Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/08—Drugs for disorders of the urinary system of the prostate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/18—Feminine contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
  • A61P5/04—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin for decreasing, blocking or antagonising the activity of the hypothalamic hormones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones

Definitions

• the gonadotropin-releasing hormone also referred to as luteinizing hormone-releasing hormone (LHRH)
• LHRH luteinizing hormone-releasing hormone
• the hormone is released from the hypothalamus and acts on the pituitary gland to stimulate the biosynthesis and secretion of luteinizing hormone (LH) and follicle- stimulating hormone (FSH).
• LH released from the pituitary gland is primarily responsible for the regulation of gonadal steroid production in both sexes, whereas FSH regulates spermatogenesis in males and follicular development in females.
• GnRH agonists and antagonists have proven effective in the treatment of certain conditions which require inhibition of LH/FSH release.
• GnRH-based therapies have proven effective in the treatment of endometriosis, uterine fibroids, polycystic ovarian disease, precocious puberty and several gonadal steroid-dependent neoplasia, most notably cancers of the prostate, breast and ovary.
• GnRH agonists and antagonists have also been utilized in various assisted fertilization techniques and have been investigated as a potential contraceptive in both men and women.
• the compounds of the invention may also be used in combination with bisphosphonates (bisphosphonic acids) and other agents, such as growth hormone secretagogues, for the treatment and the prevention of disturbances of calcium, phosphate and bone metabolism, in particular, for the prevention of bone loss during therapy with the GnRH antagonist, and in combination with estrogens, progesterones, antiestrogens, antiprogestins and/or androgens for the prevention or treatment of bone
• a compound of the present invention may be co-administered with a 5a-reductase 2 inhibitor, such as finasteride or epristeride; a 5a-reductase 1 inhibitor such as 4,7b-dimethyl-4-aza-5a- cholestan-3-one, 3-oxo-4-aza-4,7b-dimethyl-16b-(4-chlorophenoxy)-5a- androstane, and 3-oxo-4-aza-4,7b-dimethyl-16b-(phenoxy)-5a-androstane as disclosed in WO 93/23420 and WO 95/11254; dual inhibitors of 5a- reductase 1 and 5a-reductase 2 such as 3-oxo-4-aza-17b-(2,5- trifluoromethylphenyl-carbamoyl)-5a-androstane as disclosed in WO 95/07927; antiandrogens such as flutamide, casodex and c
• a compound of the present invention may be used in combination with growth hormone, growth hormone releasing hormone or growth hormone secretagogues, to delay puberty in growth hormone deficient children, which will allow them to continue to gain height before fusion of the epiphyses and cessation of growth at puberty.
• a compound of the present invention may be used in combination or co-administered with a compound having luteinizing hormone releasing activity such as a peptide or natural hormone or analog thereof.
• a compound having luteinizing hormone releasing activity such as a peptide or natural hormone or analog thereof.
• peptide compounds include leuprorelin, gonadorelin, buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterlin and recirelin.
• a compound of the present invention may be used as described in U.S. Patent No.
• 5,824,286 which discloses the administration of peptide GnRH antagonists such as Antide and azaline B to premenopausal women to enhance the readability of mammographic film relative to a mammogram effected in the absence of the administration.
• GnRH antagonists are GnRH-like decapeptides which are generally administered intravenously or subcutaneously presumably because of negligible oral activity. These have amino acid substitutions usually at positions one, two, three, six and ten.
• Non-peptide GnRH antagonists offer the possible advantage of oral adminstration.
• Non-peptide GnRH antagonists have been described in European Application 0 219 292 and in De, B. et al., J. Med. Chem., 32, 2036-2038 (1989), in WO 95/28405, WO 95/29900 and EP 0679642 all to Takeda Chemical Industries, Ltd.
• Substituted indoles known in the art include those described in the following patents and patent applications.
• US Patent No. 5,030,640 discloses alpha-heterocyclic ethanol aminoalkyl indoles which are potent ⁇ -agonists.
• US Patent No. 4,544,663 discloses indolamine derivatives which are allegedly useful as male anti-fertility agents.
• WO 90/05721 discloses alpha-amino-indole-3-acetic acids useful as anti-diabetic, anti-obesity and anti-atherosclerotic agents.
• French patent 2,181,559 discloses indole derivatives with sedative, neuroleptic, analgesic, hypotensive, antiserotonin and adrenolytic activity.
• Belgian patent 879381 discloses 3-aminoalkyl-lH-indole-5-thioamide and carboxamide derivatives as cardiovascular agents used to treat hypertension, Raynaud's disease and migraine.
• U.S. Patent Nos. 5,756,507, 5,780,437 and 5,849,764 also disclose substituted arylindoles as non-peptide antagonists of GnRH.
• the present invention relates to compounds which are non-peptide antagonists of GnRH which can be used to treat a variety of sex-hormone related conditions in men and women, to methods for their preparation, and to methods and pharmaceutical compositions containing said compounds for use in mammals.
• the compounds of the present invention are useful to treat a variety of sex-hormone related conditions in both men and women. These conditions include endometriosis, uterine fibroids, polycystic ovarian disease, hirsutism, precocious puberty, gonadal steroid- dependent neoplasias such as cancers of the prostate, breast and ovary, gonadotrophe pituitary adenomas, sleep apnea, irritable bowel syndrome, premenstrual syndrome and benign prostatic hypertophy.
• the compounds of the invention are also useful as an adjunct to treatment of growth hormone deficiency and short stature, and for the treatment of systemic lupus erythematosis.
• the compounds of the invention may be useful in in vitro fertilization and as contraceptives.
• the compounds may also be useful in combination with androgens, estrogens, progesterones, antiestrogens and antiprogestogens for the treatment of endometriosis, fibroids and in contraception. They may also be useful in combination with testosterone or other androgens or antiprogestogens in men as a contraceptive.
• the compounds may also be used in combination with an angiotensin-converting enzyme inhibitor such as Enalapril or Captopril, an angiotensin Il-receptor antagonist such as Losartan or a renin inhibitor for the treatment of uterine fibroids.
