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 perhaloalkyl, C1-C6 alkenyl, C1-C6 alkynyl, aryl, or heteroaryl, wherein the alkyl, haloalkyl, perhaloalkyl, alkenyl, alkynyl, aryl, and heteroaryl are optionally substituted with hydrogen, F, Cl, Br, C1-C4 alkyl, OR2, NR13R14, or SR2; or optionally,
R3 and R4 may be taken together form a three- to seven-membered ring optionally substituted with hydrogen, F, Cl, Br, C1-C4 alkyl, OR2, NR13R14, or SR2;
R5 and R6 each independently represent hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 perhaloalkyl, C1-C6 alkenyl, C1-C6 alkynyl, aryl, or heteroaryl, wherein the alkyl, haloalkyl, perhaloalkyl, alkenyl, alkynyl, aryl, and heteroaryl are optionally substituted with hydrogen, F, Cl, Br, C1-C4 alkyl, OR2, NR13R14, or SR2; or optionally,
R5 and R6 may be taken together form a carbonyl, an imine, or a three- to seven-membered ring optionally substituted with hydrogen, F, Cl, Br, C1-C4 alkyl, OR2, NR13R14, or SR2;
R7 and R8 each independently represent hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 perhaloalkyl, C1-C6 alkenyl, C1-C6 alkynyl, aryl, or heteroaryl, wherein the alkyl, haloalkyl, perhaloalkyl, alkenyl, alkynyl, aryl, and heteroaryl are optionally substituted with hydrogen, F, Cl, Br, C1-C4 alkyl, OR2, NR13R14, or SR2; or optionally,
R7 and R8 may be taken together form a carbonyl, an imine, or a three- to seven-membered ring optionally substituted with hydrogen, F, Cl, Br, C1 -C4 alkyl, OR2, NR13R14, or SR2;
R9 represents hydrogen, C1-C4 alkyl, F, Cl, Br, I, OR2, NR13R14, or SR2;
R10 is represents hydrogen, F, Cl, Br, CF3, CF2OR2, CH2OR2, OR2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 perhaloalkyl, aryl, or heteroaryl, wherein the alkyl, haloalkyl, perhaloalkyl, aryl, and heteroaryl are optionally substituted with hydrogen, F, Cl, Br, C1-C4 alkyl, OR2, NR13R14, or SR2;
R11 represents hydrogen, F, Cl, Br, I, C1-C6 alkyl, C1-C6 perhaloalkyl, C1-C6 perhaloalkyl, C1-C6 alkenyl, C1-C6 alkynyl, aryl, and heteroaryl, wherein the alkyl, haloalkyl, perhaloalkyl, alkenyl, alkynyl, aryl, or heteroaryl are optionally substituted with hydrogen, F, Cl, Br, C1-C4 alkyl, OR2, NR13R14, or SR2;
R12 represents hydrogen, C(O)R11, SR2, S(O)R13, S(O2)R13, C1-C6 alkyl, C1-C6 alkenyl, aryl, arylalkyl or heteroaryl, wherein the alkyl, alkenyl, aryl, arylalkyl and heteroaryl are optionally substituted with hydrogen, F, Cl, Br, C1-C4 alkyl, OR2, N13R14, or SR2;
X represents hydrogen, F, Cl, Br, I, CN, CF3, SR2, S(O)R13, SO2R13, SO3R13, NR13R14, CF3, NO2, or R13;
R13 and R14 each independently represents hydrogen, C(O)R11, SO2R3, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 haloalkyl, C1-C6 perhaloalkyl, aryl, arylalkyl or heteroaryl, wherein the alkyl, alkenyl, haloalkyl, perhaloalkyl, aryl, arylalkyl, and heteroaryl are optionally substituted with hydrogen, F, Cl, Br, C1-C4 alkyl, OR2, NR13R14, or SR2;
with the proviso that when the dotted line in the ring structure is a double bond, R6 and R7 are null;
and pharmaceutically aceptable salts thereof.
Preferred R1 groups include hydrogen, C1 -C6 alkyl, F, Cl, Br, I, NO2, OR2, NR13R14, and SR2. More preferred R1 groups include hydrogen and C1-C4 alkyl Most preferably R1 is hydrogen.
