CA2329660A1 - Inhibitors of neuraminidases - Google Patents
Inhibitors of neuraminidases Download PDFInfo
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- CA2329660A1 CA2329660A1 CA002329660A CA2329660A CA2329660A1 CA 2329660 A1 CA2329660 A1 CA 2329660A1 CA 002329660 A CA002329660 A CA 002329660A CA 2329660 A CA2329660 A CA 2329660A CA 2329660 A1 CA2329660 A1 CA 2329660A1
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- hydrogen
- alkenyl
- alkyl
- loweralkyl
- heterocyclic
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/52—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/08—Bridged systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
Abstract
Disclosed are compounds of formula (I), (II) or (III), which are useful for inhibiting neuraminidases from disease-causing microorganisms, especially, influenza neuraminidase. Also disclosed are compositions and methods for preventing and treating diseases caused by microorganisms having a neuraminidase, processes for preparing the compounds and synthetic intermediates used in these processes.
Description
Inhibitors of Neuraminidases Technical Field The present invention relates to novel compounds, compositions and methods for inhibiting neuraminidase, especially influenza neuraminidase. The invention also contemplates a composition and methods for preventing and treating an influenza infection and processes for making such compounds and synthetic intermediates employed in these processes.
Background of the Invention Many disease-causing microorganisms possess a neuraminidase neuraminidase (also known as sialidase) which is involved in the replication process of the microorganism. In particular, viruses of the orthomyxovirus and paramyxovirus groups possess a neuraminidase. Diseases associated with paramyxoviruses include RSV (respiratory syncytial virus-related diseases), pneumonia and bronchiolitis (associated with paramyxovirus type 3) and laryngotracheobronchitis (associated with paramyxovirus type 1 ). Some of the more important disease-causing microorganisms in man and/or animals which possess a neuraminidase include Vibrio cholerae, Clostridium perfringens, Streptococcus pneumoniae, Arthrobacter sialophilus, influenza virus, parainfluenza virus, mumps virus, Newcastle disease virus, fowl plague virus, equine influenza virus and Sendai virus.
Mortality due to influenza is a serious problem throughout the world. The disease is devastating to man, lower mammals and some birds. Although vaccines containing attenuated influenza virus are available, those vaccines only provide immunological protection toward a few influenza strains and are less effective in otherwise immunologically compromised populations such as the elderly, young children, and in those who suffer from chronic respiratory illness.
The productivity loss from absence due to sickness from influenza virus infection has been estimated to be more than $1 billion per year.
There are two major strains of influenza virus (designated A and B).
Currently, there are only a few pharmaceutical products approved for treating influenza. These include amantadine and rimantadine, which are active only against the A strain of influenza viruses, and ribavirin, which suffers from dose-limiting toxicity. Mutant virus which is resistant to amantadine and rirnantadine emerges quickly during treatment with these agents.
Neuraminidase is one of two major viral proteins which protrude from the envelope of influenza virus. During the release of progeny virus from infected cells, neuraminidase cleaves terminal sialic acid residues from glycoproteins, glycalipids and oligosaccharides on the cell surface. Inhibition of neuraminidase enzymatic activity leads to aggregation of progeny virus at the surface. Such virus is incapable of infecting new cells, and viral replication is therefore retarded or blocked. X-ray crystallographic studies and sequence alignments have shown that the residues which directly contact the sialic acid portion of the substrate are strictly conserved in the neuraminidase from all A and B influenza strains.
Thus, a compound which binds to the sialic acid binding region of the neuraminidase active site will block the replication of both the A and B strains of influenza virus.
Compounds which are influenza neuraminidase inhibitors will be useful for the _2_ prevention of influenza infection and will be useful for the treatment of influenza infection.
Y. Babu, et al., International Patent Application No. W097/47194, published December 18, 1997 discloses substituted cyclopentanes which are useful as neuraminidase inhibitors and treatments for influenza.
The following references disclose neuraminic acid derivatives with the disclosed utility listed after each reference:
L. Von Itzstein, et al., European Patent Application No. EP539204, published April 28, 1993 (antiviral agent);
T. Honda, et al., European Patent Application No. EP823428, published February 11, 1998 (sialidase inhibitor; influenza treatment);
T. Honda, et al., International Patent Application No. W098/06712, published February 19, 1998 {sialidase inhibitor; influenza remedy);
L. Von Itzstein, et al., International Patent Application No. W095/20583, published August 3, 1995 (viral neuraminidase inhibitor; influenza treatment);
P. Smith, International Patent Application No. W095I18800, published July 13, 1995 (viral neuraminidase inhibitor);
P. Colman, et al., International Patent Application No. W092/06691, published April 30, 1992 (viral neuraminidase inhibitor);
L. Von Itzstein, et al., U.S. Patent No. 5,648,379, issued July 15, 1997 (influenza treatment);
P. Reece, et al., International Patent Application No. W097/32214, published September 4, 1997 (bind to influenza virus neuraminidase active site); and P. Reece, et al., International Patent Application No. W098/21243, published May 23, 1998 (anti-influenza agent).
The following references disclose sialic acid derivatives with the disclosed utility fisted after each reference:
Y. Ohira, et al., International Patent Application No. W098/11083, published March 19, 1998 (antiviral agent);
Y. Ohira, European Patent Application No. EP882721, published December 9, 1998 (antiviral agent); and B. Glanzer, et al., Helvetica Chimica Acta 74 343-369 (1991 ) (Vibrio cholerae neuraminidase inhibitor).
The following references disclose benzene derivatives, cyclohexane derivatives or cyclohexene derivatives with the disclosed utility listed after each reference:
Y. Babu, et al., U.S. Patent No. 5,602,277, issued February 11, 1997 (neuraminidase inhibitors);
M. Luo, et al., U.S. Patent No. 5,453,533, issued September 26, 1995 (influenza neuraminidase inhibitor; influenza treatment);
Y. Babu, et al., International Patent Application No. W096/30329, published October 3, 1996 (neuraminidase inhibitor; viral infection treatment);
N. Bischofberger, et al., U.S. Patent No. 5,763,483, issued June 9, 1998 (neuraminidase inhibitor); and K. Kent, et al., International Patent Application No. 98/07685, published February 26, 1998 (intermediates for the preparation of neuraminidase inhibitors).
C. Kim, et al., International Patent Application No. W098/17647, published April 30, 1998 discloses piperidine derivatives which are useful as neuraminidase inhibitors.
N. Bischofberger, et al., international Patent Application No. W096/26933, published September 6, 1996 discloses various substituted 6-membered ring compounds which are useful as neuraminidase inhibitors.
The following references disclose dihydropyran derivatives which are useful as viral neuraminidase inhibitors:
D. Andrews, et al., International Patent Application No. W097/06157, published February 20, 1997; and P. Cherry, et al., International Patent Application No. W096/36628, published November 21, 1996.
C. Kim, et al., U.S. Patent No. 5,512,596, issued April 30, 1996 discloses 6-membered aromatic ring derivatives which are useful as neuraminidase inhibitors.
G. Diana, et al., International Patent Application No. W098/03487, published January 29, 1998 discloses substituted pyridazines which are useful for treatment of influenza.
B. Horenstein, et al., International Patent Application No. W099/06369, published February 11, 1999 discloses piperazine derivatives which are useful as neuraminidase inhibitors.
L. CZOllner, et al., Helvetica Chimica Acta 73 1338-1358 (1990) discloses pyrrolidine analogs of neuraminic acid which are useful as Vibrio cholerae sialidase inhibitors.
The following references disclose siastatin B analogs which are useful as neuraminidase inhibitors:
Y. Nishimura, et al., Natural Product Letters 1 39-44 (1992); and Y. Nishimura, et al., Natural Product Letters 1 33-38 (1992).
C. Penn, UK Patent Application No. GB2292081, published February 14, 1996 discloses the use of a neuraminidase inhibitor in combination with an infiuenza vaccine.
An object of the invention is to provide compounds which inhibit neuraminidase of disease-causing microorganisms; especially, viral neuraminidase; and, most especially, influenza neuraminidase.
An object of the invention is also to provide compounds which inhibit neuraminidase from both A and B strains of influenza.
Another object of the invention is to provide prohylaxis of influenza infection in humans and other mammals.
Another object of the invention is to provide treatment of influenza infection in humans and other mammals.
Another object of the invention is to provide compounds which exhibit activity against influenza A virus and and influenza B virus by virtue of inhibiting influenza neuraminidase when such compounds are administered orally.
Another object of the invention is to provide a compound which can be effectively transported from the plasma into the lung bronchoaveolar fluid of humans and other mammals in order to block the replication of influenza virus in that tissue.
Disclosure of the Invention The present invention discloses compounds having Formula I, II or III
Y
Rio Rs Z R~
Ra R' Y.
R1o R2-X ~ 1 ( ~ R
R4 ( R7 s Y
R1o ~ 1 R
R2-X, R4 / ~ R7 ~5 or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R' is selected from the group consisting of (a) -C02H, (b) -CH2C02H, (c) -S03H, (d) -CH2S03H, (e) -S02H, (f) -CH2S02H, (g) -P03H2, (h) -CH2P03H2, (i) -P02H, (j) -CH2P02H, (k) tetrazolyl, (I) -CH2-tetrazolyl, (m) -C(=O)-NH-S(O)2-R", (n) -CH2C(=O)-NH-S(O)2-R", (o) -S02N(T-R")R'Z and (p) -CH2S02N(T-R")R'2 wherein T is selected from the group consisting of (i) a bond, (ii) -C(=O)-, (iii) -C(=O)O-, (iv) -C(=O)S-, (v) -C(=O)NR3s-, (vi) -C(=S)O-, (vii) -C(=S)S-, and (viii) -C(=S)NR3s-, R"~ is selected from the group consisting of (i) C~-C~2 alkyl, (ii) C2-C~2 alkenyl, (iii) cycloalkyl, (iv) (cyclo-alkyl)alkyl, (v) (cycloalkyl)alkenyl, (vi) cycloalkenyl, (vii) (cycloalkenyl)alkyl, (viii) (cycloalkenyl)alkenyl, (ix) aryl, {x) (aryl)alkyl, (xi) (aryl)alkenyl, (xii) heterocyclic, (xiii) (heterocyclic)alkyl and (xiii) (xiv) (heterocyclic)alkenyl; and R'2 and R3s are independently selected from the group consisting of (i) hydrogen, (ii) C,-C~2 alkyl, (iii) C2-C~2 alkenyl, (iv) cycloalkyl, (v) (cycloalkyl)alkyl, (vi) (cycloalkyl)alkenyl, (vii) cycloalkenyl, (viii) (cycloalkenyl)alkyl, (ix) (cycloalkenyl)alkenyl, (x) aryl, (xi) (aryl)alkyl, (xii) (aryl)alkenyl, (xiii) heterocyclic, (xiv) (heterocyclic)alkyl and (xv) (heterocyclic)alkenyl;
X is selected from the group consisting of (a) -C(=O)-N(R*)-, (b) -N(R*)-C(=O)-, (c) -C(=S)-N(R*)-, (d) -N(R*)-C(=S)-, (e) -N(R*)-S02-, and (f) -S02-N(R*)- wherein R* is hydrogen, C~-C3 loweralkyl or cyclopropyl;
R2 is selected from the group consisting of (a) hydrogen, (b) C~-Cs alkyl, (c) C2-Cs alkenyl, (d) C3-Cs cycloalkyl, (e) CS-Cs cycloalkenyl, (f) halo C~-Cs alkyl and (g) halo CZ-Cs alkenyl;
or Rz-X- is _g_ ,o Y~' wherein Y' is -CHZ-, -O-, -S- or -NH- and Y2 is -C(=O)- or -C(Raa)(Rbb)-wherein Raa and Rbb are indepedently selected from the group consisting of hydrogen, C~-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl;
Z' Is -O-, -S-, Of C(R5)2;
R3 and R4 are independently selected from the group consisting of (a) hydrogen, (b) cycloalkyl, (c) cycloaikenyl, (d) heterocyclic, (e) aryl and (~ -Z-R'a wherein Z is (i) -C(R37a)(R37b)- (ii) -C(R47)=C(R48)- (jll) -C=C-, (IV) -C(=O)-, (v) -C(=S)-, (vi) -C(=NR'S)-, (vii) -C(Rs'a)(OR3'c)_, (viii) _ C(Rs~a)(SRs~c)-(iX) _C(R37a)(N(R37b)(R37c))_~ (X) -C(R37a)(R37b)-(~-(Xi) _C(R3~a)(Rs~b)-N(R37c)-, (Xii) -C(R3~a)(Rs~b)_N(O)(Rs~c)-, (xiii) -C(Rs'a)(Rs'b)-N(OH)-, (xiv) -C(R37a)(R37b)-S-(~) -C(R37a)(R37b)-S(O)_, (XVI) -C(R37a)(R37b)-S(0)2-_g-(XVII) -C(R37a)(R37b)-C(=O)-, (XVItI) -C(R37a)(R37b)-C(=S)-~ .
(xix) -C(Rs~a)(Rsm)-C(=NR~5)-, (xx) -C(R3~a)(ORs~c)-C(=O)-, (Xxl) -C(R3~a)(SR37c)-C(=O)- (Xxii) -C(Rs~a)(~R3~c)-C(=S)-(xxiii) -C(R3~a)(SRs~c)-C(=S)-, (xxiv) -C(=O)-C(Rs~a)(ORs~~)-, (xxv) -C(=O)-C(Rs~a)(SRs~c)-, (xxvi) -C(=S)-C(R3~a)(OR3~c)-, (xxvii) -C(=S)-C(Rs~a)(SRs~c)-, (Xxviii) -C(Rs~a)(OFts~c)-C(Rs~a)(ORs~c)-, (xxix) -C(Rs~a)(SRs~c)-C(R3~a)(ORs~c)-, (xxx) -C(Rs~a)(ORs7c)-C(R3~a)(SRs~c)-(xxxi) -C(Rs~a)(SRs~c)-C(R3~a)(SR3~c)-, (Xxxii) -C(=O)-C(=O)-, (xxxiii) -C(=S)-C(=S)-, (xxxiv) -C(=O)-O-, (xxxv) -C(=O)-S-, (xxxvi) -C(=S)-O-, (xxxvii) -C(=S)-S-, (xxxviii) -C(=O)-N(R3'a)-, (xxxix) -C(=S)-N(Rs~a)-, (x~) -C(R3~a)(Rs7b)-C(=O)-N(Rs~a)-, (X~I) -C(Rs~a)(Rs~b)-C(=S)-N(Rs~a)-, (x~ll) -C(R37a)(R37b)-C(=O)-O-(X~III) -C(R37a)(R37b)-C(=O)-S-, (x~IV) -C(R37a)(R37b)-C(=S)-O-(X~V) -C(R37a)(R37b)-C(=S)-S-, (X~VI) -C(R37a)(R37b)-N(R37b)-C(=O)-, (X~VII) -C(Rs~a)(Rs~b)-N(R37b)-C(=S)-, (Xwlll) -C(R37a)(R37b)-O-C(=O)-(xilx) -C(R37a)(R37b)-S-C(=O)-~ (i) -C(R37a)(R37b)-O-C(=S)-(Ii) -C(R37a)(R37b)-S-C(=S)-~ (iii) -C(Rs~a)(R3~b)-N(Rs~b)-C(=~)-N(Rs~a)-, (liii) -C(R37a)(Rs~b)-N(R37b)-C(=S)-N(Rs~a)-, (IIV) -C(R37a)(R37b)-N(R37b)-C(=O)-O-(Iv) _C(R37a)(R37b)-N(R37b)-C(=O)-S-(IVI) -C(R37a)(R37b)-N(R37b)-C(=S)-O-(IVII) -C(R37a)(R37b)-N(R37b)-C(=S)-S-(Iviii) -C(R3'a)(R3~b)-O-C(=O)-N(R3'a)-, (lix) -C(Rs~a)(R3~n)-S-C(=O)-N(R3~a)-, (Ix) _C(Rs~a)(Rs~b)-O-C(=S)-N(Rs~a)-, (IXI) -C(Rs~a)(Rs~b)-S-C(=S)-N(Rs~a)-, (1X11) -C(R37a)(R37b)-O-C(=O)-O-(1X111) -C(Rs~a)(R37b)-S-C(=O)-O-, (IXIV) -C(Rs~a)(R37b)-~-C(=O)-S-, (IXV) -C(R37a)(R37b)-S-C(=O)-S-~ (IXVI) -C(R37a)(R37b)-~-C(=S)-~-(IXVII) -C(R37a)(R37b)-S-C(=S)-O-, (IxVlll) -C(R37a)(R37b)-~-C(= ,~~~, )-S-(IXIX) -C(R37a)(R37b)-S-C(=S)-S- Or (IXX) -C(R37a)(R37b)-C(R37a)(OR37c)-_ R' 4 is (i) hydrogen, (ii) C1-C~2 alkyl, (iii) haloalkyl, (iv) hydroxyalkyl, (v) thiol-substituted alkyl, (vi) R3'°O-substituted alkyl, (vii) R3'°S-substituted alkyl, (viii) aminoalkyl, (ix) (R3'°)NH-substituted alkyl, (x) (R3'a)(R3~')N_susbstituted alkyl, (xi) R3'a0-(O=)C-substituted alkyl, (xii) R3'aS-(O=)C-substituted alkyl, (xiii) R3'a0-(S=)C-substituted alkyl, (xiv) R3'aS-(S=)C-substituted alkyl, (xv) (R3'a0)2-P(=O)-substituted alkyl, (xvi) cyanoalkyl, (xvi) CZ-C~z alkenyl, (xviii) haloalkenyl, (xix) C2-C~2 alkynyl, (xx) cycloalkyl, (xxi) (cycloalkyl)alkyl, (xxii) (cycloalkyl)alkenyl, (xxiii) (cycloalkyl)alkynyl, (xxiv) cycloalkenyl, (xxv) (cycloalkenyl)alkyl, (xxvi) (cycloalkenyl)alkenyl, (xxvii) (cycloalkenyl)alkynyl, (xxviii) aryl, (xxix) (aryl)alkyl, (xxx) (aryl)alkenyl, (xxxi) (aryl)alkynyl, (xxxii) heterocyclic, (xxxiii) (heterocyclic)alkyl, (xxxiv) (heterocyclic)alkenyl or (xxxv) (heterocyclic)alkynyl, with the proviso that R'4 is other than hydrogen when Z is _C(R37a)(R37b)-N(R37b)-C(=O)-O- -C(R37a)(R37b)-N(R37b)-C(=S)-O-TC(R37a)(R37b)-N(R37b)-C(=O)-S- _C(R3~a)~R3~b)-N(Rs~b)-C(=S)-S-_C(R37a)(R37b)-O-C(=O)-O- _C(R37a)(R37b)-O-C(=S)-O-'C(R37a)(R37b)-S-C(=O)-O- rC(R37a)(R37b)-S-C(-S)-O-!C(R37a)(R37b)-O-C(=O)-S- ~C(Rs~a)(Rs~b)-~-C(=S)-S-_C(R37a)(R37b)-S-C(=O)-S- ~r _C(R37a)(R37b)-S-C(=S)-S-Rs~a, R37b Ray, and R4$ at each occurrence are independently selected from the group consisting of (i) hydrogen, (ii) Ci-C~2 alkyl, (iii) haloalkyl, (iv) hydroxyalkyl, (v) alkoxyalkyl, (vi) C2-C~2 alkenyl, (vii) haloalkenyl, (viii) C2-C~2 alkynyl, (ix) cycloalkyl, (x) (cycloalkyl)alkyl, (xi) (cycloalkyl)alkenyl, (xii) (cycloalkyl)alkynyl, (xiii) cycloalkenyl, {xiv) (cycloalkenyl)alkyl, (xv) (cycloalkenyl)-alkenyl, (xvi) (cycloalkenyl)alkynyl, (xvii) aryl, (xviii) (aryl)alkyl, (xix) (aryl)alkenyl, (xx) (aryl)alkynyl, (xxi) heterocyclic, (xxii) (heterocyclic)alkyl, (xxiii) (heterocyclic)alkenyl and (xxiv) (heterocyclic)alkynyl;
R3'' at each occurrence is independently selected from the group consisting of (i) hydrogen, (ii) C~-C~z alkyl, (iii) haloalkyl, {iv) C2-C~2 alkenyl, (v) haloalkenyl, (vi) C2-C~2 alkynyl, (vii) cycloalkyl, (viii) (cycloalkyl)alkyl, (ix) (cycloalkyl)alkenyl, (x) (cycloalkyl)alkynyl, (xi) cycloalkenyl, (xii) (cycloalkenyl)alkyl, (xiii) (cycloalkenyl)alkenyl, (xiv) (cycloalkenyl)alkynyl, (xv) aryl, (xvi) (aryl)alkyl, (xvii) (aryi)alkenyl, (xviii) (aryl)alkynyl, (xix) heterocyclic, (xx) (heterocyclic)alkyl, (xxi) (heterocyclic)alkenyl, (xxii) (heterocyclic)alkynyl, (xxiii) -C(=O)-R'4, (xxiv) -C(=S)-R'4, (xxv) -S(O)2-R'4 and (xxvi) hydroxyalkyl;
or when Z is -C(R3'a)(R3'b)-N(R3'c)-, then N(R3'') and R'4 when taken together are an azido group;
or when Z is -C(R3'a)(R3~b)-N(O)(R3'°)-, then N(O)(R3~') and R'4 when taken together are an N-oxidized 3-7 membered heterocyclic ring having at least one N-oxidized ring nitrogen atom;
or when Z is -C(R3~a)(OR3~c)-, --C(R3~a)(SRs'c)- or -C(R3~a)(N(R3'b)(R3'c))_, then R3~a, R'4 and the carbon atom to which they are bonded when taken together form a cyclopentyl, cyclopentenyf, cyclohexyl or cyclohexenyl ring;
R'~ is selected from the group consisting of (i) hydrogen, (ii) hydroxy, (iii) amino, (iv) C~-C~2 alkyl, (v) haloalkyl, (vi) C2-C~2 alkenyl, (vii) haloalkenyl, (viii) cycloalkyl, (ix) (cycloalkyl)alkyl, (x) (cycloalkyl)alkenyl, (xi) cycloalkenyl, (xii) (cycloalkenyl)alkyl, (xiii) (cycloalkenyl)alkenyl, (xiv) aryl, (xv) (aryl)alkyl, (xvi) (aryl)alkenyl, (xvii) heterocyclic, (xviii) (heterocyclic)alkyl and (xix) (heterocyclic)alkenyl;
or R3 and R4 taken together, with the atom to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 8 ring atoms;
R~ at each occurrence is independently selected from the group consisting of (a) hydrogen, (b) -CH(R3$)2, (c) -(CH2),-O-R4°, (d) C2-C4 alkynyl, (e) cyclopropyl, (f) cyclobutyl, (g) -C(=Q')-R", and (h) -(CHZ)~-N(R'9)2 wherein r is 0, 1 or 2; with the proviso that when one R5 is -O-R4° or -N(R'9)2, then the other R5 is other than -O-R4° or -N(R'9)2;
wherein Q' is O, S, or N(R'B);
R" and R'8 are independently selected, at each occurrence, from the group consisting of hydrogen, methyl, and ethyl;
R'9, R38, and R4° are independently selected, at each occurrence, from the group consisting of (i) hydrogen, (ii) C,-C~2 alkyl, {iii) haloalkyl, (iv) Cz-C,2 alkenyl, (v) haloalkenyi, (vi) cycloalkyl, (vii) (cycioalkyl)alkyl, (viii) (cycloalkyl)alkenyl, (ix) cycloalkenyl, (x) (cycloalkenyl)alkyl, (xi) (cycloalkenyl)alkenyl, {xii) aryl, (xiii) (aryl)alkyl, (xiv) (aryl)alkenyl, (xv) heterocyclic, (xvi) (heterocyclic)alkyl and (xvii) (heterocyclic)alkenyl;
or one R~9 is an N-protecting group;
or the two R~ groups taken together with the carbon atom to which they are bonded, form a carbocyclic or heterocyclic ring having from 3 to 6 ring atoms;
Y is selected from the group consisting of (a) C~-C5 alkyl, (b) C,-C5 haloalkyl, (c) C2-C5 alkenyl, (d) C2-C5 haloalkenyl, (e) CZ-C5 alkynyl, (f) C3-C5 cycloalkyl, (g) C3-C5 cycloalkyl-C~-to-C3-alkyl, (h) C5 cycloalkenyl, (i) C5 cycloalkenyl-C~-to-C3-alkyl, (j) C5 cycloalkenyl-C2-to-C3-alkenyl, (k) -(CHR39)~OR2°, (I) -CH(OR2°)-CHz(OR2°), (m) -(CHR39)~SR2', (n) phenyl, (o) halo-substituted phenyl, {p) -(CHR39)~C(=Q2)R22, {q) -(CHR39)~N(=Q3), (r) -N(O)=CHCH3, (s) -(CHR39)~N(CH3)R24 and (t) a heterocyclic ring having from 3 to 6 ring atoms;
wherein n is 0, 1, or 2; Q2 is O, S, NRZ5, or CHR26; and Q3 is NR4', or CHR42;
R2° at each occurrence is independently (i) methyl, (ii) ethyl, (iii) n-propyl, (iv) isopropyl, (v) C~-C3 haloalkyl, (vi) vinyl, (vii) propenyl, (viii) isopropenyl, (ix) ally!, (x) C2-C3 haloalkenyl, (xi) amino, (xii) -NHCH3, (xiii) -N(CH3)2, (xiv) -NHCH2CH3, (xv) -N(CH3)(CH2CH3), (xvi) -N(CH2CH3)2 or (xvii) -N(=CH2);
R2' is (i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl, (vi) C,-C3 haloalkyl, (vii) vinyl, (viii) propenyl, (ix) isopropenyl, (x) ally! or (xi) C2-C3 haloalkenyl;
RZ2 is (i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl, (vi) hydroxy, (vii) thiol, (viii) methoxy, (ix) ethoxy, (x) n-propoxy, (xi) isopropoxy, (xii) cyclopropyloxy, (xiii) methylthio, (xiv) ethylthio, (xv) n-propylthio, (xvi) isopropylthio, {xvii) cyclopropylthio, (xviii) vinyl, (xix) propenyl, (xx) isopropenyl, (xxi) ally!, (xxii) -N(R28a)(RZSb), (xxiii) -CH2Rz9, (xxiv) aminomethyl, (xxv) hydroxymethyl, (xxvi) thiolmethyl, (xxvii) -NHNH2, (xxviii) -N{CH3)NH2 or (xxix) -NHNH(CH3);
R23 and R39 are independently hydrogen or methyl;
R4' and R42 are independently hydrogen, methyl, or ethyl;
R24 is selected from the group consisting of (i) hydrogen, (ii) C~-C4 alkyl, (iii) C2-C4 alkenyl, (iv) C2-C4 alkynyl, (v) cyclopropyl, (vi) -C{=Q4)-R3°, (v) -OR3', and (vi) -N(R3Z)2, wherein Q4 is O, S, or N(R3s);
Rz5 is hydroxy, methyl, ethyl, amino, -CN, or -N02;
R26 group is hydrogen, methyl or ethyl ;
RZ8a hydrogen, hydroxy, methyl, ethyl, amino, -NHCH3, -N(CH3)2, methoxy, ethoxy, or -CN;
RZ8b is hydrogen, methyl or ethyl;
or RZaa, RZab and the nitrogen to which they are bonded taken together represent azetidinyl;
R29 group is hydrogen, hydroxy, thiol, methyl, ethyl, amino, methoxy, ethoxy, methylthio, ethylthio, methylamino or ethylamino;
R3° group is hydrogen, methyl, ethyl, -OR3'°, -SR34, -N(R35)z, -NHOH, -NHNH2, -N(CH3)NHZ, or -N(CHZCH3)NH2;
R3' and R32 substituents, at each occurrence, are independently hydrogen, methyl or ethyl;
R33 group is hydrogen, hydroxy, methyl, ethyl, amino, -CN, or -N02;
R34 group is methyl or ethyl;
R35 group is independently hydrogen, methyl or ethyl;
with the proviso that when Qz is CHRzs then Rzz is selected from the group consisting of hydrogen, -CH3, -CZH$, -C3H~, -OCH3, -SCH3, -O-CZH5, and -S-CzHs;
Rs and R' are independently selected from the group consisting of (a) hydrogen, (b) C~-C~z alkyl, (c) Cz-C~2 alkenyl, (d) cycloalkyl, (e) (cycloalkyl)alkyl, (f) (cycloalkyl)alkenyl, (g) cycloalkenyl, (h) (cycloalkenyl)alkyl, (i) (cycloalkenyl)alkenyl, (j) aryl, (k) (aryl)alkyl, (I) (aryl)alkenyl, (m) heterocyclic, (n) (heterocyclic)alkyl, (o) (heterocyclic)alkenyl, (p) -OR~'a and (q) -N(R3'a)z; and R8, R9, and R'° are independently selected from the group consisting of (a) hydrogen, (b) C~-C6 alkyl, (c) Cz-C6 alkenyl, (d) C3-C6 cycloalkyl, (e) C3-C6 cycloalkenyl, and (f) fluorine, with the proviso that the total number of atoms, other than hydrogen, in each of R8, R9, and R'°, is 6 atoms or less.
Preferred compounds of the invention include compounds wherein R3 and R4 are not the same and which have the relative stereochemistry depicted by Formula IV, V, Vl, Vll, VIII or IX:
R9 .R8 ., R9 Rs R1o \ _Rs R1o Rs R2-.X Z1~...,,,,.~R1 R2'_X~~~'~~. Z1 °~'~~R1 R4 ~ R7 Ra ~ R7 R3 Rs IV V
R8 Yes.. /R
R~ o ..,.
Rio ~ R~
R~ R2-X
R2-X~~.,,,. a R~
Ra ~ R~ ~s ERs R ~ 3 ~5 R
R R R
VI VII
R
R9 Q$ .. R .
Rio ~ Rio R~
R2 -X~~.,,,.
Ra ~ R~ (s Ra Is R R5 VIII IX
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R', R2, R3, R4, R5, R6, R', R8, R9, R'°, X , Y and Z' are as defined above.
Other preferred compounds of the invention are compounds having Formula I, I1, III, IV, V, VI, VII, VIII or IX or a salt, ester or prodrug thereof wherein R' is defined as above;
-X-R2 is RZ-C(=O)-NH-, R2-NH-C(=O)-, RZ-NH-SO~- or R2-S02-NH-wherein R2 is C,-C3 loweralkyl, halo C~-C3 loweralkyl, C2-C3 alkenyl or halo alkenyl or -X-R2 is ~o Y~
\ ~N_~_ Yz wherein Y' is -CHZ-, -O-, -S- or -NH- and Y2 is -C(=O)- or -C(Raa)( Rbb)-wherein Raa and Rbb are independently selected from the group consisting of hydrogen, C~-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and -Z-R'4 wherein Z and R'4 are defined as above and wherein one of R3 and R4 is other than hydrogen;
Z' is -O-, -S- or -CH(R5)- wherein R5 is hydrogen, loweralkyl or -(CH2)~N(R'9)2 wherein r and R,9 are defined as above; or R5 is hydrogen, loweralkyl or -(CH2)~N(R'9)2 wherein r and R~9 are defined as above;
R6 and R' are independently hydrogen or loweralkyl;
R8 and Rg are independently hydrogen, fluoro or loweralkyl;
R'° is hydrogen, fluoro or loweralkyl; and Y is C2-C5 alkenyl, C2_C5 haloalkenyl, -C(=Qz)R22, -N(=Q3), -N(O)=CHCH3, -NR23R2a or a heterocyclic ring having from 3 to 6 ring atoms, wherein R22, R23, RZa, Q2 and Q3 are defined as above.
More preferred compounds of the invention are compounds having Formula I, II, III. 1V, V, VI, VII, VIII or IX or a salt, ester or prodrug thereof wherein R' is defined as above;
-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-S02- or R2-SOZ-NH-wherein R2 is C~-C3 loweralkyl, halo C~-C3 loweralkyl, C2-C3 alkenyl or halo alkenyl or -X-R2 is O
Y~
,N-wherein Y' is -CH2- and Y2 is -C(=O)- or -C(Raa)( Rbb)- wherein Raa and Rbb are independently selected from the group consisting of hydrogen, C~-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and -Z-R'4 wherein Z and R'4 are defined as above and wherein one of R3 and R4 is other than hydrogen;
Z' is -O-, -S- or -CH(R5)- wherein R5 is hydrogen, loweralkyl or -(CH2)~N(R'9)Z wherein r and R'9 are defined as above; or R5 is hydrogen, loweralkyl or-(CH2)~N(R'9)2 wherein r and R'9 are defined as above;
Rs and R' are independently hydrogen or loweralkyl;
R$ and R9 are independently hydrogen or loweralkyl;
R'° is hydrogen or loweralkyl; and Y is C2-C~ alkenyl, Cz_C5 haloalkenyl, -C(=QZ)R22, -N(=Q3), -N(O)=CHCH3 or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds, wherein R22, Q2 and Q3 are defined as above.
Even more preferred compounds of the invention are compounds having Formula Formula I, II, 111, IV, V, VI, VII, VIII or IX or a salt, ester or prodrug thereof wherein R' is defined as above;
-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SOZ- or R2-SOZ-NH-wherein R2 is C~-C3 loweralkyl, halo C~-C3 loweralkyl, CZ-C3 alkenyl or halo C~-C3 alkenyl or -X-R2 is O
Y~
,N-wherein Y' is -CH2- and Y2 is -C(=O)- or -C(Raa)( Rbb)- wherein Raa and Rbb are independently selected from the group consisting of hydrogen, C~-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and -Z-R'4 wherein Z and R'4 are defined as above and wherein one of R3 and R4 is other than hydrogen;
Z' is -O-, -S- or -CH(R5)- wherein R5 is hydrogen, loweralkyl or -(CHZ)~N(R'9)2 wherein r and R~9 are defined as above; or R5 is hydrogen, loweralkyl or -(CH2)~N(R'9)2 wherein r and R~9 are defined as above;
R6 and R' are independently hydrogen or loweralkyl;
R$ and R9 are independently hydrogen or loweralkyl;
R'° is hydrogen or loweralkyl; and Y is C2-C5 alkenyl, C2_C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
More highly preferred compounds of the invention are compounds having Formula I, II, III, IV, V, VI, VII, VIII or IX or a salt, ester or prod rug thereof wherein R' is -C02H;
-X-Rz is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-S02- or RZ-S02-NH- wherein Rz is C,-C3 loweralkyl or halo- C~-C3 loweralkyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and -Z-R'4 wherein Z and R'4 are defined as above and wherein one of R3 and R4 is other than hydrogen;
Z' is -O-, -S- or -CH2-; or R5 is hydrogen;
R6 and R' are independently hydrogen or loweralkyl;
Ra and R9 are hydrogen independently hydrogen or loweralkyl;
R'° is hydrogen or loweralkyl; and Y is C2-C5 alkenyl, C2_C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
Even more highly preferred compounds of the invention are compounds having Formula l, II, III, IV, V, VI, VII, VIII or IX or a salt, ester or prodrug thereof wherein R' is -C02H;
-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-S02- or R2-S02-NH- wherein R2 is C,-C3 loweralkyl or halo- C,-C3 ioweralkyl;
R4 is hydrogen or loweralkyl and R3 is heterocyclic or -Z-R'4 wherein Z
and R'4 are defined as above;
Z' is -O-, -S- or -CH2-; or R5 is hydrogen;
Rs and R' are hydrogen;
R$ and R9 are hydrogen;
R'° is hydrogen; and Y is C2-C5 alkenyl, C2_C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
Other even more highly preferred compounds of the invention are compounds having Formula I, II, Ill, IV, V, VI, VII, VIII or IX or a salt, ester or prodrug thereof wherein R' is -C02H;
-X-R2 is R2-C(=O)-NH-, RZ-NH-C(=O)-, RZ-NH-S02- or RZ-S02-NH- wherein RZ is C~-C3 loweralkyl or halo C~-C3 loweralkyl;
R4 is hydrogen or loweralkyl and R3 is (a) heterocyclic, (b) alkyl, (c) cycloalkyl, (d) cycloalkylalkyl, (e) alkenyl, (f) alkynyl, (g) -C(=O)-R'4, (h) -C(Rs~a)(OR3~c)-R,a or (i) -C(Rs~a)(Rs~b)-N(O)(R3~c)R~4 wherein R'4 is (i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl, (vi) haloalkenyl, (vii) aryl, (viii) arylaikyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R3'a0)-(O=)C-substituted alkyl or (xv) (R3~a0)2-P(=O)-substituted alkyl;
R3'a and R3'b are independently selected from the group consisting of (i) hydrogen, (ii) loweralkyl and (iii) loweralkenyl; and Rs~o is hydrogen, (ii) ioweralkyl or (iii) loweralkenyl;
Z' is -O-, -S- or -CH2-; or R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen;
R'° is hydrogen; and Y is C2-C5 alkenyl, C2_C5 haloalkenyi or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
Most highly preferred compounds of the invention are compounds having Formula I, II, III, IV, V, V1, VII, VIII or IX or a salt, ester or prodrug thereof wherein R' is -C02H;
-X-Rz is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-S02- or R2-SOZ-NH- wherein R2 is C,-C3 loweralkyl or halo C,-C3 loweralkyl;
R4 is hydrogen and R3 is (a) heterocyclic, (b) alkyl or (c) -C(R3'a)(OR3'°)-R'4 wherein R'4 is (i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl, (vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R3~a0)-(O=)C-substituted alkyl or (xv) (R3'a0)2-P(=O)-substituted alkyl;
R3'a and R3'b are independently selected from the group consisting of (i) hydrogen, (ii) loweralkyl and (iii) loweralkenyl; and R3'' is hydrogen, (ii) C~-C3 loweralkyl or (iii) allyl;
Z' is -O-, -S- or -CH2-; or R5 is hydrogen;
R6 and R' are hydrogen;
R8 and R9 are hydrogen ;
R'° is hydrogen; and Y is C2-C5 alkenyl, C2_C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
Other most highly preferred compounds of the invention are compounds having Formula I, II, III, IV, V, VI, VII, VIII or 1X or a salt, ester or prodrug thereof wherein R' is -C02H;
-X-RZ is Rz-C(=O)-NH- or R2-SOZ-NH- wherein R2 is C,-C3 loweralkyl or halo C~-C3 loweralkyl;
R4 is hydrogen and R3 is (a) heterocyclic, (b) alkyl or (c) -C(R3'a)(OR3'c)-R'4 wherein R'4 is (i) loweralkyl, (ii) loweralkenyl, (iii) hydroxy-substituted loweralkyl or (iv) alkoxy-substituted loweralkyl;
R37a jS
(i) hydrogen, (ii) loweralkyl or (iii) loweralkenyl; and R3'' is (i) hydrogen, (ii) C~-C3 loweralkyl or (iii) allyl;
Z' is -O-, -S- or -CH2-; or R5 is hydrogen;
R6 and R' are hydrogen;
R8 and R9 are hydrogen;
R'° is hydrogen; and Y is C2-C5 alkenyl, CZ_C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
Other most highly preferred compounds of the invention are compounds having Formula I, II, III, IV, V, VI, VII, VIII or IX or a salt, ester or prodrug thereof wherein R' is -C02H;
-X-Rz is R2-C(=O)-NH- or R2-S02-NH- wherein R2 is C~-C3 loweralkyl or halo C~-C3 loweralkyl;
R4 is hydrogen and R3 is -C(R3~a)(OR3'')-R'4 wherein R'4 is loweralkyl or loweralkenyl;
R37a jS
loweralkyl or loweralkenyl; and R3~~ is hydrogen, C,-C3 loweralkyl or allyl;
Z' is -O-, -S- or -CHZ-; or R5 is hydrogen;
R6 and R' are hydrogen;
R8 and R9 are hydrogen;
R'° is hydrogen; and Y is C2-C5 alkenyl, C2_C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
Preferred substituents R' include -C02H or esters or prodrugs thereof.
Preferred esters include C2-C6 loweralkyl esters or substituted or unsubstituted benzyl esters. Preferred substituents R' also include-S(O)2NHC(=O)R"
wherein R" is defined as above.
Most highly preferred substituents R' include -C02H or esters or prodrugs thereof. Most highly preferred esters include C2-C6 loweralkyl esters or substituted or unsubstituted benzyl esters.
Preferred substituents -X-R2 include RZ-C(=O)-NH-, R2-NH-C{=O)-, R2-NH-S02- or R2-S02-NH- wherein R2 is C,-C3 loweralkyl, halo C~-C3 loweralkyl, Cz-C3 alkenyl or halo C2-C3 alkenyl or -X-R2 is ~o Y~
\ ~N_~_ ~,2 wherein Y' is -CHz-, -O-, -S- or -NH- and Y2 is -C(=O)- or -C(Raa)( Rbb)-wherein Raa and Rbb are independently selected from the group consisting of hydrogen, C~-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl.
More preferred substituents -X-R2 include R2-C(=O)-NH-, R2-NH-C(=O)-, RZ-NH-SOz- or RZ-SOz-NH- wherein R2 is C,-C3 loweralkyl, halo C,-C3 loweralkyl, C2-C3 alkenyl or halo C2-C3 alkenyl or -X-Rz is /o Yi'-'.~~
\ ~N_~_ Yz wherein Y' is -CHZ- and Y2 is -C(=O)- or -C(Raa)( Rbb)- wherein Raa and Rbb are independently selected from the group consisting of hydrogen, _28_ C,-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl.
Even more preferred substituents -X-R2 include R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SOZ- or R2-SOZ-NH- wherein R2 is C1-C3 loweralkyl, halo C~-C3 loweralkyl, C2-C3 alkenyl or halo C2-C3 alkenyl.
More highly preferred substituents -X-R2 include R2-C(=O)-NH-, RZ-NH-C(=O)-, R2-NH-SO~- or R2-SOZ-NH- wherein R2 is C~-C3 loweralkyl or halo- C,-C3 loweralkyl.
Even more highly preferred substituents -X-R2 include R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SOZ- or R2-S02-NH- wherein R2 is C,-C2 loweralkyl or halo C~-C2 loweralkyl, and especially, CH3-C(=O)-NH-, CF3-C(=O)-NH-, CH3-S02-NH-or CF3-S02-NH-.
Preferred substituents Z' include -O-, -S- or -CH(R5)- wherein R5 is hydrogen, loweralkyl or-(CHz)fN(R'9)2 wherein r and R~9 are defined as above;
or R5 is hydrogen, loweralkyl or-(CH2)~N(R'9)2 wherein r and R~9 are defined as above;
More preferred substituents Z' are -O-, -S- or -CH(R5)- wherein R5 is hydrogen or loweratkyl.
More highly preferred substituents Z' are -O-, -S- or -CH2-.
Even more highly preferred substituents Z' are -O- or -CH2-.
Preferred substituents R3 and R4 are independently selected from the group consisting of hydrogen, heterocyclic and -Z-R'4 wherein Z and R'4 are defined as most broadly defined previously herein and wherein one of R3 and R4 is other than hydrogen.
_29_ More highly preferred, substituent R4 is hydrogen or loweralkyl and R3 includes heterocyclic or -Z-R'4 wherein Z and R'4 are defined as most broadly defined previously herein.
Even more highly preferred, substituent R4 is hydrogen or loweralkyl and R3 includes (a) heterocyclic, (b) alkyl, (c) cycloalkyl, (d) cycloalkylalkyl, (e) alkenyl, (f) alkynyl, (g) -C{=O)-R~4~ (h) -C(R3~a)(OR3~c)-R~4 or {i) -C(Rs~a)(Rs~b)-N(O)(Rs~c)R~4 wherein R'4 is (i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl, (vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R3'a0)-{O=)C-substituted alkyl or (xv) (R3'a0)2-P(=O)-substituted alkyl;
R3'a and R3'b are independently selected from the group consisting of (i) hydrogen, (ii) loweralkyl and (iii) loweralkenyl; and R3'° is (i) hydrogen, (ii) loweralkyl or (iii) loweralkenyl.
Most highly preferred, substituent R4 is hydrogen and R3 includes {a) heterocyclic, (b) alkyl or (c) -C(R3'a){OR3'°)-R'4 wherein R'4 is (i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) aikenyl, (v) haloalkyl, (vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R3'a0)-(O=)C-substituted alkyl or (xv) {R3'a0)2-P(=0)-substituted alkyl;
R3'a and R3'b are independently selected from the group consisting of (i) hydrogen, (ii) loweralkyl and (iii) loweralkenyl; and R3'' is (i) hydrogen, (ii) C~-C3 loweralkyl or (iii) alfyl.
Also most highly preferred, substituent R4 is hydrogen and R3 includes (a) heterocyclic, (b) alkyl or (c) -C(R3'a)(OR3'°)-R'4 wherein R'4 is (i) loweralkyl, (ii) loweralkenyl, (iii) hy~lroxy-substituted loweralkyl or (iv) alkoxy-substituted ioweralkyl;
R3'a is (i) hydrogen, (ii) loweralkyl or (iii) loweralkenyl; and R3'' is (i) hydrogen, (ii) C~-C3 loweralkyl or (iii) allyl.
Also most highly preferred, substituent R4 is hydrogen and R3 includes -C(R3'a)(OR3'~)-R'4 wherein R'4 is loweralkyl or loweralkenyl;
R3'a is loweralkyl or loweralkenyl; and R3'' is hydrogen, C,-C3 loweralkyl or allyl, and especially, wherein R3'' is hydrogen or methyl.
Preferred substituents R5 include those independently selected from hydrogen, loweralkyl and -(CH2)~N(R'9)2 wherein r and R'9 are defined as above.
More preferred substituents R5 are independently selected from hydrogen, lowerafkyl and -(CH2)~N(R'9)2 wherein r is 0 or 1 and one R'9 is hydrogen or loweralkyl and the other R'9 is hydrogen, loweralkyl or an N-protecting group.
Even more preferred substituents R5 are independently selected from hydrogen and loweralkyl.
Most highly preferred, R5 is hydrogen.
Preferred substituents R6 and R' include independently hydrogen and loweralkyl. Most highly preferred, R6 and R' are hydrogen.
Preferred substituents R8, R9 and R'° include independently hydrogen, fluoro and loweralkyl. Most highly preferred, R8, R9 and R'° are hydrogen.
Preferred substituent Y includes CZ-C5 alkenyl, C2_C5 haloalkenyl, -C(=Q2)R22, -N(=Q3), -N(O)=CHCH3, -NR23R2a or a heterocyclic ring having from 3 to 6 ring atoms, wherein R22, R2s, Rza, Q2 and Q3 are defined as above.
More preferred substituent Y includes C2-C5 alkenyl, C2_C5 haloalkenyl, -C(=Q2)R22, -N(=Q3), -N(O)=CHCH3 or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds, wherein R22, Q2 and Q3 are defined as above.
Even more preferred substituent Y includes Cz-C5 alkenyl, CZ_C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds. Representative alkenyl and haloalkenyl substituents Y
include:
-CH=CH2, -CH=CHF, -CH=CH-CH3, -CH=CH-CFa, -CH=CHCI, -CH=CHBr, -CH=CF2, -CH=CF(CH3), -CH=CF(CF3), -CH=CFCI, -CH=CFBr, -CH=C(CH3)2, -CH=C(CH3)(CF3), -CH=CCI(CH3), -CH=CBr(CH3), -CH=G(CF3)Z, -CH=CCl(CF3), -CH=CBr(CF3), -CH=CCIZ, -CH=CCIBr, -CF=CH2, -CF=CHF, -CF=CH-CH3, -CF=CH-CF3, -CF=CHCI, -CF=CHBr, -CF=CF2, -CF=CF(CH3), -CF=CF(CF3), -CF=CFCI, -CF=CFBr, -CF=C(CH3)2, -CF=C(CH3)(CF3), -CF=CCI(CH3), -CF=CBr(CH3), -CF=C{CF3)Z, -CF=CCI(CF3), -CF=CBr(CF3), -CF=CCIZ, -CF=CCIBr, -C(CH3)=CH2. -C(CH3)=CHF, -C{CH3)=CH-CH3, -C(CH3)=CH-CF3, -C(CH3)=CHCi, -C(CH3)=CHBr,-C(CH3)=CFz, -C(CH3)=CF(CH3), -C(CH3)=CF(CF3), -C(CH3)=CFC1, -C(CH3)=CFBr, -C(CH3)=C(CH3)z, -C(CH3)=C(CH3)(CF3), -C(CH3)=CCl{CH3), -C(CH3)=CBr(CH3), -C(CH3)=C(CF3)z, -C{CH3)=CCI(CF3), -C(CH3)=CBr(CF3), -C(CH3)=CCIz, -C(CH3}=CCIBr, -C(CF3)=CHz, -C(CF3)=CHF, -C(CF3)=CH-CH3, -C(CF3)=CH-CF3, -C(CF3)=CHCI, -C(CF3)=CHBr, -C(CF3)=CFz, -C(CF3)=CF(CH3), -C(CF3)=CF(CF3), -C(CF3)=CFCI, -C(CF3)=CFBr, -C(CF3)=C(CH3)z, -C(CF3)=C(CH3)(CF3), -C(CF3)=CCI(CH3), -C(CF3)=CBr(CH3), -C(CF3)=C(CF3)z, -C(CF3)=CCI{CF3), -C(CF3)=CBr(CF3), -C(CF3)=CCiz, -C(CF3)=CCIBr, -CCI=CHz, -CCI=CHF, -CCI=CH-CH3, -CCI=CH-CF3, -CCI=CHCI, -CCI=CHBr, -CCI=CFZ, -CCI=CF(CH3), -CCI=CF(CF3), -CCI=CFCI, -CCI=CFBr, -CCI=C(CHa)z, -CCI=C(CH3)(CF3), -CCI=CCI(CH3), -CCI=CBr{CH3), -CCI=C(CF3)z, -CCI=CCI(CF3), -CCI=CBr(CF3), -CCI=CCIz, -CCI=CCIBr, -CH=CH-CH2CH3, -CH=CF-CHZCH3, -CF=CH-CH2CH3, -CF=CF-CH2CH3, -CH=C(CH3)(CHzCH3), -CF=C(CH3)(CH2CH3), -CH=CCI(CH2CH3), -CF=CCI(CH2CH3), -C(CH3)=CH-CH2CH3, -C(CH3)=CF-CHZCH3, -CCI=CH-CH2CH3, -CCI=CF-CHZCH3, -C(CH2CH3)=CHz, -C(CHZCH3)=CHF, -C(CHZCH3)=CFz, -C(CH2CH3)=CH-CH3, -C(CH2CH3)=CF-CH3, -C(CH2CH3)=CH-CI, -C(CH2CH3)=CFCI.
Representative Y substituents which are heterocyclic rings having 5 ring atoms and also containing one or two double bonds include:
furanyl, dihydrofuranyl, didehydrodioxolanyl, dithiolyl, imidazolyl, imidazolinyl, isothiazolyl, isothiazolinyl, isoxazolyl, isoxazolinyl, oxadiazolyl, oxadiazolinyl, oxathiolyl, oxazolyl, oxazolinyl, pyrazolyl, pyrazolinyl, pyrrolyl, dihydropyrrolyl, tetrazolyl, tetrazoiinyl, thiadiazolyl, thiadiazolinyi, thiazolyl, thiazolinyl, thienyl, dihydrothienyl, triazolyl, triazolinyl.
More highly preferred substituents Y include cis-propenyl, trans-propenyl, isobutenyl, cis-2-chlorovinyl, vinyl, 2,2-difluorovinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazoiyl, thiazolyl, isoxazolyl.
Most highly preferred substituents Y include cis-propenyl, cis-2-chlorovinyl, vinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isoxazolyl.
The term "acid protecting group" as used herein refers to groups used to protect acid groups (for example, -C02H, -S03H, -SOZH, -P03H2, -PO2H groups and the like) against undesirable reactions during synthetic procedures.
Commonly used acid protecting groups are disclosed in T.H. Greene and P.G.M.
Wuts, Protective Groins in Organic Synthesis. 2nd edition, John Wiley & Sons, New York (1991 ). Most frequently, such acid protecting groups are esters.
Such esters include:
alkyl esters, especially loweralkyl esters, including, but not limited to, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl esters and the like;
arylalkyl esters including, but not limited to, benzyl, phenethyl, 3-phenylpropyl, naphthylmethyl esters and the like, wherein the aryl part of the arylalkyl group is unsubstituted or substituted as previously defined herein;
silylesters, especially, (tri-loweralkyl)silyl esters, (di-loweralkyl)(aryl)silyl esters and (loweralkyl)(di-aryl)silyl esters, including, but not limited to, trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl, methyldiphenylsilyl, isopropyldiphenylsilyl, butyldiphenylsilyl, phenyldiisopropylsilyl esters and the like;
and the like.
Preferred acid protecting groups are loweralkyl esters.
The term "activated carboxylic acid group" as used herein refers to acid halides such as acid chlorides and also refers to activated ester derivatives including, but not limited to, formic and acetic acid derived anhydrides, anhydrides derived from alkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like, anhydrides derived from reaction of the carboxylic acid with N,N'-carbonyldiimidazole and the like, N-hydroxysuccinimide derived esters, N-hydroxyphthalimide derived esters, N-hydroxybenzotriazole derived esters, N-hydroxy-5-norbornene-2,3-dicarboximide derived esters, 2,4,5-trichlorophenol derived esters, p-nitrophenol derived esters, phenol derived esters, pentachlorophenol derived esters, 8-hydroxyquinoline derived esters and the like.
The term "acyl" as used herein, refers to groups having the formula -C(=O)-R95 wherein R95 is hydrogen or an alkyl group. Preferred alkyl groups as R95 are loweralkyl groups. Representative examples of acyl groups include groups such as, for example, formyl, acetyl, propionyl, and the like.
The term "acyfamino" as used herein, refers to groups having the formula -NHR89 wherein R89 is an acyl group. Representative examples of acylamino include acetylamino, propionylamino, and the like.
The term "alkenyl" as used herein, refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond. The term "lower alkenyl" refers to straight or branched chain alkenyl radicals containing from 2 to 6 carbon atoms.
Representative examples of alkenyl groups include groups such as, for example, vinyl, 2-propenyl, 2-methyl-1-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl and the like.
The term "alkenylene" as used herein, refers to a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond. The term "lower alkenylene" refers to a divalent group derived from a straight or branched chain alkene group having from 2 to 6 carbon atoms. Representative examples of alkenylene groups include groups such as, for example, -CH=CH-, -CH2CH=CH-, -C(CH3)=CH-, -CH2CH=CHCH2-, and the like.
The term "alkenyloxy" as used herein, refers to groups having the formula -OR8' where RB' is an alkenyl group.
The term "alkoxy" as used herein, refers to groups having the formula -OR99 wherein R99 is an alkyl group. Preferred R99 groups are loweralkyl groups.
Representative examples of alkoxy groups include groups such as, for example, methoxy, ethoxy, tent-butoxy, and the like.
The term "alkoxyalkoxy" as used herein, refers to groups having the formula -O-R9s-O-R9' wherein R9' is loweralkyl, as defined herein, and R96 is a lower alkylene group. Representative examples of alkoxyalkoxy groups include groups such as, for example, rnethoxymethoxy, ethoxymethoxy, t butoxymethoxy and the like.
The term "alkoxyaikyl" as used herein refers to an alkyl radical to which is appended an alkoxy group, for example, methoxymethyl, methoxylpropyl and the like.
The term "alkoxycarbonyl" as used herein, refers to groups having the formula, -C(=O)- R8°, where R$° is an alkoxy group.
The term "alkoxycarbonylalkyl" as used herein, refers to groups having the formula, -C(=O)- R'9, appended to the parent molecular moiety through an alkylene linkage, where R'9 is an alkoxy group.
As used herein, the term "alkyl" refers to straight or branched chain hydrocarbon radicals containing from 1 to 12 carbon atoms. The term "loweralkyl" refers to straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms. Representative examples of alkyl groups include groups such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethyl-propyl, n-hell, and the like. The hydrocarbon chains in alkyl groups or the alkyl portion of an alkyl-containing substituent can be optionally interrupted by one or two heteroatoms or heterogroups independently selected from the group consisting of oxygen, -N(R2')- and sulfur wherein R2' at each occurrence is independently hydrogen, loweralkyl, cylcoalkyl, cycloalkylalkyl or arylalkyl and wherein two such heteroatoms or heterogroups are separated by at least one carbon atom.
The term "alkylamino" as used herein, refers to groups having the formula -NHR9' wherein R9' is an alkyl group. Preferred R9' groups are loweralkyl groups. Representative examples of alkylamino include methylamino, ethylamino, and the like.
The term "alkylene" as used herein, refers to a divalent group derived from a straight or branched chain saturated hydrocarbon group having from 1 to 15 carbon. The term "lower alkylene" refers to a divalent group derived from a straight or branched chain saturated hydrocarbon group having from 1 to 6 carbon atoms. Representative examples of alkylene groups include groups such as, for example, methylene (-CH2-), 1,2-ethylene (-CH2CH2-), 1,1-ethylene (-CH(CH3)-), 1,3-propylene (-CH2CH2CHz-), 2,2-dimethylpropylene (-CH2C(CH3)2CH2-), and the like. The hydrocarbon chains in alkylene groups or the alkylene portion of an alkylene-containing substituent can be optionally interrupted by one or two heteroatoms or heterogroups independently selected from the group consisting of oxygen, -N(R2')- and sulfur wherein R2' at each occurrence is independently hydrogen, loweralkyl, cylcoalkyl, cycloalkylalkyl or arylalkyl and wherein two such heteroatoms or heterogroups are separated by at least one carbon atom.
The term "alkylsulfonyl" as used herein refers to the group having the formula, -S02-R'$, where R'8 is an alkyl group. Preferred groups R'8 are loweralkyl groups.
The term "alkylsulfonylamino" as used herein refers to the group having the formula, -S02-R", appended to the parent molecular moiety through an amino linkage (-NH-), where R" is an alkyl group. Preferred groups R" are loweralkyl groups.
The term "alkynyl" as used herein, refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon triple bond. The term "lower alkynyl" refers to straight or branched chain alkynyl radicals containing from 2 to 6 carbon atoms.
Representative examples of alkynyl groups include groups such as, for example, acetylenyl, 1-propynyl, 2- propynyl, 3-butynyl, 2-pentynyl, 1-butynyl and the like.
The term "alkynylene" as used herein, refers to a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon triple bond. The term "lower alkynylene" refers to a divalent group derived from a straight or branched chain alkynylene group from 2 to 6 carbon atoms. Representative examples of alkynyfene groups include groups such as, for example, -C=C-, -CHZ-C---C-, -C---C-CH2-, -CH{CH3)-C=C-, and the like.
The term "aminoalkyl" as used herein refers to an alkyl radical to which is appended an amino (-NHZ) group.
The term "aryl" as used herein refers to a carbocyclic ring system having 6-10 ring atoms and one or two aromatic rings. Representative examples of aryl groups include groups such as, for example, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.
The aryl groups can be unsubstituted or substituted with one, two or three substituents, each independently selected from loweralkyl, halo, haloalkyl, haloalkoxy, hydroxy, oxo (=O), hydroxyalkyl, afkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, thioalkoxy, amino, alkylamino, alkylsulfonyl, dialkylamino, acylamino, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted arylalkoxy, unsubstituted aryloxy, mercapto, cyano, vitro, carboxy, carboxaldehyde, NH2C(=O)-, cycloalkyl, carboxyalkyl, alkylsulfonylamino, unsubstituted heterocyclic, unsubstituted (heterocyclic)alkyl, unsubstituted (heterocyclic)alkoxy, unsubstituted (heterocyclic)oxy and -SOaH. Preferred aryl substituents are each independently selected from the group consisting of loweralkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, alkenyloxy, alkoxy, alkoxyalkoxy, thioalkoxy, amino, alkylamino, dialkylamino, alkylsulfonyl, acylamino, cyano and vitro. Examples of substituted aryl include 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 4-methylsulfonylphenyl, and the like.
The term "(aryl)alkenyl" refers to a lower alkenyl group having appended thereto an aryl group. Representative examples of (aryl)alkenyl groups include groups such as, for example phenylethylenyl, phenylpropenyl, and the like.
The term "(aryl)alkyl" refers to a loweralkyl group having appended thereto an aryl group. Representative examples of (aryl)alkyl groups include groups such as, for example benzyl and phenylethyl.
The term "arylalkoxy" as used herein refers to the group having the formula, -O-R'6 where R'6 is an arylalkyl group.
The term "(aryl)alkynyl" refers to an alkynylene group having appended thereto an aryl group. Representative examples of (aryl)alkynyl groups include groups such as, for example phenylacetylenyl, phenylpropynyl, and the like.
The term "aryloxy" as used herein refers to the group having the formula, -O-R'z, where R'2 is an aryl group.
The term "carbamoyl" as used herein refers to the group having the formula, -C(=O)-NH2.
The term "carboxyalkyl" as used herein, refers to the group having the formula, -R~-COOH, where Rfia is a lower alkylene group.
The term "cyanoalkyl" as used herein refers to an alkyl radical to which is appended a cyano group (-CN).
The term "cycloalkenyl" as used herein refers to an aliphatic ring system having 5 to 10 carbon atoms and 1 or 2 rings containing at least one double bond in the ring structure. Representative examples of cycloalkenyl groups include groups such as, for example, cyclohexene, cyclopentene, norbornene and the like.
Cycloalkenyl groups can be unsubstituted or substituted with one, two or three substituents independently selected hydroxy, halo, amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, thioalkoxy, haloalkyl, mercapto, loweralkenyl and loweralkyl. Preferred substitutents are independently selected from loweralkyl, loweralkenyl, haloalkyl, halo, hydroxy and alkoxy.
The term "(cycloalkenyl)alkenyl" as used herein refers to a cycloalkenyl group appended to a lower alkenyl radical. Representative examples of (cycloalkenyl)alkenyl groups include groups such as, for example, cyclohexenylethylene, cyclopentenylethylene, and the like.
The term "(cycloalkenyl)alkyl" as used herein refers to a cycloalkenyl group appended to a lower alkyl radical. Representative examples of (cycloalkenyl)alkyl groups include groups such as, for example, cyclohexenylmethyl, cyclopentenylmethyl, cyclohexenylethyl, cyclopentenylethyl, and the like.
The term "(cycloalkenyl)alkynyl" as used herein refers to a cycloalkenyl group appended to a lower alkynyl radical. Representative examples of (cycloalkenyl)alkynyl groups include groups such as, for example, cyclohexenylacetylenyl, cyclopentenylpropynyl, and the like.
The term "cycloalkyl" as used herein refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 or 2 rings. Representative cylcoalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornane, bicyclo[2.2.2]octane and the like.
Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected hydroxy, halo, amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, thioalkoxy, haloalkyl, mercapto, ioweralkenyl and Ioweralkyl. Preferred substitutents are independently selected from loweralkyl, loweralkenyl, haloalkyl, halo, hydroxy and alkoxy.
The term "(cycloalkyl)alkyl" as used herein refers to a cycloalkyl group appended to a loweralkyl radical. Representative examples of (cycloalkyl)alkyl groups include groups such as, for example, cyclohexylmethyl, cyclopentylmethyl, cyclohexylethyl, cyclopentylethyl, and the like.
The term "(cycloalkyl)alkenyl" as used herein refers to a cycloalkyl group appended to a lower alkenyl radical. Representative examples of (cycloalkyl)-alkenyl groups include groups such as, for example, cyclohexylethylene, cyclopentylethylene, and the tike.
The term "(cycloalkyl)alkynyl" as used herein refers to a cycloalkyl group appended to a lower alkynyl radical. Representative examples of (cycloalkyl)-alkynyl groups include groups such as, for example, cyclohexylacetylenyl, cyclopentylpropynyl, and the like.
The term "dialkylamino" as used herein, refers to groups having the formula -N(R9°)2 wherein each R9° is independently a lower alkyl group.
Representative examples of dialkylamino include dimethylamino, diethylamino, N-methyl-N-isopropylamino and the like.
The term "halo" as used herein refers to F, C1, Br or I.
The term "haloalkenyl" as used herein refers to a lowerafkenyl group in which one or more hydrogen atoms is replaced with a halogen. Examples of haloalkenyl groups include 2-fluoroethylene, 1-chloroethylene, 1,2-difluoroethylene, trifluoroethylene, 1,1,1-trifluoro-2-propylene and the like.
The term "haloalkoxy" as used herein refers to the group having the formula, -OR69, where R69 is a haloalkyl group as defined herein. Examples of haloalkoxy include chloromethoxy, fluoromethoxy, dichloromethoxy, trifluoromethoxy and the like.
The term "haloalkyl" as used herein, refers to a loweralkyl group in which one or more hydrogen atoms has been replaced with a halogen including, but not limited to, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, fluoromethyl, chloromethyl, chloroethyl, 2,2-dichloroethyl, pentafluoroethyl and the like.
The term "heterocyclic ring" or "heterocyclic" or "heterocycle" as used herein, refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-mernbered ring containing one, two, three, or four nitrogen atoms; one oxygen atom; one sulfur atom; one nitrogen atom and one sulfur atom; two nitrogen atoms and one sulfur atom; one nitrogen atom and one oxygen atom; two nitrogen atoms and one oxygen atom;
two oxygen atoms in non-adjacent positions; one oxygen atom and one sulfur atom in non-adjacent positions; or two sulfur atoms in non-adjacent positions.
The 5-membered ring has 0-2 double bonds and the 6- and 7-membered rings have 0-3 double bonds. The nitrogen heteroatoms can be optionally quaternized.
The term "heterocyclic" also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocycfic ring, such as, for example, indolyl, dihydroindolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl and the like.
Heterocyclic groups include, but are not limited to groups such as, for example, aziridinyl, azetidinyl, epoxide, oxetanyl, thietanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, tetrahydropyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazofidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, oxetanyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, thienyl, dihydrothienyl, tetrahydrothienyl, triazolyl, triazolinyl, tetrazolyl, tetrazolinyl, isoxazolyl, 1,2,3-oxadiazoiyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, oxadiazolinyl, , 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, thiadiazolinyl,l,3-dithiolinyl, 1,2-dithiolyl, 1,3-dithiolyl, 1,3-dioxolinyl, didehydrodioxolanyl, 1,3-oxathiolinyl, oxathiolyl, pyrimidyl, benzothienyl and the like. Heterocyclic groups also include compounds of the formula x*
Y*
/ i O
where X* is -CH2 or -O- and Y* is -C(O)- or [-C(R92)2-]~ where R92 is hydrogen or C~-C4 alkyl where v is 1, 2, or 3 such as 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like. Heterocyclic groups also include bicyclic rings such as quinuclidinyl and the like.
Heterocyclic groups can be unsubstituted or substituted with from one to three substituents, each independently selected from loweralkyl, hydroxy, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino and halogen. In addition, nitrogen containing heterocyclic rings can be N-protected.
The term "(heterocyclic)alkenyl" as used herein refers to a heterocyclic group appended to a lower alkenyl radical including, but not limited to, pyrrolidinylethenyl, morpholinylethenyl and the like.
The term "(heterocyclic)alkoxy" as used herein refers to the group having the formula, -OR68, where R6$ is a (heterocyclic)alkyl group.
The term "(heterocyclic)alkyl" as used herein refers to a heterocyclic group appended to a loweralkyl radical including, but not limited to, pyrrolidinylmethyl, morpholinylmethyl and the like.
The term "(heterocyclic)alkynyl" as used herein refers to a heterocyclic group appended to a lower alkynyl radical including, but not limited to, pyrrolidinylacetylenyl, morpholinylpropynyl and the like.
The term "(heterocyclic)oxy" as used herein refers to a heterocyclic group appended to the parent molecular moiety through an oxygen atom (-O-) The term "hydroxy protecting group", "hydroxyl protecting group" or "-OH
protecting group" as used herein refers to refers to groups used to hydroxy groups against undesirable reactions during synthetic procedures. Commonly used hydroxy protecting groups are disclosed in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis. 2nd edition, John Wiley & Sons, New York (1991 ). Such hydroxy protecting groups include:
methyl ether;
substituted methyl ethers, including, but not limited to, methoxymethyl, methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl, t-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tetrahydrothiopyranyi, tetrahydrofuranyl, tetrahydrothiofuranyl ether and the like;
substituted ethyl ethers, including, but not limited to, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 2,2,2-trichloroethyl, trimethylsilylethyl, t-butyl ether and the like;
benzyl ether;
substituted benzyl ethers, including, but not limited to, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitorbenzyl, p-halobenzyl, p-cyanobenzyl, diphenylmethyl, triphenylmethyl ether and the like;
silyl ethers, including, but not limited to, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl ether and the like;
esters, including, but not limited to, formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, phenoxyacetate, pivaloate, benzoate ester and the like; and the like.
Preferred hydroxy protecting groups include substituted methyl ethers, benzyl ether, substituted benzyl ethers, silyl ethers and esters.
The term "hydroxyalkyl" as used herein refers to the group having the formula, -R65-OH, where R65 is an alkylene group The term "leaving group" as used herein refers to a group which is easily displaced from the compound by a nucleophile. Examples of leaving groups include a halide (for example, CI, Br or I) or a sulfonate (for example, mesylate, tosylate, triflate and the like) and the like.
The term "N-protecting group" or "N-protected" as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991). N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like;
sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-meth-oxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyi, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxy-benzyioxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycar-bonyl, 2-vitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycar-bonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, a,a-dimethyl-3,5-dimethoxy-benzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropyl-methoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyl-oxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-vitro-phen-oxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyl-oxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
The term "thioalkoxy" as used herein refers to groups having the formula -SR98 wherein R98 is an alkyl group. Preferred groups R9$ are loweralkyl groups.
The term "thio-substituted alkyl" as used herein refers to an alkyl radical to which is appended a thiol group (-SH).
As used herein, the terms "S" and "R" configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13 - 30.
The compounds of the invention can comprise asymmetrically substituted carbon atoms. As a result, all stereoisomers of the compounds of the invention are meant to be included in the invention, including racemic mixtures, mixtures of diastereomers, as well as individual optical isomers, including, enantiomers and single diastereomers of the compounds of the invention substantially free from their enantiomers or other diastereomers. By "substantially free" is meant greater than about 80% free of other enantiomers or diastereomers of the compound, more preferably greater than about 90% free of other enantiomers or diastereomers of the compound, even more preferably greater than about 95%
free of other enantiomers or diastereomers of the compound, even more highly preferably greater than about 98% free of other enantiomers or diastereomers of the compound and most preferably greater than about 99% free of other enantiomers or diastereomers of the compound.
In addition, compounds comprising the possible geometric isomers of carbon-carbon double bonds and carbon-nitrogen double are also meant to be included in this invention.
Individual stereoisomers of the compounds of this invention can be prepared by any one of a number of methods which are within the knowledge of one of ordinary skill in the art. These methods include stereospecific synthesis, chromatographic separation of diastereomers, chromatographic resolution of enantiomers, conversion of enantiomers in an enantiomeric mixture to diastereomers and then chromatographically separating the diastereomers and regeneration of the individual enantiomers, enzymatic resolution and the like.
Stereospecific synthesis involves the use of appropriate chiral starting materials and synthetic reactions which do not cause racemization or inversion of stereochemistry at the chiral centers.
Diastereomeric mixtures of compounds resulting from a synthetic reaction can often be separated by chromatographic techniques which are well-known to those of ordinary skill in the art.
Chromatographic resolution of enantiomers can be accomplished on chiral chromatography resins. Chromatography columns containing chiral resins are commercially available. In practice, the racemate is placed in solution and loaded onto the column containing the chiral stationary phase. The enantiomers are then separated by HPLC.
Resolution of enantiomers can also be accomplished by converting the enantiomers in the mixture to diastereomers by reaction with chiral auxiliaries.
The resulting diastereomers can then be separated by column chromatography.
This technique is especially useful when the compounds to be separated contain a carboxyl, amino or hydroxyl group that will form a salt or covalent bond with the chiral auxiliary. Chirally pure amino acids, organic carboxylic acids or organosulfonic acids are especially useful as chiral auxiliaries. Once the diastereorners have been separated by chromatography, the individual enantiomers can be regenerated. Frequently, the chiral auxiliary can be recovered and used again.
Enzymes, such as esterases, phosphatases and lipases, can be useful for resolution of derivatives of the enantiomers in an enantiomeric mixture. For example, an ester derivative of a carboxyl group in the compounds to be separated can be prepared. Certain enzymes will selectively hydrolyze only one of the enantiomers in the mixture. Then the resulting enantiomerically pure acid can be separated from the unhydrolyzed ester.
In addition, solvates and hydrates of the compounds of Formula I, II, III, IV, V, VI, VII, VIII or IX are meant to be included in this invention.
When any variable (for example R', R2, R3, m, n, etc.) occurs more than one time in any substituent or in the compound of Formula I, II, II1, IV, V, VI, VII, VIII or IX or any other formula herein, its definition on each occurrence is independent of its definition at every other occurrence. In addition, combinations of substituents are permissible only if such combinations result in stable compounds. Stable compounds are compounds which can be isolated in a useful degree of purity from a reaction mixture.
This invention is intended to encompass compounds having Formula I, I1, III, IV, V, VI, VII, VIII or IX when prepared by synthetic processes or by metabolic processes. Preparation of the compounds of the invention by metabolic processes include those occurring in the human or animal body (in vivo) or processes occurring in vitro.
Compounds of the invention can be prepared according to the methods described in Schemes 1-8 as shown below.
Throughout the schemes, methods will be illustrated wherein R' is a carboxylic acid or carboxylic acid ester substituent. It will be understood by those skilled in the art that other R' substituents can (a) be obtained either from the carboxylic acid or carboxylic acid .ester group, (b) can be introduced by similar methods to those used to introduce the carboxylic acid or carboxylic acid ester group or (c) can be introduced by other methods generally known in the art.
In adddition, throughout the schemes, methods will be illustrated wherein R4, R6, R', R8, R9 and R'° are hydrogen. It will be understood by those skilled in the art that compounds wherein one or more of these substituents is other than hydrogen can be prepared by methods analogous to those disclosed in the schemes or by other methods generally known in the art.
In addition, throughout the schemes, methods will be illustrated for obtaining compounds of the invention having the preferred relative stereochemistry. It will be understood by those skilled in the art that compounds of the invention having other relative stereochemistry can be prepared by methods analogous to those disclosed in the schemes or by other methods generally known in the art.
In addition, throughout the schemes, methods will be illustrated wherein X
is -C(=O)-NH-. It will be understood by those skilled in the art that other X
groups can be prepared by methods analogous to those disclosed in the schemes or by other methods generally known in the art.
Compounds of the invention can be prepared according to the procedure described in Scheme 1. N-protected amino acid 1 (P' is an N-protecting group, for example, t-butoxycarbonyl or the like) can be prepared by N-protection of amino acid ((t)-(2R,3S)-2-Amino-bicyclo[2.2.1]hept-5-ene-3-carboxylic acid;
Stajer, G. et al. Tetrahedron, 40, 2385 {1984)). Formation of an anhydride derivative of the acid (for example, by reaction with ethyl chloroformate or the like), followed by reduction (for example, with sodium borohydride or the like) provides alcohol 2. The alcohol group is oxidized (for example, by Swern oxidation or the like) to provide aldehyde 3. Reductive amination of the aldehyde (for example with benzyl amine and Na(Ac0)3BH or the like) provides N-protected amine 4 (P2 is an N-protecting group, such as benzyl and the like).
A
second N-protecting group can be introduced to give 5 (P3 is an N-protecting group, for example, benzyioxycarbonyl or the like). Optionally, the mono-protected amino group can be alkylated (for example, by reaction with a non-nucleophilic base and an alkyl halide). The bicyclic ring is oxidatively cleaved (for example, with RuOZ and Na104 or the like) to give a diacid which is esterified to give diester 6 (P4 is a carboxylic acid protecting group, for example, loweralkyl, such as methyl, ethyl or the like). The N-protecting groups P2 and P3 are selectively removed (for example, by hydrogenation or the like) to provide amine 7. Amine 7 can be further functionalized to complete the introduction of the X- substituent (for example, by reaction of the amine with an acylating agent such as acetic anhydride or the like) to give 8. Removal of the acid protecting groups P4 (for example, by base hydrolysis) provides diacid 9. Diacid 9 can be monoprotected (for example, by treatment with acetic anhydride, followed by methanol and triethylamine) and chromatographic separation to give 10 (P5 is a carboxylic acid protecting group, for example, loweralkyl or the like). The acid group of 10 can also be transformed to a variety of substituents Y of the compounds of the invention using methods known to those skilled in the art to give 11, followed by N-deprotection, to give compounds of the invention 12.
As shown in Scheme 2, substituents R3 can be introduced via reaction of aldehyde 3 with a Grignard reagent (for example, R3MgBr or the like) to give alcohol 13. Oxidation of alcohol 13 (for example, Swern oxidation or the like) provides ketone 14. Reductive amination of ketone 14 (for example, by reaction with ammonium acetate and sodium cyanoborohydride in methanol or the like) gives amine 15. Amine 15 can be further functionalized to complete introduction of the R2-X- substituent (for example, by reaction of the amine with an acylating agent such as acetic anhydride or the like or by other acylation methods), followed by chromatographic separation of the diastereomers to give 16a. The other diastereomer (16b) can also be isolated and further transformed according to the scheme.
Oxidation of 16a and esterification gives 17 (in a manner analogous to that disclosed in Scheme 1). Also similar to Scheme 1, the diacid resulting from hydrolysis of diester 17 can be selectively protected to give give 1$, which can then be transformed to compounds of the invention 19.
As shown in Scheme 3, diol 20 is selectively diprotected (Culbertson, et al., Journal of the American Chemical Society 82, 2541-2547 (1960)) by reaction with one equivalent of a hydroxy protecting agent, followed by reaction with a second hydroxy protecting agent, to give 21 (P6 is a hydroxy protecting group, for example, acetyl or the like and P' is a hydroxy protecting group, for example, benzyl or the like). Oxidation and esterification provide 22. Removal of protecting group P', followed by transformation of the hydroxy group to an amine, which is then N-protected, provides 24. Transformation of 24 in a manner analogous to the transformation of 2 to 11 or 12 in Scheme 1 provides compounds of the invention 27 or 28.
As shown in Scheme 4, alcohol 31 can be transformed to compounds of the invention 38 in a manner analogous to the transformation of 13 to 19 in Scheme 2.
As shown in Scheme 5, aldehyde 39 can be reacted with a Grignard reagent to introduce substituent R3 to give 40. Oxidation (for exampie, by Swern oxidation or the like) provides 41a, which can be epimerized (for example, with sodium methoxide or the like) and 41 b can be obtained by chromatography.
Ketone 41b can be transformed to compounds of the invention 47 in a manner analogous to the transformation of 14 to 19 in Scheme 2.
As shown in Scheme 6, olefin 48 (P8 is a hydroxy protecting group) is converted to alcohol 48a (for example, by reaction with borane dimethylsulfide complex and hydrogen peroxide or the like). Oxidation of the alcohol to a carboxylic acid, followed by esterification with a carboxylic acid protecting group P9 and deprotection of the diol, provides 49. Selective protection of the primary alcohol with a hydroxy protecting group P'° gives 50. Oxidation of 50 (for example, Swern oxidation or the like) provides ketone 51. Reductive amination of ketone 51 (for example, by reaction with ammonium acetate and sodium cyanoborohydride in methanol or the like) gives amine 52. Amine 52 can be further functionalized to complete the introduction of the R2-X- substituent ( for example, by reaction with an acylating agent such as acetic anhydride or the like or by other acylation methods), followed by chromatographic separation of the diastereomers to give 53a. The other diastereomeric amide (53b) can also be isolated and further functionalized according to this scheme.
Selective removal of the P8 hydroxy protecting group in 53a provides alcohol 54. Oxidation of the alcohol to an aldehyde (for example, Swern oxidation or the like) provides 55. The aldehyde can serve as a precursor for various substituents Y in the compounds of the invention. For example, olefination of 55 (for example, with Ph3PCH2, or triphenylphosine/methylene chlorideln-BuLi, or I-Ph3P+CH2CH~/KOtBu, or the like) provides 56 wherein Y
is an olefinic substituent. Removal of the P'° hydroxy protecting group gives alcohol 57.
The alcohol can serve as a precursor for a variety of R3 substituents in the compounds of the invention. For example, the alcohol of 57 can be oxidized to an aldehyde -(for example, by Dess-Martin oxidation or the like) to give 58.
Aldehyde 58 can be reacted with Grignard reagents (R'4MgBr or the like) or other organometallic reagents (for example, organolithium reagents such as R'aLi or the like) to provide 59 as a mixture of alcohol diastereomers which can be separated chromatographically to provide the major isomer 59a and the other isomer 59b. Isomer 59a or the mixture of isomers 59 can be oxidized (for example, by Dess-Martin oxidation or the like) to give ketone 62. Reduction of ketone 62 (for example, with sodium borohydride in ethanol or the like) provides alcohol 59b as the major isomer, which can be isolated by chromatography.
Ester hydrolysis provides compounds of the invention 63a or fi3b, respectively, wherein Y is an olefinic substituent.
Alkylation of alcohol 59a or 59b provides ethers 60a or 60b, respectively.
Ester hydrolysis provides compounds of the invention 61a or 61b, respectively, wherein Y is an olefinic substituent.
As shown in Scheme 7, reaction of ketone 62 with with Grignard reagents (R3'aMgBr or the like) or other organometallic reagents (for example, organolithium reagents such as R3'aLi or the like) provides alcohols 64a and 64b as a mixture of alcohol diastereomers which can be separated chromatographically. Ester hydrolysis provides compounds of the invention fi5a or 65b, respectively, wherein Y is an olefinic substituent.
