KR20010024123A - Compounds containing six-membered rings, process for their preparation, and their use as medicaments - Google Patents

Abstract

Novel compounds are described. These compounds have groups which have acidic groups, basic groups, substituted amino or N-acyl groups and optionally hydroxylated alkane moieties. Also described are pharmaceutical compositions containing the inhibitors of the present invention. Also described is a method of inhibiting neuraminidase in a sample that is believed to contain neuraminidase. Assays for screening conjugates, antibodies, polymers, antigenic substances and neuraminidase activity of labeled compounds of the invention are also described.

Description

COMPOUNDS CONTAINING SIX-MEMBERED RINGS, PROCESS FOR THEIR PREPARATION, AND THEIR USE AS MEDICAMENTS}

<a brief description of the technical field concerned>

von Itzstein, M. et al .; "Nature", 363 (6428): 418-423 (1993) described a speculative model of sialidase-based inhibitors of influenza virus replication.

Colman, P.M. Etc; International Patent Publication WO 92/06691 (International Patent Application PCT / AU90 / 00501, published April 30, 1992), Itzstein, L. M. von et al .; EP 0 539 204 A1 (EP Application No. 92309684.6, published April 28, 1993), and Itzstein, L.M. von. outside; International Publication No. WO91 / 16320 (International Application No. PCT / AU91 / 00161, International Publication Date October 31, 1991) discloses the combinations that bind neuraminidase and exhibit antiviral activity in vivo.

<Purpose of invention>

The main object of the present invention is to inhibit viruses, especially influenza viruses. In particular, one object of the present invention is to inhibit the corresponding enzymes, such as neuraminidase, which selectively inhibit viral or bacterial neuraminidase in particular.

Another object of the present invention is to slow the rate of urination, enter the nasal or pulmonary secretions from the systemic circulation, have sufficient oral biocompatibility that is therapeutically effective, enhanced efficacy, clinically acceptable toxicity profiles and other desirable It is to provide a neuraminidase inhibitor having drug properties.

Another object is to provide a method for synthesizing neuraminidase inhibitors in an improved manner at a lower cost.

Another object is to provide an improved method for administering known or novel neuraminidase inhibitors.

It is another object of the present invention to provide compositions useful for preparing polymers, surfactants or immunogens, and compositions useful for other industrial processes and articles.

Given this invention in its entirety, these and other objects will be readily apparent to those skilled in the art.

<Summary of invention>

According to the invention there is provided a compound or composition of formula (I) or (II) and salts, solvates, degraded enantiomers and purified diastereomers thereof:

In the formula,

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-;

E ₁ is — (CR ₁ R ₁ ) m ₁ W ₁ ;

G ₁ is N ₃ , —CN, —OH, —OR _6a , —NO ₂ , or — (CR ₁ R ₁ ) m ₁ W ₂ ;

T _{1 together} with —NR ₁ W ₃ , H, —R ₃ , —R ₅ , heterocycle, or U ₁ or G ₁ forms a group having the structure

U ₁ is H, R ₃ or -X ₁ W ₆ ;

J ₁ and J _1a are each R ₁ , Br, Cl, F, I, CN, NO ₂ or N ₃ ;

J ₂ and J _2a are each H or R ₁ ;

R ₁ is independently H or alkyl of 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 F, Cl, Br, I, -CN, N ₃ , -NO ₂ , -OR _6a , -OR ₁ , -N (R ₁ ) ₂ , -N (R ₁ ) (R _6b ), -N (R _6b ) ₂ , -SR ₁ , -SR _6a , -S (O) R ₁ , -S (O) ₂ R ₁ , -S (O) OR ₁ , -S (O) OR _6a ,- S (O) ₂ OR ₁ , -S (O) ₂ OR _6a , -C (O) OR ₁ , -C (O) R _6c , -C (O) OR _6a , -OC (O) R ₁ ,- N (R ₁ ) (C (O) R ₁ ), -N (R _6b ) (C (O) R ₁ ), -N (R ₁ ) (C (O) OR ₁ ), -N (R _6b ) (C (O) OR ₁ ), -C (O) N (R ₁ ) ₂ , -C (O) N (R _6b ) (R ₁ ), -C (O) N (R _6b ) ₂ , -C (NR ₁ ) (N (R ₁ ) ₂ ), -C (N (R _6b ) (N (R ₁ ) ₂ ), -C (N (R ₁ ) (N (R ₁ ) (R _6b )), -C (N (R _6b ) (N (R ₁ ) (R _6b )), -C (N (R ₁ ) (N (R _6b ) ₂ ), -C (N (R _6b ) (N (R _6b) ) ₂ ), -N (R ₁ ) C (N (R ₁ ) (N (R ₁ ) ₂ ), -N (R ₁ ) C (N (R ₁ )) (N (R ₁ ) (R _6b ) ), -N (R ₁ ) C (N (R _6b )) (N (R ₁ ) ₂ ), -N (R _6b ) C (N (R ₁ )) (N (R ₁ ) ₂ ), -N (R _6b ) C (N (R _6b )) (N (R ₁ ) ₂ ), -N (R _6b ) C (N (R ₁ )) (N (R ₁ ) (R _6b )), -N ( R ₁ ) C (N (R _6b )) (N (R ₁ ) (R _6b )), -N (R ₁ ) C (N (R ₁ )) (N (R _6b ) ₂ ), -N (R _6b ) C (N (R _6b )) (N (R ₁ ) (R _6b )), -N (R _6b ) C (N (R ₁ )) (N (R _6b ) ₂ ), -N (R ₁ ) C (N (R _6b )) (N (R _6b ) ₂ ), -N (R _6b ) C (N (R _6b )) (N (R _6b ) ₂ ), = O, = S, N (R ₁ ), N (R _6b ) Or W ₅ ;

R ₄ is alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms;

R ₅ is independently R ₄ where each R ₄ is substituted with 0-3 R ₃ groups;

R _5a is an alkylene having 1 to 12 carbon atoms, an alkenylene having 2 to 12 carbon atoms, or an alkynylene having 2 to 12 carbon atoms, and alkylene, alkenylene or alkynylene is substituted with 0 to 3 R ₃ groups;

R _6a is independently H or an ether- or ester-forming group;

R _6b is independently H, a residue or amino protecting group of a carboxyl-containing compound;

R _6c is independently H, or a residue of an amino-containing compound;

W ₁ is an R _6c amide group of an acidic hydrogen, a protected acid group, or a group containing acidic hydrogen;

W ₂ is a functional group which can be derived from a basic hetero atom or a protected basic hetero atom, or a basic hetero atom R _6b amide or a basic hetero atom;

W ₃ is W ₄ or W ₅ ;

W ₄ is R ₅ or —C (O) R ₅ , —C (O) W ₅ , —SO ₂ R ₅ , or —SO ₂ W ₅ ;

W ₅ is carbocycle or heterocycle where W ₅ is independently substituted with 0 to 3 R ₂ groups;

W ₆ is -R ₅ , -W ₅ , R _5a W ₅ , -C (O) OR _6a , -C (O) R _6c , -C (O) N (R _6b ) ₂ , -C (NR _6b ) (NR _6b ) ₂ ), -C (NR _6b ) (N (H) (R _6b )), -C (N (H) (N (R _6b ) ₂ ), -C (S) N (R _6b ) ₂ , or -C (0) R ₂ ;

X ₁ is a bond, -O-, -N (H)-, -N (W ₆ )-, -N (OH)-, -N (OW ₆ )-, -N (NH ₂ )-, -N ( N (H) (W ₆ ))-, -N (N (W ₆ ) ₂ )-, -N (H) N (W ₆ )-, -S-, -SO-, or -SO _2- ; ego

Each m ₁ is independently an integer of 0 to 2;

Provided, however, that the following compounds and their pharmaceutically acceptable salts and solvent compounds, and their salts, solvates, degraded enantiomers and purified diastereomers, are referred to in No. 3 of PCT Publication No. WO91 / 16320 On page 23 to line 5, line 6 are excluded:

(a) A ₁ is -CH = or -N- and A ₂ is -CH _2- ;

(b) E ₁ is COOH, P (O) (OH) ₂ , SOOH, SO ₃ H or tetrazole;

(c) G ₁ is CN, N (H) R ₂₀ , N ₃ , SR ₂₀ , OR ₂₀ , guanidino, -N (H) CN

(d) T ₁ is —NHR ₂₀ ;

(e) R ₂₀ is H; Acyl groups of 1-4 carbon atoms; Straight or cyclic alkyl groups of 1 to 6 carbon atoms, or halogen substituted homologs thereof; An aryl group substituted by an allyl group or an unsubstituted aryl group or 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 CH ₂ YR _20a CH ₂ YR _20a;

(i) R _20a is H or acyl of 1-4 carbon atoms;

(j) Y is O, S, H or NH;

(k) 0-2 YR _20a is H

(l) If the consecutive Y moieties in the U ₁ group are the same or different and Y is H, then R _20a is a covalent bond, provided that if G ₁ is N ₃ then U ₁ is not —CH ₂ OCH ₂ Ph.

In addition, the compounds described in page 9, line 26 to page 11, line 5 of PCT Publication No. WO92 / 06691, which appear to include the following compounds having the formula (2) and pharmaceutically acceptable salts or derivatives thereof: Excluded:

(a) A ₁ is O;

(b) E ₁ is COOH, P (O) (OH) ₂ , NO ₂ , SOOH, SO ₃ H, tetrazole, CH ₂ CHO, CHO, CH (CHO) ₂ or E ₁ is COOH, P (O) (OH) ₂ , SOOH or SO ₃ H, ethyl, methyl or pivaloyl esters thereof;

(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 a 1 to 6 carbon atom, halogen-substituted or unsubstituted straight or cyclic alkyl group, or SR ^20a , OR ^20a , COOH or Alkyl / aryl esters thereof, NO ₂ , C (R ^20a ) ₃ , CH ₂ COOH or alkyl / aryl esters thereof, CH ₂ NO ₂ or CH ₂ NHR ^20b ;

(e) R ^20a is H; Acyl groups of 1 to 4 carbon atoms; Straight or cyclic alkyl groups of 1 to 6 carbon atoms, or halogen substituted homologs thereof; Aryl groups, ie, unsubstituted aryl groups or aryl groups substituted by halogen, OH, NO ₂ , NH ₂ or COOH;

(f) J ₁ is H and J _1a is H, OR ^20a , F, Cl, Br, CN, NHR ^20a , SR ^20a or CH ₂ X, wherein X is NHR ^20a , halogen or OR ^20a ;

(g) J ₂ is H, or J _2a is H, N (R ^20a ) ₂ , SR ^20a or OR ^20a ;

(h) U ₁ is CH ₂ YR ^20a , CHYR ^20a CH ₂ YR ^20a or CHYR ^20a CHYR ^20a CH ₂ YR ^20a , wherein Y is O, S or H, and the consecutive Y moieties in the U ₁ group are the same or different , When Y is H, R ^20a represents a covalent bond).

Another embodiment of the present invention relates to compounds having the formulas III and IV and salts, solvates, degraded enantiomers and purified diastereomers thereof:

In the formula,

E ₁ is — (CR ₁ R ₁ ) m ₁ W ₁ ;

G ₁ is N ₃ , —CN, —OH, —OR _6a , —NO ₂ , or — (CR ₁ R ₁ ) m ₁ W ₂ ;

T _{1 together} with —NR ₁ W ₃ , heterocycle, or U ₁ or G ₁ forms a group having the structure

U ₁ is H or -X ₁ W ₆ , and when -X ₁ W ₆ , U ₁ is a branched chain;

J ₁ and J _1a are each R ₁ , Br, Cl, F, I, CN, NO ₂ or N ₃ ;

J ₂ and J _2a are each H or R ₁ ;

R ₁ is independently H or alkyl of 1 to 12 carbon atoms;

R ₂ is independently R ₃ or R ₄ , and each R ₄ is independently substituted with 0-3 R ₃ groups;

R ₃ is independently F, Cl, Br, I, -CN, N ₃ , -NO ₂ , -OR _6a , -OR ₁ , -N (R ₁ ) ₂ , -N (R ₁ ) (R _6b ), -N (R _6b ) ₂ , -SR ₁ , -SR _6a , -S (O) R ₁ , -S (O) ₂ R ₁ , -S (O) OR ₁ , -S (O) OR _6a ,- S (O) ₂ OR ₁ , -S (O) ₂ OR _6a , -C (O) OR ₁ , -C (O) R _6c , -C (O) OR _6a , -OC (O) R ₁ ,- N (R ₁ ) (C (O) R ₁ ), -N (R _6b ) (C (O) R ₁ ), -N (R ₁ ) (C (O) OR ₁ ), -N (R _6b ) (C (O) OR ₁ ), -C (O) N (R ₁ ) ₂ , -C (O) N (R _6b ) (R ₁ ), -C (O) N (R _6b ) ₂ , -C (NR ₁ ) (N (R ₁ ) ₂ ), -C (N (R _6b ) (N (R ₁ ) ₂ ), -C (N (R ₁ ) (N (R ₁ ) (R _6b )), -C (N (R _6b ) (N (R ₁ ) (R _6b )), -C (N (R ₁ ) (N (R _6b ) ₂ ), -C (N (R _6b ) (N (R _6b) ) ₂ ), -N (R ₁ ) C (N (R ₁ ) (N (R ₁ ) ₂ ), -N (R ₁ ) C (N (R ₁ )) (N (R ₁ ) (R _6b ) ), -N (R ₁ ) C (N (R _6b )) (N (R ₁ ) ₂ ), -N (R _6b ) C (N (R ₁ )) (N (R ₁ ) ₂ ), -N (R _6b ) C (N (R _6b )) (N (R ₁ ) ₂ ), -N (R _6b ) C (N (R ₁ )) (N (R ₁ ) (R _6b )), -N ( R ₁ ) C (N (R _6b )) (N (R ₁ ) (R _6b )), -N (R ₁ ) C (N (R ₁ )) (N (R _6b ) ₂ ), -N (R _6b ) C (N (R _6b )) (N (R ₁ ) (R _6b )), -N (R _6b ) C (N (R ₁ )) (N (R _6b ) ₂ ), -N (R ₁ ) C (N (R _6b )) (N (R _6b ) ₂ ), -N (R _6b ) C (N (R _6b )) (N (R _6b ) ₂ ), = O, = S, N (R ₁ ) or = N (R _6b );

R ₄ is alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms;

R ₅ is independently R ₄ , wherein each R ₄ is substituted with 0-3 R ₃ groups;

R _5a is independently an alkylene having 1 to 12 carbon atoms, an alkenylene having 2 to 12 carbon atoms, or an alkynylene having 2 to 12 carbon atoms, and any of alkylene, alkenylene or alkynylene is 0 to 3 Are substituted with R ₃ groups;

R _6a is independently H or an ether- or ester-forming group;

R _6b is independently H, a residue or amino protecting group of a carboxyl-containing compound;

R _6c is independently H, or a residue of an amino-containing compound;

W ₁ is an R _6c amide group of an acidic hydrogen, a protected acid group, or a group containing acidic hydrogen;

W ₂ is R _6b amide of a basic hetero atom or a protected basic hetero atom or basic hetero atom;

W ₃ is W ₄ or W ₅ ;

W ₄ is R ₅ or —C (O) R ₅ , —C (O) W ₅ , —SO ₂ R ₅ , or —SO ₂ W ₅ ;

W ₅ is carbocycle or heterocycle where W ₅ is independently substituted with 0 to 3 R ₂ groups;

W ₆ is -R ₅ , -W ₅ , R _5a W ₅ , -C (O) OR _6a , -C (O) R _6c , -C (O) N (R _6b ) ₂ , -C (NR _6b ) (N (R _6b ) ₂ ), -C (S) N (R _6b ) ₂ , or -C (O) R ₂ ;

X ₁ is a bond, -O-, -N (H)-, -N (W ₆ )-, -N (OH)-, -N (OW ₆ )-, -N (NH ₂ )-, -N ( N (H) (W ₆ ))-, -N (N (W ₆ ) ₂ )-, -N (H) N (W ₆ )-, -S-, -SO-, or -SO _2- ; ego

Each m ₁ is independently an integer from 0 to 2.

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

[Formula III]

In the formula,

E ₁ is — (CR ₁ R ₁ ) m ₁ W ₁ ;

G ₁ is N ₃ , —CN, —OH, —OR _6a , —NO ₂ , or — (CR ₁ R ₁ ) m ₁ W ₂ ;

T _{1 together} with —NR ₁ W ₃ , heterocycle, or U ₁ or G ₁ forms a group having the structure

U ₁ is H or —X ₁ W ₆ ;

J ₁ and J _1a are each R ₁ , Br, Cl, F, I, CN, NO ₂ or N ₃ ;

J ₂ and J _2a are each H or R ₁ ;

R ₁ is independently H or alkyl of 1 to 12 carbon atoms;

R ₂ is independently R ₃ or R ₄ where each R ₄ is independently substituted with 0-3 R ₃ groups;

R ₃ is independently F, Cl, Br, I, -CN, N ₃ , -NO ₂ , -OR _6a , -OR ₁ , -N (R ₁ ) ₂ , -N (R ₁ ) (R _6b ), -N (R _6b ) ₂ , -SR ₁ , -SR _6a , -S (O) R ₁ , -S (O) ₂ R ₁ , -S (O) OR ₁ , -S (O) OR _6a ,- S (O) ₂ OR ₁ , -S (O) ₂ OR _6a , -C (O) OR ₁ , -C (O) R _6c , -C (O) OR _6a , -OC (O) R ₁ ,- N (R ₁ ) (C (O) R ₁ ), -N (R _6b ) (C (O) R ₁ ), -N (R ₁ ) (C (O) OR ₁ ), -N (R _6b ) (C (O) OR ₁ ), -C (O) N (R ₁ ) ₂ , -C (O) N (R _6b ) (R ₁ ), -C (O) N (R _6b ) ₂ , -C (NR ₁ ) (N (R ₁ ) ₂ ), -C (N (R _6b ) (N (R ₁ ) ₂ ), -C (N (R ₁ ) (N (R ₁ ) (R _6b )), -C (N (R _6b ) (N (R ₁ ) (R _6b )), -C (N (R ₁ ) (N (R _6b ) ₂ ), -C (N (R _6b ) (N (R _6b) ) ₂ ), -N (R ₁ ) C (N (R ₁ ) (N (R ₁ ) ₂ ), -N (R ₁ ) C (N (R ₁ )) (N (R ₁ ) (R _6b ) ), -N (R ₁ ) C (N (R _6b )) (N (R ₁ ) ₂ ), -N (R _6b ) C (N (R ₁ )) (N (R ₁ ) ₂ ), -N (R _6b ) C (N (R _6b )) (N (R ₁ ) ₂ ), -N (R _6b ) C (N (R ₁ )) (N (R ₁ ) (R _6b )), -N ( R ₁ ) C (N (R _6b )) (N (R ₁ ) (R _6b )), -N (R ₁ ) C (N (R ₁ )) (N (R _6b ) ₂ ), -N (R _6b ) C (N (R _6b )) (N (R ₁ ) (R _6b )), -N (R _6b ) C (N (R ₁ )) (N (R _6b ) ₂ ), -N (R ₁ ) C (N (R _6b )) (N (R _6b ) ₂ ), -N (R _6b ) C (N (R _6b )) (N (R _6b ) ₂ ), = O, = S, N (R ₁ ) or = N (R _6b );

R ₄ is alkyl having 1 to 12 carbon atoms, alkenyl having 2 to 12 carbon atoms, or alkynyl having 2 to 12 carbon atoms;

R ₅ is independently R ₄ , each R ₄ is substituted with 0-3 R ₃ groups;

R _5a is independently an alkylene of 1 to 12 carbon atoms, an alkenylene of 2 to 12 carbon atoms, or an alkynylene of 2 to 12 carbon atoms, and 0 to 3 of any of alkylene, alkenylene or alkynylene Substituted with a R ₃ group;

R _6a is independently H or an ether- or ester-forming group;

R _6b is independently H, a residue or amino protecting group of a carboxyl-containing compound;

R _6c is independently H, or a residue of an amino-containing compound;

W ₁ is an R _6c amide group of an acidic hydrogen, a protected acid group, or a group containing acidic hydrogen;

W ₂ is R _6b amide of a basic hetero atom or a protected basic hetero atom or basic hetero atom;

W ₃ is W ₄ or W ₅ ;

W ₄ is R ₅ or —C (O) R ₅ , —C (O) W ₅ , —SO ₂ R ₅ , or —SO ₂ W ₅ ;

W ₅ is carbocycle or heterocycle where W ₅ is independently substituted with 0 to 3 R ₂ groups;

W ₆ is -R ₅ , -W ₅ , R _5a W ₅ , -C (O) OR _6a , -C (O) R _6c , -C (O) N (R _6b ) ₂ , -C (NR _6b ) (N (R _6b ) ₂ ), -C (S) N (R _6b ) ₂ , or -C (O) R ₂ ;

X ₁ is -O-, -N (H)-, -N (W ₆ )-, -N (OH)-, -N (OW ₆ )-, -N (NH ₂ )-,-N (N ( H) (W ₆ ))-, -N (N (W ₆ ) ₂ )-, -N (H) N (W ₆ )-, -S-, -SO-, or -SO _2- ; ego

Each m ₁ is independently an integer from 0 to 2.

Another embodiment of the invention relates to a compound having the formula and to salts, solvates, degraded enantiomers and purified diastereomers thereof:

In the formula,

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, 4, 5, 6, 7, 8, 9, 10, 11 or 12 alkyl atoms;

R ₆₀ is 3, 4, 5, 6, 7, 8, 9, 10 11, or 12 branched alkyl atoms.

Another embodiment of the invention relates to compounds having the formula VII or VIII, salts thereof, solvent compounds, degraded enantiomers and purified diastereomers:

In the formula,

E ₁ is — (CR ₁ R ₁ ) m ₁ W ₁ ;

G ₁ is N ₃ , —CN, —OH, —OR _6a , —NO ₂ , or — (CR ₁ R ₁ ) m ₁ W ₂ ;

T _{1 together} with —NR ₁ W ₃ , heterocycle, or U ₁ or G ₁ forms a group having the structure

U ₁ is H or —X ₁ W ₆ ;

J ₁ and J _1a are each R ₁ , Br, Cl, F, I, CN, NO ₂ or N ₃ ;

J ₂ and J _2a are each H or R ₁ ;

R ₁ is independently H or alkyl of 1 to 12 carbon atoms;

R ₂ is independently R ₃ or R ₄ , and each R ₄ is independently substituted with 0 to 3 R ₃ groups;

R ₃ is independently F, Cl, Br, I, -CN, N ₃ , -NO ₂ , -OR _6a , -OR ₁ , -N (R ₁ ) ₂ , -N (R ₁ ) (R _6b ), -N (R _6b ) ₂ , -SR ₁ , -SR _6a , -S (O) R ₁ , -S (O) ₂ R ₁ , -S (O) OR ₁ , -S (O) OR _6a ,- S (O) ₂ OR ₁ , -S (O) ₂ OR _6a , -C (O) OR ₁ , -C (O) R _6c , -C (O) OR _6a , -OC (O) R ₁ ,- N (R ₁ ) (C (O) R ₁ ), -N (R _6b ) (C (O) R ₁ ), -N (R ₁ ) (C (O) OR ₁ ), -N (R _6b ) (C (O) OR ₁ ), -C (O) N (R ₁ ) ₂ , -C (O) N (R _6b ) (R ₁ ), -C (O) N (R _6b ) ₂ , -C (NR ₁ ) (N (R ₁ ) ₂ ), -C (N (R _6b ) (N (R ₁ ) ₂ ), -C (N (R ₁ ) (N (R ₁ ) (R _6b )), -C (N (R _6b ) (N (R ₁ ) (R _6b )), -C (N (R ₁ ) (N (R _6b ) ₂ ), -C (N (R _6b ) (N (R _6b) ) ₂ ), -N (R ₁ ) C (N (R ₁ ) (N (R ₁ ) ₂ ), -N (R ₁ ) C (N (R ₁ )) (N (R ₁ ) (R _6b ) ), -N (R ₁ ) C (N (R _6b )) (N (R ₁ ) ₂ ), -N (R _6b ) C (N (R ₁ )) (N (R ₁ ) ₂ ), -N (R _6b ) C (N (R _6b )) (N (R ₁ ) ₂ ), -N (R _6b ) C (N (R ₁ )) (N (R ₁ ) (R _6b )), -N ( R ₁ ) C (N (R _6b )) (N (R ₁ ) (R _6b )), -N (R ₁ ) C (N (R ₁ )) (N (R _6b ) ₂ ), -N (R _6b ) C (N (R _6b )) (N (R ₁ ) (R _6b )), -N (R _6b ) C (N (R ₁ )) (N (R _6b ) ₂ ), -N (R ₁ ) C (N (R _6b )) (N (R _6b ) ₂ ), -N (R _6b ) C (N (R _6b )) (N (R _6b ) ₂ ), = O, = S, N (R ₁ ) or = N (R _6b );

R ₄ is alkyl having 1 to 12 carbon atoms, alkenyl having 2 to 12 carbon atoms, or alkynyl having 2 to 12 carbon atoms;

R ₅ is independently R ₄ , each R ₄ is substituted with 0-3 R ₃ groups;

R _5a is independently an alkylene of 1 to 12 carbon atoms, an alkenylene of 2 to 12 carbon atoms, or an alkynylene of 2 to 12 carbon atoms, and 0 to 3 of any of alkylene, alkenylene or alkynylene Substituted with a R ₃ group;

R _6a is independently H or an ether- or ester-forming group;

R _6b is independently H, a residue or amino protecting group of a carboxyl-containing compound;

R _6c is independently H, or a residue of an amino-containing compound;

W ₁ is an R _6c amide group of an acidic hydrogen, a protected acid group, or a group containing acidic hydrogen;

W ₂ is a basic hetero atom or a protected basic hetero atom, or R _6b amide of a basic hetero atom;

W ₃ is W ₄ or W ₅ ;

W ₄ is R ₅ or —C (O) R ₅ , —C (O) W ₅ , —SO ₂ R ₅ , or —SO ₂ W ₅ ;

W ₅ is carbocycle or heterocycle, wherein W ₅ is independently substituted with 0-3 R ₂ groups;

W ₆ is -R ₅ , -W ₅ , R _5a W ₅ , -C (O) OR _6a , -C (O) R _6c , -C (O) N (R _6b ) ₂ , -C (NR _6b ) (N (R _6b ) ₂ ), -C (NR _6b ) (N (H) (R _6b )), -C (N (H) (N (R _6b ) ₂ ), -C (S) N (R _6b ) ₂ , or -C (O) R ₂ ;

X ₁ is a bond, —O—, —N (H) —, —N (W ₆ ) —, —S—, —SO—, or —SO ₂ —; ego

Each m ₁ is independently an integer from 0 to 2;

Provided that compounds where U ₁ is H or —CH ₂ CH (OH) CH ₂ (OH) are excluded.

In another embodiment of the invention there is provided a composition or compound which further contains a pharmaceutically acceptable carrier.

In another embodiment of the present 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 present invention.

In another embodiment of the invention there is provided a method of inhibiting neuraminidase activity, comprising contacting a sample suspected of containing neuraminidase with a composition embodiment of the invention.

Another embodiment of the invention consists in administering a therapeutically effective amount of an antiviral active compound disclosed in WO 91/16320, WO 92/06691 or US Pat. No. 5,360,817 to the host by a route other than topical administration to the respiratory tract. In some hosts, methods are provided for treating or preventing a virus, particularly 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 using Compound 281, consisting of forming Compound 281.1 by treating Compound 281 with a compound of Formula R ₅ -X ₁ -H.

During the formula:

X ₁ and R ₅ are as defined above;

R ₅₁ is an acid stable protecting group for carboxylic acid;

R ₅₄ is an aziridine activator.

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

This method treats quinic acid with geminal dialkoxyalkane or with Geminal dialkoxy cycloalkane and an acid to form a compound having the formula:

Compound 274 was treated with metal alkoxide and alkanol to form a compound having the following formula:

Compound 275 was treated with sulfonic acid halides and amines to yield compounds having the following formula:

Treating compound 276 with a dehydrating agent followed by acid and alkanol to form a compound having the formula:

During the formula:

R ₅₀ is a 1,2 diol protecting group;

R ₅₁ is an acid stable carboxylic acid protecting group;

R ₅₂ is a hydroxy activator.

<Cross description of related patent application>

The present invention discloses U.S. Provisional Patent Application No. 60 / 060.195, filed Sep. 26, 197, US Patent Application No. 08 / 938,644, filed Sep. 26, 1997, and US, filed Sep. 17, 1997. Based on Provisional Patent Application No. 60 / 059,308.

The invention also relates to US patent application Ser. No. 08 / 653,034, filed Feb. 24, 1996, which patent application is partly filed in US patent application Ser. No. 08 / 606,624, filed Feb. 26, 1996. And the application is a partial application of US Patent Application No. 08 / 580,567, filed December 29, 1995, and the application is a partial application of US Patent Application No. 08 / 476,946, filed June 6, 195 And this application is part of US Patent Application Serial No. 08 / 395,245, filed February 27, 1995, which is incorporated by reference in its entirety. The present invention relates to US patent application Ser. No. 08 / 917,640, filed August 22, 1997, which discloses a process for the preparation of carbocyclic compounds, in particular GS4104, a process for the preparation of phosphate salts. The full text of the application is attached by reference.

<The technical field of the invention>

Neuraminidase (also known as sialidase, acylneuraminil hydrolase. EC 3.2.1.18) is a common enzyme in animals and many microorganisms. This enzyme is a glycohydrolase that cleaves alpha-ketoside linked sialic acid from glycoproteins, glycolipids, and oligosaccharides. Many microorganisms containing neuraminidase cause disease in humans and poultry, horses, pigs and seals and other animals. Such pathogenic organisms include influenza viruses.

Neuraminidase is involved in the pathogenicity of influenza viruses. This is thought to elute the newly synthesized virons from infected cells and to help the virus move (through its hydrolase activity) through the mucous membranes of the respiratory tract.

1 and 2 show GG 167 (4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid: FIG. 1), which is a known anti-influenza compound, and the compound of the present invention FIG. 2 shows the arterial oxygen saturation (SaO ₂ ) concentrations in influenza-A-infected mice treated with intraperitoneal injection at different concentrations: squares, colored circles, triangles, and diamonds and uncolored Circles represent test compounds and saline controls 50, 10, 2 and 0.5 mpk (mg / kg / day), respectively. In all figures, * P <0.05, ** P <0.01 are for the saline control.

3-5 show ribavirin (triangles), compound 203 (squares) and GG167 (coloured circles); Comparison of SaO ₂ concentrations in influenza A infected mice with po concentrations at different concentrations of saline control (uncolored circles): FIG. 3: 150 mgk for compound 203 and GG167, 100 mpk for ribavirin; 4: 50 mpk for compound 203 and GG167, 32 mpk for ribavirin; 5: 10 mpk for compound 203 and GG167, 10 mpk for ribavirin.

Figures 6-8 depict SaO ₂ concentrations in influenza A infected mice treated with small amounts po of Compounds 262 (circles) and 260 (colored squares) and GG167 (triangles); The saline control is the uncolored circle and the uninfected control is the uncolored square: Figure 6: mpk of each test compound; 7: each test compound 1 mpk; 8: 0.1 mpk of each test compound.

<Detailed explanation>

<Compositions of the present invention>

Compounds of the present invention do not include compounds known to date. However, as will be apparent from the examples described below, the antiviral purpose use of known compounds which has been produced and used only as an intermediate so far in the preparation of antiviral compounds is within the scope of the present invention. In the United States, compounds expected by 35 USC §102 or 35 USC §103 are excluded from the present invention. In particular, the claims of the present invention are foreseen by WO 91/16320, WO 92/06691, US Pat. No. 5,360,817 or Chandler M. et al. “J. Chem. Soc. Perkin Trans. I”, 1995, 1189-1197. These documents should be construed as excluding compounds that are not novel.

However, in an embodiment of the present invention, while falling within the general scope of WO 91/16320, WO 92/06691, or US Pat. No. 5,360,817, (a) the general formula Ia of the '320 application, (b) the' 320 pending group “A "C ⁵ and (c) R ⁵ in the '320 and' 691 applications are" CH ₂ YR ⁶ _, CHYR ⁶ CH ₂ YR ⁶ or -CHYR ⁶ CHYR ⁶ CH ₂ YR ⁶ "where YR ⁶ is OH or protected OH And protecting groups can be hydrolyzed under human gastrointestinal conditions to produce free OH groups, which are stable compounds for hydrolysis in the gastrointestinal tract. Thus, compounds generally excluded from embodiments of the present invention are compounds in which R ⁵ is carbasil or acetyl having from 1 to 4 carbon atoms in the '320 application and the' 691 application compound.

Methods and diets for determining the stability of compounds in surrogate gastrointestinal secretion are well known. The compound is defined as stable in the gastrointestinal tract when the protecting group deprotected in surrogate or gastric juice is less than about 50 mole percent upon incubation for 1 hour at 37 ° C. Such compounds are suitable for use in embodiments of the invention. Just because some compounds are stable in the gastrointestinal system does not mean that they cannot be hydrolyzed in vivo. Prodrugs will generally be stable in the digestive system but eventually hydrolyze into the parent drug in the digestive tract, liver, or other metabolic organs or cells.

However, other embodiments of the invention are those in which YR ⁶ is a free hydroxyl, or a hydroxyl group protected by a group that is readily hydrolyzed such as acetyl, WO 91/16320, WO 92/06691, or US Pat. No. 5,360,817 All uses of the compounds specifically disclosed in the call will be described in detail. In this case, however, these compounds will be delivered by a novel route of administration.

In another embodiment, compounds of the text do not include:

(a) E ₁ is -CO ₂ H, -P (O) (OH) ₂ , -NO ₂ , -SO ₂ H, -SO ₃ H, tetrazolyl, -CH ₂ CHO, -CHO, or CH (CHO ) ₂ ;

(b) G ₁ is -CN, N ₃ , -NHR ₂₀ , NR ₂₀ , -OR ₂₀ , guanidino, SR ₂₀ , -N (R ₂₀ ) → O, -N (R ₂₀ ) (OR ₂₀ ), -N (H) (R ₂₀ ) N (R ₂₀ ) ₂ , unsubstituted pyrimidinyl, or unsubstituted (pyrimidinyl) methyl;

(c) T ₁ is —NHR ₂₀ , —NO ₂ ; and R ₂₀ is H; Acyl groups of 1-4 carbon atoms; Straight or cyclic alkyl groups of 1 to 6 carbon atoms, or halogen-substituted homologs thereof; Allyl or unsubstituted aryl groups or halogen substituted aryl groups, OH groups, NO ₂ groups, NH ₂ groups or COOH groups;

(d) each J ₁ is H;

(e) X ₁ is a bond, —CH ₂ or —CH ₂ CH ₂ —;

Wherein W ₆ is not —CH ₂ , W ₇ or —CH ₂ W ₇ , where W ₇ is H, —OR _6a , —OR ₁ , —N (R ₁ ) ₂ , —N (R ₁ ) (R _6b ), -N (R _6b ) ₂ , -SR ₁ or -SR _6a .

Also excluded are compounds disclosed in page 9, line 26 to page 11, line 5 of WO 92/06691 and pharmaceutically acceptable salts or derivatives thereof, which appear to include the following compounds having formula II above:

(a) A is O;

(b) E ₁ is COOH, P (O) (OH) ₂ , NO ₂ , SOOH, SO ₃ H, tetrazolyl, CH ₂ CHO, CHO, or CH (CHO) ₂ or E ₁ is COOH, P (O ) (OH) ₂ , SOOH, SO ₃ H, ethyl, methyl or pivaloyl esters thereof;

(c) G ₁ is hydrogen, N (R ^20a ), SR ^20a , —OR ^20a ;

(d) T ₁ is —NHC (O) R ^20b , wherein R ^20b is a straight or cyclic alkyl group having 1 to 6 carbon atoms, or a halogen-substituted homologue thereof, or SR ^20a , OR ^20a , COOH or alkyl / Aryl esters, NO ₂ groups, C (R ^20a ) ₃ , CH ₂ COOH, or alkyl / aryl esters thereof, CH ₂ NO ₂ or CH ₂ NHR ^20b ;

(e) R ²⁰ is hydrogen; Acyl groups of 1 to 4 carbon atoms; Straight or cyclic alkyl groups having 1 to 6 carbon atoms, or halogen-substituted homologs thereof, or halogen substituted or unsubstituted aryl groups, allyl groups, OH, NO ₂ , NH ₂ or COOH groups;

(f) J ₁ is H and J _1a is H, OR ^20a , F, Cl, Br, CN, NHR ^20a , SR ^20a or CH ₂ X, X is NHR ^20a , halogen or OR ^20a ;

(g) J ₂ is H, or J ₂ 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 CHYR ^20a CH ₂ YR ^20a , wherein Y is O, S or H, and the consecutive Y moieties in the U ₁ group are the same or different, If Y is H, R ^20a is a covalent bond.

In another embodiment, the compounds of the present invention are compounds wherein U ₁ is not —CH ₂ OH, —CH ₂ OAc, or 0CH ₂ OCH ₂ Ph.

In another embodiment, the compounds of the present invention are compounds wherein E ₁ is not -CH ₂ OH, -CH ₂ OTMS, or -CHO.

In another embodiment, the compounds of the invention are those wherein U ₁ is not directly bonded to the nuclear ring by a carbon atom or U ₁ is not substituted with hydroxyl or hydroxyether, in particular U ₁ is polyhydroxyalkane , In particular -CH (OH) CH (OH) CH ₂ OH. In another embodiment, U ₁ is carbocycle substituted with a branched chain group R ₅ or at least one R ₅ group described below.

In another embodiment, compounds of the invention exclude compounds having the formula V or VI:

During the formula:

1. 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 has the following formula:

;

2. In Formula V:

A ₂ is —O— or —CH ₂ —;

E ₁ is —CO ₂ H;

G ₁ is —NH ₂ ;

T ₁ is -N (H) (Ac); and

U ₁ is —CH ₂ OH;

3. 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); and

U ₁ is —CH ₂ OCH ₂ Ph;

4. In Formula V:

A ₂ is -CH _2- ;

E ₁ is —CO ₂ H or —CO ₂ CH ₃ ;

G ₁ is -N ₃ ;

T ₁ is -N (H) (Ac); and

U ₁ is —CH ₂ OH;

5. In Formula V:

A ₂ is -CH _2- ;

E ₁ is —CO ₂ H, —CHO, or —CH ₂ OH;

G ₁ is -N ₃ ;

T ₁ is -N (H) (Ac); and

U ₁ is —CH ₂ OCH ₂ Ph;

6. In Formula VI:

A ₂ is -CH _2- ;

E ₁ is —CO ₂ H;

G ₁ is —OCH ₃ ;

T ₁ is -NH ₂ ; and

U ₁ is —CH ₂ OH;

7. 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); and

U ₁ is -CH ₂ OAc.

Where the compounds described herein are substituted with one or more identically represented groups such as "R ₁ " or "R _6a " groups, these groups should be interpreted as having or different. That is, each group should be interpreted as being independently selected.

"Heterocycle" in the text is given by way of example and Paquette, Leo A.,: "Principles of Modern Heterocyclic Chemistry" (WA Benjamin, New York, 1968), in particular Chapters 1,3,4,6,7, and 9 ; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present), especially volumes 13, 14, 16, 19 and 28; And "J. Am. Chem. Soc.", 82: 5566 (1960).

Examples of heterocycles include pyridyl, thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl , Thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidoneyl, pyrrolinyl , Tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azosinyl, triazinyl, 6H-1,2,5-thiadiazinyl , 2H, 6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, cromenyl, xenyl, phenoxatiinyl, 2H-pyrrolyl, isothiazolyl, Isoxazolyl, pyrazinyl, pyridazinyl, indolinyl, isoindolinyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolininyl, Talazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cynolinyl, pteredinyl, 4aH-carbazolyl, carbazolyl, ??-carbolinyl, phenanthridinyl, acridinyl, pyrimididi Neil, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromenyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzo Triazolyl, benzoisoxazolyl, oxyindolyl, benzoxazolinyl, and isatinoyl.

Examples of carbon bonded heterocycles include 2,3,4,5, or 6 position of pyridine, 3,4,5 or 6 position of pyridazine, or 2,4,5 or 6 position of pyrimidine, 2 of pyrazine , 3,5 or 6 position, furan, tetrahydrofuran, thiofuran, thiophene, 2,3,4 or 5 position of pyrrole or tetrahydropyrrole, 2,4, or 5 of oxazole, imidazole or thiazole Position, 3,4, or 5 position of isoxazole, pyrazole or isothiazole, position 2 or 3 of aziridine, position 2,3 or 4 of azetidine, position 2,3,4,5,6 of quinoline, And those bound at the 7 or 8 position, 1,3,4,5,6,7, or 8 position of isoquinoline, but are not limited thereto. More generally, carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-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.

Nitrogen linked heterocycles include aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole , Pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, pyrrazine, indole, indolin, 1 position of 1H-indazole, isoindole, or 2 position of isoindoleline, 4 position of morpholine And, and those bound to the 9 position of carbazole or β-carboline, but is not limited thereto. More specifically, nitrogen-bonded heterocycles include 1-aziridyl, 1-azededyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

Unless otherwise stated in the present invention, "alkyl" includes normal, secondary, tertiary, or cyclic carbon atoms as C ₁ -C ₁₂ hydrocarbons. Examples are methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), 1-propyl (n-Pr, n-propyl, -CH ₂ CH ₂ CH ₃ ), 2-propyl (i-Pr , I-propyl, -CH (CH ₃ ) ₂ , 1-butyl (n-Bu, n-butyl, -CH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-1-propyl (i-Bu, I- Butyl, -CH ₂ CH (CH ₃ ) ₂ ), 2-butyl (s-Bu, s-butyl, -CH (CH ₃ ) CH ₂ CH ₃ ), 2-methyl-2-propyl (t-Bu, t -Butyl, -C (CH ₃ ) ₃ ), 1-pentyl (n-pentyl, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH (CH ₃ ) CH ₂ CH ₂ CH ₃ ) , 3-pentyl (-CH (CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butyl (-C (CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH (CH ₃ ) CH (CH ₃ ) ₂ ), 3-methyl-1-butyl (-CH ₂ CH ₂ CH (CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH (CH ₃ ) CH ₂ CH ₃ ), 1-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH (CH ₃ ) CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH (CH ₂ CH ₃ ) (CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (-C (CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH (CH ₃ ) CH (CH ₃ ) CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH (CH ₃ ) CH ₂ CH (CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C (CH ₃ ) ( CH ₂ CH ₃ ) ₂ ), 2-methyl-3- Pentyl (-CH (CH ₂ CH ₃ ) CH (CH ₃ ) ₂ , 2,3-dimethyl- ₂ -butyl (-C (CH ₃ ) ₂ CH (CH ₃ ) ₂ ), 3,3-dimethyl-2- Butyl (-CH (CH ₃ ) C (CH ₃ ) ₃ ) Examples of alkyl groups are shown in Table 2 as groups 2-5, 7, 9 and 100-399.

Compositions of the present invention contain compounds of Formulas (I) and (II)

[Formula I]

[Formula II]

In a typical embodiment, the 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 , generally R ₁ or F, more typically H, or F, more generally H to be.

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

A ₁ is -C (J ₁ ) =, or -N =, generally -C (J ₁ ) =, more generally -CH =;

A ₂ is -C (J ₁ ) _2- , -N (J ₁ )-, -N (O) (J ₁ )-, -N (O) =, -S-, S (O)-, -S (O) ₂ -or -O-, generally -C (J ₁ ) _2- , -N (J ₁ )-, -S-, or -O-, more generally -C (J ₁ ) ₂ -, Or -O-, more generally -CH ₂ or -O-, more generally -CH ₂ .

E ₁ is — (CR ₁ R ₁ ) m ₁ W ₁ .

In general, R ₁ is H or alkyl of 1 to 12 carbon atoms, generally H or 1 to 4 carbon atoms, or 5 to 10 alkyl, more generally H, or carbon atoms 1,2,3, 4,5,6,8,9,10,11 or 12 alkyl, more generally H or alkyl of 1 to 3 carbon atoms selected from methyl, ethyl, n-propyl, and i-propyl. The most common case is when R ₁ is H.

m1 is an integer from 0 to 2, generally 0, or 1, most commonly 0.

m2 is an integer of 0-1.

m3 is an integer of 1-3.

W ₁ is a group consisting of R _6c amide of an acidic hydrogen, a protected acid group, or a group containing acidic hydrogen, which in the text represents a hydrogen atom that can be removed by a base that produces anions or a corresponding salt or solvate. It means group which has. The general definitions of acidity and basicity of organic matter are well understood and understood as W ₁ definitions. The text does not explain it in detail. However, Streitwieser, A.,; And Heathcock, CH; It is described in "Introduction to Organic Chemistry, Second Edition" (Macmillan, New York, 1981), pages 60-64. In general, the acid groups of the present invention have a lower pK value than water, usually pK = 10 min, more generally less than pK = 8 and more generally less than pK = 6. These include tetrazole and acids of carbon, sulfur, phosphorus and nitrogen, generally carboxylic acids, sulfuric acids, sulfonic acids, sulfinic acids, phosphoric acids and phosphonic acids, including R _6c amides and R _6b esters of these acids. (R _6a and R _6c are defined below). Examples of W ₁ are -CO ₂ H, -CO ₂ R _6a , -OSO ₃ H, -SO ₃ H, -SO ₂ H, -OPO ₃ H ₂ , -PO ₃ (R _6a ) ₂ , -PO ₃ H _2, may be mentioned _{-PO 3 (H) (R 6a} ) 2. W ₁ is generally E ₁ , E ₁ is generally —CO ₂ Hm —CO ₂ R _6a , —CO ₂ R ₄ or CO ₂ R ₄ or CO ₂ R ₁ , most commonly as CO ₂ R ₁₄ Wherein R ₁₄ is normal or terminal secondary C _1-6 alkyl.

W ₁ may also be a protected acid group and the text may be the aforementioned acid groups protected by one of the groups commonly used in the art for this group or described in the R _6a column below. More generally, protected W ₁ is -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 NHC (O) —R ₄ , wherein R ₁ is as defined above.

More generally E ₁ is -C (O) 0 (CH ₂ ) _b CH ((CH ₂ ) _c CH ₃ ) ₂ (where b = 0 to 4, c = 0 to 4, and b + c is 1 to) 4), or the following groups:

Exemplary 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, and, where R ₁ and m1 are as defined above. In general, G ₁ is - _{(CR 1 R 1) m1 W} 2.

W ₂ is a group comprising a R _6b amide of a basic hetero atom, a protected basic hetero atom or a basic hetero atom. In general, W ₂ is composed of basic atoms, and in the text, it refers to an acid other than carbon capable of protonation, and generally acidic hydrogen having an acidity in the range mentioned for W ₁ . The basic principles of basicity are described in the literature cited in Streitwieser and Heathcock, and those skilled in the art will appreciate the term basic heteroatoms. In general, the basic heteroatoms used in the compounds of the present invention have a pK value in the range given in the W ₁ definition above in the corresponding porotonized form. Basic heteroatoms include heteroatoms common to organic compounds having electron pairs such as non-shared, non-bonded, n-type, and the like. For example, typical basic heteroatoms are the oxygen, nitrogen, and sulfur atoms of alcohols, amines, amidines, guanidines, sulfides, and the like, often groups such as amines, amidines and guanidines. Usually, W ₂ is an amino or aminoalkyl (generally lower alkyl) group such as aminomethyl, aminoethyl or aminopropyl; Amidinoyl or an amidinoalkyl group such as amidinomethyl, amidinoethyl, or amidinopropyl; Guanidyl or guanidinoalkyl groups such as guanidinomethyl, guanidinoethyl, or guanidinopropyl (in which case the alkyl group serves to link the basic substituents to the carbocycle ring). More generally, W ₂ is an amino, amidino, guanidino, heterocycle, heterocycle substituted with one or two amino or guanidino groups (usually one), or two substituted with amino or guanidino Alkyl of from 3 to 3 carbon atoms, or such alkyl substituted with a second group selected from amino and hydroxy and amino. Heterocycles useful as W ₂ generally include N or S-containing 5 or 6 membered rings, where the ring contains 1 or 2 heteroatoms. Such heterocycles generally have a substituent on a ring carbon atom. They may be saturated or unsaturated and may be linked to the central cyclohexene by lower alkyl (m1 = 1 or 2) or -NR _1- .

More generally W ₂ is -NHR ₁ , -C (NH) (NH ₂ ), -NR ₁ -C (NR ₁ ) (NR ₁ R ₃ ), -NH-C (NH) (NR ₃ ), -NH -C (NH) (NHR ₁ ), -NH-C (NH) NH ₂ , -CH (CH ₂ NHR ₁ ) (CH ₂ OH), -CH (CH ₂ NHR ₁ ) (CH ₂ NHR ₁ ), CH (NHR ₁ ),-(CR ₁ R ₁ ) _{m 2} -CH (NHR ₁ ) R ₁ , -CH (OH)-(CR ₁ R ₁ ) _{m 2} -CH (NHR ₁ ) R ₁ , or -CH (NHR ₁ )-(CR ₁ R ₁ ) _{m 2} -CH (OH) R ₁ ,-(CR ₁ R ₁ ) _{m 2} -SC (NH) NH ₂ , -N = C (NHR ₁ ) (R ₃ ), -N = C (SR ₁ ) N (R ₁ ) ₂ , —N (R ₁ ) C (NH) N (R ₁ ) C = N, or —N = C (NHR ₁ ) (R ₁ ); Where m2 is generally 0, usually R ₁ is H and R ₃ is C (O) N (R ₁ ) ₂ .

W ₂ refers to a basic heteroatom as described above, which is an optionally protected basic heteroatom and is protected by R _6b as a group common in the art. Such groups are described in detail in Greene (see supra) and are as described below. Such groups are for example amide, carbamate, amino acetal, imine, enamine, N-alkyl or N-aryl phosphinyl, N-alkyl or N-aryl sulfen or sulfonyl, N-alkyl or N-aryl silyl, thioether , Thioesters, disulfides, sulfenyl and the like. In some embodiments, protecting group R _6b will be cleavable under physiological conditions and will generally be cleavable in vivo. For example, basic heteroatoms form amides with organic acids or amino acids, such as naturally occurring amino acids or polypeptides, as described below for the R _6a group.

In general, G ₁ is selected from the group consisting of:

Examples of G ₁ groups are also listed in Table 4.

T _{1 together} with —NR ₁ W ₃ , —R ₃ , —R ₅ or a heterocycle or U ₁ or G ₁ forms a group having the structure

Wherein R _6b is as defined below and R ₁ and W ₃ are as defined above. Typical T ₁ is -NR ₁ , W ₃ or heterocycle. In general, T ₁ is selected from the group consisting of:

Examples of T ₁ groups are shown in Table 5.

W ₃ is W ₄ or W ₅ , where W ₄ is R ₁ or —C (O) R ₅ , —C (O) W ₅ , —SO ₂ R ₅ , or —SO ₂ W ₅ . Generally W ₃ is -C (O) R ₅ or W ₅ .

R ₂ is independently R ₃ or R ₄ as defined below, provided that each R ₄ is independently substituted with 0 to 3 R ₃ groups;

R ₃ is independently F, Cl, Br, I, -CN, N ₃ , -NO ₂ , -OR _6a , -OR ₁ , -N (R ₁ ) ₂ , -N (R ₁ ) (R _6b ), -N (R _6b ) ₂ , -SR ₁ , -SR _6a , -S (O) R ₁ , -S (O) ₂ R ₁ , -S (O) OR ₁ , -S (O) OR _6a ,- S (O) ₂ OR ₁ , -S (O) ₂ OR _6a , -C (O) OR ₁ , -C (O) R _6c , -C (O) OR _6a , -OC (O) R ₁ ,- N (R ₁ ) (C (O) R ₁ ), -N (R _6b ) (C (O) R ₁ ), -N (R ₁ ) (C (O) OR ₁ ), -N (R _6b ) (C (O) OR ₁ ), -C (O) N (R ₁ ) ₂ , -C (O) N (R _6b ) (R ₁ ), -C (O) N (R _6b ) ₂ , -C (NR ₁ ) (N (R ₁ ) ₂ ), -C (N (R _6b ) (N (R ₁ ) ₂ ), -C (N (R ₁ ) (N (R ₁ ) (R _6b )), -C (N (R _6b ) (N (R ₁ ) (R _6b )), -C (N (R ₁ ) (N (R _6b ) ₂ ), -C (N (R _6b ) (N (R _6b) ) ₂ ), -N (R ₁ ) C (N (R ₁ ) (N (R ₁ ) ₂ ), -N (R ₁ ) C (N (R ₁ )) (N (R ₁ ) (R _6b ) ), -N (R ₁ ) C (N (R _6b )) (N (R ₁ ) ₂ ), -N (R _6b ) C (N (R ₁ )) (N (R ₁ ) ₂ ), -N (R _6b ) C (N (R _6b )) (N (R ₁ ) ₂ ), -N (R _6b ) C (N (R ₁ )) (N (R ₁ ) (R _6b )), -N ( R ₁ ) C (N (R _6b )) (N (R ₁ ) (R _6b )), -N (R ₁ ) C (N (R ₁ )) (N (R _6b ) ₂ ), -N (R _6b ) C (N (R _6b )) (N (R ₁ ) (R _6b )), -N (R _6b ) C (N (R ₁ )) (N (R _6b ) ₂ ), -N (R ₁ ) C (N (R _6b )) (N (R _6b ) ₂ ), -N (R _6b ) C (N (R _6b )) (N (R _6b ) ₂ ), = O, = S, = N ( R ₁ ), = N (R _{6 b} ) or W ₅ . Typically, R ₃ is F, Cl, -CN, N ₃ , NO ₂ , -OR _6a , -OR ₁ , -N (R ₁ ) ₂ , -N (R ₁ ) (R _6b ), -N (R _6b ) ₂ , -SR ₁ , -SR _6a , -C (O) OR ₁ , -C (O) R _6c , -C (O) OR _6a , -OC (O) R ₁ , -NR ₁ C (O ) R ₁ , -N (R _6b ) C (O) R ₁ , -C (O) N (R ₁ ) ₂ , -C (O) N (R _6b ) (R ₁ ), -C (O) N (R _6b ) ₂ , or = O. More specifically, the R ₃ group containing R _6b includes —C (O) N (R _6b ) ₂ or —C (O) N (R _6b ) (R ₁ ). More generally R ₃ is F, Cl, -CN, N ₃ , -OR ₁ , -N (R ₁ ) ₂ , -SR ₁ , -C (O) OR ₁ , -OC (O) R ₁ , or = O. More generally, R ₃ is F, -OR ₁ , -N (R ₁ ) ₂ or = O. In the text, "= O" is a double bonded oxygen atom (oxo) and "= S", = N (R _6b ) and "= N (R ₁ )" are sulfur and nitrogen homologues.