• an angiotensin-converting enzyme inhibitor such as Enalapril or Captopril
• an angiotensin Il-receptor antagonist such as Losartan or a renin inhibitor
• the compounds of the invention may also be used in combination with bisphosphonates (bisphosphonic acids) and other agents, for the treatment and the prevention of disturbances of calcium, phosphate and bone metabolism, in particular, for the prevention of bone loss during therapy with the GnRH antagonist, and in combination with estrogens, progesterones and/or androgens for the prevention or treatment of bone loss or hypogonadal symptoms such as hot flashes during therapy with the GnRH antagonist.
• a compound of the present invention may be co-administered with a 5a-reductase 2 inhibitor, such as fmasteride or epristeride; a 5a-reductase 1 inhibitor such as 4,7b-dimethyl-4-aza-5a- cholestan-3-one, 3-oxo-4-aza-4,7b-dimethyl-16b-(4-chlorophenoxy)-5a- androstane, and 3-oxo-4-aza-4,7b-dimethyl-16b-(phenoxy)-5a-androstane as disclosed in WO 93/23420 and WO 95/11254; dual inhibitors of 5a- reductase 1 and 5a-reductase 2 such as 3-oxo-4-aza-17b-(2,5- trifluoromethylphenyl-carbamoyl)-5a-androstane as disclosed in WO 95/07927; antiandrogens such as flutamide, casodex and c
• a compound of the present invention may be used in combination with growth hormone, growth hormone releasing hormone or growth hormone secretagogues, to delay puberty in growth
• a compound of the present invention may be used in combination or co-administered with a compound having luteinizing hormone releasing activity such as a peptide or natural hormone or analog thereof.
• a compound having luteinizing hormone releasing activity such as a peptide or natural hormone or analog thereof.
• peptide compounds include leuprorelin, gonadorelin, buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterlin and recirelin.
• a compound of the present invention may be used as described in U.S. Patent No. 5,824,286 which discloses the administration of peptide GnRH antagonists such as Antide and azaline B to premenopausal women to enhance the readability of mammographic film relative to a mammogram effected in the absence of the administration.
• peptide GnRH antagonists such as Antide and azaline B
• the present invention relates to compounds of the general formula
• A is Ci -C ⁇ alkyl, substituted Ci-C ⁇ alkyl, C3-C7 cycloalkyl, substituted C3-C7 cycloalkyl, C3-C6 alkenyl, substituted C3-C6 alkenyl, C3-C6 alkynyl, substituted C3-C6 alkynyl, Cl-C ⁇ alkoxy, or C0-C5 alkyl-S(O) n -Co-C5 alkyl, C0-C5 alkyl- O-C0-C5 alkyl, C0-C5 alkyl-NRis-Co-C ⁇ alkyl where Ri8 and
• R ⁇ is hydrogen, Ci-C ⁇ alkyl, substituted Cl-C ⁇ alkyl, wherein the substituents are as defined below; aryl, substituted aryl, aralkyl or substituted aralkyl, wherein the substituents are as defined for R3, R4 and R5;
• R2 is hydrogen, C -CQ alkyl, substituted C1-C6 alkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, alkyl -ORn,
• R7 is hydrogen, C1-C6 alkyl, or substituted C1-C6 alkyl, unless X is hydrogen or halogen, then R7 is absent;
• R 8 is C(O)OR 2 0, C(O)NR20R21, NR20R2 C(O)R 2 0, NR 2 lC(O)R 2 0,
• R9 and Rga are independently hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl; aryl or substituted aryl, aralkyl or substituted aralkyl when m ⁇ O; or
• R9 and R9a taken together form a carbocyclic ring of 3-7 atoms or when m ⁇ O;
• RlO and RlOa taken together form a carbocyclic ring of 3-7 atoms or ;
• R9 and Rio taken together form a carbocyclic ring of 3-7 carbon atoms or a heterocyclic ring containing one or more heteroatoms when m ⁇ O; or
• R9 and R2 taken together form a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms when m ⁇ O; or
• RlO and R2 taken together form a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms;
• RlO and A taken together form a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms; or
• Rll and R12 are independently hydrogen , CI-CQ alkyl, substituted C1-C6 alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, a carbocyclic ring of 3-7 atoms or a substituted carbocyclic ring containing 3-7 atoms; Rll and R12 taken together can form an optionally substituted ring of 3-7 atoms; Rl3 is hydrogen, OH, NR7R8, NRnSO2(Ci-C6 alkyl),
• Ci-C ⁇ alkyl substituted Ci-C ⁇ alkyl
• SO2NRn(C(O)-aryl substituted Ci-C ⁇ alkyl
• S ⁇ 2NRn(C(O)-substituted aryl S(0) n (Ci-C6 alkyl); S(0) n (substituted Ci-C ⁇ alkyl), S(O) n (aryl), S(O) n (substituted aryl), C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, Ci-C ⁇ alkoxy, substituted C1-C6 alkoxy, COOH, halogen, NO2 or
• Rl4 and R15 are independently hydrogen, C1-C6 alkyl, substituted Ci-C ⁇ alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, RnO(CH2)p-,
• Rl6 is hydrogen, Ci-C ⁇ alkyl, substituted C1-C6 alkyl, or N(RnRi2);
• Rl8 is hydrogen, C1-C6 alkyl, substituted Ci-C ⁇ alkyl, C(O)ORn,
• Rl9 is either the definition of R13 or R14;
• R20 and R21 are independently hydrogen , C1-C6 alkyl, substituted Ci-C ⁇ alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, a carbocyclic ring of 3-7 atoms, a substituted carbocyclic ring containing 3-7 atoms, a heterocyclic ring or bicyclic heterocyclic ring with from 1 to 4 heteroatoms selected from N, O or S which can be optionally substituted by R3, R4 and R5, Ci-C6-alkyl substituted by a heterocyclic ring or bicyclic heterocyclic ring with from 1 to 4 heteroatoms selected from N, O or S which can be optionally substituted by R3, R4 and R5;
• R20 and R21 taken together can form an optionally substituted ring of 3-7 atoms
• X is N, O, S(0) n , C(O), (CRnRi2)p, a single bond to Re, C2-C6 alkenyl, substituted C2-C6 alkenyl,C2-C6 alkynyl, or substituted C2-C6 alkynyl; when X is O, S(0)n, C(O), or CR11R12 only R ⁇ is possible;
• 11 - Z is O, S or NR11; m is 0-3; n is 0-2; p is 0-4; and the alkyl, cycloalkyl, alkenyl and alkynyl substituents are selected from Ci-C ⁇ alkyl, C3-C7 cycloalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, hydroxy, oxo, cyano, Ci-C ⁇ alkoxy, fluoro, C(O)ORll ⁇ aryl C1-C3 alkoxy, substituted aryl C1-C3 alkoxy, and the aryl substituents are as defined for R3, R4 and R5; or a pharmaceutically acceptable addition salt and/or hydrate thereof, or where applicable, a geometric or optical iso er or racemic mixture thereof.