Alkylation of alcohol 64a or 64b provides ethers 66a or 66b, respectively.
Ester hydrolysis provides compounds of the invention 67a or 67b, respectively, wherein Y is an olefinic substituent.
Scheme 8 shows the preparation of precursor 74 for compounds of the invention which are substituted tetrahydrofurans. Alcohol 68 is oxidized to a ketone (for example, by Swern oxidation or the like), followed by oxidation of the olefin to a diol (for example, by treatment with Os04 and N-methylmorpholine N-oxide or the like) to give 69. Diol 69 is protected as the acetonide 70.
Oxidation of 70 (for example, with MCPBA -or the like) provides lactone 71. Iodination via the enolate .-of 71 provides 72. Reaction of 72 with potassium carbonate and methanol provides ester 73. Reduction of the ester provides aldehyde 74. The aldehyde provides a functional group via which substituents R3 and R2-X- can be introduced. Deprotection of the diol and oxidation of the diol provides functional groups via which substituents Y and R' can be introduced.
Esters or prodrugs of the compounds of the invention can be prepared by methods known in the art.
HO HO H
O NHP~ NHP~ ~ O NHP~
H ~ p3 w NHP~ NHP~
P40~0 P40~0 ~ P2~N OP4 ~ H2N ..,~~, OP4 NPR O Np~ O
H
H
P40~0 HO~O
OP4 R2C(O)HN ., ~~I~OH
..., N
R2C(O)H
7 NPR O Np~ O
H
8 _ SCHEME 1 ycont'd.~
HO~O Y, s R2C(O)HN OH R2C(O)HN ...",'~ p NP' O ~~ Np~ O
H
Y, R2C(O)HN .",~I~ H
w ~ w H ~HO ~. O
0 NHPi R3 NHP~ R3 NHP~
_14 _ R3 NHP~
w w R2C{O)HN~,, ~ R2C(O)HN
R3 NHP~ + R3 NHP~
16a 16b HO-.l/
RZC(O)HN~,. .., ~ OP4 R2C(O)HN~,. ..,aI~OP
ll R3 NP' 0 R3 Np~ O
H H
_58_ SCHEME 2 (cont'd.) HO.-.!/ Y.
R2C(O)HN~,, ~~~~~I~OP R2C(O)HN~,, ...~~y~OH
R3 NPR O R3 NHZ 'O
w w Pa0?,, ,, HO Ps0 _ PsOp OPa OH OP7 ~ O
a P O?.,,.. P O?.,,..
Ps0 _,,~pPa Ps0 ..,~OP
P O?.,,.. H 0~.,,..
~OH
R2C(O)HN .,~OPa R2C(O)HN
p ----- O
24 NHP~
NHP~
SCHEME 3 ycont'd.) H~~.,,,, 26 R2C(O)HN OP5 ~''~O
NHP~
Y.,, R2C(O)HN .,,~ H
O
HO
NHP~ R3 HzNHP' O Hz 31 ' R3 ~H2NHP~ ~ R3 H2NHP~
w R2C(O)HN~,, RzC(O)HN
R3 CH2NHP~ + R3 CHZNHP~
34a 34b paO~O HO-..l/
R2C(O)HN.,, ." ~ OP4. RzC(O)HN~,. ..,~~'I~OH
R3 ~ R3 ~ O
CH NHP~ CH2NHP~
Background of the Invention Many disease-causing microorganisms possess a neuraminidase neuraminidase (also known as sialidase) which is involved in the replication process of the microorganism. In particular, viruses of the orthomyxovirus and paramyxovirus groups possess a neuraminidase. Diseases associated with paramyxoviruses include RSV (respiratory syncytial virus-related diseases), pneumonia and bronchiolitis (associated with paramyxovirus type 3) and laryngotracheobronchitis (associated with paramyxovirus type 1 ). Some of the more important disease-causing microorganisms in man and/or animals which possess a neuraminidase include Vibrio cholerae, Clostridium perfringens, Streptococcus pneumoniae, Arthrobacter sialophilus, influenza virus, parainfluenza virus, mumps virus, Newcastle disease virus, fowl plague virus, equine influenza virus and Sendai virus.
Mortality due to influenza is a serious problem throughout the world. The disease is devastating to man, lower mammals and some birds. Although vaccines containing attenuated influenza virus are available, those vaccines only provide immunological protection toward a few influenza strains and are less effective in otherwise immunologically compromised populations such as the elderly, young children, and in those who suffer from chronic respiratory illness.
The productivity loss from absence due to sickness from influenza virus infection has been estimated to be more than $1 billion per year.
There are two major strains of influenza virus (designated A and B).
Currently, there are only a few pharmaceutical products approved for treating influenza. These include amantadine and rimantadine, which are active only against the A strain of influenza viruses, and ribavirin, which suffers from dose-limiting toxicity. Mutant virus which is resistant to amantadine and rirnantadine emerges quickly during treatment with these agents.
Neuraminidase is one of two major viral proteins which protrude from the envelope of influenza virus. During the release of progeny virus from infected cells, neuraminidase cleaves terminal sialic acid residues from glycoproteins, glycalipids and oligosaccharides on the cell surface. Inhibition of neuraminidase enzymatic activity leads to aggregation of progeny virus at the surface. Such virus is incapable of infecting new cells, and viral replication is therefore retarded or blocked. X-ray crystallographic studies and sequence alignments have shown that the residues which directly contact the sialic acid portion of the substrate are strictly conserved in the neuraminidase from all A and B influenza strains.
Thus, a compound which binds to the sialic acid binding region of the neuraminidase active site will block the replication of both the A and B strains of influenza virus.
Compounds which are influenza neuraminidase inhibitors will be useful for the _2_ prevention of influenza infection and will be useful for the treatment of influenza infection.
Y. Babu, et al., International Patent Application No. W097/47194, published December 18, 1997 discloses substituted cyclopentanes which are useful as neuraminidase inhibitors and treatments for influenza.
The following references disclose neuraminic acid derivatives with the disclosed utility listed after each reference:
L. Von Itzstein, et al., European Patent Application No. EP539204, published April 28, 1993 (antiviral agent);
T. Honda, et al., European Patent Application No. EP823428, published February 11, 1998 (sialidase inhibitor; influenza treatment);
T. Honda, et al., International Patent Application No. W098/06712, published February 19, 1998 {sialidase inhibitor; influenza remedy);
L. Von Itzstein, et al., International Patent Application No. W095/20583, published August 3, 1995 (viral neuraminidase inhibitor; influenza treatment);
P. Smith, International Patent Application No. W095I18800, published July 13, 1995 (viral neuraminidase inhibitor);
P. Colman, et al., International Patent Application No. W092/06691, published April 30, 1992 (viral neuraminidase inhibitor);
L. Von Itzstein, et al., U.S. Patent No. 5,648,379, issued July 15, 1997 (influenza treatment);
P. Reece, et al., International Patent Application No. W097/32214, published September 4, 1997 (bind to influenza virus neuraminidase active site); and P. Reece, et al., International Patent Application No. W098/21243, published May 23, 1998 (anti-influenza agent).
The following references disclose sialic acid derivatives with the disclosed utility fisted after each reference:
Y. Ohira, et al., International Patent Application No. W098/11083, published March 19, 1998 (antiviral agent);
Y. Ohira, European Patent Application No. EP882721, published December 9, 1998 (antiviral agent); and B. Glanzer, et al., Helvetica Chimica Acta 74 343-369 (1991 ) (Vibrio cholerae neuraminidase inhibitor).
The following references disclose benzene derivatives, cyclohexane derivatives or cyclohexene derivatives with the disclosed utility listed after each reference:
Y. Babu, et al., U.S. Patent No. 5,602,277, issued February 11, 1997 (neuraminidase inhibitors);
M. Luo, et al., U.S. Patent No. 5,453,533, issued September 26, 1995 (influenza neuraminidase inhibitor; influenza treatment);
Y. Babu, et al., International Patent Application No. W096/30329, published October 3, 1996 (neuraminidase inhibitor; viral infection treatment);
N. Bischofberger, et al., U.S. Patent No. 5,763,483, issued June 9, 1998 (neuraminidase inhibitor); and K. Kent, et al., International Patent Application No. 98/07685, published February 26, 1998 (intermediates for the preparation of neuraminidase inhibitors).
C. Kim, et al., International Patent Application No. W098/17647, published April 30, 1998 discloses piperidine derivatives which are useful as neuraminidase inhibitors.
N. Bischofberger, et al., international Patent Application No. W096/26933, published September 6, 1996 discloses various substituted 6-membered ring compounds which are useful as neuraminidase inhibitors.
The following references disclose dihydropyran derivatives which are useful as viral neuraminidase inhibitors:
D. Andrews, et al., International Patent Application No. W097/06157, published February 20, 1997; and P. Cherry, et al., International Patent Application No. W096/36628, published November 21, 1996.
C. Kim, et al., U.S. Patent No. 5,512,596, issued April 30, 1996 discloses 6-membered aromatic ring derivatives which are useful as neuraminidase inhibitors.
G. Diana, et al., International Patent Application No. W098/03487, published January 29, 1998 discloses substituted pyridazines which are useful for treatment of influenza.
B. Horenstein, et al., International Patent Application No. W099/06369, published February 11, 1999 discloses piperazine derivatives which are useful as neuraminidase inhibitors.
L. CZOllner, et al., Helvetica Chimica Acta 73 1338-1358 (1990) discloses pyrrolidine analogs of neuraminic acid which are useful as Vibrio cholerae sialidase inhibitors.
The following references disclose siastatin B analogs which are useful as neuraminidase inhibitors:
Y. Nishimura, et al., Natural Product Letters 1 39-44 (1992); and Y. Nishimura, et al., Natural Product Letters 1 33-38 (1992).
C. Penn, UK Patent Application No. GB2292081, published February 14, 1996 discloses the use of a neuraminidase inhibitor in combination with an infiuenza vaccine.
An object of the invention is to provide compounds which inhibit neuraminidase of disease-causing microorganisms; especially, viral neuraminidase; and, most especially, influenza neuraminidase.
An object of the invention is also to provide compounds which inhibit neuraminidase from both A and B strains of influenza.
Another object of the invention is to provide prohylaxis of influenza infection in humans and other mammals.
Another object of the invention is to provide treatment of influenza infection in humans and other mammals.
Another object of the invention is to provide compounds which exhibit activity against influenza A virus and and influenza B virus by virtue of inhibiting influenza neuraminidase when such compounds are administered orally.
Another object of the invention is to provide a compound which can be effectively transported from the plasma into the lung bronchoaveolar fluid of humans and other mammals in order to block the replication of influenza virus in that tissue.
Disclosure of the Invention The present invention discloses compounds having Formula I, II or III
Y
Rio Rs Z R~
Ra R' Y.
R1o R2-X ~ 1 ( ~ R
R4 ( R7 s Y
R1o ~ 1 R
R2-X, R4 / ~ R7 ~5 or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R' is selected from the group consisting of (a) -C02H, (b) -CH2C02H, (c) -S03H, (d) -CH2S03H, (e) -S02H, (f) -CH2S02H, (g) -P03H2, (h) -CH2P03H2, (i) -P02H, (j) -CH2P02H, (k) tetrazolyl, (I) -CH2-tetrazolyl, (m) -C(=O)-NH-S(O)2-R", (n) -CH2C(=O)-NH-S(O)2-R", (o) -S02N(T-R")R'Z and (p) -CH2S02N(T-R")R'2 wherein T is selected from the group consisting of (i) a bond, (ii) -C(=O)-, (iii) -C(=O)O-, (iv) -C(=O)S-, (v) -C(=O)NR3s-, (vi) -C(=S)O-, (vii) -C(=S)S-, and (viii) -C(=S)NR3s-, R"~ is selected from the group consisting of (i) C~-C~2 alkyl, (ii) C2-C~2 alkenyl, (iii) cycloalkyl, (iv) (cyclo-alkyl)alkyl, (v) (cycloalkyl)alkenyl, (vi) cycloalkenyl, (vii) (cycloalkenyl)alkyl, (viii) (cycloalkenyl)alkenyl, (ix) aryl, {x) (aryl)alkyl, (xi) (aryl)alkenyl, (xii) heterocyclic, (xiii) (heterocyclic)alkyl and (xiii) (xiv) (heterocyclic)alkenyl; and R'2 and R3s are independently selected from the group consisting of (i) hydrogen, (ii) C,-C~2 alkyl, (iii) C2-C~2 alkenyl, (iv) cycloalkyl, (v) (cycloalkyl)alkyl, (vi) (cycloalkyl)alkenyl, (vii) cycloalkenyl, (viii) (cycloalkenyl)alkyl, (ix) (cycloalkenyl)alkenyl, (x) aryl, (xi) (aryl)alkyl, (xii) (aryl)alkenyl, (xiii) heterocyclic, (xiv) (heterocyclic)alkyl and (xv) (heterocyclic)alkenyl;
X is selected from the group consisting of (a) -C(=O)-N(R*)-, (b) -N(R*)-C(=O)-, (c) -C(=S)-N(R*)-, (d) -N(R*)-C(=S)-, (e) -N(R*)-S02-, and (f) -S02-N(R*)- wherein R* is hydrogen, C~-C3 loweralkyl or cyclopropyl;
R2 is selected from the group consisting of (a) hydrogen, (b) C~-Cs alkyl, (c) C2-Cs alkenyl, (d) C3-Cs cycloalkyl, (e) CS-Cs cycloalkenyl, (f) halo C~-Cs alkyl and (g) halo CZ-Cs alkenyl;
or Rz-X- is _g_ ,o Y~' wherein Y' is -CHZ-, -O-, -S- or -NH- and Y2 is -C(=O)- or -C(Raa)(Rbb)-wherein Raa and Rbb are indepedently selected from the group consisting of hydrogen, C~-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl;
Z' Is -O-, -S-, Of C(R5)2;
R3 and R4 are independently selected from the group consisting of (a) hydrogen, (b) cycloalkyl, (c) cycloaikenyl, (d) heterocyclic, (e) aryl and (~ -Z-R'a wherein Z is (i) -C(R37a)(R37b)- (ii) -C(R47)=C(R48)- (jll) -C=C-, (IV) -C(=O)-, (v) -C(=S)-, (vi) -C(=NR'S)-, (vii) -C(Rs'a)(OR3'c)_, (viii) _ C(Rs~a)(SRs~c)-(iX) _C(R37a)(N(R37b)(R37c))_~ (X) -C(R37a)(R37b)-(~-(Xi) _C(R3~a)(Rs~b)-N(R37c)-, (Xii) -C(R3~a)(Rs~b)_N(O)(Rs~c)-, (xiii) -C(Rs'a)(Rs'b)-N(OH)-, (xiv) -C(R37a)(R37b)-S-(~) -C(R37a)(R37b)-S(O)_, (XVI) -C(R37a)(R37b)-S(0)2-_g-(XVII) -C(R37a)(R37b)-C(=O)-, (XVItI) -C(R37a)(R37b)-C(=S)-~ .
(xix) -C(Rs~a)(Rsm)-C(=NR~5)-, (xx) -C(R3~a)(ORs~c)-C(=O)-, (Xxl) -C(R3~a)(SR37c)-C(=O)- (Xxii) -C(Rs~a)(~R3~c)-C(=S)-(xxiii) -C(R3~a)(SRs~c)-C(=S)-, (xxiv) -C(=O)-C(Rs~a)(ORs~~)-, (xxv) -C(=O)-C(Rs~a)(SRs~c)-, (xxvi) -C(=S)-C(R3~a)(OR3~c)-, (xxvii) -C(=S)-C(Rs~a)(SRs~c)-, (Xxviii) -C(Rs~a)(OFts~c)-C(Rs~a)(ORs~c)-, (xxix) -C(Rs~a)(SRs~c)-C(R3~a)(ORs~c)-, (xxx) -C(Rs~a)(ORs7c)-C(R3~a)(SRs~c)-(xxxi) -C(Rs~a)(SRs~c)-C(R3~a)(SR3~c)-, (Xxxii) -C(=O)-C(=O)-, (xxxiii) -C(=S)-C(=S)-, (xxxiv) -C(=O)-O-, (xxxv) -C(=O)-S-, (xxxvi) -C(=S)-O-, (xxxvii) -C(=S)-S-, (xxxviii) -C(=O)-N(R3'a)-, (xxxix) -C(=S)-N(Rs~a)-, (x~) -C(R3~a)(Rs7b)-C(=O)-N(Rs~a)-, (X~I) -C(Rs~a)(Rs~b)-C(=S)-N(Rs~a)-, (x~ll) -C(R37a)(R37b)-C(=O)-O-(X~III) -C(R37a)(R37b)-C(=O)-S-, (x~IV) -C(R37a)(R37b)-C(=S)-O-(X~V) -C(R37a)(R37b)-C(=S)-S-, (X~VI) -C(R37a)(R37b)-N(R37b)-C(=O)-, (X~VII) -C(Rs~a)(Rs~b)-N(R37b)-C(=S)-, (Xwlll) -C(R37a)(R37b)-O-C(=O)-(xilx) -C(R37a)(R37b)-S-C(=O)-~ (i) -C(R37a)(R37b)-O-C(=S)-(Ii) -C(R37a)(R37b)-S-C(=S)-~ (iii) -C(Rs~a)(R3~b)-N(Rs~b)-C(=~)-N(Rs~a)-, (liii) -C(R37a)(Rs~b)-N(R37b)-C(=S)-N(Rs~a)-, (IIV) -C(R37a)(R37b)-N(R37b)-C(=O)-O-(Iv) _C(R37a)(R37b)-N(R37b)-C(=O)-S-(IVI) -C(R37a)(R37b)-N(R37b)-C(=S)-O-(IVII) -C(R37a)(R37b)-N(R37b)-C(=S)-S-(Iviii) -C(R3'a)(R3~b)-O-C(=O)-N(R3'a)-, (lix) -C(Rs~a)(R3~n)-S-C(=O)-N(R3~a)-, (Ix) _C(Rs~a)(Rs~b)-O-C(=S)-N(Rs~a)-, (IXI) -C(Rs~a)(Rs~b)-S-C(=S)-N(Rs~a)-, (1X11) -C(R37a)(R37b)-O-C(=O)-O-(1X111) -C(Rs~a)(R37b)-S-C(=O)-O-, (IXIV) -C(Rs~a)(R37b)-~-C(=O)-S-, (IXV) -C(R37a)(R37b)-S-C(=O)-S-~ (IXVI) -C(R37a)(R37b)-~-C(=S)-~-(IXVII) -C(R37a)(R37b)-S-C(=S)-O-, (IxVlll) -C(R37a)(R37b)-~-C(= ,~~~, )-S-(IXIX) -C(R37a)(R37b)-S-C(=S)-S- Or (IXX) -C(R37a)(R37b)-C(R37a)(OR37c)-_ R' 4 is (i) hydrogen, (ii) C1-C~2 alkyl, (iii) haloalkyl, (iv) hydroxyalkyl, (v) thiol-substituted alkyl, (vi) R3'°O-substituted alkyl, (vii) R3'°S-substituted alkyl, (viii) aminoalkyl, (ix) (R3'°)NH-substituted alkyl, (x) (R3'a)(R3~')N_susbstituted alkyl, (xi) R3'a0-(O=)C-substituted alkyl, (xii) R3'aS-(O=)C-substituted alkyl, (xiii) R3'a0-(S=)C-substituted alkyl, (xiv) R3'aS-(S=)C-substituted alkyl, (xv) (R3'a0)2-P(=O)-substituted alkyl, (xvi) cyanoalkyl, (xvi) CZ-C~z alkenyl, (xviii) haloalkenyl, (xix) C2-C~2 alkynyl, (xx) cycloalkyl, (xxi) (cycloalkyl)alkyl, (xxii) (cycloalkyl)alkenyl, (xxiii) (cycloalkyl)alkynyl, (xxiv) cycloalkenyl, (xxv) (cycloalkenyl)alkyl, (xxvi) (cycloalkenyl)alkenyl, (xxvii) (cycloalkenyl)alkynyl, (xxviii) aryl, (xxix) (aryl)alkyl, (xxx) (aryl)alkenyl, (xxxi) (aryl)alkynyl, (xxxii) heterocyclic, (xxxiii) (heterocyclic)alkyl, (xxxiv) (heterocyclic)alkenyl or (xxxv) (heterocyclic)alkynyl, with the proviso that R'4 is other than hydrogen when Z is _C(R37a)(R37b)-N(R37b)-C(=O)-O- -C(R37a)(R37b)-N(R37b)-C(=S)-O-TC(R37a)(R37b)-N(R37b)-C(=O)-S- _C(R3~a)~R3~b)-N(Rs~b)-C(=S)-S-_C(R37a)(R37b)-O-C(=O)-O- _C(R37a)(R37b)-O-C(=S)-O-'C(R37a)(R37b)-S-C(=O)-O- rC(R37a)(R37b)-S-C(-S)-O-!C(R37a)(R37b)-O-C(=O)-S- ~C(Rs~a)(Rs~b)-~-C(=S)-S-_C(R37a)(R37b)-S-C(=O)-S- ~r _C(R37a)(R37b)-S-C(=S)-S-Rs~a, R37b Ray, and R4$ at each occurrence are independently selected from the group consisting of (i) hydrogen, (ii) Ci-C~2 alkyl, (iii) haloalkyl, (iv) hydroxyalkyl, (v) alkoxyalkyl, (vi) C2-C~2 alkenyl, (vii) haloalkenyl, (viii) C2-C~2 alkynyl, (ix) cycloalkyl, (x) (cycloalkyl)alkyl, (xi) (cycloalkyl)alkenyl, (xii) (cycloalkyl)alkynyl, (xiii) cycloalkenyl, {xiv) (cycloalkenyl)alkyl, (xv) (cycloalkenyl)-alkenyl, (xvi) (cycloalkenyl)alkynyl, (xvii) aryl, (xviii) (aryl)alkyl, (xix) (aryl)alkenyl, (xx) (aryl)alkynyl, (xxi) heterocyclic, (xxii) (heterocyclic)alkyl, (xxiii) (heterocyclic)alkenyl and (xxiv) (heterocyclic)alkynyl;
R3'' at each occurrence is independently selected from the group consisting of (i) hydrogen, (ii) C~-C~z alkyl, (iii) haloalkyl, {iv) C2-C~2 alkenyl, (v) haloalkenyl, (vi) C2-C~2 alkynyl, (vii) cycloalkyl, (viii) (cycloalkyl)alkyl, (ix) (cycloalkyl)alkenyl, (x) (cycloalkyl)alkynyl, (xi) cycloalkenyl, (xii) (cycloalkenyl)alkyl, (xiii) (cycloalkenyl)alkenyl, (xiv) (cycloalkenyl)alkynyl, (xv) aryl, (xvi) (aryl)alkyl, (xvii) (aryi)alkenyl, (xviii) (aryl)alkynyl, (xix) heterocyclic, (xx) (heterocyclic)alkyl, (xxi) (heterocyclic)alkenyl, (xxii) (heterocyclic)alkynyl, (xxiii) -C(=O)-R'4, (xxiv) -C(=S)-R'4, (xxv) -S(O)2-R'4 and (xxvi) hydroxyalkyl;
or when Z is -C(R3'a)(R3'b)-N(R3'c)-, then N(R3'') and R'4 when taken together are an azido group;
or when Z is -C(R3'a)(R3~b)-N(O)(R3'°)-, then N(O)(R3~') and R'4 when taken together are an N-oxidized 3-7 membered heterocyclic ring having at least one N-oxidized ring nitrogen atom;
or when Z is -C(R3~a)(OR3~c)-, --C(R3~a)(SRs'c)- or -C(R3~a)(N(R3'b)(R3'c))_, then R3~a, R'4 and the carbon atom to which they are bonded when taken together form a cyclopentyl, cyclopentenyf, cyclohexyl or cyclohexenyl ring;
R'~ is selected from the group consisting of (i) hydrogen, (ii) hydroxy, (iii) amino, (iv) C~-C~2 alkyl, (v) haloalkyl, (vi) C2-C~2 alkenyl, (vii) haloalkenyl, (viii) cycloalkyl, (ix) (cycloalkyl)alkyl, (x) (cycloalkyl)alkenyl, (xi) cycloalkenyl, (xii) (cycloalkenyl)alkyl, (xiii) (cycloalkenyl)alkenyl, (xiv) aryl, (xv) (aryl)alkyl, (xvi) (aryl)alkenyl, (xvii) heterocyclic, (xviii) (heterocyclic)alkyl and (xix) (heterocyclic)alkenyl;
or R3 and R4 taken together, with the atom to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 8 ring atoms;
R~ at each occurrence is independently selected from the group consisting of (a) hydrogen, (b) -CH(R3$)2, (c) -(CH2),-O-R4°, (d) C2-C4 alkynyl, (e) cyclopropyl, (f) cyclobutyl, (g) -C(=Q')-R", and (h) -(CHZ)~-N(R'9)2 wherein r is 0, 1 or 2; with the proviso that when one R5 is -O-R4° or -N(R'9)2, then the other R5 is other than -O-R4° or -N(R'9)2;
wherein Q' is O, S, or N(R'B);
R" and R'8 are independently selected, at each occurrence, from the group consisting of hydrogen, methyl, and ethyl;
R'9, R38, and R4° are independently selected, at each occurrence, from the group consisting of (i) hydrogen, (ii) C,-C~2 alkyl, {iii) haloalkyl, (iv) Cz-C,2 alkenyl, (v) haloalkenyi, (vi) cycloalkyl, (vii) (cycioalkyl)alkyl, (viii) (cycloalkyl)alkenyl, (ix) cycloalkenyl, (x) (cycloalkenyl)alkyl, (xi) (cycloalkenyl)alkenyl, {xii) aryl, (xiii) (aryl)alkyl, (xiv) (aryl)alkenyl, (xv) heterocyclic, (xvi) (heterocyclic)alkyl and (xvii) (heterocyclic)alkenyl;
or one R~9 is an N-protecting group;
or the two R~ groups taken together with the carbon atom to which they are bonded, form a carbocyclic or heterocyclic ring having from 3 to 6 ring atoms;
Y is selected from the group consisting of (a) C~-C5 alkyl, (b) C,-C5 haloalkyl, (c) C2-C5 alkenyl, (d) C2-C5 haloalkenyl, (e) CZ-C5 alkynyl, (f) C3-C5 cycloalkyl, (g) C3-C5 cycloalkyl-C~-to-C3-alkyl, (h) C5 cycloalkenyl, (i) C5 cycloalkenyl-C~-to-C3-alkyl, (j) C5 cycloalkenyl-C2-to-C3-alkenyl, (k) -(CHR39)~OR2°, (I) -CH(OR2°)-CHz(OR2°), (m) -(CHR39)~SR2', (n) phenyl, (o) halo-substituted phenyl, {p) -(CHR39)~C(=Q2)R22, {q) -(CHR39)~N(=Q3), (r) -N(O)=CHCH3, (s) -(CHR39)~N(CH3)R24 and (t) a heterocyclic ring having from 3 to 6 ring atoms;
wherein n is 0, 1, or 2; Q2 is O, S, NRZ5, or CHR26; and Q3 is NR4', or CHR42;
R2° at each occurrence is independently (i) methyl, (ii) ethyl, (iii) n-propyl, (iv) isopropyl, (v) C~-C3 haloalkyl, (vi) vinyl, (vii) propenyl, (viii) isopropenyl, (ix) ally!, (x) C2-C3 haloalkenyl, (xi) amino, (xii) -NHCH3, (xiii) -N(CH3)2, (xiv) -NHCH2CH3, (xv) -N(CH3)(CH2CH3), (xvi) -N(CH2CH3)2 or (xvii) -N(=CH2);
R2' is (i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl, (vi) C,-C3 haloalkyl, (vii) vinyl, (viii) propenyl, (ix) isopropenyl, (x) ally! or (xi) C2-C3 haloalkenyl;
RZ2 is (i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl, (vi) hydroxy, (vii) thiol, (viii) methoxy, (ix) ethoxy, (x) n-propoxy, (xi) isopropoxy, (xii) cyclopropyloxy, (xiii) methylthio, (xiv) ethylthio, (xv) n-propylthio, (xvi) isopropylthio, {xvii) cyclopropylthio, (xviii) vinyl, (xix) propenyl, (xx) isopropenyl, (xxi) ally!, (xxii) -N(R28a)(RZSb), (xxiii) -CH2Rz9, (xxiv) aminomethyl, (xxv) hydroxymethyl, (xxvi) thiolmethyl, (xxvii) -NHNH2, (xxviii) -N{CH3)NH2 or (xxix) -NHNH(CH3);
R23 and R39 are independently hydrogen or methyl;
R4' and R42 are independently hydrogen, methyl, or ethyl;
R24 is selected from the group consisting of (i) hydrogen, (ii) C~-C4 alkyl, (iii) C2-C4 alkenyl, (iv) C2-C4 alkynyl, (v) cyclopropyl, (vi) -C{=Q4)-R3°, (v) -OR3', and (vi) -N(R3Z)2, wherein Q4 is O, S, or N(R3s);
Rz5 is hydroxy, methyl, ethyl, amino, -CN, or -N02;
R26 group is hydrogen, methyl or ethyl ;
RZ8a hydrogen, hydroxy, methyl, ethyl, amino, -NHCH3, -N(CH3)2, methoxy, ethoxy, or -CN;
RZ8b is hydrogen, methyl or ethyl;
or RZaa, RZab and the nitrogen to which they are bonded taken together represent azetidinyl;
R29 group is hydrogen, hydroxy, thiol, methyl, ethyl, amino, methoxy, ethoxy, methylthio, ethylthio, methylamino or ethylamino;
R3° group is hydrogen, methyl, ethyl, -OR3'°, -SR34, -N(R35)z, -NHOH, -NHNH2, -N(CH3)NHZ, or -N(CHZCH3)NH2;
R3' and R32 substituents, at each occurrence, are independently hydrogen, methyl or ethyl;
R33 group is hydrogen, hydroxy, methyl, ethyl, amino, -CN, or -N02;
R34 group is methyl or ethyl;
R35 group is independently hydrogen, methyl or ethyl;
with the proviso that when Qz is CHRzs then Rzz is selected from the group consisting of hydrogen, -CH3, -CZH$, -C3H~, -OCH3, -SCH3, -O-CZH5, and -S-CzHs;
Rs and R' are independently selected from the group consisting of (a) hydrogen, (b) C~-C~z alkyl, (c) Cz-C~2 alkenyl, (d) cycloalkyl, (e) (cycloalkyl)alkyl, (f) (cycloalkyl)alkenyl, (g) cycloalkenyl, (h) (cycloalkenyl)alkyl, (i) (cycloalkenyl)alkenyl, (j) aryl, (k) (aryl)alkyl, (I) (aryl)alkenyl, (m) heterocyclic, (n) (heterocyclic)alkyl, (o) (heterocyclic)alkenyl, (p) -OR~'a and (q) -N(R3'a)z; and R8, R9, and R'° are independently selected from the group consisting of (a) hydrogen, (b) C~-C6 alkyl, (c) Cz-C6 alkenyl, (d) C3-C6 cycloalkyl, (e) C3-C6 cycloalkenyl, and (f) fluorine, with the proviso that the total number of atoms, other than hydrogen, in each of R8, R9, and R'°, is 6 atoms or less.
Preferred compounds of the invention include compounds wherein R3 and R4 are not the same and which have the relative stereochemistry depicted by Formula IV, V, Vl, Vll, VIII or IX:
R9 .R8 ., R9 Rs R1o \ _Rs R1o Rs R2-.X Z1~...,,,,.~R1 R2'_X~~~'~~. Z1 °~'~~R1 R4 ~ R7 Ra ~ R7 R3 Rs IV V
R8 Yes.. /R
R~ o ..,.
Rio ~ R~
R~ R2-X
R2-X~~.,,,. a R~
Ra ~ R~ ~s ERs R ~ 3 ~5 R
R R R
VI VII
R
R9 Q$ .. R .
Rio ~ Rio R~
R2 -X~~.,,,.
Ra ~ R~ (s Ra Is R R5 VIII IX
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R', R2, R3, R4, R5, R6, R', R8, R9, R'°, X , Y and Z' are as defined above.
Other preferred compounds of the invention are compounds having Formula I, I1, III, IV, V, VI, VII, VIII or IX or a salt, ester or prodrug thereof wherein R' is defined as above;
-X-R2 is RZ-C(=O)-NH-, R2-NH-C(=O)-, RZ-NH-SO~- or R2-S02-NH-wherein R2 is C,-C3 loweralkyl, halo C~-C3 loweralkyl, C2-C3 alkenyl or halo alkenyl or -X-R2 is ~o Y~
\ ~N_~_ Yz wherein Y' is -CHZ-, -O-, -S- or -NH- and Y2 is -C(=O)- or -C(Raa)( Rbb)-wherein Raa and Rbb are independently selected from the group consisting of hydrogen, C~-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and -Z-R'4 wherein Z and R'4 are defined as above and wherein one of R3 and R4 is other than hydrogen;
Z' is -O-, -S- or -CH(R5)- wherein R5 is hydrogen, loweralkyl or -(CH2)~N(R'9)2 wherein r and R,9 are defined as above; or R5 is hydrogen, loweralkyl or -(CH2)~N(R'9)2 wherein r and R~9 are defined as above;
R6 and R' are independently hydrogen or loweralkyl;
R8 and Rg are independently hydrogen, fluoro or loweralkyl;
R'° is hydrogen, fluoro or loweralkyl; and Y is C2-C5 alkenyl, C2_C5 haloalkenyl, -C(=Qz)R22, -N(=Q3), -N(O)=CHCH3, -NR23R2a or a heterocyclic ring having from 3 to 6 ring atoms, wherein R22, R23, RZa, Q2 and Q3 are defined as above.
More preferred compounds of the invention are compounds having Formula I, II, III. 1V, V, VI, VII, VIII or IX or a salt, ester or prodrug thereof wherein R' is defined as above;
-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-S02- or R2-SOZ-NH-wherein R2 is C~-C3 loweralkyl, halo C~-C3 loweralkyl, C2-C3 alkenyl or halo alkenyl or -X-R2 is O
Y~
,N-wherein Y' is -CH2- and Y2 is -C(=O)- or -C(Raa)( Rbb)- wherein Raa and Rbb are independently selected from the group consisting of hydrogen, C~-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and -Z-R'4 wherein Z and R'4 are defined as above and wherein one of R3 and R4 is other than hydrogen;
Z' is -O-, -S- or -CH(R5)- wherein R5 is hydrogen, loweralkyl or -(CH2)~N(R'9)Z wherein r and R'9 are defined as above; or R5 is hydrogen, loweralkyl or-(CH2)~N(R'9)2 wherein r and R'9 are defined as above;
Rs and R' are independently hydrogen or loweralkyl;
R$ and R9 are independently hydrogen or loweralkyl;
R'° is hydrogen or loweralkyl; and Y is C2-C~ alkenyl, Cz_C5 haloalkenyl, -C(=QZ)R22, -N(=Q3), -N(O)=CHCH3 or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds, wherein R22, Q2 and Q3 are defined as above.
Even more preferred compounds of the invention are compounds having Formula Formula I, II, 111, IV, V, VI, VII, VIII or IX or a salt, ester or prodrug thereof wherein R' is defined as above;
-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SOZ- or R2-SOZ-NH-wherein R2 is C~-C3 loweralkyl, halo C~-C3 loweralkyl, CZ-C3 alkenyl or halo C~-C3 alkenyl or -X-R2 is O
Y~
,N-wherein Y' is -CH2- and Y2 is -C(=O)- or -C(Raa)( Rbb)- wherein Raa and Rbb are independently selected from the group consisting of hydrogen, C~-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and -Z-R'4 wherein Z and R'4 are defined as above and wherein one of R3 and R4 is other than hydrogen;
Z' is -O-, -S- or -CH(R5)- wherein R5 is hydrogen, loweralkyl or -(CHZ)~N(R'9)2 wherein r and R~9 are defined as above; or R5 is hydrogen, loweralkyl or -(CH2)~N(R'9)2 wherein r and R~9 are defined as above;
R6 and R' are independently hydrogen or loweralkyl;
R$ and R9 are independently hydrogen or loweralkyl;
R'° is hydrogen or loweralkyl; and Y is C2-C5 alkenyl, C2_C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
More highly preferred compounds of the invention are compounds having Formula I, II, III, IV, V, VI, VII, VIII or IX or a salt, ester or prod rug thereof wherein R' is -C02H;
-X-Rz is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-S02- or RZ-S02-NH- wherein Rz is C,-C3 loweralkyl or halo- C~-C3 loweralkyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and -Z-R'4 wherein Z and R'4 are defined as above and wherein one of R3 and R4 is other than hydrogen;
Z' is -O-, -S- or -CH2-; or R5 is hydrogen;
R6 and R' are independently hydrogen or loweralkyl;
Ra and R9 are hydrogen independently hydrogen or loweralkyl;
R'° is hydrogen or loweralkyl; and Y is C2-C5 alkenyl, C2_C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
Even more highly preferred compounds of the invention are compounds having Formula l, II, III, IV, V, VI, VII, VIII or IX or a salt, ester or prodrug thereof wherein R' is -C02H;
-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-S02- or R2-S02-NH- wherein R2 is C,-C3 loweralkyl or halo- C,-C3 ioweralkyl;
R4 is hydrogen or loweralkyl and R3 is heterocyclic or -Z-R'4 wherein Z
and R'4 are defined as above;
Z' is -O-, -S- or -CH2-; or R5 is hydrogen;
Rs and R' are hydrogen;
R$ and R9 are hydrogen;
R'° is hydrogen; and Y is C2-C5 alkenyl, C2_C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
Other even more highly preferred compounds of the invention are compounds having Formula I, II, Ill, IV, V, VI, VII, VIII or IX or a salt, ester or prodrug thereof wherein R' is -C02H;
-X-R2 is R2-C(=O)-NH-, RZ-NH-C(=O)-, RZ-NH-S02- or RZ-S02-NH- wherein RZ is C~-C3 loweralkyl or halo C~-C3 loweralkyl;
R4 is hydrogen or loweralkyl and R3 is (a) heterocyclic, (b) alkyl, (c) cycloalkyl, (d) cycloalkylalkyl, (e) alkenyl, (f) alkynyl, (g) -C(=O)-R'4, (h) -C(Rs~a)(OR3~c)-R,a or (i) -C(Rs~a)(Rs~b)-N(O)(R3~c)R~4 wherein R'4 is (i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl, (vi) haloalkenyl, (vii) aryl, (viii) arylaikyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R3'a0)-(O=)C-substituted alkyl or (xv) (R3~a0)2-P(=O)-substituted alkyl;
R3'a and R3'b are independently selected from the group consisting of (i) hydrogen, (ii) loweralkyl and (iii) loweralkenyl; and Rs~o is hydrogen, (ii) ioweralkyl or (iii) loweralkenyl;
Z' is -O-, -S- or -CH2-; or R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen;
R'° is hydrogen; and Y is C2-C5 alkenyl, C2_C5 haloalkenyi or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
Most highly preferred compounds of the invention are compounds having Formula I, II, III, IV, V, V1, VII, VIII or IX or a salt, ester or prodrug thereof wherein R' is -C02H;
-X-Rz is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-S02- or R2-SOZ-NH- wherein R2 is C,-C3 loweralkyl or halo C,-C3 loweralkyl;
R4 is hydrogen and R3 is (a) heterocyclic, (b) alkyl or (c) -C(R3'a)(OR3'°)-R'4 wherein R'4 is (i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl, (vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R3~a0)-(O=)C-substituted alkyl or (xv) (R3'a0)2-P(=O)-substituted alkyl;
R3'a and R3'b are independently selected from the group consisting of (i) hydrogen, (ii) loweralkyl and (iii) loweralkenyl; and R3'' is hydrogen, (ii) C~-C3 loweralkyl or (iii) allyl;
Z' is -O-, -S- or -CH2-; or R5 is hydrogen;
R6 and R' are hydrogen;
R8 and R9 are hydrogen ;
R'° is hydrogen; and Y is C2-C5 alkenyl, C2_C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
Other most highly preferred compounds of the invention are compounds having Formula I, II, III, IV, V, VI, VII, VIII or 1X or a salt, ester or prodrug thereof wherein R' is -C02H;
-X-RZ is Rz-C(=O)-NH- or R2-SOZ-NH- wherein R2 is C,-C3 loweralkyl or halo C~-C3 loweralkyl;
R4 is hydrogen and R3 is (a) heterocyclic, (b) alkyl or (c) -C(R3'a)(OR3'c)-R'4 wherein R'4 is (i) loweralkyl, (ii) loweralkenyl, (iii) hydroxy-substituted loweralkyl or (iv) alkoxy-substituted loweralkyl;
R37a jS
(i) hydrogen, (ii) loweralkyl or (iii) loweralkenyl; and R3'' is (i) hydrogen, (ii) C~-C3 loweralkyl or (iii) allyl;
Z' is -O-, -S- or -CH2-; or R5 is hydrogen;
R6 and R' are hydrogen;
R8 and R9 are hydrogen;
R'° is hydrogen; and Y is C2-C5 alkenyl, CZ_C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
Other most highly preferred compounds of the invention are compounds having Formula I, II, III, IV, V, VI, VII, VIII or IX or a salt, ester or prodrug thereof wherein R' is -C02H;
-X-Rz is R2-C(=O)-NH- or R2-S02-NH- wherein R2 is C~-C3 loweralkyl or halo C~-C3 loweralkyl;
R4 is hydrogen and R3 is -C(R3~a)(OR3'')-R'4 wherein R'4 is loweralkyl or loweralkenyl;
R37a jS
loweralkyl or loweralkenyl; and R3~~ is hydrogen, C,-C3 loweralkyl or allyl;
Z' is -O-, -S- or -CHZ-; or R5 is hydrogen;
R6 and R' are hydrogen;
R8 and R9 are hydrogen;
R'° is hydrogen; and Y is C2-C5 alkenyl, C2_C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
Preferred substituents R' include -C02H or esters or prodrugs thereof.
Preferred esters include C2-C6 loweralkyl esters or substituted or unsubstituted benzyl esters. Preferred substituents R' also include-S(O)2NHC(=O)R"
wherein R" is defined as above.
Most highly preferred substituents R' include -C02H or esters or prodrugs thereof. Most highly preferred esters include C2-C6 loweralkyl esters or substituted or unsubstituted benzyl esters.
Preferred substituents -X-R2 include RZ-C(=O)-NH-, R2-NH-C{=O)-, R2-NH-S02- or R2-S02-NH- wherein R2 is C,-C3 loweralkyl, halo C~-C3 loweralkyl, Cz-C3 alkenyl or halo C2-C3 alkenyl or -X-R2 is ~o Y~
\ ~N_~_ ~,2 wherein Y' is -CHz-, -O-, -S- or -NH- and Y2 is -C(=O)- or -C(Raa)( Rbb)-wherein Raa and Rbb are independently selected from the group consisting of hydrogen, C~-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl.
More preferred substituents -X-R2 include R2-C(=O)-NH-, R2-NH-C(=O)-, RZ-NH-SOz- or RZ-SOz-NH- wherein R2 is C,-C3 loweralkyl, halo C,-C3 loweralkyl, C2-C3 alkenyl or halo C2-C3 alkenyl or -X-Rz is /o Yi'-'.~~
\ ~N_~_ Yz wherein Y' is -CHZ- and Y2 is -C(=O)- or -C(Raa)( Rbb)- wherein Raa and Rbb are independently selected from the group consisting of hydrogen, _28_ C,-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl.
Even more preferred substituents -X-R2 include R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SOZ- or R2-SOZ-NH- wherein R2 is C1-C3 loweralkyl, halo C~-C3 loweralkyl, C2-C3 alkenyl or halo C2-C3 alkenyl.
More highly preferred substituents -X-R2 include R2-C(=O)-NH-, RZ-NH-C(=O)-, R2-NH-SO~- or R2-SOZ-NH- wherein R2 is C~-C3 loweralkyl or halo- C,-C3 loweralkyl.
Even more highly preferred substituents -X-R2 include R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SOZ- or R2-S02-NH- wherein R2 is C,-C2 loweralkyl or halo C~-C2 loweralkyl, and especially, CH3-C(=O)-NH-, CF3-C(=O)-NH-, CH3-S02-NH-or CF3-S02-NH-.
Preferred substituents Z' include -O-, -S- or -CH(R5)- wherein R5 is hydrogen, loweralkyl or-(CHz)fN(R'9)2 wherein r and R~9 are defined as above;
or R5 is hydrogen, loweralkyl or-(CH2)~N(R'9)2 wherein r and R~9 are defined as above;
More preferred substituents Z' are -O-, -S- or -CH(R5)- wherein R5 is hydrogen or loweratkyl.
More highly preferred substituents Z' are -O-, -S- or -CH2-.
Even more highly preferred substituents Z' are -O- or -CH2-.
Preferred substituents R3 and R4 are independently selected from the group consisting of hydrogen, heterocyclic and -Z-R'4 wherein Z and R'4 are defined as most broadly defined previously herein and wherein one of R3 and R4 is other than hydrogen.
_29_ More highly preferred, substituent R4 is hydrogen or loweralkyl and R3 includes heterocyclic or -Z-R'4 wherein Z and R'4 are defined as most broadly defined previously herein.
Even more highly preferred, substituent R4 is hydrogen or loweralkyl and R3 includes (a) heterocyclic, (b) alkyl, (c) cycloalkyl, (d) cycloalkylalkyl, (e) alkenyl, (f) alkynyl, (g) -C{=O)-R~4~ (h) -C(R3~a)(OR3~c)-R~4 or {i) -C(Rs~a)(Rs~b)-N(O)(Rs~c)R~4 wherein R'4 is (i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl, (vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R3'a0)-{O=)C-substituted alkyl or (xv) (R3'a0)2-P(=O)-substituted alkyl;
R3'a and R3'b are independently selected from the group consisting of (i) hydrogen, (ii) loweralkyl and (iii) loweralkenyl; and R3'° is (i) hydrogen, (ii) loweralkyl or (iii) loweralkenyl.
Most highly preferred, substituent R4 is hydrogen and R3 includes {a) heterocyclic, (b) alkyl or (c) -C(R3'a){OR3'°)-R'4 wherein R'4 is (i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) aikenyl, (v) haloalkyl, (vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R3'a0)-(O=)C-substituted alkyl or (xv) {R3'a0)2-P(=0)-substituted alkyl;
R3'a and R3'b are independently selected from the group consisting of (i) hydrogen, (ii) loweralkyl and (iii) loweralkenyl; and R3'' is (i) hydrogen, (ii) C~-C3 loweralkyl or (iii) alfyl.
Also most highly preferred, substituent R4 is hydrogen and R3 includes (a) heterocyclic, (b) alkyl or (c) -C(R3'a)(OR3'°)-R'4 wherein R'4 is (i) loweralkyl, (ii) loweralkenyl, (iii) hy~lroxy-substituted loweralkyl or (iv) alkoxy-substituted ioweralkyl;
R3'a is (i) hydrogen, (ii) loweralkyl or (iii) loweralkenyl; and R3'' is (i) hydrogen, (ii) C~-C3 loweralkyl or (iii) allyl.
Also most highly preferred, substituent R4 is hydrogen and R3 includes -C(R3'a)(OR3'~)-R'4 wherein R'4 is loweralkyl or loweralkenyl;
R3'a is loweralkyl or loweralkenyl; and R3'' is hydrogen, C,-C3 loweralkyl or allyl, and especially, wherein R3'' is hydrogen or methyl.
Preferred substituents R5 include those independently selected from hydrogen, loweralkyl and -(CH2)~N(R'9)2 wherein r and R'9 are defined as above.
More preferred substituents R5 are independently selected from hydrogen, lowerafkyl and -(CH2)~N(R'9)2 wherein r is 0 or 1 and one R'9 is hydrogen or loweralkyl and the other R'9 is hydrogen, loweralkyl or an N-protecting group.
Even more preferred substituents R5 are independently selected from hydrogen and loweralkyl.
Most highly preferred, R5 is hydrogen.
Preferred substituents R6 and R' include independently hydrogen and loweralkyl. Most highly preferred, R6 and R' are hydrogen.
Preferred substituents R8, R9 and R'° include independently hydrogen, fluoro and loweralkyl. Most highly preferred, R8, R9 and R'° are hydrogen.
Preferred substituent Y includes CZ-C5 alkenyl, C2_C5 haloalkenyl, -C(=Q2)R22, -N(=Q3), -N(O)=CHCH3, -NR23R2a or a heterocyclic ring having from 3 to 6 ring atoms, wherein R22, R2s, Rza, Q2 and Q3 are defined as above.
More preferred substituent Y includes C2-C5 alkenyl, C2_C5 haloalkenyl, -C(=Q2)R22, -N(=Q3), -N(O)=CHCH3 or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds, wherein R22, Q2 and Q3 are defined as above.
Even more preferred substituent Y includes Cz-C5 alkenyl, CZ_C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds. Representative alkenyl and haloalkenyl substituents Y
include:
-CH=CH2, -CH=CHF, -CH=CH-CH3, -CH=CH-CFa, -CH=CHCI, -CH=CHBr, -CH=CF2, -CH=CF(CH3), -CH=CF(CF3), -CH=CFCI, -CH=CFBr, -CH=C(CH3)2, -CH=C(CH3)(CF3), -CH=CCI(CH3), -CH=CBr(CH3), -CH=G(CF3)Z, -CH=CCl(CF3), -CH=CBr(CF3), -CH=CCIZ, -CH=CCIBr, -CF=CH2, -CF=CHF, -CF=CH-CH3, -CF=CH-CF3, -CF=CHCI, -CF=CHBr, -CF=CF2, -CF=CF(CH3), -CF=CF(CF3), -CF=CFCI, -CF=CFBr, -CF=C(CH3)2, -CF=C(CH3)(CF3), -CF=CCI(CH3), -CF=CBr(CH3), -CF=C{CF3)Z, -CF=CCI(CF3), -CF=CBr(CF3), -CF=CCIZ, -CF=CCIBr, -C(CH3)=CH2. -C(CH3)=CHF, -C{CH3)=CH-CH3, -C(CH3)=CH-CF3, -C(CH3)=CHCi, -C(CH3)=CHBr,-C(CH3)=CFz, -C(CH3)=CF(CH3), -C(CH3)=CF(CF3), -C(CH3)=CFC1, -C(CH3)=CFBr, -C(CH3)=C(CH3)z, -C(CH3)=C(CH3)(CF3), -C(CH3)=CCl{CH3), -C(CH3)=CBr(CH3), -C(CH3)=C(CF3)z, -C{CH3)=CCI(CF3), -C(CH3)=CBr(CF3), -C(CH3)=CCIz, -C(CH3}=CCIBr, -C(CF3)=CHz, -C(CF3)=CHF, -C(CF3)=CH-CH3, -C(CF3)=CH-CF3, -C(CF3)=CHCI, -C(CF3)=CHBr, -C(CF3)=CFz, -C(CF3)=CF(CH3), -C(CF3)=CF(CF3), -C(CF3)=CFCI, -C(CF3)=CFBr, -C(CF3)=C(CH3)z, -C(CF3)=C(CH3)(CF3), -C(CF3)=CCI(CH3), -C(CF3)=CBr(CH3), -C(CF3)=C(CF3)z, -C(CF3)=CCI{CF3), -C(CF3)=CBr(CF3), -C(CF3)=CCiz, -C(CF3)=CCIBr, -CCI=CHz, -CCI=CHF, -CCI=CH-CH3, -CCI=CH-CF3, -CCI=CHCI, -CCI=CHBr, -CCI=CFZ, -CCI=CF(CH3), -CCI=CF(CF3), -CCI=CFCI, -CCI=CFBr, -CCI=C(CHa)z, -CCI=C(CH3)(CF3), -CCI=CCI(CH3), -CCI=CBr{CH3), -CCI=C(CF3)z, -CCI=CCI(CF3), -CCI=CBr(CF3), -CCI=CCIz, -CCI=CCIBr, -CH=CH-CH2CH3, -CH=CF-CHZCH3, -CF=CH-CH2CH3, -CF=CF-CH2CH3, -CH=C(CH3)(CHzCH3), -CF=C(CH3)(CH2CH3), -CH=CCI(CH2CH3), -CF=CCI(CH2CH3), -C(CH3)=CH-CH2CH3, -C(CH3)=CF-CHZCH3, -CCI=CH-CH2CH3, -CCI=CF-CHZCH3, -C(CH2CH3)=CHz, -C(CHZCH3)=CHF, -C(CHZCH3)=CFz, -C(CH2CH3)=CH-CH3, -C(CH2CH3)=CF-CH3, -C(CH2CH3)=CH-CI, -C(CH2CH3)=CFCI.
Representative Y substituents which are heterocyclic rings having 5 ring atoms and also containing one or two double bonds include:
furanyl, dihydrofuranyl, didehydrodioxolanyl, dithiolyl, imidazolyl, imidazolinyl, isothiazolyl, isothiazolinyl, isoxazolyl, isoxazolinyl, oxadiazolyl, oxadiazolinyl, oxathiolyl, oxazolyl, oxazolinyl, pyrazolyl, pyrazolinyl, pyrrolyl, dihydropyrrolyl, tetrazolyl, tetrazoiinyl, thiadiazolyl, thiadiazolinyi, thiazolyl, thiazolinyl, thienyl, dihydrothienyl, triazolyl, triazolinyl.
More highly preferred substituents Y include cis-propenyl, trans-propenyl, isobutenyl, cis-2-chlorovinyl, vinyl, 2,2-difluorovinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazoiyl, thiazolyl, isoxazolyl.
Most highly preferred substituents Y include cis-propenyl, cis-2-chlorovinyl, vinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isoxazolyl.
The term "acid protecting group" as used herein refers to groups used to protect acid groups (for example, -C02H, -S03H, -SOZH, -P03H2, -PO2H groups and the like) against undesirable reactions during synthetic procedures.
Commonly used acid protecting groups are disclosed in T.H. Greene and P.G.M.
Wuts, Protective Groins in Organic Synthesis. 2nd edition, John Wiley & Sons, New York (1991 ). Most frequently, such acid protecting groups are esters.
Such esters include:
alkyl esters, especially loweralkyl esters, including, but not limited to, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl esters and the like;
arylalkyl esters including, but not limited to, benzyl, phenethyl, 3-phenylpropyl, naphthylmethyl esters and the like, wherein the aryl part of the arylalkyl group is unsubstituted or substituted as previously defined herein;
silylesters, especially, (tri-loweralkyl)silyl esters, (di-loweralkyl)(aryl)silyl esters and (loweralkyl)(di-aryl)silyl esters, including, but not limited to, trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl, methyldiphenylsilyl, isopropyldiphenylsilyl, butyldiphenylsilyl, phenyldiisopropylsilyl esters and the like;
and the like.
Preferred acid protecting groups are loweralkyl esters.
The term "activated carboxylic acid group" as used herein refers to acid halides such as acid chlorides and also refers to activated ester derivatives including, but not limited to, formic and acetic acid derived anhydrides, anhydrides derived from alkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like, anhydrides derived from reaction of the carboxylic acid with N,N'-carbonyldiimidazole and the like, N-hydroxysuccinimide derived esters, N-hydroxyphthalimide derived esters, N-hydroxybenzotriazole derived esters, N-hydroxy-5-norbornene-2,3-dicarboximide derived esters, 2,4,5-trichlorophenol derived esters, p-nitrophenol derived esters, phenol derived esters, pentachlorophenol derived esters, 8-hydroxyquinoline derived esters and the like.
The term "acyl" as used herein, refers to groups having the formula -C(=O)-R95 wherein R95 is hydrogen or an alkyl group. Preferred alkyl groups as R95 are loweralkyl groups. Representative examples of acyl groups include groups such as, for example, formyl, acetyl, propionyl, and the like.
The term "acyfamino" as used herein, refers to groups having the formula -NHR89 wherein R89 is an acyl group. Representative examples of acylamino include acetylamino, propionylamino, and the like.
The term "alkenyl" as used herein, refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond. The term "lower alkenyl" refers to straight or branched chain alkenyl radicals containing from 2 to 6 carbon atoms.
Representative examples of alkenyl groups include groups such as, for example, vinyl, 2-propenyl, 2-methyl-1-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl and the like.
The term "alkenylene" as used herein, refers to a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond. The term "lower alkenylene" refers to a divalent group derived from a straight or branched chain alkene group having from 2 to 6 carbon atoms. Representative examples of alkenylene groups include groups such as, for example, -CH=CH-, -CH2CH=CH-, -C(CH3)=CH-, -CH2CH=CHCH2-, and the like.
The term "alkenyloxy" as used herein, refers to groups having the formula -OR8' where RB' is an alkenyl group.
The term "alkoxy" as used herein, refers to groups having the formula -OR99 wherein R99 is an alkyl group. Preferred R99 groups are loweralkyl groups.
Representative examples of alkoxy groups include groups such as, for example, methoxy, ethoxy, tent-butoxy, and the like.
The term "alkoxyalkoxy" as used herein, refers to groups having the formula -O-R9s-O-R9' wherein R9' is loweralkyl, as defined herein, and R96 is a lower alkylene group. Representative examples of alkoxyalkoxy groups include groups such as, for example, rnethoxymethoxy, ethoxymethoxy, t butoxymethoxy and the like.
The term "alkoxyaikyl" as used herein refers to an alkyl radical to which is appended an alkoxy group, for example, methoxymethyl, methoxylpropyl and the like.
The term "alkoxycarbonyl" as used herein, refers to groups having the formula, -C(=O)- R8°, where R$° is an alkoxy group.
The term "alkoxycarbonylalkyl" as used herein, refers to groups having the formula, -C(=O)- R'9, appended to the parent molecular moiety through an alkylene linkage, where R'9 is an alkoxy group.
As used herein, the term "alkyl" refers to straight or branched chain hydrocarbon radicals containing from 1 to 12 carbon atoms. The term "loweralkyl" refers to straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms. Representative examples of alkyl groups include groups such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethyl-propyl, n-hell, and the like. The hydrocarbon chains in alkyl groups or the alkyl portion of an alkyl-containing substituent can be optionally interrupted by one or two heteroatoms or heterogroups independently selected from the group consisting of oxygen, -N(R2')- and sulfur wherein R2' at each occurrence is independently hydrogen, loweralkyl, cylcoalkyl, cycloalkylalkyl or arylalkyl and wherein two such heteroatoms or heterogroups are separated by at least one carbon atom.
The term "alkylamino" as used herein, refers to groups having the formula -NHR9' wherein R9' is an alkyl group. Preferred R9' groups are loweralkyl groups. Representative examples of alkylamino include methylamino, ethylamino, and the like.
The term "alkylene" as used herein, refers to a divalent group derived from a straight or branched chain saturated hydrocarbon group having from 1 to 15 carbon. The term "lower alkylene" refers to a divalent group derived from a straight or branched chain saturated hydrocarbon group having from 1 to 6 carbon atoms. Representative examples of alkylene groups include groups such as, for example, methylene (-CH2-), 1,2-ethylene (-CH2CH2-), 1,1-ethylene (-CH(CH3)-), 1,3-propylene (-CH2CH2CHz-), 2,2-dimethylpropylene (-CH2C(CH3)2CH2-), and the like. The hydrocarbon chains in alkylene groups or the alkylene portion of an alkylene-containing substituent can be optionally interrupted by one or two heteroatoms or heterogroups independently selected from the group consisting of oxygen, -N(R2')- and sulfur wherein R2' at each occurrence is independently hydrogen, loweralkyl, cylcoalkyl, cycloalkylalkyl or arylalkyl and wherein two such heteroatoms or heterogroups are separated by at least one carbon atom.
The term "alkylsulfonyl" as used herein refers to the group having the formula, -S02-R'$, where R'8 is an alkyl group. Preferred groups R'8 are loweralkyl groups.
The term "alkylsulfonylamino" as used herein refers to the group having the formula, -S02-R", appended to the parent molecular moiety through an amino linkage (-NH-), where R" is an alkyl group. Preferred groups R" are loweralkyl groups.
The term "alkynyl" as used herein, refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon triple bond. The term "lower alkynyl" refers to straight or branched chain alkynyl radicals containing from 2 to 6 carbon atoms.
Representative examples of alkynyl groups include groups such as, for example, acetylenyl, 1-propynyl, 2- propynyl, 3-butynyl, 2-pentynyl, 1-butynyl and the like.
The term "alkynylene" as used herein, refers to a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon triple bond. The term "lower alkynylene" refers to a divalent group derived from a straight or branched chain alkynylene group from 2 to 6 carbon atoms. Representative examples of alkynyfene groups include groups such as, for example, -C=C-, -CHZ-C---C-, -C---C-CH2-, -CH{CH3)-C=C-, and the like.
The term "aminoalkyl" as used herein refers to an alkyl radical to which is appended an amino (-NHZ) group.
The term "aryl" as used herein refers to a carbocyclic ring system having 6-10 ring atoms and one or two aromatic rings. Representative examples of aryl groups include groups such as, for example, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.
The aryl groups can be unsubstituted or substituted with one, two or three substituents, each independently selected from loweralkyl, halo, haloalkyl, haloalkoxy, hydroxy, oxo (=O), hydroxyalkyl, afkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, thioalkoxy, amino, alkylamino, alkylsulfonyl, dialkylamino, acylamino, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted arylalkoxy, unsubstituted aryloxy, mercapto, cyano, vitro, carboxy, carboxaldehyde, NH2C(=O)-, cycloalkyl, carboxyalkyl, alkylsulfonylamino, unsubstituted heterocyclic, unsubstituted (heterocyclic)alkyl, unsubstituted (heterocyclic)alkoxy, unsubstituted (heterocyclic)oxy and -SOaH. Preferred aryl substituents are each independently selected from the group consisting of loweralkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, alkenyloxy, alkoxy, alkoxyalkoxy, thioalkoxy, amino, alkylamino, dialkylamino, alkylsulfonyl, acylamino, cyano and vitro. Examples of substituted aryl include 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 4-methylsulfonylphenyl, and the like.
The term "(aryl)alkenyl" refers to a lower alkenyl group having appended thereto an aryl group. Representative examples of (aryl)alkenyl groups include groups such as, for example phenylethylenyl, phenylpropenyl, and the like.
The term "(aryl)alkyl" refers to a loweralkyl group having appended thereto an aryl group. Representative examples of (aryl)alkyl groups include groups such as, for example benzyl and phenylethyl.
The term "arylalkoxy" as used herein refers to the group having the formula, -O-R'6 where R'6 is an arylalkyl group.
The term "(aryl)alkynyl" refers to an alkynylene group having appended thereto an aryl group. Representative examples of (aryl)alkynyl groups include groups such as, for example phenylacetylenyl, phenylpropynyl, and the like.
The term "aryloxy" as used herein refers to the group having the formula, -O-R'z, where R'2 is an aryl group.
The term "carbamoyl" as used herein refers to the group having the formula, -C(=O)-NH2.
The term "carboxyalkyl" as used herein, refers to the group having the formula, -R~-COOH, where Rfia is a lower alkylene group.
The term "cyanoalkyl" as used herein refers to an alkyl radical to which is appended a cyano group (-CN).
The term "cycloalkenyl" as used herein refers to an aliphatic ring system having 5 to 10 carbon atoms and 1 or 2 rings containing at least one double bond in the ring structure. Representative examples of cycloalkenyl groups include groups such as, for example, cyclohexene, cyclopentene, norbornene and the like.
Cycloalkenyl groups can be unsubstituted or substituted with one, two or three substituents independently selected hydroxy, halo, amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, thioalkoxy, haloalkyl, mercapto, loweralkenyl and loweralkyl. Preferred substitutents are independently selected from loweralkyl, loweralkenyl, haloalkyl, halo, hydroxy and alkoxy.
The term "(cycloalkenyl)alkenyl" as used herein refers to a cycloalkenyl group appended to a lower alkenyl radical. Representative examples of (cycloalkenyl)alkenyl groups include groups such as, for example, cyclohexenylethylene, cyclopentenylethylene, and the like.
The term "(cycloalkenyl)alkyl" as used herein refers to a cycloalkenyl group appended to a lower alkyl radical. Representative examples of (cycloalkenyl)alkyl groups include groups such as, for example, cyclohexenylmethyl, cyclopentenylmethyl, cyclohexenylethyl, cyclopentenylethyl, and the like.
The term "(cycloalkenyl)alkynyl" as used herein refers to a cycloalkenyl group appended to a lower alkynyl radical. Representative examples of (cycloalkenyl)alkynyl groups include groups such as, for example, cyclohexenylacetylenyl, cyclopentenylpropynyl, and the like.
The term "cycloalkyl" as used herein refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 or 2 rings. Representative cylcoalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornane, bicyclo[2.2.2]octane and the like.
Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected hydroxy, halo, amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, thioalkoxy, haloalkyl, mercapto, ioweralkenyl and Ioweralkyl. Preferred substitutents are independently selected from loweralkyl, loweralkenyl, haloalkyl, halo, hydroxy and alkoxy.
The term "(cycloalkyl)alkyl" as used herein refers to a cycloalkyl group appended to a loweralkyl radical. Representative examples of (cycloalkyl)alkyl groups include groups such as, for example, cyclohexylmethyl, cyclopentylmethyl, cyclohexylethyl, cyclopentylethyl, and the like.
The term "(cycloalkyl)alkenyl" as used herein refers to a cycloalkyl group appended to a lower alkenyl radical. Representative examples of (cycloalkyl)-alkenyl groups include groups such as, for example, cyclohexylethylene, cyclopentylethylene, and the tike.
The term "(cycloalkyl)alkynyl" as used herein refers to a cycloalkyl group appended to a lower alkynyl radical. Representative examples of (cycloalkyl)-alkynyl groups include groups such as, for example, cyclohexylacetylenyl, cyclopentylpropynyl, and the like.
The term "dialkylamino" as used herein, refers to groups having the formula -N(R9°)2 wherein each R9° is independently a lower alkyl group.
Representative examples of dialkylamino include dimethylamino, diethylamino, N-methyl-N-isopropylamino and the like.
The term "halo" as used herein refers to F, C1, Br or I.
The term "haloalkenyl" as used herein refers to a lowerafkenyl group in which one or more hydrogen atoms is replaced with a halogen. Examples of haloalkenyl groups include 2-fluoroethylene, 1-chloroethylene, 1,2-difluoroethylene, trifluoroethylene, 1,1,1-trifluoro-2-propylene and the like.
The term "haloalkoxy" as used herein refers to the group having the formula, -OR69, where R69 is a haloalkyl group as defined herein. Examples of haloalkoxy include chloromethoxy, fluoromethoxy, dichloromethoxy, trifluoromethoxy and the like.
The term "haloalkyl" as used herein, refers to a loweralkyl group in which one or more hydrogen atoms has been replaced with a halogen including, but not limited to, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, fluoromethyl, chloromethyl, chloroethyl, 2,2-dichloroethyl, pentafluoroethyl and the like.
The term "heterocyclic ring" or "heterocyclic" or "heterocycle" as used herein, refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-mernbered ring containing one, two, three, or four nitrogen atoms; one oxygen atom; one sulfur atom; one nitrogen atom and one sulfur atom; two nitrogen atoms and one sulfur atom; one nitrogen atom and one oxygen atom; two nitrogen atoms and one oxygen atom;
two oxygen atoms in non-adjacent positions; one oxygen atom and one sulfur atom in non-adjacent positions; or two sulfur atoms in non-adjacent positions.
The 5-membered ring has 0-2 double bonds and the 6- and 7-membered rings have 0-3 double bonds. The nitrogen heteroatoms can be optionally quaternized.
The term "heterocyclic" also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocycfic ring, such as, for example, indolyl, dihydroindolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl and the like.
Heterocyclic groups include, but are not limited to groups such as, for example, aziridinyl, azetidinyl, epoxide, oxetanyl, thietanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, tetrahydropyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazofidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, oxetanyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, thienyl, dihydrothienyl, tetrahydrothienyl, triazolyl, triazolinyl, tetrazolyl, tetrazolinyl, isoxazolyl, 1,2,3-oxadiazoiyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, oxadiazolinyl, , 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, thiadiazolinyl,l,3-dithiolinyl, 1,2-dithiolyl, 1,3-dithiolyl, 1,3-dioxolinyl, didehydrodioxolanyl, 1,3-oxathiolinyl, oxathiolyl, pyrimidyl, benzothienyl and the like. Heterocyclic groups also include compounds of the formula x*
Y*
/ i O
where X* is -CH2 or -O- and Y* is -C(O)- or [-C(R92)2-]~ where R92 is hydrogen or C~-C4 alkyl where v is 1, 2, or 3 such as 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like. Heterocyclic groups also include bicyclic rings such as quinuclidinyl and the like.
Heterocyclic groups can be unsubstituted or substituted with from one to three substituents, each independently selected from loweralkyl, hydroxy, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino and halogen. In addition, nitrogen containing heterocyclic rings can be N-protected.
The term "(heterocyclic)alkenyl" as used herein refers to a heterocyclic group appended to a lower alkenyl radical including, but not limited to, pyrrolidinylethenyl, morpholinylethenyl and the like.
The term "(heterocyclic)alkoxy" as used herein refers to the group having the formula, -OR68, where R6$ is a (heterocyclic)alkyl group.
The term "(heterocyclic)alkyl" as used herein refers to a heterocyclic group appended to a loweralkyl radical including, but not limited to, pyrrolidinylmethyl, morpholinylmethyl and the like.
The term "(heterocyclic)alkynyl" as used herein refers to a heterocyclic group appended to a lower alkynyl radical including, but not limited to, pyrrolidinylacetylenyl, morpholinylpropynyl and the like.
The term "(heterocyclic)oxy" as used herein refers to a heterocyclic group appended to the parent molecular moiety through an oxygen atom (-O-) The term "hydroxy protecting group", "hydroxyl protecting group" or "-OH
protecting group" as used herein refers to refers to groups used to hydroxy groups against undesirable reactions during synthetic procedures. Commonly used hydroxy protecting groups are disclosed in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis. 2nd edition, John Wiley & Sons, New York (1991 ). Such hydroxy protecting groups include:
methyl ether;
substituted methyl ethers, including, but not limited to, methoxymethyl, methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl, t-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tetrahydrothiopyranyi, tetrahydrofuranyl, tetrahydrothiofuranyl ether and the like;
substituted ethyl ethers, including, but not limited to, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 2,2,2-trichloroethyl, trimethylsilylethyl, t-butyl ether and the like;
benzyl ether;
substituted benzyl ethers, including, but not limited to, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitorbenzyl, p-halobenzyl, p-cyanobenzyl, diphenylmethyl, triphenylmethyl ether and the like;
silyl ethers, including, but not limited to, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl ether and the like;
esters, including, but not limited to, formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, phenoxyacetate, pivaloate, benzoate ester and the like; and the like.
Preferred hydroxy protecting groups include substituted methyl ethers, benzyl ether, substituted benzyl ethers, silyl ethers and esters.
The term "hydroxyalkyl" as used herein refers to the group having the formula, -R65-OH, where R65 is an alkylene group The term "leaving group" as used herein refers to a group which is easily displaced from the compound by a nucleophile. Examples of leaving groups include a halide (for example, CI, Br or I) or a sulfonate (for example, mesylate, tosylate, triflate and the like) and the like.
The term "N-protecting group" or "N-protected" as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991). N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like;
sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-meth-oxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyi, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxy-benzyioxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycar-bonyl, 2-vitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycar-bonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, a,a-dimethyl-3,5-dimethoxy-benzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropyl-methoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyl-oxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-vitro-phen-oxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyl-oxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
The term "thioalkoxy" as used herein refers to groups having the formula -SR98 wherein R98 is an alkyl group. Preferred groups R9$ are loweralkyl groups.
The term "thio-substituted alkyl" as used herein refers to an alkyl radical to which is appended a thiol group (-SH).
As used herein, the terms "S" and "R" configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13 - 30.
The compounds of the invention can comprise asymmetrically substituted carbon atoms. As a result, all stereoisomers of the compounds of the invention are meant to be included in the invention, including racemic mixtures, mixtures of diastereomers, as well as individual optical isomers, including, enantiomers and single diastereomers of the compounds of the invention substantially free from their enantiomers or other diastereomers. By "substantially free" is meant greater than about 80% free of other enantiomers or diastereomers of the compound, more preferably greater than about 90% free of other enantiomers or diastereomers of the compound, even more preferably greater than about 95%
free of other enantiomers or diastereomers of the compound, even more highly preferably greater than about 98% free of other enantiomers or diastereomers of the compound and most preferably greater than about 99% free of other enantiomers or diastereomers of the compound.
In addition, compounds comprising the possible geometric isomers of carbon-carbon double bonds and carbon-nitrogen double are also meant to be included in this invention.
Individual stereoisomers of the compounds of this invention can be prepared by any one of a number of methods which are within the knowledge of one of ordinary skill in the art. These methods include stereospecific synthesis, chromatographic separation of diastereomers, chromatographic resolution of enantiomers, conversion of enantiomers in an enantiomeric mixture to diastereomers and then chromatographically separating the diastereomers and regeneration of the individual enantiomers, enzymatic resolution and the like.
Stereospecific synthesis involves the use of appropriate chiral starting materials and synthetic reactions which do not cause racemization or inversion of stereochemistry at the chiral centers.
Diastereomeric mixtures of compounds resulting from a synthetic reaction can often be separated by chromatographic techniques which are well-known to those of ordinary skill in the art.
Chromatographic resolution of enantiomers can be accomplished on chiral chromatography resins. Chromatography columns containing chiral resins are commercially available. In practice, the racemate is placed in solution and loaded onto the column containing the chiral stationary phase. The enantiomers are then separated by HPLC.
Resolution of enantiomers can also be accomplished by converting the enantiomers in the mixture to diastereomers by reaction with chiral auxiliaries.
The resulting diastereomers can then be separated by column chromatography.
This technique is especially useful when the compounds to be separated contain a carboxyl, amino or hydroxyl group that will form a salt or covalent bond with the chiral auxiliary. Chirally pure amino acids, organic carboxylic acids or organosulfonic acids are especially useful as chiral auxiliaries. Once the diastereorners have been separated by chromatography, the individual enantiomers can be regenerated. Frequently, the chiral auxiliary can be recovered and used again.
Enzymes, such as esterases, phosphatases and lipases, can be useful for resolution of derivatives of the enantiomers in an enantiomeric mixture. For example, an ester derivative of a carboxyl group in the compounds to be separated can be prepared. Certain enzymes will selectively hydrolyze only one of the enantiomers in the mixture. Then the resulting enantiomerically pure acid can be separated from the unhydrolyzed ester.
In addition, solvates and hydrates of the compounds of Formula I, II, III, IV, V, VI, VII, VIII or IX are meant to be included in this invention.
When any variable (for example R', R2, R3, m, n, etc.) occurs more than one time in any substituent or in the compound of Formula I, II, II1, IV, V, VI, VII, VIII or IX or any other formula herein, its definition on each occurrence is independent of its definition at every other occurrence. In addition, combinations of substituents are permissible only if such combinations result in stable compounds. Stable compounds are compounds which can be isolated in a useful degree of purity from a reaction mixture.
This invention is intended to encompass compounds having Formula I, I1, III, IV, V, VI, VII, VIII or IX when prepared by synthetic processes or by metabolic processes. Preparation of the compounds of the invention by metabolic processes include those occurring in the human or animal body (in vivo) or processes occurring in vitro.
Compounds of the invention can be prepared according to the methods described in Schemes 1-8 as shown below.
Throughout the schemes, methods will be illustrated wherein R' is a carboxylic acid or carboxylic acid ester substituent. It will be understood by those skilled in the art that other R' substituents can (a) be obtained either from the carboxylic acid or carboxylic acid .ester group, (b) can be introduced by similar methods to those used to introduce the carboxylic acid or carboxylic acid ester group or (c) can be introduced by other methods generally known in the art.
In adddition, throughout the schemes, methods will be illustrated wherein R4, R6, R', R8, R9 and R'° are hydrogen. It will be understood by those skilled in the art that compounds wherein one or more of these substituents is other than hydrogen can be prepared by methods analogous to those disclosed in the schemes or by other methods generally known in the art.
In addition, throughout the schemes, methods will be illustrated for obtaining compounds of the invention having the preferred relative stereochemistry. It will be understood by those skilled in the art that compounds of the invention having other relative stereochemistry can be prepared by methods analogous to those disclosed in the schemes or by other methods generally known in the art.
In addition, throughout the schemes, methods will be illustrated wherein X
is -C(=O)-NH-. It will be understood by those skilled in the art that other X
groups can be prepared by methods analogous to those disclosed in the schemes or by other methods generally known in the art.
Compounds of the invention can be prepared according to the procedure described in Scheme 1. N-protected amino acid 1 (P' is an N-protecting group, for example, t-butoxycarbonyl or the like) can be prepared by N-protection of amino acid ((t)-(2R,3S)-2-Amino-bicyclo[2.2.1]hept-5-ene-3-carboxylic acid;
Stajer, G. et al. Tetrahedron, 40, 2385 {1984)). Formation of an anhydride derivative of the acid (for example, by reaction with ethyl chloroformate or the like), followed by reduction (for example, with sodium borohydride or the like) provides alcohol 2. The alcohol group is oxidized (for example, by Swern oxidation or the like) to provide aldehyde 3. Reductive amination of the aldehyde (for example with benzyl amine and Na(Ac0)3BH or the like) provides N-protected amine 4 (P2 is an N-protecting group, such as benzyl and the like).
A
second N-protecting group can be introduced to give 5 (P3 is an N-protecting group, for example, benzyioxycarbonyl or the like). Optionally, the mono-protected amino group can be alkylated (for example, by reaction with a non-nucleophilic base and an alkyl halide). The bicyclic ring is oxidatively cleaved (for example, with RuOZ and Na104 or the like) to give a diacid which is esterified to give diester 6 (P4 is a carboxylic acid protecting group, for example, loweralkyl, such as methyl, ethyl or the like). The N-protecting groups P2 and P3 are selectively removed (for example, by hydrogenation or the like) to provide amine 7. Amine 7 can be further functionalized to complete the introduction of the X- substituent (for example, by reaction of the amine with an acylating agent such as acetic anhydride or the like) to give 8. Removal of the acid protecting groups P4 (for example, by base hydrolysis) provides diacid 9. Diacid 9 can be monoprotected (for example, by treatment with acetic anhydride, followed by methanol and triethylamine) and chromatographic separation to give 10 (P5 is a carboxylic acid protecting group, for example, loweralkyl or the like). The acid group of 10 can also be transformed to a variety of substituents Y of the compounds of the invention using methods known to those skilled in the art to give 11, followed by N-deprotection, to give compounds of the invention 12.
As shown in Scheme 2, substituents R3 can be introduced via reaction of aldehyde 3 with a Grignard reagent (for example, R3MgBr or the like) to give alcohol 13. Oxidation of alcohol 13 (for example, Swern oxidation or the like) provides ketone 14. Reductive amination of ketone 14 (for example, by reaction with ammonium acetate and sodium cyanoborohydride in methanol or the like) gives amine 15. Amine 15 can be further functionalized to complete introduction of the R2-X- substituent (for example, by reaction of the amine with an acylating agent such as acetic anhydride or the like or by other acylation methods), followed by chromatographic separation of the diastereomers to give 16a. The other diastereomer (16b) can also be isolated and further transformed according to the scheme.
Oxidation of 16a and esterification gives 17 (in a manner analogous to that disclosed in Scheme 1). Also similar to Scheme 1, the diacid resulting from hydrolysis of diester 17 can be selectively protected to give give 1$, which can then be transformed to compounds of the invention 19.
As shown in Scheme 3, diol 20 is selectively diprotected (Culbertson, et al., Journal of the American Chemical Society 82, 2541-2547 (1960)) by reaction with one equivalent of a hydroxy protecting agent, followed by reaction with a second hydroxy protecting agent, to give 21 (P6 is a hydroxy protecting group, for example, acetyl or the like and P' is a hydroxy protecting group, for example, benzyl or the like). Oxidation and esterification provide 22. Removal of protecting group P', followed by transformation of the hydroxy group to an amine, which is then N-protected, provides 24. Transformation of 24 in a manner analogous to the transformation of 2 to 11 or 12 in Scheme 1 provides compounds of the invention 27 or 28.
As shown in Scheme 4, alcohol 31 can be transformed to compounds of the invention 38 in a manner analogous to the transformation of 13 to 19 in Scheme 2.
As shown in Scheme 5, aldehyde 39 can be reacted with a Grignard reagent to introduce substituent R3 to give 40. Oxidation (for exampie, by Swern oxidation or the like) provides 41a, which can be epimerized (for example, with sodium methoxide or the like) and 41 b can be obtained by chromatography.
Ketone 41b can be transformed to compounds of the invention 47 in a manner analogous to the transformation of 14 to 19 in Scheme 2.
As shown in Scheme 6, olefin 48 (P8 is a hydroxy protecting group) is converted to alcohol 48a (for example, by reaction with borane dimethylsulfide complex and hydrogen peroxide or the like). Oxidation of the alcohol to a carboxylic acid, followed by esterification with a carboxylic acid protecting group P9 and deprotection of the diol, provides 49. Selective protection of the primary alcohol with a hydroxy protecting group P'° gives 50. Oxidation of 50 (for example, Swern oxidation or the like) provides ketone 51. Reductive amination of ketone 51 (for example, by reaction with ammonium acetate and sodium cyanoborohydride in methanol or the like) gives amine 52. Amine 52 can be further functionalized to complete the introduction of the R2-X- substituent ( for example, by reaction with an acylating agent such as acetic anhydride or the like or by other acylation methods), followed by chromatographic separation of the diastereomers to give 53a. The other diastereomeric amide (53b) can also be isolated and further functionalized according to this scheme.