R ₄ is alkyl having 1 to 12 carbon atoms and alkynyl or alkenyl having 2 to 12 carbon atoms. Alkyl R ₄ is generally carbon atoms 1,2,3,4,5,6,7,8,9,10,11 or 12 and alkenyl and alkynyl R ₄ are usually carbon atoms 2,3,4 , 5, 6, 7, 8, 9, 10, 11 or 12. R ₄ is usually alkyl (as defined above). If R ₄ is alkenyl it is typically ethenyl (-CH = CH ₂ ), 1-prop-1-enyl (-CH = CHCH ₃ ), 1-prop-2-enyl (-CH ₂ CH = CH ₂ ), 2-prop-1-enyl (-C (= CH ₂ ) (CH ₃ )), 1-but-1-enyl (-CH = CHCH ₂ CH ₃ ), 1-but-2-enyl ( -CH ₂ CH = CHCH ₃ ), 1-but-3-enyl (-CH ₂ CH ₂ CH = CH ₂ ), 2-methyl-1-prop-1-enyl (-CH = C (CH ₃ ) ₂ ), 2-methyl-1-prop-2-enyl (-CH ₂ C (= CH ₂ ) (CH ₃ )), 2-but-1-enyl (-C (= CH ₂ ) CH ₂ CH ₃ ) , 2-but-2-enyl (-C (CH ₃ ) = CHCH ₃ ), 2-but-3-enyl (-CH (CH ₃ ) CH = CH ₂ ), 1-pent-1-enyl (-C = CHCH ₂ CHCH ₃ ), 1-pent-2-enyl (-CHCH = CHCH ₂ CH ₃ ), 1-pent-3-enyl (-CHCH ₂ CH = CHCH ₃ ), 1-pent-4-enyl (- CHCH ₂ CH ₂ CH = CH ₂ ), 2-pent-1-enyl (-C (= CH ₂ _CH ₂ CH ₂ CH ₃ ), 2-pent-2-enyl (-C (CH ₃ ) = CH ₂ CH ₂ CH ₃ ), 2-pent-3-enyl (-CH (CH ₃ ) CH = CHCH ₃ ), 2-pent-4-enyl (-CH (CH ₃ ) CH ₂ CH = CH ₂ ) or 3-methyl a boot-l-2-enyl _{(-CH 2 CH = C (CH} 3) 2). the more typically, R ₄ is a carbon atom 2, 3 or 4 alkenyl . R ₄ is alkynyl, in the case, typically ethynyl (-C≡CH), prop-1-ynyl-1- (-C≡CCH _3), 1- prop-2-ynyl (-CH ₂ C≡ CH), 1-but-1-ynyl (-C≡CCH ₂ CH ₃ ), 1-but- ₂ -ynyl (-CH ₂ C≡CCH ₃ ), 1-but-3-ynyl (-CH ₂ CH ₂ C≡CH), 2-but-3-ynyl (-CH (CH ₃ ) C≡CH), 1-pent-1-ynyl (-C≡CCH ₂ CH ₂ CH ₃ ), 1-pent-2-ynyl (-CH ₂ C≡CCH ₂ CH ₃ ), 1-pent-3-ynyl (-CH ₂ CH ₂ C≡CCH ₃ ) or 1-pent-4-ynyl (-CH ₂ CH ₂ CH ₂ C≡CH) to be. More generally, R ₄ is a carbon atom of 2, 3, or 4 alkynyl groups.

R ₅ is R ₄ as defined above or R ₄ substituted with 0 to 3 R ₃ groups. In general, R ₅ is alkyl of 1 to 4 carbon atoms substituted with 0 to 3 fluorine atoms.

R _5a is each an alkylene having 1 to 12 carbon atoms, an alkenylene having 2 to 12 carbon atoms, or an alkynylene having 2 to 12 carbon atoms, and any of the alkylene, alkenylene or alkynylene is 0 to 3 Is substituted with R ₃ groups. As defined by R ₄ , R _5a represents 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 alkylene, 2, 3, 4, 5, 6 carbon atoms. , 7, 8, 9, 10, 11 or 12 alkenylene or alkynylene. Each of the common R ₄ groups is a general R _5a group assuming that one of the hydrogen atoms of the R ₄ group as described above is removed to form an open valence at the carbon atom to which the second bond to R _5a is attached.

R ₁₄ is normal or terminal secondary C _1-6 alkyl.

W ₅ is a carbocycle or heterocycle 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 separated from the reaction mixture in a measurable yield, in measurable purity, at temperatures between -78 ° C and 200 ° C. Each W ₅ is independently substituted with 0 to 3 R ₂ groups. Usually, T ₁ and W ₅ are saturated, unsaturated or aromatic rings with mono- or bicyclic carbocycles or heterocycles. More generally, T ₁ or W ₅ have 3 to 10 ring atoms, more generally 3 to 7 ring atoms, typically 3 to 6 ring atoms. T ₁ and W ₅ rings are saturated when containing 3 ring atoms, saturated or monounsaturated when containing 4 ring atoms, saturated or mono- or diunsaturated when having 5 ring atoms, 6 rings Containing atoms results in saturated, mono- or diunsaturated or aromatic rings. Unsaturation of the W ₅ ring includes internal unsaturation and external unsaturation where there is an outer portion linked to the ring.

If W ₅ is carbocyclic, it is usually 3 to 7 carbon monocycles or 7 to 12 carbon atom bicycles. More generally, the W ₅ monocycle-based carbocycle has 3 to 6 ring atoms, more generally 5 or 6 ring atoms. W ₅ bicyclic carbocycles are 7 to 12 ring atoms, more generally, arranged in a bicyclo [4,5], [5,5], [5,6], or [6,6] system Having 9 or 10 ring atoms arranged in 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-saclohex-3-enyl, phenyl, spiryl and naphthyl.

T ₁ or W ₅ heterocycles are generally 3 to 7 membered monocycles (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or 7 to 10 membered bicycles (4 To 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S). More generally, T ₁ and W ₅ are 3 to 6 membered monocycles (2 to 5 carbon atoms and 1 or 2 heteroatoms selected from N, O, and S), more generally 5 or 6 membered rings Having atoms (3 to 5 carbon atoms and 1 to 2 heteroatoms selected from N and S). T ₁ and W ₅ heterocycle-based bicycles have 7 to 10 ring atoms (6 to 9) arranged in bicyclo [4,5], [5,5], [5,6] or [6,6] systems Carbon atoms and 1 or 2 heteroatoms selected from N, O, and S), more generally 9 to 10 ring atoms (8 to 8) arranged in a bicyclo [5,6] or [6,6] system Nine carbon atoms and one or two heteroatoms selected from N and S).

Generally, the T ₁ and W ₅ heterocycles are pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, Furanyl, thiofuranyl, thienyl, or pyrrolyl.

More generally, the heterocycles of T ₁ and W ₅ are bonded via their carbon or nitrogen atoms. More generally the T ₁ heterocycle is bonded to the cyclohexene of the composition of the invention by stable covalent bonds through its nitrogen atom and the W ₅ heterocycle is cyclohexene of the composition of the invention by stable covalent bonds through its carbon or nitrogen atoms It is bound to the ring. Stable covalent bonds are chemically stable structures as described above.

W ₅ is optionally selected from the group consisting of:

U ₁ is H or -X ₁ W _6, but the latter is common.

X ₁ is a bond, -O-, -N (H)-, -N (W ₆ )-, -N (OH)-, -N (OW ₆ )-, -N (NH ₂ )-, -N ( N (H) (W ₆ ))-, -N (N (W ₆ ) ₂ )-, -N (H) N (W ₆ )-, -S-, -SO-, or -SO _2- ; Generally, X ₁ is a bond, -O-, -N (H)-, -N (R ₅ )-, -N (OH)-, -N (OR ₅ )-, -N (NH ₂ )-,- N (N (H) (R ₅ ))-, -N (N (R ₅ ) ₂ )-, -N (H) N (R ₅ )-, -S-, -SO-, or -SO _2- , More generally X ₁ is a bond, -O-, -NR _1- , -N (OR ₁ )-, -N (NR ₁ R ₁ )-, -S-, -SO-, or -SO _2- to be. Generally X ₁ is —O—, —NH—, —S—, SO—, or —SO ₂ —;

W ₆ is -R ₅ , -W _5- , -R ₅ W ₅ , -R _5a W ₅ , -C (O) OR _6a , -C (O) R _6c , -C (O) N (R _6b ) ₂ , -C (NR _6b ) (NR _6b ) ₂ ), -C (NR _6b ) (N (H) (R _6b )), -C (N (H) (N (R _6b ) ₂ ), -C (S) N (R _6b ) ₂ , or -C (O) R ₂ , generally W ₆ is -R ₅ , -W _5- , -R _5a W ₅ ; in some embodiments W ₆ is R ₁ , -C (O) -R ₁ , -CHR ₁ W ₇ , -CH (R ₁ ) _a W ₇ , -CH (W ₇ ) ₂ , where W ₇ is monovalent and a is 0 or 1, Or 0 if W ₇ is divalent), or -C (O) W _{7. In} some embodiments, W ₆ is -CHR ₁ W ₇ or -C (O) W ₇ , or W ₆ is-(CH ₂ ) _m1 CH ((CH ₂ ) _m3 R ₃ ) ₂ ,-(CH ₂ ) _m1 C ((CH ₂ ) _m3 R ₃ ) _{3 ;-(} CH ₂ ) _m1 CH ((CH ₂ ) _m3 R _5a W ₅ ) _{2; - (CH 2) m1} CH ((CH 2) m3 R 3) ((CH 2) m3 R 5a W 5); - (CH 2) m1 C ((CH 2) m3 R 3) 2 (CH 2 ) _m3 R _5a W ₅ ), (CH ₂ ) _m1 C ((CH ₂ ) _m3 R _5a W ₅ ) _{3 or-} (CH ₂ ) _m1 C ((CH ₂ ) _m3 R ₃ ) ((CH ₂ ) _m3 R _5a W ₅ ) ₂ ; _m3 is an integer of 1-3.

W ₇ is R ₃ or R ₅ but is generally an alkyl group of 1 to 12 carbon atoms substituted with 0 to 3 R ₃ groups, the latter being generally -R ₁ (R _6b ), -N (R _6b ) ₂ , -OR _6a , or SR _6a . More generally W ₇ is alkyl of 3 to 12 carboatoms substituted with —OR ₁ or OR ₁ .

Generally U ₁ is selected from R ₁ O—, —OCHR ₁ W ₇ , or the following.

Table ₁ illustrates the U ₁ group.

One embodiment of the invention is a compound having the formula:

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

Wherein G ₂ is G ₁ and is typically selected from the group consisting of:

Here, T ₂ is R ₄ or R ₅ . Generally T ₂ is alkyl of 1 to 2 carbon atoms substituted with 0 to 3 fluorine atoms.

U ₂ is one of:

;

Wherein R ₇ is H, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -OCH ₃ , -OAc (-OC (O) CH ₃ ), -OH, -NH ₂ , or- SH, generally H, -CH ₃ or -CH ₂ CH ₃ .

The R _6a and R _6b groups are not very important and can vary widely. If not H, their function is to serve as an intermediate of the parent drug substance. This does not mean that they are biologically inert. In contrast, an important function of these groups is that by converting the parent drug into a prodrug, the parent drug releases upon conversion of the prodrug in vivo. Since active prodrugs are absorbed more effectively than the parent drug, they actually have greater efficacy in vivo than the parent drug. If not hydrogen, R _6a and R _6b are removed ex vivo if it is a chemical intermediate or in vivo if it is a prodrug. In the case of chemical intermediates, the physiological acceptability of the resulting pro-functional product, such as an alcohol, is not particularly important so long as it is not pharmacologically toxic (but generally more preferably physiologically acceptable).

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

Wherein V _a is _a tetravalent atom generally selected from C and Si; V _b is a trivalent atom selected from B, Al, N, and P, more generally N and P; V _c is a divalent atom selected from O, S, and Se, more generally S; V ₁ is a group bonded to V _a , V _b or V _c by _a stable single covalent bond, generally V ₁ is a W ₆ group, more generally V ₁ is H, R ₂ , W ₅ , or- R _5a W ₅ , more generally H or R ₂ ; V ₂ is a group bonded to V _a or V _b by _a stable double covalent bond, provided that V ₂ is not = O, = S, or = N-, and generally V ₂ is = C (V ₁ ) ₂ Wherein V ₁ is as defined above; V ₃ is to V _a by stable triple covalent bonds; A bonded group, generally 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 between a parent molecule and a group having the formula:

Wherein V _a , V _b and V ₁ are as defined above; V _d is a pentavalent atom selected from P and N; V _e is a hexavalent atom, generally S; V ₄ is a group bonded to V _a , V _b , V _d or V _e by _a stable double covalent bond, provided that at least one V ₄ is = O, = S or = NV ₁ , and generally V ₄ is = C (V ₁ ) ₂ when not = O, = S or = N-, where V ₁ is as defined above.

Protecting groups of —OH functional groups (hydroxy, acid or other functional groups) are embodiments of “ether- or ester-forming groups”.

Of particular interest are ether- or ester-forming groups which can act as protecting groups in the synthesis scheme of the body. However, certain hydroxyl and thio protecting groups are not ether- or ester-forming groups as would be understood by one skilled in the art and are those contained in the amide in the R _6c column described below. R _6c can protect hydroxyl or thio groups such that hydrolysis from the parent drug produces hydroxyl or thio.

In the ester-forming role, R _6a is generally bound to an acidic group such as, but not limited to, a -CO ₂ H or -C (S) OH group, resulting in -CO ₂ R _6a . R _6a is derived from, for example, the ester groups listed in WO95 / 07920.

Examples of R _6a are:

C _3-12 heterocycle (as described above) or C _6-12 aryl. These aromatic groups are optionally polycyclic or monocyclic. Such as 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, and 1-, 2-, 4- and 5-pyrimidinyl,

R ₁ , R ₁ -OC ₁ -C ₁₂ alkylene, C ₁ -C ₁₂ alkoxy, CN, NO ₂ , OH, carboxy, carboxyester, thiol, thioester, C ₁ -C ₁₂ haloalkyl (1-6 halogen atoms), C ₂ -C ₁₂ alkenyl, C ₂ -C ₁₂ alkynyl, or halo-substituted C _6-12 aryl or C _3-12 heterocycle. Examples of 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 , 2, -3,-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-, 2,6-, 3,4- and 3,5-dime Methoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6- 3,4- and 3,5-dihalophenyl (2,4-difluorophenyl and 3,5-diflo 2-, 3-, and 4-haloalkylphenyl (including 1-5 halogen atoms, C _1-12 alkyl, 4-trifluoromethylphenyl), 2-, 3- And 4-cyanophenyl, 2-, 3- and 4-nitrophenyl, 2-, 3- and 4-haloalkylbenzyl (1 to 5 halogen atoms, C _1-12 alkyl, 4-trifluoromethylbenzyl And 2-, 3- and 4-trichloromethylbenzyl and 2, -3 and 4-trichloromethylphenyl), 4-N-methylpiperidinyl, 3-N-methylpiperidinyl, 1-ethylpipera Genyl, benzyl, alkylsalicylphenyl (including C _1-4 alkyl, 2-, 3- and 4-ethylsalicylphenyl), 2-, 3- and 4-acetylphenyl, 1,8-dihydroxynaphthyl (-C ₁₀ H ₆ -OH) and aryloxy ethyl [C _6-9 aryl with phenoxyethyl], 2,2'-dihydroxybiphenyl, 2-, 3- and 4-N, N- Dialkylaminophenol, -C ₆ H ₄ CH ₂ -N (CH ₃ ) ₂ , trimethoxybenzyl, triethoxybenzyl, 2-alkyl pyridinyl (C _1-4 alkyl);

;

C _4-8 ester of 2-carboxyphenyl; And halogen, C _1-12 alkoxy (including methoxy and ethoxy), cyano, nitro, OH, C _1-12 haloalkyl (including 1 to 6 halogen atoms; —CH ₂ -CCl ₃ ), C _1- C _1-4 in which the aryl moiety is substituted by 1 to 2 or 3 to 5 halogen atoms or a group selected from ₁₂ alkyl (including methyl and ethyl), C _2-12 alkenyl or C _2-12 alkynyl -C _3-6 alkylene-aryl (benzyl, -CH ₂ - pyrrolyl, -CH ₂ - thienyl, -CH ₂ - imidazolyl, -CH ₂ - oxazolyl, -CH ₂ - iso-oxazolyl, -CH ₂ -thiazolyl, -CH ₂ -isothiazolyl, -CH ₂ -pyrazolyl, -CH ₂ -pyridinyl and -CH ₂ -pyrimidinyl);

Alkoxy ethyl [C _1-6 alkyl including —CH ₂ —CH ₂ —O—CH ₃ (methoxy ethyl)];

The groups listed in the aryl term above, in particular OH or alkyl substituted with 1 to 3 halo atoms (-CH ₃ , -CH (CH ₃ ) ₂ , -C (CH ₃ ) ₃ , -CH ₂ CH ₃ ,-( CH ₂ ) ₂ CH ₃ ,-(CH ₂ ) ₃ CH ₃ ,-(CH ₂ ) ₄ CH ₃ ,-(CH ₂ ) ₅ CH ₃ , -CH ₂ CH ₂ F, -CH ₂ CH ₂ Cl, -CH ₂ CF ₃ , and —CH ₂ CCl ₃ );

;

-N-2-propylmorpholino, 2-3, -dihydro-6-hydroxy, sesamol, catemol monoester, -CH ₂ -C (O) -N (R ¹ ) ₂ , -CH 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, enolpyruvate (HOOC-C (= CH ₂ )-), glycerol;

5 or 6 carbon monosaccharides, disaccharides or oligosaccharides (3 to 9 monosaccharide residues);

Triglycerides such as α-D-β-diglycerides linked to the acyl of the parent compound of the present invention via the glyceryl oxygen of the triglycerides, wherein fatty acid constituent glyceride lipids are generally naturally occurring saturated or unsaturated C _6-26 , C _6-18 , or C _6-10 fatty acids such as linolein, laurin, myristin, palmitine, stearin, oleine, palmitoleine, linolenin, and the like);

Phospholipids linked to carboxyl groups via phosphates of phospholipids;

Phthalidyl (illustrated in Clayton et al., Antimicrob. Agents Chemo. 5 (6): 670-671 [1974]);

Cyclic carbonates such as (5-R _d -2-oxo-1,3-dioxolen-4-yl) methyl ester (Sakamoto et al., "Chem. Pharm. Bull." 32 (6) 2241-2248 [ 1984) wherein R _d is R ₁ , R ₄ or aryl; And

; Is included.

The hydroxyl groups of the compounds of the invention may optionally be substituted by the III, IV or V groups disclosed in WO 94/21604, or may be substituted with isopropyl.

As a further embodiment, Table A lists the R _6a ester moieties capable of binding to the —C (O) O— and —P (O) (O—) ₂ groups, for example via oxygen. Some R _6c amidates that bind directly to —C (O) — or —P (O) ₂ are also known. The ester structures of 1-5, 8-10 and 16,17, 19-22 give compounds with free hydroxyls in the corresponding halides (chloride or Acyl chloride and the like) and N, N-dicyclohexyl-N-morpholine carboxamidine (or DBU, triethylamine, CsCO ₃ , N, N-dimethylaniline, etc.) to synthesize. When W ₁ is a phosphonate, esters having structures 5-7, 11, 12, 21 and 23-26 are monochlorophosphates with alcohols or alkoxide salts (or the corresponding amines when compounds 13, 14 and 15). Synthesized by reacting with ponates or dichlorophosphonates (or other activated phosphonates).

Other esters usable in the present invention are described in EP 632,048.

R _6a is also —CH ₂ OC (O) OCH ₃ ,

,

-CH ₂ SCOCH ₃ , -CH ₂ OCON (CH ₃ ) ₂ , -CH (R ₁ or W ₅ ) O ((CO) R ₃₇ ) or -CH (R ₁ or W ₅ ) ((CO) OR ₃₈ ) (Bonded to the oxygen of an acid functional group) includes "double ester" forming precursor functional groups, such as alkyl- or aryl-acyloxyalkyl groups, wherein R ₃₇ and R ₃₈ are alkyl, aryl or alkylaryl groups: US Patent 4,968,788). Often, R ₃₇ and R ₃₈ are such as branched alkyl, ortho-substituted aryl, meta-substituted aryl, or combinations thereof, including normal, secondary, iso- and tertiary alkyl of 1-6 carbon atoms. It is a bulky group. An example thereof is pivaloyloxymethyl group. They are particularly useful for prodrugs for oral administration. Examples of such useful R _6a groups include alkylacyloxymethyl esters and derivatives thereof, and include -CH (CH ₂ CH ₂ OCH ₃ ) OC (O) C (CH ₃ ) ₃ ,

Included.

For prodrug purposes, the esters selected are generally those used for antibiotics, in particular cyclic carbonates, double esters or phthalidyl, aryl or alkyl esters.

As mentioned above, R _6a , R _6c , and R _6b are optionally used to prevent side reactions with protecting groups in the synthesis process, so they act as protecting groups (PRT) during synthesis. In most cases, determining which group to protect and the nature of the PRT depend on the intended direction of the synthesis and the chemical properties of the reaction to be prevented (eg acidic, basic, oxidative, reducible or other conditions). When substituted with multiple PRTs, the PRT groups do not need to be identical and are generally not identical. The order of deprotection to produce free radicals depends on the reaction conditions to be encountered in the intended direction of synthesis and can occur in any order determined by one skilled in the art.

A number of R _6a hydroxy protecting groups and R _6c amide-forming groups and corresponding chemical degradation reactions are described in "Protective Groups in Organic Chemistry", Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991 ISBN 0-471- 62301-6) ("Greene"). See also Kotiensky, Philip J .; See also "Protecting Groups" (Gerog Thieme Verlag Stuttgart, New York, 1994). In particular Chapter 1, protectin Groups: An Overview, pages 1-20 Chapter 2, Hydroxyl Protecting Groups, pages 21-94, wp Chapter 3, Diol Protecting Groups, pages 95-117, Chapter 4, Carboxyl Protecting Grups, pges See 118-154, Chapter 5, Carbonyl Protecting Groups, pages 155-184. See Greene, below, for R _6a carboxylic acid, phosphonic acid, phosphonate, sulfonic acid and other W ₁ acid protecting groups. Such groups include, but are not limited to, esters, amides, hydrazides, and the like.

In some embodiments a R _6a protected acid group is an ester of said acid group and R _6a is a residue of a hydroxyl-containing functional group. In another embodiment, the R _6c amino compound is used to protect acid functionality. Residues of suitable hydroxyl or amino-containing functional groups have been described above and are disclosed in WO 95/07920. Of particular interest are residues of amino acids, amino acid esters, polypeptides or aryl alcohols. Typical amino acid, polypeptide and carboxyl-esterified amino acid residues are described as L1 or L2 groups on pages 11-18 of WO 95/07920 and related texts. WO 95/07920 clearly discloses amidates of phosphonic acids but it will be appreciated that such amidates may be formed with the acid groups exemplified in the text and the amino acid residues set forth in WO 95/07920.

Common R _6a esters for protecting W ₁ acid functionality are also exemplified in WO 95/07920, which can be understood to be the same ester formed with acidic groups as in the case of 920 phosphonates. have. Typical ester groups are defined in WO 95/07920, pages 89-93 (R ³¹ or R ³⁵ ), table 105, table 21-23 (R). Of particular interest are unsubstituted aryl such as phenyl, arylalkyl such as benzyl, or hydroxy-, halo-, alkoxy-, carboxy- and / or alkylestercarboxy-substituted aryl or alkylaryl, in particular phenyl, ortho- Ethoxyphenyl, or C _1-4 alkyl estercarboxyphenyl (salicylate C _1-12 alkyl ester).

It is useful as prodrugs for oral administration when using the protected acidic group W ₁ , in particular the esters or amides of WO 95/07920. However, it is not essential to protect the W ₁ acid group in order for the compounds of the present invention to be effectively orally administered. When systemically or orally administering a compound of the invention having a protecting group, particularly amino acid amidate or substituted and unsubstituted aryl esters, they may be hydrolyzed in vivo to produce free acid.

One or more acidic hydroxyls are protected. If two or more acidic hydroxyls are protected, the same or different protecting groups may be used, for example the esters may be the same or different or mixed amidates or esters may be used.

Typical R _6a hydroxy protecting groups described in Greene (pages 14-118) include ether (methyl); Substituted methyl ether (methoxymethyl, methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl) methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy) methyl, Guoacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) Methyl, 2- (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4- Methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S, S-dioxido, 1-[(2-chloro-4-methyl) phenyl] -4-methoxypiperidin-4-yl , 35, 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a, 4,5,6,6,7a-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-phenyl Benzyl, 2- and 4-picolinyl, 3-methyl-2-picolinyl N-oxido, diphenylmethyl, p, p'-dinitrobenzylhydryl, 5-dibenzosuberyl, triphenylmethyl, α -Naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di (p-methoxyphenyl) phenylmethyl, tri (p-methoxyphenyl) methyl, 4- (4'-bromophenacyloxy) phenyldiphenyl Methyl, 4,4 ', 4 "-tris (4,5-dichlorophthalimidophenyl) methyl, 4,4', 4" -tris (lebulinoyloxyphenyl) methyl, 4,4 ', 4 "- Tris (benzoyloxyphenyl) methyl, 3- (imidazol-1-ylmethyl) bis (4 ', 4 "-dimethoxyphenyl) methyl, 1,1-bis (4-methoxyphenyl) -1'-pyrene Nylmethyl, 9-Anthryl, 9- (9-phenyl) xanthenyl, 9- (9-phenyl-10-oxo) anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S , S-dioxido); Silyl ethers (trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethyltesilsilyl, 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, pivalate, adamantatoate, croto Acetate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate)); Carbonates (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-benzyl thiocarbonate, 4-ethoxy- 1-naphthyl, methyl dithiocarbonate); Auxiliary cleaved functional groups (2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl) benzoate, 2-formylbenzenesulfonate, 2- (methyl Thiomethoxy) ethyl carbonate, 4- (methylthiomethoxy) butyrate, 2- (methylthiothiomethoxymethyl) benzoate); Various esters (2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4- (1,1,3,3-tetramethylbutyl) phenoxyacetate, 2,4-bis (1,1 -Dimethylpropyl) methoxyacetate, chlorodiphenyl acetate, isobutyrate, monosuccinoate, (E) -2-methyl-2-butenoate (tigloate), o- (methoxycarbonyl) benzoate , p-poly-benzoate, α-naphthoate, nitrate, alkyl N, N, N'N'-tetramethylphosphorodiamidate, N-phenylcarbamate, borate, dimethylphosphinothioyl, 2 , 4-dinitrophenylsulfenate); And sulfonates (sulfates, methanesulfonates (mesylate), benzylsulfonates, tosylate).

More typically, R _6a hydroxy protecting groups include substituted methyl ethers, substituted benzyl ethers, silyl ethers, and sulfonic acid ester containing esters, more generally trialkylsilyl ethers, tosylate and acetates.

Typical 1,2-diol protecting groups (hence, generally two OH groups together form an R _6a protecting group) are described on pages 118-142 of Greene, which include cyclic 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-nitrobenzylidene); Cyclic ortho esters (methoxymethylene, ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene, 1-ethoxyethylidene, 1,2-dimethoxyethylidene, α-methoxybenzylidene, 1- (N, N-dimethylamino) ethylidene derivative, α- (N, N-dimethylamino) benzylidene derivative, 2-oxacyclopentylidene); Silyl derivatives (di-t-butylsilylene group, 1,3- (1,1,3,3-tetraisopropyldisiloxaneylidene), 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 more commonly include epoxides, acetonides, cyclic ketals and aryl acetals.

In the formula, R ⁹ is C ₁ -C ₆ alkyl.

R _6b is H, a residue or amino protecting group of a carboxyl containing compound, in particular H, —C (O) R ₄ , not an amino acid, polypeptide or protecting group —C (O) R _4, but an amino acid or polypeptide. Amide-forming R _6b is for example found in the G ₁ group. If R _6b is an amino acid or a polypeptide, it has the structure of R ₁₅ NHCH (R ₁₆ ) C (O) —, wherein 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, carboxyl, amide, carboxyl ester, hydroxyl, C _6-7 aryl, guanidinyl, imidazolyl, indolyl, sulfhydryl, sulfoxide and / or alkylphosphonate Is lower alkyl (C _1-6 ) substituted with R ₁₀ also together with the amino acid αN form a proline residue (R ₁₀ = —CH ₂ ) ₃ −). However, R ₁₀ is generally a side group of naturally occurring amino acids such as 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 -COOH, -CH ₂ -CH ₂ -COOH,-(CH ₂ ) ₄ -NH ₂ and-( CH ₂ ) ₃ -NH-C (NH ₂ ) -NH ₂ . R ₁₀ also includes 1-guanidinoprop-3-yl, benzyl, 4-hydroxybenzyl, imidazol-4-yl, indol-3-yl, methoxyphenyl and ethoxyphenyl.

R _6b is mostly a residue of a carboxylic acid, but may be used as long as it is the general amino protecting group described on page 315-385 of Greene. These include carbamate (methyl and ethyl, 9-fluorenylmethyl, 9- (2-sulfo) fluorenylmethyl, 9- (2,7-dibromo) fluorenylmethyl, 2,7-di- t-butyl- [9- (10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)] methyl, 4-methoxyphenanyl); Substituted ethyl (2,2,2-tricholeethyl, 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, cinnamil, 4-nitrocinnamil, 8-quinolyl, N-hydroxypiperidinyl, alkyldithio, benzyl, p-meth Oxybenzyl, p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl, diphenylmethyl); Auxiliary cleaved functional groups (2-methylthioethyl, 2-methylsulfonylethyl, 2- (p-toluenesulfonyl) ethyl, [2- (1,3-ditianyl)] methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl, 2-phosphonioethyl, 2-triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl, m-chloro-p-acyloxybenzyl, p- (di Hydroxyboryl) benzyl, 5-benzisooxazolylmethyl, 2- (trifluoromethyl) -6-chromonylmethyl); Photodegradable cleavable groups (m-nitrophenyl, 3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, phenyl (o-nitrophenyl) methyl); Urea-type derivatives (phenothiazinyl- (10) -carbonyl, N'-p-toluenesulfonylaminocarbonyl, N'-phenylaminothiocarbonyl); Various carbamates (t-amyl, S-benzyl thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl p-decylbenzyl, diisopropylmethyl, 2,2-dimeth Oxycarbonylvinyl, 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, isicotinyl, 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); Amides (N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl, N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl , N-3-pyridylcarboxamide, N-benzoylphenylalanyl, N-benzoyl, Np-phenylbenzoyl); Auxiliary cleaved amides (No-nitrophenylacetyl, No-nitrophenoxyacetyl, N-acetoacetyl, (N'-dithiobenzyloxycarbonyl amido) 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-diphenylmaleoyl, N-2,5-dimethylpyrrolyl, N-1,1,4,4- Tetramethyldisilylazacyclopentane additive, 5-substituted 1,3-dimethyl-1,3,5-tricyclocyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5 -Triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridonyl); N-alkyl and N-aryl amines (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-phenylfluoroenyl, N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, N-2-picolinylamine , N'-oxide), imine derivative (N-1,1-dimethylthiomethylene, N-benzylidene, Np-methoxybenzylidene, N-diphenylmethylene, N-[(2-pyridyl) methyl] 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 derivative, N-diphenylborinic acid derivative, N- [phenyl (pentaca Carbonyl- or -tungsten)] carbenyl, N-copper or N-zinc chelate); NN-derivative (N-nitro, N-nitroso, N-oxide); NP derivative (N-diphenylphosphinyl, N-dimethylthiophosphinyl, N-diphenylthiophosphinyl, N-dialkyl phosphoryl, N-dibenzyl phosphoryl, N-diphenyl phosphoryl); N-Si derivatives; NS derivatives; N-sulphenyl derivatives (N-benzenesulphenyl, No-nitrobenzenesulphenyl, N-2,4-dinitrobenzenesulphenyl, N-pentachlorobenzenesulphenyl, N-2-nitro-4-methoxybenzenesulphenyl, N- Triphenylmethylsulphenyl, N-3-nitropyridinesulphenyl) and N-sulfonyl derivatives (Np-toluenesulfonyl, N-benzenesulfonyl, N-2,3,6-trimethyl-4-methoxybenzene Sulfonyl, 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-methylbenzenesul Ponyyl, N-2,2,5,7,8-pentamethylchroman-6-sulfonyl, N-methanesulfonyl, N-β-trimethylsilylethanesulfonyl, N-9-anthracenesulfonyl, N-4- (4'8'-dimethoxynaphthylmethyl) benzenesulfonyl, N-benzylsulfonyl, N-trifluoromethylsulfonyl, N-phenacylsulfonyl).

More generally, protected amino groups include carbamates and amides, more generally -NHC (O) R ₁ or -N = CR ₁ N (R ₁ ) ₂ . Other protecting groups which are also useful as prodrugs in the G ₁ moiety, particularly protecting groups for amino or —NH (R ₅ ) include:

See, eg, Alexander, J. et al .; J. Med. Chem., 39, 480-486 (1996).

R _6c is a residue of an H or amino-containing compound, especially an amino acid, polypeptide, protecting group, -NHSO ₂ R ₄ , NHC (O) R ₄ , -N (R ₄ ) ₂ , NH ₂ or -NH (R ₄ ) ( Is a residue of H), for example, a carboxyl or phosphonic acid group of W ₁ is reacted with an amine -C (O) R _6c , -P (O) (R _6c ) ₂ or P (O) (OH) (R _6c To form an amide. In general, R _6c has the _structure of R ₁₇ C (O) CH (R ₁₆ ) NH—, wherein R ₁₇ is OH, OR _6a , OR ₅ , amino acid or polypeptide residue.

Amino acids are low molecular weight compounds of less than approximately 1,000 MW and contain at least one amino or imino group and at least one carboxyl group. Generally, amino acids are found in nature, ie they can be found in organisms such as bacteria or other microorganisms, plants, animals or humans. Suitable amino acids are generally compounds characterized by an alpha amino acid, ie one amino or imino nitrogen atom separated from the carbon atom of one carboxyl group by a single substituted or unsubstituted alpha carbon atom. Of particular interest are hydrophobic residues such as mono- or di-alkyl or amino acids, cycloalkylamino acids and the like. These residues contribute to cell permeability by increasing the partition coefficient of the parent drug. Generally, this residue does not contain sulfhydryl or guanidino substituents.

Naturally occurring amino acid residues are those naturally found in plants, animals or microorganisms, in particular their proteins. Polypeptides are substantially composed of these 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.

If R _6b and R _6c are single amino acid residues or polypeptides, they are usually substituted at R ₃ , W ₆ , W ₁ and / or W ₂ , and generally only at W ₁ or W ₂ . These conjugates are produced by amide bond formation between the carboxyl group of an amino acid (or such as the C-terminal amino acid of a polypeptide) and W ₂ . Likewise, conjugates are formed between W ₁ and the amino group of an amino acid or polypeptide. In general, it is also within the scope of the present invention to introduce amino acids at one or more of the permitted sites, but in general only one portion of the parent molecule is amidated with amino acids as described herein. Usually, the carboxyl group of W ₁ is amidated with amino acids. Generally, the α-amino or α-carboxyl groups of the terminal amino or carboxyl groups of an amino acid or polypeptide are linked to the parent functional group. That is, the carboxyl or amino groups in the amino acid side chain are generally not used to form amide bonds with the parent compound (although these groups need to be protected during synthesis of the conjugate as described below).

With respect to the carboxyl-containing side chain of an amino acid or polypeptide, the carboxyl group will optionally be blocked, eg by R _6a , esterified by R ₅ or amidated by R _6c . Likewise, amino subchain R ₁₆ will optionally be blocked by R _6b or substituted with R ₅ .

Such ester or amide bonds with side chain amino or carboxyl groups can be hydrolyzed under acidic (pH <3) or basic (pH> 10) conditions, optionally in vivo or ex vivo, as are esters or amides with parent molecules. On the other hand, they are actually stable in the human gastrointestinal tract but enzymatically hydrolyze in the blood or intracellular environment. Ester or amino acid or polypeptide amidates are also useful intermediates for the preparation of parent molecules containing free amino or carboxyl groups. The free acid or free base of the parent compound is readily prepared from the ester or amino acid or polypeptide conjugates of the invention, for example, by conventional hydrolysis processes.

Where amino acid residues have one or more chiral centers, D, L, meso, threo or erythro (as appropriate) racemates, scalemates or mixtures thereof can be used. Generally, D isomers are useful when non-enzymatic hydrolysis of intermediates is desired (where amide will be advantageous as a chemical intermediate of free acid or free amine). In contrast, L isomers are more versatile because they can be sensitive to both non-enzymatic and enzymatic hydrolysis and can be effectively delivered by amino acids or dipeptidyl delivery systems in the gastrointestinal tract.

Examples of suitable amino acids whose residues are represented by R _6b and R _6c include the following:

Glycine;

Aminopolycarboxylic acids such as 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-aminopimeline acid, 2-aminosuberinic acid and 2-aminocebacic acid;

Amino acid amides such as glutamine and asparagine;

Arginine, lysine, β-aminoalanine, γ-aminobutyrin, ornithine, citrulline, homoarginine, homocitrulline, hydroxylysine, allohydroxylcin and diaminobutyric acid;

Other basic amino acid residues such as histidine;

α, α'-diaminosuccinic acid, α, α'-diaminoglutaric acid, α, α'-diamonicdipic acid, α, α'-diaminopimeline acid, α, α'-diamino- diaminodicarboxylic acids such as β-hydroxypimeline acid, α, α'-diaminosuberinic acid, α, α'-diaminoazelanic acid, α, α'-diaminosevacinic acid;

Imino acids such as proline, hydroxyproline, allohydroxyproline, α-γ-methylproline, pipecolinic acid, 5-hydroxypipecolinic acid, and azetidine-2-carboxylic acid;

Mono- or di-alkyl (usually C _1-8 branched or normal) amino acids such as alanine, valine, leucine, allylglycine, butyrin, norvaline, norleucine, heptyline, α-methylserine, α-amino α-methyl-γ-hydroxyvaleric acid, α-amino-α-methyl-δ-hydroxyvaleric acid, α-amino-α-methyl-ε-hydroxycaprophosphoric 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-aminodiisoamiacetic acid, α-methylaspartic acid, α-methylglutamic acid, 1-aminocyclopropane-1-carboxylic acid, isoleucine, allo Isoleucine, tert-leucine, β-methyltryptophan and α-amino-β-ethyl-β-phenylpropionine .;

β-phenylserinyl;

Aliphatic α-amino-β-hydroxy acids such as serine, β-hydroxyleucine, β-hydroxynorleucine, β-hydroxynorvaline, and α-amino-β-hydroxystearic acid;

α-amino, α-, γ-, δ- or ε-hydroxy acids such as homoserine, γhydroxynorvaline, δ-hydroxynorvaline and epsilon-hydroxynorleucine residues; Cannabin and canalin; γ-hydroxyornithine;

2-hexosamino acids such as D-glucosamine acid or D-galactosamic acid;

α-amino-β-thiols such as penicillin, β-thiolnorvaline or β-thiolbutyrin;

Other sulfur containing amino acid residues, including cysteine; Homocystine, β-phenylmethionine, methionine, S-allyl-L-cysteine sulfoxide, 2-thiol histidine, cystathionine, and thiol esters of cysteine or homocysteine;

Phenylalanine, tryptophan and ring-substituted α amino acids such as phenyl- or cyclohexylamino acid α-aminophenylacetic acid, α-aminocyclohexylacetic acid and α-amino-β-cyclohexylpropionic acid; Derivatives of phenylalanine homologue and aryl, lower alkyl, hydroxy, guanidino, oxyalkylether, nitro, sulfur, or halo-substituted phenyl (e.g. tyrosine, methyltyrosine 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-, purinyl- or naphthyl-alanine; And derivatives including tryptophan homologs and kynurenine, 3-hydroxykynurenine, 2-hydroxytryptophan and 4-carboxycittophan;

Α-amino substituted amino acids, including sarcosine (N-methylglycine), N-benzylglycine, N-methylalanine, N-benzylalanine, N-methylphenylalanine, N-benzylphenylalanine, N-methylvaline and N-benzylvaline ; And

α-hydroxy and substituted α-hydroxyamino acids such as serine, threonine, allothreonine, phosphoserine and phosphothreonine.

A polypeptide is a polymer of amino acids in which the carboxyl group of a certain amino acid monomer is bonded to the amino or imino group of the next amino acid monomer by an amide bond. Polypeptides include dipeptides, low molecular weight polypeptides (about 1500-5000 MW) and proteins. The protein optionally contains 3, 5, 10, 50 75, 100 or more residues and is substantially sequence-homologous to human, animal, plant or microbial protein. These include not only enzymes (eg hydrogen peroxidase) but also immunogens such as KLH, or any form of antibody or protein intended to generate an immune response thereto. The nature and nature of polypeptides can vary greatly.

Polypeptide amidates are useful as immunogens for raising antibodies to epitopes for the remainder of the compounds of the invention or to the polypeptide (if it is not immunogenic in the administered animal).

For example, in the diagnosis or preparation of a parent compound, the parent compound is separated from the mixture using antibodies capable of binding to the non-peptidic parent compound. In general, conjugates of the parent compound and the polypeptide are much more immunogenic than the polypeptide in close cognate animals, making the polypeptide more immunogenic in promoting antibody challenge against it. Thus, the polypeptide or protein need not be immunogenic in animals commonly used to elicit antibodies, such as, for example, rabbits, mice, horses, or rats, but the end product conjugate should be immunogenic in at least one of these animals. do. The polypeptide optionally contains a peptidase cleavage site at the peptide bond between the first and second residues adjacent to the acidic heteroatoms. This cleavage site is followed by specific sequences of residues recognized by enzyme recognition structures such as peptide degrading enzymes.

Peptidase enzymes that cleave the polypeptide conjugates of the present invention are well known, especially carboxypeptidase. Carboxypeptidase cleaves polypeptides by removing C-terminal residues and is in many cases specific for a particular C-terminal sequence. Such enzymes and their substrate requirements are generally well known. For example, dipeptides (having a given residue pair and free carboxyl termini) covalently bind to the phosphorus or carbon atom of the compound via an α-amino group. In embodiments where W ₁ is a phosphonate, the peptide is expected to be cleaved by an appropriate peptidase, leaving the carboxyl group of the central amino acid residue to autocatalytically cleave the phosphonoamidate bond.

Suitable dipeptidyl groups (denoted by single letter codes) include:

AA, AR, AN, AD, AC, AE, AQ, AG, AH, AI, AL, AK, AM, AF, AP, AS, AT, AW, AY, AV, RA, RR, RN, RD, RC, RE, RQ, RG, RH, RI, RL, RK, RM, RF, RP, RS, RT, RW, RY, RV, NA, NR, NN, ND, NC, NE, NQ, NG, NH, NI, NL, NK, NM, NF, NP, NS, NT, NW, NY, NV, DA, DR, DN, DD, DC, DE, DQ, DG, DH, DI, DL, DK, DM, DF, DP, DS, DT, DW, DY, DV, CA, CR, CN, CD, CC, CE, CQ, CG, CH, CI, CL, CK, CM, CF, CP, CS, CT, CW, CY, CV, EA, ER, EN, ED, EC, EE, EQ, EG, EH, EI, EL, EK, EM, EF, EP, ES, ET, EW, EY, EV, QA, QR, QN, QD, QC, QE, QQ, QG, QH, QI, QL, QK, QM, QF, QP, QS, QT, QW, QY, QV, GA, GR, GN, GD, GC, GE, GQ, GG, GH, GI, GL, GK, GM, GF, GP, GS, GT, GW, GY, GV, HA, HR, HN, HD, HC, HE, HQ, HG, HH, HI, HL, HK, HM, HF, HP, HS, HT, HW, HY, HV, IA, IR, IN, ID, IC, IE, IQ, IG, IH, II, IL, IK, IM, IF, IP, IS, IT, IW, IY, IV, LA, LR, LN, LD, LC, LE, LQ, LG, LH, LI, LL, LK, LM, LF, LP, LS, LT, LW, LY, LV, KA, KR, KN, KD, KC, KE, KQ, KG, KH, KI, KL, KK, KM, KF, KP, KS, KT, KW, KY, KV, MA, MR, MN, MD, MC, ME, MQ, MG, MH, MI,ML, MK, MM, MF, MP, MS, MT, MW, MY, MV, FA, FR, FN, FD, FC, FE, FQ, FG, FH, FI, FL, FK, FM, FF, FP, FS, FT, FW, FY, FV, PA, PR, PN, PD, PC, PE, PQ, PG, PH, PI, PL, PK, PM, PF, PP, PS, PT, PW, PY, PV, SA, SR, SN, SD, SC, SE, SQ, SG, SH, SI, SL, SK, SM, SF, SP, SS, ST, SW, SY, SV, TA, TR, TN, TD, TC, TE, TQ, TG, TH, TI, TL, TK, TM, TF, TP, TS, TT, TW, TY, TV, WA, WR, WN, WD, WC, WE, WQ, WG, WH, WI, WL, WK, WM, WF, WP, WS, WT, WW, WY, WV, YA, YR, YN, YD, YC, YE, YQ, YG, YH, YI, YL, YK, YM, YF, YP, YS, YT, YW, YY, YV, VA, VR, VN, VD, VC, VE, VQ, VG, VH, VI, VL, VK, VM, VF, VP, VS, VT, VW, VY and VV.

Tripeptide residues are also useful as R _6b and R _6c . When W ₁ is phosphonate, -X4-pro-X5- (where X4 is any amino acid residue and X5 is a carboxyl ester, amino acid residue, or hydrogen of proline) is determined by luminal carboxypeptidase It is expected to be cleaved to produce X4 with free carboxyl, which again cleaves phosphonoamidate bonds autocatalytically. The carboxy group of X5 is esterified with benzyl.

Dipeptides or tripeptides can be selected based on known delivery properties and / or sensitivity to peptidase that may affect delivery to the small intestine mucosa or other cells. Dipeptides and tripeptides lacking α-amino groups are the delivery substrates of peptide carriers found in the brush barrier membranes of small intestinal mucosal cells (Bai, JPE, "Pharm Res." 9: 969-978 (1992). Peptides may be used to enhance the bioavailability of amidate compounds Di- or tripeptides having one or more amino acids in the D configuration are also compatible with the peptide carrier and may be used in the amidate compounds of the invention. The use of amino acids can reduce the susceptibility to the hydrolysis of di- or tripeptides by proteases common to brush barriers such as aminopeptidase N (EC 3.4.11.2) and proteases found in the intestinal lumen. These are selected based on the relative resistance of the di- or tripeptide to hydrolysis by, for example, lacking asp and / or glu. Tripeptides or polypeptides are insufficient substrates for aminopeptidase A (EC 3.4.11.7) and di- or tree lacking amino acid residues on the N-terminus of hydrophobic amino acids (leu, tyr, phe, val, trp) Peptides are an inadequate substrate for endopeptidase 24.11 (EC 3.4.24.11), and peptides lacking the pro residue at the end at the free carboxyl end are carboxypeptidase P (EC 3.4.17) Similar considerations can be made in selecting peptides that are relatively resistant or relatively resistant to hydrolysis by cytoplasm, kidney, liver, serum or other peptidase. Amidate is an immunogen or useful for binding to a protein for preparing an immunogen.

Another embodiment of the invention relates to a composition of formula VII or VIII and salts, solvates, degraded enantiomers and purified steric diastereomers thereof:

[Formula VII]

[Formula VIII]

Wherein E ₁ , G ₁ , T ₁ , U ₁ , J ₁ , J _1a , J ₂ and J _2a are as defined above except:

T _{1 together} with —NR ₁ W ₃ , heterocycle, or G ₁ forms a group having the structure:

;

X ₁ is a bond, —O—, —N (H) —, —N (R ₅ ) —, —S—, —SO—, or —SO ₂ ;

However, excludes compounds wherein U ₁ is H or —CH ₂ CH (OH) CH ₂ (OH).

Each of the typical or routine embodiments of Formulas (I)-(VI) described above is also a typical embodiment of Formulas (VII) and (VIII).

Synthesis of several compounds of Formulas VII and VIII, wherein U ₁ is H or —CH ₂ CH (OH) CH ₂ (OH), includes Nishimura, Y and the like; "J. Antibiotics", 46 (2): 300; 46 (12): 1883 (1993); And "Nat. Prod. Lett.", 1 (1): 39 (1992). Attachment of the U ₁ group of the present invention proceeds as described.

<Stereoisomers>

The compounds of the present invention are or are rich in resolved optical isomers for any or all asymmetric atoms. For example, chiral centers apparent from the description are provided as chiral isomers or racemic mixtures. In addition to the racemic and diastereomer mixtures, all of the separate or synthesized separate optical isomers that are actually free of their enantiomers or diastereomer partners are within the scope of the present invention.

One or more of the methods described below are used to prepare enantiomerically rich, or pure isomers. The methods are listed in approximately preferred order, that is, a synthesis with stereospecificity from chiral precursors prior to chromatographic purification prior to spontaneous crystallization must first be used.

Synthesis with stereospecificity is described in the following examples. Processes of this type can be used conveniently as long as the appropriate chiral starting material is used and the reaction step chosen does not produce the desired results. One advantage of the stereospecific synthesis method is that it does not produce undesirable enantiomers that must be removed from the final product and therefore does not lower the overall synthesis yield. In general, those skilled in the art will be well aware of the starting materials and reaction conditions which should be employed in order to be able to obtain pure isomers, which consist primarily of preferred enantiomers, by synthesis methods having stereospecificity. If the undesirable racemization occurred in a process that is believed to have stereospecificity, one of the following separation methods should be used to obtain the desired product.

If a suitable synthesis method having stereospecificity cannot be measured by conventional experimental methods or difficult to be devised in experience, one of ordinary skill in the art will be able to turn to another method. One commonly used method is the chromatographic separation of enantiomers on chiral chromatography resin. The resin is packed in a column commonly used as a so-called Pirkle column. The column contains a chiral stationary phase. The racemate is loaded with solution, loaded onto a column, and then separated by HPLC. See, eg, Proceedings Chromatographic Society-International Symposium on Chiral Separations, Sep. 3-4, 1987. Examples of chiral columns that can be used in screens for optical separation techniques include Diacel Chriacel OD, Regis Pirkle Covalent Dphenylglycine, Regis Pirkle Type 1A, Astec Cyclobond II, Astec Cyclobond III, Serva Chiral D-DL = Daltosil 100, Bakerbond DNBLeu, Sumipax OA-1000, Merk Cellulose Triacetate column, Astec Cyclobond I-Beta, or Regis Pirkle Covalent D-Naphthylalanine. None of the columns appear to be effective for all racemic mixtures. However, one of ordinary skill in the art appreciates that a certain amount of conventional screening will be needed to identify the most effective stationary phase. When using such columns, preference is given to using specific examples of compounds of the invention in which the charge is not neutralized, for example, acidic functional groups such as carboxyl groups are not etherified or amidated. Another method has been described in detail for the separation of the conjugates by conventional column chromatography after conversion of enantiomers in the mixture to diastereomers having chiral auxiliaries. This is a very suitable method, in particular in the case of embodiments having free carboxyl, amino or hydroxy groups which form salts or covalent bonds with chiral auxiliaries. In terms of chirality, pure amino acids, organic acids or organic sulfonic acids are all studied to be excellent as chiral auxiliaries. Salts with these auxiliaries may be formed or they may be covalently bonded (but reversible) to the functional groups. For example, after amidating the carboxyl groups of embodiments of the present invention using pure D or L amino acids, they can be separated by chromatography.

Enzyme separation is one of the very important methods. In this process, after producing covalently bound derivatives of enantiomers, generally lower alkyl esters (eg of carboxyl groups) in the racemic mixture, the derivatives are subjected to enzymatic degradation reactions, generally hydrolysis. In order for this method to be successful, it is often necessary to screen several enzymes in a conventional manner, since the enzyme must be selected so that a degradation reaction with stereospecificity can occur. If the ester is degraded, it may be selected from the group consisting of esterases, phosphatase and lipases, and the activity for the derivatives is measured. Typical esterases are available from the liver, pancreas or other animal organs, such as pig liver esterases.

After the ethanethiomer mixture is separated from the solution or melt into aggregates, ie mixtures of enantiomerically pure crystals, the crystals can be physically separated to produce an enantiomerically superior preparation. However, this method is not practical for mass production and is not very effective for true racemic compounds.

Asymmetric synthesis is another way to achieve enantiomeric predominance. For example, a chiral protecting group is reacted with a protected functional group and the reaction mixture is allowed to equilibrate. If the reaction has enantiomer specificity, the product will prevail over that enantiomer.

Further guidance on the separation of enantiomer mixtures is given in "Enantiomers, Racemates, and resolutions", Jean Jacques, Andre Collet, and Samuel H. Wilen (Krieger Publishing Company, Malaba, FL, 1991, ISBN 0-89464-618-4 It should be recognized as a means of illustration, but not limited to. In particular, Part 2, Resoluton of Enantiomer Mixture, pp. 217-435, more specifically, Section 4, Resolution by Direct Crystallization, pp. 217-251, section 5, Formation and Separation of Diastereomers, pp. 251-369 , Section 6, Crystallization-Induces Asymmetric Transformations, pp. 369-378, and Section 7, Experimental Aspects and Art of Resolutions, pp. 378-435; More specifically, Section 5.1.4, Resolution of Alchols, Transformation of Alcohols into Salt-Forming Dervatives, pp. 263-266, Section 5.2.3, Covalent Derivatives of Alcohols, Thiols, and Phenols, pp. 332-335, Section 5.1.1, Resolution of Acids, pp. 257-259, Section 5.1.2, Resolution of Bases, pp. 259-260, Section 5.1.3, Resolution of Amino Acids, pp. 261-263, Section 5.2.1 , Covalent Derivatives of Acids, pp. 335-339, and Section 5.2.7, Chromatographic Behavior of Covalent Diastereomers, pp. 348-354, may be cited as examples of techniques in this field.

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

The compounds of the present invention may also exist in some cases as tautomeric isomers. For example, in the case of imidazole, guanidine, amidine and tetrazole systems en-amine tautomers may be present and all of their possible tautomeric forms are within the scope of the present invention.

