KR20000052702A - Piperidine compounds - Google Patents

Abstract

PURPOSE: An object is inhibition of glycolytic enzymes such as neuraminidase, in particular the selective inhibition of viral or bacterial neuraminidases. CONSTITUTION: Compounds, or compositions having formula (IX) are provided herein: wherein E1 is -(CR1R1)m1W1; G1 is N3, -CN, -OH, -OR6a, -NO2, or -(CR1R1)m1W2; T1 is -NR1W3, or a heterocycle; Jla are independently R1, Br, Cl, F, I, CN, NO2 or N3; J2 and J2a are independently H or R1; R1 is independently H or alkyl of 1 to 12 carbon atoms; R2 is independently R3 or R4 wherein each R4 is independently substituted with 0 to 3 R3 groups.

Description

Piperidine Compounds {PIPERIDINE COMPOUNDS}

Background of the Invention

von Itzstein, L.M. "Nature", 363 (6428): 418-423 (1993), presented a rational model of sialidase-based inhibitors of influenza virus replication.

Colman, P.M. International Patent Publication No. WO 92/06691 (International Application No. PCT / AU90 / 00501, published April 30, 1992), von Itzstein, L.M. European Patent Publication No. 0 539. 204 A1 (European patent application 92309684.6, published April 28, 1993) and von Itzstien, L.M. International Patent Publication No. WO91 / 16320 (International Application No. PCT / AU91 / 00161, published October 31, 1991) discloses compounds that bind neuraminidase, which are said to exert antiviral activity in vivo.

"J. Antibiotics" 27: 963-969 (1974) by Umezawa, H., et al. Disclose the isolation of Siastatin B. Nishimura, Y et al. "J. Am. Chem. Soc." 110: 7249-7250 (1988) and "Bull. Chem. Soc. Jpn." 65: 978-986 (1992) discloses the overall synthesis of cyastatin B. Nishimura Y. et al., “J. Antibiotics” 45 (10: 1662-1668 (1992); 46 (2); 300-309 (1993); 46 (12): 1883-1889 (1993); 47 (1): 101-107 (1994); and "Nat. Prod. Lett." 1 (1): 39-44 (1992) and Japanese Patent Application 92-287381 (October 26, 1992); 90-201437 (July 31, 1990) 88-125020 (May 24, 1988) and 50046895 (April 25, 1975) disclose the synthetic conversion of cyastatin B, including certain dehydrocystatin B homologs. Zbiral, E. et al. Ann. Chem. "129-134 (1991) and" Carbohydrate Res. "244: 181-185 (1993), such as von Itzstein. LM, disclose that the hydroxy group is synthetically converted to an amino group at the C4 position of sialic acid. .

Purpose of the Invention

Selected embodiments of the present invention satisfy one or more of the following objects set forth:

The main object of the present invention is to inhibit bacteria and viruses, in particular influenza virus. In particular, it is an object of the present invention to selectively inhibit glycolytic enzymes such as neuraminidase, in particular viral or bacterial neuraminidase.

Another object of the present invention is to slow urination, enter the nasal or lung secretions through the systemic circulation, orally bioavailable enough to be therapeutically effective, have potent activity, as well as clinically acceptable It is to provide a neuraminidase inhibitor having a toxicity profile and other desirable pharmaceutical properties.

It is another object of the present invention to provide an inexpensive and improved synthesis of neuraminidase inhibitors.

Another object of the present invention is to provide a known method of administering neuraminidase and novel neuraminidase.

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

The above and other objects will be readily apparent to those skilled in the art in light of the present disclosure.

Summary of the Invention

According to the present invention there is provided a compound, or composition, having the following formula (IX) and salts, solvates, decomposed enantiomers and purified diastereomers thereof:

[Formula IX]

In the formula,

E ₁ is _{- (CR 1 R 1) m1} W 1;

G ₁ is _{N 3, -CN, -OH, -OR} 6a, -NO 2 , or _{- (CR 1 R 1) m1} W 2;

T ₁ is —NR ₁ W ₃ , or a heterocycle;

J _1a is independently R ₁ , Br, Cl, F, I, CN, NO ₂ or N ₃ ;

J ₂ and J _2a are independently H or R ₁ ;

R ₁ is independently H or alkyl 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

R ₄ is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, 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 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 these alkylenes, alkenylenes or alkynylenes are substituted with 0 to 3 R ₃ groups. Substituted;

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

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

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

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

W ₂ is a group containing a basic heteroatom or a protected basic heteroatom, or an R _6b amide of a basic heteroatom;

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 , —SO ₂ W ₅ ;

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

W ₆ is

ego

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

Provided that J _1a is H, each J ₂ is H, J _2a is H and T ₁ is —N (H) (Ac);

E ₁ is —CO ₂ H or —CO ₂ CH ₃ ,

G ₁ is -OBoc,

W ₆ is Boc,

E ₁ is —CO ₂ H or —CO ₂ CH ₃ ,

G ₁ is -OH, and

W ₆ is H;

E ₁ is -CO ₂ H, -CO ₂ CH ₃ or -CO ₂ Bn

G ₁ is -OH,

W ₆ is Boc;

E ₁ is -CONH ₂ ,

G ₁ is -OH,

W ₆ is Boc or H;

E ₁ is —CO ₂ H or —CO ₂ CH ₃ ,

G ₁ is OH

W ₆ is Bn; or

O ₂ H or —CO ₂ CH ₃ ,

G ₁ is -OH

W ₆ is -CH ₂ CH (OH) CH ₂ (OH);

(Except those compounds wherein Bn is benzyl and Boc is -CO ₂ C (CH ₃ ) ₃ )

In another embodiment, compounds of Formula (X), compositions and salts thereof, solvates,

Digested enantiomers and purified diastereomers are provided.

[Formula X]

In the formula,

One Z ₁ is W ₆ and the other Z ₁ is G ₁ ;

Z ₂ is H or W ₆ ;

E ₁ is _{- (CR 1 R 1) m1} W 1;

G ₁ is -OH, -OR _6a, or _{- (CR 1 R 1) m1} W 2;

T ₁ is —NR ₁ W ₃ or a heterocycle;

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

J ₂ is 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

R ₄ is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, 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 of 1 to 12 carbon atoms, an alkenylene of 2 to 12 carbon atoms, an alkynylene of 2 to 12 carbon atoms, and these alkylenes, alkenylenes, or alkynylenes are selected from 0 to 3 R ₃ groups Substituted;

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

R _6b is independently H, an amino protecting group or carbosyl-containing compound;

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

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

W ₂ is a group containing H or a basic heteroatom or protected basic heteroatom or R _6b amide of a basic heteroatom;

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 and W ₅ may be independently substituted with 0 to 3 R ₂ groups;

W ₆ is

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

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

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

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

Neuraminidase (also known as sialidase, acylneuraminil hydrolase and EC 3.2.1.18) is a common enzyme in animals and some microorganisms. It is glycohydrolase to cleave terminal alpha-ketosidically linked sialic acid from glycoproteins, glycolipids and oligosaccharides. Many microorganisms containing neuraminidenis cause disease in humans and poultry, horses, pigs, and other animals, including seals. Organisms having N-acetylneuramidase include Vibrio cholerae, C. a. C. perfringens and Streptococcus sp. Bacteria such as (Streptococcus sp.) And viruses such as influenza viruses and parainfluenza viruses.

Influenza neuraminidase has been implicated in the pathogenicity of the influenza virus. It is believed to help release the newly synthesized virion from infected cells and to help the virus move through the respiratory mucosa (via its hydrolase activity).

Compositions of the Invention

The compounds so far known are excluded from the compounds of the present invention. However, as will be apparent from the following description, in other embodiments, it is within the scope of the present invention to use known compounds produced and used only as intermediates for the preparation of antiviral compounds for antiviral purposes. . In the United States, the compounds or compositions of the present invention are excluded from the compounds or compositions of the present invention that are expected or obvious under 35 USC §102 or 35 USC §103. In particular, the claims of the present invention are set forth in Nishimura, Y et al. "J. Am. Chem. Soc." 110: 7249-7250 (1988) and "Bull. Chem. Soc. Jpn." 65: 978-986 (1992) (which discloses the overall synthesis of cystatin B), Nishimura Y. et al., “J. Antibiotics” 45 (10: 1662-1668 (1992); 46 (2); 300-309 (1993); 46 (12): 1883-1889 (1993); 47 (1): 101-107 (1994); and "Nat. Prod. Lett." 1 (1): 39-44 (1992) and Japan Patent Application 92-287381 (October 26, 1992); 90-201437 (July 31, 1990); 88-125020 (May 24, 1988) and 50046895 (April 25, 1975) Compounds are held to be excluded.

In another embodiment, W ₆ in the compound of the invention is not —CH ₂ Oh, —CH ₂ OAc or —CH ₂ OCH ₂ Ph.

In another embodiment, in the compounds of the invention, E ₁ is not —CH ₂ OH, —CH ₂ OTMS or —CHO.

In another embodiment, in the compounds of the present invention, W ₆ is not polyhydroxyalkane, in particular -CH (OH) CH (OH) CH ₂ OH.

In another embodiment, W ₆ in the compound of the invention is a branched chain group R ₅ as described below or a carbocycle substituted with at least one R ₅ group.

When a compound described herein is substituted with one or more of the same substituents, such as "R ₁ " or "R _6a ", the substituents may be the same or different. That is, it is to be understood that each substituent thereof is independently selected.

"Heterocycles" in the present invention include Paquette, Leo A., "Principles of Modern Heterocyclic Chemistry" (W.A. 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, present since 1950), in particular Volumes 13, 14, 16, 19 and 28; And "J. Am. Soc." 82: 5566 (1960), but are not limited to these.

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, phthalazinyl, na Thiridinyl, quinoxalinyl, quinazolinyl, cinnaolinyl, putridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolyl Neil, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromenyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, iso Indolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl and isatinoyl.

Carbon-bonded heterocycles include the 2,3,4,5 or 6 position of pyridine, the 3,4,5, or 6 position of pyridazine, the 2,4,5, or 6 position of pyrimidine, 2,3 of pyrazine , 5 or 6 position, furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole 2, 3, 4, or 5 position, oxazole, imidazole or thiazole 2, 4, or 5 position , 3, 4, or 5 position of isoxazole, pyrazole or isothiazole, 2 or 3 position of aziridine, 2, 3, or 4 position of azetidine, 2, 3, 4, 5, 6, of quinoline In position 7 or 8, or in positions 1, 3, 4, 5, 6, 7, or 8 of isoquinoline. More typically, carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5- Pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6 -Pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

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, piperazine, indole, indolin, 1 position of 1H-indazole, isoindole, or 2 position of isoindoleline, 4 position of morpholine , And carbazole, or β-carboline at the 9 position. More generally, nitrogen-bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl and 1-piperidinyl.

"Alkyl" in the text refers to C _1-12 hydrocarbons containing normal, secondary, tertiary or cyclic carbon atoms, unless stated otherwise. Examples include the following;

Examples of alkyl groups are shown in Table 2 as groups 2-5, 7, 9 and 100-399:

Compositions of the present invention include compounds having the formula:

or

In a typical embodiment, the compound of formula IX is selected.

J ₁ and R _1a are independently R ₁ , Br, Cl, F, I, CN, NO ₂ or N ₃ , generally R ₁ or F, more generally H or F, more generally H to be.

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

One of Z ₁ in formula (X) is H and the other is G ₁ .

Z ₂ in formula (X) is H or W ₆ , generally H.

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 alkyl of 1 to 4 or 5 to 10 carbon atoms, more typically H, or carbon atoms of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 alkyl, more generally alkyl having 1 to 3 carbon atoms selected from H, methyl, ethyl, n-propyl and i-propyl. The most typical case is when R ₁ is H.

m ₁ is 0 to 2 integers, generally 0 or 1, most preferably 0.

m ₂ is an integer of 0 to 1.

m ₃ is an integer of 1 to 3.

W ₁ is a group containing an acidic hydrogen, a protected acidic group or an R _6c amide group containing an acidic hydrogen, in the text, a hydrogen atom that can be removed by a base producing an anion or a corresponding salt or solvate thereof It means a group having.

The general principles of acidity and basicity of organic matter are well known and will be understood in defining W ₁ . This is not described in detail. However, a detailed description is provided in Streiwieser, A. and Heathcock, CH 60, 64, "Introduction to Organic Chemistry, 2nd Edition" (Macmillan, New York, 1981). In general, the acidic groups of the present invention have a pK value of less than the pK value of water, usually pK = 10, generally pK = 8, and more generally pK = 6. These include tetrazole and include acids of carbon, sulfur, phosphorus and nitrogen, generally carbonic acid, sulfuric acid, sulfonic acid, sulfurous acid, phosphoric acid and phosphonic acid, including R _6c amide and R _6b esters of these acids ( R _6c and R _6b are defined below). Examples of W ₁ are -CO ₂ H, -CO ₂ R _6a , -OCO 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. E ₁ is generally W ₁ and W ₁ is generally —CO ₂ H, —CO ₂ R _6a , —CO ₂ R ₄ or CO ₂ R ₁ , most preferably CO ₂ R ₁₄ , where R ₁₄ Is normal or terminal secondary C ₁ -C ₅ alkyl.

W ₁ may also be a protected acid group, meaning an acid group protected by groups commonly used in the art for the group defined as R _6a as described below within the scope of the present invention. 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 and R ₄ are as defined above.

More generally, E ₁ is —C (O) O (CH ₂ ) _b CH ((CH ₂ ) _c CH ₃ ) ₂ or wherein b = 0 to 4, c = 0 to 4, b + c = 1 to 4), or

E ₁ groups are illustrated in Tables 3a to 3b.

G ₁ of formula X is -OH, OR _6a or _{- (CR 1 R 1) m1} W 2, G 1 in formula IX 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. Typically, G ₁ in formula IX is - (CR ₁ R _{1) m1,} and G ₁ is H of formula X.

W ₂ in formula (X) is a group containing H or a R _6b amide of a basic heteroatom, a protected basic heteroatom or a basic heteroatom. W ₂ of formula (IX) is a group containing a R _6b amide of a basic heteroatom, protected basic heteroatom or basic heteroatom. W ₂ generally refers to atoms other than carbon which include basic heteroatoms and which are generally rotonizable by acidic hydrogen having an acid in the range described for W ₁ above. Basic principles of basicity are described in Streitwieser and Heathcock (in the previous book) and provide meaning for the term basic heteroatoms as those skilled in the art will understand. In general, the basic heteroatoms used in the compounds of the present invention have pK values for the corresponding protonated forms that fall within the value ranges described above for W ₁ . Basic heteroatoms include heteroatoms common to organic compounds having electron pairs, such as non-covalent, non-bonding, n-types. For example, typical basic heteroatoms include, but are not limited to, oxygen, nitrogen, and sulfur atoms of groups such as alcohols, amines, amidines, guanidines, sulfides, and the like, often amines, amidines, and guanidines. In general, W ₂ is amino or amino alkyl (generally lower alkyl C _1-6 ) such as aminomethyl, aminoethyl or aminopropyl; Amidinoyl or amidinoalkyl groups such as amidinomethyl, amidinoethyl or amidinopropyl; Or guanidinyl, or guanidinoalkyl group such as guanidinomethyl, guanidinoethyl, or guanidinopropyl (in each case, the alkyl group serves to bind the basic substituent to the carbocyclic ring) . More generally W ₂ is an amino, amidino, guanidino, heterocycle, heterocycle substituted with one or two amino or guanidino groups (usually one), or carbon substituted with amino or guanidino Such alkyl groups substituted with 2 to 3 atoms of alkyl or a second group selected from hydroxy and amino. Heterocycles useful as W ₂ are generally 5 or 6 membered rings containing N or S, wherein the ring contains 1 or 2 heteroatoms. Such heterocycles are generally substituted with ring carbon atoms. They may be saturated or unsaturated and may be bonded to the central cyclohexene by lower alkyl (m1 = 1 or 2) or -NR _1- . More generally, W ₂ may be as follows:

Wherein m2 is generally 0, generally R ₁ is H and R ₃ is C (O) N (R ₁ ) ₂ .

W ₂ is a protected basic heteroatom, optionally meaning a basic heteroatom as described above protected by R _6b as a group common in the art. Such groups are described in detail in Greene (described above). Such groups include, 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, thioester, disulfide, sulfenyl and the like. In some embodiments, the protecting group R _6b is cleaved under physiological conditions, and generally, for example, a basic heteroatom forms an amide with an organic acid or an amino acid, such as a naturally occurring amino acid, or a polypeptide to be described below in connection with an R _6a group. It will be cleavable in vivo.

Typically, G ₁ of formula X is H, and G ₁ in formula (IX) is selected from the following:

Additional G ₁ groups are shown in Table 4.

T ₁ is —NR ₁ W ₃ , —R ₃ , —R _5, or heterocycle. Generally T ₁ is —NR ₁ W ₃ or heterocycle. In general, T ₁ is selected from:

Examples of T ₁ groups are shown in Table 5.

W ₃ is W ₄ or W ₅ , where W ₄ is R ₅ 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

to be. More general R ₃ groups containing R _6b include —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 present invention, "= O" is a double bonded oxygen atom (oxo), and "= S" = N (R _6b ) and "= N (R ₁ )" mean sulfur and nitrogen homologues.

R ₄ is alkyl of 1 to 12 carbon atoms, alkynyl or alkynyl of 2 to 12 carbon atoms. Alkyl R ₄ is generally 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms and alkenyl and alkynyl R ₄ are generally 2, 3, 4, 5 , 6, 7, 8, 9, 10, 11, or 12 carbon atoms. R ₄ is generally alkyl (as defined above). If R ₄ is alkenyl it is generally ethenyl (-CH = CH ₂ ), 1-pro-1-phenyl (-CH = CHCH ₃ ), 1-pro- ₂ -phenyl (-CH ₂ CH = CH ₂ ) , 2-pro-1-phenyl (-C (= CH ₂ ) (CH ₃ )), 1-but-1-tenyl (-CH = CHCH ₂ CH ₃ ), 1-but- ₂ -tenyl (-CH ₂ CH = CHCH ₃ ), 1-but-3-tenyl (-CH ₂ CH ₂ CH = CH ₂ ), 2-methyl-1-pro-1-phenyl (-CH = C (CH ₃ ) ₂ ), 2- Methyl-1-pro- ₂ -phenyl (-CH ₂ C (= CH ₂ ) (CH ₃ )), 2-part-1-tenyl (-(C (= CH ₂ ) CH ₂ CH ₃ ), 2-part 2-tenyl (-C (CH ₃ ) = CHCH ₃ ), 2-bu-3-tenyl (-CH (CH ₃ ) CH = CH ₂ ), 1-phen-1-tenyl (-C = CHCH ₂ CH ₂ CH ₃ ), 1-phen- _2- tenyl (-CHCH = CHCH ₂ CH ₃ ), 1-phen-3-tenyl (-CHCH ₂ CH = CHCH ₃ ), 1-phen-4-tenyl (-CHCH ₂ CH ₂ CH = CH ₂ ), 2-phen-1-tenyl (-C (= CH ₂ ) CH ₂ CH ₂ CH ₃ ), 2-phen-2-tenyl (-C (CH ₃ ) = CH ₂ CH ₂ CH ₃ ), 2-phen- _3- tenyl (-CH (CH ₃ ) CH = CHCh ₃ ), 2-phen- _4- tenyl (-CH (CH ₃ ) CH ₂ CH = CH ₂ ) or 3-methyl- 1 is a part-2-butenyl _{(-CH 2 CH = C (CH} 3) 2). more typically, R ₄ alkenyl group carbon atoms 2, 3, 4 or dog. R ₄ a is alkynyl is It is typically ethynyl (-C≡CH), 1- pro-1-sulfinyl (-C≡CCH _3), 1- Pro-2-sulfinyl (-CH ₂ C≡CH), 1- ethynyl-1-unit (-C≡CCH ₂ CH ₃ ), 1-but- _2- tinyl (-CH ₂ C≡CCH ₃ ), 1-but-3-tinyl (-CH ₂ CH ₂ C≡CH), 2-part-3 -Tinyl (CH (CH ₃ ) C≡CH), 1-phen-1-tinyl (-C≡CCH ₂ CH ₂ CH ₃ ), 1-phen- _2- tinyl (-CH ₂ C≡CCH ₂ CH ₃ ) , 1-phen- _3- tinyl (-CH ₂ CH ₂ C≡CCH ₃ ) or 1-phen-4-tinyl (-CH ₂ CH ₂ CH ₂ ≡CH). More generally, R ₄ is an alkynyl group and is 2, 3 or 4 carbon atoms.

