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  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
  • C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
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  • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
  • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
  • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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  • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
  • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
  • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
  • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

• This invention relates to inhibitors of Type 3 17 ⁇ -hydroxysteroid dehydrogenase, compositions containing the inhibitors, and methods of using the inhibitors for the treatment or prevention of androgen dependent diseases.
• This patent application claims priority from U.S. provisional application, Serial No. 60/ 434,101 , filed December 17, 2002.
• Androgen dependent diseases for example, diseases whose onset or progress is aided by androgenic activity, are well known. These diseases include, but are not limited to, prostate cancer, benign prostatic hyperplasia, acne, seborrhea, hirsutism, androgenic alopecia, precocious puberty, adrenal hyperlasia and polycystic ovarian syndrome.
• Estrogen dependent diseases for example, diseases whose onset or progress is aided by estrogenic activity, are also well known. These include, but are not limited to, breast cancer, endometriosis, leiomyoma and precocious puberty.
• Androgenic and estrogenic activities can be suppressed by administering, respectively, androgen and estrogen receptor antagonists. See, for e.g., WO 94/26767 and WO 96/26201. Androgenic and estrogenic activities can also be reduced by suppressing androgen and estrogen biosyntheses using inhibitors of enzymes that catalyze one or more steps of such biosyntheses.
• 17 ⁇ -HSD3 is the primary enzyme that converts androstenedione to testosterone in the testes.
• Inhibitors of both Type 3 and Type 5 17 ⁇ -hydroxysteroid dehydrogenase are described in WO 99/46279.
• Inhibitors of Type 5 17 ⁇ -hydroxysteroid dehydrogenase is also described in WO 97/11162.
• Androgenic and estrogenic activities can also be reduced by suppressing ovarian or testicular secretions by known methods. See, for e.g., WO 90/10462, WO 91/00731 , WO 91/00733 and WO 86/01105.
• Pending provisional patent application, Serial No. 60/427,363, filed November 18, 2002 discloses certain types of inhibitors of type 3 17 ⁇ -hydroxysteroid dehydrogenase too.
• the present invention provides a novel class of compounds as inhibitors of type 3 17 ⁇ -hydroxysteroid dehydrogenase, methods of preparing such compounds, pharmaceutical compositions comprising one or more such compounds, methods of preparing pharmaceutical compositions comprising one or more such compounds, and methods of treatment, prevention, inhibition or amelioration of one or more diseases associated with type 3 17 ⁇ -hydroxysteroid dehydrogenase using such compounds or pharmaceutical compositions.
• the present application discloses a compound, or a pharmaceutically acceptable salt or solvate of said compound, said compound having the general structure shown in Formula I:
• X is CH or N
• Y is selected from the group consisting of C, CH or N, and when Y is CH or N, the optional covalent bond (represented by the dotted line between rings marked II and IV) is absent, and when Y is C, that optional covalent bond is present;
• R is selected from the group consisting of alkyl, -OR 4 , aryl, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, cycloalkyl, cycloalklyloxy, -N(R 4 ) 2 where the two R 4 moieties can be the same or different, -(CH 2 ) n -aryl, -(CH 2 ) n -heteroaryl, -(CH 2 ) n -heterocyclyl and -(CH 2 ) n -cycloalkyl, wherein each of said alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each being independently selected from the group consisting of alkyl, aryl, heteroaryl, -OR 4 , heterocyclyl, heterocyclyloxy, cycloalkyl, cycl
• R1 and R 2 can be the same or different, each being independently selected from the group consisting of:
• a and B can be the same or different, each being independently selected from the group consisting of (H2), -(OR 5 )2, (H and halo), (dihalo), (H and R 5 ), (R 5 )2, (H and
• R 3 is selected from the group consisting of H, alkyl, alkoxy and alkoxyalkyl
• R 4 is selected from the group consisting of H, alkyl, aryl and aralkyl
• R 5 is alkyl or aryl
• R 6 is H or alkyl
• n is a number from 1-4
• q is a number from 1-8.
• the compounds of Formula I can be useful as inhibitors of type 3 17 ⁇ - hydroxysteroid dehydrogenase and can be useful in the treatment and prevention of diseases associated with type 3 17 ⁇ -hydroxysteroid dehydrogenase.
• the present invention discloses compounds which are represented by structural Formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein the various moieties are as described above.
