WO2002066477A2 - Composes - Google Patents

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Publication number
WO2002066477A2
WO2002066477A2 PCT/GB2002/000634 GB0200634W WO02066477A2 WO 2002066477 A2 WO2002066477 A2 WO 2002066477A2 GB 0200634 W GB0200634 W GB 0200634W WO 02066477 A2 WO02066477 A2 WO 02066477A2
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Prior art keywords
optionally substituted
alkyl
imidazo
methyl
hydrogen
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PCT/GB2002/000634
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English (en)
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WO2002066477A3 (fr
Inventor
Alexander Graham Dossetter
Peter Kenny
Darren Mckerrecher
Michael Wardleworth
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Astrazeneca Ab
Astrazeneca Uk Limited
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Priority to AU2002229976A priority Critical patent/AU2002229976A1/en
Publication of WO2002066477A2 publication Critical patent/WO2002066477A2/fr
Publication of WO2002066477A3 publication Critical patent/WO2002066477A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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

Definitions

  • the present invention relates to compounds which are antagonists of gonadotropin releasing hormone (GnRH) activity.
  • the invention also relates to pharmaceutical formulations, the use of a compound of the present invention in the manufacture of a medicament, a method of therapeutic treatment using such a compound and processes for producing the compounds.
  • Gonadotropin releasing hormone is a decapeptide that is secreted by the hypothalamus into the hypophyseal portal circulation in response to neural and/or chemical stimuli, causing the biosynthesis and release of luteinizing hormone (LH) and follicle- stimulating hormone (FSH) by the pituitary.
  • GnRH is also known by other names, including gonadoliberin, LH releasing hormone (LHRH), FSH releasing hormone (FSH RH) and LH/FSH releasing factor (LH/FSH RF).
  • GnRH plays an important role in regulating the action of LH and FSH (by regulation of their levels), and thus has a role in regulating the levels of gonadal steroids in both sexes, including the sex hormones progesterone, oestrogens and androgens. More discussion of GnRH can be found in WO 98/5519 and WO 97/14697, the disclosures of which are incorporated herein by reference.
  • GnRH activity includes several diseases such as sex hormone related conditions such as sex hormone dependent cancer, benign prostatic hypertrophy and myoma of the uterus.
  • sex hormone dependent cancers are prostatic cancer, uterine cancer, breast cancer and pituitary gonadotrophe adenoma.
  • the present invention accordingly provides a compound of formula I or a pharmaceutically acceptable salt or solvate thereof
  • Rl, R2 and R3 are independently selected from hydrogen and a group bonded through a carbon atom, a nitrogen atom, an oxygen atom or a sulphur atom; and ring A is optionally further substituted.
  • the present invention also provides a pharmaceutical formulation comprising such a compound and a pharmaceutically acceptable diluent or carrier.
  • the present invention also relates to a method of antagonising gonadotropin releasing hormone activity in a patient, comprising administering the compound to the patient.
  • the invention provides a process of producing the compound.
  • the present invention provides a compound of formula I or II or a pharmaceutically acceptable salt or solvate thereof
  • Rl, R2 and R3 are independently selected from hydrogen and a group bonded through a carbon atom, a nitrogen atom, an oxygen atom or a sulphur atom; and ring A is optionally further substituted.
  • WO 97/40846 correspond with Rl and R2 respectively of the present invention
  • Rl and R2 are independently selected from a group of the formula R8-(CH2)b" . wherein each b independently represents zero or an integer from 1 to 5 and each R8 represents a group bonded through a nitrogen atom; a group of of the formula R9-B'-, wherein R9 is an optionally substituted phenyl and B' is a chemical bond or spacer group; R10-(CH2) C -, wherein R10 is an optionally substituted amino and c is zero or an integer from 1 to 5; an optionally substituted C6 to C14 aryl; an optionally substituted CI to C20 hydrocarbon residue; and optionally substituted CI to C6 alkyl.
  • R10-(CH2) C - wherein R10 is an optionally substituted amino and c is zero or an integer from 1 to 5
  • an optionally substituted C6 to C14 aryl an optionally substituted CI to C20 hydrocarbon residue
  • optionally substituted CI to C6 alkyl Alternative embodiments,
  • R3 is selected from (CH2) a -R4, wherein R4 represents an optionally substituted C6 to C14 aryl (eg, phenyl) or an optionally substituted homo- or bi-cyclic heterocyclic ring (eg, a 5- or 6-membered mono-cyclic ring) and a represents zero or an integer from 1 to 5 (preferably, 1 or 2); a group bonded through a heteroatom (eg, where the heteroatom is O, N or S); an optionally substituted CI to C20 hydrocarbon residue (eg, optionally substituted CI to C6 alkyl or C2 to C12 alkenyl); optionally substituted CI to C6 alkyl; CI to C6 alkyl substituted with a group bonded through a sulphur atom; OR5, wherein R5 represents H or CI to C6 alkyl; a carbonyl group optionally substituted with a hydrocarbon residue, the residue being optionally substituted; an esterified or amidated
  • d represents zero or an integer from 1 to 5 and W represents aryl having an optional substitutent selected from halogen, nitro, cyano, amino, an optionally substituted carboxyl, alkylenedioxy wherein the alkylene is CI to C6, and a group of formula -X-R', wherein X represents a chemical bond or a spacer group and R' represents an optionally substituted cycloalkyl or an optionally substituted heterocyclic group.
  • R3 represents an optionally substituted cycloalkyl or an optionally substituted heterocyclic group.