R ₅ is, R ₄ or 0 to 3 R ₃ a R ₄ substituted by a group as defined above. Generally R ₅ is 1-4 alkyl substituted with 0-3 fluorine atoms.

R _5a is independently an alkylene having 1 to 12 carbon atoms, an alkenylene having 2 to 12 carbon atoms, an alkynylene having 2 to 12 carbon atoms, and these alkylenes, alkenylene or alkynylene, etc. are each represented by 0 to 3 R ₃ groups. It is substituted. As defined above for R ₄ , R _5a has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms in the case of alkenylene or alkynylene. The common R ₄ groups are each common R _5a groups, with the exception that one of the hydrogen atoms of the R ₄ groups described above is removed to form an open valence for the carbon atoms through which a second bond to R _5a is attached. do.

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

W ₅ is carbocycle or heterocycle, provided that each W ₅ is independently substituted with 0 to 3 R ₂ groups. W ₅ is a carbocycle and T ₁ and W ₅ heterocycles are stable chemical structures. This structure can be isolated from the reaction mixture at -78 to 200 ° C in measurable yield, measurable purity. Each W ₅ is independently substituted with 0-3 R ₂ groups. Generally T ₁ and W ₅ are saturated, unsaturated or aromatic rings comprising mono- or bicyclic carbocycles or heterocycles. More generally, T ₁ or W ₅ has 3 to 10 ring atoms, more generally 3 to 7 ring atoms, more generally 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, mono- or diunsaturated when containing 5 ring atoms, or 6 Aromatic if it contains two ring atoms. Unsaturation of the W ₅ ring is internally bound to the ring atom and externally unsaturated to the outer ring

When W ₅ is carbocyclic, it is 3 to 7 carbon monocycles or 7 to 12 carbon atom bicycles. More generally, the W ₅ monocyclic carbocycle is 3 to 6 ring atoms, more generally 5 or 6 ring atoms. W ₅ bicyclic carbocycles are generally 7 to 12 ring atoms, more generally arranged as bicyclo [4,5], [5,5], [5,6] or [6,6] systems Having 9 or 10 ring atoms arranged as [5,6] or [6,6] systems. Such as cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclophen-1-tenyl, 1-cyclophen-2-tenyl, 1-cyclopent-3-tenyl, cyclohexyl, 1-cyclohex-1-senyl, 1 -Cyclohex-2-senyl, 1-cyclohex-3-senyl, phenyl, spiryl and naphthyl.

T ₁ or W ₅ heterocycles are generally monocycles having 3 to 7 ring elements (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P and S) or 7 to 10 rings Bicycles containing elements (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P and S). More generally, T ₁ and W ₅ heterocycle-based monocycles have 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 2 heteroatoms selected from N, O and S), more generally 5 or Having 6 ring atoms (3 to 5 carbon atoms and 1 to 2 heteroatoms selected from N and S). T ₁ and W ₅ heterocycle-based bicycles comprise 7 to 10 ring atoms (6 to 6) arranged as a bicyclo [4,5], [5,5], [5,6], or [6,6] system 9 or 10 rings having 9 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S), more generally arranged in a bicyclo [5,6], or [6,6] system Having atoms (8 to 9 carbon atoms and 1 to 2 heteroatoms selected from N and S).

Generally 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 atom. More generally, the T ₁ heterocycle is bonded to the cyclohexene ring of the composition of the invention by its stable covalent bond and W ₅ is the cyclohexene ring of the composition of the invention via its carbon or nitrogen atom by stable covalent bond. Is coupled to. Stable covalent bonds are chemically stable structures as described above.

W ₅ is optionally selected from the following groups:

W ₆ is

Or -C (O) R ₂ , generally W ₆ is -R ₅ , -W ₅ or -R _5a W ₅ ; In some embodiments R ₆ is _{R 1, -C (O) -R} 1, -CHR 1 W 7, -CH (R 1) a W 7, - CH (W 7) 2, ( wherein W ₇ is a monovalent 0 Or 0 if 1, 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

ego; M <_3> is an integer of 1-3 here.

W ₇ is R ₃ or R _5, but generally 1-12 alkyl of carbon atoms substituted with 0 to 3 R ₃ groups, where the latter is —NR ₁ (R _6b ) ₂ , —N (R _6b ) ₂ , -OR _6a , or SR _6a . More generally, W ₇ is alkyl of 3 to 12 carbon atoms substituted with —OR ₁ or OR ₁ .

Generally, W ₆ is R _1- , -CHR ₁ W ₇ ,

to be.

Exemplary W ₆ groups are shown in Table 2.

One embodiment of the invention includes a compound of the formula:

or

Wherein each R ₁ and R _6b is generally H and W ₂ is generally selected from the following;

W ₆ is one of the following;

Wherein R ₇ is

Generally H, CH ₃ or -CH ₂ CH ₃ .

Another embodiment of the invention relates to compounds of formula (XX) or (XXa), salts, solvates, degraded astigomers and purified diastereomers:

or

Wherein A ₃ is N, N (O) or N (S);

Z ₃ is H, W ₆ , G ₁ or R _3a ;

E ₁ is _{- (CR 1 R 1) m1} W 1;

G ₁ is _{N 3, -CN, -OH, -OR} 6a, -NO 2 , or _{- (CR 1 R 1) m1} W 2;

G ₂ is G ₁ or -X ₁ W ₆ ;

T ₁ is —NR ₁ W ₃ or a heterocycle;

J ₁ is R ₁ , Br, Cl, F, I. CN, NO ₂ or N ₃ ;

J ₂ is H or R ₁ ;

J ₃ is J ₁ when X ₁ is a bond; X ₁

If J ₂ ;

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

R _3a is independently

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

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

R _5a is independently 1 to 12 alkylenes, 2 to 12 carbon atoms, alkenylene, 2 to 12 carbon atoms, and these alkylenes, alkenylene or alkynylene are substituted with 0 to 3 R ₃ groups. Become;

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

R _6b is independently H, an aminoprotecting group or a carboxyl-containing compound residue;

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

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

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

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

X ₁ is a bond,

And

Each m ₁ is independently an integer from 0 to 2

Provided that A ₃ is N and each J ₁ , J ₂ , J _2a and J ₃ is H and T ₁ is —N (H) (Ac);

E ₁ is —CO ₂ H or —CO ₂ CH ₃ ,

G ₂ is -OBoc

Z ₃ is Boc,

E ₁ is —CO ₂ H or —CO ₂ CH ₃ ,

G ₂ is -OH

Z ₃ is H;

E ₁ is -CO ₂ H, -CO ₂ CH ₃ or -CO ₂ Bn

G ₂ is -OH,

Z ₃ is Boc;

E ₁ is -CONH ₂ ,

G ₂ is -OH,

Z ₃ is Boc or H;

E ₁ is —CO ₂ H or —CO ₂ CH ₃ ,

G ₂ is OH

Z ₃ is Bn; or

O ₂ H or —CO ₂ CH ₃ ,

G ₁ is -OH

W ₆ is -CH ₂ CH (OH) CH ₂ (OH);

Wherein Bn is benzyl and Boc is —CO ₂ C (CH ₃ ) ₃ ; Also excluded are compounds of formula (VII) or (VIII):

In the formula, E _{1 is-} (CR ₁ R ₁ ) m ¹ W ¹ _;

G ₁ is _{N 3, -CN, -OH, -OR} 6a, -NO, or _{- (CR 1 R 1) m1} W 2;

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

U ₁ is —X ₁ W ₆ ;

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

J ₂ and J _2a are independently 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 R ₄ is independently substituted with 0-3 R ₃ groups;

R ₃ is independently

;

R ₄ is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, 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 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 these alkylenes, alkenylenes or alkynylenes are substituted with 0 to 3 R ₃ groups. Substituted;

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

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

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

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

W ₂ is a group containing a basic heteroatom or a protected basic heteroatom, or an R _6b amide of a basic heteroatom;

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 , —SO ₂ W ₅ ;

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

W ₆ is

ego

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

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

Generally A ₃ is N or N (O), more generally A ₃ is N.

In a typical embodiment, one of Z ₃ and G ₂ is G ₁ or R _3a and the other is W ₆ or —X ₁ W ₆ . More generally, Z ₃ is W ₆ or R _3a and G ₂ is G ₁ or -X ₁ W ₆ . More generally, Z ₃ is W ₆ and G ₂ is G ₁ ; Or Z ₃ is R _3a and G ₂ is -X ₁ W ₆ .

J ₃ is J ₁ when X ₁ is a bond; J ₃ is X ₁

If is J ₂ . Typical embodiments of J ₁ and J ₂ described above are typical embodiments of J ₃ .

Embodiments of the invention consist of a compound of formula (XXI) or (XXIa):

One embodiment of the invention contains a compound of formula (XXII) or (XXIIa):

One embodiment of the invention contains a compound of formula (XXIII) or (XXIIIa).

One embodiment of the invention contains a compound of formula (XXIV) or (XXIVa).

Wherein one of Z ₁ is W ₆ and the other Z ₁ is G ₁ ; Z ₂ is H or W ₆ . Generally Z ₂ is H.

Embodiments of the invention include compounds of the formula (XXV) or (XXVa):

One embodiment of the invention includes a compound of formula (XXVI) or (XXVIa):

One embodiment of the invention includes compounds of the formula (XXVII) or (XXVIIa):

One embodiment of the invention includes a compound of formula (XXVIII) or (XXVIIIa):

One embodiment of the invention includes compounds of the formula (XXIX) or (XXIXa):

One embodiment of the invention includes compounds of the formula (XXX) or (XXXa):

It is to be understood that each of the typical embodiments of Formulas (XXX) and (XXXa) set forth above and described in the claims are also embodiments of Formulas (XXI)-(XXX) and (XXIa)-(XXXa) set forth immediately above. It is important.

The R _6a and R _6b groups are not important functional groups and can vary widely. If not H, their function is to serve as an intermediate to the parent drug substance. This does not mean that they are biologically inert. In contrast, the main function of these groups is to convert the parent drug into prodrugs, thereby releasing the parent drug upon conversion of the prodrugs in vivo. Since active prodrugs are absorbed more effectively than the parent drug, they actually have greater activity in vivo than the parent drug. If R _6a and R _6b are not hydrogen, they are removed ex vivo for chemical intermediates or in vivo for prodrugs. It is generally more preferred if the product is generally pharmaceutically harmless, but it is not particularly important that the resulting pro-functional product, such as an alcohol, will be physiologically acceptable, along with the chemical intermediate.

R _6a is H or an ether- or ester-forming group. "Ether-forming group" means a group having the following formula:

In between, it means group which can form stable covalent bond.

In the formula, V _a is typically a tetravalent atom selected from C and Si; V _b is typically 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, assuming that V ₂ is not = O, = S, or = N, in general V ₂ is = C (V ₁ ) ₂ , Wherein V ₁ is as described above; V ₃ is a group bonded to V _a by _a stable triple covalent bond, generally V ₃ is ≡C (V ₁ ), where V ₁ is as defined above.

"Ester-forming group" is a group having a parent molecule and the following structure

A group capable of forming stable covalent bonds between:

Wherein V _a , V _b , and V ₁ are as defined above; V _d is a pentavalent atom generally 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 if at least one of V ₄ is = O, = S, or = NV ₁ , and = O, = S Or, other than = N-, = C (V ₁ ) ₂ where V ₁ is as defined above.

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

Of particular interest are ether- or ester-forming groups which can function as protecting groups in the schemes presented herein. However, some hydroxyl and thio protecting groups are not ether-forming groups or ester-forming groups as will be understood by those skilled in the art and are included in the amides discussed under R _6c described below. Since R _6c can protect hydroxyl or thio groups, hydroxyl or thio is produced by hydrolysis from the parent molecule.

In the role of ester-forming, R _6a is generally bound to an acidic group such as, but not limited to, a -CO ₂ H or -C (S) OH group to yield -CO ₂ R _6a . R _6a can be deduced, for example, from the esters described in WO95 / 07920.

Examples of R _6a include C _3-12 heterocycle (as described above) or C _6-12 aryl. These aromatic groups may optionally be polycyclic or monocyclic. Examples are phenyl, spiryl, 2- and 3-pyrrolyl, 2- and 3-thienyl, 2- and 4-imidazolyl, 2-, 4- and 5-oxazolyl, 3- and 4-isoxa Zolyl, 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,

C _6-12 aryl, R ₁ , R ₁ -OC _1-12 alkylene, C _1-12 alkoxy, CN, NO ₂ , OH, carboxy, carboxyester, thiol, thio substituted C _3-12 heterocycle or halo Esters, C _1-12 haloalkyl (1-6 halogen atoms), C _2-12 alkenyl or C _2-23 alkynyl. Such groups include 2-, 3- and 4-alkoxyphenyl (C _1-12 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-, 2,5-, 2,6-, 3, 4- and 3,5-dimethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dipallophenyl (2,4-difluoro Rophenyl and 3,5-difluorophenyl), 2-, 3-, and 4-haloalkylphenyl (including 4-trifluoromethylphenyl, 1 to 5 halogen atoms, C _1-12 alkyl), 2-, 3- and 4-cyano Phenyl, 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-trichloromethylphenyl and 2- 3-, and 4-trichloromethylphenyl), 4-N-methylpiperidine, 3-N-methylpiperidinyl, 1-ethylpiperazinyl, benzyl, alkylsalicyl Phenyl (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 phenoxy ethyl], 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 1-6 halogen atoms; -CH ₂ -CCl ₃ ), C _1- C _1-4 alkyl substituted with an aryl moiety by 1 to 2 atoms or groups or 3 to 5 halogen atoms 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 - isoxazolyl, -CH ₂ -Thiazolyl, -CH ₂ -isothiazolyl, -CH ₂ -pyrazolyl, -CH ₂ -pyridinyl and -CH ₂ -pyrimidinyl);

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

Groups given for said aryl, in particular OH or alkyl substituted by one to three halo atoms (

include);

;

N-2-propylmorpholino, 2,3-dihydro-6-hydroxyindene, sesamol, catechol monoesters, -CH ₂ -C (O) -N (R ¹ ) ₂ , -CH ₂ -S (O) (R), -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, ethylpyruvate (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 via the glyceryl oxygen of the triglycerides, where fatty acids with glyceride lipids are generally naturally occurring saturated or unsaturated C _6-26 , C _6-18 or C _6-10 fatty acids such as linoleic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, palmitoleic acid, linolenic acid and the like);

Phospholipids linked to carboxyl groups via phosphates of phospholipids;

Phthalidyl (as shown in Figure 1 of Clyton et al. "Antimicrob. Agents Chemo." 5 (6): 670-671 [1974]);

(5-R _d -2-oxo-1,3-dioxolen-4-yl) methyl ester (Sakamoto et al., “Chem. Pharm. Bull.” 32 (60: 2241-2248 [1984] where R _d is Cyclic carbonates such as R ₁ , R ₄ or aryl: and

Can be mentioned.

The hydroxyl groups of the compounds of the invention may be optionally substituted with group III, IV or Group V or isopropyl as disclosed in WO94 / 21604.

As a further embodiment, Table A provides examples of R _6a ester moieties that may be bonded to the —C (O)) — and —P (O) (O—) ₂ groups, for example via oxygen. Some R _6c amidates directly attached to —C (O) — or —P (O) ₂ are also shown. The esters of the formulas 1-5, 8-10, and 16, 17, 19-22 have free hydrides and the compounds of the present invention have corresponding halides (such as chloride or acyl chloride) and N, N-dicyclohexyl-N It is synthesized by reacting morpholine carboxamidine (or a base such as DBU, triethylamine, CsCO ₃ , N, N-dimethylaniline, etc.) in DMF (or a solvent such as acetonitrile or N-methylpyrrolidone). If W ₁ is a phosphonate, the esters of structures 5-7, 11, 12, 21 and 23-26 are monochlorophos to alcohol or alkoxide salts (or the corresponding amines for compounds such as compounds 13, 14 and 15) Synthesized by reacting with phonates or dichlorophosphonates (or other activating phosphonates).

#-Chiral dopant is (R), (S) or racemate.

Other esters suitable for use in the present invention are described in EP 632,048. R _6a also includes “double ester” forming profunctional groups, for example

Or structure—CH (R ₁ or W ₅ ) O ((CO) R ₃₇ ) or —CH (R ₁ or W ₅ ) ((CO) OR ₃₈ ) (linked to the oxygen of an acid group), where R ₃₇ and R ₃₈ may be an alkyl, aryl or alkylaryl group, see US Pat. No. 4,968,788). Often, R ₃₇ and R ₃₈ are bulky groups such as branched alkyl, ortho-substituted aryl, meta-substituted aryl, or combinations thereof, such as C _1-6 normal, secondary, iso- and Tertiary alkyl. Pivaloyloxymethyl group is mentioned as an example. They are particularly useful as prodrugs for oral administration. Examples of such useful R _6a groups include alkylacyloxymethyl esters and derivatives thereof such as:

For prodrug purposes, the esters generally selected are antibiotic drugs, in particular cyclic carbonates, double esters or phthalidyl, aryl or alkyl esters.