• R20 and R21 Preferred substituents when R20 and R21 are taken together include 7-aza-bicyclo[2.2.1]heptane and 2-aza-bicyclo[2.2.2] octane.
• variable e.g., aryl, heterocycle, Rl, etc.
• its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
• alkyl is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, e.g., methyl (Me), ethyl (Et), propyl, butyl, pentyl, hexyl, heptyl, octyl, nonanyl, decyl, undecyl, dodecyl, and the isomers thereof such as isopropyl (i-Pr), isobutyl (i-Bu), sec-butyl (s-Bu), tert-butyl (t-Bu), isopentane, isohexane, etc.
• aryl includes phenyl and naphthyl. In a preferred embodiment, aryl is phenyl.
• halogen or halo is intended to include fluorine, chlorine, bromine and iodine.
• heterocycle or “heterocyclic ring” is defined by all non-aromatic, heterocyclic rings of 3-7 atoms containing 1-3 heteroatoms selected from N, O, and S, such as oxirane, oxetane, tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine, tetrahydropyridine, tetrahydropyrimidine, tetrahydrothiophene, tetrahydrothiopyran, morpholine, hydantoin, valerolactam, pyrrolidinone, and the like.
• 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.
• optical isomeric forms that is mixtures of enantiomers, e.g., racemates, or diastereomers as well as individual enantiomers or diastereomers of the instant compound are included.
• These individual enantiomers are commonly designated according to the optical rotation they effect by the symbols (+) and (-), (L) and (D), (1) and (d) or combinations thereof.
• These isomers may also be designated according to their absolute spatial configuration by (S) and (R), which stands for sinister and rectus, respectively.
• the individual optical isomers may be prepared using conventional resolution procedures, e.g., treatment with an appropriate optically active acid, separating the diastereomers and then recovering the desired isomer.
• the individual optical isomers may be prepared by asymmetric synthesis.
• a given chemical formula or name shall encompass pharmaceutically acceptable addition salts thereof and solvates thereof, such as hydrates.
• the compounds of the present invention may be administered in the form of pharmaceutically acceptable salts.
• pharmaceutically acceptable salt is intended to include all acceptable salts.
• acid salts are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic, methanesulfonic, benzenesulfonic and the like which can be used as a dosage form for modifying the solubility or hydrolysis characteristics or can be used in sustained release or prodrug formulations.
• salts of the compounds of this invention include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethyl-ammonium hydroxide.
• bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminome
• esters can be employed, e.g. methyl, ethyl, butyl, acetate, maleate, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
• the compounds of the present invention may have chiral centers other than those centers whose stereochemistry is depicted in formula I, and therefore may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers, with all such isomeric forms being included in the present invention as well as
• crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention.
• some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of this invention.
• a preferred method for the synthesis of the substituted tryptamines described in this invention utilizes a palladium-catalyzed cross coupling reaction as a key step as shown in Scheme A.
• This 7- azaindole synthesis involves the reaction of a suitably functionalized 3- iodo-2-aminopyridine (1) with substituted acetylenes such as 2 in the presence of a base like sodium carbonate, lithium chloride, and a
• acetylene utilized in this reaction may be a terminal acetylene (2a) or be optionally substituted on the terminal carbon atom with a substituent Z (2b, 2c).
• the substituent abbreviated PG X indicates an alcohol protecting group such as a benzyl ether, tert -butyl ether or the like.
• the nature of the Z substituent determines the distribution of the 7- azaindole isomers (3 and 4) produced in the reaction. For example, if the substituent Z on the acetylene is a hydrogen atom then the isomer 4a is the major product of the reaction.
• the substituent Z is chosen to be a substituted silyl group such as trimethylsilyl, triethylsilyl (as shown), or the like, then isomer 3b is formed almost exclusively.
• both isomers 3c and 4c may be formed and the product mixture is separated using chromatographic or crystallization techniques to afford the individual isomers. If the synthesis is conducted with a silyl-substituted acetylene 2b to produce a silyl-substituted 7-azaindole 3b, then the silyl group is next converted to an aryl or substituted aryl group of general formula 3c using the reactions described later in Scheme E.
• 3-iodo-2-aminopyridines (1) which are utilized in the Larock 7-azaindole synthesis described in Scheme A.
• the 3-iodo-2-aminopyri dines (1) may be prepared in several ways described in the literature of organic synthesis.
• a preferred method involves the o /io-iodination of substituted 2-aminopyridine derivatives of general formula 9 with an electrophilic iodination reagent such as iodine, iodine monochloride, ⁇ Xiodosuccinimide or the like.
• 2-aminopyridine derivatives such as 9 may be commercially available or alternatively they may be prepared using methodologies known in organic chemistry. For instance, application
• Acetylenic compounds of general structure 2 are prepared using one of several methods depending upon the choice of the desired substituents.
• substituents R 9 , R 9a , R 10 and R 10a are selected to be hydrogen or lower alkyl groups
• compounds of formula 2 may be prepared from known acetylenic alcohols such as 3-butyn-l-ol, 4-pentyn- 2-ol or similar acetylenic alcohols reported in the chemical literature.
• the conversion of acetylenic alcohols of general formula 10 to acetylene derivatives of general formula 2 is shown in Scheme C.
• the hydroxyl protecting group (PG X ) illustrated in Scheme C is exemplified as an O-benzyl ether.
• reaction of 10 with 0-benzyl-2,2,2-trichloro- acetimidate in the presence of a catalytic amount of a strong acid such as trifluoromethanesulfonic acid and in a suitable inert organic solvent like carbon tetrachloride at room temperature affords after 2 to 24 hours the protected acetylenic alcohol 2a.
