Title:
MACROLIDE LHRH ANTAGONISTS
Document Type and Number:
WIPO Patent Application WO/1999/050275
Kind Code:
A2
Abstract:
Disclosed are 3'-N-desmethyl-3'-N-susbstituted-6-O-methyl-11-deoxy-11, 12-cyclic carbamate erythromycin A derivatives which are antagonists of lutenizing hormone-releasing hormone (LHRH). Also disclosed are pharmaceutical compositions comprising the compounds, to methods of using the compounds and to the process of making the same.
Inventors:
SAUER DARYL R
HAVIV FORTUNA
RANDOLPH JOHN
MORT NICHOLAS A
DALTON CHRISTOPHER R
BRUNCKO MILAN
KAMINSKI MICHELE A
CRAWFORD BRADLEY W
FREY LISA MARIE
GREER JONATHON
HAVIV FORTUNA
RANDOLPH JOHN
MORT NICHOLAS A
DALTON CHRISTOPHER R
BRUNCKO MILAN
KAMINSKI MICHELE A
CRAWFORD BRADLEY W
FREY LISA MARIE
GREER JONATHON
Application Number:
PCT/US1999/004658
Publication Date:
October 07, 1999
Filing Date:
March 11, 1999
Export Citation:
Assignee:
ABBOTT LAB (US)
International Classes:
A61K31/7042; A61K31/7048; A61K31/7056; A61P5/24; A61P13/08; A61P15/00; A61P35/00; A61P43/00; C07H17/08; (IPC1-7): C07H/
Domestic Patent References:
| WO1997021704A1 | 1997-06-19 | |||
| WO1997042206A1 | 1997-11-13 |
Foreign References:
| EP0487411A1 | 1992-05-27 | |||
| EP0716093A1 | 1996-06-12 | |||
| EP0559896A1 | 1993-09-15 |
Other References:
FERNANDES, PRABHAVATHI B. ET AL: "New macrolides active against Streptococcus pyogenes with inducible or constitutive type of macrolide - lincosamide - streptogramin B resistance" ANTIMICROB. AGENTS CHEMOTHER. (1989), 33(1), 78-81, XP002085920
Attorney, Agent or Firm:
Anand, Mona (IL, US)
Download PDF:
Claims:
We Claim:
| 1. | A compound represented by the formula: I, or a pharmaceutically acceptable salt or ester thereof, wherein A is selected from the group consisting of: (a)C, (b)N, and (c)0; X and Y are independently at each occurrence selected from the group consisting of: (a) hydrogen. (b) halide, (c) trifluoromethyl, (d) alkoxy. |
| 2. | (e) alkyl, (f) aryl. and (g) substituted aryl; R is selected from the group consisting of: (a) alkyl, (b) cycloalkyl, (c) heterocylic, (d) substituted heterocyclic, (e) alkylcycloalkyl, (f) substituted alkylcycloalkyl, (g) alkylaryl, (f) alkylheterocyclic, (g) alkenyl, (h) alkynyl, i)C (S)NHR4, C (NR4)NHR4, wherein R4 is hydrogen, alkyl, or aryl; and (j)(CH2) nC (CH2) mRs, wherein m is 2,3,4, or 5, and R5 is alkyl, alkoxy, aryl, or substituted aryl; R2 and R3 are independently at each occurrence (a) hydrogen, (b) methyl, or R2 and R3 together form a cyclic moiety, when A is C; R3 is absent when A is N; and 1,2or3.n=. |
| 3. | The compound of Claim 1, wherein R is alkyl, alkenyl, cycloalkyl, heterocyclic, (heterocyclic) alkyl or alkylcycloalkyl; X and Y are independently at each occurrence chloro, fluoro, dioxalano, hydrogen, or alkoxy; A isC or N; R2 and R3 are independently at each occurrence hydrogen or together they form cylopropyl moiety and n is 1. |
