BRPI0610477A2 - compound, pharmaceutical composition comprising the same, method of treating a bacterial infection, inflammation and cystic fibrosis in a patient in need thereof - Google Patents

Abstract

The present invention discloses compounds of formula I, or pharmaceutically acceptable salts, esters or prodrugs thereof (see formula I) which exhibit antibacterial properties. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a patient in need of antibiotic treatment. The invention also relates to methods of treating a bacterial infection in a patient by administering a pharmaceutical composition comprising the compounds of the present invention. The invention also includes processes by which the compounds are prepared.

Description

COMPOUND, PHARMACEUTICAL COMPOSITION UNDERSTANDING THE METHOD OF TREATMENT OF A BACTERIAL INFECTION, INFLAMMATION AND CYSTIC FIBROSIS IN A PATIENT WITH NEED FOR THE SAME

Related Requests

The present application claims the benefit of US application No. 11 / 122,251 filed May 4, 2005 and US provisional application No. 60 / 677,675 filed May 4, 2005. All of the above applications are incorporated in this context by reference.

Technical Field

The present invention relates to novel semisynthetic macrolides having antibacterial activity and usefulness in the treatment and prevention of bacterial infections. More particularly, the invention relates to bicyclic 6-11 macrolides, ketolides, their anhydrolid derivatives, compositions containing such compounds and methods for using them, as well as processes for producing such compounds.

Background of the Invention

Macrolide antibiotics play a therapeutically important function, particularly with the emergence of new pathogens. Structural differences are related to the size of the lactone ring and the number and nature (neutral or basic) of sugars. Macrolides are classified according to the size of the lactone ring (12, 14.15 or 16 atoms). The family of raacroide antibiotics (14-, 15- and 16-element ring derivatives) shows a wide range of characteristics (antibacterial spectrum, side effects and bioavailability). Commonly used macrolides include erythromycin, calythromycin, and azithromycin. Macrolides having a 3-oxo moiety instead of 3-cladinose sugar are known as ketolides and have shown increased activity towards gram-negative bacteria and macrolides resistant gram-positive bacteria. Macrolides having a degree of unsaturation of from 2 to 3 carbons or from 3 to 4 carbons of the erythromycin macrocyl are known as anhydrides. The search for macrolides compounds that are active against MLSB-resistant varieties (MLSB = Macrolides-Lincosamides-type B Streptogramins) has become a major goal, along with retention of the overall macrolides profile in terms of stability, tolerance and pharmacokinetics.

International Application WO 97/42205 by El-liott et al, published November 13, 1997, discloses derivatives of 3-descladinosis-2,3-anhydroerythromycin which are provided with the basic nuclear structure of cyclic carbamate and cyclic carbazate. Other details were also set forth in J. Med Chem. , 41, pp 1651-1659 (1998) and J. Med Chem., 41, pp 1660-1670 (1998) by Elliott et al, and Griesgraber et al, respectively. US Patent 5,444,051 discloses certain derivatives of 6-0-substituted-3-5 oxoerythromycin A. PCT application WO 97/10251, published March 20, 1997, sets forth utility intermediates for the preparation of 6-methyl 3-descladinosis erythromycin derivatives. U.S. Patent 5,631,355 discloses certain 6-methyl-3-oxo erythromycin-cyclic derivatives. US 5,527,780 discloses certain bi-cyclic 6-O-methyl-3-oxo erythromycin A derivatives (Agouridas, ROUSSEL) corresponding to EP 596802, published May 11, 1994. Patents US Nos. . Nos. 5,866,549 and 6,075,011, and PCT application WO 00/78773, published December 28, 2000, discloses certain 6-0-substituted erythromycin derivatives. U.S. Patent 6,124,269 and PCT Application WO 00/62783, published October 26, 2000, disclose certain 2-halo-6-0-substituted ketolide derivatives. U.S. Patent 6,046,171 and PCT Application WO 99/21864, issued May 6, 1999, expose 6,11-linked erythromycin derivatives.

PCT Application WO 03/095466 A1, published November 20, 2003 and PCT Application WO03 / 097659 A1, published November 27, 2003, set forth a series of bicyclic erythromycin derivatives.

Summary of the Invention

The present invention provides a novel class of C6-Cl1 linked erythromycin oxime derivatives having antibacterial activity.

In one aspect of the present invention there are provided novel bound erythromycin compounds represented by the formulas as illustrated below:

<formula> formula see original document page 5 </formula>

or racemates, enantiomers, regio-isomers, salts, esters or prodrugs thereof, wherein

X and Y are independently selected from the group consisting of hydrogen, deuterium, halogen, R 1, OR 1, S (0) n R 1, -NR 1 C (0) R 2, -NR 1 C (O) NR 3 R 4, -NR 1 (n) 2 R 2, - C (O) NR 3 R 4, and -NR 3 R 4;

R 1 and R 2 are each independently selected from the group consisting of:

hydrogen, acyl, silane, a substituted or unsubstituted saturated or unsaturated aliphatic group, a substituted or unsubstituted substituted alicyclic group, a non-substituted substituted aromatic group, a substituted or unsubstituted substituted heteroaromatic group, or a substituted or unsubstituted heterocyclic group;

R 3 and R 4 are each independently selected from the group consisting of: hydrogen, acyl, a substituted or unsubstituted saturated or unsaturated aliphatic group, a substituted or unsaturated saturated or unsaturated alicyclic group substituted, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted heterocyclic group; or may be taken together as a nitrogen atom to which they are attached to form a substituted or unsubstituted heterocyclic or heteroaromatic ring;

or X and Y, taken together with the carbon atom to which they are attached, are selected from the group consisting of: CO, C = CHRi, C = NRi, C = NC (0) Ri, C = NORi, C = NO (CH2) mRi, C = NNHRi, C = NNHCORi, C = NNHCONRiR2, C = NNHS (0) nRi, C = NN = CHRi, C = N-NO2, or C = N-NO0;

one of U or V is hydrogen and the other is independently selected from the group consisting of: R1 0Rif 0C (0) Ri, OC (0) NR3R4, S (0) nR1,

or U and V, taken together with the carbon atom to which they are attached, are C = 0;

one of J or G is hydrogen and the other is selected from: R 1, OR 1, or NR 3 R 4;

or, J and G, taken together with the carbon atom to which they are attached, are selected from: C = 0, C = NRi, C = NORlf C = NO (CH2) mRx, C = NNHRi, C = NNHCORi, C = NNHCONRiR2, C = NNRS (0) nRi, or C = NN = CHRi;

L is selected from the group consisting of: hydrogen, a substituted or unsubstituted saturated or unsaturated aliphatic group, a substituted or unsubstituted saturated or unsaturated alicyclic group, a substituted or unsubstituted aromatic group, a unsubstituted substituted heteroaromatic or unsubstituted or substituted heterocyclic group;

M is R1;

W is NR3 R4;

Z is hydrogen, alkyl or halogen;

Rp is hydrogen, hydroxyl protecting group or hydroxyl prodrug group;

m is an integer; and

n is 0, 1, or 2.

A is

on what:

Q 'is N, CH or CF;

Xi is 0, N, NRi, S, or CR5 Yi is O, N, NRi, S, CR5, or Se Zi is 0, N, NRi, S, or CR5;

Rs is independently selected from hydrogen, acyl, silane, a saturated or unsaturated, substituted or unsubstituted aliphatic group, a saturated or unsaturated, substituted or unsubstituted alicyclic group, a substituted or unsubstituted aromatic group, a heteroaromatic group substituted or unsubstituted, a substituted or unsubstituted heterocyclic group, NR 3 R 4, OH, NHCOR 1 or NHCONH 2, and is preferably NH 2 or NHR 1.

Provided that a compound of Formula I is not selected from a compound of the following form, where A, Q, and Ztais as defined below in Table A. Table A

<table> table see original document page 9 </column> </row> <table> Where Xi is O, NH or S, and R5 is as defined above.

In yet another embodiment, A is:

<formula> formula see original document page 10 </formula>

wherein X 1 is 0, NH or S, and R 5 is as defined above.

In yet another embodiment, A is:

<formula> formula see original document page 10 </formula>

wherein R5 is as defined above.

In yet another embodiment, A is:

<formula> formula see original document page 10 </formula>

According to a preferred embodiment, A is selected from the compounds shown in <formula> formula see original document page 11 </formula> <formula> formula see original document page 12 </formula>

<table> table see original document page 13 </column> </row> <table> <table> table see original document page 14 </column> </row> <table> <table> table see original document page 15 < / column> </row> <table> A preferred compound of the invention has formula III:

<formula> formula see original document page 16 </formula>

wherein Rp, U, V, W, X, Y, L, and Z are as previously defined.

Another preferred compound of the invention has formula IV:

<formula> formula see original document page 16 </formula>

wherein Z and Rp are as defined above.

Yet another preferred compound of the invention is provided with formula V: <formula> formula see original document page 17 </formula>

wherein Z and Rp are as defined above.

In another aspect of the invention, there are provided novel 5-acyl erythromycin compounds represented by Formula VI:

<formula> formula see original document page 17 </formula>

or any racemates, enantiomers, regioisomers, salts, esters or prodrugs thereof, wherein X, Y, L, W, and Rp are as defined above;

B is independently selected from hydrogen, acyl, silane, a substituted or unsubstituted saturated or unsaturated aliphatic group, a unsubstituted substituted or unsaturated alicyclic group, a substituted or unsubstituted aromatic group, a heteroaromatic group unsubstituted or a substituted or unsubstituted heterocyclic group.

A preferred compound of Formula VI has formula VII:

<formula> formula see original document page 18 </formula>

wherein Rp is as previously defined.

Detailed Description of the Invention

Definitions

Listed below are definitions of various terms used to describe this invention.

These definitions apply to terms when they are used throughout the report and claims, unless otherwise limited in specific cases, either individually or as part of a larger group.