Selective removal of the P8 hydroxy protecting group in 53a provides alcohol 54. Oxidation of the alcohol to an aldehyde (for example, Swern oxidation or the like) provides 55. The aldehyde can serve as a precursor for various substituents Y in the compounds of the invention. For example, olefination of 55 (for example, with Ph3PCH2, or triphenylphosine/methylene chlorideln-BuLi, or I-Ph3P+CH2CH~/KOtBu, or the like) provides 56 wherein Y
is an olefinic substituent. Removal of the P'° hydroxy protecting group gives alcohol 57.
The alcohol can serve as a precursor for a variety of R3 substituents in the compounds of the invention. For example, the alcohol of 57 can be oxidized to an aldehyde -(for example, by Dess-Martin oxidation or the like) to give 58.
Aldehyde 58 can be reacted with Grignard reagents (R'4MgBr or the like) or other organometallic reagents (for example, organolithium reagents such as R'aLi or the like) to provide 59 as a mixture of alcohol diastereomers which can be separated chromatographically to provide the major isomer 59a and the other isomer 59b. Isomer 59a or the mixture of isomers 59 can be oxidized (for example, by Dess-Martin oxidation or the like) to give ketone 62. Reduction of ketone 62 (for example, with sodium borohydride in ethanol or the like) provides alcohol 59b as the major isomer, which can be isolated by chromatography.
Ester hydrolysis provides compounds of the invention 63a or fi3b, respectively, wherein Y is an olefinic substituent.
Alkylation of alcohol 59a or 59b provides ethers 60a or 60b, respectively.
Ester hydrolysis provides compounds of the invention 61a or 61b, respectively, wherein Y is an olefinic substituent.
As shown in Scheme 7, reaction of ketone 62 with with Grignard reagents (R3'aMgBr or the like) or other organometallic reagents (for example, organolithium reagents such as R3'aLi or the like) provides alcohols 64a and 64b as a mixture of alcohol diastereomers which can be separated chromatographically. Ester hydrolysis provides compounds of the invention fi5a or 65b, respectively, wherein Y is an olefinic substituent.
Alkylation of alcohol 64a or 64b provides ethers 66a or 66b, respectively.
Ester hydrolysis provides compounds of the invention 67a or 67b, respectively, wherein Y is an olefinic substituent.
Scheme 8 shows the preparation of precursor 74 for compounds of the invention which are substituted tetrahydrofurans. Alcohol 68 is oxidized to a ketone (for example, by Swern oxidation or the like), followed by oxidation of the olefin to a diol (for example, by treatment with Os04 and N-methylmorpholine N-oxide or the like) to give 69. Diol 69 is protected as the acetonide 70.
Oxidation of 70 (for example, with MCPBA -or the like) provides lactone 71. Iodination via the enolate .-of 71 provides 72. Reaction of 72 with potassium carbonate and methanol provides ester 73. Reduction of the ester provides aldehyde 74. The aldehyde provides a functional group via which substituents R3 and R2-X- can be introduced. Deprotection of the diol and oxidation of the diol provides functional groups via which substituents Y and R' can be introduced.
Esters or prodrugs of the compounds of the invention can be prepared by methods known in the art.
HO HO H
O NHP~ NHP~ ~ O NHP~
H ~ p3 w NHP~ NHP~
P40~0 P40~0 ~ P2~N OP4 ~ H2N ..,~~, OP4 NPR O Np~ O
H
H
P40~0 HO~O
OP4 R2C(O)HN ., ~~I~OH
..., N
R2C(O)H
7 NPR O Np~ O
H
8 _ SCHEME 1 ycont'd.~
HO~O Y, s R2C(O)HN OH R2C(O)HN ...",'~ p NP' O ~~ Np~ O
H
Y, R2C(O)HN .",~I~ H
w ~ w H ~HO ~. O
0 NHPi R3 NHP~ R3 NHP~
_14 _ R3 NHP~
w w R2C{O)HN~,, ~ R2C(O)HN
R3 NHP~ + R3 NHP~
16a 16b HO-.l/
RZC(O)HN~,. .., ~ OP4 R2C(O)HN~,. ..,aI~OP
ll R3 NP' 0 R3 Np~ O
H H
_58_ SCHEME 2 (cont'd.) HO.-.!/ Y.
R2C(O)HN~,, ~~~~~I~OP R2C(O)HN~,, ...~~y~OH
R3 NPR O R3 NHZ 'O
w w Pa0?,, ,, HO Ps0 _ PsOp OPa OH OP7 ~ O
a P O?.,,.. P O?.,,..
Ps0 _,,~pPa Ps0 ..,~OP
P O?.,,.. H 0~.,,..
~OH
R2C(O)HN .,~OPa R2C(O)HN
p ----- O
24 NHP~
NHP~
SCHEME 3 ycont'd.) H~~.,,,, 26 R2C(O)HN OP5 ~''~O
NHP~
Y.,, R2C(O)HN .,,~ H
O
HO
NHP~ R3 HzNHP' O Hz 31 ' R3 ~H2NHP~ ~ R3 H2NHP~
w R2C(O)HN~,, RzC(O)HN
R3 CH2NHP~ + R3 CHZNHP~
34a 34b paO~O HO-..l/
R2C(O)HN.,, ." ~ OP4. RzC(O)HN~,. ..,~~'I~OH
R3 ~ R3 ~ O
CH NHP~ CH2NHP~
O
HO-l/ Y, R2C(O)HN~,, ."" OP R2C(O)FiN~,, .."" OH
n CH2NHP~ CH2NHP~
37 3$
w ,.. w 39 4~ 41a R3 ~ Rs 41 b 42 RZC(O)HN~,, R C(O)HN
R3 + Rs 43a 43b 1 p P40~0 HO-.~/
RzC(O)HN~,. .."" OP4 R2C(O)HN~,, I
HO-l/ Y, R2C(O)HN~,, ."" OP R2C(O)FiN~,, .."" OH
n CH2NHP~ CH2NHP~
37 3$
w ,.. w 39 4~ 41a R3 ~ Rs 41 b 42 RZC(O)HN~,, R C(O)HN
R3 + Rs 43a 43b 1 p P40~0 HO-.~/
RzC(O)HN~,. .."" OP4 R2C(O)HN~,, I
Rs O R O
SCHEME 5 ,(cont'd.~
HO~O Y, RZC(O)HN~,.~-~"~~I~OP R2C(O)HN~,.~w.~~'I~OH
Rr3 v O~ R~[ s '''' O
Pap ;, P80-.
",~~OH
O O
48 48a Pap-., P80-.
HO Op9 HO OP9 48a ~~~ -- II
HO O plop O
P80- P80-,, p~o0 O plop O
Pap-,, P80-R2C(O)HN~,, ..,~I~OP9 RZC(O)HN~,, .,,~I~OP9 52 PioO Or + p,o0 1O
53a 53b SCHEME 6 (cont'd.) HO-,, H-!O
R2C(O)HN,,, Op9 R2C(O)HN, OP9 53a - I~ -p~o0 O p~o0 O
Y, Y, R2C(O)HN,,, OP9 R2C(O)HN,, Op9 - p~o0 O HO O
_56 Y is an alkene or haloalkene Y, R2C(O)HN,,, OP9 H O
O
SCHEME 6 ~cont'd.) Y. Y.
R2C(O)HN,,, OP9 R2C(O)HN,,,, OP9 Rya .~~OH O + Rya OH O
59a 59b Y. Y.
R2C(O)HN,,, OP9 RZC(O)HN , OP9 Rya O Ria O
%pR37a pR37a 60a 60b Y. Y, R2C(O)HN,,, OH R2C(O)HN'~. OH
~I~
Rya O R14 O
'~R37a pR37a 61 a 61 b _57_ SCHEME 6 ~cont'd.1 Y. Y, R2C(O)HN,,, OP9 R2C(O)HN,,, OP9 59a ~''~~ il Rya O O ~. Rya OH O
62 59b Y, R2C(O)HN,,, OH
Y.
Rya O RZC(O)HN,,, OH
.~OH
63a R,a OH O
63b Y, Y, R C(O)HN,,, OP9 R2C(O)HN,,, OP9 s2 ~f ~i~
- R1a OH O + Rya O
R3~a R3~a ~OH
64a 64b Y, Y, R2C(O)HN,, OH R2C(O)HN,,, OH
~I~ ~~I~
Rya OH O Rya O
R3~a R37a ~OH
65a 65b SCHEME 7 i(cont'd.) Y, Y, R C(O)HN,,, OP9 R2C(O)HN, OP9 ~I~ ~'I~
Rya OH O + Rya O
R37a R37a ~OH
64a 64b Y, Y, R2C(O)HN,,, OP9 R2C(O)HN,,, OP9 ~ ~I~~I~ ~I~
Rya O Rya O
37c 37c R37a OR R37a ~OR
66a 66b Y, Y, R2C(O)HN,,, OH R2C(O)HN,,, OH
~I~ ~'I~
Rya O Ria O
37c 37c R37a OR ~OR
R37a 67a 67b i .-~ HO O
OH HO O
68 o O
o ~, ~ i ~o ~ o 0 0 ~o C02Me O
CHO
The other compounds of the invention can be readily prepared from the compounds available through commercial sources, in the chemical (literature or as described herein using techniques well known in the chemical literature.
The procedures required are well known and can be readily practiced by those having ordinary skill in the art.
Afl patents, patent applications, and literature references cited in the specification are hereby incorporated by reference in their entirety. In the case of inconsistencies, the present disclosure, including definitions, will prevail.
The reagents required for the synthesis of the compounds of the invention are readily available from a number of commercial sources such as Aldrich Chemical Co. (Milwaukee, WI, USA); Sigma Chemical Co. (St. Louis, MO, USA);
and Fluka Chemical Corp. (Ronkonkoma, NY, USA); Alfa Aesar (Ward Hill, MA
01835-9953); Eastman Chemical Company (Rochester, New York 14fi52-3512);
Lancaster Synthesis Inc. (Windham, NH 03087-9977); Spectrum Chemical Manufacturing Corp. (Janssen Chemical) (New Brunswick, NJ 08901 ); Pfaltz and Bauer (Waterbury, CT. 06708). Compounds which are not commercially available can be prepared by employing known methods from the chemical literature.
The following examples will serve to further illustrate the preparation of the compounds of the invention, without limitation.
_72_ Example 1 fit) (1 S 2S 3R 4R) 2 (N Met~l-N-f-butylo~carbonylamino)-3-acetamidomethyl-4-methoxycarbonyl-c~clopentane-1-carboxylic Acid HO
O NHZ
1A. ~,t) (2R 3S)-2-Aminobicyclo[-2 2 1]hept-5-ene-3-carboxylic acid.
The title compound was synthesized from norbornadiene by a cycloaddition reaction with chlorosulfonyl isocyanate followed by a reduction and acidic hydrolysis as reported by Stajer, G. ef al. Tetrahedron; 40, 2385 (1984).
HO
O NHBoc 1 B. (t) (2R 3S)-2-(t-Butylox~carbonylamino~bicyclo[2.2.11hept-5-ene-3-carboxylic acid.
A solution of (t)-(2R,3S)-2-aminobicyclo[2.2.1]hept-5-ene-3-carboxylic acid (6.3 g, 0.04 mole) , NaOH (3.3 g, 0.082 mole), and di-fert-butyl Bicarbonate (0.082 mmole) in water (200 mL) was stirred at room temperature for 48 hours.
The reaction mixture was acidified using 1 M aqueous HCI, while cooling the solution in an ice/water bath. The reaction mixture was extracted with dichloromethane {3 X 250 mL). The organic layer was dried over MgS04, filtered and concentrated to provide the title compound as a white solid (yield: 5.6 g, 55%).
' H NMR (CDCi3) 81.44 (s, 9H), 1.64 (d, 1 H), 2.08 (d, 1 H), 2.58 (m, 1 H), 2.72 (s, 1 H), 2.97 (s,1 H), 6.18 (m, 2H), 6.96 (d, 1 H).
HO
NHBoc 1 C. ~t~~2R 3S)-2- t Butyloxycarbonylamino)-3-hydroxymethvlbicyclof2.2.11hept-5-ene.
Ethyl chloroformate (2.3 mL, 23.7 mmole) was added slowly to a solution of (t)-(2R,3S)-2-(t-butyloxycarbonylamino)bicyclo[2.2.1]hept-5-ene-3-carboxylic acid (6 g, 23.7 mmole) and N-methylmorpholine (2.6 mL, 23.~ mmole) in THF
(110 mL) at -20 °C . The reaction mixture was warmed to 0 °C, and the slurry-like reaction became nearly homogeneous. The reaction mixture was cooled to -20 °C, and treated with sodium borohydride ( 3.7g, 66 mmole). Methanol (10 mL) was added dropwise, over 20 minutes. The reaction mixture was neutralized with 1 N HCI and the reaction mixture was concentrated by removal of volatile materials, in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with 1 N HCI, water, and brine, dried over MgS04, filtered and concentrated in vacuo. Purification by silica gel column chromatography using 15% ethyl acetate/hexanes provided the title compound (yield: 4.27 g, 75 %).
' H NMR (CDC13) b 1.45 (s, 9H), 1.52 (m, 2H), 1.85 {q, 1 H), 2.09 (bs, 1 H}, 2.68 {m, 2H), 3.66 (m, 3H), 4.83 (bs, 1 H), 6.11 (m, 1 H), 6.27 (m, 1 H).
W
O
H NHBoc 1 D. fit)-(2R 3S)-2-(t Butyloxycarbonylamino -3-formylbicyclof2.2.11hept-5-ene.
DMSO (3.4 mL) in dichloromethane (5 mL) was added slowly to oxalyl chloride (2 mL, 22 mmole) in dichloromethane (50 mL) at -78 ~C. After 5 minutes, (t)-(2R,3S)-2-(t-butyloxycarbonylamino)-3-hydroxymethyl-bicycloj2.2.1 ]hept-5-ene (4.27g, 17.8 mmole) in 15 mL of dichioromethane and 10 mL of DMSO was added. Stirring was continued for 20 minutes at -78 ~C. The solution was treated with triethylamine (14 mL). After 5 minutes, the cooling bath was removed and the reaction stirred for an additional 30 minutes. The reaction mixture was partitioned with water (100 mL). The aqueous layer was extracted with dichloromethane (3 x 50 mL). The organic layers were combined, washed with brine, dried over MgS04, filtered and concentrated. The crude product was chromatographed on silica gel with 0-10% ethyl acetate/dichloromethane, to provide the title compound. (yield: 3.8 g, 90%) H NMR (CDC13) b1.43 (s, 9H), 1.63 (m, 2H), 2.74 (m, 2H), 3.11 (s, 1 H), 3.99 (t, 1 H). 4.85 (d, 1 H), 6.22 (m, 2H), 9.81 (s, 1 H).
H
BnN
NHBoc 1 E. (t)-(2R 3R)-2-~Bu loxycarbonylamino)-3-N-ben~laminomethylbicyclo-j2.2.1~he~t-5-ene.
A solution of (t)-(2R,3S)-2-(f-butyloxycarbonylamino)-3-formyl-bicyclo[2.2.1]kept-5-ene (3.8g, 16.0 mmole), benzylamine (1.9 mL, 17.6 mmole) and acetic acid (1 mL) in dichloromethane (80 mL) was stirred at 0 °C
for 10 minutes followed by addition of Na(Ac0)sBH (5.09g, 24 mmole). The reaction mixture was stirred at 0 °C for 2 hours then allowed to warm slowly to room temperature for 2 hours. After completion, the reaction mixture was washed with aqueous sodium bicarbonate, dried over MgS04, filtered and concentrated. The crude product was purified by silica gel chromatography using 0-2.5%
methanollchloroform to provide the title compound (yield: 4.0 g, 77%).
' H NMR (CDC13) 81.47 (s, 9H), 1.51 (m, 2H), 1.78 (t, 1 H), 2.72 (m, 4H), 3.57 (t, 1 H), 3.78 (s, 1 H), 6.10 (m, 1 H), 6.21 (m, 1 H), 7.30 (m, 5H).
MS: (M+H)+ = 329.
Cbz BnN
NHSoc 1 F. {t~~2R 3RL2 (f But~rloxycarbonylamino~ 3-(N-benzyl-N-(benzyloxycarbonyl-amino)methyl bicyclo(2.2.11hept-5-ene.
A solution of (t)-(2R,3R)-2-(t-butyloxycarbonylamino)-3-N-benzylaminomethylbicyclo[2.2.1]kept-5-ene (2.8 g, 8.5 mmole) and N-(benzyloxycarbonyloxy)succinimide (2.3 g) in 50 mL of dichloromethane was reacted at room temperature for 6 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous NaHC03 and brine, dried over MgS04 and concentrated in vacuo. The product was purified by silica gel chromatography using hexanes/ethyl acetate (3:1) to provide the title compound (yield: 3.37 g, 85%).
' H NMR (CDC13) 51.32 (m,2H), 1.36 (s, 9H), 1.56 (m, 1 H), 1.88 (m, 1 H), 2.63 (m, 2H), 3.06 (m, 1 H), 4.34 {m, 1 H), 4.63 (m, 1 H), 5.18 (m, 2H), 6.05 (bs, 2H), 7.28 (m, 11 H).
CbzN NBoc Bn CH3 1 G. (t)-(2R 3R)-2-(N-Methyl-N-t butyloxycarbonylamino)-3-(N-benzyl-N-benzyl-oxycarbonylamino)methLrl-bicyclo[2.2.1 ]hept-5-ene.
Sodium hydride (300 mg , 60% in oil) was added to a solution of (t)-(2R,3R}-2-(t butyloxycarbonylamino)-3-(N-benzyl-N-benzyloxycarbonylamino)-methylbicyclo[2.2.1]hept-5-ene (3.37 g, 7.27 mmole) and iodomethane (0.9 mL) in anhydrous DMF (60 mL) at 0 °C. After 4 hours, the reaction mixture was concentrated in vacuo and purified by silica gel chromatography using hexanes/ethyl acetate (4:1 ) to provide the title compound (yield: 3.3 g, 95%).
H NMR (CDC13) b1.40 (s, 9H}, 1.82 (m, 2H), 2.26 (m, 1 H), 2.78 (m, 1 H), 2.85 (m, 1 H), 2,90 (s, 3H), 2.94 (m, 2H), 3.63 (m, 1 H), 4.22 (m, 2H), 5.34 (s, 2H), 5.60 (m, 2H), 7.15 (m, 10H).
MS: (M+H)+ = 477.
O
CH30-l~
CbzN NBoc O
Bn 'CH3 1 H. !t)-( 1 S 2S 3R 4R~2-(N-Methyl-N-t-butyloxycarbonylamino)-3-(N-benzyl-N-benzyloxycarbonylamino)meth~cyclopentane-1 4-dicarboxylic Acid Dimethyl Este r.
A mixture of Na104 (10 g, 47 mmole) and Ru02 (45 mg, 0.3 mmol) in 25 mL of carbon tetrachloride 50 mL of acetonitrile, and 75 mL of water was rapidly stirred for 30 minutes. A solution of (t)-(2R,3R)-2-(N-methyl-N-t butyloxycarbonylamino)-3-(N-benzyl-N-benzyloxycarbonylamino)methyl-bicyclo[2.2.1]hept-5-ene (3.3 g, 6.9 mmole) in 25 mL of carbon tetrachloride was added to the bright yellow mixture. The resultant black mixture was stirred at room temperature for 1.5 hours and diluted with 250 mL of water. The aqueous layer was extracted with ethyl acetate (5 x 200 mL). The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated in vacuo. The residue was dissolved in ethyl acetate and treated with a solution of diazomethane in ethyl ether. The reaction mixture was concentrated in vacuo, and the crude product purified by silica gel chromatography using ethyl acetate/hexanes (1:1} to provide the title compound as a white solid (yield:
1.91 g, 50%).
'H NMR (CDC13) 81.41 (s, 9H), 2.21 (m, 2H), 2.33 (m, 1H), 2.90 (s, 3H), 2.92 (m, 2H), 2.96 (m, 1 H), 3.38 (t, 1 H), 3.67 (s, 6H), 4.23 (m, 3H), 5.38 (s, 2H), 7.12 (m, 10H).
MS: (M+H)+ = 569.
O
CH30-'l~
'"If NH2 NBoc O
11. fit) (1S 2S 3R 4R) 2 (N Methyl N t Bu~loxycarbonylamino)-3-aminomethvl-cyclopentane-1 4-dicarboxylic Acid Dimethvl Ester.
A mixture of (t)-(1S,2S,3S,4R)-2-(N-methyl-N-t-butyloxycarbonylamino)-3-(N-benzyl-N-benzyloxycarbonylamino)methyl-cyclopentane-1,5-dicarboxylic acid dimethyl ester (1.91 g, 3.36 mmole) and Pd(OH)z (380 mg, 20% on carbon) in 50 mL of isopropanol was stirred at room temperature under an hydrogen atmosphere, for 16 hours. The catalyst was removed by vacuum filtration through a bed of Celite~, and the filtrate concentrated in vacuo to provide the title compound (yield: 1.2 g 100 %).
'H NMR (CDC13) 61.48 (s, 9H), 2.00 (m, 2H), 2.42 (m, 1H), 2.64 (m, 2H), 2.90 ( bs, 3H), 3.00 (m, 2H), 3.71 (s, 3H), 3.73 (s, 3H), 4.4 (bs, 1 H), 5.4 (bs, 2H).
MS: (M+H)+ = 345.
_79_ O
CH30-~~
AcHN Ngoc O
1 J. (~1 S 2S 3R 4R)-~N-Methyl-N-t but~ycarbonylamino)-3-acetamido-methyl-cyclopentane-1 4-dicarboxylic Acid Dimethv I E~ stet.
A solution of (t)-(1S,2S,3R,4R)-2-(N-methyl-t butyloxycarbonylamino)-3-aminomethylcyclopentane-1,5-dicarboxylic acid dimethyl ester (1.2 g, 3.5 mmole), acetic anhydride (0.5 mL) and triethylamine (1 mL) in 25 mL of dichloromethane was stirred at room temperature for 2 hours.
The reaction mixture was diluted with ethyl acetate and washed successively with 1 N HCI, water and brine, dried over MgS04, and concentrated in vacuo. The residue was purified by silica gel chromatography using ethyl acetate/hexanes (1:1) to provide the title compound (yield: 790 mg, 58 %).
' H NMR (CDCI~) 61.45 (s, 9H), 1.92 (s, 3H), 2.05 (m, 1 H), 2.40 (m, 1 H), 2.62 (m, 1 H), 2.85 (s, 3H), 3.1 (m, 1 H), 3.3 {m, 1 H), 3.42 (m, 1 H), 3.71 (s, 6H), 4.62 (bs, 1 H), 6.38 (bs, 1 H).
MS: (M+H)+= 387.
O
HO--~~
OH
'''I
AcHN Ngoc O
1 K. fit) (1 S 2S 3R 4R)-2-(N-Methyl-N-f but~oxLrcarbonylamino)-3-acetamido-methyl-cyclopentane-1 4-dicarboxylic Acid.
A solution of (t)-(1 S,2S,3S,4R)-2-(N-methyl-N-t-butyloxycarbonylamino)-3-acetamidomethylcyclopentane-1,5-dicarboxylic acid dimethyl ester (720 mg, 1.86 mmole) and 5 equivalents of lithium hydroxide in methanol (40 mL) and H20 (10 mL) was stirred at room temperature for two hours. The solution was concentrated in vacuo. The residue was partitioned between 1 N HCI and ethyl acetate. The aqueous layer was back extracted with ethyl acetate (3 x 50 mL). The organic layers were combined and washed with brine, dried over Na2S04, filtered, and concentrated in vacuo to provide the title compound {yield: 500 mg, 75 %).
H NMR (CDC13) 81.45 (s, 9H), 1.92 (s, 3H), 2.05 (m, 1 H), 2.40 (m, 1 H), 2.62 (m, 1 H), 2.85 (s, 3H), 3.1 (m, 1 H), 3.3 (m, 1 H), 3.42 (m, 1 H), 3.71 (s, 6H), 4.62 (bs, 1 H), 6.38 (bs, 1 H).
O
CH30-l/
..~~~~oH
AcHN Ngoc ~
1 L. ,fit)-(1 S 2S 3R 4R)-2-lN-Methyl-N-t-butylox~carbonylamino)-3-acetamido-methyl-4-methox cay rbonylcyclopentane-1-carboxylic Acid A solution of (t)-(1 S,2S,3R,4R)-2-(N-methyl-N-t butyloxycarbonylamino)-3-acetamidomethylcyclopentane-1,5-dicarboxylic acid (500 mg, 11.4 mmole), in 5 mL of dichloromethane and 5 mL of acetic anhydride, was stirred at room temperature for two hours. The solution was concentrated in vacuo, at 20 °C. The residue was dissolved in 10 mL of methanol and 0.2 mL of triethylamine and reacted for 16 hours at room temperature, under a nitrogen atmosphere. The reaction mixture was diluted with 100 mL of chloroform, and washed successively with 0.1 N HCI and brine. The solution was dried over MgS04, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using chloroformlmethanol/acetic acid (97:2:1 ) to provide the title compound (yield: 155 mg, 30 %).
'H NMR (CDC13) 81.47 (s, 9H), 1.95 (s, 3H), 2.10 (m, 2H), 2.43 (m, 1H), 2.64 (m, 1 H), 2.88 ( m, 4H), 3.20 (m, 1 H), 3.30 (m, 1 H), 3.44 (m, 1 H), 3.72 (s, 3H), 4.66 (t, 1 H), 6.48 (bs, 1 H).
MS (M+H)+= 373.
Example 2 CH30-'l~
OH
~~~''If AcHN NH O
!t)-(1 S 2S 3R 4Rl-2-N-Methyl-3-acetamidomethyl-4-methoxycarbonyl-cyclo~entanecarboxylic Acid Hydrochloride.
A solution of (t)-(1 S,2S,3R,4R)-2-(N-methyl-N-t-butyloxycarbonylamino)-3-acetamidomethyl-4-methoxycarbonylcyclopentanecarboxylic acid (130 mg, 0.35 mmole) in 4.5 mL of dichloromethane was reacted with trifluoroacetic acid (1.5 mL) for 1 hr, at room temperature. The solution was concentrated in vacuo, at °C. The residue was treated with 1 N HCI and concentrated in vacuo to provide the title compound as a white solid (yield: 100 mg, 92 %).
'H NMR (D20) 82.02 (s, 3H), 2.08 (m, 1H), 2.54 (m, 2H), 2.76 (s, 3H), 2.85 (m, 2H), 3.36 (m, 2H), 3.76 (s, 3H), 3.81 (t, 1 H).
Example 3 CH30~~
OH
AcHN NCbz O
fit)-(1 S 2S 3R 4R)-2~N-Methyl-N-benzyloxycarbonylamino)-3-acetamidomethyl-4-methoxycarbonyl-cyclopentanecarboxLrlic Acid.
A solution of (t)-{1S,2S,3R,4R)-2-N-methyl-3-acetamidomethyl-4-methoxycarbonyl-cyclopentanecarboxylic acid hydrochloride (100 mg), N-(benyloxycarbonyloxy)succinimide (183 mg) and triethylamine (0.160 mL) in dichloromethane (10 mL) was stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate and washed successively with 1 N HCI, and brine, dried over MgS04, and concentrated in vacuo. The residue was purified by silica gel chromatography using chloroform/methanol/acetic acid (97:2:1 ) to provide the title compound as a white solid.
~ H NMR (CDC13) b1.88 (s, 3H), 2.08 (m, 2H), 2.46 (m, 1 H), 2.66 (m, 1 H), 2.92 (m, 1 H), 2.96 (s, 3H), 3.18 (m, 1 H), 3.35 (m, 1 H), 3.70 (s, 3H), 4.64 (bs, 1 H), 5.14 (s, 2H), 6.29 (bs, 1 H), 7.34 (m, 5H).
MS: (M+H)+ = 407.
Example 4 fit) (1 S 2S 3R 4R)-2-lt-Butyloxycarbonylamino)-3-(acetamidomethyl)-4-(methoxy-carbonyl -cyclopentane-1-carboxylic Acid.
Ac0 NHBoc 4A. ~t~~2R 3S~ 2 t But~loxycarbonylamino-3-acetoxymethylbicyclof2.2.11hept-5-ene.
A solution of (t)-(2R,3S)-2-(t butyloxycarbonylamino)-3-hydroxymethylbicyclo[2.2.1]hept-5-ene (1.0 g, 4.18 mmole), acetic anhydride (0.55 mL), triethylamine (2 mL) and N,N-dimethylaminopyridine (catalytic) in mL of dichloromethane was reacted for 2 hours, at room temperature. The reaction mixture was diluted with 200 mL of ethyl acetate, washed with 0.5 N
HCI, water, saturated sodium bicarbonate, and brine. The organic layer was dried over MgS04, filtered and concentrated. The crude product was purified by silica gel chromatography using 10% ethyl acetate/hexanes to provide the title compound. (yield: .92 g, 78 %) MS: (M+H)+ = 282.
H O-J
Ac0 OH
BocHN O
4B. (t) 1 S 2S 3S 4R) 2 (t Butt'loxycarbonylamino)-3-(acetoxymethyl)-cycio-pentane-1 4-dicarboxylic Acid Ruthenium dioxide hydrate (43mg, 0.32 mmole) was added to a vigorously stirred mixture of Na104 (7.12 g, 33 mmole) in 33 mL of acetonitrile, 33 mL of carbon tetrachloride and 58 mL of water. The mixture was stirred at room temperature for 5 minutes or until a homogeneous yellow color was attained. A
solution of (t)-(2R,3S)-2-(t-butyloxycarbonylamino)-3-acetoxymethyl-bicyclo[2.2.1 ]hept-5-ene (2.28 g, 8.11 mmole) in 10 mL of (1:1 ) acetonitrile:carbon tetrachloride was added rapidly to the reaction mixture.
The mixture was stirred vigorously for 1 hour at room temperature. The reaction mixture was partitioned between ethyl acetate and 0.5 N HCI. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated to provide the diacid compound which was used in the following reaction without additional purification.
_gb_ O
HO--~~
HO OH
BocHN O
4C. (t) (1S 2S 3S 4R)-2-(t-ButYloxycarbon~rlamino -3~-(h_ydroxymethyl)-cyclo-pentane-1 4-dicarboxylic Acid.
The crude diacid, (t)-(1 S,2S,3S,4R)-2-(t butyloxycarbonylamino)-3-(acetoxymethyl)-cyclopentane-1,4-dicarboxylic acid, prepared in example 4B, and sodium hydroxide (1.2 g) in 45 mL of water was reacted for 6 hours, at room temperature. The reaction mixture was acidified to pH 1 with and extracted with ethyl acetate (3 x 40 mL). The organic layer was washed with brine and dried over Na2S04, filtered and concentrated. The crude diacid-alcohol was used in the following reaction without additional purification.
CH30--!~
HO ,,~~~OCH3 BocHN 1O
4D. (t,~ (1 S 2S 3S 4R~ 2-(t Butyloxycarbonylamino)-3-(hydroxymethyl)-cyclo-pentane-1 4-dicarboxylic Acid Dimethyl Ester.
The diacid-alcohol, (t)-(1S,2S,3S,4R)-2-(t-butyloxycarbonylamino)-3-(hydroxymethyl)-cyclopentane-1,5-dicarboxyiic acid, prepared in Example 4C, was dissolved in 40 mL of tetrahydrofuran {THF) and reacted with diazomethane in ethyl ether until complete conversion to the dimethyl ester. The reaction mixture was monitored by TLC, using 10% methanol in chloroform with 1 % acetic acid. The reaction was concentrated in vacuo to provide the title compound as a colorless oil (yield: 1.3 g, 85 %).
MS: (M+H)+ = 331.
O
CH30--l~
N3 .,~~~~ CH3 BocHN
4E. ,~~1S 2S 3R 4R)-2-(f Butyloxycarbonylamino)-3-(azidomethyl)-cyclo-pentane-1 4-dicarboxylic Acid Dimethyl Ester.
Methanesulfonyl chloride (1.3 mL, 17.0 mmole) was added slowly to a solution of (t)-(1S,2S,3S,4R)-2-(t butyloxycarbonylamino)-3-(hydroxymethyl)-cyclopentane-1,4-dicarboxylic acid dimethyl ester (2.76g, 8.34 mmole) and triethylamine (2.4 mL, 17.0 mmole) in 80 mL of 1:1 dichloromethaneaetrahydrofuran, maintained at -30 °C. The reaction mixture was stirred for 2.5 hours, at -30 °C then diluted with ethyl acetate washed with 0.1 N
HCI and brine, dried over MgS04, filtered and concentrated in vacuo to provide the crude mesyiate. The mesylate and lithium azide (4 g) were reacted in 35 mL
of N,N-dimethylformamide for 1 hour, at 90 °C. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgS04, filtered and concentrated. The crude product was purified by silica gel chromatography using 20% ethyl acetate in hexanes to provide the title compound. (yield: 1.8 g, 48%) MS: (M+H)+ = 373.
O
CH30-~~
AcHN OCH3 BocHN O
4F. (t)_(1 S 2S 3R 4R~-2-(t-But~loxycarbonylamino)-3-(acetamidomethyl)-cycfopentane-1 5-dicarboxylic Acid Dimethyl Ester.
(t)-(1 S,2S,3R,4R)-2-(t-Butyloxycarbonylamino)-3-(azidomethyl)-cyclopentane-1,4-dicarboxylic acid dimethyl ester (506 mg, 1.42 mmole) and thiolacetic acid (0.4 mL) were reacted at room temperature for 6 hours. The reaction mixture was concentrated in vacuo and the crude product was purified by silica gel chromatography using 3% methanol in chloroform to provide the title compound (yield: 255 mg, 48%).
MS: (M+H)+ = 373.
o HO--l~
AcHN OH
O
NHBoc 4G. (t)~1S 2S 3R 4R)-2-(t Butyloxycarbonylamino)-3-(acetamidomethyl)-~clopentane-1.4-dicarboxylic Acid (t)-(1 S,2S,3R,4R)-2-(t-Butyloxycarbonylamino)-3-(acetamidomethyl)-cyclopentane-1,4-dicarboxylic acid dimethyl ester (255 mg, 0.68 mmole) and lithium hydroxide (2.2 equivalents) in 15 mL of 4:1 methanol:water were reacted at room temperature for 2 hours. The reaction was acidified with dilute HCI
and extracted with ethyl acetate (3 X 60 mL). The organic layers were combined, dried over Na2S04, filtered and concentrated to provide the title compound.
-88_ O
AcHN OH
BocHN O
4H. fit) (1 S 2S 3R 4R)-2-(t Buyloxycarbonylamino)-3-(acetamidomethvl)-4-(methoxycarbonyl)-cyclopentane-1-carboxylic Acid The crude diacid, (t)-(1S,2S,3R,4R)-2-(t-butyloxycarbonylamino)-3-(acetamidomethyl)-cyclopentane-1,4-dicarboxylic acid, prepared in Example 4G
was reacted with acetic anhydride (20 mL) for approximately 1 hour at 60 °C to provide the bicyclic anhydride. The reaction mixture was concentrated in vacuo and the crude anhydride was treated with methanol (50 mL) and triethylamine (2-3 equivalents) at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with 0.5N HCl and brine. The organic solution was dried over Na2S04, filtered and concentrated. Chromatographic separation of the diastereomers was accomplished by silica gel chromatography using 25% ethyl acetate in hexanes and 0.5% acetic acid to provide the title compound (yield:
mg, 60 %).
'H NMR (methanol-d4) 5 1.44 (s, 9H), 1.90 (s, 3H), 2.04 (m, 1H), 2.32 (m,1 H), 2.54 (m,1 H), 2.72 (m,2H), 3.11 (m, 1 H), 3.36 (m,1 H), 4.38 (m,1 H), 6.92 (broad d, 1 H), 7.8 (broad s, 1 H).
MS: (M+H)'' = 359.
_89_ Example 5 CH30--!~
AcH N OH
~'I~
HCI
(t)-(1 S.2S.3R.4R~-2-Amino-~acetamidomethyl)-4-(methoxycarbonyl)-cyclopentane-1-carboxylic Acid Hydrochloride A solution of (t)-(1S,2S,3R,4R)-2-(t butyloxycarbonylamino)-3-(acetamido-methyl)-4-(methoxycarbonyl)-cyclopentane-1-carboxylic acid (66 mg, 0.18 mmole) in 3 mL of dichloromethane was reacted with trifluoroacetic acid (1.0 mL) for 1 hr, at room temperature. The solution was concentrated in vacuo at 25 °C.
The crude product was treated with 1 N HCI and concentrated in vacuo to provide the title compound as a white solid.
' H NMR {D20) 82.01 (s, 3H), 2.19 (m, 1 H), 2.58 (m, 1 H), 2.81 (t, 1 H), 2.95 {m, 1 H), 3.15 (m, 1 H), 3.38 (m, 3H), 3.75 (s, 3H), 4.08 (t, 1 H).
MS = (M+H)+ = 259.
Example 6 (~S 2S 3R 4R) 3 Acetamidomethyl-2-(N-t-butoxycarbonylamino)methyl-4-metho~carbonyl-cyclopentane-1-carboxylic Acid Ac0 OBn 6A. (t) exo exo 3 Acetoxymethyl-2-benzyioxymethyl-bicyclof2.2.11hept-5-ene.
(t)-exo-exo-2,3-Dihydroxymethylbicyclo[2.2.1]hept-5-ene (620 mg, 4.0 mmole), prepared according to the procedure described by Culberson, C. et al., Journal of the American Chemical Society 82, 2541-2547, (1960), was reacted with sodium hydride (300mg, 60% oil dispersion) in 10 mL of N,N-dimethyl-formamide (DMF) for 15 min, at 0 °C. This was followed by treatment of the dianion with benzyl bromide (0.5 mL) for an additional 2 hours. The reaction mixture was diluted with ethyl acetate washed with wafer, and brine, dried over MgS04, filtered and concentrated in vacuo.
The crude benzylated product was reacted with acetic anhydride (0.7 mL), triethylamine (3 mL) and N,N-dimethylaminopyridine (catalytic) in dichloromethane (20 mL) at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography using 10%
ethyl acetate in hexanes to provide the title compound (yield: .845 g, 74%).
'H NMR (CDC13) 81.41 (m, 2H), 1.85 (m, 2H), 2.05 (s, 3H), 2.73 (brs, 1H), 2.78(brs, 1 H), 3.38 (m, 1 H), 3.57 (m, 1 H), 3.95 (m, 1 H), 4.31 (m, 1 H), 4.51 (m, 2H), 6.18 (m, 2H), 7.33 (m, 5H).
MS: (M+H)+ = 287.
O
CH30~/
Ac0 OCH3 OBn 6B. fit)-( 1 S 2S 3R 4RZ 3-AcetoxvmethYl-2-benzvlo~methyl-cyclopentane-1.4-dicarboxylic Acid Dimethyl Ester.
A rapidly stirred mixture of Na104 (10 g) and Ru02 (45 mg) in 25 mL of carbon tetrachloride, 50 mL of acetonitrile, and 75 mL of water was reacted for 30 minutes. A solution of (t)-(2R,3S)-2-acetoxymethyl-3-benzyloxymethyl-bicyclo[2.2.1 ]hept-5-ene (3.3 g, 11.5 mmole) in 25 mL of carbon tetrachloride was added to the bright yellow mixture. The resultant black mixture was stirred for 1.5 hours, at room temperature. Water (250 mL) was added to the reaction mixture and the aqueous layer was extracted with ethyl acetate (5 x 200 mL) . The combined organic layers were washed with brine, dried over MgS04, and concentrated in vacuo.
The residue was dissolved in ethyl acetate and treated with a solution of diazomethane in ethyl ether. The reaction mixture was concentrated in vacuo, and the crude product purified by silica gel chromatography using ethyl acetate:
hexanes (1:1 ) to provide the title compound as a white solid (yield: 1.91 g, 44%).
' H NMR (CDC13) 82.00 (s, 3H), 2.14 (m, 1 H), 2.34 (m, 1 H), 2.77 (m, 3H), 2.89 (m, 1 H), 3.51 (m, 2H), 3.67 (s, 3H), 3.70 (s, 3H), 4.18 (m, 2H), 4.47 (s, 2H), 7.32 (m, 5H).
MS: (M+H)+ = 379.
O
CH30-l Ac0 ,,~~~OCH3 tO
OH
6C. SOS 2S 3R 4R) -3-Acetox~methyl-2-~droxymethYl_cyclopentane-1.4-dicarboxylic Acid Dimethyl Ester.
A mixture of (t)-(1S,2S,3R,4R)-3-acetoxymethyl-2-benzyloxymethylcyclopentane-1,4-dicarboxylic acid dimethyl ester {3.3 g, 8.72 mmole) and palladium (600 mg, 10% on carbon) in ethanol (100 mL) was stirred vigorously at room temperature under an hydrogen atmosphere. Upon completion, as determined by TLC, the reaction mixture was filtered and concentrated in vacuo to provide the title compound (yield: 2.56 g, 100%).
' H NMR (CDC13) 81.84 (t, 1 H), 2.05 (s, 3H), 2.16 (m, 1 H), 2.36 (m, 1 H), 2.75 (m, 4H), 3.70 (s, 3H), 3.71 (s, 3H), 3.73 (m, 1 H), 4.19 {m, 2H).
MS = (M+H)+ = 289.
O
CH30~
Ac0 .,,~~~OCH3 O
6D. {t)-{1 S 2S 3R 4R~ 3-Acetoxymethyl-2-azidomethylcyclopentane-1,4-di-carboxylic Acid Dimethyl Ester.
Methanesulfonyl chloride (2.1 mL, 26.6 mmole) was added slowly to a solution of (t)-(1S,2S,3R,4R)-3-acetoxymethyl-2-hydroxymethylcyclopentane-1,4-dicarboxylic acid dimethyl ester (2.56g, 8.72 mmole) and triethylamine {3.7 mL, 26.6 mmole) in 100 mL of dichloromethane at -30 °C. The reaction mixture was stirred at -30 °C for 0.5 hour then allowed to warm to 0 °C
over 1 hour. The reaction mixture was diluted with ethyl acetate washed with 0.1 N HCI and brine, dried over MgS04, filtered and concentrated in vacuo to provide 4.32 g of crude mesylate.
The crude mesylate, prepared above, and lithium azide (4.2 g, 87.2 mmole) were reacted at 90 °C in 50 mL of N,N-dimethylformamide for 1 hour.
The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgS04, filtered and concentrated. The crude product was purified by silica gel chromatography using 25 % ethyl acetate in hexanes to provide the title compound (yield: 2.0 g, 72%).
' H NMR (CDC13) 82.07 (s, 3H), 2.17 (m, 1 H), 2.37 (m, 1 H), 2.76 (m, 4H), 3.47 (m, 2H), 3.71 (s, 3H), 3.73 (s, 3H), 4.16 (m, 2H).
CH30-l/
Ac0 OCH3 ~'If NHBoc 6E. (t)~1S 2S 3R 4R~-3-Acetoxymethyl-2-(N-t butoxycarbonylamino)methyl-cycloeentane-1 4-dicarboxvlic Acid Dimethyl Ester.
A mixture of (t)-(1 S,2S,3R,4R)-3-acetoxymethyl-2-azidomethylcyclo-pentane-1,4-dicarboxylic acid dimethyl ester (2.0 g, 6.6 mmole), di-t-butyl-dicarbonate (3.79 g), and palladium (900mg, 10% on carbon) in 100 mL of ethyl acetate was stirred vigorously at room temperature under an hydrogen atmosphere. Upon completion, as determined by TLC, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 50% ethyl acetate in hexanes to provide the title compound (Yield: 2.3 g, 94%).
' H NMR (CDC13) 81.43 (s, 9H), 2.06 (s, 3H), 2.17 (m, 1 H), 2.35 (m, 1 H), 2.72 (m, 4H), 3.21 (m, 2H), 3.70 (s, 3H), 3.72 {s, 3H), 4.12 (m, 2H), 4.74 (t, 1 H).
MS = (M+H)+ = 388.
CH30-'~
HO .,~~~~ CH3 O
NHBoc 6F. (t)-(1S 2S 3R 4R)-2-(N-t Butoxycarbonylamino),methyl-3-hydroxymethyl-cyclopentane-1 4-dicarboxylic Acid Dimethyl Ester.
(t)-(1 S,2S,3R,4R)-3-Acetoxymethyf-2-(N-t-butoxycarbonylamino)-methylcyclopentane-1,4-dicarboxylic acid dimethyl ester (600 mg,11.55 mmole) was treated with potassium carbonate (catalytic) in 10 mL of methanol, at room temperature for Bh. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and brine. The organic layer was dried over MgS04, filtered and concentrated to provide the title compound.
(yield:
510 mg, 95%) 'H NMR (CDC13) 81.44 (s, 9H), 2.24 (m, 2H), 2.59 (m, 2H), 2.77 (m, 2H), 3.28 (m, 2H), 3.73 (m, 8H), 5.04 (t, 1 H).
O
CH30--!~
O
NHBoc 6G. (t,~1 S 2S 3R 4R)-3-Azidomethyl-2-(N-t butox~carbonylamino)methylcyc-lopentane-1 4-dicarboxylic Acid Dimethyl Ester.
Methanesulfonyl chloride (0.35 mL, 4.5 mmole) was added slowly to a solution of (t)-(1 S,2S,3R,4R)-2-(N-t-butoxycarbonylamino)methyl-3-hydroxymethyl-cyclopentane-1,4-dicarboxylic acid dimethyl ester {560 mg, 1.48 mmole) and triethylamine (0.6 mL) in dichloromethane (10 mL) at -30 °C.
The reaction mixture was stirred at -30 °C for 2 hours then allowed to warm to 0 °C
over 1 hour. The reaction mixture was then diluted with ethyl acetate washed with 0.1 N HCI and brine, dried over MgS04, filtered and concentrated in vacuo to provide the crude mesylate.
The crude mesylate, prepared above, and lithium azide (0.7 g, 14.3 mmole) were reacted at 85 °C in 10 mL of N,N-dimethylformamide for 1 hour.
The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgS04, filtered and concentrated. The crude product was purified by silica gel chromatography using 25% ethyl acetate in hexanes to provide the title compound (yield: 386 mg, 70%).
'H NMR (CDC13) 81.43 (s, 1H), 2.26 {m, 2H), 2.69 (m, 4H), 3.23 (m, 2H), 3.46 (m, 2H), 3.70 (s, 3H), 3.71 (s, 3H), 4.74 (bs, 1 H).
O
CH30~
AcHN OCH3 O
NHBoc 6H. ,{t)~1 S 2S 3R 4R)-3-Acetamidomethyl-2-LN-t butoxycarbonylamino)methyl-~clopentane-1,4-dicarboxylic Acid Dimethyl Ester.
A mixture of (t)-(1S,2S,3R,4R)-3-azidomethyl-2-(N-t butoxycarbonyl-amino)methylcyclopentane-1,4-dicarboxylic acid dimethyl ester (386 mg, 1.04 mmole) , acetic anhydride (0.25 mL) and palladium (25 mg, 10% on carbon) in 10 mL of ethyl acetate was stirred vigorously at room temperature under an hydrogen atmosphere. Upon completion, as determined by TLC, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 75% ethyl acetate in hexanes to provide the title compound. (yield: 232 mg, 58%).
'H NMR (CDC13) x1.44 (s, 9H), 1.97 (s, 3H), 2.27 (m, 2H), 2.64 (m, 2H), 3.18 (m, 2H), 3.32 (t, 1 H), 3.71 (s, 3H), 3.73 (s, 3H), 7.78 {bs, 1 H), 6.19 (bs, 1 H).
MS = (M+H)+ = 387.
_97_ O
CH30-~~
AcHN OH
O
NHBoc 61. (,t~~1 S 2S 3R 4R~-3-Acetamidomethvl-2-~N-t butoxycarbonylamino)methyl-4-methoxycarbonylcyclopentane-1-carboxylic Acid.
(t)-( 1 S,2S, 3R,4 R)-3-Acetamidomethyl-2-(N-t butoxycarbonylamino)methylcyclopentane-1,4-dicarboxylic acid dimethyl ester (232 mg, 0.60 mmole) was reacted with 5 equivalents of lithium hydroxide in 5 mL
of (4:1 ) methanol:water for 2 hours, at room temperature. The reaction mixture was neutralized with 0.1 N HCI and partitioned between ethyl acetate and brine.
The organic layer was concentrated to provide 194 mg of crude diacid.
The crude diacid (190 mg), prepared above, was reacted with acetic anhydride (10 mL) for 3 hours, at room temperature. The reaction mixture was concentrated in vacuo. The crude product was treated with methanol (10 mL) and triethylamine (.250 mL) for 16 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and 0.1 N HCI. The organic layer was dried over NaZS04, filtered and concentrated. The diastereomeric mixture of methyl esters (174 mg) was chromatographed on silica gel using (5-10%) methanol in chloroform and acetic acid (0.5%) to provide the title compound. (yield: 72 mg, 32%) 'H NMR (CD30D) 81.44 (s, 9H), 1.93 (s, 3H), 2.24 (m, 2H), 2.64 (m, 4H), 3.12 (m, 3H), 3.67 (s, 3H).
MS = (M+H)+ = 373.
_98_ Example 7 CH30-!~
AcHN OH
O
HCI NHZ
fit) (1 S 2S 3R 4R~-2-Aminomethyl-3-acetamidomethyl-4-methoxycarbonyl-cyclo-pentane-1-carboxylic Acid Hydrochloride.
A solution of (t)-(1 S,2S,3R,4R)-3-Acetamidomethyl-2-(N-t-butoxycarbonyl-amino)methyl-4-methoxycarbonylcyclopentane-1-carboxylic acid (62 mg, 0.16 mrnol) in of dichloromethane (4 mL) was reacted with trifluoroacetic acid (1.0 mL) for 1 hour, at room temperature. The solution was concentrated in vacuo, at 25 °C. The residue was treated with 1 N HCI and concentrated in vacuo to provide the title compound as a white solid (yield: 39 mg, 75 %).
' H NMR (D20) 81.95 (s, 3H), 2.22 (m, 1 H), 2.46 (m, 1 H), 2.71 (m, 2H), 2.83 (m, 1 H), 2.96 (q, 1 H), 3.10 (m, 2H), 2.31 (m, 2H), 3.72 (s, 3H).
MS : (M+H)+ = 273.
-99_ Example 8 St)-(1S 2S 3R 4R)-2-N-t-Butoxycarbonylamino-3-(acetamidomethyl}-4-carbamoyl-c rclopentane-1-carboxylic Acid.
AcHN OCH3 O
NHBoc 8A. (t~~1 S 2S 3R 4R)-2-N-t-Butoxycarbonyiamino-3 ~acetarnidomethyl)-4-carbamoyl-cyclo~entane-1-carboxylic Acid Methyl Ester.
The title compound was prepared ih two steps starting by reacting (t)-(1 S,2S,3R,4R)-2-(N-t-butyloxycarbonylamino)-3-(acetamidomethyl)-cyclopentane-1,4-dicarboxylic acid in place of (t)-(1 S,2S,3R,4R)-2-(t butyloxycarbonylamino)-3-(acetamidomethyl)-cyclopentane-1,4-dicarboxylic acid, according to the method described in Example 4H, and substituting anhydrous liquid ammonia for methanol and triethylamine.
In the second step the crude product (54 mg, 0.16 mmole), prepared above, in 4 ml of THF was cooled to 0 °C and treated with an ethereal solution of CHZN2 until the yellow reaction color persisted. The reaction mixture was warmed slowly to room temperature and concentrated in vacuo to provide a colorless oil. Purification using flash chromatography eluting with 5%
methanol/chloroform provided the title compound as a white solid (yield: 16 mg, 28%).
'H NMR (CDC13) 51.43 (s, 9H), 1.90 (s, 3H), 2.03 (m, 1 H), 2.24 (m, 1 H), 2.65 (m, 4H), 3.68 (s, 3H), 4.30 (m, 2H).
MS: (M+H)+ = 358.
O
HZN~/
AcHN OH
~'If NHBoc 8B. ~t~~1S 2S,3R 4R)-2-N-t-Butox)rcarbonYlamino-3-(acetamidomethyl)-4-carbamoyl-cyclopentane-1-carboxylic Acid.
A solution of (t)-(1 S,2S,3R,4R)-2-N-t butoxycarbonylamino-3-(acetamido-methyl)-4- carbamoyl-cyclopentane-1-carboxylic acid methyl ester (16 mg, 0.045 mrnole) in 0.2 ml methanoI/H20 (3:1 ) was treated with (1 mg, 0.045 mmole) of LiOH. After stirring at room temperature overnight, the reaction mixture was quenched with 5% HCI and extracted 3 times with ethyl acetate. The combined extracts were dried over Na2SOa, filtered and concentrated in vacuo to provide the title compound as a white solid (yield: 11 mg, 73%).
'H NMR (methanol-d4) 81.44 (s, 9H), 1.91 (s, 3H), 2.02 (m, 1H), 2.24 (m, 1 H), 2.60 (m, 5H), 4.32 (m, 1 H), 6.90 (br d, 1 H).
MS (M-H)- = 342.
Example 9 ~t)-(1S,2S,3R.4R)-2.3-Acetamidomethyl-4-methoxycarbon r~yclopentane-1-carboxylic Acid.
Ac0 OAc 9A. (t)-exo-exo-2.3-diacetoxymethyl-bi~clo[2.2.1Lept-5-ene.
(t)-exo-exo-2,3-dihydroxymethyl-bicyclo[2.2.1]hept-5-ene was treated with acetic anhydride and triethylamine in dichloromethane. Standard workup provided the title compound.
MS: (M+H)+ = 329.
O
CH30-!~
Ac0 OCH3 .,,, OAc 9B. Lt)-(1 S 2S.3R 4R~-2.3-Diacetoxymethylcyclopentane-1,4-dicarboxylic Acid Dimethvi Ester.
The title compound was prepared according to the method described in Example 6B, substituting (t)-exo-exo-2,3-diacetoxymethylbicyclo[2.2.1]hept-5-ene (1 g, 4.2 mmol) in place of (t)-(2R,3S)-2-acetoxymethyl-3-benzyloxymethyl-bicyclo[2.2.1]hept-5-ene. Purification, using flash chromatography eluting with 50% ethyl acetate/hexanes, provided the title compound as a colorless oil.
(yield:
0.8 g, 58%).
' H NMR (CDC13) 62.05 (s, 6H), 2.29 (m, 2H), 2.79 (m, 4H), 3.72 (s, 6H), 4.14 (m, 4H).
MS: (M+H)+ = 331.
O
CH30-l~
OH
9C. fit)-~1S 2S 3R 4R~2 3-DihYdroxymet~fcyclopentane-1.4-dicarboxylicAcid Dimethyl Ester.
A solution of (t)-(1S,2S,3R,4R)-2,3-diacetoxymethylcyclopentane-1,4-dicarboxylic acid dimethyl ester (5.0 g, 0.015 mole) in 60 ml of methanol was treated with a catalytic amount of K2C03. The reaction mixture was stirred, under a nirogen amosphere, at room temperature, for 16 hours. The reaction mixture was diluted with ethyl acetate and quenched with 5% HCI. The organic layer was separated, dried over Na2S04, filtered, and concentrated in vacuo, at 30 °C to provide the title compound as a colorless oil. (yield: 3.3 g, 89%) 'H NMR (CDC13) 82.06 (m, 1H), 2.29 (m, 2H), 2.54 (m, 3H), 2.80 (m, 2H), 3.67 (m, 8H).
MS: (M+H)+ = 247.
CH30-J~
Ms0 OCH3 ..,, OMs 9D. ~f)-(1 S.2S.3R.4R)-2.3-Dimethansulfonyloxymeth rLlcyclopentane-1.4-di-carbox~rlic Acid Dimethyl Ester.
A solution of (t)-(1 S,2S,3R,4R)-2,3-dihydroxymethylcyciopentane-1,4-dicarboxylic acid dimethyl ester (200 mg, 0.81 mmole) in 4 ml of THF and 4 ml of dichloromethane was cooled to -30 °C and treated with methanesulfonyl chloride (0.19 mL, 2.4 mmole) followed by dropwise addition of triethylamine (0.34 mL, 2.4 mmole). After 30 minutes of stirring under a nirogen amosphere, at -30 °C, the mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over Na2S04 , filtered and concentrated in vacuo to provide the title compound as a colorless oil (yield: 302 mg, 93%).
'H NMR (CDC13) b 62.16 (m, 1 H), 2.45 (m, 1 H), 2.87 (m, 4H), 3.06 (s, 6H), 3.72 (s, 6H), 4.38 (m, 4H).
MS: (M+H)+ = 403.
O
CH30-l~
~'I~
9E. (t)-(1 S 2S 3R 4R~-2 3-Diazidometh~-cyclopentane-1 4-dicarboxylic Acid Dimeth~ Ester.
A solution of (t)-(1 S,2S,3R,4R)-2,3-dimethansulfonyloxymethyl-cyclopentane-1,4-dicarboxylic acid dimethyl ester (300 mg, 0.75 mmole) in 3 mL
of DMF was treated with LiN3 (400 mg, 8.2 mmole) and heated to 100 °C
under a nitrogen amosphere. After heating for 1 hour, the reaction mixture was diluted with ethyl acetate and washed twice with water, brine, dried over Na2S04, filtered and concentrated in vacuo to provide the title compound as a copper colored oil (yield: 204 mg, 92%).
'H NMR (CDC13) 8 62.12 (m, 1 H), 2.37 (m, 1 H), 2.71 (m, 4H), 3.50 (m, 4H), 3.72 (m, 6H).
MS: (M+H)+ = 297.
O
CH30~~
AcHN OCH3 NHAc 9F. (t)-(1 S 2S 3R 4R)-2 3-Acetamidomethyl-cyclopentane-1 4-dicarboxylic Acid Dimethyl Ester.
A solution of (t)-(1S,2S,3R,4R)-2,3-diazidomethyl-cyclopentane-1,4-dicarboxylic acid dimethyl ester (145 mg, 0.49 mmole) in 2 ml of isopropyl alcohol was treated with Pd/C. The reaction mixture stirred vigorously overnight under a hydrogen atmosphere, at room temperature. The reaction mixture was filtered over Celite'~ and concentrated in vacuo to provide a pale yellow oil.
The crude product was then taken up in dichloromethane and treated with excess acetic anhydride and N,N-dimethylaminopyridine. The reaction mixture was stirred at room temperature for 1 hour before concentrating in vacuo to provide a pale yellow oil. Purification, by flash chromatography eluting with 10%
methanol/chloroform provided the title compound as a colorless oil (yield: 40 mg, 25%).
'H NMR (CDC13) X1.98 (s, 6H), 2.30 (m, 1H), 2.36 (m, 1H), 2.56 (m, 2H), 2.68 (m, 2H), 3.30~(m, 4H), 3.71 (s, 6H), 6.16 (br s, 2H).
MS: (M+H)* = 329.
O
CH30--l~
AcHN ,,,~~OH
NHAc 9F. ~(1S 2S 3R4R)-2 3-Acetamidomethyl-4-methoxYcarbonylcvclopentane-1-carboxylic Acid.
A solution of (t)-(1S,2S,3R,4R)-2,3-acetamidomethyl-cyclopentane-1,4-dicarboxylic acid dimethyl ester (100 mg, 0.33 mmole) in 1 m! of a mixture of methanoI/H20 (3:1 ) was treated with LiOH (16 mg, 0.66 mmole). After stirring for 1 hour, at room temperature, the reaction mixture was acidified with 5% HCI
and extracted three times with ethyl acetate. The organic extracts were dried over Na2S04, filtered and concentrated in vacuo to provide the diacid intermediate as a white solid (69 mg, 70%). The diacid was taken up in acetic anhydride (2 ml) and heated for 1 hour at 60°C. The reaction mixture was then concentrated in vacuo, taken up in 1 mL of methanol and treated with triethyl amine. The mixture was stirred at room temperature for 3 hours, under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate and washed 3 times with 5%
HCI.
The organic layer was dried over Na2S04 , filtered and concentrated in vacuo.
Purification, using flash chromatography, eluting with 20% ethyl acetate/hexanes with 1 % acetic acid provided the title compound as a white solid. (yield: 6 mg, 6%) 'H NMR (methanol-d4) 81.92 (d, J=3 Hz, 6H), 2.15 (m, 2H), 2.35 (m, 2H), 2.67 (m, 4H), 3.15 (m, 2H), 3.67 (s, 3H).
MS: (M+H)+ = 315.
Example 10 _{t)-(1S 2S 3R 4R~2-N-t Butoxycarbonylamino-3-Lacetamidomethyl)-4-N-methylcarboxamido-cyclopentane-1-carboxylic Acid and~t~1 R,2R.3S,4S)-3-N-t butoxycarbonylamino-2-{acetamidomethyl)-4-N-methylcarboxamido-cyclopent-ane-1-carboxylic Acid.
H3CHN-~~ HO-~~
AcHN OH AcHN NHCH3 O O
NHBoc NHBoc 10A. {t~1S 2S 3R 4R~2-N-t butox~carbonylamino-3- acetamidomethyl)-4-N-methylcarboxamido-cyclopentane-1-carboxylic Acid Methyl Ester and (t)-(1 R.-~R 3S 4Sy-3-N-t butoxycarbonylamino-2-(acetamidomethyl)-4-N-methylcarbox-amido-cvclopentane-1-carboxylic Acid Methyl Ester.
A solution of (t)-(1S,2S,3R,4R)-2-N-t butoxycarbonylamino-3-(acetamido-methyl)-4-N-methylcarboxamido-cyclopentane-1-carboxylic acid methyl ester and (t)-(1 R,2R,3S,4S)-3-N-t-butoxycarbonylamino-2-{acetamidomethyl)-4-N-methyl-carboxamido-cyclopentane-1-carboxylic acid methyl ester (1:1) (260 mg, 0.72 mmole) in 3 ml of dichloromethane was treated with hydroxybenzotriazole (1 equiv.), 1-(3-dimethyiaminopropyl)-3-ethylcarbodiimide (1.5 equivalents), and methylamine (5 equivalents). After stirring at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate and washed 3 times with 5%
HCI.
The organic layer was dried over Na2S04 , filtered and concentrated in vacuo to provide the title ester-amide compounds as a white solid. (yield: 111 mg, 42%) MS: (M+H)+ = 372.
O O
CH3N-~~ HO~
Ac0 OH Ac0 NHCH3 ~''I'~ ~'I~
NHBo NHBo 1 OB. (t)-(1 S 2S 3R 4R)-2-N-t Butoxycarbonylamino-3-(acetamidomethvl)-4-N-methylcarboxamido-cyclopentane-1-carboxylic Acid and ~t)~1 R,2SR,3S,4S)-3-N-t-butoxycarbonylamino-2 ~acetamidomethyl)-4-N-methYlcarboxamido-cyclopent-ane-1-carboxylic Acid.
A solution of the ester-amide mixture (125 mg, 0.34 mmole) prepared in Example 10A, in 1 ml of methanoI/H20 (3:1 ) was treated with LiOH (8 mg, 0.34 mmole). After stirring for 1 hour at room temperature, the reaction mixture was quenched with 5% HCI and extracted 3 times with ethyl acetate. The combined organic extracts were dried over Na2S04 , filtered and concentrated in vacuo to provide the title compound as a white solid. (yield: 85 mg, 70%) 1 H NMR (methanol-d4) 81.44 (br d, 18H), 1.91 (d, J=5 Hz, 6H), 2.00 {m, 2H), 2.20 (m, 2H), 2.60 (m, 6H), 2.72 (br s, 6H), 3.08 (m, 4H), 4.35 (m, 2H).
MS: (M+H)+ = 358.
Example 11 (t)-(1 S 2S 3R 4RZ 3-AcetamidomethYl-2 4-diamino-cyclopentane-1-carboxylic Acid Hydrochloride.
O O
CH30-l~ HO~~
Ns~,. ,~~~I~OH N3~,. .,, ~~OCH3 BocHN O BocHN rO
11A. (t)-y1S 2S 3R 4R)-2-(t-Butyloxycarbonylamino)-3-(azidomethyl)-4-meth-oxycarbonyl-cyclopentane-1-carboxylic Acid and (t)-(1 S 2S.3R.4R)-2-(t-butyl-oxycarbonylamino)-3-~azidomethyl)-1-methox~carbonyl-cyclopentane-4-carbox-ylic Acid.
The title compound was prepared, in two steps, first following the procedure described in Example 4G and 4H substituting (t)-(1S,2S,3R,4R)-2-(i-butyloxycarbonylamino)-3-(azidomethyl)-cyclopentane-1,4-dicarboxylic acid dimethyl ester ( 98 mg, 0.28 mmole) in place of (t)-(1 S,2S,3R,4R)-2-(t-butyloxycarbonylamino)-3-(acetamidomethyl)-cyclopentane-1,4-dicarboxylic acid dimethyl ester (yield: 76 mg, 79 %).
MS: '(M+H)+ = 343 O
CbzHN, H3C0-~~
N3 ,"~~I~OCHg N3 "'~NHCbZ
BocHN O BocHN
11 B. StL(1 S 2S 3S 4R)-2-(f-Butyloxycarbonylamino)-3-(azidomethyl)-4-benzyl-oxycarbonylamino-cyclo~entane-1-carboxylic Acid Methyl Ester and (t)-(1 R.2R.-3S 4S) 3 t ButYloxycarbon la~mino)-2-(azidomethyl)-4-benzvloxycarbonylamino-cyclopentane-1-carboxylic Acid Methyl Ester.
A solution of (250 mg,0.73 mmole) of the above mixture of regioisomers of methyl ester azide cycfopentanes, prepared in Example 11A, was treated with diphenylphosphorylazide, in 8 ml of toluene, Et3N, ( 0.2 mL) and 0.75 mL of benzyl alcohol, under a nitrogen atmosphere, and heated to 80 °C for 3 hours.
The reaction mixture was diluted with ethyl acetate and washed 3 times with 5%
HC1. The organic layer was dried over Na2SOa, filtered and concentrating in vacuo to provide a pale yellow oil. Purification using flash chromatography on silica gel eluting with 20% ethyl acetate/hexanes provided the title compounds (mixture of regioisomers) as a white solid (yield: 278 mg, 85%) MS: (M+H)+ = 448.
CbzHN, AcHN~,, ",~~~~OCH3 BocHN O
11 C. ft)~1 S 2S 3S 4R)-2-ff But~oxycarbonylaminoZ 3-(acetamido)methyl-4-benzyloxycarbonylamino-cyclo~pentane-1-carboxylic Acid Methyl Ester.
A solution of the methyl ester diastereomers (278 mg, 0.62 mmoie), prepared in Example 11 B, in 0.2 ml of thiolacetic acid was stirred under a nitrogen atmosphere at room temperature for 6 hours. The reaction mixture was concentrated in vacuo to provide a yellow oil. The crude oil was purified using flash chromatography, eluting with 50% ethyl acetatelhexanes to provide the title compound as a white solid. (yield: 70 mg, 24%) MS: (M+H)+ = 464.
WO 99/54290 PCTlUS99/07949 CbzHN, AcHN~,, O
BocHN O
11 D. ~t}-(1 S 2S 3S 4R)-2-~t Butylox~rcarbonylamino)-3-(acetamido)methyl-4-benzyloxycarbonylamino-cyclopentane-1-carboxylic Acid.
A solution of (t)-(1S,2S,3S,4R)-2-(t-butyloxycarbonylamino)-3-(acetamido)methyl-4-benzyloxycarbonylamino-cyclopentane-1-carboxylic acid methyl ester (70 mg, 0.15 mmole) in 1 mL of methanoI/H20 (3:1 ) was treated with (4 mg, 0.15 mmole) of LiOH. After stirring at room temperature for 2 hours the reaction mixture was quenched with 5% HCI and extracted 3 times with ethyl acetate. Standard workup, as described above, provided the title compound as a white solid (yield: 51 mg, 76%).
MS: (M+H)+ = 450.
H2N, AcHN OH
NH ,/'G 2 HC~
11 E. (rt)-(1 S 2S 3S 4R~-3-Acetamidomethyl-2 4-diamino-cyclopentane-1-car-boxylic Acid Dihrdrochloride A solution of (t)-(1 S,2S,3S,4R)-2-(t-butyloxycarbonylamino)-3-(acetamido)methyl-4-benzyloxycarbonylaminocyclopentane-1-carboxylic acid (51 mg, 0.11 mmole) in 0.2 ml of isopropyl alcohol and Pd/C was reacted under 1 atmosphere of hydrogen for 18 hours. The reaction mixture was filtered through Celite° and concentrated in vacuo to provide the title compound as a tan foam.
(yield: 30 mg, 86%) MS: (M+H)+ = 216.
Example 12 (t)-(1 R.2R,4R,1'S~-4-(1'-Acetamido-3'-ethy~pentyl-3-methoxycarbonyl-cKclopentane-1-carboxylic Acid.
12A. {t~exo,1'RS~and (endo.1'RS)-2-(~3-eth~rl-1-hydroxy~pentylbicyclo[2.2.1 jhept-5-ene.
1-bromo-2-ethylbutane (12.5 mL) and a catalytic amount of 1,2-dibromoethane were added to a suspension of 2.1 g Mg turnings in 200 mL of tetrahydrofuran. This mixture was heated to 50 °C for 2 hours, and cooled to -78 °C. A solution of 5.4 mL (t)-endo-2-formylbicyclo[2.2.1 jhept-5-ene, in 75 mL
tetrahydrofuran, was added dropwise to the Grignard solution. The mixture was warmed to 0 °C and stirred for 1 hour. The reaction was quenched by addition of 20 mL saturated ammonium chloride and ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate, filtered and the solvent is evaporated. The crude material was purified by flash chromatography using 10% ethyl acetate:hexanes (1:9) to provide the title compounds. (yield:
4.9 g, 53%) 'H NMR (CDC13) 8 0.78-0.91 (m, 6H), 1.15-1.50 (m, 11H ), 1.70-2.10 (m, 1 H), 2.60-2.95 {m, 2H), 2.95-3.55 (m, 1 H),6.0-6.2(m,2H), MS: (M+H)~' = 208.
12B. (t)-exo and endo-2-(1'-oxo-3'-ethyl)pentyl-bic~rcloL2.2.1]hept-5-ene.
A solution of of oxalyl chloride, (2.3 mL) in 100 mL dichloromethane, maintained at -78 °C, was treated dropwise with dimethyl sulfoxide, (4.0 mL).
The mixture was stirred under nitrogen for 20 minutes and a solution of (t)-(2S,1'R) and (2S,1'S)-2-(1'-hydroxy-3'ethyl)pentyl-bicyclo[2. 2.1]hept-5-ene (4.9 g) in 50 mL of dichloromethane was added. The mixture was stirred at -78 °C for 0.5 hours warmed to 0 °C for 15 minutes, treated with 16.4 mL
triethylamine at 0 °C and stirred for 10 minutes. Water (100 mL), at 25 °C, was added over 10 minutes. The organic layer was separated, washed with brine, dried over MgS04, filtered and the solvent evaporated. The crude ketone mixture was purified by flash chromatography using chloroform:hexanes (1:3) to provide the products (yield: 3.72 g, 77%}.
The ketone mixture prepared above (3.1 g, 14.9 mmole) was dissolved in 50 mL of methanol and combined with 22 mL of 1 M sodium methoxide. This mixture is heated to 70 °C for 18 hours. The solvent was evaporated and the residue dissolved in 300 mL ethyl acetate. The organic layer was washed with 100 mL of 0.5M HC1, brine, dried over magnesium sulfate, filtered, and the solvent is evaporated. The ketones were separated by flash chromatography using chloroform:hexanes (1:3) to provide title compound (t) (2R)-2-(3-ethyl-1-oxo)pentyl-bicyclo[2.2.1 Jhept-5-ene (yield: 0.99 g, exo ketone) (higher Rf) and (t) (2S)-2-(3-ethyl-1-oxo)pentyl-bicyclo[2.2.1]hept-5-ene (yield: 1.7 g, endo ketone, 87%).
~ H NMR (CDC13) 8 0.85 (2t, 6H), 1.19-1.42 (m, 7H ), 1.70-1.92 (m, 2H), 2.32-2.39 (m, 1 H), 2.39-2.47 (2d, 2H), 2.88-2.98 (d,2H), 6.10-6.17 (m, 2H).
12C. (t)-f2R)-2-(1-Hydroxyimino-3-ether pentyl-bicyclo(2.2.11heat-5-ene.
A solution of (t) (2R)-2-(1'-oxo-3'ethyl)pentyl-bicyclo[2.2.1]hept-5-ene (1.1 g, 5.4 mmole) in 45 mL methanol was reacted with hydroxylamine hydrochloride (1.5 g, 21.6 mmole) and 1 N NaOH (16.3 mL). This mixture was heated at 40 °C
for 2 days. The solvent was evaporated and the residue was partitioned between ethyl acetate and brine. The organic layer was dried over MgS04, filtered, and the solvent evaporated to provide the title compound (yield: 1.16 g, 97%).
~ H NMR (CDC13) 8 0.87 (2t, 6H), 1.24-1.40 (m, 8H ), 1.50 (d, 1 H), 1.65 (m, 1 H), 1.78 (m, 1 H), 2.15 (m,1 H), 2.35 (m, 2H), 2.90 (m,2H), 6.13 (m, 2H), 2.87(m, 1 H), 3.68 (s,3H), 3.85 (m, 1 H ) MS: (M+H)+= 222 HZN~, H
12D. ~)-(2R 1'S)-2-(1-Amino-3-ethyl)pentyl-bicyclof2.2.11hept-5-ene.
The crude (t)-(2R)-2-(1-hydroxyimino-3-ethyl)pentylbicyclo[2.2.1]hept-5-ene (0.49 g, 2.13 mmole), prepared in Example 12C, in 10 mL toluene, was treated with 1 M lithium aluminum hydride bis(tetrahydrofuran) (4.3 mL). The mixture was heated to 100 °C for 2 hours, under a nitrogen atmosphere.
The mixture was cooled to 0 °C, and consecutively combined with water (0.16 mL), 15% NaOH (0.16 mL), and water (0.49 mL). The solids were filtered, and the solution diluted with 150 mL ethyl acetate. The organic layer was washed with water, and brine, dried over MgS04, filtered and the solvent evaporated. The crude amines were separated by flash chromatography using ether:methanol:ammonium hydroxide (98:2:0.2) to provide the title compound, (t)-(2R,1'S)-2-(1-amino-3-ethyl)pentylbicyclo[2.2.1]hept-5-ene (yield: 79 mg), and the (t)-(2R,1'R)- isomer (77 mg) and 77 mg of a mixture of the amines overall yield 52%.
AcHN,,, H
12E. (t)-(2R 1'S)-2-(1-Acetamido-3-ethyl-)pentyl-bicYclo[2.2.1]hept-5-ene.
(t)-(2R,1'S)-2-(1'-amino-3'-ethyl-)pentyl-bicyclo[2.2.1]hept-5-ene (78 mg, 0.38 mmole) was dissolved in 3 mL dichloromethane . Triethylamine (0.16 mL) and acetic anhydride (0.07 mL) were added to the mixture. After 1 hour at 25 °C
the solvent was evaporated and the residue purified by flash chromatography using ethyl acetate:hexanes (1:4) to provide the title compound (yield: 78 mg, 83%).
~ H NMR (CDC13, 300 MHz) b 0.77-0.88 (m, 6H), 1.10-1.57 (m, 11 H ), 2.02 (s, 3H), 2.65 (s, 1 H), 2.84 (s, 1 H), 3.80-3.95 (m,1 H), 5.0-5.15(m, 1 H), 6.05 (s,2H).
MS: (M+H)+= 250.
12F (t)-(1 R 3R 4R 1'S)-4-(1-Acetamido-3-eth r~l pent~cyclopentane-1,3-Dicarboxylic Acid.
A solution of ruthenium tetroxide was prepared from 5.5 mg of ruthenium dioxide, suspended in carbon tetrachloride:acetonitriie (2:1 ), and 219 mg sodium periodate in 3 mL of water. The mixture was stirred 15 minutes at 0 °C.
A
solution of (t)-(2R,1'S)-2-(1'-acetamido-3'-ethyl)pentylbicyclo[2.2.1]hept-5-ene (64 mg, 0.256 mmol) in 1 mL of carbon tetrachloride was added to the ruthenium mature. The reaction mixture was allowed to warm to 25 °C and stirred for 3 hours. 1 M Sodium bicarbonate (2 mL) was added and the aqueous layer was separated and acidified with 5 mL 1 M HCI and extracted with ethyl acetate.
The organic layer was filtered through Celite~ and the solvents were evaporated in vacuo. The crude mixture was purified by flash chromatography using WO 99!54290 PC'T/US99/07949 methanol:dichloromethane :acetic acid (3:20:0.5) to provide the title compound (yield: 50 mg, 62%).
~ H NMR (CD30D) s 0.78-0.92 (2t, 6H), 1.14-1.47 (m, 7H ), 1.62-1.75 (m, 1 H), 1.92 (s, 3H), 1.95-2.03 {m, 1 H), 2.08-2.20 (m,1 H), 2.22-2.33 (m, 1 H), 2.35-2.49 (m,1 H), 2.58-2.68 (m, 1 H), 2.82-2.94 (m, 1 H), 3.83-3.95 (m,1 H),.
MS: (M+H)+= 314 CH30-f~
AcHN~,, .,,~~~OH
H O
12G. (t) (1R 3R 4R 1'S)-4-(1'-Acetamido-3'-ethyl)pentyl-3-methoovcarbonyl-~clopentane-1-carboxylic Acid.
(t)-(1 R,3R,4R,1'S)-2-(1-Acetamido-3-ethyl}pentylcyclopentane-1,3-dicarboxylic acid was reacted with acetic anhydride (0.1 mL), suspended in 3 mL
of chloroform, in a sealed tube, and heated to 70 °C for 3 hours. The solvents were evaporated and the residue was added to 1 mL of methanol and 0.1 mL of triethylamine, and heated for 1 hour, at 70 °C. The solvents were evaporated and the crude acidlester purified by flash chromatography using ethyl acetate:methanol:acetic acid (97:2:1) to provide of the mixture of acidlesters (yield: 30 mg, 57%). The two isomers were separated by preparative thin layer chromatography using ethyl acetate:methanol:acetic acid (97:2:1) to provide the title compound (yield: 6.9mg, 13%).
~H NMR (CD30D, 300 MHz) 8 0.83 (2t, 6H), 1.14-1.48 (m, 8H ), 1.67 (m, 1 H), 1.91 (s, 3H), 1.98 (m, 1 H), 2.11 (m,1 H), 2.25 (m, 1 H}, 2.42 {m,1 H), 2.62 (m, 1 H), 2.92 (m, 1 H), 3.68 (s,3H), 3.89 (m, 1 H ) MS: (M+H}+= 328 Example 13 ~1 R 3Rj4R 1'S)-3-Hydroxymetf~rl-4~1'-acetamido-3'-ethyl)pentyl-c~clopentane-1-carboxylic Acid.
CH30-l~ CH30 O - O
hi ~ H
O O
13A. (t)-1 R 2R 4'S) and (t)-(1 S 2S 4'S)-2~2 2-dimethKl-1,3-dioxolan-4-yl)-4-methylenecyclopentane-1-carboxylic Acid Methyl Ester.
A solution of 2-[(trimethylsilyl)methyl]-2-propen-1-yl-acetate (5 g, 26.9 mmole), methyl (S}-(+}-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-trans-2-propenoate (5 g, 26.9 mmole), Pd(OAc)2 {0.42 g, 1.8 mmole) and (i-Pr0)3P (2 mL, 8.1 mmole) in 27 mL of toluene was heated under an argon atmosphere for 24 hours. The reaction was cooled and concentrated in vacuo. The crude product was chromatographed on silica gel with 5-15% ethyl acetate in hexanes to provide the title compound (yield: 4.68 g, 73%}.
'H NMR {CDC13) 84.88 (m, 2H), 4.18-3.95 (m, 2H), 3.70 (s), 3.69 (s) [3H
overall], 3.68-3.55 (m, 1 H), 2.78-2.29 (m, 6H), 1.40 (s), 1.38 (s) [3H, overall], 1.34 (s), 1.32 {s) [3H, overall].
MS: (M+H)*=241.
OH
O H
13B. (1R 2R 4'S~-2-Hydroxymethyl-1-(2 2-dimethyl-1 3-dioxolan-4-yl)-4-methvlene-c~ciopentane Lithium aluminum hydride (0.63g, 16.6 mmole) was added to a solution of (1 R,2R,4'S) and (1 R,2S,4'S)-methyl 2-(2,2-dimethyl-1,3-dioxolan-4-yl)-4-methylene-cyclopentane-1-carboxylate (2.Og, 8.33 mmole) in 40 mL of THF
maintained at -78 °C. The reaction was allowed to warm to 0 °C
and stirred for 1 hour. The reaction was quenched (at 0 °C) by adding sequentially H20 (1.9 mL), 10% NaOH (2.8 mL), and H20 (2.8 mL). The reaction was allowed to warm to room temperature then dried over MgS04. The reaction was filtered and the solids were washed with ethyl acetate (200 mL). The filtrate was concentrated in vacuo to provide 1.83 g of the crude product mixture. Preparative HPLC on silica gel with (0-75%) ethyl acetate in hexanes provided the title compound (yield;
1.15 g, 65%).