| 4. | A compound of Claim 1 selected from the group consisting of: <BR> <BR> <BR> <BR> 3'Ndesmethyl3'Ncyclopentyl11deoxy11 [carboxy (3, 4dichlorophenethylamino)]6 0methylerythromycin A 11,12 (cyclic carbamate); <BR> <BR> <BR> <BR> 3'Ndesmethyl3'Ncyclopropyl11deoxy11 [carboxy (3, 4dichlorophenethylamino)]6 0methylerythromycin A 11,12 (cyclic carbamate); <BR> <BR> <BR> <BR> <BR> <BR> 3'Ndesmethyl3'Nnpropyl11deoxy11 [carboxy (3, 4dichlorophenethylamino)]6O methylerythromycin A 11, 12 (cyclic carbamate); <BR> <BR> <BR> <BR> <BR> <BR> 3'Ndesmethyl3'Ncyclobutyl11deoxy11 [carboxy (3, 4dichlorophenethylamino)]6 Omethylerythromycin A 11, 12 (cyclic carbamate); 3'Ndesmethyl3'Ncyclohexyl11deoxy11 [carboxy (3, 4dichlorophenethylamino)]6 0methylerythromycin A 11,12 (cyclic carbamate); <BR> <BR> <BR> <BR> 3'Ndesmethyl3'Nisovaleryl11deoxyl l[carboxy(3. 4dichlorophenethylamino)]6O methylerythromycin A carbamate); 3'Ndesmethyl3'N (3methylthiopropyl)11deoxy11 [carboxy (3,4 dichlorophenethylamino)]6Omethylerythromycin A 11, 12 (cyclic carbamate); 3'Ndesmethyl3'N (3tetrahydrothienyl)11deoxy11 [carboxy (3,4 dichlorophenethylamino)]6Omethylerythromycin A 11, 12 (cyclic carbamate); 3'Ndesmethyl3'N (3, 4dimethylcyclopentyl)11deoxy11 [carboxy (3,4 dichlorophenethylamino)]6Omethylerythromycin A 11,12(cyclic carbamate); 3'Ndesmethyl3'Nisopropyl11deoxy11 [carboxy (a, acyclopropyl3,4 11,12(cycliccarbamate);dichlorophenethylamino)]6OmethylerythromycinA 3'Ndesmethyl3'Ncyclobutyl11deoxy11 [carboxy (a, acyclopropyl3,4 dichlorophenethylamino)]6Omethylerythromycin A 11,12(cyclic carbamate); 3'Ndesmethyl3'Ncyclopentyl11deoxy11[carboxy(a, acyclopropyl3,[carboxy(a, acyclopropyl3, 4 dichlorophenethylamino)]6Omethylerythromycin A 11,12(cyclic carbamate) ; 3'Ndesmethyl3'Ncyclohexyl11deoxy11[carboxy(a, acyclopropyl3,[carboxy(a, acyclopropyl3, 4 dichlorophenethylamino)]6Omethylerythromycin A 11,12 (cyclic carbamate); 3'Ndesmethyl3'Nnpropyl11deoxy11[carboxy(3,4dioxolanophenethylamin)]6 0methylerythromycin A 11, 12 (cyclic carbamate); <BR> <BR> <BR> <BR> <BR> <BR> 3'Ndesmethyl3'Ncyclopentyl11deoxy11 [carboxy (3,4dioxolanophenethylamino)] 6Omethylerythromycin A 11,12(cyclic carbamate) ; 3'Ndesmethyl3'Nnpropyl11deoxy11[carboxy(4chloro3fluorophenethylamino)] 60methylerythromycin A 11, 12(cyclic carbamate); 3'Ndesmethyl3'Nisopropyl11deoxy11[carboxy(4chloro3 11,12(cycliccarbamate);fluorophenethylamin)]6OmethylerythromycinA 3'Ndesmethyl3'Ncyclopentyl11deoxy11[carboxy(4chloro3 fluorophenethylamino)]6Omethylerythromycin A 11, 12 (cyclic carbamate); <BR> <BR> <BR> <BR> <BR> <BR> 3'Ndesmethyl3'Ncyclobutylmethyl11deoxy11 [carboxy (4chlorophenethylamino)] 6Omethylerythromycin A 11, 12 (cyclic carbamate); 3'Ndesmethyl3'Ncyclobutylmethyl11deoxy11[carboxy(4chlorophenethylamino)] 60methylerythromycin A 11, 12 (cyclic carbamate); <BR> <BR> <BR> <BR> <BR> <BR> 3'Ndesmethyl3'Nethyl11deoxy11 [carboxy (4chlorophenethylamino)]6Omethyl erythromycin A 11,12 (cyclic carbamate); <BR> <BR> <BR> <BR> <BR> <BR> 3'Ndesmethyl3'Nisopropyl11deoxy11 [carboxy (4chlorophenethylamino)]6O methylerythromycin A 11, 12(cyclic carbamate); <BR> <BR> <BR> <BR> <BR> <BR> 3'Ndesmethyl3'Ncyclopentyl11deoxy11 [carboxy (4chlorophenethylamino)]6O methylerythromycin A 11, 12 (cyclic carbamate); <BR> <BR> <BR> <BR> <BR> <BR> 3'Ndesmethyl3'Ncyclopentyl11deoxy11 [carboxy (3chlorophenethylamino)]6O methylerythromycin A 11, 12(cyclic carbamate); 3'Ndesmethyl3'Nnpropyl11deoxy11 [carboxy (3chlorophenethylamino)]6O methylerythromycin A 11, 12 (cyclic