An "aliphatic group" is a non-aromatic moiety that may contain any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, and optionally contains one or more unsaturation units, for example, bonds. double and / or triple. An aliphatic group may be normal, branched or cyclic and preferably contain from about 1 to about 24 carbon atoms, more typically from about 1 to about 12 carbon atoms. In addition to aliphatic hydrocarbon groups, aliphatic groups include, for example, polyalkoxyalkyls such as polyalkylene glycols, polyamines, and polymines, for example. These aliphatic groups may still be substituted.

The terms "C1-C3 alkyl," "C1-C6 alkyl," or "C1-C12 alkyl," as used herein, refer to saturated, normal or branched hydrocarbon radicals containing between one and three, one and twelve, or one and six carbon atoms, respectively. Examples of C1 -C3 alkyl radicals include methyl, ethyl, propyl and isopropyl radicals; examples of C1 -C6 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, and hexyl radicals, and examples of C1 -C12 alkyl radicals include, wherein: not limited thereto are ethyl, propyl, hexyl heptyl, octyl, nonyl, decyl, unde-cil, dodecyl radicals and the like.

The term "substituted alkyl" as used herein refers to an alkyl, such as a group of C1 -C12 alkyl or C1 -C6 alkyl, substituted by one, two, three or more aliphatic or aromatic substituents. Suitable aliphatic or Î ± -romatic substituents include, but are not limited to, -F, -Cl, -Br, -I, -OH, protected hydroxy, aliphatic ethers, aromatic ethers, oxo, NO 2 -C 2 -C 1 -C 12 alkyl optionally halogen substituted (such as perhaloalkyl), optionally halogen substituted C 2 -C 12 alkenyl, optionally halogen substituted -C 2 -C 12 alkynyl, -NH 2 amino protected, -NH -C 1 -C 12 alkyl, -NH -C 2 -C 12 alkenyl, -NH -C 2 -C 12 alkynyl, -NH -C 3 -C 12 cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH heterocycloalkyl , -dialkylamino, -diarylamino, diheteroarylamino, -O-C 1 -C 2 alkyl, -0-C 2 -C 12 alkenyl, -0-C 2 -C 12 alkynyl, -O-C 3 -C 12 cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C (O) -Cl-C 12 -alkyl, -C (O) -C 2 -C 12 alkenyl, -C (O) -C 2 -C 12 alkynyl, -C (O ) -C3-C12-cycloalkyl, -C (O) -aryl, -C (O) -heteroaryl, -C (O) -heterocycloalkyl, -CONH2, -CONH-Cl-C12-alkyl, -CONH-C2-C12 alkeni la, -CONH-C2 -C12 -alkynyl, -CONH-C3-C12-cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -C02-C1-C12-alkyl, -C02-C2-C12 -alkenyl, -C02-C2-C12-alkynyl, -C02-C3-C12-cycloalkyl, -C02-aryl, -C02 -heteroaryl, -C02-heterocycloalkyl, -OCO2-C1-C12-alkyl, -CO2-C2 -C 1 -C 2 alkenyl, -OC 2 -C 2 -C 12 alkynyl, -CO 2 -C 3 -C 12 cycloalkyl, -OC 2 aryl, -OC O 2 heteroaryl, -CO 2 heterocycloalkyl, -OCONH 2, -OCONH-C 1 -C 12 -OCONH-C2 -C12 -alkenyl, OCONH-C2-C12-alkynyl, -OCONH-C3-C12-cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH-

heterocycloalkyl, -NHC (O) -C 1 -C 12 alkyl, -NHC (O) -C 2 -C 12 alkenyl, -NHC (O) -C 2 -C 12 alkynyl, -NHC (0) -C 3 C 12 cycloalkyl, -NHC (O) -aryl, -NHC (O) -heteroaryl, NHC (O) -heterocycloalkyl, -NHCO2-C1-C12-alkyl, NHCO2-C2-C2-alkenyl, -NHCO2-C2-C2-alkynyl, NHCO2 -C3 -C12-cycloalkyl, -NHCO2 -aryl, -NHCO2heteroaryl, -NHCO2 -heterocycloalkyl, NHC (0) NH2NHC (O) NH-C1 -C12 alkyl, -NHC (O) NH-C2 -C12 alkenyl, NHC (O ) NH-C 2 -C 12 alkynyl, -NHC (O) NH-C 3 -C 12 -cycloalkyl, -NHC (O) NH-aryl, -NHC (O) NH-heteroaryl, NHC (O) NH-heterocycloalkyl, NHC ( S) NH 2, NHC (S) NH-C 1 -C 12 alkyl, -NHC (S) NH-C 2 -C 12 alkenyl, -NHC (S) NHC 2 -C 12 alkynyl, -NHC (S) NH-C 3 -C 12 -cycloalkyl, NHC (S) NH-aryl, -NHC (S) NH-heteroaryl, -NHC (S) NHheterocycloalkyl, -NHC (NH) NH2, NHC (NH) NH-C1 -C12 alkyl, -NHC (NH) NH -C 2 -C 12 alkenyl, -NHC (NH) NH-C 2 -C 12 alkynyl, -NHC (NH) NH-C 3 -C 12 cycloalkyl, NHC (NH) NH-aryl, -NHC (NH) NH-heteroaryl, -NHC (NH) NHheterocycloalkyl 1α, NHC (NH) -C 1 -C 12 alkyl, -NHC (NH) C 2 -C 12 alkenyl, -NHC (NH) -C 2 -C 12 alkynyl, -NHC (NH) C 3 -C 12 cycloalkyl, -NHC ( NH) -aryl, -NHC (NH) heteroaryl, -NHC (NH) -heterocycloalkyl, -C (NH) NH-C 1 -C 12 alkyl, -C (NH) NH-C 2 -C 12 alkenyl, -C (NH) NH -C 2 -C 12 alkynyl, -C (NH) NH-C 3 -C 12 -cycloalkyl, -C (NH) NHaryl, -C (NH) NH-heteroaryl, -C (NH) NH-heterocycloalkyl, -S (O) -C 1 -C12-alkyl, -S (O) -C2-C12alkenyl, -S (O) -C2-C12-alkynyl, -S (O) -C3-C12-cycloalkyl, -S (O) -aryl, -S (O) -heteroaryl, -S (O) heterocycloalkyl -SO 2 NH 2, -SO 2 NH-C 1 -C 12 alkyl, SO 2 NH-C 2 -C 12 alkenyl, -SO 2 NH-C 2 -C 12 alkynyl, SO 2 NH-C 3 -C 12 cycloalkyl, -SO 2 NH-aryl , -SO 2 NH-heteroaryl, -SO 2 NH-heterocycloalkyl, NHSO 2 -C 1 -C 12 alkyl, -NHS 2 -C 2 -C 12 alkenyl, -NHS 2 -C 2 -C 12 alkynyl, -NHS 2 -C 3 -C 12 cycloalkyl, -NHS 2 -aryl, NHS02 -heteroaryl, -NHS02 -heterocycloalkyl, -CH2NH2, -CH2SO2CH3, -aryl, -arylalkyl, -heteroaryl, heteroarylalkyl, -heterocycloalkyl, -C3-C12-cycloalkyl, polyalkoxyalkyl, polyalkoxy, methoxymethoxy, -methoxyethoxy, -SH, -S-C 1 -C 12 -alkyl, -S-C 2 -C 12 -alkenyl, -S 2 -C 12 -C 2 -alkyl, -S-aryl ,. -S-heteroaryl, -S-heterocycloalkyl, or methylthiomethyl. It is understood that aryls, heteroaryls, alkyls and the like may be further substituted.

The terms "C 2 -C 12 alkenyl" or "C 2 -C 6 alkenyl," as used herein, indicate a monovalent group derived from a hydrocarbon moiety containing from two to twelve or two to six carbon atoms. which has at least one carbon-carbon double bond by removing a single hydrogen atom. Alkenyl groups include, but are not limited to, for example ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, alkadienes and the like.

The term "substituted alkenyl," as used herein, refers to a group of "C 2 -C 12 alkenyl" or "C 2 -C 6 alkenyl" as defined above, substituted by one, two, three or more aliphatic substituents.

The terms "C 2 -C 12 alkynyl" or "C 2 -C 6 alkynyl" as used herein refer to a monovalent group derived from a hydrocarbon moiety containing two to twelve or two such carbon atoms having at least least one triple carbon-carbon bond by removing a single hydrogen atom. Representative alkynyl groups include, but are not limited to, for example, ethinyl, 1-propynyl, 1-butynyl, and the like.

The term "substituted alkynyl," as used herein, refers to a group of "C 2 -C 12 alkynyl" or "C 2 -C 6 alkynyl" as defined above, substituted by one, two, three or more aliphatic substituents.

The term "C 1 -C 6 alkoxy" as used herein refers to a C 1 -C 6 alkyl group as defined above, attached to the parent molecular moiety through an oxygen atom. -Nio. Examples of C1 -C6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, neopentoxy and n-hexoxy.

The terms "halo" and "halogen," as used herein, refer to an atom selected from fluorine, chlorine, bromine and iodine. The terms "aryl" or "aromatic", as used herein, refers to a mono- or bicyclic carboxylic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyl and the like.

The terms "substituted aryl" or "substituted aromatics," as used herein, refer to an aryl group as defined above substituted by one, two, three or more aromatic substituents.

The term "arylalkyl," as used herein, refers to an aryl group linked to the parent compound by means of a C1 -C3 alkyl or C1 -C6 alkyl residue. Examples include, but are not limited to benzyl, phenethyl and the like.

The term "substituted arylalkyl" as used herein refers to an arylalkyl group as defined above substituted by one, two, three or more aromatic substituents.