' H NMR (CDC13) 84.84 (m, 2H), 4.21 (m, 1 H), 4.03 (dd, J=6, 8 Hz, 1 H), 3.64 (t, J=8 Hz, 1 H), 3.56 (m, 2H), 2.60-2.05 (m, 6H), 1.44 (s, 3H), 1.36 (s, 3H).
MS: (M+H)*=213.
OTBDPS
13C. (1R 2R 4'S)-2-(t-ButXldiphenylsilyloxymethy!)-1-(2 2-dimethyl-1,3-dioxolan-4-yl)-4-methylenecyclopentane A solution of (1 R,2R,4'S)-2-hydroxymethyl-1-(2,2-dimethyl-1,3-dioxolan-4-yl)-4-methylenecyclopentane (1.158, 5.4 mmole), t-butyldiphenylsilyl chloride (1.6 mL, 6.8 mmole) and imidazole (1.11g, 16.3 mmole) in 30 mL of dichlorornethane was stirred at room temperature for 1.5 hours. The reaction mixture was quenched with methanol (.2 mL) and stirred for 1 hour. The mixture was partitioned between ethyl acetate and 10% citric acid. The organic layer was washed with water and saturated NaHC03, dried over MgS04, filtered and concentrated to provide the title compound.
' H NMR (CDC13) 67.65 (m, 4H), 7.39 (m, 6H), 4.82 (m, 2H), 4.00 (m, 1 H), 3.89 (dd, J=6, 8 Hz, 1 H), 3.62-3.48 (m, 3H), 2.51-1.98 (m, 6H), 1.37 (s, 3H), 1.31 (s, 3H), 1.05 (s, 9H).
MS: (M+H)+= 451.
OTBDPS
HO
H
HO
13D. (1 R 2R 1'S~ 2-(t-Butyldiphen~silylox~meth~Z 1-(1 2-dihydroxy)ethyl-4-methylene-cyclopentane (1 R,2R,4'S)-2-(t-Butyldiphenylsilyioxymethyl)-1-(2,2-dimethyl-1,3-dioxolan-4-yl)-4-methylene-cyclopentane and pyridinium p-toluenesulfonate (0.68g, 2.7 mmole) in 110 mL of methanol were heated to 45 °C for 16 hours. The reaction was cooled, concentrated in vacuo and partitioned between dichloromethane and water. The organic layer was washed with brine, dried over MgS04, filtered and concentrated. The crude product was chromatographed on silica gel with 15%
ethyl acetate in hexanes to provide the title compound and recovered starting material (yield: 1.2 g, 54%).
'H NMR (CDC13) 87.65 (m, 4H), 7.39 (m, 6H), 4.81 (m, 2H), 3.75-3.46 (m, 5H), 2.54-1.89 (m, 6H), 1.06 (s, 9H).
MS: (M+H)+= 411.
OTBDPS
O_~.
H H
13E. ~1 R 2R) 2 (t-Butyldi~henylsi~lox rLmethyl)-1-formyl-4-methylene-cyclopentane A solution of (1R,2R,1'S)-2-(t-butyldiphenylsilyloxymethyl)-1-(1,2-dihydroxy)ethyl-4-methylene-cyclopentane (1.2 g, 2.92 mmole), Na104 (2.5 g, 11.6 mmole) in ethanol {4 mL) and water (4 mL) was stirred at 0 °C for 4 hours.
The reaction was diluted with ethyl ether (90 mL) and filtered through a celite pad.
The filtrate was concentrated in vacuo. The crude product was dissolved in toluene and concentrated in vacuo to azeotropically remove water. The reaction was redissolved in ethyl ether and filtered again followed by concentration to provide the title compound as a crude oil.
'H NMR (CDC13) 89.68 (d, J=3 Hz, 1H), 7.65 (m, 4H), 7.39 {m, 6H), 4.87 (m, 2H), 3.68 (dd, J=5, 10 Hz, 1 H), 3.56 {dd, J=7, 10 Hz, 1 H), 2.83-2.09 (m, 6H), 1.04 (s, 9H).
MS: (M+H)+= 379.
13F. {1 R 2R 1'R) 2 (t Butyldit~henylsi~loxYmethyl)-1-(3-ethyl-1-hydroxylpentyl-4-methylene-cyclopentane A 0.9 M solution of 2-ethylbutyl magnesium bromide (15.3 mL), prepared from 1-bromo-2-ethylbutane (3.8 mL, 27.1 mmole), magnesium (1 g, 41.6 mmole) and iodine (170 mg) in ethyl ether (30 mL) and stirred overnight at room temperature, was added to a solution of (1 R,2R)-2-(t-butyldiphenylsilyloxy-methyl)-1-formyl-4-methylene-cyclopentane (2.92 mmole) in ethyl ether (15 mL) at 0 °C for 20 minutes. The reaction was quenched with saturated ammonium chloride and stirred for 30 minutes. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSOa, filtrered and concentrated. The crude product was purified by preparative HPLC
on silica gel with (5-50%) ethyl acetate in hexanes to provide the title compound (yield: 0.7 g, 51 %).
' H NMR (CDC13) 87.65 (m, 4H), 7.39 (m, 6H), 4.80 (m, 2H), 3.79 (m, 1 H), 3.64 (dd, J=5, 10 Hz, 1 H), 3.56 (dd, J=7, 10 Hz, 1 H), 2.46-1.9 (m, 6H), 1.5-1.21 (m, 7H), 1.05 (s, 9H), 0.84 (t, J=8 Hz, 3H), 0.83 (t, J=8 Hz, 3H).
MS: {M+H)+= 465.
OTBDPS
13G. {1 R 2R 1'S~-1-jt-Butyldi~,henylsilyloxymethyl)-2-(3-ethyl-1-azido)pentyl-methylene-cyclopentane A solution of (1R,2R,1'R)-2-(t-butyldiphenylsiiyloxymethyl)-1-(3-ethyl-1-hydroxy)pentyl-4-methylene-cyclopentane (0.7g, 1.51 mmole), methanesulfonyl chloride (.25 mL, 3.23 mmole) and triethylamine {1 mL) in dichloromethane (15 mL) was stirred for 0.5 hours, at 0 °C. The reaction was quenched with saturated NaHC03 solution (3 mL) and then partitioned between ethyl acetate and 10%
citric acid. The organic layer was washed with saturated NaHC03 and brine, dried over MgS04, filtered and concentrated in vacuo to provide the intermediate mesylate. A solution of the crude mesylate and sodium azide (1g, 15.3 mmole) in dimethylformamide (15 mL) was reacted at 65 °C for 16 hours. The reaction was cooled and diluted with ethyl acetate. The organic layer was washed with water and brine, dried over MgS04, filtered and concentrated to provide the title compound.
'H NMR (CDC13) 87.66 (m, 4H), 7.39 (m, 6H), 4.81 (m, 2H), 3.64 (dd, J=6, Hz, 1 H), 3.52 (dd, J=7, 10 Hz, 1 H), 3.22 (m, 1 H), 2.58-2.0 (m, 6H), 1.48-1.11 (m, 7H), 1.05 (s, 9H), 0.86 (t, J=7 Hz, 3H), 0.80 (t, J=7 Hz, 3H) .
OTBDPS
AcH N.
w U W
H
13H. (1R 2R 1'S)-1-(t-Butyldiphenylsilyloxymethyl)-2-(1'-acetamido-3'-ethy~pentyl-4-methylene-c~clopentane A solution of the crude (1R,2R,1'S)-1-(t-butyldiphenylsilyloxymethyl)-2-(3-ethyl-1-azido)pentyl-4-methylene-cyclopentane (~1.5 mmole), prepared in Example 13G, and triphenylphosphine (1.39g, 5.3 mmole) in 20% H20 in THF (25 mL) was stirred at 75 °C for 16 hours. The reaction was cooled and concentrated in vacuo to provide the crude amine. The amine, acetic anhydride (.25 mL) and pyridine (.55 mL) in dichloromethane (13 mL) were stirred at room temperature for 2 hours. The reaction was quenched with methanol (2 mL) and stirred for an additional 1 hour. The reaction was diluted with ethyl acetate and washed sequentially with 10% citric acid, saturated NaHC03, and brine, dried over MgS04, filtered and concentrated. Chromatography on silica gel with 2.5 -10%-ethyl acetate in dichloromethane provided the title compound (yield: 0.404 g, 60%).
'H NMR (CDC13) 57.65 (m, 4H), 7.39 (m, 6H), 4.93 (d, J=10 Hz, 1H), 4.77 (m, 2H), 3.92 (m, 1 H), 3.60 (dd, J=6, 10 Hz, 1 H), 3.52 (dd, J=6, 10 Hz, 1 H}, 2.54-1.83 (m, 6H), 1.71 (s, 3H), 1.40-1.10 (m, 7H), 1.07 (s, 9H), 0.83 (t, J=7 Hz, 3H), 0.77 (t, J=7 Hz, 3H).
MS: (M+H)+= 506.
DPS
AcH N, .~~~I
OH
131. ~1 R 2R 4R 1'S)-1-(t-But~diphenylsilyloxymethyl)-2-(1'-acetamido-3'-ethyl) pentXl-4.-hydroxymethyl-cyclopentane A solution of (1R,2R,1'S)-1-(t-butyldiphenylsilyloxymethyl)-2-(1'-acetamido-3'-ethyl)pentyl-4-methylene-cyclopentane (50 mg, 0.1 mmole) and 2M borane dimethylsulfide complex, in THF ( 75 uL, 0.15 mmole) in THF (1 mL) was stirred at 0 °C for 7 hours. Water (0.1 mL) and 1 N NaOH (0.2 mL) were added and the reaction allowed to warm to room temperature. After 15 minutes, 30% hydrogen peroxide (2 mL) was added and the reaction was stirred for an additional 0.5 hour. The reaction was diluted with ethyl acetate washed with water (2X) and with brine. The organic layer was dried over MgS04, filtered and concentrated in vacuo. The crude product was purified by chromatography using preparative HPLC in silica gel using 0-15% ethyl acetate in dichloromethane to provide the title compound (yield: 22 mg, 42%).
'H NMR (CDC13) 87.65 (m, 4H), 7.43 (m, 6H), (m, H), 5.00 (d, J=10 Hz, 1 H), 3.84 (m, 1 H), 3.66-3.54 (m, 2H), 3.52 (d, J=7 Hz, 2H), 2.20-1.04 (m, 14H), 1.66 (s, 3H), 1.08 (s, 9H), 0.83 (t, J=7 Hz, 3H), 0.78 (t, J=7 Hz, 3H).
MS: (M+H)+= 524.
AcHN, _ .,,~('O
H OH
13J. (1 Ri3R 4R 1'S), 3-(t-ButyldiphenylsilyloxYmethyl)-4-(1'-acetamido-3'-eth r~l pentyl-cyclopentane-1-carboxylic Acid A solution of (1R,2R,4R,1'S) 1-(t-butyldiphenylsilyloxymethyl)-2-(1'-acetamido-3'-ethyl) pentyl-4-hydroxymethyl-cyclopentane (22 mg, 0.042 mmole) and pyridinium dichromate (100mg, 0.26 mmole) in N,N-dimethylformamide (0.75 mL) was stirred at room temperature for 48 hours. The reaction was partitioned between ethyl acetate and 10% citric acid. The organic layer was separated and washed with brine, dried over MgSOa, filtered and concentrated to provide the title compound, which was used without further purification.
OH
AcH N, _ ..,,.1 0 H v OH
13K. (1 R 3R 4R 1'S) 3-Hydroxymethyl~-(1'-acetamido-3'-ethyl) oentyl-~clopentane-1-carboxylic Acid A solution of (1R,3R,4R,1'S) 3-(t-butyl-diphenylsilyloxymethyl)-4-(1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carboxylic acid from 1 L and 1 M
tetrabutylammonium fluoride in THF (0.8 mL) in THF (2 mL) was stirred for 16 hours at room temperature. The reaction was partitioned between ethyl acetate and 10% citric acid. The organic layer was separated and washed with brine, dried over MgS04, filtered and concentrated in vacuo. The crude product was chromatographed using a C-18 reverse phase column with 10-25% acetonitrile in water to provide the title compound (yield: 6.6 mg, 52 %).
' H NMR (CD30D) 87.81 (d, J=10 Hz, 1 H), 3.88 (m, 1 H), 3.61 (dd, J=5, 11 Hz, 1 H), 3.38 (dd, J=8, 11 Hz, 1 H), 2.75 (m, 1 H), 2.19-1.00 (m, 13H), 1.95 (s, 3H), 0.87 (t, J=7 Hz, 3H), 0.83 (t, J=7 Hz, 3H).
MS. (M+H)+= 300.
Example 14 H
AcH N, OH
(1R 3R 4R 1'S) 3-Formyl-4~1'-acetamido-3'-ethvl)pentyl-cyclopentane-1-carbolic Acid.
A solution of (1R,3R,4R,1'S)-3-hydroxymethyl-2-(1'-acetamido-3'-ethyl)-pentyl-cyclopentane-1-carboxylic acid (34 mg, 0.11 mmole) and pyridinium dichromate (40 mg, 0.1 mmoie) in dichloromethane (1.5 mL) was stirred at room temperature for 0.5 hours. The reaction was partitioned between ethyl acetate and 10% citric acid. The organic layer was separated and washed with brine, dried over MgS(~4, filtered and concentrated. The crude product was chromatographed on a C18 column with 10-50% acetonitrile in water to provide the title compound.
Example 15 ~1 R 3R 4R 1'S) 3 (Imidazol 2 ~)-4 (1-acetamido-3-ethyl)pentyl-cvclopentane-1-carboxylic Acid OTBDPS
..
AcHN, OTrityl 15A. (1 R 2R 4R 1'S) 1 (t Butyldiphenylsilyloxymethyl)-2-(1'-acetamido-3'-ethy~pentYl-4-triphenylmethyloxymethyl-cyclopentane A solution of (1 R,2R,4R,1'S) 1-(t-butyldiphenylsilyloxymethyl)-2-(1-acetamido-3-ethyl)pentyl-4-hydroxymethylcyclopentane (0.357 g, 0.682 mmol) in pyridine (0.165 mL, 2.05 mmol) and dichloromethane (2 mL) was reacted with trityl chloride (0.248 g, 0.89 mmol) and DMAP (16.3 mg, 0.13 mmol) at room temperature for 16 hours. The reaction was partitioned between ethyl acetate and 10% citric acid. The organic layer was separated and washed with brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 2% methanoildichloromethane to provide the title compound (yield: 0.5 g, 95%).
' H NMR (CDC13) s 7.62 (m, 4H), 7.4 (m, 12H), 7.23 (m, 9H), 3.57 (s, 2H), 2.96 (s, 2H), 2.26 (m, 1 H), 1.97 (m, 2H), 1.62 (m, 3H), 1.52 (s, 3H), 1.25-1.5 (m, 7H), 1.06 (s, 9H), 0.83 (br s, 6H).
MS: (M+Na)+ = 788 OH
AcH N, OTrityl 15B. ;~R 2RL4R 1'S)-1-Hydroxymethyl-2-y1'-acetamido-3'-ethvllpentyl-4-triphenylmethyloxy~meth~lc~clopentane The title compound was prepared according to the method described in Example 13K substituting (1R,2R,4R,1'S)-1-(t-butyldiphenylsilyloxymethyl)-2-(1'-acetamido-3'-ethyl)pentyl-4-(triphenylmethyloxy)methyl-cyclopentane for (1R,3R,4R,1'S) 3-(t-butyldiphenylsilyloxymethyl)-4-(1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carboxylic acid (yield: 0.33 g, 98%).
'H NMR (CDC13) b 7.42 (m, 6H), 7.26 (m, 9H), 5.59 (d, 1 H), 3.86 (m, 1 H), 3.6 (2d, 1 H), 3.42 (2d, 1 H), 3.95 (2d, 2H), 2.25 (m, 1 H), 1.95 (s, 3H), 1.7-2.02 (m, 2H), 1.5-1.7 (m, 4H), 1.1-1.5 (m, 9H), 0.83 (2t, 6H) MS: (M-H)- = 526, (M+35)- = 562; (M+Na)+ = 550 O
H ~/
AcH N, H .~~~~I
OTrityl 15C. (1 R 2R 4R 1'S)-1-Form-5-~1'-acetamido-3'-ethyl)pentyl-3-(triphenylmethyloxy)methyl-c rLclopentane The title compound was prepared according to the method described in Example 13L substituting (1 R,2R,4R,1'S)-1-hydroxymethyl-2-(1'-acetamido-3'-ethyl)pentyl-4-(triphenylmethyloxy)methyl-cyclopentane for (1 R,3R,4R,1'S)-3-hydroxymethyl-4-(1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carboxylic acid (yield: 0.3 g, 91 %).
H NMR (CDCI~) b 9.56 (d, 1 H), 7.42 (m, 6H), 7.27 (m, 9H), 5.13 (d, 1 H), 3.86 (m, 1 H), 2.94 (m, 2H), 2.72 (m, 1 H), 2.42 (m, 1 H), 2.16 (m, 2H), 1.90 (s, 3H), 1.1-1.7 (m, 10H), 0.83 (2t, 6H) MS: (M-H)- = 524 ~N
HN
AcHN, ~~~~~I
OTrityl 15D. (1 R 3R 4R 1'S)-3-(Imidazol-2-yl)-4-(1-acetarnido-3-ethyl)pentyl-1-(triphen I~e#h)rloxy)methyl-cyclopentane ( 1 R,3R,4R,1'S)-1-Formyl-2-(1'-acetamido-3'-ethyl)pentyl-4-(triphenylmethyloxy)methyl-cyclopentane (80 mg, 0.15 mmol) was reacted with ammonia and 40% glyoxal (0.264mL, 7.5 mmol) in methanol (7 mL) according the procedure of Rothenberg, A. and coworkers in Angew. Chem. Int. Ed. 1983, 22, p. 560 to provide the title compound (yield: 60 mg, 70%).
' H NMR (CDC13) 8 7.7 (d, 1 H), 7.42 (m, 7H), 7.27 (m, 9H), 5.72 (d, 1 H), 3.86 {m, 1 H), 3.2 (m, 2H), 3.08 (m, 2H), 2.54 (m, 1 H), 2.42 (m, 2H), 1.77 (s, 3H), 1.1-1.7 (m, 10H), 0.78 (2t, 6H).
MS: (M-H)- = 562, (M+35)- = 598; {M+H)+ = 564, (M+Na)+ = 586 ~N
HN~, AcHN, .~~~I
OH
15E. ~1 R 3R 4R 1'S}-3-~Imidazol-2-yl~-4-(1'-acetamido-3'-ethyt)pentyl-1-hydroxymeth~-c~clo~entane (1 R,3R,4R,1'S)-3-(Imidazol-2-yl)-4-(1'-acetamido-3-ethyl)pentyl-1-(triphenylmethyloxy)methyl-cyclopentane (60 mg, 0.106 mmol) was reacted with p-toiuenesulfonic acid monohydrate (61 mg, 0.32 mmol) in MeOH (1 mL) for 1 hour. The reaction was quenched with water (10 mL) and diluted with ethyl acetate (25 mL). The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 10% methanol/dichloromethane to provide the title compound (yield: 30 mg, 88%).
' H NMR (CDC13) 8 7.83 (d, 1 H), 7.2 (d, 1 H), 6.47 (d, 1 H), 3.86 (m, 1 H), 3.6 (m, 2H), 3.2 (m, 1 H), 2.61 (m, 1 H), 2.32 (m, 2H), 1.82 {m, 1 H), 1.72 (s, 3H), 1.62 (m, 2H), 1.1-1.4 (m, 7H), 0.78 (2t, 6H) MS: (M-H)- = 320, (M+35)- = 356; (M+H)+ = 322, (M+Na)+ = 344 N
~J..
AcHNH
_ ..,,~~0 H v OH
15F. {1 R 3R 4R 1'S)-3-(Imidazol-2-yl)-4-(1-acetamido-3-ethyl)pentyl-cyclopentane-1-carboxylic Acid The title compound was prepared according to the procedure described ing Example 13J substituting (1R,3R,4R,1'S)-3-(imidazol-2-yl)-4-(1-acetamido-3-ethyl)pentyl-1-hydroxymethylcyclopentane for (1 R,2R,4R,1'S) 1-(t-butyldiphenylsilyloxymethyl)-2-(1'-acetamido-3'-ethyl) pentyl-4-hydroxymethyl-cyclopentane (yield: 5.2 mg, 17%).
H NMR (dg-MeOH) 8 7.12 (br s, 2H), 3.92 (m, 1 H), 2.95 (m, 1 H), 2.42 {m, 1 H), 2.22 (m, 1 H), 1.96 (m, 1 H), 1.82 (m, 1 H), 1.72 (s, 3H), 1.15-1.45 (m, 7H), 0.82 (2t, 6H) MS: (M-H)- = 334, (M+35)- = 370; (M+H)+ = 33fi, (M+Na)+ = 358 Example 16 ~1R 3R 4R 1'SL~oxazol-5-yl)-4-(1'-acetamido-3'-ethyl)pentyl-cvclopentane-1-carboxylic acid N~O
U
AcH N, _ ..,,.1 0 H v OCHPh2 16A (1 R 3R 4R 1'S)-Diphenylmethyl 3-(oxazol-5-YI)-4-(1'-acetamido-3'-ethyl) pentylcyclopentane-1-carboxylate (1R,3R,4R,1'S)- Diphenylmethyl 3-formyl-4-(1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carboxylate is reacted with p-toluensulfonylmethylisocyanide following the procedure of van Leusen and coworkers in Tetrahedron Letters, 2369 (1977) to provide the title compound.
NCO
., AcHN, _ ..,,.1 0 H v OH
16B. (1 R.3R.4R 1'S)-3-(oxazol-5-yl)-4-(1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carbox~c acid (1 R,3R,4R,1'S)-diphenylmethyl 3-(oxazol-5-yt)-4-(1'-acetamido-3'-ethyl)pentyl-cyclopentane-1-carboxylate is reacted with anhydrous trifluoroacetic acid in dichloromethane concentration in vacuo provides the title compound.
Example 17 ~1R 3R 4R 1'S)-3-(N N-dimeth~carbamoyl~(1'-acetamido-3'-ethyl)pentyl-~clopentane-1-carboxylic Acid HO~~
AcH N, H v OCHPh2 17A (1 R 3R 4R 1'S)-Di~henylmethyl 3-carboxy-4~1'-acetamido-3'-ethyl)pentyl-c~rclo~~,entane-1-carboxylate The title compound is prepared according to the procedure described in Example 14J substituting (1R,3R,4R,1'S)-diphenylmethyl-3-hydroxymethyl-4-(1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carboxylate for (1 R,2R,4R,1'S) 1-(t-butyldiphenylsilyloxymethyl)-2-(1'-acetamido-3'-ethyl) pentyl-4-hydroxymethyl-cyclopentane H3C'~N~l/
AcHN, . ,~iO
H ,OCHPh2 17B (1 R 3Ri4R 1'S)-Diphenylmethyl 3-IN N-dimethylcarbamoyl)-4-(1'-acetamido-3'-ethyl)pentyl-cyclopentane-1-carboxylate (1R,3R,4R,1'S)- Diphenylmethyl 3-carboxy-4-(1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carboxylate is reacted with isobutyl chloroformate in the presence of N-methylmorpholine at 0°C. The intermediate activated ester is reacted with N,N-dimethylamine to provide the title compound.
H3C, AcHN, _ .,,.~0 H OH
17B (1 R~3R 4R 1'S)-3-(N N-dimethxlcarbamoyl)-4-(1'-acetamido-3'-ethyLpentyl-c rLclopentane-1-carboxylic Acid The title compound is prepared according to the procedure described in Example 16B substituting (1R,3R,4R,1'S)- diphenylmethyl-3-(N,N-dimethylcarbamoyl)-4-(1'-acetamido-3'-ethyl) pentyl-cyciopentane-1-carboxylate for (1R,3R,4R,1'S)-diphenylmethyl-3-(imidazol-2-yl)-4-(1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carboxylate.
Example 18 (1 R 3R 4R 1'SZ-3-propionvl-4-(1'-acetamido-3'-ethyl)pentyl-cyclopentane-1 carboxylic Acid ~OH
., AcH N, _ ..,,.ISO
H v OCHPh2 18A (1 R 3R 4R 1'S 1 "S~, and (1 R 3R 4R 1'S 1 "R)-Diphenylmethyl 3-(1-hydroxypropyl) 4-~1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carboxylate (1R,3R,4R,1'S)- Diphenylmethyl 3-formyl-4-(1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carboxylate is reacted with ethyl magnesium bromide in THF at 0°C. The reaction is quenched with aqueous ammonium chloride and partitioned between ethyl acetate and water. The organic layer is dried over MgS04, filtered, and concentrated in vacuo to provide the title compound.
~.!%
AcH N, O
_ H , OCHPhz 18B (1 R 3R 4R 1'S~ Diphen~methyl 3~ropionyl~1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carboxylate The title compound is prepared according to the procedure of Example 12B substituting (1R,3R,4R,1'S,1"S)- and (1R,3R,4R,1'S,1"R)-diphenylmethyl3-(1-hydroxypropyl)-4-(1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carboxylate for (t)-{2S,1'R) and (2S,1'S)-2-(3'ethyl-1'-hydroxy)pentyl-bicyclo[2.2.1]hept-5-ene.
WO 99/54290 PC'f/US99/07949 AcH N, OH
18C ,~1 R 3R 4R 1'S)-3-propionyl-4-,(1'-acetamido-3'-ethYl)pentyl-cyclopentane-1-carboxylic Acid The title compound is prepared according to the procedure described in Example 16B substituting (1R,3R,4R,1'S)-diphenylmethyl 3-propionyl-4-{1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carboxylate for (1 R,3R,4R,1'S)-diphenylmethyl 3-(imidazol-2-yl)-4-(1'-acetamido-3'-ethyl) pentyl-cyclopentane-carboxylate.
Example 19 (t)-(2R 3R 5R 1'S)-2-{1'-acetamido-3'-methyl)butyl-3-methoxycarbonyl-tetrahydrofuran-5-carboxylic acid ~~'To 19~t1-Bicyclo(2.2.1 ]hept-5-en-2-one In a three-necked flask equipped with a mechanical stirrer, a N2 inlet and an additional funnel, a solution of oxalyl chloride (2.0 M in dichloromethane, mL, 0.272 mole) in dichloromethane (250 mL) was cooled to -78 °C and a solution of DMSO (40 mL) in 40 mL of dichloromethane was added dropwise over 30 min. After stirring for 5 additional minutes, a solution of 5-norbornen-2-of (24 g, 0.218 mole) in 40 mL of dichloromethane was added dropwise. The solution was stirred for another 10 minutes and triethylamine (150 mL) was added over minutes. The mixture was then stirred for 10 minutes at -78 °C and allowed to warm up to 0 °C over 1 hour. Water (250 mL) was added. Following the separation of two layers, the organic layer was washed with 0.2 N HCI (4 x 200 mL) and brine (2 x 200 mL). After drying (MgS04), the solution was concentrated to about 80 mL. The residue was distilled with a 12" Vigreux column at reduced pressure to give the title compound b.p. 100-105 °C /15 mmHg, (yield:
20.1 g, 86%).
' H NMR (CDC13): 1.85 (dd, 1 H), 1.90-2.00 (m, 2H), 3.00 (brs, 1 H), 3.20 (b.s, 1 H), 6.01 (t, 1 H), 6.58 (t, 1 H).
HC~~O
H ~O
19~t)-exo exo-5 6-DihydroxYbicyclo~2 .2.1]heptan-2-one A solution of (t)-bicyclo[2.2.1]hept-5-en-2-one (10.8 g, 0.1 mole) and N-methyl morpholine oxide (12.7 g, 0.12 mole) in 300 mL of 90% THF-water was reacted with a solution of osrniurn tetroxide (2.5% wt in t-BuOH, 8.0 mL) for hours at ambient temperature. The solvents were evaporated and the resulting residue was dried in vacuo. The residue was then taken up in 100 mL of ethyl acetate, dried (MgS04) and filtered. The filtrate was passed through a short silica gel plug, eluting with ethyl acetate. Concentration gave the title compound as a thick oil (14.5 g) which was used directly for the next step.
p 19C (t)-exo exo-5 6-Dihydroxyacetonide-bicyclo[2.2.11heptan-2-one A solution of (t)-exo,exo-5,6-dihydroxybicyclo[2.2.1]heptan-2-one (14.5 g, crude) in 250 mL of 2,2-dimethoxypropane was cooled to 0 °C and p-toluensulfonic acid (125 mg) was added. The solution was stirred for 30 minutes when TLC indicated complete reaction. The solution was loaded on an aluminum oxide (neutral) column and eluted with 15-30% ethyl acetate in hexane, to give the title compound as a white solid (yield: 11.9 g, 65% for two steps).
MS (DCI-NH3): m/z 200 for (M+NH4), base peak.
1H NMR (CDC13): b 1.34 (s, 3H), 1.50 (s, 3H), 1.63-1.74 (m, 2H), 2.72-2.20 (m, 2H), 2.70-2.76 (m, 2H), 4.28 (d, 1 H), 4.34 (d, 1 H). '3C NMR (CDC13): 8 21.1, 25.3, 31.2, 39.4, 39.5, 55.3, 76.8, 81.2, 111.2, 214Ø Analysis: C~oH,403, calc.
65.92% C, 7.75% H;: found, 66.01 % C, 7.79% H.
19D ~t~-exo exo-6 7-dihydroxyacetonide-2-oxabicyclof3.2.11octan-3-one To a solution of (t)-exo,exo-5,6-dihydroxyacetonide-bicyclo[2.2.1]heptan-2-one (14.76 g, 0.081 mole) in 500 mL of dichloromethane was added NaHC03 (13.6 g, 0.16 mole). The mixture was cooled with a water bath and MCPBA (30.3 g, ~60%) was added portionwise over 30 minutes. The solution was then stirred for 2 hours at ambient temperature and washed with 10% aqueous NazS205 (500 mL), saturated NaHC03 solution (3 x 200 mL) and brine (3 x 200 mL). The organic solution was then dried (MgS04}, filtered and concentrated. The residue was loaded on an aluminum oxide (neutral) column for 30 minutes, then eluted with 10-25% ethyl acetate in hexane to give the title compound as a white solid (yield: 7.7 g, 50%) MS (DCI-NH3): mlz 216 for (M+NH4)+, base peak.
'H NMR (CDC13): 8 1.30 (s, 3H), 1.45 (s, 3H), 1.84 (d, 1H), 2.10-2.20 (m;
1 H), 2.48-2.56 (m, 2H), 2.80 (dd, 1 H), 4.56 (d, 1 H), 4.60 (s, 1 H), 4.70 (d, 1 H). '3C
NMR (CDC13): 23.79, 25.58, 29.17, 35.97, 36.51, 80.70, 82.49, 82.55, 83.24, 110.83, 167.95. Analysis: C~pH~4O4, cal. 60.59% C, 7.12% H; found, 60.52% C;
6.97% H.
O
O
O
19E t) exo exo-6 7-dihydroxyacetonide-4-exo-iodo-2-oxabicyclof3.2.11octan-3-one To a mixture of lithium bis(trimethylsilyl)amide (1.0 M in THF, 32.6 mL) and distilled THF (60 mL), cooled to -78 °C, was added a solution of (t)-exo,exo-6,7-dihydroxyacetonide-2-oxabicyclo[3.2.1]octan-3-one (5.87 g, 29.6 mrnol) in 60 mL
of THF over 30 minutes. After stirring for another 30 minutes, the solution was then cannulated into a flask containing a solution of iodine (8.3 g, 32.6 mmol) in 60 mL of THF cooled to -78 °C over 30 minutes. The resulting solution was stirred for another 10 minutes and quenched with 300 mL of 5% aqueous citric acid. The mixture was then extracted with ethyl acetate (3 x 100 mL). The combined ethyl acetate solution was washed with 10% aqueous Na2S203 solution (2 x 100 mL) and brine (2 x 200 mL), and dried (MgSOa). After filtration, the solution was evaporated and the residue chromatograhed on a silica gel column eluting with 15-25% ethyl acetate in hexane, to give a white crystalline solid (yield:
7.55 g, 79%).
MS (DCI-NH3): m/z= 342 for (M+NH4)'', base peak.
'H NMR (CDC13): a 1.30 (s, 3H), 1.45 (s, 3H), 1.55 (s, 1H), 2.12-2.20 (m, 1 H), 2.42 (d, 1 H), 2.80 (m, 1 H), 4.56 (d, 1 H), 4.54 (d, 1 H), 4.70 (m, 2H).
Analysis: C~pH~3IO4, cal. 37.06% C, 4.04% H, 39.15% I; found, 37.08% C, 3.98% H, 39.55% I.
O
0'~>~CO Me 19F ~-Methyl-exo exo-5 6-dihydroxyacetonide-2-oxabicyclof2.2.11heptane-3-exo-carboxylate.
To a solution of (t)-exo,exo-6,7-dihydroxyacetonide-4-exo-iodo-2-oxabicyclo[3.2.1]octan-3-one (7.55 g, 23.3 mmol) in 300 mL of methanol (pre-dried with 4 A sieves) was added K2C03 (3.54 g, 25.6 mmol). The mixture was stirred vigorously for 30 min. The undissolved potassium carbonate was removed by filtration and the filtrate was concentrated to dryness. The residue was triturated with ethyl acetate several times until complete extraction of the product (TLC). The ethyl acetate solution was then concentrated and directly chromatographed on a silica gel column eluting with 10-25% ethyl acetate in hexane, giving 4.86 g of the title compound as a white solid. Yield: 92.0%.
MS (DCI-NH3): m/z 246 for (M+NH4), base peak.
~ H NMR (CDC13): 8 1.30 (s, 3H), 1.45 (s, 3H), 1.62 (d, 1 H), 1.85 (d, 1 H), 2.82 (s, 1 H), 3.78 (s, 3H), 3.80 (s, 1 H), 4.20 (d, 1 H), 4.30 (d, 1 H), 4.40 (s, 1 H).
Analysis:C»H,605, calc.: 57.88% C, 7.07% H; found: 57.98% C, 7.10% H.
/' O~~'' O
O~~~CHO
19G (t)-exo-3-Form r~l-exo exo-5.6-dihydroxyacetonide-2-oxabicycloj2.2.1 Leptane To a well-stirred solution of (t)-methyl-exo,exo-5,6-dihydroxyacetonide-2-oxabicyclo[2.2.1]heptane-exo-3-carboxylate (0.82 g, 3.62 mmol) in 30 mL of anhydrous dichloromethane at -78 °C was added a solution of diisobutylaluminum hydride in toluene (1.0 M, 5.77 mL) dropwise. The mixture was then stirred at -°C for 1 hour and quenched with 2 mL of methanol and 15 mL of saturated aqueous sodium potassium tartrate solution. The mixture was then stirred vigorously and allowed to warm to ambient temperature over 1 hour. The phases were separated and the aqueous phase was extracted with Et20 (5 x 50 mL).
After drying, solvent removal gave the title compound as an oil (0.8 g) which was used directly for the next step.
o OH
19H ~,t)-(1'RS)-exo-3-(1'-hydrox~r-3'-methyl~butyl-exo.exo-5.6-dihYdroxyacetonide-2-oxabicyclo[2.2.1 ]heptane.
To a solution of (t)-exo-3-formyl-exo,exo-5,6-dihydroxyacetonide-2-oxabicyclo[2.2.1]heptane (0.99 g, 5.0 mmol) in 50 mL of anhydrous THF at -78 °C
was added a solution of isobutylmagnesium chloride (2.0 M in ether, 30 mL) dropwise over 30 minutes. The mixture was then allowed to warm up to ambient temperature over 2 hours and quenched with 100 mL of saturated aqueous NH4C1 solution. The solution was then extracted with EtzO (3x100 mL). The combined organic layers were washed with brine (3x100 mL) and dried. After filtration, evaporation of solvent gave title compound as an oil (1.28 g) which was used directly for the next step.
O
O
O
191 ~t)-exo-3-L'-oxo-3'-methYl)but~-exo exo-5 6-dihydroxyacetonide-2-oxabic~clof2.2.11he~tane A solution of oxalyl chloride (2.0 M in dichloromethane, 3.76 mL, 7.3 mmol) was mixed with 10 mL of anhydrous dichloromethane and the solution was cooled to -78 °C. A solution of DMSO (1.06 mL) in 10 mL of anhydrous dichloromethane was then added dropwise. After stirring for 10 minutes, a solution of (t)-(1'RS)-exo-3-(1'-hydroxy-3'-methyl)butyl-exo,exo-5,6-dihydroxyacetonide-2-oxabicyclo[2.2.1]heptane 01.28 g, 5.0 mmol) in anhydrous dichloromethane (10 mL) was added dropwise and the solution was stirred for another 10 minutes. Triethylamine (4.3 mL) in 10 mL of dichloromethane was then added. The mixture was then stirred at -78 °C for 2 hours and allowed to warm up to ambient temperature. The solution was washed with water (100 mL), 5% aqueous citric acid (100 mL), saturated NaHC03 (100 mL) and brine. After drying and concentration, the crude material was purified by flash chromatography on a silica gel column using 5%-20% ethyl acetate-hexane to give the title compound as a white solid, 0.65 g, 51% for three steps.
MS (DCI-NH3): mlz 272 for (M+NH4)+ base peak.
'H NMR (CDC13): b 0.84 (dd, 6H), 1.30 (s, 3H), 1.34, 1.38 (bd, 1H), 1.43 (s, 3H), 1.77, 1.82 (dd, 1 H), 2.10-2.10 (m, 1 H), 2.30-2.50 (dq, 2H), 2.86 (s, 1 H), 3.62 (s, 1 H), 4.16-4.20 (m, 1 H), 4.28-4.32 (bd, 1 H), 4.37 (s, 1 H).
Analysis: C~4H22O4, cal. 66.12% C, 8.72% H; found, 65.99% C, 8.58% H.
HO ~.", O
HO
O
19J (t)-exo-3-(1'-oxo-3'-methyl)butYl-exo exo-5 6-dihydroxy-2-oxabicyclof2.2.1 ]heptane.
(t)-exo-3-(1'-Oxo-3'-methyl)butyl-exo, exo-5,6-d ihydroxyacetonide-2-oxabicyclo[2.2.1]heptane (0.64 g, 0.25 mmol) was dissolved in 12.5 mL of methanol and 12.5 mL of 2M HCI. The solution was stirred at 60 °C for 2.5 hours.
After cooling to ambient temperature, the solution was partially concentrated and then extracted with ethyl acetate (4x50 mL). The combined ethyl acetate solution was washed with saturated aqueous NaHC03 solution (2x50 mL) and brine (2x50 mL), and dried. After filtration, removal of solvent gave the title compound as an off-white crystalline solid, (yield: 0.53 g, 98.0%).
MS (DCl-NHs): mlz 232 for (M+NH4)+, base peak.
' H NMR (CDC13): 8 0.92 (dd, 6H), 1.34, 1.44 (bd, 1 H), 1.77, 1.82 (dd, 1 H), 2.10-2.20 (m, 1 H), 2.30-2.45 (dq, 2H), 2.65 (d, 1 H), 2.74-2.80 (m, 2H), 3.72 (s, 1 H), 3.94-4.00 (m, 1 H), 4.00-4.05 (bd, 1 H), 4.24 (s, 1 H).
Me02C, O , p~~~''C02Me 19~t)-l2R 3R 5R)-Dimethvl 2-(1'-oxo-3'-methyl)butyltetrahydrofuran-3,5-dicarboxylate (t)-exo-3-( 1 '-Oxo-3'-methyl) b uty I-exo, exo-5 , 6-d i hyd roxy-2 oxabicyclo[2.2.1]heptane.(0.50 g, 2.3 mmol) was dissolved in a mixture of acetonitrile (6.5 mL), carbon tetrachloride (6.5 mL) and water (10 mL). To this solution was added sodium periodate (2.1 g, 10 mmol) and RuC13.H20 (10 mg).
The solution was stirred at ambient temperature for 3 hours and filtered to remove the solid. The filtrate was loaded on a short silica gel column, eluted with 5% methanol in ethyl acetate containing 5% acetic acid. The resulting crude diacid (yellow oil, 0.53 g) was dissolved in ethyl acetate (25 mL). N,N-diisopropylethylamine (1.73 mL, 12 mmol) and methyl iodide (2.98 mL, 46 mmol) were added and the mixture was stirred at 50 °C for 2 hours. The mixture was filtered to remove the solid and the filtrate was concentrated. The residue was purified by flash chromatography on a silica gel column eluting with 10-40%
ethyl acetate in hexane, giving the title compound as a colorless liquid (0.40g, 68.0%
for two steps).
MS (DCI-NH3): mlz 290 for (M+NH4)+, base peak.
' H NMR (CDC13): 8 0.92 (d, 3H, CH3), 0.93 (d, 3H, CH3), 2.19 (m, 1 H, H~), 2.40-2.60 (m, 4H, H6a, H6b, H3a, H3b), 3.30 (m, 1 H, H3), 3.75 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 4.65 (dd, 1 H, H5), 4.85 (d, 1 H, H2).
Me02C, HO'N O~w~COZMe 19L (t~-(2R 3R 5R -Dimethyl-2-(1'-N-hvdroxyimino-3'-methyl)butyl-tetrahydrofuran-3.5-dicarboxylate A solution of (t)-(2R,3R,5R)-dimethyl-2-(1'-oxo-3'-methyl)butyl-tetrahydrofuran-3,5-dicarboxylate(0.3 g, 1.09 mole), hydroxylamine hydrochloride (0.23 g, 3.3 mmol), diisopropylethylamine (0.57 mL, 3.3 mmol) and tetrabutylammonium iodide in 10 mL of methanol was stirred at 40 °C for 2 hours.
The solution was concentrated and purified directed on a 10-g silica gel cartridge, eluting with 30% ethyl acetate in hexane, giving the title compound as a mixture of cis and trans oximes.
MS (DCI-NH3): m/z 287 (M+H), 305 (M+NH4)+.
' H NMR (CDC13): 8 0.95-1.0 (m, 6H), 2.19 (m, 1 H), 2.40-2.60 (m, 4H,), 3.45 (m, 1 H), 3.65-3.80 (4 s, 6H), 4.50-4.60 (bs, 1 H), 4.70 (m, 1 H), 5.0 (bs, 1 H) MeO2C,, MeOZC, H N
Boc'N~,. ~ ~'''COZMe Boc' p)~'''C02Me 19M (t)-(2R 3R 5R 1'S) and (t)-{2R 3R 5R 1'R) Dimethyl 2-(1'-t butoxycarbonylamino-3'-methyl)but~-tetrah~drofuran-3 5-dicarboxylate.
A solution of (t)-(2R,3R,5R)-dimethyl-2-(1'-N-hydroxyimino-3'-methyl)butyl-tetrahydrofuran-3,5-dicarboxylate (0.27 g, 0.94 mmol) and Boc20 (2.11 mL, 10x) in 70 mL of isopropanol was hydrogenated with Raney Nickel at 4 atm of hydrogen for 15 hours. After concentration of the solution, separation on a silica gel column with 10% ethyl acetate in hexane gave (t)-(2R,3R, 5R,1'S) isomer (137 mg) and (t)-(2R,3R, 5R,1'R) isomer {176 mg).
(t)-(2R,3R, 5R,1'S) MS (DCI-NH3): mlz 374, 391, 317, 335.
'H NMR (CDC13): 0.9-0.95 (2d, 6H), 1.22-1.31 (m, 1H), 1.49 (s, 9H), 1.50-1.55 (m, 1 H), 1.62-1.75 (m, 1 H), 2.40-2.60 (m, 2H), 2.95-3.10 (m, 1 H), 3.70 (s, 3H), 3.75 (s, 3H), 4.20 (t, 1 H), 4.37 (bd, 1 H), 4.60 (dd, 1 H).
MHO2C,, ~N, ' ~.~~'C02Me O
19N (t)-(2R 3R 5R 1S)-Dimethyl 2-(1'-acetamido-3'-methyl)butvl-tetrahydrofuran-3.5-dicarboxylate.
A solution of (t)-(2R,3R, 5R,1'S) dimethyl 2-(1'-t-butoxycarbonylamino-3'-methyl)butyl-tetrahydrofuran-3,5-dicarboxylate (40 mg, 0.11 mmol).in 2 mL of 50% trifluoroacetic acidldichloromethane was stirred at ambient temperature for 1 hours. The solution was then evaporated to dryness. The residue was dissolved in 0.5 mL of dichloromethane. Acetic anhydride (104 mL, 10.0 eq.) and diisopropylethylamine {192 mL, 10.0 eq.) were added. After stirring for 2 hours, the mixture was directly loaded on a 5-g silica gel cartridge and eluted with 60%
ethyl acetate in hexane, giving the title compound as a solid (34 mg ,100%).
MS (DCI-NH3): mlz 316 (M+H) +, 333 (M+NH4)+
'H NMR (CDC13): b 0.9-0.95 (2d, 6H), 1.25-1.35 (m, 1H), 1.50-1.70 (m, 2H), 1.99 (s, 3H), 2.40-2.60 (m, 2H), 2.95-3.10 (m, 1 H), 3.70 (s, 3H), 3.75 (s, 3H), 4.20-4.40 (m, 2H), 4.60 (dd, 1 H), 5.30 (bd, 1 H).
MH02C,, ~N~ p~~~''C02H
O
190 (t)-(2R 3R~ 5R 1'S}-2-(1'-acetamido-3'-methy~butyl-3-methoxycarbonyl-tetrahydrofuran-5-carboxylic acid To a solution of (t)-(2R,3R,5R,1'S}-dimethyl 2-(1'-acetamido-3' methyl)butyl-tetrahydrofuran-3,5-dicarboxylate (32 mg, 0.1 mmol) in 1.0 mL of THF cooled to 0 °C was added a solution of LiOH (0.1 M, 1.0 mL) slowly dropwise. The solution was then stirred for 15 minutes and quenched with 1.0 mL of acetic acid. After extracting with ethyl acetate (3x1 mL), the organic solution was dried (MgS04) and purified on a 5-g silica gel cartridge, eluting with 0-20% methanol/ethyl acetate containing 5% acetic acid. The product obtained was further purified by recrystallization from ethyl acetate and isopropanol.
(yield:
22 mg, 71 %).
HRMS: C~4H24O6N, calculated: 302.1604, found: 302.1592.
'H NMR (CDC13): 8 0.9-0.95 (2d, 6H), 1.25-1.35 (m, 1H), 1.50-1.70 (m, 2H), 1.99 (s, 3H), 2.40-2.50 (m, 1 H), 2.60-2.70 (m, 1 H), 2.95-3.10 (m, 1 H), 3.70 (s, 3H), 4.10-4.40 (m, 2H), 4.60 (dd, 1 H), 5.30 (bd, 1 H). The relative stereochemistry was confirmed by the X-ray structure of a single crystal.
Example 20 MFi02C, /N, , ~~~~'C02t8u O
20A t~,-(2R 3R 5R 1'S~2 ~1'-Acetamido-3'-methyt)but~l-3-methoxycarbonyl-tetrahydrofuran-5-carboxylic Acid t-Bu I Ester.
To a solution of (t)-(2R,3R,5R,1'S)-2-(1'-acetamido-3'-methyl)butyl-3-methoxycarbonyltetrahydrofuran-5-carboxylic acid {25 mg, 0.08 mmol) in 1.0 mL
of dichloromethane was added a solution of tent-butyl 2,2,2-trichloroacetimidate (54 mg, 0.24 mmol) in 0.3 mL of cyclohexane. After cooling to 0 °C, 3 drops of boron trifluoride etherate was added. The mixture was stirred for another 40 minutes and quenched with 2 mL of 5% NaHC03 solution. After diluting with 10 mL of dichloromethane, the mixture was filtered to remove insoluble by-product WO 99!54290 PCT/US99/07949 and the organic phase was further washed with 5% NaHC03 solution, dried, arid concentrated. The residue was purified on a 5-g silica gel cartridge to give the title compound as an oil (26 mg) which was used directly for the next step.
Ho2c,, H
\ /N, , 0~ ~~'C02~Bu O
20B !t)-(2R 3R 5R 1'Sl-2-(1'-acetamido-3'-methyl)butyl-3-carboxyl-tetrahydrofuran 5-carboxylic acid t-Butyl Ester A solution of (t)-(2R,3R,5R,1'S)-2-(1'-acetamido-3'-methyl)butyl-3-methoxycarbonyl-tetrahydrofuran-5-carboxylic acid t-butyl ester (26 mg, 0.073 mmol) in 1.5 mL of THF was cooled to 0 °C and a solution of 0.1 N LiOH
(0.73 mL) was added. The mixture was allowed to warm up to ambient temperature over 90 minutes, then acidified to pH 2-3 with 1 N HCI and extracted with ethyl acetate. The combined ethyl acetate solution was dried and concentrated. The residue was purified on a 5-g silica gel cartridge to give the title compound (10 mg) as a solid.
MS (DCI-NH3): mlz 344 (M+H)+, 361 (M+NH4)+.
' H NMR (methanol-d4): 8 0.87, 0.89 (d, 3H), 0.92, 0.94 (d, 3H), 1.35-1.45 (m, 1 H), 1.47 (s, 9H), 1.50-1.70 (m, 2H), 1.92 (s, 3H), 2.30-2.37 (m, 1 H), 2.45-2.55 (m, 1 H), 2.90-2.97 (m, 1 H), 4.00-4.07 (m, 1 H), 4.20 (t, 1 H), 4.45 (dd, 1 H).
-Br O->., H
"N, O O
20C (t)-(2R 3R 5R 1'S~-2-~1'-acetamido-3'-methyl butyl-3-(1"-oxo-2"-bromo)ethyl-tetrahydrofuran-5-carbox~ic Acid t-Butyl Ester To a solution of (t)-methyl (2R,3R,5R,1'S)-2-(1'-acetamido-3'-methyl)butyl-3-carboxyl-tetrahydrofuran-5-carboxylic acid t-butyl ester (10 mg, 0.029 mmol) in 1.0 mL of THF, cooled to 0 °C, was added N-methyl morpholine (0.13 mL) and iso-butyl chloroformate (0.15 mL, 0.12 mmol). The mixture was stirred at 0 °C for 1 h. A solution of diazomethane generated from Diazald (0.21 g, 1.0 mmol) and KOH (0.8 g) in 2 mL of Et20 was then added via a syringe until the yellow color persisted. The solution was then stirred for 3 hours, washed with brine (2 x 2.0 mL) and dried (MgS04). Evaporation of solvent gave a yellow solid which was redissolved in 1.5 mL of dioxane. To this solution was added 48% HBr (aq.) solution (0.125 mL) and the mixture was stirred for 10 minutes. Saturated NaHC03 solution (0.5 mL) was then added slowly and the mixture was extracted with ethyl acetate (5 x 1.0 mL). The combined ethyl acetate solution was dried (MgS04), filtered and concentrated. Chromatography on a 5-g silica gel cartridge eluting with 60% ethyl acetate-hexane give the title compound (7.3 mg) as a solid which was used directly for the next step.
WO 99/54290 PC'T/US99/07949 H
/N
<N~..
H
~N~,. f O
20~t)-(2R 3S 5R 1'S)-2-(1'-acetamido-3'-methyl)bufirl-3-(imidazol-4-yl)-tetrahydrofuran-5-carboxylic Acid t-Butyl Ester To a vial containing (t)-(2R,3R,5R,1'S)-2-(1'-acetamido-3'-methyl)butyl-3-(1"-oxo-2"-bromo)ethyl-tetrahydrofuran-5-carboxylic acid t-butyl ester (7 mg, 0.014 mmol) and formamidine acetate (30 mg, excess) was added liquid ammonia (~2.0 mL). The vial was sealed and stirred at 45 °C overnight.
The ammonia was allowed to evaporate slowly. The residue was taken up in 5%
Na2C03 (aq. 1.0 mL) and extracted with ethyl acetate (4x1.0 mL). The combined ethyl acetate solution was dried and concentrated. The residue was chromatographed on a 2-g silica gel cartridge eluting with ethyl acetate to give the title compound as a solid (1.0 mg).
MS (APCI+): mlz 36fi (M+H)+, 310 (M-C4H9)+, base peak.
'H NMR (methanol-d4): 8 0.87, 0.89 (d, 3H), 0.95, 0.97 (d, 3H), 1.27-1.37 (m, 1 H), 1.47 (s, 9H), 1.42-1.67 (m, 2H), 1.84 (s, 3H), 2.10-2.17 (dt, 1 H), 2.77-2.87 (dt, 1 H), 3.50 (q, 1 H), 4.02-4.06 (m, 1 H), 4.16 (t, 1 H), 4.55 (t, 1 H), 7.34 (s, 1 H), 8.64 (s, 1 H).
H
/N~' \N
H
~N~,. Ol~.,,I~OH
IOI ,O
HCI
20~t)-(2R 3S 5R 1'S~l-~1'-Acetamido-3'-methyl}butyl-3-(imidazol-4-vl)-tetrahydrofuran 5-carboxylic Acid A solution of (t)-(2R,3S,5R,1'S)-2-(1'-acetamido-3'-methyl)butyl-3-(imidazol-4-yl}-tetrahydrofuran-5-carboxylic acid t-butyl ester (1.0 mg) in 1.0 mL
of 6N aqueous HCi was stirred for 1 h. The solution was then concentrated to give the title compound as a white solid (0.8 mg).
'H NMR (D20): a 0.81, 0.83 (d, 3H), 0.87, 0.89 (d, 3H), 1.30-1.58 (m, 4H), 1.84 (s, 3H), 2.10-2.22 (m, 1 H), 2.85-2.95 (m, 1 H), 3.58 (q, 1 H), 3.90-3.94 (m, 1 H}, 4.00-4.04 (m, 1 H), 4.20 (t, 1 H), 7.32 (s, 1 H), 8.64 (s, 1 H).
Example 21 ,~S 3R 4S 1'S)-3-(1'-Acetamido-3'-ethyllpentyl-4-vinyl-cyclopentane-1-carboxylic Acid AcH N, U
OTrity l 21A-(1 S,3R.4S,1'S)-3-(1'-acetamido-3'-ethyl-)pentyl-1-(triphen rLlmethylo~)methyl-4-vinyl-cyclopentane A solution of (1 R.2R,4R,1'S)-1-formyl-2-(1'-acetamido-3'-ethyl)pentyl-4-(triphenylmethyloxy)methyl-cyclopentane (60 mg, 0.11 mmol) prepared according to the method of Example 15C in THF (1 mL) was added to a mixture prepared from the reaction of methyltriphenylphosphonium iodide (69 mg, 0.17 mmol) and 2.5M n-BuLi/hexane (64 mg, 0.16 mmol) in THF (1 mL) for 2 hours at room temperature. After 1.5 hours, the reaction was partitioned between ethyl acetate and 10% citric acid. The organic layer was separated and washed with brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 3% methanolldichloromethane to provide the title compound (yield: 29 mg, 49%).
'H NMR {CDC13) a 7.52 (m, 6H), 7.24 (m, 9H), 5.64 (m, 1H), 4.84-5.04 {m, 3H), 3.98 (m, 1 H), 2.95 (m, 2H), 2.7 {m, 2H), 2.0 (m, 1 H}, 1.88 (m, 2H), 1.66 (m, 1 H), 1.56 (s, 3H), 1.1-1.5 (m, 9H), 0.83 (m, 6H).
MS: {M-H)- = 522, (M+35)- = 558; (M+Na)+ = 546.
= =.
AcHN, ~I~~~I
OH
21B. (1S 3R 4S 1'S~,3-vine-4-(1-acetamido-3-ethyl)pentyl-1-hydroxymethvl-~clo~entane The title compound was prepared according to the method described in Example 15E substituting (1S,3R,4S,1'S)-3-{1-acetamido-3-ethyl)pentyl-1-(triphenylmethyloxy)methyl-4-vinyl-cyclopentane for (1 R,3R,4R,1'S)-3-(irnidazol-2-yl)-4-(1'-acetamido-3'-ethyl)pentyl-1-(triphenylmethyloxy)methyl-cyclopentane (yield: 7 mg, 87%).
H NMR (CDC13) b 5.68 (m, 1 H), 4.84-5.05 (m, 3H), 3.98 (m, 1 H), 3.54 (2d, 2H), 2.4 (m, 1 H), 2.18 (m, 1 H), 1.92 (s, 3H), 1.1-1.5 (m, 1 OH), 0.83 {2t, 6H).
MS: (M+H)+ = 282, (M+18)+ = 299 -.
AcHN.
_ ..,..1 0 H v OH
21C. {1S 3R 4S 1'S)-3-(1-acetamido-3-ethyl-)pentyl-4-vinyl-cyclopentane-1-carboxylic Acid The title compound was prepared according to the procedure described in Example 13J substituting (1S,3R,4S,1'S) 3-(1-acetamido-3-ethyi)pentyl-1-hydroxymethyl-4-vinyl-cyclopentane for (1 R,2R,4R,1'S)-1-(t butyldiphenylsilyloxymethyl)-2-(1'-acetamido-3'-ethyl)pentyl-4-hydroxymethyl-cyclopentane (yield: 4.2 mg, 33%).
' H NMR (CDC13) a 5.65-5.78 (m, 1 H), 5.05 (d, 1 H), 5.02 (2d, 1 H), 4.92 (2d, 1 H), 3.99 (q, 1 H), 2.88 (m, 1 H), 2.43 (m, 1 H), 2.15 (m, 2H), 1.91 (s, 3H), 1.87 (m, 1 H), 1.71 (m, 1 H), 1.1-1.5 (m, 8H), 0.83 (2t, 6H) MS: (M-H)- = 294; (M+H)+ = 296, (M+Na)+ = 318 Example 22 (,tL(1 R 3R 4R 1'S)-3-N-methylcarbamoyl-4-(1'-acetamido-3'-ethyl)pentyl-cyclopentane-1-carboxylic Acid O
MeHN-~
AcHN.
H 'OH
The title compound was prepared according to the procedure described ing Example 12G substituting methylamine for methanol (yield: .029 g, 30%).
' H NMR (CD30D) 8 7.52 (d, 1 H), 3.78-3.90 (m, 1 H), 2.80-2.95 (m, 1 H), 2.71 (s, 3H), 2.46-2.50 (m, 2H), 2.09-2.24 (m, 2H), 1.87 (s, 3H), 1.59-1.72 (m, 1 H}, 1.10-1.49 (m, 7H), 0.82, 0.87 (2t, 6H).
MS: (M+H)+= 327, (M+NH4)+=344 Example 23 ~1 R 3R 4R 1'S) 3 (imidazol-4-yl)-4-~1'-acetamido-3'-methyl)butyl-cyclopentane-carboxylic Acid OTBDPS
AcH N, _ ..,,~('O
H v OH
23A. (1 R 3R 4R 1'S) 3-(t-Butyldiphenylsilyloxymethyl)-4-(1'-acetamido-3'-methyl)butyl-cycio~entane-1-carboxylic Acid.
The title compound was prepared by the methods described in Examples 13F-13J substituting isobutylmagnesium bromide for 3-pentylmagnesium bromide in Example 13F and substituting the resulting products in the subsequent steps.
' H NMR (d4-methanol) 8 7.68 (m, 4H), 7.42 (m, 6H), 3.88 (m, 1 H), 3.74 (2d, 1 H), 3.48 (2d, 1 H), 2.77 (m, 1 H), 2.15-2.27 (m, 2H), 1.68-2.05 (m, 3H), 1.80 (s, 3H), 1.5 (m, 1 H), 1.1-1.32 (m, 2H), 1.03 (s, 9H), 0.84 (2d, J=6.44 Hz, 6H).
MS: (M-H}- = 508; (M+H)+ = 510, (M+Na)+ = 532 OTBDPS
AcH N, ' O
_ H ,O a 23B. L1 R 3R 4R 1'S}-3-(t-Butyldi~henvlsilyloxyrnethYl)-4-(1'-acetamido-3'-methyl)butyl-cyclopentane-1-carboxylic Acid t-Butyl Ester.
(1 R,3R,4R,1'S)-3-(t-Butyldiphenylsilyloxymethyl)-4-(1'-acetamido-3'-methyl)butyl-cyclopentane-1-carboxylic acid (0.65 g, 1.27 mmol) was reacted with t-butyl trichloroacetimidate (1.36 mL, 7.56 mmol) in toluene at 100°C for 16 hours. The reaction was quenched with water (20 mL) and diluted with ethyl acetate {50 mL). The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 7% methanol/dichloromethane to provide the title compound (yield: 0.65 g, 90%).
' H NMR (d4-methanol) 8 7.65 (m, 4H), 7.4 (m, 6H), 3.88 (m, 1 H), 3.72 {2d, 1 H), 3.46 (2d, 1 H). 2.68 (m, 1 H), 2.12 (m, 1 H), 1.76-2.0 (m, 2H), 1.79 (s, 3H), 1.68 (m, 1 H), 1.48 (m, 1 H), 1.42 (s, 9H), 1.1-1.32 (m, 2H), 0.84 (2d, J=6.44 Hz, 6H).
MS: (M-H)- = 564, {M+35)- = 600; (M+H)+ = 566, (M+Na)+ = 588 OH
..
AcH N, H v O'Bu 23C. ~1 R 3R 4R 1'S)-3-H~droxymethyl-4-f~1'-acetamido-3'-methyl)butyl-cyclopentane-1-carbox rLlic Acid t-Butyl Ester The title compound was prepared according to the method described in Example 13K substituting (1R,3R,4R,1'S) 3-(t-butyldiphenylsilyloxymethyl)-4-(1'-acetamido-3'-methyl)butyl-cyclopentane-1-carboxylic acid t-butyl ester for (1 R,3R,4R,1'S)-3- (t-butyldiphenylsilyloxymethyl)-4-(1'-acetamido-3'-ethyl)pentyl-cyclopentane-1-carboxylic acid (yield: 0.35 g, 93%).
' H NMR (d4-methanol) 8 3.88 (m, 1 H), 3.58 (2d, 1 H), 3.35 {2d, 1 H), 2.7 (m, 1 H), 2.08 {m, 1 H), 1.95 (s, 3H), 1.94 (m, 1 H), 1.78 (m, 1 H), 1.5-1.7 (m, 3H), 1.43 (s, 9H), 1.2-1.4 (m. 2H), 0.9 (2d, J=6.44 Hz, 6H) WO 99/54290 PC'T/US99/07949 MS: (M-H)- = 326, (M+35)- = 362; (M+H)+ = 328, (M+Na)+= 350 O
H ~~
AcHN, O
'O a 23D. (1 R 3R 4R 1'S)-3-Form-4-(1'-acetamido-3'-meth~)butyl-cyclopentane-1-carboxylic Acid t-Butyl Ester The title compound was prepared according to the method described in Example 1 D substituting (1 R,3R,4R,1'S)-3-hydroxymethyl-4-(1'-acetamido-3'-methyl)butyl-cyclopentane-1-carboxylic acid t-butyl ester for (t)-{2R,3S)-2-(t-butyloxycarbonylamino)-3-hydroxymethylbicyclo(2.2.1]hept-5-ene (yield: 0.32 g, 92%).
' H NMR (d4-methanol) 8 9.5 (d, 1 H), 7.85 (d, 1 H), 3.88 (m, 1 H), 2.85 (m, 1 H), 2.62 (m, 1 H), 2.47 (m, 1 H), 2.05 (m, 2H), 1.91 (m, 1 H), 1.87 (s, 3H), 1.5-1.72 (m, 2H), 1.44 (s, 9H), 1.23-1.4 (m, 2H), 0.9 (2d, J=6.44 Hz, 6H).
MS: (M-H)- = 324; (M+H)+ = 326, (M+Na)+ = 348.
OH
O
AcHN, _ ..,,.1 0 H v OtBu 23E. (1 R 3R 4R 1'Sl-3-Carbox~-4-~'-acetamido-3'-methyl)butyl-cyclopentane-1-carboxylic Acid t-Butyl Ester A solution of (1R,3R,4R,1'S)-3-formyl-4-(1'-acetamido-3'-methyl)butyl-cyclopentane-1-carboxylic acid t-butyl ester (0.3 g, 0.93 mmol) and 2-methyl-2-butene (1.5 mL, 14.15 mmol) dissolved in t-BuOH (7.5 mL) and acetonitrile (7.5 mL) was reacted with a solution of NaCl02 (0.3 g, 3.31 mmol) and NaH2P04.H20 (0.3 g, 2.17 mmol) in water (6 mL) at 0 °C for 1 hour. The reaction was quenched with 10% aqueous NaZS203 and extracted with dichloromethane. The organic layer was washed with water and brine, dried (MgS04) and concentrated in vacuo. The residue was purified by chromatography on silica gel using 9%
methanol/dichloromethane to provide the title compound (yield: 0.286 g, 90.8%).
' H NMR (d4-methanol) b 3.86 (m, 1 H), 2.8 (m, 1 H), 2.7 (m, 1 H), 2.4 (m, 1 H), 2.22 (m, 1 H), 2.08 (m, 1 H), 1.97 (m, 1 H), 1.90 {s, 3H), 1.5-1.68 (m, 2H), 1.44 (s, 9H), 1.23-1.4 (m, 2H), 0.9 (2d, J=6.44 Hz, 6H).
MS: (M-H)- = 340, (M+35)- = 376; (M+H)+ = 342, (M+Na)+ = 364.
o--~:
AcH
N
, _ ..,,~~0 v H OtBu 23F. (1 R 3R 4R 1'S) 3-(2-Bromo-1-oxo ethyl~1-acetamido-3-methyl)butyl-cycloaentane-1-carboxylic Acid t-Bu I Ester (1 R,3R,4R,1'S)-3-Carboxyl-4-(1'-acetamido-3'-methyl)butyl-cyclopentane-1-carboxylic acid t-butyl ester (286 mg, 0.84 mmol) and N-methylmorpholine (111 pL, 1.01 mmol) in ether {15 mL) was reacted with isobutyl chloroformate {120 pL, 0.93 mmol) at 0°C for 45 minutes. To the reaction flask was cannulated a distilled diazomethane solution in ether prepared from the reaction of Diazald (2.4 g) in ether (60 mL) with a solution of potassium hydroxide (2.4 g) in ethanol (15 mL) and water (15 mL). The reaction was stirred for 8 hours at room temperature then diluted with ether. The organic layer was washed with brine, dried (Na2S04) and concentrated to give the intermediate diazo ketone. The diazoketone was reacted with 48% HBr {90 pL) in dioxane (10 mL) at 23°C for 45 minutes.
The reaction was quenched with water (50 mL) and diluted with ethyl acetate (200 mL). The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 20% ethyl acetatelhexane to provide the title compound (yield:
105 mg, 33%).
' H NMR (d4-methanol) 8 4.18 (2d, J=14.07 Hz, 2H), 3.8 (m, 1 H), 3.08 (m, 1 H}, 2.83 (m, 1 H), 2.48 (m, 1 H), 2.3 (m, 1 H), 2.07 (m, 1 H), 1.89 (s, 3H), 1.45 (m, 1 H), 1.5-1.7 (m, 2H), 1.15-1.4fi (m, 2H), 1.43 (s, 9H), 1.2-1.4 (m, 3H), 0.88 (2d, J=6.44 Hz, 6H).
MS: (M-H)- = 372; (M+H)+ = 374 HN~N
AcH N, _ .,..1 0 H v OtBu 23G. ~1R 3R 4R 1'S)-3~midazol-4-yl)-4-(1'-acetamido-3'-methyl)butyl-cyclopentane-1-carboxylic Acid t-Butyl Ester (1 R,3R,4R,1'S)-3-(2-Brorno-1-oxo)ethyl-4-( 1'-acetamido-3'-methyl)butyl-cyclopentane-1-carboxylic acid t-butyl ester (105 mg, 0.28 mmol) was reacted with formamidine acetate (0.52 g, 4.99 mmol) in liquid ammonia (5 mL) and heated at 45 °C in a sealed tube for 18 hours. The reaction was concentrated in vacuo. The residue was treated with aqueous NaHC03 and extracted with dichloromethane (5x20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 10% methanol in dichloromethane to provide the title compound as an oil {40 mg, 39%).
' H NMR(d4-methanol) s 7.57 (br s, 1 H), 6.81 (br s, 1 H), 3.93 (m, 1 H), 2.96 (m, 1 H), 2.7 (m, 1 H), 2.1-2.4 (m, 3H), 1.85 (m, 1 H), 1.72 (s, 3H), 1.48 (m, 1 H), 1.43 (s, 9H), 1.15-1.46 (m, 2H), 0.85 {2d, J=6.44 Hz, 6H).
MS: (M-H)- = 362, (M+35)- = 398; (M+H)+ = 364, (M+Na)+ = 386 HN~N
AcHN, _ ..,,~~0 H v IOH
HCI
23G. {1 R 3R 4R 1'S)-3-{imidazol-4-vl)-4-(1'-acetamido-3'-meth I)~ butyl-cyclo~entane-1-carboxylic Acid Hydrochloride (1R,3R,4R,1'S) 3-(imidazol-4-yl)-4-(1'-acetamido-3'-methyl)butyl-cyclopentane-1-carboxylic acid t-butyl ester (40 mg, 0.11 mmol) was reacted with 6N HCI (4 mL) for 1 hour. The reaction concentrated in vacuo to provide the title compound (yield: 37mg, 98%).
' H NMR (d4-methanol) b 8.83 (d, J=1.01 Hz, 1 H), 7.36 (d, J=1.01 Hz, 1 H}, 3.92 (m, 1 H), 3.18 (m, 1 H), 2.98 (m, 1 H), 2.49 (m, 2H), 2.22 (m, 1 H), 1.90 (m, 2H), 1.77 (s, 3H), 1.53 (m, 1 H), 1.41 (m, 1 H), 1.25 (m, 1 H), 0.86 (2d, J=6.45 Hz, 6H).
MS: (M-H}- = 306, (M+35)- = 342; (M+H)+ = 308, (M+Na)+ = 330 Example 24 (3R 4R 1'S)-4-(imidazol-2-yl)-3-(1'-acetamido-3'-ethyl)pentyl-cyclopent-1-ene-carboxylic Acid OTBDPS
O
= v H
24A f3R 4R 1'S)-3-(t-ButYldiphen rLlsilyioxymethyl)-4-(1'-azido-3'-ethyl)pentyl-~clopentan-1-one (3R,4R,1'S)-3-(t-Butyldiphenylsilyloxymethyl)-4-(1'-azido-3'-ethyl)pentyl-1-methylene-cyclopentane (0.4558, 0.93 mmol) was reacted with 4% osmium tetroxide in water (0.59 mL, 0.093 mmol) and sodium periodate (0.8 g, 3.73 mmol) in THF (15 mL) and water (3 mL) at room temperature for 3 hours. The mixture was filtered and the filtrate was diluted with ethyl acetate, washed with 10% Na2Sz03 solution, water, dried over MgS04, filtered, and concentrated in vacuo. Chromatography on silica gel using 10% ethyl acetate/hexane afforded the title compound (yield: 240 mg, 52%).
'H NMR (CDC13) 8 7.64 (m, 4H), 7.4 (m, 6H), 3.68 (m, 2H), 3.36 (m, 1H), 2.3-2.6 (m, 4H), 2.23 (2d, 1 H), 2.08 (m, 1 H), 1.16-1.52 (m, 6H), 1.05 (s, 9H), 0.78-0.88 (2t, J=7.12 Hz, 6H) MS: (M+18)+ = 509, (M+Na)+= 514 OTBDPS OTBDPS
Na,,, / Ns,,, H ~OTf H ~OTf 24B. ~3R 4R 1'S~-4-(t-Butyldiphe~IsilYloxymethy~-~1'-azido-3'-ethyl)pentyl-1-trifluoromethansulfonyloxy-cyclopent-1-ene and (3R,4R.1'S)-3-(t-Butyldiphenylsilyloxymethyl)-4-(,1'-azido-3'-ethyl)~entyl-1-trifluoromethansulfonyloxy-cyclopent-2-ene (3R,4R,1'S)-3-(t-Butyldiphenylsilyloxymethyl)-4-(1-azido-3-ethyl)pentyl-cyclopentan-1-one (230 mg, 0.468 mmol) was reacted with 1M lithium hexamethyldisilazide (1.17 mL) in THF (1 mL) at -78°C for 45 minutes.
The reaction mixture was treated with N-phenyltrifluoromethanesuifonimide (0.2 g, 0.56 mmol) and reacted at 0°C for 0.5 hour. The reaction was quenched with water (10 mL) and diluted with ethyl acetate (50 mL). The organic layer was washed with water, brine, dried over MgS04, filtered and concentrated in vacuo.
The residue was purified by chromatography on silica gel using 5% ethyl acetate/hexane to provide a mixture of the title compounds in a ratio of 3: 2 (yield:
280 mg, 96%).
'H NMR (CDC13) b 7.64 (m, 4H), 7.4 (m, 6H), 5.58-5.5 (m, 1H), 3.55-3.72 (m, 2H), 3.36 (m, 1 H), 2.7-2.83 (m, 2H), 2.3-2.47 (m, 2H), 1.16-1.5 (m, 6H), 1.05 (s, 9H), 0.78-0.9 (m, 6H) OTBDPS
hi O
24C. j3R 4R 1'S)-4-~-Butyldiphenylsilylox~methyl -~1'-azido-3'-ethyl)pentyl-cyclopent-1-ene-1-carboxylic Acid Methyl Ester and (3R.4R.1'S)-3-(t-Butyldiphenylsilyloxymethyl)-4- 1'-azido-3'-ethyl)pentyl-1-cyclopent-1-ene1-carboxylic Acid Methyl Ester Carbon monoxide was bubbled into a mixture consisting of (3R,4R,1'S)-4-(t-Butyldiphenylsilyloxymethyl)-3-(1'-azido-3'-ethyl)pentyl-1-trifluoromethansulfonyloxy-cyclopent-1-ene and (3R,4R,1'S)-3-(t-Butyldiphenylsiiyioxymethyl)-4-(1'-azido-3'-ethyl)pentyl-1-trifluoromethansulfonyloxy-cyclopent-1-ene (280 mg, 0.45 mmol), triethylamine (0.125 mL, 0.9 mmol), bis(acetato)bis(triphenylphosphine)palladium(II) (34 mg, 0.045 mmol) in DMF (4 mL) and methanol (2 mL) at 40°C for 2 hours. The reaction was quenched with water (10 mL) and diluted with ethyl acetate (50 mL).
The organic layer was washed with water, brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 5% ethyl acetate/hexane to provide the title compounds in a ratio of 3:
2 as a mixture (yield: 181 mg, 75%).
'H NMR (CDC13) 8 7.64 (m, 4H), 7.4 (m, 6H), 6.58-6.7 (2 br s, 1 H), 3.74 (br s, 3H), 3.25-3.62 {m, 3H), 2.7-2.95 (m, 2H), 2.22-2.49 (m, 2H), 1.16-1.5 (m, 6H), 1.05 (s, 9H), 0.78-0.9 (m, 6H) MS: (M+18)+ = 551, (M+Na)+ = 556 OTBDPS OTBDPS
.. ..
AcHN, ' / OCH3 AcHN, 1. ~ OCH
H O H O
24D. (3R 4R 1'S)-4-(t-Butyldiphen~yloxymeth~~1'-acetamido-3'-eth~l)pentyl-cyclopent-1-ene-1-carboxylic Acid Methy! Ester and (3R.4R,1'S)-3-(t-Butyldiphenylsilyloxymethyl)-4-(1'-acetamido-3'-ethyl~pentyl-cyclopent-1-ene-1-carboxylic Acid Methyl Ester A solution of the mixture of (3R,4R,1'S)-4-(t-butyldiphenylsilyloxymethyl)-3-(1'-azido-3'-ethyl)pentyl-1-trifluoromethansulfonyloxy-cyclopent-1-ene-1-carboxylic acid methyl ester and (3R,4R,1'S)-3-(t-butyldiphenylsilyloxymethyl)-(1'-azido-3'-ethyl)pentyl-1-trifluoromethansulfonyloxy-cyclopent-1-ene-1-carboxylic acid methyl ester (0.18 g, 0.33 mmol) in THF (12 mL) and water (3 mL) was reacted with triphenylphosphine {0.265 mg, 1.01 mmol) at 65°C for 4 hours.
The reaction mixture was concentrated in vacuo, redissolved in chloroform, dried over MgS04, filtered and concentrated in vacuo. The crude amine was reacted with acetic anhydride (64 ~L, 0.67 mmol) in pyridine (0.135 mL, 1.67 mmol) and dichloromethane (1 mL) at room temperature for 2 hours. The reaction was quenched with 10% citric acid solution (10 mL) and diluted with ethyl acetate (50 mL). The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 40% ethyl acetate/hexane to provide the title compounds (3R,4R,1'S)-4-(t-butyldiphenylsilyloxymethyl)-3-(1'-acetamido-3'-ethyl)pentyl-cyclopent-1-ene-1-carboxylic acid methyl ester (yield: 109 mg, 60%) and (3R,4R,1'S)-3-(t-butyldiphenylsilyloxymethyl)-4-(1'-acetamido-3'-ethyl)pentyl-cyclopent-1-ene-1-carboxylic acid methyl ester (yield: 37mg, 20%).
(3R,4R,1'S)-4-(t-butyldiphenylsilyloxymethyl) 'H NMR (CDC13) 8 7.63 (m, 4H), 7.4 (m, 6H), 6.58 (s, 1 H), 4.95 (br s, 1 H), 4.0 (br s, 1 H), 3.73 (s, 3H), 3.57 (d, 2H), 2.72 (m, 2H), 1.78 (s, 3H}, 1.47 (m, 3H), 1.18 (m, 3H), 1.06 (s, 9H), 0.74-0.88 (2t, J=7.12 Hz, 6H) MS: (M-H)- = 548, (M+35)- = 584; (M+H)+ = 550, (M+Na)+ = 572 (3R,4R,1'S)-3-(t-butyldiphenylsilyloxymethyl) 'H NMR (CDC13) 8 7.63 (m, 4H), 7.4 (m, 6H), 6.64 (d, 1 H), 4.72 (d, 1 H), 3.95 (m, 1 H), 3.74 (s, 3H), 3.73 (2d, 1 H), 3.57 (2d, 1 H), 2.9 (m, 1 H), 2.75 (m, 1 H), 2.3 (m, 1 H), 2.14 (m, 1 H), 1.71 (s, 3H), 1.45 (m, 3H), 1.18 (m, 3H), 1.05 {s, 9H), 0.72-0.86 (2t, J=7.12 Hz, 6H) MS: (M-H)- = 548, (M+35)- = 584; (M+H)+ = 550, (M+Na)+ = 574 OH
..
AcHN, H O
24E. ~3R 4R 1'S~-4-hydroxymethyl-3-f1'-acetamido-3'-ethyl)pentyl-cycloaent-1-enel-carbox~ic acid methyl ester The title compound was prepared according to the method described in Example 13K substituting (3R,4R,1'S)-4-(t-butyldiphenylsilyloxymethyl)-3-(1-acetamido-3-ethyl)pentyl-1-trifluoromethansulfonyloxy-cyclopent-1-ene-1-carboxylic acid methyl ester for (1R,3R,4R,1'S)-3-(t-butyldiphenylsilyloxymethyl)-4-(3-ethyl-1-acetamido)pentyl-cyclopentane-1-carboxylic acid (yield: 53 mg, 85%).
' H NMR (CDC13) 8 6.63 (m, 1 H), 5.49 (d, 1 H), 3.98 {m, 1 H), 3.74 (s, 3H), 3.5-3.7 (m, 2H), 2.87 (m, 1 H), 2.75 (m, 1 H), 2.2-2.4 (m, 2H), 1.99 (s, 3H), 1.17-1.48 (m, 8H), 0.78-0.87 {2t, J=7.12 Hz, 6H) MS: (M-H)- = 310, (M+35)- = 346; (M+H)+ = 312, (M+Na)+ = 334 24F. {3R 4R 1'SZ-4-formvl-3-~-acetamido-3-ethyl)pentyl-cycioaent-1-ene-1-carboxylic acid methyl ester The title compound was prepared according to the method described in Example 1D substituting (3R,4R,1'S)-4-hydroxymethyl-3-(1'-acetamido-3'-ethyl)pentyl-cyclopent-1-ene-1-carboxylic acid methyl ester for (t)-(2R,3S)-2-(t-butyloxycarbonylamino)-3-hydroxymethyl-bicyclo[2.2.1 ]hept-5-ene (yield: 38 mg, 72%).
' H NMR (CDC13) a 9.71 (s, 1 H), 6.62 {m, 1 H), 5.2 (d, 1 H), 4.06 (m, 1 H), 3.75 (s, 3H), 3.25 (m, 1 H), 3.1 (m, 1 H), 2.96 (m, 1 H), 2.83 (m, 1 H), 1.96 (s, 3H), 1.2-1.5 (m, 8H), 0.77-0.9 (2t, J=7.12 Hz, 6H) MS: (M-H)- = 308; (M+H)+ = 310 / N
~J.;
AcHNH / O
U
24G. ~3R 4R 1'S)-4~imidazol-2-yl)-3-(1'-acetamido-3'-eth rLl)pentyl-cyclopent-ene1-carboxylic acid methyl ester The title compound was prepared according to the method described in Example 15D substituting (3R,4R,1'S)-4-formyl-3-(1'-acetamido-3'-ethyl)pentyl-cyclopent-1-ene1-carboxylic acid methyl ester for (1 R,3R,4R,1'S)-1-formyl-2-(1'-acetamido-3'-ethyl)pentyl-4-(triphenylmethyloxy)methyl-cyclopentane (yield: fi mg, 14%).