• Compounds of formula 2a may in turn be converted to acetylenes (2b) of general formula 2 wherein Z is a trialkylsilyl group by deprotonation of the acetylene with a base such as ⁇ i-butyllithium in an inert organic solvent like tetrahydrofuran followed by reaction with a trialkylsilyl chloride such as triethylchlorosilane.
• the deprotonation and silylation reactions are generally conducted at low temperatures, for instance between about -78°C and room temperature, and after standard workup and purification a silylacetylene of formula 2b is obtained.
• acetylenes of general formula 2c wherein Z is an aryl or substituted aryl group are also useful in the 7- azaindole synthesis illustrated in Scheme A.
• Arylacetylenes 2c may be prepared using a coupling reaction of cuprous acetylides derived from acetylenic alcohols of formula 2a with various aryl halides or aryl triflates (11). Such coupling reactions produce aryl acetylenes of general formula 12 as shown at the bottom of Scheme C.
• arylacetylenes of general formula 12 can be protected with a suitable protecting group such as the O-benzyl ether group shown in Scheme C, to afford an arylacetylene (2c) of general formula 2 wherein Z is an aryl or substituted aryl group. It is also recognized that in some cases it may be preferable to reverse the order of the steps illustrated in Scheme C. For instance, acetylenic alcohols (7) may be subjected to silylation or arylation prior to the hydroxyl group protection step.
• acetylenic compounds of general formula 2a employs an ethynylation reaction sequence of aldehydes of general formula 16 as shown in Scheme D.
• the aldehydes (16) used in the ethynylation sequence may be prepared using various methods known in organic synthesis starting with hydroxy- esters of general formula 13, from protected hydroxyesters of formula 14, or from alcohols related to the mono-hydroxyl protected diols of formula
• aldehydes of formula 16 are reacted with carbon tetrabromide and triphenylphosphine in an inert organic solvent like dichloro- methane to produce the dibromo olefins of formula 17.
• the dibromo olefins (17) are treated with two equivalents of a strong base such as n-butyllithium in tetrahydrofuran at low temperature, for instance at about -78°C.
• the strong base induces dehydrohalogenation and metal- halogen exchange to afford lithium acetylides which upon quenching and workup afford acetylenes of general formula 2a.
• the intermediate lithium acetylides formed in the reaction may be treated with a trialkylsilyl chloride, such as triethylchlorosilane, to afford silylacetylenes of general formula 2b.
• the conversion of 2-silyl-substituted 7-azaindoles of general formula 3b to 2-aryl-substituted 7-azaindoles of general formula 3c may be accomplished in two steps as shown in Scheme E.
• the first step is a halodesilylation reaction which converts silyl-substituted 7-azaindoles of formula 3b into 2-halo-7-azaindoles of general formula 18.
• Scheme E illustrates this process using iodine monochloride so that the product obtained is a 2-iodoindole of general formula 18.
• Silver tetrafluoro- borate is also employed in this example to increase the reactivity of the halogenating reagent.
• the second step is a palladium-catalyzed cross coupling reaction of the 2-halo-7-azaindole 18 with a suitable aryl or substituted aryl organometallic reagent 19.
• Scheme E illustrates this process with an aryl or substituted arylboronic acid as the organometallic reagent, however, other organometallic reagents known to participate in palladium-catalyzed cross-coupling reactions such as arylboronic esters or arylstannanes may also be employed.
• arylboronic esters or arylstannanes may also be employed.
• arylboronic esters or arylstannanes may also be employed.
• arylboronic esters or arylstannanes may also be employed.
• arylboronic esters or arylstannanes may also be employed.
• arylboronic esters or arylstannanes may also be employed.
• - 22 - azaindole of general formula 18 is coupled with a generalized boronic acid (19) using a catalyst such as [l,l'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with dichloromethane (shown), tetrakis (triphenylphosphine)-palladium(O) or the like.
• a catalyst such as [l,l'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with dichloromethane (shown), tetrakis (triphenylphosphine)-palladium(O) or the like.
• the reaction is usually conducted at temperatures between room temperature and about 100°C, for instance at about 80°C.
• This palladium catalyzed cross-coupling reaction may be effected using various combinations of palladium catalysts and solvent compositions known in organic chemistry, and the selection of the conditions is made depending upon the type of organometallic reagent (19) used and the identity of the substituent groups in the two starting materials.
• organometallic reagent is a boronic acid or boronate ester
• a preferred solvent mixture consists of toluene, ethanol and an aqueous solution of a base like cesium or sodium carbonate.
• the organometallic reagent 19 is an arylstannane, then no additional base is required, and a polar aprotic solvent such as tetrahydrofuran or dimethylformamide is employed.
• PG 2 The choice of an appropriate amine protecting group (PG 2 ) for the 7-azaindole is determined primarily by which protecting group (PG X ) is present on the hydroxyl group in the C-3 sidechain, and by consideration of the chemical stability of the amine protecting group (PG X ) required in the remaining steps of the synthesis.
• PG j When the hydroxyl protecting group (PG j ) is anO-benzyl
• the 7-azaindole may be protected as a carbamate derivative such as a er£-butylcarbamate (BOC).
• BOC er£-butylcarbamate
• the BOC-protected 7-azaindole is stable under the hydrogenolysis conditions which are used to remove the O-benzyl ether and it may be conveniently removed at the end of the synthesis using acidic conditions. If it is desired to synthesize compounds of formula (I) wherein R 0 is alkyl, substituted alkyl or the like, then it is possible to introduce that substituent at this point and the use of a protecting group and its subsequent removal is not required.
• An alcohol of general formula 21 may be converted to a primary amine of general formula 23 using a variety of methods known in the literature of organic chemistry.
• the bottom of Scheme F illustrates a process where the alcohol 21 is first converted to an azide of general formula 22, followed by reduction to afford the amine derivative 23.
• the synthesis of an azide of general formula 22 from alcohols like 21 is best accomplished by performing a Mitsunobu reaction in the presence of an appropriate azide source such as diphenylphosphoryl azide or zinc azide pyridine complex.
• Scheme F illustrates the reaction of alcohol 21 with triphenylphosphine, diethylazodicarboxylate, zinc azide pyridine complex and a proton source such as imidazole in an inert solvent like methylene chloride or tetrahydrofuran.
• the reaction is usually conducted at room temperature for periods between 1-24 hours, typically overnight or about 15 hours, and affords the azide of general formula 22 in good yield.