  • R4 represents a group of the formula:'
  • R6 is selected from hydrogen; halogen; and a group bonded through a carbon atom, a nitrogen atom, an oxygen atom or a sulphur atom;
  • R7 is selected from hydrogen; halogen; nitro; cyano; and a hydrocarbon residue optionally substituted by a group bonded through an oxygen atom, a nitrogen atom or a sulphur atom.
  • R3 represents hydrogen; optionally substituted CI to C6 alkyl; optionally substituted aryl; CI to C3 perfluoroalkyl; CN; NO2; halogen; or
  • R12, R13 and R14 independently represent hydrogen; optionally substituted CI to C6 alkyl; optionally substituted C2 to C6 alkenyl; CN; nitro; CI to C3 perfluoroalkyl; CI to
  • R12 meets the definition in (a) and R13 and R14 together represent a 3C to 7C carbocyclic ring or a heterocyclic ring comprising from 1 to 3 heteroatoms selected from O, N and S;
  • R15 represents hydrogen; optionally substituted CI to C6 alkyl; CI to C3 perfluoroalkyl; or optionally substituted aryl; e and f independently represent 0, 1, 2, 3, 4 or 5; and g represents 0, 1 or 2.
  • ring A has a further substituent selected from halogen and-Q(R16)R17, wherein:-
  • Q represents N; O; S(O)h; C(O); (CR18R19)i ; a single bond to R16; optionally substituted C2 to C6 alkenyl; or optionally substituted C2 to C6 alkynyl; with the proviso that when Q is O; S(O) h ; C(O); (CR18R19) ⁇ ; or a single bond, R17 is absent; and
  • R16 represents hydrogen or optionally substituted CI to C6 alkyl; and R17 represents hydrogen; C(O)NR18R19; C(O)R20; NR18R19; C(O)R18;
  • the structure -Q(R16)R17 represents a heterocyclic ring comprising one or more heteroatoms selected from O, N and S and optionally substituted by R21, R22 and R23; or
  • Each Rl 8 and Rl 9 independently represents a bond; hydrogen; optionally substituted CI to C6 alkyl; optionally substituted aryl; optionally substituted aralkyl; an optionally substituted carbocyclic ring of 3-7 atoms; or a mono- or bi-cyclic heterocyclic ring comprising from 1 to 4 heteroatoms selected from O, N and S and being optionally substituted by R21, R22 and R23, or being optionally substituted by CI to C6 alkyl substituted by a mono- or bi-cyclic heterocyclic ring comprising from 1 to 4 heteroatoms selected from O, N and S and which ring is optionally substituted by R21, R22 and R23; or (g) Rl 8 and Rl 9 together form part of an optionally substituted 3 to 9-membered ring;
  • R20 represents hydrogen; optionally substituted CI to C6 alkyl; optionally substituted aryl; or optionally substituted aralkyl;
  • Each R21, R22 and R23 independently represents hydrogen; optionally substituted CI to C6 alkyl; optionally substituted C2 to C6 alkenyl; CN; nitro; CI to C3 perfluoroalkyl; CI to C3 perfluoroalkoxy; optionally substituted aryl; optionally substituted aralkyl; Rl 8O(CH2) , where Rl 8 meets the definition in section (f); (CH2)kS(O) ⁇ R24; or halogen; or
  • R21 is as defined in section (h) and R22 and R23 together represent a C3 to C7 carbocyclic ring or a heterocyclic ring containing from 1 to 3 heteroatoms selected from O, N and S;
  • R24 represents hydrogen; optionally substituted CI to C6 alkyl; CI to C3 perfluoroalkyl; or optionally substituted aryl;
  • i and k independently represent 0, 1, 2, 3, 4 or 5; and each h, j and 1 independently represent 0, 1 or 2.
  • Rl represents the group
  • B represents R29-Y-R29, wherein Y represents optionally substituted aryl
  • R25, R25a, R27, R28 and R28a either:-
  • R25, R25a, R27, R28 and R28a are independently selected from hydrogen; optionally substituted CI to C6 alkyl; optionally substituted aryl; and optionally substituted aralkyl;
  • R25 and R28 together represent a heterocyclic ring comprising from 3 to 7 carbon atoms and at least one heteroatom; and R25a, R27 and R28a meet the definition in section (m) R27 and R28 together represent a heterocyclic ring comprising from 3 to 7 carbon atoms and at least one heteroatom; and R25, R25a and R28a meet the definition in section (i); or
  • R25 and R27 together represent a heterocyclic ring comprising from 3 to 7 carbon atoms and at least one heteroatom; and R25a, R28 and R28a meet the definition in section
  • R26 represents a substituent selected from III to XXIX or an N-oxide thereof: -
  • Each R29 is independently selected from a bond and optionally substituted CI to C4 alkyl
  • R30 represents hydrogen; optionally substituted CI to C6 alkyl; C(O)OR37; C(O)N(R37) 2 ; C(O)R37; or S(O) 0 R37;