• position a in ring I is N or N + O " .
• a and B in ring II are H 2 , i.e., the optional bond is absent, and the C5-C6 bridge is unsubstituted.
• R 1 and R 2 can be the same or different, each being independently H or halo.
• R is selected from the group consisting of unsubstituted alkyl, alkyl substituted with a heterocyclyl, -N(R 4 ) 2 where the two R 4 moieties can be the same or different, and -OR 4 , wherein said heterocyclyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each being independently selected from the group consisting of alkyl, aryl, -OR 4 , -N(R 4 ) 2 where the two R 4 moieties can be the same or different, -C(O)R 4 , and -C(O)N(R 4 ) 2 where the two R 4 moieties can be the same or different.
• X is CH.
• X is N.
• Y is N.
• Y is CH.
• R 3 is H and q is 8.
• R 3 is alkyl and q is 1.
• R 3 is alkoxyalkyl and q is 1.
• R 3 is aralkyl
• R 4 is H, alkyl or aryl.
• R 5 is alkyl. In another preferred embodiment, R 6 is H.
• position a in ring I is N.
• position a in ring I is N and positions b, c and d are all the same and are C(R 1 ).
• R 1 and R 2 are the same or different, each being independently selected from H, Br, F and CI.
• Non- limiting, illustrative substitutions on rings I and III of formula 1 include trihalo, dihalo and monohalo substituted compounds, such as, for example: (i) 3,8,10- trihalo; (ii) 3,7,8-trihalo; (iii) 3,8-dihalo; (iv) 8-halo; (v) 10-halo; and (vi) 3-halo (i.e., no substituent in Ring III) substituted compounds; wherein each halo is independently selected.
• Preferred compounds of formula I include: (1) 3-Br-8- CI-10-Br-substituted compounds; (2) 3-Br-7-Br-8-CI-substituted compounds; (3) 3-Br-8-CI-substituted compounds; (4) 3-CI-8-CI-substituted compounds; (5) 3-F-8-CI-substituted compounds; (6) 8-CI-substituted compounds; (7) 10- Cl-substituted compounds; (8) 3-CI-substituted compounds; (9) 3-Br- substituted compounds; and (10) 3-F-substituted compounds.
• R is selected from the group consisting of unsubstituted alkyl, alkyl substituted with a heterocyclyl, -NH 2 , and t-butoxy, wherein said heterocyclyl can be unsubstituted or optionally substituted with one or more moieties selected from the group consisting of -C(O)alkyl, and -C(O)N(alkyl) 2 where the two alkyl moieties can be the same or different.
• R 3 is tert-butyl and q is 1
• R d is 2-(methoxy)ethyl and q is
• R 3 is n-butyl and q is 1. In an additiona preferred embodiment, R 3 is benzyl and q is 1. In an additiona preferred embodiment, R 4 is H. In an additiona preferred embodiment, R 4 is alkyl. In an additiona preferred embodiment, R 5 is methyl, In an additiona preferred embodiment, n is 1. In an additiona preferred embodiment, q is 1. In an additiona preferred embodiment, p is 1.
• Patient includes both human and animals.
• “Mammal” means humans and other mammalian animals.
• Alkyl means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl” means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched.
• Aryl means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms.
• suitable aryl groups include phenyl and naphthyl.
• Heteroaryl means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination.
• Preferred heteroaryls contain about 5 to about 6 ring atoms.
• the prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom.
• a nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide.
• Non- limiting examples of suitable heteroaryls include pyridyl, N-oxide of pyridyl, pyrazinyl, furanyl (furyl), thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1 ,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1 ,5-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyi
• Aralkyl or “arylalkyl” means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2- phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.
• Cycloalkyl means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms.
• suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
• Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like.
• Halogen or "halo” means fluorine, chlorine, bromine, or iodine.
• Heterocyclyl (or heterocycloalkyl) means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
• Preferred heterocyclyls contain about 5 to about 6 ring atoms.
• the prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
• the heterocyclyl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
• the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
• Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,3-dioxolanyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
• Ring system substituent means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system.
• Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, aryl
• Ring system substituent also means a cyclic ring of 3 to 7 ring atoms of which 1-2 may be a heteroatom, attached to an aryl, heteroaryl, heterocyclyl or heterocyclenyl ring by simultaneously substituting two ring hydrogen atoms on said aryl, heteroaryl, heterocyclyl or heterocyclenyl ring.