carbamate); 3'Ndesmethyl3'Ncyclopentyl11deoxy11 [carboxy (3chloro4 fluorophenethylamino)]6Omethylerythromycin A 11, 12(cyclic carbamate); 3'Ndesmethyl3'Ncyclobutyl11deoxy11 [carboxy (3chloro4 fluorophenethylamino)]6Omethylerythromycin A 11, 12 (cyclic carbamate); 3'Ndesmethyl3'Nisopropyl11deoxy11 [carboxy (3chloro4 fluorophenethylamino)]6Omethylerythromycin A 11,12(cyclic carbamate); 3'Ndesmethyl3'Ncyclopropylmethyl1deoxy11[carboxy(3chloro4 fluorophenethylamino)]6Omethylerythromycin A 11,12(cyclic carbamate) ; 3'Ndesmethyl3'Ncyclobutyl11deoxy11[(carboxy(3,4difluorophenethylamino)]6 0methylerythromycin A 11, 12 (cyclic carbamate); 3'Ndesmethyl3'Ncyclopentyl11deoxy11[(carboxy(3,4difluorophenethylamino)]6 0methylerythromycin A 11,12 (cyclic carbamate); 3'Ndesmethyl3'Nnpropyl11deoxy11[carboxy(3,4difluorophenethylamino)]6O methylerythromycin A 11,12 (cyclic carbamate); and 3'Ndesmethyl3'Ncyclopropylmethyl11deoxy11 [carboxy (3,4 difluorophenethylamino)]6Omethylerythromycin A 11,12 (cyclic carbamate). 3'Ndesmethyl3'N(4pyridylmethyl)11deoxy11[carboxy4(chlorophenethylamino)] 6Omethylerythromycin A 11,12 (cyclic carbamate) 3'Ndesmethyl3'N (2butyl)11deoxy11 [carboxy (4chlorophenethylamino)]6O methylerythromycin A 11. 12(cyclic carbamate) 3'Ndesmethyl3'N (3pentyl)11deoxy11 [carboxy (4chlorophenethylamino)]6O methylerythromycin A 11,12 (cyclic carbamate). 3'Ndesmethyl3'N (cyclopropylmethyl)11deoxy11 [carboxy (4 chlorophenethylamino)]6Omethylerythromycin A 11,12(cyclic carbamate) 3'Ndesmethyl3'N (2cyclopropylethyl)11deoxy11 [carboxy (4 chlorophenethylamino)]6Omethylerythromycin A 11,12(cyclic carbamate) 3'Ndesmethyl3'Npropyl11deoxyl l[carboxy(4methoxyphenethylamino)]6O methylerythromycin A 11, 12(cyclic carbamate) <BR> <BR> <BR> <BR> <BR> <BR> 3'Ndesmethyl3'Ncyclopentyl11deoxy11 [carboxy (4methoxyphenethylamino)]6O methylerythromycin A 11. 12(cyclic carbamate). 3'Ndesmethyl3'Npropyl11deoxy11 [carboxy (3, 4dimethylphenethylamino)]6O methylerythromycin A 11,12 (cyclic carbamate). 3'Ndesmethyl3'Ncyclopentyl11deoxy11 [carboxy (3bromo4 methoxyphenethylamino)]6Omethylerythromycin A 11.12 (cyclic carbamate). <BR> <BR> <BR> <BR> <BR> <BR> <P>3'Ndesmethyl3'Npropyl11deoxy11 [carboxy (3bromo4methoxyphenethylamino)] 6Omethylerythromycin A 11, 12 (cyclic carbamate). <BR> <BR> <BR> <BR> <BR> <BR> <P>3'Ndesmethyl3'Npropyl11deoxy11 [carboxy (3chloro4fluorophenethylamino)]6 Omethylerythromycin A 11, 12 (cyclic carbamate). 3'Ndesmethyl3'N (2furyl) methyl11deoxy11 [carboxy (3chloro4 fluorophenethylamino)]6Omethylerythromycin A 11, 12 (cyclic carbamate). 3'Ndesmethyl3'N[2(5hydroxymethyl)furyl]methyl11deoxy11[carboxy(3chloro 4fluorophenethylamino)]6Omethylerythromycin A 11, 12 (cyclic carbamate) 3'Ndesmethyl3'N (2pyridyl) methyl11deoxy11 [carboxy (3chloro4 11,12(cycliccarbamate).fluorophenethylamin)]6OmethylerythromycinA 3'Ndesmethyl3'N [2 (6methyl) pyridyl] methyl11deoxy11 [carboxy (3chloro4 fluorophenethylamin)]6Omethylerythromycin A 11,12 (cyclic carbamate) 3'Ndesmethyl3'N (4hydroxyethoxybenzyl)11deoxy11 [carboxy (3chloro4 fluorophenethylamino)]6Omethylerythromycin A 11, 12 (cyclic carbamate). 3'Ndesmethyl3'N(3methylthio)butyl11deoxy11[carboxy(3chloro4 fluorophenethylamino)]6Omethylerythromycin A 11, 12 (cyclic carbamate). 