• an azide of formula 22 may then be reduced to an amine of formula 23 using one of several methods common in organic synthesis.
• One preferred method is catalytic hydrogenation in a solvent like methanol or ethanol in the presence of a catalyst such as 10% palladium on carbon.
• azides like 22 may be reacted with triphenylphosphine to form an iminophosphorane which upon hydrolysis with water affords the amine of formula 23 and triphenylphophine oxide.
• the final stage of the synthesis of the novel 7-azaindole derivatives (I) involves elaboration of the sidechain at the C-3 position of the 7-azaindole core.
• One method for the completion of the synthesis is illustrated in Scheme G.
• the 2-aryltryptamine (23) may be condensed with a carboxylic acid of type 24 using the coupling reagent l-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (EDC), 1,3-dicyclohexyl-carbodiimide (DCC) or the like with or without 1- hydroxybenzotriazole (HOBt) and a tertiary amine base such as N- methylmorpholine (NMM), triethylamine or the like in an inert organic solvent such as methylene chloride, chloroform, dimethylformamide, or mixtures thereof at or near room temperature for a period of 3-24 hours to provide the corresponding amide
• 2- aryltryptamine 23 can be treated with an active ester or acid chloride of formula 26 in an inert organic solvent such as methylene chloride, chloroform, tetrahydrofuran, diethyl ether, or the like and a tertiary amine base such as triethylamine, diisopropylethylamine, pyridine or the like at a temperature of 0°-25°C for 30 minutes to 4 hours to give compound 25.
• an inert organic solvent such as methylene chloride, chloroform, tetrahydrofuran, diethyl ether, or the like
• a tertiary amine base such as triethylamine, diisopropylethylamine, pyridine or the like
• the amide carbonyl of 25 can be reduced by treatment with borane, lithium aluminum hydride, or equivalent hydride sources in an inert organic solvent such as tetrahydrofuran, diethyl ether, 1,4-dioxane or the like at about 25° to about 100°C, preferably about 65°C, for a period of 1-8 hours to give the corresponding amine 27.
• borane, lithium aluminum hydride, or equivalent hydride sources in an inert organic solvent such as tetrahydrofuran, diethyl ether, 1,4-dioxane or the like at about 25° to about 100°C, preferably about 65°C, for a period of 1-8 hours to give the corresponding amine 27.
• the 2-aryltryptamine 23 can be modified by treatment with an aldehyde or ketone of type 28 in the presence of a weak acid such as trifluoroacetic acid (TFA), acetic acid or the like, with or without a dessicant such as 3A molecular sieves or magnesium sulfate, and a hydride source such as sodium borohydride or sodium cyanoborohydride, in an inert organic solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, dichlorom ethane,
• a weak acid such as trifluoroacetic acid (TFA), acetic acid or the like
• a dessicant such as 3A molecular sieves or magnesium sulfate
• a hydride source such as sodium borohydride or sodium cyanoborohydride
• the tryptamine 23 can be modified using the Fukuyama modification of the Mitsunobu reaction (Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373- 74).
• the tryptamine 23 may be reacted with an arylsufonyl chloride such as 2-nitrobenzene-sulfonyl chloride, 4-nitrobenzenesulfonyl chloride or 2,4-dinitrobenzene-sulfonyl chloride and a hindered amine base such as 2,4,6-collidine, 2,6-lutidine or the like in an inert organic solvent such as methylene chloride to provide the corresponding sulfonamide 30.
• an arylsufonyl chloride such as 2-nitrobenzene-sulfonyl chloride, 4-nitrobenzenesulfonyl chloride or 2,4-dinitrobenzene-sulfonyl chloride and a hindered amine base such as 2,4,6-collidine, 2,6-lutidine or the like
• an inert organic solvent such as methylene chloride
• the sulfonamides can be further modified by reaction with an alcohol of type 31 in the presence of triphenylphosphine and an activating agent such as diethylazodicarboxylate (DEAD), diisopropylazodicaboxylate or the like in an inert organic solvent such as benzene, toluene, tetrahydrofuran or mixtures thereof to give the dialkylsulfonamide adduct. Removal of a dinitrobenzenesulfonyl group is accomplished by treatment
• nucleophilic amine such as ra-propylamine or the like in an inert organic solvent such as methylene chloride to give secondary amines of type 32.
• an inert organic solvent such as methylene chloride
• the removal of the sulfonamide is accomplished with a more nucleophilic reagent such as thiophenol or mercaptoacetic acid in combination with lithium hydroxide in DMF.
• Reaction Scheme K illustrates a method that is complimentary to reaction Scheme J for completing the synthesis of the novel compounds of formula (I).
• Scheme K also employs the Fukuyama modification of the Mitsunobu reaction similar to that illustrated in reaction Scheme J.
• the alcohol partner employed is a 2-aryltryptophol of general formula 21 which has been decribed previously in reaction Scheme F.
• the 2-aryltryptophol (21) is reacted with a substituted sulfonamide of general formula 33, triphenylphosphine and diethylazodicarboxylate in a suitable inert organic solvent such as benzene, tetrahydrofuran, 1,4-dioxane or the like.
• the reaction is generally conducted at room temperature for a period of 2 to 24 hours, typically overnight or for about 12-16 hours.
• - 29 product is an iV,iV-disubstituted sulfonamide which is then separately subjected to reaction with a base such as rc-propylamine which removes the sulfonamide substituent and furnishes a secondary amine related to formula 32.
• the sulfonamides of formula 33 employed are readily obtained from a primary amine and either 2-nitrobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride or 2,4-dinitrobenzenesulfonyl chloride (as shown) in the presence of a hindered amine base such as 2,4,6-collidine, 2,6-lutidine or the like in an inert organic solvent such as methylene chloride.
• PG 2 7-azaindole nitrogen atom
• the ligand binding assay is conducted with the human GnRH receptor (hGnRHR) obtained from CHO-Kl cells stably expressing the cloned receptor. Crude membrane suspensions are prepared from large batches of hGnRHR-CHO-Kl cells and stored as aliquots at -80° C .
• the radioactive peptide ligand [5-( 125 Iodo-Tyr)-Buserelin] is obtained from Woods Assays (Portland, Oregon) and has a radioactive specific activity of 1000 Ci/mmol.