• Non-limiting examples include:
• heteroarylkyl or “heteroarylalkyl” means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described.
• Preferred heteroarylalkyls comprise a lower alkyl group.
• suitable heteroarylalkyl groups include pyridin-4-ylmethyl, thien-3-ylmethyl and the like. The bond to the parent moiety is through the alkyl.
• heterocyclylalkyl means a heterocyclyl-alkyl- group in which the heterocyclyl and alkyl are as previously described.
• Preferred heterocyclylalkyls comprise a lower alkyl group.
• suitable heterocyclylalkyl groups include piperidin-4-ylmethyl, pyrrolidin-3- ylmethyl and the like. The bond to the parent moiety is through the alkyl.
• substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
• stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
• any open- ended nitrogen atom with unfulfilled valence in the chemical structures herein refers to NH, or in the case of a terminal nitrogen, -NH 2 .
• any open- ended oxygen atom or carbon atom with unfulfilled valence in the chemical structures herein refers to -OH and any open-ended carbon atom with unfilled valence is appropriately filled with -H.
• protecting groups When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in organic Synthesis (1991 ), Wiley, New York.
• variable e.g., aryl, heterocycle, R 2 , etc.
• its definition on each occurrence is independent of its definition at every other occurrence.
• composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
• Prodrugs and solvates of the compounds of the invention are also contemplated herein.
• the term "prodrug”, as employed herein, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of Formula III or a salt and/or solvate thereof.
• a discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference thereto.
• Solvate means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolat.es, and the like. "Hydrate” is a solvate wherein the solvent molecule is H 2 O.
• Effective amount or “therapeutically effective amount” is meant to describe an amount of compound or a composition of the present invention effective in inhibiting the type 3 17 ⁇ -hydroxysteroid dehydrogenase and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.
• salts form salts which are also within the scope of this invention.
• Reference to a compound of formula I herein is understood to include reference to salts thereof, unless otherwise indicated.
• a compound of formula I contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts”) may be formed and are included within the term "salt(s)" as used herein.
• Salts of the compounds of the formula I may be formed, for example, by reacting a compound of formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
• Acids (and bases) which are generally considered suitable for the formation of pharmaceutically useful salts from basic (or acidic) pharmaceutical compounds are discussed, for example, by S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J.
• Exemplary acid addition salts include acetates, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2- hydroxyethanesulfonates, lactates, maleates, methanesulfonates, methyl sulfates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pamoates, pectinates, persulfates,
• Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, aluminum salts, zinc salts, salts with organic bases (for example, organic amines) such as benzathines, diethylamine, dicyclohexylamines, hydrabamines (formed with N,N- bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines, N-methyl-D- glucamides, t-butyl amines, piperazine, phenylcyclohexylamine, choline, tromethamine, and salts with amino acids such as arginine, lysine and the like.
• organic bases for example, organic amines
• organic bases for example, organic amines
• benzathines diethylamine, dicyclohexylamines, hydrabamines (formed with N,N-
• Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
• lower alkyl halides e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
• dialkyl sulfates e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates
• long chain halides
• All stereoisomers for example, geometric isomers, optical isomers and the like
• of the present compounds including those of the salts, solvates and prodrugs of the compounds as well as the salts and solvates of the prodrugs
• those which may exist due to asymmetric carbons on various substituents including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl).
• Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
• the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
• the use of the terms "salt”, “solvate” "prodrug” and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
• the invention also includes compounds of Formula I in isolated and purified form.
• the compounds according to the invention have pharmacological properties; in particular, the compounds of Formula I can be inhibitors of type 3 17 ⁇ -hydroxysteroid dehydrogenase.
• the novel compounds of Formula I are expected to be useful in the therapy of proliferative diseases associated with type 3 17 ⁇ -hydroxysteroid dehydrogenase.
• the compounds of Formula I can be useful in the treatment or prevention of androgen or estrogen dependent diseases in a patient in need thereof, which comprises administering to said patient a therapeutically effective amount of at least one compound of formula I.