  • R31 and R36 independently represent hydrogen; optionally substituted CI to C6 alkyl; optionally substituted aryl; optionally substituted aralkyl; an optionally substituted carbocyclic ring of 3-7 atoms; or a mono- or bi-cyclic heterocyclic ring comprising from 1 to 4 heteroatoms selected from O, N and S and being optionally substituted by R38, R39 and R40, or being optionally substituted by CI to C6 alkyl substituted by a mono- or bi- cyclic heterocyclic ring comprising from 1 to 4 heteroatoms selected from O, N and S and which ring is optionally substituted by R38, R39 and R40;
  • R32 represents hydrogen; OH; NR41R42; NR37SO 2 (optionally substituted CI to C6 alkyl); NR37SO 2 (optionally substituted aryl); NR37SO 2 (Cl to C3 perfluoroalkyl); SO 2 NR37(o ⁇ tionally substituted CI to C6 alkyl); SO 2 NR37 (optionally substituted aryl); SO 2 NR37(Cl to C3 perfluoroalkyl); SO 2 NR37(C(O)-optionally substituted CI to C6 alkyl); SO 2 NR37(C(O)-optionally substituted aryl); S(O) p (optionally substituted CI to C6 alkyl); S(O)p(optionally substituted aryl); CI to C3 perfluoroalkyl; CI to C3 perfluoroalkoxy; optionally substituted CI to C6 alkoxy; COOH; halogen; O2; or CN;
  • R33 and R34 are independently selected from hydrogen; optionally substituted CI to C6 alkyl; optionally substituted C2 to C6 alkenyl; CN; nitro; CI to C3 perfluoroalkyl; CI to C3 perfluoroalkoxy; optionally substituted aryl; optionally substituted aralkyl;
  • R35 meets a definition of either R32 or R33;
  • Each R37 independently represents hydrogen; optionally substituted CI to C6 alkyl; optionally substituted aryl; optionally substituted aralkyl; or an optionally substituted 3 to 7-membered carbocyclic ring;
  • R38, R39 and R40 independently represent hydrogen; optionally substituted CI to C6 alkyl; optionally substituted C2 to C6 alkenyl; CN; nitro; CI to C3 perfluoroalkyl; CI to C3 perfluoroalkoxy; optionally substituted aryl; optionally substituted aralkyl; (CH 2 ) s S(O) t R43; or halogen;
  • R41 represents hydrogen or optionally substituted CI to C6 alkyl
  • R42 represents hydrogen; C(O)NR18'R19'; C(O)R20'; NR18'R19'; C(O)R18'; NR19'C(O)R18'; NR19'C(O)NR18'R19'; NR19'S(O) 2 R18'; NR19'S(O) 2 NR18'R19'; OC(O)R18'; OC(O)NR18'R19'; OR18'; S(O) u R18'; S(O) u NR18'R19'; a mono- or bi- cyclic heterocyclic ring comprising from 1 to 4 heteroatoms selected from O, N and S and being optionally substituted by R21 ', R22' and R23', or being optionally substituted by an optionally substituted CI to C6 alkyl; wherein R18', R19', R20', R21 ', R22' and R23' meet a definition respectively of R18, R
  • the structure -N(R41)R42 represents a heterocyclic ring comprising one or more heteroatoms selected from O, N and S and optionally substituted by R 1 ', R22' and R23 ' ; wherein R21 ', R22 ' and R23 ' meet a definition respectively of R21 , R22 and R23 in claim 7;
  • R43 represents hydrogen; optionally substituted CI to C6 alkyl; CI to C3 perfluoroalkyl; or optionally substituted aryl;
  • Z represents O, S or NR18 ' ;
  • R18' meets a definition of R18 in section (f) of claim 7;
  • Each m, q and s independently represent 0, 1, 2, 3, 4 or 5; and n, o, p, r, t and u independently represent 0, 1 or 2.
  • R2 represents represents a substituent of formula XXX:-
  • R44, R45 and R46 independently represent hydrogen; optionally substituted CI to C6 alkyl; optionally substituted C2 to C6 alkenyl; CN; nitro; CI to C3 perfluoroalkyl; CI to C3 perfluoroalkoxy; optionally substituted aryl; optionally substituted aralkyl; (CH 2 ) v S(O) w R47; or halogen;
  • R47 represents hydrogen; optionally substituted CI to C6 alkyl; CI to C3 perfluoroalkyl; or optionally substituted aryl;
  • Rl meets the definition of-X-(A)-CR9(R9 a )-(B)-NR ⁇ o(R ⁇ ) disclosed in WO 97/44037, WO 99/41251 or WO 97/44339, and these disclosures are explicitly incorporated herein by reference.
  • R2 meets the definition of Y disclosed in WO 97/44037 or the definition of the phenyl substituted by R 2 , R3 and R4 given in the formula I disclosed in WO 97/44339 or WO 99/41251, and these disclosures are explicitly incorporated herein by reference.
  • R3 meets a definition of R5, R , R7 or R ⁇ disclosed in WO 97/44037 or WO 97/44339, and ring A optionally has at least one further substituent meeting the definition of R 5 , R 6 , R 7 or R 8 disclosed in WO 97/44037 or WO 97/44339.
  • the disclosure in WO 97/44037 and WO 97/44339 relating to R 5 , R 6 , R 7 or R 8 is explicitly incorporated herein by reference.
  • an alkyl, alkylene or alkenyl moiety may be linear or branched.
  • CI to C6 alkyl preferably this is C2 to C4 alkyl, and more preferably methyl.
  • C2 to C6 alkenyl is mentioned, preferably this is C2 to C4 alkenyl, most preferably C2 or C3 alkenyl.
  • alkylene refers to -CH 2 -.