As will be appreciated, the groups R _6a , R _6c and R _6b serve as protecting groups (PRTs) in synthesis since they can optionally be used to prevent side reactions with protecting groups during the synthesis process. In most cases the decision of which group to protect and the nature of the PRT will depend on the chemistry of the reaction to be defended (eg, acidic, basic, oxidative, reductive or other conditions) and the intended synthesis direction. If the compound is substituted with a plurality of PRTs, the PRT groups need not be identical to one another and are generally not identical. Generally, PRTs will be used to protect carboxyl, hydroxyl or amino groups. The order of deprotection to produce free radicals will depend on the intended synthesis direction and the reaction conditions to be encountered and can occur in any order determined by those skilled in the art.

"Protective Groups in Organic Chemistry", Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991, ISBN 0-471-62301-6) ("Greene") and Kocienski, Philip J. "Protecting Groups" (Georg Thieme Verlag Stuttgart, New York, 1994) describes numerous R _6a hydroxy protecting groups and R _6c amide-forming groups and corresponding chemical cleavage reactions, all of which are referred to herein. In particular Chapter 1, Protecting Groups; An Overview, pp. 1-20, Chapter 2, Hydroxyl Protecting Groups, Pages 21-94, Chapter 3, Diol Protecting Groups, Pages 95-117, Chapter 4, Carboxyl Protecting Goroups, pp. 118-154, Chapter 5, Carbonyl Protecting Group See pages 155-184. See Greene described below for R _6a carboxylic acid, phosphonic acid, phosphonate, sulfonic acid and other protecting groups for W ₁ acid. Such groups include, but are not limited to, esters, amides, hydrazides, and the like.

In some embodiments the R _6a protected acidic group is an ester of an acidic 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 also disclosed in WO95 / 07920. Of particular interest are amino acids, amino acid esters, polypeptides or aryl alcohol residues. Typical amino acid, polypeptide and carboxyl-esterified amino acid residues are described as L ₁ or L ₂ in WO95 / 07920 pages 11-18 and related parts. Although WO 95/07920 discloses amidates of phosphoric acid clearly, it should be understood that such amidates can be produced using any of the acid groups set forth herein and the amino acid residues set forth in WO 95/07920.

Typical R _6a esters for protecting W ₁ acid functionality are also _shown in WO95 / 07920 and it will be appreciated that the same ester can be formed using the same acidic group as the phosphonate of the '920 publication. General ester groups are defined in at least WO95 / 07920 89-93 (under the definition of R ³¹ or R ³⁵ ), table 105, page 21-23 (as R). Of particular interest is unsubstituted aryl such as phenyl or benzyl or hydroxy-halo-, alkoxy-, carboxy- and / or alkylestercarboxy-substituted aryl or alkylaryl, arylalkyl, in particular phenyl, ortho-e. Oxyphenyl, or an ester of C _1-4 alkyl estercarboxyphenyl (salicylate C _1-12 alkyl ester).

The protected acidic groups W _1, W ₁ in the case, especially with the esters or amides of WO95 / 07920 is useful as prodrugs for oral administration. However, the W ₁ acidic group does not necessarily have to be protected to effectively administer the compounds of the present invention by the oral route. When systemically or orally administered compounds of the invention having protecting groups, especially amino acid amidates or substituted and unsubstituted aryl esters, they may be hydrolytically cleaved in vivo to produce free acid.

One or more acidic hydrolysis is protected. If more than one acidic hydroxyl is protected, the same or different protecting groups are used, for example the esters may be the same or different and mixed amidates and esters may be used.

Typical R _6a hydroxy protecting groups described in Greene (pp. 14-118) include ether (methyl); Substituted methyl ether (methoxymethyl, methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl) methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy) methyl, sphere Iacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl , 2- (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiothioranil, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4-meth Oxytetrahydrothiopyranyl, 4-methoxytetrahydratethiopyranyl, S, S-dioxido, 1-[(2-chloro-4-methyl) phenyl] -4-methoxypiperidin-4-yl , 35, 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a, 4,5,6,7,7a-octahydro-7,8,8- Trimethyl-4,7-methanebenzofuran-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); Chihoned benzyl ethers (p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, ㅔ -cyanobenzyl, p- Phenylbenzyl, 2- and 4-picolinyl, 3-methyl-2-picoli N-oxido, diphenylmethyl, p, p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl p-methoxyphenyldiphenylmethyl, di (p-methoxyphenyl) phenylmethyl, tri (p-methoxyphenyl) methyl, 4- (4'-bromophenacyloxy) phenyl Diphenylmethyl, 4,4 ', 4 "-tris (4,5-dichlorophthalimidophenyl) methyl, 4,4', 4" -tris (lebulinoyloxyphenyl) methyl, 4, 4 ', 4 " -Tris (benzoyloxyphenyl) methyl, 3- (imidazolyl-1-ylmethyl) bis (4 ', 4 "-dimethoxyphenyl) methyl, 1,1-bis (4-methoxyphenyl) -1' -Pyrenylmethyl, 9-A-anthryl, 9- (9-phenyl) zantenyl, 9- (9-phenyl-10-oxo) anthryl, 1,3-benzodithiolan-2-yl, benziso Thiazolyl, S, S-dioxido); Silyl ether (trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethyltecsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, tri-p Xylylsilyl, triphenylsilyl, diphenylmethylsilyl, t-butylmethoxyphenylsilyl); Esters (formate, benzoylformate acetate, dichloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, p-poly- Phenylacetate, 3-phenylpropionate, 4-oxopentanate (levulinate), 4,4- (ethylenedithio) pentanoate, pivalate, adamantatoate, crotonate, 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); Groups With Assisted Cleavage (2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl) benzoate, 2-formylbenzenesulfonate, 2- (Methylthiomethoxy) ethyl carbonate, 4- (methylthiomethoxy) butyrate, 2- (methylthiomethoxy) ethyl carbonate, 4- (methylthiomethoxy) butyrate, 2- (methylthiometh Oxymethyl) benzoate); Other esters (2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4- (1,1,3,3-tetramethylbutyl) phenoxyacetate, 2,4-bis (1,1 -Dimethylpropyl) phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E) -2-methyl-2-butenoate (Tigoloate), o- (methoxycarbonyl) benzoate, p Poly-benzoate, α-naphthoate, nitrate, alkyl N, N, N'N'-tetramethylphosphorodiamidate, N-phenylcarbamate, borate, dimethylphosphinothiolyl, 2, 4-dinitrophenylsulfenate); And sulfonates (sulfates, methanesulfonates (mesylate), benzylsulfonates, tosylate).

More typically, R _6a hydroxy protecting groups include substituted methyl ethers, substituted benzel ethers, silyl ethers, and esters, such as sulfonic acid esters, more generally trialkylsilyl ethers, tosylate and acetates. .

Typical 1,2-diol protecting groups (thus generally two OH groups are taken together with R _6a protecting groups) are described on pages Greene 118-142 and by way of example cyclic acetals and ketals (methylene, ethylidene, 1-t -Butylethylidene, 1-phenylethylidene, (4-methoxyphenyl) ethylidene, 2,2,2-trichloroethylidene, acetonide (isopropylidene), cyclopentylidene, cyclohex Sillydene, 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-tetraisopropyldisiloxanylidene), and tetra-t-butoxydisiloxane-1,3-diylidene ), Cyclic carbonate, cyclic moronate, ethyl boronate and phenyl boronate.

More generally 1,2-diol protecting groups include those described in Table B, more generally epoxides, acetonites, cyclic ketals and aryl acetals.

In the above formula, R ⁹ is C _1-6 alkyl.

R _6b is a protecting group of an H, amino or carboxyl-containing compound residue, in particular H, —C (O) R ₄ , an amino acid, polypeptide protecting group or —C (O) R ₄ , a protecting group that is not 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, then R ₁₅ NHCH (R ₁₆ ) C (O) —, where R ₁₅ is H, an amino acid or polypeptide residue or R ₅ and R ₁₆ is as defined below.

R ₁₆ is lower alkyl or amino, carboxyl, amide, carboxyl ester, hydroxyl,

C_6-7Lower substituted with aryl, guanidinyl, imidazolyl, indolyl, sulfhydryl, sulfoxide and / or alkylphosphate Alkyl (C_1-6)to be. R₁₆Together with amino acid αN is a proline residue (R₁₆= -CH₂)₃To form-). However, R₁₆Is generally an immediate chain group of naturally occurring amino acids, for example,

to be. R ₁₆ is also 1-guanidinoprop-3-fil, benzyl, 4-hydroxybenzyl, imidazol-4-yl, indol-3-yl, methoxyphenyl and ethoxyphenyl.

R _6b is in most cases a residue of a carboxylic acid, but the typical aminoprotecting groups described on pages 315-385 of Greene are useful. These are 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-methoxyphenacyl); Substituted ethyl (2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-phenylethyl, 1- (1-adamantyl) -1-methylethyl, 1,1-dimethyl-2-haloethyl , 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1- (4-biphenylyl) ethyl, 1- ( 3,5-di-t-butylphenyl) -1-methylethyl, 2- (2'- and 4'-pyridyl) ethyl, 2- (N, N-dicyclohexylcarboxamido) ethyl, t- Butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamil, 4-nitrocinnamil, 8-quinolyl, N-hydroxypiperidinyl, alkyldithio, benzyl, p-methoxy Benzyl, p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl, diphenylmethyl); Groups With Assisted Cleavage (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- (dihydrate Oxyboryl) benzyl, 5-benzisoxazolylmethyl, 2- (trifluoromethyl) -6-chromonylmethyl); Groups Capable of Photolytic Cleavage (m-nitrobenzyl, 3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, phenyl (o-nitrophenyl0methyl); urea-type derivatives (Phenothiazinyl- (10) -carbonyl, N'-toluenesulfonylaminocarbonyl, N'-phenylaminothiocarbonyl); other carbamates (t-amyl, S-benzyl thiocarbamate p- Cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl, 2,2-dimethoxycarbonylvinyl, o- (N, N-dimethylcarboxamido) Benzyl, 1,1-dimethyl-3- (N, N-dimethylcarboxamido) propyl, 1,1-dimethylpropynyl, di (2-pyridyl) methyl, 2-furanylmethyl, 2-iodoethyl , Isofonyl, isobutyl, isonicotinyl, p- (p'-methoxyphenylazo) benzyl, 1-methylcyclobutyl, 1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl, 1-methyl- 1- (3,5-dimethoxyphenyl) ethyl, 1-methyl-1- (p-phenylazo Phenyl) 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-coroacetyl, N-tricorroacetyl, N-trifluoroacetyl, N-phenyl Acetyl, N-3-phenylpropionyl, N-tricholoacetyl, N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl, N-3-pyridylcarbox Mead, N-benzoylphenylalanyl, N-benzoyl, Np-phenylbenzoyl); Amide With Assisted Cleavage (No-nitrophenylacetyl, No-nitrophenoxyacetyl, N-acetoacetyl, (N'-dithiobenzyloxy Carbonylamino) 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-nitrosine Together, N- acetyl-methionine, No- nitrobenzoyl, No- (benzoyloxy-methyl) benzoyl, 4,5-diphenyl-3-oxazoline-2-one); Cyclic imide derivatives (N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenylmaleoyl, N-2,5-dimethylpyrrolyl, N-1,1,4,4- Tetramethyldisilazacyclopentane additive, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-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-phenylfluorenyl, N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, N-2-picolinylamine N'-oxide), imine derivative (TT-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 (pentacar Carbonylyl- 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-triphenyl Methylsulphenyl, N-3-nitropyridinesulphenyl) and N-sulfonyl derivatives (Np-toluenesulfonyl, N-benzenesulfonyl, N-2,3,6-trimethyl-4-methoxybenzenesulfonyl , N-2,4,6-trimethoxybenzenesulfonyl, N-2,6-dimethyl-4-methoxybenzenesulfonyl, N-pentamethylbenzenesulfonyl, N-2,3,5,6- Tetramethyl-4-methoxybenzenesulfonyl, N-4-methoxybenzenesulfonyl, N-2,4,6-trimethylbenzenesulfonyl, N-2,6-dimethoxy-4-methylbenzenesulfo Nyl, 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 . Another protecting group that may be usefully used as a prodrug at the G ₁ position, particularly for amino or b-NH (R ₅ ) is:

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

R _6c is H or an amino-containing compound, particularly an amino acid, polypeptide, protecting group, -NHSO ₂ R ₄ , NHC (O) R ₄ , -N (R ₄ ) ₂ , NH ₂ or -NH (R ₄ ) (H) As a residue of, for example, a carboxyl or phosphonic acid group of W ₁ reacts with an amine to form -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— where R ₁₇ is OH, OR _6a , OR ₅ , amino acid or polypeptide residue.

Amino acids are lower 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. In general, amino acids may be found or searched in nature, ie, among biological substances such as bacteria or other microorganisms, plants, animals or humans. Suitable amino acids are alpha amino acids, ie compounds characterized by one amino or imino nitrogen atom separated from a carbon atom of one carboxyl group by a single substituted or unsubstituted alpha carbon atom. Of particular interest are hydrophobic moieties such as mono- or di-alkyl or aryl amino acids, cycloalkylamino acids and the like. These residues contribute to cell permeability by increasing the fractionation of the parent drug. Generally, residues contain sulfhydryl or guanidino substituents.

Naturally-occurring amino acid residues are found in plants, animals or microorganisms, in particular their proteins. Polypeptides are the most representative examples of these naturally occurring amino acid residues. These amino acids are glycine, alanine, valine, leucine, isoleucine, serine, threonine, cystine, methionine, glutamic acid, aspartic acid, lysine, hydroxylysine, arginine, Histidine, phenylalanine, tyrosine, tryptophan, proline, asparagine, glutamine and hydroxyproline.

When R _6b and R _6c are single amino acid residues or polypeptides they are usually substituted with R ₃ , W ₆ , W ₁ and / or W ₂ , and generally only with W ₁ or W ₂ . These conjugates are produced by forming an amide bond between the carboxyl group of an amino acid (or such as the C-terminal amino acid of a polypeptide) and W ₂ . Likewise, a conjugate is formed between the amino group and W ₁ of an amino acid or polypeptide. Although it is within the scope of the present invention to introduce an amino acid at one or more allowed sites, only one site of the parent molecule is amidated with the above-mentioned amino acids. Generally, the terminal amino group or carboxyl group of the polypeptide or the α-amino group or α-carboxyl group of the amino acid is bonded to the parent functional group, ie the carboxyl or amino group in the amino acid side chain is generally not used to form an amide bond with the parent compound (although Although these groups need to be protected in the synthesis of the conjugate as described below).

With respect to the carboxyl-containing side chain of the amino acid or polypeptide, it will be understood that the carboxyl group is optionally blocked, for example by R _6a , esterified by R ₅ or amidated by R _6c . Likewise, the amino side chain R ₁₆ will optionally be blocked with R _6b or substituted with R ₅ .

Like esters or amides and parent molecules, the side chain amino or carboxyl groups and such ester or amide bonds are optionally hydrolysable under acidic (pH <3) or basic (> pH 10) conditions in vivo or ex vivo. 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 as intermediates in the preparation of oral molecules containing free amino or carboxyl groups. The free acid or free base of the parent compound can be readily produced, for example, from the ester or amino acid or polypeptide conjugates of the invention by conventional hydrolysis processes.

If the amino acid residues contain one or more chiral centers, their D, L, meso, threo or erythro (appropriately) racemates, scalemates or mixtures thereof can be used. In general, D isomers are useful if the intermediate is non-enzymatically hydrolyzed (as is the case with amides as chemical intermediates in free acids or free amines). Conversely, L isomers are more versatile because they are sensitive to both non-enzymatic and enzymatic hydrolysis, and are more efficiently delivered by amino acids or dipeptidyl delivery systems in the gastrointestinal tract.

Examples of suitable amino acids having residues 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-aminopimelic acid, 2-aminosuberic acid and 2-aminosebacic acid;

Amino acid amides such as glutamine and asparagine;

Polyamino- or polybasic-monocarboxyl such as arginine, lysine, β-aminoalanine, γ-aminobutyrin, ornithine, citrulline, homoarginine, homocitrulline, hydroxylysine, arohydroxylcin and diaminobutyric acid mountain;

Other basic amino acid residues such as histidine;

α, α'-diaminosuccinic acid, α, α'-diaminoglutaric acid, α, α'-diaminoadipic acid, α, α'-diaminopimelic acid, α, α'-diamino-β Diaminodicarboxylic acids such as hydroxypimelic acid, α, α'-diaminosuberic acid, α, α'-diaminoazelaic acid, and α, α'-diaminosebacic acid;

Imino acids such as proline, hydroxyproline, allohydroxyproline, γ-methylproline, pipecolic acid, 5-hydroxypipecolic acid, and azetidine-2-carboxylic acid;

Alanine, valine, leucine, allylglycine, butyrin, norvaline, norleucine, heptilin, 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-butylacetic acid, α-aminoethylisopropylacetic acid, α-amino-n-propylacetic acid, α-aminodiisoamylacetic acid, α-methylaspartic acid, α-methylglutamic acid, 1-aminocyclo Mono- or di-alkyl such as propane-1-carboxylic acid, isoleucine, alloisoleucine, tert-leucine, β-methyltryptophan and α-amino-β-ethyl-β-phenylpropionic acid (generally C _1-8 Branched or normal) amino acids;

β-phenylserinyl;

Aliphatic α-amino- such as serine, β-hydroxyleucine, β-hydroxynorvaline, and mono- or di-alkyl (usually C _1-8 branched or normal) amino acids-amino-β-hydroxystearic acid β-hydroxy acid;

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

2-hexosamine acids, such as D-glucosamine acid or D-galactosamic acid;

Α-amino-β-thiols such as penicylamine, β-thiolnorvaline or β-thiolbutyrin;

Other sulfur rock oil amino acid residues including cystine; Homocystine, β-phenylmethionine, methionine, S-allyl-L-cystine sulfoxide, 2-thiol histidine, cystathionine, and thiol esters of cystine or homocystine;

Phenylalanine, tryptophan and ring-substituted αamino acids such as phenyl- or cyclohexylamino acid α-aminophenylacetic acid, α-aminocyclohexylacetic acid and α-amino-β-heterohexylpropionic acid; Phenylalanine homologues and derivatives containing 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-54-nitro-, 2-hydroxy-5-nitro- and p-nitrophenylalanine) ; Furyl-, thienyl-, pyridyl-, pyrimidinyl-, purinyl- or naphthyl-alanine; And tryptophan homologues and derivatives, including tryptophan homologues and kynurenine, 3-hydroxykynurenine, 2-hydroxytryptophan and 4-carboxycittophan;

Α-amino substituted such as sarcosine (N-methylglycine), N-benzylglycine, N-methylalanine, N-benzylalanine, N-methylphenylalanine, N-benzylphenylalanine, N-methylvaline and N-benzylvaline amino acid;

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

A polypeptide is a polymer of amino acids, in which a carboxyl group of one amino acid monomer is bonded by an amide bond to an amino or imino group of the next amino acid monomer. 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 preferably suitably sequence-homologous to human, animal, plant or microbial protein. These include not only enzymes (eg hydrogen peroxide enzymes) but also immunogens such as KLH, or antibodies or proteins against a subject to which an immune response is to be raised. The nature and identity of polypeptides can vary greatly.