• the invention provides a method of treating or preventing prostate cancer, and other androgen-dependent neoplasms, benign prostatic hyperplasia, prostatic intraepithelial neoplasia, androgenic alopecia (i.e. pattern baldness in both male and female patients), hirsutism, polycystic ovary syndrome and acne in a patient in need thereof, which comprises administering to said patient, a therapeutically effective amount of at least one compound of formula I.
• the invention provides a method of treating or preventing androgen-dependent diseases in a patient in need thereof, comprising administering (concurrently or sequentially) to said patient an effective amount of at least one compound of formula I in combination or association with at least one anti-androgenic agent (i.e. agents that decrease androgen synthesis or activity).
• at least one anti-androgenic agent i.e. agents that decrease androgen synthesis or activity.
• This invention also provides a method of treating or preventing benign prostatic hyperplasia in a patient in need thereof, comprising administering (concurrently or sequentially) to said patient an effective amount of at least one compound of formula I in combination or association with at least one agent useful in the treatment or prevention of benign prostatic hyperplasia.
• This invention also provides a method of treating or preventing hair loss in a patient in need thereof, comprising administering (concurrently or sequentially) to said patient an effective amount of at least one compound of formula I in combination or association with at least one agent useful in the treatment or prevention of alopecia, e.g., potassium channel agonists or 5 ⁇ - reductase inhibitors.
• at least one agent useful in the treatment or prevention of alopecia e.g., potassium channel agonists or 5 ⁇ - reductase inhibitors.
• This invention also provides a method of treating or preventing hair loss, comprising administering (concurrently or sequentially) to a patient in need thereof, an effective amount of a compound of formula I in combination with at least one potassium channel agonist e.g. minoxidil and KC-516, or 5 ⁇ - reductase inhibitor, e.g., finasteride.
• a potassium channel agonist e.g. minoxidil and KC-516
• 5 ⁇ - reductase inhibitor e.g., finasteride.
• the invention also provides a method of treating or preventing proliferative diseases in a patient in need thereof, especially cancers (tumors), comprising administering (concurrently or sequentially) to said patient an effective amount of (1) at least one compound of formula I in combination or association with (2) an effective amount of at least one anti-cancer agent i.e., a chemotherapeutic agent, biological agent, and/or surgery, e.g., prostatectomy and/or radiation therapy.
• a chemotherapeutic agent e.e., a chemotherapeutic agent, biological agent, and/or surgery, e.g., prostatectomy and/or radiation therapy.
• Non-limiting examples of cancers which may be inhibited or treated include, but are not limited to, lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), renal cancers, myeloid leukemias (for example, acute myelogenous leukemia (AML), thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma, melanoma, breast cancer and prostate cancer.
• lung cancer e.g., lung adenocarcinoma
• pancreatic cancers e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma
• colon cancers e.g., colorectal carcinomas, such as, for example, colon aden
• the method of treating proliferative diseases includes a method for treating (inhibiting) the abnormal growth of cells, including transformed cells, in a patient in need of such treatment, by administering, concurrently or sequentially, an effective amount of at least one compound of this invention and an effective amount of at least one chemotherapeutic agent, biological agent, surgery (e.g. prostatectomy) and/or radiation.
• Abnormal growth of cells means, for example, cell growth independent of normal regulatory mechanisms (e.g., contact inhibition or apoptosis), including the abnormal growth of: (1) tumor cells (tumors) expressing an activated ras oncogene; (2) tumor cells in which the ras protein is activated as a result of oncogenic mutation in another gene; and (3) benign and malignant cells of other proliferative diseases.
• tumor cells tumor cells (tumors) expressing an activated ras oncogene
• tumor cells in which the ras protein is activated as a result of oncogenic mutation in another gene and (3) benign and malignant cells of other proliferative diseases.
• the present invention includes methods for treating or inhibiting tumor growth in a patient in need of such treatment, by administering, concurrently or sequentially, (1) an effective amount of at least one compound of this invention and (2) an effective amount of at least one antineoplastic/microtubule agent, biological agent, and/or surgery (e.g. prostatectomy) and/or radiation therapy.
• tumors which may be treated include, but are not limited to, epithelial cancers, e.g., prostate cancer, lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), breast cancers, renal cancers, colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), ovarian cancer, and bladder carcinoma.