  • C8 alkylene for example is -(CH 2 ) ⁇ -. Where optional substitution is mentioned at various places above, this refers to one, two, three or more optional substituents. Unless otherwise indicated above (ie, where a list of optional substituents is provided), each substituent can be independently selected from CI to C8 alkyl (preferably C2 to C6 alkyl, and most preferably methyl); O(C3 to C8 cycloalkyl), preferably O-cyclopropyl, or O-cyclobutyl or O-cyclopentyl; O(Cl to C6 alkyl), preferably Omethyl or O(C2 to C4 alkyl); halo, preferably CI or F; CHal 3 , CHHal 2 , CH 2 Hal, OCHal 3 , OCHHal 2 or OCH 2 Hal, wherein Hal represents halogen (preferably F);
  • NRCOR' NRSO 2 R' or N-R-R', wherein R and R' independently represent H or CI to C8 alkyl (preferably methyl or C2 to C6 alkyl or C2 to C4 alkyl) , or N-R-R' represents an optionally substituted C3 to C8, preferably C3 to C6, heterocyclic ring optionally containing from 1 to 3 further heteroatoms independently selected from O, N and S; H; or COOR” or COR", R" representing H, optionally substituted phenyl or CI to C6 alkyl (preferably methyl, ethyl, t-propyl or t-butyl).
  • At least one (eg, one, two or three) substituents may be provided independently selected from CI to C6 alkyl (preferably C2 to C4 alkyl, more preferably methyl); phenyl; OCF 3 ; OCHF 2 ; -O(Cl-C8 alkyl), preferably -O-methyl, - O-ethyl or -O(C3 to C6 alkyl); -C(O)O(Cl-C8 alkyl), preferably -C(O)O-methyl, - C(O)O-ethyl, -C(O)O-tert-butyl or -C(O)O(C3 to C6 alkyl); -C(O)O-phenyl; -O-phenyl; - C(O) (CI -C8 alkyl), preferably -C(O)-methyl, -C(O)-eth
  • Particularly preferred compounds according to the present invention are:-
  • the invention also contemplates pharmaceutically acceptable salts and solvates of these compounds and other compounds of formula I or II.
  • Compounds of formula I or II may be converted to pharmaceutically acceptable salts and solvates thereof, preferably acid addition salts, such as hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartarate, citrate, oxalate, methanesulphonate or j->-toluenesulphonate, or alkali metal salts such as sodium or potassium salts.
  • R2 H; optionally substituted CI to C8 alkyl; optionally substituted aryl; optionally substituted aralkyl; -R7-R8, wherein R7 represents optionally substituted CI to C8 alkyl and R8 represents an optionally substituted 5- to 10-membered mono- or bi-cyclic heterocyclic ring structure containing from 1 to 5 heteroatoms independently selected from O, N and S; optionally substituted C2 to C12 alkenyl; or optionally substituted alkenylaryl, wherein the alkenyl moiety is C2 to C12; and
  • A a single bond; optionally substituted CI to C8 alkylene; a C2 to C12 group having at least one alkene double bond; or -R-Ar-R'-, where R and R' are independently selected from a bond,
  • N-R1R2 represents a 3- to 8- membered heterocyclic ring optionally containing from 1 to 3 further heteroatoms independently selected from O, N and S and optionally fused to a C5 to CIO ring structure, N-R1R2 being optionally substituted;
  • R3 is selected from (iii) and R4 selected from (iv); or R3 is selected from (iv) and R4 selected from (iii):—
  • M represents a mono- or bi-cyclic aromatic ring structure optionally having at least one substituent selected from CN; NR12R13; an optionally substituted CI to C8 alkyl; optionally substituted CI to C8 alkoxy; halogen; (CH 2 ) -C(O)NR12R13; NR12- C(O)NR13R14; (CH 2 ) b -SO 2 NR12R13; NR12C(O)R13; NR12SO 2 R13; (CH 2 ) b OH; NR12CN; and CR12(CN) 2 ;
  • each R5, R6, RIO, Rl 1, R12, R13 and R14 is independently selected from H; optionally substituted CI to C8 alkyl and optionally substituted aryl;
  • R9 is selected from H; optionally substituted CI to C8 alkyl; optionally substituted aryl; -R-Ar, where R represents CI to C8 alkylene and Ar represents optionally substituted aryl; and optionally substituted 3- to 8- membered heterocyclic ring optionally containing from 1 to 3 further heteroatoms independently selected from O, N and S;
  • X O; S; or NR'", where R'" is H or CI to C8 alkyl;
  • Y a bond; CI to C8 alkylene; a C2 to C12 group having at least one alkene double bond; or a C2 to C12 group having at least one alkyne triple bond; Z — a bond; CI to C8 alkylene; a C2 to C12 group having at least one alkene double bond; a C2 to C12 group having at least one alkyne triple bond; or -CR(R'), where
  • R and R' are independently selected from H, CN, halogen, CI to C8 alkyl, CH 2 F,
  • Z' a bond; CI to C8 alkylene; a C2 to C12 group having at least one alkene double bond; a C2 to C12 group having at least one alkyne triple bond; or -CR(R'), where R and R' are independently selected from H, CN, halogen, CI to C8 alkyl, CH 2 F,
  • a zero or an integer from 1 to 8; each b independently represents zero or an integer from 1 to 8;
  • ring B is optionally further substituted.
  • W. group for elaboration into N(-(A)-R1 )R2.
  • Imidazo[l,2- ⁇ ]pyridines of the structure (A) can be prepared by the condensation of a suitable substituted 2-aminopyridine 1 and a ketone 2 bearing a leaving group ⁇ to the carbonyl group (Br preferred group). Heating at a temperature between 25 °C and 120 °C, preferably 80 °C, in a suitable solvent such as N.N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), toluene, xylene, t-BuOH, preferable DMF, with or without the molecular sieves, for a period of 1 to 24 h, effects the condensation.
  • a suitable solvent such as N.N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), toluene, xylene, t-BuOH, preferable DMF, with or without the molecular sieves, for
  • Scheme b shows a general synthesis of 5-carbonyl-2-aryl-3- aminomethylimidazo[l,2- ]pyridine commencing with commercially available 2- aminopyridine and 2'-bromoacetophenone.