The terms "heteroaryl" or "heteroaromatic" as used herein refer to a mono-, bi-, or tricyclic aromatic radical or ring having from five to ten ring atoms of which at least one atom ring are selected from S, O and N; zero, one, two, three, or more additional ring atoms heteroatoms independently selected from S, 0 and N; and the remaining ring atoms are carbon, wherein any N or S contained within the ring may be optionally oxidized. Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazo-lil, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, benzimidazole, benzoylazole, , quinoxalinyl, tetrazolil and the like. The heteroaromatic ring may be attached to the chemical structure through a carbon atom or heteroatom.

The terms "substituted heteroaryl" or "substituted heteroaromatic" as used herein refer to a group of heteroaryltal as defined above substituted by one, two, three or fourth aromatic substituents.

The term "alicyclic" as used herein denotes a monovalent group derived from a monocyclic or bicyclic saturated carbocyclic ring compound by the removal of a single hydrogen atom. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl.

The term "substituted alicyclic" group as defined above is substituted by one, two, three or more aliphatic substituents. The term "heterocyclic" as used herein refers to a 5-, 6- or 7-ring. non-aromatic elements or a fused bi- or tri-cyclic group system, where (i) each ring contains one and three heteroatoms selected independently from oxygen, sulfur and nitrogen, (ii) each 5-element ring has 0 to 1 du-plas bonds and each 6-element ring has 0 to 2 du-plas bonds, (iii) nitrogen and sulfur heteroatoms may be optionally oxidized, (iv) nitrogen heteroatom may be optionally quaternized, (iv ) any of the above rings may be fused to a benzene ring, and (v) the remaining ring atoms are carbon atoms which may be optionally oxo-substituted. Representative heterocycloalkyl groups include, but are not limited to, [1,3] dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, oxazolidinyl, isoxazolidinyl, morphololidinyl, thiazolidinyl, thiazolidinyl, thiazolidinyl, thiazolidinyl , quinoxalinyl, pyridazinonyl, tetrahydrofuril, and the like.

The term "substituted heterocyclic" as used herein refers to a heterocyclic group as defined above substituted by one, two, three or more aliphatic substituents.

The term "heteroarylalkyl" as used herein refers to a heteroaryl group attached to the parent compound via a C1-C3 alkyl or C1-C6 alkyl residue. Examples include but are not is limited to the same pyridinylmethyl, pyrimidinylethyl and the like.

The term "substituted heteroarylalkyl" as used herein refers to a heteroarylalkyl group as defined above substituted by the independent substitution of one, two, three or more aromatic substituents.

The term "C 1 -C 3 alkylamino," as used herein, refers to one or two C 1 -C 3 alkyl groups as defined above, attached to the parent molecular moiety through a nitrogen atom. Examples of C 1 -C 3 -alkylamino include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, and propylamino.

The term "alkylamino" refers to a group having the structure -NH (C1-C12 alkyl) wherein C1-C12 alkyl is as defined above.

The term "dialkylamino" refers to a group having the structure -N (C 1 -C 12 alkyl) (C 1 -C 12 alkyl), wherein C 1 -C 12 alkyl is as defined above. Examples of dialkylamino are, but are not limited to, dimethylamino, diethylamino, methylethylamino, piperidino, and the like. The term "alkoxycarbonyl" represents an ester group, that is, an alkoxy group, linked to the molecular moiety of origin. through a carbonyl group such as methoxycarbonyl, ethoxycarbonyl, and the like.

The term "carboxaldehyde" as used herein refers to a group of the formula -CHO.

The term "carboxyl" as used herein refers to a group of the formula -COOH.

The term "carboxamide" as used herein refers to a group of the formula -C (O) NH (C 1 -C 12 alkyl) or -C (O) N (C 1 -C 12 alkyl) ( C 1 -C 12 alkyl), -C (O) NH 2, -NHC (O) (C 1 -C 12 alkyl), -N (C 1 -C 12 alkyl) C (O) (C 1 -C 12 alkyl) and the like.

The term "hydroxyl protecting group" as used herein refers to a labile chemical moiety that is known in the art to protect a hydroxyl group against undesirable reactions during procedures. After these synthetic procedures, the hydroxyl protecting group as described herein may be selectively removed. Hydroxyl protecting groups as known in the art are generally described in T.H. Greeneand P.G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of hydroxy-protecting groups include benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-tricarbonyl 2- (trimethylsilyl) ethoxycarbonyl, 2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylethyl ethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butyl, allyl, benzyl, para-methoxybenzyldiphenylmethyl, triphenylmethyl (trityl), tetrahydrofuryl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2,2,2 -trichloroethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, methanesulfonyl, para-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, and the like. Hydroxyl protecting groups which are preferred for the present invention include acetyl (Ac or C (O) CH 3), benzoyl (Bz or -C (O) C 6 H 5), and trimethylsilyl (TMS or -Si (CH 3) 3).

The term "protected hydroxyl" as used herein refers to a dehydroxyl group protected with a hydroxyl protecting group as defined above which includes, for example, benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl. The term "hydroxyl prodrug group" as used herein refers to a moiety group which is known in the art to change the physicochemical, and consequently, properties. of a drug of origin in a transient way by covering or masking the hydroxyl group. Following said synthetic procedures, the hydroxy-prodrug group as described herein should be able to revert back to the hydroxyl group in vivo.

Hydroxyl prodrug groups as known in the art are generally described in Kenneth B. Sloan, Prodrugs, Topical and Ocular Drug Delivery, (Drugs and the Pharmaceutical Sciences; Volume 53). , Mareei Dekker, Inc., New York (1992).

The term "amino protecting group" as used herein refers to a labile chemistry meta-chemistry that is known in the art to protect an amino group against undesirable reactions during synthetic procedures. Following the synthetic procedures, the amino-protecting group as described in this context may be selectively removed. Amino protecting groups such as are known are generally described in T.H. Greene and P.G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, and the like.

The term "protected amino" as used herein refers to an amino group protected with an amino protecting group as defined above.

The term "acyl" includes acid-derived residues including, but not limited to, carboxylic acids, carbamic acids, carbonic acids, sulfonic acids, and phosphoric acids. Examples include aliphatic carbonyls, aromatic carbonyls, aliphatic sulfonyls, aromatic sulfinyls, aliphatic sulfinyls, aromatic phosphates and aliphatic phosphates.

The term "aprotic solvent" as used herein refers to a solvent that is relatively inert to proton activity, that is, not acting as a proton donor. Examples include, but are not limited to, hydrocarbons such as hexane and toluene, for example halogenated hydrocarbons such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heterocyclic compounds. -Cyclics, such as, for example, tetrahydrofuran and N-methylpyrrolidinone, and ethers, such as diethyl ether, bismethoxymethyl ether. These components are well known to those skilled in the art, and it is obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending on factors such as solubility. of reactants, reactivity of reactants and preferred temperature ranges, for example. Other discussions related to aprotic solvents can be found in publications on organic chemistry or in specialized monographs, for example:

Organic Solvents Physical Properties and Methods of Purification, 4th ed., Edited by John A. Riddick et al., Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.

The term "protogenic organic solvent" or "protic solvent" as used herein refers to a solvent that tends to provide protons, such as an alcohol, for example methanol, ethanol, propanol, isopropanol, butanol, t-butanol, water and the like. Such solvents are widely known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending on factors such as reagent solubility, reagent reactivity, for example, preferred temperature ranges. Other discussions on protogenic solvents may be found in organic chemistry publications or in specialized monographs, for example: Orgic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick etal., Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.

Combinations of substituents and variables considered by this invention are only those that result in the formation of stable compounds. The term "stable" as used herein refers to compounds which have sufficient stability to permit manufacture and maintain the integrity of the compound for a period of time sufficient to be of use for the purposes detailed in this context (for example, therapeutic or prophylactic administration to a patient).

The synthesized compounds may be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization. As may be appreciated by one of ordinary skill in the art, other methods of synthesizing formula compounds in this context will be apparent to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to provide the desired compounds. Synthetic chemistry transformations and protecting group (protection and deprotection) methodologies useful in synthesizing the compounds described in this context are known in the art and include, for example, those as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene andP.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser andM. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and their subsequent editions.

The term "patient" as used herein refers to an animal. Preferably the animal is a mammal. Most preferably the mammal is a human being. A patient also refers, for example, to dogs, cats, horses, cows, pigs, guinea pigs, fish, birds and the like.

The compounds of this invention may be modified by appropriate functionalities subordinated to increase selective biological properties. Such modifications are known in the art and may include those that increase biological penetration within a given biological system (eg, blood, lymphatic system, central nervous system), increased oral availability, increased solubility to allow injection administration, metabolism impairment, and alteration. excretion detax.

The compounds described in this context contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms which may be defined as absolute stereochemical terms such as (R) - or (S) - or as (D) - or (L) - for amino acids. The present invention is intended to include all such possible isomers as well as their racemic and optically pure forms. Optical isomers may be prepared from their respective optically active precursors by the procedures described above or by decomposition of racemic mixtures. The recomposition may be carried out in the presence of a decomposition agent, by repeated chromatography or recrystallization or by some other combination of these techniques which are known to those of skill in the art. Further details regarding de-compositions can be found in Jacques, et al., Enantiomers, Racemates, and Resolutions (JohnWiley & Sons, 1981). Where the compounds described herein contain olefinic double bonds, other unsaturations, or other asymmetry centers, and unless otherwise specified, the compounds are intended to include both E and Z isomers or eisetrans isomers. Similarly, all tautomeric forms are intended to be equally included. The configuration of any carbon-carbon double bond that appears in this context is selected for convenience only and is not intended to designate a particular configuration unless the text so assumes; thus a carbon-carbon double bond or carbon-heteroatom double bond arbitrarily illustrated in this context as it may be useful, trans, or a mixture of the two in any proportion.