• epithelial cancers e.g., prostate cancer
• lung cancer e.g., lung adenocarcinoma
• pancreatic cancers e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma
• breast cancers e.g., renal cancers
• colon cancers e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma
• cancers that can be treated include melanoma, myeloid leukemias (for example, acute myelogenous leukemia), sarcomas, thyroid follicular cancer, and myelodysplastic syndrome.
• myeloid leukemias for example, acute myelogenous leukemia
• sarcomas for example, thyroid follicular cancer
• myelodysplastic syndrome as used herein the following terms have the following meanings unless indicated otherwise:
• Antineoplastic agent means a chemotherapeutic agent effective against cancer
• “Sequentially” means (1) administration of one component of the method ((a) compound of the invention, or (b) antineoplastic agent and/or radiation therapy) followed by administration of the other component; after administration of one component, the second component can be administered substantially immediately after the first component, or the second component can be administered after an effective time period after the administration of the first component; the effective time period is the amount of time given for realization of maximum benefit from the administration of the first component.
• a preferred dosage is about 0.001 to 500 mg/kg of body weight/day of the compound of Formula I.
• An especially preferred dosage is about 0.01 to 25 mg/kg of body weight/day of a compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound.
• Classes of compounds that can be used as the chemotherapeutic agent include: alkylating agents, antimetabolites, natural products and their derivatives, hormones and steroids (including synthetic analogs), and synthetics.
• alkylating agents include: alkylating agents, antimetabolites, natural products and their derivatives, hormones and steroids (including synthetic analogs), and synthetics.
• compounds within these classes are:
• Alkylating agents including nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes: Uracil mustard, Chlormethine, Cyclophosphamide (Cytoxan ® ), Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, dacarbazine, and Temozolomide.
• Antimetabolites including folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors: Methotrexate, 5- Fluorouracil, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, Pentostatine, and Gemcitabine.
• Natural products and their derivatives including vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins: Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, paclitaxel (paclitaxel is commercially available as Taxol ® and is described in more detail below in the subsection entitled "Microtubule Affecting Agents”), Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Interferons- ⁇ and ⁇ (especially IFN- ⁇ ), Etoposide, and Teniposide.
• Vinblastine Vincristine
• Vindesine Bleomycin
• Dactinomycin Daunorubicin
• Doxorubicin Doxorubicin
• Epirubicin Idarubicin
• paclitaxel paclitaxel is commercially available
• Hormonal agents and steroids include synthetic analogs: 17 ⁇ - Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Tamoxifen, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin and Zoladex.
• Synthetics including inorganic complexes such as platinum coordination complexes: Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, CPT-11, Anastrazole, Letrazole, Capecitabine, Ralozifine, Droloxifine and Hexamethylmelamine.
• Non-limiting examples of biological agents useful in the methods of this invention include but are not limited to, interferon- ⁇ , interferon- ⁇ and gene therapy.
• a microtubule affecting agent is a compound that interferes with cellular mitosis, i.e., having an anti-mitotic effect, by affecting microtubule formation and/or action.
• agents can be, for instance, microtubule stabilizing agents or agents which disrupt microtubule formation.
• Non-limiting examples of microtubule affecting agents useful in the invention include allocolchicine (NSC 406042), Halichondrin B (NSC 609395), colchicine (NSC 757), colchicine derivatives (e.g., NSC 33410), dolastatin 10 (NSC 376128), maytansine (NSC 153858), rhizoxin (NSC 332598), paclitaxel (Taxol ® , NSC 125973), Taxol ® derivatives (e.g., derivatives (e.g., NSC 608832), thiocolchicine (NSC 361792), trityl cysteine (NSC 83265), vinblastine sulfate (NSC 49842), vincristine sulfate (NSC 67574), epothilone A, epothilone, discodermolide, estramustine, nocodazole, MAP4, and the like.
• NSC 406042
• Paclitaxel-like activity examples include, but are not limited to, paclitaxel and paclitaxel derivatives (paclitaxel-like compounds) and analogues. Paclitaxel and its derivatives are available commercially. More specifically, the term "paclitaxel” as used herein refers to the drug commercially available as Taxol ® .
• Such agents include, but are not limited to, inhibitors of 5 ⁇ -reductase type 1 and/or type 2, e.g. finasteride, SKF105,657, LY191.704 , LY320.236, dutasteride, flutamide, nicalutamide, bicalutamide, LHRH agonists e.g. leuprolide and zoladex, LHRH antagonists, e.g. abarelix and cetrorelix, inhibitors of 17 ⁇ -hydroxylase/C17-20 lyase, e.g.