  • Michael addition reactions can be achieved by the condensation of methyl vinyl ketone with the bicycle 5 by heating in an organic acid, such as acetic acid, to yield a ketone product.
  • Reductive amination under typical conditions of an appropriately substituted amine and a hydride source, such as sodium cyanoborohydride, sodium borohyride, zinc borohyride, lithium borohydride and the like, yields products such as 6.
  • a hydride source such as sodium cyanoborohydride, sodium borohyride, zinc borohyride, lithium borohydride and the like
  • products such as 6 Using classical Mannich chemistry an aminomethyl group can be introduced by treatment of 5 with a mixture of a suitably substituted amine (NH(A-R1)(R2)) and paraformaldehyde.
  • an organic acid such as acetic acid and the like and stirring at room temperature or heating between 40 and 100°C in this manner compounds such as 8 which correspond to the general structure (A) where Y
  • CH 2 are formed.
  • a two step procedure may be employed, where a Nilsmeier reaction, classically employing DMF and phosphorus oxychloride at a temperature between -10 °C and 25 °C, installs a formyl group at the 3-position of the imidazo[l,2- ajpyridine to give 7.
  • Reduction amination employing a suitably substituted amine [H ⁇ (- (A)-R1)R2] and a reducing agent such as sodium borohydride, sodium cyanoborohydride, zinc borohydride and the such like, under acid or neutral conditions in a suitable solvent such as methylene chloride, chloroform, benzene, toluene and alcohols such as ethanol and the like, yields the 3-ammomethyl-imidazo[l,2-a]pyridines (8).
  • a suitable solvent such as methylene chloride, chloroform, benzene, toluene and alcohols such as ethanol and the like
  • Scheme c shows another general synthesis of 5-carbonyl-2-aryl-3- aminomethylimidazo[l,2- ]pyridine commencing with commercially available 2- aminopyridines and 2'-bromoacetophenone.
  • condensation of 2-aminopyridine 9 and a 2'-bromoacetophenone 3 under the preferred conditions noted above for the key cyclisation yields the bicycle 10.
  • the Mannich reaction conditions described above for Scheme b again install the substituted aminomethyl group leading to the bicycle 11.
  • L' is chloride, bromide, iodide, O-trifluoromethanesulfonate, trialkyltin or like
  • 11 can be treated under palladium(O) catalysis with carbon monoxide at latm or higher pressure in the presence of a substituted amine (N(R9) RIO as shown), alcohol (R9OH - not shown) or thiol (R9SH - not shown) in an inert solvent such as toluene, benzene, dioxane, THF, DMF and the like to yield 5-carbonyl-2-aryl-3-aminomethylimidazo[l,2- ⁇ ]pyridines such as 8.
  • L' is chloride, bromide, iodide, O-trifluoromethanesulfonate, trialkyltin or like 11 can be treated under palladium(O), a weak base such aqueous sodium carbonate and the like and a substituted aryl boronic acid from commercial sources or prepared (as described in: Gronowitz, S.; Hornfeldt, A.-B.; Yang, Y.,-H Chem. Sci.
  • Groups Rl and R2 can be introduced by a modified Mitsunobu reaction.
  • Mitsunobu coupling of the sulfonamide and an alcohol can be achieved by treatment with an activating agent such as diethyldiazocarboxylate (DEAD), diisopropyldiazocarboxlate or the like with triphenylphosphine, tri-butylphosphine and the like, in an inert solvent such as benzene, toluene, tetrahydrofuran or mixtures thereof to give the dialkylated sulfonamide adduct. Removal of the sulfonamide group is accomplished by treatment with a nucleophilic amine such as /z-propylamine to give substituted amine 23.
  • an activating agent such as diethyldiazocarboxylate (DEAD), diisopropyldiazocarboxlate or the like with triphenylphosphine, tri-butylphosphine and the like
  • an inert solvent such as benzene, toluene,
  • the primary amine 22 can be converted to a cyano-guanidine (24) by the two step process of reaction with diphenyl cyanocarbonimidate in an inert organic solvent such as methylene chloride, chloroform, benzene, tetrahydrofuran and the like, followed by condensation with an appropriately substituted amine (HNR5R6) in an inert organic from the list above.
  • an inert organic solvent such as methylene chloride, chloroform, benzene, tetrahydrofuran and the like
  • substitutents on the nitrogen atom can be installed by the Mitsunobu strategy (28— >29) or by condensation with an acid chloride in the presence of a hindered amine base such as triethylamine, in an inert solvent such as methylene chloride, then reduction of this product with lithium aluminium hydride, in an inert solvent such as tetrahydrofuran, or by reduction with borane in a similarly inert solvent (27 ⁇ 29).
  • a hindered amine base such as triethylamine
  • inert solvent such as methylene chloride
  • L * leaving group e.g. CI, Br, I.
  • Substituted ketones (20) can be prepared, as outlined in Scheme g starting from appropriate acid chlorides such as 30. Treatment of the acid chloride with N,N- dimethylhydroxylamine in the presence of an amine base such as triethylamine, and a suitable solvent such as methylene chloride at a temperature of -10 °C to 25 °C, yields the amide 31. Further reaction with a substituted aryl organolithium (prepared essentially as described in Wakefield B, J.; Organolithium Methods Academic Press Limited, 1988, pp.
  • the nitrogen atom can be installed directly by the route shown in Scheme h. Protection of the amine group of 33 with a tert-butylcarbamate group is achieved by condensation with di-tert-butyl dicarbonate in the presence of an amine base, for example triethylamine, in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran and mixtures thereof and the like, at a temperature of -10 °C to 25 °C.