Preferred R2 groups include hydrogen, C1-C6 alkyl or C1-C6 alkenyl, wherein the C1-C6 alkyl and C1-C6 alkenyl are preferably substituted with C1-C6 alkyl, arylalkyl or heteroaryl. More preferred R2 groups include hydrogen and C1-C4 alkyl. Most preferably R2 is hydrogen.
Preferred R3 groups include hydrogen, C1-C6 alkyl, C1-C6 perhaloalkyl, C1-C6 alkenyl, C1-C6 alkynyl, aryl, and heteroaryl, wherein the alkyl, perhaloalkyl, alkenyl, alkynyl, aryl, and heteroaryl may be optionally substituted. More preferred R3 groups include hydrogen, C1-C6 alkyl, C1-C6 perhaloalkyl, C1-C6 alkenyl, C1-C6 alkynyl, and C1-C6 allyl. Most preferably, R3 is hydrogen or C1-C6 alkyl.
Also preferred are compounds where R3 is taken with R4 to form a three- to seven-membered ring that is optionally substituted.
Preferred R4 groups include hydrogen, C1-C6 alkyl, C1-C6 perhaloalkyl, C1-C6 alkenyl, C1-C6 alkynyl, aryl, and heteroaryl, wherein the alkyl, perhaloalkyl, alkenyl, alkynyl, aryl, and heteroaryl are optionally substituted. More preferred R4 groups include hydrogen, C1-C6 alkyl, C1-C6 perhaloalkyl, C1-C6 alkenyl, C1-C6 alkynyl, and C1-C6 allyl. Most preferably, R4 is hydrogen or C1-C6 alkyl.
Preferred R5 groups include hydrogen, C1-C6 alkyl, C1-C6 perhaloalkyl, C1-C6 alkenyl, C1-C6 alkynyl, aryl, and heteroaryl, wherein the alkyl, perhaloalkyl, alkenyl, alkynyl, aryl, and heteroaryl are optionally substituted. More preferred R5 groups include hydrogen, C1-C6 alkyl, C1-C6 perhaloalkyl, C1-C6 alkenyl, C1-C6 alkynyl, and C1-C6 allyl. Most preferably, R5 is hydrogen or C1-C6 alkyl.
Also preferred are compounds where R5 is taken with R6 to form a carbonyl, an imine, or a three- to seven-membered ring that is optionally substituted.
Preferred R6 groups include hydrogen, C1-C6 alkyl, C1-C6 perhaloalkyl, C1-C6 alkenyl, C1-C6 alkynyl, aryl, and heteroaryl, wherein the alkyl, perhaloalkyl, alkenyl, alkynyl, aryl, and heteroaryl are optionally substituted. More preferred R6 groups include hydrogen, C1-C6 alkyl, C1-C6 perhaloalkyl and null. Most preferably, R6 is hydrogen.
Preferred R7 groups include hydrogen, C1-C6 alkyl, C1-C6 perhaloalkyl, C1-C6 alkenyl, C1-C6 alkynyl, aryl, and heteroaryl, wherein the alkyl, perhaloalkyl, alkenyl, alkynyl, aryl, and heteroaryl are optionally substituted.
Also preferred are compounds where R7 is taken with R8 to form a carbonyl, an imine, or a three- to seven-membered ring that is optionally substituted. More preferred R7 groups include hydrogen, C1-C6 alkyl, C1-C6 perhaloalkyl and null. Most preferably R7 is hydrogen.
Preferred R8 groups include hydrogen, C1-C6 alkyl, C1-C6 perhaloalkyl, C1-C6 alkenyl, C1-C6 alkynyl, aryl, and heteroaryl, wherein the alkyl, perhaloalkyl, alkenyl, alkynyl, aryl, are heteroaryl are optionally substituted. More preferred R8 groups include hydrogen, C1-C6 alkyl, C1-C6 perhaloalkyl, C1-C6 alkenyl, and C1-C6 alkynyl. Most preferably R8 is hydrogen or C1-C6 alkyl.
Preferred R9 groups include hydrogen, C1-C4 alkyl, F, Cl, Br, I, OR2, NR13RI4, and SR2. More preferred R9 groups include hydrogen, C1-C4 alkyl, F, Cl, Br, and I. Most preferably, R9 is hydrogen, F, Cl, Br, or I.
