JP2001516739A - Compounds containing 6-membered rings, their preparation process and their use as medicaments - Google Patents

Abstract

  (57) [Summary] New compounds have been described. The compounds generally contain an acidic group, a basic group, a substituted amino or N-acyl, and optionally a group having a hydroxylated alkane moiety. Pharmaceutical compositions comprising the inhibitors of the present invention have also been described. Methods for inhibiting neuraminidase in a sample suspected of containing neuraminidase have also been described. Antigenic agents, polymers, antibodies, conjugates of the compounds of the invention with a label, and assays for the detection of neuraminidase activity are also described.

Description

DETAILED DESCRIPTION OF THE INVENTION

(Citation of Related Application) This application is related to US Provisional Application No. 60 / 060,195 (filed on Sep. 26, 1997) and US Patent Application No. 08 / 938,644 (September 1997). 26/26) and US Provisional Application No. 60 / 059,308 (filed September 17, 1997).

[0002] This application is also related to US patent application Ser. No. 08 / 653,034, filed Mar. 24, 1996, which is incorporated by reference in US patent application Ser. No. 08 / 606,624.
No. 08 / 580,567 (filed on Dec. 29, 1995), which is a continuation-in-part application of U.S. Pat. This application is related to U.S. patent application Ser. No. 08 / 476,946 (199).
(Filed on June 6, 2005), which is filed in US patent application Ser.
No. 8 / 395,245, filed Feb. 27, 1995, all of which are incorporated herein by reference in their entirety. This application is related to US patent application Ser. No. 08 / 917,640, filed Aug. 22, 1997, which describes a process for making carbocyclic compounds in a specific process for making GS4104, a phosphate. And are incorporated by reference in their entirety.

FIELD OF THE INVENTION [0003] Neuraminidase (also known as sialidase, acylneuraminyl hydrolase, and EC 3.2.1.18) is a common enzyme among animals and many microorganisms. It is a glycolytic enzyme that cleaves terminal α-ketoside linked sialic acids from glycoproteins, glycolipids, and oligosaccharides. Many microorganisms, including neuraminidase, are pathogenic to humans and other animals, including chickens, horses, pigs, and seals. These pathogenic organisms include the influenza virus.

[0004] Neuraminidase has been implicated in the pathogenicity of influenza viruses. This helps to elute newly synthesized virions from infected cells and is thought to assist in the movement of the virus (through hydrolytic enzyme activity) through the mucus of the respiratory tract.

BRIEF DESCRIPTION OF RELATED ART von Itzstein, M.S. Nature, 363 (6428).
): 418-423 (1993) disclose the theoretical design of sialidase-based inhibitors of influenza virus replication.

[0006] Colman, P .; M. International Patent Publication No. WO 92/06691 (International Application No. PCT / AU90 / 00501, published on April 30, 1992), v.
on Itzstein, L.C. M. Et al., European Patent Publication No. 0 539 204
A1 (European Patent Application No. 923099684.6, published on April 28, 1993), and von Itzstein, L.A. M. Et al., International Publication Number WO 91
/ 16320 (International Application No. PCT / AU91 / 00161, published October 31, 1991) discloses compounds that bind to neuraminidase and exhibit antiviral activity in vivo.

(Object of the Invention) The main object of the present invention is the inhibition of viruses, especially influenza viruses. In particular, it is aimed at the inhibition of glycolytic enzymes such as neuraminidase, in particular the selective inhibition of viral or bacterial neuraminidase.

[0008] It is a further object of the invention that the rate of urinary excretion is slow, enters the nasal or pulmonary secretions from the systemic circulation, has sufficient therapeutically effective oral bioavailability,
It is to provide neuraminidase inhibitors with improved potency, exhibiting a clinically acceptable toxicity profile and having other desirable pharmacological properties.

[0009] Another object is to provide an improved and low cost method for the synthesis of neuraminidase inhibitors.

A still further object is to provide improved methods of administering known and novel neuraminidase inhibitors.

A further object is to provide compositions useful for preparing polymers, surfactants, or immunogens, and for use in other industrial processes and articles.

[0012] These and other objects will be readily apparent to one of ordinary skill in the art in light of the present invention as a whole.

SUMMARY OF THE INVENTION Compounds or compositions having formula (I) or (II), and salts thereof,
Solvates, resolved enantiomers, and purified diastereomers are
Provided herein:

[0014]

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Wherein A ₁ is —C (J ₁ ) =, —N = or —N (O) =; A ₂ is —C (J ₁ ) ₂ —, —N (J ₁ ) —, − _{N (O) (J 1)} -, - S -, - S (O) -, - S (O) 2 -, or -O- and is; E ₁ is - in _{(CR 1 R 1) m1 W} 1 There; G _{1 is, N 3, -CN, -OH,} -OR 6a, -NO 2 , or, - (CR ₁ R ₁₎ be _m1 W _2; T _{1 is, -NR 1 W 3, H,} - R ₃ , —R ₅ , a heterocyclic ring, or together with U ₁ or G ₁ , form a group having the following structure;

[0016]

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U ₁ is H, —R ₃ or —X ₁ W ₆ ; J ₁ and J _1a are independently R ₁ , Br, Cl, F, I, CN, NO ₂ , or N ₃ J ₂ and J _2a are independently H or R ₁ ; R ₁ is independently H or alkyl having 1 to 12 carbon atoms; R ₂ is independently R ₃ or R _4, wherein each R ₄ is independently substituted with 0-3 R ₃ groups; R ₃ is independently

[0018]

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R_FourIs independently alkyl having 1 to 12 carbon atoms, alkenyl having 2 to 12 carbon atoms, or alkyl having 2 to 12 carbon atoms.
Nyl; R_FiveIs independently R_FourWhere each R_FourIs 0 to 3 R_ThreeSubstituted with a group; R_5aIs independently an alkylene having 1 to 12 carbon atoms, 2 to 12
Alkenylene having 2 carbon atoms, or alkenylene having 2 to 12 carbon atoms
Quinylene; these alkylene, alkenylene, or alkynylene
Any one of the 0 to 3 R_ThreeSubstituted with a group; R_6aIs independently H, or an ether-forming group or an ester-forming group;_6bIs independently a protecting group for H, amino, or a carboxyl-containing compound
R_6cIs independently H or the residue of an amino-containing compound; W₁Is a group containing an acidic hydrogen, a protected acidic group, or a group containing an acidic hydrogen._6cAmide; W_TwoIs a basic heteroatom or a protected basic heteroatom, or a basic heteroatom R_6bA group containing an amide or a group derivatizable to a basic hetero atom
R; W_ThreeIs W_FourOr W_FiveAnd W_FourIs R_FiveOr -C (O) R_Five, -C (O) W_Five, -SO_TwoR_FiveOr -SO _Two W_FiveAnd W_FiveIs a carbocyclic or heterocyclic ring, wherein W_FiveIndependently represent 0 to 3 R_Two Substituted with a group; W₆Is -R_Five, -W_Five, -R_5aW_Five, -C (O) OR_6a, -C (O) R_6c, -C
(O) N (R_6b)_Two, -C (NR_6b) (N (R_6b)_Two), -C (NR_6b) (N (H
) (R_6b)), -C (N (H) (N (R_6b)_Two), -C (S) N (R_6b)_Two,Also
Is -C (O) R_TwoAnd X₁Is a bond, -O-, -N (H)-, -N (W₆)-, -N (OH)-, -N
(OW₆)-, -N (NH_Two)-, -N (N (H) (W₆))-, -N (N (W₆) _Two )-, -N (H) N (W₆)-, -S-, -SO-, or -SO_TwoAnd each m1 is independently an integer of 0 to 2, provided that the compound described in WO 91/16320, page 3, line 23 to page 5, line 6,
And their pharmaceutically acceptable salts and solvates. These compounds
Seems to include the following compounds: Where: (a) A₁Is -CH = or -N =, and A_TwoIs -CH_Two(B) E₁Is COOH, P (O) (OH)_Two, SOOH, SO_ThreeH, or tetrazole; (c) G₁Is CN, N (H) R₂₀, N_Three, SR₂₀, OR₂₀, Guanidino, -N
(H) CN,

[0020]

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(D) T ₁ is —NHR ₂₀ ; (e) R ₂₀ is H; an acyl group having 1 to 4 carbon atoms; a straight chain having 1 to 6 carbon atoms. A chain or cyclic alkyl group or a halogen-substituted analog thereof; an allyl group or an unsubstituted aryl group or an aryl substituted with a halogen, OH group, NO ₂ group, NH ₂ group, or COOH group; (f) J ₁ is H And J _1a is H, F, Cl, Br, or CN; (g) J ₂ is H, and J _2a is H, CN, or N ₃ ; (h) U ₁ is CH ₂ YR _20a , CHYR _20a CH ₂ YR _20a , or CHYR _20a CHYR _20a CH ₂ YR _20a ; (i) R _20a is H or an acyl having 1 to 4 carbon atoms. (J) Y is O, S, H or NH; (k) Number to 2 amino YR _20a is H, and (l) successive Y moieties in U ₁ group is the same or different, and when Y is H is R _20a is a covalent bond, however, G ₁ in the case of N ₃ U ₁ is not -CH ₂ OCH ₂ Ph.

In the present specification, compounds described in WO 92/06691, page 9, line 26 to page 11, line 5, and pharmacologically acceptable salts or derivatives thereof are also excluded. These compounds appear to include compounds of formula II. Where: (a) A ₂ is O; (b) E ₁ is COOH, P (O) (OH) ₂ , NO ₂ , SOOH, SO ₃ H, tetrazole, CH ₂ CHO, CHO, CH (CHO) ) if ₂ or where E ₁ is CO OH, P (O) ( OH) 2, SOOH or SO ₃ H, their ethyl, methyl or pivaloyl ester; (c) G ₁ is Hydrogen, N (R ^20a ) ₂ , SR ^20a or OR ^20a ; (d) T ₁ is —NHC (O) R ^20b, wherein R ^20b is unsubstituted or halogen-substituted from 1 to 6 carbon atoms. A linear or cyclic alkyl group), or SR ^20a , OR ^20a , COOH or an alkyl / aryl ester thereof, NO ₂ , C (
R ^20a ) ₃ , CH ₂ COOH or their alkyl / aryl esters, CH ₂ N
Be O ₂ or ^{_{CH 2 NHR 20b; (e)}} R 20a is hydrogen; linear or cyclic alkyl group or a halogen having 1 to 6 carbon atoms; an acyl group having 1 to 4 carbon atoms Substituted analogs;
Or an unsubstituted aryl group or an aryl substituted by a halogen, allyl group, OH group, NO ₂ group, NH ₂ group or COOH group; (f) J ₁ is H, and J _1a is H , OR ^20a , F, Cl, Br, CN,
NHR ^20a , SR ^20a or CH ₂ X, where X is NHR ^20a , halogen or OR ^20a ; (g) J ₂ is H or J _2a is hydrogen, N (R ^20a ) ₂ , SR ^20a or OR ^20a ; (h) U ₁ is CH ₂ YR ^20a , CHYR ²⁰ CH ₂ YR ^20a , or CHYR ^20a C
A HYR ^20a CH ₂ YR ^20a, wherein Y is O, S or H, and successive Y moieties in U ₁ are the same or different, and when Y is hydrogen R ^{20 a} is a covalent bond Represents

Another embodiment of the present invention relates to compounds having the formula: and salts, solvates, resolved enantiomers, and purified diastereomers thereof:

[0024]

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Wherein E ₁ is — (CR ₁ R ₁ ) _m1 W ₁ ; G ₁ is N ₃ , —CN, —OH, —OR _6a , —NO ₂ , or — (CR ₁ R ₁ ) _{m 1} W ₂ ; T ₁ is —NR ₁ W ₃ , is a heterocyclic ring, or forms together with U ₁ or G ₁ a group having the following structure:

[0026]

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U ₁ is H or —X ₁ W ₆ , and when —X ₁ W ₆ , U ₁ is branched; J ₁ and J _1a are independently R ₁ , Br , Cl, F, I, CN, NO ₂ , or N ₃ ; J ₂ and J _2a are independently H or R ₁ ; R ₁ is independently H or 1 to 12 R ₂ is independently R ₃ or R ₄ , wherein each R ₄ is independently substituted with 0 to 3 R ₃ groups; R ₃ is alkyl having carbon atoms; ,Independently

[0028]

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R_FourIs independently alkyl having 1 to 12 carbon atoms, alkenyl having 2 to 12 carbon atoms, or alkynyl having 2 to 12 carbon atoms.
R; R_FiveIs independently R_FourWhere each R_FourIs 0 to 3 R_ThreeSubstituted with a group; R_5aIs independently an alkylene having 1 to 12 carbon atoms, 2 to 12
Alkenylene having 2 carbon atoms, or alkenylene having 2 to 12 carbon atoms
Quinylene; of these alkylene, alkenylene or alkynylene
Any one of 0 to 3 R_ThreeSubstituted with a group; R_6aIs independently H, or an ether-forming group or an ester-forming group;_6bIs independently a protecting group for H, amino, or a carboxyl-containing compound
R_6cIs independently H or the residue of an amino-containing compound; W₁Represents a group containing an acidic hydrogen, a protected acidic group, or a group containing an acidic hydrogen._6cAn amide; W_TwoIs a group containing a basic heteroatom or a protected basic heteroatom, or R_6bAn amide; W_ThreeIs W_FourOr W_FiveAnd W_FourIs R_FiveOr -C (O) R_Five, -C (O) W_Five, -SO_TwoR_FiveOr -SO _Two W_FiveAnd W_FiveIs a carbocyclic or heterocyclic ring, wherein W_FiveIs independently 0 to 3 R_Two Substituted with a group; W₆Is -R_Five, -W_Five, -R_5aW_Five, -C (O) OR_6a, -C (O) R_6c, -C
(O) N (R_6b)_Two, -C (NR_6b) (N (R_6b)_Two), -C (S) N (R_6b)_Two Or -C (O) R_TwoAnd X₁Is a bond, -O-, -N (H)-, -N (W₆)-, -N (OH)-, -N
(OW₆)-, -N (NH_Two)-, -N (N (H) (W₆))-, -N (N (W₆) _Two )-, -N (H) N (W₆)-, -S-, -SO-, or -SO_TwoAnd each m1 is independently an integer from 0 to 2.

Another embodiment of the present invention relates to compounds having the formula: and salts, solvates, resolved enantiomers, and purified diastereomers thereof:

[0031]

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Wherein E ₁ is — (CR ₁ R ₁ ) _m1 W ₁ ; G ₁ is N ₃ , —CN, —OH, —OR _6a , —NO ₂ , or — (CR ₁ R ₁ ) _{m 1} W ₂ ; T ₁ is —NR ₁ W ₃ , is a heterocyclic ring, or forms together with U ₁ or G ₁ a group having the following structure;

[0033]

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U ₁ is H or —X ₁ W ₆ ; J ₁ and J _1a are independently R ₁ , Br, Cl, F, I, CN, NO ₂ , or N ₃ ; J ₂ And J _2a are independently H or R ₁ ; R ₁ is independently H or alkyl having 1 to 12 carbon atoms; R ₂ is independently R ₃ or R ₄ Wherein each R ₄ is independently substituted with 0 to 3 R ₃ groups; R ₃ is independently

[0035]

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R is_FourIs independently alkyl having 1 to 12 carbon atoms, alkenyl having 2 to 12 carbon atoms, or alkyl having 2 to 12 carbon atoms.
Nyl; R_FiveIs independently R_FourWhere each R_FourIs 0 to 3 R_ThreeSubstituted with a group; R_5aIs independently an alkylene having 1 to 12 carbon atoms, 2 to 12
Alkenylene having 2 carbon atoms, or alkenylene having 2 to 12 carbon atoms
Quinylene; of these alkylene, alkenylene or alkynylene
Any one of 0 to 3 R_ThreeSubstituted with a group; R_6aIs independently H, or an ether-forming group or an ester-forming group;_6bIs independently a protecting group for H, amino, or a carboxyl-containing compound
R_6cIs independently H or the residue of an amino-containing compound; W₁Is a group containing an acidic hydrogen, a protected acidic group, or a group containing an acidic hydrogen._6cAmide; W_TwoIs a group containing a basic heteroatom or a protected basic heteroatom, or R_6bA group containing an amide; W_ThreeIs W_FourOr W_FiveAnd W_FourIs R_FiveOr -C (O) R_Five, -C (O) W_Five, -SO_TwoR_FiveOr -SO _Two W_FiveAnd W_FiveIs a carbocyclic or heterocyclic ring, wherein W_FiveIndependently represent 0 to 3 R_Two Substituted with a group; W₆Is -R_Five, -W_Five, -R_5aW_Five, -C (O) OR_6a, -C (O) R_6c, -C
(O) N (R_6b)_Two, -C (NR_6b) (N (R_6b)_Two), -C (S) N (R_6b)_Two Or -C (O) R_TwoAnd X₁Represents -O-, -N (H)-, -N (W₆)-, -N (OH)-, -N (OW ₆ )-, -N (NH_Two)-, -N (N (H) (W₆))-, -N (N (W₆)_Two)-, -N (H) N (W₆)-, -S-, -SO-, or -SO_TwoAnd each m1 is independently an integer from 0 to 2.

Another embodiment of the invention relates to compounds having the formula: and salts, solvates, resolved enantiomers, and purified diastereomers thereof:

[0038]

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Where: E ₁ is —CO ₂ R ₁ ; G ₁ is —NH ₂ , —N (H) (R ₅ ), or —N (H) (C (N (H)) ( NH ₂ )); T ₁ is —N (H) (C (O) CH ₃ ); U ₁ is —OR ₆₀ ; R ₁ is H or 1, 2, 3, R ₆₀ is alkyl having 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms; and R ₆₀ is 3, 4, 5, A branched alkyl having 6, 7, 8, 9, 10, 11, or 12 carbon atoms.

Another embodiment of the present invention relates to compounds having the following formula (VII) or (VIII), and salts, solvates, resolved enantiomers, and purified diastereomers thereof:

[0041]

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Where E ₁ is — (CR ₁ R ₁ ) _m1 W ₁ ; G ₁ is N ₃ , —CN, —OH, —OR _6a , —NO ₂ , or — (CR ₁ R ₁ ) _{m 1} W ₂ ; T ₁ is —NR ₁ W ₃ , is a heterocyclic ring or forms together with G ₁ a group having the following structure:

[0043]

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U ₁ is -X ₁ W ₆ ; J ₁ and J _1a are independently R ₁ , Br, Cl, F, I, CN, NO ₂ , or N ₃ ; J ₂ and J _2a is independently H or R ₁ ; R ₁ is independently H or alkyl having 1 to 12 carbon atoms; R ₂ is independently R ₃ or R ₄ , wherein each R ₄ is independently substituted with 0-3 R ₃ groups; R ₃ is independently

[0045]

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R;_FourIs independently alkyl having 1 to 12 carbon atoms, alkenyl having 2 to 12 carbon atoms, or alkynyl having 2 to 12 carbon atoms.
R; R_FiveIs independently R_FourWhere each R_FourIs 0 to 3 R_ThreeSubstituted with a group; R_5aIs independently an alkylene having 1 to 12 carbon atoms, 2 to 12
Alkenylene having 2 carbon atoms, or alkenylene having 2 to 12 carbon atoms
Quinylene; these alkylene, alkenylene, or alkynylene
Any one of the 0 to 3 R_ThreeSubstituted with a group; R_6aIs independently H, or an ether-forming group or an ester-forming group;_6bIs independently a protecting group for H, amino, or a carboxyl-containing compound
R_6cIs independently H or the residue of an amino-containing compound; W₁Is a group containing an acidic hydrogen, a protected acidic group, or a group containing an acidic hydrogen._6cAmide; W_TwoIs a group containing a basic heteroatom or a protected basic heteroatom, or R_6bA group containing an amide; W_ThreeIs W_FourOr W_FiveAnd W_FourIs R_FiveOr -C (O) R_Five, -C (O) W_Five, -SO_TwoR_FiveOr -SO _Two W_FiveAnd W_FiveIs a carbocyclic or heterocyclic ring, wherein W_FiveIndependently represent 0 to 3 R _Two Substituted with a group; W₆Is -R_Five, -W_Five, -R_5aW_Five, -C (O) OR_6a, -C (O) R_6c, -C
(O) N (R_6b)_Two, -C (NR_6b) (N (R_6b)_Two), -C (NR_6b) (N (H
) (R_6b)), -C (N (H) (N (R_6b)_Two), -C (S) N (R_6b)_Two,Also
Is -C (O) R_TwoAnd X₁Is a bond, -O-, -N (H)-, -N (W₆)-, -S-, -SO-,
Or -SO_TwoAnd each m1 is independently an integer from 0 to 2;₁Is H or -CH_TwoCH (OH) CH_TwoCompounds that are (OH) are excluded.

In another embodiment of the present invention, a compound or composition of the present invention is provided to further include a pharmaceutically acceptable carrier.

In another embodiment of the invention, the activity of neuraminidase is inhibited by a method comprising treating a sample suspected of containing neuraminidase with a compound or composition of the invention.

Another embodiment of the present invention provides a method of inhibiting neuraminidase activity comprising contacting a sample suspected of containing neuraminidase with a composition of an embodiment of the present invention.

Another embodiment of the present invention is described in WO 91/16320, WO 92/0669.
No. 1 or US Pat. No. 5,360,817, comprising administering a therapeutically effective dose of an antivirally active compound to a host by a non-local route to the respiratory tract, particularly a virus in the host. A method for the treatment or prevention of influenza virus infection.

In another embodiment, a novel method for synthesizing a compound of the present invention is provided. In one such embodiment, there is provided a method of using a compound of formula 281:
Here, the method of the compound 281 is treated with a compound of formula R ₅ -X ₁ -H Formula 28
1.1 forming a compound of:

[0052]

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Wherein: X ₁ and R ₅ are as described above; R ₅₁ is an acid-stable protecting group for carboxylic acids; and R ₅₄ is an aziridine activating group.

In another embodiment, there is provided a method of using a compound having the formula:

[0055]

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Here, the method comprises the step of treating quinic acid with a geminal dialkoxyalkane or geminal dialkoxycycloalkane and an acid to form a compound having the formula:

[0057]

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Treating compound 274 with a metal alkoxide and an alkanol to form a compound having the formula:

[0059]

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Treatment of compound 275 with a sulfonic halide and an amine to form a compound having the formula:

[0061]

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And treating compound 276 with a dehydrating agent followed by treatment with an acid and an alkanol to form a compound having the formula:

[0063]

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Wherein R ₅₀ is a 1,2 diol protecting group; R ₅₁ is an acid stable carboxylic acid protecting group; and R ₅₂ is a hydroxy activating group.

(Detailed description) (Composition of the present invention) The compounds of the present invention exclude compounds known so far. However, as will become more apparent below in other embodiments, the known compounds, which have heretofore been produced and used only as intermediates in the preparation of antiviral compounds, can be used for the purpose of antiviral agents. Use is within the scope of the present invention. With respect to the United States, compounds or compositions herein exclude compounds that are described under 35 USC 102 or are obvious under 35 USC 103. In particular, the appended claims refer to WO 91/16320, WO 92/06691, and U.S. Patent No. 5,360,817, or Chandler, M.A. J. et al. Chem. Soc. Perkin Trans. 1 ", 1189
-1197 (1995) or should be construed as meaning excluding compounds which are not novel to these documents.

Nevertheless, in an embodiment of the invention, WO 91/16320
Nos. WO 92/06691, or US Pat. No. 5,360,817 are recognized, but these compounds are (a) '
320 has the formula Ia the application, (b) '320 has a carbon for group "A" in the application, and (c)' 320 and '691 R ⁵ application "-CH ₂ YR ^6, - CHYR ⁶ CH ₂ YR ^6, or -CHYR ⁶ CHYR ⁶ CH ₂ YR ⁶ ". Here, YR ⁶ cannot be either OH or protected OH, where the protecting group is hydrolysable, producing free OH under conditions of the human gastrointestinal tract (ie, the compound is Is stable against hydrolysis in Therefore, '320 or'
691 A compound of application, compounds wherein R ⁵ is other Karuboashiru having an acetyl or 1 to 4 carbon atoms in its application is typically excluded from this embodiment.

Formulations and methods for measuring the stability of compounds in gastrointestinal secretions as substitutes are known. A compound is defined herein to be stable in the gastrointestinal tract if less than about 50 mol% of the protecting groups are deprotected in a substitute intestinal or gastric juice when incubated at 37 ° C. for 1 hour. You. Such compounds are suitable for use in this embodiment. It should be noted that the fact that the compounds are stable to the gastrointestinal tract does not mean that they cannot hydrolyze in vivo. Prodrugs are typically stable in the digestive system, but are substantially hydrolyzed to the parent drug in the gastrointestinal lumen, liver, or other metabolic organs, or generally within cells.

However, another embodiment of the present invention, described in further detail below, is described in WO 9
No. 1/16320, WO 92/06691, or US Pat. No. 5,360,
No. 817, with the intention of using the compounds specifically disclosed, including those wherein YR ⁶ is free hydroxyl, or hydroxyl protected by a readily hydrolysable group such as acetyl. It should be understood that However, in this case, the compound is delivered by a new route of administration.

In another embodiment, the compounds herein exclude the following compounds: (a) E₁Is -CO_TwoH, -P (O) (OH)_Two, -NO_Two, -SO_TwoH, -SO_ThreeH, tetrazolyl, -CH_TwoCHO, -CHO, or -CH (CHO)_Two(B) G₁Is -CN, N_Three, -NHR₂₀, NR₂₀, -OR₂₀, Guanidino, S
R₂₀, -N (R₂₀) → O, -N (R₂₀) (OR₂₀), -N (H) (R₂₀) N (R ₂₀ )_Two, Unsubstituted pyrimidinyl, or unsubstituted (pyrimidinyl) methyl; (c) T₁Is -NHR₂₀, -NO_TwoAnd R₂₀Is H; 1 to 4
An acyl group having carbon atoms; a linear or cyclic alkyl having 1 to 6 carbon atoms
Alkyl groups or their halogen-substituted analogs; allyl groups or unsubstituted
Reel group, or halogen, OH group, NO_TwoGroup, NH_TwoGroup or COOH group
(D) each J₁Is H; and (e) X₁Is a bond, -CH_Two-Or -CH_TwoCH_Two-In this case, W₆But H, W₇Or -CH_TwoW₇Not (where W ₇ Is H, -OR_6a, -OR₁, -N (R₁)_Two, -N (R₁) (R_6b), -N (R_{6 b} )_Two, -SR₁, Or -SR_6aIs).

The compounds described in WO 92/06691, page 9, line 26 to page 11, line 5, and their pharmaceutically acceptable salts or derivatives are also excluded herein. These compounds appear to include compounds of formula II. Where: (a) A ₂ is O; (b) E ₁ is COOH, P (O) (OH) ₂ , NO ₂ , SOOH, SO ₃ H, tetrazole, CH ₂ CHO, CHO, CH (CHO) ) if ₂ or where E ₁ is CO OH, P (O) ( OH) 2, SOOH or SO ₃ H, their ethyl, methyl or pivaloyl ester; (c) G ₁ is Hydrogen, N (R ^20a ) ₂ , SR ^20a or OR ^20a ; (d) T ₁ is —NHC (O) R ^20b, wherein R ^20b is unsubstituted or halogen-substituted from 1 to 6 carbon atoms. A linear or cyclic alkyl group), or SR ^20a , OR ^20a , COOH or an alkyl / aryl ester thereof, NO ₂ , C (
R ^20a ) ₃ , CH ₂ COOH or their alkyl / aryl esters, CH ₂ N
Be O ₂ or ^{_{CH 2 NHR 20b; (e)}} R 20a is hydrogen; linear or cyclic alkyl group or a halogen having 1 to 6 carbon atoms; an acyl group having 1 to 4 carbon atoms Substituted analogs;
An unsubstituted aryl group or an aryl substituted by a halogen, allyl group, OH group, NO ₂ group, NH ₂ group, or COOH group; (f) J ₁ is H and J _1a is H, OR ^20a , F, Cl, Br, CN,
NHR ^20a , SR ^20a or CH ₂ X, where X is NHR ^20a , halogen or OR ^20a ; (g) J ₂ is H or J _2a is hydrogen, N (R ^20a ) ₂ , SR ^20a or OR ^20a ; (h) U ₁ is CH ₂ YR ^20a , CHYR ²⁰ CH ₂ YR ^20a , or CHYR ^20a C
A HYR ^20a CH ₂ YR ^20a, wherein Y is O, S or H, and successive Y moieties in U ₁ are the same or different, and when Y is hydrogen R ^{20 a} is a covalent bond Represents

In a further embodiment, the compounds of the invention are those wherein U ₁ is not —CH ₂ OH, —CH ₂ OAc, or —CH ₂ OCH ₂ Ph.

In a further embodiment, the compounds of the invention are those wherein E ₁ is not —CH ₂ OH, —CH ₂ OTMS, or —CHO.

In a further embodiment, the compounds of the present invention₁Is not directly attached to the core ring by a carbon atom, or₁Is not substituted with hydroxyl or hydroxyester, especially U₁Is a polyhydroxyalkane, especially -CH (OH) CH (OH) CH_TwoA compound that is not OH. In a further embodiment, U₁Is a branched group R as described below._FiveOr at least one group R _Five Is a carbocycle substituted with

In a further embodiment, compounds having the following formula are excluded from the invention:

[0075]

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Here: In formula (V): A ₂ is —O— or —CH ₂ —; E ₁ is —CO ₂ H; G ₁ is —N (H) (C (NH) (NH ₂ )) T ₁ is —N (H) (Ac); and U ₁ is of the formula:

[0077]

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2. In formula (V): A ₂ is -O- or -CH ₂ -; E ₁ is an -CO ₂ H; G ₁ is an -NH _2; T ₁ is -N (H) (Ac) And U ₁ is —CH ₂ OH; In formula (V): A ₂ is —CH ₂ —; E ₁ is —CH ₂ OH or —CH ₂ OTMS; G ₁ is —N ₃ ; T ₁ is —N (H) (Ac _3. ) and U ₁ is —CH ₂ OCH ₂ Ph; Wherein in (V): A ₂ is -CH ₂ -; E ₁ is an -CO ₂ H or -CO ₂ CH _3; G ₁ is an -N _3; T ₁ is -N (H) ( 4. Ac); and U ₁ is —CH ₂ OH; In formula (V): A ₂ is -CH ₂ -; E ₁ is an -CO ₂ H, -CHO or -CH ₂ OH,; G ₁ is an -N _3; T ₁ is -N ( H) (Ac); and U ₁ is —CH ₂ OCH ₂ Ph; In formula (VI): A ₂ is -CH ₂ -; E ₁ is an -CO ₂ H; G ₁ is an -OCH _3; T ₁ is an -NH _2; and U ₁ is -CH 6. ₂ OH; and In formula (VI): A ₂ is —CH ₂ —; E ₁ is —CO ₂ H; G ₁ is —OCH ₃ ; T ₁ is —N (H) (Ac); U ₁ is —CH ₂ OAc.

The compounds described herein may contain more than one group of the same expression (eg, “R ₁ "Or" R_6a)), It is understood that these groups can be the same or different (ie, each group is independently selected).

The “heterocycle” as used herein includes, for example, Paquette,
Leo A. , "Principles of Modern Hetero
cyclic Chemistry "(WA Benjamin, New
York, 1968), especially chapters 1, 3, 4, 6, 7, and 9;
Chemistry of Heterocyclic Compounds,
A series of Monographs "(John Wiley
& Sons, New York, 1950 to present), especially Nos. 13, 14, 1
6, 19, and 28; and "J. Am. Chem. Soc."
82: 5566 (1960), but is not limited to these heterocycles.

Examples of heterocycles include, but are not limited to, pyridyl, thiazolyl, tetrahydrothiophenyl, sulfurated tetrahydrothiophenyl, pyrimidinyl,
Furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl Isoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azosinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H, 6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, iso Benzofuranyl, chromenil, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl Isoindolyl, 3H- indolyl, 1H-indazolyl (1H-indazoly), purinyl, 4H-quinolizinyl, phthalazinyl,
Naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiadinil, furazanil, phenoxazinyl, isochrominil, chrominyl, chromanil, chromanil , Pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxyindolyl,
Benzoxazolinyl, and isatinoyl.

By way of example, and not limitation, a carbon-bonded heterocycle may be a pyridine with a few
At position 3, 4, 5, or 6; at position 3, 4, 5, or 6 of pyridazine; at position 2, 4, 5, or 6 of pyrimidine; at position 2, 3, 5, or 6 of pyrazine; ,
At position 2, 3, 4, or 5 of tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole; at position 2, 4, or 5 of oxazole, imidazole, or thiazole; 3,4 of isoxazole, pyrazole, or isothiazole Or at position 5; at position 2 or 3 of aziridine; at position 2, 3, or 4 of azetidine; at position 2, 3, 4, 5, 6, 7, or 8 of quinoline; or 1, 3 of isoquinoline The bond is at position 4, 4, 6, 7, or 8. Even more typically, carbon-bonded heterocycles include 2-pyridyl, 3-pyridyl,
-Pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl ,
5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5
-Thiazolyl.

By way of example, and not limitation, a nitrogen-linked heterocycle can be an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole,
Imidazolidin, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazolin, 3-pyrazolin, piperidine, piperazine, indole,
Indoline is attached at position 1 of 1H-indazole; at position 2 of isoindole or isoindoline; at position 4 of morpholine; and at position 9 of carbazole or β-carboline. Even more typically, the nitrogen-bonded heterocycle includes 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl,
And 1-piperidinyl.

“Alkyl” as used herein, unless otherwise indicated, refers to normal,
C containing tertiary, tertiary, or cyclic carbon atoms₁~ C₁₂It is a hydrocarbon. Examples include methyl (Me, -CH_Three), Ethyl (Et, -CH_TwoCH_Three), 1-propyl (n-Pr, n-propyl, -CH_TwoCH_TwoCH_Three), 2-propyl (i-Pr, i-propyl, -CH (CH_Three)_Two), 1-butyl (n-Bu, n-butyl, -C
H_TwoCH_TwoCH_TwoCH_Three), 2-methyl-1-propyl (i-Bu, i-butyl,-
CH_TwoCH (CH_Three)_Two), 2-butyl (s-Bu, s-butyl, -CH (CH_Three)
CH_TwoCH_Three), 2-methyl-2-propyl (t-Bu, t-butyl, -C (CH _Three )_Three), 1-pentyl (n-pentyl, -CH_TwoCH_TwoCH_TwoCH_TwoCH_Three), 2-pentyl (-CH (CH_Three) CH_TwoCH_TwoCH_Three), 3-pentyl (-CH (CH_Two CH_Three)_Two), 2-methyl-2-butyl (-C (CH_Three)_TwoCH_TwoCH_Three), 3-meth
2-butyl (-CH (CH_Three) CH (CH_Three)_Two), 3-methyl-1-butyl (—CH_TwoCH_TwoCH (CH_Three)_Two), 2-methyl-1-butyl (—CH_TwoCH (CH_Three) CH_TwoCH_Three), 1-hexyl (-CH_TwoCH_TwoCH_TwoCH_TwoCH_TwoCH_Three), 2-hexyl (-CH (CH_Three) CH_TwoCH_TwoCH_TwoCH_Three), 3-hexyl (-CH (CH_TwoCH_Three) (CH_TwoCH_TwoCH_Three)), 2-methyl-2-pentyl (-C (C H_Three)_TwoCH_TwoCH_TwoCH_Three), 3-methyl-2-pentyl (-CH (CH_Three) CH (
CH_Three) CH_TwoCH_Three), 4-methyl-2-pentyl (-CH (CH_Three) CH_TwoCH (CH_Three)_Two), 3-methyl-3-pentyl (-C (CH_Three) (CH_TwoCH_Three)_Two),
2-methyl-3-pentyl (-CH (CH_TwoCH_Three) CH (CH_Three)_Two), 2,3-
Dimethyl-2-butyl (-C (CH_Three)_TwoCH (CH_Three)_Two), 3,3-dimethyl-
2-butyl (-CH (CH_Three) C (CH_Three)_Three). Examples of alkyl groups are shown in Table 2 as groups 2-5, 7, 9, and 100-399.

The composition of the present invention comprises a compound having any of the following formulas:

[0086]

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In an exemplary embodiment, a compound of formula I is selected.

J ₁ and J _1a are independently R ₁ , Br, Cl, F, I, CN, NO ₂ , or N ₃ , typically R ₁ or F, more typically Is H or F;
Even more typically, it is H.

J ₂ and J _2a are independently H or R ₁ , typically H.

A ₁ is -C (J ₁ ) = or -N =, typically -C (J ₁ ) =, and more typically -CH =.

A ₂ represents -C (J ₁ ) _2- , -N (J ₁ )-, -N (O) (J ₁ )-, -N (O) =, -S-, -S (O ) -, - S (O) 2 -, or -O-, and typically a -C _{(J 1) 2 -, -} N (J 1) -, - S-, or -O-, and More typically, it is —C (J ₁ ) ₂ — or —O—, even more typically —CH ₂ — or —O—, and even more typically —CH ₂ —.

E ₁ is — (CR ₁ R ₁ ) _m1 W ₁ .

Typically, R ₁ is H or alkyl having 1 to 12 carbon atoms, usually H or alkyl having 1 to 4 or 5 to 10 carbon atoms. Or more typically H, or 1, 2, 3, 4, 5, 6, 7, 8, 9
Alkyl having 10, 11, or 12 carbon atoms, still more typically H or 1 to 3 carbon atoms selected from methyl, ethyl, n-propyl, and i-propyl. Is an alkyl having Most typically, R ₁ is H.

M1 is an integer of 0 to 2, typically 0 or 1, and most typically 0.

M2 is an integer of 0 to 1.

M3 is an integer of 1 to 3.

W₁Is a group containing an acidic hydrogen, a protected acidic group, or a group containing an acidic hydrogen._6cAn amide, which in the context of the present invention can be removed by a base and
Or a group having a hydrogen atom that produces a corresponding salt or solvate thereof.
. The general principles of acidic and basic nature of organic substances are well understood, and
W₁Should be understood to define They are not detailed here. However, the description is given in Streetwireer, A .; And Heathcock,
C. H. , "Introduction to Organic Chemis
try, 2nd edition "(Macmillan, New York, 1981) 60
Pp. 64. Generally, the acidic groups of the present invention have a lower pK value than water.
And usually has a pK = less than 10, typically less than pK = 8, and often
Often, pK is less than 6. These include tetrazole, as well as carbon,
C, phosphorus, and nitrogen acids; typically, carboxylic acids, sulfuric acids,
Acids, sulfinic acids, phosphoric acids, and phosphonic acids, and the R of these acids_6cA
Mid and R_6bEsters (R_6cAnd R_6bIs defined below). W ₁ Is -CO_TwoH, -CO_TwoR_6a, -OSO_ThreeH, -SO_ThreeH, -SO_TwoH, -O
PO_ThreeH_Two, -PO_Three(R_6a)_Two, -PO_ThreeH_Two, -PO_Three(H) (R_6a), And -OPO_Three(R_6a)_TwoIt is. E₁Is typically W₁And W₁Is typically -CO_TwoH, -CO_TwoR_6a, -CO_TwoR_FourOr CO_TwoR₁And most
It is CO_TwoR₁₄Where R₁₄Is normal or terminal C 2₁~ C ₆ Alkyl.

W ₁ may also be a protected acidic group, which is, within the context of the present invention, an acidic group as described above, of the groups commonly used in the art for such groups Means a group protected by one and is described below as R _6a . More typically, protection W ₁ comprises —CO ₂ R ₁ —, —SO ₃ R ₁ —, —S (O) OR ₁ , —P (O) (OR ₁ ) ₂ , —C (O) NHSO ₂ R ₄ or —SO ₂ N
HC (O) a -R _4, wherein, R ₁ and R ₄ are as defined above.

Most typically, E ₁ is —C (O) O (CH ₂ ) _b CH ((CH ₂ ) _c CH ₃ ) ₂ , where b = 0-4, c = 0 4, and b + c = 1-4) or selected from the following group:

[0100]

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Examples of E ₁ groups are shown in Tables 3a-3b.

G ₁ is N ₃ , —CN, —OH, OR _6a , —NO ₂ , or — (CR ₁ R ₁ ) _m1 W ₂ , where R ₁ and m1 are as defined above. As expected. Typically, G ₁ is - _{(CR 1 R 1) m1 W} 2.

W_TwoIs a basic heteroatom, a protected basic heteroatom, or a basic heteroatom R_6bAmide-containing groups. W_TwoGenerally contains a basic heteroatom. A basic heteroatom is typically, within the context of the present invention, a W atom.₁Means an atom other than carbon that can be protonated by acidic hydrogen having an acidity in the range described above.
I do. The basic principle of basicity is that of Stretwieser and Heathcoc
k (supra) and as understood by those skilled in the art.
Gives meaning about the atom. In general, the basic
The terrorist atom has a W for the corresponding protonated form.₁Have a pK value that is in the range of values described above. Basic heteroatoms include lone pairs, unbonded pairs
Heteroatoms common to organic compounds having an electron pair, an n-type electron pair, etc.
. By way of example, and not limitation, representative basic heteroatoms include:
Most are amines, such as alcohols, amines, amidines, guanidines, and sulfides.
Oxygen, nitrogen, and sulfur atoms in groups such as amidine and guanidine
Is mentioned. Usually W_TwoIs amino or aminoalkyl (generally lower alkyl C₁-C₆) Groups (eg, aminomethyl, aminoethyl, or aminopro
Pill); an amidinyl or amidinoalkyl group (eg, amidinomethyl,
Dinoethyl, or amidinopropyl); or guanidinyl or guanidinium
A nonalkyl group (eg, guanidinomethyl, guanidinoethyl, or guanidinium)
(In each case, the alkyl group is a basic substituent
Works to crosslink the ring). More typically, W_TwoIs an amino, amidino, guanidino, heterocyclic, one or two amino or guanidino groups (usually one)
Substituted heterocycle, or two or three substituted with amino or guanidino
Alkyl having two carbon atoms, or amino, and hydroxy and a
Such an alkyl substituted with a second group selected from the group consisting of mino
. W_TwoHeterocycles useful as include typically 5- or 6-membered rings containing N or S, wherein the ring contains one or two heteroatoms. This
Such heterocycles are generally substituted at a ring carbon atom. They are saturated or unsaturated
And may be with lower alkyl (m1 = 1 or 2) or ₁ -Can be attached to the core cyclohexene. Even more typically, W_TwoIs

[0104]

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Where each m2 is usually 0, usually R ₁ is H, and R ₃ is C
(O) N (R ₁ ) ₂ .

W ₂ is an optionally protected basic heteroatom. This protected basic heteroatom means, in the context of the present invention, a basic heteroatom as defined above, protected by R _6b as one of the groups common in the art. Such groups are described in detail in Greene (supra) as shown below. Such groups include, by way of example and not limitation, amide, carbamate, amino, acetal, imine, enamine, N-alkyl or N-arylphosphinyl, N-alkyl or N-arylsulfenyl or sulfonyl,
Examples include N-alkyl or N-arylsilyl, thioether, thioester, disulfide, sulfenyl and the like. In some embodiments, the protecting group R _6b is cleavable under physiological conditions, typically in vivo, wherein, for example, a basic heteroatom is selected for the R _6a group. Form amides with organic acids or amino acids, such as the naturally occurring amino acids or polypeptides described below.

[0107] Typically, G ₁ is selected from the group consisting of:

[0108]

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Further examples of G ₁ groups are shown in Table 4.

[0110] T₁Is -NR₁W_Three, -R_Three, -R_FiveOr a heterocycle, or U₁Or G ₁ Together with to form a group having the following structure,

[0111]

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Wherein R _6b is as defined below, and R ₁ and W ₃ are as defined above. Typically, T ₁ is —NR ₁ , W ₃ or heterocycle. Generally, T ₁ is selected from the group consisting of:

[0113]

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Table 5 shows examples of T ₁ groups.

W ₃ is W ₄ or W ₅ , wherein W ₄ is R ₅ , or —C (O) R ₅ , —C
(O) W ₅ , —SO ₂ R ₅ , or —SO ₂ W ₅ . Typically, W ₃ is -C (O
) Is an R ₅ or W _5.

[0116] R ₂ is R ₃ or R ₄ as defined below, independently, wherein each R ₄ is independently substituted with 0-3 R ₃ groups; R ₃ is Independently

[0117]

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Is as follows. Typically, R_ThreeIs F, Cl, -CN, N_Three, NO_Two, -OR_6a, -OR₁, -N (R₁)_Two, -N (R₁) (R_6b), -N (R_6b)_Two, -SR₁, -SR_6a , -C (O) OR₁, -C (O) R_6c, -C (O) OR_6a, -OC (O) R₁, −
NR₁C (O) R₁, -N (R_6b) C (O) R₁, -C (O) N (R₁)_Two, -C (O) N (R_6b) (R₁), -C (O) N (R_6b)_TwoOr = O. R_6bincluding
, A more representative R_ThreeAs a group, -C (O) N (R_6b)_TwoOr -C (O) N (R _6b ) (R₁). An even more representative R_ThreeIs F, Cl, -CN, N_Three , -OR₁, -N (R₁)_Two, -SR₁, -C (O) OR₁, -OC (O) R₁,Also
Is = O. An even more representative R_ThreeIs F, -OR₁, -N (R₁)_TwoOr
= O. In the context of this specification, “＝ O” means a double-bonded oxygen atom (O
Oxo) and "= S", = N (R_6b) And "= N (R₁) "Indicates sulfur and nitrogen analogs.

R_FourIs alkyl having 1 to 12 carbon atoms, and alkynyl or alkenyl having 2 to 12 carbon atoms. Alkyl R_FourIs typically 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms
And alkenyl and alkynyl R_FourHas typically 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. R_FourIs usually alkyl (as defined above). R_FourWhen is alkenyl, typically R_FourIs ethenyl (-CH = CH_Two), 1-prop-1-enyl (-
CH = CHCH_Three), 1-prop-2-enyl (-CH_TwoCH = CH_Two), 2-prop-1-enyl (-C (= CH_Two) (CH_Three)), 1-but-1-enyl (—C
H = CHCH_TwoCH_Three), 1-but-2-enyl (—CH_TwoCH = CHCH_Three), 1
-But-3-enyl (-CH_TwoCH_TwoCH = CH_Two), 2-methyl-1-prop-1-enyl (—CH ＝ C (CH_Three)_Two), 2-methyl-1-prop-2-enyl (
-CH_TwoC (= CH_Two) (CH_Three)), 2-but-1-enyl (-C (= CH_Two) C
H_TwoCH_Three), 2-but-2-enyl (-C (CH_Three) = CHCH_Three), 2-but-
3-enyl (-CH (CH_Three) CH = CH_Two), 1-pent-1-enyl (-C =
CHCH_TwoCH_TwoCH_Three), 1-pent-2-enyl (-CHCH = CHCH_TwoCH _Three ), 1-pent-3-enyl (—CHCH_TwoCH = CHCH_Three), 1-pent-4-enyl (-CHCH_TwoCH_TwoCH = CH_Two), 2-pent-1-enyl (-C (= CH_Two) CH_TwoCH_TwoCH_Three), 2-pent-2-enyl (-C (CH_Three) = CH_TwoCH_TwoCH_Three), 2-pent-3-enyl (-CH (CH_Three) CH = CHCH_Three ), 2-pent-4-enyl (-CH (CH_Three) CH_TwoCH = CH_Two) Or 3-methyl-1-but-2-enyl (—CH_TwoCH = C (CH_Three)_Two). More typically, R_FourAn alkenyl group has 2, 3, or 4 carbon atoms. R_FourBut
When alkynyl, typically R_FourIs ethynyl (-C≡CH), 1-prop-1-ynyl (-C≡CCH_Three), 1-prop-2-ynyl (-CH_TwoC≡C
H), 1-but-1-ynyl (-C≡CCH_TwoCH_Three), 1-but-2-ynyl (
-CH_TwoC @ CCH_Three), 1-but-3-ynyl (-CH_TwoCH_TwoC≡CH), 2-
But-3-ynyl (CH (CH_Three) C≡CH), 1-pent-1-ynyl (—C≡CCH)_TwoCH_TwoCH_Three), 1-pent-2-ynyl (-CH_TwoC @ CCH_TwoCH_Three)
, 1-pent-3-ynyl (-CH_TwoCH_TwoC @ CCH_Three) Or 1-pent-4-ynyl (—CH_TwoCH_TwoCH_TwoC≡CH). More typically, R_FourAlkini
The radical has 2, 3, or 4 carbon atoms.

R ₅ is R ₄ as defined above, or R ₄ substituted with 0 to 3 R ₃ groups. Typically, R ₅ is 1 to 3 substituted with 0 to 3 fluorine atoms.
It is an alkyl having 4 carbon atoms.

R _5a is independently alkylene having 1 to 12 carbon atoms, 2 to 12
Alkenylene having 2 carbon atoms or alkynylene having 2 to 12 carbon atoms, wherein any one of the alkylene, alkenylene or alkynylene is substituted with 0 to 3 R ₃ groups . In so that defined above for R4, R _5a in the case of alkylene, 1,2,3,4,5,6,7,8,9,
It has 10, 11, or 12 carbon atoms and, in the case of alkenylene or alkynylene, has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. Each of the representative R ₄ groups is typically a R _5a group, provided that one of the listed hydrogen atoms of the R ₄ group is deviated and the carbon atom to which the second bond to R _5a is attached To form an empty valency.

R ₁₄ is normal or a C ₂ -C ₆ alkyl having a secondary terminal.

W ₅ is a carbocyclic or heterocyclic ring, provided that each W ₅ is independently substituted with 0 to 3 R ₂ groups. W ₅ carbocycles and T ₁ and W ₅ heterocycles are stable chemical structures. Such a structure can be isolated from the reaction mixture at a temperature between −78 ° C. and 200 ° C. with a measurable yield and a measurable purity. Each W ₅ is independently substituted with 0 to 3 R ₂ groups. Typically, T ₁ and W ₅ are saturated, unsaturated, or aromatic rings, including monocyclic or bicyclic carbocyclic or heterocyclic rings. More typically,
T ₁ or W ₅ has 3 to 10 ring atoms, even more typically 3 to 7 ring atoms.
Ring atoms, and usually has 3 to 6 ring atoms. The T ₁ and W ₅ rings are saturated when they contain 3 ring atoms and are saturated or monounsaturated when they contain 4 ring atoms, saturated when they contain 5 ring atoms, Alternatively, it is monounsaturated or diunsaturated, and contains 6 ring atoms, is saturated, monounsaturated,
Or diunsaturated or aromatic. W ₅ unsaturated ring includes an internal unsaturation and external unsaturated, wherein the external unsaturated capture ring atoms.