' H NMR (CDC13) 8 7.06 (s, 2H), 6.69 (s, 1 H), 3.95 (m, 1 H), 3.74 (s, 3H), 3.5-3.7 (m, 2H), 3.23 (m, 1 H), 2.8 (m, 1 H), 1.90 (s, 3H), 1.1-1.5 (m, 8H), 0.73-0.87 (2t, J=7.12 Hz, 6H) MS: (M-H)- = 346, (M+35)- = 382; (M+H)+ = 348, (M+Na)+ = 370 ~J.;
AcHNH / O
a H OH
24H. ~3R 4R 1'S~-4-(Irnidazol-2-yl)-3-~1'-acetamido-3'-ethyl)pentyl-cyclopent-ene-1-carboxylic Acid (3R,4R,1'S)-4-(Imidazol-2-yl)-3-(1'-acetamido-3'-ethyl)pentyl-cyclopent-1-ene-1-carboxylic acid methyl ester (6 mg, 0.017 mmol) was reacted with lithium hydroxide (1 mg, 0.026 mmol) in THF (0.5 mL) and water (0.2 mL) at 0°C
for 4 hours. The reaction was quenched with 10% citric acid (1 mL) and diluted with 25% isopropanol/dichloromethane (10 mL). The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 1:3:1:1 waterlethyl acetate/n-butanol/acetic acid followed by extraction into 25%
isopropanol/dichloromethane to provide the title compound (yield: 4.3 mg, 74%).
' H NMR (d4-methanol) 8 7.06 (br s, 2H), 6.48 (br s, 1 H), 4.08 (m, 1 H), 3.45-3.7 (m, 2H), 3.1 (m, 1 H), 2.62 (m, 1 H), 1.98 (br s, 2H), 1.82 (br s, 3H), 1.1-1.42 (m, 8H), 0.73-0.87 (m, 6H) MS: (M-H)- = 332, (M+35)- = 368; (M+H)+ = 334, (M+Na)+ = 356 Using the methods described above and the general knowledge of one skilled in the art, compounds of the invention can be prepared which are represented by taking one core from Table 1 (wherein Ac is acetyl), one Y
substituent from Table 2, one R substituent from Table 3, one R3 substituent from Table 4a, 4b, 4c, 4d, 4e, 4f or 4g and one R5 substituent from Table 5.
Table 1 Y, Y, AcHN, ~ OR AcHN ~ OR
Y, Y, CH3S02+iN, 3 H 0,.. ~OR CH3S02i-IN 3 H 0~.. ~OR
R IOI R I'O
O Y, O Y, II 1i CF3C-HN, 3 H O~. ~OR CF3C-HN 3 H O~ ~OR
R IOI R I IO
Y, Y, AcHN, OR AcHN OR
Y, Y, CH3SO2+iN, ). ~OR CH3S02+iN ~OR
g 10 O Y, O Y, II II
CF C-HN, OR CF C-HN OR
R3 H ~ 3 R3 H
Y~ Y
AcHN OR AcHN OR
Y, Y, CH3S02i~-IN / ~OR CH3S02+iN , ~OR
O Y, O Y, II II
CF3C-HN, f~ OR CF3C-HN / OR
Y
AcHN ,OR AcHN OR
R
Y, Y, CH3S02tiN, ~ ~OR CH3S02i-IN ~OR
fI I1 2p 21 p Y, p Y, CF3C-HN, OR CF3C-HN OR
R
Table 2 ~ HN/=( ",.,.,.. CI~ N ' / O
O~ H3 H3C ,~"~ ""."
/v F
H~ S~=--C F
g 10 11~ 12 HN~ N~~' N=(O CI~
H3 ~ H3 ~ ~ F3 F ~ CI ,~~,. F3C H '~"",' HN~ N NCO N~O
N=~, ~, N=-C"".",., F3 ~ F~ F3 ~ NHS
F ,~,.,., F3C .,.""- CI .,.~,., N~, -.l H F
Et ~~~~ Et Et F3 ~ I F~CI Et, H3C
,N
C
H
F .",.~",F3C .",."", H ~"",.. .""..
H\ CH3 F\ HN~ CI, H~,"".,..C I /~~~~ H~~..--~~~~~~
HO O
~ \ N-N
=
~
N N
-HN~~ ~ N~N> ~N~
' N -N N-N
~' N HN~~ HN~ ~ HN =N
N N
~ ' N ; ~ o ' H c .
N ~~~~~
N-N
S~ S --( N --t S ~ N ~ S
O N\ S Nw N-'( S , , F~ Hi \
"""N, F ,~",.",. ,~""",. F ,,.,.,."..
H
, 66 67 68 F~F F~F ~ H3 H3C, CH3 H~~.-(~~ F~~-.(~~~~ H ~--(~
C
H3 ~ H ~ I CI"CI CI, CI
H ~~~~ H~~.--~(~~~~~CI~~-~(~~~~~
C ~
CI, ~ I ~ F3 Fa ~ Fs C I ~~-.-~,~~~~~C I .""~~~ ,"~",.' .,.""~'' F3 ~ CI~ CI, CH3 C .~,...". F3C .~.~. H3C/ ,M,r . CI~~-."(~",."..
F
I ~ H3 F3 ~ F3 H3 ~ i C .,.""". CI ,M,r,.. C ..,~,.",. H3C
H F
3 8s 3 88 s5 s7 CI, CH3 H3 ~ I H3 ~ H3 C~ H3 w. C~--,M,w.
CI H
",. 90 ,M, 3 F~ H3C~ F ' Ci CI, CI ~ H3 F~CH3 C~~-".",.,. F H3C .""~,.., H3C~~--...(,~...~.
H
H3 ~ F~CH3 H3 ~ F~F
C~~--(~
H
.""",., F ...."",. "....
101 102 103 ...
H3 ~ F3 ~ Hs ~ Fs H3 ~ Hs ."""". C .~,~", C ."~,.",. C .,~,.",.
F H H F
C
H3 ~ F3 F3 ~ Hs ~ F3 F3 ~ H3 F
C
""". H3C ..~....,..",.,....
H3 H3 ~ F3 F3 ~ F3 CI~
.,... ~"",.. H F
,r F C
F C
C
. . 3 116 " 3 115 F~CI F~CI CI, F ~ I
F~~-."(.~."~.~-."(~"",.,. F ,"""....
Cl, F CI, CI F\ .F
CI ~ CI~~-(~ F~~ CI/u\~~~
CI, .F CI, CI Ci~ CI, ,CF3 F~~-,~(~~~~~ F3C~~--~(~~~~, F3C/ \w~~~~~r F3 ~ I F3 ~ I Fs ~ I F3 ~ Fs F3C ~ CI ~~~~~- .~..,~. CI ."
F3 ~ I CI"CF3 CI, CF3 CI F3C CI ~~--~~ F3C~)--..,.(~",.~.
F~CF3 F~~ F3 F~CF3 F~F
F ~-.~~ F3C~~-(~~~ F3 ~~-(~C
F3 ~ F3 ~ ~ F3 F3 F ~ ~ F F3C ..."....
F ~ F3 ~ Fs H3 ~ H3 ~ I
3C ,~~~~ F ~~~~~ CI ~~~~ F
CI, .F F\ ,CI F~CH3 CI, CH3 H~ ~ F3 H3C CI CI CF3 F3C CI
CI .~ F3 ~"",~",. H3C ~
F3 ~ H3 CI/ \ H3 H3 ~ F3 H3 CI ~,~~~~ FsC '~'~~' F """"". FsC .",."",.
F~CF3 F~CF3 F3 ~ F3 ~ Hs H3C~--"~~,.~~ H3C~~-.-,M,w. H3C .~,.,.~~ F "".",.'' F\ ,CHs CI, CF3 CI, F F' ,CFs F3C/~.~(\~~,.~ F~~..(~~ ",~ F3C~~~_~(~~~~~ C
Table 3 -H 1 CHs ~ ~CH3 3 ~~CH3 /~CH3 ~~CH3 1~/ 4 6 CHs 5 --~-CHs ~~ Hs CHs ~ CHs 8 H C / CH CHs ,f,.,~CH3 ~-~-CHs J 10 CHs Il CHs 12 ,CHs ~~ CHs ~~ CHs ~ N N
, '-CHs 13 CHs 14 ~CH3 15 Table 4a .""". '"""' CH3 ."~".
~OH OH OH
w ~ H3C w CHs ~~
HsC OH OH I OH OH
HsC CH
CHs H C~ CHs 3 CHs ~ ",.."
~OH OH HOH OH
H3C CHs C 3 " HsC CH3~ ~ \
OH ~OH H3C CH~H H C OH
3 CHs CHs C
\~ H3C~ ~ H3C \ OCH3 I OCHs OCHs OCHs CHs CHs ~~~.
H C \ ~ HsC \ CH OCH
s OCH OCH 1 0 3 3 s HsC CH
CHs HsCJ CHs 3 ~OCH3 OCH3 CHOCH3 OCH3 H C CH3~' ~ \ .,.,.",.
H3C~OCH3 ~OCH OCH3 OCH3 OH ~ OH ~ ".",.' HsC HsC
~OCH3 ~OCH3 ~OH
~OH H3C CH HsC CH3 H3C CH3 H3C CH3 s H3C., H3C ~~ ~~
H3C OH OH H3C _ -OH
OH
'OH - _OH
OH 'OH
.,."". ~~~, H3C
H3~,~ ~
\ _ \
v 'OCH ~ - -OCH3 OCH3 H3C CH ~CH3 Table 4b ~OH ~OCH3 ~O~CH3 ~O~
~'OH ~'OCH3 ~'O~CH3 ~'O~
HO~OH HO~OCH3 HO~o~CH3 HO~O
HO' Y 'OH HO' 1"OCH3 HO~o'~CH3 HO~O
HO"Y 'OH HO~'OCH3 HO~'O~CH3 HO~'O
HO~'OH HO~'OCH3 HO~ O CH3 HO~'O
~O ~'O HO~O HO~O
OH ~ OH ~ OH ~ OH
HO' Y ~O HO~ ~O ~OCH3 ~ ~OCH3 OH ~ OH ~ OCH3 OCH3 2g 30 31 32 CH30 OCH3 CH30"Y 'OCH3 CH30~ ~OCH3 CH30~ ~OCH3 H3C~OH H3C~OCH3 H3C~O~CH3 H3C O
CH3""".,.
H3C OH HsC- x _OCH3 H3C~0~CH3 H3C
~O
H3C OH H3C OH HsC OH CH3 H3C~OH H3C~OCH3 H3C~O~CH3 HsC OH H3C~OCH3 H3C~O~CH3 H3C~0 OH
~ ~ ~~ HsC Y
H3CY 'OH H3CY _OCH3 H C O~CH3 s ~
~ ~ ~~ i ~ HaC
~C~OH HsC Y _OCH3 H3C~0 CH3 O
OH OH ~H OH CH3 H3C~'OH H3C~ ~OCH3 H3C~ ~O~CHs H3C~ 'O~
HsC OH HsC OH OH OH CHs ~~~~ CHI""""
HsC ~OH H3C~ ~OCH3 H3C~ ~O~CHs H3C .O
OH
H C OH HsC OH H3C OH CHs H3C~OH H3C~OH H3C~OCH3 H3C~OCH3 [OH ~CH3 [OH ,~CH3 jOH ~CH3 'OH ''CH3 H3C~OH H3C~OH H3C---~-OCH3 H3C~OCH3 OH CHs OH ~CH3 OH CHs OH 'CHs H3C~OH H3C~OH H3C~OCH3 H3C~OCH3 HsC~'(OH CHs HsC~OH ,'-CHs H3C OH CHs HsC~'(OH ~'-CHs ~~~~' CH~~~~ CHs H3C
H C~OH ~ OH ~OCH3 H3C~OCHs IOH CHs ~'-CHs H3C~..~OH CHs ''OOH ~~CH3 HsC CHs Table 4c H3C/' CH3 ~ CH
OH NH2 OH s ~-CH3 ~ CH3 ~CHa ~'CH3 CH3 ~ CH3 ~.CH H3C ~ 'CH3 \ 'CH3 H3C~'CH3 CH3 CH3 ~~~, ~CH3 H3C I\ ~'CH H3C \ 'CH3 3 ~ CH3 HsC CHs HsC CHa H3C 'CH3 H3C~'CH3 ~C~"'~3 'CH3 CH3 """' CH3 "'."' CH3 "'""
'CH 'CH ''T' 'CH ~CH3 3 3 , CH3 '.."" H3C ..."."
i H3C~'CH3 ~'CH3 .CH3 'CH3 OH OH OH OH
CH CH i HsC """,, Y 'CH 1' 'CH ~~' ~' H
3 ~ 3 'r 'CHg ~ C 3 OH OH ~H OH
.""". OH OH """' OH """' ~CH3 ~CH3 ~CH3 CH
OH OH HsC CH3 CH3 H3C _ H3C ~ ~
HsC CH3 CH3 ~CH3 CH3 ~ CH3 ~CH3 CH. 3 ; ~ CH3 ,~,.
CH3 HsC \ CH3 ~CH3 HsC~CH3 CH3 ~~~~ CH3 ~~~. \ ,w",, CHs HaC " 'CH HsC \ CH
3 ~ s CH3 HaC CHs HsC CHs H3C CH3 H3C~CH3 CH3 CH3 CH3 '~"" CH3 ""r' CH3 '"'~' CH CH ''r 'CH ~CH3 3 3 ~ 3 CH3 '~"' H3C \
H3C~CH3 ~CH3 CH CH3 OH OH
OH OH
CH i CH HaC
Y 'CH3 ~CH3 ~ CH
, ~ Y 'CH3 ~ s OH OH ~H OH
6~ 66 67 68 OH OH OH
Y 'CH ~CH3 ~CH3 CH , OH OH
CH, 3 ; HaC
H3C~ . ~CHg HsCwi\~CH3 ~ . ~CH3 . ~CH3 ~'~CH3 ~. CH3 ~'~CH3 ~.~CH3 CH3 ~~~, i CH3 .~"..
~~ JCH3 ~3~~.~CH3 \ ,~CH3 H3C~.~CH3 CIH3 I CH3.~..~. \
~. ~CH3 H3C~ _ ~CH3 H C ~ . ~CH3 ~ CH
3 ~ . ,/ 3 HsC CHs HaC CHs 8~ 86 87 88 H3C , ~CH3 H3C , ~CH3 , ~CH3 . ~CH3 CH3 ',."" CH3 i CH3 .,..."..
~ ~CH3 , ~CH3 ~ , ~CH3 ~ , ~CH3 , CIH3 '~"" H3~ _ \
H3C~.~CH3 ~.~CH3 ~,~GH3 ,~CH3 OOH OH OH OH
CH CH H3G \~ ~
~.~CH3 ~.,~CH3 ~..~GH3 ~.~CH3 , , , , OH OH OH OH
,~~~- OH i OH OH
CH ~/' ~ .~CH3 ~. ~CH3 ~. ~~CH3 ~.i CH3 HsG
H3C~CH3 HsC~CH3 ~CH3 ~ GH3 C
C~
C' 3 CH3 ~CH3 ~1 .,\ H3C
CH3 CHs w,n. ~~H3 i '''H3 .rwr \ w.w CHs HsC ~ ~ CHs H C~CH3 CHs H3C CHs HsC CHs HsC CHs H3C I CHs CHs CHs v CHs HsC CHs 12~ 12b 127 128 CHs """" CHs j CHs """"
CHs ~CH3 ~CH3 ~ /CHs H3C CHs CHs CHs H3C CHs CHs j HsC _ \ '"""
H3C~CH3 ~CH3 ~CN3 CHs TOH - OH ~OH ~ OH
CHs i HsCl I \1 I
H3C.~CH3 ~~CH3 ~CH3 1~CH3 OH OH OH OH
i OH ~ OH """" OH '""
CHs ~CH3 CHs CHs OH HsC CHs '~""' CHs CHs CH3 ; CHs HsC1 .M... CHs H3C'l . J H3~J~ . J . J
14~ 146 147 148 CHs \ _ CH '.~"' CHs J. J ~. ~H3 J..J 3 . J
J J
CHs CHs CH CHs CHs ~ CH '~ Hs J.J s H3C~.J \ .J s HsCJ
CHs CHs 1~1 1S2 153 154 "'~'.~ Hs HsC C~. CHs CHs ~~ Hs \ CH
H3C~ ~'~ 3 H3C '~(C~~H3 H3C CHs 1>j 156 157 158 HsC "..""~ Hs HsC ...".. J Hs .,."",~ Hs .~.,..~ Hs CHs HsC CHs 1~9 160 161 162 CHs '".."~ Hs CHs '~"'~ Hs CH, 3 ' j ~ Hs ~ .",."~ Hs ~'Y~.~
H3C CHs CHs CHs H3C CHs ' ~ Hs lHs .~.",.~ Hs HsC .~"".~ Hs \ .",~,.~ Hs OH OH OH OH
CH3 j 'J Hs CH3 j 'J Hs H3C~'~ H3 ~'w""~ H3 OH OH OH OH
CH Oi H I ' ~ H3 OH ~~ H3 OH ~~ H3 ~~ ~J
HC
OH OH 3 CHg H C~CH3 i ,CH3 CH3 ; CH3 H3C~~CH
H3C'v~vJ [\
~CH3 ~ ~ CH ~CH3 ~ CH3 \~
CH3 CH3 ~ ' CH3 CH3 ~ CH3 CH3 HsC ~ \ HsC l CH3 CHs CH3 CH3 CH3 \ .",..,.
~~ 1 J CH3 H3C~ H3C
H3C HsC CH3 CHs ,."" CHs CHs """" CHs CH3 "j ' ,CHs ~ CHs H3C CHs CHs CHs H3C CHs CHs CHs i CHs HsC CHs \ CHs ~OH ~ OH OH OH
CH~~CHs lHs i cHs H3C1 ; CH3 \ CHs ~~J~~~
OH OH OH OH
i CHs lH j CHs OH CHs OH "."" CHs OH OH HsC CHs 211 2x2 213 214 CHs ~ HsC
H3~~ J H3~~ . J ~.J~ . J ~ , J
UJ ~:, ~ ~. J ~.J
J
CHs cue:. J H3~-,.~. J ~~ . J H3~ \ ~J
CHs CHs CH3 ~ CH3 '....." \ ,......, . J H3~~.~=. J H3~ ~ . ~ . J
HsC CHs HsC CHs H3C ~.J H~C ~.J ~.J . J
CH3 "~C CH3 CH3 ~ J l 3 ~~ CHI, J ~ ~:J
H C ~:~ ~3 ~:.J "3c ~:~ \ ~:J
OH OH O" OH
CHI, J ~~,~ "3~ ~:J ~.J
OH OH ~H OH
O~,J OH~~ °"~:J
OH OH "3C CH3 HsC
H3C~ ~ C~ "3C
\ ,w.".
\~
CH3 ; " """'' ~ CH3 ,~~~.
HaC'~ w H3C 1 CH3 ~ ~ CH3 ,~~~, ~ \
H3C~~ H3C \
HsC CHa HsC CHs H3C ~ ~ H3C
i CH3 '""" ( ~H3 '~"~' ~ CH
~H3 ~ ~ H3C
OH OH OH OH
CH3 '~"' , i H~ H3C ~ \
OH OH pH OH
-".". OH ; ii OH ( OH ".
~I~IJ
HsC HsC
Table 4d H3C i O O H3C' O H3C O
SCHEME 5 ,(cont'd.~
HO~O Y, RZC(O)HN~,.~-~"~~I~OP R2C(O)HN~,.~w.~~'I~OH
Rr3 v O~ R~[ s '''' O
Pap ;, P80-.
",~~OH
O O
48 48a Pap-., P80-.
HO Op9 HO OP9 48a ~~~ -- II
HO O plop O
P80- P80-,, p~o0 O plop O
Pap-,, P80-R2C(O)HN~,, ..,~I~OP9 RZC(O)HN~,, .,,~I~OP9 52 PioO Or + p,o0 1O
53a 53b SCHEME 6 (cont'd.) HO-,, H-!O
R2C(O)HN,,, Op9 R2C(O)HN, OP9 53a - I~ -p~o0 O p~o0 O
Y, Y, R2C(O)HN,,, OP9 R2C(O)HN,, Op9 - p~o0 O HO O
_56 Y is an alkene or haloalkene Y, R2C(O)HN,,, OP9 H O
O
SCHEME 6 ~cont'd.) Y. Y.
R2C(O)HN,,, OP9 R2C(O)HN,,,, OP9 Rya .~~OH O + Rya OH O
59a 59b Y. Y.
R2C(O)HN,,, OP9 RZC(O)HN , OP9 Rya O Ria O
%pR37a pR37a 60a 60b Y. Y, R2C(O)HN,,, OH R2C(O)HN'~. OH
~I~
Rya O R14 O
'~R37a pR37a 61 a 61 b _57_ SCHEME 6 ~cont'd.1 Y. Y, R2C(O)HN,,, OP9 R2C(O)HN,,, OP9 59a ~''~~ il Rya O O ~. Rya OH O
62 59b Y, R2C(O)HN,,, OH
Y.
Rya O RZC(O)HN,,, OH
.~OH
63a R,a OH O
63b Y, Y, R C(O)HN,,, OP9 R2C(O)HN,,, OP9 s2 ~f ~i~
- R1a OH O + Rya O
R3~a R3~a ~OH
64a 64b Y, Y, R2C(O)HN,, OH R2C(O)HN,,, OH
~I~ ~~I~
Rya OH O Rya O
R3~a R37a ~OH
65a 65b SCHEME 7 i(cont'd.) Y, Y, R C(O)HN,,, OP9 R2C(O)HN, OP9 ~I~ ~'I~
Rya OH O + Rya O
R37a R37a ~OH
64a 64b Y, Y, R2C(O)HN,,, OP9 R2C(O)HN,,, OP9 ~ ~I~~I~ ~I~
Rya O Rya O
37c 37c R37a OR R37a ~OR
66a 66b Y, Y, R2C(O)HN,,, OH R2C(O)HN,,, OH
~I~ ~'I~
Rya O Ria O
37c 37c R37a OR ~OR
R37a 67a 67b i .-~ HO O
OH HO O
68 o O
o ~, ~ i ~o ~ o 0 0 ~o C02Me O
CHO
The other compounds of the invention can be readily prepared from the compounds available through commercial sources, in the chemical (literature or as described herein using techniques well known in the chemical literature.
The procedures required are well known and can be readily practiced by those having ordinary skill in the art.
Afl patents, patent applications, and literature references cited in the specification are hereby incorporated by reference in their entirety. In the case of inconsistencies, the present disclosure, including definitions, will prevail.
The reagents required for the synthesis of the compounds of the invention are readily available from a number of commercial sources such as Aldrich Chemical Co. (Milwaukee, WI, USA); Sigma Chemical Co. (St. Louis, MO, USA);
and Fluka Chemical Corp. (Ronkonkoma, NY, USA); Alfa Aesar (Ward Hill, MA
01835-9953); Eastman Chemical Company (Rochester, New York 14fi52-3512);
Lancaster Synthesis Inc. (Windham, NH 03087-9977); Spectrum Chemical Manufacturing Corp. (Janssen Chemical) (New Brunswick, NJ 08901 ); Pfaltz and Bauer (Waterbury, CT. 06708). Compounds which are not commercially available can be prepared by employing known methods from the chemical literature.
The following examples will serve to further illustrate the preparation of the compounds of the invention, without limitation.
_72_ Example 1 fit) (1 S 2S 3R 4R) 2 (N Met~l-N-f-butylo~carbonylamino)-3-acetamidomethyl-4-methoxycarbonyl-c~clopentane-1-carboxylic Acid HO
O NHZ
1A. ~,t) (2R 3S)-2-Aminobicyclo[-2 2 1]hept-5-ene-3-carboxylic acid.
The title compound was synthesized from norbornadiene by a cycloaddition reaction with chlorosulfonyl isocyanate followed by a reduction and acidic hydrolysis as reported by Stajer, G. ef al. Tetrahedron; 40, 2385 (1984).
HO
O NHBoc 1 B. (t) (2R 3S)-2-(t-Butylox~carbonylamino~bicyclo[2.2.11hept-5-ene-3-carboxylic acid.
A solution of (t)-(2R,3S)-2-aminobicyclo[2.2.1]hept-5-ene-3-carboxylic acid (6.3 g, 0.04 mole) , NaOH (3.3 g, 0.082 mole), and di-fert-butyl Bicarbonate (0.082 mmole) in water (200 mL) was stirred at room temperature for 48 hours.
The reaction mixture was acidified using 1 M aqueous HCI, while cooling the solution in an ice/water bath. The reaction mixture was extracted with dichloromethane {3 X 250 mL). The organic layer was dried over MgS04, filtered and concentrated to provide the title compound as a white solid (yield: 5.6 g, 55%).
' H NMR (CDCi3) 81.44 (s, 9H), 1.64 (d, 1 H), 2.08 (d, 1 H), 2.58 (m, 1 H), 2.72 (s, 1 H), 2.97 (s,1 H), 6.18 (m, 2H), 6.96 (d, 1 H).
HO
NHBoc 1 C. ~t~~2R 3S)-2- t Butyloxycarbonylamino)-3-hydroxymethvlbicyclof2.2.11hept-5-ene.
Ethyl chloroformate (2.3 mL, 23.7 mmole) was added slowly to a solution of (t)-(2R,3S)-2-(t-butyloxycarbonylamino)bicyclo[2.2.1]hept-5-ene-3-carboxylic acid (6 g, 23.7 mmole) and N-methylmorpholine (2.6 mL, 23.~ mmole) in THF
(110 mL) at -20 °C . The reaction mixture was warmed to 0 °C, and the slurry-like reaction became nearly homogeneous. The reaction mixture was cooled to -20 °C, and treated with sodium borohydride ( 3.7g, 66 mmole). Methanol (10 mL) was added dropwise, over 20 minutes. The reaction mixture was neutralized with 1 N HCI and the reaction mixture was concentrated by removal of volatile materials, in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with 1 N HCI, water, and brine, dried over MgS04, filtered and concentrated in vacuo. Purification by silica gel column chromatography using 15% ethyl acetate/hexanes provided the title compound (yield: 4.27 g, 75 %).
' H NMR (CDC13) b 1.45 (s, 9H), 1.52 (m, 2H), 1.85 {q, 1 H), 2.09 (bs, 1 H}, 2.68 {m, 2H), 3.66 (m, 3H), 4.83 (bs, 1 H), 6.11 (m, 1 H), 6.27 (m, 1 H).
W
O
H NHBoc 1 D. fit)-(2R 3S)-2-(t Butyloxycarbonylamino -3-formylbicyclof2.2.11hept-5-ene.
DMSO (3.4 mL) in dichloromethane (5 mL) was added slowly to oxalyl chloride (2 mL, 22 mmole) in dichloromethane (50 mL) at -78 ~C. After 5 minutes, (t)-(2R,3S)-2-(t-butyloxycarbonylamino)-3-hydroxymethyl-bicycloj2.2.1 ]hept-5-ene (4.27g, 17.8 mmole) in 15 mL of dichioromethane and 10 mL of DMSO was added. Stirring was continued for 20 minutes at -78 ~C. The solution was treated with triethylamine (14 mL). After 5 minutes, the cooling bath was removed and the reaction stirred for an additional 30 minutes. The reaction mixture was partitioned with water (100 mL). The aqueous layer was extracted with dichloromethane (3 x 50 mL). The organic layers were combined, washed with brine, dried over MgS04, filtered and concentrated. The crude product was chromatographed on silica gel with 0-10% ethyl acetate/dichloromethane, to provide the title compound. (yield: 3.8 g, 90%) H NMR (CDC13) b1.43 (s, 9H), 1.63 (m, 2H), 2.74 (m, 2H), 3.11 (s, 1 H), 3.99 (t, 1 H). 4.85 (d, 1 H), 6.22 (m, 2H), 9.81 (s, 1 H).
H
BnN
NHBoc 1 E. (t)-(2R 3R)-2-~Bu loxycarbonylamino)-3-N-ben~laminomethylbicyclo-j2.2.1~he~t-5-ene.
A solution of (t)-(2R,3S)-2-(f-butyloxycarbonylamino)-3-formyl-bicyclo[2.2.1]kept-5-ene (3.8g, 16.0 mmole), benzylamine (1.9 mL, 17.6 mmole) and acetic acid (1 mL) in dichloromethane (80 mL) was stirred at 0 °C
for 10 minutes followed by addition of Na(Ac0)sBH (5.09g, 24 mmole). The reaction mixture was stirred at 0 °C for 2 hours then allowed to warm slowly to room temperature for 2 hours. After completion, the reaction mixture was washed with aqueous sodium bicarbonate, dried over MgS04, filtered and concentrated. The crude product was purified by silica gel chromatography using 0-2.5%
methanollchloroform to provide the title compound (yield: 4.0 g, 77%).
' H NMR (CDC13) 81.47 (s, 9H), 1.51 (m, 2H), 1.78 (t, 1 H), 2.72 (m, 4H), 3.57 (t, 1 H), 3.78 (s, 1 H), 6.10 (m, 1 H), 6.21 (m, 1 H), 7.30 (m, 5H).
MS: (M+H)+ = 329.
Cbz BnN
NHSoc 1 F. {t~~2R 3RL2 (f But~rloxycarbonylamino~ 3-(N-benzyl-N-(benzyloxycarbonyl-amino)methyl bicyclo(2.2.11hept-5-ene.
A solution of (t)-(2R,3R)-2-(t-butyloxycarbonylamino)-3-N-benzylaminomethylbicyclo[2.2.1]kept-5-ene (2.8 g, 8.5 mmole) and N-(benzyloxycarbonyloxy)succinimide (2.3 g) in 50 mL of dichloromethane was reacted at room temperature for 6 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous NaHC03 and brine, dried over MgS04 and concentrated in vacuo. The product was purified by silica gel chromatography using hexanes/ethyl acetate (3:1) to provide the title compound (yield: 3.37 g, 85%).
' H NMR (CDC13) 51.32 (m,2H), 1.36 (s, 9H), 1.56 (m, 1 H), 1.88 (m, 1 H), 2.63 (m, 2H), 3.06 (m, 1 H), 4.34 {m, 1 H), 4.63 (m, 1 H), 5.18 (m, 2H), 6.05 (bs, 2H), 7.28 (m, 11 H).
CbzN NBoc Bn CH3 1 G. (t)-(2R 3R)-2-(N-Methyl-N-t butyloxycarbonylamino)-3-(N-benzyl-N-benzyl-oxycarbonylamino)methLrl-bicyclo[2.2.1 ]hept-5-ene.
Sodium hydride (300 mg , 60% in oil) was added to a solution of (t)-(2R,3R}-2-(t butyloxycarbonylamino)-3-(N-benzyl-N-benzyloxycarbonylamino)-methylbicyclo[2.2.1]hept-5-ene (3.37 g, 7.27 mmole) and iodomethane (0.9 mL) in anhydrous DMF (60 mL) at 0 °C. After 4 hours, the reaction mixture was concentrated in vacuo and purified by silica gel chromatography using hexanes/ethyl acetate (4:1 ) to provide the title compound (yield: 3.3 g, 95%).
H NMR (CDC13) b1.40 (s, 9H}, 1.82 (m, 2H), 2.26 (m, 1 H), 2.78 (m, 1 H), 2.85 (m, 1 H), 2,90 (s, 3H), 2.94 (m, 2H), 3.63 (m, 1 H), 4.22 (m, 2H), 5.34 (s, 2H), 5.60 (m, 2H), 7.15 (m, 10H).
MS: (M+H)+ = 477.
O
CH30-l~
CbzN NBoc O
Bn 'CH3 1 H. !t)-( 1 S 2S 3R 4R~2-(N-Methyl-N-t-butyloxycarbonylamino)-3-(N-benzyl-N-benzyloxycarbonylamino)meth~cyclopentane-1 4-dicarboxylic Acid Dimethyl Este r.
A mixture of Na104 (10 g, 47 mmole) and Ru02 (45 mg, 0.3 mmol) in 25 mL of carbon tetrachloride 50 mL of acetonitrile, and 75 mL of water was rapidly stirred for 30 minutes. A solution of (t)-(2R,3R)-2-(N-methyl-N-t butyloxycarbonylamino)-3-(N-benzyl-N-benzyloxycarbonylamino)methyl-bicyclo[2.2.1]hept-5-ene (3.3 g, 6.9 mmole) in 25 mL of carbon tetrachloride was added to the bright yellow mixture. The resultant black mixture was stirred at room temperature for 1.5 hours and diluted with 250 mL of water. The aqueous layer was extracted with ethyl acetate (5 x 200 mL). The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated in vacuo. The residue was dissolved in ethyl acetate and treated with a solution of diazomethane in ethyl ether. The reaction mixture was concentrated in vacuo, and the crude product purified by silica gel chromatography using ethyl acetate/hexanes (1:1} to provide the title compound as a white solid (yield:
1.91 g, 50%).
'H NMR (CDC13) 81.41 (s, 9H), 2.21 (m, 2H), 2.33 (m, 1H), 2.90 (s, 3H), 2.92 (m, 2H), 2.96 (m, 1 H), 3.38 (t, 1 H), 3.67 (s, 6H), 4.23 (m, 3H), 5.38 (s, 2H), 7.12 (m, 10H).
MS: (M+H)+ = 569.
O
CH30-'l~
'"If NH2 NBoc O
11. fit) (1S 2S 3R 4R) 2 (N Methyl N t Bu~loxycarbonylamino)-3-aminomethvl-cyclopentane-1 4-dicarboxylic Acid Dimethvl Ester.
A mixture of (t)-(1S,2S,3S,4R)-2-(N-methyl-N-t-butyloxycarbonylamino)-3-(N-benzyl-N-benzyloxycarbonylamino)methyl-cyclopentane-1,5-dicarboxylic acid dimethyl ester (1.91 g, 3.36 mmole) and Pd(OH)z (380 mg, 20% on carbon) in 50 mL of isopropanol was stirred at room temperature under an hydrogen atmosphere, for 16 hours. The catalyst was removed by vacuum filtration through a bed of Celite~, and the filtrate concentrated in vacuo to provide the title compound (yield: 1.2 g 100 %).
'H NMR (CDC13) 61.48 (s, 9H), 2.00 (m, 2H), 2.42 (m, 1H), 2.64 (m, 2H), 2.90 ( bs, 3H), 3.00 (m, 2H), 3.71 (s, 3H), 3.73 (s, 3H), 4.4 (bs, 1 H), 5.4 (bs, 2H).
MS: (M+H)+ = 345.
_79_ O
CH30-~~
AcHN Ngoc O
1 J. (~1 S 2S 3R 4R)-~N-Methyl-N-t but~ycarbonylamino)-3-acetamido-methyl-cyclopentane-1 4-dicarboxylic Acid Dimethv I E~ stet.
A solution of (t)-(1S,2S,3R,4R)-2-(N-methyl-t butyloxycarbonylamino)-3-aminomethylcyclopentane-1,5-dicarboxylic acid dimethyl ester (1.2 g, 3.5 mmole), acetic anhydride (0.5 mL) and triethylamine (1 mL) in 25 mL of dichloromethane was stirred at room temperature for 2 hours.
The reaction mixture was diluted with ethyl acetate and washed successively with 1 N HCI, water and brine, dried over MgS04, and concentrated in vacuo. The residue was purified by silica gel chromatography using ethyl acetate/hexanes (1:1) to provide the title compound (yield: 790 mg, 58 %).
' H NMR (CDCI~) 61.45 (s, 9H), 1.92 (s, 3H), 2.05 (m, 1 H), 2.40 (m, 1 H), 2.62 (m, 1 H), 2.85 (s, 3H), 3.1 (m, 1 H), 3.3 {m, 1 H), 3.42 (m, 1 H), 3.71 (s, 6H), 4.62 (bs, 1 H), 6.38 (bs, 1 H).
MS: (M+H)+= 387.
O
HO--~~
OH
'''I
AcHN Ngoc O
1 K. fit) (1 S 2S 3R 4R)-2-(N-Methyl-N-f but~oxLrcarbonylamino)-3-acetamido-methyl-cyclopentane-1 4-dicarboxylic Acid.
A solution of (t)-(1 S,2S,3S,4R)-2-(N-methyl-N-t-butyloxycarbonylamino)-3-acetamidomethylcyclopentane-1,5-dicarboxylic acid dimethyl ester (720 mg, 1.86 mmole) and 5 equivalents of lithium hydroxide in methanol (40 mL) and H20 (10 mL) was stirred at room temperature for two hours. The solution was concentrated in vacuo. The residue was partitioned between 1 N HCI and ethyl acetate. The aqueous layer was back extracted with ethyl acetate (3 x 50 mL). The organic layers were combined and washed with brine, dried over Na2S04, filtered, and concentrated in vacuo to provide the title compound {yield: 500 mg, 75 %).
H NMR (CDC13) 81.45 (s, 9H), 1.92 (s, 3H), 2.05 (m, 1 H), 2.40 (m, 1 H), 2.62 (m, 1 H), 2.85 (s, 3H), 3.1 (m, 1 H), 3.3 (m, 1 H), 3.42 (m, 1 H), 3.71 (s, 6H), 4.62 (bs, 1 H), 6.38 (bs, 1 H).
O
CH30-l/
..~~~~oH
AcHN Ngoc ~
1 L. ,fit)-(1 S 2S 3R 4R)-2-lN-Methyl-N-t-butylox~carbonylamino)-3-acetamido-methyl-4-methox cay rbonylcyclopentane-1-carboxylic Acid A solution of (t)-(1 S,2S,3R,4R)-2-(N-methyl-N-t butyloxycarbonylamino)-3-acetamidomethylcyclopentane-1,5-dicarboxylic acid (500 mg, 11.4 mmole), in 5 mL of dichloromethane and 5 mL of acetic anhydride, was stirred at room temperature for two hours. The solution was concentrated in vacuo, at 20 °C. The residue was dissolved in 10 mL of methanol and 0.2 mL of triethylamine and reacted for 16 hours at room temperature, under a nitrogen atmosphere. The reaction mixture was diluted with 100 mL of chloroform, and washed successively with 0.1 N HCI and brine. The solution was dried over MgS04, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using chloroformlmethanol/acetic acid (97:2:1 ) to provide the title compound (yield: 155 mg, 30 %).
'H NMR (CDC13) 81.47 (s, 9H), 1.95 (s, 3H), 2.10 (m, 2H), 2.43 (m, 1H), 2.64 (m, 1 H), 2.88 ( m, 4H), 3.20 (m, 1 H), 3.30 (m, 1 H), 3.44 (m, 1 H), 3.72 (s, 3H), 4.66 (t, 1 H), 6.48 (bs, 1 H).
MS (M+H)+= 373.
Example 2 CH30-'l~
OH
~~~''If AcHN NH O
!t)-(1 S 2S 3R 4Rl-2-N-Methyl-3-acetamidomethyl-4-methoxycarbonyl-cyclo~entanecarboxylic Acid Hydrochloride.
A solution of (t)-(1 S,2S,3R,4R)-2-(N-methyl-N-t-butyloxycarbonylamino)-3-acetamidomethyl-4-methoxycarbonylcyclopentanecarboxylic acid (130 mg, 0.35 mmole) in 4.5 mL of dichloromethane was reacted with trifluoroacetic acid (1.5 mL) for 1 hr, at room temperature. The solution was concentrated in vacuo, at °C. The residue was treated with 1 N HCI and concentrated in vacuo to provide the title compound as a white solid (yield: 100 mg, 92 %).
'H NMR (D20) 82.02 (s, 3H), 2.08 (m, 1H), 2.54 (m, 2H), 2.76 (s, 3H), 2.85 (m, 2H), 3.36 (m, 2H), 3.76 (s, 3H), 3.81 (t, 1 H).
Example 3 CH30~~
OH
AcHN NCbz O
fit)-(1 S 2S 3R 4R)-2~N-Methyl-N-benzyloxycarbonylamino)-3-acetamidomethyl-4-methoxycarbonyl-cyclopentanecarboxLrlic Acid.
A solution of (t)-{1S,2S,3R,4R)-2-N-methyl-3-acetamidomethyl-4-methoxycarbonyl-cyclopentanecarboxylic acid hydrochloride (100 mg), N-(benyloxycarbonyloxy)succinimide (183 mg) and triethylamine (0.160 mL) in dichloromethane (10 mL) was stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate and washed successively with 1 N HCI, and brine, dried over MgS04, and concentrated in vacuo. The residue was purified by silica gel chromatography using chloroform/methanol/acetic acid (97:2:1 ) to provide the title compound as a white solid.
~ H NMR (CDC13) b1.88 (s, 3H), 2.08 (m, 2H), 2.46 (m, 1 H), 2.66 (m, 1 H), 2.92 (m, 1 H), 2.96 (s, 3H), 3.18 (m, 1 H), 3.35 (m, 1 H), 3.70 (s, 3H), 4.64 (bs, 1 H), 5.14 (s, 2H), 6.29 (bs, 1 H), 7.34 (m, 5H).
MS: (M+H)+ = 407.
Example 4 fit) (1 S 2S 3R 4R)-2-lt-Butyloxycarbonylamino)-3-(acetamidomethyl)-4-(methoxy-carbonyl -cyclopentane-1-carboxylic Acid.
Ac0 NHBoc 4A. ~t~~2R 3S~ 2 t But~loxycarbonylamino-3-acetoxymethylbicyclof2.2.11hept-5-ene.
A solution of (t)-(2R,3S)-2-(t butyloxycarbonylamino)-3-hydroxymethylbicyclo[2.2.1]hept-5-ene (1.0 g, 4.18 mmole), acetic anhydride (0.55 mL), triethylamine (2 mL) and N,N-dimethylaminopyridine (catalytic) in mL of dichloromethane was reacted for 2 hours, at room temperature. The reaction mixture was diluted with 200 mL of ethyl acetate, washed with 0.5 N
HCI, water, saturated sodium bicarbonate, and brine. The organic layer was dried over MgS04, filtered and concentrated. The crude product was purified by silica gel chromatography using 10% ethyl acetate/hexanes to provide the title compound. (yield: .92 g, 78 %) MS: (M+H)+ = 282.
H O-J
Ac0 OH
BocHN O
4B. (t) 1 S 2S 3S 4R) 2 (t Butt'loxycarbonylamino)-3-(acetoxymethyl)-cycio-pentane-1 4-dicarboxylic Acid Ruthenium dioxide hydrate (43mg, 0.32 mmole) was added to a vigorously stirred mixture of Na104 (7.12 g, 33 mmole) in 33 mL of acetonitrile, 33 mL of carbon tetrachloride and 58 mL of water. The mixture was stirred at room temperature for 5 minutes or until a homogeneous yellow color was attained. A
solution of (t)-(2R,3S)-2-(t-butyloxycarbonylamino)-3-acetoxymethyl-bicyclo[2.2.1 ]hept-5-ene (2.28 g, 8.11 mmole) in 10 mL of (1:1 ) acetonitrile:carbon tetrachloride was added rapidly to the reaction mixture.
The mixture was stirred vigorously for 1 hour at room temperature. The reaction mixture was partitioned between ethyl acetate and 0.5 N HCI. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated to provide the diacid compound which was used in the following reaction without additional purification.
_gb_ O
HO--~~
HO OH
BocHN O
4C. (t) (1S 2S 3S 4R)-2-(t-ButYloxycarbon~rlamino -3~-(h_ydroxymethyl)-cyclo-pentane-1 4-dicarboxylic Acid.
The crude diacid, (t)-(1 S,2S,3S,4R)-2-(t butyloxycarbonylamino)-3-(acetoxymethyl)-cyclopentane-1,4-dicarboxylic acid, prepared in example 4B, and sodium hydroxide (1.2 g) in 45 mL of water was reacted for 6 hours, at room temperature. The reaction mixture was acidified to pH 1 with and extracted with ethyl acetate (3 x 40 mL). The organic layer was washed with brine and dried over Na2S04, filtered and concentrated. The crude diacid-alcohol was used in the following reaction without additional purification.
CH30--!~
HO ,,~~~OCH3 BocHN 1O
4D. (t,~ (1 S 2S 3S 4R~ 2-(t Butyloxycarbonylamino)-3-(hydroxymethyl)-cyclo-pentane-1 4-dicarboxylic Acid Dimethyl Ester.
The diacid-alcohol, (t)-(1S,2S,3S,4R)-2-(t-butyloxycarbonylamino)-3-(hydroxymethyl)-cyclopentane-1,5-dicarboxyiic acid, prepared in Example 4C, was dissolved in 40 mL of tetrahydrofuran {THF) and reacted with diazomethane in ethyl ether until complete conversion to the dimethyl ester. The reaction mixture was monitored by TLC, using 10% methanol in chloroform with 1 % acetic acid. The reaction was concentrated in vacuo to provide the title compound as a colorless oil (yield: 1.3 g, 85 %).
MS: (M+H)+ = 331.
O
CH30--l~
N3 .,~~~~ CH3 BocHN
4E. ,~~1S 2S 3R 4R)-2-(f Butyloxycarbonylamino)-3-(azidomethyl)-cyclo-pentane-1 4-dicarboxylic Acid Dimethyl Ester.
Methanesulfonyl chloride (1.3 mL, 17.0 mmole) was added slowly to a solution of (t)-(1S,2S,3S,4R)-2-(t butyloxycarbonylamino)-3-(hydroxymethyl)-cyclopentane-1,4-dicarboxylic acid dimethyl ester (2.76g, 8.34 mmole) and triethylamine (2.4 mL, 17.0 mmole) in 80 mL of 1:1 dichloromethaneaetrahydrofuran, maintained at -30 °C. The reaction mixture was stirred for 2.5 hours, at -30 °C then diluted with ethyl acetate washed with 0.1 N
HCI and brine, dried over MgS04, filtered and concentrated in vacuo to provide the crude mesyiate. The mesylate and lithium azide (4 g) were reacted in 35 mL
of N,N-dimethylformamide for 1 hour, at 90 °C. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgS04, filtered and concentrated. The crude product was purified by silica gel chromatography using 20% ethyl acetate in hexanes to provide the title compound. (yield: 1.8 g, 48%) MS: (M+H)+ = 373.
O
CH30-~~
AcHN OCH3 BocHN O
4F. (t)_(1 S 2S 3R 4R~-2-(t-But~loxycarbonylamino)-3-(acetamidomethyl)-cycfopentane-1 5-dicarboxylic Acid Dimethyl Ester.
(t)-(1 S,2S,3R,4R)-2-(t-Butyloxycarbonylamino)-3-(azidomethyl)-cyclopentane-1,4-dicarboxylic acid dimethyl ester (506 mg, 1.42 mmole) and thiolacetic acid (0.4 mL) were reacted at room temperature for 6 hours. The reaction mixture was concentrated in vacuo and the crude product was purified by silica gel chromatography using 3% methanol in chloroform to provide the title compound (yield: 255 mg, 48%).
MS: (M+H)+ = 373.
o HO--l~
AcHN OH
O
NHBoc 4G. (t)~1S 2S 3R 4R)-2-(t Butyloxycarbonylamino)-3-(acetamidomethyl)-~clopentane-1.4-dicarboxylic Acid (t)-(1 S,2S,3R,4R)-2-(t-Butyloxycarbonylamino)-3-(acetamidomethyl)-cyclopentane-1,4-dicarboxylic acid dimethyl ester (255 mg, 0.68 mmole) and lithium hydroxide (2.2 equivalents) in 15 mL of 4:1 methanol:water were reacted at room temperature for 2 hours. The reaction was acidified with dilute HCI
and extracted with ethyl acetate (3 X 60 mL). The organic layers were combined, dried over Na2S04, filtered and concentrated to provide the title compound.
-88_ O
AcHN OH
BocHN O
4H. fit) (1 S 2S 3R 4R)-2-(t Buyloxycarbonylamino)-3-(acetamidomethvl)-4-(methoxycarbonyl)-cyclopentane-1-carboxylic Acid The crude diacid, (t)-(1S,2S,3R,4R)-2-(t-butyloxycarbonylamino)-3-(acetamidomethyl)-cyclopentane-1,4-dicarboxylic acid, prepared in Example 4G
was reacted with acetic anhydride (20 mL) for approximately 1 hour at 60 °C to provide the bicyclic anhydride. The reaction mixture was concentrated in vacuo and the crude anhydride was treated with methanol (50 mL) and triethylamine (2-3 equivalents) at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with 0.5N HCl and brine. The organic solution was dried over Na2S04, filtered and concentrated. Chromatographic separation of the diastereomers was accomplished by silica gel chromatography using 25% ethyl acetate in hexanes and 0.5% acetic acid to provide the title compound (yield:
mg, 60 %).
'H NMR (methanol-d4) 5 1.44 (s, 9H), 1.90 (s, 3H), 2.04 (m, 1H), 2.32 (m,1 H), 2.54 (m,1 H), 2.72 (m,2H), 3.11 (m, 1 H), 3.36 (m,1 H), 4.38 (m,1 H), 6.92 (broad d, 1 H), 7.8 (broad s, 1 H).
MS: (M+H)'' = 359.
_89_ Example 5 CH30--!~
AcH N OH
~'I~
HCI
(t)-(1 S.2S.3R.4R~-2-Amino-~acetamidomethyl)-4-(methoxycarbonyl)-cyclopentane-1-carboxylic Acid Hydrochloride A solution of (t)-(1S,2S,3R,4R)-2-(t butyloxycarbonylamino)-3-(acetamido-methyl)-4-(methoxycarbonyl)-cyclopentane-1-carboxylic acid (66 mg, 0.18 mmole) in 3 mL of dichloromethane was reacted with trifluoroacetic acid (1.0 mL) for 1 hr, at room temperature. The solution was concentrated in vacuo at 25 °C.
The crude product was treated with 1 N HCI and concentrated in vacuo to provide the title compound as a white solid.
' H NMR {D20) 82.01 (s, 3H), 2.19 (m, 1 H), 2.58 (m, 1 H), 2.81 (t, 1 H), 2.95 {m, 1 H), 3.15 (m, 1 H), 3.38 (m, 3H), 3.75 (s, 3H), 4.08 (t, 1 H).
MS = (M+H)+ = 259.
Example 6 (~S 2S 3R 4R) 3 Acetamidomethyl-2-(N-t-butoxycarbonylamino)methyl-4-metho~carbonyl-cyclopentane-1-carboxylic Acid Ac0 OBn 6A. (t) exo exo 3 Acetoxymethyl-2-benzyioxymethyl-bicyclof2.2.11hept-5-ene.
(t)-exo-exo-2,3-Dihydroxymethylbicyclo[2.2.1]hept-5-ene (620 mg, 4.0 mmole), prepared according to the procedure described by Culberson, C. et al., Journal of the American Chemical Society 82, 2541-2547, (1960), was reacted with sodium hydride (300mg, 60% oil dispersion) in 10 mL of N,N-dimethyl-formamide (DMF) for 15 min, at 0 °C. This was followed by treatment of the dianion with benzyl bromide (0.5 mL) for an additional 2 hours. The reaction mixture was diluted with ethyl acetate washed with wafer, and brine, dried over MgS04, filtered and concentrated in vacuo.
The crude benzylated product was reacted with acetic anhydride (0.7 mL), triethylamine (3 mL) and N,N-dimethylaminopyridine (catalytic) in dichloromethane (20 mL) at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography using 10%
ethyl acetate in hexanes to provide the title compound (yield: .845 g, 74%).
'H NMR (CDC13) 81.41 (m, 2H), 1.85 (m, 2H), 2.05 (s, 3H), 2.73 (brs, 1H), 2.78(brs, 1 H), 3.38 (m, 1 H), 3.57 (m, 1 H), 3.95 (m, 1 H), 4.31 (m, 1 H), 4.51 (m, 2H), 6.18 (m, 2H), 7.33 (m, 5H).
MS: (M+H)+ = 287.
O
CH30~/
Ac0 OCH3 OBn 6B. fit)-( 1 S 2S 3R 4RZ 3-AcetoxvmethYl-2-benzvlo~methyl-cyclopentane-1.4-dicarboxylic Acid Dimethyl Ester.
A rapidly stirred mixture of Na104 (10 g) and Ru02 (45 mg) in 25 mL of carbon tetrachloride, 50 mL of acetonitrile, and 75 mL of water was reacted for 30 minutes. A solution of (t)-(2R,3S)-2-acetoxymethyl-3-benzyloxymethyl-bicyclo[2.2.1 ]hept-5-ene (3.3 g, 11.5 mmole) in 25 mL of carbon tetrachloride was added to the bright yellow mixture. The resultant black mixture was stirred for 1.5 hours, at room temperature. Water (250 mL) was added to the reaction mixture and the aqueous layer was extracted with ethyl acetate (5 x 200 mL) . The combined organic layers were washed with brine, dried over MgS04, and concentrated in vacuo.
The residue was dissolved in ethyl acetate and treated with a solution of diazomethane in ethyl ether. The reaction mixture was concentrated in vacuo, and the crude product purified by silica gel chromatography using ethyl acetate:
hexanes (1:1 ) to provide the title compound as a white solid (yield: 1.91 g, 44%).
' H NMR (CDC13) 82.00 (s, 3H), 2.14 (m, 1 H), 2.34 (m, 1 H), 2.77 (m, 3H), 2.89 (m, 1 H), 3.51 (m, 2H), 3.67 (s, 3H), 3.70 (s, 3H), 4.18 (m, 2H), 4.47 (s, 2H), 7.32 (m, 5H).
MS: (M+H)+ = 379.
O
CH30-l Ac0 ,,~~~OCH3 tO
OH
6C. SOS 2S 3R 4R) -3-Acetox~methyl-2-~droxymethYl_cyclopentane-1.4-dicarboxylic Acid Dimethyl Ester.
A mixture of (t)-(1S,2S,3R,4R)-3-acetoxymethyl-2-benzyloxymethylcyclopentane-1,4-dicarboxylic acid dimethyl ester {3.3 g, 8.72 mmole) and palladium (600 mg, 10% on carbon) in ethanol (100 mL) was stirred vigorously at room temperature under an hydrogen atmosphere. Upon completion, as determined by TLC, the reaction mixture was filtered and concentrated in vacuo to provide the title compound (yield: 2.56 g, 100%).
' H NMR (CDC13) 81.84 (t, 1 H), 2.05 (s, 3H), 2.16 (m, 1 H), 2.36 (m, 1 H), 2.75 (m, 4H), 3.70 (s, 3H), 3.71 (s, 3H), 3.73 (m, 1 H), 4.19 {m, 2H).
MS = (M+H)+ = 289.
O
CH30~
Ac0 .,,~~~OCH3 O
6D. {t)-{1 S 2S 3R 4R~ 3-Acetoxymethyl-2-azidomethylcyclopentane-1,4-di-carboxylic Acid Dimethyl Ester.
Methanesulfonyl chloride (2.1 mL, 26.6 mmole) was added slowly to a solution of (t)-(1S,2S,3R,4R)-3-acetoxymethyl-2-hydroxymethylcyclopentane-1,4-dicarboxylic acid dimethyl ester (2.56g, 8.72 mmole) and triethylamine {3.7 mL, 26.6 mmole) in 100 mL of dichloromethane at -30 °C. The reaction mixture was stirred at -30 °C for 0.5 hour then allowed to warm to 0 °C
over 1 hour. The reaction mixture was diluted with ethyl acetate washed with 0.1 N HCI and brine, dried over MgS04, filtered and concentrated in vacuo to provide 4.32 g of crude mesylate.
The crude mesylate, prepared above, and lithium azide (4.2 g, 87.2 mmole) were reacted at 90 °C in 50 mL of N,N-dimethylformamide for 1 hour.
The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgS04, filtered and concentrated. The crude product was purified by silica gel chromatography using 25 % ethyl acetate in hexanes to provide the title compound (yield: 2.0 g, 72%).
' H NMR (CDC13) 82.07 (s, 3H), 2.17 (m, 1 H), 2.37 (m, 1 H), 2.76 (m, 4H), 3.47 (m, 2H), 3.71 (s, 3H), 3.73 (s, 3H), 4.16 (m, 2H).
CH30-l/
Ac0 OCH3 ~'If NHBoc 6E. (t)~1S 2S 3R 4R~-3-Acetoxymethyl-2-(N-t butoxycarbonylamino)methyl-cycloeentane-1 4-dicarboxvlic Acid Dimethyl Ester.
A mixture of (t)-(1 S,2S,3R,4R)-3-acetoxymethyl-2-azidomethylcyclo-pentane-1,4-dicarboxylic acid dimethyl ester (2.0 g, 6.6 mmole), di-t-butyl-dicarbonate (3.79 g), and palladium (900mg, 10% on carbon) in 100 mL of ethyl acetate was stirred vigorously at room temperature under an hydrogen atmosphere. Upon completion, as determined by TLC, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 50% ethyl acetate in hexanes to provide the title compound (Yield: 2.3 g, 94%).
' H NMR (CDC13) 81.43 (s, 9H), 2.06 (s, 3H), 2.17 (m, 1 H), 2.35 (m, 1 H), 2.72 (m, 4H), 3.21 (m, 2H), 3.70 (s, 3H), 3.72 {s, 3H), 4.12 (m, 2H), 4.74 (t, 1 H).
MS = (M+H)+ = 388.
CH30-'~
HO .,~~~~ CH3 O
NHBoc 6F. (t)-(1S 2S 3R 4R)-2-(N-t Butoxycarbonylamino),methyl-3-hydroxymethyl-cyclopentane-1 4-dicarboxylic Acid Dimethyl Ester.
(t)-(1 S,2S,3R,4R)-3-Acetoxymethyf-2-(N-t-butoxycarbonylamino)-methylcyclopentane-1,4-dicarboxylic acid dimethyl ester (600 mg,11.55 mmole) was treated with potassium carbonate (catalytic) in 10 mL of methanol, at room temperature for Bh. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and brine. The organic layer was dried over MgS04, filtered and concentrated to provide the title compound.
(yield:
510 mg, 95%) 'H NMR (CDC13) 81.44 (s, 9H), 2.24 (m, 2H), 2.59 (m, 2H), 2.77 (m, 2H), 3.28 (m, 2H), 3.73 (m, 8H), 5.04 (t, 1 H).
O
CH30--!~
O
NHBoc 6G. (t,~1 S 2S 3R 4R)-3-Azidomethyl-2-(N-t butox~carbonylamino)methylcyc-lopentane-1 4-dicarboxylic Acid Dimethyl Ester.
Methanesulfonyl chloride (0.35 mL, 4.5 mmole) was added slowly to a solution of (t)-(1 S,2S,3R,4R)-2-(N-t-butoxycarbonylamino)methyl-3-hydroxymethyl-cyclopentane-1,4-dicarboxylic acid dimethyl ester {560 mg, 1.48 mmole) and triethylamine (0.6 mL) in dichloromethane (10 mL) at -30 °C.
The reaction mixture was stirred at -30 °C for 2 hours then allowed to warm to 0 °C
over 1 hour. The reaction mixture was then diluted with ethyl acetate washed with 0.1 N HCI and brine, dried over MgS04, filtered and concentrated in vacuo to provide the crude mesylate.
The crude mesylate, prepared above, and lithium azide (0.7 g, 14.3 mmole) were reacted at 85 °C in 10 mL of N,N-dimethylformamide for 1 hour.
The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgS04, filtered and concentrated. The crude product was purified by silica gel chromatography using 25% ethyl acetate in hexanes to provide the title compound (yield: 386 mg, 70%).
'H NMR (CDC13) 81.43 (s, 1H), 2.26 {m, 2H), 2.69 (m, 4H), 3.23 (m, 2H), 3.46 (m, 2H), 3.70 (s, 3H), 3.71 (s, 3H), 4.74 (bs, 1 H).
O
CH30~
AcHN OCH3 O
NHBoc 6H. ,{t)~1 S 2S 3R 4R)-3-Acetamidomethyl-2-LN-t butoxycarbonylamino)methyl-~clopentane-1,4-dicarboxylic Acid Dimethyl Ester.
A mixture of (t)-(1S,2S,3R,4R)-3-azidomethyl-2-(N-t butoxycarbonyl-amino)methylcyclopentane-1,4-dicarboxylic acid dimethyl ester (386 mg, 1.04 mmole) , acetic anhydride (0.25 mL) and palladium (25 mg, 10% on carbon) in 10 mL of ethyl acetate was stirred vigorously at room temperature under an hydrogen atmosphere. Upon completion, as determined by TLC, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 75% ethyl acetate in hexanes to provide the title compound. (yield: 232 mg, 58%).
'H NMR (CDC13) x1.44 (s, 9H), 1.97 (s, 3H), 2.27 (m, 2H), 2.64 (m, 2H), 3.18 (m, 2H), 3.32 (t, 1 H), 3.71 (s, 3H), 3.73 (s, 3H), 7.78 {bs, 1 H), 6.19 (bs, 1 H).
MS = (M+H)+ = 387.
_97_ O
CH30-~~
AcHN OH
O
NHBoc 61. (,t~~1 S 2S 3R 4R~-3-Acetamidomethvl-2-~N-t butoxycarbonylamino)methyl-4-methoxycarbonylcyclopentane-1-carboxylic Acid.
(t)-( 1 S,2S, 3R,4 R)-3-Acetamidomethyl-2-(N-t butoxycarbonylamino)methylcyclopentane-1,4-dicarboxylic acid dimethyl ester (232 mg, 0.60 mmole) was reacted with 5 equivalents of lithium hydroxide in 5 mL
of (4:1 ) methanol:water for 2 hours, at room temperature. The reaction mixture was neutralized with 0.1 N HCI and partitioned between ethyl acetate and brine.
The organic layer was concentrated to provide 194 mg of crude diacid.
The crude diacid (190 mg), prepared above, was reacted with acetic anhydride (10 mL) for 3 hours, at room temperature. The reaction mixture was concentrated in vacuo. The crude product was treated with methanol (10 mL) and triethylamine (.250 mL) for 16 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and 0.1 N HCI. The organic layer was dried over NaZS04, filtered and concentrated. The diastereomeric mixture of methyl esters (174 mg) was chromatographed on silica gel using (5-10%) methanol in chloroform and acetic acid (0.5%) to provide the title compound. (yield: 72 mg, 32%) 'H NMR (CD30D) 81.44 (s, 9H), 1.93 (s, 3H), 2.24 (m, 2H), 2.64 (m, 4H), 3.12 (m, 3H), 3.67 (s, 3H).
MS = (M+H)+ = 373.
_98_ Example 7 CH30-!~
AcHN OH
O
HCI NHZ
fit) (1 S 2S 3R 4R~-2-Aminomethyl-3-acetamidomethyl-4-methoxycarbonyl-cyclo-pentane-1-carboxylic Acid Hydrochloride.
A solution of (t)-(1 S,2S,3R,4R)-3-Acetamidomethyl-2-(N-t-butoxycarbonyl-amino)methyl-4-methoxycarbonylcyclopentane-1-carboxylic acid (62 mg, 0.16 mrnol) in of dichloromethane (4 mL) was reacted with trifluoroacetic acid (1.0 mL) for 1 hour, at room temperature. The solution was concentrated in vacuo, at 25 °C. The residue was treated with 1 N HCI and concentrated in vacuo to provide the title compound as a white solid (yield: 39 mg, 75 %).
' H NMR (D20) 81.95 (s, 3H), 2.22 (m, 1 H), 2.46 (m, 1 H), 2.71 (m, 2H), 2.83 (m, 1 H), 2.96 (q, 1 H), 3.10 (m, 2H), 2.31 (m, 2H), 3.72 (s, 3H).
MS : (M+H)+ = 273.
-99_ Example 8 St)-(1S 2S 3R 4R)-2-N-t-Butoxycarbonylamino-3-(acetamidomethyl}-4-carbamoyl-c rclopentane-1-carboxylic Acid.
AcHN OCH3 O
NHBoc 8A. (t~~1 S 2S 3R 4R)-2-N-t-Butoxycarbonyiamino-3 ~acetarnidomethyl)-4-carbamoyl-cyclo~entane-1-carboxylic Acid Methyl Ester.
The title compound was prepared ih two steps starting by reacting (t)-(1 S,2S,3R,4R)-2-(N-t-butyloxycarbonylamino)-3-(acetamidomethyl)-cyclopentane-1,4-dicarboxylic acid in place of (t)-(1 S,2S,3R,4R)-2-(t butyloxycarbonylamino)-3-(acetamidomethyl)-cyclopentane-1,4-dicarboxylic acid, according to the method described in Example 4H, and substituting anhydrous liquid ammonia for methanol and triethylamine.
In the second step the crude product (54 mg, 0.16 mmole), prepared above, in 4 ml of THF was cooled to 0 °C and treated with an ethereal solution of CHZN2 until the yellow reaction color persisted. The reaction mixture was warmed slowly to room temperature and concentrated in vacuo to provide a colorless oil. Purification using flash chromatography eluting with 5%
methanol/chloroform provided the title compound as a white solid (yield: 16 mg, 28%).
'H NMR (CDC13) 51.43 (s, 9H), 1.90 (s, 3H), 2.03 (m, 1 H), 2.24 (m, 1 H), 2.65 (m, 4H), 3.68 (s, 3H), 4.30 (m, 2H).
MS: (M+H)+ = 358.
O
HZN~/
AcHN OH
~'If NHBoc 8B. ~t~~1S 2S,3R 4R)-2-N-t-Butox)rcarbonYlamino-3-(acetamidomethyl)-4-carbamoyl-cyclopentane-1-carboxylic Acid.
A solution of (t)-(1 S,2S,3R,4R)-2-N-t butoxycarbonylamino-3-(acetamido-methyl)-4- carbamoyl-cyclopentane-1-carboxylic acid methyl ester (16 mg, 0.045 mrnole) in 0.2 ml methanoI/H20 (3:1 ) was treated with (1 mg, 0.045 mmole) of LiOH. After stirring at room temperature overnight, the reaction mixture was quenched with 5% HCI and extracted 3 times with ethyl acetate. The combined extracts were dried over Na2SOa, filtered and concentrated in vacuo to provide the title compound as a white solid (yield: 11 mg, 73%).
'H NMR (methanol-d4) 81.44 (s, 9H), 1.91 (s, 3H), 2.02 (m, 1H), 2.24 (m, 1 H), 2.60 (m, 5H), 4.32 (m, 1 H), 6.90 (br d, 1 H).
MS (M-H)- = 342.
Example 9 ~t)-(1S,2S,3R.4R)-2.3-Acetamidomethyl-4-methoxycarbon r~yclopentane-1-carboxylic Acid.
Ac0 OAc 9A. (t)-exo-exo-2.3-diacetoxymethyl-bi~clo[2.2.1Lept-5-ene.
(t)-exo-exo-2,3-dihydroxymethyl-bicyclo[2.2.1]hept-5-ene was treated with acetic anhydride and triethylamine in dichloromethane. Standard workup provided the title compound.
MS: (M+H)+ = 329.
O
CH30-!~
Ac0 OCH3 .,,, OAc 9B. Lt)-(1 S 2S.3R 4R~-2.3-Diacetoxymethylcyclopentane-1,4-dicarboxylic Acid Dimethvi Ester.
The title compound was prepared according to the method described in Example 6B, substituting (t)-exo-exo-2,3-diacetoxymethylbicyclo[2.2.1]hept-5-ene (1 g, 4.2 mmol) in place of (t)-(2R,3S)-2-acetoxymethyl-3-benzyloxymethyl-bicyclo[2.2.1]hept-5-ene. Purification, using flash chromatography eluting with 50% ethyl acetate/hexanes, provided the title compound as a colorless oil.
(yield:
0.8 g, 58%).
' H NMR (CDC13) 62.05 (s, 6H), 2.29 (m, 2H), 2.79 (m, 4H), 3.72 (s, 6H), 4.14 (m, 4H).
MS: (M+H)+ = 331.
O
CH30-l~
OH
9C. fit)-~1S 2S 3R 4R~2 3-DihYdroxymet~fcyclopentane-1.4-dicarboxylicAcid Dimethyl Ester.
A solution of (t)-(1S,2S,3R,4R)-2,3-diacetoxymethylcyclopentane-1,4-dicarboxylic acid dimethyl ester (5.0 g, 0.015 mole) in 60 ml of methanol was treated with a catalytic amount of K2C03. The reaction mixture was stirred, under a nirogen amosphere, at room temperature, for 16 hours. The reaction mixture was diluted with ethyl acetate and quenched with 5% HCI. The organic layer was separated, dried over Na2S04, filtered, and concentrated in vacuo, at 30 °C to provide the title compound as a colorless oil. (yield: 3.3 g, 89%) 'H NMR (CDC13) 82.06 (m, 1H), 2.29 (m, 2H), 2.54 (m, 3H), 2.80 (m, 2H), 3.67 (m, 8H).
MS: (M+H)+ = 247.
CH30-J~
Ms0 OCH3 ..,, OMs 9D. ~f)-(1 S.2S.3R.4R)-2.3-Dimethansulfonyloxymeth rLlcyclopentane-1.4-di-carbox~rlic Acid Dimethyl Ester.
A solution of (t)-(1 S,2S,3R,4R)-2,3-dihydroxymethylcyciopentane-1,4-dicarboxylic acid dimethyl ester (200 mg, 0.81 mmole) in 4 ml of THF and 4 ml of dichloromethane was cooled to -30 °C and treated with methanesulfonyl chloride (0.19 mL, 2.4 mmole) followed by dropwise addition of triethylamine (0.34 mL, 2.4 mmole). After 30 minutes of stirring under a nirogen amosphere, at -30 °C, the mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over Na2S04 , filtered and concentrated in vacuo to provide the title compound as a colorless oil (yield: 302 mg, 93%).
'H NMR (CDC13) b 62.16 (m, 1 H), 2.45 (m, 1 H), 2.87 (m, 4H), 3.06 (s, 6H), 3.72 (s, 6H), 4.38 (m, 4H).
MS: (M+H)+ = 403.
O
CH30-l~
~'I~
9E. (t)-(1 S 2S 3R 4R~-2 3-Diazidometh~-cyclopentane-1 4-dicarboxylic Acid Dimeth~ Ester.
A solution of (t)-(1 S,2S,3R,4R)-2,3-dimethansulfonyloxymethyl-cyclopentane-1,4-dicarboxylic acid dimethyl ester (300 mg, 0.75 mmole) in 3 mL
of DMF was treated with LiN3 (400 mg, 8.2 mmole) and heated to 100 °C
under a nitrogen amosphere. After heating for 1 hour, the reaction mixture was diluted with ethyl acetate and washed twice with water, brine, dried over Na2S04, filtered and concentrated in vacuo to provide the title compound as a copper colored oil (yield: 204 mg, 92%).
'H NMR (CDC13) 8 62.12 (m, 1 H), 2.37 (m, 1 H), 2.71 (m, 4H), 3.50 (m, 4H), 3.72 (m, 6H).
MS: (M+H)+ = 297.
O
CH30~~
AcHN OCH3 NHAc 9F. (t)-(1 S 2S 3R 4R)-2 3-Acetamidomethyl-cyclopentane-1 4-dicarboxylic Acid Dimethyl Ester.
A solution of (t)-(1S,2S,3R,4R)-2,3-diazidomethyl-cyclopentane-1,4-dicarboxylic acid dimethyl ester (145 mg, 0.49 mmole) in 2 ml of isopropyl alcohol was treated with Pd/C. The reaction mixture stirred vigorously overnight under a hydrogen atmosphere, at room temperature. The reaction mixture was filtered over Celite'~ and concentrated in vacuo to provide a pale yellow oil.
The crude product was then taken up in dichloromethane and treated with excess acetic anhydride and N,N-dimethylaminopyridine. The reaction mixture was stirred at room temperature for 1 hour before concentrating in vacuo to provide a pale yellow oil. Purification, by flash chromatography eluting with 10%
methanol/chloroform provided the title compound as a colorless oil (yield: 40 mg, 25%).
'H NMR (CDC13) X1.98 (s, 6H), 2.30 (m, 1H), 2.36 (m, 1H), 2.56 (m, 2H), 2.68 (m, 2H), 3.30~(m, 4H), 3.71 (s, 6H), 6.16 (br s, 2H).
MS: (M+H)* = 329.
O
CH30--l~
AcHN ,,,~~OH
NHAc 9F. ~(1S 2S 3R4R)-2 3-Acetamidomethyl-4-methoxYcarbonylcvclopentane-1-carboxylic Acid.
A solution of (t)-(1S,2S,3R,4R)-2,3-acetamidomethyl-cyclopentane-1,4-dicarboxylic acid dimethyl ester (100 mg, 0.33 mmole) in 1 m! of a mixture of methanoI/H20 (3:1 ) was treated with LiOH (16 mg, 0.66 mmole). After stirring for 1 hour, at room temperature, the reaction mixture was acidified with 5% HCI
and extracted three times with ethyl acetate. The organic extracts were dried over Na2S04, filtered and concentrated in vacuo to provide the diacid intermediate as a white solid (69 mg, 70%). The diacid was taken up in acetic anhydride (2 ml) and heated for 1 hour at 60°C. The reaction mixture was then concentrated in vacuo, taken up in 1 mL of methanol and treated with triethyl amine. The mixture was stirred at room temperature for 3 hours, under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate and washed 3 times with 5%
HCI.
The organic layer was dried over Na2S04 , filtered and concentrated in vacuo.
Purification, using flash chromatography, eluting with 20% ethyl acetate/hexanes with 1 % acetic acid provided the title compound as a white solid. (yield: 6 mg, 6%) 'H NMR (methanol-d4) 81.92 (d, J=3 Hz, 6H), 2.15 (m, 2H), 2.35 (m, 2H), 2.67 (m, 4H), 3.15 (m, 2H), 3.67 (s, 3H).
MS: (M+H)+ = 315.
Example 10 _{t)-(1S 2S 3R 4R~2-N-t Butoxycarbonylamino-3-Lacetamidomethyl)-4-N-methylcarboxamido-cyclopentane-1-carboxylic Acid and~t~1 R,2R.3S,4S)-3-N-t butoxycarbonylamino-2-{acetamidomethyl)-4-N-methylcarboxamido-cyclopent-ane-1-carboxylic Acid.
H3CHN-~~ HO-~~
AcHN OH AcHN NHCH3 O O
NHBoc NHBoc 10A. {t~1S 2S 3R 4R~2-N-t butox~carbonylamino-3- acetamidomethyl)-4-N-methylcarboxamido-cyclopentane-1-carboxylic Acid Methyl Ester and (t)-(1 R.-~R 3S 4Sy-3-N-t butoxycarbonylamino-2-(acetamidomethyl)-4-N-methylcarbox-amido-cvclopentane-1-carboxylic Acid Methyl Ester.
A solution of (t)-(1S,2S,3R,4R)-2-N-t butoxycarbonylamino-3-(acetamido-methyl)-4-N-methylcarboxamido-cyclopentane-1-carboxylic acid methyl ester and (t)-(1 R,2R,3S,4S)-3-N-t-butoxycarbonylamino-2-{acetamidomethyl)-4-N-methyl-carboxamido-cyclopentane-1-carboxylic acid methyl ester (1:1) (260 mg, 0.72 mmole) in 3 ml of dichloromethane was treated with hydroxybenzotriazole (1 equiv.), 1-(3-dimethyiaminopropyl)-3-ethylcarbodiimide (1.5 equivalents), and methylamine (5 equivalents). After stirring at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate and washed 3 times with 5%
HCI.
The organic layer was dried over Na2S04 , filtered and concentrated in vacuo to provide the title ester-amide compounds as a white solid. (yield: 111 mg, 42%) MS: (M+H)+ = 372.
O O
CH3N-~~ HO~
Ac0 OH Ac0 NHCH3 ~''I'~ ~'I~
NHBo NHBo 1 OB. (t)-(1 S 2S 3R 4R)-2-N-t Butoxycarbonylamino-3-(acetamidomethvl)-4-N-methylcarboxamido-cyclopentane-1-carboxylic Acid and ~t)~1 R,2SR,3S,4S)-3-N-t-butoxycarbonylamino-2 ~acetamidomethyl)-4-N-methYlcarboxamido-cyclopent-ane-1-carboxylic Acid.
A solution of the ester-amide mixture (125 mg, 0.34 mmole) prepared in Example 10A, in 1 ml of methanoI/H20 (3:1 ) was treated with LiOH (8 mg, 0.34 mmole). After stirring for 1 hour at room temperature, the reaction mixture was quenched with 5% HCI and extracted 3 times with ethyl acetate. The combined organic extracts were dried over Na2S04 , filtered and concentrated in vacuo to provide the title compound as a white solid. (yield: 85 mg, 70%) 1 H NMR (methanol-d4) 81.44 (br d, 18H), 1.91 (d, J=5 Hz, 6H), 2.00 {m, 2H), 2.20 (m, 2H), 2.60 (m, 6H), 2.72 (br s, 6H), 3.08 (m, 4H), 4.35 (m, 2H).
MS: (M+H)+ = 358.
Example 11 (t)-(1 S 2S 3R 4RZ 3-AcetamidomethYl-2 4-diamino-cyclopentane-1-carboxylic Acid Hydrochloride.
O O
CH30-l~ HO~~
Ns~,. ,~~~I~OH N3~,. .,, ~~OCH3 BocHN O BocHN rO
11A. (t)-y1S 2S 3R 4R)-2-(t-Butyloxycarbonylamino)-3-(azidomethyl)-4-meth-oxycarbonyl-cyclopentane-1-carboxylic Acid and (t)-(1 S 2S.3R.4R)-2-(t-butyl-oxycarbonylamino)-3-~azidomethyl)-1-methox~carbonyl-cyclopentane-4-carbox-ylic Acid.
The title compound was prepared, in two steps, first following the procedure described in Example 4G and 4H substituting (t)-(1S,2S,3R,4R)-2-(i-butyloxycarbonylamino)-3-(azidomethyl)-cyclopentane-1,4-dicarboxylic acid dimethyl ester ( 98 mg, 0.28 mmole) in place of (t)-(1 S,2S,3R,4R)-2-(t-butyloxycarbonylamino)-3-(acetamidomethyl)-cyclopentane-1,4-dicarboxylic acid dimethyl ester (yield: 76 mg, 79 %).
MS: '(M+H)+ = 343 O
CbzHN, H3C0-~~
N3 ,"~~I~OCHg N3 "'~NHCbZ
BocHN O BocHN
11 B. StL(1 S 2S 3S 4R)-2-(f-Butyloxycarbonylamino)-3-(azidomethyl)-4-benzyl-oxycarbonylamino-cyclo~entane-1-carboxylic Acid Methyl Ester and (t)-(1 R.2R.-3S 4S) 3 t ButYloxycarbon la~mino)-2-(azidomethyl)-4-benzvloxycarbonylamino-cyclopentane-1-carboxylic Acid Methyl Ester.
A solution of (250 mg,0.73 mmole) of the above mixture of regioisomers of methyl ester azide cycfopentanes, prepared in Example 11A, was treated with diphenylphosphorylazide, in 8 ml of toluene, Et3N, ( 0.2 mL) and 0.75 mL of benzyl alcohol, under a nitrogen atmosphere, and heated to 80 °C for 3 hours.
The reaction mixture was diluted with ethyl acetate and washed 3 times with 5%
HC1. The organic layer was dried over Na2SOa, filtered and concentrating in vacuo to provide a pale yellow oil. Purification using flash chromatography on silica gel eluting with 20% ethyl acetate/hexanes provided the title compounds (mixture of regioisomers) as a white solid (yield: 278 mg, 85%) MS: (M+H)+ = 448.
CbzHN, AcHN~,, ",~~~~OCH3 BocHN O
11 C. ft)~1 S 2S 3S 4R)-2-ff But~oxycarbonylaminoZ 3-(acetamido)methyl-4-benzyloxycarbonylamino-cyclo~pentane-1-carboxylic Acid Methyl Ester.
A solution of the methyl ester diastereomers (278 mg, 0.62 mmoie), prepared in Example 11 B, in 0.2 ml of thiolacetic acid was stirred under a nitrogen atmosphere at room temperature for 6 hours. The reaction mixture was concentrated in vacuo to provide a yellow oil. The crude oil was purified using flash chromatography, eluting with 50% ethyl acetatelhexanes to provide the title compound as a white solid. (yield: 70 mg, 24%) MS: (M+H)+ = 464.
WO 99/54290 PCTlUS99/07949 CbzHN, AcHN~,, O
BocHN O
11 D. ~t}-(1 S 2S 3S 4R)-2-~t Butylox~rcarbonylamino)-3-(acetamido)methyl-4-benzyloxycarbonylamino-cyclopentane-1-carboxylic Acid.
A solution of (t)-(1S,2S,3S,4R)-2-(t-butyloxycarbonylamino)-3-(acetamido)methyl-4-benzyloxycarbonylamino-cyclopentane-1-carboxylic acid methyl ester (70 mg, 0.15 mmole) in 1 mL of methanoI/H20 (3:1 ) was treated with (4 mg, 0.15 mmole) of LiOH. After stirring at room temperature for 2 hours the reaction mixture was quenched with 5% HCI and extracted 3 times with ethyl acetate. Standard workup, as described above, provided the title compound as a white solid (yield: 51 mg, 76%).
MS: (M+H)+ = 450.