As used herein, the term "pharmaceutically acceptable salt" refers to those salts that are, within the scope of perfect medical judgment, suitable for use with human and lower animal tissues without toxicities, irritation, allergic responses and the like. -due, and are commensurate with an acceptable benefit / risk ratio. Pharmaceutically acceptable salts are widely known in the art. For example, S. M. Berge, et al., Describe them as pharmaceutically acceptable in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts may be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reaction of the free base function with a suitable inorganic acid or inorganic acid. Examples of pharmaceutically acceptable non-toxic acid addition salts include, but are not limited to, salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, lactobionic acid or malonic acid or by the use of other methods used such as ion exchange. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfone, citrate, cyclopentanopropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoeptonate, glycerophosphate, gluconate, hemisulphate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, 2-methanesulfonate -naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pi-valate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate -noate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, where appropriate, toxic ammonion, quaternary ammonium, and amine cations formed using counterions such as halogen, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl which are endowed with 1. at 6 carbon, sulfonate and aryl sulfonate atoms.

As used herein, the term "pharmaceutically acceptable ester" refers to esters which hydrolyze in vivo and include those which readily dissolve in the human body to the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenic, cycloalkanoic and alkanedioic acids, wherein each alkyl or alkenyl moiety advantageously has no more than 6 carbon atoms. Examples of particular esters include, but are not limited to, formats, acetates, propionates, butyrates, acrylates and ethyl succinates.

The term "pharmaceutically acceptable prodrugs" as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of perfect medical evaluation, suitable for use in contact with drugs. human beings and animals with undue toxicity, irritation, allergic response, and similar, commensurate with an acceptable benefit / risk ratio and effective for their intended use, as well as zuiterionic forms, where possible, of the compounds of the present invention. "Prodrug" as used herein means a compound that is capable of being converted in vivo by metabolic means (e.g., by hydrolysis) to a compound of the invention. Various forms of prodrugs are widely known in the art, for example, as discussed in Bundga-ard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, A-Academic Press (1985); Krogsgaard-Larsen, et al., (Ed). "Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliverings, 8: 1-38 (1992); Bundgaard, J. of Pharmaceuticals; cal Sciences, 77: 285 et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975); and Bernard Test & Joachim Mayer, "Hydrolysis In Drug And Pro-drug Metabolism" : Chemistry, Biochemistry And Enzymo-logy, "John Wiley and Sons, Ltd. (2002).

This invention also encompasses pharmaceutical compositions containing, and methods of treating bacterial infections by administering decomposed pharmaceutically acceptable prodrugs of the invention. For example, compounds of the invention having free amino, starch, hydroxyl or carboxylic groups may be converted to prodrugs. Prodrugs include compounds wherein one amino acid residue, or two or more polypeptide chain (e.g. two, three or four) amino acid residues are covalently joined by an amide or ester bond to a free carboxylic acid, hydroxyl, or mino group of the compounds of the invention. Amino acid residues include, but are not limited to, naturally occurring amino acids commonly designated by three-letter symbols and also include 4-hydroxyproline, hydroxylysine, demosine, isodemine, 3-methylistidine, norvalin , beta-alanine, gamma-aminobutyric acid, homocysteine citrulline, homoseoline, ornithine and methionine sulfone. Additional types of prodrugs are also covered. For example, free carboxyl groups may be derived as amides or alkyl esters. Free hydroxyl groups may be derived using groups which include, but are not limited to, the same, hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as highlighted in Advanced Drug Delivery 30 Reviews , 1996, 19, 115. Carbamate prodrugs of deamino and hydroxyl groups are also included; as are the carbonate prodrugs, sulfonate esters and sulfate esters of the hydroxyl groups. Derivatives of hydroxyl groups such as (acyloxy) methyl and (acyl-xi) ethyl ethers are also contemplated, wherein the acyl group may be an alkyl ester, optionally substituted with groups which include, but are not limited to, ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above. Prodrugs of this type are described in J. Med. Chem. 1996, 39.10. Free amines may also be derived as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups which include, but are not limited to, ether, amine and carboxylic acid functionalities.

As used herein, unless otherwise indicated, the term "bacterial infection (s)" or "protozoal infections"; including, but not limited to, bacterial infections and protozoal infections occurring in mammals, fish and birds, as well as disorders related to disorders related to bacterial infections and protozoal infections which may be treated or prevented. by administering antibiotics such as the compounds of the present invention. These bacterial infections and protozoal infections and disorders related to these infections include, but are not limited to, the following: pneumonia, otitis media, sinusitis, bronchitis, tonsillitis, cystic fibrosis (CF), and mastoiditis related to Streptococcus pneumoniae infection, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, Pep-tostreptococcus spp. or Pseudomonas spp .; pharyngitis, rheumatic fever, and glomerulonephritis related to Streptococcus pyogenes, Group C and G streptococci, Clostridium diptheriae, or Actino-bacillus haemolyticum infection; respiratory tract infections related to infection by Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae, or Chlamydia pneumoniae; simple in-closures of skin and soft tissue, osteomyelitis abscess, and puerperal fever related to Staphylococcus aureus infection, decoagulase-positive staphylococci (ie, S. epidermidis, S. he-molyticus, and others), S. pyogenes, S agalactiae, CF streptococcal groups (miniature colony streptococci), viridans streptococci, Corynebacte-rium spp., Clostridium spp., or Bartonella henselae; simple acute urinary tract infections related to S. saprophyticus or Entero- infection. coccus spp .; urethritis and cervicitis; and sexually transmitted diseases related to Chlamydia trachomatis, Haemophilus ducreyi, Trepone-ma pallidum, Ureaplasma urealyticum, or Nesseria go-norrheae infections; toxin diseases related to S. aureus infection (food poisoning and toxic shock syndrome), or streptococci of Groups A, S. and C; Helicobacter pylori infection-related ulcers; systemic febrile syndromes related to Borrelia recurrentis infection Lyme disease related to Borrelia burgdorferi infection; conjunctivitis, keratitis, and da-crocystitis related to C. trachoma-tis infection, N. gonorrhoeae, S. aureus, S. pneumoniae, S.pyogenes, H. influenzae, or Listeria spp .; disseminated Mycobacterium avium complex (MAU) disease related to infection by Mycobacterium avium, or Mycobacterium intracellulare; tuberculosis-related disease with Mycobacterium tubercu-losis infection; gastroenteritis related to Campylobacter jejuni infection; intestinal protozoa related to Cryptosporidium spp. infection; odontogenic infection related to vi-ridans streptococci infection; persistent cough related to Bordetella pertussis infection; gangrene degas related to Clostridium per-fringens or Bacteroides spp. infection; skin infection byS. aureus, Propionibacterium acne; atherosclerosis related to infection by Helicobacter pylori orChlamydia pneumoniae; or similar.

Bacterial infections and deprotozoal infections and disorders related to such infections that can be treated or prevented in animals include, but are not limited to, the following: bovine respiratory disease related to P. haemolytica infection., P.multocida , Mycoplasma bovis, or Bordetella spp .; enteric disease related to infection by E. coli or protozoa (i.e. coccidia, cryptosporidia, and others), dairy cattle mastitis related to S. aureus infection, S. uberis, S.agalactiae, S dysgalactiae, Klebsiella spp., Cory-nebacterium, or Enterococcus spp .; swine respiratory disease related to infection by A. pleurop-neumoniae., P. multocida, or Mycoplasma spp .; swine enteric disease related to E infection. coli, Lawsonia intracellularis, Salmonella spp., or Serpulina hyodyisinteriae; hoof disease related to Fusobacterium spp. infection; metritis vacum related to E. coli infection; fuzzy warts related to Fusobacterium necrophorum or Bacteroidesnodosus infection; acute conjunctivitis vacum related to infection by Moraxella bovis; premature abortion related to protozoan infection (ie, neosporium); urinary tract infection in dogs and cats related to E. coli infection, skin and soft tissue infections in dogs and cats related to S. epidermidis, S.intermedius, coagulase neg. Staphylococcus or P.multocida; and dental or oral infections in cats and cats related to Alcaligenesspp infection., Bacteroides spp., Clostridium spp., Entero-bacter spp., Eubacterium spp., Peptostreptococcusspp., Porphfyromonas spp., Campylobacter spp., Ac-tinomyces spp. Erysipelothrix spp., Rhodococcusspp., Trypanosoma spp., Plasmodium spp., Babesiaspp., Toxoplasma spp., Pneumocystis spp., Leishma-nia spp., And Trichomonas spp. or Prevotella spp. Other bacterial infections and protozoan infections and diseases related to such infections which can be treated or prevented according to the method of the present invention are referred to in JP Sanford et al., "The Sanford Guide To Antimicrobial Therapy, "26th Edition, (Antimicrobial Therapy, Inc., 1996).

Antibacterial activity studies may be performed using suitable assays as known in the art. Desusceptibility tests can be used to quantitatively measure the in vitro activity of an antimicrobial agent against a given bacterial segregate. The compounds are tested for in vitro antibacterial activity by a micro-dilution method. Minimum Inhibitory Concentration (MIC) is determined in 96-well microtiter plates using Mueller Hinton Broth (CAMHB) media appropriate for the observed bacterial secretions. Antimicrobial agents are serially diluted (2-fold) in DMSO to produce a concentration range of from about 64 µg / ml to about 0.03 µg / ml. Diluted compounds (2 µl / well) are then transferred into sterile, uninoculated CAIvllB (0.2 ml) using a fixed pipetting station of 96. The inoculum for each bacterial variety is standardized. 5 x 105 CFU / ml by optical comparison with a McFarland turbidity standard of 0.5. Plates are inoculated with 10 µl / well of adjusted bacterial inoculum. 96-well plates are covered and incubated at 35 +/- 2 ° C for 24 hours in ambient air. Following incubation, the plate wells are visually examined by measuring Optical Density for the presence of development (turbidity). The lowest concentration of an antimicrobial agent under which no visible growth occurs is defined as the MIC. Generally the compounds of the invention have demonstrated a MIC in the range from about 64 µg / ml to about 0.03 µg / ml.