3'Ndesmethyl3'N (4, 4, 4trifluorobutyl)11deoxy11 [carboxy (3chloro4 fluorophenethylamino)]6Omethylerythromycin A 11,12(cyclic carbamate). 3'Ndesmethyl3'Ncyclobutyl11deoxy11 [carboxy (4chloro3 fluorophenethylamino)]6Omethylerythromycin A 11,12 (cyclic carbamate). <BR> <BR> <BR> <BR> <BR> <BR> <P>3'Ndesmethyl3'Nisopropyl11deoxy11 [carboxy (3. 4difluorophenethylamino)]6O methylerythromycin A 11.12 (cyclic carbamate) 3'Ndesmethyl3'Npropyl11deoxy11[carboxy[3,4(1,4dioxano)phenethylamin)]} 6Omethylerythromycin A 11,12 (cyclic carbamate) 3'Ndesmethyl3'Ncyclopropylmethyl11deoxy11 [carboxy (3,4 11,12(cycliccarbamate)dichlorophenethylamin)]6OmethylerythromycinA 3'Ndesmethyl3'N[3(methylsulfoxy)propy]11deoxy11[carboxy(3,4 dichlorophenethylamino)]6Omethylerythromycin A 11. 12 (cyclic carbamate) 3'Ndesmethyl3'Nethylthiourea11deoxy11[carboxy(3,4dichlorophenethylamino)] 60methylerythromycin A 11,12(cyclic carbamate) 3'Ndesmethyl3'N [2 (5hydroxymethyl) furyl] methyl11deoxy11 [carboxy (3,4 dichlorophenethylamino)]6Omethylerythromycin A 11,12 (cyclic carbamate). 3'Ndesmethyl3'Ncyclopropylmethyl11deoxy11[carboxy(a, acyclopropyl3,[carboxy(a, acyclopropyl3, 4 dichlorophenethylamino)]6Omethylerythromycin A 11, 12 (cyclic carbamate) 3'Ndesmethyl3'Npropyl11deoxy11 [carboxy (4chloroanilinoethylamino)]6O methylerythromycin A 11,12(cyclic carbamate) 3'Ndesmethyl3'Ncyclopentyl11deoxy11 [carboxy (4chloroanilinoethylamino)]60 methylerythromycin A 11,12 (cyclic carbamate) <BR> <BR> <BR> <BR> <BR> <BR> 3'Ndesmethyl3'Nisopropyl11deoxy11 [carboxy (3, 4diflorophenethylamino)]6O methylerythromycin A 11, 12 (cyclic carbamate) 3'Ndesmethyl3'N (2imidazolo) methyl11deoxy11 [carboxy (3,4 dichlorophenethylamino)]6Omethylerythromycin A 11,12 (cyclic carbamate) 3'Ndesmethyl3'N (3pyridyl) methyl11deoxy11 [carboxy (3,4 dichlorophenethylamino)]6Omethylerythromycin A 11,12 (cyclic carbamate) 3'Ndesmethyl3'N(2pyridyl)methyl11deoxy11[carboxy(3,4 dichlorophenethylamino)]6Omethylerythromycin A 11,12 (cyclic carbamate) 3'Ndesmethyl3'N[(5nitro)2thienyl]methyl11deoxy11[carboxy(3,4 dichlorophenethylamino)]6Omethylerythromycin A 11,12 (cyclic carbamate) 3'Ndesmethyl3'N [5 (4chlorophenyl)2furyl] methyl11deoxy11 [carboxy (3,4 dichlorophenethylamino)]6Omethylerythromycin A 11,12 (cyclic carbamate) 3'Ndesmethyl3'N[5nitro2furyl]methyl1deoxy11[carboxy(3,4 dichlorophenethylamino)]6Omethylerythromycin A 11,12 (cyclic carbamate) 3'Ndesmethyl3'N[2, 5dimethoxy3tetrahydrofuryl] methyl11deoxy11[carboxy (3,4dichlorophenethylamino)]6Omethylerythromycin A 11.12 (cyclic carbamate) 3'Ndesmethyl3'N [6methyl2pyridyl] methyl11deoxy11 [carboxy (3,4 dichlorophenethylamino)]6Omethylerythromycin A 11,12 (cyclic carbamate) 3'Ndesmethyl3'N(4,4,4trifluorobutyl)11deoxy11[carboxy(3,4 dichlorophenethylamino)]6Omethylerythromycin A 11, 12 (cyclic carbamate) 3'Ndesmethyl3'N(1bromo2napthyl)methyl11deoxy11[carboxy(3,4 dichlorophenethylamino)]6Omethylerythromycin A 11, 12 (cyclic carbamate) 3'Ndesmethyl3'N (4methyl1napthyl) methyl11deoxy11 [carboxy (3,4 dichlorophenethylamino)]6Omethylerythromycin A 11,12 (cyclic carbamate) 3'Ndesmethyl3'N (4dimethylamino1napthyl) methyl11deoxy11 [carboxy (3,4 dichlorophenethylamino)]6Omethylerythromycin