Polypeptide amidates are useful as immunogens that raise antibodies to the epitope of a polypeptide (if it does not produce immunogenicity in the animal taking it) or the remaining compounds of the invention.

Antibodies that can bind to non-peptidic parent compounds can be used to isolate the parent compound from the mixture in the diagnosis or preparation of the parent compound. Because conjugates and polypeptides of the parent compound are generally more immunogenic than closely related animal polypeptides, they are more immunogenic to allow the polypeptide to readily raise antibodies to it. Thus, the polypeptide or protein may not need to be immunogenic in animals commonly used to raise 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. The polypeptide may contain a peptidase cleavage site optionally between a first residue and a second residue adjacent to an acidic heteroatom. Such cleavage sites are flanked by enzymatic recognition structures such as, for example, specific residue sequences recognized by peptidase.

Peptidase enzymes for cleaving polypeptide conjugates of the invention are well known and particularly include carboxypeptides. Carboxypeptides degrade polypeptides by removing C-terminal residues and are specific in many cases for specific C-terminal sequences. These enzymes and their general substrate requirements are well known. For example, the dipeptides (having free residues with a given residue pair) covalently bind to the phosphorus or carbon atoms of the compounds of the present invention. In embodiments where W ₁ is a phosphonate, it is expected that the peptide will be cleaved by an appropriate peptidase to autocatalytically cleave the phosphoamidate linkage to the carboxyl of the terminal amino acid residue.

Appropriate dipeptidyl groups (denoted in their single letter code) are as follows:

Tripeptide residues are also useful as R _6b or R _6c . If W ₁ is phosphonate, then -X ₄ -pro-X _5- (wherein X ₄ is an amino acid residue and X ₅ is an amino acid residue, a carboxyl ester of proline, or hydrogen) is assigned to the luminal carboxypeptides Is cleaved to produce X ₄ with free carboxyl, which in turn is expected to autocatalytically degrade phosphonoamidate bonds. The carboxy group of X ₅ is esterified with benzyl.

Dipeptide or tripeptide species may be selected based on sensitivity to the peptides and / or known delivery properties that may affect delivery to visceral mucosa or other cell types. Dipeptides and tripeptides lacking an α-amino group are transfer substrates for peptide carriers found in the brush border of small intestinal mucosal cells (Bai, JPF, "Pharm Res." 9: 969-978 (1991). Peptides can therefore be used to increase the bioavailability of amidate compounds Di- or tripeptides having one or more amino acids in the D configuration can also be used for peptide delivery and in the amidate compounds of the invention. Amino acids of the D configuration can be used to reduce the sensitivity of di- or tripeptides to hydrolysis by proteases common to brush boundaries such as aminopeptides N (EC 3.4.11.2). Peptides, on the other hand, were also selected based on their relative resistance to hydrolysis by proteases found in the visceral cavity. For example, polypeptides or tripeptides that bind asp and / or glu are poor substrates for Aminopeptides A (EC 3.4.11.7) and on the N-terminus side of hydrophobic amino acids (leu, tyr, phe, val, trp) Di- or tripeptides lacking amino acid residues are poor substrates for endopeptides 24.11 (EC 3.4.17) Relatively resistant or relatively sensitive to hydrolysis by cytoplasm, kidney, liver, serum or other peptides Similar criteria can be applied to selecting peptides: Such poorly truncated polypeptide amidates are useful or immunogens for binding to proteins to produce immunogens.

Stereoisomer

The compounds of the present invention are optical isomers or resolved optical isomers which are enriched in any or all asymmetric atoms. For example, chiral centers apparent from the description are provided as chiral isomers or racemic mixtures. As well as both racemic mixtures and diastereomeric mixtures, individual optical isomers that are actually separated or synthesized without their enantiomers or diastereomeric partners are within the scope of the present invention.

One or more of the methods illustrated below are used to prepare enantiomerically rich or pure isomers. This method is listed according to the order of approximate preferences, ie, those skilled in the art should typically use stereospecific synthesis from chiral precursors prior to chromatographic degradation prior to spontaneous crystallization.

Stereospecific synthesis is described below. This type of method is often used when a suitable chiral starting material is available and the chosen reaction step does not result in undesirable racemization at the chiral position. One advantage of stereospecific synthesis is that it does not produce undesirable enantiomers that must be removed from the final product, ie lower the overall synthesis yield. In general, those skilled in the art will understand what starting materials and reaction conditions should be used to produce the desired enantiomerically rich or pure isomers by steric synthesis. If unexpected racemization occurs in a method that is considered stereospecific, the following separation method should be used to obtain the desired product.

If the proper stereospecific synthesis method is not experimentally devised or determined by conventional experimentation, one of ordinary skill in the art would choose another method. A commonly used method is the chromatographic decomposition of enantiomers on chiral chromatography resins. Such resins are packed in a column, commonly called a Pirkle column, and are commercially available. This column contains the chiral normal phase. The racemates are placed in solution and loaded on a column and separated by HPLC. For example, Proceedings Chromatographic Society-International Symposium on Chiral Separations, September 3, 1987. 3-4. Examples of chiral columns that can be used to identify optimal separation techniques include Diacel Chriacel OD, Regis Pirkle Covalend Dphenylglycine, Regis Pirkle Type 1A, Astec Cyclobond II, Astec Cyclobond III, Serva Chiral DDL = Daltosil 100, Bakerbond DNBLeu, Sumipax OA-1000, Merck Cellulose Triacetate column, Astec Cyclobond I-Beta or Regis Pirkle Covalent D-Naphthylalanine. Not all of these columns are effective for all racemic mixtures. However, those skilled in the art will understand that a certain amount of screening is required to identify the most effective steady phase. When using such a column, preference is given to using embodiments of the compounds of the invention in which the charge is not neutralized, for example, in which no acidic functional groups such as carboxyl are esterified or amidated.

Another method is to convert enantiomers in the mixture to diastereomers using chiral auxiliaries and then the conjugates are separated by conventional column chromatography. This is a particularly suitable method when the embodiments contain free carboxyl, amino or hydroxyl to form covalent bonds or salts for chiral assistants. Chirally pure amino acids, organic acids or organosulfonic acids are all valuable as chiral assistants and they are all well known in the art. Salts with these auxiliaries can also be produced or they can be covalently (but reversibly) bound to functional groups. For example, pure D or L amino acids can be used to amidate the carboxyl groups of embodiments of the invention and then separated by chromatography.

Enzymatic digestion is another potentially valuable method. In this process, covalent derivatives of enantiomers are prepared in a racemic mixture, generally a lower alkyl ester (such as of carboxyl), and then the derivatives are enzymatically cleaved, usually hydrolyzed. In order for this method to be successful, it is often necessary to screen several enzymes regularly, since it is necessary to select an enzyme that can be stereospecifically cleaved. When the ester is to be cleaved, esterases, phosphatides, lyphases and the like are selected and the activity of their derivatives is measured. Typical esterases are derived from organs of the liver, pancreas or other animals, and also include pork liver esterases.

When the enantiomer mixture is separated from the solution or melt as aggregates, ie enantiomerically-pure crystal mixtures, it is possible to produce enantiomerically rich formulations by mechanically separating the crystals. However, this method is not suitable for large scale production and is of no value for true racemic compounds.

Asymmetric synthesis is another technique for producing enantiomer enrichment. For example, the chiral protecting group is reacted with the group to be protected and the reaction mixture is equilibrated. If the reaction is enantiomerically specific, the product will be enriched for that enantiomer.

Additional information on the separation of enantiomer mixtures can be found in "Enantiomers, Racemates, and Resolutions", Jean Jacques, Andre Collet, and Samuel H. Wilen (Krieger Publishing Company, Malabar, FL, 1991, ISBN 0-89464-618-4 ) But is not limited thereto. In particular, Part 2, Resolution of Enantiomer Mixture, 217-435aus; More specifically, Section 4, Resolution by Direct Crystallization, pages 217-251, Section 5, Formation and Separation of Diastereomers, pages 251-369, Section 6, Crystallization-Induced Asymmetric Transformations, pages 369-378, and Section 7, Experimental Aspects and Art of Resolutions, pp. 378-435; More specifically, Section 5.1.4, Resolution of Alcohols, Transformation of Alcohols into Salt = Forming Derivatives, pages 263-266, Section 5.2.3, Covalent Derivatives of Alcohols, Thiols, and Phenols, pages 332-335, section 5.1. 1, Resolution of Acids, pp. 257-259, tprtus 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 Derivaties of Acids, Pages 329, section 5.2.2, Covalent derivatives of Amines, pages 330-331, section 5.2.4, Covalent Derivatives of Aldehydes, Ketones, and Sulfoxides, pages 335-339, and section 5.2.7, Chromatographic Behavior of covalent Diastereomers, Pages 348-354 are cited as related art examples.

The compounds of the present invention may also exist in some cases as tautomers. 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.

Exemplary Compounds.

For purposes of illustration and not for purposes of limitation, the names of specific compounds are given in the following table (Table 6). In general, each compound is indicated as a substituted nucleus, with the nucleus capitalized, and each substituent in lowercase or numeric order. Table 1 sets forth the different nuclear schedules primarily by the properties of the ring unsaturated positions and the ring substituents. Each nucleus is represented by an alphabetic representation from Table 1, which appears first in each compound name. Similarly, Tables 2, 3, 4 and 5 show the selected Q ₁ , Q ₂ , Q ₃ and Q ₄ substituents as alphanumeric representations. Thus, each named compound is represented in Table 1 by a capital letter indicating the nucleus, followed by a number indicating a Q ₁ substituent, a lower case indicating a Q ₂ substituent, a number indicating a Q ₃ substituent and a lower case indicating a Q ₄ substituent. Therefore, the compound having the following structure is named as follows.

Salts and hydrates

The compositions of the present invention optionally consist of pharmaceutically acceptable non-toxic salts which contain salts of the compounds, in particular Na ⁺ , Li ⁺ , K ⁺ , Ca ⁺⁺ and Mg ⁺⁺ and the like. Such salts may also include those derived by combining an alkali metal or alkaline earth metal ion or a suitable cation such as ammonium and a quaternary amino ion with an anionic portion of an acid, typically a W ₁ group of carboxylic acid. If a water-soluble salt is preferable, a monovalent salt is preferable.

Metal salts are typically prepared by reacting metal hydroxides with the compounds of the present invention. Examples of the metal salts produced by such a method include salts containing Li ⁺ , Na ⁺ and K ⁺ . By addition of a suitable metal compound, the non-soluble salt can be precipitated from the soluble salt solution.

In addition, salts may be prepared from acidic addition reactions to the basic centers of any organic and inorganic acids such as HCl, HBr, HSO, HPO or organic sulfonic acid, typically to amines in the G ₁ group, or to an acidic group such as E _1. have. Finally, it is to be understood that the compositions in this text include zwitterionic forms and combination forms with water in quantitative form, including their non-ionized forms.

Also included in the scope of the invention are salts of the parent compound with one or more amino acids. Any of the above amino acids is suitable, although the amino acids typically have a basic or acidic group such as lysine, arginine or glutamic acid, or a side chain to a neutral group such as glycine, serine, threonine, alanine, isoleucine or leucine In particular, natural amino acids found as protein components are suitable.

Neuraminidase Inhibition Method

The present invention also relates to a method of inhibiting neuraminidase activity, which comprises reacting a compound of the present invention with a sample suspected of containing neuraminidase.

The composition of the present invention acts as an inhibitor of neuraminidase and acts as an intermediate of such inhibitors or has other utility as described below. This inhibitory factor will bind to the surface or intraluminal position of neuraminidase, which has a form specific to neuraminidase. The neuraminidase binding composition may be combined in varying steps of reversibility. Substantially irreversibly bound compounds are ideal candidates for use in the methods of the present invention. In a typical example, these compositions bind neuraminidase with a binding index of less than 10 ⁻⁴ M, typically less than 10 ⁻⁶ M, more typically less than 10 ⁻⁸ M. If so, substantially irreversible binding compositions are useful as diagnostic probes of Neuraminidase. Accordingly, the present invention relates to reacting a sample presumed to contain neuraminidase with a composition containing a compound of the present invention in combination with a label, and observing the effect of the sample on the activity of the labeling agent. And a method for diagnosing neuraminidase in a sample presumed to contain neuraminidase. Suitable labels are known in the art of diagnosis, including stable free substituents, fluoropores, radioisotopes, enzymes, chemiluminators, chromogens and the like. The compounds of the present invention are labeled by conventional methods using substituents such as hydroxyl groups or amino groups.

Within the scope of the present invention, samples suspected of containing neuraminidase include living organisms, tissues or cell cultures, biological material samples (blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, etc.) and biological samples, Natural or artificial materials such as laboratory samples, food, water or air samples, bio-producing samples such as cell (especially, recombinant cells that synthesize glycoprotein). Typically this sample will be assumed to contain organisms that produce neuraminidase, usually pathogenic organisms such as viruses. Samples can be contained in any medium containing water and an organic solvent / water mixture. Samples include living organisms such as humans and artificial materials such as cell culture fluids.

The reaction step of the present invention consists in adding the composition of the present invention to a sample, or adding the precursor of this composition to this sample. The addition step may consist of any of the methods of administration as described above.

Where possible, the activity of neuraminidase after administration of this composition can be observed by any method, including direct or indirect methods of diagnosing neuraminidase activity. Both quantitative, qualitative or semi-quantitative methods of diagnosing neuraminidase activity are available. Typically, one of the screen methods as described above applies, but any other method may also be applied, such as observing the physiological properties of living organisms.

Organisms containing neuraminidase include bacteria (cholera bacteria, Welch bacteria, pneumonia streptococci and Athrobacter sialophilus) and viruses (especially orthomyxoviruses such as influenza viruses A and B or Paramyxoviruses, parainfluenza viruses, mumps virus, Newcastle disease virus, poultry fest and Sendai virus). It is included in the object of the present invention to inhibit neuraminidase activity obtained from or found in any of these organisms. 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 the treatment or prevention of such infectious diseases in animals or humans, such as, for example, ducks, rodents, or swans.

However, in the screening of compounds capable of inhibiting influenza virus, the results of the enzyme assay may not be correlated with the cell culture assay, as described in Table 1 of Chandler et al. Therefore, a plaque reduction assays must be the primary screening technique.

Neuraminiday's Suppressor's Screen

Some of the compounds of the present invention will be specific for certain organisms, such as neuraminidase from influenza Dan parainfluenza or bacterial versus viral neuraminidase. Such compositions are identified by conventional screening.

The compositions of the present invention are screened for inhibitory activity against neuraminidase by any conventional technique of measuring enzyme activity. Within the scope of the present invention, compositions are typically screened for inhibition of neuraminidase in vitro, and compositions that exhibit inhibitory activity are screened for in vivo activity. Compositions with in vitro K _i (inhibition constant) of less than about 5 × 10 ⁻⁶ M, typically less than about 1 × 10 ⁻⁷ M and preferably less than about 5 × 10 ⁻⁸ M are preferred for in vivo use. .

Since useful screens are known in vitro, the description thereof is omitted. However, in von Itzstein, M. et al., "Nature", 363 (6428): 418-423 (1993), in particular 420, column 2, the full text of monologues 3 to 421, column 2, the first partial section, Chong, AKJ, etc. In vitro suitable assays of "Anlyt. Biochem.", 94: 287-296 (1979) by Potier, M. et al., As modified by "Biochem. Biophys. Acta", 1077: 65-71 (1991). Is described; Colman, P.M. International Patent Publication No. Another useful in vitro screen is described in WO 92/06691 (Int. App. No. PCT / AU90 / 00501, published date: April 30, 1992) page 34, line 13 to page 35, line 16. have.

In vivo screens are also known in detail, see von Itzstein, M. et al., Page 421, column 2, first column to page 423, column 2, first partial column, see Colman, P.M. Suitable in vivo screens are described in lines 1-38 on page 36 of the above reference.

In the screening assays used herein, compositions with IC indices above 1 μM (micromolar) are considered inactive against influenza neuraminidase.

Pharmaceutical Formulations and Routes of Administration

The compounds of the present invention are combined with conventional carriers and excipients, which will be selected according to the general method. Tablets will contain excipients, lubricants, fillers, binders and the like. Aqueous formulations are prepared in sterile form and, if administered by a method other than oral administration, will consist of an isotonic solution. All formulations may optionally contain excipients as disclosed in "Handbook of Pharmaceutical Excipients" (1986). Excipients include ascorbic acid and other oxidizing agents, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcelluloses, hydroxyalkylmethylcelluloses, stearic acid, and the like. The pH of the blend is in the range of about 3-11 degrees, but is typically about 7-10 degrees.

One or more compounds of the invention may be administered by any route suitable for the condition being treated. Suitable routes include oral administration, rectal administration, intranasal administration, topical administration (including oral and sublingual), intravaginal and parenteral administration (subcutaneous, intramuscular, intravenous, transdermal, intrathecal and analgesic). ), And the like. It can be seen that the preferred route may vary depending on the symptoms of the patient. An advantage of the compounds of the invention is that they have oral bioavailability and are orally administrable, but they do not necessarily have to be administered by pulmonary or nasal route.

Although the active ingredients may be administered alone, it is preferred to administer them as pharmaceutical combinations. The formulations of the present invention, both for veterinary use and for human use, contain one or more active ingredients together with one or more acceptable carriers and any other therapeutic ingredients, as described above. The carrier is combined with the other ingredients of the formulation and must be "acceptable" in the sense of being physiologically harmless to its recipient (patient).

Formulations include those suitable for the route of administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any method known in the art of pharmacy. The methods and combinations are generally disclosed 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. In general, formulations are prepared by uniformly and cohesively binding the active ingredient to a liquid carrier or an undifferentiated solid carrier or both and optionally forming into a product.

Formulations of the present invention suitable for oral administration are discrete units, such as capsules, cachets or tablets, each containing a predetermined amount of active ingredient, as powders or granules, as solutions or suspensions of aqueous or non-aqueous solutions, oil-in-water liquids. It is prepared as an emulsion or as a water-in-oil liquid emulsion. The active ingredient may also be provided as a pill, softener or paste.

Tablets are prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersant. Molded tablets can be made by moistening the powdered active ingredient with an inert liquid diluent and molding in a suitable machine. Tablets may optionally be coated or graduated, and optionally formulated so that the active ingredient from the tablet may be released slowly or in a controlled form. In one example, acid hydrolysis of the agent is prevented using an enteric coating.

In the case of an infectious disease of the eye or other external tissue, such as the mouth or skin, the combination preferably contains the active ingredient (s), for example 0.075-20% w / w (0.6% w / w, 0.7% w / w, etc.). Active ingredient (s) in the range between 0.1% and 20% in increments of 0.1% w / ww), preferably 0.2-15% w / w, most preferably 0.5-10% w / w It is administered as a topical ointment or cream containing. When formulated into an ointment, the active ingredient may be used with ointment bases that are paraffinic or miscible with water. The active ingredient (s) may also be formulated in a cream with an oil-in-water cream base.