H2N, AcHN OH
NH ,/'G 2 HC~
11 E. (rt)-(1 S 2S 3S 4R~-3-Acetamidomethyl-2 4-diamino-cyclopentane-1-car-boxylic Acid Dihrdrochloride A solution of (t)-(1 S,2S,3S,4R)-2-(t-butyloxycarbonylamino)-3-(acetamido)methyl-4-benzyloxycarbonylaminocyclopentane-1-carboxylic acid (51 mg, 0.11 mmole) in 0.2 ml of isopropyl alcohol and Pd/C was reacted under 1 atmosphere of hydrogen for 18 hours. The reaction mixture was filtered through Celite° and concentrated in vacuo to provide the title compound as a tan foam.
(yield: 30 mg, 86%) MS: (M+H)+ = 216.
Example 12 (t)-(1 R.2R,4R,1'S~-4-(1'-Acetamido-3'-ethy~pentyl-3-methoxycarbonyl-cKclopentane-1-carboxylic Acid.
12A. {t~exo,1'RS~and (endo.1'RS)-2-(~3-eth~rl-1-hydroxy~pentylbicyclo[2.2.1 jhept-5-ene.
1-bromo-2-ethylbutane (12.5 mL) and a catalytic amount of 1,2-dibromoethane were added to a suspension of 2.1 g Mg turnings in 200 mL of tetrahydrofuran. This mixture was heated to 50 °C for 2 hours, and cooled to -78 °C. A solution of 5.4 mL (t)-endo-2-formylbicyclo[2.2.1 jhept-5-ene, in 75 mL
tetrahydrofuran, was added dropwise to the Grignard solution. The mixture was warmed to 0 °C and stirred for 1 hour. The reaction was quenched by addition of 20 mL saturated ammonium chloride and ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate, filtered and the solvent is evaporated. The crude material was purified by flash chromatography using 10% ethyl acetate:hexanes (1:9) to provide the title compounds. (yield:
4.9 g, 53%) 'H NMR (CDC13) 8 0.78-0.91 (m, 6H), 1.15-1.50 (m, 11H ), 1.70-2.10 (m, 1 H), 2.60-2.95 {m, 2H), 2.95-3.55 (m, 1 H),6.0-6.2(m,2H), MS: (M+H)~' = 208.
12B. (t)-exo and endo-2-(1'-oxo-3'-ethyl)pentyl-bic~rcloL2.2.1]hept-5-ene.
A solution of of oxalyl chloride, (2.3 mL) in 100 mL dichloromethane, maintained at -78 °C, was treated dropwise with dimethyl sulfoxide, (4.0 mL).
The mixture was stirred under nitrogen for 20 minutes and a solution of (t)-(2S,1'R) and (2S,1'S)-2-(1'-hydroxy-3'ethyl)pentyl-bicyclo[2. 2.1]hept-5-ene (4.9 g) in 50 mL of dichloromethane was added. The mixture was stirred at -78 °C for 0.5 hours warmed to 0 °C for 15 minutes, treated with 16.4 mL
triethylamine at 0 °C and stirred for 10 minutes. Water (100 mL), at 25 °C, was added over 10 minutes. The organic layer was separated, washed with brine, dried over MgS04, filtered and the solvent evaporated. The crude ketone mixture was purified by flash chromatography using chloroform:hexanes (1:3) to provide the products (yield: 3.72 g, 77%}.
The ketone mixture prepared above (3.1 g, 14.9 mmole) was dissolved in 50 mL of methanol and combined with 22 mL of 1 M sodium methoxide. This mixture is heated to 70 °C for 18 hours. The solvent was evaporated and the residue dissolved in 300 mL ethyl acetate. The organic layer was washed with 100 mL of 0.5M HC1, brine, dried over magnesium sulfate, filtered, and the solvent is evaporated. The ketones were separated by flash chromatography using chloroform:hexanes (1:3) to provide title compound (t) (2R)-2-(3-ethyl-1-oxo)pentyl-bicyclo[2.2.1 Jhept-5-ene (yield: 0.99 g, exo ketone) (higher Rf) and (t) (2S)-2-(3-ethyl-1-oxo)pentyl-bicyclo[2.2.1]hept-5-ene (yield: 1.7 g, endo ketone, 87%).
~ H NMR (CDC13) 8 0.85 (2t, 6H), 1.19-1.42 (m, 7H ), 1.70-1.92 (m, 2H), 2.32-2.39 (m, 1 H), 2.39-2.47 (2d, 2H), 2.88-2.98 (d,2H), 6.10-6.17 (m, 2H).
12C. (t)-f2R)-2-(1-Hydroxyimino-3-ether pentyl-bicyclo(2.2.11heat-5-ene.
A solution of (t) (2R)-2-(1'-oxo-3'ethyl)pentyl-bicyclo[2.2.1]hept-5-ene (1.1 g, 5.4 mmole) in 45 mL methanol was reacted with hydroxylamine hydrochloride (1.5 g, 21.6 mmole) and 1 N NaOH (16.3 mL). This mixture was heated at 40 °C
for 2 days. The solvent was evaporated and the residue was partitioned between ethyl acetate and brine. The organic layer was dried over MgS04, filtered, and the solvent evaporated to provide the title compound (yield: 1.16 g, 97%).
~ H NMR (CDC13) 8 0.87 (2t, 6H), 1.24-1.40 (m, 8H ), 1.50 (d, 1 H), 1.65 (m, 1 H), 1.78 (m, 1 H), 2.15 (m,1 H), 2.35 (m, 2H), 2.90 (m,2H), 6.13 (m, 2H), 2.87(m, 1 H), 3.68 (s,3H), 3.85 (m, 1 H ) MS: (M+H)+= 222 HZN~, H
12D. ~)-(2R 1'S)-2-(1-Amino-3-ethyl)pentyl-bicyclof2.2.11hept-5-ene.
The crude (t)-(2R)-2-(1-hydroxyimino-3-ethyl)pentylbicyclo[2.2.1]hept-5-ene (0.49 g, 2.13 mmole), prepared in Example 12C, in 10 mL toluene, was treated with 1 M lithium aluminum hydride bis(tetrahydrofuran) (4.3 mL). The mixture was heated to 100 °C for 2 hours, under a nitrogen atmosphere.
The mixture was cooled to 0 °C, and consecutively combined with water (0.16 mL), 15% NaOH (0.16 mL), and water (0.49 mL). The solids were filtered, and the solution diluted with 150 mL ethyl acetate. The organic layer was washed with water, and brine, dried over MgS04, filtered and the solvent evaporated. The crude amines were separated by flash chromatography using ether:methanol:ammonium hydroxide (98:2:0.2) to provide the title compound, (t)-(2R,1'S)-2-(1-amino-3-ethyl)pentylbicyclo[2.2.1]hept-5-ene (yield: 79 mg), and the (t)-(2R,1'R)- isomer (77 mg) and 77 mg of a mixture of the amines overall yield 52%.
AcHN,,, H
12E. (t)-(2R 1'S)-2-(1-Acetamido-3-ethyl-)pentyl-bicYclo[2.2.1]hept-5-ene.
(t)-(2R,1'S)-2-(1'-amino-3'-ethyl-)pentyl-bicyclo[2.2.1]hept-5-ene (78 mg, 0.38 mmole) was dissolved in 3 mL dichloromethane . Triethylamine (0.16 mL) and acetic anhydride (0.07 mL) were added to the mixture. After 1 hour at 25 °C
the solvent was evaporated and the residue purified by flash chromatography using ethyl acetate:hexanes (1:4) to provide the title compound (yield: 78 mg, 83%).
~ H NMR (CDC13, 300 MHz) b 0.77-0.88 (m, 6H), 1.10-1.57 (m, 11 H ), 2.02 (s, 3H), 2.65 (s, 1 H), 2.84 (s, 1 H), 3.80-3.95 (m,1 H), 5.0-5.15(m, 1 H), 6.05 (s,2H).
MS: (M+H)+= 250.
12F (t)-(1 R 3R 4R 1'S)-4-(1-Acetamido-3-eth r~l pent~cyclopentane-1,3-Dicarboxylic Acid.
A solution of ruthenium tetroxide was prepared from 5.5 mg of ruthenium dioxide, suspended in carbon tetrachloride:acetonitriie (2:1 ), and 219 mg sodium periodate in 3 mL of water. The mixture was stirred 15 minutes at 0 °C.
A
solution of (t)-(2R,1'S)-2-(1'-acetamido-3'-ethyl)pentylbicyclo[2.2.1]hept-5-ene (64 mg, 0.256 mmol) in 1 mL of carbon tetrachloride was added to the ruthenium mature. The reaction mixture was allowed to warm to 25 °C and stirred for 3 hours. 1 M Sodium bicarbonate (2 mL) was added and the aqueous layer was separated and acidified with 5 mL 1 M HCI and extracted with ethyl acetate.
The organic layer was filtered through Celite~ and the solvents were evaporated in vacuo. The crude mixture was purified by flash chromatography using WO 99!54290 PC'T/US99/07949 methanol:dichloromethane :acetic acid (3:20:0.5) to provide the title compound (yield: 50 mg, 62%).
~ H NMR (CD30D) s 0.78-0.92 (2t, 6H), 1.14-1.47 (m, 7H ), 1.62-1.75 (m, 1 H), 1.92 (s, 3H), 1.95-2.03 {m, 1 H), 2.08-2.20 (m,1 H), 2.22-2.33 (m, 1 H), 2.35-2.49 (m,1 H), 2.58-2.68 (m, 1 H), 2.82-2.94 (m, 1 H), 3.83-3.95 (m,1 H),.
MS: (M+H)+= 314 CH30-f~
AcHN~,, .,,~~~OH
H O
12G. (t) (1R 3R 4R 1'S)-4-(1'-Acetamido-3'-ethyl)pentyl-3-methoovcarbonyl-~clopentane-1-carboxylic Acid.
(t)-(1 R,3R,4R,1'S)-2-(1-Acetamido-3-ethyl}pentylcyclopentane-1,3-dicarboxylic acid was reacted with acetic anhydride (0.1 mL), suspended in 3 mL
of chloroform, in a sealed tube, and heated to 70 °C for 3 hours. The solvents were evaporated and the residue was added to 1 mL of methanol and 0.1 mL of triethylamine, and heated for 1 hour, at 70 °C. The solvents were evaporated and the crude acidlester purified by flash chromatography using ethyl acetate:methanol:acetic acid (97:2:1) to provide of the mixture of acidlesters (yield: 30 mg, 57%). The two isomers were separated by preparative thin layer chromatography using ethyl acetate:methanol:acetic acid (97:2:1) to provide the title compound (yield: 6.9mg, 13%).
~H NMR (CD30D, 300 MHz) 8 0.83 (2t, 6H), 1.14-1.48 (m, 8H ), 1.67 (m, 1 H), 1.91 (s, 3H), 1.98 (m, 1 H), 2.11 (m,1 H), 2.25 (m, 1 H}, 2.42 {m,1 H), 2.62 (m, 1 H), 2.92 (m, 1 H), 3.68 (s,3H), 3.89 (m, 1 H ) MS: (M+H}+= 328 Example 13 ~1 R 3Rj4R 1'S)-3-Hydroxymetf~rl-4~1'-acetamido-3'-ethyl)pentyl-c~clopentane-1-carboxylic Acid.
CH30-l~ CH30 O - O
hi ~ H
O O
13A. (t)-1 R 2R 4'S) and (t)-(1 S 2S 4'S)-2~2 2-dimethKl-1,3-dioxolan-4-yl)-4-methylenecyclopentane-1-carboxylic Acid Methyl Ester.
A solution of 2-[(trimethylsilyl)methyl]-2-propen-1-yl-acetate (5 g, 26.9 mmole), methyl (S}-(+}-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-trans-2-propenoate (5 g, 26.9 mmole), Pd(OAc)2 {0.42 g, 1.8 mmole) and (i-Pr0)3P (2 mL, 8.1 mmole) in 27 mL of toluene was heated under an argon atmosphere for 24 hours. The reaction was cooled and concentrated in vacuo. The crude product was chromatographed on silica gel with 5-15% ethyl acetate in hexanes to provide the title compound (yield: 4.68 g, 73%}.
'H NMR {CDC13) 84.88 (m, 2H), 4.18-3.95 (m, 2H), 3.70 (s), 3.69 (s) [3H
overall], 3.68-3.55 (m, 1 H), 2.78-2.29 (m, 6H), 1.40 (s), 1.38 (s) [3H, overall], 1.34 (s), 1.32 {s) [3H, overall].
MS: (M+H)*=241.
OH
O H
13B. (1R 2R 4'S~-2-Hydroxymethyl-1-(2 2-dimethyl-1 3-dioxolan-4-yl)-4-methvlene-c~ciopentane Lithium aluminum hydride (0.63g, 16.6 mmole) was added to a solution of (1 R,2R,4'S) and (1 R,2S,4'S)-methyl 2-(2,2-dimethyl-1,3-dioxolan-4-yl)-4-methylene-cyclopentane-1-carboxylate (2.Og, 8.33 mmole) in 40 mL of THF
maintained at -78 °C. The reaction was allowed to warm to 0 °C
and stirred for 1 hour. The reaction was quenched (at 0 °C) by adding sequentially H20 (1.9 mL), 10% NaOH (2.8 mL), and H20 (2.8 mL). The reaction was allowed to warm to room temperature then dried over MgS04. The reaction was filtered and the solids were washed with ethyl acetate (200 mL). The filtrate was concentrated in vacuo to provide 1.83 g of the crude product mixture. Preparative HPLC on silica gel with (0-75%) ethyl acetate in hexanes provided the title compound (yield;
1.15 g, 65%).
' H NMR (CDC13) 84.84 (m, 2H), 4.21 (m, 1 H), 4.03 (dd, J=6, 8 Hz, 1 H), 3.64 (t, J=8 Hz, 1 H), 3.56 (m, 2H), 2.60-2.05 (m, 6H), 1.44 (s, 3H), 1.36 (s, 3H).
MS: (M+H)*=213.
OTBDPS
13C. (1R 2R 4'S)-2-(t-ButXldiphenylsilyloxymethy!)-1-(2 2-dimethyl-1,3-dioxolan-4-yl)-4-methylenecyclopentane A solution of (1 R,2R,4'S)-2-hydroxymethyl-1-(2,2-dimethyl-1,3-dioxolan-4-yl)-4-methylenecyclopentane (1.158, 5.4 mmole), t-butyldiphenylsilyl chloride (1.6 mL, 6.8 mmole) and imidazole (1.11g, 16.3 mmole) in 30 mL of dichlorornethane was stirred at room temperature for 1.5 hours. The reaction mixture was quenched with methanol (.2 mL) and stirred for 1 hour. The mixture was partitioned between ethyl acetate and 10% citric acid. The organic layer was washed with water and saturated NaHC03, dried over MgS04, filtered and concentrated to provide the title compound.
' H NMR (CDC13) 67.65 (m, 4H), 7.39 (m, 6H), 4.82 (m, 2H), 4.00 (m, 1 H), 3.89 (dd, J=6, 8 Hz, 1 H), 3.62-3.48 (m, 3H), 2.51-1.98 (m, 6H), 1.37 (s, 3H), 1.31 (s, 3H), 1.05 (s, 9H).
MS: (M+H)+= 451.
OTBDPS
HO
H
HO
13D. (1 R 2R 1'S~ 2-(t-Butyldiphen~silylox~meth~Z 1-(1 2-dihydroxy)ethyl-4-methylene-cyclopentane (1 R,2R,4'S)-2-(t-Butyldiphenylsilyioxymethyl)-1-(2,2-dimethyl-1,3-dioxolan-4-yl)-4-methylene-cyclopentane and pyridinium p-toluenesulfonate (0.68g, 2.7 mmole) in 110 mL of methanol were heated to 45 °C for 16 hours. The reaction was cooled, concentrated in vacuo and partitioned between dichloromethane and water. The organic layer was washed with brine, dried over MgS04, filtered and concentrated. The crude product was chromatographed on silica gel with 15%
ethyl acetate in hexanes to provide the title compound and recovered starting material (yield: 1.2 g, 54%).
'H NMR (CDC13) 87.65 (m, 4H), 7.39 (m, 6H), 4.81 (m, 2H), 3.75-3.46 (m, 5H), 2.54-1.89 (m, 6H), 1.06 (s, 9H).
MS: (M+H)+= 411.
OTBDPS
O_~.
H H
13E. ~1 R 2R) 2 (t-Butyldi~henylsi~lox rLmethyl)-1-formyl-4-methylene-cyclopentane A solution of (1R,2R,1'S)-2-(t-butyldiphenylsilyloxymethyl)-1-(1,2-dihydroxy)ethyl-4-methylene-cyclopentane (1.2 g, 2.92 mmole), Na104 (2.5 g, 11.6 mmole) in ethanol {4 mL) and water (4 mL) was stirred at 0 °C for 4 hours.
The reaction was diluted with ethyl ether (90 mL) and filtered through a celite pad.
The filtrate was concentrated in vacuo. The crude product was dissolved in toluene and concentrated in vacuo to azeotropically remove water. The reaction was redissolved in ethyl ether and filtered again followed by concentration to provide the title compound as a crude oil.
'H NMR (CDC13) 89.68 (d, J=3 Hz, 1H), 7.65 (m, 4H), 7.39 {m, 6H), 4.87 (m, 2H), 3.68 (dd, J=5, 10 Hz, 1 H), 3.56 {dd, J=7, 10 Hz, 1 H), 2.83-2.09 (m, 6H), 1.04 (s, 9H).
MS: (M+H)+= 379.
13F. {1 R 2R 1'R) 2 (t Butyldit~henylsi~loxYmethyl)-1-(3-ethyl-1-hydroxylpentyl-4-methylene-cyclopentane A 0.9 M solution of 2-ethylbutyl magnesium bromide (15.3 mL), prepared from 1-bromo-2-ethylbutane (3.8 mL, 27.1 mmole), magnesium (1 g, 41.6 mmole) and iodine (170 mg) in ethyl ether (30 mL) and stirred overnight at room temperature, was added to a solution of (1 R,2R)-2-(t-butyldiphenylsilyloxy-methyl)-1-formyl-4-methylene-cyclopentane (2.92 mmole) in ethyl ether (15 mL) at 0 °C for 20 minutes. The reaction was quenched with saturated ammonium chloride and stirred for 30 minutes. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSOa, filtrered and concentrated. The crude product was purified by preparative HPLC
on silica gel with (5-50%) ethyl acetate in hexanes to provide the title compound (yield: 0.7 g, 51 %).
' H NMR (CDC13) 87.65 (m, 4H), 7.39 (m, 6H), 4.80 (m, 2H), 3.79 (m, 1 H), 3.64 (dd, J=5, 10 Hz, 1 H), 3.56 (dd, J=7, 10 Hz, 1 H), 2.46-1.9 (m, 6H), 1.5-1.21 (m, 7H), 1.05 (s, 9H), 0.84 (t, J=8 Hz, 3H), 0.83 (t, J=8 Hz, 3H).
MS: {M+H)+= 465.
OTBDPS
13G. {1 R 2R 1'S~-1-jt-Butyldi~,henylsilyloxymethyl)-2-(3-ethyl-1-azido)pentyl-methylene-cyclopentane A solution of (1R,2R,1'R)-2-(t-butyldiphenylsiiyloxymethyl)-1-(3-ethyl-1-hydroxy)pentyl-4-methylene-cyclopentane (0.7g, 1.51 mmole), methanesulfonyl chloride (.25 mL, 3.23 mmole) and triethylamine {1 mL) in dichloromethane (15 mL) was stirred for 0.5 hours, at 0 °C. The reaction was quenched with saturated NaHC03 solution (3 mL) and then partitioned between ethyl acetate and 10%
citric acid. The organic layer was washed with saturated NaHC03 and brine, dried over MgS04, filtered and concentrated in vacuo to provide the intermediate mesylate. A solution of the crude mesylate and sodium azide (1g, 15.3 mmole) in dimethylformamide (15 mL) was reacted at 65 °C for 16 hours. The reaction was cooled and diluted with ethyl acetate. The organic layer was washed with water and brine, dried over MgS04, filtered and concentrated to provide the title compound.
'H NMR (CDC13) 87.66 (m, 4H), 7.39 (m, 6H), 4.81 (m, 2H), 3.64 (dd, J=6, Hz, 1 H), 3.52 (dd, J=7, 10 Hz, 1 H), 3.22 (m, 1 H), 2.58-2.0 (m, 6H), 1.48-1.11 (m, 7H), 1.05 (s, 9H), 0.86 (t, J=7 Hz, 3H), 0.80 (t, J=7 Hz, 3H) .
OTBDPS
AcH N.
w U W
H
13H. (1R 2R 1'S)-1-(t-Butyldiphenylsilyloxymethyl)-2-(1'-acetamido-3'-ethy~pentyl-4-methylene-c~clopentane A solution of the crude (1R,2R,1'S)-1-(t-butyldiphenylsilyloxymethyl)-2-(3-ethyl-1-azido)pentyl-4-methylene-cyclopentane (~1.5 mmole), prepared in Example 13G, and triphenylphosphine (1.39g, 5.3 mmole) in 20% H20 in THF (25 mL) was stirred at 75 °C for 16 hours. The reaction was cooled and concentrated in vacuo to provide the crude amine. The amine, acetic anhydride (.25 mL) and pyridine (.55 mL) in dichloromethane (13 mL) were stirred at room temperature for 2 hours. The reaction was quenched with methanol (2 mL) and stirred for an additional 1 hour. The reaction was diluted with ethyl acetate and washed sequentially with 10% citric acid, saturated NaHC03, and brine, dried over MgS04, filtered and concentrated. Chromatography on silica gel with 2.5 -10%-ethyl acetate in dichloromethane provided the title compound (yield: 0.404 g, 60%).
'H NMR (CDC13) 57.65 (m, 4H), 7.39 (m, 6H), 4.93 (d, J=10 Hz, 1H), 4.77 (m, 2H), 3.92 (m, 1 H), 3.60 (dd, J=6, 10 Hz, 1 H), 3.52 (dd, J=6, 10 Hz, 1 H}, 2.54-1.83 (m, 6H), 1.71 (s, 3H), 1.40-1.10 (m, 7H), 1.07 (s, 9H), 0.83 (t, J=7 Hz, 3H), 0.77 (t, J=7 Hz, 3H).
MS: (M+H)+= 506.
DPS
AcH N, .~~~I
OH
131. ~1 R 2R 4R 1'S)-1-(t-But~diphenylsilyloxymethyl)-2-(1'-acetamido-3'-ethyl) pentXl-4.-hydroxymethyl-cyclopentane A solution of (1R,2R,1'S)-1-(t-butyldiphenylsilyloxymethyl)-2-(1'-acetamido-3'-ethyl)pentyl-4-methylene-cyclopentane (50 mg, 0.1 mmole) and 2M borane dimethylsulfide complex, in THF ( 75 uL, 0.15 mmole) in THF (1 mL) was stirred at 0 °C for 7 hours. Water (0.1 mL) and 1 N NaOH (0.2 mL) were added and the reaction allowed to warm to room temperature. After 15 minutes, 30% hydrogen peroxide (2 mL) was added and the reaction was stirred for an additional 0.5 hour. The reaction was diluted with ethyl acetate washed with water (2X) and with brine. The organic layer was dried over MgS04, filtered and concentrated in vacuo. The crude product was purified by chromatography using preparative HPLC in silica gel using 0-15% ethyl acetate in dichloromethane to provide the title compound (yield: 22 mg, 42%).
'H NMR (CDC13) 87.65 (m, 4H), 7.43 (m, 6H), (m, H), 5.00 (d, J=10 Hz, 1 H), 3.84 (m, 1 H), 3.66-3.54 (m, 2H), 3.52 (d, J=7 Hz, 2H), 2.20-1.04 (m, 14H), 1.66 (s, 3H), 1.08 (s, 9H), 0.83 (t, J=7 Hz, 3H), 0.78 (t, J=7 Hz, 3H).
MS: (M+H)+= 524.
AcHN, _ .,,~('O
H OH
13J. (1 Ri3R 4R 1'S), 3-(t-ButyldiphenylsilyloxYmethyl)-4-(1'-acetamido-3'-eth r~l pentyl-cyclopentane-1-carboxylic Acid A solution of (1R,2R,4R,1'S) 1-(t-butyldiphenylsilyloxymethyl)-2-(1'-acetamido-3'-ethyl) pentyl-4-hydroxymethyl-cyclopentane (22 mg, 0.042 mmole) and pyridinium dichromate (100mg, 0.26 mmole) in N,N-dimethylformamide (0.75 mL) was stirred at room temperature for 48 hours. The reaction was partitioned between ethyl acetate and 10% citric acid. The organic layer was separated and washed with brine, dried over MgSOa, filtered and concentrated to provide the title compound, which was used without further purification.
OH
AcH N, _ ..,,.1 0 H v OH
13K. (1 R 3R 4R 1'S) 3-Hydroxymethyl~-(1'-acetamido-3'-ethyl) oentyl-~clopentane-1-carboxylic Acid A solution of (1R,3R,4R,1'S) 3-(t-butyl-diphenylsilyloxymethyl)-4-(1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carboxylic acid from 1 L and 1 M
tetrabutylammonium fluoride in THF (0.8 mL) in THF (2 mL) was stirred for 16 hours at room temperature. The reaction was partitioned between ethyl acetate and 10% citric acid. The organic layer was separated and washed with brine, dried over MgS04, filtered and concentrated in vacuo. The crude product was chromatographed using a C-18 reverse phase column with 10-25% acetonitrile in water to provide the title compound (yield: 6.6 mg, 52 %).
' H NMR (CD30D) 87.81 (d, J=10 Hz, 1 H), 3.88 (m, 1 H), 3.61 (dd, J=5, 11 Hz, 1 H), 3.38 (dd, J=8, 11 Hz, 1 H), 2.75 (m, 1 H), 2.19-1.00 (m, 13H), 1.95 (s, 3H), 0.87 (t, J=7 Hz, 3H), 0.83 (t, J=7 Hz, 3H).
MS. (M+H)+= 300.
Example 14 H
AcH N, OH
(1R 3R 4R 1'S) 3-Formyl-4~1'-acetamido-3'-ethvl)pentyl-cyclopentane-1-carbolic Acid.
A solution of (1R,3R,4R,1'S)-3-hydroxymethyl-2-(1'-acetamido-3'-ethyl)-pentyl-cyclopentane-1-carboxylic acid (34 mg, 0.11 mmole) and pyridinium dichromate (40 mg, 0.1 mmoie) in dichloromethane (1.5 mL) was stirred at room temperature for 0.5 hours. The reaction was partitioned between ethyl acetate and 10% citric acid. The organic layer was separated and washed with brine, dried over MgS(~4, filtered and concentrated. The crude product was chromatographed on a C18 column with 10-50% acetonitrile in water to provide the title compound.
Example 15 ~1 R 3R 4R 1'S) 3 (Imidazol 2 ~)-4 (1-acetamido-3-ethyl)pentyl-cvclopentane-1-carboxylic Acid OTBDPS
..
AcHN, OTrityl 15A. (1 R 2R 4R 1'S) 1 (t Butyldiphenylsilyloxymethyl)-2-(1'-acetamido-3'-ethy~pentYl-4-triphenylmethyloxymethyl-cyclopentane A solution of (1 R,2R,4R,1'S) 1-(t-butyldiphenylsilyloxymethyl)-2-(1-acetamido-3-ethyl)pentyl-4-hydroxymethylcyclopentane (0.357 g, 0.682 mmol) in pyridine (0.165 mL, 2.05 mmol) and dichloromethane (2 mL) was reacted with trityl chloride (0.248 g, 0.89 mmol) and DMAP (16.3 mg, 0.13 mmol) at room temperature for 16 hours. The reaction was partitioned between ethyl acetate and 10% citric acid. The organic layer was separated and washed with brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 2% methanoildichloromethane to provide the title compound (yield: 0.5 g, 95%).
' H NMR (CDC13) s 7.62 (m, 4H), 7.4 (m, 12H), 7.23 (m, 9H), 3.57 (s, 2H), 2.96 (s, 2H), 2.26 (m, 1 H), 1.97 (m, 2H), 1.62 (m, 3H), 1.52 (s, 3H), 1.25-1.5 (m, 7H), 1.06 (s, 9H), 0.83 (br s, 6H).
MS: (M+Na)+ = 788 OH
AcH N, OTrityl 15B. ;~R 2RL4R 1'S)-1-Hydroxymethyl-2-y1'-acetamido-3'-ethvllpentyl-4-triphenylmethyloxy~meth~lc~clopentane The title compound was prepared according to the method described in Example 13K substituting (1R,2R,4R,1'S)-1-(t-butyldiphenylsilyloxymethyl)-2-(1'-acetamido-3'-ethyl)pentyl-4-(triphenylmethyloxy)methyl-cyclopentane for (1R,3R,4R,1'S) 3-(t-butyldiphenylsilyloxymethyl)-4-(1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carboxylic acid (yield: 0.33 g, 98%).
'H NMR (CDC13) b 7.42 (m, 6H), 7.26 (m, 9H), 5.59 (d, 1 H), 3.86 (m, 1 H), 3.6 (2d, 1 H), 3.42 (2d, 1 H), 3.95 (2d, 2H), 2.25 (m, 1 H), 1.95 (s, 3H), 1.7-2.02 (m, 2H), 1.5-1.7 (m, 4H), 1.1-1.5 (m, 9H), 0.83 (2t, 6H) MS: (M-H)- = 526, (M+35)- = 562; (M+Na)+ = 550 O
H ~/
AcH N, H .~~~~I
OTrityl 15C. (1 R 2R 4R 1'S)-1-Form-5-~1'-acetamido-3'-ethyl)pentyl-3-(triphenylmethyloxy)methyl-c rLclopentane The title compound was prepared according to the method described in Example 13L substituting (1 R,2R,4R,1'S)-1-hydroxymethyl-2-(1'-acetamido-3'-ethyl)pentyl-4-(triphenylmethyloxy)methyl-cyclopentane for (1 R,3R,4R,1'S)-3-hydroxymethyl-4-(1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carboxylic acid (yield: 0.3 g, 91 %).
H NMR (CDCI~) b 9.56 (d, 1 H), 7.42 (m, 6H), 7.27 (m, 9H), 5.13 (d, 1 H), 3.86 (m, 1 H), 2.94 (m, 2H), 2.72 (m, 1 H), 2.42 (m, 1 H), 2.16 (m, 2H), 1.90 (s, 3H), 1.1-1.7 (m, 10H), 0.83 (2t, 6H) MS: (M-H)- = 524 ~N
HN
AcHN, ~~~~~I
OTrityl 15D. (1 R 3R 4R 1'S)-3-(Imidazol-2-yl)-4-(1-acetarnido-3-ethyl)pentyl-1-(triphen I~e#h)rloxy)methyl-cyclopentane ( 1 R,3R,4R,1'S)-1-Formyl-2-(1'-acetamido-3'-ethyl)pentyl-4-(triphenylmethyloxy)methyl-cyclopentane (80 mg, 0.15 mmol) was reacted with ammonia and 40% glyoxal (0.264mL, 7.5 mmol) in methanol (7 mL) according the procedure of Rothenberg, A. and coworkers in Angew. Chem. Int. Ed. 1983, 22, p. 560 to provide the title compound (yield: 60 mg, 70%).
' H NMR (CDC13) 8 7.7 (d, 1 H), 7.42 (m, 7H), 7.27 (m, 9H), 5.72 (d, 1 H), 3.86 {m, 1 H), 3.2 (m, 2H), 3.08 (m, 2H), 2.54 (m, 1 H), 2.42 (m, 2H), 1.77 (s, 3H), 1.1-1.7 (m, 10H), 0.78 (2t, 6H).
MS: (M-H)- = 562, (M+35)- = 598; {M+H)+ = 564, (M+Na)+ = 586 ~N
HN~, AcHN, .~~~I
OH
15E. ~1 R 3R 4R 1'S}-3-~Imidazol-2-yl~-4-(1'-acetamido-3'-ethyt)pentyl-1-hydroxymeth~-c~clo~entane (1 R,3R,4R,1'S)-3-(Imidazol-2-yl)-4-(1'-acetamido-3-ethyl)pentyl-1-(triphenylmethyloxy)methyl-cyclopentane (60 mg, 0.106 mmol) was reacted with p-toiuenesulfonic acid monohydrate (61 mg, 0.32 mmol) in MeOH (1 mL) for 1 hour. The reaction was quenched with water (10 mL) and diluted with ethyl acetate (25 mL). The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 10% methanol/dichloromethane to provide the title compound (yield: 30 mg, 88%).
' H NMR (CDC13) 8 7.83 (d, 1 H), 7.2 (d, 1 H), 6.47 (d, 1 H), 3.86 (m, 1 H), 3.6 (m, 2H), 3.2 (m, 1 H), 2.61 (m, 1 H), 2.32 (m, 2H), 1.82 {m, 1 H), 1.72 (s, 3H), 1.62 (m, 2H), 1.1-1.4 (m, 7H), 0.78 (2t, 6H) MS: (M-H)- = 320, (M+35)- = 356; (M+H)+ = 322, (M+Na)+ = 344 N
~J..
AcHNH
_ ..,,~~0 H v OH
15F. {1 R 3R 4R 1'S)-3-(Imidazol-2-yl)-4-(1-acetamido-3-ethyl)pentyl-cyclopentane-1-carboxylic Acid The title compound was prepared according to the procedure described ing Example 13J substituting (1R,3R,4R,1'S)-3-(imidazol-2-yl)-4-(1-acetamido-3-ethyl)pentyl-1-hydroxymethylcyclopentane for (1 R,2R,4R,1'S) 1-(t-butyldiphenylsilyloxymethyl)-2-(1'-acetamido-3'-ethyl) pentyl-4-hydroxymethyl-cyclopentane (yield: 5.2 mg, 17%).
H NMR (dg-MeOH) 8 7.12 (br s, 2H), 3.92 (m, 1 H), 2.95 (m, 1 H), 2.42 {m, 1 H), 2.22 (m, 1 H), 1.96 (m, 1 H), 1.82 (m, 1 H), 1.72 (s, 3H), 1.15-1.45 (m, 7H), 0.82 (2t, 6H) MS: (M-H)- = 334, (M+35)- = 370; (M+H)+ = 33fi, (M+Na)+ = 358 Example 16 ~1R 3R 4R 1'SL~oxazol-5-yl)-4-(1'-acetamido-3'-ethyl)pentyl-cvclopentane-1-carboxylic acid N~O
U
AcH N, _ ..,,.1 0 H v OCHPh2 16A (1 R 3R 4R 1'S)-Diphenylmethyl 3-(oxazol-5-YI)-4-(1'-acetamido-3'-ethyl) pentylcyclopentane-1-carboxylate (1R,3R,4R,1'S)- Diphenylmethyl 3-formyl-4-(1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carboxylate is reacted with p-toluensulfonylmethylisocyanide following the procedure of van Leusen and coworkers in Tetrahedron Letters, 2369 (1977) to provide the title compound.
NCO
., AcHN, _ ..,,.1 0 H v OH
16B. (1 R.3R.4R 1'S)-3-(oxazol-5-yl)-4-(1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carbox~c acid (1 R,3R,4R,1'S)-diphenylmethyl 3-(oxazol-5-yt)-4-(1'-acetamido-3'-ethyl)pentyl-cyclopentane-1-carboxylate is reacted with anhydrous trifluoroacetic acid in dichloromethane concentration in vacuo provides the title compound.
Example 17 ~1R 3R 4R 1'S)-3-(N N-dimeth~carbamoyl~(1'-acetamido-3'-ethyl)pentyl-~clopentane-1-carboxylic Acid HO~~
AcH N, H v OCHPh2 17A (1 R 3R 4R 1'S)-Di~henylmethyl 3-carboxy-4~1'-acetamido-3'-ethyl)pentyl-c~rclo~~,entane-1-carboxylate The title compound is prepared according to the procedure described in Example 14J substituting (1R,3R,4R,1'S)-diphenylmethyl-3-hydroxymethyl-4-(1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carboxylate for (1 R,2R,4R,1'S) 1-(t-butyldiphenylsilyloxymethyl)-2-(1'-acetamido-3'-ethyl) pentyl-4-hydroxymethyl-cyclopentane H3C'~N~l/
AcHN, . ,~iO
H ,OCHPh2 17B (1 R 3Ri4R 1'S)-Diphenylmethyl 3-IN N-dimethylcarbamoyl)-4-(1'-acetamido-3'-ethyl)pentyl-cyclopentane-1-carboxylate (1R,3R,4R,1'S)- Diphenylmethyl 3-carboxy-4-(1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carboxylate is reacted with isobutyl chloroformate in the presence of N-methylmorpholine at 0°C. The intermediate activated ester is reacted with N,N-dimethylamine to provide the title compound.
H3C, AcHN, _ .,,.~0 H OH
17B (1 R~3R 4R 1'S)-3-(N N-dimethxlcarbamoyl)-4-(1'-acetamido-3'-ethyLpentyl-c rLclopentane-1-carboxylic Acid The title compound is prepared according to the procedure described in Example 16B substituting (1R,3R,4R,1'S)- diphenylmethyl-3-(N,N-dimethylcarbamoyl)-4-(1'-acetamido-3'-ethyl) pentyl-cyciopentane-1-carboxylate for (1R,3R,4R,1'S)-diphenylmethyl-3-(imidazol-2-yl)-4-(1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carboxylate.
Example 18 (1 R 3R 4R 1'SZ-3-propionvl-4-(1'-acetamido-3'-ethyl)pentyl-cyclopentane-1 carboxylic Acid ~OH
., AcH N, _ ..,,.ISO
H v OCHPh2 18A (1 R 3R 4R 1'S 1 "S~, and (1 R 3R 4R 1'S 1 "R)-Diphenylmethyl 3-(1-hydroxypropyl) 4-~1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carboxylate (1R,3R,4R,1'S)- Diphenylmethyl 3-formyl-4-(1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carboxylate is reacted with ethyl magnesium bromide in THF at 0°C. The reaction is quenched with aqueous ammonium chloride and partitioned between ethyl acetate and water. The organic layer is dried over MgS04, filtered, and concentrated in vacuo to provide the title compound.
~.!%
AcH N, O
_ H , OCHPhz 18B (1 R 3R 4R 1'S~ Diphen~methyl 3~ropionyl~1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carboxylate The title compound is prepared according to the procedure of Example 12B substituting (1R,3R,4R,1'S,1"S)- and (1R,3R,4R,1'S,1"R)-diphenylmethyl3-(1-hydroxypropyl)-4-(1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carboxylate for (t)-{2S,1'R) and (2S,1'S)-2-(3'ethyl-1'-hydroxy)pentyl-bicyclo[2.2.1]hept-5-ene.
WO 99/54290 PC'f/US99/07949 AcH N, OH
18C ,~1 R 3R 4R 1'S)-3-propionyl-4-,(1'-acetamido-3'-ethYl)pentyl-cyclopentane-1-carboxylic Acid The title compound is prepared according to the procedure described in Example 16B substituting (1R,3R,4R,1'S)-diphenylmethyl 3-propionyl-4-{1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carboxylate for (1 R,3R,4R,1'S)-diphenylmethyl 3-(imidazol-2-yl)-4-(1'-acetamido-3'-ethyl) pentyl-cyclopentane-carboxylate.
Example 19 (t)-(2R 3R 5R 1'S)-2-{1'-acetamido-3'-methyl)butyl-3-methoxycarbonyl-tetrahydrofuran-5-carboxylic acid ~~'To 19~t1-Bicyclo(2.2.1 ]hept-5-en-2-one In a three-necked flask equipped with a mechanical stirrer, a N2 inlet and an additional funnel, a solution of oxalyl chloride (2.0 M in dichloromethane, mL, 0.272 mole) in dichloromethane (250 mL) was cooled to -78 °C and a solution of DMSO (40 mL) in 40 mL of dichloromethane was added dropwise over 30 min. After stirring for 5 additional minutes, a solution of 5-norbornen-2-of (24 g, 0.218 mole) in 40 mL of dichloromethane was added dropwise. The solution was stirred for another 10 minutes and triethylamine (150 mL) was added over minutes. The mixture was then stirred for 10 minutes at -78 °C and allowed to warm up to 0 °C over 1 hour. Water (250 mL) was added. Following the separation of two layers, the organic layer was washed with 0.2 N HCI (4 x 200 mL) and brine (2 x 200 mL). After drying (MgS04), the solution was concentrated to about 80 mL. The residue was distilled with a 12" Vigreux column at reduced pressure to give the title compound b.p. 100-105 °C /15 mmHg, (yield:
20.1 g, 86%).
' H NMR (CDC13): 1.85 (dd, 1 H), 1.90-2.00 (m, 2H), 3.00 (brs, 1 H), 3.20 (b.s, 1 H), 6.01 (t, 1 H), 6.58 (t, 1 H).
HC~~O
H ~O
19~t)-exo exo-5 6-DihydroxYbicyclo~2 .2.1]heptan-2-one A solution of (t)-bicyclo[2.2.1]hept-5-en-2-one (10.8 g, 0.1 mole) and N-methyl morpholine oxide (12.7 g, 0.12 mole) in 300 mL of 90% THF-water was reacted with a solution of osrniurn tetroxide (2.5% wt in t-BuOH, 8.0 mL) for hours at ambient temperature. The solvents were evaporated and the resulting residue was dried in vacuo. The residue was then taken up in 100 mL of ethyl acetate, dried (MgS04) and filtered. The filtrate was passed through a short silica gel plug, eluting with ethyl acetate. Concentration gave the title compound as a thick oil (14.5 g) which was used directly for the next step.
p 19C (t)-exo exo-5 6-Dihydroxyacetonide-bicyclo[2.2.11heptan-2-one A solution of (t)-exo,exo-5,6-dihydroxybicyclo[2.2.1]heptan-2-one (14.5 g, crude) in 250 mL of 2,2-dimethoxypropane was cooled to 0 °C and p-toluensulfonic acid (125 mg) was added. The solution was stirred for 30 minutes when TLC indicated complete reaction. The solution was loaded on an aluminum oxide (neutral) column and eluted with 15-30% ethyl acetate in hexane, to give the title compound as a white solid (yield: 11.9 g, 65% for two steps).
MS (DCI-NH3): m/z 200 for (M+NH4), base peak.
1H NMR (CDC13): b 1.34 (s, 3H), 1.50 (s, 3H), 1.63-1.74 (m, 2H), 2.72-2.20 (m, 2H), 2.70-2.76 (m, 2H), 4.28 (d, 1 H), 4.34 (d, 1 H). '3C NMR (CDC13): 8 21.1, 25.3, 31.2, 39.4, 39.5, 55.3, 76.8, 81.2, 111.2, 214Ø Analysis: C~oH,403, calc.
65.92% C, 7.75% H;: found, 66.01 % C, 7.79% H.
19D ~t~-exo exo-6 7-dihydroxyacetonide-2-oxabicyclof3.2.11octan-3-one To a solution of (t)-exo,exo-5,6-dihydroxyacetonide-bicyclo[2.2.1]heptan-2-one (14.76 g, 0.081 mole) in 500 mL of dichloromethane was added NaHC03 (13.6 g, 0.16 mole). The mixture was cooled with a water bath and MCPBA (30.3 g, ~60%) was added portionwise over 30 minutes. The solution was then stirred for 2 hours at ambient temperature and washed with 10% aqueous NazS205 (500 mL), saturated NaHC03 solution (3 x 200 mL) and brine (3 x 200 mL). The organic solution was then dried (MgS04}, filtered and concentrated. The residue was loaded on an aluminum oxide (neutral) column for 30 minutes, then eluted with 10-25% ethyl acetate in hexane to give the title compound as a white solid (yield: 7.7 g, 50%) MS (DCI-NH3): mlz 216 for (M+NH4)+, base peak.
'H NMR (CDC13): 8 1.30 (s, 3H), 1.45 (s, 3H), 1.84 (d, 1H), 2.10-2.20 (m;
1 H), 2.48-2.56 (m, 2H), 2.80 (dd, 1 H), 4.56 (d, 1 H), 4.60 (s, 1 H), 4.70 (d, 1 H). '3C
NMR (CDC13): 23.79, 25.58, 29.17, 35.97, 36.51, 80.70, 82.49, 82.55, 83.24, 110.83, 167.95. Analysis: C~pH~4O4, cal. 60.59% C, 7.12% H; found, 60.52% C;
6.97% H.
O
O
O
19E t) exo exo-6 7-dihydroxyacetonide-4-exo-iodo-2-oxabicyclof3.2.11octan-3-one To a mixture of lithium bis(trimethylsilyl)amide (1.0 M in THF, 32.6 mL) and distilled THF (60 mL), cooled to -78 °C, was added a solution of (t)-exo,exo-6,7-dihydroxyacetonide-2-oxabicyclo[3.2.1]octan-3-one (5.87 g, 29.6 mrnol) in 60 mL
of THF over 30 minutes. After stirring for another 30 minutes, the solution was then cannulated into a flask containing a solution of iodine (8.3 g, 32.6 mmol) in 60 mL of THF cooled to -78 °C over 30 minutes. The resulting solution was stirred for another 10 minutes and quenched with 300 mL of 5% aqueous citric acid. The mixture was then extracted with ethyl acetate (3 x 100 mL). The combined ethyl acetate solution was washed with 10% aqueous Na2S203 solution (2 x 100 mL) and brine (2 x 200 mL), and dried (MgSOa). After filtration, the solution was evaporated and the residue chromatograhed on a silica gel column eluting with 15-25% ethyl acetate in hexane, to give a white crystalline solid (yield:
7.55 g, 79%).
MS (DCI-NH3): m/z= 342 for (M+NH4)'', base peak.
'H NMR (CDC13): a 1.30 (s, 3H), 1.45 (s, 3H), 1.55 (s, 1H), 2.12-2.20 (m, 1 H), 2.42 (d, 1 H), 2.80 (m, 1 H), 4.56 (d, 1 H), 4.54 (d, 1 H), 4.70 (m, 2H).
Analysis: C~pH~3IO4, cal. 37.06% C, 4.04% H, 39.15% I; found, 37.08% C, 3.98% H, 39.55% I.
O
0'~>~CO Me 19F ~-Methyl-exo exo-5 6-dihydroxyacetonide-2-oxabicyclof2.2.11heptane-3-exo-carboxylate.
To a solution of (t)-exo,exo-6,7-dihydroxyacetonide-4-exo-iodo-2-oxabicyclo[3.2.1]octan-3-one (7.55 g, 23.3 mmol) in 300 mL of methanol (pre-dried with 4 A sieves) was added K2C03 (3.54 g, 25.6 mmol). The mixture was stirred vigorously for 30 min. The undissolved potassium carbonate was removed by filtration and the filtrate was concentrated to dryness. The residue was triturated with ethyl acetate several times until complete extraction of the product (TLC). The ethyl acetate solution was then concentrated and directly chromatographed on a silica gel column eluting with 10-25% ethyl acetate in hexane, giving 4.86 g of the title compound as a white solid. Yield: 92.0%.
MS (DCI-NH3): m/z 246 for (M+NH4), base peak.
~ H NMR (CDC13): 8 1.30 (s, 3H), 1.45 (s, 3H), 1.62 (d, 1 H), 1.85 (d, 1 H), 2.82 (s, 1 H), 3.78 (s, 3H), 3.80 (s, 1 H), 4.20 (d, 1 H), 4.30 (d, 1 H), 4.40 (s, 1 H).
Analysis:C»H,605, calc.: 57.88% C, 7.07% H; found: 57.98% C, 7.10% H.
/' O~~'' O
O~~~CHO
19G (t)-exo-3-Form r~l-exo exo-5.6-dihydroxyacetonide-2-oxabicycloj2.2.1 Leptane To a well-stirred solution of (t)-methyl-exo,exo-5,6-dihydroxyacetonide-2-oxabicyclo[2.2.1]heptane-exo-3-carboxylate (0.82 g, 3.62 mmol) in 30 mL of anhydrous dichloromethane at -78 °C was added a solution of diisobutylaluminum hydride in toluene (1.0 M, 5.77 mL) dropwise. The mixture was then stirred at -°C for 1 hour and quenched with 2 mL of methanol and 15 mL of saturated aqueous sodium potassium tartrate solution. The mixture was then stirred vigorously and allowed to warm to ambient temperature over 1 hour. The phases were separated and the aqueous phase was extracted with Et20 (5 x 50 mL).
After drying, solvent removal gave the title compound as an oil (0.8 g) which was used directly for the next step.
o OH
19H ~,t)-(1'RS)-exo-3-(1'-hydrox~r-3'-methyl~butyl-exo.exo-5.6-dihYdroxyacetonide-2-oxabicyclo[2.2.1 ]heptane.
To a solution of (t)-exo-3-formyl-exo,exo-5,6-dihydroxyacetonide-2-oxabicyclo[2.2.1]heptane (0.99 g, 5.0 mmol) in 50 mL of anhydrous THF at -78 °C
was added a solution of isobutylmagnesium chloride (2.0 M in ether, 30 mL) dropwise over 30 minutes. The mixture was then allowed to warm up to ambient temperature over 2 hours and quenched with 100 mL of saturated aqueous NH4C1 solution. The solution was then extracted with EtzO (3x100 mL). The combined organic layers were washed with brine (3x100 mL) and dried. After filtration, evaporation of solvent gave title compound as an oil (1.28 g) which was used directly for the next step.
O
O
O
191 ~t)-exo-3-L'-oxo-3'-methYl)but~-exo exo-5 6-dihydroxyacetonide-2-oxabic~clof2.2.11he~tane A solution of oxalyl chloride (2.0 M in dichloromethane, 3.76 mL, 7.3 mmol) was mixed with 10 mL of anhydrous dichloromethane and the solution was cooled to -78 °C. A solution of DMSO (1.06 mL) in 10 mL of anhydrous dichloromethane was then added dropwise. After stirring for 10 minutes, a solution of (t)-(1'RS)-exo-3-(1'-hydroxy-3'-methyl)butyl-exo,exo-5,6-dihydroxyacetonide-2-oxabicyclo[2.2.1]heptane 01.28 g, 5.0 mmol) in anhydrous dichloromethane (10 mL) was added dropwise and the solution was stirred for another 10 minutes. Triethylamine (4.3 mL) in 10 mL of dichloromethane was then added. The mixture was then stirred at -78 °C for 2 hours and allowed to warm up to ambient temperature. The solution was washed with water (100 mL), 5% aqueous citric acid (100 mL), saturated NaHC03 (100 mL) and brine. After drying and concentration, the crude material was purified by flash chromatography on a silica gel column using 5%-20% ethyl acetate-hexane to give the title compound as a white solid, 0.65 g, 51% for three steps.
MS (DCI-NH3): mlz 272 for (M+NH4)+ base peak.
'H NMR (CDC13): b 0.84 (dd, 6H), 1.30 (s, 3H), 1.34, 1.38 (bd, 1H), 1.43 (s, 3H), 1.77, 1.82 (dd, 1 H), 2.10-2.10 (m, 1 H), 2.30-2.50 (dq, 2H), 2.86 (s, 1 H), 3.62 (s, 1 H), 4.16-4.20 (m, 1 H), 4.28-4.32 (bd, 1 H), 4.37 (s, 1 H).
Analysis: C~4H22O4, cal. 66.12% C, 8.72% H; found, 65.99% C, 8.58% H.
HO ~.", O
HO
O
19J (t)-exo-3-(1'-oxo-3'-methyl)butYl-exo exo-5 6-dihydroxy-2-oxabicyclof2.2.1 ]heptane.
(t)-exo-3-(1'-Oxo-3'-methyl)butyl-exo, exo-5,6-d ihydroxyacetonide-2-oxabicyclo[2.2.1]heptane (0.64 g, 0.25 mmol) was dissolved in 12.5 mL of methanol and 12.5 mL of 2M HCI. The solution was stirred at 60 °C for 2.5 hours.
After cooling to ambient temperature, the solution was partially concentrated and then extracted with ethyl acetate (4x50 mL). The combined ethyl acetate solution was washed with saturated aqueous NaHC03 solution (2x50 mL) and brine (2x50 mL), and dried. After filtration, removal of solvent gave the title compound as an off-white crystalline solid, (yield: 0.53 g, 98.0%).
MS (DCl-NHs): mlz 232 for (M+NH4)+, base peak.
' H NMR (CDC13): 8 0.92 (dd, 6H), 1.34, 1.44 (bd, 1 H), 1.77, 1.82 (dd, 1 H), 2.10-2.20 (m, 1 H), 2.30-2.45 (dq, 2H), 2.65 (d, 1 H), 2.74-2.80 (m, 2H), 3.72 (s, 1 H), 3.94-4.00 (m, 1 H), 4.00-4.05 (bd, 1 H), 4.24 (s, 1 H).
Me02C, O , p~~~''C02Me 19~t)-l2R 3R 5R)-Dimethvl 2-(1'-oxo-3'-methyl)butyltetrahydrofuran-3,5-dicarboxylate (t)-exo-3-( 1 '-Oxo-3'-methyl) b uty I-exo, exo-5 , 6-d i hyd roxy-2 oxabicyclo[2.2.1]heptane.(0.50 g, 2.3 mmol) was dissolved in a mixture of acetonitrile (6.5 mL), carbon tetrachloride (6.5 mL) and water (10 mL). To this solution was added sodium periodate (2.1 g, 10 mmol) and RuC13.H20 (10 mg).
The solution was stirred at ambient temperature for 3 hours and filtered to remove the solid. The filtrate was loaded on a short silica gel column, eluted with 5% methanol in ethyl acetate containing 5% acetic acid. The resulting crude diacid (yellow oil, 0.53 g) was dissolved in ethyl acetate (25 mL). N,N-diisopropylethylamine (1.73 mL, 12 mmol) and methyl iodide (2.98 mL, 46 mmol) were added and the mixture was stirred at 50 °C for 2 hours. The mixture was filtered to remove the solid and the filtrate was concentrated. The residue was purified by flash chromatography on a silica gel column eluting with 10-40%
ethyl acetate in hexane, giving the title compound as a colorless liquid (0.40g, 68.0%
for two steps).
MS (DCI-NH3): mlz 290 for (M+NH4)+, base peak.
' H NMR (CDC13): 8 0.92 (d, 3H, CH3), 0.93 (d, 3H, CH3), 2.19 (m, 1 H, H~), 2.40-2.60 (m, 4H, H6a, H6b, H3a, H3b), 3.30 (m, 1 H, H3), 3.75 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 4.65 (dd, 1 H, H5), 4.85 (d, 1 H, H2).
Me02C, HO'N O~w~COZMe 19L (t~-(2R 3R 5R -Dimethyl-2-(1'-N-hvdroxyimino-3'-methyl)butyl-tetrahydrofuran-3.5-dicarboxylate A solution of (t)-(2R,3R,5R)-dimethyl-2-(1'-oxo-3'-methyl)butyl-tetrahydrofuran-3,5-dicarboxylate(0.3 g, 1.09 mole), hydroxylamine hydrochloride (0.23 g, 3.3 mmol), diisopropylethylamine (0.57 mL, 3.3 mmol) and tetrabutylammonium iodide in 10 mL of methanol was stirred at 40 °C for 2 hours.
The solution was concentrated and purified directed on a 10-g silica gel cartridge, eluting with 30% ethyl acetate in hexane, giving the title compound as a mixture of cis and trans oximes.
MS (DCI-NH3): m/z 287 (M+H), 305 (M+NH4)+.
' H NMR (CDC13): 8 0.95-1.0 (m, 6H), 2.19 (m, 1 H), 2.40-2.60 (m, 4H,), 3.45 (m, 1 H), 3.65-3.80 (4 s, 6H), 4.50-4.60 (bs, 1 H), 4.70 (m, 1 H), 5.0 (bs, 1 H) MeO2C,, MeOZC, H N
Boc'N~,. ~ ~'''COZMe Boc' p)~'''C02Me 19M (t)-(2R 3R 5R 1'S) and (t)-{2R 3R 5R 1'R) Dimethyl 2-(1'-t butoxycarbonylamino-3'-methyl)but~-tetrah~drofuran-3 5-dicarboxylate.
A solution of (t)-(2R,3R,5R)-dimethyl-2-(1'-N-hydroxyimino-3'-methyl)butyl-tetrahydrofuran-3,5-dicarboxylate (0.27 g, 0.94 mmol) and Boc20 (2.11 mL, 10x) in 70 mL of isopropanol was hydrogenated with Raney Nickel at 4 atm of hydrogen for 15 hours. After concentration of the solution, separation on a silica gel column with 10% ethyl acetate in hexane gave (t)-(2R,3R, 5R,1'S) isomer (137 mg) and (t)-(2R,3R, 5R,1'R) isomer {176 mg).
(t)-(2R,3R, 5R,1'S) MS (DCI-NH3): mlz 374, 391, 317, 335.
'H NMR (CDC13): 0.9-0.95 (2d, 6H), 1.22-1.31 (m, 1H), 1.49 (s, 9H), 1.50-1.55 (m, 1 H), 1.62-1.75 (m, 1 H), 2.40-2.60 (m, 2H), 2.95-3.10 (m, 1 H), 3.70 (s, 3H), 3.75 (s, 3H), 4.20 (t, 1 H), 4.37 (bd, 1 H), 4.60 (dd, 1 H).
MHO2C,, ~N, ' ~.~~'C02Me O
19N (t)-(2R 3R 5R 1S)-Dimethyl 2-(1'-acetamido-3'-methyl)butvl-tetrahydrofuran-3.5-dicarboxylate.
A solution of (t)-(2R,3R, 5R,1'S) dimethyl 2-(1'-t-butoxycarbonylamino-3'-methyl)butyl-tetrahydrofuran-3,5-dicarboxylate (40 mg, 0.11 mmol).in 2 mL of 50% trifluoroacetic acidldichloromethane was stirred at ambient temperature for 1 hours. The solution was then evaporated to dryness. The residue was dissolved in 0.5 mL of dichloromethane. Acetic anhydride (104 mL, 10.0 eq.) and diisopropylethylamine {192 mL, 10.0 eq.) were added. After stirring for 2 hours, the mixture was directly loaded on a 5-g silica gel cartridge and eluted with 60%
ethyl acetate in hexane, giving the title compound as a solid (34 mg ,100%).
MS (DCI-NH3): mlz 316 (M+H) +, 333 (M+NH4)+
'H NMR (CDC13): b 0.9-0.95 (2d, 6H), 1.25-1.35 (m, 1H), 1.50-1.70 (m, 2H), 1.99 (s, 3H), 2.40-2.60 (m, 2H), 2.95-3.10 (m, 1 H), 3.70 (s, 3H), 3.75 (s, 3H), 4.20-4.40 (m, 2H), 4.60 (dd, 1 H), 5.30 (bd, 1 H).
MH02C,, ~N~ p~~~''C02H
O
190 (t)-(2R 3R~ 5R 1'S}-2-(1'-acetamido-3'-methy~butyl-3-methoxycarbonyl-tetrahydrofuran-5-carboxylic acid To a solution of (t)-(2R,3R,5R,1'S}-dimethyl 2-(1'-acetamido-3' methyl)butyl-tetrahydrofuran-3,5-dicarboxylate (32 mg, 0.1 mmol) in 1.0 mL of THF cooled to 0 °C was added a solution of LiOH (0.1 M, 1.0 mL) slowly dropwise. The solution was then stirred for 15 minutes and quenched with 1.0 mL of acetic acid. After extracting with ethyl acetate (3x1 mL), the organic solution was dried (MgS04) and purified on a 5-g silica gel cartridge, eluting with 0-20% methanol/ethyl acetate containing 5% acetic acid. The product obtained was further purified by recrystallization from ethyl acetate and isopropanol.
(yield:
22 mg, 71 %).
HRMS: C~4H24O6N, calculated: 302.1604, found: 302.1592.
'H NMR (CDC13): 8 0.9-0.95 (2d, 6H), 1.25-1.35 (m, 1H), 1.50-1.70 (m, 2H), 1.99 (s, 3H), 2.40-2.50 (m, 1 H), 2.60-2.70 (m, 1 H), 2.95-3.10 (m, 1 H), 3.70 (s, 3H), 4.10-4.40 (m, 2H), 4.60 (dd, 1 H), 5.30 (bd, 1 H). The relative stereochemistry was confirmed by the X-ray structure of a single crystal.
Example 20 MFi02C, /N, , ~~~~'C02t8u O
20A t~,-(2R 3R 5R 1'S~2 ~1'-Acetamido-3'-methyt)but~l-3-methoxycarbonyl-tetrahydrofuran-5-carboxylic Acid t-Bu I Ester.
To a solution of (t)-(2R,3R,5R,1'S)-2-(1'-acetamido-3'-methyl)butyl-3-methoxycarbonyltetrahydrofuran-5-carboxylic acid {25 mg, 0.08 mmol) in 1.0 mL
of dichloromethane was added a solution of tent-butyl 2,2,2-trichloroacetimidate (54 mg, 0.24 mmol) in 0.3 mL of cyclohexane. After cooling to 0 °C, 3 drops of boron trifluoride etherate was added. The mixture was stirred for another 40 minutes and quenched with 2 mL of 5% NaHC03 solution. After diluting with 10 mL of dichloromethane, the mixture was filtered to remove insoluble by-product WO 99!54290 PCT/US99/07949 and the organic phase was further washed with 5% NaHC03 solution, dried, arid concentrated. The residue was purified on a 5-g silica gel cartridge to give the title compound as an oil (26 mg) which was used directly for the next step.
Ho2c,, H
\ /N, , 0~ ~~'C02~Bu O
20B !t)-(2R 3R 5R 1'Sl-2-(1'-acetamido-3'-methyl)butyl-3-carboxyl-tetrahydrofuran 5-carboxylic acid t-Butyl Ester A solution of (t)-(2R,3R,5R,1'S)-2-(1'-acetamido-3'-methyl)butyl-3-methoxycarbonyl-tetrahydrofuran-5-carboxylic acid t-butyl ester (26 mg, 0.073 mmol) in 1.5 mL of THF was cooled to 0 °C and a solution of 0.1 N LiOH
(0.73 mL) was added. The mixture was allowed to warm up to ambient temperature over 90 minutes, then acidified to pH 2-3 with 1 N HCI and extracted with ethyl acetate. The combined ethyl acetate solution was dried and concentrated. The residue was purified on a 5-g silica gel cartridge to give the title compound (10 mg) as a solid.
MS (DCI-NH3): mlz 344 (M+H)+, 361 (M+NH4)+.
' H NMR (methanol-d4): 8 0.87, 0.89 (d, 3H), 0.92, 0.94 (d, 3H), 1.35-1.45 (m, 1 H), 1.47 (s, 9H), 1.50-1.70 (m, 2H), 1.92 (s, 3H), 2.30-2.37 (m, 1 H), 2.45-2.55 (m, 1 H), 2.90-2.97 (m, 1 H), 4.00-4.07 (m, 1 H), 4.20 (t, 1 H), 4.45 (dd, 1 H).
-Br O->., H
"N, O O
20C (t)-(2R 3R 5R 1'S~-2-~1'-acetamido-3'-methyl butyl-3-(1"-oxo-2"-bromo)ethyl-tetrahydrofuran-5-carbox~ic Acid t-Butyl Ester To a solution of (t)-methyl (2R,3R,5R,1'S)-2-(1'-acetamido-3'-methyl)butyl-3-carboxyl-tetrahydrofuran-5-carboxylic acid t-butyl ester (10 mg, 0.029 mmol) in 1.0 mL of THF, cooled to 0 °C, was added N-methyl morpholine (0.13 mL) and iso-butyl chloroformate (0.15 mL, 0.12 mmol). The mixture was stirred at 0 °C for 1 h. A solution of diazomethane generated from Diazald (0.21 g, 1.0 mmol) and KOH (0.8 g) in 2 mL of Et20 was then added via a syringe until the yellow color persisted. The solution was then stirred for 3 hours, washed with brine (2 x 2.0 mL) and dried (MgS04). Evaporation of solvent gave a yellow solid which was redissolved in 1.5 mL of dioxane. To this solution was added 48% HBr (aq.) solution (0.125 mL) and the mixture was stirred for 10 minutes. Saturated NaHC03 solution (0.5 mL) was then added slowly and the mixture was extracted with ethyl acetate (5 x 1.0 mL). The combined ethyl acetate solution was dried (MgS04), filtered and concentrated. Chromatography on a 5-g silica gel cartridge eluting with 60% ethyl acetate-hexane give the title compound (7.3 mg) as a solid which was used directly for the next step.
WO 99/54290 PC'T/US99/07949 H
/N
<N~..
H
~N~,. f O
20~t)-(2R 3S 5R 1'S)-2-(1'-acetamido-3'-methyl)bufirl-3-(imidazol-4-yl)-tetrahydrofuran-5-carboxylic Acid t-Butyl Ester To a vial containing (t)-(2R,3R,5R,1'S)-2-(1'-acetamido-3'-methyl)butyl-3-(1"-oxo-2"-bromo)ethyl-tetrahydrofuran-5-carboxylic acid t-butyl ester (7 mg, 0.014 mmol) and formamidine acetate (30 mg, excess) was added liquid ammonia (~2.0 mL). The vial was sealed and stirred at 45 °C overnight.
The ammonia was allowed to evaporate slowly. The residue was taken up in 5%
Na2C03 (aq. 1.0 mL) and extracted with ethyl acetate (4x1.0 mL). The combined ethyl acetate solution was dried and concentrated. The residue was chromatographed on a 2-g silica gel cartridge eluting with ethyl acetate to give the title compound as a solid (1.0 mg).
MS (APCI+): mlz 36fi (M+H)+, 310 (M-C4H9)+, base peak.
'H NMR (methanol-d4): 8 0.87, 0.89 (d, 3H), 0.95, 0.97 (d, 3H), 1.27-1.37 (m, 1 H), 1.47 (s, 9H), 1.42-1.67 (m, 2H), 1.84 (s, 3H), 2.10-2.17 (dt, 1 H), 2.77-2.87 (dt, 1 H), 3.50 (q, 1 H), 4.02-4.06 (m, 1 H), 4.16 (t, 1 H), 4.55 (t, 1 H), 7.34 (s, 1 H), 8.64 (s, 1 H).
H
/N~' \N
H
~N~,. Ol~.,,I~OH
IOI ,O
HCI
20~t)-(2R 3S 5R 1'S~l-~1'-Acetamido-3'-methyl}butyl-3-(imidazol-4-vl)-tetrahydrofuran 5-carboxylic Acid A solution of (t)-(2R,3S,5R,1'S)-2-(1'-acetamido-3'-methyl)butyl-3-(imidazol-4-yl}-tetrahydrofuran-5-carboxylic acid t-butyl ester (1.0 mg) in 1.0 mL
of 6N aqueous HCi was stirred for 1 h. The solution was then concentrated to give the title compound as a white solid (0.8 mg).
'H NMR (D20): a 0.81, 0.83 (d, 3H), 0.87, 0.89 (d, 3H), 1.30-1.58 (m, 4H), 1.84 (s, 3H), 2.10-2.22 (m, 1 H), 2.85-2.95 (m, 1 H), 3.58 (q, 1 H), 3.90-3.94 (m, 1 H}, 4.00-4.04 (m, 1 H), 4.20 (t, 1 H), 7.32 (s, 1 H), 8.64 (s, 1 H).
Example 21 ,~S 3R 4S 1'S)-3-(1'-Acetamido-3'-ethyllpentyl-4-vinyl-cyclopentane-1-carboxylic Acid AcH N, U
OTrity l 21A-(1 S,3R.4S,1'S)-3-(1'-acetamido-3'-ethyl-)pentyl-1-(triphen rLlmethylo~)methyl-4-vinyl-cyclopentane A solution of (1 R.2R,4R,1'S)-1-formyl-2-(1'-acetamido-3'-ethyl)pentyl-4-(triphenylmethyloxy)methyl-cyclopentane (60 mg, 0.11 mmol) prepared according to the method of Example 15C in THF (1 mL) was added to a mixture prepared from the reaction of methyltriphenylphosphonium iodide (69 mg, 0.17 mmol) and 2.5M n-BuLi/hexane (64 mg, 0.16 mmol) in THF (1 mL) for 2 hours at room temperature. After 1.5 hours, the reaction was partitioned between ethyl acetate and 10% citric acid. The organic layer was separated and washed with brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 3% methanolldichloromethane to provide the title compound (yield: 29 mg, 49%).
'H NMR {CDC13) a 7.52 (m, 6H), 7.24 (m, 9H), 5.64 (m, 1H), 4.84-5.04 {m, 3H), 3.98 (m, 1 H), 2.95 (m, 2H), 2.7 {m, 2H), 2.0 (m, 1 H}, 1.88 (m, 2H), 1.66 (m, 1 H), 1.56 (s, 3H), 1.1-1.5 (m, 9H), 0.83 (m, 6H).
MS: {M-H)- = 522, (M+35)- = 558; (M+Na)+ = 546.
= =.
AcHN, ~I~~~I
OH
21B. (1S 3R 4S 1'S~,3-vine-4-(1-acetamido-3-ethyl)pentyl-1-hydroxymethvl-~clo~entane The title compound was prepared according to the method described in Example 15E substituting (1S,3R,4S,1'S)-3-{1-acetamido-3-ethyl)pentyl-1-(triphenylmethyloxy)methyl-4-vinyl-cyclopentane for (1 R,3R,4R,1'S)-3-(irnidazol-2-yl)-4-(1'-acetamido-3'-ethyl)pentyl-1-(triphenylmethyloxy)methyl-cyclopentane (yield: 7 mg, 87%).
H NMR (CDC13) b 5.68 (m, 1 H), 4.84-5.05 (m, 3H), 3.98 (m, 1 H), 3.54 (2d, 2H), 2.4 (m, 1 H), 2.18 (m, 1 H), 1.92 (s, 3H), 1.1-1.5 (m, 1 OH), 0.83 {2t, 6H).
MS: (M+H)+ = 282, (M+18)+ = 299 -.
AcHN.
_ ..,..1 0 H v OH
21C. {1S 3R 4S 1'S)-3-(1-acetamido-3-ethyl-)pentyl-4-vinyl-cyclopentane-1-carboxylic Acid The title compound was prepared according to the procedure described in Example 13J substituting (1S,3R,4S,1'S) 3-(1-acetamido-3-ethyi)pentyl-1-hydroxymethyl-4-vinyl-cyclopentane for (1 R,2R,4R,1'S)-1-(t butyldiphenylsilyloxymethyl)-2-(1'-acetamido-3'-ethyl)pentyl-4-hydroxymethyl-cyclopentane (yield: 4.2 mg, 33%).
' H NMR (CDC13) a 5.65-5.78 (m, 1 H), 5.05 (d, 1 H), 5.02 (2d, 1 H), 4.92 (2d, 1 H), 3.99 (q, 1 H), 2.88 (m, 1 H), 2.43 (m, 1 H), 2.15 (m, 2H), 1.91 (s, 3H), 1.87 (m, 1 H), 1.71 (m, 1 H), 1.1-1.5 (m, 8H), 0.83 (2t, 6H) MS: (M-H)- = 294; (M+H)+ = 296, (M+Na)+ = 318 Example 22 (,tL(1 R 3R 4R 1'S)-3-N-methylcarbamoyl-4-(1'-acetamido-3'-ethyl)pentyl-cyclopentane-1-carboxylic Acid O
MeHN-~
AcHN.
H 'OH
The title compound was prepared according to the procedure described ing Example 12G substituting methylamine for methanol (yield: .029 g, 30%).
' H NMR (CD30D) 8 7.52 (d, 1 H), 3.78-3.90 (m, 1 H), 2.80-2.95 (m, 1 H), 2.71 (s, 3H), 2.46-2.50 (m, 2H), 2.09-2.24 (m, 2H), 1.87 (s, 3H), 1.59-1.72 (m, 1 H}, 1.10-1.49 (m, 7H), 0.82, 0.87 (2t, 6H).
MS: (M+H)+= 327, (M+NH4)+=344 Example 23 ~1 R 3R 4R 1'S) 3 (imidazol-4-yl)-4-~1'-acetamido-3'-methyl)butyl-cyclopentane-carboxylic Acid OTBDPS
AcH N, _ ..,,~('O
H v OH
23A. (1 R 3R 4R 1'S) 3-(t-Butyldiphenylsilyloxymethyl)-4-(1'-acetamido-3'-methyl)butyl-cycio~entane-1-carboxylic Acid.
The title compound was prepared by the methods described in Examples 13F-13J substituting isobutylmagnesium bromide for 3-pentylmagnesium bromide in Example 13F and substituting the resulting products in the subsequent steps.
' H NMR (d4-methanol) 8 7.68 (m, 4H), 7.42 (m, 6H), 3.88 (m, 1 H), 3.74 (2d, 1 H), 3.48 (2d, 1 H), 2.77 (m, 1 H), 2.15-2.27 (m, 2H), 1.68-2.05 (m, 3H), 1.80 (s, 3H), 1.5 (m, 1 H), 1.1-1.32 (m, 2H), 1.03 (s, 9H), 0.84 (2d, J=6.44 Hz, 6H).
MS: (M-H}- = 508; (M+H)+ = 510, (M+Na)+ = 532 OTBDPS
AcH N, ' O
_ H ,O a 23B. L1 R 3R 4R 1'S}-3-(t-Butyldi~henvlsilyloxyrnethYl)-4-(1'-acetamido-3'-methyl)butyl-cyclopentane-1-carboxylic Acid t-Butyl Ester.
(1 R,3R,4R,1'S)-3-(t-Butyldiphenylsilyloxymethyl)-4-(1'-acetamido-3'-methyl)butyl-cyclopentane-1-carboxylic acid (0.65 g, 1.27 mmol) was reacted with t-butyl trichloroacetimidate (1.36 mL, 7.56 mmol) in toluene at 100°C for 16 hours. The reaction was quenched with water (20 mL) and diluted with ethyl acetate {50 mL). The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 7% methanol/dichloromethane to provide the title compound (yield: 0.65 g, 90%).
' H NMR (d4-methanol) 8 7.65 (m, 4H), 7.4 (m, 6H), 3.88 (m, 1 H), 3.72 {2d, 1 H), 3.46 (2d, 1 H). 2.68 (m, 1 H), 2.12 (m, 1 H), 1.76-2.0 (m, 2H), 1.79 (s, 3H), 1.68 (m, 1 H), 1.48 (m, 1 H), 1.42 (s, 9H), 1.1-1.32 (m, 2H), 0.84 (2d, J=6.44 Hz, 6H).
MS: (M-H)- = 564, {M+35)- = 600; (M+H)+ = 566, (M+Na)+ = 588 OH
..
AcH N, H v O'Bu 23C. ~1 R 3R 4R 1'S)-3-H~droxymethyl-4-f~1'-acetamido-3'-methyl)butyl-cyclopentane-1-carbox rLlic Acid t-Butyl Ester The title compound was prepared according to the method described in Example 13K substituting (1R,3R,4R,1'S) 3-(t-butyldiphenylsilyloxymethyl)-4-(1'-acetamido-3'-methyl)butyl-cyclopentane-1-carboxylic acid t-butyl ester for (1 R,3R,4R,1'S)-3- (t-butyldiphenylsilyloxymethyl)-4-(1'-acetamido-3'-ethyl)pentyl-cyclopentane-1-carboxylic acid (yield: 0.35 g, 93%).
' H NMR (d4-methanol) 8 3.88 (m, 1 H), 3.58 (2d, 1 H), 3.35 {2d, 1 H), 2.7 (m, 1 H), 2.08 {m, 1 H), 1.95 (s, 3H), 1.94 (m, 1 H), 1.78 (m, 1 H), 1.5-1.7 (m, 3H), 1.43 (s, 9H), 1.2-1.4 (m. 2H), 0.9 (2d, J=6.44 Hz, 6H) WO 99/54290 PC'T/US99/07949 MS: (M-H)- = 326, (M+35)- = 362; (M+H)+ = 328, (M+Na)+= 350 O
H ~~
AcHN, O
'O a 23D. (1 R 3R 4R 1'S)-3-Form-4-(1'-acetamido-3'-meth~)butyl-cyclopentane-1-carboxylic Acid t-Butyl Ester The title compound was prepared according to the method described in Example 1 D substituting (1 R,3R,4R,1'S)-3-hydroxymethyl-4-(1'-acetamido-3'-methyl)butyl-cyclopentane-1-carboxylic acid t-butyl ester for (t)-{2R,3S)-2-(t-butyloxycarbonylamino)-3-hydroxymethylbicyclo(2.2.1]hept-5-ene (yield: 0.32 g, 92%).
' H NMR (d4-methanol) 8 9.5 (d, 1 H), 7.85 (d, 1 H), 3.88 (m, 1 H), 2.85 (m, 1 H), 2.62 (m, 1 H), 2.47 (m, 1 H), 2.05 (m, 2H), 1.91 (m, 1 H), 1.87 (s, 3H), 1.5-1.72 (m, 2H), 1.44 (s, 9H), 1.23-1.4 (m, 2H), 0.9 (2d, J=6.44 Hz, 6H).
MS: (M-H)- = 324; (M+H)+ = 326, (M+Na)+ = 348.
OH
O
AcHN, _ ..,,.1 0 H v OtBu 23E. (1 R 3R 4R 1'Sl-3-Carbox~-4-~'-acetamido-3'-methyl)butyl-cyclopentane-1-carboxylic Acid t-Butyl Ester A solution of (1R,3R,4R,1'S)-3-formyl-4-(1'-acetamido-3'-methyl)butyl-cyclopentane-1-carboxylic acid t-butyl ester (0.3 g, 0.93 mmol) and 2-methyl-2-butene (1.5 mL, 14.15 mmol) dissolved in t-BuOH (7.5 mL) and acetonitrile (7.5 mL) was reacted with a solution of NaCl02 (0.3 g, 3.31 mmol) and NaH2P04.H20 (0.3 g, 2.17 mmol) in water (6 mL) at 0 °C for 1 hour. The reaction was quenched with 10% aqueous NaZS203 and extracted with dichloromethane. The organic layer was washed with water and brine, dried (MgS04) and concentrated in vacuo. The residue was purified by chromatography on silica gel using 9%
methanol/dichloromethane to provide the title compound (yield: 0.286 g, 90.8%).
' H NMR (d4-methanol) b 3.86 (m, 1 H), 2.8 (m, 1 H), 2.7 (m, 1 H), 2.4 (m, 1 H), 2.22 (m, 1 H), 2.08 (m, 1 H), 1.97 (m, 1 H), 1.90 {s, 3H), 1.5-1.68 (m, 2H), 1.44 (s, 9H), 1.23-1.4 (m, 2H), 0.9 (2d, J=6.44 Hz, 6H).
MS: (M-H)- = 340, (M+35)- = 376; (M+H)+ = 342, (M+Na)+ = 364.
o--~:
AcH
N
, _ ..,,~~0 v H OtBu 23F. (1 R 3R 4R 1'S) 3-(2-Bromo-1-oxo ethyl~1-acetamido-3-methyl)butyl-cycloaentane-1-carboxylic Acid t-Bu I Ester (1 R,3R,4R,1'S)-3-Carboxyl-4-(1'-acetamido-3'-methyl)butyl-cyclopentane-1-carboxylic acid t-butyl ester (286 mg, 0.84 mmol) and N-methylmorpholine (111 pL, 1.01 mmol) in ether {15 mL) was reacted with isobutyl chloroformate {120 pL, 0.93 mmol) at 0°C for 45 minutes. To the reaction flask was cannulated a distilled diazomethane solution in ether prepared from the reaction of Diazald (2.4 g) in ether (60 mL) with a solution of potassium hydroxide (2.4 g) in ethanol (15 mL) and water (15 mL). The reaction was stirred for 8 hours at room temperature then diluted with ether. The organic layer was washed with brine, dried (Na2S04) and concentrated to give the intermediate diazo ketone. The diazoketone was reacted with 48% HBr {90 pL) in dioxane (10 mL) at 23°C for 45 minutes.
The reaction was quenched with water (50 mL) and diluted with ethyl acetate (200 mL). The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 20% ethyl acetatelhexane to provide the title compound (yield:
105 mg, 33%).
' H NMR (d4-methanol) 8 4.18 (2d, J=14.07 Hz, 2H), 3.8 (m, 1 H), 3.08 (m, 1 H}, 2.83 (m, 1 H), 2.48 (m, 1 H), 2.3 (m, 1 H), 2.07 (m, 1 H), 1.89 (s, 3H), 1.45 (m, 1 H), 1.5-1.7 (m, 2H), 1.15-1.4fi (m, 2H), 1.43 (s, 9H), 1.2-1.4 (m, 3H), 0.88 (2d, J=6.44 Hz, 6H).
MS: (M-H)- = 372; (M+H)+ = 374 HN~N
AcH N, _ .,..1 0 H v OtBu 23G. ~1R 3R 4R 1'S)-3~midazol-4-yl)-4-(1'-acetamido-3'-methyl)butyl-cyclopentane-1-carboxylic Acid t-Butyl Ester (1 R,3R,4R,1'S)-3-(2-Brorno-1-oxo)ethyl-4-( 1'-acetamido-3'-methyl)butyl-cyclopentane-1-carboxylic acid t-butyl ester (105 mg, 0.28 mmol) was reacted with formamidine acetate (0.52 g, 4.99 mmol) in liquid ammonia (5 mL) and heated at 45 °C in a sealed tube for 18 hours. The reaction was concentrated in vacuo. The residue was treated with aqueous NaHC03 and extracted with dichloromethane (5x20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 10% methanol in dichloromethane to provide the title compound as an oil {40 mg, 39%).