All in vitro tests follow the guidelines described in the Approved Stan-dards M7-A4 protocol, published by the National Committee for Clinical Laboratory Standards (NCCLS).

The invention further provides compositions and methods of treating patients suffering from an inflammatory condition comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound of the invention. Specific examples of inflammatory conditions that may be treated according to the invention include, but are not limited to, scleritis; allergic conjunctivitis; inflammatory inflammatory diseases, in particular CF, asma, chronic obstructive pulmonary disease (COPD), allergic bronchopulmonary aspergillosis (ABPA), and sarcoidosis; proctosigmoiditis; allergic rhinitis; arthritis; tendonitis; apthous stomatitis; and inflammatory bowel disease.

The invention further provides compositions and methods for (i) prophylactic treatment of patients susceptible to CYLINDER DEFINITION symptoms, including pulmonary infection and inflammation associated with CF; ii) treatment in the early stages of pulmonary infection and inflammation associated with CF, and iii) treatment of ongoing symptoms or recurrence of infection and inflammation associated with CF. In accordance with the present invention, a compound of the invention is administered to a patient in need of CF treatment in an amount sufficient to prevent, decrease or eradicate CF symptoms, including chronic pulmonary inflammation and inflammation. of the present invention comprise a therapeutically effective amount of a compound of the present invention together with one or more pharmaceutically acceptable carriers or excipients.

As used herein, the term "pharmaceutically acceptable carrier or excipient" means a filler, diluent, encapsulating material or formulation aid of any solid, semi-solid or liquid type. non-toxic, inert. Some examples of materials that may serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and saccharin; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; pulverized tragacanth; malt gelatin; baby powder; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; damping agents such as magnesium hydroxide and aluminum hydroxide; alkycin acid; pyrogen free water; i-sotonic saline solution; Ringer's solution; alcohol, and phosphate buffering solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulphate and magnesium stearate, as well as coloring agents, release agents, Coating agents, sweeteners, flavoring and odorants, preservatives and anti-oxidants may also be present in the composition, at the formulator's discretion.

The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally deformally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to increase the stability of the formulated compound or its distribution form. As used in this context, the term parenteral includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional injection or infusion techniques. and intracranial.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilising agents and emulsifiers, such as ethyl alcohol, alcohol. isopropyl, ethyl carbonate, acetateethyl, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular cottonseed oil, groundnut, maize, wheat germ, olive, castor, egergelin), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvant agents such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents and perfumers.

Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable suspension or emulsion in a generally acceptable non-toxic diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and i-sotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any soft oleofix may be employed, including synthetic mono- or diglycerides. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectables.

Injectable formulations may be sterile, for example, by filtering through a bacterial retention filter, or by incorporating sterilizing agents in the form of sterile solid compositions which may be dissolved or dispersed in sterile water or other sterile injectable medium before use.

In order to prolong the effect of a drug, it is often desirable to delay absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends on its rate of dissolution which, in turn, may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oily vehicle. Injectable depot forms are pre-stopped by the formation of dadroga microencapsulated matrices in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by inducing the drug in liposomes or microemulsions that are compatible with body tissues.

Compositions for oral rectal administration are preferably suppositories which may be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid under temperature. environment, but liquids under body temperature and consequently fuse into the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms the active compound is admixed with at least one inert, pharmaceutically acceptable carrier or carrier such as sodium citrate or dicalcium phosphate and / or: a) fillers or extenders such as starches, lactose, saccharin, glucose, mannitol and acid silicic; b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, saccharin, and acacia; c) humectants, such as glycerol; d) disintegrating agents such as agar agar, decalcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents, such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate h) absorbers such as kaolin and bentonite clay e) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene solids, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise non-killing agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

Solid dosage forms of tablets, pills, capsules, pills and granules may be prepared with coatings and wraps such as enteric coatings and other coatings widely known in the pharmaceutical formulation art. They may optionally contain opacifying agents as well as they may be of a composition wherein they release only the active ingredient (s), or preferably in a certain part of the intestinal tract, optionally in a delayed manner. Examples of implantable compositions that may be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a component of this invention include ointments, creams, lotions, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or plasters. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers that may be required. Ophthalmic formulations, optical drops, ophthalmic ointments, post-solutions are also considered to be within the scope of this invention.

Ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays may additionally contain the compounds of this invention such as excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures thereof. Sprays may additionally contain usual propellants, such as chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms may be prepared by dissolving or dispensing them in the appropriate medium. Absorbing enhancers can also be used to increase the composite flow through the skin. The ratio may be controlled either by providing a ratio controlling membrane or by dispersing the compound into a polymer matrix or gel.

For pulmonary delivery, a therapeutic composition of the invention is formulated and administered to the patient in a solid or liquid particulate form by direct administration, e.g. inhalation to the respiratory system. Solid or liquid particulate forms of the active compound prepared for the practice of the present invention include respirable size particles: that is, particles of a size sufficiently small to pass through the mouth and larynx upon inhalation and in the bronchi and alveoli of the lungs. Aerosolized therapeutic distribution, particularly aerosolized antibiotics, is in the art (see, for example, US Patent No. 5,767,068 issued to VanDevanteret al., US Patent No. 5,508,269 issued to Smi-th et al., and WO 98 / 43,650 by Montgomery, all of which are incorporated herein by reference). A discussion of antibiotic pulmonary distribution is also found in U.S. Patent No. 6,014,969, incorporated herein by reference.

According to the treatment methods of the present invention, bacterial infections, cisplastic fibrosis, and inflammatory conditions are treated or prevented in a patient, such as a human or other animal, by administering to the patient a therapeutically effective amount of a compound. of the present invention, in such amounts and for as long as is necessary to achieve the desired result.

By a "therapeutically effective amount" of a compound of the invention is meant an amount of the compound conferring a therapeutic effect on the treated patient at a reasonable benefit / risk ratio for any medical treatment. The therapeutic effect can be objective (that is, measurable by a certain test or marker) or subjective (that is, the patient gives an indication or feels an effect).

An effective amount of the compound described above may range from about 0.1 mg / kg to about 500 mg / kg, preferably from about 1 to about 50 mg / kg. Actual doses will also vary depending on the route of administration as well as the possibility of co-use with other agents. It will be understood, however, that the full daily use of the compounds and compositions of the present invention will be decided by the attending physician within the scope of judicious medical judgment. The therapeutically effective dose level specific to any particular patient will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; age, body weight, general health status, patient's fair sex; administration time via administration and excretion ratio of the specific compound employed; the duration of treatment; of the drugs used in combination or simultaneously with the specific body employed; as well as similar factors widely known in the medical field.

The total daily dose of the inventive compounds administered to a human or other animal in single or divided doses may vary in amounts, for example, from 0.01 to 50 mg / kg body weight or more usually from 0.1 to 25 mg / kg. kg of bodyweight. Single dose compositions may contain amounts or submultiples thereof to provide daily doses. Generally, the treatment regimens according to the present invention comprise administering to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound (s) of this invention per day in one single or multiple doses.

The compounds of the formulas described in this context may, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or porinally, with a dosage ranging from about 0.1 to about 500 mg / kg body weight; alternatively dosages between 1 mg and 1000 mg / dose every 4 to 120 hours or according to drug requirements. Methods in this context consider administering an effective amount of compound or compound composition to achieve the desired effect. or established. Typically, the pharmaceutical compositions of this invention will be administered about 1 to about 6 times per day or alternatively as a continuous infusion. Such administration may be used as a chronic or acute therapy. The amount of effective ingredient that may be combined with pharmaceutical excipients or carriers to produce a single dosage form will vary depending upon the recipient treated and the mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w / w). Alternatively, such preparations may contain from about 20% to about 80% active compound.

Lower or higher doses may be required than previously mentioned. Specific dosages and treatment regimens for any particular patient will depend on a variety of factors, including the activity of the particular compound employed, age, body weight, general health status, sex, diet, time of administration. -action, excretion rate, drug combination, seriousness and course of the disease, condition or symptoms, from patient's disposition to the disease, condition or symptoms, and physician's discretion in treatment.

Upon improvement of a patient condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced as a function of the symptoms to a level at which the ameliorating condition is maintained when the symptoms have been alleviated to the desired level. However, patients may require intermittent treatment on a long-term basis due to any reappearance of disease symptoms.

When the compositions of this invention comprise a combination of a compound of the formulas described herein and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent should be present in dosage levels ranging from about 1 to 100%. and most preferably from about 5 to 95% of the dosage normally administered under a monotherapy regimen. Additional agents may be administered separately as part of a multiple dose regimen from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.

The pharmaceutical compositions of this invention may be orally administered to fish by the mixture of said fish food pharmaceutical compositions or said pharmaceutical compositions may be dissolved in the water in which the infected fish are placed, a method of - commonly called a medicated bath. The dosage for fish treatment differs depending on the purpose of administration (prevention or cure of disease) and the type of administration, size and extent of the infestation of the fish to be treated. Generally, a dosage of 5-1000 mg, preferably 20-100 mg, per kg body weight of the fish may be administered per day, either at once or divided several times. It will be understood that the dosage specified above is only a general range which may be reduced or increased depending on the age, body weight, disease condition and the like of the fish.

Unless otherwise defined, all technical and scientific terms used in this context are in accordance with the commonly recognized meaning of that commonly understood in the art.

All publications, patents, published patent applications, and other references referenced herein are incorporated herein by reference in their entirety.