Where possible, the water-soluble phases of the cream origin include, for example, at least 30% w / w of polyhydric alcohols such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. Alcohols having two or more hydroxy groups can be included. Examples of such skin dosing enhancers include dimethylsulfoxide and related homologues.

The oil phase of the emulsions of the invention may be constructed in a known manner with known ingredients. Although this phase may contain only emulsfiers (or known as emulgents), it preferably contains at least one emulsifier and a mixture of fats or oils or a mixture of both fats and oils. do. It is preferred that hydrophilic emulsifiers be included together with lipophilic emulsifiers that act as stabilizers. It is also desirable to contain both oils and fats. On the other hand, emulsifiers combined with or without a stabilizer are made of so-called emulsion waxes, which together with oils and fats are made of so-called emulsion ointment bases, which form the oil dispersion phase of the cream formulation.

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

Selection of suitable oils or fats for use in the formulation is based on achieving the desired cosmetic properties. The cream should preferably be of a water soluble product with a suitable density so as not to be excessively greasy, unstained, and to prevent leakage from tubs or other containers. Straight or branched SARS, mono- or divalent alkyl esters such as di-isoadiate, isocetyl stearate, propylene glycol diesters of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl Stearates, 2-ethylhexyl palmitate or mixtures of branched chain esters known as Crodamol CAP and the like can be used, with the last three being the preferred esters. These may be used alone or in combination according to the desired properties. Alternatively, high melting lipids such as white paraffin and / or liquid paraffin or other mineral oils are used.

Formulations suitable for topical administration of the eye also include dropping eye drops, in particular aqueous solutions of the active ingredient, in which the active ingredient is dissolved or suspended in a suitable carrier. The active ingredient is preferably contained in such formulations at a concentration of 0.5-20% w / w, preferably 0.5-10% w / w, in particular about 1.5% w / w.

Formulations suitable for topical administration of the mouth include lozenges consisting of the active ingredient in a sweet base, usually sucrose and gum arabic or tragacanth; Pastilles consisting of the active ingredient on an inert base such as gelatin and glycerin or sucrose and gum arabic; And toothpaste composed of the active ingredient in a suitable liquid carrier.

Formulations for rectal administration may be supplied as suppositories with suitable substrates such as cocoa butter or salicylates.

Formulations suitable for intrapulmonary or intranasal administration are those in which the particle size falls within the range of 0.1-500 microns (particle size is in the range between 0.1-500 microns in micron increments such as 0.5, 1, 30 microns, 35 microns, etc.). Inhalation through the mouth, or rapid inhalation through the nasal passages, can reach the alveolar sac. Formulations suitable for aerosol or dry powder administration can be prepared according to known methods and delivered with other therapeutic agents, such as conventional compounds used for the prevention or treatment of influenza A or B infections, as described below.

Formulations suitable for vaginal administration may be presented as a parsley, tampon, cream, gel, paste, foam or spray formulation consisting of a suitable combination of carriers as known in the art, suitably for the active ingredient.

Formulations suitable for parenteral administration include solute and bacteriostatic agents, buffers, water-soluble and non-aqueous sterile injectable solutions containing antioxidants, and suspensions and excipients which provide a formulation that is isotonic in the blood of the patient to be treated. Aqueous and nonaqueous sterile suspensions are included.

This formulation is provided in unit dose or in multiple doses, such as sealed ampoules and vials, and stored as a lyophilized (freeze-dried) state, which is added only immediately before using a sterile liquid carrier such as water for injection. May be Instant injections and suspensions are prepared from sterile powders, granules and tablets of the kind described above. Preferred unit dose combinations are those containing a daily dose or unit daily sub-dose, or an appropriate fraction thereof, of the active ingredient, as described above.

Formulations of the present invention may include other agents conventional in the art for the type of formulation in question, in addition to the components as described above, for example, those suitable for oral projection may include seasoning agents. It should be understood that.

The present invention also provides a veterinary composition consisting of a veterinary carrier thereof with at least one active ingredient as described above.

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

The compounds of the present invention also provide controlled release pharmaceutical formulations ("controlled release formulations") containing one or more compounds of the present invention as active ingredients, wherein the release of the active ingredient is a drug of a given active ingredient. Adjustments and adjustments are made to allow for improved or more frequent administration of an epidemiological or toxic profile.

The effective dosage of the active ingredient depends at least on the symptoms, toxicity, and whether the compound is intended to be used prophylactically (in small dosages) or to treat active influenza infections, as well as delivery methods and pharmaceutical combinations. And will be determined by the attending physician using conventional dose escalation studies. It can be estimated that it will be about 0.0001-100 mg / kg body weight / day. Typically, it will be 0.01-10 mg / kg body weight / day. More typically, it will be 0.01-5 mg / kg body weight / day. For example, for inhalation, the recommended daily dose of an adult 70 kg body weight will be in the range of about 1-1000 mg, preferably 5-500 mg, and can be administered in the form of a single dose or multiple doses.

The active ingredients of the present invention may also be used in combination with other active ingredients. Such a combination is selected based on the condition to be treated, the cross reactivity between the components and the drug properties of the combination. For example, when treating viral infections of the respiratory system, especially influenza infections, the compositions of the present invention can be used in antiviral agents (such as amantidine, rimantadine, and ribavirin), mucolytics, expectorants, bronchodilators, antibacterials, antipyretics Or in combination with analgesics. Typically, antimicrobials, antipyretics and analgesics are administered with the compounds of the present invention.

Underclothing protection

The present invention also relates to the protected forms for internal use of the compounds of the present invention. As used herein, "enteric protection" refers to protecting (shielding) a compound of the invention such that a portion of the gastrointestinal system, typically the upper gastrointestinal system, particularly the stomach and esophagus, is not exposed to the compound of the invention. Means that. In this way, gastric mucosal tissue is ensured for the rate of exposure with a compound of the invention that causes side effects such as nausea, and the compound of the invention is also present in the gastrointestinal system, in particular in one or more parts of the upper gastrointestinal system. It is protected from the conditions.

These undergarments protected forms include undercoat coating excipients such as undercoat coating tablets, undercoat coating granules, undercoat coating beads, undercoat coating particles, undercoat coating microparticles and undercoat coating capsules. For example, but not limited to. In a preferred embodiment, the compounds of the present invention are contained in suitable excipients such as tablets, granules or capsules, which are covered by a pharmaceutically acceptable oral coating. In another preferred embodiment, the compounds of the invention are prepared as orally protected protected granules, particles, microparticles, rings, microcycles or colloids, wherein the orally protected protected granules, particles, microparticles, rings, microcycles or colloids are It is prepared as a pharmaceutically acceptable dosage form such as tablet, granule, tablet or suspension.

As one of the features of the present invention, a pharmaceutical composition containing about 0.1-1000 mg of a therapeutically effective amount of an active ingredient and any pharmaceutically acceptable excipients is for effectively delivering to the intestine, preferably the small intestine of a human or other mammal. And to an oral coating coated dosage form of a compound of the invention.

As used herein, "vehicle" includes pharmaceutically acceptable dosage excipients. Many excipients are known in the art and are tablets, dragees, capsules, hard capsules, soft gelatin capsules, particles, microparticles, rings, microcycles, colloids, microencapsulated, sustained release, semisolid Suppositories or granular excipients are cited in the text.

"Pharmaceutically acceptable excipients" as used herein include any of the physiologically stable, pharmacologically inactive substances known to those skilled in the art, and include the physiological and chemical properties of certain compounds of the invention selected for use. It must match well. Such excipients are also described herein. Excipients may, but not necessarily, provide for oral protection.

By "unit administration" is meant, in conventional practice, to be administered or applied once to an object to be treated with the compound of the invention in an amount as described below. It is to be understood that the therapeutic or prophylactic dosage may be given in single unit doses, or may be given in duplicate of two or more of these dosage units in a total dose up to the desired amount of the compound over a period of time. will be.

In general, the oral unit dosage form composition of the present invention preferably contains about 1-1000 mg (mg), typically about 10-500 mg, more preferably about 50-300 mg of the compound for each unit dose. More typically, about 75 mg. Actual usage will vary depending on the active compound selected.

In a typical example, an oral protective agent is applied to an excipient containing a compound or to a compound without an excipient, which protects against nausea-induced exposure, oral or esophageal or gastric exposure, but in dosage forms When is passed adjacent to the lower gastrointestinal system, or in some instances, releases the compound to be absorbed substantially only in the colon.

The relative properties of the compounds of the invention with the protective agents are changed to achieve the proper absorption action according to the selected compound. The minimum or maximum amount in weight percent of the protective agent for internal use is not critical. Typically, the undergarment protected example contains less than about 50% by weight of the undercoat coating. More typically about 1-25%, more typically about 1-15%, even more typically about 1-10% (all wt%).

Related Fields:

Numerous monographs describe the topical protection and related technologies. Such monographs include: "Theory and Practice of Industrial Pharmacy," 3rd ed. Lea & Febiger, Philadelphia, 1986 (ISBN 0-8121-0977-5); Lehmann, 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, Margaret 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: 92-4-154418-X); Karsa, DR, Editor; Stephenson, RA, Editor, "Excipients & Delivery Systems for Pharmaceutical Formulations: Proceedings of the "Formulate '94" British Association for Chemical Specialties Symposium ", 1995, CRC Pr (ISBN: 0-85404-715-8); Ansel, Howard C .; Popovich, Nicholas G. Allen, Lioyd V., "Pharmaceutical Dosage Forms & Dru g Delivery Systems, 6th ed. ", 1994, Williams & Wilkins (ISBN: 0-683-01930-9); "The Sourcebok for Innovative Drug Delivery: Manufacturers of Devices & Pharmaceuticals, Suppliers of Products & Services, 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); Avid; Lieberman, L .; Lachman, "Pharmaceutical Dosage Forms: Parenteral Medication, 2nd Expanded; Revised ed.", 1992, Dekker (ISBN: 0-8247-9020-0); Laffer, U., Editor; Bachmann, I., Editor; Metzger, U., Editor, "Implantable Drug Delivery Systems", 1991, S Karger (ISBN: 3-8055-5434-6); Borchardt, Ronald T., Editor; Repta, Arnold J., Editor; Stella, Valentino J., Editor, "Directed Drug Delivery: A Multidisciplinary Approach", 1985, Humana (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 & Wikins (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 Solids & Solid Dosage Forms", 1977, Wiley (ISBN: 0-471-13726-X); Robinson, Joseph R., Eidtor, "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 Sciences: Dosage Form Design & Bioavailability", 1985, Lea & Febiger (ISBN: 0-318-79917-0); Sprowls, Joseph B., Editor, "Prescription Pharmacy: Dosage Formulation & Pharmaceutical Adjuncts, 2nd ed.", 1970, Lippincott (ISBN: 0-397-52050-6); and Polderman, J., Editor, "Formulation & Preparation of Dosage Forms: Proceedings of the 37th International Congress of Pharmaceutical Sciences of FIP, The Hague, Netherlands, September, 1977", Elsevier (ISBN: 0-444-800033-6) .

Specific example:

In another example, the compositions of the present invention have an oral coating coated tablet dosage form. In this example, the blend is molded into a hard tablet by conventional methods and the tablets are coated with an internal coating according to conventional methods.

In a preferred embodiment, the compounds of the present invention have an oral coating coated powder dosage form. In this example, the formulation is filled into a hard or soft-shell capsule or equivalent thereof, which is coated with an internal coating according to conventional methods.

In one example, the composition of the present invention has the form of a suspension of the internal coating coated particles of the compound of the present invention. In this example, the suspension of the inhibitor in the liquid phase is filled into a hard or soft-shell capsule or equivalent thereof, and the capsule is coated with an internal coating according to conventional methods.

As an alternative to the above examples, the capsule or other dosage container itself constitutes an oral protective agent or protective component or is a component of the container.

In another example, an oral protective agent is used to administer a compound of the present invention to the colon. The delivery system is a tablet consisting of three layers: 1) a core layer containing the active ingredient of the present invention; 2) a non-expandable, corrosive polymer layer surrounding the core layer (in combination of the core with a corrosive polymer layer referred to as a "dual matrix tablet"); 3) An internal coating layer applied to the dual matrix tablet. The composition and function of the components of this colon targeted delivery system are also incorporated by reference in U.S. Pat. Patent No. 5,482,718, in particular column 2, line 29 through column 4, line 12 has a close relationship with the text.

Another example of the invention relates to orally protected, protected emulsions, suspensions, tablets, dragees, hard capsules, soft gelatin capsules, microcapsules, sustained release, liquid, semisolid, suppository, and aerosol dosage forms of the compounds of the invention. will be. "Theory and Practice of Industrial Pharmacy", 3rd ed. Lea & Febiger, Philadelphia, 1986 (ISBN 0-8121-0977-5) describes each of these standard dosage forms in detail in the following sections: emulsion and suspension forms (pp. 100-122), tablets (pp. 293). -345), dragees (pp. 346-373), hard capsules (pp. 374-397), soft gelatin capsules (pp. 398-411), microcapsules (pp. 412-430), sustained release (pp. 430-456), liquid form (pp. 457-478), pharmaceutical suspension (pp. 479-501), emulsion (pp. 502-533), semisolid form (pp. 534-563), suppository (pp. 564-587 ) And about ?? Aerosol (pp. 589-618).

In another example, the dosage forms of the compounds of the present invention in the form of orally protected, sustained release, controlled release, particulate, microcapsule, multiparticulate, microparticulate, colloidal, non-resistant, inhalable, oral mucosa , Colonic, dermal, transdermal, ocular, topical and veterinary dosage forms. Each such dosage form technique is described in detail in "Drugs and the Pharmaceutical Sciences" (edited by James Swarbrick, Marcel Dekker, New York).

Substances:

Conventional oral protective agent polymers, or mixtures of polymers, usable in the present invention are insoluble at or below about pH 5.5, ie, generally found in the stomach, but soluble at or above about pH 5.5, i.e., indices present in the small and large intestine. Phosphorus material is included. The effectiveness of certain oral protective agent materials can be measured using known US patented methods.

Representative oral protective polymers that may be used in this example include cellulose acetate phthalate, methyl acrylate-methylacrylic acid copolymer, polyvinyl acetate phthalate and methyl methacrylate-methacrylic acid copolymer. As another example, anionic carboxyl copolymers based on methacrylic acid and methacrylate which are commercially available as Eudragit (r) can be given. Typical examples include cellulose acetate phthalate ("CAP"), cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate ("HPMCP"), hydroxypropyl methylcellulose phthalate succinate, polyvinyl acetate phthalate ("PVAP"). ), Methacrylic acid and methacrylic acid esters. More typically, this protective agent is selected from PVAP and / or HPMCP, in particular PVAP. PVAP is well known as a trademark of Sureteric (r) manufactured by Colorcon, Inc.

This oral protective agent material can be prepared using conventional plasticizers, acetylated monoglycerides, propylene glycol, glycerol, glyceryl triacetate, polyethylene glycol, triethyl citrate, tributyl citrate, diethyl phthalate using methods known to those skilled in the art. Or an excipient with or without dibutyl phthalate or the like.

Embodiments illustrating oral protection are as follows:

Embodiment 1 Internal Protection Protected A.141.x.4.1 Capsules

In an exemplary embodiment of the present invention, Compound A.141.x.4.i, phosphate salt form, 100 mg / capsule, contains Croscarmellose Sodium (2.6 mg / capsule) and a size 4 white opaque hard gelatin capsule shell (captang) Composition: Gelatin NF, Titanium Dioxide USP) was mixed and this capsule was coated with an internal coating.

The following internal coating formulations are applied to capsules according to methods known to those skilled in the art:

Formulation A:

ingredient % w / w Hydroxypropyl Methylcellulose Phthalate ("HPMCP") 5.0 Triacetin 0.5 Alcohol USP 7.9 water 15.5

Formulation B:

ingredient % w / w HPMCP 10.0 Titanium dioxide 0.2 Dimethyl Polysiloxane 0.05 Triethyl citrate 1.0 Alcohol USP 72.75 water 16.00

Formulation C:

ingredient % w / w Cellulose Acetate Phthalate ("CAP") 8.5 Diethyl phthalate 1.5 Titanium dioxide 0.2 Acetone 44.9 Denatured alcohol 44.9

Formulation D:

ingredient % w / w Polyvinyl Acetate Phthalate ("PVAP") 5.0 Acetylated Glyceride 0.8 Methylene chloride 47.1 Denatured alcohol 47.1

Formulation E:

ingredient % w / w Methacrylic acid or methacrylic acid esters (Eudrgit (r) S or L, Rohm Pharma, GMBH, Wetterstadt, West Germany) 8.0 Acetone 46.0 Anhydrous alcohol 46.0 Plasticizer q.s.

Typically the internally coated coating polymer (with or without plasticizer) is dissolved in the solvents described under each formulation designation to produce a suspension / solution. Optionally, an opaque agent such as titanium dioxide is added. Under conditions that allow the oral protective coating to be placed at the bottom of the container without dissolving or grinding the excipient, the excipient is sprayed with a coating suspension / solution in a suitable container. About 1-50 wt%, typically 1-15 wt%, more typically 5-10 wt% of the final coated excipient of the oral polymer coating will be useful for proper oral protection.

Embodiment 2: Protected Tablet for Internal Use

In another exemplary embodiment, the coated tablet was coated with an internal coating. Optionally, subcoating may be used.

Core Tablets:

The core tablets of the present invention comprise (a) active ingredients in a mixture including, for example, diluents, binders, disintegrants and optionally: one or more components selected from compression aids, flavors, flavor enhancers, sweeteners, dyes, pigments, buffers and preservatives. By combining with a pharmaceutically acceptable excipient, (b) lubricating the mixture with lubricant, and (c) compressing the resulting lubricated mixture into the desired tablet form using various tableting techniques available to those skilled in the art. have. The term "tablet" in the text is intended to include pharmaceutical dosage forms of all shapes and sizes that are compressed or shaped.

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

Typical binders that may be used in this embodiment include, but are not limited to, povidone. Povidone is commercially available from ISP Corporation under the trade name "Avicel".

The disintegrant can be one of several modified starches, or modified cellulose polymers. Generally croscarmellose sodium is used.

Crosscapmellose sodium NF Type A is commercially available under the trade name "Ac-di-sol".

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

Flavoring agents include Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, 1990, pp. Included are those described in 1288-1300.

Common sweeteners include saccharin, aspartame, or edible mono- or disaccharides such as glucose or sucrose.

Dyes and pigments are described in Handbook of Pharmaceutical Excipients, pp. 81-90, 1986 (American Pharmaceutical Associateion & the Pharmaceutical Society of Greaty Britain).