When W ₅ is a carbocycle, it is typically a monocyclic ring of 3 to 7 carbon atoms, or a bicyclic ring of 7 to 12 carbon atoms. More typically, W ₅ monocyclic carbocycles have 3 to 6 ring atoms, still more typically having 5 or 6 ring atoms. W ₅ bicyclic carbocycles typically bicyclo [4,5], [5,5], [5,6], or [6,6] 7 to 12 amino arranged as system It has ring atoms, and even more typically has 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2 -Enyl, 1-cyclohex-3-enyl, phenyl, spiryl, and naphthyl.

The T ₁ or W ₅ heterocyclic ring typically has 3 to 7 members (2 to 6 carbon atoms and 1 to 3 hetero atoms selected from N, O, P, and S). Atom), a monocyclic ring having
Or a bicyclic ring having 7 to 10 members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S). More typically, T ₁ and W ₅ heterocyclic monocycles have from 3 to 6 ring atoms (2 to 5 carbon atoms and 1 selected from N, O, and S). And 2 or more heteroatoms), and even more typically 5 or 6 ring atoms (3 to 5 carbon atoms and 1 to 2 ring atoms selected from N and S). Heteroatom). The T ₁ and W ₅ heterocyclic bicycles are 7-10 rings arranged as a bicyclo [4,5], [5,5], [5,6], or [6,6] system. Atoms (6-9 carbon atoms, and N, O,
And 1 to 2 heteroatoms selected from S and S), and even more typically arranged as a bicyclo [5, 6] or [6, 6] system. Atoms (8-9 carbon atoms and 1-2 heteroatoms selected from N and S).

Typically, the T ₁ and W ₅ heterocycles are pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl,
It is selected from isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl, or pyrrolyl.

More typically, the T ₁ and W ₅ heterocycles are linked via their carbon or nitrogen atom. Even more typically, the T ₁ heterocycle is attached to the cyclohexene ring of the composition of the invention by a stable covalent bond via their nitrogen atom, and the W ₅ heterocycle is a compound of the invention. To the cyclohexene ring of the product via a stable covalent bond through their carbon or nitrogen atom. A stable covalent bond is a chemically stable structure as described above.

W ₅ is optionally selected from the group consisting of:

[0129]

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U ₁ is H or —X ₁ W ₆ , but is typically the latter.

X₁Is a bond, -O-, -N (H)-, -N (W₆)-, -N (OH)-, -N
(OW₆)-, -N (NH_Two)-, -N (N (H) (W₆))-, -N (N (W₆) _Two )-, -N (H) N (W₆)-, -S-, -SO-, or -SO_Two-Is typically X₁Is a bond, -O-, -N (H)-, -N (R_Five)-, -N (OH
)-, -N (OR_Five)-, -N (NH_Two)-, -N (N (H) (R_Five))-, -N (N (R_Five)_Two)-, -N (H) N (R_Five)-, -S-, -SO-, or -SO_Two And more typically X₁Is a bond, -O-, -NR₁-, -N (OR₁)-, -N (NR₁R₁)-, -S-, -SO-, or -SO_Two-. Usually X₁Is -O-, -NH-, -S-, -SO-, or -SO_Two-.

W₆Is -R_Five, -W_Five, -R_5aW_Five, -C (O) OR_6a, -C (O) R_6c, -C
(O) N (R_6b)_Two, -C (NR_6b) (N (R_6b)_Two), -C (NR_6b) (N (H
) (R_6b)), -C (N (H) (N (R_6b)_Two), -C (S) N (R_6b)_Two,Also
Is -C (O) R_TwoAnd typically, W₆Is -R_Five, -W_FiveOr -R_5aW_FiveIn some embodiments, W is₆Is R₁, -C (O) -R₁, -CHR₁W₇, -CH (R₁)_aW₇, -CH (W₇)_Two(Where W₇Is monovalent and a is
0 or 1, but W₇Is 0 if is divalent), or -C (O) W₇so
is there. In some embodiments, W₆Is -CHR₁W₇Or -C (O) W₇ Or W₆Is-(CH_Two)_m1CH ((CH_Two)_m3R_Three)_Two,-(CH_Two) _m1 C ((CH_Two)_m3R_Three)_Three;-( CH_Two)_m1CH ((CH_Two)_m3R_5aW_Five)_Two;-( CH_Two)_m1CH ((CH_Two)_m3R_Three) ((CH_Two)_m3R_5aW_Five) ;-( CH_Two)_m1C (
(CH_Two)_m3R_Three)_Two(CH_Two)_m3R_5aW_Five), (CH_Two)_m1C ((CH_Two)_m3R_5aW_Five )_ThreeOr-(CH_Two)_m1C ((CH_Two)_m3R_Three) ((CH_Two)_m3R_5aW_Five)_TwoAnd m3 is an integer of 1 to 3.

W ₇ is R ₃ or R ₅ , but is typically an alkyl having 1 to 12 carbon atoms substituted with 0 to 3 R ₃ groups, the latter being representative -NR ₁ (R _{6 b)} in the _{manner, - N (R 6b) 2} , is selected from the group consisting of -OR _6a or SR _6a,. More typically, W ₇ is an alkyl having 3 to 12 carbon atoms substituted with -OR ₁ or OR _1.

In general, U ₁ is R ₁ O—, —OCHR ₁ W ₇ ,

[0135]

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Is as follows.

Table 2 shows examples of the U ₁ group.

Embodiments of the present invention include compounds having the formula:

[0139]

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Wherein E ₂ is E ₁ , but is typically selected from the group consisting of:

[0141]

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And here, G ₂ is G ₁ , but is typically selected from the group consisting of:

[0143]

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And here, T ₂ is R ₄ or R ₅ . In general, T ₂ is alkyl having 0-3 1 to 2 carbon atoms substituted with fluorine atoms.

U ₂ is one of the following:

[0146]

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Here, R ₇ is H, —CH ₃ , —CH ₂ CH ₃ , —CH ₂ CH ₂ CH ₃ , —OCH ₃ ,
—OAc (—O—C (O) CH ₃ ), —OH, —NH ₂ , or —SH, typically H, —CH ₃ , or —CH ₂ CH ₃ .

The groups R _6a and R _6b are not important functional groups and can vary widely. If not H, these functions are to act as intermediates for the parent drug substance. This does not mean that they are biologically inert. On the contrary, an important function of these groups is to convert the parent drug into a prodrug,
As a result, the parent drug is released by conversion of the prodrug in vivo.
Since active prodrugs are more effectively absorbed than the parent drug, they are
Often has greater potency in vivo than the parent drug. If not hydrogen, R _6a and R _6b are removed either in vitro (for chemical intermediates) or in vivo (for prodrugs). For chemical intermediates, it is not particularly important that the resulting pro-functionality product (e.g., alcohol) be physiologically acceptable, but generally the product is pharmacologically non-toxic. It is more desirable if there is.

R _6a is H or an ether-forming group or an ester-forming group. "Ether-forming group" means a group capable of forming a stable covalent bond with a parent molecule and is a group having the formula:

[0150]

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Where V _a is a tetravalent atom typically selected from C and Si; V _b is typically B, Al, N, and P, more typically It is a trivalent atom selected from N and P; V _c is typically a divalent atom selected O, S, and the Se, more typically be S; V ₁ is more V _a stable one covalent bond, a group bonded to V _b or V _c, typically V ₁ was in is W ₆ groups, yo Ri typically V ₁ was in the H, R _2, W _5, or be a -R _5a W _5, still more typically H or R _2; V ₂ is a group bonded to V _a or V _b by a stable covalent double bond, provided that, V ₂ is not = O, = S or = N-; typically, V ₂ is = C
(V ₁ ) ₂ , where V ₁ is as defined above; and V ₃ is a group attached to Va by _a stable covalent triple bond, typically V ₃ is ≡ C (V ₁ ), where V ₁ is as defined above.

“Ester-forming group” means a group capable of forming a stable covalent bond with a parent molecule and is a group having the formula:

[0153]

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[0154] Here, V _a, V _b, and V ₁ was, is as defined above; V _d is typically located at a pentavalent atom selected from P and N; V _e is an hexavalent atom (typically S); and V ₄ is V _a, V _b by a stable covalent double bond, a group bonded to V _d or V _e, provided that at least one Two V ₄ are ＯO, = S or =
N−V ₁ , typically V ₄ is ＣC, except for ＯO, ＳS, or ＮN−.
(V ₁ ) ₂ , where V ₁ is as defined above.

A protecting group for the -OH functionality (either hydroxy, acid or other functionality) is a specific example of an "ether or ester forming group".

Of particular interest are ether or ester forming groups that can function as protecting groups in the synthetic schemes provided herein. However, some hydroxyl and thio protecting groups are neither ether forming groups nor ester forming groups, as will be appreciated by those skilled in the art, and are included in the amides discussed below for R _6c . R _6c can protect a hydroxyl or thio group such that hydrolysis from the parent molecule gives the hydroxyl or thio.

In its ester forming role, R _6a is typically linked to any acidic group, such as, but not limited to, a —CO ₂ H or —C (S) OH group. the results in -CO ₂ R _6a. R _6a is derived, for example, from the ester groups listed in WO 95/07920.

Examples of R _6a include: C ₃ -C ₁₂ heterocycle (as described above) or C ₆ -C ₁₂ aryl. These aromatic groups are polycyclic or monocyclic as required. Examples include phenyl; spiryl; 2-
And 3-pyrrolyl; 2- and 3-thienyl; 2- and 4-imidazolyl;
2-, 4-, and 5-oxazolyl; 3- and 4-isoxazolyl; 2-,
4-, and 5-thiazolyl; 3-, 4-, and 5-isothiazolyl; 3- and 4-pyrazolyl; 1-, 2-, 3-, and 4-pyridinyl;
, 2-, 4-, and 5-pyrimidinyl; halo, R ₁ , R ₁ -O-C ₁ -C ₁₂ alkylene, C ₁ -C ₁₂ alkoxy, CN, N
O ₂ , OH, carboxy, carboxyester, thiol, thioester, C _1-
C ₁₂ haloalkyl, (1 to 6 halogen atoms), C ₂ -C ₁₂ alkenyl, or is C ₃ -C ₁₂ heterocycle or C ₆ -C ₁₂ aryl Le substituted by C ₂ -C ₁₂ alkynyl . Such groups include 2-, 3-, and 4-alkoxyphenyl (C ₁ -C ₁₂ alkyl); 2-, 3-, and 4-methoxyphenyl; 2-, 3-, and 4-ethoxyphenyl 2,3-, 2,4-, 2,5-, 2,6-, 3,4
-, And 3,5-diethoxyphenyl; 2- and 3-carboethoxy-4-
Hydroxyphenyl; 2- and 3-ethoxy-4-hydroxyphenyl; 2-
And 3-ethoxy-5-hydroxyphenyl; 2- and 3-ethoxy-6-
Hydroxyphenyl; 2-, 3-, and 4-O-acetylphenyl;
-, And 4-dimethylaminophenyl; 2-, 3-, and 4-methylmercaptophenyl; 2-, 3-, and 4-halophenyl (2-, 3-, and 4-
Fluorophenyl, and 2-, 3-, and 4-chlorophenyl);
2,3-, 2,4-, 2,5-, 2,6-, 3,4-, and 3,5-dimethylphenyl; 2,3-, 2,4-, 2,5-, 2, 6-, 3,4-, and 3,5
-Biscarboxyethylphenyl; 2,3-, 2,4-, 2,5-, 2,6-,
3,4- and 3,5-dimethoxyphenyl; 2,3-, 2,4-, 2,5-
, 2,6-, 3,4-, and 3,5-dihalophenyl (including 2,4-difluorophenyl and 3,5-difluorophenyl); 2-, 3-, and 4-haloalkylphenyl (one 5 halogen atoms, (including 4-trifluoromethylphenyl) C ₁ -C ₁₂ alkyl); 2-, 3-, and 4-cyanophenyl;
2-, 3-, and 4-nitrophenyl; 2-, 3-, and 4-halo alkylbenzyl (one to five halogen atoms, C ₁ -C ₁₂ alkyl (4-trifluoromethylbenzyl and 2- , 3-, and 4-trichloromethylphenyl,
And 2-, 3-, and 4-trichloromethylphenyl)); 4-N
- piperidinyl; 3-N-methylpiperidinyl; 1-ethylpiperazinyl; benzyl; alkyl salicylic phenyl (C ₁ -C ₄ alkyl (2-, 3-, and 4-ethyl salicyl phenyl) ); 2-, 3-, and 4-acetylphenyl; 1,8-dihydroxy-naphthyl (-C ₁₀ H ₆ -OH) and Ariruo Kishiechiru [C ₆ -C ₉ aryl (including phenoxy ethyl)]; 2,2 '- dihydroxybiphenyl; 2-, 3-, and 4-N, N-dialkylamino _{phenol; -C 6 H 4 CH 2 -N} (CH 3) 2; trimethoxybenzyl; Torietokishibe Njiru; 2-alkylpyridinyl (C _1-4 alkyl);

[0159]

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The C of 2-carboxyphenyl_Four~ C₈Esters; and three to three aryl moieties.
5 halogen atoms, or halogen, C₁~ C₁₂Alkoxy (including methoxy and ethoxy), cyano, nitro, OH, C₁~ C₁₂Haloalkyl (1 to 6 halogen atoms; -CH_Two-CCl_Three), C₁~ C₁₂Alkyl (including methyl and ethyl), C_Two~ C₁₂Alkenyl or C_Two~ C₁₂Selected from alkynyl
C substituted by one or two selected atoms or groups₁~ C_FourAlkylene-C _Three ~ C₆-Aryl (benzyl, -CH_Two-Pyrrolyl, -CH_Two-Thienyl, -CH _Two -Imidazolyl, -CH_Two-Oxazolyl, -CH_Two-Isoxazolyl, -CH_Two -Thiazolyl, -CH_Two-Isothiazolyl, -CH_Two-Pyrazolyl, -CH_Two-Pyridinyl, and -CH_Two-Pyrimidinyl); alkoxyethyl [C₁~ C₆Alkyl (-CH_Two-CH_Two-O-CH_Three(Including methoxyethyl))]; any of the groups described above for aryl, especially OH, or 1-3 halogens.
Child (-CH_Three, -CH (CH_Three)_Two, -C (CH_Three)_Three, -CH_TwoCH_Three,-(CH_Two) _Two CH_Three,-(CH_Two)_ThreeCH_Three,-(CH_Two)_FourCH_Three,-(CH_Two)_FiveCH_Three, -CH_Two CH_TwoF, -CH_TwoCH_TwoCl, -CH_TwoCF_Three, And -CH_TwoCCl_ThreeAlkyl) substituted by:

[0161]

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-N-2-propylmorpholino; 2,3-dihydro-6-hydroxyindene;
Sesamol; catechol _{monoester; -CH 2 -C (O) -N} (R 1) 2; -C H 2 -S (O) (R 1); - CH 2 -S (O) 2 (R 1); —CH ₂ —CH (OC (O
^{_{) CH 2 R 1) -CH 2}} (OC (O) CH 2 R 1); cholesteryl; Enorupirube over preparative _{(HOOC-C (= CH 2} ) -); glycerol; 5 or 6 monosaccharide carbon, Disaccharides or oligosaccharides (3 to 9 monosaccharide residues); triglycerides, such as α-D-β-diglyceride linked to the acyl of the parent compound herein via the glyceryl oxygen of the triglyceride ( Here, the fatty acid constituting the glyceride lipid is generally a naturally-occurring saturated or unsaturated C _6-26 , C _6-18 , or C _6-10 fatty acid (for example, linoleic acid, lauric acid, myristic acid). Fatty acids such as palmitic acid, stearic acid, oleic acid, palmitolic acid, and linolenic acid); phospholipids bonded to carboxyl groups via phospholipid phosphates; phthalidyl (Cla) ton et al., Antimicrob. Agents C
hemo. 5 (6): 670-671 [1974]); cyclic carbonates such as (5-R _d- 2-oxo-1,3-dioxolen-4-yl) methyl ester (Sakamoto) Chem. Pharm.
Bull. 32 (6) 2241-2248 [1984]), wherein R _d is R ₁ , R ₄ , or aryl;

[0163]

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The hydroxyl group of the compounds of the invention is optionally substituted with one of the groups III, IV or V disclosed in WO 94/21604, or isopropyl.

As a further embodiment, Table A may include, for example, via oxygen —C (O) O— and
And -P (O) (O-)_TwoR which can be bonded to a group_6aThe example of an ester part is shown. Some R_6cAmidates have also been shown, these being -C (O)-or -P (O) _Two Directly. Esters of structures 1-5, 8-10, and 16,17, 19-22 have the compounds herein having a free hydroxyl and the corresponding halogen
(Eg, chloride or acyl chloride) and N, N-dicyclohexyl
Ru-N-morpholine carboxamidine (or DBU, triethylamine, C
sCO_Three, N, N-dimethylaniline or another base) in DMF (or other solvent such as acetonitrile or N-methylpyrrolidone).
Are synthesized by W₁Is a phosphonate, the ester of structures 5-7, 11, 12, 21, and 23-26 is an alcohol or alkoxide salt
(Or the corresponding amine in the case of compounds such as 13, 14, and 15)
And monochlorophosphonate or dichlorophosphonate (or another activation
(Phosphonate).

[0166]

[Table 1]

Other esters suitable for use herein are described in EP 632,048.

R _6a can also be a “double ester” forming profunctionality (eg,

[0169]

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Alternatively, the structure —CH (R ₁ or W ₅ ) O ((CO 2 bonded to the oxygen of the acidic group)
Or aryl - -) R ₃₇₎ or -CH (R ₁ or W ₅₎ ((CO) alkyl OR ₃₈₎ includes acyloxyalkyl group), wherein, R ₃₇ and R _38, alkyl, aryl or alkyl, An aryl group (US Pat. No. 4,968,7
No. 88). Often, R ₃₇ and R ₃₈ are bulky groups (eg, branched alkyl, ortho-substituted aryl, meta-substituted aryl, or a combination thereof)
Includes normal, secondary, iso, and tertiary alkyls having one to six carbon atoms. An example is the pivaloyloxymethyl group. These are particularly used in prodrugs for oral administration. Examples of such useful R _6a groups are alkylacyloxymethyl esters and their derivatives, including:

[0171]

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For prodrug purposes, the esters typically selected are those previously used for antibiotic drugs, especially cyclic carbonates,
Heavy ester, or phthalidyl, aryl, or alkyl ester.

As indicated, the R _6a , R _6c , and R _6b groups are optionally used to prevent side reactions with protected groups during synthetic procedures. Thus, they can be protected during the synthesis by the protecting group (P
RT). Often, when protection is performed, the determination of which groups to protect, and the nature of the PRT, will depend on the chemical nature of the reaction to be protected (eg, acidic, basic, oxidative, reductive, or other conditions). And the intended synthesis direction (direc
). If a compound is substituted with more than one PRT, the PRT groups need not be, and generally are not, the same. Generally, PRT is used to protect carboxyl, hydroxyl, or amino groups. The order of deprotection to obtain free radicals depends on the intended direction of synthesis and the reaction conditions employed, and is performed in any order as determined by one skilled in the art.

A large number of R _6a hydroxy protecting groups and R _6c amide forming groups, and the corresponding chemical cleavage reactions, are described in “Protective Groups in Organ”.
ic Chemistry, "Theodora W.C. Greene (Joh
n Wiley & Sons, Inc. , New York, 1991, IS
BN-0-471-62301-6) ("Greene").
Kocienski, Philip J. et al. "Protecting Grou
ps "(Georg Thimeme Verlag Stuttgart, Ne
See also w York, 1994), which is incorporated by reference herein in its entirety. In particular, Chapter 1, Protecting Groups: Overview, pages 1-20, Chapter 2, hydroxyl protecting groups, pages 21-94, Chapter 3, diol protecting groups, pages 95-117, Chapter 4, carboxyl protection Group, pages 118 to 154, chapter 5, carbonyl protecting group, 15
See pages 5 to 184. For other protecting groups for R _6a carboxylic acids, phosphonic acids, phosphonates, sulfonic acids, and W ₁ acids, see Greene, described below. Such groups include esters, amides, hydrazides, and the like, but are by way of illustration and not limitation.

In some embodiments, the R _6a protected acidic group is an ester of an acidic group, and R _6a is the residue of a hydroxyl-containing functional group. In other embodiments,
R _6c amino compounds are used to protect the acid function. Suitable hydroxyl or amino containing functional group residues are those described above or WO 95/079
20 found. Of particular interest are residues of amino acids, amino acid esters, polypeptides, or aryl alcohols. Representative amino acids, polypeptides, and carboxyl esterified amino acid residues are described on pages 11-18 and in the relevant text of WO 95/07920 as groups L1 or L2. WO 9
5/07920 explicitly teaches the amidates of phosphonic acids, but such amidates use any of the acid groups described herein and any of the amino acids described in WO 95/07920. It should be understood that

A representative R _6a ester for protecting the W ₁ acidic functionality is also described in WO 95/07920, but the same ester is formed using the phosphonate of the '920 publication. As such, it should also be understood that they can be formed using the acidic groups herein. Representative ester groups are at least WO 95 /
07920,89 pp 93 (as R ³¹ or R ^35), defined in 105, page tables, and 21 pp to 23 (as R). Esters or unsubstituted aryl (eg, phenyl) or arylalkyl (eg, benzyl) or hydroxy-, halo-, alkoxy-, carboxy-, and / or alkyl esters carboxy-substituted aryl or alkylaryl (especially phenyl, ortho-
Of importance are the esters of ethoxyphenyl or C ₁ -C ₄ alkyl esters carboxyphenyl (salicylic acid C ₁ -C ₁₂ alkyl esters).

The protected acidic groups W ₁ are useful as prodrugs for oral administration, especially when using esters or amides of WO 95/07920. However, since the compounds of the present invention is effectively administered by the oral route, W ₁ Rukoto acidic group is protected is not essential. Compounds of the present invention having a protected group (especially amino acid amidates, or substituted and unsubstituted aryl esters), when administered systemically or orally, are hydrolyzed in vivo by hydrolysis. Can be cleaved to give the free acid.

[0178] One or more acidic hydroxyls are protected. If more than one acidic hydroxyl is protected, the same or different protecting groups are used. For example, the esters can be different or identical, or a mixture of amidate and ester can be used.

Representative R _6a hydroxy protecting groups described in Greene (pages 14-118) include: ether (methyl); substituted methyl ethers (methoxymethyl, methylthiomethyl, t-butyl) Thiomethyl, (phenyldimethylsilyl) methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy) methyl, guaiacolmethyl, t-
Butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl, 2- (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, -Bromotetrahydropyranyl, tetrahydro p-thiopyranyl (tet
rahydroxythiopylyl), 1-methoxycyclohexyl, 4
-Methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, 4
-Methoxytetrahydrop-thiopyranyl (4-methoxytetrahyd
ropiopyranyl), S, S-dioxide, 1-[(2-chloro-4
-Methyl) phenyl] -4-methoxypiperidin-4-yl, 35, 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,
3,3a, 4,5,6,7,7a-octahydro-7,8,8-trimethyl-4
, 7-methanobenzofuran-2-yl)); substituted ethyl ether (1-ethoxyethyl, 1- (2-chloroethoxy) ethyl, 1-methyl-1-methoxyethyl,
1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2
-Fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2- (phenylselenyl) ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl ); Substituted benzyl ethers (p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, -And 4-picolyl, 3
-Methyl-2-picolyl N-oxide, diphenylmethyl, p, p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di (p- Methoxyphenyl) phenylmethyl, tri (p-methoxyphenyl) methyl, 4- (4′-
Bromophenacyloxy) phenyldiphenylmethyl, 4,4 ′, 4 ″ -tris (4,5-dichlorophthalimidophenyl) methyl, 4,4 ′, 4 ″ -tris (
Levulinoyloxyphenyl) methyl, 4,4 ′, 4 ″ -tris (benzoyloxyphenyl) methyl, 3- (imidazol-1-ylmethyl) bis (4 ′, 4
"-Dimethoxyphenyl) methyl, 1,1-bis (4-methoxyphenyl) -1
'-Pyrenylmethyl, 9-anthryl, 9- (9-phenyl) xanthenyl, 9
-(9-phenyl-10-oxo) anthryl, 1,3-benzodithiolane-2
-Yl, benzisothiazolyl S, S-dioxide); silyl ether (trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethyltexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl) , Tribenzylsilyl, tri-
p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, t-butylmethoxyphenylsilyl); esters (formate, benzoylformate,
Acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate,
Triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, p-poly-phenylacetate, 3-phenylpropionate,
4-oxopentanoate (levulinate), 4,4- (ethylenedithio) pentanoate, pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitate) )); Carbonate (methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2- (trimethylsilyl) ethyl, 2- (phenylsulfonyl) ethyl, 2- (triphenylphosphonio) ethyl, Isobutyl, vinyl, allyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzylthiocarbonate, 4-ethoxy-1-naphthyl, methyl Dithiocarbonate ); Groups that assist cleavage (2-iodobenzoate, 4-azido butyrate, 4-nitro (Niotro)-4-methyl-pentanoate, o
-(Dibromomethyl) benzoate, 2-formylbenzenesulfonate, 2-
(Methylthiomethoxy) ethyl carbonate, 4- (methylthiomethoxy) butyrate, 2- (methylthiomethoxymethyl) benzoate); other esters (2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4)
-(1,1,3,3-tetramethylbutyl) phenoxyacetate, 2,4-bis (1,1-dimethylpropyl) phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E) -2-methyl-2-butenoate (tigroate), o
-(Methoxycarbonyl) benzoate, p-poly-benzoate, α-naphthoate, nitrate, alkyl N, N, N ′, N′-tetramethylphosphorodiamidate, N-phenylcarbamate, borate, dimethylphosphinothioyl, 2,4-dinitrophenylsulfenate); and sulfonates (sulfate, methanesulfonate (mesylate), benzylsulfonate, tosylate).

More typically, R _6a hydroxy protecting groups include substituted methyl ethers, substituted benzyl ethers, silyl ethers, and esters, including sulfonate esters, and even more typically, trialkyl Silyl ethers, tosylate and acetate.

Representative 1,2-diol protecting groups (therefore, generally two OH groups are R _6a protecting functional groups) are described in Greene at pages 118-142, Formula acetals and ketals (methylene, ethylidene, 1-t-butylethylidene, 1-phenylethylidene, (4-methoxyphenyl) ethylidene, 2,
2,2-trichloroethylidene, acetonide (isopropylidene), cyclopentylidene, cyclohexylidene, cycloheptylidene, benzylidene, p-methoxybenzylidene, 2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene, 2-nitro Benzylidene); cyclic orthoesters (methoxymethylene, ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene, 1-ethoxyethylidene, 1,2-dimethoxyethylidene, α-methoxybenzylidene,
1- (N, N-dimethylamino) ethylidene derivative, α- (N, N-dimeramino) benzylidene derivative, 2-oxacyclopentylidene); silyl derivative (di-t-butylsilylene group, 1,3- (1 , 1,3,3-tetraisopropyldisiloxanilidene), and tetra-t-butoxydisiloxane-1,3-diylidene), cyclic carbonates, cyclic boronates, ethyl boronates and phenyl boronates.

More typically, 1,2-diol protecting groups include those shown in Table B, and even more typically are epoxides, acetonides, cyclic ketals, and aryl acetals.

[0183]

[Table 2]

Here, R ⁹ is C ₁ -C ₆ alkyl.

R _6b is H, an amino protecting group, or a residue of a carboxyl-containing compound, especially H, —C (O) R ₄ , an amino acid, a polypeptide, or —C (O) R ₄ , an amino acid, or A protecting group that is not a polypeptide. The amide forming R _6b is found, for example, in the G ₁ group. If R _6b is an amino acid or polypeptide, R _6b structure _{R 15 NHCH (R 16) C} (O) - ( wherein, either R ₁₅ is H, an amino acid or polypeptide residue, or R ₅ And R ₁₆ is defined below).

R ₁₆ is lower alkyl or amino-substituted lower alkyl (C ₁ -C ₆ ), carboxyl, amide, carboxyester, hydroxyl, C ₆ -C ₇ aryl, guanidinyl, imidazolyl, indoriyl, sulfhydryl, sulfoxide, and / or Or an alkyl phosphate. R ₁₆ also forms a proline residue (R ₁₆ = — (CH ₂ ) ₃ —) together with the amino acid αN. However, R ₁₆ is generally a side chain of a natural amino acid (eg, H, —CH ₃ , —CH (CH ₃ ) ₂ , —CH ₂ —CH
_{(CH 3) 2, -CHCH 3} -CH 2 -CH 3, -CH 2 -C 6 H 5, -CH 2 CH 2 -S
_{-CH 3, -CH 2 OH, -CH} (OH) -CH 3, -CH 2 -SH, -CH 2 -C 6 H 4 OH, -CH 2 -CO-NH 2, -CH 2 -CH 2 - _{CO-NH 2, -CH 2 -C} OOH, -CH 2 -CH 2 -COOH, - with _{(CH 2) 3 -NH-C} (NH 2) -NH 2) - (CH 2) 4 -NH 2 and is there. R ₁₆ also includes 1-guanidinoprop-3-yl, benzyl, 4-hydroxybenzyl, imidazol-4-yl,
Indole-3-yl, methoxyphenyl and ethoxyphenyl.

While R _6b is largely a residue of a carboxylic acid, any of the representative amino protecting groups described on Greene, pages 315 to 383, are useful. These include carbamates (methyl and ethyl, 9-fluorenylmethyl, 9 (
2-sulfo) fluoroenylmethyl, 9- (2,7-dibromo) fluorenylmethyl, 2,7-di-t-butyl- [9- (10,10-dioxo-10,10,
10,10-tetrahydrothioxanthyl] methyl, 4-methoxyphenacyl)
A substituted ethyl (2,2,2-trichloroethyl)
, 2-trimethylsilylethyl, 2-phenylethyl, 1- (1-adamantyl) -1-methylethyl, 1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1 -Dimethyl-2,2,2-trichloroethyl, 1-methyl-1- (4-biphenylyl) ethyl, 1- (3,5-di-t-butylphenyl) -1-methylethyl, 2, (2 ′ -And 4'-pyridyl) ethyl, 2- (N, N-dicyclohexylcarboxamido) ethyl, t-butyl, 1-
Adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl, 4-nitrocinnamyl, 8-quinolyl, N-hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl, diphenylmethyl); an auxiliary cleavage group (
2-methylthioethyl, 2-methylsulfonylethyl, 2- (p-toluenesulfonyl) ethyl, [2- (1,3-dithianyl)] methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl, 2-phosphonioethyl , 2-triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl, m-chloro (p-acyloxybenzyl), p- (dihydroxyboryl) benzyl, 5-benzisoxazolylmethyl, 2- (Trifluoromethyl) -6-chromonylmethyl); photocleavable groups (m-nitrophenyl, 3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, phenyl ( o-nitrophenyl) methyl); urea-type derivative (phenothiazinyl- (10) -carbo Le, N'-p-toluenesulfonyl-aminocarbonyl, N
'-Phenylaminothiocarbonyl); other carbamates (t-amyl, S
-Benzylthiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl, 2,2-dimethoxycarbonylvinyl, o- (N, N-dimethylcarboxamido) benzyl, 1 , 1-Dimethyl-3- (N, N-dimethylcarboxamido) propyl, 1,1-dimethylpropynyl, di (2-pyridyl)
Methyl, 2-furanylmethyl, 2-iodoethyl, isobornyl, isobutyl,
Isonicotinyl, p- (p'-methoxyphenylazo) benzyl, 1-methylcyclobutyl, 1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl, 1-methyl-1- (3,5-dimethoxyphenyl) ethyl , 1-methyl-1
-(P-phenylazophenyl) ethyl, 1-methyl-1-phenylethyl, 1
-Methyl-1- (4-pyridyl) ethyl, phenyl, p- (phenylazo) benzyl, 2,4,6-tri-t-butylphenyl, 4- (trimethylammonium) benzyl, 2,4,6-trimethylbenzyl ); Amide (N-formyl, N-
Acetyl, N-chloroacetyl (N-chloroacetyl), N-trichloroacetyl (N-trichloroacetyl), N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl,
N-3-pyridylcarboxamide, N-benzoylphenylalanyl, N-benzoyl, Np-phenylbenzoyl); amide that is cleaved auxiliary (No-
Nitrophenylacetyl, No-nitrophenoxyacetyl, N-acetoacetyl, (N'-dithiobenzyloxycarbonylamido) acetyl, N-3- (
p-hydroxyphenyl) propionyl, N-3- (O-nitrophenyl) propionyl, N-2-methyl-2- (o-nitrophenoxy) propionyl, N-
2-methyl-2- (o-phenylazophenoxy) propionyl, N-4-chlorobutyryl, N-3-methyl-3-nitrobutyryl, No-nitrocinnamoyl, N-acetylmethionine, No-nitrobenzoyl , No- (benzoyloxymethyl) benzoyl, 4,5-diphenyl-3-oxazolin-2-one); cyclic imide derivatives (N-phthalimide, N-dithiasuccinoyl, N-2)
, 3-Diphenylmaleoil, N-2,5-dimethylpyrrolyl, N-1,1,4
, 4-Tetramethyldisilylazacyclopentane adduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, 5-substituted 1,3-dibenzyl-1,3,5 -Triazacyclohexane-2-one, 1-substituted 3,5-dinitro-4-pyridonyl); N-alkyl and N-arylamines (N-methyl, N-allyl, N- [2- (trimethylsilyl) ethoxy]) Methyl, N-3-
Acetoxypropyl, N- (1-isopropyl-4-nitro-2-oxo-3-
Pyrrolin-3-yl), quaternary ammonium salt, N-benzyl, N-di (4-methoxyphenyl) methyl, N-5-dibenzosuberyl, N-triphenylmethyl, N- (4-methoxyphenyl) Diphenylmethyl, N-9-phenylfluorenyl, N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, N-2-picolylamine N'-oxide), imine derivative (N -1,1-
Dimethylthiomethylene, N-benzylidene, Np-methoxybenzylidene, N
-Diphenylmethylene, N-[(2-pyridyl) mesityl] methylene, N, (N
', N'-dimethylaminomethylene, N, N'-isopropylidene, Np-nitrobenzylidene, N-salicylidene, N-5-chlorosalicylidene, N- (5
-Chloro-2-hydroxyphenyl) phenylmethylene, N-cyclohexylidene); enamine derivatives (N- (5,5-dimethyl-3-oxo-1-cyclohexenyl)); N-metal derivatives (N-borane derivatives) , N-diphenylborinic acid derivative (N-diphenylborinic acid derivative)
N- [phenyl (pentacarbonylchromium or tungsten)] carbenyl, N-copper or N-zinc chelate); N-N derivatives (N-nitro, N-nitroso, N-oxide); N-P derivatives (N- Diphenylphosphinyl, N-dimethylthiophosphinyl, N-diphenylthiophosphinyl, N-dialkylphosphoryl, N-dibenzylphosphoryl, N-diphenylphosphoryl); N-Si derivative; NS derivative; Sulfenyl derivatives (N-benzenesulfenyl, No
-Nitrobenzenesulfenyl, N-2,4-dinitrobenzenesulfenyl,
N-pentachlorobenzenesulfenyl, N-2-nitro-4-methoxybenzenesulfenyl, N-triphenylmethylsulfenyl, N-3-nitropyridinesulfenyl); and N-sulfonyl derivatives (Np-toluenesulfonyl) , N-benzenesulfonyl, N-2,3,6-trimethyl-4-methoxybenzenesulfonyl, N-2,4,6-trimethoxybenzenesulfonyl, N-2,6
-Dimethyl-4-methoxybenzenesulfonyl, N-pentamethylbenzenesulfonyl, N-2,3,5,6-tetramethyl-4-methoxybenzenesulfonyl, N-4-methoxybenzenesulfonyl, N-2,4,6 -Trimethylbenzenesulfonyl, N-2,6-dimethoxy-4-methylbenzenesulfonyl, N-2
, 2,5,7,8-Pentamethylchroman-6-sulfonyl, N-methanesulfonyl, N-β-trimethylsilyethanesulfonyl (N-β-trimethylyl)
silyethanesulfonyl), N-9-anthracenesulfonyl,
N-4- (4 ', 8'-dimethoxynaphthylmethyl) benzenesulfonyl, N-
Benzylsulfonyl, N-trifluoromethylsulfonyl, N-phenacylsulfonyl).

More typically, protected amino groups include carbamates and amides
And even more typically, -NHC (O) R₁Or -N = CR₁N (R ₁ )_TwoIs mentioned. G₁Sites, especially amino or -NH (R_FiveAbout Prodora
Other protecting groups that are also useful as groups are:

[0189]

Embedded image

See, eg, Alexander, J et al .; “J. Med. Chem.” 39: 4.
80-486 (1996).

R _6c is H or the residue of an amino-containing compound, especially amino acids, polypeptides, protecting groups, —NHSO ₂ R ₄ , NHC (O) R ₄ , —N (R ₄ ) ₂ , NH ₂ , Or-
NH (R ₄ ) (H). Here, for example, the carboxylic acid or phosphate group of W ₁ reacts with the amine to form —C (O) R _6c , —P (O) (R _6c ) ₂ or —P (O) (OH) (R _6c Form amides as in (1). Generally, R _6c has the structure R ₁₇ C (O) CH (R ₁₆ ) NH—, where R ₁₇ is OH, OR _6a , OR ₅ , an amino acid or polypeptide residue.

Amino acids are low molecular weight (on the order of less than about 1000 MW) compounds and include at least one amino or imino group and at least one carboxyl group. Generally, amino acids are found in nature. That is, amino acids can be detected in a biological material, such as bacteria or other microorganisms, plants, animals or humans. Suitable amino acids are typically alpha amino acids. That is, compounds characterized by one amino or imino nitrogen atom separated from one carboxyl group carbon atom by a mono- or unsubstituted alpha carbon atom. Of particular interest are hydrophobic residues (eg, mono- or di-alkyl or aryl amino acids, cycloalkyl amino acids, etc.). These residues contribute to cell permeability by increasing the partition coefficient of the parent drug. Typically, the residue does not contain a sulfhydryl or guanidino substituent.

[0193] Naturally occurring amino acid residues are found naturally in plants, animals, or microorganisms, particularly those proteins. Polypeptides are most typically substantially composed of such naturally occurring amino acid residues. These amino acids are glycine, alanine,
Valine, leucine, isoleucine, serine, threonine, cysteine, methionine, glutamic acid, aspartic acid, lysine, hydroxylysine, arginine,
Histidine, phenylalanine, tyrosine, tryptophan, proline, asparagine, glutamine, and hydroxyproline.

When R _6b and R _6c are a single amino acid residue or polypeptide, they are usually substituted with R ₃ , W ₆ , W ₁ and / or W ₂ , but typically ₁ or is substituted by only W _2. These conjugates (conjugate) is the carboxyl group of the amino acid (or, for example, the C-terminal amino acid of the polypeptide) is produced by forming an amide bond between the W _2. Similarly, a bond is formed between W ₁ and an amino acid or amino group of a polypeptide. Generally, only one of any part of the parent molecule will be amidated with an amino acid as described herein, but introducing an amino acid at more than one allowed site is a feature of the present invention. Within range. Usually, a carboxyl group of W ₁ is amidated with an amino acid. Generally, the α-amino or α-carboxy group of an amino acid, or the terminal amino or carboxyl group of a polypeptide is attached to the parent functional group. That is, the carboxyl or amino group of the amino acid side chain is not normally used to form an amide bond with the parent compound (these groups are used during the synthesis of the conjugate as described further below). May need protection).

For carboxyl-containing side chains of amino acids or polypeptides, the carboxyl group can be optionally blocked, eg, with R _6a , esterified with R ₅ , or amidated with R _6c. Understood. Similarly, the amino side chain R ₁₆ is optionally blocked with R _6b or substituted with R ₅ .

Such ester or amide linkages at the side chain amino or carboxyl groups can be performed in vivo or in vitro under acidic (pH <3) or basic conditions, such as esters or amides in the parent molecule. Under (pH> 10), optionally hydrolysable. Alternatively, they are substantially stable in the human gastrointestinal tract, but are hydrolyzed by enzymes in the blood or intracellular environment. Esters or amino acids, or polypeptide amidates, are also useful as intermediates for the preparation of parent molecules containing free amino or carboxyl groups. The free acid or base of the parent compound is readily formed, for example, from an ester, or amino acid, or polypeptide conjugate of the invention by conventional hydrolysis procedures.

Where an amino acid residue contains one or more chiral centers, any D, L, meso, threo, or erythro (suitable) racemate, scalemate
mate) or any of these mixtures can be used. The D isomer is useful if the intermediate is generally hydrolyzed without an enzyme (as when the amide is used as a chemical intermediate of the free acid or free amine). On the other hand, L
Isomers are more versatile. Because the L-isomer can be sensitive to both non-enzymatic and enzymatic hydrolysis, and can be more efficiently transported by the amino acid or dipeptidyl transport system in the gastrointestinal tract.

Examples of suitable amino acids whose residues are represented by R _6b and R _6c include: glycine; aminopolycarboxylic acids (eg, aspartic acid, β-hydroxyaspartic acid, glutamic acid, β- Hydroxyglutamic acid, β-methylaspartic acid, β-methylglutamic acid, β, β-dimethylaspartic acid, γ-hydroxyglutamic acid, β, γ-dihydroxyglutamic acid, β-phenylglutamic acid, γ-methyleneglutamic acid, 3-aminoadipic acid, 2-aminopimelic acid,
2-aminosuberic acid, and 2-aminosebacic acid); amino acid amides (eg, glutamine and asparagine); polyamino- or polybasic-monocarboxylic acids (eg, arginine, lysine,
β-aminoalanine, γ-aminobutyrin, ortinine, citrulline, homoarginine, homocitrulline, hydroxylysine, allohydroxylysine, and diaminobutyric acid); other basic amino acid residues (eg, histidine); diaminodicarboxylic acids (eg, α, α′-diaminosuccinic acid, α, α′-diaminoglutaric acid, α, α′-diaminoadipic acid, α, α′-diaminopimelic acid, α, α′-diamino-β-hydroxypimelic acid, α , Α'-diaminosuberic acid, α, α'-diaminoazelaic acid, and α, α'-diaminosebacic acid); imino acids (eg, proline, hydroxyproline, allohydroxyproline, γ-methylproline, pipecolic acid, 5-hydroxypipecolic acid and azetidine-2-carboxylic acid); mono- or dial- Killed (typically C ₁ -C ₈ branched or straight chain) amino acids (
For example, alanine, valine, leucine, allylglycine, butyrine (butyr)
ine), norvaline, norleucine, heptillin, α-methylserine, α-amino-α-methyl-γ-hydroxyvaleric acid, α-amino-α-methyl-δ-hydroxyvaleric acid, α-amino-α-methyl-ε -Hydroxycaproic acid, isovaline, α-methylglutamic acid, α-aminoisobutyric acid, α-aminodiethylacetic acid,
α-aminodiisopropylacetic acid, α-aminodi-n-propylacetic acid, α-aminodiisobutylacetic acid, α-aminodi-n-butylacetic acid, α-aminoethylisopropylacetic acid, α-amino-n-propylacetic acid, α-aminodiacetic acid Isoamylacetic acid (α-
aminodiisoamyacetic acid), α-methylaspartic acid, α-methylglutamic acid, 1-aminocyclopropane-1-carboxylic acid,
Isoleucine, alloisoleucine, tert-leucine, β-methyltryptophan, and α-amino-β-ethyl-β-phenylpropionic acid); β-phenylserinyl; aliphatic α-amino-β-hydroxy acids (eg, serine , Β-hydroxyleucine, β-hydroxynorleucine, β-hydroxynorvaline, and α-amino-β-hydroxystearic acid); α-amino, α-, γ-, δ- or ε-hydroxy acids (homoserine, [gamma] -hydroxynorvaline, [delta] -hydroxynorvaline, and [epsilon] -hydroxynorleucine residues; canavine and canaline; [gamma] -hydroxyortinine; 2-hexosaminic acid (e.g., D-glucosamic acid, or D-galactosamic acid); α- Mino-β-thiol (eg, penicylamine, β-thiolnorvaline, or β-thiolbutyrin); other sulfur-containing amino acid residues including cysteine; homocysteine, β-phenylmethionine, methionine, S-allyl-L Cysteine sulfoxide, 2-thiol histidine, cystathionine, and thiol ether of cysteine or homocysteine; phenylalanine, tryptophan, and ring-substituted α-amino acids (eg, phenyl- or cyclohexyl amino acids α-aminophenylacetic acid, α-aminocyclohexylacetic acid, α-amino-β-cyclohexylpropionic acid; phenyla containing aryl, lower alkyl, hydroxy, guanidino, oxyalkyl ether, nitro, sulfur, or halo-substituted phenyl Nin analogs and derivatives (e.g., tyrosine, methyl tyrosine, and o- chloro, p- chloro,
3,4-dichloro, o-, m-, or p-methyl, 2,4,6-trimethyl,
2-ethoxy-5-nitro, 2-hydroxy-5-nitro and p-nitro-phenylalanine); furyl-, thienyl-, pyridyl-, pyrimidinyl-, prenyl-, or naphthyl-alanine; and tryptophan analogs and derivatives (kynurenine) , 3-hydroxykynurenine, 2-hydroxytryptophan and 4-carboxytryptophan); α-amino-substituted amino acids (sarcosine (N-methylglycine), N-benzylglycine, N-methylalanine, N-benzylalanine, N- Methylphenylalanine, N-benzylphenylalanine, including N-methylvaline and N-benzylvaline); and α-hydroxy and substituted α-hydroxy amino acids (serine, threonine, allothreonine, phosphoserine, Including the fine phosphothreonine).

Polypeptides are polymers of amino acids in which the carboxyl group of one amino acid monomer is linked to the amino or imino group of an adjacent amino acid monomer by an amide bond. Polypeptides include dipeptides and low molecular weight polypeptides (about 15
00-5000 MW), and proteins. The protein optionally contains 3, 5, 10, 50, 75, 100 or more residues and more suitably is substantially homologous in sequence to a human, animal, plant, or microbial protein. is there. This includes enzymes (eg, hydrogen peroxidase) and KLH
And any type of protein against which it is desired to generate an immune response thereto. The nature and type of polypeptide can vary very widely.

Polypeptide amidates are useful as immunogens in raising antibodies against either the polypeptide (if not immunogenic in the animal to which it is administered) or an epitope on the remainder of the compound of the invention. is there.

Antibodies that can bind to a parent non-peptidyl compound are used to separate the parent compound from the mixture, for example, in diagnosis or in the preparation of a parent compound. Conjugates of the parent compound and the polypeptide are generally more immunogenic in highly homologous animals than the polypeptide, thus making the polypeptide more immunogenic and raising antibodies thereto. Promoted. Thus, polypeptides or proteins can be obtained from animals commonly used to raise antibodies (eg, rabbits, mice,
Although not necessarily immunogenic in horses, or rats), the final product, the conjugate, should be immunogenic in at least one such animal. The polypeptide optionally has a peptidase cleavage site at the peptide bond between the first and second residues adjacent to the acidic heteroatom. Such a cleavage site is adjacent to an enzyme recognition structure (eg, a particular residue sequence recognized by a peptidase).

Peptidolytic enzymes that cleave polypeptide conjugates of the invention are well known and include, in particular, carboxypeptidases. Carboxypeptidases cleave polypeptides by removing the C-terminal residue, and are often specific for a particular C-terminal sequence. The conditions required for such enzymes and their general substrates are well known. For example, a dipeptide (with a given pair of residues and a free carboxyl terminus) is covalently linked to the phosphorus or carbon atom of the compounds herein by its α-amino group. In embodiments where W ₁ is a phosphonate, the peptide is cleaved by a suitable peptidase so that the carboxyl of the adjacent amino acid residue cleaves the phosphonoamidate bond autocatalytically. It is considered to be.

A suitable dipeptidyl group (indicated by these one-letter codes) is

[0204]

[Table 3]

Tripeptide residues are also useful as R _6b or R _6c . If W ₁ is phosphonate over preparative sequence -X4-pro-X5- (where, X4 is any amino acid residue, and X5 is an amino acid residue, a carboxyl ester of proline,
Or hydrogen) is cleaved by luminal carboxypeptidase to yield X4 with a free carboxyl, which in turn is thought to cleave the phosphonoamidate bond autocatalytically. The carboxy group of X5 is optionally esterified with benzyl.

The dipeptide or tripeptide species can be selected based on known transport properties and / or sensitivity to peptidases that can affect transport to the intestinal mucosa or other cell types. Dipeptides or tripeptides that lack an α-amino group are transport substrates for peptide transporters found in the brush border membrane of intestinal mucosal cells (Bai
J. P. F. "Pharm Res." 9: 969-978 (1992).
). Thus, transport competent peptides can be used to enhance the bioavailability of the amidate compound. Di- or tripeptides having one or more amino acids in the D configuration are also compatible with peptide transport and can be used in the amidate compounds of the present invention. Amino acids in the D configuration are di- at the brush border for hydrolysis by common proteases (eg, aminopeptidase N (EC. 3.4.11.2)).
Alternatively, it can be used to reduce the sensitivity of the tripeptide. In addition, di- or tripeptides are alternatively selected based on their relative resistance to hydrolysis by proteases found in the gut lumen. For example, a tripeptide or polypeptide lacking asp and / or glu can be aminopeptidase A (E
C. It is not sufficient as a substrate for 3.4.1.7), and di-amino acids lacking hydrophobic amino acid residues (leu, tyr, phe, val, trp) on the N-terminal side.
Alternatively, the tripeptide is endopeptidase 24.11 (EC 3.4.24.
A peptide that is not sufficient as a substrate for 11) and lacks the pro residue of the second moiety from the free carboxyl terminus is carboxypeptidase P (EC 3
. Not enough as a substrate for 4.17). Similar considerations apply to the cytosol,
This applies to the selection of peptides that are either relatively resistant or susceptible to hydrolysis by kidney, lung, serum and other peptidases. Such noncleavable polypeptide amidates are immunogenic or useful for binding proteins to prepare immunogens.

Another embodiment of the present invention relates to compositions of formula (VII) or (VIII), and salts, solvates, resolved enantiomers, and purified diastereomers thereof:

[0208]

Embedded image

Wherein E ₁ , G ₁ , T ₁ , U ₁ , J ₁ , J _1a , J ₂ and J _2a are as defined above, except for the following: T ₁ is —NR ₁ Forms a group having the following structure together with W ₃ , a heterocycle, or G ₁

[0210]

Embedded image

And X ₁ is a bond, —O—, —N (H) —, —N (R ₅ ) —, —S—, —SO—, or —SO ₂ —; ₁ is H or —CH ₂ CH (OH) CH ₂ (OH)
Are excluded.

Each representative or usual embodiment of formulas (I)-(VI) described in detail above is also a representative embodiment of formulas (VII) and (VIII).