Preferred R10 groups include hydrogen, F, Cl, Br, CF3, CF2OR2, CH2OR2, OR2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 perhaloalkyl, aryl, and heteroaryl, wherein the alkyl, haloalkyl, perhaloalkyl, aryl, and heteroaryl are optionally substituted. More preferred R10 groups include hydrogen, F, Cl, Br, CF3, CF2OR2, CH2OR2, OR2, and C1-C6 alkyl. Most preferably, R10 is hydrogen, F, Cl, Br, I, or CF3.
Preferred R11 groups include hydrogen, F, Cl, Br, CF3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 perhaloalkyl, C1-C6 alkenyl, C1-C6 alkynyl, aryl, and heteroaryl, wherein the alkyl, haloalkyl, perhaloalkyl, alkenyl, alkynyl, aryl, and heteroaryl are optionally substituted. More preferred R11 groups include hydrogen, F, Cl, Br, I, and C1-C4 alkyl. Most preferably, R11 is hydrogen, F, Cl, Br, or I.
Preferred R12 groups include hydrogen, C(O)R11, SR2, S(O)R13, SO2R13, C1-C6 alkyl, C1-C6 alkenyl, aryl, arylalkyl, and heteroaryl, wherein the alkyl, alkenyl, aryl, arylalkyl and heteroaryl are optionally substituted. More preferred R12 groups include hydrogen, C1-C6 alkyl, arylalkyl, and heteroaryl, wherein the alkyl, arylalkyl and heteroaryl are optionally substituted. Most preferably, R12 is hydrogen.
Preferred X groups include hydrogen, F, Cl, Br, I, CN, SR2, S(O)R13, SO2R13, SO3R13, NR13R14, CF3, NO2, and R13. More preferred X groups include hydrogen, F, Cl, Br, I, CF3 and CN.
Preferred R13 groups include hydrogen, C(O)R11, SO2R3, C1-C6 alkyl C1-C6 haloalkyl, C1-C6 perhaloalkyl, aryl, arylalkyl or heteroaryl, wherein the alkyl, haloalkyl, perhaloalkyl, aryl, arylalkyl, and heteroaryl are optionally substituted. More preferred R13 groups include hydrogen and C1-C6 alkyl.
Preferred R14 groups include hydrogen, C(O)R11, SO2R3, C1-C6 alkyl C1-C6 haloalkyl, C1-C6 perhaloalkyl, aryl, arylalkyl and heteroaryl, wherein the alkyl, perhaloalkyl, aryl, arylalkyl and heteroaryl are optionally substituted. More preferred R14 groups include hydrogen and C1-C6 alkyl.
In a preferred embodiment of the invention, R1 is hydrogen or C1-C4 alkyl; R2, R3, R4, and R5 each independently is hydrogen or C1-C6 alkyl; R6 and R7 are hydrogen; R8 and R9 each independently is hydrogen or C1-C6 alkyl; R10 is hydrogen, F, Cl, Br, I, or CF3; R11 is hydrogen, F, Cl, Br, or I; R12 is hydrogen; and X is hydrogen, F, Cl, Br, I or CN.
In another preferred embodiment of the invention, R1 is hydrogen or C1-C4 alkyl; R2, R3, R4, R8 each independently is hydrogen or C1-C6 alkyl; R5, R6, R7, and R9 are each hydrogen; R10 is CF3; R11 is hydrogen or F; and X is hydrogen, F, Cl, Br, I or CN.
In a preferred aspect, the present invention provides a pharmaceutical composition comprising an effective amount of an androgen receptor modulating compound of formulas I or II or combinations thereof as shown above wherein R1 through R14 and X have the same definitions as given above.
In a further preferred aspect, the present invention comprises a method of modulating processes mediated by androgen receptors comprising administering to a patient an effective amount of compounds of formulas 1 or 11 or combinations thereof as shown above, wherein R1 through R14 have the same definitions as those given above.