A 11,12 (cyclic carbamate) 3'Ndesmethyl3'N (2furyl) methyl11deoxy11 [carboxy (3,4 dichlorophenethylamino)]6Omethylerythromycin A 11,12 (cyclic carbamate) 3'Ndesmethyl [3'N3 (4pyridyl) propyl]11deoxy11 [carboxy (3,4 dichlorophenethylamino)]6Omethylerythromycin A 11,12 (cyclic carbamate) 3'Ndesmethyl3'N[3(2pyridyl)propyl]11deoxy11[carboxy(3,4 dichlorophenethylamino)]6Omethylerythromycin A 11,12 (cyclic carbamate) 3'Ndesmethyl3'N3[4(4pyridyl)butyl]11deoxy11[carboxy(3,4 dichlorophenethylamino)]6Omethylerythromycin A 11,12 (cyclic carbamate) 3'Ndesmethyl3'N [3 (3pyridyl) propyl]11deoxy11 [carboxy (3,4 dichlorophenethylamino)]6Omethylerythromycin A 11, 12(cyclic carbamate) 3'Ndesmethyl3'N [3 (3pyridyl) propyl]11deoxy11 [carboxy (3chloro4 fluorophenethylamino)]6Omethylerythromycin A 11,12 (cyclic carbamate) 3'Ndesmethyl3'N [3 (4pyridyl) propyl]l 1deoxyl 1 [carboxy (3chloro4 fluorophenethylamino)]6Omethylerythromycin A 11,12 (cyclic carbamate) 3'Ndesmethyl3'N[3(2pyridyl)propyl]11deoxy11[carboxy(3chloro4 fluorophenethylamino)]6Omethylerythromycin A 11,12 (cyclic carbamate) 3'Ndesmethyl3'N [4 (4pyridyl) butyl]11deoxy11 [carboxy (3chloro4 fluorophenethylamino)]6Omethylerythromycin A 11,12 (cyclic carbamate) <BR> <BR> <BR> <BR> <BR> <BR> 3'Ndesmethyl3'N [4 (6methyl2pyridyl)] butyl11deoxy11 [carboxy (3chloro4 fluorophenethylamino)]6Omethylerythromycin A 11, 12(cyclic carbamate) 3'Ndesmethyl3'N[1methyl3(4hydroxyphenyl)propyl]11deoxy11[carboxy(3,4 dichlorophenethylamino)]6Omethylerythromycin A 11,12 (cyclic carbamate) 3'Ndesmethyl3'N[(1methyl)3(4hydroxyphenyl)propyl]11deoxy11[carboxy(3 chloro4fluorophenethylamino)]6Omethylerythromycin A 11,12 (cyclic carbamate) <BR> <BR> <BR> <BR> <BR> <BR> 3'Ndesmethyl3'N [3 (6methyl2pyridyl) propyl]11deoxy11 [carboxy (3chloro4 fluorophenethylamino)]6Omethylerythromycin A 11,12 (cyclic carbamate) 3'Ndesmethyl3'N[3(5methyl2pyridyl)propyl]11deoxy11[carboxy(3chloro4 fluorophenethylamino)]6Omethylerythromycin A 11, 12(cyclic carbamate) 3'Ndesmethyl3'N(2pyridylethyl)11deoxy11[carboxy(3,4 dichlorophenethylamino)]6Omethylerythromycin A 11, 12 (cyclic carbamate). 3'Ndesmethyl3'N (2pyridylethyl)11deoxy11 [carboxy (3chloro4 fluorophenethylamino)]6Omethylerythromycin A 11,12 (cyclic carbamate) 3'Ndesmethyl3'N (4hydroxybenzyl)11deoxy11 [carboxy (3,4 dichlorophenethylamino)]6Omethylerythromycin A 11, 12 (cyclic carbamate) 3'Ndesmethyl3'N(4pyridyl)methyl11deoxy11[carboxy(3,4 dichlorophenethylamino)]6Omethylerythromycin A 11,12 (cyclic carbamate) 3'Ndesmethyl3'N[(3methylthio)butyl]11deoxy11[carboxy(3,4 dichlorophenethylamino)]6Omethylerythromycin A 11,12 (cyclic carbamate) 3'Ndesmethyl3'N (1methylcyclopropyl) methyl11deoxy11 [carboxy (3,4 dichlorophenethylamino)]6Omethylerythromycin A 11,12 (cyclic carbamate); 3'Ndesmethyl3'N(1methylcyclopropyl)methyl11deoxy11[carboxy(3chloro4 11,12(cycliccarbamate);fluorophenethylamino)]6OmethylerythromycinA 3'Ndesmethyl3'Noxiranylmethyl11deoxy11 [carboxy (3,4 dichlorophenethylamino)]6Omethylerythromycin A 11,12 (cyclic carbamate); 3'Ndesmethyl3'guanidino11deoxy11[carboxy(3,4dichlorophenethylamino)]6O methylerythromycin A 11, 12 (cyclic carbamate); and 3'Ndesmethyl3'N2 (4, 5dihydroimidazolyl)11deoxy11 [carboxy (3,4 dichlorophenethylamino)]6Omethylerythromycin A 11, 12 (cyclic carbamate). |