Formulas (VII) and (VIII) wherein U ₁ is H or —CH ₂ CH (OH
) Synthesis Many of the compounds of the CH ₂ is (OH)) may, Nishimura, Y et al., "J.Antibiotics" 46 (2): 300; 46 (12): 188
3 (1993); and "Nat. Prod. Lett.", 1 (1): 39.
(1992). The attachment of the U ₁ group of the present invention is performed as described therein.

(Stereoisomer) The compound of the present invention is an optical isomer enriched or resolved at any or all asymmetric atoms. For example, a chiral centroid apparent from the notation is provided as a chiral isomer or a racemic mixture. Both racemic and diastereomeric mixtures,
All individual optical isomers that are isolated or synthesized and are substantially free of the other enantiomer or the other diastereomer are all within the scope of the present invention.

One or more of the following listed methods are used to prepare the enantiomerically enriched or pure isomers herein. The methods are listed approximately in that order. That is, one of skill in the art would employ a stereospecific synthesis from a chiral precursor before chromatographic separation prior to spontaneous crystallization.

[0216] Stereospecific syntheses are described in these examples. This type of method is convenient,
Used when suitable chiral starting materials are available and the reaction step chosen does not result in undesired racemisation at the chiral site. One advantage of the stereospecific synthesis is that it must be removed from the end product (so that
Does not produce undesired enantiomers (which reduces the overall synthesis yield). In general, one skilled in the art will understand what starting materials and reaction conditions should be used to obtain the desired enantiomerically enriched or pure isomer by stereospecific synthesis. If unexpected racemization occurs in a method that is considered to be stereospecific, it is only necessary to use one of the following separation methods to obtain the desired product.

If a suitable stereospecific synthesis could not be designed or determined empirically using routine experimentation, one of skill in the art would work with other methods. One method that has general utility is the chromatographic separation of enantiomers on chiral chromatography resins. These resins are packed in columns and are generally
It is called a kle column and is commercially available. These columns contain a chiral stationary phase. The racemate is placed in solution, loaded onto the column, and then
Separated by PLC. For example, Proceedings Chromato
graphic Society-International Sympos
ium on Chiral Separations (September 3, 1987-
4). Examples of chiral columns that can be used to screen for optimal separation techniques include Diacel Christian OD, Regis Pirk
le Covalent Dphenylglycine, Regis Pir
kle Type 1A, Astec Cyclobond II, Astec
Cyclobond III, Serva Chiral D-DL = Dal
tosil 100, Bakerbond DNBLeu, Sumipax O
A-1000, Merck Cellulose Triacetate column, Astec Cyclobond I-Beta, or Regis Pir
kle Covalent D-Naphthylalanine. Not all of these columns appear to be effective for all racemic mixtures. However, those skilled in the art will appreciate that a certain amount of conventional screening may be required to identify the most effective stationary phase. When using such columns, it is desirable to use embodiments of the compounds of the present invention in which the charge is not neutralized, for example, acidic functional groups such as carboxyl are not esterified or amidated.

Another method involves converting the enantiomers in the mixture to diastereomers using a chiral auxiliary and then separating the conjugate by conventional column chromatography. This is especially true if the embodiment forms a salt or covalent bond with the chiral auxiliary,
It is a very suitable method if it contains free carboxyl, amino or hydroxyl. All chirally pure amino acids, organic acids or organic sulfonic acids,
It is worth investigating as chiral auxiliaries, all of which are well known in the art. Salts with such auxiliaries may be formed or covalent (but reversible) bonds may be formed with the functional groups. For example, a pure D or L amino acid can be used to amidate a carboxyl group of an embodiment of the present invention and then separated by chromatography.

[0219] Enzymatic separation is another method of potential value. In such a method, a covalent derivative of the enantiomer (generally a lower alkyl ester (in the case of the carboxyl example)) is prepared in a racemic mixture, which is then enzymatically cleaved (generally hydrolyzed). Decomposition). In order for this method to be successful, enzymes that can cleave stereospecifically must be selected, and therefore it is often necessary to routinely screen some enzymes. If the ester is to be cleaved, the group of esterases, phosphatases, and lipases is selected and its activity on the derivative is determined. Typical esterases are derived from liver, pancreas, or other animal organs, including pig liver esterase.

If the enantiomeric mixture is separated from a solution or agglomerate melt (ie, a mixture of enantiomerically pure crystals), the crystals can be separated mechanically, thereby enantiomerically A rich preparation is produced. However, this method
It is not practical for large-scale preparations, and true racemates have no value.

Asymmetric synthesis is another technique for achieving enantiomeric enrichment. For example, a chiral protecting group reacts with the group to be protected and the reaction mixture is equilibrated. If the reaction is enantiomerically specific, the product is enriched in enantiomers.

Further guidance in the separation of enantiomeric mixtures can be found in “Enantiomers”.
ers, Racemates, and resolutions ", Jean
Jacques, Andre Collet and Samuel H .; Wile
n (Krieger Publishing Company, Malabar
, FL, 1991, ISBN 0-89464-618-4), which may be found for illustrative and not limiting purposes. See Part 2, Resol
union of Enantomer Mixture, 217-435
Page; more specifically, Section 4, Resolution by Direct Crystallization, pp. 217-251, Section 5, Format.
ion and Separation of Diastereomers,
Pages 251 to 369, Section 6, Crystallization-Induce
d Asymmetric Transformations, 369-37
Page 8, and Section 7, Experimental Aspects and A
rt of Resolutions, pp. 378-435; even more particularly, Section 5.1.4, Resolution of Alcohols, Tra.
nsformation of Alcohols into Salt-Fo
rming Derivatives, pages 263-266, section 5.2.3,
Covalent Derivatives of Alcohols, Thi
ols, and Phenols, pp. 332-335, section 5.1.1, Re.
solution of Acids, pp. 257-259, section 5.1.2,
Resolution of Bases, pp. 259-260, 5.1.3.
Section, Resolution of Amino Acids, Nos. 261-263
Page, Section 5.2.1, Covalent Derivatives of Ac
ids, page 329, section 5.2.2, Covalent derivatives.
es of Amines, pp. 330-331, section 5.2.4, Coval.
ent Derivatives of Aldehydes, Ketones
, And Sulfoxides, pp. 335-339, and section 5.2.7, Chromatographic Behavior of Covalen.
t Diastereomers, pages 348-354, are cited as examples of art in the art.

Exemplary stereochemistry of the compounds of the present invention is set forth in Table C below.

[0224]

[Table 4]

The compounds of the present invention may, in certain cases, exist as tautomers. For example, for the imidazole, guanidine, amidine, and tetrazole systems, ene-amine tautomers may exist, and all possible tautomeric forms are within the scope of the invention.

Exemplarily Listed Compounds For purposes of illustration and not limitation, the compounds of the embodiments are named in the following tabular format (Table 6). In general, each compound is represented as a substituted nucleus, the nucleus is shown in uppercase, and each substituent is shown in lowercase, or numerical order. Tables 1a and 1b are a list of nuclei that differ primarily depending on the position of ring unsaturation and the nature of the ring substituents. Each nucleus is given the alphabetic symbol from Table 1a and Table 1b, and this symbol precedes the name of each compound. Similarly, Tables 2a-av, 3a-b, 4a-c, and 5a-d show the selected Q ₁ , Q ₂ , Q ₃ , and Q ₄ substituents as well as letter and number symbols. List. Each named compounds therefore uppercase indicating the nucleus from Table 1a-1b, followed by a number indicating the Q ₁ substituent, lowercase showing the Q ₂ substituent, a number indicating the Q ₃ substituent, and Q ₄ substituents It is represented by the lowercase letter (s) shown. Therefore, the structure 8 of the scheme 1 is based on A.I. 49. a. 4. It is represented as i. It is to be understood that Q ₁ -Q ₄ do not represent a group or atom, but are merely a connectivity symbol.

[0227]

[Table 5]

[0228]

[Table 6]

[0229]

[Table 7]

[0230]

[Table 8]

[0231]

[Table 9]

[0232]

[Table 10]

[0233]

[Table 11]

[0234]

[Table 12]

[0235]

[Table 13]

[0236]

[Table 14]

[0237]

[Table 15]

[0238]

[Table 16]

[0239]

[Table 17]

[0240]

[Table 18]

[0241]

[Table 19]

[0242]

[Table 20]

[0243]

[Table 21]

[0244]

[Table 22]

[0245]

[Table 23]

[0246]

[Table 24]

[0247]

[Table 25]

[0248]

[Table 26]

[0249]

[Table 27]

[0250]

[Table 28]

[0251]

[Table 29]

[0252]

[Table 30]

[0253]

[Table 31]

[0254]

[Table 32]

[0255]

[Table 33]

[0256]

[Table 34]

[0257]

[Table 35]

[0258]

[Table 36]

[0259]

[Table 37]

[0260]

[Table 38]

[0261]

[Table 39]

[0262]

[Table 40]

[0263]

[Table 41]

[0264]

[Table 42]

[0265]

[Table 43]

[0266]

[Table 44]

[0267]

[Table 45]

[0268]

[Table 46]

[0269]

[Table 47]

[0270]

[Table 48]

[0271]

[Table 49]

[0272]

[Table 50] (Salts and hydrates) The composition of the present invention may optionally contain a salt of the compound of the present specification, particularly, for example,
And pharmaceutically acceptable non-toxic salts, including Na ⁺ , Li ⁺ , K ⁺ , Ca ⁺⁺ , and Mg ⁺⁺ . Such salts are derived from combinations of a suitable cation, such as an alkali metal ion and an alkaline earth metal ion or ammonium ion and a quaternary amino ion, with an acid anion moiety, typically a W ₁ carboxylic acid. Salts may be included. If water-soluble salts are desired, monovalent salts are preferred.

Typically, metal salts are prepared by reacting a metal hydroxide with a compound of the present invention.
It is. Examples of metal salts prepared by such a method include Li⁺, Na⁺, And K ⁺ It is a salt containing. Smaller soluble metal salts precipitate from solutions of larger soluble salts by addition of the appropriate metal compound.

In addition, the salts may be selected from basic centers (typically amines of the G ₁ group, or E ₁ ) of certain organic and inorganic acids (eg, HCl, HBr, H ₂ SO ₄ , or organic sulfonic acids). Acid group). Finally, it is understood that the compositions herein include the compounds of the invention in unionized as well as zwitterionic forms, and combinations with stoichiometric amounts of water as in hydrates.

[0275] Salts of the parent compound with one or more amino acids are also included within the scope of the invention. Any of the above amino acids (especially naturally occurring amino acids found as components of proteins) are suitable, but typically the amino acids are amino acids having a side chain of a basic or acidic group (eg, lysine , Arginine, or glutamic acid), or an amino acid having a neutral side chain (eg, glycine, serine, threonine, alanine, isoleucine, or leucine).

(Method of Inhibiting Neuraminidase) Another aspect of the present invention relates to a method of inhibiting the activity of neuraminidase, comprising treating a sample suspected of containing neuraminidase with a compound of the present invention.

The compositions of the invention may act as inhibitors of neuraminidase, act as intermediates for such inhibitors, or have other utilities as described below. The inhibitor binds to a location on the surface or in the cavity of neuraminidase that has a geometry unique to neuraminidase. Compositions that bind neuraminidase may bind to varying degrees of reversibility. Those compounds that bind substantially irreversibly are ideal candidates for use in this method of the invention. In an exemplary embodiment, these compositions comprise less than 10 ^-4 M, more typically less than 10 ^-6 M,
Even more typically binds to neuraminidase with a binding coefficient of 10 ^-8 M. Once labeled, compositions that bind substantially irreversibly are useful as probes for the detection of neuraminidase. Accordingly, the present invention relates to a method of detecting neuraminidase in a sample suspected of containing neuraminidase, comprising the steps of: comprising a sample suspected of containing neuraminidase in a composition comprising a compound of the invention bound to a label. Treating; and observing the effect of the sample on the activity of the label. Suitable labels are well known in the diagnostic arts and include stable free radicals, fluorescent materials, radioisotopes, enzymes,
Chemiluminescent groups, and chromogens. The compounds herein are conventionally labeled with a functional group, such as a hydroxyl or amino group.

Within the context of the present invention, a sample suspected of containing neuraminidase is a natural or artificial material (eg, a living organism); a tissue or cell culture; a biological material sample (blood, serum, Biological samples such as urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, etc.); laboratory samples; food, water, or air samples; biological products (eg, cell extracts, particularly desired glycoproteins) Recombinant cells). Typically, the sample is suspected of containing a neuraminidase producing organism, often a pathogenic organism such as a virus. The sample can be contained in any medium, including water, and organic solvent / water mixtures. Samples include living organisms, such as humans, and artificial materials, such as cell cultures.

The treatment step of the invention comprises adding a composition of the invention to a sample or comprises adding a precursor of the composition to a sample. The addition process is
Includes any method of administration as described above.

If desired, the activity of neuraminidase after application of the composition can be observed by any method, including methods for direct or indirect detection of neuraminidase activity. Quantitative, qualitative, and semi-quantitative methods of measuring neuraminidase activity are all contemplated. Typically, one of the screening methods described above is applied, but any other method is also applicable, such as observing the physiological properties of living organisms.

An organism containing neuraminidase includes bacteria (Vibrio chole)
rae, Clostridium perfringens, Streptoc
occus pneumoniae and Arthobacter sial
ophirus) and viruses, especially orthomyxoviruses or paramyxoviruses (eg, influenza viruses A and B, parainfluenza virus, mumps virus, Newcastle disease virus, poultry plague, and Sendai virus). Inhibition of neuraminidase activity obtained or found from any of these organisms is within the scope of the present invention. Virology of influenza virus is "Fundamental Virology"
(Raven Press, New York, 1986), Chapter 24. The compounds of the invention may be used in animals (eg, ducks, rodents, or pigs).
Or in humans for the treatment or prevention of such infections.

However, in screening for compounds that can inhibit influenza virus, it should be noted that the results of the enzyme assays may not correlate with the cell culture assays, as shown in Chandler et al., Table 1, above. Therefore, the plaque reduction assay should be a primary screening tool.

Screening for Neuraminidase Inhibitors The compositions of the present invention are screened for inhibitory activity against neuraminidase by any conventional technique for assessing enzyme activity. Within the context of the present invention, compositions are typically first screened for inhibition of neuraminidase in vitro, and then compositions exhibiting inhibitory activity are screened for activity in vivo. Compositions having an in vitro Ki (inhibition constant) of less than about 5 × 10 ⁻⁶ M, typically less than about 1 × 10 ⁻⁷ M, and preferably less than about 5 × 10 ⁻⁸ M are useful in vivo. Preferred for use.

Useful in vitro screens have been described in detail and will not be described in detail here. However, von Itzstein, M.S. Et al., “Nature”, 3
63 (6428): 418-423 (1993), especially page 420, column 2, column 3
The entire paragraph to page 421, second column, part of the first paragraph, Chong, A .; K. J. "Biochem. Biophys. Acta", 1077: 65-7.
1 (1991). "Analyt.
Biochem. , 94: 287-296 (1979); and Colman, P .; M. International Publication No. WO 92/06691 (International Application No. PCT / AU90 / 00501,
(Publication date April 30, 1992), page 34, line 13 to page 35, line 16, describes another useful in vitro screen.

In vivo screening has also been described in detail (von Ittzut).
ein, M .; In the above publication, in particular, page 421, column 2, column 1 whole to page 423, page 2
(See part of column 1 paragraph)) and Cloman, P .; M. Et al., Supra, p. 36, lines 1-38, describe suitable in vivo screening.

Pharmaceutical Formulations and Routes of Administration The compounds of the present invention are formulated with conventional carriers and excipients, which are chosen to suit normal practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. All formulations may be used, as needed, with the "Handbook of Pharmaceuticals"
l Excipients "(1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA,
Carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like can be mentioned. The pH of the formulation ranges from about 3 to about 11, but is usually about 7-10.

[0287] One or more compounds of the present invention (herein referred to as the active ingredient) are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal, sublingual), vaginal, and parenteral (subcutaneous, intramuscular,
Intravenous, intradermal, intrathecal, and epidural) and the like. It will be appreciated that the preferred route may vary, for example, with the condition of the recipient. An advantage of the compounds of the present invention is that they are bioavailable orally and can be administered orally; it is not necessary to administer them by pulmonary or nasal route.
Surprisingly, (among others, Bamford, MJ, "J. Enzyme
Inhibition "10: 1-6 (1995), and especially in light of the entire first paragraph at page 15), WO 91/16320, WO 92/06691, and the anti-influenza compounds of US Pat. No. 5,360,817. It is successfully administered by the oral or intraperitoneal route. See Example 161 below.

While it is possible for the active ingredients to be administered alone, it may be preferable for them to be present as a pharmaceutical composition. The formulations according to the invention, both for veterinary medicine and for human use, comprise at least one active ingredient as defined above, together with one or more acceptable carriers and, if necessary, Include with other therapeutic ingredients as appropriate. The one or more carriers must be "acceptable" in terms of being compatible with the other ingredients of the formulation, and must be physiologically harmless to the recipient.

The formulations include those suitable for the foregoing administration routes. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well-known in the art of pharmacy. The technology or formulation is generally based on Remington's Pha
rmaceutical Sciences (Mack Publishing
Co. , Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations comprise a liquid carrier or finely divided solid carrier with the active ingredient,
Or equally and intimately associate with both,
If necessary, it is prepared by molding the product.

[0290] Formulations of the present invention suitable for oral administration include a discrete unit containing a predetermined amount of active ingredient, such as a capsule, cachet, or tablet; as a powder or granule; It is prepared as a solution or suspension in a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or pasta.

A tablet is made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing the active ingredient in free flowing form, such as a powder or granules, with a suitable machine, optionally with binders, lubricants, inert diluents, It is mixed with a preservative, surfactant or dispersant. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. Tablets may be coated or scored if desired, and are formulated to release the active ingredient (s) from the tablet, delayed or controlled, as appropriate. In one embodiment, the acid hydrolysis of the medicament is eliminated by the use of an enteric coating.

For infections of the eye or other external tissues (eg, mouth and skin), the formulations are preferably formulated, for example, with a 0.1% w / w increase (eg, 0.6% w / w,
(E.g. 0.7% w / w) with one or more active ingredients in the range between 0.1% and 20%) in an amount of 0.075-20% w / w, preferably 0. 2 to 15% w /
w, and most preferably in the form of a topical ointment or cream containing the active ingredient (s) in an amount of 0.5 to 10% w / w. When formulated in an ointment, the active ingredients may be formulated with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base.

If desired, the aqueous phase of the cream base may include, for example, at least 30% w / w of a polyhydric alcohol, ie, an alcohol having two or more hydroxyl groups (eg, propylene glycol, butane 1, 3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG400)
), And mixtures thereof. Topical formulations may desirably include a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogs.

The oil phase of the emulsion of the present invention can be composed of known components in a known manner.
This phase may contain only emulsifiers (otherwise known as emulgents), but desirably comprises a mixture of at least one emulsifier with fats or oils, or a mixture of both fats and oils. Including. Preferably,
A hydrophilic emulsifier is included with the lipophilic emulsifier acting as a stabilizer. Further, it is preferable to include both oil and fat. At the same time, one or more emulsifiers, with or without stabilizer (s), make a so-called emulsified wax, which, together with oil and fat, makes a so-called emulsified ointment base, Forms the oily dispersed phase of the cream formulation.

Suitable emulsion and emulsion stabilizers for use in the formulations of the present invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate , And sodium lauryl sulfate.

The selection of an appropriate oil or fat for the formulation is based on achieving the desired cosmetic properties. The cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, monobasic or dibasic alkyl esters (eg diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate) , 2-ethylhexyl palmitate, or a blend of branched-chain esters known as Crodamol CAP), the last three being the preferred esters. These can be used alone or in combination depending on the properties required. Alternatively, high melting point lipids (eg, white soft paraffin and / or liquid paraffin) or other mineral oils are used.

Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier for the active ingredient, especially an aqueous solvent. The active ingredient is preferably from 0.5 to 20%, advantageously from 0.5 to 10%, especially about 1.
Preferably it is present in such a formulation at a concentration of 5% w / w.

Formulations suitable for topical administration in the mouth include lozenges containing the active ingredient in a flavoring base, usually sucrose and acacia or tragacanth.
ge); pastilles containing the active ingredient in an inert base (eg, gelatin and glycerin, or sucrose and acacia); and mouthwashes containing the active ingredient in a suitable liquid carrier.

Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

Formulations suitable for pulmonary or nasal administration may be, for example, in the range of 0.1-500 microns (0.5 microns increments, such as 0.5, 1, 30 microns, 35 microns, etc.). (Including particle sizes in the range between 1 and 500 microns), which are administered by rapid inhalation via the nasal route to reach the alveolar sac or by inhalation via the mouth. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration can be prepared by conventional methods, and include compounds such as those described herein above for use in treating or preventing influenza A or B infection as described below. Can be delivered with any other therapeutic agent.

[0301] Formulations suitable for vaginal administration include pessaries, tampons, creams, gels, pastas,
It may be present as a foam or spray formulation and contains, in addition to the active ingredient, a carrier as known in the art to be suitable.

Formulations suitable for parenteral administration include sterile aqueous and non-aqueous injections which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient. And aqueous and non-aqueous sterile suspensions which can include suspending and thickening agents.

The formulations are presented in unit-dose or multi-dose containers (eg, sealed ampules and vials) and require only the addition of a sterile liquid carrier (eg, water for injection) immediately before use. It can be stored dry. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.

It should be understood that, in addition to the active ingredients specifically mentioned above, the formulations of the present invention may include other agents conventional in the art, given the type of formulation in question. . For example, agents suitable for oral administration can include flavoring agents.

The present invention further provides a veterinary composition comprising at least one active ingredient as defined above together with a veterinary carrier therefor.

A veterinary carrier is a substance useful for the purpose of administering the compositions, including solids, liquids,
Or may be gaseous substances, which are otherwise inert or acceptable in veterinary technology and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.

The compounds of the present invention are used to provide controlled-release pharmaceutical formulations containing one or more compounds of the present invention as active ingredients ("controlled-release formulations"). In this, the release of the active ingredient is controlled and regulated, allowing a lower frequency of administration or improving the pharmacokinetic or toxicological profile of a given active ingredient.

An effective dose of active ingredient will at least depend on the nature of the condition being treated, the toxicity, whether the compound is used prophylactically (low doses) or can be used for active influenza infection, methods of delivery, and Depends on the pharmaceutical formulation and is determined by the clinician using conventional dose escalation studies. About 0.0001 to about 100 mg / day
It can be expected to be kg body weight. Typically, about 0.01 to about 10 m per day
g / kg body weight. More typically, from about 0.01 to about 5 mg / kg per day
Weight. More typically, from about 0.05 to about 0.5 mg / kg body weight per day. For example, a daily candidate dose for inhalation would range from 1 mg to 1000 mg, preferably between 5 mg and 500 mg for an adult human of about 70 kg body weight, and would be in the form of a single or multiple doses obtain.

Typical dosages include GS4104 (phosphate) once or twice daily, 5,
10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65,
70, 75, 80, 85, 90, 95, 100, 110, 115, 120, 12
5, 130, 135, 140, 145, 150, 157, 200, 225, 25
0, 275, 300, 325, 350, 375, 400, 425, 450, 47
5,500,550,600,650,700,750,800,850,90
0, 950, and 1000 mg; more typically, 20, 25, 30, 35, 40, 45, 5, of GS4104 (phosphate) once or twice daily.
0, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110
, 115, 120, 125, 130, 135, 140, 145, 150, 157
, 200 mg; even more typically, GS4 once or twice daily.
20, 50, 75, 100, 150 and 200 mg of 104 (phosphate); even more typically, 75 or 150 mg of GS4104 (phosphate) once or twice daily. No.

The active ingredients of the present invention are also used in combination with other active ingredients. Such combinations are selected based on the condition to be treated, the cross-reactivity of the components, and the pharmaceutical properties of the combination. For example, when treating viral infections of the respiratory system (particularly influenza infections), the compositions of the invention may include antiviral agents (amantidine,
Limantadine, and ribavirin), mucolytics, expectorants, bronchodilators, antibiotics, antipyretics, or analgesics. Usually, antibiotics, antipyretics, and analgesics are administered with the compounds of the present invention.

Metabolites of the Compounds of the Invention The in vivo metabolites of the compounds described herein are also within the scope of the present invention, to the extent that such products are novel and non-obvious from the prior art. is there. Such products result primarily from enzymatic processes, for example, from oxidation, reduction, hydrolysis, amidation, esterification, and the like, of the administered compound. Accordingly, the present invention includes novel and non-obvious compounds produced by processes that include the step of contacting a compound of the present invention with a mammal for a time sufficient to produce its metabolite. Such products are typically prepared by preparing a radiolabeled (eg, C ¹⁴ or H ³ ) compound of the invention and producing a detectable dose (eg, greater than about 0.5 mg / kg) in an animal. (Eg, rats, mice, guinea pigs, monkeys), or humans, administered parenterally and metabolized for a sufficient period of time (typically, about 30 seconds to 30 hours) to produce its conversion product, and , Blood, or other biological sample. These products are easily isolated because they are labeled (others are isolated by the use of antibodies capable of binding epitopes remaining in metabolites). Metabolite structures can be determined in conventional fashion (eg, by MS or NMR analysis).
Is determined. Generally, metabolite analysis is performed in a manner similar to conventional drug metabolism studies well known to those skilled in the art. The conversion product, unless otherwise found in vivo,
Even if they do not have their own neuraminidase inhibitory activity, they are still useful in diagnostic assays for therapeutic doses of the compounds of the present invention.

Alternative Uses of the Compounds of the Invention The compounds of the invention or biologically active substances resulting from these compounds by hydrolysis or in vivo metabolism are used as immunogens, or Used for protein binding. The compound of the present invention can thereby act as a component of an immunogenic composition and specifically bind to a protein, compound, or metabolite thereof that retains an immunologically recognized epitope (antibody binding site). Prepare antibodies. Thus, immunogenic compositions are useful as intermediates in preparing antibodies for use in methods such as diagnostics, quality control, or assays for compounds or their novel metabolites. The compounds are useful for antibodies that would otherwise be raised against non-immunogenic polypeptides. That is, the compound acts as a hapten site that stimulates an immune response that cross-reacts with the unmodified binding protein.

[0313] Hydrolysis products of interest include the products of hydrolysis of the protected acidic or basic groups described above. As noted above, acidic or basic amides, including immunogenic polypeptides such as albumin or keyhole limpet hemocyanin, are generally useful as immunogens. The above metabolites may retain a substantial degree of immunological cross-reactivity with the compounds of the present invention. Thus, an antibody of the invention may bind to an unprotected compound of the invention without binding to the protected compound; alternatively, a metabolite may bind to a protected compound without binding to a protected compound of the invention. May bind to a given compound and / or metabolite, or may specifically bind to any one or all three. Desirably, the antibodies do not substantially cross-react with naturally occurring substances. Substantial cross-reactivity is reactive under specific assay conditions for sufficient specific analyte to interfere with the results of the assay.

The immunogens of the present invention include those compounds of the present invention that display a desired epitope associated with an immunogenic substrate. Within the context of the present invention, such an association means a covalent bond, forming an immunogenic conjugate (where applicable) or a mixture of non-covalently linked substances, or a combination of the above. Immunogenic substances include adjuvants (eg, Freund's adjuvant), immunogenic proteins (eg, viral, bacterial, yeast, plant, and animal polypeptides, particularly keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin Or soybean trypsin inhibitor), and immunogenic polysaccharides. Typically, compounds having the structure of the desired epitope are covalently linked to the immunogenic polypeptide or polysaccharide by using a multifunctional (usually bifunctional) crosslinker. The methods for producing hapten immunogens are per se common, and any previously used method for coupling haptens to immunogenic polypeptides or the like is available for precursors or hydrolysates that are available for crosslinking. It is also suitably used in the present invention, taking into account the possibility of generating antibodies specific for the functional group on the degradation product or for the epitope in question as opposed to an immunogenic substance.

Typically, a polypeptide binds to a site on a compound of the invention that is remote from the epitope to be recognized.

The conjugate is prepared in a conventional manner. For example, the crosslinker N-hydroxysuccinimide, succinic anhydride, or alkN = C = Nalk is useful for preparing the conjugates of the invention. The number of conjugates is 1 to 100, typically 1 to 25.
And, more typically, a compound of the invention attached to the immunogenic agent by a bond or linking group of 1 to 10 carbon atoms. The conjugate is separated from starting materials and by-products, such as by chromatography, then sterile filtered, and placed in vials for storage.

[0317] Compounds of the present invention, for example, be cross-linked via any one or more of the following groups: U ₁ hydroxyl; carboxyl group of E _1, U _1, E _1, G _1, or, A carbon atom at T ₁ (in substitution of H); and an amine group at G ₁ . Amides of polypeptides are included in such compounds, where the polypeptide acts as an R _6c or R _6b group as described above.

The animal is typically an immunogenic conjugate or derivative prepared in a conventional manner,
And immunized against antisera or monoclonal antibodies.

The compounds of the present invention are useful for maintaining the structural integrity of the glycoprotein in recombinant cell culture. That is, the glycoprotein is added to the fermentation produced for recovery to inhibit neuraminidase-catalyzed cleavage of the desired glycoprotein. This is particularly valuable for the recombinant synthesis of proteins in heterologous host cells, which can disadvantageously degrade the carbohydrate portion of the protein being synthesized.

The compounds of the present invention are polyfunctional. As such, the compounds of the present invention represent a unique class of monomers for polymer synthesis. By way of example, polymers prepared from the compounds of the present invention include, but are not limited to, polyamides and polyesters.

The compounds of the present invention can be used as monomers to provide access to polymers with unique pendant functional groups. The compounds of the present invention are useful in homopolymers or as comonomers with monomers that do not fall within the scope of the present invention.
Homopolymers of the compounds of the present invention include molecular sieves (polyamides), fabrics,
It has utility as a cation exchanger (polyester or polyamide) in the preparation of fibers, films, molded articles and the like. Here, the acid functionality E ₁ is esterified to a hydroxyl group in U ₁ , for example, whereby the pendant basic group G ₁ attaches an acidic functional group as found in the polypeptide for which purification is desired. obtain. Polyamides are prepared by cross-linking E ₁ and G ₁ with U ₁ , and the adjacent part of the ring remains free to function as a hydrophilic or hydrophobic affinity group. Depends on the choice of _one . The preparation of these polymers from the compounds of the present invention is conventional per se.

The compounds of the present invention are also useful as a unique class of multifunctional surfactants. In particular, when U ₁ contains no hydrophilic substituents and is, for example, alkyl or alkoxy, the compound has the properties of a bifunctional surfactant. Thus, they have useful surfactant properties, surface coat properties, emulsion modifying properties, rheology modifying properties, and surface wetting properties.

As a multifunctional compound having a defined geometry and having both polar and non-polar moieties, the compounds of the present invention represent a unique class of phase transfer agents (ph
It is useful as an transfer agent. By way of example, the compounds of the present invention are useful in, but not limited to, phase transfer catalysis and liquid / liquid ion extraction (LIX).

The compounds of the present invention optionally contain asymmetric carbon atoms in the U ₁ , E ₁ , G ₁ , and T ₁ groups. Thus, they are a unique class of chiral auxiliaries for use in the synthesis or resolution of other optically active substances. For example, a racemic mixture of carboxylic acids can be resolved into its component enantiomers by the following steps: 1) forming a mixture of a diastereomeric ester or amide with a compound of the present invention, where U ₁ is Asymmetric hydroxyalkane or aminoalkane groups); 2) separating the diastereomers; and 3) hydrolyzing the ester structure. Alcohol racemic are separated by ester formation with an acid group of E _1. In addition, such methods can be used to resolve the compounds of the present invention themselves if an optically active acid or alcohol is used instead of the racemic starting material.

The compounds of the present invention are useful as linkers or spacers in preparing affinity adsorption matrices, immobilized enzymes for process control, or immunoassay reagents. The compounds herein contain a variety of functional groups that are suitable as sites for crosslinking a desired substance. For example, it is customary to bind affinity reagents (eg, hormones, peptides, antibodies, drugs, etc.) to an insoluble substrate. These insolubilized reagents are used in a known manner to absorb binding partners for affinity reagents from prepared preparations, diagnostic samples, and other impure mixtures. Similarly, immobilized enzymes are used to perform catalytic conversion with easy recovery of the enzyme. Bifunctional compounds are commonly used to attach an analyte to a detectable group in the preparation of a diagnostic reagent.

Many functional groups of the compounds of the present invention are suitable for use in crosslinking. For example, E ₁ The group carboxic acid or phosphonic acid is used to form an ester with the alcohol of the reagent to be cross-linked, or an amide with the amine. OH, N
HR₁, SH, azide (if desired reduced to amino prior to crosslinking), CN, NO_TwoSubstituted with amino, guanidino, halo, etc.₁The site is an appropriate site
is there. If appropriate protection of the reactive groups is required during assembly of the cross-linked reagent,
It is used to prevent polymerization of the bifunctional compounds of the present invention. Generally, the
The compound is linked to the hydroxyl group of the first binding partner via a carboxylic or phosphonic acid.
Or attach them to an amino group and then₁Group or G₁Another bond through the group
Used by being covalently bonded to toner. For example, the first binding partner
(Eg, steroid hormones) are esterified to carboxylic acids of the compounds of the invention.
And then the conjugate is G₁Crosslinked to cyanogen bromide-activated Sepaharose via hydroxyl groups. This gives an immobilized steroid. Another to join
The chemistry of is well known. For example, Maggio "Enzyme-Immunoas"
say "(CRC, 1988, pp. 71-135) and the references cited therein.
See bibliography.

As noted above, the therapeutically useful compounds of the present invention, wherein the W ₁ or G ₁ carboxyl, hydroxyl, or amino group is protected, may be administered in oral or sustained release form Useful as In these uses, protecting groups are removed in vivo (eg, hydrolyzed or oxidized to yield a free carboxyl, amino, or hydroxyl). Suitable esters or amides for this use are selected based on the substrate specificity of esterases and / or carboxypeptidases that are expected to be found in cells where hydrolysis of the precursor is desired. Unless the specificity of these enzymes is known, multiple compounds of the invention are screened until the desired substrate specificity is found. This is evident from the appearance of free compounds or antiviral activity. Generally, an amide or ester of the compound of the present invention is selected. They are (i) not hydrolyzed or relatively slowly hydrolyzed in the upper gastrointestinal tract, (ii) are gastrointestinal tract or cell permeable, and (iii) have cytoplasmic and / or systemic circulation of cells. Is hydrolyzed. The screening assay preferably uses cells from a particular tissue suspected of being infected with influenza (eg, broncho-pulmonary tracheal mucosa). Assays known in the art are suitable for determining in vivo bioavailability, and include intestinal lumen stability assays, cell permeability assays, liver homogenate stability assays, and plasma stability assays. However, even if esters, amides, or other protected derivatives are not converted to free carboxyl, amino, or hydroxyl groups in vivo, they are still useful as chemical intermediates.

Exemplary Methods of Making the Compounds of the Invention The present invention also relates to methods of making the compositions of the present invention. The composition is prepared by any applicable technique of organic synthesis. Many such techniques are well-known in the art. However, many of the known methods are based on the “Compendium of O
rgnic Synthetic Methods "(John Wiley
& Sons, New York), Volume 1, Ian T. Harris
on and Shuyen Harrison, 1971; Volume 2, Ian.
T. Harrison and Shuyen Harrison, 19
74; Volume 3, Louis S.M. Hegedus and Leroy Wa
de, 1977; Volume 4, Leroy G .; Wade, jr. , 198
0; Volume 5, Leroy G. Wade, jr. , 1984; and Volume 6, Michael B. et al. Smith; , "A
advanced Organic Chemistry, 3rd edition ", (Joh
n Wiley & Sons, New York, 1985), "Com
prehensive Organic Synthesis. Select
life, Strategies & Efficiency in Mode
rn Organic Chemistry. 9 ", Barry M. T
rost, Editor in Chief (Pergamon Press, New York,
1993).

A number of exemplary methods for the preparation of the compositions of the present invention are provided below. These methods are intended to illustrate the nature of such preparations and are not intended to limit the scope of applicable methods.

In general, reaction conditions (eg, temperature, reaction time, solvents, work-up procedures, and the like) are routine in the art for the particular reaction to be performed. The cited reference material contains a detailed description of such conditions, together with the material cited therein. Typically, the temperature is from -100C to 200C, the solvent is aprotic or protic, and the reaction time is from 10 seconds to 10 days. Workup typically consists of quenching any unreacted reagent, then partitioning (extracting) between the aqueous / organic layer system, and separating the product-containing layer.

The oxidation and reduction reactions are typically performed at temperatures near room temperature (about 20 ° C.), but for the reduction of metal hydrides, the temperature is often reduced to 0 ° C. to −100 ° C. Solvents are typically aprotic for reduction and can be either protic or aprotic for oxidation. The reaction time is
It is adjusted to achieve the desired conversion.

The condensation reaction is typically carried out at a temperature close to room temperature, but for non-equilibrium kinetic controlled condensation, reduced temperatures (0 ° C. to −100 ° C.) are also common. It is. Solvents can be either protic (common in equilibration reactions) or aprotic (common in kinetically controlled reactions).

Standard synthetic techniques (eg, azeotropic removal of reaction by-products and the use of anhydrous reaction conditions (eg, an inert gas environment)) are common in the art and, where applicable, Applied.

One exemplary method of preparing compounds of the present invention is shown in Scheme 1 below.
A detailed description of this method can be found in the Examples section below.

[0335]

Embedded image Modifications of Scheme 1 to form another embodiment are shown in Schemes 2-4.

[0336]

Embedded image (Scheme 2) Utimoto and co-workers “Tetrahedron Lett.”
31: 6379 (1990), aziridine 5 is converted to aminonitrile 9 by addition of TMSCN catalyzed by Yb (CN) ₃ .

The conversion of nitrile 9 to the corresponding amidine 10 consists of three standard steps: i
_{) H 2 S; ii) CH} 3 I; iii) is accomplished using NH ₄ OAc. Representative conversions are found in J. Med. Chem., 36: 1811 (1993).

The nitrile 9 can be obtained from “Modern Synthetic Reactions”
Second edition H. O. House, Benjamin / Cummings Pub
living Co. , 1972, is converted to aminomethyl compound 11 by reduction using any available method.

The aminomethyl compound 11 was obtained from “Tetrahedron Lett.”, 36
: 299 (1995) is converted to the bis-Boc protected guanidino compound 12 by treating 11 with N, N'-bis-Boc-1H-pyrazole-1-carboxyamine.

[0340]

Embedded image (Scheme 3) Aziridine 5 is obtained by opening the ring with α-cyanoacetic acid t-butyl ester.
Give 3. This type of aziridine ring opening is described in Tetrahedron Le.
tt. 23: 5021 (1982). T under acidic conditions
Selective hydrolysis of the -butyl ester moiety followed by decarboxylation gives nitrile 14.

The reduction of 14 to the aminoethyl derivative 15 is achieved in a similar manner as the conversion of 9 to 11. Amine 15 was then replaced by "Tetrahedron Lett."
36: 299 (1995), according to the method found in N, N'-bis-.
Converted to guanidino derivative 16 with Boc-1H-pyrazole-1-carboxamidine.

The nitrile 14 is converted to the corresponding amidine 17 by using the same sequence as above for the conversion of 9 to 10.

[0343]

Embedded image (Scheme 4) Epoxy alcohol 1 is protected with, for example, MOMCl (PG = protecting group).
A typical condition is “Protective Groups in Organic”
Synthesis, 2nd edition, T.W. W. Greene and P.M. G. FIG. M. Wu
ts, John Wiley & Sons, New York, NY, 1
991.

Epoxide 19 is available from Sharless and co-workers, “J. Org.
hem. 50: 1557 (1985), with NaN ₃ / NH ₄ Cl to open the amino alcohol 20.

The reduction of 20 to N-acetylaziridine 21 involves three sequential steps: 1) M
sCl / triethylamine; 2) H ₂ / Pd; 3) AcCl / pyridine. Such a conversion is described in "Angew. Chem. Int. Ed.
Engl. 33: 599 (1994).

Aziridine 21 is described in “J. Chem. Soc. Perkin Trans I
801 (1976), converted to azidoamide 22 by opening the ring with NaN ₃ / NH ₄ Cl in DMF at 65 ° C.

Removal of the MOM protecting group at 22 is described in “Protective Groups in
Organic Synthesis "2nd edition, T.M. W. Greene and P.M. G. FIG. M. Wuts, Jon Wiley & Sons, New
This is accomplished using the method described in York, NY, 1991. The resulting alcohol is converted directly to aziridine 24 using TsCl in pyridine. Such a conversion is described in "Angew. Chem. Int. Ed. Eng.
l. 33: 599 (1994).

The aziridine 24 then reacts with ROH, RNH ₂ , RSH or an organometallic (metal-R) to form the corresponding ring-opened derivatives 25, 26, 27 and 27.1, respectively.
Is generated. This type of aziridine ring opening is described in "Tetrahedron Let."
t. 23: 5021 (1982) and Angew. Chem. In.
t. Ed. Engl. 33: 599 (1994).

(Scheme 5) Another class of compounds of the present invention are prepared by the methods of Schemes 5a and 5b. Quinic acid is described in Shing, T .; K. M. ; Tetrahedron 4
7 (26): converted to 28 by the method of 4571 (1991). TEA /
Mesylation with MsCl in CH ₂ Cl ₂ gives 29, 29 in DMF
Reacts with NaN ₃ to give 30. Reaction of 30 with TFA in CH ₂ Cl ₂ gives 31, and 31 in Mesylation with MsCl in TEA / CH ₂ Cl ₂ gives 32. Reaction with triphenylphosphine in water yields 33, which is converted to 35 by continuous application of 1) CH ₃ C (O) Cl in pyridine, 2) NaN ₃ in DMF, and 3) NaH in THF. You. Alkylation of 35 with a wide variety of nucleophiles common in the art provides many compounds, such as 36. Compounds such as 36 are in other embodiments of the invention (elaboration).
Is the same as the above method.

[0350]

Embedded image

[0351]

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[0352]

Embedded image (Scheme 6) Another class of compounds of the present invention is prepared by the method of Scheme 6. Protected alcohol 22 (PG = methoxymethyl ether) is described in “Protecti
ve Groups in Organic Synthesis "2nd edition, T
. W. Greene and P.M. G. FIG. M. Wuts, John Wiley
& Sons, New York, NY, 1991. Alcohol 51 is converted to acetate 52 using acetic anhydride and pyridine under standard conditions. Acetate 52 is TMS
Treated with OTf or BF ₃ OEt to give oxazoline 53. Such conversions are described, respectively, in “Liebigs Ann. Chem.” 129 (199).
1) and "Carbohydrate Research" 181 (1993).
)It is described in. Alternatively, alcohol 51 is converted to the corresponding mesylate or tosylate 23, followed by "J. Org. Chem." 50: 1126 (1
985) and “J. Chem. Soc” 1385 (1970) by ring closure under standard conditions to oxazoline 53.
Is converted to Oxazoline 53, ROH, RR'NH, or RSH (wherein, R and R 'are the chosen to match the definition of W ₆₎ to react with, the corresponding ring-opened derivatives 54, 55, And 56 are provided. Such conversions are described in “J. Org. Chem.” 49: 4889 (1984) and “Chem.
m. Rev .. 71: 483 (1971).

(Scheme 7-63) Another exemplary method of preparing compounds of the present invention is shown in Schemes 7-35 below. A detailed description of the method can be found in the Examples section below.

[0354]

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[0375]

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[0391]

Embedded image Further embodiments of methods of making and using the compositions of the present invention are described in Schemes 36-4.
Shown at 0.1. One aspect of the invention is a process A of Schemes 36-40.1,
B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S,
It relates to a process for the preparation of the compounds according to the invention, including processes of T, U, V or W alone or in combination with one another. Table 27 describes exemplary method embodiments of Processes A-W. Each embodiment is an individual method using the unit processes A to W alone or in combination. Embodiments of each method in Table 27 are separated by ";". If the embodiment is in one-letter notation, it corresponds to one of processes A-W. If the embodiment is more than one character, it corresponds to each successive process in the order shown.

Another aspect of the invention is a method of using shikimic acid to prepare compound 270 shown as A in Scheme 36, compound 27 shown as B in Scheme 36
Method of using compound 270 to prepare Compound 1, Method of using compound 271 to prepare compound 272 shown as C in Scheme 36, Scheme 36
Using compound 272 to prepare compound 273, shown as D in Scheme 37, using quinic acid to prepare compound 274, shown as E in Scheme 37, compound 275 shown as F in Scheme 37 Using compound 274 to prepare, using compound 275 to prepare compound 276 shown as G in Scheme 37, using compound 276 to prepare compound 272 shown as H in Scheme 37 A method of using compound 273 to prepare compound 277 shown as I in Scheme 38; a method of using compound 277 to prepare compound 278 shown as J in Scheme 38; Using compound 278 to prepare compound 279 as shown Using compound 279 to prepare compound 280 shown as L in Scheme 38, using compound 280 to prepare compound 281 shown as M in Scheme 38, shown as N in Scheme 39 Methods of using compound 281 to prepare compound 282, methods of using compound 282 to prepare compound 283 shown as O in Scheme 39, compounds to prepare compound 284 shown as P in Scheme 39 2
83, the use of compound 283 to prepare compound 285, shown as Q in Scheme 40, the compound 2 shown as R in Scheme 40
A method using compound 285 to prepare 86, a method using compound 287 to prepare compound 288 shown as S in Scheme 40.1, and preparing a compound 289 shown as T in Scheme 40.1 Using compound 288 to prepare compound 290, shown as U in Scheme 40.1, compound 2 shown as V in Scheme 40.1.
The use of compound 290 to prepare 91 and to the use of compound 291 to prepare compound 292, shown as W in Scheme 40.1.

The general aspects of these exemplary methods are described below and in the Examples. The products of each of the following processes are optionally separated, isolated, and / or purified before use in the next process.

[0394] "treated", "treating", "
Terms such as "treatment" include contacting, mixing, reacting,
Reacting, contacting, and other terms commonly used in the art to indicate that one or more chemicals are processed to be converted to one or more other chemicals. This means that “treatment of compound 1 with compound 2” is the same as “compound 1 is treated with compound 2”.
, "Compound 1 is contacted with compound 2", "compound 1 is compound 2
Reacts with, and compound 1 is "treated,""reacts,"
"Reacting" and the like are synonymous with other expressions common in the art of organic synthesis that justify such things as "react".

“Treating” refers to a legitimate and normal manner in which organic compounds react. Normal concentrations (0.01 M to 10 M, typically 0.1 M to 1 M), temperature (-100
C to 250C, typically -78C to 150C, more typically -78C to 10C.
0 ° C., even more typically 0 ° C. to 100 ° C.), reaction vessels (typically glass, plastic, metal), solvents, pressures, atmospheres (typically oxygen and water insensitive reactions) Air or oxygen or water sensitive to nitrogen or argon) and the like, unless otherwise indicated. Similar reaction knowledge known in the art of organic synthesis is used in selecting the conditions and equipment to "treat" in a given process. In particular, those skilled in the art of organic synthesis will select, based on their knowledge in the art, the conditions and equipment that justify the successful completion of the chemistry of the described process.

(Process A, Scheme 36) Compound 270 is prepared using shikimic acid by the following process.

The cis-4,5-diol function of shikimic acid is distinguished from the carboxylic acid at carbon 1 by the selective protection of these two functionalities. Typically, the cis-4,5-diol function is protected as a cyclic ketal and the carboxylic acid function is protected as an ester.

R ₅₀ is an acid labile 1 as described in the Greene reference cited above.
, 2-diol protecting groups, typically cyclic ketals or acetals, more typically cyclohexanone or acetone ketals. R ₅₁ is an acid-stable carboxylic acid protecting group as described in the above-cited Greene literature, typically from groups 2 to 7, 9 to 10, 15, or 100 to 66 in Table 2
Linear, branched, or cyclic alkyl, alkenyl, or alkynyl of 1 to 12 carbon atoms as shown as 0, more typically groups 2-5 of Table 2,
9, or straight or branched alkyl of 1 to 8 carbon atoms, as shown as 100 to 358, even more typically groups 2 to 5, 9, or 1 of Table 2.
Is a straight or branched alkyl of 1 to 6 carbon atoms as shown as 00 to 141; even more typically, R ₅₁ is methyl, ethyl, n-propyl, i
-Propyl, n-butyl, sec-butyl, i-butyl, or t-butyl.

The carboxylic acid is protected with an R ₅₁ group by reacting shikimic acid and cis-4,5
- protecting the diol with R ₅₀ groups. Typically, shikimic acid is an alcohol (eg, methanol, ethanol, n-propanol, or i-propanol), and an acid catalyst (eg, a mineral or sulfonic acid (eg, methanesulfonic acid, benzenesulfonic acid, or Toluenesulfonic acid)) and then in the presence of the corresponding ketone or aldehyde, such as acetone or cyclohexanone,
Treatment with a dialkyl ketal or acetal of a ketone or aldehyde such as 2,2-dimethoxy-propane or 1,1-dimethoxy-cyclohexane. Optionally, the product of the alcohol and acid catalyzed treatment is separated, isolated, and / or purified prior to treatment with a dialkyl ketal or acetal. Alternatively shikimic acid is treated with CH ₂ N _2.

Typically, the process involves treating shikimic acid with an alkanol and a sulfonic acid, followed by treatment with a geminal-dialkoxyalkane or geminal dialkoxycycloalkane and an alkanone or cycloalkanone to give compound 270. Forming step. More typically, the process comprises treating shikimic acid with an alkanol and a sulfonic acid; evaporating excess alkanol to form a residue; disposing the residue in a geminal-dialkoxyalkane or geminal-dialkoxycycloalkane. And treatment with an alkanone or cycloalkanone to form compound 270. Even more typically, the process comprises treating shikimic acid with methanol and para-toluene sulfonic acid; evaporating excess methanol to form a residue; removing the residue from 2,2-dimethoxypropane and acetone Compound 27
0 is formed.

An exemplary embodiment of this process is shown in Example 55 below.

(Process B, Scheme 36) Using compound 270, compound 271 is prepared by the following process.

The hydroxy group at position 3 is activated, typically for a substitution reaction. More typically, it is activated for epoxide ring-forming substitution with an alcohol at position 4.

[0404] R₅₂Is an alcohol activating group, typically an activating group for a substitution reaction.
You. More typically, together with the alcohol at position 4, for epoxide ring forming substitution
Activating group. Such groups include sulfonic esters, typically methanesulfonate.
Sulfonic acid ester, benzenesulfonic acid ester or toluenesulfonic acid ester
Representative groups in the art, such as tell, are mentioned. In one embodiment, R ₅₂ Is O (that is, -OR₅₂), Together with a leaving group common in the art.
.