Compounds of the present invention may be synthesized as pharmaceutically acceptable salts for incorporation into various pharmaceutical compositions. As used herein, pharmaceutically acceptable salts include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, hydrofluoric, sulfuric, citric, maleic, acetic, lactic, nicotinic, succinic, oxalic, phosphoric, malonic, salicylic, phenylacetic, stearic, pyridine, ammonium, piperazine, diethylamine, nicotinamide, formic, urea, sodium, potassium, calcium, magnesium, zinc, lithium, cinnamic, methylamino, methanesulfonic, picric, tartaric, triethylamino, dimethylamino, and tris(hydroxymethyl)aminomethane. Additional pharmaceutically acceptable salts are known to those skilled in the art.
AR agonist, partial agonist and antagonist compounds including compounds with tissue-selective AR modulator activity of the present invention are useful in the treatment of acne (antagonist), male-pattern baldness (antagonist), male hormone replacement therapy (agonist), wasting diseases (agonist), hirsutism (antagonist), stimulation of hematopoiesis (agonist), hypogonadism (agonist), prostatic hyperplasia (antagonist), osteoporosis (agonist), male contraception (agonist), impotence (agonist), cancer cachexia (agonist), various hormone-dependent cancers, including, without limitation, prostate (antagonist) and breast cancer and as anabolic agents (agonist). It is understood by those of skill in the art that a partial agonist may be used where agonist activity is desired, or where antagonist activity is desired, depending upon the AR modulator profile of the particular partial agonist.
It is understood by those skilled in the art that while the compounds of the present invention will typically be employed as a selective agonists, partial agonists or antagonists, that there may be instances where a compound with a mixed steroid receptor profile is preferred. For example, use of a PR agonist (i.e., progestin) in female contraception often leads to the undesired effects of increased water retention and acne flare ups. In this instance, a compound that is primarily a PR agonist, but also displays some AR and MR modulating activity, may prove useful. Specifically, the mixed MR effects would be useful to control water balance in the body, while the AR effects would help to control acne flare ups.
Furthermore, it is understood by those skilled in the art that the compounds of the present invention, including pharmaceutical compositions and formulations containing these compounds, can be used in a wide variety of combination therapies to treat the conditions and diseases described above. Thus, the compounds of the present invention can be used in combination with other hormones and other therapies, including, without limitation, chemotherapeutic agents such as cytostatic and cytotoxic agents, immunological modifiers such as interferons, interleukins, growth hormones and other cytokines, hormone therapies, surgery and radiation therapy.
Representative AR modulator compounds (i.e., agonists and antagonists) according to the present invention include:
8-chloro-1,2-dihydro-2,2,4-trimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 101);
8-chloro-1,2-dihydro-1,2,2,4-tetramethyl-6-trifluoromethyl-9-pyrido [3,2-g]quinoline (Compound 102);
(R/S)-8-chloro-1,2,3,4-tetrahydro-2,2,4,10-tetramethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 103);
8-chloro-1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 104);
8-chloro-1,2,3,4-tetrahydro-1,2,2-trimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 105);
8-chloro-7-fluoro-1,2,3,4-tetrahydro-2,2,4,10-tetramethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 106);
8-chloro-7-fluoro-1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 107);
(R/S)-8-chloro-4-ethyl-1,2,3,4-tetrahydro-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 108);
(R/S)-8-chloro-4-ethyl-7-fluoro-1,2,3,4-tetrahydro-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 109);
8-fluoro-1,2-dihydro-2,2,4-trimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 110);
8-fluoro-1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 111);
8-fluoro-1,2,3,4-tetrahydro-1,2,2-trimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 112);
7,8-difluoro-1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 113);
(R/S)-8-fluoro-1,2,3,4-tetrahydro-2,2,4,10-tetramethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 114);
7,8-difluoro-1,2,3,4-tetrahydro-2,2,4,10-tetramethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 115);
(R/S)-4-ethyl-8-fluoro-1,2,3,4-tetrahydro-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 116);