<Compounds listed by way of example.>

Examples of specific compounds are shown in the following table (Table 6). In general, each compound is represented as a substituted nucleus in a capitalized manner and each substituent in lowercase or numeric order. Tables 1a and 1b are a list of nuclei that differ mainly depending on the ring unsaturated position and the properties of the ring substituents. Each nucleus is numbered alphabetically from Tables 1a and 1b, with the marking shown at the beginning of the compound name. Similarly, Tables 2a-av, 3a-b, 4a-c, and 5a-d list the selected Q ₁ , Q ₂ , Q ₃ and Q ₄ substituents, and the same letter or number system was used here. Thus, each of the named compounds represents from uppercase letters representing the nucleus, followed by numbers representing Q ₁ substituents, lowercase letters representing Q ₂ substituents, numbers representing Q ₃ substituents, numbers representing Q ₃ substituents, and Q ₄ substituents from Tables 1a-1b. Displayed by lowercase letters. Thus, Structural Formula 8, Scheme 1, is represented by A.49.a.4.i. It is to be understood that Q1-Q4 does not represent a group or an atom, but is merely a linked representation.

<Salts and hydrates>

The compositions of the present invention optionally consist of pharmaceutically acceptable non-toxic salts containing the salts of the compounds of the invention, in particular Na ⁺ , Li ⁺ , K ⁺ , Ca ⁺⁺ , and Mg ⁺⁺ . Such salts may include those derived by combining acid and anionic moieties, typically W ₁ group carboxylic acids, with suitable cations such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions. Monovalent salts are preferred if water soluble salts are desired.

Metal salts are generally prepared by reacting a metal hydroxide with a compound of the present invention. Examples of metal salts prepared in this way include salts containing Li ⁺ , Na ⁺ , and K ⁺ . Metal salts with low solubility can be precipitated from a solution of a better dissolved salt by adding an appropriate metal compound.

In addition, salts may be formed by adding certain organic and inorganic acids, such as, for example, HCl, HBr, H ₂ SO ₄ , H ₃ PO ₄ or organic sulfonic acids, to an acidic group such as an amine of the basic center, generally a G ₁ group, or E _1. It may be. Finally, it is to be understood that the compositions of the present invention include not only the ionized form but also the zwitterionic form and compounds in the form of a combination with a stoichiometric amount of water, as in the case of hydrates.

The scope of the present invention also includes salts of the parent compound with one or more amino acids. The amino acids mentioned above are all suitable, although amino acids typically produce basic or acidic groups such as lysine, arginine or glutamic acid, or side chains having neutral groups such as glycine, serine, threonine, alanine, isoleucine, or leucine. However, especially naturally occurring amino acids found as protein components are suitable.

<Inhibition method of neuraminidase>

Another aspect of the invention is directed to a method of inhibiting neuraminidase activity, comprising treating a compound of the invention that is presumed to contain neuraminidase.

The compositions of the present invention serve as inhibitors of neuraminidase and act as intermediates of such inhibitors or have other uses described below. These inhibitors will bind to any point on the surface of the neuraminidase or its empty space with the unique geometry of neuraminidase. Compositions that bind neuraminidase can bind with varying reversibility. These compounds which in fact bind irreversibly are ideal candidates for use in the methods of the present invention. In general embodiments, the compositions bind neuramidase with a binding constant of less than 10 ⁻⁴ M, more generally less than 10 ⁻⁶ M, and even more generally 10 ⁻⁸ M. Once labeled, compositions that bind substantially irreversibly are useful as probes to search for neuraminidase. Accordingly, the present invention is directed to treating a sample suspected of containing neuraminidase with a composition containing a compound of the present invention in association with a label; The present invention also relates to a method for retrieving neuraminidase in a sample suspected of containing neuraminidase, which comprises observing the effect of the sample on label activity. Suitable labels are well known in the field of diagnostics and include stable free radicals, fluoropores, radioisotopes, enzymes, chemilumines, and chromogens. Compounds of the present invention are labeled in a conventional manner using functional groups such as hydroxyl or amino.

Samples suspected of containing neuraminidase within the scope of the present invention include natural or artificial materials such as living organisms; Tissue or cell cultures; Biological samples such as biological material samples (blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, etc.); Laboratory samples; Food, water, or air samples; Biological product samples, such as cell excretion, particularly recombinant cells that synthesize the desired glycoproteins; Etc. are included. In general, a sample suspected of containing an organism that produces neuraminidase is a pathogenic organism such as a virus. Samples 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 present invention includes adding the composition of the present invention to the sample or adding a precursor of the composition to the sample. The addition step consists of any of the administration methods described above.

If desired, the activity of neuraminidase after application of the composition can be observed by direct and indirect screening methods of neuraminidase activity. Quantitative, qualitative and semiquantitative methods for measuring the activity of neuraminidase are well known. In general, one of the screening methods described above applies, but other methods, such as observing the physiological properties of living organisms, are also applicable.

Organisms containing neuraminidase include bacteria (Vibrio cholera, Clostridium perfringens, Streptococcus pneumoniae, and Arthrobacter sialophilus) and viruses (especially orthomyxoviruses or influenza viruses). Paramyxoviruses such as A and B, parainfluenza virus, mumps virus, Newcastle disease virus, poultry plaque virus, and Sendai virus. Inhibition of neuraminidase activity obtained from or found in such organisms is within the object of the present invention. Virology of influenza viruses is described in Chapter 24 of "Fundamental Virology" (Raven Press, New York, 1986). The compounds of the present invention are useful for treating or preventing such infections, for example in ducks, rodents or pigs or humans.

However, in screening for compounds that may inhibit influenza virus, it should be borne in mind that the results of the enzyme assay may not be consistent with the results of cell culture assays as shown in Chandler et al., Supra. Therefore, plaque reduction assays should be the primary screening tool.

<Screen of neuraminidase inhibitor>

Compositions of the Invention Screen for their inhibitory activity against neuraminidase by using conventional enzyme activity assessment techniques. In the present invention, general compositions are first screened for inhibition of neuraminidase in vitro and then compositions that exhibit inhibitory activity are screened for in vivo activity. Compositions having an in vitro Ki (inhibition constant) of less than 5 × 10 ⁻⁶ M, typically less than about 1 × 10 ⁻⁷ M, preferably less than about 5 × 10 ⁻⁸ M are preferred for in vivo use.

Although effective in vitro screening has been described in detail, it is not limited thereto. However, von Itzstein, M. et al., "Nature", 363 (6428): 418-423 (1993), in particular page 420, column 2, paragraph 3 full, to 421, column 2, part of the first paragraph. A suitable in vitro analysis of Potier, M. is described; Chong, A.K.J. Modified by "Analyt. BIochem." 94: 287-296 (1979); "Biochem. Biophys. Acta", 1077: 65-71 (1991); And Colman, P.M. Etc; International publication WO92 / 06691 (International Application No. PCT / AU90 / 00501, published April 30, 1992), page 34, line 13 to page 35, line 16 describes another useful in vitro screening method.

In vivo screening methods are also described in von Itzstein, M. et al .; supra, in particular 2 columns on page 421, 1st paragraph to 423, 2 columns, part of the first paragraph, and Colman, P. M. et al .; This document, p. 36, lines 1-38 is also described.

<Pharmaceutical composition and route of administration>

The compounds of the present invention are formulated with conventional carriers and excipients selected according to routine practice. Tablets contain excipients, lubricants, fillers, binders and the like. Aqueous formulations are prepared in sterile form and are generally isotonic if desired to be delivered by a route other than oral administration. All formulations will optionally contain excipients as set forth in "Handbook of Pharmaceutical Excipients" (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, hydroxyalkylcelluloses, hydroxyalkylmethylcelluloses, carbohydrates such as stearic acid, dextrins, and the like. The pH of the formulation is in the range of about 3 to 11, but about 7 to 10 is the general range.

One or more compounds of the invention, referred to herein as active ingredients, are administered by a route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, topical (ball, sublingual), vaginal, and parenteral (subcutaneous, intramuscular, intravenous, endothelial, intrathecal, and epidural). Of course, for example, the preferred route may vary depending on the subject's symptoms. One of the advantages of the compounds of the present invention is that they are orally bioavailable and oral available; Thus there is no need to administer them in the pulmonary or nasal route. Surprisingly (particularly in view of Bamford, MJ, "J. Enzyme Inhibition" 10: 1-6 (1995) and in particular the first monograph on page 15), WO 91/16320, WO 92/06691 and US Patent The anti-influenza compounds of 5,360,817 are successfully administered by the oral or intraperitoneal route. See Example 161, below.

The active ingredient may be administered alone but it may be desirable to administer it as a pharmaceutical preparation. The formulations of the present invention contain one or more acceptable carriers and optionally other therapeutic ingredients, together with one or more active ingredients, both veterinary and human. The carrier (s) must be "acceptable" in terms of compatibility with other ingredients in the formulation and must be physiologically toxic to the subject.

Formulations include those suitable for the routes of administration described above. The formulations may conveniently be presented in unit dosage form and may be prepared by methods well known in the art of pharmacy. Generally related techniques and formulations are described in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier consisting of one or more accessory ingredients. Generally, preparations are prepared by combining the active ingredient homogeneously with the liquid carrier or the finely divided solid carrier or both, and then molding it if necessary.

Formulations of the invention suitable for oral administration include discrete units such as capsules, cachets or tablets containing a predetermined amount of the active ingredient; Powder or granules; As a solution or a suspension in an aqueous liquid or 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 prepared in the form of large pills, soft pills or pastes.

Tablets are made by compression or molding with one or more accessory ingredients. Compressed tablets may be made by compressing the active ingredient, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersant, into a free-flowing form, such as powder or granule, in a suitable machine. Molded tablets are made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. Tablets may be optionally coated, golded or optionally to release the active ingredient slowly or in a controlled manner. In one embodiment, acid hydrolysis of the medicament can be prevented by using an enteric coating.

For infections of the eye or other external tissues, such as the mouth and skin, the active ingredient (s) may be added in 0.1% w / w increments, such as 0.075 to 20% w / w (0.6% w / w, 0.7% w / w, etc.). Topical ointment or cream containing the active ingredient (s) in the range of 0.1% to 20%), preferably 0.2 to 15% w / w, most preferably 0.5 to 10% w / w It is preferable to apply as. When formulated as an ointment, the active ingredients are used with ointment bases that can be mixed with paraffin or water. On the other hand, the active ingredients may also be formulated in creams with oil-in-water cream bases.

If desired, the aqueous base of the cream base is, for example, polyhydric alcohols, ie propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and these It may contain at least 30% w / w of an alcohol having three or more hydroxyl groups, such as a mixture of Topical formulations may preferably include a compound that promotes absorption or penetration of the active ingredient through the skin or other site requiring treatment. Examples of such dermal penetration promoters are dimethyl sulfoxide and related homologues.

The oil phase of the emulsion of the invention can be formulated from known ingredients in a known manner. This phase may consist solely of an emulsifier (also known as an emulsion), but preferably consists of one or more emulsifiers and a mixture of fats or oils or both fats and oils. Preferably a hydrophilic emulsifier is included together with an oily emulsifier that acts as a stabilizer. Along with this, the emulsifier (s), in the presence or absence of stabilizer (s), make the so-called emulsifying wax, and the wax together with the oil and the fat form the so-called emulsifying ointment base, which forms the oily dispersed phase of the cream formulation.

Emulsion and emulsion stabilizers suitable for use in the compositions of the present invention include ^Tween® 60, ^Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate do.

The oil or fat suitable for the formulation is selected based on achieving the desired cosmetic properties. The cream is preferably a washable product having a suitable viscosity so that it does not get greasy or stained, and does not leak from a tube or other container. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadiate, isocetyl stearate, propylene glycol diesters of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, Mixtures of branched chain esters known as butyl stearate, 2-ethylhexyl palmitate or Crodamol CAP are available, the last three being the preferred esters. These may be used alone or in combination depending on the properties required. On the other hand, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils are used.

Formulations suitable for topical application to the eye also include drops in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present at a concentration of 0.5 to 20%, preferably 0.5 to 10, in particular about 1.5% w / w in such preparations. Formulations suitable for topical administration in the mouth include lozenges containing the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; Pastilles containing the active ingredient in an inert base such as gelatin and glycerine or sucrose and acacia; And mouthwashes comprising the active ingredient in a suitable liquid carrier.

Rectal formulations may be formulated as suppositories with suitable bases such as, for example, cocoa butter or salicylate.

Formulations suitable for intrapulmonary or nasal administration are, for example, 0.1 to 500 microns in particle size (including particle sizes ranging from 0.1 to 500 microns in increasing sizes such as 0.5, 1, 30 microns and 35 microns), which are rapidly Or by inhalation through the mouth to reach the alveolar sac. Suitable preparations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional practice and may be delivered in conjunction with other therapeutic agents such as compounds used so far for the treatment or prevention of influenza A or B infections, as described below.

Formulations suitable for vaginal administration may be presented in the form of pessaries, tampons, creams, gels, pastes, foams or spray formulations containing the active ingredient plus a carrier known to be suitable in the art.

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions which may contain antioxidants, buffers, bacteriostatics and solutes that render the preparation isotonic with the blood of the subject; And aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

Formulations may be provided in unit-dose or multi-dose containers, such as sealed ampoules and vials, to be stored in a lyophilized state and immediately prior to use, eg, by adding a sterile liquid carrier such as water for injection. Just do it. Instant injectable solutions and suspensions are prepared from sterile powders, granules and tablets of the aforementioned type. Preferred unit dose formulations contain a daily dose or unit daily split-dose as described above of the active ingredient, or preferably an appropriate fraction thereof.

In addition to the compositions of the present invention specifically mentioned above, other agents conventional in the art with respect to the undiluted formulation form may also be included, for example flavoring agents suitable for oral administration.

The present invention also provides a veterinary composition consisting of one or more active ingredients as defined above together with the veterinary carrier.

Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous substances which are acceptable or inert in the veterinary art and are compatible with the active ingredient. These veterinary compositions can be administered orally, parenterally or by any other desired route.

The compounds of the present invention are used to provide controlled release pharmacological preparations ("controlled release formulations") containing at least one compound of the present invention as an active ingredient, wherein the active ingredient is not taken frequently. Is controlled and controlled so as to improve the pharmacokinetic or toxicological profile of a given active ingredient.

The effective dosage of the active ingredient depends at least on the nature of the condition to be treated, the toxicity, whether to prevent (in small doses) or to treat active influenza infection, or the method of delivery, and the pharmacological preparation, The escalation study allows the clinician to decide. However, the amount is expected to range from about 0.0001 to 100 mg / kg body weight per day. Generally about 0.01 mg / (kg body weight) to 10 mg / (kg body weight) per day, more generally about 0.1-5 mg / (kg body weight) per day, and more generally about 0.05- per day It will be in the range of 0.5 mg / kg body weight. For example, for an adult weighing 70 kg, the daily candidate dose range is 1-1000 mg, preferably 5-500 mg, which can be taken once or in several portions.

Typical dosages include GS 4104, phosphate salts, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, once or twice daily. , 80, 85, 90, 95, 100, 110, 115, 120, 125, 130, 135, 140, 145, 150, 157, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425 , 450, 475, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 and 1000 mg; More typically, once or twice daily, GS 4104, phosphate salts, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 95, 100, 110, 115, 120, 125, 130, 135, 140, 145, 150, 157, 200 mg; More typically, once or twice daily administration includes GS 4104, phosphate salts, 20, 50, 75, 100, 150 and 200 mg; Even more typically, once or twice daily dosing includes GS 4104, phosphate salts, 75 or 150 mg.

The active ingredient of the present invention is also used in combination with other active ingredients. This combination is selected based on the condition to be treated, the pharmacology of the combination and the cross-reactivity of the components. For example, when treating viral infections of the respiratory system, especially influenza infections, the compositions of the invention are combined with antiviral agents (such as amantidine, rimantadine, and ribavirin), mucolytic agents, expectorants, bronchodilators, antibiotics, antipyretics, or analgesics Let's do it. Routinely, antibiotics, antipyretics and analgesics are administered with the compounds of the present invention.

<Metabolites of Compounds of the Invention>

In vivo metabolites of the compounds described herein also fall within the scope of the present invention to the extent that such metabolites are novel and are not apparent compared to the prior art. Such metabolites result from, for example, oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, mainly caused by enzymatic reactions. Thus, the present invention includes novel and non-obvious compounds produced by the method of contacting a compound of the present invention with a mammal for a time sufficient for its metabolites to be produced. Such products generally produce the radiolabeled compounds (eg, C ¹⁴ or H ³ ) compounds of the present invention and then in detectable amounts (eg, greater than about 0.5 mg / kg) in rats, mice, guinea pigs, monkeys or humans. It is identified by parenteral administration to such animals, allowing metabolism to proceed for a sufficient time (typically 30 seconds to 30 hours), and then separating its conversion product from urine, blood or other biological samples. These products are easily separated because they are labeled (others are separated by the use of antibodies capable of binding epitopes retained in the metabolite). The structure of the metabolite is determined in a conventional manner such as, for example, MS or NMR analysis. In general, the analysis of metabolites is performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. Conversion products are useful in diagnostic assays for the therapeutic administration of a compound of the invention, even if they do not have their own neuraminidase inhibitory activity, unless otherwise found in vivo.

Additional Uses of Compounds of the Invention

Compounds of the invention, biologically active substances produced from these compounds by metabolism or hydrolysis in vivo are used for conjugation to an immunogen or protein, thus they are the protein, the compound or immunologically recognized epitope It serves as components of an immunogen composition for producing antibodies capable of specifically binding to their metabolites carrying (antibody binding sites). Thus, immunogenic compositions are useful as intermediates in the manufacture of antibodies used in the diagnosis, quality control, etc., analysis of the compounds or their novel metabolites. These compounds are useful for eliciting antibodies to non-immunogenic polypeptides in compounds that act as hapten sites that promote an immune response that cross-reacts with the unmodified conjugate protein.

Hydrolysis products of interest include the hydrolysis products of the protected acid and basic groups discussed above. As noted above, generally acidic or basic amides comprising immunogenic polypeptides such as albumin or keyhole limpet hemocyanin are useful as immunogens. The metabolites described above can retain to a substantial degree immunological cross-reactivity with the compounds of the present invention. Thus, the antibodies of the present invention may bind to an unprotected compound of the present invention without binding to the protected compound; Metabolites, on the other hand, may bind to protected compounds and / or metabolites without binding to the protected compounds of the present invention, or may specifically bind to any or all three of these. . Antibodies are required that they will not substantially cross react with naturally occurring substances. Substantial cross-reactivity is the reactivity under specific assay conditions for analytes that are specific enough to interfere with the assay results.

Immunogens of the present invention contain a compound of the present invention that produces the desired epitope in combination with an immunogenic material. Such binding in the context of the present invention means a covalent bond that forms an immunogenic conjugate (if applicable) or a non-covalent binding agent or combination thereof. Immunogenic agents include Freund's adjuvant, viruses, bacteria, yeasts, plant and animal polypeptides, especially adjuvant such as keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin or soy trypsin inhibitor, and immunogenic polysaccharides. In general, compounds having a desired epitope structure are covalently bound to an immunogenic polypeptide or polysaccharide by using a multifunctional (usually difunctional) crosslinking agent. Methods of preparing hapten immunogens are well known and all methods used to conjugate hapten with immunogenic polypeptides and the like are also specific to epitopes in question as opposed to functional groups and immunogenic materials on hydrolysates or precursors available for crosslinking. It may be appropriately used in consideration of the possibility of producing an antibody.

Generally, polypeptides are conjugated to sites on the compounds of the invention that are recognized and remote from epitopes. These conjugates are prepared in a conventional manner. For example, in preparing the conjugate of the present invention, N-hydroxysuccinimide, succinic anhydride or alkN = C = Nalk which is a crosslinking agent is useful. These conjugates include compounds attached to linkages or bonds of 1-100, generally 1-25, more generally 1-10 carbon atoms to the immunogenic material. The conjugates are separated from the starting materials and by-products by chromatography or the like and then sterile filtered and stored in vials.

Compounds of the invention are crosslinked, for example, via one or more of the following groups: a hydroxyl group of U ₁ ; Carboxyl group of E ₁ ; Carbon atom instead of H of U ₁ , E ₁ , G ₁ or T ₁ ; And an amine group of G ₁ . Such compounds include the amide of a polypeptide, in which case the polypeptide acts as the aforementioned R _6c or R _6b group.

Animals are immunized against immunogenic conjugates or derivatives prepared in a conventional manner and against antisera or monoclonal antibodies. Compounds of the invention are useful for maintaining the structural integrity of glycoproteins in recombinant cell culture. That is, they are added to the fermentation to recover the glycoprotein, thereby inhibiting the neuraminidase-catalyzed cleavage reaction of the desired glycoprotein. This is particularly valuable in the recombinant synthesis of proteins in heterogeneous host cells that can physically degrade the carbohydrate portion of the protein being synthesized. The compounds of the present invention are multifunctional. They therefore represent a unique class of monomers for polymer synthesis. For example, polymers made from the compounds of the present invention include polyamides and polyesters.

The compounds of the present invention are used as monomers to provide a means of access to polymers with unique accessory functionalities. The compounds of the present invention are useful as homopolymers or comonomers with monomers not within the scope of the present invention. The homopolymers of the compounds of the present invention are capable of binding to acidic functional groups, as found in polypeptides in which the acidic functional group E ₁ is esterified, for example, with a hydroxyl group in U ₁ , such that the accessory basic group G ₁ is required to be purified. , Molecular sieves (polyamides), textiles, fibers, films, shaped articles and the like, and will have use as cation exchangers (polyesters or polyamides). Polyamides are prepared by crosslinking E ₁ and G ₁ with a vacant ring contiguous portion that acts as a hydrophilic or hydrophobic affinity group depending on the choice of the U ₁ and U ₁ groups. It is well known to prepare these polymers from the compounds of the invention.

The compounds of the present invention are also useful as a unique class of multifunctional surfactants. Especially when U ₁ does not contain hydrophilic substituents, such as alkyl or alkoxy, these compounds have the properties of difunctional surfactants. They therefore have useful surfactants, surface coatings, emulsion deformations, property deformations and surface moisturizing properties. As multifunctional compounds having a defined geometry and having both polar and non-polar moieties, the compounds of the invention are useful as a unique class of phase transfer agents. For example, the compounds of the present invention are useful for phase transfer catalysts 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 degradation of other optically active materials. For example, a racemic mixture of carboxylic acids may comprise 1) forming a mixture of a diastereomeric ester or amide with a compound of the invention wherein U ₁ is an asymmetric hydroxyalkane or aminoalkane group; 2) diastereomer separation; And 3) its component enantiomers by hydrolysis of the ester structure. Racemic alcohols are separated by ester formation with acid groups of E ₁ . This method can also be used to decompose the compounds of the present invention when optically active acids or alcohols are used instead of racemic starting materials.

The compounds of the present invention are useful as linkers or spacers in the manufacture of affinity absorbent mattresses, process control immobilized enzymes, or immunoassays. The compounds of the present invention contain several functional groups useful as sites for crosslinking the desired material. For example, it is common to link affinity reagents such as hormones, peptides, antibodies, drugs, and the like to insoluble substrates. Binding partners for affinity reagents are absorbed from preparations, diagnostic samples, and other impure mixtures prepared using these insoluble reagents in a known manner. Likewise, the catalytic conversion is carried out while the enzyme is easily recovered using the fixed enzyme. Difunctional compounds are usually used to connect the assayite to a detectable group in the preparation of diagnostic reagents.

Many functional groups of the compounds of the present invention are suitable for crosslinking applications. For example, the carboxylic acid or phosphonic acid of the E ₁ group is used to form an amide with the amine of the reagent to be crosslinked or to form an ester with alcohol. Suitable sites are G ₁ moieties OH, NHR ₁ , SH, azido (reduced to amino before crosslinking if required), CN, NO ₂ , amino, guanidino, halo and the like. If necessary, the crosslinking agent is assembled to prevent polymerization of the bifunctional compound of the present invention while the reactor is adequately protected. In general, compounds of the invention are used by linking them to the hydroxyl or amino group of the first linking partner via carboxylic acid or phosphonic acid and then covalently linking to another binding partner via a T ₁ or G ₁ group. An immobilized steroid is obtained by esterifying a first binding partner, such as, for example, a steroid hormone, with a carboxylic acid of the compound of the invention and then crosslinking this conjugate with G ₁ hydroxyl to the cyanogen bromide activated Sepharose. Other conjugation chemistries are also well known. See, eg, Maggio "Enzyme-Immunoassay" (CRC, 1988, pp 71-135) and references cited therein.

As mentioned above, the therapeutically effective compounds of the present invention having protected W ₁ or G ₁ carboxyl, hydroxyl or amino groups are available in oral or sustained release form. In such applications, protecting groups are removed in vivo, such as by hydrolysis or oxidation, to produce uracarboxyl, amino or hydroxyl. Suitable esters or amides for this utility are selected based on the substrate specificities of the esterases and / or carboxypeptidase expected to be found in cells that require precursor hydrolysis. Within, it will be necessary to screen various compounds of the present invention until the desired substrate specificity is found. This will also be apparent from the emergence of free compound or antiviral activity. In general, the amides or esters of the compounds of the present invention that (i) are not hydrolyzed in the upper intestine or are relatively slowly hydrolyzed, (ii) intestinal and cell permeable and (iii) hydrolyzed in the cytoplasmic and / or systemic circulation of cells Is selected. Screening assays preferably utilize cells from certain tissues susceptible to influenza, such as, for example, mucosa of bronchial lung catheter. Assays known in the art, including intestinal lumen stability, cell infiltration, liver homogenate stability, and plasma stability assays, are suitable for measuring bioavailability. However, even if esters, amides or other protected derivatives are converted in vivo to free carboxyl, amino or hydroxyl groups, they are still useful as chemical intermediates.

<Typical Method for Preparing Compound of the Invention>

The invention also relates to a process for the preparation of the composition of the invention. These compositions are prepared by applicable organic synthesis techniques. Many such techniques are known in the art. However, many known techniques are described in "Compendium of Organic Synthetic Methods" (John Wiley & Sons, New York), Vol. 1, Ian T. Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, jr., 1980; Vol. 5, Leroy G. Wade, Jr. 1984; And Vol. 6, Michael B. Smith; And March, J., "Advanced Organic Chemistry, Third Edition", (John Wiley & Sons, New York, 1985), "Comprehensive Organic Synthesis. Selectivity, Straategy & Efficiency in Modern Organic Chemistry. In 9 Volumes". Barry M. Trost, Editor-in-Chief (Pergamon Press, New York, 1993).

Some typical preparations of the compositions of the present invention are described below. These methods are only intended to explain the characteristics of these preparations, but the scope of the applicable methods is not limited thereto.

In general, reaction conditions such as temperature, reaction time, solvent, work-up process, etc. will be general in the art of the particular reaction to be performed. The cited references and references cited describe these conditions in detail. Generally the temperature will be from -100 ° C. to 200 ° C., the solvent will be aprotic or protic, and the reaction time will be 10 seconds to 10 days. The workup generally consists of quenching all unreacted reagents and then partitioning (extracting) the water / organic layer system and separating the layer containing the product.

Although metal hydrides are frequently reduced at temperatures between 0 ° C. and −100 ° C., solvents are generally aprotic for reduction reactions and may be protic or aprotic for oxidation, although oxidation and reduction reactions are common. In the vicinity of room temperature (about 20 ° C). The reaction time is appropriately adjusted to achieve the desired conversion reaction.

Although low temperatures (0 ° C. to -100 ° C.) are common for non-equilibrium, kinematically controlled condensation reactions, condensation reactions are generally performed near room temperature. The solvent may be protic (common in equilibrium reactions) or aprotic (common in kinetic controlled reactions).

Standard synthetic techniques such as azeotropic removal of reaction by-products and anhydrous reaction conditions (such as inert gas atmospheres) are commonly used in the art and may be used where applicable.

Examples of representative methods for preparing the compounds of the present invention are shown in Scheme 1 below. These methods were described in detail in the experiment column described later.

Scheme 1 was modified to make additional embodiments, and is shown in Scheme 2-4.

<Scheme 2>

Aziridine 5 is converted to amino nitrile 9 by the addition of Yb (CN) ₃ catalyzed TMSCN according to the method of Utimoto and co-worker “Tetrahedron Lett.”, 31: 6379 (1990). Standard three stages i) H ₂ S; ii) CH ₃ I; iii) Convert nitrile 9 to the corresponding amidine 10 using NH ₄ OAc in sequence. Representative conversions are described in "J. Med. Chem.", 36: 1811 91993.

"Modern Synthetic Reactions" Second Edition, H.O. Nitrile 9 is converted to amino methyl compound 11 by reduction using the method described in House, Benjamin / Cummings Publishing Co., 1972.

Treating amino methyl compound 11 with bis-Boc by treating 11 with N, N'-bis-Boc-1H-pyrazole-1-carboxamidine according to the method described in "Tetrahedron Lett.", 36: 299 (1995). Convert to protected guanidino compound 12.

<Scheme 3>

13 is obtained by ring opening aziridine 5 with α-cyanoacetic acid t-butyl ester. This type of aziridine ring opening is described in "Tetrahedron Lett", 23: 5021 (1982). Nitrile 14 is obtained by selectively hydrolyzing the t-butyl ester moiety under acidic conditions followed by decarboxylation.

Reducing 14 to the amino ethyl derivative 15 is carried out in the same manner as converting 9 to 11. Subsequently, 15 is converted to guanidino derivative 16 using N, N'-bis-Boc-1H-pyrazole-1-carboxamide according to the method described in "Tetrahedron Lett", 36: 299 (1995). .

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

<Scheme 4>

Epoxy alcohol 1 is protected, for example with MOMCl (PG = protecting group). General conditions are described in the second edition of "Protective Groups in Organic Synthesis," TW Greene and PGM Wuts, John Wiley & Sons, New York, NY 1991. Sharpless and co-author "J. Org. Chem.", 50: 1577 (1985) According to the method, epoxide 19 is ring-opened with amino alcohol 20 using NaN ₃ / NH ₄ Cl.

Reduction of 20 to N-acetyl aziridine 21 is carried out in three steps: 1) MsCl / triethyl amine; 2) H ₂ / Pd; 3) AcCl / pyridine. This transformation is described in Angew. Chem. Int. Ed. Engl., 33: 599 (1994).

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

"Protective Groups in Organic Synthesis" 2nd Edition, T.W. Greene and P.G.M. Remove 22 MOM protectors using the method described in Wutw, John Wiley & Sons, New York, NY 1991. The alcohol obtained is converted directly to aziridine 24 using TsCl in pyridine. This transformation is described in Angew. Chem. Int. Ed. Engl., 33: 599 (1994).

Aziridine 24 is then reacted with ROH, RNH ₂ , RSH or organometallic (metal-R) to give the corresponding ring-opening derivatives 25, 26, 27 and 27.1, respectively. This type of aziridine ring opening is described in "Tetrahedron Lett.", 23: 5021 (1982) and "Angew. Chem. Int. Ed. Engl." 33, 599 (1994).

<Scheme 5>

Another class of compounds of the present invention are prepared according to the methods of Schemes 5a and 5b. The quinic acid is converted to 28 by the method of Shing, TKM et al., "Tetrahedron", 47 (26): 4571 (1991). Mesylated with MsCl in TEA / CH ₂ Cl to get 29, which was reacted with NaN _{3 in} DMF to give 30. Reaction of 30 with TFA in CH ₂ Cl ₂ gives 31 which is mesylated with MsCl in TEA / CH ₂ Cl ₂ to give 32. Reaction with triphenylphosphine in water gives 33 which is 1) CH ₃ C (O) Cl in pyridine, 2) NaN _{3 in} DMF; And 3) conversion to 35 by sequentially applying NaH in THF. Various compounds such as 36 are prepared by reacting 35 with various nucleophiles common in the art. Making a compound such as 36 into another embodiment of the present invention is similar to that described above.

<Scheme 6>

Another class of compounds of the invention is prepared by the method of Scheme 6 above. Deprotect the protected alcohol 22 (PG = methoxymethyl ether) under the standard conditions described in the second edition of “Protected Groups in Organic Synthesis”, TW Greene and PGM Wutw, John Wiley & Sons, New York, NY, 1991. Alcohol 51 is converted to acetate 52 under standard conditions using acetic anhydride and pyridine. Acetate 52 is treated with TMSOTf or BF3 ₃ · OEt to give oxazoline 53. Such conversions are described in Liebbigs Ann. Chem., 129 (1991) and Carbohydrate Research, 181 (1993), respectively. On the other hand, "J. Org. Chem.", 50: 1126 (1985) and "J. Chem. Soc." As described in 1385, (1970), alcohol 51 is converted to oxazoline 53 by conversion to the corresponding mesylate or tosylate 23 and then cyclized to oxazoline under standard conditions. Oxazoline 53 is reacted with ROH, RR'NH, or RSH, where R and R 'are selected to be consistent with the definition of W ₆ above to obtain the corresponding ring-opening derivatives 54, 55 and 56, respectively. Such conversions are described in "J. Org. Chem.", 48: 4889 (1984) and "Chem. Rev.", 71: 483 (1971).

<Scheme 7-63>

Other representative methods for preparing the compounds of the present invention are shown in Schemes 7-63. These methods were described in detail in the experimental section below.

Additional embodiments of methods for making and using the compositions of the present invention are shown in Schemes 36-40.1. One aspect of the invention relates to processes A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, of Scheme 36-40.1. A method for preparing a compound of the present invention consisting of T, U, V, or W alone or in combination. Table 27 describes an embodiment of a typical method of Process A-W. Each embodiment is a separate method of using unit processes A-W alone or in combination. Each method embodiment of Table 27 was separated by ";". If an embodiment is a single letter it corresponds to any of the A-W processes. If it exceeds one character, this corresponds to each of the processes carried out in the order specified.

Another aspect of the present invention provides a method for preparing compound 270 using Schikimic acid as shown in Scheme 36, a method for preparing Compound 271 using compound 270 as shown in Scheme 36, Scheme 36 A method for preparing compound 272 using compound 271 as shown by C, a method for preparing compound 273 using compound 272 as shown by D in Scheme 36, and quinic acid as shown by E in Scheme 37 A method of preparing compound 274 using Compound 274 to prepare compound 275 as shown by F in Scheme 37, and a method of preparing compound 276 using compound 275 as shown by G in Scheme 37 To prepare a compound 272 using compound 276, as shown by H in Scheme 37, using a compound 273 as shown by I in Scheme 38 A method for preparing compound 277, a method for preparing compound 278 using compound 277 as shown by J in Scheme 38, a method for preparing compound 279 using compound 278 as shown by K in Scheme 38, A method for preparing compound 280 using compound 279 as shown by L in Scheme 38, a method for preparing compound 281 using compound 280 as shown by M in Scheme 38, as shown by N in Scheme 39 A method for preparing compound 282 using compound 281, a method for preparing compound 283 using compound 282 as shown by O in Scheme 39, and a compound 284 using compound 283 as shown by P in Scheme 39 A process for preparing compound 285 using compound 283 as shown by Q in Scheme 40, as shown by Scheme 40 as R A method for preparing compound 286 using compound 285, a method for preparing compound 288 using compound 287 as shown by S in Scheme 40.1, and a compound 289 using compound 288 as shown by T in Scheme 40.1. A process for preparing compound 290 using compound 289 as shown by U in Scheme 40.1, a process for preparing compound 291 using compound 290 as shown by V in Scheme 40.1, and Scheme 40.1. A method for preparing compound 292 using compound 291 as shown by W is provided.

General aspects of this typical method are described below and shown in the Examples. Each product of the following process is optionally separated, segregated and / or purified prior to use in the process described below.

The terms "treated", "treating", "treatment", and the like are used to treat one or more other chemical entities for conversion into one or more other chemical entities, including contacting, mixing, reacting, reacting, contacting, and the like. Is a term widely used in the technical field. This indicates that the phrase "treat Compound 1 with Compound 2" causes "Compound 1 to react with Compound 2", "Compound 1 with Compound 2", "Compound 1 with Compound 2", and Compound It is synonymous with other expressions widely used in the field of organic synthesis to reasonably indicate "processed".

"Treatment" refers to a suitable and general manner of causing organic chemicals to react. Unless otherwise indicated, normal conditions (0.01 to 10M, generally 0.1 to 1M), temperature (-100 ° C to 250 ° C, generally -78 ° C to 150 ° C, more generally -78 ° C to 100 ° C, and more Generally 0 ° C. to 100 ° C.), reaction vessel (generally glass, plastic, metal), solvent, pressure, atmosphere (typically nitrogen, for reactions that are not sensitive to oxygen and water, or nitrogen or Argon), and the like. Similar reactions known in the art of organic synthesis are used to select conditions and apparatus for "treatment" in a given process. In particular, those skilled in the art of organic synthesis will select conditions and apparatus that are reasonably anticipated to be able to successfully perform the chemical reactions of the desired process based on the knowledge in the art.

<Step A, Scheme 36>

Using schikimic acid, compound 270 is prepared according to the following procedure.

The cis-4,5-diol functional groups of the schimnic acid are distinguished from carboxylic acids at carbon 1 by selectively protecting these two functional groups. Generally the cis-4,5-diol functional groups are protected as cyclic ketals and the carboxylic acid functional groups are protected as esters.

R ₅₀ is an acid labile 1,2-diol protecting group, such as those described in Greene, supra, generally ketal or acetone of cyclohexanone, more generally cyclohexanone. R ₅₁ is an acid stable carboxylic acid protecting group such as those described in Greene's literature, as described above, usually having carbon atoms 1- as shown in Table 2 as groups 2-7, 9-10, 15 or 100-660. 12 straight, branched or cyclic alkyl, alkenyl, or alkynyl, more commonly straight or branched from 1 to 8 carbon atoms as shown in groups 2-5, 9, or 100-358 of Table 2 Alkyl, more generally a straight or branched table 2 of 1 to 6 carbon atoms as shown in groups 2-5, 9, or 100-141 of Table 2, more generally R ₅₁ is methyl, ethyl, n -Propyl, i-propyl, n-propyl, sec-butyl, i-butyl, or t-butyl.

Reaction of the Schimcic acid to protect the carboxylic acid with the R ₅₁ group and the cis-4,5-diol with the R ₅₀ group. Generally, the shikimic acid is treated with an alcohol such as methanol, ethanol, n-propanol, or i-propanol, and an acid catalyst such as mineral acid, or sulfonic acid such as methane, benzene or toluene sulfonic acid followed by dialkyl ketal or aldehyde or ketone. Is reacted with an acetal such as 2,2-dimethoxy-propane or 1,1-dimethoxy-cyclohexane in the presence of the corresponding ketone or aldehyde such as acetone or cyclohexanone. Optionally, the alcohol and acid catalyzed product is separated and / or purified prior to treatment with dialkyl ketals or acetals. Otherwise, the shikimic acid is treated with CH ₂ N ₂ .

Usually, this process consists of treating the shikimic acid with an alkanol and sulfonic acid followed by treatment with a geminal-alkoxyalkane or geminal alkoxycycloalkane and an alkanone or cycloalkanone to form compound 270. More generally, this process treats the shikimic acid with alkanols and sulfonic acids; Excess alkanol was evaporated to form a residue; The residue consists of treating compound 270 with a geminal-alkoxyalkane or a gemalal-alkoxycycloalkane and an alkanone or cycloalkanone. More generally, this process treats the shikimic acid with methanol and para-toluenesulfonic acid; Excess methanol was evaporated to form a residue; The residue consists of treating with 2,2-dimethoxypropane and acetone to form compound 270.

A typical embodiment of this process is described in Example 55 below.

<Step B, Scheme 36>

Compound 271 is prepared using compound 270 according to the following steps.

The hydroxyl group at position 3 is activated, usually a displacement reaction, more generally at alcohol at position 4, in the direction in which the epoxide ring is formed.

R ₅₂ is an alcohol activator, generally an activator directed to a transposition reaction, more generally an activator that is translocated with alcohol at the 4 position to form an epoxide ring. Such groups include groups common in the art, such as sulfonic acid esters, more generally methane, benzene or toluene sulfonic acid esters. In one embodiment, R ₅₂ together with O (ie —OR ₅₂ ) form a leaving group common in the art.

Typically this process results in treating compound 270 with an acid halide to form compound 271. More generally, this process results in treating compound 270 with sulfonic acid halide in a suitable solvent to form compound 271. More typically, this process results in the treatment of compound 270 with sulfonic acid halides in a suitable solvent such as an amine or optionally in the presence of a cosolvent such as haloalkane to afford compound 271. More generally, this process results in treating compound 270 with methane sulfonyl chloride in triethylamine / dichloromethane to form compound 271.

A typical embodiment of this process is described in Example 56.

<Step C, Scheme 36>

Compound 272 is produced using compound 271 by the following process.

Remove acid labile protecting groups (R ₅₀ ) for the hydroxyl groups at positions 4 and 5. Generally, R ₅₀ is removed without substantially removing the base labile carboxylic acid protecting group (such as R ₅₁ ) or hydroxy activating group (such as R ₅₂ ). More generally, R ₅₀ is cleaved under acidic conditions.

Typically, this process involves treating Compound 271 with a protic solvent, and more generally in the presence of the acid catalyst described above. More generally this process involves treating compound 271 with the alkanols described above and the acid catalysts described above. More generally, this process results in treating compound 271 with methanol and para-toluene sulfonic acid to produce compound 272.

Representative embodiments of this process are described in Example 57 below.

<Step D, Scheme 36>

Compound 273 is prepared using compound 272 by the following process.

Epoxide compound 273 is obtained by replacing the hydroxyl group activated at the 3-position of compound 272 with the hydroxyl group at the 4-position of compound 272. In general, this translocation is catalyzed by a suitable base, more generally an amine base such as DBU or DBN.

Generally this process involves treating Compound 272 with a basic catalyst and optionally proceeds in the presence of a suitable solvent. More generally, this process involves treating compound 272 with an amine base in a polar, non-protic solvent such as diethyl ether THF. More generally, this process results in treating Compound 272 with DBU in THF to give Compound 273.

A typical embodiment of this process is described in Example 58.

<Step E, scheme 37>

Compound 274 is prepared using quinic acid according to the following method.

The cis-4,5-diol functional groups of quinic acid are differentiated from carboxylic acids at carbon 1 by selectively protecting these two functional groups. In general, the cis-4,5-diol functional groups are protected as cyclic ketals and the carboxylic acid functional groups are protected as hydroxy groups and lactones at the 3 position.

R ₅₀ is as described above.

In general, this process is carried out by treating quinic acid with a Geminal-alkoxyalkane or Geminal dialkoxycycloalkane, as described above, and an alkanone or cycloalkanone, optionally in the presence of an acid catalyst as described above. It is to obtain compound 274. More typically, this process will result in the treatment of quinic acid with a geminal-alkoxyalkane or geminal alkoxycycloalkane, and an alkane or cycloalkanone and an acid catalyst to form compound 270. More specifically, this method results in the treatment of quinic acid with 2,2-dimethoxypropane, acetone, and paratoluenesulfonic acid to form compound 274.

A typical embodiment of this process is shown in Example 101.

<Step F, Scheme 37>

Compound 275 is prepared from a compound according to the following procedure.

The ringtone is ring-opened to form compound 275. Generally, the lactone is ring-opened to produce the protected carboxylic acid at position 1 and the free hydroxyl acid at position 3. More typically, the lactone is opened under basic conditions to produce the R ₅₁ protected carboxylic acid at one position and the free hydroxy group at the third position.

R ₅₁ is as described above.

In general, compound 274 is treated with a suitable base in a suitable protic solvent. More generally, compound 275 is treated with a metal alkoxide base, such as sodium, potassium, or lithium alkoxide, in alkanol, as described above. More generally, compound 274 is treated with NaOMe in MeOH to give compound 275.

A typical example of this process is described in Example 102 below.

<Step G, Scheme 37>

Compound 276 is prepared from compound 275 as follows.

The hydroxy group at position 3 is activated, generally activated by a transposition reaction, and more generally activated to be directed to the epoxide ring which forms the alcohol position at position 4.

R ₅₂ is an alcohol activator, generally an activator directed to a transposition reaction, more generally an activator directed to an epoxide ring that forms an alcohol transposition in the 4 position. Such groups include sulfonic acid esters, more commonly methane, benzene or toluene sulfonic acid esters. In one embodiment, R _{52 together} with O (ie —OR ₅₂ ) form a leaving group common in the art.

In general, this process results in treating compound 275 with an acid halide to form compound 276. More generally, this process forms compound 276 by treating compound 275 with sulfonic acid halide in a suitable solvent. More generally, this process prepares Compound 276 by treating Compound 275 with sulfonic acid halide in a suitable solvent such as an amine, optionally in the presence of a cosolvent such as haloalkane. More generally, this process results in treating compound 275 with p-toluene sulfonyl chloride in pyridine dichloromethane to form compound 276.

A typical embodiment of this process is described in Example 103 below.

<Step H, Scheme 37>

Compound 276 is prepared from compound 272 according to the following procedure.

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

In general, this process involves treating Compound 276 with a suitable dehydrating agent such as an inorganic acid (HCl, H ₂ SO ₄ ) or SO ₂ Cl ₂ . More generally, compound 276 is treated with SO ₂ Cl ₂ and optionally with alkanol in the presence of an acid catalyst. More specifically, compound 276 is treated with SO ₂ Cl ₂ in a suitable polar, aprotic solvent such as an amine to form an olefin; This olefin is treated with an alkanol and an acid catalyst as described above to form compound 272. More typically, -100 ℃ to 0 ℃, more generally, the olefin by treatment at -10 to -100 ℃ ℃, more typically -78 ℃ pyridine / CH ₂ Cl ₂ of the compound 276 as SO ₂ Cl ₂ Getting; The olefin is treated with methanol and para-toluene sulfonic acid to give compound 272.

Typical embodiments of this process are described in Example 104 below.

<Step I, Scheme 38>

According to the following process, compound 277 is prepared from compound 273.

Protects hydroxyl groups at the 5 position. Generally, protecting groups are acid labile hydroxy protecting groups. More generally, protecting groups refuse to transition to adjacent hydroxy groups.

R ₅₃ is an acid labile hydroxy protecting group as cited in Greene, supra. More generally, R ₅₃ is an acid cleavable ether, more generally R ₅₃ is methoxymethyl (MOM, CH ₃ —O—CH ₂ —).

In general, this process involves treating Compound 273 with the hydroxy protecting group reagent described in Greene. More generally this process treats compound 273 with substituted or unsubstituted haloalkanes or alkenes such as methoxymethyl chloride (MOM chloride, CH ₃ -O-CH ₂ -Cl) in a suitable solvent such as a polar, aprotic solvent. It is done. More specifically, this process is to treat compound 273 with MOM chloride in amine solvent. More generally, this process involves treating Compound 273 with MOM chloride in diisopropyl ethyl amine.

A typical embodiment of this process is shown in Example 59.

<Step I, Scheme 38>

Compound 278 is prepared using compound 277 according to the following procedure.

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

In general, this process results in the treatment of compound 277 with an azide salt in a suitable solvent. More generally, this process consists of treating Compound 277 with a mild base and sodium azide such as ammonium halide in a polar, protic solvent such as alkanol or water. More generally, this process results in treating Compound 277 with sodium azide and ammonium chloride in water / methanol solution to form Compound 278.

A typical embodiment of this process is shown in Example 60 below.

<Step K, Scheme 38>

According to the following procedure, compound 279 is prepared using compound 278.

The hydroxyl group at position 4 of compound 278 is transposed with a 3-azido group to produce aziridine compound 279.

This process generally involves treating Compound 278 with a hydroxy activator, organophosphine and base as described above. More specifically, this process treats compound 278 with a sulfonic acid halide as described above to obtain an activated hydroxy compound, treating this activated hydroxy compound with trialkyl or triarylphosphine, such as trifetylphosphine , Phosphonium salt is obtained, and then the phosphonium salt is treated with a base such as amine to obtain compound 279. More generally, this process treats compound 278 with mesyl chloride to form an activated hydroxy compound, and treats this activated hydroxy compound with triphenylphosphine to obtain a phosphonium salt, Treatment with triethylamine and H ₂ O affords Compound 279.

Typical embodiments of this process are shown in Examples 61 and 62 below.

<Step L, Scheme 38>

Compound 280 is obtained using compound 279 according to the following procedure.

Aziridine compound 279 is opened with azide to form azido amine 280.

This process generally involves treating Compound 279 with an azide salt in a suitable solvent. More typically, this process involves treating Compound 279 with sodium azide and a mild base such as ammonium halide in a polar, aprotic solvent such as ether, amine or amide. More generally, this process results in treating Compound 279 with sodium azide ammonium chloride in DMF solution to produce Compound 280.

A typical embodiment of this process is shown in Example 63 below.

<Step M, Scheme 38>

According to the following procedure, compound 281 is prepared using compound 280.

The protected hydroxy group at position 5 is displaced with the amine at position 4 to form aziridine 281. Generally, aziridine 281 is substituted with an acid labile group, more generally with an aziridine activator.

R ₅₄ is an acid labile group, typically an acid labile amine protecting group as described in Greene, supra. More typically, R ₅₄ is an aziridine activator and more generally a group that activates aziridine to enable acid catalyzed ring opening. Typical R ₅₄ groups include, for example, straight or branched 1-oxo-al-1-kill groups having 1 to 12 carbon atoms, wherein the alkyne moiety is a straight or branched chain alkyl group having 1 to 11 carbon atoms, such as CH ₃ (CH ₂ ) _z C (O)-, z is an integer from 0 to 10, ie acetyl CH ₃ (O)-, etc.), substituted methyl (eg, triphenylmethyl, Ph ₃ C-, trityl, Tr), or BOC Or carbamates, such as Cbz, or sulfonates (eg, sulfonates, such as methyl sulfonate). More generally the R ₅₄ group is a 1-oxo-al-1-alkyl group having 1 to 8 carbon atoms, more generally 1, 2, 3, 4, 5, 6, more generally 2 or 3 carbon atoms. Triphenylmethyl.

Typically, this process produces a reagent R ₅₄ (R _54, such as that by treating the compound 280 zero deprotection described in the R ₅₃ group, Greene - halides such as acetylchloride, or Tr-Cl, or R ₅₄ -OR _54, e.g. Acetic anhydride), and hydroxy activator as described in Process, B, Scheme 36. More generally, this process comprises treating Compound 280 with a polar, protic solvent in the presence of any of the aforementioned acid catalysts to produce a primary intermediate; Treating the primary intermediate with Tr-Cl in a polar, aprotic solvent such as an amine to obtain a secondary intermediate; The secondary intermediate is treated with a sulfonic acid halide such as mesyl chloride or para toluene sulfonyl chloride in a polar aprotic solvent such as an amine to give compound 281. More typically, this process treats compound 280 with methanol and HCl to form a primary intermediate; Treating the secondary intermediate with Ti-Cl and triethylamine to obtain the secondary intermediate; The secondary intermediate is treated with mesyl chloride and triethylamine to give compound 281.

A typical embodiment of this process is shown in Example 64.

<Step N, Scheme 39>

Compound 282 is produced using compound 281 according to the following procedure.

Compound 281 is opened to replace the resulting amine with an R ₅₅ group to form compound 282. Generally the amine obtained by opening aziridine 281 by acid catalyzed ring opening is acylated.

R ₅₅ is W ₃ described above. In general, R ₅₅ is —C (O) R ₅ . More generally, R ₅₅ is —C (O) R ₁ . More generally, R ₅₅ is -C (O) CH ₃ .

R ₅₆ is U ₁ described above. Generally R ₅₆ is W ₆ -O-, W ₆ -S, or W ₆ -N (H)-. More generally R ₅₆ is R ₅ -O-, R ₅ -S-, or R ₅ -N (H)-, more generally R ₅₆ is R ₅ -O-, more generally R ₅₆ is R ₁ -O -to be.

Typically this process involves treating compound 281 with an acid catalyst and a compound of formula W ₆ -X ₁ -H where X ₁ is as defined above to obtain an amine intermediate; The amine intermediate is treated with a compound of the formulas W ₃ -X ₁ -X ₃ , W ₃ -X ₁₀ where X ₁₀ is a leaving group to give compound 282. Acid catalysts are generally common in the art, BF ₃ · Et ₂ O, TiCl ₃ , TMSOTf, SmI ₂ (THF) ₂ , LiClO ₄ , Mg (ClO ₄ ) ₂ , Ln (OTf) ₃ (where Ln = Yb , Gd, Nd), Ti (Oi-Pr) ₄ , AlCl ₃ , AlBr ₃ , BeCl ₂ , CdCl ₂ , ZnCl ₂ , BF ₃ , Bcl ₃ , BBr ₃ , GaCl ₃ , GaBr ₃ , TiCl ₄ , TiBr ₄ , ZrCl ₄ , SnCl ₄ , SnBr ₄ , SbCl ₅ , SbCl ₃ , BiCl ₃ , FeCl ₃ , UCl ₄ , ScCl ₃ , YCl ₃ , LaCl ₃ , CeCl ₃ , PrCl ₃ , NdCl ₃ , SmCl ₃ , EuCl ₃ , GdCl ₃ , Lewis acid catalysts such as TbCl ₃ , LuCl ₃ , DyCl ₃ , HoCl ₃ , ErCl ₃ , TmCl ₃ , YbCl ₃ , ZnI ₂ , Al (OPr ⁱ ) ₃ , Al (acac) ₃ , ZnBr ₂ , SnCl ₄ . X ₁ is generally —O—, —S—, or —N (H) —. X ₁₀ is generally a halide such as Cl, Br, or I. More generally, this process treats compound 281 with the compounds of formula R ₅ —OH, R ₅ —SH, or R ₅ —NH ₂ and BF ₃ .Et ₂ O to form an intermediate; The intermediate is treated with an alkanophosphoric anhydride to give compound 282. More typically, this process treats compound 281 with a compound of formula R ₅ —OH and BF ₃ · Et ₂ O to obtain intermediates; The intermediate is treated with substituted or unsubstituted acetic anhydride to afford compound 282. Examples of compounds of the formula R ₅ -OH include groups 2-7, 9-10, 15 and 100-660 described in Table 2 wherein Q ₁ is —OH. Further typical compounds of the formula R ₅ —OH include those described in Table 25 (with their Chemical Abstracts Service Registry Numbers) and the following Table 26 (with their Chemical Abstracts Service Registry Numbers, and Aldrich Chemical Company Product Numbers). Included are shown. More typically further typical compounds of the formula R ₅ —OH are those described by Table 2, groups 2-5, 9 and 100-141, where Q ₁ is —OH.