Typically, this process involves treating compound 270 with an acid halide to give compound 2
71. More typically, the process involves treating compound 270 with a sulfonic halide in a suitable solvent to form compound 271. Even more typically, the process involves compound 27 in a suitable solvent (eg, an amine), optionally in the presence of a co-solvent such as a haloalkane.
0 with sulfonic acid halide to form compound 271. Even more typically, the process comprises the steps of:
Treating compound 270 with sulfonyl chloride to form compound 271.

An exemplary embodiment of this process is shown in Example 56 below.

(Process C, Scheme 36) Compound 272 is prepared using compound 271 by the following process.

The acid labile protecting group (R ₅₀ ) for the hydroxy groups at the 4- and 5-positions is removed. Typically, R ₅₀ is removed without substantially removing a base-labile carboxylic acid protecting group (eg, R ₅₁ ) or a hydroxy activating group (eg, R ₅₂ ). Even more typically, R ₅₀ is cleaved off under acidic conditions.

Typically, the process involves treating compound 271 with a protic solvent, more typically in the presence of an acid catalyst as described above. Even more particularly, the process involves treating compound 271 with an alkanol as described above and an acid catalyst as described above. Even more typically, the process involves treating compound 271 with methanol and para-toluenesulfonic acid to produce compound 272.

An exemplary embodiment of this process is shown in Example 57 below.

(Process D, Scheme 36) Using compound 272, compound 273 is prepared according to the following process.

The activated hydroxy group at position 3 of compound 272 is replaced by hydroxy at position 4 of compound 272 to produce epoxide compound 273. Typically, this substitution is catalyzed by a suitable base, more typically an amine base such as DBU or DBN.

Typically, the process involves compound 272 with a basic catalyst, optionally
Treating in the presence of a suitable solvent. Even more particularly, the process is carried out in a polar aprotic solvent such as diethyl ether or THF,
Treating compound 272 with an amine base. Even more typically, the process involves treating compound 272 with DBU in THF to produce compound 273.

An exemplary embodiment of this process is shown in Example 58 below.

(Process E, Scheme 37) Compound 274 is prepared using quinic acid by the following process.

The cis-4,5-diol function of quinic acid is distinguished from carboxylic acids at carbon 1 by the selective protection of these two functionalities. Typically, the cis-4,5-diol function is protected as a cyclic ketal, and the carboxylic acid function is protected as a lactone along with the 3-position hydroxy group.

R ₅₀ is as described above.

Typically, this process is carried out, optionally in the presence of an acid catalyst as described above,
Treating quinic acid with a geminal-dialkoxyalkane or geminal dialkoxycycloalkane, as described above, and an alkanone or cycloalkanone, as described above, to form compound 274. More typically, the process involves treating quinic acid with a geminal-dialkoxyalkane or geminal-dialkoxycycloalkane, alkanone or cycloalkanone, and an acid catalyst to form compound 270. Even more typically, this process involves converting quinic acid to 2,2-dimethoxypropane, acetone, and para-
Treating with toluene sulfonic acid to form compound 274.

An exemplary embodiment of this process is shown in Example 101 below.

(Process F, Scheme 37) Compound 275 is prepared using compound 274 by the following process.

The lactone is opened to form compound 275. Typically, the lactone is opened to produce a carboxylic acid protected at position 1 and a free hydroxy at position 3. More typically, the lactone is opened under basic conditions to produce a carboxylic acid protected R _{51 at} position 1 and a free hydroxy group at position 3.

R ₅₁ is as described above.

Typically, compound 274 is treated with a suitable base in a suitable protic solvent. More typically, compound 275 is prepared in an alkanol as described above in a metal alkoxide base (eg, sodium alkoxide, potassium alkoxide,
Or lithium alkoxide). Even more typically, compound 2
74 is treated with NaOMe in MeOH to produce compound 275.

An exemplary embodiment of this process is shown in Example 102 below.

(Process G, Scheme 37) Compound 276 is prepared using compound 275 by the following process.

The hydroxy group at position 3 is activated, typically for a substitution reaction. More typically, it is activated for epoxide ring forming substitution together with the alcohol at position 4.

[0427] R₅₂Is an alcohol activating group, typically an activating group for a substitution reaction.
More typically for epoxide ring-forming substitution with an alcohol at position 4.
Activating group. Such groups include sulfonic esters, typically methanesulfonate.
Sulfonic acid ester, benzenesulfonic acid ester or toluenesulfonic acid ester
Representative groups in the art, such as tell, are mentioned. In one embodiment, R ₅₂ Is O (that is, -OR₅₂), Together with a leaving group common in the art.
.

Typically, this process involves treating compound 275 with an acid halide to give compound 2
76. More typically, the process involves treating compound 275 with a sulfonic acid halide in a suitable solvent to form compound 276. Even more typically, the process involves compound 27 in a suitable solvent (eg, an amine), optionally in the presence of a co-solvent such as a haloalkane.
5 with sulfonic acid halide to form compound 276. Even more typically, the process involves the compound 27 in pyridine dichloromethane.
5 with p-toluenesulfonyl chloride to form compound 276.

An exemplary embodiment of this process is shown in Example 103 below.

(Process H, Scheme 37) Compound 272 is prepared using compound 276 by the following process.

The hydroxy group at position 1 is removed and the cis-4,5-diol protecting group is removed. The hydroxy group at position 1 is removed to form an olefinic bond between positions 1 and 6, and the cis-4,5-diol protecting group is removed to remove cis-4,5.
-Regenerate the diol.

Typically, this process involves converting compound 276 to a suitable dehydrating agent, such as a mineral acid (
HCl, H ₂ SO ₄ ) or SO ₂ Cl ₂ ). More typically, compound 276 is treated with SO ₂ Cl ₂ and then with an alkanol, optionally in the presence of an acid catalyst. Even more typically, compound 276 is treated with SO ₂ Cl ₂ in a suitable polar aprotic solvent (eg, an amine) to form an olefin; the olefin is an alkanol as described above, and Treatment with an acid catalyst as described above forms compound 272. More typically still, compound 276 is prepared in pyridine / CH ₂ Cl ₂ at between −100 ° C. and 0 ° C., typically between −100 ° C. and −10 ° C., more typically Treatment with SO ₂ Cl ₂ at a temperature of −78 ° C. to form an olefin; this olefin is treated with methanol and para-toluenesulfonic acid to form compound 272.

An exemplary embodiment of this process is shown in Example 104 below.

(Process I, Scheme 38) Using compound 273, compound 277 is prepared by the following process.

The 5-position hydroxy group is protected. Typically, the protecting group is an acid labile hydroxy protection. More typically, protecting groups prevent rearrangement to an adjacent hydroxy group.

R ₅₃ is an acid labile hydroxy protecting group as described in the Greene reference cited above. More typically, R ₅₃ is an acid cleavable ether, and even more typically, R ₅₃ is methoxymethyl (MOM, CH ₃ —O—CH ₂ —).

Typically, the process involves treating compound 273 with a hydroxy protecting group reagent as described in Greene. More typically, the process is carried out in a suitable solvent (e.g., a polar aprotic solvent) in, substituted or unsubstituted, such as methoxymethyl chloride (MOM _{chloride, CH 3 -O-CH 2 -Cl} ) Treating the compound 273 with a haloalkane or alkene. Even more typically, this process involves converting compound 273 to MOM in an amine solvent.
Treating with chloride. Even more typically, this process involves:
Treating compound 273 with MOM chloride in diisopropylethylamine.

An exemplary embodiment of this process is shown in Example 59 below.

(Process J, Scheme 38) Using compound 277, compound 278 is prepared according to the following process.

The epoxides at the 3- and 4-positions are opened to form azides. More typically, the epoxides at the 3- and 4-positions are opened to form the 3-azido-4-hydroxy compound 278.

Typically, the process involves treating compound 277 with an azide salt in a suitable solvent. More typically, the process involves treating compound 277 with sodium azide and a weak base (eg, ammonium halide) in a polar protic solvent (eg, alkanol or water). Even more typically, the process involves reacting compound 277 in a water / methanol solution.
Is treated with sodium azide and ammonium chloride to produce compound 278.

An exemplary embodiment of this process is shown in Example 60 below.

(Process K, Scheme 38) Using compound 278, compound 279 is prepared according to the following process.

The 4-position hydroxy group of compound 278 is substituted with a 3-azido group to form aziridine compound 279.

Typically, the process involves treating compound 278 with a hydroxy activating group, an organophosphine and a base as described above. More typically, the process comprises treating compound 278 with a sulfonic acid halide as described above to form an activated hydroxy compound, wherein the activated hydroxy compound is a trialkyl or triaryl such as triphenylphosphine. Treating the phosphine with a phosphine to form a phosphonium salt, and treating the phosphonium salt with a base such as an amine to form compound 279. More typically, the process comprises treating compound 278 with mesyl chloride to form an activated hydroxy compound, treating the activated hydroxy compound with triphenylphosphine to form a phosphonium salt, and Treating the phosphonium salt with triethylamine and H ₂ O to form compound 279.

A typical embodiment of this process is shown in Examples 61 and 62 below.

(Process L, Scheme 38) Compound 280 is prepared using compound 279 by the following process.

The aziridine compound 279 is opened with an azide to form an azidoamine 280.

Typically, the process involves treating compound 279 with an azide salt in a suitable solvent. More typically, the process involves treating compound 279 with sodium azide and a weak base (eg, ammonium halide) in a polar aprotic solvent (eg, ether, amine, or amide). I do. Even more typically, the process involves compound 2 in DMF solution.
79 with sodium azide and ammonium chloride to produce compound 280.

An exemplary embodiment of this process is shown in Example 63 below.

(Process M, Scheme 38) Using compound 280, compound 281 is prepared by the following process.

The protected hydroxy group at the 5-position is replaced by an amine at the 4-position to give aziridine 2
81 is formed. Typically, aziridine 281 is substituted with an acid labile group, and more typically, with an aziridine activating group.

R ₅₄ is an acid labile group, typically an acid labile amine protecting group as described in the Greene reference cited above. More typically, R ₅₄ is
An aziridine activating group, more typically a group capable of activating aziridine for acid-catalyzed ring opening reactions. Typically, R ₅₄ groups, 1-12 straight or branched chain of carbon of 1-oxo - encompasses the alk-1-yl group as an example, but not limited to: wherein the alkyl moiety Is a linear or branched alkyl group of 1 to 11 carbons (for example, CH ₃ (CH ₂ ) _z C (O) —, wherein z is an integer of 0 to 10, that is, acetyl CH ₃ C (O ) -, etc.), substituted methyl (e.g., triflate Enirumechiru, Ph ₃ C-, trityl, Tr), or a carbamate such as BOC or Cbz or a sulfonate (e.g., alkyl sulfonates such as methyl sulfonate). More typically, the R ₅₄ group is triphenylmethyl and 1 to 8 carbon atoms, even more typically 1, 2, 3, 4, 5,
Or 6 carbon atoms, even more typically 1- of 2 or 3 carbon atoms.
Oxo-alk-1-yl groups.

[0454] Typically, the process is a compound 280 is treated with a deprotecting agent, comprising the step of removing the R ₅₃ group, R ₅₃ group is R ₅₄ generating reagents as described in Greene ( R ₅₄ -halides, such as acetyl chloride, or Tr-Cl, or R ₅₄ -O-R ₅₄ , such as acetic anhydride), and hydroxy activating groups as described in Process B of Scheme 36. More typically, the process comprises treating compound 280 with a polar protic solvent, optionally in the presence of an acid catalyst as described above, to form a first intermediate; Solvent (eg, amine)
Treating the first intermediate with Tr-Cl to form a second intermediate;
And treating the second intermediate with a sulfonic acid halide, such as mesyl chloride or paratoluenesulfonyl chloride, in a polar aprotic solvent to produce compound 281. Even more typically, the process comprises treating compound 280 with methanol and HCl to form a first intermediate; treating the first intermediate with Tr-Cl and triethylamine to form a second intermediate. Forming an intermediate; and treating this second intermediate with mesyl chloride and triethylamine to produce compound 281.

An exemplary embodiment of this process is shown in Example 64 below.

(Process N, Scheme 39) Compound 282 is prepared using compound 281 by the following process.

Aziridine 281 is opened and the resulting amine is substituted with an R ₅₅ group to form compound 282. Typically, the aziridine 281 is opened by an acid catalyzed ring opening reaction and the resulting amine is acylated.

R ₅₅ is W ₃ as defined above. Typically, R ₅₅ is —C (O) R ₅ . More typically, R ₅₅ is —C (O) R ₁ . Even more typically, R ₅₅ is —C (O) CH ₃ .

[0459] R₅₆Is U as defined above₁It is. Typically, R₅₆Is W₆-O-, W ₆ -S- or W₆-N (H)-. More typically, R₅₆Is R_Five-O-, R_Five-S- or R_Five—N (H) —, and even more typically, R₅₆Is R_Five —O—, and still more typically, R₅₆Is R₁—O—.

Typically, this process involves reacting compound 281 with an acid catalyst and a compound of formula W₆-X₁-H
Compound (where X₁Is defined above to form an amine intermediate); and reacting the amine intermediate with a compound of formula W_Three-X₁-W_Three, W_Three-X_TenOf
Compound (where X_TenIs a leaving group) to form compound 282
Include. The acid catalyst is typically a Lewis acid catalyst conventional in the art.
For example, BF_Three・ Et_TwoO, TiCl_Three, TMSOTf, SmI_Two(THF)_Two , LiClO_Four, Mg (ClO_Four)_Two, Ln (OTf)_Three(Where Ln = Yb, Gd
, Nd), Ti (Oi-Pr)_Four, AlCl_Three, AlBr_Three, BeCl_Two, CdCl _Two , ZnCl_Two, BF_Three, BCl_Three, BBr_Three, GaCl_Three, GaBr_Three, TiCl_Four,
TiBr_Four, ZrCl_Four, SnCl_Four, SnBr_Four, SbCl_Five, SbCl_Three, BiC
l_Three, FeCl_Three, UCl_Four, ScCl_Three, YCl_Three, LaCl_Three, CeCl_Three, Pr Cl_Three, NdCl_Three, SmCl_Three, EuCl_Three, GdCl_Three, TbCl_Three, LuCl_Three , DyCl_Three, HoCl_Three, ErCl_Three, TmCl_Three, YbCl_Three, ZnI_Two, Al (
OPrⁱ)_Three, Al (acac)_Three, ZnBr_Two, And SnCl_FourIt is. X₁Is
Typically, it is -O-, -S-, or -N (H)-. X_TenIs typically
, Cl, Br, or I. More typically, this process
Uses compound 281 of formula R_Five-OH, R_Five-SH or R_Five-NH_TwoCompound of the
And BF_Three・ Et_TwoTreating with O to form an intermediate; and
Treating with lucanonic anhydride to form compound 282. Even better
Typically, this process converts compound 281 to a compound of formula R_Five-OH compound and BF_Three・ Et_TwoTreating with O to form an intermediate; and
Comprises treating compound 282 with unsubstituted acetic anhydride to form compound 282. Formula R_Five-Typical compounds of OH include groups 2 to 7, 9 to 10, 15, and 100 in Table 2.
~ 660 (where Q₁Is -OH). Formula R_FiveMore typical compounds of -OH are the compounds shown in Table 25 below (their Chemical Abstracts Services Registry).
And the compounds shown in Table 26 (their Chemic).
al Abstracts Service Registry Number
, And Aldrich Chemical Company Product
 Number). Formula R_FiveMore representative exemplary compounds of -OH are groups 2-5, 9 and 100-141 of Table 2 (where Q₁Is -OH).

In another embodiment of Process N, Scheme 39, R ₅₅ is H.

Typically, an embodiment of this process provides compound 281 with an acid catalyst and a compound of formula R₅₆ -X₁-H compound (where X₁Is defined above to form an amine intermediate
To form compound 282. Acid catalyst and X ₁ Is as described above. More typically, the process converts compound 281 to a compound of formula R_Five-OH, R_Five-SH or R_Five-NH_TwoAnd BF_Three・ Et_TwoO
To form compound 282. Even more typically, this
Roses converts compound 281 to a compound of formula R_Five-OH compound and BF_Three・ Et_TwoTreating with O to form compound 282. Formula R_FiveTypical compounds of -OH are as described above.

Exemplary embodiments of this process are described in Examples 65, 86, 92, and 95 below.
Shown in

(Process O, Scheme 39) Using compound 282, compound 283 is prepared according to the following process.

The azide of compound 282 is reduced to form amino compound 283.

Typically, this process involves treating compound 282 with a reducing agent to give compound 283
The step of forming More typically, the process involves reacting compound 282 with hydrogen gas and a catalyst (eg, platinum on carbon or Lindlar).
) A catalyst) or a reducing agent (eg, a trialkylphosphine or triarylphosphine as described above). Even more typically, the process involves treating compound 282 with triphenylphosphine in water / THF to form compound 283.

Exemplary embodiments of this process are shown in Examples 87, 93, and 96 below.

(Process P, Scheme 39) Using compound 283, compound 284 is prepared according to the following process.

The carboxylic acid protecting group is removed.

Typically, the process involves treating compound 283 with a base. More typically, the process involves treating compound 283 with a metal hydroxide in a suitable solvent, such as an aprotic polar solvent. Even more typically, the process involves treating compound 283 with aqueous potassium hydroxide in THF to produce compound 284.

[0472] Exemplary embodiments of this process are shown in Examples 88, 94, and 97 below.

(Process Q, Scheme 40) Using compound 283, compound 285 is prepared according to the following process.

The amine is converted to a protected guanidine.

R ₅₇ is a guanidine protecting group conventional in the art, such as BOC or Me.

Typically, the process involves treating compound 283 with a guanidylating reagent conventional in the art. Typical reagents are Bis-BOC Thio
-Urea aminoiminomethanesulfonic acid (Kim et al .; "Tet. Lett.
29 (26): 3183-3186 (1988) and 1-guanylpyrazole (Bernatowickz et al., "Tet. Lett." 34 (21): 33.
89-3392 (1993). More typically, the process involves treating compound 283 with Bis-BOC Thio-Urea acid to form compound 285. Even more typically, the process involves compound 28
3 was treated with Bis-BOC Thio-Urea acid and HgCl ₂ comprising the step of forming the compound 285.

A typical embodiment of this process is shown in Example 67 below.

(Process R, Scheme 40) Using compound 285, compound 286 is prepared according to the following process.

The carboxylic acid protecting group and the guanidine protecting group are removed.

Typically, the process involves treating compound 285 with a base; and then treating with an acid as described above. More typically, the process comprises treating compound 285 with a metal hydroxide to form an intermediate as described above; and treating the intermediate with an acid to form compound 286. Include. Even more typically, the process involves treating compound 285 with aqueous potassium hydroxide and THF to form an intermediate; and treating the intermediate with TFA to form compound 286. I do.

(Process S, Scheme 40.1) Using compound 287, compound 288 is prepared according to the following process.

The E ₁ , J ₁ , and J ₂ of compounds 287 and 288 are as described above. Typically, E ₁ is —CO ₂ R ₅₁ as described above. Typically, J ₁ is H, F 2 or methyl, more typically H. Typically, J ₂ is H or a straight or branched alkyl of 1 to 6 carbon atoms, more typically
H, methyl, ethyl, n-propyl, or i-propyl; even more typically, H.

R ₆₀ and R ₆₁ are groups capable of reacting to form R ₆₃ (defined below) substituted for the aziridine ring of compound 288. Typically, one of R ₆₀ or R ₆₁ is a primary or secondary amine, or a group that can be converted to a primary or secondary amine. Such groups for R ₆₀ and R _{61 are, -NH 2, -N (H)} (R 6b), - N (R 6b) 2, -N (H) (R 1), - N (R 1 ) (R _6b), and - although N ₃ is included as an example without limitation. The other of R ₆₀ and R ₆₁ is typically a group that can be substituted by a primary or secondary amine to form an aziridine. Such groups are encompassed by, but not limited to, the following examples:
_{-OH, -OR 6a, Br, Cl} , and I. Typically, R ₆₀ and R ₆₁ are in the trans configuration. More typically, R ₆₀ is a primary or secondary amine, or a group that can be converted to a primary or secondary amine, and R ₆₁ is a group that can be substituted by a primary or secondary amine to form an aziridine. It is. Even more typically, R ₆₀ is β-azido or β-NH ₂ and R ₆₁ is α-OH, α-OMesyl, or α-OTosyl.

R ₆₂ is described below in Process U, Scheme 40.1.

The process involves treating compound 287 to form compound 288.
I do. This is typically represented by R₆₁To R₆₀Treating compound 287 to replace with
Process. More typically, compound 287 is R₆₀According to
R₆₁Is activated. Even more typically, the compound
287 is R₆₀R for substitution by₆₁And activated to activate R ₆₁ R for substitution by₆₀Is activated. R₆₀And R₆₁Both are activated
If this is the case, the activation can be performed simultaneously or sequentially. This activation is performed continuously.
If this is done, this can be done in any order, typically₆₁Activation of R₆₀of
Performed before activation.

Activation of R ₆₁ for displacement by R ₆₀ is typically achieved by treating compound 287 with a hydroxy activating reagent such as mesyl chloride or tosyl chloride. Activation of R ₆₀ for displacement by R ₆₁ is typically achieved by treating compound 287 to form a primary or secondary amine, and treating the amine with a base. By way of example and not limitation, Compound 2
87 is treated with a reducing agent and a base capable of reducing azide to an amine.

In one embodiment of this process, compound 287 has R₆₁Activating reagents and
And R₆₀Treatment with an activating reagent produces compound 288. In another embodiment,
Compound 287 is prepared by reacting R in a suitable solvent.₆₁Activating reagent, and R₆₀Treated with activating reagent
To produce compound 288. In another embodiment, compound 287 is R₆₁Activity
Chemical reagent, R₆₀Treatment with an activating reagent and a base produces compound 288. other
In another embodiment, compound 287 is a compound of the formula₆₁Activating reagent, R₆₀Activity
Compound 288 is prepared by treatment with a chemical reagent and a base. In other embodiments,
R₆₀Is an azide;₆₁Activating reagent and azide reduction test
Treatment with a drug produces compound 288. In another embodiment, R₆₀Is azide
Certain compounds 287 are prepared by reacting R in a suitable solvent.₆₁Activating reagent and azide reduction test
Treatment with a drug produces compound 288. In another embodiment, R₆₀Is azide
Certain compounds 287 have R₆₁Treated with activating reagent, azide reducing reagent, and base
To produce compound 288. In another embodiment, R₆₀Is azide
287 represents R in a suitable solvent₆₁With activating reagent, azide reducing reagent, and base
Treated to produce compound 288. In another embodiment, R₆₀Is azide
, And R₆₁287 is a hydroxy activating reagent, and
Treatment with an azide reducing reagent produces compound 288. In another embodiment, R ₆₀ Is an azide and R₆₁287 is a suitable solvent
In a compound 28 treated with a hydroxy activating reagent and an azide reducing reagent
8 is manufactured. In another embodiment, R₆₀Is an azide and R₆₁Is hydroxy
Compound 287 is a hydroxy activating reagent, an azide reducing reagent, and a salt.
To produce compound 288. In another embodiment, R₆₀Is azide
Yes and R₆₁Is a hydroxy compound 287 in a suitable solvent.
Treated with activating reagent, azide reducing reagent, and base to produce compound 288
I do.

An exemplary embodiment of this process is shown in Process K, Scheme 38 above.

(Process T, Scheme 40.1) Using compound 288, compound 289 is prepared by the following process.

R ₆₄ is typically H, R _6b , or a group that can be converted to H or R _6b . More typically, R ₆₄ is H. R ₆₅ is typically G ₁ or a group that can be converted to G ₁ . More typically, R ₆₅ is —N ₃ , —CN, or — (CR ₁ R ₁ ) _m1 W ₂ . More typically, R ₆₅ is —N ₃ , —NH ₂ , —N (H) (R _6b ), —N (R _6b ) ₂ , —CH ₂ N ₃ , or —CH ₂ CN.

Typically, compound 288 is processed to form amine 289. More typically, compound 288, nucleophile, typically, a cationic salt of R _65, R ₆₅ or is treated with a nitrogen nucleophile such as protonated analog of R _65, (e.g., NH ₃ , azide salts (eg, NaN ₃ , KN ₃ etc.), HCN, cyanide salts (eg, NaCN, KCN etc.), or cyanoalkyl (eg, (CH ₂ CN) ⁻ )
(For example, but not limited to, NaCH ₂ CN, KCH ₂ CN, etc.). Even more typically, compound 288 is treated with an azide salt. If necessary, a base, typically a weak base such as an ammonium halide, and a solvent, typically a polar aprotic solvent such as an ether, amine, or amide, is used.

In one embodiment, compound 288 is treated with a nucleophile. In another embodiment, compound 288 is treated with a nucleophile in a suitable solvent to produce compound 289. In another embodiment, compound 288 is treated with a nucleophile and a base to produce compound 289. In another embodiment, compound 288 is treated with a nucleophile and a base in a suitable solvent to produce compound 289. In another embodiment, compound 288 is treated with a nitrogen nucleophile to produce compound 289. In another embodiment, compound 288 is treated with a nitrogen nucleophile in a suitable solvent to produce compound 289. In another embodiment, compound 288 is treated with a nitrogen nucleophile and a base to produce compound 289. In another embodiment, compound 288 is treated with a nitrogen nucleophile and a base in a suitable solvent to produce compound 289. In another embodiment, compound 288 is treated with an azide salt to produce compound 289. In another embodiment, compound 288 is treated with an azide salt in a suitable solvent to produce compound 289. In another embodiment, compound 288 is treated with an azide salt and a base to produce compound 289. In another embodiment, compound 288 is treated with an azide salt and a base in a suitable solvent to produce compound 289.

An exemplary embodiment of this process is shown in Process L, Scheme 38 above.

(Process U, Scheme 40.1) Using compound 289, compound 290 is prepared by the following process.

R ₆₂ is a group that can react with an amine to form a substituted R ₆₆ (defined below) on the aziridine ring of compound 290. Typically, R ₆₂ is a group that can be substituted by a primary or secondary amine to form an aziridine. Such _{groups, -OR 53, -OH, -OR 6a} , Br, including Cl, and I as an example without limitation. Typically, R ₆₂ is in the trans configuration with respect to the nitrogen at position 4. More typically, R ₆₂ is -OR _53.

R ₆₄ is H or R _6b , typically an acid labile protecting group such as R ₅₄ .

R ₆₆ is H, R _6b , or R ₅₄ .

The process involves treating compound 289 to form compound 290. This is typically a compound to replace the R ₆₂ by the amine at position 4 2
89 is achieved. More typically, compound 289 is treated to activate the amine at position 4 to the substitutions of R _62. Still more typically, compound 289 is treated to activate the amine at position 4 relative to the substitution of R _62, and R ₆₂ is activated toward displacement by the amine at position 4. If both the amine at R ₆₂ and the 4-position are activated, this activation can be performed simultaneously or sequentially. If the activation is performed sequentially, they may be performed in any order, typically the activation of R ₆₂ is performed first of amine activation of fourth.

R for substitution at the 4-position by an amine₆₂The activation of is typically performed in process B,
Treating compound 289 with a hydroxy activator as described in Scheme 36
This is achieved by: If necessary, R₆₂Is deprotected before activation. R ₆₂ Activation of the amine at the 4 position for substitution typically treats compound 289
Forming a primary or secondary amine with the above process N,
Achieved by treating with an acid catalyst as described in Scheme 39.

Typically, when R ₆₂ is —OR ₅₃ and R ₆₆ is R ₅₆ , this process involves treating compound 289 with a deprotecting agent to give an R ₅₃ group, as described in Greene. R ₅₄ protecting group reagent such as R ₅₄ -halide such as acetyl chloride, or T
r-Cl, or R ₅₄ -O-R ₅₄ , such as acetic anhydride), and process B, removing the hydroxy activating group as described in Scheme 36. More typically, the process is carried out, optionally in the presence of an acid catalyst as described above,
Treating compound 289 with a polar protic solvent to form a first intermediate;
This first intermediate is converted to Tr-C in a polar aprotic solvent (eg, an amine).
1 to form a second intermediate; and a polar aprotic solvent (
Treating the second intermediate with a sulfonic acid halide, such as mesyl chloride or paratoluenesulfonyl chloride in an amine) to produce compound 290. Even more typically, the process involves compound 289
With methanol and HCl to form a first intermediate; treating the first intermediate with Tr-Cl and triethylamine to form a second intermediate; and the second intermediate Treating the body with mesyl chloride and triethylamine to produce compound 290.

In one embodiment, compound 289 is treated with an acid catalyst to produce compound 290. In another embodiment, compound 289 is treated with an acid catalyst in a suitable solvent to produce compound 290. In another embodiment, compound 289 is treated with a hydroxy activator and an acid catalyst to produce compound 290. In another embodiment, compound 289 is treated with a hydroxy activator and an acid catalyst in a suitable solvent to produce compound 290. In another embodiment, compound 289 is treated with a hydroxy deprotecting agent, a hydroxy activator, and an acid catalyst to produce compound 290. In another embodiment, compound 289 is treated with a hydroxy activator and an acid catalyst in a suitable solvent to produce compound 290.

An exemplary embodiment of this process is shown in Process M, Scheme 38 above.

(Process V, Scheme 40.1) Using compound 290, compound 291 is prepared by the following process.

The aziridine 290 is processed to form compound 291. Typically, aziridine 290 is opened by an acid-catalyzed ring opening reaction, and the resulting amine is acylated.

R ₆₈ is independently H, R _6b , R ₁ , or R ₅₅ described above. Typically, R ₅₅ is -C (O) R _5. Typically, one R ₆₈ is H or R _6b , and the other is W ₃ .

R ₆₇ is U ₁ described above. Typically, R _{67 is, W 6 -O-, W 6 -S-} , or W ₆ -N (H) - is. More typically, R ₆₇ is R ₅ -O-, R ₅ -S-, were or R ₅ -N (H) - is.

Typically, this process converts compound 290 to an acid catalyst and a compound of formula W₆-X₁-H
Compound (where X₁Is defined above to form an amine intermediate); and reacting the amine intermediate with a compound of formula W_Three-X₁-W_ThreeOr W_Three-X _Ten (Where X is_TenIs a leaving group) to form compound 291
Process. Formula W₆-X₁The treatment with a compound of formula -H and an acid catalyst is represented by formula W_Three-X₁ -W_ThreeOr W_Three-X_TenPrior to or simultaneously with treatment with the compound of formula (I). Acid catalyst
, Typically one of the acid catalysts described in Process N, Scheme 39 above.
You. More typically, this process converts compound 290 to a compound of formula R_Five-OH, R_Five-S
H or R_Five-NH_TwoTreating with a compound of formula (I) and an acid catalyst; and an intermediate
With alkanoic anhydride to form compound 291.

In one embodiment, compound 290 is of the formula W₆-X₁-H compound and acid catalyst
To produce compound 291. Other embodiments include suitable solvents
In compound 290, compound of formula W₆-X₁-H and a compound treated with an acid catalyst to give a compound
291. Another embodiment is a compound of formula W₆-X₁ -H, an acid catalyst, and a compound of formula W_Three-X₁-W_ThreeOr W_Three-X_TenCompound
To produce compound 291. Other embodiments include suitable solvents
In compound 290, compound of formula W₆-X₁-H, an acid catalyst, and a compound of formula W_Three-X₁-W _Three Or W_Three-X_TenTo produce compound 291.
You.

An exemplary embodiment of this process is shown in Process N, Scheme 39 above.

(Process W, Scheme 40.1) Compound 292 is prepared using compound 291 by the following process.

Compound 291 is processed to form compound 292. Typically, R ₆₅ is transformed to form G ₁ . U ₁ is one embodiment of R ₆₇ and T ₁ is _one embodiment of —N (R ₆₈ ) ₂ prepared in Process V, Scheme 40.1 above.

In one embodiment, R ₆₅ is deprotected, alkylated, guanidinylated, oxidized, or reduced to form G ₁ . Any number of such operations may be performed in any order or simultaneously. By way of example, and not limitation, when R ₆₅ is azide, embodiments of this process include processes O, OQ, O
QR, and OP. Representative alkylating agents are conventional in the art and include, but are not limited to, the following: methyl iodide, methyl bromide, ethyl iodide, ethyl bromide, n-iodide. Propyl, n-propyl bromide,
Alkyl halides such as i-propyl iodide, i-propyl bromide; and olefin oxides such as ethylene oxide or propylene oxide. The base catalyst described herein can be used in the alkylation step, if necessary.

[0512] One embodiment is represented by R₆₅Is treated with a reducing agent to give a compound
Producing the compound 292. In another embodiment, in a suitable solvent, R ₆₅ A compound 292, which is an azide, is treated with a reducing agent to produce a compound 292.
Process. In another embodiment, R₆₅Is a compound 291 wherein is amino
Treating with an agent to produce compound 292. In other embodiments,
In a suitable solvent, R₆₅Treating compound 291 wherein is an amino with an alkylating agent,
A step of producing compound 292. In another embodiment, R₆₅Is azide
Compound 291 is treated with a reducing agent and an alkylating agent to produce Compound 292.
Step. In another embodiment, in a suitable solvent, R₆₅Is an azide
Compound 291 is treated with a reducing agent and an alkylating agent to produce compound 292.
Process. In another embodiment, R₆₅Is a compound 291 wherein is amino
Treating compound 292 with an agent and a base catalyst to produce compound 292. other
In an embodiment, in a suitable solvent, R₆₅Of compound 291 wherein is amino
And treating with an agent and a base catalyst to produce compound 292. Other fruit
In an embodiment, R₆₅Is azide, a reducing agent, an alkylating agent, and
And producing a compound 292 by treating with a base catalyst. Other embodiments
Now, in a suitable solvent, R₆₅Is azide, a reducing agent, alkyl
Treating the compound with an agent and a base catalyst to produce compound 292.

An exemplary embodiment of this process is shown in Process O, Scheme 39 above.

An exemplary embodiment of this process is shown in Examples 68 and 69 below.

[0515]

[Table 51]

[0516]

[Table 52]

[0517]

[Table 53]

[0518]

Embedded image Scheme 41 Amine 300 (intermediate in Example 52, optionally purified prior to use) is treated with Boc anhydride to give mono-Boc protected amine 301. Such a conversion is described in Greene, T .; W. "Protective Grou
ps in Organic Synthesis "2nd edition (John Wil
eye & Sons, New York, 1991) pp. 327-328.

The methyl ester 301 is reduced to the corresponding primary allylic alcohol 302 using DIBAL at low temperature. Such a conversion is described in Garner, P .;
And Park, J .; M. "J. Org. Chem.", 52: 2361.
(1987).

Primary alcohol 302 is protected as its p-methoxybenzyl ether derivative 303 by treatment with 4-methoxybenzyl chloride under basic conditions. Such a conversion is described in Horita, K .; "Tetrahedron",
42: 3021 (1986).

The MOM and Boc protecting groups of 303 are removed by treatment with TFA / CH ₂ Cl ₂ to give amino alcohol 304. Such a transformation is described in Greene,
T. W “Protective Groups in Organic Sy
nthesis "2nd edition (John Wiley & Sons, New Yo
rk, 1991).

Conversion of 304 to the corresponding trityl-protected aziridine 305 is a two-step process of a one pot reaction: 1) TrCl / TE
A, 2) achieved with MsCl / TEA. Such a conversion has already been described.

The aziridine 305 is then converted to the corresponding Boc protected derivative 307, and the first removal of the trityl group with HCl / acetone gives 306. Such a conversion is described in Hanson, R .; W. And Law, H .; D. "J. C
hem. Soc. , 7285 (1965). Aziridine 3
06 is then converted to the corresponding Boc derivative 307 by treatment with Boc anhydride. Such a conversion is described in Fitremann, J .; "Tetrahe
drone Lett. 35: 1201 (1994).

The allylic aziridine 307 is selectively opened at the allylic position using a higher organic cuprate at a low temperature in the presence of BF ₃ .Et ₂ O, and the ring is opened. 308 is obtained. Such ring opening is known as Hudrick
y, T. "Synlett." 1125 (1995).

The Boc-protected amine 308 was prepared in two sequential steps: 1) TFA / CH ₂ Cl ₂ ;
) Converted to N-acetyl derivative 309 with Ac ₂ O / pyridine. Such a conversion is described in Greene, T .; W. "Protective Groups i
n Organic Synthesis "2nd edition (John Wiley &
Sons, New York, 1991) pages 327-328 and 351-3.
Found on page 52.

The benzyl ether 309 is deprotected using DDQ at room temperature to give the primary allylic alcohol 310. Such a conversion is described in Horita, K. et al. "T
etrahedron ", 42: 3021 (1986).

The alcohol 310 is oxidized and converted to the methyl ester 311 in a one-pot reaction via Corey oxidation with MnO ₂ / AcOH / MeOH / NaCN. Such a conversion is described in Corey, E .; J. "J. Am. C
hem. Soc. 90: 5616 (1968).

The azide ester 311 can be prepared in two consecutive steps: 1) Ph ₃ P / H ₂ O / THF; 2) K
In OH / THF, it is converted to amino acid 312. Such a conversion has already been described.

[0529]

Embedded image (Scheme 42) Known fluoroacetate 320 (Sutherland, JK et al.
. Chem. Soc. Chem. Commun. 464 (1993)
) Is deprotected to free alcohol, then 2 steps: 1) NaOMe; 2
) Converted to the corresponding mesylate 321 by MsCl / TEA. Such a conversion is described in Greene, T .; W. "Protective Groups in
Organic Synthesis "Second Edition (John Wiley & S
ons, New York, 1991).

Deprotection of 321 under acidic conditions gives diol 322, which is cyclized to epoxy alcohol 323 under basic conditions. Such a conversion has already been described.

Conversion of 323 to N-trityl protected aziridine 324 is accomplished using the following sequential steps: 1) MOMCl / TEA; 2) NaN ₃ / NH ₄ Cl;
) MsCl / TEA; 4) PPh ₃ / TEA / H ₂ O; 5) NaN ₃ / NH ₄ Cl;
6) HCl / MeOH; 7) i) TrCl, ii) MsCl / TEA. Such a continuous process has already been described.

The aziridine 324 is then opened with the appropriate alcohol under Lewis acid conditions, and then treated with Ac ₂ O / pyridine to give the acetylated product 325. Such a conversion has already been described.

The ester 325 can be prepared in two consecutive steps: 1) PPh ₃ / H ₂ O / THF; 2) KOH /
In THF, it is converted to the corresponding amino acid 326. Such a conversion has already been described.

US Pat. No. 5,214,165, and in particular, “Description and Examples” at column 9, line 61 to column 18, line 26 (“Description and Example”).
s ") describes the preparation of 6α and 6β fluoroshikimic acid (numbered as described therein). These fluoro compounds are suitable starting materials for the preparation of the compounds of the present invention using shikimic acid.

[0535]

Embedded image (Scheme 43) Unsaturated ester 330 (Campbell, MM et al., "Syntheses"
is ”179 (1993) can be obtained by standard acetylation methods from acetonide alcohols), where R ′ is a ligand that is rearranged from an organocuprate (R ′ is J _1a ) Reacts with various organic cuprates. The resulting intermediate is then captured with PhSeCl to give 331. This is then treated with 30% H ₂ O ₂ to give the α, β-unsaturated ester 332. Such a conversion is described in Hayashi, Y .; Et al., J. Org. Chem., 47: 3428 (19)
82).

Acetate 332 was then converted into two sequential steps: 1) NaOMe / MeOH; 2)
It is converted to the corresponding mesylate 333 by MsCl / TEA. Such conversions have already been described, and also in Greene, T .; W. "Prote
active Groups in Organic Synthesis "2nd
Editions (John Wiley & Sons, New York, 1991).

The acetonide 333 was then converted into two successive steps: 1) p-TsOH / MeOH / Δ
2) converted to epoxy alcohol 334 by DBU / THF; Such a conversion has already been described.

Conversion of epoxide 334 to N-tritylaziridine 335 is accomplished in the following sequential steps: 1) MOMCl / TEA; 2) NaN ₃ / NH ₄ Cl; 3) Ms
Cl / TEA; 4) PPh ₃ / TEA / H ₂ O; 5) NaN ₃ / NH ₄ Cl; 6) H
Cl / MeOH; 7) i) TrCl, ii) MsCl / TEA. Such a continuous process has already been described.

The aziridine 335 is then opened with a suitable alcohol under Lewis acid conditions and then treated with Ac ₂ O / pyridine to give the acetylated product 336. Such a conversion has already been described.

The azide ester 336 can be obtained in two consecutive steps: 1) PPh ₃ / H ₂ O / THF; 2) K
In OH / THF, it is converted to the corresponding amino acid 337. Such a conversion has already been described.

Schemes 44 and 45 are referenced in the examples below.

[0542]

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[0543]

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[0544]

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[0545]

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[0546]

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[0547]

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[0548]

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[0549]

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[0550]

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[0551]

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[0552]

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[0553]

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[0554]

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[0555]

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[0556]

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[0557]

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[0558]

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[0559]

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[0560]

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[0561]

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[0562]

Embedded image Modifications of typical starting materials to form different E ₁ groups have been described in detail and will not be described in detail herein. Fleet G. W. J. ";
J. Chem. Soc. Perkin Trans. I "905-90
8 (1984); W. J. "J. Chem. Soc.
Chem. Commun. 849-850 (1983), Yee, Yi
ng K. "J. Med. Chem." 33: 2437-2451 (1
990); Olsen, R .; E. FIG. "Bioorganic & Medi
Cinal Chemistry Letters "4 (18): 2229-2.
234 (1994); Santella, J. et al. B. III et al; "Bioor
ganic & Medicinal Chemistry Letters "
4 (18): 2235-2240 (1994); Judd, D.C. B. "J.
Med. Chem. 37: 3108-3120 (1994), and Lo.
mbaert, S.M. De et al; "Bioorganic &Medicin"
al Chemistry Letters "5 (2): 151-154 (19
94).

The E ₁ sulfur analogs of the carboxylic compounds of the present invention are prepared by any standard technique. By way of example and not limitation, the carboxylic acid is reduced to an alcohol by standard methods. The alcohol is converted to a halide or sulfonic ester by standard methods, and the resulting compound is reacted with NaSH to produce a sulfide compound. Such a reaction is described in Patai "The Chem.
issue of the Thiol Group "(John Wiley
, New York, 1974) Part 2 and especially pages 721-735.

Each modification of the above scheme leads to various analogs of the specific exemplary substances produced above. The references cited above, describing suitable methods of organic synthesis, are applicable to such modifications.

In each of the above exemplary schemes, it may be advantageous to separate the reaction products from each other and / or from starting materials. The desired product of each step or series of steps is separated and / or purified to a desired degree of homogeneity by techniques conventional in the art (hereinafter referred to as separated). Typically, such separations include multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography includes, for example, size exclusion chromatography or ion exchange chromatography, high pressure,
Any method, including medium pressure or low pressure liquid chromatography, small scale and preparative thin layer chromatography or thick layer chromatography, as well as small scale thin layer and flash chromatography techniques can be included.

Another class of separation methods is the treatment of mixtures with reagents selected to bind the desired products, unreacted starting materials, reaction by-products, etc., or to make them separable. Is included. Such reagents include adsorbents or absorbents, such as activated carbon, molecular sieves, ion exchange media, and the like. Alternatively, the reagent is
Acids for basic substances, bases for acidic substances, binding reagents (eg, antibodies, binding proteins), selective chelators (eg, crown ethers), liquid / liquid ion extraction reagents (LIX), and the like. .

The selection of an appropriate separation method depends on the nature of the substances involved. For example, the boiling point and molecular weight in distillation and sublimation, the presence or absence of polar functional groups in chromatography, and the stability of materials in acidic and basic media in multiphase extraction. Those skilled in the art will apply the most promising techniques to achieve the desired separation.

The citations of all references and patents mentioned above are specifically incorporated herein by reference at the location of that reference. The sections or pages cited in detail in the above cited references are specifically incorporated by reference. The present invention has been described in sufficient detail to make and use the subject matter of the following claims. It is clear that certain modifications of the methods and compositions of the following claims can be made within the scope and spirit of the invention. Enteric Protection Another embodiment of the present invention relates to enteric protected forms of the compounds of the present invention. The term "enteric protection", as used herein, refers to a compound of the present invention used to avoid exposing portions of the gastrointestinal tract, typically the upper gastrointestinal tract, particularly the stomach and esophagus, to compounds of the present invention. Means protecting the compound of formula (I). Thus, gastric mucosal tissue is protected against the rate of exposure to the compounds of the present invention, which produces deleterious effects such as vomiting; Protected from conditions present in one or more parts, typically the upper gastrointestinal tract.

Such enteric-protected forms, by way of example but not limitation, include enteric-coated vehicles, such as enteric-coated tablets, enteric-coated granules, enteric-coated granules, and the like. Beads, enteric coated particles, enteric coated microparticles, and enteric coated capsules. In a preferred embodiment, the compounds of the invention are packaged in a suitable vehicle, for example tablets, granules or capsules, and the vehicle is coated with a pharmaceutically acceptable enteric coating. In alternative preferred embodiments, the compounds of the invention are prepared as enteric-protected granules, particles, microparticles, spheres, microspheres, or colloids, and the enteric-protected granules, particles, microparticles, spheres, Microspheres, or colloids, are prepared as pharmaceutically acceptable dosage forms such as tablets, granules, capsules, or suspensions.

One aspect of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of about 0.1-1000 mg of an active ingredient and any pharmaceutically acceptable excipient, in a human or other animal. It relates to an enteric dosage form of a compound of the present invention for delivery to the intestine, preferably to the small intestine.

The term “vehicle” as used herein includes pharmaceutically acceptable dose vehicles. Many vehicles include tablets, coated tablets, capsules, hard capsules, soft gelatin capsules, particles, microparticles, spheres, microspheres, colloids, microencapsulated, sustained release, semi-solid, suppository or granular vehicles such as It is well known in the art described herein.

The term “pharmaceutically acceptable excipient” as used herein includes any physiologically inert, pharmacologically inert material known to those skilled in the art. . This is comparable to the physical and chemical properties of the particular compound of the invention chosen for use. These excipients are described elsewhere herein. Excipients may, but need not, provide enteric protection.

The term “unit dose” is used herein in the conventional sense, meaning a single application or administration of a compound of the present invention to a subject treated with the amounts described below. . Therapeutic or prophylactic dosing may be in a single unit dose or, alternatively, in two or more such dosage units with a total addition to the desired amount of the compound during a given period of time. It should be understood that it can be given by

In general, the compositions of the present oral unit dosage form are preferably from about 1 to about 1000
Milligrams (mg), typically about 10 to about 500 mg, more typically about 50
From about 300 mg, and more typically about 75 mg, of each unit dose of the compound is used. The actual amount will vary depending on the active compound chosen.

In an exemplary embodiment, enteric protection is applied to the compound, with or without the vehicle containing the compound, wherein the protection vomits exposure, contact or exposure rate with the compound of the mouth, esophagus or stomach. Which releases the compound when the dosage form passes through the proximal portion of the lower gastrointestinal tract or, in some embodiments, for absorption substantially only into the colon.

The relative proportions of the protective agents and compounds of the present invention are varied to achieve the optimum absorption depending on the compound selected. The minimum or maximum amount by weight of enteric protective agent is not critical. Typically, enteric-protected embodiments include less than about 50% enteric coating by weight. More typically from about 1% to about 25%, even more typically from about 1% to about 15%, even more typically from about 1% to about 10% (all by weight).

Many research articles describe enteric protection and related techniques, which are useful for preparing the enteric protected compositions of the present invention. Such research papers include: "Theory and Practice of Ind.
U.S.A., US Pat.
Philadelphia, 1986 (ISBN 0-8121-0977-5)
); Lehmann, K .; "Practical Course in La
queer Coating ", Eudragit, 1989; Lieberma
n; Lachman, L .; Schwartz, "Pharmaceutica;
l Dosage Forms: Tablets ", 1990, Dekker (
ISBN: 0-8247-8289-5); Lee, Ping I .; Editor, G
wood, William R. Editor, "Controlled-Releas
e Technology: Pharmaceutical Applicat
ions ", ACS Symposium Ser. Vol. 348 (ISBN
: 0-608-03871-7); Wilson, Billie E .; ; Sha
Nonnon, Margaret T .; , "Dosage Calculation
: A Simplified Approach ", 1996, Appleto
n and Language (ISBN: 0-8385-9297-X); Lieber
man, Herbert A .; Editor Rieger, Martin M. , "
Pharmaceutical Dosage Forms-Disperse
Systems, "1996, Dekker (ISBN: 0-8247-93).
87-0); "Basic Tests for Pharmaceutical"
Dosage Forms ", 1995, World Health (ISB
N: 92-4-154418-X); R. , Editor; Step
Henson, R .; A. , Editor, "Excipients & Delivery
Systems for Pharmaceutical Formula
ions: Proceeding of the "Formulate '9
4 "British Association for Chemical S
Specialties Symposium ”, 1995, CRC Pr (IS
BN: 0-85404-715-8); Ansel, Howard C .; ; Po
povich, Nicholas G .; Allen, Lloyd V .; , "P
Pharmaceutical Dosage Forms & Drug Deli
very Systems, 6th edition ", 1994, Williams and Wi.
Ikins (ISBN: 0-683-01930-9); "The Source
ebook for Innovative Drug Delivery: M
annufactors of Devices & Pharmaceutical
als, Suppliers of Products & Services, S
sources of Information ", 1987, Canon Co.
mns (ISBN: 0-9618649-0-7); Chiellini, E .;
Giusti, G .; Editor; Migliaresi, C .; Editor;
Nicolais, L .; Editor, "Polymers in Medicine"
II: Biomedical & Pharmaceutical Applic
nations ", 1986, Plenum (ISBN: 0-306-42390)
-1); "Pharmaceutical Aerosol: A Drug De
livery System in Transition ", 1994, Te
chnomic (ISBN: 0-87762-971-4); Avis; Lie
berman, L .; Lachman, "Pharmaceutical Do
Sage Forms: Parental Medicine, 2nd
Expanded; Revised ed ", 1992, Dekker (IS
BN: 0-8247-9020-0); Laffer, U.S.A. , Editor; Bach
mann, I .; Editor; Metzger, U.S.A. , Editor, "Implantab
le Drug Delivery Systems ", 1991, S Kar
ger (ISBN: 3-8055-5434-6); Borchardt, Ro
nald T. Repta, Arnold J., editor. , Editor; Stel
la, Valentino J .; , Editor, "Directed Drug D
elivery: A Multidisciplinary Approach
", 1985, Humana (ISBN: 0-89603-089-X); An
derson, James M .; , Editor, "Advances in Dru
g Delivery Systems 5: Proceedings of
the Fifth International Symposium on
Recent Advances in Drug Delivery Sy
stems, Salt Lake City, UT, U.S.A. S. A. , Febru
ary 25-28, 1991 ", Elsevier (ISBN: 0-444).
88664-8); Turco, Salvatore J .; King, Rob
ert E.E. , “Sterile Dosage Forms: Their P
reparation & Clinical Application ", 198
7, Williams & Wilkins (ISBN: 0-8121-1067-
6); Tomlinson, E .; Editors; Davis, S .; S. ,Editor,"
Site-Specific Drug Delivery: Cell Bio
logic, Medical & Pharmaceutical Aspects "
1986, Wiley (ISBN: 0-471-91236-0); Hess.
, H .; Editor, “Pharmaceutical Dosage Forms &
Their Use ", 1986, Hogrefe & Huber Pubs (I
SBN: 3-456-81422-4); Avis; Lieberman; La
chman, "Pharmaceutical Dosage Forms, Volume 2," 1986, Dekker (ISBN: 0-8247-7085-4);
Carstensen, Jens T .; , "Pharmaceutics of
Solids & Solid Dosage Forms ", 1977, Wil
eye (ISBN: 0-471-13726-X); Robinson, Jose
phR. , Editor, "Ophthalmic Drug Delivery
Systems, "1980, Am Pharm Assn (ISBN: 0-9
17330-32-3); Ansel, Howard C .; , "Introdu
Ction to Pharmaceutical Dosage Forms
, 4th Edition ", 1985, Williams and Wilkins (ISBN: 0).
-8121-0957-2); "High Tech Drug Deliver".
ry Systems ", 1984, Intl Res Dev (ISBN: 0)
-88694-622-0); Swarbrick, James, "Curre.
nt Concepts in Pharmaceutical Science
es: Dosage Form Design & Bioavailabilit
y ", 1985, Lea and Febiger (ISBN: 0-318-799).
17-0); Sprowls, Joseph B .; Editor, "Prescript
Tion Pharmacy: Dosage Formulation & Pha
rmeutical Adjuncts, 2nd edition ", 1970, Lippi
ncott (ISBN: 0-397-52050-6); and Polderm.
an, J .; , Editor, "Formulation & Preparation o
f Dosage Forms: Proceedings of the 37
the International Congress of Pharmac
electronic Sciences of F.E. I. P. , The Hague
, Netherlands, September, 1977 ", Elsevier
r (ISBN: 0-444-80033-6).