8-bromo-1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 117);
8-bromo-1,2,3 ,4-tetrahydro-1,2,2-trimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 118);
8-bromo-7-fluoro-1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 119);
(R/S)-8-bromo-1,2,3,4-tetrahydro-2,2,4,10-tetramethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 120);
(R/S)-8-bromo-4-ethyl-1,2,3,4-tetrahydro-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 121);
1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 122);
(R/S)1,2,3,4-tetrahydro-2,2,4,10-tetramethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 123);
1,2,3,4-tetrahydro-1,2,2-trimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 124);
(R/S)-4-ethyl-1,2,3,4-tetrahydro-6-trifluoromethy1-9-pyrido[3,2-g]quinoline (Compound 125);
7-fluoro-1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 126);
8-cyano-1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 127);
8-cyano-1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 128);
(R/S)-8-cyano-4-ethyl-1,2,3,4-tetrahydro-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 129);
(R/S)-8-cyano-4-ethyl-1,2,3,4-tetrahydro-1-methyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 130);
(R/S)-9-benzoyl-8-cyano-1,2,3,4,8,9-hexahydro-2,2-dimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 131);
(R/S)-8-cyano-1,2,3,4,8,9-hexahydro-2,2-dimethyl-9-p-toluoyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 132);
1,2,3,4-tetrahydro-2,2-dimethyl-8-methylthio-6-trifluoromethyl-9-9-pyrido[3,2-g]quinoline (Compound 134);
(R/S)-1,2,3,4-tetrahydro-2,2-dilmethyl-8-methylsulfinyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 135);
1,2,3,4-tetrahydro-2,2-dimethyl-8-methylsulfonyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 136);
(R/S)-7-fluoro-1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-8-methylsulfinyl-9-pyrido[3,2-g]quinoline (Compound 137);
1,2,3,4-tetrahydro-2,2-dimethyl-8-(1-n-butylthio)-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 138);
(R/S)-1,2,3,4-tetrahydro-2,2-dimethyl-8-(1-n-butylsulfinyl)-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 139);
1,2,3,4-tetrahydro-2,2-dimethyl-8-(2,2,2-trifluoroethyl-1-thio)-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 140);
(R/S)-4-ethyl-1,2,3,4-tetrahydro-8-methylthio-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 142);
(R/S)-4-ethyl-1,2,3,4-tetrahydro-8-methylsulfinyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 143);
1,2,3,4-tetrahydro-2,2-dimethyl-6,8-di(trifluoromethyl)-9-pyrido[3,2-g]quinoline (Compound 148);
(R/S)-4-ethyl-1,2,3,4-tetrahydro-6,8-di(trifluoromethyl)-9-pyrido[3,2-g]quinoline (Compound 149);
1,2,3,4-tetrahydro-8-(4xe2x80x2-methoxybenzylamino)-2,2-dimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 144);
8-amino-1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 145);
1,2,3,4-tetrahydro-8-methanesulfonamido-2,2-dimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 146);
1,2,3,4-tetrahydro-8-bis(methanesulfon)amido-2,2-dimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline (Compound 147).
Schemes I-IV show examples of substitutions at the C-8 carbon of the quinolinone compounds. Compounds of the present invention, comprising classes of heterocyclic nitrogen compounds and their derivatives, may be obtained by routine chemical synthesis by those skilled in the art, e.g., by modification of the heterocyclic nitrogen compounds disclosed or by a total synthesis approach.
The sequence of steps for several general schemes to synthesize the compounds of the present invention are shown below. In each of the Schemes the R groups (e.g., R1, R2, etc.) correspond to the specific substitution patterns noted in the Examples. However, it is understood by those skilled in the art that other functionalities disclosed herein at the indicated positions of compounds of formulas I and II also comprise potential substituents for the analogous positions on the structures within the Schemes.
Quinoline compounds (e.g., Compound 1), employed as starting materials in Schemes I-IV are obtained by routine synthetic methods shown to those skilled in the art. Chloro-substitution at C-8 is accomplished by treatment of a 8-pyridinoquinoline (e.g., Structure 1) with a dehydrative halogenation reagent such as phosphorous oxychloride to yield 8-chloro-9-pyridoquinolines (e.g., Structure 2) (Scheme I). 8-Fluoro-9-pyridoquinolines (3) are prepared in a halex reaction by treatment of a 8-halo-9-pyridoquinoline with an inorganic fluoride source, such as KF, in a high boiling polar solvent, such as sulpholane, at elevated temperatures. 