| 5. | A compound according to Claim 3 selected from the group consisting of: <BR> <BR> <BR> <BR> 3'Ndesmethyl3'Ncyclopentyl11deoxy11 [carboxy (3,4dichlorophenethylamino)]6 0methylerythromycin A 11, 12 (cyclic carbamate); <BR> <BR> <BR> <BR> 3'Ndesmethyl3'Ncyclopropyl11deoxy11 [carboxy (3,4dichlorophenethylamino)]6 0methylerythromycin A 11, 12 (cyclic carbamate); 3'Ndesmethyl3'Nnpropyl11deoxy11[carboxy(3,4dichlorophenethylamino)]6O methylerythromycin A 11, 12 (cyclic carbamate); 3'Ndesmethyl3'Nisopropyl11deoxy11 [carboxy (3chloro4 fluorophenethylamino)]6Omethylerythromycin A 11,12 (cyclic carbamate); 3'Ndesmethyl3'Ncyclopropylmethyl11deoxy11 [carboxy (3chloro4 11,12(cycliccarbamate);fluorophenethylamino)]6OmethylerythromycinA <BR> <BR> <BR> <BR> <BR> <BR> 3'Ndesmethyl3'Ncyclobutyl11deoxy11 [carboxy (3, 4difluorophenethylamino)]6 0methylerythromycin A 11, 12 (cyclic carbamate) ; 3'Ndesmethyl3'Ncyclopentyl11deoxy11[carboxy(3,4difluorophenethylamino)]6 Omethylerythromycin A carbamate); 3'Ndesmethyl3'Nnpropyl11deoxy11[carboxy(3, 4difluorophenethylamino)]6O methylerythromycin A 11, 12 (cyclic carbamate); and 3'Ndesmethyl3'Ncyclopropylmethyl11deoxy11[carboxy(3, 4 difluorophenethylamino)]6Omethylerythromycin A 11, 12 (cyclic carbamate). |
| 6. | A pharmaceutical composition for inhibiting the release of LH comprising a therapeutically effective amount of a compound according to Claim 1 in combination with a pharmaceutically acceptable carrier. |
| 7. | A method of inhibiting LH release in a mammal in need of such treatment comprising administering to the mammal a therapeuticallyeffective amount of a compound according to Claim 1. |
| 8. | A process for preparing a compound represented by the formula: I, or a pharmaceutically acceptable salt or ester thereof, wherein A is selected from the group consisting of: (a)C, (b)N, and <BR> <BR> <BR> (clos<BR> <BR> <BR> <BR> <BR> X and Y are independently at each occurrence selected from the group consisting of: (a) hydrogen, (b) halide, (c) trifluoromethyl, (d) alkoxy, (e) alkyl, (f) aryl, and (g) substituted aryl; R is selected from the group consisting of: (a) alkyl, (b) cycloalkyl, (c) heterocylic, (d) substituted heterocyclic, (e) alkylcycloalkyl, (f) substituted alkylcycloalkyl, (g) alkylaryl, (f) alkylheterocyclic, (g) alkenyl, (h) alkynyl, i)C (S)NHR4, C (NR4)NHR4, wherein R4 is hydrogen, alkyl, or aryl; and (j)(CH2) nC (CH2) mRs, wherein m is 2,3,4, or 5, and R5 is alkyl, alkoxy, aryl, or substituted aryl; R2 and R3 are independently at each occurrence (a) hydrogen, (b) methyl, or R2 and R3 together form a cyclic moiety, when A is C; R3 is absent when A is N; andn= lw2Or3 : comprising the steps of: (a) reacting a compound of formula: with sodium hexamethyldisilazide and carbonyldiimidazole to afford a compound of the formula: (b) reacting the compound obtained in step (a) with a compound an amino compound of the formula: follow by deprotection of 2', 4"protected (c) desmethylating the 3'amino by treating the compound obtained in step (b) to afford a compound of the formula: (d) alkylating the 3'Ndesmethylated compound obtained in step (c) with an alkylating agent. |