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

Undercoat Coatings:

Eudragit L-30-D (r), a methacrylic acid copolymer manufactured by Rohm Pharma GmbH (Weiterstad, West Germany) is a suitable internal use polymer. Eudragit L-30-D (r) has a ratio of free carboxyl groups to ester groups of about 1: 1 and is freely soluble at pH 5.5 and above. In general, the higher the percentage of Eudragit L-30-D (r) contained in the internal coating, the more proximal the release of the active drug in the lower gastrointestinal tract. The location in the lower gastrointestinal tract in which the coating releases the compounds of the present invention is operable by adjusting the composition and the thickness of the internal coating used.

Generally, plasticizers such as those described above are included. Other additives such as talc or silica may also be used to separate the coating process.

Sub-coating:

Sub-coating agents are optionally used to improve stability on the core tablets to minimize the interaction between the compounds of the present invention and the oral coatings. It also allows the use of a single 10-300 micron-thick inner coat without adversely affecting production stability. This subcoating inhibits the migration of the active ingredient from the core tablet into the oral coating, thus improving shelf life and production stability, but the subcorning material dissolves rapidly in the sera once, causing the external oral coating to break.

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

Metabolism of Compounds of the Invention

In vivo metabolic products of the compounds described herein are also within the scope of the present invention, unless they are novel and unambiguous with respect to the prior art. Such products can result from oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, mainly due to the enzymatic process. Accordingly, the present invention includes novel and nonobvious compounds produced by a process that results in contacting a compound of the present invention with a mammal for a period of time sufficient to produce its metabolites. Such products produce radiolabeled (such as C ¹⁴ or H ³ ) compounds of the present invention and can be used in searchable dosages (such as greater than about 0.5 mg / kg) such as rats, mice, guinea pigs, monkeys or humans. Administration to animals is followed by sufficient metabolism (typically about 30 seconds to 30 hours) and identification by separating their conversion products from urine, blood or other body fluids. These products are easily separated because they are labeled (others are separated by using antibodies capable of binding epitopes surviving 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 done in the same manner as in conventional drug metabolism studies well known to those skilled in the art. Conversion products are useful in diagnostic assays for therapeutic dosages of compounds of the invention, even if they do not have neuraminidase inhibitory activity, unless otherwise found in vivo.

Another Use of the Compounds of the Invention

The compound of interest and the biologically active substance prepared by metabolism in vivo of the compound and the compound of the present invention can be used as a conjugator of an immunogen or protein. In addition, by conjugating to a protein, a component of an immunogenic composition for producing an antibody that specifically binds only to a protein having an epitope (epitope-antibody binding site) which is recognized immunologically, the compound or a product of metabolism thereof, and the like. It may be provided as. Thus, the composition of an immunogen is useful as an intermediate used to prepare antibodies for use in diagnosis, quality control or the like, or to analyze a compound of the invention or a metabolite thereof. Compounds of the present invention are useful for inducing antibodies to other non-immunogenic polypeptides as they serve as hapten sites that stimulate an immune response that cross reacts with unmodified conjugated proteins.

Important hydrolysis products include the hydrolysis products of the protected acids and bases described above. As mentioned above, amides of acids and bases consisting of immunogenic polypeptides such as albumin or keyhole limpet homocyannin are useful as immunogens. The aforementioned metabolites may have a significant degree of crossreactivity with the compounds of the present invention. Thus, the antibodies of the present invention may selectively bind unprotected compounds without binding to the protected compounds of the present invention, whereas metabolites do not bind with unprotected compounds and with protected compounds and / or metabolites May be selectively coupled, or may be coupled to any one or all three.

Immunogens of the invention contain a compound of the invention that provides an epitope suitable for binding to an immunogenic material. Within the context of the present invention, binding means a mixture of covalently or non-covalently bound substances forming an immunogenic conjugate, or a combination of the two. Immunogenic agents include adjuvants such as Freund's adjuvant, immunogenic proteins such as viruses, bacteria, yeast, animal and animal polypeptides, in particular keyhole limpet homocyanin, cerum albumin, bobbin tyroglobulin or soybean trypsin inhibitors, and It contains immunogenic polysaccharides. Compounds with appropriate epitope structures are covalently conjugated to an immunogenic polypeptide or polysaccharide using crosslinking reagents of multiple functional groups (generally two functional groups). Methods of making hapten immunogens are conventional and any method of conjugating previously used hapten to an immunogenic polypeptide or the like may be appropriately employed. However, the possibility of producing antibodies specific to the epitope in question may be considered, as opposed to functional groups and immunogenic substances possessed by precursors or hydrolysis products and useful for crosslinking.

In general, polypeptides are conjugated at positions remote from the recognized epitopes present in the compounds of the invention. Conjugates were prepared by conventional methods. For example, cross-linking reagents such as N-hydroxysuccinimide, succinic anhydride, alkN = C = Nalk and the like are useful for preparing the conjugate of the present invention. The conjugate constitutes a compound of the present invention that is attached to the immunogenic material by a linkage or a linking group having 1 to 100, preferably 1 to 25, more preferably 1 to 10 carbon atoms. The conjugate is distinguished from the starting materials and by-products by chromatography or the like and is sterile filtered and stored in the vial.

The compound of the present invention crosslinks through any one or more of, for example, a hydroxyl group of W6, a carboxyl group of E1, a carbon atom of W6, E1, G1, or T1 (substituted hydrogen) and an amine group of G1. . Included in such compounds are the amides of the polypeptides provided in the aforementioned R6c or R6b groups.

Animals are generally immune to antibodies which are immunogenic conjugates or derivatives thereof and immune serum or cells produced by traditional methods.

Compounds of the invention are useful for maintaining the structural integrity of glycoproteins in recombinant cell culture. That is, the compound of the present invention may be added to the fermentation in which the glycoproteins necessary for recovery are prepared in order to prevent the destruction of the glycoproteins catalyzed by the neuraminidase. This is of great value for the recombinant synthesis of proteins in heterologous host cells which disadvantageously reduces the carbohydrate portion of the protein being synthesized.

The compound of the present invention has a plurality of functional groups. Thus they can act as monomers in polymer synthesis. Polymers synthesized from the compounds of the present invention, by way of example or without limitation, include polyamides and polyesters.

The compounds of the present invention are used as monomers that are unique and facilitate access to polymers with unknown functional groups. The compounds of the present invention are useful in single polymers, and are also useful as monomers of monomers that do not fall within the scope of the present invention. Monomeric polymers of the compounds of the invention may be used in the preparation of molecular sieves (polyamides), textiles, fibers, films, articles in which functional groups E1 of acids are esterified by hydroxyl groups W6, and the like, in the preparation of cation exchangers (polyesters or poly Amide). For example, purification is possible by binding G1, a basic functional group of a polyester, to an acidic functional group found in a polypeptide. Polyamides are prepared by the crosslinking of E1 and G1, where W6 and the portion adjacent to W6 in the ring have nucleophilic or electrophilic affinity. Methods for preparing such polymers from the compounds of the present invention are well known.

The compounds of the present invention are also useful as surfactants. Especially when W6 does not have a nucleophilic substituent, for example an alkyl or alkoxy group, the compound has the property as a bi-functional surfactant. Thus, the compound has surface activity, surface coating, emulsion deformation, fluidity deformation and surface wetting properties.

Because of having the specified geometry and polar and nonpolar moieties, the compounds of the present invention are used as phase transfer reagents. By way of example or without limitation, the compounds of the present invention are useful as phase transfer catalysts and liquid / liquid ion extraction (LIX).

The compounds of the present invention may optionally have asymmetric carbons among the W6, E1, G1, and T1 groups. Accordingly, the compounds of the present invention are used as chiral auxiliaries for the synthesis or separation of optically active substances. For example, the racemate of carboxylic acid

1) forming a diastereomeric ester or amide with a compound of the invention wherein W6 is an asymmetric hydroxyalkane or aminoalkane,

2) separating diastereomers,

3) can be separated into each component enantiomer by the step of hydrolyzing the ester. Alcohol racemates can also be separated by the formation of esters with the acidic group E1. Furthermore, this method can be used for the separation of the compounds of the present invention, provided that the starting material is not a racemate but an optically active material.

The compounds of the present invention are used for the use of linkers or spacers in affinity absorption substrates, process control non-flowing enzymes or immunoassays. The compound contains a plurality of functional groups therein suitable for bonding with substances requiring crosslinking. For example, it is common to combine hormones, peptides, antibodies, medicines and similar affinity reagents with insoluble substrates. This insoluble substrate can be employed for the purpose of absorbing affinity reagents as binding partners from pharmaceuticals, diagnostic samples and mixtures containing impurities by known methods. Similarly, non-flowing enzymes can be used for the purpose of performing catalytic conversion while recovering themselves easily. In the preparation of diagnostic reagents, dual functional compounds are commonly used for linking analytes to detectable groups.

The plural functional groups possessed by the compounds of the present invention are suitable for cross-linking applications. For example, the carboxylic or phosphonic acid functional groups of El are suitable for forming amides with alcohols or esters or amines. G1 substituted by OH, NHR1, SH, azido (converted to amino group before crosslinking), CN, NO2, amino, guanidino, halo and the like is also crosslinkable. Appropriate protection of the functional groups can be done to prevent polymerisation between the compounds of the invention. Generally, the carboxy or posophonic acid functional group of the compound of the present invention is bonded to the hydroxy or amino group of the first binding partner, followed by binding to another partner using a T1 or G1 group. Non-flowable steroids are obtained by, for example, ester-linking a first binding partner, such as a steroid, with a carboxylic acid of the invention and covalently linking a G1 hydroxy group with a cyanozenbromide-activated sephaarose. Chemistry for other conjugations is well known. For example, look at Maggio's "Enzyme-immunoessay" (CRC, 1988, pp 71-135) and references cited therein. As mentioned above, clinically useful compounds of the invention wherein the W1 or G1 carboxyl, hydroxyl or amino groups are protected are used orally or sustained release. In such use, the protecting group is removed by hydrolysis or oxidation in vivo to yield an unprotected carboxyl, amino or hydroxy group. Suitable esters or amides for this use are selected based on the substrate specificity of the esterases and / or carboxypeptidases found in cells in need of hydrolysis of the precursors. As the substrate specificity of the enzyme is unknown, screens for a plurality of compounds of the invention are needed until the desired substrate specificity is found. Substrate specificity is confirmed by the appearance of unprotected acid or antiviral activity. The reason for the general choice of ester or amide form among the compounds of the invention is i) not hydrolyzed or very slowly hydrolyzed in the upper gut, ii) penetrated into gut and cells, iii) cytoplasmic or systemic circulation This is because hydrolysis takes place during the process. Screen assays use cells from tissues susceptible to influenza (eg, mucosa of the bronchial lineage). Assays known in the art are useful for determining bioavailability in vivo, including intestinal lumen stability, cell penetration, hepatic liquor stability and plasma stability assays. However, esters, amides or other protected derivatives are useful as chemical intermediates even if they do not change in carboxyl, amino or hydroxy groups in vivo.

Sample Methods of Making Compounds of the Invention

The invention also relates to a process for preparing the compounds of the invention. The compound may be prepared by any technique applicable to organic synthesis. Many techniques are known in the art and are described in the literature below.

"Compendium of Organic Synthetic Method" (John Wiley & Sons, New York), Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol 2, Ian T. Harrison and Shuyen 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; Vol 6, Michael B. Smith; as well as March, J., "Advanced Organic Chemistry, Third Edition", (John Wiley & Sons, New York, 1985), "Comprehensive Organic Synthesis.Selectivity, strategy & Efficiency in Modern Organic Chemistry.In 9 Volumes", Barry M. Trost, Editor-1n-chief (Pergamon Press, New York, 1993 Printing).

Various sample methods for preparing the compounds of the present invention are disclosed below. These methods are intended to illustrate the nature of such manufacture and do not limit the scope of the application.

In general, the reaction conditions of a particular reaction, such as temperature, reaction time, solvent, workup procedure and the like, are common in the art. The references cited above detail the reaction conditions for each material.

In general, the reaction temperature is -100 ~ 200 ℃, the solvent may be a protic or aprotic solvent, the reaction time is about 10 seconds to 10 days. The reaction termination procedure usually consists of quenching and extraction.

Oxidation and reduction reactions are carried out at -100 to 0 ° C in the case of metal hydrides, but are generally carried out near room temperature (about 20 ° C). Protic or aprotic solvents can be used. The reaction time is adjusted to a time suitable for the desired reaction to occur.

Condensation reactions occur mainly at or near room temperature, while non-equilibrium or kinematically controlled condensation occurs at low temperatures (-100 to 0 ° C). The solvent can be protic (mainly equilibrium) or aprotic (mainly kinematically controlled).

Basic synthetic techniques such as azotropic removal of reaction byproducts and anhydrous reaction conditions (eg inert gas atmosphere) are common in the art and may be applied where applicable.

A sample preparation method of the compound of the present invention is shown in the following scheme. The general view of the sampling method is as follows. Each product of the process below can be optionally separated, isolated and purified before proceeding to the next process.

"Treated", "treating", "treatment" and similar words mean contacting, mixing, reacting, reacting, contacting, converting one chemical entity to another, and the like. In other words, "treatment of compound 1 with compound 2" means that compound 1 can react with compound 2, contact of compound 1 with compound 2, reaction of compound 1 with compound 2, and the field of organic synthesis Is used synonymously with "other" to mean "treating", "reacting", "reacting", etc., with Compound 2.

Normal concentration (0.01 M to 10 M, typically 0.1 M to 1 M), temperature (-100 to 250 ° C, generally -78 to 150 ° C, more generally 0 to 100 ° C), reaction vessel (generally glass , Plastics, metals), solvents, pressures, atmospheres (insensitive to oxygen and water, air, oxygen and water sensitive reactions are generally nitrogen or argon) and so on unless otherwise noted. Based on the knowledge of similar reactions known in the art of organic synthesis, the reaction conditions and apparatus for determining successful reactions were determined. One of ordinary skill in the art would be able to do this.

In one embodiment, a method for preparing a compound of the present invention as described in Scheme 1 is disclosed. Cyastatin B (1) obtained from natural substances [Umezawa, H, et al. "J. Am. Chem. Soc", 27; 963-969, (1974) or ribose (Nishimura, Y. et al. "J. Am. Chem. Soc ", 110; 7249-7250, 1988; and" Bull. Chem. Soc. Jpn. ", 65: 978-986, (1992) can be used with any enantiomer. The conversion was done by known methods (Nishimura, Y. et al. "J. Antibiotics", 46 (2): 300-309, 1993). Reductive alkylation to form compound 3 is also known (Nishimura, Y. et al. "J. Antibiotics", 45 (10): 1662-1668, 1992) The conversion of an alcohol group of compound 3 to an amine group of compound 4 is described by Zbiral, E. et al. ["Liebigs Ann Chem. ", 129-134 (1991) and von Itzstein, M. et al." Carbohydrate Res., 244: 181-185 (1993). "Compounds by removal of protecting groups 5 was prepared.

By way of example or without limitation, R ¹ is ethyl (Et, -CH ₂ CH ₃ ), 1-propyl (n-Pr, n-propyl, -CH ₂ CH ₂ CH ₃ ), 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 ), 1-pentyl (n -pentyl, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 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-ethyl-1-butyl (-CH ₂ CH (CH ₂ CH ₃ ) ₂ ), 2- Ethyl-4-phenyl-1-butyl (-CH ₂ CH (CH ₂ CH ₃ ) (CH ₂ CH ₂ Ph)), or 2- (2-phenylethyl) -4-phenyl-1-butyl (-CH ₂ Compound 5, CH (CH ₂ CH ₂ Ph) ₂ ), was prepared by the method of Scheme 1.

In another example, a method for preparing a compound of the present invention as described in Scheme 2 is disclosed. Enantiomers (6) of cyastatin B were prepared by ribose (Nishimura, Y. et al. "J. Am. Chem. Soc", 110; 7249-7250, 1988; and "Bull. Chem. Soc. Jpn. ", 65: 978-986, 1992). The conversion to protected compound 7 was accomplished by known methods (eg Pg = Boc, Nishimura, Y. et al. "J. Antibiotics", 46 (2): 300-309, 1993). Conversion of the alcohol group of compound 7 to an amine group of compound 8 is described by Zbiral, E. et. al. ("Liebigs Ann. Chem.", 129-134 (1991)) and von Itzstein, M. et. al. ("Carbohydrate Res.", 244: 181-185 (1993)). Reductive alkylation to form compound 9 was also accomplished by known methods (Nishimura, Y. et al. "J. Antibiotics", 45 (10): 1662-1668, 1992). Compound 10a was prepared by removing the protecting group. Compound 10a is the same material as compound 10b.

By way of example or without limitation, R ² is hydrogen and R ³ is ethyl (Et, -CH ₂ CH ₃ ), 1-propyl (n-Pr, n-propyl, -CH ₂ CH ₂ CH ₃ ), 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 ), 1-pentyl (n-pentyl, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 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-ethyl-1-butyl (-CH ₂ CH (CH ₂ CH ₃ ) ₂ ), 2-ethyl-4-phenyl-1-butyl (-CH ₂ CH (CH ₂ CH ₃ ) (CH ₂ CH ₂ Ph)), or 2- (2-phenylethyl) -4-phenyl-1- Compound 10b, which is butyl (-CH ₂ CH (CH ₂ CH ₂ Ph) ₂ ), was prepared by the method of Scheme 2.

As another example, a method for preparing a compound of the present invention as described in Scheme 3 is disclosed. Cyastatin B (1) obtained from natural substances (Umezawa, H, et al. "J. Am. Chem. Soc", 27; 963-969, 1974 or ribose (Nishimura, Y. et al. "J. Am. Chem. Soc ", 110; 7249-7250, 1988; and" Bull. Chem. Soc. Jpn. ", 65: 978-986, 1992) can be used with any enantiomers. By known methods (eg Pg = Boc, Nishimura, Y. et al. "J. Antibiotics", 46 (2): 300-309, 1993) Conversion of the alcohol group of compound 11 to an amine group [Zbiral , E. et. Al. ("Liebigs Ann. Chem.", 129-134 (1991) and von Itzstein, M. et. Al. ("Carbohydrate Res.", 244: 181-185 (1993)) and reduction Compound 12 was prepared by red alkylation (Nishimura, Y. et al. "J. Antibiotics", 45 (10): 1662-1668, 1992) Compound 13 was prepared by removal of the protecting group.

By way of example or without limitation, R ² is hydrogen, R ³ is ethyl (Et, -CH ₂ CH ₃ ), 1-propyl (n-Pr, n-propyl, -CH ₂ CH ₂ CH ₃ ) , 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 ) , 1-pentyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 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-ethyl-1-butyl (-CH ₂ CH (CH ₂ CH ₃ ) ₂ ), 2-ethyl-4-phenyl-1-butyl (-CH ₂ CH (CH ₂ CH ₃ ) (CH ₂ CH ₂ Ph)), or 2- (2-phenylethyl) -4-phenyl-1 Compound 13, which is -butyl (-CH ₂ CH (CH ₂ CH ₂ Ph) ₂ ), was prepared by the method of Scheme 3.

Scheme 4 is described in the Examples section below.

The description of Scheme 5 and Scheme 6 is as follows.