Particular Embodiments: In another embodiment, the compositions of the invention are in the form of an enteric coated tablet dosage form. In this embodiment, the formulation is formed into a hard tablet by conventional means, and the tablet is coated with an enteric coating according to conventional techniques.

In a preferred embodiment, the compounds of the invention are in the form of an enteric coated powder. In this embodiment, the formulation is filled into hard or soft shell capsules, or their equivalent, and the capsules are coated with an enteric coating according to conventional techniques.

In one embodiment, the compositions of the present invention are in the form of a liquid suspension of enteric coated particles of a compound of the present invention. In this embodiment, a suspension of the inhibitor in a liquid is filled into a hard or soft shell capsule, or equivalent, which is coated with an enteric coating according to conventional techniques.

As an alternative to the above-described embodiments, the capsule or other administration container is itself composed of an enteric protective reagent or ingredient, or is otherwise integrated into the container.

In another embodiment, enteric protection is used to administer the compound of the invention to the colon. The delivery system is a tablet consisting of three layers: 1) a core containing the active compound of the invention; 2) a non-swellable, erodible polymer layer surrounding the core, which is a "dual matrix tablet (dual matrix tablet). and a 3) enteric coating applied to the dual matrix tablet. The function of this composition and the components of such a colon targeted delivery system is further described in US Pat. No. 5,482,718, which is hereby incorporated by reference in its entirety herein. In particular, column 2, line 29 to column 4, line 12 is specifically incorporated herein.

In another embodiment of the present invention, an enteric protected emulsion of a compound of the present invention,
Suspensions, tablets, coated tablets, hard capsules, soft gelatin capsules, microencapsulated, sustained release, liquid, semi-solid, suppository, and aerosol dosage forms. "T
heavy and Practice of Industrial Pha
rmacy ", 3rd edition, Lea and Febiger, Philadelphia
a, 1986 (ISBN 0-8121-0977-5) describes each of these standard dosage forms in detail when: emulsion and suspension dosage forms (pages 100-122), tablets (293) 345 pages), coated tablets (346-3 pages)
73 capsules), hard capsules (pages 374-397), soft gelatin capsules (398-4)
11), microencapsulation (pages 412-430), sustained release dosage form (430
456), liquids (457-478), pharmaceutical suspensions (479-501)
, Emulsion (pages 502-533), semi-solid (pages 534-563), suppositories (5
64-587), and pharmaceutical aerosols (pages 589-618).

Alternative embodiments include enteric-protected sustained release, controlled release, particulate, microencapsulated, multiparticulate, particulate, colloidal, nasal, inhaled, Oral mucosal, colon, dermal, transdermal, ocular, topical, and veterinary dosage forms. Each of these dosage form technologies is described in James Swarbrick.
"Dru" edited by Marcel Dekker (New York)
gs and the Pharmaceutical Sciences ".

Materials: Mixtures of conventional enteric protective polymers and polymers for use herein are insoluble at pH below about 5.5 (ie, this is commonly found in the stomach). Some include those that are soluble at a pH of about 5.5 or higher (ie, present in the small and large intestine). The effect of certain enteric protective materials is known from USP
Can be measured using the procedure of

Exemplary enteric protective polymers that may be used in this embodiment include cellulose acetate phthalate, methyl acrylate-methacrylic acid copolymer, cellulose acetate succinate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, And methyl methacrylate-methacrylic acid copolymer. Another example is an anionic carboxylic acid copolymer based on methacrylic acid and methacrylate (commercially available as Eudragit (r)). Representative examples include cellulose acetate phthalate ("CAP"), cellulose acetate trimellitate, hydroxypropylmethylcellulose phthalate ("HPMCP"),
Examples include hydroxypropyl methylcellulose succinate phthalate, polyvinyl acetate phthalate ("PVAP"), methacrylic acid, and methacrylic acid esters. More typically, the protective agent is PVAP and / or HPMCP, especially PVA
Selected from P. PVAP is known under the trademark Sureteric® manufactured by Colorcon, Inc.

The enteric protective materials may be any of the conventional plasticizers such as acetylated monoglycerides, propylene glycol, glycerol, glyceryl triacetate, polyethylene glycol, triethyl citrate, tributyl citrate, diethyl acrylate used in a manner known to those skilled in the art. Phthalate, or dibutyl phthalate) with or without a vehicle.

Exemplary Embodiment of Enteric Protection: (Embodiment 1: Enteric Protection GS 4104 Capsule) In this exemplary embodiment, GS 4104 (Compound 262, Example 116)
, Phosphate form, 131.4 mg / capsule, 100 mg free base equivalent) in a size 4 milky white opaque hard gelatin capsule shell (capsule composition: gelatin NF, titanium dioxide USP), croscarmellose sodium (Croscarmel).
mix (2.6 mg / capsule) and the capsules were enterically coated.

The following enteric coating formulations are applied to capsules by procedures known to those skilled in the art.

[0590]

[Table 54] Typically, the enteric polymer (with or without a plasticizer) dissolves in the solvents described under each formulation to form a suspension / solvent. If necessary, opacifying agents such as titanium dioxide are added. The vehicle is sprayed with the coating suspension / solution into a suitable container under conditions such that the enteric-protected coating is installed in the vehicle without dissolving or disintegrating the vehicle.
About 1-50% by weight, typically 1-15% by weight, more typically 5-10% by weight
An enteric polymer coating finish coat vehicle is useful for proper enteric protection.

Embodiment 2: Enteric Protective Tablet In another exemplary embodiment, the core tablet is encased in an enteric coating. If necessary, sub-coatings are used.

Core Tablets: The core tablets of the present invention comprise (a) the active ingredient, eg, diluents, binders, disintegrants, compression aids, flavors, flavor enhancers, sweeteners, dyes. Combining a pharmaceutically acceptable excipient in a mixture comprising, and any one or more components selected from the group consisting of: pigments, buffer systems, and preservatives;
b) lubricating the mixture with a lubricant; and (c) compressing the resulting lubricated mixture into the desired tablet form using various tableting techniques available to those skilled in the art. Can be formed. The term “tablet” as used herein is intended to encompass compressed or formed pharmaceutical dosage formulations of all shapes and sizes.

[0593] Representative diluents that can be used in this embodiment include lactose or microcrystalline cellulose.

[0594] Representative binders that can be used in this embodiment include, but are not limited to, povidone. Povidone is available from ISP Corporation under the trade name “Avicel”.

The disintegrant may be one of several modified starches or modified cellulose polymers.
One. Typically, croscarmellose
) Sodium is used. Croscarmellose sodium NF type A is commercially available under the trade name "Ac-di-sol".

[0596] Representative lubricants include magnesium stearate, stearic acid, hydrogenated vegetable oils or talc.

[0597] Fragrance agents include Remington's Pharmaceutical Sc.
geneses, 18th edition, Mack Publishing Company,
1990, pages 1288 to 1300.

Representative sweeteners include saccharin, Aspartame, or an edible mono- or disaccharide (eg, glycol or sucrose).

Dyes and pigments include Pharm from the American Pharmaceutical Association and the British Pharmaceutical Association.
Acoustic Excipients Handbook, pp. 81-90, 1
986.

Typical preservatives include methylparaben, propylparaben, cetylpyridinium chloride, and salts thereof, sorbic acid and its salts, thimerosal, or benzalkonium chloride.

Enteric Coating: Eudragit L-30-D (r), methacrylic acid copolymer (Rohm
Pharma GmbH, manufactured by Weiterstadt, West Germany) is a suitable enteric polymer. Eudragit L-30-D (r
Has a ratio of free carboxyl groups to ester groups of about 1: 1 and a pH of 5.
Dissolve freely at 5 or more. Generally, Eudrag contained in enteric coatings
The higher the percentage of it L-30-D (r), the more proximal the release of activity in the lower gastrointestinal tract. The location in the lower gastrointestinal tract, where the coating releases the compound, is manipulated by control of the composition and thickness of the enteric coating applied by those skilled in the art.

[0602] Typically, a plasticizer (eg, as described above) is included.

Other additives, such as talc or silica, can be used as detackifiers to improve the coating process.

Subcoating: Optionally, a stability enhancing subcoat is used on the core tablet to minimize the interaction between the compound of the present invention and the enteric coating. This also allows the use of a single 10-300 micron thick enteric film without affecting product stability. This subcoat inhibits the transfer of the active ingredient from the core tablet to the enteric coating, thereby improving shelf life and product stability, but once the outer enteric coating has cleaved, the subcoat is Quickly dissolves in intestinal fluid.

[0605] Representative subcoating polymers that can be used in this embodiment include hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxypropylethylcellulose, or polyvinylpyrrolidone.

(Examples) (General) The following examples are shown in the scheme.

Some examples were performed multiple times. In the repeated example, the time, temperature,
Reaction conditions, such as concentration, and yields were within the normal experimental range. In the example repeated with significant modifications, if the result significantly changed from the described result,
These are noted. These are noted in the examples using different starting materials. Where the repeated examples show a "corresponding" analog of the compound (e.g., the "corresponding ethyl ester"), this means that the otherwise present group (in this case, typically the methyl ester) is indicated. It is intended that the same modified group is used.
For example, “the corresponding ethyl ester of compound 1” is as follows:

[0608]

Embedded image Example 1 Epoxy Alcohol 1: McGowan and Berchold, JO
rg. Chem. , 46: 2381 (1981).

Example 2 Epoxy Allyl Ether 2: To a solution of epoxy alcohol 1 (2.37 g, 14.08 mmol) in dry benzene (50 ml) was added thallium (I) ethoxide (1.01 ml) at once. Was added. After 2 hours, the reaction was concentrated under reduced pressure and the residue was dissolved in acetonitrile. Allyl iodide (3.0 ml) was added and the mixture was stirred for 16 hours in the dark. Filter the solid through a pad of celite,
Then, it was washed with chloroform. Concentration under reduced pressure followed by flash chromatography (40% EtOAc in hexane) provided 1.24 g (42%) of 2 as a pale white viscous oil.

[0610]

(Equation 1) Example 3 Azide alcohol 3: Epoxide 2 (1.17 g, 5.57 mmol), sodium azide (1.82 g) and ammonium chloride (658 mg) in MeOH
Refluxed in / H ₂ O (8: 1) (35 ml) for 18 hours. The reaction was then concentrated under reduced pressure and the residue was partitioned between ethyl ether and water. The organic layer was washed with brine and dried. Concentrate under reduced pressure to obtain 1.3 g of pale oil.
(92%) which was used without further purification.

[0611]

(Equation 2) Example 4 Aziridine 4: alcohol 3 (6 in CH ₂ Cl ₂ (20 ml) cooled to 0 ° C.
To a solution of 37 mg, 2.52 mmol) was added DMAP (with few crystals) and triethylamine (442 μl). Then, MsCl (287 μl
) Was added and the reaction was stirred at 0 ° C. for 2 hours. Volatiles were removed and the residue was partitioned between ethyl ether and water. The organic layer was washed with saturated bicarbonate, brine and then dried. Concentration under reduced pressure gave 881 mg of crude mesylate.

[0612]

(Equation 3) The crude mesylate was dissolved in dry THF (20 ml), and treated with Ph ₃ P (727m g). After stirring at room temperature for 3 hours, water (15 ml) and solid NaHCO ₃ (1.35 g) were added and the mixture was stirred overnight at room temperature. The reaction was then concentrated under reduced pressure and the residue was partitioned between EtOAc, saturated bicarbonate and brine. The organic layer was separated and dried over MgSO _4. Concentrate under reduced pressure and subject the residue to flash chromatography to give 170 mg of aziridine (170 mg).
33%) as a pale yellow oil.

[0613]

(Equation 4) (Example 5) N-acetylaziridine 5: aziridine 4 (170 mg, 0.814 mmol)
) Was dissolved in CH ₂ Cl ₂ (2 ml) and pyridine (4 ml) and cooled to 0 ° C. Acetyl chloride (87 μl) was then added and the reaction was added to 0
Stirred at C for 1 hour. Volatiles were removed under reduced pressure and the residue was partitioned between ethyl ether, saturated bicarbonate and brine. The organic layer was separated and dried over MgSO _4. Concentration gave crude 5196 mg (96%) which was used without further purification.

[0614]

(Equation 5) Example 6 Azidoallyl ether 6: aziridine 5 (219m) in dry DMF (7ml)
g, 0.873 mmol), sodium azide (426 mg) and ammonium chloride (444 mg) were heated at 65 ° C. under argon overnight. The reaction was poured into saturated bicarbonate / brine and extracted several times with ethyl ether. The combined ether layers were washed with brine and dried. Concentration followed by flash chromatography (EtOAc only) 77 mg (35%) of azidoamine
Which was dissolved in CH ₂ Cl ₂ (1 ml) and pyridine (1 ml) and
And cooled. Acetyl chloride (38 μl) was added and after 45 minutes solid N
aHCO ₃ was added and volatiles were removed under reduced pressure. The residue was partitioned between EtOAc and brine. The organic layer was dried over MgSO _4, and concentrated under reduced pressure. 90 mg (99%) of 6 by flash chromatography (EtOAc only)
I got it.

[0615]

(Equation 6) Example 7 Azidodiol 7: To a solution of olefin 6 (90 mg, 0.306 mmol) in acetone (3 mL) and water (258 μl) was added N-methylmorpholine-N-
Oxide (39 mg) and OsO ₄ (73 μl of 2.5% w / w in t-butanol) were added. The reaction was then stirred at room temperature for 3 days. Solid sodium bisulfite was added and after stirring for 20 minutes, the reaction was filtered through a pad of celite and washed with sufficient acetone. Concentration under reduced pressure followed by flash chromatography (10% MeOH in CH ₂ Cl ₂ ) afforded 750 mg (50%) of the diol.

[0616]

(Equation 7) Example 8 Amino Acid Diol 8: Diol 7 (23 mg, 0.07 in THF (1 ml))
mmol) was treated with aqueous KOH (223 μl of a 0.40 M solution) at room temperature. After 1.5 hours of stirring, the reaction was amberlite IR-120 (+)
Acidified to pH = 4 with ion exchange resin. The resin is filtered and MeOH
And washed. Concentration under reduced pressure gave a crude carboxylic acid, which was ethanol (1.5 m
l). To this solution was added Lindlar's catalyst (20 mg) and the reaction was stirred under a hydrogen atmosphere (1 atm via a balloon) for 20 h. The reaction mixture was filtered through a pad of celite and washed with hot ethanol and water. The ethanol was removed under reduced pressure and the resulting aqueous layer was lyophilized to give a mixture of the desired amino acid 8 and starting azide 7 as a white powder. Compound 8:

[0617]

(Equation 8) Example 9 Compound 62: quinic acid (60 g) in benzene (450 ml), cyclohexano
(160 ml) and a suspension of toluenesulfonic acid (600 mg)
Reflux for 14 hours using Dean-Stark. Chamber the reaction mixture
Cooled to warm, saturated NaHCO_ThreePoured into the solution (150 ml). CH layer_TwoCl _Two (3x). The combined organic layers were washed with water (2 ×), brine (1 ×), and_TwoSO_FourAnd dried. Concentration gave a white solid, which was
(75 g, 95%):

[0618]

(Equation 9) Example 10 Compound 63: Lactone 62 (12.7 g, 50 in methanol (300 ml))
mmol) was added in one portion to the solution of sodium methoxide (2.7 g, 50 mmol). The mixture was stirred at room temperature for 3 hours and quenched with acetic acid (3ml) and stirred for 10 minutes. The mixture was poured into a saturated NH ₄ Cl solution (300 ml) and extracted with CH ₂ Cl ₂ (3 ×). The combined organic layers were washed with brine (1 ×) and dried over MgSO ₄ . Purification by flash column chromatography (hexane / EtOAc = 1/1 to 1/2) gave the diol (11.5 g, 8
0%) and starting material (1.2 g, 10%) were obtained:

[0619]

(Equation 10) (Example 11) Compound _{64: CH 2 Cl 2 (15ml} ) diol in 63 (1.100 g, 3.
9 mmol), molecular sieves (3A, 2.2 g) and pyridine (1.1 g)
) Was added all at once with PCC (3.3 g, 15.6 mmol). The mixture was stirred at room temperature for 26 hours and diluted with ether (30ml). The suspension was filtered through a pad of celite and washed with ether (2 × 20 ml).
The combined ether was washed with brine (2 ×) and dried over MgSO _4. Concentration and purification by flash column chromatography (hexane / EtOAc = 3/1) gave the ketone (0.690 g, 67%):

[0620]

[Equation 11] Example 12 Compound 28: Ketone 64 (0.630 g, 2.4 m) in MeOH (12 ml)
mol) in NaBH at 0 ° C._FourWas added over 30 minutes. The mixture was stirred at 0 ° C. for a further 1.5 hours and 15 ml of saturated NH_FourQuenched with Cl solution. CH solution_TwoCl_Two(3x), and combine the combined organic extracts with MgSO _Four And dried. Purification by flash column chromatography (hexane / EtOAc = 2/1) gave the alcohol (0.614 g, 97%):

[0621]

(Equation 12) Example 13 Compound 66: Alcohol 28 (2.93 g, 10.9 mmol) and toluenesulfonic acid (1.5 g) were dissolved in acetone (75 ml) and the mixture was stirred at room temperature for 15 hours. The reaction was quenched with water (30 ml), and conc. NH ₃ - was basified until pH = 9 using H ₂ O. The acetone was removed under reduced pressure, and the aqueous phase was extracted with CH ₂ Cl ₂ (3 ×). Combine the organic extracts with brine (1
×) and dried over Na ₂ SO ₄ . Concentration gave the desired product:

[0622]

(Equation 13) Example 14 Compound 67: Alcohol 66 (10.9 mmol) in CH ₂ Cl ₂ (60 ml)
)) At 0 ° C. was added pyridine (4.4 ml, 54.5 mmol) followed by trimethylacetyl chloride (2.7 ml, 21.8 mmol). The mixture was warmed to room temperature and stirred for 14 hours. The mixture was diluted with CH ₂ Cl ₂ and washed with water (2 ×), brine (1 ×) and dried over MgSO ₄ . Flash column chromatography (Hexane / EtOAc = 9/1)
To give the diester (2.320 g, 68%):

[0623]

[Equation 14] Example 15 Compound 68: Diester 67 (2.32 g, 2.3 mmol) was converted to acetone / H. _Two Dissolved in O (1/1, 100 ml) and heated at 55 ° C. for 16 hours. The solvent was removed, water (2 × 50 ml) was added and evaporated. Toluene (2
X 50 ml) to give the diol, which is used without further purification.
Used:

[0624]

(Equation 15) Example 16 Compound 69: Diol 68 (0.410 g, 1.5 mm in THF (8 ml))
ol) at 0 ° C. in triethylamine (0.83 ml, 6.0 mmol).
Was added, followed by slow addition of thionyl chloride (0.33 ml, 4.5 mmol). The mixture was warmed to room temperature and stirred for 3 hours. CHC mixture
diluted with l _3, and water (3 ×), washed brine (1 ×), and dried over MgSO _4. Flash column chromatography (hexane / EtOAc = 5
/ 1) to give an exo / endo mixture (0.430 g, 90%):

[0625]

(Equation 16) Example 17 Compound 70: Sulfone 69 (0.400 g, 1.3 m) in DMF (10 ml)
mol) and sodium azide (0.410 g, 6.29 mmol) was stirred for 20 hours. The reaction mixture was then diluted with ethyl acetate, saturated NH ₄ C l solution, water, brine, and dried over MgSO _4. Concentration gave the azide (0.338 g, 90%):

[0626]

[Equation 17] Example 18 Compound 71: Alcohol 70 (0.338 g, 1 in CH ₂ Cl ₂ (11 ml))
. 1 mmol) at 0 ° C. in triethylamine (0.4 ml, 2.9 mm).
ol), followed by methyl sulfonic acid chloride (0.18 ml, 2.3 mm
ol) was added slowly. The mixture was stirred at 0 ° C. for 30 minutes and diluted with CH ₂ Cl ₂ . The organic layer was washed with water (2 ×), washed with brine, and dried over MgSO _4. Flash column chromatography (Hexane / EtOAc = 3/1)
To give the desired compound (0.380 g, 82%):

[0627]

(Equation 18) Example 19 Compound 72: Azide 71 (0.380 g, 0.94 m) in THF (19 ml)
mol) and triphenylphosphine (0.271 g, 1.04 mmol) was stirred for 2 hours. The reaction was carried out with water (1.9 ml) and triethylamine (0.
. (39 ml, 2.82 mmol) and the mixture was stirred for 14 hours. The solvent was removed under reduced pressure and the mixture was used for the next step. To a solution of the above mixture in CH ₂ Cl ₂ (20 ml) at 0 ° C. pyridine (0.68 ml, 8.
4 mmol), followed by acetyl chloride (0.30 ml, 4.2 mmol).
l) was added slowly. The mixture was stirred at 0 ° C. for 5 minutes and diluted with ethyl acetate. The mixture was washed with water (2 ×), brine (1 ×) and dried over MgSO ₄ . Flash column chromatography (hexane / EtOAc = 3 /
Purification according to 1) gave aziridine (0.205 g, 83%):

[0628]

[Equation 19] Example 20 Compound 73: Aziridine 72 (0.200 g, 0.6 in DMF (10 ml))
A mixture of 8 mmol), sodium azide (0.221 g, 3.4 mmol), and ammonium chloride (0.146 g, 2.7 mmol) was stirred at room temperature for 14 hours. The mixture was then diluted with ethyl acetate and water (5 ×), brine (5 ×).
1 ×) and dried over MgSO ₄ . Purification by flash column chromatography (hexane / EtOAc = 2/1) provided the desired product and deacetylamine (0.139 g). The mixture was dissolved in acetic anhydride (2ml) and stirred for 2 hours. The excess anhydride is removed under reduced pressure and the desired product (
149 mg) were obtained:

[0629]

(Equation 20) (Example 21) Compound 74: A solution of potassium hydroxide in _{MeOH / H 2 O (0.5M,} 4.4 ml, 2.2mmol) and ester 73 (149 mg, 0.44 mmol) was added to the mixture Was stirred at room temperature for 3 hours. The mixture was cooled to 0 ° C. and
Acidified to pH = 3-4 using rlite (acidic). The mixture was filtered and washed with MeOH. Concentration provided the carboxylic acid as a white solid (73 mg, 69%):

[0630]

(Equation 21) Example 22 Compound 75: Azide 74 (8 mg) and Pd-C in ethanol (2 ml)
A mixture of (Lindler) (15 mg) was stirred under hydrogen for 16 hours. The mixture was filtered through Celite and washed with hot _{MeOH-H 2 O (1/1)} . A solid was obtained by concentration. This solid was dissolved in water and passed through a short C-8 column and washed with water. Concentration gave a white solid (6 mg):

[0631]

(Equation 22) Example 23 Compound 76: Carboxylic acid 74 (68 mg, 0.28 mmol) and diphenyldiazomethane (61 mg, 0.31 mmol) were dissolved in ethanol (12 ml) and stirred for 16 hours. The reaction was quenched with acetic acid (0.5 ml) and the mixture was stirred for 10 minutes. The solvent was removed under reduced pressure. Purification by flash column chromatography (EtOAc) provided the ester (56 mg, 50%):

[0632]

(Equation 23) (Example 24) Compound _{77: CH 2 Cl 2 (1ml} ) solution of alcohol 76 (20 mg, 0.05
pyridine (40 μl, 0.5 mmol) was added, followed by acetic anhydride (24 μl, 0.25 mmol). The mixture was stirred for 24 hours and the solvents and reagents were removed under reduced pressure. Purification by flash column chromatography (hexane / EtOAc = 1/2) gave the diester (20 mg,
91%):

[0633]

(Equation 24) (Example 25) Compound _{78: CH 2 Cl 2 (1ml} ) solution of the diester 77 (20 mg, 0.04
5 mmol), anisole (50 μl, 0.45 mmol), and TFA (1
ml) of the mixture was stirred for 20 minutes. Solvents and reagents were removed under reduced pressure. Flash column chromatography (EtOAc vs. EtOAc / AcOH = 100 /
Purification according to 1) gave the carboxylic acid (6 mg):

[0634]

(Equation 25) (Example 26) Compound _{79: EtOH / H 2 O (} 2.2ml, 10/1) azide 78 (6 mg, 0.02 mmol) in and Pd-C (Lindlar) mixture under hydrogen (15 mg) And stirred for 3 hours. The mixture was filtered through a celite pad and washed with hot _{MeOH / H 2 O (1/1)} . Evaporation gave a white solid. This solid was dissolved in water and passed through a C-8 column. The water was evaporated to give a white powder (3mg):

[0635]

(Equation 26) (Example 27) Compound _{80: CH 2 Cl 2 (1ml} ) solution of alcohol 76 (35 mg, 0.08
To a solution of 6 mmol), Boc-glycine (30 mg, 0.172 mmol), and a catalytic amount of DMAP, DCC (35 mg, 0.172 mmol) was added. The mixture was stirred for 30 minutes and filtered, and washed with CHCl _3. The CH Cl ₃ solution was washed with water (2 ×). Concentration gave a white solid. Purification by flash column chromatography (hexane / EtOAc = 1/2) gave the product (30 mg):

[0636]

[Equation 27] (Example 28) Compound _{81: CH 2 Cl 2 (1ml} ) solution of the diester 80 (30 mg, 0.05
mmol), anisole (150 μl), and TFA (1 ml).
Stirred for hours. Solvents and reagents were evaporated. The mixture was dissolved in water and washed with CHCl ₃ (3 ×). The aqueous phase was evaporated to give a white solid (15 mg):

[0637]

[Equation 28] (Example 29) Compound _{82: EtOH / H 2 O (} 4ml, 1/1) azide in 81 (15 mg, 0.05 mmol) and Pd-C (Lindlar) 3 hours under hydrogen mixture (30 mg) Stirred. The mixture was filtered through a pad of celite and hot M
Washed with OH / H ₂ O (1/1). Concentration gave a glassy solid. This solid was dissolved in water and passed through a C-8 column. Evaporation of water gave the amino acids:

[0638]

(Equation 29) Example 30 Bis-Boc guanidinyl methyl ester 92: Kim and Qian, "T
etrahedron Lett. , 34: 7677 (1993). Amine 91 (42) in dry DMF (310 μl) cooled to 0 ° C.
mg, 0.154 mmol), bis-Boc thiourea (43 mg, 0.155 m
mol) and triethylamine (72 μl) were added to a solution of mercuric chloride (46 mg,
0.170 mmol) was added in one portion. After 30 minutes, warm the reaction to room temperature,
Then, the mixture was further stirred for 2.5 hours. The reaction mixture was then filtered through a pad of celite, concentrated and purified by flash column chromatography (100% ethyl acetate) to give 70 mg (89%) of 92 as a colorless foam.

[0639]

[Equation 30] Example 31 Bis-Boc guanidinyl carboxylic acid 93: THF cooled to 0 ° C (3 ml)
To a solution of ester 92 (70 mg, 0.136 mmol) in aqueous KOH (
350 μl of a 0.476 M solution) was added. The reaction was then warmed to room temperature and stirred for 2 hours. The reaction was then transferred to Amberlite IR-120.
(+) Acidified to pH = 4.5 using acidic resin. The resin is then filtered,
Then, it was washed with ethanol and H ₂ O. Concentration under reduced pressure gave 66 mg (97%) of carboxylic acid 93 as a white solid.

[0640]

(Equation 31) (Example 32) guanidine carboxylic acid TFA salt 94: 0 ° C. bis in chilled CH ₂ Cl ₂ (1ml) -Boc- guar Nizhny Le carboxylic acid 93 (23 mg, 0.046 mmol
To this solution was added neat trifluoroacetic acid (500 μl). 30 minutes later,
The reaction was warmed to room temperature and stirred for an additional 1.25 hours. The volatiles removed under reduced pressure and then the residue with several H ₂ O and coevaporated (co-evapo rate) to give a pale orange solid. The residue was purified by reverse phase C _{1 8} chromatography of H ₂ O as eluant. Fractions containing the desired product were pooled and lyophilized to give 15 mg of 93 as a white powder.

[0641]

(Equation 32) Example 33 Synthesis of 102: Azidoallyl ether 6 (24 mg) in ethanol (1 ml)
, 0.082 mmol) using a hydrogen gas (1 atm).
The mixture was treated with a medium (30 mg) for 1.5 hours. The reaction mixture was filtered through a pad of celite.
And washed with hot ethanol. Concentration in vacuo to give a pale white solid, and
This was dissolved in THF (1.5 ml) and aqueous KOH (246 μl of 0.
(50M solution). After stirring for 2 hours at ambient temperature, the reaction was
It was acidified to pH = 4.0 using item IR-120 (+) acidic resin and filtered.
And ethanol and H_TwoWashed with O. Concentration under reduced pressure gave an orange solid which was eluted with water.₁₈Purified by column chromatography. This product
Are pooled and lyophilized to obtain 102 and fully saturated
A 2: 1 mixture of compound 103 was obtained as a white powder. For compound 102 ¹ 1 H NMR data is as follows:

[0642]

[Equation 33] Example 34 Synthesis of 115: amino acid 114 (10.10) in water (1.3 ml) cooled to 0 ° C.
7 mg, 0.038 mmol) using 1.0 M NaOH to pH = 9.
Adjusted to zero. Then, benzylformimidate hydrochloride (26 mg, 0.15
3 mmol) is added in one portion and the reaction is brought to pH with 1.0 M NaOH.
Was stirred between 0-5 ° C. for 3 hours while maintaining between 8.5-9.0. The reaction was then concentrated under reduced pressure and the residue was applied to a _C18 column and eluted with water. Fractions containing this product were pooled and lyophilized to give formamidine carboxylic acid 115 (10 mg) as a white powder.

[0643]

(Equation 34) Example 35 Compound 123: alcohol 63 (5.842 g, 2 in pyridine (40 ml)
0.5 mmol) and DMAP (200 mg) in a solution of tosyl chloride (4
. (3 g, 22.6 mmol). The mixture was stirred at room temperature for 40 hours and pyridine was removed under reduced pressure. The reaction is quenched with water and EtOAc (3 ×
). The combined organic extracts were washed with water, brine, and dried over MgSO _4. Flash column chromatography (hexane / EtOAc = 2
/ 1) to give tosylate (8.04 g, 89%):

[0644]

(Equation 35) Example 36 Compound 124: Alcohol 123 (440 mg, 1 .1) in pyridine (3 ml).
0 mmol) was added POCl ₃ (100 μl, 1.1 mmol). The mixture was stirred for 12 hours at room temperature, and quenched with saturated NH ₄ Cl solution. The aqueous phase was extracted with ether (3x). The combined ether layers were washed with water (2 ×), 2N
HCl solution (2 ×), washed with brine, and dried over MgSO _4. Purification by flash column chromatography (hexane / EtOAc = 2/1) gave a mixture of the desired product 124 and some impurities (350 mg, 83%,
2/1).

Example 37 Compound 1: Known acetonide of methylshikimate (877 mg, 3.85 mmol, "Tetrahedron Lett") in dichloromethane (15 ml).
, 26:21 (1985)) at −10 ° C. was added methanesulfonyl chloride (330 μl, 4.23 mmol) followed by triethylamine (640).
μl, 4.62 mmol) was added dropwise. The solution was stirred at −10 ° C. for 1 hour, then at 0 ° C. for 2 hours, at which time methanesulfonyl chloride (30 μl), triethylamine (64 μl) were added. After 1 hour, cold water was added, the organic layer was separated, washed with water, dried (MgSO ₄ ) and evaporated. The crude product is chromatographed on silica gel (1 / 1-hexane / ethyl acetate) to give mesylate 13
0 (1.1 g, 93%) was obtained as an oil. Mesylate 130 (990 mg,
3.2 mmol) in tetrahydrofuran (5 ml) and 1M HC
1 (5 ml). The solution was stirred at room temperature for 19 hours, diluted with water (5ml) and stirred for another 7 hours. The organic solvent was evaporated to precipitate an oil residue, which was extracted into ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO _4), and evaporated. CH ₂ Cl ₂ was added to the crude residue to precipitate a white solid, which was filtered and washed with CH ₂ Cl ₂ to give diol 131 (323 mg, 38%). Diol 131 in THF (5 ml)
(260 mg, 0.98 mmol) in a DBU (154 μμ) at 0 ° C.
1, 1.03 mmol). The solution was stirred at 0 ° C. for 3 hours, then warmed to room temperature and stirred for 5 hours. The solvent was evaporated and the crude residue was partitioned between ethyl acetate (40ml) and 5% citric acid (20ml). The organic phase was washed with brine. The aqueous phase was back extracted with ethyl acetate (15 ml), and the combined organic extracts were dried (MgSO ₄₎ and and evaporated to give an epoxide (117m g, 70%) as a white solid. It shows a ¹ H NMR spectrum consistent with structure 1 prepared by literature methods.

Example 38 Alcohol 51: Protected alcohol (342 mg, 10 mL) in CH ₂ Cl ₂
To a solution of 1.15 mmol) (PG = methoxymethyl) was added trifluoroacetic acid (8 ml) at 0 ° C. After 5 minutes at 0 ° C., the solution was stirred at room temperature for 1 hour and evaporated. The crude product was purified on silica gel (ethyl acetate) to give alcohol 51 (237 mg, 82%) as an oil:

[0647]

[Equation 36] Example 39 Methyl ether 150: Alcohol 51 (46 mg) in THF (0.7 ml)
, 0.18 mmol) and methyl iodide (56 μl, 0.90 mmol) in NaH (8 mg, 0.20 mmol) as a 60% mineral oil dispersion at 0 ° C.
Was added. The solution was stirred at 0 ° C. for 2.5 hours and a second portion of NaH (2 mg)
Was added. After an additional hour at 0 ° C. and 4 hours at room temperature, the solution was cooled to 0 ° C. and 5% citric acid (0.5 ml) was added. The mixture was diluted with ethyl acetate (4 × 2 ml
) And the combined organic extracts were dried (MgSO ₄ ) and evaporated. The crude residue is purified on silica gel (ethyl acetate) to give methyl ether 15
0 (12 mg, 25%) was obtained as a solid:

[0648]

(37) Example 40 Amino acid 151: Methyl ether 1 in THF (1 ml) / water (100 μl)
To a solution of 50 (12mg, 0.45mmol), polymer supported _{Ph 3 P (75m g, 3mmol} P / g resin) was added. The mixture was stirred at room temperature for 19 hours.
The resin was filtered, washed several times with THF, and the combined filtrate and washings were evaporated to give 8 mg of a crude residue. The residue was dissolved in THF (0.5 ml) and 0.5 M KOH (132 μl) / water (250 μl) was added. The solution was stirred at room temperature for 1.25 hours and the pH was adjusted to 3-4 using IR120 ion exchange resin. The resin was filtered and stirred with 1M HCl. After filtration, until the acidic wash is no longer tested positive for amines with ninhydrin
The resin was subjected to the same treatment using 1M HCl. The combined resin washes were evaporated and the residue was purified on C-18 reverse phase silica, eluting with water, and after lyophilization,
Amino acid 151 (1.8 mg, 15%) was obtained as a white solid:

[0649]

(38) Example 41 Amino Acid Allyl Ether 153: To a solution of azide 6 (16 mg, 0.054 mmol) in THF (0.5 ml) and H ₂ O (35 μl) was added PPh _{3 on} polystyrene (50 mg). The reaction was stirred at ambient temperature for 24 hours, filtered through a sintered glass funnel and washed with hot methanol. Concentration under reduced pressure gave the crude amino ester, which was dissolved in THF (1.0 ml) and treated with aqueous KOH (220 μl of a 0.5 M solution). After stirring at ambient temperature for 2 hours, Amberlite IR-120 (+) acidic resin was added until the solution reached pH = 4.5. The resin was filtered and washed with ethanol and H ₂ O. Concentration under reduced pressure gave a pale orange solid which was purified by reverse phase _C18 chromatography using water as eluent. Fractions containing the desired product were pooled and lyophilized to give the amino acids as a white powder.

[0650]

[Equation 39] Example 42 Epoxide 161: MCPBA (690 mg) was prepared according to Example 14 by olefin 160 (532 mg, 1.61 mmol, Example 14) in dichloromethane (15 ml) cooled to 0 ° C. and crude mesylate was reduced to 30% prior to use. (Filtered through silica gel with EtOAc / hexanes). The mixture was warmed to room temperature and stirred overnight. Most of the solvent was removed under reduced pressure, and the mixture was diluted with ethyl acetate. The organic layer aqueous sodium bisulfite, saturated sodium bicarbonate, washed with brine, and dried over MgSO _4. The mixture was concentrated under reduced pressure, and the residue was subjected to flash column chromatography (30% hexane in ethyl acetate).
37 mg (78%) of 161 were obtained as a pale oil.

[0651]

(Equation 40) Example 43 Diol 162: Epoxide 161 (437 mg, 1.23 mmol) was added to 5
1 h in THF (20 ml) and H ₂ O (10ml) containing 70% HClO ₄ of droplets was gently refluxed. Solid NaHCO ₃ was added and the mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with brine and dried.
The crude diol 162 was obtained as a pale white oil in quantitative yield by concentration under reduced pressure.
Used without purification for the next reaction.

Example 44 The oxidation of aldehyde 163: diol 162 was performed according to the procedure of Vo-Quang and coworkers, "Synthesis", 68 (1988). To a slurry of silica gel (4.3 g) in dichloromethane (30 ml) was added a solution of NaIO ₄ (4.4 ml of a 0.65 M aqueous solution). Add this slurry to EtO
The crude diol 162 (52 ml) in Ac (5 ml) and dichloromethane (15 ml)
(0 mg). After 1 hour, the solid was filtered and 20% hexane /
Washed with EtOAc. And concentrated to give an oily residue, which was dissolved in EtOAc, and dried over MgSO _4. Concentration under reduced pressure gave aldehyde 163 as a pale oil which was used immediately for the next reaction.

[0653]

[Equation 41] Example 45 Alcohol 164: Crude aldehyde 163 was prepared using Borch and co-workers,
J. Amer. Chem. Soc. "93: Following the procedure of 2897 (1971), was treated with NaCNBH _3, alcohol 164 flash chromatography after subjecting the (40% hexanes in ethyl acetate), 269 mg (65%)
I got

[0654]

(Equation 42) Example 46 Aziridine 165: alcohol 164 (208 mg, 0.62 mmol) was acetylated by conventional methods (AcCl, pyridine, dichloromethane, catalyst DMAP) to give acetate (241 mg, 100%). Crude acetate (202 mg,
The 0.54 mmol), and 2 hours with THF (Ph ₃ P in 12 ml) (155 mg) at room temperature. Then H ₂ O (1.1 ml) and triethylamine (224 μl) were added and the solution was stirred overnight. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and saturated bicarbonate / brine. The organic layer was dried, concentrated under reduced pressure, and purified by flash chromatography (10% MeOH in EtOAc) to give 125 mg (90%) of the aziridine 165 as a white solid.

[0655]

[Equation 43] (Example 47) N-Boc aziridine 166: Boc anhydride (113 mg, 0.52 mmol)
) With aziridine 165 (125 mg, 0.49) in dichloromethane (7 ml).
mmol) and triethylamine (70 μl) in DMAP (catalytic amount). After 1 hour, the reaction was concentrated and the residue was flash chromatographed (
(40% EtOAc in hexanes) to give 154 mg (88%) of N Boc aziridine 166 as a pale oil.

[0656]

[Equation 44] (Example 48) Azide ester 167: aziridine 166 (154 mg, 0.43 mmol)
, Sodium azide (216 mg), and ammonium chloride (223 mg) were heated in DMF (5 ml) at 100 ° C. for 18 hours. The cooled reaction mixture was partitioned between ethyl ether and brine. The ether layer was washed with H ₂ O, brine, and dried over MgSO _4. Concentration gave a crude residue, which was treated with 40% TFA in dichloromethane at room temperature. After 2 hours, the reaction was concentrated under reduced pressure to give a pale oil which was passed through a short column of silica gel, eluting with EtOAc. The product is then acylated in the usual way (AcCl, pyridine, dichloromethane, catalytic DMAP) and subjected to flash chromatography (5% MeOH in chloroform) before the azide ester 167 is converted to a pale yellow oil 16
mg (11% for 3 steps).

[0657]

[Equation 45] Example 49 Amino acid 168: Ester 167 (16 in THF (1 ml) cooled to 0 ° C
mg, 0.047 mmol) in an aqueous KOH solution (20% of a 0.476 M solution).
8 μl) was added. The reaction was then warmed to room temperature and stirred for 2 hours
. The reaction was then purified using Amberlite IR-120 (+) acidic resin.
Acidified to pH = 4.0. The resin is then filtered and ethanol and H _Two Washed with O. Concentration under reduced pressure gave 14 mg (100%) of azidocarboxylic acid as a white solid. The azide acid is dissolved in ethanol (2 ml) and
y and co-workers, following the procedure of “Synthesis”, 590 (1975).
The mixture was treated with hydrogen gas (1 atm) over a Lindlar catalyst (15 mg) for 16 hours.
The reaction mixture was filtered through a pad of celite and hot ethanol and H_TwoWashed with O 2. Concentration under reduced pressure gave an orange solid, which was_TwoC eluted with O₁₈Purified by column chromatography. The fractions containing this product are pooled and
And lyophilized to give 9.8 mg of 168 as a white powder.

[0658]

[Equation 46] Example 50 Epoxy MOM Ether 19 (PG = methoxymethyl): Prepared from epoxy alcohol 1 at 74% according to the procedure of Mordini and co-workers, "J. Org. Chem.", 59: 4784 (1994). .

[0659]

[Equation 47] Example 51 Aziridine 170: Prepared according to the general protocol described in Examples 3 and 4 from epoxide 19 (PG = methoxymethyl) at a total of 77%.

[0660]

[Equation 48] (Example 52) Azide ester 22 (PG = methoxymethyl): aziridine 170 (329 m
g, 1.54 mmol), NaN ₃ (446 mg) and NH ₄ Cl (151 mg).
) Was heated in DMF (20 ml) for 18 hours at 65 ° C. The cooled reaction mixture was partitioned between ethyl ether and brine. The ether layer was washed with H ₂ O, Bligh down, dried over MgSO _4. Concentration in vacuo gave the crude azidoamine as a pale oil which was dissolved in CH ₂ Cl ₂ (15 ml) and pyridine (
4 ml) and AcCl (150 μl). Aqueous solution followed by flash chromatography of the residue afforded 350 mg (76%) of azide ester 22 (PG = methoxymethyl) as a pale oil.

[0661]

[Equation 49] Example 53 Amino acid 114: Corey and coworkers, "Synthesis", 5
Azide 22 (PG = methoxymethyl) (39m
g, 0.131 mmol) with a Lindlar catalyst (39 mg) in ethanol.
Treated with hydrogen gas at 1 atmosphere for 5 hours. The reaction mixture was filtered through a pad of celite, washed with hot ethanol and concentrated to give 33 mg (92%) of the crude amine as a pale white foam. The amine in THF (1 ml) was treated with an aqueous KOH solution (0.
(380 μl of a 476 M solution). After 1 hour, the reaction was amberlit
e Acidified to pH = 4.0 using IR-120 (+) acidic resin. Then
The resin was filtered and washed with H ₂ O and concentrated to give a pale solid which was purified by C ₁₈ column chromatography eluting with H ₂ O. Fractions containing this product were pooled and lyophilized to give 20 mg of 114 as a white powder.

[0662]

[Equation 50] (Example 54) Amino acid 171: Solid amino acid 114 (4 mg, 0.015 mmol) was added with C
40% TFA in H ₂ Cl ₂ (1 ml, cooled to 0 ° C. before addition) was added. After stirring at room temperature for 1.5 hours, the reaction mixture was concentrated to give a white foam. Several co-evaporations from H ₂ O followed by lyophilization gave 5.5 mg of 117 as a white solid.
Was obtained as the TFA salt.

[0663]

(Equation 51) Example 55 Acetonide 180: Shikimic acid (25 g, 144) in methanol (300 ml)
mmol, Aldrich) in p-toluenesulfonic acid (274 mg).
, 1.44 mmol, 1 mol%) and the mixture is heated to reflux for 2 hours
Shed. After addition of p-toluenesulfonic acid (1 mol%),
Refluxed for 26 hours and evaporated. Crude methyl ester (28.17 g)
Are suspended in acetone (300 ml) and dimethoxypropane (35 ml)
288 mmol) and stir at room temperature for 6 hours, then evaporate
I did it. The crude product is dissolved in ethyl acetate (400 ml) and saturated NaHCO _Three (3 × 125 ml) and saturated NaCl. Dry the organic phase (MgSO_Four ), Filtered and evaporated to give crude acetonide 180 (about 29.4 g).
Got and used this directly:

[0664]

(Equation 52) (Example 56) Mesylate _{130: CH 2 Cl 2 (250ml} ) solution of acetonide 180 (29.
4 g, 141 mmol) solution at 0 ° C. with triethylamine (29.5 ml, 29.5 ml, 141 mmol).
12 mmol), followed by methanesulfonyl chloride (13.6 ml,
176 mmol) was added over 10 minutes. The reaction was stirred at 0 ° C. for 1 hour and ice-cold water (250 ml) was added. After transfer to a separatory funnel, the organic phase was washed with water,
Washed with 5% citric acid (300 ml), saturated NaHCO ₃ (300 ml), dried (MgSO ₄ ), filtered and evaporated. The crude product was filtered through a short plug of silica gel on a fritted glass funnel eluting with ethyl acetate.
The filtrate was evaporated to give mesylate 130 (39.5 g, 91%) as a viscous oil used directly in the next step:

[0665]

(Equation 53) Example 57 Diol 131: Mesylate 130 (35.8) in methanol (500 ml).
5 g, 117 mmol) solution and p-toluenesulfonic acid (1.11 g, 5.8).
5 mmol, 5 mol%) and the solution was refluxed for 1.5 hours and evaporated. The residue was redissolved in methanol (500 ml) and
Refluxed for hours. Evaporate the solvent and remove the crude oil with diethyl ether (
250 ml). After ending the overnight crystallization at 0 ° C., the solid is filtered and washed with cold diethyl ether and dried to give diol 131 (24
. 76g) was obtained as a white solid. The filtrate was evaporated and methanol /
The residue was crystallized from diethyl ether to give an additional 1.55 g. 26.3 g (85%) of diol 131 were obtained:

[0666]

(Equation 54) Example 58 Epoxy Alcohol 1: Diol 13 in Tetrahydrofuran (400 ml)
A suspension of 1 (20.78 g, 78 mmol) was treated with 1,8-diazabicyclo [5.4.0] undec-7-ene (11.7 ml, 78 mmol) at 0 ° C. and 9% at room temperature. After stirring for an hour, the reaction was terminated. The reaction was evaporated and the crude residue was dissolved in CH ₂ Cl ₂ (200 ml) and saturated NaCl
(300 ml). The aqueous phase was extracted with _{CH 2 Cl 2 (2 × 200ml} ).
The combined organic extracts were dried (MgSO ₄ ), filtered and evaporated. The crude product was purified on silica gel (ethyl acetate) to give epoxy alcohol 1 (12
g, 90%) as a white solid. The ¹ H NMR spectrum is described in the literature: McGowan, D .; A. Berchold, G .; A. , "J. Org
. Chem. 46: consistent with the spectrum reported in 2381 (1981).

Example 59 Methoxymethyl Ether 22 (PG = methoxymethyl): CH ₂ Cl ₂ (100
solution of epoxy alcohol 1 (4 g, 23.5 mmol) in N, N
'-Diisopropylethylamine (12.3 ml, 70.5 mmol) was added, followed by chloromethyl methyl ether (3.6 ml, 47 mmol, distilled from industrial grade). The solution was refluxed for 3.5 hours and the solvent was evaporated. The residue was partitioned between ethyl acetate (200ml) and water (200ml). The aqueous phase was extracted with ethyl acetate (100ml). The combined organic extracts were washed with saturated NaCl
(100 ml), dried (MgSO ₄ ), filtered and evaporated to give 4.9 g solid residue. This was of a purity suitable for direct use in the next step: mp 62-65 ° C (crude); mp 64-66 ° C (diethyl ether / hexane);

[0668]

[Equation 55] Ethyl ester analog of compound 19: compound 1 in CH ₂ Cl ₂ (277 ml)
To a corresponding ethyl ester solution of (12.0 g, 0.065 mol) was added diisopropylethylamine (34.0 ml, 0.13 mol) at room temperature, followed by chloromethyl methyl ether (10.0 ml, 0.19 mol). . The reaction mixture was then gently refluxed for 2 hours, cooled, concentrated under reduced pressure, and EtOAc
Partitioned between c and water. The organic layer was separated, and dilute HCl, saturated bicarbonate, and washed successively with brine, dried over MgSO _4. Concentration under reduced pressure followed by flash chromatography on silica gel (50% hexane in EtOAc) provided 13.3 g (90%) of the corresponding ethyl ester of compound 22 as a colorless liquid.