Analogously, 8-bromo-substitution is accomplished by treatment of a pyridonoquinoline with a dehydrative brominating reagent, such as phosphorous oxybromide to yield 8-bromo-9-pyridoquinolines (e.g., Structure 4, Scheme II). Reductive dehalogenation of the 8-position is achieved by treatment of a 8-halo-compound with a hydride source such as tri-n-butyltin hydride, in the presence of a free radical initiator, such as 2,2xe2x80x2-azobisisobutyronitrile (AIBN) to yield 8-hydro derivatives (e.g., Structure 5). Treatment of 8-hydro-derivatives such as Structure 5 with a nucleophilic cyanide salt, such as potassium cyanide, in the presence of para-toluenesulfonyl chloride affords 8-cyano-9-pyridoquinolines (e.g., Structure 6). Alternatively, use of an benzoic acid chloride (e.g., Structure 7), such as benzoyl chloride, in place of the para-toluenesulfonyl chloride, affords the 9-benzoyl-8-cyano-8,9-dihydro-adducts as shown in Structure 8. 
Sulfoxy or sulfonyl substitution at C-8 is introduced by a 3-step procedure from pyridonoquinolines (e.g., Structure 1, Scheme III). First, the quinoline is converted to the corresponding thiopyridonoquinoline (e.g., Structure 9) by treatment with a thionation reagent such as 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (Lawesson""s Reagent). Second, the thiopyridonoquinoline is converted to an alkylsulfide such as Structure 10 by exposure to an alkyl halide. Finally, the alkylsulfide is converted to a corresponding sulfoxide compound such as Structure 11 subsequent treatment with a mild peroxidant, such as magnesium monoperoxyphthalate (MMPP). Oxidation to a corresponding sulfone such as 12 is achieved using a stronger peroxidant, such as meta-chloroperoxybenzoic acid (mCPBA). 
Amino-substitution at C-8 and subsequent derivatives of the 8-aminopyridoquinolines (e.g., Structure 13) are synthesized from parent 8-pyridonoquinolines (e.g., Structure 1) by treatment with an aryl or alkyl amine, such as para-methoxybenzylamine, in the presence of hexamethyldisilazane (HMDS) and an acid catalyst, such as para-toluenesulfonic acid (p-TsOH), at elevated temperatures to afford aminated products (e.g., Structure 13, as shown in Scheme IV). Removal of a benzyl protecting group is accomplished using a strong organic acid, such as trifluoroacetic acid (TFA) at elevated temperatures to afford unsubstituted aminopyridoquinolines (e.g., Structure 14). This removal is optionally performed before further derivatization, or after further derivatization, such as N-alkylation, which can be achieved by treatment with a base, such as sodium hydride, and subsequent trapping with an alkyl halide to afford mono-substituted compounds (e.g., Structure 15). Iterative alkylation by this process is achieved, leading to optionally di-substituted 8-aminopyridoquinolines (e.g., Structure 18). N-Acylations and N-sulfonylations are achieved under standard conditions, using an electrophilic acylation reagent such as acetic anhydride, or a sulfonylating reagent, such as methanesulfonyl chloride, in the presence of a mild base, such as triethylamine to afford mono or disubstituted compounds as shown in Structures 16 and 17. 
Scheme V shows the preparation of trifluoromethyl substituted quinolines. Trifluoromethyl-substitution at C-8 is accomplished starting with 7-amino-1,2-dihydroquinolines or a tetrahydroquinoline (e.g., Structure 19) followed by treatment with a trifluoromethyl-dione such as 1,1,1,5,5,5-hexafluoropentane-2,4-dione in the presence of an acid catalyst, such as p-TsOH, at elevated temperatures to afford 6,8-bis-trifluoromethylated compounds, an example of which is shown in Structure 20. 
A method for alkylating amino-quinoline compounds is shown in Scheme VI. Alkylation at N-1 is achieved using standard reductive amination conditions as follows. An 8-substituted pyridoquinoline such as Structure 21, is treated with an aldehyde, such as paraformaldehyde, and a mild reductant, such as sodium cyanoborohydride, in the presence of an acid, such as acetic acid, to afford N-1-alkylated products (as shown in Structure 22, Scheme VI). 
The compounds of the present invention also include racemates, stereoisomers and mixtures of said compounds, including isotopically-labeled and radio-labeled compounds. Such isomers can be isolated by standard resolution techniques, including fractional crystallization and chiral column chromatography.