• the membranes and the radioligand are diluted in assay buffer which consists of 50 mM Tris-HCl (pH 7.5), 2 mM MgCl 2 and 0.1% bovine serum albumin.
• assay buffer which consists of 50 mM Tris-HCl (pH 7.5), 2 mM MgCl 2 and 0.1% bovine serum albumin.
• the ligand binding assay is performed at 22°C for 1 hour in 96-well polypropylene plates in a final volume of 200 ul. Each well in the assay plate contains 0.1 nM 125 I- buserelin, 10-15 ug of hGnRH receptor-membrane protein and the test
• Test compounds are examined over a range of concentrations from 0.01 to 10,000 nM. The incubation is terminated by vacuum filtration onto 96-well Packard GF/C Unifilter plates (pretreated with 0.1% polyethyleneimine) and then washed with 2 mL of cold phosphate buffered saline (pH 7.5). The Unifilter plates are dried prior to addition of scintillation fluid and counting in a Packard TopCount detector
• PI Phosphoinositide
• GnRH receptor functionally coupled to phospholipase C were established and seeded at a concentration of 60,000 cells/mL/well in inositol-free F12 medium containing 10% dialyzed fetal bovine serum, 1% Pen/Strep, 2 mM glutamine, 500 ⁇ g/mL G418 and 1 ⁇ Ci ( 3 H)inositol in 24-well tray. Forty-eight hours after seeding, cells were washed with 3 x 1 mL of PBS containing 10 mM LiCl and treated with various concentrations of GnRH antagonist for 2 hrs at 37°C before the addition of 0.5 nM GnRH.
• Sex-hormone dependent cancers which may benefit from the administration of the compounds of this invention include prostatic cancer, uterine cancer, breast cancer and pituitary gonadotrophe adenomas.
• Other sex-hormone dependent conditions which may benefit from the administration of the compounds of this invention include endometriosis, polycystic ovarian disease, uterine fibroids and precocious puberty.
• the compounds may also be used in combination with an angiotensin-converting enzyme inhibitor
• an angiotensin Il-receptor antagonist such as Losartan or a renin inhibitor for the treatment of uterine fibroids.
• the compounds of the invention may also be useful for controlling pregnancy, as a contraceptive in both men and women, for in vitro fertilization, in the treatment of premenstrual syndrome, in the treatment of lupus erythematosis, in the treatment of hirsutism, in the treatment of irritable bowel syndrome and for the treatment of sleep disorders such as sleep apnea.
• a further use of the compounds of this invention is as an adjunct to growth hormone therapy in growth hormone deficient children.
• the compounds may be administered with growth hormone or a compound which increases the endogenous production or release of growth hormone. Certain compounds have been developed which stimulate the release of endogenous growth hormone.
• Peptides which are known to stimulate the release of endogenous growth hormone include growth hormone releasing hormone, the growth hormone releasing peptides GHRP-6 and GHRP-1 (described in U.S. Patent No. 4,411,890, PCT Patent Pub. No. WO 89/07110, and PCT Patent Pub. No. WO 89/07111) and GHRP-2 (described in PCT Patent Pub. No. WO
• Representative preferred growth hormone secretagoues employed in the present combination include the following:
• the compounds of the invention may also be used in combination with bisphosphonates (bisphosphonic acids) and other agents, such as growth hormone secretagogues, for the treatment and the prevention of disturbances of calcium, phosphate and bone metabolism, in particular, for the prevention of bone loss during therapy with the GnRH antagonist, and in combination with estrogens, progesterones and or androgens for the prevention or treatment of bone loss or hypogonadal symptoms such as hot flashes during therapy with the GnRH antagonist.
• bisphosphonates bisphosphonic acids
• other agents such as growth hormone secretagogues
• Bisphosphonates (bisphosphonic acids) are known to inhibit bone resorption and are useful for the treatment of bone lithiasis as disclosed in U.S. Patent 4,621,077 to Rosini, et al.
• the literature discloses a variety of bisphosphonic acids which are useful in the treatment and prevention of diseases involving bone resorption. Representative examples may be found in the following: U.S. Patent No. 3,251,907; U.S. Patent No. 3,422,137; U.S.
• Patent No. 4,578,376 U.S. Patent No. 4,621,077; U.S. Patent No. 4,624,947; U.S. Patent No. 4,746,654; U.S. Patent No. 4,761,406; U.S. Patent No.
• bisphosphonates are selected from the group of the following compounds: alendronic acid, etidrononic acid, clodronic acid, pamidronic acid, tiludronic acid, risedronic acid, 6-amino-l-hydroxy-hexylidene-bisphosphonic acid, and 1-hydroxy- 3(methylpentylamino)-propylidene-bisphosphonic acid; or any pharmaceutically acceptable salt thereof.
• a particularly preferred bisphosphonate is alendronic acid (alendronate), or a pharmaceutically acceptable salt thereof.
• An especially preferred bisphosphonate is alendronate sodium, including alendronate sodium trihydrate. Alendronate sodium has received regulatory approval for marketing in the United States under the trademark FOSAMAX®.
• a compound of the present invention may be co-administered with a 5 ⁇ -reductase 2 inhibitor, such as finasteride or epristeride; a 5 -reductase 1 inhibitor such as 4,7 ⁇ -dimethyl-4-aza-5 ⁇ - cholestan-3-one, 3-oxo-4-aza-4,7 ⁇ -dimethyl-16 ⁇ -(4-chlorophenoxy)-5 ⁇ - androstane, and 3-oxo-4-aza-4,7 ⁇ -dimethyl-16 ⁇ -(phenoxy)-5 ⁇ -androstane as disclosed in WO 93/23420 and WO 95/11254; dual inhibitors of 5 ⁇ - reductase 1 and 5 ⁇ -reductase 2 such as 3-oxo-4-aza-17 ⁇ -(2,5- trifluoromethylphenyl-carbamoyl)-5 -androstane as disclosed in WO 95/07927; antiandrogens such as flutamide, casodex and c
• a compound of the present invention may be used in combination with growth hormone, growth hormone releasing hormone or growth hormone secretagogues, to delay puberty in growth hormone deficient children, which will allow them to continue to gain height before fusion of the epiphyses and cessation of growth at puberty. Further, a compound of the present invention may be used in combination or co-administered with a compound having luteinizing hormone releasing activity such as a peptide or natural hormone or
• Such peptide compounds include leuprorelin, gonadorelin, buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterlin and recirelin.