' H NMR(d4-methanol) s 7.57 (br s, 1 H), 6.81 (br s, 1 H), 3.93 (m, 1 H), 2.96 (m, 1 H), 2.7 (m, 1 H), 2.1-2.4 (m, 3H), 1.85 (m, 1 H), 1.72 (s, 3H), 1.48 (m, 1 H), 1.43 (s, 9H), 1.15-1.46 (m, 2H), 0.85 {2d, J=6.44 Hz, 6H).
MS: (M-H)- = 362, (M+35)- = 398; (M+H)+ = 364, (M+Na)+ = 386 HN~N
AcHN, _ ..,,~~0 H v IOH
HCI
23G. {1 R 3R 4R 1'S)-3-{imidazol-4-vl)-4-(1'-acetamido-3'-meth I)~ butyl-cyclo~entane-1-carboxylic Acid Hydrochloride (1R,3R,4R,1'S) 3-(imidazol-4-yl)-4-(1'-acetamido-3'-methyl)butyl-cyclopentane-1-carboxylic acid t-butyl ester (40 mg, 0.11 mmol) was reacted with 6N HCI (4 mL) for 1 hour. The reaction concentrated in vacuo to provide the title compound (yield: 37mg, 98%).
' H NMR (d4-methanol) b 8.83 (d, J=1.01 Hz, 1 H), 7.36 (d, J=1.01 Hz, 1 H}, 3.92 (m, 1 H), 3.18 (m, 1 H), 2.98 (m, 1 H), 2.49 (m, 2H), 2.22 (m, 1 H), 1.90 (m, 2H), 1.77 (s, 3H), 1.53 (m, 1 H), 1.41 (m, 1 H), 1.25 (m, 1 H), 0.86 (2d, J=6.45 Hz, 6H).
MS: (M-H}- = 306, (M+35)- = 342; (M+H)+ = 308, (M+Na)+ = 330 Example 24 (3R 4R 1'S)-4-(imidazol-2-yl)-3-(1'-acetamido-3'-ethyl)pentyl-cyclopent-1-ene-carboxylic Acid OTBDPS
O
= v H
24A f3R 4R 1'S)-3-(t-ButYldiphen rLlsilyioxymethyl)-4-(1'-azido-3'-ethyl)pentyl-~clopentan-1-one (3R,4R,1'S)-3-(t-Butyldiphenylsilyloxymethyl)-4-(1'-azido-3'-ethyl)pentyl-1-methylene-cyclopentane (0.4558, 0.93 mmol) was reacted with 4% osmium tetroxide in water (0.59 mL, 0.093 mmol) and sodium periodate (0.8 g, 3.73 mmol) in THF (15 mL) and water (3 mL) at room temperature for 3 hours. The mixture was filtered and the filtrate was diluted with ethyl acetate, washed with 10% Na2Sz03 solution, water, dried over MgS04, filtered, and concentrated in vacuo. Chromatography on silica gel using 10% ethyl acetate/hexane afforded the title compound (yield: 240 mg, 52%).
'H NMR (CDC13) 8 7.64 (m, 4H), 7.4 (m, 6H), 3.68 (m, 2H), 3.36 (m, 1H), 2.3-2.6 (m, 4H), 2.23 (2d, 1 H), 2.08 (m, 1 H), 1.16-1.52 (m, 6H), 1.05 (s, 9H), 0.78-0.88 (2t, J=7.12 Hz, 6H) MS: (M+18)+ = 509, (M+Na)+= 514 OTBDPS OTBDPS
Na,,, / Ns,,, H ~OTf H ~OTf 24B. ~3R 4R 1'S~-4-(t-Butyldiphe~IsilYloxymethy~-~1'-azido-3'-ethyl)pentyl-1-trifluoromethansulfonyloxy-cyclopent-1-ene and (3R,4R.1'S)-3-(t-Butyldiphenylsilyloxymethyl)-4-(,1'-azido-3'-ethyl)~entyl-1-trifluoromethansulfonyloxy-cyclopent-2-ene (3R,4R,1'S)-3-(t-Butyldiphenylsilyloxymethyl)-4-(1-azido-3-ethyl)pentyl-cyclopentan-1-one (230 mg, 0.468 mmol) was reacted with 1M lithium hexamethyldisilazide (1.17 mL) in THF (1 mL) at -78°C for 45 minutes.
The reaction mixture was treated with N-phenyltrifluoromethanesuifonimide (0.2 g, 0.56 mmol) and reacted at 0°C for 0.5 hour. The reaction was quenched with water (10 mL) and diluted with ethyl acetate (50 mL). The organic layer was washed with water, brine, dried over MgS04, filtered and concentrated in vacuo.
The residue was purified by chromatography on silica gel using 5% ethyl acetate/hexane to provide a mixture of the title compounds in a ratio of 3: 2 (yield:
280 mg, 96%).
'H NMR (CDC13) b 7.64 (m, 4H), 7.4 (m, 6H), 5.58-5.5 (m, 1H), 3.55-3.72 (m, 2H), 3.36 (m, 1 H), 2.7-2.83 (m, 2H), 2.3-2.47 (m, 2H), 1.16-1.5 (m, 6H), 1.05 (s, 9H), 0.78-0.9 (m, 6H) OTBDPS
hi O
24C. j3R 4R 1'S)-4-~-Butyldiphenylsilylox~methyl -~1'-azido-3'-ethyl)pentyl-cyclopent-1-ene-1-carboxylic Acid Methyl Ester and (3R.4R.1'S)-3-(t-Butyldiphenylsilyloxymethyl)-4- 1'-azido-3'-ethyl)pentyl-1-cyclopent-1-ene1-carboxylic Acid Methyl Ester Carbon monoxide was bubbled into a mixture consisting of (3R,4R,1'S)-4-(t-Butyldiphenylsilyloxymethyl)-3-(1'-azido-3'-ethyl)pentyl-1-trifluoromethansulfonyloxy-cyclopent-1-ene and (3R,4R,1'S)-3-(t-Butyldiphenylsiiyioxymethyl)-4-(1'-azido-3'-ethyl)pentyl-1-trifluoromethansulfonyloxy-cyclopent-1-ene (280 mg, 0.45 mmol), triethylamine (0.125 mL, 0.9 mmol), bis(acetato)bis(triphenylphosphine)palladium(II) (34 mg, 0.045 mmol) in DMF (4 mL) and methanol (2 mL) at 40°C for 2 hours. The reaction was quenched with water (10 mL) and diluted with ethyl acetate (50 mL).
The organic layer was washed with water, brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 5% ethyl acetate/hexane to provide the title compounds in a ratio of 3:
2 as a mixture (yield: 181 mg, 75%).
'H NMR (CDC13) 8 7.64 (m, 4H), 7.4 (m, 6H), 6.58-6.7 (2 br s, 1 H), 3.74 (br s, 3H), 3.25-3.62 {m, 3H), 2.7-2.95 (m, 2H), 2.22-2.49 (m, 2H), 1.16-1.5 (m, 6H), 1.05 (s, 9H), 0.78-0.9 (m, 6H) MS: (M+18)+ = 551, (M+Na)+ = 556 OTBDPS OTBDPS
.. ..
AcHN, ' / OCH3 AcHN, 1. ~ OCH
H O H O
24D. (3R 4R 1'S)-4-(t-Butyldiphen~yloxymeth~~1'-acetamido-3'-eth~l)pentyl-cyclopent-1-ene-1-carboxylic Acid Methy! Ester and (3R.4R,1'S)-3-(t-Butyldiphenylsilyloxymethyl)-4-(1'-acetamido-3'-ethyl~pentyl-cyclopent-1-ene-1-carboxylic Acid Methyl Ester A solution of the mixture of (3R,4R,1'S)-4-(t-butyldiphenylsilyloxymethyl)-3-(1'-azido-3'-ethyl)pentyl-1-trifluoromethansulfonyloxy-cyclopent-1-ene-1-carboxylic acid methyl ester and (3R,4R,1'S)-3-(t-butyldiphenylsilyloxymethyl)-(1'-azido-3'-ethyl)pentyl-1-trifluoromethansulfonyloxy-cyclopent-1-ene-1-carboxylic acid methyl ester (0.18 g, 0.33 mmol) in THF (12 mL) and water (3 mL) was reacted with triphenylphosphine {0.265 mg, 1.01 mmol) at 65°C for 4 hours.
The reaction mixture was concentrated in vacuo, redissolved in chloroform, dried over MgS04, filtered and concentrated in vacuo. The crude amine was reacted with acetic anhydride (64 ~L, 0.67 mmol) in pyridine (0.135 mL, 1.67 mmol) and dichloromethane (1 mL) at room temperature for 2 hours. The reaction was quenched with 10% citric acid solution (10 mL) and diluted with ethyl acetate (50 mL). The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 40% ethyl acetate/hexane to provide the title compounds (3R,4R,1'S)-4-(t-butyldiphenylsilyloxymethyl)-3-(1'-acetamido-3'-ethyl)pentyl-cyclopent-1-ene-1-carboxylic acid methyl ester (yield: 109 mg, 60%) and (3R,4R,1'S)-3-(t-butyldiphenylsilyloxymethyl)-4-(1'-acetamido-3'-ethyl)pentyl-cyclopent-1-ene-1-carboxylic acid methyl ester (yield: 37mg, 20%).
(3R,4R,1'S)-4-(t-butyldiphenylsilyloxymethyl) 'H NMR (CDC13) 8 7.63 (m, 4H), 7.4 (m, 6H), 6.58 (s, 1 H), 4.95 (br s, 1 H), 4.0 (br s, 1 H), 3.73 (s, 3H), 3.57 (d, 2H), 2.72 (m, 2H), 1.78 (s, 3H}, 1.47 (m, 3H), 1.18 (m, 3H), 1.06 (s, 9H), 0.74-0.88 (2t, J=7.12 Hz, 6H) MS: (M-H)- = 548, (M+35)- = 584; (M+H)+ = 550, (M+Na)+ = 572 (3R,4R,1'S)-3-(t-butyldiphenylsilyloxymethyl) 'H NMR (CDC13) 8 7.63 (m, 4H), 7.4 (m, 6H), 6.64 (d, 1 H), 4.72 (d, 1 H), 3.95 (m, 1 H), 3.74 (s, 3H), 3.73 (2d, 1 H), 3.57 (2d, 1 H), 2.9 (m, 1 H), 2.75 (m, 1 H), 2.3 (m, 1 H), 2.14 (m, 1 H), 1.71 (s, 3H), 1.45 (m, 3H), 1.18 (m, 3H), 1.05 {s, 9H), 0.72-0.86 (2t, J=7.12 Hz, 6H) MS: (M-H)- = 548, (M+35)- = 584; (M+H)+ = 550, (M+Na)+ = 574 OH
..
AcHN, H O
24E. ~3R 4R 1'S~-4-hydroxymethyl-3-f1'-acetamido-3'-ethyl)pentyl-cycloaent-1-enel-carbox~ic acid methyl ester The title compound was prepared according to the method described in Example 13K substituting (3R,4R,1'S)-4-(t-butyldiphenylsilyloxymethyl)-3-(1-acetamido-3-ethyl)pentyl-1-trifluoromethansulfonyloxy-cyclopent-1-ene-1-carboxylic acid methyl ester for (1R,3R,4R,1'S)-3-(t-butyldiphenylsilyloxymethyl)-4-(3-ethyl-1-acetamido)pentyl-cyclopentane-1-carboxylic acid (yield: 53 mg, 85%).
' H NMR (CDC13) 8 6.63 (m, 1 H), 5.49 (d, 1 H), 3.98 {m, 1 H), 3.74 (s, 3H), 3.5-3.7 (m, 2H), 2.87 (m, 1 H), 2.75 (m, 1 H), 2.2-2.4 (m, 2H), 1.99 (s, 3H), 1.17-1.48 (m, 8H), 0.78-0.87 {2t, J=7.12 Hz, 6H) MS: (M-H)- = 310, (M+35)- = 346; (M+H)+ = 312, (M+Na)+ = 334 24F. {3R 4R 1'SZ-4-formvl-3-~-acetamido-3-ethyl)pentyl-cycioaent-1-ene-1-carboxylic acid methyl ester The title compound was prepared according to the method described in Example 1D substituting (3R,4R,1'S)-4-hydroxymethyl-3-(1'-acetamido-3'-ethyl)pentyl-cyclopent-1-ene-1-carboxylic acid methyl ester for (t)-(2R,3S)-2-(t-butyloxycarbonylamino)-3-hydroxymethyl-bicyclo[2.2.1 ]hept-5-ene (yield: 38 mg, 72%).
' H NMR (CDC13) a 9.71 (s, 1 H), 6.62 {m, 1 H), 5.2 (d, 1 H), 4.06 (m, 1 H), 3.75 (s, 3H), 3.25 (m, 1 H), 3.1 (m, 1 H), 2.96 (m, 1 H), 2.83 (m, 1 H), 1.96 (s, 3H), 1.2-1.5 (m, 8H), 0.77-0.9 (2t, J=7.12 Hz, 6H) MS: (M-H)- = 308; (M+H)+ = 310 / N
~J.;
AcHNH / O
U
24G. ~3R 4R 1'S)-4~imidazol-2-yl)-3-(1'-acetamido-3'-eth rLl)pentyl-cyclopent-ene1-carboxylic acid methyl ester The title compound was prepared according to the method described in Example 15D substituting (3R,4R,1'S)-4-formyl-3-(1'-acetamido-3'-ethyl)pentyl-cyclopent-1-ene1-carboxylic acid methyl ester for (1 R,3R,4R,1'S)-1-formyl-2-(1'-acetamido-3'-ethyl)pentyl-4-(triphenylmethyloxy)methyl-cyclopentane (yield: fi mg, 14%).
' H NMR (CDC13) 8 7.06 (s, 2H), 6.69 (s, 1 H), 3.95 (m, 1 H), 3.74 (s, 3H), 3.5-3.7 (m, 2H), 3.23 (m, 1 H), 2.8 (m, 1 H), 1.90 (s, 3H), 1.1-1.5 (m, 8H), 0.73-0.87 (2t, J=7.12 Hz, 6H) MS: (M-H)- = 346, (M+35)- = 382; (M+H)+ = 348, (M+Na)+ = 370 ~J.;
AcHNH / O
a H OH
24H. ~3R 4R 1'S~-4-(Irnidazol-2-yl)-3-~1'-acetamido-3'-ethyl)pentyl-cyclopent-ene-1-carboxylic Acid (3R,4R,1'S)-4-(Imidazol-2-yl)-3-(1'-acetamido-3'-ethyl)pentyl-cyclopent-1-ene-1-carboxylic acid methyl ester (6 mg, 0.017 mmol) was reacted with lithium hydroxide (1 mg, 0.026 mmol) in THF (0.5 mL) and water (0.2 mL) at 0°C
for 4 hours. The reaction was quenched with 10% citric acid (1 mL) and diluted with 25% isopropanol/dichloromethane (10 mL). The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 1:3:1:1 waterlethyl acetate/n-butanol/acetic acid followed by extraction into 25%
isopropanol/dichloromethane to provide the title compound (yield: 4.3 mg, 74%).
' H NMR (d4-methanol) 8 7.06 (br s, 2H), 6.48 (br s, 1 H), 4.08 (m, 1 H), 3.45-3.7 (m, 2H), 3.1 (m, 1 H), 2.62 (m, 1 H), 1.98 (br s, 2H), 1.82 (br s, 3H), 1.1-1.42 (m, 8H), 0.73-0.87 (m, 6H) MS: (M-H)- = 332, (M+35)- = 368; (M+H)+ = 334, (M+Na)+ = 356 Using the methods described above and the general knowledge of one skilled in the art, compounds of the invention can be prepared which are represented by taking one core from Table 1 (wherein Ac is acetyl), one Y
substituent from Table 2, one R substituent from Table 3, one R3 substituent from Table 4a, 4b, 4c, 4d, 4e, 4f or 4g and one R5 substituent from Table 5.
Table 1 Y, Y, AcHN, ~ OR AcHN ~ OR
Y, Y, CH3S02+iN, 3 H 0,.. ~OR CH3S02i-IN 3 H 0~.. ~OR
R IOI R I'O
O Y, O Y, II 1i CF3C-HN, 3 H O~. ~OR CF3C-HN 3 H O~ ~OR
R IOI R I IO
Y, Y, AcHN, OR AcHN OR
Y, Y, CH3SO2+iN, ). ~OR CH3S02+iN ~OR
g 10 O Y, O Y, II II
CF C-HN, OR CF C-HN OR
R3 H ~ 3 R3 H
Y~ Y
AcHN OR AcHN OR
Y, Y, CH3S02i~-IN / ~OR CH3S02+iN , ~OR
O Y, O Y, II II
CF3C-HN, f~ OR CF3C-HN / OR
Y
AcHN ,OR AcHN OR
R
Y, Y, CH3S02tiN, ~ ~OR CH3S02i-IN ~OR
fI I1 2p 21 p Y, p Y, CF3C-HN, OR CF3C-HN OR
R
Table 2 ~ HN/=( ",.,.,.. CI~ N ' / O
O~ H3 H3C ,~"~ ""."
/v F
H~ S~=--C F
g 10 11~ 12 HN~ N~~' N=(O CI~
H3 ~ H3 ~ ~ F3 F ~ CI ,~~,. F3C H '~"",' HN~ N NCO N~O
N=~, ~, N=-C"".",., F3 ~ F~ F3 ~ NHS
F ,~,.,., F3C .,.""- CI .,.~,., N~, -.l H F
Et ~~~~ Et Et F3 ~ I F~CI Et, H3C
,N
C
H
F .",.~",F3C .",."", H ~"",.. .""..
H\ CH3 F\ HN~ CI, H~,"".,..C I /~~~~ H~~..--~~~~~~
HO O
~ \ N-N
=
~
N N
-HN~~ ~ N~N> ~N~
' N -N N-N
~' N HN~~ HN~ ~ HN =N
N N
~ ' N ; ~ o ' H c .
N ~~~~~
N-N
S~ S --( N --t S ~ N ~ S
O N\ S Nw N-'( S , , F~ Hi \
"""N, F ,~",.",. ,~""",. F ,,.,.,."..
H
, 66 67 68 F~F F~F ~ H3 H3C, CH3 H~~.-(~~ F~~-.(~~~~ H ~--(~
C
H3 ~ H ~ I CI"CI CI, CI
H ~~~~ H~~.--~(~~~~~CI~~-~(~~~~~
C ~
CI, ~ I ~ F3 Fa ~ Fs C I ~~-.-~,~~~~~C I .""~~~ ,"~",.' .,.""~'' F3 ~ CI~ CI, CH3 C .~,...". F3C .~.~. H3C/ ,M,r . CI~~-."(~",."..
F
I ~ H3 F3 ~ F3 H3 ~ i C .,.""". CI ,M,r,.. C ..,~,.",. H3C
H F
3 8s 3 88 s5 s7 CI, CH3 H3 ~ I H3 ~ H3 C~ H3 w. C~--,M,w.
CI H
",. 90 ,M, 3 F~ H3C~ F ' Ci CI, CI ~ H3 F~CH3 C~~-".",.,. F H3C .""~,.., H3C~~--...(,~...~.
H
H3 ~ F~CH3 H3 ~ F~F
C~~--(~
H
.""",., F ...."",. "....
101 102 103 ...
H3 ~ F3 ~ Hs ~ Fs H3 ~ Hs ."""". C .~,~", C ."~,.",. C .,~,.",.
F H H F
C
H3 ~ F3 F3 ~ Hs ~ F3 F3 ~ H3 F
C
""". H3C ..~....,..",.,....
H3 H3 ~ F3 F3 ~ F3 CI~
.,... ~"",.. H F
,r F C
F C
C
. . 3 116 " 3 115 F~CI F~CI CI, F ~ I
F~~-."(.~."~.~-."(~"",.,. F ,"""....
Cl, F CI, CI F\ .F
CI ~ CI~~-(~ F~~ CI/u\~~~
CI, .F CI, CI Ci~ CI, ,CF3 F~~-,~(~~~~~ F3C~~--~(~~~~, F3C/ \w~~~~~r F3 ~ I F3 ~ I Fs ~ I F3 ~ Fs F3C ~ CI ~~~~~- .~..,~. CI ."
F3 ~ I CI"CF3 CI, CF3 CI F3C CI ~~--~~ F3C~)--..,.(~",.~.
F~CF3 F~~ F3 F~CF3 F~F
F ~-.~~ F3C~~-(~~~ F3 ~~-(~C
F3 ~ F3 ~ ~ F3 F3 F ~ ~ F F3C ..."....
F ~ F3 ~ Fs H3 ~ H3 ~ I
3C ,~~~~ F ~~~~~ CI ~~~~ F
CI, .F F\ ,CI F~CH3 CI, CH3 H~ ~ F3 H3C CI CI CF3 F3C CI
CI .~ F3 ~"",~",. H3C ~
F3 ~ H3 CI/ \ H3 H3 ~ F3 H3 CI ~,~~~~ FsC '~'~~' F """"". FsC .",."",.
F~CF3 F~CF3 F3 ~ F3 ~ Hs H3C~--"~~,.~~ H3C~~-.-,M,w. H3C .~,.,.~~ F "".",.'' F\ ,CHs CI, CF3 CI, F F' ,CFs F3C/~.~(\~~,.~ F~~..(~~ ",~ F3C~~~_~(~~~~~ C
Table 3 -H 1 CHs ~ ~CH3 3 ~~CH3 /~CH3 ~~CH3 1~/ 4 6 CHs 5 --~-CHs ~~ Hs CHs ~ CHs 8 H C / CH CHs ,f,.,~CH3 ~-~-CHs J 10 CHs Il CHs 12 ,CHs ~~ CHs ~~ CHs ~ N N
, '-CHs 13 CHs 14 ~CH3 15 Table 4a .""". '"""' CH3 ."~".
~OH OH OH
w ~ H3C w CHs ~~
HsC OH OH I OH OH
HsC CH
CHs H C~ CHs 3 CHs ~ ",.."
~OH OH HOH OH
H3C CHs C 3 " HsC CH3~ ~ \
OH ~OH H3C CH~H H C OH
3 CHs CHs C
\~ H3C~ ~ H3C \ OCH3 I OCHs OCHs OCHs CHs CHs ~~~.
H C \ ~ HsC \ CH OCH
s OCH OCH 1 0 3 3 s HsC CH
CHs HsCJ CHs 3 ~OCH3 OCH3 CHOCH3 OCH3 H C CH3~' ~ \ .,.,.",.
H3C~OCH3 ~OCH OCH3 OCH3 OH ~ OH ~ ".",.' HsC HsC
~OCH3 ~OCH3 ~OH
~OH H3C CH HsC CH3 H3C CH3 H3C CH3 s H3C., H3C ~~ ~~
H3C OH OH H3C _ -OH
OH
'OH - _OH
OH 'OH
.,."". ~~~, H3C
H3~,~ ~
\ _ \
v 'OCH ~ - -OCH3 OCH3 H3C CH ~CH3 Table 4b ~OH ~OCH3 ~O~CH3 ~O~
~'OH ~'OCH3 ~'O~CH3 ~'O~
HO~OH HO~OCH3 HO~o~CH3 HO~O
HO' Y 'OH HO' 1"OCH3 HO~o'~CH3 HO~O
HO"Y 'OH HO~'OCH3 HO~'O~CH3 HO~'O
HO~'OH HO~'OCH3 HO~ O CH3 HO~'O
~O ~'O HO~O HO~O
OH ~ OH ~ OH ~ OH
HO' Y ~O HO~ ~O ~OCH3 ~ ~OCH3 OH ~ OH ~ OCH3 OCH3 2g 30 31 32 CH30 OCH3 CH30"Y 'OCH3 CH30~ ~OCH3 CH30~ ~OCH3 H3C~OH H3C~OCH3 H3C~O~CH3 H3C O
CH3""".,.
H3C OH HsC- x _OCH3 H3C~0~CH3 H3C
~O
H3C OH H3C OH HsC OH CH3 H3C~OH H3C~OCH3 H3C~O~CH3 HsC OH H3C~OCH3 H3C~O~CH3 H3C~0 OH
~ ~ ~~ HsC Y
H3CY 'OH H3CY _OCH3 H C O~CH3 s ~
~ ~ ~~ i ~ HaC
~C~OH HsC Y _OCH3 H3C~0 CH3 O
OH OH ~H OH CH3 H3C~'OH H3C~ ~OCH3 H3C~ ~O~CHs H3C~ 'O~
HsC OH HsC OH OH OH CHs ~~~~ CHI""""
HsC ~OH H3C~ ~OCH3 H3C~ ~O~CHs H3C .O
OH
H C OH HsC OH H3C OH CHs H3C~OH H3C~OH H3C~OCH3 H3C~OCH3 [OH ~CH3 [OH ,~CH3 jOH ~CH3 'OH ''CH3 H3C~OH H3C~OH H3C---~-OCH3 H3C~OCH3 OH CHs OH ~CH3 OH CHs OH 'CHs H3C~OH H3C~OH H3C~OCH3 H3C~OCH3 HsC~'(OH CHs HsC~OH ,'-CHs H3C OH CHs HsC~'(OH ~'-CHs ~~~~' CH~~~~ CHs H3C
H C~OH ~ OH ~OCH3 H3C~OCHs IOH CHs ~'-CHs H3C~..~OH CHs ''OOH ~~CH3 HsC CHs Table 4c H3C/' CH3 ~ CH
OH NH2 OH s ~-CH3 ~ CH3 ~CHa ~'CH3 CH3 ~ CH3 ~.CH H3C ~ 'CH3 \ 'CH3 H3C~'CH3 CH3 CH3 ~~~, ~CH3 H3C I\ ~'CH H3C \ 'CH3 3 ~ CH3 HsC CHs HsC CHa H3C 'CH3 H3C~'CH3 ~C~"'~3 'CH3 CH3 """' CH3 "'."' CH3 "'""
'CH 'CH ''T' 'CH ~CH3 3 3 , CH3 '.."" H3C ..."."
i H3C~'CH3 ~'CH3 .CH3 'CH3 OH OH OH OH
CH CH i HsC """,, Y 'CH 1' 'CH ~~' ~' H
3 ~ 3 'r 'CHg ~ C 3 OH OH ~H OH
.""". OH OH """' OH """' ~CH3 ~CH3 ~CH3 CH
OH OH HsC CH3 CH3 H3C _ H3C ~ ~
HsC CH3 CH3 ~CH3 CH3 ~ CH3 ~CH3 CH. 3 ; ~ CH3 ,~,.
CH3 HsC \ CH3 ~CH3 HsC~CH3 CH3 ~~~~ CH3 ~~~. \ ,w",, CHs HaC " 'CH HsC \ CH
3 ~ s CH3 HaC CHs HsC CHs H3C CH3 H3C~CH3 CH3 CH3 CH3 '~"" CH3 ""r' CH3 '"'~' CH CH ''r 'CH ~CH3 3 3 ~ 3 CH3 '~"' H3C \
H3C~CH3 ~CH3 CH CH3 OH OH
OH OH
CH i CH HaC
Y 'CH3 ~CH3 ~ CH
, ~ Y 'CH3 ~ s OH OH ~H OH
6~ 66 67 68 OH OH OH
Y 'CH ~CH3 ~CH3 CH , OH OH
CH, 3 ; HaC
H3C~ . ~CHg HsCwi\~CH3 ~ . ~CH3 . ~CH3 ~'~CH3 ~. CH3 ~'~CH3 ~.~CH3 CH3 ~~~, i CH3 .~"..
~~ JCH3 ~3~~.~CH3 \ ,~CH3 H3C~.~CH3 CIH3 I CH3.~..~. \
~. ~CH3 H3C~ _ ~CH3 H C ~ . ~CH3 ~ CH
3 ~ . ,/ 3 HsC CHs HaC CHs 8~ 86 87 88 H3C , ~CH3 H3C , ~CH3 , ~CH3 . ~CH3 CH3 ',."" CH3 i CH3 .,..."..
~ ~CH3 , ~CH3 ~ , ~CH3 ~ , ~CH3 , CIH3 '~"" H3~ _ \
H3C~.~CH3 ~.~CH3 ~,~GH3 ,~CH3 OOH OH OH OH
CH CH H3G \~ ~
~.~CH3 ~.,~CH3 ~..~GH3 ~.~CH3 , , , , OH OH OH OH
,~~~- OH i OH OH
CH ~/' ~ .~CH3 ~. ~CH3 ~. ~~CH3 ~.i CH3 HsG
H3C~CH3 HsC~CH3 ~CH3 ~ GH3 C
C~
C' 3 CH3 ~CH3 ~1 .,\ H3C
CH3 CHs w,n. ~~H3 i '''H3 .rwr \ w.w CHs HsC ~ ~ CHs H C~CH3 CHs H3C CHs HsC CHs HsC CHs H3C I CHs CHs CHs v CHs HsC CHs 12~ 12b 127 128 CHs """" CHs j CHs """"
CHs ~CH3 ~CH3 ~ /CHs H3C CHs CHs CHs H3C CHs CHs j HsC _ \ '"""
H3C~CH3 ~CH3 ~CN3 CHs TOH - OH ~OH ~ OH
CHs i HsCl I \1 I
H3C.~CH3 ~~CH3 ~CH3 1~CH3 OH OH OH OH
i OH ~ OH """" OH '""
CHs ~CH3 CHs CHs OH HsC CHs '~""' CHs CHs CH3 ; CHs HsC1 .M... CHs H3C'l . J H3~J~ . J . J
14~ 146 147 148 CHs \ _ CH '.~"' CHs J. J ~. ~H3 J..J 3 . J
J J
CHs CHs CH CHs CHs ~ CH '~ Hs J.J s H3C~.J \ .J s HsCJ
CHs CHs 1~1 1S2 153 154 "'~'.~ Hs HsC C~. CHs CHs ~~ Hs \ CH
H3C~ ~'~ 3 H3C '~(C~~H3 H3C CHs 1>j 156 157 158 HsC "..""~ Hs HsC ...".. J Hs .,."",~ Hs .~.,..~ Hs CHs HsC CHs 1~9 160 161 162 CHs '".."~ Hs CHs '~"'~ Hs CH, 3 ' j ~ Hs ~ .",."~ Hs ~'Y~.~
H3C CHs CHs CHs H3C CHs ' ~ Hs lHs .~.",.~ Hs HsC .~"".~ Hs \ .",~,.~ Hs OH OH OH OH
CH3 j 'J Hs CH3 j 'J Hs H3C~'~ H3 ~'w""~ H3 OH OH OH OH
CH Oi H I ' ~ H3 OH ~~ H3 OH ~~ H3 ~~ ~J
HC
OH OH 3 CHg H C~CH3 i ,CH3 CH3 ; CH3 H3C~~CH
H3C'v~vJ [\
~CH3 ~ ~ CH ~CH3 ~ CH3 \~
CH3 CH3 ~ ' CH3 CH3 ~ CH3 CH3 HsC ~ \ HsC l CH3 CHs CH3 CH3 CH3 \ .",..,.
~~ 1 J CH3 H3C~ H3C
H3C HsC CH3 CHs ,."" CHs CHs """" CHs CH3 "j ' ,CHs ~ CHs H3C CHs CHs CHs H3C CHs CHs CHs i CHs HsC CHs \ CHs ~OH ~ OH OH OH
CH~~CHs lHs i cHs H3C1 ; CH3 \ CHs ~~J~~~
OH OH OH OH
i CHs lH j CHs OH CHs OH "."" CHs OH OH HsC CHs 211 2x2 213 214 CHs ~ HsC
H3~~ J H3~~ . J ~.J~ . J ~ , J
UJ ~:, ~ ~. J ~.J
J
CHs cue:. J H3~-,.~. J ~~ . J H3~ \ ~J
CHs CHs CH3 ~ CH3 '....." \ ,......, . J H3~~.~=. J H3~ ~ . ~ . J
HsC CHs HsC CHs H3C ~.J H~C ~.J ~.J . J
CH3 "~C CH3 CH3 ~ J l 3 ~~ CHI, J ~ ~:J
H C ~:~ ~3 ~:.J "3c ~:~ \ ~:J
OH OH O" OH
CHI, J ~~,~ "3~ ~:J ~.J
OH OH ~H OH
O~,J OH~~ °"~:J
OH OH "3C CH3 HsC
H3C~ ~ C~ "3C
\ ,w.".
\~
CH3 ; " """'' ~ CH3 ,~~~.
HaC'~ w H3C 1 CH3 ~ ~ CH3 ,~~~, ~ \
H3C~~ H3C \
HsC CHa HsC CHs H3C ~ ~ H3C
i CH3 '""" ( ~H3 '~"~' ~ CH
~H3 ~ ~ H3C
OH OH OH OH
CH3 '~"' , i H~ H3C ~ \
OH OH pH OH
-".". OH ; ii OH ( OH ".
~I~IJ
HsC HsC
Table 4d H3C i O O H3C' O H3C O
H3C ~ H3C ~ H3C
H3C O ~ O O
'O H3C .O H3C' .O H3C .O
H3C ~ H3C H3C
H3C .O ~ .O
~O ~O ~O ~O
w H3C H3~
'O I ~O H3C ~O H3C ~O
H3C H3C HsC
Table 4e I CH~ ~ H3C
H3C~ . OOH HsC~OH ~ , OOH OH
"""' \ ,.,."., ~.~OH ~, ~.~OH ~.~OH
OOH
CH3 ""~' CH3 "",...
OOH H3C~ . OOH \ , OOH H3C \ ~. OOH
CH3 CH3 ~ \
~..,iOH H C~ . OOH H C ~ , OOH ~~OH
HsC CHs HsC CHs H3C . OOH H3C . OOH , OOH , OOH
CH3 """' CH3 '~"' C'H3 I
.,OOH ,OOH ~,~OH ~~OH
WO 99/54290 PC'fNS99/07949 ....." CHs .~",, H3C '.. "."", H3C~ . OOH ~ , OOH ~~OH , OOH
CH CH HsC
~.,~OH ~.~OH ~~pH .OOH
OH OH pH OH
OH OH OH
OH ~~' . .iOH ~. OOH ~. OOH
OH OH HsC CHs CHs H3C
H3C~OH HaC~OH ~OH OH
",M, ~OH OH ~OH OH
CHs CHs "~"~- CHs .~,..
~OH H3C~OH W OH HsC ~ ~ OH
CHs CHs '~""' CHs CHs ~~~~
OH H3C~OH HsC ~ OH OH
HsC CHs HsC CHs HsC OH H3C OH OH OH
CHs HsC CHs CHs ,M". OH CHs ".",.. OH CH., i OH ~ OH
H3C CHs CHs CHs H3C CHs """' CHs """' HsC .~..". \
H3C~OH ~OH OH OH
OOH - 'O~H '' OH OH
CHs H3C
H3C~.,~OH ~OH OH ~OH
OH OH OH OH
i ~ OH i OIH "'"I" OH
\ I OH ~OH ~OH ~OH
'OH _ HsC CCH ~'3 OH ",.."" OH ".""
HO~OH ~ HgCO~OCH3 Table 4f '~"" H3C
H3C' '-CHs 1 OH NH2 OH ~.~-CHs CHs '""" ~ CHs ~-CH3 ~CH3 ~CH3 CHs CHHs CHs HsC CHs CHs CHs ~ '"""' ~'CH HsC \ '' Hs ~~ -CHs HsC W -CHs s I -CH ~CH
CHs C~3 CH s CHs 3 CHs ~ CHs ~CH3 H3C~ CHs HsC ~ -CHs -CHs CHs CH ~CH3 HsC s CHs H3C CHCHs H3C -CHs HsC -CHs CHs CHs CHs H C CHs CHs CHs CHs s CHs CHs ,M". CHs '"""' CHs """' _CHs _CH3 ~ CHs ~ -CHs ~CH3 ~CH3 ~ CHs ~CH3 H3C CHs CHs CHs H3C CHs CHs '~"' HsC .,...". \ ~~~, H3C~CHH3 l I CHHs -CHs -CHs OH s OH s ~ CHs OH CHs OH
CH '"'"' CH HsC \
CHs ~'CH3 ~CH ~ CHs CHs CHs ~ s CH
OH OH OH CHs pH s ~CH ~_CHs 'CHs ,,."",CHs OH OH """'~' OH
s ~ CH ~CH CHs CHs OH s OH s HsC CHs 33 34 3~ 36 CHs CHs CHs '.."" CH H3C
HsC 3 CH3 "3~ 1 CHs H3C CHs CH3 CHs \ CH \ ~ CHs ~~ CHs H
CH3 CHs CHs C s CHs ~ ~ CHs CW ~~CH3 H3C~.~CH3 CW ~J H C W-./CHs NCH
CHs s CHs CHs CHs CHs CHs ~ CHs CH3 ~ CHs \ ., ~CH3 H3C~J HsC ~ -~ - ~CH3 s CH s HsC ~CH3 CH 3 CHs H3C CHs CH
H C CHs H C CHs CHs CHs CHsCHs CH3CHs CHs CHs CHs """' JCHs CHs ~ ~ Hs CH~CH3 I ~ ~ Hs CHs ~-CHs , CHs ~~-CHs H3C CHs CHs CHs H3C CHs _ CH3 CHs ~ ' ~ Hs H3C~ CH ~ CH
H3C~CH 1 '-CH ! '-CH CHs 61 6? 63 64 CHs "'.".'~ Hs IH~~CH3 HsC CHs \~~ s CH
J
CH CHs CHs , CHs OH s OH OH OH
/~ OH j OH "'"~" OH '~"~' CHs i ~ ~ ! ~CH3 ~.,/CH3 ~-iCH3 ~CH3 OH CHs OH CHs H3C CHs CHs H3C "."". H3C H3C
HsC
\ ~ / HsC
H3C .~",.. H3C H3C
HsC HsC HsC HsC
8J $6 87 88 HsC HsC HsC HsC
CH3 ~~,- H3C
~'CH3 CH3 CH3 CH
I CH3 ~ \ CH3 CH3 CH3 i \
CH3 ~ H3C
\ H3C \ \
I ~ ~ i I ~ I
i ~ I ~H3-Il los l06 l07 los HO~_CH3 HO CH3 HO HO
CH
HO -CHs HO~CH3 HO HO
CH3 'CH3 OH ~ OH CH3 ,~."' OH H3C
H3C~ OH
OH
HO OH OH
~~~~ .,.",.. H
'-OH ~OH OH '-OH
Table 4g .,....~' CH 3 .,~,.
H3C~ CH3 H 3C ~-CH 3 ~-CH 3 ~..~-CH3 OH OH OH OH
H3C' ' CHs H C~_ J Hs CH~_ ./ Hs ~ ~ Hs 3 V' OH OH OH OH
~_ I CHs H3C~_~CH3 CH~CH3 ~ ~CH3 H3C~ ~''~'~~/ ~
H OH O
OH H
H3C' ' _ ~ H3C~_ ~ CH~_ OH OH pH OH
'~~"' CHs _ HsC'' CHs H3C~-CH3 ~-CHs ~-CHs OCHs OCHs OCHs OCHs CHs I CHs CHs CHs I CHs H3C/'-_ / HsC~_ J ~_ J ~_ J
'''' ~' OCH3 OCHs OCHs OCHs H3C'' ~CH3 H C~_.~CH3 CH~CH3 ~_~CHs 3 ''/ ~
OCHs OCHs OCH OCHs ~ ' ~ CHs HsC' ' H3C~_ ~ _ OCHs OCHs OCHs OCHs '~"' CHs / HsC~-OH ~-OH ~-OH
OH
' CHs CHs CHs CHs "'~" CHs "~". '"""' H3C~H HsC~H -OH ~H
~CH3 CHs ~CH CHs CHs HsC ~-OH HsC ~-OH -OH I ~ OH
CHs CHs CHs CHs '~"" CHs .M".
HsC -OH HsC -OH -OH -OH
CHs H3C' ' OCHs HsC.,,.~-OCH3 ~-OCHs ~-OCHs CHs CHs CHs CHs ~ ~ CHs H3C~CH3 H3C~CH3 -OCHs ~CH3 ~--CH3 CHs ~CH CHs '~~" CHs ~~~, H C -OCHs HsC -OCHs -OCHs -OCHs CHs ~ CHs CHs CHs .~.. CHs ."~", H C ~OCH3 HsC -OCHs -OCHs ~ ~'OCH3 'M" CHs '~"" ~ ,M".
-CH3 ~-CH3 '~ -CH3 ~-CH
OH %' \ OH
~~OH
OH
- CH3 '~~" ~ H3 CH3 ~~~, ~ H3 '\ "".". ~ H3 OH OH OH OH
_ ! CH3 ~~CH3 CH3 .,.""-~CH3 OH ~ OH ~ pH OH
73 74 75 7s _ ~ ~ CH3 ~ ~ \ .,.
OH ~ OH OH OH
CH3 ~ \
_CHs y_CHs _CHs _CHa OCH3 ~7~\ 'OCH3 LOCH
- CH3 .,."" ~ H3 CH3 ,~~~ ~ H3 \ ."",.. ~ H3 OCH3 ~ OCH3 OCH3 OCH3 _ I CH3 ~ ~CH3 CH3 ~ r-CH3 \ ,-CH3 J i .,."" _ CH3 .~",., _ ~.., _ ~ _~ _ OCH3 ' ~ OCH3 1 OCH3 OCH3 CH3 ""~' \
-OH ( -OH -OH ~OH
CH3 ~CH3 CH3 CH3 CH3 "~.", \
~-OH ~ I -OH -OH ~-OH
CH3 '~-CH3 CH3 CH3 CH3 ,~",. \
-OH ~ I -OH -OH ~-OH
CH3 ,",.", ~\ "".", -OH -OH -OH -OH
CH3 '""" \
~-OCfv3 I -OCH3 -OCH3 ~-OCH3 CH3 ~CH3 CH3 CH3 CH3 ,...",. \ ""H.
CH3 ~-CH3 CH3 CH3 CH3 ..",... \
-OCH3 ~ -OCH3 -OCH3 -OCH3 i CHs ,,..",. \ .".,.....
-OCHs I -OCHs -OCHs -OCHs \ I '\~ \
CHs ~ , \ .""".
HsC -OH -OH -OH -OH
OH OH OH OH
CHs ~ I \
HsC -OCH3 -OCHs -OCHs -OCHs OH OH OH OH
CHs ~ I \
HsC -OCHs ~ -OCH3 -OCHs ~-OCH
CH ~ CH3 OCHs OCH
,~"" CHs ~ \ ."
H3C~ H ~~ H O~H -OH
OH OH OH
CHs I ~ \
H3C~OH3 l~~-CHs OOHS ~ OCH
OH
,,."". CHs I I ,"...", \ .,d.,..
HsC -OCHs l -OCHs CHs -OCHs ~OCH ~- OCHs 3 OCHs OCHs -OH '~~ OH -OH -OH
OH ~~OH OH
OH
-OCH3 '~~ CH3 -OCH3 -OCH3 ~-OH OH OH OOH
~ I
-OCH3 \ ~-OCH3 H3C~CHg ~' ~OCH3 N ~~
~
I CH3 ~I ~ \
HsC~OH ~OH ~OH ~
OH
OH OH OH O
H
HsC~OCH ~-OCH ~OCH3 s 3 OCH3 OH OH OH O
H
CH3 I II I \
HaC~OCH ~ ~OCH """,.
~OCH ~
~
~
3 . 3 OCH3 CH3 ~~~, ( \
H3C~OH ~ ~OH ~
~OH
, ...OH
-OH ~'OH '-OH ~~--OH
H3C~-OCH3 ~,~-OCH3 ~OCH3 , OCH3 OH ~-OH OH ,--OH
CH3 I I ~ ","", H3C~OCH3 ~~-OCH3 ~OCH3 ~ ~
~OCH3 OCH 'OCH3 OCH3 ~-OCH
OH OH OH ~pH
~~-OH ~'-OH ~'--OH
'-OH
OCH3 OCH3 OCH3 ~ ~
~OCH3 '~OH ~'-OH ~-OH
'-OH
HOC pCH3 OCH3 ~ OCH3 ~OCH3 ~'-OCH ~'-OCH ~-OCH
CH 3 3 s ~-OCH3 ".,.". ,~"", .,..",.
~OH I OCH3 O - ~-O~
OCH3 O~CH3 OCH3 O CHs -CH3 r~ 1 , CH3 , O ~O CH3 O O CH3 221 ~/ 222 223 224 Table 5 The ability of the compounds of the invention to inhibit neuraminidase in vitro can be determined according to the method described below.
Neuraminidase Inhibition Assav:
Influenza virus A/N1/PRIB/34 was grown in the allantoic cavity of fertilized eggs and purified by sucrose density gradient centrifugation (Layer, W. G.
(1969) in "Fundamental Techniques in Virology" (K. Habel and N. P. Salzman, eds.) pp.
92-86, Academic Press, New York). Influenza virus A/N2/Tokyo/3/67 was obtained from the tissue culture supernatents of virus grown on MDCK cells.
Neuraminidase from B/Memphis/3/89 virus was prepared by digestion of the virus with TPCK-trypsin followed by centrifugation and then purification of the neuraminidase catalytic fragment using sucrose density gradient centrifugation and dialysis as described previously (Air, G. M., Layer, W. G., Luo, M., Stray, S. J., Legrone, G., and Webster, R. G. (1990) Virolo 177, 578-587).
The neuraminidase inhibition assays used the neuraminidase enzymatic activity associated with the A/N11PR/8/34 or A/N2ITokyo/3167 whole virus, or the B/Memphisl3/89 catalytic head fragment. The whole virus or catalytic fragment was diluted appropriately with 20 mM N-ethylmorpholine, 10 mM calcium choride, pH 7.5 buffer on the day of the experiment. Neuraminidase inhibition assays were conducted in 20 mM N-ethylmorpholine, 10 mM calcium choride, pH 7.5 buffer with 5% DMSO. Reaction mixtures included neuraminidase, inhibitor (test compound) and 20-30,uM 4-methylumbeiliferyl sialic acid substrate in a total volume of 200,uL and were contained in white 96-well U-shaped plates.
Typically, five to eight concentrations of inhibitor were used for each Ki value measurement.
The reactions were initiated by the addition of enzyme and allowed to proceed for 30-60 minutes at room temperature. The fluorescence for each well of the plate was measured once each minute during the reaction period by a Fluoroskan Il plate reader (ICN Biomedical) equipped with excitation and emission filters of +/- 35 nm and 460 +/- 25 nm, respectively. The plate reader was under the control of DeItaSoft II software {Biometallics) and a Macintosh computer. If the compound exhibited linear reaction velocities during the reaction period, then ttie reaction velocities for the dose-response study were fit to equation 1 using a nonlinear regression program (Kaleidagraph) to determine the overall Ki value (Segel, I. H. (1975) in Enzyme Kinetics, pp. 105-106, Wiley-Interscience, New York).
(1 - Vi/Vo) _ [I]/ {[I] + Ki(1 + [S]/Km)} eqn 1 In equation 1, Vi and Vo represent inhibited and uninhibited reaction velocities, respectively, and Km = 16 - 40,uM depending on the neuraminidase strain tested. For those compounds exhibiting slow-binding inhibition (Morrison, J.
F.
{1982) Trends Biochem. Sci. 7, 102-105), a second experiment was performed in a manner identical to the first except that neuraminidase and inhibitor were preincubated in the absence of substrate for 2 hours at room temperature prior to initiating the reactions with substrate. Data analysis for the resulting linear velocities was conducted as described above.
Equation 2 was used to measure Ki values in the sub-nanomofar range (Morrison; J. F. And Stone, S. R. (1985) Comments Mol. Cell Biophys. 2, 347-368).
V = A{sqrt{(Ki' + It -Et)~2 + 4Ki'Et} - (Ki' + It - Et)] eqn. 2 In equation 2, V = velocity; A = akcat[S]I2(Km + [S]); a is a factor to convert fluorescence units to molar concentrations; Ki' = Ki(1 + [S]IKm); It = total inhibitor concentration and Et = total active concentration. of neuraminidase.
The compounds of the invention inhibit influenza A neuraminidase and influenza B neuraminidase with Ki values between about 24 micromolar and about 0.9 micromolar.
The ability of the compounds of the invention to inhibit plaque formation in cell culture can be determined by the method described below.
Cell Culture Pla4ue Formation Inhibition Assay Cell Cultures: MDCK cells obtained from the American Type Culture Collection were grown in Dulbecco's Modified Eagle Medium (DMEM) high glucose (GibcoBRL) supplemented with 10% fetal calf serum (JRH Biosciences), 40 mM
HEPES buffer (GibcoBRL) and antibiotics {GibcoBRL). Cells were routinely cultured in flasks or roller bottles at 37°C and 5% C02. At confluence cells were reduced to a density of 500,000 cells in a ml using trypsin/EDTA (GibcoBRL) treatment of the monolayer followed by cell centrifugation, resuspension, and dilution into growth media. Cells were planted at a volume to surface area ratio of 1 ml over 1 cm2 of growth surface.
Plaque Assay Protocol: On MDCK cell confluent 6 well plates growth media was removed and the cells were overlaid with 1.5 ml of assay media (DMEM with 1 % fetal calf serum, 40 mM HEPES buffer and antibiotics) containing pre-mixed virus (influenza A/Tokyo/3167 [H2N2]) (40 -100 plaque forming units) and 2x concentration test compound. The plates were placed on a rocker and incubated for 2 hours at room temperature. During the virus adsorption period agar overlay media was prepared. In a microwave oven 2X agarose (final concentration of 0.6% agarose) in overlay media (DMEM with 40 mM HEPES buffer) was melted and then placed in a 48°C water bath for temperature equilibration.
After the virus adsorption period was completed 1.5 ml agar over media was added and mixed with the 1.5 ml virus and test compound containing media per well.
Cultures were incubated at 35°C for the period required for plaque development, usually several days. Plaques were fixed with 3.7% formaiin in PBS for 20 minutes followed by removal of the agar overlay and staining with 0.1 % crystal violet in distilled water for 15 minutes. Plaques were counted and EC 50 concentration determined from multiple concentrations of the tested compound using regression analysis.
Viral Stocks: Stocks were prepared in MDCK confluent roller bottles incubated at 37°C in DMEM supplemented with 1 % FCS, 40mM HEPES buffer, and antibiotics. Bottles were inoculated with a multiplicity of infection of approximately 0.1 plaque forming unit for each cell. Roller bottles were harvested after the cytopathic effect of the virus was observed to be complete. Stocks were prepared from the supernatant resulting from the low speed centrifugation of the media and cell iysate. Stocks were titered and stored at -80°C.
The compounds of the invention can be tested for in vivo antiviral activity using the method described below.
In Vivo Antiviral Efficac rLMethod Female BALB/c mice were placed under anesthesia {sevoflurane) and inoculated intranasally (IN) with 0.1 ml of influenza A VR-95 (Puerto Rico PR8-34) at 10-2 (diluted from frozen stock). This viral concentration consistently produced disease in mice within 5 days of inoculation. Animals were treated 4h.
pre-infection and 4h. post-infection, and periodically thereafter, with one of the following therapies: no treatment; test compound (100, 25, 6.25, 1.39 mg/kg/day BID, PO); or vehicle (sterile water BID, PO). A group of ten animals (designated as control) was inoculated with 0.9% saline. Percent survival was determined.
On day five, lungs were harvested, weighed and assigned scores of 0,1, 2, 3 or based on percentage consolidation (0; 10-20; 25-50; 50-75; 75-100%, respectively). In addition, each lung pair was image analyzed to determine objective lung consolidation percentages.
The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Also, basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyi and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid and such organic acids as oxalic acid, malefic acid, succinic acid and citric acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, Lithium, calcium or magnesium or with ammonium or N(R**)4+ salts (where R** is loweralkyl).
In addition, salts of the compounds of this invention with one of the naturally occurring amino acids are also contemplated.
Preferred salts of the compounds of the invention include hydrochloride, methanesulfonate, suifonate, phosphonate and isethionate.
The compounds of the Formula I, II, III, IV, V, VI, VII, VIII or IX of this invention can have a substituent which is an acid group (for example, -COZH, -S03H, -S02H, -P03H2, -P02H). Compounds of the Formula I, II, III, IV, V, VI, VII, VIII or IX of this invention having a substituent which is an ester of such an acidic group are also encompassed by this invention. Such esters may serve as prodrugs. The prodrugs of this invention are metabolized in vivo to provide the above-mentioned acidic substituent of the parental compound of Formula I, II, III, IV, V, VI, VII, VIII or IX. Prodrugs may also serve to increase the solubility of these substances and/or absorption from the gastrointestinal tract. These prodrugs may also serve to increase solubility for intravenous administration of the compounds. Prodrugs may also serve to increase the hydrophobicity of the compounds. Prodrugs may also serve to increase the oral bioavailability of the compounds by increasing absorption and/or decreasing first-pass metabolism.
Prodrugs may also serve to increase tissue penetration of the compounds, thereby leading to increased activity in infected tissues andlor reduced rate of clearance.
Such esters contemplated by this invention include:
alkyl esters, especially loweralkyl esters, including, but not limited to, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl esters and the like;
alkoxyalkyl esters, especially, loweralkoxyloweralkyl esters, including, but not limited to, methoxymethyl, 1-ethoxyethyl, 2-methoxyethyl, isopropoxymethyl, t-butoxymethyl esters and the like;
alkoxyalkoxyalkyl esters, especially, alkoxyalkoxy-substituted loweralkyl esters, including, but not limited to, 2-methoxyethoxymethyl esters and the like;
aryloxyalkyl esters, especially, aryloxy-substituted loweralkyl esters, including, but not limited to, phenoxymethyl esters and the like, wherein the aryl group is unsubstituted or substituted as previously defined herein;
haloalkoxyalkyl esters, especially, haloalkoxy-substituted loweralkyl esters, including, but not limited to, 2,2,2-trichloroethoxymethyl esters and the like;
alkoxycarbonylalkyl esters, especially, loweralkoxycarbonyl-substituted loweralkyl esters, including, but not limited to, methoxycarbonylmethyl esters and the like;
cyanoalkyl esters, especially, cyano-substituted loweralkyl esters, including, but not limited to, cyanomethyl, 2-cyanoethyl esters and the like;
thioalkoxymethyl esters, especially, lowerthioalkoxy-substituted methyl esters, including, but not limited to, methylthiomethyl, ethylthiomethyl esters and the like;
alkylsulfonylalkyl esters, especially, loweralkylsulfonyl-substituted ioweralkyl esters, including, but not limited to, 2-methanesulfonylethyl esters and the like;
arylsulfonylalkyl esters, especially, arylsulfonyl-substituted loweralkyl esters, including, but not limited to, 2-benzenesulfonylethyl and 2-toluenesulfonylethyl esters and the like;
acyloxyalkyl esters, especially, loweralkylacyloxy-substituted loweralkyl esters, including, but not limited to, formyloxymethyl, acetoxymethyl, pivaloyloxymethyl, acetoxyethyl, pivaioyloxyethyl esters and the like;
cycloalkylcarbonyloxyalkyl esters including, but not limited to, cyclopentanecarbonyloxymethyl, cyclohexanecarbonyloxymethyl, cyclopentanecarbonyloxyethyl, cyclohexanecarbonyloxyethyl esters and the like;
arylcarbonyloxyalkyl esters including, but not limited to, benzoyloxymethyl esters and the like;
(alkoxycarbonyloxy)alkyl esters, especially, (loweralkoxycarbonyloxy)-substituted loweralkyl esters, including, but not limited to, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, 1-(methoxycarbonyloxy)ethyl, 2-(ethoxycarbonyloxy)ethyi esters and the like;
(cycloalkyloxycarbonyloxy)alkyl esters, especially, (cycloalkyloxycarbonyloxy)-substituted loweralkyl esters, including, but not limited to, cyclohexyloxycarbonyloxymethyl, cyclopentyloxycarbonyloxyethyl, cyclohexyloxycarbonyloxypropyl esters and the like;
oxodioxolenylmethyl esters including, but not limited to, (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl, [5-(4-methylphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-methoxyphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-fluorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-chlorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, (2-oxo-1,3-dioxolen-4-yl)methyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-ethyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-propyl-2-oxo-1,3-dioxolen-4-yl)methyl, {5-isopropyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-butyl-2-oxo-1,3-dioxolen-4.-yl)methyl esters and the like;
phthalidyl esters wherein the phenyl ring of the phthalidyl group is unsubstituted or substituted as defined previously herein, including, but not limited to, phthalidyi, dimethylphthalidyl, dimethoxyphthalidyl esters and the like;
aryl esters including, but not limited to, phenyl, naphthyl, indanyl esters and the like;
arylalkyl esters, especially, aryl-substitued loweralkyl esters, including, but not limited to, benzyl, phenethyl, 3-phenylpropyl, naphthylmethyl esters and the like, wherein the aryl part of the arylalkyl group is unsubstituted or substituted as previously defined herein;
dialkylaminoalkyl esters, especially dialkylamino-substituted loweralkyl esters, including, but not limited to, 2-{N,N-dimethylamino)ethyl, 2-(N,N-diethylarnino)ethyl ester and the like (heterocyclic)alkyl esters, especially, heterocyclic-substituted loweralkyl esters wherein the heterocycle is a nitrogen-containing heterocycle, including, but not limited to, (heterocyclic)methyl esters and the like, wherein the heterocyclic part of the (heterocyclic)alkyl group is unsubstituted or substituted as previously defined herein; and carboxyalkyl esters, especially, carboxy-substituted loweralkyl esters, including, but not limited to carboxymethyl esters and the like;
and the like.
Preferred prodrug esters of acid-containing compounds of the Formula I, II, III, IV, V, VI, VI1, VIII or IX are loweralkyl esters, including, but not limited to, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl esters and benzyl esters wherein the phenyl ring is unsubstituted or substituted as previously defined herein.
Methods for the preparation of prodrug esters of compounds of the Formula I, II, I11, IV, V, Vl, VI1, VIII or IX are well-known in the art and include:
reacting the acid with the corresponding halide (for example, chloride or acyl chloride) and a base (for example, triethylamine, DBU, N,N-dimethylaminopyridine and the like) in an inert solvent (for example, DMF, acetonitrile, N-methylpyrrolidone and the like);
reacting an activated derivative of the acid (for example, an acid chloride, sulfonyl chloride, monochlorophosphonate and the like) with the corresponding alcohol or alkoxide salt; and the like.
Other examples of prodrugs of the present invention include esters of hydroxyl-substituted compounds of Formula I, II, III, IV, V, VI, VI1, VIII or IX which have been acylated with a blocked or unblocked amino acid residue, a phosphate function, a hemisuccinate residue, an acyl residue of the formula R'°°C(O)- or R'°°C(S}- wherein R'°° is hydrogen, lower alkyl, haloalkyl, alkoxy, thioalkoxy, alkoxyalkyl, thioaikoxyalkyl or haloalkoxy, or an acyl residue of the formula Ra-C(Rb)(Rd)-C(O)- or Ra-C(Rb)(Rd)-C(S)- wherein Rb and Rd are independently selected from hydrogen or lower alkyl and Ra is -N(Re)(Rf), -ORe or -SRe wherein Re and Rf are independently selected from hydrogen, lower alkyl and haloaikyl, or an amino-acyl residue having the formula R'°'NH(CH2)2NHCH2C(O)- or R'°'NH(CHZ)20CHZC(0}- wherein R'°' is hydrogen, lower alkyl, (aryl)alkyl, (cycloalkyl)alkyl, acyl, benzoyl or an a-amino acyl group. The amino acid esters of particular interest are of glycine and lysine; however, other amino acid residues can also be used, including any of the naturally occuring amino acids and also including those wherein the amino acyl group is -C(O)CH2NR'°zR'°3 wherein R'°2 and R'°3 are independently selected from hydrogen and lower alkyl, or the group -NR'°2 R'°3, where R'°2 and R'°3, taken together, forms a nitrogen containing heterocyclic ring.
Other prodrugs include a hydroxyl-substituted compound of Formula I, II, III, IV, V, VI, VII, Vlll or IX wherein the hydroxyl group is functionalized with a substituent of the formula -CH(R'°4)OC(O)R'°5 or -CH(R'°4)OC(S)R'o5 wherein R'°5 is lower alkyl, haloalkyl, alkoxy, thioalkoxy or haloalkoxy and R'°4 is hydrogen, lower alkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl. Such prodrugs can be prepared according to the procedure of Schreiber (Tetrahedron Lett. 1983, 24, 2363) by ozonolysis of the corresponding rnethallyl ether in methanol followed by treatment with acetic anhydride.
The preparation of esters of hydroxyl-substituted compounds of formula Formula I, II, III, IV, V, VI, VII, Vlli or IX is carried out by reacting a hydroxyl-substituted compound of formula Formula I, II, III, IV, V, VI, VII, VIII or IX, with an activated amino acyl, phosphoryl, hemisuccinyl or acyl derivative.
Prodrugs of hydroxyl-substituted-compounds of the invention can also be prepared by alkylation of the hydroxyl substituted compound of formula Formula I, II, III, IV, V, VI, VI1, VIII or IX, with (halo)alkyl esters, transacetalization with bis-(alkanoyl)acetals or condensation of the hydroxyl group with an activated aldehyde followed by acylation of the intermediate hemiacetal.
In preparing prodrugs it often is necessary to protect other reactive functional groups, in order to prevent unwanted side reactions. After protection of the reactive groups the desired group can be functionalized. The resulting functionalized product is then deprotected, to remove the protecting groups that were added to prevent unwanted side reactions. This will provide the desired prodrug. Suitable reaction conditions for preparing protecting groups are well known in the art. One source for reaction conditions is found in T.H. Greene and P.G.M. Wuts, Protective Groups in Or acLnic Synthesis, 2nd edition, John Wiley &
Sons, New York (1991 ).
This invention also encompasses compounds of the Formula I, II, III, IV, V, VI, VII, VIII or IX which are esters or prodrugs and which are also salts. For example, a compound of the invention can be an ester of a carboxylic acid and also an acid addition salt of an amine or nitrogen-containing substituent in the same compound.
The compounds of the present invention are useful for inhibiting neuraminidase from disease-causing microorganisms which comprise a neuraminidase. The compounds of the invention are useful (in humans, other mammals and fowl) for treating or preventing diseases caused by microorganisms which comprise a neuraminidase The compounds of the present invention are useful for inhibiting influenza A virus neuraminidase and influenza B virus neuraminidase, in vitro or in vivo (especially in mammals and, in particular, in humans). The compounds of the present invention are also useful for the inhibition of influenza viruses, orthomyxoviruses, and paramyxoviruses in vivo, especially the inhibition of influenza A viruses and influenza B viruses in humans and other mammals. The compounds of the present invention are also useful for the treatment of infections caused by influenza viruses, orthomyxoviruses, and paramyxoviruses in vivo, especially the human diseases caused by influenza A and influenza B viruses.
The compounds of the present invention are also useful for the prophylaxis of infections caused by influenza viruses, orthomyxoviruses, and paramyxoviruses in vivo in humans and other mammals, especially the prophylaxis of influenza A
and influenza B viral infections; and, in particular, the prophylaxis of influenza A
and influenza B viral infections in human subjects who are at high risk of developing other respiratory diseases concurrent with or as a consequence of influenza virus infections, or who suffer from chronic respiratory illness, such as asthma, emphysema, or cystic fibrosis.
Total daily dose administered to a human or other mammal host in single or divided doses may be in amounts, for example, from 0.001 to 300 mg/kg body weight daily and more usually 0.1 to 10 mg/kg body weight daily. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
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.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.
Administration of a compound of this invention will begin before or at the time of infection or after the appearance of established symptoms andlor the confirmation of infection.
The compounds of the present invention may be administered orally, parenterally, sublingually, intranasally, by intrapulmonary administration, by inhalation or insufflation as a solution, suspension or dry powder (for example, in a spray), or rectally, in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
Injectable preparations, for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-propanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
in addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch.
Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or mufti-lamellar hydrated liquid crystals that are dispersed in an aqueous medium.
Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic.
Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Bioloay, Volume XIV, Academic Press, New York, N.Y. {1976}, p. 33 et seq.
While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more anti-infective agents and/or other agents used to treat other acute or chronic respiratory ailments. Other agents to be administered in combination with a compound of the present invention include: an influenza vaccine; other influenza inhibitors such as, for example, amantadine, rimantadine, ribavirin, and the like; another influenza neuraminidase inhibitor, such as, for example, zanamivir or GS 4104 and the like; agents used to treat respiratory bacterial infections and bronchitis, such as, for example, erythromycin, clarithromycin, azithromycin and the like; and agents used to treat asthma, such as, for example, zileuton, albuterol (safbutamol), salmeterol, formoterol, ipratropium bromide, inhaled steroids and the like, or anti-inflammatory agents for treating asthma such as, for example, beclomethasone dipropionate, fluticasone propionate, budesonide, triamcinolone acetonide, flunisolide, cromolyn, zafirlukast, montelukast used in combination with a compound of the present invention.
When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or different times, or the therapeutic agents can be given as a single composition.
The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.
H3C O ~ O O
'O H3C .O H3C' .O H3C .O
H3C ~ H3C H3C
H3C .O ~ .O
~O ~O ~O ~O
w H3C H3~
'O I ~O H3C ~O H3C ~O
H3C H3C HsC
Table 4e I CH~ ~ H3C
H3C~ . OOH HsC~OH ~ , OOH OH
"""' \ ,.,."., ~.~OH ~, ~.~OH ~.~OH
OOH
CH3 ""~' CH3 "",...
OOH H3C~ . OOH \ , OOH H3C \ ~. OOH
CH3 CH3 ~ \
~..,iOH H C~ . OOH H C ~ , OOH ~~OH
HsC CHs HsC CHs H3C . OOH H3C . OOH , OOH , OOH
CH3 """' CH3 '~"' C'H3 I
.,OOH ,OOH ~,~OH ~~OH
WO 99/54290 PC'fNS99/07949 ....." CHs .~",, H3C '.. "."", H3C~ . OOH ~ , OOH ~~OH , OOH
CH CH HsC
~.,~OH ~.~OH ~~pH .OOH
OH OH pH OH
OH OH OH
OH ~~' . .iOH ~. OOH ~. OOH
OH OH HsC CHs CHs H3C
H3C~OH HaC~OH ~OH OH
",M, ~OH OH ~OH OH
CHs CHs "~"~- CHs .~,..
~OH H3C~OH W OH HsC ~ ~ OH
CHs CHs '~""' CHs CHs ~~~~
OH H3C~OH HsC ~ OH OH
HsC CHs HsC CHs HsC OH H3C OH OH OH
CHs HsC CHs CHs ,M". OH CHs ".",.. OH CH., i OH ~ OH
H3C CHs CHs CHs H3C CHs """' CHs """' HsC .~..". \
H3C~OH ~OH OH OH
OOH - 'O~H '' OH OH
CHs H3C
H3C~.,~OH ~OH OH ~OH
OH OH OH OH
i ~ OH i OIH "'"I" OH
\ I OH ~OH ~OH ~OH
'OH _ HsC CCH ~'3 OH ",.."" OH ".""
HO~OH ~ HgCO~OCH3 Table 4f '~"" H3C
H3C' '-CHs 1 OH NH2 OH ~.~-CHs CHs '""" ~ CHs ~-CH3 ~CH3 ~CH3 CHs CHHs CHs HsC CHs CHs CHs ~ '"""' ~'CH HsC \ '' Hs ~~ -CHs HsC W -CHs s I -CH ~CH
CHs C~3 CH s CHs 3 CHs ~ CHs ~CH3 H3C~ CHs HsC ~ -CHs -CHs CHs CH ~CH3 HsC s CHs H3C CHCHs H3C -CHs HsC -CHs CHs CHs CHs H C CHs CHs CHs CHs s CHs CHs ,M". CHs '"""' CHs """' _CHs _CH3 ~ CHs ~ -CHs ~CH3 ~CH3 ~ CHs ~CH3 H3C CHs CHs CHs H3C CHs CHs '~"' HsC .,...". \ ~~~, H3C~CHH3 l I CHHs -CHs -CHs OH s OH s ~ CHs OH CHs OH
CH '"'"' CH HsC \
CHs ~'CH3 ~CH ~ CHs CHs CHs ~ s CH
OH OH OH CHs pH s ~CH ~_CHs 'CHs ,,."",CHs OH OH """'~' OH
s ~ CH ~CH CHs CHs OH s OH s HsC CHs 33 34 3~ 36 CHs CHs CHs '.."" CH H3C
HsC 3 CH3 "3~ 1 CHs H3C CHs CH3 CHs \ CH \ ~ CHs ~~ CHs H
CH3 CHs CHs C s CHs ~ ~ CHs CW ~~CH3 H3C~.~CH3 CW ~J H C W-./CHs NCH
CHs s CHs CHs CHs CHs CHs ~ CHs CH3 ~ CHs \ ., ~CH3 H3C~J HsC ~ -~ - ~CH3 s CH s HsC ~CH3 CH 3 CHs H3C CHs CH
H C CHs H C CHs CHs CHs CHsCHs CH3CHs CHs CHs CHs """' JCHs CHs ~ ~ Hs CH~CH3 I ~ ~ Hs CHs ~-CHs , CHs ~~-CHs H3C CHs CHs CHs H3C CHs _ CH3 CHs ~ ' ~ Hs H3C~ CH ~ CH
H3C~CH 1 '-CH ! '-CH CHs 61 6? 63 64 CHs "'.".'~ Hs IH~~CH3 HsC CHs \~~ s CH
J
CH CHs CHs , CHs OH s OH OH OH
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HsC
\ ~ / HsC
H3C .~",.. H3C H3C
HsC HsC HsC HsC
8J $6 87 88 HsC HsC HsC HsC
CH3 ~~,- H3C
~'CH3 CH3 CH3 CH
I CH3 ~ \ CH3 CH3 CH3 i \
CH3 ~ H3C
\ H3C \ \
I ~ ~ i I ~ I
i ~ I ~H3-Il los l06 l07 los HO~_CH3 HO CH3 HO HO
CH
HO -CHs HO~CH3 HO HO
CH3 'CH3 OH ~ OH CH3 ,~."' OH H3C
H3C~ OH
OH
HO OH OH
~~~~ .,.",.. H
'-OH ~OH OH '-OH
Table 4g .,....~' CH 3 .,~,.
H3C~ CH3 H 3C ~-CH 3 ~-CH 3 ~..~-CH3 OH OH OH OH
H3C' ' CHs H C~_ J Hs CH~_ ./ Hs ~ ~ Hs 3 V' OH OH OH OH
~_ I CHs H3C~_~CH3 CH~CH3 ~ ~CH3 H3C~ ~''~'~~/ ~
H OH O
OH H
H3C' ' _ ~ H3C~_ ~ CH~_ OH OH pH OH
'~~"' CHs _ HsC'' CHs H3C~-CH3 ~-CHs ~-CHs OCHs OCHs OCHs OCHs CHs I CHs CHs CHs I CHs H3C/'-_ / HsC~_ J ~_ J ~_ J
'''' ~' OCH3 OCHs OCHs OCHs H3C'' ~CH3 H C~_.~CH3 CH~CH3 ~_~CHs 3 ''/ ~
OCHs OCHs OCH OCHs ~ ' ~ CHs HsC' ' H3C~_ ~ _ OCHs OCHs OCHs OCHs '~"' CHs / HsC~-OH ~-OH ~-OH
OH
' CHs CHs CHs CHs "'~" CHs "~". '"""' H3C~H HsC~H -OH ~H
~CH3 CHs ~CH CHs CHs HsC ~-OH HsC ~-OH -OH I ~ OH
CHs CHs CHs CHs '~"" CHs .M".
HsC -OH HsC -OH -OH -OH
CHs H3C' ' OCHs HsC.,,.~-OCH3 ~-OCHs ~-OCHs CHs CHs CHs CHs ~ ~ CHs H3C~CH3 H3C~CH3 -OCHs ~CH3 ~--CH3 CHs ~CH CHs '~~" CHs ~~~, H C -OCHs HsC -OCHs -OCHs -OCHs CHs ~ CHs CHs CHs .~.. CHs ."~", H C ~OCH3 HsC -OCHs -OCHs ~ ~'OCH3 'M" CHs '~"" ~ ,M".
-CH3 ~-CH3 '~ -CH3 ~-CH
OH %' \ OH
~~OH
OH
- CH3 '~~" ~ H3 CH3 ~~~, ~ H3 '\ "".". ~ H3 OH OH OH OH
_ ! CH3 ~~CH3 CH3 .,.""-~CH3 OH ~ OH ~ pH OH
73 74 75 7s _ ~ ~ CH3 ~ ~ \ .,.
OH ~ OH OH OH
CH3 ~ \
_CHs y_CHs _CHs _CHa OCH3 ~7~\ 'OCH3 LOCH
- CH3 .,."" ~ H3 CH3 ,~~~ ~ H3 \ ."",.. ~ H3 OCH3 ~ OCH3 OCH3 OCH3 _ I CH3 ~ ~CH3 CH3 ~ r-CH3 \ ,-CH3 J i .,."" _ CH3 .~",., _ ~.., _ ~ _~ _ OCH3 ' ~ OCH3 1 OCH3 OCH3 CH3 ""~' \
-OH ( -OH -OH ~OH
CH3 ~CH3 CH3 CH3 CH3 "~.", \
~-OH ~ I -OH -OH ~-OH
CH3 '~-CH3 CH3 CH3 CH3 ,~",. \
-OH ~ I -OH -OH ~-OH
CH3 ,",.", ~\ "".", -OH -OH -OH -OH
CH3 '""" \
~-OCfv3 I -OCH3 -OCH3 ~-OCH3 CH3 ~CH3 CH3 CH3 CH3 ,...",. \ ""H.
CH3 ~-CH3 CH3 CH3 CH3 ..",... \
-OCH3 ~ -OCH3 -OCH3 -OCH3 i CHs ,,..",. \ .".,.....
-OCHs I -OCHs -OCHs -OCHs \ I '\~ \
CHs ~ , \ .""".
HsC -OH -OH -OH -OH
OH OH OH OH
CHs ~ I \
HsC -OCH3 -OCHs -OCHs -OCHs OH OH OH OH
CHs ~ I \
HsC -OCHs ~ -OCH3 -OCHs ~-OCH
CH ~ CH3 OCHs OCH
,~"" CHs ~ \ ."
H3C~ H ~~ H O~H -OH
OH OH OH
CHs I ~ \
H3C~OH3 l~~-CHs OOHS ~ OCH
OH
,,."". CHs I I ,"...", \ .,d.,..
HsC -OCHs l -OCHs CHs -OCHs ~OCH ~- OCHs 3 OCHs OCHs -OH '~~ OH -OH -OH
OH ~~OH OH
OH
-OCH3 '~~ CH3 -OCH3 -OCH3 ~-OH OH OH OOH
~ I
-OCH3 \ ~-OCH3 H3C~CHg ~' ~OCH3 N ~~
~
I CH3 ~I ~ \
HsC~OH ~OH ~OH ~
OH
OH OH OH O
H
HsC~OCH ~-OCH ~OCH3 s 3 OCH3 OH OH OH O
H
CH3 I II I \
HaC~OCH ~ ~OCH """,.
~OCH ~
~
~
3 . 3 OCH3 CH3 ~~~, ( \
H3C~OH ~ ~OH ~
~OH
, ...OH
-OH ~'OH '-OH ~~--OH
H3C~-OCH3 ~,~-OCH3 ~OCH3 , OCH3 OH ~-OH OH ,--OH
CH3 I I ~ ","", H3C~OCH3 ~~-OCH3 ~OCH3 ~ ~
~OCH3 OCH 'OCH3 OCH3 ~-OCH
OH OH OH ~pH
~~-OH ~'-OH ~'--OH
'-OH
OCH3 OCH3 OCH3 ~ ~
~OCH3 '~OH ~'-OH ~-OH
'-OH
HOC pCH3 OCH3 ~ OCH3 ~OCH3 ~'-OCH ~'-OCH ~-OCH
CH 3 3 s ~-OCH3 ".,.". ,~"", .,..",.
~OH I OCH3 O - ~-O~
OCH3 O~CH3 OCH3 O CHs -CH3 r~ 1 , CH3 , O ~O CH3 O O CH3 221 ~/ 222 223 224 Table 5 The ability of the compounds of the invention to inhibit neuraminidase in vitro can be determined according to the method described below.
Neuraminidase Inhibition Assav:
Influenza virus A/N1/PRIB/34 was grown in the allantoic cavity of fertilized eggs and purified by sucrose density gradient centrifugation (Layer, W. G.
(1969) in "Fundamental Techniques in Virology" (K. Habel and N. P. Salzman, eds.) pp.
92-86, Academic Press, New York). Influenza virus A/N2/Tokyo/3/67 was obtained from the tissue culture supernatents of virus grown on MDCK cells.
Neuraminidase from B/Memphis/3/89 virus was prepared by digestion of the virus with TPCK-trypsin followed by centrifugation and then purification of the neuraminidase catalytic fragment using sucrose density gradient centrifugation and dialysis as described previously (Air, G. M., Layer, W. G., Luo, M., Stray, S. J., Legrone, G., and Webster, R. G. (1990) Virolo 177, 578-587).
The neuraminidase inhibition assays used the neuraminidase enzymatic activity associated with the A/N11PR/8/34 or A/N2ITokyo/3167 whole virus, or the B/Memphisl3/89 catalytic head fragment. The whole virus or catalytic fragment was diluted appropriately with 20 mM N-ethylmorpholine, 10 mM calcium choride, pH 7.5 buffer on the day of the experiment. Neuraminidase inhibition assays were conducted in 20 mM N-ethylmorpholine, 10 mM calcium choride, pH 7.5 buffer with 5% DMSO. Reaction mixtures included neuraminidase, inhibitor (test compound) and 20-30,uM 4-methylumbeiliferyl sialic acid substrate in a total volume of 200,uL and were contained in white 96-well U-shaped plates.
Typically, five to eight concentrations of inhibitor were used for each Ki value measurement.
The reactions were initiated by the addition of enzyme and allowed to proceed for 30-60 minutes at room temperature. The fluorescence for each well of the plate was measured once each minute during the reaction period by a Fluoroskan Il plate reader (ICN Biomedical) equipped with excitation and emission filters of +/- 35 nm and 460 +/- 25 nm, respectively. The plate reader was under the control of DeItaSoft II software {Biometallics) and a Macintosh computer. If the compound exhibited linear reaction velocities during the reaction period, then ttie reaction velocities for the dose-response study were fit to equation 1 using a nonlinear regression program (Kaleidagraph) to determine the overall Ki value (Segel, I. H. (1975) in Enzyme Kinetics, pp. 105-106, Wiley-Interscience, New York).
(1 - Vi/Vo) _ [I]/ {[I] + Ki(1 + [S]/Km)} eqn 1 In equation 1, Vi and Vo represent inhibited and uninhibited reaction velocities, respectively, and Km = 16 - 40,uM depending on the neuraminidase strain tested. For those compounds exhibiting slow-binding inhibition (Morrison, J.
F.
{1982) Trends Biochem. Sci. 7, 102-105), a second experiment was performed in a manner identical to the first except that neuraminidase and inhibitor were preincubated in the absence of substrate for 2 hours at room temperature prior to initiating the reactions with substrate. Data analysis for the resulting linear velocities was conducted as described above.
Equation 2 was used to measure Ki values in the sub-nanomofar range (Morrison; J. F. And Stone, S. R. (1985) Comments Mol. Cell Biophys. 2, 347-368).
V = A{sqrt{(Ki' + It -Et)~2 + 4Ki'Et} - (Ki' + It - Et)] eqn. 2 In equation 2, V = velocity; A = akcat[S]I2(Km + [S]); a is a factor to convert fluorescence units to molar concentrations; Ki' = Ki(1 + [S]IKm); It = total inhibitor concentration and Et = total active concentration. of neuraminidase.
The compounds of the invention inhibit influenza A neuraminidase and influenza B neuraminidase with Ki values between about 24 micromolar and about 0.9 micromolar.
The ability of the compounds of the invention to inhibit plaque formation in cell culture can be determined by the method described below.
Cell Culture Pla4ue Formation Inhibition Assay Cell Cultures: MDCK cells obtained from the American Type Culture Collection were grown in Dulbecco's Modified Eagle Medium (DMEM) high glucose (GibcoBRL) supplemented with 10% fetal calf serum (JRH Biosciences), 40 mM
HEPES buffer (GibcoBRL) and antibiotics {GibcoBRL). Cells were routinely cultured in flasks or roller bottles at 37°C and 5% C02. At confluence cells were reduced to a density of 500,000 cells in a ml using trypsin/EDTA (GibcoBRL) treatment of the monolayer followed by cell centrifugation, resuspension, and dilution into growth media. Cells were planted at a volume to surface area ratio of 1 ml over 1 cm2 of growth surface.
Plaque Assay Protocol: On MDCK cell confluent 6 well plates growth media was removed and the cells were overlaid with 1.5 ml of assay media (DMEM with 1 % fetal calf serum, 40 mM HEPES buffer and antibiotics) containing pre-mixed virus (influenza A/Tokyo/3167 [H2N2]) (40 -100 plaque forming units) and 2x concentration test compound. The plates were placed on a rocker and incubated for 2 hours at room temperature. During the virus adsorption period agar overlay media was prepared. In a microwave oven 2X agarose (final concentration of 0.6% agarose) in overlay media (DMEM with 40 mM HEPES buffer) was melted and then placed in a 48°C water bath for temperature equilibration.
After the virus adsorption period was completed 1.5 ml agar over media was added and mixed with the 1.5 ml virus and test compound containing media per well.
Cultures were incubated at 35°C for the period required for plaque development, usually several days. Plaques were fixed with 3.7% formaiin in PBS for 20 minutes followed by removal of the agar overlay and staining with 0.1 % crystal violet in distilled water for 15 minutes. Plaques were counted and EC 50 concentration determined from multiple concentrations of the tested compound using regression analysis.