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

In general, an embodiment of this process results in treating compound 281 with an acid catalyst and a compound of the formula R ₅₆ -X ₁ -H where X ₁ is as defined above to obtain an amine intermediate from which compound 282 is obtained. . The acid catalyst and X ₁ are as defined above. More generally, this process results in treating compound 281 with a compound of the formula R ₅ —OH, R ₅ —SH, or R ₅ —NH ₂ , and BF ₃ · Et ₂ O to give compound 282. More generally, this process results in treating compound 281 with a compound of the formula R ₅ —OH and BF ₃ · Et ₂ O to give compound 282. Typical compounds of the formula R ₅ -OH are as described above.

Typical embodiments of this process are shown in Examples 65, 86, 92 and 95.

<Step O, Scheme 39>

Compound 283 is prepared using compound 282 according to the following procedure.

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

Generally this process results in treating compound 282 with a reducing agent to give compound 283. More generally this process involves treating compound 282 with hydrogen gas and a catalyst (such as platinum on carbon or Lindlar's catalyst), or a reducing agent (such as trialkyl or triaryl phosphine described above). More specifically, this process results in treating compound 282 with triphenylphosphine in water / THF to give compound 283.

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

<Step P, Scheme 39>

Compound 284 is prepared using compound 283 according to the following steps.

Remove the carboxylic acid protecting group.

This process generally involves treating Compound 283 with a base. More specifically, this process involves treating compound 283 with metal hydroxide in a suitable solvent such as an aprotic, polar solvent. More generally, this process results in the treatment of compound 283 with aqueous potassium hydroxide in THF to give compound 284.

Typical embodiments of this process are shown in Examples 88, 94, and 97 below.

<Step O, Scheme 40>

Compound 285 is prepared using compound 283 according to the following steps.

The amine is converted to protected guanidine.

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

Typically this process involves treating Compound 283 with guanidylating reagents common in the art. Typical reagents include Bis-BOC thio-urea aminoiminomethanesulfonic acid (Kim et al., "Tet. Lett." 29 (26): 3183-3186 91988) and 1-guanylpyrazole (Bernatowicz, Et al. "Tet. Lett." 34 (21): 3389-3392 (1993) More generally, this process results in treating Compound 283 with Bis-BOC thio-ureaic acid. Compound 283 is treated with Bis-BOC thio-ureaic acid and HgCl ₂ to give compound 285.

Typical embodiments of this process are shown in Example 67 below.

<Step R, Scheme 40>

Compound 286 is prepared using compound 285 according to the following procedure.

Remove carboxylic acid and guanidine protecting groups.

Generally this process treats compound 285 with a base; This is followed by treatment with acid as described above. More specifically, this process treats Compound 285 with metal hydroxide bases as described above to make intermediates; The intermediate is treated with acid to give compound 286. More generally, this process treats compound 285 with aqueous potassium hydroxide and THF to produce an intermediate; The intermediate is treated with TFA to afford compound 286.

<Step S, scheme 40.1>

Compound 288 is prepared using compound 287 according to the following steps.

E ₁ , J ₁ and J ₂ of compounds 287 and 288 are as described above. Generally E ₁ is —CO ₂ R ₅₁ as described above. In general, J ₁ is H, F or methyl, more generally H. In general, J ₂ is H or straight or branched alkyl of 1 to 6 carbon atoms, more generally H, methyl, ethyl, n-propyl, or i-propyl, more generally H.

R ₆₀ and R ₆₁ are groups capable of reacting to form R ₆₃ (as described below) substituted aziridine ring of compound 288. Generally one of R ₆₀ and R ₆₁ is a primary or secondary amine or a group that can be converted to a primary or secondary amine. Such R ₆₀ and R ₆₁ groups include, for example, -NH ₂ , -N (H) (R _6b ), -N (R _6b ) ₂ , -N (H) (R ₁ ), -N (R ₁ ) (R _6b ) and -N ₃ . Other examples of R ₆₀ and R ₆₁ include groups which are generally displaced by primary or secondary amines to form aziridine. Such groups include, for example, -OH, -OR _6a , Br, Cl, and I. In general, R ₆₀ and R ₆₁ are trans arrays. More generally 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 displaced by a primary or secondary amine to form aziridine. More generally, R ₆₀ is β-NH ₂ and R ₆₁ is α-OH, α-Omesyl, or α-Otosyl.

R ₆₂ is described in Process U, Scheme 40.1.

This step is supposed to treat compound 287 to produce compound 288. This is generally accomplished by treating Compound 287 to displace R ₆₁ to R ₆₀ . More generally, compound 287 is treated to activate R ₆₁ in the direction displaced by R ₆₀ . Thereby more specifically, the treatment of the compound 287 in the direction to activate the R ₆₁ that is displaced by the R ₆₀ and, R ₆₀ is activated to transpose the R _61. If both R ₆₀ and R ₆₁ are activated, activation can be performed simultaneously or sequentially. When activation is performed in sequence, they can be performed in any order, but in general, activation of R ₆₁ is performed in a manner preceding the activation of R ₆₀ .

Pre-activation by R ₆₀ of R ₆₁ is generally carried out by treating compound 287 with a hydroxy activating reagent such as mesyl or tosyl chloride. Activation of R ₆₀ for R ₆₁ translocation is generally accomplished by treating compound 287 to form a primary or secondary amine and then treating the amine with a base. For example, compound 287 is treated with a reducing agent capable of reducing azide to amines and bases.

In one embodiment of this process, compound 287 is treated with an R ₆₁ activating reagent and an R ₆₀ activating reagent to produce compound 288. In another embodiment, compound 287 is treated with an R ₆₀ activating reagent and an R ₆₁ activating reagent in an appropriate solvent to form compound 288. In another embodiment, compound 287 is treated with R ₆₀ activating reagent, R ₆₁ activating reagent, and base to produce compound 288. In another embodiment, compound 287 is treated with R ₆₁ activating reagent, R ₆₀ activating reagent, and base in a suitable solvent to obtain compound 288. In yet another embodiment, compound 287, wherein R ₆₀ is an azide, is treated with R ₆₁ activating reagent and an azide reducing agent to give compound 288. In another embodiment, Compound 287 wherein R ₆₀ is an azide is treated with an R ₆₁ activating reagent and an azide reducing agent in an appropriate solvent to afford compound 288. In another embodiment, Compound 287 wherein R ₆₀ is an azide is treated with R ₆₁ activating reagent, an azide reducing agent, and a base to give Compound 288. In another embodiment, Compound 287 wherein R ₆₀ is an azide is treated with an R ₆₁ activating reagent, an azide reducing agent, and a base in an appropriate solvent to give compound 288. In another embodiment, Compound 288 is treated with a hydroxy activator and an azide reducing agent, wherein Compound 287 wherein R ₆₀ is azide and R ₆₁ is hydroxy is obtained. In yet another embodiment, Compound 287, wherein R ₆₀ is azide and R ₆₁ is hydroxy, is treated with a hydroxy activator and an azide reducing agent in a suitable solvent to afford compound 288. In yet another embodiment, compound 287, wherein R ₆₀ is azide and R ₆₁ is hydroxy, is treated with a hydroxy activator, an azide reducing agent, and a base to give compound 288. In yet another embodiment, Compound 287, wherein R ₆₀ is azide and R ₆₁ is hydroxy, is treated with a hydroxy activator and an azide reducing agent in a suitable solvent to afford compound 288.

Typical embodiments of this process are shown in Process K, Scheme 38, above.

<Step T, Scheme 40.1>

Compound 289 is prepared using compound 288 according to the following steps.

R ₆₄ is generally H, R _6b or a group convertible to H or R _6b . More generally R ₆₄ is H. R ₆₅ is generally a group convertible to G ₁ or G ₁ . Is _{(CR 1 R 1) m1 W} 2 - More generally, R ₆₅ is -N _3, -CN, or. More generally, R ₆₅ is —N ₃ , —NH ₂ , or —N (H) (R _6b ) ₂ , —CH ₂ N ₃ , or —CH ₂ CN.

Generally, compound 288 is treated to produce amine 289. More typically nucleophile of the compound 288, for example, a nitrogen nucleophile such as R _65, with the R ₆₅ cationic salt, or the proton of the R ₆₅ Tue analogs, such as NH _3, an azide salt (NaN _3, KN _3, etc.), HCN, Cyanide salts (NaCN, KCN, etc.), salts of cyanoalkyl (eg (CH ₂ CN) ^- ) (eg NaCH ₂ CN, KCH ₂ CN, etc.). More typically, compound 288 is treated with an azide salt. Optionally, a base, typically a mild base such as ammonium halide and a solvent, typically a polar, aprotic solvent such as ether, amine or amide is used.

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

Typical embodiments of this process are shown in Process L, Scheme 38, above.

<Step U, Scheme 40.1>

Compound 290 is produced using compound 289 according to the following procedure.

R ₆₂ is a group capable of reacting with an amine to form a R ₆₆ (defined below) substituted aziridine ring of compound 290. In general, R ₆₂ is a group which can be displaced by primary or secondary amines to form aziridine. Such groups include -OR ₅₃ , -OH, -OR _6a , Br, Cl and I. In general, R ₆₂ has a trans configuration relative to nitrogen at the 4 position. More generally, R ₆₂ is -OR ₅₃ .

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

R ₆₆ is H, R _6b or R ₅₄ .

This process involves treating Compound 289 to yield Compound 290. This is generally done by treating compound 289 such that R ₆₂ is displaced by the amine at the 4 position. More generally, compound 289 is treated to activate the amine at position 4 so that R ₆₂ is transposed. More specifically, compound 289 is treated to activate the amine at position 4 so that R ₆₂ is displaced, and R ₆₂ is activated to be displaced by amine at position 4. If both R ₆₂ and 4 amines are to be activated, they can be carried out simultaneously or sequentially. In the case of sequential activation, any order may be used, but in general, activation of R ₆₂ is performed before amine activation in the 4-position.

Activation for R ₆₂ translocation by the amine at position 4 is generally carried out by treating compound 289 with the hydroxy activator described in Process B, Scheme 36. Optionally, R ₆₂ deprotects prior to activation. Activation of the amine at position 4 to transpose R ₆₂ is usually accomplished by treating Compound 289 to form a primary or secondary amine and then treating the amine with the acid catalyst described in Process N, Scheme 39.

In general, R ₆₂ is —OR ₅₃ and R ₆₆ is R ₅₆ , and this process involves the removal of R ₅₃ groups, with R ₅₄ production reagents (R ₅₄ -halides such as acetyl as described in Greene) Chloride, or Tr-Cl, or R ₅₄ -OR ₅₄ such as acetic anhydride) and a hydroxy activator as described in Process B, Scheme 36. More generally this process involves treating compound 289 with a polar, protic solvent, optionally in the presence of the acid catalyst described above, to obtain a primary intermediate; Treating the primary intermediate with Tr-Cl in a polar, aprotic solvent such as an amine to form a secondary intermediate; The secondary intermediate is treated with a sulfonic acid halide such as mesyl chloride or para toluene sulfonyl chloride in a polar aprotic solvent such as an amine to form compound 290. More typically, this process treats compound 289 with methanol and HCl to obtain a twelfth intermediate; Treating the primary intermediate with Tr-Cl and triethylamine to form a secondary intermediate; Treatment of the secondary intermediate with mesyl chloride and triethylamine yields compound 290.

In one embodiment, compound 289 is treated with an acid catalyst to give compound 290. In another embodiment, compound 289 is treated with an acid catalyst in a suitable solvent to give compound 290. In another embodiment, compound 289 is treated with a hydroxy activator and an acid catalyst to yield compound 290. In another embodiment, compound 289 is treated with a hydroxy activator and an acid catalyst in an appropriate solvent to produce compound 290. In yet another embodiment, compound 289 is prepared by treating compound 289 with a hydroxy deprotectant, a hydroxy activator and an acid catalyst. In another embodiment, compound 289 is treated with a hydroxy activator and an acid catalyst in a suitable solvent to yield compound 290.

Typical embodiments of this process are shown in Process M, Scheme 38, above.

<Step V, Scheme 40.1>

Compound 291 is prepared using compound 290 according to the following procedure.

Aziridine 290 is treated to form Compound 291. Generally, aziridine 290 is opened by acid catalyzed ring opening and the resulting amine is acylated.

R ₆₈ is independently H, R _6b , R ₁ or R ₅₅ as defined above. In general, R ₅₅ is —C (O) R ₅ . Usually one R ₆₈ is H or R _6b and the other is W ₃ .

R ₆₇ is U ₁ as described above. Generally R ₆₇ is W ₆ -O-, W ₆ -S-, or W ₆ -N (H)-. More generally R ₆₇ is R ₅ -O-, R ₅ -S-, or R ₅ -N (H)-.

Generally this process involves treating compound 290 with an acid catalyst and a compound of formula W ₆ -X ₁ -H where X ₁ is as defined above to form an amine intermediate; This amine intermediate consists of treating Compound 291 with a compound of the formula W ₃ -X ₁ -W ₃ or W ₃ -X ₁₀ , wherein X ₁₀ is a leaving group. Compounds of formula W ₆ -X ₁ -H and acid catalysis may be performed simultaneously with or prior to treatment of formula W ₃ -X ₁ -W ₃ or W ₃ -X ₁₀ compounds. Acid catalysts are generally those described in Process N, Scheme 39, above. More specifically, this process treats compound 290 with a compound of the formula R ₅ —OH, R ₅ —SH or R ₅ —NH ₂ and an acid catalyst; The intermediate consists of treating compound a91 with alkanophosphoric anhydride.

One embodiment consists of treating Compound 290 with a compound of Formula W ₆ -X ₁ -H with an acid catalyst to make Compound 291. Another embodiment consists of treating Compound 290 with a compound of Formula W ₆ -X ₁ -H with an acid catalyst in a suitable solvent to form Compound 291. Another embodiment consists of treating Compound 290 with a compound of Formula W ₆ -X ₁ -H, an acid catalyst and a compound of Formula W ₃ -X ₁ -W ₃ or W ₃ -X ₁₀ to make Compound 291. Another embodiment relates to treating compound 290 with a compound of formula W ₆ -X ₁ -H, an acid catalyst and a compound of formula W ₃ -X ₁ -W ₃ or W ₃ -X ₁₀ in a suitable solvent to form compound 291 Is done.

Typical embodiments of this process are shown in Process N, Scheme 39, above.

<Step W, Scheme 40.1>

Compound 292 is prepared using compound 291 according to the following steps.

Compound 291 is treated to yield compound 292. In general, R ₆₅ converts to form G ₁ . T ₁ is one example of —N (R ₆₈ ) ₂ prepared in Process V, Scheme 40.1 and U ₁ is one example of R ₆₇ .

In one example, R ₆₅ is deprotected, alkylated, guanidylated, oxidized or reduced to form G ₁ . This process can be done several times simultaneously or in any order. If R ₆₅ is azido, specific examples of this process include, but are not limited to, processes O, OQ, OQR and OP. Typical alkylating agents are those well known in the art, such as methyl iodide, methyl bromide, ethyl iodide, ethyl bromide, n-propyl iodide, n-propyl bromide, i-propyl iodide, i-propyl Alkyl halides such as bromide; And olefin oxides such as ethylene oxide or propylene oxide. Base catalysts described herein can optionally be used in the alkylation step.

One embodiment is to prepare compound 292 by treating compound 291 wherein R ₆₅ is azido with a reducing agent. Another embodiment is to prepare compound 292 by treating compound 291 wherein R ₆₅ is azido with a reducing agent in a suitable solvent. Another embodiment is to prepare compound 292 by treating compound 291 wherein R ₆₅ is azido with an alkylating agent. Another embodiment is to prepare compound 292 by treating compound 291 wherein R ₆₅ is azido with an alkylating agent in a suitable solvent. Another embodiment is to prepare Compound 292 by treating Compound 291 wherein R ₆₅ is azido with a reducing agent and an alkylating agent. Another embodiment is to prepare compound 292 by treating compound 291 wherein R ₆₅ is azido with a reducing agent and an alkylating agent in a suitable solvent. Another embodiment is the preparation of compound 292 by treating compound 291 wherein R ₆₅ is amino with an alkylating agent and a basic catalyst. Another embodiment is the treatment of compound 291 wherein R ₆₅ is azido with reducing agents, alkylating agents and basic catalysts to produce compound 292. Another embodiment is to prepare compound 292 by treating compound 291 wherein R ₆₅ is azido with a reducing agent, an alkylating agent, and a basic catalyst in a suitable solvent.

A typical embodiment of this process is shown in Process O, Scheme 39 above.

Typical embodiments of this process are shown in Examples 68 and 69 described below.

Typical compound of formula R ₅ -OH (CAS No.) C4 fluoro alcohols (R ^* , R ^* )-(±) -3-fluoro-2-butanol (139755-61-6) 1-fluoro-2-butanol (124536-12-5) (R) -3-fluoro-1-butanol (120406-57-7) 3-fluoro-1-butanol (19808-95-8) 4-fluoro-2-butanol (18804-31-4) (R ^* , S ^* )-3-fluoro-2-butanol (6228-94-0) (R ^* , R ^* )-3-fluoro-2-butanol (6133-82-0) 2-fluoro-1-butanol (4459-24-9) 2-fluoro-2-methyl-1-propanol (3109-99-7) 3-fluoro-2-butanol (1813-13-4) 4-fluoro-1-butanol (372-93-0) 1-fluoro-2-methyl-2-propanol (353-80-0)

C5 fluoro alcohols 2-fluoro-1-pentanol (123650-81-7) (R) -2-fluoro-3-methyl-1-butanol (113943-11-6) (S) -2-fluoro-3-methyl-1-butanol (113942-98-6) 4-fluoro-3-methyl-1-butanol (104715-25-5) 1-fluoro-3-pentanol (30390-84-2) 4-fluoro-2-pentanol (19808-94-7) 5-fluoro-2-pentanol (18804-35-8) 3-fluoro-2-methyl-2-butanol (7284-96-0) 2-fluoro-2-methyl-1-butanol (4456-02-4) 3-fluoro-3-methyl-2-butanol (1998-77-2) 5-fluoro-1-pentaol (592-80-3)

C6 fluoro alcohols (R- (R ^* , S ^* ))-2-fluoro-3-methyl-1-pentanol (168749-88-0) 1-fluoro-2,3-dimethyl-2-butanol (161082-90-2) 2-fluoro-2,3-dimethyl-1-butanol (161082-89-9) (R) -2-fluoro-4-methyl-1-pentanol (157988-30-2) (S- (R ^* , R ^* ))-2-fluoro-3-methyl-1-pentanol (151717-18-9) (R ^* , S ^* )-2-fluoro-3-methyl-1-pentanol (151657-14-6) (S) -2-fluoro-3,3-dimethyl-1-butanol (141022-94-8) (M) -2-fluoro-2-methyl-1-pentanol (137505-57-8) (S) -2-fluoro-1-hexanol (127608-47-3) 3-fluoro-3-methyl-1-pentanol (112754-22-0) 3-fluoro-2-methyl-2-pentanol (69429-54-5) 2-fluoro-2-methyl-3-pentanol (69429-53-4) 1-fluoro-3-hexanol (30390-85-3) 5-fluoro-2-methyl-2-pentanol (21871-78-3) 5-fluoro-3-hexanol (19808-92-5) 4-fluoro-3-methyl-2-pentanol (19808-90-3) 4-fluoro-4-methyl-2-pentanol (19031-69-7) 1-fluoro-3,3-dimethyl-2-butanol (4604-66-4) 2-fluoro-2-methyl-1-pentanol (4456-03-5) 2-fluoro-4-methyl-1-pentanol (4455-95-2) 2-fluoro-1-hexanol (1786-48-7) 3-fluoro-2,3-dimethyl-2-butanol (661-63-2) 6-fluoro-1-hexanol (373-32-0)

C7 fluoro alcohols 5-fluoro-5-methyl-1-hexanol (168268-63-1) (R) -1-fluoro-2-methyl-2-hexanol (153683-63-7) (S) -3-fluoro-1-heptanol (141716-56-5) (S) -2-fluoro-2-methyl-1-hexanol (132354-09-7) (R) -3-fluoro-1-heptanol (120406-54-4) (S) -2-fluoro-1-heptanol (110500-31-7) 1-fluoro-3-heptanol (30390-86-4) 7-fluoro-2-heptanol (18804-38-1) 2-ethyl-2- (fluoromethyl) -1-butanol (14800-35-2) 2- (fluoromethyl) -2-methyl-1-pentanol (13674-80-1) 2-fluoro-5-methyl-1-hexanol (4455-97-4) 2-fluoro-1-heptanol (1786-49-8) 7-fluoro-1-heptanol (408-16-2)

C8 fluoro alcohols (M) -2-fluoro-2-metal-1-heptanol (137505-55-6) 6-fluoro-6-methyl-1-heptanol (135124-57-1) 1-fluoro-2-octanol (127296-11-1) (R) -2-fluoro-1-octanol (118205-91-7) (±) -2-fluoro-2-methyl-1-heptanol (117169-40-1) (S) -2-fluoro-1-octanol (110500-32-8) (S) -1-fluoro-1-octanol (110270-44-5) (R) -1-fluoro-2-octanol (110270-42-3) (±) -1-fluoro-2-octanol (110229-70-4) 2-fluoro-4-methyl-3-heptanol (87777-41-1) 2-fluoro-6-methyl-1-heptanol (4455-99-6) 2-fluoro-1-octanol (4455-93-0) 8-fluoro-1-octanol (408-27-5)

C9 fluoro alcohols 6-fluoro-2,6-dimethyl-2-heptanol (160981-64-6) (S) -3-fluoro-1-nonanol (160706-24-1) (R- (R ^* , R ^* ))-3-fluoro-2-nonanol (137909-46-7) (R- (R ^* , S ^* ))-3-fluoro-2-nonanol (137909-45-6) 3-fluoro-2-nonanol (137639-20-4) (S- (R ^* , R ^* ))-3-fluoro-2-nonanol (137639-19-1) (S- (R ^* , S ^* ))-3-fluoro-2-nonanol (137639-18-0) (±) -3-fluoro-1-nonanol (134056-76-1) 2-fluoro-1-nonanol (123650-79-3) 2-fluoro-2-methyl-1-octanol (120400-89-7) (R) -2-fluoro-1-nonanol (118243-18-8) (S) -1-fluoro-2-nonanol (111423-41-7) (S) -2-fluoro-1-nonanol (110500-33-9) 1-fluoro-3-nonanol (30390-87-5) 2-fluoro-2,6-dimethyl-3-heptanol (684-74-2) 9-fluoro-1-nonanol (463-24-1)

C10 fluoro alcohols 4-fluoro-1-decanol (167686-45-5) (P) -10-fluoro-3-decanol (145438-91-1) (R- (R ^* , R ^* ))-3-fluoro-5-methyl-1-nonanol (144088-79-9) (P) -10-fluoro-2-decanol (139750-57-5) 1-fluoro-2-decanol (130876-22-1) (S) -2-fluoro-1-decanol (127608-48-4) (R) -1-fluoro-2-decanol (119105-16-7) (S) -1-fluoro-2-decanol (119105-15-6) 2-fluoro-1-decanol (110500-35-1) 1-fluoro-5-decanol (106533-31-7) 4-fluoro-2,2,5,5-tetramethyl-3-hexanol (24212-87-1) 10-fluoro-1-decanol (334-64-5)

C11 fluoro alcohols 10-fluoro-2-methyl-1-decanol (139750-53-1) 2-fluoro-1-undecanol (110500-34-0) 8-fluoro-5,8-dimethyl-5-nonanol (110318-90-6) 11-fluoro-2-undecanol (101803-63-8) 11-fluoro-1-undecanol (463-36-5)

C12 fluoro alcohols 11-fluoro-2-methyl-1-undecanol (139750-52-0) 1-fluoro-2-dodecanol (132547-33-2) (R ^* , S ^* )-7-fluoro-6-dodecanol (130888-52-7) (R ^* , R ^* )-7-fluoro-6-dodecanol (130876-18-5) (S) -2-fluoro-1-dodecanol (127608-49-5) 12-fluoro-2-pentyl-heptanol (120400-91-1) (R ^* , S ^* )-(±) -7-fluoro-6-dodecanol (119174-39-9) (R ^* , R ^* )-(±) -7-fluoro-6-dodecanol (119174-38-8) 2-fluoro-1-dodecanol (110500-36-2) 11-fluoro-2-methyl-2-undecanol (101803-67-2) 1-fluoro-1-dodecanol (100278-87-3) 12-fluoro-1-dodecanol (353-31-1)

C4 Nitro Alcohols (R) -4-nitro-2-butanol (129520-34-9) (R) -4-nitro-2-butanol (120293-74-5) 4-nitro-1-butanol radical ion (1-) (83051-13-2) (R ^* , S ^* )-3-nitro-2-butanol (82978-02-7) (R ^* , R ^* )-3-nitro-2-butanol (82978-01-6) 4-nitro-1-butanol (75694-90-5) (±) -4-nitro-2-butanol (72959-86-5) 4-nitro-2-butanol (55265-82-2) 1-aci-nitro-2-butanol (22916-75-2) 3-aci-nitro-2-butanol (22916-74-1) 2-methyl-3-nitro-1-propanol (21527-52-6) 3-nitro-2-butanol (6270-16-2) 2-methyl-1-nitro-2-propanol (5447-98-3) 2-aci-nitro-1-butanol (4167-97-9) 1-nitro-2-butanol (3156-74-9) 1-nitro-1-butanol (609-31-4) 2-methyl-2-nitro-1-propanol (76-39-1)

C5 Nitro Alcohols (R) -3-methyl-3-nitro-2-butanol (154278-27-0) 3-methyl-1-nitro-1-butanol (153977-20-9) (±) -1-nitro-3-pentanol (144179-64-6) (S) -1-nitro-3-pentanol (144139-35-5) (R) -1-nitro-3-pentanol (144139-34-4) (R) -3-methyl-1-nitro-2-butanol (141434-98-2) (±) -3-methyl-1-nitro-2-butanol (141377-55-1) (R ^* , R ^* )-3-nitro-2-pentanol (138751-72-1) (R ^* , S ^* )-3-nitro-2-pentanol (138751-71-0) (R ^* , R ^* )-2-nitro-3-pentanol (138668-26-5) (R ^* , S ^* )-2-nitro-3-pentanol (138668-19-6) 3-nitro-1-pentanol (135462-98-5) (R) -5-nitro-2-pentanol (129520-35-0) (S) -5-nitro-2-pentanol (120293-75-6) 4-nitro-1-pentanol (116435-64-4) (±) -3-methyl-3-nitro-2-butanol (114613-30-8) (S) -3-methyl-3-nitro-2-butanol (109849-50-5) 3-methyl-4-nitro-2-butanol (96597-30-7) (±) -5-nitro-2-pentanol (78174-81-9) 2-methyl-2-nitro-1-butanol (77392-55-3) 3-methyl-2-nitro-1-butanol (77392-54-2) 3-methyl-4-nitro-1-butanol (75694-89-2) 2-methyl-4-nitro-2-butanol (72183-50-7) 3-methyl-3-nitro-1-butanol (65102-50-3) 5-nitro-2-pentanol (54045-33-9) 2-methyl-3-aci-nitro-2-butanol (22916-79-6) 2-methyl-1-aci-nitro-2-butanol (22916-78-5) 2-methyl-3-nitro-2-butanol (22916-77-4) 2-methyl-1-nitro-2-butanol (22916-76-3) 5-nitro-1-pentanol (21823-27-8) 2-methyl-3-nitro-1-butanol (21527-53-7) 2-nitro-3-pentanol (20575-40-0) 3-methyl-3-nitro-2-butanol (20575-38-6) 3-nitro-2-pentanol (5447-99-4) 2-nitro-1-pentanol (2899-90-3) 3-methyl-1-nitro-2-butanol (2224-38-6) 1-nitro-2-pentanol (2224-37-5)

C6 Nitro Alcohols (-)-4-methyl-1-nitro-2-pentanol (158072-33-4) 3- (nitromethyl) -3-pentanol (156544-56-8) (R ^* , R ^* )-3-methyl-2-nitro-3-pentanol (148319-17-9) (R ^* , S ^* )-3-methyl-2-nitro-3-pentanol (148319-16-8) 6-nitro-2-hexanol (146353-95-9) (±) -6-nitro-3-hexanol (144179-63-5) (S) -6-nitro-3-hexanol (144139-33-3) (R) -6-nitro-3-hexanol (144139-32-2) 3-nitro-2-hexanol (127143-52-6) 5-nitro-2-hexanol (110364-37-9) 4-methyl-1-nitro-2-pentanol (102014-44-8) (R ^* , S ^* )-2-methyl-4-nitro-3-pentanol (82945-29-7) (R ^* , R ^* )-2-methyl-4-nitro-3-pentanol (82945-20-8) 2-methyl-5-nitro-2-pentanol (79928-61-3) 2,3-dimethyl-1-nitro-2-butanol (68454-59-1) 2-methyl-3-nitro-2-pentanol (59906-62-6) 3,3-dimethyl-1-nitro-2-butanol (58054-88-9) 2,3-dimethyl-3-nitro-2-butanol (51483-61-5) 2-methyl-1-nitro-2-pentanol (49746-26-1) 3,3-dimethyl-2-nitro-1-butanol (37477-66-0) 6-nitro-1-hexanol (31968-54-4) 2-methyl-3-nitro-1-pentanol (21527-55-9) 2,3-dimethyl-3-nitro-1-butanol (21527-54-8) 2-methyl-4-nitro-3-pentanol (20570-70-1) 2-methyl-2-nitro-3-pentanol (20570-67-6) 2-nitro-3-hexanol (5548-00-0) 4-nitro-3-hexanol (5342-71-2) 4-methyl-4-nitro-1-pentanol (5215-92-9) 1-nitro-2-hexanol (2224-40-0)

C7 nitro alcohols 1-nitro-4-heptanol (167696-66-4) (R) -1-nitro-2-heptanol (146608-19-7) 7-nitro-1-heptanol (133088-94-5) (R ^* , S ^* )-3-nitro-2-heptanol (127143-73-1) (R ^* , R ^* )-3-nitro-2-heptanol (127143-72-0) (R ^* , S ^* )-2-nitro-3-heptanol (127143-71-9) (R ^* , R ^* )-2-nitro-3-heptanol (127143-70-8) (R ^* , S ^* )-2-methyl-5-nitro-3-hexanol (103077-95-8) (R ^* , R ^* )-2-methyl-5-nitro-3-hexanol (103077-87-8) 3-ethyl-4-nitro-1-pentanol (92454-38-1) 3-ethyl-2-nitro-3-pentanol (77922-54-4) 2-nitro-3-heptanol (61097-77-6) 2-methyl-1-nitro-3-hexanol (35469-17-1) 2-methyl-4-nitro-3-hexanol (20570-71-2) 2-methyl-2-nitro-3-hexanol (20570-69-8) 5-methyl-5-nitro-2-hexanol (7251-87-8) 1-nitro-2-heptanol (6302-74-5) 3-nitro-4-heptanol (5462-04-4) 4-nitro-3-heptanol (5342-70-1)

C8 Nitro Alcohols (±) -1-nitro-3-octanol (141956-93-6) 1-nitro-4-octanol (167642-45-7) (S) -1-nitro-4-octanol (167642-18-4) 6-methyl-6-nitro-2-heptanol (142991-77-3) (R ^* , S ^* )-2-nitro-3-octanol (135764-74-8) (R ^* , R ^* )-2-nitro-3-octanol (135764-73-7) 5-nitro-4-octanol (132272-46-9) (R ^* , R ^* )-3-nitro-4-octanol (130711-79-4) (R ^* , S ^* )-3-nitro-4-octanol (130711-78-3) 4-ethyl-2-nitro-3-hexanol (126939-74-0) 2-nitro-3-octanol (126939-73-9) 1-nitro-3-octanol (126495-48-5) (R ^* , R ^* )-(±) -3-nitro-4-octanol (118869-22-0) (R ^* , S ^* )-(±) -3-nitro-4-octanol (118869-21-9) 3-nitro-2-octanol (127143-53-7) (R ^* , S ^* )-2-methyl-5-nitro-3-heptanol (103078-03-1) (R ^* , R ^* )-2-methyl-5-nitro-3-heptanol (103077-90-3) 8-nitro-1-octanol (101972-90-1) (±) -2-nitro-1-octanol (96039-95-1) 3,4-dimethyl-1-nitro-2-hexanol (64592-02-5) 3- (nitromethyl) -4-heptanol (35469-20-6) 2,5-dimethyl-1-nitro-3-hexanol (35469-19-3) 2-methyl-1-nitro-3-heptanol (35469-18-2) 2,4,4-trimethyl-1-nitro-2-pentanol (35223-67-7) 2,5-dimethyl-4-nitro-3-hexanol (22482-65-1) 2-nitro-1-octanol (2882-67-9) 1-nitro-2-octanol (2224-39-7)

C9 nitro alcohols 4-nitro-3-nonanol (160487-89-8) (R ^* , R ^* )-3-ethyl-2-nitro-3-heptanol (148319-18-0) 2,6-dimethyl-6-nitro-2-heptanol (117030-50-9) (R ^* , S ^* )-2-nitro-4-nonanol (103077-93-6) (R ^* , R ^* )-2-nitro-4-nonanol (103077-85-6) 2-nitro-3-nonanol (99706-65-7) 9-nitro-1-nonanol (81541-84-6) 2-methyl-1-nitro-3-octanol (53711-06-1) 4-nitro-5-nonanol (34566-13-7) 2-methyl-3- (nitromethyl) -3-heptanol (5582-88-7) 1-nitro-2-nonanol (4013-87-0)

C10 Nitro Alcohols 2-nitro-4-decanol (141956-94-7) (R ^* , S ^* )-3-nitro-4-decanol (135764-76-0) (R ^* , R ^* )-3-nitro-4-decanol (135764-75-9) 5,5-dimethyl-4- (2-nitroethyl) -1-hexanol (133088-96-7) (R ^* , R ^* )-(±) -3-nitro-4-decanol (118869-20-8) (R ^* , S ^* )-(±) -3-nitro-4-decanol (118869-19-5) 5-nitro-2-decanol (112882-29-8) 3-nitro-4-decanol (93297-82-6) 4,6,6-trimethyl-1-nitro-2-heptanol (85996-72-1) 2-methyl-2-nitro-3-nonanol (80379-17-5) 1-nitro-2-decanol (65299-35-6) 2,4,4,4-tetramethyl-3- (nitromethyl) -3-pentanol (58293-26-8)

C11 nitro alcohols 11-nitro-5-undecanol (167696-69-7) (R ^* , R ^* )-2-nitro-3-undecanol (144434-56-0) (R ^* , S ^* )-2-nitro-3-undecanol (144434-55-9) 2-nitro-3-undecanol (143464-92-0) 2,2-dimethyl-4-nitro-3-nonanol (126939-76-2) 4,8-dimethyl-2-nitro-1-nonanol (118304-30-6) 11-nitro-1-undecanol (81541-83-5)

C12 nitro alcohols 2-methyl-2-nitro-3-undecanol (126939-75-1) 2-nitro-1-dodecanol (62322-32-1) 1-nitro-2-dodecanol (62322-31-0) 2-nitro-3-dodecanol (82981-40-6) 12-nitro-1-dodecanol (81541-78-8)

Typical compound of formula R ₅ -OH (CAS No./Aldrich No.) 3-bromo 1-propanol 627189 167169 1,3-dichloro-2-propanol 96231 184489 3-chloro-2,2-dimethyl-1-propanol 13401564 189316 2,2-bis (chloromethyl) -1-propanol 5355544 207691 1,3-difluoro-2-propanol 453134 176923 2- (methylthio) ethanol 5271385 226424 2- (dibutylamino) ethanol 102818 168491 2- (diisopropylamino) ethanol 96800 168726 3-methyl-3-buten-1-ol 763326 129402 2-methyl-3-buten-2-ol 115184 136816 3-methyl-2-buten-1-ol 556821 162353 4-hexene-1-ol 928927 237604 5-hexene-1-ol 821410 230324 cis-2-hexene-1ol 928949 224707 trans-3-hexen-1-ol 928972 224715 trans-2-hexene-1-ol 928950 132667 (±) -6-methyl-5-heptene-2-ol 4630062 195871 Dihydromarsenol 18479588 196428 trans, trans-2,4-hexadiene-1ol 17102646 183059 2,4-dimethyl-2,6-heptadiene-1-ol 80192569 238767 Geraniol 106241 163333 3-butyn-1-ol 927742 130850 3-pentin-1-ol 1029104 208698 Acetionic acid, sodium salt 1562001 220078 (4- (2-hydroxyethyl) -1-piperazine-propanesulfonic acid 16052065 163740 Hepes, Sodium Salt 75277393 233889 1-methylcyclopropanemethanol 2746147 236594 2-methylcyclopropanemethanol 6077721 233811 (±) -methacrylate alcohol 18383590 194654 Cyclobutanmethanol 4415821 187917 3-cyclopentyl-1-propanol 767055 187275 1-ethylcyclopentanol 17356193 130869 3-methylcyclohexanol 591231 139734

3,3,5,5-tetramethylcyclohexanol 2650400 190624 4-cyclohexyl-1-butanol 4441570 197408 Dihydrocarveol 619012 218421 (1S, 2R, 5S)-(+)-menthol 15356704 224464 (1S, 2S, 5R)-(+)-neomenthol 2216526 235180 (1S, 2R, 5R)-(+)-isomenthol 23283978 242195 (±) -3-cyclohexene-1-methanol 72581329 162167 (+)-P-ment-1-ene-9-ol 13835308 183741 (S)-(-)-perylyl alcohol 536594 218391 Terpinene-4-ol 562743 218383 α-terpineol 98555 218375 (±) -trans-P-ment-6-ene-2,8-diol 32226543 247774 Cycloheptanmethanol 4448753 138657 Tetrahydrofurfuryl alcohol 97994 185396 (S)-(+)-2-pyrrolidinemethanol 23356969 186511 1-methyl-2-pyrrolidineethanol 67004642 139513 1-ethyl-4-hydroxypiperidine 3518830 224634 3-hydroxypiperidine hydrochloride 64051792 174416 (±) -2-piperidinemethanol 3433372 155225 3-piperidinemethanol 4606659 155233 1-methyl-2-piperidinemethanol 20845345 155241 1-methyl-3-piperidinemethanol 7583531 146145 2-piperidineethanol 1484840 131520 4-hydroxypiperidine 5382161 128775 4-methyl-1-piperazinpropanol 5317339 238716 exo-norborneol 497370 179590 endo-norborneol 497369 186457 5-norbornene-2-methanol 95125 248533 (±) -3-methyl-2-norbornanemethanol 6968758 130575 ((1S) -endo)-(-)-borneneol 464459 139114 (1R) -endo-(+)-pentyl alcohol 2217029 196444 9-ethylbicyclo (3.3.1) nonan-9-ol 21951333 193895 (±) -isofinocampenol 51152115 183229 (S) -cis-verbenol 18881044 247065 (1R, 2R, 3R, 5S)-(-)-isofinocampenol 25465650 221902 (1R)-(-)-meitenol 515004 188417

1-adammantanol 768956 130346 3,5-dimethyl-l-adammantanol 707379 231290 2-adamantanol 700572 153826 1-adammantanmethanol 770718 184209 1-adamantaneethanol 6240115 188115 3-furanmethanol 4412913 196398 Perfuryl alcohol 98000 185930 2- (3-thienyl) ethanol 13781674 228796 4-methyl-5-imidazolmethanol hydrochloride 38585625 227420 Metronidazole 443481 226742 4- (hydroxymethyl) imidazole hydrochloride 32673419 219908 4-methyl-5-thiazoleethanol 137008 190675 2- (2-hydroxyethyl) pyridine 103742 128643 2-hydroxy-6-methylpyridine 3279763 128740 4-pyridylcarbinol 586958 151629 3-pyridylcarbinol N-oxide 6968725 184446 1-benzyl-4-hydroxypiperidine 4727724 152986 1- (4-chlorophenyl) -1-cyclopentanmethanol 80866791 188697 (4S, 5S)-(-)-2-methyl-5-phenyl-2-oxazoline-4-methanol 53732415 187666 6- (4-Chlorophenyl) -4,5-dihydro-2- (2-hydroxybutyl) -3 (2H) -pyridazinone 38958826 243728 N- (2-hydroxyethyl) phthalimide 3891074 138339 2-naphthaleneethanol 1485070 188107 1-naphthaleneethanol 773999 183458 2-isopropylphenol 88697 129526 4-chloro-α, α-dimethylphenyl alcohol 5468973 130559 4-fluoro-α-methylbenzyl alcohol 403418 132705 3-phenyl-1-propanol 122974 140856 3- (4-methoxyphenyl) -1-propanol 5406188 142328 4-fluoropheneethyl alcohol 7589277 154172 4-methoxyphenethyl alcohol 702238 154180

trans-2-methyl-3-phenyl-2-propene-1-ol 1504558 155888 2-anilinoethanol 122985 156876 3-fluorobenzyl alcohol 456473 162507 2-fluorobenzyl alcohol 446515 162515 2-methyl-1-phenyl-2-propanol 100867 170275 α- (chloromethyl) -2,4-dichlorobenzyl alcohol 13692143 178403 2-phenyl-1-propanol 1123859 179817 4-chlorophenethyl alcohol 1875883 183423 4-bromophenethyl alcohol 4654391 183431 4-nitropenethyl alcohol 100276 183466 2-nitropenethyl alcohol 15121843 183474 β-ethylphenethyl alcohol 2035941 183482 4-phenyl-1-butanol 3360416 184756 2-methoxyphenethyl alcohol 7417187 187925 3-methoxyphenethyl alcohol 5020417 187933 3-phenyl-1-butanol 2722363 187976 2-methylphenethyl alcohol 19819988 188123 3-methylphenethyl alcohol 1875894 188131 4-methylphenethyl alcohol 699025 188158 5-phenyl-1-pentanol 10521912 188220 4- (4-methoxyphenyl) -1-butanol 22135508 188239 4- (4-nitrophenyl) -1-butanol 79524202 188751 3,3-diphenyl-1-propanol 20017678 188972 1-phenyl-2-propanol 14898874 189235 (±) -α-ethylphenethyl alcohol 701702 190136 1,1-diphenyl-2-propanol 29338496 190756 3-chlorophenethyl alcohol 5182445 193518 2-chlorophenethyl alcohol 19819955 193844 (±) -1-phenyl-2-pentanol 705737 195286 2,2-diphenylethanol 1883325 196568 4-ethoxy-3-methoxyphenethyl alcohol 77891293 197599

3,4-dimethoxyphenethyl alcohol 7417212 197653 3- (3,4-dimethoxyphenyl) -1-propanol 3929473 197688 2- (4-bromophenoxy) ethanol 34743889 198765 2-fluorophenethyl alcohol 50919067 228788 3- (trifluoromethyl) phenethyl alcohol 455016 230359 2- (phenylthio) ethanol 699127 232777 1- (2-methoxyphenyl) -2-propanol 15541261 233773

<Scheme 41>

Amine 300 (intermediate of Example 52, optionally purified before use) is treated with Boc anhydride to give mono Boc protected amine 301. This transition is in Greene, T.W. "Protective Groups in Organic Synthesis" 2nd Edition (John Wiley & Sons, New York, 1991) pp. 327-328.

At low temperature DIBAL is used to reduce methyl ester 301 to the corresponding primary allyl alcohol. Such conversions can be found in Garner, P. and Park, J.M., "J. Org. Chem.", 52: 2361 91987).

Primary alcohol 302 is protected as its p-methoxy benzyl ether derivative 303 by treating with 4-methoxybenzyl chloride under basic conditions. This conversion is described in Horita, K. et al. "Tetrahedron", 42: 3021 (1986).

The MOM and 303 protecting groups of 303 are removed by TFA / CH ₂ Cl ₂ treatment to afford amino alcohol 304. This transformation can be found in Greene, TW "Protective Groups in Organic Synthesis" 2nd edition (John Wiley & Sons, New York, 1991).

Conversion of 304 to the corresponding trityl protected aziridine 305 is carried out in one reactor by the following two stage reactions: 1) TrCl / TEA, 2) MsCl / TEA. This conversion has already been described.

The aziridine 305 is then converted to the corresponding Boc protected derivative 307 by first removing the trityl group with HCl / acetone followed by 306. This conversion is described in Hanson, R.W. And Law, H.D. J. Chem. Soc., 7285 (1965). Aziridine 306 is then converted to the corresponding Boc derivative 307 by Boc anhydride treatment. This transformation can be found in Fitremann, J. et al. "Tetrahedron Lett", 35: 1201 (1994).

Allyl aziridine 307 is selectively opened at the allyl position with a higher order organic-cuprate in the presence of BF ₃ · Et ₂ O at low temperature to obtain an open additive 308. This opening is described in Hudlicky, T. et al. "Synlett.", 1125 (1995).

Boc protected amine 308 is converted to N-acetyl derivative 309 in two steps: 1) TFA / CH ₂ Cl ₂ ; 2) Ac ₂ O / pyridine. This conversion can be found in Greene, TW "Protective Groups in Organic Synthesis" 2nd edition (John Wiley & Sons, New York, 1991) pp 327-328 and pp.351-352.

Benzyl ether 309 is deprotected at room temperature with DDQ to give primary allyl alcohol 310. This transformation can be found in Horita, K., et al. "Tetrahedron" 42: 3021 (1986).

Alcohol 310 is oxidized and converted to a reaction with methyl esters via Corey oxidation using MnO ₂ / AcOH / MeOH / NaCN. Such a conversion can be found in Corey, EJ, et al., “J. Am. Chem. Soc.”, 90: 5616 (1968).

Two-step reaction with azido ester 311 1) Ph ₃ P / H ₂ O / THF; 2) conversion to amino acid 312 by KOH / THF. This conversion has been described above.

<Scheme 42>

Known fluoro acetate 320 (Sutherland, J.K. et al., “J. Chem. Soc. CHem. Commun.” 464 (1993)) was deprotected from free alcohol followed by two steps, namely 1) NaOMe; 2) conversion to the corresponding mesylate 321 by MsCl / TEA. This transition is in Green, T.W. "Protective Groups in Organic Synthesis", 2nd edition (John Wiley & Sons, New York, 1991). Deprotection of 321 under acidic conditions affords diol 322 which is cyclized to epoxy alcohol 323 under basic conditions. This conversion has been described above.

Next order: ie 1) MOMCl / TEA; 2) NaN ₃ / NH ₄ Cl; 3) MsCl / TEA; 4) PPh ₃ / TEA / H ₂ O; 5) NaN ₃ / NH ₄ Cl; 6) HCl / MeOH; 7) Convert 323 to N-trityl protected aziridine 324 with i) TrCl, ii) MsCl / TEA. This order has been described above.

The aziridine 324 is then opened with appropriate alcohol under Lewis acid conditions followed by Ac ₂ O / pyridine treatment to give the acylation product 325. This conversion has been described above.

Ester 325 in two steps: 1) PPh ₃ / H ₂ O / THF; 2) Convert to the corresponding amino acid 326 according to KOH / THF. This conversion has been described above.

US Pat. No. 5,214,165, in particular the "Detailed Description and Examples" column of column 9, column 61 to column 18 to column 26, describes the preparation of 6α and 6β fluorosuccinic acids. equivalence). These fluoro compounds are suitable starting materials for the preparation of the compounds of the present invention using shikimic acid.

<Scheme 43>

Unsaturated ester 330 (Campbell, MM et al., Obtainable from acetonide alcohols according to the standard acetylation method of "Synthesis" 179 (1993)) is a suitable organic-cuprate whose R 'is a ligand to be converted from an organic-cuprate. (R 'is J _1a ). The obtained intermediate is then trapped with PhSeCl to give 331 which is treated with 30% H ₂ O ₂ to give α, β-unsaturated ester 332. This conversion is Hayashi, Y. et al. "J. Org. Chem." 47: 3428 (1982).

Acetate 332 was then subjected to a two step reaction: 1) NaOMe / MeOH; 2) conversion to the corresponding mesylate 333 by MsCl / TEA. This transformation has been described above and can also be found in Greene, T.W., "Protective Groups in Organic Synthesis", 2nd edition (John Wiley & Sons, New York, 1991).

Next, acetonide 333 was reacted in two steps: 1) p-TsOH / MeOH / Δ; 2) conversion to epoxy alcohol 334 by DBU / THF. This conversion has been described above.

Conversion of epoxide 334 to N-trityl aziridine 335 is carried out by the following steps: 1) MOMCl / TEA; 2) NaN ₃ / NH ₄ Cl; 3) MsCl / TEA; 4) PPh ₃ / TEA / H ₂ O; 5) NaN ₃ / NH ₄ Cl; 6) HCl / MeOH / 7) i) TrCl, ii) MsCl / TEA. This reaction sequence has been described above.

The aziridine 335 is then opened with the appropriate alcohol under leunic acid conditions and then treated with Ac ₂ O / pyridine to give the acylated product 336. This conversion has been described above.

Azido ester 336 is converted to the corresponding amino acid 337 according to the following two step reaction: 1) PPh ₃ / H ₂ O / THF; 2) KOH / THF. This conversion has been described above.

Schemes 44 and 45 are described by way of examples.

The transformation of typical starting materials into different E ₁ groups has been described in detail and thus the description is omitted here. Fleet, GWJ et al., “J. Chem. Soc. Perkin Trans. I”, 905-908 (1984), Fleet, GWJ et al .; "J. Chem. Soc. Chem. Commun.", 849-850 (1983), Yee, Ying K. et al .; "J. Med. Chem.", 33: 2437-2451 (1990); Olson, RE et al; "Bioorganic & Medicinal Chemistry Letters", 4 (18): 2229-2234 (1994); Santella, JB III et al., "Bioorganic & Medicinal Chemistry Letters", 4 (18): 2235-2240 (1994); Judd. DB and others; "J. Med. Chem."37; 3108-3120 (1994) and Lombaert, S.De et al., "Bioorganic & Medicinal Chemistry Letters", 5 (2): 151-154 (1994).

E ₁ sulfur homologues of the carboxylic acid compounds of the invention are prepared by standard techniques. Examples include, but are not limited to, reducing these carboxylic acids to alcohols according to standard methods. That is, alcohol is converted to halides or sulfonic acids according to standard methods and the resulting compound is reacted with NaSH to produce the sulfide product. This reaction is described in Patai, "The Chemistry of the Thiol Group" (John Wiley, New YO, 1974) pp. 2, and pp. 721-735.

Each scheme is modified to obtain various homologues of the specific typical materials produced above. Such modifications can be induced by reference to the above cited documents describing suitable organic synthesis.

In each of the above typical schemes it may be advantageous to separate the reaction products from one another and / or from the starting materials. The desired product of each step or series of steps is separated and / or purified (hereinafter referred to as separation) until the desired homogeneity is obtained using conventional techniques. This separation is generally accomplished through complex layer extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can be performed in a variety of ways, including, for example, size exclusion or ion exchange chromatography, high pressure, atmospheric or low pressure liquid chromatography, small and preparative thin or thick layer chromatography, as well as small scale thin layer and flash chromatography.

Another class of separation methods is the treatment of the mixture with reagents that bind to or make the separable products, unreacted starting materials, reaction by-products, and the like. Such reagents include absorbents or adsorbents such as activated carbon, molecular sieves, ion exchange media and the like. On the other hand, such reagents may be acids for basic materials, bases for antibodies, bases, antibodies, binding reagents such as binding proteins, selective chelators such as crown ethers, liquid / liquid ion exchange reagents (LIX).

Select the appropriate separation method according to the nature of the material involved. For example, molecular weight, boiling point, the presence or absence of polar functional groups in chromatography, the stability of materials in acidic and basic media during recovery phases, and the like. Those skilled in the art will be able to apply techniques that are likely to yield the desired separation results.

It is made clear that all the above-mentioned documents and patent documents are referred to in the text together with the publication of the citations. In particular, the cited portions of the documents or the cited pages are clearly indicated. Thus far, the present invention has been described in detail so as to enable those skilled in the art to make and use the claimed subject matter. Certain modifications to the methods and compositions of the appended claims are, of course, within the scope and spirit of the invention.

<Jang protection>

Another embodiment of the present invention includes the enteric protection form of the compounds of the present invention. By "intestinal protection" is meant herein the protection of a compound of the invention to avoid exposing the gastrointestinal tract, in particular the upper gastrointestinal tract, more specifically the stomach and esophagus, to the compound of the invention. . In this way, gastric mucosal tissue is protected against the rate of exposure to a compound of the present invention that can cause side effects such as nausea; Compounds of the invention may be protected from conditions present in the gastrointestinal tract, typically one or more portions of the upper gastrointestinal tract.

Examples of such enteric protected forms include enteric coated tablets, enteric coated granules, enteric coated beads, enteric coated particles, enteric coated microparticles and Enteric coating excipients, such as enteric coating capsules, are illustrative, but not limited to. In a preferred embodiment, the compounds of the present invention may be supported in suitable excipients such as tablets, granules or capsules, which may be coated with a pharmaceutically acceptable coating. In another preferred embodiment, the compounds of the invention can be prepared as enteric protected granules, granules, micropowders, spheres, microspheres or colloids, which are enteric protected granules, granules, Microparticulates, spheres, microspheres or colloids are prepared as pharmaceutically acceptable dosage forms such as tablets, granules, capsules or suspensions.

On the other hand, the present invention provides a method for effectively delivering a pharmaceutical composition containing a therapeutically effective amount of an active ingredient of about 0.1 to 1000 mg and any pharmaceutically acceptable excipients to the intestine, particularly the small intestine, of a human or other mammal. It also relates to enteric coating dosage forms of the compounds of the invention.

As used herein, "excipient" includes pharmaceutically acceptable dosage excipients. Many excipients are known in the art, including tablets, coated tablets, capsules, hard capsules, soft gelatin capsules, granules, micropowders, colloids, micro-encapsulationed, delayed release, semi-solids, It is cited in the text as suppositories or granule excipients.

As used herein, "pharmaceutically acceptable carrier" includes all physiologically stable, pharmaceutically inert materials known to those of ordinary skill in the art, and include the physical properties of certain compounds of the present invention selected for use. And chemical properties. Such excipients are described separately in the text. The carrier may, but not always, provide intestinal protection.

As used herein, "unit dosage" means, in a conventional sense, the amount that a single application or administration of a compound of the invention to a subject to be treated, as described below. It is to be understood that a therapeutic or prophylactic dosage may be given in one single dose, or in two or more multiple administrations of such dosage units totally administered to the desired dose of the compound for a given period of time.