  • an amine base for example triethylamine
  • An isomeric series of imidazo [l,2- ⁇ ]pyridines can be synthesised as described in Scheme j.
  • Condensation of a suitably substituted 2-aminopyridine 1, under the general conditions described above, with a ketone bearing two leaving groups ⁇ to the carbonyl (36) yields an imidazo[l,2- ⁇ ]pyridine such as 37.
  • the substituted amino group can be installed by direct alkylation to yield 39, or by an indirect multistep route as shown above in scheme j (compound 37 to compound 38 via intermediate 39), both routes are analogous to those shown in Schemes e.
  • amine group can be elaborated further to a cyano-guanidine 40 or a nitroethylene moiety such as compound 41 by the same methods as described in Scheme e.
  • an inert solvent such as toluene, benzene, dioxane, THF and the like
  • a Heck coupling reaction can be achieved using palladium (0) and a vinyl substituted aromatic compound in the presence of an organic amine base such as triethylamine and the like, in an inert solvent such as toluene, benzene, dioxane, THF and the like, with heating between 25 °C and 100 °C, preferably 80 °C, for a period of 1-12 hours to give the imidazo[l,2- ⁇ ]pyridine 43.
  • an organic amine base such as triethylamine and the like
  • an inert solvent such as toluene, benzene, dioxane, THF and the like
  • an organic base such as triethylamine, pyridine and the like
  • the amide product from this step can then be reduced by an appropriate hydride reducing agent such as lithium aluminium hydride or borane in an appropriate inert solvent such as dichloromethane, 1,2-dichloroethane, benzene, toluene, tetrahydrofuran, thus, a fully substituted compound such as 48 can be synthesised.
  • an appropriate hydride reducing agent such as lithium aluminium hydride or borane
  • an appropriate inert solvent such as dichloromethane, 1,2-dichloroethane, benzene, toluene, tetrahydrofuran
  • Step Al 2-(4-bromophenyl)-5-methyl-imidazo fl ,2-fll p ridine.
  • Step A2 N-BenzyI-N-methyl-2-(4-bromophenyI)-3-methylamino-5- ethyHmidazo[l.,2- a] pyridine.
  • Step B 1 2-(4-bromophenyl)-5-carboxy-imidazo [1 ,2- «l pyridine.
  • Step B2 2-(4-bromophenyl)-5-diethylamido-imidazofl,2-g1pyridine.
  • HOBt (426 mg 3.15mmol) was added in one portion to a stirred solution of 2-(4- bromophenyl)-5-carboxylic-imidazo[l,2- ]pyridine (1.00 g 3.15 mmol) and EDC (605 mg 3.15 mmol) in CH 2 C1 2 (30 mL) under N 2 at O°C. The mixture was stirred for lh then diethylamine (1.63 mL 15.8 mmol) was added and the mixture allowed to stir at RT for 20h.
  • Step B3 N-Benzyl-N-methyl-2-f4-bromophenyl)-5-diethylamido-3-methylamino- imidazo [1 J,- ⁇ p ridine.
  • Step CI Ethyl 5-bromo-imidazo[l.,2-fllpyridine-2-carboxylate.
  • Step C2 Ethyl N-Benzyl-N-methyl-5-bromo-3-methylan-dno-imidazo[l t 2- lpyridine-2- carboxylate.
  • Step C3 Ethyl N-benzyl-N-methyI-5-(3-acetamidophenyl)-3-methylamino- imidazo[1.2- «lpyridine-2-carboxylate.
  • Tetrakis(triphenylphosphine) palladium(O) (58.0 mg 0.050 mmol) was added in one portion to a degassed mixture of ethyl N-Benzyl-N-methyl-5-bromo-3-methylamino- imidazo[l,2- ⁇ ]pyridine-2-carboxylate (200 mg 0.498 mmol) and ⁇ -acetyl-3- aminobenzeneboronic acid (89.0 mg 0.498 mmol) in toluene (2 mL), ethanol (2 mL) and saturated NaHCO 3 (aq) (1 mL). The mixture was heated at 80 °C_with vigorous stirring for 4 h then cooled to RT.
  • Step Dl Preparation of l-Imidazo[l,2-alpyridin-2-ylmethyl-3-cyano-2-phenyl- isourea
  • Step D2 Prep ar ation of N-Cyano-N imidazo ⁇ 1 ,2-g] pyridin ⁇ -ylmethyD-N' '-methyl- guanidine
  • Step D3 N-Cyano-NM3-bromo-imidazo n,2-a1 pyridin-2-ylmethvD- V , '-methyl- guanidine
  • Step D4 Preparation of N-Cyano-N 3-(lH-indol-5-yIHmidazori,2--zlpyridin-2- ylmethyll -N' '-methyl-guanidine
  • D4 N-C ano-N'-[3-(3,5-dimethylphenyl)-imidazo[l,2-fl]p ridin-2-ylmethyl]-V , '- methyl-guanidine
  • Step E2 Preparation of N,N-Dibenzyl-2-methylamino-3-bromoimidazo [1,2- fl]pyridine
  • Step E3 Preparation of N,N-Dibenzyl-2-methyIamino-3-(3,4- dimethoxyphenyl)imidazo [1 ,2-al pyridine
  • Step Gl Preparation of 2-chloromethylimidazo[l,2-fl1 pyridine
  • Step G2 Preparation ofN-benzyl-N-methyl-2-methylaminoimidazo[l,2- ⁇ 1pyridine
  • Step G3 Preparation of N-benzyI-N-methyl-2-methyIamino-3-bromoimidazo f 1,2- ⁇ l pyridine
  • Step G4 Preparation of N-benzyl-N-methyl-2-methylamino-3-(4- chlorophenyl)imidazo[l,2-aIpyridme
  • Step J2 5-bromo-3-(3-oxo-butyl)-2-(4-methoxyphenyl)imidazo[l,2-fl1pyridine
  • Step J3 N-Benzyl-5-bromo-3-(3-methylpropylaminoV2-(4- methoxyphenyPimidazo [1 ,2- ⁇ l pyridine
  • benzylamine (0.090 mL, 0.820 mmol) was added to a solution of 5-bromo-3-(3-oxo-butyl)-2-(4-methoxyphenyl)imidazo[l,2- ⁇ ]pyridine (300 mg, 0.810 mmol) and toluene sulphonic acid (1 mg, catalytic amount) in anhydrous methanol (10 mL). The reaction mixture was then allowed to reflux over molecular sieves for 16 h.