Abbreviations

Abbreviations that can be used in the following schema descriptions and examples are:

Ac for acetyl;

AIBN for azobisisobutyronitrile;

Bu3 SnH for tributyltin hydride;

CDI for carbonyldiimidazole;

dba to dibenzylidene acetone:

dppb for diphenylphosphino butane;

DBU for 1,8-diazabicyclo [5.4.0] undec-7-ene;

DEAD for diethylazodicarboxylate;

DMAP for dimethylaminopyridine;

DMF for dimethyl formamide;

DPPA for diphenylphosphoryl azide;

EtOAc for ethyl acetate;

EtOH for ethanol;

MeOH to methanol;

Ms for mesylate or O-SO2-CF3 NaN (TMS) 2 for bis (trimethylsilyl) amide disodium;

NMMO for N-methylmorpholine N-oxide;

TEA for triethylamine;

THF for tetrahydrofuran;

TPP or PPh3 for triphenylphosphine;

MOM for methoxymethyl;

Boc for t - butoxycarbonyl;

Bz for benzoyl;

Bn for benzyl;

Ph for phenyl;

POPd for dihydrogen dichlorobis (di-tert-butylphosphinite-kP) paladate (II);

TBS for tert-butyl dimethylsilyl; orTMS for trimethylsilyl.

Synthetic Methods

The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes which illustrate the methods by which the compounds of the invention may be prepared.

A preferred intermediate for the preparation of the compounds represented by formula I is a compound represented by formula VIII as shown below <formula> formula see original document page 63 </formula>

wherein Rp, U, V, W, X, Y and Z are as defined above.

Schemes 1-2 describe processes for preparing compounds according to the invention.

The compounds of formula VIII which are deutability as starting materials for the preparation of the compounds of the present invention are prepared from erythromycin using the procedures described in US Patent No. 6,878,691 and US Patent Publication No. 2004/0053861, incorporated in this context by reference.

Scheme 1

<formula> formula see original document page 63 </formula>

Scheme 1 illustrates a process for preparing compounds of the present invention by converting bound VIII ketone to an oxime of formula (1-2) using the appropriate substituted hydroxylamine formula:

<formula> formula see original document page 64 </formula>

wherein A is as defined above. This oxime formation may be performed using the appropriate substituted hydroxylamine either under acidic or basic conditions in a variety of solvents. Representative acids include, but are not limited to, hydrochloric acid, phosphoric acid, sulfuric acid, p-toluensulfonic acid, and pyridiniop-toluene sulfonate and the like. In a similar manner, representative bases include, but are not limited to, triethylamine, pyridine, diisopropylethyl amine, 2,6-lutidine, and the like. Suitable solvents include, but are not limited to, methanol, ethanol, water, tetrahydrofuran, 1,2-dimethoxyethane, ethyl acetate and the like. Preferably, the reaction is carried out in ethanol using aqueous hydrochloric acid. The reaction temperature generally varies, and is not limited thereto from -20 ° C to 40 ° C and the reaction time ranges from 1 to 8 hours, preferably the reaction is carried out at 0 ° C.

Scheme 2 <formula> formula see original document page 65 </formula>

Scheme 2 illustrates the procedure by which the compounds of

of formula (2-1) may be converted to compounds of formula (2-2) by treatment with isocyanates of formula R1-NC0, acid chlorides of formula R1 -C (O) C1or alkyl isocyanates in the presence of bases such as not limited thereto, sodium hydride, potassium hydride, potassium tert-butoxide, potassium hydroxide, KHMDS, and the like. The reaction is typically performed on aprotic solvents such as, but not limited to, THF, DMSO, DMF, or dioxane and the like. The reaction temperature ranges from 25 ° C to 80 ° C. The preferred reaction time ranges from 5 to 20 hours.

Alternatively, some of the ester compounds of formula (2-2) may be prepared by treating the compounds of formula (2-1) with acids of formula R1-C (O) OH in the presence of bases such as, but not limited to same EtsN, pyridine, DMAP and coupling agents such as, but not limited to, EDC, BOPC1, HATU, and the like in aprotic solvents such as, but not limited to, -chloromethane, ethylene chloride, THF, DMF, acetonitrile and the like at a temperature of 25 ° C to 80 ° C and the reaction time ranges from 2 to 24 hours.

The compounds of formula (2-1) may also be treated with substituted tert-butyl allyl carbonate in the presence of a palladium catalyst and a phosphine additive to provide allyl ethers.

Examples

The compounds and processes of the present invention will be better understood in connection with the following examples, which are intended to illustrate only and not to limit the scope of the invention. Various changes and modifications to the foregoing embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those related to the chemical structures, substituents, derivatives, formulations and / or methods of the invention may be made without thereby escape the spirit of the invention and the scope of the appended claims.

Example 1 <formula> formula see original document page 67 </formula>

Step la:

<formula> formula see original document page 67 </formula>

To a solution of 2-amino-4-methylphenol (157.6g, 1.28mol) in 1500 ml EtOH at room temperature under stirring condition was added bromocyanogen (135.00 g, 1.28 mol) in about 30 minutes. It was hot and a water bath was used to cool the reaction to room temperature. After 5-6 hours, the reaction solvent was evaporated under reduced pressure. The residue was dissolved in about 1500 mL of EtOAc and washed with saturated NaHCO3 (1.5 L). The organic layer was separated dried over anhydrous MgSO4. Removal of solvent High vacuum drying provided about 150g of the title compound in light brown color, which can be used in the next step. ESI MSm / e: 149 (M + H) + Step 1b:

<formula> formula see original document page 68 </formula>

A solution of succinic anhydride (141.1g, 1.41 mol) and 70 g (about 0.47 mol) of the compound of step 1a (70 g, 0.47 mol) in 2500 ml of toluene anhydride was refluxed during After that, HATU (100g, 0.26 mol) and 4-methylmorpholine (41.36 ml, 0.376 mol) were added and the mixture was refluxed for 2-3 hours. TLC showed that the main point was product. (Rf = 0.35, acetone: hexane = 1: 2). After the reaction was completed, the solvent was evaporated and the residue was dissolved in about 2000 ml of CH 2 Cl 2. The solution was washed with aqueous NaHCO 3. Then the pH was adjusted to 7-8 and washed with brine, the organic phase was separated and dried over MgSO4. Solvent filtration and removal provided the title compound (98g) as white crystalline needles ESI MS m / e: 231 (M + H) +.

Step 1c:

<formula> formula see original document page 68 </formula>

To a solution of the compound from step 1b (44.37g, 0.193mol) in CCl4 (1.5 L) was added NBS (41.16g, 0.23mol) and then the mixture was heated to reflux. Benzoyl peroxide (0.75g) was added three times. After refluxing for 24 hours, the sand was cooled to room temperature and the mixture was diluted with 1.5 L of CH 2 Cl 2. The organic phase was separated and washed with 4 l of saturated NaHC? 3 twice to adjust the pH to 7-8. Drying over MgSO4 and removing the solvent under reduced pressure afforded the title compound (57.3 g) as a light yellow solid which was used in the next step without further purification. ESI MS m / e: 309/311 (M + H) +.

Step ld:

<formula> formula see original document page 69 </formula>

To a solution of the compound of step 1c (57.3g, 0.185mol) in 450 ml MeCN was added N-hydroxyfantalimide (60.51 g, 0.371 mol) and 80 ml detiethylamine. The reaction mixture was stirred at 50 ° C for 5 hours and refrigerated to room temperature. Water was added to the reaction (200 ml) and filtered. The light yellow solid was collected, washed with 100 ml MeOH and ether 1: 1. Vacuum dried to afford the title compound (48 g) as a clear solid. ESI MSm / e: 392

(M + H) +.

Step le: <formula> formula see original document page 70 </formula>

A mixture of the compound from step 1d (39.1g, 0.1 mol) in 500 ml of 2M methanolfo ammonia was stirred at room temperature for 16 hours and filtered. The filtrate was concentrated and purified on silica gel (2M NH 3 in Me-OH: CH 2 Cl 2 = 5:95) to afford the title compound (17g, 95%). ESI MS m / e: 180 (M + H) +.

Step lf:

<formula> formula see original document page 70 </formula>

To a solution of the compound from step 1d (215 g, 1.2 mmol) in 15 mL of ethanol was added IN HCl (2 mL). The mixture was cooled to 0 ° C and added to the compound of formula VIII wherein X and Yto taken together with the atom to which they are bound is C = N-Ac and e and V taken together with the atom to which they are attached is C = O, Z = H, Rp = Ac and W = NMe2 (711 mg, 1 mmol). The mixture was stirred at 0 ° C for 1 hour and quenched with saturated NaHCO3 (50 mL). Cometyl acetate (100 ml) is extracted and washed with brine (100 ml x 2). Dried over anhydrous Na 2 SO 4 and concentrated to afford the crude title compound (828 mg, 95%, as a mixture of oximes, oxime E / Z = 4/1), which was used for the next step without further purification. ESI MS m / e: 872 (M + H) +.

Step lg:

<formula> formula see original document page 71 </formula>

A solution of the compound from step 1f (828mg, 0.95 mmol) in 15 mL of methanol was stirred at 60 ° C for 5 hours. The solvent was removed and the residue was purified on silica gel (2MNH3 in McOH / CH 2 Cl 2 = 5/95) to afford the title compound (765mg, 97% as a mixture of E / Z oximes E / Z - 4/1). The compound was further separated on HPLC to afford E-oxime isomer (430 mg) and Z-oxime isomer (HOmg).