Acetonide 111 is treated with diol 112 by treatment with an acid catalyst in methanol solvent as described in "Protective Groups in Organic Chemistry" 2nd. (TW Greene and PGM Wuts, John Wiley & Sons, New York, NY, 1991). Is switched. Diol 112 is converted to primary tosylate by treatment with p-toluenesulfonyl chloride in pyridine solvent and to epoxide 113 by treatment with potassium carbonate in methanol solvent. This conversion is described in "J. Org. Chem.", 57:86 (1992).

Epoxide 113 is converted to allylic alcohols 114 and 115 by treatment of base. Isomerization of epoxides to allyl alcohols is described in "Org. React.", 29: 345 (1979). The allylic alcohols 114 and 115 are separated by chromatography. On the other hand, the synthesis of allyl alcohol may be done by a continuous reaction with trimethylsilyl triflate and DBU as described in "J. Am. Chem. Soc", 101; 2738 (1979).

Allyl alcohol 114 is converted to the corresponding aldehyde 116 using MnO ₂ . This oxidation reaction is described in "Synthesis", 601 (1986). Gastric oxidation may also be carried out by treatment with pyridine-SO ₃ complex / DMSO / Et ₃ N. This is described in "Synthesis", 274 (1988).

α, β-unsaturated aldehyde 116 is oxidized to carboxylic methyl ester 117 by treatment with sodium cyanide, MnO ₂ and acetic acid in methanol solvent as described in “J. Am. Chem. Soc”, 90; 5616 (1968). .

Conversion to the alcohol 118 by removal of the protecting group of the silyl ether is carried out by the use of tetrabutylammonium fluoride, and conversion to the carboxylic acid by hydrolysis of the methyl ester is carried out by KOH. Both methods are described in "Protective Groups in Organic Chemistry" 2nd. (T. W. Greene and P. G. M. Wuts, John Wiley & Sons, New York, NY, 1991).

Allyl alcohol 115 is converted to carboxylic acid 121 by a similar method as done at 114.

Diol 112 is oxidized by pyridine.SO ₃ complex / DMSO / Et ₃ N to α-hydroxyaldehyde 122 as described in "J. Chem. Soc. Chem. Commun.", 18: 2197 (1994). Is switched. The conversion to the corresponding α-hydroxycarboxylic acids by treating the α-hydroxyaldehydes with NaClO ₂ / NaH ₂ PO ₄ / 2-methyl-2butene is described in the same reference. Treatment of carboxylic acid with diazomethane provides carboxylic ester 123. Such esterification is described in "tetrahedron lett.", 1397 (1973).

α-hydroxyester 123 is dehydrated using SOCl ₂ and pyridine to convert to unsaturated esters 117 and 120. Similar methods are described in "J. Org. Chem.", 60: 2753 (1995).

Hydroxy esters 117 and 120 are removed and converted to 119 and 121, respectively, by the method described above.

Modifications of sample starting materials to prepare another group of E1 are described in detail in the literature below, which will not be elaborated herein.

G.W.J. 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); Santal, JB III et al., "Bioorganic & Medicinal Chemistry Letters", 4 (18): 2235- 2240 (1994); Judd, D. B. et al., 'J. Med. Chem. ", 37: 3108-3102 (1994) and De Lombaert, S. et al.," Bioorganic & Medicinal Chemisteu Letters ", 5 (2): 151-154 (1994).

E1 sulfur analogues of the carboxylic acid compounds of the present invention can be prepared by any of the basic techniques. By way of example or without limitation, the carboxylic acid is reduced to alcohol by a basic method. The alcohol is converted to a halide or sulfonic acid by a basic method, and the resulting compound is reacted with NaSH to form a sulfide product. This reaction is described in "The Chemistry of the Thiol Group" (John Wiley, New York, 1974), pt. 2, 721-735.

By modifying each of the reaction schemes described above, various analogs can be prepared for the specified sample material produced above. In addition, the above cited references describing suitable organic synthesis methods can be applied to such modifications.

In each of the above schemes, the reaction products are preferably separated from each other and / or from the starting material. The product synthesized in each step or several steps was separated and purified to the degree of homogeneity required by the general art in the art. Typical separation methods include multilayer extraction, crystallization using one solvent or mixed solvent, distillation, sublimation or chromatography. Chromatography is carried out by methods such as size-exclusion chromatography, ion exchange chromatography, high pressure, medium or low pressure chromatography, small scale thin or thick membrane chromatography for production, and small scale thin layer chromatography.

Another method of separation is to treat the mixture with reagents that bind only to the desired product or vice versa. Such reagents include absorbents and adsorbents such as activated carbon, molecular sieves, ion exchange media, or the like. Such reagents may also be acids for basic materials, bases for acidic materials, and include antibodies, proteins, selective chelates such as crown ethers, liquid / liquid ion extraction reagents (LIX), or the like. The choice of the appropriate separation method depends on the nature of the material involved. For example, boiling point and molecular weight in distillation and sublimation, presence of polar functional groups in chromatography, stability of substances in acid and base media in multilayer extraction, and the like. Those skilled in the art will apply the most appropriate technique to achieve the required separation.

Example 1: Alcohol 101

Put magnesium flakes (0.9 g, 37.2 mmol) in THF (50 mL) solvent, add a few drops of 1,2-dibromoethane with initiator, and then add 2-bromopropene (4.5 g, 37.2 mmol) to 1 Add over time. 2-bromopropene (0.68 g, 5.6 mmol) was added additionally and stirred for 1.5 h. The Grignard reagent was added to THF (30 mL) CuI (0.7 g, 3.7 mmol) gruel for 15 minutes while maintaining -30 ° C via cannula and then added for 20 minutes. To the solution of epoxide 100 (9.4 g, 29.8 mmol) dissolved in THF (40 mL) was added the Grignard / CuI mixture and stirred at -30 ° C for 1 hour. The reaction was quenched by addition of NH ₄ Cl (100 mL) at 0 ° C. and 1N NH ₄ OH was added to dissolve the precipitated solid. Brine is added and extracted with ether. The organic layer was washed with brine, dried (MgSO ₄ ), filtered and distilled to synthesize alcohol 101 (11.8 g) suitable for the next step.

Example 2: Silyl Ether 102

After dissolving alcohol 101 (1.77 g, 4.9 mmol) and imidazole (1.5 g, 22 mmol) in DMF (5 mL), tert-butyldiphenylsilyl chloride (2.0 g, 7.4 mmol) was added. After stirring for 1 hour at room temperature, the reaction mixture was diluted with water and extracted with ether 2-3 times. The combined organic extracts were washed with water and brine, dried (MgSO 4) and filtered and evaporated. The residue was subjected to silica gel (20 / 1-hexane / ethyl acetate) chromatography to synthesize silyl ether 102 (2.85 g, 97%) in oil form.

Example 3: epoxide 103

Dissolve silyl alcohol 102 (44.3 g, 74.2 mmol) in CH ₂ Cl ₂ (600 mL), then NaHCO ₃ (31 g, 371 mmol) and MCPBA (32 g, 50-60% MCPBA w / w) Added at ° C. After stirring at 0 ° C. for 1 hour, water (100 mL) was added and the mixture was stirred again for 1 hour. After evaporating CH ₂ Cl ₂ , water is added to the product and the mixture is boiled and extracted with ether. The organic layer is washed with 0.5 M sodium thiosulfate, saturated NaHCO ₃ , brine, dried (MgSO ₄ ) and filtered and evaporated. The residue was subjected to silica gel (2 / CH ₂ Cl ₂ / hexane) chromatography to synthesize epoxide 103 (35.2 g) as a mixture of diastereoisomers of 1.5: 1.

Example 4: Allyl Alcohol 104

To a solution of ether (400 mL) lithium diethylamide (prepared by 11.5 mL diethylamine and 2.1 M butyllithium in 52 mL hexane) was added 0 (33.5 g) of epoxide 103 of ether (150 mL). Added at ° C. The reaction was stirred at room temperature for 17 hours. The reaction was cooled to 0 ° C. and poured into ice cold water (500 mL). The organic layer is washed with water and brine, dried (MgSO ₄ ) and filtered and evaporated. The residue was subjected to silica gel (3 / 1-hexane / ethyl acetate) chromatography to synthesize allyl alcohol 104 (15.4 g, 46%) in oil form.

Experimental Example 5: Alik Azide 105

To a solution of alcohol 104 (13.1 g, 21.4 mmol) in CH ₂ Cl ₂ (100 mL) was added triethylamine (7.45 g, 53.5 mL) at 0 ° C., followed by methanesulfonyl chloride (1.82 g, 23.5 mmol). Was added. After 30 minutes cold water was added at 0 ° C., CH ₂ Cl ₂ was evaporated and the residue was partitioned between ether and water. The organic layer was washed with water and brine, dried (MgSO 4) and filtered and evaporated. The crude mesylate was dissolved in DMF (100 mL) and sodium azide (2.8 g, 42.8 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The volatiles were evaporated and the residue was partitioned between ether and water. The organic layer was washed with water and brine, dried (MgSO ₄ ) and filtered and evaporated. The residue was subjected to silica gel (10 / 1-hexane / ethyl acetate) chromatography to synthesize allylic azide 105 (11.9 g, 87%) in oil form.

Example 6: Carbamate 106

Trimethylphosphine (2.3 mL, 22 mmol) was added to a solution of azide 105 (9.3 g, 14.6 mmol) in CH ₃ CN (100 mL) and water (5 mL). After stirring at 0 ° C. for 2 hours, the mixture was adjusted to room temperature and restirred for 18 hours. To the solution was added potassium carbonate (4.0 g, 29.2 mmol) and water (20 mL), followed by benzylchloroformate (3.1 mL, 95% purity, ˜21 mmol). After adding water, the organics are extracted with ether. The combined organic extracts were washed with water and brine, dried (MgSO 4) and filtered and evaporated. The residue was subjected to silica gel (3 / 1-hexane / ethyl acetate) chromatography to synthesize carbamate 106 (10.6 g, 97%) in the form of a thick oil.

Example 7: Alcohol 107

Formic acid (25 mL) was added at 0 ° C. to a solution of 106 (10.6 g, 14.2 mmol) in CH ₂ Cl ₂ (20 mL) and methanol (20 mL). The solution was stirred at 0 ° C. for 2.5 h and poured into saturated NaHCO ₃ (600 mL) with stirring. The aqueous layer was saturated with NaCl and extracted with ethyl acetate. The combined organic extracts were evaporated after drying (MgSO 4) and filtration. The residue was subjected to silica gel (2 / 1-hexane / ethyl acetate) chromatography to synthesize alcohol 107 (10.6 g, 97%) in oil form.

Example 8 Phthalimide Adduct 108

To a solution of DMSO (0.76 mL, 10.8 mmol) in CH ₂ Cl ₂ (4 mL) was added oxalyl chloride (0.39 mL) at −78 ° C. After stirring for 5 minutes, an alcohol 107 (2.19 g, 4.3 mmol) solution of CH ₂ Cl ₂ (5 mL) was added, stirred for 25 minutes, triethylamine (3 mL) was added, 30 at -78 ° C. Stir for minutes and adjust to room temperature. After 1 hour the reaction was diluted with ether, filtered and evaporated. The residue was dissolved in ethyl acetate, washed with water and brine, dried (MgSO 4) and evaporated after filtration. To the residue of DMF (20 mL) was added Ph ₃ P (2.2 g, 8.3 mmol) and phthalimide (1.22 g, 8.3 mmol), cooled to 0 ° C. and diethylazodicarboxylate (1.3 mL, 8.3 mmol). ) Was added. The reaction was stirred at 0 ° C. for 1 hour and then adjusted to room temperature and stirred for 3.5 hours. Water was added to quench and the excess diethylazodicarboxylate and DMF were evaporated. The residue was subjected to silica gel (2% ethyl acetate in CH2Cl2) chromatography and then to silica gel (1% ethyl acetate in CH2Cl2) chromatography to give phthalimide adduct 108 (1.95 g, 72%) in oil form. Synthesized.

Example 9 Acetimide 109

A 108 (4.2 g, 6.7 mmol) solution of MeOH (100 mL) was treated with hydrazine monohydrate (1.6 mL, 33 mmol) at 40 ° C. for 5 hours. The solvent was evaporated and the residue was treated with ethyl acetate and then the solid residue was removed by filtration. The filtered solution was evaporated, dissolved in ethyl acetate and washed with water and brine. The organic layer was evaporated after drying (MgSO ₄ ) and filtration. The residue was subjected to silica gel (1 / 1-hexane / ethyl acetate) chromatography to give 2.7 g of purified product. Acetamide 109 (1.89 g, 52%) was synthesized as a white solid by recrystallization with ether / hexane.

Example 10: Acetonide 110

To a solution of 109 (478 mg, 0.88 mmol) of ecetone (3 mL) was added a 0.04 M OsO ₄ solution of 4-methyl morpholine N-oxide (291 mg, 2.5 mmol) and water (1 mL). The reaction was stirred at ambient temperature for 16 hours, cooled to 0 ° C. and treated with 10 sodium thiosulfate solution (10 mL). Diluted with brine and extracted with ethyl acetate. The combined organic extracts were dried (MgSO 4), filtered and evaporated and the residue was dissolved in ethyl acetate and passed through a pad of silica gel. The strain was evaporated and the residue was taken up in acetone (10 mL) and treated with dimethoxypropane and a catalytic amount of p-toluenesulfonic acid. After stirring for 15 minutes at room temperature saturated NaHCO ₃ was added and the solvent was evaporated. The product is extracted with ethyl acetate and the combined organic extracts are dried (MgSO ₄ ) and filtered and evaporated. The residue was subjected to silica gel (1 / 1-hexane / ethyl acetate) chromatography to synthesize acetonide 110 (465 mg, 85%) in the form of a white solid.

Example 11 N-alkyl Derivatives 111

A solution of 110 (465 mg, 0.75 mmol) was treated with 10% Pd / C (90 mg) and then stirred for 4 hours under hydrogen (balloon) atmosphere. The catalyst was removed by celite filtration and the residue obtained by evaporation of the filtered liquor was used directly. To a solution of amine (324 mg, 0.67 mmol) in methanol (4 mL) was added 2-ethylbutyraldehyde (0.83 mg, 67 mmol) and cooled to 0 ° C. To methanol (10 mL) was added 1.34 mL of NaCNBH ₃ / ZnCl ₂ reagent obtained by adding NaCNBH ₃ (314 mg, 5 mmol) and ZnCl ₂ (340 mg, 2.5 mmol) to the solution. The reaction was stirred at 0 ° C. for 40 minutes and then evaporated. The residue was partitioned between ether and 0.1N NaOH and the organic layer was evaporated after drying (MgSO 4) and filtration. The residue was subjected to silica gel (2 / 1-hexane / ethyl acetate) chromatography to give the N-alkyl derivative 111 (212 mg, 56%). Analytical samples were recrystallized in the form of thin needles with hexane.

All of the above documents and patent citations are expressly embodied in the places where they are cited. The paragraphs and pages specifically cited in the work cited above are specifically specified. The present invention has been described in detail so that those skilled in the art can use or prepare the materials of the present invention. It is apparent that modifications may be made to the method or composition of the claims below within the scope and spirit of the invention.

Claims (125)