  • Step Kl 5-methyl-2-(4-methoxyphenyl)imidazo[l,2--zlpyridine
  • Step K2 5-methyl-3-bromo-2-(4-methoxyphenyl)imidazo[1.2- ⁇ lpyridine
  • Step K3 N-Benzyl-N-Methyl-5-methyl-3-propargylamino-2-(4- methoxyphenyl)imidazo[l,2-fllpyridine
  • Pargyline hydrochloride (202 mg, 1.26 mmol) was added to a solution of 5-methyl-3- bromo-2-(4-methoxyphenyl)imidazo[l,2- ]pyridine (20mg, 0.63mmol) in diethylamine (15 mL), and the solution bubbled with nitrogen. Copper Iodide (12.0 mg, 0.060 mmol) was added followed by the addition of bis(triphenylphosphine)palladium di chloride (22.0 mg, 0.030 mmol), and the solution again bubbled with nitrogen. The reaction was then stirred at reflux for 3h, and then at 55 °C for 10 h.
  • reaction mixture was added to water (50 mL) and extracted with dichloromethane (2 x 50 mL). The organics were dried over magnesium sulfate, filtered, evaporated in vacuo and purified by flash chromatography (silica gel, eluting from 10% ethyl acetate :hexane to 40% ethyl acetate:hexane) to give the product and the hydrochloride salt was formed with HCl/ether to give the title compound as an off white solid (37.0 mg, 14%).
  • Example KZ Preparation of N-( ⁇ methylphenethyl)-N-Methyl-5-methyl-3- propargylamino-2-(4-methoxyphenyl)imidazo[l,2-fl1pyridine
  • Example L Preparation of 5-bromo-3-(2J5 , -cyanoethenyl)-2-(4- chIorophenyl)imidazo[l,2-g]pyridine
  • Step LI 5-bromo-2-(4-chlorophenyl)imidazo[l,2- ⁇ ] pyridine
  • Step L2 5-bromo-3-formyl-2-(4-chlorophenyl)imidazo[l,2- ⁇ ]pyridine
  • Step L3 5-bromo-3-(2--i-cyanoethenyl)-2-(4-chlorophenyl)imidazo[l,2- ⁇ ]pyridine.
  • sodium bis(trimethylsilyl)amide (l.OM solution in THF, 1.1 L, 1.1 mmol) was added to a solution of (cyanomethyl)triphenylphosphoniumchloride (303 mg, 0.900 mmol) in THF, and the reaction allowed to warm to room temperature over 2 h.
  • reaction was cooled to -78 °C, and 5-bromo-3-formyl-2-(4-chlorophenyl)imidazo[l,2-- ⁇ ]pyridine (100 mg, 0.300 mmol) in THF was added dropwise.
  • the reaction was stirred at -78 °C-»RT for 14h, and for a further 4h at 40 °C.
  • the reaction mixture was partitioned between water and dichloromethane, the organics separated, dried over magnesium sulfate, filtered and evaporated.
  • the crude product was purified by flash chromatography (silica gel, eluting from 10%) ethyl acetate/hexane to 50% ethyl acetate/hexane) to give the title compound as an off-white solid (45.0 mg, 42%).
  • Step Ml 4-Chloro-2-bromopropyl-3,5-dimethylphenyl ketone.
  • Step M2 2-(3,5-dimethylphenyl)-3-ethylamino-5-methylimidazo[l,2- 1pyridine.
  • Step M2 N-Benzyl-iV-methyl-2-(3,5-dimethylphenyl)-3-ethylamino-5- methylimidazo f 1,2-fl] pyridine.
  • N-Methyl-N-benzylamine (95 ⁇ L 0.737 mmol) was added in one portion to a stirred solution of 2-(3,5-dimethylphenyl)-3-ethylamino-5-methylimidazo[l,2- ⁇ ]pyridine (200 mg 0.670 mmol) and di-isopropylethylamine (128 mL 0.736 mmol) in DMF (25 mL) was heated overnight at 100°C. The mixture was partitioned EtOAc (2 x 50 mL) and saturated ⁇ aHCO 3 (250 mL) and the combined organics were dried (MgSO 4 ) and concentrated in vacuo.
  • a compound of formulae I and II are provided as medicaments for antagonising gonadotropin releasing hormone (GnRH) activity in men and women.
  • a compound of formulae I and II can be provided as part of a pharmaceutical formulation which also includes a pharmaceutically acceptable diluent or carrier (eg, water).
  • the formulation may be in the form of tablets, capsules, granules, powders, syrups, emulsions (eg, lipid emulsions), suppositories, ointments, creams, drops, suspensions (eg, aqueous or oily suspensions) or solutions (eg, aqueous or oily solutions).