E-oxime isomer: ESI MS m / e: 830 (M + H) + E-oxime isomer: 13 C NMR (125 MHz, CDCl 3): δ 205.9, 191.4; 186.8; 184.7; 178.1; 167.8; 162.1; 153.3; 148.5; 143.0; 134.1; 125.6; 121.9; 116.8; 108.7; 103.0; 79.4; 76.4; 74.6; 70.5; 69.8; 66.1; 63.2; 62.9; 50.8; 40.5; 38.8; 31.2; 28.5; 25.3; 23.8; 21.5; 19.5; 17.8; 15.1; 14.1; 12.8,

Z-oxime isomer: ESI MS m / e: 830 (M + H) + Z-oxime isomer: C NMR (125 MHz, CDCl 3): δ 206.2, 184.7; 176.9; 169.3; 163.0; 155.9; 148.5; 143.2; 133.6; 121.6; 116.7; 108.5; 103.0; 79.5; 79.0; 76.7; 76.2; 75.8; 70.5; 70.2; 69.7; 66.1; 58.2; 53.7; 51.0; 45.3; 40.5; 39.7; 39.0; 36.9; 28.5; 25.5; 23.4; 21.5; 20.3; 19.6; 17.3; 15.7; 14.5; 12.9; 12.0,

Example 2

<formula> formula see original document page 72 </formula>

Step 2a:

<formula> formula see original document page 72 </formula>

The title compound from step 2a was prepared according to experimental procedure from U.S. Patent Pat. No. 6,878,691 incorporated herein by reference.

Step 2b: <formula> formula see original document page 73 </formula>

To a solution of the compound from step 2a

(711 mg, 1 mmol) in 8 mL of acetonitrile was added 1 N HCl (10 mL) at room temperature. The mixture was stirred at room temperature for 4 hours and was quenched with saturated NaHCÜ3 (30 ml). Extracted with ethyl acetate (40 mL) and the organic phase was washed with brine (40 mL X 2). After drying over anhydrous Na2 SO4, the solvent was removed and the residue was purified on silica gel column (hexane: acetone = 1: 1) to afford the title compound (330 mg, 49%).

Step 2b (215 mg, 1.2 mmol) in 15 mL of 1N ethanol was added (2 mL). The mixture was cooled to 0 ° C and bound ketone ketone was added, as in step 2a (670 mg, 1 mmol). The mixture was stirred at 0 ° C for 1 hour and cooled.

Step 2c:

<formula> formula see original document page 73 </formula>

To a solution of compound from which is blunt with saturated NaHCO3 (50 ml). Extracted with ethyl acetate (100 mL) and washed with brine (100 mL X 2). Dried over anhydrous Na 2 SO 4 and concentrated to afford the crude title compound (764 mg, 92%, E / Z 1/1). ESI MS m / e: 831 (M + H) +.

Step 2d:

<formula> formula see original document page 74 </formula>

A solution of compound from step 2c (764mg, 0.92 mmol) in 15 mL of methanol was stirred at 60 ° C for 6 hours. The solvent was removed and the residue was purified on silica gel (2M NH3in McOH / CH2 Cl2 = 5/95) to afford the title compound as a mixture of E / Z oxime isomers (690mg, 95%, E / Z 1/1). The compound was further separated on HPLC to provide E-oxime isomer (280 mg) and Z-oxime isomer (230mg). E-oxime isomer: ESI MS m / e: 789 (M + H) +. Approximate: 13 C NMR (125 MHz, CDCl 3): δ 218.5, 205.6; 191.7; 168.0; 162.0; 152.8; 148.6; 143.0; 134.0; 122.1; 117.0; 108.7; 103.3; 79.3; 79.0; 76.5, 75.8; 74.5; 70.5; 69.8; 66.1; 63.0; 61.5; 51.0; 47.0; 46.2; 40.5; 39.5; 39.3; 28.5; 23.5; 21.4; 20.0; 18.6; 18.0; 14.6; 14.2; 12.6; 12.2.Z-oxime isomer: ESI MS m / e: 789 (M + H) + Z-oxime isomer: 13 C NMR (125 MHz, CDCl 3): δ 215.0205.7; 169.6; 162.2; 156.2; 149.0; 142.8; 131.4124.8; 116.3; 109.7; 102.5; 79.9; 78.7; 76.3; 76,270.5; 69.7; 66.1; 59.2; 50.8; 46.3; 45.7; 40.5; 40.039.1; 28.5; 23.1; 21.6; 19.7; 18.5; 17.2; 14.5; 13,112.9; 11.8.

Example 3

According to Schemes 1 and 2, the following compounds of the invention are prepared which are provided with Formula II:

<formula> formula see original document page 75 </formula>

wherein A, Q and Z are as defined in Table I.

TABLE I

<table> table see original document page 75 </column> </row> <table> <table> table see original document page 76 </column> </row> <table> <table> table see original document page 77 < / column> </row> <table> <table> table see original document page 78 </column> </row> <table> <table> table see original document page 79 </column> </row> <table> <table> table see original document page 80 </column> </row> <table> <table> table see original document page 81 </column> </row> <table>

According to Scheme I, there are prepared compounds of the invention having Formula X;

<formula> formula see original document page 81 </formula>

wherein A, X and Z are as defined in Table III.

TABLE III

<table> table see original document page 81 </column> </row> <table>

Example 4

<formula> formula see original document page 81 </formula>

Step 4a: <formula> formula see original document page 82 </formula>

A solution of 5-bromo-2-thiophenecarboxaldehyde (13.08 g, 68.46 mmol) in isopropanol (100 mL) was treated with NaBH4 (1.30 g, 34.23 mmol) at 0 ° C for 1, 5 hours with stirring before loading HCl (1M, 60 mL, 60 mmol). The mixture was stirred for 0.5 hour before being partitioned (ethyl acetate and saturated NaHCO3). The organic layers were washed with water, brine, and then dried (Na2 SO4). The volatile was evaporated off and dried in a vacuum to afford the title compound (12.55 g, 95%).

Step 4b:

<formula> formula see original document page 82 </formula>

A solution of the compound from Step 4a (5.02g, 26.00 mmol) in THF (80 mL) was treated with NaH (95%, 730 mg, 28.9 mmol) at room temperature for 50 minutes with stirring. It was frozen to -78 ° C before loading n-BuLi (1.6 M in hexanes, 20 mL, 32 mmol). The mixture was kept at -78 ° C for 1 hour before n-Bu 3 SnCl (17.6ml, 65 mmol) was introduced. The mixture was naturally warmed to room temperature and stirred overnight. The volatile was evaporated and the residue was partitioned (ethyl acetate and saturated NaHCO3). The organic layers were washed with water, brine, and then dried (Na2 SO4). Evaporation followed by chromatography (silica, hexanes / ethyl acetate) afforded the title compound (4.51 g, 43%).

Step 4c:

<formula> formula see original document page 83 </formula>

In a 250 ml Round bottomed glass flask was charged 2-amino-6-bromopyridine (25.0 g, 0.144 mol) and phthalic anhydride (21.4 g, 0.144 mol). The solid mixture in the open glass flask (with a N 2 fluxolent) was heated to 175 ° C and the temperature was maintained for 1 hour or until no further vapor was released. It was cooled to room temperature and vacuumed for 10 hours to afford the title compound as a tan solid (100% yield).

Step 4d:

<formula> formula see original document page 83 </formula>

The mixture of the compound from Step 4b (4.50 g, 11.16 mmol), the compound from Step 4c (3.72 g, 12.28 mmol), and Pd (PPh3) 4 (645 mg, 0.56 mmol) in PhMe (50 ml) was degassed and heated to 100 ° C under N 2 for 17 hours before being refrigerated to 0 ° C. The insoluble was collected by filtration and washed with PhMe to afford the title compound (2.90g). The filtrate and washings were evaporated and the residue was chromatographed (silica, hexanes / ethyl acetate) to provide another collection of the title compound (0.20 g).

ESIMS m / e: 337 (M + H) +.

Step 4e:

<formula> formula see original document page 84 </formula>

A suspension of Step 4d compound (3.10 g, 9.22 mmol) in methylene chloride (50 mL) was treated with thionyl chloride (3.35 mL, 46.08 mmol) at 0 ° C. The mixture was naturally warmed to room temperature and stirred for 16 hours. The volatiles were removed by evaporation. The residue was partitioned (saturated CH 2 Cl 2 / NaHCO 3). The organic layers were washed with water, brine, and then dried (Na2 SO4). The volatiles were evaporated off and dried in vacuo to afford the title compound (3.253 g, 100%).

ESIMS m / e: 355/357 (M + H) +.

Step 4f: <formula> formula see original document page 85 </formula>

To a solution of N-hydroxylphthalimide (2.40 g, 14.7 iranol) in DMF (20 mL) was added NaH (95%, 332 mg, 13.8 mmol) at 0 ° C. It was warmed to room temperature and stirred for 1 hour. It was then added to a solution of the compound from Step 4e (3.25 g, 9.2 mmol) in DMF (25ml). The mixture was stirred at 40 ° C for 16 hours before being cooled to room temperature. It was diluted with saturated NaHCO3 and water. The insoluble was collected by filtration, washed with saturated NaHCO3 and water, and dried to afford the title compound (3.930 g, 89%). ESIMS m / e: 482 (M + H) +.

Step 4g:

<formula> formula see original document page 85 </formula>

A suspension of Step 4f compound (1.00 g, 2.08 mmol) in methanolic ammonia (2M, 20 mL, 40 mmol) was heated at 55 ° C for 2 hours before being cooled to room temperature. The insolubles were removed by filtration and washed with MeOH. The combined filtrate and washings were evaporated. The residue was added to CH 2 Cl 2 to dissolve the crude title compound (548 mg) after evaporation.

ESIMS m / e: 222 (M + H) +.

Step 4h:

<formula> formula see original document page 86 </formula>

A mixture of the compound of formula VIII where X and Y taken together with the atom to which they are attached is C = N-Ac, = = H, V = OH, Z = H, Rp = Ac and W = NMe2 (356 mg, 0.50 mmol), hydrochloride

2-pyridylacetic acid (174 mg, 1.0 10 mmol), 1- (3-dimethylaminopropyl) -3-ethylcabodiimide hydrochloride (EDC-HCl, 192 mg, 1.0 mmol), triethylamine (0.28 ml, 2.0 mmol) and DMAP (10.0 mg) in methylene chloride (5.0 ml) were stirred at room temperature for 22 hours before further 2-pyridylacetic acid hydrochloride (87 mg, 0.5 mmol) eEDC'HCl (192 mg, 1.0 mmol). It was stirred for another 3 hours before being partitioned (ethyl acetate and 10% K2CO3). The organic layers were washed with water, brine, and then dried (Na2SÜ4).