As noted above, any of the steroid modulator compounds of the present invention may be combined in a mixture with a pharmaceutically acceptable carrier to provide pharmaceutical compositions useful for treating the biological conditions or disorders noted herein in mammalian, and more preferably, in human patients. The particular carrier employed in these pharmaceutical compositions may take a wide variety of forms depending upon the type of administration desired, e.g., intravenous, oral, topical, suppository or parenteral.
In preparing the pharmaceutical compositions of the present invention in oral liquid dosage forms (e.g., suspensions, elixirs and solutions), typical pharmaceutical media such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be employed. Similarly, when preparing oral solid dosage forms (e.g., powders, tablets and capsules), carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like may be employed. Due to their ease of administration, tablets and capsules represent the most advantageous oral dosage form for the pharmaceutical compositions of the present invention.
For parenteral administration, a carrier will typically comprise sterile water although other ingredients that aid in solubility or serve as preservatives, may also be included. Furthermore, injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
For topical administration compounds of the present invention may be formulated using bland moisturizing bases such as ointments or creams. Examples of suitable ointment bases are petrolatum, petrolatum plus volatile silicones, lanolin, and water in oil emulsions such as Eucerin(trademark) (Beiersdorf). Examples of suitable cream bases are Nivea(trademark) Cream (Beiersdorf), cold cream (USP), Purpose Cream(trademark) (Johnson and Johnson), hydrophilic ointment (USP), and Lubriderm(trademark) (Warner-Lambert).
The pharmaceutical compositions and compounds of the present invention may generally be administered in the form of a dosage unit (e.g., tablet, capsule etc.) at concentrations from about 1 xcexcg/kg of body weight to about 500 mg/kg of body weight, more preferably from about 10 xcexcg/kg to about 250 mg/kg, and most preferably from about 20 xcexcg/kg to about 100 mg/kg. As recognized by those skilled in the art, the particular quantity of pharmaceutical composition according to the present invention administered to a patient will depend upon a number of factors, including, without limitation, the biological activity desired, the condition of the patient, and tolerance for the drug.
The compounds of this invention also have utility when radio- or isotopically-labeled as ligands for use in assays to determine the presence of AR in a cell background or extract. They are particularly useful due to their ability to selectively activate androgen receptors, and can therefore be used to determine the presence of such receptors in the presence of other steroid receptors or related intracellular receptors.
Due to the selective specificity of the compounds of this invention for steroid receptors, these compounds can be used to purify samples of steroid receptors in vitro. Such purification can be carried out by mixing samples containing steroid receptors with one or more of the compounds of the present invention so that the compounds bind to the receptors of choice, and then separating out the bound ligand/receptor combination by separation techniques which are known to those of skill in the art. These techniques include column separation, filtration, centrifugation, tagging and physical separation, and antibody complexing, among others.
The compounds and pharmaceutical compositions of the present invention may advantageously be used in the treatment of the diseases and conditions described herein. In this regard, the compounds and compositions of the present invention are particularly useful as modulators of male sex steroid-dependent diseases and conditions such as the treatment of acne, male-pattern baldness, male hormone replacement therapy, wasting diseases, hirsutism, stimulation of hematopoiesis, hypogonadism, prostatic hyperplasia, osteoporosis (agonist), male contraception (agonist), impotence (agonist), cancer cachexia (agonist), various hormone-dependent cancers including without limitation prostate cancer and breast cancer, and as anabolic agents.
The compounds and pharmaceutical compositions of the present invention possess a number of advantages over previously identified steroidal and non-steroidal compounds. Furthermore, the compounds and pharmaceutical compositions of the present invention possess a number of advantages over previously identified steroid modulator compounds. For example, the compounds are extremely potent AR activators preferably displaying 50% maximal activation of AR at a concentration of less than 100 nM, more preferably at a concentration of less than 50 nM, more preferably yet at a concentration of less than 20 nM, and most preferably at a concentration of 10 nM or less. Also, the selective compounds of the present invention generally do not display undesired cross-reactivity with other steroid receptors, as is seen with the compound mifepristone (RU486; Roussel Uclaf). Mifepristone is a known PR antagonist that displays an undesirable cross reactivity on GR and AR, thereby limiting its use in long-term, chronic administration. In addition, the small organic molecules of the present invention are easier to synthesize, provide greater stability and are more easily administered in oral dosage forms than other known steroidal compounds.