  • the formulation may include one or more additional substances independently selected from stabilising agents, wetting agents, emulsifying agents, buffers, lactose, sialic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter and ethylene glycol.
  • the compound is preferably orally administered to a patient, but other routes of administration are possible, such as parenteral or rectal administration.
  • intravenous, subcutaneous or intramuscular administration the patient may receive a daily dose of O.lmgkg "1 to 30mgkg _1 (preferably, 5mgkg _1 to 20mgkg _1 ) of the compound, the compound being administered 1 to 4 times per day.
  • the intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection.
  • the intravenous dose may be given by continuous infusion over a period of time.
  • the patient may receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.
  • a suitable pharmaceutical formulation is one suitable for oral administration in unit dosage form, for example as a tablet or capsule, which contains between lOmg and lg (preferably, 100 mg and lg) of the compound of the invention.
  • the following illustrate representative pharmaceutical dosage forms containing a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof (hereafter referred to as "compound X"), for use in humans.
  • Buffers eg, pharmaceutically acceptable cosolvents (eg, polyethylene glycol, propylene glycol, glycerol or EtOH) or complexing agents such as hydroxy-propyl ⁇ cyclodextrin may be used to aid formulation.
  • pharmaceutically acceptable cosolvents eg, polyethylene glycol, propylene glycol, glycerol or EtOH
  • complexing agents such as hydroxy-propyl ⁇ cyclodextrin may be used to aid formulation.
  • One aspect of the invention relates to the use of compounds according to the invention for reducing the secretion of LH and/or FSH by the pituitary gland of a patient.
  • the reduction may be by way of a reduction in biosynthesis of the LH and FSH and/or a reduction in the release of LH and FSH by the pituitary gland.
  • compounds according to the invention can be used for therapeutically treating and/or preventing a sex hormone related condition in the patient.
  • preventing we mean reducing the patient's risk of contracting the condition.
  • treating we mean eradicating the condition or reducing its severity in the patient.
  • sex hormone related conditions are: a sex honnone dependent cancer, benign prostatic hypertrophy, myoma of the uterus, endometriosis, polycystic ovarian disease, uterine fibroids, prostatauxe, myoma uteri, birsutism and precocious puberty.
  • sex hormone dependent cancers are: prostatic cancer, uterine cancer, breast cancer and pituitary gonadotrophe adenoma.
  • the assay is performed as follows:-
  • the IC50 of the test compound can be determined as the concentration of the compound required to inhibit radio-ligand binding to GnRH receptors by 50%.
  • Crude membranes prepared from CHO cells expressing human GnRH receptors are sources for the GnRH receptor.
  • the binding activity of compounds according to the invention can be determined as an IC50 which is the compound concentration required to
  • the LH release assay can be used to demonstrate antagonist activity of compounds, as demonstrated by a reduction in GnRH-induced LH release.
  • Suitable rats are Wistar male rats (150-200g) which have been maintained at a constant temperature (eg, 25°C) on a 12 hour light/12 hour dark cycle.
  • the rats are sacrificed by decapitation before the pituitary glands are aseptically removed to tube containing Hank's Balanced Salt Solution (HBSS).
  • HBSS Hank's Balanced Salt Solution
  • test compound is dissolved in DMSO to a final concentration of 0.5%> in the incubation medium.
  • the cells are washed three times with DMEM containing 0.37% NaHCO3, 10% horse serum, 2.5% foetal bovine serum, 1% non essential amino acids (100X), 1% glutamine (100X), 1% penicillin/streptomycin (10,000 units of each per ml) and 25 mM HEPES at pH 7.4. Immediately prior to the assay, the cells are again washed twice in this medium .
  • test compound 1ml of fresh medium containing the test compound and 2nM GnRH is added to two wells.
  • test compounds where it is desired to test more than one compound
  • these are added to other respective duplicate wells. Incubation is then carried out at 37°C for three hours.
  • each well is analysed by removing the medium from the well and centrifuging the medium at 2000 x g for 15 minutes to remove any cellular material. The supernatant is removed and assayed for LH content using a double antibody radio-immuno assay. Comparison with a suitable control (no test compound) is used to determine whether the test compound reduces LH release.
  • Compounds according to the present invention have activity at a concentration from InM to 30 ⁇ M.

Abstract

La présente invention concerne des composés représentés par la formule (I), dans laquelle R1, R2 et R3 représentent des éléments définis dans la partie descriptive de la présente demande et le noyau A est éventuellement davantage substitué. Ces composés sont des antagonistes de l'activité de l'hormone de libération de la gonadotrophine (GnRH). L'invention concerne également des préparations pharmaceutiques, l'utilisation d'un composé de la présente invention dans la fabrication d'un médicament, une méthode de traitement thérapeutique qui utilise ce composé et des procédés destinés à la production de ces composés.
PCT/GB2002/000634 2001-02-20 2002-02-15 Composes WO2002066477A2 (fr)

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DE10247271A1 (de) * 2002-10-10 2004-08-26 Grünenthal GmbH Substituierte C-Imidazo[1,2-a]pyridin-3-yle
EP2018865A2 (fr) 2003-09-05 2009-01-28 AstraZeneca AB Combinaison a base de n-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyridine-3-sulfonamide et d'un analogue de la lhrh et/ou d'un bisphosphonate
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WO2005080400A1 (fr) * 2004-02-20 2005-09-01 Astrazeneca Ab Derives de thienopyrrole servant d'antagonistes de gnrh
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