| 9. | The process according to Claim 7, wherein the reaction in step (a) is carried out in an aprotic solvent at 0 to 25°C. |
| 10. | The process according to Claim 7, wherein the reaction in step (b) is carried out without solvent or in acetonitrile at 25 to 80°C. |
| 11. | The process according to Claim 7, wherein the desmethylation is carried out by reaction of the compound obtained in step (b) with iodine in the presence of a base and a light or heat source. |
| 12. | The process according to Claim 7, wherein the desmethylation is carried out by reaction of the compound obtained in step (b) with a chloroformate selected from the group consisting of benzyl chloroformate, allyl chloroformate and vinyl chloroformate. |
| 13. | The process according to Claim 7, wherein the alkylation in step (d) is achieved by reaction of the compound obtained in step (c) with an aldehyde or ketone in the presence of a hydride metal or in the presence of Pd/C catalyst in a protic or nonprotic solvent under hydrogen. |
| 14. | The process according to Claim 7, wherein the alkylation in step (d) is achieved by reaction of the compound obtained in step (c) with an alkyl halide in presence of a base. |
| 15. | The process of Claim 7, wherein R is alkyl, alkenyl, cycloalkyl, heterocyclic, (heterocyclic) alkyl or alkylcycloalkyl; X and Y are independently at each occurrence chloro, fluoro, dioxalano, hydrogen, or alkoxy; A isC; R2 and R3 are independently at each occurrence hydrogen or together they form cylopropyl moiety and n is 1. |
| 16. | The process of Claim 7, wherein the alkylating agent is cyclopentanone and the alkylation is carried out in the presence of sodium cyanoborohydride in methanol. |
Description:
INTERNATIONAL SEARCH REPORT intw-"ational Application No Pb,/US 99/04658 C. (Continuation) DOCUMENTS CONSIDERED TO BE RELEVANT Category'Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. A WO 97 21704 A (MERCK & CO INC; GOULET MARK 1, 5, 6 (US); ASHTON WALLACE T (US); CHU LIN () 19 June 1997 (1997-06-19) cited in the application page 1 claims A EP 0 716 093 A (ROUSSEL UCLAF) 1,5,7 12 June 1996 (1996-06-12) claims1,12 A WO 97 42206 A (ABBOTT LAB) 1,7 13 November 1997 (1997-11-13) page 158, formula (VII) A EP 0 559 896 A (TAISHO PHARMACEUTICALS CO. 1,7 LTD) 15 September 1993 (1993-09-15) page 3, line 19-page 5, line 44 1 rnationai application No. INTERNATIONAL SEARCH REPORT PCT/US 99/04658 Box I Observations where certain claims were found unsearchable (Continuation of Item 1 of first sheet) This International Search Report has not been established in respect of certain claims under Article 17 (2) (a) for the following reasons: 1. m Claims Nos. : 6 because they relate to subject matter not required to be searched by this Authority, namely: Remark: Although claim 6 is directed to a method of treatment of the human/animal body, the search has been carried out and based on the alleged effects of the compound/composition. 