• the active agents may be administered separately or in conjunction.
• the administration of one element may be prior to, concurrent to, or subsequent to the administration of the other agent.
• compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
• Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
• excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
• the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
• a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Patent 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
• Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert
• Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
• excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl- cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
• dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin
• the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
• preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
• coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
• coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
• flavoring agents such as sucrose, saccharin or aspartame.
• sweetening agents such as sucrose, saccharin or aspartame.
• Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
• the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
• Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting
• agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
• the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions.
• the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
• Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy beans, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
• the emulsions may also contain sweetening and flavouring agents.
• Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
• sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
• Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
• the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
• This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
• the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil may be employed including synthetic mono- or diglycerides.
• fatty acids such as oleic acid find use in the preparation of injectables.
• Compounds of Formula I may also be administered in the form of a suppositories for rectal administration of the drug.
• These compositions can be prepared by mixing the drug with a suitable non- irritating excipient which is solid at ordinary temperatures but liquid at
• the compounds for the present invention can 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 those of ordinary skill in the art.
• the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
• Compounds of the present invention may also be delivered as a suppository employing bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
• 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 thereof employed.
• a physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter, arrest or reverse the progress of the condition.
• Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.
• doses of the compound of structural formula I useful in the method of the present invention range from 0.01 to 1000 mg per adult human per day. Most preferably, dosages range from 0.1 to 500 mg/day.
• the compositions are preferably provided in the
• an effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0002 mg/kg to about 50 g/kg of body weight per day.
• the range is more particularly from about 0.001 mg/kg to 1 mg/kg of body weight per day.
• the active agent of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in dividend doses of two, three or four times daily.
• the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
• Step 1A Methyl (S)-2-[3-(2-benzyloxy-l-methylethyl)-2-triethylsilyl- lH-pyrrolo[2.3-61pyridin-5-yll-2-methylpropanoate
• reaction mixture was diluted with ethyl acetate and filtered through celite ® washing copiously with ethyl acetate.
• the filtrate was poured into water and extracted with ethyl acetate (x3).
• the combined organic extract was washed with brine, dried (MgSO 4 ) and concentrated in vacuo.
• the residue was purified by flash chromatography on silica gel (gradient elution; 20-25% ethyl acetate/hexanes as eluent) to give the title compound as an oil (6.11 g).
• Step IB Methyl (S)-2-[3-(2-benzyloxy-l-methylethyl)-2-iodo-lH- pyrrolor2.3-blpyridin-5-yn-2-methylpropanoate
• Step IC Methyl (S)-2-[3-(2-benzyloxy-l-methylethyl)-2-(3,5-dimethyl- phenyl)-lH-pyrrolo[2.3-61pyridin-5-yll-2-methylpropanoate
• methyl (S)-2-[3-(2- benzyloxy-l-methylethyl)-2-iodo-lH-pyrrolo[2,3-6]pyridin-5-yl]-2- methylpropanoate (4.00 g, 8.12 mmol), 2,5-dimethylphenylboronic acid (1.83 g, 12.2 mmol) and Pd(dppf)Cl 2 »C ⁇ 2 Cl 2 (0.33 g, 0.406 mmol) in toluene/MeOH (5:2; 140 mL) was degassed via three vacuum/nitrogen ingress cycles and the resulting mixture was heated to approximately 80°C.
• Step IE GS)-l-(7-Azabicyclo[2.2.1]hept-7-yl)-2-[3-(2-benzyloxy-l- methyl-ethyl)-2-(3,5-dimethylphenyl)-lH-pyrrolo[2,3-6]- pyridin-5-yl1-2-methylpropan-l-one
• Step IG (S)-l-(7-Azabicyclo[2.2.1]hept-7-yl)-2-[3-(2-hydroxy-l- methylethyl)-2-(3,5-dimethylphenyl)-lH-l-(t;ert butoxy- carbonyl)pyrrolo[2.3-61pyridin-5-yl]-2-methylpropan-l-one
• Step lH (S)-l-(7-Azabicyclo[2.2.1]hept-7-yl)-2-[3-(2-azido-l-methyl- ethyl)-2-(3,5-dimethylphenyl)-lH-l-(t;er -butoxycarbonyl)- pyrrolof2.3-6]pyridin-5-yll-2-methyIpropan-l-one
• Step II (S)-l-(7-Azabicyclo[2.2.1]hept-7-yl)-2-[3-(2-amino-l-methyl- ethyl)-2-(3,5-dimethylphenyl)-lH-l-(tert-butoxycarbonyl)- pyrrolo[2.3-61pyridin-5-yl1-2-methylpropan-l-one
• Step lJ (S)-l-(2-Azabicyclo[2.2.1]hept-7-yl)-2-[3-(2-(2,4-dinitro- benzenesulfonylamino)-l-methylethyl)-2-(3,5-dimethyl- phenyl)-lH-l-( ert ⁇ butoxycarbonyl)pyrrolo[2,3-6]pyridin-5- yll-2-methylpropan-l-one
• 2,4-Dinitrobenzenesulfonyl chloride (245 mg, 0.918 mmol) was added in one portion to a stirred solution of CS)-l-(7-azabicyclo[2.2.1] hept-7-yl)-2-[3-(2-amino-l-methylethyl)-2-(3,5-dimethyl-phenyl)-lH-l- ( er -butoxycarbonyl)pyrrolo [2,3-6] pyridin-5-yl]-2-methyl-propan-l-one (250 mg, 0.459 mmol) and 2,4,6-collidine (243 ⁇ L, 0.918 mmol) in C ⁇ 2 C1 2 (5 mL) at approximately 0°C.
• Step IK (S) 6- ⁇ 2-[ ⁇ X(5-[2-(2-Azabicyclo[2.2.1]hept-7-yl)-l,l-dimethyl-2- oxoethyl]-2-(3,5-dimethylphenyl)-lH-l-(tert-butoxycarbonyl)- pyrrolo[2,3-6]pyridin-3-yl]propyl)-iV-(2,4-dinitrobenzene- sulfonyl)]aminoethyl ⁇ -3-(2-trimethylsilylethoxymethyl)-3H- imidazo[4.5-61pyridine
• DEAD 122 ⁇ L, 0.774 mmol
• reaction mixture was concentrated in vacuo and the residue was partially purified by flash chromatography on silica gel (gradient elution; 60-80% ethyl acetate/hexanes as eluent) to give a mixture of the title compound, 1,2-dicarbethoxyhydrazine and triphenylphosphine oxide as an oil.