In general, the oral unit dosage form composition of the present invention is preferably about 1 to 1000 milligrams (mg), typically 10 to 500 mg, more typically about 50 to 300 mg, even more typically for each unit dose. Uses 75 mg of compound. The actual amount can vary greatly depending on the active compound chosen.

In typical embodiments, enteric protectants are applied to excipients containing the compound, or to the compounds themselves without excipients, the protectants being mouth, esophagus or stomach exposure, contact or exposure to the compound of the present invention, and the like. To prevent nausea, but release the compound so that it can be absorbed substantially only in crystals when, or in some cases, the drug passes through the proximal portion of the lower gastrointestinal tract.

The relative ratio of the compound of the present invention to the protecting agent is varied so as to achieve an appropriate absorption range depending on the compound selected. Although the minimum or maximum weight percent of enteric protective agent is not strictly applied, in typical enteroprotected embodiments less than about 50 weight percent enteric coating is included. More typically from about 1% to about 25%, more typically from about 1% to about 15%, more typically from about 1% to about 10% (all in weight percent).

Numerous monographs disclose enteroprotection and related techniques, and the present invention can be usefully used to prepare enteroprotected compositions. An example of such a monograph is as follows: "Theory and Practice of Industrial Pharmacy," 3rd ed. Lea & Febiger, Philadelphia, 1986 (ISBN 0-8121-0977-5); Lihmann, K .; "Practical Course in Laquer Coating," Eudragit, 1989; Lieberman; Lachman, L .; Schwartz, "Pharmaceutical Dosage Forms: TAblets", 1990, Dekker (ISBN: 0-8247-8289-5); Lee, Ping I. Editor Good, William R. Editor, "Controlled-Release Technology: Pharmaceutical Applications", ACS Symposium Ser. Vol. 348 (ISBN: 0-608-03871-7); Wilson, Billie E .; Shannon, Margret T., "Dosage Calculation: A Simplified Approach," 1996, Appleton & Lange (ISBN: 0-8385-9297-X); Lieberman, Herbert A. Editor Rieger, Martin M., "pharmaceutical Dosage Forms-Disperse Systems," 1996, Dekker (ISBN: 0-8247-9387-0); "Basic Tests for Pharmaceutical Dosage Forms," 1995, World Health (ISBN: 91-4-154418-X); Harsa, D. R., Editor; Stephenson, R. A., Editor, "Excipients & Delivery Systems for Pharmaceuticla Formulations: Proceedings of the" Formulate '94 "British Association for Chemical Specialities Symposium", 1995, CRC Pr (ISBN: 0-85404-715-8); Ansel, Howard C .; Popovich, Nicholas G .; Allen, Lloyd V., "Pharmaceutical Dosafe Forms & Drug Delivery Systems, 6th ed.", 1994, Williams & Wilkins (ISBN: 0-683-01930-9); "The Sourcebook for Innovative Drug Delivery: Manufacturers of Devices & Pharmaceuticals, Suppliers of Products & Servies, Sources of Information," 1987, Canon Comns (ISBN: 0-9618649-0-7); Chiellini, E., Editor; Giusti, G., Editor; Migliaresi, C., Editor; Nicolais, L., Editor, "Polymers in Medicine II: Biomedical & Pharmaceutical Applications", 1986, Plenum (ISBN: 0-306-42390-1); "Pharmaceutical Aerosol: A Drug Delivery System in Transition", 1994, Technomic (ISBN: 0-87762-971-4); Laffer, U., Editor; Bachmann, I., Editor; Metzger, U., Editor, "Implantable Drug Delivery Systems", 1991, S Karger (ISBN: 3-805-5434-6); Borchardt, Ronald T., Editor; Repta, Arnold J., Editor; Stella, Valentino J., Editor (ISBN: 0-89603-089-X); Anderson, James M., Editor, "Advances in Drug Delivery Systems 5: Proceedings of the Fifth International Symposium on Recent Advances in Drug Delivery Systems, Salt Lake City, UT, USA, February 25-28, 1991", Elsevier (ISBN: 0-444-88664-8); Turco, Salvatore J .; King, Robert E., "Sterile Dosage Forms: Their Preparation & Clinical Application", 1987, Williams & Wilkins (ISBN: 0-8121-1067-6); Tomlinson, E., Editor; Davis, S.S., Editor, "Site-Specific Drug Delivery: Cell Biology, Medical & Pharmaceutical Aspects", 1986, Wiley (ISBN: 0-471-91236-0); Hess, H., Editor, "Pharmaceutical Dosage Forms & Their Use", 1986, Hogrefe & Huber Pubs (ISBN: 3-456-81422-4); Avis; Lieberman; lachman, "Pharmaceutical Dosage Forms, Vol. 2", 1986, Dekker (ISBN: 0-8247-7085-4); Carstensen, Jens T., "Pharmaceutics of Solid Dosage Forms", 1977, Wiley (ISBN: 0-471-13726-X); Robinson, Joseph R., Editor, "Ophthalmic Drug Delivery Systems", 1980, Am Pharm Assn (ISBN: 0-917330-32-3); Ansel, Howard C., "Introduction to Pharmaceutical Dosage Forms, 4th ed.", 1985, Williams & wilkins (ISBN: 0-8121-0956-2); "High Tech Drug Delivery Systems", 1984, Intl Res Dev (ISBN: 0-88694-622-0); Swarbrick, James, "current Concepts in Pharmaceutical Science: Dosage Form Design & Bioavailability", 1985, Lea & Febiger (ISBN: 0-318-79917-0); Sprowls, Joseph B., Editor, "Prescription Pharmacy: Dosage Forms: Proceedings of the 37th International Congress of Pharmaceutical Sciences of F.I.P., The Hague, Netherlands, September, 1977", Elsevier (ISBN: 0-444-80033-6).

Specific embodiments:

In another embodiment, the compositions of the present invention have the form of enteric coated tablet dosage forms. In this embodiment, the formulations of the present invention are molded into hard tablets by conventional methods, which are coated with enteric coatings according to conventional technical methods.

In a preferred embodiment, the compounds of the invention have the form of enteric coated powder dosage forms. In this embodiment, the formulations of the present invention are filled into hard or soft-shell capsules or equivalents thereof which are coated with enteric coatings according to conventional techniques.

In another embodiment, the composition of the present invention is in the form of a liquid suspension of enteric coating granules of the compound of the present invention. In this embodiment a liquid inhibitor suspension is filled into a hard or soft-shell capsule or equivalent thereof, which capsule is coated with an enteric coating according to conventional techniques.

As an alternative to the above embodiments, the capsule or other administration container itself may be made of intestinal protective reagents or components, or otherwise bound as essential components to the container.

In another embodiment, enteroprotectants are used to administer the compounds of the present 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) an intumescent, erosive polymer layer surrounding the core (combined core and erosive polymer layer, sometimes referred to as a "dual matrix tablet"); And 3) enteric coating applied to the dual matrix tablet. The composition and function of the components of such a colon targeted delivery system are described in detail in US Pat. No. 5,482,718, which publication is incorporated by reference in its entirety. In particular, it is clearly stated in column 2, line 29 to column 4, line 12 of the publication.

Another embodiment of the present invention is directed to enteric protective emulsions, suspensions, tablets, coated tablets, hard capsules, soft gelatin capsules, microcapsules, delayed release, liquid, semisolid, suppository and aerosol dosage forms of the compounds of the invention. It is about. "Theory and Practice of Industrial Pharmacy," 3rd ed. Lea & Febiger, Philadelphia, 1986 (ISBN 0-8121-0977-5) describe each of these standard dosage forms in detail in the following sections: emulsion and suspension dosage forms (pp. 100-122), tablets (pp) 293-345), coated tablets (pp. 346-373), hard capsules (pp. 374-393), soft gelatin capsules (pp. 398-411), microcapsules (pp. 412-430), delayed release (Pp. 430-456), liquid (pp. 457-478), semisolid (pp. 534-563), suppositories (pp. 564-587) and aerosol (pp. 589-618).

Other embodiments include delayed release, controlled release, granules, microcapsules, multiparticulates, microparticulates, colloidal, nasal, inhalable, oral mucosa, colon, Dermal, transdermal, oral, topical and veterinary dosage forms are included. Techniques for each dosage form are described in detail in "Drugs and the Pharmaceutical Sciences" compiled by James Swabrick, Marcel Dekker, New York.

Substances:

Conventional enteroprotectant polymers and mixtures of polymers usable in the text include those that are insoluble at pH about 5.5 or less, ie generally in the range found above, but soluble at pH above 5.5, ie, in the small and large intestine. do. The effectiveness of certain enteroprotectant materials can be measured using known USP methods.

Examples of enteric protective polymers that can be used in such embodiments are cellulose acetate phthalate, methyl acrylate-methacrylic acid copolymer, cellulose acetate succinate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate and methyl methacrylate- Methacrylic acid copolymer is mentioned. Other examples include anionic carboxylic copolymers based on methacrylic acid and methacrylate, which are commercially available as Eudragit (r). Typical examples include cellulose acetate phthalate ("CAP"), cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate ("HPMCP"), hydroxypropyl methylcellulose phthalate succinate, polyvinyl acetate phthalate ("PVAP"), meta Acrylic acid and methacrylic acid esters are mentioned.

Enteric protector materials can be prepared using acetylated monoglycerides, propylene glycol, glycerol, glyceryl triacetate, polyethylene glycol, triethyl citrate, tributyl citrate, diethyl phthalate, using methods known to those skilled in the art of this distribution. Or with conventional plasticizers such as dibutyl phthalate or without the use of plasticizers.

Typical embodiments of intestinal protection:

<Example 1: Intestinal Protected GS 4104 Capsule>

In this typical embodiment, GS 4104 (Compound 262, Example 116, phosphate salt form, 131.4 mg / capsule, 100 mg free base equivalent) was converted to Croscarmellose Sodium (2.6 mg / capsule) and size. 4 Mix in white opaque hard gelatin capsule shell (capsule composition: gelatin NF, titanium dioxide USP) and enteric coated.

The following enteric coating formulations are applied to the capsules by conventional methods known in the art.

ingredient % w / w Formulation A: Hydroxypropyl methylcellulose phthalate ("HPMCP") 5.0 Triacetin 0.5 Alcohol USP 7.9 water 15.5 Formulation B: HPMCP 10.0 Titanium dioxide 0.2 Dimethyl Polysiloxane 0.05 Triethyl citrate 1.0 Alcohol USP 72.75 water 16.00 Formulation C: Cellulose acetate phthalate ("CAP") 8.5 Diethyl phthalate 1.5 Titanium dioxide 0.2 Acetone 44.9 Denatured alcohol 44.9 Formulation D: Polyvinyl acetate phthalate ("PVAP") 5.0 Acetylated Glyceride 0.8 Methylene chloride 47.1 Denatured alcohol 47.1 Formulation E: Methacrylic acid or methacrylic acid esters (Eudragit (r) S or L, Rohm Pharma. GMBH, Wetterstadt, West Germany) 8.0 Acetone 46.0 Anhydrous alcohol 46.0 Plasticizer q.s.

Typically, the enteric polymer (with or without plasticizer) is dissolved in the solvent described after each formulation to produce a suspension / solution. Optionally, an opaque agent such as titanium dioxide was added. The excipient is sprayed with the coating suspension / solution in a suitable container under conditions such that the enteric protective coating flows onto the excipient without dissolving or inhibiting the excipient. About 1-50% by weight, typically 1-15%, more typically 5-10% by weight of the final coated excipient of the enteric polymer coating will be useful for proper bowel protection.

<Example 2: Intestinal Protected Tablet>

In another exemplary embodiment, the core tablet is wrapped into an enteric coating. Optionally, subcoatings may be used.

Core tablets:

The core tablet of the present invention comprises (a) combining the active ingredient with a pharmaceutically acceptable carrier, such as a diluent, a binder, a disintegrant and one or more optional ingredients selected from the following groups: Condensation aids, fragrances, flavor enhancers, sweeteners, dyes, pigments, buffers, and preservatives; (b) smoothing the mixture with a lubricant; (c) The resulting lubricated mixture can be prepared by compacting it into the desired tablet form using various purification techniques well known to those skilled in the art. As used herein, the term "tablet" includes any form or size of a compressed or uncompressed pharmaceutical dosage formulation.

Typical diluents usable in this embodiment include lactose or microcrystalline cellulose.

Typical binders usable in this embodiment include, but are not limited to, povidone. Povidone is available under the trade name "Avicel" from ICP Corporation.

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

Typical lubricants include magnesium stearate, stearic acid, hydrogen substituted vegetable oils or talc.

Perfumes include Remingston's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, 1990, pp. As disclosed in 1288-1300.

Typical sweeteners include saccharin, aspartame, or edible mono- or disaccharides, glucose or sucrose, and the like.

Dyes and pigments include those disclosed in the Pharmaceutical Excipients, pp. 81-90, 1986 Handbook of the Americal Pharmaceutical Association & the Pharmaceutical Society of Great Britain.

Typical preservatives include methyl paraben, propyl paraben, cetylpyridinium chloride and salts thereof, sorbic acid and salts thereof, thimerosal, or benzalkonium chloride.

Sheet coating:

Eudragit L-30-D (r), a methacrylic acid copolymer from Rohm Pharma GmbH, Weiterstadt, West Germany is suitable as enteric polymer. Eudragit L-30-D (r) has a ratio of free carboxyl groups to ester groups of about 1: 1 and dissolves in large quantities at pH 5.5 and above. In general, the larger the% content of Eudragit L-30-D (r) contained in the enteric coating, the closer the release of the active ingredient in the lower gastrointestinal tract occurs. One skilled in the art will be able to sufficiently adjust the position in the lower gastrointestinal tract where the compound of the invention is released from the coating by adjusting the composition and thickness of the enteric coating applied.

Typically, plasticizers as described above are included.

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

Sub-coating:

Optically stable enhancement subcoatings on the core tablets can be used to minimize the interaction between the compounds of the invention and enteric coatings. It may also utilize a single 10-300 micron thick long film that does not affect the stability of the product. This sub-coating prevents the active ingredient of the core tablets from moving to the enteric coating, improving shell life and manufacturing stability. However, this sub-coating quickly dissolves in the intestinal fluid as long as the outer enteric coating cracks.

Typical sub-coating polymers usable in this embodiment include hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl ethylcellulose, or polyvinylpyrrolidone.

<General matter>

See schemes in the description of the following examples.

Some examples were performed several times. In the repeated examples, reaction conditions and yields such as time, temperature, and concentration were within the general experimental range. In repeated examples with significant modifications, such modifications are indicated when the results differ significantly from those described. If different starting materials were used, this was noted. In the repeated examples the "corresponding" homologue of a compound, such as "corresponding ethyl ester", is intended to be taken as the group otherwise indicated, in this case typically the same group in which the methyl ester is modified as specified. For example, "the corresponding ethyl ester of formula 1" is as follows.

<Example 1>

Epoxy Alcohol 1: Prepared from Schkimic acid according to the method of McGowan and Berchtold, "J. Org. 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) in one portion. After 2 hours, the reaction was concentrated in vacuo and the residue dissolved in acetonitrile. Allyl iodide (3.0 mL) was added and the mixture was stirred in the dark for 16 h. The solid was filtered through a pad of celite and washed with chloroform. Flash chromatography (40% EtOAc in hexane) after concentration in vacuo gave 1.24 g (42%) of 2 as a pale viscous oil: ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.75 (1H, m), 6.10-5.90 (1H, m, -CH =, allyl), 5.40-5.15 (2H, m, = CH ₂ , allyl), 4.47-4.43 (1H, m), 4.30-4.15 (2H, m, -CH _2- , allyl ), 3.73 (3H, s), 3.55-3.50 (1H, m), 3.45-3.40 (1H, m), 3.15-3.00 (1H, dm, J = 19.5 Hz), 2.50-2.35 (1H, dm, J = 2.7, 19.5 Hz).

<Example 3>

Azido alcohol 3: epoxide 2 (1.17 g, 5.57 mmol), sodium azide (1.82 g) and ammonium chloride (658 mg) were refluxed in MeOH / H ₂ O (8: 1) (35 mL) for 18 hours. I was. The reaction was concentrated in vacuo and the residue was separated between ethyl ether and water. The organic layer was washed with brine and dried. Concentration in vacuo afforded 1.3 g (92%) as a light oil, which was not further purified when used: ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.95-6.85 (1H, m), 6.00-5.85 (1H, m, -CH =, allyl), 5.35-5.25 (2H, m, = CH ₂ , allyl), 4.25-4.10 (2H, m, -CH _2- , allyl), 4.12 (1H, bt, J = 4.2 Hz), 3.95-3.75 (2H, m), 3.77 (3H, s), 2.85 (1H, dd, J = 5.3, 18.3 Hz), 2.71 (1H, bs), 2.26 (1H, dd, J = 7.2, 18.3 Hz).

<Example 4>

Aziridine 4: To a solution of alcohol 3 (637 mg, 2.52 mmol) in CH ₂ Cl ₂ (20 mL) cooled to 0 ° C. was added DAMP (some crystals) and triethylamine (442 μL). MsCl (287 μL) was added and the reaction stirred at 0 ° C. for 2 hours. The 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 in vacuo gave 881 mg of crude mesylate: ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.87-6.84 (1H, s), 6.00-5.85 (1H, m, -CH =, allyl), 5.40-5.25 (2H, m, = CH ₂ , allyl), 4.72 (1H, dd, J = 3.9, 8.5 Hz), 4.32 (1H, bt, J = 3.9 Hz), 4.30-4.15 (2H, m, -CH _2- , Allyl), 3.77 (3H, s), 3.14 (3H, s), 2.95 (1H, dd, J = 5.7, 18.6 Hz), 2.38 (1H, dd, J = 6.7, 18.6 Hz).

The crude mesylate was dissolved in dry THF (20 mL) and treated with Ph ₃ P (727 mg). After 3 h stirring at room temperature, water (15 mL) and solid NaHCO ₃ (1.35 g) were added and the mixture was stirred at rt overnight. The reaction was then concentrated and the residue was separated between EtOAc, saturated bicarbonate and brine. The organic layer was separated and dried over MgSO ₄ . The residue was concentrated in vacuo and flash chromatographed to give 170 mg (33%) of aziridine 4 as pale yellow oil: ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.82-6.80 (1H, m), 6.04- 5.85 (1H, m, -CH =, allyl), 5.35-5.20 (2H, m, = CH ₂ , allyl), 4.39 (1H, bd, J = 2.4 Hz), 4.20-4.05 (2H, m, -CH ₂ -allyl), 3.73 (3H, s), 2.90-2.80 (1H, bd, J = 18.9 Hz), 2,65-2.40 (2H, m).

<Example 5>

N-acetyl aziridine 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 stirred at 0 ° C. for 1 hour. The volatiles were removed under vacuum and the residue was separated between ethyl ether, saturated bicarbonate and brine. The organic layer was separated and dried over MgSO ₄ . Concentration gave 196 mg (96%) of compound 5 and was no longer purified when used: ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.88-6.86 (1H, m), 6.00-5.85 (1H, m, − CH =, allyl), 5.40-5.20 (2H, m, = CH ₂ , allyl), 4.45-4.40 (1H, m), 4.16 (2H, d, J = 6.0 Hz, -CH _2- , allyl), 3.76 (3H, s), 3.00-2.95 (2H, m), 2.65 (1H, bd, J = 18.5 Hz), 2.14 (3H, s).

<Example 6>

Azido allyl ether 6: Aziridine 5 (219 mg, 0.873 mmol), sodium azide (426 mg) and ammonium chloride (444 mg) in dry DMF (7 mL) were heated under argon to 65 ° C. 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 was followed by flash chromatography (EtOAc alone) to give 77 mg (35%) of azido amide, which was dissolved in CH ₂ Cl ₂ (1 mL) and pyridine (1 mL) and cooled to 0 ° C. Acetyl chloride (38 μL) was added and after 45 minutes solid NaHCO ₃ was added and the volatiles were removed under vacuum. The residue was separated between EtOAc and brine. The organic layer was dried over MgSO ₄ and concentrated in vacuo. Flash chromatography (EtOAc alone) gave 90 mg (99%) of compound 6: ¹ H NMR (500 MHz, CDCl ₃ ) δ 6.86 (1H, bt, J = 2.2 Hz), 5.95-5.82 (1H, m , CH =, allyl), 5.68 (1H, bd, J = 7.3 Hz), 5.35-5.20 (2H, m, = CH ₂ , allyl), 4.58-4.52 (1H, m), 4.22-4.10 (2H, m ), 4.04 (1H, dd, J = 5.9, 12.5 Hz), 3.77 (3H, s), 3.54-3.53 (1H, m), 2.89 (1H, dd, J = 5.9, 17.6 Hz), 2.32-2.22 ( H, m), 2.06 (3H, s).

<Example 7>

Azido diol 7: In a solution of olefin 6 (90 mg, 0.306 mmol) in acetone (3 mL) and water (258 μL) in N-methyl morpholine-N-oxide (39 mg) and OsO ₄ (in t-butanol) 2.5 w / w: 73 μL) was added. The reaction was then stirred for 3 days at room temperature. Solid sodium hydrosulfite was added and stirred for 20 minutes before the reaction was filtered through a pad of celite and washed with a large amount of acetone. Concentration in vacuo by flash chromatography (10% MeOH in CH ₂ Cl ₂ ) gave 50 mg (50%) of diol 7: ¹ H NMR (300 MHz, CD ₃ CN) δ 6.80-6.70 (1H, m), 4.20-4.15 (1H, bm), 3.95-3.80 (1H, m), 3.80-3.25 (6H, m), 3.70 (3H, s), 3.10 (1H, bs), 2.85 (1H, bs), 2.85- 2.75 (1H, m), 2.30-2.15 (1H, m), 2.16 (1H, bs), 1.92 (3H, s).

<Example 8>

Amino acid diol 8: A solution of diol 7 (23 mg, 0.07 mmol) in THF (1 mL) was treated with aqueous KOH (223 μL, 0.04 M solution) at room temperature. After stirring for 1.5 hours the reaction was acidified to pH = 4 using Amberlite IR-120 (plus) ion exchange resin. The resin was filtered off and washed with MeOH. It was concentrated in vacuo to afford the crude carboxylic acid which was dissolved in ethanol (1.5 mL). Lindlar catalyst (20 mg) was added to this solution and the reaction was stirred for 20 hours in a hydrogen atmosphere (1 atm, through a balloon). The reaction mixture was filtered through a pad of celite and washed with hot ethanol and water. After the ethanol was removed under reduced pressure, the aqueous layer obtained was lyophilized to obtain a mixture of the desired amino acid 8 and the starting material 7 as a white powder. Compound 8: ¹ H NMR (500 MHz, D ₂ O) δ 6.5 (1H, s), 4.24-4.30 (2H, m), 4.25-4.18 (1H, m), 3.90-3.55 (5H, complex m), 2.96-2.90 (1H, m), 2.58-2.50 (1H, complex m), 2.12 (3H, s).

<Example 9>

Compound 62: A suspension of quinic acid (60 g), cyclohexanone (160 mL) and toluenesulfonic acid (600 mg) in benzene (450 mL) was refluxed for 14 hours using a Dean-Stark column. The reaction mixture was cooled to room temperature and poured into saturated NaHCO ₃ solution (150 mL). The water layer was extracted with CH ₂ Cl ₂ (3 ×). The combined organic layers were washed with water (2 ×), brine (1 ×) and dried over Na ₂ SO ₄ . It was concentrated to give a white solid, which was recrystallized with ether (75 g, 95%) ¹ H NMR (CDCl ₃ ) δ 4.73 (dd, J = 6.1, 2.5 Hz, 1H), 4.47 (ddd, J = 7.0, 7.0, 3.0 Hz, 1H), 4.30 (ddd, J = 5.4, 2.6, 1.4 Hz, 1H), 2.96 (s, 1H), 2.66 (d, J = 11.7 Hz, 1H), 2.40-2.15 (m , 3H), 1.72-1.40 (m, 10H).

<Example 10>

Compound 63: To a solution of lactone 62 (12.7 g, 50 mmol) in methanol (300 mL) was added sodium methoxide (2.7 g, 50 mmol) in one portion. The mixture was stirred at rt for 3 h, quenched with acetic acid (3 mL) and then stirred for 10 min. The mixture was poured into 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 . Flash column chromatography (hexane / EtOAc = 1/1 to 1/2) gave diol (11.5 g, 80%) and starting material (1.2 g, 10%): ¹ H NMR (CDCl ₃ ) δ 4.47 ( ddd, J = 7.4, 5.8, 3.5 Hz, 1H), 4.11 (m, 1H), 3.98 (m, 1H), 3.81 (s, 3H), 3.45 (s, 1H), 2.47 (d, J = 3.3 Hz , 1H), 2.27 (m, 2H), 2.10 (dd, J = 11.8, 4.3 Hz, 1H), 1.92-1.26 (m, 10H).

<Example 11>

Compound 64: PCC (3.3 g, 15.6) in a mixture of diol 63 (1.100 g, 3.9 mmol), molecular sieves (3A, 2.2 g) and pyridine (1.1 g) in CH ₂ Cl ₂ (15 mL). mmol) was added in one portion. The mixture was stirred at rt for 26 h and diluted with ether (30 mL). The suspension was filtered through a pad of celite and washed with ether (2 × 20 mL). The combined ethers were washed with brine (2 ×) and dried over MgSO ₄ . It was concentrated and purified by flash column chromatography (hexane / EtOAc = 3/1) to give ketone (0.690 g, 67%): ¹ H NMR (CDCl ₃ ) δ 6.84 (d, J = 2.8 Hz, 1H), 4.69 (ddd, J = 6.4, 4.9, 1.6 Hz, 1H), 4.30 (d, J = 5.0 Hz, 1H), 3.86 (s, 3H), 3.45 (d, J = 22.3 Hz, 1H), 2.86 (m , 1H), 1.69-1.34 (m, 10H).

<Example 12>

Compound 28: NaBH ₄ was added to a solution of ketone 64 (0.630 g, 2.4 mmol) in MeOH (12 mL) at 0 ° C. for 30 minutes. The mixture was stirred again at 0 ° C. for 1.5 h and quenched with 15 mL of saturated NH ₄ Cl solution. This solution was extracted with CH ₂ Cl ₂ (3 ×) and the combined organic extracts were dried over MgSO ₄ . Purification by flash chromatography (hexane / EtOAc = 2/1) gave an alcohol (0.614 g, 97%): ¹ H NMR (CDCl ₃ ) δ 6.94 (d, J = 0.5 Hz, 1H), 4.64 (ddd) , J = 9.8, 6.7, 3.2 Hz, 1H), 4.55 (dd, J = 7.1, 4.2 Hz, 1H), 4.06 (m, 1H), 3.77 (s, 3H), 3.04 (dd, J = 16.5, 2.1 Hz, 1H), 2.73 (d, J = 10.2 Hz, 1H), 1.94 (m, 1H), 1.65-1.29 (m, 10H).

<Example 13>

Compound 66: Dissolve alcohol 28 (2.93 g, 10.9 mmol) and toluenesulfonic acid (1.5 g) in acetone (75 mL) and stir the mixture at room temperature for 15 hours. The reaction was quenched with water (30 mL) and basified with concentrated NH ₃ -H ₂ O until pH = 9. Acetone was removed under reduced pressure, and the water layer was extracted with CH ₂ Cl ₂ (3 ×). The combined organic extracts were dried over MgSO ₄ . It was concentrated to give the desired product: ¹ H NMR (CDCl ₃ ) δ 7.01 (m, 1H), 4.73 (m, 1H), 4.42 (m, 1H), 3.97 (m, 1H), 3.76 (s, 3H ), 2,71-2.27 (m, 2H), 2.02 (s, 3H), 1.98 (s, 3H).

<Example 14>

Compound 67: To a solution of 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 rt and stirred for 14 h. The mixture was diluted with CH ₂ Cl ₂ and washed with water (2 ×), brine (1 ×) and then dried over MgSO ₄ . Purification by flash chromatography (hexane / EtOAc = 9/1) gave diester (2.320 g, 68%): ¹ H NMR (CDCl ₃ ) δ 6.72 (m, 1H), 5.04 (m, 1H), 4.76 (m, 1H), 4.40 (m, 1H), 3.77 (s, 3H), 2.72-2.49 (m, 2H), 1.37 (s, 3H), 1.35 (s, 3H), 1.23 (s, 9H) .

<Example 15>

Compound 68: Diester 67 (2.32 g, 2.3 mmol) was dissolved in acetone / H ₂ O (1/1, 100 mL) and heated at 55 ° C. for 16 h. The solvent was removed, water (2 x 50 mL) was added and then evaporated. Concentration with toluene (2 x 50 mL) gave the diol, which was not further purified when used: ¹ H NMR (CDCl ₃ ) δ 6.83 (m, 1H), 5.06 (m, 1H), 4.42 (m, 1H ), 4.09 (m, 1H), 3.77 (s, 3H), 2.68-2.41 (m, 2H), 1.22 (s, 9H).

<Example 16>

Compound 69: To a solution of diol 68 (0.410 g, 1.5 mmol) in THF (8 mL) at 0 ° C. was added triethylamine (0.83 mL, 6.0 mmol) followed by the slow addition of thionyl chloride (0.33 mL, 4.5 mmol). Added. This mixture was warmed to room temperature and stirred for 3 hours. The mixture was diluted with CHCl ₃ , washed with water (3 ×), brine (1 ×) and dried over MgSO ₄ . Purification by flash chromatography (hexane / EtOAc = 5/1) gave an exo / endo mixture (0.430 g, 90%): ¹ H NMR (CDCl ₃ ) δ 6.89-6.85 (m, 1H), 5.48-4.84 (m, 3H), 3.80, 3.78 (s, 3H), 2.90-2.60 (m, 2H), 1.25, 1.19 (s, 9H).

<Example 17>

Compound 70: A mixture of sulfone 69 (0.400 g, 1.3 mmol) and sodium azide (0.410 g, 6.29 mmol) in DMF (10 mL) was stirred for 20 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated NH ₄ Cl solution, water, brine and dried over MgSO ₄ . It was concentrated to give azide (0.338 g, 90%): ¹ H NMR (CDCl ₃ ) δ 6.78 (m, 1H), 5.32 (m, 1H), 4.20 (m, 1H), 3.89 (m, 1H) , 3.78 (s, 3H), 3.00-2.60 (m, 2H), 1.21 (s, 9H).

<Example 18>

Compound 71: triethylamine (0.4 mL, 2.9 mmol) was added to a solution of alcohol 70 (0.338 g, 1.1 mmol) in CH ₂ Cl ₂ (11 mL) at 0 ° C., followed by methylsulfonic acid chloride (0.18 mL, 2.9 mmol) was added slowly. The mixture was stirred at 0 ° C. for 30 minutes and diluted with CH ₂ Cl ₂ . Purification by flash chromatography (hexane / EtOAc = 3/1) gave the desired compound (0.380 g, 82%): ¹ H NMR (CDCl ₃ ) δ 6.82 (m, 1H), 5.44 (m, 1H) , 4.76 (dd, J = 7.3, 1.4 Hz, 1H), 4.48 (m, 1H), 3.80 (s, 3H), 3.11 (s, 3H), 2.82-2.61 (m, 2H), 1.21 (s, 9H ).

<Example 19>

Compound 72: A mixture of azide 71 (0.380 g, 0.94 mmol) and triphenylphosphine (0.271 g, 1.04 mmol) in THF (19 mL) was stirred for 2 hours. The mixture was quenched with water (1.9 mL) and triethylamine (0.39 mL, 2.82 mmol) and the mixture was stirred for 14 hours. This solvent was removed under reduced pressure and the mixture was used for the next step. To a solution of the mixture in 0 ° C., CH ₂ Cl ₂ (20 mL) was added pyridine (0.68 mL, 8.4 mmol) followed by the slow addition of acetyl chloride (0.30 mL, 4.2 mmol). 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 . Purification by flash chromatography (hexane / EtOAc = 3/1) gave aziridine (0.205 g, 83%): ¹ H NMR (CDCl ₃ ) δ 7.19 (m, 1H), 5.58 (m, 1H), 3.77 (s, 3H), 3.14 (m, 2H), 2.85 (dd, J = 7.0, 1.6 Hz, 1H), 2.34 (m, 1H), 2.16 (s, 3H), 1.14 (s, 9H).

<Example 20>

Compound 73: A mixture of aziridine 72 (0.200 g, 0.68 mmol), sodium azide (0.221 g, 3.4 mmol) and ammonium chloride (0.146 g, 2.7 mmol) in DMF (10 mL) was stirred at rt for 14 h. The mixture was then diluted with ethyl acetate and washed with water (5 ×), brine (1 ×) and dried over MgSO ₄ . Purification by flash chromatography (hexane / EtOAc = 2/1) afforded the desired product and deacetyl amine (0.139 g). This mixture was dissolved in acetic anhydride (2 mL) and stirred for 2 hours. Excess anhydride was removed under reduced pressure to give the desired product (149 mg): ¹ H NMR (CDCl ₃ ) δ 6.76 (m, 1H), 5.53 (d, J = 8.5 Hz, 1H), 5.05 (m, 1H) , 4.31 (m, 1H), 4.08 (m, 1H), 3.79 (s, 3H), 2.91 (m, 1H), 2.51 (m, 1H), 1.99 (s, 3H), 1.20 (s, 9H).

<Example 21>

Compound 74: Ester 73 (149 mg, 0.44 mmol) was added to a potassium hydroxide solution in MeOH / H ₂ O (0.5 M, 4.4 mL, 2.2 mmol) and the mixture was stirred at rt for 3 h. The mixture was then cooled to 0 [deg.] C. and acidified to Amber = 3-4 with acid. This mixture was filtered and washed with MeOH. It was concentrated to give carboxylic acid as a white solid (73 mg, 69%): ¹ H NMR (CD ₃ OD) δ 6.62 (m, 1H), 4.15 (m, 1H), 3.95-3.72 (m, 2H) , 2.84 (dd, J = 6.7, 1.4 Hz, 1H), 2.23 (m, 1H), 1.99 (s, 3H).

<Example 22>

Compound 75: A mixture of azide 74 (8 mg) and Pd-C (Lindlar: 15 mg) in ethanol (2 mL) was stirred for 16 h under hydrogen. The mixture was filtered through celite and washed with hot MeOH-H ₂ O (1/1). It was concentrated to a solid. The solid was dissolved in water, passed through a short C-8 column and washed with water. It was concentrated to give a white solid (6 mg): ¹ H NMR (D ₂ O) δ 6.28 (m, 1H), 4.06-3.85 (m, 3H), 2.83 (dd, J = 17.7, 5.4 Hz, 1H), 2.35 (m, 1 H), 2.06 (s, 3 H).

<Example 23>

Compound 76: A 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 chromatography (EtOAc) yielded the ester (56 mg, 50%): ¹ H NMR (CD ₃ OD) δ 7.36-7.23 (m, 10H), 6.88 (s, 1H), 6.76 (s, 1H), 4.21 (m, 1H), 3.93-3.79 (m, 2H), 2.89 (dd, J = 17.7, 5.0 Hz, 1H), 2.34 (m, 1H), 2.00 (s, 3H).

<Example 24>

Compound 77: To a solution of alcohol 76 (20 mg, 0.05 mmol) in CH ₂ Cl ₂ (1 mL) was added pyridine (40 μL, 0.5 mmol) followed by acetic anhydride (40 μL, 0.5 mmol). The mixture was stirred for 24 hours and the solvent and reagents were removed under reduced pressure. Purification by flash chromatography (hexane / EtOAc = 1/2) gave diester (20 mg, 91%): ¹ H NMR (CDCl ₃ ) δ 7.40-7.27 (m, 10H), 6.95 (s, 1H ), 6.87 (m, 1H), 5.60 (m, 1H), 5.12 (ddd, J = 16.4, 10.2, 5.9 Hz, 1H), 4.28 (dd, J = 20.0, 9.4 Hz, 1H), 4.15 (m, 1H), 2.93 (dd, J = 17.8, 5.2 Hz, 1H), 2.57 (m, 1H), 2.09 (s, 3H), 2.01 (s, 3H).

<Example 25>

Compound 78: A mixture of diester 77 (20 mg, 0.045 mmol), anisole (50 μL, 0.45 mmol) and TFA (1 mL) in CH ₂ Cl ₂ (1 mL) was stirred for 20 min. The solvent and reagents were removed under reduced pressure. Purification by flash chromatography (EtOAc in EtOAc / AcOH = 100/1) afforded carboxylic acid (6 mg): ¹ H NMR (CDCl ₃ ) δ 6.85 (m, 1H), 5.54 (m, 1H), 5.12 (m, 1H), 4.31-4.03 (m, 2H), 2.89 (m, 1H), 2.60-2.41 (m, 1H), 2.11 (s, 3H), 2.03 (s, 3H).

<Example 26>

Compound 79: A mixture of azide 78 (6 mg, 0.02 mmol) and Pd-C (Lindlar: 15 mg) in EtOH / H ₂ O (2.2 mL, 10/1) was stirred under hydrogen atmosphere for 3 hours. This mixture was filtered through a pad of celite 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. Water was evaporated to give white powder (3 mg): ¹ H NMR (D ₂ O) δ 6.32 (m, 1H), 5.06 (m, 1H), 4.06 (t, J = 10.4 Hz, 1H), 3.84 ( m, 1H), 2.83 (m, 1H), 2.42 (m, 1H), 2.06 (s, 3H), 2.00 (s, 3H).

<Example 27>

Compound 80: DCC (35 mg, 0.172 mmol) was added to a solution of alcohol 76 (35 mg, 0.086 mmol), Boc-glycerine (30 mg, 0.172 mmol), and a catalytic amount of DMAP in CH ₂ Cl ₂ (1 mL). . The mixture was stirred for 30 minutes, filtered and washed with CHCl ₃ . CHCl ₃ solution was washed with water (2 ×). It was concentrated to give a white solid. Purification by flash chromatography (hexane / EtOAc = 2/1) gave the product (30 mg): ¹ H NMR (CDCl ₃ ) δ 7.39-7.26 (m, 10H), 6.95 (s, 1H), 6.86 ( m, 1H), 5.77 (m, 1H), 5.27 (m, 1H), 4.99 (m, 1H), 4.18-4.01 (m, 2H), 3.94-3.84 (m, 2H), 2.96 (dd, J = 7.8, 5.9 Hz, 1H), 2.57 (m, 1H), 2.02 (s, 3H), 1.45 (s, 9H).

<Example 28>

Compound 81: A mixture of diester 80 (30 mg, 0.05 mmol), anisole (150 μL) and TFA (1 mL) in CH ₂ Cl ₂ (1 mL) was stirred for 3 h. The solvent and reagents were removed under reduced pressure. The water layer was evaporated to give a white solid (15 mg): ¹ H NMR (CD ₃ OD) δ 6.73 (m, 1H), 5.25-5.15 (m, 1H), 4.35 (m, 1H), 4.17 (m, 1H) ), 3.82 (m, 2H), 2.93 (dd, J = 17.7, 5.6 Hz, 1H), 2.42 (m, 1H), 1.97 (s, 3H).

<Example 29>

Compound 82: A mixture of azide 81 (15 mg, 0.05 mmol) and Pd-C (Lindlar: 30 mg) in EtOH / H ₂ O (4 mL, 1/1) was stirred under hydrogen atmosphere for 3 hours. The mixture was filtered through a pad of celite and washed with hot MeOH / H ₂ O (1/1). Concentration gave a glassy solid. This solid was dissolved in water and passed through a C-8 column. Water was evaporated to give amino acids: ¹ H NMR (D ₂ O) δ 6.68 (m, 1H), 5.28 (m, 1H), 4.29 (m, 1H), 4.08-3.79 (m, 3H), 2.85 (m , 1H), 2.41 (m, 1H), 2.04 (s, 3H).

<Example 30>

Bis-Boc-guanidinyl methyl ester 92: treated according to Kim and Quian, "Tetrahedon Lett.", 34: 7677 (1993). Mercury chloride (46 mg) in a solution of amine 91 (42 mg, 0.154 mmol), bis-Boc thiourea (43 mg, 0.155 mmol) and triethylamine (72 μL) in dry DMF (310 μL) cooled to 0 ° C. , 0.170 mmol) was added in one portion. After 30 minutes the reaction was allowed to warm to room temperature and stirred for another 2.5 hours. The reaction mixture was then filtered through a pad of celite, concentrated and purified by flash chromatography (100% ethyl acetate) to give 70 mg (89%) of compound 92 as a colorless foam: ¹ H NMR (CDCl ₃₎ , 300 MHz) δ 11.37 (s, 1H), 8.60 (d, 1H, J = 7.8 Hz), 6.83 (t, 1H, J = 2.1 Hz), 6.63 (d, 1H, J = 8.4 Hz), 4.76 ( d, 1H, J = 7.0 Hz), 4.71 (d, 1H, J = 7.0 Hz), 4.45-4.10 (complex m, 2H), 3.76 (s, 3H), 3.39 (s, 3H), 2.84 (dd, 1H, J = 5.4, 17.4 Hz), 2.45-2.30 (m, 1H), 1.92 (s, 3H), 1.49 (s, 18H).

<Example 31>

Bis-Boc-guanidinyl carboxylic acid 93: To a solution of ester 92 (70 mg, 0.136 mmol) in THF (3 mL) cooled to 0 ° C. was added an aqueous KOH solution (0.476 M solution, 350 μL). The reaction was warmed to room temperature and stirred for 2 hours. The reaction was then acidified to pH = 4.5 using Amberlite IR-120 (plus) acidic resin. The resin was filtered off and washed with ethanol and H ₂ O. It was concentrated in vacuo to give 66 mg (97%) of carboxylic acid 93 as a white solid: ¹ H NMR (CDCl ₃ , 300 MHz) δ 11.40 (br s, 1H), 8.67 (d, 1H, J = 7.8 Hz ), 6.89 (s, 1H), 6.69 (br d, 1H, J = 8.4 Hz), 4.77 (d, 1H, J = 7.2 Hz), 4.70 (d, 1H, J = 7.2 Hz), 4.40-4.15 ( m, 2H), 3.39 (s, 3H), 2.84 (dd, 1H, J = 4.8, 17.1 Hz), 2.45-2.30 (m, 1H), 1.95 (s, 3H), 1.49 (s, 9H), 1.48 (s, 9H).

<Example 32>

Guanidinyl carboxylic acid TMA salt 94: Pure trifluoroacetic acid in a solution of bis-Boc guanidinyl carboxylic acid 93 (23 mg, 0.046 mmol) in CH ₂ Cl ₂ (1 mL) cooled to 0 ° C. 500 μL) was added. After 30 minutes the reaction was allowed to warm to room temperature and stirred again for 1.25 h. The volatiles were removed in vacuo and the residue was co-evaporated several times with H ₂ O to give a pale orange solid. The residue was purified by reverse phase C ₁₈ chromatography using H ₂ O as eluent. Fractions containing the desired product were combined and lyophilized to give 15 mg of compound 93 as a white powder: ¹ H NMR (D ₂ O, 500 MHz) δ 6.82 (t, 1H, J = 2.0 Hz), 4.51-4.47 ( m, 1H), 3.93 (dd, 1H, J = 9.0, 11.2 Hz), 3.87-3.80 (apparent ddd, 1H), 2.88 (m, 1H), 2.48-2.45 (complex m), 2.07 (s, 3H) . ¹³ C NMR (D ₂ O) δ 176.1, 170.0, 157.1, 139.2, 129.5, 69.4, 56.2, 50.9, 30.3, 22.2.

<Example 33>

Synthesis of 102: A solution of azido allyl ether 6 (24 mg, 0.082 mmol) in ethanol (1 mL) was treated with Lindlar catalyst (30 mg) for 1.5 h. The reaction mixture was filtered through a pad of celite and washed with hot ethanol. Concentration in vacuo gave a pale solid which was dissolved in THF (1.5 mL) and treated with aqueous KOH solution (0.50 M, 246 μL). After stirring for 2 hours at room temperature, the reaction was acidified to pH = 4.0 using Amberlite IR-120 (plus) acid resin, which was then filtered and washed with ethanol and H ₂ O. It was concentrated in vacuo to give an orange solid, eluted with H ₂ O and purified by C ₁₈ column chromatography. Fractions containing product were combined and lyophilized to give a 2: 1 mixture with Compound 102 and fully saturated Compound 103 as a white powder: ¹ H NMR (D ₂ O, 500 MHz) δ: 7.85 (s, 1H), 4.29 (br d, 1H, J = 9.2 Hz), 4.16 (dd, 1H, J = 11.6, 11.6 Hz), 3.78-3.72 (m, 2H), 3.62 (apparent ddd, 1H), 2.95 (apparent dd, 1H) , 2.58-2.52 (m, 1H), 2.11 (s, 3H), 1.58 (q, 2H, J = 7.3 Hz), 0.91 (t, 3H, J = 7.3 Hz).

<Example 34>

Synthesis of 115: A solution of amino acid 114 (10.7 mg, 0.038 mmol) in water (1.3 mL) cooled to 0 ° C. was adjusted to pH = 9.0 using 1.0 M NaOH. Benzyl formimidate hydrochloride (26 mg, 0.153 mmol) was then added in one portion and the reaction stirred at 0-5 ° C. for 3 hours, while maintaining the pH at 8.5-9.0 with 1.0 M NaOH. The reaction was then concentrated in vacuo and the residue was added to a C ₁₈ column, eluting with water. Fractions containing the product were combined and lyophilized to give formamidine carboxylic acid 115 (10 mg) as a white powder: ¹ H NMR (D ₂ O, 300 MHz, mixture isomer): δ 7.83 (s, 1H) ; [6.46 (s) & 6.43 (s); Total 1H]; 4.83 (d, 1 H, J = 7.3 Hz); 4.73 (d, 1 H, J = 7.3 Hz); 4.50-4.35 (m, 1 H); 4.10-4.05 (m, 1 H); [4.05-3.95 (m) & 3.80-3.65 (m), total 1H]; 3.39 (s, 3 H); 2.90-2.75 (m, 1 H); 2.55-2.30 (m, 1 H); [2.03 (s) & 2.01 (s), total 3H].

<Example 35>

Synthesis of 123: Tosyl chloride (4.3 g, 22.6 mmol) was added to a solution of alcohol 63 (5.842 g, 20.5 mmol) and DMAP (200 mg) in pyridine (40 mL). The mixture was stirred at rt for 40 h and the pyridine was removed under reduced pressure. The reaction was cooled with water and extracted with EtOAc (3x). The combined organic layers were washed with water, brine and dried over MgSO ₄ . Purification by flash chromatography (hexane / EtOAc = 2/1) gave tosylate (8.04 g, 89%): ¹ H NMR (CDCl ₃ ) δ 7.84 (d, J = 8.3 Hz, 2H), 7.33 ( d, J = 8.1 Hz, 2H), 4.78 (m, 1H), 4.43 (m, 1H), 4.06 (m, 1H), 3.79 (s, 3H), 2.44 (s, 3H), 2.43-1.92 (m 4H), 1.61-1.22 (m, 10H).

<Example 36>

Synthesis of 124: POCl in a solution of alcohol 123 (440 mg, 1.0 mmol) in pyridine (3 mL)₃(100 μL, 1.1 mmol) was added. The mixture was stirred at rt for 12 h, saturated NH₄Cl Quenched with solution. The water layer was washed with ether (3 ×). The combined ether layers were washed with water (2x), 2N HCl solution (2x), and brine and then MgSO₄Dried over. Purification by flash column chromatography (hexane / EtOAc = 2/1) afforded a mixture of the desired product 124 and impurities (350 mg, 83%, 2/1).

<Example 37>

Compound 1: methanesulfonyl chloride (330 μL) in a known acetonide solution of methyl schimate (877 mg, 3.85 mmol, “Tetrahedron Lett.”, 26:21 (1985)) in −10 ° C., dichloromethane (15 mL) , 4.23 mmol) was added followed by the dropwise addition of triethylamine (640 μL, 4.62 mmol). Methanesulfonyl chloride (30 μL), triethylamine (64 μL) was added while stirring the solution at −10 ° C. for 1 hour and then at 0 ° C. for 2 hours. After 1 hour, cold water was added, the organic layer was separated, washed with water, dried (MgSO ₄ ) and evaporated. The crude product was chromatographed on silica gel (hexane / ethyl acetate = 1/1) to give mesylate 130 (1.1 g, 93%) as an oil phase. Mesylate 130 (990 mg, 3.2 mmol) was dissolved in tetrahydrofuran (5 mL) and treated with 1 M HCl (5 mL). The solution was stirred at rt for 19 h, diluted with water (5 mL) and then stirred for 7 h. Evaporation of the organic solvent gave an oily residue which was extracted with 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%). To a partition suspension of diol 131 (260 mg, 0.98 mmol) in THF (5 mL) was added DBU (154 μL, 1.03 mmol). The solution was stirred at 0 ° C. for 3 hours and then warmed to room temperature and stirred for 5 hours. The solvent was evaporated and the crude residue was separated by partitioning between ethyl acetate (40 mL) and 5% citric acid (20 mL). The organic layer was washed with brine. The water layer was back extracted with ethyl acetate (15 mL) and the combined organic extracts were dried (MgSO ₄ ) and then evaporated to give epoxide (117 mg, 70%) as a white solid. Its ¹ H NMR spectrum was consistent with Structure 1 prepared by the method described in the literature.

<Example 38>

Alcohol 51: Trifluoroacetic acid (8 mL) was added to a solution of protected alcohol (PG = methoxymethyl: 342 mg, 1.15 mmol) in CH ₂ Cl ₂ (10 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 phase: ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.11 (s, 3H), 2.45 (m, 1H), 2.97 (dd, 1H, J = 3.8, 18.8 Hz), 3.66 (m, 2H), 3.78 (s, 3H), 4.40 (br s, 1H), 5.22 (br s, 1H), 6.19 (br s, 1 H), 6.82 (m, 1 H).

<Example 39>

Methyl ether 150: A solution of alcohol 51 (46 mg, 0.18 mmol) and methane iodide (56 μL, 0.90 mmol) in THF (0.7 mL) at 0 ° C. was dissolved in NaH as a 60% mineral oil dispersion (8 mg, 0.20 mmol). Was added. This solution was stirred at 0 ° C. for 2.5 h and an additional portion of NaH (2 mg) was added. After another 1 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 extracted with ethyl acetate (4 x 2 mL), the organic layers were combined together, dried (MgSO ₄ ) and evaporated. The crude residue was purified on silica gel (ethyl acetate) to give methylether 150 (12 mg, 25%) as a solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.07 (s, 3H), 2.23-2.34 (m, 1H), 2.89 (app ddd, 1H), 3.43 (s, 3H), 3.58 (m, 1H), 3.78 (s, 3H), 4.13 (m, 1H), 4.40 (m, 1H), 5.73 (d, 1H, J = 7.6 Hz), 6.89 (m, 1H).

<Example 40>

Amino acid 151: To a solution of methylether 150 (12 mg, 0.45 mmol) in THF (1 mL) was added polymeric support Ph ₃ P (75 mg, 3 mmol P / g resin). The mixture was stirred at rt for 19 h. After the resin was filtered and washed several times with THF, the filtrate and washings were combined and evaporated to yield 8 mg of crude residue. The residue was added THF (0.5 mL) and 0.5 M KOH (132 μL) / water (250 μL). The solution was stirred at rt for 1.25 h and the pH was adjusted to pH 3-4 on IR-120 ion exchange resin. The resin was filtered off and stirred with 1M HCl. After filtration, the resin was treated identically with 1M HCl until the acidic washes were no longer tested positive for amines and ninhydrine. The combined resin wash was evaporated and the residue eluted with water and purified on C-18 reversed phase silica to freeze-dried to afford amino acid 151 (1.8 mg, 15%) as a white solid: ¹ H NMR (300 MHz, D ₂ O). ) δ 2.09 (s, 3H), 2.48-2.59 (app qt, 1H), 2.94 (dd, 1H, J = 5.7, 17.4 Hz), 3.61 (m, 1H), 4.14-4.26 (m, 2H), 6.86 (br s, 1H).

<Example 41>

Amino acid allyl ether 153: Polystyrene supported PPh ₃ (50 mg) was added to a solution of azide 6 (16 mg, 0.054 mmol) in THF (0.50 mL) and H ₂ O (35 μL). The reaction was stirred at room temperature for 24 hours, filtered through a sintered glass funnel and washed with hot methanol. Concentration in vacuo gave a crude amino ester which was dissolved in THF (1.0 mL) and treated with aqueous KOH solution (0.5 M, 220 μL). After stirring for 2 hours at room temperature, Amberlite IR-120 (plus) acidic resin was added until the solution pH = 4.5. The resin was filtered and washed with ethanol and H ₂ O, then concentrated in vacuo to give a pale orange solid, which was purified by reverse phase C ₁₈ chromatography using H ₂ O as eluent. Fractions containing the desired product were combined and lyophilized to yield amino acids as white powder: ¹ H NMR (D ₂ O, 300 MHz) δ6.51 (br t, 1H), 6.05-5.80 (m, 1H, -CH = , Allyl), 5.36-5.24 (m, 2H, = CH ₂ , allyl), 4.35-4.25 (m, 1H), 4.25-4.05 (m, 2H, -CH _2- , allyl), 4.02-3.95 (m, 1H), 3.81-3.70 (m, 1H), 2.86-2.77 (apparent dd, 1H), 2.35-2.24 (complex m, 1H), 2.09 (s, 3H).

<Example 42>

Epoxide 161: of olefin 160 (532 mg, 1.61 mmol, prepared from Example 14, crude mesylate was filtered prior to use with 30% EtOAc / hexanes) in dichloromethane (15 mL) cooled to 0 ° C. To the solution was added MCPBA (690 mg). The mixture was warmed to room temperature and stirred overnight. The solvent was removed under vacuum and the mixture was diluted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and brine, and then dried over MgSO ₄ . The resulting residue was concentrated in vacuo and then subjected to flash column chromatography (30% hexanes in ethyl acetate) to give 437 mg (78%) as a pale oil: ¹ H NMR (CDCl ₃ , 300 MHz). ) [Mixture of 1: 1 diastereomer] δ [4.75 (dd, J = 3.9, 8.2 Hz) & 4.71 (dd, J = 3.9, 8.4 Hz), 1H total], 4.37 (m, 1H), 4.25- 4.00 (m, 2H), 3.78 (s, 3H), [3.68 (dd, J = 5.7, 11.7 Hz) & 3.51 (dd, J = 6.6, 11.7 Hz), 1H total], [3.17 (s) & 3.16 (s), 3H total], [2.99 (m) & 2.93 (m), 1H total], [2.83 (t, J = 4.1 Hz) & 2.82 (t, J = 4.5 Hz), 1H total], 2.70- 2.60 (m, 1 H), 2.45-2.30 (m, 1 H).