[0669]

[Equation 56] (Example 60) Alcohol 181: 8/1-MeOH / H 2 O (175ml, v / v) in the main butoxy methyl ether 19 (PG = methoxymethyl) (4.9 g, 22.9 mm
ol) solution, sodium azide (7.44 g, 114.5 mmol) and ammonium chloride (2.69 g, 50.4 mmol) were added and the mixture was refluxed for 15 hours. The reaction was diluted with water (75 ml) to dissolve the precipitated salts and the solution was concentrated to remove methanol. The aqueous phase containing the precipitated oily residue obtained is diluted with water to a volume of 200 ml and ethyl acetate (3 × 100
ml). The combined organic extracts were washed with saturated NaCl (100 ml), dried (MgSO ₄ ), filtered and evaporated. The crude product was purified on silica gel (1 / 1-hexane / ethyl acetate) to give alcohol 181 (5
. (09 g, 86%) as a pale yellow oil. Then, alcohol 181
Was obtained without further purification, with sufficient purity for use in the next step.

[0670]

[Equation 57] (Example 61) Mesylate _{184: CH 2 Cl 2 (100ml} ) alcohol in 181 (6.4
7 g, 25.2 mmol) solution at 0 ° C. first with triethylamine (4.4 ml).
, 31.5 mmol) followed by methanesulfonyl chloride (2.14 ml,
27.7 mmol) was added. The reaction was stirred at 0 ° C. for 45 minutes, then warmed to room temperature and stirred for 15 minutes. The reaction was evaporated and the residue was ethyl acetate (
(200 ml) and water (100 ml). The organic phase was washed with water (100 ml
), Saturated NaHCO ₃ (100 ml), saturated NaCl (100 ml). The water wash was washed once with the same NaHCO ₃ / NaCl solution and extracted once with ethyl acetate. The combined organic extracts were dried (MgSO ₄ ), filtered and evaporated. The crude product was of appropriate purity to use directly in the next step:

[0671]

[Equation 58] Example 62 Aziridine 170: mesylate 184 (8.56 g) in THF (150 ml)
, 25 mmol) solution at 0 ° C. with Ph ₃ P (8.2 g, 31 mmol) first added in 1/3 with cooling, then the ice bath was removed and the remaining Ph ₃ P was added to 10-15 mg. Added over minutes. After the addition of Ph ₃ P, the reaction was stirred at room temperature for 3 hours, forming a white precipitate. To this suspension was added triethylamine (5.2 m
1, 37.5 mmol) and water (10 ml) were added and the mixture was stirred at room temperature for 12 hours. The reaction was concentrated to remove the THF and the residue was washed with CH ₂ Cl ₂ (200 m
1) and saturated NaCl (200 ml). The aqueous phase was extracted with several portions of CH ₂ Cl ₂ and the combined organic extracts were dried (Na ₂ SO ₄ ), filtered and
Then, evaporation was performed to obtain a crude product. This crude product is converted to silica gel (10%
Purified with MeOH / EtOAc) to give aziridine 170 (4.18 g, 78%).
Was obtained as an oil. It typically contained trace amounts of triphenylphosphine oxide impurities:

[0672]

[Equation 59] Example 63 Amine 182: Aziridine 170 (3.2 g, 15 m) in DMF (30 ml)
mol) solution was evacuated for several minutes using a rotary evaporator (40 ° C.)
The solution was degassed. To this solution was added sodium azide (4.9 g, 75 mmol
) And ammonium chloride (1.6 g, 30 mmol) were added and the mixture was cooled to 65
Heated at ℃ 70 ° C. for 21 hours. The reaction mixture was cooled to room temperature and ethyl acetate (about 1
00 ml) and filtered. The filtrate was evaporated and the residue was partitioned between diethyl ether (100ml) and saturated NaCl (100ml). The organic phase was washed again with saturated NaCl (100 ml), dried (MgSO ₄ ), filtered and evaporated. Further crude product was obtained from the aqueous wash by extraction with ethyl acetate and treated in a similar manner as described above. The crude product was purified on silica gel (5% MeOH / CH ₂ Cl ₂ ) to give amine 182 (2.95 g) as an oil. It contained a small amount of triphenylphosphine oxide impurity from the previous step:

[0673]

[Equation 60] (Example 64) N-tritylaziridine 183: amine 182 (2.59 g, 10.2 mmol)
l) is dissolved in 5% HCl / MeOH (30 ml) and the solution is added at room temperature for 3 hours.
Stirred for hours. Add additional 5% HCl / MeOH (10 ml) and stir for 1 hour
And evaporated to 2.52 g as a tan solid after high vacuum.
The HCl salt of was obtained. CH_TwoCl_Two(50 ml) to a suspension of the HCl salt at 0 ° C.
Triethylamine (3.55 ml, 25.5 mmol) was added followed by solid triethylamine.
Tyl chloride (5.55 g, 12.8 mmol) was added in one portion. Mix 0
Stirred at C for 1 hour, then warmed to room temperature and stirred for 2 hours. Reaction to 0 ° C
Cool, add triethylamine (3.6 ml, 25.5 mmol) and add
Tansulfonyl chloride (0.97 ml, 12.5 mmol) was added to give
The resulting mixture was stirred for 1 hour at 0 ° C. and 22 hours at room temperature. Evaporate the reactants
And the residue is taken up between diethyl ether (200 ml) and water (200 ml).
Distributed. The organic phase is washed with water (200 ml) and the combined aqueous phases are
Extracted with ether (200 ml). The combined organic extracts are combined with water (100 ml
), Washed with saturated NaCl (200 ml) and dried (Na_TwoSO_Four) Then filtration
And then evaporated. The crude product was purified on silica gel (1 / 1-hexane / CH _Two Cl_Two) To give N-tritylaziridine 183 (3.84 g, 86%).
Obtained as a white foam:

[0674]

[Equation 61] Example 65 Compound 190: N-tritylaziridine 183 (100 mg, 0.23 mmol)
l), cyclohexanol (2 ml) and boron trifluoride etherate (
42 μL, 0.35 mmol) was heated at 70 ° C. for 1.25 h and evaporated. The residue was dissolved in pyridine (2 ml) and acetic anhydride (110
μL, 1.15 mmol) and the catalyst DMAP. After stirring at room temperature for 3 hours, the reaction was evaporated. The residue was partitioned between ethyl acetate and 5% citric acid. The aqueous phase was extracted with ethyl acetate and the combined organic extracts were washed with saturated Na
Washed with HCO ₃ and saturated NaCl. The organic phase was dried (MgSO ₄ ), filtered and evaporated. The crude product was purified on silica gel (1 / 1-hexane / ethyl acetate) to give compound 190 (53 mg, 69%) as a solid: mp 105-107 ° C. (ethyl acetate / hexane);

[0675]

(Equation 62) Example 66 Compound 191: To a solution of compound 190 (49 mg, 0.15 mmol) in THF was added triphenylphosphine (57 mg, 0.22 mmol) and water (270).
μL) was added and the solution was heated at 50 ° C. for 10 hours. The reaction was evaporated, the residue dissolved in ethyl acetate, dried (Na ₂ SO ₄ ), filtered and evaporated. The crude product was purified on silica gel (1 / 1-methanol / ethyl acetate) to give the amine (46 mg) as a pale yellow solid. Amine solution in THF (1.5 ml) was combined with a 1.039 N KOH solution (217 μL) and water (200 μL).
Added. The mixture is stirred at room temperature for 1 hour, then cooled to 0 ° C. and
Acidified to pH 6-6.5 with 120 ion exchange resin. The resin was filtered, washed with methanol, and the filtrate was evaporated. The solid residue was dissolved in water and passed through a column of C-18 reverse phase silica gel (4 × 1 cm) eluting with water, then 2.5% acetonitrile / water. The product fractions were combined and evaporated, and the residue was dissolved in water and lyophilized to give amino acid 191 (28 mg) as a white solid:

[0676]

[Equation 63] Example 67 Bis-Boc guanidino ester 201: Kim and Qian, "Tetr
ahedron Lett. 34: 7677 (1993). Amine 200 (52 ml) in dry DMF (5.0 ml) cooled to 0 ° C.
HgCl ₂ (593 mg, 2.18 mmol) was added once to a solution of 9 mg, 1.97 mmol, prepared by the method of Example 109), bis-Boc thiourea (561 mg, 2.02 mmol) and Et ₃ N (930 μL). Added to The heterogeneous reaction mixture was stirred at 0 ° C. for 45 minutes, then at room temperature for 15 minutes. Thereafter, the reaction was diluted with EtOAc and filtered through a pad of celite. Concentration under reduced pressure followed by flash chromatography of the residue on silica gel (10% hexane in ethyl acetate) gave 904 mg (90%) of 201 as a pale oil.

[0677]

[Equation 64] Example 68 Carboxylic acid 202: Methyl ester 201 (904m) in THF (10ml)
g, 1.77 mmol) solution was added KOH aqueous solution (3.45 ml of a 1.039N solution). The reaction mixture is stirred at room temperature for 17 hours, cooled to 0 ° C. and
Acidified to pH 4.0 with mberlite IR-120 (H ⁺ ) acidic resin. The resin was filtered and washed with water and methanol. Concentration under reduced pressure provided the free acid as a pale white foam which was used in the next reaction without further purification.

Example 69 Guanidine carboxylic acid 203: To a solution of bis-Boc guanidnyl acid 202 (crude product of the previous reaction) in CH ₂ Cl ₂ (40 ml) cooled to 0 ° C., neat Trifluoroacetic acid (25 ml) was added. The reaction mixture was stirred at 0 ° C. for 1 hour and then at room temperature for 2 hours. Concentration under reduced pressure gave a pale orange solid. This was purified by _C18 reverse phase chromatography, eluting with water. Fractions containing the desired product are pooled and lyophilized to 495 mg (
Guanidine carboxylic acid 203 (68%, two steps) was obtained as the trifluoroacetate salt.

[0679]

[Equation 65] Example 70 Formamidine carboxylic acid 204: amino acid 102 (2 in water (500 μL)
5 mg, 0.10 mmol, prepared by the method of Example 110)
Was adjusted to pH 8.5 with 1.0 N NaOH. Benzylformimidate hydrochloride (45 mg, 0.26 mmol) was added in one portion and the reaction mixture was added to 1.0 N
Stir at this temperature for 3 hours while maintaining the pH at 8.5-9.0 with NaOH.
The reaction was then concentrated under reduced pressure and purified by _C18 reverse phase chromatography, eluting with water. Fractions containing the desired product were pooled and lyophilized to give 4.0 mg (13%) of formamidine carboxylic acid 204.

[0680]

[Equation 66] Example 71 Amino Acid 206: Aminomethyl Ester 205 (8 in THF (1.0 ml)
To a solution of 4 mg, 0.331 mmol, prepared according to Example 107), an aqueous KOH solution (481 μL of a 1.039N solution) was added. The reaction mixture was stirred at room temperature for 2.5 hours and acidified to pH 6.5 with Amberlite IR-120 (H ⁺ ) acidic resin. The resin was filtered and washed with water and methanol. Concentration under reduced pressure provided the amino acid as a white solid. It was purified by _C18 reverse phase chromatography, eluting with water. Fractions containing the desired product were pooled and lyophilized to give 59 mg (74%) of amino acid 206.

[0681]

[Equation 67] Example 72 Trifluoroacetamide 207: To a degassed solution of amino acid 206 (59 mg, 0.246 mmol) in dry methanol (1.0 ml) under argon, Et ₃ N (35 μL) followed by trifluoro Methyl acetate (35 μL) was added. The reaction was stirred at room temperature for one week and concentrated. Analysis by ¹ H NMR indicated that the reaction was 40% complete. The crude reaction product, dry methanol (1.0 ml), redissolved in methyl trifluoroacetate (1.0 ml) and Et ₃ N (0 .5ml), and stirred at room temperature for 5 days. The reaction was then concentrated under reduced pressure, dissolved in 50% aqueous THF (2.0 ml) and Amberlite
Acidified to pH 4 with IR-120 (H ⁺ ) acidic resin and filtered. Concentration gave crude trifluoroacetamidocarboxylic acid. This was used without further purification for the next reaction.

Example 73 Amino Acid 208: Azide 2 in THF (2.0 ml) and Water (160 μL)
The 07 (crude product of the previous reaction) solution was treated at room temperature with polymer supported triphenylphosphine (225 mg). After stirring for 20 hours, the polymer was filtered and washed with methanol. Concentration under reduced pressure gave a pale white solid. It was purified by _C18 reverse phase chromatography, eluting with water. Fractions containing the desired product were pooled and lyophilized to give 6.5 mg (9%) of trifluoroacetamide amino acid 208.

[0683]

[Equation 68] (Example 74) Methyl sulfonamide methyl ester 209: methanesulfonyl chloride (
19 μL) at 0 ° C. with amine 205 (58 mg, 1.0 mL) in CH ₂ Cl ₂ (1.0 ml).
0.23 mmol, prepared according to Example 107), Et ₃ N (97 μL) and a catalytic amount of DMAP (little crystals). After 30 minutes, the reaction mixture was warmed to room temperature and stirred for another hour. Concentration under reduced pressure followed by flash chromatography of the residue on silica gel (50% hexane in ethyl acetate) gave 61 mg (79%) of the sulfonamide 209.

[0684]

[Equation 69] Example 75 Amino Ester 210: A solution of azide 209 (61 mg, 0.183 mmol) in THF (2.0 ml) and water (118 μL) was treated with polymer supported triphenylphosphine (170 mg) at room temperature. . After stirring for 17.5 hours, the polymer was filtered and washed with methanol. Concentration under reduced pressure followed by flash chromatography of the residue through a short silica gel column (100% methanol) gave 45 mg (80%) of amino ester 210 as a pale foam.

[0685]

[Equation 70] Example 76 Amino Acid 211: Methyl Ester 210 (21 mg) in THF (200 μL)
, 0.069 mmol) solution was treated with aqueous KOH (135 μL of a 1.039 N solution). The reaction mixture was stirred at room temperature for 40 minutes and Amberlite
Neutralized to pH 7.0 with IR-120 (H ⁺ ) acidic resin. The resin was filtered and washed with water and methanol. Concentration under reduced pressure gave the amino acid as a pale white solid. This was purified by _C18 reverse phase chromatography, eluting with water. Fractions containing the desired product are pooled and lyophilized to 3.5 mg (
17%) of amino acid 211 was obtained.

[0686]

[Equation 71] Example 77 Bis-Boc guanidino ester 212: Kim and Qian, "Tetr
ahedron Lett. 34: 7677 (1993). The amine 210 (31) in dry DMF (203 μL) cooled to 0 ° C.
mg, 0.101 mmol), bis-Boc thiourea (28.5 mg, 0.10
To a solution of 3 mmol) and _{Et 3 N (47μL), HgCl} 2 (30mg, 0.
11 mmol) were added all at once. The heterogeneous reaction mixture was stirred at 0 ° C. for 30 minutes, then at room temperature for 30 minutes. Thereafter, the reaction was diluted with EtOAc and filtered through a pad of celite. Concentrate under reduced pressure, followed by flash chromatography of the residue on silica gel (40% hexane in ethyl acetate) to give 49 mg
(89%) of 212 was obtained as a pale oil.

[0687]

[Equation 72] Example 78 Carboxylic acid 213: Methyl ester 212 (49m) in THF (1.0ml)
g, 0.090 mmol) solution was added an aqueous KOH solution (260 μL of a 1.039N solution). The reaction mixture was stirred at room temperature for 16 hours, cooled to 0 ° C and
Acidified to pH 4.0 with mberlite IR-120 (H ⁺ ) acidic resin. The resin was filtered and washed with water and methanol. Concentrate under reduced pressure,
The free acid was obtained as a pale foam. This was used in the next reaction without further purification.

Example 79 Guanidine carboxylic acid 214: To a solution of bis-Boc guanidonic acid 213 (crude product of the previous reaction) in CH ₂ Cl ₂ (2.0 ml) cooled to 0 ° C. Fluoroacetic acid (2.0 ml) was added. The reaction mixture was stirred at 0 ° C. for 1 hour and then at room temperature for 1 hour. Concentration under reduced pressure gave a pale orange solid. This was purified by _C18 reverse phase chromatography, eluting with water. Fractions containing the desired product were pooled and lyophilized to give 10 mg (25%, two steps) of guanidine carboxylic acid 214.

[0689]

[Equation 73] (Example 80) Propionamide methyl ester 215: propionyl chloride (96 µL
, 1.1 mmol) was added to a solution of amine 205 (178 mg, 0.70 mmol, prepared according to Example 107) and pyridine (1.5 ml) in CH ₂ Cl ₂ (2.0 ml) cooled to 0 ° C. Was. After 30 minutes at 0 ° C., the reaction was concentrated and partitioned between ethyl acetate and brine. The organic layer was separated, washed with saturated sodium bicarbonate, followed by brine, and dried over MgSO _4. Concentration under reduced pressure followed by flash chromatography of the residue on silica gel (40% hexane in ethyl acetate) gave 186 mg (86%) of propionamide methyl ester 215 as a pale yellow solid.

[0690]

[Equation 74] Example 81 Aminomethylester 216: THF (5.0 ml) and water (400 μL)
A solution of azide 215 (186 mg, 0.60 mmol) in was treated with polymer supported triphenylphosphine (560 mg) at room temperature. After stirring for 21 hours,
The polymer was filtered and washed with methanol. Concentration under reduced pressure gave crude amino ester 216. It was used without further purification for the next step.

Example 82 Amino Acid 217: A solution of methyl ester 216 (crude product of the previous reaction) in THF (500 μL) was treated with aqueous KOH (866 μL of a 1.039N solution). The reaction mixture is stirred at room temperature for 3 hours and Amberlite IR-120
Neutralized to pH 7.0 with (H ⁺ ) acidic resin. The resin was filtered and washed with water and methanol. Concentration under reduced pressure provided the amino acid as a pale white solid. This was purified by _C18 reverse phase chromatography, eluting with water. Fractions containing the desired product were pooled and lyophilized to give 49 mg (31%, two steps) of amino acid 217.

[0692]

[Equation 75] Example 83 (Monomethyl) bis-Boc Guanidino Ester 218: DMF (1.0
amine 200 (51 mg, 0.19 mmol) and monomethylbis
-Boc thiourea (36 mg, 0.19 mmol) was added to a solution of 1- (3-dimethyl).
Ruaminopropyl) -3-ethylcarbodiimide hydrochloride (38 mg) and Et _Three N (56 μL) was added at room temperature. After 1.5 hours at room temperature, HgCl_Two(About 75mg
, Excess) were added all at once. Stir the heterogeneous reaction mixture for 45 minutes and add ethyl acetate
Dilute and filter through a pad of celite. The filtrate is washed with more ethyl acetate
And washed with dilute HCl, saturated sodium bicarbonate, brine, and
MgSO_FourAnd dried. Concentrate under reduced pressure, followed by flash chromatography of the residue on silica gel (10% methanol in ethyl acetate) to give 13 mg (
16%) of (monomethyl) bis-Boc guanidino ester 218 as a colorless foam
Obtained as body.

[0693]

[Equation 76] Example 84 (Monomethyl) bis-Boc Guanidinoic Acid 219: To a solution of methyl ester 218 (13 mg, 0.031 mmol) in THF (500 μL) was added an aqueous KOH solution (60 μL of a 1.039N solution). The reaction mixture is stirred at room temperature for 1 hour,
It was then refluxed gently for 1 hour. The reaction was cooled to 0 ° C. and Amberl
Acidified to pH 6.0 with an item IR-120 (H ⁺ ) acidic resin. The resin was filtered and washed with water and methanol. Concentrate under reduced pressure to give free acid 21
9 was obtained. This was used in the next reaction without further purification.

Example 85 (Monomethyl) guanidinoamino acid 220: CH ₂ Cl ₂ cooled to 0 ° C. (1.
To a solution of (monomethyl) bis-Bocguanidonylic acid 219 (crude product of the previous reaction) in 0 ml) was added neat trifluoroacetic acid (1.0 ml). The reaction mixture was stirred at 0 ° C. for 1 hour and then at room temperature for 1 hour. Concentration under reduced pressure gave a pale white solid. This was purified by _C18 reverse phase chromatography, eluting with water.
Fractions containing the desired product were pooled and lyophilized to give 4.4 mg (3
Guanidine carboxylic acid 220 (3%, 2 steps) was obtained.

[0696]

[Equation 77] (Example 86) (R) -methylpropyl ester 221: BF ₃ .Et ₂ O (63 μL, 0.5
1 mmol) was added to a solution of N-tritylaziridine 183 (150 mg, 0.341 mmol) in (R)-(-)-2-butanol (1.2 ml) with stirring at room temperature under argon. The pale solution was heated at 70 ° C. for 2 hours and then concentrated under reduced pressure to give a brown residue. This was dissolved in dry pyridine (2.0 ml) and treated at 0 ° C. with acetic anhydride (225 μL) and a catalytic amount of DMAP (little crystals). The reaction was warmed to room temperature and stirred for 2 hours,
Concentrated under reduced pressure and partitioned between ethyl acetate and brine. The organic layer was separated, and dilute HCl, saturated sodium bicarbonate, washed successively with brine, and dried over MgSO _4. Concentrate under reduced pressure followed by flash chromatography of the residue on silica gel (50% hexane in ethyl acetate) to give 75 mg (7
(2%) of (R) -methylpropyl ester 221 was obtained as a pale white solid.

[0696]

[Equation 78] (Example 87) (R) - methylpropyl amino ester _{222: Ph 3 P (95mg,} 0.3 6mmol) and azide 221 (75 mg in THF (3.0 ml), 0.24
mmol) and water (432 μL) were added in one portion. The pale yellow solution was then heated at 50 ° C. for 10 hours, cooled and concentrated under reduced pressure to give a pale white solid. Purification by flash chromatography on silica gel (50% methanol in ethyl acetate) provided 66 mg (97%) of the amino ester 222 as a pale solid.

Example 88 Amino Acid 223: Methyl Ester 222 in THF (1.0 ml) (34 mg)
, 0.12 mmol) solution in KOH aqueous solution (175 μL of 1.039 N solution)
Processed. The reaction mixture was stirred at room temperature for 3 hours and Amberlite I
Acidified to pH 6.0 with R-120 (H ⁺ ) acidic resin. The resin was filtered and washed with water and methanol. Concentration under reduced pressure provided the amino acid as a pale white solid. It was purified by _C18 reverse phase chromatography, eluting with water. Fractions containing the desired product are pooled and lyophilized to 11.5 m
g (36%) of amino acid 223 were obtained.

[0698]

[Expression 79] Example 89 Bis-Boc guanidino ester 224: Kim and Qian, "Tetr
ahedron Lett. 34: 7677 (1993). The amine 222 (32) in dry DMF (350 μL) cooled to 0 ° C.
mg, 0.113 mmol), bis-Boc thiourea (32 mg, 0.115 m
mol) and Et ₃ N (53 μL) were added to HgCl ₂ (34 mg, 0.12
5 mmol) were added in one portion. The heterogeneous reaction mixture was stirred at 0 ° C. for 45 minutes, then at room temperature for 1 hour. Thereafter, the reaction was diluted with EtOAc and filtered through a pad of celite. Concentration under reduced pressure followed by flash chromatography of the residue on silica gel (20% hexane in ethyl acetate) gave 57 mg (9
6%) of 224 was obtained as a colorless foam.

[0699]

[Equation 80] Example 90 Carboxylic acid 225: Methyl ester 224 (57m) in THF (1.5ml)
g, 0.11 mmol) solution was added an aqueous KOH solution (221 μL of a 1.039N solution). The reaction mixture was stirred at room temperature for 16 hours, cooled to 0 ° C. and
Acidified to pH 4.0 with berlite IR-120 (H ⁺ ) acidic resin. The resin was filtered and washed with water and methanol. Concentration under reduced pressure provided the free acid as a pale white foam. This was used in the next reaction without further purification.

Example 91 Guanidine carboxylic acid 226: To a solution of bis-Boc guanidonic acid 225 (crude product of the previous reaction) in CH ₂ Cl ₂ (4.0 ml) cooled to 0 ° C. Fluoroacetic acid (4.0 ml) was added. The reaction mixture was stirred at 0 ° C. for 1 hour and then at room temperature for 2 hours. Concentration under reduced pressure gave a pale orange solid. This was purified by _C18 reverse phase chromatography, eluting with water. Fractions containing the desired product were pooled and lyophilized to give 18.4 mg (40%, two steps) of guanidine carboxylic acid 226.

[0701]

[Equation 81] (Example 92) (Diethyl) methyl ether ester 227: BF ₃ .Et ₂ O (6.27 ml)
, 51 mmol) was added to a solution of N-tritylaziridine 183 (15 g, 34 mmol) in 3-pentanol (230 ml) with stirring at room temperature under argon. The pale solution was heated at 70-75 ° C. for 1.75 hours, then concentrated under reduced pressure to give a brown residue. This was dissolved in dry pyridine (2.0 ml),
Then acetic anhydride (16 ml, 170 mmol) and catalytic amount of DMAP 200m
g. The reaction was stirred at room temperature for 18 hours, concentrated under reduced pressure, and partitioned between ethyl acetate and 1M HCl. The organic layer was separated and saturated sodium bicarbonate, washed successively with brine, and dried over MgSO _4. Concentration under reduced pressure followed by flash chromatography of the residue on silica gel (50% hexane in ethyl acetate) gave 7.66 g of (diethyl) -methyl ether ester. This was recrystallized from ethyl acetate / hexane to give 227 (7.
(25 g, 66%) as colorless needles:

[0702]

(Equation 82) (Example 93) (Diethyl) methyl ether amino ester 228: Ph_ThreeP (1.21 g, 4.6 mmol) was added to azide 227 (1 g, 3.1 mm) in THF (30 ml).
ol) and water (5.6 ml) were added in one portion. Then the pale yellow solution
Was heated at 50 ° C. for 10 hours, cooled and concentrated under reduced pressure. Aqueous oily
Residue was partitioned between EtOAc and saturated NaCl. Dry the organic phase (MgSO _Four ), Filtered and evaporated. Purification by flash chromatography on silica gel (50% methanol in ethyl acetate) gave 830 mg (9
(0%) amino ester 228 was obtained as a pale white solid.

[0703]

[Equation 83] Example 94 Amino acid 229: Methyl ester 228 (830 mg) in THF (15 ml)
2.8 mmol) solution was treated with aqueous KOH (4 ml of a 1.039 N solution). The reaction mixture was stirred at room temperature for 40 minutes and acidified with Dowex 50WX8 acidic resin to pH 5.5-6.0. The resin was filtered and washed with water and methanol. Concentration under reduced pressure provided the amino acid as a pale white solid.
This was eluted with water and then purified by C ₁₈ reverse phase of chromatography, eluting with 5% CH ₃ CN / water. Fractions containing the desired product were pooled and lyophilized to give 600 mg (75%) of amino acid 229.

[0704]

[Equation 84] (Example 95) t-amyl ether ester 230: BF ₃ .Et ₂ O (43 μL, 0.35 m
mol) was added to a solution of N-tritylaziridine 183 (104 mg, 0.24 mmol) in t-amyl alcohol (2.5 ml) with stirring at room temperature under argon. The pale solution was heated at 75 ° C. for 3 hours and then concentrated under reduced pressure to give a brown residue. This was dissolved in dry pyridine (2.0 ml) and treated with acetic anhydride (250 μL) and a catalytic amount of DMAP (little crystals). The reaction was stirred at room temperature for 1.5 hours, concentrated under reduced pressure, and partitioned between ethyl acetate and brine. The organic layer was separated, and dilute HCl, saturated sodium bicarbonate, washed successively with brine, and dried over MgSO _4. Concentration under reduced pressure followed by flash chromatography of the residue on silica gel (50% hexane in ethyl acetate) afforded 27 mg (35%) of t-amyl ether ester 230 as a pale orange oil.

[0705]

[Equation 85] (Example 96) t-amyl ether amino ester _{231: Ph 3 P (35mg,} 0.133 mmol) , and azide 230 in THF (1.5 ml) (27 mg, 0.083
mmol) and water (160 μL) were added in one portion. The pale orange solution was then heated at 50 ° C. for 10 hours, cooled and concentrated under reduced pressure to give a pale white solid. Purification by flash chromatography on silica gel (50% methanol in ethyl acetate) provided 20 mg (82%) of the amino ester 231 as a pale oil.

Example 97 Amino Acid 232: Methyl Ester 231 (20 mg) in THF (1.0 ml)
, 0.068 mmol) solution was treated with aqueous KOH (131 μL of a 1.039 N solution). The reaction mixture was stirred at room temperature for 2.5 hours and Amberlit
e Acidified to pH 5.0 with IR-120 (H ⁺ ) acidic resin. The resin was filtered and washed with water and methanol. Concentration under reduced pressure provided the amino acid as a pale white solid. It was purified by _C18 reverse phase chromatography, eluting with water. 7. Fractions containing the desired product are pooled and lyophilized.
6 mg (45%) of amino acid 232 was obtained.

[0707]

[Equation 86] (Example 98) n-propylthioether ester 233: BF ₃ .Et ₂ O (130 μL, 1
. 06 mmol) was added to a solution of N-tritylaziridine 183 (300 mg, 0.68 mmol) in 1-propanethiol (8.0 ml) with stirring at room temperature under argon. The pale solution was then heated at 65 ° C. for 45 minutes, concentrated, and partitioned between ethyl acetate and brine. The organic layer was separated and washed with saturated sodium bicarbonate, brine, and dried over MgSO _4. Concentration under reduced pressure followed by flash chromatography of the residue on silica gel (30% hexane in ethyl acetate) gave 134 mg (73%) of n-propylthioetherester 233 as a pale oil.

[0708]

[Equation 87] Example 99 n-propylthioether azide ester 234: Neat acetyl chloride (60 μL, 0.84 mmol) was added to amine 233 (134 mg, 0.50 mmol) in pyridine (1.5 ml) cooled to 0 ° C. added. After stirring for 1 hour, the reaction mixture was warmed to room temperature and stirred for another 15 minutes. The reaction was concentrated and partitioned between ethyl acetate and brine, and diluted HCl, water,
Saturated sodium bicarbonate, washed successively with brine, and dried over MgSO _4. Concentration under reduced pressure followed by flash chromatography of the residue on silica gel (30% hexane in ethyl acetate) afforded 162 mg (100%) of n-propylthioether azide ester 234 as a pale yellow solid.

[0709]

[Equation 88] Example 100 n-propylthioether amino ester 235: Azide 234 (130 mg, 0.416 mmol) in ethyl acetate (10 ml) was treated with a Lindlar catalyst (15
0 mg) and hydrogenated (1 atm) at room temperature for 18 hours. The catalyst was then filtered through a pad of celite and washed with hot ethyl acetate and methanol.
Concentration under reduced pressure, followed by flash chromatography of the orange residue, 6
2 mg (53%) of n-propylthioether aminoester 235 were obtained.

[0710]

[Equation 89] Example 101 Compound 240: A suspension of quinic acid (103 g), 2,2-dimethoxypropane (200 ml) and toluenesulfonic acid (850 mg) in acetone (700 ml) was stirred at room temperature for 4 days. Solvent and excess reagent were removed under reduced pressure. Flash column chromatography (hexane / EtOAc = 2 / 1-1.
Purification by 5/1) gave lactone 240 (84 g, 73%):

[0711]

[Equation 90] The reaction was carried out at reflux temperature for 4 hours to form an aqueous work-up (aqueous work-up).
Ethyl acetate / water partition), and the crude product from ethyl acetate / hexane was recrystallized to give lactone 240 in 71% yield.

Example 102 Compound 241: Lactone 240 (43.5 g) in methanol (1200 ml)
, 203 mmol) solution in sodium methoxide (4.37 M, 46.5 ml)
, 203 mmol) were added in one portion. The mixture was stirred at room temperature for 3 hours and quenched with acetic acid (11.62ml). The methanol was removed under reduced pressure.
The mixture was diluted with water and extracted with EtOAc (3x). The combined organic phases were washed with water (1 ×) and brine (1 ×) and dried over MgSO ₄ . Flash column chromatography (hexane / EtOAc = 1/1 to 1/4)
To give the diol (43.4 g, 87%):

[0713]

[Equation 91] Alternatively, treatment of lactone 240 with catalytic sodium ethoxide (1 mol%) in ethanol provided the corresponding ethyl ester in 67% after crystallization of the crude product from ethyl acetate / hexane. Mother liquor (consisting of starting materials and products)
Was re-exposed to the same reaction conditions to give further product after recrystallization. The overall yield was 83%.

Example 103 Compound 242: diol 241 (29.8 g, 1 in pyridine (230 ml))
21 mmol) and 4- (N, N-dimethylamino) pyridine (500 mg)
To solution was added tosyl chloride (27.7 g, 145 mmol). The mixture was stirred at room temperature for 3 days and the pyridine was removed under reduced pressure. The mixture was diluted with water and extracted with EtOAc (3x). The combined organic phases were washed with water (2 ×) and brine (1 ×), and dried over MgSO _4. Concentrate and flash column chromatography (hexane / EtOAc = 2/1 to 1/1)
To give tosylate 242 (44.6 g, 92%):

[0715]

(Equation 92) The corresponding ethyl ester of compound 241 was treated with methanesulfonyl chloride and triethylamine in CH ₂ Cl ₂ at 0 ° C. to give the mesylate derivative in quantitative yield after aqueous solution. This mesylate was used directly without further purification.

Example 104 Compound 243: Tosylate 242 (44.6 g) in CH ₂ Cl ₂ (450 ml)
Pyridine (89 ml) was added to the solution at −78 ° C., followed by slow addition of SO ₂ Cl ₂ (26.7 ml, 335 mmol). The mixture was stirred at -78 ° C for 5 hours, and methanol (45ml) was added dropwise. The mixture was warmed to room temperature and stirred for 12 hours. Add ethyl ether,
Then the mixture was washed with water (3 ×) and brine (1 ×) and dried over MgSO ₄ . Concentration gave the intermediate as an oil (44.8 g). MeOH
(500 ml) in a solution of this intermediate (44.8 g, 111.5 mmol)
TsOH (1.06 g, 5.6 mmol) was added. The mixture was refluxed for 4 hours.
The reaction mixture was cooled to room temperature and the methanol was removed under reduced pressure. Fresh methanol (500 ml) was added and the entire mixture was refluxed for another 4 hours.
The reaction mixture was cooled to room temperature and the methanol was removed under reduced pressure. Purification by flash column chromatography (hexane / EtOAc = 3/1 to 1/3) gave a mixture of two isomers (26.8 g). Recrystallization from EtOAc / hexane provided the pure desired product 243 (20.5 g, 54%):

[0717]

[Equation 93] The corresponding mesylate-ethyl ester derivative of compound 242 was treated in a similar manner as described above. Removal of the acetonide protecting group was performed using acetic acid in refluxing ethanol and precipitation directly from the crude reaction mixture with ether gave the diol in 39% yield.

Example 105 Compound 1: Diol 243 (20.0 g, 58.5 in THF (300 ml)
mmol) solution at 0 ° C. was added DBU (8.75 ml, 58.5 mmol). The reaction mixture was warmed to room temperature and stirred for 12 hours. The solvent (THF) was removed under reduced pressure. Flash column chromatography (hexane / EtO
Purification by Ac = 1/3) gave epoxide 1 (9.72 g, 100%):

[0719]

[Equation 94] The corresponding mesylate-ethyl ester derivative of compound 243 was treated in a similar manner as described above to give the epoxide in almost quantitative yield.

Example 106 Aziridine 244: Allyl ether 4 (2 in anhydrous ethanol (8.0 ml)
23 mg, 1.07 mmol) and a Lindlar catalyst (200 mg).
The substrate was treated with hydrogen gas (1 atm) at room temperature for 50 minutes. The catalyst was then filtered through a pad of celite and washed with hot methanol. Concentrate under reduced pressure to about 2
30 mg of 244 were obtained as a pale yellow oil. This was used for the next reaction without further purification.

Example 107 Azidoamine 205: Crude aziridine 244 (23) in dry DMF (10 ml)
0 mg), sodium azide (309 mg, 4.75 mmol) and ammonium chloride (105 mg, 1.96 mmol) were heated at 70 ° C. for 16 hours under an argon atmosphere. The reaction was cooled, filtered through a fritted glass funnel to remove solids, and partitioned between ethyl acetate and brine. The organic layer was separated and dried over MgSO _4. Concentrate under reduced pressure, followed by flash chromatography of the residue on silica gel (10% hexane in ethyl acetate) to give
4 mg (57%, two steps) of 205 were obtained as a yellow viscous oil of sufficient purity for the next reaction.

Example 108 N-acetylazide 245: acetyl chloride (70 μl, 0.98 mmol)
l) was treated with amine 205 (154m) in CH ₂ Cl ₂ (4.0ml) cooled to 0 ° C.
g, 0.61 mmol) and pyridine (1.3 ml). After 1.5 hours at 0 ° C., the reaction was concentrated and partitioned between ethyl acetate and brine. The organic layer was separated and saturated sodium bicarbonate, washed successively with brine, and dried over MgSO _4. Concentration under reduced pressure followed by flash chromatography of the residue on silica gel (ethyl acetate) gave 167 mg (93%) of 24%.
5 was obtained as a pale yellow solid.

Example 109 Amino Ester 200: Triphenylphosphine (1.7 g, 6.48 mmol)
l) was treated with 245 (1.78 g, THF, 40 ml) and water (1.5 ml).
6.01 mmol) was added in several portions to the solution. The reaction was then allowed to cool at room temperature to 42
. Stir for 5 hours. Volatiles are removed under reduced pressure and the crude solid is adsorbed on silica gel and silica gel (100% ethyl acetate, then 100% methanol)
Purification by flash chromatography on 1.24 g (77%) of 2
00 was obtained as a pale white solid.

Example 110 Amino Acid 102: Methyl Ester 2 in THF (4.0 ml) Cooled to 0 ° C.
00 (368 mg, 1.37 mmol) solution and NaOH aqueous solution (1.37 ml)
Of a 1.0N solution). The reaction mixture was stirred at 0 ° C. for 10 minutes and at room temperature for 1.5 hours, and then acidified to pH 7.0-7.5 with Amberlite IR-120 (H ⁺ ) acidic resin. The resin was filtered and washed with water and methanol. Concentration under reduced pressure provided the amino acid as a white solid. It was purified by _C18 reverse phase chromatography, eluting with water. Fractions containing the desired product were pooled and lyophilized to give 290 mg (83%) of amino acid 102.

Example 111 Amine Hydrochloride 250: Amine 228 (15.6 mg, 0.05 mmol) in 0
. Treated with 1N HCl and evaporated. The residue was dissolved in water and filtered through a small column of C-18 reverse phase silica gel. After lyophilization, the hydrochloride salt 250 (12 mg) was obtained as a solid.

[0726]

[Equation 95] Example 112 Bis-Boc-guanidine 251: Amine 228 (12 in DMF (4 ml)
6 mg, 0.42 mmol), N, N'-bis-tert-butoxycarbonylthiourea (127 mg, 0.46 mmol), and triethylamine (123
HgCl ₂ (125 mg, 0.46 mmol) was added to the solution (μL, 0.88 mmol) at 0 ° C. The mixture was stirred at 0 ° C. for 30 minutes and at room temperature for 1.5 hours. The reaction was diluted with ethyl acetate and filtered through celite. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. Organic layer is saturated with N
Washed with aCl and dried (MgSO ₄ ), filtered and the solvent was evaporated. The crude product was purified on silica gel (2/1, 1 / 1-hexane / ethyl acetate) to give bis-Boc-guanidine 251 (155 mg, 69%) as a solid:

[0727]

[Equation 96] Example 113 Guanidino-acid 252: bis-Boc-guanidine 25 in THF (3 ml)
1 (150 mg, 0.28 mmol) in 1.039 N KOH solution (33
7 μL) and water (674 μL). The mixture is stirred for 3 hours and a further 1
. 039N KOH solution (67 μL) was added and stirring was continued for 2 hours. The reaction was filtered to remove a small amount of dark precipitate. The filtrate was cooled to 0 ° C. and acidified with IR-120 ion exchange resin to pH 4.5-5.0. The resin was filtered and washed with methanol. The filtrate was evaporated to give a residue. This was dissolved in CH ₂ Cl ₂ (3 ml), cooled to 0 ° C. and trifluoroacetic acid (
3 ml). After stirring at 0 ° C for 10 minutes, the reaction was stirred at room temperature for 2.5 hours. The solvent was evaporated and the residue was dissolved in water and chromatographed on C-18 reverse phase silica gel on a short column (3 × 1.5 cm) eluting first with water and then with 5% acetonitrile / water. . Combine the product fractions,
And it was evaporated. The residue is dissolved in water and lyophilized to give guanidino-
The acid 252 (97 mg, 79%) was obtained as a white solid.

Example 114 Azido Acid 260: Methyl Ester 227 (268m) in THF (7.0ml)
g, 0.83 mmol) solution at room temperature in KOH aqueous solution (1.60 ml of 1.03
(9N solution). After stirring at room temperature for 19 hours, the reaction was amberlite
Acidified to pH 4.0 with IR-120 (H ⁺ ) acidic resin. The resin was filtered and washed with water and ethanol. Concentrate under reduced pressure to give crude azido acid 260
Was obtained as a pale orange foam. This was used in the next reaction without further purification.

Example 115 Azidoethyl ester 261: carboxylic acid 26 in CH ₂ Cl ₂ (6.0 ml)
0 (crude product from the previous reaction, assuming 0.83 mmol), ethyl alcohol (150 μL), and catalyst DMAP at room temperature in DCC (172 mg).
, 0.83 mmol) were added in one portion. After a few minutes a precipitate was formed and after stirring for an additional 1 hour, the reaction was filtered and washed with CH ₂ Cl _2. Concentration under reduced pressure gave a pale white solid. This was purified by flash chromatography on silica gel (50% hexane in ethyl acetate) to give 272 mg (96
261 was obtained as a white solid. When the DCC was replaced by diisopropylcarbodiimide, the yield of 261 was 93%. However, when DCC was used, the urea impurities present were removed by chromatographic purification.

Example 116 Aminoethyl Ester 262: Triphenylphosphine (342 mg, 1.3
0 mmol) was added to 261 (27 ml) in THF (17 ml) and water (1.6 ml).
(2 g, 0.80 mmol) in one portion. The reaction was then brought to 50 ° C. for 1
Heat for 0 h, cool, and concentrate under reduced pressure to give a pale white solid. The crude solid was purified by flash chromatography on silica gel (50% methanol in ethyl acetate) to give 242 mg (96%) of aminoethyl ester 262 as a pale white solid. The aminoethyl ester was dissolved in 3N HCl and lyophilized to give the corresponding water-soluble HCl salt form.

[0731]

(97) Example 117 Bis-Boc guanidinoethyl ester 263: Kim and Qian, "T
etrahedron Lett. 34: 7677 (1993). Amine 262 (in dry DMF (600 μL) cooled to 0 ° C.)
72 mg, 0.23 mmol), bis-Boc thiourea (66 mg, 0.24 m
mol) and Et ₃ N (108 μL) were added to HgCl ₂ (69 mg, 0.2 mg).
5 mmol) were added in one portion. The heterogeneous reaction mixture was stirred at 0 ° C. for 1 hour, then at room temperature for 15 minutes. Thereafter, the reaction was diluted with EtOAc and filtered through a pad of celite. Concentrate under reduced pressure, followed by flash chromatography of the residue on silica gel (20% hexane in ethyl acetate) to give 113 mg (
89%) of 263 as a colorless foam.

[0732]

[Equation 98] Example 118 Guanidinoethyl ester 264: CH ₂ Cl ₂ cooled to 0 ° C. (5.0 ml)
Bis-Boc guanidonyl ethyl ester 263 (113 mg, 0.20 m
mol) solution, neat trifluoroacetic acid (5.0 ml) was added. The reaction mixture was stirred at 0 ° C. for 30 minutes, then at room temperature for 1.5 hours. The reaction was then concentrated under reduced pressure to give a pale orange solid. This was purified by _C18 reverse phase chromatography eluting with water. Fractions containing the desired product were pooled and lyophilized to give 63 mg (66%) of guanidine ethyl ester 264 as a white solid.

[0733]

[Equation 99] Example 119 Enzyme Inhibition: The following activities were observed using the in vitro activity screening method described above (+ 10-100 μm, ++ 1-10 μm, +++ <1.0 μm)
):

[0734]

[Table 55] Example 120 Compound A. 113. b. 4. i. 113. x. 4. i were separately incubated in enzyme assay buffer and tested for activity as described in Example 119. The activities were both> 100 μm. If each compound was incubated separately in rat plasma prior to testing as described in Example 119, both activities were compound A. 113. a. 4. Same as i.

Example 121 A study was performed to determine the comparative anti-influenza A activity of compound 203 (Example 69), GG167, and ribavirin, with Institute for A
natural Research of Utah State Univ
This was performed in vivo by intraperitoneal or oral administration in mice under the supervision of Dr. Robert Sidwell of ER. GG167 and ribavirin are known as anti-influenza virus compounds.

[0736]

Embedded image Mice: Female 13-15 g BALB / c mice free of specific pathogens were
Obtained from Monsen Laboratories (Gilloy, CA).
They were quarantined 24 hours before use and maintained with Wayne Lab Blox and tap water. Once infected, 0.006% oxytetracycline (Pfizer, New York) was added to drinking water to control the potential for secondary bacterial infection.
York, NY).

Virus: Influenza A / NWS / 33 (H1N1) was isolated from K. W. Coc
hran, University of Michigan (Ann Ar
bor, MI). Confluent monolayer of Madi virus pool
infecting n Darby canine kidney (MDCK) cells, incubating them at 37 ° C. in 5% CO ₂ , and reducing the cytopathic effect of the virus by 90-1.
The cells were prepared by collecting cells on days 3 to 5 when the cells became 00%. The virus stock was packed into ampoules and stored at -80 C until use.

Compounds: Compound 203 and GG167 were dissolved in sterile saline for this study.

[0739] Arterial Blood Oxygen Saturation (SaO ₂ ) Measurement: SaO ₂ was measured using
Measured using a 740 pulse oximeter (Ohmeda, Louisville, OH). Using an ear probe accessory, the probe was placed on the animal's thigh in a slow instrument style of choice. Readings were taken after a 30 second stabilization time for each animal. The use of this device to measure the effect of influenza virus on arterial oxygen saturation is described in Sidwell et al., "Antimicrob. Agents.
Chemother. 36: 473-476 (1992).

Experimental design for intraperitoneal administration study: Groups of 11 mice infected intranasally with approximately 95% lethal dose of virus received each dose of test compound. 203 and GG1
Both doses of 67 were 50, 10, 2, and 0.5 mg / kg / day.
Treatments were treated intraperitoneally twice daily for 5 days, beginning with a 4 hour previrus exposure. Eight infected mice treated at each dose and 16 infected controls treated with saline were assayed for SaO ₂ levels from day 3 to day 10; mortality recorded daily for 21 days for these animals did. The remaining three animals in each group as well as six saline-treated control mice were sacrificed on day 6, and their lungs were removed, weighed, and a consolidation score was given based on the degree of dark purple color of the lungs. (0 = normal, 4 = 100% of lungs infected). 203 300m
Toxicity control was not included in this study because no toxicity was seen at the g / kg / day dose and the literature reports that GG167 is similarly non-toxic.

[0741] Experimental design for oral administration study: A group of 11 mice was infected intranasally with approximately 95% lethal dose of virus, and 203, GG167 or 100, 250, 50, or 10 mg / kg / day. Treatment with 32, or 10 mg / kg / day ribavirin. Beginning with a 4 hour previrus exposure, the animals were treated by oral gavage (oral administration) twice daily for 5 days. Each group 8 animals, the number of deaths and held daily recorded while 21 days, and measured the SaO ₂ levels in 3-10 days. The remaining three infected mice in each group were sacrificed on day 6, and their lungs were removed, weighed, and given a consolidation score of 0 (normal) to 4 (100% lung infected). . Fifteen infected mice were treated with saline only, and kept for 21 days while measuring SaO ₂ as described above, and six other infected mice treated with saline were used for lung assays. Sacrificed on day 6. Three normal controls were kept for 21 days while measuring SaO ₂ in parallel with the above, and three other normal animals were sacrificed on day 6 for lung weight and score.

Experimental Design for Low Dose Oral Study: Nasal with approximately 90% lethal dose of virus
Groups of 8 mice infected intracavitically received each dose of compound. The dose of each compound is 1
0, 1, and 0.1 mg / kg / day. 4 hours pre-virus exposure
At least twice daily for 5 days by oral gavage. 8 treated at each dose
Control mice and 16 saline-treated infection controls were _Two Levels were assayed on days 3-11; mortality was recorded daily in these animals for 21 days.

[0743] Statistical evaluation: an increase in survival was evaluated by chi ² analysis with Yates' correction. Increases in mean survival and differences in SaO ₂ , lung weight and lung virus titer were analyzed by t-test. Differences in lung scores were evaluated by class sum analysis (r
evaluated by an aggregated sum analysis. In all cases, the differences between drug treatment and saline treated control were studied.

The results of the intraperitoneal dosing experiments are summarized in Table I and FIGS. 1 and 2. In this model, both compounds were significantly inhibitory at the high dose used, but 203 treatment also resulted in significant survival at the 10 mg / kg / day dose. SaO ₂ reduction was particularly inhibited by both compounds at a dose of 50 mg / kg / day. further,
GG167 also appears to prevent this reduction at doses of 10 and 2 mg / kg / day. Lung score data shows that GG167 is effective at more than one dose
Seem to show a similar tendency. Some irregularities in lung weight are shown, with lungs taken from mice receiving the highest dose of GG167 having a higher average weight than saline-treated controls.

The oral dosing studies are summarized in Table II with daily SaO ₂ values shown in FIGS. Oral treatment with all three drugs in this model is significantly inhibitory to influenza virus infection, prevents mortality, reduces lung score and infection-related lung weight, and reduces normal SaO Inhibited the decrease in ₂ .

The results of the oral low dose study are summarized in Table III and FIGS. In this experiment, the infection was lethal in 14 of the 16 saline-treated animals, with an average survival of 9.6 days in this group. All three compounds respond to viral infection
Although showing some inhibitory effect, 262 (ethyl ester prodrug) was the most effective at all doses, as evidenced by survival, mean survival, and prevention of SaO ₂ reduction.

Table III also shows the average SaO ₂ % for all assay times. The daily values for each compound are shown graphically in FIGS. Figure 6 illustrates the SaO ₂ data for each compound at the highest concentration; FIG. 7, the intermediate dose The value for a of each compound; the SaO ₂ values for and low dose of each compound FIG. 8 To compare.