• Step IL (S) 6- ⁇ 2-[2-[5-[2-(2-Azabicyclo[2.2.2]hept-7-yl)-l,l-dimethyl-2- oxoethyl]-2-(3,5-dimethylphenyl)-lH-l-(t;ert butoxycarbonyl)- pyrrolo [2,3-6] pyridin-3-yl]propylamino]ethyl ⁇ -3-(2-trim ethyl - silylethoxymethyI)-3H-imidazo[4.5-61pyridine ra-Propylamine (1.59 mL, 19.4 mmol.) was added to a stirred solution of crude (S) 6- ⁇ 2-[iV-(5-[2-(2-azabicyclo[2.2.1]hept-7-yl)-l,l- dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-lH-l-( ⁇ er ⁇ -but
• Step lM GS)-l-(7-Azabicyclo[2.2.1]hept-7-yl)-2- ⁇ 2-(3,5-dimethylphenyl)- 3-[l-methyl-2-(imidazo[4,5-6]pyridin-6-yl)ethyl]-:ii ⁇ pyrrolo[2.3-61pyridin-5-yl ⁇ -2-methylpropan-l-one
• Step B Ethyl 2-methyl-2-(pyridin-3-yl)propanoate-A " -oxide eta-chloroperoxybenzoic acid (55%; 21.3 g, 67,9 mmol) was added in one portion to a vigorously stirred emulsion of ethyl 2- methyl-2-(pyridin-3-yl)propanoate and NaHCO 3 (17.5 g, 0.209 mmol) in water/chloroform (1:1; 500 mL) at ambient temperature. After approximately 12 h, the organic phase was separated and the aqueous phase extracted with chloroform (x3). The combined organic extract was washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The residue (10.9 g) was judged pure by a combination of TLC and 1 H nmr analysis and was used without further purification in the subsequent reaction.
• Step C Ethyl 2-[6-(2,2-dimethyl-4-oxo-4H-l,3-benzoxazin-3-yl)- pyridin-3-yl1-2-methylpropanoate
• Step F Methyl 2-(6-amino-5-iodopyridin-3-yl)-2-methylpropanoate
• Step AA Methyl ( ⁇ S0-3-benzyloxy-2-methylpropanoate
• Step BB ()S)-3-Benzyloxy-2-methylpropan-l-ol
• reaction was stirred an additional 6 h at room temperature at which point TLC analysis (20% EtOAc-hexane) indicated complete reaction.
• the reaction mixture was then cooled with an external ice-water bath and quenched by serial addition of 11.4 mL water, 11.4 mL of 15% aqueous NaOH, and 34.2 mL water.
• the reaction mixture was then filtered, the solids were washed with EtOAc, the filtrate and washings were combined and evaporated in vacuo.
• Step DD (S)-4-Benzyloxy-l.l-dibromo-3-methylbutene An oven dried three-necked 2 L round bottom flask was equipped with a mechanical stirrer, a thermometer, an N 2 inlet, and a septum. The flask was charged with 180.71 g (0.689 mol) of triphenylphosphine and 925 mL of CH 2 C1 2 . The reaction mixture was stirred under an N 2 atmosphere and cooled to 0-5°C with an external ice-
• the stirrer was started and the crude reaction mixture was introduced as a slow stream which resulted in formation of a granular precipitate. After the transfer was complete the reaction mixture was filtered and the solids were carefully washed with hexane. The filtrate was evaporated in vacuo and additional solids were deposited. The residue was resuspended in hexane, filtered and the filtrate reevaporated. The resulting oil was purified by Kugelrohr distillation to afford 46.54 g of the title compound as an oil.
• Step EE ( ⁇ S -(4-benzyloxy-3-methylbut-l-ynyl)triethylsilane
• An oven dried 100 mL single-necked round bottom flask was equipped with a magnetic stir bar and a septum then charged with 5.171 g (15.5 mmol) of (S)-4-benzyloxy-l,l-dibromo-3-methylbutene and 20 mL of anhydrous THF.
• the reaction mixture was stirred at -78°C under an N 2 atmosphere and 12.4 mL of a 2.5 M solution of rc-butyllithium (31.0 mmol) was added dropwise via syringe over 15 min.
• Step DDD 6-Bromo-3-(2-trimethysilylethoxymethyl) -3H-imidazo [4.5-61 -pyridine
• 5-Bromoimidazopyridine (3.0 g, 15.1 mmol) was dissolved in dry N, N- dimethylformamide (50 mL) and cooled to 0 °C, at which time a 60% oil dispersion of Na ⁇ (0.667 g, 16.7 mmol) was added in portions over 10 min. After 15 min at 0 °C, the reaction was allowed to warm to ambient temperature for an additional 90 min. To the homogeneous solution was added dropwise 2-(trimethylsilyl)ethoxymethyl chloride (SEM-C1, 3.03 g, 18.2 mmol). The reaction was maintained at ambient temperature for 40 h, at which time the mixture was poured into ice- water.
• SEM-C1 2-(trimethylsilyl)ethoxymethyl chloride
• the aqueous layer was extracted with diethyl ether 3 times, and the combined organic extracts were washed with brine, dried (MgSO 4 ), filtered, and concentrated to dryness in vacuo.
• the crude residue was loaded onto a silica-gel column and eluted with ethyl acetate/ hexane (20, 30, to 40 %). According to this procedure, 2.55 g of the title compound was obtained.
• Step EEE 6-Ethenyl-3-(2-trimethysilylethoxymethyl) -3H-imidazo- [4.5-61 -pyridine To a solution of 6-bromo-3-(2-trimethysilylethoxymethyl) -
• Step FFF 6-(2-Bromo-l-hydroxyethyl)-3-(2-trimethysilylethoxymethyl)- 3H-imidazo[4.5-6]-pyridine
• Step GGG 6-Oxiranyl-3-(2-trimethylsilylethoxymethyl)-3H-imidazo-
• Step HHH 2-[3-(2-Trimethylsilylethoxymethyl) -3H-imidazo- [4.5-61 pyridin-6-yll -ethanol

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