2. Claims Nos.: because they relate to parts of the International Application that do not comply with the prescribed requirements to such an extent that no meaningful International Search can be carried out, specifically : 3. je Claims Nos.: because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4 (a). Box 11 Observations where unity of invention Is lacking (Continuation of item 2 of first sheet) This International Searching Authority found multiple inventions in this international application, as follows: 1. As As all required additional search fees were timely paid by the applicant, this International Search Report covers all searchable claims. 2. As As all searchable claims could be searched without effort justifying an additional fee, this Authority did not invite payment of any additional fee. 3. j As only some of the required additional search fees were timely paid by the applicant, this International Search Report covers only those claims for which fees were paid, specifically claims Nos.: 4. No required additional search fees were timely paid by the applicant. Consequently, this International Search Report is restricted to the invention first mentioned in the claims ; it is covered by claims Nos.: Remark on Protest F-I The additional search fees were accompanied by the applicant's protest. ! No protest accompanied the payment of additional search fees. INTERNATIONAL SEARCH REPORT IntP^tional Appiication No lformatlon on patentfamily members PUS 99/04658 Patent document Publication Patent family Publication cited in search report date member (s) date EP 0487411 A 27-05-1992 FR 2669337 A 22-05-1992 FR 2677025 A 04-12-1992 FR 2680790 A 05-03-1993 AT 133683 T 15-02-1996 AU 640290 B 19-08-1993 AU 8798691 A 28-05-1992 CA 2055912 A 21-05-1992 CN 1065069 A, B 07-10-1992 CS 9103508 A 17-06-1992 DE 69116815 D 14-03-1996 DE 69116815 T 17-10-1996 DK 487411 T 15-04-1996 ES 2082952 T O1-04-1996 FI 915469 A 22-05-1992 GR 3018848 T 31-05-1996 IE 74713 B 30-07-1997 IL 99995 A 20-11-1997 JP 4290893 A 15-10-1992 NZ 240684 A 26-08-1994 OA 9523 A 15-11-1992 PL 167448 B 30-09-1995 PL 169422 B 31-07-1996 PT 99569 A, B 30-10-1992 RU 2100367 C 27-12-1997 US 5444051 A 22-08-1995 US 5561118 A O1-10-1996 US 5770579 A 23-06-1998 WO 9721704 A 19-06-1997 AU 707641 B 15-07-1999 AU 1410697 A 03-07-1997 CA 2240108 A 19-06-1997 CN 1208412 A 17-02-1999 CZ 9801839 A 14-10-1998 EP 0873336 A 28-10-1998 JP 11506471 T 08-06-1999 NO 982729 A 13-08-1998 PL 327146 A 23-11-1998 SK 77298 A 11-01-1999 US 5780437 A 14-07-1998 EP 0716093 A 12-06-1996 FR 2727969 A 14-06-1996 AT 172467 T 15-11-1998 AU 697876 B 22-10-1998 AU 4032495 A 20-06-1996 CA 2164798 A 10-06-1996 CN 1133291 A 16-10-1996 DE 69505487 D 26-11-1998 DE 69505487 T 12-05-1999 ES 2123934 T 16-01-1999 HU 74075 A, B 28-10-1996 JP 8231583 A 10-09-1996 US 5786339 A 28-07-1998 ZA 9510447 A 09-12-1996 WO 9742206 A 13-11-1997 AU 2340797 A 26-11-1997 AU 2998797 A 26-11-1997 CZ 9803518 A 14-04-1999 EP 0918783 A 02-06-1999 INTERNATIONAL SEARCH REPORT ! nt°""'Mona) App) ! cat ! on No nformatlon on patent family members P/US 99/04658 Patent document Publication Patent family Publication cited in search report date member (s) date WO 9742206 A WO 9742204 A 13-11-1997 EP 0559896 A 15-09-1993 DE 69127457 D 02-10-1997 DE 69127457 T 22-01-1998 US 5403923 A 04-04-1995 AT 157368 T 15-09-1997 CA 2096969 A 29-05-1992 ES 2104889 T 16-10-1997 WO 9209614 A 11-06-1992