Table III and FIGS. 6-8 show that all three compounds are orally active against experimentally induced influenza A (H1N1) virus infection, with 262 appearing to be the most active It indicates that. It was not determined whether the improved antiviral efficacy of 262 was accompanied by concomitant increased animal toxicity, but this does not appear to be concomitant. Because greater potency is expected to be the result of its increased oral bioavailability.

[0749]

[Table 56]

[0750]

[Table 57]

[0751]

[Table 58] Footnote ^a for Tables I-III a Five runs beginning with ^a 4 hour previrus exposure. ^b Animals that died before day 21. ^c Average of values measured on days 3-10. ^d Measured on day 6. ^* P <0.05, ^** P <0.01, ^*** P compared to saline treated control
<0.001.

Surprisingly, Ryan et al. (“Antimicrob. Agents Ch.
emother. 38, (10): 2270-2275) [1994]).
Nevertheless, as noted above, this model demonstrates that oral or intraperitoneal administration of GG167 is effective in reducing mortality in influenza infected mice at actual therapeutic doses. Ryan et al. Concluded that, despite good bioavailability, GG167 was observed in mice after intraperitoneal administration.
Is relatively low due to its rapid clearance from plasma, resulting in poor penetration into respiratory secretions and the ability to penetrate and maintain cells inside. Seems to lead to nothing. … Similarly, poor efficacy after oral dosing is probably the result of poor oral bioavailability, in addition to these other factors. (P. 2274). These observations are described in Von Izstein et al., WO 91/16320, WO 9
No. 2/06691 and U.S. Pat. No. 5,360,817. These particularly include or relate to GG167. These patents do not teach or suggest administering GG167 by any route other than intranasally. However, intranasal administration is considered inconvenient and expensive in certain circumstances. GG167 and WO 91/16320, WO 9
It would be advantageous if an easier route of administration could be used for the related compounds described in US Pat. No. 2,066,91 and US Pat. No. 5,360,817.

Thus, one embodiment of the present invention is a method of treating or preventing an influenza virus infection in a host. The method comprises administering a therapeutically effective dose of an antiviral active compound having the following formula (X) or (Y), and a pharmaceutically acceptable salt thereof, by a route other than topical administration to the respiratory system: Administering the derivative to a host including:

[0754]

Embedded image Here, in the general formula (x), A is oxygen, carbon, or sulfur, and in the general formula (y), A is nitrogen or carbon; R ¹ is COOH, P (O) (OH ) ₂ , NO ₂ , SOOH, SO ₃ H, tetrazole, CH ₂ CHO, CHO, or CH (CHO) ₂ , wherein R ² is H, OR ⁶ , F, Cl, Br, CN, NHR ⁶ , SR ⁶ , or CH ₂ X, wherein X is NHR ⁶ , halogen, or OR ⁶ , and R ⁶ is hydrogen; an acyl group having 1-4 carbon atoms; A linear or cyclic alkyl group having an atom, or a halogen-substituted analog thereof;
An aryl group, or an unsubstituted aryl group or an aryl substituted with a halogen, OH group, NO ₂ group, NH ₂ group, or COOH group, wherein R ³ and R ³ ′ are the same or different and each is hydrogen, _{^{CN, NH R 6, N 3}} , SR 6, = N-OR 6, OR 6, guanidino,

[0755]

Embedded image R ⁴ represents NHR ⁶ , SR ⁶ , OR ⁶ , COOR ⁶ , NO ₂ , C (R ⁶ ) ₃ , CH ₂ COOR ⁶ , CH ₂ NO ₂ , or CH ₂ NHR ⁶ ; _{^{5, CH 2 YR 6, CHYR 6}} CH 2 YR 6, or indicates _{^{CHYR 6 CHYR 6 CH 2 YR 6}} , wherein, Y is, O, S, NH or a H,, and in R ⁵ groups The consecutive Y moieties are the same or different, with the proviso that, in the general formula (x), when (i) R ³ or R ³ ′ is OR ⁶ or hydrogen and A is oxygen or sulfur, the compound is represented by (a) R ² which is hydrogen, and (b) R ⁴ which is NH-acyl, and (ii) when Y is hydrogen, R ⁶ represents a covalent bond and has the general formula (y) in (i) R ³ or R ³ 'is oR ⁶ or hydrogen, and a is nitrogen In some cases, the compounds do not give a (a) R ² is hydrogen, and (b) NH- R ⁴ is acyl simultaneously, and (ii) if Y is hydrogen, the R ⁶ is a covalent bond Show.

The compounds of the formulas x and y are described in WO 91/16320, page 3, line 23 to page 7, 1
Row, WO 92/06691, and US Pat. No. 5,360,817, and x and y are described therein as "I" and "Ia", respectively.

For the purposes herein, administration by the “other than topical administration to the respiratory tract means” route does not preclude administration of the compound by the buccal or sublingual route, and does not include oral, buccal, or sublingual administration. In the meantime, it does not rule out secondary absorption of the compound in the esophagus. However, for example, buccal, oral, sublingual, or esophageal absorption is not secondary to administration to the pulmonary or nasal routes, such as by inhalants. Typically, the compounds will be administered as a molding, slurry, or solution.

In an exemplary embodiment of the invention, the compound is GG167, the host is an animal other than a mouse (eg, ferret or human), the route of administration is oral, and the purpose of treatment and prevention is death. It is a decrease in the number. If necessary, formula (X)
Alternatively, a prodrug of the compound of (Y) is used and need not be so achieved to achieve an antiviral effect by oral administration as set forth above. For the prodrug of GG167 and its concurrently disclosed compounds, any ester, amide or other prodrug described elsewhere herein for compounds of the present invention may be a compound of formula (X) and (Y) Suitable for use with similar groups of (eg, carboxyl esters or amides).

Therapeutically effective doses of GG167 and its related compounds when administered by the oral or other non-nasal route of administration may be determined by the clinician of ordinary skill in the art, taking into account the discussion above regarding the dose of the compounds of the present invention. It is determined. For the most part, the main considerations are the route of administration and the host species. In general, higher doses are required from the intravenous to subcutaneous administration and the subcutaneous to oral administration route. And according to conventional pharmacological scaling principles, larger animals require higher doses. Determination of a therapeutically active dose is well within the skill in the art, but, in general, the dose will be substantially the same as that used for the compounds of the present invention.

Example 122 Each reaction shown in Table 50 was previously performed according to Scheme 50. The preliminary reaction is indicated by "V". Unless indicated in Table 50, steps AA, AB, and AC
Was performed in advance according to Examples 92, 93, and 94, respectively, and step AD was performed in advance according to the combination of Examples 112 and 113.

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Embedded image

[0762]

[Table 59] Table 50 (Note) a) azide reduction previous ester hydrolysis b) at room temperature Ph ₃ Ph ₃ supported on ester hydrolysis d) polymer at room temperature to use the azide reduction c) an aqueous KOH / MeOH to use P P azide reduction e) azide reduction g) diastereomeric mixture using Ph ₃ P in isolated _{f) MeOH / THF / H 2} O in as the HCl salt to use, h shows the major diastereomer) also, Azide reduction performed with Me ₃ P i) Aziridine ring opening performed at 55 ° C. j) C-alkylated product isolated

[0763]

Embedded image k) The alcohol was not evaporated before the acylation. 1) The diastereomeric mixture was separated by chromatography / recrystallization.

Example 123 Trifluoroacetamide 340: A solution of amine 228 (100 mg, 0.34 mmol) in CH ₂ Cl ₂ (3.5 mL) at 0 ° C. was treated with pyridine (41 μL, 0.1 mL).
51 mmol) and trifluoroacetic anhydride (TFAA) (52 μL, 0.37
mmol) and the solution is stirred for 45 minutes, at which time more TFAA
(0.5 equivalent) was added. After 15 minutes, the reaction was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and 1M HCl. The organic layer was washed with sat. NaHCO ₃ , sat. NaCl, and dried (MgSO ₄ ), filtered and evaporated. The residue was chromatographed on silica gel (2 / 1-hexane / ethyl acetate) to give trifluoroacetamide 340 (105 mg, 78%):

[0765]

[Equation 100] Example 124 N-Methyltrifluoroacetamide 341: A solution of trifluoroacetamide 340 (90 mg, 0.23 mmol) in DMF (2 mL) at 0 ° C. was treated with sodium hydride (10 mg, 60% dispersion in mineral oil, 0.25 mmol) was added. After 15 minutes at 0 ° C., methyl iodide (71 μL, 1.15 mmol) was added and the reaction was stirred at 0 ° C. for 2 hours and at room temperature for 1 hour. Acetic acid (28 μL) was added and the solution was evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated NaCl, dried (MgSO ₄ ), filtered and evaporated. The residue was chromatographed on silica gel (1 / 1-hexane / ethyl acetate) to give N-methyltrifluoroacetamide 341 (81 mg, 87%) as a colorless glass:

[0766]

[Equation 101] Example 125 N-methylamine 342: To a solution of N-methyltrifluoroacetamide 341 (81 mg, 0.20 mmol) in THF (3 mL) was added 1.04 N KOH (
480 μL, 0.50 mmol) was added and the mixture was stirred at room temperature for 14 hours. The reaction was acidified to a pH of about 4 with an IR120 ion exchange resin. The resin was filtered, washed with THF, and the filtrate was evaporated. The residue was treated with 10% TFA /
Dissolved in water (5 mL) and evaporated. The residue is eluted with water with C-
Passed through a column of 18 reverse phase silica gel (1.5 × 2.5 cm). Product fractions were pooled and lyophilized to give N-methylamine 342 (46m) as a white solid.
g, 56%).

[0767]

[Equation 102] (Example 126) Compound 346: 8/1-MeOH / H 2 O (440mL, v / v) in, epoxy Sid 345 (13.32 g, 58.4 mmol) was added sodium azide (1
9.0 g, 292.0 mmol) and ammonium chloride (2.69 g, 129
. 3 mmol) was added and the mixture was refluxed for 15 hours. Cool the reaction,
Concentrated under reduced pressure, and partitioned between EtOAc and H ₂ O. The organic layer was washed successively with saturated baking soda and brine, and dried over MgSO _4. After concentration in vacuo, 11.81 g (75%) of azido alcohol 34 as a viscous oil was obtained by flash chromatography on silica gel (30% EtOAc in hexane).
Gave 6:

[0768]

[Equation 103] Example 127 Compound 347: DIBAL (5.1 mL of a 1.0 M solution in toluene) in a solution of ethyl ester 346 (420 mg, 1.55 mmol) in dry THF (8.0 mL) cooled to -78 ° C. Was dropped with a syringe. The bright yellow reaction mixture was stirred at −78 ° C. for 1.25 h, then slowly hydrolyzed by the slow addition of MeOH (1.2 mL). Volatiles were removed under reduced pressure and the residue was removed with Et.
Partitioned between OAc and cold diluted HCl. Separate the organic layer and separate the aqueous layer with Et
Back extracted with OAc. The combined organic layers, and washed sequentially with saturated sodium bicarbonate and brine, and dried over MgSO _4. After concentration in vacuo, flash chromatography on silica gel (20% hexane in EtO Ac) gave 127 mg (36%) of diol 347 as a colorless viscous oil:

[0769]

[Equation 104] Example 128 Methyl Ester 600: Frost, J.M. W. Et al., "J. Org. Chem.
. 61: 3897 (1996), from D-(-)-quinic acid.
% Overall yield.

Example 129 Ketone 601: Diol 600 in dichloromethane (200 mL) (15.
PCC (40.5 g, 187.9 mmol) was added in portions to a slurry of 0 g, 46.9 mmol), pyridine (13.7 mL), and celite (equivalent to PCC), and the reaction was allowed to stand at room temperature for 21 hours. Stirred. Excess PCC is replaced with excess 2-
Broken by addition of propanol. After stirring for a further 30 minutes, the reaction mixture was diluted with diethyl ether, filtered through a pad of celite and washed with ethyl acetate. The organic layer was then passed through a short column of silica gel and eluted with ethyl acetate. Concentration under reduced pressure gave a yellow solid. this is,
Recrystallized from methanol / ethyl acetate / hexane to give ketone 6 as crystalline powder
01 (10.9 g, 74%) was obtained. _{HRMS (FAB): C 14 H} 22 O 8 (ML i +) Calculated 325.1474, found 325.1471. Example 130 Olefin 602: n-BuLi (1.61 M solution in hexane) in a slurry of butyltriphenylphosphonium bromide (16.6 g, 41.6 mmol) in dry THF (150 mL) cooled to 0 ° C. 26.0 mL) was added dropwise.
After stirring at 0 ° C. for 20 minutes, the mixture was warmed to room temperature, stirred for 5 minutes, and recooled to 0 ° C. To this bright orange solution was added 601 (6.0 g, 18.9 mmol).
) In dry THF (75.0 mL) was added via cannula. The reaction mixture was warmed to room temperature, stirred for 10 minutes, and then gently refluxed for 2.5 hours. The reaction mixture was cooled, saturated NaHCO ₃ was added and diluted with ethyl acetate. The organic layer was separated, washed with brine, dried over MgSO _4. Concentration under reduced pressure followed by flash column chromatography on silica gel (3 in acetic acid).
(0% hexanes) gave 5.5 g (81%) of 602 as a viscous pale oil consisting of a 4: 1 mixture of olefin isomers.

Example 131 Triethylsilyl ether 603: dichloromethane (12
To a solution of 602 (5.5 g, 15.37 mmol) in 5 mL) was added 2,6-lutidine (3.6 mL) followed by triethylsilyl trifluoromethanesulfonate (5.35 mL, 23.66 mmol). It was dropped. The reaction mixture was slowly warmed to room temperature and stirred for 15 hours. Volatiles were removed under reduced pressure and the crude residue was partitioned between diethyl ether and water. HC diluted organic layer
1, washed with saturated NaHCO ₃ , brine and dried over MgSO ₄ . Concentration under reduced pressure followed by flash column chromatography on silica gel (2 in hexane).
(0% ethyl acetate) gave 6.78 g (93%) of 603 as a mobile liquid.

Example 132 Butylcyclohexyl Ester 604: A degassed solution of olefin 603 (6.78 g, 14.34 mmol) in ethanol (140 mL) was charged with carbon-supported 1
0% palladium (5.0 g) was added. The reaction mixture was then stirred at room temperature under a hydrogen gas atmosphere (1 atm by balloon) for 22 hours. The reaction was filtered through a pad of celite and washed with hot methanol. Concentration under reduced pressure followed by flash column chromatography on silica gel (10% ethyl acetate in hexane) provided 5.44 g (80%) of 604 as a colorless oil.

Example 133 Alcohol 605: Tetrabutylammonium Fluoride Solution (THF
1.0M solution (17.1 mL) in 604 (5.44 g, 11.46 mm).
ol) in THF (50 mL) at room temperature. After 45 minutes, a large amount of THF was removed under reduced pressure and the crude reaction was partitioned between diethyl ether and water.
The organic layer was washed with saturated ammonium chloride, washed with water, brine and Drying over MgSO _4. Concentration under reduced pressure followed by flash column chromatography on silica gel (20% ethyl acetate in hexane) gave 3.18 g (77%) of 60%.
5 was obtained as a colorless viscous oil.

Example 134 Olefin 606: Alcohol 605 (3.18 g, 8.82 mmol) in pyridine (39 mL) and dry dichloromethane (35 mL) cooled to −78 ° C.
To the solution of 1), sulfuryl chloride (1.07 mL, 13.32 mmol) was added dropwise via a syringe. The reaction mixture was slowly warmed to -40 ° C over 30 minutes and maintained between -40 ° C and -30 ° C for 30 minutes. This reaction system is -78 ° C
Re-cooled and added methanol (1.0 mL). The reaction was then slowly warmed to room temperature over 3 hours and then diluted with diethyl ether. The organic layer was washed successively with water, diluted HCl, water, saturated NaHCO ₃ , brine and dried over MgSO ₄ . Concentration under reduced pressure followed by flash column chromatography on silica gel (25% ethyl acetate in hexane) gave 2.73.
g (90%) of 606 were obtained as a colorless viscous oil, which was contaminated with about 3% of the isomeric cyclohexene carboxylate.

Example 135 Diol 607: A solution of 606 (2.73 g, 7.97 mmol) in dichloromethane (58 mL) was treated with 40% aqueous trifluoroacetic acid (37 mL) at room temperature for 14 hours. Volatiles were removed under reduced pressure and the residue was partitioned between diethyl ether and water. The organic layer was washed carefully with saturated NaHCO ₃ , water, brine and dried over MgSO ₄ . Concentration under reduced pressure followed by flash column chromatography on silica gel (10% hexane in ethyl acetate) gave 1
. 36 g (75%) of 607 were obtained as a viscous oil.

Example 136 Mesylates 608 and 609: dichloromethane (2
To a solution of diol 607 (1.06 g, 4.64 mmol) and triethylamine (1.31 mL) in 5 mL) was added methanesulfonyl chloride (360 μL,
(4.64 mmol) was added dropwise. The reaction was stirred at -78 ° C for 1 hour, then slowly warmed to 0 ° C over 1 hour. After an additional hour at this temperature, the reaction was diluted with diethyl ether, washed with water, saturated NaHCO ₃ , brine and dried over MgSO ₄ . Concentration under reduced pressure followed by flash column chromatography on silica gel (20% ethyl acetate in hexane) gave 1.23 g.
(87%) of 608 and 609 were each obtained as an inseparable 6: 1 ratio mixture.

Example 137 Epoxide 610: To a solution of a 6: 1 mixture of 608 and 609 (1.23 g, 4.02 mmol) in dry THF (20 mL) cooled to 0 ° C.
(601 μL, 4.02 mmol) was added. The ice bath was removed and the reaction was stirred at room temperature for 18 hours. The reaction was diluted with diethyl ether, washed with water, brine, dried over MgSO _4. Concentration under reduced pressure followed by flash column chromatography on silica gel (20% ethyl acetate in hexane) gave 490 mg (58%) of pure epoxide 610 as a mobile fluid, 100%.
mg (13%) of methyl-3-butylbenzoate 611 was obtained as an oil.
Analysis calculated for _{C 12 H 18 O 3: C} , 68.55; H, 8.63. Found: C, 68.29; H, 8.52. Example 138 Azido alcohols 612 and 613: 610 (490 mg, 2.33 mm
ol), sodium azide (764 mg, 11.75 mmol) and ammonium chloride (281 mg, 5.25 mmol) in methanol / water (8: 1, 17.
0 mL) solution was gently refluxed for 15 hours. The cooled reaction mixture was concentrated under reduced pressure and partitioned between diethyl ether and water. The organic layer was washed with brine, dried over MgSO _4. Concentration under reduced pressure followed by flash column chromatography on silica gel (20% ethyl acetate in hexane) gave 562 m.
g (95%) of 612 and 613 were each obtained as an inseparable 2: 1 mixture.

Example 139 Azido Mesylate 614 and 615: dichloromethane cooled to 0 ° C.
To a solution of 612 and 613 (642 mg, 2.54 mmol), triethylamine (1.8 mL) and the catalyst DMAP in 15 mL) was added methanesulfonyl chloride (232 μL, 3.00 mmol) dropwise. The reaction was run at 0 ° C for 1.
Stir for 5 hours then at room temperature for 30 minutes. The reaction was diluted with diethyl ether, washed with water, diluted HCl, saturated NaHCO ₃ , brine and dried over MgSO ₄ . Concentration under reduced pressure gave a yellow fluid. This was passed through a short plug of silica gel eluting with 25% ethyl acetate in hexanes, 840 mg (100 mg).
%) 614 and 615 were obtained as inseparable mixtures.

Example 140 Aziridine 616: 614 and 615 (840 mg, 2.53 mmol)
To a solution of dry THF (20 mL) at room temperature was added triphenylphosphine (750 mg). After 2.5 hours, triethylamine (550 μL) and water (5.50 mL) were added, and the reaction was stirred at room temperature for 16 hours. Volatiles were removed under reduced pressure and the residue was diluted with ethyl acetate. The organic layer was washed with water, saturated N
Washed with aHCO ₃ , brine and dried over MgSO ₄ . Concentration under reduced pressure followed by flash column chromatography on silica gel (5% methanol in ethyl acetate) provided 375 mg (71%) of 616 as a viscous oil.

Example 141 Azidoamine 617: 616 (354 mg, 1.70 mmol), sodium azide (555 mg, 8.54 mmol) and ammonium chloride (182 m
g, 3.40 mmol) in dry DMF (8.0 mL) was heated at 80 ° C. for 17 hours. A large amount of DMF was removed under reduced pressure and the residue was partitioned between diethyl ether and water. The organic layer was washed with water, brine, dried over MgSO _4. Concentration under reduced pressure gave a yellow liquid. This was passed through a short plug of silica gel eluting with ethyl acetate to give 380 mg (86%) of 617 as a yellow liquid, which was used immediately in the next reaction.

Example 142 N-Acetyl Azide 618: Crude amine 617 (380 mg, 1.51 mmol) in dry pyridine (3.0 mL) and dichloromethane (7.0 mL) was added to acetyl chloride (173 μL, 2.40 mmol). ) At 0 ° C. After 40 minutes, the reaction was warmed to room temperature and stirred for 5 minutes. Volatiles were removed under reduced pressure and the residue was partitioned between diethyl ether and water. The organic layer was washed with dilute HCl, saturated NaHCO ₃ , brine and dried over MgSO ₄ . Concentration under reduced pressure followed by flash column chromatography on silica gel (20% hexane in ethyl acetate) gave 349 mg of an off-white solid, which was recrystallized from ethyl acetate and hexane to give 304 mg (68%). 618 of colorless needles (
needles).

Example 143 N-acetylamino ester 619: water (1.8 mL) and THF (15
A solution of 618 (292 mg, 0.99 mmol) and triphenylphosphine (393 mg, 1.50 mmol) in 50 mL) was heated at 50 ° C. for 10 hours.
The reaction was evaporated to dryness, applied to a silica gel column and eluted with 40% methanol in ethyl acetate to give 250 mg (93%) of 619 as a pale gummy solid.

Example 144 Amino Acid 620: 619 (142 mg, 0.53 mmol) in THF (2.
0 mL) solution at room temperature with an aqueous KOH solution (1.039 M solution (770 μL)) for 3.5 hours, then acidify to pH = 3.0 using Amberlite IR-120 (H ⁺ ) ion exchange resin. Has become The reaction was filtered and the resin was washed with water and methanol. Concentration under reduced pressure to give a Blue white solid, which was purified by C ₈ reverse phase column chromatography eluting with water. Fractions containing the desired product are pooled and evaporated to 87 mg (
65%) of 620 as a colorless powder.

Example 145 Azidopropyl ester 265: carboxylic acid 260 (55 mg, 0.18 mmol), 1-propanol (67 μL, 0.8 in CH ₂ Cl ₂ (1.0 mL)
9 mmol) and diisopropyl carbodiimide (31 μL, 0.19 mmol) were added dropwise at room temperature to a solution of the catalyst DMAP. After stirring for 1 hour, the reaction was concentrated and purified by flash column chromatography on silica gel (50% hexane in ethyl acetate) to give 53 mg (85%) of 265 as a colorless crystalline solid.

Example 146 Aminopropyl Ester 266: Triphenylphosphine (65 mg, 0.1 mg)
25 mmol) was added to 265 (25 mL) in THF (4.0 mL) and water (300 μL).
(53 mg, 0.15 mmol). The reaction was then heated at 50 ° C. for 10 hours, cooled and concentrated under vacuum to give a pearl white solid. Purification of the crude solid by flash chromatography on silica gel (50% methanol in ethyl acetate) gave a pale oil which was 3
Evaporation from N HCl afforded a solid, which was purified by _C18 reverse phase column chromatography, eluting with water. Fractions containing the desired product were pooled and lyophilized to give 41 mg (75%) of 266 as a colorless powder.

Example 147 Sulfide 700 was prepared according to literature procedures (Rebert H. Rich, Brian).
M. Lawrence, Paul A. Bartlett, "J. Org. C
hem. 59: 693-694 (1994)).

Example 148 Sulfoxide 701: To a solution of sulfide 700 (16.0 g, 32.7 mmol) in CH ₂ Cl ₂ (750 mL) at −45 ° C., add CH ₂ Cl ₂ (250 mL)
A solution of m-chloroperoxybenzoic acid (8.5 g, 57-86%) in 0.5 g
It was dropped over time. The reaction was stirred at −40 ° C. for 1 hour and then at room temperature for 0.5 hour. The reaction mixture was evaporated and a solid began to precipitate, then was diluted with hexane. The solid was removed by filtration and the filtrate was evaporated. The residue was dissolved in ethyl acetate, washed with saturated NaHCO ₃ , dried (MgSO ₄ ), filtered and evaporated. The crude product was purified by chromatography on silica gel (ethyl acetate / hexane) to give the sulfoxide 701 (14
. 2 g, 86%, mixture of diastereomers, ratio = 2.2: 1) was obtained as a colorless solid.

Example 149 Vinyl chloride 702: Sulfoxide 701 (14.0 g, 27.7 mmol)
Was refluxed in xylene (180 mL) for 50 minutes. The reaction mixture was cooled to room temperature and evaporated. The residue was chromatographed on vinyl chloride 702 (7.6).
g, 79%) as an oil.

Example 150 Triol 703: Vinyl chloride 7 in anhydrous methanol (80 mL) at room temperature
02 (7.3 g, 20.9 mmol) in sodium methoxide (0.3
mL, 25% 1.3 mmol) was added. The reaction was stirred for 1 hour at room temperature,
It was then quenched with HCl / CH ₃ OH (1.0 mL, 1.4 M, 1.4 mmol). The reaction mixture was evaporated and the residue was treated with ethyl acetate / hexane to give triol 703 (4.6 g, 99%) as a colorless solid.
^{_{C 8 H 11 ClO 5 · 1}} /14 Calcd for NaCl: C, 42.36; H, 4.89; Cl, 16.75. Found: C, 42.29; H, 4.90; Cl,
16.56.

Example 151 Acetonide 704: Triol 703 (4.6 g, 20.7 mmol), 2
, 2-dimethoxypropane (4.0 mL, 32.5 mmol) and acetone (
50 mL) was stirred at room temperature for 1.5 hours. The reaction mixture was evaporated and fresh 2,2-dimethoxypropane (1.5 mL, 12.2 mm
ol) and acetone (30 mL) were added. The reaction was stirred for another 1.5 hours. The reaction mixture was evaporated and the crude product was filtered through a short plug of silica gel. The filtrate was evaporated and acetonide 704 (5.4)
g, 99%) as an oil. ^{_{C 11 H 15 ClO 5 · 1}} /4 H 2 O Calcd for: C, 49.45; H, 5.85 ; Cl, 13.27. Obtained value: C, 49
. 67; H, 5.82; Cl, 13.60.

Example 152 Mesylate 705: Acetonide 704 in CH ₂ Cl ₂ (30 mL) at 0 ° C.
(2.63 g, 10.0 mmol) in a solution of triethylamine (2.23 mL).
, 16 mmol) followed by methanesulfonyl chloride (1.16 mL, 15 mm
ol) was added. The reaction was stirred at 0 ° C. for 1 hour and then evaporated. The residue was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (MgSO ₄ ), filtered and evaporated. The crude product was filtered through a short plug of silica gel. The filtrate was evaporated to give mesylate 705 (3.4 g, 100%
) Was obtained as an oil.

Example 153 3-pentyl ketal 706: mesylate 7 in 3-pentanone (40 mL)
05 (3.4 g, 10.0 mmol) and perchloric acid (30 mg, 70%, 0.1%).
2 mmol) was stirred at 45 ° C. for 2 hours. The reaction was evaporated and fresh 3-pentanone (40 mL) was added. The reaction was stirred for a further 0.5 h, then evaporated. The crude product was filtered through a short plug of silica gel. The filtrate was evaporated to give 3-pentyl ketal 706 (3.7 g, 100%) as an oil.

Example 154 Mesylate alcohol 707: A solution of ketal 706 (1.68 g, 4.55 mmol) in CH ₂ Cl ₂ (20 mL) at −5 ° C. was added to a borane-methyl sulfide complex (0 (0.7 mL, 10 M, 7.0 mmol), followed by trimethylsilyl trifluoromethanesulfonate (0.82 mL, 4.6 mmol). At 0 ° C., the resulting mixture was stirred for 1 hour, then very slowly saturated NaHCO ₃ (first 5 drops 1 drop / 10 min, 1 mL) was added. The resulting mixture was filtered through a short plug of silica gel. The filtrate was evaporated and purified by chromatography on silica gel (ethyl acetate / hexane) to give regioisomers 707 and 708 (1.2 g, 71%, 8/9 = 3).
/ 2) as an oil.

Example 155 A mixture of epoxides 709: 707 and 708 (1.95 g, 5.26 mmol) was mixed with KHCO ₃ (1.0 g, 10 mmol) in methanol (15 mL) and water (10 mL). . The reaction was stirred at 50 ° C. for 1 hour, then evaporated to remove methanol. The remaining mixture was extracted with ethyl acetate. The combined extracts were dried (MgSO ₄ ), filtered and evaporated. The residue was chromatographed to give epoxide 709 (0.88 g).
, 61%) as an oil.

Example 156 Azide Alcohol 710: Epoxide 709 (0.95 g, 3.46 mmol), sodium azide (0 mL) in methanol (40 mL) and water (10 mL)
. 65 g, 10 mmol), and ammonium chloride (0.40 g, 7.5 mm
ol) was stirred at 65 ° C. for 18 hours. The reaction mixture was diluted with water and evaporated to remove methanol, and then extracted with ethyl acetate. The organic extract was dried (MgSO ₄ ), filtered and evaporated. The crude product was recrystallized from hexane / ethyl acetate to give azido alcohol 710 (0.
8g, 73%) as a colorless solid. Analysis calculated for _{C 13 H 20 ClN 3 O 4} : C, 49.14; H, 6.34; N, 13.22; Cl, 11.16. Found: C, 49.14; H, 6.47; N, 13.21; Cl, 11.38.

Example 157 Azido mesylate 711: At 0 ° C., a solution of azido alcohol 710 (1.0 g, 3.15 mmol) in CH ₂ Cl ₂ (20 mL) was added to triethylamine (1
. 1 mL, 8.0 mmol) followed by methanesulfonyl chloride (0.5 mL
, 6.5 mmol) was added. The resulting mixture is allowed to stand at 0 ° C. for 0.5 hours,
It was then stirred at room temperature for another 0.5 hour. Two drops of water were added to the reaction, which was then diluted with hexane and filtered through a short plug of silica gel. The filtrate was evaporated to give azido mesylate 711 (1.27 g, 100%)
Was obtained as an oil.

Example 158 Azidophenethyl ester 800: 260 (63 mg, 0.20 mmol) in 1 / 1-CH ₂ Cl ₂ / THF (2 mL), phenethyl alcohol (26 μL,
0.22 mmol) and DMAP (7.8 mg) at room temperature was added diisopropylcarbodiimide (34 μL, 0.22 mmol). After stirring for 4 hours, the solvent was evaporated and the residue was chromatographed on silica gel (1 / 1-hexane / ethyl acetate) to give 800 (60 mg) as an oil containing traces of phenethyl alcohol. This material was used directly in the next step without any further purification.

Example 159 Aminophenethyl Ester 801: Triphenylphosphine (55 mg, 0.1 mg)
21 mmol) in 800 (60 m2) in THF (2 mL) and water (252 μL).
g, 0.14 mmol). The reaction was then brought to 50 ° C.
For 10 hours, cooled and evaporated. The residue was purified by silica gel chromatography (1 / 1-ethyl acetate / methanol) to give 53 m
g oil was obtained, which was dissolved in 0.1 N HCl (1 mL) and evaporated. The residue was dissolved in water and passed through a column of _C18 reverse phase silica gel to give, after lyophilization, 801 (41 mg, 69%) as a white solid.

Example 160 Azidobutyl ester 802: 2 in 2-1 / CH ₂ Cl ₂ / THF (3 mL)
60 (60 mg, 0.19 mmol), n-butanol (87 μL, 0.95 m
mol) and DMAP (4 mg) at room temperature was added diisopropylcarbodiimide (33 μL, 0.21 mmol). After stirring for 2 hours, the solvent was evaporated and the residue was chromatographed on silica gel (1 / 1-hexane / ethyl acetate) to give 802 (48 mg, 68%) as an oil.

Example 161 Aminobutyl Ester 803: Triphenylphosphine (51 mg, 0.19
mmol) in THF (1.5 mL) and water (234 μL).
g, 0.13 mmol). The reaction was then brought to 50 ° C.
For 10 hours, cooled and evaporated. This residue was dissolved in ethyl acetate, dried (Na ₂ SO ₄ ), filtered and evaporated. Purification of the residue by silica gel chromatography (1 / 1-ethyl acetate / methanol) yielded 38 mg.
This was dissolved in 0.1 N HCl (2 mL) and evaporated. The residue was dissolved in water and passed through a column of _C18 reverse phase silica gel to give, after lyophilization, 803 (23 mg, 47%) as a white solid.

Example 162 1-Phenyl-3-pentanol 804: At 0 ° C., ether (325 m
L) in a solution of ethyl magnesium bromide (75 mmol) in ether (5
Hydrocinnamaldehyde (6.71 g, 50 mmol) in 0 mL) was added. The solution was stirred for 1 hour and warmed to room temperature. This reaction solution was added to ice water (
1000 mL) and the mixture was acidified to pH = 3 with concentrated HCl. The layers were separated and the aqueous phase was extracted with ether. The combined organic extracts were washed with sat. NaHCO ₃ , brine and dried (MgSO ₄ ), filtered and evaporated. The crude product was distilled under high vacuum (bp 90-93 ° C) to give 804 (5.3 g, 64%) as a colorless oil.

Example 163 1,5-Diphenyl-3-pentanol 805: At 0 ° C., ether (100
phenethylmagnesium bromide (25 mL, 0.9 M in THF)
) To a solution of hydrocinnamaldehyde (3.0 g, 30 mL) in ether (30 mL).
22.5 mmol) was added. The solution was stirred for 5 minutes, warmed to room temperature and stirred for 1 hour. The reaction solution is poured into ice water (200 mL) and the mixture is concentrated
Acidified to pH = 3 with Cl. The layers were separated and the aqueous phase was extracted with ether. The combined organic extracts were washed with saturated NaHCO ₃ , brine, dried (MgSO ₄ ), filtered and evaporated. Chromatography on silica gel (4 / 1-hexane / ethyl acetate) gave a pale yellow oil (3.74 g).
And cooled to solidify. A white needle-like 805 was obtained by recrystallization from hexane.
(1.35 g, 25%).

Example 164 1,3-diphenyl-2-propanol 806: Ethanol (10
1,3-diphenylacetone (17.08 g, 81.2 mmol) in 0 mL)
To the solution was added NaBH ₄ (3.07g, 81.2mmol), and the mixture was stirred for 2 hours. The reaction was acidified with 1 N HCl to pH = 3,
Then the ethanol was evaporated. The reaction was diluted with water and the aqueous phase was extracted with several portions of ethyl acetate. The combined organic extracts were washed with saturated NaHCO ₃ , brine, dried (MgSO ₄ ), filtered and evaporated to give 806 (17 g, 99%) as a pale yellow oil.

Example 165 Ethers 807: 183 (200 mg, 0.46 mmol) and 804 (1
mL) of the solution_Three・ OEt_Two(85 μL, 0.69 mmol) was added.
The solution was then heated at 75-80 ° C for 1.25 hours. After cooling to room temperature,
The reaction was diluted with pyridine (5 mL), cooled to 0 ° C., and acetic anhydride (1.
25 mL) and DMAP (50 mg). Bring the reaction to 0 ° C
And stirred for 15 minutes, then at room temperature for 14 hours. Evaporate this solvent
And the residue is partitioned between ethyl acetate and 1N HCl and the residue is extracted.
The phases were washed again with 1N HCl. The combined aqueous cleaning solution (wa
sh) with ethyl acetate and combine the combined organic extracts with saturated NaHCO 3 _Three , Washed with brine, dried (MgSO 4)_Four), Filtered and evaporated
did. The residue is chromatographed on silica gel (1 / 1-hexane / ethyl acetate).
To give 807 (116 mg, 63%) as a mixture of diastereomers.
It was chromatographed again (2 / 1-hexane / ethyl acetate). as soon as you can
The fractions containing the eluting diastereomers were combined and 807a (4
4 mg), which was recrystallized (hexane / ethyl acetate): mp131-1
33 ° C. The slower eluting diastereomer was obtained as a solid which was recrystallized.
(Hexane / ethyl acetate) to give 807b (41 mg) as needles: mp1
11-112 ° C.

Example 166 Azide esters 807a and 807b were treated with triphenylphosphine in a manner similar to that described in Example 93 to give amino esters 808a and 808b, Treatment with aqueous potassium hydroxide as described in 94 gave amino acids 809a and 809b.

Example 167 Ether 810: 183 (200 mg, 0.46 mmol) and 805 (7
(50 mg, 3.1 mmol, mp 43-45 ° C.) formed by mild heating. To this solution was added BF ₃ OEt ₂ (85 μL, 0.69 mmol) and the solution was heated at 70-75 ° C. for 1.5 hours. After cooling to room temperature, the reaction was diluted with pyridine (2 mL), cooled to 0 ° C., and acetic anhydride (660 μL, 7.0
mmol) and the catalyst DMAP. The reaction was stirred at 0 ° C. for several minutes, then at room temperature for 16 hours. The solvent was evaporated, and the residue was partitioned between ethyl acetate and 1N HCl, and the organic phase was washed again with 1N HCl. The combined aqueous washes were extracted with ethyl acetate and the combined organic extracts were washed with saturated NaHCO ₃ , brine, dried (MgSO ₄ ), filtered and evaporated. The residue was chromatographed on silica gel (1 / 1-hexane / ethyl acetate) to give a solid residue, which was recrystallized (hexane / ethyl acetate) to give 810 (63 mg,
28%): mp 139-140 ° C.

Example 168 The azide ester 810 was treated with triphenylphosphine in a similar manner as described in Example 93 to give the amino ester 811. This is referred to as Example 94
Treatment with aqueous potassium hydroxide as described in provides amino acid 812.

Example 169 Ethers 813: 183 (100 mg, 0.23 mmol) and 806 (1
To a solution of mL), dried added _{BF 3 · OEt 2 (42μL,} 0.35mmol), and was heated 1.25 hours at the solution 70-75 ° C.. After cooling the reaction to room temperature, the reaction was diluted with pyridine (5 mL), cooled to 0 ° C., and
Treated with acetic anhydride (680 μL, 7.2 mmol) and catalytic DMAP. The reaction was stirred at 0 ° C. for several minutes, then at room temperature for 15 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate and 1N HCl, and the organic phase was washed again with 1N HCl. The combined aqueous washes were extracted with ethyl acetate, and the combined organic extracts were washed with saturated NaHSO ₃ , brine, dried (MgSO ₄ ), filtered and evaporated. The residue was chromatographed (1 / 1-hexane / ethyl acetate) to give 813 (
(57 mg, 55%) as a pale yellow solid: mp 132-133 ° C (needle from hexane / ethyl acetate).

Example 170 The azide ester 813 was treated with triphenylphosphine in a manner similar to that described in Example 93 to give the amino ester 817, which was treated with aqueous water as described in Example 94. Treatment with potassium oxide provided amino acid 815.

Example 171 N-Boc aziridine 817: 816 (700 m) in CH ₂ Cl ₂ (10 mL)
g, 3.1 mmol, prepared from quinic acid in the same manner as described for the methyl ester derivative 170) in CH ₂ Cl ₂ (5 mL).
t-butyl carbonate (1.0 g, 4.6 mmol) and catalytic DMAP (
10 mol%). After stirring at room temperature for 45 minutes, the solvent was evaporated and the residue was purified directly by silica gel chromatography (3 / 1-hexane / ethyl acetate) to give 817 (880 mg, 87%) as an oil.

Example 172 Alcohol 818: 817 (826 mg, 2.52 m in DMF (20 mL)
mol), ammonium formate (1.59 g, 2.52 mmol) was added and the mixture was heated at 130 ° C. for 1 hour. Ammonium formate (1.5
(9 g, 25.2 mmol) after the second addition, the reaction was heated for 1.5 hours,
And it was evaporated. The residue was placed between ethyl acetate and saturated NaHCO _3. The organic phase was washed with brine, dried (MgSO _4), filtered and d Baporeto. The residue was purified by silica gel chromatography (1 / 2-hexane / ethyl acetate) to give 818 (556 mg, 64%) as a pale yellow solid.

Example 173 Acetate 819: 818 (500 mg, 1.45) in pyridine (10 mL).
Dmmol (20 mg, 0.16 mmol) and acetic anhydride (216 μL, 2.3 mmol). The solution was stirred for 1 hour at room temperature,
And it was evaporated. This residue was subjected to silica gel chromatography (1 / 1-
Purification by hexane / ethyl acetate) provided 819 (557 mg, 94%) as a solid.

Example 174 N-tritylaziridine 820: 819 (459 mg) in 1.24 M HCl
, 1.18 mmol) in ethyl acetate (20 mL) at room temperature for 2.5 hours
Stirred. The solvent was evaporated to give a white solid, which was left under high vacuum overnight.
Was. CH at 0 ° C_TwoCl_TwoTrityl to a solution of the solid (315 mg) in (10 mL)
Chloride (346 mg, 1.24 mmol) and Et_ThreeN (354 μL, 2.54 mmol) was added. The solution was stirred for 1.75 hours, at which time Et. _Three N (354 μL, 2.54 mmol) and methanesulfonyl chloride (105 μL, 1.36 mmol) were added. The reaction mixture is stirred at 0 ° C. for 1.5 hours.
Stir and warm to room temperature and stir for 5 hours. Evaporate the solvent, and
The residue was partitioned between ether and water. Wash the organic phase with water and combine
The washed aqueous solution was extracted with ether. Wash the combined organic extracts with brine
And dried (MgSO 4)_Four), Filtered and evaporated. Silica gel chromatography (CH_TwoCl_TwoPurification of the residue according to) gives 8 as a white foam.
20 (440 mg, 83%) was obtained.

Example 175 Pentyl ether 821: 820 (100 m) in 3-pentanol (2 mL)
g, 0.21 mmol) in a solution of BF ₃ .OEt ₂ (39 μL, 0.32 mmol).
l) was added and the solution was heated at 75-80 ° C for 1.5 hours. After evaporation of the solvent, the residue is dissolved in pyridine (2 mL) and acetic anhydride (
100 μL, 1.05 mmol) and DMAP. The reaction was stirred at room temperature for 14 hours, evaporated, and the residue was washed with ethyl acetate and 1N HC1.
and 1 between. The aqueous phase was extracted with ethyl acetate, the combined organic extracts were saturated NaHSO _3, brine, dried (MgSO _4), filtered, and evaporated. The residue was chromatographed on silica gel (1 / 1-ethyl acetate / CH ₂ Cl ₂ ) to give 821 (46 mg, 62%) as a solid.

Example 176 Hydroxy Acid 822: 821 (42 mg, 0.12 mm in THF (2 mL)
ol), 1N KOH (260 μL, 0.27 mmol) was added and the mixture was stirred at room temperature for 5.5 hours. This solution was added to Amberlite I
Acidify with R120 ion exchange resin (pH 3), filter the resin and
Washed with F. The solvent was evaporated and a residue was obtained. This was dissolved in water and chromatographed C ₈ reversed-phase silica gel eluting with water. The water was evaporated and the residue was evaporated from methanol, 822 (29 mg,
85%) as a solid.

Example 177 Methyl ether 823: 816 (200 mg, 0.1 mL) in methanol (5 mL).
(88 mmol) was added BF ₃ OEt ₂ (120 μL, 0.97 mmol). The solution is refluxed for 2 hours, evaporated and the residue is treated with pyridine (
4 mL) and treated with acetic anhydride (415 μL, 4.4 mmol). After stirring at room temperature for 1 hour, the solvent was evaporated and the residue was partitioned between ethyl acetate and 5% citric acid. The organic phase was washed with saturated NaHCO ₃ , brine, dried (MgSO ₄ ), filtered and evaporated. The residue was purified by silica gel Le chromatography (10% methanol in CH ₂ Cl _2), as a white solid 823 (76mg, 29%).

Example 178 Hydroxy Acid 824: 823 (33 mg, 0.11 mm in 2.5 M HCl)
ol) was stirred in ethyl acetate (2 mL) at room temperature for 2.5 hours and evaporated. Dissolve the residue in THF (2 mL) and add 1N K
Treated with OH (154 μL, 0.16 mmol) and water (300 μL). The reaction was stirred at room temperature for 6 hours and acidified with Dowex 50WX8 ion exchange resin. The resin was filtered and the filtrate was evaporated to give a residue. This was dissolved in water and chromatographed on _C18 reverse phase silica gel. After lyophilization, 824 (24 mg, 95%) was isolated as a white solid.

Example 179 Methyl Ester 825: 820 (80 mg, 0.1 in methanol (2 mL)
7 mmol) was added to BF ₃ OEt ₂ (32 μL, 0.26 mmol). The solution is refluxed for 2 hours, evaporated and the residue is treated with pyridine (
2 mL). Acetic anhydride (80 μL, 0.85 mmol) and catalytic DMAP were added to the solution. Stir for 14 h, evaporate the solvent, and chromatograph the residue on silica gel (ethyl acetate), 825 (46
mg, 90%) as a white solid.

Example 180 Hydroxy Acid 826: 825 (46 mg, 0.15 mm) in THF (2 mL)
ol), 1N KOH (433 μL, 0.45 mmol) was added and the mixture was stirred at room temperature for 5 hours. The solution was acidified with Dowex 50WX8 ion exchange resin, and the resin was filtered and washed with methanol. The solvent was evaporated to give a residue. This was dissolved in water and passed through a column of _C18 reverse phase silica eluted with water. The solvent was evaporated to give 826 (33 mg, 96%) as a white solid.

Example 181 Methyl ether 827: 816 (612 mg, 0% in methanol (25 mL)
. BF ₃ .OEt ₂ (370 μL, 3.0 mmol) was added to the solution (27 mg). The solution was refluxed for 2 hours, evaporated and the residue was taken up in CH ₂ Cl ₂ (5
mL) and di-tert-butyl dicarbonate therein (880 mg
, 4.1 mmol) and Et ₃ N (570 μL, 4.1 mmol). After stirring for 5 hours at room temperature, the solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water, brine, dried (MgSO _4), filtered filtration, and evaporated. The residue is subjected to silica gel chromatography (2
/ 1-hexane / ethyl acetate) to give 827 (630 mg, 65%) as an oil.

Example 182 N-Tritylaziridine 828: 827 in 2.5 M HCl (574 mg,
(1.6 mmol) was stirred in ethyl acetate (20 mL) at room temperature for 5 hours. The solvent was evaporated to give a white solid (400mg). At 0 ° C., to a suspension of the solid in CH ₂ Cl ₂ (5 mL) was added trityl chloride (490 mg, 1.6 mmol) and Et ₃ N (278 μL, 3.6 mmol). The solution was stirred for 2 hours, at which time Et ₃ N (278 μL, 3.6 mmol) and methanesulfonyl chloride (136 μL, 1.76 mmol) were added. The reaction mixture was stirred at 0 ° C. for 1 hour and warmed to room temperature and stirred for 4 hours. The solvent was evaporated and the residue was partitioned between ether and water. The organic phase was washed with water and the combined aqueous washes were extracted with ether. The combined organic extracts were washed with brine, dried (MgSO _4), filtered and Ebapore bets. Purification of the residue by silica gel chromatography (CH ₂ Cl _2), as a white foam 828 (170mg, 25%).

Example 183 Bis-methyl ether 829: 828 in methanol (2 mL) (60 mg,
0.14 mmol) in a solution of BF ₃ .OEt ₂ (26 μL, 0.21 mmol)
Was added. The solution was refluxed for 1 hour, evaporated and the residue was dissolved in pyridine (1 mL) and treated with acetic anhydride (66 μL, 0.70 mmol). After stirring at room temperature for 18 hours, the solvent was evaporated and the residue was partitioned between ethyl acetate and 1N HCl. The organic phase was washed with sat. NaHCO ₃ , brine and dried (MgSO ₄ ), filtered and evaporated. The residue was purified by silica dim chromatography (10% methanol in CH ₂ Cl _2), as a white solid 829 (13mg, 34%).

Example 184 Carboxylic Acid 830: 829 (13 mg, 0.048 mm) in THF (1 mL)
ol), 1N KOH (69 μL, 0.072 mmol) was added and the mixture was stirred at room temperature for 48 hours. The solution was acidified with Dowex 50WX8 ion exchange resin and the resin was filtered and washed with methanol. The solvent was evaporated and a residue was obtained, which was dissolved in water, passed through a column of _C18 reverse phase silica and lyophilized to give 830 (8 m
g, 68%).

Example 185 Lactone 900: Quinic acid (20 kg, 104 mo in acetone (80 kg)
1, [α] _D −43.7 ° C. (c = 1.12, water); Merck Index, 11th edition, 8071: [α] _D −42 to −44 ° C. (water)), 2,2-dimethoxypropane (38.0 kg, 365 mmol) and p-toluenesulfonic acid monohydrate (0.200 kg, 1.05 mol) were heated under reflux for 2 hours. The reaction was quenched by the addition of 21% sodium ethoxide in ethanol (0.340 kg, 1.05 mmol) and most of the solvent was distilled under vacuum. The residue was partitioned between ethyl acetate (108kg) and water (30kg). The aqueous layer was back-extracted with ethyl acetate (13 kg) and the combined organic layers were washed with 5% aqueous sodium bicarbonate (14 kg). Most of the ethyl acetate was distilled under vacuum to give a pale yellow solid residue 900 which was used directly in the next step.

Example 186 Hydroxy Ester 901: Crude Lactone 90 in Absolute Ethanol (70 kg)
0 (104 mol (-)-quinic acid) in ethanol (0.340 kg, 1
. 05 mol) with 20% sodium ethoxide. After 2 hours at room temperature,
Acetic acid (0.072 kg, 1.2 mol) was added and the solvent was distilled under vacuum. Ethyl acetate (36 kg) was added and distillation continued to near dryness. A yellow-brown solid residue consisting of an approximately 5: 1 mixture of 901: 900 was dissolved in ethyl acetate (9 kg) at reflux and hexane (9 kg) was added. Upon cooling, a white crystalline solid formed, which was isolated by filtration and a 901: 900 approximately 6.5: 1 mixture (19.0 kg
, 70% yield).