• inhibitors of 5 ⁇ -reductase type 1 and/or type 2 e.g. finasteride, SKF105,657, LY191.704 , LY320.236, dutasteride, flutamide, nicalutamide, bicalutamide, LHRH agonists e.g. leuprolide and zoladex, LHRH antagonists,
• YM116, CB7630 and liarozole inhibitors of 17 ⁇ -hydroxysteroid dehydrogenase type 5 and/or other 17 ⁇ -hydroxysteroid dehydrogenase/17 ⁇ -oxidoreductase isoenzymes, e.g. EM- 1404.
• Types of androgen or estrogen dependent diseases include, but are not limited to, prostate cancer, benign prostatic hyperplasia, prostatic intraepithelial neoplasia, acne, seborrheas, hirsutism, androgenic alopecia, precocious puberty, adrenal hyperplasia, and polycystic ovarian syndrome, breast cancer, endometriosis and leiomyoma.
• agents useful in the treatment or prevention of benign prostatic hyperplasia include, but are not limited to, ⁇ -1 adrenergic antagonists, e.g. tamsulosin and terazosin.
• the pharmacological properties of the compounds of this invention may be confirmed by a number of pharmacological assays.
• the exemplified pharmacological assays which are described later have been carried out with the compounds according to the invention and their salts.
• compositions which comprise at least one compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound and at least one pharmaceutically acceptable carrier.
• inert, pharmaceutically acceptable carriers can be either solid or liquid.
• Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.
• the powders and tablets may be comprised of from about 5 to about 95 percent active ingredient.
• Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18 th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania.
• Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
• Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.
• a pharmaceutically acceptable carrier such as an inert compressed gas, e.g. nitrogen.
• solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
• liquid forms include solutions, suspensions and emulsions.
• the compounds of the invention may also be deliverable transdermally.
• the transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
• the compounds of this invention may also be delivered subcutaneously.
• the compound is administered orally.
• the pharmaceutical preparation is in a unit dosage form.
• the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
• the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg, according to the particular application.
• the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
• a typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two to four divided doses.
• the chemotherapeutic agent and/or radiation therapy can be administered in combination or association with the compounds of the present invention according to the dosage and administration schedule listed in the product information sheet of the approved agents, in the Physicians Desk Reference (PDR) as well as therapeutic protocols well known in the art.
• PDR Physicians Desk Reference
• Table A below gives ranges of dosage and dosage regimens of some exemplary chemotherapeutic agents useful in the methods of the present invention. It will be apparent to those skilled in the art that the administration of the chemotherapeutic agent and/or radiation therapy can be varied depending on the disease being treated and the known effects of the chemotherapeutic agent and/or radiation therapy on that disease.
• the therapeutic protocols e.g., dosage amounts and times of administration
• the administered chemotherapeutic agents i.e., antineoplastic agent or radiation
• the observed responses of the disease to the administered therapeutic agents can be varied in view of the observed effects of the administered chemotherapeutic agents (i.e., antineoplastic agent or radiation) on the patient, and in view of the observed responses of the disease to the administered therapeutic agents.
• Taxotere 60 - 100 mg/m 2 every 3 weeks (IV)
• Taxol 65 - 175 mg/m2 every 3 weeks (I V)
• Anti-androgenic agents, anti-benign prostatic hyperplasia agents, potassium channel agonists and biological agents can be administered in association with the compounds of the present invention according to the dosage and administration schedule listed in the product information sheet of the approved agents, in the Physicians Desk Reference (PDR) as well as therapeutic protocols well known in the art. It will be apparent to those skilled in the art that the administration of the agents can be varied depending on the disease being treated and the known effects of the agents on that disease. Also, in accordance with the knowledge of the skilled clinician, the therapeutic protocols (e.g., dosage amounts and times of administration) can be varied in view of the observed effects of the administered agents on the patient, and in view of the observed responses of the disease to the administered therapeutic agents.
• PDR Physicians Desk Reference
• kits comprising a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound and a pharmaceutically acceptable carrier, vehicle or diluent.
• kits comprising an amount of at least one compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound and an amount of at least one additional agent listed above, wherein the amounts of the two or more ingredients result in desired therapeutic effect.