Compositions having the formula (IX), salts, solvates, decomposed enantiomers and purified diastereomers thereof: Formula IX In the formula, E ₁ is _{- (CR 1 R 1) m1} W 1; G ₁ is _{N 3, -CN, -OH, -OR} 6a, -NO 2 , or _{- (CR 1 R 1) m1} W 2; T ₁ is —NR ₁ W ₃ , or a heterocycle; J _1a is independently R ₁ , Br, Cl, F, I, CN, NO ₂ or N ₃ ; J ₂ and J _2a are independently H or R ₁ ; R ₁ is independently H or alkyl 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 R ₄ is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, 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 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 these alkylenes, alkenylenes or alkynylenes are substituted with 0 to 3 R ₃ groups. Substituted; R _6a is independently H or an ether- or ester-forming group; R _6b is independently H, an amino protecting group or a residue of a carboxyl-containing compound; R _6c is independently H or a residue of an amino-containing compound; W ₁ is a group containing R _6c amide of an acidic hydrogen, a protected acidic group, or a group containing acidic hydrogen; W ₂ is a group containing a basic heteroatom or a protected basic heteroatom, or an R _6b amide of a basic heteroatom; 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 , —SO ₂ W ₅ ; W ₅ is a carbocycle or heterocycle wherein W ₅ is independently substituted with 0 to 3 R ₂ groups; W ₆ is ego Each m ₁ is independently an integer from 0 to 2; Provided that J _1a is H, each J ₂ is H, J _2a is H and T ₁ is —N (H) (Ac); E ₁ is —CO ₂ H or —CO ₂ CH ₃ , G ₁ is -OBoc, W ₆ is Boc, E ₁ is —CO ₂ H or —CO ₂ CH ₃ , G ₁ is -OH, and W ₆ is H; E ₁ is -CO ₂ H, -CO ₂ CH ₃ or -CO ₂ Bn G ₁ is -OH, W ₆ is Boc; E ₁ is -CONH ₂ , G ₁ is -OH, W ₆ is Boc or H; E ₁ is —CO ₂ H or —CO ₂ CH ₃ , G ₁ is OH W ₆ is Bn; or O ₂ H or —CO ₂ CH ₃ , G ₁ is -OH W ₆ is -CH ₂ CH (OH) CH ₂ (OH); (Except those compounds wherein Bn is benzyl and Boc is -CO ₂ C (CH ₃ ) ₃ ) Compositions having the formula (X), salts, solvates, decomposed enantiomers and purified diastereomers thereof: Formula X In the formula, One Z ₁ is W ₆ and the other Z ₁ is G ₁ ; Z ₂ is H or W ₆ ; E ₁ is _{- (CR 1 R 1) m1} W 1; G ₁ is -OH, -OR _6a, or _{- (CR 1 R 1) m1} W 2; T ₁ is —NR ₁ W ₃ or a heterocycle; J ₁ and J _1a are independently R ₁ , Br, Cl, F, I, CN, NO ₂ or N ₃ ; J ₂ is 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 R ₄ is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, 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 of 1 to 12 carbon atoms, an alkenylene of 2 to 12 carbon atoms, an alkynylene of 2 to 12 carbon atoms, and these alkylenes, alkenylenes, or alkynylenes are selected from 0 to 3 R ₃ groups Substituted; R _6a is independently H, or an ether- or ester-forming group; R _6b is independently H, an amino protecting group or carbosyl-containing compound; R _6c is independently H, or a residue of an amino-containing compound; W ₁ is a group containing R _6c amide of an acidic hydrogen, a protected acidic group, or a group containing acidic hydrogen; W ₂ is a group containing H or a basic heteroatom or protected basic heteroatom or R _6b amide of a basic heteroatom; 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 and W ₅ may be independently substituted with 0 to 3 R ₂ groups; W ₆ is Each m ₁ is independently an integer of 0 to 2; The composition of claim ₁ , wherein the compound wherein G ₁ is -OH, -OR _6a is excluded. The composition of claim 1, wherein G ₁ is —NR ₁ W ₃ . The composition of claim 1 having the formula (XI): Formula XI The composition of claim 2 having the formula (XII). The composition of claim 6, wherein G ₁ is R _6b . 7. The composition of claim 6, wherein R ₁ is H. The composition of claim 2 having the formula (XIII): Formula XIII The composition of claim 1 or 2, wherein R _6a is H or a protecting group of hydroxyl or thio. 3. The composition of claim 1, wherein W ₆ is C _1-3 alkyl substituted with 1 to 3 OR _6a or SR _6a , wherein the OR _6a or SR _6a group is stable to hydrolysis in gastric juice. The compound of claim 1 or 2, wherein W ₆ is ego; m ₃ is an integer of 1 to 3. The composition of claim 1 or 2, wherein W ₆ is —R ₅ , —W ₅ , or —R _5a W ₅ . The composition of claim 1 or 2, wherein W ₆ is R ₅ . The composition of claim 14, wherein R ₅ is R ₄ substituted with 0-3 occurrences of -OR ₁ . The composition of claim 14, wherein R ₅ is R ₄ substituted with from 0 to 3 —NO ₂ or N ₃ groups. The composition of claim 15, wherein -OR ₁ is present and at least one of R ₁ is C _4-12 . The composition of claim 1 or 2, wherein W ₆ is a branched R ₅ group. 19. The composition of claim 18, wherein R ₅ is a branched R ₄ group. 3. The carbon atom of claim 1, wherein the W ₆ group is R _5e , wherein R _5e is 1 to 12 carbon atoms substituted with 1 to 3 OR _1a or SR _1a , wherein R _1a is C _1-4 alkyl Compositions which are two normal or secondary alkyls. The compound of claim 20, wherein W ₆ is R ₅ substituted with _1-3 R ₃ and at least one R ₃ group Is, R ₅ is one Composition characterized by substituted by. The composition of claim 21, wherein R ₅ is alkyl of 4 to 8 carbon atoms substituted with 0 to 3 R ₃ groups. The composition of claim 21, wherein R ₅ is substituted with 0 to 2 R ₃ groups. The method of claim 23, wherein R ₅ is substituted with 1 to 2 R ₃ groups, and at least one of the R ₃ groups is —OH, —COOH, —NH ₂ , —C (O) H, Phosphorus composition. The composition of claim 1 or 2, wherein W ₆ is W ₄ having from 1 to 7 carbon atoms. The composition of claim 1 or 2, wherein W ₆ is not OH or C _1-3 alkyl substituted with OH protected with an aralkyl, acyl, silicone protecting group or tetrahydropyran. 27. The compound of claim 26, wherein the aralkyl protecting group is benzyl, triphenylmethyl or diphenylmethyl; Acyl group is acetyl; Wherein the silicone protecting group is trimethylsilyl. The compound of claim 1, wherein G ₁ is And m2 is independently an integer from 0 to 1. The compound of claim 1 or 2, wherein G ₁ is And m2 is independently an integer from 0 to 1. The composition of claim 1 or 2, wherein W ₁ is —CO ₂ R ₁ . According to claim 1 or 2, wherein, E _1-phenyl ester of a carboxylic acid, The composition is characterized in that selected from. The composition of claim 1, wherein G ₁ is amino, amidino, or guanidino, or guanidino substituted with amino, amidino, or C _1-6 alkyl. The compound of claim 1, wherein G ₁ is C _1-6 monoalkylamine, Composition characterized in that the group selected from. The composition of claim 1 or 2, wherein W ₃ is — (CO) —R ₅ . 3. A composition according to claim 1 or 2 wherein W ₆ is alkyl of 1 to 6 carbon atoms substituted with 0 to 3 F, Br, Cl, N ₃ , NO ₂ or CN. The composition of claim 1 or 2, wherein W ₅ is selected from: The composition of claim 1 or 2, wherein T ₁ is selected from: 3. The composition of claim 2, wherein J ₁ is H, C _1-2 alkyl or F. 3. The composition of claim 1, wherein J _1a is H. 4. The composition of claim 1, wherein J _2a is H or C _1-2 alkyl. 2. The composition of claim 1, wherein J _2a is H. 3. The compound of claim 1, wherein W ₆ is secondary or tertiary alkyl containing 4 to 12 carbon atoms and W ₆ is NO ₂ , N ₃ , F, Br, Cl, OR ₁ or SR ₁ . Substituted or unsubstituted composition. 43. The composition of claim 42 substituted with nitro, azido or F. According to claim 1 or 2, W ₆ is _{- (CH 2) m1 CH (} R 1) a W 7 , and wherein W ₇ is 0 to 3 R ₃ substituted alkyl of 1 to 4 carbon atoms, a Is 0 or 1 and when a is 0, W ₇ is bonded to CH by a double bond. 45. The composition of claim 44, wherein W ₆ is -CH ₂ CH (R ₁ ) W ₇ . 46. The composition of claim 45, wherein W ₇ is -CH ₂ OR ₁ and R ₁ is C _4-12 alkyl. The compound of claim 1 or 2, wherein W ₆ is The composition is cyclohexyl or cyclopentyl. The compound of claim 1, wherein E ₁ is -COOR ₅ , G ₁ is —N (R ₅ ) ₂ , -NH (R ₅ ) ₂ , And W ₆ is alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms or alkynyl of 2 to 12 carbon atoms and W ₆ is F, Cl, Br, I, -CN, NO ₂ , N ₃ , A composition characterized by being substituted with 0 to 3 groups selected from -OR _6a , -NR _6b R _6b , -SR _6a , -OC (O) R _6a , or -NR _6b -C (O) R _6a . 49. The compound of claim 48, wherein W ₆ is Composition selected from cyclohexyl or cyclopentyl. The compound of claim 2, wherein E ₁ is G ₁ is H; W ₆ is alkyl having 1 to 12 carbon atoms, alkenyl having 2 to 12 carbon atoms and alkynyl having 2 to 12 carbon atoms and W ₆ is F, Cl, Br, I, -CN, NO ₂ , N ₃ ,- A composition characterized by being substituted with 0 to 3 groups selected from OR _6a , -NR _6b R _6b , -SR _6a , -OC (O) R _6a , or -NR _6b -C (O) R _6a . 51. The compound of claim 50, wherein W ₆ is Composition selected from cyclohexyl or cyclopentyl. Compounds having the formula (XX) or (XXa) and salts, solvates, decomposed enantiomers and purified diastereomers thereof: Formula XX or Formula XXa Wherein A ₃ is N, N (O) or N (S); Z ₃ is H, W ₆ , G ₁ or R _3a ; E ₁ is _{- (CR 1 R 1) m1} W 1; G ₁ is _{N 3, -CN, -OH, -OR} 6a, -NO 2 , or _{- (CR 1 R 1) m1} W 2; G ₂ is G ₁ or -X ₁ W ₆ ; T ₁ is —NR ₁ W ₃ or a heterocycle; J ₁ is R ₁ , Br, Cl, F, I. CN, NO ₂ or N ₃ ; J ₂ is H or R ₁ ; J ₃ is J ₁ when X ₁ is a bond; X ₁ If J ₂ ; 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 R _3a is independently R ₄ is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, alkynyl of 2 to 12 carbon atoms; R ₅ is independently R ₄ where R ₄ is substituted with 0-3 R ₃ groups; R _5a is independently 1 to 12 alkylenes, 2 to 12 carbon atoms, alkenylene, 2 to 12 carbon atoms, and these alkylenes, alkenylene or alkynylene are substituted with 0 to 3 R ₃ groups. Become; R _6a is independently H, ether- or ester-forming group; R _6b is independently H, an aminoprotecting group or a carboxyl-containing compound residue; R _6c is independently H or a residue of an amino-containing compound; W ₁ is R _6c amide of an acidic hydrogen, a protected acidic group, or a group containing acidic hydrogen; W ₂ is R _6b amide of a basic heteroatom or a protected basic heteroatom or a basic heteroatom; 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 X ₁ is a bond, And Each m ₁ is independently an integer from 0 to 2 Provided that A ₃ is N and each J ₁ , J ₂ , J _2a and J ₃ is H and T ₁ is —N (H) (Ac); E ₁ is —CO ₂ H or —CO ₂ CH ₃ , G ₂ is -OBoc Z ₃ is Boc, E ₁ is —CO ₂ H or —CO ₂ CH ₃ , G ₂ is -OH Z ₃ is H; E ₁ is -CO ₂ H, -CO ₂ CH ₃ or -CO ₂ Bn G ₂ is -OH, Z ₃ is Boc; E ₁ is -CONH ₂ , G ₂ is -OH, Z ₃ is Boc or H; E ₁ is —CO ₂ H or —CO ₂ CH ₃ , G ₂ is OH Z ₃ is Bn; or O ₂ H or —CO ₂ CH ₃ , G ₁ is -OH W ₆ is -CH ₂ CH (OH) CH ₂ (OH); Wherein Bn is benzyl and Boc is —CO ₂ C (CH ₃ ) ₃ ; Also excluded are compounds of formula (VII) or (VIII): Formula VII Formula VIII In the formula, E _{1 is-} (CR ₁ R ₁ ) m ¹ W ¹ _; G ₁ is _{N 3, -CN, -OH, -OR} 6a, -NO, or _{- (CR 1 R 1) m1} W 2; T _{1 together} with —NR ₁ W ₃ , heterocycle, or G ₁ forms a group having the structure U ₁ is —X ₁ W ₆ ; J ₁ and J _1a are independently R ₁ , Br, Cl, F, I, CN, NO ₂ or N ₃ ; J ₂ and J _2a are independently 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 R ₄ is independently substituted with 0-3 R ₃ groups; R ₃ is independently ; R ₄ is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, 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 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 these alkylenes, alkenylenes or alkynylenes are substituted with 0 to 3 R ₃ groups. Substituted; R _6a is independently H or an ether- or ester-forming group; R _6b is independently H, an amino protecting group or a residue of a carboxyl-containing compound; R _6c is independently H or a residue of an amino-containing compound; W ₁ is a group containing R _6c amide of an acidic hydrogen, a protected acidic group, or a group containing acidic hydrogen; W ₂ is a group containing a basic heteroatom or a protected basic heteroatom, or an R _6b amide of a basic heteroatom; 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 , —SO ₂ W ₅ ; W ₅ is a carbocycle or heterocycle wherein W ₅ is independently substituted with 0 to 3 R ₂ groups; W ₆ is ego X ₁ is a bond, —O—, —N (H) —, —N (W ₆ ) —, —S—, —SO—, or —SO ₂ —; Each m ₁ is independently an integer from 0 to 2 The compound of claim 52 having the formula (XXI) or (XXIa): Formula XXI Formula XXIa The compound of claim 53, having the formula (XXII) or (XXIIa): Formula XXII Formula XXIIa The compound of claim 54 having the formula (XXIII) or (XXIIIa): Formula XXIII Formula XXIIIa The compound of claim 52 having the formula (XXIV) or (XXIVa): Formula XXIV Formula XXIVa The compound of claim 56 having the formula (XXV) or (XXVa): Formula XXV Chemical Formula XXVa The compound of claim 57 having the formula (XXVI) or (XXVIa): Formula XXVI Formula XXVIa 59. A compound according to claim 58 having the formula (XXVII) or (XXVIIa): Formula XXVII Formula XXVIIa The compound of claim 52 having the formula (XXVIII) or (XXVIIIa): Formula XXVIII Formula XXVIIIa The compound of claim 60 having the formula (XXIV) or (XXIXa): Chemical Formula XXIX Chemical Formula XXIXa 62. A compound according to claim 61 having the formula (XXX) or (XXXa): Formula XXX Formula XXXa The compound of claim 52, wherein G ₂ is G ₁ . 64. The compound of claim 63, wherein G ₁ is N ₃ , -CN, -NO ₂ or-(CR ₁ R ₁ ) _ma W ₂ . 65. The compound of claim 64, wherein G ₁ is N ₃ , -CN, or -NO ₂ . The method of claim 64 wherein, G ₁ is _{- (CR 1 R 1) m1} W 2 of compound. 67. The compound of claim 66, wherein G ₁ is amino, amidino or guanidino, or amino, amidino or guanidino substituted with C _1-6 alkyl. 67. The compound of claim 66, wherein G ₁ is C _1-6 monoalkylamine, A compound selected from among them. The compound of claim 52, wherein G ₂ is —X ₁ W ₆ . The method of claim 52, wherein, W ₂ is amino, aminoalkyl, amidinyl, alkyl amidino, guanidyl pyridinyl or guanidino alkyl. 53. The compound of claim 52, wherein W2 is amino, amidino or guanidino, heterocycle, heterocycle substituted with one or two amino or guanidino groups, or two or three carbon atoms substituted with amino or guanidino Alkyl or such an alkyl group substituted with a second group selected from amino and hydroxy and amino. 72. The compound of claim 71, wherein said heterocycle is a 5 or 6 membered cyclic ring containing N or S atoms. 53. The compound of claim 52 wherein G2 is Phosphorus compounds. The compound of claim 52, wherein G ₂ is m ₂ is independently an integer of 0-1. The compound of claim 52, wherein G ₂ is —NHR ₁ . The compound of claim 52, wherein E ₁ is W ₁ . 77. The compound of claim 76, wherein W ₁ is -CO ₂ R ₅ . 78. The compound of claim 77, wherein R ₅ is R ₄ . 80. The compound of claim 78, wherein R ₄ is R ₁ . 53. The compound of claim 1, 2 or 52, wherein E ₁ is -COOH or a carboxyl ester or carboxylamide hydrolyzable to -COOH in vivo. 53. The compound of claim 52, wherein E ₁ is a phenethyl ester of carboxy, Compound selected from among. The compound of claim 52, wherein T ₁ is —N (R ₁ ) (W ₃ ). 83. The compound of claim 82, wherein R ₁ is H. 84. The compound of claim 83, wherein W ₃ is -C (O) -R ₅ . 85. The compound of claim 84, wherein T ₁ is a group selected from: 53. The compound of claim 52, wherein J ₁ is H, C _1-2 alkyl or F. 87. The compound of claim 86, wherein J ₁ is H. The compound of claim 52, wherein J ₂ is H or C _1-2 alkyl. 89. The compound of claim 88, wherein J ₂ is H The compound of claim 52, wherein J _2a is H or C _1-2 alkyl. 91. The compound of claim 90, wherein J _2a is H. The compound of claim 5, wherein R _6a is H or a protecting group of hydroxyl or thio. 53. The compound of claim 52, wherein A ₃ is N. The compound of claim 52, wherein Z ₃ is R _3a and G ₂ is —X ₁ W ₆ . The compound of claim 52, wherein Z ₃ is W ₆ and G ₂ is G ₁ . 95. The compound of claim 94 or 95, wherein W ₆ is C _1-3 alkyl substituted with 1 to 3 OR _6a or SR _6a . 97. The compound of claim 96, wherein said OR _6a or SR _6a is stable against hydrolysis in gastric juice. 95. The compound of claim 94 or 95, wherein W ₆ is And m3 is an integer of 1 to 3. 95. The compound of claim 94 or 95, wherein W ₆ is -R ₅ , -W ₅ or -R _5a W ₅ . The compound of claim 99, wherein W ₆ is R ₅ . 101. The compound of claim 100, wherein R ₅ is R ₄ substituted with 0-3 occurrences of -OR ₁ . 102. The compound of claim 101, wherein -OR ₁ is present and at least one of R ₁ is alkyl of 1 to 12 carbon atoms. 101. The compound of claim 100, wherein R ₅ is R ₄ substituted with 0-3 groups -NO ₂ or N ₃ . 95. The compound of claim 94 or 95, wherein W ₆ is a branched chain R ₅ group. 105. The compound of claim 104, wherein R ₅ is branched R ₄ group. 95. The carbon atom of claim 94 or 95, wherein W ₆ is R _5e wherein R _5e is 1 to 12 carbon atoms substituted with 1 to 3 OR _1a or SR _1a , wherein R _1a is C _1-4 alkyl Two normal or secondary alkyls. 95. The compound of claim 94 or 95, wherein W ₆ is R ₄ substituted with 1 to 3 R ₃ groups, wherein one unique R ₃ group is Phosphorus compounds. 95. The compound of claim 94 or 95, wherein W ₆ is alkyl of 1 to 10 carbon atoms substituted with 0 to 3 R ₃ groups. 109. The compound of claim 108, wherein W ₆ is alkyl of 2 to 8 carbon atoms substituted with 0 to 3 R ₃ groups. 109. The compound of claim 108, wherein W ₆ is alkyl of 3 to 8 carbon atoms substituted with 0 to 3 R ₃ groups. 109. The compound of claim 108, wherein W ₆ is alkyl of 4 to 8 carbon atoms substituted with 0 to 2 R ₃ groups. 109. The compound of claim 108, wherein W ₆ is alkyl of 4 to 6 carbon atoms substituted with 0 to 1 R ₃ groups. 109. The compound of claim 108, wherein W ₆ is substituted with 0-2 R ₃ groups. 116. The group of claim 113, wherein R ₃ group is Compound selected from among. 98. The compound of claim 94 or 95, wherein secondary or tertiary alkyl containing 1 to 12 carbon atoms and W ₆ is substituted with NO ₂ , N ₃ , F, Br, Cl, OR ₁ or SR _1; Compounds characterized by unsubstituted. 116. The compound of claim 115, substituted with nitro, azido or F. 95. The compound of claim 94 or 95, wherein W _{6 is-} (CH ₂ ) _m1 CH (R ₁ ) _a W ₇ wherein W ₇ is 1-4 alkyl of carbon atoms substituted with 0 to 3 R ₃ ; Is 0 or 1, wherein if a is 0, W ₇ is bonded to CH by a double bond. 118. The compound of claim 117, wherein W ₆ is -CH ₂ CH (R ₁ ) W ₇ . 119. The compound of claim 118, wherein W ₇ is -CH ₂ OR ₁ and R ₁ is C _4-12 alkyl. 95. The compound of claim 94 or 95, wherein W ₆ is -Cyclohexyl or cyclopentyl. 95. The method of claim 94 or 95, E ₁ is -COOR ₅ , G ₁ is —N (R ₅ ) ₂ , -NH (R ₅ ) ₂ , And W ₆ is alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms or alkynyl of 2 to 12 carbon atoms and W ₆ is F, Cl, Br, I, -CN, NO ₂ , N ₃ , A composition characterized by being substituted with 0 to 3 groups selected from -OR _6a , -NR _6b R _6b , -SR _6a , -OC (O) R _6a , or -NR _6b -C (O) R _6a . 124. The compound of claim 121, wherein W ₆ is A compound selected from among them. 53. The compound of claim 1, 2 or 52, containing a pharmaceutically acceptable carrier. A method of inhibiting the activity of neuraminidase comprising contacting a sample suspected of containing neuraminidase with a compound of claim 1, 52 or 52. Compounds listed in Table 6.