<Example 43>

Diol 162: Epoxide 161 (437 mg, 1.23 mmol) was refluxed briefly in H ₂ O (10 mL) and THF (20 mL) containing 70% HClO ₄ 5 drops for 1 hour. NaHCO ₃ in solid phase was added and the mixture was concentrated in vacuo. The residue was dissolved in EtOAc, washed with brine and dried. Concentration in vacuo gave crude diol 162 in quantitative yield. This was used directly without purification in the next step.

<Example 44>

Aldehyde 163: Diol 162 was oxidized according to the method of Vo-Quang and co-workers, "Synthesis", 68 (1988). To a slurry of silica gel (4.3 g) in dichloromethane (30 mL) was added NaIO ₄ solution (4.4 mL of 0.65 M aqueous solution). To this slurry was added crude diol 162 (520 mg) in dichloromethane (15 mL) and EtOAc (5 mL). After 1 hour, the solid was filtered off and washed with 20% hexanes / EtOAc. Concentration gave an oily residue that was dissolved in EtOAc and dried over MgSO ₄ . Concentration in vacuo gave aldehyde 163 as a pale oil which was used immediately in the following steps: ¹ H NMR (CDCl ₃ , 300 MHz) δ 9.69 (s, 1H), 6.98 (m, 1H), 4.72 (dd, 1H, J = 3.7, 9.1 Hz), 4.53 (d, 1H, J = 18.3 Hz), 4.45 (d, 1H, J = 18.3 Hz), 4.31 (m, 1H), 4.26-4.18 (m, 1H), 3.79 ( s, 3H), 3.19 (s, 3H), 3.05 (dd, 1H, J = 5.7, 18.6 Hz), 2.20-2.45 (m, 1H).

<Example 45>

Alcohol 164: The crude aldehyde 163 was treated with NaCNBH ₃ and flash chromatography (40% hexane in ethyl acetate) according to the method of Borch and co-workers "J. Amer. Chem. Soc.", 93: 2897 (1971). To give 269 mg (65%) of alcohol: ¹ H NMR (CDCl ₃ , 300 MHz) δ 6.91 (m, 1H), 4.75 (dd, 1H, J = 3.9, 8.7 Hz), 4.34 (br t, 1H, J = 4.1 Hz), 4.25-4.15 (m, 1H), 3.85-3.70 (m, 4H), 3.77 (s, 3H), 3.16 (s, 3H), 2.95 (dd, 1H, J = 5.7, 18.6 Hz ), 2.37 (dd, 1H, J = 7.1, 18.6 Hz), 2.26 (br s, 1H).

<Example 46>

Aziridine 165: Acetylate 164 (208 mg, 0.62 mmol) of alcohol 164 (208 mg, 100%) was obtained according to a conventional method (AcCl, pyridine, dichloromethane, cat.DMAP). Crude acetate (202 mg, 0.54 mmol) was treated with Ph ₃ P (155 mg) in THF (12 mL) solvent at room temperature for 2 hours. H ₂ O (1.1 mL) and triethylamine (224 μL) were added and the solution stirred overnight. After concentration of the reaction mixture, the residue was partitioned between ethyl acetate and saturated hydrogen carbonate / brine. The organic layer was dried, concentrated in vacuo and flash chromatography (10% MeOH in EtOAc) gave 125 mg (90%) of aziridine 165 as a white solid: ¹ H NMR (CDCl ₃ , 300 MHz) δ6.80 ( m, 1H), 4.44 (br s, 1H), 4.23 (t, 2H, J = 4.8 Hz), 3.82-3.65 (m, 2H), 3.74 (s, 3H), 2.85 (br d, 1H, J = 19.2 Hz), 2.65-2.40 (m, 3H), 2.09 (s, 3H), 1.25 (br s, 1H).

<Example 47>

N-Boc aziridine 166: Boc anhydride (113 mg, 0.52 mmol) in a solution of aziridine 165 (125 mg, 0.49 mmol), triethylamine (70 μL), DMAP (cat. Amount) in dichloromethane (7 mL). Added. After 1 h the reaction was concentrated and the residue was subjected to flash chromatography (40% EtOAc in hexane) to give 154 mg (88%) of N Boc aziridine 166 as light oil: ¹ H NMR (CDCl ₃ , 300 MHz). ) δ6.82 (m, 1H), 4.47 (br m, 1H), t, 2H, J = 4.7 Hz, 3.81 (t, 2H, J = 4.7 Hz), 3.75 (s, 3H), 3.00 (br) d, 1H, J = 18.0 Hz, 2.90-2.85 (m, 2H), 2.65-2.55 (m, 1H), 2.10 (s, 3H), 1.44 (s, 9H).

<Example 48>

Aziridine 166 (154 mg, 0.43 mmol), sodium azide (216 mg), and ammonium chloride (223 mg) were heated in DMF (5 mL) to 100 ° C. for 18 hours. The cooled reaction mixture was separated by partitioning 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 in vacuo to give a pale oily phase which was passed through a short silica gel column eluting with EtOAc. The product was then acylated according to conventional methods (AcCl, pyridine, dichloromethane, cat.DMAP) and subjected to flash chromatography (5% MeOH in chloroform) to give 16 mg of azido ester 167 in light yellow oil: ¹ H NMR (CDCl ₃ , 300 MHz) δ6.85 (m, 1H), 5.80 (br d, 1H, J = 7.8 Hz), 4.55 (m, 1H), 4.25-4.10 (m, 3H), 3.90-3.85 (m, 2H), 3.78 (s, 3H), 3.55 (m, 1H), 2.90 (dd, 1H, J = 5.4, 17.0 Hz), 2.45-2.25 (m, 1H), 2.10 (s, 3H), 2.05 (s, 3 H).

<Example 49>

Aqueous OH solution (208 μL, 0.476 M solution) was added to a solution of ester 167 (16 mg, 0.047 mmol) in amino acid 168: THF (1 mL). The reaction was warmed to room temperature and stirred for 2 hours. The reaction was then acidified with Amberlite IR-120 (plus) acidic resin. The resin was then filtered off and washed with ethanol and H ₂ O. Concentration in vacuo gave 14 mg (100%) of azido carboxylic acid as a white solid. Azido acid was dissolved in ethanol (2 mL) and treated with Lindlar catalyst (15 mg) for 16 hours according to Corey and co-investigator's method, "Synthesis", 590 (1975). The reaction mixture was filtered using a pad of celite and washed with hot ethanol and H ₂ O. Concentration in vacuo gave a pale orange solid, which was purified by C ₁₈ column chromatography eluting with H ₂ O. Fractions containing the product were combined and lyophilized to give 9.8 mg of 168 as a white powder: ¹ H NMR (D ₂ O, 500 MHz) δ: 6.53 (br s, 1H), 4.28 (br m, 1H), 4.08 (dd, 1H, J = 11.0, 11.0 Hz), 3.80-3.65 (complex m, 4H), 3.44 (m, 1H), 2.84 (apparent dd, 1H), 2.46-2.39 (complex m, 1H), 2.08 (s, 3 H).

<Example 50>

Epoxy MOM Ether 19 (PG = methoxymethyl): 74% was prepared from epoxy alcohol 1 according to Mordini and co-workers method, “J. Org. Chem.”, 59: 4784 (1994): ¹ H NMR (CDCl ₃ , 300 MHz) δ 6.73 (m, 1H), 4.87 (s, 2H), 4.59 (t, 1H, J = 2.4 Hz), 3.76 (s, 3H), 3.57 (m, 1H), 3.50-3.40 (m, 1H), 3.48 (s, 3H), 3.10 (d, J = 19.5 Hz), 2.45 (m, 1H).

<Example 51>

Aziridine 170: A total of 77% was obtained from epoxide 19 (PG = methoxymethyl) according to the general protocol described in Examples 3 and 4: ¹ H NMR (CDCl ₃ , 300 MHz) δ6.85 (m, 1H ), 4.78 (s, 2H), 4.54 (m, 1H), 3.73 (s, 3H), 3.41 (s, 3H), 2.87 (d, 1H, J = 18.9 Hz), 2.70-2.45 (m, 3H) .

<Example 52>

Azido ester 22 (PG = methoxetmethyl): Aziridine 170 (329 mg, 1.54 mmol), NaN ₃ (446 mg) and NH ₄ Cl (151 mg) at 65 ° C. in DMF (20 mL) for 18 hours. Heated. 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 in vacuo gave the crude azido amine as a pale oily phase which was taken up in a solvent of CH ₂ Cl ₂ (15 mL) and treated with pyridine (4 mL) and AcCl (150 μL). After work up with aqueous solution, the residue was flash chromatographed to give 350 mg (76%) of azido ester 22 (PG = methoxymethyl) as pale oily phase: ¹ H NMR (CDCl). ₃ , 300 MHz) δ6.78 (s, 1H), 6.39 (br d, 1H, J = 7.8 Hz), 4.72 (d, 1H, J = 6.9 Hz), 4.66 (d, 1H, J = 6.9 Hz) , 4.53 (br d, 1H, J = 8.4 Hz), 4.00-3.90 (m, 1H), 3.80-3.65 (m, 1H), 3.75 (s, 3H), 3.37 (s, 3H), 2.85 (dd, 1H, J = 5.4, 17.7 Hz), 2.35-2.20 (m, 1H), 2.04 (s, 3H).

<Example 53>

Amino acid 114: Azide 22 (PG = methoxymethyl) (39 mg, 0.131 mmol) in ethanol on a Lindlar catalyst (39 mg) under 1 atmosphere according to the method of Corey and co-worker "Synthesis", 590 (1975). Treated with hydrogen. The reaction mixture was filtered through a pad of celite, washed with hot ethanol and concentrated to give 33 mg (92%) of crude amine as light foam. The amine in THF (1 mL) was treated with aqueous KOH solution (0.476 M, 380 μL). After 1 hour the reaction was acidified to pH = 4.0 using Amberlite IR-120 (plus) acid resin. The resin was then filtered, 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 the product were combined and lyophilized to give 20 mg of compound 114 as a white powder: ¹ H NMR (D ₂ O, 300 MHz) δ 6.65 (s, 1H), 4.87 (d, 1H, J = 7.5 Hz ), 4.76 (d, 1H, J = 7.5 Hz), 4.47 (br d, 1H, J = 8.7 Hz), 4.16 (dd, 1H, J = 11.4, 11.4 Hz), 3.70-3.55 (m, 1H), 3.43 (s, 3H), 2.95 (dd, 1H, J = 5.7, 7.4 Hz), 2.60-2.45 (m, 1H), 2.11 (s, 3H).

<Example 54>

Amino Acid 171: To solid amino acid 114 (4 mg, 0.015 mmol) was added 40% TFA in CH ₂ Cl ₂ (1 mL, cooled to 0 ° C. before addition). After stirring at room temperature for 1.5 hours, the reaction mixture was concentrated to give a white foam. Co-evaporation several times from H ₂ O and then lyophilized gave 5.5 mg of compound 117 as a white solid phase of TFA salt: ¹ H NMR (D ₂ O, 300 MHz) δ 6.85 (m, 1H), 4.45 (m, 1H), 4.05 (dd, 1H, J = 11.4, 11.4 Hz), 3.65-3.55 (m, 1H), 3.00-2.90 (m, 1H), 2.60-2.45 (m, 1H), 2.09 (s, 3H) .

<Example 55>

Acetonide 180: p-toluenesulfonic acid (274 mg, 1.44 mmol, 1 mol%) is added to a suspension of schimnic acid (25 g, 144 mmol, Aldrich) in methanol (300 mL) and the mixture is stirred for 2 hours. Heated to reflux. Additional p-toluenesulfonic acid (1 mol%) was added and the reaction was refluxed for 26 hours and then evaporated. The crude methyl ester (28.17 g) was suspended in acetone (300 mL), treated with dimethoxypropane (35 mL, 288 mmol), then stirred at room temperature for 6 hours and then evaporated. The crude product was dissolved in ethyl acetate (400 mL) and washed with saturated aqueous NaHCO ₃ (3 × 125 mL) and saturated aqueous NaCl solution. The organic layer was dried (MgSO ₄ ), filtered and evaporated to afford crude acetonide 180 (˜29.4 g) which was used directly: ¹ H NMR (CDCl ₃ ) δ6.91 (t, 1H, J = 1.1 Hz ), 4.74 (t, 1H, J = 4.8 Hz), 4.11 (t, 1H, J = 6.9 Hz), 3.90 (m, 1H), 2.79 (dd, 1H, J = 4.5, 17.4 Hz), 2.25 (m , 2H), 1.44 (s, 3H), 1.40 (s, 3H).

<Example 56>

Mesylate 130: triethylamine (29.5 mL, 212 mmol) was added to a solution of acetonide 180 (29.4 g, 141 mmol) in CH ₂ Cl ₂ (250 mL) at 0 ° C., followed by methanesulfonyl chloride (13.6). mL, 176 mmol) was added over 10 minutes. The reaction was stirred at 0 ° C for 1 h and ice cold water (250 mL) was added. After transferring to a separatory funnel, the organic layer was washed with water, 5% citric acid (300 mL), saturated aqueous NaHCO ₃ (300 mL), and then dried (MgSO ₄ ), filtered and evaporated. The crude product was filtered eluting with ethyl acetate through a silica gel short plug on a fritted glass funnel. The filtrate was evaporated to give mesylate 130 (39.5 g, 91%) as a viscous oil phase, which was used directly in the next step: ¹ H NMR (CDCl ₃ ) δ 6.96 (m, 1H), 4.80 (m, 2H ), 4.28 (dd, 1H, J = 6.6, 7.5 Hz), 3.79 (s, 3H), 3.12 (s, 3H), 3.01 (dd, 1H, J = 5, 17.7 Hz), 2.56-2.46 (m, 1H).

<Example 57>

Diol 131: p-toluenesulfonic acid (1.11 g, 5.85 mmol, 5 mol%) was added to a solution of mesylate 130 (35.85 g, 117 mmol) in methanol (500 mL), and the solution was refluxed for 1.5 h. Evaporated. The residue was redissolved in methanol (500 mL) and again refluxed for 4 h. The solvent was evaporated and the crude oil was triturated with diethyl ether (250 mL). After complete crystallization at 0 ° C. overnight, the solid was filtered, washed with cold diethyl ether and dried to give diol 131 (24.76 g) as a white solid. The filtrate was evaporated and the residue was crystallized from methanol / diethyl ether to give another 1.55 g again. Finally, 26.3 g (85%) of diol 131 were obtained: ¹ H NMR (CD ₃ OD) δ6.83 (m, 1H), 4.86 (m, 1H), 4.37 (t, 1H, J = 4.2 Hz), 3.87 (dd, 1H, J = 4.2, 8.4 Hz), 3.75 (s, 3H), 3.13 (s, 3H), 2.98-2.90 (m, 1H), 2.53-2.43 (m, 1H).

<Example 58>

Epoxy Alcohol 1: A suspension of diol 131 (20.78 g, 78 mmol) in a solvent of tetrahydrofuran (400 mL) at 0 ° C. was charged with 1,8-diazabicyclo [5.4.0] und-7-cene (11.7 mL, 78 mmol) and stirred at room temperature for 9 hours to complete the reaction. The reaction was evaporated and the crude residue was dissolved in CH ₂ Cl ₂ (200 mL) and washed with saturated NaCl (300 mL). The water layer was extracted with CH ₂ Cl ₂ (2 × 200 mL). After combining together the organic extracts, 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 of this compound is described in McGowan, DA; Berchtold, GA, "J. Org. Chem.", 46: 2381 (1981).

<Example 59>

Methoxymethyl ether 19 (PG = methoxymethyl): CH ₂ Cl ₂ (100 mL) was added N, N'-diisopropylethylamine (12.3 mL) to a solution of epoxy alcohol 1 (4 g, 23.5 mmol) under solvent. , 70.5 mmol), followed by chloromethyl methyl ether (3.6 mL, 47 mmol, distilled from tech grade). The solution was refluxed for 3.5 hours and the solvent was evaporated. The residue was partitioned between ethyl acetate (200 mL) and water (200 mL). The water layer was extracted with ethyl acetate (100 mL). The combined organic extracts were all washed with saturated aqueous NaCl solution (100 mL), then dried (MgSO ₄ ), filtered and evaporated to give 4.9 g of solid residue. It has a suitable purity for direct use in the following steps: mp 62-65 ° C. (crude); mp 64-66 ° C. (diethyl ether / hexane); ¹ H NMR (CDCl ₃ ) δ6.73 (m, 1H), 4.87 (s, 2H), 4.59 (m, 1H), 3.75 (s, 3H), 3.57 (m, 1H), 3.48 (m overlapping s, 4H), 3.07 (dd, 1H, J = 1.2, 19.8 Hz), 2.47 (dq, 1H, J = 2.7, 19.5 Hz).

Ethyl ether homologue of compound 19:

At room temperature, chloromethyl methyl ether is added after addition of diisopropylethyl amine (34.0 mL, 0.13 mol) to a solution of the corresponding ethyl ester of compound 1 (12.0 g, 0.065 mol) in CH ₂ Cl ₂ (277 mL) solvent. (10.0 mL, 0.19 mol) was added. Thereafter, the reaction mixture was gently refluxed for 2 hours, cooled, concentrated in vacuo, and then separated between EtOAc and water. The organic layer was separated and washed successively with dilute HCl aqueous solution, saturated aqueous hydrogen carbonate solution and brine, and then dried over MgSO ₄ . Concentration in vacuo followed by flash chromatography on silica gel (50% hexanes in EtOAc) gave 13.3 g (90%) of the corresponding ethyl ester of compound 19 as colorless liquid: ¹ H NMR (300 MHz, CDCl ₃ ) δ6.73 -6.71 (m, 1H), 4.87 (s, 2H), 4.61-4.57 (m, 1H), 4.21 (q, 2H, J = 7.2 Hz), 3.60-3.55 (m, 1H), 3.50-3.45 (m , 1H), 3.48 (s, 3H), 3.12-3.05 (m, 1H), 2.52-2.42 (m, 1H), 1.29 (t, 3H, J = 7.2 Hz).

<Example 60>

Alcohol 181: sodium azide (7.44 g, 114.5) in a solution of methoxymethyl ether 19 (PG = methoxymethyl) (4.9 g, 22.9 mmol) in 8 / 1-MeOH / H ₂ O (175 mL, v / v) mmol) and ammonium chloride (2.69 g, 50.4 mmol) were added and the mixture was refluxed for 15 h. The reaction was diluted with water (75 mL) to dissolve the precipitated salts and the solution was concentrated to remove methanol. The final water layer containing the precipitated oily residue was diluted with water to 200 mL and extracted with ethyl acetate (3 × 100 mL). All organic extracts were combined, washed with aq. NaCl aqueous solution (100 mL), dried (MgSO ₄ ), filtered and evaporated. This crude product was purified on silica gel (hexane / ethyl acetate = 1/1) to give alcohol 181 (5.09 g, 86%) as a pale yellow oil. In the subsequent preparation of additional alcohol 181, it was found that the preparation provided a sufficiently high purity to be used directly without further purification in the next step: ¹ H NMR (CDCl ₃ ) δ 6.86 (m, 1H) , 4.79 (s, 2H), 4.31 (br t, 1H, J = 4.2 Hz), 3.90-3.75, 3.77 (m overlapping s, 5H), 3.43 (s, 3H), 2.92 (d, 1H, J = 6.6 Hz), 2.87 (dd, 1H, J = 5.4, 18.6 Hz), 2.21-2.30 (m, 1H).

<Example 61>

Mesylate 184: triethylamine (4.4 mL, 31.5 mmol) was first added to a solution of alcohol 181 (6.47 g, 25.2 mmol) in CH ₂ Cl ₂ (100 mL) at 0 ° C., 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. After evaporation of the reaction, the residue was separated using ethyl acetate (200 mL) and water (100 mL). The organic layer was washed with water (100 mL), saturated aqueous NaHCO ₃ solution (100 mL), and saturated aqueous NaCl solution (100 mL). The water layer was extracted once with ethyl acetate and washed with the same NaHCO ₃ / NaCl solution. After all organic extracts were combined, dried (MgSO ₄ ), filtered and evaporated. The crude product also had sufficient purity for direct use in the following steps: ¹ H NMR (CDCl ₃ ) δ 6.85 (m, 1H), 4.82 (d, 1H, J = 6.9 Hz), 4.73 (d, 1H, J = 6.9 Hz), 4.67 (dd, 1H, J = 3.9, 9.0 Hz), 4.53 (br t, 1H, J = 4.2 Hz), 3.78 (s, 3H), 3.41 (s, 3H), 3.15 (s, 3H), 2.98 (dd, 1H, J = 6.0, 18.6 Hz), 2.37 (m, 1H), ¹³ C NMR (CDCl ₃ ) δ 165.6, 134.3, 129.6, 96.5, 78.4, 69.6, 55.8, 55.7, 52.1 , 38.2, 29.1.

<Example 62>

Aziridine 170: Ph ₃ P (8.2 g, 31 mmol) was first added to a solution of mesylate 184 (8.56 g, 25 mmol) in THF (150 mL) at 0 ° C., initially cooling, in an amount of 1/3 Afterwards the ice bath was removed and the remaining Ph ₃ P was added over 10-15 minutes. After all of Ph ₃ P was added, the reaction was stirred at room temperature for 3 hours to form a white precipitate. To this suspension triethylamine (5.2 mL, 37.5 mmol) and water (10 mL) were added and the mixture was stirred at rt for 12 h. The reaction was concentrated to remove THF and the residue was partitioned between CH ₂ Cl ₂ (200 mL) and saturated aqueous NaCl solution (200 mL). After extracting the water layer several times with CH ₂ Cl ₂ , the organic extracts were combined, dried (Na ₂ SO ₄ ), filtered and evaporated to afford the crude product which was purified on silica gel (10% MeOH / EtOAc) to aziridine 170 (4.18 g, 78%) was obtained as an oil phase. These contained common traces of triphenylphosphine oxide as impurities: ¹ H NMR (CDCl ₃ ) δ6.81 (m, 1H), 4.78 (s, 2H), 4.54 (m, 1H), 3.73 ( s, 3H), 3.41 (s, 3H), 2.87 (app dd, 1H), 2.64 (br s, 1H), 2.56-2.47 (m, 2H), NH signal not shown; ¹³ C NMR (CDCl ₃ ) δ 166.9, 132.5, 128.0, 95.9, 69.5, 55.2, 51.6, 31.1, 27.7, 24.1.

<Example 63>

Amine 182: A solution of aziridine 170 (3.2 g, 15 mmol) in DMF (30 mL) was vacuumed on a rotary evaporator (40 ° C.) for several minutes to degas the solution. To this solution sodium azide (4.9 g, 75 mmol) and ammonium chloride (1.6 g, 30 mmol) were added and the mixture was heated at 65-70 ° C for 21 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (˜100 mL) and filtered. After evaporation of the filtrate, the residue was partitioned between diethyl ether (100 mL) and saturated aqueous NaCl solution (100 mL). The organic layer was washed again with saturated aqueous NaCl solution (100 mL), then dried (MgSO ₄ ), filtered and evaporated. Extraction with ethyl acetate gave further crude product from the water layer and treated in the same 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 phase. It contained a small amount of triphenylphosphine oxide impurity from the previous step: ¹ H NMR (CDCl ₃ ) δ6.82 (t, 1H, J = 2.3 Hz), 4.81 (d, 1H, J = 7.2 Hz), 4.77 (d, 1H, J = 6.9 Hz), 4.09-4.04 (m, 1H), 3.76 (s, 3H), 3.47 and 3.44 (m overlapping s, 4H), 2.94-2.86 (m, 2H), 2.36- 2.24 (m, 1 H); ¹³ C NMR (CDCl ₃ ) δ 165.9, 137.3, 128.2, 96.5, 79.3, 61.5, 55.7, 55.6, 51.9, 29.5.

<Example 64>

N-trityl aziridine 183: amine 182 (2.59 g, 10.2 mmol) was dissolved in 5% HCl / MeOH (30 mL) and the solution was stirred at room temperature for 3 hours. Additional 5% HCl / MeOH (10 mL) was added, stirred for 1 hour and the solvent was evaporated to give 2.52 g of HCl salt as a tan solid under high vacuum. Triethylamine (3.55 mL, 25.5 mmol) was added to a suspension of HCl salt in CH ₂ Cl ₂ (50 mL) at 0 ° C., followed by the addition of solid trityl chloride (5.55 g, 12.8 mmol) in one portion. The mixture was stirred at 0 ° C. for 1 hour and then warmed to room temperature and stirred for 2 hours. The reaction was cooled to 0 ° C., triethylamine (3.6 mL, 25.5 mmol) was added, methane sulfonyl chloride (0.97 mL, 12.5 mmol) was added, and the resulting mixture was stirred at 0 ° C. for 1 hour and at room temperature 22. Stir for hours. After evaporation of the reaction, the residue was separated using diethyl ether (200 mL) and water (200 mL). The organic layer was washed with water (200 mL), and then the water layers were combined and extracted again with diethyl ether (200 mL). The combined organic extracts were combined, washed with water (100 mL), saturated aqueous NaCl solution (200 mL), dried (Na ₂ SO ₄ ), and then filtered and evaporated. The crude product was purified on silica gel (hexane / CH ₂ Cl ₂ = 1/1) to give N-trityl aziridine 183 (3.84 g, 86%) as a white foam: ¹ H NMR (CDCl ₃ ) δ7. 4-7.23 (m, 16H), 4.32 (m, H), 3.81 (s, 3H), 3.06 (dt, 1H, J = 1.8, 17.1 Hz), 2.94-2.86 (m, 1H), 2.12 (m, 1H), 1.85 (t, 1H, J = 5.0).

<Example 65>

Compound 190: A solution of N-trityl aziridine 183 (100 mg, 0.23 mmol) and cyclohexanol (2 mL), boron trifluoride etherate (42 μL, 0.35 mmol) was heated at 70 ° C. for 1.25 h. Then evaporated. The residue was dissolved in pyridine (2 mL) and treated with acetic anhydride (110 μL, 1.15 mmol) and catalyst DMAP. After stirring for 3 hours at room temperature the reaction was evaporated. The residue was separated using ethyl acetate and 5% citric acid. The water layer was extracted with ethyl acetate, and all the organic layers were combined and washed with saturated aqueous solution of NaHCO ₃ and NaCl. The organic layer was dried (MgSO ₄ ), filtered and evaporated. The crude product was purified on silica gel (hexane / ethyl acetate = 1/1) to give compound 190 (53 mg, 69%) as a solid: mp 105-107 ° C. (ethyl acetate / hexane): ¹ H NMR (CDCl ₃ ) δ6.78 (m, 1H), 6.11 (d, 1H, J = 7.4 Hz), 4.61 (m, 1H), 4.32-4.23 (m, 1H), 3.76 (s, 3H), 3.44-3.28 ( m, 2H), 2.85 (dd, 1H, J = 5.7, 17.6 Hz), 2.28-2.17 (m, 1H), 2.04 (s, 3H), 1.88-1.19 (m, 10H).

<Example 66>

Compound 191: To a solution of compound 190 (49 mg, 0.15 mmol) with THF as a solvent was added triphenylphosphine (57 mg, 0.22 mmol) and water (270 μL), and the solution was added at 50 ° C. for 10 hours. Heated. After the reaction was evaporated, the residue was dissolved in ethyl acetate, dried (Na ₂ SO ₄ ), filtered and evaporated. The crude product was purified on silica gel (methanol / ethyl acetate = 1/1) to afford amine (46 mg) as a pale yellow solid. An amine solution of THF (1.5 mL) solvent was added to 1.039 N KOH solution (217 μL) and water (200 μL). The mixture was stirred at room temperature for 1 hour, cooled to 0 ° C. and acidified to pH 6-6.5 using IR-120 ion exchange resin. The resin was filtered off, washed with methanol and the filtrate was evaporated. The solid residue was dissolved in water, eluted with water, passed through a C-18 reversed-phase silica gel color (4 × 1 cm), then eluted with 2.5% acetonitrile / water. The product fractions were combined and evaporated, then the residue was dissolved in water and lyophilized to give amino acid 191 (28 mg) as a white solid: ¹ H NMR (D ₂ O) δ6.47 (br s, 1H), 4.80 (br d, 1H), 4.00 (dd, 1H, J = 8.9, 11.6 Hz), 3.59-3.50 (m, 2H), 2.87 (dd, 1H, J = 5.5, 17.2 Hz), 2.06 (s, 3H ), 1.90-1.15 (series of m, 10H), Analysis shows C ₁₅ H ₂₄ N ₂ O ₄ Acid side for H ₂ O: C, 57.31, H, 8.34, N, 8.91. Found: C, 57.38, H, 8.09, N, 8.77.

<Example 67>

Bis-Boc guanidino ester 201: Kim and Quian "Tetrahedron Lett.", 34: 7677 (1993). Amine 200 (529 mg, 1.97 mmol, prepared according to the method of example 109), bis-Boc thiourea (561 mg, 2.02 mmol) and Et ₃ , cooled to 0 ° C. with dry DMF (5.0 mL) as solvent To a solution of N (930 μL) HgCl ₂ (593 mg, 2.18 mmol) was added in one portion. The non-uniform reaction mixture was stirred at 0 ° C. for 45 minutes and then at room temperature for 15 minutes, then the reaction was diluted with EtOAc and filtered through a pad of celite. It was concentrated in vacuo and the residue was flash chromatographed on silica gel (10% hexanes in ethyl acetate) to give 904 mg (90%) of compound 201 as a light oil: ¹ H NMR (CDCl ₃ , 300 MHz) δ 11.39 ( s, 1H), 8.63 (d, 1H, J = 7.8 Hz), 6.89 (t, 1H, J = 2.4 Hz), 6.46 (d, 1H, J = 8.7 Hz), 4.43-4.32 (m, 1H), 4.27-4.17 (m, 1H), 4.13-4.06 (m, 1H), 3.77 (s, 3H), 3.67-3.59 (m, 1H), 2.83 (dd, 1H, J = 5.1, 17.7 Hz), 2.45- 2.33 (m, 1H), 1.95 (s, 3H), 1.65-1.50 (m, 2H), 1.45 (s, 18H), 0.90 (t, 3H, J = 7.5 Hz).

<Example 68>

To a solution of carboxylic acid 202: methyl ester (904 mg, 1.77 mmol) in THF (10 mL) was added an aqueous KOH solution (1.039 N, 3.45 mL). The reaction mixture was stirred at rt for 17 h, cooled to 0 ° C and acidified to pH 4.0 using Amberlite IR-120 (H ⁺ ) acid resin. The resin was filtered off and washed with water and methanol. Concentration in vacuo gave the free acid as a light foam which was used for the next step without further purification.

<Example 69>

Guanidine carboxylic acid 203: Pure trifluoroacetic acid (25 mL) in a solution of bis-Boc guanidinyl acid 202 (crude obtained from the previous reaction) in CH ₂ Cl ₂ (40 mL) solvent cooled to 0 ° C. Was added. The reaction mixture was stirred at 0 ° C. for 1 hour and at room temperature for 2 hours. It was concentrated in vacuo to give a pale orange solid, which was purified by C ₁₈ reverse phase chromatography eluting with water. Fractions containing the desired product were combined and lyophilized to give 495 mg (68%, 2 steps) of guanidine carboxylic acid 203 as trifluoroacetic acid: ¹ H NMR (D ₂ O, 300 MHz) δ6.66 ( s, 1H), 4.29 (bd, 1H, J = 9.0 Hz), 4.01 (dd, 1H, J = 10.8, 10.8 Hz), 3.87-3.79 (m, 1H), 3.76-3.67 (m, 1H), 3.60 -3.50 (m, 1H), 2.83 (dd, 1H, J = 5.1, 17.4 Hz), 2.47-2.36 (m, 1H), 2.06 (s, 3H), 1.65-1.50 (m, 2H), 0.90 (t , 3H, J = 7.2 Hz). Analysis result: Acid for C ₁₅ H ₂₃ O ₆ N ₄ F ₃ : C, 43.69, H, 5.62, N, 13.59. Found: C, 43.29, H, 5.90, N, 13.78.

<Example 70>

Formamidine carboxylic acid 204: A solution of amino acid 102 (25 mg, 0.010 mmol, prepared by Example 110) in water (500 μL) at 0-5 ° C. was adjusted to pH 8.5 with 0.1 N NaOH. . Benzyl formimidate hydrochloride (45 mg, 0.26 mmol) was added in one portion and the reaction mixture was maintained at PH 8.5-9.0 with 1.0 N NaOH while stirring at this temperature for 3 hours. The reaction was concentrated in vacuo, then purified by eluting with water by C ₁₈ reverse phase chromatography. Fractions containing the desired product were combined and lyophilized to yield 4.0 mg (13%) of formamidine carboxylic acid 204: ¹ H NMR (D ₂ O, 300 MHz) δ 7.85 (s, 1H), 6.53 ( bd, 1H, J = 7.8 Hz), 4.32-4.25 (bm, 1H), 4.10-3.97 (m, 1H), 3.76-3.67 (m, 2H), 3.57-3.49 (m, 1H), 2.86-2.81 ( m, 1H), 2.55-2.40 (m, 1H), 2.04 (s, 3H), 1.65-1.50 (m, 2H), 0.90 (t, 3H, J = 7.4 Hz).

<Example 71>

Aqueous KOH solution (1.039 N, 481 μL) was added to a solution of amino methyl ester 205 (84 mg, 0.331 mmol, prepared from Example 107) with amino acid 206: THF (1.0 mL) as solvent. The reaction mixture was stirred at rt for 2.5 h and adjusted to pH 6.5 using Amberlite IR-120 (H ⁺ ) acidic resin. The resin was filtered off and washed with water and methanol. It was concentrated in vacuo to give the amino acid as a white solid, which was then purified by eluting with water by C ₁₈ reverse phase chromatography. Fractions containing the desired product were combined and lyophilized to yield 59 mg (74%) of amino acid 206: ¹ H NMR (CD ₃ OD, 300 MHz) δ 6.60 (bd, 1H, J = 1.8 Hz), 4.01- 3.95 (m, 1H), 3.71-3.60 (m, 2H), 3.50-3.42 (m, 1H), 3.05-2.85 (m, 2H), 2.39-2.28 (m, 1H), 1.70-1.55 (m, 2H ), 0.95 (t, 3H), J = 7.5 Hz).

<Example 72>

Trifluoroacetamide 207: Et ₃ N (35 μL) and methyl trifluoroacetate (35) in a degassed solution of amino acid 206 (59 mg, 0.246 mmol) in dry methanol (1.0 mL) as solvent under argon atmosphere. μL) was added. The reaction was stirred for 1 week at room temperature and then concentrated. Analysis by ¹ H NMR showed the reaction was 40% complete. The crude reaction product was redissolved in dry methanol (1.0 mL), methyl trifluoroacetate (1.0 mL) and Et ₃ N (0.5 mL) and stirred at room temperature for 5 days. The reaction was then concentrated in vacuo and dissolved in 50% aqueous THF (2.0 mL), then adjusted to pH 4 with Amberlite IR-120 (H ⁺ ) acidic resin and filtered. Concentration gave crude trifluoroacetamide carboxylic acid which was used in the next step without further purification.

<Example 73>

A solution of Azide 207 (crude obtained from the previous step) with amino acid 208: water (160 μL) and THF (2.0 mL) as solvent was treated with polymer supported triphenyl phosphine (225 mg) at room temperature. After stirring for 20 hours, the polymer was filtered off and washed with methanol. A light solid was obtained by vacuum concentration, which was purified by eluting with water by C ₁₈ reverse phase chromatography. Fractions containing the desired product were combined and lyophilized to give 6.5 mg (9%) of trifluoroacetamide amino acid 208: ¹ H NMR (D ₁ O, 300 MHz) δ 6.59 (bs, 1H), 4.40- 4.30 (m, 1H), 4.26 (t, 1H, J = 10.1 Hz), 3.80-3.66 (m, 2H), 3.56-3.47 (m, 1H), 2.96 (bdd, 1H, J = 5.4, 17.7 Hz) , 2.58-2.45 (m, 1H), 1.62-1.50 (m, 2H), 0.89 (t, 3H, J = 7.5 Hz).

<Example 74>

Methylsulfonamide methyl ester 209: amine 205 (58 mg, 0.23 mmol, prepared according to Example 107) with methanesulfonyl chloride (19 μL) at 0 ° C. and CH ₂ Cl ₂ (1.0 mL) as solvent, Et ₃ N (97 μL) and DMAP catalyst amount (a few crystals) were added to the solution. After 30 minutes the reaction mixture was warmed to room temperature and stirred for 1 hour again. The residue was concentrated in vacuo and then flash chromatographed on silica gel (50% hexane in ethyl acetate) to give 61 mg (79%) of sulfonamide 209: ¹ H NMR (CDCl ₃ , 300 MHz) δ6.87 ( t, 1H, J = 2.3 Hz, 5.08 (d, 1H, J = 7.5 Hz), 4.03-3.90 (m, 1H), 3.78 (s, 3H), 3.75-3.45 (m, 4H), 3.14 (s , 3H), 2.95 (dd, 1H, J = 5.2 17.3 Hz), 2.42-2.30 (m, 1H), 1.75-1.55 (m, 2H), 0.95 (t, 3H, J = 7.5 Hz).

<Example 75>

Amino ester 210: A solution of azide 209 (61 mg, 0.183 mmol) in water (118 μL) and THF (2.0 mL) as solvent was treated with polymer supported triphenyl phosphine (170 mg) at room temperature. After stirring for 17.5 hours, the polymer was filtered off and washed with methanol. The residue was flash chromatographed through a short silica gel column (100% methanol) and concentrated in vacuo to give 45 mg (80%) of amino ester 210 as light foam: ¹ H NMR (CDCl ₃ , 300 MHz) δ6. 85 (s, 1H), 3.94 (bd, 1H, J = 7.8 Hz), 3.77 (s, 3H), 3.74-3.60 (m, 2H), 3.55-3.45 (m, 1H), 3.25-3.15 (m, 1H), 3.11 (s, 3H), 2.94-2.85 (m, 1H), 2.85 (bs, 2H), 2.22-2.10 (m, 1H), 1.70-1.56 (m, 1H), 0.94 (t, 3H, J = 7.5 Hz).

<Example 76>

Amino acid 211: A solution of methyl ester (21 mg, 0.069 mmol) with THF (200 μL) as a solvent was treated with aqueous KOH solution (1.039 N, 135 μL). The reaction mixture was stirred for 40 minutes at room temperature and neutralized to pH 7.0 using Amberlite IR-120 (H ⁺ ) acidic resin. This resin was filtered off and washed with water and methanol. It was concentrated in vacuo to afford the amino acid as a light solid, which was purified by C ₁₈ reverse phase chromatography, eluting with water. Fractions containing the desired product were combined and lyophilized to yield 3.5 mg (17%) of amino acid 211.

¹ H NMR (D ₂ O, 300 MHz): δ 6.60 (d, 1H, J = 1.8 Hz); 4.30-4.20 (m, 1 H); 3.84-3.75 (m, 1 H); 3.68-3.58 (m, 1 H); 3.60-3.40 (m, 2 H); 3.20 (s, 3 H); 2.96-2.88 (m, 1 H); 2.55-2.45 (m, 1 H); 1.72-1.59 (m, 2 H); 0.93 (t, 3H, J = 7.4 Hz).

<Example 77>

Bis-Boc guanidino ester 212: Kim and Qian, "Tetrahedron Lett." Treatment was performed according to the method described in 34: 7677 (1993). HgCl _{2 in} a solution of amine 210 (31 mg, 0.101 mmol), bis-Boc thiourea (28.5 mg, 0.103 mmol) and Et ₃ N (47 μL) with a dry DMF solvent (203 μL) cooled to 0 ° C. (30 mg, 0.11 mmol) was added in one portion. The non-uniform reaction mixture was stirred at 0 ° C. for 30 minutes, then at room temperature for 30 minutes, then the reaction was diluted with EtOAc and filtered through a pad of celite. After concentration in vacuo the residue was purified by flash chromatography on silica gel (40% hexanes in ethyl acetate) to give 49 mg (89%) as light oily oil: ¹ H NMR (CDCl ₃ , 300 MHz) δ 11 .47 (s, 1H), 8.66 (d, 1H, J = 8.4 Hz), 6.87 (s, 1H), 6.01 (bs, 1H), 4.50-4.35 (m, 1H), 4.04 (bd, 1H, J = 8.4 Hz), 3.76 (s, 3H), 3.70-3.60 (m, 1H), 3.53-3.45 (m, 2H), 3.02 (s, 3H), 2.85 (dd, 1H, J = 5.3, 17.3 Hz) , 2.42-2.30 (m, 1H), 1.66-1.55 (m, 2H), 1.49 (s, 9H), 1.48 (s, 9H), 0.93 (t, 3H, J = 7.3 Hz).

<Example 78>

To a solution of methyl ester 212 (49 mg, 0.090 mmol) in carboxylic acid 213: THF (1.0 mL) solvent was added KOH aqueous solution (1.039 N, 260 μL). The reaction mixture was stirred at rt for 16 h, cooled to 0 ° C. and acidified to pH 4.0 using Amberlite IR-120 (H ⁺ ) acid resin. The resin was filtered off and washed with water and methanol. The free acid was obtained as a light foam by vacuum concentration, which was used for next step without further purification.

<Example 79>

Guanidine carboxylic acid 214: pure trifluoroacetic acid (2.0 mL) in a solution of bis-Boc guanidinylic acid 213 (crude obtained from the previous step) in a CH ₂ Cl ₂ (2.0 mL) solvent cooled to 0 ° C. Was added. The reaction mixture was stirred at 0 ° C. for 1 hour and at room temperature for 1 hour. A light orange solid was obtained by vacuum concentration, which was purified by eluting with water by C ₁₈ reverse phase chromatography. Fractions containing the desired product were combined and lyophilized to yield 10 mg (25%, 2 steps) of guanidine carboxylic acid 214. ¹ H NMR (D ₂ O, 300 MHz): δ 6.60 (bs, 1H); 4.42 (bd, 1 H, J = 9.0 Hz); 3.82-3.66 (m, 2 H); 3.65-3.54 (m, 1 H); 3.43 (bt, 1 H, J = 9.9 Hz); 3.15 (s, 3 H); 2.82 (dd, 1H, J = 5.0, 17.5 Hz); 2.48-2.30 (m, 1 H); 1.71-1.58 (m, 2 H); 0.93 (t, 3H, J = 7.3 Hz).

<Example 80>

Propionamide methyl ester 215: Propyl in a solution of amine 205 (178 mg, 0.070 mmol, prepared according to Example 107) and pyridine (1.5 mL) in CH ₂ Cl ₂ (2.0 mL) cooled to 0 ° C. Onyl chloride (96 μL, 1.1 mmol) was added. After 30 minutes at 0 ° C., the reaction was concentrated and separated using ethyl acetate and brine. The organic layer was separated, washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, and then dried over MgSO ₄ . After concentration in vacuo, the residue was flash chromatographed on silica gel (40% hexanes in ethyl acetate) to yield 186 mg (86%) of propionamide methyl ester 215 as a pale yellow solid: ¹ H NMR (CDCl ₃ , 300 MHz). ) δ6.86 (t, 1H, J = 2.3 Hz), 5.72 (bd, 1H, J = 7.8 Hz), 4.52-4.49 (m, 1H), 4.25-4.15 (m, 1H), 3.77 (s, 3H) ), 3.65-3.37 (complex m, 3H), 2.87 (dd, 1H, J = 5.7, 17.7 Hz), 2.28 (q, 2H, J = 7.5 Hz), 2.25-2.20 (m, 1H), 1.65-1.50 (m, 2H), 1.19 (t, 3H, J = 7.5 Hz), 0.92 (t, 3H, J = 7.5 Hz)

<Example 81>

Amino methyl ester 216: Azide 215 (186 mg, 0.60 mmol) in water (400 μL) and THF (5.0 mL) solvent was treated with polymer supported triphenyl phosphine (560 mg) at room temperature. After stirring for 21 hours, the polymer was filtered off and washed with methanol. Concentration in vacuo gave crude amino ester 216, which was used in the next step without further purification.

<Example 82>

Amino acid 217: A solution of methyl ester 216 (crude obtained in the previous step) in THF (500 μL) solvent was treated with aqueous KOH solution (1.039 N, 866 μL). The reaction mixture was stirred at rt for 3 h and neutralized to pH 7.0 with Amberlite IR-120 (H ⁺ ) acidic resin. The resin was filtered off and washed with water and methanol. The amino acid was obtained as a light solid by vacuum concentration, which was purified by eluting with water by C ₁₈ reversed phase chromatography. Fractions containing the desired product were combined and lyophilized to yield 49 mg (31%, 2 steps) of amino acid 217: ¹ H NMR (D ₂ O, 300 MHz) δ6.54 (s, 1H), 4.25 (bd, 1H, J = 8.7 Hz), 4.13 (dd, 1H, J = 9.0, 11.3 Hz), 3.74-3.60 (m, 1H), 3.61-3.40 (m, 2H), 2.85 (dd, 1H, J = 5.9, 17.1 Hz), 2.55-2.40 (m, 1H), 2.35 (q, 2H, J = 7.5 Hz), 1.65-1.45 (m, 2H), 1.13 (t, 3H, J = 7.5 Hz), 0.88 (t, 3H, J = 7.5 Hz).

<Example 83>

(Mono methyl) bis-Boc guanidino ester 218: In a solution of amine (51 mg, 0.19 mmol) and mono methyl bis-Boc thiourea (36 mg, 0.19 mmol) in dry DMF (1.0 mL) solvent, (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (38 mg) and Et ₃ N (56 μL) were added at room temperature. After 1.5 hours, HgCl ₂ (˜75 mg, excess) was added in one portion at room temperature. The non-uniform reaction mixture was stirred for 45 minutes, diluted with ethyl acetate and filtered through a pad of celite. The filtrate was diluted with additional ethyl acetate, washed with dilute HCl aqueous solution, saturated aqueous sodium hydrogen carbonate solution and brine and dried over MgSO ₄ . After concentration in vacuo the residue was flash chromatographed on silica gel (10% methyl in ethyl acetate) to give (mono methyl) bis-Boc guanidino ester 218 as colorless foam 13 mg (16%): ¹ H NMR (CDCl ₃ , 300 MHz) δ 6.84 (s, 1H), 6.20 (bd, 1H, J = 5.1 Hz), 5.45 (bs, 1H), 4.25-4.40 (bm, 1H), 4.20-4.05 (bm, 2H ), 3.76 (s, 3H), 3.60-3.50 (m, 1H), 3.43-3.30 (m, 1H), 2.90 (dd, 1H, J = 5.4, 17.7 Hz), 2.77 (d, 3H, J = 4.8 Hz), 2.35-2.25 (m, 1H), 1.96 (s, 3H), 1.60-1.50 (m, 2H), 1.47 (s, 9H), 0.91 (t, 3H, J = 7.2 Hz).

<Example 84>

To a solution of (mono methyl) bis-Boc guanidinoic acid 219: methyl ester 218 (13 mg, 0.031 mmol) in THF (500 μL) solvent was added aqueous KOH solution (1.039 N, 60 μL). The reaction mixture was stirred at rt for 1 h and then refluxed lightly for 1 h. The reaction mixture was cooled to 0 ° C. and acidified to pH 6.0 using Amberlite IR-120 (H ⁺ ) acid resin. The resin was filtered off and washed with water and methanol. Free acid 219 was obtained by vacuum concentration and used in the next step without further purification.

<Example 85>

(Monomethyl) guanidino amino acid 220: pure trifluoro in a solution of (monomethyl) bis-Boc guanidinyl acid 219 (crude obtained from the previous step) in a CH ₂ Cl ₂ (1.0 mL) solvent cooled to 0 ° C. Roacetic acid (1.0 mL) was added. The reaction mixture was stirred at 0 ° C. for 1 hour and at room temperature for 1 hour. A light solid was obtained by vacuum concentration, which was purified by C ₁₈ reverse phase chromatography, eluting with water. Fractions containing the desired product were combined and lyophilized to yield 4.4 mg (33%, 2 steps) of guanidine carboxylic acid 220: ¹ H NMR (D ₂ O, 300 MHz) δ 6.52 (bs, 1H) , 4.27 (bd, 1H, J = 8.4 Hz), 4.01 (dd, 1H, J = 9.2, 10.3 Hz), 3.86-3.75 (m, 1H), 3.75-3.67 (m, 1H), 3.60-3.49 (m , 1H), 2.85 (s, 3H), 2.80 (dd, 1H, J = 5.1, 17.7 Hz), 2.47-2.37 (m, 1H), 2.04 (s, 3H), 1.64-1.50 (m, 2H), 0.90 (t, 3H, J = 7.2 Hz).

<Example 86>

(R) -Methyl propyl ester 221: BF ₃ .Et ₂ O (63 μL, 0.51 mmol) was stirred at room temperature under argon atmosphere, while N- of (R)-(-)-2-butanol (1.2 mL) solvent was used. Trityl aziridine 183 (150 mg, 0.341 mmol) was added to the solution. The light solution was heated at 70 ° C. for 2 hours, then concentrated in vacuo, and the brown residue was dissolved in dry pyridine (2.0 mL), followed by acetic anhydride (225 μL) and catalytic amount of DMAP (several crystals) at 0 ° C. Treated. The reaction was warmed to room temperature, stirred for 2 hours, concentrated in vacuo and separated using ethyl acetate and brine. The organic layer was separated, washed successively with dilute aqueous HCl solution, saturated aqueous sodium hydrogen carbonate solution and brine, and then dried over MgSO ₄ . After concentration in vacuo, the residue was flash chromatographed on silica gel (50% hexane in ethyl acetate) to give (R) -methyl propyl ester 221 as a light solid (75 mg (72%)): ¹ H NMR (CDCl ₃ , 300 MHz) δ 6.79 (t, 1H, J = 2.2 Hz), 6.14 (d, 1H, J = 7.3 Hz), 4.55 (bd, 1H, J = 8.7 Hz), 4.33-4.23 (m, 1H), 3.77 (s, 3H), 3.56-3.45 (m, 1H), 3.40-3.27 (m, 1H), 2.85 (dd, 1H, J = 5.5, 17.5 Hz), 2.30-2.15 (m, 1H), 2.04 (s , 3H), 1.59-1.40 (m, 2H), 1.10 (d, 3H, J = 6.0 Hz), 0.91 (t, 3H, J = 7.4 Hz).

<Example 87>

(R) -methyl propyl amino ester 222: Ph ₃ P (95 mg, 0.36 mmol) was added to a solution of water (432 μL) and azide 221 (75 mg, 0.24 mmol) in THF (3.0 mL) solvent at once It was. The pale yellow solution was heated at 50 ° C. for 10 hours, cooled and concentrated in vacuo to give a pale solid. Purification by flash chromatography on silica gel (50% methanol in ethyl acetate) afforded 66 mg (97%) of amino ester 222 as a light solid.

<Example 88>

Amino acid 223: A solution of methyl ester 222 (34 mg, 0.12 mmol) in THF (1.0 mL) solvent was treated with aqueous KOH solution (1.039 N, 175 μL). The reaction mixture was stirred for 3 hours at room temperature and acidified to pH 6.0 using Amberlite IR-120 (H ⁺ ) acid resin. This resin was filtered off and washed with water and methanol. It was concentrated in vacuo to afford the amino acid as a light solid, which was purified by C ₁₈ reverse phase chromatography, eluting with water. Fractions containing the desired product were combined and lyophilized to yield 11.5 mg (36%) of amino acid 223: ¹ H NMR (D ₂ O, 300 MHz) δ 6.52 (bs, 1H), 4.28 (bd, 1H, J = 8.7 Hz), 4.04 (dd, 1H, J = 8.8, 11.5 Hz), 3.74-3.65 (m, 1H), 3.50-3.60 (m, 1H), 2.90 (dd, 1H, J = 5.5, 17.2 Hz ), 2.50-2.40 (m, 1H), 2.10 (s, 3H), 1.60-1.45 (m, 2H), 1.14 (d, 3H, J = 6.2 Hz), 0.91 (t, 3H, J = 7.4 Hz) .

<Example 89>

Bis-Boc guanidino ester 224: Kim and Qian, "Tetrahedron Lett." Treatment was performed according to the method in 34: 7677 (1993). HgCl ₂ (34 mg) in a solution of amine 222 (32 mg, 0.113 mmol), bis-Boc thiourea (32 mg, 0.115 mmol) and Et ₃ N (53 μL) in a dry DMF (350 μL) solvent cooled to 0 ° C. , 0.125 mmol) was added in one portion. The heterogeneous reaction mixture was stirred at 0 ° C. for 45 minutes and at room temperature for 1 hour, then the reaction was diluted with EtOAc and filtered through a pad of celite. After concentration in vacuo, the residue was purified by flash chromatography on silica gel (20% hexanes in ethyl acetate) to give 57 mg (96%) as a colorless foam: ¹ H NMR (CDCl ₃ , 300 MHz) δ 11 .40 (s, 1H), 8.65 (d, 1H, J = 7.8 Hz), 6.82 (s, 1H), 6.36 (d, 1H, J = 8.7 Hz), 4.46-4.34 (m, 1H), 4.20- 4.10 (m, 1H), 4.10-3.95 (m, 1H), 3.76 (s, 3H), 2.79 (dd, 1H, J = 5.4, 17.7 Hz), 2.47-2.35 (m, 1H), 1.93 (s, 3H), 1.60-1.45 (m, 2H), 1.49 (s, 18H), 1.13 (d, 3H, J = 6.0 Hz), 0.91 (t, 3H, J = 7.5 Hz).

<Example 90>

To a solution of methyl ester 224 (57 mg, 0.11 mmol) in carboxylic acid 225: THF (1.5 mL) solvent was added aqueous KOH solution (1.039 N, 212 μL). The reaction mixture was stirred at rt for 16 h, cooled to 0 ° C. and acidified to pH 4.0 using Amberlite IR-120 (H ⁺ ) acid resin. The resin was filtered off and washed with water and methanol. The free acid was obtained as a light colored foam by vacuum concentration and used for the next step without further purification.