• the above-described kits may contain the said ingredients in one or more containers within said kit.
• Varian VXR-200 (200 MHz, H), Varian Gemini-300 (300 MHz) or XL-400 (400 MHz) and are reported as ppm down field from Me4Si with number of protons, multiplicities, and coupling constants in Hertz indicated parenthetically.
• analyses was performed using an Applied Biosystems API-100 mass spectrometer and Shimadzu SCL-10A LC column: Altech platinum C18, 3 micron, 33mm x 7mm ID; gradient flow: 0 min - 10% CH 3 CN, 5 min - 95% CH 3 CN, 7 min - 95% CH 3 CN, 7.5 min - 10% CH 3 CN, 9 min - stop. The retention time and observed parent ion are given.
• the desired piperidine-piperazine intermediate in Scheme 1 can be prepared from an appropriate piperidone (Scheme 2).
• the substituted piperazines can be prepared through the reduction of commercially available diketopiperazines or alternatively from the desired amino acids (Scheme 6). Scheme 6
• N-BOC or N-acyl piperidine acetic acid can be prepared as described previously through the reduction of 4-pyridine acetic acid (Scheme 7).
• N-Boc-4-piperidineacid acid prepared as described in US Pat. No. 5,874,442; 35.0 g, 144 mmol
• TEA 20.0 mL, 1.0 eq.
• trimethylacetyl chloride 17.7 mL, 1.0 eq.
• the resulting slurry was stirred at 0°C 1.5 hours before adding the title compound from Preparative Example 8 (33.5 g, 151 mmol, 1.05 eq.) in toluene (100 mL) and the resulting solution was warmed to room temperature and stirred overnight.
• 4,4'-Bipiperidine (17.5 g, 72.55 mmol) was dissolved in H 2 O (70 mL), treated with 5 N NaOH to pH 8-9, and diluted to 400 mL with EtOH.
• di-t-butyl dicarbonate (16.8 g, 76.96 mmol) in 200 mL of EtOH in one portion.
• the reaction mixture was treated with 5 N NaOH periodically to pH 8-9. After 5 hours, the mixture was concentrated.
• the residue was dissolved in 500 mL of 1:1 H 2 O:Et 2 O and the PH was adjusted to 12 with 5 N NaOH.
• the aqueous phase was extracted with Et 2 O and combined organic phase was washed with brine, 5% aq.
• the compounds of the invention can be useful as inhibitors of type 3 17 ⁇ -hydroxysteroid dehydrogenase. This utility was demonstrated by the following assay.
• HEK-293 cells stably transfected with human 17 ⁇ - HSD type 3 were cultured to confluency and harvested for enzyme.
• the cells were suspended in isolation buffer (20 mM KH 2 PO 4 , 1 mM EDTA, 0.25 M Sucrose, 1 mM PMSF, 5 Dg/ml pepstatin A, 5 ⁇ g/ml antipain and 5 Dg/ml leupeptin) to a concentration between 5.0 x 10 6 and 1.0 x 10 7 cells/ml.
• the cells were sonicated on ice using a micro-ultrasonic cell disrupter at an output setting of No.
• reaction buffer (12.5 mM KH 2 PO 4 , 1 mM EDTA), NADPH cofactor (1 mM final)
• test compound 17 ⁇ -HSD3 enzyme (30 ⁇ g protein) and 14 C- androstenedione substrate (100 nM; 2.7 nCi/tube) were added to 13 x 100 borosilicate glass tubes to a total volume of 0.5 mL/tube.
• the tubes were placed in a prewarmed 37°C water bath for 30 minutes. The reaction was then stopped by adding 1 ml of ethyl ether. The tubes were centrifuged for 20 minutes at 3000 rpm at 4°C in a table top centrifuge and then snap frozen in a dry ice-methanol bath. The ether layer was decanted into another glass tube, and then evaporated to dryness using compressed nitrogen gas. The samples were resuspended in chloroform (20 mL) and spotted onto silica G60 thin layer chromatography plates. 14 C-Androstenedione substrate and 14 C- testosterone product were separated by placing the plates in chloroform:ethyl acetate (3:1). The plates were dried, exposed overnight, scanned and quantitated on a FUJI FLA2000 phosphorimager.

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