The volatiles were removed by evaporation and dried in vacuo to afford a yellow foam (450 mg) as crude title compound. ESIMS m / e: 832 (M + H) +.

Step 41:

<formula> formula see original document page 87 </formula>

To a solution of the crude compound from Step 4g (166 mg, ~ 0.62 mmol) in ethanol (5.0 mL) and HCl (1 M, 2.5 mL) at -5 ° C was added the crude compound. from Step 4h (450 mg, maximum 0.5 mmol). After stirring for one hour, additional crude compound from Step 4g (50 mg, ~ 0.18 mmol) was added. The mixture was stirred for another 1 hour before division (ethyl acetate and saturated NaHCO3). The organic layers were washed with water, brine, and then dried (Na2 SO4). They were evaporated and the residue was chromatographed (silica, hexanes / acetone) to afford the title compound (332 mg, 64%) as a 2: 1 mixture.

ESIMS m / e: 1035 (M + H) + Step 4j:

<formula> formula see original document page 88 </formula>

A solution of the compound from Step 4i (100 mg) in MeOH (3 ml) was stirred at room temperature for 70 hours before evaporation to afford the title compound.

The two bound oxime isomers were separated by HPLC.

E-oxime isomer: ESIMS m / e: 993 (M + H) +. NMR (CDCl3, 125 MHz): 184.6; 178.0; 172.5; 170.4; 158.0; 127.5; 124.4; 123.7; 122.3; 70.8; 70.5; 69.1; 65.4, 63.1; 62.4; 43.8; 42.7; 40.4; 39.9; 38.3; 36.8; 35.8; 29.7; 29.2; 25.1; 23.2; 21.0; 19.9; 19.1; 17.5; 15.0; 14.3; 12.1; 9.0

Z-oxime isomer: ESIMS m / e: 993 (M + H) +. 13c NMR (CDCl3, 125 MHz): 184.4; 176.6; 173.7; 170.2; 158.0; 156.1; 153.9; 151.1; 149.1; 145.5; 141.2; 138.1; 136.6; 128.0; 124.4; 123.8; 122.3; 109.1; 106.7; 103.0; 83.3; 80.2; 79.0; 77.7; 77.5; 75.8; 70.8; 70.6; 70.5; 69.1; 65.4; 58.7; 43.2; 40.3; 39.1; 38.5; 36.5; 36.0; 29.7; 29.2; 25.2; 22.7; 21.1; 20.1; 19.6; 16.8; 15.4; 14.6; 11.3; 9,1.Example 5. Compounds with improved antibacterial activities.

The following Table IV provides MIC data of species from U.S. Patent No. 6,878,691 and U.S. Patent Application Publication No..2004 / 0053861.

The values in the table correspond to the minimum inhibition concentration (MIC) and are expressed as µg / ml.

The assays for MIC are described above.Table IV

<table> table see original document page 90 </column> </row> <table> Table IV (continued)

<table> table see original document page 91 </column> </row> <table> The following Table V provides data for compounds of the present invention which demonstrate improved microbiological activities against gram-negative bacteria and resistant organisms. The values shown in Table V refer to the minimum inhibition concentration and are expressed in | j, / ml. Table V

<table> table see original document page 93 </column> </row> <table> Patents and scientific literature referenced in this context establish the knowledge available to those skilled in the art. All United States patents and applications published or unpublished patents cited in this context are incorporated by reference. All foreign patents and patent applications published in this context are incorporated by reference. All other references, documents, manuscripts, and scientific literature cited in this context are incorporated by reference.

While this invention has been set forth and particularly described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in shape and detail may be made without thereby departing from the scope of the invention encompassed by the appended claims.

Claims (19)

1. A compound, characterized in that it is represented by the formula: <formula> formula see original document page 95 </formula> or their racemates, enantiomers, regio-isomers, salts, esters or their prodrugs, wherein X and Y are independently selected from the group consisting of hydrogen, deuterium, halogen, RIr ORi, S (0) nRi, -NRiC (0) R2, -NRiC (O) NR3R4, -NRiS (0) nR2 / -C (0) NR3R4 and -NR 3 R 4; R 1 and R 2 are each independently selected from the group consisting of: hydrogen, acyl, silane, a substituted or unsubstituted saturated or unsaturated aliphatic group, a saturated or unsaturated alicyclic group substituted or unsubstituted, substituted or unsubstituted aromatic group, substituted or unsubstituted heteroaromatic group, or substituted or unsubstituted heterocyclic group, each of R3 and R4 is independently selected from the group which consists of: hydrogen, acyl, a group substituted or unsubstituted saturated or unsaturated aliphatic, substituted or unsubstituted saturated or unsaturated alicyclic group, substituted or unsubstituted aromatic group, unsubstituted substituted heteroaromatic group, substituted heterocyclic group, or unsubstituted; or may be taken together as the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocyclic or heteroaromatic ring, or X and Y taken together with the carbon atom to which they are attached are selected. from the group consisting of: CO, C = CHRi, C = NRi, C = NC (0) Ri, C = NORi, C = N0 (CH2) mRi, C = NNHCORi, C = NNHCONRIR2 , C = NNHS (0) n R 1, C = NN = CHR 1, C = N-NO 2, or C = N-NO 0 independently selected from the group consisting of: R 1, OR 1, 0 C (0) R 1, C (0) NR3R4, S (0) nR1, or U and V, taken together with the carbon atom to which they are attached, are C = 0, one of J or G is hydrogen and the other is selected from. from: R 1, OR 1, or NR 3 R 4, or, J and G, taken together with the carbon atom to which they are attached, are selected from: C = 0, C = NRi, C = N0Ri, C = N0 (CH2) mRi, C = NNHRi, C = NNHCOR1, C = NNHCONRIR2, C = NNRS (0) nRi, or C = N-one of U or V is hydro and the other is if-N = CHRi; L is selected from the group consisting of: hydrogen, a substituted or unsubstituted saturated or unsaturated aliphatic group, a substituted or unsubstituted saturated or unsaturated alicyclic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, or a substituted or unsubstituted heterocyclic group; M is R1; W is NR3 R4; Z is hydrogen, alkyl or halogen; Rp is hydrogen; hydroxy or hydroxyl prodrug group; m is an integer; en is 0, 1, or 2.A is <formula> formula see original document page 97 </formula> where: Q 'is N, CH or CF; Xi is 0, N, NRi, S, or CR5; Yi is 0, N, NRi, S, CR5, or If; Zi is 0, N, NRi, S, or CR5; R5 is independently selected from hydrogen, acyl, silane, a saturated or unsaturated, substituted or unsaturated aliphatic group. substituted or unsubstituted, substituted or unsubstituted alicyclic group, substituted or unsubstituted aromatic group, substituted or unsubstituted heteroaromatic group, substituted or unsubstituted heterocyclic group, NR3R4, OH, NHCORi or NHCONH2, and preferably NH2 or NHR1, provided that a compound of Formula I is not selected from a compound of the following form, where A, Q, and Z as defined below in Table A. Table A <table> table see original document page 99 </column> </row> <table> 2. A compound according to claim 1 wherein A is wherein X 1, and R 5 are as defined in claim 1. <table> table see original document page 99 </column> </row> <table > 3. A compound according to claim 1 wherein A is: wherein X 1 is O, NH or S and R 5 is as defined in claim 1. 4. A compound according to claim 1 wherein A is: wherein X 1 is O, NH or S and R 5 is as defined in claim 1. 5. A compound according to claim 1 wherein A is: wherein R 5 is as defined in claim 1. 6. A compound according to claim 1 wherein A is: 7. A compound according to claim 1, wherein A is selected from the compounds shown in Table B. <table> table see original document page 101 </column> </row> <table> < table> table see original document page 102 </column> </row> <table> 8. A compound according to claim 1 having formula II: wherein A, Q and Z are as defined in Table C: Table C <table> table see original document page 10 </column> </row> <table> <table> table see original document page 104 </column> </row> <table> <table> table see original document page 105 </column></row> <table> A compound according to claim 1, comprising the formula: wherein Rp, U, V, W, X, Y, L, and Z are as defined in claim 1. 10. A compound according to claim 9 comprising formula IV: wherein Z and Rp are as defined in claim 1. A compound according to claim 9, characterized in that it is represented by the formula V: wherein Z and Rp are as defined above in claim 1. Compound according to Claim 10, characterized in that Rp is hydrogen and Z is hydrogen. Compound according to Claim 11, characterized in that Rp is hydrogen and Z is hydrogen. 14. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt, ester or prodrug thereof in combination with a pharmaceutically acceptable carrier. 15. A method of treating a bacterial infection in a patient in need of such treatment, characterized in that it comprises administering to said patient a pharmaceutical composition according to claim 14. 16. A method of treating an inflammation in a patient in need of such treatment comprising administering said patient to a pharmaceutical composition according to claim 14. A method of treating cisplastic fibrosis in a patient in need of such treatment, comprising administering said patient to a pharmaceutical composition according to claim 14. 18. A compound characterized in that it is represented by Formula VI: or any racemates, enantiomers, regioisomers, salts, esters or prodrugs thereof, wherein X, Y, L, W, and Rp are as defined above; B is independently selected from hydrogen, acyl, silane, a substituted or unsubstituted saturated or unsaturated aliphatic group, a substituted or unsubstituted saturated or unsaturated alicyclic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic or substituted or unsubstituted heterocyclic group. A compound according to claim 18, characterized in that it is represented by formula VII: wherein Rp is as defined in claim 1.