<Example 91>

Guanidine carboxylic acid 226: Pure trifluoroacetic acid (4.0 mL) was added to a solution of bis-Boc guanidinyl acid 225 (crude obtained from the previous step) in a CH ₂ Cl ₂ (4.0 mL) solvent cooled to 0 ° C. Added. The reaction mixture was stirred at 0 ° C. for 1 hour and at room temperature for 2 hours. A light orange solid was obtained by vacuum concentration, which was eluted with water and purified by C ₁₈ reverse phase chromatography. Fractions containing the desired product were combined and lyophilized to yield 18.4 mg (40%, 2 steps) of guanidine carboxylic acid 225: ¹ H NMR (D ₂ O, 300 MHz) δ6.47 (s, 1H), 4.28 (bd, 1H, J = 8.4 Hz), 3.93-3.74 (m, 2H), 3.72-3.63 (m, 1H), 2.78 (dd, 1H, J = 4.8, 17.4 Hz), 2.43-2.32 (m, 1H ), 1.58-1.45 (m, 2H), 1.13 (d, 3H, J = 6.0 Hz), 0.90 (t, 3H, J = 7.4 Hz).

<Example 92>

(Diethyl) methyl ether ester 227: N-trityl aziridine 183 (15) in 3-pentanol (230 mL) solvent while stirring BF ₃ .Et ₂ O (6.27 mL, 51 mmol) to room temperature under argon atmosphere. g, 34 mmol). The light solution was heated at 70-75 ° C. for 1.75 hours and then concentrated in vacuo to give a brown residue, which was dissolved in dry pyridine (2.0 mL), followed by acetic anhydride (16 mL, 170 mmol) and catalytic amount of DMAP 200 treated with mg. The reaction was stirred at room temperature for 18 hours, concentrated in vacuo and extracted with ethyl acetate and 1M HCl aqueous solution. The organic layer was separated, washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, and then dried over MgSO ₄ . After concentration in vacuo, the residue was flash chromatographed on silica gel (50% hexane in ethyl acetate) to give 7.66 g of (diethyl) methyl ether ester, which was recrystallized from ethyl acetate / hexanes to give compound 277 as a colorless needle. (7.25 g, 66%): ¹ H NMR (CDCl ₃ , 300 MHz) δ6.79 (t, 1H, J = 2.1 Hz), 5.92 (d, 1H, J = 7.5 Hz), 4.58 (bd, 1H, J = 8.7 Hz), 4.35-4.25 (m, 1H), 3.77 (s, 3H), 3.36-3.25 (m, 2H), 2.85 (dd, 1H, J = 5.7, 17.4 Hz), 2.29-2.18 (m, 1H), 2.04 (s, 3H), 1.60-1.45 (m, 4H), 0.91 (t, 3H, J = 3.7 Hz), 0.90 (t, 3H, J = 7.3 Hz).

<Example 93>

(Diethyl) methyl ether amino ester 228: To a solution of water (5.6 mL) and azide 227 (1 g, 3.1 mmol) in THF (30 mL) was added Ph ₃ P (1.21 g, 4.6 mmol). At a time. The pale yellow solution was heated at 50 ° C. for 10 h, then cooled and concentrated in vacuo. The aqueous residue in oil phase was separated by extraction with EtOAc and saturated aqueous NaCl solution. The organic layer was dried (MgSO ₄ ), filtered and evaporated. Purification by flash chromatography on silica gel (50% methanol in ethyl acetate) yielded 830 mg (90%) of amino acid 228: ¹ H NMR (CDCl ₃ , 300 MHz) δ6.78 (t, 1H, J = 2.1 Hz), 5.68 (bd, 1H, J = 7.8 Hz), 4.21-4.18 (m, 1H), 3.75 (s, 3H), 3.54-3.45 (m, 1H), 3.37-3.15 (m, 2H), 2.74 (dd, 1H, J = 5.1, 17.7 Hz), 2.20-2.07 (m, 1H), 2.03 (s, 3H), 1.69 (bs, 2H, -NH ₂ ), 1.57-1.44 (m, 4H), 0.90 (t, 3H, J = 7.5 Hz), 0.89 (t, 3H, J = 7.5 Hz).

<Example 94>

A solution of methyl ester 228 (830 mg, 2.8 mmol) in amino acid 229: THF (15 mL) solvent was treated with aqueous KOH solution (1.039 N, 4 mL). The reaction mixture was stirred for 40 minutes at room temperature and acidified to pH 5.5-6.0 using Dowex 50WX8 acid resin. The resin was filtered off and washed with water and methanol. After concentration in vacuo the amino acid was obtained as a light solid, which was purified by C ₁₈ reverse phase chromatography, eluting with 5% CH ₃ CN / water. Fractions containing the desired product were combined and lyophilized to yield 600 mg (75%) of amino acid 229: ¹ H NMR (D ₂ O, 300 MHz) δ6.50 (t, 1H, J = 2.1 Hz), 4.30- 4.26 (m, 1H), 4.03 (dd, 1H, J = 9.0, 11.7 Hz), 3.58-3.48 (m, 2H), 2.88 (dd, 1H, J = 5.4, 16.8 Hz), 2.53-2.41 (m, 1H), 1.62-1.40 (m, 4H), 0.90 (t, 3H, J = 7.5 Hz), 0.85 (t, H, J = 7.5 Hz).

<Example 95>

t-amyl ether ester 230: A solution of N-trityl aziridine 183 (104 mg, 0.24 mmol) in t-amyl alcohol (2.5 mL) with BF ₃ · Et ₂ O (43 μL, 0.35 mmol) under argon atmosphere Was added to and stirred at room temperature. The light solution was heated at 75 ° C. for 3 hours and then concentrated in vacuo to dissolve the brown residue in dry pyridine (2.0 mL) and then treated with acetic anhydride (250 μL) and a catalytic amount of DMAP (several crystals). The reaction was stirred at rt for 1.5 h and then concentrated in vacuo and then separated by extraction with ethyl acetate and brine. The organic layer was separated separately and washed successively with dilute aqueous HCl solution, saturated aqueous sodium hydrogen carbonate solution and brine and dried over MgSO ₄ . After concentration in vacuo, the residue was flash chromatographed on silica gel (50% hexane in ethyl acetate) to give 27 mg (35%) of t-amyl ether ester 230 as light oil. ¹ H NMR (CDCl ₃ , 300 MHz): δ 6.72 (t, 1H, J = 2.1 Hz); 5.83 (d, 1 H, J = 7.2 Hz); 4.71 (bd, 1 H, J = 8.1 Hz); 4.45-4.35 (m, 1 H); 3.75 (s, 3 H); 3.27-3.17 (m, 1 H); 2.84 (dd, 1H, J = 5.7, 17.4 Hz); 2.27-2.15 (m, 1 H); 2.05 (s, 3 H); 1.57-1.47 (m, 2 H); 1.19 (s, 3 H); 1.15 (s, 3 H); 0.90 (t, 3H, J = 7.5 Hz).

<Example 96>

t-amyl ether amino ester 231: Ph ₃ P (35 mg, 0.133 mmol) was added in one portion to a solution of water (160 μL) and azide 230 (27 mg, 0.083 mmol) in THF (1.5 mL) as a solvent It was. The pale yellow solution was heated at 50 ° C. for 10 hours, cooled and concentrated in vacuo to give a pale solid. Purification by flash chromatography on silica gel (50% methanol in ethyl acetate) yielded 20 mg (82%) of amino ester 231 as light oil.

<Example 97>

A solution of methyl ester 231 (20 mg, 0.068 mmol) in amino acid 232: THF (1.0 mL) solvent was treated with aqueous KOH solution (1.039 N, 131 μL). The reaction mixture was stirred at room temperature for 2.5 hours and acidified to pH 5.0 using Amberlite IR-120 (H ⁺ ) acid resin. The resin was filtered off and washed with water and methanol. Concentration in vacuo afforded the amino acid as a light solid, which was eluted with water and purified by C ₁₈ reverse phase chromatography. The fractions containing the desired product were collected and lyophilized to yield 8.6 mg (45%) of amino acid 232: ¹ H NMR (D ₂ O, 300 MHz) δ6.47 (bs, 1H), 4.42 (bd, 1H , J = 8.1 Hz), 3.97 (dd, 1H, J = 8.4, 11.4 Hz), 3.65-3.54 (m, 1H), 2.88 (dd, 1H, J = 5.5, 17.3 Hz), 2.51-2.39 (m, 1H), 2.08 (s, 3H), 1.61-1.46 (m, 2H), 1.23 (s, 3H), 1.18 (s, 3H), 0.86 (t, 3H, J = 7.5 Hz).

<Example 98>

n-propyl thio ether ester 233: BF ₃ · Et ₂ O (130 μL, 1.06 mmol) was added N-trityl aziridine 183 (300 mg, 0.68 mmol) in 1-propanethiol (8.0 mL) solvent under argon atmosphere. Was added to the solution of and stirred at room temperature. The light solution was heated at 65 ° C. for 45 minutes and then concentrated, then layered using ethyl acetate and brine. The organic layer was separated and washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, and then dried over MgSO ₄ . After concentration in vacuo, the residue was flash chromatographed on silica gel (30% hexane in ethyl acetate) to give 134 mg (73%) of n-propyl thio ether ester 233 as a pale oil: ¹ H NMR (CDCl ₃ , 300). MHz) δ6.87 (t, 1H, J = 2.4 Hz), 3.77 (s, 3H), 3.48-3.38 (m, 1H), 3.22-3.18 (m, 1H), 2.93 (dd, 1H, J = 5.4 , 17.4 Hz), 2.80 (t, 1H, J 9.9 Hz), 2.51 (t, 2H, J = 7.2 Hz), 2.32-2.20 (m, 1H), 1.96 (bs, 2H, -NH ₂ ), 1.69- 1.56 (m, 2 H), 1.00 (t, 3 H, J = 7.2 Hz).

<Example 99>

n-propyl thio ether azido ester 234: To a solution of amine 233 (134 mg, 0.50 mmol) in pyridine (91.5 mL) solvent cooled to 0 ° C. was added pure acetyl chloride (60 μL, 0.84 mmol). After stirring for 1 hour, the reaction mixture was warmed to room temperature and stirred for another 15 minutes. The reaction was concentrated, extracted with ethyl acetate and brine, separated, and the organic layer was washed sequentially with dilute HCl aqueous solution, water, saturated aqueous sodium bicarbonate solution and brine, and dried over MgSO ₄ . After concentration in vacuo, the residue was purified by flash chromatography on silica gel (30% hexane in ethyl acetate) to give 162 mg (100%) of n-propyl thioether azido ester 234 as a pale yellow solid: ¹ H NMR (CDCl ₃ , 300 MHz) δ6.90 (t, 1H, J = 2.7 Hz), 5.87 (bd, 1H, J = 7.8 Hz), 4.07-3.98 (m, 1H), 3.77 (s, 3H), 3.65 -3.55 (m, 1H), 2.95-2.85 (m, 1H), 2.60-2.45 (m, 2H), 2.30-2.18 (m, 1H), 2.08 (s, 3H), 1.65-1.53 (m, 2H) , 0.98 (t, 3H, J = 7.2 Hz).

<Example 100>

n-propyl thio ether amino ester 235: Azide 234 (130 mg, 0.416 mmol) in ethyl acetate (10 mL) solvent was reacted with Lindlar catalyst (150 mg) for 18 hours at room temperature and hydrogenated (1 atm). The catalyst was filtered through a pad of celite and then washed with hot ethyl acetate and methanol. Concentration in vacuo gave flash chromatography on an orange residue to give 62 mg (53%) of n-propyl thioether amino ester 235: ¹ H NMR (CDCl ₃ , 300 MHz) δ 6.88 (t, 1H, J = 2.7 Hz), 5.67 (bd, 1H, J = 8.7 Hz), 3.76 (s, 3H), 3.75-3.65 (m, 1H), 3.45-3.35 (bm, 1H), 3.05-2.95 (m, 1H), 2.87-2.78 (m, 1H), 2.56-2.40 (m, 2H), 2.18-2.05 (m, 1H), 2.09 (s, 3H), 1.65-1.50 (m, 2H), 1.53 (bs, 2H,- NH ₂ ), 0.98 (t, 3H, J = 7.2 Hz).

<Example 101>

Compound 240: A suspension of toluenesulfonic acid (850 mg), 2,2-dimethoxypropane (200 mL) and quinic acid (103 g) using acetone (700 mL) as a solvent was stirred at room temperature for 4 days. The solvent and excess reagents were removed under reduced pressure. Purification by flash column chromatography (hexane / EtOAc = 2/1 to 1.5 / 1) afforded lactone 240 (84 g, 73%): ¹ H NMR (CDCl ₃ ) δ4.72 (dd, J = 2.4 , 6.1 Hz, 1H), 4.50 (m, 1H), 4.31 (m, 1H), 2.67 (m, 2H), 2.4-2.2 (m, 3H), 1.52 (s, 3H), 1.33 (s, 3H) . The reaction was refluxed for 4 hours, worked up with an aqueous solution (ethyl acetate / water layer separation) and the crude material was recrystallized from ethyl acetate / hexanes to give lactone 240 in 71% yield.

<Example 102>

Compound 241: To a solution of lactone 240 (43.5 g, 203 mmol) in methanol (1200 mL) solvent was added sodium methoxide (4.37 M, 46.5 mL, 203 mmol) in one portion. The mixture was stirred at rt for 3 h and quenched with acetic acid (11.62 mL). The solvent methanol was removed under reduced pressure. The mixture was diluted with water and then extracted with EtOAc (3 ×). The combined organic layers were washed with water (1x) and brine (1x) and then dried over MgSO ₄ . Purification by flash chromatography (hexane / EtOAc = 1/1 to 1/4) afforded diol (43.4 g, 87%): ¹ H NMR (CDCl ₃ ) δ 4.48 (m, 1H), 4.13 (m , 1H), 3.99 (t, J = 6.4 Hz, 1H), 3.82 (s, 3H), 3.34 (s, 1H), 2.26 (d, J = 3.8 Hz, 2H), 2.08 (m, 1H), 1.91 (m, 1 H), 1.54 (s, 3 H), 1.38 (s, 3 H). On the other hand, lactone 240 was treated with a catalytic amount of sodium ethoxide (1 mol%) in an ethanol solvent and crystallized the crude product from ethyl acetate / hexanes to give 67% of the corresponding ethyl ester compound. The residue obtained from the mother liquor (composed of starting material and product) was reacted again under the same reaction conditions and then recrystallized to give additional product. Total yield was 83%.

<Example 103>

Compound 242: Tosyl chloride (27.7 g, 145 mmol) was added to a solution of 4- (N, N-dimethylamino) pyridine (500 mg) and diol 241 (29.8 g, 121 mmol) in pyridine (230 mL) solvent. . The mixture was stirred for 3 days at room temperature and the pyridine was removed under reduced pressure. The mixture was diluted with water and extracted with EtOAc (3 ×). The combined organic layers were washed with water (2x) and brine (1x) and dried over MgSO ₄ . Purification by concentration after flash chromatography (hexane / EtOAc = 2/1 to 1/1) gave tosylate 242 (44.6 g, 92%): ¹ H NMR (CDCl ₃ ) δ 7.84 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 4.76 (m, 1H), 4.42 (m, 1H), 4.05 (dd, J = 5.5, 7.5 Hz, 1H), 3.80 (s, 3H), 2.44 (s, 3H), 2.35 (m, 1H), 2.24 (m, 2H), 1.96 (m, 1H), 1.26 (s, 3H), 1.13 (s, 3H). The corresponding ethyl ester compound of compound 241 was treated with methanesulfonyl chloride and triethylamine in a CH ₂ Cl ₂ solvent at 0 ° C. to give a quantitative mesylate derivative after an aqueous work-up. The mesylate could be used without further purification.

<Example 104>

Compound 243: pyridine (89 mL) was added to a solution of tosylate 242 (44.6 g, 111.5 mmol) in a CH ₂ Cl ₂ (450 mL) solvent at -78 ° C, followed by SO ₂ Cl ₂ (26.7 mL, 335 mmol). ) Was added slowly. The mixture was stirred at -78 ° C for 5 hours and methanol (45 mL) was added dropwise. The mixture was warmed to room temperature and stirred for 12 hours. Ethyl ether was added and the mixture was washed with water (3 ×) and brine (1 ×) and then dried over MgSO ₄ . Concentration gave the intermediate as an oil (44.8 g). To a solution of intermediate (44.8 g, 111.5 mmol) with MeOH (500 mL) as solvent was added TsOH (1.06 g, 5.6 mmol). This mixture was refluxed for 4 hours. The reaction mixture was cooled to room temperature and the methanol was removed under reduced pressure. After addition of fresh methanol (500 mL), the whole mixture was again refluxed for 4 h. The reaction mixture was cooled to room temperature and methanol was removed under reduced pressure. Purification by flash column chromatography (hexane / EtOAc = 3/1 to 1/3) gave a mixture of the two isomers (26.8 g). Recrystallization from EtOAc / hexanes gave the pure desired product 243 (20.5 g, 54%): ¹ H NMR (CDCl ₃ ) δ 7.82 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H), 6.84 (m, 1H), 4.82 (dd, J = 5.8, 7.4 Hz, 1H), 4.50 (m, 1H), 3.90 (dd, J = 4.4, 8.2 Hz, 1H), 3.74 (s, 3H ), 2.79 (dd, J = 5.5, 18.2 Hz, 1H), 2.42 (dd, J = 6.6, 18.2 Hz, 1H). The corresponding mesylate-ethyl ester derivative of compound 242 was treated in the same manner as described above. Ethanol was refluxed and the acetonide protecting group was removed with acetic acid to give diol in 39% yield from the crude reaction mixture via direct precipitation with ether.

<Example 105>

Compound 1: DBU (8.75 mL, 58.5 mmol) was added to a solution of diol 243 (20.0 g, 58.5 mmol) in 0 ° C., THF (300 mL) solvent. The reaction mixture was warmed to room temperature and stirred for 12 hours. Solvent (THF) was removed under reduced pressure. Purification by flash column chromatography (hexane / EtOAc = 1/3) yielded epoxide 1 (9.72 g, 100%): ¹ H NMR (CDCl ₃ ) δ 6.72 (m, 1H), 4.56 (td, J = 2.6, 10.7 Hz, 1H), 3.76 (s, 3H), 3.56 (m, 2H), 3.0 (d, J = 21 Hz, 1H), 2.50 (d, J = 20 Hz, 1H), 2.11 ( d, 10.9 Hz, 1H). The corresponding mesylate-ethyl ester derivative of compound 243 was treated in the same manner as described to give epoxide in near quantitative yield.

<Example 106>

Aziridine 244: A solution of Lindlar catalyst (200 mg) and allyl ether 4 (223 mg, 1.07 mmol) using anhydrous ethanol (8.0 mL) as a solvent was treated with hydrogen gas (1 atm) at room temperature for 50 minutes. Thereafter, the catalyst was filtered through a pad of celite and washed with hot methanol. Concentration in vacuo gave ~ 230 mg of compound 244 as a pale yellow oil which was used in the next reaction without further purification.

<Example 107>

Azido amine 205: Ammonium chloride (105 mg, 1.96 mmol), crude aziridine 244 (230 mg), sodium azide (309 mg, 4.75 mmol) in a dry DMF (10 mL) solvent at an argon atmosphere and 70 ° C. Heated under conditions for 16 hours. The reaction was cooled and filtered through a fritted glass funnel to remove solids and layered using ethyl acetate and brine. The organic layer was separated and dried over MgSO ₄ . After concentration in vacuo, the residue was subjected to flash chromatography on silica gel (10% hexane in ethyl acetate) to give 154 mg (57%, step 2) of compound 205 as a yellow viscous oil with sufficient purity to carry out the next reaction. Got it.

<Example 108>

N-acetyl azide 245: To a solution of pyridine (1.3 mL) and amine 205 (154 mg, 0.61 mmol) in CH ₂ Cl ₂ (4.0 mL) at 0 ° C. was added acetyl chloride (70 μL, 0.98 mmol). Added. After 1.5 hours at 0 ° C., the reaction was concentrated and layered using ethyl acetate and brine. The organic layer was separated, washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, and dried over MgSO ₄ . After concentration in vacuo, the residue was subjected to flash chromatography on silica gel (ethyl acetate) to give 167 mg (93%) of compound 245 as a pale yellow solid.

<Example 109>

Amino ester 200: Triphenylphosphine (1.7 g, 6.48 mmol) was added in several portions to a solution of compound 245 (1.78 g, 6.01 mmol) using water (1.5 mL) and THF (40 mL) as a solvent. The reaction was then stirred for 42.5 hours at room temperature. The volatiles were removed in vacuo and the crude solid was absorbed on silica gel and purified by flash chromatography on silica gel (100% ethyl acetate, then 100% methanol) to yield 1.24 g (77%) as a pale solid. Got it.

<Example 110>

Amino acid 102: To a solution of methyl ester 200 (368 mg, 1.37 mmol) in THF (4.0 mL) cooled to 0 ° C. was added aqueous NaOH solution (1.0 N, 1.37 mL). The reaction mixture was stirred at 0 ° C. for 10 minutes, stirred at room temperature for 1.5 hours and then acidified to pH 7.0-7.5 using Amberlite IR-120 (H ⁺ ) acid resin. The resin was filtered off and washed with water and methanol. Concentration in vacuo afforded the amino acid as a white solid, which was eluted with water and purified by C ₁₈ reverse phase chromatography. Fractions containing the desired product were combined and lyophilized to yield 290 mg (83%) of amino acid 102.

<Example 111>

Amine Hydrochloride 250: Amine 228 (15.6 mg, 0.05 mmol) was treated with 0.1 N HCl and then evaporated. The residue was dissolved in water and filtered through a small C ₁₈ reversed phase silica gel column. After lyophilization hydrochloride salt 250 (12 mg) was obtained as a solid: ¹ H NMR (D ₂ O) δ 6.86 (s, 1H), 4.35 (br d, J = 9.0 Hz), 4.06 (dd, 1H, J = 9.0, 11.6 Hz), 3.79 (s, 3H), 3.65-3.52 (m, 2H), 2.97 (dd, 1H, J = 5.5, 17.2 Hz), 2.58-2.47 (m, 1H), 2.08 (s, 3H), 1.61-1.41 (m, 4H), 0.88 (t, 3H, J = 7.4 Hz), 0.84 (t, 3H, J = 7.4 Hz).

<Example 112>

Bis-Boc-guanidine 251: amine 228 (126 mg, 0.42 mmol), N, N'-bis-tert-butoxycarbonylthiourea (127 mg, 0.46 mmol) at 0 ° C., DMF (4 mL) solvent And HgCl ₂ (125 mg, 0.46 mmol) were added to a solution of triethylamine (123 μL, 0.88 mmol). 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 separated by extraction with ethyl acetate and water. The organic layer was washed with saturated aqueous NaCl solution, dried (MgSO ₄ ), filtered and the solvent was evaporated. The crude product was purified on silica gel (hexane / ethyl acetate = 2/1, 1/1) to give bis-Boc-guanidine 251 (155 mg, 69%) as a solid: ¹ H NMR (CDCl ₃ ) δ11. 40 (s, 1H), 8.66 (d, 1H, J = 7.9 Hz), 6.8 (s, 1H), 6.22 (d, 1H, J = 8.9 Hz), 4.43-4.34 (m, 1H), 4.19-4.08 (m, 1H), 4.03 (m, 1H), 3.76 (s, 3H), 3.35 (m, 1H), 2.79 (dd, 1H, J = 5.4, 17.7 Hz), 2.47-2.36 (m, 1H), 1.92 (s, 3H), 1.50, 1.49 (2s, 18H), 0.89 (m, 6H).

<Example 113>

To a solution of bis-Boc-guanidine 251 (150 mg, 0.28 mmol) with guanidinoic acid 252: THF (3 mL) was added 1.039 N KOH solution (337 μL) and water (674 μL). The mixture was stirred for 3 hours, and additional 1.039 N KOH solution (67 μL) was added and stirring 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 to pH 4.5-5.0 with IR-120 ion exchange resin. The resin was filtered off and washed with methanol. The filtrate was evaporated to give a residue, which was dissolved in CH ₂ Cl ₂ (3 mL), cooled to 0 ° C. and treated with 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 to dissolve the residue in water, then eluted first with water, then with 5% acetonitrile / water and purified by chromatography on a short column (3 × 1.5 cm) of C ₁₈ reversed phase silica gel. After collecting the product fractions and evaporating, the residue was dissolved in water and lyophilized to give guanidinoic acid 252 (97 mg, 79%) as a white solid.

<Example 114>

Azidoic acid 260: Aqueous KOH solution (1.039 N, 1.60 mL) was added to a solution of methyl ester 227 (268 mg, 0.83 mmol) in THF (7.0 mL) solvent at room temperature. After stirring for 19 hours at room temperature the reaction was acidified to pH 4.0 with Amberlite IR-120 (H ⁺ ) acid resin. The resin was filtered off and washed with water and ethanol. Concentration in vacuo gave crude azidoic acid 260 as a pale orange foam which was used in the next step without further purification.

<Example 115>

Azido ethyl ester 261: at room temperature, in a solution of carboxylic acid 260 (crude from previous step, about 0.83 mmol), ethyl alcohol (150 μL), DMAP catalytic amount in CH ₂ Cl ₂ (6.0 mL) solvent 172 mg, 0.83 mmol) was added in one portion. After several minutes, a precipitate was formed. After stirring for 1 hour, the reaction mixture was filtered and washed with CH ₂ Cl ₂ . After concentration in vacuo a light solid was obtained which was purified by flash chromatography on silica gel (50% hexane in ethyl acetate) to give 272 mg (96%, with a small amount of DCU impurities) of compound 261 as a white solid. When DCC was substituted with diisopropyl carbodiimide, the yield of Compound 261 was 93%. However, when DCC was used, chromatographic purification was performed to remove urea impurities.

<Example 116>

Amino ethyl ester 262: Triphenylphosphine (342 mg, 1.30 mmol) was added in one portion to a solution of compound 261 (272 g, 0.80 mmol) in water (1.6 mL) and THF (17 mL) as solvent. The reaction was then heated at 50 ° C. for 10 hours, then cooled and concentrated in vacuo to yield a pale white solid. The crude solid was subjected to flash chromatography on silica gel (50% methanol in ethyl acetate) to give 242 mg (96%) of amino ethyl ester 262 as a light solid. This amino ethyl ester was dissolved in 3N HCl and then lyophilized to give the corresponding water soluble HCl salt form: ¹ H NMR (D ₂ O, 300 MHz) δ6.84 (s, 1H), 4.36-4.30 (br m, 1H), 4.24 (q, 2H, J = 7.2 Hz), 4.05 (dd, 1H, J = 9.0, 11.7 Hz), 3.63-3.50 (m, 2H), 2.95 (dd, 1H, J = 5.7, 17.1 Hz ), 2.57-2.45 (m, 1H), 1.60-1.39 (m, 4H), 1.27 (t, 3H, J = 7.2 Hz), 0.89-0.80 (m, 6H).

<Example 117>

Bis-Boc guanidino ethyl ester 263: Kim and Quian "Tetrahedron Lett." 34: 7677 (1993). HgCl ₂ (69) in a solution of amine 262 (72 mg, 0.23 mmol), bis-Boc-thiourea (66 mg, 0.24 mmol) and Et ₃ N (108 μL) in a dry DMF (600 μL) solvent cooled to 0 ° C mg, 0.25 mmol) was added in one portion. The heterogeneous reaction mixture was stirred at 0 ° C. for 1 hour and then at room temperature for 15 minutes, after which the reaction was diluted with EtOAc and filtered through a pad of celite. Concentration in vacuo and the residue was purified by flash chromatography on silica gel (20% hexanes in ethyl acetate) to give 113 mg (89%) of compound 263 as a colorless foam: ¹ H NMR (CDCl ₃ , 300 MHz) δ11. 41 (s, 1H), 8.65 (d, 1H, J = 8.1 Hz), 6.83 (s, 1H), 6.22 (d, 1H, J = 9.0 Hz), 4.46-4.34 (m, 1H), 4.21 (q , 2H, J = 6.9 Hz, 4.22-4.10 (m, 1H), 4.04-4.00 (m, 1H), 3.36 (quintet, 1H, J = 5.7 Hz), 2.78 (dd, 1H, J = 5.4, 17.7 Hz), 2.46-2.35 (m, 1H), 1.94 (s, 3H), 1.60-1.40 (m, 4H), 1.49 (s, 9H), 1.50 (s, 9H), 1.30 (t, 3H, J = 6.9 Hz), 0.93-0.84 (m, 6H).

<Example 118>

Guanidino ethyl ester 264: Pure trifluoroacetic acid (5.0 mL) in a solution of bis-Boc guanidinyl ethyl ester 263 (113 mg, 0.20 mmol) in CH ₂ Cl ₂ (5.0 mL) solvent cooled to 0 ° C. Was added. The reaction mixture was stirred at 0 ° C. for 30 minutes and then at room temperature for 1.5 hours. The reaction was then concentrated in vacuo to give a pale orange solid, which was eluted with water and purified by C ₁₈ reversed phase chromatography. Fractions containing the desired product were combined and lyophilized to give 63 mg (66%) of guanidine ethyl ester 264 as a white solid: ¹ H NMR (D ₂ O, 300 MHz) δ6.82 (s, 1H), 4.35 -4.31 (m, 1H), 4.24 (q, 2H, J = 7.1 Hz), 3.95-3.87 (m, 1H), 3.85-3.76 (m, 1H), 3.57-3.49 (m, 1H), 2.87 (dd , 1H, J = 5.1, 17.7 Hz), 2.46-2.34 (m, 1H), 2.20 (s, 3H), 1.60-1.38 (m, 4H), 1.28 (t, 3H, J = 7.1 Hz), 0.90- 0.80 (m, 6 H).

<Example 119>

Enzyme Inhibition: Using the in vitro activity screening method described above, the following activity was observed (+ 10-100 μm, ++ 1-10 μm, +++ <1.0 μm):

<Example 120>

Compounds A.113.b.4.i and A.113.x.4.i were incubated separately in the enzyme assay buffer and then the activity was tested as described in Example 119 above. Both activities were> 100 μm.

<Example 121>

Under the supervision of Dr. Robert Sidwell of the Institute for antiviral Research of Utah State University, the relative anti-influenza A activity in vivo in mice with Compound 203 (Example 69), GG167 and ribavirin was measured in i.p. Or p.o. Test was by route of administration. GG167 and ribavirin are known anti-influenza compounds.

Mice: 13-15 g of female BALB / c mice without specific-pathogens were obtained from Simonsen Laboratories (Gilroy, Calif.). They were weighed 24 hours before being used for testing and kept in Wayne Lab Blox and tap water. Following infection, 0.002% oxytetracycline (Pfizer, New York, NY) was added to drinking water to control possible secondary bacterial infections.

Virus: Influenza A / NWS / 33 (H1N1) was obtained from KW Cochran, University of Michigan (Ann Arbor, MI). Viral pools are infected by infecting confluent monolayers of Madin Darby canine kidney (MDCK) cells, incubating them at 37 ° C. in 5% CO ₂ , and then harvesting the cells by the time the virus cytopathic effect reaches 90-100% by 3-5 days. created a pool. Virus stocks were stored in ampoules and stored at −80 ° C. until use.

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

Arterial Oxygen Saturation (SaO ₂ ) Measurement: SaO ₂ was measured using an Ohmeda Biox plus oximeter (Ohmeda, Louisville, OH). The slow instrument mode was selected and ear probe attachment attached to the thighs of the animal was used. Readings were made after 30 seconds of stabilization in each animal. The use of this device to measure the effects of influenza virus on arterial oxygen saturation is described in Sidwell et al., "Antimicrob. Agents Chemother." 36: 473-476 (1992).

Experimental Design for Intraperitoneal Dose Studies: A group of 11 mice infected with approximately 95% lethal virus in the nose were dosed with each test compound. Doses of Compound 203 and GG167 were 50, 10, 2 and 0.5 mg / kg / day. IP was treated twice daily for 5 days starting 4 hours before exposure to the virus. For each dose, infected, 8 treated mice and 16 infected, saline treated controls were analyzed for SaO ₂ levels over days 3-10; Death records for these animals were made daily for 21 days. On day 6, the remaining three animals and six saline-treated controls in each group were killed, their lungs removed, and weighed based on the degree of lung color in the lungs (0 = normal, 4 = 100% lung infection). ) Scored an integration. No toxicity was observed for Compound 203 at the 300 mg / kg / day dose, and the literature showed that GG167 was likewise non-toxic, so no toxicity control was included in this study.

Experimental Design for Oral Dosing Study: Groups of 11 mice infected with approximately 95% lethal virus in the nose were 250, 50, or 10 mg / kg / day, with ribavirin at 100, 32, or Treatment was at 10 mg / kg / day. Treatments were performed by oral gavage (po) twice a day for 5 days starting 4 hours prior to exposure to the virus. Infected, treated 8 mice in each group were maintained for 21 days, death records were made daily and SaO ₂ levels were measured on days 3-10. The remaining three infected animals in each group were killed on day 6, their lungs removed, and weighed to obtain integration scores based on the degree of lung color in the lungs (0 = normal, 4 = 100% lung infection). Rated. SaO ₂ was measured as above while 15 infected mice were treated only with saline and maintained for 21 days, 6 more infected, and saline treated mice were killed on day 6 to analyze lungs. Three general controls were maintained for 21 days, SaO ₂ was measured as described above, and additionally three general controls were killed on day 6 to weigh and score lungs.

Experimental Design for Small Dose Oral Dosing Study: Compounds were administered to a group of eight mice infected with approximately 90% lethal virus in the nose. Doses of each compound were 10, 1 and 0.1 mg / kg / day. Treatments were performed twice daily for 5 days starting 4 hours before exposure to the virus. Infections, 8 treated mice and 16 infected, saline-treated controls per group were measured for SaO ₂ levels on days 3-11; Death records of these animals were made for 21 days.

Statistical Assessment: Survival was assessed according to chi square analysis and Yates correction. By t-test, the mean survival time increase and the difference in SaO ₂ , lung weight and lung virus titration were analyzed. Lung score differences were assessed by total grading analysis. In all cases, differences between drug treated and saline-treated controls were studied.

Table 1 and the results of the intraperitoneal administration experiments are summarized in FIGS. Although both compounds in this model showed significant inhibitory effects at high doses, the Compound 203 treatment group also resulted in significant survivors at the 10 mg / kg / day dose. SaO ₂ degradation was markedly suppressed for both compounds at the 50 mg / kg / day dose, and GG167 was also shown to inhibit this degradation even at 10, even 2 mg / kg / day. Pulmonary score data show that GG 167 is equally effective at one overdose. There was some variation in lung weight for lungs from mice administered at maximum dose of GG167, which weighed more than the saline-treated controls.

The po dose studies are summarized in Table II. Daily SaO ₂ values are shown in FIGS. 3-5. In this model, oral treatment of all three drugs markedly inhibited influenza virus infection, prevented death, lowered lung score and infection-related lung weight, and inhibited routine degradation of SaO ₂ .

The low dose po study results are summarized in Table III and FIGS. 6-8. In this experiment, 14 of 16 saline-treated animals died and the mean survival time was 9.6 days for this group. Although all three compounds had some degree of inhibitory effect against viral infections, compound 262 (ethyl ester prodrug) was most effective at all doses, as evidenced in terms of survival, mean survival time, and prevention of SaO ₂ degradation. It was.

Table III shows the average SaO ₂ over time for all analyzes. 6 to 8 show the daily values for each compound. 6 shows SaO ₂ data according to the highest concentration of each compound; Fig. 7 shows the values in the average dosage of each compound, and Fig. 8 compares SaO ₂ when a small amount of each compound is administered.

According to Table III and Figures 6-8 all three compounds are orally active against experimentally induced influenza A (H1N1) virus infection, but among them Compound 262 is considered to be the most effective. It was not determined whether an increase in animal toxicity was accompanied by an improvement in the antiviral efficacy of 262 of the compound, but since such an increase is believed to be a result of its enhanced oral bioavailability, the toxicity is unlikely to increase.

Surprisingly, although Ryan et al. ("Antimicrob. Agents Chemother.", 38 (10): 2270-2275 [1994]) said that, despite the superior bioavailability of GG167, relatively poor in vivo activity upon intraperitoneal administration in mice This is attributed to their rapid removal from plasma and poor penetration into respiratory secretions, as well as lack of intracellular penetration and intracellular persistence. Despite the conclusion that oral bioavailability may be a poor result ”(p. 2274), the above-mentioned facts indicate that oral or intraperitoneal administration of GG167 in this model may reduce mortality in influenza-infected mice. To demonstrate effectiveness at actual therapeutic dosages. This observation is consistent with the contents of WO 91/16320, WO 92/06691 and US Pat. No. 5,360,817 to GG167 and dealing with it. These patent documents do not disclose or suggest any route of administration other than administration of GG167 into the nose. However, nasal administration is considered expensive and inconvenient in some circumstances. It would be much more advantageous to be able to provide a simpler route of administration of GG167 and related compounds set forth in WO91 / 16320, WO92 / 066991 and US Pat. No. 5,360,817.

Thus, one embodiment of the invention consists in administering to a host a therapeutically effective amount of an antiviral active compound having the formula X or Y, or a pharmacologically acceptable salt or derivative thereof, in the respiratory system by a route other than topical administration: The present invention provides a method of treating or preventing influenza virus infection.

In formula (X), A is generally oxygen, carbon or sulfur and in formula (Y) generally 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 .

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

R ⁶ is hydrogen; Acyl groups having 1 to 4 carbon atoms; Linear or cyclic alkyl groups having 1 to 6 carbon atoms, or halogen-substituted homologs thereof; An aryl group substituted with an allyl group or an unsubstituted aryl group or a halogen, OH group, NO ₂ group, NH ₂ group or COOH group

R ³ and R ^{3 '} are the same or different and each is hydrogen, CN, NHR ⁶ , N ₃ , SR ⁶ , OR ⁶ , guanidino, ^{^}

R ⁴ is 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

R ⁵ is CH ₂ YR ⁶ , CHYR ⁶ CH ₂ YR ⁶ , or CHYR ⁶ CHYR ⁶ CH ₂ YR ⁶ (where Y is O, S, NH or H) and the consecutive Y portions of the R ⁵ groups are the same or different; Provided that

(i) if R ³ or R ^{3 '} is OR ⁶ or hydrogen, then A is oxygen or sulfur and the compound is (a) hydrogen with R ^2;

(b) cannot simultaneously have R ⁴ , which is NH-acyl,

(ii) when Y is hydrogen, R ⁶ is a covalent bond,

(i) if R ³ or R ^{3 '} is OR ⁶ or hydrogen, then A is nitrogen and the compound is

(a) R ² and hydrogen

(b) cannot simultaneously have R ⁴ , which is NH-acyl,

(ii) when Y is hydrogen, R ⁶ is a covalent bond;

Compounds of formulas x and y are described in detail in WO 91/16320, page 3, line 23 to page 8, line 1, WO 92/06691 and US Pat. No. 5,360,817, wherein x and y are "I" and "Ia, respectively". Is indicated.

For the purposes of the present invention, the route other than "administration locally to the respiratory tract means" does not exclude administration of the compound by buccal or sublingual route, and the esophagus upon oral, buccal or sublingual administration Adsorption of incidental compounds to the furnace is also not ruled out. However, such buccal, oral, sublingual or esophageal adsorption is not accompanied by administration to the lung or nasal route by inhalers or the like. Usually the compound is administered in the form of a molded article, slurry or solution.

In a typical embodiment of the invention, the compound is GG167, the host is an animal other than a mouse (such as a ferret or a human) and the route of administration is oral, the purpose of treatment and prevention is to reduce mortality. As mentioned above, although not necessarily required to obtain an antiviral effect by oral administration, a precursor of Formula X or Y may optionally be used. As precursors of GG167 and the compounds disclosed therewith, any esters, amides or other precursors described in the compounds of the invention are suitable for use as homologues of compounds of formulas X and Y, such as for example carboxyl esters or amides.

When administered by oral or other non-co-administrative route of administration, the therapeutically effective dosage of GG167 and its related compounds can be determined by the skilled clinician by taking into account the points set forth in connection with the administration of the inventive combinations. Most important considerations are the route of administration and type of host. In general, higher doses are required intravenously and subcutaneously, followed by oral route of administration, and larger animals will require higher doses in accordance with conventional pharmaceutical proportional guidelines. Determination of therapeutically active dosages is within the skill of the art and generally the dosage is substantially the same as the dosage used in the compounds of the present invention.

<Example 122>

Each reaction shown in Table 50 was made in advance according to Scheme 50. The preformed reactants are marked with "√". Unless otherwise indicated in Table 50, AA, AB and AC steps were performed in advance according to Examples 92, 93 and 94, respectively, and AD steps were performed according to the combination of Examples 112 and 113.

Scheme 50

<Example 123>

Trifluoroacetamide 340: Pyridine (41 μL, 0.51 mmol) and anhydrous trifluoroacetic acid (TFAA) in a solution of amine 288 (100 mg, 0.34 mmol) with CH ₂ Cl ₂ (3.5 mL) as solvent at 0 ° C. , 52 μL, 0.37 mmol) and additional TFAA (0.5 eq) was added while stirring the solution for 45 min. 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 saturated NaHCO ₃ , saturated NaCl and dried (MgSO ₄ ), filtered and evaporated. The residue was chromatographed on silica gel (hexane / ethyl acetate = 2/1) to give trifluoroacetamide 340 (105 mg, 78%): ¹ H NMR (CDCl ₃ ) δ 8.64 (d, 1H, J = 8.2 Hz), 6.81 (s, 1H), 6.48 (d, 1H, J = 8.2 Hz), 4.25-4.07 (m, 3H), 3.75 (s, 3H), 3.37 (m, 1H), 2.76 (dd , 1H, J = 4.5, 18.7 Hz), 2.54 (m, 1H), 1.93 (s, 3H), 1.48 (m, 4H), 0.86 (m, 6H).

<Example 124>

N-methyl trifluoroacetamide 341: sodium hydride (10 mg, 60% dispersion in mineral oil, in a solution of trifluoroacetamide 340 (90 mg, 0.23 mmol) in DMF (2 mL) at 0 ° C., 0.25 mmol) was added. After 15 minutes at 0 ° C., methane iodide (71 μL, 1.15 mmol) was added and the reaction 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 separated using 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 (hexane / ethyl acetate = 1/1) to give N-methyl trifluoroacetamide 341 (81 mg, 87%) as colorless glass: ¹ H NMR (CDCl ₃ ) δ 6.80 (s, 1H), 6.26 (d, 1H, J = 9.9 Hz), 4.67 (m, 1H), 4.32 (m, 1H), 4.11 (m, 1H), 3.78 (s, 3H), 3.32 (m, 1H), 3.07 (brs, 3H), 2.60 (m, 2H), 1.91 (s, 3H), 1.48 (m, 4H), 0.87 (m, 6H).

<Example 125>

N-methyl amine 342: To a solution of N-methyl trifluoroacetamide 341 (81 mg, 0.20 mmol) in THF (3 mL) was added 1.04 N KOH (480 μL, 0.50 mmol) and the mixture was cooled to room temperature. Stirred for 14 h. The reaction was acidified to pH ˜4 using IR 120 ion exchange resin. The resin was filtered off, washed with THF and the filtrate was evaporated. The residue was dissolved in 10% TFA / water (5 mL) and evaporated. The residue was passed through a C-18 reversed phase silica gel column (1.5 × 2.5 cm) eluting with water. The product fractions were combined and lyophilized to give N-methyl amine 342 (46 mg, 56%) as a white solid: ¹ H NMR (D ₂ O) δ6.80 (s, 1H), 4.31 (brd, 1H, J = 8.8 Hz), 4.09 (dd, 1H, J = 8.9, 11.6 Hz), 3.53 (m, 2H), 2.98 (dd, 1H, J = 5.4, 16.9 Hz), 2.73 (s, 3H), 2.52-2.41 ( m, 1H), 2.07 (s, 3H), 1.61-1.39 (m, 4H), 0.84 (m, 6H).

<Example 126>

Compound 346: Sodium azide (19.0 g, 292.0 mmol) and ammonium chloride in a solution of epoxide 345 (13.32 g, 58.4 mmol) using 8 / 1-MeOH / H ₂ O (440 mL, v / v) as a solvent (2.69 g, 129.3 mmol) was added and the mixture was refluxed for 15 h. The reaction was cooled and concentrated under reduced pressure and then layered using EtOAc and H ₂ O. The organic layer was washed successively with saturated aqueous hydrogen carbonate solution and brine, and dried over MgSO ₄ . Concentration in vacuo followed by flash chromatography on silica gel (30% EtOAc in hexanes) gave 11.81 g (75%) of azido alcohol 346 as a viscous oil: ¹ H NMR (300 MHz, CDCl ₃ ) δ6.90-6.86 (m , 1H), 4.80 (s, 2H), 4.32 (bt, 1H, J = 4.2 Hz), 4.22 (q, 2H, J = 7.2 Hz), 3.90-3.74 (overlapped m, 2H), 3.44 (s, 3H ), 2.90 (d, 1H, J = 6.9 Hz), 2.94-2.82 (m, 1H), 2.35-2.21 (m, 1H), 1.30 (t, 3H, J = 7.2 Hz).

<Example 127>

Compound 347: To a solution of ethyl ester 346 (420 mg, 1.55 mmol) in dry THF (8.0 mL), cooled to -78 ° C, was added dropwise using a syringe with DIBAL (5.1 mL of 1.0 M solution in toluene). This bright yellow reaction mixture was stirred at −78 ° C. for 1.25 h and then slowly lyophilized with slowly adding MeOH (1.2 mL). The volatiles were removed under reduced pressure and the residue was layered using EtOAc and cold HCl diluted aqueous solution. The organic layer was separated and the water layer was extracted again with EtOAc. The organic layers were collected, washed successively with a saturated aqueous solution of hydrogen carbonate and brine, and dried over MgSO ₄ . Concentration in vacuo followed by flash chromatography on silica gel (20% hexanes in EtOAc) yielded 127 mg (36%) of diol 347 as a colorless viscous oil: ¹ H NMR (300 MHz, CDCl ₃ ) δ5.83-5.82 ( m, 1H), 4.78 (s, 2H), 4.21 (bt, 1H, J = 4.4 Hz), 4.06 (bs, 2H), 3.85-3.65 (overlapped m, 2h), 3.43 (s, 3H), 3.18 ( d, 1H, J = 8.1 Hz), 2.51 (dd, 1H, J = 5.5, 17.7 Hz), 2.07-1.90 (m, 1H), 1.92 (bs, 1H).

<Example 128>

Methyl Ester 600: Frost., J. W., et al. "J. Org. Chem." 61: 3897 (1996) Prepared 51% total yield from D-(-)-quinic acid.

<Example 129>

Ketone 601: PCC (40.5 g, 187.9 mmol) in portions in a slurry of diol 600 (15.0 g, 46.9 mmol), pyridine (13.7 mL) and celite (PCC and eastern blood) in dichloromethane (200 mL) Dividedly added, the reaction mixture was stirred at rt for 21 h. Excess PCC was removed by adding excess 2-propanol. After stirring for an additional 30 minutes, the reaction mixture was diluted by addition of ethyl ether, filtered through a pad of celite, and then washed with ethyl acetate. The organic layer was then passed through a short silica gel column and eluted with ethyl acetate. After concentration under reduced pressure, a yellow solid was obtained, which was recrystallized from methanol / ethylacetate / hexane to give 10.9 g (74%) of ketone 601 as a crystalline powder: HRMS (FAB): acid side for C ₁₄ H ₂₂ O (MLi +) 325.1474, found 325.1471.

<Example 130>

Olefin 602: n-BuLi (26.0 mL, 1.61 M hexane solution) was added dropwise to a slurry of butyltriphenylphosphonium bromide (16.6 g, 41.6 mmol) in dry THF (150 mL) cooled to 0 ° C. After stirring at 0 ° C. for 20 minutes, the mixture was warmed to room temperature, stirred for 5 minutes and then cooled to 0 ° C. To this light orange solution was added a solution of compound 601 (6.0 g, 18.9 mmol) in dry THF using cannula. After the reaction mixture was warmed to room temperature, it was stirred for 10 minutes and gently refluxed for 2.5 hours. The reaction mixture was cooled, saturated aqueous NaHCO ₃ solution was added, and diluted by addition of ethyl acetate. The organic layer was separated, washed with brine and dried using MgSO ₄ . After concentration under reduced pressure, flash column chromatography on silica gel (30% hexane in ethyl acetate) gave 5.5 g (81%) of compound 602 as a sticky pale oil consisting of a 4: 1 mixture of olefin isomers.

<Example 131>

Triethylsilyl ether 603: To a solution of compound 602 (5.5 g, 15.37 mmol) in dichloromethane (125 mL) cooled to 0 ° C., after addition of 2,6-lutidine (3.6 mL), triethylsilyl tri Fluoromethanesulfonate (5.35 mL, 23.66 mmol) was added dropwise. The reaction mixture was slowly warmed to room temperature and then stirred for 15 hours. The volatiles were removed under reduced pressure and the crude residue was layered using diethyl ether and water. The organic layer was washed with dilute HCl, saturated aqueous NaHCO ₃ and brine, and then dried over MgSO ₄ . After concentration under reduced pressure, flash column chromatography on silica gel (20% ethyl acetate in hexane) gave 6.78 g (93%) of compound 603 as a mobile liquid.

<Example 132>

Butyl cyclohexyl ester 604: 10% Pd / C (5.0 g) was added to a degassing solution of olefin 603 (6.78 g, 14.34 mmol) in ethanol (140 mL). Thereafter, the reaction mixture was stirred for 22 hours at room temperature under hydrogen gas atmosphere (using 1 atm: ballon). The reaction mixture was filtered through a pad of celite and washed with hot methanol. After concentration under reduced pressure, flash column chromatography on silica gel (10% ethyl acetate in hexane) gave 5.44 g (80%) of the compound 604 as a colorless oil.

<Example 133>

Alcohol 605: Tetrabutylammonium fluoride solution (17.1 mL, 1M THF solution) was added dropwise to a solution of compound 604 (5.44 g, 11.46 mmol) in THF (50 mL) at room temperature. After 45 minutes, most of the THF was removed under reduced pressure and the crude reaction mixture was layered using dietelether and water. The organic layer was washed with saturated aqueous ammonium chloride solution, water and brine, and then dried over MgSO ₄ . After concentration under reduced pressure, flash column chromatography on silica gel (20% ethyl acetate in hexane) gave 3.18 g (77%) of the compound 605 as a colorless viscous oil.

<Example 134>

Olefin 606: Sulfuryl chloride (1.07 mL, 13.32 mmol) in a solution of alcohol 605 (3.18 g, 8.82 mmol) with dry dichloromethane (35 mL) and pyridine (39 mL), cooled to -78 ° C. ) Was added dropwise using a syringe. The reaction mixture was slowly warmed up to -40 [deg.] C. over 30 minutes and then held at -40--30 [deg.] C. for 30 minutes. After cooling the reaction back to -78 ° C, methanol (1.0 mL) was added dropwise. The reaction mixture was then warmed to room temperature over 3 hours and then diluted with diethyl ether. The organic layer was washed successively with water, diluted aqueous HCl solution, saturated aqueous NaHCO ₃ solution and brine, and then dried over MgSO ₄ . After concentration under reduced pressure, flash column chromatography on silica gel (25% ethyl acetate in hexane) gave 2.73 g (90%) of compound 606 as a colorless viscous oil consisting of -3% of isomeric cyclohexane carboxylate. .

<Example 135>

Diol 607: A solution of compound 606 (2.73 g, 7.97 mmol) in dichloromethane (58 mL) was treated with 40% aqueous trifluoroacetic acid solution (37 mL) and reacted at room temperature for 14 hours. The volatiles were removed under reduced pressure and the residue was separated using diethyl ether and water. The organic layer was washed carefully with saturated aqueous NaHCO ₃ , water and brine, and dried over MgSO ₄ . After concentration under reduced pressure, flash column chromatography on silica gel (10% hexane in ethyl acetate) gave compound 607, 1.36 g (75%) as a viscous oil.

<Example 136>

Mesylate 608 and 609: methanesulfonyl chloride (360 μL, 4.64 mmol) in a solution of diol 607 (1.06 g, 4.64 mmol) and triethylamine (1.31 mL) in dichloromethane (25 mL), cooled to −78 ° C. ) Was added dropwise. The reaction mixture was stirred at -78 ° C for 1 hour and then slowly warmed to 0 ° C over 1 hour. After another hour at this temperature, diethyl ether was added to terminate the reaction, washed with water, saturated aqueous NaHCO ₃ and brine, and dried over MgSO ₄ . After concentration under reduced pressure, flash column chromatography on silica gel (20% ethyl acetate in hexane) was carried out to obtain 1.23 g (87%) of Compounds 608 and 609, respectively, as a 6: 1 ratio difficult to separate mixture.

<Example 137>

Epoxide 610: To a solution of a 6: 1 mixture of compounds 608 and 609 (1.23 g, 4.02 mmol) in dry THF (20 mL), cooled to 0 ° C., DBU (601 μL, 4.02 mmol) was added. The ice bath was removed and the reaction stirred for 18 hours at room temperature. The reaction was terminated by addition of diethyl ether, washed with water and brine and dried over MgSO ₄ . After concentration under reduced pressure, flash column chromatography on silica gel (20% ethyl acetate in hexane) gave 490 mg (58%) of pure epoxide as a mobile liquid, methyl-3-butyl-benzoate 611, 100 mg (13%) was obtained as an oil. Assay: Acid for C ₁₂ H ₁₈ O ₃ : C, 68.55; H, 8.63. Found C, 68.29; H, 8.52.

<Embodiment 138>

Azido alcohol 612 and 613: of compound 610 (490 mg, 2.33 mmol), sodium azide (764 mg, 11.75 mmol) and ammonium chloride (281 mg, 5.25 mmol) in methanol / water (8: 1, 17.0 mL) The solution was gently refluxed for 15 hours. The cooled reaction mixture was concentrated under reduced pressure and separated using diethyl ether and water. The organic layer was washed with brine and then dried over MgSO ₄ . After concentration under reduced pressure, flash column chromatography on silica gel (20% ethyl acetate in hexane) was carried out to obtain 612, 613, and 562 mg (95%) of Compound 612 as a 2: 1 ratio difficult mixture, respectively.

<Example 139>

Azido mesylate 614 and 615: To a solution of a mixture of compounds 612 and 613 (642 mg, 2.54 mmol), triethylamine (1.8 mL) and DMAP catalytic amount in dichloromethane (15 mL), cooled to 0 ° C. Sulfonyl chloride (232 μL, 3.00 mmol) was added dropwise. The reaction was stirred at 0 ° C. for 15 hours and then at room temperature for 30 minutes. The reaction was terminated by addition of diethyl ether, washed with water, dilute HCl aqueous solution, saturated aqueous NaHCO ₃ and brine, and dried over MgSO ₄ . Concentration under reduced pressure gave a yellow liquid, which was eluted with 25% ethyl acetate in hexane through a short plug of silica gel to give 614 and 615, 840 mg (100%) as a difficult to separate mixture.