Viral Stocks: Stocks were prepared in MDCK confluent roller bottles incubated at 37°C in DMEM supplemented with 1 % FCS, 40mM HEPES buffer, and antibiotics. Bottles were inoculated with a multiplicity of infection of approximately 0.1 plaque forming unit for each cell. Roller bottles were harvested after the cytopathic effect of the virus was observed to be complete. Stocks were prepared from the supernatant resulting from the low speed centrifugation of the media and cell iysate. Stocks were titered and stored at -80°C.
The compounds of the invention can be tested for in vivo antiviral activity using the method described below.
In Vivo Antiviral Efficac rLMethod Female BALB/c mice were placed under anesthesia {sevoflurane) and inoculated intranasally (IN) with 0.1 ml of influenza A VR-95 (Puerto Rico PR8-34) at 10-2 (diluted from frozen stock). This viral concentration consistently produced disease in mice within 5 days of inoculation. Animals were treated 4h.
pre-infection and 4h. post-infection, and periodically thereafter, with one of the following therapies: no treatment; test compound (100, 25, 6.25, 1.39 mg/kg/day BID, PO); or vehicle (sterile water BID, PO). A group of ten animals (designated as control) was inoculated with 0.9% saline. Percent survival was determined.
On day five, lungs were harvested, weighed and assigned scores of 0,1, 2, 3 or based on percentage consolidation (0; 10-20; 25-50; 50-75; 75-100%, respectively). In addition, each lung pair was image analyzed to determine objective lung consolidation percentages.
The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Also, basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyi and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid and such organic acids as oxalic acid, malefic acid, succinic acid and citric acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, Lithium, calcium or magnesium or with ammonium or N(R**)4+ salts (where R** is loweralkyl).
In addition, salts of the compounds of this invention with one of the naturally occurring amino acids are also contemplated.
Preferred salts of the compounds of the invention include hydrochloride, methanesulfonate, suifonate, phosphonate and isethionate.
The compounds of the Formula I, II, III, IV, V, VI, VII, VIII or IX of this invention can have a substituent which is an acid group (for example, -COZH, -S03H, -S02H, -P03H2, -P02H). Compounds of the Formula I, II, III, IV, V, VI, VII, VIII or IX of this invention having a substituent which is an ester of such an acidic group are also encompassed by this invention. Such esters may serve as prodrugs. The prodrugs of this invention are metabolized in vivo to provide the above-mentioned acidic substituent of the parental compound of Formula I, II, III, IV, V, VI, VII, VIII or IX. Prodrugs may also serve to increase the solubility of these substances and/or absorption from the gastrointestinal tract. These prodrugs may also serve to increase solubility for intravenous administration of the compounds. Prodrugs may also serve to increase the hydrophobicity of the compounds. Prodrugs may also serve to increase the oral bioavailability of the compounds by increasing absorption and/or decreasing first-pass metabolism.
Prodrugs may also serve to increase tissue penetration of the compounds, thereby leading to increased activity in infected tissues andlor reduced rate of clearance.
Such esters contemplated by this invention include:
alkyl esters, especially loweralkyl esters, including, but not limited to, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl esters and the like;
alkoxyalkyl esters, especially, loweralkoxyloweralkyl esters, including, but not limited to, methoxymethyl, 1-ethoxyethyl, 2-methoxyethyl, isopropoxymethyl, t-butoxymethyl esters and the like;
alkoxyalkoxyalkyl esters, especially, alkoxyalkoxy-substituted loweralkyl esters, including, but not limited to, 2-methoxyethoxymethyl esters and the like;
aryloxyalkyl esters, especially, aryloxy-substituted loweralkyl esters, including, but not limited to, phenoxymethyl esters and the like, wherein the aryl group is unsubstituted or substituted as previously defined herein;
haloalkoxyalkyl esters, especially, haloalkoxy-substituted loweralkyl esters, including, but not limited to, 2,2,2-trichloroethoxymethyl esters and the like;
alkoxycarbonylalkyl esters, especially, loweralkoxycarbonyl-substituted loweralkyl esters, including, but not limited to, methoxycarbonylmethyl esters and the like;
cyanoalkyl esters, especially, cyano-substituted loweralkyl esters, including, but not limited to, cyanomethyl, 2-cyanoethyl esters and the like;
thioalkoxymethyl esters, especially, lowerthioalkoxy-substituted methyl esters, including, but not limited to, methylthiomethyl, ethylthiomethyl esters and the like;
alkylsulfonylalkyl esters, especially, loweralkylsulfonyl-substituted ioweralkyl esters, including, but not limited to, 2-methanesulfonylethyl esters and the like;
arylsulfonylalkyl esters, especially, arylsulfonyl-substituted loweralkyl esters, including, but not limited to, 2-benzenesulfonylethyl and 2-toluenesulfonylethyl esters and the like;
acyloxyalkyl esters, especially, loweralkylacyloxy-substituted loweralkyl esters, including, but not limited to, formyloxymethyl, acetoxymethyl, pivaloyloxymethyl, acetoxyethyl, pivaioyloxyethyl esters and the like;
cycloalkylcarbonyloxyalkyl esters including, but not limited to, cyclopentanecarbonyloxymethyl, cyclohexanecarbonyloxymethyl, cyclopentanecarbonyloxyethyl, cyclohexanecarbonyloxyethyl esters and the like;
arylcarbonyloxyalkyl esters including, but not limited to, benzoyloxymethyl esters and the like;
(alkoxycarbonyloxy)alkyl esters, especially, (loweralkoxycarbonyloxy)-substituted loweralkyl esters, including, but not limited to, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, 1-(methoxycarbonyloxy)ethyl, 2-(ethoxycarbonyloxy)ethyi esters and the like;
(cycloalkyloxycarbonyloxy)alkyl esters, especially, (cycloalkyloxycarbonyloxy)-substituted loweralkyl esters, including, but not limited to, cyclohexyloxycarbonyloxymethyl, cyclopentyloxycarbonyloxyethyl, cyclohexyloxycarbonyloxypropyl esters and the like;
oxodioxolenylmethyl esters including, but not limited to, (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl, [5-(4-methylphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-methoxyphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-fluorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-chlorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, (2-oxo-1,3-dioxolen-4-yl)methyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-ethyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-propyl-2-oxo-1,3-dioxolen-4-yl)methyl, {5-isopropyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-butyl-2-oxo-1,3-dioxolen-4.-yl)methyl esters and the like;
phthalidyl esters wherein the phenyl ring of the phthalidyl group is unsubstituted or substituted as defined previously herein, including, but not limited to, phthalidyi, dimethylphthalidyl, dimethoxyphthalidyl esters and the like;
aryl esters including, but not limited to, phenyl, naphthyl, indanyl esters and the like;
arylalkyl esters, especially, aryl-substitued loweralkyl esters, including, but not limited to, benzyl, phenethyl, 3-phenylpropyl, naphthylmethyl esters and the like, wherein the aryl part of the arylalkyl group is unsubstituted or substituted as previously defined herein;
dialkylaminoalkyl esters, especially dialkylamino-substituted loweralkyl esters, including, but not limited to, 2-{N,N-dimethylamino)ethyl, 2-(N,N-diethylarnino)ethyl ester and the like (heterocyclic)alkyl esters, especially, heterocyclic-substituted loweralkyl esters wherein the heterocycle is a nitrogen-containing heterocycle, including, but not limited to, (heterocyclic)methyl esters and the like, wherein the heterocyclic part of the (heterocyclic)alkyl group is unsubstituted or substituted as previously defined herein; and carboxyalkyl esters, especially, carboxy-substituted loweralkyl esters, including, but not limited to carboxymethyl esters and the like;
and the like.
Preferred prodrug esters of acid-containing compounds of the Formula I, II, III, IV, V, VI, VI1, VIII or IX are loweralkyl esters, including, but not limited to, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl esters and benzyl esters wherein the phenyl ring is unsubstituted or substituted as previously defined herein.
Methods for the preparation of prodrug esters of compounds of the Formula I, II, I11, IV, V, Vl, VI1, VIII or IX are well-known in the art and include:
reacting the acid with the corresponding halide (for example, chloride or acyl chloride) and a base (for example, triethylamine, DBU, N,N-dimethylaminopyridine and the like) in an inert solvent (for example, DMF, acetonitrile, N-methylpyrrolidone and the like);
reacting an activated derivative of the acid (for example, an acid chloride, sulfonyl chloride, monochlorophosphonate and the like) with the corresponding alcohol or alkoxide salt; and the like.
Other examples of prodrugs of the present invention include esters of hydroxyl-substituted compounds of Formula I, II, III, IV, V, VI, VI1, VIII or IX which have been acylated with a blocked or unblocked amino acid residue, a phosphate function, a hemisuccinate residue, an acyl residue of the formula R'°°C(O)- or R'°°C(S}- wherein R'°° is hydrogen, lower alkyl, haloalkyl, alkoxy, thioalkoxy, alkoxyalkyl, thioaikoxyalkyl or haloalkoxy, or an acyl residue of the formula Ra-C(Rb)(Rd)-C(O)- or Ra-C(Rb)(Rd)-C(S)- wherein Rb and Rd are independently selected from hydrogen or lower alkyl and Ra is -N(Re)(Rf), -ORe or -SRe wherein Re and Rf are independently selected from hydrogen, lower alkyl and haloaikyl, or an amino-acyl residue having the formula R'°'NH(CH2)2NHCH2C(O)- or R'°'NH(CHZ)20CHZC(0}- wherein R'°' is hydrogen, lower alkyl, (aryl)alkyl, (cycloalkyl)alkyl, acyl, benzoyl or an a-amino acyl group. The amino acid esters of particular interest are of glycine and lysine; however, other amino acid residues can also be used, including any of the naturally occuring amino acids and also including those wherein the amino acyl group is -C(O)CH2NR'°zR'°3 wherein R'°2 and R'°3 are independently selected from hydrogen and lower alkyl, or the group -NR'°2 R'°3, where R'°2 and R'°3, taken together, forms a nitrogen containing heterocyclic ring.
Other prodrugs include a hydroxyl-substituted compound of Formula I, II, III, IV, V, VI, VII, Vlll or IX wherein the hydroxyl group is functionalized with a substituent of the formula -CH(R'°4)OC(O)R'°5 or -CH(R'°4)OC(S)R'o5 wherein R'°5 is lower alkyl, haloalkyl, alkoxy, thioalkoxy or haloalkoxy and R'°4 is hydrogen, lower alkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl. Such prodrugs can be prepared according to the procedure of Schreiber (Tetrahedron Lett. 1983, 24, 2363) by ozonolysis of the corresponding rnethallyl ether in methanol followed by treatment with acetic anhydride.
The preparation of esters of hydroxyl-substituted compounds of formula Formula I, II, III, IV, V, VI, VII, Vlli or IX is carried out by reacting a hydroxyl-substituted compound of formula Formula I, II, III, IV, V, VI, VII, VIII or IX, with an activated amino acyl, phosphoryl, hemisuccinyl or acyl derivative.
Prodrugs of hydroxyl-substituted-compounds of the invention can also be prepared by alkylation of the hydroxyl substituted compound of formula Formula I, II, III, IV, V, VI, VI1, VIII or IX, with (halo)alkyl esters, transacetalization with bis-(alkanoyl)acetals or condensation of the hydroxyl group with an activated aldehyde followed by acylation of the intermediate hemiacetal.
In preparing prodrugs it often is necessary to protect other reactive functional groups, in order to prevent unwanted side reactions. After protection of the reactive groups the desired group can be functionalized. The resulting functionalized product is then deprotected, to remove the protecting groups that were added to prevent unwanted side reactions. This will provide the desired prodrug. Suitable reaction conditions for preparing protecting groups are well known in the art. One source for reaction conditions is found in T.H. Greene and P.G.M. Wuts, Protective Groups in Or acLnic Synthesis, 2nd edition, John Wiley &
Sons, New York (1991 ).
This invention also encompasses compounds of the Formula I, II, III, IV, V, VI, VII, VIII or IX which are esters or prodrugs and which are also salts. For example, a compound of the invention can be an ester of a carboxylic acid and also an acid addition salt of an amine or nitrogen-containing substituent in the same compound.
The compounds of the present invention are useful for inhibiting neuraminidase from disease-causing microorganisms which comprise a neuraminidase. The compounds of the invention are useful (in humans, other mammals and fowl) for treating or preventing diseases caused by microorganisms which comprise a neuraminidase The compounds of the present invention are useful for inhibiting influenza A virus neuraminidase and influenza B virus neuraminidase, in vitro or in vivo (especially in mammals and, in particular, in humans). The compounds of the present invention are also useful for the inhibition of influenza viruses, orthomyxoviruses, and paramyxoviruses in vivo, especially the inhibition of influenza A viruses and influenza B viruses in humans and other mammals. The compounds of the present invention are also useful for the treatment of infections caused by influenza viruses, orthomyxoviruses, and paramyxoviruses in vivo, especially the human diseases caused by influenza A and influenza B viruses.
The compounds of the present invention are also useful for the prophylaxis of infections caused by influenza viruses, orthomyxoviruses, and paramyxoviruses in vivo in humans and other mammals, especially the prophylaxis of influenza A
and influenza B viral infections; and, in particular, the prophylaxis of influenza A
and influenza B viral infections in human subjects who are at high risk of developing other respiratory diseases concurrent with or as a consequence of influenza virus infections, or who suffer from chronic respiratory illness, such as asthma, emphysema, or cystic fibrosis.
Total daily dose administered to a human or other mammal host in single or divided doses may be in amounts, for example, from 0.001 to 300 mg/kg body weight daily and more usually 0.1 to 10 mg/kg body weight daily. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
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.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.
Administration of a compound of this invention will begin before or at the time of infection or after the appearance of established symptoms andlor the confirmation of infection.
The compounds of the present invention may be administered orally, parenterally, sublingually, intranasally, by intrapulmonary administration, by inhalation or insufflation as a solution, suspension or dry powder (for example, in a spray), or rectally, in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
Injectable preparations, for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-propanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
in addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch.
Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or mufti-lamellar hydrated liquid crystals that are dispersed in an aqueous medium.
Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic.
Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Bioloay, Volume XIV, Academic Press, New York, N.Y. {1976}, p. 33 et seq.
While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more anti-infective agents and/or other agents used to treat other acute or chronic respiratory ailments. Other agents to be administered in combination with a compound of the present invention include: an influenza vaccine; other influenza inhibitors such as, for example, amantadine, rimantadine, ribavirin, and the like; another influenza neuraminidase inhibitor, such as, for example, zanamivir or GS 4104 and the like; agents used to treat respiratory bacterial infections and bronchitis, such as, for example, erythromycin, clarithromycin, azithromycin and the like; and agents used to treat asthma, such as, for example, zileuton, albuterol (safbutamol), salmeterol, formoterol, ipratropium bromide, inhaled steroids and the like, or anti-inflammatory agents for treating asthma such as, for example, beclomethasone dipropionate, fluticasone propionate, budesonide, triamcinolone acetonide, flunisolide, cromolyn, zafirlukast, montelukast used in combination with a compound of the present invention.
When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or different times, or the therapeutic agents can be given as a single composition.
The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.
Claims
What is claimed is:
1. A compound of the formula:
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R1 is selected from the group consisting of (b) -CO2H, (b) -CH2CO2H, (c) -SO3H, (d) -CH2SO3H, (e) -SO2H, (g) -CH2SO2H, (g) -PO3H2, (h) -CH2PO3H2, (i) -PO2H, (j) -CH2PO2H, (l) tetrazolyl, (l) -CH2-tetrazolyl, (m) -C(=O)-NH-S(O)2-R11, (o) -CH2C(=O)-NH-S(O)2-R11, (o) -SO2N(T-R11)R12 and (p) -CH2SO2N(T-R11)R12 wherein T is selected from the group consisting of (i) a bond, (ii) -C(=O)-, (iii) -C(=O)O-, (iv) -C(=O)S-, (v) -C(=O)NR36-, (vi) -C(=S)O-, (vii) -C(=S)S-, and (viii) -C(=S)NR36-, R11 is selected from the group consisting of (i) C1-C12 alkyl, (ii) C2-C12 alkenyl, (iii) cycloalkyl, (iv) (cycloalkyl)alkyl, (w) (cycloalkyl)alkenyl, (vi) cycloalkenyl, (vii) (cycloalkenyl)alkyl, (ix) (cycloalkenyl)alkenyl, (ix) aryl, (x) (aryl)alkyl, (xi) (aryl)alkenyl, (xviii) heterocyclic, (xiii) (heterocyclic)alkyl and (xix) (xiv) (heterocyclic)alkenyl; and R12 and R36 are independently selected from the group consisting of (i) hydrogen, (ii) C1-C12 alkyl, (iii) C2-C12 alkenyl, (iv) cycloalkyl, (v) (cycloalkyl)alkyl, (vi) (cycloalkyl)alkenyl, (vii) cycloalkenyl, (viii) (cycloalkenyl)alkyl, (ix) (cycloalkenyl)alkenyl, (x) aryl, (xi) (aryl)alkyl, (xii) (aryl)alkenyl, (xiii) heterocyclic, (xiv) (heterocyclic)alkyl and (xv) (heterocyclic)alkenyl;
X is selected from the group consisting of (a) -C(=O)-N(R*)-, (b) -N(R*)-C(=O)-, (c) -C(=S)-N(R*)-, (d) -N(R*)-C(=S)-, (e) -N(R*)-SO2-, and (f) -SO2-N(R*)- wherein R* is hydrogen, C1-C3 loweralkyl or cyclopropyl;
R2 is selected from the group consisting of (a) hydrogen, (b) C1-C6 alkyl, (c) C2-C6 alkenyl, (d) C3-C6 cycloalkyl, (e) C5-C6 cycloalkenyl, (f) halo C1-C6 alkyl and (g) halo C2-C6 alkenyl;
or R2-X- is wherein Y1 is -CH2-, -O-, -S- or -NH- and Y2 is -C(=O)- or -C(R aa)(R bb)-wherein R aa and R bb are indepedently selected from the group consisting of hydrogen, C1-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl;
Z1 is -O-, -S-, or C(R5)2;
R3 and R4 are independently selected from the group consisting of (a) hydrogen, (b) cycloalkyl, (c) cycloalkenyl, (d) heterocyclic, (e) aryl and (f) -Z-R14 wherein Z is (ii) -C(R37a)(R37b)-, (ii) -C(R47)=C(R48)-, (iii) -C~C-, (iv) -C(=O)-, (v) -C(=S)-, (vi) -C(=NR15)-, (vii) -C(R37a)(OR37c)-, (viii) -C(R37a)(SR37c)-, (ix) -C(R37a)(N(R37b)(R37c))-, (x) -C(R37a)(R37b)-O-, (xi) -C(R37a)(R37b)-N(R37c)-, (xii) -C(R37a)(R37b)-N(O)(R37c)-, (xiii) -C(R37a)(R37b)-N(OH)-, (xiv) -C(R37a)(R37b)-S-, (xv) -C(R37a)(R37b)-S(O)-, (xvi) -C(R37a)(R37b)-S(O)2-, (xviii) -C(R37a)(R37b)-C(=O)-, (xviii) -C(R37a)(R37b)-C(=S)-, (xxi) -C(R37a)(R37b)-C(=NR15)-, (xx) -C(R37a)(OR37c)-C(=O)-, (xxi) -C(R37a)(SR37c)-C(=O)-, (xxii) -C(R37a)(OR37c)-C(=S)-, (xxiii) -C(R37a)(SR37c)-C(=S)-, (xxiv) -C(=O)-C(R37a)(OR37c)-, (xxv) -C(=O)-C(R37a)(SR37c)- (xxvi) -C(=S)-C(R37a)(OR37c)-, (xxvii) -C(=S)-C(R37a)(SR37c)-, (xxviii) -C(R37a)(OR37c)-C(R37a)(OR37c)-, (xxix) -C(R37a)(SR37c)-C(R37a)(OR37c)-, (xxx) -C(R37a)(OR37c)-C(R37a)(SR37c)-, (xxxi) -C(R37a)(SR37c)-C(R37a)(SR37c)-, (xxxii) -C(=O)-C(=O)-, (xxxiii) -C(=S)-C(=S)-, (xxxiv) -C(=O)-O-, (xxxv) -C(=O)-S-, (xxxvi) -C(=S)-O-, (xxxvii) -C(=S)-S-, (xxxviii) -C(=O)-N(R37a)-, (xxxix) -C(=S)-N(R37a)-, (xi) -C(R37a)(R37b)-C(=O)-N(R37a)-, (xli) -C(R37a)(R37b)-C(=S)-N(R37a)-, (xlii) -C(R37a)(R37b)-C(=O)-O-, (xliii) -C(R37a)(R37b)-C(=O)-S-, (xliv) -C(R37a)(R37b)-C(=S)-O-, (xlv) -C(R37a)(R37b)-C(=S)-S- (xlvi) -C(R37a)(R37b)-N(R37b)-C(=O)-, (xlvii) -C(R37a)(R37b)-N(R37b)-C(=S)-, (xlviii) -C(R37a)(R37b)-O-C(=O)-, (xlix) -C(R37a)(R37b)-S-C(=O)-, (l) -C(R37a)(R37b)-O-C(=S)-, (li) -C(R37a)(R37b)-S-C(=S)-, (lii) -C(R37a)(R37b)-N(R37b)-C(=O)-N(R37a)-, (liii) -C(R37a)(R37b)-N(R37b)-C(=S)-N(R37a)-, (liv) -C(R37a)(R37b)-N(R37b)-C(=O)-O-, (lv) -C(R37a)(R37b)-N(R37b)-C(=O)-S-, (lvi) -C(R37a)(R37b)-N(R37b)-C(=S)-O-, (lvii) -C(R37a)(R37b)-N(R37b)-C(=S)-S-, (lviii) -C(R37a)(R37b)-O-C(=O)-N(R37a)-, (lix) -C(R37a)(R37b)-S-C(=O)-N(R37a)-, (lx) -C(R37a)(R37b)-O-C(=S)-N(R37a)-, (lxi) -C(R37a)(R37b)-S-C(=S)-N(R37a)-, (lxii) -C(R37a)(R37b)-O-C(=O)-O-, (lxiii) -C(R37a)(R37b)-S-C(=O)-O-, (lxiv) -C(R37a)(R37b)-O-C(=O)-S-, (lxv) -C(R37a)(R37b)-S-C(=O)-S-, (lxvi) -C(R37a)(R37b)-O-C(=S)-O-, (lxvii) -C(R37a)(R37b)-S-C(=S)-O-, (lxviii) -C(R37a)(R37b)-O-C(=S)-S-, (lxix) -C(R37a)(R37b)-S-C(=S)-S- or (lxx) -C(R37a)(R37b)-C(R37a)(OR37c)-;
R14 is (i) hydrogen, (ii) C1-C12 alkyl, (iii) haloalkyl, (iv) hydroxyalkyl, (v) thioi-substituted alkyl, (vi) R37c O-substituted alkyl, (vii) R37c S-substituted alkyl, (viii) aminoalkyl, (ix) (R37c)NH-substituted alkyl, (x) (R37a)(R37c)N-susbstituted alkyl, (xi) R37a O-(O=)C-substituted alkyl, (xii) R37a S-(O=)C-substituted alkyl, (xiii) R37a O-(S=)C-substituted alkyl, (xx) R37a S-(S=)C-substituted alkyl, (xxi) (R37a O)2-P(=O)-substituted alkyl, (xvi) cyanoalkyl, (xxii) C2-C12 alkenyl, (xviii) haloalkenyl, (xix) C2-C12 alkynyl, (xxii) cycloalkyl, (xxi) (cycloalkyl)alkyl, (xxii) (cycloalkyl)alkenyl, (xxiv) (cycloalkyl)alkynyl, (xxiv) cycloalkenyl, (xxv) (cycloalkenyl)alkyl, (xxvii) (cycloalkenyl)alkenyl, (xxvii) (cycloalkenyl)alkynyl, (xxviii) aryl, (xxx) (aryl)alkyl, (xxx) (aryl)alkenyl, (xxxi) (aryl)alkynyl, (xxxii) heterocyclic, (xxxiii) (heterocyclic)alkyl, (xxxiv) (heterocyclic)alkenyl or (xxxv) (heterocyclic)alkynyl, with the proviso that R14 is other than hydrogen when Z is -C(R37a)(R37b)-N(R37b)-C(=O)-O-, -C(R37a)(R37b)-N(R37b)-C(=S)-O-, -C(R37a)(R37b)-N(R37b)-C(=O)-S-, -C(R37a)(R37b)-N(R37b)-C(=S)-S-, -C(R37a)(R37b)-O-C(=O)-O-, -C(R37a)(R37b)-O-C(=S)-O-, -C(R37a)(R37b)-S-C(=O)-O-, -C(R37a)(R37b)-S-C(=S)-O-, -C(R37a)(R37b)-O-C(=O)-S-, -C(R37a)(R37b)-O-C(=S)-S-, -C(R37a)(R37b)-S-C(=O)-S-, or -C(R37a)(R37b)-S-C(=S)-S-;
R37a, R37b, R47, and R48 at each occurrence are independently selected from the group consisting of (i) hydrogen, (ii) C1-C12 alkyl, (iii) haloalkyl, (iv) hydroxyalkyl, (v) alkoxyalkyl, (vi) C2-C12 alkenyl, (vii) haloalkenyl, (viii) C2-C12 alkynyl, (ix) cycloalkyl, (x) (cycloalkyl)alkyl, (xi) (cycloalkyl)alkenyl, (xii) (cycloalkyl)alkynyl, (xiii) cycloalkenyl, (xiv) (cycloalkenyl)alkyl, (xv) (cycloalkenyl)-alkenyl, (xvi) (cycloalkenyl)alkynyl, (xvii) aryl, (xviii) (aryl)alkyl, (xix) (aryl)alkenyl, (xx) (aryl)alkynyl, (xxi) heterocyclic, (xxii) (heterocyclic)alkyl, (xxiii) (heterocyclic)alkenyl and (xxiv) (heterocyclic)alkynyl;
R37a at each occurrence is independently selected from the group consisting of (i) hydrogen, (ii) C1-C12 alkyl, (iii) haloalkyl, (iv) C2-C12 alkenyl, (v) haloalkenyl, (vi) C2-C12 alkynyl, (vii) cycloalkyl, (viii) (cycloalkyl)alkyl, (ix) (cycloalkyl)alkenyl, (x) (cycloalkyl)alkynyl, (xi) cycloalkenyl, (xii) (cycloalkenyl)alkyl, (xiii) (cycloalkenyl)alkenyl, (xiv) (cycloalkenyl)alkynyl, (xv) aryl, (xvi) (aryl)alkyl, (xvii) (aryl)alkenyl, (xviii) (aryl)alkynyl, (xix) heterocyclic, (xx) (heterocyclic)alkyl, (xxi) (heterocyclic)alkenyl, (xxiii) (heterocyclic)alkynyl, (xxiii) -C(=O)-R14, (xxiv) -C(=S)-R14, (xxv) -S(O)2-R14 and (xxvi) hydroxyalkyl;
or when Z is -C(R37a)(R37b)-N(R37c)-, then N(R37c) and R14 when taken together are an azido group;
or when Z is -C(R37a)(R37b)-N(O)(R37c)-, then N(O)(R37c) and R14 when taken together are an N-oxidized 3-7 membered heterocyclic ring having at least one N-oxidized ring nitrogen atom;
or when Z is -C(R37a)(OR37c)-, -C(R37a)(SR37c)- or -C(R37a)(N(R37b)(R37c))-, then R37a, R14 and the carbon atom to which they are bonded when taken together form a cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl ring;
R15 is selected from the group consisting of (i) hydrogen, (ii) hydroxy, (iii) amino, (iv) C1-C12 alkyl, (v) haloalkyl, (vi) C2-C12 alkenyl, (vii) haloalkenyl, (viii) cycloalkyl, (ix) (cycloalkyl)alkyl, (x) (cycloalkyl)alkenyl, (xi) cycloalkenyl, (xii) (cycloalkenyl)alkyl, (xiii) (cycloalkenyl)alkenyl, (xiv) aryl, (xv) (aryl)alkyl, (xvi) (aryl)alkenyl, (xvii) heterocyclic, (xviii) (heterocyclic)alkyl and (xix) (heterocyclic)alkenyl;
or R3 and R4 taken together, with the atom to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 8 ring atoms;
R5 at each occurrence is independently selected from the group consisting of (a) hydrogen, (b) -CH(R38)2, (c) -(CH2)r-O-R40, (d) C2-C4 alkynyl, (e) cyclopropyl, (f) cyclobutyl, (g) -C(=Q1)-R17, and (h) -(CH2)r-N(R19)2 wherein r is 0, 1 or 2; with the proviso that when one R5 is -O-R40 or -N(R19)2, then the other R5 is other than -O-R40 or -N(R19)2;
wherein Q1 is O, S, or N(R18);
R17 and R18 are independently selected, at each occurrence, from the group consisting of hydrogen, methyl, and ethyl;
R19, R38, and R40 are independently selected, at each occurrence, from the group consisting of (i) hydrogen, (ii) C1-C12 alkyl, (iii) haloalkyl, (iv) C2-C12 alkenyl, (v) haloalkenyl, (vi) cycloalkyl, (vii) (cycloalkyl)alkyl, (viii) (cycloalkyl)alkenyl, (ix) cycloalkenyl, (x) (cycloalkenyl)alkyl, (xi) (cycloalkenyl)alkenyl, (xii) aryl, (xiii) (aryl)alkyl, (xiv) (aryl)alkenyl, (xv) heterocyclic, (xvi) (heterocyclic)alkyl and (xxiii) (heterocyclic)alkenyl;
or one R19 is an N-protecting group;
or the two R5 groups taken together with the carbon atom to which they are bonded, form a carbocyclic or heterocyclic ring having from 3 to 6 ring atoms;
Y is selected from the group consisting of (a) C1-C5 alkyl, (b) C1-C5 haloalkyl, (c) C2-C5 alkenyl, (d) C2-C5 haloalkenyl, (e) C2-C5 alkynyl, (f) C3-C5 cycloalkyl, (g) C3-C5 cycloalkyl-C1-to-C3-alkyl, (h) C5 cycloalkenyl, (i) C6 cycloalkenyl-C1-to-C3-alkyl, (j) C5 cycloalkenyl-C2-to-C3-alkenyl, (k) -(CHR39)n OR20, (l) -CH(OR20)-CH2(OR20), (m) -(CHR39)n SR21, (n) phenyl, (o) halo-substituted phenyl, (p) -(CHR39)n C(=Q2)R22, (q) -(CHR39)n N(=Q3), (r) -N(O)=CHCH3, (s) -(CHR39)n N(CH3)R24 and (t) a heterocyclic ring having from 3 to 6 ring atoms;
wherein n is 0, 1, or 2; Q2 is O, S, NR25, or CHR26; and Q3 is NR41, or CHR42;
R20 at each occurrence is independently (i) methyl, (ii) ethyl, (iii) n-propyl, (iv) isopropyl, (v) C1-C3 haloalkyl, (vi) vinyl, (vii) propenyl, (viii) isopropenyl, (ix) allyl, (x) C2-C3 haloalkenyl, (xi) amino, (xii) -NHCH3, (xiii) -N(CH3)2, (xiv) -NHCH2CH3, (xv) -N(CH3)(CH2CH3), (xvi) -N(CH2CH3)2 or (xvii) -N(=CH2);
R21 is (i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl, (vi) C1-C3 haloalkyl, (vii) vinyl, (viii) propenyl, (ix) isopropenyl, (x) allyl or (xi) C2-C3 haloalkenyl;
R22 is (i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl, (vi) hydroxy, (vii) thiol, (viii) methoxy, (ix) ethoxy, (x) n-propoxy, (xi) isopropoxy, (xii) cyclopropyloxy, (xiii) methylthio, (xiv) ethylthio, (xv) n-propylthio, (xvi) isopropylthio, (xvii) cyclopropylthio, (xviii) vinyl, (xix) propenyl, (xx) isopropenyl, (xxi) allyl, (xxii) -N(R28a)(R28b), (xxiii) -CH2R29, (xxiv) aminomethyl, (xxv) hydroxymethyl, (xxvi) thiolmethyl, (xxvii) -NHNH2, (xxviii) -N(CH3)NH2 or (xxix) -NHNH(CH3);
R23 and R39 are independently hydrogen or methyl;
R41 and R42 are independently hydrogen, methyl, or ethyl;
R24 is selected from the group consisting of (i) hydrogen, (ii) C1-C4 alkyl, (iii) C2-C4 alkenyl, (iv) C2-C4 alkynyl, (v) cyclopropyl, (vi) -C(-Q4)-R30, (v) -OR31, and (vi) -N(R32)2, wherein Q4 is O, S, or N(R33);
R25 is hydroxy, methyl, ethyl, amino, -CN, or -NO2;
R26 group is hydrogen, methyl or ethyl;
R28a hydrogen, hydroxy, methyl, ethyl, amino, -NHCH3, -N(CH3)2, methoxy, ethoxy, or -CN;
R28b is hydrogen, methyl or ethyl;
or R28a, R28b and the nitrogen to which they are bonded taken together represent azetidinyl;
R29 group is hydrogen, hydroxy, thiol, methyl, ethyl, amino, methoxy, ethoxy, methylthio, ethylthio, methylamino or ethylamino;
R30 group is hydrogen, methyl, ethyl, -OR34, -SR34, -N(R35)2, -NHOH, -NHNH2, -N(CH3)NH2, or -N(CH2CH3)NH2;
R31 and R32 substituents, at each occurrence, are independently hydrogen, methyl or ethyl;
R33 group is hydrogen, hydroxy, methyl, ethyl, amino, -CN, or -NO2;
R34 group is methyl or ethyl;
R35 group is independently hydrogen, methyl or ethyl;
with the proviso that when Q2 is CHR26 then R22 is selected from the group consisting of hydrogen, -CH3, -C2H5, -C3H7, -OCH3, -SCH3, -O-C2H5, and -S-C2H5;
R6 and R7 are independently selected from the group consisting of (b) hydrogen, (b) C1-C12 alkyl, (c) C2-C12 alkenyl, (d) cycloalkyl, (e) (cycloalkyl)alkyl, (f) (cycloalkyl)alkenyl, (g) cycloalkenyl, (h) (cycloalkenyl)alkyl, (j) (cycloalkenyl)alkenyl, (j) aryl, (k) (aryl)alkyl, (l) (aryl)alkenyl, (m) heterocyclic, (n) (heterocyclic)alkyl, (o) (heterocyclic)alkenyl, (p) -OR37a and (q) -N(R37a)2; and R8, R9, and R10 are independently selected from the group consisting of (a) hydrogen, (b) C1-C6 alkyl, (c) C2-C6 alkenyl, (d) C3-C6 cycloalkyl, (e) C3-C6 cycloalkenyl, and (f) fluorine, with the proviso that the total number of atoms, other than hydrogen, in each of R8, R9, and R10, is 6 atoms or less.
2. The compound according to Claim 1 having the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X , Y and Z1 are as defined therein.
3. The compound according to Claim 2 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, Y and Z1 are as defined therein and wherein R3 and R4 are not both the same.
4. The compound according to Claim 1 wherein R1 is defined as therein;
-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyl, halo C3-C3 loweralkyl, C2-C3 alkenyl or halo C2-C3 alkenyl or -X-R2 is wherein Y1 is -CH2-, -O-, -S- or -NH- and Y2 is -C(=O)- or -C(R aa)(R bb)-wherein R aa and R bb are independently selected from the group consisting of hydrogen, C1-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and -Z-R14 wherein Z and R14 are defined as above and wherein one of R3 and R4 is other than hydrogen;
Z1 is -O-, -S- or -CH(R5)- wherein R5 is hydrogen, loweralkyl or -(CH2)r N(R19)2 wherein r and R19 are defined as above; or R5 is hydrogen, loweralkyl or-(CH2)r N(R19)2 wherein r and R19 are defined as above;
R6 and R7 are independently hydrogen or loweralkyl;
R8 and R9 are independently hydrogen, fluoro or loweralkyl;
R10 is hydrogen, fluoro or loweralkyl; and Y is C2-C5 alkenyl, C2-C5 haloalkenyl, -C(=Q2)R22, -N(=Q3), -N(O)=CHCH3, -NR23R24 or a heterocyclic ring having from 3 to 6 ring atoms, wherein R22, R23, R24, Q2 and Q3 are defined as therein.
5. The compound according to Claim 4 having the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, Y and Z1 are as defined therein.
6. The compound according to Claim 4 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X , Y and Z1 are as defined therein and wherein R3 and R4 are not both the same.
7. The compound according to Claim 1 wherein R1 is defined as therein;
-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyl, halo C1-C3 loweralkyl, C2-C3 alkenyl or halo C2-C3 alkenyl or -X-R2 is wherein Y1 is -CH2- and Y2 is -C(=O)- or -C(R aa)(R bb)- wherein R aa and R bb are independently selected from the group consisting of hydrogen, C1-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and -Z-R14 wherein Z and R14 are defined as above and wherein one of R3 and R4 is other than hydrogen;
Z1 is -O-, -S- or -CH(R5)- wherein R5 is hydrogen, loweralkyl or (CH2)r N(R19)2 wherein r and R19 are defined as above; or R5 is hydrogen, loweralkyl or -(CH2)r N(R19)2 wherein r and R19 are defined as above;
R6 and R7 are independently hydrogen or loweralkyl;
R8 and R9 are independently hydrogen or loweralkyl;
R10 is hydrogen or loweralkyl; and Y is C2-C5 alkenyl, C2-C5 haloalkenyl, -C(=Q2)R22, -N(=Q3), -N(O)=CHCH3 or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds, wherein R22, Q2 and Q3 are defined as above.
8. The compound according to Claim 7 having the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, Y and Z1 are as defined therein.
9. The compound according to Claim 7 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, Y and Z1 are as defined therein and wherein R3 and R4 are not both the same.
11. The compound according to Claim 1 wherein R1 is defined as above;
-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyl, halo C1-C3 loweralkyl, C2-C3 alkenyl or halo C1-C3 alkenyl or -X-R2 is wherein Y1 is -CH2- and Y2 is -C(=O)- or -C(R aa)(R bb)- wherein R aa and R bb are independently selected from the group consisting of hydrogen, C1-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and -Z-R14 wherein Z and R14 are defined as above and wherein one of R3 and R4 is other than hydrogen;
Z1 is -O-, -S- or -CH(R5)- wherein R5 is hydrogen, loweralkyl or -(CH2)r N(R19)2 wherein r and R19 are defined as above; or R5 is hydrogen, loweralkyl or -(CH2)r N(R19)2 wherein r and R19 are defined as above;
R6 and R7 are independently hydrogen or loweralkyl;
R8 and R9 are independently hydrogen or loweralkyl;
R10 is hydrogen or loweralkyl; and Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
12. The compound according to Claim 11 having the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, Y and Z1 are as defined therein.
13. The compound according to Claim 11 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X , Y and Z1 are as defined therein and wherein R3 and R4 are not both the same.
14. The compound according to Claim 1 wherein R1 is -CO2H;
-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyl or halo- C1-C3 loweralkyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and -Z-R14 wherein Z and R14 are defined as above and wherein one of R3 and R4 is other than hydrogen;
Z1 is -O-, -S- or -CH2-; or R5 is hydrogen;
R6 and R7 are independently hydrogen or loweralkyl;
R8 and R9 are hydrogen independently hydrogen or loweralkyl;
R10 is hydrogen or loweralkyl; and Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
14. The compound according to Claim 14 having the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, Y and Z1 are as defined therein.
15. The compound according to Claim 14 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4. R5, R6, R7, R8, R9, R10, X , Y and Z1 are as defined therein and wherein R3 and R4 are not both the same.
16. The compound according to Claim 1 wherein R1 is -CO2H;
-X-R2 is R2-C(=O)-NH-. R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyl or halo- C1-C3 loweralkyl;
R4 is hydrogen or loweralkyl and R3 is heterocyclic or -Z-R14 wherein Z
and R14 are defined as above;
Z1 is -O-, -S- or -CH2-; or R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen;
R10 is hydrogen; and Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
17. The compound according to Claim 16 having the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X , Y and Z1 are as defined therein.
18. The compound according to Claim 16 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X , Y and Z1 are as defined therein and wherein R3 and R4 are not both the same.
19. The compound according to Claim 1 wherein R1 is -CO2H;
-X-R2 is R2-C(=O)-NH-. R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyl or halo C1-C3 loweralkyl;
R4 is hydrogen or loweralkyl and R3 is (a) heterocyclic, (b) alkyl, (c) cycloalkyl, (d) cycloalkylalkyl, (e) alkenyl, (f) alkynyl, {g) -C(=O)-R14, {h) -C(R37a)(OR37c)-R14 or (i) -C(R37a)(R37b)-N(O)(R37c)R14 wherein R14 is (j) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, {v) haloalkyl, (vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, {xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R37aO)-(O=)C-substituted alkyl or (xv) {R37aO)2-P(=O)-substituted alkyl;
R37a and R37b are independently selected from the group consisting of (i) hydrogen, (ii) loweralkyl and (iii) loweralkenyl; and R37c is hydrogen, (ii) loweralkyl or (iii) loweralkenyl;
Z1 is -O-, -S- or -CH2-; or R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen;
R10 is hydrogen: and Y is C2-C5 alkenyl. C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
19. The compound according to Claim 19 having the formula:
wherein R1, R2, R3, R4. R5, R6, R7, R8, R9, R10, X , Y and Z1 are as defined therein.
21. The compound according to Claim 19 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X , Y and Z1 are as defined therein and wherein R3 and R4 are not both the same.
22. The compound according to Claim 1 wherein R1 is -CO2H;
-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyl or halo C1-C3 loweralkyl;
R4 is hydrogen and R3 is (a) heterocyclic, (b) alkyl or (c) -C(R37a)(OR37c)-wherein R14 is (ii) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl, (vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R37aO)-(O=)C-substituted alkyl or (xv) (R37aO)2-P(=O)-substituted alkyl;
R37a and R37b are independently selected from the group consisting of (i) hydrogen, (ii) loweralkyl and (iii) loweralkenyl; and R37c is hydrogen, (ii) C1-C3 loweralkyl or (iii) allyl;
Z1 is -O-, -S- or -CH2-; or R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen ;
R10 is hydrogen; and Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
23. The compound according to Claim 22 having the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X , Y and Z1 are as defined therein.
24. The compound according to Claim 22 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X , Y and Z1 are as defined therein and wherein R3 and R4 are not both the same.
25. The compound according to Claim 1 wherein R1 is -CO2H;
-X-R2 is R2-C(=O)-NH- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyl or halo C1-C3 loweralkyl;
R4 is hydrogen and R3 is (a) heterocyclic, (b) alkyl or (c) -C(R37a)(OR37c)-wherein R14 is {i) loweralkyl, (ii) loweralkenyl, (iii) hydroxy-substituted loweralkyl or (iv) alkoxy-substituted loweralkyl;
R37a is (i) hydrogen, (ii) loweralkyl or (iii) loweralkenyl; and R37c is (i) hydrogen, (ii) C1-C3 loweralkyl or (iii) allyl;
Z1 is -O-, -S- or -CH2-; or R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen;
R10 is hydrogen; and Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
26. The compound according to Claim 25 having the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X , Y and Z1 are as defined therein.
27. The compound according to Claim 25 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X , Y and Z1 are as defined therein and wherein R3 and R4 are not both the same.
28. The compound according to Claim 1 wherein R1 is -CO2H;
-X-R2 is R2-C(=O)-NH- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyl or halo C1-C3 loweralkyl;
R4 is hydrogen and R3 is -C(R37a)(OR37c)-R14 wherein R14 is loweralkyl or loweralkenyl;
R37a is loweralkyl or loweralkenyl; and R37c is hydrogen, C1-C3 loweralkyl or allyl;
Z1 is -O-, -S- or -CH2-; or R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen;
R10 is hydrogen; and Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
29. The compound according to Claim 28 having the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X , Y and Z1 are as defined therein.
30. The compound according to Claim 28 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X , Y and Z1 are as defined therein and wherein R3 and R4 are not both the same.
31. A pharmaceutical composition for inhibiting influenza neuraminidase comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.
32. A pharmaceutical composition for treating an influenza infection comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.
33. A pharmaceutical composition for preventing an influenza infection comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.
34. A method for inhibiting neuraminidase from a disease-causing microorganism comprising administering to a human or other mammal in need thereof, a therapeutically effective amount of a compound of Claim 1.
35. The method of Claim 34 wherein the disease-causing microorganism is a virus.
36. The method of Claim 35 wherein the virus is influenza virus.
37. A method for treating a disease caused by a microorganism which has a neuraminidase, comprising administering to a human or other mammal in need thereof, a therapeutically effective amount of a compound of Claim 1.
38. The method of Claim 37 wherein the disease-causing microorganism is a virus.
39. The method of Claim 38 wherein the virus is influenza virus.
40. A method for preventing a disease caused by a microorganism which has a neuraminidase, comprising administering to a human or other mammal in need thereof, a therapeutically effective amount of a compound of Claim 1.
41. The method of Claim 40 wherein the disease-causing microorganism is a virus.
42. The method of Claim 41 wherein the virus is influenza virus.
1. A compound of the formula:
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R1 is selected from the group consisting of (b) -CO2H, (b) -CH2CO2H, (c) -SO3H, (d) -CH2SO3H, (e) -SO2H, (g) -CH2SO2H, (g) -PO3H2, (h) -CH2PO3H2, (i) -PO2H, (j) -CH2PO2H, (l) tetrazolyl, (l) -CH2-tetrazolyl, (m) -C(=O)-NH-S(O)2-R11, (o) -CH2C(=O)-NH-S(O)2-R11, (o) -SO2N(T-R11)R12 and (p) -CH2SO2N(T-R11)R12 wherein T is selected from the group consisting of (i) a bond, (ii) -C(=O)-, (iii) -C(=O)O-, (iv) -C(=O)S-, (v) -C(=O)NR36-, (vi) -C(=S)O-, (vii) -C(=S)S-, and (viii) -C(=S)NR36-, R11 is selected from the group consisting of (i) C1-C12 alkyl, (ii) C2-C12 alkenyl, (iii) cycloalkyl, (iv) (cycloalkyl)alkyl, (w) (cycloalkyl)alkenyl, (vi) cycloalkenyl, (vii) (cycloalkenyl)alkyl, (ix) (cycloalkenyl)alkenyl, (ix) aryl, (x) (aryl)alkyl, (xi) (aryl)alkenyl, (xviii) heterocyclic, (xiii) (heterocyclic)alkyl and (xix) (xiv) (heterocyclic)alkenyl; and R12 and R36 are independently selected from the group consisting of (i) hydrogen, (ii) C1-C12 alkyl, (iii) C2-C12 alkenyl, (iv) cycloalkyl, (v) (cycloalkyl)alkyl, (vi) (cycloalkyl)alkenyl, (vii) cycloalkenyl, (viii) (cycloalkenyl)alkyl, (ix) (cycloalkenyl)alkenyl, (x) aryl, (xi) (aryl)alkyl, (xii) (aryl)alkenyl, (xiii) heterocyclic, (xiv) (heterocyclic)alkyl and (xv) (heterocyclic)alkenyl;
X is selected from the group consisting of (a) -C(=O)-N(R*)-, (b) -N(R*)-C(=O)-, (c) -C(=S)-N(R*)-, (d) -N(R*)-C(=S)-, (e) -N(R*)-SO2-, and (f) -SO2-N(R*)- wherein R* is hydrogen, C1-C3 loweralkyl or cyclopropyl;
R2 is selected from the group consisting of (a) hydrogen, (b) C1-C6 alkyl, (c) C2-C6 alkenyl, (d) C3-C6 cycloalkyl, (e) C5-C6 cycloalkenyl, (f) halo C1-C6 alkyl and (g) halo C2-C6 alkenyl;
or R2-X- is wherein Y1 is -CH2-, -O-, -S- or -NH- and Y2 is -C(=O)- or -C(R aa)(R bb)-wherein R aa and R bb are indepedently selected from the group consisting of hydrogen, C1-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl;
Z1 is -O-, -S-, or C(R5)2;
R3 and R4 are independently selected from the group consisting of (a) hydrogen, (b) cycloalkyl, (c) cycloalkenyl, (d) heterocyclic, (e) aryl and (f) -Z-R14 wherein Z is (ii) -C(R37a)(R37b)-, (ii) -C(R47)=C(R48)-, (iii) -C~C-, (iv) -C(=O)-, (v) -C(=S)-, (vi) -C(=NR15)-, (vii) -C(R37a)(OR37c)-, (viii) -C(R37a)(SR37c)-, (ix) -C(R37a)(N(R37b)(R37c))-, (x) -C(R37a)(R37b)-O-, (xi) -C(R37a)(R37b)-N(R37c)-, (xii) -C(R37a)(R37b)-N(O)(R37c)-, (xiii) -C(R37a)(R37b)-N(OH)-, (xiv) -C(R37a)(R37b)-S-, (xv) -C(R37a)(R37b)-S(O)-, (xvi) -C(R37a)(R37b)-S(O)2-, (xviii) -C(R37a)(R37b)-C(=O)-, (xviii) -C(R37a)(R37b)-C(=S)-, (xxi) -C(R37a)(R37b)-C(=NR15)-, (xx) -C(R37a)(OR37c)-C(=O)-, (xxi) -C(R37a)(SR37c)-C(=O)-, (xxii) -C(R37a)(OR37c)-C(=S)-, (xxiii) -C(R37a)(SR37c)-C(=S)-, (xxiv) -C(=O)-C(R37a)(OR37c)-, (xxv) -C(=O)-C(R37a)(SR37c)- (xxvi) -C(=S)-C(R37a)(OR37c)-, (xxvii) -C(=S)-C(R37a)(SR37c)-, (xxviii) -C(R37a)(OR37c)-C(R37a)(OR37c)-, (xxix) -C(R37a)(SR37c)-C(R37a)(OR37c)-, (xxx) -C(R37a)(OR37c)-C(R37a)(SR37c)-, (xxxi) -C(R37a)(SR37c)-C(R37a)(SR37c)-, (xxxii) -C(=O)-C(=O)-, (xxxiii) -C(=S)-C(=S)-, (xxxiv) -C(=O)-O-, (xxxv) -C(=O)-S-, (xxxvi) -C(=S)-O-, (xxxvii) -C(=S)-S-, (xxxviii) -C(=O)-N(R37a)-, (xxxix) -C(=S)-N(R37a)-, (xi) -C(R37a)(R37b)-C(=O)-N(R37a)-, (xli) -C(R37a)(R37b)-C(=S)-N(R37a)-, (xlii) -C(R37a)(R37b)-C(=O)-O-, (xliii) -C(R37a)(R37b)-C(=O)-S-, (xliv) -C(R37a)(R37b)-C(=S)-O-, (xlv) -C(R37a)(R37b)-C(=S)-S- (xlvi) -C(R37a)(R37b)-N(R37b)-C(=O)-, (xlvii) -C(R37a)(R37b)-N(R37b)-C(=S)-, (xlviii) -C(R37a)(R37b)-O-C(=O)-, (xlix) -C(R37a)(R37b)-S-C(=O)-, (l) -C(R37a)(R37b)-O-C(=S)-, (li) -C(R37a)(R37b)-S-C(=S)-, (lii) -C(R37a)(R37b)-N(R37b)-C(=O)-N(R37a)-, (liii) -C(R37a)(R37b)-N(R37b)-C(=S)-N(R37a)-, (liv) -C(R37a)(R37b)-N(R37b)-C(=O)-O-, (lv) -C(R37a)(R37b)-N(R37b)-C(=O)-S-, (lvi) -C(R37a)(R37b)-N(R37b)-C(=S)-O-, (lvii) -C(R37a)(R37b)-N(R37b)-C(=S)-S-, (lviii) -C(R37a)(R37b)-O-C(=O)-N(R37a)-, (lix) -C(R37a)(R37b)-S-C(=O)-N(R37a)-, (lx) -C(R37a)(R37b)-O-C(=S)-N(R37a)-, (lxi) -C(R37a)(R37b)-S-C(=S)-N(R37a)-, (lxii) -C(R37a)(R37b)-O-C(=O)-O-, (lxiii) -C(R37a)(R37b)-S-C(=O)-O-, (lxiv) -C(R37a)(R37b)-O-C(=O)-S-, (lxv) -C(R37a)(R37b)-S-C(=O)-S-, (lxvi) -C(R37a)(R37b)-O-C(=S)-O-, (lxvii) -C(R37a)(R37b)-S-C(=S)-O-, (lxviii) -C(R37a)(R37b)-O-C(=S)-S-, (lxix) -C(R37a)(R37b)-S-C(=S)-S- or (lxx) -C(R37a)(R37b)-C(R37a)(OR37c)-;
R14 is (i) hydrogen, (ii) C1-C12 alkyl, (iii) haloalkyl, (iv) hydroxyalkyl, (v) thioi-substituted alkyl, (vi) R37c O-substituted alkyl, (vii) R37c S-substituted alkyl, (viii) aminoalkyl, (ix) (R37c)NH-substituted alkyl, (x) (R37a)(R37c)N-susbstituted alkyl, (xi) R37a O-(O=)C-substituted alkyl, (xii) R37a S-(O=)C-substituted alkyl, (xiii) R37a O-(S=)C-substituted alkyl, (xx) R37a S-(S=)C-substituted alkyl, (xxi) (R37a O)2-P(=O)-substituted alkyl, (xvi) cyanoalkyl, (xxii) C2-C12 alkenyl, (xviii) haloalkenyl, (xix) C2-C12 alkynyl, (xxii) cycloalkyl, (xxi) (cycloalkyl)alkyl, (xxii) (cycloalkyl)alkenyl, (xxiv) (cycloalkyl)alkynyl, (xxiv) cycloalkenyl, (xxv) (cycloalkenyl)alkyl, (xxvii) (cycloalkenyl)alkenyl, (xxvii) (cycloalkenyl)alkynyl, (xxviii) aryl, (xxx) (aryl)alkyl, (xxx) (aryl)alkenyl, (xxxi) (aryl)alkynyl, (xxxii) heterocyclic, (xxxiii) (heterocyclic)alkyl, (xxxiv) (heterocyclic)alkenyl or (xxxv) (heterocyclic)alkynyl, with the proviso that R14 is other than hydrogen when Z is -C(R37a)(R37b)-N(R37b)-C(=O)-O-, -C(R37a)(R37b)-N(R37b)-C(=S)-O-, -C(R37a)(R37b)-N(R37b)-C(=O)-S-, -C(R37a)(R37b)-N(R37b)-C(=S)-S-, -C(R37a)(R37b)-O-C(=O)-O-, -C(R37a)(R37b)-O-C(=S)-O-, -C(R37a)(R37b)-S-C(=O)-O-, -C(R37a)(R37b)-S-C(=S)-O-, -C(R37a)(R37b)-O-C(=O)-S-, -C(R37a)(R37b)-O-C(=S)-S-, -C(R37a)(R37b)-S-C(=O)-S-, or -C(R37a)(R37b)-S-C(=S)-S-;
R37a, R37b, R47, and R48 at each occurrence are independently selected from the group consisting of (i) hydrogen, (ii) C1-C12 alkyl, (iii) haloalkyl, (iv) hydroxyalkyl, (v) alkoxyalkyl, (vi) C2-C12 alkenyl, (vii) haloalkenyl, (viii) C2-C12 alkynyl, (ix) cycloalkyl, (x) (cycloalkyl)alkyl, (xi) (cycloalkyl)alkenyl, (xii) (cycloalkyl)alkynyl, (xiii) cycloalkenyl, (xiv) (cycloalkenyl)alkyl, (xv) (cycloalkenyl)-alkenyl, (xvi) (cycloalkenyl)alkynyl, (xvii) aryl, (xviii) (aryl)alkyl, (xix) (aryl)alkenyl, (xx) (aryl)alkynyl, (xxi) heterocyclic, (xxii) (heterocyclic)alkyl, (xxiii) (heterocyclic)alkenyl and (xxiv) (heterocyclic)alkynyl;
R37a at each occurrence is independently selected from the group consisting of (i) hydrogen, (ii) C1-C12 alkyl, (iii) haloalkyl, (iv) C2-C12 alkenyl, (v) haloalkenyl, (vi) C2-C12 alkynyl, (vii) cycloalkyl, (viii) (cycloalkyl)alkyl, (ix) (cycloalkyl)alkenyl, (x) (cycloalkyl)alkynyl, (xi) cycloalkenyl, (xii) (cycloalkenyl)alkyl, (xiii) (cycloalkenyl)alkenyl, (xiv) (cycloalkenyl)alkynyl, (xv) aryl, (xvi) (aryl)alkyl, (xvii) (aryl)alkenyl, (xviii) (aryl)alkynyl, (xix) heterocyclic, (xx) (heterocyclic)alkyl, (xxi) (heterocyclic)alkenyl, (xxiii) (heterocyclic)alkynyl, (xxiii) -C(=O)-R14, (xxiv) -C(=S)-R14, (xxv) -S(O)2-R14 and (xxvi) hydroxyalkyl;
or when Z is -C(R37a)(R37b)-N(R37c)-, then N(R37c) and R14 when taken together are an azido group;
or when Z is -C(R37a)(R37b)-N(O)(R37c)-, then N(O)(R37c) and R14 when taken together are an N-oxidized 3-7 membered heterocyclic ring having at least one N-oxidized ring nitrogen atom;
or when Z is -C(R37a)(OR37c)-, -C(R37a)(SR37c)- or -C(R37a)(N(R37b)(R37c))-, then R37a, R14 and the carbon atom to which they are bonded when taken together form a cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl ring;
R15 is selected from the group consisting of (i) hydrogen, (ii) hydroxy, (iii) amino, (iv) C1-C12 alkyl, (v) haloalkyl, (vi) C2-C12 alkenyl, (vii) haloalkenyl, (viii) cycloalkyl, (ix) (cycloalkyl)alkyl, (x) (cycloalkyl)alkenyl, (xi) cycloalkenyl, (xii) (cycloalkenyl)alkyl, (xiii) (cycloalkenyl)alkenyl, (xiv) aryl, (xv) (aryl)alkyl, (xvi) (aryl)alkenyl, (xvii) heterocyclic, (xviii) (heterocyclic)alkyl and (xix) (heterocyclic)alkenyl;
or R3 and R4 taken together, with the atom to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 8 ring atoms;
R5 at each occurrence is independently selected from the group consisting of (a) hydrogen, (b) -CH(R38)2, (c) -(CH2)r-O-R40, (d) C2-C4 alkynyl, (e) cyclopropyl, (f) cyclobutyl, (g) -C(=Q1)-R17, and (h) -(CH2)r-N(R19)2 wherein r is 0, 1 or 2; with the proviso that when one R5 is -O-R40 or -N(R19)2, then the other R5 is other than -O-R40 or -N(R19)2;
wherein Q1 is O, S, or N(R18);
R17 and R18 are independently selected, at each occurrence, from the group consisting of hydrogen, methyl, and ethyl;
R19, R38, and R40 are independently selected, at each occurrence, from the group consisting of (i) hydrogen, (ii) C1-C12 alkyl, (iii) haloalkyl, (iv) C2-C12 alkenyl, (v) haloalkenyl, (vi) cycloalkyl, (vii) (cycloalkyl)alkyl, (viii) (cycloalkyl)alkenyl, (ix) cycloalkenyl, (x) (cycloalkenyl)alkyl, (xi) (cycloalkenyl)alkenyl, (xii) aryl, (xiii) (aryl)alkyl, (xiv) (aryl)alkenyl, (xv) heterocyclic, (xvi) (heterocyclic)alkyl and (xxiii) (heterocyclic)alkenyl;
or one R19 is an N-protecting group;
or the two R5 groups taken together with the carbon atom to which they are bonded, form a carbocyclic or heterocyclic ring having from 3 to 6 ring atoms;
Y is selected from the group consisting of (a) C1-C5 alkyl, (b) C1-C5 haloalkyl, (c) C2-C5 alkenyl, (d) C2-C5 haloalkenyl, (e) C2-C5 alkynyl, (f) C3-C5 cycloalkyl, (g) C3-C5 cycloalkyl-C1-to-C3-alkyl, (h) C5 cycloalkenyl, (i) C6 cycloalkenyl-C1-to-C3-alkyl, (j) C5 cycloalkenyl-C2-to-C3-alkenyl, (k) -(CHR39)n OR20, (l) -CH(OR20)-CH2(OR20), (m) -(CHR39)n SR21, (n) phenyl, (o) halo-substituted phenyl, (p) -(CHR39)n C(=Q2)R22, (q) -(CHR39)n N(=Q3), (r) -N(O)=CHCH3, (s) -(CHR39)n N(CH3)R24 and (t) a heterocyclic ring having from 3 to 6 ring atoms;
wherein n is 0, 1, or 2; Q2 is O, S, NR25, or CHR26; and Q3 is NR41, or CHR42;
R20 at each occurrence is independently (i) methyl, (ii) ethyl, (iii) n-propyl, (iv) isopropyl, (v) C1-C3 haloalkyl, (vi) vinyl, (vii) propenyl, (viii) isopropenyl, (ix) allyl, (x) C2-C3 haloalkenyl, (xi) amino, (xii) -NHCH3, (xiii) -N(CH3)2, (xiv) -NHCH2CH3, (xv) -N(CH3)(CH2CH3), (xvi) -N(CH2CH3)2 or (xvii) -N(=CH2);
R21 is (i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl, (vi) C1-C3 haloalkyl, (vii) vinyl, (viii) propenyl, (ix) isopropenyl, (x) allyl or (xi) C2-C3 haloalkenyl;
R22 is (i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl, (vi) hydroxy, (vii) thiol, (viii) methoxy, (ix) ethoxy, (x) n-propoxy, (xi) isopropoxy, (xii) cyclopropyloxy, (xiii) methylthio, (xiv) ethylthio, (xv) n-propylthio, (xvi) isopropylthio, (xvii) cyclopropylthio, (xviii) vinyl, (xix) propenyl, (xx) isopropenyl, (xxi) allyl, (xxii) -N(R28a)(R28b), (xxiii) -CH2R29, (xxiv) aminomethyl, (xxv) hydroxymethyl, (xxvi) thiolmethyl, (xxvii) -NHNH2, (xxviii) -N(CH3)NH2 or (xxix) -NHNH(CH3);
R23 and R39 are independently hydrogen or methyl;
R41 and R42 are independently hydrogen, methyl, or ethyl;
R24 is selected from the group consisting of (i) hydrogen, (ii) C1-C4 alkyl, (iii) C2-C4 alkenyl, (iv) C2-C4 alkynyl, (v) cyclopropyl, (vi) -C(-Q4)-R30, (v) -OR31, and (vi) -N(R32)2, wherein Q4 is O, S, or N(R33);
R25 is hydroxy, methyl, ethyl, amino, -CN, or -NO2;
R26 group is hydrogen, methyl or ethyl;
R28a hydrogen, hydroxy, methyl, ethyl, amino, -NHCH3, -N(CH3)2, methoxy, ethoxy, or -CN;
R28b is hydrogen, methyl or ethyl;
or R28a, R28b and the nitrogen to which they are bonded taken together represent azetidinyl;
R29 group is hydrogen, hydroxy, thiol, methyl, ethyl, amino, methoxy, ethoxy, methylthio, ethylthio, methylamino or ethylamino;
R30 group is hydrogen, methyl, ethyl, -OR34, -SR34, -N(R35)2, -NHOH, -NHNH2, -N(CH3)NH2, or -N(CH2CH3)NH2;
R31 and R32 substituents, at each occurrence, are independently hydrogen, methyl or ethyl;
R33 group is hydrogen, hydroxy, methyl, ethyl, amino, -CN, or -NO2;
R34 group is methyl or ethyl;
R35 group is independently hydrogen, methyl or ethyl;
with the proviso that when Q2 is CHR26 then R22 is selected from the group consisting of hydrogen, -CH3, -C2H5, -C3H7, -OCH3, -SCH3, -O-C2H5, and -S-C2H5;
R6 and R7 are independently selected from the group consisting of (b) hydrogen, (b) C1-C12 alkyl, (c) C2-C12 alkenyl, (d) cycloalkyl, (e) (cycloalkyl)alkyl, (f) (cycloalkyl)alkenyl, (g) cycloalkenyl, (h) (cycloalkenyl)alkyl, (j) (cycloalkenyl)alkenyl, (j) aryl, (k) (aryl)alkyl, (l) (aryl)alkenyl, (m) heterocyclic, (n) (heterocyclic)alkyl, (o) (heterocyclic)alkenyl, (p) -OR37a and (q) -N(R37a)2; and R8, R9, and R10 are independently selected from the group consisting of (a) hydrogen, (b) C1-C6 alkyl, (c) C2-C6 alkenyl, (d) C3-C6 cycloalkyl, (e) C3-C6 cycloalkenyl, and (f) fluorine, with the proviso that the total number of atoms, other than hydrogen, in each of R8, R9, and R10, is 6 atoms or less.
2. The compound according to Claim 1 having the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X , Y and Z1 are as defined therein.
3. The compound according to Claim 2 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, Y and Z1 are as defined therein and wherein R3 and R4 are not both the same.
4. The compound according to Claim 1 wherein R1 is defined as therein;
-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyl, halo C3-C3 loweralkyl, C2-C3 alkenyl or halo C2-C3 alkenyl or -X-R2 is wherein Y1 is -CH2-, -O-, -S- or -NH- and Y2 is -C(=O)- or -C(R aa)(R bb)-wherein R aa and R bb are independently selected from the group consisting of hydrogen, C1-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and -Z-R14 wherein Z and R14 are defined as above and wherein one of R3 and R4 is other than hydrogen;
Z1 is -O-, -S- or -CH(R5)- wherein R5 is hydrogen, loweralkyl or -(CH2)r N(R19)2 wherein r and R19 are defined as above; or R5 is hydrogen, loweralkyl or-(CH2)r N(R19)2 wherein r and R19 are defined as above;
R6 and R7 are independently hydrogen or loweralkyl;
R8 and R9 are independently hydrogen, fluoro or loweralkyl;
R10 is hydrogen, fluoro or loweralkyl; and Y is C2-C5 alkenyl, C2-C5 haloalkenyl, -C(=Q2)R22, -N(=Q3), -N(O)=CHCH3, -NR23R24 or a heterocyclic ring having from 3 to 6 ring atoms, wherein R22, R23, R24, Q2 and Q3 are defined as therein.
5. The compound according to Claim 4 having the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, Y and Z1 are as defined therein.
6. The compound according to Claim 4 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X , Y and Z1 are as defined therein and wherein R3 and R4 are not both the same.
7. The compound according to Claim 1 wherein R1 is defined as therein;
-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyl, halo C1-C3 loweralkyl, C2-C3 alkenyl or halo C2-C3 alkenyl or -X-R2 is wherein Y1 is -CH2- and Y2 is -C(=O)- or -C(R aa)(R bb)- wherein R aa and R bb are independently selected from the group consisting of hydrogen, C1-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and -Z-R14 wherein Z and R14 are defined as above and wherein one of R3 and R4 is other than hydrogen;
Z1 is -O-, -S- or -CH(R5)- wherein R5 is hydrogen, loweralkyl or (CH2)r N(R19)2 wherein r and R19 are defined as above; or R5 is hydrogen, loweralkyl or -(CH2)r N(R19)2 wherein r and R19 are defined as above;
R6 and R7 are independently hydrogen or loweralkyl;
R8 and R9 are independently hydrogen or loweralkyl;
R10 is hydrogen or loweralkyl; and Y is C2-C5 alkenyl, C2-C5 haloalkenyl, -C(=Q2)R22, -N(=Q3), -N(O)=CHCH3 or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds, wherein R22, Q2 and Q3 are defined as above.
8. The compound according to Claim 7 having the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, Y and Z1 are as defined therein.
9. The compound according to Claim 7 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, Y and Z1 are as defined therein and wherein R3 and R4 are not both the same.
11. The compound according to Claim 1 wherein R1 is defined as above;
-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyl, halo C1-C3 loweralkyl, C2-C3 alkenyl or halo C1-C3 alkenyl or -X-R2 is wherein Y1 is -CH2- and Y2 is -C(=O)- or -C(R aa)(R bb)- wherein R aa and R bb are independently selected from the group consisting of hydrogen, C1-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and -Z-R14 wherein Z and R14 are defined as above and wherein one of R3 and R4 is other than hydrogen;
Z1 is -O-, -S- or -CH(R5)- wherein R5 is hydrogen, loweralkyl or -(CH2)r N(R19)2 wherein r and R19 are defined as above; or R5 is hydrogen, loweralkyl or -(CH2)r N(R19)2 wherein r and R19 are defined as above;
R6 and R7 are independently hydrogen or loweralkyl;
R8 and R9 are independently hydrogen or loweralkyl;
R10 is hydrogen or loweralkyl; and Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
12. The compound according to Claim 11 having the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, Y and Z1 are as defined therein.
13. The compound according to Claim 11 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X , Y and Z1 are as defined therein and wherein R3 and R4 are not both the same.
14. The compound according to Claim 1 wherein R1 is -CO2H;
-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyl or halo- C1-C3 loweralkyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and -Z-R14 wherein Z and R14 are defined as above and wherein one of R3 and R4 is other than hydrogen;
Z1 is -O-, -S- or -CH2-; or R5 is hydrogen;
R6 and R7 are independently hydrogen or loweralkyl;
R8 and R9 are hydrogen independently hydrogen or loweralkyl;
R10 is hydrogen or loweralkyl; and Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
14. The compound according to Claim 14 having the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, Y and Z1 are as defined therein.
15. The compound according to Claim 14 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4. R5, R6, R7, R8, R9, R10, X , Y and Z1 are as defined therein and wherein R3 and R4 are not both the same.
16. The compound according to Claim 1 wherein R1 is -CO2H;
-X-R2 is R2-C(=O)-NH-. R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyl or halo- C1-C3 loweralkyl;
R4 is hydrogen or loweralkyl and R3 is heterocyclic or -Z-R14 wherein Z
and R14 are defined as above;
Z1 is -O-, -S- or -CH2-; or R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen;
R10 is hydrogen; and Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
17. The compound according to Claim 16 having the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X , Y and Z1 are as defined therein.
18. The compound according to Claim 16 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X , Y and Z1 are as defined therein and wherein R3 and R4 are not both the same.
19. The compound according to Claim 1 wherein R1 is -CO2H;
-X-R2 is R2-C(=O)-NH-. R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyl or halo C1-C3 loweralkyl;
R4 is hydrogen or loweralkyl and R3 is (a) heterocyclic, (b) alkyl, (c) cycloalkyl, (d) cycloalkylalkyl, (e) alkenyl, (f) alkynyl, {g) -C(=O)-R14, {h) -C(R37a)(OR37c)-R14 or (i) -C(R37a)(R37b)-N(O)(R37c)R14 wherein R14 is (j) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, {v) haloalkyl, (vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, {xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R37aO)-(O=)C-substituted alkyl or (xv) {R37aO)2-P(=O)-substituted alkyl;
R37a and R37b are independently selected from the group consisting of (i) hydrogen, (ii) loweralkyl and (iii) loweralkenyl; and R37c is hydrogen, (ii) loweralkyl or (iii) loweralkenyl;
Z1 is -O-, -S- or -CH2-; or R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen;
R10 is hydrogen: and Y is C2-C5 alkenyl. C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
19. The compound according to Claim 19 having the formula:
wherein R1, R2, R3, R4. R5, R6, R7, R8, R9, R10, X , Y and Z1 are as defined therein.
21. The compound according to Claim 19 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X , Y and Z1 are as defined therein and wherein R3 and R4 are not both the same.
22. The compound according to Claim 1 wherein R1 is -CO2H;
-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyl or halo C1-C3 loweralkyl;
R4 is hydrogen and R3 is (a) heterocyclic, (b) alkyl or (c) -C(R37a)(OR37c)-wherein R14 is (ii) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl, (vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R37aO)-(O=)C-substituted alkyl or (xv) (R37aO)2-P(=O)-substituted alkyl;
R37a and R37b are independently selected from the group consisting of (i) hydrogen, (ii) loweralkyl and (iii) loweralkenyl; and R37c is hydrogen, (ii) C1-C3 loweralkyl or (iii) allyl;
Z1 is -O-, -S- or -CH2-; or R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen ;
R10 is hydrogen; and Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
23. The compound according to Claim 22 having the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X , Y and Z1 are as defined therein.
24. The compound according to Claim 22 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X , Y and Z1 are as defined therein and wherein R3 and R4 are not both the same.
25. The compound according to Claim 1 wherein R1 is -CO2H;
-X-R2 is R2-C(=O)-NH- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyl or halo C1-C3 loweralkyl;
R4 is hydrogen and R3 is (a) heterocyclic, (b) alkyl or (c) -C(R37a)(OR37c)-wherein R14 is {i) loweralkyl, (ii) loweralkenyl, (iii) hydroxy-substituted loweralkyl or (iv) alkoxy-substituted loweralkyl;
R37a is (i) hydrogen, (ii) loweralkyl or (iii) loweralkenyl; and R37c is (i) hydrogen, (ii) C1-C3 loweralkyl or (iii) allyl;
Z1 is -O-, -S- or -CH2-; or R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen;
R10 is hydrogen; and Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
26. The compound according to Claim 25 having the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X , Y and Z1 are as defined therein.
27. The compound according to Claim 25 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X , Y and Z1 are as defined therein and wherein R3 and R4 are not both the same.
28. The compound according to Claim 1 wherein R1 is -CO2H;
-X-R2 is R2-C(=O)-NH- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyl or halo C1-C3 loweralkyl;
R4 is hydrogen and R3 is -C(R37a)(OR37c)-R14 wherein R14 is loweralkyl or loweralkenyl;
R37a is loweralkyl or loweralkenyl; and R37c is hydrogen, C1-C3 loweralkyl or allyl;
Z1 is -O-, -S- or -CH2-; or R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen;
R10 is hydrogen; and Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
29. The compound according to Claim 28 having the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X , Y and Z1 are as defined therein.
30. The compound according to Claim 28 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X , Y and Z1 are as defined therein and wherein R3 and R4 are not both the same.
31. A pharmaceutical composition for inhibiting influenza neuraminidase comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.
32. A pharmaceutical composition for treating an influenza infection comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.
33. A pharmaceutical composition for preventing an influenza infection comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.
34. A method for inhibiting neuraminidase from a disease-causing microorganism comprising administering to a human or other mammal in need thereof, a therapeutically effective amount of a compound of Claim 1.
35. The method of Claim 34 wherein the disease-causing microorganism is a virus.
36. The method of Claim 35 wherein the virus is influenza virus.
37. A method for treating a disease caused by a microorganism which has a neuraminidase, comprising administering to a human or other mammal in need thereof, a therapeutically effective amount of a compound of Claim 1.
38. The method of Claim 37 wherein the disease-causing microorganism is a virus.
39. The method of Claim 38 wherein the virus is influenza virus.
40. A method for preventing a disease caused by a microorganism which has a neuraminidase, comprising administering to a human or other mammal in need thereof, a therapeutically effective amount of a compound of Claim 1.
41. The method of Claim 40 wherein the disease-causing microorganism is a virus.
42. The method of Claim 41 wherein the virus is influenza virus.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US6580398A | 1998-04-23 | 1998-04-23 | |
| US09/065,803 | 1998-04-23 | ||
| PCT/US1999/007949 WO1999054290A1 (en) | 1998-04-23 | 1999-04-12 | Inhibitors of neuraminidases |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2329660A1 true CA2329660A1 (en) | 1999-10-28 |
Family
ID=22065213
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002329660A Abandoned CA2329660A1 (en) | 1998-04-23 | 1999-04-12 | Inhibitors of neuraminidases |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP1087938A1 (en) |
| JP (1) | JP2002521312A (en) |
| CA (1) | CA2329660A1 (en) |
| WO (1) | WO1999054290A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104387288A (en) * | 2014-11-25 | 2015-03-04 | 广东东阳光药业有限公司 | Compound as neuraminidase inhibitor and application of compound in medicine |
| CN104496838A (en) * | 2014-12-03 | 2015-04-08 | 广东东阳光药业有限公司 | Substituted-cyclobutane neuraminidase inhibitor as well as using method and application of substituted-cyclobutane neuraminidase inhibitor |
| CN104496839A (en) * | 2014-12-03 | 2015-04-08 | 广东东阳光药业有限公司 | Substituted-cyclobutane neuraminidase inhibitor as well as using method and application of substituted-cyclobutane neuraminidase inhibitor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3481255B2 (en) | 1996-06-14 | 2003-12-22 | バイオクリスト ファーマシューティカルズ インク． | Cyclopentane-substituted compounds useful as neuraminidase inhibitors |
| ES2324746T3 (en) | 1997-12-17 | 2009-08-13 | Biocryst Pharmaceuticals Inc. | CYCLOPENTANE AND CYCLOPENTENE COMPOUNDS REPLACED USEFUL AS INHIBITORS OF NEURAMINIDASA. |
| US6455571B1 (en) * | 1998-04-23 | 2002-09-24 | Abbott Laboratories | Inhibitors of neuraminidases |
| US6518305B1 (en) | 1998-04-23 | 2003-02-11 | Abbott Laboratories | Five-membered carbocyclic and heterocyclic inhibitors of neuraminidases |
| WO2000028328A1 (en) | 1998-11-05 | 2000-05-18 | Biocryst Pharmaceuticals, Inc. | New cyclopentane and cyclopentene compounds and use for detecting influenza virus |
| US8048147B2 (en) * | 2007-06-27 | 2011-11-01 | Aga Medical Corporation | Branched stent/graft and method of fabrication |
| CN102964267B (en) * | 2011-09-01 | 2015-06-10 | 中山大学 | Cyclohexene compound having influenza virus neuraminidase inhibition activity, preparation method and application |
| KR101568974B1 (en) | 2015-02-26 | 2015-11-13 | 전남대학교산학협력단 | Vectors and processes for expression of neuraminidase N1 of avian influenza virus in E. coli, methods of using the same, and agents for inhibiting activities of the neuraminidase |
| KR101566157B1 (en) | 2015-02-26 | 2015-11-05 | 전남대학교산학협력단 | Vectors and processes for expression of neuraminidase N1 of avian influenza virus in E. coli, methods of using the same, and agents for inhibiting activities of the neuraminidase |
| KR101566156B1 (en) | 2015-02-26 | 2015-11-05 | 전남대학교산학협력단 | Vectors and processes for expression of neuraminidase N1 of avian influenza virus in E. coli, methods of using the same, and agents for inhibiting activities of the neuraminidase |
| JP2019530664A (en) * | 2016-09-08 | 2019-10-24 | ザ テキサス エー アンド エム ユニバーシティ システム | Antifibrotic sialidase inhibitor compounds and methods of use |
| KR20210145787A (en) | 2019-04-02 | 2021-12-02 | 알리고스 테라퓨틱스 인코포레이티드 | Compounds targeting PRMT5 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AP249A (en) * | 1990-04-24 | 1993-03-17 | Biota Scient Management Pty Ltd | Anti-viral compounds. |
| GB9400206D0 (en) * | 1994-01-07 | 1994-03-02 | Glaxo Group Ltd | Chemical compound |
| GB9516276D0 (en) * | 1995-08-08 | 1995-10-11 | Biota Scient Management | Chemical compounds |
| JP3481255B2 (en) * | 1996-06-14 | 2003-12-22 | バイオクリスト ファーマシューティカルズ インク． | Cyclopentane-substituted compounds useful as neuraminidase inhibitors |
| ES2324746T3 (en) * | 1997-12-17 | 2009-08-13 | Biocryst Pharmaceuticals Inc. | CYCLOPENTANE AND CYCLOPENTENE COMPOUNDS REPLACED USEFUL AS INHIBITORS OF NEURAMINIDASA. |
-
1999
- 1999-04-12 JP JP2000544631A patent/JP2002521312A/en not_active Withdrawn
- 1999-04-12 CA CA002329660A patent/CA2329660A1/en not_active Abandoned
- 1999-04-12 EP EP99918495A patent/EP1087938A1/en not_active Withdrawn
- 1999-04-12 WO PCT/US1999/007949 patent/WO1999054290A1/en not_active Application Discontinuation
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104387288A (en) * | 2014-11-25 | 2015-03-04 | 广东东阳光药业有限公司 | Compound as neuraminidase inhibitor and application of compound in medicine |
| CN104496838A (en) * | 2014-12-03 | 2015-04-08 | 广东东阳光药业有限公司 | Substituted-cyclobutane neuraminidase inhibitor as well as using method and application of substituted-cyclobutane neuraminidase inhibitor |
| CN104496839A (en) * | 2014-12-03 | 2015-04-08 | 广东东阳光药业有限公司 | Substituted-cyclobutane neuraminidase inhibitor as well as using method and application of substituted-cyclobutane neuraminidase inhibitor |
| CN104496838B (en) * | 2014-12-03 | 2016-04-20 | 广东东阳光药业有限公司 | Substituted ring butanes neuraminidase inhibitor and using method thereof and purposes |
| CN104496839B (en) * | 2014-12-03 | 2016-04-20 | 广东东阳光药业有限公司 | Substituted ring butanes neuraminidase inhibitor and using method thereof and purposes |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1999054290A1 (en) | 1999-10-28 |
| JP2002521312A (en) | 2002-07-16 |
| EP1087938A1 (en) | 2001-04-04 |
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| Date | Code | Title | Description |
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| EEER | Examination request | ||
| FZDE | Dead |