Example 187 Mesyl ester 902: about 6.5: 1 mixture of hydroxy ester 901 and lactone 900 in dichloromethane (77 kg) (18.7 kg, about 72 mol)
Is cooled to 0-10 ° C and methanesulfonyl chloride (8.23 k
g, 71.8 mol) followed by triethylamine (10.1 kg, 1
00 mol) was added slowly. An additional portion of methanesulfonyl chloride (0
. 84 kg, 7.3 mmol) were added. After 1 hour, water (10 kg) and 3
% Hydrochloric acid (11 kg) was added. The layers were separated and the organic layer was washed with water (9 kg).
And then distilled under vacuum to give mesyl ester 902 and mesyl lactone 9
A semi-solid residue consisting of an approximately 6.5: 1 mixture with 03 was obtained. This residue was dissolved in ethyl acetate (11 kg) and cooled to -10 ° to -20 ° C for 2 hours. Mesyl lactone 903 is crystallized and separated by filtration, cold ethyl acetate (ethyl
acetae) (11 kg). The filtrate was concentrated to give the mesyl ester 902 as an orange resin (20.5 kg, 84.3% yield).

Example 188 Mesyl acetonide 904: Mesyl ester 9 in dichloromethane (63 kg)
02 (10.3 kg, 30.4 mol) and pyridine (10.4 kg, 183
mol) was cooled to −20 ° to −30 ° C. and treated with several portions of sulfuryl chloride (6.22 kg, 46 mol). After the exothermic reaction subsided, the resulting slurry was quenched with ethanol (2.4 kg), warmed to 0 ° C., and successively 16% sulfuric acid (35 kg), water (15 kg) and 5% aqueous sodium bicarbonate ( 1 kg). About 904: 905: 906 4:
The organic layer containing the 1: 1 mixture was concentrated under vacuum and ethyl acetate (14 kg) was added. Allyl mesylate 905 was treated with pyrrolidine (2.2) at ambient temperature for 5 hours.
7 kg, 31.9 mol) and treatment selectively with tetrakis (triphenylphosphine) palladium (0) (0.0704 kg, 0.061 mol), followed by 16% sulfuric acid (48 kg). Washed. The organic layer was filtered through a pad of silica gel (11 kg) and ethyl acetate (4
2 kg). The filtrate was concentrated under vacuum to give a dark orange oil consisting of an approximately 4: 1 mixture of 904: 906. This residue was refluxed with ethyl acetate (5.3 kg).
) And hexane (5.3 kg) was added. After cooling, mesylacetonide 9
04 was crystallized, separated by filtration, and 1 in hexane (2.1 kg).
Washed with 4% ethyl acetate. After drying under vacuum, 904 was obtained as pale yellow needles (4.2
8 kg, 43.4% yield), mp 102-3 ° C.

(Example 189) Pentyl ketal 907: acetonide 904 (8.9 kg, 27.8 mol)
, 3-pentanone (24 kg, 279 mol) and 70% perchloric acid (0.056 kg)
, 0.39 mol) was stirred for 18 hours. Volatiles were distilled in vacuo at ambient temperature and fresh 3-pentanone (30 kg, 348 mol) was added slowly as the distillation proceeded. The reaction mixture was filtered and toluene (18 k
g) was added and the resulting solution was washed successively with 6% aqueous sodium bicarbonate (19 kg), water (18 kg) and brine (24 kg). The organic layer was concentrated under vacuum and as the distillation proceeded, toluene (28 kg)
Was slowly added. Upon further distillation, the orange oil residue was converted to pentyl ketal 9
07 (9.7 kg, 100 yield) and toluene (about 2 kg).

Example 190 Pentyl Ether 908: Ketal 907 (90 kg) in dichloromethane (90 kg)
(8.9 kg, 25 mol) was cooled to −30 to −20 ° C. and treated with borane-methyl sulfide complex (2.1 kg, 27.5 mol) and trimethylsilyl trifluoromethanesulfonate (7.2 kg, 32.5 mol). did. 1
After hours, a 10% aqueous sodium bicarbonate solution (40 kg) was slowly added.
The mixture was warmed to ambient temperature and stirred for 12 hours. The organic layer was filtered and concentrated in vacuo to give an approximately 8: 1 mixture of 908: 909, a gray waxy solid (7
. 8 kg, 90% yield).

Example 191 Epoxide 910: Pentyl ether 9 of the isomer in ethanol (26 kg)
08: 909 (7.8 kg, 22.3 mmol) in water (22
kg) of potassium bicarbonate (3.52 kg, 35 mol). 5
After heating at 5-65 ° C for 2 hours, the solution was cooled and hexane (31k
g, then 22 kg). Unreacted 909 remained in the aqueous ethanol layer. The combined hexane extracts were filtered and concentrated under vacuum to give epoxide 910 as a flocculent white crystalline solid (3.8 kg, 60% yield). Melting point 5
4-6 ° C.

Example 192 Hydroxyazide 911: Water (0.265 L) and Ethanol (1.065)
L) epoxide 910 (548 g, 2.0 mol), sodium azide (1
56 g, 2.4 mol), and ammonium chloride (128.4 g, 2.4 mo)
The mixture of 1) was heated at 70 ° -75 ° C. for 8 hours. Aqueous sodium bicarbonate solution (0.42 L of a 8% solution) was added and the ethanol was distilled under vacuum.
The aqueous residue was extracted with ethyl acetate (1L) and the extract was washed with water (0.5L). The water wash was back-extracted with ethyl acetate (0.5 L). The combined organic extracts were washed with brine (0.5 L), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the isomeric hydroxyazide 911: 912 about 10: 912:
One mixture (608 g, 102% yield) was obtained as a dark brown oil.

Example 193 Aziridine 913: Hydroxyazide 911: 912 (608 g, 2.0 mo
An approximately 10: 1 mixture of l) was azeotroped under vacuum three times from anhydrous acetonitrile (3 x 0.3 L) and then dissolved in anhydrous acetonitrile (1 L). A solution of anhydrous triphenylphosphine (483 g, 1.84 mol) in anhydrous tetrahydrofuran (0.1 L) and anhydrous acetonitrile (0.92 L) was added dropwise over 2 hours. The mixture is heated at reflux for 6 hours and then concentrated in vacuo to give aziridine 91
3. A golden paste consisting of triphenylphosphine oxide and a trace amount of triphenylphosphine was obtained. This paste was triturated with diethyl ether (0.35 L). Most of the insoluble triphenylphosphine oxide was removed by filtration and washed with diethyl ether (1.5L). The filtrate was concentrated under vacuum to give a dark brown oil, which was dissolved in 20% aqueous methanol and extracted three times with hexane (3 × 1 L) to remove triphenylphosphine. Back-extract the hexane extract with 20% aqueous methanol (0.5 L),
Then the combined aqueous methanol layers were concentrated under vacuum. The residue was azeotroped twice from anhydrous acetonitrile (2 × 0.5 L) under vacuum to give aziridine (azir).
Idene) 913 (490 g, 96.8% yield) and triphenylphosphine oxide (約 108 g) were obtained, which was used directly in the next step.

Example 194 Acetamide azide 915: Aziridine 913 (490 g, 1.93 mol) and triphenylphosphine oxide (about 108 g), sodium azide (151 g, 2.33 mol) in dimethylformamide (1.3 L). And a mixture of ammonium chloride (125 g, 2.33 mol) was heated at 80 ° -85 ° C. for 5 hours. Sodium bicarbonate (32.8 g, 0.39 mol) and water (0
. 66 L) was added. Aminoazide 914 was extracted six times with hexane (6 ×
1 L) from the reaction mixture. The combined hexane extracts were concentrated under vacuum to a total volume of about 4.5 L and dichloromethane (1.04 L) was added.
Aqueous sodium bicarbonate (4.2 L of a 8% solution, 3.88 mol) was added, followed by acetic anhydride (198 g, 1.94 mol). After stirring for 1 hour at ambient temperature, the aqueous layer was discarded. The organic phase was concentrated under vacuum to a total weight of 1.74 kg and dissolved at reflux with ethyl acetate (0.209 L). After cooling, acetamido azide 915 crystallized and was isolated by filtration. Cold 1 in hexane (1 L)
After washing with 5% ethyl acetate and drying under vacuum at ambient temperature, pure 915 was obtained as off-white crystals (361 g, 55% yield), mp126-1.
32 ° C.

Example 195 Acetamide amine 916: Azide 91 in absolute ethanol (3.25 L)
5 (549 g, 1.62 mol) and a mixture of Lindlar catalyst (50 g)
Stir for 8 h, during which hydrogen (1 atm.) Was bubbled through the mixture. Filtration through celite and concentration of the filtrate under vacuum gave 916 as a foam which solidified on standing (496 g, 98% yield).

Example 196 Phosphate Salt of 916: A solution of acetamidoamine 916 (5.02 g, 16.1 mmol) in acetone (75 mL) at reflux was added to absolute ethanol (
25% phosphoric acid (1.85 g, 16.1 mmol) in 25 mL). Crystallization started immediately, and after cooling to 0 ° C. for 12 hours, the precipitate was collected by filtration to obtain 916 · H ₃ PO ₄ as a colorless long needle (4.94 g, 75% yield; [α]) _D- 39.9 ° (c = 1, water)), mp 203-4 ° C.

Example 197 Hydrochloride of 916: Acetamidoamine 916 (9 mL) in absolute ethanol (9 mL)
A solution of 2.8 g (8.96 mmol) in ethanol (8.6 mL, 17.9 mm)
ol) with 2.08 M hydrochloric acid in water. Evaporate most of the ethanol under vacuum and remove the oil residue to ethyl acetate (20 mL) until a solid formed.
With stirring. Hexane (20 mL) was added into the slowly stirred mixture. After stirring at ambient temperature for 1 hour, the solid was collected by filtration, washed with diethyl ether and dried under vacuum. This gave a gray solid (2.54 g, 81% yield;
α] _D -43 ° (c = 0.4, water)) to give 916 · HCl, mp 206 ° C.

Example 198 Aziridine 712: Azido mesylate 7 in anhydrous THF (10 mL) at room temperature
To a solution of 11 (1.27 g, 3.15 mmol) was added triphenylphosphine (1.0 g, 3.8 mmol) in four portions. The reaction was stirred at room temperature for 3.5 hours, then cooled to 0 ° C and triethylamine (0.53 ml, 3.
8 mmol) and water (0.5 mL) were added. The resulting mixture was stirred at room temperature for 3 hours, then at 45 ° C. for another 3 hours. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO _4), filtered, and evaporated. The residue is chromatographed and treated with ethyl acetate / hexane (to remove most of the triphenylphosphine oxide) to give the desired aziridine 712 (0.56 g, 65%, having about 15% triphenylphosphine oxide). ) Got.

Example 199 N-acetyl azide 713: Aziridine 712 (5.0 mL) in DMF (5.0 mL)
0.56 g, 17 mmol), sodium azide (0.65 g, 10.0 mmol)
l) and a mixture of ammonium chloride (0.4 g, 7.5 mmol) was stirred at 65 ° C for 18 hours. The reaction mixture was diluted with hexane (20 ml) and filtered through a short plug of silica gel (eluting with ethyl acetate / hexane). The filtrate was evaporated. The residue was dissolved in pyridine (5.0 mL) and acetic anhydride (1.0 mL) was added. The resulting mixture was stirred at room temperature for 14 hours, then evaporated. The residue was dissolved in ethyl acetate, saturated NaHCO _3, and washed with brine. The organic phase was dried (MgSO ₄ ), filtered and evaporated. The residue was chromatographed and crystallized from ethyl acetate / hexane to give N-acetyl azide 713 (20 mg, 3.3%) as a solid.

[0839]

[Equation 105] All references and patent citations mentioned above are expressly incorporated herein by reference in their entirety. In particular, the citations or pages of the above-cited studies are specifically incorporated by reference. The present invention has been described in detail to enable one to make and use the subject matter of the following claims. It will be apparent that certain modifications of the methods and compositions of the above claims may be made within the scope and spirit of the invention.

[Brief description of the drawings]

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows a known anti-influenza compound, GG167 (4-guanidino-
2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid) i. p
. Arterial oxygen saturation (S) of influenza-A infected mice treated at different doses
Indicate aO ₂ ) levels: 50, 10, ₂ , and 0.5 mpk (mg / kg / day) of test compound and saline control are represented by squares, filled circles, triangles, diamonds, and open circles, respectively. ^* P <0.05, ^** P <0.01 in all figures as compared to the saline control.

FIG. 2 shows i.v. of compound 203 of the present invention. p. 5 shows arterial oxygen saturation (SaO ₂ ) levels in influenza-A infected mice treated at varying doses: 50, 10, 2, and 0.5 mpk (mg / kg / day) of test compound and saline control. , Each represented by a square, a black circle, a triangle, a diamond, and a white circle. ^* P <0.05, ^** P <0.01 compared to saline control in all figures.

FIG. 3 shows p.b. of ribavirin (triangles), compound 203 (squares), and GG167 (solid circles). o. Compare SaO ₂ levels achieved in influenza A infected mice treated with dose; saline controls are open circles: 150 mpk of Compound 203 and GG167, 100 mpk of Ribavirin, respectively.

FIG. 4 shows p.b. of ribavirin (triangles), compound 203 (squares), and GG167 (solid circles). o. The SaO ₂ levels achieved in influenza A infected mice treated with the doses are compared; the saline controls are open circles: 50 mpk of compound 203 and GG167, 32 mpk of ribavirin, respectively.

FIG. 5 shows p.b. of ribavirin (triangles), compound 203 (squares), and GG167 (solid circles). o. The SaO ₂ levels achieved in influenza A infected mice treated with the doses are compared; the saline controls are open circles: 10 mpk compound 203 and GG167, 10 mpk ribavirin, respectively.

FIG. 6 shows the low p.O. of compounds 262 (circles) and 260 (solid squares) and GG167 (triangles). o. Shows SaO ₂ levels in influenza A infected mice treated with dose; saline controls are open circles and uninfected controls are open squares: each test compound in mpk.

FIG. 7 shows the low p.O. of compounds 262 (circles) and 260 (solid squares) and GG167 (triangles). o. Shows SaO ₂ levels in influenza A infected mice treated with dose; saline controls are open circles and uninfected controls are open squares: 1 mpk of each test compound.

FIG. 8 shows the low p.o. of compounds 262 (circles) and 260 (solid squares) and GG167 (triangles). o. Shows SaO ₂ levels in influenza A infected mice treated with dose; saline controls are open circles and uninfected controls are open squares: 0.1 mpk of each test compound.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme court ゛ (Reference) // C07C 233/52 C07C 233/52 247/14 247/14 279/16 279/16 (31) Priority Claim No. 08 / 938,644 (32) Priority Date September 26, 1997 (September 26, 1997) (33) Priority Claimed States United States (US) (81) Designated States EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD) , RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, GH, GM, HR, HU , ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW (72) Inventor Dar, Terrence C. United States of America 94087, Sunnyvale, Kennewick Drive 1646 (72) Inventors Hitchcock, Michael Jay. Em. United States California 94402, San Mateo, Lakewood Circle 50 (72) Inventor Kim, Chong Yu. United States California 94070, San Carlos, Elizabeth Street 1750 (72) Inventor Leu, William United States California 94402, San Mateo, Guildford Avenue 717 (72) Inventor Riu, Hong Tao United States of America 94404, Foster City, Merlin Ave 1354 (72) Inventor Mills, Roger Gee. United States of America 94025, Menlo Park, Tioga Drive 2260 (72) Inventor Williams, Matthew A. United States California 94404, Foster City, Foster City Boulevard 1077, Apartment Number Sea F-term (reference) 4C20 6 AA01 AA03 FA35 MA01 MA04 NA14 ZB33 ZC20 4H006 AA01 AA03 AB29 BJ20 BM10 BM71 BN10 BN20 BP20 BP40 BS20 BT14 BT22 BU32 BU42 BV24

Claims (10)

[Claims] 1. Compounds of the following formula (I) or (II):
Salts, solvates, resolved enantiomers, and purified diastereomers
A composition comprising:Where A₁Is -C (J₁A) =, -N = or -N (O) =;_TwoIs -C (J₁)_Two-, -N (J₁)-, -N (O) (J₁)-, -S-, -S (O)-, -S (O)_Two-Or -O-; E₁Is-(CR₁R₁)_m1W₁G₁Is N_Three, -CN, -OH, -OR_6a, -NO_Two, Or-(CR₁R₁)_m1 W_TwoAnd T₁Is -NR₁W_Three, H, -R_Three, -R_Five, A heterocycle, or U₁Or
G₁Forms a group having the following structure together with U₁Is H, -R_ThreeOr -X₁W₆And J₁And J_1aIs independently R₁, Br, Cl, F, I, CN, NO_TwoOr N_Three And J_TwoAnd J_2aIs independently H or R₁R₁Is independently H or alkyl having 1 to 12 carbon atoms;_TwoIs independently R_ThreeOr R_FourWhere each R_FourIs independently 0 to 3
R_ThreeSubstituted with a group; R_ThreeIs independentlyR_FourIs independently alkyl having 1 to 12 carbon atoms, alkenyl having 2 to 12 carbon atoms, or alkyl having 2 to 12 carbon atoms.
Nyl; R_FiveIs independently R_FourWhere each R_FourIs 0 to 3 R_ThreeSubstituted with a group; R_5aIs independently an alkylene having 1 to 12 carbon atoms, 2 to 12
Alkenylene having 2 carbon atoms, or alkenylene having 2 to 12 carbon atoms
Quinylene; these alkylene, alkenylene, or alkynylene
Any one of the 0 to 3 R_ThreeSubstituted with a group; R_6aIs independently H, or an ether-forming group or an ester-forming group;_6bIs independently H, an amino protecting group, or a residue of a carboxyl-containing compound.
Yes; R_6cIs independently H or the residue of an amino-containing compound; W₁Is a group containing an acidic hydrogen, a protected acidic group, or a group containing an acidic hydrogen._{6 c} An amide; W_TwoIs a basic heteroatom or a protected basic heteroatom, or a basic heteroatom R_6bA group containing an amide; W_ThreeIs W_FourOr W_FiveAnd W_FourIs R_FiveOr -C (O) R_Five, -C (O) W_Five, -SO_TwoR_FiveOr -SO _Two W_FiveAnd W_FiveIs a carbocyclic or heterocyclic ring, wherein W_FiveIndependently represent 0 to 3 R_Two Substituted with a group; W₆Is -R_Five, -W_Five, -R_5aW_Five, -C (O) OR_6a, -C (O) R_6c, -C
(O) N (R_6b)_Two, -C (NR_6b) (N (R_6b)_Two), -C (NR_6b) (N (H
) (R_6b)), -C (N (H) (N (R_6b)_Two), -C (S) N (R_6b)_Two,Also
Is -C (O) R_TwoAnd X₁Is a bond, -O-, -N (H)-, -N (W₆)-, -N (OH)-, -N
(OW₆)-, -N (NH_Two)-, -N (N (H) (W₆))-, -N (N (W₆) _Two )-, -N (H) N (W₆)-, -S-, -SO-, or -SO_TwoAnd each m1 is independently an integer from 0 to 2, with the proviso that the following compounds and their pharmaceutically acceptable salts and solvates are
Except where: (a) A₁Is -CH = or -N =, and A_TwoIs -CH_Two(B) E₁Is COOH, P (O) (OH)_Two, SOOH, SO_ThreeH, or tetrazole; (c) G₁Is CN, N (H) R₂₀, N_Three, SR₂₀, OR₂₀, Guanidino, -N
(H) CN, embedded image(D) T₁Is -NHR₂₀(E) R₂₀Is H; an acyl group having 1 to 4 carbon atoms; 1 to 6 carbon atoms
Linear or cyclic alkyl groups having atoms or halogen-substituted analogs thereof;
Or an unsubstituted aryl group, halogen, OH group, NO_TwoGroup, NH_TwoBase
Is an aryl substituted by a COOH group; (f) J₁Is H and J_1aIs H, F, Cl, Br or CN; (g) J_TwoIs H and J_2aIs H, CN or N_Three(H) U₁Is CH_TwoYR_20a, CHYR_20aCH_TwoYR_20aOr CHYR_20aC HYR_20aCH_TwoYR_20a(I) R_20aIs H or acyl having 1 to 4 carbon atoms; (j) Y is O, S, H or NH; (k) 0 to 2 YR_20aIs H, and (l) U₁Consecutive Y moieties in the group are the same or different and when Y is H, R_20aIs a covalent bond, provided that G₁Is N_ThreeIf U₁Is -CH_Two OCH_TwoNot Ph; and the following compounds of formula II and their pharmaceutically acceptable salts or
Except for derivatives, where: (a) A_TwoIs O; (b) E₁Is COOH, P (O) (OH)_Two, NO_Two, SOOH, SO_ThreeH, Tet
Lazole, CH_TwoCHO, CHO, CH (CHO)_TwoOr E₁Is C OOH, P (O) (OH)_Two, SOOH or SO_ThreeIf H, then their etch
G) methyl, pivaloyl esters;₁Is hydrogen, N (R^20a)_Two, SR^20aOr OR^20a(D) T₁Is -NHC (O) R^20bWhere R^20bIs a straight-chain or cyclic alkyl having 1 to 6 carbon atoms, unsubstituted or substituted by halogen.
Group, or SR^20a, OR^20a, COOH or their alkyl / aryl esters
Steal, no_Two, C (R^20a)_Three, CH_TwoCOOH or their alkyl / ant
Ester, CH_TwoNO_TwoOr CH_TwoNHR^20b(E) R^20aIs hydrogen; an acyl group having 1 to 4 carbon atoms; a linear or cyclic alkyl group having 1 to 6 carbon atoms, or a halogen-substituted analog thereof.
An unsubstituted aryl group, halogen, allyl group, OH group, NO_TwoGroup, NH_TwoGroup
Or aryl substituted by a COOH group; (f) J₁Is H and J_1aIs H, OR^20a, F, Cl, Br, CN,
NHR^20a, SR^20aOr CH_TwoX (where X is NHR^20a, Halogen or O
R^20a(G) J_TwoIs H or J_2aIs hydrogen, N (R^20a)_Two, SR^20aOr
OR^20a(H) U₁Is CH_TwoYR^20a, CHYR²⁰CH_TwoYR^20aOr CHYR^20aCH
YR^20aCH_TwoYR^20aWhere Y is O, S or H;₁ The consecutive Y moieties in are the same or different and when Y is hydrogen^{20 a} Represents a covalent bond. 2. A compound of formula (I) or (II):
Salts, solvates, resolved enantiomers, and purified diastereomers
And a composition comprising an enteric protective reagent:Where A₁Is -C (J₁A) =, -N = or -N (O) =;_TwoIs -C (J₁)_Two-, -N (J₁)-, -N (O) (J₁)-, -S-, -S (O)-, -S (O)_Two-Or -O-; E₁Is-(CR₁R₁)_m1W₁G₁Is N_Three, -CN, -OH, -OR_6a, -NO_Two, Or-(CR₁R₁)_m1 W_TwoAnd T₁Is -NR₁W_Three, H, -R_Three, -R_Five, A heterocycle, or U₁Or
G₁To form a group having the following structure: U₁Is H, -R_ThreeOr -X₁W₆And J₁And J_1aIs independently R₁, Br, Cl, F, I, CN, NO_TwoOr N_Three And J_TwoAnd J_2aIs independently H or R₁R₁Is independently H or alkyl having 1 to 12 carbon atoms;_TwoIs independently R_ThreeOr R_FourWhere each R_FourIs independently 0 to 3
R_ThreeSubstituted with a group; R_ThreeIs independentlyR_FourIs independently alkyl having 1 to 12 carbon atoms, alkenyl having 2 to 12 carbon atoms, or alkyl having 2 to 12 carbon atoms.
Nyl; R_FiveIs independently R_FourWhere each R_FourIs 0 to 3 R_ThreeSubstituted with a group; R_5aIs independently an alkylene having 1 to 12 carbon atoms, 2 to 12
Alkenylene having 2 carbon atoms, or alkenylene having 2 to 12 carbon atoms
Quinylene; these alkylene, alkenylene, or alkynylene
Any one of the 0 to 3 R_ThreeSubstituted with a group; R_6aIs independently H, or an ether-forming group or an ester-forming group;_6bIs independently H, an amino protecting group, or a residue of a carboxyl-containing compound.
Yes; R_6cIs independently H or the residue of an amino-containing compound; W₁Is a group containing an acidic hydrogen, a protected acidic group, or a group containing an acidic hydrogen._{6 c} An amide; W_TwoIs a basic heteroatom or a protected basic heteroatom, or a basic heteroatom R_6bA group containing an amide; W_ThreeIs W_FourOr W_FiveAnd W_FourIs R_FiveOr -C (O) R_Five, -C (O) W_Five, -SO_TwoR_FiveOr -SO _Two W_FiveAnd W_FiveIs a carbocyclic or heterocyclic ring, wherein W_FiveIndependently represent 0 to 3 R_Two Substituted with a group; W₆Is -R_Five, -W_Five, -R_5aW_Five, -C (O) OR_6a, -C (O) R_6c, -C
(O) N (R_6b)_Two, -C (NR_6b) (N (R_6b)_Two), -C (NR_6b) (N (H
) (R_6b)), -C (N (H) (N (R_6b)_Two), -C (S) N (R_6b)_Two,Also
Is -C (O) R_TwoAnd X₁Is a bond, -O-, -N (H)-, -N (W₆)-, -N (OH)-, -N
(OW₆)-, -N (NH_Two)-, -N (N (H) (W₆))-, -N (N (W₆) _Two )-, -N (H) N (W₆)-, -S-, -SO-, or -SO_TwoAnd each m1 is independently an integer from 0 to 2, with the proviso that the following compounds and their pharmaceutically acceptable salts and solvates are
Except where: (a) A₁Is -CH = or -N =, and A_TwoIs -CH_Two(B) E₁Is COOH, P (O) (OH)_Two, SOOH, SO_ThreeH, or tetrazole; (c) G₁Is CN, N (H) R₂₀, N_Three, SR₂₀, OR₂₀, Guanidino, -N
(H) CN, embedded image(D) T₁Is -NHR₂₀(E) R₂₀Is H; an acyl group having 1 to 4 carbon atoms; 1 to 6 carbon atoms
A linear or cyclic alkyl group having an atom, or a halogen-substituted analog thereof;
Ryl group or unsubstituted aryl group or halogen, OH group, NO_TwoGroup, NH_TwoBase
Or aryl substituted by a COOH group; (f) J₁Is H and J_1aIs H, F, Cl, Br or CN; (g) J_TwoIs H and J_2aIs H, CN or N_Three(H) U₁Is CH_TwoYR_20a, CHYR_20aCH_TwoYR_20aOr CHYR_20aC HYR_20aCH_TwoYR_20a(I) R_20aIs H or acyl having 1 to 4 carbon atoms; (j) Y is O, S, H or NH; (k) 0 to 2 YR_20aIs H, and (l) U₁Consecutive Y moieties in the group are the same or different and when Y is H, R_20aIs a covalent bond, provided that G₁Is N_ThreeIf U₁Is -CH_Two OCH_TwoNot Ph; and the following compounds of formula II and their pharmaceutically acceptable salts or
Except for derivatives, where: (a) A_TwoIs O; (b) E₁Is COOH, P (O) (OH)_Two, NO_Two, SOOH, SO_ThreeH, Tet
Lazole, CH_TwoCHO, CHO, CH (CHO)_TwoOr E₁Is C OOH, P (O) (OH)_Two, SOOH or SO_ThreeIf H, then their etch
G) methyl, pivaloyl esters;₁Is hydrogen, N (R^20a)_Two, SR^20aOr OR^20a(D) T₁Is -NHC (O) R^20bWhere R^20bIs a straight-chain or cyclic alkyl having 1 to 6 carbon atoms, unsubstituted or substituted by halogen.
Group, or SR^20a, OR^20a, COOH or their alkyl / aryl esters
Steal, no_Two, C (R^20a)_Three, CH_TwoCOOH or their alkyl / ant
Ester, CH_TwoNO_TwoOr CH_TwoNHR^20b(E) R^20aIs hydrogen; an acyl group having 1 to 4 carbon atoms; a linear or cyclic alkyl group having 1 to 6 carbon atoms, or a halogen-substituted analog thereof.
An unsubstituted aryl group or a halogen, an allyl group, an OH group, NO_TwoGroup, NH_TwoAryl substituted by a group or a COOH group; (f) J₁Is H and J_1aIs H, OR^20a, F, Cl, Br, CN,
NHR^20a, SR^20aOr CH_TwoX (where X is NHR^20a, Halogen or O
R^20a(G) J_TwoIs H or J_2aIs hydrogen, N (R^20a)_Two, SR^20aOr
OR^20a(H) U₁Is CH_TwoYR^20a, CHYR²⁰CH_TwoYR^20aOr CHYR^20aCH
YR^20aCH_TwoYR^20aWhere Y is O, S or H;₁ The consecutive Y moieties in are the same or different and when Y is hydrogen^{20 a} Represents a covalent bond. 3. A compound of formula (I) or (II):
Salts, solvates, resolved enantiomers, and purified diastereomers
And a composition comprising an enteric protected compound:Where A₁Is -C (J₁A) =, -N = or -N (O) =;_TwoIs -C (J₁)_Two-, -N (J₁)-, -N (O) (J₁)-, -S-, -S (O)-, -S (O)_Two-Or -O-; E₁Is-(CR₁R₁)_m1W₁G₁Is N_Three, -CN, -OH, -OR_6a, -NO_Two, Or-(CR₁R₁)_m1 W_TwoAnd T₁Is -NR₁W_Three, H, -R_Three, -R_Five, A heterocycle, or U₁Or
G₁To form a group having the following structure: U₁Is H, -R_ThreeOr -X₁W₆And J₁And J_1aIs independently R₁, Br, Cl, F, I, CN, NO_TwoOr N_Three And J_TwoAnd J_2aIs independently H or R₁R₁Is independently H or alkyl having 1 to 12 carbon atoms;_TwoIs independently R_ThreeOr R_FourWhere each R_FourIs independently 0 to 3
R_ThreeSubstituted with a group; R_ThreeIs independentlyR_FourIs independently alkyl having 1 to 12 carbon atoms, alkenyl having 2 to 12 carbon atoms, or alkyl having 2 to 12 carbon atoms.
Nyl; R_FiveIs independently R_FourWhere each R_FourIs 0 to 3 R_ThreeSubstituted with a group; R_5aIs independently an alkylene having 1 to 12 carbon atoms, 2 to 12
Alkenylene having 2 carbon atoms, or alkenylene having 2 to 12 carbon atoms
Quinylene; these alkylene, alkenylene, or alkynylene
Any one of the 0 to 3 R_ThreeSubstituted with a group; R_6aIs independently H, or an ether-forming group or an ester-forming group;_6bIs independently H, an amino protecting group, or a residue of a carboxyl-containing compound.
Yes; R_6cIs independently H or the residue of an amino-containing compound; W₁Is a group containing an acidic hydrogen, a protected acidic group, or a group containing an acidic hydrogen._{6 c} An amide; W_TwoIs a basic heteroatom or a protected basic heteroatom, or a basic heteroatom R_6bA group containing an amide; W_ThreeIs W_FourOr W_FiveAnd W_FourIs R_FiveOr -C (O) R_Five, -C (O) W_Five, -SO_TwoR_FiveOr -SO _Two W_FiveAnd W_FiveIs a carbocyclic or heterocyclic ring, wherein W_FiveIndependently represent 0 to 3 R_Two Substituted with a group; W₆Is -R_Five, -W_Five, -R_5aW_Five, -C (O) OR_6a, -C (O) R_6c, -C
(O) N (R_6b)_Two, -C (NR_6b) (N (R_6b)_Two), -C (NR_6b) (N (H
) (R_6b)), -C (N (H) (N (R_6b)_Two), -C (S) N (R_6b)_Two,Also
Is -C (O) R_TwoAnd X₁Is a bond, -O-, -N (H)-, -N (W₆)-, -N (OH)-, -N
(OW₆)-, -N (NH_Two)-, -N (N (H) (W₆))-, -N (N (W₆) _Two )-, -N (H) N (W₆)-, -S-, -SO-, or -SO_TwoAnd each m1 is independently an integer from 0 to 2, with the proviso that the following compounds and their pharmaceutically acceptable salts and solvates are
Except where: (a) A₁Is -CH = or -N =, and A_TwoIs -CH_Two(B) E₁Is COOH, P (O) (OH)_Two, SOOH, SO_ThreeH, or tetrazole; (c) G₁Is CN, N (H) R₂₀, N_Three, SR₂₀, OR₂₀, Guanidino, -N
(H) CN, embedded image(D) T₁Is -NHR₂₀(E) R₂₀Is H; an acyl group having 1 to 4 carbon atoms; 1 to 6 carbon atoms
A linear or cyclic alkyl group having an atom, or a halogen-substituted analog thereof;
Ryl group or unsubstituted aryl group or halogen, OH group, NO_TwoGroup, NH_TwoBase
Or aryl substituted by a COOH group; (f) J₁Is H and J_1aIs H, F, Cl, Br or CN; (g) J_TwoIs H and J_2aIs H, CN or N_Three(H) U₁Is CH_TwoYR_20a, CHYR_20aCH_TwoYR_20aOr CHYR_20aC HYR_20aCH_TwoYR_20a(I) R_20aIs H or acyl having 1 to 4 carbon atoms; (j) Y is O, S, H or NH; (k) 0 to 2 YR_20aIs H, and (l) U₁Consecutive Y moieties in the group are the same or different and when Y is H, R_20aIs a covalent bond, where G₁Is N_ThreeIf U₁Is -CH_TwoOCH_TwoNot Ph; and the following compounds of formula II and their pharmaceutically acceptable salts or
Except for derivatives, where: (a) A_TwoIs O; (b) E₁Is COOH, P (O) (OH)_Two, NO_Two, SOOH, SO_ThreeH, Tet
Lazole, CH_TwoCHO, CHO, CH (CHO)_TwoOr E₁Is C OOH, P (O) (OH)_Two, SOOH or SO_ThreeIf H, then their etch
G) methyl, pivaloyl esters;₁Is hydrogen, N (R^20a)_Two, SR^20aOr OR^20a(D) T₁Is -NHC (O) R^20bWhere R^20bIs a straight-chain or cyclic alkyl having 1 to 6 carbon atoms, unsubstituted or substituted by halogen.
Group, or SR^20a, OR^20a, COOH or their alkyl / aryl esters
Steal, no_Two, C (R^20a)_Three, CH_TwoCOOH or their alkyl / ant
Ester, CH_TwoNO_TwoOr CH_TwoNHR^20b(E) R^20aIs hydrogen; an acyl group having 1 to 4 carbon atoms; a linear or cyclic alkyl group having 1 to 6 carbon atoms, or a halogen-substituted analog thereof.
An unsubstituted aryl group or a halogen, an allyl group, an OH group, NO_TwoGroup, NH_TwoAryl substituted by a group or a COOH group; (f) J₁Is H and J_1aIs H, OR^20a, F, Cl, Br, CN,
NHR^20a, SR^20aOr CH_TwoX (where X is NHR^20a, Halogen or O
R^20a(G) J_TwoIs H or J_2aIs hydrogen, N (R^20a)_Two, SR^20aOr
OR^20a(H) U₁Is CH_TwoYR^20a, CHYR²⁰CH_TwoYR^20aOr CHYR^20aCH
YR^20aCH_TwoYR^20aWhere Y is O, S or H;₁ The consecutive Y moieties in are the same or different and when Y is hydrogen^{20 a} Represents a covalent bond. 4. A composition comprising an enteric protective reagent and a compound of the formula: Wherein E ₁ is —CO ₂ H, —CO ₂ R ₅ , —CO ₂ R _5a W ₅ or —CO ₂ W ₅ ; G ₁ is —N (R ₁₁ ) ₂ , —N (R ₁₁ ) C (N (R ₁₁ )) (N (R ₁₁ ) ₂ ) or —C (R ₁₁ ) ₂ —N (R ₁₁ ) ₂ ; T ₁ is —NH (C (O) CH _{3), - NH (C (} O) CH 2 F), - be a _{NH (C (O) CHF 2} ), or _{-NH (C (O) CF 3} ); U 1 is -OR _4, -SR ₄ , NHR ₄ or N (R ₄ ) ₂ ; each R ₁ is independently H or alkyl having 1 to 12 carbon atoms; each R ₂ is independently R ₃ or R ₄ Wherein each R ₄ is independently 0 to 3
R ₃ is independently substituted with each R ₃ group; R ₄ is independently alkyl having 1 to 12 carbon atoms, alkenyl having 2 to 12 carbon atoms, or alkynyl having 2 to 12 carbon atoms; and R ₅ is, independently, R _4, wherein each R ₄ is substituted with 0-3 R ₃ groups; R _5a is independently alkylene having 1 to 12 carbon atoms Alkenylene having 2 to 12 carbon atoms, or alkynylene having 2 to 12 carbon atoms, wherein any one of these alkylene, alkenylene, or alkynylene is 0 to 3 R substituted with ₃ groups; R _6a is independently H or an ether or ester-forming groups,; R _6b is independently H, a residue of an amino protecting group or carboxyl-containing compounds,; R _6c is independently H Or the residue of an amino-containing compound; W ₅ is carbocycle or heterocycle wherein, W ₅ is independently substituted with 0 to 3 R ₂ groups; and R ₁₁ is independently And H or R ₅ . 5. A composition comprising a compound according to claim 4, wherein the composition comprises ₁ Is C (O) OCH_TwoCH_ThreeAnd G₁Is NH_TwoAnd T₁Is NH (C (O) CH _Three ); And U₁Is OCH (CH_TwoCH_Three)_TwoA composition. 6. A composition comprising an enteric protective compound of the formula: 7. The composition of claim 6, comprising the following formula compound and an enteric coating:
A composition according to the formula: 8. A method for inhibiting the activity of neuraminidase, the method comprising:
A sample suspected of containing neuraminidase, a composition comprising an enteric protective composition
Wherein the enteric protective composition comprises the following formula (I) or (II):
) And their salts, solvates, resolved enantiomers and purified
Methods, including prepared diastereomers:Where A₁Is -C (J₁A) =, -N = or -N (O) =;_TwoIs -C (J₁)_Two-, -N (J₁)-, -N (O) (J₁)-, -S-, -S (O)-, -S (O)_Two-Or -O-; E₁Is-(CR₁R₁)_m1W₁G₁Is N_Three, -CN, -OH, -OR_6a, -NO_Two, Or-(CR₁R₁)_m1 W_TwoAnd T₁Is -NR₁W_Three, H, -R_Three, -R_Five, A heterocycle, or U₁Or
G₁To form a group having the following structure: U₁Is H, -R_ThreeOr -X₁W₆And J₁And J_1aIs independently R₁, Br, Cl, F, I, CN, NO_TwoOr N_Three And J_TwoAnd J_2aIs independently H or R₁R₁Is independently H or alkyl having 1 to 12 carbon atoms;_TwoIs independently R_ThreeOr R_FourWhere each R_FourIs independently 0 to 3
R_ThreeSubstituted with a group; R_ThreeIs independentlyR_FourIs independently alkyl having 1 to 12 carbon atoms, alkenyl having 2 to 12 carbon atoms, or alkynyl having 2 to 12 carbon atoms.
R; R_FiveIs independently R_FourWhere each R_FourIs 0 to 3 R_ThreeSubstituted with a group; R_5aIs independently an alkylene having 1 to 12 carbon atoms, 2 to 12
Alkenylene having 2 carbon atoms, or alkenylene having 2 to 12 carbon atoms
Quinylene; these alkylene, alkenylene, or alkynylene
Any one of the 0 to 3 R_ThreeSubstituted with a group; R_6aIs independently H, or an ether-forming group or an ester-forming group;_6bIs independently H, an amino protecting group, or a residue of a carboxyl-containing compound.
Yes; R_6cIs independently H or the residue of an amino-containing compound; W₁Is a group containing an acidic hydrogen, a protected acidic group, or a group containing an acidic hydrogen._{6 c} An amide; W_TwoIs a group containing a basic heteroatom or a protected basic heteroatom, or R_6bAn amide; W_ThreeIs W_FourOr W_FiveAnd W_FourIs R_FiveOr -C (O) R_Five, -C (O) W_Five, -SO_TwoR_FiveOr -SO _Two W_FiveAnd W_FiveIs a carbocyclic or heterocyclic ring, wherein W_FiveIndependently represent 0 to 3 R_Two Substituted with a group; W₆Is -R_Five, -W_Five, -R_5aW_Five, -C (O) OR_6a, -C (O) R_6c, -C
(O) N (R_6b)_Two, -C (NR_6b) (N (R_6b)_Two), -C (NR_6b) (N (H
) (R_6b)), -C (N (H) (N (R_6b)_Two), -C (S) N (R_6b)_Two,Also
Is -C (O) R_TwoAnd X₁Is a bond, -O-, -N (H)-, -N (W₆)-, -N (OH)-, -N
(OW₆)-, -N (NH_Two)-, -N (N (H) (W₆))-, -N (N (W₆) _Two )-, -N (H) N (W₆)-, -S-, -SO-, or -SO_TwoAnd each m1 is independently an integer from 0 to 2, with the proviso that the following compounds and their pharmaceutically acceptable salts and solvates are
Except where: (a) A₁Is -CH = or -N =, and A_TwoIs -CH_Two(B) E₁Is COOH, P (O) (OH)_Two, SOOH, SO_ThreeH, or tetrazole; (c) G₁Is CN, N (H) R₂₀, N_Three, SR₂₀, OR₂₀, Guanidino, -N
(H) CN, embedded image(D) T₁Is -NHR₂₀(E) R₂₀Is H; an acyl group having 1 to 4 carbon atoms; 1 to 6 carbon atoms
Linear or cyclic alkyl groups having atoms or halogen-substituted analogs thereof;
Or an unsubstituted aryl group, halogen, OH group, NO_TwoGroup, NH_TwoBase
Is an aryl substituted by a COOH group; (f) J₁Is H and J_1aIs H, F, Cl, Br or CN; (g) J_TwoIs H and J_2aIs H, CN or N_Three(H) U₁Is CH_TwoYR_20a, CHYR_20aCH_TwoYR_20aOr CHYR_20aC HYR_20aCH_TwoYR_20a(I) R_20aIs H or acyl having 1 to 4 carbon atoms; (j) Y is O, S, H or NH; (k) 0 to 2 YR_20aIs H, and (l) U₁Contiguous Y moieties in the group are the same or different, and if Y is H_20aIs a covalent bond, where G₁Is N_ThreeIf U₁Is -CH_TwoOCH_TwoNot Ph; and the following compounds of formula II and their pharmaceutically acceptable salts or
Except for derivatives, where: (a) A_TwoIs O; (b) E₁Is COOH, P (O) (OH)_Two, NO_Two, SOOH, SO_ThreeH, Tet
Lazole, CH_TwoCHO, CHO, CH (CHO)_TwoOr E₁Is C OOH, P (O) (OH)_Two, SOOH or SO_ThreeIn the case of H, those ethyls,
Methyl or pivaloyl ester; (c) G₁Is hydrogen, N (R^20a)_Two, SR^20aOr OR^20a(D) T₁Is -NHC (O) R^20bWhere R^20bIs a straight-chain or cyclic alkyl having 1 to 6 carbon atoms, unsubstituted or substituted by halogen.
Group, or SR^20a, OR^20a, COOH or their alkyl / aryl esters
Steal, no_Two, C (R^20a)_Three, CH_TwoCOOH or their alkyl / ant
Ester, CH_TwoNO_TwoOr CH_TwoNHR^20b(E) R^20aIs hydrogen; an acyl group having 1 to 4 carbon atoms; a linear or cyclic alkyl group having 1 to 6 carbon atoms, or a halogen-substituted analog thereof.
An unsubstituted aryl group or a halogen, an allyl group, an OH group, NO_TwoGroup, NH_TwoAryl substituted by a group or a COOH group; (f) J₁Is H and J_1aIs H, OR^20a, F, Cl, Br, CN,
NHR^20a, SR^20aOr CH_TwoX (where X is NHR^20a, Halogen or O
R^20a(G) J_TwoIs H or J_2aIs hydrogen, N (R^20a)_Two, SR^20aOr
OR^20a(H) U₁Is CH_TwoYR^20a, CHYR²⁰CH_TwoYR^20aOr CHYR^20aCH
YR^20aCH_TwoYR^20aWhere Y is O, S or H;₁ The consecutive Y moieties in are the same or different and when Y is hydrogen^{20 a} Represents a covalent bond. 9. The method of claim 8, wherein said neuraminidase is influenza neuraminidase in vivo. 10. A method for treating or preventing influenza infection in a host.
A method of administering to the host a therapeutically effective amount of the composition.
Wherein the composition comprises an enteric coating containing a compound of formula (I) or (II) below:
Protection compositions, and their salts, solvates, resolved enantiomers and
Methods, including purified diastereomers:Where A₁Is -C (J₁A) =, -N = or -N (O) =;_TwoIs -C (J₁)_Two-, -N (J₁)-, -N (O) (J₁)-, -S-, -S (O)-, -S (O)_Two-Or -O-; E₁Is-(CR₁R₁)_m1W₁G₁Is N_Three, -CN, -OH, -OR_6a, -NO_Two, Or-(CR₁R₁)_m1 W_TwoAnd T₁Is -NR₁W_Three, H, -R_Three, -R_Five, A heterocycle, or U₁Or
G₁To form a group having the following structure: U₁Is H, -R_ThreeOr -X₁W₆And J₁And J_1aIs independently R₁, Br, Cl, F, I, CN, NO_TwoOr N_Three And J_TwoAnd J_2aIs independently H or R₁R₁Is independently H or alkyl having 1 to 12 carbon atoms;_TwoIs independently R_ThreeOr R_FourWhere each R_FourIs independently 0 to 3
R_ThreeSubstituted with a group; R_ThreeIs independentlyR_FourIs independently alkyl having 1 to 12 carbon atoms, alkenyl having 2 to 12 carbon atoms, or alkynyl having 2 to 12 carbon atoms.
R; R_FiveIs independently R_FourWhere each R_FourIs 0 to 3 R_ThreeSubstituted with a group; R_5aIs independently an alkylene having 1 to 12 carbon atoms, 2 to 12
Alkenylene having 2 carbon atoms, or alkenylene having 2 to 12 carbon atoms
Quinylene; these alkylene, alkenylene, or alkynylene
Any one of the 0 to 3 R_ThreeSubstituted with a group; R_6aIs independently H, or an ether-forming group or an ester-forming group;_6bIs independently H, an amino protecting group, or a residue of a carboxyl-containing compound.
Yes; R_6cIs independently H or the residue of an amino-containing compound; W₁Is a group containing an acidic hydrogen, a protected acidic group, or a group containing an acidic hydrogen._{6 c} An amide; W_TwoIs a group containing a basic heteroatom or a protected basic heteroatom, or R_6bAn amide; W_ThreeIs W_FourOr W_FiveAnd W_FourIs R_FiveOr -C (O) R_Five, -C (O) W_Five, -SO_TwoR_FiveOr -SO _Two W_FiveAnd W_FiveIs a carbocyclic or heterocyclic ring, wherein W_FiveIndependently represent 0 to 3 R_Two Substituted with a group; W₆Is -R_Five, -W_Five, -R_5aW_Five, -C (O) OR_6a, -C (O) R_6c, -C
(O) N (R_6b)_Two, -C (NR_6b) (N (R_6b)_Two), -C (NR_6b) (N (H
) (R_6b)), -C (N (H) (N (R_6b)_Two), -C (S) N (R_6b)_Two,Also
Is -C (O) R_TwoAnd X₁Is a bond, -O-, -N (H)-, -N (W₆)-, -N (OH)-, -N
(OW₆)-, -N (NH_Two)-, -N (N (H) (W₆))-, -N (N (W₆) _Two )-, -N (H) N (W₆)-, -S-, -SO-, or -SO_TwoAnd each m1 is independently an integer from 0 to 2, with the proviso that the following compounds and their pharmaceutically acceptable salts and solvates are
Except where: (a) A₁Is -CH = or -N =, and A_TwoIs -CH_Two(B) E₁Is COOH, P (O) (OH)_Two, SOOH, SO_ThreeH, or tetrazole; (c) G₁Is CN, N (H) R₂₀, N_Three, SR₂₀, OR₂₀, Guanidino, -N
(H) CN, embedded image(D) T₁Is -NHR₂₀(E) R₂₀Is H; an acyl group having 1 to 4 carbon atoms; 1 to 6 carbon atoms
Linear or cyclic alkyl groups having atoms or halogen-substituted analogs thereof;
Or an unsubstituted aryl group, halogen, OH group, NO_TwoGroup, NH_TwoBase
Is an aryl substituted by a COOH group; (f) J₁Is H and J_1aIs H, F, Cl, Br or CN; (g) J_TwoIs H and J_2aIs H, CN or N_Three(H) U₁Is CH_TwoYR_20a, CHYR_20aCH_TwoYR_20aOr CHYR_20aC HYR_20aCH_TwoYR_20a(I) R_20aIs H or acyl having 1 to 4 carbon atoms; (j) Y is O, S, H or NH; (k) 0 to 2 YR_20aIs H, and (l) U₁Consecutive Y moieties in the group are the same or different and when Y is H, R_20aIs a covalent bond, where G₁Is N_ThreeIf U₁Is -CH_TwoOCH_TwoNot Ph; and the following compounds of formula II and their pharmaceutically acceptable salts or
Except for derivatives, where: (a) A_TwoIs O; (b) E₁Is COOH, P (O) (OH)_Two, NO_Two, SOOH, SO_ThreeH, Tet
Lazole, CH_TwoCHO, CHO, CH (CHO)_TwoOr E₁Is C OOH, P (O) (OH)_Two, SOOH or SO_ThreeIf H, then their etch
G) methyl, pivaloyl esters;₁Is hydrogen, N (R^20a)_Two, SR^20aOr OR^20a(D) T₁Is -NHC (O) R^20bWhere R^20bIs a straight-chain or cyclic alkyl having 1 to 6 carbon atoms, unsubstituted or substituted by halogen.
Group, or SR^20a, OR^20a, COOH or their alkyl / aryl esters
Steal, no_Two, C (R^20a)_Three, CH_TwoCOOH or their alkyl / ant
Ester, CH_TwoNO_TwoOr CH_TwoNHR^20b(E) R^20aIs hydrogen; an acyl group having 1 to 4 carbon atoms; a linear or cyclic alkyl group having 1 to 6 carbon atoms, or a halogen-substituted analog thereof.
An unsubstituted aryl group or a halogen, an allyl group, an OH group, NO_TwoGroup, NH_TwoAryl substituted by a group or a COOH group; (f) J₁Is H and J_1aIs H, OR^20a, F, Cl, Br, CN,
NHR^20a, SR^20aOr CH_TwoX (where X is NHR^20a, Halogen or O
R^20a(G) J_TwoIs H or J_2aIs hydrogen, N (R^20a)_Two, SR^20aOr
OR^20a(H) U₁Is CH_TwoYR^20a, CHYR²⁰CH_TwoYR^20aOr CHYR^20aCH
YR^20aCH_TwoYR^20aWhere Y is O, S or H;₁ The consecutive Y moieties in are the same or different and when Y is hydrogen^{20 a} Represents a covalent bond.