<Example 140>

Aziridine 616: To a solution of compounds 614 and 615 (840 mg, 2.53 mmol) in dry THF (20 mL), triphenylphosphine (750 mg) was added in portions at room temperature. After 2.5 hours, triethylamine (550 μL) and water (5.50 mL) were added and the reaction mixture was stirred for 16 hours at room temperature. After the volatiles were removed under reduced pressure, the residue was diluted with ethyl acetate. The organic layer was washed with water, saturated aqueous NaHCO ₃ and brine, and then dried over MgSO ₄ . After concentration under reduced pressure, flash column chromatography on silica gel (5% methanol in ethyl acetate) was performed to give 375 mg (%) of compound 616 as a viscous oil.

<Example 141>

Azido amine 617: A solution of compound 616 (354 mg, 1.70 mmol), sodium azide (555 mg, 8.54 mmol) and ammonium chloride (182 mg, 3.40 mmol) in dry DMF (8.0 mL) at 80 ° C. for 17 hours. Heated. After most of the DMF was removed under reduced pressure, the residue was separated using diethyl ether and water. The organic layer was washed with water and brine, and then dried over MgSO ₄ . Concentration under reduced pressure gave a yellow liquid material which was eluted with ethyl acetate through a short plug of silica gel to give 380 mg (86%) of compound 617 as a yellow liquid which was used immediately in the next reaction.

<Example 142>

N-acetyl azide 618: A solution of crude amine 617 (380 mg, 1.51 mmol) in dry pyridine (3.0 mL) and dichloromethane (7.0 mL) was dissolved at 0 ° C. in acetyl chloride (173 μL, 2.40 mmol). ). After 40 minutes had elapsed, the reaction was allowed to warm to room temperature and then stirred for 5 minutes. The volatiles were removed under reduced pressure and the residue was separated using diethyl ether and water. The organic layer was washed with dilute HCl aqueous solution, saturated aqueous NaHCO ₃ and brine, and then dried over MgSO ₄ . After concentration under reduced pressure, 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 compound 618, 304 mg (68%) as a colorless needle. Obtained as phase.

<Example 143>

N-acetyl amino ester 619: solution of compound 618 (292 mg, 0.99 mmol) and triphenyl phosphine (393 mg, 1.50 mmol) in water (1.8 mL) and THF (15 mL) was heated at 50 ° C for 10 h It was. The reaction was evaporated to dryness, loaded onto a silica gel column, eluted with 40% methanol in ethyl acetate to give 250 mg (93%) of compound 619 as a pale gummy solid.

<Example 144>

Amino acid 620: A solution of compound 619 (142 mg, 0.53 mmol) in THF (2.0 mL) was treated with an aqueous KOH solution (770 μL, 1.039 M solution) at room temperature for 3.5 hours, followed by Amberlite IR-120 (H ⁺ ) Acidified to pH = 3.0 using an ionic crosslinked resin. After filtering the reaction, the resin was washed with water and methanol. Concentration under reduced pressure afforded a pale solid, eluted with water and purified by C ₁₈ reversed phase column chromatography. Fractions containing the desired product were combined and evaporated to yield 87 mg (65%) of compound 620 as a colorless powder.

<Example 145>

Azido propyl ester 265: diisopropyl carbodiimide in a solution of 260 (55 mg, 0.18 mmol), 1-propanol (67 μL, 0.89 mmol) and DMAP catalytic amount in CH ₂ Cl ₂ (1.0 mL) ( 31 μL, 0.19 mmol) was added dropwise at room temperature. After stirring for 1 hour, the reaction mixture was concentrated and subjected to flash column chromatography on silica gel (50% hexane in ethyl acetate) to give 53 mg (85%) of compound 265 as a colorless crystalline solid.

<Example 146>

Amino propyl ester 266: triphenylphosphine (65 mg, 0.25 mmol) was added in one portion to a solution of compound 265 (53 mg, 0.15 mmol), using THF (4.0 mL) and water (300 μL) as solvent. The reaction mixture was then heated at 50 ° C. for 10 hours, cooled and concentrated under reduced pressure to give a pale white solid. This crude solid was purified by flash column chromatography on silica gel (50% methanol in ethyl acetate) to give a pale oil, which was evaporated from 3N HCl to give a solid compound, eluting with C _18. Purification by reverse phase column chromatography. Fractions containing the desired product were combined and lyophilized to give 41 mg (75%) of compound 266 as a colorless powder.

<Example 147>

Sulfide 700 was prepared from Schikimic acid according to known methods (Rovert H. Rich, Brian M. Laerence, Paul A. Bartlett, "J. Org. Chem.", 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., m-chloroperoxybenzoic acid (8.5 g, 57 in CH ₂ Cl ₂ (750 mL). -86%) dyddordf was added over 0.5 h. The reaction mixture was stirred at −40 ° C. for 1 hour and then at room temperature for 0.5 hour. The reaction mixture was evaporated to a solid to precipitate a solid and then diluted with hexanes. After the solid was removed by filtration, the filtrate was evaporated. The residue was dissolved in ethyl acetate, washed with saturated aqueous NaHCO ₃ solution, dried over MgSO ₄ , filtered and evaporated. The crude product was purified by flash column chromatography on silica gel (ethyl acetate / hexane) to give compound 701 (14.2 g, 86%, diastereomer mixture, ratio = 2.2: 1) as a colorless solid.

<Example 149>

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

<Example 150>

Triol 703: To a solution of vinyl chloride 702 (7.3 g, 20.9 mmol) in anhydrous methanol (80 mL) at room temperature was added sodium methoxide (0.3 mL, 25%, 1.3 mmol). After the reaction mixture was stirred for 1 hour at room temperature, the reaction was terminated using 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 / hexanes to give triol 703 (4.6 g, 99%) as a colorless solid. Assay: Acid side for C ₈ H ₁₁ ClO ₅ .1 / 14NaCl: 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) were stirred at rt for 1.5 h. The reaction mixture was evaporated and 2,2-dimethoxypropane (1.5 mL, 12.2 mmol) and acetone (30 ml) added fresh. The reaction was further stirred for 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 to give acetonide 704 (5.4 g, 99%) as an oil. Analysis Results: Acid for C ₁₁ H ₁₅ ClO ₅ · ¼H ₂ O: C, 49.45; H, 5.85; Cl, 13.27. Found: C, 49.67; H, 5. 82; Cl, 13.60.

<Example 152>

Mesylate 705: To a solution of acetonide 704 (2.63 g, 10.0 mmol) in CHCl (30 mL) at 0 ° C., triethylamine (2.23 mL, 16 mmol) was added and methanesulfonyl chloride (1.16 mL, 15 mmol) ) Was added. The reaction was stirred at 0 ° C. for 1 h and then evaporated. The residue was separated using ethyl acetate and water. The water layer was extracted with ethyl acetate. The combined organic layers were dried (MgSO ₄ ), filtered and evaporated. The crude product was filtered through a short silica gel plug. The filtrate was evaporated to give mesylate 705 (3.4 g, 100%) as an oil.

<Example 153>

3-pentyl ketal 706: a mixture of mesylate 705 (3.4 g, 10.0 mmol) and perchloro acid (30 mg, 70%, 0.2 mmol) in 3-pentanone (40 mL) was stirred at 45 ° C. for 2 hours. . The reaction mixture was evaporated and 3-pentanone (40 mL) was added fresh. The reaction was stirred for 0.5 h and then evaporated. The crude product was filtered through a short silica gel plug. The filtrate was evaporated to give 3-pentyl ketal 706 (3.7 g, 100%) as an oil.

<Example 154>

Mesylate alcohol 707: borane-methyl sulfide complex (0.7 mL, 10M, 7.0 mmol) in a solution of ketal 706 (1.68, 4.55 mmol) in CH ₂ Cl ₂ (20 mL) at −5 ° C. After addition, trimethylsilyl trifluoromethanesulfonate (0.82 mL, 4.6 mmol) was added. The resulting mixture was stirred at 0 ° C. for 1 h, then very slowly added saturated NaHCO ₃ aqueous solution (1 drop / 10 min., 1 mL for the first 5 drops) was added dropwise. The resulting mixture was filtered through a short plug of silica gel. After evaporation of the filtrate, the residue was purified by flash column chromatography on silica gel (ethylacetate / hexane) to give a mixture of regio-isomers of compounds 707 and 708 (1.2 g, 71%, 708/709). = 3/2) as an oil.

<Example 155>

Epoxide 709: A mixture of compounds 707 and 708 (1.95 g, 5.26 mmol) was mixed with methanol (15 mL) and KHCO ₃ (1.0 g, 10 mmol) in water (10 mL). The reaction mixture was stirred at 50 ° C. for 1 hour and then methanol was removed by evaporation. The remaining mixture was extracted with ethyl acetate. The extracts were combined, 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) in solvent with methanol (40 mL) and water (10 mL), sodium azide (0.65 g, 10 mmol) and ammonium chloride (0.40 g, 7.5 mmol) ) Was stirred at 65 ° C. for 18 h. The reaction mixture was diluted with water and then evaporated to remove methanol and then extracted with ethyl acetate. The organic extract was dried (MgSO ₄ ), then filtered and evaporated. The crude product was crystallized using hexane / ethyl acetate to give azide alcohol 710 (0.8 g, 73%) as a colorless solid. Assay: Acid side 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>

Azide mesylate 711: After addition of triethylamine (1.1 mL, 8.0 mmol) to a solution of azide alcohol 710 (1.0 g, 3.15 mmol) in CH ₂ Cl ₂ (20 mL) at 0 ° C., methanesulfonyl Chloride (0.5 mL, 6.5 mmol) was added. The resulting reaction mixture was stirred at 0 ° C. for 0.5 h and then at RT for a further 0.5 h. After adding 2 drops of water to the reaction mixture, it was diluted with hexane and filtered through a short plug of silica gel. The filtrate was evaporated to give azide mesylate 711 (1.27 g, 100%) as an oil.

<Example 158>

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

<Example 159>

Amino phenethyl ester 801: triphenylphosphine (55 mg, 0.21 mmol) was added all at once to a solution of compound 800 (60 mg, 0.14 mmol) with THF (2 mL) and water (252 μL) as solvent. Thereafter, the reaction was heated to 50 ° C. for 10 hours, cooled and evaporated. The residue was purified by silica gel chromatography (1 / 1-ethylacetate / methanol) to give 53 mg of an oily compound, which was dissolved in 0.1 N HCl (1 mL) and evaporated. The residue was dissolved in water and then lyophilized through a C ₁₈ reversed phase silica gel column to give compound 801 (41 mg, 69%) as a white solid.

<Example 160>

Azido Butyl Ester 802: Compound 260 (60 mg, 0.19 mmol), n-butanol (87 μL, 0.95 mmol) and DMAP (4 mg) with 1 / 2-CH ₂ Cl ₂ / THF (3 mL) as solvent To a solution of diisopropylcarbodiimide (33 μL, 0.21 mmol) was added at room temperature. After stirring for 2 hours, the solvent was evaporated and the residue was chromatographed on silica gel (1 / 1-hexane / ethylacetate) to give compound 802 (48 mg, 68%) as an oil.

<Example 161>

Amino Butyl Ester 803: Triphenylphosphine (51 mg, 0.19 mmol) was added all at once to a solution of Compound 802 (48 mg, 0.13 mmol) with THF (1.5 mL) and water (234 μL) as solvent. Thereafter, the reaction was heated to 50 ° C. for 10 hours, cooled and evaporated. The residue was dissolved in ethyl acetate, dried (Na ₂ SO ₄ ), filtered and evaporated. Purification of the residue by silica gel chromatography (1 / 1-ethylacetate / methanol) gave 38 mg of an oily compound, which was dissolved in 0.1N HCl (2 mL) and evaporated. The residue was dissolved in water and then lyophilized by passing through C ₁₈ reversed phase silica gel to give compound 803 (23 mg, 47%) as a white solid.

<Example 162>

1-phenyl-3-pentanol 804: To a solution of ethylmagnesium bromide (75 mmol) in ether (325 mL) at 0 ° C., hydrocinnamaldehyde (6.71 g, 50 mmol) in ether (50 mL) was added. The solution was stirred for 1 hour and then warmed to room temperature. The reaction solution was poured into ice-water (1000 mL) and the mixture was acidified to pH = 3 with concentrated aqueous HCl solution. Each layer was separated and the water layer was extracted with ether. The combined organic layers were washed with saturated aqueous NaHCO ₃ and brine, dried (MgSO ₄ ), filtered and evaporated. The crude product was distilled under high vacuum (bp 90-93 ° C.) to give compound 804 (5.3 g, 64%) as a colorless oil.

<Example 163>

1,5-diphenyl-3-pentanol 805: To a solution of phenethylmagnesium bromide (25 mL, 0.9 M THF solution) in ether (100 mL) at 0 ° C., hydrocinnamaldehyde (3.0 mL) in ether (30 mL) g, 22.5 mmol). After stirring this solution for 5 minutes, it heated up to room temperature and stirred for 1 hour. The reaction solution was poured into ice-water (200 mL) and the mixture was acidified to pH = 3 with concentrated aqueous HCl solution. Each layer was separated and the water layer was extracted with ether. The combined organic layers were washed with saturated aqueous NaHCO ₃ and brine, dried (MgSO ₄ ), filtered and evaporated. Flash column chromatography on silica gel (4 / 1-hexane / ethyl acetate) afforded a pale oily compound (3.74 g) which became solid upon cooling. By recrystallization using hexane, compound 805 (1.35 g, 25%) was obtained as a white needle phase.

<Example 164>

1,3-diphenyl-2-propanol 806: To a solution of 1,3-diphenylacetone (17.08 g, 81.2 mmol) in ethanol (100 mL) at 0 ° C., NaBH ₄ (3.07 g, 81.2 mmol) was added. And the mixture was stirred for 2 hours. The reaction was diluted with water, and the aqueous layer was extracted several times with ethyl acetate. The combined organic extracts were all washed with saturated aqueous NaHCO ₃ and brine, dried (MgSO ₄ ), filtered and evaporated to yield 806 (17 g, 99%) as a yellow oil.

<Example 165>

Ether 807: BF ₃ · OEt ₂ (85 μL, 0.69 mmol) was added to a solution of compound 183 (200 mg, 0.46 mmol) and 804 (1 mL), and the solution was heated to 75-80 ° C. for 1.25 h. . After cooling to room temperature, the reaction was diluted with pyridine (5 mL) and cooled to 0 ° C and reacted with acetic anhydride (1.25 mL) and DMAP (50 mg). The reaction mixture was stirred at 0 ° C. for 15 minutes and then at room temperature for 14 hours. The solvent was evaporated and the residue was separated using ethyl acetate and 1N HCl, and the organic layer was washed again with 1N HCl. The washed water layers were collected, extracted with ethyl acetate, and the organic extracts were collected, washed with saturated aqueous NaHCO ₃ and brine, dried (MgSO ₄ ), filtered and evaporated. The residue was chromatographed on silica gel (1 / 1-hexane / ethyl acetate) to give compound 807 (116 mg, 63%) as a mixture of diastereomers, which was then chromatographed (2 / 1-hexane / ethyl Acetate). The fractions containing the eluted diastereomer were first collected to give compound 807a (44 mg), which was recrystallized (hexane / ethyl acetate) to give a solid: mp 131-133 ° C. The eluted diastereomer was later obtained as a solid through recrystallization (hexane / ethyl acetate) from which compound 807b (41 mg) was produced as a needle phase: mp 111-112 ° C.

<Example 166>

Azidoesters 807a and 807b were reacted with triphenylphosphine in the same manner as described in Example 93 to obtain amino esters 808a and 808b, which were treated with aqueous potassium hydroxide solution as described in Example 94 above. To amino acids 809a and 809b.

<Example 167>

Ether 810: A solution of compound 183 (200 mg, 0.46 mmol) and 805 (750 mg, 3.1 mmol, mp 43-45 ° C.) was produced by gentle heating. To the resulting solution was added BF ₃ · OEt ₂ (85 μL, 0.69 mmol) and the solution was heated to 70-75 ° C. for 1.25 h. After cooling to room temperature, the reaction was diluted with pyridine (2 mL) and cooled to 0 ° C., reacted with acetic anhydride (660 μL, 7.0 mmol) and a catalytic amount of DMAP. The reaction mixture was stirred at 0 ° C. for several minutes and then at room temperature for 16 hours. The solvent was evaporated and the residue was separated using ethyl acetate and 1N HCl, and the organic layer was washed again with 1N HCl. The washed water layers were collected, extracted with ethyl acetate, and the organic extracts were collected, washed with saturated aqueous NaHCO ₃ and 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 compound 810 (63 mg, 28%) as a needle phase. : mp 139-140 ° C.

<Example 168>

Azido ester 810 was reacted with triphenylphosphine in the same manner as in Example 93 to obtain amino ester 811, which was treated with aqueous potassium hydroxide solution as described in Example 94 to give amino acid 812. Got it.

<Example 169>

Ether 813: To a solution of compound 183 (100 mg, 0.23 mmol) and 806 (1 mL), BF ₃ · OEt ₂ (42 μL, 0.35 mmol) was added and the solution was heated to 70-75 ° C. for 1.25 h. . After cooling to room temperature, the reaction was diluted with pyridine (5 mL) and cooled to 0 ° C., reacted with acetic anhydride (680 μL, 7.2 mmol) and a catalytic amount of DMAP. The reaction mixture was stirred at 0 ° C. for several minutes and then at room temperature for 15 hours. The solvent was evaporated and the residue was separated using ethyl acetate and 1N HCl, and the organic layer was washed again with 1N HCl. The washed water layers were collected, extracted with ethyl acetate, and the organic extracts were collected, washed with saturated aqueous NaHCO ₃ and brine, dried (MgSO ₄ ), filtered and evaporated. The residue was purified by chromatography (1 / 1-hexane / ethyl acetate) to give compound 813 (57 mg, 55%) as a pale yellow solid: mp 132-133 ° C. (crystallized from hexane / ethyl acetate as needle). ).

<Example 170>

Azido ester 813 was reacted with triphenylphosphine in the same manner as in Example 93 to obtain amino ester 817, which was treated with aqueous potassium hydroxide solution as described in Example 94 to amino acid 815. Got it.

<Example 171>

N-BOc aziridine 817: To a solution of CH ₂ Cl ₂ (10 mL) of compound 816 (700 mg, 3.1 mmol, methyl ester prepared from quinic acid by the same method as described for derivatives 170), CH ₂ Cl ₂ Di- (t-butyl) dicarbonate (1.0 g, 4.6 mmol) and DMAP catalyst amount (10 mol%) in (5 mL) were added. After stirring at room temperature for 45 minutes, the solvent was evaporated and the residue was purified by silica gel chromatography (3 / 1-hexane / ethyl acetate) to give compound 817 (880 mg, 87%) as an oil.

<Example 172>

Alcohol 818: Ammonium formate (1.59 g, 25.2 mmol) was added to a solution of compound 817 (826 mg, 2.52 mmol) in DMF (20 mL) and the mixture was heated at 130 ° C for 1 h. After the addition of ammonium formate (1.59 g, 25.2 mmol), the reaction mixture was heated for 1.5 h and evaporated. The residue was separated using ethyl acetate and saturated aqueous NaHCO ₃ solution. The organic layer was washed with brine, dried (MgSO ₄ ), filtered and evaporated. The residue was purified by silica gel chromatography (1 / 2-hexane / ethyl acetate) to give compound 818 (556 mg, 94%) as a pale yellow solid.

<Example 173>

Acetate 819: To a solution of compound 818 (500 mg, 1.45 mmol) in pyridine (10 mL) was added DMAP (20 mg, 0.16 mmol) and acetic anhydride (216 μL, 2.3 mmol). The solution was stirred at room temperature for 1 hour and then evaporated. The residue was purified by silica gel chromatography (1 / 1-hexane / ethyl acetate) to give compound 819 (557 mg, 94%) as a solid.

<Example 174>

N-trityl aziridine 820: A solution of compound 819 (459 mg, 1.18 mmol) with 1.24M HCl in ethylacetate (20 mL) as solvent was stirred at room temperature for 2.5 hours. The solvent was evaporated to give a white solid, which was dried under high vacuum overnight. Trityl chloride (346 mg, 1.24 mmol) and Et ₃ N (354 μL, 2.54 mmol) were added to a solution of the solid (315 mg) with CH ₂ Cl ₂ (10 mL) as solvent. After the solution was stirred at this temperature for 1.75 hours, Et ₃ N (354 μL, 2.54 mmol) and methane sulfonyl chloride (105 μL, 1.36 mmol) were added. The reaction mixture was stirred at 0 ° C. for 1.5 hours and at room temperature for 5 hours. After evaporation of the solvent the residue was partitioned using ether and water. After the organic layer was washed with water, the aqueous layers were collected and extracted again with ether. After all the organic extracts were collected, washed with brine, dried (MgSO ₄ ) and then filtered and evaporated. The residue was purified by silica gel chromatography (CH ₂ Cl ₂ ) to give compound 820 (440 mg, 83%) as a white foam.

<Example 175>

Pentyl ether 821: BF ₃ · OEt ₂ (39 μL, 0.21 mmol) was added to a solution of compound 820 (100 g, 0.21 mmol) in 3-pentanol (2 mL), and the solution was added at 75 to 80 ° C. for 1.5 hours. Heated. After evaporation of the solvent, the residue was dissolved in pyridine (2 mL) and then treated with acetic anhydride (100 μL, 1.05 mmol) and DMAP. The reaction was stirred at room temperature for 14 hours, evaporated and the residue was partitioned between ethyl acetate and 1M HCl aqueous solution. The water layer was extracted with ethyl acetate, and the organic layers were collected, washed with saturated aqueous NaHCO ₃ and brine, dried (MgSO ₄ ), filtered and evaporated. The residue was purified by chromatography on silica gel (1 / 1-ethyl acetate / CH ₂ Cl ₂ ) to give compound 821 (46 mg, 62%) as a solid.

<Example 176>

Hydroxy acid 822: To a solution of compound 821 (42 mg, 0.12 mmol) in THF (2 mL) was added 1N KOH (260 μL, 0.27 mmol) and the mixture was stirred at rt for 5.5 h. The solution was acidified with Amberlite IR120 ion exchange resin (pH 3) and then the resin was filtered and washed with THF. The residue obtained by evaporating the solvent was dissolved in water and then chromatographed, eluting with water on C ₁₈ reversed phase silica gel. Water was evaporated and the residue was evaporated from methanol to give compound 822 (29 mg, 85%) as a solid.

<Example 177>

Methyl ether 823: To a solution of compound 816 (200 mg, 0.88 mmol) in methanol (5 mL) was added BF ₃ .OEt ₂ (120 μL, 0.97 mmol). After evaporating the solution by refluxing for 2 hours, the residue was dissolved in pyridine (4 mL) and treated with acetic anhydride (415 μL, 4.4 mmol). After stirring for 1 hour at room temperature, the solvent was evaporated and the residue was layered using ethyl acetate and 5% citric acid. The organic layer was washed with saturated aqueous NaHCO ₃ and brine, dried (MgSO ₄ ) and evaporated by filtration. The residue was purified by silica gel chromatography (10% methanol in CH ₂ Cl ₂ ) to give compound 823 (76 mg, 29%) as a white solid.

<Example 178>

Hydroxy acid 824: A solution of compound 823 (33 mg, 0.11 mmol) with 2.5M HCl as solvent in ethyl acetate (2 mL) was stirred at room temperature for 2.5 hours and then evaporated. The residue was dissolved in THF (2 mL) and treated with 1N KOH (154 μL, 0.16 mmol) and water (300 μL). The reaction was stirred at rt for 6 h and acidified with Dowex 50WX8 ion exchange resin. The resin was filtered and the residue obtained by evaporating the filtrate was dissolved in water and then chromatographed on C ₁₈ reversed phase silica gel. After lyophilization Compound 824 (24 mg, 95%) was purified as a white solid.

<Example 179>

Methyl ether 825: To a solution of compound 820 (80 mg, 0.17 mmol) in methanol (2 mL) was added BF ₃ · OEt ₂ (32 μL, 0.26 mmol). The solution was refluxed for 2 hours and evaporated before the residue was dissolved in pyridine (2 mL). To the solution was added acetic anhydride (80 μL, 0.85 mmol) and catalytic amount of DMAP. After stirring for 14 h, the solvent was evaporated and the residue was chromatographed (ethyl acetate) on silica gel to give compound 825 (46 mg, 90%) as a white solid.

<Example 180>

Hydroxy acid 826: To a solution of compound 825 (46 mg, 0.15 mmol) in THF (2 mL) was added 1N KOH (433 μL, 0.45 mmol) and the mixture was stirred at rt for 5 h. The solution was acidified with Dowex 50WX8 ion exchange resin, and the resin was filtered off and washed with methanol. The residue obtained by evaporating the solvent was dissolved in water and eluted with water through a C ₁₈ reversed phase silica column. The solvent was evaporated to purify compound 826 (33 mg, 96%) as a white solid.

<Example 181>

Methyl ether 827: To a solution of compound 816 (612 mg, 0.27 mmol) in methanol (25 mL) was added BF ₃ · OEt ₂ (370 μL, 3.0 mmol). After evaporation of this solution by reflux for 2 hours, the residue was dissolved in CH ₂ Cl ₂ (5 mL) to di-tert-butyldicarbonate (880 mg, 4.1 mmol) in CH ₂ Cl ₂ (3 mL). And EtN (570 μL, 4.1 mmol). After stirring for 5 hours at room temperature, the solvent was evaporated and the residue was separated using ethyl acetate and water. The organic layer was washed with water and brine, dried (MgSO ₄ ), filtered and evaporated. The residue was purified by silica gel chromatography (2 / 1-hexane / ethyl acetate) to give compound 827 (630 mg, 65%) as an oil.

<Example 182>

N-trityl aziridine 828: A solution of compound 827 (574 mg, 1.6 mmol) with 2.5 M HCl in ethyl acetate (20 mL) as a solvent was stirred at room temperature for 5 hours. The solvent was evaporated to give a white solid (400 mg). Trityl chloride (490 mg, 1.6 mmol) and Et ₃ N (278 μL, 3.6 mmol) were added to the solid suspension with CH ₂ Cl ₂ (5 mL) as solvent at 0 ° C. The solution was stirred at this temperature for 2 hours and Et ₃ N (278 μL, 3.6 mmol) and methane sulfonyl chloride (136 μL, 1.76 mmol) were added. The reaction mixture was stirred at 0 ° C. for 1 hour, then warmed to room temperature and stirred for 4 hours. After evaporation of the solvent the residue was partitioned using ether and water. After the organic layer was washed with water, the aqueous layers were collected and extracted again with ether. After all organic extracts were collected, washed with brine, dried (MgSO ₄ ), and then filtered and evaporated. The residue was purified by silica gel chromatography (CH ₂ Cl ₂ ) to give compound 828 (170 mg, 25%) as a white foam.

<Example 183>

Bis-methyl ether 829: BF ₃ .OEt ₂ (39 μL, 0.21 mmol) was added to a solution of compound 828 (60 mg, 0.14 mmol) in methanol (2 mL), which was refluxed for 1 hour and evaporated. The residue was then dissolved in pyridine (mL) and treated with acetic anhydride (66 μL, 0.70 mmol). The reaction was stirred at rt for 18 h, evaporated and the residue was partitioned between ethyl acetate and 1M HCl aqueous solution. The combined organic layers were washed with saturated aqueous NaHCO ₃ and brine, dried (MgSO ₄ ), filtered and evaporated. The residue was purified by silica gel chromatography (10% methanol in CH ₂ Cl ₂ ) to give compound 829 (13 mg, 34%) as a white solid.

<Example 184>

Carboxylic acid 830: 1N KOH (69 μL, 0.072 mmol) was added to a solution of compound 829 (13 mg, 0.048 mmol) in THF (1 mL) and the mixture was stirred at rt for 48 h. After acidifying this solution with Dowex 50WX8 ion exchange resin, the resin was filtered off and washed with methanol. The residue obtained by evaporation of the solvent was dissolved in water and then passed through a C ₁₈ reversed phase silica column to give 830 (8 mg, 68%) as a white solid after lyophilization.

<Example 185>

Lactone 900: quinic acid (20 kg, 104 mol; [α] _D -43.7 ° (c = 1.12, water); Mw) with acetone (80 kg) as solvent Index 11th ed, 8071: [α] _D -42 ° to -44 ° (water)), 2,2-dimethoxypropane (38.0 kg, 365 mol) and p-toluenesulfonic acid monohydrate (0.200 kg, 1.05 mol mg) were heated to reflux for 2 hours. 21% sodium ethoxide (0.340 kg, 1.05 mol) in ethanol was added to terminate the reaction and most of the solvent was distilled off under reduced pressure. The residue was partitioned using ethyl acetate (108 kg) and water (30 kg). The water layer was back-extracted with ethyl acetate (13 kg) and the organic layers were collected and washed with 5% aqueous sodium hydrogen carbonate solution (14 kg). Most of the ethyl acetate was distilled under reduced pressure to give a pale yellow solid residue of compound 900, which was used for the next step.

<Example 186>

Hydroxy ester 901: A solution of crude lactone 900 (produced from 104 moles of (-)-quinic acid) in anhydrous ethanol (70 kg) was treated with 20% sodium ethoxide (0.340 kg, 1.05 mol) in ethanol. After 2 hours at room temperature, acetic acid (0.072 kg, 1.2 mol) was added and the solvent was distilled off under reduced pressure. Ethyl acetate (36 kg) was added and distillation continued until nearly dry. A tan solid residue consisting of about 5: 1 mixture of 901: 900 was refluxed, dissolved in ethyl acetate (9 kg) and hexane (9 kg) added. Upon cooling, a white crystalline solid was produced, which was separated by filtration to give an about 6.5: 1 mixture (19.0 kg, 70% yield) of compound 901: 900.

<Example 187>

Mesyl ester 902: A solution of about 6.5: 1 mixture (18.7 kg, ca. 72 mol) of hydroxy ester 901 and lactone 900 in dichloromethane (77 kg) was cooled to 0-10 ° C. and methanesulfonyl chloride (8.23 kg, 71.8 mol), and triethylamine (10.1 kg, 100 mol) was added slowly. Additional portion of methanesulfonyl chloride (0.84 kg, 7.3 mol) was added. After 1 hour, water (10 kg) and 3% hydrochloric acid (11 kg) were added. After separating each layer, the organic layer was washed with water (9 kg) and distilled under reduced pressure to obtain a semi-solid containing about 6.5: 1 mixture of mesyl ester 902 and mesylactone 903. This residue was dissolved in ethyl acetate (11 kg) and cooled to -10--20 ° C for 2 hours. Mesyl lactone 903 was crystallized, filtered off and washed with cold ethyl acetate (11 kg). The filtrate was concentrated to give mesyl ester 902 (20.5 kg, yield 84.3%) as orange resin.

<Example 188>

Mesyl acetonide 904: A solution of mesyl ester 902 (10.3 kg, 30.4 mol) and pyridine (10.4 kg, 183 mol) in dichloromethane (63 kg) as a solvent is cooled to -20 ° C to -30 ° C, and sulfuryl Chloride (6.22 kg, 46 mol) was treated in portions. After the exothermic reaction had subsided, ethanol (2.4 kg) was added to the resulting slurry to terminate the reaction, and the temperature was raised to 0 ° C to 16% sulfuric acid (35 kg), water (15 kg) and 5% aqueous sodium hydrogencarbonate solution 1 kg). The organic layer containing about 4: 1: 1 mixture of compound 904: 905: 906 was concentrated under reduced pressure and ethyl acetate (14 kg) was added. Ethylallylic mesylate 905 was treated with pyrrolidine (2.27 kg, 31.9 mol) and tetrakis (triphenylphosphine) palladium (0) (0.0704 kg, 0.061 mol) for 5 hours at room temperature, followed by 16% sulfuric acid ( 48 kg) to remove it selectively. The organic layer was filtered through a pad of silica gel eluting with ethyl acetate (42 kg). The filtrate was concentrated under reduced pressure to give a dark orange oil consisting of about 4: 1 mixture of compound 904: 906. This residue was dissolved under reflux in ethyl acetate (5.3 kg) and hexane (5.3 kg) was added. Upon cooling, mesyl acetonide 904 crystallized, filtered off and washed with 14% ethyl acetate (2.1 kg) in hexane. After drying under reduced pressure, compound 904 (4.28 kg, yield 43.4%) was obtained as a pale yellow needle: mp 102-103 ° C.

<Example 189>

Pentyl ketal 907: A solution of acetonide 904 (8.9 kg, 27.8 mol), 3-pentanone (24 kg, 279 mol) and 70% perchloroic acid (0.056 kg, 0.39 mol) was stirred for 18 hours. The volatiles were distilled under reduced pressure at room temperature, and 3-pentanone (30 kg, 348 mol) was slowly added while performing distillation. The reaction mixture was filtered, toluene (18 kg) was added, and the resulting pig solution was washed with 6% aqueous sodium bicarbonate solution (19 kg), water (18 kg) and brine (24 kg). The organic layer was concentrated under reduced pressure, and toluene (28 kg) was slowly added while performing a distillation process. Upon further distillation, an orange oil consisting of pentyl ketal 907 (9.7 kg, 100% yield) and toluene (ca. 2 kg) was obtained.

<Example 190>

Pentyl ether 908: A solution of ketal 907 (8.6 kg, 25 mol) in dichloromethane (90 kg) was cooled to -30 ° C to -20 ° C, borane-methyl sulfide complex (2.1 kg, 27.5 mol) and trimethylsilyltri Treated with fluoromethanesulfonate (7.2 kg, 32.5 mol). After 1 hour, 10% aqueous sodium hydrogen carbonate solution (40 kg) was added slowly. The mixture was warmed to room temperature and stirred for 12 hours. The organic layer was filtered and concentrated under reduced pressure to give an about 8: 1 mixture (7.8 kg, 90% yield) of compound 908: 909 as a gray waxy solid.

<Example 191>

Epoxide 910: Treatment of about 8: 1 mixture (7.8 kg, 22.3 mol) of isomeric pentyl ester 908: 909 in ethanol (26 kg) with an aqueous solution of potassium hydrogen carbonate (3.52 kg, 35 mol) in water (22 kg) It was. After heating at 55-65 ° C. for 2 hours, the solution was cooled and extracted twice with hexane (31 kg, then 22 kg). Unreacted compound 909 remained in the ethanol water layer. The hexane layers were combined, filtered and concentrated under reduced pressure to give epoxide 910 (3.8 kg, 60% yield) as a white, white fleece: mp 54-56 ° C.

<Example 192>

Hydroxy azide 911: epoxide 910 (548 g, 2.0 mol), sodium azide (156 g, 2.4 mol) and ammonium chloride (128.4 g, in solvent with water (0.265 L) and ethanol (1.065 L) 2.4 mol) was heated at 70-75 ° C for 8 hours. An aqueous sodium hydrogen carbonate solution (0.42 L, 8% solution) was added and ethanol was distilled off under reduced pressure. The aqueous residue was extracted with ethyl acetate (1 L) and the extract was washed with water (0.5 L). The washed water layer was back extracted with ethyl acetate (0.5 L). Gather all organic extracts, wash with brine (0.5 L), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to give an approximate 10: 1 mixture of isomeric hydroxy azide 911: 912 (608 g, 102% yield) dark brown Obtained as an oil.

<Example 193>

Aziridine 913: Approximately 10: 1 mixture of hydroxy azide 911: 912 (608 g, 2.0 mol) was co-evaporated three times under reduced pressure from anhydrous acetonitrile (3 x 0.3 L) followed by anhydrous acetonitrile (1 L )). A solution of anhydrous triphenylphosphine (483 g, 1.84 mol) with anhydrous tetrahydrofuran (0.1 L) and anhydrous acetonitrile (0.92 L) as a solvent was added dropwise over 2 hours. The mixture was heated to reflux for 6 hours and concentrated under reduced pressure to yield a golden paste consisting of aziridine 913, triphenylphosphine oxide and traces of triphenylphosphine. This paste was triturated using diethyl ether (0.35 L). Most of the insoluble triphenylphosphine oxide was removed by filtration and washed with diethyl ether (1.5 L). The filtrate was concentrated under reduced pressure to give a dark brown oil, which was dissolved in 20% aqueous methanol solution and extracted three times with hexane (3 x 1 L) to remove triphenylphosphine. The hexane extract was back-extracted with 20% aqueous methanol solution (0.5 L), and then all the aqueous methanol layers were collected and concentrated under reduced pressure. The residue was co-evaporated twice (2 x 0.5 L) from dry acetonitrile to give aziridine 913 (490 g, 96.8% yield) and triphenylphosphine oxide (about 108 g) as a dark brown oil. It was used directly in the next step.

<Example 194>

Acetamido azide 915: aziridine 913 (490 g, 1.93 mol) in dimethylchloromethane (1.3 L), triphenylphosphine oxide (ca. 108 g), sodium azide (151 g, 2.33 mol) ) And ammonium chloride (125 g, 2.33 mol) were heated at 80-85 ° C for 5 hours. Sodium bicarbonate (32.8 g, 0.39 mol) and water (0.66 L) were obtained. Amino azide 914 was extracted six times with hexane (6 × 1 L) and separated from the reaction mixture. The hexane extracts were collected, concentrated under reduced pressure to about 4.5 L of total volume, and dichloromethane (1.04 L) was added. An aqueous solution of sodium hydrogen carbonate (4.2 L, 8% aqueous solution, 3.88 mol) was added and acetic anhydride (198 g, 1.94 mol) was added. After stirring for 1 hour at room temperature, the water layer was removed. The organic layer was concentrated under reduced pressure to about 1.74 kg in total weight, and dissolved under reflux with ethyl acetate (0.209 L). Upon cooling, acetamido azide 915 crystallized and was isolated by filtration. Washed with 15% ethyl acetate (1 L) in cold hexane and dried under reduced pressure at room temperature to give pure Compound 915 as off-white crystals (361 g, 55% yield): mp 126-132 ° C.

<Example 195>

Acetamido amine 916: A mixture of Azide 915 (549 g, 1.62 mol) and Lindlar catalyst (50 g) in anhydrous ethanol (3.25 L) was stirred under hydrogen atmosphere (1 atm) for 18 hours. Filtration through celite and concentration of the filtrate under reduced pressure afforded compound 916 as a foam, which solidified on standing (496 g, 98% yield).

<Example 196>

Phosphate Salt of Compound 916: A solution of amine 916 (5.02 g, 16.1 mmol) in acetone (75 mL) was refluxed and treated with 85% phosphoric acid (1.85 g, 16.1 mmol) in anhydrous ethanol (25 mL). Crystallization immediately started, cooled to 0 ° C. for 12 hours, and then collected by filtration to collect precipitates as colorless long needles that gave compound 916.H ₃ PO ₄ (4.94 g, 75% yield; [α] _D -39.9 ° ( c = 1, water)): mp 203-204 캜.

<Example 197>

Hydrochloride of Compound 916: A solution of acetamido amine 916 (2.8 g, 8.96 mmol) in anhydrous ethanol (9 mL) was treated with 2.08 M hydrogen chloride (8.6 mL, 17.9 mmol) in ethanol. Most of the ethanol was distilled off under reduced pressure, and the oily residue was stirred with ethyl acetate (20 mL) until a solid formed. Hexane (20 mL) was added slowly to the stirring mixture. After 1 hour at room temperature, the solids were collected by filtration, washed with diethyl ether and dried under reduced pressure. Compound 916.HCl was obtained as an off-white solid (2.54 g, 81% yield; [α] _D -43 ° (c = 0.4, water)): mp 206 ° C.

<Example 198>

Aziridine 712: Triphenylphosphine (1.0 g, 3.8 mmol) was added in four portions to a solution of azide mesylate 711 (1.27 g, 3.15 mmol) using anhydrous THF (10 mL) as a solvent at room temperature. . The reaction was stirred at rt for 3.5 h before it was 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 and then further stirred at 45 ° C. for 3 hours. The reaction mixture was evaporated and the residue was layered using ethyl acetate and water. The water layer was extracted with ethyl acetate. The organic layers were collected, washed with brine, dried (MgSO ₄ ), filtered and evaporated. The residue was subjected to chromatographic purification and treated with ethyl acetate / hexanes (until most of the triphenylphosphine oxide was removed) to give the desired aziridine 712 (0.56 g, 65%, ca. 15% triphenylphosphate). Fin oxides are included).

<Example 199>

N-acetyl azide 713: A mixture of aziridine 712 (0.56 g, 17 mmol), sodium azide (0.65 g, 0.0 mmol) and ammonium chloride (0.4 g, 7.5 mmol) in DMF (5.0 mL) at 65 ° C. Stir for 18 hours. The reaction mixture was diluted with hexane (20 mL) and filtered through a short plug of silica gel (eluted with ethyl acetate / hexanes). 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 rt for 14 h before evaporating. The residue was dissolved in ethyl acetate and washed with saturated aqueous NaHCO ₃ solution and brine. The organic layer was dried (MgSO ₄ ) and filtered and evaporated. The residue was chromatographed and recrystallized in ethylacetate / hexane solvent to give N-acetyl azide 713 (20 mg, 3.3%) as a solid: ¹ H NMR (CDCl ₃ ) δ 5.68 (d, 1H, J = 7.9 Hz), 4.31 (d, 1H, J = 5.2 Hz), 4.09 (m, 1H), 3.94 (m, 1H), 3.83 (s, 3H), 3.65 (m, 1H), 2.83 (ddd, 1H, J = 1.5, 7.3, 17.7 Hz), 2.06 (s, 3H), 1.62 (m, 4H), 0.96 (m, 6H).

It is made clear that all the above-mentioned documents and patent documents are referred to in the text together with the publication of the citations. In particular, the cited portions of the documents or the cited pages are clearly indicated. Thus far, the present invention has been described in detail so as to enable those skilled in the art to make and use the claimed subject matter. Certain modifications to the methods and compositions of the appended claims are, of course, within the scope and spirit of the invention.

Claims (10)

A compound of formula (I) or (II), a pharmaceutically acceptable salt or derivative thereof; Compositions containing salts, solvates, isolated enantiomers and purified diastereomers thereof: [Formula I] [Formula II] In the formula, 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-; E ₁ is — (CR ₁ R ₁ ) m ₁ W ₁ ; G ₁ is N ₃ , —CN, —OH, —OR _6a , —NO ₂ , or — (CR ₁ R ₁ ) m ₁ W ₂ ; T _{1 together} with —NR ₁ W ₃ , H, —R ₃ , —R ₅ , heterocycle, or U ₁ or G ₁ forms a functional group having the structure U ₁ is H, R ₃ or -X ₁ W ₆ ; J ₁ and J _1a are each R ₁ , Br, Cl, F, I, CN, NO ₂ or N ₃ ; J ₂ and J _2a are each H or R ₁ ; R ₁ is independently H or alkyl of 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 F, Cl, Br, I, -CN, N ₃ , -NO ₂ , -OR _6a , -OR ₁ , -N (R ₁ ) ₂ , -N (R ₁ ) (R _6b ), -N (R _6b ) ₂ , -SR ₁ , -SR _6a , -S (O) R ₁ , -S (O) ₂ R ₁ , -S (O) OR ₁ , -S (O) OR _6a ,- S (O) ₂ OR ₁ , -S (O) ₂ OR _6a , -C (O) OR ₁ , -C (O) R _6c , -C (O) OR _6a , -OC (O) R ₁ ,- N (R ₁ ) (C (O) R ₁ ), -N (R _6b ) (C (O) R ₁ ), -N (R ₁ ) (C (O) OR ₁ ), -N (R _6b ) (C (O) OR ₁ ), -C (O) N (R ₁ ) ₂ , -C (O) N (R _6b ) (R ₁ ), -C (O) N (R _6b ) ₂ , -C (NR ₁ ) (N (R ₁ ) ₂ ), -C (N (R _6b ) (N (R ₁ ) ₂ ), -C (N (R ₁ ) (N (R ₁ ) (R _6b )), -C (N (R _6b ) (N (R ₁ ) (R _6b )), -C (N (R ₁ ) (N (R _6b ) ₂ ), -C (N (R _6b ) (N (R _6b) ) ₂ ), -N (R ₁ ) C (N (R ₁ ) (N (R ₁ ) ₂ ), -N (R ₁ ) C (N (R ₁ )) (N (R ₁ ) (R _6b ) ), -N (R ₁ ) C (N (R _6b )) (N (R ₁ ) ₂ ), -N (R _6b ) C (N (R ₁ )) (N (R ₁ ) ₂ ), -N (R _6b ) C (N (R _6b )) (N (R ₁ ) ₂ ), -N (R _6b ) C (N (R ₁ )) (N (R ₁ ) (R _6b )), -N ( R ₁ ) C (N (R _6b )) (N (R ₁ ) (R _6b )), -N (R ₁ ) C (N (R ₁ )) (N (R _6b ) ₂ ), -N (R _6b ) C (N (R _6b )) (N (R ₁ ) (R _6b )), -N (R _6b ) C (N (R ₁ )) (N (R _6b ) ₂ ), -N (R ₁ ) C (N (R _6b )) (N (R _6b ) ₂ ), -N (R _6b ) C (N (R _6b )) (N (R _6b ) ₂ ), = O, = S, N (R ₁ ), = N (R _6b Or W ₅ ; R ₄ is independently 1-12 alkyl of carbon atoms, alkenyl of 2-12 carbon atoms, or alkynyl 2-12 carbon atoms; R ₅ is independently R ₄ where each R ₄ is substituted with 0-3 R ₃ groups; R _5a is alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, or alkynylene of 2 to 12 carbon atoms, and alkylene, alkenylene or alkynylene is substituted with 0 to 3 R ₃ groups ; R _6a is independently H or an ether- or ester-forming group; R _6b is independently H, a residue or amino protecting group of a carboxyl-containing compound; R _6c is independently H, or a residue of an amino-containing compound; W ₁ is an R _6c amide group of an acidic hydrogen, a protected acid group, or a group containing acidic hydrogen; W ₂ is a basic hetero atom or a protected basic hetero atom or a basic hetero atom R _6b amide group; W ₃ is W ₄ or W ₅ ; W ₄ is R ₅ or —C (O) R ₅ , —C (O) W ₅ , —SO ₂ R ₅ , or —SO ₂ W ₅ ; W ₅ is carbocycle or heterocycle where W ₅ is independently substituted with 0 to 3 R ₂ groups; W ₆ is -R ₅ , -W ₅ , R _5a W ₅ , -C (O) OR _6a , -C (O) R _6c , -C (O) N (R _6b ) ₂ , -C (NR _6b ) (NR _6b ) ₂ ), -C (NR _6b ) (N (H) (R _6b )), -C (N (H) (N (R _6b ) ₂ ), -C (S) N (R _6b ) ₂ , or -C (0) R ₂ ; X ₁ is a bond, -O-, -N (H)-, -N (W ₆ )-, -N (OH)-, -N (OW ₆ )-, -N (NH ₂ )-, -N ( N (H) (W ₆ ))-, -N (N (W ₆ ) ₂ )-, -N (H) N (W ₆ )-, -S-, -SO-, or -SO _2- ; ego Each m ₁ is independently an integer of 0 to 2; Provided that the following compounds and their pharmaceutically acceptable salts and solvent compounds, and their salts and solvent compounds, ie: (a) A ₁ is -CH = or -N- and A ₂ is -CH _2- ; (b) E ₁ is COOH, P (O) (OH) ₂ , SOOH, SO ₃ H or tetrazole; (c) G ₁ is CN, N (H) R ₂₀ , N ₃ , SR ₂₀ , OR ₂₀ , guanidino, -N (H) CN (d) T ₁ is —NHR ₂₀ ; (e) R ₂₀ is H; Acyl groups of 1 to 4 carbon atoms; Straight or cyclic alkyl groups of 1 to 6 carbon atoms, or halogen substituted homologs thereof; An aryl group substituted by an allyl group or an unsubstituted aryl group or a halogen or an OH group, a NO ₂ group, an NH ₂ group or a 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 CH ₂ YR _20a CH ₂ YR _20a; (i) R _20a is H or acyl of 1 to 4 carbon atoms; (j) Y is O, S, H or NH; (k) 0-2 YR _20a is H (l) If the consecutive Y moieties in the U ₁ group are the same or different and Y is H, then the compound when R _20a is covalent is excluded, and if G ₁ is N ₃ then U ₁ is -CH ₂ OCH ₂ Ph No, Further, among the compounds having the above formula II, the following compounds, namely: (a) A ₁ is O; (b) E ₁ is COOH, P (O) (OH) ₂ , NO ₂ , SOOH, SO ₃ H, tetrazole, CH ₂ CHO, CHO, CH (CHO) ₂ or E ₁ is COOH, P (O) (OH) ₂ , SOOH or SO ₃ H, ethyl, methyl or pivaloyl esters thereof; (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 a 1 to 6 carbon atom, halogen-substituted or unsubstituted straight or cyclic alkyl group, or SR ^20a , OR ^20a , COOH or Alkyl / aryl esters thereof, NO ₂ , C (R ^20a ) ₃ , CH ₂ COOH or alkyl / aryl esters thereof, CH ₂ NO ₂ or CH ₂ NHR ^20b ; (e) R ^20a is H; Acyl groups of 1 to 4 carbon atoms; Straight or cyclic alkyl groups of 1 to 6 carbon atoms, or halogen substituted homologs thereof; Aryl groups, ie, unsubstituted aryl groups or aryl groups substituted by halogen, OH, NO ₂ , NH ₂ or COOH; (f) J ₁ is H and J _1a is H, OR ^20a , F, Cl, Br, CN, NHR ^20a , SR ^20a or CH ₂ X, wherein X is NHR ^20a , halogen or OR ^20a ; (g) J ₂ is H, or J _2a is H, N (R ^20a ) ₂ , SR ^20a or OR ^20a ; (h) U ₁ is CH ₂ YR ^20a , CHYR ^20a CH ₂ YR ^20a or CHYR ^20a CHYR ^20a CH ₂ YR ^20a , wherein Y is O, S or H, and the consecutive Y moieties in the U ₁ group are the same or different , If Y is H, R ^20a represents a covalent bond). A composition comprising the compound according to claim 1 and an enteric protective agent. A composition containing the compound according to claim 1, which is enteric protected. A composition containing a compound having the formula and an enteric protective agent: In the formula, 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 ) ₂ ), or —C (R ₁₁ ) ₂ —N (R ₁₁ ) ₂ ; T ₁ is —NH (C (O) CH ₃ ), —NH (C (O) CH ₂ F), —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 of 1 to 12 carbon atoms; Each R ₂ is independently R ₃ or R ₄ , wherein each R ₄ is independently substituted with 0-3 R ₃ groups; Each R ₃ is independently F, Cl, Br, I, -CN, N ₃ , -NO ₂ , -OR _6a , -OR ₁ , -N (R ₁ ) ₂ , -N (R ₁ ) (R _6b ), -N (R _6b ) ₂ , -SR ₁ , -SR _6a , -S (O) R ₁ , -S (O) ₂ R ₁ , -S (O) OR ₁ , -S (O) OR _6a , -S (O) ₂ OR ₁ , -S (O) ₂ OR _6a , -C (O) OR ₁ , -C (O) R _6c , -C (O) OR _6a , -OC (O) R ₁ , -N (R ₁ ) (C (O) R ₁ ), -N (R _6b ) (C (O) R ₁ ), -N (R ₁ ) (C (O) OR ₁ ), -N (R _6b ) (C (O) OR ₁ ), -C (O) N (R ₁ ) ₂ , -C (O) N (R _6b ) (R ₁ ), -C (O) N (R _6b ) ₂ , -C (NR ₁ ) (N (R ₁ ) ₂ ), -C (N (R _6b ) (N (R ₁ ) ₂ ), -C (N (R ₁ ) (N (R ₁ ) (R _6b ) ), -C (N (R _6b ) (N (R ₁ ) (R _6b )), -C (N (R ₁ ) (N (R _6b ) ₂ ), -C (N (R _6b ) (N ( R _6b ) ₂ ), -N (R ₁ ) C (N (R ₁ ) (N (R ₁ ) ₂ ), -N (R ₁ ) C (N (R ₁ )) (N (R ₁ ) (R _6b )), -N (R ₁ ) C (N (R _6b )) (N (R ₁ ) ₂ ), -N (R _6b ) C (N (R ₁ )) (N (R ₁ ) ₂ ), -N (R _6b ) C (N (R _6b )) (N (R ₁ ) ₂ ), -N (R _6b ) C (N (R ₁ )) (N (R ₁ ) (R _6b )),- N (R ₁ ) C (N (R _6b )) (N (R ₁ ) (R _6b )), -N (R ₁ ) C (N (R ₁ )) (N (R _6b ) ₂ ), -N (R _6b ) C (N (R _6b )) (N (R ₁ ) (R _6b )), -N (R _6b ) C (N (R ₁ )) (N (R _6b ) ₂ ), -N ( R ₁ ) C (N (R _6b )) (N (R _6b ) ₂ ), -N (R _6b ) C (N (R _6b )) (N (R _6b ) ₂ ), = O, = S, N (R ₁ ), = N (R _6b ) or W ₅ ; R ₄ is independently 1-12 alkyl of carbon atoms, alkenyl of 2-12 carbon atoms, or alkynyl 2-12 carbon atoms; R ₅ is independently R ₄ where each R ₄ is substituted with 0-3 R ₃ groups; R _5a is alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, or alkynylene of 2 to 12 carbon atoms, and alkylene, alkenylene or alkynylene is substituted with 0 to 3 R ₃ groups ; R _6a is independently H or an ether- or ester-forming group; R _6b is independently H, a residue or amino protecting group of a carboxyl-containing compound; R _6c is independently H, or a residue of an amino-containing compound; W ₅ is carbocycle or heterocycle, wherein W ₅ is independently substituted with 0-3 R ₂ groups; R ₁₁ is independently H or R ₅ . The compound of claim 4, wherein E ₁ is C (O) OCH ₂ CH ₃ ; G ₁ is NH ₂ ; T ₁ is NH (C (O) CH ₃ ); And a compound wherein U ₁ is OCH (CH ₂ CH ₃ ) ₂ . Enteric protected, composition containing a compound having the formula: . The composition of claim 6 comprising a compound having the formula and an enteric coating: . A method of inhibiting neuraminidase activity, comprising contacting a sample suspected of containing neuraminidase with an enteric protected composition containing a compound according to claim 1. The method of claim 8, wherein said neuraminidase is an influenza neuraminidase in vivo. A method of treating and preventing influenza infection in a host, comprising administering to the host a therapeutically effective amount of an enteric protected composition containing a compound according to claim 1.